WO2001021620A2

WO2001021620A2 - Amine derivatives of benzo-4,5-thieno-2,3-d pyrimidines

Info

Publication number: WO2001021620A2
Application number: PCT/EP2000/008256
Authority: WO
Inventors: Volker Eiermann; Rochus Jonas
Original assignee: Merck Patent Gmbh
Priority date: 1999-09-17
Filing date: 2000-08-24
Publication date: 2001-03-29
Also published as: DE19944604A1; NO20021310D0; BR0014052A; AU7412700A; EP1212329A2; PL353319A1; WO2001021620A3; KR20020027652A; NO20021310L; CZ2002817A3; JP2003509511A; CA2387520A1

Abstract

The invention relates to the amine derivatives of the formula (I), and to their physiologically acceptable salts and solvates, wherein R?1, R2, R8, R9, R10, R11¿, Q, X, Y, Z, r, ring A and ring C have the meaning indicated in claim 1. The inventive derivatives are characterized by a phosphodiesterase-V inhibiting effect and are used for treating diseases of the cardiovascular system and for the treatment and/or the therapy of potency disorders.

Description

amine derivatives

The invention relates to compounds of the formula I.

wherein

R ¹ , R ² each independently of one another H, A, OA, OH, Hai, SH,

SA, SOA, SO ₂ A, SO ₂ NH ₂ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH,

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-,

XR ⁴ , R ⁵ or R ⁶ ,

Y C or N,

z CH or N,

Q is a linear or branched alkylene chain with 1-10 C-

Atoms, R ⁴ linear or branched simply substituted by R ⁷

Alkylene with 1-10 C atoms, in which one, two or three CH ₂ groups can be replaced by -CH = CH and / or -C≡C groups, R ⁼ - (CH ₂ ) _n -R ¹² - (CH ₂ ) _m -R ⁷ ,

R ⁷ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ , CN, tetrazol-5-yl, SO ₂ NH ₂ ,

^ ^N ) ^

\ / or N-S N-

^H o ^H O

R ⁸ H or A,

R ⁹ , R ¹⁰ , R ¹ each independently of one another H, A, OA, OH, Hai, SH, SA, SOA, SO ₂ A, NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH,

A alkyl with 1 to 10 C atoms, where 1-7 H atoms can be replaced by F and / or Cl,

Ac acyl with 1-10 C atoms,

R ¹² cycloalkylene with 4-7 C atoms, in which one or two CH ₂ -

Groups can be replaced by N, O and / or S,

Shark F, Cl, Br or I,

n, m, o, p each independently 0, 1, 2, 3, 4, 5 or 6, r 0, 1 or 2,

in ring A one or two carbon atoms can be replaced by N,

wherein the ring B is an unsaturated 5- or 6-membered ring and one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms by A, OA, shark, NO ₂ and / or CN can be replaced,

wherein the ring C is a saturated or unsaturated 5- or 6-membered ring and one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms by A, OA, Shark, NO ₂ and / or CN can be replaced,

mean,

and their physiologically acceptable salts and solvates.

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

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

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

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

Quinazolines with cGMP phosphodiesterase inhibitory activity are described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994). The biological activity of the compounds of the formula I can be determined by methods 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 e.g. described 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. Urol., 150, 1310-1315 (1993). The inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.

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

Intermediates are used to manufacture other active pharmaceutical ingredients.

The invention accordingly relates to the compounds of the formula I and a process for their preparation of compounds of formula I according to claim 1 and their salts and Solvateπ,

characterized in that one

a) a compound of formula II

wherein

X, Y, Z, R ⁹ , R ¹⁰ , R ¹¹ , r and the ring A have the meanings given in claim 1,

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

with a compound of the formula

R ¹

K

wherein

R ¹ , R ² , R ⁸ , Q and the ring C have the meanings given in claim 1,

implements, or

b) converting a radical X into another radical X in a compound of the formula I, for example by an ester group to a COOH

Group hydrolyzed or converted a COOH group into an amide or a cyan group

and / or converting a compound of formula I into one of its salts.

Above and below, the radicals R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , r, Q, X, Y, Z and L and the rings A and C have the formulas I, II and III meanings, unless expressly stated otherwise.

The compounds of formula I can have one or more chiral centers and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula I.

So-called prodrug derivatives are also included in the compounds according to the invention, i. H. with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.

