SK60397A3 - Chromans, preparation method thereof, drugs containing the same and their use - 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 acyl, F, Cl, Br, I, NO2, 1-6C alkyl.

Description

Chromates, process for their preparation, medicaments containing them and their use

Technical field

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 formulas I and Ia below are related to a group of 4-acylaminochroman derivatives, extensively investigated over the last decade in drug chemistry, particularly 2,2-dialkyl-4-acylamino-3-chromanols.

The most prominent representative of such 4-acylaminochromans is cromakalim of formula XII

and many subsequent preparations derived therefrom (e.g., Edwards and Weston, TIPS 11, 417-422 (1990), Structure Activity Relationships of K * channel openers).

Cromakalim and other related 4-acylaminochroman derivatives are compounds with a 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. It is common to all of these preparations 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 negative charge in the cell (hyperpolarization) induced by the secretion of potassium ions, treated with secondary mechanisms the increase in intracellular Ca ² *, and thus cell activation, e.g. muscle contraction.

Existing publications describing the correlation between the inhibitory action on the I _sc- channel and the prevention of life-threatening cardiac arrhythmias such as induced by β-adrenergic hyperstimulation include, for example, TJColatsky, CHFollmer, and CFStarmer: 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; AEBusch, K. Malloy, WJGroh, MDVarnum, JPAdelman, and J.Maylie; The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit both _ax channels in xenopus oocytes and I in guinea pig cardiac myocytes, Biochem. Biophys. Res. Commun. (1994) 202: 265-270.

In addition to the aforementioned cromakalime or acylaminochroman derivatives, compounds having a 4-sulfonylaminochroman structure have also been described in the literature over the past years which clearly differ in structure or biological action from the compounds of formula I of the invention and compounds of formula la. European Publication No. 315,009 discloses chroman 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, as regards the basic groups, differently substituted from the compounds of the formula I or Ia below. 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 the so-called adenosine triphosphate (K * (ATP) -sensitive potassium channels). As is known, the pharmacological effects of K * (ATP) channel opening agents are quite different from those described by the IsK channel blockers 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-opening agent described 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 agents opening K * (ATP) channels do not act antiarrhythmically on poorly supplied oxygen 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 K * (ATP) channels. In contrast, the life-threatening profibrilatory effects of the K * (ATP) -channel opening agents on the ill, poorly supplied heart, under these conditions, K * (cAMP) -channel blockers should exhibit antifibrilatory action. As a prominent representative of the now synthesized compounds of formula la, 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 of a highly specific blocker of I- or N -channels with corresponding prolongation of the action potential on the heart (Sufibrich et al., Naunyn Schiedebergs Ar. Pharm. (1996) 353 (4, Supplement), R72; Pflugers Ar. - Eur. J.

Physiol. 431 (6) (Supplement), A. Busch et al., Pflugers Árch. - 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 (EP-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-hydroxy-substituted chromates have been found to effectively block K * (cAMP) -channels (Pflúgers 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 the I-channels on the heart. However, the action of 3-hydroxysubstituted chromates on blocking I of the [ _{alpha] -channels} is clearly less pronounced than that of the corresponding non-hydroxyl-containing chromates of the formula I.

In 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, exhibit 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 agents) have also been described in the prior art , L. 702 958 and L-706 000 (MK 499) J. Pharmakol Exp Ther (1994) 269: 541-

- 554; T.J. Colatsky and T.M. 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 (P.S. Spector, M.E. Curran, M.T. Keating, M. C. Sanguinetti, Circulation Res. (1996) 78: 499 -

- 503; J.J. Lynch et al., J. Pharmacol. Exp. Ther. (1994) 269

541-554). 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 (I-channel). Therefore, spirobenzopyran-piperidines are characterized as being a proarrhythmic component with a risk of increased mortality compared to placebo, as demonstrated by the 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 rectifier K * -channel (I -channel) and thus lacking this proarrhythmic component.

SUMMARY OF THE INVENTION

The invention relates to chromates of the formula I

wherein the radicals R ^x and R ² independently of one another are H, CF, alkyl having 1, 2, 3, 4, 5 or 6 2p + l carbon atoms 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, sulfamoyl group, methylsulfonylamino group and methylsulfonyl group, and p are 1, 2 or 3, or R ¹ and R ² together form an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms,

R ³ represents a group R ⁹ -CH [NR ¹¹ ] -, n 2λ 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,

4, 5 or 6 carbon atoms, or R ¹¹ together with R ⁹ forms an alkylene group having 1, 2,

3,4, 5, 6, 7 or 8 carbon atoms, wherein one CH ₂ in the ^c n ^H 2ri group may be replaced by an oxygen atom, -SO 4 or -NR ¹⁰ , q is 0, 1 or 2, and

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

R ⁴ is R ¹² _{2 R-C r} H _.

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

5, 6, 7 or 8 carbon atoms, piperidyl,

1-pyrrolidinyl, N-morpholino, N-methylpiperazino, C? a pyridyl group, a thienyl group, an imidazolyl group 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, methyl sulfamoyl group and methylsulfonylamino, ar is 1, 2, 3,

4.

