DE10064992A1 - Drug formulation useful e.g. for treating angina or hypertension contains thieno (2,3-d) pyrimidine derivative phosphodiesterase V inhibitor and antithrombotic agent, calcium antagonist or prostaglandin, - Google Patents

Abstract

New pharmaceutical formulations contain a thieno (2,3-d) pyrimidine derivative PDE V inhibitor (I) and an antithrombotic agent (II), a calcium antagonist (III) or a prostaglandin or its derivative (IV). New pharmaceutical formulations contain at least one of thieno (2,3-d) pyrimidine derivative PDE V inhibitors of formula (I) and their salts and/or solvates, and at least one antithrombotic agent (II), calcium antagonist(s) (III) or prostaglandin(s) or their derivative(s) (IV). R1, R2 = H, A or hamn lo, but not both H; or R1 + R2 = 3-5C alkylene; R3, R4 = H, A, OH, OA or halo; or R3 + R4 = 3-5C alkylene, OCH2CH2, OCH2O or OCH2CH2O; X = R5 or R6, both monosubstituted by R7; R5 = 1-10C alkylene (optionally having one or two CH2 groups replaced by CH=CH) or -C6H4-(CH2)m-; R6 = 6-12C cycloalkylalkylene; R7 = COOH, COOA, CONH2, CONHA, CON(A)2 or CN; A = 1-6C alkyl; m = 1 or 2; and n = 0-3. Independent claims are also included for: (1) the use of 5-(4-(3-chloro-4-methoxy-benzylamino)-4,5,6,7-tetrahydro-(1)-benzothieno (2,3-d) pyrimidin-2-yl)-valeric acid (Ia) as the ethanolamine salt for the production of a medicament for treating pulmonary hypertension, congestive heart failure, chronic obstructive pulmonary disease, cor pulmonale and/or right cardiac insufficiency; and (2) kits including (Ia) ethanolamine salt and (II), (III) or (IV) in separate packaging.

Description

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

wherein
R ¹ , R ² each independently of one another H, A or Hal, 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 H, A, OH, OA or Hal,
R ³ and R ⁴ together also alkylene with 3-5 C atoms, -O-CH ₂ -CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-,
X is simply R ⁵ or R ⁵ substituted by R ⁷ ,
R ⁵ 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 -C ₆ H ₄ - (CH ₂ ) _m -,
R ⁶ cycloalkylalkylene with 6-12 C atoms,
R ⁷ COOH, COOA, CONH ₂ , CONHA, CON (A) or CN,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 or 2 and
n is 0, 1, 2 or 3,
and / or their physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative.

The invention further relates to the use of the formulation for Production of a drug 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 decreased Patency of the cardiovascular system, peripheral vascular diseases, Stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, Renal failure, cirrhosis, erectile dysfunction and Treatment of female sexual disorders.

Pharmaceutical formulations consisting of other phosphodi esterase V (PDE V) inhibitors together with a prostaglandin or Prostaglandin derivatives are in WO 00/15639 and WO 0015228 described.

The use of (other) phosphodiesterase IV or V inhibitors in Combination with a prostaglandin or prostaglandin derivative Local treatment for erectile dysfunction is in WO 9921558 described.

RT Schermuly et al. describe the therapeutic option in the American Journal of Respiratory and Critical Care Medicine, 160, 1500-6 (1999). Prostaglandin I ₂ (PGI ₂ ) in aerosol form with systemic PDE inhibitors, preferably dual-selective PDE III / IV inhibitors, to be used in low doses with acute and chronic pulmonary high pressure.

Pneumology (54, Suppl. 1, S42, 2000) is described by R. Schermuly et al. the Influence of PDE V inhibition on those induced by prostacyclin Vasorelaxation in experimental pulmonary hypertension described.  

The invention was based, new pharmaceuticals in the form of the task to provide pharmaceutical preparations, the better Properties as known, used for the same purposes bare drugs.

This task was solved by finding the new preparation.

The compounds of formula I and their salts show good Tolerance possess very valuable pharmacological properties. In particular, they show a specific inhibition of cGMP phospho diesterase (PDE V).

