SK3322002A3 - Use of thienopyrimidines - Google Patents

Abstract

The invention relates to the use of thienopyrimidines of formula (I) and to their physiologically safe salts and/or solvates, wherein R<1>, R<2> and X have the meanings cited in Claim No. 1. According to the invention, the thienopyrimidines are used in order to produce a medicament for treating angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the heart vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, cirrhosis of the liver, and for treating female impotence.

Description

The invention relates to the use of thienopyrimidine derivatives of the general formula I

where

2

R, R are independently hydrogen, A, OA, hydroxyl or Hal, or

R and R together are also alkylene having 3-5 C atoms, _{-O-CH2 -CH2} -, _{-CH2 -O-CH2} -, -O-CH ₂ -O- or _-O-CH2 -CH ₂ -O-,

X is one of R ⁷ substituted by R ⁴ , R ⁵ or R ⁶ ,

R ⁴ represents a linear group having from 1 to 10, optionally one or -CH = CH-, or branched alkylene carbon atoms, two CH ₂ groups being replaced by i

R ⁵ represents a C 5 -C 12 cycloalkyl or cycloalkylalkylene group,

R ⁶ represents a phenyl or phenylmethyl group,

R ⁷ is COOH, COOA, CONH ₂ ,

CONHA, CON (A) ₂ or CN

A is C 1 -C 6 alkyl,

Hal represents a fluorine, chlorine, bromine or iodine atom and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, cardiovascular impairment, peripheral vascular disease , stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, kidney insufficiency, liver cirrhosis, and for treating female impotence.

BACKGROUND OF THE INVENTION

The use of PDE V-valves is described, for example, in WO 94/28902. Pyrimidine derivatives are known, for example, from the German patent DE 19819023, the European patent EP 201188 and the world patent WO 93/06104.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds with valuable properties, in particular compounds which could be used in the manufacture of medicaments.

SUMMARY OF THE INVENTION

I

It has been found that the compounds of formula I and their salts have good pharmaceutical properties with good tolerability.

In particular, they exhibit specific inhibition of cGMP phosphodiesterase (PDE V).

Quinazolines with cGMT-phosphodiesterase inhibiting activity are described, for example, in J. Med. Chem. 36, p. 3765 (1993) and J. Med. Chem. 37, p. 2106 (1994).

The biological activity of the compounds of formula I can be determined, for example, by the methods described in WO 93/06104 and WO 94/28902.

The affinity of the compounds of formula I according to the invention for cGMP-phosphodiesterase and cAMP-phosphodiesterase is determined by determining their IC50 values (the concentration of inhibitor required to achieve 50% inhibition of enzyme activity).

Enzymes isolated by known methods can be used to perform the assay (e.g., W. J. Thompson et al., Biochem. 10, 311 (1971)). The modified batch method described by W. J. Thompson and M. M. Appleman (Biochem. 18, 5228 (1979)) may be used to perform the assay.

The use of substituted pyrazolopyrimidinones for the treatment of female impotence is described, for example, in WO 94/28902.

The compounds of formula (I) are effective as inhibitors of phenylephrine-induced contraction in rabbit corpus cavernosum. This biological action can be demonstrated, for example, by the method of F. Holmquist et al., (J. Urol. 150: 1310-1315, 1993).

Inhibition of contraction demonstrates the efficacy of the compounds of the invention in the treatment and / or treatment of potency disorders.

. The invention relates to compounds of formula I, their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, cardiovascular impairment, peripheral vascular disease, stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, kidney insufficiency, liver cirrhosis, and for treating female impotence.

The compounds of the formula I can be used as medicaments in human and veterinary medicine. In addition, they can be used as intermediates for the production of other drug-acting active ingredients.

The radicals R ^1, R ^2, R ^3, R ^4, R ^5, R ⁶ and R ^7, X and L have the formulas I, II and III as defined above, unless otherwise indicated.

A represents an alkyl group having 1 to 6 carbon atoms. In the above formulas, the alkyl group is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.

