EP1513536A1

EP1513536A1 - Use of compounds that stimulate cgmp

Info

Publication number: EP1513536A1
Application number: EP03755960A
Authority: EP
Inventors: Helmut Haning; Erwin Bischoff; Ulrich DI NIEWÖHNER
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2002-06-03
Filing date: 2003-05-30
Publication date: 2005-03-16
Also published as: US20060148802A1; JP2005532339A; WO2003101456A1; CA2487905A1; DE10224462A1; AU2003250819A1

Abstract

The invention relates to the use of compounds that stimulate cGMP, in particular imidazo[1,3,5]triazinones, for producing a medicament for the treatment and/or prophylaxis of diseases, in which the clinical picture can be improved and/or cured by the improvement of the micro-circulation of tissue containing a phosphodiesterase that metabolises cGMP.

Description

Use of cGMP stimulating compounds

The present invention relates to the use of cGMP-stimulating compounds, in particular imidazo [1,3,5] triazinones, for the manufacture of a medicament for the treatment and / or prophylaxis of diseases in which the microcirculation of a tissue which metabolizes a cGMP is improved Contains phosphodiesterase, an improvement and / or healing of a clinical picture can be achieved.

Compounds with cGMP stimulating activity are known.

The synthesis of imidazo [1,3,5] triazinones is described in J. Org. Chem. (1979), 44 (10), 1740-2; in J. Org. Chem. (1979), 44 (22), 3835-9; in J. Org. Chem. (1981), 46 (18), 3681-5 and J. Chem. Res. Synop. (1994), (3), 96-7. A biological effect is not reported.

Imidazo [1,3,5] triazinones with antiviral and / or antitumor activity are described in Nucleosides Nucleotides (1987), 6 (4), 663-78; in Eur. J. Med. Chem. (1992), 27 (3), 259-66; in J. Heterocycl. Chem. (1993), 30 (5), 1341-9; in J. Med. Chem.

(1995), 38 (18), 3558-68 and Biorg. Med. Chem. Lett. (1996), 6 (2), 185-8. The compounds mentioned in these references were mostly produced as guanine or guanosine analogues and are therefore generally substituted in the 2-position with -NH ₂ , -SH or -H. None of the compounds described contains a phenyl ring or a substituted phenyl ring in the 2-position. None of the described

Compounds an inhibitory effect against phosphodiesterases is described.

The compounds used according to the invention are potent inhibitors of the cyclic guanosine 3 ', 5'-monophophate metabolizing phosphodiesterases

(cGMP - PDE's). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Be. 11, 150-155, 1990) is the phosphodiesterase isoenzyme PDE-I, PDE-II and PDE-V.

WO 0147928 describes imidazo [1,3,5] triazinones which are suitable, inter alia, for the treatment of erectile dysfunction and impotence.

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. Lugnier, Exp. Opin. Luvest. Drugs (1995), 4 (11 ), 1081-1100).

The relaxing effect on smooth muscles leads to a healing improvement in the microcirculation in tissues that cGMP metabohsian

Include phosphodiesterases.

The present invention relates to the use of cGMP-stimulating compounds, in particular imidazo [1,3,5] triazinones of the general formula (I)

in which

R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms, R represents straight-chain or branched alkyl having up to 4 carbon atoms or (C ₃ -C ₈ ) cycloalkyl,

R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R ⁴ and R ^{5 are the} same or different and represent hydrogen, (-CC ₆ ) alkoxy, hydroxy or (-C- ₈ ) - alkyl, which may be up to 3 times, identical or different, by hydroxy, (-C-C ₆ ) alkoxy or by residues of the formulas

is substituted,

wherein

R ⁶ and R ^{7 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,

and / or in turn (C 1 -C ₈ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by halogen, hydroxy, (C] -C ₆ ) alkoxy, (C 1 -C ₆ ) alkyl or are substituted by a radical of the formula -Sθ ₂ NR ⁸ R ⁹ ,

wherein

R and R are identical or different and denote hydrogen or (d-Cβ) alkyl, or

R, 4 represents hydrogen or methyl

and

R ⁵ for residues of the formulas

or

represents phenyl, which is optionally up to 3 times, identical or different, by halogen, acetyl, (-CC ₆ ) alkoxy or by radicals of the formulas

