AU711986B2

AU711986B2 - Sulfonamide-substituted chromans, processes for their preparation, their use as a medicament or diagnostic, and medicament comprising them

Info

Publication number: AU711986B2
Application number: AU20806/97A
Authority: AU
Inventors: Helmut Bohn; Joachim Brendel; Andreas Busch; Heinrich Christian Englert; Uwe Gerlach; Heinz Gogelein; Rainer Greger; Andreas Herling; Max Hropot; Hans Jochen Lang
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1996-05-15
Filing date: 1997-05-13
Publication date: 1999-10-28
Anticipated expiration: 2017-05-13
Also published as: AR007115A1; TW496866B; NO972211D0; CA2205477A1; KR19980024020A; AU2080697A; HUP9700903A2; PL319995A1; AR010314A1; CZ149497A3; HUP9700903A3; PL191330B1; JP4234798B2; MX9703534A; DK0807629T3; NO972211L; PT807629E; EP0807629A1; IL120827A0; HK1006640A1

Description

A..

P/UU/U11 2/S91 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged:

A

Invention Title: SULFONAMIDE-SUBSTITUTED CHROMANS, PROCESSES FOR THEIR PREPARATION, THEIR USE AS A MEDICAMENT OR DIAGNOSTIC, AND MEDICAMENT COMPRISING THEM The following statement is a full description of this invention, including the best method of performing it known to us Hoechst Aktiengesellschaft HOE 96/F 119 K Dr. v. F.ISt Description Sulfonamide-substituted chromans, processes for their preparation, their use as a medicament or diagnostic, and medicament comprising them The invention relates to chromans of the formula I R(6) .r 9

N

9 R(7) R(8) in which: R(1) and R(2) independently of one another are hydrogen, CpF2p+ 1 alkyl having 1, 2, 3, 4, or 6 carbon atoms or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, CI, Br, I, CF 3 methyl, methoxy, sulfamoyl, methylsulfonylamino and methylsulfonyl; p is1, 2 or3; or R(1) and R(2) together are an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R(3) is R(9)-CnH 2 n[NR(1 1 R(9) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; n is zero,l, 2, 3, 4, 5, 6, 7, 8, 9 or m is zero or 1; R(11) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R(11), together with is an alkylene group having from 1, 2, 3, 4, 5, 6, 7 2 or 8 carbon atoms; where one CH 2 group of the group CnH 2 n can be replaced by -SOq or q is zero, 1 or 2; R(10) is hydrogen, methyl or ethyl; R(4) is R(12)-CrH 2 r; R(12) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, C F 2 p+, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or where one CH 2 group of the group CrH 2 r can be replaced by a -SOq- or q is zero, 1 or 2; is hydrogen, methyl or ethyl; R(7) and R(8) 20 independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms,-CN, -CF 3

-C

2

F

5

-C

3

F

7

-N

3

-NO

2 -CONR(13)R(14), -COOR(15), R(16)-CsH 2 s-Y- or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, CI, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; R(13) and R(14) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; R(15) is hydrogen, methyl, ethyl, phenyl or -CuH 2 u-NR(13)R(14); u is 2 or 3; R(16) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 3 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CtF 2 t+ 1 or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl or methylsulfonyl; s is zero, 1, 2, 3, 4, 5 or 6; t is 1, 2 or 3; Y is SOq, -SO 2 -NR(10)- or but where R(6) cannot be -OCF 3 or -OC 2

F

5 and their physiologically tolerable salts.

Preferred compounds of the formula I are those in which: S R(1) and R(2) Sindependently of one another are hydrogen,CF3, alkyl having 1, 2 or 3 carbon atoms, jointly an alkylene chain having 4 or 5 carbon atoms or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 methyl, methoxy, sulfamoyl and methylsulfonyl; R(3) is R(9)-CnH 2 n[NR(11)]m-; R(9) is hydrogen; n is zero, 1, 2, 3, 4, 5 or 6; m is zero or 1; R(11) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R(4) is R(12)-CrH 2 r; R(12) is hydrogen, cycloalkyl having 5, 6, 7 or 8 carbon atoms, CF3, pyridyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF 3 sulfamoyl or methylsulfonyl; r is 1, 2 3 4, 5, 6, 7, 8, 9 or where one CH 2 group of the group CrH 2 r can be replaced by -CO-, -CO-O- or -SOq-; q is zero, 1 or 2; 4 R(7) and R(8) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1 or 2 carbon atoms, -CN, -CF 3

-NO

2 -CONR(13)R(14), R(16)-CsH 2 s-Y- or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl and CF 3 R(13) and R(14) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; R(15) is methyl, ethyl, phenyl or -CuH 2 u-NR(13)R(14); u is 2 or 3; R(16) is hydrogen, cycloalkyl having 5 or 6 carbon atoms, CtF2t+l or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, Br, CF3, methyl, methoxy, sulfamoyl or methylsulfonyl; t is 1, 2 or 3; s is zero, 1, 2, 3 or 4; Y is SOq, -S0 2 -NR(10)- or q is zero, 1 or 2; R(10) is hydrogen or methyl; but where R(6) cannot be -OCF 3 or and their physiologically tolerable salts.

Particularly preferred compounds of the formula I are those in which: R(1) and R(2) independently of one another are CF 3 methyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; R(3) is alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino or diethylamino; R(4) is R(12)-CrH 2 r; R(12) is hydrogen, cycloalkyl having 5 or 6 carbon atoms or CF 3 r is1, 2, 3, 4,5, 6,7or 8; where one CH 2 group of the group CrH2r can be replaced by -Ca-, -CO-0- or -SOq-; q is zero, 1 or 2; R(7) and R(8) independently of one another are hydrogen, F, Cl, Br, 1, alkyl having 1 or 2 carbon atoms, -CN, -NO 2 -COOR(1 R(1 6)-CSH 2 s-Y- or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F or CI; R(1 5) is methyl, ethyl, phenyl or -CuH 2 u-NR(1 3)R(1 4); u is 2 or 3; R(1 3) and R(1 4) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; 15 R(16) is hydrogen, CF 3 or phenyl, s is zero, 1, 2, 3or 4; Y is SOq ,-0-NR(1 -NR(1O0)- or q is zero, 1 or 2; R(1 0) is hydrogen or methyl; but where R(6) cannot be -OCF 3 and their physiologically tolerable salts.

Very particularly preferred compounds of the formula I are the following: 4 -(N-ethyl su Ifonyl-Nmethyl) am ino6fl uoro22-d imethyl ch roman, 6 -cyano- 4 -(N-ethyl su Ifonyl-Nmethyl)am ino22-d imethyl ch roman, 4 -(N-ethylsulfonylNmethyl)am in omethoxyca rbonyl22d imethyl-ch roman, 6 -cyano- 4 -Nethyl sufonylN(444trifl uorobutyl)]am ino22di methyl chroa n, 4 -(N-butyl-N-ethylsulfonyl)amino6cyano2,2dimethylchroman, 4 -(N-ethylsulfonyl-Nmethyl)amino22,6trimethylchroman, 3D 7-hlr--Nehls fnlNmehla n--lur-,-iehlhrmn 6, 7 -dichloro- 4 -(N-ethylsulfonyl.Nmethyl)amino22dimethylchroman, 4 -(N-butyl-N-ethylsufonyl)amino6fluoro2,2dimethylchroman, 4 -(N-ethylsu lfonylN methyl) am ino6fluoro22tetram ethylenech roman, 6 4-[N-ethylsulfonyl-N-( 4 4 ,4-trifluorobutyl)]amino-6-fluoro-2,2-dimethyl-chroman, 4 -(N-ethylsulfonyl-N-hexyl)amino-6-fluoro-2,2-dimethylchroman, 6 -ethyl- 4 -[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2-dimethyl-chroman.

If the compounds I contain an acidic or basic group or a basic heterocycle, the corresponding, pharmacologically and toxicologically tolerable salts are also a subject of the invention. Thus the compounds I which carry one or more -COOH groups, for example as alkali metal salts, can preferably be used as sodium or potassium salts. Compounds I which carry a basic, protonatable group or a basic heterocyclic radical can also be used in the form of their organic or inorganic, pharmacologically and toxicologically tolerable acid addition salts, for example as hydrochlorides, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates etc. If the compounds I contain an acidic and basic group in the same molecule, the invention also includes, beside the salt forms described internal salts, so-called betaines.

If the substituents of the compounds of the formula I or alternatively of the formula la contain groups with different stereochemical possibilities, the invention also includes the individual possible stereoisomers. Thus the compounds I and la contain a chiral center in position 4 of the chroman system, so the individual pure optical antipodes and any desired mixtures of the optical isomers are part of the invention.

The compounds of the formula I can be prepared by different chemical processes, which are likewise part of the invention.

Thus a compound of the formula I is obtained by a) reacting a compound of the formula II

L

R(6) I I 1) R(2) R(1) R(8) in which R(7) and R(8) have the meaning indicated and L is the nucleofugic leaving group customary for an alkylation, in particular Cl, Br, I, MeSO 2 a p-toluenesulfonyloxy radical, with a sulfonamide or its salt of the formula III 00 R(4) I N SR(3)

I

M

in a manner known per se, in which R(3) and R(4) have the meaning indicated, but r in the substituent R(4) also has the meaning zero, and M is hydrogen or preferably a metal atom, particularly preferably lithium, sodium or potassium; or by b) reacting a compound of the formula IV R(4) R(5) NH 1 5 R(6)

S*IV

R(2) R(7) 1) R(1) R(8) in which R(7) and R(8) have the meaning indicated, but r in the substituent R(4) also has the meaning zero, with a sulfonic acid derivative of the formula V R(3) SO2-W

V

in which R(3) has the meaning indicated and W is a nucleofugic leaving group, such as fluorine, bromine, 1-imidazolyl, but in particular chlorine; or by c) reacting a compound of the formula VI

I

e C r s r .r 8 S0O M N NR(3) R(6) v oVI R(2)

O

R(7) R(1) R(8) in which R(8) and M have the meaning indicated, in a manner known per se with an alkylating agent of the formula VII R(4)-L VII in the sense of an alkylation reaction, in which with the exception of hydrogen, and L have the meaning indicated; or by carrying out, d) in a compound of the formula I 0 0 \4) 20 R(5) N SR( 3 R(6)

I

R(2) R(7)

\R

R(

1 R(8) in which R(1) to R(4) have the meaning indicated, an electrophilic substitution reaction in at least one position R(5) to if this position is hydrogen and the remaining substituents R(5) to R(8) have the meaning indicated.

Procedure a) describes the alkylation, which is known per se, of a sulfonamide or of one of its salts of the formula III by a chroman derivative of the formula II having alkylating action. As the alkylation of a sulfonamide is carried out from the salt form, when using a free sulfonamide (formula III, M H) a sulfonamide salt (formula III, M 9 cation), which is distinguished by higher nucleophilicity and thus by higher reactivity, must be produced by action of a base. If free sulfonamide (M H) is employed, the deprotonation of the sulfonamide to the salt is carried out in situ with preferred use of those bases which are themselves not alkylated or only slightly alkylated, such as sodium carbonate, potassium carbonate, a sterically strongly hindered amine, e.g.

dicyclohexylamine, N,N,N-dicyclohexylethylamine or other strong nitrogen bases of low nucleophilicity, for example DBU, N,N',N"'-triisopropylguanidine etc. However, other bases customarily used for the reaction can also be employed, such as potassium tert-butoxide, sodium methoxide, alkali metal hydrogen carbonates, alkali metal hydroxides, such as, for example, LiOH, NaOH or KOH, or alkali metal hydroxides, for example Ca(OH) 2 In this case, the reaction is preferably carried out in aprotic polar solvents such as dimethylformamide, dimethylacetamide, tetramethylurea, 15 hexamethylphosphoramide, tetrahydrofuran etc. In principle, however, the reaction can also be carried out in polar protic solvents, such as water, methanol, ethanol, isopropanol, ethylene glycol or its oligomers and their corresponding semiethers and ethers. The reaction is carried out in a preferred temperature range from 20 to 140 0 C, particularly preferably from 40 to 100°C. Conveniently, procedure a) can also be carried out under the conditions of a two-phase catalysis. The compounds of the formula II are obtained by methods known from the literature, for example from the corresponding alcohols (formula III, L -OH by action of hydrogen halide HL (L Cl, Br, I) or by action of an inorganic acid halide (POCI3, PCI 3

PCI

5

SOCI

2 SOBr 2 or by free-radical halogenation of the corresponding chroman derivatives (formula II, L H) with elemental chlorine or bromine, or with free radical-activatable halogenating agents such as N-bromo-succinimide (NBS) or SO 2 Cl 2 (sulfuryl chloride) in the presence of a free radical chain initiator such as energy-rich light of the visible or ultraviolet wave range or by use of a chemical free-radical initiator such as azobisisobutyronitrile.

Procedure b) describes the reaction, which is known per se and frequently used, of an activated sulfonyl compound of the formula V, in particular of a chlorosulfonyl compound (W Cl), with an amine of the formula IV to give the corresponding sulfonamide derivative of the formula I. In principle, the reaction can be carried out without a solvent, but reactions of this type are in most cases carried out using a solvent.

The reaction procedure is preferably carried out using a polar solvent, preferably in the presence of a base which itself can be used as a solvent, e.g. when using triethylamine, pyridine and its homologs. Solvents preferably used are, for example, water, aliphatic alcohols, e.g. methanol, ethanol, isopropanol, sec-butanol, ethylene glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA, and also TMU and HMPT. The reaction is in this case carried out at a temperature from 0 to 160 0

C,

preferably from 20 to 100°C.

The amines of the formula IV are obtained in a manner known per se from the literature, preferably from the corresponding carbonyl compounds of the formula X R(5) R(5) A 15 R(6) .I X

R

R(2)

X

R(7) 1) R(1) (8) 20 in which R(7) and R(8) have the meaning indicated and A is oxygen, either using ammonia or an amine of the formula XI R(4)-NH 2

XI

with R(4) having the meaning indicated, but in which r in the substituent R(4) also has the meaning zero, under reductive catalytic conditions, preferably at relatively high temperature in an autoclave. In this case, the Schiff bases of the formula X where A is equal to are formed primarily by condensation reaction of the ketones X (where A oxygen) and amines (XI) in situ and immediately converted reductively without isolation thereof into the amine of the formula IV.

Correspondingly, the Schiff bases intermediately resulting from X and XI in this reaction (formula X, A: can be prepared and isolated in order to convert them subsequently in a separate step with a suitable reductant such as NaBH 4 LiAIH 4 NaBH 3 CN or by catalytic hydrogenation into the compounds of the formula

IV.

The compounds IV where R(4) is equal to hydrogen can advantageously be obtained in a manner known from the literature by reduction of oximes or oxime 11 ethers (formula X, A is equal to hydrazones (formula X, A: R(18)R(19)Nby use of a complex metal hydride or by catalytic hydrogenation. The necessary oximes and hydrazones are preferably prepared conveniently and in a manner known per se from the ketones of the formula X (A is equal to oxygen) using hydrazine or one of its derivatives or, for example, using hydroxylamine hydrochloride under dehydrating conditions.

Procedure c) describes, like procedure the alkylation reaction of a sulfonamide, which is known per se, or of one of its salts VI with an alkylating agent of the formula VII.

Corresponding to this reaction analogy, the reaction conditions already described in detail under procedure a) apply for procedure c).

