CA2320354A1 - Novel compounds and their use as positive ampa receptor modulators - Google Patents
Novel compounds and their use as positive ampa receptor modulators Download PDFInfo
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
The invention provides novel compounds represented by general formula (I) wherein the bond represented by the broken line may be a single, double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen and R2; X represents SO2 or C=O of CH2; Y represents -CH(R4)-, -N(R4)-or -N(R4)-CH2-, O; and the meaning of R2, R3, R4, R5, R6, R7, and R8 are as defined in the application. The compounds are useful as positive modulators of the AMPA-receptor.
Description
Novel compounds and their use as positive AMPA receptor modulators This invention relates to novel compounds useful as modulators of the AMPA
sensitive glutamate receptors, pharmaceutical compositions comprising such compounds and their use in therapy BACKGROUND OF TH1= INVENTION
~-Glutamate is the major excitatory neunoiransmitter in the mammalian central nervous system which activates several subtypes of ionotropic and metabotropic receptors. The ionotropic receptors can be divided into threE; subtypes, NMCrA, AMPA and kainate receptors, based on structural and pharmacological differences.
Impairment of glutamatergic neurotran:~rr~ission has been implicated in the learning and memory loss observed in numerous neurological disorders such as e.g.
Alzheimer's decease, senile dementia: stroke (McEntee and Crook, F'sycopharmacology 111:391-401 (1993)). It is widely accepted that learning and memory is related to the induction of long-term potentiation (LTP) which is a stable increase in the synaptic strength following repetitive high frequency stimulations. Experimental studies have shown that increasing the synaptic response mediated by AMF'A receptors enhances the induction of LTP (Arai and Lynch, Brain Research, 598:173-184 (1992)). For the reason:; stated above, compounds that stimulates AMPA receptor response in the brain, may induce improvements in the intellectual behavior and performance.
Activation of AMI'A receptors with mglutamate or the selective agonist AMPA
leads to a rapid receptor desensitization; i.e. tie receptor channel fails to open despite the continued presence of agonist. It i's therefore possible to obtain an increase of the synaptic strength by attenuating the AMPA, receptor desensitization normally elicited by the endogenous neurotransmitter ~-glutamate.
In 1990 Ito et al. reported (J. physial., 424:53;x-543) that the nootropic drug aniracetam (lV-anisoyl-2-p~yrrolidinor~e) increased AMPA induced currents in oocytes injected with rat brain mRNA. In another study, it has been shown that 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine, a compound that enhances synaptic transmission mediated by AMPA receptors, is effective at improving mennary in experimental animals at a ,7 very high dose 120 mg/kg (Stauble et al., Proc. Natl. Acad. Sci. USA, 91:11158-(1994)).
The benzothiadiazide cyclothiazide is a more potent and efficacious modulator of AMPA receptor current in-vitro than aniracetarn (Johansen et al., MoLPharmacol. 48:946-955 (1995)). The effect of cyclothiazide on tf~Ea kinetic properties of AMPA
receptor currents appear to be by a different mechanism to that of aniracetam (Partin et al., J.
Neuroscience 16:6634-6647 (1996)). However, cyclothiazide has no therapeutic potential for AMPA
receptor modulation <~s it can n~~t cross the blood-brain-barrier following peripheral administration. The low potency of know compounds also meets with higher demands for a high solubility due to the higher doses used for ;administration.
BACKGROUND ART
US 5,488,049 describe;; the use of benzothiadiazide derivatives to treat memory and learning disorders. The compounds are structurally closely related to the compounds of the present invention. However the compounds of the present invention shows greater potentiation at lower concentrations. (f=ig. 3 of US 5 488,049) US 4,184,039 disclose:> benzothiadiazides for use in the promotion of hair growth;
DE 1470316 describes a method for producing some benzothiadiazides for use as additives in galvanizing baths.
In Synthesis (10), 183, p. 851 a method for prE;paration of benzothiadiazine-1,1-dioxides are described. The compounds are described as useful as antihypertensive and antimicrobial reagents.
In J. Med. Chem. (15, no. 4), 1972. p. 400-403 bcanzothiadiazine-1,1-dioxides are investigated for their ~--substituents constants as structure activity study for anti hypertensive activity.
WO 9812185 describes benzothiad~azines of different structure as the compounds of the present invention.
Object of the invention It is an object of the present invention to provide positive AMPA modulators which are useful in the treatment of disorders or diseases in mammals, including a human, and especially in the treatment of diseases and disorders which are responsive to modulation of the AMPA
receptors in the brain.
Another object of the present invention is tc:~ provide a method of treating disorders or diseases of a mammal, including a human, responsive to AMP,A receptor modulators which comprises administering to a mammal in need thereof a compound of the invention.
A third object of the pnasent invention is to provide novel pharmaceutical compositions for the treatment of disorders. or diseasEa of mammals, including a human, responsive to AMPA
modulators.
Other objectives of the present invention will be apparent to the skilled person hereinafter.
Summary of thre invention The invention then, inter alia, comprises the fotdo~wing, alone-; or in combination:
A compound represented by the general formula:
Ra ~.X.~ N, R2 R I~ .~.Y~ R
wherein the bond represented by the brokE;n line may be a single, a double bond or absent;
and if the band is absent, then the nitrogen is substituted with a hydrogen and R2;
X represents S02 or C=O or CH~,;
Y represents -CH(IR4)-, -N(R4)- or -N(R°)-C~E~a-, O;
R2 represents hydrogen, alkyl, cycfoalkyl, ;aryl, benzyl;
CO-R9 wherein R9 repre:>ents alkyl, cycloalkyl, benzyl, aryl; or R2 together with R3 arid together with the atF.~ms to which they are attached, forms a 4- to 7-rnembered rin~~ optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, aikoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alko:Kyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR'3R'4 , alkyl-S-R'3 wherein R'3 and R'"' independE:ntly represents hydrogen, alkyl, cycloalkyl; or R'3 and R'° together with the nitrogen to which they are attached forms a 3- to 8 memberE;d heterocyclic: ring structure;
A c:arbocyclic 7- to 12- membered ring ol7tionally substituted with halogen, alkyl, hydroxy or alkoxy; or A heterocyclic 3- to 8 membered ring optionally substituted with halogen, alkyl, hydroxy or alkox:y; and optionally the hcaerocyclic rind is fused to an aryl;
Benzyl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cyc:loalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;
Aryl which is optionally substituted onE: or more times with substituents selected from the group consi~~ting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or WO 99/42456 I'CT/DK99/00070 R3 together with R' or R4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyi, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl 5 groups.
R' represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R'°, or CCf2R'° wherein R'° represents hydrogen, cycloalkyl, alkyl, aryl or benzyl;
or R4 together with R'3 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally aubstitute~d c>ne or morEy times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hycfroxy, alkoxy, amino or thio and optionally containing one or more heteroatom s and optionally containing carbonyl groups.
R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -S02-NR"R'2 wherein R" and R'' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'z together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thin, aryl, benzyl, SOz-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyi, hydroxyalkyl, cycloalkyl, cyc:iohaloalkyl, -NR'SR'6, NHSO2-R'~', NI-ISOd~-aryl wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, arnino, thio, CF~3, OCF°, N02. aryl;
Aryl optionally substituted one or more times with substituents selected from the group consisting of al~;yl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
HET optionally substituted oroe or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;
-(alkyl)m-S-R'S; ..(alkyl)m-SO-R'S ; -(alkyl)r"-S02-R'S. _(alkyl)m-S020R'S, -(alkyl)m-SOz-NR'SR'6, -(alkyl)m-NHCOR'~', -(alkyl)",-C;C)PJR'SR'~', -(alkyl),~,-CR'=NOR", -(alkyl)m-CO-R'S, -(alkyl)m-CO 2-R'S wherein misoorl;and R' and F." independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, ~~ryl, ben-r_yi; and R'S and R'" independently reprcaents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'S and 'R''' together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ~riracf structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alko:xy, amino or thio, aryl, benzyl, S02-alkyl, SOz-aryl, S02-benzyl'; and optionally the heterocyclic ring is fused to an aryl;
R' represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, vitro, nitroalkyl;
alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, c:yc:loalkyl, cyclohaloalkyl, -NR"R'8, NHSC)2-R", NHSO~-aryl wherEein the aryl is optionally substituted one or more times with substituents selected frcjrn halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF~, NOz, aryl;
-(alkyl)m-S-R"; -(alkyl)m-SO-R" ; (alkyl)m..,;02_R"; _(alkyl)",-SO20R", (alkyl)m-S02-NR"R'8, -(alkyl)mNHCOR", -(alkyl),r,CONR"R'8, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R''' (alkyl)mC0?-R", wherein misoorl;
and R' and R" independently reprEasents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, <~ryl, benzyl; and R" and IR"~ independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" arid R'e together with the nitrogen to which they are attached forms a heterocyclic :3- to 8 membered ring structure a~ptionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, SOz-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HST optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO~-alkyl, S02-aryl, ;aO?NR"R'g;
Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alk:enyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO~-NFi"R'~, wherein R" and R'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they .are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, Ihydroxy, alkoxy, amino or thio, aryl, t>enzyl, SO2-alkyl, S02-aryl, benzyl; anti aptionally the heterocyclic ring is fused to an aryl;
or R' together with Rf' or together with RB forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-; wherein ra is 1, 2 or 3; -SO~-NR-(CH2)n-wherein n is 1 or 2; -SO-NR- (CH2)~- wherein n is 1 or 2; -SO2-(CH2)~- wherein n is 2 or 3; -SO-(CH2)~-wherein n is 2 or 3; -CO-C;H=CH-NH- ;-CO-CH=C;H-O-; -CO-(CH2)~-NH- wherein n is 1 or 2; -CO-NH-(C;H,~)~ wherein n cs 1 or 2; -CO- (CH2)~-f7-;-O-(CH2)rn-O-; wherein n is 1, 2 or 3;
R8 represents hydrogen, alkyl, alkoxy, hydro;Kyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitraalkyl;
Aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF;3, OCF3, N02, alkyl, cycloalkyl, alkoxy;
HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF-3, IV02, alkyl, cycloalkyl, alkoxy;
-(alkyl)rt,-S-R'9; .. (alkyl)m-SC7-R'9 ; -(alkyl)n,-S02-R''~; -(alkyl)m-S020R'9, (alkyl)n,-SOZ-NR'9R2°, -(alkyl)mNHCOR'9. -(alkyl)mCOf~IR'9R2°, -(alkyl)rn-CR'=NOR", -(alkyl)m-CO-R'9;
(alkyl)m-C02-R''~, and m is CI or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl" alkenyl, alkynyl, aryl, benzyl; and R'9 and R2° indE:pendently represents hydrogen, alkyl, cycfoalkyl, benzyl, aryl, or R'9 and R2° togethE~r with the nitrogen to which they are attached forms a heterocyclic 3-to 8 membered ring structure optionallyr substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amir7o or thio, aryl, benzyl, SO?-alkyl, SO2-aryl, S02-benzyl;
and optionally the heterocycli~; ring is fusE:d to an aryl;
provided that when the broken line in fon~nula I represents a double bond and X
represents S02 and Y represent NH and the corrrpound is nnanosubstituted then it is not monosubstituted with FI3 representing OCH3, rnel:hyl, pentyl, t-butyl, aminophenyl, 2-phenylethylene, phene!lhyl, cyclopE~ntyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornene, benzyl, thienyl, furyl, aryl, aryl substituted with 4-methyl, 4-methoxy, 4-chloro, 4-nitro or 3-nitro;
and when the compound is disubstitutc:d with R3 being methyl then R5 is not CI, CH3;
or then R' is not F, CI, 13r, I, CH3 C:F,, nitro, SO;>N(CH3)2; or then R6 is not CI, Br, CH3, CF3, ethyl, methoxy;
or when R' is chloro then R3 is not ethyl, butyl, sec- butyl, t-butyl, cyclobutyl, 2,2-dimethylpropyl, phenyl;
and when the corrrpound is disubstitutE:d then it is not with R6=OMe, R3=ethyl;
R6=methyl, R3=propyl; iR' =S02NH7, R~=Cl; R'=SOzNH2, R3=::phenyl; R'=Br, R3=phenyl;
And provided that when the compouncl is trisubstituted then it is not R3=CH3 , R5=N02, R'=CI; R3=CH3 , R6=NO 2, R'=CI; R3=CH3 , R5=:NI-i2, R'=CI;
and provided that when the broken IinE: in formula I represents a single bond and X
represents S02 and Y represent NH
Then the compound is not a disubstituted compounds with R' or R6 being chloro and R3 being alkyl, cyclobutyl, cycfopropyl, cyclohexyl, cyclohexen, norbornenyl, norbornanyl, ethylthiomethyl, ethylo>;ymethyl, ethyloxyethyl, methyloxymE~thyl, methylamino, 2-chloroethyl, chloromethyl, dichloromethyl, trifluoromethyl, arnina;
and the compound is not a trisubstituted compound with R3 being CH3 and R5=isopropyl , R'=F; R5=ethyl , R'=C:I; IR''=:propyl , R':=CI; R5=ethyl , R'=F; R5=methyl , R'=CI; R5=ethyl , R'=methyl; R5=CI , R'-=Methyl; RS=methyl , R'=CI; R4=methyl , R5=ethyl; or trisubstituted with R'=methyl, R5=methyi , R'---F;
A pharmaceutical composition comprising an therapeutically effective amount of a compound as above tol~ether with pharmaceutically acceptable carriers or exipients;
The use of a compound represented by the general formula R$
R~' Ra wherein the bond represented by the broken line may be a single, a double bond or absent;
and if the bond is absent, then tt~e nitrogen is substituted with a hydrogen and R2;
2o X represents S02 or C=O or C;H2;
Y represents -CH(R4j-, -N(R4)- or -N(R'1)-CI-i~~-, O;
R2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl;
CO-R9 wherein R9 repre:>ents alkyl, cycloalkyl, benzyl, aryl; or R2 together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring optionally substituted c>ne or more times with substituents selected from halogen, alkyl, alkenyl, alkynyf, hydroxy, alkoxy, amino or thio and optionally containing one or more heteruatoms and optionally containing carbonyl groups;
R3 represents hydrogen, cycloalkyl, alkyl, cyc;loalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR'3R'4 , alkyl-S-R'3 wherein R'3 and R'~ independently represents hydrogen, alkyl, cycloalkyl; or R'3 and R'° togei:her with the nitrogen to which they are attached forms a 3- to 8 membered heterocyclic ring structure;
A carbocyclic 7- to 12- membered ring optionally substituted with halogen, alkyl, hydroxy or alko>cy; or A heterocyclic 3- to 8 membered ring optionally substituted with halogen, alkyl, hydraxy or alko>cy; and optionally the heterocyclic ring is fused to an aryl;
Benzyl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, c:ycloalkyl, alkyl, hydroxy, alkoxy, amino or thin, haloalkyl, hydro:Kyalkyl, alkoxyalkyl, alkylthio, alkylamino;
Aryl which is optionally substituted one or more times with substituents selected from the group consistirng of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thin, haloalkyl, hydro:Kyalkyl, alkoxyalkyl, alkylthio, alkylamino; or R3 together with R2 or R4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
R4 represents hydrogen, alkyl, cycloalkyl, cyc:loalkylalkyl, aryl, -CO-R'°, or C02R'° wherein R'° repre:>ents hydrogen, cycloalkyl, alkyl, aryl or benzyl;
or R4 together with R3 and together with the .atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl. h~,rdroxy, alkoxy, amino or thio and optionally cantaining one ~or more heteroatoms and optionally containing carbonyl groups.
R5 represents hydrogen, halogen, alkyl, alkenyl, alkyny,l, aryl, -S02-NR"R'2 wherein R" and R''' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl"
or R" and R" together with the nitrogen to whic::h they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thin, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
Rs represents hydrogen, halocfen, alkyl, oyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydro~xyalkyl, cycloalkyl, cycloh,aloalkyl, -NR'SR'6, NHSO 2-R'S, NHSOa-aryl wherein the aryl i;~ optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, aikoxy, amino, thio, CF=3, OCF3, NG2, aryl;
Aryl optionally :substituted one or more tunes with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkc~xy, halogen, haloalkyl, haloalkoxy;
-{alkyl)m-S-R'S; -(alkyl)m-SG-R'S ; -(alkyl),-S02-R'S; ..(alkyl)m-SO20R'S, -(alkyl)m-S02_ NR'SR'~, -(alkylh,-NHCOR'S, -(alkyi)m-(~ONR''R'6, -(alkyl)m-CR'=NOR", -(alkyi)m-CO-R'S; -(alkyl)m-CO 2-R~''' wherein misoorl:and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R'S and F~'6 independently represents hydrogE:n, alkyl, cycloalkyl, benzyl, aryl, or R'S and F3'6 together with the nitrogen to which they are attached forms a heterocyclic: 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, SU2-benzyl; and optionally the heterocyclic ring is fused to an aryl;
R' represents hydrogE:n, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl;
alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -NR"R'a, NHS02-R'', NHS02-aryl wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF;~, N02, aryl;
-(alkyl)m-S-R", -(alkyl)",-SO-R" ; (alkyl)m~-S02-R"; _(alkyl)~,-S020R", (alkyl)m-SOz_ NR"R'e, -(alkyl)mNHCOR'7, -(alkyl)",CC>NR"R'e, -(alk:yl)m-CR'=NOR", -(alkyl)m-CO-R";
(alkyl)mCOrR", wherein misoorl;
20 and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, <~ryl, benzyl; and R" and I~"' independently reprE;sents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with thE: nitrogen to which they are attached forms a 25 heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl. alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SOralkyl, ;~02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
30 HFT optionally substituted one or more limes with substituents selected from halogen, alkyl, alkf:nyl, alkynyl, hydroxy, alkoxy, amiroo, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SOz-alkyl, SO?-aryl. ;a02NR"R'8;
Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy., aikoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO~~-~NR"R'~, wherein R" and R'8 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'e together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 member~ed ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alk:oxy, amino ar thio, aryl, t>enzyl, S02-alkyl, S02-aryl, benzyl; and optionally the heteroc:yclic ring is fused to an aryl;
or R' together with R~' or together with R8 forms a 5- to 7-rnembered ring having the one of the following structures -O-(CH2~n-O-; wherein r7 is 1, 2 or 3: -SO~-NR-(CH2)n-wherein n is 1 or 2; -SO-~NR- (CHZ)~- wherein n is 1 or 2; -SO2-(CH2)n- wherein n is 2 or 3; -SO-(CH2)n-wherein n is 2 or 3; -CC)-CH=CH-NH- ;-CO-CFI=C;H-O-; -CO-~(CH2)"-NH- wherein n is 1 or 2; -CO-NH-(CH~)~ wherein n is 1 or 2; -CO- (CH2)~-O-;-O-(CH2)r~-O-; wherein n is 1, 2 or 3;
Re represents hydrogen, alkyl, alkoxy, hy<iro:Kyalkyl, halogen, haloafkyl, CN, cyanoalkyl, nitro, nitroalkyl;
Aryl optionally substituted ane or more times with substituents selected from the group consisting of halogen, CF;3, OCF3, N02, alkyl, cycloalkyl, alkoxy;
HST optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF~3, N02, alkyl, cycloalkyl, alkoxy;
-(afkyl)m-S-R'9; -~ (alkyl)m-SO-R'''' ; -(alkyl)m~-S02-R'''; ~~(alkyl)m-S020R'9, (alkyl)rt,-S02-NR'9R2°, -(alkyl)mNHCOR'9. -(alkyl)mCCJNR'9R2°, -(alkyl)n,-CR'=NOR", -(alkyl)rt,-CO-R'9;
(ai'kyl)m-C02-R'''~, and m is U or 1; and f~' and R" independently represents hydrogen, alkyl, cycloalkyl. alkenyl, alkynyl, aryl, benzyl; and R'9 and R2° independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'9 and R2° together with the nitrogen to which they are attached forms a heterocyclic 3-to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl;
and optionally the heterocyclic ring is fused to an aryl;
'I 4 for the manufacture of a medicament for the treatment of disorders or diseases responsive to modulation of the AMPA receptor complex.
A method for the treatment of disorder, or diseases responsive to the modulation of the AMPA receptor complex wherein a therapeutically efficic.~nt amount of a compound represented by the general formula R~' Rz ~ ,~,X\N, R:>
Rsr ~ 'y'~'~. Ra wherein the bond represented by the broken line may bE: a single, a double bond or absent;
and if the bond is absent, then the nitrogen is substituted with a hydrogen and R2;
X represents S02 or C=O or C;Hz;
Y represents -CH(R4)-, -N(R'')- or -N(R4)~-CH;z-, O;
R2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl;
CO-R9 wherein R9 repre:;ents alkyl, cycloalkyl, bc:nzyl, aryl; or R2 together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring optionally substituted c>ne or more times with substituents selected from halogen, allkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more hetc:roatoms and optionally containing carbonyl groups;
R3 represents hydrngen, cycloalkyl, alkyl, cycloalkylalkyN, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR'3R'4 , alkyl-S-R'3 wherein R'3 and R'4 independently represents hydrogen, alkyl, cycloalkyl; or R'3 and R'4 together with the nitrogen to which they are attached forms a 3- to 8 membered heterocyclic ring structure;
5 A carbocyclic 7- to 12- membered ring optionally sukastituted with halogen, alkyl, hydroxy or alko:Ky; or A heterocyclic ;:~- to 8 membered ring optionally substituted with halogen, alkyl, hydroxy or alko:Ky; and optionally the heterocyclic ring is fused to an aryl;
Bc:nzyl which is optionally substituted orre or more times with substituents selected from the group consisting of halogen, c:ycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alN;ylthio, alkylanoino;
Aryl which is optionally substituted one car more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hyciroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alH;ylthio, alkylannino; or R3 together with R'~ or R4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and captionally containing carbonyl groups.
R4 represents hydrogen, alkyl, cycloalkyl, cyc:loalkylalkyl, aryl, -t;0-R'°, or C02R'° wherein R'° represents hydrogen, cycloalkyl, alkyl, aryl or benzyl;
or R4 together with R'' and together with the ai:oms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hyc~roxy, alkoxy, amino ar thio and optionally containing one or more heteroatoms ancj optionally containing carbonyl groups.
R5 represents hydrogen, halogen, alkyl, aNkenyl, alkynyl~ aryl, -SOrNR"R'2 wherein R" and R'' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R''' together with the nitrogen to whit..~.h they are attached forms a heterocyclic 3- to 8 membered rind structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SOz-alkyl, SOz-aryl, S02-ber~zyl; and optionally the helerocyclic ring is fused to an aryl;
R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cyciaalkyl, cyclohaloalkyl, -NR'SR'~, NHSO2-R'S, NHSO,-aryl wherein the aryl i:~ optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, arnino, thio, CF~3, OCF3, NO 2, aryl;
Aryl optionally substituted one or more times with substituents selected from the group cansisting of alH;yl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
HET optionally substituted one or more times with substituents selected from the group consistin~~ of alkyl, cycloalkyl, alkoxy, halogen,, haloalkyl, haloafkoxy;
-(alkyl)m-S-R'S; ..(alkyl)m-SO-R'S ; -(alkyl)",-S02-R'S; -(alkyl)m-SOzOR'S, -(alkyl)m-S02_ NR'SR'6, -(alkyl)m-NHCOR"', -(alkyl),n-C:C)IVR'''R's, -(alkyl)m-CR'=NOR", -(alkyl)n,-CO
R'S; -(alkyl)m-CO 2-R'S wherein m is o or 1; and R' and Ft" independently repre:>ents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, bent yl; and R'S and R"' independently represE:nts hydrogen, alkyl, cycloalkyl, benzyl, aryl, ar R'S and R't' together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen" alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin, aryl, benzyl, WO 99/4245fi PCT/DK99/00070 1%
S02-alkyl, S02-aryl, SO~-benzyl; and optionally the heterocyclic ring is fused to an aryl;
R' represents hydrogen, halogen, alkyl, c;yano, cyanoalkyl, nitro, nitroalkyl;
alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -NR"R'8, NHSO2-R", NHSO~-aryl wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, Cf=3, OCF3, NO?, aryl;
-(alkyl)m-S-R"; -(alkyl)m-SG-R" ; (alkyl),-S02-R"; -(alkyl)m-S020R", (alkyl)m-NR''R'~, -(alkyl)mNHCOR", -(alkyl)mCONR"R'e, -(alkyl)n,-CR'=NOR", -(alkyl)rt,-CO-R";
(a.lkyl)mC02-R", wherein misoorl;
and R' and R" independently rE~presents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R" and R'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'H together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyi, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HFT optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, S02-alkyl, S02-aryl, ',.~OZNR"R'8;
Aryl optionally substituted one or mare times with substituents selected from the group consisting of alkyl, al~;enyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, C>CF3, -SO,~--NR"R'8, wherein R" and R'8 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 memberc:d ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, SOZ-benzyl; a,nd optionally the heteroc:yclic ring is fused to an aryl;
or R' together with R6 or together with Rg forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -S02-NR-(CH2)n-wherein n is 1 or 2; -SO-NR- (CH2)~- wherein n is 7 ~r 2; -SO2-(CH2)~- wherein n is 2 or 3; -SO-(CH2)~-wherein n is 2 or 3; -CO-CH=CH-NH- ;-CO-CH=CH-O-; -CO-(CH2)~-NH- wherein n is 1 or 2; -CO-NH-(C;H2)~ wherein n is 1 or '~; -CO- (CH2)~:-(J-;-O-(CH2)n-O-; wherein n is 1, 2 or 3;
Re represents hydrogen, alkyl, alkoxy, hydrc~xyalkyl, halc:~gen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
Aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, N02, alkyl, cycloalkyl, alkoxy;
HE:T optionally ~~ubstituted one or morE~ tirnes with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, c;ycloalkyl, alkoxy;
-(alkyl)m-S-R'9; - (alkyl)m-SO-R'9 ; -(alkyl),n-S02-R'9; -(alkyl)m-S020R'9, (alkyl)m-S02-NR'9R2°, -(alkyl)imNHCOR'q, -(alkyl)rnCONR'9R2°, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R'9;
(alkyl)m-C02-R'9, and m is 0 or 1; and Fi' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R''~ and R2° independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'9 and R2° togethE~r with the nitrogen to which they are attached forms a heterocyclic 3-to 8 membered firing structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl;
and optionally the heterocyclic ring is fused to an aryl, is administered.
Detailed disclosure of the invention The invention provides novel compounds of formula f as shown above.
Preferred embodiments of the invention are compounds of formula I as above wherein R2 represents hydrogen, alkyl, c;ycloalkyl, phenyl, benzyl;
or R2 together with F13 and together with the atoms to which they are attached forms a 5- to 5-membered ring optionally substituted one or more times with substituents selected from halogen, ~~Ikyl, hydroxy, alkoxy, arnino or thio; and aptionally containing one or more heteroatoms and optionally containing carbonyl groups;
R3 represents hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic 7- to 10-membered ring; a heterocyclic 5- to E3 rnErmbered ring; benzyl; aryl;
or R3 together with Rz or R4 forrns a 5- to 6- membered ring;
R4 represents hydrogen, alkyl, or R4 together with R3 and together with the atoms to which they are attached, forms a 5- to 6- membered ring; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
RS represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl -S02-NR"R'2 wherein R" and R'2 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R" together with the nitrogen to which they are attached forms a heterocyclic 5- to 6- memberecl ring structure;
R~ represents hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxy, alkoxyalkyl, Phenyl optionally substituted one or more times with substituents selected from the group consisting of 2Ci alkyl, alhoxy;
HET;
-S-R,s; -SO-Ris _ -S02-R,s; -S020R's, -;aO2-NR'sR,s _NHCOR's, -CONR'sR,s _ CR'=NOR", -CO-R'~'; -CO2-R's, wherein f3' 4~nd R" independently represents kaydrogen, alkyl, cycloalkyl, phenyl, benzyl; and f3''' and R's independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R's and F3's together with the nitrogen to which they are attached forms a hetE:rocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio., phenyl, benzyl, S02-alkyl, S02-aryl, S02-benzyl;
ancf optionally the hetero,;yclic ring is fused to an aryl;
R' represents hydrogen, Br, F, I, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)m-NR"R'e, NHS02-R", -S-R'", -SO-R" ; -302-R"; -SO 2OR", -SO 2-NR"R'°, NfvCOR", CONR"R'8, CR'=NOR", -CcJ-R"; -C02-R ", wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, I~enzyl; and R" and R"' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'E' together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl, SOZ-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HET optionally substituted one or morE: tunes with substituents selected from halogen, alkyl, phenyl, S(J2NR"R'8;
Phenyl optionally substituted one or rru~re times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy , halogen, Inaloalkyl, amino, NHCO-alkyl, nitro, OCF3, -S02-NR"R's wherein R" and F;"' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R~' and R'e together with the nitrogen to which they are attached forms a heterocyclic: ;3- to 8 menobered ring structure optionally substitui:ed with halogen, alkyl, SO 2-alkyl, SU2-aryl, S02-benzyl; and optionally the heterocyclic rind is fused to an aryl;
or R' together with R6 or together with Re forms a 5- to '7-membered ring having the one of thc: following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -S02-NR-(CH2)n- wherein n is 1 or 2; -SO-NR- {CH2)~- wherein n is 1 or ~; -S02-(CH~),~- wherein n is 2 or 3; -SO-(CH2)~-wherein n is 2 or 3; -CO-C;H=CH-NH-- ;-CO-CH=:C;H-O-; -CO-(CHz)~-NH- wherein n is 1 or 2; -CO-NH-{CH2)~ wherein n is ~ or 2; -C;O- (CH?)2-O-;-O-(CH2)n-O-; wherein n is 1, 2 or 3;
Rs represents hydrogen, alkyl, alkoxy. hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;
H F_T"
-S-R'9; -SO-R'9 ; -S02-R'9; -S020R'9, -~~Oz-NR'9R2°, NHCOR'9, -CONR'9R2°, CR'=NOR", -CC)-R'9; -CO?-R'9, wherein R' and Fi" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
and R'9 and R2° independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'~ and R'" together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered rind structure rcptionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, aikoxy, amino or thio, phenyl, benzyl, SO?-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
provided that when X represents S02 and Y represents N and the broken line 3o represents a single bond then neither of R' or R6 are chlaro when R2, R4, R5, Ra and the remaining of R6 and R' are all hydrogen; and provided that R3 can represent CH3 only when RS is hydrogen or R' is not sulfamoyl;
and provided that when X represents S02 and Y represents N and the broken line represents a double bond then neither of R' or R6 are chloro when R2, R4, R''', R8 and the remaining of R6 2,c'.
and R' are all hydrogen; and provided that R', R4, R5, R6, R' and R8 are not all hydrogen; and provided that the compound is not disubstituted with R3 is being CH3 when R' is fluoro, bromo, iodo, CF3, CH3, NO,, SO2N(CH3)2, or R'' is broma, C; F3, CH3, ethyl, methoxy; or RS is chloro, CH3; or R8 is chloro; and provided that: the compound is not 3-ethyl-f3-methoxy-1,2,4-benzothi<~diazine-1,1-dioxide;
3-propyl-6-methyl-1,2,4-benzothiadiazine-1,1-dioxide;
3-ethyl-fi-methoxy-1,2,4-benzothiadiazine-1, ~i -dioxide;
3-phenyl -I-bromo- t ,2,4-benzott~iadiazine-1,1 ~-dioxide;
3-phenyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide;
5-bromc-7-chloro-3~-methyl-1,2,4-benzothiadiazine-1,1-dioxide;
5-iodo-7-chloro-3-methyl-1,2,4-benzothiadiazir~e-1,1-dioxide;
5-vitro-T-chloro-3-methyl-1,2,4-~benzothiadiazine-1,1-dioxide;
6-vitro-7-chloro-3-methyl-1,2,4-~berrzothiadiazir~e-1,1-dioxide; or 6-amino-7-chloro-3-methyl-1,2,4-~benzothiadiazine-1,1-dioxide;
A more preferred embodiment of the invention is a compound of formula I as above , wherein Rz represents hydrogen, alkyl, cycloalkyl;
or R2 together with R3 forms a 5- tc> 6-membered ring; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
And a preferred embodiment is wherein R3 represents hydrogen, cyclo;alkyl, alkyl, haloalkyl, alkoxy, a carbocyciic 7- to 10-membered ring; a heterocyclic 5- t~o Ei membered ring; benzyl; aryl;
or R3 together with R2 or R' forms a 5- to 6- rnembered rind; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, aikoxy, amino or thio and o~7tionally containing one or more heteroatoms and optionally containing carbonyl groups.
And another preferred Embodiment is wherein R° represents hydrogen, alkyl, or R4 together with R3 ;end together with the atoms to which they are attached, forms ,~ E>- to 6- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or rnorc~ heteroatoms and optionally containing carbonyl group:>.
And another preferred embodiment is wherein R5 represents hydrogen, halogen, alkyl, alkenyl, alkyynyl, phenyl, -S02-NR" R'2 wherein R" and R'' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'' together with the nitrogen to vvhich they are attached forms a heterocyclic 3- to 8 membered ring structure;
And another preferred .embodiment is wherein R6 represents hydrogen, halogen, cycloalkyl, alkyl, alk<axy, alkoxyalkyl, Aryl optionally substituted one or more times with substituents selected from the group consisting of alH;yl~ alkoxy;
H ET;
-S-R,s; -SO-R,s ; -S02-R,s; -S020R'S, .-S02_NR'SR'6, -NHCOR'S, -CONR'SR,s -CR'=NOR", -CC>-R'S; -CO2-R'S, wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
and R'S and R'~' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'S and ~i'~ together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered rir7g structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alko.xy, amino or thio, phenyl, benzyl, S02-alkyl, SOz-aryl, SO2-benzy~l; and optionally the heterocyclic ring is fused to an aryl;
And another preferred embodiment is wherein R' represents hydragen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, 3o hydroxyalkyl, cycloalkyl, cyc;lohaloalkyl" -(alkyl)m-NR"R'8, NHS02-R", _5._R"; -SO-R" ; -SOz-R"; -SO20R", -.SC>2-NR"R,B, NHCOR'', CONR"R'8, CR'=NOR", -CC~-R", -CO~-R'', wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl; ~~nct 2~
R" and R'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'e together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl, S02-alkyl, S02-aryl, SO~-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HET optionally substituted one or more times with substituents selected from h<~logen, alkyl, phenyl, SO,~NR"R'~;
1o Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, aikoxy , halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, S02-NR"R'e wherein R" and R"' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" ~~nd R"' together with the nitrogen to which they are attached forms a heterocyclica 3- to 8 mernbered ring structure optionally substituted with halogen, alkyl, SC>2-alkyl, SG2-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to a.n aryl;
or R' together with Rf' or together with R8 forms a 5- to 7-rnembered ring having the one of the following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -S~G2-NR-(CH2)n- wherein n is 1 or 2; -SO-NR-(CH2)n- wherein n is 1 or 2; -S02-(CH2)n-'wherein n is 2 or 3; -SO-(CH2)n-wherein n is 2 or 3; -CO-CH=:CH-NH ;-CO-CH=CH-tJ~-; -CO-(CH2)"-NH- wherein n is 1 or 2; -CO-NH-(CH2)~ wherein n is 1 or 2; -CO- (CH,~)>-O-; O-(CH2)~-O-; wherein n is 1, 2 or 3;
And another preferred Embodiment is wherein R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloaikyl, CN, cyanoalkyl, nitro, nitroalkyl;
Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;
H ET;
-S-R"3; -SO-R'9 ; -S02-R''3; -S020R''~, -SO2-NR'9R2°, NHCOR'9, -CONR'9R2°, CR'=NOR", -CO-R'9; -C02-R'°, wherein R' and Ft" independently repre:;ents hydrogen, alkyl, cycloalkyl, phenyl, 5 benzyl; and R'9 and R 2° independently represents hydrogEyn, alkyl, cycloalkyl, benzyl, aryl, or R'9 and R~° together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, 1o S02-alkyl, S02-aryl, SC>2-benzyl; and optionally the heterocyclic ring is fused to an aryl;
An especially preferred embodiments is a compounds of formula I as above wherein X represents S02; Y represents N and the broken fine represents a single band;
represents H;
15 R3 represents cycloalkyl, a carbocyclic ~- to 10- membered ring; a heterocyclic 5- to 6 membered ring;
R4 represents H;
R5 represents H;
R6 represents hydrogen, alkyl or halogen;
20 R' represents cyanoalkyl, nitroalkyl, haloalkyl, -{alkyl)m-SO-R" ; {alkyl)m-SO 2-R"; (alkyl)"-S02-NR"R'e , -(alkyl)mCONR"R'B, -(alkyl)m-CR'=NOR", -(alkyl)",-CO-R"; {alkyl)mCC)2-R", wherein misoorl;
25 R' and R" independently represents hydroger7, alkyl, cycloalkyl, phenyl, benzyl; and R" and FI'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they are attached forms a heterocyc;lic 3- to fi mernbered ring structure optionally substituted with alkyl, 3o S02-alkyl, 502-aryl, S02-benzyi; and optionally the heterocyclic ring is fused to an aryl; or H ET;
or 2.6 R' together with Fis or together with R8 forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -SO2-NR-(CH2)n- wherein n is 1 or 2; -SO-NR-(CH2)n- wherein n is 1 or 2; -S02-(C;H~)n~- wherein n is 2 or 3; -SO-(CH2)n-wherein n is 2 or 3; -CO-CH=CH-NH~-;-(:,O-CH=CH-O-~; -CO-(CH~~)"-NH- wherein n is 1 or 2; -CO-NH-(CH2)~ wherein n is '1 er 2; -CO- {C;E~~)2-O-; O-(CH2)~-O-; wherein n is 1, 2 or 3;
R8 represents alkyl, halogen, cyanoalkyl, nitroalkyl, haioalkyl, -~(alkyl)m-SO-R" ; (alkyl)",-SO2-R"; (alkyl)",-S02-NR''R'e , -(alkyl)mCONR"R'8, -(alkyl)m-CR'-NOR", -(alkyl),-CO-R"; {alkyl)mC-O2-R", wherein t0 misoorl;
R' and R" independently reprE;sents hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R" and R'~ independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they are attached forms a heterocyclic 5- to 8 membered ring structure optionally substituted with alkyl, S02-alkyl, S02-aryl, SOZ-benzyl; and optionaliy the heterocyclic ring is fused to an aryl; or H FT;;
Special embodiments of the invention are the following all referring to formula I as above.
An embodiment of the invention is wherein R3 represents hydrogen, cyclopropyl, cyclopentyl, cyc:lohexyl, methyl, ethyl, propyl, isopropyl, CF3, ethoxy, norbornene, norbornane, adamantane, benzyl; phenyl;
or R3 together with R2 or R4 and together with the atoms to which they are attached forms a 5-membered ring;
Another embodiment of the invention is wherein R4 represents hydrogen, methyl, ethyl; or R4 together with R3 and together with the atoms to which they are attached, forms a 5-membered ring;
And another embodiment of the invention is wherein RS represents hydrogen, chloro, bromo, methyl, phenyl, -S02NH~;
2%
And another embodiment of the invention is wherein R6 represents hydrogen, 2-methoxyphenyl, 2-pyridyl, ;f-pyridyl, methyl, methoxy, chloro or bromo;
And another embodiment of the invention is wherein R' represents hydrogen, chloro, broma, methyl, 1-hydroxyethyl, acetyl, -~(CH3)C=N-OH, CONH2, CO 2-ethyl, cyano, phenyl, 2-N-acetylarninophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4-trifluaromethyl-~~-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N,N-dirnethylsulfamoylphenyl, 2- chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2-~tY~ienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-~yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH3CONH-, CH3S02NH-, N02, SO 2OH, phenyl-SOz-, sulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl, N-cyclohea;yl-sulfamoyl, -502-heterocyclic ring, wherein thc: heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine, morpholine;
And another embodiment is wherein R8 represents hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy;
Especially preferred embodiments are a compounds represented by formula I as above wherein X is S0~2 and Y is N and the broken line represents a single bond and R2 represents hydrogen or CH3;
and R3 represents cyclohexyl, cyclopentyl, norbornene, norbornane, adamantane, phenyl, ethoxy;
and R4 represents hydrogen or CH3;
and R5 represents hydrogen, CH3, phenyl, sulfamoyl, chloro, bromo, and R6 represents hydrogen, CH3, 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, 3 pyridyl;
and R' represents hydrogen, chloro, bromo, methyl, 1-hydroxyethyl, acetyl, -(CH3)C=N-OH, CONH2, ethyl, cyano, ph~anyl, 2-N~-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, trifluoromethyl-2-methoxyphenyl, 2,4-dirnethoxyphenyl, 2-N,N-dirnethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2~-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5~-yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH3CONH-, CH3S02NH-, N02, SO 20H, phenyl-SOz-, sulfamoyl, N,N-dimethylsulfarnoyl, N,N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl, N-cyclohexyl-sulfamoyl, -S02-heterocyclic ring, wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1,2,5,6-tekrahydropyridine. tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine, marpholine;
R8 represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy, Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X is S02 and Y is N and the broleen line represents a double bond and R3 represents CH3 or CF3 or R3 together vvith R4 and together with the atoms to which and R4, R6 and RB are all hydroger3;
and RS is hydrogen or halogen;
and R' is N-methylsulfamoyl, N,N-dimethylsulfarnoyl, N-cyclohexylsulfamoyl, tetrahydropyridyl-sulfonyl; S020H, sulfamoyl;
Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X is C=c~ and Y is N, O or CH; and R2 represents hydrogen; and R3 represents hydrogen, C~H3, CF3, cyclohexyl, norbornene, phenyl, ethyl; and R' represents hydrogen, N,N-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyridyl-sulfonyl, rnorpholino-sulfonyl sulfarnoyl, bromo; and RS represents hydrogen or bromo; and R4, R6 and RB all represent hydrogen;
Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X represents CH2 and Y is N; and R3 represents cyclohexyl or narbornene; and R5 represents hydrogen or bromo; and R' represents bromo or sulfamoyf; arid R2, R4, R~' and R8 all represent hydrogen;
sensitive glutamate receptors, pharmaceutical compositions comprising such compounds and their use in therapy BACKGROUND OF TH1= INVENTION
~-Glutamate is the major excitatory neunoiransmitter in the mammalian central nervous system which activates several subtypes of ionotropic and metabotropic receptors. The ionotropic receptors can be divided into threE; subtypes, NMCrA, AMPA and kainate receptors, based on structural and pharmacological differences.
Impairment of glutamatergic neurotran:~rr~ission has been implicated in the learning and memory loss observed in numerous neurological disorders such as e.g.
Alzheimer's decease, senile dementia: stroke (McEntee and Crook, F'sycopharmacology 111:391-401 (1993)). It is widely accepted that learning and memory is related to the induction of long-term potentiation (LTP) which is a stable increase in the synaptic strength following repetitive high frequency stimulations. Experimental studies have shown that increasing the synaptic response mediated by AMF'A receptors enhances the induction of LTP (Arai and Lynch, Brain Research, 598:173-184 (1992)). For the reason:; stated above, compounds that stimulates AMPA receptor response in the brain, may induce improvements in the intellectual behavior and performance.
Activation of AMI'A receptors with mglutamate or the selective agonist AMPA
leads to a rapid receptor desensitization; i.e. tie receptor channel fails to open despite the continued presence of agonist. It i's therefore possible to obtain an increase of the synaptic strength by attenuating the AMPA, receptor desensitization normally elicited by the endogenous neurotransmitter ~-glutamate.
In 1990 Ito et al. reported (J. physial., 424:53;x-543) that the nootropic drug aniracetam (lV-anisoyl-2-p~yrrolidinor~e) increased AMPA induced currents in oocytes injected with rat brain mRNA. In another study, it has been shown that 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine, a compound that enhances synaptic transmission mediated by AMPA receptors, is effective at improving mennary in experimental animals at a ,7 very high dose 120 mg/kg (Stauble et al., Proc. Natl. Acad. Sci. USA, 91:11158-(1994)).
The benzothiadiazide cyclothiazide is a more potent and efficacious modulator of AMPA receptor current in-vitro than aniracetarn (Johansen et al., MoLPharmacol. 48:946-955 (1995)). The effect of cyclothiazide on tf~Ea kinetic properties of AMPA
receptor currents appear to be by a different mechanism to that of aniracetam (Partin et al., J.
Neuroscience 16:6634-6647 (1996)). However, cyclothiazide has no therapeutic potential for AMPA
receptor modulation <~s it can n~~t cross the blood-brain-barrier following peripheral administration. The low potency of know compounds also meets with higher demands for a high solubility due to the higher doses used for ;administration.
BACKGROUND ART
US 5,488,049 describe;; the use of benzothiadiazide derivatives to treat memory and learning disorders. The compounds are structurally closely related to the compounds of the present invention. However the compounds of the present invention shows greater potentiation at lower concentrations. (f=ig. 3 of US 5 488,049) US 4,184,039 disclose:> benzothiadiazides for use in the promotion of hair growth;
DE 1470316 describes a method for producing some benzothiadiazides for use as additives in galvanizing baths.
In Synthesis (10), 183, p. 851 a method for prE;paration of benzothiadiazine-1,1-dioxides are described. The compounds are described as useful as antihypertensive and antimicrobial reagents.
In J. Med. Chem. (15, no. 4), 1972. p. 400-403 bcanzothiadiazine-1,1-dioxides are investigated for their ~--substituents constants as structure activity study for anti hypertensive activity.
WO 9812185 describes benzothiad~azines of different structure as the compounds of the present invention.
Object of the invention It is an object of the present invention to provide positive AMPA modulators which are useful in the treatment of disorders or diseases in mammals, including a human, and especially in the treatment of diseases and disorders which are responsive to modulation of the AMPA
receptors in the brain.
Another object of the present invention is tc:~ provide a method of treating disorders or diseases of a mammal, including a human, responsive to AMP,A receptor modulators which comprises administering to a mammal in need thereof a compound of the invention.
A third object of the pnasent invention is to provide novel pharmaceutical compositions for the treatment of disorders. or diseasEa of mammals, including a human, responsive to AMPA
modulators.
Other objectives of the present invention will be apparent to the skilled person hereinafter.
Summary of thre invention The invention then, inter alia, comprises the fotdo~wing, alone-; or in combination:
A compound represented by the general formula:
Ra ~.X.~ N, R2 R I~ .~.Y~ R
wherein the bond represented by the brokE;n line may be a single, a double bond or absent;
and if the band is absent, then the nitrogen is substituted with a hydrogen and R2;
X represents S02 or C=O or CH~,;
Y represents -CH(IR4)-, -N(R4)- or -N(R°)-C~E~a-, O;
R2 represents hydrogen, alkyl, cycfoalkyl, ;aryl, benzyl;
CO-R9 wherein R9 repre:>ents alkyl, cycloalkyl, benzyl, aryl; or R2 together with R3 arid together with the atF.~ms to which they are attached, forms a 4- to 7-rnembered rin~~ optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, aikoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alko:Kyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR'3R'4 , alkyl-S-R'3 wherein R'3 and R'"' independE:ntly represents hydrogen, alkyl, cycloalkyl; or R'3 and R'° together with the nitrogen to which they are attached forms a 3- to 8 memberE;d heterocyclic: ring structure;
A c:arbocyclic 7- to 12- membered ring ol7tionally substituted with halogen, alkyl, hydroxy or alkoxy; or A heterocyclic 3- to 8 membered ring optionally substituted with halogen, alkyl, hydroxy or alkox:y; and optionally the hcaerocyclic rind is fused to an aryl;
Benzyl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cyc:loalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino;
Aryl which is optionally substituted onE: or more times with substituents selected from the group consi~~ting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or WO 99/42456 I'CT/DK99/00070 R3 together with R' or R4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyi, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl 5 groups.
R' represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R'°, or CCf2R'° wherein R'° represents hydrogen, cycloalkyl, alkyl, aryl or benzyl;
or R4 together with R'3 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally aubstitute~d c>ne or morEy times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hycfroxy, alkoxy, amino or thio and optionally containing one or more heteroatom s and optionally containing carbonyl groups.