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )

is substituted,

wherein

R ¹⁰ and R ^{11 are} identical or different and are hydrogen or (-CC ₄ ) alkyl,

R ¹² and R ^{13 are} identical or different and denote hydrogen or (dC ^ alkyl, or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are residues of the formulas

form, bliss

R ¹⁴ and R ^{15 are the} same or different and denote hydroxy, hydrogen or (-CC) alkyl, which is optionally substituted by hydroxy,

or

R ¹⁴ means hydrogen

and

R ^{15 is} a radical of the formula

means

or

R. 14 "and Rτ, 15 together form a radical of the formula = NO-CH ₃ , R ^{16 is} hydrogen or (-CC ₆ ) alkyl, which is optionally substituted by hydroxy, or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means

and their salts, N-oxides, hydrates and hydrates of the salts and isomeric forms for the production of medicaments for the treatment of 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, as well as macular degeneration, diabetes, in particular diabetic gastro-deresis, for the treatment of gastroparesis disorders Esophagus, female infertility, premature labor, preeclampsia, alopecia,

Renal syndrome psoriasis, cystic fibrosis, cancer, to improve perception, to improve concentration, to improve learning and / or memory, especially if the disorder is a consequence of dementia, to improve perception, concentration, learning and / or memory performance after cognitive disorders, as is particularly the case with

Simulations / diseases / syndromes occur such as "mild cognitive impairment", age-related learning and memory disorders, age-associated memory loss, vascular dementia, traumatic brain injury, stroke, dementia that occurs after strokes ("post stroke dementia"), post- traumatic skull brain trauma, general concentration disorders, concentration disorders in children with learning and memory problems, vascular dementia, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with cortico-basal Degeneration, amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, new variant Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis.

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

The substances used according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts can be salts of the compounds used according to the invention with inorganic or organic acids. To be favoured

Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid , Toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, and also ammonium salts derived from ammonia, or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

(C ₃ -C ₈ ) Cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl. (-C ₈ ) alkyl, (-C ₆ ) alkyl or (-C ₄ ) alkyl represents a straight-chain or branched alkyl radical having 1 to 8, 1 to 6 or 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. A straight-chain or branched alkyl radical having 1 to 3 carbon atoms is particularly preferred.

(-C-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. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is particularly preferred.

Halogen generally represents fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.

A 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, O and / or N represents, for example, pyridyl, pyrimidyl, pyridazinyl,

Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.

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

in which

R ^{1 represents} methyl or ethyl, R ^{2 represents} straight-chain or branched alkyl having up to 3 carbon atoms or (C ₃ -C ₆ ) cycloalkyl,

R ^{3 represents} straight-chain or branched alkyl having up to 3 carbon atoms,

R ⁴ and R ^{5 are the} same or different and represent hydrogen, (-CC ₄ ) alkoxy, hydroxy or (-C-C ₇ ) -alkyl, which may be up to 3 times the same or different, by hydroxy, (-C-C ₄ ) alkoxy or by residues of the formulas

is substituted,

embedded image in which

R ⁶ and R ^{7 are the} same or different and are hydrogen or methyl,

and / or in turn (C 1 -C ₇ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by fluorine, chlorine, hydroxy, (C 1 -C ₄ ) alkoxy, ( C 1 -C ₄ ) alkyl or are substituted by a radical of the formula -SO ₂ NH ₂ ,

or

R ^{4 represents} hydrogen or methyl

and R ⁵ for residues of the formulas

stands

or

represents phenyl, optionally up to 3 times, the same or different, by fluorine, chlorine, acetyl, (-CC ₄ ) alkoxy or by radicals of the formulas

