SK283837B6 - Sulphonamide substituted chromane derivatives, method for their preparation, their use as medicaments or diagnostic agents as well as medicaments containing them - Google Patents

Abstract

Chromans of formula (I) and their salts are new: where R(1), R(2) = H, fluoroalkyl, 1-6C alkyl, optionally substituted phenyl; or R(1) and R(2) = 2-10C alkyl chain; R(3) = substituted alkylsulphonamide; R(4) = substituted 1-20C alkyl; R(5), R(6), R(7), R(8) = H, halogen, 1-4C alkyl, 3-8C cycloalkyl, CN, CF3, C2F5, C3F7, N3, NO2, amido, ester, substituted alkyl-sulphone, -ketone, -amine, -ether, or -amide, optionally substituted phenyl; where R(6) 9 OCF3 or OC2F5. Also claimed are compounds of formula (Ia): where R(A) = H, OH, O(CO)-(1-4C alkyl), O(SO2)-(1-4C alkyl); R(B) = H; or R(A) and R(B) = a bond; R(1) -R(4) = as for (I);and R(C) = CN, 1-6C aryl, F, Cl, Br, I, NO2, 1-6C alkyl.

Description

The invention relates to sulfonamide-substituted chromates, to processes for their preparation, to their use as a medicament or diagnostic agent, as well as to medicaments containing them.

BACKGROUND OF THE INVENTION

The compounds of the above formulas (I) and (Ia) are related to a group of 4-acylaminochroman derivatives, extensively studied in the last decade in drug chemistry, in particular 2,2-dialkyl-4-acylamino-3-chromanols.

The most prominent representative of such 4-acylaminochromanates is cromakalim of formula (XII)

and many subsequent preparations derived therefrom (e.g., Edwards and Weston, T1PS 11, 417-422 (1990), "Structure Activity Relationships of 1C channel openers").

Cromakalim and other related 4-acylaminochroman derivatives are compounds with a relaxant effect on smooth muscle, so that they can be used to lower elevated blood pressure by relaxation of vascular muscles and to treat asthma by relaxation of airway smooth muscle. Common to all these preparations is that they act at the cellular level, for example, smooth muscle cells, where they lead to the opening of certain ATP-sensitive potassium channels (K ⁺ channels). The increase in the negative charge in the cell (hyperpolarization) induced by potassium ion excretion acts by secondary mechanisms against increasing intracellular Ca ²⁺ and thereby against cell activation, for example muscle contraction.

Existing publications in which is described the correlation between inhibitory effect on _de l potassium channel and preventing cardiac arrhythmias life-threatening, such as, for example, caused by β-adrenergic hyperstimulation include, for example Colatsky TJ, CH Follmer and CF 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 Vamum, JP Adelman, and J. Maylie; "The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit _de l channels in Xenopus oocytes and I _FCS in guinea pig cardiac myocytes", Biochem. Biophys. RCS. Commun. (1994) 202: 265-270.

In addition to the cromakalime or acylaminochroman derivatives mentioned above, compounds having a 4-sulfonylaminochroman structure have also been described in the literature in the past years which clearly differ in structure or biological action from the compounds of formula (I) according to the invention and compounds of formula (Ia). European Publication No. 315,009 discloses chromate derivatives having 4-phenylsulfonylamino groups which possess antithrombotic and antiallergic properties.

European Publication No. 370 901 discloses 3-hydroxychroman derivatives with 4-phenylsulfonylamino in which the remaining valency of the nitrogen atom carries a hydrogen atom. These compounds are, for basic groups, differently substituted from the compounds of formula (I) or (Ia). Correspondingly, for these compounds, effects on the central nervous system are described in European Publication 370 370, so that these compounds also differ in pharmacological terms.

European Patent Publication 389,861 discloses 3-hydroxychroman derivatives having 4-sulfonylamino. The benzopyran derivatives described in this European publication are activators. or openers of so-called adenosine triphosphate (K ⁺ (ATP) -channel) sensitive potassium channels. As is known, the pharmacological effects of látok, '(ΑΤΡ) -channel opening agents are quite different from the IsK-channel blocking agents described herein. Thus, K ⁺ (ATP) channel opening agents have been shown to have typical vasodilatory properties and blood pressure lowering properties. The authors of the synthesized K ⁺ (ATP) channel opener described above have, as expected, typical, special antiarrhythmic properties for this potassium channel opening mechanism. In the basic work published by Lucchesi et al. (J. Cardiovasc. Pharmacol. 15, 452-464 (1990)), it is conclusively shown that K ⁺ (ATP) channel opening agents do not act antiarrhythmically on an oxygen-deficient heart or sudden ischemia, but even have life-threatening profibrilatory effects. These dangerous conditions occur due to a shortening of the repolarization time caused by activation of the K ⁺ (ATP) channels. In contrast to these life-threatening profibrilatory effects of K ⁺ (ATP) channel opening agents on the ill, poorly supplied heart, K ⁺ (cAMP) -channel blockers are expected to have anti-fibrillatory action under these conditions. As a prominent representative of the now synthesized compounds of formula (Ia), it has so far found its way into the latest literature 6-cyano-4- (n-ethylsulfonyl-N-methyl) amino-2,2-dimethyl-3-chromanol under the designation 293B, as an example a highly specific blocker of 1 _pc - or 1 _sk- channels with a corresponding increase in heart action potential (Soubrich et al., Naunyn Schiedebergs Ar. Pharm. (1996) 353 (4, Supplement), R72; Pflugers Ar. - Eur. J. Physiol 431 (6) (Supplement), A. Busch et al., Pflugers ARCH - Eur J. Physiol 432 (6) (Supplement), 1094-1096 (1996).

On the basis of special structural knowledge, some compounds which are known from the aforementioned publication (ΈΡ-0 389 861), but which have not been described, synthesized or their therapeutic effect, have now been synthesized and investigated. Surprisingly, these special, now prepared and investigated 3-hydroxysubstituted chromates have found effective K ⁺ (cAMP) -channel blocking (Pflugers Árch. - 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) and inhibition of I _k5- channels on the heart. Treatment of 3-hydroxy-substituted chromates blocking the _IL-Channel I, but is clearly less marked than for the corresponding chromate of the formula (I) not containing a hydroxyl group.

In 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, special trifluoromethyl-substituted 4-sulfonylaminochroman derivatives are described which, however, unlike the structurally different K ⁺ (cAMP) -channel blockers, have a biologically different pharmacological action and thus other therapeutic uses.

In addition, spiro [2H-1-benzopyran-2,4'-piperidines] with an essential basic side group such as MK-499 ("Cardiac electrophysiology and antiarrhythmic actions of two long-acting spirobenzopyran piperidine class III") have also been described in the prior art agents, L. 702 958 and L-706 000 (MK 499) "J. Pharmakol. Exp. Ther. (1994) 269: 541-554; TJ Colatsky and TM Argentieri," Potassium channel blockers as antiarrhythmic drugs ", Drug Develop Res (1994) 33: 235-249).

These "spirobenzopyran-piperidine group III agents" have been quite clearly characterized in the literature as to their mode of action (PS Spector, ME Curran, MT Keating, MC Sanguinetti, Circulation Res. (1996) 78: 499-503; JJ Lynch et al. (J. Pharmacol. Exp. Ther. (1994) 269: 541-554). It has been unambiguously described and shown in the literature that the antiarrhythmic action of these compounds is due to the inhibition of the HERG channels and the rapidly activatable component of the delayed K ⁺ channel rectifier (Ikr channel). Therefore, spirobenzopyranpiperidines are characterized as being a proarrhythmic component with a risk of increased mortality compared to placebo, as demonstrated in this Sword study for this class of active substances. This is in clear contrast to the compounds of the invention, which have the advantage of blocking the slow (activatable) component of the delayed K ⁺ -rectifier (I-channel) and which therefore do not have this proarrhythmic component.

SUMMARY OF THE INVENTION

The invention relates to chromates of the general formula (I)

^(I) wherein R ¹ and R ² each independently represent a hydrogen atom, a C 1 F 3 β + 1 group, an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms or a phenyl group which is unsubstituted or substituted one or two substituents selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy, sulfamoyl, methylsulfonylamino and methylsulfonyl, and p is 1, 2 or 3, or R ¹ and R ² together form an alkylene chain with

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 represents a hydrogen atom or a cycloalkyl group s

3, 4, 5, 6, 7 or 8 carbon atoms, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, m is 0 or 1, and

R ¹¹ represents a hydrogen atom or an alkyl group having 1, 2, 3,

Or R ¹¹ together with R ⁹ form an alkylene group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, with one CH ₂ in C _n H _2n being replaced by an oxygen atom, -SO _q, or -NR ¹⁰ , q is 0, 1 or 2;

R ¹⁰ represents a hydrogen atom, a methyl group or an ethyl group,

R ⁴ is R ^{L 2} -C _r H _2r,

R ¹² represents a hydrogen atom, a cycloalkyl group having 3,4,

5, 6, 7 or 8 carbon atoms, piperidyl, 1-py rolidinylovú, N-morpholino, N-metylpiperazinoskupinu, a C _p F _{2p + b} pyridyl, thienyl, imidazolyl or phenyl, which is unsubstituted or substituted with one or two substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino, ar is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein one CH ₂ in the C 1 H _{2 R} group may be replaced by an oxygen atom, -C = C-, -C = C-, -CO-, -CO-O-, -SO _q - or -NR ¹⁰ -, q is 0, 1 or 2, and

R ¹⁰ represents a hydrogen atom, a methyl group or an ethyl group and R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or an alkyl group having 1, 2 , 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, cyano, trifluoromethyl, a group -C2F5, -C3F7, -N 3, -NO 2, -CONR ¹³ R ^14, -COOR ^{15, R16} -CsH _2s -Y- or phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, I, trifluoromethyl, 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 H, methyl, ethyl, phenyl or -C _u H _2u -NR ¹³ R ¹⁴ , u is 2 or 3,

R ¹⁶ represents hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, -COOR ¹⁵ , thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl , N-morpholino, N-methylpiperazino, C1F4 + j or phenyl which is unsubstituted or substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, methyl group, methoxy group , a sulfamoyl group and a methylsulfonyl group, s having a value of 0, 1,2, 3, 4, 5 or 6, t having a value of 1,2 or 3, and

Y is SO _q, -CO-, -SO ₂ -NR ¹⁰ -, -O-, -NR ¹⁰ or -CO-NR ^10, wherein R ⁶ can not represent a group -OCF ₃ or -OC ₂ F _5, and their physiologically acceptable salts.

Preferred are the compounds of formula (I) in which R ^{@ 1} and R ^{@ 2 are} each independently hydrogen, trifluoromethyl, alkyl having 1, 2 or 3 carbon atoms, together forming an alkylene chain having 4 or 5 carbon atoms, or in each case represents a phenyl group which is unsubstituted or substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, methyl group, methoxy group, sulfamoyl group and methylsulfonyl group,

R ³ represents a group R ⁹ -C _n H _{2 n} [NR '

R ⁹ represents a hydrogen atom, n is 0, 1, 2, 3, 4, 5 or 6, m is 0 or 1, and

R ( ¹¹⁾ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,

R ⁴ is R ^12, -C _r H _2r,

R ¹² represents a hydrogen atom, a cycloalkyl group having 5, 6, 7 or 8 carbon atoms, a trifluoromethyl group, a pyridyl group or a phenyl group which is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, trifluoromethyl, sulfamoyl and methylsulfonyl, and ar is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein one CH ₂ in the C 1 H _{2 r} group may be replaced by an oxygen atom, -CO- , -CO-O- or -SO, -, q is 0, 1 or 2, and R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, fluorine, chlorine, bromine , iodine, alkyl having 1 or 2 carbon atoms, cyano, trifluoromethyl, nitro, CONR ¹⁴ R ^I3, -COOR ^{15, R 6} -C _p H _2s -Y- or phenyl, which is unsubstituted or substituted with one substituent selected from s boron consisting of F, Cl and CF; R ¹³ and R ¹⁴ independently of one another are hydrogen or alkyl having 1, 2 or 3 C atoms,

R ¹⁵ is methyl, ethyl, phenyl or -C _u H _2u -NR ¹⁴ R ^I3, at a value of 2 or 3,

R ¹⁶ represents a hydrogen atom, a cycloalkyl group having 5 or 6 carbon atoms, a group or a phenyl group which is unsubstituted or substituted by one substituent selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy, sulfamoyl and methylsulfonyl, t is 1, 2 or 3, s is 0, 1, 2, 3 or 4,

Y is SO _q , -CO-, -SO ₂ -NR ¹⁰ -, -O-, -NR ¹⁰ or -CO-NR ¹⁰ -, q is 0, 1 or 2, and

R ¹⁰ represents a hydrogen atom or a methyl group, but R ⁶ cannot be -OCF ₃ or -OC ₂ F ₅ , and physiologically acceptable salts thereof.

Particularly preferred are compounds of formula (I) wherein R ¹ and R ^{2 are} each independently trifluoromethyl, methyl or phenyl which is unsubstituted or substituted by one or two substituents selected from the group consisting of fluorine, chlorine , a bromine atom, an iodine atom, a trifluoromethyl group, a methyl group, a methoxy group, a sulfamoyl group and a methylsulfamoyl group,

R ³ is alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino or diethylamino, R ⁴ is R ^12, -C _r H _2r,

R ¹² is hydrogen, cycloalkyl having 5 or 6 carbon atoms or a trifluoromethyl group, ar is 1, 2, 3, 4, 5, 6, 7 or 8, wherein one CH ₂ group CJH _2, may be replaced an oxygen atom, a -CO- group. -CO-O- or -SO _q -, q is 0, 1 or 2 and R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, fluorine, chlorine, bromine, atom I, alkyl having 1 or 2 carbon atoms, acylamino cyano, nitro, -COOR ^15, R ^l6 -C _s H _2s -Yalebo phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F and Cl,

R ( ¹⁵⁾ is methyl, ethyl, phenyl, or -C (H2 ₎ -NR ( ¹³⁾ R ( ¹⁴⁾ , u is 2 or 3, R ( ¹³⁾ and R ( ¹⁴⁾ independently of one another are hydrogen or alkyl having 1; , 2 or 3 carbon atoms,

R ¹⁶ represents a hydrogen atom, a trifluoromethyl group or a phenyl group having a value of 0, 1, 2, 3 or 4,

Y is SO _q , -CO-, -SO ₂ NR ¹⁰ , -O-, NR ¹⁰ - or -CO-NR ¹⁰ , q is 0, 1 or 2 and R ¹⁰ is hydrogen or methyl, but with R ⁶ cannot be -OCF ₃ , and physiologically acceptable salts thereof.

