EP1252165A1

EP1252165A1 - Isoxazolo pyrimidinones and the use thereof

Info

Publication number: EP1252165A1
Application number: EP00987389A
Authority: EP
Inventors: Ulrich Niewöhner; Helmut Haning; Thomas Lampe; Mazen Es-Sayed; Gunter Schmidt; Erwin Bischoff; Klaus Dembowsky; Elisabeth Perzborn; Karl-Heinz Schlemmer
Original assignee: Bayer AG; Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 1999-12-24
Filing date: 2000-12-12
Publication date: 2002-10-30
Also published as: WO2001047934A1; JP2003519153A; US20030149033A1; CA2395418A1; US6777416B2; AU2365001A

Abstract

The invention relates to novel isoxazolo pyrimidinones of general formula (I), a method for producing the same and the pharmaceutical use thereof.

Description

ISOXAZOLOPYRIMIDINONE AND THEIR USE

The present invention relates to new isoxazolopyrimidinones, processes for their preparation and their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.

In the Bull. Soc. Chim. Belg. (1994), 103 (5-6), 181-4 describes the synthesis of isoxazolo [4,5-d] pyrimineones which are unsubstituted in the 5-position. Compounds with a phenyl or substituted phenyl radical in the 5-

Position are not described. A biological effect of the substances described, in particular an inhibition of phosphodiesterases, is not reported.

The compounds according to the invention are potent inhibitors of cyclic

Guanos n 3 ', 5'-monophophate metabolizing phosphodiesterases (cGMP -PDE's). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), the phosphodiesterase isoenzymes PDE-I, PDE-H and PDE-V are concerned.

An increase in the cGMP concentration can lead to curative, anti-aggregatory, anti-thrombotic, anti-proliferative, anti-vasospastic, vasodilating, natriuretic and diuretic effects. It can affect short or long-term modulation of vascular and cardiac inotropy, cardiac rhythm and cardiac conduction (J.C. Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin.

Invest. Drugs (1995), 4 (11), 1081-1100). The inhibition of the cGMP-PDE's can also lead to an enhancement of the erection. Such compounds are therefore suitable for the treatment of erectile dysfunction. _^ The present invention now relates to novel isoxazolidinones the general formula (I)

in which

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

A for residues of the formulas

stands,

wherein

R ² and R ^{7 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are hydrogen, a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O or aryl with 6 to 10 carbon atoms , where the ring systems are optionally substituted up to three times, identically or differently, by hydroxy, halogen, (C Cs) - alkyl or (-C-C ₆ ) alkoxy, or

R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and are (C ₁ -C 6) -alkyl, which is optionally substituted by aryl having 6 to 10 carbon atoms and in turn up to 3 times, identical or different, by (-C ^ alkyl, (-C ^ alkoxy, hydroxy or halogen may be substituted,

or

R ³ and R ⁴ and / or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached, residues of the formulas

form where

R ⁸ denotes hydrogen or (-C ^ alkyl, which is optionally substituted by hydroxy,

and

R ^{9 represents} hydrogen or hydroxy,

and their salts, N-oxides and isomeric forms.

The compounds according to the invention 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 to both the enantiomers or 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 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 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, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid are preferred , 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. May be mentioned: cyclopropyl, cyclopentyl and

Cyclohexyl.

(C _ά - gVAryl stands for an aromatic radical with 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

(C _j -C ^ alkyl stands for a straight-chain or branched alkyl radical having 1 to 6 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 ₁ 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, ter-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 is, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.

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

in which

R ¹ for (C ₃ -C ₆ ) cycloalkyl or for. is n-propyl,

A for residues of the formulas

stands in what

R, 2 and j τ R.7 are the same or different and are hydrogen, methyl or ethyl, R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are hydrogen, pyridyl, pyrimidyl, pyridazinyl, furyl, tmidazolyl, thienyl, pyrryl or phenyl, the ring systems optionally up to 2 times, identical or different, by Hydroxy, fluorine, chlorine, (-G -alkyl or (-CC) alkoxy are substituted,

or

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are (CC ^ -alkyl, which is optionally substituted by phenyl, which in turn is up to 2 times the same or different, by (dC ^ -alkoxy, fluorine or chlorine can be substituted,

or

form where

and

R ⁹ denotes hydroxy,

and their salts, N-oxides and isomeric forms. Compounds of the general formula (I) according to the invention are particularly preferred

in which

R ^{1 represents} cyclopentyl or n-propyl,

A for residues of the formulas

stands in what

R ² and R ^{7 are the} same or different and are methyl or ethyl,

R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and represent hydrogen, pyridyl or phenyl, the ring systems optionally being substituted up to 2 times, identical or different, by fluorine, methoxy or ethoxy,

or

R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and are (C ₁ -C ₃ ) -alkyl, which is optionally substituted by phenyl, which in turn is up to 2-fold, identical or different, by methoxy or ethoxy is substituted,

or R ³ and R ⁴ and / or R ⁵ and R ⁶ together with the nitrogen atom are residues of the formulas

form where

R _> s is hydrogen or (-C-C3) alkyl or a radical of the formula

- (CH ₂ ) ₂ means -OH, and

R, 9 denotes hydroxy,

and their salts, N-oxides and isomeric forms.