··. . *- in"· . .

X is one of R ⁷ substituted by R ⁴ , R ⁵ or R ⁶ .

R ⁴ represents a linear or branched alkylene group having 1 to 10 carbon atoms, the alkylene group being preferably, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2 , 2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1,1,2- or 1,2,2-trimethylpropylene, linear or a branched heptylene, octylene, nonylene or decylene group. R ⁴ is furthermore a but-2-enylene or a hex-3-enylene group. In particular, it is ethylene, propylene or butylene.

R ⁵ represents a C 5 -C 12 cycloalkylalkylene group, preferably, for example, a cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene group. The symbol R ⁵ is also cycloalkyl, preferably of 5 to 7 carbon atoms, e.g., cyclopentyl, cyclohexyl or cycloheptyl.

Hal is preferably fluorine, chlorine or bromine, but also iodine.

The groups R ¹ and R ² may be the same or different and are preferably in the 3 or 4 position of the phenyl ring. They are, for example, independently of one another hydrogen, alkyl, fluorine, chlorine, bromine or iodine, or together an alkylene group, for example a propylene, butylene or pentylene group, furthermore also ethyleneoxy, methylenedioxy or ethylenedioxy. They are also preferably alkoxy, such as methoxy; ethoxy or propoxy groups, and also a hydroxyl group.

R ⁷ is preferably, for example, COOH, COOCH ₃ , COOC ₂ H ₅ , CONH ₂ , CON (CH ₃ ) ₂ , CONHCH ₃ or CN.

The groups which occur several times in the general formulas can be independently the same or different from each other.

The invention thus relates in particular to compounds of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula (I) are the following compounds of formulas (Ia) to (Id), wherein in particular the not-listed symbols have the meanings given in formula (I) but in the formulas:

la X COOH, COOA, CONH ₂ , CONHA, CONA ₂ or CN substituted by R ⁴ , phenyl or phenylmethyl; Ib R ¹ and R ² together, a (C až-C alky ₎ alkylene group, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-, X COOH, COOA, CONH ₂ , CONHA, CONA ₂ or CN substituted by R ⁴ , phenyl or phenylmethyl; In Ic R ¹ and R ² independently of one another hydrogen, A, OA or, - Hal, or ............. . . . R ¹ and R ² together, a (C až-C alky ₎ alkylene group, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-, X COOH, COOA, CONH ₂ , CONHA, CONA ₂ or CN substituted by R ⁴ , phenyl or phenylmethyl; Id R ¹ and R ² independently of one another hydrogen, A, OA or Hal, or R ¹ and R ² together, a (C až-C alky ₎ alkylene group, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-, X R is a substituted alkylene group having 2 up to 5 carbon atoms, cyclohexyl, phenyl or phenylmethyl,

a COOH or COOA group, an alkyl group having 1 to 6 carbon atoms,

Hal is fluorine, chlorine, bromine or iodine.

Compounds of formula I and starting materials therefor. The preparation is prepared by known methods which are described in the literature (for example, in standard publications such as Houben-Weyl, Methoden den organischen Chemie, Georg Thieme Verlag, Stittgart) under reaction conditions that are known and suitable for said reactions. It is also possible in this case to use known variants, not described here in greater detail.

In the compounds of formula II or III, R ¹ , R ² , R ³ , R ⁴ and X have the meanings given above, in particular the abovementioned preferred meaning.

When L is a reactive esterified hydroxyl group, it is preferably C1-6 alkylsulfonyloxy (especially methylsulfonyloxy) or C6-10 arylsulfonyloxy (especially phenylsulfonyloxy or p-tolylsulfonyloxy) and furthermore 2-naphthyloxy.

Compounds of formula I, wherein the individual symbols have the meanings given above, may advantageously be obtained by providing a compound of formula II

L

(II) wherein X is as defined above and wherein L represents a chlorine, bromine, hydroxyl, SCH ₃ or reactive esterified hydroxyl group, is reacted with a compound of formula III

(III) wherein R ¹ and R ² and X are as defined above.