Particularly preferred are the following compounds of formula (1): 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman, 6-cyano-4- (N-ethylsulfonyl-N-methyl) ) amino-2,2-dimethylchroman, 4- (N-ethylsulfonyl-N-methyl) amino-6-methoxycarbonyl-2,2-dimethylchroman,

6-cyano-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman, 4- (N-butyl-N-ethylsulfonyl) amino-6-cyano-2, 2-dimethylchroman, 4- (N-ethylsulfonyl-N-methyl) amino-2,2,6-trimethylchroman,

7-Chloro-4-N (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman, 6,7-dichloro-4- (N-ethylsulfonyl-N-methyl) amino-2,2 -dimethylchroman, 4- (N-butyl-N-ethylsulfonyl) amino-6-fluoro-2,2-dimethylchroman, 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-tetramethylchroman, 4 - [N-Ctylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-dimethylchroman, 4- (N-ethylsulfonyl-N-hexyl) amino-6-fluoro-2,2 -dimethylchroman and 6-ethyl-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman.

When the compounds of formula (f) contain an acidic or basic group or an optionally basic heterocycle, the invention also relates to the corresponding pharmacologically and toxicologically acceptable salts. Thus, compounds of formula (1) containing one or more carboxyl groups can be used, for example, in the form of alkali metal salts, preferably sodium or potassium salts. The compounds of formula (I) which contain a basic protonable group or a basic heterocyclic radical can also be used in the form of their pharmacologically and toxicologically acceptable addition salts with organic or inorganic acids, for example in the form of hydrochlorides, metasulfonates, acetates, lactates, maleates, fumarates , malate, glucanate, etc. When the compounds of formula (I) contain an acidic or basic moiety in a single molecule, the invention also includes, within the scope of the present invention, internal salts, so-called betaines.

When substituents of the compounds of formula (I) and optionally also of formula (Ia) contain groups permitting different stereochemistry, the possible stereoisomers are also included within the scope of the invention. The compounds of formula (I) or (Ia) optionally contain a chiral center at the 4-position of the chromate system, and the invention thus includes individual pure optical antipodes as any mixtures of optical isomers.

The compounds of formula (I) may be prepared by a variety of chemical methods, which also form part of the invention.

The compound of formula (I) is obtained by:

(a) a compound of formula (II)

in which R ^{@ 1} , R ^{@ 2} , R ^{@ 3} , R @ ⁴ , R @ ⁵ , R @ ⁶ , R @ ⁷ and R @ ^{8 are} as defined above and L is a nucleofugue leaving group customary for alkylation, especially chlorine, bromine, iodine, The CH ₃ SO ₂ -O- or p-toluenesulfonyloxy radical is reacted in a known manner with the sulfonamide of the general formula (III) or its salts

M in which R ³ and R ⁴ as above, but with the symbol RH substituent R ⁴ may also have a value of 0, and M is H or preferably a metal equivalent, particularly preferably lithium, sodium or potassium, or by the

(b) a compound of formula (IV)

_(iv) wherein the symbols R ^1, R ^2, R ^4, R ^5, R ^6, R ⁷ and R ⁸ are as defined above, wherein, the symbol RH substituent R ⁴ may also have a value of 0, is reacted with a sulfonic acid derivative of formula (V)

R ³ -SO ₂ -W (V), wherein R ³ is as defined above and W represents a nucleofunctional leaving group such as a fluorine atom, a bromine atom or a 1-imidazolyl group, in particular a chlorine atom, or

c) a compound of formula (VI)

R 5 1 \ N R3 1 R 'x zA T! Γ A RJ IN °> 1

Where R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ and M have the meanings given, they are subjected in an art-known manner to an alkylation reaction with an alkylating agent of formula (VII)

R ⁴ -L (VII), wherein R ⁴ is as defined with the exception of a hydrogen atom and L is as defined or

d) in a compound of formula (I)

R \ W W R 5 ^with R 3

wherein the symbols R ¹ to R ⁴ are defined as above, effected by electrophilic substitution reaction in at least one of the positions of R ⁵ to R ^8, wherein the substituent at this position is hydrogen and the remaining substituents R ⁵ to R ⁸ are defined as above.

Process a) describes the known alkylation of sulfonamides or a salt thereof of formula (III) with an alkylating chromate derivative of formula (II). As the alkylation of the sulfonamide proceeds from the salt form, the free sulfonamide (compound of formula (III) where M is hydrogen) must be prepared by treatment with a base by treatment with a base of the sulfonamide (compound of formula (III) where M is a cation). higher nucleophilia and also higher reactivity. When the free sulfonamide (M is hydrogen) is used, deprotonation of the sulfonamide to form the salt in situ takes place, preferably with bases which are not alkylated or alkylated only, such as sodium carbonate, potassium carbonate, a highly sterically protected amine, for example dicyclohexylamine, Ν, Ν, d-dicyclohexylethylamine or other strong, low nucleophile nitrogenous bases such as DBU (1,8-diazabicyclo [5,4,0] undec-7-ene), N, N ', N'-triisopropylguanidine etc. The reaction may also be carried out by other commonly used bases such as potassium tert-butoxide, sodium methoxide, alkali metal bicarbonates, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or alkaline earth metal hydroxides, e.g. calcium.

Preferably, the reaction is carried out in aprotic polar solvents such as dimethylformamide, dimethylacetamide, tetramethylurea, hexamethylphosphoric triamide, tetrahydrofuran, etc. However, in principle, it is also possible to work in polar protic solvents such as water, methanol, ethanol, isopropanol, ethylene glycol or its ethylene glycol. their corresponding semi-ethers and ethers. The reaction is preferably carried out in a temperature range of from 20 to 140 ° C, particularly preferably between 40 and 100 ° C. More preferably, the method may be

a) carry out under the conditions of two-phase catalysis. Compounds of formula (II) are obtained by methods known in the literature, for example from the corresponding alcohols (compounds of formula (III) wherein L is hydroxy) by treatment with hydrogen halide HL (where L represents chlorine, bromine or iodine) or by inorganic treatment. acid halide (POC1 _3, PC1 _3, PCl _5, SOC1 _2, sobre ₂₎ or a radical halogenation of the corresponding chroman derivatives (formula (II), wherein L = H) with elemental chlorine or bromine, or the radical-activatable halogenating agents such as is N-bromosuccinimide (NBS) or SO ₂ Cl ₂ (sulfuryl chloride), in the presence of a radical-inducing action, such as an energy-rich light visible or ultraviolet wavelength range, or using a radical-inducing chemical such as azodiisobutyronitrile.

Process b) describes a known and frequently used reaction of an activated sulfonyl compound of formula (V), in particular a chlorosulfonyl compound (W represents a chlorine atom), with an amine of formula (IV) to give the corresponding sulfonamide derivative of formula (I). The reaction may in principle be carried out without a solvent, but reactions of this type are in most cases carried out using a solvent.

The reaction is preferably carried out using a polar solvent, preferably in the presence of a base which can be used alone as the solvent, for example using triethylamine, pyridine and its homologues. Preferred solvents are, for example, water, aliphatic alcohols such as methanol, ethanol, isopropanol, sec-butanol, ethylene glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, dioxane, dialkylated amides such as dimethylformamide, dimethylacetamide and tetramethylurea (TM). and hexamethylphosphoric triamide (HMPT). The reaction is carried out at a temperature of 0 to 160 ° C, preferably 20 to 100 ° C.

The amines of formula (IV) are obtained in a manner known per se from the literature, preferably from the corresponding carbonyl compound of formula (X)

R5 A R ^S x R2 (X). Rľ ' R8

wherein the symbols R ^1, R ^2, R ^5, R ^6, R ⁷ and R ^a are as defined above and A is oxygen, either using ammonia or an amine of formula (XI)

R ⁴ -NH ₂ (XI) wherein R ⁴ is as defined above, but wherein the symbol for R ⁴ may also be 0 under reducing catalytic conditions, preferably at a higher temperature in the autoclave. At first, the condensation reaction of a ketone of formula (X) (wherein A is oxygen) and the amine (XI) in situ formed Schiff's base of formula (X) wherein A is R ⁴ -N =, which is then directly without isolation, it is converted to the amine of formula (IV). Accordingly, we can prepare and isolate Schiff's base (a compound of formula (X) wherein A is R ⁴ -N =) formed as an intermediate in this reaction, followed by separation in a separate step using a suitable reducing agent such as sodium borohydride, lithium aluminum hydride or sodium cyanoborohydride, or by catalytic hydrogenation to convert the compound of formula (IV). Compounds of formula (IV) in which R ⁴ represents a hydrogen atom may advantageously be obtained by methods known in the literature by reduction of oximes or oximeters (compounds of formula X wherein A is RO-N =) or hydrazones (compounds of formula) (X), wherein A represents a group R ¹⁸ R ¹⁹ NN =) using a complex metal hydride or catalytic hydrogenation. The required oximes and hydrazones are preferably readily prepared in a manner known per se from the ketones of formula (X) (wherein A is oxygen) by reaction with hydrazine or a derivative thereof, or, for example, with hydroxylamine hydrochloride under conditions where water is split off.

Process c) describes, as in process a), the known alkylation reaction of the sulfonamide or its salt of formula (VI) with an alkylating agent of formula (VII). According to this reaction analogy, the reaction conditions already described in detail for process a) apply to process c).

The preparation of the sulfonamide derivative of general formula (VI) and its intermediates has already been described in process b). The preparation of the alkylating agent of formula (VII) is carried out according to literature procedures, optionally as described in process a), preferably from the corresponding hydroxy compound (of formula VII, wherein L is hydroxy).

Process d) describes a further chemical conversion of the compounds of formula (I) according to the invention into other compounds of formula (I), an electrophilic substitution reaction at one or more positions bearing R ⁵ to R ⁸ , which in each case represent a hydrogen atom. Preferred substitution reactions are:

1. nitration on the aromatic ring to introduce one or more nitro groups as well as their subsequent reduction to amino groups,

2. halogenation on the aromatic ring especially for the introduction of chlorine, bromine or iodine;

3. chlorosulfonation to introduce a chlorosulfonyl group by treatment with chlorosultonic acid;

4. the Friedel-Crafts acylation reaction to introduce an acyl radical R-CO- ^L6 -C5H2s or a sulfonyl radical R ¹⁶ -CsH _{2s -SO2} - by treatment of the corresponding acid chloride R ¹⁶ -CsH2s-CO-C 1, or R _{2 s} -CsH ^L6 - SO ₂ -CI in the presence of a Lewis acid as Friedel-Crafts catalyst, preferably anhydrous aluminum chloride.

In contrast to said 4-acylaminochroman derivatives, which have been found to be ATP-sensitive potassium channel opener, as shown above, the compounds of formula (I) according to the invention or compounds of formula (Ia) have

(la) in which:

R ^A is hydrogen, hydroxy, -O (CO) -alkyl of 1, 2, 3 or 4 carbon atoms in the alkyl moiety or -O-SO ₂ -alkyl of 1, 2, 3 or 4 carbon atoms, R ^b represents a hydrogen atom.

or R ^A and R ^B together form a bond, R ¹ to R ⁴ have the meanings indicated and

R ^c is cyano, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group or alkyl group having 1, 2, 3, 4, 5 or 6 surprisingly, a strong and specific blocking action on the potassium channel, which is opened by cyclic adenosine monophosphate (cAMP) and is fundamentally different from said K ⁺ (ATP) -channel. The new investigation rather show that this K ⁺ (cAMP) channel identified in the large intestine appears to be very similar or even identical to the I _channel-sk identified in the cardiac muscle. Due to this blocking of the K (cAMP) -channel (= I _sk -channel), these compounds have a pharmacological action in the living organism with a higher therapeutic utility.

The preparation of compounds of formula (Ia) from suitable 3,4-epoxychromans by reaction with sulfonamides of formula (III) has been described by Lohrmann et al., Pfliigers Árch. - Eur. J. Physiol. (1995) 429: 517-530.

The compounds of formula (I) or (Ia) are, as a new class of active compounds, potent inhibitors of stimulated gastric acid secretion. The compounds of formula (I) or (Ia) are therefore valuable drugs for the treatment of gastric and intestinal ulcers, for example the duodenum. Because of their strong inhibitory action on gastric juice secretion, they are as well suited as excellent drugs for the treatment of reflux esophagitis.

The compounds of formula (I) or (Ia) are further characterized by anti-diarrheal action and are therefore useful as medicaments for the treatment of diarrhea.

Furthermore, the compounds of formula (I) or (Ia) can be used as medicaments for the treatment and prevention of all types of arrhythmias, including atrial, ventricular and supraventricular arrhythmias. They can be used in particular to control rcentry arrhythmias and to prevent sudden cardiac death due to ventricular fibrillation.

The present invention is also the use of compounds of formula (Ia) for the treatment of sudden cardiac death, ventricular fibrillations and generally of arrhythmias of the heart of the patient, involving the I _p -channel.

The compounds of formula (I) or (Ia) can also be combined with other active ingredients for advantageous therapeutic action. Thus, for the treatment of cardiovascular diseases, combinations with cardiovascular active agents are preferably conceivable. Suitable anti-arrhythmic agents, for example group I, II or III anti-arrhythmic agents, such as so-called antiarrhythmic agents, are suitable for use in combination for the treatment of cardiovascular diseases. IKr-channel blockers such as dofetilide, blood pressure lowering agents such as ACE-inhibitors (angiotensin converting enzyme inhibitors such as enalapril, captopril, ramipril), angiotensin antagonists, potassium channel activators as well as α- and β-receptor blockers, and as well as sympathomimetic and adrenergic compounds, Na ⁺ / H ⁺ exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other positive inotropic agents such as digitalisglycosides and diuretics.

Furthermore, a combination with antibiotic agents and anti-ulcer agents such as H2-antagonists (ranitidine, cimetidine, famotidine, etc.) may be advantageous, as in particular for use in the treatment of gastric and intestinal diseases.

Drugs containing a compound of formula (I) or a compound of formula (Ia) of the invention may be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred route of administration being dependent on the immediate clinical picture of the disease. The compounds of formula (I) or (Ia) can be used alone or together with galenic auxiliaries, both in veterinary and in human medicine.