The following compounds are very particularly preferred:

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention was found, characterized in that

initially compounds of the general formula (IT)

in which

R ^{1 has} the meaning given above,

by reaction with compounds of the general formula (DI) A'-CO-Cl,

in which

A 'for residues of the formulas

stands in what

R ² and R ^{7 have} the meaning given above,

in inert solvents, optionally in the presence of a base, into the compounds of the general formula (IV)

in which

A 'and R ^{1 have} the meaning given above,

convicted

then, in the presence of POCl ₃ or of alkali or alkaline earth metal hydroxide, cyclization to give the compounds of the general formula (V) in which

A 'and R ^{1 have} the meaning given above,

performs,

in a further step by reaction with CISO3H the compounds of the general formula (VI)

in which

A 'and R ^{1 have} the meaning given above,

manufactures

and finally with amines of the general formula (VH)

HNR ¹⁰ R ⁿ (V), in which

R ¹⁰ and R ¹¹ include the scope of R ³ , R ⁴ , R ⁵ and R ⁶ given above, implements.

The method according to the invention can be illustrated by the following formula schemes:

The usual organic solvents which do not change under the reaction conditions are suitable as solvents for the individual steps. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fuctions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, trichlorethylene or chlorine or chlorine or chlorine thylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the solvents mentioned.

The reaction temperatures can generally vary within a substantial range. Generally one works in a range from -20 ° C to 200 ° C, preferably from 0 ° C to 70 ° C.

The process steps according to the invention are generally carried out at normal pressure. However, it is also possible to carry out at overpressure or at underpressure (e.g. in a range from 0.5 to 5 bar).

The reactions can take place, for example, in a temperature range from 0 ° C. to room temperature and at normal pressure.

The compounds of the general formula (D are new and can be prepared (for example analogously to Gazz. Chim. Ital. 97, 1967, 25-33) by using compounds of the general formula (VD)

R ^ CHO (VD), in which

R ^{1 has} the meaning given above,

by reaction in the system 1.) CH ₃ -NO ₂ / KF and 2.) K ₂ Cr ₂ O ₄ in the compounds of the general formula (VDI)

R ¹ -CO-CH ₂ -NO ₂ (Vm), in which

R ^{1 has} the meaning given above, convicted

then the compounds of the general formula (IX) by reaction with hydroxylamine

in which

R ^{1 has} the meaning given above,

manufactures

these with oxalic acid ethyl chloride in a solvent (e.g. ether) to give the compounds of the general formula (X)

in which

R ^{1 has} the meaning given above,

cycHsiert, by the action of ammonia in the compounds of the general formula (XI)

in which

R ^{1 has} the meaning given above,

transferred, and reduced in a last step with Zn / NH C1 to the compounds of general formula (II).

The compounds of the general formula (DI) are known.

The compounds of the general formula (IV) are not known. The compounds of the general formula (V) are not known.

The compounds of the general formula (VI) are not known.

The compounds of the general formula (VD) are known.

The compounds of the general formula (VTII) are known.

The compounds of the general formula (EX) are known. The compounds of the general formula (X) are known.

The compounds of the general formula (XI) are known.

The compounds of the general formula (T) according to the invention show an unforeseeable, valuable spectrum of pharmacological action.

They inhibit either one or more of the c-GMP metabolizing phosphodiesterases (PDE I, PDE D and PDE V). This leads to an increase in c-GMP. The differentiated expression of the phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in combination with the selective inhibitors according to the invention, enable a selective addressing of the various processes regulated by cGMP.

In addition, the compounds according to the invention enhance the action of substances such as EDRF (endothelium derived relaxing factor), ANP (atrial natriuretic peptide), nitrovasodilators and all other substances which increase the cGMP concentration in a manner other than phosphodiesterase inhibitors. The compounds of the general formula (T) according to the invention are therefore suitable for the prophylaxis and / or treatment of diseases in which an increase in the cGMP concentration is healing, ie diseases which are related to cGMP-regulated processes (in English usually simply as 'cGMP-related diseases'). These include cardiovascular diseases, diseases of the genitourinary system and cerebrovascular explanations.

