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AU2006323952A1 - Novel N-sulfamoyl-piperidineamides for the prophylaxis or treatment of obesity and related conditions - Google Patents

Novel N-sulfamoyl-piperidineamides for the prophylaxis or treatment of obesity and related conditions Download PDF

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AU2006323952A1
AU2006323952A1 AU2006323952A AU2006323952A AU2006323952A1 AU 2006323952 A1 AU2006323952 A1 AU 2006323952A1 AU 2006323952 A AU2006323952 A AU 2006323952A AU 2006323952 A AU2006323952 A AU 2006323952A AU 2006323952 A1 AU2006323952 A1 AU 2006323952A1
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alkyl
substituted
formula
halogen
alkoxy
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Jochen Antel
Michael Firnges
Peter-Colin Gregory
Dania Reiche
Uwe Schoen
Harald Waldeck
Michael Wurl
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Abbott Products GmbH
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Solvay Pharmaceuticals GmbH
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Diabetes (AREA)
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  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
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  • Child & Adolescent Psychology (AREA)
  • Endocrinology (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

WO 2007/065948 PCT/EP2006/069482 Novel N-sulfamoyl-piperidineamides for the 5 prophylaxis or treatment of obesity and related conditions The present invention relates to novel N-sulfamoyl-piperidineamides and their physiologically acceptable acid addition salts, to pharmaceutical compositions comprising them, processes for their preparation, and their use for the treatment of obesity and re 10 lated conditions. WO 03/088908 discloses N-sulfamoyl-piperidineamides with a specific substitution pattern at the piperidine ring. The compounds of W003/088908 are assuredly useful for treating arrhythmia, IKur-associated conditions, gastrointensinal disorders, diabetes, cogni tive disorders, and related conditions. 15 US2004/0167185 describes several N-sulfamoyl-piperidineamides in the area of treating or preventing cancer. A method of discovering compounds suitable for the treatment and/or prophylaxis of obesity by inhibiting lipogenesis via the inhibition of carbonic anhydrases in mammals and humans is known from document WO 02/07821. 20 It was an object of the present invention to provide novel medicaments for the treat ment and/or prophylaxis of obesity and its concomitant and/or secondary diseases or con ditions, which are very effective and can be obtained in simple manner. It has now surprisingly been found that certain novel N-sulfamoyl-piperidineamides and their physiologically acceptable acid addition salts are suitable for the treatment 25 and/or prophylaxis of obesity and its concomitant and/or secondary diseases or condi tions. The invention is directed to compounds of general Formula I, WO 2007/065948 PCT/EP2006/069482 2 R2 I R4 g R R3-N, N ISI 0 0 wherein R1 is selected from the group consisting of: H; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen,
CF
3 , CN; alkylenearyl; alkylenearylenealkyl; alkylenearylenehalogen; alkylenearylene 5 oxyalkyl; alkylenearylenedialkylamin; heteroaryl; alkyleneheteroaryl unsubstituted or sub stituted with alkyl, alkoxy, halogen, CN, CF 3 ; wherein R2 is selected from the group consisting of: cycloalkyl; aryl unsubstituted or sub stituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; heteroaryl; CO 10 alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CF 3 , CN; CO heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-0-alkyl; CO-0-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0 alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0 15 heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2
-NH
2 ; S0 2 -alkyl; S0 2 -aryl unsubstiuted or sub stituted by alkyl, alkoxy, halogen, CF 3 , CN; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally con 20 tain from 1 to 2 additional heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 and/or heteroaryl; and which may also con tain a carbonyl group; and which may also be condensed with aryl; 25 wherein R3 and R4 are independently selected from the group consisting of: H, alkyl, cycloalkyl, cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen; cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxy gen, and optionally substituted with alkyl, alkoxy, halogen, CF 3 , CN; aryl; aryl substituted with alkyl, alkoxy, halogen, CF 3 , CN; heteroaryl unsubstiututed or substituted with alkyl, WO 2007/065948 PCT/EP2006/069482 3 alkoxy, halogen, CF 3 , CN; alkylenearyl; or wherein R3 and R4 together form a 5 or 6 membered ring which may optionally contain from 1 to 2 heteroatoms independently se lected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl or aryl substituted with alkyl, alkoxy, halogen, CF 3 and CN; 5 and their physiologically acceptable acid addition salts. Compounds of general Formula I are suitable for the treatment and/or prophylaxis of glau coma, epilepsy, bipolar disorders, migraine, neuropathic pain, obesity, type 11 diabetes, metabolic syndrome, alcohol dependence, and/or cancer, and its concomitant and/or sec ondary diseases or conditions in mammals and humans. 10 More specifically, in compounds of general Formula I, R1 is selected from the group consisting of: H; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; alkylenearyl; heteroaryl; alkyleneheteroaryl unsubstituted or substituted with halogen; R2 is selected from the group consisting of: cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, 15 CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; al kylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylenearyl; CO heteroaryl; CO-0-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halo gen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; 20 CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO NH-heteroaryl; S0 2
-NH
2 ; or; R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consist ing of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or 25 substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl; R3 and R4 are independently selected from the group consisting of: H, alkyl, cycloalkyl; or R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 het eroatoms independently selected from the group consisting of nitrogen and/or oxygen 30 atoms and which may also be substituted by aryl. Even more specifically, in compounds of general Formula I R1 is selected from the group consisting of: H, alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; al- WO 2007/065948 PCT/EP2006/069482 4 kylenearyl; heteroaryl; alkyleneheteroaryl substituted with halogen; R2 is selected from the group consisting of: alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, 5 CF 3 ; CO-NH-heteroaryl; S0 2
-NH
2 ; or; R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubsti tuted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and 10 which may also contain a carbonyl group; and which may also be condensed with aryl; R3 and R4 are independently selected from the group consisting of: H, alkyl, cycloalkyl; or R3 and R4 together form a ring selected from the group consisting of: pyrrolidinyl, piperidinyl p-phenyl, piperazinyl-p-phenyl and morpholino. 15 In a particularly preferred embodiment of the present invention, R1 is only H if R2 does not contain a CO group. In another particularly preferred embodiment of the present invention, R3 and R4 are both H. 20 Where in the compounds of Formula I or in other compounds described within the scope of the present invention substituents are or contain alkyl, cycloalkyl, alkylene, alkoxy, these may each be straight-chain or branched and possess 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms. Suitable are methyl, ethyl, propyl, iso-propyl, 25 butyl, isobutyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylene, eth ylene, propylene, iso-propylene, butylenes, iso-butylene, tert-butylene, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, and tert.-butoxy. Where substituents in compounds of Formula I stand for halogen, fluorine, chlorine, bromine or iodine are suitable. Chlorine and bromine are preferred. 30 Where substituents in compounds of Formula I stand for aryl single aromatic ring systems with an adequate number of hydrogen atoms dependent upon the substitution pattern are meant. However, condensed and spiro aryl systems are also included in this WO 2007/065948 PCT/EP2006/069482 5 definition. Suitable aryl substituents are phenyl, 1 H-indene, 9H-fluorene, naphthalene, anthracene, and phenathrene. Where substituents in compounds of Formula I stand for heteroaryl, aryl ring sys tems are meant wherein one or more carbon atoms from the aromatic ring system are 5 replaced by a heteroatome selected from oxygen and/or nitrogen and/or sulphur. Suitable heteroaryls are pyrrol, furane, thiophene, indolizine, indole, isoindole, cumarone, thionaphthene, pyrozole, imidozole, oxazole, isooxazole, thiazole, isothiazole, triazole, tetrazole, thiadiazole, pyridine, pyrane, thiopyrane, chinoline, isochinoline, pyridazine, pyrimidine, pyrazine, and triazine. 10 Physiologically compatible acid addition salts of compounds of general Formula I are their conventional salts with inorganic acids, for example sulphuric acid, phosphoric acids or hydrohalic acids, preferably hydrochloric acid, or with organic acids, for example lower aliphatic monocarboxylic, dicarboxylic or tricarboxylic acids such as maleic acid, fumaric 15 acid, lactic acid, tartaric acid, citric acid, or with sulphonic acids, for example lower al kanesulphonic acids such as methanesulphonic acid or trifluoromethanesulphonic acid, or benzenesulphonic acids optionally substituted in the benzene ring by halogen or lower alkyl, such as p-toluenesulphonic acid. Hydrochloric acid salts of the compounds of gen eral Formula I are preferred. 20 Compounds of Formula I, wherein R3 and R4 are both not H, and their physiologi cally acceptable acid addition salts can be prepared by reacting a compound of Formula II 0 N H with a sulfamoylchloride of Formula Ill, R3 N-S-Cl ||| 25 R4 to give compound of Formula IV WO 2007/065948 PCT/EP2006/069482 6 0 N IV O=S=O N R4 R3 Compounds of Formula IV are then reacted with an amine H 2 NR1 to give com pounds of Formula V R1 NH N V N O=S=O N R4 R3 5 Compounds of Formula V are further reacted with R2X wherein X is selected from the group consisting of Cl, Br, and I, to give compounds of Formula I R1,N R2 N N 0=6=0 N R4 R3 Alternatively, compounds of Formula I wherein R3 and R4 are both not H, can be 10 prepared by reacting compounds of Formula IV with an amine HNR1 R2 to give com pounds of Formula I WO 2007/065948 PCT/EP2006/069482 7 R1\ ,R2 N N o=s=o N R4 R3 Compounds of Formula I wherein R3 and R4 are both H, can be prepared by react ing a compound of Formula II 0 || N 5 H with sulfamoylchloride, which is protected with a protecting group PG, preferably tert.
butyloxycarbonyl or benzyl, of Formula Vla, or with the reagent of Formula VIb, 0 0 PG-N-S-Cl Vla PG-N-S-N N + Vlb || || o 0 to give a compound of formula VII 0 N VIl O=S=O ,N\ 10 H PG Compounds of Formula VII are then reacted with an amine H 2 NR1 to give com pounds of Formula VIII WO 2007/065948 PCT/EP2006/069482 8 R1\ NH N Vill o=s=o N H PG Compounds of Formula VIII are further reacted with R2X wherein X is selected from the group consisting of Cl, Br, and I, to give compounds of Formula IX R1 ,N 'R2 N IX N N, H PG 5 and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate products, then leads to compounds of Formula I wherein R3 and R4 both H. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride. If the 10 protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd. Alternatively, compounds of Formula I wherein R3 and R4 are both H, can be pre pared by reacting a compound of Formula VII with an amine HNR1 R2 to give compounds 15 of Formula IX WO 2007/065948 PCT/EP2006/069482 9 R1\, R2 N N o=s=o N H PG and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate products, then leads to compounds of Formula I wherein R3 and R4 5 both H. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd. 10 Compounds of Formula I wherein R2 contains a methylene spacer CH 2 , can be pre pared by reacting a compound of Formula X
NH
2 x N H with a protecting agent PG, to give a compound of formula XI
NH
2 N PG 15 Compounds of Formula XI are then reacted with an aldehyde R2'-CHO, to give compounds of Formula XII, WO 2007/065948 PCT/EP2006/069482 10 R2' H N N PG wherein R2' is selected from the group consisting of: alkyl; cycloalkyl; alkylenearyl, unsub stituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; and alkyle necycloalkyl; 5 Then, the protecting group PG of compounds of Formula XII is cleaved off under suitable conditions and the unprotected compound is then reacted with sulfamoylchloride CIS0 2 NH 2 to give compounds of Formula 1. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, preferably in the pres ence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can 10 be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd. Alternatively, compounds of Formula I wherein R2 contains a methylene spacer
CH
2 , can be prepared by cleaving off the protecting group PG of compounds of Formula 15 XII under suitable conditions and the then unprotected compound is reacted with sulfa moylchloride, which is protected with a protecting group PG, preferably tert.
