EP1355649A2

EP1355649A2 - Pharmaceutical formulation containing pyrazolo 4,3-d]pyrimidine and nitrates or thienopyrimidines and nitrates

Info

Publication number: EP1355649A2
Application number: EP01988079A
Authority: EP
Inventors: Hans-Michael Eggenweiler; Volker Eiermann; Pierre Schelling
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2001-01-31
Filing date: 2001-12-27
Publication date: 2003-10-29
Also published as: WO2002060449A2; CA2436209A1; HUP0302987A2; AR035741A1; JP2004517940A; CN1499969A; SK10762003A3; BR0116849A; WO2002060449A3; PL362408A1; MXPA03006717A; CZ20032339A3; KR20030070149A; US20040077664A1

Abstract

The invention relates to a pharmaceutical preparation containing at least one pyrazolo(4, 3-d)pyrimidine or thienopyrimidine phosphodiesterase V inhibitor and at least one nitrate for producing a pharmaceutical for the treatment of angina, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart disease, right ventricular failure, arteriosclerosis, conditions of reduced patency of the heart vessels, peripheral vascular diseases, apoplexy, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, kidney failure and cirrhosis of the liver.

Description

Containing pharmaceutical formulation

Pyrazolo [4,3-d] pyrimidines and nitrates or

Thienopyrimidines and nitrates

The invention relates to pharmaceutical formulations containing at least one phosphodiesterase V inhibitor of the formula I.

wherein R ¹ , R ^{2 are} each independently of one another H, A, OH, OA or shark,

R and R ² together also alkylene with 3-5 C atoms,

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

-O-CH ₂ -CH ₂ -O-,

R ³ , R ⁴ each independently of one another H or A, X simply substituted by R ^8, R ⁵ , R ⁶ or R ⁷ ,

R ³ linear or branched alkylene with 1-10 C atoms, in which one or two CH ₂ groups by -CH = CH-

Groups, O, S or SO can be replaced,

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

R ⁷ phenyl or phenylmethyl,

R ^δ 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, and / or their physiologically acceptable salts and / or solvates and at least one nitrate for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive Heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, right heart failure, atherosclerosis, conditions of reduced cardiac patency, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome , Renal failure and cirrhosis.

The invention further relates to pharmaceutical formulations containing at least one phosphodiesterase V inhibitor of the formula

wherein

R \, R ² each independently of one another H, A or Hai, where one of the radicals R ¹ or R ^{2 is} always ≠ H,

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

R ³ , R ⁴ each independently of one another are H, A, OH, OA or shark,

R ³ and R ⁴ together also contain alkylene with 3-5 C atoms,

-O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or

-O-CH ₂ -CH ₂ -O-,

X is monosubstituted by R ⁷ R ⁵ or R ^6,

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

R ° cycloalkylalkylene with 6-12 C atoms, R ⁷ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN, A alkyl with 1 to 6 carbon atoms,

Hai F, Cl, Br or I, m is 1 or 2 and n is 0, 1, 2 or 3, and / or their physiologically acceptable salts and / or solvates and at least one nitrate for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, right ventricular insufficiency, atherosclerosis, conditions of reduced cardiac patency, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, allergic rhinitis Bowel syndromes, tumors, renal failure and cirrhosis.

The invention further relates to pharmaceutical formulations containing at least one phosphodiesterase V inhibitor of the formula I-II

wherein

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

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

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

-O-CH ₂ -CH ₂ -O-, X simple R ⁴ , R ⁵ or R ⁶ substituted by R ⁷ , R ⁴ 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 ⁵ cycloalkyl or cycloalkylalkylene with 5-12 C atoms, R

R phenyl or phenylmethyl,

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

A alkyl with 1 to 6 carbon atoms and

Hai F, Cl, Br or I mean, and / or their physiologically acceptable salts and / or solvates and at least one nitrate for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease ( COPD), cor pulmonale, right heart failure, atherosclerosis, conditions of reduced cardiac patency, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure and cirrhosis of the liver.

Pharmaceutical formulations consisting of other phosphodiesterase V (PDE V) inhibitors together with a nitrate are described in WO 00/15228.

The well-known contraindication of the administration of nitrates with simultaneous intake of PDE V inhibitors for the indication erectile dysfunction is e.g. described in WO 00/10542. At the same time, however, it discloses that nitrates can be administered as an antianginal agent, even though phosphodiesterase V inhibitors are used at the same time for the treatment of erketile dysfunction.

Pharmaceutical preparations containing both a nitrate and a phosphodiesterase inhibitor for use in the treatment of erectile dysfunction and / or in therapy are also described there of cardiovascular diseases in the presence of the other indication.

The invention was based on the object of providing new medicaments in the form of pharmaceutical preparations which have better properties than known medicaments which can be used for the same purposes.

This task was solved by finding the new preparation.

The compounds of the formula I, I-I and I-II and their salts show 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, I-I and I-II can be determined by methods such as are described, for example, in WO 93/06104.

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 (e.g. W. J. Thompson et al., Biochem. 1971, 10, 311). A modified "batch" method by W.J. Thompson and M.M. Appleman (Biochem. 1979, 18, 5228) can be used.

The compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular heart failure and for the treatment and / or therapy of erectile dysfunction. The use of substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in WO 94/28902.

The compounds are effective as inhibitors of phenylephrine-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. Ural., 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

Potency disorders.

The effectiveness of the pharmaceutical formulations according to the invention especially for the treatment of pulmonary hypertension can be demonstrated in Heart Disease ^5th edition as described by E. Braunwald, WB Saunders Company, 1997, chapter 6: Cardiac catheterization 177-200.

The compounds of the formula I, I-I and I-II can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.

Compounds of formula I:

The compounds of the formula I according to claim 1 and their salts are prepared by a process

characterized in that one

a) a compound of formula II

R4 in which

R ³ , R ⁴ and X have the meanings given,

and L denotes Cl, Br, OH, SCH ₃ or a reactive esterified OH group,

with a compound of formula III

wherein

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

implements,

or

b) in a compound of formula I one radical X into another

Convert rest X by e.g. hydrolyses an ester group to a COOH group or converts a COOH group to an amide or a cyano group

and / or converting a compound of formula I into one of its salts. Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

Above and below, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X and L have the meanings given in the formulas I, II and III, unless expressly stated otherwise specified. A means alkyl with 1-6 carbon 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 a R ⁵ , R ^δ or R ⁷ radical which is simply substituted by R.

R ⁵ denotes a linear or branched alkylene radical with 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. A CH ₂ group in R ⁵ can preferably be replaced by oxygen. Ethylene, propylene, butylene or CH ₂ -O-CH ₂ is very particularly preferred.

R ⁶ denotes cycloalkylalkylene with 5-12 C atoms, preferably for example cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene. R ^{6 also} means cycloalkyl, preferably having 5-7 carbon atoms.

Cycloalkyl means e.g. 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, OH, F, Cl, Br or | or together alkylene, such as propylene, butylene or pentylene, further

Ethyleneoxy, methylenedioxy or ethylenedioxy. They preferably also each represent alkoxy, such as e.g. for methoxy, ethoxy or propoxy.

The radical R ⁸ is preferably, for example, COOH, COOA such as COOCH ₃ or COOC ₂ H ₅ , CONH ₂ , CON (CH ₃ ) ₂ , CONHCH ₃ or CN, but in particular COOH or COOA.

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.

