AU6703200A - Use of thienopyrimidines - Google Patents

Description

WO 01/19369 PCT/EPOO/08258 Use of thienopyrimidines The invention relates to the use of compounds of the formula I 5 HN CH 2 C / R2 S N X in which 10 R 1 , R 2 in each case independently of one another are H, A, OA, OH or Hal, R' and R 2 together are also alkylene of 3-5 carbon atoms, -O-CH 2

-CH

2 -, -CH 2 -0-CH 2 -, -O-CH 2 -0- or 15 -O-CH 2

-CH

2 -0-, X is R , Rs or R 6 , monosubstituted by R 7 ,

R

4 is linear or branched alkylene of 1-10 carbon 20 atoms, in which one or two CH 2 groups may have been replaced by -CH=CH- groups, R 5 is cycloalkyl or cycloalkylalkylene of 5-12 carbon atoms, 25

R

6 is phenyl or phenylmethyl, R7 is COOH, COOA, CONH 2 , CONHA, CON(A) 2 or CN, 30 A is alkyl of 1 to 6 carbon atoms and Hal is F, Cl, Br or I - 2 and their physiologically acceptable salts and/or solvates for preparing a medicament for treating angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, conditions 5 of reduced circulation through the cardiac vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency and cirrhosis of the liver and for 10 treating female impotence. The use of other PDE V inhibitors is described, for example in WO 94/28902. Pyrimidine derivatives are known, for example, from 15 DE 198/9023, EP 201 188 or WO 93/06104. The invention was based on the object of discovering new compounds having valuable properties, especially those which may be used to prepare medicaments. 20 It has been found that the compounds of the formula I and their salts combine very valuable pharmacological properties with good tolerability. 25 In particular, they exhibit specific inhibition of cGMP phosphodiesterase (PDE V). Quinazolines having cGMP phosphodiesterase inhibitor activity are described, for example, in J. Med. Chem. 30 36, 3765 (1993) and ibid. 37, 2106 (1994). The biological activity of the compounds of the formula I may be determined by methods such as are described, for example, in WO 93/06104 or in WO 94/28902. 35 The affinity of the compounds of the invention for cGMP and cAMP phosphodiesterase is measured by determining their IC 50 values (the concentration of inhibitor required to achieve 50% inhibition of the enzyme activity).

-3 The measurements may be made using enzymes isolated by known methods (e.g. W.J. Thompson et al., Biochem. 1971, 10, 311). The experiments may be conducted using a modified "batch" method of W.J. Thompson and 5 M.M. Appleman (Biochem. 1979, 18, 5228). The use of substituted pyrazolopyrimidinones for treating female impotence is described, for example, in WO 94/28902. 10 The compounds are effective as inhibitors of phenylephrine-induced contractions in cavernous-body preparations of hares. This biological activity may be demonstrated, for example, by the method described by 15 F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993). The inhibition of the contraction shows the activity of the compounds of the invention for the therapy and/or treatment of impaired potency. 20 The invention provides for the use of the compounds of formula I and their physiologically acceptable salts and/or solvates for preparing a medicament for treating angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, conditions 25 of reduced circulation through the cardiac vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency and cirrhosis of the liver and for 30 treating female impotence. The compounds of the formula I may be used as medicament active principles in human and veterinary medicine. Furthermore, they may be used as 35 intermediates for preparing further medicament active principles. [lacuna] -4 Above and below, the radicals R 1 , R 2 , R 3 , R 4 , R, R 6 , R, X and L have the definitions stated for the formulae I, II and III unless expressly stated otherwise. 5 A is alkyl of 1-6 carbon atoms. In the above formulae, alkyl 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 or tert-butyl, 10 but also n-pentyl, neopentyl, isopentyl or hexyl. X is a radical R 4 , R 5 or R 6 that is monosubstituted by R. 15 R 4 is a linear or branched alkylene radical of 1-10 carbon atoms, the alkylene radical being preferably, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 20 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 25 heptylene, octylene, nonylene or decylene. R 5 is also, for example, but-2-enylene or hex-3-enylene. Very particular preference is given to ethylene, propylene or butylene. 30 R 5 is cycloalkylalkylene of 5-12 carbon atoms, preferably for example cycclopentylmethylene [sic], cyclohexylmethylene, cyclohexylethylene, cyclo hexylpropylene or cyclohexylbutylene.

