WO1998037083A1 - Sulphonamide-substituted thiophenes and a method for their production, their use as a medicament or diagnostic agent, as well as a medicament containing them - Google Patents

Abstract

The invention relates to sulphonamide-substituted thiophenes and a method for their production, their use as a medicament or diagnostic agent, as well as a medicament containing them. Compounds of the formula (I) are valuable in the production of medicaments for treating and preventing stimulated stomach acid secretion, stomach ulcers and the intestinal area, reflux oesophagitis; diarrhoea, all types of arrhythmia including ventricular and supraventricular arrhythmia, and reentry arrhythmia, and for preventing sudden cardiac death as a result of ventricular fibrillation.

Description

Sulfonamide-substituted thiophenes, processes for their preparation, their use as medicaments or diagnostic agents and medicaments containing them

The invention relates to compounds of the formula I.

living mean:

X -O-, -SO _NuBt ! _{or 2} - or -NR (8) -;

R (8) is hydrogen or - (C _r H _2r ) -R (9); r zero, 1, 2, 3, 4, 5, 6, 7 or to 8;

R (9) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, wherein pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; where a CH ₂ group of the group C _r H _2r can be replaced by -O-, -CH = CH-, -CsC-, -CO-, -CO-O-, -SO _{zero or 2} - or -NR ( 10) -; R (10) is hydrogen, methyl or ethyl; R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or 1} -;

R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ , C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where one of the CH ₂ groups of the group C _n H _{2n is} replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _NuK ! _{or 2} - or -NR (10) - can be replaced; R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡ C-, -CO-, -CO-O-, -SO _Nullι ., _{Or 2} - or -NR (10) - can be replaced; R (4) R (13) -C ₃ H _2s ;

R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonyiamino ; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; where a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C _≡ C-, -CO-, -CO-O-, -SO _nullι ., _{or 2} - or -NR (10) -; or R (3) and R (4) together form an alkylene group with 3, 4, 5, 6, 7 or 8 carbon atoms, a CH 2 group of the alkylene group being represented by -O-, -SO _{NuM 1 or 2} -, -CO- or -NR (10) - can be replaced;

R (5) H, OH, Cl, F, Br, NR (10), alkoxy with 1, 2, 3 or 4 carbon atoms or alkyl with

1, 2, 3, or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms -Atoms, alkylsulfonyl with 1,

2, 3, 4, 5 or 6 carbon atoms or NR (10); and their physiologically tolerable salts.

Preference is given to compounds of the formula I in which: X denotes -O-, -SO _Nullt , _{or 2} - or -NR (8) -;

R (8) is hydrogen or - (C _r H _2r ) -R (9); r zero, 1, 2, 3, 4, 5, 6, 7 or to 8;

R (9) is hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , CF ₅ , C ₃ F ₇ ; where a CH ₂ group of the group C _r H _2r can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _{Nullι or 2} - or - NR (10) -; R (10) is hydrogen, methyl or ethyl; R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or 1} -; R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ ,

C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein a CH2 group of the alkylene group C _n H _{2n can be} replaced by -O-, SO _Nu n _{or 2} -, -CO- or -NR (10) -;

R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡ C-, -CO-, -CO-O-, -SO _{Null) or 2} - or -NR (10) - can be replaced; R (4) R (13) -C ₃ H _2s ;

R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; where a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO ^., _{or 2} - or -NR (10) -; or R (3) and R (4) together form an alkylene group having 3, 4, 5, 6, 7 or 8 carbon atoms, a CH 2 group of the alkylene group being represented by -O-, -SO _Nu n., _or 2 "'-CO- or -NR (10) - can be replaced; R (5) H, OH, Cl, F, Br, NR (10), alkoxy with 1, 2, 3, or 4 carbon atoms or alkyl with 1, 2, 3, or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3 or 4 carbon atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10); and their physiologically tolerable salts.

Compounds of the formula I are particularly preferred in which:

X -0- or -SO _{Nu |} , _{1 or 2} -;

R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or r} ;

R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ ,

C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein a CH2 group of the alkylene group C _n H _{2n can be} replaced by -O-, SO _{Nuü or 2} -, -CO- or -NR (10) -;

R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡ C-, -CO-, -CO-O-, -SO _Nullι ., _{Or 2} - or -NR (10) - can be replaced; R (4) R (13) -C ₃ H _2s ; R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; where a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _NuBι -, _{or 2} - or -NR (10) -; or R (3) and R (4) together form an alkylene group with 3, 4, 5, 6, 7 or 8 carbon atoms, with a CH 2 group of the alkylene group being represented by -O-, -SO _Nuü ^ _or 2 "_>"CO- or -NR (10) - can be replaced; R (5) H, OH, Cl, F, Br, NR (10), alkoxy with 1, 2, 3 or 4 carbon atoms or alkyl with

1, 2, 3, or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3 or 4 carbon atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10); and their physiologically tolerable salts.