Alternatively, the starting materials can also be formed in situ, i.e., they are not isolated from the reaction mixture, but the reaction mixture is immediately used to prepare compounds of formula I. Alternatively, it is also possible to carry out the reaction stepwise.

The compounds of formulas II and III are generally known. If they are not known, they can be prepared by known methods.

Compounds of formula II can be prepared, for example, by reaction with phosphorus oxychloride from the corresponding hydroxypyrimidines, which are prepared from thiophene derivatives and cyano-substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453, 1988).

Hydroxypyrimidines are prepared by dehydrogenation of the corresponding tetrahydrobenzothienopyrimidine compounds or for the preparation of pyrimidine derivatives by the known cyclization of 2-aminobenzthiophene-3-carboxylic acid derivatives with aldehydes or nitriles (Houben-Weyl E9b / 2).

The reaction of compounds of formula II with compounds of formula III is carried out in the presence or absence of an inert solvent at a temperature of about -20 to about 150 ° C, preferably 20 to 100 ° C;

Addition of an acid-binding agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other weak acid salt of an alkali metal or alkaline earth metal, preferably potassium, sodium or calcium, or an organic base such as for example triethylamine, dimethylamine, pyridine or quinoline, or use of an excess of the amine component.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone, dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; or mixtures of these solvents.

io

It is also possible in the compound of formula I to convert the X group to another X group, for example by hydrolyzing the ester or cyano group to the COOH group. The ester group can, for example, be saponified at 0 to 100 ° C with sodium hydroxide or potassium hydroxide in water, water-tetrahydrofuran or water-dioxane.

For example, carboxylic acids can be converted to the corresponding carboxylic acid chlorides by reaction with thionyl chloride, which can be converted to acid amides. Cleavage of water in a known manner yields carbonitriles from these amides.

The acid of formula (I) may be converted into the corresponding base addition salt by, for example, reaction of an equivalent amount of acid and base in an inert solvent such as ethanol and subsequent evaporation. Suitable bases for this reaction are, in particular, those which give physiologically acceptable salts. Thus, the acids of the formula I can be converted by a base (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal salts, in particular the alkali metal or alkaline earth metal salts or the corresponding ammonium salts. Suitable bases for this reaction are, in particular, those organic bases which give physiologically acceptable salts, for example ethanolamine.

On the other hand, the base of formula I can be converted into an appropriate acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and subsequently evaporating the solvent. For this reaction, n

especially acids that provide physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polyhydric carboxylic, sulfonic or sulfuric acids may be used. acids such as formic, acetic, propionic, pivalic, diethyl acetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic, ethanesulfonic, ethanesulfonic, ethanesulfonic, ethanesulfonic, ethanesulfonic

2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid and naphthalene sulfonic acid, and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

The invention furthermore relates to pharmaceutical compositions comprising at least one compound of the formula I and / or a physiologically acceptable salt and / or solvate thereof for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, peripheral vascular diseases, stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhosis, and for treating female impotence.

The compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration and which do not react with the compounds of the general formula I, such as water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate , gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, for rectal use of lace, for parenteral use solutions, in particular oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the lyophilizates obtained used, for example, for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more other active ingredients. such as vitamins.

The compounds of formula (I) and their physiologically acceptable salts can be used to eliminate diseases in which an increase in the level of cycloguanosine monophosphate (cGMP) results in inhibition or prevention of inflammation and muscle tension. The compounds of the invention are particularly useful for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, cardiovascular conditions, peripheral vascular disease, stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritability bowel syndrome, tumors, kidney insufficiency, liver cirrhosis, and for the treatment of female impotence.

The compounds of the formula I according to the invention are generally used in doses of approximately 1 to 500 mg, preferably 5 to 100 mg per dosage unit. The daily dose is preferably about 0.02 to 10 mg / kg body weight. The dosage for each individual depends on a variety of factors, such as the efficacy of the particular compound employed, age, body weight, general health, sex, diet, time and route of administration, Kd excretion rate, drug combination, and severity of the disease being treated. Oral administration is preferred.

