EP1519730A1

EP1519730A1 - Novel use of imidazotriazinones

Info

Publication number: EP1519730A1
Application number: EP03735668A
Authority: EP
Inventors: Helmut Haning; Erwin Bischoff; Maria NIEWÖHNER; Ulrich Niewöhner
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2002-07-03
Filing date: 2003-06-24
Publication date: 2005-04-06
Also published as: CA2491455A1; JP2005535646A; DE10229778A1; US20080096880A1; WO2004004736A1; AU2003238034A1

Abstract

The invention relates to novel uses of imidazo[1,2,4]triazinones for producing a medicament for the treatment and/or prophylaxis of coronary cardiopathy, heart failure, pulmonary hypertension, bladder complaints, prostatic hyperplasia, nitrate-induced tolerance, or diseases of the eye, such as glaucoma, for the treatment or prophylaxis of central, retinal or posterior ciliary artery occlusion, central retinal vein occlusion, optical neuropathy, such as anterior ischaemic optical neuropathy and glaucomatous optical neuropathy, in addition to macular degeneration, diabetes, in particular diabetic gastroparesis, for the treatment of dysperistalsis of the stomach and oesophagus, female infertility, premature contractions, pre-eclampsia, alopecia, psoriasis associated with renal syndrome, cystic fibrosis, cancer and for improving cognition, powers of concentration, learning skills or hypermnesia, in particular if the disorder is a symptom of dementia.

Description

New use of imidazotriazinones

The present invention relates to the use of known fmidazotriazinones for the manufacture of a medicament for the treatment and / or prophylaxis of coronary heart disease, heart failure, pulmonary hypertension, bladder disorders, prostate hyperplasia, nitrate-induced tolerance, eye diseases such as glaucoma, for the treatment or prophylaxis of central retinal or posterior cillary artery occlusion, central retinal venous occlusion, optical neuropathy such as anterior ischemic optical neuropathy and glaucomatous optical neuropathy, as well as macular degeneration, diabetes, especially diabetic gastroparesis, for the treatment of peristalsis of the stomach and esophagus, female, pre-gastro-esophageal, female Preeclampsia, alopecia, psoriasis the renal syndrome, cystic fibrosis, cancer, to improve perception, to improve concentration, to

Improvement of learning and / or memory performance, especially if the disorder is a result of dementia.

Ihridazotriazinones are described in WO-A-01/64677, the compounds disclosed there are suitable for the treatment of erectile dysfunction.

In the published patent application DE-OS 2811780, imidazotriazines are described as bronchodilators with spasmolytic activity and master activity against phosphodiesterases metabolizing cyclic adenosine monophosphate (cAMP-PDE's, also referred to as PDE HI and PDE IV according to the Beavo nomenclature).

A hernia effect against cyclic guanosine monophosphate metabolizing phosphodiesterases [cGMP-PDE's, also referred to as PDE I, PDE H and PDE V according to the Beavo and Reifsnyder nomenclature (Trends in Pharmacol. Sci. 11, 150-155, 1990)] is not described. Furthermore, ji idazotriazinones in FR-22 13 058, CH-594671, DE-22 55 172, DE-23 64 076 and

EP-000 9384, which has no substituted aryl radical in the 2-position own, and are also described as bronchodilators with cAMP-PDE inhibitory activity.

WO-A-99/24433 likewise describes hnidazotriazinones as cGMP-metabolizing phosphodiesterase inhibitors, but in the para position to

Alkoxy group in the phenyl ring necessarily include a sulfonamide group.

An increase in the cGMP concentration can lead to curative, antiaggregatory, antithrombotic, antiproliferative, antivasospastic, vasodilating, natriuretic and diuretic effects. It can affect short or long-term modulation of vascular and cardiac inotropy, cardiac rhythm and cardiac conduction (JC Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).

The relaxing effect on smooth muscles leads to a wholesome one

Improving microcirculation in tissues that contain cGMP metabolizing phosphodiesterases.

It has now been found that the compounds of the general formula (I)

in which

R ^{1 represents} (C _r C ₆ ) -alkyl,

R ^{2 represents} (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₁₂ ) alkyl, R3 represents (C _r C ₆ ) -alkyl,

R ⁴ for a remainder of the formulas

stands,

embedded image in which

R ⁵ , R ⁶ and R ^{7 are the} same or different and are vinyl or (Ci-Cg ^ alkyl, which may be up to 3 times, the same or different, by trifluoromethyl, halogen, (-C-C6) -Alko y or by Remains of

formulas

F F F F

I I I I / .CF,

- O— C— C— F, - C— C— F, \

CF,

F F F F is substituted,

embedded image in which

R ^{8 is} hydrogen or (Ci-C ^ alkyl,

or

R ⁵ , R ⁶ and / or R ^{7 are} (C ₆ -C ₁₂ ) aryl, which may be up to 3 times, identical or different, by halogen, trifluoromethyl, nitro, cyano, carboxyl, (C ₁ -C6) -AlJk 1 or (C ₁ -C 6) alkoxy is substituted or

R ^{5 is} quinolyl or a 5- to 6-membered, aromatic or saturated heterocycle with up to 3 heteroatoms from the series S, N and / or O which, if appropriate, in the case of an N function also via this, up to 3- times, the same or different, can be substituted by halogen or (-C-Cg) alkyl

or

R ^{5 is} a residue of the formulas

or -NR ^Q R ¹⁰ means

wherein

R ⁹ and R ^{10 are} identical or different and are hydrogen, (Ci-Cg) - alkyl or phenyl,

or

R ⁴ for carboxyl or for a radical of the formulas

-CO-R ¹³ or -OR ¹⁴ ,

embedded image in which

R ¹¹ and R ^{12 are the} same or different and are hydrogen or (C1-C4) -

Al yl mean

R ¹³ denotes (C _r C ₆ ) alkyl,

R ¹⁴ denotes (C 1 -C 4 -alkyl which is optionally substituted up to 3 times, identically or differently, by hydroxyl, phenyl or by a radical of the formula -NR ¹⁵ R ¹⁶ ,

embedded image in which

R ¹⁵ and R ^{16 are} identical or different and are hydrogen, phenyl or (Ci-C ^ alkyl, which in turn may be substituted by phenyl, or

R ^{4 represents} a radical of the formula -NH-CO-NR ^ R ¹⁸ ,

embedded image in which

R ¹⁷ and R ^{18 are the} same or different and are hydrogen or (C _j -Cg) -

Alkyl means that optionally by hydroxy or by a radical of the formulas

or -NR ¹⁹ R ^{20 is} substituted, embedded image in which

R ¹⁹ and R ^{20 are the} same or different and are hydrogen, phenyl or (Ci-C ^ alkyl or

R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a heterocyclic ring of the formulas

form,

embedded image in which

R ² 1 is hydrogen or (C _x -C ₆ ) alkyl,

a means either 1 or 2,

R ^{22 is} hydroxy or (Ci-Cg ^ alkyl, which is optionally substituted by hydroxy, or

R ¹⁷ and / or R ¹⁸ (Cg-C ^ aryl mean, which is optionally substituted by halogen, trifhiorefhyl or by -SCF ₃

or

R ^{17 is} hydrogen and Rl ^{8 represents} a radical of the formula -SO2-R ²³ ,

wherein

R ²³ denotes (C _r C6) alkyl or (Cg-C ^ aryl, which is optionally substituted by halogen,

or for a rest of the formulas

stands,

or

R ⁴ for a radical of the formula

-NH-CO-R ²⁴ stands,

embedded image in which

R ^{24 is} a radical of the formula

means

embedded image in which R ²⁵ and R ^{26 are} identical or different and are hydrogen, (Cj-Cg) - alkyl or (Cι-Cg) -alkoxycarbonyl,

or

R ^{24 means} (-C-Cg) alkyl, which is optionally substituted by (Cg-C ^ aryl, which in turn can be substituted by hydroxy or (C ₁ -C ₆ ) alkoxy or