Compounds of the formula I are very particularly preferred in which:

X -O-;

R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together an alkylene group with 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or r} ;

R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ ,

C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein a CH2 group of the alkylene group C _n H _{2n can be} replaced by -O-, SO _Nu n _{1 or 2} - or -NR (10) -;

R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡ C-, -CO-, -CO-O-, -SO _{Nullι or 2} - or -NR (10) - can be replaced; R (4) R (13) -C ₃ H _2s ;

R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and Methylsulfonylamino; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; where a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _Nullι ^ _{or 2} - or -NR (10) -; or R (3) and R (4) together form an alkylene group having 3, 4, 5, 6, 7 or 8 carbon atoms, a CH 2 group of the alkylene group being replaced by -O-, -SO _{Nuj | to er 2} -, -CO- or -NR (10) - can be replaced; R (5) H, OH, Cl, F, NR (10), alkoxy with 1, 2, 3 or 4 carbon atoms or alkyl with 1, 2, 3 or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3 or 4 carbon atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10); and their physiologically tolerable salts.

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 can be used, for example, as alkali salts, preferably 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, maleinates, fumarates, malates , Gluconates etc. If the compounds I contain an acidic and basic group in the same molecule, in addition to the salt forms described, internal salts, so-called betaines, also belong to the invention.

If the substituents of the compounds I contain groups with different stereochemical possibilities, the individual possible stereoisomers also belong to the invention, so that in the case of optical isomerism the individual pure enantiomers and any mixtures of these optical isomers are part of the invention.

Alkyl and alkylene radicals can be straight-chain or branched.

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

How to obtain a compound of formula I by a) a compound of formula II

worin R(1), R(2), R(5), R(6), R(7) und X die angegebene Bedeutung besitzen und L eine übliche nucleofuge Fluchtgruppe, insbesondere F, Cl, Br, I, MeSθ2-O-, einen p-Toluolsulfonyloxy-Rest, oder R(5) und L einen Epoxidring bilden, bedeutet, mit einem Sulfonamid oder dessen Salz der Formel III

wherein R (1), R (2), R (5), R (6), R (7) and X have the meaning given and L is a customary nucleofugic escape group, in particular F, Cl, Br, I, MeSO 2 -O -, a p-toluenesulfonyloxy radical, or R (5) and L form an epoxy ring, means with a sulfonamide or its salt of the formula III

implemented in a manner known per se, in which R (3) and R (4) have the meaning indicated and M represents hydrogen or preferably a metal atom, particularly preferably lithium, sodium or potassium;

or that b) a compound of formula IV

worin R(1 ), R(2), R(4), R(5), R(6), R(7) und X die angegebene Bedeutung besitzen, mit einem Sulfonsäure-Derivat der Formel V

wherein R (1), R (2), R (4), R (5), R (6), R (7) and X have the meaning given, with a sulfonic acid derivative of formula V

umsetzt, worin R(3) die angegebene Bedeutung besitzt und W eine nucleofuge Fluchtgruppe, wie Fluor, Brom, 1 -Imidazolyl, insbesondere aber Chlor bedeutet;

implements in which R (3) has the meaning given and W is a nucleofugic leaving group such as fluorine, bromine, 1-imidazolyl, but especially chlorine;

or that c) a compound of formula VI

worin R(1 ), R(2), R(3), R(5), R(6), R(7), X und M die angegebene Bedeutung besitzen, in an sich bekannter Weise mit einem Alkyl ierungsmittel der Formel VII

wherein R (1), R (2), R (3), R (5), R (6), R (7), X and M have the meaning given, 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 R (4) with the exception of hydrogen and L have the meaning given;

or that d) in a compound of formula I

worin R(1 ) bis R(5) und X die angegebene Bedeutung besitzen, in mindestens einer der Positionen R(6) und R(7) des Thiophenringsystems eine elektrophile Substitutionsreaktion durchführt, sofern diese Position Wasserstoff bedeutet und der andere der Substituenten R(6) und R(7) die angegebene Bedeutung besitzt.

wherein R (1) to R (5) and X have the meaning given, carries out an electrophilic substitution reaction in at least one of the positions R (6) and R (7) of the thiophene ring system, provided that this position is hydrogen and the other of the substituents R ( 6) and R (7) has the meaning given.