The invention is illustrated, but not limited, by the following examples. Temperatures are always given in degrees Celsius. - The expression 'normal processing' in the following practical examples means:

optionally adding water, optionally adjusting the pH to 2-10 according to the constitution of the final product, extracting the reaction mixture with ethyl acetate or dichloromethane, separating, drying the organic phase with sodium sulfate, scalding and purifying by silica gel chromatography and / or crystallization.

Mass Spectrometry (MS); EI (electron beam - ionization) M ⁺

FAB (fast atom bombardment) (M + H) ⁺

In particular, the present invention provides the use of the following compounds of formula I and their physiologically acceptable salts and / or solvates thereof for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, , peripheral vascular diseases, stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, kidney insufficiency, liver cirrhosis, and for treating female impotence.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- (4-Chloro-benzothieno [2,3-d] pyrimidin-2-yl) -propionic acid methyl ester [obtainable by cyclisation of 2-amino-5,6,7,8-tetrahydro-benzo [eta] &lt; 6 &gt; -phenyl-3-carboxylic acid methyl ester with 3- methyl ester cyanopropionic acid, sulfur dehydrogenation followed by chlorination using phosphorus oxychloride / dimethylamine] and 3-chloro-4-methoxybenzylamine ("A") in N-methylpyrrolidine are stirred for 5 hours at 110 ° C. The solvent is removed and the residue is worked up as usual. 3- [4- (3-Chloro-4-methoxybenzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester is obtained as a colorless oil.

Similarly, methyl 2- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3- d] methyl ester is obtained by reaction of "A" with methyl 2- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) acetic acid methyl ester. d] pyrimidin-2-yl] -acetic acid.

Similarly, by reaction of 3,4-methylenedioxybenzylamine with 3- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -propionic acid methyl ester, 3- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3- d] pyrimidin-2-yl] -propionic acid.

Similarly, 4- [4- (3-chloro-4-methoxybenzylamino) methyl ester] is obtained by reaction of "A" with 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester. benzothieno [2,3-d] pyrimidin-2-yl] butyric acid.

Similarly obtained by reacting 3,4-methylenedioxybenzylamine with 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] methyl ester pyrimidin-2-yl] butyric acid.

Similarly, by reaction of "A" with 5- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -valeric acid methyl ester 5- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-methyl] methyl ester -d] pyrimidin-2-yl] -valeric acid.

Similarly, by reacting 3,4-methylenedioxybenzylamine with 5- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -valeric acid methyl ester 5- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] methyl ester -d] pyrimidin-2-yl] -valeric acid.

Similarly, by reacting "A" with 7- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -heptanoic acid methyl ester, 7- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-methyl] methyl ester -d] pyrimidin-2-yl] -heptanoic acid.

Similarly, by reacting 3,4-methylenedioxybenzylamine with 7- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -heptanoic acid methyl ester, 7- [4- (3,4-methylenedioxybenzylamino) methyl ester is obtained. benzothieno [2,3-d] pyrimidin-2-yl] -heptanoic acid.

Similarly, it is obtained by reacting "A" with 2- [4- (4-chlorobenzothieno [2,3-d] pyrimidine methyl ester)

2-yl) -cyclohex-1-yl] -acetic acid 2- {4- [4- (3-chloro-4- ....... -...

methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) cyclohex-1-yl} acetic acid

Similarly, it is obtained by reaction of 3,4-methylenedioxybenzylamine with 2- [4- (4-chlorobenzothieno [2,3-d] pyrimidine) methyl ester

2-yl) -cyclohex-1-yl] acetic acid 2- {4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -cyclohex-1-yl ester acetic acid

Similarly, 3- (4-benzylaminobenzothieno [2,3-d] pyrimidine methyl ester) is obtained by reacting benzylamine with methyl 3- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) propionate.