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )

is substituted,

wherein

R ¹⁰ and R ^{n are} identical or different and are hydrogen or methyl,

1 11 R and R are identical or different and are hydrogen or methyl,

or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached, residues of

formulas form,

Wonn

R ¹⁴ and R ^{15 are the} same or different and denote hydroxy, hydrogen or (C ₁ -C ₃ ) alkyl, which is optionally substituted by hydroxy,

or

R »14 means hydrogen

and

R ^{15 is} a radical of the formula

means

or

R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,

R ^{16 is} hydrogen or (-CC ₅ ) alkyl, which is optionally substituted by hydroxy, or means pyridyl, pyrimidyl, furyl, pyrryl or thienyl

and their salts, hydrates, N-oxides and isomeric forms. The use according to the invention of compounds of the general formula (I) is particularly preferred

in which

R ^{1 represents} methyl or ethyl,

R ^{2 represents} n-propyl or cyclopentyl,

R ^{3 represents} methyl, ethyl or n-propyl,

R and R are identical or different and represent hydrogen, (C] -C ₃ ) -alkoxy, hydroxy or (Cι-C ₆ ) -alkyl, which may be up to 3 times, identical or different, by hydroxy, ( -C-C ₃ ) alkoxy or by residues of the formulas

is substituted,

wherein

f. 7 •

R and R are identical or different and mean hydrogen or methyl,

and / or in turn (C ₁ -C ₆ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by fluorine, hydroxyl, methoxy or by a radical of the formula —SO ₂ NH _{2 are} substituted, or

R ^{4 represents} hydrogen or methyl

and

R ⁵ for residues of the formulas

O H stands

or

represents phenyl, optionally up to 3 times, the same or different, by fluorine, acetyl, methoxy or by radicals of the formulas

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )

is substituted,

wherein

R ¹ and R ^1! are identical or different and are hydrogen or methyl,

R ¹² and R ^{13 are} methyl,

or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are residues of the formulas

form,

wherein

R ¹⁴ and R ^{15 are} identical or different and denote hydroxy, hydrogen or a radical of the formula - (CH ₂ ) ₂ -OH,

or

R ¹⁴ means hydrogen

and

R ^{15 is} a radical of the formula

means or

R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH,

R ^{16 is} hydrogen, pyrimidyl or a radical of the formula - (CH ₂ ) ₂ -OH

and their salts, hydrates, hydrates of the salts, N-oxides and isomeric forms. The use of the following compounds according to the invention is very particularly preferred:

and their salts, hydrates, hydrates of the salts, N-oxides and isomeric forms.

The compounds used according to the invention and their preparation are described in WO / 0147928. The disclosure of WO / 0147928 is explicit

Referred.

The compounds 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, i.e. Diseases related to cGMP-regulated processes (usually simply referred to as 'cGMP-related diseases' in English).

The relaxing effect on smooth muscles makes them suitable for the treatment of diseases in which an improvement and / or healing of a clinical picture can be achieved by improving the microcirculation of a tissue which contains a cGMP metabohsive phosphodiesterase.

The inhibition of one or more phosphodiesterases leads to an increase in the cGMP concentration. This makes the connections interesting for everyone Therapies in which an increase in the cGMP concentration can be assumed to be beneficial.

In particular, the compounds mentioned are used 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 disorders 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 optic optic

Neuropathy, as well as macular degeneration, diabetes, especially diabetic gastroparesis, 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.

In particular, the compounds mentioned are also used to manufacture medicaments for improving perception, for improving concentration, for improving learning and / or memory, especially if the disorder is a consequence of dementia, for improving perception, concentration, learning and / or memory performance after cognitive disorders, as they occur in particular in situations / diseases / syndromes such as "mild cognitive impairment", age-related learning and memory disorders, age-associated memory loss, vascular dementia, traumatic brain injury, stroke, dementia that occurs after a stroke ("Post stroke dementia"), post-traumatic traumatic brain injury, general

Concentration disorders, concentration disorders in children with learning and memory problems, vascular dementia, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease Multiple

Sclerosis, thalamic degeneration, Creutzfeld acob dementia, new variant of Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis.