Procedure a) describes the reaction of a sulfonamide or one of its salts of the formula III by means of a reactive heterocycle of the formula II. Since the reaction of a sulfonamide III takes place from the salt form, when using a free sulfonamide (formula III, M = H) a sulfonamide salt (formula III, M = cation) can be produced by the action of a base, which is characterized by higher nucleophilicity and thus by higher reactivity. If free sulfonamide (M = H) is used, the sulfonamide is deprotonated to the salt in situ using preferred bases which are themselves not or only slightly alkylated, such as sodium carbonate, potassium carbonate, a sterically hindered amine, e.g. B. dicyclohexylamine, N, N, N-dicyclohexyl-ethylamine or other strong nitrogen bases with low nucleophilicity, for example DBU, N, N ', N ^, "-Triisopropylguanidin etc. However, other commonly used bases can be used for the reaction, such as potassium tert-butoxide, sodium methylate, alkali metal bicarbonates, alkali metal hydroxides such as LiOH, NaOH or KOH, or alkaline earth metal hydroxides, for example Ca (OH) 2-

It is preferably carried out in polar organic solvents such as dimethylformamide, dimethylacetamide, tetramethyl urea, hexamethylphosphoric triamide, tetrahydrofuran, dimethoxyethane, toluene, a halogenated hydrocarbon such as chloroform or methylene chloride etc. In principle, however, it is also possible to work in polar protic solvents, such as water, methanol, ethanol , Isopropanol, ethylene glycol or its oligomers and their corresponding shark ethers and ethers. The reaction is carried out in a preferred temperature range from -10 to 140 ° C, particularly preferably from 20 to 100 ° C. Procedure a) can also be carried out in a favorable manner under the conditions of a two-phase catalysis.

durch Einwirkung eines anorganischen oder organischen Peroxides, wie beispielsweise H₂O₂, Metachlorperbenzoesäure, Peressigsäure. Die Anlagerung von Halogen/Hydroxy ist auch durch die Reaktion der Verbindung X mit NCS, NBS, Chlor oder Brom in wäßrigen Lösungsmitteln möglich.The compounds of the formula II are obtained by methods known from the literature, for example from the corresponding unsaturated compounds of the formula X.

by the action of an inorganic or organic peroxide, such as H ₂ O ₂ , metachloroperbenzoic acid, peracetic acid. The addition of halogen / hydroxy is also possible by the reaction of compound X with NCS, NBS, chlorine or bromine in aqueous solvents.

It is advantageous to work in a solvent which is sufficiently inert to these halogenating, high-energy reagents, such as, for example, in DMSO or a halogenated hydrocarbon, e.g. in chloroform, methylene chloride.

Procedure b) describes the known and frequently used reaction of a reactive sulfonyl compound of the formula V, in particular a chlorosulfonyl compound (W = Cl), with an amino derivative of the formula IV to give the corresponding sulfonamide derivative of the formula I. The reaction can in principle be carried out without Solvents are carried out, but in most cases such reactions are carried out using a solvent.

The reaction is preferably carried out using a polar solvent, preferably in the presence of a base which itself can advantageously be used as a solvent, for example when using triethylamine, in particular pyridine and its homologues. Solvents also used are, for example, water, aliphatic alcohols, for example methanol, ethanol, isopropanol, sec. Butanol, ethylene glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA, as well as TMU and HMPT. The process is carried out at a temperature of from 0 to 160 ° C., preferably from 20 to 100 ° C. The amino derivatives of the formula IV are obtained in a manner known per se, preferably by reacting the reactive compounds of the formula II with R (1), R (2), R (5), R (6) and L in the meaning given, either with ammonia or an amine of formula XI

R (4) -NH ₂ XI with R (4) in the meaning given.

Procedure c) represents the known alkylation reaction of a sulfonamide or one of its salts VI with an alkylating agent of the formula VII. According to the reaction analogy with procedure a), the reaction conditions already described in detail under procedure a) apply to procedure c). The preparation of the sulfonamide derivatives VI and their precursors has already been described in procedure b). The alkylating agents VII are prepared according to the analogous instructions in the literature or as described under procedure a), preferably from the corresponding hydroxy compounds (formula VII with L equal to -OH).