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

The biological activity of the compounds of formula I can according to Methods are determined, such as. B. described in WO 93/06104 are.

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).

Known methods can be used to carry out the determinations isolated enzymes can be used (e.g. W.J. Thompson et al., Biochem. 1971, 10, 311). A modified can be used to carry out the tests "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, especially heart failure and Treatment and / or therapy for erectile dysfunction Dysfunction).

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

The compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations of rabbits.

This biological effect can e.g. B. detected by the method by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993) is described.

The inhibition of 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 formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used. They can also be used as Intermediates for the production of other active pharmaceutical ingredients be set.

The compounds of formula I according to claim 1 and their salts are prepared by a process, characterized in that

• a) a compound of formula II
  wherein
  R ¹ , R ² 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 ³ , R ⁴ and n have the meanings given,
  implements,
  or
• b) in a compound of formula I one radical X into another Rest X converted by z. B. an ester group to a COOH Group hydrolyzed or a COOH group into an amide or into a Converts cyano group

and / or that a compound of formula I in one of its salts transferred.

Solvates of the compounds of the formula I include additions of inert solvent molecules to the compounds of formula I. understood that due to their mutual attraction form. Solvates are e.g. B. 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 I, II and III, unless expressly stated otherwise is specified.

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, further preferably isopropyl, butyl, isobutyl, sec-butyl or tert.- 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, preferably 1-8 carbon atoms, the alkylene radical preferably being, for. B. 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 z. B. but-2-en-ylene or hex-3-en-ylene.

R ⁶ denotes cycloalkylalkylene with 6-12 C atoms, preferably e.g. B. cycclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.

Of the radicals R ¹ and R ² , one is preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R ¹ and R ² together preferably also mean propylene, butylene or pentylene.

Hal is preferably F, Cl or Br, but also I.

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. As propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are preferably also each alkoxy, such as. B. for methoxy, ethoxy or propoxy.

The radical R ⁷ preferably means z. B. COOH, COOCH ₃ , COOC ₂ H ₅ , CONH ₂ , CON (CH ₃ ) ₂ , CONHCH ₃ or CN.

For the entire invention applies that all residues that occur multiple times kick, may be the same or different, d. H. independently of each other are.

The invention relates in particular to pharmaceutical formulations containing a prostaglandin or prostaglandin derivative 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 partial formulas Ia to Ie, 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 Ia
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 Hal, where at least one of the radicals R ¹ or R ^{2 is} always ≠ H,
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 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 Hal, where at least one of the radicals R ¹ or R ^{2 is} always ≠ H,
R ³ , R ⁴ each independently of one another H, A, OA or Hal,
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 is R ⁵ or R ⁶ substituted by COOH or COOA,
n represents 1 or 2;
in Id
R ¹ , R ² each independently of one another H, A or Hal, 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 H, A, OA or Hal,
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
-C ₆ H ₄ -CH ₂ -,
R ⁷ COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n represents 1 or 2;
in Ie
R ¹ , R ² each independently of one another H, A or Hal, 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 H, A, OH, OA or Hal,
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 -C ₆ H ₄ -CH ₂ -,
R ⁷ COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n is 1 or 2.

The invention preferably relates to a formulation  5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid and its physiological harmless salts and / or solvates and at least one prostaglandin or prostaglandin derivative.

In addition to the free acid, the ethanolamine salt is preferred.

Prostaglandins or prostaglandin derivatives are preferably selected from the group PGE ₀ , PGA ₁ , PGB ₁ , PGF _{1 α} , PGA ₂ , PGB ₂ , 19-hydroxy-PGA ₁ , 19-hydroxy-PGB ₁ , 19-hydroxy-PGA ₂ , 19 -Hydroxy-PGB ₂ , PGE ₃ , PGF _{3 α} , alprostadil (PGE ₁ ), dinoprost (PGF ₂ ), dinoprostone (PGE ₂ ), epoprostenol sodium (PGI ₂ ; prostacyclin sodium), gemeprost, iloprost, latanoprost, misoprostol, sulprostone , Carboprost thromethamine, dinoprost thromethamine, lipoprost, metenoprost, tiaprost.

