DE19944604A1 - Amine derivatives - Google Patents

Abstract

The invention relates to the amine derivatives of the formula (I), and to their physiologically acceptable salts and solvates, wherein R<1>, R<2>, R<8>, R<9>, R<10>, R<11>, 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

The invention relates to compounds of the formula I.

wherein
R ¹ , R ² each independently of one another H, A, OA, OH, Hal, 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 ,
YC 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 ⁵ (CH ₂ ) _n -R ¹² - (CH ₂ ) _m -R ⁷
R ⁶

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

R ⁸ H or A,
R ⁹ , R ¹⁰ , R ¹¹ each independently of one another H, A, OA, OH, Hal, 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,
Hal 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, Hal, 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, Hal, NO ₂ and / or CN can be replaced,
mean,
and their physiologically acceptable salts and solvates.

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

The invention was based on the object, new compounds with valuable len properties to find, especially those that are used to manufacture of drugs can be used.

It has been found that the compounds of formula I and their salts good tolerance very valuable pharmacological properties Zen.

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 be determined according to the method as used for. B. are described 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).

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 action and / or therapy of erectile 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) be is written.

The inhibition of the contraction shows the effectiveness of the Invention moderate connections for the therapy and / or treatment of erectile dysfunction stanchions.

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 invention accordingly relates to the compounds of the formula I and a process for the preparation of compounds of the formula I as well as their salts and solvates,
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 formula III

wherein
R ¹ , R ² , R ⁸ , Q and the ring C have the meanings given in claim 1,
implements
or
b) in a compound of formula I converts a radical X into another radical X by z. B. hydrolyses an ester group to a COOH group or converts a COOH group into an amide or into a cy 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 indicated meanings, unless expressly stated otherwise.

The compounds of formula I can have one or more chiral centers possess 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- Including derivatives, i. H. with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which in Or quickly to the active compounds according to the invention will split.

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 z. B. trifluoromethyl, pentafluoroethyl or -CCl ₂ -CF ₃ .

Ac means acyl with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably wise z. B. formyl, acetyl, propionyl, butyryl, also benzoyl.  

R ⁴ simply means linear or branched alkyl substituted with R ⁷ 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. Alkylene here preferably means a linear or branched alkylene radical having 1-10 C 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 means.

Alkylene also means z. B. but-2-en-ylene or hex-3-en-ylene.

Ethylene, propylene or butylene is very particularly preferred.

Q preferably denotes a linear or branched alkylene radical 1-10 carbon atoms, the alkylene radical preferably z. B. methylene, ethyl len, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1- Ethyl propylene, 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- methyl propylene, 1-ethyl-2-methyl propylene, 1,1,2- or 1,2,2-tri methyl propylene, linear or branched heptylene, octylene, nonylene or decylene means.

Ethylene, propylene or butylene is very particularly preferred.

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

Hal is preferably 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 mean in each case, independently of one another, H, A, OA, OH, shark, 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. But 1 or 2 carbon atoms must be replaced by nitrogen.

Ring B is preferably 1,4-phenylene, one or two times is substituted by A, OA, Hal and / or CN. Ring B also means egg NEN unsaturated heterocycle such. B. thiophene-2,5-diyl or pyrimidine 2,4-diyl or pyridine-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, Hal, 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 z. B. 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 such as indicated, it preferably means z. B. 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 means cyclopentylene or cyclohexylene, further z. B. 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 preferably 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 - Morpholinyl, 2,3-, 3,4- or 2,4-thiomorpholinyl.

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.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following partial formulas Ia to Id, 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 Ia ZN,
YC mean;
in Ib Z CH,
Mean YN;
in Ic R ⁸ denotes A;
in Id R ⁷ tetrazol-5-yl, SO ₂ NH ₂ ,

means;
in Ie 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 If R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
ZN,
YN,
R ⁸ 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
mean,
in Ig R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
n, m 0,
ZN,
YN,
R ⁸ H,
Q CH ₂ ,
R ¹ tetrazol-5-yl, SO ₂ NH ₂ ,

mean,
in Ih R ¹ , R ² each independently of one another H, A, OA, OH or Hal,
R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
XR ⁶ ,
ZN,
YN,
R ⁸ H,
Q CH ₂ ,
o, p each independently 1, 2 or 3,
mean and
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, Hal, NO ₂ and / or CN can be replaced,
in Ii R ¹ , R ² each independently of one another H, A, OA, OH or Hal,
R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
ZN,
YN,
XR ⁵ ,
R ⁸ H,
Q CH ₂ ,
n, m each independently of the other 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;
in Ik R ¹ , R ² each independently of one another H, A, OA, OH or Hal,
R ⁹ , R ¹⁰ _, R ¹¹ H,
r 0,
ZN,
YN,
XR ⁵ ,
R ⁸ H,
Q CH ₂ ,
R ⁷ tetrazol-5-yl, SO ₂ NH ₂ ,

