CN1241188A

CN1241188A - Heterocyclylmethyl-substed pyrazol derivs.

Info

Publication number: CN1241188A
Application number: CN 97180638
Authority: CN
Inventors: A·斯特劳布; C·福尔斯特纳; U·尼沃纳; T·杰特施; A·福伊雷尔; R·卡斯特; J·-P·斯塔施; E·佩兹波恩; J·许特尔; K·德姆波夫斯基; D·阿尔特
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1996-10-14
Filing date: 1997-10-02
Publication date: 2000-01-12

Abstract

The invention relates to new heterocyclylmethyl-substituted pyrazol derivates, the preparation thereof and their use as drug products, particularly for treating cardiovascular diseases.

Description

Novel heterocyclylmethyl-substituted pyrazole derivatives

The present invention relates to novel heterocyclylmethyl-substituted pyrazole derivatives, to processes for their preparation and totheir use as medicaments, in particular for the treatment of cardiovascular diseases.

1-benzyl-3- (substituted heteroaryl) -fused pyrazole derivatives are known to inhibit stimulated platelet aggregation in vitro (see EP 667345A 1). I is

In the embodiments designated as I (roman numerals one), the present invention relates to novel heterocyclylmethyl-substituted pyrazole derivatives of the general formula (I-I) and the isomeric forms, salts and N-oxides thereof:

wherein:

R¹represents a 5-membered heteroaromatic ring containing one heteroatom selected from S, N and/OR O OR represents phenyl, which heteroaromatic ring OR phenyl group can optionally be substituted up to 3 times by identical OR different substituents selected from formyl, carboxyl, mercapto, hydroxyl, straight-chain OR branched acyl, alkylthio, alkoxy OR alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl OR straight-chain OR branched alkyl having up to 6 carbon atoms, which in turn can be substituted by hydroxyl, amino, carboxyl, straight-chain OR branched acyl, alkoxy, alkoxycarbonyl OR acylamino having in each case up to 5 carbon atoms OR by the formula-OR⁴Is substituted with a group (b) of (a),

wherein:

R⁴refers to straight or branched chain acyl groups containing up to 5 carbon atoms or groups of the formula-SiR⁵R⁶R⁷The group of (a) or (b),

wherein:

R⁵，R⁶and R⁷Identical or different, each represents an aryl group having 6 to 10 carbon atoms or a group containingAlkyl having up to 6 carbon atoms, and/or substituted by groups of the formula

or-S (O)_c1NR⁹R¹⁰

Wherein

b1 and b 1', which are identical or different, each represent a number 0, 1, 2 or 3,

a1 represents a number of 1, 2 or 3,

R⁸represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

c1 represents a number of 1 or 2,

R⁹and R¹⁰Identical or different, each represents hydrogen or a linear or branched alkyl radical having up to 10 carbon atoms, which may optionally be substituted by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen, or,

R⁹and R¹⁰Represents an aryl group containing 6 to 10 carbon atoms, which may optionally be substituted by halogen, or,

R⁹and R¹⁰Represents a cycloalkyl group having 3 to 7 carbon atoms, or,

R⁹and R¹⁰Taken together with the nitrogen atom to form a 5-to 7-membered saturated heterocyclic ring, which may optionally contain a further oxygen atom or group-NR¹¹，

Wherein

R¹¹Denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

Or represents benzyl or phenyl, wherein the ring system may optionally be substituted by halogen,

R²and R³Including the double bond, form a 5-membered heteroaromatic ring or phenyl ring containing one heteroatom selected from S, N and/or O, said heteroaromatic ring or phenyl ring being optionally substituted up to 3 times bythe same or different substituents selected from formyl, carboxy, hydroxy, aminoA radical, a straight-chain or branched acyl radical, alkoxy or alkoxycarbonyl radical, each having up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or a straight-chain or branched alkyl radical having up to 6 carbon atoms, where the radicals may in turn be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl radical, alkoxy or alkoxycarbonyl radical, each having up to 5 carbon atoms,

and/or optionally of the formula-S (O)_c1’NR^9’R^10’Is substituted with a group (b) of (a),

wherein c 1' and R^9’And R^10’Having the above-mentioned c1 and R⁹And R¹⁰And the same or different therefrom,

A¹denotes a 5-to 6-membered aromatic or saturated heterocyclic ring containing up to 3 heteroatoms from the group S, N and/or O, which heterocyclic ring may optionally be substituted up to 3 times by identical or different substituents from the group consisting of mercapto, hydroxyl, formyl, carboxyl, straight-chain or branched acyl having in each case up to 6 carbon atoms, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl having in each case up to 5 carbon atoms, alkoxy or alkoxycarbonyl,

and/or is of the formula- (CO)_d1-NR¹²R¹³Is substituted with a group (b) of (a),

wherein:

d1 represents a number of 0 or 1,

R¹²and R¹³Identical or different, each represent hydrogen, phenyl, benzyl or a linear or branched alkyl or acyl radical each containing up to 5 carbon atoms.

The compounds of the general formula (I-I) according to the invention can also be present in the form of their salts. The salts generally include those formed with organic or inorganic bases or acids.

In embodiment I of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of heterocyclylmethyl-substituted pyrazole derivatives may be salts of the substances of the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds of the invention with free carboxyl groups. Particularly preferred salts are, for example, the 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 or ethylenediamine.

The compounds of the present invention may exist as stereoisomers, which may or may not be mirror images (enantiomers). The invention also relates to enantiomers or diastereomers or mixtures thereof. Racemic forms and diastereomers can be resolved into the individual stereoisomeric components in a known manner.

The heterocyclic ring in embodiment I of the present invention generally means a 5-6 membered heterocyclic ring depending on the above substituents, for R¹The heterocyclic ring of (5) may contain one heteroatom, and for a the heterocyclic ring may contain up to 3 heteroatoms selected from S, N and/or O. Examples of heterocycles are pyridazinyl, pyridyl, pyrimidinyl, thienyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofuranyl. Furyl, pyridyl, thienyl, pyrrolyl, pyrimidinyl, pyridazinyl, morpholinyl, tetrahydropyranyl or tetrahydrofuranyl are preferred.

