RU2041875C1 - Sulfur-containing heterocyclic compounds or pharmaceutically acceptable salts thereof - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: the product: sulfur- containing heterocyclic compounds of the formula:

Description

 The invention relates to sulfur-containing heterocyclic compounds and their salts, which are useful for the treatment of osteoporosis.

 The compounds and salts of the invention have an inhibitory effect on bone resorption and inhibit the quantitative loss of bones caused by the release of calcium from bones into the blood.

 With a disease such as osteoporosis, the loss of calcium in the bone leads to bone fragility and its tendency to fracture.

 The main manifestations of osteoporosis are kyphosis and destruction of the thoracic vertebra, destruction of the lumbar vertebra, femoral neck, peripheral ends, radial endings, ribs, proximal ends of the humerus, etc. The cause of these diseases is different and it depends on a number of factors, ranging from endocrine disorders to nutrition-related disorders. The drugs used for such diseases are estrogens, calcitonin (a calcium-regulating hormone), vitamin D, calcium preparations, etc.

 However, these drugs are not effective enough in that the number of symptoms and patients to be treated is limited and, in addition, they are not effective enough in preventing or reducing bone loss.

 Preferred Aspects of the Invention

(I) заместитель или заместители кольца (А), т. е. бензольного кольца, которое может быть замещенным, включают наряду с другими галогены, нитрогруппы, алкильные группы, которые могут быть замещенными; оксигруппы, которые могут быть замещенными; тиол, который может быть замещенным, амино, ацильные группы, моно- или диалкоксифосфорил, фосфоногруппу, арильные группы, которые могут быть замещенными, аралкильные группы, которые могут быть замещенными, и/или ароматические гетероциклические группы, которые могут быть замещенными. Бензольное кольцо может быть замещенным указанными заместителями в количестве от 1 до 4, и предпочтительно 1 или 2, которые могут иметь одинаковые или различные значения.In the formula

(I) a substituent or substituents of a ring (A), i.e., a benzene ring which may be substituted, include, among others, halogens, nitro groups, alkyl groups which may be substituted; hydroxy groups which may be substituted; thiol, which may be substituted, amino, acyl groups, mono- or dialkoxyphosphoryl, phosphono group, aryl groups which may be substituted, aralkyl groups which may be substituted, and / or aromatic heterocyclic groups which may be substituted. The benzene ring may be substituted by the indicated substituents in an amount of from 1 to 4, and preferably 1 or 2, which may have the same or different meanings.

 Said halogens include fluoro, chloro, bromo and iodo. Alkyl groups or alkyl units of substituted alkyl groups are preferably straight or branched chain alkyl groups containing from 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. and cycloalkyl groups containing 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, etc. and these alkyl groups may be substituted with 1-3 substituents such as halogen (e.g. fluorine, chlorine, bromine and iodine), hydroxy group, alkoxy group containing 1-6 carbon atoms (e.g. methoxy, ethoxy, propoxy, butoxy and hexyloxy) mono- or di (alkoxy with a content of 1-6 at. C) phosphoryl groups, phosphono group, etc.

 Examples of such substituted alkyl groups are trifluoromethyl, trifluoroethyl, trichloromethyl, hydroxymethyl: 2-hydroxyethyl, methoxyethyl, 1-methoxyethyl, 2-methoxyethyl, 2,2-diethoxyethyl, 2-diethoxyphosphoryl, 2-phosphonoethyl, etc.

Substituted oxy groups include, among others, alkoxy, alkenyloxy, aralkyloxy, acyloxy and aryloxy groups. Said alkoxy groups are preferably straight or branched chain alkoxy groups having from 1 to 10 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, nonyloxy, etc. or cycloalkoxy groups containing 4-6 carbon atoms, such as cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. Said alkenyloxy group is preferably an alkenyloxy group of 2-10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylyloxy, 2-cyclohexenyloxy group, etc. The aralkyloxy group is preferably an aralkyloxy group containing from 6 to 19 carbon atoms or more, preferably a C _6-14 aryl-C _1-4 alkoxy group such as benzyloxy, phenethyloxy, etc. The acyloxy group is preferably an alkanoyloxy group, a C _2-10 alkanoyloxy group such as an acetyloxy, propionyloxy, n-butyryloxy, hexanoyloxy group, etc. The aryloxy group is preferably a C _6-14 aryloxy group such as a phenyloxy, biphenyloxy group, etc. These groups can be further substituted by 1-3 substituent groups, such as the indicated halogens, hydroxy, C _1-6 alkoxy groups and mono- or di (C _1-6 alkoxy) phosphoryl groups. Examples of such substituted hydroxy groups are trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl) ethoxy, etc.

A thiol that may be substituted includes, among others, alkylthio, aralkylthio and acylthio groups. Alkylthio groups are preferably straight or branched chain alkylthio groups of 1 to 10 C atoms, such as methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, nonylthio, etc. or With _4-6 cycloalkylthio groups such as cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. Aralkylthio groups are preferably C _7-9 aralkylthio groups, and even more preferably C _6-14 aryl-C _1-4 alkylthio groups such as benzylthio, phenethylthio, etc. Acylthio groups are preferably alkanoylthio groups, especially C _2-10 alkanoylthio groups such as acetylthio, propionylthio, n-butyrylthio, hexanoylthio, etc. These groups can be further substituted by 1-3 substituent groups, such as the indicated halogens, hydroxy group, C _1-6 alkoxy groups and / or mono- or di (C _1-6 alkoxy) phosphoryl groups. Examples of such substituted thiol are trifluoromethylthio, 2,2,2-trifluoroethylthio, 2-methoxyethylthio, 4-chlorobenzylthio, 3,4-dichlorobenzylthio, 4-fluorobenzylthio, 2- (3,4-dimethoxyphenyl) ethylthio, etc. .

Substituents of said substituted amino groups include, among others, the above C _1-10 alkyl groups, C _2-10 alkenyl groups (such as allyl, vinyl, 2-penten-1-yl, 3-penten-1-yl, 2- hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2-methyl-2-propen-1-yl, 3-methyl-2-buten-1-yl, etc. .), aryl groups with a content of 6-14 at. C, aralkyl groups with a content of 7-19 at. C. These substituents may have the same or different meanings and their number may be 1 or 2. These substituents may be further substituted by various groups of substituents, such as said halogens, alkoxy groups containing 1 to 3 C atoms, mono or di (C _{1 -6} alkoxy) phosphoryl groups and phosphono groups. Examples of said substituted amino group are methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, N-methyl-N- (4-chlorobenzyl) amino, N, N-di (2- methoxyethyl) amino groups, etc.

The acyl group includes acyl groups derived from organic carboxylic acids and groups derived from sulfonic acids having hydrocarbon groups of 1 to 6 C atoms (such as methyl, ethyl, n-propyl, hexyl, pentyl, etc. ) Acyl groups derived from organic carboxylic acids include formyl, C _1-10 alkylcarbonyl groups (such as acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, octanoyl, cyclobutanecarbonyl, cyclohexanecarbonyl, cyclopentanecarbonyl, etc.), C _{2 -10} alkenylcarbonyl groups (such as crotonyl, 2-cyclohexenecarbonyl, etc.), _C6-14 arylcarbonyl groups (such as benzoyl, etc.), _C7-19 aralkylcarbonyl groups (such as benzylcarbonyl, benzhydrocarbonyl , etc.), 5- or 6-membered aromatic heterocyclo-carbonyl groups ( Which as the nicotinyl, 4-thiazolylcarbonyl, etc.), 5- or 6-membered aromatic geterotsikloatsetilnye groups (such as 3-pyridylacetyl, 4-tiazolilatsetil, etc.), and others. Acyl groups derived from sulfonic acids having C _1-6 hydrocarbon groups include methanesulfonyl, ethanesulfonyl, etc. These groups can be further substituted by 1-3 substituent groups, such as the indicated halogens, hydroxy groups, C _1-6 alkoxy groups, amino groups. Examples of said substituted acyl groups are trifluoroacetyl, trichloroacetyl, 4-methoxybutyryl, 3-cyclohexyloxypropionyl, 4-chlorobenzoyl, 3,4-dimethoxybenzoyl, etc.

 Mono- or dialkoxyphosphoryl groups are preferably di-lower alkoxyphosphoryl groups, such as dimethoxyphosphoryl, diethoxyphosphoryl, dibutoxyphosphoryl, etc. Preferred examples of the aryl units of said substituted aryl groups are aryl groups containing 6-14 carbon atoms, such as phenyl, naphthyl, antryl, etc. and these groups can be substituted by 1-3 substituent groups, such as said alkyl groups containing 1-6 C atoms, halogens, hydroxy groups and alkoxy groups containing 1-6 C atoms. Examples of such substituted aryl are 4-chlorophenyl, 3,4- dimethoxyphenyl, 4-cyclohexylphenyl, 5,6,7,8-tetrahydro-2-naphthyl, etc.

The aralkyl unit of said aralkyl group which may be substituted includes most preferably C _7-19 aralkyl groups such as benzyl, naphthylethyl, trityl, etc. and these groups may be substituted in the ring by 1-3 substituent groups, such as the indicated C _1-6 alkyl groups, halogens, hydroxy groups and C _1-6 alkoxy groups. Examples of such substituted aralkyl groups are 4-chlorobenzyl, 3,4-dimethoxybenzyl, 4-cyclohexylbenzyl, 2- (5,6,7,8-tetrahydro-2-naphthyl) ethyl, etc.

The aromatic heterocyclic units of said aromatic heterocyclic groups which may be substituted are preferably 5- or 6-membered aromatic heterocyclic groups containing 1-4 nitrogen, oxygen and / or sulfur atoms, such as furyl, thienyl, imidazolyl, thiazolyl, oxazolyl thiadiazolyl, etc. and these groups can be substituted with 1-3 substituent groups, such as the above C _1-6 alkyl groups, halogens, hydroxy groups and C _1-6 alkoxy groups.

When the benzene ring is substituted with two alkyl groups in adjacent positions, these groups can form an alkylene group of the formula - (CH ₂ ) _m in which m is an integer of 3 to 5 (such as trimethylene, tetramethylene and pentamethylene), and when substituted with two alkoxy groups in adjacent positions, they can form an alkylenedioxy group of the formula —O— (CH ₂ ) _n —O— in which n is an integer of 1-3 (such as a methylenedioxy group, an ethylenedioxy group and a trimethylene dioxo group). In such cases, a 5-7 membered ring with carbon atoms of the benzene ring is formed.

 Hydrocarbons of said hydrocarbon groups which may be substituted, R include, among others, said alkyl groups (preferably alkyls containing 1-10 at. C), alkenyl groups (preferably alkenyls containing 2-10 at. C), aryl groups (preferably aryls containing 4-16 at. C) and aralkyl groups (preferably aralkyls containing 7-19 at. C). Substituents of such hydrocarbons include, among others, these 5- or 6-membered aromatic heterocyclic groups, halogens, dialkoxyphosphoryl groups, phosphono groups, etc.

Preferred examples of R are unsubstituted C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc.

The carboxyl B esterified to the ester includes, among others, alkoxycarbonyl groups, preferably alkoxycarbonyl groups containing 1-10 at. C (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), aryloxycarbonyl groups, preferably C _6-14 aryloxycarbonyl groups (such as phenoxycarbonyl, etc.) and aralkyloxycarbonyl groups, preferably C _7-19 aralkyloxycarbonyl groups (such as benzyloxycarbonyl, etc.).

The amidated carboxyl group B is preferably a carbamoyl group of the formula —CONR ₁ R ₂ in which R ₁ and R ₂ each represents a hydrogen atom, a hydrocarbon group which may be substituted or a 5- or 7-membered heterocyclic group which may be substituted .

The hydrocarbons of said hydrocarbon groups which may be substituted, R ₁ and R ₂ , include, among others, alkyl groups, preferably said C _1-10 alkyl groups, alkenyl groups, preferably said C _2-10 groups, aryl groups, preferably said C _6-14 aryl groups, and aralkyl groups, preferably said C _7-19 aralkyl groups, and these groups can be substituted with 1-3 substituent groups, such as, for example, halogens (such as fluorine, chlorine, bromine and iodine), hydroxy groups, _C1-6 alkoxy groups, amino groups, to torye may be substituted with C _1-6 alkyl (e.g. dimethylamino, diethylamino, dipropylamino, etc.), amino substituted by acyl (e.g., C _1-10 alkanoyl groups) (such as atsetilaminopropionilamino, benzoylamino, etc.) carbamoyl, which may be substituted C _1-6 alkyl (such as dimethylcarbamoyl, ethoxycarbamoyl, dipropylcarbamoyl, etc.), C _1-6 alkoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), mono- or dialkoxyphosphoryl ( such as dimethoxyphosphoryl, etc.), a phosphino group and said aromatic heterocyclic groups.

