CZ2002817A3 - Amine derivative - 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

(57)

The amine derivative of formula I wherein R ^1, R ² independently denote H, A, OA, OH, Hal, SH, SA, SOA, SO2A, SO2NH2, NO2, NHA, NA2, Ac, NHAc, CN, COOA or COOH; R ¹ and R ² together are also C3. ₅ alkylene, -OCH ₂ -CH ₂ -, -CH ₂ -O-CH ₂ -, -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O-; X is R ^4, R ⁵ or R ^6; YC or N; Z is CH or N; Q linear or branched C 1-10 alkylene; R ⁴ one R ⁷ substituted linear or branched C .10alkylen, wherein optionally 1, 2 or 3 -CH ₂ - replaced by -CH = CH- and / or -C = C-; R ⁵ - (CH 2) n -R ¹² , (CH 2) _r -R ⁷ ; R ⁶ is (CH 2) n -B- (CH 3) n R ⁷ ; R ⁷ is COOH, COOA, CONHA, CON (A) 2 or CN, tetrazolyl-5-yl, SO ₂ NH ₂ , groups (a); R ⁸ is H or A; R ^9, R ^10, R ¹¹ 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; AC, 10alkyl, optionally substituted with 1 to 7 H atoms by F and / or Cl; Ac C1-10acyl; R ¹² C4. ₇ cycloalkylene wherein optionally 1 or 2 CH _{2 is} replaced by N, O and / or S; Hal is F, Cl, Br or J and n, m, o, p are independently 0, 1, 2, 3, 4, 5 or 6; 0.1 or 2 and its physiologically acceptable salts and solvates exhibit inhibition of phosphodiesterase and can be used to treat circulatory diseases and to treat and / or treat potency disorders.

(and)

TO.

K, fa) ·· • 9 • 99

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 * 9

01-361-02-Ma

Amine derivative

Technical field

The invention relates to amine derivatives of the general formula I

where it means

R ^1, R ² independently are hydrogen, A, 0A, OH, Hal, SH, SA, SOA, SO ₃ A, SO2NH2. NO ₂ , NH ₂ , NHA, NA ₂ , Ac, NHAc, CN, COOA or COOH,

R @ ¹ and R @ ² together are also C3 -C5 alkylene, -O-CH2-CH2-, -CH2-O-CH2-, -O-CH3-O- or

-O-CH2-CH2-O-

X is R ^4, or R ^a R ^b,

Y C or N,

From CH or N,

A linear or branched alkylene group having 1 to 1 carbon atoms, 9 9 9 9 9

9 9 9 9 9 ‘999 ·} ··· ··············

R ⁴ one R ⁷ substituted linear or branched alkylene group having 1 to 10 carbon atoms wherein optionally one or two or three _CH2 groups are replaced by -CH-CH- and / or -C≡C-,

R 5 - (CH ₂ ) _n -R ¹² - (CH ₂ ) m R ⁷ ,

R ° group '(CH ₂ ) _O - (CH ₂ ) _p -R',

R ⁷ is COOH. COOA, CONH ₂ . CONHA. CON (A) ₂ or CN, tetrazolyl-5-y1, SO2NH3,

R ⁸ is hydrogen or A,

R @ ³ , R @ ^{1, J.} R ( ¹¹⁾ independently of one another is H, A, O, OH,

Hal, SH, SA, SOA, SO3A. NO ₂ , HH 3. MHA. NA ₂ , Ac, NHAc, CH, COOA or COOH.

A is an alkyl group having 1 to 10 carbon atoms, wherein, in the case of 1 to 7 hydrogen atoms, it is replaced by a fluorine and / or chlorine atom

C 1 -C 10 acyl.

a C12-C7 cycloalkylene group, optionally with one or two CH2 groups being replaced by a nitrogen, oxygen and / or sulfur atom;

Hal is fluorine, chlorine, bromine or iodine and n, m, o, p independently of one another 0, 1, 2, 3, 4, 5 or 6, r 0, 1 or 2, optionally in ring A having one or two atoms is replaced by a nitrogen atom, ring B is an unsaturated five- or six-membered ring and optionally one or two carbon atoms are replaced by nitrogen, oxygen and / or sulfur, and one, two or three hydrogen atoms are optionally replaced by A, OA, Hal, NO2 and / or CN, ring C is a saturated or unsaturated five- or six-membered ring and optionally one or two carbon atoms are replaced by nitrogen, oxygen and / or sulfur and one, two or three hydrogen atoms are optionally replaced by A, OA, Hal, NO2 and / or CN, and physiologically acceptable salts and solvates thereof.