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

wherein:

R¹denotes furyl, pyrrolyl, thienyl OR phenyl, which are optionally substituted up to 2 times by identical OR different substituents, such as formyl, carboxyl, hydroxyl, straight-chain OR branched acyl having in each case up to 5 carbon atoms, alkoxy OR alkoxycarbonyl, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl OR straight-chain OR branched alkyl having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain OR branched acyl having up to 4 carbon atoms, alkoxy, alkoxycarbonyl OR acylamino OR by the formula-OR⁴Is substituted with a group (b) of (a),

wherein:

R⁴refers to straight or branched chain acyl groups containing up to 4 carbon atoms,

and/or substituted by groups of the formula

Or

Wherein

a1 represents a number of 1, 2 or 3,

R⁸represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms,

R²and R³Including the double bond, to form a furyl, thienyl or phenyl ring, which may optionally be substituted up to 3 times by identical or different substituents being formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl having in each case up to 5 carbon atoms,Alkoxy or alkoxycarbonyl, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or a linear or branched alkyl radical having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, linear or branched acyl radicals each having up to 4 carbon atoms, alkoxy or alkoxycarbonyl,

A¹represents tetrahydropyranyl, thienyl, furanyl, tetrahydrofuranyl, pyrazinyl, morpholinyl, pyrimidinyl, pyridazinyl or pyridinyl, which groups may optionally be substituted up to 2 times by identical or different substituents from the group consisting of hydroxy, formyl, carboxy, straight-chain or branched acyl having up to 4 carbon atoms each, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which groups in turn may be substituted by hydroxy, carboxy, straight-chain or branched acyl having up to 4 carbon atoms each, alkoxy or alkoxycarbonyl,

and/or is of the formula- (CO)_d1-NR¹²R¹³The substitution is carried out by the following steps,

wherein:

d1 represents a number of 0 or 1,

R¹²and R¹³Identical or different, each represents hydrogen, phenyl, benzyl or a linear or branched alkyl or acyl radical each having up to 4 carbon atoms,

their isomeric forms, their salts and their N-oxides.

Particularly preferred compounds of the general formula (I-I) according to the invention are,

wherein:

R¹denotes furyl, pyrrolyl, thienyl or phenyl, which are optionally substituted up to 2 times by identical or different substituents,such as formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 4 carbon atoms in each case or by straight-chain or branched alkyl having up to 4 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having up to 3 carbon atoms in each case,

and/or substituted by groups of the formula

Or

Wherein

a1 represents a number of 1 or 2,

R⁸represents hydrogen or a methyl group,

R²and R³Including the double bond, to form a furyl, thienyl or phenyl ring, which may optionally be substituted up to 2 times by identical or different substituents being formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

A¹represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl or pyridinyl, which may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, straight-chain or branched acyl having up to 3 carbon atoms each, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 3 carbon atoms, which may in turn be substituted by hydroxyl, carboxyl, straight-chain or branched acyl having up to 3 carbon atoms each, optionally substituted by methyl, trifluoromethyl, amino,An alkoxy group or an alkoxycarbonyl group, or a substituted alkoxy group,

wherein:

d1 represents a number of 0 or 1,

R¹²and R¹³Identical or different, each represent hydrogen or a linear or branched alkyl or acyl radical each containing up to 3 carbon atoms,

their isomeric forms, their salts and their N-oxides.

Very particularly preferred compounds of the general formula (I-I) according to the invention are,

wherein:

R¹represents furyl, which may optionally be substituted by formyl or by the formula-CH₂-OH orIs substituted with a group (b) of (a),

R²and R³Including the double bond, to form a phenyl ring substituted by phenyl, fluorine or nitro,

A¹is furyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, tetrahydrofuranOr tetrahydropyranyl, which groups may optionally be substituted by chloro, bromo, methoxy, methoxycarbonyl or carboxy,

their isomeric forms, their salts and their N-oxides.

The invention also relates to a method for producing compounds of the general formula (I-I) according to the invention, characterised in that [ A1]]Reacting a compound of the general formula (I-II)

Wherein

R¹、R²And R³Has the meaningof the above-mentioned formula,

with compounds of the general formula (I-III)

D¹-CH₂-A¹(I-III)

Wherein

A¹Has the meaning of the above-mentioned formula,

D¹represents trifluoromethanesulfonate or halogen, preferably bromine，

In an inert solvent, if desired in the presence of a base, or [ B1]Reacting a compound of the general formula (I-IV)

Wherein

A¹、R²And R³Has the meaning of the above-mentioned formula,

L¹represents a group-SnR¹⁴R¹⁵R¹⁶、ZnR¹⁷Iodine or trifluoromethanesulfonate (triflate),

wherein

R¹⁴、R¹⁵And R¹⁶Identical or different, each represents a linear or branched alkyl radical containing up to 4 carbon atoms,

R¹⁷represents halogen, with a compound of the general formula (I-V)

R¹-T¹(I-V)

Wherein

R¹Has the meaning of the above-mentioned formula,

and the number of the first and second electrodes,

when L is¹＝SnR¹⁴R¹⁵R¹⁶Or ZnR¹⁷When the temperature of the water is higher than the set temperature,

T¹represents trifluoromethanesulfonate or halogen, preferably bromine, and

whenL is¹When the compound is iodine or trifluoromethanesulfonate,

T¹represents a group SnR^14’R^15’R^16’、ZnR^17’Or BR¹⁸R¹⁹，

Wherein R is^14’、R^15’、R^16’And R^17’Having the above-mentioned R¹⁴、R¹⁵、R¹⁶And R¹⁷And the same or different from these groups,

R¹⁸and R¹⁹Identical or different, each represents a hydroxyl group, an aryloxy group having 6 to 10 carbon atoms or a linear or branched alkyl or alkoxy group having up to 5 carbon atoms in each case, or a mixtureTogether form a5 or 6 membered carbocyclic ring,

the palladium-catalyzed reaction is carried out in an inert solvent,

and for the group-S (O)_c1NR⁹R¹⁰and-S (O)_c1’NR^9’R^10’Starting from the unsubstituted compound of the general formula (I-I), the compound is first reacted with thionyl chloride and subsequently with an amine,

and, R can be changed or introduced by a conventional method if necessary¹、R²、R³And/or A¹The substituents listed below are preferably prepared by reduction, oxidation, cleavage of protecting groups and/or nucleophilic substitution.

The process of the present invention can be illustrated by the following reaction equation.

Suitable solvents in the individual steps of the process [ A1]are inert organic solvents which do not change under the reaction conditions. The solvent includes ethers such as diethyl ether or tetrahydrofuran; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions; nitromethane; dimethylformamide; acetone; acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Particular preference is given to tetrahydrofuran, toluene or dimethylformamide.