The term “cardiovascular diseases” in the sense of the present invention includes diseases such as, for example, high blood pressure, neuronal hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, arrhythmias, thromboembolic diseases and ischemia such as myocardial infarction, stroke, transitory and ischemic attacks pectoris, peripheral circulatory disorders, prevention of restenosis after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) and bypass.

Furthermore, the compounds of the general formula (I) according to the invention can also be of importance for cerebrovascular diseases. These include, for example, cerebral ischemia, stroke, reperfusion damage, brain trauma, edema, cerebral thrombosis, dementia and Alzheimer's disease.

The relaxing effect on smooth muscles makes them suitable for the treatment of diseases of the genitourinary system such as prostate hypertrophy, incontinence and in particular for the treatment of erectile dysfunction and female sexual

Dysfunction.

Activity of phosphorus diesterases (PDE's)

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

Ca ⁺ -calmodulin stimulable PDE I was from porcine aorta, Schwemehi or preferably isolated 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.

Bioche ical 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, which contains 5 mM MgCl ₂ , 0.1 mg / ml bovine serum albumin and contains 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 D To test, ³ HcAMP is used as substrate and 10 ^"6 mol / l unlabeled cGMP is added to the batch. 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, 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. The substance concentration is measured at which the reaction rate is around

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 [ ³ H] cAMP SPA assay was used to determine the PDE II activity, the reaction approach

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 with the [ ³ H] cGMP SPA assay.

Basically, the inhibition of one or more phosphodiesterases of this type leads to an increase in the cGMP concentration. This makes the connections interesting sant 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 dogs. The substances were administered intravenously or orally.

The investigation for erection-inducing effects was carried out on the awake rabbit [H. Naganuma, T. Egashira, J. Fuji, Clinical and Experimental Pharmacology and Physiology 20, 177-183 (1993)]. The substances were administered orally or parenterally.

The new active ingredients and their physiologically acceptable salts (for example hydrochlorides, maleinates or lactates) 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 suitable carriers or solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. 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, z. B. in the case of the use of water as a diluent, optionally organic solvents as auxiliary

, solvents can be used.

The application is carried out in the customary manner, preferably orally, transdermally or parenterally, for example peringuically, buccally, intravenously, nasally, rectally or by inhalation. For oral administration, doses of 0.001 to 50 mg / kg, preferably 0.01 mg / kg - 20 mg kg, are generally administered for oral administration. In the case of parenteral administration, such as nasal, buccal, or inhalative via mucous membranes, a dosage of 0.001 mg / kg -0.5 mg kg is advisable.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, the individual behavior towards the medication, 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 according to the invention are also suitable for use in veterinary medicine. For veterinary applications, the compounds or their non-toxic salts can be administered in a suitable formulation 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.

Production of the preliminary stages

Example I

cyclopentanecarbaldehyde

669 ml of a 2 M solution of cyclopentyl magnesium chloride in diethyl ether (1.1 mol) are added dropwise at 0 ° C. with a solution of 128.7 g (1.1 mol) of N-formylpiperidine in 450 ml of diethyl ether. After the dropwise addition, the reaction mixture is stirred at room temperature for 1.5 hours. It is poured onto water, extracted three times with diethyl ether, the organic phase is washed with sodium hydrogen carbonate solution, dried over sodium sulfate and the solvent is removed in vacuo. 84.4 g of crude product (HPLC purity 75%) are obtained, which is further implemented as such.

Example II

1-Cyclopentyl-2-nitro-1-ethanone

84.36 g (859 mmol) of cyclopentane carbaldehyde (Example I), 262 g (4.29 mol) of nitiomethane and 9.99 g (171 mmol) of anhydrous potassium fluoride are stirred in 900 ml of isopropanol at room temperature overnight. It is filtered and the solvent is removed in vacuo. 136.28 g (89%) of oil are obtained.

21.67 g (136 mmol) of this oil are dissolved with 4.62 g of tetia-n-butylammonium hydrogen sulfate in 200 ml of dichloromethane and cooled to -10 ° C. Be at the same time 210 ml of 30% sulfuric acid and 52.06 g (177 mmol) of calcium dichromate were slowly added at this temperature. After 2 hours at -10 ° C., 180 ml of 10% iron (D) sulfate solution are added, the phases are separated and the organic phase is dried over sodium sulfate. Filtration through silica gel gives 14.92 g (62%)> oil.