(-C-Cg) alkyl optionally by a radical of the formula

- (Sθ ₂ ) _b -R ^{27 is} substituted,

embedded image in which

b is either 0 or 1 and

R ²⁷ for a remainder of the formulas

stands,

or

R ^{4 represents} (-CC ₁₂ ) -alkyl, which may be up to 3 times, identical or different, by hydroxy, azide, phenyl or by radicals of the formulas -NR ²⁸ R ²⁹ , -O-CO-R ³⁰ or -P (O) {O - [(C _r C ₆ ) alkyl]} _{2 is} substituted,

embedded image in which R ²⁸ and R ^{29 are the} same or different, are hydrogen, phenyl or (C ^ -Cg) - alkyl, which is optionally substituted by hydroxy, (-C-Cg) alkoxy or phenyl,

or

R ²⁸ and R ²⁹ together with the nitrogen atom to which they are attached form a heterocyclic ring of the formulas

Form R ³² or - NR ³³ ,

embedded image in which

R ³¹ and R ^{32 are the} same or different and are hydrogen or (C _r C ₆ ) alkyl

R ³³ (C _r C ₆ ) alkyl, benzyl, (C _r C ₆ ) alkoxycarbonyl, (C _r C ₆ ) - alkylcarbonyl, carboxyl, pyridyl, pyrimidyl or phenyl, which is optionally by (-C-Cg) alkoxy is substituted,

and

R ³⁰ denotes (C _r C ₆ ) alkyl,

or (CrCi2) - alkyl is optionally substituted by triazolyl, which in turn is up to 2-fold, identical or different, by halogen, phenyl, tetrahydrofuranyl, tetrahydropyranyl, (-C-Cg) alkoxycarbonyl, aminocarbonyl or by (Cι-Cg) Alkyl can be substituted, the latter optionally being substituted by hydroxy, (C _j -Cg) alkoxy or by a radical of the formulas NR ³ R ³⁵ or -O-CO-R ³⁶ ,

embedded image in which

R ³⁴ and R ^{35 are the} same or different and are hydrogen or (C ^ -Cg) -

Alkyl mean

R ^{3 represents} (C _r C ₆ ) alkyl,

or

R ^{4 represents} a radical of the formula -CO-R ³⁷ ,

Wonn

R ³⁷ for a remainder of the formulas

-CH "2r- -UCNN

- (CH2) _C -NR ³⁹ R ⁴⁰ or -CH ₂ -P (O) (OR ⁴¹ ) (OR ⁴² ), wherein

R ³⁸ denotes hydrogen or (C _r Cg) alkyl,

c means either 0 or 1,

R ³⁹ and R ^{40 are} identical or different and denote hydrogen or (Ci-C ^ alkyl, which is optionally substituted by hydroxy,

R ⁴¹ and R ^{42 are the} same or different and are (-C-Cg) alkyl,

or

R ^{4 represents} a 5-membered heterocycle with up to 3 heteroatoms from the series S, N and / or O which, in the case of an N function, also via these, optionally up to 3 times in total, identically or differently, by halogen , Trifluoromethyl or substituted by phenyl, which in turn can be substituted one or more times by halogen or trifluoromethyl,

and / or optionally substituted by (C3-Cg) cycloalkyl, pyrryl or by (ι-Ci2) alkyl, which in turn is replaced by cyano, trifluoromethyl, (Cι-Cg) alkoxycarbonyl, (C ₁ -Cg) alkoxy, Amino or substituted by phenyl or nitro-substituted phenyl,

and / or optionally by -NR ⁴³ R ⁴⁴ , -NH-CO-CO-R ⁴ 5, -NH-CO-R ⁴⁶ ,

-NH-CO-CH ₂ -R ⁴⁷ , -CO-R ⁴⁸ or may be substituted,

wherein R ⁴³ and R ^{44 are} identical or different and denote hydrogen, benzyl, (Cj-Cg) - alkyl or phenyl, which is optionally substituted by halogen or trifluoromethyl,

R ⁴⁵ denotes (C _r Cg) alkoxy,

R ⁴⁶ denotes (C _r C ₆ ) alkyl or phenyl,

R ^{47 is} hydroxy, (C _r C ₆ ) alkoxy or a radical of the formula -O-CO-R ⁴⁹ ,

embedded image in which

R ^{49 means} (C _r C ₄ ) alkyl

R ⁴⁸ denotes a radical of the formula -CH ₂ -CN or phenyl which is optionally substituted by halogen, trifluoromethyl or (C ₁ -Cg) alkoxy,

and their salts, tautomers, N-oxides, prodrugs and hydrates and isomeric forms,

also suitable for the manufacture of medicinal products for the treatment of and or prophylaxis of coronary heart disease, heart failure, pulmonary

Hypertension, bladder disorders, prostate hyperplasia, nitrate-induced tolerance, eye deficiency such as glaucoma, for the treatment or prophylaxis of central retinal or posterior ciliary artery occlusion, central retinal venous occlusion, optical neuropathy such as anterior ischemic optical neuropathy, optic neuropathy, and glaucoma, neuropathy, and glaucoma,

Diabetes, especially diabetic gastroparesis, for the treatment of disorders Stomach and esophageal peristalsis, female infertility, premature labor, preeclampsia, alopecia, psoriasis, renal syndrome, cystic fibrosis, cancer, to improve perception, improve concentration, improve learning and / or memory, especially if the disorder is a result of dementia.

Depending on the substitution pattern, the compounds of the general formula (I) can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

Furthermore, certain compounds of the general formula (1) can be used in tautomers

Shapes are available. This is known to those skilled in the art and such compounds are also within the scope of the invention.

Physiologically harmless, d. H. pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzene - sulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

As the pharmaceutically acceptable salts also include salts there may be mentioned übhchen bases such as alkali metal salts (eg sodium or potassium salts), Erdalkahsalze (eg calcium or magnesium salts) or Ammom ^'umsalze derived from ammonia or organic Arninen such as Diemylarnin, triethyl- anrin, ethyldiisopropylarnine, procaine, dibenzyl-iπiin, N-methylmorpholine, dihydroabietylamine or methylpiperidine.

According to the invention, “hydrates” refer to those forms of the compounds of the above general formula (I) which are in the solid or liquid state

Hydration with water form a molecular compound (solvate). In the hydrates, the water molecules are attached in a secondary manner due to intermolecular forces, in particular hydrogen bonds. Solid hydrates contain water as so-called crystal water in stoichiometric proportions, whereby the water molecules do not have to be equivalent in terms of their binding state.

Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally, the hydrates of salts of the compounds according to the invention can also be used.

According to the invention, “prodrugs” refer to those forms of the compounds of the general formula (I) above which can themselves be biologically active or inactive, but which can be converted into the corresponding biologically active form (for example metabolically, solvolytically or in some other way).

(-C-C ₁ ) alkyl represents a straight-chain or branched alkyl radical with 1 to

12 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. The corresponding alkyl groups with fewer carbon atoms, such as, for example, can be derived from this definition and (-C-C) alkyl. In general, (C ₁ -C ₄ ) alkyl is preferred.