5 6 7 8 9 10 11 12 13

14, 15, 16, 17, 18, or 20,

CH is O, -CO-O-, -SO- or -NR ¹⁰ -, CZ where one group in the group CH and 2r is replaced by the group -C = C-, -C = c-, may be

-CO- is 0, 1 or 2,

RX ° is hydrogen, methyl, ethyl, or the radicals R and ^S, R, R and ^W R®, independently of one another are hydrogen, F, Cl, I, alkyl having 1, 2, carbon cycloalkyl having 3 8 carbon atoms, cyano, bromo, or 4 C 3 4, 5, 6, 7 or trifluoromethyl, -C ₂ F _s, -C ₃ F ^, -N _3, -N0 _and , -CONR ¹³ R ^14, -COOR ^{1 s,} R-C ^s H _2s -Y- _with 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,

^{1 S} R is hydrogen, methyl, ethyl, phenyl or -C _u H _2u -NR ¹³ R ^14, u is 2 or 3,

R ^s is hydrogen, cycloalkyl having 3, 4,

5, 6, 7 or 8 carbon atoms, -COOR ^{1 S} , thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, 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, sulfamoyl group and methylsulfonyl group, s is 0, 1, 2, 3 , 4, 5 or 6, t is 1, 2 or 3, and

Y is SO, -C0-, -NR ¹⁰ -SO -, -0-, -NR ^{10 <2} 3 or -CO-NR ^10, wherein R ^e, however, can not represent _a group -OCF ₃ or -0C F _p, and their physiologically acceptable salts.

Preference is given to compounds of the formula I in which R ^{@ 1} and R ^{@ 2} each independently represent a hydrogen atom, a trifluoromethyl group, an alkyl group having 1, 2 or 3 carbon atoms, together form an alkylene chain having 4 or 5 carbon atoms or in each case 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 -CH [NR ¹¹ ] -, n 2n xq

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

R ^xx represents a hydrogen atom or an alkyl group having 1, 2 or 4 carbon atoms,

R ⁴ represents a group R ^X 2 -C 1 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 _and in the group ^C r ^H 2a_ optionally replaced by O, -C0- , -CO-O- or -SO '3 and q is 0, 1 or 2 and the symbols R ^s, R ^6, R ⁷ and R®, independently of one another are hydrogen, F, Cl, Br, iodine atom, alkyl group having 1 or 2 carbon atoms, cyano group, trifluoromethyl group, nitro group,

CONR ^{X 3 X 4} R ,, -COOR ^{XS, X6} R-C _p H _2s -Y- or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl and CF; R ³ and R ^x * independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms,

R ¹⁵ is methyl, ethyl, phenyl or -C _u H _2u -NR ¹³ R ^14, u is 2 or 3,

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

Y is SO ^, -C0-, -NR ¹⁰ -SO ^ -, -0-, -NR ~ ^{1 O,} or NR ¹⁰ -C 0 -, q is 0, 1 or 2, and

R ¹⁰ is H or methyl, wherein R ^e, however, can not represent a group -OCF ₃ or -OC _{of the} F, and the physiologically acceptable salts thereof.

Particular preference is given to compounds of the formula I in which R ^{@ 1} and R ^{@ 2} each independently represent a trifluoromethyl, methyl or phenyl group which is unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy, sulfamoyl and methylsulfamoyl,

R ³ is alkyl having 1, 2, 3 or 4 carbon atoms, dimethylamino or diethylamino,

R ⁴ is R ¹² _{2 R-C r} H _.

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 C _r H _2r may be replaced by an oxygen atom, -CO-, -CO-O- or

-SO q

q is 0, 1 or 2, while R ^a, R ^p, R ⁷ and R® independently of one another, are hydrogen, fluorine, chlorine, bromine, iodine, alkyl having 1 or 2 carbon atoms , cyano, nitro, -COOR ^{1 s,} R-C ^s H _2s -Y _a, or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F and Cl,

R ^X is methyl, ethyl, phenyl or -C H _2u -NR ^{X 3 R: L 4,} in 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 ^, -C0-, -SO ₂ NR ^X °, -O-, NR ^XO or -CO-NR ^xo, q is 0, 1 or 2, and

R ¹⁰ represents a hydrogen atom or a methyl group, but R ^e cannot be -OCF ₃ , and physiologically acceptable salts thereof.

Particularly preferred are the following compounds of formula

I:

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-ethylsulfonyl-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 the formula I contain an acidic or basic group or an optionally heterocyclic group, the invention also relates to the corresponding pharmacologically and toxicologically acceptable salts. Thus, compounds of formula I which contain 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 the 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 the formula I contain an acidic or basic group in a single molecule, the invention also includes, in addition to the abovementioned salts, internal salts, the so-called betaines.

When the substituents of the compounds of the formula I and optionally also of the formula Ia below contain groups permitting different stereochemistry, the possible stereoisomers are also within the scope of the invention. Compounds of formula I or Ia, respectively, contain a chiral center at the 4-position of the chromate system, and the invention includes both the individual pure optical antipodes and 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

(II) in which R ^1, R ^3, R ^3, R ^4, R ^s, R ^6, R ⁷ and R ⁸ defined as above and L is a nucleofugic leaving group customary for the alkylation, in particular Cl, Br, an iodine atom, a CH ₃ SO ₂ -O- group, or a p-toluenesulfonyloxy radical, is reacted in a known manner with the sulfonamide of the formula III or its salts

(III) wherein R ³ and R ⁴ have the same meanings as above but wherein R ⁴ can also be o, and M represents a hydrogen atom or preferably a metal atom, particularly preferably lithium, sodium or potassium, or so, that is

b) a compound of formula IV

(IV) wherein the symbols R ^1, R ^a, R, R ^a, R ^e, R · "R®, and are as defined above, but wherein the symbol RH substituent R ⁴ may also have a value of 0, is reacted with a derivative of sulfonic acid of an acid of formula V

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

c) a compound of formula VI (VI)

wherein the symbols R ^1, R ^2, R ^S, R ^6, R ^W, R ^and M are as defined above, in a conventional manner are subjected to an alkylation reaction with an alkylating agent of formula VII

R ⁴ -L (VII) wherein R ⁴ is as defined above except for hydrogen and L is as defined above, or by

d) in a compound of formula I

R \ w P

R5 N ^{/ Sx} R3

(i) wherein the symbols R ¹ to R ⁴ are as defined above, carried out an electrophilic substitution reaction in at least one of the positions ^R and ^{R, and} wherein the substituent at this position is hydrogen and the remaining substituents R ⁵ and R ^a are as defined above meanings.