R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -S02-NR"R'2 wherein R" and R'' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'z together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thin, aryl, benzyl, SOz-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyi, hydroxyalkyl, cycloalkyl, cyc:iohaloalkyl, -NR'SR'6, NHSO2-R'~', NI-ISOd~-aryl wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, arnino, thio, CF~3, OCF°, N02. aryl;
Aryl optionally substituted one or more times with substituents selected from the group consisting of al~;yl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
HET optionally substituted oroe or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;
-(alkyl)m-S-R'S; ..(alkyl)m-SO-R'S ; -(alkyl)r"-S02-R'S. _(alkyl)m-S020R'S, -(alkyl)m-SOz-NR'SR'6, -(alkyl)m-NHCOR'~', -(alkyl)",-C;C)PJR'SR'~', -(alkyl),~,-CR'=NOR", -(alkyl)m-CO-R'S, -(alkyl)m-CO 2-R'S wherein misoorl;and R' and F." independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, ~~ryl, ben-r_yi; and R'S and R'" independently reprcaents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'S and 'R''' together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ~riracf structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alko:xy, amino or thio, aryl, benzyl, S02-alkyl, SOz-aryl, S02-benzyl'; and optionally the heterocyclic ring is fused to an aryl;
R' represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, vitro, nitroalkyl;
alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, c:yc:loalkyl, cyclohaloalkyl, -NR"R'8, NHSC)2-R", NHSO~-aryl wherEein the aryl is optionally substituted one or more times with substituents selected frcjrn halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF~, NOz, aryl;
-(alkyl)m-S-R"; -(alkyl)m-SO-R" ; (alkyl)m..,;02_R"; _(alkyl)",-SO20R", (alkyl)m-S02-NR"R'8, -(alkyl)mNHCOR", -(alkyl),r,CONR"R'8, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R''' (alkyl)mC0?-R", wherein misoorl;
and R' and R" independently reprEasents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, <~ryl, benzyl; and R" and IR"~ independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" arid R'e together with the nitrogen to which they are attached forms a heterocyclic :3- to 8 membered ring structure a~ptionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, SOz-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HST optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO~-alkyl, S02-aryl, ;aO?NR"R'g;
Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alk:enyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO~-NFi"R'~, wherein R" and R'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they .are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, Ihydroxy, alkoxy, amino or thio, aryl, t>enzyl, SO2-alkyl, S02-aryl, benzyl; anti aptionally the heterocyclic ring is fused to an aryl;
or R' together with Rf' or together with RB forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-; wherein ra is 1, 2 or 3; -SO~-NR-(CH2)n-wherein n is 1 or 2; -SO-NR- (CH2)~- wherein n is 1 or 2; -SO2-(CH2)~- wherein n is 2 or 3; -SO-(CH2)~-wherein n is 2 or 3; -CO-C;H=CH-NH- ;-CO-CH=C;H-O-; -CO-(CH2)~-NH- wherein n is 1 or 2; -CO-NH-(C;H,~)~ wherein n cs 1 or 2; -CO- (CH2)~-f7-;-O-(CH2)rn-O-; wherein n is 1, 2 or 3;
R8 represents hydrogen, alkyl, alkoxy, hydro;Kyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitraalkyl;
Aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF;3, OCF3, N02, alkyl, cycloalkyl, alkoxy;
HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF-3, IV02, alkyl, cycloalkyl, alkoxy;
-(alkyl)rt,-S-R'9; .. (alkyl)m-SC7-R'9 ; -(alkyl)n,-S02-R''~; -(alkyl)m-S020R'9, (alkyl)n,-SOZ-NR'9R2°, -(alkyl)mNHCOR'9. -(alkyl)mCOf~IR'9R2°, -(alkyl)rn-CR'=NOR", -(alkyl)m-CO-R'9;
(alkyl)m-C02-R''~, and m is CI or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl" alkenyl, alkynyl, aryl, benzyl; and R'9 and R2° indE:pendently represents hydrogen, alkyl, cycfoalkyl, benzyl, aryl, or R'9 and R2° togethE~r with the nitrogen to which they are attached forms a heterocyclic 3-to 8 membered ring structure optionallyr substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amir7o or thio, aryl, benzyl, SO?-alkyl, SO2-aryl, S02-benzyl;
and optionally the heterocycli~; ring is fusE:d to an aryl;
provided that when the broken line in fon~nula I represents a double bond and X
represents S02 and Y represent NH and the corrrpound is nnanosubstituted then it is not monosubstituted with FI3 representing OCH3, rnel:hyl, pentyl, t-butyl, aminophenyl, 2-phenylethylene, phene!lhyl, cyclopE~ntyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornene, benzyl, thienyl, furyl, aryl, aryl substituted with 4-methyl, 4-methoxy, 4-chloro, 4-nitro or 3-nitro;
and when the compound is disubstitutc:d with R3 being methyl then R5 is not CI, CH3;
or then R' is not F, CI, 13r, I, CH3 C:F,, nitro, SO;>N(CH3)2; or then R6 is not CI, Br, CH3, CF3, ethyl, methoxy;
or when R' is chloro then R3 is not ethyl, butyl, sec- butyl, t-butyl, cyclobutyl, 2,2-dimethylpropyl, phenyl;
and when the corrrpound is disubstitutE:d then it is not with R6=OMe, R3=ethyl;
R6=methyl, R3=propyl; iR' =S02NH7, R~=Cl; R'=SOzNH2, R3=::phenyl; R'=Br, R3=phenyl;
And provided that when the compouncl is trisubstituted then it is not R3=CH3 , R5=N02, R'=CI; R3=CH3 , R6=NO 2, R'=CI; R3=CH3 , R5=:NI-i2, R'=CI;
and provided that when the broken IinE: in formula I represents a single bond and X
represents S02 and Y represent NH
Then the compound is not a disubstituted compounds with R' or R6 being chloro and R3 being alkyl, cyclobutyl, cycfopropyl, cyclohexyl, cyclohexen, norbornenyl, norbornanyl, ethylthiomethyl, ethylo>;ymethyl, ethyloxyethyl, methyloxymE~thyl, methylamino, 2-chloroethyl, chloromethyl, dichloromethyl, trifluoromethyl, arnina;
and the compound is not a trisubstituted compound with R3 being CH3 and R5=isopropyl , R'=F; R5=ethyl , R'=C:I; IR''=:propyl , R':=CI; R5=ethyl , R'=F; R5=methyl , R'=CI; R5=ethyl , R'=methyl; R5=CI , R'-=Methyl; RS=methyl , R'=CI; R4=methyl , R5=ethyl; or trisubstituted with R'=methyl, R5=methyi , R'---F;
A pharmaceutical composition comprising an therapeutically effective amount of a compound as above tol~ether with pharmaceutically acceptable carriers or exipients;
The use of a compound represented by the general formula R$
R~' Ra wherein the bond represented by the broken line may be a single, a double bond or absent;
and if the bond is absent, then tt~e nitrogen is substituted with a hydrogen and R2;
2o X represents S02 or C=O or C;H2;
Y represents -CH(R4j-, -N(R4)- or -N(R'1)-CI-i~~-, O;
R2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl;
CO-R9 wherein R9 repre:>ents alkyl, cycloalkyl, benzyl, aryl; or R2 together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring optionally substituted c>ne or more times with substituents selected from halogen, alkyl, alkenyl, alkynyf, hydroxy, alkoxy, amino or thio and optionally containing one or more heteruatoms and optionally containing carbonyl groups;
R3 represents hydrogen, cycloalkyl, alkyl, cyc;loalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR'3R'4 , alkyl-S-R'3 wherein R'3 and R'~ independently represents hydrogen, alkyl, cycloalkyl; or R'3 and R'° togei:her with the nitrogen to which they are attached forms a 3- to 8 membered heterocyclic ring structure;
A carbocyclic 7- to 12- membered ring optionally substituted with halogen, alkyl, hydroxy or alko>cy; or A heterocyclic 3- to 8 membered ring optionally substituted with halogen, alkyl, hydraxy or alko>cy; and optionally the heterocyclic ring is fused to an aryl;
Benzyl which is optionally substituted one or more times with substituents selected from the group consisting of halogen, c:ycloalkyl, alkyl, hydroxy, alkoxy, amino or thin, haloalkyl, hydro:Kyalkyl, alkoxyalkyl, alkylthio, alkylamino;
Aryl which is optionally substituted one or more times with substituents selected from the group consistirng of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thin, haloalkyl, hydro:Kyalkyl, alkoxyalkyl, alkylthio, alkylamino; or R3 together with R2 or R4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
R4 represents hydrogen, alkyl, cycloalkyl, cyc:loalkylalkyl, aryl, -CO-R'°, or C02R'° wherein R'° repre:>ents hydrogen, cycloalkyl, alkyl, aryl or benzyl;
or R4 together with R3 and together with the .atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl. h~,rdroxy, alkoxy, amino or thio and optionally cantaining one ~or more heteroatoms and optionally containing carbonyl groups.
R5 represents hydrogen, halogen, alkyl, alkenyl, alkyny,l, aryl, -S02-NR"R'2 wherein R" and R''' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl"
or R" and R" together with the nitrogen to whic::h they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thin, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
Rs represents hydrogen, halocfen, alkyl, oyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydro~xyalkyl, cycloalkyl, cycloh,aloalkyl, -NR'SR'6, NHSO 2-R'S, NHSOa-aryl wherein the aryl i;~ optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, aikoxy, amino, thio, CF=3, OCF3, NG2, aryl;
Aryl optionally :substituted one or more tunes with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkc~xy, halogen, haloalkyl, haloalkoxy;
-{alkyl)m-S-R'S; -(alkyl)m-SG-R'S ; -(alkyl),-S02-R'S; ..(alkyl)m-SO20R'S, -(alkyl)m-S02_ NR'SR'~, -(alkylh,-NHCOR'S, -(alkyi)m-(~ONR''R'6, -(alkyl)m-CR'=NOR", -(alkyi)m-CO-R'S; -(alkyl)m-CO 2-R~''' wherein misoorl:and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R'S and F~'6 independently represents hydrogE:n, alkyl, cycloalkyl, benzyl, aryl, or R'S and F3'6 together with the nitrogen to which they are attached forms a heterocyclic: 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, SU2-benzyl; and optionally the heterocyclic ring is fused to an aryl;
R' represents hydrogE:n, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl;
alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -NR"R'a, NHS02-R'', NHS02-aryl wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF;~, N02, aryl;
-(alkyl)m-S-R", -(alkyl)",-SO-R" ; (alkyl)m~-S02-R"; _(alkyl)~,-S020R", (alkyl)m-SOz_ NR"R'e, -(alkyl)mNHCOR'7, -(alkyl)",CC>NR"R'e, -(alk:yl)m-CR'=NOR", -(alkyl)m-CO-R";
(alkyl)mCOrR", wherein misoorl;
20 and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, <~ryl, benzyl; and R" and I~"' independently reprE;sents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with thE: nitrogen to which they are attached forms a 25 heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl. alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SOralkyl, ;~02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
30 HFT optionally substituted one or more limes with substituents selected from halogen, alkyl, alkf:nyl, alkynyl, hydroxy, alkoxy, amiroo, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SOz-alkyl, SO?-aryl. ;a02NR"R'8;
Aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy., aikoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO~~-~NR"R'~, wherein R" and R'8 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'e together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 member~ed ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alk:oxy, amino ar thio, aryl, t>enzyl, S02-alkyl, S02-aryl, benzyl; and optionally the heteroc:yclic ring is fused to an aryl;
or R' together with R~' or together with R8 forms a 5- to 7-rnembered ring having the one of the following structures -O-(CH2~n-O-; wherein r7 is 1, 2 or 3: -SO~-NR-(CH2)n-wherein n is 1 or 2; -SO-~NR- (CHZ)~- wherein n is 1 or 2; -SO2-(CH2)n- wherein n is 2 or 3; -SO-(CH2)n-wherein n is 2 or 3; -CC)-CH=CH-NH- ;-CO-CFI=C;H-O-; -CO-~(CH2)"-NH- wherein n is 1 or 2; -CO-NH-(CH~)~ wherein n is 1 or 2; -CO- (CH2)~-O-;-O-(CH2)r~-O-; wherein n is 1, 2 or 3;
Re represents hydrogen, alkyl, alkoxy, hy<iro:Kyalkyl, halogen, haloafkyl, CN, cyanoalkyl, nitro, nitroalkyl;
Aryl optionally substituted ane or more times with substituents selected from the group consisting of halogen, CF;3, OCF3, N02, alkyl, cycloalkyl, alkoxy;
HST optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF~3, N02, alkyl, cycloalkyl, alkoxy;
-(afkyl)m-S-R'9; -~ (alkyl)m-SO-R'''' ; -(alkyl)m~-S02-R'''; ~~(alkyl)m-S020R'9, (alkyl)rt,-S02-NR'9R2°, -(alkyl)mNHCOR'9. -(alkyl)mCCJNR'9R2°, -(alkyl)n,-CR'=NOR", -(alkyl)rt,-CO-R'9;
(ai'kyl)m-C02-R'''~, and m is U or 1; and f~' and R" independently represents hydrogen, alkyl, cycloalkyl. alkenyl, alkynyl, aryl, benzyl; and R'9 and R2° independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'9 and R2° together with the nitrogen to which they are attached forms a heterocyclic 3-to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl;
and optionally the heterocyclic ring is fused to an aryl;
'I 4 for the manufacture of a medicament for the treatment of disorders or diseases responsive to modulation of the AMPA receptor complex.
A method for the treatment of disorder, or diseases responsive to the modulation of the AMPA receptor complex wherein a therapeutically efficic.~nt amount of a compound represented by the general formula R~' Rz ~ ,~,X\N, R:>
Rsr ~ 'y'~'~. Ra wherein the bond represented by the broken line may bE: a single, a double bond or absent;
and if the bond is absent, then the nitrogen is substituted with a hydrogen and R2;
X represents S02 or C=O or C;Hz;
Y represents -CH(R4)-, -N(R'')- or -N(R4)~-CH;z-, O;
R2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl;
CO-R9 wherein R9 repre:;ents alkyl, cycloalkyl, bc:nzyl, aryl; or R2 together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring optionally substituted c>ne or more times with substituents selected from halogen, allkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more hetc:roatoms and optionally containing carbonyl groups;
R3 represents hydrngen, cycloalkyl, alkyl, cycloalkylalkyN, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR'3R'4 , alkyl-S-R'3 wherein R'3 and R'4 independently represents hydrogen, alkyl, cycloalkyl; or R'3 and R'4 together with the nitrogen to which they are attached forms a 3- to 8 membered heterocyclic ring structure;
5 A carbocyclic 7- to 12- membered ring optionally sukastituted with halogen, alkyl, hydroxy or alko:Ky; or A heterocyclic ;:~- to 8 membered ring optionally substituted with halogen, alkyl, hydroxy or alko:Ky; and optionally the heterocyclic ring is fused to an aryl;
Bc:nzyl which is optionally substituted orre or more times with substituents selected from the group consisting of halogen, c:ycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alN;ylthio, alkylanoino;
Aryl which is optionally substituted one car more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hyciroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alH;ylthio, alkylannino; or R3 together with R'~ or R4 and together with the atoms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and captionally containing carbonyl groups.
R4 represents hydrogen, alkyl, cycloalkyl, cyc:loalkylalkyl, aryl, -t;0-R'°, or C02R'° wherein R'° represents hydrogen, cycloalkyl, alkyl, aryl or benzyl;
or R4 together with R'' and together with the ai:oms to which they are attached, forms a 4- to 7- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hyc~roxy, alkoxy, amino ar thio and optionally containing one or more heteroatoms ancj optionally containing carbonyl groups.
R5 represents hydrogen, halogen, alkyl, aNkenyl, alkynyl~ aryl, -SOrNR"R'2 wherein R" and R'' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R''' together with the nitrogen to whit..~.h they are attached forms a heterocyclic 3- to 8 membered rind structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SOz-alkyl, SOz-aryl, S02-ber~zyl; and optionally the helerocyclic ring is fused to an aryl;
R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cyciaalkyl, cyclohaloalkyl, -NR'SR'~, NHSO2-R'S, NHSO,-aryl wherein the aryl i:~ optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, arnino, thio, CF~3, OCF3, NO 2, aryl;
Aryl optionally substituted one or more times with substituents selected from the group cansisting of alH;yl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;
HET optionally substituted one or more times with substituents selected from the group consistin~~ of alkyl, cycloalkyl, alkoxy, halogen,, haloalkyl, haloafkoxy;
-(alkyl)m-S-R'S; ..(alkyl)m-SO-R'S ; -(alkyl)",-S02-R'S; -(alkyl)m-SOzOR'S, -(alkyl)m-S02_ NR'SR'6, -(alkyl)m-NHCOR"', -(alkyl),n-C:C)IVR'''R's, -(alkyl)m-CR'=NOR", -(alkyl)n,-CO
R'S; -(alkyl)m-CO 2-R'S wherein m is o or 1; and R' and Ft" independently repre:>ents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, bent yl; and R'S and R"' independently represE:nts hydrogen, alkyl, cycloalkyl, benzyl, aryl, ar R'S and R't' together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen" alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin, aryl, benzyl, WO 99/4245fi PCT/DK99/00070 1%
S02-alkyl, S02-aryl, SO~-benzyl; and optionally the heterocyclic ring is fused to an aryl;
R' represents hydrogen, halogen, alkyl, c;yano, cyanoalkyl, nitro, nitroalkyl;
alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -NR"R'8, NHSO2-R", NHSO~-aryl wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, Cf=3, OCF3, NO?, aryl;
-(alkyl)m-S-R"; -(alkyl)m-SG-R" ; (alkyl),-S02-R"; -(alkyl)m-S020R", (alkyl)m-NR''R'~, -(alkyl)mNHCOR", -(alkyl)mCONR"R'e, -(alkyl)n,-CR'=NOR", -(alkyl)rt,-CO-R";
(a.lkyl)mC02-R", wherein misoorl;
and R' and R" independently rE~presents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R" and R'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'H together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyi, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HFT optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, S02-alkyl, S02-aryl, ',.~OZNR"R'8;
Aryl optionally substituted one or mare times with substituents selected from the group consisting of alkyl, al~;enyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, C>CF3, -SO,~--NR"R'8, wherein R" and R'8 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 memberc:d ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, SOZ-benzyl; a,nd optionally the heteroc:yclic ring is fused to an aryl;
or R' together with R6 or together with Rg forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -S02-NR-(CH2)n-wherein n is 1 or 2; -SO-NR- (CH2)~- wherein n is 7 ~r 2; -SO2-(CH2)~- wherein n is 2 or 3; -SO-(CH2)~-wherein n is 2 or 3; -CO-CH=CH-NH- ;-CO-CH=CH-O-; -CO-(CH2)~-NH- wherein n is 1 or 2; -CO-NH-(C;H2)~ wherein n is 1 or '~; -CO- (CH2)~:-(J-;-O-(CH2)n-O-; wherein n is 1, 2 or 3;
Re represents hydrogen, alkyl, alkoxy, hydrc~xyalkyl, halc:~gen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
Aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, N02, alkyl, cycloalkyl, alkoxy;
HE:T optionally ~~ubstituted one or morE~ tirnes with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, c;ycloalkyl, alkoxy;
-(alkyl)m-S-R'9; - (alkyl)m-SO-R'9 ; -(alkyl),n-S02-R'9; -(alkyl)m-S020R'9, (alkyl)m-S02-NR'9R2°, -(alkyl)imNHCOR'q, -(alkyl)rnCONR'9R2°, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R'9;
(alkyl)m-C02-R'9, and m is 0 or 1; and Fi' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R''~ and R2° independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'9 and R2° togethE~r with the nitrogen to which they are attached forms a heterocyclic 3-to 8 membered firing structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, S02-alkyl, S02-aryl, S02-benzyl;
and optionally the heterocyclic ring is fused to an aryl, is administered.
Detailed disclosure of the invention The invention provides novel compounds of formula f as shown above.
Preferred embodiments of the invention are compounds of formula I as above wherein R2 represents hydrogen, alkyl, c;ycloalkyl, phenyl, benzyl;
or R2 together with F13 and together with the atoms to which they are attached forms a 5- to 5-membered ring optionally substituted one or more times with substituents selected from halogen, ~~Ikyl, hydroxy, alkoxy, arnino or thio; and aptionally containing one or more heteroatoms and optionally containing carbonyl groups;
R3 represents hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic 7- to 10-membered ring; a heterocyclic 5- to E3 rnErmbered ring; benzyl; aryl;
or R3 together with Rz or R4 forrns a 5- to 6- membered ring;
R4 represents hydrogen, alkyl, or R4 together with R3 and together with the atoms to which they are attached, forms a 5- to 6- membered ring; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
RS represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl -S02-NR"R'2 wherein R" and R'2 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R" together with the nitrogen to which they are attached forms a heterocyclic 5- to 6- memberecl ring structure;
R~ represents hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxy, alkoxyalkyl, Phenyl optionally substituted one or more times with substituents selected from the group consisting of 2Ci alkyl, alhoxy;
HET;
-S-R,s; -SO-Ris _ -S02-R,s; -S020R's, -;aO2-NR'sR,s _NHCOR's, -CONR'sR,s _ CR'=NOR", -CO-R'~'; -CO2-R's, wherein f3' 4~nd R" independently represents kaydrogen, alkyl, cycloalkyl, phenyl, benzyl; and f3''' and R's independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R's and F3's together with the nitrogen to which they are attached forms a hetE:rocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio., phenyl, benzyl, S02-alkyl, S02-aryl, S02-benzyl;
ancf optionally the hetero,;yclic ring is fused to an aryl;
R' represents hydrogen, Br, F, I, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)m-NR"R'e, NHS02-R", -S-R'", -SO-R" ; -302-R"; -SO 2OR", -SO 2-NR"R'°, NfvCOR", CONR"R'8, CR'=NOR", -CcJ-R"; -C02-R ", wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, I~enzyl; and R" and R"' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'E' together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl, SOZ-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HET optionally substituted one or morE: tunes with substituents selected from halogen, alkyl, phenyl, S(J2NR"R'8;
Phenyl optionally substituted one or rru~re times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy , halogen, Inaloalkyl, amino, NHCO-alkyl, nitro, OCF3, -S02-NR"R's wherein R" and F;"' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R~' and R'e together with the nitrogen to which they are attached forms a heterocyclic: ;3- to 8 menobered ring structure optionally substitui:ed with halogen, alkyl, SO 2-alkyl, SU2-aryl, S02-benzyl; and optionally the heterocyclic rind is fused to an aryl;
or R' together with R6 or together with Re forms a 5- to '7-membered ring having the one of thc: following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -S02-NR-(CH2)n- wherein n is 1 or 2; -SO-NR- {CH2)~- wherein n is 1 or ~; -S02-(CH~),~- wherein n is 2 or 3; -SO-(CH2)~-wherein n is 2 or 3; -CO-C;H=CH-NH-- ;-CO-CH=:C;H-O-; -CO-(CHz)~-NH- wherein n is 1 or 2; -CO-NH-{CH2)~ wherein n is ~ or 2; -C;O- (CH?)2-O-;-O-(CH2)n-O-; wherein n is 1, 2 or 3;
Rs represents hydrogen, alkyl, alkoxy. hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl;
Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;
H F_T"
-S-R'9; -SO-R'9 ; -S02-R'9; -S020R'9, -~~Oz-NR'9R2°, NHCOR'9, -CONR'9R2°, CR'=NOR", -CC)-R'9; -CO?-R'9, wherein R' and Fi" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
and R'9 and R2° independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'~ and R'" together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered rind structure rcptionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, aikoxy, amino or thio, phenyl, benzyl, SO?-alkyl, S02-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to an aryl;
provided that when X represents S02 and Y represents N and the broken line 3o represents a single bond then neither of R' or R6 are chlaro when R2, R4, R5, Ra and the remaining of R6 and R' are all hydrogen; and provided that R3 can represent CH3 only when RS is hydrogen or R' is not sulfamoyl;
and provided that when X represents S02 and Y represents N and the broken line represents a double bond then neither of R' or R6 are chloro when R2, R4, R''', R8 and the remaining of R6 2,c'.
and R' are all hydrogen; and provided that R', R4, R5, R6, R' and R8 are not all hydrogen; and provided that the compound is not disubstituted with R3 is being CH3 when R' is fluoro, bromo, iodo, CF3, CH3, NO,, SO2N(CH3)2, or R'' is broma, C; F3, CH3, ethyl, methoxy; or RS is chloro, CH3; or R8 is chloro; and provided that: the compound is not 3-ethyl-f3-methoxy-1,2,4-benzothi<~diazine-1,1-dioxide;
3-propyl-6-methyl-1,2,4-benzothiadiazine-1,1-dioxide;
3-ethyl-fi-methoxy-1,2,4-benzothiadiazine-1, ~i -dioxide;
3-phenyl -I-bromo- t ,2,4-benzott~iadiazine-1,1 ~-dioxide;
3-phenyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide;
5-bromc-7-chloro-3~-methyl-1,2,4-benzothiadiazine-1,1-dioxide;
5-iodo-7-chloro-3-methyl-1,2,4-benzothiadiazir~e-1,1-dioxide;
5-vitro-T-chloro-3-methyl-1,2,4-~benzothiadiazine-1,1-dioxide;
6-vitro-7-chloro-3-methyl-1,2,4-~berrzothiadiazir~e-1,1-dioxide; or 6-amino-7-chloro-3-methyl-1,2,4-~benzothiadiazine-1,1-dioxide;
A more preferred embodiment of the invention is a compound of formula I as above , wherein Rz represents hydrogen, alkyl, cycloalkyl;
or R2 together with R3 forms a 5- tc> 6-membered ring; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;
And a preferred embodiment is wherein R3 represents hydrogen, cyclo;alkyl, alkyl, haloalkyl, alkoxy, a carbocyciic 7- to 10-membered ring; a heterocyclic 5- t~o Ei membered ring; benzyl; aryl;
or R3 together with R2 or R' forms a 5- to 6- rnembered rind; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, aikoxy, amino or thio and o~7tionally containing one or more heteroatoms and optionally containing carbonyl groups.
And another preferred Embodiment is wherein R° represents hydrogen, alkyl, or R4 together with R3 ;end together with the atoms to which they are attached, forms ,~ E>- to 6- membered ring optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or rnorc~ heteroatoms and optionally containing carbonyl group:>.
And another preferred embodiment is wherein R5 represents hydrogen, halogen, alkyl, alkenyl, alkyynyl, phenyl, -S02-NR" R'2 wherein R" and R'' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'' together with the nitrogen to vvhich they are attached forms a heterocyclic 3- to 8 membered ring structure;
And another preferred .embodiment is wherein R6 represents hydrogen, halogen, cycloalkyl, alkyl, alk<axy, alkoxyalkyl, Aryl optionally substituted one or more times with substituents selected from the group consisting of alH;yl~ alkoxy;
H ET;
-S-R,s; -SO-R,s ; -S02-R,s; -S020R'S, .-S02_NR'SR'6, -NHCOR'S, -CONR'SR,s -CR'=NOR", -CC>-R'S; -CO2-R'S, wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl;
and R'S and R'~' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R'S and ~i'~ together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered rir7g structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alko.xy, amino or thio, phenyl, benzyl, S02-alkyl, SOz-aryl, SO2-benzy~l; and optionally the heterocyclic ring is fused to an aryl;
And another preferred embodiment is wherein R' represents hydragen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, 3o hydroxyalkyl, cycloalkyl, cyc;lohaloalkyl" -(alkyl)m-NR"R'8, NHS02-R", _5._R"; -SO-R" ; -SOz-R"; -SO20R", -.SC>2-NR"R,B, NHCOR'', CONR"R'8, CR'=NOR", -CC~-R", -CO~-R'', wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, benzyl; ~~nct 2~
R" and R'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'e together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with alkyl, S02-alkyl, S02-aryl, SO~-benzyl; and optionally the heterocyclic ring is fused to an aryl;
HET optionally substituted one or more times with substituents selected from h<~logen, alkyl, phenyl, SO,~NR"R'~;
1o Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, aikoxy , halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, S02-NR"R'e wherein R" and R"' independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" ~~nd R"' together with the nitrogen to which they are attached forms a heterocyclica 3- to 8 mernbered ring structure optionally substituted with halogen, alkyl, SC>2-alkyl, SG2-aryl, S02-benzyl; and optionally the heterocyclic ring is fused to a.n aryl;
or R' together with Rf' or together with R8 forms a 5- to 7-rnembered ring having the one of the following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -S~G2-NR-(CH2)n- wherein n is 1 or 2; -SO-NR-(CH2)n- wherein n is 1 or 2; -S02-(CH2)n-'wherein n is 2 or 3; -SO-(CH2)n-wherein n is 2 or 3; -CO-CH=:CH-NH ;-CO-CH=CH-tJ~-; -CO-(CH2)"-NH- wherein n is 1 or 2; -CO-NH-(CH2)~ wherein n is 1 or 2; -CO- (CH,~)>-O-; O-(CH2)~-O-; wherein n is 1, 2 or 3;
And another preferred Embodiment is wherein R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloaikyl, CN, cyanoalkyl, nitro, nitroalkyl;
Phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;
H ET;
-S-R"3; -SO-R'9 ; -S02-R''3; -S020R''~, -SO2-NR'9R2°, NHCOR'9, -CONR'9R2°, CR'=NOR", -CO-R'9; -C02-R'°, wherein R' and Ft" independently repre:;ents hydrogen, alkyl, cycloalkyl, phenyl, 5 benzyl; and R'9 and R 2° independently represents hydrogEyn, alkyl, cycloalkyl, benzyl, aryl, or R'9 and R~° together with the nitrogen to which they are attached forms a heterocyclic 3- to 8 membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, 1o S02-alkyl, S02-aryl, SC>2-benzyl; and optionally the heterocyclic ring is fused to an aryl;
An especially preferred embodiments is a compounds of formula I as above wherein X represents S02; Y represents N and the broken fine represents a single band;
represents H;
15 R3 represents cycloalkyl, a carbocyclic ~- to 10- membered ring; a heterocyclic 5- to 6 membered ring;
R4 represents H;
R5 represents H;
R6 represents hydrogen, alkyl or halogen;
20 R' represents cyanoalkyl, nitroalkyl, haloalkyl, -{alkyl)m-SO-R" ; {alkyl)m-SO 2-R"; (alkyl)"-S02-NR"R'e , -(alkyl)mCONR"R'B, -(alkyl)m-CR'=NOR", -(alkyl)",-CO-R"; {alkyl)mCC)2-R", wherein misoorl;
25 R' and R" independently represents hydroger7, alkyl, cycloalkyl, phenyl, benzyl; and R" and FI'e independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they are attached forms a heterocyc;lic 3- to fi mernbered ring structure optionally substituted with alkyl, 3o S02-alkyl, 502-aryl, S02-benzyi; and optionally the heterocyclic ring is fused to an aryl; or H ET;
or 2.6 R' together with Fis or together with R8 forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-; wherein n is 1, 2 or 3; -SO2-NR-(CH2)n- wherein n is 1 or 2; -SO-NR-(CH2)n- wherein n is 1 or 2; -S02-(C;H~)n~- wherein n is 2 or 3; -SO-(CH2)n-wherein n is 2 or 3; -CO-CH=CH-NH~-;-(:,O-CH=CH-O-~; -CO-(CH~~)"-NH- wherein n is 1 or 2; -CO-NH-(CH2)~ wherein n is '1 er 2; -CO- {C;E~~)2-O-; O-(CH2)~-O-; wherein n is 1, 2 or 3;
R8 represents alkyl, halogen, cyanoalkyl, nitroalkyl, haioalkyl, -~(alkyl)m-SO-R" ; (alkyl)",-SO2-R"; (alkyl)",-S02-NR''R'e , -(alkyl)mCONR"R'8, -(alkyl)m-CR'-NOR", -(alkyl),-CO-R"; {alkyl)mC-O2-R", wherein t0 misoorl;
R' and R" independently reprE;sents hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R" and R'~ independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R" and R'8 together with the nitrogen to which they are attached forms a heterocyclic 5- to 8 membered ring structure optionally substituted with alkyl, S02-alkyl, S02-aryl, SOZ-benzyl; and optionaliy the heterocyclic ring is fused to an aryl; or H FT;;
Special embodiments of the invention are the following all referring to formula I as above.
An embodiment of the invention is wherein R3 represents hydrogen, cyclopropyl, cyclopentyl, cyc:lohexyl, methyl, ethyl, propyl, isopropyl, CF3, ethoxy, norbornene, norbornane, adamantane, benzyl; phenyl;
or R3 together with R2 or R4 and together with the atoms to which they are attached forms a 5-membered ring;
Another embodiment of the invention is wherein R4 represents hydrogen, methyl, ethyl; or R4 together with R3 and together with the atoms to which they are attached, forms a 5-membered ring;
And another embodiment of the invention is wherein RS represents hydrogen, chloro, bromo, methyl, phenyl, -S02NH~;
2%
And another embodiment of the invention is wherein R6 represents hydrogen, 2-methoxyphenyl, 2-pyridyl, ;f-pyridyl, methyl, methoxy, chloro or bromo;
And another embodiment of the invention is wherein R' represents hydrogen, chloro, broma, methyl, 1-hydroxyethyl, acetyl, -~(CH3)C=N-OH, CONH2, CO 2-ethyl, cyano, phenyl, 2-N-acetylarninophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4-trifluaromethyl-~~-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N,N-dirnethylsulfamoylphenyl, 2- chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2-~tY~ienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-~yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH3CONH-, CH3S02NH-, N02, SO 2OH, phenyl-SOz-, sulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl, N-cyclohea;yl-sulfamoyl, -502-heterocyclic ring, wherein thc: heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine, morpholine;
And another embodiment is wherein R8 represents hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy;
Especially preferred embodiments are a compounds represented by formula I as above wherein X is S0~2 and Y is N and the broken line represents a single bond and R2 represents hydrogen or CH3;
and R3 represents cyclohexyl, cyclopentyl, norbornene, norbornane, adamantane, phenyl, ethoxy;
and R4 represents hydrogen or CH3;
and R5 represents hydrogen, CH3, phenyl, sulfamoyl, chloro, bromo, and R6 represents hydrogen, CH3, 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, 3 pyridyl;
and R' represents hydrogen, chloro, bromo, methyl, 1-hydroxyethyl, acetyl, -(CH3)C=N-OH, CONH2, ethyl, cyano, ph~anyl, 2-N~-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, trifluoromethyl-2-methoxyphenyl, 2,4-dirnethoxyphenyl, 2-N,N-dirnethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2~-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5~-yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH3CONH-, CH3S02NH-, N02, SO 20H, phenyl-SOz-, sulfamoyl, N,N-dimethylsulfarnoyl, N,N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl, N-cyclohexyl-sulfamoyl, -S02-heterocyclic ring, wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1,2,5,6-tekrahydropyridine. tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine, marpholine;
R8 represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy, Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X is S02 and Y is N and the broleen line represents a double bond and R3 represents CH3 or CF3 or R3 together vvith R4 and together with the atoms to which and R4, R6 and RB are all hydroger3;
and RS is hydrogen or halogen;
and R' is N-methylsulfamoyl, N,N-dimethylsulfarnoyl, N-cyclohexylsulfamoyl, tetrahydropyridyl-sulfonyl; S020H, sulfamoyl;
Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X is C=c~ and Y is N, O or CH; and R2 represents hydrogen; and R3 represents hydrogen, C~H3, CF3, cyclohexyl, norbornene, phenyl, ethyl; and R' represents hydrogen, N,N-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyridyl-sulfonyl, rnorpholino-sulfonyl sulfarnoyl, bromo; and RS represents hydrogen or bromo; and R4, R6 and RB all represent hydrogen;
Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X represents CH2 and Y is N; and R3 represents cyclohexyl or narbornene; and R5 represents hydrogen or bromo; and R' represents bromo or sulfamoyf; arid R2, R4, R~' and R8 all represent hydrogen;
Another especially preferred embodiment of the invention is a compounds of formula I as above wherein X represents SO, and Y represents NH; and the broken line is absent and R2, R4, R5 and R~ all represent hydrogen;
R3 represents cyclohexyl, methyl or hydrogen; and R' represents N,N-dimethylsulfamc>yl. tetrahydropyridyl-sulfonyl, bromo;
and R6 represents bromo or hydrogen;
Another especially pref~srred embodiment of the invention is a compounds of formula I as above wherein X is SO;~ and N is -NHCH2-; arid R3 represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R'reprEaents 1-piperidino-sulfonyl.
The most preferred embodiment of the invention are compounds of formula I as above wherein the compounds are the following:
2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline;
2-Phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline;
2-Methyl-3,4-dihydro-1,3-benzoxazine-4-one;
2-Phenyl-3,4-dihydro-1,3-benzoxazine-4-one;
3-Bicyclo[2.2.1 ]hept-5'-E:n--2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-i ,1-dioxide;
1,2,3,5,10,1 Oa-Hexahydrobenzo[e]pyrrolo[1,2-b]- t ,2,4-thiadiazine-5,5-dioxide;
2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazine-4~-crne;
3-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetr<~hydro-1,2,4-krenzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,~1-benzothiadiazine-1,1-dioxide;
3-Cyciohexyl-6-(3-pyridyl)-1,2,3,4-tEarahydro-1,2r4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyiminoethyl)-1,2,3,4-tetrahydro-1,2,4~-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl~-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-ethoxycarbonyl-1,2, 3,4-tetrahyciro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohe:Kyl-7-cyana-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 ]hept-5'-Eon-2'-yl-7-phenyl-1,2,3,~1-tetrahydro-1,2,4-benzothiadiazine-1,1-3o dioxide;
3-Cyclohexyl-~7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-nitro~rhenyl)-1,2.,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-methoxyphenyl)-1,'?,3,4-tetr;~t~ydro-1,2,4-benzothiadiazine-1,1-dioxide;
3() 3-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2',4'-diimethoxyphenyl)-1,2,3, 4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE:xyl-7-(2'-{N,~J-c!imethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;3-Cyclohexyl-~-(2'-fluorophenyl)-1,2,3,4-tetrahynro-1,2,4-benaothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyf-7-(2'-pyrir~yl )-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazine-1,1-dioxide;
3-CycIohE~xyl-7-(3'-pyridyl )-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE:xyl-7-(2'-pyrirnidinyl)-1,2,3,4-tetrahy~iro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,.4-~benzothiacdiazine-1,1-dioxide;
3-CycIohE:xyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-methyl-1H-2-imidazolyl)-1,2,3,.4-tetrahydna-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE;xyl-7-(1',2',3'-triazol-4'-yl)-1,2,3,4-teirrahydro-7 ,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1 ,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE;xyl-7-acetamido-1,2,3,4-tetrahydro-1,'2.,4-benzothiadiazine- 1,1-dioxide;
3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-vitro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-phenylsulfonyl-1,2,3,4-tetrahycfro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-qurnazoline sulfonamide;
3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1 ,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-.7-dimethylsulfamoyl-1,2,3,4-tetrahyd ro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline N,N-climethylsulfonamide;
3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2.,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N,N-diE~thylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4~-benzothiadiazine-1,1-dioxide;
3-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-propyl-7-piperidinosulfonyl-1,2,~s,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Benzyl-7-piperidinos~ulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyciopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-piperidinasulfonyl-1,2,3,4-tetraloydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicycla[2-2.1 )hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidin~o)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1'-(1',2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-me~thylpiperazino)sulfonyl-1,2 ,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-mel:hylsulfonylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyi-7-morpholinosulfonyl-1,2,3,4-tetr<~hydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 jhept-5'-err-2'-yl-7-bromo-1,2,1,4-tetrahydro-1,2,4--benzothiadiazine-1,1-dioxide;
2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-1',2',3',6'-tetrahydropiperidinosulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide;
2-Cyclohexyl-4-oxo-3,~1-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
3-Methyl-7-sulfamoyl-1,2~-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-dimethylsulfarnoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl--7-cyclohexyi~;ulfamoyt-1,2-dihydro-1,2 ,.4-benzothiadiazine-1,1-dioxide;
3-Trifluoromethyl-7-dimethylsulfamoyt-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Trifluoromethyt-4-oxo-3,4-dihydro-6-quinazolinesulfonic acid;
3-Cyclohexyl-8-methyl-~1,2,3,4-tetrahydro-1,2,4-~benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-hydroxymethyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(3-methoxyphenyl)-1,2,3,4-tet~rahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-pyrictyl)-1,2,3,4-tetrahydro--I ,2,4-benzothiadiazine~-1,1-dioxide;
3-Cyclohexyl-8-methox:y-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazinc:-1,1-dioxide;
3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,a?,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
R3 represents cyclohexyl, methyl or hydrogen; and R' represents N,N-dimethylsulfamc>yl. tetrahydropyridyl-sulfonyl, bromo;
and R6 represents bromo or hydrogen;
Another especially pref~srred embodiment of the invention is a compounds of formula I as above wherein X is SO;~ and N is -NHCH2-; arid R3 represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R'reprEaents 1-piperidino-sulfonyl.
The most preferred embodiment of the invention are compounds of formula I as above wherein the compounds are the following:
2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline;
2-Phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline;
2-Methyl-3,4-dihydro-1,3-benzoxazine-4-one;
2-Phenyl-3,4-dihydro-1,3-benzoxazine-4-one;
3-Bicyclo[2.2.1 ]hept-5'-E:n--2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-i ,1-dioxide;
1,2,3,5,10,1 Oa-Hexahydrobenzo[e]pyrrolo[1,2-b]- t ,2,4-thiadiazine-5,5-dioxide;
2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazine-4~-crne;
3-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetr<~hydro-1,2,4-krenzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,~1-benzothiadiazine-1,1-dioxide;
3-Cyciohexyl-6-(3-pyridyl)-1,2,3,4-tEarahydro-1,2r4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyiminoethyl)-1,2,3,4-tetrahydro-1,2,4~-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl~-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-ethoxycarbonyl-1,2, 3,4-tetrahyciro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohe:Kyl-7-cyana-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 ]hept-5'-Eon-2'-yl-7-phenyl-1,2,3,~1-tetrahydro-1,2,4-benzothiadiazine-1,1-3o dioxide;
3-Cyclohexyl-~7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-nitro~rhenyl)-1,2.,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-methoxyphenyl)-1,'?,3,4-tetr;~t~ydro-1,2,4-benzothiadiazine-1,1-dioxide;
3() 3-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2',4'-diimethoxyphenyl)-1,2,3, 4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE:xyl-7-(2'-{N,~J-c!imethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;3-Cyclohexyl-~-(2'-fluorophenyl)-1,2,3,4-tetrahynro-1,2,4-benaothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyf-7-(2'-pyrir~yl )-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazine-1,1-dioxide;
3-CycIohE~xyl-7-(3'-pyridyl )-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE:xyl-7-(2'-pyrirnidinyl)-1,2,3,4-tetrahy~iro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,.4-~benzothiacdiazine-1,1-dioxide;
3-CycIohE:xyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-methyl-1H-2-imidazolyl)-1,2,3,.4-tetrahydna-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE;xyl-7-(1',2',3'-triazol-4'-yl)-1,2,3,4-teirrahydro-7 ,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1 ,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-CycIohE;xyl-7-acetamido-1,2,3,4-tetrahydro-1,'2.,4-benzothiadiazine- 1,1-dioxide;
3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-vitro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-phenylsulfonyl-1,2,3,4-tetrahycfro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-qurnazoline sulfonamide;
3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1 ,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-.7-dimethylsulfamoyl-1,2,3,4-tetrahyd ro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline N,N-climethylsulfonamide;
3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2.,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N,N-diE~thylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4~-benzothiadiazine-1,1-dioxide;
3-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-propyl-7-piperidinosulfonyl-1,2,~s,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Benzyl-7-piperidinos~ulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyciopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-piperidinasulfonyl-1,2,3,4-tetraloydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicycla[2-2.1 )hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidin~o)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1'-(1',2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-me~thylpiperazino)sulfonyl-1,2 ,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-mel:hylsulfonylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyi-7-morpholinosulfonyl-1,2,3,4-tetr<~hydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 jhept-5'-err-2'-yl-7-bromo-1,2,1,4-tetrahydro-1,2,4--benzothiadiazine-1,1-dioxide;
2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-1',2',3',6'-tetrahydropiperidinosulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide;
2-Cyclohexyl-4-oxo-3,~1-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
3-Methyl-7-sulfamoyl-1,2~-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-dimethylsulfarnoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl--7-cyclohexyi~;ulfamoyt-1,2-dihydro-1,2 ,.4-benzothiadiazine-1,1-dioxide;
3-Trifluoromethyl-7-dimethylsulfamoyt-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Trifluoromethyt-4-oxo-3,4-dihydro-6-quinazolinesulfonic acid;
3-Cyclohexyl-8-methyl-~1,2,3,4-tetrahydro-1,2,4-~benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-hydroxymethyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(3-methoxyphenyl)-1,2,3,4-tet~rahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-pyrictyl)-1,2,3,4-tetrahydro--I ,2,4-benzothiadiazine~-1,1-dioxide;
3-Cyclohexyl-8-methox:y-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazinc:-1,1-dioxide;
3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,a?,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
7-Methyl sulfonylamino-~1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Methylsulfamoyl-1,2, 3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Cyclohexylsulfamoyl-~1,2,3,3a,4,5-hexahydrobenzo[ e] pyrrolo[2,1-c[-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrober~zo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Methylsulfamoyl-1,2,:3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1, 2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-y-1,2,4-th iadiazine-5,5-dioxide;
7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,'1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4 thiadiazine-5,5-dioxide;
3-Bicyclo[2.2.1 jhept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyt-7-(N,N~iiEahylsulphamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 jhept-5'-en-2'-yl-5,7~-diphenyl-1,2, 3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-5,7-disulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 ]hept-5'-en~-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5-Bromo-3-cyclohexyl-~'-sulfamoyl-1,2,3,4-tetr,ahydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-6,8~-dibromo-1,2,3,4-tetrahydroquinazoline;
2-Bicyclo[2.2.1 ]kept-5'-~en-2'-yl-6,8-dibromo--4-oxo-1,2,3,4-tetrahydroquinazoline;
3-Bicyclo[2.2.1 ]hept-5'-.en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5,7-Dibrorno-3-bicyclo[a?.2.1 ]heptan-2'-yl-1,2,3,4-tetrahydro-"I ,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-5,7-dibrorno-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Phenyl-;5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
75 3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-5,7-dibromo-1,2-dihydro-7 ,2,4-benzothiadiazine-1,v-dioxide;
3-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4~-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-;7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide ;
3-Cyclohexyl-6-methyl-;7-sulfamayl~-1,2,3,4-tetrahydro-1,2,4-h~enzothiadiazine-1,1-dioxide;
3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,;?,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-;~-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-meth~oxyphenyl)-7-methyl-1,2.3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methoxy-T-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;3-Cyclohexyl-6-chioro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Phenyl-Fi-chloro-7-sullramoyl-1,2,3,4-tetrahydr<>-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-bromo-T-piperidinosulfonyl-1,2 ,3,4-tetrahydrc>-1,2,4-benzothia-diazine-1,1-dioxide;
2-cyclohexylmethylamino-5-N,N-dimethylsulfannaylbenzenesulfonamide;
WO 99,/42456 PCT/DK99/00070 2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzene sulfonamide;
3-Isobutyl-8-(piperidinos;ulfonyl)-2,3,4, 5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide;
3-Cyclohe:Kyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-cyciopentylsulfinyl-1,2,3,4-tetrah~rdro-1,2,4-benzothiadiazine-1,1-dioxide; or 3-Cyclohe:Kyl-7-cyclopentylsulfinyl-~1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide or a pharmaceutical acceptable salt thereof.
Pharmaceutically Acceptable Salts The chemical c:ompounc~ of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e.
physiologically) acceptable salts, and pre- or prodrug forms of the chemical c:;ompound of the invention.
Examples of pharmaceutically accE;ptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the acetate derived from acetic acicl, the aconate derived from aconitic ,ac:id, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the formate derived from formic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobrornic acid, the lactate derived from lactic acid, the maleate derived from malefic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulfonate derived from methane sulphonic acid, the naphthalene-2-suiphonate derived from naphtalene-2-sulphonic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric: acid, the phthalate derived from phth~lic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the :~uccinate derived from succinic acid, the sulphate derived from sulphuric acid, the tartrate derived from tartaric acid, the toluene-p-sulphonatEl derived from p-toluene sulfonic acid, and the like. Such salts may be formed by procedures well known and described in the art.
W
Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be u:>eful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemic<~I compouryd of the invc.~ntion containing a carboxy group.
The chemical compound of the irrvention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvents such as water, ethanol, and the like. Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate:, the tetrahydrate, and the like. In general, l:he dissoluble forms are considered ~ecfuivaient to indissoluble forms for the purposes of this invention.
Definitions of substituents:
Halogen is fluorine, chlorine, bromine, or iodine.
Alkyl means a straight chain or branched chain of from one to six carbon atoms or cyclic alkyl of from three to seven carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl; methyl, ethyl, propyl and isopropyl are preferred groups.
Haloalkyl means alkyl as above substitutecl one or more times with halogen as defined above. Preferred embodiments arE: CF3, C2F5, (:;H2CI, CHCI;a, -CHFCH2F, -CHCICH2CI;
Cycloalkyl means cyclic alkyl of from three to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclahexyl, cycloheptyl.
Cycloalkylalkyl means cyclic alkyE as above arid alkyl as above wherein the alkyl can be regarded as a substituent on the cycloalkyl and vice versa . Preferred groups are C3_s-cycloalkyl and C,_4-alkyl such as -(CH2)-cyc:lopropyl, -cyclopropyl-(C,_4-alkyl), -(CH2)~ -cyclohexyl, -cyclohexyl-(C,.4-alkyl), (C,.4-alkyl)-cyclobutyl, -cyclobutyl(C,_4-alkyl) -(C,_4-alkyl)cyclopentyl, -cyclopentyl(C,_4-alkyl), -(C,_4-alkyl)cyclohE=xyl, cyclohexyl(C,_4-alkyl);
WO 99/42456 PCT/DK99/000'70 Halocycloalkyl means cyclic alkyl as above which is substituted with one or more halogen as above, including but not limited to chlorocycfopropyl, fluorocyclopropyl, iodocyclopropyl, dichlorocyclopropyl, difluorocyclopropyl, chlorocyclobutyl, fluorocyclobutyl, chlorocyclopentyl, fluorocyclopentyl, iodocyclopenyl, chlorocyclohexyl, fluorocyclohexyl, dichlorocyclohexyl, difluorocyclohexyl, iodocyclohexyl. Preferred embodiments are mono- and di-substituted cycioalkyl of 3 to 1:> carbons, such as dichlorocyclopropyl, difluorocyclopropyl, chlorocyclohexyl, fluorocyclohexyl, iadocyclohexyl, chlorocyclopentyl, fluorocyclopentyl.
Alkenyl means a straight chain ar branched chain of from two to six carbon atoms containing one double bond, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.
Alkynyl means a straight chain or branched chain of from two to six carbon atoms containing one triple bond, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
Alkoxy is O-alkyl, wherein alkyl is as defined above.
Alkoxyalkyl is -alkyl-O-alkyl, wherein alkyl is as defined above.
Hydroxyalkyl is alkyl as. defined above substituted with OH;
Amino is NH2 or NH-alH;yl or N-(alkyl), wherein alkyl is as defined above.
Alkylamino is alkyl as defined above whrch is substituted with amino as defined above.
Preferred embodiments are -CHI-N(alkyl)z, -C;Fi-N(alkyl)2CH;~, -CH2CH2 N(alkyl)2, -CH2-NH2, -CH-(NHS)-CH3, -CH2Chl2 NHS>~
Cyano is CN;
Cyanoalkyl is alkyl as clefined above substituted with CN;
Nitro is -N02;
Nitroalkyl is alkyl as defined above subsituted with vitro as defined above;
Thio is SH or S-alkyl, wherein alkyl is as defined above;
Alkylthio is alkyl as above substituted with a thin group which is as defined above.