The invention relates in particular to those pharmaceutical formulations comprising a nitrate and at least one compound of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to If, 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

CN is substituted R ⁵ , phenyl or phenylmethyl;

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

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

CN is substituted R ⁵ , phenyl or phenylmethyl; in Ic R ¹ , R ² each independently of one another H, A, OH, OA or

Shark, R ¹ and R ² together also alkylene with 3-5 C atoms, -O-CH ₂ -CH ₂ -, -O-CHrO- or -O-CH ₂ -CH ₂ -O, X by COOH, COOA , CONH ₂ , CONA ₂ , CONHA or

CN is substituted R ⁵ , phenyl or phenylmethyl;

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

R ¹ and R ² together also alkylene with 3-5 C atoms, -O-CH ₂ -CH ₂ -, -O-CH2-O- or -O-CH ₂ -CH ₂ -O-, X simply by R ⁸ substituted alkylene with 2-5 C atoms, cyclohexyl, phenyl or phenylmethyl,

R ³ alkyl with 1-6 C atoms,

R ⁴ alkyl with 1-6 C atoms,

R ⁸ COOH or COOA,

A is alkyl having 1 to 6 carbon atoms, ^' Shark F, Cl, Br or I;

in le R ¹ , R ² each independently of one another H, A, OH, OA or

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

-O-CH ₂ -CH ₂ -O-, R ³ alkyl with 1-6 C atoms,

R ⁴ alkyl with 1 -6 carbon atoms,

X is - (CH ₂₎ ₂ - ₅ -R ^8, R ⁸ 4-cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -methyl) -phenyl.

in If R ¹ , R ² each independently of one another H, A, OH, OA or

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

-O-CH ₂ -CH ₂ -O-, R ³ alkyl with 1-6 C atoms,

R ⁴ alkyl with 1-6 C atoms,

X - (CH ₂ ) 2-5-R ⁸ , in which a CH ₂ group can be replaced by O, 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or

4- (R ⁸ -methyl) phenyl, R ⁸ COOH or COOA.

The invention preferably relates to a formulation comprising [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid and its physiologically acceptable salts and / or solvates and a nitrate. In addition to the free acid, the ethanolamine salt is preferred.

Nitrates are preferably selected from the group pentaerythrityltetra, pentaerythrityltri, pentaerythrityldi, pentaerythrityl mononitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate.

Nitrates are particularly preferably selected from the group pentaerythrityl tetranitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate, and pentaerythrityl tetranitrate is very particularly preferred.

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 (e.g. 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 and X have the meanings indicated, in particular the preferred ones indicated

Meanings. 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 the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.

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 using methods known from the literature, e.g. be prepared from 4-amino-3-alkoxycarbonylpyrazoles by cyclization with nitriles and subsequent reaction of the cyclization products with phosphorus oxychloride (analogously to 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 an 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, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, l ^ -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 acetonithl; 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 hydrolyzing an ester or a cyano group 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 with a base into the associated acid addition salt, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and then evaporating. 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 (e.g. 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. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon, sulfonic or sulfuric acids, for example 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, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2- Hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.

The invention furthermore relates to pharmaceutical formulations comprising at least one compound of the formula I and / or one of its physiologically acceptable salts and at least one nitrate and also comprising one or more carriers and / or auxiliaries.

The pharmaceutical preparations are produced in particular by a non-chemical route. The active ingredients are brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary.

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, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and suspensions for parenteral use.

Emulsions or implants, for topical application of ointments, creams or powders. 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. They can also be administered as nasal sprays.

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 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 elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred.

The invention relates in particular to the use of the formulations according to the invention for the production of a medicament for the treatment of pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonary and / or right heart failure.

The components of the new pharmaceutical preparation are preferably administered in combination. However, they can also be administered individually at the same time or in succession. The invention also relates to a set (kit) consisting of separate packs of

(a) an effective amount of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid,

Ethanolamine salt and

(b) an effective amount of a nitrate.

The invention relates in particular to a set (kit) consisting of separate packs of

(a) an effective amount of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid, Ethanolamine salt and

(b) an effective amount of a nitrate, used to treat pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonary and / or right heart failure.

The set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can e.g. contain separate ampoules, each containing an effective amount of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxyj -Acetic acid, ethanolamine salt and the nitrate dissolved or in lyophilized form.

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, separated, dried 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) ⁺

example 1

3 g of methyl 3- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] propionate and 1.9 g of 3-chloro-4-methoxybenzylamine ("A") in 50 ml of dimethylformamide (DMF) are stirred for 12 hours at 60 ° in the presence of potassium carbonate. After filtration, the solvent is removed and worked up as usual. 4.6 g of 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid methyl ester are obtained as a colorless oil.

Analogously, by converting "A"

with 2- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] methyl acetate

Methyl 2- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -acetate.

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

with methyl 3- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionate

Methyl 3- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionate.

Analogously, by converting "A"

with 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester

Methyl 4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -butyrate.

Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained with 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid remethyl ester

Methyl 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -butyrate.

Analogously, by converting "A"

with 5- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid methyl ester 5- [7- (3-chloro-4-methoxy-benzylamino) -1-Methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid methyl ester.

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

with 5- [7-chloro-1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid methyl ester

5- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid methyl ester.

Analogously, by converting "A"

with 7- [7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid methyl ester

Methyl 7- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoate.

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

Methyl 7- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoate.

Analogously, by converting "A" with 2- [4- (7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl) cyclohex-1-yl] acetic acid methyl ester

2- {4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid methyl ester.

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

with 2- [4- (7-chloro-1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl) - cyclohex-1-yl] acetic acid methyl ester 2- {4- [7- (3,4-Methylenedioxy-benzylamino) -1 -methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} acetic acid methyl ester ,

One obtains analogously by conversion of benzylamine

3- [7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid methyl ester;

4- [7-Benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid methyl ester;

Methyl 5- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valerate.

Analogously, by converting "A"

with 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid methyl ester

Methyl 4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylate and by reacting 3,4-methylenedioxybenzylamine

Methyl 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylate.

Example 2

4.3 g of methyl 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionate are added in 30 ml of tetrahydrofuran (THF) dissolved and after addition of 10 ml of 10% NaOH stirred at 60 ° for 8 hours. After adding 10% HCl, the precipitated crystals are separated off and recrystallized from methanol. 3.7 g of 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid are obtained, F. 178 °.

Evaporation with the equivalent amount of methanolic potassium hydroxide solution gives the potassium salt of the acid as an amorphous powder.

The compounds are obtained analogously from the esters listed in Example 1

2- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] acetic acid,

3- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyhmidin-5-yl] propionic acid,

4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 152 °;

4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 172 °;

5- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 159 °; 5- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] -valeric acid, ethanolamine salt, F. 160 °;

7- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H ~ pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,

7- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-dpyrimidin-5-yl] -heptanoic acid,

2- {4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid,

2- {4- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} -acetic acid,

3- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

4- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,

5- [7-benzylamino-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 185 °;

4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-dpyrimidin-5-yl] cyclohexane carboxylic acid,

4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid.

The connections are obtained analogously

5- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-isopropyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, cyclohexylamine salt, F . 148 ° 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 176 °;

4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-ethyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 187 °;

4- [7- (3-chloro-4-methoxybenzylamino) -1-ethyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 206 °;

4- [7- (3,4-methylenedioxybenzylamino) -1-ethyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 177 °;

4- [7-benzylamino-1-methyl-3-ethyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 208 °;

4- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 250 °;

4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-methyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 225 °;

4- [7-benzylamino-1-methyl-3-methyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 201 °;

5- [7- (4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 160 °;

5- [7- (3-methoxy-benzylamino) -1-methyl-3-propyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 141 °; '

5- [7- (4-chloro-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 148 °;

5- [7- (3-chloro-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 151 °; Example 3

A mixture of 1.8 g of 4- [7-chloro-1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylcarboxylic acid methyl ester ("B") and 1.5 g 3-chloro-4-methoxy-benzylamine in 20 ml of N-methylpyrrolidone is heated to 110 ° for 4 hours. After cooling, working up as usual. 2.2 g of methyl 4- [7- (3-chloro-4-methoxy-benzylamino1-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoate) are obtained.