The preparation of the sulfonamide derivatives VI and their precursors have already been described in procedure The preparation of the alkylating agents VII is carried out according to analogous procedures of the literature or as described Sunder procedure preferably from the corresponding hydroxyl compounds (formula VII where L is equal to -OH).

Procedure d) 20 describes the further chemical conversion of compounds of the formula I according S. to the invention into other compounds of the formula I by electrophilic substitution reactions in one or in more of the positions designated by R(5) to which in each case are hydrogen.

a Preferred substitution reactions are 1. aromatic nitration to introduce one or more nitro groups, and their subsequent reduction to NH 2 2. aromatic halogenation, in particular to introduce chlorine, bromine or iodine, 3. chlorosulfonation to introduce a chlorosulfonyl group by action of chlorosulfonic acid, 4. the Friedel-Crafts acylation reaction to introduce an acyl radical R(16)-CsH 2 s-COor a sulfonyl radical R(16)-CsH 2 s-SO 2 by action of the corresponding acid chlorides R(16)-CsH 2 s-CO-CI or R(16)-CsH 2 s-SO 2 -CI in the presence of a Lewis acid as a Friedel-Crafts catalyst, preferably of anhydrous aluminum chloride.

12 The compounds I and la are related to the class of 4-acylaminochroman derivatives, in particular of 2,2-dialkyl-4-acylamino-3-chromanols, worked on intensively in pharmaceutical chemistry in the last decade. The most prominent representative of 4-acylaminochromans of this type is cromakalim of the formula XII and numerous secondary preparations derived from this preparation Edwards and Weston, TIPS 11,417-422 (1990), "Structure Activity Relationships of K channel openers" Cromakalim and other related 4-acylaminochroman derivatives are compounds having a relaxant action on smooth muscular organs, so that they are used for lowering increased blood pressure as a result of vascular muscle relaxation and in the treatment of asthma as a result of the relaxation of the smooth musculature of the airways. It is common to all these preparations that they act at the cellular level, 20 for example, of smooth muscle cells and lead there to an opening of specific ATPsensitive K channels. The increase in negative charge in the cell ("hyperpolarization") induced by the efflux of K ions counteracts by means of secondary mechanisms the increase of intracellular Ca 2 and thus cell activation, e.g. muscle contraction.

In contrast to these 4-acylaminochroman derivatives which, as mentioned, were identified as openers of the ATP-sensitive K channel, the compounds of the formula land the compounds of the formula la according to the invention 3N S R(3)

R(B)

R(A) la R(C) II /R(2) 13 where R(A) is hydrogen, OH, -O(CO)alkyl having 1, 2, 3 or 4 carbon atoms or -O-SO2-alkyl having 1, 2, 3 or 4 carbon atoms; R(B) is hydrogen; or R(A) and R(B) together are a bond; R(1) to R(4) are as indicated above; R(C) is CN, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms, F, Cl, Br, I, NO 2 or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; with the 4-sulfonylamino structure surprisingly show a strong and specific blocking (closing) action on a K channel which is opened by cyclic adenosine monophosphate (cAMP) and differs fundamentally from the K+(ATP) channel mentioned. More recent investigations on the contrary show that this K+(cAMP) channel identified in the large intestine appears to be very similar, perhaps even identical, to the IsK channel identified in cardiac muscle. As a result of this blocking of the K (cAMP) channel IsK channel), the compounds develop in the living body pharmacological actions of high therapeutic utility.

20 The preparation of compounds of the formula la from suitable 3,4-epoxychromans and sulfonamides of the formula III is described in Lohrmann et al., Pfl0gers Arch. Eur. J. Physiol. (1995) 429: 517 530.

Thus the compounds I and la are distinguished as a novel active compound class of potent inhibitors of stimulated gastric acid secretion. The compounds of the formula I or la are thus useful medicaments for the treatment of ulcers of the stomach and of the intestinal region, for example of the duodenum. On account of their strong gastric secretion-inhibiting action, they are also suitable as excellent therapeutics for the treatment of reflux esophagitis.

The compounds I and la are furthermore distinguished by an antidiarrheal action and are therefore suitable as pharmaceuticals for the treatment of diarrheal illnesses.

The compounds I and la can furthermore be used as pharmaceuticals for the 14 treatment and prevention of all types of arrhythmias including atrial, ventricular and supraventricular arrhythmias. They can be used in particular for the control of reentry arrhythmias and for the prevention of sudden heart death as a result of ventricular fibrillation.

Meanwhile, publications exist from which a correlation between IsK channelinhibitory action and the suppression of life-threatening cardiac arrhythmias is described, such as are caused, for example, by 13-adren-ergic hyperstimulation (e.g.

T. J. Colatsky, C. H. Follmer and C Starmer: "Channel Specificity in Antiarrhythmic Drug Action; Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias", Circulation (1990) 82: 2235 2242; A. E. Busch, K. Malloy, W. J. Groh, M. D. Varnum, J. P. Adelman and J.

Maylie; "The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channels in xenopus oocytes and IKs in guinea pig cardiac myocytes", Biochem.

Biophys. Res. Commun. (1994) 202: 265- 270).

Beside the abovementioned cromakalim and acylaminochroman derivatives, in the course of the last years compounds of 4-sulfonyl-aminochroman structure have also been described in the literature, which either differ markedly in structure or in biological action from the compounds of the formula land the compounds of the formula la according to the invention. Thus, European Offenlegungsschrift 315 009 describes chroman derivatives of 4-phenylsulfonylamino structure, which are distinguished by antithrombotic and antiallergic properties.

European Offenlegungsschrift 370 901 describes 3-hydroxychroman derivatives having a 4-phenylsulfonylamino group, in which the remaining valency of the nitrogen atom carries a hydrogen atom. These compounds are thus substituted differently in essential groups of the formula I or la. Accordingly, actions on the central nervous system are found for these compounds of European Offenlegungsschrift 370 901, so that they also differ in a pharmacological respect.

European Offenlegungsschrift 389 861 describes 3-hydroxychroman derivatives having a 4-sulfonylamino group. In this case, the benzopyran derivatives described in the EP Offenlegungsschrift are activators or openers of the so-called adenosine triphosphate-sensitive K channel [K+(ATP) channel]. Now, as is known, the pharmacological actions of K+(ATP) channel openers are completely different from the blockers of the IsK channel described here. Thus for the K+(ATP) channel openers, typical vasodilating and hypotensive properties were demonstrated for this mechanism. As expected, the described K+(ATP) channel openers synthesized by the authors show typical, specific antiarrhythmic properties for this mechanism of K channel opening. In a basic study, Lucchesi et al. (J.Cardiovasc. Pharmacol. 452 464 [1990]) were impressively able to show that K+(ATP) channel openers do not have an antiarrhythmic action on the diseased heart which is undersupplied with oxygen or in sudden ischemias, but in contrast even cause life-threatening profibrillatory effects. These dangerous conditions are caused as a consequence of the reductions in the repolarization period resulting from the activation of the K+(ATP) channel. Unlike these life-threatening profibrillatory effects on the diseased, defectively supplied heart due to the action of K+(ATP) channel openers, blockers of the K+(cAMP) channel should show antifibrillatory action under these conditions. As a prominent representative of the compounds of the formula la S synthesized by us, in the meantime 6 -cyano-4-(n-ethylsulfonyl-N-methyl)amino-2,2dimethyl-3-chromanol found its way into the most recent literature under the name 293B as an example of a highly specific IKs or IsK channel blocker having a corresponding lengthening of the action potential on the heart (Sulabrich et al, 20 Naunyn Schiedebergs Arch.Pharm. [1996] 353 (4,Suppl.), R72; PflOgers Arch.-Eur.

J. Physiol. 431 [Suppl], R 22 [1996], A. Busch et al., PflCgers Arch.-Eur. J.

Physiol. 432 [Suppl], 1094-1096 [1996]).

On the basis of specific structural knowledge, a few compounds were synthesized and investigated by us which admittedly are already disclosed in the Offenlegungsschrift mentioned (EP Offenlegungsschrift 389 861), but were not described, synthesized or recognized in their therapeutic action by the authors. For these specific 3-hydroxy-substituted chromans prepared and investigated by us, a potent blockade of the K+(cAMP) channel (Pfligers Arch. Eur. J. Physiol. [1995] 429: 517 530 A new class of inhibitors of cAMP-mediated ClI secretion in rabbit colon, acting by the reduction of cAMP-activated K conductance) has now surprisingly been found and the inhibition of the IKs channel on the heart. The IsK channel-blocking action of the 3-hydroxy-substituted chromans, however, is markedly less pronounced than that of the corresponding hydroxyl group-free chromans of the formula I.

The invention therefore also relates to the use of compounds of the formula la for the treatment of sudden cardiac death, ventricular fibrillations and generally of arrhythmias of the diseased heart which are to be attributed to the IKs channel The publication "N-Sulfonamides of benzopyran-related potassium channel openers: conversion of glyburyde insensitive smooth muscle relaxants to potent smooth muscle contractors" in Bioorg. Med. Chem. Lett. (1994) 4: 769 773 describes specific trifluoromethyl-substituted 4-sulfonyl-aminochroman derivatives which, however, in contrast to the structurally different K+(cAMP) channel blockers described here have biologically different pharmacological actions and thus other therapeutic application areas.

Most recently, spiro[2H-1-benzopyran-2,4'-piperidines] having an essential basic side group have additionally been described in the literature, e.g. MK-499 "Cardiac electrophysiology and antiarrhythmic actions of two long-acting spirobenzopyran *-15 piperidine class III agents, L-702,958 and L-706,000 (MK 499)" J. Pharmakol. Exp.

Ther. (1994) 269: 541 554; T. J. Colatsky und T. M. Argentieri, "Potassium channel blockers as antiarrhythmic drugs"; Drug Develp. Res. (1994) 33: 235 249.

SThese "spirobenzopyran piperidine class III agents" are, however, very clearly S 20 characterized in the literature with respect to their mode of action S. Spector, M.

E. Curran, M. T. Keating, M. C. Sanguinetti, Circulation Res. (1996) 78: 499 503; J.J. Lynch et al., J. Pharmacol. Exp. Ther. (1994) 269: 541 554]. In this case, it is clearly described and shown in the literature cited that the antiarrhythmic action of these compounds is caused by the inhibition of the HERG channel and of the rapidly activating component of the delayed rectifier K channel, of the IKr channel. Thus the spirobenzopyran piperidines are characterized as substances having a proarrhythmic component and having the danger of an increased mortality compared to placebo, as has been shown for this active compound class in the Sword study. This is in clear contrast to the compounds according to the invention, whose advantage consists in the blocking of the slow-activating component of the delayed rectifier K channel, of the IKs channel, which compounds do not have this proarrhythmic component.

The compounds of the formula I or la can also be combined with other active 17 compounds to achieve an advantageous therapeutic action. But in the treatment of cardiovascular disorders, advantageous combinations with cardiovascular substances are conceivable. Possible advantageous combination components of this type for cardiovascular disorders can be, for example, other antiarrhythmics, i.e.

class I, II or III antiarrhythmics, such as, for example, so-called IKr channel blockers, e.g. dofetilide, furthermore hypotensive substances such as ACE inhibitors (for example enalapril, captopril, ramipril), angiotensin antagonists, K channel activators, and also alpha- and 13-receptor blockers, but also sympathomimetic compounds and compounds having an adrenergic action, as well as Na+/H exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances having positive inotropic action such as digitalis glycosides and diuretics.

A combination with substances having antibiotic action and with antiulcer agents, for example with H 2 antagonists (ranitidine, cimetidine, famotidine etc.) can furthermore be advantageous, such as, in particular, in the application for the treatment of gastrointestinal illnesses.

Pharmaceuticals which contain a compound I or a compound of the formula la according to the invention can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration being dependent on the particular clinical picture of the illness. The compounds I and la can in this case be used on their own or together with pharmaceutical auxiliaries, namely both in veterinary and in human medicine.

The auxiliaries which are suitable for the desired pharmaceutical formulation are familiar to the person skilled in the art on the basis of his expert knowledge. Beside solvents, gel-forming agents, suppository bases, tableting auxiliaries and other active compound excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants.

For a form for oral use, the active compounds I and la are mixed with the additives 18 suitable for this purpose, such as excipients, stabilizers or inert diluents, and are brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds of the formula I or of the formula la are brought into solution, suspension or emulsion, if desired with the substances customary for this purpose such as solubilizers, emulsifiers or other auxiliaries. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or alternatively i a mixture of the various solvents mentioned. As solubilizers, for example, oligosaccharides such as cyclodextrins are also used.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I or of the formula la in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents. If required, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation customarily contains the active compound in a concentration of approximately 0.1 to in particular of approximately 0.3 to 3% by weight.

The dose of the active compound of the formula I or of the formula la to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; but also on the nature and severity of the illness to be treated as well as on the sex, age, weight and individual responsiveness of the mammal to be treated.

19 On average, the daily dose of a compound of the formula I in the case of a patient of weight approximately 75 kg is at least 0.1 mg, preferably 10 mg to at most 100 mg, preferably at most 1 g; or for compounds of the formula la at least 1 mg, preferably mg, up to at most 300 mg, preferably 1 g.

Explanation of the abbreviations used in the text DMA Dimethylacetamide HMPT Hexamethylphosphoramide TMU Tetramethylurea hr Hour(s) mol Mole mmol Millimole min Minutes TEA Triethylamine THF Tetrahydrofuran Examples: 0. Example 1: 4 -(N-Ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman o Of//

\NS

a) 2,2-Dimethyl-4-chromanone oxime A reaction mixture prepared from 10 mmol of 2,2-dimethyl-4-chromanone, 12 mmol of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine is heated with stirring over the course of 2 hours to 80 85 0 C, the solvent is distilled off on a rotary evaporator and the oily residue is crystallized under water.

Crystalline substance, melting point 115 118 "C.

b) 4 -Amino-2,2-dimethylchroman hydrochloride A solution of 10 mmol of 2 ,2-dimethyl-4-chromanone oxime and 75 ml of methanol is hydrogenated, after addition of Raney nickel as a catalyst, in an autoclave with hydrogen at 60°C, 100 atm. pressure for a period of 6 hours. After filtration and the removal of the solvent by distillation, the amorphous residue is dissolved in ethyl acetate and the solution is treated with diethyl ether saturated with HCI gas until it has a strongly acidic reaction. The crystalline precipitate of 2,2-dimethyl-4aminochroman hydrochloride is filtered off, washed several times with ethyl acetate and dried.

Colorless crystals, melting point 268°C.

c) 4 -N-Ethylsulfonylamino-2,2-dimethylchroman Variant 1: a solution of 4.5 mmol of ethanesulfonyl chloride in 5 ml of THF is added at 0°C in portions to a stirred solution prepared from 4.3 mmol of 4-amino-2,2dimethylchroman hydrochloride, 15 ml of THF and 1.25 ml of TEA. The mixture is stirred for about 2 hours at 0°C and for 1 hour further at room temperature, the precipitate is filtered and the solvent is distilled off on a rotary evaporator. The residual oil crystallizes under petroleum ether.

Colorless crystals, melting point 106 -108°C.

S Variant 2: 0.83 g (0.0065 mol) of ethanesulfonyl chloride is added in portions between 0 and 5"C to a suspension of 1.06 g (0.005 mol) of 4-amino-2,2dimethylchroman hydrochloride and 2.0 g (0.02 mol) of TEA in 25 ml of DMA and the mixture is stirred at room temperature for 2 days. After removal of the solvent by distillation on a rotary evaporator, the residue is treated with water, whereupon the oil which separates solidifies in crystalline form after a short time.