R

5 is also cycloalkyl of preferably with of [sic] 5-7 35 carbon atoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl. Hal is preferably F, Cl or Br, but also I.

- 5 The radicals R 1 and R 2 may be identical or different and are preferably in position 3 or 4 of the phenyl ring. They are, for example, in each case independently of one another H, alkyl, F, Cl, Br or I or together are 5 alkylene, such as propylene, butylene or pentylene, for example, and also ethyleneoxy, methylenedioxy or ethylenedioxy. Preferably, they are in each case also alkoxy, such as methoxy, ethoxy or propoxy, for example, and also hydroxyl. 10 The radical R 7 is preferably for example COOH, COOCH 3 ,

COOC

2

H

5 , CONH 2 , CON(CH 3

)

2 , CONHCH 3 or CN. For the entire invention it is the case that all 15 radicals which occur more than once may be identical or different, i.e. are independent of one another. Accordingly, the invention provides in particular for the use of those compounds of the formula I in which at 20 least one of the specified radicals has one of the preferred definitions stated above. Some preferred groups of compounds may be expressed by the following subformulae Ia to Id, which correspond to the formula I and in which the radicals not designated in any greater 25 detail have the definition stated for the formula I, but in which in Ia X is COOH-, COOA-, CONH 2 -, CONA 2 -, CONHA- or CN-substituted R, phenyl 30 or phenylmethyl; in Ib Ri and R 2 together are alkylene of 3-5 carbon atoms, -O-CH 2

-CH

2 -, -O-CH 2 -0- or

-O-CH

2

-CH

2 -0, 35 X is COOH-, COOA-, CONH 2 -, CONA 2 -, CONHA- or CN-substituted R, phenyl or phenylmethyl; in Ic - 6 R, R 2 in each case independently of one another are H, A, OA or Hal, Ri and R 2 together are alkylene of 3-5 carbon atoms, -O-CH 2

-CH

2 -, -O-CH 2 -0- or 5 -O-CH 2

-CH

2 -0, X is COOH-, COOA-, CONH 2 -, CONA 2 -, CONHA- or CN-substituted R 4 , phenyl or phenylmethyl; 10 in Id Ri, R 2 in each case independently of one another are H, A, OA or Hal, Ri and R 2 together are also alkylene of 3-5 carbon atoms, -O-CH 2

-CH

2 -, -O-CH 2 -0 or -O-CH 2

-CH

2 -0-, 15 X is alkylene of 2-5 carbon atoms monosubstituted by R 7 , or is cyclohexyl, phenyl or phenylmethyl, RT 7is COOH or COOA, A is alkyl of 1 to 6 carbon atoms, 20 Hal is F, Cl, Br or I. The compounds of the formula I and also the starting substances for preparing them are otherwise prepared by methods which are known per se as are described in the 25 literature (e.g. in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), i.e. under reaction conditions which are known and suitable for the stated reactions. Use may also be made of variants 30 which are known per se and are not mentioned in any greater detail here. In the compounds of the formulae II or III, Ri, R 2 , R 3 , R , X and n have the stated definitions, especially the 35 stated preferred definitions. If L is a reactive esterified OH group, it is preferably alkylsulfonyloxy of 1-6 carbon atoms (preferably methylsulfonyloxy) or arylsulfonyloxy of 6- - 7 10 carbon atoms (preferably phenyl- or p tolylsulfonyloxy, and also 2-naphthalenesulfonyloxy). The compounds of the formula I may preferably be 5 obtained by reacting compounds of the formula II L N~ S N X with compounds of the formula in which X has the slated definition 10 and L is Cl, Br, OH, SCH 3 or a reactive esterified OH group H2N "CH2 R R2 III in which R1 and R2 have the slated definitions. 15 The starting substances may also if desired be formed in situ, so that they are not isolated from the reaction mixture but instead are reacted further immediately to the compounds of the formula I. 20 Alternatively, it is possible to carry out the reaction in stages. Generally, the starting compounds of the formulae II and III are known. Where they are unknown, they may be 25 prepared by methods which are known per se. Compounds of the formula II may be obtained, for example, by reaction with POCl 3 from the corresponding hydroxypyrimidines, which are synthesized from thiophene derivatives and CN-substituted alkylene 30 carboxylic esters (Eur. J. Med. Chem. 23, 453 (1988)). The hydroxypyrimidines are prepared either by dehydrogenating corresponding tetrahydrobenzothieno pyrimidine compounds or by the cyclization, customary - 8 for preparing pyrimidine derivatives, of 2 aminobenzothiophene-3-carboxylic acid derivatives with aldehydes or nitriles (e.g. Houben Weyl E9b/2). 5 Specifically, the reaction of the compounds of the formula II with the compounds of the formula III takes place in the presence or absence of an inert solvent at temperatures between about -20 and about 1500, preferably between 20 to 1000. 10 The addition of an acid-binding agent, for example of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, 15 preferably of potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylamine, pyridine or quinoline or of an excess of the amine component, may be favourable. 20 Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloro ethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as 25 methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ether such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), 30 ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethyl formamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro 35 compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the said solvents.

