WO2001019369A1

WO2001019369A1 - Use of thienopyrimidines

Info

Publication number: WO2001019369A1
Application number: PCT/EP2000/008258
Authority: WO
Inventors: Rochus Jonas; Volker Eiermann; Sabine Bernotat-Danielowski
Original assignee: Merck Patent Gmbh
Priority date: 1999-09-14
Filing date: 2000-08-24
Publication date: 2001-03-22
Also published as: RU2002107441A; AU6703200A; NO20021234L; CN1377271A; ZA200202868B; CA2387123A1; JP2003509370A; CZ2002818A3; HUP0202614A2; BR0013957A; MXPA02002746A; KR20020026011A; HUP0202614A3; NO20021234D0; EP1212062A1; PL353343A1; DE19943815A1; AR025645A1; SK3322002A3

Abstract

The invention relates to the use of thienopyrimidines of formula (I) and to their physiologically safe salts and/or solvates, wherein R1, R2 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

Use of tienopyrimidines

The invention relates to the use of compounds of the formula

wherein

R »1, r R-.2 each independently of one another H, A, OA, OH or Hai,

R ¹ and R ² together also alkylene with 3-5 C atoms, -0-CH ₂ -CH ₂ -, -CH ₂ -0-CH ₂ -, -0-CH ₂ -0- or -0-CH ₂ -CH ₂ -O-,

X is simply substituted by R ^7, R ⁴ , R ⁵ or R ⁶ ,

R linear or branched alkylene with 1 -10 C atoms, in which one or two CH ₂ groups can be replaced by -CH = CH groups,

R ^b cycloalkyl or cycloalkylalkylene with 5-12 C atoms,

R ⁶ phenyl or phenylmethyl,

R ⁷ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,

Alkyl with 1 to 6 carbon atoms and

Shark F, Cl, Br or I

mean, as well as 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, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female impotence.

The use of other PDE V inhibitors is described e.g. in the WO

94/28902.

Pyrimidine derivatives are known for example from DE 19819023, EP 201 188 or WO 93/06104.

The invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.

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

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

Quinazolines with cGMP phosphodiesterase inhibitory activity are e.g. in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994).

The biological activity of the compounds of the formula I can be determined by methods as described, for example, in WO 93/06104 or in WO

94/28902 are described.

The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by determining their IC 50 values (concentration of the inhibitor which is required in order to achieve a 50% inhibition of the enzyme activity). Enzymes isolated according to known methods can be used to carry out the determinations (for example WJ Thompson et al., Biochem. 1971, 10, 311). A modified "batch" method by WJ Thompson and MM Appleman (Biochem. 1979, 18, 5228) can be used to carry out the experiments.

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

The compounds are effective as inhibitors of phenyiephrine-induced contractions in corpus cavemosum preparations from rabbits. This biological effect can e.g. can be detected by the method described by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993). The inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.

The invention relates to the use of the compounds of the formula I 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, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases , Stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female impotence.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as

Intermediates are used to manufacture other active pharmaceutical ingredients.

Above and below, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and L have the meanings given in the formulas I, II and III, unless expressly stated otherwise , A means alkyl with 1-6 C atoms.

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

X denotes an R ⁴ , R ⁵ or R ⁶ radical which is simply substituted by R ⁷ .

R ^{4 represents} a linear or branched alkylene radical having 1-10 C atoms, the alkylene radical preferably being, 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 branched heptylene, octylene, nonylene or decylene. R ^{5 also} means, for example, but-2-en-ylene or hex-3-en-ylene. Ethylene, propylene or butylene is very particularly preferred.

R ⁵ denotes cycloalkylalkylene with 5-12 C atoms, preferably for example

Cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.

R ^{5 also} means cycloalkyl, preferably having 5-7 carbon atoms. Cycloalkyl means, for example, cyclopentyl, cyclohexyl or cycloheptyl.

Shark preferably means F, Cl or Br, but also I.

The radicals R ¹ and R ² can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, independently of one another H, alkyl, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They also preferably each represent alkoxy, such as methoxy, ethoxy or propoxy, furthermore hydroxy. The radical R ⁷ is preferably, for example, COOH, COOCH ₃ , COOC ₂ H ₅ , CONH ₂ , CON (CH ₃ ) ₂ , CONHCH3 or CN.

It applies to the entire invention that all residues which occur more than once can be the same or different, i.e. are independent of each other.