Acyl is (C;=O)-R° or (C=S)-R° wherein R° is alkyl; phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, N02, amino, alkyl, alkoxy, phenyl and S02NR'R" wherein R' and R" each independently are hydrogen or alkyl or wherein R' and R" together ~s (CH~)n, wherein m is 2, 3, 4, 5 or 6;
or R° is benzyl; or NR"' Rw wherein R"' an~~ R'v each independently are hydrogen or alkyl or wherein R~° and R'v together is (CH2)P wherein p is 2, 3, 4, 5 or 6.
Acylamino is acyl-NH- wherein aryl is as defined above.
Aryl is aromatic carbocycles such as phenyl or biphenyl and fused carbocycles such as naphtyl;
HET is an 5- to 6-membered cyclic heteroaryl and include: for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxa:zol-3-yl, isoxazol-4-yl, iso:xazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazal-3-yl, isolhiazol-4-yl, isothiazol-5--y1, 1,2,4-ox:adiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiacfiazol-5-yl, 1,2,5~-oxadiazol~-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidaz:olyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thiE:nyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrirnidinyl, 3-pyrictazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl, furanyl, tetrahydrofuranyl, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl, pyridyl, thieroyl, isooxazolyl, pyrimidyl, pyrazole, triazoiyl.
Especially preferred heteroaryl of the invention are pyridyl, pyrimidyl, triazole, furyl, thienyl, oxadiazolyl, imidazolyl;
A carbocyclic 7- to 12- membered ring structure includes mono- bi- and tricyclic structures.
Preferred embodiments are 7- to 10 membered ring structures such as WO 99I'42456 PCT/DK99/00070 $$
1~7 ~7:i~ ~J~ ~W L~ ~~
'~CW '~ ! ~~: ~
a heterocyclic 3- to 8 membered ring structure includes a partly or completely saturated heterocyclic ringstructure such as aziridine, pyrrcslidine, piperidine, piperazine, homopiperidine, homopiperazine, azacyclooctane, 1,.3-diazacyclooctane, 1,4-diazacyclooctane, tetrahydrofuran, tetrahydrothiophene, mc:~rpholine, tetrahydropyridine, and compounds such as N
N N
l The preferred embodiments are 5- to 6-membered rings containing at least one nitrogen such as pyrrolidine, piperidin~~, piperazine, morpholinc;, tetrahydropyridine.
The described 4- to T-membered rings fused to the ring structure of formula I, formed between the substituents R' and R3 or R3 and R4 or RS and R6 or R6 and R' or R' and R8 are carbocyclic rings optionally containing a heteroatom and optionally containing a carbonyl group. PrE;ferred rings are 5- and F-membered c:arbocyclic rings;
The rings formed between the substituents R' and R6 or Rg are 5- or 6-membered and containing O, C=O, S=O, or S02-groups and optionally containg nitrogen.
Preferred rings are -O-(CH2)n-O-; wherein n is 1, 2 or 3; -SC)z-NR-(CH2)n-wherein n is 1 or 2;
-SO-NR-((:,Hz)n- wherein n is 1 or a?; -S02-(CH2)n- wherein n is 2 or 3; -SO-(CH2)n- wherein n is 2 or 3; -CO-CH=CH-NH-;-CO-CH=CH-O-; -C;O-(CH2)~-Nlwl- wherein n is 1 or 2; -CO-NH
(CH2)~ wherein n is 1 or 2; -CO- (CH2j2-O-;
The compounds of this invention rnay exist in unsolvated ,:~s well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to tf-re unsolvated forms for the purposes of this invention.
Steric Isomers The chemical compounds of the ;present invention may exist in (+) and (-) forms as well as in racemic forms. Thc: racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
Racemic forms can be resolved intca the optical antipodes by known methods and techniques. One way of separating the diastereomeric salts is by use of an optically active acid, and liberating thc: optically active amine compound k:~y treatment with a base. Another method for resolving racemates into the optical antipodes as based upon chromatography on an optical active matrix. Racemic cc>mpound:> of the present invention can thus be resolved into their optical antipodes, e.g., by fractional) crystallisation of d- or I-(tartrates, mandelates, or camphorsulphonate 1 salts for example.
The chemical compounds of the present invention rnay also be resolved by the formation of diastereomeric amides by reaclion of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglyc:ine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical cc:~mpound of the present invention with an optically active chloroformate or the like.
Additional methods for the resolvinca the optical isomers are known in the art.
Such methods include those described by Jaques J, Collet A, & tNilen S in "Enantiomers, Racemates. and Resolutions", John Wiley and Sons, New Fork (1981 ).
Moreover, Borne of thE: chemical compounds of the invention being oximes, may thus exist in two forms., syn- and anti-form {Z- arid E-form), depending on the arrangement of the substituents around the -C=N- double band. A chE>mical compound of the present invention may thus be vthe syn- or the anti-forrn (a?- and E-form), or it may be a mixture hereof.
A compound of the invention includes endo- and exo-forms and tautomers where possible.
Pharmaceutical Comaositions An aspect of the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention and the use of compounds of the invention for the manufacture of a medicament for the treatment of specific: diseases or disorders;
White a chemical compound Gf the inventican for use in therapy may be administered in the fornn of the raw chemical compound, it is preferred to introduce the active 5 ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adju~dants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliarie s.
In a preferr~ad embodirnent, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or 10 derivative thereof, tagethc:r with one or mare taharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients. The carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
Pharmaceutical compositions of the invention may be those suitable for oral, 15 rectal, bronchial, nasal, topical (including buc~aal and sub-lingual), transdermal, vaginal or parentera'I (including cutaneous, subcutaneous, intramusc:ular, and intravenous injection) administration, or those in a form suitable for administration by inhalation or insufflation.
The chemical compound of the irtvE:ntion, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit 20 dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and Liquids, in p;~rticular aducyous or non-aqueous solutions, suspensions, emutsions~, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in 25 conventional proportions, with or without additional active ccampounds or principles, and such unit dosage forms may contain any suifab~le effective aamount of the active ingredient commensurate with the intended daily dosagE: range to be employed.
The chemical compound of the present invention can be administered in a wide variety of oral and pare~nteral dosage forms. It will be obvious to those skilled in the art that 30 the following dosage forms may comprise, as the activc:a component, either a chemical compound of the inveni:ior~ or a pharmaceutically acceptably-w salt of a chemical compound of the invention.
For preparing pharmaceutical c;ornpositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or mare substances which may also act as diluents, flavouring agents, solubilizers~ lubricants, suspending agents, binders, preservatives, tablet di~~integrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, tihe active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
The powdeirs and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are m<~gnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dexkrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa: butter, and the like.
The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus; in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitablE: for oral administration.
For preparing suppositores, a low rr~elting wax, such as a mixture of fatty acid glyceride or cocoa butter" is first melted and the <:~ctive component is dispersed homogenE~ously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid preparations include solutions., suspensions, and emulsions, for example, water or water-propyler7e glycol solutions;. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
The chemical compounc:i according to the f:~resent invention may thus be formulated for parenteral administration {e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion car in mult~-dose c:oratainers with an added preservative. The compositions may take such forms as suspen.;ic>rrs, solutions, or emulsions in oily or aqueous vehicles, and may cont<~in formulation agents such as, suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization fronn solution, for constitution with a suitable vehicle, e.g. s~lerile, pyrogen-free wager, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water arid adding suitable colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use cart be rnade by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymei:hylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsion;. These preparations may contain, in addition to the active component, colorants, flavours;, stabilisers, buffers, artificial and natural sweeteners., dispersants, thickeners. solubilizing agents, arid the like.
for topical administration to the epidermis the chemical compound according to the invention may be formulated as ointmenla, creams or lotions, or as a transdermal patch.
Ointments and creams. may, for example, be formulated wish an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
Compositions suitable for topicaG~ administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth;
pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose .and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper. pipette or spray. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
In the case of a spray, this may be achieved' for example by means of a metering atomising spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroEatt~ane, carbon dioxide, or other suitable gas.
The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients rnay be provided in the form of a dry powder, for example a powder mix of the compounc9 in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and poiyvinylpyrrolidone (PVP). Gonveniently the powder carrier will form a gel in the nasal cavity.
The powder composition may be presented in unit dose forim for example in capsules or cartridges of, 1o e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
In composil:ior7s intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by microrrization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharm<~ceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. Thc~ unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit do:~age form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desored.
The active ingredient rnay be adrninistered in one or several doses per day. A
satisfactory result can, in certain instances, bf; obtained at a dosage as tow as 0.1 pg/kg i.v.
and 1 pg/kg p.o. The upper limit of the dosage r;~nge is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.1 pg/kg to about 10 mg/kg/day i.v., and from about 1 yg/kg to about 100 mg/kg/day p.o.
Method of Treating The compounds of the present invention are ,AMPA receptor stimulators and therefore useful for the treatment of a range of disorders or diseases responsive to AMPA
receptor modulators. As en embodiment of the invention the disease are responsive to positive modulation of the AMF'A receptor. The compounds may be used in the treatment, prevention, profylaxis or alleviation of a disease, disorder or condition crf the central nervous system as for example: neurodegenerative disorders, cognitive or memory dysfunction, memory and learning disorders, attention disorder, learning and memory disorders resulting from ageing, 1o trauma, stroke, epilepsy; Alzheimer's disease, depression, schizophrenia, memory loss, AIDS-dementia, senile dementia, learning deficit, cognition deficit, sexual dysfunctions, psychotic; disorder, se>cual dysfuncaion, intellectual impairment disorders, schizophrenia, depression or autism, .attention deficit, or a disorder or disease resulting from neurotoxic agents, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia;
Suitable dosage range are 0.1-X00 milligrams daily, and especially 10-70 milligrams daily, administered once or twice a day, dependent as usual upon the exact mode of administration, form in wtuch administered, th,e indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
I.p. means intraperetoneally, which is a well known route of administration.
P.o. means peroral, which is a well known route of administration.
The invention then cornprises the following alone or in combination:
The use of a compound as above wherein the disease to be treated is responsive to the AMPA receptor modulation.
The use of a compound as above for the manufacture of a medicament for the treatment of disease which are responsive to the AMPA receptor modulation.
The use as above whE~rem the disease is memory and learning disorders, psychotic disorder, sexual dysfunction, intellectual impairment di:,c~rders, schizophrenia, depression or autism;
Alzheimer's disease, learning deficit, attention deficit, memory loss or senile dementia; or a disorder or disease resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorder, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia;
Bialoety In vitro inhibition of ~sH-AMPA binding 1o L-glutamate (GLU) is the major excitatory neurotransmitter in the mammalian central nervous system. Frorn eiectrophysiological- and binding studies, there appear to be at least three subtypes of GLU receptors, tentatively named N-methyl-D-aspartate (NMDA)-, quisqualate-and kainate receptors. Gl_U receptor subtypes sE:nsitive to quisqualate and kainate as a group are often referred to as non-NMDA receptors. Receptor binding studies using the 15 labelled agonists 3H-AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (for quisqualate receptors) and ~H-kainate (for kainate receptors) have shown different antagonist selectivities and regional distribution. AMPA has been known for several years to be a potent and selective agonist at the traditionally named quisqualate receptors.
Activation of quisqualate receptors by AMPA is associated with Na' influx and K' efflux leading to 2o depolarizatian.
The non-IVMDA receptors have recently been re<;lassified to include the quisqualate activated metabotropic receptor hype, linked to the inositol triphosphate and diacylglycerate me-tabolism. AMPA does not interact with the metabotropic quisqualate receptor but only the 25 ionotropic quisqualate receptor. SE:lective activation of the metabotropic type has been claimed for trans-ACPC). f-iecentfy, the potent and competitive non-NMDA
receptor antagonists CNQX and NBQX have been described, and CNOX have been reported not to block the effect of quisc~ualate at the metabotropuc receptor subtype. 3H-AMPA
is a selective radioligand for labelling the ionotropic quisqualate (AMPA) receptors.
TISSUE PREPARATION
Preparations are performed at 0-4"C unless otherwise indicated. Cerebral cortex from male Wistar rats (150-200 g) is homogenized for 5-1C) aec in 20 rrrl Tris-HCI (30 mM, pH 7.4) using an Ultra-Turrax homogE~nizer. The suspension is centrifuged at 27,000 x g for 15 min and the pellet is washed three times with buffer {centrifuged at 27,0()0 x g for 10 min). The washed pellet is homogenized in 20 ml of buffer anct incubated an a water bath (37°C) for 30 min to remove endogenous glutamate and then centrifuged for 10 min at 27,000 x g. The pellet is then homogenized in buffer and centrifuged at: far 10 min at 27,000 x g. The final pellet is resuspended in 30 ml buffer and the preparation is frozen and stared at -20°C.
ASSAY
The membrane preparation is thawed and centrifuged at 2°C for 10 min at 27,000 x g for 10 min. The pellet is washed twice with 20 ml 30 mM Tris-HCI containing 2.5 mM
CaCl2, pH 7.4 using an Ultra-Turrax homogenizes and centrifuged for 10 min at 27,000 x g.
The final pellet is resuspended in 30 mM Tris-HCI containing a?..5 mM CaCl2 and 100 mM KSCN, pH
7.4 (100 ml per g of original tissue) and used for binding assays. Aliquots of 0.5(0.2) ml are added to 25(20) NI of test solution and 25(20) pl of 3H-AMF'A (5 nM, final concentration), mixed and incubated for 30 min at 2"C. Non-specific binding is determined using L-glutamate (0.6 mM, final concentration). After incubation the 550 yl samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibre filters under suction and immediately washed with 5 ml ~of ice-cold buffer. The 240 pl samples are filtered over glass fibre filter using a Skatron cell harvrester. The filters are washed with 3 ml ice-cold buffer. The amount of 2o radioactivity on the filters is determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.
RESULT S
The test value will be given as the ICso (the concentration (NM) of the test substance which inhibits the specific binding of 3H-AMPA by 50°/a) Test results The compound numbers refer to the table below.
Compound -._ ICS( (pM) _ - 22.0 14 45.0 15 ~ 39.0 ~~ 44 ~ 3.5 47 _ ~ 5.3.
SUBSTITUTE SHEET (RULE 26~
~7 48 ~ 4.4 ~
49 17.0 - i ~7 26.0 ~
58 3.4~
~
Ei 1 8.5 Ei2 6.0 Ei3 ~ 6.0 ~
113 13.(:) 114 ~ 33.(:1 ~
115 7.0 F~otentiation ofi AMPA induced f3HIGABA release from cultured cortical neurons Neurons which express receptors for excitatory amino acids can be depolarized by such compounds and this depolarization will ultimately lead to a release of transmitter substance from the neurons. Cultured neurons obtained from 16-day-old mouse embryo cortex are mainly GABAergic andl express all types of excitatory aminc:~ acid receptors.
This means that they can be stimulated by high potassium (55 mM) or by the excitatory amino acids NMDA
(20 NM), AMPA (5 NM) and kainate (5 NM) to release their neurotransmitter GABA.
3H-GABA may be used to label the GABA transmitter pool in the neurons and the release of 3H-GABA from the neutrons may be used as a simple functional model for studies of the effects of excitatory amino acid receptor agonists, antagonists, and modulators.
METHODS
Cell cultures Cerebral cortices of 15-16 day-old NMRI mouse embryos are chapped in 0.4 x 0.4 mm cubes and the tissue is dissociated by mild trypsinization (0.1 % (wt/vol) trypsin, 37°C, 10 min).
Subsequently the cell suspension (3 mill/ml) is inoculated into poly-L-lysine-coated 30 mm Petri dishes (3 ml/dish;l containing a slightly modified DMEM (24.5 mM KCI) supplemented with p-aminobenzoate (7 pM), insulin (100 mlJ/L) and 10% (vol/vol) horse serum. Cells are maintained in culture fnr 5-7 days with the addition of the antimitotic agent cytosine SUBSTITUTE SHEf=T' (RULE 26) arbinoside (5 NM) from clay 2 in vitro to prevent glial proliferation. For further details and references, see Drejer et al. (Exp. Brao Res. 47, 259 (1982)).
Release experiments Release experiments am performed using the model described by Drejer et al.
(Life Sci. 38, 2077 (198(i)). Cerebral cortex neurons cultured in Petri dishes (30 mm) are added 100 mM y-vinyl-GAGA one hour before the' experiment: in order to inhibit degradation of GAGA in the neurons. 30 min before the experiment 5 uCi 3H-GABA is added to each culture.
After this preloading period the cell monolayer ai the bottom of the dish is covered with a piece of nylon mesh to protect the cells against: mechanical damage and to facilitate dispersion of medium over the cell layer. The prE:loading medium is removed and the Petri dishes are placed in a s!uperfusion system consisting of a peristaltic pump continuously delivering thermostated 37°C superfusion mediium (HEPES buffered saline (HBS): 10 mM
HEPES, 135 mM NaCI, 5 rnM KCI, 0.6 mM MgSO.,, 1.0 mM C;aCl2 and 6 mM D-glucose; pH
7.4) from a reservoir to i:he top of the slightly tilted Petri dish. The medium is continuously collected from the lower part of the dish and dE:lirrc~red to a fr;~ction collector. Initially, the cells are superfused with HB;S for 30 min (tlow rate :? ml/min). Then cells are stimulated for 30 sec every 4 min by changinc) the superfusion medium from HBS to a corresponding medium containing 5 NM AMPA in the absence or presence of modulators.
Test subsl:ances are dissowed in 50% DMSO. 48"io ethanol. 'The final DMSO and ethanol concentration in the assay must not exceed 0.1 °>o RESULTS
The induced release of 3H-GAGA (c;pm) is corrected for the mean basal release (cpm) before and after the stimulation and used ror calculation of the test value.
The potentiation of the ~4MPA response by a test substance is expressed relative to the potentiation of the AMPA response induced by c:yclothiazide (30 NM).
Results The result of the test is shown in Figures 1 anc~ 2. The results show significantly increased Figur 1 shows potentiation of AMPA induced '"'H]GAGA release from cultured cortical neurons by compound 115. The patentiation is expressed relative to the potentiation induced by 30 uM cyclothiazide.
Figur 2 shows potentiation of AMPA induced (''H]GABA release from cultured cortical neurons by compound 114. The patentiation is expressed relative to the potentiation induced by 30 NM cyclothiazide.
Voltage Clamp.
METHODS
7 o Experiments were performed in voltage clamp using conventional whole cell patch clamp methods (Hamill et al., 1981 ), essentially as dE~scribed previausly (Mathiesen et al., 1998).
The following salt solutions were used (mM): NaC;I (140), KC;I (4), CaCl2 (2), MgCl2 (1 ), Sucrose (30), Tetrodotaxin (0.0003), Bicuculline Methiodide (0.005) and HEPES
(10, pH 7.4).
Intracellular solution (mM): CsCI (120), CsF (20), MgCl2 (2), EGTA (10), HEPES
(10, pH =
7.2).
Cell cultures Mouse neocortical neurons were cultured essentially as described by Drejer et al. (1987).
Briefly, the forebrains from embryonic (E17} NMRI mice were removed under sterile conditions. The tissue was chopped in 0.4 rnrn ~aubes and the triturated with trypsin (12.5 Ng/ml) and DNAse (2.5 ug/ml), 15 min, 37 °C. The cells were suspended at a concentration of 1 x 106 cells/ml in a slil~htly modified DMEM which contained horse serum (10 % (vlv)), penicillin (333 U/ml), paraaminobenzoic acid (1 mg/ ml), L-glutamine (0.5 mM), insulin (0.08 U/ml) and KCI (23.8 mM). The cell suspension was subsequently inoculated into poly-L-lysine coated 35 mm Petri dishes (2 mlldish). Glass c<averslips (3.5 mm) were placed in the dishes before coating. After 24 hr in culture, the medium was replaced by freshly made medium containing 1 % N2 supplement instead of seruno.
The cells were kept in culture for 7-14 days at 37 °C (5% CO;>/95% O2) before experiments were carried out.
Electronics. programs and data acquisition: The amplifier used was the EPC-9 (HEKA-electronica, Lambrect, Germany) run by a Power Macintosh G3 computer via an interface. Experimentall conditions were set with the Pulse-software accompanying the amplifier. Data were lo~nr pass filtered and samptc~d directly to hard-disk at a rate of 3 times the cut-aff frequency.
Pipettes and electrodes: Pipettes were pulled from borosilicate glass (Modulohm, Copenhagen, Denmark) using a horizontal elecarode puller (Zeitz-(nstrumente, Augsburg, Germany). The pipette resistances were 1.7 - 2.4 MW in the salt solutions used in these experiments. The pipette electrode was a chloridized silver wire, and the reference was a 5 silverchloride pellet electrode (In Vivo Metric, I-lealdsburg, USA) fixed to the experimental chamber. The electrodes were zeroed with the open pipette in the bath just prior to sealing.
Experimental procedurE_ Coverslips were transferred to a l::p ml experimental chamber mounted on the stage of an inverted microscope I;IMT-2, Olympus) supplied with Nomarski optics. The neurons were continuously superfused with extracellular saline at a rate of 2,5 10 ml/min. After giga-seal formation (1-5 GW, success-rate = 9t) %) the whole cell configuration was attained by suction.
The cells were held at a holding voltage of -60 mV and at the start of each experiment the current was continuously measured for at least ;30 sec to ensure a stable leak current.
AMPA-containing solutions were delivered to thE: chamber through a custom-made gravity-15 driven flowpipe, the tip of which was placed approximately 50 pm from the cell. Application was triggered when the tubing connected to the flow pipe wcas compressed by a valve controlled by the Pulse-software. AMPA (30 NM) was applieri for 1 sec every 45 sec. After obtainment of responses of a repeatable amplitude the compound to be tested was included in both the chamber and in the AMPA-containing solution. The compound was present until 20 responses of a new repeatable was obtained.
The sample interval in <~II experiments was 310 Nsec.
All experiments were performed at room temperature (20 - 25 °C).
MATERIALS
25 Pregnant (9 days) NMRI mice were obtained from Bomholtgaard Breeding and Research Center, Ry, Denmark.
Horse serum, N2 supplement and culture media were purchased from Life Technologies (GIBCO), Roskilde, Denmark.
AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolE:propionic acid) was synthesized at 30 NeuroSearch A/S. Tetnodotoxin was purchased from Alomone Labs, Jerusalem, Israel and Bicuculline Methiodide from RBI, MA, USA. Stacrose was from Fluka Chemie, Buchs, Switzerland. All other reagents were from SIGMA, USA.
Results The results are shown in Fig. 3-I.
The compounds 56 (Fig. 3), 63 (Fig. 4), 111(F'ig. 6), 114(Fig. 7) and 115 (Fig. 5) all potentiated the current induced by application of 30 NM AMPA. An example for each compour7d is shown below. It is seen that the potentiation in every case is reversible, even though the effect of 56 and 63 persit.s for several minutes after wash out of the compounds.
The time between AMF'A stirnulations was 45 sec. Scalebars: 63: 200 pA/2 sec;
56: 500 pA/5 sec; 115: 50 pA/2 sec; 111: 400 pA/3 sec; 114: 40 pA/ 3 sec. In the experiments shown the concentration of the compounds was 3 NM (56. 63 and 114) or 10 NM (111 and 115) The effect of the compounds were concentratlion-dependent, as exemplified for 114 below (scale bars 200 pA/ 5 sec).(Fig. 8) REFERENCES
Drejer J., Honore T. and Schousboe A. (1987; f~xcitatory amino acid-induced release of 3H-GABA from cultured mouse cerebral cortex interneurons. J. Neurosci. 7: 2910-2916.
Hamill O.P., Marty A., f~eher E., Sakmann B. ~~r~d Sigworth F.J. (1981 ) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
Pflugers Arch. 39: 85-10C).
Mathiesen C., Varming T. and Jensen L.H. (1!398) In vivo arnd in vitro evaluation of AMPA
2o receptor antagonists in rat hippc>campal neurones and cultured mouse cortical neurones. Eur.
J. Pharmacol. 353: 15~~-1 fi7..
lontophoretic Application PURPOSE
Evaluation of the in vivo effects of positive AMF'A modulators (PAMs) on the AMPA evoked spike activity in rat hipporampus.
PRINCIPLE
Hippocampai single neuron spike activity is strongly influenced by excitatory input, and iontophoretic application of AMF'A induces spike activity in vivo in a dose-dependent manner (Mathiesen ef al. 1998;1. The AMPA evoked spike activity is inhibited by intravenous (i.v.) administration of a wide range of AMPA receptor antagonists (Mathiesen et al.
1998), which indicated that the excitation is primarily mediated via AMPA receptors. PAMs potentate AMPA
receptor activation in vi~'ro, and if this mechani sm also operates in vivo, the i.v. injection of an PAM should enhance AMPA evoked spike activity. Thus, the aim of this study was to test the in vivo effect of a group of in vitro actme PAM;. This have been done by studying their ability to enhances AMPA evoked spike activity after i.v. administration.
PREPARATION
Experiments were performed on male Wistar rat (M & B, Denmark) weighing 280-380 g, housed in two per cage with free access to food and water. The rats were anaesthetised with mebumal (50 mg kg~' i.p.) and the femoral artE~ry was catheterised for the purpose of monitoring blood pressure and the vein for intravenous injection of drugs and continuous injection of 0.9% NaCI (O.p-1.U ml h-'~ and mebumal (5-10 mg h-'). Additional anaesthetic was given i.v. if the rat responded to a pinch of the back foot. The trachea was cannulated and the rats were placed in a stereotaxic frame arid ventilated by a rodent ventilator (Ugo Basile, Comerio-~Jarese, Italy). Core body temperature was maintained at 37.5°C
by a DC heating pad. The left and dorsal part of the parietal bone was removed by craniotomy and the dura was withdrawn exposing the pia mater and underlying brain., covered with 0.9%
NaCI.
COMPOUNDS/REAGENTS
AMPA (Sigma, USA) was dissolved at 10 mM in 0.2 M NaCI. NMDA (Sigma, USA) was dissolved at 100 mM in 100 mM NaCI. Both solutions were adjusted to pH 7.5-8.0 with NaOH.
COMPOUND 61 was diissolved in a'_O~J mM CH3;>O 3- Na' at <:r contration of 10 mM for iontophoretic application (pH 5.7) and in isotor~i~; glucose (278 mM) for i.v.
administration.
Cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 115 and COMPOUND 114 were all dissolved at in 5°ro chrernophore solution at a concentration of 5 mg ml~'.
PARAMETERS
Evoked neuronal spike activity was analyzed on-line by a ccamputer, saving single spikes and time of event. Neuronal spike activity (number of action potentials s-') was monitored on a pulse rate histogram together with indicators for AMPA, COMPOUND 61 and vehicle application.
PROCEDURE
ExtracellUlar recordings of single; hippocampal neuron spikes were made with five-barrel glass microelectrodes (5B120F-6, World Precision Instruments Inc., Sarasota, Florida, USA) with a tip diameter of 10-12 prn. The individual barrels were filled with 5 M NaCI
(recording), 400 rnM
NaCI (current balancing), 10 mM COMPOUNC> 61 in 200 mM CH~S03~ Na~ (pH 4.7), 200 mM
CH3SOs Na+ (pH 4.7, ~Jehicle), and the Vast k>;~rrc:l was filled with the AMPA.
Experiments were performed on hippocampal neurons (A = 5.5-6.5 mm, L = 1.5-2.0 mm, H =
2.0-3.0 mm, according to Paxinos & Watson, 1 X386). Neuronal spike activity was evoked by iontophoretic: application of AMPA for periods of 10 to 15 s with 1.5 min intervals. Single neuron spike activity w;~s amplified 5000 times with a bandwidth of 0.3 and 3 kHz (CyberAmp 320 with a AI 402 x50 smartprobe, Axon Instrurnents, California, USA). On-fine and off-line analyses were performed by the Spike2 program with a 1401 plus interface (Cambridge Electronic Design Limited, England). The computer program also recorded mean arterial blood pressure and monitored and controlled iontophoretic rapplication.
AMPA was ejected into hippocampus in regular cycles of 1()0-105 s. When neuronal responses were stable (when the AMPA responses did not vary more than 10%, measured over a 10 s time period) for at least 3z hour, then a single dose of either cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61 or COMPOUND 114 (10 mg kg-') was injected into the lemoral vein. Recording of neuronal spike activity was continued for at least 45 min after intravenous: injection. The PAM reactivity was tested by microiontophoretic application of COMPOUND G1 (20 nA, Fig. ).
RESULTS
Fig. 8 shows that iontophoretic application of COMPOUND 61 enhanced AMPA
evoked spike activity, whereas the vehicle did not influence the evoked spike activity.
Intravenous administration cyclothiazide (10 mg kg-') did not enhance AMPA evoked spike activity (Fig.
10).
Fig. 9. lontophoretic application of COMPOUND 61 enhanced AMPA evoked single neuron spike activity. The iontophoretic application of the vehicle did not influence AMPA evoked spike activity.
Fig. 10. Cyclothiazide 1;10 m kg-' i.v.) did not affect AMPA evoked spike activity in hippocampus. Shaded box above the AMPA1 trace indicatE, time of administration (1500 s 3o after onset of registrating).
The in viwo effects of the PAMs on AMPA evoked spike activity was dependent on the control spike activity level. COMPOUND 63 enhanced small AMPA responses, evoked by low WO 99!42456 PCT/DK99/00070 ti4 intensity AMPA stimulation, but had only marginal effect on large AMPA
responses, evoked by high intensity AMPA. stimulation (Fig. 111. There was an initial inhibition of the AMPA
responses and the onset of the enhancement occur 15 to 30 min after i.v.
administration (Fig.
11 ). Fig. shows an example of enhancement of AMPA responses by COMPOUND 56 (10 mg kg-'). The onset occurred approximately 10 min after administration (Fig. 12).
Fig. 11. COMPOUND Ei3 (10 mg kg--1 i.v.) enhanced the low intensity AMPA
responses (12 nA), but had only marginal effect on high intensity AMPA responses (17 nA). 10 mg kg-1 COMPOUND 63 was given 1500 s after onset c>f recording. The time of injection is marked by a shaded box above the AMPA2 trace.
Fig. 12. COMPOUND Ei6 (10 mg kg~' i.v.) enhanced AMPA Evoked spike activity.
The compound was injected 1250 s after onset of registration. The time of injection is marked with a shaded box above the AMPA trace.
Fig. 13 shows an example of enhancemenl of AMPA spike activity after i.v.
administration of COMPOUND 115 (10 rng kg-'). 'The effect started 2 min aftE:r i.v.
administration and lasted for more than 2 hours. COMPOUND 61 (10 mg kg' ) also enhanced AMPA responses in hippocarnpus. The 3-field increase in AMPA evoked spike activity induced by COMPOUND
61 started 20 minutes ~~fter administration and lasted for more than 2 hours (Fig. 14).
COMPOUND 114 (10 mg kg-' ) induced a 10-fold increase of the AMPA responses, when control level of the AMIPA responses were low (from 21 to 209 spikes response-', mean response,Fig. 15), while only smaller enhancE;mc~nt observed with larger control responses (from 124 to 204 spikes response-',Fig. 16).
Fig. 13. COMPOUND '115 (10 mg kg~' i.v.) enhances AMPA evoked spike activity in hippocampus. The shaded bax indicate the time in i.v. injection, 1900 s after onset of registration. The effect of COMPOUND 115 IustE~d for more than 2 hours.
Fig. 14. COMPOUND Ei1 enhanced AMPA responses in hippocampus. 10 mg kg-' i.v.
was given 1000 s after onset of registration (marked by a shaded box above the trace). The effect of COMPOUND 61 lasted for more than 2.5 hour.
Fig. 15. COMPOUND '114 (10 mg kg-' i.v.) enhanced AMPA evoked spike activity.
The compound was given 11730 s after onset of registration, which is marked by a shaded box above the AMPA trace.
Fig. 16. COMPOUND 114 (10 mg kg' i.v.) approximately doubled the AMPA
responses. The i.v. administration occurred at time 3900 s and is indicated by shaded box above the AMPA
trace The results show that C;yc~lothiazide did not show' any in viva effects after i.v, administration.
5 However, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61 and COMPOUND 114 enhanced AMPA evoked s~>ike activity in an activity-dependent manner.
References MATHIESEN, C., VARMING, T. & JENSEN, L. H. (1998). In vivo and in vitro evaluation of AMPA receptor antagonists in rat hippocampal neurones and cultured mouse cortical 10 neurones.. European Jr~urnal of Pharmacology 353, 159-r 67.
PAXINOS, G. & WATSON, C. (1986). The rat train in stereotaxic coordinates.
Second Edition.
Passive avoidence 15 PURPOSE: To test the: pharmacological effect of compounds on associative memory.
PRINCIPLE: A Mouse is placed in a light compartment with access to a dark compartment. If it enter the dark compartment it will receive a foot-shock {0.4 mA). After a delay (24 hours) the association to risk an unpleasant foot-shock by re-entering the dark compartment is 2o tested.
ANIMALS: Female NMRI mice (Bomholdtgaard, DK) weighing 22-25 g were used. The mice were kept in Macrolon plastic cages with free access to food (Altromin, DK) and tap water.
The mice were habituated to the laboratory for at least 3 days before testing (light on 25 7:OOam/light off 7:00 pm).
EGZUIPMENT: The passive avoidance apparatus consisted of a modular test chambers (ENV-307, MED-Associates, US). The light and the dark compartment consisted of plexiglas boxes of equal size (15x17x13 cm; width x length x height) with metal grid floors. A
sliding guillotine 30 door was located at thc: aperture (4x4cm) connecting the two compartments.
A manual grid scrambler (ENV-412, AHED-Associates, US) was used to provide the 0.4 mA foot-shock.
~6 PARAMETERS: Entry I;atency (sec) to re-enter the dark compartment was measured.
PROCEDURE: The mice are pre-treated (usually 30 min) before training with the test compound.
Training: One mouse is placed in the light compartment and the guillotine door to the dark compartment is openedl. When the mouse has Entered the dark compartment with all 4 paws it will receive one foot-shock (0.4 mAi and it will be taken to its home cage.
Test: After a delay (24 hours) the mouse will re-enter the light compartment ancJ time latency to enter the dark compartment is measured with a time limit at ~~ minutes. Time latency is noted as 2 minutes if the mouse has not entered the dark compartment within maximal test time (2 minutes).
Vehicle: 10°/« Tween BCI.
Dosis vol.: 10 ml/kg n=10;
RESULTS: Mean (~SEM) entry latency for each group is presented.
The result in Fig. 17 shows the memory enhancing effect of different concentrations of the compound 61;
2o Brief description of the drawings Fig. 1 and Fig. 2 show; the potentiataon of AMPA induced [3H]GABA release from cultured cortical neurons by compounds of the invention.
Fig. 3-8 shows the voltage clamp experiments c>n compounds of the invention.
The compounds 56 (Fig. 3), 63 (Fig. 4), 111 (Fig. 6), 114(Fig. 7) and 115 (Fig. 5) all potentiated the current induced by application of 30 NM AMPA.
Fig. 8 shows the concentration-dependent effect of a cornpc:~und of the invention (114).
Fig. 9 - Fig. 16 are experiments of iontophoresis.
Fig. 9. lontophoretic application of COMPOUND 61 and the iantophoretic application of the 3o vehicle;
Fig. 10. Cyclothiazide is applied in hippocampu:~.
Fig. 11. COMPOUND 6.3 is applied;
Fig. 12. COMPOUND 5.6 is applied.
r~
Fig. 13 COMPOUND 115 is applied.;
Fig. 13. COMPOUND 115 in hippocampus.
Fig. 14. COMPOUND 6.1 in hippocampus;
Fig. 15. COMPOUND 114;
Fig. 16. COMPOUND 114;
Fig. 17. Passive avoidance test of compound 61.
EXAMPLES
GENERAL TRANSFORMATION METHODS
Method A.
Suffamoylation in general.
i, CISCl"H 4 R'. OSp w w NR ii. HNR',, N~ ~l ~~ NRz _..__.,.
~NR2 R, R~." NHa The compound (32.5 rnmol) to be chlorosulfonated was dissolved in chlorosulfonic acid (75 ml) and heated in an oil bath at 110 °C, until TLC indicated that the reaction had gone to completion'. The reaction mixture was poured onto ice and the precipitate formed, was isolated by filtration. The isolated solid was vvashed with a small amount of water and dried on the filter. The solid was dissolved in dry T'HF (200 ml) and added an excess of the amine (230 mmol) and the reaction mixture was left over night with stirring at rt.
The reaction mixture was evaporated to dryness" then stirred with water to afford a solid which was isolated by filtration .and washed with EtOAc: on the fili:er. Further purification was possible either by column chromatography or recrystallization from EtOAc/hexane. Yields were typically: 60-90%.
* la small aliquot was taken out, added to ice in a test tube, neutralized with Na2C03 and then extracted with EtOAc. The aqueous phase was removed and the organic phase was added piperidine (xs) and left for some time. rLC; was taken from this small scale reaction mixtureJ.
Method I3.
o-Sulfamoylation of anilines.t i. clsolNCo ii. AICh D \ S ~'PJH HZSO4 (6 M, aq.) ~ ~ ">~
-_-_- ~ NHz ~NHFI R N' W, '1 /.~ NF-IR
I R
I-;
To a stirred solution of the aminobenzene derivative (250 mmol) in nitroethane or nitromethane (100 ml) at -50 "c:,, was addE:d a solution of CIS02NC0 (275 mmol) in nitroethane or nitromei:hane (75 ml) so that the reaction temperature did not exceed -30 °C.
The coating bath was removed and the thick reaction mixture allowed to heat up to 0 °C.
Solid AIC;13 (300 mmol) was added in one portion. The clear brown reaction mixture was WO 99/42456 PCT/DK99/000'70 heated in an oil bath at 120 "C for 20 min, then cooled to rt. and poured into a beaker with stirred ice water (1 I). The precipitate formed, was isolated by filtration.' The urea intermediate (98 mmol) was suspended in a mixture of dioxane (250 ml) and 6 M H2S04 (or only conc.
HCI) (500 ml) and healed to reffux over night. 'The reaction mixture was cooled to rt., filtered and dioxane was remrwed from thc: filtrale by evaporation. The aqueous remanense was neutralized to pH = 7-8 using 4 M iVaOH. The precipitate formed, was isolated by filtration and washed with water arod EtOAc.* Overall yields ranged from 10 % to 75 %.
t see also Girard Y., Atkinson J.G. and Rokach J., J. Chem. Soc., Perkm l, (1979} 1043.
'(Meta substituted anilines gives rice '.:o a mixture of the two possible isomers which at the stage of the urea intermediate may be ::>eparated by crystallization from MeC:)E-I or at the stage of end product by crystallization from EtOAc/hexane or c:hromatography.l Method G.
Trifluoroacetyl protection.
°wi' c~~ ° °ai°
S~nIHZ (CF3C0)p0 ~I~'~~~5'NFj PPA ~ ~ S'IVF
Ill .~l , ~NH ~.% ~N_..f 1 / Ni R ~ R ~F;
To a stirred solution of the 2-aminobenzenesulfonamide derivative (27 mmol) in dry THF (75 ml) at 0 °C was added trifluoroacetic anhydride ouch that the reaction mixture did not exceed +10 °C. The reaction mixture was stirred ai rt. until all starting material was consumed. The reaction mixture was evaporated to dryness, atirred with water, filtered and washed with hexane. 'The isolated solid was added PPA (250 g) and heated in an oil bath at 140 °C for 2~h h. The reaction mixture was cooled to 60~~70 "C; and poured onto a mechanically stirred ice water solution. The precipitated formed was isolated by filtration and air dried. Overall yields were typically 85-90%.
Method D.
Trifluoroacetyl deprotection.
c\c~o 'NR KoHiFr2o ~-\ :.>~n~r~, I z ~yN:~~cF~ n ~ ~y~i~NH
i A stirred solution of the trifluoroac:etyl protected compouncl (3.6 mmol) dissolved in 1 M KOH
(30 ml) was heated to 80 °C for 1 h. The reaction mixture was cooled to rt. and pH adjusted to ~0 7 using cone. HCI (aq.). -The reaction mixture was cooled to 0 °C and filtered. The isolated solid was washed with water and air dried. Yields typically ratnged from 85-95%.
Method E.
Formation of dihydrobenzothiadiazines-1,1-dioxide from 2-aminobenzene-sulfonamides.
o O~~O i. R'-COCI, DM AP, TEA
,S_ . S' Nl~p ii. t M NaOH. d, ~~ W N(t i) NHR f?~.. H) R, To a stirred solution of the 2-aminobenzenesulfonamide derivative (148 mmol), triethylamine (150 mmol), 4-(N,N-dimethylamino)pyridine (7.5 mmol) in 6t)U ml THF at 5 °C was added the carboxylic acid chloride. The reaction mixturE, was left with stirring over night and then 1o evaporateld to dryness. The crude material was stirred with water and filtered. The isolated solid was dissolved in 1 M NaOI-1 (250 ml) and heated to 80 °C for 3 h.
The reaction mixture was coolE;d to rt. and pH adjusted to 7 using c~~nc. HCI. The precipitate formed was isolated and recrystallized from i-F~rOH. Overall yields ranged from 80-90°,'°.
Method F'.
Reduction of dihydrobenzothiadiazines-1,1-dioxide to tetrahydrobenzo-thiadiazines-1,1-dioxide.
o~~o ~wi a N(H) DIBALH S
NH
-W , ~ vi ~._N; .R, R SH) R F~ FI
To a stirred solution of the dihydrabenzothiadiaz:ine-1,1-dioxide {19.4 mmol) in dry THF (200 ml) at -70 °C was added a solution of DIBA~H 1.5 M in toluene (33 ml;
50 mmol). The reaction mixture was left with stirring over night while the temperature slowly increases from -70 °C to -15 °C'. Water { 10 ml) was added tc~ the reaction mixture followed by 1 M NaOH (5 ml). The reaction mixture was then warmed 1:o I~t. and extracted with EtOAc.
The combined organic fractions were dried with MgS04 and evaporated to dryness. In some cases the product was further purified by column chromatography. Yields ranged from 45-85 %.
'[The product aminal is further reduced to the ring opened alkylarnine if the temperature is not controlled carefully.
Method G.
Formation of tetrahydrobenzothiadiazines-1,1-dioxides from 2-3o aminobenzenesulfonamides.
WO 99/'42456 PCT/DK99/00070 0~~0 0~~~
S~NH~ R'-CHO, MgS04, ~ ~ ~J.'NH
__"
NHz '~ ~PJ~'~R, Fi A stirred solution of the 2-aminobenzenesulforr~mide derivative (7 mmol), an aldehyde (10 mmol) and MgS04 (20 mmol) in dry THF or dry dioxane (~0 ml) was refluxed under N2 until TLC indicated comptet~a consumption of the 2:-aminobenzenesulfonamide derivative (typically 12-36 h). The reaction mixture was filtered, at t:he precipitate washed thoroughly with THF or dioxane. The filtrate was evaporated to dryness, added water and extracted with EtOAc. The combined organic fractions were dried with MgS04 and evaporated to dryness.
Column chromatography (EtOP,c/hexane) afforded the pure product. Yields typically ranged from 25-75%.
Method H.
Formation of aryl or hetaryl substituted compounds by use of Pd catalyzed cross coupling.
pd-cat.
X~ ~ ~-additives Fietaryl/Aryl~~, I t Metalated Arene/Hetarene - -----.-»
R li X=Br,l Suzuki coupling: A stirred mixture of an arylh<~lide (2 mmol), an aryl or hetarylboronic acid, boronic acid ester or dialkylborane (6 mrnol), K2C03 (10 mmol), Pd(PPh3)4 (30 mg), 1,3-propanediol (10 moral), dimethoxyethane (50 ml) and E-120 (25 ml) under N2 was heated to 70 °C for 3 h. The reaction mixture was cooled to rt. t=urther water was added and the reaction mixture was E>xtracted with EtOAc. -ft~e combined organic fractions were dried with MgS04 and evaporated to dryness. Column chromatography afforded the pure product.
Yields ranged from 40-100 %.
Method I.
Formation of compounds containing triazolyl substitutian.
WO 99142456 P(.'.T/DK99/00070 fit R R, Pd-cat additives ~ r~~, TMSN~ Nv N-.h I~' - H --. ~--.-,.. _-.-.. I I
I~ ~ R
X-Bi,l R TMS
H TMSN,~
h;OhIIMeOH
R
Sonogasl~ira coupling: A mixture of an aryliodide or arylbrc7mide (2 mmol); an acetylene (10 mmol); Pd(PPh3)2CI2 (1~0 rng; 0.2 mmol); Cul (40 mg; 0.1 mmol) and triethylamine (10 ml) under N2 was stirred at rt. (in the case of arylbromides prolonged heating at 60 °C was necessary) over night. THF was added and the reaction mixture filtered through celite and the filtrate evaporated to dryness. Column chromatography gave the ethynylated arene.
Yields ranged from 40-53"/° for arylbromides to 07% for aryliodides.
Detrimelhylsilylation for R'--TMS: A solution of the ethynylated arene (1.7 mmol) in MeOH (8 ml) was added a solution of 1 M KOH in MeOFi (2 ml; 2 mmol) and stirred at rt.
for 2h. The reaction mixture was diiluted with THF, adsorbed onto silica and chromatographed to give the desilylated ethynyl arene. Yields ranged from 61"/° to 73%.
Formation of trizoles: The ethynylarene (0.'7 rnrnol) and TMS-N3 (2 ml; 15 mmol) was heated to 170 °C; in an ampule for 50 h. The reaction mixture was cooled to rt. and evaporated to nearly dryness (CAUTION ! evaporation to dryness may lead to explosion due to the presence of some HN3) and added MeOH. The reaction mixture was stirred for 1 h (to remove the TMS-group in the TMS-triazole), then adsorbed onto silica, and purified by chromatography. Yield; ranged from 20-72 °ra.
Ei3 SYNTHESIS OF INDIVIDUAL COMPOUNDS
Compound 1 2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazaline Anthranilamide was transformed by Method G (using cyclohexanecarboxaldehyde).
M.p. 172-174 °C.
Compound 2 2-Phenyl-4-oxo-1,2,3,X1-tetrahydraquinazaline Anthranilamide was transformed by Method G (using benzaidehyde). M.p. 221-222 °C.
Compound 3 2-Methyl-3,4-dihydro-1,3-benzoxazine-4-anE~
2-Hydroxybenzamide v~ras transformed by ME;i:hod G (using paraldehyde). M.p.
124-126 °C.
Compound 4 2-Phenyl-3,4-dihydro-1,3-benzoxazine-4-one 2-Hydroxybenzamide eras transformed by Mefhod G {using benzaldehyde). M.p. 157-160 °C.
Compound 5 3-Bicycla[2.2.1]hept-5~'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was transformed by Method G (using a racemic endo/exo mixture of 2-norbornencarboxaldehyde). M.p. 205-209 °C.
Compound 6 3-Phenyl-1,2,3,4-tetralhydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was transformecJ by Method G (using benzaldehyde).
M.p.
125.5-12!3.5 °C.
Compound 7 1,2,3,5,10,10a-Hexahydrobenzo[e]pyrrolo[1,2-b]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfanamide was used a~~ starl:ing material for the following transformation sequence: Method E (using 4-c:hlorobutanayl chloride. The reaction mixture was NOT
subjected to NaOH catalyzed ring closure, bui: dissolved in H2SU4 and heated at 100 °C for 72 h and precipitated on ice). M.p. 149-154 °C.
Compound g 2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazine-4-one 2-Hydroxybenzamide was transforrned by MetGnod G (using ?-butanone). M.p. 76-78 °C.
Compound 9 3-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Bromo-aniline was transformed by Method h'~ (see corr7pound 121 ) to give 4-bromo-2-aminobenzenesulfonarrride.
A mixture of 4-broma-2-aminobenzenes,ulfonamide (140 mg, 0.56 mmol), 2-methoxyphenylboronic acid (1 OG md, 0.70 rnmol), F'd(PPh3)2C12 (20 mg, 5 mol %) in 1,2-dimethoxyethane (30 mil) and Na2C;03 (2M, 3 ml, 6 mmol) was refluxed under NZ
for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHC03 (20 ml) and extracted with EtOAc (2' x 40 ml). The organic layer was washed with brine (20 ml), dried (Na2'30a) and tk7e solvent was removed under reduced pressure. The product was purified b~~ flash chromatography on SiO~ using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 155 mg (100 ~;/°) of 2-amino-4-(2-methoxyphenyl)-benzenesulfonamide as colorless powder. Tl~e product was further transf<:~rmed by Method G (using cyclohexanecarboxaldehyde). M.p. 219-221 °C.
Compound 10 3-Cyclohexyl-6-(2-pyri~dyl)-1,2,3,4-tetrahydra-'1,2,4-benzothiadiazine-1,1-dioxide 3-Aminophenylboronic acid hemisulphate (5.58 g, 30 mmol), 2-bromopyridine (2.7 ml, 28 mmol), Pd(PPh3)2C12 (100 mg, 0.5 mol °/>), 2M K2C03 (50 ml) were refluxed in 1,2-dimethoxyethane (50 ml) for 24 h under N~. The mixture was diluted with CH2CI2 (100 ml) and washed with sat. NaHCO i (50 ml). The organic layer was dried (Na2S04) and the solvent was removed under reduced pressure. Flash-chromatography with CH2CI2 as eluent gave 3-(2-pyridyl)aniline as a yellow oil, 1.0 g (~1 %). 3-(2-t'yridyl)aniline was transformed by Method B
and Method G (using cyclohexanec;arboxaldel-Hyde). M.p. 21.:3-216 °C.
Compound 11 3-Cyclohexyl-6-(3-pyridyl}-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Bromo-aniline was trar7sformed by Method E3 (see compound 121 ) to give 4-bromo-2-aminobenzenesulfonarnide.
A mixture of 4-brorno-2-aminobenzenesulfonamide (250 mg, 1.0 mmol), diethyl-3 5 pyridylborane (225 mg, i.5 mmol), Pd(PPh~)2(~I_. (35 mg, 5 rnol %) in 1,2-dimethoxyethane (30 ml) and IVa2C03 (2M, 3 ml, 6 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residme was treated with saturated NaHC03 (20 ml) and extracted with EtOAc (2 x 40 m11. The organic layer was washed with brine (20 ml), dried (Na2S04) and the solvent was removed under reduced pre:rsure. The product was purified by 10 flash chromatography on SiO~ using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 240 mg (96 %) of 2-amino-4-(3-pyridyl)-benzenesulfonarnsde as colorless powder. The product was further transformed by Method Ca (using cyclohexanecarboxaldehyde). M.p. 240-243 °C.