- 9 It is also possible to convert one radical X in a compound of the formula I to another radical X, for example by hydrolysing an ester or a cyano group to a COOH group. 5 Ester groups may be hydrolysed, for example, with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 1000. Carboxylic acids may be converted to the corresponding carbonyl chlorides, for example using thionyl chloride, 10 and these chlorides may in turn be converted to carboxamides. From these carboxamides, carbonitriles are obtained in a known manner by elimination of water. An acid of the formula I may be converted to the 15 associated acid addition salt using a base, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol, followed by evaporative concentration. Particularly suitable bases for this reaction are those which give physiologically 20 acceptable salts. For instance, the acid of the formula I may be converted with a base (e.g. sodium or potassium hydroxide or carbonate) to the corresponding metal salt, especially alkali metal or alkaline earth metal 25 salt, or to the corresponding ammonium salt. Suitable bases for this reaction include, in particular, organic bases which give physiologically acceptable salts, such as ethanolamine, for example, 30 Alternatively, a base of the formula I may be converted to the corresponding 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, followed by evaporative concentration. Particularly 35 suitable acids for this reaction are those which give physiologically acceptable salts. For instance, inorganic acids may be used, examples being sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids - 10 such as orthophosphoric acid, sulfamic acid, and also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, 5 examples being formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, 10 isonicotinic acid, methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically 15 unacceptable acids, e.g. picrates, may be used to isolate and/or purify the compounds of the formula I. The invention additionally provides pharmaceutical preparations comprising at least one compound of the 20 formula I and/or one of its physiologically acceptable salts and/or solvates for treating angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, conditions of reduced circulation through the cardiac vessels, peripheral 25 vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency and cirrhosis of the liver and for treating female impotence. 30 These preparations may be used as medicaments in human or veterinary medicine. Suitable excipients include organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application 35 and which do not react with the novel compounds, examples being water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, and petroleum jelly.

- 11 For oral administration use is made in particular of tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops; for rectal administration particular use is made of suppositories; 5 for parenteral administration particular use is made of solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants; for topical application, particular use is made of ointments, creams or powders. The novel compounds may also be 10 lyophilized and the resulting lyophilizates used, for example to produce preparations for injection. The preparations indicated may be sterilized and/or may comprise auxiliaries such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for 15 influencing the osmotic pressure, buffer substances, colorants, flavourings and one or more further active substances, for example one or more vitamins. The compounds of the formula I and their 20 physiologically acceptable salts may be used in the control of diseases where an increase in the level of cGMP (cyclic guanosine monophosphate) leads to inhibition or prevention of inflammation and to muscle relaxation. Particular use may be made of the compounds 25 of the invention in treating angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, conditions of reduced circulation through the cardiac vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, 30 chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency and cirrhosis of the liver and for treating female impotence. 35 In these indications the substances are generally administered preferably in doses of between approximately 1 and 500 mg, in particular between 5 and 100 mg per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight.