butyloxycarbonyl or benzyl, of Formula Vla, or with the reagent of Formula VIb, 0 0 PG-N-S-Cl Vla PG-N-S-N N + VIb || || 0 0 to give a compound of formula XIII WO 2007/065948 PCT/EP2006/069482 11 R2 H HN ,CH2 N N N PG H and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate product, then leads to compounds of Formula I wherein R3 and R4 both H. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be 5 achieved under acidic conditions, preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd. In another alternative, compounds of Formula I wherein R2 contains a methylene 10 spacer CH 2 , can be prepared by reacting a compound of Formula X
NH
2 x N H with a protecting agent PG, to give a compound of formula XI
NH
2 N PG Compounds of Formula XI are then reacted with a ketone R2'-COR1', to give com 15 pounds of Formula XIV, WO 2007/065948 PCT/EP2006/069482 12 R2 H N H R1' N PG wherein R1' is selected from the group consisting of: alkyl; alkylenealkoxy; alkylenecy cloalkyl; alkylenearyl; alkylenearylenealkyl; alkylenearylenehalogen; alkylenearylene oxyalkyl, alkylenearylenedialkylamin; and alkyleneheteroaryl unsubstituted or substituted 5 with alkyl, alkoxy, halogen, CN, CF 3 ; wherein R2' is selected from the group consisting of: alkyl; cycloalkyl; alkylenearyl, unsub stituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; and alkyle necycloalkyl; The protecting group PG of compounds of Formula XIV is then cleaved off under suitable 10 conditions and the then unprotected compound is reacted with sulfamoylchloride, which is protected with a protecting group PG, preferably tert.-butyloxycarbonyl or benzyl, of For mula Vla, or with the reagent of Formula VIb, 0 0 PG-N-S-Cl Vla PG-N-S-N N,+ VIb || || -x 0 0 to give a compound of formula XV R2 HN H NkR1' N X N 15 PG H WO 2007/065948 PCT/EP2006/069482 13 and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate product, then leads to compounds of Formula I wherein R3 and R4 both H. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride. If the 5 protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd. Compounds of Formula I can also be prepared by reacting a compound of Formula II 0 II N 10 H with a protecting agent PG to give a compound of formula XVII 0 N XVIl PG Compounds of Formula XVII are then reacted with an amine NHR1 R2 to give com pounds of Formula XVIII, R1, ,R2 N N XVIll 15 PG The protecting group PG of compounds of Formula XVIII is then cleaved off under suitableconditions and the then unprotected compound is reacted with sulfamide to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Vla or VIb to give a compound of formula XIX WO 2007/065948 PCT/EP2006/069482 14 R1, ,R2 N N o=s=o N, H PG and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate product, then leads to compounds of Formula 1. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic con 5 ditions, preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd. In another embodiment compounds of Formula I are prepared by reacting a com 10 pound of Formula VXIIIa wherein R1 is H H\ ,R2 N N XVIlla PG with a compound of formula XX R5-N=C=O XX wherein R5 is selected from the group consisting of: alkyl; cycloalkyl; aryl substituted with 15 alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; and heteroaryl; to give a compound of formula XXI WO 2007/065948 PCT/EP2006/069482 15 0 R5\ ,R2 ,N N H N PG The protecting group PG of compounds of Formula XXI is then cleaved off under suitable conditions and wherein the unprotected compound is then reacted with sulfamide to give compounds of Formula I, or with a compound of formula III to give compounds of 5 Formula I, or with a compound of formulae Vla or VIb to give a compound of formula XXII 0 R5\ ,R2 /N N H N XI O=S=O N H PG and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate product, then leads to compounds of Formula 1. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic con 10 ditions, preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydrogen and a catalyst, such as Pd. Compounds of Formula I can alternatively also be prepared by reacting a compound 15 of Formula VXIIIa wherein R1 is H WO 2007/065948 PCT/EP2006/069482 16 H\ ,R2 N N XVIlla PG with a compound of formula XXIII 0 11 l- S-R6 XXIll II 0 wherein R6 is selected from the group consisting of: alkyl; aryl unsubstiuted or substituted 5 by alkyl, alkoxy, halogen, CF 3 , CN; to give a compound of formula XXIV 0 O0 // /S\ ,R2 R6 N N XXIV PG The protecting group PG of compounds of Formula XXIV is then cleaved off under suitable conditions and wherein the unprotected compound is then reacted with sulfamide to give compounds of Formula I, or with a compound of formula III to give compounds of 10 Formula I, or with a compound of formulae Vla or VIb to give a compound of formula XXV 0 O. // S\ R2 R6 N N XXV O=S=O N H PG WO 2007/065948 PCT/EP2006/069482 17 and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate product, to give compounds of formula 1. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the 5 removal of PG can be achieved with hydrogenation, preferably in the presence of hydro gen and a catalyst, such as Pd. In another embodiment of the present invention, compounds of Formula I can be prepared by reacting a compound of Formula XI
NH
2 N 10 PG with a compound of formula XXIII to give compounds of Formula XXVI 0 O // R6 N N XXVI PG The protecting group PG of compounds of Formula XXVI is then cleaved off under suitable conditions and wherein the unprotected compound is then reacted with sulfamide 15 to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Vla or VIb to give a compound of formula
XXVII
WO 2007/065948 PCT/EP2006/069482 18 0 R6 N N XXVII N 0=6=0 H PG and subsequently cleaving off the protecting group PG under suitable conditions from the obtained intermediate product, to give compounds of formula 1. If the protecting group is tert.-butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, 5 preferably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydro gen and a catalyst, such as Pd. In another embodiment of the present invention, compounds of Formula I can be 10 prepared by reacting a compound of Formula VIII R1\ NH N Vill O=S=O N H PG with compounds of formula XX R5-N=C=O XX to give compounds of Formula XXVIII WO 2007/065948 PCT/EP2006/069482 19 0 R1 A N NH R5 XXVIll N O=S=O N H PG The protecting group PG of compounds of Formula XXVIII is then cleaved off under suit able conditions to give compounds of Formula 1. If the protecting group is tert.
butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, pref 5 erably in the presence of hydrogen chloride. If the protecting group is benzyl, then the removal of PG can be achieved with hydrogenation, preferably in the presence of hydro gen and a catalyst, such as Pd. In another embodiment of the present invention, compounds of Formula I can be 10 prepared by reacting a compound of Formula XI
NH
2 N PG with compounds of formula XXIX o R5 N\ XXIX to give compounds of Formula XXX WO 2007/065948 PCT/EP2006/069482 20 0 H, N NH R5 XXX N PG The protecting group PG of compounds of Formula XXX is then cleaved off under suitable conditions to give compounds of Formula XXXI 0 ,JA N NH R5 XXXI N H 5 Further on, the compound of Formula XXXI is then reacted with sulfamoylchlorid of For mula III to give compounds of Formula I, or the compound of Formula XXXI is then re acted with a compound of Formulae Vla or VIb to give a compound of Formula XXXII 0 Hx N NH R5 XXXII N O=S=O I N H PG The protecting group PG of compounds of Formula XXXII is then cleaved off under suit 10 able conditions to give compounds of Formula 1. If the protecting group is tert.
butyloxycarbonyl, then the removal of PG can be achieved under acidic conditions, pref erably in the presence of hydrogen chloride. If the protecting group is benzyl, then the WO 2007/065948 PCT/EP2006/069482 21 removal of PG can be achieved with hydrogenation, preferably in the presence of hydro gen and a catalyst, such as Pd. If desired, the resulting free bases of compounds of Formula I independently of their 5 substitution pattern at R3 and R4 can be converted into their physiologically acceptable acid addition salts, or, the resulting acid addition salts of the compounds of Formula I in dependently of their substitution pattern at R3 and R4, can be converted into the free bases of Formula 1. 10 In yet another aspect, the present invention also relates to a method of treating or preventing glaucoma, epilepsy, bipolar disorders, migraine, neuropathic pain, obesity, type II diabetes, metabolic syndrome, alcohol dependence, and/or cancer, and its con comitant and/or secondary diseases or conditions in mammals and humans, comprising administering to a subject in need thereof a therapeutically effective amount of a com 15 pound of general Formula I or its physiologically compatible acid addition salts. Obesity according to the present invention is meant to comprise any increase in body fat that results in increased bodyweight, comprising as a preferred alternative but not limited to the medical definition of obesity. The invention thus also relates to non-medical weight loss, such as cosmetic weight loss and includes improving bodily appearance in 20 general. Further, the term obesity also is meant to comprise drug induced obesity and/or juvenile obesity. The concomitant diseases of obesity and its concomitant and/or secondary diseases or conditions in mammals and humans according to the invention include in particular the metabolic syndrome and/or syndrome X and cardiovascular diseases. 25 The term "metabolic syndrome" as used in this application is meant to cover a com plex of clinical pictures which - besides central obesity - mainly comprises hypertension, in particular arterial hypertension; insulin resistance, in particular diabetes mellitus type II; glucose intolerance; dyslipoproteinaemia, in particular as hypertriglyceridaemia, accom panied by dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also hyperuri 30 caemia, which can lead to gout. According to information from the American Heart Asso ciation, the metabolic syndrome is closely linked to insulin resistance. Some people are genetically predisposed to insulin resistance. Acquired factors, such as excess body fat WO 2007/065948 PCT/EP2006/069482 22 and physical inactivity, can elicit insulin resistance and the metabolic syndrome in these people. Most people with insulin resistance have central obesity. The biologic mecha nisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and appear to be complex. One group of people at risk for developing 5 metabolic syndrome are those with diabetes who have a defect in insulin action and can not maintain a proper level of glucose in their blood. Another is people, mainly those with high blood pressure, who are nondiabetic and insulin-resistant but who compensate by secreting large amounts of insulin. This condition is known as hyperinsulinemia. A third group is heart attack survivors who, unlike hypertensives, have hyperinsulinemia without 10 having abnormal glucose levels. The metabolic syndrome has become increasingly com mon in higher developed countries like the United States, where it is estimated that about 20-25 percent of US adults have it. There are no well-accepted criteria for diagnosing the metabolic syndrome. The criteria proposed by the Third Report of the National Cholesterol Education Pro 15 gram (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cho lesterol in Adults (Adult Treatment Panel Ill) are the most current and widely used. Ac cording to the ATP III criteria, the metabolic syndrome is identified by the presence of three or more of these components: " Central obesity as measured by waist circumference (Men - Greater than 40 20 inches; Women - Greater than 35 inches). " Fasting blood triglycerides greater than or equal to 150 mg/dL. " Blood HDL cholesterol (Men - Less than 40 mg/dL; Women - Less than 50 mg/dL) " Blood pressure greater than or equal to 130/85 mmHg. " Fasting glucose greater than or equal to 110 mg/dL. 25 The term "syndrome X" is closely related to the term "metabolic syndrome" and usu ally is supposed to denominate the identical disease or condition. According to information from the American Heart Association, the term "Syndrome X" refers, however, additionally to a heart condition where chest pain and electrocardiographic changes that suggest ischemic heart disease are present, but where there are no angiographic findings of coro 30 nary disease. Patients with cardiac syndrome X also sometimes have lipid abnormalities. The term "cardiovascular diseases" in conjunction with obesity is usually understood to mean coronary heart disease, which can lead to heart failure, cerebrovascular dis- WO 2007/065948 PCT/EP2006/069482 23 eases, which may for example be accompanied by an increased risk of strokes, and pe ripheral occlusive arterial disease. Due to their inherent properties, the compounds of general Formula I or their physio logically compatible acid addition salts are also expected to be useful in the treatment of 5 diabetic conditions or diseases which are unrelated to obesity. Such diabetic conditions or diseases comprise e.g. diabetes mellitus type II, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy or diabetic macroangiopathy. Further concomitant and/or secondary diseases of obesity may be gall-bladder dis eases such as formation of gallstones, sleep apnoea syndrome, orthopaedic complica 10 tions such as osteoarthritis and psychosocial disorders. The compounds of general Formula I are further deemed to be useful as anticonvul sants for the prophylaxis or treatment of epilepsy in mammals and humans. The compounds of general Formula I according to the invention are inhibitors of mammalian carbonic anhydrases, in particular of human carbonic anhydrase isozymes of 15 subtypes II and/or V (= hCA II and/ or hCA V). Pharmacological Test Methods The example numbers quoted in the pharmacological test methods relate to the preparation examples described below. 20 1. In vitro inhibition of human carbonic anhydrase isoenzyme II (hCA II) The test compounds of general Formula I in 96 well microplates were diluted with aqua bidest by using an automatic pipettor (CyBiWell*). From the different dilution plates, aliquots of 20 pl were transferred to the 96 well black assay plates with a pipetting station (Tecan Genesis®). In a second step, 148 pl of potassium phosphate buffer (20 mM, pH 25 7.4) was added, and as a third step, 20 pl of enzyme solution (1 pM human carbonic an hydrase isoenzyme II from erythrocytes (Sigma-Aldrich), dissolved in potassium phos phate buffer) incubated for 60 min at room temperature and the fluorescence signal (Tecan Ultra® fluorescence reader; excitation wavelength: 280 nm; emission wavelength: 465 nm) read at the end of the preincubation period (FLU-1). After the preincubation time, 30 20 pl of aqueous dansylamide solution (1 mM dansylamide (Sigma-Aldrich), dissolved in hydrochloric acid) were added and the fluorescence signal read every 10 min for a period of 60 min at 370C. For calculation, the fluorescence data of the time point 60 min (FLU-2) WO 2007/065948 PCT/EP2006/069482 24 were used. The total volume of assay mixture amounted to 208 pl. The final concentration of carbonic anhydrase II was 10-7 M/L, of dansylamide 2.25x10- 6 and of compounds from 10-8 M/L up to 10-5 M/L. Final concentration of DMSO as compound solvent was 0.1 mM. Each microplate also contained blanks without compound and enzyme, controls without 5 compound and ethoxzolamide (final concentration 5x1 0-8 M/L). All data reflect single measurements. Data were expressed as % inhibition after calculation by the formula: % inhibition = 100((1 -(FLU-2cpd-FLU-2iank-FLU-1 cpd+FLU-1 blan)/(FLU-2controi-FLU-2Iank FLU-1 contro-FLU-1 blank)) The %inhibition data for each compound and the respective final concentrations 10 were used for IC50 calculations by using the Prism 4 software. Concentration action fig ures were calculated by applying the Prism algorithm for nonlinear regression (curve-fit): sigmoidal dose response with variable slope and the constraints: top: 100 and bottom 0. In this test model, the test substances of general Formula I listed in Table 1 below showed the IC50 values given below: 15 Table 1: hCA II inhibiting effect of the test substances in vitro Example No. IC50 [pM] 9 7,2 10 7,3 11 6,5 28 6,6 2. Acute in vivo food intake test in mice The studies were carried out in male or female C57B1/6 mice (n=8-12 per group). The mice were kept on an inverted 12/12h light/dark cycle (lights on 22:00). They were 20 allowed food (high caloric diet) and water ad libitum. Food intake and water consumption was measured daily. The test compound of general Formula I was suspended in 1% me thylcellulose in water and 2% (v/v) of Poloxamer 188 (Lutrol F68*) and administered by oral gavage at a dose of 100 mg/kg/day. One half of the dose was administered at 7.00 9.00 h; the remaining half of the dose was administered between 15.00-15.30 h.
WO 2007/065948 PCT/EP2006/069482 25 In the test model described above, the test substances caused a decrease of the animals' 24h food intake to the percentages of food intake when compared to control as given in Table 2 below. Table 2: Influence of test substances on food intake Example No. food intake [%of control] 1 83 17 84 19 93 26 63 5 The present invention further provides a pharmaceutical composition or medicament comprising a pharmacologically effective quantity of a compound of general Formula I or its physiologically compatible acid addition salts and further comprising conventional phar maceutically acceptable auxiliaries and/or carriers. 10 Suitable pharmaceutically acceptable auxiliaries and/or carriers are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose (or other sugar), magnesium car bonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably sterile). The com position may be a mixed preparation of a composition or may be a combined preparation 15 for simultaneous, separate or sequential use (including administration). The compounds according to the invention or their physiologically compatible acid addition salts for use in the aforementioned indications may be administered by any convenient method, for ex ample by oral (including by inhalation), parenteral, mucosal (e.g. buccal, sublingual, na sal), rectal or transdermal administration and the compositions adapted accordingly. For 20 oral administration, the compounds can be formulated as liquids or solids, for example solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid for mulation will generally consist of a suspension or solution of the compound or physiologi cally acceptable salt in a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or an oil.