The activity of phosphorus diesterases (PDE's) can be determined as follows. The cGMP-stimulable PDE II, the cGMP-inhibitable PDE IQ and the cAMP-specific PDE IV were isolated from either pig or bovine myocardium. The Ca ²⁺ -calmodulin stimulable PDE I was isolated from pig aorta, pig brain or preferably from bovine aorta. The c-GMP 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 according to 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 μl in

20 mM Tris / HCl buffer pH 7.5 containing 5 mM MgCl ₂ , 0.1 mg / ml bovine 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. PDE stimulated by the cGMP

To test II, HcAMP is used as the substrate and 10 ^" mol / 1 of unlabeled cGMP is added to the batch. In order to test the Ca2 ⁺ -calmodulin-dependent PDE I, 1 μM CaCl ₂ and 0.1 μM calmodulin are added to the reaction batch The reaction is stopped by adding 100 μl of acetonitrile, which contains 1 mM cAMP and 1 mM AMP, 100 μl of the reaction mixture are separated by means of HPLC, and the cleavage products are determined “online” using a flow scintillation counter, and the substance concentration at which the In addition, the "Phosphodiesterase [H] cAMP-SPA enzyme assay" and the "Phosphodiesterase [H] cGMP-SPA enzyme assay" from Amersham Life Science were used for testing. The test was carried out according to the manufacturer's instructions specified test protocol the activity determination of the PDE II, the [ ³ H] cAMP SPA assay was used, with 10 ^"6 M cGMP being added to the reaction mixture to activate the enzyme. For the measurement of the PDE I 10 ^{" 7} M calmodulin and 1 μM CaCl were added to the reaction mixture. The PDE V was measured with the [H] cGMP SPA assay.

Memory performance can be determined by an object recognition test. The test measures the ability of rats (and mice) to distinguish between known and unknown objects.

The test is carried out as in 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.

The inhibition of one or more phosphodiesterases of this type leads to an increase in the cGMP concentration.

The compounds used according to the invention and their physiologically harmless salts (for example hydrochlorides, maleinates or lactates) and hydrates can be converted into the customary formulations in a known manner, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, Suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. Here, the therapeutically active compound should in each case be in a concentration of about 0.5 to 90% by weight of the

Total mix present, d. H. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, for example in the case of use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.

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. A dose of 0.001 mg / kg - 0.5 mg / kg is advisable via mucous membranes nasally, buccally, or by inhalation.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the drug, the type of its formulation 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 upper limit mentioned must 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 used 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 in a suitable formulation in

In accordance with general veterinary practices. The veterinarian can determine the type of application and the dosage according to the type of animal to be treated.

Claims

claims

1. Use of cGMP stimulating compounds for the production of a medicament for the treatment and / or prophylaxis of diseases in which an improvement and / or healing of a clinical picture can be achieved by improving the microcirculation of a tissue which contains a cGMP metabohsive phosphodiesterase.

2. Use according to claim 1 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, for the treatment and / or prophylaxis of central retinal or posterior cillaries Artery occlusion, central retinal venous occlusion, 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, renal syndrome, cystic fibrosis and / or cancer.

3. Use according to claim 1, for the manufacture of medicaments for improving perception, concentration, learning and / or memory, for improving perception, concentration, learning and / or memory after cognitive disorders, age-related learning and memory disorders, age-associated memory - Luster, vascular dementia, traumatic brain injury, stroke, dementia that occurs after stroke ("post stroke dementia"), post-traumatic traumatic brain injury, general concentration disorders, concentration disorders in children with learning and memory problems, vascular dementia , Lewy body dementia, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease,

Progressive nuclear palsy, dementia with corticobasal degeneration, Amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, new variant of Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis.