(C ₃ -C ₈ ) Cycloalkyl stands for a cyclic alkyl radical with 3 to 8 coblene atoms.

Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Cycloheptyl or cyclooctyl. The corresponding cycloalkyl groups with fewer carbon atoms, e.g.

(C ₃ -C ₅ ) cycloalkyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. (C ₆ -C ₆ ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. The corresponding alkoxy groups with fewer carbon atoms, such as, for example, (C 1-4 alkoxy and (C 1-4 alkoxy), are derived analogously from this definition. In general, it is preferred that (C 1-4 alkoxy is preferred).

The meaning of the corresponding constituent of other more complex substituents, such as e.g. B. Alkoxycarbonyl.

(C ₆ -C ₁₂ ) aryl represents an aromatic radical having 6 to 12 carbon atoms. Examples include: phenyl and naphthyl.

5- to 6-membered, aromatic or saturated heterocycle with up to 3

Heteroatoms from the series S, N and / or O either represent a heteroaromatic which is linked via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic; Examples include: pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, where pyridyl, pyrimidyl,

Pyridazinyl, furyl and thienyl are preferred, or for a saturated heterocycle linked via a ring carbon atom or a ring nitrogen atom, or for a (C ₅ -C ₆ ) cycloalkyl radical, as defined above; Examples include: tetrahydrofuryl, pyrrohdinyl, piperidinyl, piperazinyl, morpholinyl, TMomorpholinyl, cyclopentyl and cyclohexyl where piperidinyl, morpholinyl and

PyiTohdinyl are preferred.

Preferred is the use according to the invention of compounds of the general formula (I)

in which R ^{1 represents} (C _r C ₄ ) alkyl,

R ² is (1 ₀ C ι-C) alkyl, cyclopentyl, cycloheptyl or,

R ^{3 represents} (C _r C ₄ ) alkyl,

R ⁴ for a remainder of the formulas

stands,

embedded image in which

R ⁵ , R ⁶ and R ^{7 are the} same or different and are vinyl or (-CC) alkyl, which may be up to 3 times, the same or different, by trifluoromethyl, chlorine, (Ci-C ^ -Alko y or by remnants of the formulas

-N is NR ^{8 or} substituted,

wherein

R ^{8 represents} hydrogen, methyl or ethyl,

or R ⁵ , R ⁶ and or R ^{7 are} phenyl, optionally up to 3 times, identical or different, by halogen, trifluoromethyl, nitro, cyano, carboxyl, (C ₁ -C4) alkyl or (C ₁ -C4) Alkoxy is substituted

or

R ⁵ quinolyl or a radical of the formulas

means

which can optionally be substituted up to 2 times, identically or differently, by chlorine or (C 1 -C 4) -alkyl

or

R ^{5 is} a residue of the formulas

means

embedded image in which R ⁹ and R ^{10 are the} same or different and are hydrogen, (Cj-Cg) - alkyl or phenyl,

or

R ⁴ for carboxyl or for a radical of the formulas

-CO-R ¹³ or -OR ¹⁴ ,

Wonn

R ¹¹ and R ^{12 are} identical or different and are hydrogen or (-C4) alkyl,

RI ³ denotes (C _r C4) alkyl,

R ¹⁴ (Ci -C ^ alkyl means, optionally up to 3 times, the same or different, by hydroxy, phenyl or by a radical of the formula

-NR ¹⁵ R ^{16 is} substituted,

embedded image in which

R ¹⁵ and R ^{16 are} identical or different and are hydrogen, phenyl or (C1-C4) alkyl, which in turn can be substituted by phenyl, or represents a radical of the formula -NH-CO-NR ^ R ¹⁸ ,

embedded image in which

R ¹⁷ and R ^{18 are the} same or different and are hydrogen or (C1-C4) alkyl, optionally by hydroxy or by a radical of the formulas

or -NR ¹⁹ R ^{20 is} substituted,

embedded image in which

R ¹⁹ and R ^{20 are the} same or different and are hydrogen, phenyl or (-C-C4) alkyl or

form,

embedded image in which

R ²¹ denotes hydrogen or (C _r C ₄ ) -alkyl,

means either 1 or 2, R ^{22 is} hydroxy or (C ₁ -C 4) alkyl, which is optionally substituted by hydroxy, or

R ¹⁷ and / or R ^{18 are} phenyl which is optionally substituted by chlorine, trifluoroethyl or by -SCF3

or

R ^{17 is} hydrogen and

Rl ^{8 represents} a radical of the formula -SO ₂ -R ²³ ,

wherein

R ²³ denotes (C 1 -C 4) -alkyl or phenyl, which is optionally substituted by halogen,

or for a rest of the formulas

stands,

or

R ⁴ for a radical of the formula

-NH-CO-R ²⁴ stands, embedded image in which

R ^{24 is} a radical of the formula

means

embedded image in which

R ²⁵ and R ^{26 are the} same or different and are hydrogen, (C1-C4) alkyl or (Cι-C4) alkoxycarbonyl,

or

R ^{24 means} (-C-C4) alkyl, which is optionally substituted by phenyl, which in turn can be substituted by hydroxy or (C ₁ -C4) alkoxy or

(C 1 -C 4) -Al yl is optionally substituted by a radical of the formula - (SO ₂ ) -R ²⁷ ,

Wonn

b is either 0 or 1 and R ²⁷ for a remainder of the formulas

-NO -CH ₉ -NO - N ΓΛ, N-CH,

or

R ^{4 represents} (-CC) -alkyl, which may be up to 3 times, identical or different, by hydroxy, azide, phenyl or by radicals of the formulas ~ NR ²⁸ R ²⁹ , -O-CO-R ³⁰ or P (O) {O - [(C _r C ₆ ) -alkyl]} _{2 is} substituted,

embedded image in which

R ²⁸ and R ^{29 are the} same or different, are hydrogen, phenyl or (C1-C4) - alkyl, which is optionally substituted by hydroxy, (-C-C4) alkoxy or phenyl,

or

embedded image in which R ³¹ and R ^{32 are the} same or different and are hydrogen or (C ₁ -C ₄ ) alkyl

R ^{33 is} (C _r C ₄ ) -alkyl, benzyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C _r C ₄ ) -alkylcarbonyl, carboxyl, pyridyl, pyrimidyl or phenyl, which is optionally replaced by (C ₁ -C 4) Alkoxy is substituted,

and

R ³⁰ denotes (C _r C ₆ ) alkyl,

or

(C ^ -Ci ι) alkyl is optionally substituted by triazolyl, which in turn up to 2 times, the same or different, by halogen, phenyl, tetrahydrofuranyl, tetrahydropyranyl, (C ₁ -C4) alkoxycarbonyl, aminocarbonyl or (C ₁ -C 4) alkyl may be substituted, the latter optionally being substituted by hydroxy, (C 1 -C 4) alkoxy or by a radical of the formulas NR ³⁴ R ³⁵ or -O-CO-R ³⁶ ,

Wonn

R ³⁴ and R ^{35 are} identical or different and are hydrogen or (C1-C4) alkyl,

R ³⁶ denotes (C _r C4) alkyl,

or

R ^{4 represents} a radical of the formula -CO-R ³⁷ , embedded image in which

R ³⁷ for a remainder of the formulas

-CH CN - O - N N-R

- (CH ₂ ) _C -NR ³⁹ R ⁴⁰ or -CH ₂ -P (O) (OR ⁴¹ ) (OR ⁴² ),

wherein

R ^{38 is} hydrogen or (C _r C ₄ ) -alkyl,

c means either 0 or 1,

R ³⁹ and R ^{40 are the} same or different and are hydrogen or

(C 1 -C 4) alkyl, which is optionally substituted by hydroxy,

R ⁴¹ and R ^{42 are} identical or different and are (C _r C4) -alkyl,

or

R ⁴ for a radical of the formula stands,

which, in the case of pyrazole, is also substituted by chlorine, trifluoromethyl or by phenyl, optionally in total up to 3 times, identically or differently, which in turn is substituted one or more times by