BACKGROUND OF THE INVENTION

Pyrimidine derivatives are known, for example, from European Patent Specification No. EP 2011SS and from World Patent Publication No. WO 93/06104.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds having valuable properties, in particular compounds which could be used in the manufacture of medicaments.

• · · · · · ·

SUMMARY OF THE INVENTION

It has been found that the compounds of formula (I) and their salts have good pharmaceutical properties with good tolerability.

In particular, they exhibit specific inhibition of cGMP-phosphodiesterase (PDE V).

Quinazolines with cGMT-phosphodiesterase inhibiting activity are described, for example, in J. Med. Chem. 36, p. 3765 (1993) and J. Med. Chem., 37, 2106 (1994).

The biological activity of the compounds of formula I can be determined, for example, by the methods described in WO 93/06104. The affinity of the compounds of formula I according to the invention for cGMP-phosphodiesterase and cAMP-phosphodiesterase is determined by determining its IC50 values (inhibitor concentration required to achieve 50% inhibition of enzyme activity).

For carrying out methods known per se (10, 311, 1971), a modified W.J. Thompson and M.M.

For example, enzymes isolated from the assay (e.g., W.J. Thompson et al., Biochem.

. The batch method described in Appleman (Biochem. 18, 5228 (1979)) may be used to perform the assay.

Thus, the compounds of the invention are useful for the treatment of cardiovascular diseases, particularly for the treatment of cardiac insufficiency and for the treatment and / or therapy of potency disorders (erectile dysfunction).

The use of substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in WO 94/28902.

··························································· I · They are effective as inhibitors of the hare corpus can be exemplified by, for example, a coli (J. Uro1, 150, p.

Compounds of formula I as well as phenylephrine-induced cavernosum contractions. This biological action was as described by F. Holmquist

(1310 to 1315, 1993).

Inhibition of contraction of the finding in therapy and / or demonstrates the efficacy of the compounds in the treatment of potency disorders.

according to the invention, they can be used as medicaments in human and veterinary medicine. In addition, they can be used as intermediates for the manufacture of other medicament active ingredients.

Accordingly, the present invention provides the compounds of formula (I), salts and solvates thereof, and processes for their preparation.

The process for the preparation of the compounds of the formula I, in which the individual symbols have the meanings given above, is characterized in that a) reacting a compound of the general formula I with its salts and solvates of formula II.

Y, where X, I know and where is

L is a chlorine, bromine, hydroxyl, SCH3 or reactive esterified hydroxyl group.

r and ring A have the above compound of formula (III) above

where R ¹ . R · ² . ^R, Q, and Ring C have the above meanings, or

b) in the compound of formula I, the group X is converted to another group X, for example so. wherein the ester group is hydrolyzed to a COOH group or the COOH group is converted to an amide or cyano group and / or the compound of formula I is converted to its salt.

Individual symbols R ¹ . R * ⁵ , R ^p . R ^y . R ¹⁰ . R ¹¹ , r, Q, X, Y. Z and L as well as rings A and C have the aforementioned denominations in formulas I, II and III, unless explicitly stated otherwise.

The compounds of formula I have at least one chiral center and can therefore be in several stereoisomeric forms. The invention includes all such forms (e.g., D- and L-forms) and mixtures thereof (e.g., DL-forms).

The compounds of the present invention also include the lacquer called prodroc derivatives, i.e., alkyl or acyl groups, sugars or oligopeptides of a compound of formula (I) which is rapidly cleaved in the body into the active compounds of the invention.