WO 2007/065948 PCT/EP2006/069482 26 The formulation may also contain a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and microcrystalline 5 cellulose. A composition in the form of a capsule can be prepared using routine encapsu lation procedures. For example, powders, granules or pellets containing the active ingre dient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceuti cal carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or 10 suspension then filled into a soft gelatin capsule. Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example by an outer coating of the formulation on a tablet or capsule. Typical parenteral compositions consist of a solution or suspension of the compound or physiologically compatible acid addition salts in a sterile aqueous or non-aqueous carrier 15 or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, leci thin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then re constituted with a suitable solvent just prior to administration. Compositions for nasal or oral administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active 20 substance in a physiologically acceptable aqueous or non-aqueous solvent and are usu ally presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once 25 the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a pharmaceutically acceptable propellant. The aerosol dosage forms can also take the form of a pump-atomiser. Compositions suitable for buc cal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin 30 and glycerin. Compositions for rectal or vaginal administration are conveniently in the form of suppositories (containing a conventional suppository base such as cocoa butter), pes saries, vaginal tabs, foams or enemas. Compositions suitable for transdermal administra tion include ointments, gels, patches and injections including powder injections. Conven iently the composition is in unit dose form such as a tablet, capsule or ampoule. The 35 pharmaceutical compositions according to the invention are useful in the prevention WO 2007/065948 PCT/EP2006/069482 27 and/or treatment of obesity, concomitant and/or secondary diseases of obesity; other medical weight loss and non-medical related weight loss; and/or diabetic conditions or diseases. The compounds of the present invention and their physiologically compatible acid 5 addition salts are generally administered as pharmaceutical compositions which are im portant and novel embodiments of the invention because of the presence of the com pounds disclosed herein. In embodiments of the invention, a pharmaceutical pack or kit is provided comprising one or more container(s) filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such container(s) can be 10 various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals prod ucts, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration. Yet a further aspect of the invention provides a process for the manufacture of a 15 pharmaceutical composition as described hereabove. The manufacture can be carried out by standard techniques well known in the art and involves combining a compound accord ing to the invention and the pharmaceutically acceptable auxiliaries and/or carriers. The composition may be in any form including a tablet, a liquid, a capsule, and a powder or in the form of a food product, e.g. a functional food. In the latter case the food product itself 20 may act as the pharmaceutically acceptable carrier. The compound or composition is preferably administered to a patient in need thereof and in a quantity sufficient to prevent and/or treat the symptoms of the condition, disorder or disease. For all aspects of the invention, particularly medical ones, the administration of a compound or composition has a dosage regime which will ultimately be determined by 25 the attending physician and will take into consideration such factors such as the com pound being used, animal type, age, weight, severity of symptoms, method of administra tion, adverse reactions and/or other contraindications. Specific defined dosage ranges can be determined by standard design clinical trials with patient progress and recovery being fully monitored. Such trials may use an escalating dose design using a low percent 30 age of the maximum tolerated dose in animals as the starting dose in man. The physio logically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, pref- WO 2007/065948 PCT/EP2006/069482 28 erably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the general Formula I or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. The compound used according to the invention can also be administered to children or juveniles while the individual dosage 5 regimens in these cases will need to be particularly thoroughly adjusted by the physician and will usually comprise lower doses than will be administered to adults. Suitably the compounds will be administered for a period of continuous therapy, for example for at least a week, but usually for a longer period of several weeks to several months. The invention also provides a cosmetic method (non-therapeutic) for maintaining 10 a given weight, or for cosmetic weight loss, the method comprising the administration of a compound according to the other aspects of the invention, preferably in combination with a pharmaceutically acceptable carrier or diluent. The compound or composition is preferably administered to a subject in need or in desideratum thereof and in a quantity sufficient to maintain a given weight or for cosmetic 15 weight loss. In still a further aspect, the compounds of general Formula I and their physiologically compatible acid addition salts may favourably be administered in combination with one or more active agents (as a pharmaceutical combination composition) selected from antidia betics; antiobesity or appetite-regulating agents; cardiovascular active agents, in particular 20 antihypertensives; diuretics; active agents altering lipid levels, in particular lipid-lowering agents; and active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes. Suitable antidiabetics comprise e.g. insulins, amylin, derivatives of GLP-1 and GLP 2 such as, for example, those disclosed in WO 98/08871 and orally active hypoglycemic 25 active ingredients. The orally active hypoglycemic active ingredients preferably comprise sulfonylureas, e.g tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, gli soxepide, glibomuride or gliclazide; biguanides, e.g. metformin; meglitinides, e.g. repag linide; beta3 adrenergic agonists; oxadiazolidinediones; glucosidase inhibitors e.g. alpha glucosidase inhibitors such as miglitol or acarbose; glucagon receptor antagonists, GLP 30 1 agonists, potassium channel openers like diazoxide or those disclosed in WO 97/26265 or WO 99/03861; CB-1 (cannabinoid-1 receptor) antagonists/inverse agonists; insulin sensitizers like thiazolidinediones, e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4 oxo-2-quinazolinylmethoxy]pheny-1]methyl]-2,4-thiazolidinedione; activators of insulin re- WO 2007/065948 PCT/EP2006/069482 29 ceptor kinase; inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example inhibitors of glycogen phosphorylase; and modulators of glucose uptake and glucose excretion. Suitable antiobesity or appetite-regulating agents comprise one or more of a 5-HT 5 (serotonin) transporter inhibitor, a NE (norepinephrine) transporter inhibitor, a CB-1 (can nabinoid-1 receptor) antagonist/inverse agonist, a ghrelin antibody, a ghrelin antagonist, a H3 (histamine H3) antagonist/inverse agonist, a MCH R (melanin concentrating hormone 1 R) antagonist, a MCH2R (melanin concentrating hormone 2R) agonist/antagonist, a NPY1 (neuropeptide Y Y1) antagonist, a NPY2 (neuropeptide Y Y2) agonist, a NPY5 10 (neuropeptide Y Y5) antagonist, leptin, a leptin derivative, an opioid antagonist, an orexin antagonist, a BRS3 (bombesin receptor subtype 3) agonist, a CCK-A (cholecystokinin-A) agonist, a CNTF (ciliary neurotrophic factor), a CNTF derivative, a GHS (growth hormone secretagogue receptor) agonist, SHT2c (serotonin receptor 2c) agonist, a Mc3r (melano cortin 3 receptor) agonist, a Mc4r (melanocortin 4 receptor) agonist, a monoamine reup 15 take inhibitor, a serotonin reuptake inhibitor, a GLP-1 (glucagon-like peptide 1) agonist, topiramate, phytopharm compound 57, an ACC2 (acetyl-CoA carboxylase-2) inhibitor, a beta3 adrenergic agonist, a DGAT1 (diacylglycerol acyltransferase 1) inhibitor, a DGAT2 (diacylglycerol acyltransferase 2) inhibitor, a FAS (fatty acid synthase) inhibitor, a PDE (phosphodiesterase) inhibitor, a thyroid hormone B agonist, an UCP-1 (uncoupling protein 20 1), 2, or 3 activator, an acyl-estrogen, a glucocorticoid antagonist, an 11 HSD-1 (11-beta hydroxy steroid dehydrogenase type 1) inhibitor, a SCD-1 (stearoyl-CoA desaturase-1) inhibitor, a dipeptidyl peptidase IV (DP-IV) inhibitor, a lipase inhibitor, a fatty acid trans porter inhibitor, a dicarboxylate transporter inhibitor, a glucose transporter inhibitor, a phosphate transporter inhibitor, and pharmaceutically acceptable salts and esters thereof. 25 Suitable appetite-regulating agents (appetite suppressants) comprise sibutramine or the mono- and bisdemethylated active metabolites of sibutramine; fenfluramine or dexfen fluramine; mazindol, diethylpropion or phentermine; leptin or modified leptin; dexam phetamine and amphetamine. Suitable lipase inhibitors comprise orlistat, panclicins, lipase inhibitors isolated from 30 micro organisms such as lipstatin (from Streptomyces toxytricin), ebelactone B (from Streptomyces aburaviensis), synthetic derivatives of these compounds; 2-oxy-4H-3,1 benzoxazin-4-one derivatives like Alizyme's ATL-962 or structurally related compounds; 2 amino-4H-3,1-benzoxazin-4-one derivatives or extracts of plants known to possess lipase WO 2007/065948 PCT/EP2006/069482 30 inhibitory activity, e.g. extracts of Alpinia officinarum or compounds isolated from such extracts like 3-methylethergalangin (from A. officinarum); Suitable CB 1 -cannabinoid antagonists include rimonabant, SLV319, SR147778 and CP-945598. 5 Suitable cardiovascular active agents comprise angiotensin II receptor antagonists, e.g. abitesartan, benzyllosartan, candesartan, elisartan, embusartan, enoltasosartan, ep rosartan, fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B/057, 10 Lusofarmaco LR-B/081, Lusofarmaco LR B/087, Searle SC-52458, Sankyo CS-866, Ta keda TAK-536, Uriach UR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-222, BMS 180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV 11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177, EMD 66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, 15 EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-1177, KT3-671, KW-3433, L-158809, L-158978, L-159282, L-159689, L-159874, L-161177, L 162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-285434, LY-301875, LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018, UP-269-6, 20 UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510, YM-358, YM-31472, ZD-6888, ZD-7155 and ZD-8731 or any physiologically compatible salts, sol vates, prodrugs or esters thereof; daglutril; non-selective alpha-adrenoceptor antagonists, e.g. tolazoline or phenoxybenzamine; selective alpha-adrenoceptor antagonists, e.g. doxazosin, prazosin, terazosin or urapidil; beta-adrenoceptor antagonists, e.g. acebutolol, 25 alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, celiprolol, me pindolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol; mixed antagonists of alpha- and beta-adrenoceptors, e.g. carvedilol or labetolol; ganglion blockers, e.g. reserpine or guanethidine; alpha2-adrenoceptor agonists (including centrally acting alpha2-adrenoceptor agonists), e.g. clonidine, guanfacine, gua 30 nabenz methyldopa and moxonidine; renin-inhbitors, e.g. alskiren; ACE-inhbitors, e.g. benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, perindopril, ramipril, spirapril or trandolapril; mixed or selective endothelin recep tor antagonists e.g. atrasentan, bosentan, clazosentan, darusentan, sitaxsentan, tezosen tan, BMS-193884 or J-104132; direct vasodilators, e.g. diazoxide, dihydralazine, hydra- WO 2007/065948 PCT/EP2006/069482 31 lazine or minoxidil; mixed ACE/NEP-inhbitors, e.g. omapatrilat; ECE-inhbitors, e.g. FR 901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084; CGS-35066; SM-19712; Ro0677447; selective NEP-inhibitors; vasopressin antagonists, aldosterone receptor antagonists, e.g. eplerenone or spironolactone; angiotensin vaccine; and uro 5 tensin 11 receptor antagonists. Suitable diuretics comprise thiazide diuretics, e.g. althiazide, bemetizide, bendroflu methiazide, benzylhydrochlorothiazide, benzthiazide, buthiazide, chlorothiazide, cyclothi azide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, paraflutizide, polythi azide, teclothiazide, trichlormethiazide; thiazide analogue diuretics, e.g. chloraminofena 10 mide, chlortalidone, clofenamide, clopamide, clorexolone, fenquizone, indapamide, mefru side, metolazone, quinethazone, tripamide, xipamide; loop diuretics, e.g. azosemide, bu metanide, furosemide, piretanide, torsemide; potassium sparing diuretics, e.g. amiloride, potassium canrenoate, spironolactone, triamterene or any physiologically compatible tautomers, salts, solvates, prodrugs or esters of any afore mentioned diuretic. 15 Suitable active agents which alter lipid levels comprise compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredi ents like HMGCoA reductase inhibitors, e.g. atorvastatin, berivastatin, cerivastatin, crilvas tatin, fluvastatin, glenvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvas tatin, simvastatin or any physiologically compatible salts, solvates, prodrugs or esters 20 thereof; inhibitors of cholesterol transport/of cholesterol uptake; inhibitors of bile acid re absorption or inhibitors of the microsomal triglyceride transfer protein (MTP); compounds which reduce food intake, PPAR (= peroxisome proliferator-activated receptors) and RXR agonists and active agents which act on the ATP-dependent potassium channel of the beta cells; fibric acids, e.g. bezafibrate, ciprofibrate, clofibrate, fenofibrate or gemfibrozil; 25 cholestyramine, colestipol, probucol, ezetimibe and dextrothyroxine; HMGCoA synthase inhibitor, a cholesterol absorption inhibitor, an acyl coenzyme A-cholesterol acyl trans ferase (ACAT) inhibitor, a cholesteryl ester transfer protein (CETP) inhibitor, a squalene synthetase inhibitor, an anti-oxidant, a PPAR a agonist, a FXR receptor modulator, a LXR receptor agonist, a lipoprotein synthesis inhibitor, a renin angiotensin system inhibitor, a 30 microsomal triglyceride transport inhibitor, a bile acid reabsorption inhibitor, a PEAR8 agonist, a triglyceride synthesis inhibitor, a transcription modulator, a squalene epoxidase inhibitor, a low density lipoprotein receptor inducer, a platelet aggregation inhibitor, a 5-LO or FLAP inhibitor, a PPAR 8 partial agonist, and niacin or a niacin receptor agonist, and pharmaceutically acceptable salts and esters thereof.