Compound 12 15 3-Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-.5-(1-hydroxyethyl)benzenesulfonamide: 5-Acetyl-a:e-aminobenzenesulfonamide (see compound 13) (0.95 g, 4 4 mmol) was suspended in 96% EtOH (50 ml) and NaBH4 (0.46 g, 12 mmol;l was added in one portion. The mixture was stirred at 25°C for 4 h and filtered through Celite and the solvent was removf:d under reduced pressure. The residue was 20 treated with sat. NaHCO;, (50 ml) and extracted with EtOAc (2 x 50 ml), dried (Na2SOa) and evaporated to dryness.. Flash-chromatography with EtOAc:n-hexane:Et3N
(200:100:4, v/v/v) as eluent gave 0.35 c~ (37 %) of 2-amino-Ei-(1-hydroxyethyl)benzenesulfonamide as light-brown powder. M.p. 160-162 °C.
25 Compound 13 3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-~benzothiadiazine-1,1-dioxide To a solution of ethylvinylether (5.8 ml, 60 mnu>Ij in dry Th-IF (50 ml) at -78°C was added t-BuLi (1.7 M in pentane, 25 ml, 40 mmol) and the yellow mixture was stirred for 1 h at -78°C.
3o The cooling bath was removed and the mixture was warmed slowly to 0°C and stirred for another 30 min. The mixture was recooled to ~-78°C and a solution of ZnCl2 (2M in THF, 20 ml, 40 mmol) was added slowly and the cooling bath was removed and varmed to 20°C. 5-lodo-2-aminabenzenesulfonamide (see compound 37) (1.8 g, 6 mmol) and Pd(PPhs)4 (0.2 g, 3 mol%) was added and tt~e mixture was refluxc~d for 6 h. -i-he THF was evaporated and the residue w<~s boiled in 1 M hydrochloric acid (30 ml) and MeOH (30 ml) far 30 min. EDTA (14.6 g, 50 mmol) was added and made slightly basic (pH == 8-9) with 1 M NaOH
followed by extraction with EtOAc (3 x 150 ml), drying (Na,S04) and evaporation of the solvent gave a brown solid. Trituratiort with r~-hexane gave 0.9E~ g (74 %) of 5-acetyl-2-aminobenzenesulfonamide as aff-white powder. The product was further transformed by Method G (using cyclohexanecarboxaldehydej. fvl.p. 224-225 °C
(decomp).
Comaound 14 3-Cyclohexyl-7-(1-hyd~roxyiminoethyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide To a suspension of 5-acetyl-2-<~minabenzenEasulfonamide (see compound 13) (0.45 g, 2.1 mmol) in 96% EtOH (40 rnl) was added H2NOE~~HCI (0.28 g, 4 mmol) and 2M NaOH
(2 ml}.
The mixture was boiled fcar 2 h and the solvent was evaporated. The residue was triturated with water (25 ml) and the product was filtered off and dried, yielding 0.39 g (81%) of 2-amino-5-(1-hydroxyiminoethyl)benzenesulfona.mide as yellow powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 230-233 °C.
Compound 15 3-Cyclohexyl-7-carbarnoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2o A mixture of 5-cyano-2~-aminobenzenesulfonamicfe (see cornpound 37) (2 g;
10 mmol), conc.
H2S04 (4. ml) and abs. EtOH (4 ml) was heated to 80 °C for 5 h and over night at 50 °C. The reaction mixture was poured onto ice and extracted with EtOAc (1 x)". The organic phase was discarded and the aqueous phase neutralized with Na2C03 and extracted with EtOAc (3x).
The organic phase was evaporated to drynt::;s and subjected to column chromatography (EtOAc/hE:xane=2/1 ) to give 200 mg (9 %) of the carboxamide. The carboxamide was further transformed by use of A/lethod G (using cyclohexanecarboxaldehyde}. M.p. 235-237 °C.
'[The first extraction contains the ~itrile (starting material) and anothor biproduct]
Compound 16 3-Cyclohexyl-7-ethoxycarbony!-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide A mixture of 5-cyano-2~-aminobenzenesulfonamicfe (see cornpound 37) (3 g; 15 mmol), cone H2S04 (5 ml) and abs. EtOH (15 ml) was heated to 80 °C over night. The reaction mixture was poured onto ice. -i~hf~ precipitatkJ formed was isolated by filtration.
The precipitate was b7 washed with EtOAc to ~~ive 2.01 r~ (55%) of the pure ethyl ester. The ester was further transformed by use of (Method G (using cyclohexanecarboxaldehyde). M.p. 234-236 °C.
Compound 17 3-Cyclohexyl-7-cyano~-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Cyano-2-aminobenzenesulfor7arnicte (see compound 3T) was transformed by Method G
(using cyciohexanecar',ooxaldehyde) M.p. 231-2.37.
Compound 18 3-Bicyclo(2.2.1Jhept-fi'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Bromo-2-aminobenzenese~lfonamide: A stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) in AcOH (15 ml) was added ;:~ solution of Br2 (0.55 ml; 10.5 mmol) in AcOH
(5 ml). The reaction mixture was poured into H~,O (100 ml) .and filtered. The isolated solid was adsorbed onto silica and subjected to flash cloromatography to give 1.428 g (57%) product (and 650 mg (20%) of the 3,5-dibromo derivativE:).
3-Bicycloj2.2.1Jhept-5'-en-2'-.yl-7-phenyl-1,2,;a,.J-tetrahydro-1,2,4-benzothiadiazine-1, J-dioxide (78): 5-Bromo-2-amir~obenzenesulfonamide was transformed by Method H (using 2o phenylboronic acid) and Method Ca (using a rac;emic endo/E:xo mixture of bicyclo[2.2.1 ]hept-5-ene-2-carboxaldehyde). M.p. 190.5-195.0 "C.
Compound 19 3-Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Nitrophenylboronic acid: A solution of phenyuboronic acrid (10 g; 82 mmol) in acetic acid anhydride (100 ml) at -15 °C was added Turning HN03 (5 ml; 120 mmol) over 30 min such that reaction temperature was kept belaw -10 "i:,. The reaction mixture was allowed to warm up to r1. and left with stirring over night. The reaction mixture was poured onto ice and concentrated to 50 ml. The remanense was tf~en re-evaporated 5 times from additional H20 (100 ml) and finally filtered to givE 7.1 g crude product as a mixture of isomers. Column chromatography (CH2~C1~,/EtOH=1010.5) gave ~f.8 g (35°io) pure product as an oil.
fib 2-Acefamidaphenylbon~nic acid.. A mixture of .?-nitrophenyfboronic acid (2 g;
12 mmol) and 5% Pd/C (100 mg) in E.tGH (100 ml) was hydrogenated at 1 bar until TLC
indicated complete conversion of starting rnaterial. The reaction mixture was filtered through celite and the filtrate evaporated to dryness. The remar~ense was washed with hexane and filtered to give 900 mg of (55%) 2-aminophenylbaronic acid.
A mixture of 2-aminophenylboronic acid (900 mg; 6.6 mmol), triethylamine (0.57 ml; 7 mmol) and acetylchloride (0.5 rnl; 7 mmol) was stirrE:d at rt. fc7r 1 h. The reaction mixture was evaporated to dryness, stirred with H20 and filtered to give 750 mg (63%) product.
3-Cyclohexyl-7-(2'-acefarnidophenyl)-1,2,3,4-fetr;~hydro-1,2,4-benzothiadiazine-1,7-dioxide (19): 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2-Acetamidophenylboronic acid) and IVlethod G (using cyclahexanecarboxaldehyde).
M.p. 245-249 °C.
Compound 20 3-Cyclohexyl-7-(2'-nitrophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2-nitrophenylboronic acid (see compound 19)) and Method G (using cyclohexanecarboxaldf:hyde). M.p. 204-207 °C.
Compound 21 3-Cyclohexyl-7-(2'-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compaund 37) was transformed by Method H
(using 2-methoxyphenylboronic acid) and CV9ethod G (using cyclohexanecarboxaldehyde).
M.p. 219-222 °C.
Compound 22 3-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 4-Trifluon~mefhylanisole: Sodium (12.78 g; Ei55 mmol) was added to dry MeOH
(100 ml).
When the gas evolution ceased, the reactian mixture was evaporated to dryness and dry NMP (250 ml) followed by Cu (s) (35.3; 555 mmol) and 4-bromo-trifluoromethylbenzene (25 g;
111 mmol) was added. The reaction mixture was heated tc:~ 130 °C for 4 h, cooled to rt. and filtered. Water {500 ml) was added to the filtral:e and it was extracted with Et20 {2x 200 ml).
The combined organic. fractions were washE~d with H20 (2x 100 ml), dried (MgS04) and evaporatE:d to dryness. Column chromatography gave 8.05 g {41 %) of product.
2-Methoxy-5-trifluorom~ethylphenylboronic acid: A solution c:~f 4-trifluoromethylanisole (8 g; 45 mmol) in dry THF (80 rnl) at -30 °C under N2 was added a ;:solution of 2.5 M n-BuLi in hexane (20 ml; 50 mmol). The reaction mixture was stirred for 1 h at -30 "C, then cooled to -70 °C and added B(Oi-Pr)3 (14.1 ml; 64 mmol). The reaction mixture was allowed to slowly warm up to rt. over night. The reaction mixture was addecJ 2 M HCI (40 mi) and THF was removed by evaporation.. The aqueous remanense was extracted with E~t20 (4x 20 ml) and the combined organic fractions were extracted with 1 M NaOI-i (5x 17 ml). The combined aqueous fractions were neutralized by 10 M HCI. The precipitai:e formed was isolated by filtration and washed with 1 M HCI to give 8.1 g (81 %;) product.
3-Cyclohcxyl-7-(2'-methoxy-4'-triouoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-a'ioxide (22): 5-lodo-'~-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2-methoxy-5-triflucaromethylphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 255-2fs7 °C.
Compound 23 3-Cyctohexyl-7-(2',4'-dimethoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothi adiazi ne-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2,4-dimethoxypher~ylboranic acid) and Method G (using cyclohexanecarboxaldehyde).
M.p. 208213 °C.
Compound 24 3-Cyclohexyl-7-(2'-(N,N-dimethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-(N,N-dimethylsulfamoyl)phenylbor~nic acid.' A solution of benzenesulfonylchloride (10 ml;
78 mmol) in THF (100 ml) was added a 40°/> solution of dimethylamine in H20 (20 ml; 160 mmol) such that the reaction temperature w<~~; kept below 50 °C. The reaction mixture was stirred 1 h at rt. The reaction mixture was added H20 and THF removed by evaporation. The precipitate formed was isolated by filtration and air dried to give 14 g (97%) of N,N-dimethylbenzenesulfonamide.
A solution of N,N~tiimethylbenzenesulfonamide (!x.25 g; 50 mmol) in dry Et20 (150 ml) under N2 was cooled to -70 "C and added a solution of 2.5 M n-BuLi in hexane (24 ml;
60 mmol) 5 such that the reaction temperature was kept below -60 °C.. The cooling bath was removed and the reaction mixture ~~Ilowed to slowly wa.rrn up to +20 "C. The reaction mixture was re-cooled to -70 °C and B(Oi-pr)3 (16.1 ml; 70 rnrrrol) was added. The reaction mixture was left cold and allowed to warm up over night, 1 M HCI (100 ml) was added and stirring was continued at rt. for 1 h. The reaction mixture was then extracted with Et20 (2x 50 ml) and the ~o combined organic fractions extracted with 1 M NaOH (4x 50 ml). The combined aqueous fractions were neutrali~:ed with 1 M HCI and extracted with Et20 (4x 100 ml).
The combined organic fractions were cried (Na2S0,~) and evaporated to dryness, washed with Et20/hexane to give 3.4 g (30%) product.
15 3-Cyclohexyl-7-(2'-(N,N-dimethyisulfamoyl)~hc~rryl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (24): 5-lodo-2-aminobenzenesulfonarnide (see compound 37) was transformed by Method H (using 2-(N,N-dimethylsulfamoyl)phenylboronic acid) and Method G
(using cyclohexanecarboxaldehyde). M.p. 290-300 "(~.
2o Comaound 25 3-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzen~esulfonamide (see compound 37) was transformed by Method H
(using 2-chlorophenylboranic acid) and Method G (using cyclohexanecarboxaldehyde). M.p.
233-236 "C.
Compound 26 3-Cyclohexyl-7-(2'-fl uorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazine-1,1-dioxide 5-lodo-2--aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2-fluorophenylboronic acid) and Method G (using c:yclohexanecarboxaldehyde). M.p.
249-250 "C.
Compound 27 a1 3-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-hydroxyphenylboronic acid: A stirred solution of 3-aminophenylboronic acid hemisulfate (6.2 g; 33.3 rrimol) and 50°,~o H2S04 (3. i' ml; 33.~~ rnmol) in H20 (100 ml) at -2 °C was added a solution of NaN02 (2.5 g; 36.3 mmol) in Hpt) (20 ml) over 1 h. The reaction mixture was slowly added to a stirred solution csf cone. h~>S04 (25 ml) in H20 (20 ml) at reflux. After complete addition, the reaction mixture was refluxed for 30 min., cooled, added activated charcoal, heated to reflux, cooled and filtered through celite. The filtrate was saturated with NaCI (s), filtered and extracted with Et20 (5x: '100 ml). The combined organic fractions were dried (Na2S04) and evaporated to dryness to give 4.3 g (94°io) product.
3-Cyclohexyl-7-(3'-hydroxyphen.yl)-1,2,3,4-tetiahydro-1,2,4-benzothiadiazine-1,1-dioxide (27):
3-Hydroxyphenylboronic acid was transformed by Mei:hod H and Method G (using cyclohexanecarboxaldc:hyde). M.p. 238-246 °C
Compound 28 3-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide 4-(2'-Pyridyl)-2-aminobenzenesulfonamide: A stirred mixture of 5-iodo-2-aminobenzenesulfonarnide (1 g; 3.3 mmoli), 2-tributylstannylpyridine (5.5 g;
15 mmol), Pd(PPh3)4 (240 mg, 0.34 mmol) and Ag20 (780 mg; 3.3E~ mmol) in DMF (50 ml) under N2 was heated at 100 °C for 6h and over night at rt. The reaction mixture was evaporated to dryness and resuspended and stirred in H20/E.tOAc and finally filtered. The organic phase was isolated and the aqueous phase extracted with EtC:>Ac (2x aq, vol.). The combined organic fractions were dried (Na2S04), ev<~porated to dryness and subjected to column chromatography to give 200 mg (24 %) product.
3-Cyclohexyl-7-(2'-pyri~alyl)-1,2,3,4-tetrahydro-1,2',4-benzothiadiazine-1,1-dioxide (28): 4-(2'-Pyridyl)-2-aminobenzenesulfonamidc~ was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 222-224 "C.
3o Compound 29 3-Cyclohexyl-7-(3'-pyridyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzencaulfonamide (see compound 37) was transformed by Method H
(using diethyl-3-pyridylk>orane) and Method G (using cyclohexanecarboxaldehyde). M.p. 240-242 °C.
Compound 30 3-Cyclohexyl-7-(2'-pyrimidinyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 4-((2,2-Dimethylpropanoyl)amino)phenylboror,~ic acid: To a solutian of 4-bromo-N-pivaloylaniline (1.56 g, 6 mmol) in dry THF (50 rril) at -78°C was added t-BuLi (1.5 M in pentane, 13.3 ml, 20 mmol) and the yellow mi:Kture was stirred for 1 h at -78°C under N2. The reaction was quenched with B(OCH3)3 (1.7 rnl, 15 mmol) and stirred for another 1 h at -78°C.
The reaction mixture w,~s then warmed to morn temperature and hydrolysed with 0.5 M
hydrochloric acid (50 ml) and extracted with EtC>Ac (3 x 80 ml), dried (Na2S04) and concentrated to ca. 40 ml n-Hexane (120 m!) was added slowly and the colorless crystalline product was filtered off and dried, yielding 1.26 g (95%).
N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide: ~'v mixture of 4-((2,2-dimethylpropanoyl)amino)phenylboranic acid (2.0 g, 9 mmol), 2-chloropyrimidine (0.8 g, 7 mmol), Pd(PPh3)2C12 (100 mg, 2 mol %) 1,2-dimc~thoxyethane (40 ml) and Na2C03 (2M, 7 ml, 14 mmol) were refluxed under N2 for 5 h. The mixture was diluted with 10 %
Na2C03 (20 ml) and extracted with EtOAc; (3 x 50 ml). The organic layer was dried (Na2SOa) and the solvent was removed in vacuo. The crude product was recrystallisE=d from MeOH/water (1:1 ) yielding 0.52 g (85%) of N-(4-(c'-pyrimidinyi)phenyl)-2,:?-dimethylproi:~anamide as colorless crystals.
4-(2-Pyrirnidinyl)aniline: N-(4-(2-pyrimidinyl)phenyl)-2,2-dinnethylpropanamide (1.41 g, 5.48 mmol) was boiled in 6 IM hydrochloric acid (40 ml) for 2 h. The mixture was cooled and made strongly basic with NaOH (s) and extracted with CH2C12 (2 x 50 ml), dried (Na2S04) and the solvent vvas removed irn vacuo. Trituration with n-hexane gave 0.83 g (88%) of 4-(2-pyrimidinyl)aniline as a light-yellow powder. ThE; product was further transformed by Method B
and Method G (using cyclohexanecarboxaldehyde). M.p. 236-238°C.
Compound 31 3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide WO 99/42456 f'CT/DK99/00070 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using furyl-2-boronic acid) and Method G {usinct cyclohexanecarboxaldehyde).
M.p. 226-228 °C.
Compound 32 3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see cornpound 37) was transformed by Method H
(using furyl-3-boronic acid) and Method G (using cyclohexanecarboxaldehyde).
M.p. 204-205 °C.
Compound 33 3-Cyclohexyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using thienyl-2-boronic acid) and Method G (using cyclohexanecarboxaldehyde).
M.p. 234-236 °C.
Compound 34 3-Cyclohexyt-7-(1-methyl-1 !-f-2-imidazolyt)-'1,2,3,4-tetrahydro-1,2,4-benzothiad iazi ne-1,1-dioxide To a solution of 1-methyl~midazole (4.8 ml, 60 mmol) in dry THF (120 ml) at -78°C was added n-BuLi (2.5 M in hexane., 26 ml, 65 mmol) and the yellow mixture was stirred for 45 min at -78°C. A solution of ZnClz (2M in THF, 75 rrol, 150 mmol) was added slowly and the cooling bath was removed. The colorless solution was stirred for another 10 min at 0°C. 5-lodo-2-aminobenzenesulfonamide (see compound 37) (2.1 g, 7 mmol) and Pd(PPh3)4 (0.5 g, 5 mol%) was added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was treated with EDTA (53 g, 0.18 mol) and made slightly basic (pH = 8-9) with 1 M
NaOH followed by extraction with EtOAc (3 x 150 ml), drying (Na2SO4) and evaporation of the solvent gave a dark oil. Flash-chromatography with 5% MeOH in CH2C1;~ as eluent gave 1.33 g (75 "/°) of 2-amino-5-(1-methyl-1 H-2-irnidazolyl)-1-benzenesulfonamide as colorless crystals. The product was further transformEad by Method G (using cyclohexanecarboxaldehyde). M.p. >>250 °(:, (decomp).
r4 Compound 35 3-Cyclohexyl-7-(1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method I
(using trimethylsilylacetyiene) and Method G (using cyclohexanecarboxaldehyde). M.p.
230-234 °C
(dec.).
Compound 36 3-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzen~esulfonarnide (see compound 37} w<xs transformed by Method I (using phenylacetylene) and Method G (using cyclohexanecarboxaldehyde}. M.p. 231-232 °C (dec.).
Compound 37 3-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide To a cold (0 °C) stirred solution of 2-aminobenzenesulfonarnide (17.2 g; 100 mmol) in CHC13 1;200 ml) was added a solution of iodine manochloride (17.1 g; 105 mrnol) in CHc~l3 (50 ml) over 1 h. The reaction mixture was slowly warmed up to rt. and left with stirring aver night. ThE: reaction mixture was filtered and the isolated solid was washed on the filter with CHCI3 (3x 20 ml), NaHC03 (sat. aq., 1 x 20 ml), H20 (4x 50 ml). The isolated solid was air dried to give 27.3 g (92%) of product.
5-Cyano-2-aminobenznnesulfonamide: A mixture of 5-iodo-2-aminobenzene-sulfonamide (17.9 g; 60 mmol), Zn(CN)2 (4.9 g; 41.9 mmol) and Pd(PPh3)4 (2.5 g; 2.2 mmol) in DMF (150 ml) under N2 was heated to 80 °C for 2 h. ThE: reaction mixture was poured into NaHC03 (sat. aq., 600 ml) and extracted with EtOAc (9x 200 ml). The combined organic fractions were washed with NaHC03 (sat. aq.} and NaCI (sat. aq.), dried (Na2S04), filtered and evaporated to dryness. The remanense was washed with water and hexane and filtered of to give 10.9 g (92%) of praduct.
5-(N-hydroxyamidino)-.2-aminobenzenesulfon.amide: A mixture of hydroxylamine hydrochloride (764 mg; t 1 mmol} and NaOAAe (616 mg; '11.4 mmol) in MeOH (10 ml) was stirred at rt. for 1 h and then added 5-cyano-2-aminobenzenesulfonamide (1 g;
5 mmol). The reaction mixture was left with stirring for 48 h and poured into water and extracted with EtOAc (2x 50 mi). The combined organic fractions were dried (Na2S04), evaporated to dryness and purified by column chromatography to give 200 mg (17%) of product.
5 3-Cyclohexyl-7-(5'-methyl-7',2',4'-axadiazol-3-yl)-1,2,3,4-fetrahydro-1,2,4-benzothiadiazine-i, l-dioxide (37): A mixture of 5-(N-hydroxyamidino)-2-aminobenzenesulfonamide (200 mg;
0.9 mmol), NaOMe (5C mg; 1 mmol), EtOAc (5 ml), crushed MS3A (2 g) in anhydrous EtOH
(20 ml) was heated over night at 70 °C. 'rh~e reaction mixture was evaporated to dryness, stirred with water and extracted with EtOAc:. The combined organic fractions were dried 10 (Na2S04) and evaporated to dryness to a brown oil, whici~ way: subjected to transformation by Method G (using cyclohexanecarboxaldehyde) to give 8 mg product after chromatography.
M.p. 249-251 °C.
Compound 38 15 3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 7-Amino-3-cyclohexyl-~1,2,3,4-tetrahydro-1,2,4-bc~nzothiadiazine-1,1-dioxide:
To a stirred solution of 7-amino-~~-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.5 g; 2 mmol) in dry THF (10 rnl) at -70 °C; was added a solution of 1.5 M
DIBALH in toluene (2.7 ml;
4 mmol) under N2. The reaction n-cixture was stirred for 2 h at -70 °C;
2 h at -40 °C and then 20 warmed to 0 °C. The reaction was quenched with H20 and stirred for 30 min. at 0 °C and left over night without stirring at +5 °C. The mixture was evaporated to dryness, resuspended in MeOH and filtered. The isolated solid was washed thoroughly with MeOH and filtered. The combined filtrates was adsorped onto silica c~E;l., Column chromatography (EtOAc) gave 200 mg of product.
7-Acetylamino-3-cyclohexyl-1,2,3,4-tetrahydro-1"2,4-benzothiadiazine-1,1-dioxide (38): A
mixture ~of 7-amino-3-cyclohexyl--1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide (100 mg; 0.26 mmol), acetylchloride (20 pl; 0.29 rnol) and triethylamine (42 pl;
0.3 mmol) was stirred fur 2 h at r.t. The reaction mixture was resuspended in H20 and filtered. The isolated solid was purified by column chrornatography (EtOAc) to give 22 mg 27a. M.p.
202-206 °C.
Compound 39 3-Cyclohexyl-7-methylsuffonylamino-1,2,3,4-tetrahydro-1 "2,4-benzothiadiazine-1,1-dioxide 3-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: 2-Aminobenzenesulfonamide was transformed by Me~rhad E (using cyclohexanecarbonyl chloride).
3-Cyclohexyl-7-vitro-1,2-dihydro-~y,2,4-benzothiadiazine-1,1-dioxide: To a stirred solution of KN03 (1.2 g; 11.5 mnnol) and cone. H2SO~i (f3 ml) at 5 °C was added a solution of 3-cyclohexyl-1,2-dihydro-1,2,4-benzoth~adiazine-1.11-dioxide in conc. H2S04 {8 ml). The reaction mixture was allowed to warm up to r.t. ;end left with stirring over night. The product 1 o was precipitated by slow addition of ice and isolated by filtration. The crude product {4.3 g) was used without further purification.
7-Amino-3-cyclohexyl-1,2-dihydro-~I,~n,4-benzothiadiazine-1, a-dioxide: A
stirred suspension of 3-cyclohexyl-7-vitro-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (4.2 g; 14 mmol) and 10%
Pd/C (40G mg) in abs. EtOH (100 ml) was hydrogenated at 1 bar. After consumption of the calculated amount of H2, the reaction mixture was filtered through celite. The celite was washed twice with DfUIF {75 ml) and the comk>ined organic fractions were evaporated to dryness. The remanense was resuspended in E=tOAc/i-PrOhi and the precipitate formed, was isolated by filtration. The isolated solid was dissolved in 0.5 M NaOH (aq.) and reprecipitated 2o with 4 M HCI (aq.). Filtr;~tion gave 1.6 g produca.
7-MethyJsulfonyJamino-3-cyclohexyl-l,2-dihyd~o-;1,2,4-benzothiadiazine-1,1-dioxide: A stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (1 g; 3.6 mmol) and triethylarnine (1.2 ml; 8 mrnol) in dry THF (25 ml) was added methanesulfonylchloride {0.6 ml; 8. mmol) and stirred at rt. for 2 h. The reaction mixture was evaporated to dryness, resuspended in H2O/E=tOAc and filtered. The filtrate was adsorbed onto silica gel. Column chromatography (CH2C12:acetone = G:1 ) gave 210 mg of product.
3-Cyclohexyl-7-methyls;ultonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3o (39): 7-Methylsulfonylamino-3-cyciohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method F. M.p. 255-258 °C.
Compound 40 ?7 3-Cyclohexyl-7-nitro-f ,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Trifluoromethyl-1,2,4-benzofhiadiazine-7, 1-dioxide: 2-Aminobenzenesulfonamide was trifluoroac:etyl protected by using Method G. A solution of this (1 g; 4 mmol) in H2S04 (16 ml) at 0 °C was added solid KN03 (4.4 mmol). The reaction mixture was allowed to warm up to rt.
and stirred over night. The reaction mixture was poured into ice water (150 ml), filtered and air dried to give 1.11 g (94%) of pure product as a yellow solid.
3-Cyclohexyl-7-nitro-1, 2, 3, 4-to tra h ydro-1,2, 4-berrzothiadiazine-1,1-dioxide (40):
3-Trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide was subjected to the following transformation scheme: Method U and Methoc:i F (using cyclohexanecarboxaldehyde). M.p.
209-211 "C.
Comaound 41 3-Cyclohexyl-7-phenylsulfonyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 4-Phenylsulfonylaniline~ was used as starting material for the following transformation sequence: Method B and Method G fusing cyclohexanecark:roxaldehyde). M.p. 243-245 °C.
Comaound 42 2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide A solution of 2-aminok>enzylamine (3 g; 25 rnmol) in THF (50 ml) was added trifluoroacetic acid anhydride (3.8 nnl; 27 mmol) and stirrE~d at rt. for 2 h. The reaction mixture was evaporated to dryness, stirred with H20 and filtered. The <:rude product was transformed by Method A (using 25% NH,3 (aq.) as amine) and Method G (using cyclohexanecarboxaldc:hyde). M.p. 178-180 "C.
Compound 43 3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazi ne-1,1-dioxide 4-Sulfamoylanthranilarnide: A stirred solution caf CIS03H (20 ml) was added anthranilamide (7.5 g; 5 5 mmol) in small portions. The reacaior~ mixture was heated to 100 °C for 1 h and 3o then poured into ice water (300 mi). A precipitate formed, which was isolated by filtration and dried on the filter. The isolated solid was dissolved in 25°/~ NH3 (aq.) and stirred at rt. over night. The aqueous phase was washed with LtOAc and concentrated to 20 ml. The aqueous phase was saturated with NaCI (s) and extracted with THF (3x 50 ml). The combined organic fractions were evaporated to dryness and subjected to column chromatography to yield 13 mg product.
3-Cyclohcxyl-7-sulfamnyl-7,2,3,~f-tet~ahydro-l,~t,~4-benzofhia:rdiazine-1,1-dioxide (43): 4-Sulfamoylanthranilamicie was transformed by MEahod G (u;:>ing cyclohexanecarboxaldehyde).
Fab+ 31 U. 'H-NMR (DiMSO-d6): 8.1 (1 H; br.), 8.0 (1 H; d), 7.58 (1 H; dd), 7.3 (1 H; br.), 7.05 {2H; br.), 6.79 (1 H; d), 4.5 (1 H; rn), 1.8-1.5 (6hi; rn), 1.2-1.0 {5H; m).
Compound 44 3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-sulfamoylbenzenesulfonamide (see compound 101 ) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. x!52-254 "C.
Compound 45 3-Methyl-7-dimethylsulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-7-dimethylsul~farnoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced by use of Method F. M.p. 210-212 "C.
Compound 46 2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazofine N,N-dimethylsulfonamide A solution of 2-aminobenzylamine (3 g; 25 mmol) in THF (50 rnl) was added trifluoroacetic acid anhydride (3.8 rnl; 27 mmol) and stirred at rt. for 2 h. The reaction mixture was evaporated to dryness, stirred with H20 and filtered. The crude product was transformed by Method A (using dimethylamine as amine), Method D and Method G (using cyclohexanecarboxaldehyde). M.p. > 300 °C. M;> (electrospray) M+ 323.
'H-NMR (DMSO-d6):
7.2 (1 H; dd); 7.1 (1 H; cl); 6.68 (1 H; br); 6.62 (11 H; d); 3.85 (1 H; s);
3.8 (2H; s); 2.2 (1 H; br); 1.8-1.0 (11 H; m).
Compound 47 3-Cyclohexyl-7-dimethylaminosutfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using dimethylamine as amine), Method F. Nl.p. 243-245 °C.
Compound 48 3-Cyclohexyl-7-(N,N-diiethylamina)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfon.arnide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using diethyiamine as amine), Method F. M.p. 207-209 °C.
Compound 49 3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazine-1,1-dioxide 2-Aminobenzenesulfon.amide was used as starting material for the following transformation sequence: Method E (u,~sing cyclohexanecarb~onyl chloride), Method A (using pyrrolidine as amine), Method F. M.p. 244-246 °C..
Compound 50 3-Methyl-7-piperidinosulfony!-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfon.amide was used as starting material for the following transformation sequence: Method C, Method A (using piperidine as amir7e), Method D, Method G
[using paraldehyde and a cat. amount of 'TsOH]. Nl.p. 2!55-256 °C.
Compound 51 3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfon.amide was used as starting material for the following transformation sequence: Method C, Method A (using pipericiine as amirne), Method D, Method G
[using cyclopropancarboxaldehyde]. M.p. 228-231 °C.
Compound 52 3-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using piperidine as amirne), Method D, Method G
[using isobutyraidehyde]. M.p. 2,'.37-239 "C.
Comaound 53 3-propyl-7-piperidinosulfonyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation 5 sequence: Method C, Method A (u~~ing piperidine as amine), Method D, Method G (using butyraldehyde]. M.p. 14 7.4-151.:2 °C
Compound 54 3-Benzyl-7-piperidinosutfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 10 2-Aminobenzenesulfonanride was used as sl:arting material for the following transformation sequence: Method C, Method A (using piperidine as amine), Method D, Method G
(using phenylacetaldehyde I. M.p. 242-244 °C.
Comaound 55 15 3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide Cyclopenfanecarboxaldehyde: A stirred solution of cyclopentanecarboxylic acid (2.16 ml; 20 mmol) in dry THF (50 rnl) at rt. under N2 was added NaBH4 (2.28 g; fi0 mmol) and left with stirring for 20 min. The reaction mixture was cooled to 0 °(:; and added BF30Et2 (10 ml; 80 mmol) over 1 h, while 'the reaction temperaturEa was kept below +3 °C.
The reaction mixture 20 was allowed to warm up to rt. and left with stirring aver night. The reaction mixture was added NaHC03 (sat., aq.), H20 and extracted with EtOAc. The combined organic fractions were washed with NaCI (sat., aq.), dried (Na2SO4) and evaporated to dryness to give 1.4 g of an oil which was used without further purification.
The oil (1.4 g) was dissolved in CH2CI2 (75 rnl) and added PCC on AI203 (30 g;
30 mmol)' 25 and left with stirring for 1 h at rt. The reaction rnixture was filtered and the filtrate evaporated onto silica. Column chromatography afforded the pure aldehyde which was used as a solution in CH2C12.
'[see Cheng'~'.-S, Liu W.-L. and Chen S -H., Synthesis, (1980) 2.?3 J
30 3-Cyclopenty!-7-piperid'inosulfonyl-1,2,3,4-tetr,~hyrdro-1,2,4-benzothiadiazlne-1,1-dioxide (55):
2-Aminobenzenesulfonamide was used as sl:arting material for the following transformation sequence: Method C, Method A (using piperidine as amine), Method D, Method G
[using cyclopentanecarboxaldehydey. M.p. '~?58-260 "C..
WO 99!42456 PCT/DK99/00070 Compound 56 3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as darting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using piperidine as amine), Method F. M.p. 262-264 "C.
Compound 57 3-Bicyclo[2.2.1 )hept-5'-en-2'-yl-7-pi peridinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-diaxide 2-Aminobenzenesulfonamide was used as sl:arting material for the following transformation sequence: Method C, Method A (using piperiidine as amine), Method D, Method G
[using a racemic endolexo mixaure of 2-norbornencarboxaldehyde). Two separate diastereomeric mixtures were isolated with m.p. (A) ;?40-242 "C and m.p. (B) 234-238 °C.
Compound 58 3-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidina)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonarrride was used as starting material for the following transformation 2o sequence;: Method E (using cyclohexanecarbonyl chloride), Method A (using 7 ,2,3,6-tetrahydropyridine as amine), Method F. M.p. 23J-239 °C.
Compound 59 3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride)., Method A (using N-methylaniline as amine), Method F. M.p. 210-212 °C.
Compound 60 3-Cyclohexyl-7-(1'-(1',2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide $2 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanec:arbonyl chloride), Method A (using 1,2,3,4-tetrahydroquinoline as amine), Method F. M.p. 218-220 °C.
Compound 61 3-Cyclohexyl-7-(4'-methyl piperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using N-methylpiperazinEa as amine), Method D, Method G
(using cyclohexanecarboxaldehyde) M.p. 227-229 °C.
61 methane sulfonate salt: 61 (0.6 g; 1.4 mmol) was dissolved in 99% EtOH {30 ml) and added a solution of 1 M C:,H3SO3H in 99°ia EtOH. The mixture was left for precipitation for 2 h and the salt isolated by filtration. The composition of thc~ sall was checked by HPLC for stability compared to the free base. The salt was found to be stable towards hydrolysis under these conditions and had a water solubility of 10 mg/ml.
Compound 62 3-Cyclohexyl-7-(4'-methylsulfonylpiperazi no)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide N-Mesylpiperazinium chloride: To a stirred solution of piperazine (4.3 g; 50 mmol) in CH2C12 (50 ml) at +5 °C was added a solution of CH3SO2C1 (4.25 ml; 55 mmol) in CH2CI2 (15 ml).
The thick reaction mixture was stirred at rt. for 12 h, added CH2C12 (100 ml), and extracted with 1 M HCI (300 ml). A precipitate formed in the aqueous phase was filtered of to give 2.66 g of N-mesylpiperazinium chloride (32 %).
3-Cyclohexyl-7-(4'-men"hylsulfonylpiperazino)suifnnyl-1,2, 3,~-tetrahydro-1,2, benzofhiadiazine-1,1-dioxide (62): 2--Aminobenzenesulfonamide was used as starting material for the following transformation sequence: AAethod E (using cyclohexanecarbonyl chloride), Method A (using N-Mesylpiperazinium chloride as amine (1.5 eq.), 3 eq. K2C03 was used for neutralization), Method F. M.p. 272-274 °C.
Compound 63 3-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as amine), Method F. M.p. 262-264 °C..
Compound 64 3-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-7-bromo-1,2.,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Bromo~-2-aminobenzenesulfonarr~ide (see compound 18) was transformed by Method G
(using a racemic endo/exo mixture of bicyclo[2.2.1 ]hept-5-E:ne-2-carboxaldehyde). M.p. 200-204 °C.
Compound 65 2-Methyl-4-axo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide 2-Methyl-4-oxo-3,4-dihydroquinazoline: A solution of anthranilamide (13.6 g;
100 mmol) in acetic acid (100 ml) was refluxed for 60 h. The reaction mixture was evaporated to dryness, suspended in H20, filtered and washed thoroughly with Nal-IC03 until the filtrate had a pH of 8-8.5.
2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-~dirrrethylsulfonamide: 2-Methyl-4-oxo-3,4-dihydroquinazoline was transformed by Method A (using dirnethylamine as amine). M.p. 264-266 ° C.
Comaound 66 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoiine sulfonamide 2-Trilfluoroacetamidobenzamide (seE~ compound 68) was transformed by Method A
{Using 0.5 M NH,3 in THF as amine). M.p. 311-314 °C.
Compound 67 2-Trifluoromethyl-4-oxo-3,4-dihydra-6-quinazoiine N,N-dimethylsulfonamide 2-Trilfluoroacetamidobenzamide (see compound 68) was transformed by Method A
(Using dimethylamine as aminE~). M.p. 257-258 °C.
Compound 68 2-Trifluoromethyl-4-ox:o-3,4-dihydro-6-quinazoline-1',2',3'',6'-tetrahydropiperidinosulfonamide A stirred mixture of anthranilamide (13.6 g; 100 mmol) in ~~fHF (100 ml) at 0 °C was added trifluoroacetic acid anhydride (15.2 rr7l; 110 mmol) and allowed to warm up to rt. and left with stirring over night. The reaction mixture was evaporated to dryness, suspended in H20 and filtered. The isolated solid was air dried to give 21.6 g (93°/«) 2-trilfluoroacetamidobenzamide.
2-TriIfIuoroacetamidobE:nzamide was transformed by Method A (using 1,2,3,6-tetrahydropyridine as amine). M.p. 2~'7-230 °C.
Compound 69 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide 2-Trilfluoroacetamidobenzamide (sere compouncl 68) was transformed by Method A
(Using cyclohexylamine as amine). M.p. 261-263 °C.
Compound 70 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide 2-Trilfluoroacetamidobenzamide (see compound 68) was transformed by Method A
(Using morpholine as amine). M.p. 282-285 °C.
Compound 71 2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide Antranilamide was used as starting material for the following transformation sequence:
Method A (Using 25% NF-13 (aq.) as amine. The reaction mixture contained both the 5-mono and 5,7-disulfonamide, which were separated by chromatography), Method G
(using cyclohexanecarboxaldehyde. The arninal auto oxidizes to the aromatic hydroxyquinazoline).
M.p. 306-310 °C.
Compound 72 3-Methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,~!-dioxide (see compound 73) was transformed by Method A (using 0.5M NH3 in THi= as amine). M.p. 295-297 °C.
WO 99/42456 PC'.T/DK99/00070 Compound 73 3-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide (17.2 g; 100 rnrnol) was refluxed in AcOH for 5 days. The precipitate formed was isolated by filtration and washed with water to give 17.8 g (91 %) of 3-5 methyl-1,2-dihydro-1,2,4-benzothiadcazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method A {using dimethylamine as amine).
M.p. 260-261 °C.
Compound 74 10 3-Methyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) was transformed by Method A (using 1,~~,3,6-tetrahydropiperidine .as amine). M.p. 265-268 °C.
15 Compound 75 3-Methyl-7-cyclohexyisulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-11,'1-dioxide (see compound 73) was transformed by Method A (using cyc:lohexylamine as amine). M.p. 239-242 °C.
2o Compound 76 3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C and Method A fusing dirnEahylamine as amine). M.p. 240-242 °C.
25 Compound 77 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinaxolinesulfonic acid 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequencE~: Method C and Method A fusing Na~Of~i instead of an amine). M.p.
>330 °C.
3o Compound 78 3-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide m-Toluidine was used as starting material for the following transformation sequence: Method B [2-amino-6-methylbenzenesultonamide was separated from 2-amino-4-methylbenzenesulfonamide by recry:>tallization (EtOAc/hexane)]. 2-Amino-6-methylbenzenesulfonamide was further purified by column chromatography and transformed by Method G (using cyclohexanecarboxaldehydca). M.p. 228-230 °C.
Compound 79 3-Cyclohexyl-8-hydrox:ymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-7,2-dihydro-t,~',4-benzothiadiazine-1,1-dioxide-8-carboxylic acid: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 80) (0.30 d, t .0 mmol) in dry THF' (15 ml) ,~t: -78 °C was added s-BuLi in cyclohexane (1.3 M, 1.E~ ml, 2.1 mmoi) under i'J2. 'The yellow mixture was stirred for 15 min at -78 °C and dry gaseous. C02 was bubbled throucth the solution for 30 min. The cooling bath was removed and the rnixture was allowed to warm to 0 ''C. -The solvent was removed under reduced pressure and the residue was triturated with hydrochloric acid (0.2 M, 12 ml). The crude product was rec:rystallised from 50 °~~ MeOH yielding 300 mg (82%) of 5-chloro-3 cyclohexyl-1,2-dihydro-1,2,4-benzoth~adiazine-1,1-dioxide-8-carboxylic acid as colorless ~ 5 crystals.
3-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-l, l-dioxide-8-carboxylic acid: 5-Chloro-3-cyclohexyl-1,2-dihydro-1,a?,4-benzothiadiazine-1,1-dioxide-8~-carboxylic acid (160 mg, 0.47 mmol) was dissolved in 90 % EtOH (50 ml) and hydrogenated using Pd/C (10 %, 10 mg) at 1 bar pressure for 24 h. NaOH (1 M, 12 ml) was added and the mixture was filtered through a pad of CeliteT"' and concentrated to 10 ml and concentrated hydrachloric acid was added slowly to precipitate the product yielding 11 l) mg (76%) of 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid as colorless powder.
3-Cyclohexyl-8-hydroxymeth.yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (79):
NaBH4 in triglyme (2M, 0.75 ml, 1.5 mmol) was dissolved in dry THF (20 ml) and cooled to -50 °C under N2,. BF3-etherate (0.25 ml, 2.0 mmol) was added and the mixture was stirred for 10 min at -50 °C. Solid 3-cyclohexyl-1,2-dihydro-1,,?,4-benzothiadiazine-1 ,1-dioxide-8-carboxylic acid (170 mg, 0.55 mmol) was added in one portion and the suspension was stirred for 6 h at -50 °C and overnight at 20 °C. The mixture was hydrolysed with hydrochloric acid (1 M, 2 ml) and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (50 ml) and the organic; layer was washed with brine (10 ml), dried (Na2S04) and the evaporated to dryness. The product was purified by flash chromatography on Si02 using EtOAc:n-hexane (2:1, v/v) as eluerzt, yielding 1 C>C) mg (62 %;) of 3-cyclohexyl-8-hydroxymethyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless needles. The product was further transformed by Method F. M.p. 220-223 °C.
Compound 80 3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-1,2-dihydro-1,~,4-benzothiadiazine-1,-1-dioxide: 3-Chloroaniline was used as starting material for the following transformation sequence: Method B
followed by Method E (using cycloh~sxylcarbanyl chloride).
5-Chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,~?,4-t>E~nzothiadiazine-~, i-dioxide: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydrc>-1,2,4-benzot:hiadiazine-1,1-dioxide (596 mg, 2 mmol) in dry THF (20 ml) at -78 °C was added s-BuLi in c.yclohexane (-1.3 M, 3.8 ml, 5 mmol) under N2.
The yellow mixture was stirred for 15 min at -T8 °C and a solution of 12 (1.27 g, 5 mmol) in dry THF (5 ml) was added. The cooling bath was removed and the mixture was allowed to warm to 0 °C. NaHS03 (5 °ro, 20 ml) was added and extracteca with EtOAc (2 x 30 ml), dried (Na2S04) and evaporated to dryness to give 0.76 g (90 %) of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1.1-dioxide.
5-Chloro-3-cyclohexyl-8-(2-methoxyphenyl)-l,a?-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: A
mixture of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (290 mg, 0.68 mmol), 2-methoxyphenylboronic acid {122 mg, 0.80 mmol), Pd(PPh3)2C12 (10 mg, 2 mol %) in 1,2-dimethoxyethane (50 rnl) and Na2C03 (2M, 2 rnl, 4 mmol) were refluxed under N2 for 2 h. The solvE~nts were removed under reduced pressure and the residue was extracted with EtOAc (:? x 40 ml) and the organic layer was washed with saturated NaHC03 (20 ml), dried (Na2SOa; and the solvent was iremoved undc:~r reduced pressure.
The product was purified by flash chromatography on SicJ; using EtOAc:n-hexane (1:2, v/v) as eluent, yielding 200 mg {73 °~~) of 5-chioro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-t~enzothiadiazine-1,1-dioxide (80):
5-Chloro-3-cyclohexyl-8-(2-methoxyphenyl)-~1,;2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (190 mg, 0.47 mmol) was dissolved ~n 99 °~o EaOH (30 ml) and hydrogenated using Pd/C (10 %, 10 mg) at 1 bar pressure. 'The mixture vva~~ filtered through a pad of CeliteT"" and the solvent was removed under reduced pressure yielding 174 mg (100 %) of 5-chloro-cyclohexyV-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals. The product w<~s transformed by Method F. M.p. 100-105 °C.
Compound 81 3-Cyclohexyl-8-(3-methoxyphenyf)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide Synthesis as for compound 80 (using 3-methoxyphenylbc:~ronic acid for the Pd-cat. cross coupling). M.p. 108-115 °C:;.
Compound 82 3-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-b'-(dihydraxyboryl)-l,a?-a'ihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a solution of 5-chlo~ro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 80) (0.60 d, 2.0 mmol) in dry Tf-IF (15 ml) at -78 °C was added s-BuLi in cyclohexane (1.3 M, 3.l3 ml, 5 mmol) under N,~. The yellow mixture was stirred for 15 min at -78 °C and B(OCH3)3 (0.57 ml, 5 mmol) was added. The ccaoling bath was removed and the mixture was allowed to warm to 0 "C and stirred for another 1 h. The mixture was hydrolysed with hydrochloric acid (0.5 M, 12 rnl) and extracted with EI:OAc (2 x 50 ml), dried (Na2S04) and evaporated to dryness to give 0.65 g {95 °,~o) of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.
5-Chloro-;3-cyclohexyl-~~-(2-pyridyl)~-1,2-dihydra-P,2,4-benzofhiadiazine-1,1-dioxide: A mixture of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl;i-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440 mg" 1.28 mmol), ~'--bromopyridine (0.14 ml, 1.50 mmol), Pd(PPh3)2Clz (10 mg, 2 mol %) in 1,2-dirnethoxyethane (30 ml) and Na2C0;, (2M, 3 ml, 6 mrnol) were refluxed under N2 for 24 h. The solvents were removed under reduced pressure and the residue was treated with saturated NH4C1 (10 ml) and extracted with EtOAc (2 x 40 nol). The organic layer was washed with water (20 ml), dried (NalS04) and the solvent was remcpved under reduced pressure. The product was purified by flash chromatography on Si02 using EtOAc:n-hexane (2.1, v/v) as eluent, yielding 280 mc~ (,58 °/>) of 5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-3o benzothiadiazine-1,1-dioxide as colorless crystals.
3-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-fetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (82): 5-chioro-3-cycfohexyl-8-(a?-pyridyl)--1,2-dihydro-1,2,,4-benzothiadiazine-1,1-dioxide (0.268 g, 0.713 mrnol) was dissolved in 99 % EtOH (50 rnl) and hycarogenated using Pd/C
(10 %, 10 mg) at 4 bar pressure for 24 h. The mixture was filtered through a pad of CeliteT"" and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 ml) and washed with phosphate buffer (pH=7, 10 ml), dried (NazSO4) and the solvent was removed under reduced pressure, yielding 20() mg (82 %) of 3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide a:~ colorless crystals. The product was further transformed by Method F M.p. 200-203 °C.
Compound 83 3-Cyclohexyl-8-methoxy-1,2,3,4-tetrahyd ro-1,2,4-benzoth iadiazi ne-1,1-dioxide m-Anisidine was used as starting material for the following transformation sequence: Method B (2-amino-6-methoxybenzenesulfonamide was separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtC:)Ac/hexane)] and then Method G
(using cyclohexanecarboxaldehyde). M.p. 221-223 °C.
Compound 84 5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobenzenesulfonamide (;see compound 125) was transformed by Method G {using ethylformiat and a catalytic amount of triethylamine). M.p. 289-292 °C.
Compound 85 and compound 86 3-Cyclohexyl-2-methyl-T-morpholinosulfonyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (85) and 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazinc~-1,1-dioxide (86) 3-Cyclohexyl-7-morpholinosulfonyl-?~2-dihydro-?,,2,4-benzothiadiazine-?, ?-dioxide: 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarborryl chloride) and Method A (using morpholine as amine) which gave 3-cyclohexyl-7-morpholinosulfonyl-1,,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.
3-Cyclohsxyl-2-methyl-7-morpholinasulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,?-dioxide and 3-cyclohexyl-4-methyl-7-morpholincrsulfonyl-?,2-dihydro-?,2,4-benzofhiadiazine-1, ?-dioxide: A mixture of 3-cyclohexyi-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (2 g; 5 mmol), DEAC> (2.35 ml; 15 mrnol), PPh3 (4 g; 15 mmol) in dry THF (30 ml) was cooled to 0 °C and added MeOH (1.25 ml; 30 mmol). The reaction mixture was stirred over night at rt., evaporated to dryness, stirred with EaOAc and filtered. The isolated precipitate was stirred with CH2C12 and filtered to leave the 2-methyl isomer in the filtrate and the 4-methyl isomer as the precipitatE:.