A represents an alkyl group having 1, 2, 3, 4, 5, 6, 7,

8. 9 or 10 carbon atoms. In the above formulas, A is preferably an unbranched group having 1, 2, 3, 4, 5 or 6 carbon atoms, and preferably A is a methyl, ethyl or propyl group, further preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. A is furthermore, for example, trifluoromethyl, pentafluoroethyl or -CCl2-CF3.

Ac represents an acyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably a formyl, acetyl, propionyl, butyryl, further benzoyl group.

R ⁴ represents one R- ⁷ substituted linear or branched alkylene group having 1 to 10 carbon atoms, optionally one or two CH 2 groups being replaced by -CH = CH- and / or -C = C-. Preferably, the alkylene group is linear or branched and has 1 to 10 carbon atoms. Preferably it is 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, 1,12- or 1,2, 2-tri-methylpropylene, linear or a branched heptylene, octylene, nonylene or decylene group. R ⁴ is furthermore a but-2-enylene or a hex-3-enylene group. However, it is very much ethylene, propylene or butylene.

Q is preferably a linear or branched C1-C10 alkylene group, wherein the alkylene group is preferably 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 a 1,2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene group. It is, however, very significantly an ethylene, propylene or butylene group.

R @ ⁵ represents a cycloalkyl group having preferably 4-7 carbon atoms, for example cyclopentyl or cyclohexyl. One or two CH2 groups may be replaced by nitrogen, oxygen and / or sulfur. R ⁵ is therefore also a group

1,4-piperidinyl or 1,4-piperazinyl.

Hal is preferably fluorine, chlorine or bromine, but also iodine.

The groups R ¹ and R ² may be the same or different and are preferably in the 3 or 4 position of the phenyl ring. Represent independently for example H, A, OA, OH, Hal, SH, SA, SOA, SO ₂ A, SO2NH2, N0 _2, NH _2, NHA, NA _2, Ac, NHAc, CN, COOH or COOA.

Ring A preferably contains no heteroatom. However, 1 or 2 carbon atoms may be replaced by nitrogen atoms.

Ring B is preferably a 1,4-phenylene group having one or two substituents A, OA, Hal and / or CN. Ring B is furthermore an unsaturated heterocyclic group, for example a thiophene-2,4-diyl or parimidine-2,4-diyl or pyridine-2,6-diyl group.

Ring C represents a saturated or unsaturated five or six membered ring and optionally one or two carbon atoms are replaced by nitrogen, oxygen and / or sulfur and one, two or three hydrogen atoms are optionally replaced by A, OA, Hal, NO2 and / or CN ,

When ring C is unsaturated and contains one or more heteroatoms as mentioned above, it is 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, 2,4,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-,

3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl or pyrazinyl groups.

When ring C is saturated and contains one or more heteroatoms as mentioned above, it is preferably, 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; -, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro -1 -,

-3-, -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, hexahydro-1-

A 3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl group. Particularly preferably ring C is a phenyl group.

R ¹² represents a cycloalkylene group having 4, 5, 6 or 10 carbon atoms, optionally one or two CH 2 groups being replaced by a nitrogen, oxygen and / or sulfur atom. R @ ¹² is preferably 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-isothiazolinyl, 1,2-, 2,3-, 3,4- or

1,4-piperidinyl 1,4- or 1,2-piperazinyl, further preferably 1,2,3-tetrahydrotriazol-1,2- or 1,4-yl, 1,2,4-tetrahydrotriazole-1,2 - or 3,5-yl, 1,2- or

2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydrooxadiazole-2,3-,

-3,4-, -4,5- or 1,5-yl, 1,2,4-tetrahydrooxadiazole-2,3-,

-3,4- or -4,5-yl, 1,3,4-tetrahydrothiadiazole-2,3-, -3,4-,

-4,5- or -1,5-yl, 1,2,4-tetrahydrothiadiazole-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.

The groups which occur several times in the general formulas can be independently of one another or different.