- 12 The specific dose for each patient depends, however, on a wide variety of factors, for example on the efficacy of the specific compound used, on age, body weight, general state of health, gender, on the diet, on the 5 time and route of administration, on the excretion rate, medicament combination and severity of the particular disease to which the therapy is applied. Oral administration is preferred. 10 Above and below, all temperatures are stated in 0 C. In the examples below, "customary workup" means the following: water is added if necessary, the formulation is adjusted to a pH of between 2 and 10 if necessary, depending on the constitution of the end product, and 15 is extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and concentrated by evaporation, and the residue is purified by chromatography on silica gel and/or by crystallization. 20 Mass spectrometry (MS): EI (electronic impact ionization)M* FAB (fast atom bombardment) (M+H)* The invention provides in particular for the use of the 25 compounds of the formula I set out in the examples below, and their physiologically acceptable salts and/or solvates, for preparing a medicament for treating angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, 30 conditions of reduced circulation through the cardiac vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency and cirrhosis of the liver and for 35 treating female impotence. Example 1 - 13 Methyl 3-(4-chlorobenzothieno[2,3-d]pyrimidin-2-yl) propionate [obtainable by cyclizing methyl 2-amino 5,6,7,8-tetrahydrobenzothiophene-3-carboxylate with methyl 3-cyanopropionate, dehydrogenating the product 5 with sulfur and then chlorinating that product with phosphorus oxychloride/dimethylamine] and 3-chloro-4 methoxybenzylamine ("A") in N-methylpyrrolidone are stirred at 1100 for 5 hours. The solvent is removed and the product is subjected to customary workup. This 10 gives methyl 3- [4- (3-chloro-4-methoxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl]propionate as a colourless oil. Analogous reaction of "A" 15 with methyl 2-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)acetate gives methyl 2-[4-(3-chloro-4-methoxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl]acetate. 20 Analogous reaction of 3,4-methylenedioxybenzylamine with methyl 3-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)propionate gives 25 methyl 3-[4-(3,4-methylenedioxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl]propionate. Analogous reaction of "A" 30 with methyl 4-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)butyrate gives methyl 4-[4-(3-chloro-4-methoxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl)butyrate. 35 Analogous reaction of 3,4-methylenedioxybenzylamine with methyl 4-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)butyrate gives - 14 methyl 4-[4-(3,4-methylenedioxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl]butyrate. Analogous reaction of "A" 5 with methyl 5-(4-chlorobenzothieno[2,3-dlpyrimidin-2 yl)valerate gives methyl 5-[4-(3-chloro-4-methoxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl]valerate. 10 Analogous reaction of 3,4-methylenedioxybenzylamine with methyl 5-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)valerate gives 15 methyl 5-[4-(3,4-methylenedioxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl]valerate. Analogous reaction of "A" 20 with methyl 7-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)heptanoate gives methyl 7-[4-(3-chloro-4-methoxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl)heptanoate. 25 Analogous reaction of 3,4-methylenedioxybenzylamine with methyl 7-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)heptanoate gives methyl 7-[4-(3,4-methylenedioxybenzylamino)benzo 30 thieno[2,3-djpyrimidin-2-yl]heptanoate. Analogous reaction of "A" with methyl 2-[4-(4-chlorobenzothieno[2,3-dlpyrimidin 35 2-yl)cyclohex-1-yl]acetate gives methyl 2-{4-[4-(3-chloro-4-methoxybenzylamino) benzothieno[2,3-dlpyrimidin-2-yl]cyclohexyl-1 yl acetate.