In particular, prostaglandins or prostaglandin derivatives selected from the group alprostadil (PGE ₁ ), dinoprost (PGF ₂ ), dinoprostone (PGE ₂ ), epoprostenol sodium (PGI ₂ ; prostacyclin sodium), gemeprost, iloprost, latanoprost, misoprostol, sulprostone, carboprost thromethamine , Dinoprost thromethamine, lipoprost, metenoprost, tiaprost.

PGE or prostacyclin is particularly preferred, particularly preferred is prostacyclin.

The compounds of formula I and also the starting materials for their Production are otherwise made according to methods known per se as described in literature (e.g. in 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 implementations mentioned. It can one also of known variants not mentioned here in detail Make use.

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

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

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

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of 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 made using methods known per se getting produced.

Compounds of formula II can, for. B. be obtained 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 detail, the compounds of the formula II are reacted with the compounds of formula III in the presence or absence of a inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.

The addition of an acid-binding agent, for example an alkali or Alkaline earth metal hydroxides, carbonates or bicarbonates or one other weak acid salt 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 may be beneficial.  

Suitable inert solvents are, for. B. 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 mono methyl 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 dimethyl form amide (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 use a radical X in in a compound of the formula I. convert another radical X, e.g. B. by using an ester or hydrolyzed a cyano group to a COOH group.

Ester groups can e.g. B. with NaOH or KOH in water, water-THF or saponified water-dioxane at temperatures between 0 and 100 ° become.

Carboxylic acids can e.g. B. with thionyl chloride in the corresponding Carboxylic acid chlorides and these converted into carboxamides become. By dehydration in a known manner, one obtains from this carbonitrile.

An acid of formula I can with a base in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the acid and the base in an inert solvent such as ethanol and subsequent evaporation. For this implementation bases are particularly suitable, the physiologically harmless Deliver salts.

For example, the acid of formula I can be mixed with a base (e.g. sodium or Potassium hydroxide or carbonate) in the corresponding metal, ins special alkali metal or alkaline earth metal, or in the corresponding Ammonium salt can be converted.

Organic bases are particularly suitable for this implementation Question that provide physiologically acceptable salts, such as. B. ethanol  amine.

An acid of formula I can with a base in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the acid and the base in an inert solvent such as ethanol and subsequent evaporation. For this implementation bases are particularly suitable, the physiologically harmless Deliver salts.

For example, the acid of formula I can be mixed with a base (e.g. sodium or Potassium hydroxide or carbonate) in the corresponding metal, ins special alkali metal or alkaline earth metal, or in the corresponding Ammonium salt can be converted.

Organic bases are particularly suitable for this implementation Question that provide physiologically acceptable salts, such as. B. ethanol amine.

On the other hand, a base of formula I with an acid in the associated acid addition salt are transferred, for example by Implementation of equivalent amounts of the base and the acid in an inert Solvents such as ethanol and subsequent evaporation. For this Implementation include acids that are physiological deliver safe salts. So inorganic acids can be used be, e.g. B. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, esp special aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfone or sulfur acids, e.g. B. formic acid, acetic acid, propionic acid, pivalic acid, Diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumar 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 disulfone acids, lauryl sulfuric acid. Salts with physiologically not harmless union acids, e.g. B. picrates, can be used for isolation and / or purification of the compounds of formula I can be used.  

The invention further relates to pharmaceutical formulations containing at least one compound of formula I and / or one of them physiologically acceptable salts and at least one prostaglandin or prostaglandin derivative and containing one or more carrier and / or auxiliary substances.

The pharmaceutical preparations are manufactured especially by non-chemical means. Here the active ingredients together with at least one solid, liquid and / or semi-liquid Carrier or auxiliary are brought into a suitable dosage form.