A means alkyl with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 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. A also means, for example, trifluoromethyl, pentafluoroethyl or -CCI ₂ -CF ₃ .

Ac means acyl with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably, for example, formyl, acetyl, propionyl, butyryl, and also benzoyl. R ⁴ simply means linear or branched alkylene with 1-10 C atoms substituted by R ⁷ , in which one, two or three CH ₂ groups can be replaced by - CH = CH and / or -C≡C groups. Alkylene here preferably means 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 means.

Alkylene also means e.g. But-2-en-ylene or Hex-3-en-ylene. Ethylene, propylene or butylene is very particularly preferred.

Q is preferably a linear or branched alkylene radical having 1-10 C atoms, the alkylene radical preferably being e.g. 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. Ethylene, propylene or butylene is very particularly preferred.

R ⁵ denotes cycloalkylene with 4-7 C atoms, preferably for example cyclopentylene or cyclohexylene. One or two CH ₂ groups can also be replaced by N, O and / or S therein. R ⁵ therefore also means, for example, 1,4-piperidinyl or 1,4-piperazinyl.

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, A, OA, OH, Hai, SH, SA, SOA, SO ₂ A, SO ₂ NH ₂ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH.

Ring A preferably contains no hetero atom. However, 1 or 2 carbon atoms can be replaced by nitrogen.

The ring B is preferably 1, 4-phenylene which is mono- or disubstituted by A, OA, shark and / or CN. Ring B also means an unsaturated heterocycle such as e.g. Thiophene-2,5-diyl or pyrimidine-2,4-diyl or pyhdin-2,6-diyl.

Ring C denotes a saturated or unsaturated 5- or 6-membered ring in which one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms can be replaced by A, OA, shark, NO ₂ and / or CN can be replaced.

If the ring C is unsaturated and contains one or more heteroatoms as indicated, it preferably means e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5 -yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol- 2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5 - or 6- 2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl or pyrazinyl.

If the ring C is saturated and contains one or more heteroatoms as indicated, it preferably means, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2- , -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, - 4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-dihydro-1-, - 2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3 -, -4-, -5- or -6- pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro- 2-, -3- or -4- pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4- or -5-yl, hexahy- dro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-

, 2- or 3-piperazinyl.

The ring C very particularly preferably denotes phenyl.

R ¹² denotes cycloalkylene with 4, 5, 6 or 7 carbon atoms, in which one or two CH ₂ groups can be replaced by N, O and / or S. R ¹² preferably denotes cyclopentylene or cyclohexylene, furthermore, for example, also 1, 2-, 2,3- or 1, 3-pyrrolidinyl, 1, 2-, 2,4-, 4,5- or 1, 5-imidazolidinyl, 1, 2-, 2,3-, or 1, 3-pyrazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-oxazolidinyl, 1, 2-, 2,3-, 3,4- or 1, 4- isoxazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-thiazolidinyl, 2,3-,

3,4-, 4,5- or 2,5-isothiazolidinyl, 1, 2-, 2,3-, 3,4- or 1, 4-piperidinyl, 1, 4- or 1, 2-piperazinyl, further preferred 1, 2,3-tetrahydro-triazol-1, 2- or -1, 4-yl, 1, 2,4-tetrahydro-triazol-1, 2- or 3, 5-yl, 1, 2- or 2, 5-tetrahydro-tetrazolyl, 1, 2,3-tetrahydro-oxadiazol-2,3-, -3,4-, -4,5- or -1, 5-yl, 1, 2,4-tetrahydro-oxadiazol- 2,3-, -3,4- or -4, 5-yl, 1, 3,4-tetrahydro-thiadiazol- 2,3-, -3,4-, -4,5- or -1, 5- yl, 1, 2,4-tetrahydro-thiadiazol-2,3-, -3,4-, -4,5- or -1, 5-yl, 1, 2,3-thiadiazol-2,3-, - 3,4-, -4,5- or -1, 5-yl, 2,3- or 3,4-morpholinyi, 2,3-, 3,4- or 2,4-thiomorpholinyl.