- 15 Analogous reaction of 3,4-methylenedioxybenzylamine with methyl 2-[4-(4-chlorobenzothieno[2,3-d]pyrimidin 2-yl)cyclohex-1-yl]acetate gives 5 methyl 2-{4-[4-(3,4-methylenedioxybenzylamino) benzothieno[2,3-dlpyrimidin-2-yl)cyclohexyl-l yl}acetate. Analogous reaction of benzylamine 10 with methyl 3-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)propionate gives methyl 3-(4-benzylaminobenzothieno[2,3-d] pyrimidin-2-yl)propionate; 15 with methyl 4-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)butyrate gives methyl 4-(4-benzylaminobenzothieno[2,3-d] pyrimidin-2-yl)butyrate; 20 with methyl 5-(4-chlorobenzothieno[2,3-d~pyrimidin-2 yl)valerate gives methyl 5-(4-benzylaminobenzothieno[2,3-d] pyrimidin-2-yl)valerate. 25 Analogous reaction of "A" with methyl 4-(4-chlorobenzothieno[2,3-d]pyrimidin-2 yl)cyclohexanecarboxylate gives 30 methyl 4-[4-(3-chloro-4-methoxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-ylcyclohexanecarboxylate and analogous reaction of 3,4-methylenedioxybenzylamine gives 35 methyl 4-[4-(3,4-methylenedioxybenzylamino)benzo thieno[2,3-d]pyrimidin-2-yl]cyclohexane carboxylate.

- 16 Example 2 Methyl 3-[4- (3-chloro-4-methoxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yl]propionate is dissolved in 5 ethylene glycol monomethyl ether and following addition of 32% NaOH the solution is stirred at 1100 for 5 hours. Following the addition of 20% HCl it is extracted with dichloromethane. Addition of petroleum ether gives 3- [4- (3-chloro-4-methoxybenzylamino) 10 benzothieno[2,3-d]pyrimidin-2-yl]propionic acid, m.p. 2180. The precipitated crystals are dissolved in isopropanol, and ethanolamine is added. Crystallization gives 3-[4 15 (3-chloro-4-methoxybenzylamino)benzothieno[2, 3-d] pyrimidin-2-yl]propionic acid, ethanolamine salt. The following compounds are obtained analogously: 20 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d]pyrimidin-2-yllbutyric acid, m.p. 2250; ethanolamine salt m.p. 1500; 5- [4- (3-chloro-4-methoxybenzylamino) benzothieno 25 [2,3-d]pyrimidin-2-yl]valeric acid, m.p. 2100; ethanolamine salt m.p. 1410; 4- [4- (3, 4-methylenedioxybenzylamino) benzothieno [2, 3-d]pyrimidin-2-yl]butyric acid, hydrochloride, 30 m.p. 2450. The carboxylic acids below are obtained analogously from the esters set out under Example 1: 35 2-[4-(3-chloro-4-methoxybenzylamino)benzothieno [2,3-dlpyrimidin-2-yl]acetic acid, 3- [4- (3, 4-methylenedioxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yllpropionic acid, - 17 5-[4-(3,4-methylenedioxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yl]valeric