The person skilled in the art is familiar on the basis of his expert knowledge with which excipients are suitable for the desired drug formulation. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, solubilizers or colorants can be used.

For the preparation of an oral dosage form, the active compounds of formula (I) or (Ia) are mixed with suitable excipients, such as carriers, stabilizers or inert diluents, and formulated into suitable dosage forms, such as tablets, by conventional means, dragees, push-fit capsules or aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch. The preparation can also take place by dry or wet granulation. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, a solution, suspension or emulsion is prepared from the active compounds of formula (I) or formula (Ia), optionally together with suitable substances such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerol, and in addition, sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned. Oligosaccharides such as cyclodextrin are used, for example, as solubilizers.

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 (Ia) in a pharmaceutically acceptable solvent, in particular ethanol or water, or in a mixture of such solvents. If desired, the formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation usually contains the active ingredient in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3% by weight.

The dosage of the active compound of the formula (I) or (Ia) to be administered and the frequency of dosing depend on the potency and duration of action of the compounds used, as well as the type and severity of the disease to be treated and sex, age, weight and individual responses. the mammal being treated.

On average, the daily dose of a compound of formula I in a patient weighing about 75 kg is at least 0.1 mg, preferably 10 mg to at most 100 mg, preferably at most 1 g, in the case of compounds of formula Ia at least 1 mg, preferably 50 mg, up to a maximum of 300 mg, preferably 1 g.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 4- (N-Ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman o

a) 2,2-Dimethyl-4-chromanone oxime

The reaction mixture prepared from 10 mmol of 2,2-dimethyl-4-chromanone and 12 mmol of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine is heated to 80-85 ° C for 2 hours with stirring, the solvent is distilled off on a rotary evaporator. and the oily residue is crystallized with water. The product is a crystalline solid having a melting point of 115-118 ° C.

b) 4-Amino-2,2-dimethylchroman hydrochloride

A solution of 10 mmol of 2,2-dimethyl-4-chromanone oxime in 75 ml of methanol was hydrogenated in an autoclave with hydrogen at 60 ° C and 10 MPa for 6 hours after addition of Raney nickel as a catalyst. After filtration and distillation of the solvent, the amorphous residue is dissolved in ethyl acetate and diethyl ether saturated with hydrogen chloride gas is added until a strongly acidic reaction is obtained. The crystalline precipitate of 2,2-dimethyl-4-aminochroman hydrochloride is filtered off, washed several times with ethyl acetate and dried. Colorless crystals, m.p. 268 ° C.

The title compound is obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2-dimethylchroman and benzyl bromide, as colorless crystals, m.p. 95-97 ° C.

c) 4-N-Ethylsulfonylamino-2,2-dimethylchroman

Variant 1: To a stirred solution prepared from 4.3 mmol of 4-amino-2,2-dimethylchroman hydrochloride, 15 mL of tetrahydrofuran and 1.25 mL of triethylamine was added portionwise at 0 ° C a solution of 4.5 mmol of ethanesulfonic acid chloride. in 5 ml of tetrahydrofuran. The mixture is stirred for about 2 hours at 0 ° C and for a further one hour at room temperature, the precipitate is filtered off and the solvent is distilled off on a rotary evaporator. The oily residue is crystallized using petroleum ether. The product is colorless crystals having a melting point of 106-108 ° C.

Option 2: To a suspension of 1.06 g (0.005 mol) of 4-amino-2,2-dimethylchroman hydrochloride and 2.0 g (0.02 mol) of triethylamine in 25 ml of dimethylacetamide was added at a temperature between 0 and 5 ° C. 0.83 g (0.0065 mol) of ethanesulfonic acid chloride was added in portions and the mixture was stirred for 2 days at room temperature. After the solvent has been distilled off on a rotary evaporator, water is added and the separating oil crystallizes after a short time. Mp 106-109 ° C.

d) 4-N-Ethylsulfonyl-N-methylamino-2,2-dimethylchroman

To a sodium methoxide solution prepared from 0.0166 mol of sodium in 20 ml of anhydrous methanol is slowly added a solution of 0.0111 mol of 4-N-ethylsulfonylamino-2,2-dimethylchroman in 15 ml of anhydrous methanol. To this mixture was then added portionwise a solution of 0.014 mol of methyl iodide in 5 ml of anhydrous methanol, and the mixture was heated to reflux at 50 ° C for 6 hours. The solvent was distilled off on a rotary evaporator, the residue was treated with ethyl acetate and extracted with 2N sodium hydroxide. The organic phase is dried over anhydrous sodium sulphate and the solvent is distilled off again to give 4-N-ethylsulfonyl-N-methylamino-2,2-dimethylchroman as a colorless crystalline substance, m.p. 90-92 ° C.

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

To a suspension of 0.0122 mol of sodium hydride in 30 ml of anhydrous dimethylacetamide was added portionwise 0.0111 mol of 4-N-ethylsulfonylamino-2,2-dimethylchroman under stirring in an argon atmosphere and stirred for an additional hour at room temperature. Ethyl bromide (0.0122 mol) was then added and the mixture stirred for an additional 24 hours at room temperature. The solvent was distilled off under reduced pressure, then ethyl acetate was added to the residue and extracted with water. After separation and drying over anhydrous sodium sulfate, the organic phase is distilled off on a rotary evaporator. Crystallization using petroleum ether gave 4-N-ethylamino-N-ethylsulfonyl-2,2-dimethylchroman as a colorless crystalline solid, m.p. 85 ° C.

Example 3

4- (N-benzyl-N-ethylsulfonyl) amino-2,2-dimethylchroman

Example 4

4- [N-Ethylsulfonyl-N- (2-dimethylaminoethyl)] amino-2,2-dimethylchroman o

I

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2-dimethylchroman and 2-chloroethyldimethylamine hydrochloride using twice the amount of sodium hydride as colorless crystals, m.p. 90-93 ° C.

Example 5

4-N-Ethylsulfonylamino-2,2-dimethyl-6,8-dinitrochróman

At -15 to -20 ° C, 3.71 mmol of 4-N-ethylsulfonylamino-2,2-dimethylchroman is added portionwise with stirring, and the mixture is stirred for an additional 20 minutes while cooling. The reaction mixture is poured into 50 ml of ice-water, then 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 ethanol and 7 parts ethyl acetate as the eluent and then crystallized using petroleum ether. The product is a yellow crystalline compound with a melting point of 140-142 ° C.

Example 6

4-N-Ethylsulfonylamino-2,2-dimethyl-6-nitrochroman o

To a mixture of 3.71 mmol of 4-N-ethylsulfonylamino-2,2-dimethylchroman in 2.54 mL of acetic acid at -20 ° C was added portionwise 0.54 mL of 100% nitric acid and stirred for an additional 5 minutes at -20 ° C. The reaction mixture is poured into 50 ml of ice-water, the violet-colored precipitate is filtered off and washed several times on the filter with cold water. The crystals were dissolved in a small amount of ethyl acetate and chromatographed on silica gel using a mixture of 3 parts petroleum ether and 2 parts ethyl acetate as eluent. The product is light yellow crystals having a melting point of 198 to 201 ° C.

Example 7

4- (N-ethyl-N-ethylsulfonyl) amino-2,2-dimethyl-6-nitrochroman

The title compound was obtained in analogy to Example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-nitrochroman and ethyl bromide, as pale yellow crystals, m.p. 180-185 ° C.

Example 8 4- (N-Ethylsulfonyl-N-methyl) amino-2,2-dimethyl-6-nitrochroman

The title compound was obtained in analogy to Example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-nitrochroman and methyl iodide, as pale yellow crystals, m.p. 190-192 ° C.

Example 9 6-Amino-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman hydrochloride

The title compound is obtained by catalytic hydrogenation of 7.21 mmol of 4-N-ethylsulfonyl-N-methylamino-2,2-dimethyl-6-nitrochromate with hydrogen gas in 150 ml of methanol using Raney nickel as catalyst until the theoretical amount of hydrogen is taken up. within about 1.5 hours at 100 kPa. After filtration and evaporation of the solvent, the amorphous residue is dissolved in ethyl acetate and the product is purified by adding a saturated solution of hydrogen chloride gas in diethyl ether to precipitate the hydrochloride. The product is colorless crystals with a melting point of 75-78 ° C.

Example 10 6-Amino-4- (N-ethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman hydrochloride

The title compound was obtained in an analogous manner to that described in Example 9 from 4-N-ethyl-N-ethylsulfonylamino-2,2-dimethyl-6-nitrochroman by catalytic hydrogenation using Raney-nickel as colorless crystals, m.p. - 100 ° C.

Example 11 4-N- (Dimethylaminosulfonyl) amino-2,2-dimethylchroman

To a suspension of 4 mmol of 4-amino-2,2-dimethylchroman hydrochloride in 75 mL of anhydrous tetrahydrofuran was added a solution of 0.03 mmol of triethylamine in 30 mL of dimethylacetamide. The mixture is stirred for about 30 minutes at room temperature and a solution of 12 mmol of Ν, Ν-dimethylsulfamoyl chloride in 10 ml of anhydrous tetrahydrofuran is added dropwise to the suspension while cooling to about 10 ° C. After removal of the cooling bath, the mixture was stirred at room temperature for an additional 24 hours. The solvent is then distilled off on a rotary evaporator and the residue is stirred in water, whereupon crystallization occurs after some time. After filtering off the crystals and washing with water, 4-N- (dimethylamino) sulfonylamino-2,2-dimethylchroman is obtained as colorless crystals, m.p. 77-79 ° C.

Example 12 4-N-Methyl-N- (dimethylaminosulfonyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 2 from 4-N- (dimethylaminosulfonyl) amino-2,2-dimethylchroman and methyl iodide, as colorless crystals, m.p. 146-148 ° C.

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

a) 4-Fluorophenyl acetic acid is obtained as an oily residue by boiling 4-fluorophenol in acetic anhydride followed by evaporation of the solvent.

b) 5-Fluoro-2-hydroxyacetophenone is obtained from 0.0376 moles of 4-fluorophenyl acetic acid and 0.083 moles of anhydrous aluminum chloride (for Friedel-Crafts reactions) by heating at 120 ° C for 2-3 hours followed by the addition of ice water after cooling. The mixture is extracted with ethyl acetate, after drying over sodium sulfate, the solvent is distilled off and the amorphous viscous residue is crystallized using cyclohexane. The product is obtained in the form of a colorless crystalline substance, m.p. 46-47 ° C.

c) 6-Fluoro-2,2-dimethyl-4-chromanone was obtained in analogy to Example 18b) from 5-fluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine as a colorless to yellowish amorphous residue.

d) 6-Fluoro-2,2-dimethyl-4-chromanone oxime was obtained in analogy to Example 1a) from 6-fluoro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride. Crystallization of the product using water and recrystallization from cyclohexane using activated carbon gave colorless crystals of m.p. 108-110 ° C.

e) 4-Amino-6-fluoro-2,2-dimethyl-4-chroman-hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation in an autoclave from 6-fluoro-2,2-dimethyl-4-chromanone oxime Raney nickel and water, in the form of colorless crystals, m.p. 226 ° C, sublimating at a temperature of 296 ° C.

f) 4-N-Ethylsulfonylamino-6-fluoro-2,2-dimethylchroman

To a suspension of 5 mmol of 4-amino-6-fluoro-2,2-dimethyl-4-chroman hydrochloride in 20 ml of dimethylacetamide and 15 mmol of triethylamine was added 5.5 mmol of ethanesulfonic acid chloride with stirring and cooling to 10 ° C. After stirring for an additional 24 hours at room temperature, the solvent was then distilled off on a rotary evaporator and the residue was stirred in 75 ml of water. The oil which separated was extracted with ethyl acetate, the ethyl acetate extract was separated and dried over anhydrous sodium sulfate. After distilling off the solvent on a rotary evaporator, 4-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman is obtained as an amorphous product.

Example 14

4- (N-Ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and methyl iodide as an amorphous oily product.

Example 15

6-Fluoro-4-N- (dimethylaminosulfonyl) amino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 11 from 4-amino-6-fluoro-2,2-dimethylchroman and Ν, Ν-dimethylsulfamoyl chloride in colorless dimethylacetamide, as colorless crystals, m.p. 86-88 ° C. .

Example 16 6-Fluoro-4- [N-methyl-N- (dimethylaminosulfonyl)] amino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that in Example 2 from 6-fluoro-4-N- (dimethylaminosulfonyl) amino-2,2-dimethylchroman and methyl iodide, as an amorphous oily product.

Example 17 6-Cyano-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman

a) 6-Cyano-2,2-dimethylchroman

A suspension formed from 10 mmol of 6-cyano-2,2-dimethyl-3,4-chromate, 50 ml of methanol and about 500 mg of palladium catalyst on sulfur sulphate (10%) is shaken in a shaking duck under a hydrogen atmosphere at 100 kPa and at 20 ° C until the theoretical amount of hydrogen has been taken. After filtering off the catalyst, the solvent was distilled off on a rotary evaporator to give 6-cyano-2,2-dimethylchroman as a colorless to slightly yellowish oil.

b) 4-Bromo-6-cyano-2,2-dimethylchroman

To a solution of 10 mmol of 6-cyano-2,2-dimethylchroman in 30 ml of carbon tetrachloride was added 11 mmol of N-bromosuccinimide and 0.22 g of azodiisobutyronitrile (from Aldrich), and the suspension thus obtained was heated under reflux for 3 hours. The insoluble succinimide is then filtered off, the solvent is distilled off and the residue is crystallized using a mixture of n-hexane and diisopropyl ether. The product is obtained in the form of pale yellow crystals having a melting point of 93-94 ° C.

c) 6-Cyano-4- [N-ethylsulfonyl-N-methyl] amino-2,2-dimethylchroman

To a suspension of 11 mmol of sodium hydride (as an 80% oil suspension) in 5 ml of anhydrous dimethylacetamide was added dropwise a solution of 11 mmol of ethanesulfonic acid N-methylamide and stirred for about 1 hour at room temperature under argon. A solution of 4 mmol of 4-bromo-6-cyano-2,2-dimethylchroman in 7 ml of anhydrous dimethylacetamide is then added and the mixture is stirred at 70 ° C for 72 hours. The reaction mixture is poured into 75 ml of water with stirring, the oily amorphous precipitate is extracted with ethyl acetate and the organic phase is dried over anhydrous sodium sulphate. The solvent was distilled off on a rotary evaporator and the amorphous residue was chromatographed on a silica gel column using a solvent mixture of 1 part toluene and 1 part ethyl acetate as eluent. After distillation of the eluents on a rotary evaporator, 6-cyano-4- [N-ethylsulfonyl-N-methyl] amino-2,2-dimethylchroman is obtained in the form of a colorless crystalline product, m.p. 166-168 ° C.