Melting point 106 1090C.

d) 4-N-Ethylsulfonyl-N-methylamino-2,2-dimethylchroman: A solution of 0.0111 mol of 4 -N-ethylsulfonylamino-2,2-dimethylchroman in 15 ml of anhydrous methanol is slowly added to a sodium methoxide solution, prepared from 0.0166 gram atom of sodium in 20 ml of anhydrous methanol. A solution of 0.014 mol of methyl iodide in 5 ml of anhydrous methanol is then added in portions to this mixture and it is heated for 6 hours at 50°C under a reflux condenser. The solvent is distilled off on a rotary evaporator, and the residue is treated with ethyl acetate and extracted with 2 N NaOH. The organic phase is dried over anhydrous sodium sulfate and 4 -N-ethylsulfonyl-N-methylamino-2,2-dimethylchroman is obtained by again removing the solvent by distillation.

Colorless crystalline substance, melting point: 90 92 0

C.

Example 2: 4 -(N-Ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman:

O

0.0111 mol of 4 -N-ethylsulfonylamino-2,2-dimethylchroman is added with stirring in portions to a suspension of 0.0122 mol of sodium hydride in 30 ml of anhydrous dimethylacetamide under an argon atmosphere and the mixture is stirred at room temperature for a further hour. After subsequent addition of 0.0122 mol of ethyl bromide, the mixture is stirred at room temperature for a further 24 hours. The solvent is distilled off under reduced pressure, the residue is then treated with ethyl acetate and extracted with water and the organic phase is distilled off in a rotary evaporator after separation and drying over anhydrous sodium sulfate. 4-(N-Ethyl-Nethylsulfonylamino-2,2-dimethylchroman is obtained by crystallization under petroleum ether as a colorless crystalline substance, melting point Example 3: 4-(N-Benzyl-N-ethylsulfonyl)amino-2,2-dimethylchroman 0 0 is obtained analogously to the procedure indicated in Example 2 from 4-Nethyl sulfonylamino-2,2-di methyl ch rom an and benzyl bromide.

Colorless crystals, melting point 95 97 0

C.

Example 4: 4 -LN-Ethyl sufonyl-N-(2-d imethyl am inoethyl)]am ino22-d imethylch roman 0 1I''/ N o Is\I- 20 is obtained analogously to the procedure indicated in Example 2 from 4-Nethyl su lfonylamino-2,2-d imethyl ch roman and 2-chloroethyldimethylamine hydrochloride using double the amount of sodium hydride.

Colorless crystals, melting point 90 93 0

C.

Example 5: 4 -N-Ethy s u Ifonyl am ino-2,2-d imethyl-6,-d in itroch roman 3.71 mmol of 4-N-ethyl sulIfonyla m ino-2,2-d im ethylch roman are added in portions

I

4 23 with stirring to 4.3 ml of 100% strength nitric acid cooled to -15 to -20 0 C and the mixture is stirred for a further 20 minutes while maintaining the cooling. The reaction mixture is poured into 50 ml of ice water and filtered, and the yellow crystals are washed several times with water. The compound is purified by chromatography on silica gel using a mixture of 3 parts of ethanol and 7 parts of ethyl acetate and subsequently crystallized using petroleum ether.

Yellow crystalline compound, melting point 140 -142 0

C.

Example 6: 4-N-Ethylsulfonylamino-2,2-dimethyl-6-nitrochroman

O

0 N .0.54 ml of 100% strength nitric acid is added in portions at -20 0 C to a mixture of 3.71 mmol of 4-N-ethylsulfonylamino-2,2-dimethylchroman in 2.54 ml of acetic acid and the mixture is stirred at -20 0 C for a further 5 min. The reaction mixture is poured into 50 ml of ice water, and the violet-colored precipitate is filtered and washed several times with cold water on the filter. The crystals are dissolved in a little ethyl acetate and chromatographed on silica gel using a mixture of 3 parts of petroleum ether and 2 parts of ethyl acetate.

Pale yellow crystals, melting point 198 201 C.

Example 7: 4 -(N-Ethyl-N-ethylsulfonyl)amino-2,2-dimethyl-6-nitrochroman

O

o.e"

S/

N

O0 is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-2,2-dimethyl-6-nitrochroman and ethyl bromide.

Pale yellow crystals, melting point 180 185 0

C.

Example 8: 4 -(N-Ethylsulfonyl-N-methyl)amino-2,2-dimethyl-6-nitrochroman is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-2,2-dimethyl-6-nitrochroman and methyl iodide.

Pale yellow crystals, melting point 190 192°C.

Example 9: 6-Amino-4-(N-ethylsuIfonyl-N-methyl)amino-2,2-dimethylchroman hydrochloride o a H2N.

0* W :i is obtained by catalytic hydrogenation of 7.21 mmol of 4-N-ethylsulfonyl-Nmethylamino-2,2-dimethyl-6-nitrochroman with hydrogen gas in 150 ml of methanol using Raney nickel as a catalyst until the theoretical amount of hydrogen has been absorbed over a period of approximately 1.5 hr at 760 torr. After filtration and evaporation of the solvent, the amorphous residue is dissolved in ethyl acetate and the product is purified, by addition of a saturated solution of HCI gas in diethyl ether, by precipitation of the hydrochloride.

Colorless crystals, melting point 75 78 0

C.

Example 10: 6 -Amino- 4 -(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethyl-chroman hydrochloride

O

x HCI

S

N

H2 is obtained analogously to the procedure indicated in Example 9 from 4-N-ethyl-Nethylsulfonylamino-2,2-dimethyl-6-nitrochroman by catalytic hydrogenation with Raney nickel.

Colorless crystals, melting point 95 100 0

C.

S: Example 11: 4 -N-(Dimethylaminosulfonyl)amino-2,2-dimethylchroman 0 0 HN N 20 0 A solution of 0.03 mmol of TEA in 30 ml of DMA is added to a suspension of 10 mmol of 4 -amino-2,2-dimethylchroman hydrochloride in 75 ml of anhydrous THF.

The mixture is stirred at room temperature for approximately 30 min and a solution of 12 mmol of N,N-dimethylsulfamoyl chloride in 10 ml of anhydrous THF is added dropwise to the suspension with cooling at approximately 10°C. After removing the cooling bath, the mixture is stirred at room temperature for a further 24 hr. The solvent is then distilled off on a rotary evaporator and the residue is stirred under water, crystallization taking place after some time. After filtering off the crystals and washing with water, 4 -N-(dimethylaminosulfonyl)amino-2,2-dimethylchroman is obtained as colorless crystals, melting point 77 790C.

Example 12: 4-N-Methyl-N-(dimethylaminosulfonyl)amino-2,2-dimethyl-chroman _j 0 0 NS N 0 is obtained analogously to the procedure indicated in Example 2 from 4-N- (dimethylaminosulfonyl)amino-2,2-dimethylchroman and methyl iodide.

Colorless crystals, melting point 146 148 0

C.

Example 13: 4 -N-Ethylsulfonylamino-6-fluoro-2,2-dimethylchroman 0

HN

F

O

a) 4-Fluorophenyl acetate is obtained as an oily residue by boiling 4-fluorophenol in acetic anhydride and then evaporating the solvent.

S

b) 5-Fluoro-2-hydroxyacetophenone is obtained from 0.0376 mol of 4-fluorophenyl acetate and 0.083 mol of anhydrous AICl 3 (for Friedel-Crafts reactions) at 120°C for 2 to 3 hours and by then decomposing with ice water after cooling. The mixture is extracted with ethyl acetate and, after drying over sodium sulfate, the solvent is removed by distillation and the amorphous viscous residue is crystallized under cyclohexane.

Colorless crystalline substance, melting point 46 47"C.

c) 6 -Fluoro-2, 2 -dimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from 5-fluoro-2hydroxyacetophenone and acetone in the presence of pyrrolidine.

27 Colorless to slightly yellow amorphous residue.

d) 6-Fluoro-2,2-dimethyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro- 2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride, by crystallization of the product under water and recrystallization from cyclohexane using activated carbon.

Colorless crystals, melting point 108 110°C.

e) 4-Amino-6-fluoro-2,2-dimethyl-4-chroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation in an autoclave from 6-fluoro-2,2-dimethyl-4-chromanone oxime, Raney nickel and hydrogen.

Colorless crystals, melting point 226 0 C, sublimation from 296 0

C.

f) 4-N-Ethylsulfonylamino-6-fluoro-2,2-dimethylchroman S 5.5 mmol of ethanesulfonyl chloride are added to a suspension of 5 mmol of 4amino-6-fluoro-2,2-dimethyl-4-chroman hydrochloride in 20 ml of DMA and 15 mmol of TEA with stirring and cooling to 10°C. The mixture is stirred for a further 24 hours at room temperature, then the solvent is distilled off on a rotary evaporator and the residue is stirred under 75 ml of water. The oil which separates is extracted with ethyl acetate, and the organic phase is separated off and dried over anhydrous sodium sulfate. After distilling off the solvent in a rotary evaporator, 4ethylsulfonylamino-6-fluoro-2,2-dimethylchroman is obtained as an amorphous product.

Example 14: 4 -(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethyl-chroman

O

0

N//

1NS is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylam ino-6-fl uoro-2,2-d imethyl ch roman and methyl iodide.

Amorphous oily product.

Example 15: 6-Fluoro-4-N-(d imethyl ami nosu Ifonyl) am ino-2,2-d imethyl-ch roman 0 is obtained analogously to the procedure indicated in Example 11 from 4-amino-6fluoro-2,2-dimethylchroman and N,N-dimethylsulfamoyl chloride in anhydrous DMA.

Colorless crystals, melting point 86 88 0

C.

Example 16: 6 -Fluoro-4-[N-methyl-N-(dimethylaminosulfonyl)]amino- Z,2-dimethylchroman 0 is obtained analogously to the procedure indicated in Example 2 from 6-fluoro-4-N- (dimethylaminosulfonyI)amino-2,2-dimethylchroman and methyl iodide.

Amorphous oily product.

Example 17: 6 -CyanOA-(N-ethyl su IfonylNm ethyl)a m ino2,2-d imethyl ch roman

O

o

N

NC

a) 6-Cyano-2,2-dimethylchroman A suspension consisting of 10 mmol of 6-cyano-2,2-dimethyl-3,4-chromene, 50 ml of methanol and about 500 mg of palladium catalyst on barium sulfate(10% strength) is shaken in a shaking duck under a hydrogen atmosphere at 1 atm and at 20 0 C until the theoretical amount of hydrogen has been absorbed. After filtration of the S. catalyst, the solvent is distilled off on a rotary evaporator and 6-cyano-2,2dimethylchroman is obtained as a colorless to slightly yellowish oil.

b) 4-Bromo-6-cyano-2,2-dimethylchroman 11 mmol of N-bromosuccinimide and 0.22 g of azobisisobutyronitrile (Aldrich) are added to a solution of 10 mmol of 6-cyano-2,2-dimethyl-chroman in 30 ml of carbon 20 tetrachloride and the suspension thus obtained is heated to boiling under a reflux condenser for 3 hours. Insoluble succinimide is then filtered off, the solvent is distilled off and the residue is crystallized under a mixture of n-hexane and diisopropyl ether.

Slightly yellow crystals, melting point 93 94 0

C.

c) 6 -Cyano- 4 -[N-ethylsulfonyl-N-methyl]amino-2,2-dimethylchroman A solution of 11 mmol of ethanesulfonic acid N-methylamide is added dropwise under a protective gas atmosphere of argon to a suspension of 11 mmol of sodium hydride (as an 80% strength oil suspension) in 5 ml of anhydrous DMA and the mixture is stirred for about one hour at room temperature. It is then treated with a solution of 10 mmol of 4 -bromo-6-cyano-2,2-dimethylchroman in 7 ml of anhydrous DMA and stirred for 72 hours at 70 0 C. The reaction mixture is poured with stirring into 75 ml of water, the oily amorphous precipitate is extracted with ethyl acetate and the organic phase is dried over anhydrous sodium sulfate. The solvent is distilled off on a rotary evaporator and the amorphous residue is separated by column chromatography on the silica gel column using a solvent mixture consisting of 1 part of toluene and 1 part of ethyl acetate as eluent. After distilling off the elution liquid in the rotary evaporator, the 6 -cyano-4-[N-ethylsulfonyl-Nmethyl]amino-2,2-dimethylchroman is obtained as a colorless crystalline product, Melting point 166 168°C.

Example 18: 4-N-Ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman

O

o a) 3 -Acetyl-4-hydroxybenzoic acid 36.6 g (0.274 mol) of AICI 3 are suspended in 50 ml of 1, 2 ,4-trichloro-benzene and treated with 9 g (50 mmol) of 4-acetoxybenzoic acid. After dropwise addition of 7.84 g (0.1 mol) of acetyl chloride, the reaction mixture is heated to 130 140 0 C, the evolution of HCI gas occurring from approximately 60 0 C. The mixture is stirred for approximately 1 hour at 130 0 C and then allowed to cool to 60 70"C, and the mixture is poured cautiously into stirred ice water. It is extracted several times with ethyl acetate, then the combined organic phases are extracted with saturated aqueous sodium bicarbonate solution and the combined aqueous phases are adjusted carefully to pH 1 using concentrated HCI, the 3-acetyl-4-hydroxybenzoic acid separating as sparingly soluble material.

Colorless crystalline substance, melting point 228 233 0

C.

b) 6-Carboxy-2,2-dimethyl-4-chromanone 13.8 g of pyrrolidine and 40 ml of acetone are added to a suspension of 14.7 g (0.0815 mol) of 3 -acetyl-4-hydroxybenzoic acid in 200 ml of acetonitrile. The slowly discoloring solution is allowed to stand at room temperature for 2 days, the solvent is distilled off on a rotary evaporator, the residue is treated with water and adjusted to acidic pH 1 using conc. hydrochloric acid and the crystalline substance is filtered off.

Colorless crystals, melting point 154 160*C.

c) 6 -Carboxy-2,2-dimethyl-4-chromanone oxime 14.9 g of 6 -carboxy-2,2-dimethyl-3-chromanone are dissolved in 100 ml of ethanol and 100 ml of pyridine, and after addition of 5.16 g of hydroxylamine hydrochloride the mixture is heated at 80 0 C with stirring for 6 hours. The solvent is distilled off on a rotary evaporator. The residue is treated with water and adjusted to pH 1 using conc. hydrochloric acid, and the colorless crystals are filtered off.

Melting point 223 225 0

C.

d) 4-Amino-6-carboxy-2,2-dimethylchroman 35.2 g (0.15 mol) of 6 -carboxy- 2 ,2-dimethyl-4-chromanone oxime are dissolved in 300 ml of methanol by addition of 600 ml of concentrated aqueous ammonia and, after addition of a few grams of Raney nickel catalyst, hydrogenated at 80 0 C for hours under 100 atm hydrogen pressure. After filtering off the catalyst, approximately 3/4 of the solvent is distilled off in a rotary evaporator. The crystalline 20 precipitate of 4-amino-6-carboxy-2,2-dimethylchroman is filtered off.

Colorless crystals, melting point 307 310°C.