The 4-methyl was purified by recrystalizalion from DMSO/H2O. The 2-methyl isomer was 5 purified by column chromatography (EtOAcl.
3-Cyclohexyl-2-methyl-7-rnorpholinosulfon yl-1,~, 3, 4-tetrahydro-1,2, 4-benzothiadiazine-1,1-dioxide (85): 3-Cyclohexyl-2-methyl-7-morpholir~osulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced by use of method F. M.p. 243-245 "C.
3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahyc:fro-1,2,4-benzofhiadiazine-1,1-dioxide (86): 3-CycIohE~xyl-4-methyl-7-morpholinosulfonyi-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced by use of method F. M.p. 207-210 °C.
Compound 87 7-Methylsulfonylamin~o-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 1,2,3,5-tefrahydrobenz~[eJpyrralo/2,1-cJ-1,2,4-ihiadiazine-5,5-dioxide: 2-Aminobenzene-sulfonamide was transformed by Method E (uaing 4-chlorobutanoyl chlaride).
7-Nitro-1,2,3,5-tetrahydrobenzo~eJpyrrolo(2,1-cJ-1,2,4-thiadnzine-5,5-dioxide:
A stirred solution of 1,2,3,5-tetr.ahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (222 mg; 1 mmol) in H2S04 (2 ml) at 5 °C was added a solution of KNO3 (122 mg; 1.2 mmol) in H2S04 (2 ml). The reaction mixture was allowed to warm up to rt. and stirred for 2h.
The reaction mixture was poured into ice water, filtered and air dried to give 190 mg {71 %) product.
7-Amino-1,2,3,5-tefrah.ydrobenzo[e~pyrrolo(2,1-~c)-1,2,4-thiadiazine-5,5-dioxide: A stirred solution of 7-nitro-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-7,2,4-thiadiazine-5,5-dioxide (167 mg; 0.6 mmol) in dry THF (2 ml) at -50 °(~ was addeca LiAIH4 (115 mg; 3 mmol) in one portion. The reaction mixture was allowed to warm up to rt, and stirred over night. The reaction mixture was quenched by addition of H20 and 10 M NaOH, stirred, filtered through celite and evaporated to dryness to give 150 mg product.
7-Methylsulfonylamino- i,2,3, 3a,4,:i-hexahydrobErnzo~e/pyrrolo(2, l -c(-1,2,4-thiadiazine-5,5-dioxide (87): A stirre~~ solution of 7-amino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c~-1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mrnol) and triethylamine (70 pl;
0.5 mmol) in THF
(1 ml) was added a solution of CH3S02C1 (4~0 lal; 0.5 mmol) in THF (1 ml) and stirred at rt.
over night. The reaction mixture was evaporated to dryness, suspended in H20 and extracted by EtOAc. The combined organic fractions were evaporated to dryness.
Column chromatography gave ~10 mg product. M.p. 177-180 °C.
Compound 88 7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c~-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonarnide was used a:~ stari:ing material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using 0.5 M
NH3 in THF as amine), Method F (using LiAIH4 and rt.). M.p, 260-262 °C.
Compound 89 7-Methylsulfamoyl-1,:?,3,3a,4,5-hexahydrobenzo[e]pyrroio[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using methylamine as amine), Method F (using LiAIH4 and rt.). M p. 244-245 °C.
Compound 90 7-Cyclohexylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e] pyrrolo[2,1-c]-1,2,4-th iadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyll c:hloride), ME=thod A (using cyclohexylamine as amine), Method F (using LiAIH4 and rt.). M.p. 195-197 °C.
Compound 91 7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesuifonamide was used as startnng material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using dimethylamine as amine), Method F (using l_iAIH4 and rt.). M.p. ;?40-243 °C.
Compound 92 7-Methylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as si:arting materia:~l for the following transformation sequence: Method E (using 4~chlorobutanoyl c:hloride), Method A (using methylamine as amine). M.p. 244-247 °C.
Compound 93 7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo[e)pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was transformed by Method E (using 4-chlorobutanoyl chloride) and Method A (using dimethylamine). M.p. 251 ~~2~53 °C.
Compound 94 7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrabenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl <:hloride), Method A (using cyciohexyiamine as amine). M.p. 151-153 "C.
Compound 95 7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonarnide was used as starting material for the following transformation sequence: Method E (usinc) 4-chlorobui:anoyl chloride), Method A (using 1,2,3,6-tetrahydropyridine as amine). M.p. 204-206 "c;.
Compound 96 3-Bicyclo[2.2.1]hept-!5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2,4-Dimethylaniline was used as si:arting material for the following transformation sequence:
Method B, Method G psing a racemic endoi'exo mixture of bicyclo[2.2.1 ]hept-5-ene-2 carboxaldehyde. Column chromatography gave two diastereomeric fractions each being a mixture of two diastereomers~. Isomeric mixture b, m.p. 160-165 °C;
isomeric mixture B, m.p.
182-187 °C.
Compound 97 3-Cyclohexyl-7-(N,N-diethylsulphamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide io 3-Cyclohexyl-7-(N,N-diethylsulpharno~yl)-5-formyl-1,2-dihydrc7-7,2,4-benzothiadiazine-1,1-dioxide: 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cy<;Ic7hexanecarbonyl chloride) and Method A
(using diethylamine as amine). The product from this transformation (0.60 g, 1.5 mmol) dissolved in dry THF (1:5 rnl) at -78 °C was added s-BuLi in c;yclohexane (1.3 M, 2.5 ml, 3.2 mmol) under N2. The yE:llow mixture was stirred for 25 min at ~-78 "C. The reaction was quenched with dry DMF (0.3 ml, 4 mrnol) and'rhe mixture was stirred for 20 min at -78 °C. The cooling bath was removed and the mixture was allowed to warm to 0 °C.
Hydrochloric acid (0.5 M, 10 ml) was added and the mixture was extracted with EtOAc (40 ml). The organic layer was washed with brine (10 ml), dried (Na2SO4) and evaporated to dryness.
The residue 2o was dissolved in acetone (8 ml). Et2C> (30 ml) waa added and within few minutes the product crystallises, yielding O.~t1 g (64%) of 3-cyclahexy6'-7-(N,N-diethylsulphamoyl)-5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
3-Cyclohexyl-7-(N, N-di~efhylsulphamoyl)-5-me thyl-1,2,3, 4-tetrahydro-1,2, 4-ben2othiadiazine-1,1-dioxide (97): 3-Cyclohexyl-7~-(N,N-diethylsulphamoyl)-5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.20 g, 0.46 rnmol) was dissolved in 99 % EtOH
(60 ml). One small drop of concentrated hydrochloric acid vvas added to ensure fully hydrogenation. The mixture was hydrogenated using PdiC (10 '%, 10 mg) at 4 bar pressure for 24 h.
The mixture was filtered through a pad of CeliteT"" and evaporated to dryness. The residue was dissolved in EtOAc (50 ml) and washed with water (10 nnl}, dried (Na2SO4) and evaporated to dryness yielding 0.18 mg (95%) of 3-cyclohexyl-7-(N,hJ-~liethylsulphamoyl)-5-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless po~nrde~r. The product was further transformed by Method F'. M.p. 206-208 "C.
Compound 98 3-Bicyclo[2.2.1 ]kept-5'-en-2'-yl-5,7-Biphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3,5-Dibromo-2-aminobe;nzenesulfonamide (see compound 125) was transformed by Method H (using phenylboronic acid) and Method Ca (using a, racemic endo/exo mixture of bicyclo[2.2.1]hept-5-ene-2-carboxaidehyde). M.p. 222-225 °~~.
Compound 99 3-Bicyclo[2.2.1]hept-5'-en-2'-yi-5,7-disulfamoyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was transformed by Method A (using 25% NHg (aq.) as amine) and Method G (using using a racemic endo/exo mixture of bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde). M.p. 172-180 "C.
Compound 100 3-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2,4-Dichloroaniline was transformed by Method B and Method G (using a racemic endo/exo mixture of bicyclo[2.a?.1 Jhept-5-ene-2-carboxaldehyde. The product was isolated as a diastereomeric mixture). M.p. 149-151 °C.
Compound 101 5-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-sulfamoylbenzenesulfonamide: A :>tirred suspension of 2-amino-4-chloro-5-sulfamoylbenzenesulfonamide (11.4 g; 40 mmol) and 10°/a Pd/C (750 mg) in EtOH (300 ml) was hydrogenated at 1 bar until hydrogen consumption ceased (24 h). The reaction mixture was evaporated to dryness, resuspended in THF and filtered through celite. The filtrate was evaporated to dryness and the isolated solid washed with boiling EtOAc (2x 150 ml) to give 9.58 g (95%) product.
2-Amino-3-bromo-5-sulfamoylbenzenesulfc>namide: A stirred solution of 2-amino-sulfamoylbenzenesulfonamide (3.77 g; 15 mmol) in AcOH (50 ml) was added a solution of Br2 (0.78 ml; 15 mmol) in AcOH (10 ml). The reaction mixture was heated to 70 °C for 6 days, evaporated to dryness, resuspended in MeOf-I (85 ml) and added solid KOH (3.8 g; 68 mmol).
The reaction mixture was heated to 60 °C for 2.5 h (hydrolysis of 3-methyl-, 3-bromomethyl-, 3-dibromomethyl and ~s-tribromomethyl-1,2-dihydro-i ,2,4-bEanzothiadiazine isomers formed in 5 situ), filtered, neutralized and evaporated to dryness. Column chromatography gave 3.1 g (63%) product.
5-Broma-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tef~ahydro-1,2,4-benzothiadiazine-1,1-dioxide (i01): 2-Amino-3-bromo-5-sulfamoylbenzene~sulfonamide was transformed by Method G
7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Methylsulfamoyl-1,2, 3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Cyclohexylsulfamoyl-~1,2,3,3a,4,5-hexahydrobenzo[ e] pyrrolo[2,1-c[-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrober~zo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Methylsulfamoyl-1,2,:3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1, 2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-y-1,2,4-th iadiazine-5,5-dioxide;
7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,'1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4 thiadiazine-5,5-dioxide;
3-Bicyclo[2.2.1 jhept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyt-7-(N,N~iiEahylsulphamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 jhept-5'-en-2'-yl-5,7~-diphenyl-1,2, 3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-5,7-disulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1 ]hept-5'-en~-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5-Bromo-3-cyclohexyl-~'-sulfamoyl-1,2,3,4-tetr,ahydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-6,8~-dibromo-1,2,3,4-tetrahydroquinazoline;
2-Bicyclo[2.2.1 ]kept-5'-~en-2'-yl-6,8-dibromo--4-oxo-1,2,3,4-tetrahydroquinazoline;
3-Bicyclo[2.2.1 ]hept-5'-.en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5,7-Dibrorno-3-bicyclo[a?.2.1 ]heptan-2'-yl-1,2,3,4-tetrahydro-"I ,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-5,7-dibrorno-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Phenyl-;5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
75 3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-5,7-dibromo-1,2-dihydro-7 ,2,4-benzothiadiazine-1,v-dioxide;
3-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4~-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-;7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide ;
3-Cyclohexyl-6-methyl-;7-sulfamayl~-1,2,3,4-tetrahydro-1,2,4-h~enzothiadiazine-1,1-dioxide;
3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,;?,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-;~-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-meth~oxyphenyl)-7-methyl-1,2.3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methoxy-T-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;3-Cyclohexyl-6-chioro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Phenyl-Fi-chloro-7-sullramoyl-1,2,3,4-tetrahydr<>-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-bromo-T-piperidinosulfonyl-1,2 ,3,4-tetrahydrc>-1,2,4-benzothia-diazine-1,1-dioxide;
2-cyclohexylmethylamino-5-N,N-dimethylsulfannaylbenzenesulfonamide;
WO 99,/42456 PCT/DK99/00070 2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzene sulfonamide;
3-Isobutyl-8-(piperidinos;ulfonyl)-2,3,4, 5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide;
3-Cyclohe:Kyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-cyciopentylsulfinyl-1,2,3,4-tetrah~rdro-1,2,4-benzothiadiazine-1,1-dioxide; or 3-Cyclohe:Kyl-7-cyclopentylsulfinyl-~1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide or a pharmaceutical acceptable salt thereof.
Pharmaceutically Acceptable Salts The chemical c:ompounc~ of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e.
physiologically) acceptable salts, and pre- or prodrug forms of the chemical c:;ompound of the invention.
Examples of pharmaceutically accE;ptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the acetate derived from acetic acicl, the aconate derived from aconitic ,ac:id, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the formate derived from formic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobrornic acid, the lactate derived from lactic acid, the maleate derived from malefic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulfonate derived from methane sulphonic acid, the naphthalene-2-suiphonate derived from naphtalene-2-sulphonic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric: acid, the phthalate derived from phth~lic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the :~uccinate derived from succinic acid, the sulphate derived from sulphuric acid, the tartrate derived from tartaric acid, the toluene-p-sulphonatEl derived from p-toluene sulfonic acid, and the like. Such salts may be formed by procedures well known and described in the art.
W
Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be u:>eful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemic<~I compouryd of the invc.~ntion containing a carboxy group.
The chemical compound of the irrvention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvents such as water, ethanol, and the like. Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate:, the tetrahydrate, and the like. In general, l:he dissoluble forms are considered ~ecfuivaient to indissoluble forms for the purposes of this invention.
Definitions of substituents:
Halogen is fluorine, chlorine, bromine, or iodine.
Alkyl means a straight chain or branched chain of from one to six carbon atoms or cyclic alkyl of from three to seven carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl; methyl, ethyl, propyl and isopropyl are preferred groups.
Haloalkyl means alkyl as above substitutecl one or more times with halogen as defined above. Preferred embodiments arE: CF3, C2F5, (:;H2CI, CHCI;a, -CHFCH2F, -CHCICH2CI;
Cycloalkyl means cyclic alkyl of from three to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclahexyl, cycloheptyl.
Cycloalkylalkyl means cyclic alkyE as above arid alkyl as above wherein the alkyl can be regarded as a substituent on the cycloalkyl and vice versa . Preferred groups are C3_s-cycloalkyl and C,_4-alkyl such as -(CH2)-cyc:lopropyl, -cyclopropyl-(C,_4-alkyl), -(CH2)~ -cyclohexyl, -cyclohexyl-(C,.4-alkyl), (C,.4-alkyl)-cyclobutyl, -cyclobutyl(C,_4-alkyl) -(C,_4-alkyl)cyclopentyl, -cyclopentyl(C,_4-alkyl), -(C,_4-alkyl)cyclohE=xyl, cyclohexyl(C,_4-alkyl);
WO 99/42456 PCT/DK99/000'70 Halocycloalkyl means cyclic alkyl as above which is substituted with one or more halogen as above, including but not limited to chlorocycfopropyl, fluorocyclopropyl, iodocyclopropyl, dichlorocyclopropyl, difluorocyclopropyl, chlorocyclobutyl, fluorocyclobutyl, chlorocyclopentyl, fluorocyclopentyl, iodocyclopenyl, chlorocyclohexyl, fluorocyclohexyl, dichlorocyclohexyl, difluorocyclohexyl, iodocyclohexyl. Preferred embodiments are mono- and di-substituted cycioalkyl of 3 to 1:> carbons, such as dichlorocyclopropyl, difluorocyclopropyl, chlorocyclohexyl, fluorocyclohexyl, iadocyclohexyl, chlorocyclopentyl, fluorocyclopentyl.
Alkenyl means a straight chain ar branched chain of from two to six carbon atoms containing one double bond, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.
Alkynyl means a straight chain or branched chain of from two to six carbon atoms containing one triple bond, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
Alkoxy is O-alkyl, wherein alkyl is as defined above.
Alkoxyalkyl is -alkyl-O-alkyl, wherein alkyl is as defined above.
Hydroxyalkyl is alkyl as. defined above substituted with OH;
Amino is NH2 or NH-alH;yl or N-(alkyl), wherein alkyl is as defined above.
Alkylamino is alkyl as defined above whrch is substituted with amino as defined above.
Preferred embodiments are -CHI-N(alkyl)z, -C;Fi-N(alkyl)2CH;~, -CH2CH2 N(alkyl)2, -CH2-NH2, -CH-(NHS)-CH3, -CH2Chl2 NHS>~
Cyano is CN;
Cyanoalkyl is alkyl as clefined above substituted with CN;
Nitro is -N02;
Nitroalkyl is alkyl as defined above subsituted with vitro as defined above;
Thio is SH or S-alkyl, wherein alkyl is as defined above;
Alkylthio is alkyl as above substituted with a thin group which is as defined above.
Acyl is (C;=O)-R° or (C=S)-R° wherein R° is alkyl; phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF3, N02, amino, alkyl, alkoxy, phenyl and S02NR'R" wherein R' and R" each independently are hydrogen or alkyl or wherein R' and R" together ~s (CH~)n, wherein m is 2, 3, 4, 5 or 6;
or R° is benzyl; or NR"' Rw wherein R"' an~~ R'v each independently are hydrogen or alkyl or wherein R~° and R'v together is (CH2)P wherein p is 2, 3, 4, 5 or 6.
Acylamino is acyl-NH- wherein aryl is as defined above.
Aryl is aromatic carbocycles such as phenyl or biphenyl and fused carbocycles such as naphtyl;
HET is an 5- to 6-membered cyclic heteroaryl and include: for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxa:zol-3-yl, isoxazol-4-yl, iso:xazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazal-3-yl, isolhiazol-4-yl, isothiazol-5--y1, 1,2,4-ox:adiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiacfiazol-5-yl, 1,2,5~-oxadiazol~-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidaz:olyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thiE:nyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrirnidinyl, 3-pyrictazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl, furanyl, tetrahydrofuranyl, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl, pyridyl, thieroyl, isooxazolyl, pyrimidyl, pyrazole, triazoiyl.
Especially preferred heteroaryl of the invention are pyridyl, pyrimidyl, triazole, furyl, thienyl, oxadiazolyl, imidazolyl;
A carbocyclic 7- to 12- membered ring structure includes mono- bi- and tricyclic structures.
Preferred embodiments are 7- to 10 membered ring structures such as WO 99I'42456 PCT/DK99/00070 $$
1~7 ~7:i~ ~J~ ~W L~ ~~
'~CW '~ ! ~~: ~
a heterocyclic 3- to 8 membered ring structure includes a partly or completely saturated heterocyclic ringstructure such as aziridine, pyrrcslidine, piperidine, piperazine, homopiperidine, homopiperazine, azacyclooctane, 1,.3-diazacyclooctane, 1,4-diazacyclooctane, tetrahydrofuran, tetrahydrothiophene, mc:~rpholine, tetrahydropyridine, and compounds such as N
N N
l The preferred embodiments are 5- to 6-membered rings containing at least one nitrogen such as pyrrolidine, piperidin~~, piperazine, morpholinc;, tetrahydropyridine.
The described 4- to T-membered rings fused to the ring structure of formula I, formed between the substituents R' and R3 or R3 and R4 or RS and R6 or R6 and R' or R' and R8 are carbocyclic rings optionally containing a heteroatom and optionally containing a carbonyl group. PrE;ferred rings are 5- and F-membered c:arbocyclic rings;
The rings formed between the substituents R' and R6 or Rg are 5- or 6-membered and containing O, C=O, S=O, or S02-groups and optionally containg nitrogen.
Preferred rings are -O-(CH2)n-O-; wherein n is 1, 2 or 3; -SC)z-NR-(CH2)n-wherein n is 1 or 2;
-SO-NR-((:,Hz)n- wherein n is 1 or a?; -S02-(CH2)n- wherein n is 2 or 3; -SO-(CH2)n- wherein n is 2 or 3; -CO-CH=CH-NH-;-CO-CH=CH-O-; -C;O-(CH2)~-Nlwl- wherein n is 1 or 2; -CO-NH
(CH2)~ wherein n is 1 or 2; -CO- (CH2j2-O-;
The compounds of this invention rnay exist in unsolvated ,:~s well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to tf-re unsolvated forms for the purposes of this invention.
Steric Isomers The chemical compounds of the ;present invention may exist in (+) and (-) forms as well as in racemic forms. Thc: racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
Racemic forms can be resolved intca the optical antipodes by known methods and techniques. One way of separating the diastereomeric salts is by use of an optically active acid, and liberating thc: optically active amine compound k:~y treatment with a base. Another method for resolving racemates into the optical antipodes as based upon chromatography on an optical active matrix. Racemic cc>mpound:> of the present invention can thus be resolved into their optical antipodes, e.g., by fractional) crystallisation of d- or I-(tartrates, mandelates, or camphorsulphonate 1 salts for example.
The chemical compounds of the present invention rnay also be resolved by the formation of diastereomeric amides by reaclion of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglyc:ine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical cc:~mpound of the present invention with an optically active chloroformate or the like.
Additional methods for the resolvinca the optical isomers are known in the art.
Such methods include those described by Jaques J, Collet A, & tNilen S in "Enantiomers, Racemates. and Resolutions", John Wiley and Sons, New Fork (1981 ).
Moreover, Borne of thE: chemical compounds of the invention being oximes, may thus exist in two forms., syn- and anti-form {Z- arid E-form), depending on the arrangement of the substituents around the -C=N- double band. A chE>mical compound of the present invention may thus be vthe syn- or the anti-forrn (a?- and E-form), or it may be a mixture hereof.
A compound of the invention includes endo- and exo-forms and tautomers where possible.
Pharmaceutical Comaositions An aspect of the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention and the use of compounds of the invention for the manufacture of a medicament for the treatment of specific: diseases or disorders;
White a chemical compound Gf the inventican for use in therapy may be administered in the fornn of the raw chemical compound, it is preferred to introduce the active 5 ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adju~dants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliarie s.
In a preferr~ad embodirnent, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or 10 derivative thereof, tagethc:r with one or mare taharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients. The carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
Pharmaceutical compositions of the invention may be those suitable for oral, 15 rectal, bronchial, nasal, topical (including buc~aal and sub-lingual), transdermal, vaginal or parentera'I (including cutaneous, subcutaneous, intramusc:ular, and intravenous injection) administration, or those in a form suitable for administration by inhalation or insufflation.
The chemical compound of the irtvE:ntion, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit 20 dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and Liquids, in p;~rticular aducyous or non-aqueous solutions, suspensions, emutsions~, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in 25 conventional proportions, with or without additional active ccampounds or principles, and such unit dosage forms may contain any suifab~le effective aamount of the active ingredient commensurate with the intended daily dosagE: range to be employed.
The chemical compound of the present invention can be administered in a wide variety of oral and pare~nteral dosage forms. It will be obvious to those skilled in the art that 30 the following dosage forms may comprise, as the activc:a component, either a chemical compound of the inveni:ior~ or a pharmaceutically acceptably-w salt of a chemical compound of the invention.
For preparing pharmaceutical c;ornpositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or mare substances which may also act as diluents, flavouring agents, solubilizers~ lubricants, suspending agents, binders, preservatives, tablet di~~integrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, tihe active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
The powdeirs and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are m<~gnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dexkrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa: butter, and the like.
The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus; in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitablE: for oral administration.
For preparing suppositores, a low rr~elting wax, such as a mixture of fatty acid glyceride or cocoa butter" is first melted and the <:~ctive component is dispersed homogenE~ously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid preparations include solutions., suspensions, and emulsions, for example, water or water-propyler7e glycol solutions;. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
The chemical compounc:i according to the f:~resent invention may thus be formulated for parenteral administration {e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion car in mult~-dose c:oratainers with an added preservative. The compositions may take such forms as suspen.;ic>rrs, solutions, or emulsions in oily or aqueous vehicles, and may cont<~in formulation agents such as, suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization fronn solution, for constitution with a suitable vehicle, e.g. s~lerile, pyrogen-free wager, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water arid adding suitable colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use cart be rnade by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymei:hylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsion;. These preparations may contain, in addition to the active component, colorants, flavours;, stabilisers, buffers, artificial and natural sweeteners., dispersants, thickeners. solubilizing agents, arid the like.
for topical administration to the epidermis the chemical compound according to the invention may be formulated as ointmenla, creams or lotions, or as a transdermal patch.
Ointments and creams. may, for example, be formulated wish an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
Compositions suitable for topicaG~ administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth;
pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose .and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper. pipette or spray. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
In the case of a spray, this may be achieved' for example by means of a metering atomising spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroEatt~ane, carbon dioxide, or other suitable gas.
The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients rnay be provided in the form of a dry powder, for example a powder mix of the compounc9 in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and poiyvinylpyrrolidone (PVP). Gonveniently the powder carrier will form a gel in the nasal cavity.
The powder composition may be presented in unit dose forim for example in capsules or cartridges of, 1o e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
In composil:ior7s intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by microrrization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharm<~ceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. Thc~ unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit do:~age form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desored.
The active ingredient rnay be adrninistered in one or several doses per day. A
satisfactory result can, in certain instances, bf; obtained at a dosage as tow as 0.1 pg/kg i.v.
and 1 pg/kg p.o. The upper limit of the dosage r;~nge is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.1 pg/kg to about 10 mg/kg/day i.v., and from about 1 yg/kg to about 100 mg/kg/day p.o.
Method of Treating The compounds of the present invention are ,AMPA receptor stimulators and therefore useful for the treatment of a range of disorders or diseases responsive to AMPA
receptor modulators. As en embodiment of the invention the disease are responsive to positive modulation of the AMF'A receptor. The compounds may be used in the treatment, prevention, profylaxis or alleviation of a disease, disorder or condition crf the central nervous system as for example: neurodegenerative disorders, cognitive or memory dysfunction, memory and learning disorders, attention disorder, learning and memory disorders resulting from ageing, 1o trauma, stroke, epilepsy; Alzheimer's disease, depression, schizophrenia, memory loss, AIDS-dementia, senile dementia, learning deficit, cognition deficit, sexual dysfunctions, psychotic; disorder, se>cual dysfuncaion, intellectual impairment disorders, schizophrenia, depression or autism, .attention deficit, or a disorder or disease resulting from neurotoxic agents, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia;
Suitable dosage range are 0.1-X00 milligrams daily, and especially 10-70 milligrams daily, administered once or twice a day, dependent as usual upon the exact mode of administration, form in wtuch administered, th,e indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
I.p. means intraperetoneally, which is a well known route of administration.
P.o. means peroral, which is a well known route of administration.
The invention then cornprises the following alone or in combination:
The use of a compound as above wherein the disease to be treated is responsive to the AMPA receptor modulation.
The use of a compound as above for the manufacture of a medicament for the treatment of disease which are responsive to the AMPA receptor modulation.
The use as above whE~rem the disease is memory and learning disorders, psychotic disorder, sexual dysfunction, intellectual impairment di:,c~rders, schizophrenia, depression or autism;
Alzheimer's disease, learning deficit, attention deficit, memory loss or senile dementia; or a disorder or disease resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorder, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia;
Bialoety In vitro inhibition of ~sH-AMPA binding 1o L-glutamate (GLU) is the major excitatory neurotransmitter in the mammalian central nervous system. Frorn eiectrophysiological- and binding studies, there appear to be at least three subtypes of GLU receptors, tentatively named N-methyl-D-aspartate (NMDA)-, quisqualate-and kainate receptors. Gl_U receptor subtypes sE:nsitive to quisqualate and kainate as a group are often referred to as non-NMDA receptors. Receptor binding studies using the 15 labelled agonists 3H-AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (for quisqualate receptors) and ~H-kainate (for kainate receptors) have shown different antagonist selectivities and regional distribution. AMPA has been known for several years to be a potent and selective agonist at the traditionally named quisqualate receptors.
Activation of quisqualate receptors by AMPA is associated with Na' influx and K' efflux leading to 2o depolarizatian.
The non-IVMDA receptors have recently been re<;lassified to include the quisqualate activated metabotropic receptor hype, linked to the inositol triphosphate and diacylglycerate me-tabolism. AMPA does not interact with the metabotropic quisqualate receptor but only the 25 ionotropic quisqualate receptor. SE:lective activation of the metabotropic type has been claimed for trans-ACPC). f-iecentfy, the potent and competitive non-NMDA
receptor antagonists CNQX and NBQX have been described, and CNOX have been reported not to block the effect of quisc~ualate at the metabotropuc receptor subtype. 3H-AMPA
is a selective radioligand for labelling the ionotropic quisqualate (AMPA) receptors.
TISSUE PREPARATION
Preparations are performed at 0-4"C unless otherwise indicated. Cerebral cortex from male Wistar rats (150-200 g) is homogenized for 5-1C) aec in 20 rrrl Tris-HCI (30 mM, pH 7.4) using an Ultra-Turrax homogE~nizer. The suspension is centrifuged at 27,000 x g for 15 min and the pellet is washed three times with buffer {centrifuged at 27,0()0 x g for 10 min). The washed pellet is homogenized in 20 ml of buffer anct incubated an a water bath (37°C) for 30 min to remove endogenous glutamate and then centrifuged for 10 min at 27,000 x g. The pellet is then homogenized in buffer and centrifuged at: far 10 min at 27,000 x g. The final pellet is resuspended in 30 ml buffer and the preparation is frozen and stared at -20°C.
ASSAY
The membrane preparation is thawed and centrifuged at 2°C for 10 min at 27,000 x g for 10 min. The pellet is washed twice with 20 ml 30 mM Tris-HCI containing 2.5 mM
CaCl2, pH 7.4 using an Ultra-Turrax homogenizes and centrifuged for 10 min at 27,000 x g.
The final pellet is resuspended in 30 mM Tris-HCI containing a?..5 mM CaCl2 and 100 mM KSCN, pH
7.4 (100 ml per g of original tissue) and used for binding assays. Aliquots of 0.5(0.2) ml are added to 25(20) NI of test solution and 25(20) pl of 3H-AMF'A (5 nM, final concentration), mixed and incubated for 30 min at 2"C. Non-specific binding is determined using L-glutamate (0.6 mM, final concentration). After incubation the 550 yl samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibre filters under suction and immediately washed with 5 ml ~of ice-cold buffer. The 240 pl samples are filtered over glass fibre filter using a Skatron cell harvrester. The filters are washed with 3 ml ice-cold buffer. The amount of 2o radioactivity on the filters is determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.
RESULT S
The test value will be given as the ICso (the concentration (NM) of the test substance which inhibits the specific binding of 3H-AMPA by 50°/a) Test results The compound numbers refer to the table below.
Compound -._ ICS( (pM) _ - 22.0 14 45.0 15 ~ 39.0 ~~ 44 ~ 3.5 47 _ ~ 5.3.
SUBSTITUTE SHEET (RULE 26~
~7 48 ~ 4.4 ~
49 17.0 - i ~7 26.0 ~
58 3.4~
~
Ei 1 8.5 Ei2 6.0 Ei3 ~ 6.0 ~
113 13.(:) 114 ~ 33.(:1 ~
115 7.0 F~otentiation ofi AMPA induced f3HIGABA release from cultured cortical neurons Neurons which express receptors for excitatory amino acids can be depolarized by such compounds and this depolarization will ultimately lead to a release of transmitter substance from the neurons. Cultured neurons obtained from 16-day-old mouse embryo cortex are mainly GABAergic andl express all types of excitatory aminc:~ acid receptors.
This means that they can be stimulated by high potassium (55 mM) or by the excitatory amino acids NMDA
(20 NM), AMPA (5 NM) and kainate (5 NM) to release their neurotransmitter GABA.
3H-GABA may be used to label the GABA transmitter pool in the neurons and the release of 3H-GABA from the neutrons may be used as a simple functional model for studies of the effects of excitatory amino acid receptor agonists, antagonists, and modulators.
METHODS
Cell cultures Cerebral cortices of 15-16 day-old NMRI mouse embryos are chapped in 0.4 x 0.4 mm cubes and the tissue is dissociated by mild trypsinization (0.1 % (wt/vol) trypsin, 37°C, 10 min).
Subsequently the cell suspension (3 mill/ml) is inoculated into poly-L-lysine-coated 30 mm Petri dishes (3 ml/dish;l containing a slightly modified DMEM (24.5 mM KCI) supplemented with p-aminobenzoate (7 pM), insulin (100 mlJ/L) and 10% (vol/vol) horse serum. Cells are maintained in culture fnr 5-7 days with the addition of the antimitotic agent cytosine SUBSTITUTE SHEf=T' (RULE 26) arbinoside (5 NM) from clay 2 in vitro to prevent glial proliferation. For further details and references, see Drejer et al. (Exp. Brao Res. 47, 259 (1982)).
Release experiments Release experiments am performed using the model described by Drejer et al.
(Life Sci. 38, 2077 (198(i)). Cerebral cortex neurons cultured in Petri dishes (30 mm) are added 100 mM y-vinyl-GAGA one hour before the' experiment: in order to inhibit degradation of GAGA in the neurons. 30 min before the experiment 5 uCi 3H-GABA is added to each culture.
After this preloading period the cell monolayer ai the bottom of the dish is covered with a piece of nylon mesh to protect the cells against: mechanical damage and to facilitate dispersion of medium over the cell layer. The prE:loading medium is removed and the Petri dishes are placed in a s!uperfusion system consisting of a peristaltic pump continuously delivering thermostated 37°C superfusion mediium (HEPES buffered saline (HBS): 10 mM
HEPES, 135 mM NaCI, 5 rnM KCI, 0.6 mM MgSO.,, 1.0 mM C;aCl2 and 6 mM D-glucose; pH
7.4) from a reservoir to i:he top of the slightly tilted Petri dish. The medium is continuously collected from the lower part of the dish and dE:lirrc~red to a fr;~ction collector. Initially, the cells are superfused with HB;S for 30 min (tlow rate :? ml/min). Then cells are stimulated for 30 sec every 4 min by changinc) the superfusion medium from HBS to a corresponding medium containing 5 NM AMPA in the absence or presence of modulators.
Test subsl:ances are dissowed in 50% DMSO. 48"io ethanol. 'The final DMSO and ethanol concentration in the assay must not exceed 0.1 °>o RESULTS
The induced release of 3H-GAGA (c;pm) is corrected for the mean basal release (cpm) before and after the stimulation and used ror calculation of the test value.
The potentiation of the ~4MPA response by a test substance is expressed relative to the potentiation of the AMPA response induced by c:yclothiazide (30 NM).
Results The result of the test is shown in Figures 1 anc~ 2. The results show significantly increased Figur 1 shows potentiation of AMPA induced '"'H]GAGA release from cultured cortical neurons by compound 115. The patentiation is expressed relative to the potentiation induced by 30 uM cyclothiazide.
Figur 2 shows potentiation of AMPA induced (''H]GABA release from cultured cortical neurons by compound 114. The patentiation is expressed relative to the potentiation induced by 30 NM cyclothiazide.
Voltage Clamp.
METHODS
7 o Experiments were performed in voltage clamp using conventional whole cell patch clamp methods (Hamill et al., 1981 ), essentially as dE~scribed previausly (Mathiesen et al., 1998).
The following salt solutions were used (mM): NaC;I (140), KC;I (4), CaCl2 (2), MgCl2 (1 ), Sucrose (30), Tetrodotaxin (0.0003), Bicuculline Methiodide (0.005) and HEPES
(10, pH 7.4).
Intracellular solution (mM): CsCI (120), CsF (20), MgCl2 (2), EGTA (10), HEPES
(10, pH =
7.2).
Cell cultures Mouse neocortical neurons were cultured essentially as described by Drejer et al. (1987).
Briefly, the forebrains from embryonic (E17} NMRI mice were removed under sterile conditions. The tissue was chopped in 0.4 rnrn ~aubes and the triturated with trypsin (12.5 Ng/ml) and DNAse (2.5 ug/ml), 15 min, 37 °C. The cells were suspended at a concentration of 1 x 106 cells/ml in a slil~htly modified DMEM which contained horse serum (10 % (vlv)), penicillin (333 U/ml), paraaminobenzoic acid (1 mg/ ml), L-glutamine (0.5 mM), insulin (0.08 U/ml) and KCI (23.8 mM). The cell suspension was subsequently inoculated into poly-L-lysine coated 35 mm Petri dishes (2 mlldish). Glass c<averslips (3.5 mm) were placed in the dishes before coating. After 24 hr in culture, the medium was replaced by freshly made medium containing 1 % N2 supplement instead of seruno.
The cells were kept in culture for 7-14 days at 37 °C (5% CO;>/95% O2) before experiments were carried out.
Electronics. programs and data acquisition: The amplifier used was the EPC-9 (HEKA-electronica, Lambrect, Germany) run by a Power Macintosh G3 computer via an interface. Experimentall conditions were set with the Pulse-software accompanying the amplifier. Data were lo~nr pass filtered and samptc~d directly to hard-disk at a rate of 3 times the cut-aff frequency.
Pipettes and electrodes: Pipettes were pulled from borosilicate glass (Modulohm, Copenhagen, Denmark) using a horizontal elecarode puller (Zeitz-(nstrumente, Augsburg, Germany). The pipette resistances were 1.7 - 2.4 MW in the salt solutions used in these experiments. The pipette electrode was a chloridized silver wire, and the reference was a 5 silverchloride pellet electrode (In Vivo Metric, I-lealdsburg, USA) fixed to the experimental chamber. The electrodes were zeroed with the open pipette in the bath just prior to sealing.
Experimental procedurE_ Coverslips were transferred to a l::p ml experimental chamber mounted on the stage of an inverted microscope I;IMT-2, Olympus) supplied with Nomarski optics. The neurons were continuously superfused with extracellular saline at a rate of 2,5 10 ml/min. After giga-seal formation (1-5 GW, success-rate = 9t) %) the whole cell configuration was attained by suction.
The cells were held at a holding voltage of -60 mV and at the start of each experiment the current was continuously measured for at least ;30 sec to ensure a stable leak current.
AMPA-containing solutions were delivered to thE: chamber through a custom-made gravity-15 driven flowpipe, the tip of which was placed approximately 50 pm from the cell. Application was triggered when the tubing connected to the flow pipe wcas compressed by a valve controlled by the Pulse-software. AMPA (30 NM) was applieri for 1 sec every 45 sec. After obtainment of responses of a repeatable amplitude the compound to be tested was included in both the chamber and in the AMPA-containing solution. The compound was present until 20 responses of a new repeatable was obtained.
The sample interval in <~II experiments was 310 Nsec.
All experiments were performed at room temperature (20 - 25 °C).
MATERIALS
25 Pregnant (9 days) NMRI mice were obtained from Bomholtgaard Breeding and Research Center, Ry, Denmark.
Horse serum, N2 supplement and culture media were purchased from Life Technologies (GIBCO), Roskilde, Denmark.
AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolE:propionic acid) was synthesized at 30 NeuroSearch A/S. Tetnodotoxin was purchased from Alomone Labs, Jerusalem, Israel and Bicuculline Methiodide from RBI, MA, USA. Stacrose was from Fluka Chemie, Buchs, Switzerland. All other reagents were from SIGMA, USA.
Results The results are shown in Fig. 3-I.
The compounds 56 (Fig. 3), 63 (Fig. 4), 111(F'ig. 6), 114(Fig. 7) and 115 (Fig. 5) all potentiated the current induced by application of 30 NM AMPA. An example for each compour7d is shown below. It is seen that the potentiation in every case is reversible, even though the effect of 56 and 63 persit.s for several minutes after wash out of the compounds.
The time between AMF'A stirnulations was 45 sec. Scalebars: 63: 200 pA/2 sec;
56: 500 pA/5 sec; 115: 50 pA/2 sec; 111: 400 pA/3 sec; 114: 40 pA/ 3 sec. In the experiments shown the concentration of the compounds was 3 NM (56. 63 and 114) or 10 NM (111 and 115) The effect of the compounds were concentratlion-dependent, as exemplified for 114 below (scale bars 200 pA/ 5 sec).(Fig. 8) REFERENCES
Drejer J., Honore T. and Schousboe A. (1987; f~xcitatory amino acid-induced release of 3H-GABA from cultured mouse cerebral cortex interneurons. J. Neurosci. 7: 2910-2916.
Hamill O.P., Marty A., f~eher E., Sakmann B. ~~r~d Sigworth F.J. (1981 ) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
Pflugers Arch. 39: 85-10C).
Mathiesen C., Varming T. and Jensen L.H. (1!398) In vivo arnd in vitro evaluation of AMPA
2o receptor antagonists in rat hippc>campal neurones and cultured mouse cortical neurones. Eur.
J. Pharmacol. 353: 15~~-1 fi7..
lontophoretic Application PURPOSE
Evaluation of the in vivo effects of positive AMF'A modulators (PAMs) on the AMPA evoked spike activity in rat hipporampus.
PRINCIPLE
Hippocampai single neuron spike activity is strongly influenced by excitatory input, and iontophoretic application of AMF'A induces spike activity in vivo in a dose-dependent manner (Mathiesen ef al. 1998;1. The AMPA evoked spike activity is inhibited by intravenous (i.v.) administration of a wide range of AMPA receptor antagonists (Mathiesen et al.
1998), which indicated that the excitation is primarily mediated via AMPA receptors. PAMs potentate AMPA
receptor activation in vi~'ro, and if this mechani sm also operates in vivo, the i.v. injection of an PAM should enhance AMPA evoked spike activity. Thus, the aim of this study was to test the in vivo effect of a group of in vitro actme PAM;. This have been done by studying their ability to enhances AMPA evoked spike activity after i.v. administration.
PREPARATION
Experiments were performed on male Wistar rat (M & B, Denmark) weighing 280-380 g, housed in two per cage with free access to food and water. The rats were anaesthetised with mebumal (50 mg kg~' i.p.) and the femoral artE~ry was catheterised for the purpose of monitoring blood pressure and the vein for intravenous injection of drugs and continuous injection of 0.9% NaCI (O.p-1.U ml h-'~ and mebumal (5-10 mg h-'). Additional anaesthetic was given i.v. if the rat responded to a pinch of the back foot. The trachea was cannulated and the rats were placed in a stereotaxic frame arid ventilated by a rodent ventilator (Ugo Basile, Comerio-~Jarese, Italy). Core body temperature was maintained at 37.5°C
by a DC heating pad. The left and dorsal part of the parietal bone was removed by craniotomy and the dura was withdrawn exposing the pia mater and underlying brain., covered with 0.9%
NaCI.
COMPOUNDS/REAGENTS
AMPA (Sigma, USA) was dissolved at 10 mM in 0.2 M NaCI. NMDA (Sigma, USA) was dissolved at 100 mM in 100 mM NaCI. Both solutions were adjusted to pH 7.5-8.0 with NaOH.
COMPOUND 61 was diissolved in a'_O~J mM CH3;>O 3- Na' at <:r contration of 10 mM for iontophoretic application (pH 5.7) and in isotor~i~; glucose (278 mM) for i.v.
administration.
Cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 115 and COMPOUND 114 were all dissolved at in 5°ro chrernophore solution at a concentration of 5 mg ml~'.
PARAMETERS
Evoked neuronal spike activity was analyzed on-line by a ccamputer, saving single spikes and time of event. Neuronal spike activity (number of action potentials s-') was monitored on a pulse rate histogram together with indicators for AMPA, COMPOUND 61 and vehicle application.
PROCEDURE
ExtracellUlar recordings of single; hippocampal neuron spikes were made with five-barrel glass microelectrodes (5B120F-6, World Precision Instruments Inc., Sarasota, Florida, USA) with a tip diameter of 10-12 prn. The individual barrels were filled with 5 M NaCI
(recording), 400 rnM
NaCI (current balancing), 10 mM COMPOUNC> 61 in 200 mM CH~S03~ Na~ (pH 4.7), 200 mM
CH3SOs Na+ (pH 4.7, ~Jehicle), and the Vast k>;~rrc:l was filled with the AMPA.
Experiments were performed on hippocampal neurons (A = 5.5-6.5 mm, L = 1.5-2.0 mm, H =
2.0-3.0 mm, according to Paxinos & Watson, 1 X386). Neuronal spike activity was evoked by iontophoretic: application of AMPA for periods of 10 to 15 s with 1.5 min intervals. Single neuron spike activity w;~s amplified 5000 times with a bandwidth of 0.3 and 3 kHz (CyberAmp 320 with a AI 402 x50 smartprobe, Axon Instrurnents, California, USA). On-fine and off-line analyses were performed by the Spike2 program with a 1401 plus interface (Cambridge Electronic Design Limited, England). The computer program also recorded mean arterial blood pressure and monitored and controlled iontophoretic rapplication.
AMPA was ejected into hippocampus in regular cycles of 1()0-105 s. When neuronal responses were stable (when the AMPA responses did not vary more than 10%, measured over a 10 s time period) for at least 3z hour, then a single dose of either cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61 or COMPOUND 114 (10 mg kg-') was injected into the lemoral vein. Recording of neuronal spike activity was continued for at least 45 min after intravenous: injection. The PAM reactivity was tested by microiontophoretic application of COMPOUND G1 (20 nA, Fig. ).
RESULTS
Fig. 8 shows that iontophoretic application of COMPOUND 61 enhanced AMPA
evoked spike activity, whereas the vehicle did not influence the evoked spike activity.
Intravenous administration cyclothiazide (10 mg kg-') did not enhance AMPA evoked spike activity (Fig.
10).
Fig. 9. lontophoretic application of COMPOUND 61 enhanced AMPA evoked single neuron spike activity. The iontophoretic application of the vehicle did not influence AMPA evoked spike activity.
Fig. 10. Cyclothiazide 1;10 m kg-' i.v.) did not affect AMPA evoked spike activity in hippocampus. Shaded box above the AMPA1 trace indicatE, time of administration (1500 s 3o after onset of registrating).
The in viwo effects of the PAMs on AMPA evoked spike activity was dependent on the control spike activity level. COMPOUND 63 enhanced small AMPA responses, evoked by low WO 99!42456 PCT/DK99/00070 ti4 intensity AMPA stimulation, but had only marginal effect on large AMPA
responses, evoked by high intensity AMPA. stimulation (Fig. 111. There was an initial inhibition of the AMPA
responses and the onset of the enhancement occur 15 to 30 min after i.v.
administration (Fig.
11 ). Fig. shows an example of enhancement of AMPA responses by COMPOUND 56 (10 mg kg-'). The onset occurred approximately 10 min after administration (Fig. 12).
Fig. 11. COMPOUND Ei3 (10 mg kg--1 i.v.) enhanced the low intensity AMPA
responses (12 nA), but had only marginal effect on high intensity AMPA responses (17 nA). 10 mg kg-1 COMPOUND 63 was given 1500 s after onset c>f recording. The time of injection is marked by a shaded box above the AMPA2 trace.
Fig. 12. COMPOUND Ei6 (10 mg kg~' i.v.) enhanced AMPA Evoked spike activity.
The compound was injected 1250 s after onset of registration. The time of injection is marked with a shaded box above the AMPA trace.
Fig. 13 shows an example of enhancemenl of AMPA spike activity after i.v.
administration of COMPOUND 115 (10 rng kg-'). 'The effect started 2 min aftE:r i.v.
administration and lasted for more than 2 hours. COMPOUND 61 (10 mg kg' ) also enhanced AMPA responses in hippocarnpus. The 3-field increase in AMPA evoked spike activity induced by COMPOUND
61 started 20 minutes ~~fter administration and lasted for more than 2 hours (Fig. 14).
COMPOUND 114 (10 mg kg-' ) induced a 10-fold increase of the AMPA responses, when control level of the AMIPA responses were low (from 21 to 209 spikes response-', mean response,Fig. 15), while only smaller enhancE;mc~nt observed with larger control responses (from 124 to 204 spikes response-',Fig. 16).
Fig. 13. COMPOUND '115 (10 mg kg~' i.v.) enhances AMPA evoked spike activity in hippocampus. The shaded bax indicate the time in i.v. injection, 1900 s after onset of registration. The effect of COMPOUND 115 IustE~d for more than 2 hours.
Fig. 14. COMPOUND Ei1 enhanced AMPA responses in hippocampus. 10 mg kg-' i.v.
was given 1000 s after onset of registration (marked by a shaded box above the trace). The effect of COMPOUND 61 lasted for more than 2.5 hour.
Fig. 15. COMPOUND '114 (10 mg kg-' i.v.) enhanced AMPA evoked spike activity.
The compound was given 11730 s after onset of registration, which is marked by a shaded box above the AMPA trace.
Fig. 16. COMPOUND 114 (10 mg kg' i.v.) approximately doubled the AMPA
responses. The i.v. administration occurred at time 3900 s and is indicated by shaded box above the AMPA
trace The results show that C;yc~lothiazide did not show' any in viva effects after i.v, administration.
5 However, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61 and COMPOUND 114 enhanced AMPA evoked s~>ike activity in an activity-dependent manner.
References MATHIESEN, C., VARMING, T. & JENSEN, L. H. (1998). In vivo and in vitro evaluation of AMPA receptor antagonists in rat hippocampal neurones and cultured mouse cortical 10 neurones.. European Jr~urnal of Pharmacology 353, 159-r 67.
PAXINOS, G. & WATSON, C. (1986). The rat train in stereotaxic coordinates.
Second Edition.
Passive avoidence 15 PURPOSE: To test the: pharmacological effect of compounds on associative memory.
PRINCIPLE: A Mouse is placed in a light compartment with access to a dark compartment. If it enter the dark compartment it will receive a foot-shock {0.4 mA). After a delay (24 hours) the association to risk an unpleasant foot-shock by re-entering the dark compartment is 2o tested.
ANIMALS: Female NMRI mice (Bomholdtgaard, DK) weighing 22-25 g were used. The mice were kept in Macrolon plastic cages with free access to food (Altromin, DK) and tap water.
The mice were habituated to the laboratory for at least 3 days before testing (light on 25 7:OOam/light off 7:00 pm).
EGZUIPMENT: The passive avoidance apparatus consisted of a modular test chambers (ENV-307, MED-Associates, US). The light and the dark compartment consisted of plexiglas boxes of equal size (15x17x13 cm; width x length x height) with metal grid floors. A
sliding guillotine 30 door was located at thc: aperture (4x4cm) connecting the two compartments.
A manual grid scrambler (ENV-412, AHED-Associates, US) was used to provide the 0.4 mA foot-shock.