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

(a) 3-Acetyl-4-hydroxybenzoic acid

36.6 g (0.274 mol) of aluminum chloride are suspended in 50 ml of 1,2,4-trichlorobenzene and 9 g (50 mmol) of 4-acetoxybenzoic acid are added. After the dropwise addition of 7.84 g (0.1 mol) of acetyl chloride, the reaction mixture is heated to a temperature of 130 to 140 ° C, with hydrogen chloride gas evolving from about 60 ° C. The mixture is stirred at 130 ° C for about 1 hour, then allowed to cool to 60-70 ° C and poured carefully into stirred ice water. The mixture is extracted several times with ethyl acetate, the combined organic phases are then extracted with saturated aqueous sodium bicarbonate solution, and the pH of the combined aqueous phases is then carefully adjusted to less than 1 with concentrated hydrochloric acid, separating the poorly soluble 3-acetyl-4-hydroxybenzoic acid. The product is a colorless crystalline substance with a melting point of 228-233 ° C.

b) 6-Carboxy-2,2-dimethyl-4-chromanone

Example 20

6-methoxycarbonyl-4-N- (dimethylaminosulfonyl) amino-2,2-

To a suspension of 14.7 g (0.0815 mol) of 3-acetyl-4-hydroxybenzoic acid in 200 ml of acetonitrile was added 13.8 g of pyrrolidine and 40 ml of acetone. The solution, which slowly changes color, is left to stand for 2 days at room temperature, the solvent is distilled off on a rotary evaporator, water is added to the residue, the pH is adjusted to less than 1 with concentrated hydrochloric acid and the crystalline substance is filtered off. The product is obtained in the form of colorless crystals, m.p. 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 ° C for 6 hours with stirring. . The solvent was distilled off on a rotary evaporator. Water is added to the residue, the pH is adjusted to less than 1 with concentrated hydrochloric acid, and the colorless crystals are filtered off. Melting point: 223-225 ° C.

d) 4-Amino-6-carboxy-2,2-dimethylchroman

35.2 g (0.15 mmol) 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 as catalyst, hydrogenated over a period of time. 10 hours at 80 ° C at a hydrogen pressure of 10 MPa. After filtering off the catalyst, about 3/4 of the solvent is distilled off on a rotary evaporator. The crystalline precipitate 4-amino-6-carboxy-2,2-dimethylchroman is filtered off. The product is obtained in the form of colorless crystals having a melting point of 307-310 ° C.

e) 4-Amino-6-methoxycarbonyl-2,2-dimethylchroman

To 0.05 mol of 4-amino-6-carboxy-2,2-dimethylchroman in 200 ml of methanol was added 9.5 ml of concentrated sulfuric acid and the dark solution was heated under reflux for 6 hours. After cooling, the pH of the reaction mixture was adjusted to 9 by the sequential addition of saturated aqueous potassium carbonate solution and the precipitated salt was filtered off. The solvent was distilled off on a rotary evaporator, water was added to the oily residue and extracted several times with diethyl ether. After distilling off the solvent, the oily amorphous residue is crystallized using n-heptane. The product is obtained in the form of a colorless crystalline substance, m.p. 62-65 ° C.

f) 4-N-Ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 1c) from 0.0184 mol of 4-amino-6-methoxycarbonyl-2,2-dimethylchroman by reaction with 0.021 mol. ethanesulfonic acid chloride in tetrahydrofuran with an excess of triethylamine, as colorless crystals, m.p. 111-113 ° C.

Example 19 4- (N-Ethylsulfonyl-N-methyl) amino-6-methoxycarbonyl-2,2-

The title compound was obtained in an analogous manner to that described in Example 2 from 0.0155 mol of 4-N-ctylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.0232 mol of sodium hydride (as an 80% suspension in oil) and 0.0217 mol of methyl iodide in anhydrous dimethylacetamide. The product is a colorless crystalline solid, m.p. 184-187 ° C.

The title compound is obtained in an analogous manner to that described in Example 11 from 4-amino-6-carboxy-2,2-dimethylchroman, dimethylamidosulfonic acid chloride and triethylamine in tetrahydrofuran. The product of the result in the form of colorless crystals, m.p. 127-129 ° C.

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

The title compound was obtained in an analogous manner to that described in Example 2 from 6-methoxycarbonyl-4-N- (dimethylamino) sulfonylamino-2,2-dimethylchroman, sodium hydride and methyl iodide in dimethylacetamide. The product is a colorless crystalline solid, m.p. 125-129 ° C.

Example 22 4- (N-Butyl-N-ethylsulfonyl) amino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, sodium hydride and 1-butyl iodide in dimethylacetamide. The product resulted in a colorless to slightly yellowish amorphous oil.

Example 23 6-Carboxy-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman

A suspension made up of 1 g (0.00305 mol) of 4-N-ethylsulfonyl-N-methylamino-6-methoxycarbonyl-2,2-dimethylchroman, 30 ml of methanol and a solution of 0.36 g (0.0091 mol) of sodium hydroxide in 20 ml. ml of water is stirred under reflux until a solution is formed, for about 10 hours. The solvent is distilled off on a rotary evaporator, water is added to the residue, the pH is adjusted to 0 to 1 with hydrochloric acid and the colorless crystals are filtered off. Melting point: 235-237 ° C.

Example 24

6-Aminocarbonyl-4- (N-ethylsulfonyl-N-methyl) amino-2,2-

To a solution of 0.7 g (0.0021 mol) of 6-carboxy-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman in 25 ml of anhydrous tetrahydrofuran is added 0.38 g (0.0023 mol) of carbonyldiimidazole, the mixture is stirred for 3 hours at room temperature and then 10 ml of concentrated (25%) aqueous ammonia solution are added. The mixture is stirred at room temperature for about 15 hours, then the solvent is distilled off thoroughly on a rotary evaporator, water is added to the residue and the white crystalline substance is filtered off. Mp 202-204 ° C.

Example 25 6-Cyano-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman

0.5 g (0.0015 mol) of 6-aminocarbonyl-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman was mixed with 0.72 g (0.0045 mol) of N- in an argon atmosphere. trimethylsilylpyrrolidone and 0.0013 g (0.000075 mol) of sodium bis (trimethylsilyl) amide and the mixture was heated to 90 ° C (bath temperature). The starting solid mixture resulted in a solution which was stirred for 4 hours at 90 ° C and then allowed to stand overnight at room temperature. After the protective inert gas is removed and mixed with water, the oil crystallizes. The crystals are filtered off with suction and purified from the starting product still contained therein by chromatography on silica gel using a mixture of 10 parts methylene chloride and 1 part methanol as eluent. Mp 164-167 ° C.

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

The title compound is obtained in an analogous manner to that described in Example 1a) from 4-amino-6-methoxycarbonyl-2,2-dimethylchroman by treatment with isopropylsulfonic acid chloride in tetrahydrofuran with an excess of triethylamine. The product is obtained as colorless crystals, m.p. 112-115 ° C.

Example 27 4- [N-Ethylsulfonyl-N- (4,4,4-trifluorobutyl) amino] -6-methoxycarbonyl-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and 4,4,4-trifluoro-1-iodobutane in dimethylacetamide. The product is a light yellow to colorless oily amorphous substance.

Example 28 6-Carboxy-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl) amino] -2,2-dimethylchroman

The title compound is obtained in an analogous manner to that in Example 23 by alkaline hydrolysis of 4-N-ethylsulfonyl-N- (4,4,4-trifluorobutyl) amino-6-methoxycarbonyl-2,2-dimethylchroman, as a colorless crystalline solid at temperature mp 189-192 ° C.

Example 29 4- (N-Butyl-N-ethylsulfonyl) amino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and butyl iodide in dimethylacetamide. The product is a colorless crystalline solid having a melting point of 81-84 ° C.

Example 30 6-Methoxycarbonyl-4-N-methylsulfonylamino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 1c) from 4-amino-6-methoxycarbonyl-2,2-dimethylchroman by reaction with methanesulfonic acid chloride. The product is a colorless crystalline solid, m.p. 159-163 ° C.

Example 31

6-Aminocarbonyl-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl) amino] -2,2-dimethylchroman

The title compound is obtained in an analogous manner to that in Example 24 from 6-carboxy-4-N-ethylsulfonyl-N- (4,4,4-trifluorobutyl) amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia, in the form of colorless crystalline solid, m.p. 170-174 ° C.

Example 32 6-Carboxy-4- [N-methyl-N- (dimethylsulfonyl) amino] -2,2-dimethylchroman

The title compound is obtained in an analogous manner to that in Example 25 from 6-aminocarbonyl-4- [N-methyl-N- (dimethylaminosulfonyl) amino] -2,2-dimethylchroman, as a colorless crystalline solid, m.p. 102 ° C.

Example 36 4- (N-Butyl-N-ethylsulfonyl) amino-6-carboxy-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that in Example 23 from 6-methoxycarbonyl-4- [N-methyl-N- (dimethylsulfonyl) amino] -2,2-dimethylchroman, as a colorless crystalline compound, m.p. 248 [deg.] C.

Example 33 6-Cyano-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl) amino] -2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4-N-ethylsulfonyl-N- (4,4,4-trifluorobutyl) amino-2,2-dimethylchroman, followed by purification by column chromatography on Silica gel, eluting with 10 parts methylene chloride and 1 part methanol. The product is obtained in the form of a colorless to pale yellow crystalline substance, m.p. 172-176 ° C.

Example 34 6-Aminocarbonyl-4- [N-methyl-N- (dimethylamino) sulfonylamino] -2,2-dimethylchroman

The title compound is obtained in an analogous manner to that in Example 24 from 6-carboxy-4- [N-methyl-N- (dimethylaminosulfonyl) amino] -2,2-dimethylchroman, as a colorless crystalline solid, m.p. 218 ° C.

Example 35

6-Cyano-4- [N-methyl-N- (dimethylaminosulfonyl) amino] -2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 23 from 4-N- (butyl-N-ethylsulfonyl) amino-6-methoxycarbonyl-2,2-dimethylchroman, as a colorless crystalline compound, m.p. 148-151 °. C.

Example 37 6-Aminocarbonyl-4- (N-butyl-N-ethylsulfonyl) amino-2,2-dimethylchroman

The title compound was obtained in analogy to Example 24 from 4- (N-butyl-N-ethylsulfonyl) amino-6-carboxy-2,2-dimethylchroman, as a colorless crystalline solid, m.p. 195-199 ° C. C.

Example 38 4- (N-Butyl-N-ethylsulfonyl) amino-6-cyano-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4-N-butyl-N-ethylsulfonylamino-2,2-dimethylchroman as a colorless crystalline solid, m.p. 96-98 ° C.

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

The title compound is obtained in an analogous manner to that described in Example 2 from 0.005 mol of 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.015 mol of sodium hydride and 0.007 mol of 4-picolyl chloride.

hydrochloride. The product resulted as a dark colored oily amorphous substance.

Example 40

6-Carboxy [4-N-ethylsulfonyl-N- (4-picolyl) amino] -2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 23 from 4- [N-ethylsulfonyl-N- (4-picolyl) amino] -6-methoxycarbonyl-2,2-dimethylchroman, as a colorless crystalline solid, m.p. Mp 210-212 ° C.

Example 41 6-Aminocarbonyl- [4-N-ethylsulfonyl-N- (4-picolyl) amino] -2,2-dimethylchroman

The title compound is obtained in an analogous manner to that in Example 24 from 6-carboxy-4- [N-ethylsulfonyl-N- (4-picolyl) amino] -2,2-dimethylchroman, as a colorless crystalline compound, m.p. Mp 193-196 ° C.

Example 42

6-Piperidinocarbonyl-4-N-ethylsulfonyl-N-methylamino-2,2-

The title compound is obtained in an analogous manner to that described in Example 24 from 0.003 mol of 6-carboxy-4- [N-ethylsulfonyl-N-methylamino] -2,2-dimethylchroman, 0.0033 mol of Ν, karb-carbonyldiimidazole and 0.012 mol of piperidine. The product is obtained from ethanol as colorless crystals, m.p. 184 ° C.

Example 43 4-N-Isopropylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 1c) from 0.024 mol of 4-amino-6-methoxycarbonyl-2,2-dimethylchroman with 0.0319 mol of ethanesulfonic acid chloride with excess triethylamine in tetrahydrofuran by heating to reflux. Cooling for 12 hours followed by purification of the product by column chromatography on silica gel using a mixture of 1 part ethyl acetate and 3 parts toluene as eluent. The product is obtained as colorless crystals, m.p. 111-113 ° C.

Example 44

4- (N-isopropylsulfonyl-N-methyl) amino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 2 from 4-N-isopropylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and methyl iodide, as colorless crystals, m.p. 115-119 ° C.

Example 45

6-Carboxy-4- (N-isopropylsulfonyl-N-methyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 23 from 4- (N-isopropylsulfonyl-N-methyl) amino-6-methoxycarbonyl-2,2-dimethylchroman, as colorless crystals, m.p. 228-233 ° C. .

Example 46 6-Aminocarbonyl-4- (N-isopropylsulfonyl-N-methyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 24 from 6-carboxy-4- (N-isopropylsulfonyl-N-methyl) amino-2,2-dimethylchroman, as colorless crystals, m.p. 217-220 ° C. .

Example 47 6-Cyano-4- (N-isopropylsulfonyl-N-methyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 25 from 6-aminocarbonyl

Example 52

6-cyano-4-N-butylsulfonyl-N-methylamino-2,2-dimethylchroman

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 as the eluent and, after distilling off the solvent, crystallization is carried out using diisopropyl ether. The product is obtained as colorless crystals, m.p. 129-135 ° C.

Example 48 4-N-Butylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 1c) from 4-amino-2,2-dimethylchroman hydrochloride and 1-butylsulfonyl chloride. Melting point: 117-120 ° C.

Example 49 4- (N-Butylsulfonyl-N-methyl) amino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 2 from 4-N-butylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and methyl iodide as a colorless to pale yellow amorphous oily product.