99 9 9 e) 4-Amino-6-methoxycarbonyl-2,2-dimethylchroman 0.05 mol of 4-amino-6-carboxy-2,2-dimethylchroman is treated with 9.5 ml of conc.

sulfuric acid in 200 ml of methanol and the dark solution is heated to reflux for 6 hours. The reaction mixture is adjusted to pH 9 with ice cooling by addition in portions of saturated aqueous potassium carbonate solution and the precipitated salt is filtered off. The solvent is distilled off on a rotary evaporator, the oily residue is treated with water and the mixture is extracted several times with diethyl ether.

After removing the solvent by distillation, the oily amorphous residue is crystallized under n-heptane.

Colorless crystalline substance, melting point 62 32 f) 4 -N-Ethylsuffonylam ino-6-.methoxycarbonyl.2 ,2-d imethylch roman is obtained analogously to the procedure indicated in Example 1 c) from 0.0184 mcI of 4 -amino-6-methoxycarbonyl-2,2-dimethylchroman with 0.021 mol of ethanesulfonyl chloride in THF using excess TEA.

Colorless crystals, melting point 111 11 3 0

C.

Example 19: 4 -(N-Ethyl sulfonyl-N-m ethyl) am ino-6-methoxycarbonyl.2 2dimethylchroman 0 100 0660 0 4 tysloyaio6mtoyabnl.2dimethylchroman0.22mlo is Colorles crysallineoustotanceprmeltingepincte 84 Exml 118rm7 0 C.n Eabxample 20: 6 Methycronl4 dimethylamiosulfonyl lrd ndtyamin e in

THFE

Colorless crystals, melting point 127 129 0

C.

Example 21: 6-Methoxycarbonyl-4-[N-methyl-N-(dimethylaminosulfonyl)]amino-2,2dimethylchroman

NN.

is obtained analogously to the procedure indicated in Example 2 from 010 6 -methoxycarbonyl-4-N-(di methyl am inos u fonyl) am ino22d imethylch roman, NaH and methyl iodide in DMA.

Colorless crystalline substance, melting point 125 129 0

C

*.Example 22: 4 -(N-Butyl-N-ethylsulfonyl)amino6methoxycarbonyl2,2 dimethylchroman 0 0

N

200 is obtained analogously to the procedure indicated in Example 2' from 4-Nethylsu Ifonyl am ino-6m ethoxycarbonyl22-dimethyl ch roman, NaH and I -butyl iodide in DMA.

Colorless to slightly yellow oily amorphous product.

Example 23: 6 -C arboxy-4-(Nethyl su fonylNmethyl) am ino2,2d imethylch roman A suspension consisting of 1 g (0.00305 mol) of 4-N-ethylsulfonyl-N-methylamino-6methoxycarbonyl-2,2-dimethylchroman, 30 ml of methanol and a solution of 0.36 g (0.0091 mol) of NaOH in 20 ml of water is stirred under reflux conditions for approximately 10 hours until the formation of a solution. The solvent is distilled off on a rotary evaporator, the residue is treated with water, the mixture is adjusted to pH 0 to 1 using HCI and the colorless crystals are filtered off.

Melting point 235 237°C.

Example 24: 6 -Aminocarbonyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2- .10 dimethylchroman

H

O

°o° o 0.38 g (0.0023 mol) of carbonyldiimidazole is added to a solution of 0.7 g of 6carboxy- 4 -(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman (0.0021 mol) in ml of anhydrous THF, and the mixture is stirred for 3 hours at room temperature and then treated with 10 ml of conc. aqueous ammonia solution (25% strength). After S* stirring at room temperature for about 15 hours, the solvent is largely distilled off on a rotary evaporator, the residue is treated with water and the white crystalline substance is filtered off.

Melting point 202 204"C.

Example 25: 6 -Cyano- 4 -(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman

O

N g (0.0015 mol) of 6-aminocarbonyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2dimethylchroman is treated, as a mixture with 0.72 g (0.0045 mol) of Ntrimethylsilylpyrrolidone, with 0.0013 g (0.000075 mol) of sodium bis(trimethylsilyl)amide under an argon atmosphere and the mixture is heated to 90C (bath temperature). From the initial solid mixture is formed a solution, which is stirred at 90*C for 4 hours and then allowed to stand overnight at room temperature.

After removing the inert gas protection and stirring with water, crystallization of the oil occurs. The crystals are filtered off with suction and purified from still-present starting material by chromatography on silica gel using a mixture of 10 parts of methylene chloride and 1 part of methanol as elution medium.

Melting point 164 167 0

C.

Example 26: 6-Carboxy-4-N-ethylsulfonylamino-2,2-dimethylchroman 0

OS

HN

I

HO

o is obtained analogously to the procedure indicated in Example 1 a) from 4-amino-6methoxycarbonyl-2,2-dimethylchroman with isopropylsulfonyl chloride in THF using excess TEA.

Colorless crystals, melting point 112 115°C.

Example 27: 4-[N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino]-6-methoxy-carbonyl- 2,2-dimethylchroman F 0 0

N

1 is obtained analogously to the procedure described in Example 2 from 4-Nethyl sulIfonyl amino-6-m ethoxyca rbonyl2,2d imethylch roman and 4,4,4-trifluoro-1 iodobutane in DMA.

Pale yellow to colorless oily amorphous product.

Example 28: 6-Carboxy-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobuty)amino]2,2 dimethylchroman F0 0 F n 0 .o is obtained analogously to the procedure described in Example 23 by alkaline hydrolysis of 4 -N-ethylsulfonyl-N(4,4,4trifluorobutyl)amino6methoxycarbony-2,2 dimethylchroman.

Colorless crystalline substance, melting point 189 192 0

C.

**SExample 29: 4 -(N-Butyl-N-ethylsulfonyl)amino-6methoxycarbonyl2,2 dimethylchroman 0 is obtained analogously to the procedure described in Example 2 from 4-Nethyl s u fonylam in o-6-methoxycarbo nyl 2,2di methylch romanl and butyl iodide in DMA. Colorless crystalline substance, melting point 81 84 0

C.

Example 30: 6-Methoxycarbonyl-4-N-methylsulfonylamino22dimethylchroman is obtained analogously to the procedure described in Example 1 c) from 4-amino-6methoxycarbonyl-2,2-dimethylchroman with methanesulfonyl chloride.

Colorless crystalline substance, melting point 159 163 0

C.

Example 31: 6-Aminocarbonyl4[NethysulfonyN(444trifluorobutyl)amino]-2,2 dimethylchroman F 0

O\

F N1 15H

F

S*.2 is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4 -N-ethyl sulfonylN(4,4,rifl uoro butyl)am ino22d imethyl-ch roman, carbonyldiimidazole and ammonia.

Colorless crystalline substance, melting point 170 174 0

C.

Example 32: 6-C arboxy-4-[N-m ethyl-N(d imethy am inos u fony)amino]2,2 dimethylchroman 0 HO N N

I

is obtained analogously to the procedure indicated in Example 23 from 6 -methoxycarbonyl--[N-methy..N-.(dimethylaminosulfonyl)amino]-2,2dim ethyl chroman.

Colorless crystalline compound, melting point 245 248 0

C.

Example 33: 6-Cyano-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino]2,2 dimethylchroman Fn F 0oil/

FN

NC

is obaie anlgul otepoeueidctdi 6-mn c rb nl4Netys loylN(,,-tiloo utla io.,-ieh Cslobtaiednaooul to plyeowctle rceuretinced ling Eple 125 fromC Exampl 34 6 -ainoarb nyl-4-N-eth -mhysulonkN(,44timrtylamino22dlonlaimeth 2sin i xtuycrof 0prso etyeeclrd ad1pr fmthnla let

S.

isotie*nlgosyt h rceueidctdi Example 34;ro 6 -AmncarbonyxyN-m4y-.(dmtyamn~ufnyai 0 2 dimethylchroman 10 is obtained analogously to the procedure indicated in Example 25 from 6-aminocarbonyl-4-[N-methyl-N-(d imethylam in os ufonyl am ino-22d imethylch roman.

Colorless crystalline substance, melting point 100 102 0

C.

Example 36: 4 utyl-N -ethyl su lfonyl)am ino-6-carboxy22d imethylch roman obtained analogously to the procedure indicated in Example 23 from 4-N-(butyl-Nethyl su IfonyI)am in o-6-methoxycarbony 2,2-d imethy Ichroman.

Colorless crystalline compound, melting point 148 151 0

C.

Example 37: 6 -Am inoca rbonyI-4-(N-buty -N ethyl su Ifo nyl)am ino2,2 dimethylchroman 0 0

H

2

NN

0 is obtained analogously to the procedure indicated in Example 24 from 4-(N-butyl-Nethyl su Ifonyl)a m ino-6-ca rboxy-2,2-d imethyl ch roman.

Colorless crystalline substance, melting point 195 1 99 0

C.

Example 38: 4 utyl-N -ethyl sufonyl) am ino-6-cyano-22d imethyl-ch roman *..1o is obtained analogously to the procedure indicated in Example 25 from 6 -amin ocarbonyl-4-N-butyl-Nethyl su Ifonyl am ino22-d imethylch roman.

Colorless crystalline substance, melting point 96 98 0

C.

Example 39: 4 -[N-Ethylsulfonyl-N-(4-picolyl)amino]6methoxycarbonyl2,2 dimethylchroman

N

0 N0N is obtained analogously to the procedure indicated in Example 2 from 0.005 mol of 4 -N-ethylsulfonylamino-6-methoxycarbonyl22-dimethylchroman, 0.015 mol of NaH and 0.007 mol of 4-picolyl chloride hydrochloride.

Dark-colored, oily amorphous substance.

Example 40: 6 -Carboxy- 4 -[N-ethysulfonylN(4picolyl)amino]2,2dimethylchroman is obtained analogously to the procedure indicated in Example 23 from 4-[Nethylsulfonyl-N-(4-picolyl)am inol-6-methoxycarbonyl,2 2-dimethyl-chroman.

Colorless crystalline substance, melting point 210 212 0

C.

Example 41:6-m irnocarony4[ Nety su fonylN (4pi colyl) am i no]-2 dimethylchroman Rb. S is obtained analogously to the procedure indicated in Example 24 from 6-carboxy-4- N-tysloy--4pcllaio22dmtycrmn Colorless crystalline compound, melting point 193 196 0

C.

Example 42: 6 -Piperidinocarbonyl4NethylsulfonyINmethylamino- 2 2 dimethylchroman 0 0 0 is obtained analogously to the procedure indicated in Example 24 from 0.003 mcI of 6 -carboxy- 4 -[N-ethylsulfonylNmethylamino]2,2-dimeth-ylchroman, 0.0033 mol of N,N-carbonyldiimidazole and 0.012 mol of piperidine.

Colorless crystals from ethanol, melting point 184 0

C.

Example 43: 4 -N-lsopropyl s ulfonyl am ino6m ethoxyca rbonyl2,2d imethyl chroman 0 0 is obtained analogously to the procedure indicated in Example 1 c) from 0.024 mol of 4 -amino- 6 -methoxycarbonyl-2,2dimethylchroman with 0.0319 mcI of ethanesulfonyl chloride using excess TEA in THF under reflux conditions in the course of 12 hours and by additional purification of the product by column chromatography on silica gel using a mixture of 1 part of ethyl acetate and 3 parts of toluene as eluent.

Colorless crystals, melting point 111 11 3 0

C.

Example 44: 4 -(N-lsopropylsulfonylNmethyl)amino6methoxycarbonyl2,2 dimethylchroman 43 0 00 is obtained analogously to the procedure described in Example 2 from 4-Nisopropylsulfonylamino-6-methoxycarbony-2,2dimethylchroman and methyl iodide.

:10 Colorless crystals, melting point 115 -11 9 0

C.

Example 45: 6-Carboxy-4-(N-isopropylsulfonyl-Nmethyl)amino2,2 dimethylchroman 0 0 HO

N

is obtained analogously to the procedure described in Example 23 from 4-(Nisopropylsulfonyl-Nmethyl)amino6methoxycarbonyl2,2dimethylchroman.

Colorless crystals, melting point 228 233 0

C.

Example 46: 6 -AminocarbonyI-4(NisopropylsulfonylNmethyl)amino2,2 dimethylchroman 300 is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4 -(N-isopropylsu Ifonyl-N methyl) am ino22-dim ethyl ch rom an.

44 Colorless crystalline product, melting point 217 22011C.

Example 47: 6-Cyano-4-(N-isopropylsulfonyl-N-methyl)amino-2,2-dimethylchroman ::10 is obtained analogously to the procedure described in Example 25 from 6-aminocarbonyl-4-(N-isopropylsulfonyl-N-methyl)amino-.2,2-dimethylchroman. After isolation of the product by filtration, it is purified by chromatography on silica gel using a mixture of 10 parts of methylene chloride and 1 part of methanol and the substance is crystallized under dilsopropyl ether after removing the solvent by distillation.

Colorless crystals, melting point 129 135 0

C.

Example 48: 4 -N -13utyl sulIfonyl am ino-6-methoxycarbonyl-2,2d imethyl ch roman *999 0 is obtained analogously to the procedure described in Example 1 c) from 4-amino- 2,2-dimethylchroman hydrochloride and 1 -butylsulfonyl chloride.

Melting point 117 1 20 0

C.

Example 49: 4 -(N-Butylsulfonyl-N-methyl)amino-6-methoxycarbonylI2,2dimethylchroman 10 S. e.

ft ft.

S S

S

S. ft

S

is obtained analogously to the procedure described in Example 2 from 4-Nbutyl sulIfonyl am ino-6-methoxyca rbonyl-2,2-d im ethyl chro man and methyl iodide.

Colorless to pale yellow amorphous oily product.

Example 50: 4-(N-Butylsulfonyl-N-methyl)amino-6-carboxy-2,2-dimethylchroman is obtained analogously to the procedure described in Example 23 from 4-(Nbutylsu lfonyl-N -m ethyl) am ino-6-methoxycarbonyl-2,2-d im ethyl -chrom an.

Colorless crystalline product, melting point 200 205 0

C.

Example 51: 6-Aminocarbonyl-4-(N-butylsulfonyl-N-methyl)amino-2,2dimethylchroman is obtained analogously to the procedure described in Example 24 from 4-(Nbutyl su Ifonyl-N-methyl) amin o-6-carboxy-2,2-d imethy Ich roman.

Colorless crystalline product, melting point 162 166 0

C.

46 Example 52: 6-Cyano- 4 -N-butylsulfonyl-N-methylamino-2,2-dimethyl-chroman

O

o

\N"S

NC

is obtained analogously to the procedure described in Example 25 from 6 -aminocarbonyl- 4 -(N-butylsulfonyl-N-methyl)amino-2,2-dimethylchroman. After isolation of the product by filtration, it is purified by chromatography on silica gel S. using a mixture of 10 parts of methylene chloride and 1 part of methanol and the substance is crystallized under diisopropyl ether after removing the solvent by distillation.

Colorless crystals, melting point 57 62 0

C.

9 99 Example 53: 6 -Methoxycarbonyl-4-(N-methyl-N-methylsulfonyl)amino-2,2dimethylchroman 0 O 20

O

is obtained analogously to the procedure described in Example 2 from 6-methoxycarbonyl-4-N-methylsulfonylamino-2,2-dimethylchroman and methyl iodide.

Colorless crystalline substance, melting point 160 164°C.

Example 54: 6 -Carboxy- 4 -(N-methyl-N-methylsulfonyl)amino2,2-dimethylchroman is obtained analogously to the procedure described in Example 23 from 6 -methoxycarbonyl-4-Nm ethylNmethyl su Ifony am ino2,2d imethylch roman by alkaline hydrolysis.