acid, 7-[4-(3-chloro-4-methoxybenzylamino)benzothieno 5 [2,3-dlpyrimidin-2-yl]heptanoic acid, 7-[4-(3,4-methylenedioxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yl]heptanoic acid, 10 2-{4-[4-(3-chloro-4-methoxybenzylamino) benzothieno[2,3-djpyrimidin-2-yl]cyclohexyl 1-yl}acetic acid, 2-{4-[4-(3,4-methylenedioxybenzylamino) 15 benzothieno[2,3-d]pyrimidin-2-yl]cyclohexyl 1-yl}acetic acid, 3-(4-benzylaminobenzothieno[2,3-djpyrimidin-2-yl) propionic acid, 20 4-(4-benzylaminobenzothieno[2,3-d]pyrimidin-2-yl) butyric acid, 5-(4-benzylaminobenzothieno[2,3-d]pyrimidin-2-yl) 25 valeric acid, 4-[4-(3-chloro-4-methoxybenzylamino)benzothieno [2,3-dpyrimidin-2-yl]cyclohexanecarboxylic acid, ethanolamine salt, m.p. 1670; 30 4-[4-(3,4-methylenedioxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, ethanolamine salt, m.p. 1430. 35 Example 3 A mixture of 1.5 g of methyl 4-(4-chlorobenzo thieno[2,3-d]pyrimidin-2-yl)phenylcarboxylate ("B"), prepared by dehydrogenating the corresponding 5,6,7,8- - 18 tetrahydrobenzothieno [2, 3-d]pyrimidine compound with sulfur and chlorinating the product with phosphorus oxychloride/dimethylamine, and 1.5 g of 3-chloro-4 methoxybenzylamine in 20 ml of N-methylpyrrolidone is 5 heated at 1100 for 4 hours. After cooling, it is subjected to customary workup. This gives 2.6 g of methyl 4- [4- (3-chloro-4-methoxybenzylamino) [l]benzo thieno[2,3-d]pyrimidin-2-yl]benzoate, m.p. 203-2040. 10 In analogy to Example 2, 1.2 g of the ester gives 1.0 g of 4-[4- (3-chloro-4-methoxybenzylamino) [1J benzothieno[2,3-dlpyrimidin-2-yl]benzoic acid, ethanolamine salt, m.p. 189-1900. 15 In analogy to Example 1, "B" and 3,4-methylenedioxy benzylamine give methyl 4-[4-(3,4-methylenedioxy benzylamino) [1]benzothieno [2, 3-djpyrimidin-2-yl] benzoate, whose ester hydrolysis gives 4-[4-(3,4 20 methylenedioxybenzylamino) [1]benzothieno(2, 3-d] pyrimidin-2-yl]benzoic acid, sodium salt, m.p. >2600. Analogous reaction gives the compound 4- [4- (3-chloro-4-methoxybenzylamino) [1J 25 benzothieno [2, 3-d]pyrimidin-2-yl) phenylacetic acid, ethanolamine salt, m.p. 1300; and 4- [4- (3, 4-methylenedioxybenzylamino) [1] benzothieno [2, 3 -dJ pyrimidin-2 -yl] phenylacetic 30 acid, ethanolamine salt, m.p. 2020. Example 4 One equivalent of 3- [4- (3-chloro-4-methoxybenzylamino) 35 benzothieno[2,3-d]pyrimidin-2-yl]propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed to give 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2, 3-d]'pyrimidin-2-yllpropionyl chloride.