200 MHz 1H NMR (CDC1 ₃ ): 1.69, m, 8H; 3.02, quin, 1H; 5.91, s, 2H.

Example III 1-Cyclopentyl-2-nitro-1-ethanone oxime

9.90 g (63 mmol) of l-cyclopentyl-2-nitroethanone (Example II) and 20.688 g (126 mmol) of hydroxylamine sulfate are heated under reflux in 310 ml of a toluene / ethanol mixture (1: 1) for 4 hours. The solvent is removed in vacuo, the residue is taken up in ethyl acetate, the organic phase is washed twice with water, dried over sodium sulfate and the solvent is removed in vacuo. 9.62 g (74%) of a light yellow solid are obtained. 200 MHz 1H NMR (CDC1 ₃ ): 1.65, m, 6H; 1.93, m, 2H: 2.80, quin., 1H; 5.20, s, 2H; 9.19, s, broad, 1H.

Example IV

3-cyclopentyl-4-nitro-isoxazole-5-carboxylate

137.2 g (798 mmol) l-cyclopentyl-2-nitroethanone oxime (example DI) and 119.78 g

(877 mmol) ethyl oxalate chloride are stirred in 1.4 l of anhydrous ether overnight at room temperature. The reaction mixture is cooled to 0 ° C. and 246 ml of triethylamine are added dropwise. After 2 hours at room temperature, the mixture is diluted with ether, extracted with ammonium chloride solution and water and the organic phase is dried over sodium sulfate. chromatographic

Purification (toluene) gives 51.59 g (82% purity, 20.7%) yellow oil. 200 MHz 1H NMR (CDC1 ₃ ): δ = 1.44, t, 3H; 1.80, m, 6H; 2.11, m, 2H; 3.44, m, 1H; 4.51, quarter, 2H.

Example V

3-cyclopentyl-4-nitro-isoxazole-5-carboxamide

51.59 g (203 mmol) of 3-cyclopentyl-4-nitro-isoxazole-5-carboxylic acid ethyl ester

(Example IV) are stirred in 600 ml of a 2 M solution of ammonia for 3 hours at room temperature. The solvent is removed in vacuo, the residue is stirred with cyclohexane and dried in vacuo. 31.17 g (62%) of a colorless solid are obtained. 200 MHz 1H NMR (CDC1 ₃ ): δ = 1.78, m, 6H; 2.13, m, 2H; 3.52, m, 1H; 7.92, s, broad, 1H; 8.28, s, broad, 1H.

Example VI

4-amino-3-cyclopentyl-isoxazole-5-carboxamide

3.15 g (13.9 mmol) of 3-cyclopentyl-4-nitro-isoxazole-5-carboxamide (Example V) and 17.51 g (327 mmol) of ammonium chloride are suspended in 70 ml of water and the suspension is cooled to 0.degree. 8.5 g (118 mmol) of zinc powder are added in small portions with vigorous stirring. The reaction mixture is stirred for 30 minutes at room temperature. For working up, the mixture is filtered through kieselguhr, washed with ethyl acetate and the filtrate is evaporated to dryness in vacuo. The residue is stirred with ethyl acetate. After filtering, the solvent is removed in vacuo. 1.95 g (70%) of a colorless solid are obtained. 200 MHz 1H NMR (CDC1 ₃ ): δ = 1.80, m, 6H; 2.06, m, 2H; 3.07, m, 1H; 4.28, s, broad, 2H; 5.74, s, broad, 1H; 6.02, s, broad, 1H.

Example VII

3-cyclopentyl-4 - [(2-ethoxybenzoyl) amino-3-isoxazol-5-carbonsäurearnid

390.5 mg (2.0 mmol) of 4-amino-3-cyclopentyl-isoxazole-5-carboxamide

(Example VI) are introduced with a catalytic amount of 4-N, N-dimethylaminopyridine (DMAP) in 2.0 ml of pyridine. 553.9 mg (3.0 mmol) of 2-ethoxybenzoic acid chloride are added and the mixture is stirred at 60 ° C. for 5 h before a further 277 mg of 2-ethoxybenzoic acid chloride are added. After an additional 5 h at 60 ° C., the reaction mixture is taken up in dichloromethane and washed twice with saturated

Sodium bicarbonate solution. It is dried over magnesium sulfate, concentrated on a rotary evaporator and dried in a high vacuum. It is purified by flash chromatography with dichloromethane / methanol 95: 5. Yield: 168 mg (21% of theory) Rr value = 0.368, dichloromethane / methanol 95: 5

MS (DCI, NH ₃ ): m / z (%) = 344 (M + H) (100)

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.61 (t, 3 H); 1.62-1.89 (m, 6H); 2.03-2.17 (m, 2H); 3.54 (qui, 1H); 4.35 (q, 2H); 5.74 (bs, 1H); 6.48 (bs, 1H); 7.02-7.15 (m, 2H); 7.52 (dt, 1H); 8.27 (dd, 1H); 10.30 (bs, 1H).