2-yl) -propionic acid;

with 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -butyric acid methyl ester methyl 4- (4-benzylaminobenzothieno [2,3-d] pyrimidin-2-yl) -butyric acid methyl ester;

with 5- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -valeric acid methyl ester 5- (4-benzylaminobenzothieno [2,3-d] pyrimidin-2-yl) -valeric acid methyl ester;

Similarly, by reacting "A" with 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -cyclohexanecarboxylic acid methyl ester 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-methyl] methyl ester (d) -pyrimidin-2-yl) -cyclohexanecarboxylic acid; * ...................> and reaction of 3,4-methylenedioxybenzylamine with 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -cyclohexanecarboxylic acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) -cyclohexanecarboxylic acid methyl ester

Example 2

3- [4- (3-Chloro-4-methoxybenzylamino) -benzothieno [2,3-d] pyrimidin-2-yl) -propionic acid methyl ester is dissolved in ethylene glycol monoethyl ether and stirred for 5 hours after the addition of 32% sodium hydroxide. at 110 [deg.] C. After addition of 20% hydrochloric acid, the reaction mixture is extracted with dichloromethane. Addition of petroleum ether gave 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) propionic acid, m.p. 218 ° C. The obtained crystals are dissolved in isopropanol and the solution is mixed with ethanolamine. Crystallization gave 3- [4- (3-chloro-4-methoxybenzylamino) -benzothieno [2,3-d] pyrimidin-2-yl) propionic acid ethanolamine salt.

Similarly, the following compounds are obtained:

4- [4T (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) butyric acid, m.p. 225 [deg.]; ethanolamine salt, m.p. 150 ° C;

5- [4- (3-Chloro-4-methoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl) -valeric acid, m.p. 210 ° C; ethanolamine salt, mp 141 ° C; _________ ______...... =,. ¾ ...... ....

4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) butyric acid; hydrochloride, m.p. 245 ° C.

Similarly, the following carboxylic acids are obtained from the esters listed in Example 1:

2- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) acetic acid;

3- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) propionic acid,

5- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyridinidin-2-yl) valeric acid,

7- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid,

7- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid,

2- {4- [4- (3-Chloro-4-methoxy-benzylamino) -benzothieno [2,3d] -pyrimidin-2-yl] -cyclohex-1-yl} -acetic acid,

2- {4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3d] pyrimidin-2-yl] -cyclohex-1-yl} acetic acid,

3- (4-Benzylaminobenzothieno [2,3-d] pyrimidin-2-yl) propionic acid,

4- (4-Benzylaminobenzothieno [2,3-d] pyrimidin-2-yl) butyric acid.

5- (4-Benzylaminobenzothieno [2,3-d] pyrimidin-2-yl) valeric acid,

4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) -cyclohexanecarboxylic acid, ethanolamine salt, m.p. 167 ° C;

4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl) cyclohexanecarboxylic acid, ethanolamine salt, m.p. 143 ° C.

Example 3

A mixture of 1.5 g of 4- [4-chlorobenzothieno [2,3-d] pyrimidin-2-yl] -phenylacetic acid methyl ester ("B") prepared by dehydrogenation corresponding to 5,6,7,8-tetrahydrobenzthieno [2,3- d] -pyrimidine compound with sulfur and subsequent chlorination using phosphorus oxychloride / dimethylamine and 1.5 g

3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidine was heated at 110 ° C for 4 hours. After cooling, the residue is worked up as usual. It will be obtained

2.6 g of 4- [4- (3-chloro-4-methoxybenzylamino) [1] benzothieno [2,3-d] pyrimidin-2-yl) -benzoic acid methyl ester, m.p. 203-204 ° C.

Analogously to Example 2, 1.0 g is obtained from 1.2 g of ester

4- [4- (3-chloro-4-methoxybenzylamino) - [1] benzothieno [2,3d] pyrimidin-2-yl) -benzoic acid, ethanolamine salt, m.p. 189-190 ° C.