Process a) describes the known alkylation of sulfonamides or a salt thereof of formula III with an alkylating chroman derivative of formula II. As the alkylation of the sulfonamide takes place from the salt form, the free sulfonamide (compound of formula III where M is hydrogen) must be prepared by treatment with a base with a base of a sulfonamide (compound of formula III where M is a cation) with higher nucleophilia. 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 using a base commonly used, such as potassium tert-butoxide, sodium methoxide, alkali metal bicarbonates, alkali metal hydroxides such as lithium hydroxide, sodium or potassium hydroxide, or alkaline earth metal hydroxides, for example calcium hydroxide.

It is preferably 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 20 to 140 ° C, particularly preferably between 40 and 100 ° C. More preferably, process a) can be carried out under two-phase catalysis conditions. 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 acid halide (POCl ₃ , PC1 _3, PCl _s, SOC1 _2, sobre ₂₎ or a radical halogenation of the corresponding chroman derivatives (formula II, L = H) with elemental chlorine or bromine or the radical-activatable halogenating agents such as 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 solvent. however, reactions of this type are in most cases carried out using a solvent.

The reaction is preferably carried out by a solvent, preferably in the presence of itself as a solvent, using a polar base which is possible, 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). It is operated at a temperature of 0 to 160 ° C, preferably 20 to 100 ° C.

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

(X) wherein the symbols R ^x, R ^2, R ^S, R ^S, R ⁷ and R® are as defined above and A is oxygen, either using ammonia

or with an amine of formula XI R ⁴ -NH 2 (XI) wherein R ⁴ has the above meaning, while However symbol r v substituent R ⁴ may also have value 0, per reduction catalytic conditions, preferably at higher temperature

autoclaving. In this case, the Schiff base of formula X is formed first by condensation reaction of a ketone of formula X (where A is O) and an amine of formula XI in situ, where A is R @ ⁴ -N =, which is then converted to an 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 form a compound of formula IV. Compounds of formula IV in which R ⁴ represents a hydrogen atom may be advantageously obtained by a method 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 ^XS R ^{X 9} 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 (where A is oxygen) by reaction with hydrazine or a derivative thereof or, for example, with hydroxylamine hydrochloride under conditions in which 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 the formula I according to the invention into other compounds of the formula I, an electrophilic substitution reaction at one or more positions bearing R ^s to R ^s , which in each case represent a hydrogen atom. Preferred substitution reactions are:

1. nitration on the aromatic ring for introduction of 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 chlorosulfonic acid;

4. the Friedel-Crafts acylation reaction to introduce an acyl radical R ^xe -CsH2s-CO- or a sulfonyl radical R _{2 s} ^s -CsH -SO ₂ - by treatment of the corresponding acid chloride R ^s CH-CO or C 1 R ^s CH -SO - C1 in the presence

^ 2 ^ 3,213 2

Lewis acid as Friedel-Crafts catalyst, preferably anhydrous aluminum chloride.

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

in which

R ^A is hydrogen, hydroxy, -O (CO) -alkyl of 1, 2, 3, or 4 carbon atoms in the alkyl portion, or -O-SO ₂ -alkyl of 1, 2, 3, or 4 carbon atoms,

R ^B is H, or the radicals R * · · and R ^B together form a bond, the symbols R ¹ to R ⁴ are as defined above, and

R * ³ represents cyano, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms, fluorine, chlorine, bromine, iodine, nitro or alkyl having 1, 2, 3, 4, 5 or Surprisingly, a strong and specific blocking action on the potassium channel, which opens with cyclic adenosine monophosphate (cAMP) and is fundamentally different from said K * (ATP) channel. Rather, new investigations show that this K * (cAMP) channel identified in the colon appears to be very similar or even identical to the I _sc channel identified in the heart muscle. As a result of this blocking of the K * (cAMP) -channel (= I _sjc -channel), these compounds exhibit pharmacological activity in the living organism with 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., Pflügers Árch. - Eur. J. Physiol. (1995) 429: 517-530.

The compounds of formula I or Ia, as a new class of active compounds, are potent inhibitors of stimulated gastric acid secretion. Thus, the compounds of formula I or Ia are valuable medicaments 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 the formulas I and Ia are furthermore characterized by anti-diarrhea action and are therefore suitable as medicaments for the treatment of diarrhea.

Furthermore, the compounds of formula I may optionally 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 reentry arrhythmias and to prevent sudden cardiac death due to ventricular fibrillation.

The invention also relates to the use of the compounds of formula Ia for the treatment of sudden cardiac death, ventricular fibrillation and, generally, diseased cardiac arrhythmias in which the I-channel is involved.

The compounds of the formulas I and Ia can also be combined with other active substances in order to obtain an advantageous therapeutic effect. Thus, for the treatment of cardiovascular diseases, combinations with cardiovascular active agents are preferably conceivable. Suitable anti-arrhythmic agents, e.g. group I, II or III anti-arrhythmic agents, such as e.g. 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 according to the invention can 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 the formula I or Ia can be used alone or together with galenic auxiliaries, both in veterinary and in human medicine.

One skilled in the art for which excipients are medicaments. In addition to solvents, suppository bases, active ingredient auxiliary agents, agents, dispersants, foaming agents, agents adapted to his / her expert knowledge, it is known to use, for example, antioxidant emulsifiers, flavorants, preservatives, solubilizers or colorants.

For the preparation of an oral dosage form, the active compounds of the formula I are optionally mixed with suitable excipients, such as carriers, stabilizers or inert diluents, and formulated into suitable dosage forms, such as tablets, 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 also sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned above. 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 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 formula I to be administered optionally and the frequency of dosing depends on the potency and duration of action of the compounds used and, moreover, on the type and severity of the disease to be treated as well as the sex, age, weight and individual responses of the mammal being treated.