- 19 This is transferred to aqueous ammonia, the mixture is stirred for an hour, and customary workup gives 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2, 3-d] pyrimidin-2-yl)propionamide. 5 Example 5 One equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 00. 10 Thereafter, 1 equivalent of 3-[4-(3-chloro-4 methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl] propionamide is added. The mixture is subsequently stirred for an hour. Customary workup gives 3-[4-(3 chloro-4-methoxybenzylamino) benzothieno [2, 3-d] 15 pyrimidin-2-yljpropionitrile. Example 6 In analogy to Examples 1, 2 and 3, reaction of the 20 corresponding chloropyrimidine derivatives with 3, 4-ethylenedioxybenzylamine gives the following carboxylic acids: 4-[4- (3, 4-ethylenedioxybenzylamino)benzothieno 25 [2, 3-d]pyrimidin-2-yl]butyric acid, 3- [4- (3, 4-ethylenedioxybenzylamino)benzothieno [2, 3-djpyrimidin-2-yljpropionic acid, 30 5- [4- (3, 4-ethylenedioxybenzylamino) benzothieno [2, 3-d]pyrimidin-2-yllvaleric acid, 7- [4- (3, 4-ethylenedioxybenzylamino)benzothieno [2, 3-d]pyrimidin-2-yl]heptanoic acid, 35 2-(4-[4-(3,4-ethylenedioxybenzylamino)benzothieno [2, 3-d]pyrimidin-2-yl]cyclohexyl-1-yllacetic acid, - 20 4-[4-(3,4-ethylenedioxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, 4-[4-(3,4-ethylenedioxybenzylamino) [1] benzothi 5 eno[2,3-d]pyrimidin-2-yl]benzoic acid, decomp. 220-2300; 4-[4-(3,4-ethylenedioxybenzylamino)[1]benzothieno [2,3-d]pyrimidin-2-yllbenzoic acid, ethanolamine 10 salt, m.p. 2520; 4-[4-(3,4-ethylenedioxybenzylamino)[1]benzothieno [2,3-d]pyrimidin-2-yljphenylacetic acid. 15 Analogous reaction with 3,4-dichlorobenzylamine gives the following compounds: 4-[4-(3,4-dichlorobenzylamino)benzothieno[2,3-d] pyrimidin-2-yl]butyric acid, 20 3-[4-(3,4-dichlorobenzylamino)benzothieno[2,3-d] pyrimidin-2-yl]propionic acid, 5-[4-(3,4-dichlorobenzylamino)benzothieno[2,3-d] 25 pyrimidin-2-yl]valeric acid, ethanolamine salt, m.p. 1600; 7-[4-(3,4-dichlorobenzylamino)benzothieno[2,3-d] pyrimidin-2-ylJheptanoic acid, 30 2-{4-[4-(3,4-dichlorobenzylamino)benzothieno [2,3-d]pyrimidin-2-yl]--cyclohexyl-1-yl acetic acid, 35 4-[4-(3,4-dichlorobenzylamino)benzothieno[2,3-d] pyrimidin-2-yl]cyclohexanecarboxylic acid, 4-[4-(3,4-dichlorobenzylamino)[llbenzothieno [2,3-d]pyrimidin-2-yljbenzoic acid, - 21 4-[4-(3,4-dichlorobenzylamino)[1]benzothieno [2,3-dlpyrimidin-2-yl]phenylacetic acid. Analogous reaction with 3-chloro-4-ethoxybenzylamine 5 gives the following compounds: 4-[4-(3-chloro-4-ethoxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yljbutyric acid, 10 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]pyrimidin-2-yl]valeric acid, 15 7-[4-(3-chloro-4-ethoxybenzylamino)benzothieno (2,3-d]pyrimidin-2-yl]heptanoic acid, 2-{4-[4-(3-chloro-4-ethoxybenzylamino)benzothieno 20 [2,3-d]pyrimidin-2-yl]-cyclohexyl-1-yl acetic acid, 4-[4-(3-chloro-4-ethoxybenzylamino)benzothieno [2,3-d]pyrimidin-2-yl]cyclohexanecarboxylic acid, 25 4-[4-(3-chloro-4-ethoxybenzylamino)[lbenzothieno [2,3-d]pyrimidin-2-yl]benzoic acid, m.p. 185-1870; 4-[4-(3-chloro-4-ethoxybenzylamino)[l]benzothieno 30 [2,3-d]pyrimidin-2-yl]phenylacetic acid. Analogous reaction with 3-chloro-4-isopropoxybenzyl amine gives the following compounds: 35 4-[4-(3-chloro-4-isopropoxybenzylamino) benzothieno[2,3-dlpyrimidin-2-yl]butyric acid, 3-[4-(3-chloro-4-isopropoxybenzylamino) benzothieno[2,3-d]pyrimidin-2-yllpropionic acid, - 22 5- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno[2,3-d]pyrimidin-2-yl]valeric acid, ethanolamine salt, m.p. 1300; 5 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]pyrimidin-2-yl] -cyclohexy-1-yl 10 acetic acid, 4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2, 3-d]pyrimidin-2-yl] cyclohexane carboxylic acid, 15 4- [4- (3-chloro-4-isopropoxybenzylamino) [1] benzothieno[2,3-dpyrimidin-2-yl]benzoic acid, m.p. 240-2410; 20 4- [4- (3-chloro-4-isopropoxybenzylamino) [1] benzothieno [2, 3-dlpyrimidin-2-yllphenylacetic acid. The examples below relate to pharmaceutical 25 preparations: Example A: Injection vials A solution of 100 g of an active substance of the 30 formula I and 5 g of disodium hydrogen phosphate in 3 1 of double-distilled water is adjusted to a pH of 6.5 using 2 N hydrochloric acid, subjected to sterile filtration, dispensed into injection vials, lyophilized under sterile conditions and aseptically sealed. Each 35 injection vial contains 5 mg of active substance. Example B: Suppositories - 23 A mixture of 20 g of an active substance of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active substance. 5 Example C: Solution A solution is prepared from 1 g of an active substance of formula I, 9.38 g of NaH 2