These preparations can be used as medicinal products in human or Veterinary medicine can be used. Organic come as carriers or inorganic substances that are suitable for enteral (e.g. oral), parenteral or topical application and with the new Compounds do not react, e.g. water, vegetable oils, Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline. Tablets, pills, Dragees, capsules, powders, granules, syrups, juices or drops, for rectal application suppositories, for parenteral application solutions gene, preferably oily or aqueous solutions, further suspensions, Emulsions or implants, for topical use, ointments, creams or powder. The new compounds can also be lyophilized and the obtained lyophilisates z. B. for the production of injectables be used. The specified preparations can be sterilized be and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmo table pressure, buffer substances, color, taste and / or contain several other active ingredients, e.g. B. one or more vitamins. she can also be administered as nasal sprays.

The substances are usually preferably in doses between about 1 and 500 mg, in particular between 5 and 100 mg per Dosage unit administered. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. The special dose for  however, each patient depends on a variety of factors, for example on the effectiveness of the special used Connection, age, body weight, general health, Gender, the diet, the time and route of administration, the Elimination rate, drug combination and severity of respective disease to which the therapy applies. The oral application is prefers.

The invention therefore also relates to the use of the described benen pharmaceutical preparations 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 patency of the heart barrels, peripheral vascular diseases, stroke, bronchitis, all genetic asthma, chronic asthma, allergic rhinitis, glaucoma, Irritable Bowel Syndrome, tumors, renal failure, cirrhosis of the liver, erectile dysfunction and to treat female sexual disorders.

The invention relates in particular to the use of the Formulations according to the invention for the manufacture 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 invention further relates to the use of a pharmaceutical formulation containing at least one phosphodiesterase V inhibitors and at least one prostaglandin or one 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 ingredients of the new pharmaceutical preparation are preferably administered in combination. But you can also do it individually administered simultaneously or sequentially.  

The invention also relates to a 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] pyrimidin-2-yl] - valeric acid, ethanolamine salt

and

• a) an effective amount of a prostaglandin or prostaglandin derivative.

The set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can e.g. B. separate Contain 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 prostaglandin or prostaglandin derivative 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):
EI (electron impact ionization) M ⁺ ,
FAB (Fast Atom Bombardment) (M + H) ⁺

example 1

1.9 g 3- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-2-yl) - methyl propionate [obtainable by cyclization of 2-amino 4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid methyl ester with 3- Methyl 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 are obtained 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno Methyl [2,3-d] pyrimidin-2-yl] propionate as a colorless oil.

Analogously, by converting "A"
with methyl 3- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) propionate
3- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester;
with methyl 3- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionate;
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.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
with methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl) propionate;
3- [4- (3,4-methylenedioxy-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
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- (4- (3,4-methylenedioxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionate;
with methyl 3- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) propionate
Methyl 3- [4- (3,4-methylenedioxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionate.

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

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
with 4- (4-chloro-5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
Methyl 4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
with 4- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3,4-methylenedioxy-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- (3,4-methylenedioxy-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- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] 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] pyrimidin-2-yl) butyric acid methyl ester
4- [4- (3,4-Methylenedioxy-benzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] butyric acid methyl ester;
with 4- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) butyric acid methyl ester
Methyl 4- [4- (3,4-methylenedioxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyrate.

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
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclopenteno- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with methyl 5- (4-chloro-5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl)
Methyl 5- (4- (3-chloro-4-methoxy-benzylamino) -5,6-cyclohepteno [1] benzothieno [2,3-d] pyrimidin-2-yl] valerate;
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
5- [4- (3-chloro-4-methoxy-benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
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
Methyl 5- [4- (3-chloro-4-methoxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valerate.

An analogous reaction is obtained by reacting 3,4-methylenedioxybenzylamine
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;
with 5- (4-chloro-5,6-cyclopenteno [1] benzothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
Methyl 5- [4- (3,4-methylenedioxy-benzylamino) -5,6-cyclopenteno [1] 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- (3,4-methylenedioxy-benzylamino) -5,6-cyclohepteno- [1] - 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
Methyl 5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valerate;
with 5- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl ester
5- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid methyl ester;
with 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valeric 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
Methyl 5- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valerate.