Accordingly, the invention relates in particular to the use of those compounds of the formula I in which at least one of the radicals mentioned is one of the preferred ones indicated above

Has meanings. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Id, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

in la X by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or

C denotes CNSsubstituted R ⁴ , phenyl or phenylmethyl;

in Ib R and R ² together alkylene with 3-5 C atoms, -0-CH ₂ -CH ₂ -,

-O-CH ₂ -0- or -O-CH ₂ -CH ₂ -0, X by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or

CN is substituted R ⁴ , phenyl or phenylmethyl;

in Ic

R ¹ , R ² each independently of one another H, A, OA or shark,

R ¹ and R ² together alkylene with 3-5 C atoms, -O-CH ₂ -CH ₂ -,

-0-CH ₂ -0- or -0-CH ₂ -CH ₂ -0, X by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or

CN is substituted R ⁴ , phenyl or phenylmethyl;

in Id R ¹ , R ² each independently of one another H, A, OA or shark,

R ¹ and R ² together also alkylene with 3-5 C atoms, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or

-0-CH ₂ -CH ₂ -0-, X alkylene substituted by R ⁷ with 2-5 C-

Atoms, cyclohexyl, phenyl or phenylmethyl, R ⁷ COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Shark F, Cl, Br or I.

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart), are described, under reaction conditions that are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

In the compounds of the formulas II or III, R ¹ , R ² , R ³ , R ⁴ , X and n have the meanings indicated, in particular the preferred meanings indicated.

If L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, further also 2- naphthalenesulfonyloxy).

The compounds of formula I can preferably be obtained by using compounds of formula II

wherein

X has the meaning given, and L denotes Cl, Br, OH, SCH ₃ or a reactive esterified OH group,

with compounds of formula III

wherein

R ¹ and R ^{2 have} the meanings given,

implements.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I. On the other hand, it is possible to carry out the reaction in stages.

The starting compounds of the formula II and III are generally known.

If they are not known, they can be produced by methods known per se. Compounds of the formula II can be obtained, for example, by reaction with POCI ₃ from the corresponding hydroxypyrimidines which are built up from thiophene derivatives and CN-substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453 (1988)).

The hydroxypyrimidines are prepared either by dehydration of corresponding tetrahydrobenzthienopyrimidine compounds or by the cyclization of 2-aminobenzthiophene-3-carboxylic acid derivatives customary for the preparation of pyrimidine derivatives or with aldehydes or

Nitriles (e.g. Houben Weyl E9b / 2).

In particular, the compounds of the formula II are reacted with the compounds of the formula III in the presence or absence of a inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.

The addition of an acid-binding agent, for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base such as triethylamine, Dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, 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 or 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 or 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 the solvents mentioned.

It is also possible to convert one radical X into another radical X in a compound of formula I, e.g. by using an ester or a

Cyan group hydrolyzed to a COOH group. Ester groups can e.g. can be saponified with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °. Carboxylic acids can e.g. with thionyl chloride in the corresponding carboxylic acid chlorides and these are converted into carboxamides. By splitting off water in a known manner, carbonitriles are obtained from these.

An acid of the formula I can be converted into the associated acid addition salt using a base, for example by reaction valent amounts of the acid and the base in an inert solvent such as ethanol and subsequent evaporation. Bases that provide physiologically acceptable salts are particularly suitable for this implementation. For example, the acid of formula I can be converted with a base (for example sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt. Organic bases which provide physiologically acceptable salts, such as ethanolamine, are particularly suitable for this reaction.

On the other hand, a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as

Orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts and / or solvates for treatment of 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, liver cirrhosis, liver cirrhosis for the treatment of female impotence.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets,

Capsules, powders, granules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use ointments, creams or powder. The new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, e.g. one or more vitamins.

The compounds of the formula I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation. The compounds according to the invention can be used particularly in the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chro- African asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female impotence.

The substances are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.

Mass spectrometry (MS): El (electron impact ionization) M ⁺ FAB (Fast Atom Bombardment) (M + H) ⁺

The invention relates in particular to the use of the compounds of the formula I listed in the examples below and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhosis and for the treatment of female impotence. example 1

Methyl 3- (4-chloro-benzothieno- [2,3-d] -pyamin-2-yl) -propionate [obtainable by cyclization of methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylic acid with 3-cyanopropionic acid methyl ester, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxichlo d / dimethylamine] and 3-chloro-4-methoxybenzylamine ("A") in N-methylpyrrolidone are stirred at 110 ° for 5 hours. The solvent is removed and worked up as usual. 3- [4- (3-Chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester is obtained as a colorless oil.