Analogously to Example 2, 1.2 g of the ester are used to obtain 1.0 g of 4- [7- (3-chloro-4-methoxy-benzylamino1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid, ethanolamine salt, mp 139 °.

Analogously to Example 1, "B" and 3,4-methylenedioxybenzylamine give 4- [7- (3,4-methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyhmidine -5-yl] -benzoic acid methyl ester and therefrom by ester hydrolysis

4- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyhmidin-5-yl] benzoic acid.

The connection is obtained analogously

4- [7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-djpyrimidin-5-yl] phenylacetic acid, glucamine salt, mp 114 ° and

4- [7- (3,4-Methylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

Example 4

1 equivalent of 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid and 1,2 Equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylj-propionic acid chloride is obtained , It is transferred into aqueous ammonia, stirred for one hour and 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidine is obtained after customary working up -5-yl] -propionsäureamid.

Example 5

1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0 °. Then 1 equivalent of 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid amide is added , It is stirred for an hour. After customary working up, 3- [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionitrile is obtained.

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- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,

3- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

5- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,

7- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,

2- {4- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylj-cyclohexyl-1-yl} - acetic acid,

4- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid, 4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3,4-ethylenedioxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

The following compounds are obtained analogously by reaction with 3,4-dichlorobenzylamine

4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yi] butyric acid, mp 209 °;

3- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

5- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,

7- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1f -pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,

2- {4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 - / - pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1-yl} - acetic acid,

4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,

4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid. - b -

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

4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,

3- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,

5- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,

7- [7- (3-chloro-4-ethoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,

2- {4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- yl} -acetic acid,

4- [7- (3-chloro-4-ethoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-dpyrimidin-5-yl] cyclohexane carboxylic acid,

4- [7- (3-chloro-4-ethoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-djpyrimidin-5-yl] benzoic acid,

4- [7- (3-Chloro-4-ethoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylj-phenylacetic acid.

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

4- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,

3- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid, 5- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,

7- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] -heptanoic acid,

2- {4- [7- (3-Chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1 / - / - pyrazolo [4,3-d] pyrimidin-5-ylj-cyclohexyl-1 yl} acetic acid,

4- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexane carboxylic acid,

4- [7- (3-chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,

4- [7- (3-Chloro-4-isopropoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid.

Example 7

The compound is obtained analogously to Examples 1 and 2

[7- (3-Chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid, ethanolamine salt, mp 138 °.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I, 100 g of the nitrate 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 and sterile under sterile conditions locked. Each injection jar contains 5 mg of each active ingredient.

Example B: Suppositories

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

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula 1, 1 g of a nitrate, 9.38 g of NaH ₂ PO ₄ • 2 H ₂ O, 28.48 g of Na ₂ HPO ₄ • 12 H ₂ O and 0.1 g Benzalkonium chloride in 940 ml of 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, 500 mg of a nitrate 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, 1 kg of a nitrate, 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 the usual way, such that each tablet contains 10 mg of each 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 and 2 kg of a nitrate are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of each active ingredient.

Example H: ampoules

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

Example I: Inhalation spray

14 g of active ingredient of the formula I and 14 g of a nitrate 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 of each active ingredient.

Compounds of formula l-l:

The compounds of formula II and their salts are prepared by a process, characterized in that a) a compound of formula II-1

wherein

R ¹ , R ² and X have the meanings given and L is Cl, Br, OH, SCH ₃ or a reactive esterified OH group,

with a compound of the formula

wherein

R ³ , R ⁴ and n have the meanings given,

implements,

or

b) in a compound of the formula I-1 one radical X into another

and / or that a compound of the formula II is converted into one of its salts. Solvates of the compounds of the formula II are understood to mean the addition of inert solvent molecules to the compounds of the formula II, which are formed on account of their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

Above and below, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, L and n have the meanings given in the formulas II, II-1 and III, unless expressly stated something else is specified.

0

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.-c Butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.

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

R ^{5 represents} a linear or branched alkylene radical having 1-10, Q preferably 1-8 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- 5 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.

QR ⁶ means cycloalkylalkylene with 6-12 C atoms, preferably for example cycclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.

^{One of} the radicals R ¹ and R ² is preferably H, while the other _{5 is} preferably propyl or butyl, but particularly preferably ethyl or - όΔ -

Methyl means. Furthermore, R ¹ and R ² together preferably also mean propylene, butylene or pentylene.

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

The radicals R ³ and R ⁴ 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, OH, alkyl, F, Cl, Br or I or together alkylene, such as propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are also preferably each alkoxy, such as methoxy, ethoxy or propoxy.

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.

The invention particularly relates to those pharmaceutical

Formulations containing a nitrate and at least one compound of the formula I-1, in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ie, which correspond to the formula I-I and in which the radicals not specified have the meaning given for the formula I-I, but in which

in la X is R ⁵ or R ⁶ substituted by COOH or COOA;

in Ib R ¹ , R ² each independently of one another H, A or shark, where at least one of the radicals R ¹ or R ^{2 is} always ≠ H, R ³ and R ⁴ together are alkylene with 3-5 C atoms, -O-CH2 -CH ₂ -,

-O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O, X is R ⁵ or R ⁶ substituted by COOH or COOA;

in Ic R ¹ , R ² each independently of one another H, A or shark, at least one of the radicals R ¹ or R ² always

≠ is H, R ³ , R ^{4 are} each independently H, A, OA or shark,

R ³ and R ⁴ together alkylene with 3-5 C atoms, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O, X by COOH or COOA substituted R ⁵ or R ⁶ , n is 1 or 2;

in Id R ¹ , R ² each independently of one another H, A or shark, one of the radicals R ¹ or R ² always being ≠ H,

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

R ³ , R ⁴ each independently of one another H, A, OA or

Shark, R ³ and R ⁴ together also -O-CH ₂ -O-, X R ⁵ substituted simply by R ⁷ ,

R ⁵ linear or branched alkylene with 1-10 C atoms, or

R ⁷ COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Shark F, Cl, Br or I, m is 1 and n is 1 or 2;

in le R ¹ , R ² each independently of one another are H, A or shark, one of the radicals R ¹ or R ² always being ≠ H,

R ¹ and R ² together also alkylene with 3-5 C atoms, R ³ , R ⁴ each independently of one another H, A, OH, OA or

Hai,

R ³ and R ⁴ together also -O-CH ₂ -O-, X is simply substituted by R ^7, R ⁵ ,

R ⁵ linear or branched alkylene with 1-10 C atoms, or

R ⁷ COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Shark F, Cl, Br or I, m 1 and 0 n 1 or 2 mean.

The invention preferably relates to a formulation containing 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine -2-ylj-valeric acid and its physiologically acceptable salts and / or solvates and at least one nitrate. In addition to the free acid, the ethanolamine salt is preferred.

Nitrates are preferably selected from the group pentaerythrityltetra, pentaerythrityltri, pentaerythrityldi, pentaerythrityl mononitrate, isosorbide Q mononitrate, isosorbide dinitrate, glycerol trinitrate.