[0057] Ib

Accordingly, the invention relates in particular to compounds of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula (I) are the following compounds of formulas (Ia) to (Ip), wherein not particularly indicated symbols have the meanings given in formula (I) but in the formulas:

la Z N,

Y c;

OF

Y

CH,

N;

1

Ic R ¹

Id R ⁷

AND;

tetrazol-5-yl. SO2NH3

O

N _x

Γ °

N-7

H

NS _K H or

Ν _χ

N 'H

SH independently SH. SA, SOA. NH3. NHA. ON-. Ac, NHftc, CN,

SO ₂ A, SO ₂ NH 2, NO ₂ COOA or COOH:

If

R ^C) . R ^{1 1} r

OF

Y

RQ

R ¹ .

R * il.

0.

N,

N,

H.

CH-, independently of one another SH. MHz, NHA. NA2, Ac,

SA. SOA. SO2A. SO3 NH2, NO2 NHAc. CM. COOA or COOH;

R ⁹ , R ^{11 Cl} .

R ^{1 1} H.

r 0.

n. m O.

Z N,

Y N.

R ² H.

Q CH ₂ ,

R ⁷ tetrazol-5-yl. SO3NH3 a * · a a * a a a a 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 ·· ··· · · · 9 · f

Ih R ¹ , R ² R ¹ , R ¹ R ¹ independently of one another Η, A, OA. OH, or Hal.

H.

r

X

OF

Y

R ²

Q o, p ring B

O,

R ^D

N,

11.

H,

CH ₃ , independently of one another, 1, 2 or 3.

an unsaturated five- or six-membered ring and optionally one or two C are replaced by t, O and / or S and one, two or three H are optionally replaced by A, OA. Hal, NO 2 and / or CN;

if

R ¹ ,

R-,

R ^{1 1}

R ¹ is independently H.

OA. OH. or Hal r

OF

Y

X

R ²

Q

n. m R12

11.

M.

R ^s ,

H.

CH ₂ , independently of one another, 1, 2 or 3, cyclopentylene or cyclohexylene. where they are · · · · · · · · · · · · · · · · · · · · · · · · · · · A day or two CH2 - replaced by N, O and / or S;

Ik R ¹ , R ² independently of one another Η, A, OA, OH, or Hal,

R ^{3 *,} R ^10,

R ^{1 1} H.

r O,

Z N,

Y N,

XR ^s ,

R ² H,

Q CHs

R ⁷ tetrazol-5-yl. SO2NH2

N,

N.

N - S H '' or

N.

R ^with ring C

H, phenyl;

II R ¹ , R ²

X ring C independently of one another SH. SA. SOA. SO2A, SO2NH2, NO ILH _second NHA, -3. Ac. NHAc. CN. COOA or COOH;

R ^s , pheny1:

I m R * ³ , R ^{1 µ}

R ^{1 1} r

OF

H,

O,

N,

In

Y N, R ^s H, R ¹² H. Q CH ₃ , R ^1, R ² independently of each other SH, SA. SOA, SO ₂ A, Sat ₂ nh ₂ , no ₂ NH _2, NHA, NA _2, Ac, NHAc. CN, COOA or COOH; X R ⁵ , ring C phenyl; R ⁹ . R ^w , R ^{1 1} H, r 0, OF N, Y N, R ^s H, Q CH ₂ . R ⁷ Letrazol-5-yl, SO ₂ NH ₂

Ν _χ s

N _x / ° or .N _x

O

N-S H

O

X R 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 circle B 1. 4-Phenylene a

ring C phenyl:

• · · · ·

Rο R ¹ , R ² R ⁹ , R ^1Q R ¹ 1Y

X

OF

Y

R ^s

Q o, p ring B ring C

Ip R ¹ , R ³ R ⁹ , R ¹⁰ , R ^{1 1} y

OF

Y

X

R ^s

Q, m

R12 ring B ring C independently of one another H, A, OA, OH, or Hal,

H,

0,

R ⁵ or R ⁶ ,

N,

N,

H,

CH _2, independently of one another 1, 2 or 3, unsaturated five- or six-membered ring and one C is replaced by N, 0 or S, and one, two or three H are optionally substituted by A, OA, Hal, N0 ₂ and / or CN f enyl:

independently of one another H, A, OA, OH, or Hal,

H,

O,

N,

N,

R ^s or R ⁶ ,

H,

CH _2, independently of one another 1, 2 or 3, cyklopenty1en or cyclohexylene wherein one or two -CH 2 replaced with a N, O and / or S, unsaturated five or six membered ring and one C is replaced by N, O or S and one , two or three H are optionally replaced by A, OA, Hal, NO 2 and / or CN and phenyl.