Use according to at least one of claims 1 to 3, characterized in that at least one imi- dazo [1,3,5] triazinone of the general formula (I) is used as the cGMP-stimulating compound

in which

R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms,

R ^{2 represents} straight-chain or branched alkyl having up to 4 carbon atoms or (C ₃ -C ₈ ) cycloalkyl,

R ^{3 represents} hydrogen or straight-chain or branched alkyl with up to 4

Carbon atoms,

R ⁴ and R ^{5 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) alkoxy,

Hydroxy or for (-CC ₈ ) - alkyl, optionally up to 3 times, the same or different, by hydroxy, (-C ^ alkoxy or by residues of the formulas

is substituted,

worm

R ⁶ and R ^{7 are the} same or different and are hydrogen or (-CC ₆ ) - alkyl,

and / or in turn (CrC ₈ ) - alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by halogen, hydroxy, (-C-C ₆ ) alkoxy, (Cι-C ₆ ) - Alkyl or substituted by a radical of the formula -SO ₂ NR R,

wherein

R ⁸ and R ^{9 are the} same or different and are hydrogen or (-CC ₆ ) - alkyl,

or

R ^{4 represents} hydrogen or methyl

and

R ⁵ for residues of the formulas stands

or

represents phenyl, which may be up to 3 times, identical or different, by halogen, acetyl, (-CC ₆ ) alkoxy or by radicals of the formulas

-NR ¹⁰ R ¹¹ or -CH ₂ -P (0) (OR ¹² ) (OR ¹³ )

is substituted,

embedded image in which

R ¹⁰ and R ^{11 are the} same or different and are hydrogen or

(-CC ₄ ) - alkyl mean

R ¹² and R ^{13 are} identical or different and are hydrogen or (Ci-Cβ) alkyl,

or

R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are residues of the formulas ^or form,

wherein

R ¹⁴ and R ^{15 are the} same or different and denote hydroxy, hydrogen or (C 1 -C ₄ ) -alkyl, which is optionally substituted by hydroxy,

or

R ¹⁴ means hydrogen

and

R ^{15 is} a radical of the formula

means

or

R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,

R ^{16 is} hydrogen or (-CC ₆ ) - alkyl, which is optionally substituted by hydroxy, or

is a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means and their salts, hydrates, hydrates of the salts, N-oxides and isomeric forms are used.

Use according to claim 4, characterized in that as a cGMP stimulating compound, compounds of general formula (I),

in which

R ^{1 represents} methyl or ethyl,

R 2 represents straight-chain or branched alkyl having up to 3 carbon atoms or (C ₃ -C ₆ ) cycloalkyl,

R ^{3 represents} straight-chain or branched alkyl having up to 3 carbon atoms,

R ⁴ and R ^{5 are the} same or different and represent hydrogen, (-CC) alkoxy, hydroxy or (C _t -C ₇ ) alkyl, which may optionally be up to 3 times, identical or different, by hydroxy, (Ci-G alkoxy or by residues of the formulas

is substituted,

wherein R ⁶ and R ^{7 are the} same or different and are hydrogen or methyl,

and / or in turn (C 1 -C ₇ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by fluorine, chlorine, hydroxy, (C 1 -C ₄ ) alkoxy, (Cι- C) alkyl or are substituted by a radical of the formula -SO NH ₂ ,

or

R represents hydrogen or methyl

and

R ⁵ for residues of the formulas

stands

or

represents phenyl, which is optionally up to 3 times, identical or different, by fluorine, chlorine, acetyl, (-C-C ₄ ) alkoxy or by radicals of the formulas

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )

is substituted, embedded image in which

R ¹⁰ and R ^{11 are the} same or different and are hydrogen or methyl,

R ¹² and R ^{13 are the} same or different and are hydrogen or methyl,

or

R and R together with the nitrogen atom to which they are attached are residues of the formulas

wherein

or

R ¹⁴ means hydrogen

and

R ^{15 is} a radical of the formula means

or

R. 14. and R. 15 together form a radical of the formula = NO-CH ₃ ,

R ^{16 is} hydrogen or (C ₁ -C ₅ ) alkyl, which is optionally substituted by hydroxy, or pyridyl, pyrimidyl, furyl, pyrryl or thienyl

and their salts, hydrates, hydrates of the salts, N-oxides and isomeric forms are used.