Nitrates are particularly preferably selected from the group pentaerythrityl tetranitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate, and pentaerythrityl tetranitrate is very particularly preferred. 5

The compounds of formula I-1 and also the starting materials for their

Manufacture are otherwise prepared according to 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, Q Stuttgart), under reaction conditions that are known and suitable for the implementations mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

5 In the compounds of the formulas II-1 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 the formula I-1 can preferably be obtained by reacting compounds of the formula II-1 with compounds of the formula III.

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-1. On the other hand, it is possible to carry out the reaction in stages.

The starting compounds of the formula II-I and III are generally known. If they are not known, they can be produced by methods known per se.

Compounds of the formula II-1 can be obtained, for example, by reaction with POCI ₃ from compounds which are built up from thiophene derivatives and CN-substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453 (1988).

In particular, the reaction of the compounds of the formula II-1 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 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 a organic base such as triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component can be favorable.

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 (ethyl glycol or ethyl glycol _M.), 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 a radical X into another radical X in a compound of the formula I-1, e.g. by hydrolyzing an ester or a cyano group 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 °.

An acid of the formula II can be converted into the associated acid addition salt with a base, for example by reacting equivalent 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 II can be mixed with a base (eg sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular special alkali metal or alkaline earth metal, or be converted into the corresponding ammonium salt.

Organic bases which provide physiologically acceptable salts, such as e.g. Ethanolamine.

An acid of the formula I-1 can be converted into the associated acid addition salt with a base, for example by reacting equivalent 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.

Thus, the acid of formula I-1 can be converted with a base (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.

On the other hand, a base of the formula II can be converted into the associated acid addition salt with 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. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon, sulfonic or sulfuric acids, for example 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, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2- hydroxyethane Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.

The invention furthermore relates to pharmaceutical formulations comprising at least one compound of the formula I-1 and / or one of its physiologically acceptable salts and at least one nitrate and also comprising one or more carriers and / or auxiliaries. The pharmaceutical preparations are produced in particular by a non-chemical route. The active ingredients are brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary.

These preparations can be used as medicinal products in human or

Veterinary medicine can be used. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. 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, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral use topical application ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. The specified preparations can be sterilized and / or contain auxiliaries 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, for example one or more vitamins. They can also be administered as nasal sprays. 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 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 elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred.

The components of the new pharmaceutical preparation are preferably administered in combination. However, they can also be administered individually at the same time or in succession.

The invention also relates to a set consisting of separate packs of (a) an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] - valeric acid, ethanolamine salt and

(b) an effective amount of a prostaglandin or prostaglandin derivative.

(a) an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) - 5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidine- 2-yl] - valeric acid, ethanolamine salt and

The set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can e.g. contain separate ampoules, each containing an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d ] - pyrimidin-2-yl] -valeric acid, ethanolamine salt and the nitrate dissolved or in lyophilized form.

Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺

example 1

1.9 g of methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-dj-pyrimidin-2-yl) propionate [obtainable by cyclization of 2-amino - 4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid methyl ester with methyl 3-cyanopropionate and subsequent chlorination with

Phosphorus oxychloride / dimethylamine] and 2.3 g of 3-chloro-4-methoxybenzylamine ("A") in 20 ml of N-methylpyrrolidone are stirred at 110 ° for 5 hours. The solvent is removed and worked up as usual. 2.6 g of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidine-2 are obtained -yl] -propionic acid methyl ester as a colorless oil. Analogously, by converting "A"

with methyl 3- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-dj-pyrimidin-2-yl) propionate 3- [4- (3-chloro-4-methoxy-benzylamino ) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3-chloro-4-methoxy- benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3-chloro-4-methoxybenzylamino) -6 -methyl-thieno- [2,3-d] - pyrimidin-2-yl] -propionic acid methyl ester;

with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-ylj-propionic acid methyl ester;

with methyl 3- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3-chloro-4-methoxybenzylamino) -6 -ethyl-thieno- [2,3-d] - pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno - [2,3-d] - pyrimidin-2-yrj-propionic acid methyl ester;

with 2- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) methyl acetate

Methyl 2- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno [2,3-d] pyrimidin-2-yl] acetic acid. Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained

with methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) - propionate 3- [4- (3,4- Methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4-chloro-6-methylthieno [2,3-d] pyhmidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) -6-methyl -thieno- [2,3-d] - pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyhmidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) -5 , 6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;

with methyl 3- (4-chloro-6-ethylthieno [2,3-dj-pyrimidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) -6-ethyl] methyl thieno [2,3-d] pyrimidin-2-yl] propionate;

with methyl 3- (4,6-dichlorothieno [2,3-d] pyhmidin-2-yl) propionate 3- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-d] - pyrimidin-2-yl] propionic acid methyl ester. Analogously, by converting "A"

with 4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) - butyric acid methyl ester 4- [4- (3-chloro 4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] -butyric acid methyl ester;

with 4- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy- benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy- benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy-benzylamino) -6 -methyl-thieno- [2,3-d] - pyrimidin-2-yl] -butyric acid methyl ester;

with 4- (4-chloro-5,6-dimethylthieno [2,3-dj-pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy-benzylamino) - 5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethyl -thieno- [2,3-d] - pyrimidin-2-yl] -butyric acid methyl ester;

with 4- (4,6-chloro-6-chlorothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester

Methyl 4- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyrate. Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained

with 4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4- Methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1j-benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -6-methyl -thieno- [2,3-dj-pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -5 , 6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4-chloro-6-ethylthieno [2,3-d] pyhmidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno - [2,3-dj-pyrimidin-2-yl] butyric acid methyl ester;

with 4- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester 4- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-d] - pyrimidin-2-yl] butyric acid methyl ester.

Analogously, by converting "A" with 5- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester

5- [4- (3-Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;

with 5- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester

Methyl 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1j-benzothieno [2,3-d] pyrimidin-2-yl] valerate;

with methyl 5- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl)

5- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1j-benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;

with 5- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester

5- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;

with 5- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester

Methyl 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-dj-pyrimidin-2-yl] valerate;

with 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester

5- [4- (3-Chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;

with 5- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester 5- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno - [2,3-d] - pyrimidin-2-yl] valeric acid methyl ester.

Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained with 5- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester

Methyl 5- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;

Methyl 5- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] valerate;

5- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;

Methyl 5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valerate;

5- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valehanoic acid methyl ester;

5- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;

with 5- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester 5- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-d] - pyrimidin-2-yl] -valeric acid methyl ester.

Analogously, by converting "A" with 7- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester

7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;

with 7- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester

7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1j-benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;

with 7- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyhmidin-2-yl) heptanoic acid methyl ester

7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;

with 7- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester

7- [4- (3-Chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;

with 7- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester

7- [4- (3-Chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yrj-heptanoic acid methyl ester;

with methyl 7- (4-chloro-6-ethylthieno [2,3-dj-pyrimidin-2-yl) -heptanoate

7- [4- (3-Chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid methyl ester;

with 7- (4-chloro-6-chlorothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester

Methyl 7- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] -heptanoate. Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained

with 7- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4- Methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid methyl ester;

with 7- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid methyl ester;

with 7- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid methyl ester;

with 7- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno - [2,3-d] - pyhmidin-2-yl] -valeric acid methyl ester;

with 7- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4-methylenedioxybenzylamino) -5,6 -dimethylthieno- [2,3-dj-pyrimidin-2-yl] heptanoic acid methyl ester;

with 7- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno - [2,3-d] - pyrimidin-2-yl] heptanoic acid methyl ester;

with 7- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) heptanoic acid methyl ester 7- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno- [ 2,3-d] - pyrimidin-2-yl] -heptanoic acid methyl ester. Analogously, by converting "A"

with 2- [4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) cyclohexyl-1-yl] acetic acid methyl ester 2- {4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -cyclohexyl-1-yl} - methyl acetate;

with 2- [4- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) cyclohexyl-1-yl] methyl acetate

Methyl 2- {4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid;

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

with 2- [4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) cyclohexyl-1-yl] acetic acid methyl ester

2- {4- [4- (3,4-Methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] cyclohexyl -1-yl} - methyl acetate.