* - ··; . Similar to Example 1, 4- [4- (3,4-methylenedioxybenzylamino) [1] benzothieno [2,3-d] pyrimidin-2-yl] -benzoic acid methyl ester was obtained by reaction of "B" and 3,4-methylenedioxybenzylamine. by esterolysis of 4- [4- (3,4-methylenedioxybenzylamino) [1] benzothieno [2,3-d] pyrimidin-2-yl] -benzoic acid, sodium salt, m.p. &gt; 260 ° C.

Similarly, they are obtained

4- [4- (3-chloro-4-methoxybenzylamino) - [1] benzothieno- [2,3d] -pyrimidin-2-yl] -phenylocytic acid, ethanolamine salt, m.p. 130 ° C; and

4- [4- (3,4-methylenedioxybenzylamino) - [1] benzothieno [2,3d] pyrimidin-2-yl] -phenylacetic acid, ethanolamine salt, m.p. 202 ° C.

Example 4

Stir 1 equivalent of 3- [4- (3-chloro-4-methoxybenzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -propionic acid and 1.2 equivalents of thionyl chloride for 2 hours in dichloromethane. The solvent was removed to give 3- [4- (3-chloro-4-methoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -propionic acid chloride. The compound was taken up in aqueous ammonia, the mixture was stirred for 1 hour, and the usual work-up gave 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid amide.

- Example 5 .................. ....

Dissolve 1 equivalent of dimethylformamide and 1 equivalent of oxalyl chloride at 0 ° C in acetonitrile. 1 equivalent of 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid amide was added. The reaction mixture was stirred for 1 hour. Customary work-up gave 3- [4- (3-chloro-4-methoxybenzylamino) -benzothieno [2,3d] pyrimidin-2-yl] -propionitrile.

Example 6 i

As in Examples 1, 2 and 3, the following carboxylic acids are obtained by reacting the corresponding chloropyrimidine derivative with 3,4-ethylenedioxybenzylamine:

4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;

3- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid,

5- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid,

I

7- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,

2- {4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} acetic acid,

4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -cyclohexanecarboxylic acid,

4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -benzoic acid, decomposition at 220-230 ° C,

4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -benzoic acid, ethanolamine salt, mp 252 ° C,

4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -phenylocytic acid.

Similarly, the following compounds are obtained by reaction with 3,4-dichlorobenzylamine:

4- [4- (3,4-Dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,

3- [4- (3,4-Dichlorobenzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -propionic acid,

5- [4- (3,4-Dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -valeric acid, ethanolamine salt, m.p. 160 ° C,

7- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,

2- {4- [4- (3,4-Dichloro-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -cyclohex-1-yl} -acetic acid,

4- [4- (3,4-Dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -cyclohexanecarboxylic acid,

4- [4- (3,4-Dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -benzoic acid,

4- [4- (3,4-Dichlorobenzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -phenylocytic acid.

Similarly, the following compounds are obtained by reaction with 3-chloro-4-ethoxybenzylamine:

4- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,

3- [4- (3-Chloro-4-ethoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -propionic acid,

5- [4- (3-Chloro-4-ethoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -valeric acid,

7- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,

2- {4- [4- (3-Chloro-4-ethoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -cyclohex-1-yl} -acetic acid, i

4- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid,

4- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] -benzoic acid, m.p. 185-187 ° C,

4- [4- (3-Chloro-4-ethoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -phenylocytic acid.

Similarly, the following compounds are obtained by reaction with 3-chloro-4-isopropoxybenzylamine:

4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno- [2,3d] pyrimidin-2-yl] butyric acid,

3- [4- (3-Chloro-4-isopropoxy-benzylamino) -benzothieno [2,3d] -pyrimidin-2-yl] -propionic acid,

5- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno- [2,3d] pyrimidin-2-yl] -valeric acid, ethanolamine salt, m.p. 130 ° C,

7- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3d] pyrimidin-2-yl] heptanoic acid,

2- {4- [4- (3-Chloro-4-isopropoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] -cyclohex-1-yl} -acetic acid,

4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3d] pyrimidin-2-yl] -cyclohexanecarboxylic acid,

I

4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno- [2,3d] pyrimidin-2-yl] -benzoic acid, m.p. 240-241 ° C,

4- [4- (3-Chloro-4-isopropoxy-benzylamino) -benzothieno [2,3d] pyrimidin-2-yl] -phenylocytic acid.