WO 2007/065948 PCT/EP2006/069482 32 Further active agents which may be suitable for use in combination with the com pound of general Formula I according to the present invention may be selected from the group consisting of CART agonists, H3 antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, beta3-agonists, MSH (melanocyte-stimulating hor 5 mone) agonists, serotonin-reuptake inhibitors, mixed serotonin- and noradrenaline reuptake inhibitors, 5HT modulators, MAO inhibitors, galanin antagonists, growth hor mone, growth hormone-releasing compounds, TRH agonists, modulators of uncoupling proteins 2 or 3, leptin agonists, dopamine agonists (bromocriptine, doprexin), RXR modu lators, hCNTF agonists and TR-beta-agonists. 10 Preferred pharmaceutical combination compositions according to the invention com prise combinations of at least one compound of general Formula I and at least one bigua nide; at least one compound of general Formula I and at least one fibric acid; at least one compound of general Formula I and at least one HMGCoA reductase inhibitor; and at least one compound of general Formula I and at least one insulin sensitizer. 15 Preferred compounds of general Formula I for combination with one or more of the above mentioned active agents are 4-phenyl-piperazine-1-sulfonic acid amide; 4-(2 chloro-phenyl)-piperazine-1-sulfonic acid amide; 4-(2-methoxy-phenyl)-piperazine-1 sulfonic acid amide; 4-pyridin-4-yl-piperazine-1-sulfonic acid amide; 4-pyrimidin-2-yl piperazine-1-sulfonic acid amide; 4-(4-fluoro-phenyl)-piperazine-1-sulfonic acid amide; 4 20 (4-chloro-3-trifluoromethyl-phenyl)-piperazine-1-sulfonic acid amide and/or 4-(3-chloro-5 trifluoromethyl-pyridin-2-yl)-piperazine-1 -sulfonic acid amide. Metformine is the preferred biguanide for combination with at least one compound of general Formula 1. Preferred fibric acids for combination with at least one compound of general Formula 25 I are bezafibrate, ciprofibrate, clofibrate, fenofibrate and/or gemfibrozil. Fenofibrate is most preferred. Preferred HMGCoA reductase inhibitors for combination with at least one compound of general Formula I are atorvastatin, berivastatin, cerivastatin, crilvastatin, fluvastatin, glenvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and/or simvas 30 tatin or any physiologically compatible salts, solvates, prodrugs or esters thereof. Most preferred are simvastatin, lovastatin and/or pravastatin.
WO 2007/065948 PCT/EP2006/069482 33 Preferred insulin sensitizers for combination with at least one compound of general Formula I are thiazolidinediones, in particular troglitazone, ciglitazone, pioglitazone and/or rosiglitazone. Rosiglitazone and pioglitazone are most preferred. More preferred combinations according to the invention are the combinations of 4 5 phenyl-piperazine-1-sulfonic acid amide with metformine; 4-phenyl-piperazine-1-sulfonic acid amide with fenofibrate; 4-phenyl-piperazine-1-sulfonic acid amide with simvastatin and 4-phenyl-piperazine-1 -sulfonic acid amide with rosiglitazone. In one embodiment of the pharmaceutical combination compositions as described above and according to the invention, the compounds of general Formula I can be ob 10 tained and administered together with the different active agents, e.g. in one combined unit dosage form like in one tablet or capsule, i.e. in a physical combination. In such a combined unit dosage form, the compound of general Formula I and the different active agents can be segregated from each other, e.g. by means of different layers in said tablet, e.g. by the use of inert intermediate layers known in the art; or by means of different com 15 partments in said capsule. The corresponding active agents or their pharmaceutically ac ceptable salts may also be used in form of their hydrates or include other solvents used for crystallization. A unit dosage form may be a fixed combination. A unit dosage form, in particular a fixed combination of the compound of general Formula I and one or more of the different active agents is a preferred alternative of this embodiment. 20 In another embodiment the compounds of general Formula I and the different active agents can be obtained and administered in two or more separate unit dosage forms, e.g. in two or more tablets or capsules, the tablets or capsules being physically segregated from each other. The two or more separate unit dosage forms can be administered simul taneously or stepwise (separately), e.g. sequentially one after the other in either order. 25 Thus, the compounds of general Formula I and the different active agents can be adminis tered in either order at the same time or at different times spread over the day, the optimal dosage regimen usually being determined by prescription of a physician. The following examples are intended to explain the invention further, without limiting its scope. 30 WO 2007/065948 PCT/EP2006/069482 34 Example 1: Urea-analoques (R1 = H, R2 = CO-NH-C 6
H
4 F: boc = tert.-butyloxycarbonyl) H H
NH
2 Na N N boc<N boc" N 'F H H H H NNrNaN N H2N N0N F HN N N F 0 0 1.1 To an ice-cooled solution of 0.7 g 1-fluoro-4-isocyanatobenzene in 25 ml dichloro 5 methane was added dropwise a solution of 1.0 g tert.-butyl-4-aminopiperidine-1 carboxylate in 25 ml dichloromethane under an atmosphere of nitrogen. This mixture was stirred 10 min. at 0 C and then 16 hrs. at room temperature. The reaction mixture was diluted with water and then washed with a saturated solution of NaCI in water. Af ter separation the organic layer was dried over sodium sulfate and evaporated under 10 reduced pressure, yielding 1.6 g tert.-butyl-4-{[[(4fluorophenyl)-amino] carbonyl]amino}-piperidine-1 -carboxylate. 1 H NMR (6 ppm, 400 MHz): 7.37 [2H], 7.04 [2H], 8.34 [1H, NH], 6.13 [1H, NH], 1.40 [9H]. 15 1.2 1.6 g tert.-butyl-4-{[[(4fluorophenyl)amino]carbonyl]amino}piperidine-1 -carboxylate were dissolved in 50 ml dichloromethane. This solution was cooled to 0 C and then 2.3 ml trifluoroacetic acid were added. After stirring for 40 hrs. at room temperature the reaction mixture was evaporated under reduced pressure and twice treated with toluene. After drying in vacuum 2.4 g of 1-(4-fluorophenyl)-3-piperidine-4-yl-urea as 20 trifluoroacetic acid-salt were obtained. H NMR (6 ppm, 400 MHz): 7.39 [2H], 7.05 [2H], 8.51 [1 H, NH], 6.56 [1 H, NH].
WO 2007/065948 PCT/EP2006/069482 35 1.3 2.4 g of 1-(4-fluorophenyl)-3-piperidine-4-yl-urea-trifluoroacetic-acid-salt, 7 ml triethyl amine and 1.17 g sulfamide were dissolved in 70 ml dioxane and refluxed (1300C) for 5 hrs. After removal of the solvent under reduced pressure the crude product was pu rified by flash-chromatography using a 9:1 mixture of dichloromethane/methanol as 5 eluent. 1.0 g 4-{[[(4fluorophenyl)amino]-carbonyl]amino}piperidine-1-sulfonamide, melting point 219.6 - 221.20C, were obtained. ExamNle 2: Urea-analoques (R1 = CHPC 6
H
5 , R2 = CO-NH-C 6
H
5 : boc = tert.-butyloxycarbonyl) H N N 'N boc boc N rN,,rN aNyC:
H
2 N N N HN 10 0 0 2.1 2.6 g sodium acetate, 5.0 g tert.-butyl-4-aminopiperidine-1-carboxylate, 2.0 ml acetic acid and 2.1 ml benzaldehyde were combined in 200 ml THF and stirred for 4 hrs. at room temperature. After addition of 8.8 g trisacetoxy sodiumborohydride the mixture 15 was stirred for 20 hrs. Then solvent was removed under reduced pressure and the residue was dissolved in a mixture of methyl-tert.-butylether and water. The aqueous layer was made alkaline with NaOH and extracted twice with methyl-tert.-butylether. The combined organic layers were washed three times with 30 ml 0.1 N HCI and 5 times with 50 ml 0.1 N HCI. Then the aqueous layers were combined and made basic 20 with NaOH, followed by two extractions with methyl-tert.-butylether. The organic lay ers were washed with water and a saturated solution of NaCI in water, dried over so dium sulfate and then evaporated in vacuum. 4.9 g tert.-butyl 4 (benzylamino)piperidine-1 -carboxylate were obtained as oily product.
WO 2007/065948 PCT/EP2006/069482 36 1 H NMR (6 ppm, 400 MHz): 3.82 [s, 2H], 4.01 [2H], 2.81 [2H], 2.67 [1H], 1.86 [2H], 1.30 [2H], 1.45 [s, 9H]. 2.2 To a solution of 0.187 ml phenylisocyanate in 25 ml dichloromethane was added drop 5 wise under ice cooling a solution of 0.5 g tert.-butyl 4-(benzylamino)piperidine-1 carboxylate in 20 ml dichloromethane. After 5 hrs. stirring at room temperature the re action mixture was washed 3 times with water and with a saturated solution of NaCI in water. The organic layer was separated, dried over sodiumsulfate and evaporated in vacuum. The crude product was crystallized from ethylacetate/n-hexane in the refrig 10 erator, yielding 0.55 g tert.-butyl-4-[(anilinocarbonyl)(benzyl)amino]piperidine-1 carboxylate. 1 H NMR (6 ppm, 400 MHz): 4.61 [1H], 4.46 [s, 2H], 4.21 [2H], 2.83 [2H], 2.67 [1H], 1.83 [2H], 1.56 [2H], 1.44 [s, 9H]. 15 2.3 Under ice-cooling was added 0.94 ml trifluoroacetic acid to a solution of 0.5 g tert.
butyl-4-[(anilino-carbonyl)(benzyl)amino]piperidine-1-carboxylate in 50 ml dichlorome thane. After stirring for 16 hrs. at room temperature the reaction mixture was evapo rated under reduced pressure and the residue was taken up in a mixture of methyl tert.-butylether and water. The aqueous layer was made basic by addition of NaOH 20 solution and extracted 3 times with methyl-tert.-butylether. The combined methyl-tert.
butylether layers were washed with a saturated solution of NaCI in water, dried over sodium sulfate and then evaporated in vacuum, yielding 0.23 g of 1-benzyl-3-phenyl-1 piperidin-4yl-urea. 1 H NMR (6 ppm, 400 MHz): 4.52 [1H], 4.52 [s, 2H], 3.13 [2H], 2.75 [2H], 1.84 [2H], 25 1.59 [2H]. 2.4 0.2 g of 1-benzyl-3-phenyl-1-piperidin-4yl-urea and 0.075 g sulfamide were dissolved in 50 ml dioxane and refluxed for 5 hrs. The reaction mixture was then concentrated in vacuum and the residue dissolved in water. After stirring for 3 hours the residue 30 was separated by filtration and stirred with methyl-tert.butylether. Filtration and drying in vacuum yielded 0.23 g of crude product, which was purified by flash chromatography using dichloromethane/methanol (19:1) as eluent. 50 mg of pure 4- WO 2007/065948 PCT/EP2006/069482 37 [(anilinocarbony)-(benzyl)amino]piperidine-1-sulfonamide were isolated (melting point: 188 - 189-C). ExamNle 3: 5 Substituted amides (R1 = CH3: R2 = C 6
H
1 boc = tert.-butyloxycarbonyl) boc<N boc' N N
H
2 N, N N HN N 0 0 3.1 2.0 g tert.-butyl 4-oxopiperidine-1-carboxylate, 1.23 g sodium acetate, 0.98 ml acetic acid and 1.56 ml N-methylcyclohexanamine were dissolved in 100 ml THF and stirred for one hour at room temperature. Then 4.25 g trisacetoxy sodiumborohydride were 10 added and the reaction mixture was stirred for 18 hours at room temperature. The re action mixture was concentrated under reduced pressure and the residue was taken up in a mixture of water and methyl-tert.-butylether. The aqueous layer was made al kaline and extracted twice with methyl-tert.-butylether. Finally, the organic layer was washed 2 times with 0.1 N HCI, the aqueous layers were combined and made alkaline 15 (pH 10) by addition of NaOH solution. After extraction (2 times) with methyl-tert.
butylether the organic layer was dried over sodium sulfate and evaporated in vacuum. 1.3 g of oily tert-butyl 4-[cyclohexyl-(methyl)amino]piperidine-1-carboxylate were iso lated and used without further purification. 1 H NMR (6 ppm, 400 MHz): 4.12 [2H], 2.69 [2H], 2.63 [1H], 2.50 [1H], 2.23 [s, 3H], 20 1.45 [s, 9H]. 3.2 1.25 g of tert-butyl 4-[cyclohexyl(methyl)amino]piperidine-1 -carboxylate were dissolved in 100 ml dichloromethane, treated with 3.0 ml trifluoroacetic acid and kept for 2 days WO 2007/065948 PCT/EP2006/069482 38 at room temperature. Then the reaction mixture was concentrated under reduced pressure and the residue was taken up in a mixture of water and methyl-tert.
butylether. The aqueous layer was saturated with sodium chloride and extracted 3 times with methyl-tert.-butylether. The organic layer was dried over sodium sulfate 5 and the solvent removed in vacuum, yielding 0.8 g N-cyclohexyl-N-methylpiperidin-4 amine, which was used without further purification. 1 H NMR (6 ppm, 400 MHz): 3.12 [2H], 2.60 [1 H], 2.59 [2H], 2.53 [1 H], 2.26 [s, 3H]. 3.3 0.8 g N-cyclohexyl-N-methylpiperidin-4-amine and 0.47 g sulfamide were dissolved in 10 70 ml dioxane and refluxed for 3 hours. Then the reaction mixture was concentrated under reduced pressure and the residue was taken up in a mixture of water and methyl-tert.-butylether. The organic layer was washed with water and with a saturated soluteion of NaCI in water, dried over sodium sulfate and then evaporated in vacuum, yielding 0.7 g of 4-[cyclohexyl(methyl)amino]piperidine-1 -sulfonamide. 15 1H NMR (6 ppm, 400 MHz): 6.66 [s, 2H], 3.44 [2H], 2.52 [2H], 2.48 [1H], 2.48 [1H], 2.15 [s, 3H]. The hydrochloride acid salt was formed by treating the amine with HCI in isopropanol and subsequent evaporation of the solvent. The melting point was determined to be 20 240 - 242 C. 1 H NMR (6 ppm, 400 MHz): 6.86 [2H], 3.34 [2H], 3.32 [s, 3H] . ExamNle 4: Substituted amides (R1 = H; R2 = C 6
H
1 boc = tert.-butyloxycarbonyl) WO 2007/065948 PCT/EP2006/069482 39 H boc N NH bo< N N H H
H
2 N -Na N HNa N 0 0 4.1 1.23 g sodium acetate, 2.4 g tert.-butyl-4-aminopiperidine-1-carboxylate, 1.0 ml acetic acid and 1.0 g cyclohexanone were combined in 150 ml THF and stirred for 3 hrs. at 5 room temperature. Then 4.25 g trisacetoxy sodiumborohydride were added and the reaction mixture was stirred for 16 hrs. at room temperature. After concentrating the reaction mixture under reduced pressure the residue was taken up in a mixture of methyl-tert.-butylether and water, which was made alkaline with sodium carbonate to pH 9. The organic layer washed 4 times with 0,1 N HCI. Then the aqueous layer was 10 made alkaline with NaOH and extracted twice with methyl-tert.-butylether. The com bined organic layers were washed with water and with a saturated solution of NaCI in water, dried over sodium sulfate and then evaporated under reduced pressure, yield ing 2.4 g of oily tert-butyl 4-(cyclohexylamino)piperidine-1 -carboxylate. 1 H NMR (6 ppm, 400 MHz): 4.03 [2H], 2.78 [2H], 2.74 [1H], 2.56 [1H], 1.83 [4H], 1.73 15 [2H], 1.45 [9H]. 4.2 2.3 g of tert-butyl 4-(cyclohexylamino)piperidine-1-carboxylate were dissolved in 100 ml dichloromethane and treated with 6.3 ml trifluoroacetic acid under ice-cooling. Af ter stirring for 16 hrs. at room temperature the reaction mixture was concentrated un 20 der reduced pressure. The residue was taken up in a mixture of water and methyl tert.-butylether. The aqueous layer was made basic with sodium hydroxide and ex tracted 5 times with methyl-tert.-butylether. Then, the organic layer was washed with water and with a saturated solution of NaCI in water, dried over sodium sulfate and the solvent was removed in vacuum. 1.15 g of oily N-cyclohexyl-piperidin-4-amine were 25 isolated and used without further purification.