Example 50 4- (N-Butylsulfonyl-N-methyl) amino-6-carboxy-2,2-dimethylchroman

The title compound was obtained in analogy to Example 23 from 4- (N-butylsulfonyl-N-methyl) amino-6-methoxycarbonyl-2,2-dimethylchroman, as colorless crystals, m.p. 200-205 ° C. .

Example 51 6-Aminocarbonyl-4- (N-butylsulfonyl-N-methyl) amino-2,2-

The title compound was obtained in an analogous manner to that in Example 24 from 4- (N-butylsulfonyl-N-methyl) amino-6-carboxy-2,2-dimethylchroman, as colorless crystals, m.p. 162-166 ° C. .

The title compound is obtained in an analogous manner to that 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 using a mixture of 10 parts of methylene chloride and 1 part of methanol as the eluent and, after distilling off the solvent, crystallization is carried out using diisopropyl ether. The product resulted in colorless crystals, mp 57-62 ° C.

Example 53 6-Methoxycarbonyl-4- (N-methyl-N-methylsulfonyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 2 from 6-methoxycarbonyl-4-N-methylsulfonylamino-2,2-dimethylchroman and methyl iodide, as a colorless crystalline solid, m.p. 160-164 ° C.

Example 54 6-Carboxy-4- (N-methyl-N-methylsulfonyl) amino-2,2-dimethylchroman

HO IN r

The title compound is obtained in an analogous manner to that in Example 23 from 6-methoxycarbonyl-4-N-methyl-N-methylsulfonylamino-2,2-dimethylchroman by alkaline hydrolysis. The product is a colorless crystalline compound, m.p. 214-216 ° C.

Example 55 6-Aminocarbonyl-4- (N-methyl-N-methylsulfonyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that in Example 24 from 6-carboxy-4- (N-methyl-N-methylsulfonyl) amino-2,2-dimethylchroman, as a colorless crystalline solid, m.p. 179-182 ° C. C.

Example 56

6-Cyano-4- (N-methyl-N-methylsulfonyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4- (N-methyl-N-methylsulfonyl) 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 as the eluent and, after distilling off the solvent, crystallization is carried out using diisopropyl ether. The product resulted in colorless crystals, m.p. 196-200 ° C.

Example 57 4- (N-Ethylsulfonyl-N-ethyl) amino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 from 0.0091 mol of 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 mol of sodium hydride (80% suspension in oil) and 0.0126 mol. ethyl iodide in anhydrous dimethylacetamide. The product is a colorless crystalline solid, m.p. 114-116 ° C.

Example 58 4- (N-Ethylsulfonyl-N-propyl) amino-6-methoxycarbonyl-2,2-

The title compound is obtained in an analogous manner to that described in Example 2 from 0.0091 mol of 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 mol of sodium hydride (80% suspension in oil) and 0.0126 mol. 1-propyl iodide in anhydrous dimethylacetamide. The product is a colorless crystalline solid, m.p. 106-108 ° C.

Example 59 4- (N-Ethylsulfonyl-N-cyclopropyl) amino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 0.0091 mol of 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 mol of sodium hydride (80% suspension in oil) and

0.0126 mol of bromomethyl cyclopropane in anhydrous dimethylacetamide. The product is a colorless crystalline solid, m.p. 108-110 ° C.

Example 60

4- (N-ethylsulfonyl-N-1-pentyl) amino-6-methoxycarbonyl-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 from 0.0091 mol of 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman. 0.013 mol of sodium hydride (80% suspension in oil) and 0.0126 mol of pentyl iodide in anhydrous dimethylacetamide. An oily amorphous product is obtained.

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

The title compound is obtained in an analogous manner to that described in Example 2 from 0.0091 mol of 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.013 mol of sodium hydride (80% suspension in oil) and 0.0126 mol. hexyl iodide in anhydrous dimethylacetamide. An oily amorphous product is obtained.

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

a) 6,7-Dimethoxy-2,2-dimethyl-4-chromanone oxime is obtained by reacting 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 over a period of 20 hours at 60-80 ° C. After distilling off the solvent, a colorless crystalline product is obtained from the residue using water, m.p. 110 ° C.

b) 4-Amino-6,7-dimethoxy-2,2-dimethyl-4-chroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6,7-dimethoxy-2,2-dimethyl-4- chromanonone oxime and subsequent treatment in the presence of hydrochloric acid. The product is a colorless crystalline substance having a melting point of 210-215 ° C.

c) 4-N-Ethylsulfonylamino-β-7-dimethoxy-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 1c) (variant 1) from 4-amino-6,7-dimethoxy-2,2-dimethyl -4-chroman hydrochloride and ethanesulfonic acid chloride in tetrahydrofuran in the presence of triethylamine. The product results in colorless crystals, m.p. 132-135 ° C.

d) 4- (N-Ethylsulfonyl-N-methyl) amino-6,7-dimethoxy-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 2 from 0.0036 mol of 4-N-ethylsulfonylamino-6, 7-dimethoxy-2,2-dimethylchroman, 0.00504 mol of sodium hydride (80% suspension in oil) and 0.0054 mol of methyl iodide in anhydrous dimethylacetamide. The product results in the form of an amorphous viscous oil.

Example 63

7-Chloro-4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimetylfroman

a) 2-Fluoro-5-acetoxychlorobenzene was obtained by heating 3-chloro-4-fluorophenol in acetic anhydride at 80 ° C for 6 hours. The product resulted in colorless crystals having a melting point of 42-46 ° C.

b) 4-Chloro-5-fluoro-2-hydroxyacetophenone is obtained by heating a mixture of 0.0705 mol of 2-fluoro-5-acetoxychlorobenzene with 0.148 mol of anhydrous aluminum chloride at 120 ° C with mechanical stirring for about 3 hours, adding ice mixture. water and ice to the reaction mixture and filtering off the precipitate. Treatment with activated carbon in methanol and distillation of the solvent by subsequent digestion from n-heptane / diisopropyl ether mixtures gave a colorless crystalline compound, m.p. 66-71 ° C.

c) 7-Chloro-6-fluoro-2,2-dimethyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 4-chloro-5-fluoro-2-hydroxyacetophenone in the presence of pyrrolidine in acetonitrile as solvent. The product resulted as a colorless to slightly yellow amorphous residue.

d) 7-Chloro-6-fluoro-2,2-dimethyl-4-chromanone oxime was obtained in an analogous manner to that described in Example 1a) from 7-chloro-6-fluoro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride. The product is a crystalline substance having a melting point of 120-125 ° C.

e) 7-Chloro-6-fluoro-2,2-dimethyl-4-aminochroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 7-chloro-6-fluoro-2,2-dimethyl-4- of chromanonone oxime and treatment in the presence of hydrochloric acid. The product has two melting points. The first melting point is 258-260 ° C, with new crystallization of the melt, the second melting point is higher than 310 ° C.

f) 7-Chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman is obtained in an analogous manner to that described in Example 1c) by reaction of 7-chloro-6-fluoro-2,2-dimethyl-4-aminochroman hydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran.

g) 7-Chloro-4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 2 by reaction of 7-chloro-6-fluoro-2,2 -dimethyl-4-ethylsulfonylaminochroman with sodium hydride and methyl iodide. The product is a colorless crystalline solid, m.p. 104-107 ° C.

Example 64

4- (N-ethylsulfonyl-N-methyl) amino-2,2,6-trimethylchroman

a) 2,2,6-Trimethyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 5-methyl-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as a solvent, as an amorphous oily product.

b) 2,2,6-Trimethyl-4-chromanone oxime is obtained in an analogous manner to that described in Example 1a) from 2,2,6-trimethyl-4-chromanone and hydroxylamine hydrochloride. The product is a crystalline substance having a melting point of 120-125 ° C.

c) 4-Amino-2,2,6-trimethylchroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 2,2,6-trimethyl-4-chromanone oxime and treatment in the presence of hydrochloric acid. The product has two melting points. The first melting point is 245-248 ° C, with new melt crystallization, the second melting point is higher than 310 ° C.

d) 4-Ethylsulfonylamino-2,2,6-trimethylchroman is obtained in an analogous manner to that described in Example 1c) by reacting 4-amino-2,2,6-trimethylchroman hydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product resulted in colorless crystals having a melting point of 114-117 ° C.

e) 4- (N-Ethylsulfonyl-N-methyl) amino-2,2,6-trimethylchroman is obtained in an analogous manner to that described in Example 2 by reacting 4-ethylsulfonylamino-2,2,6-trimethylchroman with sodium hydride and methyl iodide. The product is a colorless crystalline solid, m.p. 107 ° C.

Example 65

6,7-Dichloro-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman

(a) 4,5-Dichloro-2-hydroxyacetophenone is obtained in an analogous manner to that described in Example 63b) from (3,4-dichlorophenyl) acetic acid and anhydrous active aluminum chloride, which results in a colorless to slightly yellowish crystalline solid, m.p. Mp 100-103 ° C.

The acetic acid (3,4-dichlorophenyl) ester used is obtained from 3,4-dichlorophenol and acetic anhydride in an analogous manner to that described in Example 63a) as a brown oil.

b) 6,7-Dichloro-2,2-dimethyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 4,5-dichloro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent. The product resulted as an amorphous brown oil.

c) 6,7-Dichloro-2,2-dimethyl-4-chromanone oxime was obtained in an analogous manner to that described in Example 1a) from 6,7-dichloro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride. The product is a crystalline solid having a melting point of 115-121 ° C.

d) 4-Amino-6,7-dichloro-2,2-dimethylchroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6,7-dichloro-2,2-dimethyl-4-chromanone oxime and treatment with presence of hydrochloric acid. The product has two melting points. The first melting point is 260-262 ° C, with new crystallization of the melt, the second melting point is higher than 310 ° C.

e) 6,7-Dichloro-2,2-dimethyl-4-N-ethylsulfonylaminochroman is obtained in an analogous manner to that described in Example 1c) by the reaction of 4-amino-6,7-dichloro-2,2-dimethylchroman-chroma-

of ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product is obtained as colorless crystals, m.p. 116-120 ° C.

f) 6,7-Dichloro-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 2 by reaction of 6,7-dichloro-2,2-dimethyl-4. -N-ethylsulfonylaminochromate with sodium hydride and methyl iodide. The product is a colorless crystalline solid, m.p. 102-106 ° C.

Example 66

4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-7-pyrrolidino-2,2-

a) 4,5-Difluoro-2-hydroxyacetophenone was obtained in an analogous manner to that described in Example 63b) from acetic acid (3,4-difluorophenyl) ester and anhydrous active aluminum chloride. The product is a colorless to slightly yellowish crystalline solid, m.p. 43-46 ° C (crystallization from n-heptane).

The acetic acid (3,4-difluorophenyl) ester used is obtained from 3,4-difluorophenol and acetic anhydride by a method analogous to that described in Example 63a) as a light oil.

b) 6-Fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 4,5-difluoro-2-hydroxyacetophenone and acetone in the presence of 1.1 molar equivalents of pyrrolidine in acetonitrile as the solvent, furthermore, in addition to the chromanone ring closure, the fluorine atom present in the 7-position is replaced by a pyrrolidine. The product is further purified by chromatography on silica gel using toluene / ethyl acetate (8: 1). Crystallization was performed using n-heptane. The product resulted in colorless to slightly yellow crystals, m.p. 96-98 ° C.

c) 6-Fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone oxime is obtained in an analogous manner to that described in Example 1a) from 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride. The product is a crystalline solid having a melting point of 148-152 ° C.

d) 6-Fluoro-7-pyrrolidino-2,2-dimethyl-4-aminochromanedihydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6-fluoro-7-pyrrolidino-2,2-dimethyl-4- chromanonone oxime and treatment in the presence of hydrochloric acid. The product resulted as colorless crystals melting at 124-137 ° C with decomposition.

e) 6-Fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethylsulfonylaminochroman is obtained in an analogous manner to that described in Example 1c) by reaction of 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-aminochroman dihydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product is obtained as colorless crystals, m.p. 157-159 ° C (from a mixture of diisopropyl ether and methanol).

r) 4- (N-Ethylsulfonyl-N-methyl) amino-6-fluoro-7-pyrrolidino-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 2 by reaction of 6-fluoro-7-pyrrolidino-2,2 -dimethyl-4-N-ethylsulfonylaminochroman with sodium hydride and methyl iodide. The product is a colorless crystalline solid, m.p. 136-138 ° C.

Example 67

4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-chroman

a) 6-Fluoro-4-chromanone oxime was obtained in an analogous manner to that described in Example 1a) from 6-fluoro-4-chromanone and hydroxylamine hydrochloride. The product is a crystalline solid having a melting point of 106-107 ° C.

b) 6-Fluoro-4-aminochroman hydrochloride was obtained in an analogous manner to that described in Example 1 b) by catalytic hydrogenation of 6-fluoro-4-chromanone oxime and treatment in the presence of hydrochloric acid. The product melts with decomposition at 252 ° C.

c) 6-Fluoro-4-ethyisulfonylaminochroman is obtained in an analogous manner to that described in Example 1c) by reaction of 6-fluoro-4-aminochroman hydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product is a colorless crystalline solid, m.p. 107-108 ° C.

d) 4- (N-Ethylsulfonyl-N-methyl) amino-6-fluorochroman was obtained in an analogous manner to that described in Example 2 by reacting 6-fluoro-4-ethylsulfonylaminochroman with sodium hydride and methyl iodide. The product is a colorless to light yellow oil.

Example 68

4- (N-Butyl-N-ethylsulfonyl) amino-6-fluoro-chroman

The title compound is obtained in an analogous manner to that described in Example 2 by reacting 6-fluoro-4-ethyisulfonylaminochroman with sodium hydride and iodobutane. The product is a colorless to light yellow oil.

Example 69

4- (N-ethylsulfonyl-N-ethyl) amino-6-fluoro-2,2-dimetyichroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and ethyl iodide. The product results in the form of an amorphous oil.

Example 70

4- (N-ethylsulfonyl-N-propyl) amino-6-fluoro-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and propyl iodide. The product results in the form of an amorphous oil.

Example 71 4- (N-Butyl-N-ethylsulfonyl) amino-6-fluoro-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and butyl iodide. The product results in the form of an amorphous oil.

Example 72 4- [N-Ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide. The product results in the form of an amorphous oil.