One obtains analogously by conversion of benzylamine

with methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate

3- (4-Benzylamino-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) propionic acid methyl ester;

with 4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester

4- (4-Benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) -butyric acid methyl ester;

with 5- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester 5- (4-Benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] - pyrimidin-2-yl) -valeric acid methyl ester;

with 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester

4- [4-benzylamino-6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;

with methyl 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valehanoate

5- [4-Benzylamino-6-ethylthieno [2,3-d] pyrimidin-2-ylj-valeric acid methyl ester.

Example 2

2.2 g of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl ] -propionic acid methyl ester is dissolved in 20 ml of ethylene glycol monomethyl ether and, after addition of 10 ml of 32% NaOH, stirred at 110 ° for 5 hours. After adding 20% HCl, the mixture is extracted with dichloromethane. Adding petroleum ether gives 2.0 g of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] -pyrimidin-2-yl] -propionic acid, mp 229 °. The precipitated crystals are dissolved in 30 ml of isopropanol and mixed with 0.5 g of ethanolamine. After crystallization, 1.35 g of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine are obtained -2-yl] propionic acid, ethanolamine salt, mp 135 °.

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

3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-ylj-propionic acid; 3- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionic acid;

2- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] acetic acid, Ethanolamine salt, mp 126 °;

3- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;

3- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionic acid; 4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 142 °;

4- [4- (3-chloro-4-methoxy-benzylamino) -5,6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 170 °;

4- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3,4-methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, F. 114 °;

4- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 170 °; 4- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] butyric acid;

4- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyric acid;

5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyhmidin-2-yl] valeric acid, F. 165 °; Ethanol amine salt, mp 112 °;

5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;

5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;

5- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 156 °;

5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyhmidin-2-yl] valeric acid;

5- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-dj-pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 156 °;

5- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valeric acid;

5- [4- (3,4-methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-dj-pyrimidin-2-yl] valeric acid;

5- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] valeric acid; 5- [4- (3,4-Methyiendioxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid;

5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 167 °;

5- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;

5- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;

5- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valeric acid;

7- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid, Ethanolamine salt, mp 130 °;

7- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid;

7- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] heptanoic acid;

7- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;

7- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-ylj-heptanoic acid;

7- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid; 7- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-y ^π- heptanoic acid;

7- [4- (3,4-methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -heptanoic acid, ethanolamine salt, Mp 137 °;

7- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;

7- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] - benzothieno- [2,3-d] pyhmidin-2-yl] heptanoic acid;

7- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid;

7- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;

7- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;

7- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;

2- {4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] -cyclohexyl} -acetic acid;

2- {4- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] cyclohexyl} acetic acid;

2- {4- [4- (3,4-Methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyhmidin-2-yl] cyclohexyl }-acetic acid;

3- (4-Benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl) propionic acid, ethanolamine salt, mp 126 °; 4- (4-benzylamino-5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl) butyric acid, ethanolamine salt, mp 133 °;

5- (4-benzylamino-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid, ethanolamine salt, mp 135 °;

4- [4-benzylamino-6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, mp 165 °;

5- [4-Benzylamino-6-ethylthieno [2,3-dj-pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 162 °.

Example 3

1 equivalent of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - 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 and 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidine- 2-yl] - propionic acid chloride.

It is transferred into aqueous ammonia, stirred for one hour and, after customary working up, 3- [4- (3-chloro-4-methoxy-benzylamino) -5, 6,7,8-tetrahydro- [1] -benzothieno- [2, 3-d] -pyrimidin-2-yl] -propionsäureamid.

Example 4

1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0 °. Thereafter, 1 equivalent of 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl ] - propionic acid amide added. It is stirred for an hour. After the usual work-up, 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidine-2- yl] -propionitrile.

Example 5 The following compounds are obtained analogously to Examples 1 and 2

6- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] hexanoic acid, F. 165 °;

2- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] propionic acid, Ethanolamine salt, mp 150 °;

4- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl] -2, 2-dimethyl-butyric acid, ethanolamine salt, mp 130 °;

4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] -2,2- dimethyl butyric acid, ethanolamine salt, mp 126 °;

5- [4- (3-chloro-4-hydroxy-benzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyhmidin-2-yl] valeric acid, F. 179 °;

5- [4- (3,4-dichlorobenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-dj-pyrimidin-2-yl] valeric acid, ethanolamine salt F. 136 °;

5- [4- (3-Chloro-4-isopropyloxy-benzylamino) -5,6,7,8-tetrahydro- [1j-benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt , M. 118 °;

2- [4- (4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl) -phenyl] acetic acid, ethanolamine salt, mp 119 °;

2- [4- (4- (3,4-Methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] pyrimidin-2-yl) phenyl ] acetic acid, F. 214. The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula II, 100 g of the nitrate 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 and sterile under sterile conditions locked. Each injection jar contains 5 mg of each active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I-1, of 20 g of a nitrate with 100 g of soy lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool. Each suppository contains 20 mg of each active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula II, 1 g of a nitrate, 9.38 g of NaH ₂ PO • 2 H ₂ O, 28.48 g of Na ₂ HPO ₄ • 12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of 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-1, 500 mg of a nitrate are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of formula II, 1 kg of a nitrate, 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 the usual way, such that each tablet contains 10 mg of each active ingredient.

Example F: coated tablets

Example G: capsules

2 kg of active ingredient of the formula I-1 and 2 kg of a nitrate are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of each active ingredient.

Example H: ampoules

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

Example I: Inhalation spray

14 g of active ingredient of the formula I-1 and 14 g of a nitrate are dissolved in 10 I of isotonic NaCl solution and the solution is poured 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 of each active ingredient.

Compounds of formula I-II:

The compounds of the formula I-II according to claim 1 and their salts are prepared by a process

characterized in that one a) a compound of formula II-ll

wherein

X has the meaning given,

and L denotes Cl, Br, OH, SCH ₃ or a reactive esterified OH group,

with a compound of formula III

wherein

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

implements,

or

b) in a compound of the formula I-II one radical X into another

and / or that a compound of the formula I-II is converted into one of its salts. Solvates of the compounds of the formula I-II are understood to mean the addition of inert solvent molecules to the compounds of the formula I-II, which are formed on account of their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

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, II-II and III, unless expressly stated something else is specified. A means alkyl with 1-6 C atoms.

X denotes a R ⁴ , R ⁵ or R ^δ residue 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 cycclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene. R ^{5 also} means cycloalkyl, preferably having 5-7 carbon atoms.

Cycloalkyl means e.g. Cyclopentyl, cyclohexyl or cycloheptyl.

Shark preferably means F, Cl or Br, but also I. The radicals R 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, hydroxyl, alkyl, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are also preferably each alkoxy, such as methoxy, ethoxy or propoxy.