On average, a 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; at most 300 mg, preferably 1 g.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

(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 with stirring for 2 hours, the solvent is distilled off on a rotary evaporator. and the oily residue is crystallized with water. The product is a crystalline substance with a melting point of 115-118 ° C.

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

A solution of 2,2-dimethyl-4-chromanone oxime (10 mmol) in methanol (75 ml) was hydrogenated in a hydrogen autoclave 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. A crystalline precipitate which is 2,2-dimethyl-4-aminochroman 25

The hydrochloride is filtered off, washed several times with ethyl acetate and dried. The product is colorless crystals having a melting point of 268 ° C.

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

Option 1: To a stirred solution prepared from 4.3 mmol

4-Amino-2,2-dimethylchroman hydrochloride, 15 ml of tetrahydrofuran and 1.25 ml of triethylamine are added in portions 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. Ethanesulfonic acid chloride (0.83 g, 0.0065 mol) was added in portions and the mixture was stirred at room temperature for 2 days. After the solvent has been distilled off on a rotary evaporator, water is added and the separating oil crystallizes after a short time. Melting point 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 at reflux for 50 hours at 50 ° C. 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-ethylsulphonyl-N-methyl-26 amino-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-dimethylchromane under stirring under argon 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

ABOUT

The title compound was 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.

Example 4

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

The title compound was obtained in an analogous manner to that in Example 2 of 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-dinitrochroman

To 4.3 mL of 100% nitric acid cooled to -15 to -20 ° C was added portionwise with stirring, 3.71 mmol of 4-N-ethylsulfonylamino-2,2-dimethylchroman, and the mixture was stirred for further cooling while continuing to cool. 20 minutes. 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 of ethanol and 7 parts of 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

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 pale yellow crystals having a melting point of 198 to 201 C. 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-nitrochroman with hydrogen gas in 150 ml of methanol using Raney nickel as catalyst until the theoretical amount of hydrogen is taken. 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 of melting point 95 - 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 N, N-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

Ο

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 with a melting point of 46-47 ° C.

c) 6-Fluoro-2,2-dimethyl-4-chromanone was obtained analogously 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 gives colorless crystals having a melting point of 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 DEG C., sublimating at a temperature of 296 DEG 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 is 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 was obtained in analogy to 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-chroman, 50 ml of methanol and about 500 mg of palladium catalyst on barium sulfate (10%) is shaken in a shaking duck under a hydrogen atmosphere at 100 kPa. and at 20 ° C until the theoretical amount of hydrogen was 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 6 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 as 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 130-140 ° C, from about 60 ° C, the evolution of hydrogen chloride gas. The mixture is stirred for about 1 hour at 130 ° C, then allowed to cool to 60 to 70 ° C and the mixture is carefully poured 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

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 DEG 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 during 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 to 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, in the form of colorless crystals, m.p. 111-113 ° C.

Example 19

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

The title compound is obtained in an analogous manner to that described in Example 2 from 0.0155 mol of 4-N-ethylsulfonylamino-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 substance with a melting point of 184-187 ° C.

Example 20

6-Methoxycarbonyl-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-carboxy-2,2-dimethylchroman, dimethylamidosulfonic acid chloride and triethylamine in tetrahydrofuran. The product resulted in colorless crystals having a melting point of 127-129 ° C.

Example 21

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

ABOUT

The title compound is 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 described in Example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, sodium hydride and 1-butyl iodide in dimethylacetamide. The product results in the form of a colorless to slightly yellow oily amorphous substance.

Example 23

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

ABOUT

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 was distilled off on a rotary evaporator, water was added to the residue, the pH was adjusted to 0 to 1 with hydrochloric acid, and the colorless crystals were filtered off. Melting point: 235-237 ° C.

Example 24

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

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. The melting point of the product is 202-204 ° C.

Example 25

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

Ο

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 aspirated 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. Melting point: 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 reaction with isopropylsulfonic acid chloride in tetrahydrofuran with an excess of triethylamine. The product results in colorless crystals having a melting point of 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 pale 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 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 described in Example 2 from 4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and butyl iodide in dimethylacetamide. The product is a colorless crystalline substance 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 in Example 1c) from 4-amino-6-methoxycarbonyl-2,2-dimethylchroman by treatment with methanesulfonic acid chloride. The product is a colorless crystalline substance having a melting point of 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 was 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. 245-248 ° C.

Example 33

6-Cyano-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 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 using a mixture of 10 parts of methylene chloride and 1 part of methanol as the eluent. The product is obtained in the form of a colorless to pale yellow crystalline solid, 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 described 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 was obtained in an analogous manner to that in Example 23 from 4-N- (butyl-N-ethylsulfonyl) amino-48-n-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 is 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.

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. 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 described in Example 24 from 6-carboxy-4- [N-ethylsulfonyl-N- (4-picolyl) amino] -2,2-dimethylchroman, as a colorless crystalline compound, m.p. 193-196 ° C.

Example 42

6-piperidinocarbonyl-4-N-ethylsulfonyl-N-methylamino-2,2-dimethylchroman

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 N, N-carbonyldiimidazole and 0.012 mol of piperidine. The product is obtained from ethanol as colorless crystals, m.p. 184 DEG 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 an excess of triethylamine in tetrahydrofuran by heating to reflux. Refluxing 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 results in colorless crystals having a melting point of 111-113 ° C.

Example 44

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

The title compound is 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 described 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

ABOUT

The title compound was obtained in an analogous manner to that described in Example 25 from 6-aminocarbonyl-4- (N-isopropylsulfonyl-N-methyl) amino-2,2-dimethylchroman. After isolation of the product by filtration, it is purified by chromatography on silica gel using a mixture of 10 parts of methylene chloride and 1 part of methanol as the eluent and, after distilling off the solvent, crystallization is carried out using diisopropyl ether. The product results in colorless crystals having a melting point of 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 an analogous manner to that in 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-dimethylchroman

The title compound is 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. .