(5 -) - (7)-membered heterocycles of the indicated (5 -) - (7)-membered heterocyclic groups which may be substituted, R ₁ and R ₂ include, among others, (-5) - (7) - membered heterocycles containing one atom of sulfur, nitrogen or oxygen, 5- or 6-membered heterocycles containing from 2 to 4 nitrogen atoms, and 5- or 6-membered heterocycles containing 1-2 nitrogen atoms, and one sulfur atom or oxygen, each of these heterocycles can be condensed with a 6-membered ring containing a maximum of 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom.

 Preferred examples of (5-) - (7)-membered heterocyclic groups are pyridyl, pyrimylyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,8-naphthyridinyl, quinolyl , thieno [2,3-b] pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpolinyl, d.

и примерами такого кольца являются морфолин, пиперидин, тиоморфолин, гомопиперидин, пиперидин, пирролидин, тиазолидин, азепин и т.д.R ₁ and R ₂ together with each other can form a (5 -) - (7) -membered ring of the type -N

and examples of such a ring are morpholine, piperidine, thiomorpholine, homopiperidine, piperidine, pyrrolidine, thiazolidine, azepine, etc.

Examples of said substituted alkyl groups, R ₁ or R ₂ , are trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl, 2-pyridylmethyl, 3 -pyridylmethyl, 4-pyridylmethyl, 2- (2-thienyl) ethyl, 3- (3-furyl) propyl, 2-morpholinoethyl, 3-pyrrolylbutyl, 2-piperidinoethyl, 2- (N, N-dimethylamino) ethyl, 2- (N-methyl-N ethylamino) ethyl, 2- (N, N-diisopropylamino) ethyl, 5- (N, N-dimethylamino) pentyl, N, N-dimethylcarbamoylethyl, N, N-dimethylcarbamoylpentyl, ethoxycarbonylmethyl, isopropoxycarbonylethyl, butoxycarbon ilpropyl, 2-diethoxyphosphoryl ethyl, 3-dipropoxyphosphorylpropyl, 4-dibutoxyphosphorylbutyl, ethylenedioxyphosphorylmethyl, 2-phosphonoethyl, 3-phosphonopropyl, etc. Examples of said substituted aralkyl groups, R ₁ or R ₂ , are 4-chlorobenzyl, 3- (2-fluorophenyl) propyl, 3-methoxybenzyl, 3,4-dimethoxyphenethyl, 4-ethylbenzyl, 4- (3-trifluorophenyl) butyl, 4 -acetylaminobenzyl, 4-dimethylaminophenethyl, 4-diethoxyphosphorylbenzyl, 2- (4-dipropoxyphosphorylmethylphenyl) ethyl and others. Examples of said substituted aryl, R ₁ or R ₂ , are 4-chlorophenyl, 4-cyclohexylphenyl, 5,6,7,8-tetrahydro-2-naphthyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 6-methoxy-2-naphthyl, 4- (4-chlorobenzyloxy) phenyl, 3,4-methylenedioxyphenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4-propionylphenyl, 4-cyclohexanecarbonylphenyl, 4-dimethylaminophenyl, 4- benzoylaminophenyl, 4-diethoxycarbamoylphenyl, 4-tert-butoxycarbonylphenyl, 4-diethoxyphosphorylphenyl, 4-diethoxyphosphorylmethylphenyl, 4- (2-diethoxyphosphorylethyl) phenyl, 2-diethoxyphosphorylmethylphenyl, 3-diethoxyphosphorylmethylphenyl phenyl, 4-dipropoksifosforilfenil, 4- (2-phosphonoethyl) phenyl, 4-fosfonome- tilfenil, 4-fosfonofenil and others. Examples of the indicated (5 -) - (7)-membered heterocyclic groups, R ₁ or R ₂ , are 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, 5-methyl-2-benzothiazolyl, 5- methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl, 4- (4-chlorophenyl) -5-methyl-2-oxazolyl, 3-phenyl-1,2,4-thiadiazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5-dimethyl-2-furanyl, 4-methyl-2-morpholinyl and others. Of these groups, ring A is preferably a benzene ring, which may be substituted by halogen, alkyl and / or alkoxy.

The substituent group B is preferably an alkoxycarbonyl group or a group of the formula —CONR ₁ R ₂ in which R ₁ and R ₂ each represents a hydrogen atom, a hydrocarbon group which may be substituted, or a (5 -) - (7)-membered heterocyclic a group that may be substituted.

 The substituent R is preferably a hydrogen atom, an alkyl containing 1-10 C atoms or a phenyl group.

 A compound of formula (I) or a salt thereof can be prepared by conventional methods.

 For example, these processes can be used (A to E). Salts of the following compounds are similar or the same as the salts of compound (I).

 1) Process A.

(Ia') в которой B' представляет собой этерифицированную до сложного эфира карбоксильную группу и другие символы имеют соответственно указанные значения, или соль этого соединения могут быть получены путем обработки соединения общей формулы (II) или его соли с протеканием реакции циклизации

(II) где B' этерифицированная до сложного эфира карбоцильная группа;
Y оксигруппа или галоген.The compound of General formula Ia '

(Ia ') in which B' represents an esterified carboxyl group and other symbols have the indicated meanings, respectively, or a salt of this compound can be obtained by treating a compound of general formula (II) or a salt thereof with a cyclization reaction

(II) where B 'is an esterified carbocyl group;
Y is hydroxy or halogen.

The esterified ester group B 'may be the same as group B. For example, B' is preferably an alkyl ester, especially an ester with a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl , tert-butyl, pentyl, neopetyl, hexyl, etc. or an aralkyl ester, especially an ester of a C _7-19 aralkyl group such as benzyl, phenethyl, 3-phenylpropyl, etc. This cyclization reaction is carried out in the same manner as the usual Friedel-Krafz reaction. This cyclization reaction can proceed in a known manner (see Organic Reactions, Vol. 2, p. 114, John Wiley and Sons Inc. New York, 1962 and Shin Jikken Kagaku Koza 14). Syntheses and reactions of organic compounds (II) (Maruzen, 1977).

 This reaction usually takes place in a solvent that does not affect the course of the reaction, or in the absence of a solvent. Examples of solvents used are aromatic hydrocarbons such as benzene, toluene, xylene, etc. halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and others, ethers such as diethyl ether, dioxane, tetrahydrofuran, etc. nitrobenzene, nitromethane and carbon disulfide, as well as various mixtures thereof.

 The reaction proceeds in the presence of a Lewis acid.

 Examples of Lewis acids are hydrogen fluoride, sulfuric acid, phosphoric acid, phosphoric anhydride, aluminum chloride, tin tetrachloride and zinc chloride.

The proportion of Lewis acid is preferably from 2 to 10 mol per 1 mol of compound (II) or its salt. In any case, the reaction temperature is from about -20 ° C to ^about 200 ^{° C,} and preferably from about 0 ^C to 100 ^C. The reaction time is usually from about 30 to 100 hours, preferably from about 1 to 30 hours.

 2). Process B.

(Ia") в которой каждый символ имеет указанные значения или соль этого соединения могут быть получены путем реакции гидролиза соединения формулы (Ia') или его соли.The compound of General formula Ia "

(Ia ") in which each symbol has the indicated meanings or a salt of this compound can be obtained by hydrolyzing a compound of formula (Ia ') or a salt thereof.

 The hydrolysis reaction proceeds in an aqueous solvent or in water in the usual manner.

 Examples of an aqueous solvent used are mixtures of water with alcohols such as methanol, ethanol and others, with ethers such as tetrahydrofuran, dioxane, etc. with imides, such as N, N-dimethylformamide, etc. sulfoxides, such as dimethyl sulfoxide, etc. with methyl ethyl ketone, etc.

 This reaction proceeds in the presence of a base or acid.

 Inorganic bases, for example, alkali metal carbonates such as potassium carbonate, sodium carbonate, etc., can be used as the base. and alkali metal hydrates, such as sodium oxide hydrate, potassium oxide hydrate, lithium oxide hydrate, etc. or organic bases, for example various alkoxides, such as sodium methylate, sodium ethylate, potassium tert-butylate, etc. The acid may be an inorganic acid, such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc. or an organic acid such as acetic acid, trifluoroacetic acid, etc. The acid or base is preferably used in an excess amount relative to compound (Ia '). A preferred base proportion is from about 1.2 to 6 equivalents based on compound (Ia ′). A preferred proportion of acid is from about 2 to about 50 equivalents based on compound (Ia ′).

This reaction usually proceeds at a temperature of from about −20 to ^about 150 ° C., preferably from about −10 to ^about 100 ° C.

 3). Process C.

(=O)_k′ (Ic) в которой B" представляет собой амидированную карбоксильную группу, и другие символы имеют соответственно указанные значения или соль этого соединения могут быть получены путем реакции амидирования соединения (Ia") или его соли. Данная реакция осуществляется как реакция соединения (Ia") или его соли с аминовым соединением.The compound of General formula Ic

(= O) _{k ′} (Ic) in which B ″ represents an amidated carboxyl group and the other symbols have the indicated meanings or the salt of this compound can be obtained by amidation of compound (Ia ") or its salt. This reaction is carried out as the reaction of compound (Ia ") or its salt with an amine compound.

NH (III) в которой каждый символ имеет указанные значения. Реакция между соединением (Ia") или его солью и аминовым соединением протекает таким же образом, как реакция конденсации, хорошо известная в области синтеза пептидов.The amine compound is preferably a compound of general formula III

NH (III) in which each symbol has the indicated meanings. The reaction between the compound (Ia ") or its salt and the amine compound proceeds in the same manner as the condensation reaction, well known in the field of peptide synthesis.

 This reaction can be carried out by various known techniques (see M. Bodansky and MA Ondetti, “Peptide Synthesis,” Interscience, New York, 1966. FM Finn and K. Hofmann, “Proteins,” Volume 2, ed. H. Nenrath and RL Hill, Academic Pres, New York, 1976; and Nobuo Izumija et al. Peptide Gosei no Kiso to Zikken, Maruzen, 1985), e.g., acyl azide method, acyl chloride method, acid anhydride method, mixed anhydride method, DCC method, activated method ester, method K of Woodward's reagent, carbonylimidazole method, by redox process, DCC / HONB method, etc. For example, this reaction may be carried out under the following conditions.

 The starting material, the amine compound, can be used in a proportion of about 1 to 10 mol per 1 mol of the compound (Ia ") or its salt. This reaction proceeds in a solvent which does not affect the course of the reaction.

 Examples of such solvents are amides, such as dimethylformamide, and others, sulfoxides, such as dimethyl sulfoxide, and others, pyridines, such as pyridine, picoline, lutidine, etc. halogenated hydrocarbons such as chloroform, dichloromethane, etc. ethers, such as tetrahydrofuran, etc., and nitriles, such as acetonitrile, etc. as well as suitable mixtures of such solvents. These solvents can be used in anhydrous or aqueous conditions.

The reaction temperature is usually about -20 ^to 50 ° C, preferably about -10 to 30 ^C. The reaction time is from about 1 to 100 hours, preferably from about 2 to 40 hours.

 Process D.

(Id) в которой k" равно 1 или 2, другие символы соответственно имеют указанные значения или соль этого соединения могут быть получены путем окислительной реакции соединения формулы (Ia'), (Ia") или (Ic), в которых k' неизменно равно 0, или соли этого соединения.The compound of General formula Id

(Id) in which k "is 1 or 2, other symbols respectively have the indicated meanings or a salt of this compound can be obtained by the oxidative reaction of a compound of formula (Ia '), (Ia") or (Ic) in which k' 0, or salts of this compound.

 The oxidative reaction is carried out as a normal oxidation procedure using an oxidizing reagent.

 The oxidizing reagent used for this reaction is a weakly oxidizing reagent that does not significantly affect the skeletal structure of sulfur-containing heterocyclic compounds, such as perbenzoic acid, meta-chloroperbenzoic acid, hydrogen peroxide, esters, sodium metaperiodate, phenyl dichloroiodide, ozone, peroxide hydrogen and sodium hypochloride are just a few of the most preferred examples.