The invention relates in particular to pharmaceutical formulations containing a nitrate and at least one compound of the formula I-II in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be identified by the following

Sub-formulas la to le are expressed which correspond to the formula I-II and in which the radicals not specified have the meaning given for the formula I-II, but in which

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

C is CNN-substituted R ⁴ , phenyl or phenylmethyl;

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

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 -,

-O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O, X by COOH, COOA, CONH ₂ , CONA _2l 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-CH2-CH2-, -O-CH2-O- or

-O-CH ₂ -CH ₂ -O-, 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 C atoms,

Shark means F, Cl, Br or I;

in le R ¹ , R ² each independently of one another H, A, OH, OA or

Shark, R ¹ and R ² together also alkylene with 3-5 carbon atoms,

-O-CH ₂ -CH2-, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-, 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 invention preferably relates to a formulation comprising 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid and its physiologically acceptable salts and / or solvates and at least one nitrate. In addition to the free acid, the ethanolamine salt is preferred. Nitrates are preferably selected from the group pentaerythrityltetra, pentaerythrityltri, pentaerythrityldi, pentaerythrityl mononitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate.

The compounds of the formula I-II 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-II or III, R ¹ , R ² , R ³ , R ⁴ , X and n have the meanings indicated, in particular the preferred meanings indicated.

The compounds of the formula I-II can preferably be obtained by reacting compounds of the formula II-II with compounds of the formula III.

The starting materials can, if desired formed in situ, so that ¹ are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I-II is reacted. On the other hand, it is possible to carry out the reaction in stages. The starting compounds of the formula II-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-II can be obtained, for example, by reaction with POCI ₃ from the corresponding hydroxypyrimidines which consist of

Thiophene derivatives and CN-substituted alkylene carboxylic acid esters can be built up (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 with aldehydes or nitriles (e.g. Houben Weyl E9b / 2).

Specifically, the reaction of the compounds of the formula II-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 150 °, preferably between 20 and 100 °.

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 a radical X into another radical X in a compound of the formula I-II, e.g. by hydrolyzing an ester or a cyano group 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-II can be converted into the 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 and subsequent evaporation. Bases that provide physiologically acceptable salts are particularly suitable for this implementation.

For example, the acid of formula I-II can be converted with a base (e.g. 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 e.g. Ethanolamine.

An acid of the formula I-II can be converted into the associated acid addition salt with a base, for example by reacting equivalent 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-II can be mixed with a base (eg sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular special alkali metal or alkaline earth metal, or be converted into the corresponding ammonium salt.

On the other hand, a base of the formula I-II 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, furthermore 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, 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, isonicotinic acid, methane or ethanesulfonic acid, 2-ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, ethane sulfonic acid, 2and , p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric 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-II.

The invention furthermore relates to pharmaceutical formulations comprising at least one compound of the formula I-II and / or one of its physiologically acceptable salts and at least one nitrate and also comprising one or more carriers and / or auxiliaries. The pharmaceutical preparations are produced in particular by a non-chemical route. The active ingredients are brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary. 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, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral 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. They can also be administered as nasal sprays.

The invention relates in particular to the use of the formulations according to the invention for the production of a medicament for the treatment of pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and / or right heart failure.

The invention further relates to the use of a pharmaceutical preparation containing at least one phosphodiesterase

V inhibitors and at least one prostaglandin or a prostaglandin derivative for the manufacture of a medicament for the oral treatment of pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and / or right heart failure

The invention also relates to a set (kit) consisting of separate packs of

(a) an effective amount of 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid, ethanolamine salt and

(b) an effective amount of a nitrate.

(a) an effective amount of 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid, ethanolamine salt, and (b) an effective amount of one Nitrates, for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonary and / or right heart failure.

The set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can, for example, be separate Contain ampoules, in each of which an effective amount of 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] - cyclohexane carboxylic acid, ethanolamine salt and the nitrate dissolved or is in lyophilized form.

example 1

3- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) propionate [obtainable by cyclization of 2-amino-5,6,7,8-tetrahydrobenzothio- ^ι phen-3-carbonsäuremethylester with 3-cyanopropionic acid methyl ester, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxychloride / 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.

Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained 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

Methyl 4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyrate.

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 methyl 5- (4-chloro-benzothieno [2,3-dj-pyrimidin-2-yl) valerate 5- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d ] -pyrimidin

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

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.

Analogously, reaction of 3,4-methylenedioxybenzylamine is obtained 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] pyrimidin-2-yl) cyclohex-1-yl] methyl acetate

Methyl 2- {4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} -acetate.

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

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) - methyl butyrate;

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] pyrimidin-2-yl) cyclohexane carboxylic acid methyl ester Methyl 4- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidine-2-yrj-cyclohexanecarboxylic acid

and by reaction of 3,4-methylenedioxybenzylamine 4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidine -

2-yl] -cyclohexancarbonsäuremethylester.

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 ethanolamine is added. After crystallization, 3- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-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] pyrimidine -yl] acetic acid,

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

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

7- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidineyl] 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 [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,

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

3- (4-benzylamino-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] pyrimidin-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] pyrimidin-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 heated to 110 ° for 4 hours. 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, F. 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, 4- [4- (3,4-methylenedioxybenzylamino) - [1] benzothieno- [2,3-d] pyrimidin-2-yl] - is obtained from "B" and 3,4-methylenedioxybenzylamine. methyl benzoate and therefrom by ester hydrolysis 4- [4- (3,4-methylenedioxy-benzylamino) - [1] benzothieno- [2,3-d] - pyrimidin-2-yl] -benzoic acid, sodium salt, melting point> 260 °.

The connection is obtained analogously

4- [4- (3-chloro-4-methoxy-benzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid, ethanolamine salt, mp 130 °; and 4- [4- (3,4-methylenedioxybenzylamino) - [1] benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid, ethanolamine salt, mp 202 °.

Example 4

1 equivalent of 3- [4- (3-chloro-4-methoxy-benzylamino) 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 and 3- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid chloride is obtained. It is transferred into aqueous ammonia, stirred for one hour and, after customary working up, 3- [4- (3-chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid amide is obtained.

Example 5

1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0 °. Then 1 equivalent of 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid amide is added. It is stirred for an hour. After customary working up, 3- [4- (3-chloro-4-methoxy-benzylamino) -benzothieno [2,3-d] pyrimidin-2-yl] propionitrile is obtained.

Example 6

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-yl} 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-ethylenedioxy-benzylamino) - [1] benzothieno [2,3-d] -pyrimidine

2-yl] benzoic acid, ethanolamine salt, mp 252 °;

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

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] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,

4- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-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] pyrimidin-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] 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-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.

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

2- {4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-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-II, 100 g of the nitrate 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 and lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of each active ingredient.

Example B: Suppositories

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

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I-II, 1 g of a nitrate, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ .12H 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-II, 500 mg of a nitrate 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-II, 1 kg of a nitrate, 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 the usual way, such that each tablet contains 10 mg of each active ingredient.

Example F: coated tablets

Example G: capsules

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

Example H: ampoules

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

Example I: Inhalation spray

14 g of active ingredient of the formula I-II and 14 g of a nitrate are dissolved in 10 I of isotonic NaCI 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 of each active ingredient.

Claims

Patent claims

1. Pharmaceutical formulation containing at least one compound of formula I

in which R ¹ , R ² each independently H, A, OH, OA or Hai, R ¹ and R ² together also alkylene with 3-5 carbon atoms,

-O-CH ₂ -CH ₂ -, -CH2-O-CH2-, -O-CH ₂ -O- or

-O-CH ₂ -CH ₂ -O-,

R ³ , R ⁴ each independently H or A, X is R ⁵ , R ⁶ or R ⁷ simply substituted by R ⁸ ,

R ^a linear or branched alkylene with 1-10 carbon atoms, in which one or two CH ₂ groups are replaced by -CH=CH-

Groups, O, S or SO can be replaced,

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

R ⁷ phenyl or phenylmethyl,

R ⁸ COOH, COOA, CONH _2l CONHA, CON(A) ₂ or CN,

A alkyl with 1 to 6 carbon atoms and

Hai F, Cl, Br or l, and/or their physiologically acceptable salts and/or solvates and at least one nitrate for the production of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease. nal disease (COPD), cor pulmonale, right heart failure, atherosclerosis, conditions of reduced cardiac vascular patency, peripheral vascular diseases, stroke,

bronchitis, allergic asthma, chronic asthma, allergic

Rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency and liver cirrhosis.