The following examples illustrate, but do not limit, the pharmaceutical compositions of the invention:

Example A

Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered, injected into ampoules, lyophilized under sterile conditions and sterile closed. Each vial contains 5 g of active ingredient.

Example B

lace

A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to solidify. Each suppository contains mg of active ingredient.

Example C

solution

A solution of 1 g of an active compound of the formula I, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of sodium hydrogen phosphate dihydrate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH of the solution is adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used, for example, as eye drops.

Example D

ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E

tablets

A mixture of 1 kg of the active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in known manner into tablets, each tablet containing 10 mg of the active compound of the general formula Formula I.

Example F

dragee

Similarly, the activates of Example E are compressed tablets which are conventionally coated with sucrose, potato starch, talc, tragacanth and colorant.

Example G

capsules

2 kg of the active compound of the formula I are filled into hard gelatine capsules, each capsule containing 20 mg of the active compound of the formula I.

Example H

ampoule

A solution of 1 kg of an active compound of the formula I in 60 liters of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and the ampoules sealed. Each ampoule contains 10 mg of active ingredient.

Example I

Inhalation spray

Dissolve 14 g of an active compound of the formula I in 10 liters of isotonic sodium chloride solution and fill in conventional commercial spray canisters with a pump mechanism. The solution may be sprayed into the mouth or nose. Each injection (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Industrial usability

The use of thienopyrimidine derivatives for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, cardiovascular conditions, peripheral vascular disease, stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, allergic rhinitis, allergic rhinitis, allergic rhinitis bowel syndrome, tumors, kidney insufficiency, liver cirrhosis, and for the treatment of female impotence.

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Claims (2)

Use of a thienopyrimidine derivative of the general formula I, wherein R ¹ , R ² are independently hydrogen, A, OA, hydroxyl or Hal, or R and R together are also alkylene having 3-5 C atoms, -O-CH2-CH2-, -CH2-O-CH2, O-CH2-O- or _{-O-CH2 -CH2} -O-, X is one of R ⁷ substituted by R ⁴ , R ⁵ or R ⁶ , R ⁴ represents a linear or branched alkylene group having 1 to 10 carbon atoms, optionally one or two CH ₂ groups being replaced by -CH = CH- groups, R ⁵ represents a C 5 -C 12 cycloalkyl or cycloalkylalkylene group, R ⁶ is phenyl or phenylmethyl, COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN, A is C 1 -C 6 alkyl, Hal represents a fluorine, chlorine, bromine or iodine atom and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, cardiovascular impairment, peripheral vascular disease , stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, kidney insufficiency, liver cirrhosis, and for treating female impotence. Use of compounds according to claim 1 with the general formula from the group consisting of (a) 3- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] propionic acid; (b) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] butyric acid; c) 7- [4- (3,4-methyleneoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] heptanoic acid, d) 7- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] heptanoic acid, (e) 5- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] valeric acid, (f) 2- {4- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3d] pyrimidin-2-yl] -cyclohex-1-yl} acetic acid, (g) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] -cyclohexanecarboxylic acid; (h) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] -benzoic acid; 0 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] -phenylacetic acid, k) 2- {4- [4- (3-Chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3d] pyrimidin-2-yl] -cyclohex-1-yl} -cyclohexanecarboxylic acid , and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, cardiac patency, peripheral vascular disease, stroke, bromchitis, allergic asthma, chronic asthma , allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, kidney insufficiency, liver cirrhosis, and for the treatment of female impotence.