WO 2007/065948 PCT/EP2006/069482 40 1 H NMR (6 ppm, 400 MHz): 3.08 [2H], 2.68 [1H], 2.60 [2H], 2.58 [1H], 1.85 [4H], 1.72 [2H]. 4.3 1.1 g N-cyclohexyl-piperidin-4-amine and 0.7 g sulfamide were dissolved in 100 ml 5 dioxane and refluxed for 5 hours. Then the solvent was removed under reduced pres sure and the remaining residue was taken up in a mixture of water and dichloro methane. The organic layer was washed with water and with a saturated solution of NaCI in water, dried over sodium sulfate and then evaporated in vacuum, yielding 0.8 g 4-(cyclohexylamino)piperidine-1 -sulfonamide. 10 1H NMR (6 ppm, 400 MHz): 6.83 [2H], 3.36 [2H], 2.59 [1 H], 2.57 [2H], 2.48 [1 H], 1.79 [4H]. The hydrochloride acid salt was formed by treating the amine with HCI in isopropanol and subsequent evaporation of the solvent. The melting point was determined to be 15 higher than 2400C. 1 H NMR (6 ppm, 400 MHz): 6.83 [2H], 3.53 [2H], 3.25 [1H], 3.08 [1H], 2.56 [2H], 2.10 [2H]. ExamNle 5: 20 Sulfonamides (R1 = CH 2
C
6
H
5 : R2 = S0 2
C
6
H
4
CH
3 boc = tert.-butyloxycarbonyl) WO 2007/065948 PCT/EP2006/069482 41 H
NH
2 N boc boc< 0 N N HN N 00 bock 0 0 0 5.1 1.5 g tert.-butyl-4-aminopiperidine-1-carboxylate and 1.13 ml triethylamine were dis solved in 20 ml dichloromethane. To this mixture was added under an atmosphere of nitrogen a solution of 1.57 g p-toluenesulfonylchloride in 15 ml dichloromethane under 5 ice cooling. The reaction mixture was then stirred for 2 days at room temperature. Af ter washing with water, sodium hydrogencarbonate solution, water and with a satu rated solution of NaCI in water the organic layer was dried over sodium sulfate and evaporated in vacuum to yield after drying in vacuum 2.6 g tert-butyl 4-{[(4 methylphenyl)sulfonyl]amino}piperidine-1 -carboxylate. 10 1H NMR (6 ppm, 400 MHz): 7.70 [2H], 7.67 [d, 1H], 7.39 [2H], 3.70 [2H], 3.13 [1H], 2.75 [1 H], 2.39 [s, 3H], 1.36 [s, 9H]. 5.2 To a solution of 1.3 g tert-butyl 4-{[(4-methylphenyl)sulfonyl]amino}piperidine-1 carboxylate in 40 ml DMF were added under cooling with ice and an atmosphere of ni 15 trogen 0.62 g potassium tert.-butylate. After 30 min. 0.69 g benzylbromide in 5 ml DMF were added dropwise. This mixture was stirred at room temperature for 20 hours. For workup, the solvent was removed under reduced pressure and the residue was taken up in methyl-tert.-butylether. This solution was washed with water and with a saturated solution of NaCI in water, dried over sodium sulfate and finally concen 20 trated in vacuum. The crude product was purified by flash chromatography, using a mixture of n-hexane and ethylacetate (9:1) as eluent. Besides the recovery of 0.69 g starting material 0,51 g tert-butyl 4-{benzyl[(4-methylphenyl)sulfonyl]amino}piperidine 1 -carboxylate were isolated.
WO 2007/065948 PCT/EP2006/069482 42 1 H NMR (6 ppm, 400 MHz): 7.76 [2H], 7.41 [2H], 7.38 [2H], 7.33 [2H], 7.25 [1H], 4.39 [s, 2H], 3.86 [1 H], 3.80 [2H], 2.63 [2H], 2.41 [s, 3H], 1.31 [s, 9H]. 5.3 0.5 g tert-butyl 4-{benzyl[(4-methylphenyl)sulfonyl]amino}piperidine-1 -carboxylate and 5 0.86 ml trifluoroacetic acid were dissolved in 15 ml dichloromethane and stirred for 60 hours at room temperature. The mixture was diluted with dichloromethane and stirred with 0.1 N sodium hydroxide solution. Then, the organic layer was separated, was with a saturated solution of NaCI in water, dried over sodium sulfate and evaporated in vacuum, yielding 0.36 g N-benzyl-4-methyl-N-piperidin-4-ylbenzenesulfonamide. 10 1H NMR (6 ppm, 400 MHz): 7.74 [2H], 7.40 [2H], 7.39 [2H], 7.34 [2H], 7.25 [1 H], 4.40 [s, 2H], 3.69 [1 H], 2.77 [2H], 2.40 [s, 3H], 2.31 [2H]. 5.4 0.36 g N-benzyl-4-methyl-N-piperidin-4-ylbenzenesulfonamide and 0.12 g sulfamide were refluxed in 5 ml dioxane for 8 hours. The reaction mixture was concentrated in 15 vacuum and the residue was taken up in methyl-tert.-butylether, then washed with wa ter, sodium carbonate solution, water and with a saturated solution of NaCI in water. After drying over sodium sulfate the organic layer was evaporated in vacuum to yield 0.4 g 4-{benzyl[(4-methylphenyl)sulfonyl]amino}piperidine-1 -sulfonamide. 1 H NMR (6 ppm, 400 MHz): 7.78 [2H], 7.41 [2H], 7.40 [2H], 7.35 [2H], 7.27 [1H], 6.67 20 [s, 2H], 4.42 [s, 2H], 3.70 [1 H], 3.35 [2H], 2.43 [2H], 2.41 [s, 3H]. ExamNle 6: Sulfonamides (R1 and R2 build up a phenyl-substituted piperazine-system boc = tert.
butyloxycarbonyl) WO 2007/065948 PCT/EP2006/069482 43 N boc N bocN N N N N N
H
2 N N HN 0 0 6.1 2.0 g tert-butyl 4-oxopiperidine-1-carboxylate, 1.23 g sodium acetate, 0.98 ml acetic acid and 1.83 ml 1-phenylpiperazine were combined in 150 ml THF and stirred for 2 5 hours at room temperature. Then, 4.25 g trisacetoxy sodiumborohydride were added and stirred for additional 16 hours. For work-up, the reaction mixture was concen trated in vacuum and the residue was taken up in methyl-tert.-butylether and water. This mixture was made alkaline by addition of a sodium carbonate solution (pH = 10). The organic layer was then washed 6 times with 0.1 N HCI and the aqueous layer 10 (combined fractions 3, 4 and 5) was made alkaline by the addition of diluted sodium hydroxide solution. After extraction with methyl-tert-butylether, the organic layer was washed with water and with a saturated solution of NaCI in water, dried over sodium sulfate and then concentrated in vacuum. 2.0 g tert-butyl 4-(4-phenylpiperazin-1 yl)piperidine-1 -carboxylate were isolated. 15 1H NMR (6 ppm, 400 MHz): 7.26 [2H], 6.93 [2H], 6.85 [1H], 4.15 [2H], 3.20 [2H], 2.73 [2H], 2.72 [2H], 2.42 [1 H], 1.46 [s, 9H]. 6.2 1.9 g tert-butyl 4-(4-phenylpiperazin-1-yl)piperidine-1-carboxylate and 4.25 ml trifluo roacetic acid were dissolved in 100 ml dichloromethane and stirred for 24 hours. The 20 reaction mixture was concentrated in vacuum and the remaining residue was taken up in methyl-tert.-butylether and water. After basification with sodium hydroxide solution the aqueous layer was extracted with methyl-tert-butylether. Then the precipitate in the aqueous layer was isolated by filtration, washed with water and dried in vacuum at 50 C, yielding 0.67 g 1-phenyl-4-piperidin-4-ylpiperazine.
WO 2007/065948 PCT/EP2006/069482 44 H NMR (6 ppm, 400 MHz): 7.25 [2H], 6.93 [2H], 6.85 [1H], 3.21 [2H], 3.16 [2H], 2.73 [2H], 2.61 [2H], 2.38 [1 H]. 6.3 0.65 g 1 -phenyl-4-piperidin-4-ylpiperazine and 0.30 g sulfamide were dissolved in 50 5 ml dioxane and refluxed for 3 hours. The reaction mixture was concentrated under re duced pressure. When the residue was taken up with water, a precipitation started which was completed by further stirring for 1 hour. After filtration, the precipitate was stirred in the presence of dichloromethane for 1 hour, again filtered and dried in vac uum at 500C. 0.68 g 4-(4-phenylpiperazin-1-yl)piperidine-1-sulfonamide were isolated. 10 1H NMR (6 ppm, 400 MHz): 7.20 [2H], 6.92 [2H], 6.76 [1H], 6.69 [s, 2H], 3.50 [2H], 3.11 [2H], 2.64 [2H], 2.54 [2H], 2.31 [1H]. This compound was transferred to the corresponding HCI salt by treatment with a HCI/isopropanol solution. Recrystallization yielded 0.52 g product, melting point 222 15 227 C. Example 7: Alternative introduction of the sulfonamide function 0 0 I' NH O + HNON
N(CH
3
)
2
N(CH
3
)
2 H H N, Na 0O NI .1 Na
H
2 Ns . ,N,\ 0 0 20 7.1 To an ice-cooled solution of 4.36 ml chlorosulfonyl isocyanate in 50 ml dichloro methane was added dropwise over a period of 30 minutes a solution of 4.8 ml tert.
butanol in 50 ml dichloromethane. After further stirring for 30 minutes under cooling, this mixture was added dropwise to a solution of 7.68 g 4-piperidone hydrate HCI-salt WO 2007/065948 PCT/EP2006/069482 45 and 14.6 ml triethylamine in 100 ml dichloromethane. After stirring for 45 minutes un der cooling the reaction mixture was allowed to come to room temperature and was stirred for 16 hours. The reaction mixture was diluted with dichloromethane, washed 3 times with 0.1 N HCI (60 ml each) and with a saturated solution of NaCI in water. After 5 drying over sodium sulfate the organic layer was concentrated in vacuum to yield 7.2 g of crude product. Purification via flash-chromatography, using a mixture of dichloro methane/methanol (9:1) as eluent gave 6.0 g tert-butyl [(4-oxopiperidin-1 yl)sulfonyl]carbamate. 1 H NMR (6 ppm, 400 MHz, DMSO-d 6
):
1 H-NMR: 3.56 [t, 4H], 2.44 [t, 4H], 1.42 [s, 9H]. 10 Further reaction steps as in any of the above examples 1 to 6. ExamNle 8: Alternative introduction of the sulfonamide function N,_ 0 N N N + HN ON N 0'~o 0~ 1 0 0 0
N(CH
3
)
2
N(CH
3
)
2 H H2N, ,N O N SN r 2 C r // \\ S 00 0 15 0 0 8.1 To a solution of 2.6 ml tert.-butanol in 20 ml dichloromethane were added dropwise under cooling with ice 2.4 ml chlorosulfonyl isocyanate over 15 minutes. After stirring for 15 minutes 6.9 g 4-dimethyl-amino pyridine were added. The cooling was re moved and the reaction mixture was stirred for 1 hour at room temperature, when a 20 white precipitate was formed. The mixture was diluted with 130 ml dichloromethane and washed for times with water and finally with a saturated solution of NaCI in water. After drying over sodium sulfate the organic layer was concentrated in vacuum to WO 2007/065948 PCT/EP2006/069482 46 yield 6.4 g of the crystalline reagent (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin 1(4H)-yl]sulfonyl}azanide. 1 H NMR (6 ppm, 400 MHz, CDC1 3 ): 8.46 [d, 2H], 6.98 [d, 2H], 3.23 [s, 6H], 1.26 [s, 9H]. 5 8.2 0.5 g (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1 (4H)-yl]sulfonyl}azanide, 0.26 g 4-piperidone hydrate HCI-salt and 0.205 g 4-dimethylamino pyridine were dissolved in 50 ml dioxane and heated at 500C for 4 hours. The reaction mixture was concen trated in vacuum and the residue was taken up in dichloromethane. After washing 10 twice with diluted potassium hydrogensulfate solution, the organic layer was washed with a saturated solution of NaCI in water and dried over sodium sulfate. The solvent was removed under reduced pressure, yielding 0.23 tert-butyl [(4-oxopiperidin-1 yl)sulfonyl]-carbamate. A further amount of 0.07 g of product was obtained by ex tracting the combined aqueous layers with dichloromethane. 15 1 H NMR (6 ppm, 400 MHz, CDC1 3 ): 3.74 [t, 4H], 2.58 [t, 4H], 1.49 [s, 9H]. Further reaction steps as in any of the above examples 1 to 6. ExamNle 9: 20 Substituted sulfonamides R2 0 0 NH (N (N N HII HCI H 2 0 OIO OIO N N R2\ CO- R1' N N
N
WO 2007/065948 PCT/EP2006/069482 47 9.1 10 g (65 mmol) piperidone hydrochloride and 7.7 ml (1.1 eq, 71.6 mmol) dimethyl sulfamoyl chloride were dissolved in a mixture of acetone / water (1:1, 400 ml). 20 ml (2.2 eq, 143 mmol) triethylamine was added and the reaction was stirred at room temperature for 4 days. The solvent was then evaporated and the residue dissolved 5 in ethyl acetate. The organic layer was then washed with water, dried over magne sium sulfate, and the solvent removed in vacuum, to give the required sulfamide as a white solid (12.55 g, 95% yield). 1 H NMR (6 ppm, 400 MHz, CDC1 3 ): 2.49 (t, 4H, J= 6.24 Hz), 2.79 (s, 6H), 3.53 (t, 4H, J= 6.12 Hz). 10 9.2 0.35 g (1.7 mmol) of the sulfamide from step 9.1 was dissolved in 10 ml dichloro ethan, followed by 1.05 eq (1.78 mmol) of pentylamine and 1.5 eq (2.55 mmol) trisacetoxy sodiumborohydride. The reaction was stirred at room temperature over night and was then washed with 1M NaOH. The aqueous layer was extracted with 15 ether. The combined organic layers were washed with a saturated solution of NaCI in water, then dried over magnesium sulfate, and the solvent removed in vacuum. The crude was loaded onto 0.5 g polymer-supported toluenesulfonic acid. The resin was washed with MeOH, then with 2M NH 3 in MeOH to recover pure amine. 1 H NMR (6 ppm, 400 MHz, CDC1 3 ): 0.69 (t, 3H, J= 7 Hz), 1.20 (m, 9H), 1.72 (m, 2H), 20 2.38 (m, 1 H), 2.42 (t, 2H, J = 7 Hz), 2.60 (s, 6H), 2.65 (td, 2H, J = 2, 13 Hz), 3.43 (2H, td, J= 3, 13 Hz). 13C NMR (6 ppm, 400 MHz, CDC1 3 ): 14.0, 22.6, 29.6, 30.1, 32.3, 38.2, 45.2, 46.9, 54.3. 25 9.3 0.036 mmol of the amine from step 9.2 was dissolved in 1 ml dichloromethane and mixed with 1.5 eq, 0.054 mmol acetic acid chloride and 0.054 mmol (1.5 eq, 15 mg) polymer-supported triethylamine. The reaction was shaken for 3 days at room tem perature, before 0.054 mmol (1.5 eq, 26 mg) aminomethylated polystyrene was added to the reaction mixture. It was then shaken for 1 more day. The resin was fil 30 tered off, rinsed with dichloroethane and the solvent was evaporated in vacuum to re cover the desired sulfamamides.