Procedure d) describes the further chemical conversion of the invention

Compounds of formula I in other compounds of formula I by electrophilic

Substitution reactions in one or more of the positions denoted by R (6) and R (7), each of which is hydrogen.

Preferred substitution reactions are

1. the aromatic nitration for introducing one or more nitro groups, and their subsequent reduction to NH2,

2. aromatic halogenation, in particular for the introduction of chlorine, bromine or iodine,

3. the chlorosulfonation to introduce a chlorosulfony group by the action of chlorosulfonic acid,

4. the Friedel-Crafts acylation reaction to introduce an acyl radical with 1, 2, 3, 4, 5 or 6 carbon atoms or an alkylsulfonyl radical with 1, 2, 3, 4, 5 or 6 carbon atoms by the action of the corresponding acid chlorides in Presence of a Lewis acid as Friedel-Crafts catalyst, preferably from anhydrous aluminum chloride.

The compounds I are related to the class of 4-acylaminochroman derivatives, in particular 2,2-dialkyl-4-acylamino-3-chromanols, which has been intensively worked on in pharmaceutical chemistry in the last decade. The most prominent representative of such 4-acylaminochromanes is the cromakalim of formula XII

und zahlreiche, sich von diesem Präparat ableitenden Folgepräparate, z. B. Edwards and Weston, TIPS 11 , 417-422 (1990), "Structure Activity Relationships of K⁺ Channel openers".

and numerous follow-on preparations derived from this preparation, e.g. B. Edwards and Weston, TIPS 11, 417-422 (1990), Structure Activity Relationships of K ⁺ Channel openers.

Cromakalim and other related 4-acylaminochroman derivatives are compounds with a relaxing effect on smooth muscle organs, so that they are used to lower the increased blood pressure due to vascular muscle relaxation and in the treatment of asthma due to the relaxation of the smooth muscles of the airways. All these preparations have in common that they act on the cellular level, for example of smooth muscle cells, and there lead to the opening of certain ATP-sensitive K ⁺ channels. The increase in negative charge induced in the cell by the emergence of K ⁺ ions ("hyperpolarization") acts via secondary mechanisms of increasing intracellular Ca2 ⁺ and thus cell activation, e.g. B. a muscle contraction.

In contrast to these 4-acylaminochroman derivatives, which, as mentioned, were identified as opening the ATP-sensitive K ⁺ channel, the compounds of the formula I according to the invention with the 4-sulfonylamino structure surprisingly show a strong and specific blocking (closing) effect on a K ⁺ Channel that is opened by cyclic adenosine monophosphate (cAMP) and is fundamentally different from the K ⁺ (ATP) channel mentioned. Rather, recent studies show that this K ⁺ (cAMP) identified on the large intestine Channel is most likely identical to the IsK channel identified on the heart muscle. As a result of this blocking of the K ⁺ (cAMP) channel (= IsK channel), the compounds develop pharmacological effects of high therapeutic utility in the living organism.

The compounds are characterized as a new class of active ingredients, potent inhibitors of stimulated gastric acid secretion. The compounds of the formula I are therefore valuable medicaments for the treatment of gastric and intestinal ulcers, for example the duodenum. Due to their strong gastric secretion-inhibiting effect, they are also suitable as excellent therapeutic agents for the treatment of reflux oesophagitis.

The compounds are furthermore distinguished by an antidiarrheal effect and are therefore suitable as medicaments for the treatment of diarrheal diseases.

Furthermore, the compounds I can be used as medicaments for the treatment and prevention of all types of arrhythmias, including ventricular and supraventricular arrhythmias. In particular, they can be used to control reentry arrhythmias and to prevent sudden cardiac death due to ventricular fibrillation.

There are now publications in which a correlation between the IsK channel inhibitory effect and the suppression of life-threatening cardiac arrhythmias is described, such as those triggered by ß-adrenergic hyperstimulation (e.g. BTJ Colatsky, CH Follmer and C .F. 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; AE Busch, K. Malloy, WJ Groh, MD Varnum, JP Adelman and J. Maylie; "The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit l _s κ Channels in xenopus oocytes and in guinea pig cardiac myocytes", Biochem. Biophys. Res. Commun. (1994) 202: 265-270) . In addition to the above-mentioned cromakalim or acylaminochroman derivatives, compounds having a 4-sulfonylaminochroman structure have also been described in the literature in the course of the last few years which differ significantly from the compounds of the formula I either in structure or in biological action . For example, European Offenlegungsschrift 0 315 009 describes chroman derivatives with a 4-phenylsulfonylamino structure which are distinguished by antithrombotic and anti-allergic properties.