Analogously, by converting "A"

with methyl 2- (4-chloro-benzothieno- [2,3-d] pyrimidin-2-yl) -acetate 2- [4- (3-chloro-4-methoxy-benzylamino) -benzothieno- [2,3- d] -pyrimidin-2-yl] -acetic acid methyl ester.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with methyl 3- (4-chloro-benzothieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] -pyrimidin-2-yl] -propionic acid methyl ester.

Analogously, by converting "A"

with 4- (4-chloro-benzothieno- [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno- [2,3- d] -pyrimidin-2-yl] -butyric acid methyl ester.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 4- (4-chloro-benzothieno- [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxy-benzylamino) benzothieno- [2,3-d] -pyrimidin

2-yl] -butyric acid methyl ester. Analogously, by converting "A"

with 5- (4-chloro-benzothieno- [2,3-d] pyrimidin-2-yl) -valehanoic acid methyl ester 5- [4- (3-chloro-4-methoxy-benzylamino) -benzothieno- [2,3- d] -pyrimidine

2-yl] -valeriansäuremethylester.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 5- (4-chloro-benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester

Methyl 5- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] val.

Analogously, by converting "A"

with 7- (4-chloro-benzothieno- [2,3-d] pyrimidin-2-yl) -heptanoic acid methyl ester 7- [4- (3-chloro-4-methoxy-benzylamino) -benzothieno- [2,3- d] -pyrimidin-2-yl] -heptanoic acid methyl ester.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 7- (4-chloro-benzothieno- [2,3-d] pyrimidin-2-yl) -heptanoic acid methyl ester 7- [4- (3,4-methylenedioxy-benzylamino) -benzothieno- [2,3-d] -pyrimidin-2-yl] -heptanoic acid methyl ester.

Analogously, by converting "A"

with 2- [4- (4-chloro-benzothieno [2,3-d] pyhmidin-2-yl) cyclohex-1-yl] acetic acid methyl ester 2- {4- [4- (3-chloro-4 -methoxy-benzylamino) -benzothieno- [2,3-d] pyrimidin-2-yl] -cyclohexyl-1-yl} -acetic acid methyl ester.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine

with 2- [4- (4-chloro-benzothieno- [2,3-d] pyhmidin-2-yl) cyclohex-1-yl] acetic acid methyl ester Methyl 2- {4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid.

One obtains analogously by conversion of benzylamine

with methyl 3- (4-chloro-benzothieno [2,3-d] pyrimidin-2-yl) propionate 3- (4-benzylamino-benzothieno [2,3-d] pyrimidin-2-yl) - propionate;

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

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

with 5- (4-chloro-benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester 5- (4-benzylamino-benzothieno [2,3-d] pyrimidin-2-yl) - Methyl Pentanoate.

Analogously, by converting "A"

with 4- (4-chloro-benzothieno- [2,3-d] -py midin-2-yl) - cyclohexane carboxylic acid methyl ester

Methyl 4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyhmidin-2-yl] cyclohexane

and by reacting 3,4-methylenedioxybenzylamine

Methyl 4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexane.

Example 2

3- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester is dissolved in ethylene glycol monomethyl ether and after adding 32% NaOH for 5 hours 110 ° stirred. After adding 20% HCl, the mixture is extracted with dichloromethane. Adding petroleum ether gives 3- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid, mp 218 °. The precipitated crystals are dissolved in isopropanol and mixed with ethanol laminate. After crystallization, 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyhmidin-2-yl] propionic acid, ethanolamine salt is obtained.

The connections are obtained analogously

4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid, mp 225 °; Ethanolamine salt F. 150 °;

5- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, mp 210 °; Ethanolamine salt F. 141 °;

4- [4- (3,4-methylenedioxy-benzylamino) -benzothieno [2,3-d] -pyrimidine

2-yl] butyric acid, hydrochloride, mp 245 °.

The following carboxylic acids are obtained analogously from the esters listed in Example 1:

2- [4- (3-chloro-4-methoxy-benzylamino) 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] pyrimidin-2-yl] valehanoic acid,

7- [4- (3-chloro-4-methoxy-benzylamino) -benzothieno [2,3-d] -pyrimidine

2-yl] -heptanoic acid,

y.μ ^ S ^ -methylene dioxy-benzylamino ^ benzothieno-pS-d ^ pyrimidin-2-yl] -heptanoic acid, 2- {4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyhmidin-2-yl] cyclohexyl-1-yl} acetic acid,

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

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

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

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

4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid, ethanolamine salt, mp 167 °;

4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid, ethanolamine salt, mp 143 °.