 This reaction proceeds in an organic solvent, which does not have an undesirable effect on the reaction.

 The specified solvent includes, among others, aromatic hydrocarbons such as benzene, toluene, xylene, etc. halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc. ethers, such as diethyl ether, dioxane, tetrahydrofuran, etc. and alcohols such as methanol, ethanol, propanol, etc. including various mixtures of these solvents.

 The use of said oxidizing reagent in an equimolar or superequimolar proportion with respect to compound (Ia '), (Ia ") or (Ic), where k is 0, or a salt thereof preferably leads to the formation of compound (Id) in which k" is 1 .

Compound (Id) in which k ″ is 2, is formed if the oxidizing agent is present in excess, in which case compound (Id) in which k ″ is 1 is further oxidized. This reaction proceeds at or below room temperature (30-20 ° ^C). The preferred reaction temperature is from about −50 to ^about 20 ° C. The reaction time is from about 30 minutes to 10 hours.

 Process E.

 A compound of general formula (Ib) or a salt thereof can be prepared by reducing a compound of formula (Ia '), (Ia "), (Ic) or (Id) or a salt thereof. This reaction is initiated by a compound obtained by one of processes A to D and the result is a compound of general formula (I) in which X is —CH (OH) -, that is, compound (Ib) or a salt thereof. This reaction may be carried out as a known reduction process (see Shin Jikken Kagaku Koza, 15 Oxidation and reduction (II), Maruzen 1977).

 For example, this reaction is carried out by treating compound (Ia '), (Ia "), (Ic) or (Id) or its salt with a reducing agent.

 As the reducing agent, metals and metal salts, for example, metal-hydrogen complex compounds, such as alkali metal borohydrides, for example sodium borohydride, lithium borohydride, etc., can be used. metal hydrides such as sodium hydride, an organic tin-containing compound (for example triphenyltin hydride, etc.), nickel and zinc compounds, and catalytic reduction systems including transition metals such as platinum, palladium, rhodium and others in combination with hydrogen. This reaction proceeds in an organic solvent, which does not affect the course of the reaction.

The specified solvent includes, among other aromatic hydrocarbons, such as benzene, toluene, xylene, etc. halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc. ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethylene glycol monomethyl ether, etc. alcohols, such as methanol, ethanol, propanol and others, and amides, such as dimethylformamide and others, and these solvents are used selectively for a certain type of reducing agent. The reaction temperature is from 0 to ¹³⁰ ° C, preferably from 10 to 100 ° ^C the reaction time is from about 1 to 24 hours.

 Process F.

 This is the process of obtaining a compound containing a phosphono group, or a salt of this compound, from a compound containing a monoalkoxy or dialkoxyphosphoryl group, which, along with other compounds, is synthesized by carrying out processes A to E. This reaction proceeds with an inorganic acid such as hydrochloric acid hydrobromic acid, etc. or with a trialkylsilyl halide, in a solvent that does not affect the progress of the reaction.

When an inorganic acid such as hydrochloric acid, hydrobromic acid and others is used, an alcohol such as methanol, ethanol, 2-methoxyethanol, ethylene glycol, propanol, butanol, etc. can be used as a solvent. or water, or a mixture thereof. The acid is usually used in a large excess amount, the reaction temperature is usually from 10 to ¹⁵⁰ ° C and preferably from about 30 to ^about 100 C. The reaction time is from 1 to 50 hours. In the case of using an alkylsilyl halide, such as chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane and etc., the solvent may be a halogenated hydrocarbon such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc. or acetonitrile or a mixture thereof.

The proportion of alkylsilyl halide is usually from 1 to 10 equivalents and preferably 2-5 equivalents based on the monoalkoxy or dialkoxyphosphoryl compound containing the group. The reaction temperature is usually from -30 ^to 100 ° C, preferably from -10 ^to 50 ° C, the reaction time is from 30 to 100 hours.

 The resulting sulfur-containing heterocyclic compound can be isolated and purified by well-known separation and purification procedures, such as concentration, evaporation in vacuo, recrystallization, redistribution, chromatography and others. The same separation and purification procedures are used to obtain the starting compound described below.

H-COOH
В приведенных формулах Z представляет собой удаляемую группу, Y' представляет собой атом галогена, другие символы имеют указанные значения.The starting compound (II) corresponding to this invention can be obtained in a known manner in the same way as follows:

H-cooh
In the above formulas, Z represents a leaving group, Y 'represents a halogen atom, other symbols have the indicated meanings.

 Reaction Step 1. In this reaction step, compound (V) or its salt is reacted with compound (VI) or its salt in the presence of a base, resulting in compound (IIa) or its salt.

Examples of the leaving group Z are halogens, preferably chlorine, bromine and iodine, and hydroxyl groups activated by esterification with an ester, such as organic sulfonic acid groups (e.g. paratoluenesulfonyloxy group), C _1-4 alkylsulfonyloxy (e.g. methanesulfonyloxy) and organic phosphoric groups acids such as diphenylphosphoryloxy, dibenzylphosphoryloxy, dimethylphosphoryloxy and so on.

 The reaction of compound (V) or its salt with a compound of formula (VI) or its salt is carried out in a solvent which does not affect the course of the reaction.

Examples of such solvents are aromatic hydrocarbons such as benzene, toluene, xylene and so on, ethers such as dioxane, tetrahydrofuran, dimethoxyethane and so on, alcohols such as methanol, ethanol, propanol and so on, esters such as ethyl acetate and so on, nitriles such as acetonitrile and so on, pyridines such as pyridine, lutidine and so on, amides such as N, N-dimethylformamide and so on, sulfoxides such as dimethyl sulfoxide and so on, halogenated hydrocarbons, such as chloroform, dichlo methane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and so on, ketones such as acetone, 2-butanone and so on, as well as various mixtures of such solvents. This reaction is carried out in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and so on, or an organic base such as amines, for example pyridine, triethylamine, N, N-dimethylaniline, etc. .d. A preferred proportion of such a base is about 1-5 mol per 1 mol of compound (V) or a salt thereof. This reaction is conducted usually at a temperature of from -20 ° C to ^about 150 ^C, preferably about -10 to 100 ^C.

, 3580, 1982 г, и Chem. Pharm. Bull,

, 3601, 1982 г.The starting compound (V) or a salt thereof can be synthesized by, for example, the methods described in Chem. Pharm. Bull

, 3580, 1982, and Chem. Pharm. Bull

, 3601, 1982

 Reaction Step 2. In this reaction step, the compound (IIa) or its salt is halogenated, whereby the compound (IIb) or its salt is obtained. This reaction can be carried out by known methods. For example, this reaction can be carried out by the methods described in Shin Zikken Kagaku Koza 14. Syntheses and reactions of organic compounds (II), Maruzen, 1977.

 For example, this reaction can be carried out by chemically reacting compound (IIa) or a salt thereof with a halogenating reagent such as a chlorinating reagent (e.g., phosphorus pentachloride, thionyl chloride, oxalyl chloride, etc.).

 This reaction is carried out in a solvent medium, which does not have an undesirable effect on the course of the reaction or in the absence of a solvent.

This solvent includes, among others, aromatic hydrocarbons such as benzene, toluene, xylene, etc. nitriles such as acetonitrile, amides such as N, N-dimethylformamide and so on, and halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc. as well as various mixtures of these solvents. This reaction is carried out when heated (from 35 to 120 ^about C). The reaction time is about 1 to 20 hours.

CH₂)

H-B

)

В представленных формулах R' означает группу низшего алкила, все другие символы соответственно имеют указанные значения.Reaction Step 3. In this step, compound (IIb) or its salt undergoes an oxidation reaction to produce compound (IIc) or its salt. This reaction is carried out in the same way as the process. Compound (IIa) can also be synthesized by the following process:

CH ₂ )

HB

)

In the presented formulas, R 'means a lower alkyl group, all other symbols respectively have the indicated meanings.

 The reaction step 1.

 This is a reaction step in which compound (V) is reacted with compound (VII) or a salt thereof in the presence of a base, whereby compound (VIII) is obtained.

Examples of the leaving group Z are these groups. Examples of lower alkyl groups R 'are C _1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.

 The reaction of compound (V) with compound (VII) or its salt proceeds in a solvent which does not undesirably affect the course of the reaction.

Examples of such solvents are aromatic hydrocarbons such as benzene, toluene, xylene, etc. ethers such as dioxane, tetrahydrofuran, dimethoxyethane, etc. esters such as ethyl acetate and other amides such as N, N-dimethylformamide and others, sulfoxides such as dimethyl sulfoxide and others, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2, 2-tetrachloroethane and others, and ketones, such as acetone, 2-butanone and others, and mixtures thereof. This reaction proceeds in the presence of an inorganic base, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate and others, or in the presence of an organic base, such as pyridine, triethylamine, N, N-dimethylaniline and others. The proportion of this base is preferably from about 1 to 5 mol per 1 mol of compound (V). This reaction generally proceeds at a temperature of from -20 to ¹⁵⁰ ° C and preferably in the range from about -10 to ^about 100 C. The reaction time is usually from 30 to 10 hours.

 Reaction Step 2. This is a reaction step in which compound (VIII) is hydrolyzed in the presence of a base, whereby compound (IX) is obtained. This reaction proceeds in a solvent that does not affect the course of the reaction. Examples of such solvents are alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, 2-methoxyethanol and others, and mixtures of water with these alcohols, tetrahydrofuran, acetone, N, N-dimethylformamide, dimethyl sulfoxide and others.

 This reaction proceeds in the presence of an inorganic base, such as sodium hydroxide, potassium hydroxide, potassium carbonate and others, ammonia, or in the presence of an organic base, such as secondary amines, for example dimethylamine, diethylamine, morpholine, piperidine and others.

A preferred proportion of such a base is about 1-10 mol per 1 mol of compound (VIII). This reaction is conducted usually at a temperature of from -20 to ¹⁵⁰ ° C, preferably in the range of about -10 to 80 ° ^C.

 Reaction Step 3. This is a reaction step in which a compound (IX) or a salt thereof is reacted with a compound (X) or a salt thereof in the presence of a base, thereby producing a compound (IIa) or a salt thereof.

Examples of the leaving group Z are hydroxyl groups activated by halogen, preferably chlorine, bromine or iodine, or by esterification to an ester, such as organic sulfonic acid groups (e.g. paratoluenesulfonyloxy), C _1-4 alkylsulfonyloxy (e.g. methanesulfonyloxy), and organophosphorus acid groups such as diphenylphosphoryloxy, dibenzylphosphoryloxy, dimethylphosphoryloxy and others.

 The reaction of compound (IX) or its salt with compound (X) or its salt is carried out in a solvent which does not undesirably affect the reaction. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene, xylene and others, ethers such as dioxane, tetrahydrofun, dimethoxyethane and others, alcohols such as methanol, ethanol, propanol and others, esters such as ethyl acetate and others nitriles such as acetonitrile and others; pyridines such as pyridine, lutidine and others; amides such as N, N-dimethylformamide and others, sulfoxides such as dimethyl sulfoxide and others, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and others, ketones such as acetone, 2-butanone and others, and the corresponding mixtures thereof.

 This reaction proceeds in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and others, or in the presence of an organic base such as a tertiary amine, for example pyridine, triethylamine, N, N-dimethylaniline etc.

The proportion of this base is preferably about 1-5 mol per 1 mol of compound (IX). This reaction generally proceeds at temperatures ranging from -20 to ¹⁵⁰ ° C, preferably in the range from -10 to 100 ^C.

 As the salt of compound (I) according to the invention, a pharmaceutically acceptable salt is preferably used. These pharmaceutically acceptable salts include, among others, salts formed with inorganic bases salts formed with organic bases, salts formed with organic acids, and salts formed with basic or acidic amino acids. Inorganic bases include, among others, alkali metal bases (e.g., sodium, potassium and others), and alkaline earth metal bases (e.g., calcium, magnesium, etc.), and organic bases include, among others, trimethylamine, triethylamine , pyridine, picoline, N, N-dibenzylethylenediamine, diethanolamine and others. These inorganic acids include, among others, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid and others, and these organic acids include, among others, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, paratoluene sulfonic acid, citric acid and others. Basic or acidic amino acids include arginine, lysine, aspartic acid, glutamic acid, and others.

 Of the various types of salts indicated, salts formed with bases are any and all salts that are formed when compound (I) contains a carboxyl group, denoted by B, and / or an acid group, such as a carboxyl or sulfo group in ring A or in a substituent group B or R and under salts formed when compound (I) contains a basic group, such as an amino group in ring A or in a substituent group B or R.