Colorless crystalline compound of melting point 214 216 0

C.

Example 55: 6 -Aminocarbonyl-4-(NmethylNmethylsulfonyl)amino2,2 dimethylchroman 150 0e0 a C S 0 is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4 -(N-methyl-N-methylsulfony)amino22dimethylchroman.

Colorless crystalline substance, melting point 179 182 0

C.

Example 56: 6 -Cyano- 4 ethyI-N methylsufonyl)a mino22-di methylch romanl 0 is obtained analogously to the procedure desribed in Example 25 from 48 6-aminocarbonyl-4-(N-methyl-N-methylsulfonyl)amino-2,2-dimethyl-chroman. After isolation of the product by filtration, it is purified by chromatography on silica gel using a mixture of 10 parts of methylene chloride and 1 part of methanol and the substance is crystallized under diisopropyl ether after removing the solvent by distillation.

Colorless crystals, melting point 196 200 0

C.

Example 57: 4-(N-Ethylsulfonyl-N-ethyl)amino-6-methoxycarbonyl-2,2dimethylchroman o 07 0S I[ .O.1 is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman, 0.013 mol of NaH (as an 80% strength suspension in oil) and 0.0126 mol of ethyl iodide in anhydrous

DMA.

Colorless crystalline substance, melting point 114 116°C.

49 Example 58: 4-(N -Ethyl sulIfonyl -N -propyl) am ino-6-m ethoxycarbonyl-2,2dimethylchroman 0 0N 0 .10.1 .0 is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of 4-N -ethyl sulIfonylam in o-6-methoxyca rbonyl-2,2-d im ethyl -chroman, 0.013 mol of NaH an 80% strength suspension in oil) and 0.01 26 mol of 1 -propyl iodide in anhydrous DMA.

Colorless crystalline substance, melting point 106-108 0

C.

Example 59: 4-(N-Ethylsulfonyl-N-cyclopropyl)amino-6-methoxycarbonyl-2,2dimethylchroman 0 250 is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of 4-N-ethylsulIfonylam ino-6-methoxycarbonyl-2,2-d imethyl-ch roman, 0.013 mol of NaH (as an 80% strength suspension in oil) and 0.01 26 mol of bromom ethyl cycl opropane in anhydrous DMA.

Colorless crystalline substance, melting point 108-11 0 0

C.

-M -I M Example 60: 4-(N-Ethylsulfonyl-N-1 -pentyl)amino-6-methoxycarbonyl-2,2dimethylchroman 0 0'/ is obtained analogously to the procedure indicated in Example 2 from 0.0091 moI of 4-N-ethyl sulIfonyl amin o-6-m ethoxyca rbonyl-2,2-d imethyl-ch roman, 0.013 moI of NaH (as an 80% strength suspension in oil) and 0.01 26 mol of pentyl iodide in anhydrous

DMA.

Oily amorphous product.

Example 61: 4-(N-Ethylsulfonyl-N-1 -hexyl)amino-6-methoxycarbonyl-2,2dimethylchroman 0%I

N

is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of 4-N -ethyl sulfonyl am ino-6-methoxycarbonyl-2,2-d im ethyl -chroman, 0.013 mol of NaH (as an 80% strength suspension in oil) and 0.01 26 mol of hexyl iodide in anhydrous

DMA.

Oily amorphous product.

Example 62: 4-(N-Ethylsulfonyl-N-methyl)amino-6,7-dimethoxy-2,2-dimethylchroman

O

0

NS

0 0 a) 6,7-Dimethoxy-2,2-dimethyl-4-chromanone oxime **10 is obtained by reaction of 0.0189 mol of 6 ,7-dimethoxy-2,2-dimethyl-4-chromanone with 0.02 mol of hydroxylamine hydrochloride in a mixture of 20 ml of methanol and 20 ml of pyridine for 20 hours at 60 80*C. After removing the solvent by distillation, the colorless crystalline product is obtained by treating the residue with water.

melting point 110°C.

b) 4 -Amino-6,7-dimethoxy-2,2-dimethyl-4-chroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6, 7 -dimethoxy-2,2-dimethyl-4-chromanone oxime and subsequent work-up in the presence of hydrochloric acid. Colorless crystalline substance of 20 melting point 210-215°C.

c) 4 -N-Ethylsulfonylamino-6,7-dimethoxy-2,2-dimethylchroman is obtained analogously to the procedure indicated in Example 1 c) (variant 1) from 4 -amino-6,7-dimethoxy-2,2-dimethyl-4-chroman hydrochloride and ethanesulfonyl chloride in THF in the presence of triethylamine.

Colorless crystalline product, melting point 132 135°C d) 4 -(N-Ethylsulfonyl-N-methyl)amino-6,7-dimethoxy-2,2-dimethylchroman is obtained analogously to the procedure indicated in Example 2 from 0.0036 mol of 4-N-ethylsulfonylamino-6, 7 -dimethoxy-2,2-dimethylchroman, 0.00504 mol of NaH (as an 80% strength suspension in oil) and 0.0054 mol of methyl iodide in anhydrous DMA.

Amorphous viscous oil.

52 Example 63: 7-Chloro-4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2dimethylchroman 0 0

N/

F

CI O :10 a) is obtained by reaction of 3-chloro-4-fluorophenol in acetic anhydride at 80 0 C for 6 hours.

S Colorless, crystalline product, melting point 42-46 0

C.

b) 4-Chloro-5-fluoro-2-hydroxyacetophenone is obtained by heating a mixture of 0.0705 mol of with 0.148 mol of anhydrous aluminum chloride with mechanical stirring at 120 0 C for S.about 3 hours, decomposition of the reaction mixture with an ice water/ice mixture and filtration of the precipitate. Colorless crystalline substance by treatment with activated carbon in methanol and, after distillation of the solvent, by subsequent digestion with a mixture of n-heptane and diisopropyl ether.

Colorless crystals, melting point 66 71 C.

c) 7-Chloro-6-fluoro-2,2-dimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from 4-chloro- 5-fluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Colorless to slightly yellow amorphous residue.

d) 7-Chloro-6-fluoro-2,2-dimethyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 7-chloro-6fluoro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride.

Crystalline product, 53 melting point 120 125*C.

e) 7-Chloro-6-fluoro-2,2-dimethyl-4-aminochroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 7-chloro-6-fluoro-2,2-dimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Two melting points: 1st melting point: 258 260*C with fresh crystallization of the melt, 2nd melting point 310°C.

f) 7-Chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman is obtained analogously to the procedure indicated in Example 1 c) by reaction of 7chloro-6-fluoro-2,2-dimethyl-4-aminochroman hydrochloride with ethanesulfonyl chloride in the presence of TEA in THF g) 7-Chloro-4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethyl-chroman is obtained analogously to the procedure indicated in Example 2 by reaction of 7chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman with sodium hydride and methyl iodide.

Colorless crystalline substance, melting point 104 107 0

C.

Example 64: 4-(N-Ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman

O

O N

S

H C

O

a) 2,2,6-Trimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from 2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Amorphous oily product.

54 b) 2,2,6-Trimethyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 2,2,6trimethyl-4-chromanone and hydroxylamine hydrochloride.

Crystalline product, melting point 120 125 0

C.

c) 4-Amino-2,2,6-trimethyl-4-aminochroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 2,2,6-trimethyl-4-chromanone oxime and work-up in the presence of hyrochloric acid.

4':10 Two melting points: 1st melting point.: 245 248 0 C with fresh crystallization of the melt, 2nd melting point 310°C.

d) 4-Ethylsulfonylamino -2,2,6-dimethylchroman 15 is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4amino-2,2,6-trimethylchroman hydrochloride with ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline product, melting point 114 117 °C.

4-(N-Ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman is obtained analogously to the procedure indicated in Example 2 by reaction of 4ethylsulfonylamino -2,2,6-dimethylchroman with sodium hydride and methyl iodide.

Colorless crystalline substance, melting point 107 0

C.

Example 65: 6,7-Dichloro-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman O 0 o// 'N N Cl Cln a) 4,5-Dichloro-2-hydroxyacetophenone is obtained analogously to the procedure indicated in Example 63 b) from 3,4dichlorphenyl acetate and anhydrous, active aluminum chloride.

Colorless to slightly yellowish-colored crystalline substance, melting point 100 1030C.

The 3,4-dichlorphenyl acetate used is obtained as a brown oil from 3,4dichlorophenol and acetic anhydride analogously to the procedure described in Example 63 a).

b) 6,7-Dichloro-2,2-dimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from 9*9 dichloro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

99* Amorphous brown oily product.

c) 6,7-Dichloro-2,2-dimethyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 6,7dichloro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride.

Crystalline product, melting point 115 -121 C.

9 d) 4-Amino-6,7-dichloro-2,2-dimethylchroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6,7-dichloro-2,2-dimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Two melting points: 1st melting point: 260 262°C with fresh crystallization of the melt, 2nd melting point 310°C.

e) 6,7-Dichloro-2,2-dimethyl-4-N-ethylsulfonylaminochroman is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4amino-6,7-dichloro-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline product, melting point 116 1200C.

f) 6,7-Dichloro-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman is obtained analogously to the procedure indicated in Example 2 by reaction of 6,7dichloro-2,2-dimethyl-4-N-ethylsulfonylaminochroman with sodium hydride and methyl iodide.

Colorless crystalline substance, melting point 102 106°C.

Example 66: 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-7-pyrrolidino-2,2dimethylchroman 0

S

F o a) 4,5-Difluoro-2-hydroxyacetophenone is obtained analogously to the procedure indicated in Example 63 b) from 3,4difluorophenyl acetate and anhydrous, active aluminum chloride.

Colorless to slightly yellowish-colored crystalline substance, melting point 43 46 0 C (crystallization under n-heptane).

The 3,4-difluorophenyl acetate used is obtained as a pale oil from 3,4-difluorophenol and acetic anhydride analogously to the procedure described in Example 63 a).

b) 6 -Fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from difluoro-2-hydroxyacetophenone and acetone in the presence of 1.1 mol equivalents of pyrrolidine in acetonitrile as solvent, the fluorine atom in the 7-position being exchanged for pyrrolidine in addition to the chromanone ring closure. For further purification, the product can be separated by chromatography on silica gel and an 8 1 mixture of toluene/ethyl acetate. Crystallization under n-heptane.

Colorless to slightly yellow crystalline product, 57 melting point 96 98 0

C.

c) 6 -F luoro-7-pyrroIid ino-2,2-d im ethyl -4-ch romanon e oxime is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro-7pyrrol id ino-2,2-d im ethyl -4-chroma none and hydroxylamine hydrochloride.

Crystalline product, melting point 148 1 52 0

C.

d) 6-Fluoro-7-pyrrol idino-2,2-dimethyl-4-aminochroman dihydrochioride is obtained analogously to the procedure indicated in Example 1 b) by catalytic *99* hyrogenation of 6 -fluoro- 7 -pyrrolidino-2,2-dimethyl-4-chromanone oxime and workup in the presence of hydrochloric acid.

Colorless crystalline product Melting point: 124 137 0 C with decomposition.

e) 6 -F]luoro- 7 -pyrrolIi d ino-2,2-d im ethyl-4N-ethyl su Ifonyl am inochrornan is obtained analogously to the procedure indicated in Example 1 c) by reaction of 6fluoro- 7 -pyrrol id ino-2,2-d im ethyl 4-am inochroman dihydrochloride and .9.9 ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline product, melting point 157 1 59 0 C (from a mixture of diisopropyl ether and methanol).

f 4 -(N-Ethyl su fonylN methyl)am in o6fluoro7pyrro i d ino2,2dimethylchroma n is obtained analogously to the procedure indicated in Example 2 by reaction of 6fluoro- 7 -pyrro Ii d ino-2,2-d imethyl-4-Nethyl su Ifonyl am inoch roman with sodium hydride and methyl iodide.

Colorless crystalline substance, melting point 136 1 38 0

C

Example 67: 4 -(N-Ethyls ulfonyl-Nmethyl)am ino6fl uoroch roman

O

0 0o//

F

0 a) 6-Fluoro-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro-4chromanone and hydroxylamine hydrochloride.

Crystalline product, melting point 106-107 0

C.

15 b) 6-Fluoro-4-aminochroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6-fluoro-4-chromanone oxime and work-up in the presence of hydrochloric acid.

Melting point: 252 0 C (decomposition).

c) 6-Fluoro-4-ethylsulfonylaminochroman is obtained analogously to the procedure indicated in Example 1 c) by reaction of 6fluoro-4-aminochroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline substance, melting point 107 108 0

C.

d) 4 -(N-Ethylsulfonyl-N-methyl)amino-6-fluorochroman is obtained analogously to the procedure indicated in Example 2 by reaction of 6fluoro-4-ethylsulfonylaminochroman with sodium hyride and methyl iodide, Colorless to pale yellow oil.

Example 68: 4-(N-B utyl-N-ethyl su lfonyl)am ino-6-fl uoroch roman 0 0

-S

N 0 4, 4.

see. is obtained analogously to the procedure indicated in Example 2 by reaction of 6- 0I fluoro-4-ethylsulfonylaminochroman with sodium hydride and lodobutane.

Colorless to pale yellow oil.

Example 69: 4 -Ethyl su Ifonyl-N -ethyl) amino-6fl uoro2,2d imethyl-chroman OS 0

F

200 is obtained analogously to the procedure indicated in Example 2 from 4-Nethyl sulIfonyl am ino-6-fl uoro-2,2-d imethyl ch roman and ethyl iodide.

Amorphous oily product.

M

Example 70: 4-(N-Ethyl sulIfonyl-N-propyl)a m ino-6-fluoro-2,2-d im ethyl -ch roman 0

N

F

0o is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-6-fluoro-2,2-dimethylchroman and propyl iodide.

Amorphous oily product.

0 ~Example 71: 4-(N-B utyl -N-ethyl s ulfonyl)a m ino-64fluoro-2,2-d imethyl -ch roman 0 *0a// N

S

0 0 0.20 i s~ o b a i e a n l g u l t o t e p o e u e i d c t d iSx m l r m 4 N etyslonlmn-6fur-22dmt3lhoa an1uy oie 61 is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-6-.fluoro22dimethylchroma and 4 4 ,4-trifluorobutyl iodide.

Amorphous oily product.

Example 73: 4 -(N-Ethylsulfonyl..N.hexyl)amino6fluoro-2, 2 -dimethyl-chroman 0 0 S% is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino6fluoro-2,2dimethylchroa and hexyl iodide.

15 Amorphous oily product.

E x a m p le 7 4 4 t y s f n l N m t y i -l u r e r m e h l e e h o a N*

S

F

a) 6-loo22ttaetyee4crmnn is obtained analogously to the procedure indicated in Example 18 b) from 5-fluoro-2hydroxyacetophenone and cyclopentanone in the presence of pyrrolidine in acetonitrile as solvent.

Amorphous brown product.

b) 6-lur-,-er tyee4c oann oxime is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro- 2 2 -tetramethyien e-4chroman one and hydroxylamine hydrochloride.

Colorless to pale brown-colored crystalline substance, 62 melting point 107 110°C.

c) 4 -Amino-6-fluoro-2,2-tetramethylenechroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6-fluoro-2,2-tetramethylene-4-chromanone oxime and work-up in the presence of hydrochloric acid, melting point: 259 261 C with decomposition.

d) 4-Ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4amino-6-fluoro-2,2-tetramethylenechroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline substance, melting point 111 113°C.

e) 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-tetramethylenechroman is obtained analogously to the procedure indicated in Example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman and methyl iodide.