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

Accordingly, the invention relates in particular to those compounds 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 Ip, which correspond to the formula I and in which the radicals which are not specified have the meaning given for the formula I, but in which

in la z N,

Y is C;

in lb z CH,

Mean YN; in Ic R ⁸ denotes A;

in Id R ⁷ tetrazol-5-yl, SO ₂ NH ₂ ,

means;

in le R ¹ , R ² each independently of one another SH, SA, SOA, SO ₂ A,

SO ₂ NH ₂ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH,

in If R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

Z N,

Y N,

R ⁸ H,

Q CH ₂ ,

R ¹ , R ² each independently mean SH, SA, SOA, SO ₂ A, SO ₂ NH ₂ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH,

in Ig R ⁹ , R ¹⁰ , R ¹¹ H, ro, n, mo,

ZN, YN,

R ⁸ H,

Q CH ₂ ,

R ⁷ tetrazol-5- -yl, SO ₂ NH ₂ ,

mean,

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

R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

XR ⁶ ,

Z N,

Y N,

R ⁸ H,

Q CH ₂ , o, P each independently 1, 2 or 3,

mean and

in R ¹ , R ² each independently of one another H, A, OA, OH or shark, R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

Z N,

YN, XR ⁵ ,

R ⁸ H,

Q CH ₂ , n, m each independently of one another 1, 2 or 3,

R ¹² cyclopentylene or cyclohexylene, in which one or two CH ₂ groups have been replaced by N, O and / or S,

mean;

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

R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

Z N,

Y N,

XR ⁵ ,

R ⁸ H,

Q CH ₂ ,

R ⁷ tetrazol-5-yl, SO ₂ NH ₂ ,

^RÖ H, mean and wherein the ring C is phenyl;

in II R ¹ , R ² each independently of one another SH, SA, SOA, SO ₂ A,

SO ₂ NH ₂ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH,

XR is ⁵ and the ring C is phenyl;

in Im R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

Z N,

Y N,

R ⁸ H,

R ¹² H,

Q CH ₂ ,

R ¹ , R ² each independently of one another SH, SA, SOA, SO ₂ A, SO ₂ NH ₂ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc CN, COOA or COOH,

XR ⁵ , and wherein the ring C is phenyl;

in In R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

Z N,

Y N,

R ⁸ H,

Q CH ₂ ,

R ⁷ tetrazol-5-yl, SO ₂ NH ₂ ,

XR ⁵ or R ⁵ , n 0, 1 or 2, m 0, 1 or 2,

0 0, 1 or 2,

P 0, 1 or 2,

R ^{12 is} cyclopentylene or cyclohexylene, and where the ring B is 1, 4-phenylene and the ring C is phenyl,

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

R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

XR ⁵ or R ⁶ , z N,

Y N,

R ⁸ H,

Q CH ₂ , o, p each independently represent 1, 2 or 3, and

wherein the ring B is an unsaturated 5- or 6-membered ring and a C atom is replaced by N, O or S, and wherein one, two or three H atoms by A, OA, shark, NO ₂ and / or CN can be replaced

and where the ring C is phenyl, in Ip R ¹ , R ² each independently of one another H, A, OA, OH or Hai, R ⁹ , R ¹⁰ , R ¹¹ H, r 0,

Z N,

Y N,

XR ⁵ or R ⁶ ,

R ⁸ H, Q CH ₂ , n, m each independently of one another 1, 2 or 3,

mean and

wherein ring B is an unsaturated 5- or 6-membered ring and a C atom is replaced by N, O or S, and wherein one, two or three H atoms are replaced by A, OA, shark, NO ₂ and / or CN can be replaced

and wherein the ring C is phenyl.

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) , are described, namely under reaction conditions which 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, X, Y, Z, R ⁹ , R ¹⁰ , R ¹¹ , r and the ring A, R ¹ , R ² , R ⁸ , Q and the ring C have the meanings given, in particular the given preferred 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, 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, for example, by reaction with POCI ₃ from the corresponding hydroxypyrimidines which are built up from thiophene derivatives and CN-substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453 (1988)).

The hydroxypyrimidines are prepared either by dehydration of corresponding tetrahydrobenzthienopyrimidine compounds or by the cyclization of 2-aminobenzthiophene-3-carboxylic acid derivatives with aldehydes or nitriles (e.g. Houben Weyl E9b / 2), which is customary for the preparation of pyrimidine derivatives.

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 one organic base such as T ethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as

Trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

It is also possible to convert one radical X into another radical X in a compound of formula I, e.g. by 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 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. So the acid of formula I with a base (eg sodium or potassium hydroxide or carbonate) in the corresponding metal, in particular 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.