 The toxicity of compound (I) or its salt is very low. For example, when the compounds synthesized as in Examples 18 and 22 are orally administered to the body of mice at a dose of 300 mg / kg, no mortality is observed. Compound (I) and its salt according to the invention have an excellent inhibitory effect on bone resorption. So, they have the ability to inhibit dissolution and bone loss in the body. In addition, the compound of formula (I) or a salt thereof has the ability to activate bone formation.

 Therefore, the compound (I) or the salt of the invention can be used as a medicine for humans and animals, which is a safe means for preventing the treatment of various diseases resulting from bone resorption, such as osteoporosis.

 Compound (I) or its salt may be administered orally or by any other route (e.g., by intravenous or intramuscular injection).

 Typical oral dosage forms include solid or liquid forms such as tablets (including sugar and film coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, elixirs, emulsions, suspensions, etc.

 These orally administrable dosage forms may be administered by methods known per se by diluting compound (I) or a pharmaceutically acceptable salt thereof with carriers or excipients commonly used in pharmaceutical practice.

 Examples of carriers or excipients are binders such as syrup, gum arabic and others, fillers such as lactose, sucrose and other sugars, corn starch, calcium phosphate, glycine and others, lubricants such as magnesium stearate, talc, polyethylene glycol, silicon dioxide etc. disintegrating agents such as potato starch; and wetting agents such as sodium lauryl sulfate and others. Dosage forms for parenteral administration include, among others, various injectable preparations (for example, preparations administered by subcutaneous injection, intradermal injection, intramuscular injection and other types of injection), suppositories, etc.

 Injectable preparations can be prepared by known techniques, for example, by suspension or emulsification of compound (I) or its salt in sterile aqueous or oily vehicles. An aqueous vehicle for injection includes, among others, physiological saline and various isotonic solutions and, if necessary, suitable suspending agents such as sodium carboxymethyl cellulose, or non-ionic surfactants may be used to prepare the injections. The oily carrier may be, for example, sesame oil or soybean oil, benzyl benzoate, benzyl alcohol and other products may be used as a co-solvent. Injectable preparations prepared in this way are usually enclosed in suitable ampoules.

 Another active ingredient having the ability to inhibit bone resorption (for example, Ipriflavone) can also be introduced into such a preparation, resulting in a product having an even stronger ability to inhibit bone resorption.

 Compound (I) or a salt thereof can be used as a prophylactic and therapeutic agent against diseases resulting from bone resorption, such as osteoporosis. Although the daily dose of compound (I) or its salt depends on the condition of the patient and his weight, on the method of administration of the drug and other factors, the orally administered dose for an adult (about 50 kg) is from 1 to 500 mg, preferably from 15 to 300 mg , based on the active ingredient (compounds of formula I) or its salt, this drug is administered from a single to three times divided dose per day.

 Effects achieved by the invention.

 Compound (I) or its salt has a strong inhibitory effect on bone resorption, improves bone metabolism, has a high activating effect on bone formation, and is used to prevent and treat various diseases resulting from bone resorption, such as osteoporosis, in humans and animals. .

 The compound of formula (I) or its salt is only slightly toxic and can be used safely. Tests, control examples and working examples are intended to illustrate the invention in more detail, but by no means limit the scope of this invention.

 Test 1. The study of inhibition of bone resorption.

, 103-116, 1965 г.The inhibitory effect on bone resorption was determined according to the Raisz method [Journal of Clinical Investigation (J. Clin. Invest)

103-116, 1965

· 100 где А процент ⁴⁵Са, выделившегося из кости в среду,
В количество ⁴⁵Са в среде,
С количество ⁴⁵Са в кости.So, on the 19th day of her pregnancy, a dose of 50 µ Ci ⁴⁵ Ca (calcium radioisotope, in CaCl ₂ ) was subcutaneously injected into the rat organism of the Sprague Dawley variety. The next day, rat laparotomy was performed and the fruits were aseptically removed. The right and left humerus of the fetus of each rat (towards the radius and toward the ulna) were separated from the body and examined under a dissecting magnifier. As far as possible, connective tissue and cartilage were removed to prepare bone samples. Each bone sample was incubated in 0.6 ml of medium BGJ6 modified Fitton-Jackson (trade name assigned laboratories GIBCO, USA) containing 2 mg / ml bovine serum albumin at ³⁷ ° C for 24 hours. Then the incubation was carried out for two more days in the indicated medium into which the test compound was introduced with a final concentration of 10 μg / ml. The radioactivity of ⁴⁵ Ca in the medium with culture and bone tissue was determined, and the amount of ⁴⁵ Ca released from the bone on Wednesday was calculated using the following formula:
A

· 100 where A is the percentage of ⁴⁵ Ca released from the bone on Wednesday,
In the amount of ⁴⁵ Ca in the environment,
With the amount of ⁴⁵ Ca in the bone.

 Bones taken from the fruits of the same female were incubated in the same way without administering the test compound for two days, they served as controls.

 Data for five bones per group was taken as the mean. The percentage of this value was determined for the treated group in relation to the control value.

 The results are shown in table. 1.

In the table. 1 shows that the compound of the invention inhibits the release of ⁴⁵ Ca by 44-88% compared with the control test, which thus provides an excellent inhibitory effect on bone resorption.

 Test 2. Study on the treatment of osteoporosis.

, 1923 (1983)]
После фотографирования с выделением мягких рентгеновских лучей вырезали 1/3 периферическую часть бедра справа от основной оси. После вымывания костного мозга промывочным насосом вырезанную секцию бедра помещали в фарфоровый тигель, который устанавливали в печь и высушивали при 110^оС в течение 24 ч. Затем определяли вес сухой массы.Sprague-Dawley rats of 10 weeks of age were removed from the ovaries and, starting from the next day, they were dosed with the test compound 6 days a week for three weeks, for a total of 18 days. On the day after the last dose was administered, the right femur was removed from each rat and X-rayed under exposure to soft X-rays using an X-ray machine with soft X-rays (Softex CSM, Softex). Using a microdensitometer (PDM-5, Konica Medical), a cross-section of the thigh was scanned on a film with soft x-ray radiation at a point located one fifth from the peripheral edge (metaphysis) and from the dense wave structure, and bone density was calculated by the microdensitometric method, described by Jnoue et al. [Journal of Japanese Orthopedic Association (J. Jpn. Orthop. Asc.)

, 1923 (1983)]
After photographing with the release of soft x-rays, 1/3 of the peripheral part of the thigh was cut to the right of the main axis. After washing the bone marrow rinsing pump cut femur section was put into a porcelain crucible which was set in an oven and dried at ¹¹⁰ ° C for 24 h. The dry weight was determined.

The porcelain crucible containing the bone was transferred to a muffle furnace (FP-41, Yamato Chemical) and heated at ⁵⁰⁰ ° C for 3 hours and at 800 ^{° C} for 2 hours for calcification of the bone and the ashes were weighed.

 The mean standard errors (±) of the measured values for the right thighs of 7 rats per group were determined. The results are presented in table. 2-4.

 From the table. 2-4 it follows that the proposed compound is effective in preventing bone mass disease and in suppressing in vivo calcium excretion from bone mass.

The symbols used in the test and working examples have the following meanings:
S (c.) - singlet, d (D.) doublet, t (t) triplet, q (sq.) Quartet, dd (d.d.) double-doublet, m (m.) Multiplet, br ₁ (width .) wide; J THF (THF) conjugation constant tetrahydrofuran, DMF-N, N-dimethylformamide.

Control Example 1. Ethyl oxalyl chloride (48.0 g) and phenylcyclohexane (48.0 g) were added dropwise in an ice-cooled suspension of aluminum chloride (48.0 g) in dichloromethane (500 ml) in this order, the mixture was stirred with ice cooling in within 30 minutes Then the reaction mixture is poured into ice-water, the organic layer is separated. The aqueous layer is extracted with chloroform and the extract combines with the organic layer. Then the organic solution is washed with an organic layer. The organic solution was washed with water, dried (MgSO _4), and subjected to distillation in vacuo to give ethyl 4-tsiklogeksilfenilgliok- silat (68.0 g, 87% yield), bp 163-165 ^C (0.3 mmHg.).

NMR spectrum (δ ppm CDCl ₃ ): 1.40 (3H, t. J 7 Hz), 1.4-2.1 (8H, m), 2.60 (1H, m), 4 43 (2H, q, J 7 Hz), 7.34 (2H, d. J 9 Hz), 7.96 (2H, d. J 7 Hz).

Reference Example 2. By carrying out the process in the same manner as described in Reference Example 1, ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylate was obtained. Yield: 80% Boiling point 152-154 ^C / 0.5 mm Hg. Art.

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.41 (3H, t. J 7 Hz), 1.8 (4H, m.), 2.8 (4H, m.), 4.44 ( 2H, q, J 7 Hz), 7.18 (1H, q, J 9 Hz), 7.7 (2H, m).

Control Example 3. Carrying out the process in the same manner as in Control Example 1, ethyl 3,4-dimethoxyphenyl glyoxylate was obtained. Yield: 78% Boiling point 158-160 ^C / 0.1 mm Hg. Art.

NMR spectrum (δ ppm CDCl ₃ ): 1.38 (3H, t, J 7 Hz), 3.93 (3H, s.), 3.95 (3H, s.), 4.41 ( 2H, q. J 7 Hz), 6.91 (1H, d. J 8 Hz), 7.5-7.7 (2H, m.).

 Control Example 4. Carrying out the process in the same manner as in Control Example 1, ethyl 3,4-ethylenedioxyphenyl glyoxylate was obtained.

Yield 86% Boiling point 172-175 ^C / 0.5 mm Hg. Art.

Control Example 5. Carrying out the process in the same manner as in Control Example 1, 4-hexylphenylglyoxylate is obtained. Yield 84% Boiling point 160-162 ^C / 0.5 mm Hg. Art.

NMR spectrum (δ ppm CDCl ₃ ): 0.87 (3H, t. J 7 Hz), 1.40 (3H, t. J 7 Hz), 1.2-1.8 (8H, m .), 2.67 (2H, t. J 7 Hz), 4.33 (2H, q, J 7 Hz), 7.28 (2H, d. J 9 Hz), 7.90 (2H, d. J9 Hz).

Reference Example 6. A solution of sodium borohydride (2.0 g) in ethanol (100 ml) was added dropwise to an ice-cooled solution of ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylast (34.5 g) in ethanol ( 200 ml). After stopping this input, acetic acid (6 ml) was added and the reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in ethyl 2-hydroxy-2- (5,6,7,8-tetrahydro-2-naphthyl) acetate (34.5 g, yield 99 %) as an oil.

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.22 (3H, t. J 7 Hz), 1.8 (4H, m.), 2.7 (4H, m.), 3.32 ( 1H, d. J 6 Hz), 4.0-4.4 (2H, m.), 7.1 (3H, m.).

 Control Example 7. Carrying out the process as in Control Example 6, 2-hydroxy-2- (4-cyclohexylphenyl) acetate is obtained.

Yield 83% Melting point 85-86 ^{° C} (ethanol).

Elemental analysis data: C ₁₆ H ₂₂ O ₃
Calculated, C 73.25; H, 8.45.

 Found, C, 73.26; H, 8.46.

Control Example 8. Carrying out the process as in Control Example 6, ethyl 2-hydroxy-2- (3,4-dimethoxyphenyl) acetate was obtained in the form of an oil. Yield 82%
Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.21 (3H, t. J 7 Hz), 3.10 (1H, d. J 6 Hz), 3.87 (6H, s.), 4 21 (2H, q, J 7 Hz), 5.07 (1H, d. J 6 Hz), 6.7-7.0 (3H, m.).

Control Example 9. Carrying out the process as in Control Example 6, ethyl 2-hydroxy-2- (3,4-ethylenedioxyphenyl) acetate was obtained in the form of an oil. Yield 74%
NMR spectrum (δ ppm CDCl ₃ ): 1.24 (3H, t. J 7 Hz), 3.41 (1H, d. J 6 Hz), 4.1-4.4 (2H, m .), 4.26 (4H, s.), 5.04 (1H, d. J 6 Hz), 6.8-7.0 (3H, m.).