Amorphous oily product.

Example 75: 4-[N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2tetramethylenechroman O 0 o// FC N S

F

O

is obtained analogously to the procedure indicated in Example 2 from 4ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman and 4, 4 ,4-trifluorobutyl iodide.

Viscous oily amorphous product.

63 Example 76: 4-[N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2pentamethylenechroman O 0 0

°S

F3C N S

F

1 a) 6 -Fluoro-2,2-pentamethylene-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from 5-fluoro-2hydroxyacetophenone and cyclohexanone in the presence of pyrrolidine in acetonitrile as solvent.

15 Pale amorphous product.

b) 6-Fluoro-2,2- pentamethylene-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro- 2,2- pentamethylene-4-chromanone and hydroxylamine hydrochloride.

Viscous amorphous product.

c) 4-Amino-6-fluoro-2,2- pentamethylenechroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6 -fluoro-2,2-pentamethylene-4-chromanone oxime and work-up in the presence of hydrochloric acid, melting point: 262-264 0 C with decomposition.

d) 4-Ethylsulfonylamino-6-fluoro-2,2-pentamethylenechroman is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4amino-6-fluoro-2,2-pentamethylenechroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.

Viscous amorphous product.

e) 4-IN-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2pentamethylenechroman 64 is obtained analogously to the procedure indicated in Example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-pentamethylenechroman and 4 4 ,4-trifluorobutyl iodide.

Amorphous oily product.

Example 77: 6-Ethyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman

O

0 o//

_N

S

0 a) 5 -Ethyl-2-hydroxyacetophenone is obtained analogously to the procedure indicated in Example 63 b) from 4ethylphenyl acetate and anhydrous, active aluminum chloride.

SSlightly yellowish-colored oil.

The 4-ethylphenyl acetate used is obtained as an oil from 4-ethylphenol and acetic is obtained analogously to the procedure indicated in Example 18 b) from 5-ethyl-2hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Pale oily amorphous product.

c) 6 -Ethyl- 2 ,2-dimethyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 6-ethyl-2,2dimethyl-4-chromanone and hydroxylamine hydrochloride.

Viscous oily amorphous product.

d) 4-Amino-6-ethyl-2,2-dimethylchroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6 -ethyl-2,2-d imethyl..4ch rom anone oxime and work-up in the presence of hydrochloric acid, melting point: 201 -204 0

C.

e) 6 -Ethyl- 4 -Nethylsufonylamino2,2-dimethylchroman is obained analogously to the procedure indicated in Example 1 c) by reaction of 4amino- 6 -ethyl-2,2-d im ethyl chroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline substance, melting point 104 108 0

C.

is obtained analogously to the procedure indicated in Example 2 from 6-ethyl-4-N- Ifonylam ino2,2-dimethyl ch roman and methyl iodide.

.:15 Colorless, crystalline product, melting point 76 77 0

C.

Example 78: 6-ty 4[N-ty uIoy- (444tilurbtl] o22 dimethylchroman 01~// F N

S

is obtained analogously to the procedure indicated in Example 2 from 6-ethyl-4-Nethyl sulfonylam in o-22-d imethyl chroman and 4,4,4-trifluorobutyl iodide.

Colorless to pale yellow-colored oil.

Example 79: 7-hoo4[-tysloy--444-rfurbtl]mn--loo22 dimethylchroman 66 0 is obtained analogously to the procedure indicated in Example 2 by reaction of 7chloro-6-fluoro-2, 2 -dimethyl-4-ethylsulfonylaminochroman with sodium hydride and 4 4 ,4-trifluorobutyl iodide.

.:...Viscous, pale yellow oil.

Example 80: 4[-tysloy--444tiloouy)aio226tiehlhoa 99*0 .15 0 a on is obtained analogously to the procedure indicated in Example 2 by reaction of 4ethyl sufnlm o226ti tyc oa with sodium hydride and 4,4,4trifluorobutyl iodide.

Viscous, pale yellow oil.

Example 81: 6, 7 -Dichloro.4[N-ethylsulfonyl-

N-(

4 4 4 -trifluorobutyl)]amino -2,2dimethylchroman f 67 is obtained analogously to the procedure indicated in Example 2 by reaction of 6,7dichloro-4-N-ethylsulfonylamino 2 2 -dimethylchroman with sodium hydride and 4,4,4-trifluorobutyl iodide.

Viscous, pale brown oil.

Example 82: 4-(N-Ethylsulfonyl-N-methyl)amino-6-phenyl-2,2-dimethyl-chroman

O

0 O N S o o I a) 015 is obtained analogously to the procedure indicated in Example 63 b) from 4acetoxybiphenyl and anhydrous, active aluminum chloride. Slightly yellowishcolored oil, which partially crystallizes. The 4 -acetoxybiphenyl used is obtained as a colorless crystalline solid from 4 -hydroxybiphenyl and acetic anhydride analogously to the procedure described in Example 63 a).

,-20 M.p. 84 86 0

C

b) 2,2-Dimethyl-6-phenyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from 2and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Dark oily amorphous product, which partially crystallizes.

c) 2,2-Dimethyl-6-phenyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 2,2dimethyl-6-phenyl-4-chromanone and hydroxylamine hydrochloride. Crystalline solid, m.p.130 134C.

68 d) 4 -Amino-2,2-dimethyl-6-phenylchroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 2,2-dimethyl-6-phenyl-4-chromanone oxime and work-up in the presence of hydrochloric acid, melting point: 213 214*C (decomposition).

e) 4-N-Ethylsulfonylamino-2,2-dimethyl-6-phenylchroman is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4amino-2,2-dimethyl-6-phenylchroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline substance, melting point 162 164 0

C.

f) 4-(N-Ethylsulfonyl-N-methyl)amino-6-phenyl-2,2-dimethylchroman is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-2,2-dimethyl-6-phenylchroman and methyl iodide.

Colorless, crystalline product, melting point 184 186 0

C.

20 Example 83: 4-[N-Ethylsulfonyl-

N-(

4 4 ,4-trifluorobutyl)]amino-6-phenyl-2,2dimethylchroman CF3 O0

N

is obtained analogously to the procedure indicated in Example 2 by reaction of 4-Nethylsulfonylamino-2,2-dimethyl-6-phenylchroman with sodium hydride and 4,4,4trifluorobutyl iodide.

Colorless to pale yellow crystalline substance, melting point 112 114 0

C.

69 Example 84: 6,8-Difluoro-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman

O

0 o "N S

F

O

a) 3 ,5-Difluoro-2-hydroxyacetophenone is obtained analogously to the procedure indicated in Example 63 b) from 2,4difluorophenyl acetate and anhydrous, active aluminum chloride.

Colorless crystalline solid, melting point 80-94 0

C.

The 2,4-difluorophenyl acetate used is obtained as a slightly yellowish-colored liquid from 2 ,4-difluorophenol and acetic anhydride analogously to the procedure described in Example 63 a).

9* 20 b) 6,8-Difluoro-2,2-dimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from difluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Dark oily amorphous product.

c) 6,8-Difluoro-2, 2 -dimethyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 6,8difluoro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride.

Crystalline solid, m.p.124-137°C.

d) 4 -Amino-6,8-difluoro-2,2-dimethylchroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6 8 -difluoro- 2 ,2-dimethyl4chromanone oxime and work-up in the presence of hydrochloric acid, melting point: 310 0 OC (sublimation from 300 0 C, 1 atm).

e) 4 -N-Ethyl sulIfonyla m ino.6, 8 -d ifl uoro-2,2-d imethyl ch roman is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4amino-6, 8 -difluoro-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THE.

Colorless crystalline substance.

Melting point 124 127 0

C.

f) 6 r N e h l uI o y N m e h l a n e h lc o a is ob ai e an l g ul9o t e p o e u e i d c t d i x m l r m 4 Coisobtaied anysalgly troutepoeueidctdixml rm4N melting point 84 86 0

C.

Example 85: 6, 8 -Difluoro-4-[N-ethylsulfonyl-

N-(

4 ,4,4-trifluorobutyl)]amino..2,2- 99* 9 dimethylchroman 01~// 9

S

F3 N

F

250 is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsu lfonylam ino-6, 8 -d ifl uoro-2,2-d imethylch roman and 4 ,4,4-trifluorobutyl iodide.

Colorless, crystalline product, melting point 127 129*C.

2 ,2-dimethylchroman

F

3

C

Cl

C

C.

C C

C.

C

C C

C.

C

C.

C C .eC 2 CC CC C p

C

a is obtained analogously to the procedure indicated in Example 2 by reaction of 6flur--yr ehl4NehluIoy-minc oa with sodium hydride and 4 4 ,4-trifluorobutyl iodide.

Colorless crystalline substance, melting point 137 140 0

C

Example 87: 6- bx--Nehl- ehlsuIoy)a no22di tyc oa 0 OH N .00 is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4- (NehlufnlNehlaio6mtoyabnl22dmtycrmn Colorless crystalline compound, melting point 217-220 0

C.

Example 88: 6-abx--NehlufnlNpoy~mn-,-iehlhoa 72 is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4- (N-ethylsu fonylNpropyl)am ino6methoxyca rbonyl22-d imethyl chroman Colorless crystalline compound, melting point 165-169 0

C.

:.Example 89: 6 -Carboxy-4(NcyclopropetylmNethylsulfoyl ~,fij).

2 2 dimethylchroman 00 0 E x m l 9 0 fr**-4 t y s lf n l N p n yl a i o 2 2 d i e h l h o a 99b0 OH

N

11 73 is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4- (N-ethylsulfonyl-N-pentyl)amino-6-methoxycarbonyl-2,2-dimethylchroman Colorless crystalline compound, melting point 156-158 0

C.

Example 91: 6-Carboxy-4-(N-ethylsulfonyl-N-hexyl)amino-2,2dimethylchroman 0^ 0

OSO

OH

N

0I0

O

is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4(N-ethylsulfonyl-N- hexyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.

Colorless crystalline compound, melting point 154-158°C.

0@

~HNS

O

0 is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4-(N-ethyl-N-ethylsuIfonyl)amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia.

Colorless crystalline substance.

Melting point 173 175 0

C.

74 Example 93: 6 -Carboxamido-4-(N ethylsulfonylNpropyl)amino- 2 2 dimethylchroman 0 is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4 -(N-ethylsulIfonyl4N-propyl)a mino22dim ethyl chromn carbonyldiimidazole and ammonia.

Colorless crystalline substance.

Melting point 185 188 0

C.

*Example 94: 6 -Carboxamido4(N-cyclopropylmethylNethylsulfonyl)amin -2,2dimethylchroman *0 0 is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4-NccorplehlNehlufnlaio22dmtycrmn carbonyldiimidazole and ammonia.

Colorless crystalline substance.

Melting point 196 199 0

C.

Example 95: 6 -Carboxamido-4-(N-ethylsulfonylNpentyl)amino 2 2 dimethylchroman 0 nN is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4 -(N-ethylsulfonykNpentyl)amino2,2dimethylchroman, abnlimdzl n ammonia.

Colorless crystalline substance.

Melting point 168 172 0

C.

Example 96: 6 -C arboxam ido-4(Nethyls u fonylNhexyl) am ino2,2d imethylchroa 0 *2 0I-12/N 00 is obtained analogously to the procedure described in Example 24 from 6-carboxy- 4 -(N-ethylsulfonyl-Nhexyl)amino22dimethychroman, carbonyldiimidazole and ammonia.

Colorless crystalline substance.

Melting point 148 152 0

C.

76 Example 97: 6 -Cyano-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethyl-chroman 0 0

S

NC

is obtained analogously to the procedure indicated in Example 25 from 6 -carboxamido-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman and subsequent purification by column chromatography on silica gel using a mixture of 10 parts of methylene chloride and 1 part of methanol as eluent.

Colorless to pale yellow crystalline substance, melting point: 127 130 0

C.

15 Example 98: 6-Cyano-4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethyl-chroman o// N 0 S 9 is obtained analogously to the procedure indicated in Example 25 from 6 -carboxamido-4-(N-ethylsulfonyl-N-propyl)amino-2,2dimethylchroman and subsequent purification by column chromatography on silica gel using a mixture of parts of methylene chloride and 1 part of methanol as eluent.

Colorless to pale yellow crystalline substance.

melting point: 127 130 0

C.

Example 99: 6-Cyano-4-(N-cyclopropylmethy-Nethylsulfonyl)amino-2,2dimethylchroman 77 0 o

N

is obtained analogously to the procedure indicated in Example 25 from 6-carboxamido-4-(N-cyclopropylmethyl-N-ethylsulfonylamino2,2-dimethylchroman S and subsequent purification by column chromatography on silica gel using a mixture of 10 parts of methylene chloride and 1 part of methanol as eluent.

*""Colorless to pale yellow crystalline substance, .i melting point: 127-130 0

C.

Example 100: 6-Cyano-4-(N-ethylsulfonyl-N-pentyl)amino-2,2dimethyl-chroman N no is obtained analogously to the procedure indicated in Example 25 from 6-carboxamido-4-(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethylchroman and subsequent purification by column chromatography on silica gel using a mixture of parts of methylene chloride and 1 part of methanol as eluent.

Viscous oily liquid.

Example 101: 6-Cyano-4-(N-ethylsuIfonyl-N-hexyl)amino-2,2-dimethylchroman 78

OS

N NC II is obtained analogously to the procedure indicated in Example 25 from 6-carboxamido-4-(N-ethylsulfonyl-N-hexyl)amino2,2dimethylchrom and subsequent purification by column chromatography on silica gel using a mixture of 10 parts of methylene chloride and 1 part of methanol as eluent.

Viscous yellow oily liquid.

Example 102: 4-(N-Ethoxycarbonylmethyl-N-ethysulfonyl)amino-6-fluoro-2,2dimethylchroman

S.

n° o pentamethylenechroman I O is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-6-fluoro-2,2-dimethylchroman and ethyl bromoacetate.

Colorless, crystalline product, melting point 112 114°C.

Example 103:4-[N-Ethylsulfonyl-N-methyl]amino-6-fluoro-2,2pentamethylenechroman O

N

1 S

NN

is obtained analogously to the procedure indicated in Example 2 from 4 -ethylsulfonylamino-6-fluoro-2,2-pentamethylenechrom and methyl iodide.

.:.and methyl iodide.

Colorless crystalline compound, .melting point 73-74°C Example 104: 4-(N-lsopropyloxycarbonylmethyl-N-ethylsulfonyl)amino-6-fluoro-22dimethylchroman 0o T^ is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino--fluoro-2,2-dimethylchroman and isopropyl bromoacetate.

Colorless to pale yellow liquid.

Example 105: 4-(N-Ethylsulfonyl-N-methyl)amino-6-methoxy-2,2-dimethylchroman

H

3 C a) 6-Hydroxy-2,2-dimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from dihydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent.

Crystalline compound, melting point 147 149C.

b) 6 -Methoxy-2,2-dimethyl-4-chromanone a suspension of 0.03 mol of 6 -hydroxy-2,2-dimethyl-4-chromanone, 75 ml of acetone and 16.1 g of anhydrous powdered potassium carbonate is treated with an excess of 3.6 ml of methyl iodide and the reaction mixture is heated at 50 55°C for 20 hours.