The European published documents 389 861 and 370 901 describe 3-hydroxy-chroman derivatives with 4-sulfonylamino group, which are described on the one hand as K ⁺ (ATP) channel activators or are said to have effects on the central nervous system. Such effects have not been found by us for the compounds of the mentioned invention. For example, we have synthesized and investigated a number of compounds that fall under the claims of the two aforementioned publications. For the 3-hydroxy-substituted chromanes we investigated, no activation of the K ⁺ (ATP) channel was found, but a blockade of the ^ (cAMP) or the IsK channel (Pflügers Arch. - Eur. J. Physiol. ( 1995) 429: 517-530. A new class of inhibitors of cAMP-mediated Cl- secretion in rabbit colon, acting by the reduction of cAMP- activated K + conductance).

U.S. Patent 5,284,857 describes thienopyran derivatives bearing a sulfonamide substituent at position 4. However, the compounds are characterized as K (ATP) channel openers. This publication also describes R (4) equal to hydrogen and R (3) equal to phenyl, which are not included in our patent.

Medicaments which contain a compound I according to the invention can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred application depending on the particular appearance of the disease. The compounds I can be used alone or together with pharmaceutical auxiliaries, both in veterinary medicine and in human medicine. The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulation on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers or colorants can be used.

For an oral form of use, the active compounds are mixed with the suitable additives, such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by the usual methods, such as tablets, dragées, push-fit capsules, aqueous, alcoholic or oily solutions. As inert carriers such. As gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used. The preparation can take place both as dry and as moist granules. Vegetable or animal oils, such as sunflower oil or cod liver oil, are suitable as oily carriers or as solvents.

For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired with the usual substances such as solubilizers, emulsifiers or other auxiliaries. As solvents such. B. in question: water, physiological saline or alcohols, e.g. As ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for. B. solutions, suspensions or emulsions of the active ingredient of formula I 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 Contain propellant. Such a preparation usually contains the active ingredient in a concentration of approximately 0.1 to 10, in particular approximately 0.3 to 3% by weight.

The dosage of the active ingredient of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; but also on the type and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dose of a compound of the formula I in a patient weighing approximately 75 kg is at least 0.001 mg, preferably at least 0.01 mg, in particular at least 0.1 mg, up to at most 1 g, preferably up to at most 100 mg, in particular up to 10 mg per kg body weight.

Explanation of the abbreviations used in the text

DMA dimethylacetamide

HMPT hexamethylphosphoric triamide

TMU tetramethyl urea hr hour (s)