Control Example 10. Carrying out the process as in Control Example 6, 2-hydroxy-2- (4-hexylphenyl) acetate is obtained in the form of an oil. Yield 98%
NMR spectrum (δ ppm CDCl ₃ ): 0.86 (3H, t.J 7 Hz), 1.24 (3H, t. J 7 Hz), 1.1-1.8 (8H, m .), 2.60 (2H, t. J 7 Hz), 4.0-4.4 (2H, m.), 5.11 (1H, s.), 7.13 (2H, d. J 9 Hz), 7.32 (2H, doublet, J = 9 Hz).

Control Example 11. Thionyl chloride (100 ml) was added to ethyl 2-hydroxy-2- (4-cyclohexylphenyl) acetate (52 g), and the mixture was heated under reflux for 1 h. The reaction mixture was then concentrated under reduced pressure. residual oil is diluted with water and extracted with ether. The ether layer is washed with water, dried (over MgSO ₄ ) and subjected to vacuum distillation, resulting in ethyl 2-chloro-2- (4-cyclohexylphenyl) acetate (50 g, 89% yield).

The boiling point is 160-162 ^about C / 0.5 mm RT. Art.

NMR spectrum (δ ppm CDCl ₃ ): 1.24 (3H, t. J 7 Hz), 1.2-2.0 (10H, m.), 2.5 (1H, m.), 4.21 (2H, qt. J 7 Hz), 5.3 (1H, s.), 7.18 (2H, d. J 9 Hz), 7.40 (2H, d. J 9 Hz).

Control Example 12. Carrying out the process as in Control Example 11, ethyl 2-chloro-2- (5,6,7,8-tetrahydro-2-naphthyl) acetate was obtained in the form of an oil. Yield 89% Boiling point 139-141 ^C / 0.5 mm Hg. Art.

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.24 (3H, t. J 7 Hz), 1.8 (4H, m.), 2.7 (4H, m.), 4.21 ( 2H, q. J 7 Hz), 5.26 (1H, s.), 7.0-7.2 (3H, m.).

Control Example 13. Carrying out the process as in Control Example 11, ethyl 2-chloro-2- (3,4-ethylenedioxyphenyl) acetate was obtained in the form of an oil. Yield: 90% Boiling point 165-167 ^C / 0.3 mm Hg. Art.

NMR spectrum (δ ppm CDCl ₃ ): 1.27 (3H, t. J 7 Hz), 4.1-4.4 (2H, m.), 4.27 (4H, s.), 5.25 (1H, s.), 6.8-7.1 (3H, m.).

Reference Example 14. Carrying out the process as in Reference Example 11, ethyl 2-chloro-2- (4-hexylphenyl) acetate was obtained in the form of an oil. Boiling point 152-155 ^о С / 0.5 mm RT. Art.

NMR spectrum (δ ppm CDCl ₃ ): 0.88 (3H, t. J 7 Hz), 1.26 (3H, t. J 7 Hz), 1.1-1.8 (8H, m .), 2.60 (2H, t. J 7 Hz), 4.1-4.4 (2H, m.), 5.33 (1H, s.), 7.19 (2H, d. J 9 Hz), 7.40 (2H, doublet, J = 9 Hz).

Reference Example 15 To a solution of ethyl 2-hydroxy-2- (3,4-dimethoxyphenyl) acetate (19.5 g) in benzene (200 ml) was added phosphorus tribromide (8.18) dropwise ^at 50 ° C, and the mixture was stirred at ⁶⁰ ° C for 1 h. The reaction mixture was washed successively with water, saturated aqueous NaHCO ₃ and again with water and dried (over MgSO _4). Benzene is distilled off, the residual distillation product is subjected to chromatographic separation on silica gel. Ethyl 2-bromo-2- (3,4-dimethoxyphenyl) acetate (18.5 g) was obtained from the fraction eluted with ethyl acetate hexane (1: 3, v / v), 75% yield as an oil.

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.27 (3H, t. J 7 Hz), 3.86 (3H, s.), 3.89 (3H, s.), 4.23 ( 2H, qt. J 7 Hz), 5.31 (1H, s.), 6.80 (1H, d. J 8 Hz), 7.0-7.2 (2H, m.).

Control Example 16. 4-cyclohexylaniline (50 g) was dissolved in acetone (400 ml), followed by 47% aqueous HBr (147 g). Then added dropwise a solution of NaNO ₂ (21.6 g) in water (30 ml) at 0-5 ^C. and the mixture was stirred at ⁵ ° C for an additional 30 min. After that, the mixture is heated to 15 ^° C and methyl acrylate (147 g) is added. With vigorous stirring, Cu ₂ O (1 g) is introduced in small portions and an exothermic reaction occurs with the release of gaseous nitrogen. After weakening the evolution of nitrogen gas, the reaction mixture was further stirred for 2 hours and then concentrated. The residual concentration product is diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off to give methyl 2-bromo-3- (4-cyclohexylphenyl) propionate as a crude oil (91 g, 98% yield). NMR spectrum (δ ppm CDCl ₃ ): 1.2-2.0 (10H, m), 2.5 (1H, m), 3.15 (1H, dd J 14 and 7 Hz), 3.43 (1H, dd. J14 and 7 Hz), 3.70 (3H, s.), 4.37 (1H, t. J 7 Hz), 7.10 (4H, s .).

Control Example 17. A solution of ethyl 2-chloro- (5,6,7,8-tetrahydro-2-naphthyl) acetate (32 g) in acetone (50 ml) was added to a mixture of thioglycolic acid (14 g), K ₂ CO ₃ (52.7 g) and acetone (250 ml). The mixture was refluxed for 5 hours and concentrated in vacuo. The residual concentration product is poured into water and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgCO ₄ ) and concentrated. The residual concentration product is chromatographed on silica gel. Ethoxycarbonyl (5,6,7,8-tetrahydro-2-naphthyl) methylthioacetic acid (31.8 g, 81% yield) is obtained from the fraction eluted with chloroform ethyl acetate methanol (20: 2: 1) (v / v) kind of oil.

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.23 (3H, t. J 7 Hz), 1.8 (4H, m.), 2.7 (4H, m.), 3.07 ( 1H, d. J 15 Hz), 3.30 (1H, d. J 15 Hz), 4.18 (2H, q. J 7 Hz), 4.79 (1H, s.), 6.9-7 2 (3H, m.).

 Control Example 18. Carrying out the process as in Control Example 17, ethoxycarbonyl (3,4-dimethoxyphenyl) methylthioacetic acid was obtained in the form of an oil (yield 98%).

NMR spectrum (δ ppm CDCl ₃ ): 1.23 (3H, t. J 7 Hz), 3.18 (2H, d. J 21 and 15 Hz), 3.87 (6H, s.) 4.20 (2H, q, J 7 Hz), 4.81 (1H, s.), 6.7-7.1 (3H, m.), 9.40 (1H, broad).

 Control Example 19. Carrying out the process as in Control Example 17, ethoxycarbonyl (4-cyclohexylphenyl) methylthioacetic acid was obtained in the form of an oil (85% yield).

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.23 (3H, t. J 7 Hz), 1.2-2.0 (8H, m.), 2.5 (1H, m.), 3.18 (2H, dd. J 21 and 15 Hz), 4.18 (2H, q, J 7 Hz), 4.83 (1H, s), 7.17 (2H, d. J 9 Hz), 7.38 (2H, doublet, J = 9 Hz).

Control Example 20. Triethylamine (46.5 g) was added dropwise to a mixture of thioglycolic acid (20.8 g), ethyl 2-chloro-2- (4-hexylphenyl) acetate (58 g) and dimethylformamide (250 ml ) upon cooling with ice. After the termination of this drip input, the mixture was further stirred for 1 h under ice-cooling, and the resulting reaction mixture was poured into water and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and concentrated, resulting in ethoxycarbonyl (4-hexylphenyl) methylthioacetic acid as a crude oil (63.5 g, yield 92%).

NMR spectrum (δ ppm CDCl ₃ ): 0.83 (3H, t.J 7 Hz), 1.26 (3H, t. J 7 Hz), 1.1-1.8 (8H, m .), 2.59 (2H, t. J 7 Hz), 3.11 (1H, d. J 15 Hz), 3.30 (1H, d. J 15 Hz), 4.1-4.4 ( 2H, m.), 4.84 (1H, s.), 7.26 (2H, d. J 9 Hz), 7.35 (2H, d. J 9 Hz).

 Reference Example 21. Carrying out the process as in Reference Example 20, methoxycarbonylphenylmethylthioacetic acid was obtained as an oil (98% yield).

NMR spectrum (δ ppm CDCl ₃ ): 3.11 (1H, d. J 15 Hz), 3.31 (1H, d. J 15 Hz), 3.75 (3H, s.), 4 90 (1H, s.), 7.3-7.5 (5H, m.).

 Reference Example 22. By carrying out a process such as in Reference Example 20, methoxycarbonyl (4-chlorophenyl) methylthioacetic acid was obtained as an oil (87% yield).

NMR spectrum (δ ppm CDCl ₃ ): 3.03 (1H, d. J 15 Hz), 3.35 (1H, d. J 15 Hz), 3.67 (3H, s.), 4, 81 (1H, s.), 7.1-7.5 (4H, m.).

 Control Example 23. Carrying out the process as in Control Example 20, ethoxycarbonyl (3,4-ethylenedioxyphenyl) methylthioacetic acid was obtained as an oil (yield 97%).

NMR spectrum (δ ppm CDCl ₃ ): 1.26 (3H, t. J 7 Hz), 3.13 (1H, d. J 15 Hz), 3.30 (1H, d. J 15 Hz ), 4.1-4.4 (2H, m.), 4.26 (4H, s.), 4.78 (1H, s.), 6.8-7.1 (3H, m.).

 Reference Example 24. By carrying out the process as in Reference Example 20, 2- [ethoxycarbonyl (4-cyclohexylphenyl) methylthio] propionic acid was obtained as an oil (89% yield).

NMR spectrum (δ ppm CDCl ₃ ): 1.1-2.0 (16H, m), 2.5 (1H, m), 3.49 (2H, q, J 7 Hz), 4.1-4.4 (2H, m.), 4.88 (1H, s.), 7.1-7.4 (4H, m.).

 Control Example 25. Carrying out the example as in Control Example 20, methyl 2-carboxymethylthio-3- (4-cyclohexylphenyl) propionate is obtained in the form of an oil (yield 84%).

Nuclear Magnetic Resonance Spectrum (ppm, CDCl ₃ ): 1.2-1.9 (10H, m), 2.5 (1H, m), 2.96 (1H, dd. J 15 and 7 Hz), 3.35 (1H, d. J 16 Hz), 3.49 (1H, d. J 16 Hz), 3.52 (1H, dd. J 15 and 7 Hz), 3.68 ( 3H, s.), 3.6-3.8 (1H, m.), 7.12 (4H, s.).

 Reference Examples 26-41 Carrying out the processes as in control example 1, receive the compounds shown in table. 5.

 Reference Examples 42-57 Carrying out the processes as in control example 6, receive the compounds shown in table. 6.

 Reference Examples 58-73 Carrying out the processes as in control example 11, receive the compounds shown in table. 7.

 Reference Examples 74-90 Carrying out the processes as in control example 20, receive the compounds shown in table. 8.

Reference Example 91. Potassium thioacetate (CH ₃ COSK, 8.31 g) was added in small portions to a solution of ethyl 2-chloro-2- (3,4-dimethylphenyl) acetate (15 g) in dimethylformamide (80 ml). The mixture is stirred at room temperature for 2 hours, at the end of this time it is poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in ethyl 2-acetylthio-2- (3,4-dimethylphenyl) acetate (16.5 g, 94%) as an oil.

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.22 (3H, t. J 7 Hz), 2.21 (6H, s.), 2.30 (3H, s.), 4.0- 4.35 (2H, m.), 5.2 (1H, s.), 7.05-7.2 (3H, m.).

Reference Example 92. Morpholine (21.6 g) was added dropwise to a solution of ethyl 2-acetylthio-2- (3,4-dimethylphenyl) acetate (16.5 g) in ethanol (80 ml) at room temperature, additional mixture stirred at the same temperature for 2 hours. Then this reaction mixture is poured into water, acidified with 2-normal HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off. The residual product is chromatographed on a silica gel column using a mixture of chloroform-hexane (1: 3 v / v) to give ethyl 2-thio-2- (3,4-dimethylphenyl) acetate (8.8 g, 63 %) as an oil.

Nuclear Magnetic Resonance Spectrum (δ ppm in CDCl ₃ ): 1.23 (3H, t. J 7 Hz), 2.23 (6H, broad s.), 2.53 (1H, d. J 7.5 Hz), 4.17 (1H, q. J 7 Hz), 4.60 (1H), d. J 7.5 Hz), 7.0-7.3 (3H, m.).