2. Pharmaceutical formulation according to claim 1, containing at least one compound of formula I according to claim 1, wherein

X represents R ⁵ substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN, phenyl or phenylmethyl.

3. Pharmaceutical formulation according to claim 1, containing at least one compound of formula I according to claim 1, wherein

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

-O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O, X through COOH, COOA, CONH ₂ , CONA ₂₎ CONHA or

CN represents substituted R ⁵ , phenyl or phenylmethyl.

4. Pharmaceutical formulation according to claim 1, containing at least one compound of the formula I according to claim 1, in which R ¹ , R ² are each independently H, A, OH, OA or Hai,

R ¹ and R ² together also contain alkylene with 3-5 carbon atoms,

-O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O, X R ⁵ substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN, phenyl or phenylmethyl.

5. Pharmaceutical formulation according to claim 1, containing at least one compound of the formula I according to claim 1, in which R ¹ , R ² are each independently H, A, OH, OA or Hai,

R ¹ and R ² together also contain alkylene with 3-5 carbon atoms, -O ^- CH ₂ -CH ₂ -, -O-CH2-O- or -O-CH ₂ -CH ₂ -O-,

Cyclohexyl, phenyl or phenylmethyl,

R ³ alkyl with 1-6 carbon atoms,

R ⁴ alkyl with 1-6 carbon atoms,

R ⁸ COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Hai F, Cl, Br or l mean I.

6. Pharmaceutical formulation according to claim 1, containing at least one compound of formula I according to claim 1, wherein R ¹ , R ² each independently H, A, OH, OA or Hai, R ¹ and R ² together also alkylene with 3-5 carbon atoms,

-O-CH ₂ -CH2-, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-, R ³ alkyl with 1-6 carbon atoms,

R ⁴ alkyl with 1-6 carbon atoms,

X -(CH2)2- ₅ -R ⁸ , where a CH2 group can be replaced by O, 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or

4-(R ⁸ -Methyl)-phenyl, R ⁸ mean COOH or COOA.

7. Pharmaceutical formulation according to claim 1, containing at least one compound of formula I according to claim 1 selected from the group

(a) 5-[7-(3-Chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]-pentanoic acid; (b) 4-[7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]-benzoic acid;

(c) 4-[7-(3,4-methylenedioxy-benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-butyric acid;

(d) 5-[7-(Benzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3-d]-pyrimidin-5-yl]-pentanoic acid; (e) [7-(3-Chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetic acid.

8. Pharmaceutical formulation according to claim 1, containing [7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]- acetic acid, ethanolamine salt.

9. Pharmaceutical formulation according to claims 1 to 8, wherein the nitrate is selected from the group of pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di-, pentaerythrityl mononitrate,

Isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate.

10. Pharmaceutical formulation according to claim 9, wherein the nitrate means pentaerythrityl tetranitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate.

11. Pharmaceutical formulation according to claim 10, wherein the nitrate is pentaerythrityl tetranitrate.

12. Pharmaceutical formulation according to one of the preceding claims containing one or more carriers and/or auxiliary substances.

13. Pharmaceutical preparation according to one of claims 1 to 12 for the production of a medicament for the treatment of pulmonary

Hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and/or right heart failure.

14. Set (Kit), consisting of separate packs of

(a) an effective amount of [7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1/-/-pyrazolo[4,3-d]pyrimidin-5-ylmethoxyj-acetic acid , ethanolamine salt and (b) an effective amount of a nitrate.

5. Set (Kit), consisting of separate packs of

(a) an effective amount of [7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxyj-acetic acid, ethanolamine salt and

(b) an effective amount of a nitrate, for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and/or right heart failure.

16. Pharmaceutical formulation containing at least one compound of the formula l-l

where R ¹ , R ² are each independently H, A or Hai, where one of the radicals R ¹ or R ² is always ≠ H,

R ¹ and R ² together also alkylene with 3-5 carbon atoms, R ³ , R ⁴ each independently H, A, OH, OA or Hai, R ³ and R ⁴ together also alkylene with 3-5 carbon atoms,

-O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-,

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

R ^£ linear or branched alkylene with 1-10 carbon atoms, in which one or two CH2 groups are replaced by -CH=CH-

Groups can be replaced, or

R ^c cycloalkylalkylene with 6-12 carbon atoms,

R' COOH, COOA, CONH2, CONHA, CON(A) ₂ or CN, A alkyl with 1 to 6 carbon atoms,

Hai F, Cl, Br or I, m 1 or 2 and n 0, 1, 2 or 3, and/or their physiologically acceptable salts and/or

Solvates and at least one nitrate for the manufacture of a medicament for the treatment of angina, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, right heart failure, atherosclerosis, conditions of reduced cardiac vascular patency, peripheral vascular diseases, Stroke, bronchitis, allergic asthma, chronic asthma, allergic

17. Pharmaceutical formulation according to claim 16, containing at least one compound of formula l-l according to claim 16, wherein

X represents R ⁵ or R ⁶ substituted by COOH or COOA.

18. Pharmaceutical formulation according to claim 16, containing at least one compound of formula l-l according to claim 16, wherein

R ¹ , R ² each independently H, A or Hai, where at least one of the radicals R or R ² is always

≠ H is, R ³ and R ⁴ z zusaammπmen alkylene with 3-5 carbon atoms, -O-CH ₂ -CH ₂ -

-O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O,

X represents R ⁵ or R ⁶ substituted by COOH or COOA.

19. Pharmaceutical formulation according to claim 16, containing at least one compound of formula l-l according to claim 16, wherein

R ¹ , R ² each independently H, A or Hai, where at least one of the radicals R ¹ or R ² always ≠

H is,

R ³ , R ⁴ each independently H, A, OA or Hai, R ³ and R ⁴ together alkylene with 3-5 carbon atoms, -O-CH ₂ -CH ₂ -,

-O-CHz-O- or -O-CH ₂ -CH ₂ -O,

X represents R ⁵ or R ⁶ substituted by COOH or COOA, n represents 1 or 2.

20. Pharmaceutical formulation according to claim 16, containing at least one compound of formula II according to claim 16, in which R ¹ , R ² are each independently H, A or Hai, where one of the radicals R ¹ or R ² is always ≠ H,

R ¹ and R ² together also include alkylene with 3-5 carbon atoms, R ³ , R ⁴ each independently H, A, OA or Hai, R ³ and R ⁴ together also -O-CH ₂ -O-, X simply ^R5 substituted by ^R7 ,

R ^a linear or branched alkylene with 1-10 carbon atoms, or

-C ₆ H ₄ -CH ₂ -,

^R7COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Hai F, Cl, Br or l, m 1 and n 1 or 2. 449

- 89 -

21. Pharmaceutical formulation according to claim 16, containing at least one compound of formula l-l according to claim 16, wherein

R\ R ² each independently H, A or Hai, where one of the radicals R ¹ or R ² is always ≠ H,

R ¹ and R ² together also contain alkylene with 3-5 carbon atoms,

R ³ , , R ⁴ each independently H, A, OH, OA or Hai,

R ³ and R ⁴ together also -O-CH ₂ -O-, XX R ⁵ simply substituted by R ⁷ ,

_D 5 linear or branched alkylene with 1-10 carbon atoms, or

-C ₆ H -CH ₂ -,

^R7COOH or COOA,

A alkyl with 1 to 6 carbon atoms,

Hai F, Cl, Br or I, m 1 and n 1 or 2.