M mole mM millimole min minutes

TEA triethylamine

THF tetrahydrofuran

NCS N-chlorosuccinimide

NBS N-bromosuccinimide

DMSO dimethyl sulfoxide

Claims

claims 1. Compounds of the formula

in which mean: X -O-, -SO _{NulU or 2} - or -NR (8) -; R (8) is hydrogen or - (C _r H _2r ) -R (9); r zero, 1, 2, 3, 4, 5, 6, 7 or to 8; R (9) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, wherein pyridyl, thienyl, imidazolyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; where a CH ₂ group of the group C _r H _2r can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _{NuM> 1 or 2} - or -NR (10) -; R (10) is hydrogen, methyl or ethyl; R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or 1} -; R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ , C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where one of the CH ₂ groups of the group C _n H _2n by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _Nu „ _{1 or 2} - or - NR (10) - can be replaced; R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡ C-, -CO-, -CO-O-, -SO _NuB> , _{or 2} - or -NR (10) - can be replaced; R (4) R (13) -C ₃ H _2s ; R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; where a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _{nullι or 2} - or - NR (10) -; or R (3) and R (4) together form an alkylene group with 3, 4, 5, 6, 7 or 8 carbon atoms, where a CH2 group of the alkylene group is represented by -O-, -SO _{Nui | 1 or} 2 "'~ CO- or -NR (10) - can be replaced; R (5) H, OH, Cl, F, Br, NR (10), alkoxy with 1, 2, 3, or 4 C- Atoms or alkyl with 1, 2, 3 or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms -Atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10); and their physiologically tolerable salts. 2. Compounds of formula I according to claim 1, in which: X is -O-, -SO _Nu „ _f , _{or 2} - or -NR (8) -; R (8) is hydrogen or - (C _r H _2r ) -R (9); r zero, 1, 2, 3, 4, 5, 6, 7 or to 8; R (9) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 C atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F _5l C ₃ F ₇ ; where a CH ₂ group of the group C _r H _2r can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _{zero or 2} - or - NR (10) -; R (10) is hydrogen, methyl or ethyl; R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or 1} -; R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ , C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where a CH2 ~ group of the alkylene group C _n H _2n by -O-, SO _{Nu) |} ^ _{or 2} -, -CO- or -NR (10) - can be replaced; R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡C -, -CO-, -CO-O-, -SO _Nul , _{1 or 2} - or -NR (1 can be translated; R (4) R (13) -C ₃ H _2s ; R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; wherein a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _{Nuüι 1 or 2} - or -NR (10) -; or R (3) and R (4) together form an alkylene group with 3, 4, 5, 6, 7 or 8 carbon atoms, a CH 2 group of the alkylene group being defined by -O-, -SO _Nu n _{o er 2} ^_ . -CO- or -NR (10) - can be replaced; R (5) H, OH, Cl, F, Br, NR (10), alkoxy with 1, 2, 3 or 4 carbon atoms or alkyl with 1, 2, 3, or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3 or 4 carbon atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10). 3. A compound of formula I according to claims 1 or 2, in which: X -0- or -SO _{zero 1 or 2} -; R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or r} ; R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ , C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein a CH2 group of the alkylene group C _n H _{2n can be} replaced by -O-, SO _Nu n., _or 2 "-CO- or -NR (10) -; R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡ C-, -CO-, -CO-O-, -SO _{Nullι or 2} - or -NR (10) - can be replaced; R (4) R (13) -C ₃ H _2s ; R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; where a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _Null ., _{or 2} - or -NR (10) -; or R (3) and R (4) together are an alkylene group with 3, 4, 5, 6, 7 or 8 carbon atoms, where a CH2 ~ group of the alkylene group can be replaced by -O-, -SO _{Nuü 1 or 2} - _> -CO- or -NR (10) -; R (5) H, OH, Cl, F, Br, NR (10), alkoxy with 1, 2, 3 or 4 carbon atoms or alkyl with 1, 2, 3, or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3 or 4 carbon atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10). 4. A compound of the formula I as claimed in claim 1, in which: X -O-; R (1) and R (2) independently of one another are hydrogen, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C _n H _2n [NR (12)] _{zero or 1} -; R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF ₃ , C ₂ F ₅ or C ₃ F ₇ ; n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; where a CH2 group of the alkylene group C _n H _2n by -O-, SO _{Nui | 1 or 2} - or -NR (10) - can be replaced; R (12) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or R (11) together with R (12) is an alkylene group with 4, 5, 6, 7 or 8 carbon atoms, one of the CH ₂ groups of the alkylene group being replaced by -O-, -CH = CH-, -C≡ C-, -CO-, -CO-O-, -SO _Nullι ., _{Or 2} - or -NR (10) - can be replaced; R (4) R (13) -C ₃ H _2s ; R (13) hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF ₃ , C ₂ F ₅ , C ₃ F ₇ , Pyridyl, thienyl, imidazolyl or phenyl, in which pyridyl, thienyl, imidazolyl or phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino ; s 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; where a CH ₂ group of the group C _s H _2s can be replaced by -O-, -CH = CH-, -C≡C-, -CO-, -CO-O-, -SO _Null ., _{or 2} - or -NR (10) -; or R (3) and R (4) together form an alkylene group with 3, 4, 5, 6, 7 or 8 carbon atoms, where a CH2 group of the alkylene group is represented by -O-, -SO _Nuüj ., _or 2 ' ~ CO ~ or -NR (10) - can be replaced; R (5) H, OH, Cl, F, NR (10), alkoxy with 1, 2, 3 or 4 carbon atoms or alkyl with 1, 2, 3 or 4 carbon atoms; R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3 or 4 carbon atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10). 5. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for blocking the K ⁺ channel which is opened by cyclic adenosine monophosphate (cAMP). 6. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for inhibiting gastric acid secretion. 7. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of ulcers of the stomach and intestinal area, in particular the duodenum. 8. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of reflux esophagitis. 9. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of diarrheal diseases. 10. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment and prevention of all types of arrhythmias including ventricular and supraventricular arrhythmias. 1 1. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment and prevention of all types of arrhythmias including atrial arrhythmias. 12. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the control of reentry arrhythmias and for the prevention of sudden cardiac death due to ventricular fibrillation. 1 3. Medicament containing an effective amount of a compound of formula I according to any one of claims 1 to 4.