Reference Example 93. A mixture of 2-thio-2- (3,4-dimethylphenyl) acetate (4.5 g), 2-bromobutyric acid (3.3 g), potassium carbonate (5.5 g) and dimethylformamide (30 ml ) is stirred at room temperature for 1 h, after which it is poured into water and extracted with ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether. The ether layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 2- [ethoxycarbonyl (3,4-dimethylphenyl) methylthio] butyric acid (5.5 g, 89%) as an oil.

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 0.9-1.1 (3H, m), 1.1-1.3 (3H, m), 1.6-2.0 (2H , m.), 2.25 (6Н, s.), 2.97 (1Н, х 1/2, t. J 7 Hz), 3.38 (1Н, x 1/2, t. J 7 Hz) 4.1-4.3 (2H, m.), 4.76 (1H, x 1/2, s.), 4.80 (1H x 1/2, s.), 7.0-7, 3 (3H, m.).

 Reference Examples 94-97 Carrying out the processes as in control example 93, receive the compounds shown in table. 9 in the form of oil.

 Working examples.

Example 1. Methoxycarbonyl (4-chlorophenyl) methylthioacetic acid (71 g) was dissolved in tetrahydrofuran (400 ml) and then oxalyl chloride (39 g) was added to the solution and then diametrilamide (5 drops). The mixture was kept at room temperature overnight, concentrated, and the residual concentration product was dissolved in dichloromethane (100 ml). The solution was added dropwise to a suspension of aluminum chloride (69 g) in dichloromethane (400 ml) under ice-cooling. After the termination of this drip input, the reaction mixture is additionally stirred at room temperature for 3 hours, after which it is poured into an ice-water mixture, and the organic layer is separated. The aqueous layer is extracted with chloroform. The combined organic layer was washed with water and dried (over MgSO ₄ ). Then the solvent is distilled off, and the residual distillation product is subjected to chromatographic separation on silica gel. From the fraction eluted with hexane ether (1: 1 v / v), methyl-6-chloro-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carb-oxylate is obtained in the form of crystals (27 g yield 40%). Recrystallization from ethyl acetate-hexane gives colorless plates.

Melting point 118-119 ^about C.

Elemental analysis data: C ₁₁ H ₉ O ₃ SCl
Calculated, C 51.47; H 3.53.

 Found, C, 51.40; H 3.58.

In methanol (100 ml), methyl-6-chloro-3,4-dihydro-1H-2-benzothiopyr-an-4-one-1-carboxylate (21.5 g) was suspended, followed by the introduction of 2-normal KOH (70 ml ) The mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 6-chloro-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (18.8 g, yield 98 %). Recrystallization from ethyl acetate gives colorless prismatic crystals.

Melting point 220-221 ° ^C.

Elemental analysis data: C ₁₀ H ₇ O ₃ SCl
Calculated, C 49.49; H 2.91.

 Found, C, 49.51; H 2.91.

EXAMPLE 2 Ethoxycarbonyl (4-hexylphenyl) methylthioacetic acid (63 g) was dissolved in ether (500 ml), followed by the addition of thionyl chloride (33 g) and then pyridine (5 drops). The mixture is heated under reflux for 30 minutes and then concentrated, the residual concentration product is dissolved in dichloromethane (50 ml). This solution was added dropwise to a suspension of aluminum chloride (50 g) in dichloromethane (350 ml) under ice-cooling. After the termination of this drip input, the reaction mixture was further stirred with ice cooling for 3 hours, then it was poured into an ice-water mixture. The organic layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined, washed with water and dried (over MgSO ₄ ). Then the solvent is distilled off, and the residual distillation product is subjected to separation in a chromatographic column on silica gel. From the fraction eluted with hexane ether (1: 2 v / v), ethyl 6-hexyl-2,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate is obtained in the form of an oil (42 g yield 70%).

Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 0.83 (3H, t. J 7 Hz), 1.2-1.7 (3H, m.), 1.30 (3H, t. J 7 Hz), 2.64 (2H, t. J 7 Hz), 3.27 (1H, dd. J 16 and 1 Hz), 4.24 (2H, q. J 7 Hz), 4.27 ( 1H, dd. J 16 Hz and 1 Hz), 4.41 (1H, s.), 7.1-7.4 (2H, m.), 7.94 (1H, d.J. 2 Hz).

Ethyl 6-hexyl-3,4-dihydro-1H-2-benzothiolirane-4-one-1-carboxylate (41 g) was suspended in methanol (150 ml), followed by the introduction of 2-normal KOH (150 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 6-hexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (27.5 g, yield 74 %). After recrystallization from hexane ether, colorless plate crystals are obtained. Melting point 66-67 ^about C.

Elemental analysis data: C ₁₆ H ₂₀ O ₃ S
Calculated, C 65.72; H, 6.89.

 Found, C, 65.73; H, 6.90.

 PRI me R 3. Carrying out the process as in example 2, get ethyl-6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate. Yield 69%. After recrystallization from hexane, colorless prismatic crystals are obtained.

Melting point 51-52 ^about C.

Elemental analysis data: C ₁₈ H ₂₂ O ₃ S
Calculated, C 67.89; H, 6.96.

 Found, C, 68.08; H, 7.01.

Ethyl 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (52 g) was suspended in methanol (200 ml), after which 2-normal KOH (100 ml) was added. . The mixture is stirred at room temperature for 1 h, poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (33 g, 73% yield) . After recrystallization from hexane ethyl acetate, colorless plate crystals are obtained. Melting point 171-172 ^about C.

Elemental analysis data: C ₁₆ H ₁₈ O ₃ S
Calculated, C 66.18; H, 6.25.

 Found, C, 66.16; H, 6.28.

 PRI me R 4. Carrying out the process as in example 2, get ethyl-3,4,6,7,8,9-hexahydro-1H-naphtho [2,3-c] thiopyran-4-one-1- carboxylate in the form of an oil.

Yield 81%
Nuclear Magnetic Resonance Spectrum (δ ppm CDCl ₃ ): 1.27 (3H, t. J 7 Hz), 1.75 (4H, m.), 2.75 (4H, m.), 3.19 ( 1H, d. J 16 Hz), 4.18 (1H. D. J 16 Hz), 4.19 (2H, q. J 7 Hz), 4.31 (1H, s.), 6.87 (1H , s.), 7.81 (1H, s.).

Ethyl 3,4,6,7,8,9-hexahydro-1H-naphtho [2,3-c] thio-pyran-4-one-1-carboxylate (2.9 g) was suspended in methanol (20 ml). followed by the introduction of 2-normal KOH (10 ml). The mixture is stirred at room temperature for 1 h, poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 3,4,6,7,8,9-hexahydro-1H-naphtho [2,3-c] thiopyran-4-one-1- carboxylic acid (2.3 g), yield 89% after recrystallization from ethyl acetate gave colorless prism crystals, melting point 204-205 ° ^C.

Elemental analysis data: C ₁₄ H ₁₄ O ₃ S
Calculated, C 64.10; H 5.38
Found, C 64.38; H, 5.40.

 PRI me R 5. Carrying out the process as in example 2, get ethyl-6,7-ethylenedioxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate in the form of oil.

Yield 73%
NMR spectrum (δ ppm CDCl ₃ ): 1.31 (3H, t. J 7 Hz), 3.21 (1H, dd. J 16 Hz and 1 Hz), 4.15-4, 35 (6H, m.), 6.72 (1H, s.), 7.66 (1H, s.).

 Ethanol (6,7-ethylenedioxy-3,4-dihydro-1H-2-benzo-thiopyran-4-one-1-carboxylate (55 g) was suspended in ethanol (200 ml), followed by 2-normal NaOH (200 ml) ) The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, acidified and extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 6,7-ethylenedioxy-3,4-dihydro-1H-2-benzo-thiopyran-4-one-1-carboxylic acid (32.5 g, yield 65%). Recrystallization from ethyl acetate gives colorless prismatic crystals.

Melting point 207-208 ^about C.

Elemental analysis data: C ₁₂ H ₁₀ O ₅ S
Calculated, C 54.13; H 3.79.

 Found, C 54.37; H 3.82.

PRI me R 6. Carrying out the process as in example 2, get methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate in the form of oil. Yield 73%
NMR spectrum (δ ppm CDCl ₃ ): 3.25 (1H, d. J 24 Hz), 3.77 (3H, s.), 4.26 (1H, d. J 24 Hz), 4 47 (1H, s.), 7.0-7.5 (5H, m.), 7.9-8.1 (1H, m.).

In methanol (150 ml), methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (32 g) was suspended, followed by the introduction of 2-normal KOH (150 ml). The mixture is stirred at room temperature for 1 h, poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (22 g, 73% yield). Recrystallization from ethyl acetate-hexane gives colorless prismatic crystals.

Melting point 124-125 ^about C.

Elemental analysis data: C ₁₀ H ₆ O ₃ S
Calculated, C 57.68; C 3.87.

 Found, C 57.88; H 3.90.

 PRI me R 7. Carrying out the process as in example 2, get ethyl-6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate. Yield 69%. After recrystallization from methanol, colorless rod-like crystals are obtained.

Melting point 82-83 ^about C.

Elemental analysis data: C ₁₄ H ₁₆ O ₅ S
Calculated C 56.74; H, 5.44.

 Found, C 56.95; H, 5.44.

Ethyl 6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (6 g) was suspended in methanol (20 ml), followed by 2-normal KOH (15 ml) ), the mixture is stirred at room temperature for 1 hour. Then the reaction mixture is poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (4.4 g, yield 82%). Recrystallization from methanol gives colorless prismatic crystals. Melting point 212-213 ^about C.

Elemental analysis data: C ₁₂ H ₁₂ O ₅ S
Calculated, C 53.72; H 4.51.

 Found, C, 53.76; H 4.61.

PRI me R 8. Carrying out the process as in example 2, get methyl-7-cyclohexyl-1,2,4,5-tetrahydro-3-benzothiepin-5-one-2-carboxylate. Yield 76%
NMR spectrum (δ ppm CDCl ₃ ): 1.2-2.0 (10H, m), 2.55 (1H, m), 3.21 (1H, dd. J 14 and 5 Hz), 3.4 (1H, m), 3.41 (1H, d. J 18 Hz), 3.63 (1H, dd. J 14 and 5 Hz), 3.81 (3H, sec.), 4.00 (1H, d. J 18 Hz), 7.15 (1H, d. J 8 Hz), 7.36 (1H, dd. J 8 Hz and 2 Hz), 7, 77 (1H, d. J 2 Hz).

In methanol (150 ml), methyl-7-cyclohexyl-1,2,4,5-tetrahydro-3-benzotiepin-5-one-2-carboxylate (40 g) was suspended, followed by 2-normal KOH (100 ml) ), the mixture is stirred at room temperature for 1 hour. Then the reaction mixture is poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 7-cyclohexyl-1,2,4,5-tetrahydro-3-benzothiepin-5-one-2-carboxylic acid (27.5 g, yield 72%).

Recrystallization from ethyl acetate gave clear plate crystals. Melting point 210-211 ^about C.

Elemental analysis data, C ₁₇ H ₂₀ O ₃ S
Calculated, C 67.08; H, 6.62.

 Found, C, 67.25; H, 6.63.

PRI me R 9. Carrying out the process as in example 2, get ethyl-6-cyclohexyl-T-3-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxyl at. Yield 80%
NMR spectrum (δ ppm CDCl ₃ ): 1.32 (3H, t. J 7 Hz), 1.45 (3H, d. J 7 Hz), 1.2-1.9 (10H, m .), 2.55 (1H, q. J 7 Hz), 4.43 (1H, q. J 7 Hz), 4.43 (1H, s.), 7 12 (1H, d. J 8 Hz), 7.36 (1H, dd. J 8 and 2 Hz), 7.91 (1H, d. J 2 Hz).

Ethyl 6-cyclohexyl-3-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (11.5 g) was suspended in methanol (50 ml), followed by the introduction of 2-normal KOH ( 40 ml) and the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 6-cyclohexyl-m-3-methyl-3,4-dihydro-1H-2-benz-othiopyran-4-one-rac-1- carboxylic acid (7.4 g, 70% yield). Recrystallization from ethyl acetate gives colorless plate crystals.

Melting point 185-186 ^about C.

Elemental analysis data: C ₁₇ H ₂₀ O ₃ S
Calculated, C 67.08; H, 6.62.