Example 3

A mixture of 1.5 g of 4- (4-chlorobenzothieno [2,3-d] pyhmidin-2-yl) phenylcarboxylic acid methyl ester ("B"), prepared by dehydrating the corresponding 5,6,7,8-tetrahydrobenzthieno - [2,3-d] pyrimidine compound with sulfur and subsequent chlorination with phosphorus oxychloride / dimethylamine, and 1.5 g of 3-chloro-4-methoxy-benzylamine in 20 ml of N-methylpyrrolidone is 4 hours at 110 ° heated. After cooling, work up as usual. 2.6 g of methyl 4- [4- (3-chloro-4-methoxy-benzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] benzoate, mp 203 -204 °.

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

4- [4- (3-chloro-4-methoxy-benzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid, ethanolamine salt, mp 189-190 °.

Analogously to Example 1, "B" and 3,4-methylenedioxybenzylamine are obtained 4- [4- (3,4-Methylenedιoxy-benzylamιno) - [1] benzothιeno- [2,3-d] - pyπmιdιn-2-yl] -benzoic acid methyl ester and therefrom by ester hydrolysis 4- [4- (3,4- Methylenedιoxy-benzylamιno) - [1] benzothιeno- [2,3-d] - pyrιmιdιn-2-yl] -benzoic acid, sodium salt, F> 260 °

The connection is obtained analogously

4- [4- (3-chloro-4-methoxy-benzylamιno) - [1] benzothιeno- [2,3-d] - pyrιmιdιn-2-yl] -phenylacetic acid, ethanolamine salt, F 130 °, and 4- [4 - (3,4-methylenedoxoxy-benzylamine) - [1] benzothιeno- [2,3-d] - pyrιmιdιn-2-yl] -phenylessιgsaure, ethanolamine salt, F 202 °

Example 4

1 equivalent of 3- [4- (3-chloro-4-methoxy-benzylamιno) -benzothιeno- [2,3-d] - pyrιmιdιn-2-yl] propionic acid and 1, 2 equivalents of thionylchloride are stirred for 2 hours in dichloromethane Solvent is removed and 3- [4- (3-chloro-4-methoxy-benzylamιno) -benzothιeno- [2,3-d] - pyrιmιdιn-2-yl] -propιonsaurechloπd is obtained. Transferred to aqueous ammonia, stirring for one hour and received 3- [4- (3-chloro-4-methoxy-benzylamιno) -benzothιeno- [2,3-d] -pyrιmιdιn-2-yl] -propιonsaureamιd after customary work-up

Example 5

1 equivalent of DMF and 1 equivalent of oxalylchloride are dissolved in acetonitrile at 0 °. Then 1 equivalent of 3- [4- (3-chloro-4-methoxy-benzylamine) -benzothιeno- [2,3-d] -pyπmιdιn-2- yl] -propιonsaureamιd added. The mixture is stirred for one hour. After the usual work-up, 3- [4- (3-chloro-4-methoxy-benzylamιno) -benzothιeno- [2,3-d] - pyπmιdιn-2-yl] is obtained. -propιonιtrιl

Example 6 Analogously to Examples 1, 2 and 3, the following carboxylic acids are obtained by reacting the corresponding chloropyrimidine derivatives 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,

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] cyclohexyl-1-yi} acetic acid,

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

4- [4- (3,4-ethylenedioxybenzylamino) - [1] benzothieno- [2,3-d] pyrimidin-2-yl] benzoic acid, dec. 220-230 °;

4- [4- (3,4-ethylenedioxybenzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid, ethanolamine salt, mp 252 °;

4- [4- (3,4-ethylenedioxybenzylamino) - [1] benzothieno- [2,3-d] pyhmidin-2-yl] phenylacetic acid.

The following compounds are obtained analogously 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, mp 160 °;

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

2- {4- [4- (3,4-dichlorobenzylamino) benzothieno- [2,3-d] pyhmidin-2-yl] cyclohexyl-1-yl} acetic acid,

4- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyhmidin-2-yl] cyclohexane carboxylic acid,

4- [4- (3,4-dichlorobenzylamino) - [1] benzothieno- [2,3-d] pyrimidin-2-yl] benzoic acid,

4- [4- (3,4-dichlorobenzylamino) - [1] benzothieno- [2,3-d] pyrimidin-2-yl] phenylacetic acid.