Example 73 4- (N-Ethylsulfonyl-N-hexyl) amino-6-fluoro-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and hexyl iodide. The product results in the form of an amorphous oil.

Example 74 4- (N-Ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-tetramethylene chromate

a) 6-Fluoro-2,2-tetramethylene-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 5-fluoro-2-

-hydroxyacetophenone and cyclopentanone in the presence of pyrrolidine in acetonitrile as solvent. The product resulted as an amorphous brown oil.

b) 6-Fluoro-2,2-tetramethylene-4-chromanone oxime was obtained in an analogous manner to that described in Example 1a) from 6-fluoro-2,2-tetramethylene-4-chromanone and hydroxylamine hydrochloride. The product is a colorless to light brown colored crystalline substance, m.p. 107-110 ° C.

c) 4-Amino-6-fluoro-2,2-tetramethylene chromate hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6-fluoro-2,2-tetramethylene-4-chromanone oxime and treatment in the presence of hydrochloric acid. The product melts with decomposition at 259-261 ° C.

d) 4-Ethylsulfonylamino-6-fluoro-2,2-tetramethylene chromate is obtained in an analogous manner to that described in Example 1c) by reacting 4-amino-6-fluoro-2,2-tetramethylene chromium hydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product resulted in colorless crystals, m.p. 111-113 ° C.

e) 4- (N-Ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-tetramethylene chromate is obtained in an analogous manner to that described in Example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-tetramethylene chromate and methyl iodide . The product results in the form of an amorphous oil.

Example 75

4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-tetrametylénchróman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-tetramethylene chromate and 4,4,4-trifluorobutyl iodide as a viscous oily amorphous product.

Example 76 4- [N-Ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-pentamethylene chromate

a) 6-Fluoro-2,2-pentamethylene-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 5-fluoro-2-hydroxyacetophenone and cyclohexanone in the presence of pyrrolidine in acetonitrile as a solvent as a light amorphous product.

b) 6-Fluoro-2,2-pentamethylene-4-chromanone oxime was obtained in analogy to Example 1a) from 6-fluoro-2,2-pentamethylene-4-chromanone and hydroxylamine hydrochloride, as a viscous amorphous product .

c) 4-Amino-6-fluoro-2,2-pentamethylene chromate hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6-fluoro-2,2-pentamethylene-4-chromanone oxime and treatment in the presence of hydrochloric acid. The product melts with decomposition at 262-264 ° C.

d) 4-Ethylsulfonylamino-6-fluoro-2,2-pentamethylene chromate is obtained in an analogous manner to that described in Example 1c) by reacting 4-amino-6-fluoro-2,2-pentamethylene chromium hydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in triethylamine tetrahydrofuran, in the form of a viscous amorphous product.

e) 4- [N-Ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-pentamethylene chromate is obtained in an analogous manner to that described in Example 2 from 4-ethylsulfonylamino-6-fluoro -2,2-pentamethylene chromate and 4,4,4-trifluorobutyl iodide. The product results in the form of an amorphous oil.

Example 77

6-ethyl-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman

a) 5-Ethyl-2-hydroxyacetophenone was obtained in analogy to Example 63b) from acetic acid (4-ethylphenyl) ester and anhydrous aluminum chloride. The product is a pale yellow oil.

The acetic acid (4-ethylphenyl) ester used is obtained from 4-ethylphenol and acetic anhydride by an analogous procedure to that described in Example 63a), as an oil.

b) 6-Ethyl-2,2-dimethyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 5-ethyl-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent, as a light oily amorphous product. .

c) 6-Ethyl-2,2-dimethyl-4-chromanone oxime was obtained in analogy to Example 1a) from 6-ethyl-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride, in the form of a viscous oily amorphous oil. product.

d) 4-Amino-6-ethyl-2,2-dimethylchroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6-ethyl-2,2-dimethyl-4-chromanone oxime and treatment in the presence of hydrochloric acid. Mp 201-204 ° C. '

e) 6-Ethyl-4-N-ethylsulfonylamino-2,2-dimethylchroman is obtained in an analogous manner to that described in Example 1c) by reacting 4-amino-6-ethyl-2,2-dimethylchroman hydrochloride with tannanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product resulted in colorless crystals, m.p. 104-108 ° C.

f) 6-Ethyl-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 2 from 6-ethyl-4-N-ethylsulfonylamino-2,2-dimethylchroman and methyl iodide. The product resulted in colorless crystals, m.p. 76-77 ° C.

Example 78

6-ethyl-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 6-ethyl-4-N-ethylsulfonylamino-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide. The product is a colorless to light yellow oil.

Example 79

7-Chloro-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 by reacting 7-chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman with sodium hydride and 4,4,4-trifluorobutyl iodide. The product is a viscous pale yellow oil.

Example 80 4- [N-Ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2,6-trimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 by reacting 4-ethylsulfonylamino-2,2,6-trimethylchroman with sodium hydride and 4,4,4-trifluorobutyl iodide. The product is a viscous pale yellow oil.

Example 81

6,7-Dichloro-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 by reacting 6,7-dichloro-4-N-ethylsulfonylamino-2,2-dimethylchroman with sodium hydride and 4,4,4-trifluorobutyl iodide. The product is a viscous light brown oil.

Example 82 4- (N-Ethylsulfonyl-N-methyl) amino-6-phenyl-2,2-dimethylchroman

a) 2-Hydroxy-5-phenylacetophenone was obtained in analogy to Example 63b) from 4-acetoxybiphenyl and anhydrous active aluminum chloride. The product is a pale yellow oil which partially crystallizes.

The 4-acetoxybiphenyl used is obtained from 4-hydroxybiphenyl and acetic anhydride in an analogous manner to that described in Example 63a) as a colorless crystalline solid, m.p. 84-86 ° C.

b) 2,2-Dimethyl-6-phenyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 2-hydroxy-5-phenylacetophenone and acetone in the presence of pyrrolidine in a

Cetonitrile as a solvent, in the form of a dark oily amorphous product, which partially crystallizes.

c) 2,2-Dimethyl-6-phenyl-4-chromanone oxime is obtained in analogy to Example 1a) from 2,2-dimethyl-6-phenyl-4-chromanone and hydroxylamine hydrochloride as a crystalline solid mp 130-134 ° C.

d) 4-Amino-2,2-dimethyl-6-phenylchroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 2,2-dimethyl-6-phenyl-4-chromanone oxime and treatment in the presence of hydrochloric acid. The product melts with decomposition at 213 to 214 ° C.

e) 4-N-Ethylsulfonylamino-2,2-dimethyl-6-phenylchroman is obtained in an analogous manner to that described in Example 1c) by reacting 4-amino-2,2-dimethyl-6-phenylchroman hydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product is obtained as colorless crystals, m.p. 162-164 ° C.

f) 4- (N-Ethylsulfonyl-N-methyl) amino-6-phenyl-2,2-dimethylchroman is obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-phenylchroman and methyl iodide. The product is obtained as colorless crystals, m.p. 184-186 ° C.

Example 83

4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-phenyl-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 by reacting 4-N-ethylsulfonylamino-2,2-dimethyl-6-phenylchroman with sodium hydride and 4,4,4-trifluorobutyl iodide. The product is a colorless to pale yellow crystalline solid, m.p. 112-114 ° C.

Example 84

6,8-Difluoro-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman

by the procedure of Example 63b) from acetic acid (2,4-difluorophenyl) ester and anhydrous active aluminum chloride. The product is a colorless crystalline solid, m.p. 80-94 ° C.

The acetic acid (2,4-difluorophenyl) ester used is obtained from 2,4-difluorophenol and acetic anhydride by a method analogous to that described in Example 63a), in the form of a slightly yellowish colored liquid.

b) 6,8-Difluoro-2,2-dimethyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 3,5-difluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as a solvent, in the form of of a dark oily amorphous product.

c) 6,8-Difluoro-2,2-dimethyl-4-chromanone oxime was obtained in an analogous manner to that described in Example 1a) from 6.8.

-difluoro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride, as a crystalline solid, m.p. 124-137 ° C.

d) 4-Amino-6,8-difluoro-2,2-dimethylchroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6,8-difluoro-2,2-dimethyl-4-chromanone oxime and treatment with presence of hydrochloric acid. The melting point of the product is more than 310 ° C, the product sublimates from 300 ° C at 100 kPa.

e) 4-N-Ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman is obtained in an analogous manner to that described in Example 1c) by reaction of 4-amino-6,8-difluoro-2,2-dimethylchroman hydrochloride with chloride ethanesulfonic acid in the presence of triethylamine in tetrahydrofuran. The product is a colorless crystalline solid, m.p. 124-127 ° C.

f) 6,8-Difluoro-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 2 from 4-ethylsulfonylamino-6,8-difluoro-2,2 -dimethylchroman and methyl iodide. The product resulted in colorless crystals, mp 84-86 ° C.

Example 85

6,8-Difluoro-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman

as described in Example 2 from 4-N-ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide. The product resulted in colorless crystals having a melting point of 127-129 ° C.

Example 86

4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-7-pyrrolidino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 2 by reaction of 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethylsulfonylaminochroman with sodium hydride and 4,4,4-trifluorobutyl iodide. The product is a colorless crystalline solid, m.p. 137-140 ° C.

Example 87 6-Carboxy-4- (N-ethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 23 by hydrolysis of 4- (N-ethylsulfonyl-N-ethyl) amino-6-methoxycarbonyl-2,2-dimethylchro21.

The title compound is obtained in an analogous manner to that described in Example 24 from 6-carboxy-4- (N-ethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia. The product is a colorless crystalline solid, m.p. 173-175 ° C.

Example 93 6-Aminocarbonyl-4- (N-ethylsulfonyl-N-propyl) amino-2,2-dimethylchromanede. The product is a colorless crystalline compound with a melting point of 217-220 ° C.

Example 88

6-Carboxy-4- (N-ethylsulfonyl-N-propyl) amino-2,2-dimethylchroman o c Jl

The title compound is obtained in an analogous manner to that described in Example 23 by hydrolysis of 4- (N-ctylsulfonyl-N-propyl) amino-6-methoxycarbonyl-2,2-dimethylchroman. The product is a colorless crystalline compound, m.p. 165-169 ° C.

Example 89 6-Carboxy-4- (N-cyclopropylmethyl-N-ethylsulfonyl) amino-

The title compound is obtained in an analogous manner to that described in Example 23 by hydrolysis of 4- (N-cyclopropylmethyl-N-ethylsulfonyl) amino-6-methoxycarbonyl-2,2-dimethylchroman. The product is a colorless crystalline compound, m.p. 184-188 °. C.

Example 90 6-Carboxy-4- (N-ethylsulfonyl-N-pentyl) amino-2,2-dirriethylchroman

The title compound is obtained in an analogous manner to that described in Example 23 by hydrolysis of 4- (N-ethylsulfonyl-N-pentyl) amino-6-methoxycarbonyl-2,2-dimethylchroman. The product is a colorless crystalline compound, m.p. 156-158 ° C.

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

The title compound is obtained in an analogous manner to that described in Example 23 by hydrolysis of 4- (N-ethylsulfonyl-N-hexyl) amino-6-methoxycarbonyl-2,2-dimethylchroman. The product is a colorless crystalline compound, m.p. 154-158 ° C

The title compound was obtained in an analogous manner to that described in Example 24 from 6-carboxy-4- (N-ethylsulfonyl-N-propyl) amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia. The product is a colorless crystalline substance, m.p. 185-188 ° C.

Example 94 6-Aminocarbonyl-4- (N-cyclopropylmethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 24 from 6-carboxy-4- (N-cyclopropylmethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia. The product is a colorless crystalline substance with a melting point of 196-199 ° C.

Example 95 6-Aminocarbonyl-4- (N-ethylsulfonyl-N-pentyl) amino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 24 from 6-carboxy-4- (N-ethylsulfonyl-N-pentyl) amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia. The product is a colorless crystalline solid, m.p. 168-172 ° C.

Example 96 6-Aminocarbonyl-4- (N-ctylsulfonyl-N-hexyl) amino-2,2-dimethylchroman

Example 92

6-Aminocarbonyl-4- (N-ethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman

The title compound is obtained in an analogous manner to that described in Example 24 from 6-carboxy-4- (N-ethylsulfonyl-N-hexyl) amino-2,2-dimethylchroman, carbonyidiimidazole and ammonia. The product is a colorless crystalline solid having a melting point of 148-152 ° C.

Example 97 6-Cyano-4- (N-ethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4- (N-ethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman, followed by purification by silica gel column chromatography using a 10-part mixture. methylene chloride and 1 part methanol as eluent. The product is a colorless to pale yellow crystalline substance with a melting point of 127-130 ° C.

Example 98 6-Cyano-4- (N-ethylsulfonyl-N-propyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4- (N-ethylsulfonyl-N-propyl) amino-2,2-dimethylchroman, followed by purification by silica gel column chromatography using a 10-part mixture. methylene chloride and 1 part methanol as eluent. The product is a colorless to pale yellow crystalline material with a melting point of 127-130 ° C.

Example 99 6-Cyano-4- (N-cyclopropylmethyl-N-ethylsulfonyl) amino-

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4- (N-cyclopropylmethyl-N-ethylsulfonyl) amino-2,2-dimethylchroman, followed by purification by silica gel column chromatography using 10 parts of methylene chloride and 1 part methanol as eluent. The product was a colorless to pale yellow crystalline material with a melting point of 127-130 ° C.

Example 100 6-Cyano-4- (N-ethylsulfonyl-N-pentyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4- (N-ethylsulfonyl-N-pentyl) amino-2,2-dimethylchroman, followed by purification by silica gel column chromatography using a 10-part mixture. methylene chloride and 1 part methanol as eluent. The product is a viscous oily liquid.

Example 101 6-Cyano-4- (N-ethylsulfonyl-N-hexyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4- (N-ethylsulfonyl-N-hexyl) amino-2,2-dimethylchroman, followed by purification by silica gel column chromatography using a 10-part mixture. methylene chloride and 1 part methanol as eluent. The product is a viscous yellow oil.

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

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and ethyl bromoacetate. The product is a colorless crystalline substance with a melting point of 112-114 ° C.

Example 103 4- [N-Ethylsulfonyl-N-methyl] amino-6-fluoro-2,2-pentamethylene chromate

The title compound was obtained in an analogous manner to that described in Example 2 from 4-ethylsulfonylamino-6-fluoro-2,2-pentamethylene chromate and methyl iodide. The product is a colorless crystalline substance with a melting point of 73-74 ° C.