 Found, C, 67.33; H, 6.68.

PRI me R 10. In dimethylformamide (10 ml) dissolve 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (500 mg) followed by the introduction of diethylphosphorocyanidate (85% 365 mg). The mixture is stirred for 30 minutes while cooling with ice, then 3-aminopyridine (160 mg) and triethylamine (202 mg) are added to it. Then this reaction mixture is stirred for another 1 hour while cooling with ice, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 6-cyclohexyl-N- (3-pyridyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxy d (490 mg, yield 79%). After recrystallization from hexane ethyl acetate, colorless plate crystals are obtained.

Melting point 194-195 ^about C.

Elemental analysis data: C ₂₁ H ₂₂ N ₂ O ₂ S
Calculated, C 68.82; H 6.05; N, 7.64.

 Found, C, 68.59; H 5.90; N, 7.63.

 PRI me R s 11-55. Carrying out the processes as in example 10, receive the compounds shown in table. 10.

PRI me R 56. A mixture of 7-cyclohexyl-1,2,4,5-tetrahydro-3-benzothienyl-5-one-2-carboxylic acid (1.0 g) and thionyl chloride (2 ml) is heated with reflux for 30 minutes and then concentrate. Residual oil is dissolved in dichloromethane (5 ml). This solution was added dropwise to a solution of 4-diethoxyphosphorylaniline (757 mg) in pyridine (10 ml) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was concentrated. The residual concentration product was diluted with 1-normal HCl (50 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in 7-cyclohexyl-N- (4-diethoxyphosphorylphenyl) 1,2, 4,5-tetrahydro-3-benzothiepin-5-one-2-carb - oxamide (760 mg, yield 45%). Recrystallization from ethanol gives colorless prismatic crystals. Melting point 222-223 ^about C.

Elemental analysis data: C ₂₇ H ₃₄ NO ₅ PS
Calculated, C 62.90; H, 6.65; N 2.72.

 Found, C, 62.79; H 6.55; N 2.71.

 PRI me R s 57 and 58. Carrying out the processes as in example 56, receive the compounds shown in table. eleven.

PRI me R 59. Sodium borohydride (102 mg) is introduced into a solution of 7-cyclohexyl-N- (3,4-methylenedioxyphenyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (1.1 g) in ethanol (20 ml), the mixture was stirred at room temperature for 2 hours. After addition of acetic acid (1 ml), the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, a saturated aqueous solution of NaHCO ₃ and again with water, dried (over MgSO ₄ ), the solvent was distilled off and the result was 7-cyclohexyl-N- (3,4-methylenedioxyphenyl) -c-4-hydroxy-3, 4-dihydro-1H-2-benzothiopyran-rac-1-carboxamide (0.97 g, 88% yield). Recrystallization from ethyl acetate gives colorless prismatic crystals.

Melting point 208-209 ^about C.

Elemental analysis data: C ₂₃ H ₂₅ NO ₄ S
Calculated, C 67.13; H, 6.12; N, 3.40.

 Found, C, 66.91; H, 6.19; N, 3.15.

 PRI me R s 60-62. Carrying out the processes as in example 59, receive the compounds shown in table. 12.

PRI me R 63. A solution of meta-chlorobenzoic acid (70% 662 mg) in chloroform (5 ml) is introduced into a solution of 7-cyclohexyl-N- (3,4-methylenedioxyphenyl) -3,4-dihydro-1H- 2-benzothiopyran-4-one-1-carboxamide (1.1 g) in chloroform (15 ml) under ice-cooling, the mixture was stirred for 1 h at the same temperature. This reaction mixture was washed successively with water, saturated aqueous NaHCO ₃ and again with water, dried (over MgSO ₄ ) and the solvent was distilled off. The residual distillation product is subjected to separation in a chromatographic column on silica gel using a mixture of ethyl acetate-hexane (2: 3 v / v). Removing the solvent from the first eluate gives 7-cyclohexyl-N- (3,4-methylenedioxyphenyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide-2,2-dioxide (0.28 g, yield 23%).

 After recrystallization from hexane ethyl acetate, colorless needle crystals are obtained.

Melting point 224-225 ^about C.

Elemental analysis data: C ₂₃ H ₂₃ NO ₆ S
Calculated, C 62.57; H 5.25; N, 3.17.

 Found, C, 62.41; H 5.23; N, 3.21.

Removal of the solvent from the eluate gave 7-cyclohexyl-N- (3,4-methylenedioxyphenyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide-2-oxide (0.53 g, yield 53%) (mixture of 1,2-cis and trans in a ratio of 6: 4). Recrystallization from ethanol gives colorless prismatic crystals. Melting point 208-209 ^about C.

Elemental analysis data: C ₂₃ H ₂₃ NO ₅ S
Calculated, C 64.92; H 5.45; N, 3.29.

 Found, C, 64.57; H 5.28; N, 3.45.

 PRI me R s 64-67. Carrying out the processes as in example 63, receive the compounds shown in table. thirteen.

Example 68. Into a solution of 7-cyclohexyl-N- (4-diethoxyphosphorylmethylphenyl) -1,2,3,4,5-tetrahydrobenzothiepin-5-one-2-carboxamide (0.53 g) in chloroform ( 10 ml) is added dropwise a solution of meta-chloroperbenzoic acid (80% 0.6478) in chloroform (10 ml), and the mixture is kept at room temperature overnight. The reaction mixture is then washed successively with an aqueous solution of potassium carbonate and water, dried (over MgSO ₄ ), then the solvent is distilled off, resulting in 7-cyclohexyl-N- (4-diethoxyphosphorylmethyl-phenyl) -1,2,4,5-tetrahydro 3-benzothiepin-5-one-2-carboxamide-3,3-dioxide (0.49 g, 87%). Recrystallization from chloroform-ethanol gave colorless plates melting at 237-238 ° ^C.

Elemental analysis data: C ₂₈ H ₃₈ NO ₇ PS
Calculated, C 59.88; H, 6.46; N, 2.49.

 Found, C 59.77; H 6.53; N 2.66.

 PRI me R s 69 and 70. Carrying out the processes as in example 68, receive the compounds shown in table. 14.

PRI me R 71. A mixture of ethyl 6-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carb-oxylate-2,2-dioxide (0.565 g), 2-normal KOH (10 ml) and methanol (10 ml) are stirred at room temperature for 30 minutes, after which it is acidified with 2-normal HCl and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried (over MgSO ₄ ), the solvent is distilled off. Thionyl chloride (2 ml) was added to the residual distillation product, the mixture was heated under reflux for 30 minutes, and then concentrated under reduced pressure. The oily residual product was dissolved in dichloromethane (5 ml) and the solution was added dropwise to a solution of diethyl 4-aminobenzylphosphonate (0.487 mg) in pyridine (10 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes, after which it is poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with 2-normal HCl and water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in N- (4-diethoxyphosphorylmethylphenyl) -6-methyl-3,4-dihydro-1H-2-benzothiopyran-4- he-1-carboxamide-2,2-dioxide (0.32 g, 33%). After recrystallization from ethanol, transparent needle-like crystals are obtained, mp. 212-213 ^about S.

Elemental analysis data: C ₂₂ H ₂₆ NO ₇ PS
Calculated, C 55.11; H 5.47; N, 2.92.

 Found, C, 55.37; H 5.62; N, 2.89.

PRI me R 72. Carrying out the process as in example 71, get N- (diethoxyphosphorylphenyl) -6-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide-2, 2-dioxide. Yield 55% after recrystallization from ethyl acetate hexane gave colorless prisms having a melting point of 129-130 ° ^C.

Elemental analysis data: C ₂₁ H ₂₄ NO ₇ PS
Calculated, C 54.19; H 5.20; N, 3.01.

 Found, C, 54.14; H 5.39; N, 2.92.

PRI me R 73. Ethoxycarbonyl (3,4-dimethylphenyl) methylthioacetic acid (66 g) was dissolved in ether (300 ml), followed by injection of thionyl chloride (41.7 g) and then pyridine (0.1 ml) . The mixture was stirred at room temperature for 1 hour and then heated under reflux for 30 minutes, after which it was concentrated under reduced pressure. The oily residue was dissolved in dichloromethane (100 ml), the solution was added dropwise to an ice-cooled suspension of aluminum chloride (62.4 g) in dichloromethane (300 ml) for 1 h. Then the reaction mixture was further stirred for 1 h, after which it was poured into a mixture of ice-water (1 l) and the organic layer is separated. This organic layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off, resulting in ethyl 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (49.5 g, 80%). Recrystallization from hexane gave colorless plates, mp 68-69 ° ^C.

Elemental analysis data: C ₁₄ H ₁₆ O ₃ S
Calculated C 63.61; H, 6.10.

 Found, C, 63.68; H, 6.15.

 PRI me R s 74-88. By carrying out the process as in example 73, receive the compounds shown in table. fifteen.

Example 89. 2- [Ethoxycarbonyl (3,4-dimethylphenyl) methylthio] propionic acid (40.5 g) was dissolved in ether (300 ml), followed by addition of thionyl chloride (24.4 g) and then pyridine (0.1 ml). The mixture was stirred at room temperature for 1 hour and heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the oily residue was dissolved in dichloromethane (80 ml). This solution was added dropwise to an ice-cooled suspension of aluminum chloride (38.4 g) in dichloromethane (300 ml) for 1 h. The reaction mixture was further stirred for an hour and a half with ice-cooling, then poured into ice-water (1 l) ) The organic layer is separated, washed with water, dried (MgSO ₄ ) and the solvent is distilled off. The oily residue is dissolved in an ethanol solution of sodium ethoxide (obtained from 0.315 g of sodium and 200 ml of ethanol) and the solution is heated under reflux for 15 minutes. Then the reaction mixture is poured into water, acidified with 1-normal HCl (100 ml) and extracted with ether. The ether layer is washed with water, dried (over MgSO ₄ ) and the solvent is distilled off. The residue was chromatographed on a silica gel column using ether-hexane (1: 3) to give ethyl 6,7-dimethyl-t-3-methyl-3,4-dihydro-1H-2-benzothiopyran- 4-on-rac-1-carboxylate (23.5 g, 62%). Recrystallization from hexane gave colorless prism crystals, melting point 83-84 ° ^C.

Elemental analysis data: C ₁₅ H ₁₈ O ₃ S
Calculated, C 64.72; H, 6.52.

 Found, C, 64.90; H 6.55.

 PRI me R s 90-94. Carrying out the processes in this way, get the compounds shown in table. 16.

PRI me R 95. A mixture of ethyl 6,7-dimethyl-t-3-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-rac-1-carboxylate (21 g), 2 -normal KOH (100 mL), methanol (100 ml) was stirred ^at 50 ° C for 30 minutes and after this time it was acidified with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off under reduced pressure. The result of this procedure is 6,7-dimethyl-t-3-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-rac-1-carboxylic acid (16.6 g, 87%) . Recrystallization from ethyl acetate gives colorless prismatic crystals. Melting point 203-204 ^about C.

Elemental analysis data: C ₁₃ H ₁₄ O ₃ S
Calculated, C 62.38; H, 5.64.

 Found, C, 62.67; H, 5.67.

 PRI me R s 96-116. Carrying out the procedure of example 95 obtained, the compounds shown in the table. 17.

 PRI me R s 117-199. Carrying out the processes as in example 10, receive the compounds shown in table. eighteen.

PRI me R 200. In a solution of 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (0.945 g) in tetrahydrofuran (10 ml), oxalyl chloride ( 0.609 g) and dimethylformamide (2 drops), the mixture is stirred at room temperature for 1 hour. On the other hand, a mixture of diethoxyphosphorylamine (4.9 g), sodium hydride in oil (60% 0.32 g) and tetrahydrofuran (30 ml ) is mixed with ice cooling for 30 minutes, then the indicated solution is introduced into it. The mixture was stirred under ice cooling for 30 minutes, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and the solvent was distilled off, resulting in N-diethoxyphosphoryl-6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxyme- (0.29 g, 19%). Recrystallization from ethyl acetate gave colorless prismatic crystal having a melting point of 192-193 ° ^C.

Elemental analysis data: C ₁₆ H ₂₂ NO ₂ PS
Calculated, C 51.74; H 5.97; N, 3.77.

 Found, C 51.71; H 5.86; N 3.74.

PRI me R 201. Carrying out the process as in example 200, get 6-cyclohexyl-N-diethoxyphosphoryl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide. Yield 36% after recrystallization from ethyl acetate gave colorless needles with melting point 163-164 ° ^C.