Chlorine or trifluoromethyl can be substituted,

and / or optionally substituted by cyclopentyl, cyclohexyl, pyrryl or by (Ci-C 12) alkyl, which in turn by cyano, trifluoromethyl, (C ₁ -C4) alkoxycarbonyl, (C; C4) alkoxy, amino or by Phenyl or

Nitro-substituted phenyl may be substituted,

and / or optionally by -NR ⁴³ R ⁴⁴ , -NH-CO-CO-R ⁴⁵ , -NH-CO-R ⁴⁶ ,

-NH-CO-CH ₂ -R ⁴⁷ , -CO-R ⁴⁸ or may be substituted, __ woπn

R ⁴³ and R ^{44 are} identical or different and denote hydrogen, benzyl, (C1-C4) -alkyl or phenyl, which is optionally substituted by halogen or trifluoromethyl,

R ⁴ 5 denotes (C _r C ₅ ) alkoxy,

R ⁴⁶ denotes (C _r C ₅ ) alkyl or phenyl,

R ^{47 is} hydroxy, (C _r C ₄ ) alkoxy or a radical of the formula -O-CO-R ⁴⁹ , wherein

R ^{49 means} (C _r C ₃ ) alkyl

R ⁴⁸ denotes a radical of the formula -CH2-CN or phenyl which is optionally substituted by chlorine, trifluoromethyl or (C ₁ -C4) alkoxy,

and their N-oxides and / or tautomers as well as their pharmaceutically acceptable salts, hydrates and prodrugs.

Compounds of the general formula (I) according to the invention are particularly preferred

in which

R ^{1 represents} (C _r C ₄ ) alkyl,

R ^{2 represents} cyclopentyl, cyclohexyl, cycloheptyl or (C ^ -Cio) alkyl,

R ^{3 represents} (C _r C ₄ ) alkyl,

R ⁴ for a remainder of the formulas

stands,

embedded image in which R ⁵ , R ⁶ and R ^{7 are the} same or different and are vinyl or (-CC) alkyl, which may be up to 3 times, the same or different, by trifluoromethyl, chlorine, (-C4) -alkoxy or by Remains of the formulas

Wonn

R ^{8 represents} hydrogen, methyl or ethyl,

or

R ⁵ , R ⁶ and / or R ^{7 are} phenyl which is optionally substituted up to 3 times, identically or differently, by halogen, cyano, (-CC4) -alkyl or (C1-C4) -alkoxy

or

R ^{5 is} a residue of the formulas

means

which can optionally be substituted up to 2 times, identically or differently, by chlorine or (C _j -C) alkyl or

R ^{5 represents} a radical of the formula -NR ⁹ R ¹⁰ ,

worm

R ⁹ and R ^{10 are} identical or different and are hydrogen, (C1-C4) -alkyl or phenyl,

or

R ⁴ for carboxyl or for a radical of the formulas

-CO-R ¹³ or -OR ¹⁴ ,

embedded image in which

R ¹³ denotes (C _r C ₄ ) alkyl,

R ¹⁴ denotes (C 1 -C 4) -alkyl which is optionally substituted up to 3 times, identically or differently, by hydroxyl or by a radical of the formula -NR ¹⁵ R ¹⁶ ,

wherein

R ¹⁵ and R ^{16 are} identical or different and are hydrogen or (Cj-C) -alkyl, which in turn can be substituted by phenyl,. mean or represents a radical of the formula -NH-CO-NR ^ R ¹⁸ ,

embedded image in which

R ¹⁷ and R ^{18 are} identical or different and denote hydrogen or (C1-C4) - alkyl, which is optionally substituted by hydroxy,

or

v_ / or _bildenj

embedded image in which

R ²¹ denotes hydrogen or (C _r C ₄ ) -alkyl,

or

R ¹⁷ and / or R ^{18 are} phenyl which is optionally substituted by chlorine, trifluoroethyl or by -SCF ₃

or

R ^{17 is} hydrogen and

R ^{18 represents} a radical of the formula -SO ₂ -R ²³ , embedded image in which

or for a rest of the formulas

stands,

or

R ⁴ for a radical of the formula

-NH-CO-R ²⁴ stands,

embedded image in which

R ^{24 is} (C ₁ -C4) alkyl, which is optionally substituted by phenyl, which in turn can be substituted by hydroxy or (-C-C4) alkoxy or

(C 1 -C 4) -Al yl is optionally substituted by a radical of the formula - (SO ₂ ) bR ²⁷ ,

embedded image in which

b is either 0 or 1 and R ²⁷ for a remainder of the formulas

stands,

or

R ^{4 represents} (C 1 -C 6) -alkyl which is optionally substituted up to 3 times, identically or differently, by hydroxyl, phenyl or by radicals of the formulas -NR ²⁸ R ²⁹ or -O-CO-R ³⁰ ,

embedded image in which

or

or form -NN— R ³³ ,

embedded image in which R ³¹ and R ^{32 are the} same or different and are hydrogen or mean

R ^{33 is} (C ₁ -C ₄ ) -alkyl, benzyl, (C _r C ₄ ) -alkoxycarbonyl, (C _r C ₄ ) -alkylcarbonyl, carboxyl, pyridyl, pyrimidyl or phenyl, which is optionally replaced by (C; C4) - Alkoxy is substituted,

and

R ³⁰ denotes (C ₁ -C ₆ ) alkyl,

or

(-C-Cg) -alkyl is optionally substituted by triazolyl, which in turn can be substituted up to 2 times, identically or differently, by (C ₁ -C 4) -alkyl, the latter optionally by hydroxy or (C-C4) - Alko y can be substituted

wherein

or

R ^{4 represents} a radical of the formula -CO-R ³⁷ ,

embedded image in which

R ³⁷ for a remainder of the formulas

or - (CH ₂ ) _C -NR ³⁹ R ⁴⁰ ,

embedded image in which

R ^{38 is} hydrogen or (C _r C ₄ ) -alkyl,

c means either 0 or 1,

R ³⁹ and R ^{40 are the} same or different and are hydrogen or (-CC ₄ ) -alkyl, which is optionally substituted by hydroxy,

or

R ⁴ for a radical of the formula

stands,

which, in the case of pyrazole, also via the N function, is in total up to 3 times, identical or different, substituted by trifluoromethyl or by phenyl, which in turn can be substituted one or more times by chlorine or trifluoromethyl, and / or optionally substituted by cyclopentyl, cyclohexyl or by (Cj-Cg) -alkyl, which in turn can be substituted by (-CC ₄ ) alkoxy, amino or by phenyl,

and / or optionally substituted by -NR ⁴³ R ⁴⁴ , -NH-CO-R ⁴⁶ , -NH-CO-CH ₂ -R ⁴⁷ or -CO-R ⁴⁸ ,

wherein

R ⁴³ and R ^{44 are} identical or different and denote hydrogen, benzyl, (C -C ₄ ) -alkyl or phenyl, which is optionally substituted by halogen or trifluoromethyl,

R ⁴⁶ denotes (C ₁ -C ₄ ) alkyl or phenyl,

R ⁴⁷ denotes hydroxy or (C ₁ -C ₄ ) alkoxy,

R ^{48 is} phenyl which is optionally substituted by chlorine, trifluoromethyl or (-CC ₄ ) alkoxy,

and their N-oxides and / or tautomers as well as their pharmaceutically acceptable salts, hydrates and prodrags.