WO 2007/065948 PCT/EP2006/069482 48 Example 10: Substituted sulfonamides (boc = tert.-butyloxycarbonyl) 0 0 HN R1 N N N N boc boc boc o 0 R Ri R 1 ' N RR 1 ' N R-R R 1 N N N I I N 0S=O O=S 0 H.TFA
NH
2 HNN 10.1 0.35 g (17.57 mmol) tert-butyl 4-oxopiperidine-1-carboxylate were dissolved in 100 5 ml dichloroethane, followed by the addition of 1.05 eq (18.44 mmol) of the amine and 1.5 eq. (26.36 mmol) of trisacetoxy sodiumborohydride. The reaction was stirred at room temperature overnight. The reaction mixture was then washed with 1 M NaOH, and the aqueous layer was extracted with ether. The combined organic layer was washed with a saturated solution of NaCI in water, then dried over mag 10 nesium sulfate, and the solvent was removed in vacuum to get the required pure amine substituted piperidine. 10.2 18 mmol of the amine substituted piperidine from step 10.1 were dissolved in 120 ml dichloromethane and mixed with 19.8 mmol (1.1 eq.) of the acid chloride and 27 15 mmol (3.76 ml, 1.5 eq.) of triethylamine. The reaction was stirred for 3 days at room temperature. The reaction mixture was then quenched with a saturated solution of NaCI in water, and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, and the solvent evapo rated in vacuum. The crude compound was purified by flash chromatography WO 2007/065948 PCT/EP2006/069482 49 eluting with 40-50% ethyl acetate/heptane, to give the desired carbonyl substituted piperidine. 10.3 12.21 mmol of the carbonyl substituted piperidine from step 10.2 were dissolved in 5 20% trifluoroacetic acid in 45 ml dichloromethane. The reaction was stirred for 1h. The solvent was evaporated in vacuum to get the desired carbonyl substituted piperidine as a trifluoroacetic acid salt in quantitative yield. The compound was not purified further and was used crude in the next step. 10 10.4 0.84 mmol of carbonyl substituted piperidine as a trifluoroacetic acid salt from step 10.3 were dissolved in 20 ml dichloroethane, and 9.51 mmol (3 g) tetraalkylammo nium carbonate, polymer-bound was added to the mixture. The reaction was stirred for 1 day before the resin was filtered and rinsed with dichloromethane. The solvent was removed to get the carbonyl substituted piperidine as a free base amine. 15 1.68 mmol (2 eq.) tert-butanol was added slowly to a solution of 1.68 mmol (2 eq., 0.145 ml) chlorosulfonylisocyanate 10 ml dichloromethane at 00C. The reaction was warmed to room temperature for 1h, before it was cooled down to 0 C. 0.47 ml (3.36 mmol; 4 eq.) triethylamine was added to the reaction followed by the free based amine from step 10.4 above in 5 ml dichloromethane. The reaction was 20 warmed to room temperature and stirred over night. The reaction mixture was washed with 1 N HCI, the organic layer was dried over magnesium sulfate, and the solvent evaporated in vacuum. The crude compound was purified by flash chroma tography, eluting with 50% ethyl acetate/heptane, to get the boc-protected sulfama mide as a white solid (0.185 g, 55% yield). 25 10.5 0.12 mmol of the boc-protected sulfamide from step 10.4 were dissolved in 20% TFA in 1 ml dichloromethane and the reaction was stirred for 2h. The solvent was then evaporated in vacuum to get a white solid, the desired end product as trifluoroacetic acid salt in quantitative yield (42 mg). 30 Example 11: Heteroaryl-substituted sulfonamides (boc = tert.-butyloxycarbonyl) WO 2007/065948 PCT/EP2006/069482 50 N C~N O HOjN N + N NN O + HNr ~~~KI~Nc7""' H 2 N~$ N N NN N ~ 0 I s 00 N F O-ZN H H rOY N NsN' CF, H2 N' N N0 CF, 0 0 0 0 11.1 To a solution of 26 mL tert.-butanol in 200 mL dichloromethane were added drop wise under cooling with ice (50C) 24 mL chlorosulfonyl isocyanate over 90 minutes. 5 After stirring for 60 minutes, 69 g 4-dimethylamino pyridine were added in portions. The cooling was removed and the reaction mixture was stirred for 1 hour at room temperature, when a white precipitate was formed. The mixture was diluted with 200 mL dichloromethane and washed with 500 mL water. Then 1.1 L dichloro methane was added and the resulting solution was washed four times with water 10 (0.5 L each) and finally with brine. After drying over sodium sulfate the organic layer was concentrated in vacuum to yield 76.5 g of the crystalline reagent (tert butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)-yl]sulfonyl}azanide with a melting point of 180-181 OC. 1 H-NMR (6 ppm, 400 MHz, CDC1 3 ): 8.46 [d, 2], 6.98 [d, 2], 3.23 [s, 6], 1.26 [s, 9] 15 WO 2007/065948 PCT/EP2006/069482 51 11.2 50 g (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)-yl]sulfonyl}azanide, 30.6 g 4-piperidone hydrate HCI-salt and 24.3 g 4-dimethylamino pyridine were dissolved in 1.5 L dioxane and heated at 550C for 16 hours. The reaction mixture was con centrated in vacuum and the residue was taken up in dichloromethane. After wash 5 ing three times with diluted potassium hydrogensulfate solution, the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, yielding 32.8 g tert-butyl [(4-oxopiperidin-1-yl)sulfonyl] carbamate with a melting point of 107-1090C. 1 H NMR (6 ppm, 400 MHz, CDC1 3 ): 3.74 [t, 4], 2.58 [t, 4], 1.49 [s, 9] 10 11.3 14 g tert-butyl [(4-oxopiperidin-1-yl)sulfonyl]carbamate were dissolved in 600 mL THF and 5.7 g 3-aminopyridine and 6.2 g sodium acetate were added. To this mix ture were added 4.9 mL acetic acid and 7.4 mL tetraisopropyl orthotitanate and then the reaction mixture was stirred for 5 hours at room temperature. Then, 21.3 g so 15 dium trisacetoxyborohydride were added in portions and it was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuum and the residue was taken up in a mixture of dichloromethane and water. The aqueous layer and some solid was separated and stirred with dichloromethane. For a better separation the combined organic layers were treated in a centrifuge (4000 rpm). 20 The organic layer was washed with brine and dried over sodium sulfate, to yield af ter evaporation under reduced pressure 20 g of a light green oil. Crystalization from MTB-E (100 mL) gave 8.34 g of pure tert-butyl {[4-(pyridin-3-ylamino)piperidin-1 yl]sulfonyl}carbamate having a melting point of 1700C (dec.). 1 H NMR (6 ppm, 400 MHz, DMSO-d 6 ): 10.92 [s, br, 1], 8.00 [d, 1], 7.76 [dd, 1], 7.11 25 [dd, 1], 7.02 [dd, 1], 3.62 [m, 2], 3.42 [m, 1], 2.99 [m, 2], 1.97 [m, 2], 1.44 [s, 9], 1.38 [m, 2]. 11.4 28.6 g tert-butyl {[4-(pyridin-3-ylamino)piperidin-1-yl]sulfonyl}carbamate were nearly complete dissolved in 1.5 L dichloromethane and then 15 g 4-(trifluoromethyl) 30 phenyl isocyanate were added. This reaction mixture was stirred for 24 h at 400C. The reaction mixture was filtered (0.9 g starting material was isolated) and concen trated in vacuum. The residue was stirred in a mixture of 500 mL of MTB-E and 500 mL of water for 1 hour, when the product started to precipitate. The solid was sepa rated by filtration, washed with MTB-E and water and then dried in vacuum at 600C.