The following compounds are obtained analogously by reaction with 3-chloro-4-ethoxybenzylamine

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

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

5- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyhmidin-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-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,

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

4- [4- (3-chloro-4-ethoxybenzylamino) - [1] benzothieno- [2,3-d] pyrimidin-2-yl] benzoic acid, mp 185-187 °;

4- [4- (3-chloro-4-ethoxybenzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid.

The following compounds are obtained analogously by reaction with 3-chloro-4-isopropoxybenzylamine

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

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

5- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 130 °;

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

2- {4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyhmidin-2-yl] cyclohexyl-1-yl} acetic acid,

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

4- [4- (3-chloro-4-isopropoxybenzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid, mp 240-241 °; 4- [4- (3-chloro-4-isopropoxybenzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.

Example B: Suppositories

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

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g

NaH ₂ P0 ₄ • 2 H ₂ 0, 28.48 g Na ₂ HP0 ₄ • 12 H ₂ O and 0.1 g benzalkonium chloride in 940 ml double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient 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 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 into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of formula I in 60 l of double distilled

Water is filtered sterile, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Example I: Inhalation spray

14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCl solution and the solution is filled into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

claims

1. Use of compounds of the formula

wherein

R 1 ', r R-> 2 each independently of one another H, A, OA, OH or Hai,

R ¹ and R ² together also alkylene with 3-5 C atoms, -0-CH ₂ -CH ₂ -, -CH ₂ -0-CH ₂ -, -0-CH ₂ -0- or -0-CH ₂ -CH ₂ -0-,

simply substituted by R ^7, R ⁴ , R ⁵ or R ⁶ ,

R ^« linear or branched alkylene with 1-10 C atoms, in which one or two CH ₂ groups can be replaced by -CH = CH groups,

R ^b cycloalkyl or cycloalkylalkylene with 5-12 C atoms,

R ⁶ phenyl or phenylmethyl,

R ⁷ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,

A alkyl with 1 to 6 carbon atoms and

Shark F, Cl, Br or I

mean, as well as 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, conditions of reduced patency of the heart vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis , Glaucom, Irritable Bowel Syndrome, tumors, renal failure, cirrhosis and for the treatment of female impotence

Use of compounds of formula I according to claim 1

(a) 3- [4- (3-chloro-4-methoxy-benzylamine) -benzo [4,5] thιeno- [2,3-d] - pyπmιdιn-2-yl] -propionic acid,

(b) 4- [4- (3,4-methylenedio-benzylamino) -benzo [4,5] thio-neo-2,3-d-pyrimide-2-yl] -butyric acid,

(c) 7- [4- (3,4-methylenediooxy-benzylamino) benzo [4,5] thioeno [2,3-d] pyrimide-2-yl] heptane acid,

(d) 7- [4- (3-chloro-4-methoxy-benzylamine) -benzo [4,5] thιeno- [2,3-d] - pyrιmιdιn-2-yl] -heptane acid,

(e) 5- [4- (3-chloro-4-methoxy-benzylamine) -benzo [4,5] thιeno- [2,3-d] - pyrιmιdιn-2-yl] -valeric acid,

(f) 2- {4- [4- (3-chloro-4-methoxy-benzylamιno) -benzo [4,5] thιeno- [2,3-d] -pyrιmιdm-2-yl] -cyclohexyl-1- yl} -essιgsaure,

(g) 4- [4- (3,4-methylenedoxoxy-benzyiamιno) -benzo [4,5] thιeno- [2,3-d] - pyrιmιdιn-2-yl] -cyclohexane carboxylic acid,

(h) 4- [4- (3,4-methylenedio-benzylamino) -benzo [4,5] thιeno- [2,3-d] - pyπmιdιn-2-yl] -benzoic acid, (i) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yi] phenylacetic acid;

(k) 2- {4- [4- (3-chloro-4-methoxy-benzylamino) -benzo [4,5] thieno- [2,3-d] pyrimidin-2-yl] cyclohexyl-1 - yl} cyclohexanecarboxylic acid;

as well as 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, conditions of reduced patency of the

Cardiovascular, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, cirrhosis and for the treatment of female impotence.