~6 PARAMETERS: Entry I;atency (sec) to re-enter the dark compartment was measured.
PROCEDURE: The mice are pre-treated (usually 30 min) before training with the test compound.
Training: One mouse is placed in the light compartment and the guillotine door to the dark compartment is openedl. When the mouse has Entered the dark compartment with all 4 paws it will receive one foot-shock (0.4 mAi and it will be taken to its home cage.
Test: After a delay (24 hours) the mouse will re-enter the light compartment ancJ time latency to enter the dark compartment is measured with a time limit at ~~ minutes. Time latency is noted as 2 minutes if the mouse has not entered the dark compartment within maximal test time (2 minutes).
Vehicle: 10°/« Tween BCI.
Dosis vol.: 10 ml/kg n=10;
RESULTS: Mean (~SEM) entry latency for each group is presented.
The result in Fig. 17 shows the memory enhancing effect of different concentrations of the compound 61;
2o Brief description of the drawings Fig. 1 and Fig. 2 show; the potentiataon of AMPA induced [3H]GABA release from cultured cortical neurons by compounds of the invention.
Fig. 3-8 shows the voltage clamp experiments c>n compounds of the invention.
The compounds 56 (Fig. 3), 63 (Fig. 4), 111 (Fig. 6), 114(Fig. 7) and 115 (Fig. 5) all potentiated the current induced by application of 30 NM AMPA.
Fig. 8 shows the concentration-dependent effect of a cornpc:~und of the invention (114).
Fig. 9 - Fig. 16 are experiments of iontophoresis.
Fig. 9. lontophoretic application of COMPOUND 61 and the iantophoretic application of the 3o vehicle;
Fig. 10. Cyclothiazide is applied in hippocampu:~.
Fig. 11. COMPOUND 6.3 is applied;
Fig. 12. COMPOUND 5.6 is applied.
r~
Fig. 13 COMPOUND 115 is applied.;
Fig. 13. COMPOUND 115 in hippocampus.
Fig. 14. COMPOUND 6.1 in hippocampus;
Fig. 15. COMPOUND 114;
Fig. 16. COMPOUND 114;
Fig. 17. Passive avoidance test of compound 61.
EXAMPLES
GENERAL TRANSFORMATION METHODS
Method A.
Suffamoylation in general.
i, CISCl"H 4 R'. OSp w w NR ii. HNR',, N~ ~l ~~ NRz _..__.,.
~NR2 R, R~." NHa The compound (32.5 rnmol) to be chlorosulfonated was dissolved in chlorosulfonic acid (75 ml) and heated in an oil bath at 110 °C, until TLC indicated that the reaction had gone to completion'. The reaction mixture was poured onto ice and the precipitate formed, was isolated by filtration. The isolated solid was vvashed with a small amount of water and dried on the filter. The solid was dissolved in dry T'HF (200 ml) and added an excess of the amine (230 mmol) and the reaction mixture was left over night with stirring at rt.
The reaction mixture was evaporated to dryness" then stirred with water to afford a solid which was isolated by filtration .and washed with EtOAc: on the fili:er. Further purification was possible either by column chromatography or recrystallization from EtOAc/hexane. Yields were typically: 60-90%.
* la small aliquot was taken out, added to ice in a test tube, neutralized with Na2C03 and then extracted with EtOAc. The aqueous phase was removed and the organic phase was added piperidine (xs) and left for some time. rLC; was taken from this small scale reaction mixtureJ.
Method I3.
o-Sulfamoylation of anilines.t i. clsolNCo ii. AICh D \ S ~'PJH HZSO4 (6 M, aq.) ~ ~ ">~
-_-_- ~ NHz ~NHFI R N' W, '1 /.~ NF-IR
I R
I-;
To a stirred solution of the aminobenzene derivative (250 mmol) in nitroethane or nitromethane (100 ml) at -50 "c:,, was addE:d a solution of CIS02NC0 (275 mmol) in nitroethane or nitromei:hane (75 ml) so that the reaction temperature did not exceed -30 °C.
The coating bath was removed and the thick reaction mixture allowed to heat up to 0 °C.
Solid AIC;13 (300 mmol) was added in one portion. The clear brown reaction mixture was WO 99/42456 PCT/DK99/000'70 heated in an oil bath at 120 "C for 20 min, then cooled to rt. and poured into a beaker with stirred ice water (1 I). The precipitate formed, was isolated by filtration.' The urea intermediate (98 mmol) was suspended in a mixture of dioxane (250 ml) and 6 M H2S04 (or only conc.
HCI) (500 ml) and healed to reffux over night. 'The reaction mixture was cooled to rt., filtered and dioxane was remrwed from thc: filtrale by evaporation. The aqueous remanense was neutralized to pH = 7-8 using 4 M iVaOH. The precipitate formed, was isolated by filtration and washed with water arod EtOAc.* Overall yields ranged from 10 % to 75 %.
t see also Girard Y., Atkinson J.G. and Rokach J., J. Chem. Soc., Perkm l, (1979} 1043.
'(Meta substituted anilines gives rice '.:o a mixture of the two possible isomers which at the stage of the urea intermediate may be ::>eparated by crystallization from MeC:)E-I or at the stage of end product by crystallization from EtOAc/hexane or c:hromatography.l Method G.
Trifluoroacetyl protection.
°wi' c~~ ° °ai°
S~nIHZ (CF3C0)p0 ~I~'~~~5'NFj PPA ~ ~ S'IVF
Ill .~l , ~NH ~.% ~N_..f 1 / Ni R ~ R ~F;
To a stirred solution of the 2-aminobenzenesulfonamide derivative (27 mmol) in dry THF (75 ml) at 0 °C was added trifluoroacetic anhydride ouch that the reaction mixture did not exceed +10 °C. The reaction mixture was stirred ai rt. until all starting material was consumed. The reaction mixture was evaporated to dryness, atirred with water, filtered and washed with hexane. 'The isolated solid was added PPA (250 g) and heated in an oil bath at 140 °C for 2~h h. The reaction mixture was cooled to 60~~70 "C; and poured onto a mechanically stirred ice water solution. The precipitated formed was isolated by filtration and air dried. Overall yields were typically 85-90%.
Method D.
Trifluoroacetyl deprotection.
c\c~o 'NR KoHiFr2o ~-\ :.>~n~r~, I z ~yN:~~cF~ n ~ ~y~i~NH
i A stirred solution of the trifluoroac:etyl protected compouncl (3.6 mmol) dissolved in 1 M KOH
(30 ml) was heated to 80 °C for 1 h. The reaction mixture was cooled to rt. and pH adjusted to ~0 7 using cone. HCI (aq.). -The reaction mixture was cooled to 0 °C and filtered. The isolated solid was washed with water and air dried. Yields typically ratnged from 85-95%.
Method E.
Formation of dihydrobenzothiadiazines-1,1-dioxide from 2-aminobenzene-sulfonamides.
o O~~O i. R'-COCI, DM AP, TEA
,S_ . S' Nl~p ii. t M NaOH. d, ~~ W N(t i) NHR f?~.. H) R, To a stirred solution of the 2-aminobenzenesulfonamide derivative (148 mmol), triethylamine (150 mmol), 4-(N,N-dimethylamino)pyridine (7.5 mmol) in 6t)U ml THF at 5 °C was added the carboxylic acid chloride. The reaction mixturE, was left with stirring over night and then 1o evaporateld to dryness. The crude material was stirred with water and filtered. The isolated solid was dissolved in 1 M NaOI-1 (250 ml) and heated to 80 °C for 3 h.
The reaction mixture was coolE;d to rt. and pH adjusted to 7 using c~~nc. HCI. The precipitate formed was isolated and recrystallized from i-F~rOH. Overall yields ranged from 80-90°,'°.
Method F'.
Reduction of dihydrobenzothiadiazines-1,1-dioxide to tetrahydrobenzo-thiadiazines-1,1-dioxide.
o~~o ~wi a N(H) DIBALH S
NH
-W , ~ vi ~._N; .R, R SH) R F~ FI
To a stirred solution of the dihydrabenzothiadiaz:ine-1,1-dioxide {19.4 mmol) in dry THF (200 ml) at -70 °C was added a solution of DIBA~H 1.5 M in toluene (33 ml;
50 mmol). The reaction mixture was left with stirring over night while the temperature slowly increases from -70 °C to -15 °C'. Water { 10 ml) was added tc~ the reaction mixture followed by 1 M NaOH (5 ml). The reaction mixture was then warmed 1:o I~t. and extracted with EtOAc.
The combined organic fractions were dried with MgS04 and evaporated to dryness. In some cases the product was further purified by column chromatography. Yields ranged from 45-85 %.
'[The product aminal is further reduced to the ring opened alkylarnine if the temperature is not controlled carefully.
Method G.
Formation of tetrahydrobenzothiadiazines-1,1-dioxides from 2-3o aminobenzenesulfonamides.
WO 99/'42456 PCT/DK99/00070 0~~0 0~~~
S~NH~ R'-CHO, MgS04, ~ ~ ~J.'NH
__"
NHz '~ ~PJ~'~R, Fi A stirred solution of the 2-aminobenzenesulforr~mide derivative (7 mmol), an aldehyde (10 mmol) and MgS04 (20 mmol) in dry THF or dry dioxane (~0 ml) was refluxed under N2 until TLC indicated comptet~a consumption of the 2:-aminobenzenesulfonamide derivative (typically 12-36 h). The reaction mixture was filtered, at t:he precipitate washed thoroughly with THF or dioxane. The filtrate was evaporated to dryness, added water and extracted with EtOAc. The combined organic fractions were dried with MgS04 and evaporated to dryness.
Column chromatography (EtOP,c/hexane) afforded the pure product. Yields typically ranged from 25-75%.
Method H.
Formation of aryl or hetaryl substituted compounds by use of Pd catalyzed cross coupling.
pd-cat.
X~ ~ ~-additives Fietaryl/Aryl~~, I t Metalated Arene/Hetarene - -----.-»
R li X=Br,l Suzuki coupling: A stirred mixture of an arylh<~lide (2 mmol), an aryl or hetarylboronic acid, boronic acid ester or dialkylborane (6 mrnol), K2C03 (10 mmol), Pd(PPh3)4 (30 mg), 1,3-propanediol (10 moral), dimethoxyethane (50 ml) and E-120 (25 ml) under N2 was heated to 70 °C for 3 h. The reaction mixture was cooled to rt. t=urther water was added and the reaction mixture was E>xtracted with EtOAc. -ft~e combined organic fractions were dried with MgS04 and evaporated to dryness. Column chromatography afforded the pure product.
Yields ranged from 40-100 %.
Method I.
Formation of compounds containing triazolyl substitutian.
WO 99142456 P(.'.T/DK99/00070 fit R R, Pd-cat additives ~ r~~, TMSN~ Nv N-.h I~' - H --. ~--.-,.. _-.-.. I I
I~ ~ R
X-Bi,l R TMS
H TMSN,~
h;OhIIMeOH
R
Sonogasl~ira coupling: A mixture of an aryliodide or arylbrc7mide (2 mmol); an acetylene (10 mmol); Pd(PPh3)2CI2 (1~0 rng; 0.2 mmol); Cul (40 mg; 0.1 mmol) and triethylamine (10 ml) under N2 was stirred at rt. (in the case of arylbromides prolonged heating at 60 °C was necessary) over night. THF was added and the reaction mixture filtered through celite and the filtrate evaporated to dryness. Column chromatography gave the ethynylated arene.
Yields ranged from 40-53"/° for arylbromides to 07% for aryliodides.
Detrimelhylsilylation for R'--TMS: A solution of the ethynylated arene (1.7 mmol) in MeOH (8 ml) was added a solution of 1 M KOH in MeOFi (2 ml; 2 mmol) and stirred at rt.
for 2h. The reaction mixture was diiluted with THF, adsorbed onto silica and chromatographed to give the desilylated ethynyl arene. Yields ranged from 61"/° to 73%.
Formation of trizoles: The ethynylarene (0.'7 rnrnol) and TMS-N3 (2 ml; 15 mmol) was heated to 170 °C; in an ampule for 50 h. The reaction mixture was cooled to rt. and evaporated to nearly dryness (CAUTION ! evaporation to dryness may lead to explosion due to the presence of some HN3) and added MeOH. The reaction mixture was stirred for 1 h (to remove the TMS-group in the TMS-triazole), then adsorbed onto silica, and purified by chromatography. Yield; ranged from 20-72 °ra.
Ei3 SYNTHESIS OF INDIVIDUAL COMPOUNDS
Compound 1 2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazaline Anthranilamide was transformed by Method G (using cyclohexanecarboxaldehyde).
M.p. 172-174 °C.
Compound 2 2-Phenyl-4-oxo-1,2,3,X1-tetrahydraquinazaline Anthranilamide was transformed by Method G (using benzaidehyde). M.p. 221-222 °C.
Compound 3 2-Methyl-3,4-dihydro-1,3-benzoxazine-4-anE~
2-Hydroxybenzamide v~ras transformed by ME;i:hod G (using paraldehyde). M.p.
124-126 °C.
Compound 4 2-Phenyl-3,4-dihydro-1,3-benzoxazine-4-one 2-Hydroxybenzamide eras transformed by Mefhod G {using benzaldehyde). M.p. 157-160 °C.
Compound 5 3-Bicycla[2.2.1]hept-5~'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was transformed by Method G (using a racemic endo/exo mixture of 2-norbornencarboxaldehyde). M.p. 205-209 °C.
Compound 6 3-Phenyl-1,2,3,4-tetralhydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was transformecJ by Method G (using benzaldehyde).
M.p.
125.5-12!3.5 °C.
Compound 7 1,2,3,5,10,10a-Hexahydrobenzo[e]pyrrolo[1,2-b]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfanamide was used a~~ starl:ing material for the following transformation sequence: Method E (using 4-c:hlorobutanayl chloride. The reaction mixture was NOT
subjected to NaOH catalyzed ring closure, bui: dissolved in H2SU4 and heated at 100 °C for 72 h and precipitated on ice). M.p. 149-154 °C.
Compound g 2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazine-4-one 2-Hydroxybenzamide was transforrned by MetGnod G (using ?-butanone). M.p. 76-78 °C.
Compound 9 3-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Bromo-aniline was transformed by Method h'~ (see corr7pound 121 ) to give 4-bromo-2-aminobenzenesulfonarrride.
A mixture of 4-broma-2-aminobenzenes,ulfonamide (140 mg, 0.56 mmol), 2-methoxyphenylboronic acid (1 OG md, 0.70 rnmol), F'd(PPh3)2C12 (20 mg, 5 mol %) in 1,2-dimethoxyethane (30 mil) and Na2C;03 (2M, 3 ml, 6 mmol) was refluxed under NZ
for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHC03 (20 ml) and extracted with EtOAc (2' x 40 ml). The organic layer was washed with brine (20 ml), dried (Na2'30a) and tk7e solvent was removed under reduced pressure. The product was purified b~~ flash chromatography on SiO~ using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 155 mg (100 ~;/°) of 2-amino-4-(2-methoxyphenyl)-benzenesulfonamide as colorless powder. Tl~e product was further transf<:~rmed by Method G (using cyclohexanecarboxaldehyde). M.p. 219-221 °C.
Compound 10 3-Cyclohexyl-6-(2-pyri~dyl)-1,2,3,4-tetrahydra-'1,2,4-benzothiadiazine-1,1-dioxide 3-Aminophenylboronic acid hemisulphate (5.58 g, 30 mmol), 2-bromopyridine (2.7 ml, 28 mmol), Pd(PPh3)2C12 (100 mg, 0.5 mol °/>), 2M K2C03 (50 ml) were refluxed in 1,2-dimethoxyethane (50 ml) for 24 h under N~. The mixture was diluted with CH2CI2 (100 ml) and washed with sat. NaHCO i (50 ml). The organic layer was dried (Na2S04) and the solvent was removed under reduced pressure. Flash-chromatography with CH2CI2 as eluent gave 3-(2-pyridyl)aniline as a yellow oil, 1.0 g (~1 %). 3-(2-t'yridyl)aniline was transformed by Method B
and Method G (using cyclohexanec;arboxaldel-Hyde). M.p. 21.:3-216 °C.
Compound 11 3-Cyclohexyl-6-(3-pyridyl}-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Bromo-aniline was trar7sformed by Method E3 (see compound 121 ) to give 4-bromo-2-aminobenzenesulfonarnide.
A mixture of 4-brorno-2-aminobenzenesulfonamide (250 mg, 1.0 mmol), diethyl-3 5 pyridylborane (225 mg, i.5 mmol), Pd(PPh~)2(~I_. (35 mg, 5 rnol %) in 1,2-dimethoxyethane (30 ml) and IVa2C03 (2M, 3 ml, 6 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residme was treated with saturated NaHC03 (20 ml) and extracted with EtOAc (2 x 40 m11. The organic layer was washed with brine (20 ml), dried (Na2S04) and the solvent was removed under reduced pre:rsure. The product was purified by 10 flash chromatography on SiO~ using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 240 mg (96 %) of 2-amino-4-(3-pyridyl)-benzenesulfonarnsde as colorless powder. The product was further transformed by Method Ca (using cyclohexanecarboxaldehyde). M.p. 240-243 °C.
Compound 12 15 3-Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-.5-(1-hydroxyethyl)benzenesulfonamide: 5-Acetyl-a:e-aminobenzenesulfonamide (see compound 13) (0.95 g, 4 4 mmol) was suspended in 96% EtOH (50 ml) and NaBH4 (0.46 g, 12 mmol;l was added in one portion. The mixture was stirred at 25°C for 4 h and filtered through Celite and the solvent was removf:d under reduced pressure. The residue was 20 treated with sat. NaHCO;, (50 ml) and extracted with EtOAc (2 x 50 ml), dried (Na2SOa) and evaporated to dryness.. Flash-chromatography with EtOAc:n-hexane:Et3N
(200:100:4, v/v/v) as eluent gave 0.35 c~ (37 %) of 2-amino-Ei-(1-hydroxyethyl)benzenesulfonamide as light-brown powder. M.p. 160-162 °C.
25 Compound 13 3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-~benzothiadiazine-1,1-dioxide To a solution of ethylvinylether (5.8 ml, 60 mnu>Ij in dry Th-IF (50 ml) at -78°C was added t-BuLi (1.7 M in pentane, 25 ml, 40 mmol) and the yellow mixture was stirred for 1 h at -78°C.
3o The cooling bath was removed and the mixture was warmed slowly to 0°C and stirred for another 30 min. The mixture was recooled to ~-78°C and a solution of ZnCl2 (2M in THF, 20 ml, 40 mmol) was added slowly and the cooling bath was removed and varmed to 20°C. 5-lodo-2-aminabenzenesulfonamide (see compound 37) (1.8 g, 6 mmol) and Pd(PPhs)4 (0.2 g, 3 mol%) was added and tt~e mixture was refluxc~d for 6 h. -i-he THF was evaporated and the residue w<~s boiled in 1 M hydrochloric acid (30 ml) and MeOH (30 ml) far 30 min. EDTA (14.6 g, 50 mmol) was added and made slightly basic (pH == 8-9) with 1 M NaOH
followed by extraction with EtOAc (3 x 150 ml), drying (Na,S04) and evaporation of the solvent gave a brown solid. Trituratiort with r~-hexane gave 0.9E~ g (74 %) of 5-acetyl-2-aminobenzenesulfonamide as aff-white powder. The product was further transformed by Method G (using cyclohexanecarboxaldehydej. fvl.p. 224-225 °C
(decomp).
Comaound 14 3-Cyclohexyl-7-(1-hyd~roxyiminoethyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide To a suspension of 5-acetyl-2-<~minabenzenEasulfonamide (see compound 13) (0.45 g, 2.1 mmol) in 96% EtOH (40 rnl) was added H2NOE~~HCI (0.28 g, 4 mmol) and 2M NaOH
(2 ml}.
The mixture was boiled fcar 2 h and the solvent was evaporated. The residue was triturated with water (25 ml) and the product was filtered off and dried, yielding 0.39 g (81%) of 2-amino-5-(1-hydroxyiminoethyl)benzenesulfona.mide as yellow powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 230-233 °C.
Compound 15 3-Cyclohexyl-7-carbarnoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2o A mixture of 5-cyano-2~-aminobenzenesulfonamicfe (see cornpound 37) (2 g;
10 mmol), conc.
H2S04 (4. ml) and abs. EtOH (4 ml) was heated to 80 °C for 5 h and over night at 50 °C. The reaction mixture was poured onto ice and extracted with EtOAc (1 x)". The organic phase was discarded and the aqueous phase neutralized with Na2C03 and extracted with EtOAc (3x).
The organic phase was evaporated to drynt::;s and subjected to column chromatography (EtOAc/hE:xane=2/1 ) to give 200 mg (9 %) of the carboxamide. The carboxamide was further transformed by use of A/lethod G (using cyclohexanecarboxaldehyde}. M.p. 235-237 °C.
'[The first extraction contains the ~itrile (starting material) and anothor biproduct]
Compound 16 3-Cyclohexyl-7-ethoxycarbony!-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide A mixture of 5-cyano-2~-aminobenzenesulfonamicfe (see cornpound 37) (3 g; 15 mmol), cone H2S04 (5 ml) and abs. EtOH (15 ml) was heated to 80 °C over night. The reaction mixture was poured onto ice. -i~hf~ precipitatkJ formed was isolated by filtration.
The precipitate was b7 washed with EtOAc to ~~ive 2.01 r~ (55%) of the pure ethyl ester. The ester was further transformed by use of (Method G (using cyclohexanecarboxaldehyde). M.p. 234-236 °C.
Compound 17 3-Cyclohexyl-7-cyano~-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Cyano-2-aminobenzenesulfor7arnicte (see compound 3T) was transformed by Method G
(using cyciohexanecar',ooxaldehyde) M.p. 231-2.37.
Compound 18 3-Bicyclo(2.2.1Jhept-fi'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Bromo-2-aminobenzenese~lfonamide: A stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) in AcOH (15 ml) was added ;:~ solution of Br2 (0.55 ml; 10.5 mmol) in AcOH
(5 ml). The reaction mixture was poured into H~,O (100 ml) .and filtered. The isolated solid was adsorbed onto silica and subjected to flash cloromatography to give 1.428 g (57%) product (and 650 mg (20%) of the 3,5-dibromo derivativE:).
3-Bicycloj2.2.1Jhept-5'-en-2'-.yl-7-phenyl-1,2,;a,.J-tetrahydro-1,2,4-benzothiadiazine-1, J-dioxide (78): 5-Bromo-2-amir~obenzenesulfonamide was transformed by Method H (using 2o phenylboronic acid) and Method Ca (using a rac;emic endo/E:xo mixture of bicyclo[2.2.1 ]hept-5-ene-2-carboxaldehyde). M.p. 190.5-195.0 "C.
Compound 19 3-Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Nitrophenylboronic acid: A solution of phenyuboronic acrid (10 g; 82 mmol) in acetic acid anhydride (100 ml) at -15 °C was added Turning HN03 (5 ml; 120 mmol) over 30 min such that reaction temperature was kept belaw -10 "i:,. The reaction mixture was allowed to warm up to r1. and left with stirring over night. The reaction mixture was poured onto ice and concentrated to 50 ml. The remanense was tf~en re-evaporated 5 times from additional H20 (100 ml) and finally filtered to givE 7.1 g crude product as a mixture of isomers. Column chromatography (CH2~C1~,/EtOH=1010.5) gave ~f.8 g (35°io) pure product as an oil.
fib 2-Acefamidaphenylbon~nic acid.. A mixture of .?-nitrophenyfboronic acid (2 g;
12 mmol) and 5% Pd/C (100 mg) in E.tGH (100 ml) was hydrogenated at 1 bar until TLC
indicated complete conversion of starting rnaterial. The reaction mixture was filtered through celite and the filtrate evaporated to dryness. The remar~ense was washed with hexane and filtered to give 900 mg of (55%) 2-aminophenylbaronic acid.
A mixture of 2-aminophenylboronic acid (900 mg; 6.6 mmol), triethylamine (0.57 ml; 7 mmol) and acetylchloride (0.5 rnl; 7 mmol) was stirrE:d at rt. fc7r 1 h. The reaction mixture was evaporated to dryness, stirred with H20 and filtered to give 750 mg (63%) product.
3-Cyclohexyl-7-(2'-acefarnidophenyl)-1,2,3,4-fetr;~hydro-1,2,4-benzothiadiazine-1,7-dioxide (19): 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2-Acetamidophenylboronic acid) and IVlethod G (using cyclahexanecarboxaldehyde).
M.p. 245-249 °C.
Compound 20 3-Cyclohexyl-7-(2'-nitrophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2-nitrophenylboronic acid (see compound 19)) and Method G (using cyclohexanecarboxaldf:hyde). M.p. 204-207 °C.
Compound 21 3-Cyclohexyl-7-(2'-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compaund 37) was transformed by Method H
(using 2-methoxyphenylboronic acid) and CV9ethod G (using cyclohexanecarboxaldehyde).
M.p. 219-222 °C.
Compound 22 3-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 4-Trifluon~mefhylanisole: Sodium (12.78 g; Ei55 mmol) was added to dry MeOH
(100 ml).
When the gas evolution ceased, the reactian mixture was evaporated to dryness and dry NMP (250 ml) followed by Cu (s) (35.3; 555 mmol) and 4-bromo-trifluoromethylbenzene (25 g;
111 mmol) was added. The reaction mixture was heated tc:~ 130 °C for 4 h, cooled to rt. and filtered. Water {500 ml) was added to the filtral:e and it was extracted with Et20 {2x 200 ml).
The combined organic. fractions were washE~d with H20 (2x 100 ml), dried (MgS04) and evaporatE:d to dryness. Column chromatography gave 8.05 g {41 %) of product.
2-Methoxy-5-trifluorom~ethylphenylboronic acid: A solution c:~f 4-trifluoromethylanisole (8 g; 45 mmol) in dry THF (80 rnl) at -30 °C under N2 was added a ;:solution of 2.5 M n-BuLi in hexane (20 ml; 50 mmol). The reaction mixture was stirred for 1 h at -30 "C, then cooled to -70 °C and added B(Oi-Pr)3 (14.1 ml; 64 mmol). The reaction mixture was allowed to slowly warm up to rt. over night. The reaction mixture was addecJ 2 M HCI (40 mi) and THF was removed by evaporation.. The aqueous remanense was extracted with E~t20 (4x 20 ml) and the combined organic fractions were extracted with 1 M NaOI-i (5x 17 ml). The combined aqueous fractions were neutralized by 10 M HCI. The precipitai:e formed was isolated by filtration and washed with 1 M HCI to give 8.1 g (81 %;) product.
3-Cyclohcxyl-7-(2'-methoxy-4'-triouoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-a'ioxide (22): 5-lodo-'~-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2-methoxy-5-triflucaromethylphenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 255-2fs7 °C.
Compound 23 3-Cyctohexyl-7-(2',4'-dimethoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothi adiazi ne-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2,4-dimethoxypher~ylboranic acid) and Method G (using cyclohexanecarboxaldehyde).
M.p. 208213 °C.
Compound 24 3-Cyclohexyl-7-(2'-(N,N-dimethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-(N,N-dimethylsulfamoyl)phenylbor~nic acid.' A solution of benzenesulfonylchloride (10 ml;
78 mmol) in THF (100 ml) was added a 40°/> solution of dimethylamine in H20 (20 ml; 160 mmol) such that the reaction temperature w<~~; kept below 50 °C. The reaction mixture was stirred 1 h at rt. The reaction mixture was added H20 and THF removed by evaporation. The precipitate formed was isolated by filtration and air dried to give 14 g (97%) of N,N-dimethylbenzenesulfonamide.
A solution of N,N~tiimethylbenzenesulfonamide (!x.25 g; 50 mmol) in dry Et20 (150 ml) under N2 was cooled to -70 "C and added a solution of 2.5 M n-BuLi in hexane (24 ml;
60 mmol) 5 such that the reaction temperature was kept below -60 °C.. The cooling bath was removed and the reaction mixture ~~Ilowed to slowly wa.rrn up to +20 "C. The reaction mixture was re-cooled to -70 °C and B(Oi-pr)3 (16.1 ml; 70 rnrrrol) was added. The reaction mixture was left cold and allowed to warm up over night, 1 M HCI (100 ml) was added and stirring was continued at rt. for 1 h. The reaction mixture was then extracted with Et20 (2x 50 ml) and the ~o combined organic fractions extracted with 1 M NaOH (4x 50 ml). The combined aqueous fractions were neutrali~:ed with 1 M HCI and extracted with Et20 (4x 100 ml).
The combined organic fractions were cried (Na2S0,~) and evaporated to dryness, washed with Et20/hexane to give 3.4 g (30%) product.
15 3-Cyclohexyl-7-(2'-(N,N-dimethyisulfamoyl)~hc~rryl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (24): 5-lodo-2-aminobenzenesulfonarnide (see compound 37) was transformed by Method H (using 2-(N,N-dimethylsulfamoyl)phenylboronic acid) and Method G
(using cyclohexanecarboxaldehyde). M.p. 290-300 "(~.
2o Comaound 25 3-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzen~esulfonamide (see compound 37) was transformed by Method H
(using 2-chlorophenylboranic acid) and Method G (using cyclohexanecarboxaldehyde). M.p.
233-236 "C.
Compound 26 3-Cyclohexyl-7-(2'-fl uorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazine-1,1-dioxide 5-lodo-2--aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using 2-fluorophenylboronic acid) and Method G (using c:yclohexanecarboxaldehyde). M.p.
249-250 "C.
Compound 27 a1 3-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-hydroxyphenylboronic acid: A stirred solution of 3-aminophenylboronic acid hemisulfate (6.2 g; 33.3 rrimol) and 50°,~o H2S04 (3. i' ml; 33.~~ rnmol) in H20 (100 ml) at -2 °C was added a solution of NaN02 (2.5 g; 36.3 mmol) in Hpt) (20 ml) over 1 h. The reaction mixture was slowly added to a stirred solution csf cone. h~>S04 (25 ml) in H20 (20 ml) at reflux. After complete addition, the reaction mixture was refluxed for 30 min., cooled, added activated charcoal, heated to reflux, cooled and filtered through celite. The filtrate was saturated with NaCI (s), filtered and extracted with Et20 (5x: '100 ml). The combined organic fractions were dried (Na2S04) and evaporated to dryness to give 4.3 g (94°io) product.
3-Cyclohexyl-7-(3'-hydroxyphen.yl)-1,2,3,4-tetiahydro-1,2,4-benzothiadiazine-1,1-dioxide (27):
3-Hydroxyphenylboronic acid was transformed by Mei:hod H and Method G (using cyclohexanecarboxaldc:hyde). M.p. 238-246 °C
Compound 28 3-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide 4-(2'-Pyridyl)-2-aminobenzenesulfonamide: A stirred mixture of 5-iodo-2-aminobenzenesulfonarnide (1 g; 3.3 mmoli), 2-tributylstannylpyridine (5.5 g;
15 mmol), Pd(PPh3)4 (240 mg, 0.34 mmol) and Ag20 (780 mg; 3.3E~ mmol) in DMF (50 ml) under N2 was heated at 100 °C for 6h and over night at rt. The reaction mixture was evaporated to dryness and resuspended and stirred in H20/E.tOAc and finally filtered. The organic phase was isolated and the aqueous phase extracted with EtC:>Ac (2x aq, vol.). The combined organic fractions were dried (Na2S04), ev<~porated to dryness and subjected to column chromatography to give 200 mg (24 %) product.
3-Cyclohexyl-7-(2'-pyri~alyl)-1,2,3,4-tetrahydro-1,2',4-benzothiadiazine-1,1-dioxide (28): 4-(2'-Pyridyl)-2-aminobenzenesulfonamidc~ was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 222-224 "C.
3o Compound 29 3-Cyclohexyl-7-(3'-pyridyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzencaulfonamide (see compound 37) was transformed by Method H
(using diethyl-3-pyridylk>orane) and Method G (using cyclohexanecarboxaldehyde). M.p. 240-242 °C.
Compound 30 3-Cyclohexyl-7-(2'-pyrimidinyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 4-((2,2-Dimethylpropanoyl)amino)phenylboror,~ic acid: To a solutian of 4-bromo-N-pivaloylaniline (1.56 g, 6 mmol) in dry THF (50 rril) at -78°C was added t-BuLi (1.5 M in pentane, 13.3 ml, 20 mmol) and the yellow mi:Kture was stirred for 1 h at -78°C under N2. The reaction was quenched with B(OCH3)3 (1.7 rnl, 15 mmol) and stirred for another 1 h at -78°C.
The reaction mixture w,~s then warmed to morn temperature and hydrolysed with 0.5 M
hydrochloric acid (50 ml) and extracted with EtC>Ac (3 x 80 ml), dried (Na2S04) and concentrated to ca. 40 ml n-Hexane (120 m!) was added slowly and the colorless crystalline product was filtered off and dried, yielding 1.26 g (95%).
N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide: ~'v mixture of 4-((2,2-dimethylpropanoyl)amino)phenylboranic acid (2.0 g, 9 mmol), 2-chloropyrimidine (0.8 g, 7 mmol), Pd(PPh3)2C12 (100 mg, 2 mol %) 1,2-dimc~thoxyethane (40 ml) and Na2C03 (2M, 7 ml, 14 mmol) were refluxed under N2 for 5 h. The mixture was diluted with 10 %
Na2C03 (20 ml) and extracted with EtOAc; (3 x 50 ml). The organic layer was dried (Na2SOa) and the solvent was removed in vacuo. The crude product was recrystallisE=d from MeOH/water (1:1 ) yielding 0.52 g (85%) of N-(4-(c'-pyrimidinyi)phenyl)-2,:?-dimethylproi:~anamide as colorless crystals.
4-(2-Pyrirnidinyl)aniline: N-(4-(2-pyrimidinyl)phenyl)-2,2-dinnethylpropanamide (1.41 g, 5.48 mmol) was boiled in 6 IM hydrochloric acid (40 ml) for 2 h. The mixture was cooled and made strongly basic with NaOH (s) and extracted with CH2C12 (2 x 50 ml), dried (Na2S04) and the solvent vvas removed irn vacuo. Trituration with n-hexane gave 0.83 g (88%) of 4-(2-pyrimidinyl)aniline as a light-yellow powder. ThE; product was further transformed by Method B
and Method G (using cyclohexanecarboxaldehyde). M.p. 236-238°C.
Compound 31 3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide WO 99/42456 f'CT/DK99/00070 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using furyl-2-boronic acid) and Method G {usinct cyclohexanecarboxaldehyde).
M.p. 226-228 °C.
Compound 32 3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see cornpound 37) was transformed by Method H
(using furyl-3-boronic acid) and Method G (using cyclohexanecarboxaldehyde).
M.p. 204-205 °C.
Compound 33 3-Cyclohexyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H
(using thienyl-2-boronic acid) and Method G (using cyclohexanecarboxaldehyde).
M.p. 234-236 °C.
Compound 34 3-Cyclohexyt-7-(1-methyl-1 !-f-2-imidazolyt)-'1,2,3,4-tetrahydro-1,2,4-benzothiad iazi ne-1,1-dioxide To a solution of 1-methyl~midazole (4.8 ml, 60 mmol) in dry THF (120 ml) at -78°C was added n-BuLi (2.5 M in hexane., 26 ml, 65 mmol) and the yellow mixture was stirred for 45 min at -78°C. A solution of ZnClz (2M in THF, 75 rrol, 150 mmol) was added slowly and the cooling bath was removed. The colorless solution was stirred for another 10 min at 0°C. 5-lodo-2-aminobenzenesulfonamide (see compound 37) (2.1 g, 7 mmol) and Pd(PPh3)4 (0.5 g, 5 mol%) was added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was treated with EDTA (53 g, 0.18 mol) and made slightly basic (pH = 8-9) with 1 M
NaOH followed by extraction with EtOAc (3 x 150 ml), drying (Na2SO4) and evaporation of the solvent gave a dark oil. Flash-chromatography with 5% MeOH in CH2C1;~ as eluent gave 1.33 g (75 "/°) of 2-amino-5-(1-methyl-1 H-2-irnidazolyl)-1-benzenesulfonamide as colorless crystals. The product was further transformEad by Method G (using cyclohexanecarboxaldehyde). M.p. >>250 °(:, (decomp).
r4 Compound 35 3-Cyclohexyl-7-(1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method I
(using trimethylsilylacetyiene) and Method G (using cyclohexanecarboxaldehyde). M.p.
230-234 °C
(dec.).
Compound 36 3-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzen~esulfonarnide (see compound 37} w<xs transformed by Method I (using phenylacetylene) and Method G (using cyclohexanecarboxaldehyde}. M.p. 231-232 °C (dec.).
Compound 37 3-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-lodo-2-aminobenzenesulfonamide To a cold (0 °C) stirred solution of 2-aminobenzenesulfonarnide (17.2 g; 100 mmol) in CHC13 1;200 ml) was added a solution of iodine manochloride (17.1 g; 105 mrnol) in CHc~l3 (50 ml) over 1 h. The reaction mixture was slowly warmed up to rt. and left with stirring aver night. ThE: reaction mixture was filtered and the isolated solid was washed on the filter with CHCI3 (3x 20 ml), NaHC03 (sat. aq., 1 x 20 ml), H20 (4x 50 ml). The isolated solid was air dried to give 27.3 g (92%) of product.
5-Cyano-2-aminobenznnesulfonamide: A mixture of 5-iodo-2-aminobenzene-sulfonamide (17.9 g; 60 mmol), Zn(CN)2 (4.9 g; 41.9 mmol) and Pd(PPh3)4 (2.5 g; 2.2 mmol) in DMF (150 ml) under N2 was heated to 80 °C for 2 h. ThE: reaction mixture was poured into NaHC03 (sat. aq., 600 ml) and extracted with EtOAc (9x 200 ml). The combined organic fractions were washed with NaHC03 (sat. aq.} and NaCI (sat. aq.), dried (Na2S04), filtered and evaporated to dryness. The remanense was washed with water and hexane and filtered of to give 10.9 g (92%) of praduct.
5-(N-hydroxyamidino)-.2-aminobenzenesulfon.amide: A mixture of hydroxylamine hydrochloride (764 mg; t 1 mmol} and NaOAAe (616 mg; '11.4 mmol) in MeOH (10 ml) was stirred at rt. for 1 h and then added 5-cyano-2-aminobenzenesulfonamide (1 g;
5 mmol). The reaction mixture was left with stirring for 48 h and poured into water and extracted with EtOAc (2x 50 mi). The combined organic fractions were dried (Na2S04), evaporated to dryness and purified by column chromatography to give 200 mg (17%) of product.
5 3-Cyclohexyl-7-(5'-methyl-7',2',4'-axadiazol-3-yl)-1,2,3,4-fetrahydro-1,2,4-benzothiadiazine-i, l-dioxide (37): A mixture of 5-(N-hydroxyamidino)-2-aminobenzenesulfonamide (200 mg;
0.9 mmol), NaOMe (5C mg; 1 mmol), EtOAc (5 ml), crushed MS3A (2 g) in anhydrous EtOH
(20 ml) was heated over night at 70 °C. 'rh~e reaction mixture was evaporated to dryness, stirred with water and extracted with EtOAc:. The combined organic fractions were dried 10 (Na2S04) and evaporated to dryness to a brown oil, whici~ way: subjected to transformation by Method G (using cyclohexanecarboxaldehyde) to give 8 mg product after chromatography.
M.p. 249-251 °C.
Compound 38 15 3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 7-Amino-3-cyclohexyl-~1,2,3,4-tetrahydro-1,2,4-bc~nzothiadiazine-1,1-dioxide:
To a stirred solution of 7-amino-~~-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.5 g; 2 mmol) in dry THF (10 rnl) at -70 °C; was added a solution of 1.5 M
DIBALH in toluene (2.7 ml;
4 mmol) under N2. The reaction n-cixture was stirred for 2 h at -70 °C;
2 h at -40 °C and then 20 warmed to 0 °C. The reaction was quenched with H20 and stirred for 30 min. at 0 °C and left over night without stirring at +5 °C. The mixture was evaporated to dryness, resuspended in MeOH and filtered. The isolated solid was washed thoroughly with MeOH and filtered. The combined filtrates was adsorped onto silica c~E;l., Column chromatography (EtOAc) gave 200 mg of product.
7-Acetylamino-3-cyclohexyl-1,2,3,4-tetrahydro-1"2,4-benzothiadiazine-1,1-dioxide (38): A
mixture ~of 7-amino-3-cyclohexyl--1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide (100 mg; 0.26 mmol), acetylchloride (20 pl; 0.29 rnol) and triethylamine (42 pl;
0.3 mmol) was stirred fur 2 h at r.t. The reaction mixture was resuspended in H20 and filtered. The isolated solid was purified by column chrornatography (EtOAc) to give 22 mg 27a. M.p.
202-206 °C.
Compound 39 3-Cyclohexyl-7-methylsuffonylamino-1,2,3,4-tetrahydro-1 "2,4-benzothiadiazine-1,1-dioxide 3-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: 2-Aminobenzenesulfonamide was transformed by Me~rhad E (using cyclohexanecarbonyl chloride).
3-Cyclohexyl-7-vitro-1,2-dihydro-~y,2,4-benzothiadiazine-1,1-dioxide: To a stirred solution of KN03 (1.2 g; 11.5 mnnol) and cone. H2SO~i (f3 ml) at 5 °C was added a solution of 3-cyclohexyl-1,2-dihydro-1,2,4-benzoth~adiazine-1.11-dioxide in conc. H2S04 {8 ml). The reaction mixture was allowed to warm up to r.t. ;end left with stirring over night. The product 1 o was precipitated by slow addition of ice and isolated by filtration. The crude product {4.3 g) was used without further purification.
7-Amino-3-cyclohexyl-1,2-dihydro-~I,~n,4-benzothiadiazine-1, a-dioxide: A
stirred suspension of 3-cyclohexyl-7-vitro-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (4.2 g; 14 mmol) and 10%
Pd/C (40G mg) in abs. EtOH (100 ml) was hydrogenated at 1 bar. After consumption of the calculated amount of H2, the reaction mixture was filtered through celite. The celite was washed twice with DfUIF {75 ml) and the comk>ined organic fractions were evaporated to dryness. The remanense was resuspended in E=tOAc/i-PrOhi and the precipitate formed, was isolated by filtration. The isolated solid was dissolved in 0.5 M NaOH (aq.) and reprecipitated 2o with 4 M HCI (aq.). Filtr;~tion gave 1.6 g produca.
7-MethyJsulfonyJamino-3-cyclohexyl-l,2-dihyd~o-;1,2,4-benzothiadiazine-1,1-dioxide: A stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (1 g; 3.6 mmol) and triethylarnine (1.2 ml; 8 mrnol) in dry THF (25 ml) was added methanesulfonylchloride {0.6 ml; 8. mmol) and stirred at rt. for 2 h. The reaction mixture was evaporated to dryness, resuspended in H2O/E=tOAc and filtered. The filtrate was adsorbed onto silica gel. Column chromatography (CH2C12:acetone = G:1 ) gave 210 mg of product.
3-Cyclohexyl-7-methyls;ultonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3o (39): 7-Methylsulfonylamino-3-cyciohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method F. M.p. 255-258 °C.
Compound 40 ?7 3-Cyclohexyl-7-nitro-f ,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Trifluoromethyl-1,2,4-benzofhiadiazine-7, 1-dioxide: 2-Aminobenzenesulfonamide was trifluoroac:etyl protected by using Method G. A solution of this (1 g; 4 mmol) in H2S04 (16 ml) at 0 °C was added solid KN03 (4.4 mmol). The reaction mixture was allowed to warm up to rt.
and stirred over night. The reaction mixture was poured into ice water (150 ml), filtered and air dried to give 1.11 g (94%) of pure product as a yellow solid.
3-Cyclohexyl-7-nitro-1, 2, 3, 4-to tra h ydro-1,2, 4-berrzothiadiazine-1,1-dioxide (40):
3-Trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide was subjected to the following transformation scheme: Method U and Methoc:i F (using cyclohexanecarboxaldehyde). M.p.
209-211 "C.
Comaound 41 3-Cyclohexyl-7-phenylsulfonyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 4-Phenylsulfonylaniline~ was used as starting material for the following transformation sequence: Method B and Method G fusing cyclohexanecark:roxaldehyde). M.p. 243-245 °C.
Comaound 42 2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide A solution of 2-aminok>enzylamine (3 g; 25 rnmol) in THF (50 ml) was added trifluoroacetic acid anhydride (3.8 nnl; 27 mmol) and stirrE~d at rt. for 2 h. The reaction mixture was evaporated to dryness, stirred with H20 and filtered. The <:rude product was transformed by Method A (using 25% NH,3 (aq.) as amine) and Method G (using cyclohexanecarboxaldc:hyde). M.p. 178-180 "C.
Compound 43 3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazi ne-1,1-dioxide 4-Sulfamoylanthranilarnide: A stirred solution caf CIS03H (20 ml) was added anthranilamide (7.5 g; 5 5 mmol) in small portions. The reacaior~ mixture was heated to 100 °C for 1 h and 3o then poured into ice water (300 mi). A precipitate formed, which was isolated by filtration and dried on the filter. The isolated solid was dissolved in 25°/~ NH3 (aq.) and stirred at rt. over night. The aqueous phase was washed with LtOAc and concentrated to 20 ml. The aqueous phase was saturated with NaCI (s) and extracted with THF (3x 50 ml). The combined organic fractions were evaporated to dryness and subjected to column chromatography to yield 13 mg product.
3-Cyclohcxyl-7-sulfamnyl-7,2,3,~f-tet~ahydro-l,~t,~4-benzofhia:rdiazine-1,1-dioxide (43): 4-Sulfamoylanthranilamicie was transformed by MEahod G (u;:>ing cyclohexanecarboxaldehyde).
Fab+ 31 U. 'H-NMR (DiMSO-d6): 8.1 (1 H; br.), 8.0 (1 H; d), 7.58 (1 H; dd), 7.3 (1 H; br.), 7.05 {2H; br.), 6.79 (1 H; d), 4.5 (1 H; rn), 1.8-1.5 (6hi; rn), 1.2-1.0 {5H; m).
Compound 44 3-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-sulfamoylbenzenesulfonamide (see compound 101 ) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. x!52-254 "C.
Compound 45 3-Methyl-7-dimethylsulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-7-dimethylsul~farnoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced by use of Method F. M.p. 210-212 "C.
Compound 46 2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazofine N,N-dimethylsulfonamide A solution of 2-aminobenzylamine (3 g; 25 mmol) in THF (50 rnl) was added trifluoroacetic acid anhydride (3.8 rnl; 27 mmol) and stirred at rt. for 2 h. The reaction mixture was evaporated to dryness, stirred with H20 and filtered. The crude product was transformed by Method A (using dimethylamine as amine), Method D and Method G (using cyclohexanecarboxaldehyde). M.p. > 300 °C. M;> (electrospray) M+ 323.
'H-NMR (DMSO-d6):
7.2 (1 H; dd); 7.1 (1 H; cl); 6.68 (1 H; br); 6.62 (11 H; d); 3.85 (1 H; s);
3.8 (2H; s); 2.2 (1 H; br); 1.8-1.0 (11 H; m).
Compound 47 3-Cyclohexyl-7-dimethylaminosutfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using dimethylamine as amine), Method F. Nl.p. 243-245 °C.
Compound 48 3-Cyclohexyl-7-(N,N-diiethylamina)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfon.arnide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using diethyiamine as amine), Method F. M.p. 207-209 °C.
Compound 49 3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazine-1,1-dioxide 2-Aminobenzenesulfon.amide was used as starting material for the following transformation sequence: Method E (u,~sing cyclohexanecarb~onyl chloride), Method A (using pyrrolidine as amine), Method F. M.p. 244-246 °C..
Compound 50 3-Methyl-7-piperidinosulfony!-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfon.amide was used as starting material for the following transformation sequence: Method C, Method A (using piperidine as amir7e), Method D, Method G
[using paraldehyde and a cat. amount of 'TsOH]. Nl.p. 2!55-256 °C.
Compound 51 3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfon.amide was used as starting material for the following transformation sequence: Method C, Method A (using pipericiine as amirne), Method D, Method G
[using cyclopropancarboxaldehyde]. M.p. 228-231 °C.
Compound 52 3-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using piperidine as amirne), Method D, Method G
[using isobutyraidehyde]. M.p. 2,'.37-239 "C.
Comaound 53 3-propyl-7-piperidinosulfonyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation 5 sequence: Method C, Method A (u~~ing piperidine as amine), Method D, Method G (using butyraldehyde]. M.p. 14 7.4-151.:2 °C
Compound 54 3-Benzyl-7-piperidinosutfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 10 2-Aminobenzenesulfonanride was used as sl:arting material for the following transformation sequence: Method C, Method A (using piperidine as amine), Method D, Method G
(using phenylacetaldehyde I. M.p. 242-244 °C.
Comaound 55 15 3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide Cyclopenfanecarboxaldehyde: A stirred solution of cyclopentanecarboxylic acid (2.16 ml; 20 mmol) in dry THF (50 rnl) at rt. under N2 was added NaBH4 (2.28 g; fi0 mmol) and left with stirring for 20 min. The reaction mixture was cooled to 0 °(:; and added BF30Et2 (10 ml; 80 mmol) over 1 h, while 'the reaction temperaturEa was kept below +3 °C.
The reaction mixture 20 was allowed to warm up to rt. and left with stirring aver night. The reaction mixture was added NaHC03 (sat., aq.), H20 and extracted with EtOAc. The combined organic fractions were washed with NaCI (sat., aq.), dried (Na2SO4) and evaporated to dryness to give 1.4 g of an oil which was used without further purification.
The oil (1.4 g) was dissolved in CH2CI2 (75 rnl) and added PCC on AI203 (30 g;
30 mmol)' 25 and left with stirring for 1 h at rt. The reaction rnixture was filtered and the filtrate evaporated onto silica. Column chromatography afforded the pure aldehyde which was used as a solution in CH2C12.