Example 52

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

The title compound was obtained in an analogous manner to that 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 results in colorless crystals having a melting point of 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

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 with a melting point of 214-216 ° C.

Example 55

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

The title compound was obtained in analogy to Example 24 from 6-carboxy-4- (N-methyl-N-methylsulfonyl) amino-2,2-dimethylchroman, as a colorless crystalline solid, m.p. 179-182 '. 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 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 results in colorless crystals with a melting point of 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-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-2,2,2-dimethylchroman, 0.013 mol of sodium hydride (80% suspension in oil) and 0.0126 mol of 1-propyl iodide in anhydrous dimethylacetamide. The product is a colorless crystalline solid, m.p. 106-108 ° C.

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

Example 59

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. bromomethylcyclopropane in anhydrous dimethylacetamide. The product is a colorless crystalline solid, m.p. 108-110 ° C.

Example 60

4- (N-ethylsulfonyl-N-l-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. 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 20 hours at 60-80 ° C. After distilling off the solvent, a colorless crystalline product with a melting point of 110 DEG C. is obtained from the residue using water.

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- chromanone oxime, followed by 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-6,7-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 resulted in colorless crystals having a melting point of 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-dimethylfromane

(a) 2-fluoro-5-acetoxychlorobenzene is 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 substance, 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- chromanone 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 greater 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-ethylsulfonylamino-chroman 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 was 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 is 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 crystallization of the melt, the second melting point is greater than 310 ° C.

d) 4-ethylsulfonylamino-2,2,6-trimethylchroman was 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 results in colorless crystals having a melting point of 114-117 ° C.

e) 4- (N-ethylsulfonyl-N-methyl) amino-2,2,6-trimethylchroman was 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 was obtained in an analogous manner to that described in Example 63b) from acetic acid (3,4-dichlorophenyl) ester and anhydrous active aluminum chloride. The product results in the form of a colorless to slightly yellow colored crystalline substance with a melting point of 100-103 ° C.

The acetic acid (3,4-dichlorophenyl) ester used is obtained from 34-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 greater than 310 ° C.

e) 6,7-Dichloro-2,2-dimethyl-4-N-ethylsulfonylaminochroman was obtained, analogously to the procedure described in Example 1c) by reaction of 4-amino-6,7-dichloro-2,2-dimethylchroman hydrochloride with with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product results in colorless crystals having a melting point of 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-ethylsulfonylaminochroman 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-dimethylchroman

a) 4,5-Difluoro-2-hydroxyacetophenone was obtained in an analogous manner to that described in Example 63b) from (3,4-difluorophenyl)

an ester of acetic acid and anhydrous aluminum. The product results in the form of a yellow-colored crystalline substance of the active chloride colorless to slightly melting,

- 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 solvent, in addition to the chromanone ring closure, the fluorine atom present in the 7-position is replaced by 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 results in the form of colorless to pale yellow crystals with a melting point of 96-98 ° C.

c) 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone oxime was 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 substance 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- chromanone oxime and treatment in the presence of hydrochloric acid. The product resulted in colorless crystals melting with decomposition at 124-137 ° C.

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 resulted in colorless crystals having a melting point of 157-159 ° C (from a mixture of diisopropyl ether and methanol).

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

-dimethylchroman is obtained in an analogous manner to that described in Example 2 by reacting 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

- (N-Ethylsulfonyl-N-methyl) amino-6-fluorochroman

a) 6-fluoro-4-chromanone oxime was obtained in a manner analogous to that described in Example 1a) from 6-fluoro-4-chromanone and hydroxylamine hydrochloride. The product is a crystalline substance 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 1b) 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-ethylsulfonylaminochroman 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 having a melting point of 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 pale yellow oil.

Example 68

4- (N-butyl-N-ethylsulfonyl) amino-6-fluorochroman

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

Example 69

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

F

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

// ^Ο χ //

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 pale brown crystalline substance with a melting point of 107-110 ° C.

c) 4-amino-6-fluoro-2,2-tetramethylenechroman hydrochloride is 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 results in colorless crystals having a melting point of 111-113 ° C.

e) 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-tetramethylene chromate was 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-tetramety1énchroman

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-pentametylénchroman

a) 6-Fluoro-2,2-pentamethylene-4-chromanone was obtained in analogy to 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 analogous manner to that described in Example 1a) from 6-fluoro-2,2-pentamethylene-4-chromanone and hydroxylamine hydrochloride, in the form of a viscous amorphous product.

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

e) 4- [N-ethylsulfonyl-N- (4,4,4-trifluorobutyl)] amino-6-fluoro-2,2-pentamethylenechroman was 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 (4-ethylphenyl) acetic acid esters and anhydrous aluminum chloride. The product results in the form of a light yellow colored 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 a 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. Melting point: 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 ethanesulfonic acid chloride to give presence of triethylamine in tetrahydrofuran. The product results in colorless crystals having a melting point of 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 results in colorless crystals having a melting point of 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 resulted in a colorless to pale 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 results in the form of a viscous light 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 results in the form of a viscous light 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 results in the form of 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 results in the form of a light yellow colored oil, which partially crystallizes.