Bases which can be used in the process of the invention are inorganic or organic bases. These bases include and are preferably alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as barium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; or alkali metal or alkaline earth metal alkoxides, for example sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide; or organic amines (trialkyl (C)₁-C₆) Amines), such as triethylamine; or heterocyclic compounds, e.g. 1, 4-diazabicyclo [2.2.2]Octane (DABCO), 1, 8-diazabicyclo [5.4.0]]Non-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium and hydrides thereof such as sodium hydride can also be used as the base. Preference is given to sodium carbonatePotassium carbonate, triethylamine and sodium hydride.

The amount of base used is 1 to 5mol, preferably 1 to 3mol, per mol of the compound of the formula (I-II).

The reaction is generally carried out at a temperature of from 0 ℃ to 150 ℃, preferably from +20 ℃ to +110 ℃. The reaction can be carried out under normal pressure, under increased pressure or under reduced pressure (e.g., 0.5 to 5 bar). Usually at atmospheric pressure.

Suitable solvents for the individual steps of process [ B1]are inert organic solvents which do not change under the reaction conditions. The solvent includes ethers such as diethyl ether or tetrahydrofuran, DME, dioxane; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, 1, 2-dichloroethane or trichloroethylene; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions; nitromethane; dimethylformamide; acetone; acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Particular preference is given to tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane.

The reaction is generally carried out at a temperature of from 0 ℃ to 150 ℃, preferably from +20 ℃ to +110 ℃.

The reaction can be carried out under normal pressure, under increased pressure or under reduced pressure (e.g., 0.5 to 5 bar). Usually at atmospheric pressure.

In the present invention, a suitable palladium compound is PdCl₂(P(C₆H₅)₃)₂Bis-dibenzylideneacetone palladium (Pd (dba)₂) [1, 1' -bis- (diphenylphosphino) ferrocene]Palladium (II) chloride (Pd (dppf) Cl₂) Or Pd (P (C)₆H₅)₃)₄. Pd (P (C) is preferred₆H₅)₃)₄。

The compounds of the formulae (I-III) and (I-V) are known compounds or can be prepared by customary methods.

Among the compounds of the general formula (I-II), some are known and some are novel compounds, and can be prepared by a process in which the compounds of the general formula (I-VI)

Wherein

R²And R³Has the meaning of the above-mentioned formula,

L^1’having the above-mentioned L¹And the same or different therefrom,

analogously to the above-described process [ B1]with compounds of the general formulae (I-V).

Some compounds of the formula (I-IV) are known and novel in the case of stannyl and can be prepared, for example, by a process in which a compound of the formula (I-IVa) is reacted

Wherein

R²、R³And A¹Has the meaning of the above-mentioned formula,

L^1″represents triflate or halogen, preferably iodine,

with compounds of the general formulae (I-VII)

(SnR¹⁴R¹⁵R¹⁶)₂(I-VII)

Wherein

R¹⁴、R¹⁵And R¹⁶Has the meaning of the above-mentioned formula,

the reaction was carried out under palladium catalysis as described above.

The compounds of the formulae (I-IVa) and (I-VII) are known or can be prepared by customary methods.

The reduction is generally carried out with a reducing agent, preferably those suitable for reducing carbonyl groups to hydroxyl compounds. In the present invention, a particularly suitable reduction reaction is a reduction using a metal hydride or a metal hydride complex in an inert solvent, if desired, in the presence of trialkylborane. The reduction is preferably carried out using metal hydride complexes, such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborate, diisobutylaluminum hydride or lithium aluminum hydride. The reduction reaction with diisobutylaluminum hydride and sodium borohydride is particularly preferred.

The reducing agent is generally used in an amount of 1 to 6mol, preferably 1 to 4mol, per mol of the compound to be reduced.

The reduction is generally carried out at a temperature of-78 ℃ to +50 ℃, preferably-78 ℃ to 0 ℃ for DIBAH, 0 ℃ for NaBH at room temperature₄Particular preference is given to working at-78 ℃ depending in each case on the choice of reducing agent and solvent.

The reduction is usually carried out under normal pressure, but may be carried out under increased or reduced pressure. The cleavage of the protecting groups is generally carried out in the abovementioned alcohols and/or THF or acetone, preferably in methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulfonic acid, at from 0 ℃ to 70 ℃, preferably at room temperature and under normal pressure.

When a group-S (O) is present_c1NR⁹R¹⁰and-S (O)_c1’NR^9’R^10’When this is done, the corresponding unsubstituted compound is first reacted with thionyl chloride. And then reacted with an amine in an ether as described above, preferably dioxane. When c1 is 2, the oxidation reaction is subsequently carried out by conventional methods. The reaction is carried out at 0-70 deg.C under normal pressure.

The invention also relates to the use of a compound of formula (I-I) according to the invention in combination with an organic nitrate and an NO donor.

In the present invention, the organic nitrate (or salt) and the NO donor are substances that exhibit their therapeutic effects by releasing NO or NO-like substances. Sodium Nitroprusside (SNP), nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 and the like are preferred.

The invention also relates to the use of compounds that inhibit cyclic guanosine monophosphate (cGMP) cleavage. In particular with inhibitors of phosphodiesterase 1, 2 and 5 (named according to Beavo and Reifsnyder (1990) TIPS11, page 150-155). The compounds of the invention have increased effects and their desired pharmacological effects are enhanced by these inhibitors.

The compounds of the general formula (I-I) according to the invention exhibit an unpredictable, valuable range of pharmacological effects.

The compounds of the general formula (I-I) of the present invention cause vascular relaxation and inhibit platelet aggregation and lower blood pressure, and also increase coronary blood flow. This effect is mediated by direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. In addition, the compounds of the present invention also potentiate the action of substances having a cGMP level-increasing activity, such as EDRF (endothelial derived relaxin), NO donor, hematoporphyrin IX, arachidonic acid or phenylhydrazine derivative.

They are therefore useful in the treatment of cardiovascular diseases, such as hypertension and myocardial insufficiency, stable and unstable angina pectoris and peripheral and cardiovascular diseases and arrhythmias, in the treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transient and sudden ischaemia and peripheral circulatory disorders; for the prevention of restenosis, such as restenosis following thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA), and bypass angioplasty; and for the treatment of arteriosclerosis and genitourinary disorders, such as prostatic hypertrophy, erectile dysfunction and incontinence.