'[see Cheng'~'.-S, Liu W.-L. and Chen S -H., Synthesis, (1980) 2.?3 J
30 3-Cyclopenty!-7-piperid'inosulfonyl-1,2,3,4-tetr,~hyrdro-1,2,4-benzothiadiazlne-1,1-dioxide (55):
2-Aminobenzenesulfonamide was used as sl:arting material for the following transformation sequence: Method C, Method A (using piperidine as amine), Method D, Method G
[using cyclopentanecarboxaldehydey. M.p. '~?58-260 "C..
WO 99!42456 PCT/DK99/00070 Compound 56 3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as darting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using piperidine as amine), Method F. M.p. 262-264 "C.
Compound 57 3-Bicyclo[2.2.1 )hept-5'-en-2'-yl-7-pi peridinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-diaxide 2-Aminobenzenesulfonamide was used as sl:arting material for the following transformation sequence: Method C, Method A (using piperiidine as amine), Method D, Method G
[using a racemic endolexo mixaure of 2-norbornencarboxaldehyde). Two separate diastereomeric mixtures were isolated with m.p. (A) ;?40-242 "C and m.p. (B) 234-238 °C.
Compound 58 3-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidina)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonarrride was used as starting material for the following transformation 2o sequence;: Method E (using cyclohexanecarbonyl chloride), Method A (using 7 ,2,3,6-tetrahydropyridine as amine), Method F. M.p. 23J-239 °C.
Compound 59 3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride)., Method A (using N-methylaniline as amine), Method F. M.p. 210-212 °C.
Compound 60 3-Cyclohexyl-7-(1'-(1',2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide $2 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanec:arbonyl chloride), Method A (using 1,2,3,4-tetrahydroquinoline as amine), Method F. M.p. 218-220 °C.
Compound 61 3-Cyclohexyl-7-(4'-methyl piperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, Method A (using N-methylpiperazinEa as amine), Method D, Method G
(using cyclohexanecarboxaldehyde) M.p. 227-229 °C.
61 methane sulfonate salt: 61 (0.6 g; 1.4 mmol) was dissolved in 99% EtOH {30 ml) and added a solution of 1 M C:,H3SO3H in 99°ia EtOH. The mixture was left for precipitation for 2 h and the salt isolated by filtration. The composition of thc~ sall was checked by HPLC for stability compared to the free base. The salt was found to be stable towards hydrolysis under these conditions and had a water solubility of 10 mg/ml.
Compound 62 3-Cyclohexyl-7-(4'-methylsulfonylpiperazi no)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide N-Mesylpiperazinium chloride: To a stirred solution of piperazine (4.3 g; 50 mmol) in CH2C12 (50 ml) at +5 °C was added a solution of CH3SO2C1 (4.25 ml; 55 mmol) in CH2CI2 (15 ml).
The thick reaction mixture was stirred at rt. for 12 h, added CH2C12 (100 ml), and extracted with 1 M HCI (300 ml). A precipitate formed in the aqueous phase was filtered of to give 2.66 g of N-mesylpiperazinium chloride (32 %).
3-Cyclohexyl-7-(4'-men"hylsulfonylpiperazino)suifnnyl-1,2, 3,~-tetrahydro-1,2, benzofhiadiazine-1,1-dioxide (62): 2--Aminobenzenesulfonamide was used as starting material for the following transformation sequence: AAethod E (using cyclohexanecarbonyl chloride), Method A (using N-Mesylpiperazinium chloride as amine (1.5 eq.), 3 eq. K2C03 was used for neutralization), Method F. M.p. 272-274 °C.
Compound 63 3-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as amine), Method F. M.p. 262-264 °C..
Compound 64 3-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-7-bromo-1,2.,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Bromo~-2-aminobenzenesulfonarr~ide (see compound 18) was transformed by Method G
(using a racemic endo/exo mixture of bicyclo[2.2.1 ]hept-5-E:ne-2-carboxaldehyde). M.p. 200-204 °C.
Compound 65 2-Methyl-4-axo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide 2-Methyl-4-oxo-3,4-dihydroquinazoline: A solution of anthranilamide (13.6 g;
100 mmol) in acetic acid (100 ml) was refluxed for 60 h. The reaction mixture was evaporated to dryness, suspended in H20, filtered and washed thoroughly with Nal-IC03 until the filtrate had a pH of 8-8.5.
2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-~dirrrethylsulfonamide: 2-Methyl-4-oxo-3,4-dihydroquinazoline was transformed by Method A (using dirnethylamine as amine). M.p. 264-266 ° C.
Comaound 66 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoiine sulfonamide 2-Trilfluoroacetamidobenzamide (seE~ compound 68) was transformed by Method A
{Using 0.5 M NH,3 in THF as amine). M.p. 311-314 °C.
Compound 67 2-Trifluoromethyl-4-oxo-3,4-dihydra-6-quinazoiine N,N-dimethylsulfonamide 2-Trilfluoroacetamidobenzamide (see compound 68) was transformed by Method A
(Using dimethylamine as aminE~). M.p. 257-258 °C.
Compound 68 2-Trifluoromethyl-4-ox:o-3,4-dihydro-6-quinazoline-1',2',3'',6'-tetrahydropiperidinosulfonamide A stirred mixture of anthranilamide (13.6 g; 100 mmol) in ~~fHF (100 ml) at 0 °C was added trifluoroacetic acid anhydride (15.2 rr7l; 110 mmol) and allowed to warm up to rt. and left with stirring over night. The reaction mixture was evaporated to dryness, suspended in H20 and filtered. The isolated solid was air dried to give 21.6 g (93°/«) 2-trilfluoroacetamidobenzamide.
2-TriIfIuoroacetamidobE:nzamide was transformed by Method A (using 1,2,3,6-tetrahydropyridine as amine). M.p. 2~'7-230 °C.
Compound 69 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide 2-Trilfluoroacetamidobenzamide (sere compouncl 68) was transformed by Method A
(Using cyclohexylamine as amine). M.p. 261-263 °C.
Compound 70 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide 2-Trilfluoroacetamidobenzamide (see compound 68) was transformed by Method A
(Using morpholine as amine). M.p. 282-285 °C.
Compound 71 2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide Antranilamide was used as starting material for the following transformation sequence:
Method A (Using 25% NF-13 (aq.) as amine. The reaction mixture contained both the 5-mono and 5,7-disulfonamide, which were separated by chromatography), Method G
(using cyclohexanecarboxaldehyde. The arninal auto oxidizes to the aromatic hydroxyquinazoline).
M.p. 306-310 °C.
Compound 72 3-Methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,~!-dioxide (see compound 73) was transformed by Method A (using 0.5M NH3 in THi= as amine). M.p. 295-297 °C.
WO 99/42456 PC'.T/DK99/00070 Compound 73 3-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide (17.2 g; 100 rnrnol) was refluxed in AcOH for 5 days. The precipitate formed was isolated by filtration and washed with water to give 17.8 g (91 %) of 3-5 methyl-1,2-dihydro-1,2,4-benzothiadcazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method A {using dimethylamine as amine).
M.p. 260-261 °C.
Compound 74 10 3-Methyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) was transformed by Method A (using 1,~~,3,6-tetrahydropiperidine .as amine). M.p. 265-268 °C.
15 Compound 75 3-Methyl-7-cyclohexyisulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-11,'1-dioxide (see compound 73) was transformed by Method A (using cyc:lohexylamine as amine). M.p. 239-242 °C.
2o Compound 76 3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C and Method A fusing dirnEahylamine as amine). M.p. 240-242 °C.
25 Compound 77 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinaxolinesulfonic acid 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequencE~: Method C and Method A fusing Na~Of~i instead of an amine). M.p.
>330 °C.
3o Compound 78 3-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide m-Toluidine was used as starting material for the following transformation sequence: Method B [2-amino-6-methylbenzenesultonamide was separated from 2-amino-4-methylbenzenesulfonamide by recry:>tallization (EtOAc/hexane)]. 2-Amino-6-methylbenzenesulfonamide was further purified by column chromatography and transformed by Method G (using cyclohexanecarboxaldehydca). M.p. 228-230 °C.
Compound 79 3-Cyclohexyl-8-hydrox:ymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-7,2-dihydro-t,~',4-benzothiadiazine-1,1-dioxide-8-carboxylic acid: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 80) (0.30 d, t .0 mmol) in dry THF' (15 ml) ,~t: -78 °C was added s-BuLi in cyclohexane (1.3 M, 1.E~ ml, 2.1 mmoi) under i'J2. 'The yellow mixture was stirred for 15 min at -78 °C and dry gaseous. C02 was bubbled throucth the solution for 30 min. The cooling bath was removed and the rnixture was allowed to warm to 0 ''C. -The solvent was removed under reduced pressure and the residue was triturated with hydrochloric acid (0.2 M, 12 ml). The crude product was rec:rystallised from 50 °~~ MeOH yielding 300 mg (82%) of 5-chloro-3 cyclohexyl-1,2-dihydro-1,2,4-benzoth~adiazine-1,1-dioxide-8-carboxylic acid as colorless ~ 5 crystals.
3-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-l, l-dioxide-8-carboxylic acid: 5-Chloro-3-cyclohexyl-1,2-dihydro-1,a?,4-benzothiadiazine-1,1-dioxide-8~-carboxylic acid (160 mg, 0.47 mmol) was dissolved in 90 % EtOH (50 ml) and hydrogenated using Pd/C (10 %, 10 mg) at 1 bar pressure for 24 h. NaOH (1 M, 12 ml) was added and the mixture was filtered through a pad of CeliteT"' and concentrated to 10 ml and concentrated hydrachloric acid was added slowly to precipitate the product yielding 11 l) mg (76%) of 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid as colorless powder.
3-Cyclohexyl-8-hydroxymeth.yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (79):
NaBH4 in triglyme (2M, 0.75 ml, 1.5 mmol) was dissolved in dry THF (20 ml) and cooled to -50 °C under N2,. BF3-etherate (0.25 ml, 2.0 mmol) was added and the mixture was stirred for 10 min at -50 °C. Solid 3-cyclohexyl-1,2-dihydro-1,,?,4-benzothiadiazine-1 ,1-dioxide-8-carboxylic acid (170 mg, 0.55 mmol) was added in one portion and the suspension was stirred for 6 h at -50 °C and overnight at 20 °C. The mixture was hydrolysed with hydrochloric acid (1 M, 2 ml) and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (50 ml) and the organic; layer was washed with brine (10 ml), dried (Na2S04) and the evaporated to dryness. The product was purified by flash chromatography on Si02 using EtOAc:n-hexane (2:1, v/v) as eluerzt, yielding 1 C>C) mg (62 %;) of 3-cyclohexyl-8-hydroxymethyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless needles. The product was further transformed by Method F. M.p. 220-223 °C.
Compound 80 3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-1,2-dihydro-1,~,4-benzothiadiazine-1,-1-dioxide: 3-Chloroaniline was used as starting material for the following transformation sequence: Method B
followed by Method E (using cycloh~sxylcarbanyl chloride).
5-Chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,~?,4-t>E~nzothiadiazine-~, i-dioxide: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydrc>-1,2,4-benzot:hiadiazine-1,1-dioxide (596 mg, 2 mmol) in dry THF (20 ml) at -78 °C was added s-BuLi in c.yclohexane (-1.3 M, 3.8 ml, 5 mmol) under N2.
The yellow mixture was stirred for 15 min at -T8 °C and a solution of 12 (1.27 g, 5 mmol) in dry THF (5 ml) was added. The cooling bath was removed and the mixture was allowed to warm to 0 °C. NaHS03 (5 °ro, 20 ml) was added and extracteca with EtOAc (2 x 30 ml), dried (Na2S04) and evaporated to dryness to give 0.76 g (90 %) of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1.1-dioxide.
5-Chloro-3-cyclohexyl-8-(2-methoxyphenyl)-l,a?-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: A
mixture of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (290 mg, 0.68 mmol), 2-methoxyphenylboronic acid {122 mg, 0.80 mmol), Pd(PPh3)2C12 (10 mg, 2 mol %) in 1,2-dimethoxyethane (50 rnl) and Na2C03 (2M, 2 rnl, 4 mmol) were refluxed under N2 for 2 h. The solvE~nts were removed under reduced pressure and the residue was extracted with EtOAc (:? x 40 ml) and the organic layer was washed with saturated NaHC03 (20 ml), dried (Na2SOa; and the solvent was iremoved undc:~r reduced pressure.
The product was purified by flash chromatography on SicJ; using EtOAc:n-hexane (1:2, v/v) as eluent, yielding 200 mg {73 °~~) of 5-chioro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-t~enzothiadiazine-1,1-dioxide (80):
5-Chloro-3-cyclohexyl-8-(2-methoxyphenyl)-~1,;2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (190 mg, 0.47 mmol) was dissolved ~n 99 °~o EaOH (30 ml) and hydrogenated using Pd/C (10 %, 10 mg) at 1 bar pressure. 'The mixture vva~~ filtered through a pad of CeliteT"" and the solvent was removed under reduced pressure yielding 174 mg (100 %) of 5-chloro-cyclohexyV-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals. The product w<~s transformed by Method F. M.p. 100-105 °C.
Compound 81 3-Cyclohexyl-8-(3-methoxyphenyf)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide Synthesis as for compound 80 (using 3-methoxyphenylbc:~ronic acid for the Pd-cat. cross coupling). M.p. 108-115 °C:;.
Compound 82 3-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydro-'1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-b'-(dihydraxyboryl)-l,a?-a'ihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a solution of 5-chlo~ro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 80) (0.60 d, 2.0 mmol) in dry Tf-IF (15 ml) at -78 °C was added s-BuLi in cyclohexane (1.3 M, 3.l3 ml, 5 mmol) under N,~. The yellow mixture was stirred for 15 min at -78 °C and B(OCH3)3 (0.57 ml, 5 mmol) was added. The ccaoling bath was removed and the mixture was allowed to warm to 0 "C and stirred for another 1 h. The mixture was hydrolysed with hydrochloric acid (0.5 M, 12 rnl) and extracted with EI:OAc (2 x 50 ml), dried (Na2S04) and evaporated to dryness to give 0.65 g {95 °,~o) of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.
5-Chloro-;3-cyclohexyl-~~-(2-pyridyl)~-1,2-dihydra-P,2,4-benzofhiadiazine-1,1-dioxide: A mixture of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl;i-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440 mg" 1.28 mmol), ~'--bromopyridine (0.14 ml, 1.50 mmol), Pd(PPh3)2Clz (10 mg, 2 mol %) in 1,2-dirnethoxyethane (30 ml) and Na2C0;, (2M, 3 ml, 6 mrnol) were refluxed under N2 for 24 h. The solvents were removed under reduced pressure and the residue was treated with saturated NH4C1 (10 ml) and extracted with EtOAc (2 x 40 nol). The organic layer was washed with water (20 ml), dried (NalS04) and the solvent was remcpved under reduced pressure. The product was purified by flash chromatography on Si02 using EtOAc:n-hexane (2.1, v/v) as eluent, yielding 280 mc~ (,58 °/>) of 5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-3o benzothiadiazine-1,1-dioxide as colorless crystals.
3-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-fetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (82): 5-chioro-3-cycfohexyl-8-(a?-pyridyl)--1,2-dihydro-1,2,,4-benzothiadiazine-1,1-dioxide (0.268 g, 0.713 mrnol) was dissolved in 99 % EtOH (50 rnl) and hycarogenated using Pd/C
(10 %, 10 mg) at 4 bar pressure for 24 h. The mixture was filtered through a pad of CeliteT"" and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 ml) and washed with phosphate buffer (pH=7, 10 ml), dried (NazSO4) and the solvent was removed under reduced pressure, yielding 20() mg (82 %) of 3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide a:~ colorless crystals. The product was further transformed by Method F M.p. 200-203 °C.
Compound 83 3-Cyclohexyl-8-methoxy-1,2,3,4-tetrahyd ro-1,2,4-benzoth iadiazi ne-1,1-dioxide m-Anisidine was used as starting material for the following transformation sequence: Method B (2-amino-6-methoxybenzenesulfonamide was separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtC:)Ac/hexane)] and then Method G
(using cyclohexanecarboxaldehyde). M.p. 221-223 °C.
Compound 84 5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobenzenesulfonamide (;see compound 125) was transformed by Method G {using ethylformiat and a catalytic amount of triethylamine). M.p. 289-292 °C.
Compound 85 and compound 86 3-Cyclohexyl-2-methyl-T-morpholinosulfonyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (85) and 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazinc~-1,1-dioxide (86) 3-Cyclohexyl-7-morpholinosulfonyl-?~2-dihydro-?,,2,4-benzothiadiazine-?, ?-dioxide: 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cyclohexanecarborryl chloride) and Method A (using morpholine as amine) which gave 3-cyclohexyl-7-morpholinosulfonyl-1,,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.
3-Cyclohsxyl-2-methyl-7-morpholinasulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,?-dioxide and 3-cyclohexyl-4-methyl-7-morpholincrsulfonyl-?,2-dihydro-?,2,4-benzofhiadiazine-1, ?-dioxide: A mixture of 3-cyclohexyi-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (2 g; 5 mmol), DEAC> (2.35 ml; 15 mrnol), PPh3 (4 g; 15 mmol) in dry THF (30 ml) was cooled to 0 °C and added MeOH (1.25 ml; 30 mmol). The reaction mixture was stirred over night at rt., evaporated to dryness, stirred with EaOAc and filtered. The isolated precipitate was stirred with CH2C12 and filtered to leave the 2-methyl isomer in the filtrate and the 4-methyl isomer as the precipitatE:.
The 4-methyl was purified by recrystalizalion from DMSO/H2O. The 2-methyl isomer was 5 purified by column chromatography (EtOAcl.
3-Cyclohexyl-2-methyl-7-rnorpholinosulfon yl-1,~, 3, 4-tetrahydro-1,2, 4-benzothiadiazine-1,1-dioxide (85): 3-Cyclohexyl-2-methyl-7-morpholir~osulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced by use of method F. M.p. 243-245 "C.
3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahyc:fro-1,2,4-benzofhiadiazine-1,1-dioxide (86): 3-CycIohE~xyl-4-methyl-7-morpholinosulfonyi-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was reduced by use of method F. M.p. 207-210 °C.
Compound 87 7-Methylsulfonylamin~o-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 1,2,3,5-tefrahydrobenz~[eJpyrralo/2,1-cJ-1,2,4-ihiadiazine-5,5-dioxide: 2-Aminobenzene-sulfonamide was transformed by Method E (uaing 4-chlorobutanoyl chlaride).
7-Nitro-1,2,3,5-tetrahydrobenzo~eJpyrrolo(2,1-cJ-1,2,4-thiadnzine-5,5-dioxide:
A stirred solution of 1,2,3,5-tetr.ahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (222 mg; 1 mmol) in H2S04 (2 ml) at 5 °C was added a solution of KNO3 (122 mg; 1.2 mmol) in H2S04 (2 ml). The reaction mixture was allowed to warm up to rt. and stirred for 2h.
The reaction mixture was poured into ice water, filtered and air dried to give 190 mg {71 %) product.
7-Amino-1,2,3,5-tefrah.ydrobenzo[e~pyrrolo(2,1-~c)-1,2,4-thiadiazine-5,5-dioxide: A stirred solution of 7-nitro-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-7,2,4-thiadiazine-5,5-dioxide (167 mg; 0.6 mmol) in dry THF (2 ml) at -50 °(~ was addeca LiAIH4 (115 mg; 3 mmol) in one portion. The reaction mixture was allowed to warm up to rt, and stirred over night. The reaction mixture was quenched by addition of H20 and 10 M NaOH, stirred, filtered through celite and evaporated to dryness to give 150 mg product.
7-Methylsulfonylamino- i,2,3, 3a,4,:i-hexahydrobErnzo~e/pyrrolo(2, l -c(-1,2,4-thiadiazine-5,5-dioxide (87): A stirre~~ solution of 7-amino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c~-1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mrnol) and triethylamine (70 pl;
0.5 mmol) in THF
(1 ml) was added a solution of CH3S02C1 (4~0 lal; 0.5 mmol) in THF (1 ml) and stirred at rt.
over night. The reaction mixture was evaporated to dryness, suspended in H20 and extracted by EtOAc. The combined organic fractions were evaporated to dryness.
Column chromatography gave ~10 mg product. M.p. 177-180 °C.
Compound 88 7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c~-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonarnide was used a:~ stari:ing material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using 0.5 M
NH3 in THF as amine), Method F (using LiAIH4 and rt.). M.p, 260-262 °C.
Compound 89 7-Methylsulfamoyl-1,:?,3,3a,4,5-hexahydrobenzo[e]pyrroio[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using methylamine as amine), Method F (using LiAIH4 and rt.). M p. 244-245 °C.
Compound 90 7-Cyclohexylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e] pyrrolo[2,1-c]-1,2,4-th iadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyll c:hloride), ME=thod A (using cyclohexylamine as amine), Method F (using LiAIH4 and rt.). M.p. 195-197 °C.
Compound 91 7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesuifonamide was used as startnng material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), Method A (using dimethylamine as amine), Method F (using l_iAIH4 and rt.). M.p. ;?40-243 °C.
Compound 92 7-Methylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as si:arting materia:~l for the following transformation sequence: Method E (using 4~chlorobutanoyl c:hloride), Method A (using methylamine as amine). M.p. 244-247 °C.
Compound 93 7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo[e)pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was transformed by Method E (using 4-chlorobutanoyl chloride) and Method A (using dimethylamine). M.p. 251 ~~2~53 °C.
Compound 94 7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrabenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl <:hloride), Method A (using cyciohexyiamine as amine). M.p. 151-153 "C.
Compound 95 7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonarnide was used as starting material for the following transformation sequence: Method E (usinc) 4-chlorobui:anoyl chloride), Method A (using 1,2,3,6-tetrahydropyridine as amine). M.p. 204-206 "c;.
Compound 96 3-Bicyclo[2.2.1]hept-!5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2,4-Dimethylaniline was used as si:arting material for the following transformation sequence:
Method B, Method G psing a racemic endoi'exo mixture of bicyclo[2.2.1 ]hept-5-ene-2 carboxaldehyde. Column chromatography gave two diastereomeric fractions each being a mixture of two diastereomers~. Isomeric mixture b, m.p. 160-165 °C;
isomeric mixture B, m.p.
182-187 °C.
Compound 97 3-Cyclohexyl-7-(N,N-diethylsulphamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide io 3-Cyclohexyl-7-(N,N-diethylsulpharno~yl)-5-formyl-1,2-dihydrc7-7,2,4-benzothiadiazine-1,1-dioxide: 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using cy<;Ic7hexanecarbonyl chloride) and Method A
(using diethylamine as amine). The product from this transformation (0.60 g, 1.5 mmol) dissolved in dry THF (1:5 rnl) at -78 °C was added s-BuLi in c;yclohexane (1.3 M, 2.5 ml, 3.2 mmol) under N2. The yE:llow mixture was stirred for 25 min at ~-78 "C. The reaction was quenched with dry DMF (0.3 ml, 4 mrnol) and'rhe mixture was stirred for 20 min at -78 °C. The cooling bath was removed and the mixture was allowed to warm to 0 °C.
Hydrochloric acid (0.5 M, 10 ml) was added and the mixture was extracted with EtOAc (40 ml). The organic layer was washed with brine (10 ml), dried (Na2SO4) and evaporated to dryness.
The residue 2o was dissolved in acetone (8 ml). Et2C> (30 ml) waa added and within few minutes the product crystallises, yielding O.~t1 g (64%) of 3-cyclahexy6'-7-(N,N-diethylsulphamoyl)-5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
3-Cyclohexyl-7-(N, N-di~efhylsulphamoyl)-5-me thyl-1,2,3, 4-tetrahydro-1,2, 4-ben2othiadiazine-1,1-dioxide (97): 3-Cyclohexyl-7~-(N,N-diethylsulphamoyl)-5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.20 g, 0.46 rnmol) was dissolved in 99 % EtOH
(60 ml). One small drop of concentrated hydrochloric acid vvas added to ensure fully hydrogenation. The mixture was hydrogenated using PdiC (10 '%, 10 mg) at 4 bar pressure for 24 h.
The mixture was filtered through a pad of CeliteT"" and evaporated to dryness. The residue was dissolved in EtOAc (50 ml) and washed with water (10 nnl}, dried (Na2SO4) and evaporated to dryness yielding 0.18 mg (95%) of 3-cyclohexyl-7-(N,hJ-~liethylsulphamoyl)-5-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless po~nrde~r. The product was further transformed by Method F'. M.p. 206-208 "C.
Compound 98 3-Bicyclo[2.2.1 ]kept-5'-en-2'-yl-5,7-Biphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3,5-Dibromo-2-aminobe;nzenesulfonamide (see compound 125) was transformed by Method H (using phenylboronic acid) and Method Ca (using a, racemic endo/exo mixture of bicyclo[2.2.1]hept-5-ene-2-carboxaidehyde). M.p. 222-225 °~~.
Compound 99 3-Bicyclo[2.2.1]hept-5'-en-2'-yi-5,7-disulfamoyi-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide was transformed by Method A (using 25% NHg (aq.) as amine) and Method G (using using a racemic endo/exo mixture of bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde). M.p. 172-180 "C.
Compound 100 3-Bicyclo[2.2.1 ]hept-5'-en-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2,4-Dichloroaniline was transformed by Method B and Method G (using a racemic endo/exo mixture of bicyclo[2.a?.1 Jhept-5-ene-2-carboxaldehyde. The product was isolated as a diastereomeric mixture). M.p. 149-151 °C.
Compound 101 5-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-sulfamoylbenzenesulfonamide: A :>tirred suspension of 2-amino-4-chloro-5-sulfamoylbenzenesulfonamide (11.4 g; 40 mmol) and 10°/a Pd/C (750 mg) in EtOH (300 ml) was hydrogenated at 1 bar until hydrogen consumption ceased (24 h). The reaction mixture was evaporated to dryness, resuspended in THF and filtered through celite. The filtrate was evaporated to dryness and the isolated solid washed with boiling EtOAc (2x 150 ml) to give 9.58 g (95%) product.
2-Amino-3-bromo-5-sulfamoylbenzenesulfc>namide: A stirred solution of 2-amino-sulfamoylbenzenesulfonamide (3.77 g; 15 mmol) in AcOH (50 ml) was added a solution of Br2 (0.78 ml; 15 mmol) in AcOH (10 ml). The reaction mixture was heated to 70 °C for 6 days, evaporated to dryness, resuspended in MeOf-I (85 ml) and added solid KOH (3.8 g; 68 mmol).
The reaction mixture was heated to 60 °C for 2.5 h (hydrolysis of 3-methyl-, 3-bromomethyl-, 3-dibromomethyl and ~s-tribromomethyl-1,2-dihydro-i ,2,4-bEanzothiadiazine isomers formed in 5 situ), filtered, neutralized and evaporated to dryness. Column chromatography gave 3.1 g (63%) product.
5-Broma-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tef~ahydro-1,2,4-benzothiadiazine-1,1-dioxide (i01): 2-Amino-3-bromo-5-sulfamoylbenzene~sulfonamide was transformed by Method G
10 (using cyclohexanecarboxaldehyde) M.p. 254-258 °C.
Comaound 102 2-Bicyclo[2.2.1 ]hept-5.'-en-2'-yl-6,8-dibromo-1,2,3,4-tetrahydroquinazoline 2-Amino-3,5-dibromob~enzylamine: A mixture of 2-aminobenzylamine (6.1 g; 50 mmol) in 15 CHC13 (100 ml) at 0 °(~ was added a salution Br2 (5.1 ml; 100 mmol) in CHCI3 (45 ml) such that the reaction temperature was kept below +2 °C. Cooling was then removed and the reaction mixture was stirred at rt. over night. The reaction mixture was filtered and the precipitate washed with EtOAc and purified by column chromatography.
20 2-Bicycloj2.2.1Jhept-5'-err-2'-yl-6,8-dibroma-1,2,;3,4-tetrahydroquinazoline (102): 2-Amino-3,5-dibromobenzylamine was transformed by Method G (using a racemic endo/exo mixture of 2-norbornencarboxaldehyde). M.p. 240 °C.
Compound 103 25 2-Bicyclo[2.2.1]hept-!i'-en-2'-yl-G,8-dibromo-4-oxo-1,2,3,4-tetrahydroquinazoline 3,5-Dibramoanthranilamide: A stirred suspension of anthranilamide (13.6 g; 0.1 mol) in AcOH
(350 ml) was added a solution of Br2 (10.3 ml; 0.2 mol). l-he reaction mixture was stirred at 45 °C for 120 °C, poured into H20 (1.5 I) and filtered.
Hecrystalization (including a warm filtration) from 96% EtIJH (approx. 1 I) gave 23.6 g (80%) product.
2-Bicyclo(2.2.1Jhept-5'-en-2'-yl-6,8-dibroma-4-caxo-1,2,3,4-tctrahydraquinazoline (103): 3,5-Dibromoanthranilamide was transformed by Method G (using using a racemic endo/exo mixture of bicyclo[2.2.'I]hept-5-ene-2-carboxaldE:hyde). The: product was separated into to individual diastereomeric mixtures. M.p. (A) 213-215 °C, M.~r. (B) 209-210 °C.
Compound 104 3-Bicyclo[2.2.1]hept-5'-en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobenrenesulfonamide (see compound 125) was transformed by Method G (using a racemic endo/exo mixture of bicyclo[2.2.1 ]hept-5-ene-2-carboxaldehyde). The diastereomeric mixturE: was purified by column chromatography to give three of the ~0 theoretically four possible diastereomers. M.p. (;A) 202-206 °C, M.p. (B) 796-199 °C, M.p. (C) 180-184 °C.
Compound 105 5,7-Dibromo-3-bicyclo[2.2.1]heptan-2'-yl-1,2,3"4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide Bicyclo[2.2.1 ]heptane-;?-carboxaldehyde: A stirred suspension of 2-norbornylmethanol (0.5 ml; 5.8 mmol) and PC(:, on A1203" in CH2CIp (25 ml) was stirred at 2-3 °C for 1 h and then allowed to slowly warim up to rt. The reaction mixture was filtered and the solid material washed with CH2C12 1;2x 25 ml). The combinE;d organic fractions were adsorbed onto silica and chromatographed to give 300 mg (42%) product as an oil.
'Jsee Cheng Y.-S, Liu W.-L. end Chen S.-H., Synthesis, (1980) 22".J
5,7-Dibromo-3-norbornanyt-1,2,3,4-tetrahydrc~-t,2,4-benzothiadiazine-1,1-dioxide (105): 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G
(using bicyclo[2.2.1 ]heptane-2-carboxaldehyde). M.p. 182-183 °C.
Compound 106 3-Cyclohexyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using cyclohexanec;arboxaldehyde). M.p. 16E~-167 °C.
Compound 107 3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 1-Adamantanecarboxaldehyde: 1-Adamantylrnethanol was oxidized by the method used for 2-norbornylmethanol (see compound 105)'.
'(see Cheng Y.-S, Liu W.-L. and (:hen S.-H., Synthesis, (1980) 223.
3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (107): 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G
(using 1-adamantylcarboxaldehyde). M.p. 270-2.73 °C.
Compound 108 3-Phenyl-5,7-dibromo-~1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobE~nzenesulfonamide (see compound '125) was transformed by Method G {using benzaldehyde). M.p. 186-189 °C.
Compound 109 3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide A stirred mixture of 2-aimino-3,5-dibromobenzenesulfonamide (see compound 125) (666 mg;
2 mmol), ethylorthoforrniate (15 mi; 90 mmol) and H2S04 {0.05 ml) was refluxed over night.
The reaction mixture was evaporated to dryness and subjected to column chromatography.
M.p. 96-98 °C.
Compound 110 3-Methyl-5,7-dibromo-1,2-dihydro-'1,2,4-benzothiadiazine-1,1-dioxide A stirred solution of 2-<amino-3,5-dibromobenzenesulfonamide {see compound 125) (660 mg;
2 mmol) was refluxed in Ac20 (25 ml; 265 mmol) over night. The reaction mixture was poured onto ice and filtered. The isolated solid was washed with Et20. M.p. 287-289 °C.
Compound 111 3-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide To a solution of t-BuLi (1 7 M in pentane, 25 ml, 42 mmol) in dry THF at -78°C was added 2-bromopyridine (1.9 ml, 20 mmol) in such a rate that the temperature did not exceed -70°C.
The mixture was stirred for another 30 min at -78°C. A solution of ZnCl2 (2M in THF, 30 ml, 60 mmol) was added slowly and the cooling bath was removed and warmed to 20°C. 5-lodo-2-g8 aminobenzenesulfonamide (see compound 37) (1.0 g, 3.2 mmol) and Pd(PPh3)4 (0.3 g, 8 mol%) was added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was treated wilh FDTA (5:3 g, 0.18 mol) and made slightly basic (pH =
8-9) with 1 M
NaOH followed by extraction with E=tC7Ac (3 x '100 ml), dryinc:l (Na;>SO4).
The organic layer was concentrated to ca. 40 rnl and n-hexane was added slowly. The product was filtered off, yielding 0.72 g (87 %) of 2-amino-4-methyl-5-(2-pyridyl)-1-benzenesulfonamide as light-yellow crystals. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 229-231 "c:,.
Compound 112 3-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazi ne-1,1-dioxide 5-Iodo-4-methy!-2-aminobenzenesulfonamide: m-Toluidine was transformed by method B and the two isomers separated by column chromatography to give 4-methyl-2-aminobenzenesulfonarnide.
A stirred suspension of 4-methyl-2-aminobenzenesulfonarraide (620 mg; 3.3 mmol) in CHCI3 (7 ml) at 0 °C was added a solution of iodine monochloride (1.6 g; 9.9 mmol) in CHCI3 (7 ml).
The reaction mixture was stirred at 0 °C until H-NMR indicated full conversion of starting material. The reaction mixture was filtered arid i:he isolated solid washed with small volumes of CHCI3, NaHC03 {sat. aq.), H2O and air dried to give 640 mg (62 %) of product.
3-Cyclahexyl-6-methyl~~7-(4'-triazofyl)-1,2,3,4-a~etrahydro-1,2,4-benzothiadiazine-1,1-dioxide (112J: 5-lodo-4-methyl-2-aminobenz enesulfonarnide was transformed by Method I
(using trimethylsilylacetylene) and Method G (using cyclohexanecarboxaldehyde). FAB+
348. 'H-NMR (DMSO-d6): 8.0 (1 H; br); 7.65 (1 H; br); 7.25 (1 H; s;); 7.22 (1 H; s);
6.95 (1 H; br); 6.8 (1 H;
s); 4.45 (1H; dd); 2.35 (3F-1; s); 1.95-1.8 (2H; rn); 1.8-1.6 (31-I; m); 1.3-1.0 (6H; m).
Compound 113 3-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide N-Acetyl-3-methylaniline: m-Toluidine (10 mP; 93 mmol) was added to a stirred solution of acetic anhydride (30 ml). The reaction mixture was stirred for 1,5 h at rt., evaporated to dryness, stirred with H,2O and filtered to give 13 g product (94%).
3-Cyclohexyl-6-methyl-7-sulfamoyl-7,2,3,4-tetiahydro-1,2,4-benzothiadiazine-1, i-dioxide: N-Acetyl-3-rnethylaniline was transformed by Method A (using 25% NH3 (aq.) as amine.
Deacetylation was complete) and Method G (using cyclohexanecarboxaldehyde).
M.p. 231-233 °C.
Compound 114 3-Cyclopentyl-6-methyl-7-piperidinosulfanyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide Cyclopentanecarbonyl chloride: CyclopentanE:carboxylic acid (0.55 ml; 5 mmol) was refluxed in thionylchloride (1 ml) for 3 h. The reaction mixture was cooled to rt., evaporated to dryness and used directly without any purification.
3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2, 3, 4-tetrahydro-1,2, 4-benzothia-diazine-1,1-dioxide (714): m-Toluidine was used as starting material for the following transformation sequence: Method B [2-amino-fi-rnethylbenzenE;sulfonamide was separated from 2-amino-4-methylbenzenesulfonamide by recrystalli~:ation (EtOAc/hexane)), Method E
(using cyclopentanecarbonyl chloride), Method A (using piperidine as amine), Method F. M.p. 229-230 °C.
Compound 115 3-Cyciohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide m-Toluidine was used as starting material for the following transformation sequence: Method B [2-amino-6-methylbenzenesulfanamidE: was separated from 2-amino-4 methylbenzenesulfonamide by recrystallization (EtOAc/hexane)), Method E (using cyclohexanecarbonyl chloride), Method A (ush7c~ morpholirne as amine), Method F. M.p. 268-271 °C.
Compound 116 3o 3-Cyclohexyl-6-(2-methoxyphenyl)-7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Bromo-4-methylaniline was transformed by Method B (The isomers were separated by fractional crystallization from MeQH) to give :?-amino-4-bromo-5-methylbenzenesulfonamide.
A mixture of 2-amino-4-bromo-5-rrrethylbenzenesulfonamide {100 mg, 0.38 mmol), methoxyphenylboronic acid (76 mg, 0.5C) mmol), Pd(PPh,)2C12 (13 mg, 5 mol %) in 1,2-dimethoxyethane (20 ml) and NaZC03 {2M, 1 rnl, 2 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCOs (10 ml) and extracted with EtOAc (~~ x 25 ml). The organic layer was washed with brine (20 ml), dried (Na2S04) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on Si02 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 100 mg (90 %) of 2-amino-4-(2-rnethoxyphenyl)-5-methylbenzenesulfonamide as colorless powder. The product was further tran:~formed by Method G (using cyclohexanecarboxalde:hyde). M.p. 172-175 °C.
Compound 117 3-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide m-Anisidine was used as starting material for the following transformation sequence: Method B [2-amino-6-methoxybenzenesulfonamide was separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc/hexane)), Method C, Method A (using piperidine as amine), Method D, Method G (using cyclohexanecarboxaldehyde). M.p.
237-240 °C.
Compound 118 and compound 122 3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (122) and 3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (118) 6-Amino-1,4-benzodio~;ane was used as startin<~ material and transformed into a mixture of ethylendioxy-2-aminob~enzenesulfonamide isomers by use of Method B. The two isomers were separated by column chromatography.
3-Cyclohexyl-6,7-ethylc~nedioxy-1,2,3,4-fefrah,yd~o-1,2,4-ber~zothiadiazine-1,1-dioxide (118):
2-amino-5,6-ethylendioxybenzenesulfonamidc: was transformed by use of Method G
(using cyclohexanecarboxylaldehyde). M.p. 196-200 °C.
3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (722):
2-amino-7,8-ethylendiox:ybenzenesulfonamide was transformed by use of Method G
(using cyclohexanecarboxylaldehyde). M.p. '~68-270 "C..
Compound t 19 3-Cyclohexyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-4-chloro-5-sulf~arnoylbenzenesulfonarnid~e was transformed by Method G
(using cyclohexanecarboxaldehyde). M.p. 2;'4-276 °~;.
Compound 120 3-Phenyl-6-chloro-7-sulfarnoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-4-chloro-5-sulfamoylbenzc:nesulfonarnide was transformed by Method G
(using benzaldehyde). M.p. 235-238 "C.
Compound 121 3-Cyclohexyl-6-bromo-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide m-Bromoaniline was used as starting material for the following transformation sequence:
Method B [2-amino-6-bromobenzenesulfonamide was separated from 2-amino-4-bromobenzenesulfonarnide by recrystallizatian (EtOAc/hexane)~, Method C, Method A (using piperidine as amine), Method D, Method G (u~;incl cyclohexanecarboxaldehyde).
M.p. 238-241 °C.
Compound 122 See compound 118.
Compound 123 2-cyclohexylmethylamino-5-N,N-dimethytsulfamoylbenzenesulfonamide 2-Aminobenzenesutfonamide was used as starting material for the following transformation sequence: Method E (using cyc:lohexanecarbonyl chloride;l, Method A (using dimethylamine as amine), Method F (the reaction mixture was Ic:ft over night with DIBALH at rt. with stirring).
M.p. 123-125 °C.
1 C)2 Compound 124 2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzene sulfonamide 3-Methyl-1,2-dihydro-1,a?,4-benzothiadiazine-1,1-dioxide {see compound 73) was transformed by Method A (using 1,2,3,6-tetrahydropyridine as amine) followed by Method F
(using LiAIH4 and rt.). M.p. 175-177 °(:,.
Compound 125 2-Amino-3,5-dibromobenzenesulfonamide A stirred solution of 2-aminobenzenesulfonarnide (8.6 g; 50 mrnol) in AcOH
(100 ml) was slowly added a solution of Br2 (5.13 ml; 100 mmol) in AcI.~H (20 ml). The reaction mixture was heated to 55 °C for 60 h, poured into ice vvater (800 ml), filtered, adsorbed onto silica and purified by column chromatography to give 11.1 g (67 %) product. M.p. 165-169 °C.
Compound 126 2-Acetamidobenzenesulfonamide A stirred solution of 2-aminobenzenesulfonarnide (1.72 g; 10 mmol) and triethylamine (1.53 ml; 11 mmol) in THF (25 rnl) at 0 °C was addE:d ,AcCI (0.85 ml; 12 mmol) and left with stirring at rt. over night. The reaction mixture was filtered anri adsorbed onto silica. Column chromatography gave 1I .7 g (79 %) product. M.~>. 153.5-155.5 °C.
Compound 127 3-Isobutyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide N-(3'-Methyl-1'-carboxybutyl)-2-nitrohenzenes~rlfonamide: A solution of 2-nitrobenzenesulfonylchloride (11 g; 50 mmol) and NaOH (2.1 g; 53 mmol) in H20 (100 ml) was added m-leucine (6.55 g; 50 mmol) and Is~ft over night with stirring at rt. The reaction mixture was added 4 M NaOH (12.5 ml) and filtered. The filtrate was acidified with 1 M HCI
(50 ml) and extracted with EtOAc. The combined organic fractions were dried (Na2S04) and evaporated to dryness to give 6.7 g (42%) product.
3-Isobufyl-4-oxo-2,3,4,.5-tetrahydro-T,2,5-ben:~atrhiadiazepine-1,1-dioxide: A
stirred suspension of N-(3'-methyl-1'-c;arboxybutyl)-2-nitrobenzencaulfonamide (6.7 g;
21.2 mmol) and 10°ro Pd/C (200 mg) in abs. EaOH was hydrogenated at 1 bar. The reaction mixture was filtered through celite and evaporated to dryness. A solution of the crude product in dry THF
(50 ml) at 0 °C was added N-hydroxysuccinimide (2.53 g; 22 mmol) and DCC (4.54 g; 22 mmol). The reaction mixture was slowly warimed to rt. and left with stirring over night. The reaction mixture was filtered and the solid rnaierial was washed with THF. The combined organic fractions were evaporated to dryness. and the remanense added H20 and extracted with EtOAc. The combined organic fractions were dried (Na,2SO4) and evaporated to dryness to give 3 g (53%) product.
3-lsobutyl-8-piperidinos;ulfonyl-2,3,4,5-tetrahydra-1,2,5-benzathiadiazepine-1,1-dioxide: A
solution of 3-isobutyl-4-oxo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide (500 mg;
1.8 mmol) in dry THF (20 ml) under N2 at 0 °C ~rvas added a solution of 2M BH3~SMe2 (9.2 ml; 18 mmol) in THF. After complete .addition, the reaction mixture was warmed to rt. and then to reflux for 2h. The reaction mixture was cooled to rt. and carefully quenched by addition of 6 M HCI (15 ml). The reaction mixture was made ;strongly alkaline by addition of 7.5 M NaOH
(aq.) and extracted by EtOAc. The combined organic fractions were dried (Na2S04) and evaporated to dryness to yield 320 mg (70'%) product. The product was transformed by Method A (using piperidine as amine). M.p. 2U~9-211 °C.
Compound 128 3-Cyclohexyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide D~-Cyclohexylglycine: A solution of NaCN (15.91 c;; 0.32 mol) in H20 (60 ml) was added NH4C1 {17 g; 0.32 mol) followE:d by a solution of cyc;lohexanecarboxaldehyde (37 ml;
0.31 mol) in MeOH (60 ml). The reaction mixture was stirred vigorously for 2 h at rt. The reaction mixture was diluted with H20 (100 ml) and extracted with toluene (~:ex 70 ml). The combined organic phases were washed with H20 (2x 50 ml) and e~aracted with 6 M HCI (2x 90 ml).
The acidic aqueous phase and th~a precipitate, which formed upon acidification, were combined and refluxed for 24 h. The reaction mixture was cooled to rt. and made slightly alkaline (using 25% NH3 {aq.)). The prE:cipitate formed, was isolated by filtration, washed with cold H20 and air dried to yield 13 g (2fi°/a) of the free. amino acid.
Compound 128 was synthesized by the method used for compound 127 (using m-cyclohexylglycine as amina acid).
Compound 129 3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-cyclopentyh'hicbenzenesulfonamide: A mixture of 5-iodo-2-aminobenzenesulfonarnide (1.192 g; 4 mmol), triethylamine (750 pl; 10 mmol), Cul (76 mg;
0.4 mmol); cyclopentylrnercaptane (590 pl; 6 rnmol) and PdfPPh3)4 (462 mg; 0.4 mmol) in dry dioxane (10 ml) under N2 was stirred in a screw cap ampule at 130 °C
over night. The reaction mixture was coated to rt., diluted with H20, made alkaline (using 4 M
NaOH) and filtered through celite. The filtrate was neutralized to pH 8.5 and evaporated to dryness.
Column chromatography gave 327 mg (30 ~%) product.
3-Cyclohexyl-7-cyclopentylsulfin.yl-1,~?,3,4-tE~trah,ydro-7,2,4-benzothiadiazine-1,1-dioxide (129): 2-Amino-5-cyclopentylthiobenzenesulfonarnide was ring brominated (3-position) and S-oxidized under the conditions described by Ali and Bohnert (Synthesis, (1998) 1238), using 2 equivalents of Br2. The product was reduced at 1 bar using 5% Pd/C in 96% EtOH
and transformed by Method G (using cyclohexar7ec;arboxaldehyde).
The following table summarises the compounds described:
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Comaound 102 2-Bicyclo[2.2.1 ]hept-5.'-en-2'-yl-6,8-dibromo-1,2,3,4-tetrahydroquinazoline 2-Amino-3,5-dibromob~enzylamine: A mixture of 2-aminobenzylamine (6.1 g; 50 mmol) in 15 CHC13 (100 ml) at 0 °(~ was added a salution Br2 (5.1 ml; 100 mmol) in CHCI3 (45 ml) such that the reaction temperature was kept below +2 °C. Cooling was then removed and the reaction mixture was stirred at rt. over night. The reaction mixture was filtered and the precipitate washed with EtOAc and purified by column chromatography.
20 2-Bicycloj2.2.1Jhept-5'-err-2'-yl-6,8-dibroma-1,2,;3,4-tetrahydroquinazoline (102): 2-Amino-3,5-dibromobenzylamine was transformed by Method G (using a racemic endo/exo mixture of 2-norbornencarboxaldehyde). M.p. 240 °C.
Compound 103 25 2-Bicyclo[2.2.1]hept-!i'-en-2'-yl-G,8-dibromo-4-oxo-1,2,3,4-tetrahydroquinazoline 3,5-Dibramoanthranilamide: A stirred suspension of anthranilamide (13.6 g; 0.1 mol) in AcOH
(350 ml) was added a solution of Br2 (10.3 ml; 0.2 mol). l-he reaction mixture was stirred at 45 °C for 120 °C, poured into H20 (1.5 I) and filtered.
Hecrystalization (including a warm filtration) from 96% EtIJH (approx. 1 I) gave 23.6 g (80%) product.
2-Bicyclo(2.2.1Jhept-5'-en-2'-yl-6,8-dibroma-4-caxo-1,2,3,4-tctrahydraquinazoline (103): 3,5-Dibromoanthranilamide was transformed by Method G (using using a racemic endo/exo mixture of bicyclo[2.2.'I]hept-5-ene-2-carboxaldE:hyde). The: product was separated into to individual diastereomeric mixtures. M.p. (A) 213-215 °C, M.~r. (B) 209-210 °C.
Compound 104 3-Bicyclo[2.2.1]hept-5'-en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobenrenesulfonamide (see compound 125) was transformed by Method G (using a racemic endo/exo mixture of bicyclo[2.2.1 ]hept-5-ene-2-carboxaldehyde). The diastereomeric mixturE: was purified by column chromatography to give three of the ~0 theoretically four possible diastereomers. M.p. (;A) 202-206 °C, M.p. (B) 796-199 °C, M.p. (C) 180-184 °C.
Compound 105 5,7-Dibromo-3-bicyclo[2.2.1]heptan-2'-yl-1,2,3"4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide Bicyclo[2.2.1 ]heptane-;?-carboxaldehyde: A stirred suspension of 2-norbornylmethanol (0.5 ml; 5.8 mmol) and PC(:, on A1203" in CH2CIp (25 ml) was stirred at 2-3 °C for 1 h and then allowed to slowly warim up to rt. The reaction mixture was filtered and the solid material washed with CH2C12 1;2x 25 ml). The combinE;d organic fractions were adsorbed onto silica and chromatographed to give 300 mg (42%) product as an oil.
'Jsee Cheng Y.-S, Liu W.-L. end Chen S.-H., Synthesis, (1980) 22".J
5,7-Dibromo-3-norbornanyt-1,2,3,4-tetrahydrc~-t,2,4-benzothiadiazine-1,1-dioxide (105): 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G
(using bicyclo[2.2.1 ]heptane-2-carboxaldehyde). M.p. 182-183 °C.
Compound 106 3-Cyclohexyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using cyclohexanec;arboxaldehyde). M.p. 16E~-167 °C.
Compound 107 3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 1-Adamantanecarboxaldehyde: 1-Adamantylrnethanol was oxidized by the method used for 2-norbornylmethanol (see compound 105)'.
'(see Cheng Y.-S, Liu W.-L. and (:hen S.-H., Synthesis, (1980) 223.
3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (107): 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G
(using 1-adamantylcarboxaldehyde). M.p. 270-2.73 °C.
Compound 108 3-Phenyl-5,7-dibromo-~1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-3,5-dibromobE~nzenesulfonamide (see compound '125) was transformed by Method G {using benzaldehyde). M.p. 186-189 °C.