The 4-acetoxybiphenyl used is obtained from 4-hydroxybiphenyl and acetic anhydride by an analogous procedure 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 acetonitrile as solvent, as a dark oily amorphous product. , which partially crystallizes.

c) 2,2-Dimethyl-6-phenyl-4-chromanone oxime was 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 213-214 ° C.

e) 4-N-ethylsulfonylamino-2,2-dimethyl-6-phenylchroman was obtained in an analogous manner to that described in Example 1c) by reaction

4-amino-2,2-dimethyl-6-phenylchroman hydrochloride with ethanesulfonic acid chloride in the presence of triethylamine in tetrahydrofuran. The product resulted in colorless crystals having a melting point of 162-164 ° C.

f) 4- (N-ethylsulfonyl-N-methyl) amino-6-phenyl-2,2-dimethylchroman was 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 resulted in colorless crystals having a melting point of 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 with a melting point of 112-114 ° C.

Example 84

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

a) 3,5-Difluoro-2-hydroxyacetophenone was obtained in analogy to 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 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, in 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 workup in the 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 with ethanesulfonic acid chloride 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 having a melting point of 84-86 ° C.

Example 85

6,8-Difluoro-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 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 reacting 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-2,2,2-dimethylchroman. 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

Ο

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

Example 89

6-Carboxy-4- (N-cyclopropylmethyl-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-cyclopropylmethyl-N-ethylsulfonyl) amino-6-methoxycarbonyl-2,2-dimethylchroman. The product is a colorless crystalline compound with a melting point of 184-188 ° C.

Example 90

6-Carboxy-4- (N-ethylsulfonyl-N-pentyl) 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-pentyl) amino-6-methoxycarbonyl-2,2-dimethylchroman. The product is a colorless crystalline compound with a melting point of 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 having a melting point of 154-158 ° C

Example 92

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

Ο

The title compound was 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 substance having a melting point of 173-175 ° C.

Example 93

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

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 with a melting point of 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 was 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 substance having a melting point of 168-172 ° C.

Example 96

6-aminocarbonyl-4- (N-ethylsulfonyl-N-hexyl) amino-2,2-dimethylchroman

The title compound was obtained in an analogous manner to that described in Example 24 from 6-carboxy-4- (N-ethylsulfonyl-N-hexyl) amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia. The product is a colorless crystalline substance 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 10 parts of a 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 99

6-cyano-4- (N-cyclopropylmethyl-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-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 is 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 10 parts of a 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 10 parts of methylene chloride and 1 part of 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 having a melting point of 73-74 ° C.

Example 104

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

The title compound is obtained analogously to the procedure indicated in Example 2 from 4-ethylsulfonylamino-N-6-fluoro-2 _{R2-dimethylchroman} and isopropyl bromoacetate. The product is a colorless to pale 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 substance 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 potassium carbonate powder, add the remainder (3.6 ml) of methyl iodide and heat the reaction mixture for 20 hours at 50-55 ° C. The solvent was removed by distillation in vacuo, water was added to the residue and the oil was separated and 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. The melting point of the product is 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 a manner analogous to that described in Example 2 from 4-N-ethylsulfonylamino-6-methoxy-2; 2-dimethylchroman and methyl iodide. The product results in colorless crystals having a melting point of 68-70 ° C,

Example 106

4-N-ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyloxychroman

Ο

II Ο

(a) 2,2-dimethyl-6-methylsulfonyloxychromanone

A mixture of 0.03 mol of 6-hydroxy-2,2-dimethyl-4-chromanone, 16.1 g of anhydrous powdered potassium carbonate and 10 ml of methanesulfonic acid in 80 ml of anhydrous dimethylformamide is 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 with a melting point of 108-110 ° C.

b) 2,2-Dimethyl-6-methyl-4-sulfonyloxychromanone oxime was 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. Melting point: 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 with presence of triethylamine in tetrahydrofuran. The product resulted in a colorless crystalline substance having a melting point of 97-100 ° C.

Example 107

4- (N-Ethylsulfonyl-N-methyl) amino-2,2-dimethyl-6-methylsulfonyloxychroman

ABOUT

The title compound was obtained in an analogous manner to that described in Example 2 from 4-N-ethylsulfonylamino-2,2-dimethyl-6-methylsulfonylchroman and methyl iodide. The product resulted in colorless crystals having a melting point of 137-139 ° C.

Example 108

4- (N-methylsulfonyl-N-ethyl) 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 ethyl iodide. The product results in colorless crystals having a melting point of 119-121 ° C.

4-Amino-2,2,6,7-tetramethylchroman hydrochloride (with a melting point of more than 270 ° C) is prepared by hydrogenation

2,2,6,7-tetramethyl-4-chromanone oxime (m.p. 162-163 ° C). The oxime is prepared according to known methods as described above 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-2,2, respectively. 6,7-tetramethylchroman as a colorless oil.

Example 109

4- (N-methylsulfonyl-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-methylsulfonylamino-2,2,6,7-tetramethylchroman and methyl iodide. The product results in colorless crystals having a melting point of 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-tetramethyl

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 results in colorless crystals having a melting point of 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 resulted in colorless crystals having a melting point of 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 results in colorless crystals having a melting point of 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. Reaction 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-methoxy, respectively. -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 sequential synthetic steps mentioned above, starting from 6-hydroxy- 2,2-dimethyl-4-chromanone (obtained from 2-acetoxyhydroquinone and acetone, m.p. 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-chromanone 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. The melting point of the product is 160-170 ° C.

6- (4-bromophenyl) -4-N-ethylsulfonylamino-2,2-dimethylchroman (m.p. 122-135 ° C) is obtained by the sequential synthetic steps mentioned above, 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-chromanone oxime by catalytic hydrogenation using Raney 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.

100

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 results 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 a racemic mixture of 4- (N-ethylsulfonyl-N-methyl) amino-6-fluoro-2,2-dimethylchroman by chiral chromatography (CSP Chiralpak AD 250) 4.6) using n-hexane / ethanol (40: 1) as eluent.

Example 121

(+) -4- (N-butyl-N-ethylsulfonyl) amino-6-fluoro-2,2-dimethylchroman and (-) - 4- (N-butyl-N-ethylsulfonyl) amino-6-fluoro enantiomers -2,2-dimethylchroman ([a] = -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.