The compounds according to the invention having the following structures are very particularly preferred:

and their tautomers and / or N-oxides and their pharmaceutically acceptable salts, hydrates and prodrugs.

The compounds used according to the invention and their preparation are described in WO-A-01/64677. Reference is expressly made to the disclosure of WO-A-01/64677. The compounds of the general formula (I) used according to the invention are suitable for the prophylaxis and / or treatment of diseases in which an increase in the cGMP concentration is beneficial, that is to say explanations which are related to cGMP-regulated processes 'cGMP-related diseases'). They inhibit either one or more of the cGMP-metabolizing phosphodiesterases (PDE I, PDE II and PDE V). This leads to an increase in cGMP. The differentiated expression of the phosphodiesterases in different cells, tissues and organs as well as the differentiated subcellular localization of these enzymes, in conjunction with the selective inhibitors according to the invention, enable selective addressing of the various processes regulated by cGMP.

The relaxing effect on smooth muscles makes them suitable for the treatment of diseases in which by improving the microcirculation of a tissue that contains a cGMP metabolizing phosphodiesterase, a

Improvement and / or healing of a clinical picture can be calibrated.

The present invention relates to the use of imidazotriazinones for the manufacture of a medicament for the treatment and / or prophylaxis of coronary heart disease, heart failure, pulmonary hypertension, bladder disorders,

Prostate hyperplasia, nitrate-induced tolerance, eye diseases such as glaucoma, for the treatment or prophylaxis of central retinal or posterior ciliary artery occlusion, central retinal venous occlusion, optical neuropathy such as anterior ischemic optical neuropathy and glaucomatous optical neuropathy, in particular, of macular diabetic and diabetic optic neuropathy, as well as diabetic optic neuropathy, as well as diabetic optic neuropathy as well as diabetic optic neuropathy as well as diabetic optic neuropathy and diabetic optic neuropathy, in particular of macular neuropathy, as well as diabetic optic neuropathy as well as diabetic optic neuropathy, as well as diabetic optic neuropathy, in particular, of macular neuropathy, as well as diabetic optic neuropathy, as well as diabetic optic neuropathy, as well as diabetic optic neuropathy and diabetic gastrointestinal disorders , for the treatment of disorders of the peristalsis of the stomach and esophagus, female infertility, premature labor, preeclampsia, alopecia, psoriasis, the renal syndrome, cystic fibrosis, cancer, to improve perception, to improve concentration, to improve learning and / or Memory performance, especially if the

Disorder is a result of dementia. In addition, the compounds according to the invention enhance the action of substances, such as EDRF (Endotheuum derived relaxing factor), ANP (atrial natriuretic peptide), nitrovasodilators and all other substances which increase the cGMP concentration in a manner other than phosphodiesterase inhibitors.

Activity of phosphorus diesterases (PDE's)

The cGMP-stimulable PDE π, the cGMP-inhibitable PDE HI and the cAMP-specific PDE IV were isolated from either porcine or bovine myocardium. The

Ca ²⁺ -calmodulin stimulable PDE I was isolated from porcine aorta, swine brain or preferably from bovine aorta. The cGMP specific PDE V was obtained from pig small intestine, pig aorta, human platelets and preferably from bovine aorta. The purification was carried out by anion exchange chromatography on MonoQ ^R Pharmacia, essentially using the method of M. Hoey and Miles D.

Houslay, Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al. Biochemical Pharmacology Vol. 35 1743-1751 (1986).

The enzyme activity is determined in a test batch of 100 .mu.l in 20 mM Tris HCl buffer pH 7.5 which contains 5 mM MgCl ₂ , 0.1 mg / ml hemorrhage serum albumin and either 800 Bq ³ HcAMP or ³ HcGMP. The final concentration of the corresponding nucleotides is 10 ⁶ mol / 1. The reaction is started by adding the enzyme, the amount of enzyme is such that about 50% of the substrate is converted during the incubation period of 30 min. To stimulate the cGMP PDE II test is used as the substrate ³ HcAMP and the projection 10 ^"6 mol / l of non-labeled cGMP is added. In order to test the Ca ²⁺ -calmodulin-dependent PDE I, 1 μM CaCl ₂ and 0.1 μM calmodulin are added to the reaction mixture. The reaction is stopped by adding 100 μl of acetonitrile containing 1 mM cAMP and 1 mM AMP. 100 μl of the reaction mixture are separated by means of HPLC and the cleavage products' Oriline "are determined quantitatively using a flow meter.

The substance concentration at which the reaction rate is measured is measured Is reduced by 50%. In addition, the "Phosphodiesterase [ ³ H] cAMP-SPA enzyme assay" and the "Phosphodiesterase [ ³ H] cGMP-SPA enzyme assay" from Amersham Life Science were used. The test was carried out according to the test protocol specified by the manufacturer. The [H] cAMP SPA assay was used for the activity stimulation of the PDE LI, with the reaction mixture

10 ^"6 M cGMP was added to activate the enzyme. For the measurement of PDE I 10 ^{" 7} M calmodulin and 1 μM CaCl ₂ were added to the reaction mixture. The PDE V was measured using the [H] cGMP SPA assay.

Whether j ect recognition test

The object recognition test is a mental test. It measures the ability of rats (and mice) to distinguish between known and unknown objects.

The test was carried out as described: Blokland et al, NeuroReport 1998, 9,

4205; Ennaceur et al, Behav. Brain Res. 1988, 31, 47-59; Ennaceur et al, Psychopharmacology 1992, 109, 321-330; Prickaerts et al, Eur. J. Pharmacol. 1997, 337, 125-136.

Basically, inhibition of one or more phosphodiesterases leads to this

Type to increase the cGMP concentration. This makes the compounds interesting for all therapies in which an increase in the cGMP concentration can be assumed to be beneficial.

The investigation of the cardiovascular effects was carried out on normotonic and SH-

Rats and performed on dogs. The substances were administered intravenously or orally.

The new active ingredients and their physiologically acceptable salts (e.g. hydrochlorides, maleinates or lactates) can be converted into the usual formulations in a known manner, such as tablets, dragees, pills, granules, aerosols, Syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. The therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.

The Formuherungen are prepared for example by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, z. B. in the case of the use of water as a diluent, if appropriate, organic solvents

Auxiliary solvents can be used.

The application is carried out in the usual way, preferably orally, transdermally or parenterally, e.g. perlingual, sublingual, conjunctival, otic, buccal, intravenous, nasal, rectal, inhalative or as an implant.

For oral administration, doses of 0.001 to 50 mg / kg, preferably 0.01 mg / kg - 20 mg kg, are generally administered in the case of oral administration. With parenteral administration, e.g. B. via mucous membranes nasal, buccal, inhalation, a dosage of 0.001 mg / kg - 0.5 mg kg is useful.

Nevertheless, it may be necessary to deviate from the quantities mentioned, depending on the body weight or the type of route of administration, on the individual behavior towards the medication, the type of its shape and the time or interval at which the administration takes place , In some cases it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the above upper limit has to be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day. The compounds according to the invention are also suitable for use in veterinary medicine. For applications in veterinary medicine, the compounds or their non-toxic salts can be administered in a suitable form in accordance with the general veterinary practices. The veterinarian can determine the type of application and the dosage according to the type of animal to be treated.