Compound 109 3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide A stirred mixture of 2-aimino-3,5-dibromobenzenesulfonamide (see compound 125) (666 mg;
2 mmol), ethylorthoforrniate (15 mi; 90 mmol) and H2S04 {0.05 ml) was refluxed over night.
The reaction mixture was evaporated to dryness and subjected to column chromatography.
M.p. 96-98 °C.
Compound 110 3-Methyl-5,7-dibromo-1,2-dihydro-'1,2,4-benzothiadiazine-1,1-dioxide A stirred solution of 2-<amino-3,5-dibromobenzenesulfonamide {see compound 125) (660 mg;
2 mmol) was refluxed in Ac20 (25 ml; 265 mmol) over night. The reaction mixture was poured onto ice and filtered. The isolated solid was washed with Et20. M.p. 287-289 °C.
Compound 111 3-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide To a solution of t-BuLi (1 7 M in pentane, 25 ml, 42 mmol) in dry THF at -78°C was added 2-bromopyridine (1.9 ml, 20 mmol) in such a rate that the temperature did not exceed -70°C.
The mixture was stirred for another 30 min at -78°C. A solution of ZnCl2 (2M in THF, 30 ml, 60 mmol) was added slowly and the cooling bath was removed and warmed to 20°C. 5-lodo-2-g8 aminobenzenesulfonamide (see compound 37) (1.0 g, 3.2 mmol) and Pd(PPh3)4 (0.3 g, 8 mol%) was added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was treated wilh FDTA (5:3 g, 0.18 mol) and made slightly basic (pH =
8-9) with 1 M
NaOH followed by extraction with E=tC7Ac (3 x '100 ml), dryinc:l (Na;>SO4).
The organic layer was concentrated to ca. 40 rnl and n-hexane was added slowly. The product was filtered off, yielding 0.72 g (87 %) of 2-amino-4-methyl-5-(2-pyridyl)-1-benzenesulfonamide as light-yellow crystals. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 229-231 "c:,.
Compound 112 3-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzoth iadiazi ne-1,1-dioxide 5-Iodo-4-methy!-2-aminobenzenesulfonamide: m-Toluidine was transformed by method B and the two isomers separated by column chromatography to give 4-methyl-2-aminobenzenesulfonarnide.
A stirred suspension of 4-methyl-2-aminobenzenesulfonarraide (620 mg; 3.3 mmol) in CHCI3 (7 ml) at 0 °C was added a solution of iodine monochloride (1.6 g; 9.9 mmol) in CHCI3 (7 ml).
The reaction mixture was stirred at 0 °C until H-NMR indicated full conversion of starting material. The reaction mixture was filtered arid i:he isolated solid washed with small volumes of CHCI3, NaHC03 {sat. aq.), H2O and air dried to give 640 mg (62 %) of product.
3-Cyclahexyl-6-methyl~~7-(4'-triazofyl)-1,2,3,4-a~etrahydro-1,2,4-benzothiadiazine-1,1-dioxide (112J: 5-lodo-4-methyl-2-aminobenz enesulfonarnide was transformed by Method I
(using trimethylsilylacetylene) and Method G (using cyclohexanecarboxaldehyde). FAB+
348. 'H-NMR (DMSO-d6): 8.0 (1 H; br); 7.65 (1 H; br); 7.25 (1 H; s;); 7.22 (1 H; s);
6.95 (1 H; br); 6.8 (1 H;
s); 4.45 (1H; dd); 2.35 (3F-1; s); 1.95-1.8 (2H; rn); 1.8-1.6 (31-I; m); 1.3-1.0 (6H; m).
Compound 113 3-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide N-Acetyl-3-methylaniline: m-Toluidine (10 mP; 93 mmol) was added to a stirred solution of acetic anhydride (30 ml). The reaction mixture was stirred for 1,5 h at rt., evaporated to dryness, stirred with H,2O and filtered to give 13 g product (94%).
3-Cyclohexyl-6-methyl-7-sulfamoyl-7,2,3,4-tetiahydro-1,2,4-benzothiadiazine-1, i-dioxide: N-Acetyl-3-rnethylaniline was transformed by Method A (using 25% NH3 (aq.) as amine.
Deacetylation was complete) and Method G (using cyclohexanecarboxaldehyde).
M.p. 231-233 °C.
Compound 114 3-Cyclopentyl-6-methyl-7-piperidinosulfanyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide Cyclopentanecarbonyl chloride: CyclopentanE:carboxylic acid (0.55 ml; 5 mmol) was refluxed in thionylchloride (1 ml) for 3 h. The reaction mixture was cooled to rt., evaporated to dryness and used directly without any purification.
3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2, 3, 4-tetrahydro-1,2, 4-benzothia-diazine-1,1-dioxide (714): m-Toluidine was used as starting material for the following transformation sequence: Method B [2-amino-fi-rnethylbenzenE;sulfonamide was separated from 2-amino-4-methylbenzenesulfonamide by recrystalli~:ation (EtOAc/hexane)), Method E
(using cyclopentanecarbonyl chloride), Method A (using piperidine as amine), Method F. M.p. 229-230 °C.
Compound 115 3-Cyciohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide m-Toluidine was used as starting material for the following transformation sequence: Method B [2-amino-6-methylbenzenesulfanamidE: was separated from 2-amino-4 methylbenzenesulfonamide by recrystallization (EtOAc/hexane)), Method E (using cyclohexanecarbonyl chloride), Method A (ush7c~ morpholirne as amine), Method F. M.p. 268-271 °C.
Compound 116 3o 3-Cyclohexyl-6-(2-methoxyphenyl)-7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Bromo-4-methylaniline was transformed by Method B (The isomers were separated by fractional crystallization from MeQH) to give :?-amino-4-bromo-5-methylbenzenesulfonamide.
A mixture of 2-amino-4-bromo-5-rrrethylbenzenesulfonamide {100 mg, 0.38 mmol), methoxyphenylboronic acid (76 mg, 0.5C) mmol), Pd(PPh,)2C12 (13 mg, 5 mol %) in 1,2-dimethoxyethane (20 ml) and NaZC03 {2M, 1 rnl, 2 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCOs (10 ml) and extracted with EtOAc (~~ x 25 ml). The organic layer was washed with brine (20 ml), dried (Na2S04) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on Si02 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 100 mg (90 %) of 2-amino-4-(2-rnethoxyphenyl)-5-methylbenzenesulfonamide as colorless powder. The product was further tran:~formed by Method G (using cyclohexanecarboxalde:hyde). M.p. 172-175 °C.
Compound 117 3-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide m-Anisidine was used as starting material for the following transformation sequence: Method B [2-amino-6-methoxybenzenesulfonamide was separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc/hexane)), Method C, Method A (using piperidine as amine), Method D, Method G (using cyclohexanecarboxaldehyde). M.p.
237-240 °C.
Compound 118 and compound 122 3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (122) and 3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (118) 6-Amino-1,4-benzodio~;ane was used as startin<~ material and transformed into a mixture of ethylendioxy-2-aminob~enzenesulfonamide isomers by use of Method B. The two isomers were separated by column chromatography.
3-Cyclohexyl-6,7-ethylc~nedioxy-1,2,3,4-fefrah,yd~o-1,2,4-ber~zothiadiazine-1,1-dioxide (118):
2-amino-5,6-ethylendioxybenzenesulfonamidc: was transformed by use of Method G
(using cyclohexanecarboxylaldehyde). M.p. 196-200 °C.
3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (722):
2-amino-7,8-ethylendiox:ybenzenesulfonamide was transformed by use of Method G
(using cyclohexanecarboxylaldehyde). M.p. '~68-270 "C..
Compound t 19 3-Cyclohexyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-4-chloro-5-sulf~arnoylbenzenesulfonarnid~e was transformed by Method G
(using cyclohexanecarboxaldehyde). M.p. 2;'4-276 °~;.
Compound 120 3-Phenyl-6-chloro-7-sulfarnoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-4-chloro-5-sulfamoylbenzc:nesulfonarnide was transformed by Method G
(using benzaldehyde). M.p. 235-238 "C.
Compound 121 3-Cyclohexyl-6-bromo-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide m-Bromoaniline was used as starting material for the following transformation sequence:
Method B [2-amino-6-bromobenzenesulfonamide was separated from 2-amino-4-bromobenzenesulfonarnide by recrystallizatian (EtOAc/hexane)~, Method C, Method A (using piperidine as amine), Method D, Method G (u~;incl cyclohexanecarboxaldehyde).
M.p. 238-241 °C.
Compound 122 See compound 118.
Compound 123 2-cyclohexylmethylamino-5-N,N-dimethytsulfamoylbenzenesulfonamide 2-Aminobenzenesutfonamide was used as starting material for the following transformation sequence: Method E (using cyc:lohexanecarbonyl chloride;l, Method A (using dimethylamine as amine), Method F (the reaction mixture was Ic:ft over night with DIBALH at rt. with stirring).
M.p. 123-125 °C.
1 C)2 Compound 124 2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzene sulfonamide 3-Methyl-1,2-dihydro-1,a?,4-benzothiadiazine-1,1-dioxide {see compound 73) was transformed by Method A (using 1,2,3,6-tetrahydropyridine as amine) followed by Method F
(using LiAIH4 and rt.). M.p. 175-177 °(:,.
Compound 125 2-Amino-3,5-dibromobenzenesulfonamide A stirred solution of 2-aminobenzenesulfonarnide (8.6 g; 50 mrnol) in AcOH
(100 ml) was slowly added a solution of Br2 (5.13 ml; 100 mmol) in AcI.~H (20 ml). The reaction mixture was heated to 55 °C for 60 h, poured into ice vvater (800 ml), filtered, adsorbed onto silica and purified by column chromatography to give 11.1 g (67 %) product. M.p. 165-169 °C.
Compound 126 2-Acetamidobenzenesulfonamide A stirred solution of 2-aminobenzenesulfonarnide (1.72 g; 10 mmol) and triethylamine (1.53 ml; 11 mmol) in THF (25 rnl) at 0 °C was addE:d ,AcCI (0.85 ml; 12 mmol) and left with stirring at rt. over night. The reaction mixture was filtered anri adsorbed onto silica. Column chromatography gave 1I .7 g (79 %) product. M.~>. 153.5-155.5 °C.
Compound 127 3-Isobutyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide N-(3'-Methyl-1'-carboxybutyl)-2-nitrohenzenes~rlfonamide: A solution of 2-nitrobenzenesulfonylchloride (11 g; 50 mmol) and NaOH (2.1 g; 53 mmol) in H20 (100 ml) was added m-leucine (6.55 g; 50 mmol) and Is~ft over night with stirring at rt. The reaction mixture was added 4 M NaOH (12.5 ml) and filtered. The filtrate was acidified with 1 M HCI
(50 ml) and extracted with EtOAc. The combined organic fractions were dried (Na2S04) and evaporated to dryness to give 6.7 g (42%) product.
3-Isobufyl-4-oxo-2,3,4,.5-tetrahydro-T,2,5-ben:~atrhiadiazepine-1,1-dioxide: A
stirred suspension of N-(3'-methyl-1'-c;arboxybutyl)-2-nitrobenzencaulfonamide (6.7 g;
21.2 mmol) and 10°ro Pd/C (200 mg) in abs. EaOH was hydrogenated at 1 bar. The reaction mixture was filtered through celite and evaporated to dryness. A solution of the crude product in dry THF
(50 ml) at 0 °C was added N-hydroxysuccinimide (2.53 g; 22 mmol) and DCC (4.54 g; 22 mmol). The reaction mixture was slowly warimed to rt. and left with stirring over night. The reaction mixture was filtered and the solid rnaierial was washed with THF. The combined organic fractions were evaporated to dryness. and the remanense added H20 and extracted with EtOAc. The combined organic fractions were dried (Na,2SO4) and evaporated to dryness to give 3 g (53%) product.
3-lsobutyl-8-piperidinos;ulfonyl-2,3,4,5-tetrahydra-1,2,5-benzathiadiazepine-1,1-dioxide: A
solution of 3-isobutyl-4-oxo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide (500 mg;
1.8 mmol) in dry THF (20 ml) under N2 at 0 °C ~rvas added a solution of 2M BH3~SMe2 (9.2 ml; 18 mmol) in THF. After complete .addition, the reaction mixture was warmed to rt. and then to reflux for 2h. The reaction mixture was cooled to rt. and carefully quenched by addition of 6 M HCI (15 ml). The reaction mixture was made ;strongly alkaline by addition of 7.5 M NaOH
(aq.) and extracted by EtOAc. The combined organic fractions were dried (Na2S04) and evaporated to dryness to yield 320 mg (70'%) product. The product was transformed by Method A (using piperidine as amine). M.p. 2U~9-211 °C.
Compound 128 3-Cyclohexyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide D~-Cyclohexylglycine: A solution of NaCN (15.91 c;; 0.32 mol) in H20 (60 ml) was added NH4C1 {17 g; 0.32 mol) followE:d by a solution of cyc;lohexanecarboxaldehyde (37 ml;
0.31 mol) in MeOH (60 ml). The reaction mixture was stirred vigorously for 2 h at rt. The reaction mixture was diluted with H20 (100 ml) and extracted with toluene (~:ex 70 ml). The combined organic phases were washed with H20 (2x 50 ml) and e~aracted with 6 M HCI (2x 90 ml).
The acidic aqueous phase and th~a precipitate, which formed upon acidification, were combined and refluxed for 24 h. The reaction mixture was cooled to rt. and made slightly alkaline (using 25% NH3 {aq.)). The prE:cipitate formed, was isolated by filtration, washed with cold H20 and air dried to yield 13 g (2fi°/a) of the free. amino acid.
Compound 128 was synthesized by the method used for compound 127 (using m-cyclohexylglycine as amina acid).
Compound 129 3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-cyclopentyh'hicbenzenesulfonamide: A mixture of 5-iodo-2-aminobenzenesulfonarnide (1.192 g; 4 mmol), triethylamine (750 pl; 10 mmol), Cul (76 mg;
0.4 mmol); cyclopentylrnercaptane (590 pl; 6 rnmol) and PdfPPh3)4 (462 mg; 0.4 mmol) in dry dioxane (10 ml) under N2 was stirred in a screw cap ampule at 130 °C
over night. The reaction mixture was coated to rt., diluted with H20, made alkaline (using 4 M
NaOH) and filtered through celite. The filtrate was neutralized to pH 8.5 and evaporated to dryness.
Column chromatography gave 327 mg (30 ~%) product.
3-Cyclohexyl-7-cyclopentylsulfin.yl-1,~?,3,4-tE~trah,ydro-7,2,4-benzothiadiazine-1,1-dioxide (129): 2-Amino-5-cyclopentylthiobenzenesulfonarnide was ring brominated (3-position) and S-oxidized under the conditions described by Ali and Bohnert (Synthesis, (1998) 1238), using 2 equivalents of Br2. The product was reduced at 1 bar using 5% Pd/C in 96% EtOH
and transformed by Method G (using cyclohexar7ec;arboxaldehyde).
The following table summarises the compounds described:
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Claims (30)
1. A compound represented by the general formula (I):
wherein X represents C=O or CH2; and Y represents CH(R4), N(R4) or N(R4)-CH2, or O; and R2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl, or -CO-R9, wherein R9 represents alkyl, cycloalkyl, benzyl, or aryl; or R2 together with R3, and together with the atoms to which they are attached, forms a 4- to 7-membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR13R14, or -alkyl-S-R13, wherein R13 and R14 independently represents hydrogen, alkyl, or cycloalkyl; or R13 and R14 together with the nitrogen to which they are attached forms a 3-to 8-membered heterocyclic ring structure; or R3 represents a carbocyclic 7- to 12- membered rind, which carbocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R3 represents a heterocyclic 3- to 8-membered ring, which heterocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy, and optionally the heterocyclic ring is fused to an aryl; or R3 represents benzyl, which benzyl is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, and alkylamino; or R3 represents aryl, which aryl is optionally substituted one or more: tunes with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, and alkylamino; or R3 together with R2 or R4, and together with the atoms to which they are attached, forms a 4- to 7- membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10, or -CO2R10, wherein R10 represents. hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3, and together with the atoms to which they are attached, forms a 4- to 7- membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R5 represents hydrogen, halogen, alkyl alkenyl, alkynyl, or aryl; or R5 represents -SO2-NR11R12, wherein R11 and R12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R11 and R12 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted witty halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl; or R6 represents -NR15R16, -NHSO2-R15, or-NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, and aryl;
wherein R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R15 and R16 together with the nitrogen to which they are attached form a heterocycyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R6 represents aryl, which aryl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy. haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, and amino; or R6 represents HET, which HET is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and haloalkoxy; or R6 represents -(alkyl)m-S-R15, -(alkyl)m-SO-R15, -(alkyl)m-SO2-R15, -(alkyl)m-SO2OR15, -(alkyl)m-SO2-NR15R16, -(alkyl)m,-NHCOR15, -(alkyl)m-CONR15R16, -(alkyl)m-CR'=NOR", -(alkyl)m,-CO-R15, -(alkyl)m-CO2-R15, wherein m is o or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R15 and R16 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl; or R7 represents -NR17R18, -NHSO2-R17, or -NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, aryl; or R7 represents -(alkyl)m-S-R17, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2OR17, -(alkyl)m-SO2-NR17R18, -(alkyl)mNHCOR17, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)mCO2-R17, wherein m is o or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl: or R7 represents HET, which HET is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO- alkyl, -SO-aryl, -SO2-alkyl, -SO2-aryl, or -SO2NR17R18; or R7 represents aryl, which aryl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, or -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, ar -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3;
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2 -CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents aryl, which aryl is optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3 -NO2, alkyl, cycloalkyl, and alkoxy;
or R8 represents HET, which HET is optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3, -NO2, alkyl, cycloalkyl, and alkoxy;
or R8 represents -(alkyl)m-S-R19, - (alkyl)m-SO-R19, -(alkyl)m-SO2-R19, -(alkyl)m-SO2OR19, -(alkyl)m-SO2-NR19R20, -(alkyl)mNHCOR19 -(alkyl)mCONR19R20, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R19, or -(alkyl)m-CO2-R19, wherein m is 0 or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R19 and R20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R19 and R20 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
or a compound represented by the general formula (I) wherein X represents SO2; and Y represents CH(R4), N(R4), N(R4)-CH2 or O; and R2 represents hydrogen; and R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, -alkyl-NR13R14, or -alkyl-S-R13, wherein R13 and R14 independently represents hydrogen, alkyl, or cycloalkyl; or R13 and R14 together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring structure; or R3 represents a carbocyclic 7- to 12- membered ring, which carbocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R3 represents a heterocyclic 3- to 8-membered ring, which heterocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy, and optionally the heterocyclic ring is fused to an aryl; or R3 represents benzyl, which benzyl is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, and alkylamino; or R3 together with R4, and together with the atoms to which they are attached, forms a 4- to 7-membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10, or -CO2R10, wherein R10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3, and together with the atoms to which they are attached, forms a 4- to 7-membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thin, and which ring is optionally containing one or more heteroatoms and optionally containing carbonyl groups;
and R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, or -SO2-NR11R12, wherein R11 and R12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R11 and R12 together with the nitrogen to which they are attached form a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl, or R6 represents -NR15R16, -NHSO2-R15, or -NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, and aryl;
wherein R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R15 and R16 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R6 represents aryl, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R6 represents HET, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and haloalkoxy;
or R6 represents -(alkyl)m-S-R15, -(alkyl)m-SO-R15, -(alkyl)m-SO2-R15, -(alkyl)m-SO2OR15, -(alkyl)m-SO2-NR15R16, -(alkyl)m-NHCOR15, -(alkyl)m-CONR15R16, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R15; or -(alkyl)m-CO2-R15, wherein m is o or 1;and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R15 and R16 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen,alkyl, alkenyl alkynyl,hydroxy' alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R7 represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl, or R7 represents -NR17R18, -NHSO2-R17, or -NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, and aryl;
or R7 represents -(alkyl)m-S-R17, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2OR17, -(alkyl)mNHCOR17, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)m,C02-R17, wherein m is o or1;and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached forms a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thin, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents -(alkyl)m-;SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently of each another represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted) with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio. ;aryl, -S-alkyl., -SO-aryl, -SO-alkyl, -SO--aryl, -SO2-alkyl, -SO2-aryl, and -SO2NR17R18; or Claims:
R7 represents aryl, optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, and -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3.
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents aryl, optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3, -NO2, alkyl, cycloalkyl, and alkoxy; or R8 represents HET, optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3, -NO2, alkyl, cycloalkyl, and alkoxy; or Claims R8 represents -(alkyl)m-S-R19, -(alkyl)m-SO-R18 -(alkyl)m-SO2-R19-(alkyl)m-SO2OR19, -(alkyl)m-SO2-NR19R20, -(alkyl)mNHCOR19, -(alkyl)mCONR19R20 -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R19, or -(alkyl)m-CO2-R19, wherein m is 0 or 1; and R' and R" independently represents hydrogen, ;alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl. and R19 and R20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R19 and R20 together with the nitrogen to which they are attached form a heterocyclic 3-to-8 membered ring structure, which ring structure is optionally substituted 'with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl provided however, if X represents SO2, and Y represents NR4,and if one of R5, R6, R7 or R8 is halogen or alkyl or alkoxy, then one or more of the remainder of R5, R6, R7 or R8 is/are not also halogen or alkyl, and then one or more of the remainder of R5', R6, R7 or R8 is/are not hydrogen.
wherein X represents C=O or CH2; and Y represents CH(R4), N(R4) or N(R4)-CH2, or O; and R2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl, or -CO-R9, wherein R9 represents alkyl, cycloalkyl, benzyl, or aryl; or R2 together with R3, and together with the atoms to which they are attached, forms a 4- to 7-membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR13R14, or -alkyl-S-R13, wherein R13 and R14 independently represents hydrogen, alkyl, or cycloalkyl; or R13 and R14 together with the nitrogen to which they are attached forms a 3-to 8-membered heterocyclic ring structure; or R3 represents a carbocyclic 7- to 12- membered rind, which carbocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R3 represents a heterocyclic 3- to 8-membered ring, which heterocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy, and optionally the heterocyclic ring is fused to an aryl; or R3 represents benzyl, which benzyl is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, and alkylamino; or R3 represents aryl, which aryl is optionally substituted one or more: tunes with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, and alkylamino; or R3 together with R2 or R4, and together with the atoms to which they are attached, forms a 4- to 7- membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10, or -CO2R10, wherein R10 represents. hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3, and together with the atoms to which they are attached, forms a 4- to 7- membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R5 represents hydrogen, halogen, alkyl alkenyl, alkynyl, or aryl; or R5 represents -SO2-NR11R12, wherein R11 and R12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R11 and R12 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted witty halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl; or R6 represents -NR15R16, -NHSO2-R15, or-NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, and aryl;
wherein R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R15 and R16 together with the nitrogen to which they are attached form a heterocycyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R6 represents aryl, which aryl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy. haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, and amino; or R6 represents HET, which HET is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and haloalkoxy; or R6 represents -(alkyl)m-S-R15, -(alkyl)m-SO-R15, -(alkyl)m-SO2-R15, -(alkyl)m-SO2OR15, -(alkyl)m-SO2-NR15R16, -(alkyl)m,-NHCOR15, -(alkyl)m-CONR15R16, -(alkyl)m-CR'=NOR", -(alkyl)m,-CO-R15, -(alkyl)m-CO2-R15, wherein m is o or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R15 and R16 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl; or R7 represents -NR17R18, -NHSO2-R17, or -NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, aryl; or R7 represents -(alkyl)m-S-R17, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2OR17, -(alkyl)m-SO2-NR17R18, -(alkyl)mNHCOR17, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)mCO2-R17, wherein m is o or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl: or R7 represents HET, which HET is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO- alkyl, -SO-aryl, -SO2-alkyl, -SO2-aryl, or -SO2NR17R18; or R7 represents aryl, which aryl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, or -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, ar -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3;
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2 -CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents aryl, which aryl is optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3 -NO2, alkyl, cycloalkyl, and alkoxy;
or R8 represents HET, which HET is optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3, -NO2, alkyl, cycloalkyl, and alkoxy;
or R8 represents -(alkyl)m-S-R19, - (alkyl)m-SO-R19, -(alkyl)m-SO2-R19, -(alkyl)m-SO2OR19, -(alkyl)m-SO2-NR19R20, -(alkyl)mNHCOR19 -(alkyl)mCONR19R20, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R19, or -(alkyl)m-CO2-R19, wherein m is 0 or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R19 and R20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R19 and R20 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
or a compound represented by the general formula (I) wherein X represents SO2; and Y represents CH(R4), N(R4), N(R4)-CH2 or O; and R2 represents hydrogen; and R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, -alkyl-NR13R14, or -alkyl-S-R13, wherein R13 and R14 independently represents hydrogen, alkyl, or cycloalkyl; or R13 and R14 together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring structure; or R3 represents a carbocyclic 7- to 12- membered ring, which carbocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R3 represents a heterocyclic 3- to 8-membered ring, which heterocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy, and optionally the heterocyclic ring is fused to an aryl; or R3 represents benzyl, which benzyl is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, and alkylamino; or R3 together with R4, and together with the atoms to which they are attached, forms a 4- to 7-membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10, or -CO2R10, wherein R10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3, and together with the atoms to which they are attached, forms a 4- to 7-membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thin, and which ring is optionally containing one or more heteroatoms and optionally containing carbonyl groups;
and R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, or -SO2-NR11R12, wherein R11 and R12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R11 and R12 together with the nitrogen to which they are attached form a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl, or R6 represents -NR15R16, -NHSO2-R15, or -NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, and aryl;
wherein R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R15 and R16 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R6 represents aryl, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R6 represents HET, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and haloalkoxy;
or R6 represents -(alkyl)m-S-R15, -(alkyl)m-SO-R15, -(alkyl)m-SO2-R15, -(alkyl)m-SO2OR15, -(alkyl)m-SO2-NR15R16, -(alkyl)m-NHCOR15, -(alkyl)m-CONR15R16, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R15; or -(alkyl)m-CO2-R15, wherein m is o or 1;and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R15 and R16 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen,alkyl, alkenyl alkynyl,hydroxy' alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R7 represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl, or R7 represents -NR17R18, -NHSO2-R17, or -NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, and aryl;
or R7 represents -(alkyl)m-S-R17, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2OR17, -(alkyl)mNHCOR17, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)m,C02-R17, wherein m is o or1;and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached forms a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thin, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents -(alkyl)m-;SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently of each another represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted) with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio. ;aryl, -S-alkyl., -SO-aryl, -SO-alkyl, -SO--aryl, -SO2-alkyl, -SO2-aryl, and -SO2NR17R18; or Claims:
R7 represents aryl, optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, and -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3.
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents aryl, optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3, -NO2, alkyl, cycloalkyl, and alkoxy; or R8 represents HET, optionally substituted one or more times with substituents selected from the group consisting of halogen, -CF3, -OCF3, -NO2, alkyl, cycloalkyl, and alkoxy; or Claims R8 represents -(alkyl)m-S-R19, -(alkyl)m-SO-R18 -(alkyl)m-SO2-R19-(alkyl)m-SO2OR19, -(alkyl)m-SO2-NR19R20, -(alkyl)mNHCOR19, -(alkyl)mCONR19R20 -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R19, or -(alkyl)m-CO2-R19, wherein m is 0 or 1; and R' and R" independently represents hydrogen, ;alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl. and R19 and R20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R19 and R20 together with the nitrogen to which they are attached form a heterocyclic 3-to-8 membered ring structure, which ring structure is optionally substituted 'with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl provided however, if X represents SO2, and Y represents NR4,and if one of R5, R6, R7 or R8 is halogen or alkyl or alkoxy, then one or more of the remainder of R5, R6, R7 or R8 is/are not also halogen or alkyl, and then one or more of the remainder of R5', R6, R7 or R8 is/are not hydrogen.
2. The compound of according to claim 1, being a 1,2,4-benzothiadiazine derivative having the general formula (II) wherein R3 represents hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic 7- to 10- membered ring, a heterocyclic 5- to 6 membered ring, or benzyl; or R3 together with R4 forms a 5- to 6- membered ring; and Claims-1 / March 2000 R4 represents hydrogen, or alkyl, or R4 together with R3, and together with the atoms to which they are attached, forms a 5-to 6-membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups;and R5 represents hydrogen, halogen, alkyl alkenyl, alkynyl, phenyl, or -S02-NR11R12, wherein R11 and R12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R11 and R12, together with the nitrogen to which 'they are attached, form a heterocyclic 5-to 6-membered ring structure;
R6 represents hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxy, or alkoxyalkyl;
or R6 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, and alkoxy; or R6 represents HET; orR6 represents -S-R15, -SO-R15, -SO2-R15, -SO2OR15, -SO2-NR15R16, -NHCOR15, -CONR15R16, -CR'=NOR", -CO-R15, or -CO2-R15 wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R15 and R16, together with the nitrogen to which they are attached, form a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin, phenyl, benzyl, -SO2;-alkyl, -SO2-aryl, -SO2-benzyl;
and optionally the heterocyclic ring is fused to an aryl; and R7 represents Br, F, I, alkyl. cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)m-NR17R18, -NHSO2-R17, -S-R17, -SO-R17, S02-R17, -SO2OR17", -NHCOR17', -CONR17'R18, -CR'=NOR", -CO-R17, or-C02-R17;
wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or Claims R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents -(alkyl)m-SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently of each another represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl. benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl or R7 represents HET, which HET is optionally substituted one or- more times with substituents selected from halogen, alkyl, phenyl, and -SO2NR17R18; of R7 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy , halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, or -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, -SO2-alkyl, -SO2-aryl, -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3;
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
Claims -CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2, -CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)2-O-, wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, and alkoxy; or R8 represents HET; or R8 represents -S-R19, -SO-R19, -SO2-R19, -SO2OR19, -SO2-NR19R20, -NHCOR19, -CONR19R20, -CR'=NOR", -CO-R19, or -CO2-R19, wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R19 and R20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, -SO2-alkyl, -SO2-aryl, -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
or R11 and R12, together with the nitrogen to which 'they are attached, form a heterocyclic 5-to 6-membered ring structure;
R6 represents hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxy, or alkoxyalkyl;
or R6 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, and alkoxy; or R6 represents HET; orR6 represents -S-R15, -SO-R15, -SO2-R15, -SO2OR15, -SO2-NR15R16, -NHCOR15, -CONR15R16, -CR'=NOR", -CO-R15, or -CO2-R15 wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R15 and R16, together with the nitrogen to which they are attached, form a heterocyclic 3-to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thin, phenyl, benzyl, -SO2;-alkyl, -SO2-aryl, -SO2-benzyl;
and optionally the heterocyclic ring is fused to an aryl; and R7 represents Br, F, I, alkyl. cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)m-NR17R18, -NHSO2-R17, -S-R17, -SO-R17, S02-R17, -SO2OR17", -NHCOR17', -CONR17'R18, -CR'=NOR", -CO-R17, or-C02-R17;
wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or Claims R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents -(alkyl)m-SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently of each another represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl. benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl or R7 represents HET, which HET is optionally substituted one or- more times with substituents selected from halogen, alkyl, phenyl, and -SO2NR17R18; of R7 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy , halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, or -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl;
or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, -SO2-alkyl, -SO2-aryl, -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3;
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
Claims -CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2, -CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)2-O-, wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, and alkoxy; or R8 represents HET; or R8 represents -S-R19, -SO-R19, -SO2-R19, -SO2OR19, -SO2-NR19R20, -NHCOR19, -CONR19R20, -CR'=NOR", -CO-R19, or -CO2-R19, wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R19 and R20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, -SO2-alkyl, -SO2-aryl, -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
3. The compound of formula (I) according to claim 1, wherein R2 represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl.
4. The compound according to any of the preceding claims wherein R3 represents hydrogen, cycloalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic 7-to 10-membered ring, a heterocyclic 5- to 6-membered ring, or benzyl; or R3 together with R4 forms a 5- to 6- membered ring, which ring is optionally substituted one or mare times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
Claims
Claims
5. The compound according to any of the preceding claims wherein R4 represents hydrogen, or alkyl; or R4 together with R3, and together with the atoms to which they are attached, forms a 5- to 6- membered ring, which ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, and thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups.
6. The compound according to any of the preceding claims wherein R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl, or -SO2-NR11R12, wherein R11 and R12 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R11 and R12, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure.
7. The compound according to any of the preceding claims, wherein R6 represents hydrogen, halogen, cycloalkyl, alkyl, alkoxy, or alkoxyalkyl; or R6 represents aryl, which aryl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, and alkoxy; or R6 represents HET; or R6 represents -S-R15, -SO-R15, -SO2-R15, -SO2OR15, -SO2-NR15R16, -NHCOR15, -CONR15R16, -CR'=NOR", -CO-R15, or -CO2-R15, wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R15 and R16 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R15 and R16, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl.
8. The compound according to any of the preceding claims wherein Claims R7 represents halogen, alkyl, cyano, cyanoalkyl, alkoxy, haloalkoxy haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)m-NR17R18, -NHSO2-R17, -S-R17, -SO-R17, -SO2-R17,-SO2OR17, -NHCOR17, -CONR17R18, -CR'=NOR", -CO-R17, or -CO2-R17, wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents -(alkyl)m-SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, or -SO2- benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET, which HET is optionally substituted one or more times with substituents selected from halogen, alkyl, phenyl, or-SO2NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy , halogen, haloalkyl, amino, NHCO- alkyl, nitro, OCF3, -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, Claims which ring structure is optionally substituted with halogen, alkyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6, or together with R6, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3;
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3
9. The compound according to any of the preceding claims, wherein R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, and alkoxy; or R8 represents HET; or R8 represents -S-R19, -SO-R19, -SO2-R19, -SO2OR19, -SO2-NR19R20, -NHCOR19, -CONR19R20, -CR'=NOR", -CO-R19, or -CO2-R19, wherein R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R19 and R20 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl.
Claims
Claims
10. The compound according to any of the preceding claims wherein X represents SO2; and Y represents N; and R2 represents H; and R3 represents cycloalkyl, a carbocyclic 7- to 10-membered ring, a heterocyclic 5- to 6-membered ring; and R4 represents H; and R5 represents H; and R6 represents hydrogen, alkyl or halogen; and R7 represents cyanoalkyl, nitroalkyl, haloalkyl, or -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m,CONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)mCO2-R17, wherein m is o or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, or -SO2- benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents -(alkyl)m-SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, or -SO2- benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET; or Claim R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3;
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3; and R8 represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2-NR17R18, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)mCO2-R17, wherein m is o or 1;
R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, forms a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, or -SO2- benzyl, and optionally the heterocyclic ring is fused to an aryl; or R8 represents HET.
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3; and R8 represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2-NR17R18, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)mCO2-R17, wherein m is o or 1;
R' and R" independently represents hydrogen, alkyl, cycloalkyl, phenyl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, forms a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl, or -SO2- benzyl, and optionally the heterocyclic ring is fused to an aryl; or R8 represents HET.
11. The compound according to any of the preceding claims, wherein R3 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF3, ethoxy, norbornene, norbornane, adamantane, or benzyl; or R3 together with R4, and together with the atoms to which they are attached, forms a 5-membered ring.
12. The compound according to any of the preceding claims, wherein R4 represents hydrogen, methyl, or ethyl; or Claims R4 together with R3, and together with the atoms to which they are attached forms a 5-membered ring.
13. The compound according to any of the preceding claims, wherein R5 represents hydrogen, chloro, bromo, methyl, or phenyl.
14. The compound of formula I, according to any of the preceding claims, wherein R6 represents hydrogen, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy, chloro or bromo.
15. The compound of formula I, according to any of the preceding claims, wherein R7 represents chloro, bromo, methyl, 1-hydroxyethyl, acetyl, -(CH3)C=N-OH, -CONH2, -CO2- ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N.N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH3CONH-, CH3SO2NH-, -SO2OH, phenyl-SO2-, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl, or -SO2-heterocyclic ring, wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1,2,5, 6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine, and morpholine.
16. The compound of formula I according to any of the preceding claims wherein R8 represents hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, or methoxy.
17. The compound of formula II according toclaim 2, wherein R2 represents hydrogen or CH3;
and R3 represents cyclohexyl, cyclopentyl, norbornene, norbornane, adamantane, or ethoxy;
and R4 represents hydrogen or CH3; and R5 represents hydrogen, CH3, phenyl, sulfamoyl, chloro, or bromo; and R6 represents hydrogen, CH3, 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, or 3-pyridyl; and R7 represents chloro, bromo, methyl, 1-hydroxyethyl, acetyl, -(CH3)C=N-OH, -CONH2, -CO2-ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N,N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-Claims furyl, 2-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1,2,4 oxadiazol-3-yl, -CH3CONH-, -CH3SO2NH-, -SO2OH, phenyl-SO2-, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl, or -SO2-heterocyclic ring, wherein the heterocyclic rings, are selected from the group of piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine, and morpholine; and R8 represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, or methoxy.
and R3 represents cyclohexyl, cyclopentyl, norbornene, norbornane, adamantane, or ethoxy;
and R4 represents hydrogen or CH3; and R5 represents hydrogen, CH3, phenyl, sulfamoyl, chloro, or bromo; and R6 represents hydrogen, CH3, 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, or 3-pyridyl; and R7 represents chloro, bromo, methyl, 1-hydroxyethyl, acetyl, -(CH3)C=N-OH, -CONH2, -CO2-ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N,N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-Claims furyl, 2-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1,2,4 oxadiazol-3-yl, -CH3CONH-, -CH3SO2NH-, -SO2OH, phenyl-SO2-, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl, or -SO2-heterocyclic ring, wherein the heterocyclic rings, are selected from the group of piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine, and morpholine; and R8 represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, or methoxy.
18. The compound of formula I according to claim 1, wherein X is C=O; and Y is N, O or CH; and R2 represents hydrogen; and R3 represents hydrogen, CH3, CF3, cyclohexyl, norbornene, phenyl, or ethyl;
and R7 represents hydrogen, N,N-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyrid-1-yl-sulfuric acid, morpholin-4-yl-sulfuric acid, sulfamoyl, bromo; and R5 represents hydrogen or bromo; and R4, R6 and R8 all represent hydrogen.
and R7 represents hydrogen, N,N-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyrid-1-yl-sulfuric acid, morpholin-4-yl-sulfuric acid, sulfamoyl, bromo; and R5 represents hydrogen or bromo; and R4, R6 and R8 all represent hydrogen.
19. The compound of formula I according to claim 1, wherein X represents CH2; and Y is N; and R3 represents cyclohexyl or norbornene; and R5 represents hydrogen or bromo; and R7 represents bromo or sulfamoyl; and R2, R4, R6 and R8 all represent hydrogen.
20. The compound of formula I according to claim 1, wherein X is SO2;and N is -NHCH2-; and R3 represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R7 represents 1-piperidinyl-sulfuric acid.
21. The compound of formula I according to claim 1, said compound being:
2-Cyclohexyl-4-oxo-1,2 3,4-tetrahydroquinazoline;
2-Phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline;
2-Methyl-3,4-dihydro-1,3-benzoxazine-4-one;
2-Phenyl-3,4-dihydro-1,3-benzoxazine-4-one;
Claims 2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazine-4-one;
2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-1',2',3', 6'-tetrahydropiperidinosulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide;
2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolinesulfonic acid;
2-cyclohexylmethylamino-5-N,N-dimethylsulfamoylbenzenesulfonamide; or 2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzene sulfonamide;
or a pharmaceutical acceptable salt thereof
2-Cyclohexyl-4-oxo-1,2 3,4-tetrahydroquinazoline;
2-Phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline;
2-Methyl-3,4-dihydro-1,3-benzoxazine-4-one;
2-Phenyl-3,4-dihydro-1,3-benzoxazine-4-one;
Claims 2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazine-4-one;
2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-1',2',3', 6'-tetrahydropiperidinosulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide;
2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;
2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolinesulfonic acid;
2-cyclohexylmethylamino-5-N,N-dimethylsulfamoylbenzenesulfonamide; or 2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzene sulfonamide;
or a pharmaceutical acceptable salt thereof
22. The 1,2,4-benzothiadiazine derivative according to claim 2, said compound being:
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
1,2,3,5,10,10a-Hexahydrobenzo[e]pyrrolo[1,2-b]-1,2,4-thiadiazine-5,5-dioxide;
3-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(3-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyiminoethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-nitrophenyl)-1,2 3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2',4'-dimethoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
Claims 3-Cyclohexyl-7-(2'-(N,N-dimethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-fluorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2.3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-pyrimidinyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-methyl-1H-2-imidazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1',2',3.'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,24-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-phenylsulfonyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide;
3-Methyl-7-dimethylsulfamoyl-1,2.3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline N',N-dimethylsulfonamide;
3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N,N-diethylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Isopropyl-7-piperidinosulfonyl-1,2 3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-propyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide;
3-Benzyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
Claims 3-Bicyclo[2.2.1]hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1'-(1',2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-methylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-methylsulfonylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(3-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-methoxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1.2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
7-Methylsulfonylamino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Methylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
Claim 7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c)-1,2,4-thiadiazine-5,5-dioxide;
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N,N-diethylsulphamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-5,7-diphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-methoxyphenyl)-7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; or 3-Isobutyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide;
or a pharmaceutical acceptable salt thereof.
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
1,2,3,5,10,10a-Hexahydrobenzo[e]pyrrolo[1,2-b]-1,2,4-thiadiazine-5,5-dioxide;
3-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(3-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-hydroxyiminoethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-nitrophenyl)-1,2 3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2',4'-dimethoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
Claims 3-Cyclohexyl-7-(2'-(N,N-dimethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-fluorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2.3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-pyrimidinyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1-methyl-1H-2-imidazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1',2',3.'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,24-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-phenylsulfonyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide;
3-Methyl-7-dimethylsulfamoyl-1,2.3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline N',N-dimethylsulfonamide;
3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N,N-diethylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Isopropyl-7-piperidinosulfonyl-1,2 3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-propyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzathiadiazine-1,1-dioxide;
3-Benzyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
Claims 3-Bicyclo[2.2.1]hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2,3.4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(1'-(1',2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-methylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(4'-methylsulfonylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Methyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(3-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-8-methoxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1.2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
7-Methylsulfonylamino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Methylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;
Claim 7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c)-1,2,4-thiadiazine-5,5-dioxide;
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-7-(N,N-diethylsulphamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Bicyclo[2.2.1]hept-5'-en-2'-yl-5,7-diphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-(2-methoxyphenyl)-7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1-dioxide;
3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;
3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; or 3-Isobutyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide;
or a pharmaceutical acceptable salt thereof.
23. A compound having the general formula (III) wherein Y represents CH(R4), N(R4) or N(R4)-CH2, or O; and R3 represents a carbocyclic 7- to 12- membered ring, which carbocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; and R6 represents haloalkyl, and Claims R7 represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl, or R7 represents -NR17R18, -NHSO2-R17, or -NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2, and aryl;
or R7 represents -(alkyl)m-S-R17, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2OR17, -(alkyl)mNHCOR17, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)mCO2-R17, wherein m is o or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl or R7 represents -(alkyl)m-SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently of each another represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO-alkyl, -SO--aryl, -SO2-alkyl, -SO2-aryl, and -SO2NR17R18; or R7 represents aryl, Claims optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, and -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3.
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3
or R7 represents -(alkyl)m-S-R17, -(alkyl)m-SO-R17, -(alkyl)m-SO2-R17, -(alkyl)m-SO2OR17, -(alkyl)mNHCOR17, -(alkyl)mCONR17R18, -(alkyl)m-CR'=NOR", -(alkyl)m-CO-R17, or -(alkyl)mCO2-R17, wherein m is o or 1; and R' and R" independently represents hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl; and R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached forms a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl or R7 represents -(alkyl)m-SO2-NR17R18, wherein m is o or 1; and R17 and R18 independently of each another represents alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO-alkyl, -SO--aryl, -SO2-alkyl, -SO2-aryl, and -SO2NR17R18; or R7 represents aryl, Claims optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3, and -SO2-NR17R18, wherein R17 and R18 independently represents hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, which ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl, or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl;
or R7 together with R6, or together with R8, forms a 5- to 7-membered ring having the one of the following structures -O-(CH2)n-O-, wherein n is 1, 2 or 3.
-SO2-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO-NR-(CH2)n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2;
-SO2-(CH2)n-, wherein n is 2 or 3;
-SO-(CH2)n-, wherein n is 2 or 3;
-CO-CH=CH-NH-;
-CO-CH=CH-O-;
-CO-(CH2)n-NH-, wherein n is 1 or 2;
-CO-NH-(CH2)n, wherein n is 1 or 2;
-CO-(CH2)2-O-; or -O-(CH2)n-O-, wherein n is 1, 2 or 3
24. A pharmaceutical composition comprising an effective amount of a chemical compound according to any of claims 1-23, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable excipient, carrier or diluent.
25. The use of a compound according to claim 1, for the preparation of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the modulation of the AMPA receptor complex of the central nervous system.
26. The use according to claim 25 for the preparation of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to modulation of the AMPA receptor complex of the central nervous system.
Claims
Claims
27. The use according to either of claims 25-26, wherein the disorders or diseases are selected from memory and learning disorders, psychotic disorder, sexual dysfunction, intellectual impairment disorders, schizophrenia, depression, autism, Alzheimer's disease, learning deficit, attention deficit, memory loss, and senile dementia; or from a disorder or disease resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorder, alcohol intoxication, substance abuse, cardiac bypass surgery, and cerebral ischemia.
28. A method of treating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to modulation of the AMPA receptor complex of the central nervous system, which method comprises administration of a therapeutically effective amount of a chemical compound according any of claims 1-23.
29. The method according to claim 28, wherein the disorder or disease is responsive to modulation of the AMPA receptor complex of the central nervous system.
30. The method according to either of claims 28-29, wherein the disorder or disease is selected from memory and learning disorders, psychotic disorder, sexual dysfunction, intellectual impairment disorders, schizophrenia, depression, autism, Alzheimer's disease, learning deficit, attention deficit, memory loss, and senile dementia; or from a disorder or disease resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorder, alcohol intoxication, substance abuse, cardiac bypass surgery, and cerebral ischemia.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0226/98 | 1998-02-18 | ||
| DK22698 | 1998-02-18 | ||
| PCT/DK1999/000070 WO1999042456A2 (en) | 1998-02-18 | 1999-02-18 | Novel compounds and their use as positive ampa receptor modulators |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2320354A1 true CA2320354A1 (en) | 1999-08-26 |
Family
ID=8091151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002320354A Abandoned CA2320354A1 (en) | 1998-02-18 | 1999-02-18 | Novel compounds and their use as positive ampa receptor modulators |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1071426A2 (en) |
| JP (1) | JP2002504481A (en) |
| CN (1) | CN1293665A (en) |
| AU (1) | AU751384B2 (en) |
| CA (1) | CA2320354A1 (en) |
| EE (1) | EE200000468A (en) |
| HU (1) | HUP0101280A3 (en) |
| IL (1) | IL137720A0 (en) |
| IS (1) | IS5581A (en) |
| NO (1) | NO20004121L (en) |
| NZ (1) | NZ506251A (en) |
| PL (1) | PL342843A1 (en) |
| RU (1) | RU2214405C2 (en) |
| SK (1) | SK11892000A3 (en) |
| TR (1) | TR200002427T2 (en) |
| WO (1) | WO1999042456A2 (en) |
| ZA (1) | ZA991301B (en) |
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-
1999
- 1999-02-18 CA CA002320354A patent/CA2320354A1/en not_active Abandoned
- 1999-02-18 NZ NZ506251A patent/NZ506251A/en unknown
- 1999-02-18 HU HU0101280A patent/HUP0101280A3/en unknown
- 1999-02-18 CN CN99804196A patent/CN1293665A/en active Pending
- 1999-02-18 EE EEP200000468A patent/EE200000468A/en unknown
- 1999-02-18 AU AU25123/99A patent/AU751384B2/en not_active Ceased
- 1999-02-18 RU RU2000121882/04A patent/RU2214405C2/en not_active IP Right Cessation
- 1999-02-18 JP JP2000532408A patent/JP2002504481A/en not_active Withdrawn
- 1999-02-18 SK SK1189-2000A patent/SK11892000A3/en unknown
- 1999-02-18 ZA ZA9901301A patent/ZA991301B/en unknown
- 1999-02-18 PL PL99342843A patent/PL342843A1/en unknown
- 1999-02-18 IL IL13772099A patent/IL137720A0/en unknown
- 1999-02-18 TR TR2000/02427T patent/TR200002427T2/en unknown
- 1999-02-18 EP EP99904730A patent/EP1071426A2/en not_active Withdrawn
- 1999-02-18 WO PCT/DK1999/000070 patent/WO1999042456A2/en not_active Ceased
-
2000
- 2000-08-04 IS IS5581A patent/IS5581A/en unknown
- 2000-08-17 NO NO20004121A patent/NO20004121L/en unknown
Also Published As
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|---|---|
| NZ506251A (en) | 2003-01-31 |
| IS5581A (en) | 2000-08-04 |
| NO20004121L (en) | 2000-10-17 |
| ZA991301B (en) | 1999-09-13 |
| HUP0101280A3 (en) | 2003-02-28 |
| AU751384B2 (en) | 2002-08-15 |
| WO1999042456A2 (en) | 1999-08-26 |
| AU2512399A (en) | 1999-09-06 |
| IL137720A0 (en) | 2001-10-31 |
| NO20004121D0 (en) | 2000-08-17 |
| HUP0101280A2 (en) | 2001-10-28 |
| EP1071426A2 (en) | 2001-01-31 |
| TR200002427T2 (en) | 2001-01-22 |
| EE200000468A (en) | 2002-04-15 |
| RU2214405C2 (en) | 2003-10-20 |
| WO1999042456A3 (en) | 1999-10-07 |
| SK11892000A3 (en) | 2001-02-12 |
| CN1293665A (en) | 2001-05-02 |
| PL342843A1 (en) | 2001-07-16 |
| JP2002504481A (en) | 2002-02-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20080121 |