101

Example 122

4- (N-methylsulfonyl-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

102

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:

I ~ _sic channels from man, rat or guinea-pig were expressed in Xenopus laevis oocytes (Xenopus). To this end, oocytes from Xenopus laevis were first isolated and defoliated. RNA encoding I was then injected in vitro into these oocytes. After 2 to 8 days, the expression of the .beta.-protein was determined by measuring the _.beta. -currents using a technique using two voltage-clamp microelectrodes. I-Channel _{by a cluster} are activated while generally lasting 15 s using voltage jumps to -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-piperazinethanesulfonic 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 Instrument, Foster City, USA) and a MacLab D / A converter and software (ADIinstruments, Castle Hill, Australia). 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. Data was eventually extrapolated

103 using the Hill equation in order to determine the IC values _of the 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 H. G., Waldegger S., Samarzija I., Súbrich H., Raber G., Kunzelmann K., Ruppersberg J.P. and Lang F. (1995), Inhibition of both exogenously expressed I and endogenous K + channels in Xenopus oocytes by isosorbide dinitrate. J.Physiol 491: 735-741;

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

Varnum 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].

104

compound Example # IC for IC 50 ^c ΘΚ (in gmol / l) 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 _with P ^re

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

tylchroman 293B * ' 6.9 + 0.4 trans-6-Cyano-4- (N-methylsulfonyl-N-methylamino) -3-hydroxy-2,2-dimethylchroman 374B * ' 19.2 + 1.2 trans-6-cyano-4- [N- (dimethylamino) sulfonyl-N-methylamino] -3-hydroxy-2,2-dimethylchroman 377B * ' 14.6 + 0.5 trans-6-Cyano-4- [N- (1-butylsulfonyl) -N-methylamino] -3-hydroxy-2,2-dimethylchroman 360B * ' 58.8 + 1.8

The legend:

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, Pfliigers-Arch - Eur. J. Physiol (1995) 429: 517-530.

105

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 thus obtained were treated with collagenase at a concentration of 1 mg / ml. 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 ( ^{X 4} C-AP) was determined as a measure of the acid-producing capacity of the stomach glands (3). To this end, 1 ml gland suspension samples were incubated with 1 µmol (200,000 cpm; pulses per minute) of ¹⁴ C-aminopyrine and the test compound and kept for 20-30 minutes at 37 ° C with shaking in aqueous bath. Then, histamine (100 μιηοΐ), dbcAMP (0.3 or 1 mmol) or carbachol (100 Mmol) 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 collected 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.

106

Results: 6-cyano-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethyl-3-chromanol caused a concentration-dependent inhibition of stimulated accumulation of aminopyrine with an IC 20 equal _{to the} stimulation pmoles of histamine and dbcAMP. as well as 5 Mmol 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 HOE 760 Antagonist Receptor (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 (20)