22. Pharmaceutical formulation according to claim 16, containing at least one compound of formula l-l according to claim 16 selected from the group

(a) 3-[4-(3-Chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-dj-pyrimidin-2-yl]- propionic acid;

(b) 4-[4-(3,4-methylenedioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-dj-pyrimidin-2-yl]-butyric acid;

(c) 7-[4-(3,4-methylenedioxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-heptanoic acid ;

(d) 7-[4-(3-Chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl] -heptanoic acid;

(e) 5-[4-(3-Chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-ylj- valeric acid; (f) 5-[4-(3-chloro-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-valeric acid;

(g) 4-[4-(3-chloro-4-methoxy-benzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-butyric acid;

(h) 4-[4-(3,4-methylenedioxy-benzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-butyric acid;

(i) 2-{4-[4-(3-chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine-2 -yl]-cyclohexyl-1-yl}-acetic acid; 0 (k) 5-[4-(3,4-Methylenedioxy-benzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-valeric acid.

23. Pharmaceutical formulation according to claim 16, containing 5-[4-. _ (3-Chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-

[2,3-d]-pyrimidin-2-yl]-valeric acid, ethanolamine salt.

24. Pharmaceutical formulation according to claims 16 to 23, wherein the nitrate is selected from the group of pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di-, pentaerythrityl mononitrate,

Isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate.

25. Pharmaceutical formulation according to claim 24, wherein the nitrate means pentaerythrityl tetranitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate. 5

26. Pharmaceutical formulation according to claim 25, wherein the nitrate is pentaerythrityl tetranitrate.

27. Pharmaceutical formulation according to one of the preceding

30 claims containing one or more carriers and/or auxiliary substances.

28. Pharmaceutical preparation according to one of claims 16 to _,_ 27 for the production of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and/or right heart failure.

29. Set (Kit), consisting of separate packs of

(a) an effective amount of 5-[4-(3-chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine- 2-yi]-valeric acid, ethanolamine salt and

(b) an effective amount of a nitrate.

30. Set (Kit), consisting of separate packs of

(a) an effective amount of 5-[4-(3-chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine- 2-yl]-valeric acid, ethanolamine salt and

31. Pharmaceutical formulation containing at least one compound of the formula l-ll

wherein

R ¹ , R ² each independently H, A, OA, OH or Hai,

R ¹ and R ² together also contain alkylene with 3-5 carbon atoms,

-O-CH ₂ -CH ₂ -, -CH ₂ -O-CH ₂ -, -O-CH2-O- or

-O-CH ₂ -CH ₂ -O-, X is R ⁴ , R ⁵ or R ⁶ simply substituted by R ⁷ ,

R ⁴ linear or branched alkylene with 1-10 carbon atoms, in which one or two CH groups are replaced by -CH=CH-

groups can be replaced,

R ⁵ cycloalkyl or cycloalkylalkylene with 5-12 carbon atoms,

R ⁶ phenyl or phenylmethyl,

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

A means alkyl with 1 to 6 carbon atoms and Hai F, Cl, Br or I, and/or their physiologically acceptable salts and/or solvates and at least one nitrate for the production of a drug for the treatment of angina, high blood pressure, pulmonary hypertension, congestive Heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, right heart failure, atherosclerosis, conditions of reduced cardiac patency, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors , renal insufficiency and liver cirrhosis.

32. Pharmaceutical formulation according to claim 31, containing at least one compound of the formula III according to claim 31, wherein

X represents R ⁴ substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN, phenyl or phenylmethyl.

33. Pharmaceutical formulation according to claim 31, containing at least one compound of the formula III according to claim 31, wherein

R ¹ and R ² together alkylene with 3-5 carbon atoms, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -0, X by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or

CN represents substituted R ⁴ , phenyl or phenylmethyl.

34. Pharmaceutical formulation according to claim 31, containing at least one compound of the formula l-il according to claim 31, wherein

R ¹ , R ² each independently H, A, OA or Hai,

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

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

CN represents substituted R ⁴ , phenyl or phenylmethyl.

35. Pharmaceutical formulation according to claim 31, containing at least one compound of the formula III according to claim 31, wherein

R ¹ , R ² each independently H, A, OA or Hai,

R ¹ and R ² together also include alkylene with 3-5 carbon atoms, -O-CH ₂ -CH ₂ -, -O-CH2-O- or

-O-CH ₂ -CH ₂ -O-,

X is alkylene simply 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,

Hai means F, Cl, Br or I.

36. Pharmaceutical formulation according to claim 31, containing at least one compound of formula III according to claim 31, wherein

R ¹ , R ² each independently H, A, OH, OA or Hai,

R ¹ and R ² together also include alkylene with 3-5 carbon atoms, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-, X is alkylene simply substituted by R ⁷ with 2-5 C-

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

A means alkyl with 1 to 6 carbon atoms, Hai F, Cl, Br or I.

37. Pharmaceutical formulation according to claim 31, containing at least one compound of formula III according to claim 31 selected from the group

(a) 3-[4-(3-chloro-4-methoxy-benzylamino)-benzo[4,5]thieno-[2,3-d]-pyrimidine-2-yrj-propionic acid;

(b) 4-[4-(3,4-methylenedioxy-benzylamino)-benzo[4,5]thieno-[2,3-d]-pyrimidin-2-yl]-butyric acid; (c) 7-[4-(3,4-methylenedioxy-benzylamino)-benzo[4,5]thieno-[2,3-dj-pyrimidin-2-ylj-heptanoic acid;

(d) 7-[4-(3-chloro-4-methoxy-benzylamino)-benzo[4,5]thieno-[2,3-d]-pyrimidin-2-yl]-heptanoic acid;

(e) 5-[4-(3-chloro-4-methoxy-benzylamino)-benzo[4,5]thieno-[2,3-d]-pyrimidin-2-yl]-valeric acid;

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

(g) 4-[4-(3,4-methylenedioxy-benzylamino)-benzo[4,5]thieno-[2,3-d]-pyrimidin-2-yl]-cyclohexanecarboxylic acid; (h) 4-[4-(3,4-methylenedioxy-benzylamino)-benzo[4,5]thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid; (i) 4-[4-(3,4-methylenedioxy-benzylamino)-benzo[4,5]thieno-[2,3-d]-pyrimidin-2-yl]-phenylacetic acid; (j) 4-[4-(3-Chloro-4-methoxybenzylamino)-benzothieno-[2,3-d]-pyrimidin-2-yl]-cyclohexanecarboxylic acid.

38. Pharmaceutical formulation according to claim 31, containing at least 4-[4-(3-chloro-4-methoxybenzylamino)-benzothieno-[2,3-d]-pyrimidin-2-yl]-cyclohexanecarboxylic acid, ethanolamine salt.

39. Pharmaceutical formulation according to claims 31 to 38, wherein the nitrate is selected from the group of pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di-, pentaerythrityl mononitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate.

40. Pharmaceutical formulation according to claim 39, wherein the nitrate means pentaerythrityl tetranitrate, isosorbide mononitrate, isosorbide dinitrate, glycerol trinitrate.

41. Pharmaceutical formulation according to claim 40, wherein the nitrate is pentaerythrityl tetranitrate.

42. Pharmaceutical formulation according to one of the preceding claims containing one or more carriers and/or auxiliary substances.

43. Pharmaceutical preparation according to one of claims 31 to 42 for the production of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and / or right heart failure.