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

An analogous reaction is obtained by reacting 3,4-methylenedioxybenziamine
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-Methylenedioxy-benzylamino) -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-Methylenedioxy-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- (3,4-Methylenedioxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-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-d] 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-Methylenedioxy-benzylamino) -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
Methyl 7- [4- (3,4-methylenedioxy-benzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] -heptanoate.

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

Example 2

2.2 g 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 in 20 ml Ethylene glycol monomethyl ether dissolved and after adding 10 ml 32% NaOH stirred at 110 ° for 5 hours. After adding 20% HCl is extracted with dichloromethane. Obtained by adding petroleum ether 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 with 0.5 g Ethanolamine added. After crystallization, 1.35 g of 3- [4- (3- Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] - pyrimidin-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-yl] 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-methoxybenzylamino) -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-dimethy (-thieno- [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] pyrimidin-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] pyrimidin-2-yl] valeric acid;
5- [4- (3-chloro-4-methoxy-benzylamino) -6-ethylthieno [2,3-d] 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-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno- [2,3-d] 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-methylenedioxybenzylamino) -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-yIJ-heptanoic acid, ethanolamine salt , F. 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-yl] 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-yl] heptanoic acid;
7- [4- (3,4-methylenedioxybenzylamino) -8,6,7,8-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] pyrimidin-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-Methylenedioxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidin-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-d] 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 Thionyl chloride is stirred in dichloromethane for 2 hours. The Solvent is removed to give 3- [4- (3-chloro-4-methoxy benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] - propionic acid.

It is transferred into aqueous ammonia, stirred for one hour and obtained usual work-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 in at 0 ° Acetonitrile dissolved. 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 added. It is stirred for an hour. To usual work-up gives 3- [4- (3-chloro-4-methoxy-benzylamino) - 5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-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-y] 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] pyrimidin-2-yl] valeric acid, F. 179 °;
5- [4- (3,4-dichlorobenzylamino) -5,6,7,8-tetrahydro- [1] benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt F 136 °;
5- [4- (3-chloro-4-isopropyloxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] valeric acid, Ethanolamine salt, mp 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 formula I, 100 g of Prostaglandins or prostaglandin derivatives and 5 g of disodium hydrogen phosphate is dissolved in 3 l of double distilled water with 2N hydrochloric acid pH adjusted 6.5, sterile filtered, filled into injection glasses, under sterile Conditions lyophilized and sealed sterile. Every 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 is melted 20 g of a prostaglandin or prostaglandin derivative with 100 g Soy lecithin and 1400 g cocoa butter, pour into molds and let 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, 1 g of a prostaglandin or prostaglandin derivative, 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 double distilled water. It is adjusted to pH 6.8, made up to 1 l 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 m g of one are mixed Prostaglandins or prostaglandin derivatives with 99.5 g of Vaseline under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of formula I, 1 kg of a prostaglandin or prostaglandin derivatives, 4 kg lactose, 1.2 kg potato starch, 0.2 kg Talc and 0.1 kg of magnesium stearate become tablets in the usual way pressed in such a way that each tablet contains 10 mg of each active ingredient.

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example G: capsules

2 kg of active ingredient of formula I and 2 kg of a prostaglandin or Prostaglandin derivatives are usually packaged in hard gelatin capsules filled so that each capsule contains 20 mg of each active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of formula I and 1 kg of a prostaglandin or prostaglandin derivatives in 60 liters of double distilled water 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 and 14 g of a prostaglandin or are dissolved Prostaglandin derivatives in 10 l isotonic NaCl solution and fills the Solution in standard spray jars with pump mechanism. The Solution can be sprayed into the mouth or nose. A spray (about 0.1 ml) corresponds to a dose of approximately 0.14 mg of each active ingredient.