PO

4 -2H 2 0, 28.48 g of 10 Na 2 HPO4-12H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The solution is adjusted to a pH of 6.8, made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops. 15 Example D: Ointment 500 mg of an active substance of the formula I are mixed with 99.5 g of petroleum jelly under aseptic 20 conditions. Example E: Tablets A mixture of 1 kg of active substance of the formula I, 25 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 a customary manner to tablets such that each tablet contains 10 mg of active substance. 30 Example F: Coated tablets Tablets are pressed as in Example E and are subsequently coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and 35 colorant.

- 24 Example G: Capsules 2 kg of active substance of the formula I are filled in a customary manner into hard gelatin capsules, so that 5 each capsule contains 20 mg of the active substance. Example H: Ampoules A solution of 1 kg of active substance of the formula I 10 in 60 1 of double-distilled water is subjected to sterile filtration, dispensed in ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active substance. 15 Example I: Inhalation spray 14 g of active substance of the formula I are dissolved in 10 1 of isotonic NaCl solution and the solution is filled into commercially customary spray containers 20 with a pump mechanism. The solution may be sprayed into the mouth or nose. One spray burst (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims (2)

1. Use of compounds of the formula I -R1 HN CH2 R 2 S N X in which 1 2 R , R in each case independently of one 10 another are H, A, OA, OH or Hal, R 1 and R 2 together are also alkylene of 3-5 carbon atoms, -O-CH 2 -CH 2 -, -CH 2 -0-CH 2 -, -0-CH 2 -0 or -O-CH 2 -CH 2 -0-, 15 X is R , Rs or R 6 , monosubstituted by R 7 , R 4 is linear or branched alkylene of 1-10 carbon -atoms, in which one or two CH 2 20 groups may have been replaced by -CH=CH groups, R 5 is cycloalkyl or cycloalkylalkylene of

5-12 carbon atoms, 25 R6 is phenyl or phenylmethyl, R 7 is COOH, COOA, CONH 2 , CONHA, CON(A) 2 or CN, 30 A is alkyl of 1 to 6 carbon atoms and Hal is F, Cl, Br or I - 26 and their physiologically acceptable salts and/or solvates for preparing a medicament for treating angina, high blood pressure, high pulmonary pressure, congestive heart failure, 5 atherosclerosis, conditions of reduced circulation through the cardiac vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal 10 insufficiency and cirrhosis of the liver and for treating female impotence. 2. Use of compounds of the formula I according to Claim 1 15 (a) 3-[4-(3-chloro-4-methoxybenzylamino)benzo [4,5] thieno [2, 3-d]pyrimidin-2-yl] propionic acid; 20 (b) 4-[4-(3,4-methylenedioxybenzylamino)benzo [4,5]thieno[2,3-dpyrimidin-2-yllbutyric acid; (c) 7- [4- (3, 4-methylenedioxybenzylamino) benzo 25 [4,5]thieno[2,3-d]pyrimidin-2-yljheptanoic acid; (d) 7-[4-(3-chloro-4-methoxybenzylamino)benzo [4,5]thieno[2,3-d]pyrimidin-2-yllheptanoic 30 acid; (e) 5- [4- (3-chloro-4-methoxybenzylamino)benzo [4,5]thieno[2,3-d]pyrimidin-2-yl]valeric acid; 35 (f) 2-{4-[4-(3-chloro-4-methoxybenzylamino)benzo [4, 5]thieno[2, 3-d]pyrimidin-2 yl]-cyclohexyl-1-yl)acetic acid; - 27 (g) 4-[4-(3, 4 -methylenedioxybenzylamino)benzo [4,5]thieno[2, 3 -d]pyrimidin-2-yl]cyclohexane carboxylic acid; 5 (h) 4-[4-(3, 4 -methylenedioxybenzylamino)benzo [4,5]thieno[2, 3 -dJpyrimidin-2-yljbenzoic acid; (i) 4-[4-(3, 4 -methylenedioxybenzylamino)benzo 10 [4,5]thieno[2, 3 -d]pyrimidin-2-yl]phenylacetic acid; (k)[sic] 2 -{4-[4-(3-chloro-4 methoxybenzylamino)benzo[4,5]thieno[2,3 15 d]pyrimidin-2-yl] cyclohexyl-1-yllcyclohexanecarboxylic acid; and their physiologically acceptable salts and/or solvates for preparing a medicament for treating 20 angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, conditions of reduced circulation through the cardiac vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, 25 chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency and cirrhosis of the liver and for treating female impotence.