The compounds of formula (I) and the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example, in standard publications such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme Verlag, Stuttgart). reaction conditions that are known and suitable for said reactions. It is also possible to use variants which are known per se, not described here in greater detail.

In compounds of formula II or III, X, Y, Z,

R ^9, R ^10, R ^11, r and rings A, R ^1, R ^{2, R,} Q and C above meanings, especially the preferred meanings given.

When L is a reactive ester, if it is a hydroxyl group, it is preferably C1-6 alkylsulfonyloxy (especially methylsulfonyloxy) or C6-10 arylsulfonyloxy (especially phenylsulfonyloxy or p-tolylsulfonyloxy and also 2-naphthalenesulfonyloxy).

The compounds of the formula I can advantageously be obtained by reacting a compound of the formula II with a compound of the formula III.

If desired, the starting materials can also be formed in situ, i.e. they are not isolated from the reaction mixture, but are immediately used for the preparation of the compounds of the formula I. It is also possible to carry out the reaction stepwise.

The compounds of formulas II and III are generally known. If they are not known, they can be prepared by methods known per se.

The compounds of formula (II) can be prepared, for example, by reaction with phosphorus oxychloride from the corresponding hydroxypyrimidines, which are prepared from thiophene derivatives and from cyano substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453, 1988).

·· ··· · * · · · · ····

The hydroxypyrimidines are prepared either by dehydrogenation of the corresponding tetrahydrobenzothienopyrimidine compounds or for the preparation of pyrimidine derivatives by the known cyclization of 2-aminobenzthiophene-3-carboxylic acid derivatives with aldehydes or nitriles (Houben-Weyl E9b / 2).

The reaction of compounds of formula II with compounds of formula III is carried out in the presence or absence of an inert solvent at a temperature of about -20 to about 150 ° C, preferably 20 to 100 ° C.

Addition of an acid-binding agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other weak acid salt with an alkali metal or alkaline earth metal, preferably potassium, sodium or calcium, or an organic base such as e.g. triethylamine, dimethylamine, pyridine or quinoline or use of an excess of the amine component.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or 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 ether or ethylene glycol 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, 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 these solvents.

It is also possible to convert in the compound of formula (I)

X to another X, for example by hydrolyzing the ester or cyano group to a COOH group. For example, the ester group may be saponified at a temperature of 0 to 100 ° C with sodium hydroxide or potassium hydroxide in water, water-tetrahydro-furan or water-dioxane.

For example, carboxylic acids can be converted to the corresponding carboxylic acid chlorides by reaction with thionyl chloride, which can be converted to acid amides. Cleavage of water in a manner known per se yields carbonitrile from these amides.

The acid of formula (I) can be converted into the corresponding base addition salt with a base, for example, by reacting an equivalent amount of an acid and a base in an inert solvent such as ethanol, followed by evaporation. Suitable bases for this reaction are, in particular, those which give physiologically acceptable salts. Thus, the acids of the formula I can be converted by a base (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal salts, in particular the alkali metal or alkaline earth metal salts or the corresponding ammonium salts. Suitable bases for this reaction are in particular also organic bases which give physiologically acceptable salts, for example ethanolamine.

On the other hand, the base of formula (I) can be converted into the corresponding acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and subsequently evaporating the solvent. Particularly suitable acids for this reaction are those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and ogranic acids may be used, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic acids. Mono- or polyhydric carboxylic, sulphonic or mono- or polybasic carboxylic acids sulfuric acids such as formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic, ethanesulfonic sulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic and naphthalenedisulfonic and laurylsulfonic acids. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I.

The compounds of formula I and their physiologically acceptable salts can be used for the manufacture of pharmaceutical compositions, in particular by a non-chemical route. For this purpose, they can be converted into a suitable dosage form with at least one solid or liquid and / or semi-liquid carrier or excipient and optionally in admixture with one or more other active substances.