The solvent is removed by vacuum distillation, the residue is treated with water and the oil which separates is extracted with ethyl acetate. After drying the organic phase over anhydrous sodium sulfate, the solvent is removed by distillation and 6methoxy-2,2-dimethyl-4-chromanone is obtained as an oily liquid.

c) 6-Methoxy-2,2-dimethyl-4-chromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 6-methoxy- 2 2 -dimethyl-4-chromanone and hydroxylamine hydrochloride.

20 Crystalline solid, m.p. 108 112 0

C.

0* d) 4-Amino-6-methoxy-2,2-dimethylchroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 6-methoxy-2,2-dimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid, melting point: 250 251 C.

e) 4-N-Ethylsulfonylamino-6-methoxy-2,2-dimethylchroman is obtained analogously to the procedure indicated in Example 1 c) from 4-amino-6methoxy-2,2-dimethylchroman hydrochloride and ethansulfonyl chloride in the presence of TEA in THF.

Colorless crystalline substance, melting point 131 133 0

C.

81 f) 4-(N-Ethylsulfonyl-N-methyl)amino-6-methoxy-2,2-dimethylchroman is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-6-methoxy-2,2-dimethylchroman and methyl iodide.

Colorless, crystalline product, melting point 68 70 0

C.

Example 106: 4-N-Ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyl-oxychroman

O

IS

HN

H

3 C S 0 o o I, o a) 2 2 -Dimethyl-6-methylsulfonyloxychromanone a mixture of 0.03 mol of 6-hydroxy-2,2-dimethyl-4-chromanone, 16.1 g of anhydrous powdered potassium carbonate and 10 ml of methanesulfonic acid in 80 ml of anhydrous DMF is heated at 80°C for 10 hours. The solvent is then removed by distillation under reduced pressure and the residue is stirred, after addition of 150 ml of water, for 2 hours. The crystalline precipitate is filtered, washed several *.20 times with water and dried in a stream of air.

Colorless solid, melting point 108 110 °C b) 2,2-Dimethyl-6-methylsulfonyloxychromanone oxime is obtained analogously to the procedure indicated in Example 1 a) from 2,2dimethyl-6-methylsulfonyloxychromanone and hydroxylamine hydrochloride.

Crystalline solid, m.p. 166- 167 0

C.

c) 4-Amino-6-methylsulfonyloxy-2,2-dimethylchroman hydrochloride is obtained analogously to the procedure indicated in Example 1 b) by catalytic hydrogenation of 2,2-dimethyl-6-methylsulfonyloxychromanone oxime and work-up in the presence of hydrochloric acid, melting point: 229 231 C.

82 e) 4 -N-EthylsulIfonylam ino-2,2-dimethyl-6-methyls u fonyl oxych roman is obtained analogously to the procedure indicated in Example 1 c) from 4-amino-6methylsulfonyloxy-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.

Colorless crystalline subtance, melting point 97 1 00 0

C.

Example 107: 4-(N-Ethyl sulIfonyl-N-m ethyl) am ino-2,2-d imethy-6methylsulfonyloxychroman 0

S.

0N is obtained analogously to the procedure indicated in Example 2 from 4-Nethylsulfonylamino-2,2-d imethyl..6-methylsu lfonyl oxych roman and methyl iodide.

Colorless, crystalline product, ~:20 melting point 137 -1390C.

83 Example 108 4 (N-M ethylsu Ifonyl.N-methyl) amino-2,2,6, 7-tetramethylch roman 0 was obtained analogously to the procedure Indicated In Example 2 from 4-Nmethylsulfonylemino-2, 26, 7-tetramethylohroman and ethyllodIde.

Colorless crystals, melting point; 119-121 0 The hydrochloride of 4 -Amino-2,2,6,7-tetramethylchrotnen (melting point >270 0

C)

was prepared by hydrogenation of 2 2 ,6, 7 -tetramethyl-4..chromanone oxime (melting point 162-163*C). The oxIme was generated by known methods as described above from the corresponding 2 2 6 7 -tetramethVl-4chromanone.

Conversion of 4 -Amino-2,2,6,7-tetramethylchroman with the corresponding alkylsulfonylchlorides as described In example 1 (variant 1) resulted In methylsulfonylamino2,2,6,7-tetramethyichroman (colorless oil) and ~.:ethylsulfo n yiamlIn o-22,6, 7-tetramethyich romnan (colorless oil) respectively.

.**.Example 109 4-(N-Methysufonyl..Nmthy)amino2,2,6,7tetamethylchroman

M

was obtained analogously to the procedure indicated In example 2 from 4-Nmethylsulfonylamno-22,6, 7-tetramethylchroman and methyliodide.

Colorless crystals, melting point: 105-107 0

C.

Example 110 4-(N-Ethylsulfonyl.N-hexyl)amlno-2,26, 7 -tetremethylchroman was obtained analogously to the procedure Indicated In example 2 from 4-Nethylsulfonylamlno-2,2,6,7-tetramethylchroman and hexyllodide.

Colorless oil, Example 111: 4-(N-Ethylsuifofnyl-N-ethyl)amno-2,2,6, 7 -tetramethylchroman 4a.

*0 9

S

.9 *c a 99. -9 was obtaIned analogously to the procedure Indicated In example 2 from 4-Nethylsulfonylamlno-2,2,6,7-ttramethylchroman and ethyliodide.

Colorless crystals, melting point: 93-95 0

C.

Example 112 4-(N-Ethylsulfonyl-N-Butyl) amino-2,26,7-tetramethylch roman was obtained analogously to the procedure indicated in Example 2 from 4-N- Ethylsuifonylamino-2,2,6,7-tetramethylchroman and Butyl Iodide.

Colorless crystals, melting point: 81-830C.

Example 113: 4(N-ethyhuufonyC--mthyl~amino-2,2,7-ter

I-I

0 was obtained analogously to the procedure Indicated In example 2 from 4-Nethysulfonylamlno-2,2,6,7-tetramethylchroman and methyliodide.

Colorless crystals, meltIng point: 132-134 0

C.

Example 114: 4-(N-Ethylsulfony-N-butyl) amino- 7 -methoxy-2,2-dimethylchromen *foe 0 t se .4 *,0 0000 0,0 0 a 9 $995 .9 9*

S.

*r S.

9..

9 1*

S

was obtained analogously to the procedure indicated In'example 2 from 4-Nethylsulfonylemlno-7-methoxy-2,2-dimethyfchromen and butyl Iodide.

Colorless oil.

The hydrochloride of 4 -amino-7-methoxy-2,2-dmethylchroman (melting poInt 239 241 0 C) was prepared by hydrogenation of 7 -methoxy-2,2-dimethyI-4chromanone oxime (melting point 124- 126 0 The oxlme ws generated by known methods from the corresponding 7 -methoxy-2,2-dimethyi.4-chromanone.

Conversion of 4-Amlno-7-methoxy-2,2-dlmethylchroman with the corresponding alkyisulfonylchlorides as described In example 1 (variant 1) resulted in methylsulfonylamino-7-methoxy-2,2-dimethylchromen (colorless oil) and ethysulfonylam no-7-methoxy-2,2-dimetylchroman (melting point 111 11 3 0

C)

respectively.

Example 115 (N-Ethylsuffonyl-Nethy)amlno-7-methoxy-2,-dimethylchroman

N

0

N

0 0 was obtained analogously to the procedure Indicated in example 2 from 4-N- Ethylsufonyiamlno-7-methoXy-2,2-dimethylchroman and ethyilodide.

Colorless oil.

86 Example 116 :4 4 (N-Ethylsulfo nyl-Nm ethyl) amino7rmthoxy-2,2..dimethyich roman 0 0 0 was obtained analogously to the procedure Indicated in example 2 from 4-NethylsulfonylamIno-7-methoxy-2,2-dlmethylchroman and methyliodicle.

Colorless oil.

Example 117: 4-(N-Ethylsulfo nyl-N-methyi) amlno-6-(4,4,4-trlfluorobutyl) oxy-2, 2dimethylehroman F

N

F

was obtained analogously to the procedure indicated In Example 2 from 4-N- Ethylsulfonylamlno-6-(4,4, 4-trlfluorobutyl) oxy-2,2-dlmethylchroman and methyliodide. Colorless crystalline compound from mixture of n-heptane diisopropyi ether. Melting point 68 72 OC 4-N-Ethylsulfonylamino-6-(4,4,4.trffluorobutyl) oxy 2-dimethylehroman (melting point 84 900C) was obtained In the sequence of synthetic steps Indicated above ~.starting from 6 -h ycroxy-2,2dIm ethyl-4-ch roma none (obtained from 2acetoxyhydroqui!none and acetone, melting point 147 1490C) via 6-(4,4,4trifluoro butyl) oxy-2,2-dimethyl-4-chromanone (obtained from 6-hydroxy-2,2dimethyi- 4-chromanone and 4,4,4-trifluorobutyl Iodide, melting point 53-55 0 C) and 6-(4,4,4triflIuoro butyl) oxy-2,2-d imneth yl-4-ch roman o noxme (obtained from 6-(4,4,4trifluorobutyl) oxy-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride, melting point 94 97 12C) and 4-amino-6-(4,4,4-trifluorobutyl)oxy-2,2dimethyich roman (obtained from 6-(4,4,4-trlfluorobutyi)oxy-2, 2-dlmethyl-4.

chromanoneoxime and catalytic hydrogenation with Raney nickel, melting point 47 49 0 C) and following reaction of 4 -amlno-6-(4,4,4-trifiuorobutyl)oxy-2,2dimethylchroman and ethanesulfonyichiorlde.

Example 118: 6-(4-Bromophenyl) 4-(N-ethylsulfonyi-N-methy) amino-2,2dimethylchroman 0 0 Br NNN ""o 0 was obtained analogously to the procedure Indicated In Example 2 from 6-(4- Bromophenyi)- 4 -N-ethylsulfonylamlno-2,2-dimethylchroman and methyliodide.

Melting point 160 17010.

6-(4-Bromophenyi)- 4 -N-ethylsulfonylamino-2,2-dimethylchroman (melting point 122 135 0 C) was obtained In the sequence of synthetic steps Indicated above starting from 3-acetyl-4'bromo-4-hydroxybiphenyI (obtained from 4'-bromo-4acetoxybiphenyl and aluminum chloride by Friess rearrangement, dark brown oil) via 6-(4-bromophenyl)- 2, 2-dimethyl-4-chromanone (obtained from 3-acetyl-4'bromo-4hydroxybiphenyl and acetone, viscous oil) and 6-(4-bromophenyl)- 2,2-dimethyl-4chromanon oxime (obtained from 6 -(4-bromophenyl)- 2 ,2-dimethyl-4-chromanone, viscous oil), and 8-(4-B3romophenyl)- 4-amIno 2-dimethylchroman hydrochloride (obtained from 6-(4-bromophenyl)- 2,2-dimethyi-4-chromanon oxime and catalytic hydrogenation with Raney nickel and treatment with a solution of HCI In diethylether, melting point 166 170 00) and following reaction of 4 -amino-6-(4-Bromophenyl)- 2,2-dlmethylchroman hydrochloride and ethanesulfonylchlorlde in presence of triethylamine.

Example 119: 4-(N-Ethyisulfonyl-N-methyi)amino 2 ,2-dimethyl-6-methoxychroman 0 0I 00 wa obtaine anlgul totepoeue- niae nEaml rm4 etya*oyai ty--etoyhrmnudbty oie ools .ware obtained b anloousl mitoue poceur i-ndicyated nlExmphl 2 from oo .000 imerystle rodunbctimeltngrontogah 78S -hrla 80 lto 0*00 Example 120: The enantiomers of -thysulfonmtyl)amino6fluoro22 2,dmethylhroman and (-)-4-(N-tlNethyulfonylmt)amino-6-fluoro-2, 2dimethylohroman ((eipha]= -53.51 were obtained by racemic mixture of 4-(N-Etyl N-foylsN-tyl)amino6-fluoro2,2 dimethyichroman by chiral chromatography (CSP Chlraipak AD 250*4.6, elution solvent: n-Hexane +Ethanol: 40 Example 121: The -eatiomsulof yl mn N-thyisulfonylmiomfiorn were obtained bynagmusc mtue pofeur I-ndatedi NExhaplf2yfrmio-.iuro Eamleu fny m!o 122,6 NM timetnyl Ncsrolamundsopy 2, odtidethClohrlesn crystalline product, melting point 140 *C.

88 Example 123: 4-(N-Methylsulfonyl-N-( 3-methylbutyl)] amino) -2,2,6-trimethylchroman 0 1 ~0 s-.S

NN

0o was obtained analogously to the procedure Indicated In Example 2 from 4-Nmethylsulfonylamino-2,2,6-trmethylchroman und 3-methylb utyl Iodide. Viscous oil.

Example 124: 4-[N-Ethyiulfonyl-N-(3-ethoxypropyl)]Iamino -2,2,6-trim ethyich roman "0 N~ 8 was obtained analogously to the procedure indicated in Example 2 from 4-Nethyisulfonylamlno-2,2,6-trimethylchroman und 3-ethoxypropyl Iodide. Viscous oil.

Pharmacological investigations: sK channels from man, rat or guinea-pig were expressed in Xenopus oocytes. For this purpose, oocytes from Xenopus laevis were first isolated and defolliculated. The oocytes were then injected with 'sK encoding RNA synthesized in vitro. After 2 8 days of 'sK protein expression, 'sK currents were measured using the two microelectrode voltage clamp technique. IsK channels were in this case generally activated using voltage jumps to -10 mV lasting 15 s and the bath was rinsed through with a control solution of the following composition NaCI 96, KCI 2, CaCI218 MgCI 2 1, HEPES 5 (titrated with NaOH to pH These experiments were carried out at room temperature. The software employed for raising data and analysis was: Geneclamp amplifier (Axon Instruments, Foster City, USA) and 89 MacLab 0/A converter and software (AD Instruments, Castle Hill, Australia).

Chromanols were tested by adding them to the control solution at different concentrations. The effects of the chromanols were calculated as percentage inhibition of the IsK control flux. The data were then extrapolated using the Hill equation in order to determine the IC 50 for the respective substances. The data are given as average values with standard deviation n is the number of experiments carried out. Statistical significance was determined by means of the paired Student's t-est.

References: Busch AE, Kopp H-G, Waldegger 5, Samarzija 1, SCfIbrich H, Raber G, Kunzelmann K, Ruppersberg JP and Lang F (1995) Inhibition of both exogenously expressed 'sK and endogenous K+ channels in Xenopus oocytes by isosorbide dinitrate. J Physiol 491: 735-741 Takumi T, Ohkubo H and Nakanishi S (1989) Cloning of a membrane protein that induces a slow voltage-gated potassium current. Science 242:1042-1045 Varnum MD, Busch AE, Bond CT, Maylie J and Adelman JP (1993) The mink channel underlies the cardiac potassium current and mediates species-specific responses to protein kinase C [Proc NatI Acad Sci USA 90: 11528-11532.

%Compound IExample No. lsK 1C50 trifluorobutyl)]amino2,2dimethylchroman3304 4 utyl-N ethyl su fonyl) am in o6cyano 2 2 38 0.76 trans- 6 -Cyano.4-.(Nethylsulfonyl-N-23*6. 04 trans- 6 -cya no-4(N-.m ethyl su Ifonyl-N- 7 1. m et4Byl 19. in 1.2hdoy-,-iehy hma trans- 6 -Cyano.4-[N-(dimethylamino)sulfonyl-N 377B*) 14.6 methyl amin o]-3ydroxy22dim ethyl chrom an trans-6-Cyano4[N -butyls u fonyl)Nmethyl- 360B) 58.8 81 amino -3-h droxy-2,2-d im ethylch roman SE. Lohrmann, I. Burhoff, R.B. Nitschke, H.J. Lang, D. Mania, H.C. Englert,

M.