The present invention is illustrated by the following examples, which, however, are in no way intended to limit the invention.

Claims

claims

1. Use of compounds of the general formula (I)

in which

R ^{1 represents} (C _r C ₆ ) alkyl,

R ^{2 represents} (C ₃ -C ₈ ) cycloalkyl or (C _r C ₁₂ ) alkyl,

R ^{3 represents} (C ₁ -C ₆ ) alkyl,

R ⁴ for a remainder of the formulas

, bliss

R ⁵ , R ⁶ and R ^{7 are the} same or different and are vinyl or (C _r Cg) alkyl, optionally up to 3 times, the same or different, by trifluoromethyl, halogen, (C ₁ -Cg) alkoxy or by remnants of the formulas FFFFIIII / ^CF 3

- O— C— C— F - C c

I I I I CF 3

F F F F

is substituted, where

R ^{8 is} hydrogen or (C 1 -C 4) alkyl,

or

R ⁵ , R ⁶ and / or R ⁷ (Cg-C ^ aryl mean, optionally up to 3 times, the same or different, by halogen, trifluoromethyl, nitro, cyano, carboxyl, (C -Cg) alkyl or (C -Cg) alkoxy is substituted

or

R ⁵ quinolyl or a 5- to 6-membered, aromatic or saturated heterocycle with up to 3 heteroatoms from the series S, N and / or

O means, which can optionally, in the case of an N function, be substituted by this, up to 3 times, identically or differently, by halogen or (-CC) alkyl

or

R ^{5 is} a residue of the formulas means what

R ⁹ and R ^{10 are the} same or different and are hydrogen, (C _j -Cg) alkyl or phenyl,

or

R ⁴ for carboxyl or for a radical of the formulas

-CO-R ¹³ or -OR ¹⁴ ,

wherein

R ¹¹ and R ^{12 are} identical or different and are hydrogen or (C 1 -C 4) -alkyl,

R ¹³ denotes (C _r C ₆ ) alkyl,

R ¹⁴ denotes (C ₁ -Cg) alkyl which is optionally substituted up to 3 times, identically or differently, by hydroxyl, phenyl or by a radical of the formula -NR ¹⁵ R ¹⁶ , wherein

R ¹⁵ and R ^{16 are} identical or different and are hydrogen, phenyl or (C1-C4) alkyl, which in turn can be substituted by phenyl, or

R ^{4 represents} a radical of the formula -NH-CO-NR ¹⁷ R ¹⁸ ,

wherein

R ¹⁷ and R ^{18 are the} same or different and are hydrogen or (C 1 -C 6) -alkyl, which may be by hydroxyl or by a radical of the formulas

or -NR ¹⁹ R ^{20 is} substituted,

embedded image in which

R ¹⁹ and R ^{20 are the} same or different and are hydrogen, phenyl or (-C-Cg) alkyl or

form, embedded image in which

R ²¹ denotes hydrogen or (C _r C ₆ ) alkyl,

a means either 1 or 2,

R ^{22 is} hydroxy or (-C-Cg) alkyl, which is optionally substituted by hydroxy, or

R ¹⁷ and / or R ¹⁸ (Cg-C ^ aryl mean, which is optionally substituted by halogen, trifluoroethyl or by -SCF3

or

R ^{17 is} hydrogen and

R ^{18 represents} a radical of the formula -SO ₂ -R ²³ ,

embedded image in which

R ^{23 means} (-C-Cg) -alkyl or (Cg-C ₁ 2) -aryl, which is optionally substituted by halogen,

or for a rest of the formulas

stands, or

R ⁴ for a radical of the formula

-NH-CO-R ²⁴ stands,

embedded image in which

R ^{24 is} a radical of the formula

means

embedded image in which

R ²⁵ and R ^{26 are the} same or different and are hydrogen, (-Cg) - alkyl or (-C-Cg) alkoxycarbonyl,

or

R ^{24 is} (C _r Cg) alkyl, which is optionally substituted by (Cg-C ₁ ) aryl, which in turn can be substituted by hydroxy or (-C-Cg) alkoxy or

(C ₁ -Cg) alkyl is optionally substituted by a radical of the formula - (SO ₂ ) -R ²⁷ ,

embedded image in which b is either 0 or 1 and

R27 ffo a rest of the formulas

stands,

or

R ^{4 stands} for (C ^ -C 12) - alkyl, optionally up to 3 times, identical or different, by hydroxy, azide, phenyl or by radicals of the formulas -NR ²⁸ R ²⁹ , -O-CO-R ³⁰ or -P (O) {0 - [(C ₁ -C ₆ ) al yl]} _{2 is} substituted,

wherein

R ²⁸ and R ^{29 are the} same or different, are hydrogen, phenyl or (-C-Cg) alkyl, which is optionally substituted by hydroxy, (-C-Cg) alkoxy or phenyl,

or

or form -N NR ³³ ,

embedded image in which

R ³¹ and R ^{32 are the} same or different and are hydrogen or

(C _r C ₆ ) alkyl

and

R ³⁰ denotes (C _r Cg) alkyl,

or

(C ₁ -Ci2) alkyl is optionally substituted by triazolyl, which in turn is up to 2-fold, identical or different, by halogen,

Phenyl, tetrahydrofuranyl, tetrahydropyranyl, (C ₁ -Cg) alkoxycarbonyl, ammocarbonyl or by (Ci-Cg) - alkyl may be substituted, the latter optionally by hydroxy, (C ^ -Cg) alkoxy or by a residue of Formulas NR ³⁴ R ³⁵ or -O-CO-R ³⁶ can be substituted,

embedded image in which R ³⁴ and R ^{35 are} identical or different and are hydrogen or (C _r C ₆ ) -alkyl,

R ³⁶ denotes (C _r Cg) alkyl,

or

R ^{4 represents} a radical of the formula -CO-R ³⁷ ,

embedded image in which

R ³⁷ for a remainder of the formulas

- CH -N r ^~ NR ₃ ³ ₈ ⁸

- (CH ₂ ) _C -NR ³⁹ R ⁴⁰ or -CH ₂ -P (O) (OR ⁴¹ ) (OR ⁴² ),

wherein

R ^{38 is} hydrogen or (C _r C ₆ ) -alkyl,

c means either 0 or 1, R ³⁹ and R ^{40 are the} same or different and are hydrogen or (-CC) -alkyl, which is optionally substituted by hydroxy,

R ⁴¹ and R ^{42 are the} same or different and (mean Ci-Cg ^ alkyl,

or

R ⁴ for a 5-membered heterocycle with up to 3 heteroatoms from the

Row S, N and / or O, which in the case of an N function is also substituted by this, optionally up to 3 times in total, identically or differently, by halogen, trifluoromethyl or by phenyl, which in turn is substituted one or more times Halogen or trifluoromethyl can be substituted,

and / or optionally substituted by (C3-Cg) cycloalkyl, pyrryl or by (CrCi2) alkyl, which in turn is replaced by cyano, trifluoromethyl, (Cι-Cg) alkoxycarbonyl, (Cι-Cg) alkoxy, amino or Phenyl or nitro-substituted phenyl can be substituted,

and / or optionally by -NR ⁴³ R ⁴⁴ , -NH-CO-CO-R ⁴ ^, -NH-CO-R ⁴⁶ ,

-NH-CO-CH ₂ -R ⁴⁷ , -CO-R ⁴⁸ or may be substituted,

wherein

R ⁴³ and R ^{44 are the} same or different and are hydrogen, benzyl, (-C ~ Cg) - alkyl or phenyl, which is optionally substituted by halogen or trifluoromethyl, R ⁴⁵ denotes (C _r Cg) alkoxy,

R ⁴⁶ denotes (C _r Cg) alkyl or phenyl,

wherein

R ^{49 means} (C _r C ₄ ) alkyl

R ^{48 represents} a radical of the formula -CH2-CN or phenyl, which is optionally substituted by halogen, trifluoromethyl or (-C-Cg) alkoxy,

and their salts, tautomers, N-oxides, prodrugs and hydrates and isomers

To form,

for the prophylaxis and / or treatment of diseases related to cGlVff -regulated processes ('cGMP-related diseases').