R ⁸ H,
mean and
the ring C being phenyl;
in Il 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
mean and
the ring C being phenyl;
in Im R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
ZN,
YN,
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 ,
mean
and wherein the ring C is phenyl;
in In R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
n, m 0,
ZN,
YN,
R ⁸ H,
Q CH ₂ ,
R ⁷ tetrazol-5-yl, SO ₂ NH ₂ ,

XR ⁵ or R ⁶ ,
n 0, 1 or 2,
m 0, 1 or 2,
o 0, 1 or 2,
p 0, 1 or 2,
R ¹² cyclopentylene or cyclohexylene,
mean,
and wherein the ring B is 1,4-phenylene and the ring C is phenyl;
in Io R ¹ , R ² each independently of one another H, A, OA, OH or Hal,
R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
XR ⁵ or R ⁶ ,
ZN,
YN,
R ⁸ H,
Q CH ₂ ,
o, p each independently 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, Hal, NO ₂ and / or CN can be replaced
and wherein the ring C is phenyl;
in Ip R ¹ , R ² each independently of one another H, A, OA, OH or Hal,
R ⁹ , R ¹⁰ , R ¹¹ H,
r 0,
ZN,
YN,
XR ⁵ or R ⁶ ,
R ⁸ H,
Q CH ₂ ,
n, m each independently of the other 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 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, Hal, NO ₂ and / or CN can be replaced
and wherein the ring C is phenyl.

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by 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), be are written, namely under reaction conditions for the ge mentioned implementations are known and suitable. You can also do that use of known variants not mentioned here do.

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 indicated, in particular the preferred meanings given.

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 formula I can preferably be obtained in which one around compounds of formula II with compounds of formula III puts.

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 POCl ₃ from the corresponding hydroxypyrimidines, which are built up from thio phenderivates and CN-substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453 (1988)).

The hydroxypyrimidines are either represented by dehydration tion of corresponding tetrahydrobenzthienopyrimidine compounds or after the cyclization customary for the preparation of pyrimidine derivatives of 2-aminobenzthiophene-3-carboxylic acid derivatives with aldehydes or Nitriles (e.g. Houben Weyl E9b / 2).

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 another salt of a weak acid of the alkali or alkaline earth metals preferably of 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, Te trahydrofuran (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 in a compound of the formula I to have a radical X in an egg to convert another X, e.g. B. by using an ester or a Cyan group hydrolyzed 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 ° the.

Carboxylic acids can e.g. B. with thionyl chloride in the corresponding car acid chlorides and these are converted into carboxamides. By dehydration in a known manner, you get from this car bonitrile.

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 Men in particular bases, the physiologically acceptable salts deliver.

For example, the acid of formula I can be mixed with a base (e.g. sodium or potassium umhydroxid or carbonate) in the corresponding metal, in particular  Alkali metal or alkaline earth metal, or in the corresponding ammonium salt are 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 can be added to the acid addition salt are transferred, for example by conversion equivalent amounts of the base and the acid in an inert Lö solvent such as ethanol and subsequent evaporation. For this order Settling in particular acids that are physiologically unintended delivering saline salts. So you can use inorganic acids the, 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 he terocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malein acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfone acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. Picrates, can be used to isolate and / or purify the compounds of formula I can be used.

The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts Provision of pharmaceutical preparations, especially on non-chemical paths. Here you can together with at least one fe Most liquid and / or semi-liquid carrier or auxiliary and given if necessary in combination with one or more other active ingredients a suitable dosage form.  

The invention also relates to medicaments of the formula I and their physiologically acceptable salts as phosphodiesterase V inhibitors.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts.

These preparations can be used as medicinal products in human or veteri used in medicine. Organic or inorganic substances in question that are suitable for enteral (e.g. oral), parenteral or topical application and with the new compound not react, e.g. water, vegetable oils, benzylal alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets, Capsules, powder, granules, syrups, juices or drops, for rectal application suppositories, for parenteral application solutions preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application of ointments, creams or Powder. The new compounds can also be lyophilized and obtained NEN lyophilisates e.g. B. used for the preparation of injectables become. The specified preparations can be sterilized and / or Auxiliaries such as lubricants, preservatives, stabilizers and / or Netzmit tel, emulsifiers, salts to influence the osmotic pressure, Buffer substances, color, taste and / or several other active ingredients contain substances, e.g. B. one or more vitamins.

The compounds of formula I and their physiologically acceptable Salts can be used in the fight against diseases in which an Er cGMP (cyclo-guanosine monophosphate) level increased to Ent leads to ignition inhibition or prevention and muscle relaxation, be used.

The invention also relates to the use of the compounds of Formula I and their physiologically acceptable salts and / or sol  vate for the manufacture of a medicament for the treatment of angina, blood high pressure, pulmonary high pressure, congestive heart failure, Atherosclerosis, conditions of decreased cardiac patency ß, peripheral vascular diseases, stroke, bronchitis, allergy schem asthma, chronic asthma, allergic rhinitis, Glaucom, Irri Bowel syndromes, tumors, renal failure, cirrhosis and for the treatment of male and female impotence.