Example 104 4- (N-Isopropyloxycarbonylmethyl-N-ethylsulfonyl) amino-6-fluoro-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and isopropyl bromoacetate. The product is a colorless to light yellow liquid.

Example 105

4- (N-ethylsulfonyl-N-methyl) amino-6-methoxy-2,2-dimethylchroman

a) 6-Hydroxy-2,2-dimethyl-4-chromanone was obtained in an analogous manner to that described in Example 18b) from 2,5-dihydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent. The product is a crystalline solid having a melting point of 147-149 ° C.

b) 6-Methoxy-2,2-dimethyl-4-chromanone

To 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 was added the residue (3.6 ml) of methyl iodide and the reaction mixture was heated for 20 minutes. hours at 50-55 ° C. The solvent was removed by distillation in vacuo, water was added to the residue, and the oil which separated was extracted with ethyl acetate. After drying the organic phase over anhydrous sodium sulfate, the solvent was distilled off to give 6-methoxy-2,2-dimethyl-4-chromanone as an oily liquid.

c) 6-Methoxy-2,2-dimethyl-4-chromanone oxime was obtained in analogy to Example 1a) from 6-methoxy-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride as a crystalline solid mp 108-112 ° C.

d) 4-Amino-6-methoxy-2,2-dimethylchroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 6-methoxy-2,2-dimethyl-4-chromanone oxime and treatment in the presence of hydrochloric acid. Melting point: 250-251 ° C.

e) 4-N-Ethylsulfonylamino-6-methoxy-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 1c) from 4-amino-6-methoxy-2,2-dimethylchroman hydrochloride and ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product is a colorless crystalline solid, m.p. 131-133 ° C.

f) 4- (N-Ethylsulfonyl-N-methyl) amino-6-methoxy-2,2-dimethylchroman was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6-methoxy-2,2-dimethylchroman and methyl iodide. The product resulted in colorless crystals having a melting point of 68-70 ° C.

Example 106

4-N-Ethylsulfonylamino-2,2-dimethyl-6-metylsulfonyloxychróman

a) 2,2-Dimethyl-6-methylsulfonyloxychromanone

0.03 mol of 6-hydroxy-2,2-dimethyl-4-chromanone,

16.1 g of anhydrous potassium carbonate powder and 10 ml of methanesulfonic acid in 80 ml of anhydrous dimethylformamide are heated at 80 ° C for 10 hours. Then the solvent was distilled off under reduced pressure, 150 ml of water were added to the residue and stirred for 2 hours. The crystalline precipitate is filtered off, washed several times with water and dried in a stream of air. The product is a colorless solid, m.p. 108-110 ° C.

b) 2,2-Dimethyl-6-methyl-4-sulfonyloxychromanone oxime is obtained in an analogous manner to that described in Example 1a) from 2,2-dimethyl-6-methylsulfonyloxychromanone and hydroxylamine hydrochloride, as a crystalline solid, m.p. 166 - 167 ° C.

c) 4-Amino-6-methylsulfonyloxy-2,2-dimethylchroman hydrochloride was obtained in an analogous manner to that described in Example 1b) by catalytic hydrogenation of 2,2-dimethyl-6-methylsulfonyloxychromanone oxime and treatment in the presence of hydrochloric acid. Mp 229-231 ° C.

d) 4-N-Ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyloxychroman was obtained in an analogous manner to that described in Example 1c) from 4-amino-6-methylsulfonyloxy-2,2-dimethylchroman hydrochloride and ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product is a colorless crystalline solid, m.p. 97-100 ° C.

Example 107

4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethyl-6-metylsulfonyloxychróman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyl chromate and methyl iodide. The product resulted in colorless crystals, m.p. 137-139 ° C.

Example 108 4- (N-Methylsulfonyl-N-ethyl) amino-2,2,6,7-tetramethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-methylsulfonylamino-2,2,6,7-tetramethylchroman and ethyl iodide. The product is obtained as colorless crystals, m.p. 119-121 ° C.

4-Amino-2,2,6,7-tetramethylchroman hydrochloride (m.p. > 270 ° C) was prepared by hydrogenation of 2,2,6,7-tetramethyl-4-chromanone oxime (mp 162-163 ° C). . The oxime is prepared by known methods as described from the corresponding 2,2,6,7-tetramethyl-4-chromanone. Reaction of 4-amino-2,2,6,7-tetramethylchroman with the corresponding alkylsulfonyl chlorides as described in Example 1 (variant 1) affords methylsulfonylamino-2,2,6,7-tetramethylchroman as a colorless oil and ethylsulfonylamino-2, respectively. 2,6,7-tetramethylchroman as a colorless oil.

Example 109

4- (N-methylsulphonyl-N-methyl) amino-2,2,6,7-tetramethyl

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-methylsulfonylamino-2,2,6,7-tetramethylchroman and methyl iodide. The product is obtained as colorless crystals, m.p. 105-107 ° C.

Example 110 4- (N-Ethylsulfonyl-N-hexyl) amino-2,2,6,7-tetramethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2,6,7-tetramethylchroman and hexyl iodide. The product resulted in a colorless oil.

Example 111

4- (N-ethylsulfonyl-N-ethyl) amino-2,2,6,7-tetramethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2,6,7-tetramethylchroman and ethyl iodide. The product is obtained as colorless crystals, m.p. 93-95 ° C.

Example 112 4- (N-Ethylsulfonyl-N-butyl) amino-2,2,6,7-tetramethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2,6,7-tetramethylchroman and butyl iodide. The product is obtained as colorless crystals, m.p. 81-83 ° C.

Example 113 4- (N-Ethylsulfonyl-N-methyl) amino-2,2,6,7-tetramethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2,6,7-tetramethylchroman and methyl iodide. The product is obtained as colorless crystals, m.p. 132-134 ° C.

Example 114 4- (N-Ethylsulfonyl-N-butyl) amino-7-methoxy-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-7-methoxy-2,2-dimethylchroman and butyl iodide. The product resulted in a colorless oil.

4-Amino-7-methoxy-2,2-dimethylchroman hydrochloride (m.p. 239-241 ° C) was prepared by hydrogenating 7-methoxy-2,2-dimethyl-4-chromanone oxime (mp 124-126 ° C). . This oxime is prepared by known methods from the corresponding 7-methoxy-2,2-dimethyl-4-chromanone. Treatment of 4-amino-7-methoxy-2,2-dimethylchroman with the corresponding alkylsulfonyl chlorides as described in Example 1 (variant 1) affords methylsulfonylamino-7-methoxy-2,2-dimethylchroman as a colorless oil and ethylsulfonylamino-7-, respectively. methoxy-2,2-dimethylchroman, m.p. 111-113 ° C.

Example 115 4- (N-Ethylsulfonyl-N-ethyl) amino-7-methoxy-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-7-methoxy-2,2-dimethylchroman and ethyl iodide. The product resulted in a colorless oil.

Example 116 4- (N-Ethylsulfonyl-N-methyl) amino-7-methoxy-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-7-methoxy-2,2-dimethylchroman and methyl iodide. The product resulted in a colorless oil.

Example 117 4- (N-Ethylsulfonyl-N-methyl) amino-6- (4,4,4-trifluorobutyl) oxy-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-6- (4,4,4-trifluorobutyl) oxy-2,2-dimethylchroman and methyl iodide. The product is obtained as a colorless crystalline compound from a mixture of n-heptane and diisopropyl ether. Melting point 68-72 ° C

4-N-Ethylsulfonylamino-6- (4,4,4-trifluorobutyl) oxy-2,2-dimethylchroman (m.p. 84-90 ° C) is obtained by the following synthetic steps, starting from 6-hydroxy-2,2 -dimethyl-4-chromanone (obtained from 2-acetoxyhydroquinone and acetone, melting point 147-149 ° C), through 6- (4,4,4-trifluorobutyl) oxy-2,2-dimethyl-4-chromanone (obtained from 6-hydroxy-2,2-dimethyl-4-chromanone and 4,4,4-trifluorobutyl iodide, mp 53-55 ° C), 6- (4,4,4-trifluorobutyl) oxy-2,2-dimethyl-4- chromanonone oxime (obtained from 6- (4,4,4-trifluorobutyl) oxy-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride, m.p. 94-97 ° C) and 4-amino-6- (4,4 4-trifluorobutyl) oxy-2,2-dimethylchroman (obtained from 6- (4,4,4-trifluorobutyl) oxy-2,2-dimethyl-4-chromanone oxime by catalytic hydrogenation using Raney-nickel, m.p. 47-49 ° C), followed by the reaction of 4-amino-6- (4,4,4-trifluorobutyl) oxy-2,2-dimethylchroman and ethanesulfonyl chloride.

Example 118 6- (4-Bromophenyl) -4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 6- (4-bromophenyl) -4-N-ethylsulfonylamino-2,2-dimethylchroman and methyl iodide. Mp 160-170 ° C.

6- (4-Bromophenyl) -4-N-ethylsulfonylamino-2,2-dimethylchroman (m.p. 122-135 ° C) is obtained by the following sequential synthetic steps starting from 3-acetyl-4'-bromo-4-hydroxybiphenyl (obtained from 4'-bromo-4-acetoxybiphenyl and aluminum chloride by Friess rearrangement, dark brown oil), via 6- (4-bromophenyl) -2,2-dimethyl-4-chromanone (obtained from 3-acetyl-4'-bromo-4). -hydroxybiphenyl and acetone, viscous oil), 6- (4-bromophenyl) -2,2-dimethyl-4-chromanone oxime (obtained from 6- (4-bromophenyl) -2,2-dimethyl-4-chromanone, viscous oil) , and 6- (4-bromophenyl) -4-amino-2,2-dimethylchroman hydrochloride (obtained from 6- (4-bromophenyl) -2,2-dimethyl-4-chromanonoxime by catalytic hydrogenation using Raney nickel and addition of solution of hydrochloric acid in diethyl ether, m.p. 166-170 ° C), followed by the reaction of 4-amino-6- (4-bromophenyl) -2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride in the presence of triethylamine.

Example 119 4- (N-Ethylsulfonyl-N-butyl) amino-2,2-dimethyl-6-methoxychroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-methoxychroman and butyl iodide. The product resulted in colorless crystals having a melting point of 78-80 ° C.

Example 120

(+) - 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman and (-) - 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro- 2,2-Dimethylchroman ([α] = -24.5) is obtained from racemic mixture of 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman by chiral chromatography (CSP Chiralpak AD 250 4) 6) using a 40: 1 mixture of n-hexane and ethanol as eluent.

Example 121

(+) - 4- (N-Butyl-N-ethylsulfonyl) amino-6-fluoro-2,2-dimethylchroman and (-) - 4- (N-Butyl-N-ethylsulfonyl) amino-6-fluoro-2.2 enantiomers -dimethylchroman ([ct] = -53.5) is obtained from a racemic mixture of 4- (N-butyl-N-ethylsulfonyl) amino-6-fluoro-2,2-dimethylchroman by chiral chromatography (CSP Chiralpak AD 250 * 4.6) ) using n-hexane / ethanol (80: 1) as eluent.

Example 122

4- (N-methylsulphonyl-N-isopropyl) amino-2,2,6-trimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-methylsulfonylamino-2,2,6-trimethylchroman and isopropyl iodide. The product resulted in colorless crystals having a melting point of 140 ° C.

Example 123 4- [N-Methylsulfonyl-N- (3-methylbutyl)] amino-2,2,6-trimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-methylsulfonylamino-2,2,6-trimethylchroman and 3-methylbutyl iodide. The product is a viscous oil.

Example 124 4- [N-Ethylsulfonyl-N- (3-ethoxypropyl)] amino-2,2,6-trimethylchroman

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2,6-trimethylchroman and 3-ethoxypropyl iodide. The product is a viscous oil.

Pharmacological tests:

1 _sk- channels from human, rat or guinea pig were expressed in oocyte flint (Xenopus). To this end, oocytes from Xenopus laevis were first isolated and defoliated. It was then injected into these oocytes in vitro synthesized RNA encoding the I, _Gr. After 2 to 8 days, the expression of the I _sk- protein was determined by measuring the I _sk- currents using a technique using two voltage clamp microelectrodes. I, _IL-Channel are thereby activated rule 15 with voltage jumps lasting at -10 mV, and the bath was perfused with control solution of composition 96 mM sodium chloride, 2 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 5 HEPES mmol (4- (2-hydroxyethyl) -1-piperazinanesulfonic acid); titrated sodium hydroxide to pH 7.5. The experiments were carried out at room temperature. The data acquisition and analysis software used was a Geneclamp amplifier (Axon Instruments, Foster City, USA) and a MacLab D / A converter and software (ADIinstruments, Castle Hill, Australia). The chromanols were tested by adding them to the control solution at various concentrations. The effects of chromanols were calculated as percent inhibition of control current I _sk . The data was finally extrapolated using the Hill equation to determine IC ₅₀ values for individual substances. Data are presented as means with standard deviation. The value n represents the number of experiments performed. Statistical significance was determined using the paired Student's t-test.

literature:

Busch AE, Kopp HG, S. Waldegger, I. Samarzija, SuBbrich H., G. Raber, K. Kunzelmann, Ruppersberg JP and Lang F (1995) Inhibition of both exogenously expressed _IL I and endogenous K + channels in Xenopus oocytes by isosorbiddinitrate. J. Physiol 491: 735-741;

Takumi T., Ohkubo H. and Nakanishi S. (1989), Cloning of a membraneprotein that induces a slow voltage-gated potassium current. Science 242: 1042-1045;

Vamum MD, Busch AE, Bond CT, Maylie J. and Adelman J. P. (1993), The minK channel underlies the cardiac potassium current and mediated species-specific responses to protein kinase [C Proc Natl Acad Sci USA 90: 11528-11532],

Compound Example ΙΟ ₅₀ for I _en _______________________________________ No__________ (in pmol / 1) 6-cyano-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman 33 0.42

4- (N-butyl-N-ethylsulfonyl) amino-6-cyano-2,2-dimethylchroman 38 0.76

Compound Example IC ₅₀ for _Isk

no. (in pmol) trans-6-cyano-4- (N-ethylsulfonyl-N-methylamino) -3-hydroxy-2,2-dimethyl-

tylchróman trans-6-cyano-4- (N-methylsulfonyl-N- 293B *) 6.9 ± 0.4 methylamino) -3-hydroxy-2,2-dimetychróman 374B *) 19.2 ± 1.2 trans-6-cyano-4- [N- (dimethylamino) - sulfonyl-N-methylamino] -3-hydroxy-2,2-dimethylchroman trans-6-cyano-4- [N- (1-butylsulfonyl) - 377B *) 14.6 ± 0.5 -N-methylamino] -3-hydroxy-2,2-dimethyl- chromate 360B *) 58.8 ± 1.8

The legend:

* E. E. Lohrmann, I. Burhoff, R. B. Nitschke, H. J. Lang, D.