2. Use according to claim 1, wherein in the compounds of the general formula (I),

Rl represents (C _r C4) alkyl,

R ^{2 represents} cyclopentyl, cycloheptyl or (Cj -C ₁₀ ) alkyl,

R ^{3 represents} (C _r C ₄ ) alkyl, R ⁴ for a remainder of the formulas

stands,

Wonn

R ⁵ , R ⁶ and R ^{7 are the} same or different and are vinyl or (-CC) alkyl, which may be up to 3 times, the same or different, by trifluoromethyl, chlorine, (-C -4) alkoxy or by Remains of the formulas

is substituted,

embedded image in which

R ^{8 represents} hydrogen, methyl or ethyl,

or

R ⁵ , R ⁶ and / or R ^{7 are} phenyl which may be up to 3 times, identical or different, by halogen, trifluoromethyl, nitro, cyano,

Carboxyl, (C1-C4) alkyl or (C ₁ -C ₄ ) alkoxy is substituted

or

R ⁵ quinolyl or a radical of the formulas means

or

R ^{5 is} a residue of the formulas

means

embedded image in which

R ⁹ and R ^{10 are the} same or different and are hydrogen, (Ci-Cg) -

Mean alkyl or phenyl,

or R ⁴ for carboxyl or for a radical of the formulas

-CO-R ¹³ or -OR ¹⁴ ,

Wonn

R ¹¹ and R ^{12 are the} same or different and are hydrogen or (C1-C4) alkyl,

R ¹³ denotes (C _r C ₄ ) alkyl,

R ^{14 means} (-C-C4) alkyl, optionally up to 3 times, the same or different, by hydroxy, phenyl or by a radical of the formula

-NR ¹⁵ R ^{16 is} substituted,

embedded image in which

R ¹⁵ and R ^{16 are the} same or different and are hydrogen, phenyl or (-C-C4) alkyl, which in turn can be substituted by phenyl, or

R ^{4 represents} a radical of the formula -NH-CO-NR ¹⁷ R ¹⁸ ,

embedded image in which R ¹⁷ and R ^{18 are the} same or different and are hydrogen or (C 1 -C 4) -alkyl, which may be by hydroxy or by a radical of the formulas

or -NR ¹⁹ R ^{20 is} substituted,

embedded image in which

R ¹⁹ and R ^{20 are the} same or different and are hydrogen, phenyl or (01-04) ^ 11-71 or

form,

embedded image in which

R ^{2 is} hydrogen or (C _r C ₄ ) -alkyl,

means either 1 or 2,

R ^{22 is} hydroxy or (-CC) alkyl, which is optionally substituted by hydroxy, or R ¹⁷ and / or R ^{18 are} phenyl which is optionally substituted by chlorine, trifluoroethyl or by -SCF3

or

R ^{17 is} hydrogen and

R ^{18 represents} a radical of the formula -SO2-R ²³ ,

wherein

or for a rest of the formulas

stands,

or

R ⁴ for a radical of the formula

-NH-CO-R ²⁴ stands,

wherein

R ² 4 is a radical of the formula means

Wonn

or

R ^{24 means} (C _j -C4) alkyl, which is optionally substituted by phenyl, which in turn can be substituted by hydroxy or (-C-C4) alkoxy or

(C1-C4) alkyl is optionally substituted by a radical of the formula - (SO ₂ ) bR ²⁷ ,

embedded image in which

b is either 0 or 1 and

R ²⁷ for a remainder of the formulas

or stands for (C _j -Cu) - alkyl, optionally up to 3 times, identical or different, by hydroxy, azide, phenyl or by radicals of the formulas -NR ²⁸ R ²⁹ , -O-CO-R ³⁰ or -P (O) {O - [(C _r C ₆ ) alkyl]} _{2 is} substituted,

embedded image in which

R ²⁸ and R ^{29 are the} same or different, are hydrogen, phenyl or (Ci ^^ alkyl, which may be replaced by hydroxy,

(-C-C4) alkoxy or phenyl is substituted,

or

or form,

wherein

R ³¹ and R ^{32 are the} same or different and are hydrogen or (C _r C4) alkyl

R ³³ (C ₁ -C ₄ ) alkyl, benzyl, (C _r C ₄ ) -ajkoxycarbonyl, (C _r C ₄ ) -

Alkylcarbonyl, carboxyl, pyridyl, pyrimidyl or phenyl means that is optionally substituted by (-CC) alkoxy,

and

R ³⁰ denotes (C ₁ -C ₆ ) alkyl,

or

(Ci-C ^ - alkyl optionally substituted by triazolyl, which in turn up to 2 times, the same or different, by halogen, phenyl, tefrahydrofuranyl, tetrahydropyranyl, (C ₁ -C4) alkoxycarbonyl, aminocarbonyl or by (Cι -C4) -Alkyl may be substituted, the latter optionally being substituted by hydroxy, (-C-C4) alkoxy or by a radical of the formulas NR ³⁴ R ³⁵ or -O-CO-R ³⁶ ,

embedded image in which

R ³⁴ and R ^{35 are the} same or different and are hydrogen or

(C _r C ₄ ) alkyl,

R ³⁶ denotes (C _r C ₄ ) alkyl,

or

represents a radical of the formula -CO-R ³⁷ ,

embedded image in which

R ³⁷ for a remainder of the formulas

- (CH ₂ ) _C -NR ³ R ⁴⁰ or -CH ₂ -P (O) (OR ⁴¹ ) (OR ⁴² ),

wherein

R ^{38 is} hydrogen or (C _r C ₄ ) -alkyl,

c means either 0 or 1,

R ³⁹ and R ^{40 are the} same or different and are hydrogen or (-CC) -alkyl, which is optionally substituted by hydroxy,

R ⁴¹ and R ^{42 are} identical or different and denote (C ₁ -C 4) alkyl,

or

R ⁴ for a radical of the formula

stands, the tray 3-in the case of the pyrazole, also via the N function, optionally up to a total, the same or _different. is substituted by chlorine, trifluoromethyl or by phenyl, which in turn can be substituted one or more times by chlorine or trifluoromethyl,

and / or optionally substituted by cyclopentyl, cyclohexyl, pyrryl or by (C i -C 12) alkyl, which in turn is replaced by cyano, trifluoromethyl, (C ₁ -C4) alkoxycarbonyl, (C ₁ -C 4) alkoxy, amino or can be substituted by phenyl or nitro-substituted phenyl,

-NH-CO-CH2-R ⁴⁷ , -CO-R ⁴⁸ or can be substituted,

embedded image in which

R ⁴⁵ denotes (C _r C ₅ ) alkoxy,

R ⁴⁶ denotes (C _r C ₅ ) - alkyl or phenyl,

R ^{47 is} hydroxy, (C _r C ₄ ) alkoxy or a radical of the formula -O-CO-R ⁴⁹ ,

embedded image in which

R ^{49 means} (C _r C ₃ ) alkyl R ^{48 represents} a radical of the formula -CH ₂ -CN or phenyl, which is optionally substituted by chlorine, trifluoromethyl or (CpC4) alkoxy,

and their tautomers and their pharmaceutically acceptable salts, hydrates and prodrugs.