WO 2007/065948 PCT/EP2006/069482 52 41.4 g tert-butyl {[4-(pyridin-3-yl{[4-(trifluoromethyl)phenyl]-carbamoyl}amino) piperidin-1-yl]sulfonyl}carbamate were isolated having a melting point of 1450C (foaming). 1 H NMR (6 ppm, 400 MHz, DMSO-d 6 ): 10.88 [s, br, 1], 8.61 [d, 1], 8,45 [dd, 1], 8,11 5 [s, 1], 7.70 [dd, 1], 7.61 [d, 2], 7.55 [d, 2], 7.50 [dd, 1], 4.43 [m, 2], 3.67 [m, 1], 2.95 [m, 2], 1.92 [m, 2], 1.36 [s, 9], 1.22 [m, 2]. 11.5 To a solution of 1.3 g tert-butyl {[4-(pyridin-3-yl{[4-(trifluoromethyl)phenyl] carbamoyl}amino)-piperidin-1 -yl]sulfonyl}carbamate in 100 mL dichloromethane we 10 re added 1.8 mL trifluoroacetic acid. This mixture was stirred for 30 hours at room temperature. Then the reaction mixture was concentrated in vacuum and the result ing oily residue was taken up in MTB-E, where the product begun to crystallize. Af ter 2 hours the solid was isolated by filtration and thereafter dried under reduced pressure. The resulting residue was stirred with a mixture of MTB-E and water. Af 15 ter removal of some insoluble product (0.13 g) the organic layer was separated, washed with water and sodium hydrogencarbonate solution, when the product pre cipitated. The yield of the combined crystalline material 4-(pyridin-3-yl{[4 (trifluoromethyl)phenyl]carbamoyl}-amino)piperidine-1-sulfonamide was 0.57 g hav ing a melting point of 188 -191 OC. 20 1 H NMR (6 ppm, 400 MHz, DMSO-d 6 ): 8.62 [d, 1], 8,47 [dd, 1], 8,14 [s, 1], 7.71 [dd, 1], 7.62 [d, 2], 7.55 [d, 2], 7.52 [dd, 1], 4.36 [m, 2], 3.50 [m, 1], 2.62 [m, 2], 1.93 [m, 2], 1.26 [m, 2]. 25 The following compounds have been synthesized in excellent yields in accordance with any of the examples 1 to 8 from above. Table 3: Further compounds of general Formula I Compound Example R1 R2 R3 R4 No. No. 1 1 H CO-NH-C 6
H
4 F H H 2 2 CH 2
C
6
H
5
CO-NH-C
6
H
5 H H 3 3 CH 3
C
6 H H H WO 2007/065948 PCT/EP2006/069482 53 Compound Example R1 R2 R3 R4 No. No. 4 4 H C 6
H
11 H H 5 5 CH 2
C
6
H
5
SO
2
C
6
H
4
CH
3 H H 6 6 N N \ / H H 7 7 CH 3
CH
3 H H 8 8 CH 3
CH
3 H H 9 1 ON H H N ' 10 1 o N H H N-k ON: 11 1 H H 12 2 H CO-C 6
H
4 -4- H H
OCH
3 13 2 H CO-tert.-C 4
H
9 H H 14 3 CH 3
C
6
H
5 H H 15 3 CH 3
C
6
H
11 H H 16 3 C 2
H
5
C
6
H
11 H H 17 2 H CO-NH-C 6
H
4 -4- H H F 18 2 H CO-NH-C 6
H
4 -4- H H OH 19 2 H C 6
H
5 H H 20 2 H C 6
H
11 H H 21 6 NtN /H H 22 2 H CO-NH-C 6
H
4 -3- H H F 23 2 H CO-NH-O 6
H
4 -4- H H
OF
3 24 3 CH 3
C
6
H
4 -4-OCH 3 H H 25 6 N 0 H H
\__/
WO 2007/065948 PCT/EP2006/069482 54 Compound Example R1 R2 R3 R4 No. No. 26 3 CH 2
C
6
H
5
CO-NH-CH
1 1 H H 27 3 CH 2
C
6
H
5
CO-NH-C
6
H
1 3 H H 28 3 CH 2
C
6
H
5
CO-NH-C
6
H
5 H H 29 3 CH 2
C
6
H
5
CH
2 H H H 30 2 H CO-NH-C 6
H
4 -4- H H
OCH
3 31 2 H CO-NH- H H
CH
2
C
6
H
4 -4-F 323C111CO-NH- H H 32 3 C 6
H
1 1
CH
2
C
6
H
5 33 3 CH 2
C
6
H
5 CO-NH-3- H H 0 5
H
4 N 34 2 H N H H CO-NH CO-NH 35 2 H C6H4-4-OCF3 H H 36 3 C 6
H
1 1
CO-NH-C
6
H
5 H H 37 6 N H H 38 9 (CH 2
)
2 0CH 3
COCH
3
CH
3
CH
3 39 9 (CH 2
)
2
CH(CH
3
)
2
COCH
3
CH
3
CH
3 40 9 (CH 2
)
4
CH
3
COCH
3
CH
3
CH
3 41 9 CH 2
C
6
H
1
COCH
3
CH
3
CH
3 42 9 CH 2
C
6
H
5
COCH
3
CH
3
CH
3 43 9 CH 2
C
6
H
4 -4-CH 3
COCH
3
CH
3
CH
3 44 9 CH 2
C
6
H
4 -4-F COCH 3
CH
3
CH
3 45 9 CH 2
C
6
H
4 -4- COCH 3
CH
3
CH
3
OCH
3 46 9 CH 2
C
6
H
4 -3-CI COCH 3
CH
3
CH
3 47 9 CH 2
C
6
H
4 -4- COCH 3
CH
3
CH
3 4CH 32 48 9 CH 2 -4-C 5
H
4 N COCH 3
CH
3
CH
3 49 9 CH 2 -3-C 5
H
4 N COCH 3
CH
3
CH
3 50 10 CH 3
COC
6
H-
5 H H WO 2007/065948 PCT/EP2006/069482 55 Compound Example R1 R2 R3 R4 No. No. 51 10 CH 3
CO(CH
2
)
2
C
6
H
5 H H 52 10 CH 2
C
6
H
1
COCH
5 H H 53 10 CH 2
C
6
H
1
C
2
H
5 H H 54 10 CH 2
C
6
H
1
COCH
9 H H 55 10 CH 2
C
6
H
1
CON
5
H
4 N H H 56 10 CH 2
C
6
H
4 -4-F COCH 5 H H 57 10 CH 2
C
6
H
4 -4-F COCH 11 H H 58 10 CH 2
C
6
H
5
COCH
9 H H 59 10 CH 2
C
5
H
5 N COCH 9 H H 60 9 CH 3
C
6
H
1 1 N 0 61 9 CH 3
C
6
H
1 1 H C3H5 62 9 CH 3
C
6
H
1 1 H C6H11 63 9 CH 3
C
6
H
1 1 H CH3 64 9 CH 3
C
6
H
1 1 65 9 CH 3
C
6
H
1 1 NO -0 66 9 CH 3
C
6
H
1 1 CH3 C6H11 67 9 CH 3
C
6
H
1 1 N /-\ N-0 68 11 CONH(C 6
H
4 -4- H H 68 \ / F 3 ) 69 11 H CON(C 6
H
5
)
2 H H 70 11 H CON(C 2
H
5
)
2 H H 71 11 H H H WO 2007/065948 PCT/EP2006/069482 56 Compound Example R1 R2 R3 R4 No. No. 72 11 H N H H Y'0 73 11 H N H H '.0 74 11 S(O) 2
NH
2 N) H H Example I: 5 Capsules containing Compound I from example 6 Compound I from example 6 70 mg Corn starch 60 mg Lactose 250 mg Ethylacetate (= EA) q.s. 10 The active substance, the corn starch and the lactose are processed into a homogeneous pasty mixture using EA. The paste is ground and the resulting granules are placed on a suitable tray and dried at 45 0 C in order to remove the solvent. The dried granules are passed through a crusher and mixed in a mixer with the further following auxiliaries: Talcum 5 mg 15 Magnesium stearate 5 mg Corn starch 10 mg and are then poured into 400 mg capsules (= capsule size 0).

Claims (17)

1. A compound of Formula I, R2 I R4 N N R1 I I3- , N\ 0 0 5 wherein R1 is selected from the group consisting of: H; alkyl; cycloalkyl; al kylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more al kyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; alkylenearylenealkyl; alkylenearyleneha logen; alkylenearyleneoxyalkyl; alkylenearylenedialkylamin; heteroaryl; alkylenehet 10 eroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; wherein R2 is selected from the group consisting of: cycloalkyl; aryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or sub stituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, 15 CF 3 , CN; CO-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CF 3 , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-0-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted 20 with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substi tuted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; S0 2 -alkyl; S0 2 -aryl unsubstiuted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 additional heteroatoms independently selected from the group 25 consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsub stituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 and/or het eroaryl; and which may also contain a carbonyl group; and which may also be con densed with aryl; WO 2007/065948 PCT/EP2006/069482 58 wherein R3 and R4 are independently selected from the group consisting of: H, al kyl, cycloalkyl, cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen; cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen, and optionally substituted with alkyl, alkoxy, halogen, CF 3 , CN; aryl; 5 aryl substituted with alkyl, alkoxy, halogen, CF 3 , CN; heteroaryl unsubstiututed or substituted with alkyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; or wherein R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 het eroatoms independently selected from the group consisting of nitrogen and/or oxy gen atoms and which may also be substituted by aryl or aryl substituted with alkyl, 10 alkoxy, halogen, CF 3 and CN; and their physiologically acceptable acid addition salts.
2. The compound according to Claim 1 wherein R1 is selected from the group consist ing of: H; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; alkylenearyl; het 15 eroaryl; alkyleneheteroaryl unsubstituted or substituted with halogen; wherein R2 is selected from the group consisting of: cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO alkylenearyl; CO-heteroaryl; CO-0-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted 20 with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 25 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl; wherein R3 and R4 are 30 independently selected from the group consisting of: H, alkyl, cycloalkyl; or wherein R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl. WO 2007/065948 PCT/EP2006/069482 59
3. The compound according to any of Claims 1 or 2 wherein R1 is selected from the group consisting of: H, alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; al kylenearyl; heteroaryl; alkyleneheteroaryl substituted with halogen; wherein R2 is se 5 lected from the group consisting of: alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 10 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl; wherein R3 and R4 are 15 independently selected from the group consisting of: H, alkyl, cycloalkyl; or wherein R3 and R4 together form a ring selected from the group consisting of: pyrrolidinyl, piperidinyl-p-phenyl, piperazinyl-p-phenyl and morpholino.
4. The compound according to any of Claims 1 to 3 with the proviso that R1 is only H if 20 R2 does not contain a CO group.
5. The compound according to any of Claims 1 to 4 wherein R3 and R4 are both H.
6. A pharmaceutical composition comprising 25 (a) a pharmacologically effective quantity of a compound of Formula I, R2 I R4 g R R3-, N NR 0 0 WO 2007/065948 PCT/EP2006/069482 60 wherein R1 is selected from the group consisting of: H; alkyl; cycloalkyl; al kylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more alkyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; alkylenearylenealkyl; al kylenearylenehalogen; alkylenearyleneoxyalkyl, alkylenearylenedial 5 kylamin; heteroaryl; alkyleneheteroaryl unsubstituted or substituted with al kyl, alkoxy, halogen, CN, CF 3 ; wherein R2 is selected from the group consisting of: cycloalkyl; aryl unsub stituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; al 10 kylenealkoxy; alkylenecycloalkyl; heteroaryl; CO-alkyl; CO-cycloalkyl; CO aryl substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-alkylenearyl unsub stituted or substituted with alkyl, alkoxy, halogen, CF 3 , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-0-alkyl; CO-0-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, 15 CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; S0 2 -alkyl; S0 2 -aryl unsubstiuted or sub 20 stituted by alkyl, alkoxy, halogen, CF 3 , CN; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 additional heteroatoms independently se lected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be 25 substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with al kyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl; wherein R3 and R4 are independently selected from the group consisting of: H, alkyl, cycloalkyl, cycloalkyl containing 1 or more heteroatoms se 30 lected from nitrogen and/or oxygen; cycloalkyl containing 1 or more het eroatoms selected from nitrogen and/or oxygen, and substituted with alkyl, alkoxy, halogen, CF 3 , CN; aryl; aryl substituted with alkyl, alkoxy, halogen, CF 3 , CN; heteroaryl; heteroaryl substituted with alkyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; or wherein R3 and R4 together form a 5 or 6-membered WO 2007/065948 PCT/EP2006/069482 61 ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl or aryl substituted with alkyl, alkoxy, halogen, CF 3 and CN; their physiologically acceptable acid addition salts; 5 and (b) conventional pharmaceutically acceptable auxiliaries and/or carriers.
7. The composition according to Claim 6 wherein R1 is selected from the group con sisting of: H; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; alkylenearyl; 10 heteroaryl; alkyleneheteroaryl unsubstituted or substituted with halogen; wherein R2 is selected from the group consisting of: cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO alkylenearyl; CO-heteroaryl; CO-0-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted 15 with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 20 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl; wherein R3 and R4 are 25 independently selected from the group consisting of: H, alkyl, cycloalkyl; or wherein R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl. 30
8. The composition according to any of Claims 6 or 7 wherein R1 is selected from the group consisting of: alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; al kylenearyl; heteroaryl; alkyleneheteroaryl substituted with halogen; wherein R2 is se lected from the group consisting of: alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; WO 2007/065948 PCT/EP2006/069482 62 CO-cycloalkyl; CO-alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 5 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl; wherein R3 and R4 are 10 independently selected from the group consisting of: H, alkyl, cycloalkyl; or wherein R3 and R4 together form a ring selected from the group consisting of: pyrrolidinyl, piperidinyl-p-phenyl, piperazinyl-p-phenyl and morpholino.
9. The composition according to any of Claims 6 to 8 with the proviso that R1 is only H 15 if R2 does not contain a CO group.