Hropot, R. Warth, W. Rohm, M. Bleich, R. Greger, PflOgers-Arch Eur. J. Physiol (1995) 429: 517 530.

Inhibition of gastric acid secretion, antiulcer action: Method: High pressure perfusion of the rat stomach was carried out according to the description of Berglindh and Obrink and using some modifications as reported elsewhere Rabbits (male and female, 2 3 kg) were killed painlessly under anesthesia by cervical dislocation and the stomach was perfused as reported in the S. literature The mucosa of the stomach fundus was removed using a scraper and cut into small pieces by means of scissors. The mucosal fragments thus obtained were treated with 1 mg/ml of collagenase in a medium consisting of 100 mM NaCI, mM KCI, 0.5 mM NaH 2

PO

4 1 mM Na 2

HPO

4 1 mM CaCI,, 1.5 mM MgC 2 20 mM NaHC03, 20 mM HEPES, 2 mg/ml of glucose and 1 mg/ml of rabbit albumin for 30 min at 37°C, the pH of the mixture being adjusted to 7.4 using tris buffer. The glandular tubes (gastric glands) were filtered through a nylon mesh to remove large fragments and rinsed 3 times with incubation medium. The glandular tubes were then suspended in the medium at a concentration of 2 4 mg of dry weight/ml.

*4 As a measure of the capability of the gastric glandular tubes to form acid, the accumulation of 14C-aminopyrine (14C-AP) was determined To do this, samples of 1 mi of glandular tube suspension were incubated with 1 4 C-AP (1 pM, 200,000 cpm) and the compound to be tested and treated for 20 30 min at 37 0 C in a shaking water bath. Histamine (100 pM), dbcAMP (0.3 or 1 mM) or carbachol (100 pM) were then added, followed by a second incubation period of 30 45 min. The incubation was then concluded by centrifuging the samples for half a minute. The supernatant liquid was removed and the pellets obtained were dissolved in 1 ml of NaOH. Samples of the pellets and of the liquid supernatant were measured in a scintillation counter. The AP ratio of the intraglandular and extraglandular radioactivity was calculated according to Sack and Spenney All determinations were carried out in triplicate.

91 Result: 6-Cyano-4-(n-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-3-chromanol caused a concentration-dependent inhibition of stimulated AP accumulation with ICo 0 values of 20 pM after histamine and dbcAMP stimulation, and of 5 pM after stimulation with carbachol.

References: 1. Berghlind, Obrink, K. J. A method for preparing isolated glands from the rabbit gastric mucosa, Acta Physiol. Scan. 96, 150 159 (1976) 2. Herling, A. Becht, Kelker, Ljungstrom, Bickel, Inhibition of 14

C-

'0 aminopyrine accumulation in isolated rabbit gastric glands by the H 2 -receptor antagonist HOE 760 (TZU-0460). Agents and Actions 20: 35 39 (1987) 3. Berghlind, Helander, H. Obrink, K effect of secretagogues on oxygen consumption, aminopyrine accumulation and morphology in isolated gastric glands.

Acta Physiol. Scand. 97 401 414 (1976) 4. Sack, Spenney, J. Aminopyrine accumulation by mammalian gastric glands: an analysis of the technique. Am. J. Physiol. 243: G 313 G 319 (1982).

The terms "comprise", "comprises", "comprised" and "comprising" when used in this specification are taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

S

**eee *eo

Claims

1. A chroman of the formula I R(4) 0 0 N R(6) R(2) R(7) O IR(1) S. R(8) 9* in which: R(1) and R(2) 15 independently of one another are hydrogen, CpF 2 p+,l alkyi having 1, 2, 3, 4, or 6 carbon atoms or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 methyl, methoxy, sulfamoyl, methylsulfonylamino and methylsulfonyl; 2 0 p is 1, 2 or 3; or R(1) and R(2) i together are an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R(3) is R(9)-CnH 2 n[NR(11) m R(9) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; n is zero, 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 m is zero or 1; R(11) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R(11) together with is an alkylene group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; where one CH 2 group of the group CnH 2 n can be replaced by -SOq or 93 q is zero, 1 or 2; is hydrogen, methyl or ethyl; R(4) is R(12)-CH 2 r; R(12) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CpF2p+l, pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, CI, Br, I, CF 3 methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino; r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or where one CH 2 group of the group CrH 2 r can be replaced by -CC -SOq- or 15 q is zero, 1 or 2; is hydrogen, methyl or ethyl; R(7) and R(8) S: independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1, 2, 3 or S. 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, -CN, -CF 3 -C 2 F 5 -C3F 7 -N 3 -NO 2 -CONR(13)R(14), -COOR(15), R(16)-CsH 2 s-Y- or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 methyl, methoxy, sulfamoyl and methylsulfonyl; R(13) and R(14) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; is hydrogen, methyl, ethyl, phenyl or -CuH 2 u-NR(13)R(14); u is 2 or 3; R(16) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CtF 2 t+ 1 or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 methyl, methoxy, sulfamoyl or methylsulfonyl; s is zero, 1, 2, 3, 4, 5 or 6; t is 1, 2 or 3; Y is SOq, -S0 2 -NR(10)- but where R(6) cannot be -OCF 3 or -OC 2 F 5 or its physiologically tolerable salts.

2. A chroman of the formula I as claimed in claim 1, wherein: R(1) and R(2) independently of one another are hydrogen, CF 3 alkyl having 1, 2 or 3 carbon atoms, jointly an alkylene chain having 4 or 5 carbon atoms or phenyl, ,which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 methyl, methoxy, :15 sulfamoyl and methylsulfonyl; R(3) is R(9)-CnH 2 nNR(11 R(9) is hydrogen; n is zero, 1, 2, 3, 4, 5 or 6; :m is zero or 1; 20 R(11) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R(4) is R(12)-CrH 2 r R(12) is hydrogen, cycloalkyl having 5, 6, 7 or 8 carbon atoms, CF 3 pyridyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, CI, CF 3 sulfamoyl or methylsulfonyl; r is 1 2 3, 4, 5, 6, 7, 8, 9 or where one CH 2 group of the group CrH2r can be replaced by -CO-, -CO-O- or -SOq-; q is zero, 1 or 2; S *15 a 20 R(7) and R(8) independently of one another are hydrogen, F, Cl, Br, I, alkyl having 1 or 2 carbon atoms, -CN, -CF 3 -NO 2 -CONR(13)R(14), R(16)-CsH 2 s-Y- or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl and CF3; R(13) and R(14) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; R(15) is methyl, ethyl, phenyl or-CuH 2 u-NR(13)R(14); u is 2 or 3; R(16) is hydrogen, cycloalkyl having 5 or 6 carbon atoms, CtF2t+l or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, Br, CF 3 methyl, methoxy, sulfamoyl or methylsulfonyl; t is 1, 2 or 3; s is zero, 1, 2, 3 or 4; Y is SOq, -S0 2 -NR(10)- or q is zero, 1 or 2; is hydrogen or methyl; but where R(6) cannot be -OCF 3 or -OC 2 F

3. A chroman of the formula I as claimed in claim 1 or 2, wherein: R(1) and R(2) a. R(3) R(4) independently of one another are CF 3 methyl or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 methyl, methoxy, sulfamoyl and methylsulfonyl; is alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino or diethylamino; is R(12)-CrH 2 R(12) is hydrogen, cycloalkyl having 5 or 6 carbon atoms or CF 3 r is 1, 2 3, 4, 5, 6, 7 or 8; M 9e

99.9 9 9 9 9* 9** *9*9 C. 15 *9 9 C *C9C9. where one OH 2 group of the group CrH2r can be replaced by -c0-, -00-0- or -SO q-; q is zero, 1 or 2; R(7) and R(8) independently of one another are hydrogen, F, Cl, Br, 1, alkyl having 1 or 2 carbon atoms, -ON, -NO 2 -OOOR(1 R(l 6)-CSH 2 s-Y- or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F or Cl; R(1 5) is methyl, ethyl, phenyl or -CuH 2 u-NR(1 3)R(1 4); u is 2or3; R(1 3) and R(1 4) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; R(1 6) is hydrogen, OF 3 or phenyl, s is zero, 12,3or 4; Y is SOqi -S0 2 -NR(1 or -OO-NR(1 0); q is zero, 1 or 2; R(1 0) is hydrogen or methyl; but where R(6) cannot be -00F 3 4. A chroman of the formula I as claimed in claims 1 to 3, which is selected from the group: 4-NehlufnlNmehlaio6fur-22dmtycrmn 6-y NehlsufnlNmthla o22dimehlhrm n 4-Nehl fnlNmty~ n--mtoyaroy-,- mty-homn 6-yn NehlufnlN(,,-rfu rbtl]mn -,-iehlcrm n 4-NbtlNehlufnlaio6cao22dmtycrmn 4 -(N-butyl-N-ethylsulfonyl)am ino-6fl uoro- 2 ,2-dimethyl ch roman, 4-[N-ethylsulfonyl-N-(4,4,4-rfurbtl]mn- lur-,-iehlcrm n 97 4 -(N-ethyls u fonykNh exyl)am ino6fluoro22-dim ethyl chro n 6 -ethyk-4[Nethyls ulfonylN,444trifl uorobutyl)amin mn 2 d thl h rmn A process for preparing a compound of the formula I as claimed in claim 1, which includes a) reacting a compound of the formula 11 100 in which R(7) and R(8) have the meaning indicated and L is the nucleofugic leaving group customary for an alkylation, in particular Cl, Br, 1, MeSO 2 a P-toluenesulfonyloxy radical, with a sulfonamide or its salt of the formula IlI 0 0 ~"S *N ~R(3) in which R(3) and R(4) have the meaning indicated and M is hydrogen or preferably a metal atom, particularly preferably lithium, sodium or potassium; or by 0: b) reacting a compound of the formula IV R(4) R(5) NH R(6) Z-TIV R(7) 98 in which R(7) and R(8) have the meaning indicated, with a sulfonic acid derivative of the formula V R(3) SO2-W V in which R(3) has the meaning indicated and W is a nucleofugic leaving group, such as fluorine, bromine, 1-imidazolyl, but in particular chlorine; or by c) reacting a compound of the formula VI 0 M M N SR(3) R(6) *v R* 2 R(7) O 15 RR(1) R* (8) in which R(8) and M have the meaning indicated, with an alkylating agent of the formula VII R(4)-L VII 20 in the sense of an alkylation reaction, in which with the exception of hydrogen, and L have the meaning indicated; or by carrying out d) in a compound of the formula I \N S R(3) R(6) I R(2) S R(7) R(1) R(1) R(8) in which R(1) to R(4) have the meaning indicated, an electrophilic substitution reaction in at least one position R(5) to if this position is hydrogen and the 99 remaining substituents R(5) to R(8) have the meaning indicated. 6. The use of a compound of the formula I as claimed in claim 1 for preparing a medicament for blocking the K channel which is opened by cyclic adenosine monophosphate (cAMP). 7. The use of a compound of the formula I as claimed in claim 1 for preparing a medicament for inhibiting gastric acid secretion. 8. The use of a compound of the formula I as claimed in claim 1 for preparing a medicament for the treatment of ulcers of the stomach and of the intestinal region, in particular of the duodenum. 9. The use of a compound of the formula I as claimed in claim 1 for preparing a medicament for the treatment of reflux esophagitis. The use of a compound of the formula I as claimed in claim 1 for preparing a medicament for the treatment of diarrheal illnesses. 11. The use of a compound of the formula I as claimed in claim 1 for preparing a medicament for the treatment and prevention of all types of arrhythmias, including S ventricular and supraventricular arrhythmias. 12. The use of a compound of the formula I as claimed in claim 1 for preparing a medicament for the control of reentry arrhythmias and for the prevention of sudden heart death as a result of ventricular fibrillation. 13. A therapeutic including an efficacious amount of a compound of the formula I as claimed in any one of claims 1 to 4 in combination with a pharmaceutically acceptable additive, adjuvant or carrier. 100 14. The use of a compound of the formula I a R(4) 0 0 N S -R(3) R(B) R(A) la R(C) R(2) O R(1) in which: R(A) is hydrogen, OH, -O(CO)-alkyl having 1, 2, 3 or 4 carbon atoms or -O-SO2-alkyl having 1, 2, 3 or 4 carbon atoms; R(B) is hydrogen; or R(A) and R(B) together are a bond; R(1) to R(4) are as indicated in claim 1; R(C) is CN, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms, F, Cl, Br, I, NO 2 or alkyl Shaving 1, 2, 3, 4, 5 or 6 carbon atoms for preparing a medicament for blocking the K+ channel, which is opened by cyclic adenosine monophosphate (cAMP). 0 15. The use of a compound of the formula I a as claimed in claim 14 for preparing a medicament for inhibiting gastric acid secretion. 16. The use of a compound of the formula I a as claimed in claim 14 for preparing a medicament for the treatment of ulcers of the stomach and of the intestinal region, in particular of the duodenum. 17. The use of a compound of the formula la as claimed in claim 14 for preparing a medicament for the treatment of reflux esophagitis. 18. The use of a compound of the formula la as claimed in claim 14 for a reparing a medicament for the treatment and prevention of all types of ythmias, including ventricular and supraventricular arrhythmias. 101 19. The use of a compound of the formula I a as claimed in claim 14 for preparing a medicament for the control of reentry arrhythmias and for the prevention of sudden heart death as a result of ventricular fibrillation. The use of 6-cyano-4-(N-ethylsulfonyl-N-methyl) amino-2,2-dimethyl-3- chromanol as a compound of the formula I a as claimed in claim 14 for preparing a medicament for inhibiting gastric acid secretion. 21. A method for the treatment of ulcers of the stomach and of the intestinal region, in particular of the duodenum which includes administering to a person in need of such treatment an effective amount of a compound of the formula I as claimed in claim 1. 22. A method for the treatment of reflux esophagitis which includes administering to a person in need of such treatment an effective amount of the formula of a compound of the formula I as claimed in claim 1. 23. A method for the treatment of diarrheal illnesses which includes administering to a person in need of such treatment an effective amount of a compound of the formula I as claimed in claim 1. 24. A method for the treatment and prophylaxis of all types of arrhythmias such as ventricular and supraventricular arrhythmias which includes administering to a patient in need of such treatment an effective amount of a compound of the formula I as claimed in claim 1. A method for the treatment of reentry arrhythmias and for the prevention of sudden heart death as a result of ventricular fibrillation which includes administering to a patient in need of such treatment an effective amount of a compound of the formula I as claimed in claim 1. 102 26. A method for the treatment of ulcers of the stomach and of the intestinal region, in particular of the duodenum which includes administering to a person in need of such treatment an effective amount of a compound of the formula I a as claimed in claim 14. 27. A method for the treatment and prophylaxis of all types of arrhythmias such as ventricular and supraventricular arrhythmias which includes administering to a person in need of such treatment an effective amount of a compound of the formula I a as claimed in claim 14. 28. A method for the treatment of reentry arrhythmias and for the prevention of sudden heart death as a result of ventricular fibrillation which includes administering to a patient in need of such treatment an effective amount of a compound of the formula I a as claimed in claim 14. DATED this 26th day of August 1999 HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA KJS:ALJ:MMC DOC 28 AU2080697.WPC