3. Use according to claim 1, wherein in the general formula (I)

R ^{1 represents} (C _r C ₄ ) alkyl,

R ^{2 represents} cyclopentyl, cyclohexyl, cycloheptyl or (C ^ -C ^ ₀ ) alkyl,

R ^{3 represents} (C _r C ₄ ) alkyl,

R ⁴ for a remainder of the formulas

stands,

embedded image in which

R ⁵ , R ⁶ and R ^{7 are the} same or different and are vinyl or (-C4) alkyl, which may be up to 3 times, the same or different, by trifluoromethyl, chlorine, (-C-C4) alkoxy or by radicals the

formulas

is substituted, embedded image in which

R ⁸ denotes hydrogen, methyl or ethyl,

or

R ⁵ , R ⁶ and / or R ^{7 are} phenyl which is optionally substituted up to 3 times, identically or differently, by halogen, cyano, (C ₁ -C4) alkyl or (C1-C4) alkoxy

or

R ^{5 is} a residue of the formulas

which may optionally be substituted up to 2 times, identically or differently, by chlorine or (C ₁ -C) alkyl

or

R5 is a radical of the formula -NR ⁹ R ¹⁰ ,

embedded image in which

R ⁹ and R ^{10 are} identical or different and are hydrogen, (C1-C4) -alkyl or phenyl, or

R ⁴ for carboxyl or for a radical of the formulas

O

ΔX or

-CO-R ¹³ or -OR ¹⁴ ,

embedded image in which

R ¹³ denotes (C _r C ₄ ) alkyl,

R ¹⁴ (-CC) -alkyl means that optionally up to 3 times, the same or different, by hydroxy or by a radical of the formula -NR ¹⁵ R! ^{6 is} substituted,

embedded image in which

R ¹⁵ and R ^{16 are} identical or different and are hydrogen or (Cj-C4) -Al yl, which in turn can be substituted by phenyl, or

R ^{4 represents} a radical of the formula -NH-CO-NR ¹⁷ Rl ⁸ ,

wherein

R ¹⁷ and R ^{18 are the} same or different and are hydrogen or (C _j - C ₄ ) -alkyl, which is optionally substituted by hydroxy, or

or _bildeιij

embedded image in which

R ²¹ denotes hydrogen or (C _r C ₄ ) -alkyl,

or

R ¹⁷ and / or R ^{18 are} phenyl which may be replaced by chlorine,

Trifluoroethyl or substituted by -SCF3

or

R ^{17 is} hydrogen and

R ^{18 represents} a radical of the formula -SO2-R ²³ ,

embedded image in which

R ²³ denotes (C ₁ -C 4) alkyl or phenyl which is optionally substituted by halogen,

or for a rest of the formulas stands,

or

R ⁴ for a radical of the formula

-NH-CO-R ²⁴ stands,

wherein

(C 1 -C 4) -alkyl is optionally substituted by a radical of the formula - (SO ₂ ) bR ²⁷ ,

wherein

b is either 0 or 1 and

R ²⁷ for a remainder of the formulas

or stands for (-C-Cg) -alkyl, which is optionally substituted up to 3 times, identically or differently, by hydroxy, phenyl or by radicals of the formulas -NR ²⁸ R ²⁹ or -O-CO-R ³⁰ ,

embedded image in which

R ²⁸ and R ^{29 are} identical or different, are hydrogen, phenyl or (C 1 -C 4) alkyl, which is optionally substituted by hydroxy, (C 1 -C 4) alkoxy or phenyl,

or

or form -N NR ³³ ,

worm

R ³¹ and R ^{32 are the} same or different and are hydrogen or (C _r C ₄ ) -A] alkyl

R ^{33 is} (C _r C ₄ ) -alkyl], benzyl, (C _r C ₄ ) -alkoxycarbonyl, (C _r C ₄ ) -alkylcarbonyl, carboxyl, pyridyl, pyrimidyl or phenyl, which is optionally replaced by (Cι-C4) Alkoxy is substituted, and

R ³⁰ denotes (C _r C ₆ ) alkyl,

or

(-C-Cg) -alkyl is optionally substituted by triazolyl, which in turn can be substituted up to 2 times, identically or differently, by (Cι-C4) -Al yl, the latter optionally by hydroxy or (C ^ -C4) Alkoxy can be substituted,

embedded image in which

or

R ^{4 represents} a radical of the formula -CO-R ³⁷ ,

embedded image in which

R ³⁷ for a remainder of the formulas

or - (CH ₂ ) _c -NR ³⁹ R ⁴ 0, embedded image in which

R ³⁸ denotes hydrogen or (C _λ -C ₄ ) alkyl,

c means either 0 or 1,

or

R ⁴ for a radical of the formula

stands,

which, in the case of pyrazole, is also substituted via the N function, optionally up to 3 times in all, identically or differently, by trifluoromethyl or by phenyl, which in turn can be substituted one or more times by chlorine or trifluoromethyl,

and / or optionally substituted by cyclopentyl, cyclohexyl or by (C _j -Cg) alkyl, which in turn can be substituted by (C 1 -C 4) alkoxy, amino or by phenyl,

and / or optionally substituted by -NR ³ R ⁴⁴ , -NH-CO-R ⁴⁶ , -NH-CO-CH ₂ -R ⁴⁷ or -CO-R ⁴⁸ ,

embedded image in which R ⁴³ and R ^{44 are} identical or different and denote hydrogen, benzyl, (C1-C4) -alkyl or phenyl, which is optionally substituted by halogen or trifluoromethyl,

R ⁴⁶ denotes (C _r C ₄ ) alkyl or phenyl,

R ^{47 is} hydroxy or (-C-C4) alkoxy y,

R ^{48 is} phenyl, which is optionally substituted by chlorine, trifluoromethyl or (-CC) alkoxy,

4. Use according to claim 1 of compounds having the following structures:

Use of compounds as defined in claims 1 to 4

Manufacture of pharmaceuticals for the prophylaxis and / or treatment of Diseases related to cGMP-regulated processes ('cGMP-related diseases').

6. Use of compounds as defined in claims 1 to 4 for the manufacture of medicaments for the treatment of diseases in which an improvement and / or by improving the microcirculation of a tissue which contains a cGMP-metabolizing phosphodiesterase

Healing of the clinical picture can be achieved.

7. Use of compounds as defined in claims 1 to 4 for

Manufacture of medicinal products for the treatment of and or prophylaxis of coronary heart disease, heart failure, pulmonary hypertension, bladder diseases, prostate hyperplasia, nitrate-induced tolerance, eye diseases such as glaucoma, for the treatment or prophylaxis of central retinal or posterior ciliary artery occlusion, opto-neuropathy, central retinal occlusion, central retinopathy anterior ischemic optical neuropathy and glaucomatous optical neuropathy, as well as macular degeneration, diabetes, for the treatment of disorders of the peristalsis of the stomach and esophagus, female infertility, premature labor, preeclampsia, alopecia, psoriasis of the renal syndrome, cystic

Fibrosis, cancer, to improve perception, to improve concentration, to improve learning and / or memory.