The following studies were performed to determine cardiovascular effects: in vitro studies of vascular cells were performed with or without the effect of NO donors on guanylate cyclase dependent cGMP formation. The anti-agglutination effect was demonstrated by human platelets stimulated with collagen. Vascular relaxation was measured by pre-contracting the aorta of rabbits with phenylephrine. The antihypertensive effect of the anesthetized rats was studied. Stimulation of soluble guanylate cyclase in primary endothelial cells

Primary endothelial cells were isolated from porcine aorta by treatment with collagenase solution. Then, the culture was carried out in a medium until fusion was achieved. For ease of observation, cells were plated, seeded in cell culture dishes, and subcultured until confluent. To stimulate endothelial guanylate cyclase, the medium was aspirated, the cells were washed once with Ringer solution and incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP, 1. mu.M). Thereafter, the test substance (final concentration of 1. mu.M) was pipetted into the cells. At the end of the 10 min incubation period, the buffer was aspirated off and the cells were lysed at-20 ℃ for 16 h. Intracellular cGMP was then measured by radioimmunoassay.

TABLE A

Example No. 2	Percentage of cGMP increase
Example No. 2	Percentage of cGMP increase	I-4	＞1000
I-10	217	I-4	＞1000
I-10	217	I-16	＞1000
I-17	200	I-16	＞1000
I-17	200	I-18	＞1000
I-22	146	I-18	＞1000
I-22	146	I-24	65

In vitro vascular relaxation

Aortic rings of 1.5mm width isolated from rabbits were introduced separately under pre-tension into 5ml Krebs-Henseleit organ baths warmed to 37 ℃ and filled with carbopol gold. The force of contraction is amplified and digitized and recorded in parallel with a linear recorder. To produce the contraction, phenylephrine is added cumulatively in increasing concentrations.

After several control cycles, the substances to be observed were observed in each case at increasing doses and compared with the level of contraction initially obtained in the last time. From this, the concentration (IC) required to reduce the level of the control value by 50% was calculated₅₀). The standard volume used was 5. mu.l.

TABLE B

Example No. 2	Aorta IC₅₀(μm)
Example No. 2	Aorta IC₅₀(μm)	I-4	8.0
I-10	9.0	I-4	8.0
I-10	9.0	I-16	9.1
I-18	7.2	I-16	9.1
I-18	7.2	I-19	15
I-20	8.2	I-19	15
I-20	8.2	I-21	＞27
I-22	8.8	I-21	＞27
I-22	8.8	I-23	2.9
I-24	26	I-23	2.9

Blood pressure measurement for anesthetized rats

Male Wistar rats weighing 300-350g were anesthetized with thiopental (100mg/kg i.p.). After performing tracheotomy, a catheter was inserted into the femoral artery to measure blood pressure. Various doses of the test substance in suspension in tylose solution were administered orally using a gastric tube. Inhibition of platelet aggregation in vitro

To determine the platelet aggregation inhibition, blood samples taken from healthy subjects of both sexes were used. As an anticoagulant, a 3.8% strength aqueous solution of sodium citrate was mixed with 9 blood samples. Platelet-enriched plasma citrate (PRP) was obtained from this blood sample by centrifugation.

For the study, 445. mu.l of PRP and 5. mu.l of the active compound solution were preincubated in a 37 ℃ water bath. Platelet aggregation was then measured in an aggregometer (aggregometer) at 37 ℃. For this purpose,50. mu.l of collagen, an aggregation-inducing agent, are added to the previously incubated samples and the change in optical density is recorded. For quantitative evaluation, the maximum agglutination was determined and the percentage inhibition compared to the control was calculated therefrom.

The compounds described in embodiment I of the invention are also active against diseases of the central nervous system which are characterized by impairment of the NO/cGMP system. In particular, they are suitable for eliminating cognitive impairment, improving cognitive and memory functions and for the treatment of alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system, such as anxiety, tension and depression, sexual dysfunction of central nervous origin and sleep disorders, and also for the regulation of pathological disorders of food intake and of added substances.

These active compounds are also suitable for regulating the cerebral circulation and are therefore effective against migraine.

They are also suitable for the prevention and combating of cerebral infarct events (cerebral stroke), such as stroke, cerebral ischemia and the consequences of craniocerebral injury. The compounds of the invention are also useful against pain.

The invention encompasses pharmaceutical preparations which comprise one or more compounds of the invention in addition to a non-toxic and inert pharmaceutically suitable carrier or which consist exclusively of one or more active compounds of the invention, and processes for the preparation of these preparations.

If appropriate, one or more active compounds may also be present in microencapsulated form in one or more of the carriers mentioned above.

The therapeutically active compound should preferably be present in the above mentioned pharmaceutical preparations in an amount of about 0.1-99.5%, preferably about 0.5-95% by weight of the total mixture.

The above-mentioned pharmaceutical preparations may contain other pharmaceutically active compounds in addition to the compounds of the present invention.

In general, to achieve the desired effect, it has proven advantageous in human and veterinary medicine to administer the active compound or compounds according to the invention in a total amount of from about 0.5 to about 500, preferably from 5 to 100, mg/kg of body weight per 24 hours, if appropriate in divided doses. A single dose preferably contains from about 1 to about 80, in particular from 3 to 30, mg/kg of body weight of one or more active compounds according to the invention. II

In the embodiment designated as II (roman numeral two), the present invention relates to novel 1-heterocyclyl-methyl-substituted pyrazoles of general formula (II-I) and isomeric forms, salts and N-oxides thereof:

wherein:

R²⁰denotes a 6-membered heteroaromatic ring containing up to 3 nitrogen atoms, which may optionally be substituted up to 3 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, mercapto, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl each containing up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl and/or a group of the formula

-NR²³R²⁴

Wherein

R²³And R²⁴Identical or different, each represents hydrogen or a linear or branched acyl group having up to 6 carbon atoms or a linear or branched alkyl group having up to 6 carbon atoms, which groups may optionallybe substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxy, amino or by cycloalkyl having in each case up to 5 carbon atomsSubstituted with linear or branched alkoxy, acyl or alkoxycarbonyl,

or

R²³And R²⁴Together with the nitrogen atom, form a 3-7 membered saturated or partially saturated heterocyclic ring, which may optionally contain an oxygen or sulfur atom or a compound of formula-NR²⁵The group of (a) or (b),

wherein

R²⁵Represents hydrogen OR a linear OR branched alkyl radical having up to 4 carbon atoms and/OR is substituted by a linear OR branched alkyl radical having up to 6 carbon atoms, which in turn may be substituted by hydroxyl, amino, halogen, carboxyl, linear OR branched acyl, alkoxy, alkoxycarbonyl OR acylamino, each having up to 5 carbon atoms, OR by the formula-OR²⁶Is substituted with a group (b) of (a),

wherein

R²⁶Represents a straight-chain or branched acyl group containing up to 5 carbon atoms or a compound of formula-SiR²⁷R²⁸R²⁹The group of (a) or (b),

wherein

R²⁷、R²⁸And R²⁹Identical or different, each represents an aryl radical having 6 to 10 carbon atoms or an alkyl radical having up to 6 carbon atoms,

and/or optionally substituted by a group of formula

or-S (PO)_c2NR³¹R³²

Wherein

b2 and b 2', which are identical or different, each represent a number 0, 1, 2 or 3,

a2 represents a number of 1, 2 or 3,

R³⁰represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

c2 represents a number of 1 or 2,

R³¹and R³²Identical or different, each represents hydrogen or a linear or branched alkyl radical having up to 10 carbon atoms, which may optionally be substituted by a cycloalkyl radical having 3 to 8 carbon atoms or by an aryl radical having 6 to 10 carbon atoms, which may in turn be substituted by halogenEither the first or the second substrate is, alternatively,