Example VIII

3-Cyclopen1 l-5- (2-ethoxyphenyl) isoxazolo [4,5-d] pyrin_tidin-7 (6H) -one

1.7 g (4.95 mmol) of 3-cyclopentyl-4 - [(2-ethoxybenzoyl) amino] isoxazole-5-carboxamide (Example VD) are placed in 30 ml of toluene. 1.55 g (7.4 mmol) of phosphorus oxychloride are added to the suspension and the mixture is stirred under reflux for 2 h. It is diluted with ethyl acetate and washed with 1N sodium hydroxide solution. It is dried and concentrated on a rotary evaporator. The product is isolated from the mixture by chromatography on silica gel with cyclohexane / ethyl acetate 6: 4. Yield: 79.2 mg (4.9% of theory)

MS (DCL, NH ₃ ): m / z (%) = 343 (M + 18) (100), 326 (M + H) (58), 242 (34) 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.67 (t, 3H); 1.70-2.30 (m, 8H); 3.52 (qui, 1H); 4.32 (q, 2H); 7.02-7.21 (m, 2H); 7.52 (German, .1H); 8.49 (dd, 1H); 11.68 (bs, 1H).

Example IX

3- (3-Cyclopentyl-7-oxo-6,7-dihydroisoxazolo [4,5-d] pyrimidin-5-yl) -4-ethoxybenzenesulfonic acid chloride

0.24 ml (3.6 mmol) of chlorosulfonic acid are placed under ice cooling. 130 mg (0.4 mmol) of 3-cyclopentyl-5- (2-ethoxyphenyl) isoxazolo [4,5-d] pyr_unidin-7 (6H) -one (example VTLT) are added in portions, and the mixture is then stirred under reflux overnight , diluted with dichloromethane and poured onto ice water. The organic phase is separated off and extracted again with dichloromethane, the organic phases are combined, dried and evaporated. Yield: 134 mg (81.8% of theory)

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.70 (t, 3 H); 1.65-2.35 (m, 8H); 3.58 (m, 1H); 4.49 (q, 2H); 7.28 (d, 1H); 8.18 (dd, 1H); 9.13 (d, 1H); 11.33 (bs, 1H).

Example X

3-cyclopentyl-4 - {[2- (4-methoxyphenyl) acetyl] anmιo} isoxazole-5-carboxamide

12 g (61 mmol) of 4-amino-3-cyclopentyl-isoxazole-5-carboxamide (Example VI) are dissolved in 50 ml of pyridine and mixed with 12.48 g (67 mmol) of 4-methoxyphenyl acetic acid chloride and a spatula tip DMAP. The reaction mixture is stirred for 5 hours at 60 ° C. and then the solvent is removed in vacuo. The residue is taken up in dichloromethane, the solution is shaken twice with 1N hydrochloric acid and twice with sodium hydrogen carbonate solution, dried over sodium sulfate and the solvent is removed in vacuo. The residue is stirred with a little dichloromethane, filtered, the filtrate is evaporated to dryness and the residue is purified by chromatography (cyclohexane / ethyl acetate = 2: 1). Yield: 2.56 g 200 MHz 1H NMR (DMSO-D ₆ ): 1.55, m, 8H; 2.92, m, 1H; 3.56, s, 2H; 3.72, s, 3H; ^' 6.88, d, 2H, 7.27, d, 2H; 7.92, s, broad, 1H; 8.08, s, broad, 1H; 9.76, s, 1H.

Example XI

3-cyclopentyl-5- (4-methoxyphenyl) -isoxazolo [4,5-d] pyrimidin-7 (6H) -one

2.56 g (7.45 mmol) of 3-cyclopentyl-4 - {[2- (4-methoxyphenyl) acetyl] amino} -isoxazole-5-carboxamide (Example X) are heated under reflux with 4.3 g of potassium hydroxide in 170 ml of methanol for 16 hours. The solvent is removed in vacuo, the residue is taken up in dichloromethane, the solution is washed with 1 N hydrochloric acid and water, the organic phase is dried over sodium sulfate and the solvent is removed. The residue is purified by chromatography (cyclohexane / ethyl acetate = 2: 1).