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

The present invention further provides pharmaceutical compositions comprising at least one compound of formula I and / or a physiologically acceptable salt thereof.

These compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration and which do not react with the compounds of the formula I, such as water, vegetable oils, benzyl alcohols, alkylenglycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and your li. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, suppositories for rectal use, solutions for parenteral use, especially oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds according to the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the preparation of injection preparations. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizing agents and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer additives and / or one or more, such as viruses, coloring agents, flavoring agents. several other active ingredients, there and now.

The compounds of the formula I and their physiologically acceptable salts can be used for the treatment of diseases in which an increase in the level of cycloguanosine monophosphate (cGMP) leads to braking or to the prevention of inflammation and muscle tension.

The present invention also provides the use of the compounds of formula I and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, occlusive heart failure, atherosclerosis, cardiovascular disease, peripheral vascular disease, stroke , bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhosis, and treatment of female impotence.

The compounds of the formula I according to the invention are generally used in doses of approximately 1 to 500 mg, in particular 5 to 100 mg per dosage unit. The daily dose is preferably about 0.02 to 10 mg / kg body weight. The dose for each individual depends on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, excretion rate, drug combination and the severity of the disease being treated. . Oral administration is preferred.

The invention is illustrated by the following examples. Temperatures are always given in degrees Celsius. The expression processing in the usual manner in the following examples illustrates:

If necessary, water is added, or the pH is adjusted to 2-10 depending on the constitution of the final product, the reaction mixture is extracted with ethyl acetate or dichloromethane, separated, dried over the organic phase with sodium sulfate, evaporated and purified by silica gel chromatography and / or crystallization.

Mass Spectrometry (MS): El (electron impact-isolation) M ⁺ FAB (fast atom bombardment) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- (4-Chloro-benzothieno [2,3-d] pyrimidin-2-yl) -propionic acid methyl ester [possibly due to cyclization of 2-amino-5,6,7,8-tetrahydro-benzothiophene-3-carboxylic acid methyl ester with 3-cyanopropionic acid methyl ester acid, sulfuric dehydrogenation followed by chlorination using phosphorus oxychloride / dimethylamine] and 4- (3-amino-1-methylpropyl) benzolsulfonamide in N-methylpyrrolidone are stirred for five hours at

110 DEG C. The solvent was removed and the residue was worked up in the usual manner. 3- (4- [3- (4-Sulfamoyl-phenyl) -butylamino] -benzoth 4,5] thienol-2,3-d] pyrimidin-2-yl} -propionic acid methyl ester of formula (1) is obtained. «T t t · t t t t t t t t

Example 2

3- (4- [3- (4-Sulfamoyl-phenyl) -butylaninol-benzo [4,5] thienol-2,3-d] pyrimidin-2-yl) -propionic acid methyl ester was dissolved in ethylene glycol monomethyl ether and stirred for 5 hours after addition of 32% sodium hydroxide. at 110 [deg.] C. After addition of 20% hydrochloric acid, the reaction mixture is extracted with dichloromethane. Addition of petroleum ether gave 3- [4- (3- (4-sulfamoylphenyl) butylamino) benzo [4,5] thiophen-2,3-d] pyrimidin-2-yl] propionic acid.

The obtained crystals are dissolved in isopropanol and the solution is mixed with ethanolamine. After crystallization, the 3- {4- [3- (4-sulfamoylphenyl) -butylamino] benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] propionic acid ethenoamine salt is obtained.

Similarly, the following compounds are obtained:

3- [4- (3-Chloro-4-methoxybenzylamino) benzo [4,5] thienol-2,3-d] pyridin-2-yl] propionic acid:

3- (1-Ibenzot1,3] dioxol-5-ylmethyl) amino] benzot 4,5] thienol-3,2-c] pyridin-3-ylpropionic acid:

3- {4-I (3-chloro-4-methoxybenzyl) methylamino] benzo [4,5] thieno [2,3-d] [eta] &lt; 3 &gt;

[2,3-d] pyrimidin-2-yl) propionic acid; Φ Φ 2,3 2,3 a 2,3 2,3 2,3 2,3 2,3 2,3 [2,3-dlpyrimidin-2-yl) propionic acid;