R³¹and R³²Represents an aryl group containing 6 to 10 carbon atoms, which may optionally be substituted by halogen, or,

R³¹and R³²Represents a cycloalkyl group having 3 to 7 carbon atoms, or,

R³¹and R³²Taken together with the nitrogen atom to form a 5-to 7-membered saturated heterocyclic ring, which may optionally contain a further oxygen atom or group-NR³³，

Wherein

R³³Denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

Or benzyl or phenyl, wherein the ring system may optionally be substituted by halogen,

R²¹and R²²Including the double bond, to form a 5-membered heteroaromatic ring or phenyl ring which contains one heteroatom selected from S, N and/or O and which is optionally substituted up to 3 times by identical or different substituents from the group consisting of formyl, mercapto, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms each, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms each, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 5 carbon atoms each, or optionally by the formula-S (O)_c2’NR^31’R^32’Wherein c 2', R^31’And R^32’Having the above-mentioned c2 and R³¹And R³²And the same or different therefrom,

A²represents phenyl or a 5-6 membered aromatic or saturated heterocyclic ring containing up to 3 heteroatoms selected from S, N and/or O, which heterocyclic ring may optionally be substituted up to 3 times by identical or different substituents selected from mercapto, hydroxy, formyl, carboxy, each containing up to 6 carbon atomsIs selected from the group consisting of straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each having up to 5 carbon atoms,

and/or is of the formula- (CO)_d2-NR³⁴R³⁵Is substituted with a group (b) of (a),

wherein:

d2 represents a number of 0 or 1,

R³⁴and R³⁵Identical or different, each represent hydrogen, phenyl, benzyl or a linear or branched alkyl or acyl radical each containing up to 5 carbon atoms.

In embodiment II of the present invention, preference is given to physiologically acceptable salts with inorganic or organic bases or acids. Physiologically acceptable salts of 1-heterocyclyl-methyl-substituted pyrazoles can be salts of the substances according to the invention with mineral acids,carboxylic acids or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

The compounds according to embodiment II of the present invention may exist in the form of stereoisomers, which may or may not be mirror images (enantiomers). The invention also relates to enantiomers or diastereomers or mixtures thereof. Racemic forms and diastereomers can be resolved into the individual stereoisomeric components in a known manner.

In embodiment II of the invention, for R²⁰The heterocyclic ring represents a 6-membered aromatic heterocyclic ring; for R²¹/R²²The heterocyclic ring represents a 5-membered heterocyclic ring containing 1 heteroatom; for A²The heterocyclic ring represents a 5-6 membered aromatic or saturated heterocyclic ring; for group NR²³R²⁴The heterocyclic ring represents a saturated or partially saturated 3-to 7-membered heterocyclic ring. Examples of heterocycles are pyridazinyl, quinolinyl, isoquinolinyl, pyrazinyl, pyridyl, pyrimidinyl, thienyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofuranyl.

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

wherein:

R²⁰represents a group of the formulaOr

These radicals may optionally be substituted up to 3 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl and/or of the formula-NR²³R²⁴The group of (a) or (b),

wherein

R²³And R²⁴Identical or different, each represents hydrogen or a linear or branched acyl group having up to 4 carbon atoms or a linear or branched alkyl group having up to 4 carbon atoms, which may optionally be substituted by hydroxyl, amino or a linear or branched alkoxy group having up to 3 carbon atoms, or

R²³And R²⁴Together with the nitrogen atom, form a morpholine ring or a group of the formula,

and/or by straight-chain or branched alkyl radicals having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, amino, fluorine, carboxyl, straight-chain or branched acyl radicals each having up to 4 carbon atoms, alkoxyA radical, alkoxycarbonyl OR amido radical OR of the formula-OR²⁶Is substituted with a group (b) of (a),

wherein

R²⁶Denotes straight-chain or branched acyl having up to 4 carbon atoms,

and/or optionally substituted by a group of formula

Or

Wherein

a2 represents a number of 1, 2 or 3,

R²¹and R²²Including the double bond, to form a furyl, thienyl or phenyl ring, which may optionally be substituted up to 3 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, ammoniaSubstituted by radicals, carboxyl groups, straight-chain or branched acyl groups, alkoxy groups or alkoxycarbonyl groups, each containing up to 4 carbon atoms,

A²represents phenyl or tetrahydropyranyl, furanyl, tetrahydrofuranyl, morpholinyl, pyrimidinyl, pyridazinyl or pyridinyl, which may optionally be substituted up to 2 times by identical or different substituents from the group consisting of hydroxy, formyl, carboxy, straight-chain or branched acyl having up to 4 carbon atoms each, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in turn may be substituted by hydroxy, carboxy, straight-chain or branched acyl having up to 4 carbon atoms each, alkoxy or alkoxycarbonyl,

and/or is represented by the formula: (A)CO)_d2-NR³⁴R³⁵Is substituted with a group (b) of (a),

wherein:

d2 represents a number of 0 or 1,

R³⁴and R³⁵Identical or different, each represents hydrogen, phenyl, benzyl or a linear or branched alkyl or acyl radical each having up to 4 carbon atoms,

their isomeric forms, their salts and their N-oxides.

Particularly preferred compounds of the general formula (II-I) according to the invention are,

wherein:

R²⁰represents a group of the formula

Or

Wherein the ring system may optionally be substituted up to 3 times by identical or different substituents being formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, methylamino, amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms each, which in turn may be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having up to 3 carbon atoms each,

and/or optionally substituted by a group of formula

Or

R²¹And R²²Including the double bond, to form a furyl, thienyl or phenyl ring, which may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms,which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atomsInstead of the first generation,

A²represents phenyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl or pyridinyl, which groups may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, straight-chain or branched acyl having up to 3 carbon atoms each, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or by straight-chain or branched alkyl having up to 3 carbon atoms each, which groups in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl having up to 3 carbon atoms each, alkoxy or alkoxycarbonyl,

wherein:

d2 represents a number of 0 or 1,

R³⁴and R³⁵Identical or different, each represent hydrogen or a linear or branched alkyl or acyl radical each containing up to 3 carbon atoms,

their isomeric forms, their salts and their N-oxides.