Elemental analysis data: C ₂₀ H ₂₈ NO ₅ PS
Calculated C 56.46; H, 6.63; N, 3.29.

 Found, C 56.37; H, 6.65; N, 3.09.

PRI me R 202. In tetrahydrofuran (10 ml) dissolve 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (0.473 g), followed by the introduction of oxalyl chloride (0.305 g) and then dimethylformamide (1 drop). The mixture was stirred at room temperature for 2 hours. This reaction mixture was added to an aqueous solution of ammonia (20 ml) ethyl acetate (40 ml), the whole mixture was stirred at room temperature for 30 minutes. The ethyl acetate layer is separated, washed with water, dried (over MgSO ₄ ) and the solvent is distilled off, resulting in 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (0, 38 g, 81%). Recrystallization from ethyl acetate gave colorless plates, melting point 197-198 ° ^C.

Elemental analysis data: C ₁₂ H ₁₃ NO ₂ S
Calculated C 61.25; H 5.57; N, 5.95.

 Found, C, 61.20; H 5.53; N, 6.00.

PRI me R 203. A mixture of 6,7-dimethyl-t-3-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-rac-1-carboxylic acid (0.5 g) and thionyl chloride (2 ml) is heated under reflux with stirring for 1 h, concentrated, the residual product of concentration is dissolved in chloroform (3 ml). This solution was introduced into an aqueous solution of ammonia (20 ml) -ethyl acetate (30 ml), the mixture was stirred at room temperature for 30 minutes. The ethyl acetate layer is separated, washed with water and dried (MgSO ₄ ). Then, the solvent was distilled off, resulting in 6,7-dimethyl-t-3-methyl-3,4-dihydro-1H-2-benzothiopyran-4-one-rac-1-carboxamide (0.305 g, 61%). Recrystallization from ethyl acetate gave colorless needles with melting point 190-191 ° ^C.

Elemental analysis data: C ₁₃ H ₁₅ NO ₂ S
Calculated, C 62.62; H, 6.06; N, 5.06.

 Found, C, 62.69; H, 6.12; N, 5.63.

PRI me R 204. In a mixture of N- (4-diethoxyphosphorylphenyl) -6-cyclohexyl-3,4-dihydro-1H-2-benzopyran-4-one-1-carboxamide (1.8 g) and carbon tetrachloride (30 ml) was added iodotrimethylsilane (1.6 g) under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture is concentrated, methanol (30 ml) and 2-normal HCl (100 ml) are introduced in this order. The mixture is extracted with ethyl acetate, the ethyl acetate layer is washed with water and dried (MgSO ₄ ). Then, the solvent was distilled off to obtain 6-cyclohexyl-N- (4-phosphonophenyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (0.92 g, 58%). After recrystallization from ethyl acetate-methanol, colorless prismatic crystals with a melting point of 232-233 ^about C.

Elemental analysis data: C ₂₂ H ₂₄ NO ₅ PS
Calculated, C 59.32; H 5.43; N, 3.14.

 Found C, 58.90; H 5.31; N, 3.02.

PRI me R 205. Carrying out the process as in example 204, get 6,7-dimethyl-N- (4-phosphonophenyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1- carboxamide. Yield 70% after recrystallization from ethyl acetate methanol gave colorless prismatic crystal having a melting point of 262-264 ° ^C.

Elemental analysis data: C ₁₈ H ₁₈ NO ₅ PS
Calculated, C 55.25; H 4.64; N, 3.58.

 Found, C 55.06; H 4.72; N, 3.35.

PRI me R 206. In a solution of 6-cyclohexyl-N- (4-diethoxyphosphorylmethylphenyl) -3,4-dihydro-1H-2-benzothiopyr n-4-one-1-carb-oxamide (2.6 g) bromotrimethylsilane (3.1 g) was added in acetonitrile (50 ml), the mixture was stirred at room temperature for 12 hours. Then the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (over MgSO ₄ ) and the solvent was distilled off. The result is 6-cyclohexyl-N- (4-phosphonomethylphenyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (0.91 g, 40%). After recrystallization from ethyl acetate-methanol, colorless prismatic crystals with a melting point of 226-227 ^about C.

Elemental analysis data: C ₂₃ H ₂₆ NO ₅ PS
Calculated, C 60.12; H 5.70; N, 3.05.

 Found, C 59.71; H 5.59; N, 2.98.

PRI me R 207. Carrying out the process as described in example 206, get 6,7-dimethyl-N- (4-phosphonomethylphenyl) -3,4-dihydro-1H-2-benzothiopyran-4-one-1 carboxamide. After recrystallization from ethyl acetate-methanol, colorless prismatic crystals with a melting point of 244-245 ^about C.

Elemental analysis data: C ₁₉ H ₂₀ NO ₅ PS
Calculated, C 56.29; H 4.97; N, 3.45.

 Found, C, 55.97; H 4.87; N, 3.34.

PRI me R 208. Carrying out the process as in example 59, get N- (4-chlorophenyl) -6,7-dimethyl-c-4-hydroxy-3,4-hydro-1-H-2-benzothiopyran- rac-1-carboxamide. Yield: 78% Recrystallization from ethanol chloroform gave colorless prisms melting at 244-245 ° ^C.

Elemental analysis data: C ₁₈ H ₁₈ NO ₂ SCl
Calculated, C 62.15; H 5.22; N, 4.03.

 Found, C, 62.02; H 5.18; N, 4.06.

PRI me R 209. Carrying out the process as in example 59, receive N- (4-diethoxyphosphorylphenyl) -6,7-dimethyl-c-4-hydroxy-3,4-dihydro-1H-2-benzothiopyran-rac- 1-carboxyxamide. Recrystallization from ethyl acetate hexane gave colorless prism crystals, melting point 162-163 ° ^C.

Elemental analysis data: C ₂₃ H ₃₀ NO ₅ PS
Calculated, C 59.60; H 6.52; N, 3.20.

 Found, C 59.07; H 6.55; N, 2.99.

PRI me R 210. 6-Cyclohexyl-3,4-dihydro-N- (3-pyridyl) -4-oxo-1H-2-benzothiopyran-1-carboxamide is treated in a solution of hydrogen chloride in ethanol to obtain the corresponding hydrochloride . Recrystallization from methanol ether gives pure hydrochloride. Melting point 203-204 ^about C.

Elemental analysis: C ₂₁ H ₂₂ N ₂ O ₂ S˙HCl
Calculated, C 62.60; H 5.75; N, 6.95.

 Found, C, 62.40; H 5.57; N, 6.90.

PRI me R 211. 6-Chloro-3,4-dihydro-4-oxo-1H-2-benzothiopyran-1-1-carboxylic acid is treated in a solution of aqueous sodium hydroxide (1H) to obtain the corresponding sodium salt. Recrystallization from ethanol gives colorless prisms. Melting point 173-174 ^o C.

Elemental analysis: C ₁₀ H ₆ O ₃ SCl˙Na x xH ₂ O
Calculated, C 42.49; H 2.85.

 Found, C, 42.28; H 2.70.

 The following is a comparative table showing the advantage of the proposed compounds over the known.

получено из соединения формулы

Ингибиторную активность ресорбции кости в известном соединении (Б) и соединении примера 22

определяют в соответствии с указанным методом.Comparative table Compound (B) of the formula

obtained from a compound of the formula

Inhibitory activity of bone resorption in the known compound (B) and the compound of example 22

determined in accordance with the specified method.

 The results are presented in table. nineteen.

 The table shows the superiority in the inhibitory activity of bone resorption of the proposed compound having a sulfur atom over the known compound.

 PRI me R 1 preparation of the drug. Tablets.

Composition per tablet, mg: (1) Compound (compound synthesized according to Example 22) 50 (2) Corn starch 30 (3) Lactose 113.4 (4) Oxypropyl cellulose 6 (5) Water 0.03 (6) Magnesium stearate 0 , 6
The ingredients (1), (2), (3) and (4) are mixed and plasticized with the ingredient (5) the obtained mass is dried in vacuo at ⁴⁰ ° C for 16 hours. The pulp is sprayed and sieved through sieve size of openings 16 mesh (0.54 mm) to form granules. The granules are mixed with ingredient (6) and this composition is pressed under pressure in a rotating tabletting machine (manufactured by Kikusui Seisakusho Co. Ltd.) and the result is tablets weighing 200 mg.

PRI me R 2 preparation of the drug. Enteric-coated tablets disintegrating in the intestines. (1) Compound (compound synthesized according to Example 146) 50 mg (2) Corn starch 30 mg (3) Lactose 113.4 mg (4) Oxycellulose 6 mg (5) Water 0.03 ml (6) Magnesium stearate 0, 6 mg (7) Cellulose Acetate Phthalate 10 mg (8) Acetone 0.2 ml
From the indicated ingredients (1), (2), (3), (4), (5) and (6), tablets are obtained in the same manner as in Example 1 of preparation of the preparation. These tablets are film-coated in an acetone solution of component (7) using a block-type coating device (manufactured by Freund), resulting in enteric coated tablets weighing 210 mg.

 PRI me R 3 preparation of the drug. Capsules

(1) Compound (compound,
synthesized according to example 163) 30 mg (2) Corn starch 40 mg (3) Lactose 74 mg (4) Oxypropyl cellulose 6 mg (5) Water 0.02 ml
The ingredients (1), (2), (3) and (4) are mixed and plasticized with the ingredient (5) the obtained mass is dried in vacuo at ⁴⁰ ° C for 16 hours. The dried mass is atomized and screened through a sieve holes 16 mesh. (0.54 mm), the result is granules. Using a capsule filling machine (Zanassi, Italy), the granules are packed into No. 3 gelatin capsules and capsule preparations are obtained.

 PRI me R 4 preparation of the drug. Injection solution.

(1) Compound (compound,
synthesized according to example 23) 5 mg (2) Sodium salicylate 50 mg (3) Sodium chloride 180 mg (4) Sodium metabisulfite 20 mg (5) Methylparaben 36 mg (6) Propylparaben 4 mg (7) Distilled water for injection 2 ml
The ingredients (1), (2), (3), (4), (5) and (6) are dissolved in half of said volume of distilled water for injection with stirring at 80 ^C. After cooling the resulting solution to ^about 40 C, ingredient (1) dissolves in it. The remaining volume of distilled water for injection is added to the solution obtained in this way to obtain the indicated volume, and it is aseptically filtered through the appropriate filter paper, a sterile injectable solution is obtained.

Claims (2)

1. Sulfur-containing heterocyclic compounds of General formula I

in which the benzene ring A can be substituted with one or two identical or different substituents selected from the group consisting of halogen, C ₁ C _{1 0} -alkyl and C ₁ C ₆ -alkoxyl or unsubstituted or substituted with lower alkyl C ₃ - C ₇ - cycloalkyl, or both substituents together form a lower alkylene or alkylene dihydroxy group;
R is hydrogen, C ₁ C _{1 0} -alkyl or phenyl;
To a carboxyl group, a C ₁ C _{1 0} alkoxycarbonyl group or a group of the formula —CONR ₁ R ₂ , where R ₁ and R ₂ are each hydrogen, lower alkyl that may be substituted with a lower alkoxyphenyl group, or phenyl substituted with one or two identical or various substituents selected from the group consisting of halogen, lower alkyl or lower alkoxyl, or both substituents together form a lower alkylene dihydroxy group, or the group (CH ₂ ) _n R (O) (OR ′) ₂ , where n 1 3; R ′ -C ₁ C _{6 is} alkyl, or a group —C ₆ H ₅ (CH ₂ ) _n R (O) (OR ′) ₂ , where n 0 2 and R′-C ₁ -C _{6 are} alkyl; or pyridyl, thiazolyl, which may be substituted with a lower alkoxyphenyl group, or 1,3,4-thiadiazolyl substituted with lower alkyl,
or R ₁ and R ₂ together with the adjacent nitrogen atom form a thiazoline group substituted by an imino group or a piperazino group substituted by halo phenyl or lower alkoxyphenylalkyl;
X is —CH (OH) or —CO;
K about or 1;
K′- 0,1 or 2,
or their pharmaceutically acceptable salts.  2. A composition having an inhibitory effect on bone resorption, including the active ingredient and target additives, characterized in that as the active ingredient contains sulfur-containing compounds of the formula I or their pharmaceutically acceptable salts in the following ingredients, wt. Active ingredient 1.5 25.0
Target Supplements Else

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