6. Use according to claim 4, characterized in that compounds of the general formula (I) are used as the cGMP-stimulating compound,

in which

R ^{1 represents} methyl or ethyl,

R ^{2 represents} n-propyl or cyclopentyl,

R ^{3 represents} methyl, ethyl or n-propyl,

R ⁴ and R ^{5 are the} same or different and represent hydrogen, (-CC ₃ ) alkoxy, hydroxy or (-C- ₆ ) -alkyl, which may be up to 3 times, identical or different, by hydroxy, (-C-C ₃ ) alkoxy or by residues of the formulas

is substituted,

embedded image in which

R ⁶ and R ^{7 are the} same or different and are hydrogen or methyl,

and / or in turn (dC ^ alkyl is optionally substituted by phenyl or phenoxy, which in turn are optionally substituted one to three times, identically or differently, by fluorine, hydroxyl, methoxy or by a radical of the formula -SO NH ₂ ,

or

R ^{4 represents} hydrogen or methyl

and

R ⁵ for residues of the formulas

stands

or represents phenyl, optionally up to 3 times, identical or different, by fluorine, acetyl, methoxy or by radicals of the formulas

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )

is substituted,

Wonn

R ¹⁰ and R ^{11 are the} same or different and are hydrogen or methyl,

R ¹² and R ^{13 are} methyl,

or

-V - - form ^N °,

Wonn

or R ¹⁴ means hydrogen

and

R ^{15 is} a radical of the formula

means

or

R ¹⁴ and R ¹⁵ together form a radical of the formula = N-0-CH ₃ ,

R ^{16 is} hydrogen, pyrimidyl or a radical of the formula - (CH) -OH

and their salts, hydrates, hydrates of the salts, N-oxides and isomeric forms.

7. Medicaments for the treatment and / or prophylaxis of diseases in which by improving the microcirculation of a tissue which contains a cGMP metabohsive phosphodiesterase, an improvement and / or healing of a clinical picture can be achieved, comprising at least one cGMP stimulating compounds.

8. Medicines for the treatment and / or prophylaxis of coronary heart disease, heart failure, pulmonary hypertension, bladder disorders,

Prostate hyperplasia, nitrate-induced tolerance, eye diseases, for the treatment and / or prophylaxis of central retinal or posterior ciliary artery occlusion, central retinal venous occlusion, optical neuropathy, as well as macular degeneration, diabetes, for the treatment of Disorders of peristalsis of the stomach and esophagus, female infertility, premature labor, preeclampsia, alopecia, psoriasis, renal syndrome, cystic fibrosis and or cancer containing at least one cGMP stimulating compound.

9. Medicines to improve perception, concentration, learning and / or memory, to improve perception, concentration, learning and / or memory after cognitive disorders, age-related learning and memory disorders, age-related memory loss, vascular dementia, traumatic brain injury Stroke

Dementia that occurs after a stroke ("post stroke dementia"), post-traumatic traumatic brain injury, general concentration disorders, concentration disorders in children with learning and memory problems, vascular dementia, dementia with Lewy bodies, dementia with degenera- tion of the frontal lobes including Pick's syndrome, Parkinson's

Disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, new variant of Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis containing at least one cGMP stimulating compound.

10. Medicament according to one of claims 7 to 9 containing as cGMP stimulating compound at least one compound as defined in claims 4 to 6.