Claims (16)

1. Pharmaceutical formulation containing at least one compound of the formula I.
wherein
R ¹ , R ² each independently of one another H, A or Hal, 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 H, A, OH, OA or Hal,
R ³ and R ⁴ together also 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 ⁵ 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 -C ₆ H ₄ - (CH ₂ ) m-,
R ⁶ 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,
Hal F, Cl, Br or I,
m 1 or 2 and
n 0, 1, 2 or 3
mean,
and / or their physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative. 2. Pharmaceutical formulation according to claim 2, comprising at least one compound of formula I according to claim 1, wherein
X represents R ⁵ or R ⁶ substituted by COOH or COOA;
and / or their physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative. 3. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1, wherein
R ¹ , R ² each independently of one another H, A or Hal, where at least one of the radicals R ¹ or R ^{2 is} always ≠ H,
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 is R ⁵ or R ⁶ substituted by COOH or COOA;
and / or their physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative. 4. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1, wherein
R ¹ , R ² each independently of one another H, A or Hal, where at least one of the radicals R ¹ or R ^{2 is} always ≠ H,
R ³ , R ⁴ each independently of one another H, A, OA or Hal,
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 is R ⁵ or R ⁶ substituted by COOH or COOA,
n represents 1 or 2;
and / or their physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative. 5. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula 1 according to claim 1, wherein
R ¹ , R ² each independently of one another H, A or Hal, 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 H, A, OA or Hal,
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 -C ₆ H ₄ -CH ₂ -,
R ⁷ COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n represents 1 or 2;
and / or their physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative. 6. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1, wherein
R ¹ , R ² each independently of one another H, A or Hal, 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 H, A, OH, OA or Hal,
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 -C ₆ H ₄ -CH ₂ -,
R ⁷ COOH or COOA,
A alkyl with 1 to 6 carbon atoms,
Hal F, Cl, Br or I,
m 1 and
n represents 1 or 2;
and / or their physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative. 7. Pharmaceutical formulation according to claim 1, comprising at least one compound of formula I according to claim 1 selected from the group

• a) 3- [4- (3-Chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] - propionic acid;
• b) 4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] butyric acid;
• c) 7- [4- (3,4-methylenedioxybenzylamino) -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;
• e) 5- (4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- [2,3-d] pyrimidin-2-yl] - valeric acid;
• f) 5- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
• g) 4- [4- (3-chloro-4-methoxy-benzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
• h) 4- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [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;
• j) 5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid and / or its physiologically acceptable salts and / or solvates and at least one prostaglandin or prostaglandin derivative.

8. A pharmaceutical formulation according to claim 1, containing at least 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 at least one prostaglandin or Prostaglandin. 9. Pharmaceutical formulation according to claims 1 to 8, wherein the prostaglandin or prostaglandin derivative is selected from the group alprostadil (PGE ₁ ), dinoprost (PGF ₂ ), dinoprostone (PGE ₂ ), epoprostenol sodium (PGI ₂ ; prostacyclin sodium), gemeprost , Iloprost, Latanoprost, Misoprostol, Sulprostone, Carboprost Thromethamine, Dinoprost Thromethamine, Lipoprost, Metenoprost, Tiaprost. 10. A pharmaceutical formulation according to claim 9, wherein the prostaglandin means PGE ₁ or prostacyclin. 11. A pharmaceutical formulation according to claim 10, wherein the Prostaglandin means prostacyclin. 12. Pharmaceutical formulation according to one of the preceding Claims containing one or more carrier and / or Excipients. 13. Use of a pharmaceutical preparation according to one of the Claims 1 to 12 for the manufacture of a medicament for treatment lung angina, high blood pressure, pulmonary hypertension, congesti vem heart failure (CHF), chronic obstructive pulmonary Disease (COPD), cor pulmonale, right heart failure, athero sclerosis, conditions of decreased patency of the heart barrels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, Glaucom, Irritable Bowel Syndrome, tumors, renal failure, Cirrhosis of the liver, erectile dysfunction and for the treatment of female Sexual disorders.   14. Use of a pharmaceutical preparation according to one of the Claims 1 to 12 for the manufacture of a medicament for treatment pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), Cor pulmonary and / or right heart failure. 15. Set (kit) consisting of separate packs of

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

and

• (a) an effective amount of a prostaglandin, or

Prostaglandin derivative. 16. Use of a pharmaceutical preparation containing at least one phosphodiesterase V inhibitor and at least one Prostaglandin or a prostaglandin derivative for the manufacture of a Medicinal product for oral treatment of pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and / or Right heart failure.