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

The invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the preparation of pharmaceutical preparations, in particular by a non-chemical route. Here, they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients. The invention also relates to medicaments of the formula I and their physiologically acceptable salts as phosphodiesterase V inhibitors

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts

These preparations can be used as pharmaceuticals in human or veterinary medicine. Suitable carrier substances 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, Glycenntπacetat, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline rectal application Suppositons, for parenteral application solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application ointments, creams or powders The new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the preparation of injection preparations The specified NEN preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, for example a or more vitamins

The compounds of the formula I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation

The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts and / or sol- vate for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome , Tumors, renal failure, cirrhosis of the liver and for the treatment of male and female impotence.

The substances are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a 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.

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_ (4-chloro-benzothieno [2,3-d] pyrimidin-2-yl) propionic acid methyl ester [obtainable by cyclization of methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylic acid with 3 -Cyanopropionic acid methyl ester, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxichloπ ^' d / dimethylamine] and 4- (3-amino-1-methyl-propyl) -benzenesulfonamide in N-methylpyrrolidone are stirred at 110 ° for 5 hours. The solvent is removed and worked up as usual. 3- {4- [3- (4-Sulfamoylphenyl) butylamino] benzo [4,5] thieno [2,3-d] pyrimidin-2-yl} propionic acid methyl ester is obtained

Example 2

Methyl 3- {4- [3- (4-sulfamoylphenyl) butylamino] benzo [4,5] thieno [2,3-d] pyrimidin-2-yl} propionate is dissolved in ethylene glycol monomethyl ether and after addition of 32 % NaOH stirred at 110 ° for 5 hours. After adding 20% HCl, the mixture is extracted with dichloromethane. By adding petroleum ether, 3- {4- [3- (4-sulfamoylphenyl) butylamino] benzo [4,5] thieno [2,3-d] pyhmidin-2-yl} propionic acid is obtained.

The precipitated crystals are dissolved in isopropanol and mixed with ethanol laminate. After crystallization, 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid, ethanolamine salt is obtained.

The following compounds are obtained analogously

3- [4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-b] pyridin-2-ylj-propionic acid; 3- {1 - [(Benzo [1,3] dioxol-5-ylmethyl) amino] benzo [4,5] thieno [3,2-c] pyridin-3-yl} propionic acid;

3- {4 - [(3-chloro-4-methoxybenzyl) methylamino] benzo [4,5] thieno [2,3-d] pyrimidin-2-yl} propionic acid;

4- [4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-b] pyridin-2-yl] cyclohexanesulfonamide;

3- {4- [4- (3-Chloro-4-methoxy-benzylamino) benzo [4 _I 5] thieno [2,3-b] pyridin-2-yl] cyclohexyl} -4H- [1,2 , 4] thiadiazol-5-one;

{4- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyhmidin-2-ylmethyl] phenyl} acetic acid;

3- {6- [4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-d] pyamin-2-ylmethyl] pyridin-2-yl} propionic acid ;

3- {1- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-ylmethyl] piperidin-4-yl} propionic acid;

(3-chloro-4-methoxy-benzyl) - [2- (2- {4- [2- (1 H-tetrazol-5-yl) ethyl] piperazin-1-yl} ethyl) -benπzo [ 4,5] thieno [2,3-d] pyrimidin-4-yl] -amine;

3- (4- {2- [4- (3-chloro-4-methoxybenzylamino) -9-thia-1, 3,7-triaza-fluoren-2-yl] ethyl} cyclohexyl) propionic acid;

Methyl 4- {3- [2- (4-carboxy-cyclohexyl) -9-thia-1, 3,7-triaza-fluoren-4-ylamino] -1-methyl-propyl} -benzoate. The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

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

Example B: Suppositories

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

Example C: solution

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

NaH ₂ P0 ₄ • 2 H ₂ O, 28.48 g 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 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

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

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. Example F: coated tablets

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

Example G: capsules

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

Example H: ampoules

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

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

Example I: Inhalation spray

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

Claims

claims

1. Compounds of formula I.

R ¹

wherein

R ¹ , R ² each independently of one another H, A, OA, OH, Hai, SH, SA, SOA, SO ₂ A, SO ₂ NH ₂ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH,

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

XR ⁴ R ⁵ or R ⁶ ,

Y C or N,

Z CH or N,

Q is a linear or branched alkylene chain with 1-10 C-

atoms,

R ⁴ linear or branched alkylene with 1-10 C atoms, which is simply substituted by R ⁷ , in which one, two or three CH ₂ groups can be replaced by -CH = CH and / or -C≡C groups,