4- [4- (3-chloro-4-methoxybenzylamino-benzo [4,5] thiophen-2,3-b] pyridin-2-yl] cyclohexylsulfonamide;

3- (4- [4- (3-Chloro-4-methoxybenzylamino) benzot 4,5] Lieno [2,3-bipyridin-2-ylcyclohexyl) -4H- [1,2,4] thiadiazole-5 -he;

{4- [4- (3-Chloro-4-methoxybenzylamino) benzol 4,5] thieno [2,3-d] pyrimidin-2-ylmethyl-1-phenyl) -acetic acid;

3- [6- (4- (3-chloro-4-methoxybenzylamino) benzo [4,5]) thieno [2,3-d] pyrimidin-2-ylmethyl-1-pyridin-2-yl) -propionic acid;

3- <1- [4- (3-chloro-4-methoxybenzylamino) benzot 4,51-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-chloro-4-methoxybenzyl] 3-d] pyrimidin-4-yl] amine;

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

4- [3- (2- (4-carboxycyclohexyl) -9-thia-1,3,7-triazafluoro-4-ylamino] -1-methylpropyl) benzoic acid methyl ester,

The following examples illustrate but do not limit the pharmaceutical compositions of the present invention:

Example A: Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered, filled into injection ampoules, sterile. * 0000 * »00 • 0 '00 <0 · 0 ·« 0 0 «0 · 0« 0 »0 • 0 0 0000 000 0« 000 00 * 0 0 · 0 ·· 0 conditions are lyophilized and sealed sterile. Each vial contains 5 mg of active substance.

Example B: Suppositories

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

Example C = Solution

A solution of 1 g of an active compound of the formula I and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of sodium hydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH is adjusted to 6.8, made up to one liter and sterilized by irradiation. This solution can be used, for example, as eye drops.

Example D: Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of stallion 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 in a manner known per se into tablets, each tablet containing 10 mg of the active ingredient Formula I.

Example F: Dragees

Similar to Example E, tablets are compressed which are compressed into tablets.

They are coated in a manner known per se in a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G '· Capsules

2 kg of active ingredient of the formula I are filled into hard gelatine capsules, each capsule containing 20 mg of active ingredient of the formula I.

Example H ^: Ampoules

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

EXAMPLE 1 Inhalation Spray

Dissolve 14 g of the active compound of the formula I in 10 l of isotonic sodium chloride solution and fill in conventional commercial spray cans with a pump mechanism. The solution may be sprayed into the mouth or nose. Each spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Industrial applicability

The amine derivative and its physiologically acceptable salts and solvates, exhibiting phosphodiesterase inhibition suitable for the manufacture of pharmaceutical compositions for the treatment of circulatory diseases and for the treatment and / or therapy of potency disorders.

Claims (9)