Very particularly preferred compounds of the formula (II-I) according to the invention are,

wherein:

R²⁰represents a group of the formula

Or

Wherein the above heterocyclic ring system may be optionally substituted up to 3 times by the same or different substituents being methyl, fluoro, formyl, amino, cyano, methoxy, methoxycarbonyl, methylamino, chloro or a group of formula

Or

R²¹And R²²Including the double bond, to form a benzene ring,

A²represents phenyl optionally substituted by fluorine or cyano

Their isomeric forms, their salts and their N-oxides.

The invention also relates to a method for producing compounds of the general formula (II-I) according to the invention, characterised in that [ A2]]Reacting a compound of the formula (II-II)

Wherein

R²⁰、R²¹And R²²Has the meaning of the above-mentioned formula,with compounds of the general formula (II-III)

D²-CH₂-A²(II-III)

Wherein

A²Has the meaning of the above-mentioned formula,

D²represents trifluoromethanesulfonate or halogen, preferably bromine,

in an inert solvent, if desired in the presence of a base,

alternatively, [ B2]]Reacting a compound of the formula (II-IV)

Wherein

A²、R²¹And R²²Has the meaning of the above-mentioned formula,

L²represents a group-SnR³⁶R³⁷R³⁸、ZnR³⁹Iodine or a triflate ester of an acid,

wherein

R³⁶、R³⁷And R³⁸Identical or different, each represents a linear or branched alkyl radical containing up to 4 carbon atoms,

R³⁹represents halogen, with a compound of the general formula (II-V)

R²⁰-T²(II-V)

Wherein

R²⁰Has the meaning of the above-mentioned formula,

and the number of the first and second electrodes,

when L is²＝SnR¹⁷R¹⁸R¹⁹Or ZnR²⁰When the temperature of the water is higher than the set temperature,

T²represents trifluoromethanesulfonate or halogen, preferably bromine,

and is

When L is²When the compound is iodine or trifluoromethanesulfonate,

T²represents a group SnR^36’R^37’R^38’、ZnR^39’Or BR⁴⁰R⁴¹，

Wherein R is^36’、R^37’、R^38’And R^39’Having the above-mentioned R³⁶、R³⁷、R³⁸And R³⁹And the same or different from these groups,

R⁴⁰and R⁴¹Identical or different, each represents a hydroxyl group, an aryloxy group having 6 to 10 carbon atoms or a straight-chain or branched alkyl or alkoxy group each having up to 5 carbon atoms, or together form a 5-or 6-membered carbocyclic ring,

the palladium-catalyzed reaction is carried out in an inert solvent,

for the group-S (O)_c2NR³¹R³²and-S (O)_c2’NR^31’R^32’Starting from the unsubstituted compound of the general formula (II-I), the compound is first reacted with thionyl chloride and subsequently with an amine,

and, R can be changed or introduced by a conventional method if necessary²⁰、R²¹、R²²And/or A²The substituents listed below are preferably prepared by reduction, oxidation, cleavage of protecting groups and/or nucleophilic substitution.

The process for preparing the compounds of embodiment II of the present invention can be illustrated by the following reaction scheme.

Suitable solvents in the individual steps of the process [ A2]are inert organic solvents which do not change under the reaction conditions. The solvent includes ethers such as diethyl ether or tetrahydrofuran; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions; nitromethane; dimethylformamide; acetone; acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Particular preference is given to tetrahydrofuran, toluene or dimethylformamide.

Bases that can be used in the process of embodiment II of the present invention are inorganic or organic bases. These bases include and are preferably alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as barium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; or alkali metal or alkaline earth metal alkoxides, for example sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide; or organic amines (trialkyl (C)₁-C₆) Amines), such as triethylamine; or heterocyclic compounds, e.g. 1, 4-diazabicyclo [2.2.2]Octane (DABCO), 1, 8-diazabicyclo [5.4.0]]Non-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium and hydrides thereof such as sodium hydride can also be used as the base. Preference is given to sodium and potassium carbonate, triethylamine and sodium hydride.

The amount of the base used is 1 to 5mol, preferably 1 to 3mol, per mol of the compound of the formula (II-II).

Suitable solvents for the individual steps of process [ B2]are inert organic solvents which do not change under the reaction conditions. The solvent includes ethers such as diethyl ether or tetrahydrofuran, DME or dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions; nitromethane; dimethylformamide; acetone; acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Particular preference is given to tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane.

The compounds of the formulae (II-III) and (II-V) are known compounds or can be prepared by customary methods.

Of the compounds of the formula (II-II), some are known and can be prepared by a process in which compounds of the formula (II-VI) are reacted

Wherein

R²¹And R²²Has the meaning of the above-mentioned formula,

L^2’having the above-mentioned L²And the same or different therefrom,

the reaction with the compounds of the formulae (II-V) is carried out analogously to the process [ B2]described above.

Some compounds of the formula (II-IV) are known and novel in the case of stannyl and can be prepared, for example, by a process in which a compound of the formula (II-IVa) is reacted

Wherein

R²¹、R²²And A²Has the meaning of the above-mentioned formula,

L^2″represents triflate or halogen, preferably iodine,

with compounds of the general formula (II-VII)

(SnR³⁶R³⁷R³⁸)₂(II-VII)

Wherein

R³⁶、R³⁷And R³⁸Has the meaning of the above-mentioned formula,

the reaction was carried out under palladium catalysis as described above.

The compounds of the formulae (II-VII) are known or can be prepared by customary methods.

Most of the compounds of the formula (II-IVa) are novel and can be prepared by a process in which compounds of the formula (II-VIII) are reacted

Wherein

R²¹And R²²Has the meaning of the above-mentioned formula,

with the compounds of the above general formula (II-V),

R²⁰-T²(II-V)

wherein R is²⁰And T²Has the meaning of the above-mentioned formula,

in the above solvent, preferably tetrahydrofuran, in the presence of sodium hydride, at a temperature of 0 ℃ to 40 ℃, preferably at room temperature, under an inert gas atmosphere.

Most of the compounds of the formulae (II-VIII) are known or can be prepared by customary methods.