Yield: 0.93 g (38% of theory)

200 MHz 1H NMR (DMSO-D ₆ ): 1.73, m, 6H; 2.08, m, 2H; 3.38, m, 1H; 3.71, s, 3H;

3.91, s, 2H; 6.89, d, 2H; 7.27, d, 2H; 13Λ6, s, broad, 1H. Example XII

5 - [(3-Cyclopentyl-7-oxo-6,7-dihydroisoxazolo [4,5-d] py_rim methoxybenzenesulfonic acid chloride

1.23 g (3.78 mmol) of 3-cyclopentyl-5- (4-methoxybenzyl) isoxazolo [4,5- ^ pyrimidin-7 (6H) -one (Example XI) are introduced in portions in 2.51 ml of chlorosulfonic acid at 0 ° C. The reaction mixture is stirred at room temperature for 16 hours. It is poured onto ice water, the precipitate is filtered off and dried in vacuo. Yield: 1.31 g (77% of theory)

200 MHz 1H NMR (CDC1 ₃ ): 1.78, m, 6H; 2.19, m, 2H; 3.48, quin., 1H; 4.03, s, 3H; 4.15, s, 2H; 7.11, d, 1H; 7.81, dd, 1H; 8.06, d, 1H; 12.52, s, broad, 1H.

Manufacture of active ingredients

example 1

3-Cyclopentyl-5- (2-ethoxy-5 - {[4- (2-hydroxyethyl) piperazino] sulfonyl} phenyl) isoxazolo [4,5-d] pyrimidin-7 (6H) -one

130 mg (0.31 mmol) of the sulfonic acid chloride Example IX are placed in 7 ml of dichloromethane. 120 mg (0.92 mmol) of N-hydroxyethylpiperazine are added and the mixture is stirred overnight at room temperature. It is diluted with dichloroethane, washed with water, extracted again with dichloroethane, dried and evaporated. The residue obtained is crystallized with ether and the product is filtered off with suction. Yield: 129 mg (81.3% of theory) Rr ert = 0.253, dichloromethane / methanol 95: 5 MS (DCI, NH ₃ ): m / z (%) = 518 (M + H) (100)

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.69 (t, 3 H); 1.70-2.31 (m, 9H); 2.54-2.68 (m, 6H); 3.06-3.15 (m, 4H); 3.48-3.62 (m, 3H); 4.45 (q, 2H); 7.22 (d, 1H); 7.90 (dd, 1H); 8.84 (d, 1H). Example 2

3- (3-Cyclopentyl-7-oxo-6,7-dihydroisoxazolo [4,5-d] pyrm_ήdin-5-yl) -N- (3,4-dimethoxyphenethyl) -4-e1hoxy-N-memyl-benzenesulfonamide

89.8 mg (0.46 mmol) of N-methylhomoveratrylamine are added to a solution of 65 mg (0.153 mmol) of the sulfonic acid chloride from Example IX in 5 ml of dichloromethane. The mixture is stirred overnight at room temperature before, after concentration, the crude product is purified by preparative TLC chromatography with dichloromethane / methanol 95: 5. The oily residue is crystallized with ether.

Yield: 88 mg (98.5% of theory) MS (ESI pos.): M / z (%) = 605 (M + Na) (100), 583 (+ H) (66) 1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.59 (t, 1H); 1.62-2.23 (m, 8H); 2.80 (s, 3H); 2.80-2.88 (m, 2H); 3.29 (bt, 2H); 3.51 (qui, 1H); 3.85 (s, 6H); 4.25 (q, 2H); 6.68-

6.78 (m, 2H); 7.11 (d, 2H); 7.82 (dd, 1H); 8.71 (d, 1H). Example 3

3-Cyclopentyl-5- {4-methoxy-3 - [(4-methylpiperazino) sulfonyl] benzyl} - isoxazolo [4,5-d] pyrimidin-7 (6H) -one

40 mg (0.08 mmol) of the sulfonic acid chloride Example IX are dissolved in 1 ml of dichloromethane and 20 mg (0.24 mmol) of N-methylpiperazine and a spatula tip of DMAP are added at 0 ° C. The reaction mixture is stirred for 16 hours at room temperature. After dilution with dichloromethane, the mixture is extracted with ammonium chloride solution, dried over sodium sulfate and the solvent in

Vacuum removed. The residue is purified by chromatography (dichloromethane / methanol 30: 1). Yield: 30 mg (75% of theory) 200 MHz 1H-NMR (CDC1 ₃ ): 1.84, m, 6H; 2.15, m, 2H; 2.29, s, 3H; 2.43, m, 4H; 3.21, m, 4H; 3.49, m, IH; 3.88, s, 3H; 4.05, s, 2H; 6.92, d, IH; 7.54, dd, IH; 7.91, d,

IH.

Example 4

3-Cyclopentyl-5- {3 - [(4-hydroxypiperidino) sulfonyl] -4-methoxyphenyl} isoxazolo- [4,5-d] pyrimidin-7 (6H) -one

The representation is carried out analogously to Example 3, starting from 40 mg (0.08 mmol) of the

Sulfonic acid chloride from Example IX and 30 mg (0.24 mmol) 4-hydroxypiperidine.