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 connection used, on age, body weight, general health, gender, of the food, the time and route of administration, the excretion application rate, drug combination and severity of each 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, and 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 off and dried the 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

Methyl 3- (4-chloro-benzothieno [2,3-d] pyrimidin-2-yl) propionate [obtainable by cyclization of methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylic acid with 3 Cyanopropionic acid methyl ester, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxichloride / 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

3- {4- [3- (4-Sulfamoylphenyl) butylamino] benzo [4,5] thieno [2,3-d] pyrimidine- 2-yl} propionic acid methyl ester is ge in ethylene glycol monomethyl ether dissolves and after addition of 32% NaOH stirred at 110 ° for 5 hours. After adding 20% HCl, the mixture is extracted with dichloromethane. By The addition of petroleum ether gives 3- {4- [3- (4-sulfamoyl-phenyl) - butylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl} propionic acid.

The precipitated crystals are dissolved in isopropanol and with ethano lamin offset. After crystallization, 3- [4- (3-chloro-4-methoxy benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid, ethanol min salt.

The following compounds are obtained analogously
3- (4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-b] pyridin-2-yl) 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-methoxybenzylamino) benzo [4,5] thieno [2,3-b] pyridin-2-yl] cyclohexanesulfonamide;
3- {4- [4- (3-Chloro-4-methoxy-benzylamino) benzo [4,5] 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] pyrimidin-2-ylmethyl] phenyl} acetic acid;
3- {6- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-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-methoxybenzyl) - [2- (2- {4- [2- (1H-tetrazol-5-yl) ethyl] piperazin-1-yl} ethyl) benzo [4 , 5] thieno [2,3-d] pyrimidin-4-yl] amine;
3- (4- {2- [4- (3-chloro-4-methoxy-benzylamino) -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 Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection 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 soy lecithin and 1400 g cocoa butter, pour into molds and leave cold. 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 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 of 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 are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active ingredient of formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.  

Example F Dragees

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 are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

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

example 1 Inhalation spray

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

Claims (9)

1. Compounds of formula I.
wherein
R ¹ , R ² each independently of one another H, A, OA, OH, Hal, 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 ,
YC 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 ⁵ - (CH ₂ ) _n -R ¹² (CH ₂ ) _m -R ⁷ ,
R ⁶
R ⁷ COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ , CN, tetrazol-5-yl, SO ₂ NH ₂ ,
R ⁸ H or A,
R ⁹ , R ¹⁰ , R ¹¹ each independently of one another H, A, OA, OH, Hal, 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,
Hal 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, Hal, 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, Hal, 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] pyridin-3-yl} propionic acid;
• c) 3- {4 - [(3-chloro-4-methoxybenzyl) methylamino] benzo [4,5] thieno (2,3-d] pyrimidin-2-yl} propionic acid;
• d) 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-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-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-methoxybenzylamino) -9-thia-1,3,7-triaza fluoren-2-yl] ethylj-cyclohexyl) propionic acid;
• k) methyl 4- {3- [2- (4-carboxy-cyclohexyl) -9-thia-1,3,7-triaza-fluoren-4-ylamino] -1-methyl-propyl} benzoate;

and their physiologically acceptable salts and solvates. 3. Process for the preparation of compounds of the formula I according to claim 1 and their salts and solvates,
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 formula III
wherein
R ¹ , R ² , R ⁸ , Q and the ring C have the meanings given in claim 1,
implements
or
b) in a compound of formula I converts a radical X into another radical X by z. B. hydrolyzed an ester group to a COOH group or converted a COOH group to an amide or a cyano group
and / or converting a compound of formula I into one of its salts. 4. Process for the preparation of pharmaceutical preparations, thereby characterized in that a compound of formula I according to An saying 1 and / or one of their physiologically acceptable salts together with at least one solid, liquid or semi liquid carrier or auxiliary in a suitable dosage form brings. 5. Pharmaceutical preparation, characterized by a content at least one compound of formula I according to claim 1 and / or one of their physiologically acceptable salts. 6. Compounds of formula I according to claim 1 and their physiological harmless salts to combat diseases of the heart Circulatory system and for the treatment and / or therapy of Erectile dysfunction. 7. Medicament of formula I according to claim 1 and their physiologically un questionable salts as phosphodiesterase V inhibitors. 8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a Drug. Use of compounds of formula I according to claim 1 and I or their physiologically acceptable salts for the production of a Medicinal product for the treatment of angina, high blood pressure, pulmona high pressure, congestive heart failure, atherosclerosis, bedin reduced patency of the cardiovascular, peripheral vascular diseases, stroke, bronchitis, allergic asthma ma, chronic asthma, allergic rhinitis, glaucoma, irritable Bowel syndromes, tumors, renal failure, cirrhosis and Treatment of male and female impotence.