10. The composition according to any of Claims 6 to 9 wherein R3 and R4 are both H.
11. A process for the preparation of a compound of Formula I, R2 I R4 g R R3-, N NR 20 00 wherein R1 is selected from the group consisting of: H; alkyl; cycloalkyl; al kylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more al kyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; alkylenearylenealkyl; alkylenearyleneha 25 logen; alkylenearyleneoxyalkyl, alkylenearylenedialkylamin; heteroaryl; alkylenehet eroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; wherein R2 is selected from the group consisting of: cycloalkyl; aryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or sub- WO 2007/065948 PCT/EP2006/069482 63 stituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CF 3 , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF 3 , 5 CN; CO-0-alkyl; CO-0-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substi tuted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; S0 2 -alkyl; 10 S0 2 -aryl unsubstiuted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 additional heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsub 15 stituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or het eroaryl; and which may also contain a carbonyl group; and which may also be con densed with aryl; wherein R3 and R4 are independently selected from the group consisting of: H, al kyl, cycloalkyl, cycloalkyl containing 1 or more heteroatoms selected from nitrogen 20 and/or oxygen; cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen, and substituted with alkyl, alkoxy, halogen, CF 3 , CN; aryl; aryl substi tuted with alkyl, alkoxy, halogen, CF 3 , CN; heteroaryl; heteroaryl substituted with al kyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; or wherein R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms inde 25 pendently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl or aryl substituted with alkyl, alkoxy, halogen, CF 3 and CN; and their physiologically acceptable acid addition salts. characterized in that a) compounds of Formula I wherein R3 and R4 are both not H, are prepared 30 by reacting a compound of Formula II WO 2007/065948 PCT/EP2006/069482 64 0 N H with a sulfamoylchloride of Formula III, R3\ N-S-Cl ||| R4 0 to give compound of Formula IV 0 N IV O=S=O N / \ 5 R4 R3 wherein compounds of Formula IV are then reacted with an amine H 2 NR1 to give compounds of Formula V R1 NH N V N N R4 R3 wherein compounds of Formula V are further reacted with R2X wherein X 10 is selected from the group consisting of Cl, Br, and I, to give compounds of Formula I WO 2007/065948 PCT/EP2006/069482 65 R1,N R2 N N ,N\ R4 R3 b) compounds of Formula I wherein R3 and R4 are both not H, are prepared by reacting compounds of Formula IV with an amine HNR1 R2 to give com 5 pounds of Formula I R1\ ,R2 N N N R4 R3 c) compounds of Formula I wherein R3 and R4 are both H, are prepared by 10 reacting a compound of Formula II 0 || N H with sulfamoylchloride, which is protected with a protecting group PG, pref erably tert.-butyloxycarbonyl, of Formula Vla, or with the reagent of For mula VIb, WO 2007/065948 PCT/EP2006/069482 66 0 0 PG-N-S-CI Via PG-N-S-N + Vlb || || -x 0 o to give a compound of formula VII 0 N O=S=O ,N\ H PG wherein compounds of Formula VII are then reacted with an amine H 2 NR1 5 to give compounds of Formula VIII R1, NH N ViII N N H PG wherein compounds of Formula VIII are further reacted with R2X wherein X is selected from the group consisting of Cl, Br, and I, to give compounds of Formula IX WO 2007/065948 PCT/EP2006/069482 67 R1s NR2 N N, H PG and subsequently cleaving off the protecting group PG from the obtained intermediate products, then leads to compounds of Formula I wherein R3 5 and R4 both H; d) compounds of Formula I wherein R3 and R4 are both H, are prepared by reacting a compound of Formula VII are reacted with an amine HNR1 R2 to give compounds of Formula IX R1\ ,R2 N N IX o=s=o NH 10 and subsequently cleaving off the protecting group PG under from the ob tained intermediate products, then leads to compounds of Formula I wherein R3 and R4 both H; e) compounds of Formula I wherein R2 contains a methylene spacer CH 2 , are 15 prepared by reacting a compound of Formula X NH 2 x N H WO 2007/065948 PCT/EP2006/069482 68 with a protecting agent PG, to give a compound of formula XI NH 2 N PG wherein compounds of Formula XI are then reacted with an aldehyde R2' CHO, to give compounds of Formula XII, R2' H, ,CH 2 N N 5 PG wherein R2' is selected from the group consisting of: alkyl; cycloalkyl; al kylenearyl, unsubstituted or substituted, but not substituted by furan or fu ranyl; alkylenealkoxy; and alkylenecycloalkyl; wherein the protecting group PG of compounds of Formula XII is then 10 cleaved off and wherein the unprotected compound is then reacted with sulfamoylchloride CISO 2 -NH 2 to give compounds of Formula I; compounds of Formula I wherein R2 contains a methylene spacer CH 2 , are prepared by cleaving off the protecting group PG of compounds of Formula XII and wherein the unprotected compound is then reacted with sulfamoyl 15 chloride, which is protected with a protecting group PG, preferably tert. butyloxycarbonyl, of Formula Vla, or with the reagent of Formula VIb, 0 0 PG-N-S-CI Vla PG-N-S-N N + Vlb || || - WO 2007/065948 PCT/EP2006/069482 69 to give a compound of formula XIII R2 I H, ,CH2 N N o=s=o N PG H and subsequently cleaving off the protecting group PG from the obtained intermediate product, then leads to compounds of Formula I wherein R3 5 and R4 both H; f) compounds of Formula I wherein R2 contains a methylene spacer CH 2 , are prepared by reacting a compound of Formula X NH 2 x N H with a protecting agent PG, to give a compound of formula XI NH 2 N 10 PG wherein compounds of Formula XI are then reacted with a ketone R2' COR1', to give compounds of Formula XIV, WO 2007/065948 PCT/EP2006/069482 70 R2 H N H R1' N PG wherein R1' is selected from the group consisting of: alkyl; alkylenealkoxy; alkylenecycloalkyl; alkylenearyl; alkylenearylenealkyl; alkylenearylenehalo gen; alkylenearyleneoxyalkyl, alkylenearylenedialkylamin; and alkylenehet 5 eroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; wherein R2' is selected from the group consisting of: alkyl; cycloalkyl; al kylenearyl, unsubstituted or substituted, but not substituted by furan or fu ranyl; alkylenealkoxy; and alkylenecycloalkyl; wherein the protecting group PG of compounds of Formula XIV is then 10 cleaved off and wherein the unprotected compound is then reacted with sulfamoylchloride, which is protected with a protecting group PG, prefera bly tert.-butyloxycarbonyl, of Formula Vla, or with the reagent of Formula VIb, 0 0 PG-N-S-Cl Vla PG-N-S-N N + Vlb || || 0 0 15 to give a compound of formula XV WO 2007/065948 PCT/EP2006/069482 71 R2' HN H NkR1' N X o=s=o N PG H and subsequently cleaving off the protecting group PG from the obtained intermediate product, then leads to compounds of Formula I wherein R3 and R4 both H, 5 g) compounds of Formula I are prepared by reacting a compound of Formula II 0 N H with a protecting agent PG to give a compound of formula XVII 0 N XVIl PG 10 wherein compounds of Formula XVII are then reacted with an amine NHR1 R2 to give compounds of Formula XVIII, WO 2007/065948 PCT/EP2006/069482 72 R1, ,R2 N N XVIll PG wherein the protecting group PG of compounds of Formula XVIII is then cleaved off and wherein the unprotected compound is then reacted with sulfamid to give compounds of Formula I, or with a compound of formula III 5 to give compounds of Formula I, or with a compound of formulae Vla or VIb to give a compound of formula XIX R1, ,R2 N N o=s=o N\ H PG and subsequently cleaving off the protecting group PG from the obtained intermediate product, then leads to compounds of Formula I; 10 h) compounds of Formula I are prepared by reacting a compound of Formula VXIIIa wherein R1 is H H\ R2 N N XVIlla PG with a compound of formula XX R5-N=C=O XX WO 2007/065948 PCT/EP2006/069482 73 wherein R5 is selected from the group consisting of: alkyl; cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; and heteroaryl; to give a compound of formula XXI 0 R5\ ,R2 N N H N 5 PG wherein the protecting group PG of compounds of Formula XXI is then cleaved off and wherein the unprotected compound is then reacted with sulfamid to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Vla or VIb 10 to give a compound of formula XXII 0 R5\ ,R2 /N N H N XI N 0=6=0 H PG and subsequently cleaving off the protecting group PG from the obtained intermediate product, then leads to compounds of Formula I; i) compounds of Formula I are prepared by reacting a compound of Formula 15 VXIIIa wherein R1 is H WO 2007/065948 PCT/EP2006/069482 74 H\ ,R2 N N XVIll PG with a compound of formula XXIII 0 l- S-R6 XXIll II 0 wherein R6 is selected from the group consisting of: alkyl; aryl unsubstiuted 5 or substituted by alkyl, alkoxy, halogen, CF 3 , CN; to give a compound of formula XXIV 0 O,' // /S, R2 R6 N N XXIV PG wherein the protecting group PG of compounds of Formula XXIV is then cleaved off and wherein the unprotected compound is then reacted with 10 sulfamid to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Vla or VIb to give a compound of formula XXV WO 2007/065948 PCT/EP2006/069482 75 0 S , ,R2 R6 N N 0=6=0 /N\ H PG and subsequently cleaving off the protecting group PG from the obtained intermediate product, to give compounds of formula I, j) compounds of Formula I are prepared by reacting a compound of Formula 5 XI NH 2 N PG with a compound of formula XXIII to give compounds of Formula XXVI 0 S\ H R6 N N XXVI PG wherein the protecting group PG of compounds of Formula XXVI is then 10 cleaved off and wherein the unprotected compound is then reacted with sulfamid to give compounds of Formula I, or with a compound of formula III to give compounds of Formula I, or with a compound of formulae Vla or VIb to give a compound of formula XXVII WO 2007/065948 PCT/EP2006/069482 76 0 R6 N N XXVII N 0=6=:0 H PG and subsequently cleaving off the protecting group PG from the obtained intermediate product, to give compounds of formula I, k) compounds of Formula I are prepared by reacting compounds of Formula 5 Vill R1\ NH N Vill O=S=O N, H PG with compounds of formula XX R5-N=C=O XX to give compounds of Formula XXVIII WO 2007/065948 PCT/EP2006/069482 77 0 R1 x N NH R5 XXVIll N O=S=O N H PG wherein the protecting group PG of compounds of Formula XXVIII is then cleaved off to give compounds of Formula I I) compounds of Formula I are prepared by reacting compounds of Formula 5 XI NH 2 N PG with compounds of formula XXIX o /R5 N XXIX Cl H to give compounds of Formula XXX 0 N NH R5 XXX N 10 PG WO 2007/065948 PCT/EP2006/069482 78 wherein the protecting group PG of compounds of Formula XXX is then cleaved off to give compounds of Formula XXXI 0 N NH R5 XXXI N H and wherein the compound of Formula XXXI is then reacted with sulfa 5 moylchlorid of Formula III to give compounds of Formula I, or with a com pound of Formulae Vla or VIb to give a compound of Formula XXXII 0 H\ N NH R5 XXXII N O=S=O N H PG and wherein the protecting group PG of compounds of Formula XXXII is then cleaved off to give compounds of Formula I; 10 and if desired converting resulting free bases of Formula I into their physiologically acceptable acid addition salts, or converting the acid addition salts of the com pounds of Formula I into the free bases of Formula 1.
12. The process according to Claim 11 wherein R1 is selected from the group consisting 15 of: H; alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; alkylenearyl; het eroaryl; alkyleneheteroaryl unsubstituted or substituted with halogen; wherein R2 is selected from the group consisting of: cycloalkyl; aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or substituted, but not substituted by WO 2007/065948 PCT/EP2006/069482 79 furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO alkylenearyl; CO-heteroaryl; CO-0-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-aryl substituted with 5 alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may 10 also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a carbonyl group; and which may also be condensed with aryl; wherein R3 and R4 are independently selected from the group consisting of: H, alkyl, cycloalkyl; or wherein R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 15 1 to 2 heteroatoms independently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl.
13. The process according to any of Claims 11 or 12 wherein R1 is selected from the group consisting of: alkyl; cycloalkyl; alkylenealkoxy; alkylenecycloalkyl; aryl; al 20 kylenearyl; heteroaryl; alkyleneheteroaryl substituted with halogen; wherein R2 is se lected from the group consisting of: alkylenealkoxy; alkylenecycloalkyl; CO-alkyl; CO-cycloalkyl; CO-alkylenearyl; CO-heteroaryl; CO-NH-alkylenearyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; or; wherein R1 25 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsubstituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or heteroaryl; and which may also contain a 30 carbonyl group; and which may also be condensed with aryl; wherein R3 and R4 are independently selected from the group consisting of: H, alkyl, cycloalkyl; or wherein R3 and R4 together form a ring selected from the group consisting of: pyrrolidinyl, piperidinyl-p-phenyl, piperazinyl-p-phenyl and morpholino. WO 2007/065948 PCT/EP2006/069482 80
14. The process according to any of Claims 11 to 13 with the proviso that R1 is only H if R2 does not contain a CO group.
15. The process according to any of Claims 11 to 14 wherein R3 and R4 are both H. 5
16. The use of a compound of Formula I, R2 I R4 g R R3-, NNR 0 0 wherein R1 is selected from the group consisting of: H; alkyl; cycloalkyl; al 10 kylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more al kyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; alkylenearylenealkyl; alkylenearyleneha logen; alkylenearyleneoxyalkyl, alkylenearylenedialkylamin; heteroaryl; alkylenehet eroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; wherein R2 is selected from the group consisting of: cycloalkyl; aryl unsubstituted or 15 substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or sub stituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CF 3 , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF 3 , 20 CN; CO-0-alkyl; CO-O-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substi tuted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; S0 2 -alkyl; 25 S0 2 -aryl unsubstiuted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 additional heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 WO 2007/065948 PCT/EP2006/069482 81 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsub stituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or het eroaryl; and which may also contain a carbonyl group; and which may also be con densed with aryl; 5 wherein R3 and R4 are independently selected from the group consisting of: H, al kyl, cycloalkyl, cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen; cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen, and substituted with alkyl, alkoxy, halogen, CF 3 , CN; aryl; aryl substi tuted with alkyl, alkoxy, halogen, CF 3 , CN; heteroaryl; heteroaryl substituted with al 10 kyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; or wherein R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms inde pendently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl or aryl substituted with alkyl, alkoxy, halogen, CF 3 and CN; 15 and their physiologically acceptable acid addition salts; for the preparation of a me dicament for the prophylaxis and/or treatment and/or prevention of glaucoma, epi lepsy, bipolar disorders, migraine, neuropathic pain, obesity, type II diabetes, meta bolic syndrome, alcohol dependence, and/or cancer, and its concomitant and/or secondary diseases or conditions in mammals and humans. 20
17. A method of treating or preventing glaucoma, epilepsy, bipolar disorders, migraine, neuropathic pain, obesity, type II diabetes, metabolic syndrome and/or cancer, and its concomitant and/or secondary diseases or conditions in mammals and humans, comprising administering to a subject in need thereof a therapeutically effective 25 amount of a compound of Formula I, R2 I R4 g R R3-, N NR 0 0 wherein R1 is selected from the group consisting of: H; alkyl; cycloalkyl; al kylenealkoxy; alkylenecycloalkyl; aryl unsubstituted or substituted by one or more al- WO 2007/065948 PCT/EP2006/069482 82 kyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; alkylenearylenealkyl; alkylenearyleneha logen; alkylenearyleneoxyalkyl, alkylenearylenedialkylamin; heteroaryl; alkylenehet eroaryl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; wherein R2 is selected from the group consisting of: cycloalkyl; aryl unsubstituted or 5 substituted with alkyl, alkoxy, halogen, CN, CF 3 ; alkylenearyl, unsubstituted or sub stituted, but not substituted by furan or furanyl; alkylenealkoxy; alkylenecycloalkyl; heteroaryl; CO-alkyl; CO-cycloalkyl; CO-aryl substituted by alkyl, alkoxy, halogen, CF 3 , CN; CO-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CF 3 , CN; CO-heteroaryl unsubstituted or substituted by alkyl, alkoxy, halogen, CF 3 , 10 CN; CO-0-alkyl; CO-0-cycloalkyl; CO-0-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-alkylenearyl unsubstituted or substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-0-heteroaryl; CO-NH-alkyl; CO-NH-cycloalkyl; CO-NH-aryl substituted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-alkylenearyl unsubstituted or substi tuted with alkyl, alkoxy, halogen, CN, CF 3 ; CO-NH-heteroaryl; S0 2 -NH 2 ; S0 2 -alkyl; 15 S0 2 -aryl unsubstiuted or substituted by alkyl, alkoxy, halogen, CF 3 , CN; or; wherein R1 and R2 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 additional heteroatoms independently selected from the group consisting of: nitrogen, oxygen and/or sulphur; and which may optionally bear 1 or 2 double bonds; and which may also be substituted by alkyl, halogenalkyl, aryl unsub 20 stituted or substituted with alkyl, alkoxy, hydroxy, halogen, CN, CF 3 , and/or het eroaryl; and which may also contain a carbonyl group; and which may also be con densed with aryl; wherein R3 and R4 are independently selected from the group consisting of: H, al kyl, cycloalkyl, cycloalkyl containing 1 or more heteroatoms selected from nitrogen 25 and/or oxygen; cycloalkyl containing 1 or more heteroatoms selected from nitrogen and/or oxygen, and substituted with alkyl, alkoxy, halogen, CF 3 , CN; aryl; aryl substi tuted with alkyl, alkoxy, halogen, CF 3 , CN; heteroaryl; heteroaryl substituted with al kyl, alkoxy, halogen, CF 3 , CN; alkylenearyl; or wherein R3 and R4 together form a 5 or 6-membered ring which may optionally contain from 1 to 2 heteroatoms inde 30 pendently selected from the group consisting of nitrogen and/or oxygen atoms and which may also be substituted by aryl or aryl substituted with alkyl, alkoxy, halogen, CF 3 and CN; and their physiologically acceptable acid addition salts.
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