Yield: 14 mg (33% of theory)

200 MHz 1H NMR (CDC1 ₃ ): 1.59, m, 2H; 1.89, m, 8H; 2.15, m, 2H; 3.02, m, 2H;

3.48, m, 1H; 3.81, m, IH; 3.89, s, 3H; 4.08, s, 2H, 6.98, d, IH, 7.55, dd, IH, 7.91, d,

IH.

Example 5

5 - [(3-Cyclopen1yl-7-oxo-6,7-dihy (üoisoxazolo [4,5-d] pyrin_tidin-5-yl) methyl] -2-methoxy-N- (4-pyrimidyl) benzenesulfonamide

The preparation is carried out analogously to Example 3, starting from 40 mg (0.08 mmol) of the sulfonic acid chloride from Example Xu and 20 mg (0.24 mmol) of 4-aminopyridine. Yield: 5 mg (11%) R _f value = 0.12 (dichloromethane / methanol = 10: 1)

Example 6

5 - [(3-Cyclopentyl-7-oxo-6,7-dihydroisoxazolo [4,5-d] py_rirmdin-5-yl) methyl] -N- (3-fluoro-4-methoxyphenyl) -2-methoxybenzenesulfonamide

The preparation is carried out analogously to Example 3, starting from 40 mg (0.08 mmol)) of the sulfonic acid chloride from Example XD and 30 mg (0.24 mmol) of 4-methoxy-3-fluoro-aniline.

Yield: 2 mg (4%) R _f value = 0.41 (cyclohexane / ethyl acetate = 1: 2)

Claims

claims

1. New isoxazolopyrimidinones of the general formula (I)

in which

for remnants of the formulas

stands,

wherein

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are hydrogen, one

5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O or aryl with 6 to 10 carbon atoms, the ring systems optionally up to three times, identically or differently, by Hydroxy, halogen, (CrCs ^ alkyl or (C ₁ -C ₆ ) alkoxy are substituted,

or

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and mean (-CC ₆ ) - alkyl, which is optionally substituted by aryl having 6 to 10 carbon atoms and in turn up to 3 times, the same or different, by (-CC ₆ ) alkyl, (CrC ₆ ) alkoxy, hydroxy or halogen may be substituted,

or

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

form where

R ⁸ denotes hydrogen or (Ci-C ₆ ) -alkyl, which is optionally substituted by hydroxy,

and

R ^{9 represents} hydrogen or hydroxy,

and their salts, N-oxides and isomeric forms.

New isoxazolopyrimidinones of the general formula (I) according to Claim 1,

in which represents (C ₃ -C ₆ ) cycloalkyl or n-propyl,

for remnants of the formulas

stands in what

R ² and R ^{7 are the} same or different and are hydrogen, methyl or ethyl,

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are hydrogen, pyridyl, pyrimidyl, pyridazinyl, furyl, imidazolyl, thienyl, pyrryl or phenyl, the ring systems optionally up to 2 times, identical or different, by Hydroxy, fluorine, chlorine, (CrC ^ alkyl or (dC ^ alkoxy) are substituted,

or

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and (CrC ^ -alkyl, which is optionally substituted by phenyl, which in turn up to 2 times, the same or different, by (Q-C) alkoxy , Fluorine or chlorine can be substituted,

or R ³ and R ⁴ and / or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached, residues of the formulas

° ^the form where

R ⁸ denotes hydrogen or (C ₁ -C ₆ ) alkyl, which is optionally substituted by hydroxy,

and

R ⁹ denotes hydroxy,

and their salts, N-oxides and isomeric forms.

New isoxazolopyrimidinones of the general formula (I) according to Claim 1,

in which

R ^{1 represents} cyclopentyl or n-propyl,

for remnants of the formulas

stands in what

R ² and R ^{7 are the} same or different and are methyl or ethyl, R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and represent hydrogen, pyridyl or phenyl, the ring systems optionally being substituted up to 2 times, identical or different, by fluorine, methoxy or ethoxy,

or

R ³ , R ⁴ , R ⁵ and R ^{6 are} identical or different and are (CrC ₃ ) -alkyl, which is optionally substituted by phenyl, which in turn is up to 2 times, identical or different, substituted by methoxy or ethoxy,

or

form where

R ^{8 is} hydrogen or (C ₁ -C ₃ ) alkyl or a radical of

Formula - means (CH ₂ ) ₂ -OH, and

R ⁹ denotes hydroxy,

and their salts, N-oxides and isomeric forms.