R- - (CH ₂ ) _n -R ¹² - (CH ₂ ) _m -R ⁷ ,

R ^e - (CH ₂ ) ₀ - _B V (CH ₂ ) _P -R ⁷ ,

R ⁷ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ , CN, tetrazol-5-yl, S0 ₂ NH ₂ ,

R ^ö H or A,

R ⁹ , R ¹⁰ , R ¹¹ each independently of one another H, A, OA, OH, Hai, SH, SA, SOA, S0 ₂ A, NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN,

COOA or COOH,

Ac acyl with 1-10 C atoms,

R ¹² cycloalkylene with 4-7 C atoms, in which one or two CH ₂ -

Groups can be replaced by N, O and / or S,

Shark F, Cl, Br or I, n, m, o, p each independently 0, 1, 2, 3, 4, 5 or 6,

r 0, 1 or 2,

in ring A one or two carbon atoms can be replaced by N,

wherein the ring C is a saturated or unsaturated 5- or 6-membered ring and one or two C atoms can be replaced by N, O and / or S, and in which one, two or three H atoms are replaced by A,

OA, Hai, NO ₂ and / or CN can be replaced,

mean,

and their physiologically acceptable salts and solvates.

2. Compounds of formula I according to claim 1

(a) 3- [4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-b] pyridin-2-yl] propionic acid;

(b) 3- {1 - [(Benzo [1, 3] dioxol-5-ylmethyl) amino] benzo [4,5] thieno [3,2-c] pyhdin-3-yl} propionic acid;

(c) 3- {4 - [(3-chloro-4-methoxybenzyl) methylamino] benzo [4,5] thieno [2,3-d] pyrimidin-2-yl} propionic acid;

(<j) 4- [4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-b] pyridin-2-yl] cyclohexanesulfonamide; (e) 3- {4- [4- (3-Chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,

3- b] pyridin-2-yl] cyclohexyl} -4H- [1, 2,

4] thiadiazol-5-one;

(f) {4- [4- (3-Chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-ylmethyl] phenyl} acetic acid;

(g) 3- {6- [4- (3-Chloro-4-methoxy-benzylamino) -benzo [4,5] thieno [2,3-d] pyrimidin-2-ylmethyl] pyridin-2-yl} propionic acid;

(h) 3- {1- [4- (3-chloro-4-methoxy-benzylamino) -benzo [4,5] thieno [2,3-d] pyhmidin-2-ylmethyl] piperidin-4-yl} propionic acid;

(i) (3-chloro-4-methoxy-benzyl) - [2- (2- {4- [2- (1 H-tetrazol-5-yl) ethyl] - piperazin-1-yl} ethyl) -benzo [4,5] thieno [2,3-d] pyrimidin-4-yl] amine;

(j) 3- (4- {2- [4- (3-chloro-4-methoxy-benzylamino) -9-thia-1, 3,7-triaza-fluoren-2-yl] ethyl} cyclohexyl) propionic acid;

(k) 4- {3- [2- (4-Carboxy-cyclohexyl) -9-thia-1, 3,7-triaza-fluoren-4-ylamino] -1-methyl-propyl} benzoic acid methyl ester;

and their physiologically acceptable salts and solvates.

Process for the preparation of compounds of formula I according to claim 1 and their salts and solvates

characterized in that one

a) a compound of formula II

embedded image in which

X, Y, Z, R ⁹ , R ⁰ , R ¹ , r and the ring A have the meanings given in claim 1,

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

with a combination of shapes! II!

R ¹

wherein

R ¹ , R ² , R ⁸ , Q and the ring C have the meanings given in claim 1,

implements,

or

b) converting a radical X into another radical X in a compound of the formula I, for example by 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.

, Process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and / or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary.

5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts.

6. Compounds of formula I according to claim 1 and their physiologically acceptable salts for combating diseases of the cardiovascular system and for the treatment and / or therapy of erectile dysfunction.

7. Medicament of formula I according to claim 1 and their physiologically acceptable salts as phosphodiesterase V inhibitors.

8. Use of compounds of formula I according to claim 1 and / - or their physiologically acceptable salts for the manufacture of a medicament.

9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a

Medicinal product for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced cardiac patency, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable

Bowel syndromes, tumors, renal failure, cirrhosis of the liver and for the treatment of male and female impotence.