Mania, H.C. Englert, M. Hropot, R.Warth, W.Rohm, M.

Bleich, R. Greger, Pflügers-Arch - Eur. J. Physiol

429: 517-530.

Protecting gastric acid secretion, anti-ulcer

Method: High pressure rat gastric perfusions were performed as described by Berglindh and Obrink (1) and using some modifications as described elsewhere (2). Male and female rabbits weighing 2-3 kg were painlessly killed under anesthesia by cervical dislocation and the stomachs were perfused as described in the literature (1). The gastric fundus mucosa was separated by a scraper and cut with scissors. The mucosal fragments so obtained were treated with 1 mg / ml collagenase in a medium containing 100 mmol sodium chloride, 5 mmol potassium chloride, 0.5 mmol sodium dihydrogen phosphate, 1 mmol sodium hydrogen phosphate, 1 mmol calcium chloride, 1.5 mmol magnesium chloride, 20 mmol sodium bicarbonate, 20 mmol HEPES, 2 mg / ml glucose and 1 mg / ml rabbit albumin, for 30 to 45 minutes at 37 ° C, the pH of the mixture was adjusted to 7.4 with Tris buffer . The gastric glands were filtered through a nylon mesh to remove larger fragments and washed three times with incubation medium. Then, the glands were suspended in the medium at a concentration of 2-4 mg dry weight / ml.

The accumulation of ¹⁴ C-aminopyrine ( ¹⁴ C-AP) was determined as a measure of the acid-producing capacity of the stomach glands (3). For this purpose, 1 ml gland suspension samples were incubated with 1 pmol (200,000 cpm; pulses per minute) of ¹⁴ C-aminopyrine and test compound and kept for 20-30 minutes at 37 ° C with shaking in a water bath. Then histamine (100 pmol), dbcAMP (0.3 or 1 mmol) or carbachol (100 pmol) was added, followed by a second incubation for 30-45 minutes. The incubation was then terminated by centrifuging the samples for 0.5 minutes. The supernatant was separated and the obtained pellets dissolved in 1 ml of sodium hydroxide. Pellet and supernatant samples were measured with a scintillation counter. The AP-ratio of intraglandular and extraglandular radioactivity was calculated as described by Sack and Spenney (4). All assays were performed in triplicate.

Results: 6-cyano-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethyl-3-chromanol caused a concentration-dependent inhibition of stimulated aminopyrine accumulation with IC ₅₀ values of 20 pmol after stimulation with histamine and dbcAMP as well as 5 pmol after carbachol stimulation.

literature:

1. Berghlind, T., Obrink, K.J., A method for preparing isolated glands from the rabbit gastric mucosa, Acta Physiol. Scan. 96, 150-159 (1976);

2. Herling, AW, Becht, M., Kelker, W., Ljungstrom, M., Bickel, M., Inhibition of ¹⁴ C-aminopyrine accumulation in isolated rabbit gastric glands by the H ₂ -receptor HOE 760 antagonist (TZU- 0460). Agents and Actions 20: 35-39 (1987);

3. Berghlind, T., Helander, H.F., Obrink, K.J., Effect of secretagogues on oxygen consumption, aminopyrine accumulation and morphology in isolated gastric glands. Acta Physiol. Scand. 97: 401-414 (1976);

4. Sack, J., Spenney, J. G., Aminopyrine accumulation by mammalian gastric glands: an analysis of the technique. Am. J. Physiol. 243: G3 313 - G319 (1982).

Claims (13)

I chromates of formula (I) wherein the symbols R ¹ and R ² independently of one another are hydrogen, C _p F _{2p + 1,} alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl a group which is unsubstituted or substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, methyl group, methoxy group, sulfamoyl group, methylsulfonylamino group and methylsulfonyl group, and p is 1, 2 or 3, or R ¹ and R ² together form an alkylene chain s 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, R ³ represents a group F'''-QH '' ⁽ NR ¹⁾ R ⁹ represents a hydrogen atom or a cycloalkyl group s 3, 4, 5, 6, 7 or 8 carbon atoms, n is 0, 1, 2, 3, 4, 5, 7, 8, 9 or 10, m is 0 or 1, and R ¹¹ represents a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or R ¹¹ together with R ⁹ form an alkylene group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, with one CH ₂ in C _n H _2n being replaced by an oxygen atom, -SO _q, or -NR ¹⁰ , q is 0, 1 or 2; R ¹⁰ represents a hydrogen atom, a methyl group or an ethyl group, R ⁴ is R ^{L 2} -C _r H _2r, R ¹² represents a hydrogen atom, a cycloalkyl group having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, C _p F _{2p + b} pyridyl, thienyl, imidazolyl or phenyl which is unsubstituted or substituted one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, methyl group, methoxy group, sulfamoyl group, methylsulfonyl group and methylsulfonylamino group, ar is 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein one CH ₂ in the C _r H _{2r group} may be replaced by an oxygen atom, -C = C-, -CsC-, -CO-, -CO-O-, -SO _q - or -NR ¹⁰ -, q is 0, 1 or 2, and R ¹⁰ is H, methyl or ethyl, and the radicals R ^5, R ^6, R ⁷ and R ⁸ 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, cyano, trifluoromethyl, a group -C2F5, -C3F7, -N 3, -NO ,, CONR ¹³ R ^14, -COOR ^{15, R 6} -CsH _2s -Y- or phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, I, trifluoromethyl, methyl, methoxy, sulfamoyl and methylsulfonyl, R ¹³ and R ^{14 are} each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, R ¹⁵ is H, methyl, ethyl, phenyl or -C _u H _2u -NR ¹⁴ R ^{L 3,} with a value of 2 or 3, R ¹⁶ represents hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, -COOR ¹⁵ , thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl , N-morpholino, N-metylpiperazinoskupinu, C _t F _{2t + 1} or phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, I, trifluoromethyl, methyl, , methoxy, sulfamoyl and methylsulfonyl, s having a value of 0, 1, 2, 3, 4, 5 or 6, t having a value of 1, 2 or 3, and Y is SO _q, -CO-, -SO ₂ -NR ¹⁰ -, -O-, -NR ¹⁰ or -CO-NR ^10, wherein R ⁶ can not represent a group -OCF ₃ or -OC ₂ F _5, and their physiologically acceptable salts. The chromates of formula (I) according to claim 1, in which R ¹ and R ^{2 are} each independently hydrogen, trifluoromethyl, alkyl having 1, 2 or 3 carbon atoms, taken together to form an alkylene chain of 4 or 5 or a phenyl group which is unsubstituted or substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, methyl group, methoxy group, sulfamoyl group and methylsulfonyl group, R ³ is R ⁹ -C _n H _2n [NR] _m -, R ⁹ represents a hydrogen atom. n is 0, 1, 2, 3. 4, 5 or 6, m is 0 or 1, and R ( ¹¹⁾ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, R ⁴ is R ^{L 2} -C _r H _2r, R ¹² represents a hydrogen atom, a cycloalkyl group having 5, 6, 7 or 8 carbon atoms, a trifluoromethyl group, a pyridyl group or a phenyl group which is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, trifluoromethyl, sulfamoyl and methylsulfonyl, ar is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein one CH group in the group C ₇ H _{r 2 l} can be replaced by O, -CO , -CO-O- or -SO _q -, q is 0, 1 or 2 and R ⁷ , R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, Br, I, alkyl having 1 or 2 carbon atoms, cyano, trifluoromethyl, nitro, CONR ¹⁴ R ^I3, -COOR ^15, R ^I6 C _p H _2s -Y- or phenyl, which is unsubstituted or substituted by a substituent selected from p of a fluorine atom, a chlorine atom and a trifluoromethyl group, R ¹³ and R ¹⁴ independently represent a hydrogen atom or an alkyl group having 1, 2 or 3 carbon atoms, R ¹⁵ is methyl, ethyl, phenyl or-C _{U U} H 2 NR ¹³ R ^14, u is 2 or 3, R ¹⁶ is hydrogen, cycloalkyl having 5 or 6 carbon atoms, C _t F _{2 l + 1} or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, Br, trifluoromethyl, methyl a group, a methoxy group, a sulfamoyl group and a methylsulfonyl group, t is 1, 2 or 3, s is 0, 1, 2, 3 or 4, Y is SO _q , -CO-, -SO ₂ -NR ¹⁰ -, -O-, -NR ^10, or -CO-NR ¹⁰ -, q is 0.1 or 2, and R ¹⁰ represents a hydrogen atom or a methyl group, but R ⁶ cannot be -OCF ₃ or -OC ₂ F ₅ . The chromates of formula (I) according to claim 1 or 2, wherein R ¹ and R ^{2 are} each independently trifluoromethyl, methyl or phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of: a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl group, a methyl group, a methoxy group, a sulfamoyl group and a methylsulfamoyl group, R ³ is alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino or diethylamino, R ⁴ is R ^{L 2} -C _r H _2r, R ¹² is hydrogen, cycloalkyl having 5 or 6 carbon atoms or a trifluoromethyl group, Ar is a value of 1,2, 3,4, 5,6, 7 or 8, wherein one _CH2 group of the group C _r H _2r may be replaced by an oxygen atom, a group -CO-, -CO-O- or -SO _? q is 0, 1 or 2 and R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl group having 1 or 2 atoms alkyl, cyano, nitro, -COOR ^15, R ⁱ⁶ C _p H _{2 s} -Yalebo phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F and Cl, R ¹⁵ is methyl, ethyl, phenyl or-C "H _2u -NR ¹³ R ^14, u is 2 or 3; R ¹³ and R ¹⁴ independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms, R ¹⁶ represents a hydrogen atom, a trifluoromethyl group or a phenyl group having a value of 0, 1, 2, 3 or 4, Y is SO _q , -CO-, -SO ₂ NR ¹⁰ , -O-, NR ¹⁰ - or -CO-NR ¹⁰ , q is 0, 1 or 2, and R ¹⁰ represents a hydrogen atom or a methyl group, but R ⁶ cannot be -OCF ₃ . The chromates of formula (I) according to claims 1 to 3, selected from the group consisting of 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman, 6-cyano-4- (N- ethylsulfonyl-N-methyl) amino-2,2-dimethyl-chroman, 4- (N-ethylsulfonyl-N-methyl) amino-6-methoxycarbonyl-2,2-dimethylchroman. 6-cyano-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman, 4- (N-butyl-N-ethylsulfonyl) amino-6-cyano-2, 2-dimethylchroman, 4- (N-ethylsulfonyl-N-methyl) amino-2,2,6-trimethylchroman, 7-chloro-4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman, 6,7-dichloro-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethyl-chroman, 4- (N-butyl-N-ethylsulfonyl) amino-6-fluoro-2,2-dimethylchroman, 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-tetramethylene chromate, 4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-dimethylchroman, 4- (N-ethylsulfonyl-N-hexyl) amino-6-fluoro-2, 2-Dimethylchroman a 6-ethyl-4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-2,2-dimethylchroman. A process for the preparation of a chromate of formula (I) according to claim 1, characterized in that it is: (a) a compound of formula (II) XA: ..... R8 wherein R ^{@ 1} , R @ ² , R @ ³ , R @ ⁴ , R @ ⁵ , R @ ⁶ , R @ ⁷ and R @ ^{8 are} as defined above and L is a nucleofugue leaving group customary for alkylation, especially chlorine, bromine, iodine, CH ₃ SO ₂ -O- or p-toluenesulfonyloxy radical, reacted with a sulfonamide of formula (III) or a salt thereof (V / ° trri), M wherein R ³ and R ^{4 are} as defined above and M represents a hydrogen atom or preferably a metal atom, particularly preferably lithium, sodium or potassium, or b) reacting a compound of formula (IV) wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above, with a sulfonic acid derivative of formula (V) R ³ -SO ₂ -W (V), wherein R ³ is as defined above and W represents a nucleofunctional leaving group such as a fluorine atom, a bromine atom or a 1-imidazolyl group, in particular a chlorine atom, or c) a compound of formula (VI) MW ³ F ⁵ X N R3 ABOUT J / R ² R7 L R1 wherein R ^{@ 1} , R ^{@ 2} , R ^{@ 5} , R @ ⁶ , R @ ⁷ , R @ ⁸ and M are as defined above, are subjected to an alkylation reaction with an alkylating agent of formula (VII). R ⁴ -L (VII), in which R ⁴ is as defined with the exception of hydrogen and L is as defined, or d) carrying out an electrophilic substitution reaction in at least one of the positions R ⁵ to R ⁸ in the chromate of the formula (I) in which R ¹ to R ⁴ are as defined above, the substituent at this position being a hydrogen atom and the remaining substituents R ⁵ to R ⁸ have the following meaning. Use of a chromate of formula (I) according to claim 1 for the preparation of a medicament for blocking a K ⁺ -channel that is opened by cyclic adenosine monophosphate, cAMP. Use of a chromate of formula (I) according to claim 1 for the preparation of a medicament for inhibiting gastric acid secretion. Use of a chromate of formula (I) according to claim 1 for the preparation of a medicament for the treatment of ulcers of the stomach and intestinal tract, in particular the duodenum. Use of a chromate of formula (I) according to claim 1 for the preparation of a medicament for the treatment of reflux esophagitis. Use of a chromate of formula (I) according to claim 1 for the preparation of a medicament for the treatment of diarrhea. Use of a chromate of formula (I) according to claim 1 for the preparation of a medicament for the treatment and prevention of all types of arrhythmias, including ventricular and supraventricular arrhythmias. Use of a chromate of formula (I) according to claim 1 for the preparation of a medicament for controlling reentry arrhythmias and preventing sudden cardiac death due to ventricular fibrillation. Medicament, characterized in that it contains an effective amount of a chromate of the formula (I) according to one of claims 1 to 4.