PATENT CLAIMS 1. Chromates of the formula I R 5 R \ // \\ ° 5 ° N ^{/ S x} R ³ R6 R7 R8 R 2 R1 (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, which is unsubstituted or substituted by one or two substituents selected from the group consisting of 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 having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, R ³ represents a group R ® -CH [NR ¹¹ ] * n 2n xn 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, 108 m has a value of 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 ^xx together with R ⁹ form an alkylene group having 1, 2, 3,4, 5, 6, 7 or 8 carbon atoms, wherein one CH ₂ in ^{c 1 H} _2ri may be replaced by an oxygen atom, -SO 4 or -NR ^XO , q is 0, 1 or 2, and R ¹⁰ represents a hydrogen atom, a methyl group or an ethyl group, R ⁴ represents a group ^{RX 2 -c} r ^H 3, _r / R ^{@ 2} represents a hydrogen atom, a cycloalkyl group having 3,4, 5, 6, 7 or 8 carbon atoms, piperidinyl, 1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CF, pyridyl, thienyl, imidazolyl or phenyl which is unsubstituted or substituted by one or two substituents selected from 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 group may be replaced by an oxygen atom, -C = C-, -c = c-, -CO-, -CO-O-, -SO- or -NR ^XO- , <3 109 q is 0, 1 or 2, and R ¹⁰ is H, methyl or ethyl, and the radicals R ^a, R ^e, R ⁷ and R ^s independently of one another are hydrogen, F, Cl, I, alkyl having 1, 2, carbon C 3-8 cycloalkyl, cyano, bromine, 3 or 4, 4, 5, 6, 7 or trifluoromethyl, -C ₂ F _s , -C _and F _v , -N ₃ , -NO ₂ , -CONR ^{X 3 X 4} R, -COOR ^{x s,} R ^s C _s H _{2 s} ~ 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 ^X is H, methyl, ethyl, phenyl or -C _u H _2u -NR ^{X 3 X 4} R, u is 2 or 3, R ¹⁶ represents hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, -COOR ^XS , thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 1-pyrrolidinyl , N-morpholino, N-methylpiperazino, CF or phenyl which is unsubstituted or substituted by one or two substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy, sulfamoyoy 110 is methyl and methylsulfonyl, s is 0, 1, 2, 3, 4, 5 or 6, t is 1, 2 or 3, and Y is SO ^, -C0-, -NR ¹⁰ -SO ^ -, -0-, -NR ^{1 O} ~ or -CO-NR ^ro, wherein R® but can not represent a group -OCF ₃ or -OC ₂ F _s, and physiologically acceptable salts thereof. Chromates of the 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, 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 -CH [NR ¹¹ ] n. 2 xi xn 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 _{2 S?} . 111 R ^{X 2} is hydrogen, cycloalkyl 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 the group consisting of F, Cl, trifluoromethyl, sulfamoyl and methylsulfonyl, ar is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, one CH being, _and can be replaced by an oxygen atom, -CO-, -CO- O- or -SO-, < 3 q has a value of 0, 1 or 2, and R ^s , R ^e , R ^v and R ® independently of one another are hydrogen, fluorine, chlorine, bromine, iodine , alkyl having 1 or 2 carbon atoms, cyano, trifluoromethyl, nitro, CONR ^{X 3 X 4} R, -COOR ^{x s,} R _{^16, and} C H _2s -Y- or phenyl, which is unsubstituted or substituted by a substituent selected from file including fluorine, chlorine and trifluoromethyl, R ^{@ 3} and R @ ^{14 are} each independently hydrogen or alkyl having 1, 2 or 3 carbon atoms, R ^X is methyl, ethyl, phenyl or -C _u H _2u -NR ^{X 3 X 4} R, u is 2 or 3, R ^X6 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 112 is 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 ^, -C0-, -NR ¹⁰ -SO ^ -, -0-, -NR ^XO or -CO-NR ¹⁰ -, q is 0, 1 or 2, and R ¹⁰ represents a hydrogen atom or a methyl group, but R ^e cannot be -OCFa or " ^OC 2 ^F _S" ; Chromates of formula I according to claim 1 or 2, in which 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, 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 ^12, -C _r H, R ¹² represents a hydrogen atom, a C 5 or 6 cycloalkyl group or a trifluoromethyl group, and 113 r has a value of 1, 2, 3, 4, 5, 6, 7 or 8, wherein one CH ₂ group in the group can be replaced by an oxygen atom, -CO-, -CO-O- or -SO-, q has 0, 1 or 2, while R ^a, R ^e, R @ ^-7 and R ^{independently} of one another are hydrogen, F, Cl, Br, I, alkyl having 1 or 2 carbon atoms, cyano, nitro, -COOR ^{xs, xe} R-C _p H _2Q-Y- or 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 _u H _2u -NR ^{X 3 X 4} R, u is 2 or 3; R ¹³ and R ^* *, independently of one another are hydrogen or alkyl having 1 , 2 or 3 carbon atoms, R ^x5 represents a hydrogen atom, a trifluoromethyl group or a phenyl group, with 0, 1, 2, 3, or 4 Y is SO ^, -CO-, -SO ₂ NR ^X °, -0-, -C 0 DB or DB ^xo, q is 0, 1 or 2, and R ¹⁰ is hydrogen or methyl, but R ⁶ cannot be -OCF _a . Chromates of the formula I according to claims 1 to 3, selected from the group consisting of 114 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-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-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, and 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 1, characterized in that a) a compound of formula II in which R ^x, R ^a, R ^3, R ^4, R ^s, R ^6, R ⁷ and R ^and the aforementioned meanings and L represents a nucleofugic leaving group customary for alkylation, in particular chlorine, bromine, iodine, CH ₃ SO ₂ -O-, or a p-toluenesulfonyloxy radical, are reacted with a sulfonamide of formula III or a salt thereof 115 (III) 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 wherein R ¹ , R ³ , R ⁴ , R ®, and R ⁸ are as defined above, is reacted with a sulfonic acid derivative of formula V R ³ -SO-W wherein R ³ is as hereinbefore defined nucleofugally leaving group, such as an atom or 1-imidazolyl group, but especially that (V) and W are fluorine, bromine is chlorine, or c) a compound of formula VI R 5 | N ^{/ V X} R3 R ⁶ _X r 1 Ϊ 1 _X R2 R7 ^X < _R1 (VI) 116 in which the symbols R ^X, R ^2, R ^S, R ^S, 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) wherein R ⁴ is as defined above except for hydrogen and L is as defined above, or C (d) in the chromate of the formula I (I) □ 4 θ / / θ ¾ R 5 N R 3 ^R \ AJX wherein the symbols R ¹ to R ⁴ are as defined above, carried out an electrophilic substitution reaction in at least one of the positions ^R and R ^8, wherein the substituent at this position is hydrogen and the remaining radicals R ^B to R ⁸ are as defined above. The use of a chromate of the formula I according to claim 1 for the preparation of a medicament for blocking a cyclic adenosine monophosphate, C 1 -channel, 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 the formula I according to claim 1 for the preparation of a medicament for the treatment of gastric and intestinal ulcers, in particular the duodenum. 117 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. The 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. Use of a chromate of formula Ia (Ia) in which R ^A represents -alkyl of 1, hydrogen, hydroxy, 2, 3 or 4 carbon atoms in the -O (CO) alkyl moiety or -O-SO ₂ -alkyl having 1, 2, 3 or 4 carbon atoms, 118 R ^B is H, or the radicals R ^A and ^R together form a bond, the symbols R ¹ to R ⁴ are as defined in Claim 1, and R ^c is cyano, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms, F, Cl, Br, I, nitro, alkyl having _1, 2,3,4,5 or 6 for the preparation of a medicament for blocking the K * channel, which is opened by cyclic adenosine monophosphate, cAMP. Use of a chromate of formula Ia according to claim 6 for the preparation of a medicament for inhibiting gastric acid secretion. Use of a chromate of formula Ia according to claim 6 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 Ia according to claim 6 for the preparation of a medicament for the treatment of reflux esophagitis. Use of a chromate of formula Ia according to claim 6 for the preparation of a medicament for the treatment and prevention of all types of arrhythmias, including ventricular and supraventricular arrhythmias. The use of a chromate of formula Ia according to claim 6 for the preparation of a medicament for controlling reentry arrhythmias and preventing sudden cardiac death due to ventricular fibrillation. 119 ♦ · x ' Use of 6-cyano-4- (N-ethylsulfonyl-N-methyl) amino-2,2-dimethyl-3-chromanol as a chromate of formula Ia according to claim 6 for the preparation of a medicament for inhibiting gastric acid secretion.