4. New isoxazolopyrimidinones of the general formula (T) according to Claims 1 to 3 with the following structures: A process for the preparation of Isoxazolopy_rimidinone according to claims 1 to 4, characterized in that

initially compounds of the general formula (D

in which

R ^{1 has} the meaning given above,

by reaction with compounds of the general formula (DT)

A'-CO-Cl (DI), in which

A 'for residues of the formulas

stands in what

R ² and R ^{7 have} the meaning given above,

in inert solvents, optionally in the presence of a base, in the compounds of the general formula (IV) in which

A 'and R ^{1 have} the meaning given above,

convicted

then in the presence of POCl ₃ or of alkali or alkaline earth hydroxide, a cyclization to give the compounds of the general formula (V)

in which

A 'and R ^{1 have} the meaning given above,

performs,

in a further step by reaction with CISO ₃ H the compounds of the general formula (VT)

in which

A 'and R ^{1 have} the meaning given above,

hersteUt,

and finally with amines of the general formula (VH)

HNR ¹⁰ R ^π (VD), in which

R ¹⁰ and R ¹¹ include the scope of R ³ , R ⁴ , R ⁵ and R ⁶ given above,

implements.

6. Compounds of the general formula (I) according to Claims 1 to 4 for the prophylaxis and / or treatment of diseases.

7. Medicament or pharmaceutical composition containing at least one compound of general formula (I) according to one of claims 1 to 4 and one or more pharmacologically acceptable auxiliaries and carriers.

8. Medicament or pharmaceutical composition according to claim 7 for

Prophylaxis and / or treatment of diseases related to cGMP-regulated processes ('cGMP-related diseases').

9. Medicament or pharmaceutical composition according to claim 7 or 8 for the prophylaxis and / or treatment of cardiovascular disease. urogenital disorders and cerebrovascular disorders.

10. Medicament or pharmaceutical composition according to one of claims 7 to 9 for the prophylaxis and / or treatment of cardiovascular

Diseases such as high blood pressure, neuronal hypertension, stable and unstable angina, peripheral and cardiac vascular disorders, arrhythmias, thrombo-embohem diseases and ischemia such as myocardial infarction, stroke, transistor and ischemic attacks, angina pectoris, peripheral circulation disorders, prevention of restenosis therapy, prevention of restenosis therapy, prevention of restenosis therapy percutaneous tianluminal angioplasty (PTA), percutaneous tianluminal coronary angioplasty (PTCA) and bypass.

11. Medicament or pharmaceutical composition according to one of claims 7 to 9 for the prophylaxis and / or treatment of cerebrovascular

Diseases such as cerebral ischemia, stroke, reperfusion damage, brain trauma, edema, cerebral thrombosis, dementia and Alzheimer's disease.

12. Medicament or pharmaceutical composition according to one of claims 7 to 9 for the prophylaxis and / or treatment of diseases of the genitourinary system such as prostate hypertrophy, incontinence and in particular erectile dysfunction and female sexual dysfunction.

13. Medicament or pharmaceutical composition according to one of claims 7 to 12, characterized in that the medicament or the pharmaceutical composition is administered intravenously or orally.

14. Use of the compounds of general formula (I) according to one of claims 1 to 4 for the manufacture of pharmaceuticals or pharmaceuticals

Compositions for the prophylaxis and or treatment of diseases. 15 Use according to claim 14 for the manufacture of a medicament or a pharmaceutical composition for the prophylaxis and / or treatment of diseases which are related to cGMP-regulated processes ('cGMP-related diseases').

16. Use according to claim 14 or 15 for the manufacture of a medicament or a pharmaceutical composition for the prophylaxis and / or treatment of cardiovascular diseases, diseases of the genitourinary system and cerebrovascular diseases.

17. Use according to one of claims 14 to 16 for the manufacture of a medicament or a pharmaceutical composition for the prophylaxis and / or treatment of cardiovascular diseases such as high blood pressure, neuronal hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, arrhythmias, thromboembolic diseases and Ischemia such as myocardial infarction, stroke, transistoric and ischemic attacks, angina pectoris, peripheral circulatory disorders, prevention of restenosis after thrombolysis therapy, percutaneous tianluminal angioplasty (PTA), percutaneous tianluminal coronary angioplasty (PTCA) and

Bypass.

18. Use according to any one of claims 14 to 16 for the manufacture of a medicament or a pharmaceutical composition for the prophylaxis and / or treatment of cerebrovascular diseases such as cerebral

Ischemia, stroke, reperfusion damage, brain trauma, edema, cerebral thrombosis, dementia and Alzheimer's disease.

19. Use according to any one of claims 14 to 16 for the manufacture of a medicament or a pharmaceutical composition for the prophylaxis and / or treatment of diseases of the genitourinary system such as prostate hypertrophy, incontinence and especially erectile dysfunction and female sexual dysfunction.

20. Use according to one of claims 14 to 19, characterized in that the medicaments or compositions are administered intravenously or orally.