PATENT CLAIMS The amine derivative of the general formula (I) ## STR3 ## wherein is R ² (I) R ^1, R ² independently denote H, A, OA, OH, Hal, SH, SA, SOA, SO ₂ A, SO2NH2, NO2, NH2, NHA, NA _2, Ac, NHAc, CN, COOA or COOH, , R @ ¹ and R @ ² taken together are also C3 -C5 alkylene, -O-CH2-CH2-, -CH2-O-CH2-, -O-CH2-O- or -O-CH2-CH2-O- X is R ⁴ , R ⁵ or R 0, Y C or N, CH or N, A linear or branched alkylene group having 1 to 10 carbon atoms, R &lt; ⁴ & gt ^{; is} substituted by a linear or branched C1-C10 alkylene group, R &lt; ⁷ &gt; optionally substituted by one, two or three CH2- groups by -CH = CH- and / or -C = C-, R ⁵ is - (CHzln- R ¹² - (CH 2) m R ^7, R ⁶ R ⁷ - (CH ₂₎ -O- (CH ₂₎ p R ⁷ is COOH, COOA, CONH2, CONHA, CON (A) ₂ or CN, tetrazoly1 -5-y1, SO2NH2, N, ^X S is hydrogen or A, R ^s R ⁹ , R ¹¹ AND Ac r12 Hal R ^w , independently of one another, is hydrogen, A, OA, OH, Hal, SH, SA, SOA, SO ₂ A, NO ₂ , NH 2, NHA, NA 2, Ac, NHAc, CN, COOA or COOH, an alkyl group of 1 to 10 carbon atoms, with 1 to 7 hydrogen atoms being half replaced fluorine and / or chlorine, an acyl group having 1 to 10 carbon atoms, a cycloalkylene group having 4 to 7 carbon atoms, optionally one or two CH3- groups being replaced by a nitrogen, oxygen and / or sulfur atom, a fluorine, chlorine, bromine or i, i, n, m, o, p independently of one another 0, 1, 2, 3, 4, 5 or 6; A is optionally one or two carbon atoms replaced by nitrogen, ring B is an unsaturated five- or six-membered ring, and optionally one or two carbon atoms are replaced by nitrogen, oxygen and / or sulfur, and one, two or three hydrogen atoms are optionally replaced A, OA, Hal, NO2 and / or CN, ring C is a saturated or unsaturated five or six membered ring and optionally and one or two carbon atoms are replaced by nitrogen, oxygen and / or sulfur, and one, two or three hydrogen atoms are optionally replaced by A, OA, Hal, NO 2 and / or CN, and physiologically acceptable salts and solvates thereof. An amine derivative according to claim 1 of the formula I (a) 3- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-b] pyridin-2-yl] propionic acid; b) 3- {1- [benzo [1,3] dioxo-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) 4-14- (3-chloro-4-methoxybenzyl amino) benzo [4,5] thieno [2,3-b] pyridin-2-yl] cyclohexanesulfonamide; e) 3- {4- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [29.3] [2,3,4] -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-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-ylmethyl) pyridin-2-ylpropionic acid; h) 3-N- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-ylmethyl] piperidin-4-yl } propionic acid 1 i na; (i) (3-Chloro-4-methoxybenzyl) -12- (2- {4- [2- (1H-tetrazol-5-yl) ethyl] piperazin-1-yl ethyl) benzo [4,5] thi enot of 2,3-d] pyrimidin-4-yl-amine; j) 3- (4-12- [4- (3-chloro-4-methoxybenzylamino) -9-thi-1,3,7-triazafluoro-2-yl] ethyl) cyclohexyl) propionic acid; k) 4- [3- [2- (4-carboxycyclohexyl) -9-thia-1,3,7-triazafluoren-4-ylamino] -1-methylpropyl) benzoic acid methyl ester; 3. A process for the preparation of compounds of the formula I, wherein the individual symbols are as defined above, their salts and solvates, characterized in that a) reacting a compound of formula II wherein X, Y, Z, R ⁹ , R ¹⁰ , R ¹¹ , and ring A is as defined above and wherein: L is chlorine, bromine, hydroxyl, SCH3 9 * 9 · * ·· «or a reactive esterified hydroxyl group with a compound of formula III (III) H wherein R ^1, R ^{2, R,} Q, and Ring C have the above meanings, or b) in the compound of formula I, the group X is converted to another group X, for example by hydrolyzing the ester group to a COOH group or converting the COOH group to an amide or cyano group and / or converting the compound of formula I to its salt . A process for the manufacture of pharmaceutical compositions, characterized in that the compound of the formula I according to claim 1 and / or its physiologically acceptable salt is formulated with at least one solid, liquid or semi-liquid carrier or excipient into a suitable dosage form. Pharmaceutical composition, characterized in that it contains at least one compound of the formula I as claimed in claim 1 and / or a physiologically acceptable salt thereof. Compounds of formula I according to claim 1 and their physiologically acceptable salts for the treatment of diseases of the blood circulation system and for the treatment and / or therapy of potency disorders. A medicament of the formula I according to claim 1 and its physiologically acceptable salts as a phosphodiesterase inhibitor. Use of the compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament. Use of the compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament for the treatment of angina, hypertension, pulmonary hypertension, compulsive heart failure, atherosclerosis, cardiovascular impairment, peripheral vascular disease, stroke, bromchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhosis, and treating female impotence.