The reduction reaction is generally carried out at a temperature of-78 ℃ to +50 ℃, preferably-78 ℃ to 0 ℃, for DIBAH, 0 ℃,room temperature for NaBH₄Particular preference is given to working at-78 ℃ depending in each case on the choice of reducing agent and solvent.

The reduction is usually carried out under normal pressure, but may be carried out under increased or reduced pressure.

When formula-S (O)_c2NR³¹R³²and-S (O)_c2’NR^31’R^32’When the radical(s) of (b) is substituted, the corresponding unsubstituted compound is first reacted with thionyl chloride and then with an amine in the presence of the above-mentioned ether, preferably dioxane. When c2 is 2, the oxidation reaction is subsequently carried out by conventional methods. The reaction is usually carried out at 0 ℃ to 70 ℃ under normal pressure.

The cleavage of the protecting groups is generally carried out in the abovementioned alcohols and/or THF or acetone, preferably in methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulfonic acid, at from 0 ℃ to 70 ℃, preferably at room temperature and under normal pressure.

The invention also relates to the use of a compound of formula (II-I) according to the invention in combination with an organic nitrate and an NO donor.

In the present invention, the organic nitrate (or salt) and the NO donor are substances that exhibit their therapeutic effects by releasing NO or NO-like substances. Sodium Nitroprusside (SNP), nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.

The compounds of the general formula (II-I) according to the invention exhibit an unpredictable, valuable range of pharmacological effects.

The compounds of formula (II-I) of the present invention cause vascular relaxation/inhibit platelet aggregation and lower blood pressure, and also increase coronary blood flow. This effect is mediated by direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. In addition, the compounds of the present invention also potentiate the action of substances having a cGMP level-increasing activity, such as EDRF (endothelial derived relaxin), NO donor, hematoporphyrin IX, arachidonic acid or phenylhydrazine derivative.

The following studies were performed to determine cardiovascular effects: in vitro studies of vascular cells were performed with or without the effect of NO donors on guanylate cyclase dependent cGMP formation. The anti-agglutination effect was demonstrated by human platelets stimulated with collagen. Vascular relaxation was measured by pre-contracting the aorta of rabbits with phenylephrine. The antihypertensive effect of the anesthetized rats was studied.

Stimulation of soluble guanylate cyclase in primary endothelial cells

TABLE A

Example No. 2	Percentage increase in cGMP
Example No. 2	Percentage increase in cGMP	II-36	225
II-38	＞1000	II-36	225
II-38	＞1000	II-39	909
II-40	＞1000	II-39	909
II-40	＞1000	II-41	557
II-42	611	II-41	557
II-42	611	II-43	＞1000
II-44	＞1000	II-43	＞1000

Example No. 2	Percentage increase in cGMP
Example No. 2	Percentage increase in cGMP	II-45	326
II-46	390	II-45	326
II-46	390	II-47	240
II-48	＞1000	II-47	240
II-48	＞1000	II-49	＞1000
II-50	116	II-49	＞1000
II-50	116	II-52	397
II-53	428	II-52	397
II-53	428	II-56	233
II-58	271	II-56	233
II-58	271	II-59	268

In vitro vascular relaxation

After several control cycles, the substances to be observed were observed in each case at increasing doses and the contraction levels initially obtained in the last time were compared. From this, the concentration (IC) required to reduce the level of the control value to 50% was calculated₅₀). The standard volume used was 5. mu.l.

TABLE B

Example No. 2	Aorta IC₅₀(μm)
Example No. 2	Aorta IC₅₀(μm)	II-36	13
II-39	11	II-36	13
II-39	11	II-40	2.4
II-41	13	II-40	2.4
II-41	13	II-42	10
II-38	11	II-42	10
II-38	11	II-48	13
II-49	65	II-48	13
II-49	65	II-50	＞＞31
II-51	＞＞30	II-50	＞＞31
II-51	＞＞30	II-52	14
II-53	18	II-52	14
II-53	18	II-55	＞35
II-56	＞33	II-55	＞35
II-56	＞33	II-59	＞33
II-60	＞30	II-59	＞33
II-60	＞30	II-61	＞30
II-62	13	II-61	＞30

Blood pressure measurement for anesthetized rats

For the study, 445. mu.l of PRP and 5. mu.l of the active compound solution were preincubated in a 37 ℃ water bath. Platelet aggregation was then measured by nephelometry in an agglutination meter at 37 ℃. For this purpose, 50. mu.l of collagen, an aggregation-inducing agent, are added to the previously incubated samples and the change in optical density is recorded. For quantitative evaluation, the maximum agglutination was determined and the percentage inhibition compared to the control was calculated therefrom.

The compounds described in embodiment I of the invention are also active against diseases of the central nervous system characterized by impairment of the NO/cGMP system. In particular, they are suitable for eliminating cognitive impairment, improving cognitive and memory functions and for the treatment of alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system, such as anxiety, tension and depression, sexual dysfunction of central nervous origin and sleep disorders, and also for the regulation of pathological disorders of food intake and of added substances.

The therapeutically active compound should preferably be present in the above mentioned pharmaceutical preparations in an amount of about 0.1-99.5%, more preferably about 0.5-95% by weight of the total mixture.

In general, to achieve the desired effect, it has proven advantageous in human and veterinary medicine to administer the active compound or compounds according to the invention ina total amount of from about 0.5 to about 500, preferably from 5 to 100, mg/kg of body weight per 24 hours, if appropriate in divided doses. A single dose preferably contains from about 1 to about 80, in particular from 3 to 30, mg/kg of body weight of one or more active compounds according to the invention.

Abbreviations:

me is methyl

OMe ═ methoxy

Et is ethyl

OEt ═ ethoxy

Ph ═ phenyl III

In the embodiment designated as III (roman numerals three), the present invention relates to novel 3-heterocyclyl-substituted pyrazole derivatives of the general formula (III-I) and isomeric forms thereof and salts thereof:

wherein:

R⁴²denotes a saturated 6-membered heterocyclic ring containing up to 2 heteroatoms from the group S, N and/or O or denotes a 5-membered aromatic or saturated heterocyclic ring containing 2 to 3 heteroatoms from the group S, N and/or O, the group may be attached through a nitrogen atom and may optionally be substituted up to 3 times with the same or different substituents, the substituents are selected from formyl, phenyl, mercapto, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, this radical may in turn be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain OR branched acyl, alkoxy, alkoxycarbonyl OR acylamino having in each case up to 5 carbon atoms OR by the formula-OR.⁴⁵Is substituted with a group (b) of (a),

wherein

R⁴⁵Refers to straight or branched chain acyl groups containing up to 5 carbon atoms or groups of the formula-SiR⁴⁶R⁴⁷R⁴⁸The group of (a) or (b),

wherein:

R⁴⁶，R⁴⁷and R⁴⁸Identical or different, each represents an aromatic hydrocarbon having 6 to 10 carbon atomsRadicals or alkyl radicals containing up to 6 carbon atoms,

and/or substituted by groups of the formula

or-S (O)_c3NR⁵⁰R⁵¹

Wherein

a3, b3 and b 3' each represent a number 0, 1, 2 or 3,

R⁴⁹represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

c3 represents a number of 1 or 2,

R⁵⁰and R⁵¹Identical or different, each represents hydrogen or a linear or branched alkyl radical having up to 10 carbon atoms, which may optionally be substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen,

or represents an aryl group containing 6 to 10 carbon atoms, said aryl group being optionally substituted by halogen, or

Represents a cycloalkyl group having 3 to 7 carbon atoms, or,

R⁵⁰and R⁵¹Together with the nitrogen atom, form a 5-7 membered saturated heterocyclic ring, which may optionally contain an oxygen atom or a group of formula-NR⁵²The group of (a) or (b),

wherein

R⁵²Denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms ora radical of the formula

Or benzyl or phenyl, wherein the ring system is optionally substituted by halogen,

R⁴³and R⁴⁴Including the double bond, form a 5-membered heteroaromatic ring or phenyl ring containing one heteroatom selected from S, N and/or O, said heteroaromatic ring or phenyl ring optionally being identical or differentUp to 3 times with different substituents selected from formyl, carboxy, hydroxy, amino, each containing up to 6 carbon atomsStraight-chain or branched acyl, alkoxy or alkoxycarbonyl, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each having up to 5 carbon atoms,

and/or optionally of the formula-S (O)_c3’NR^50’R^51’Wherein c 3', R^50’And R^51’Having the above-mentioned c3 and R⁵⁰And R⁵¹And the same or different therefrom,

A³denotes a 5-to 6-membered aromatic or saturated heterocycle containing up to 3 heteroatoms from the group S, N and/or O or phenyl, which may optionally be substituted up to 3 times by identical or different substituents from the group consisting of amino, mercapto, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, each containing up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl containing up to 6 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each containing up to 5 carbon atoms,

and/or is of the formula- (CO)_d3-NR⁵³R⁵⁴Is substituted with a group (b) of (a),

wherein:

d3 represents a number of 0 or 1,

R⁵³and R⁵⁴Identical or different, each represent hydrogen, phenyl, benzyl or a linear or branched alkyl or acyl radical each containing up to 5 carbon atoms.

The compounds of the general formula (III-I) according to the invention can also be present in the form of salts with organic or inorganic bases or acids.

In embodiment III of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds of the invention may be salts of the substances of the invention with inorganic acids, carboxylic acids or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

The compounds of the present invention may exist as stereoisomers, which may or may not be mirror images (enantiomers). The invention also relates to enantiomers or diastereomers or mixtures thereof. Racemic forms and diastereomers can be resolved into the individual stereoisomeric components in a knownmanner.

Depending on the substituents mentioned above, the heterocyclic ring in embodiment III of the present invention generally denotes a saturated or aromatic 5-or 6-membered heterocyclic ring which may contain 1, 2 or 3 heteroatoms selected from S, N and/or O, and if the heteroatom is a nitrogen atom, may also be attached via the chlorine atom. Examples of heterocycles are oxadiazolyl, thiadiazolyl, pyrazolyl, pyrimidinyl, pyridyl, thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 2, 3-triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidinyl. Oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, pyridyl or tetrahydropyranyl are preferred.

Preferred compounds of the formula (III-I) according to the invention are,

wherein:

R⁴²represents imidazolyl, oxazolyl, thiazolyl, 1, 2, 3-triazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyranyl or morpholinyl, which may optionally be substituted up to 2 times by identical or different substituents being formyl, trifluoromethyl, phenyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, nitro, each having up to 5 carbon atomsA radical, cyano, epichloroyl, fluorine, chlorine, bromine, phenyl OR a linear OR branched alkyl radical having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, linear OR branched acyl, alkoxy, alkoxycarbonyl OR acylamino, each having up to 4 carbon atoms, OR by the formula-OR⁴⁵Is substituted with a group (b) of (a),

wherein:

R⁴⁵represents a straight-chain or branched acyl group containing up to 4 carbon atoms or a compound of formula-SiR⁴⁶R⁴⁷R⁴⁸The group of (a) or (b),

wherein:

R⁴⁶，R⁴⁷and R⁴⁸Identical or different, each represents a linear or branched alkyl radical containing up to 4 carbon atoms,

and/or substituted by groups of the formulaOr

Wherein

a3 represents a number 0, 1, 2 or 3,

R⁴⁹represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms,

R⁴³and R⁴⁴Including the double bond, to form furyl, thienyl or phenyl, which are optionally substituted up to 3 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl having in each case up to 5 carbon atoms, alkoxy or alkoxycarbonyl, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl having in each case up to 4 carbon atoms, alkoxy or alkoxycarbonyl,

A³represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, phenyl, morpholinyl, pyrimidinyl, pyridazinyl or pyridinyl, which groups may optionally be substituted up to 2 times by the same or different substituents selected from hydroxyA radical, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms,

wherein:

d3 represents a number of 0 or 1,

R⁵³and R⁵⁴Identical or different, each represents hydrogen, phenyl, benzyl or a straight-chain or branched alkyl or acyl radical having up to 4 carbon atoms in each case, their isomeric forms and their salts.

Particularly preferred compounds of the formula (III-I) according to the invention are,

wherein:

R⁴²represents imidazolyl, oxazolyl, oxadiazolyl or thiazolyl, which are optionally substituted up to 2 times by identical or different substituents being formyl, trifluoromethyl, phenyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in turn may be substituted by hydroxy, fluorine, chlorine, trifluoromethyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms or by the formula-O-CO-CH₃Is/are as followsThe substitution of the group(s),

and/or substituted by groups of the formula

Or

Wherein

a3 represents a number 0, 1 or 2,

R⁴⁹represents hydrogen or a methyl group,

R⁴³and R⁴⁴Including double bonds, to form furyl, thienyl orPhenyl, which groups may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chainor branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,

A³represents tetrahydropyranyl, phenyl, thienyl, pyrimidinyl or pyridinyl, which groups may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 3 carbon atoms, which groups in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,

wherein:

d3 represents a number of 0 or 1,

R⁵³and R⁵⁴Identical or different, each represent hydrogen or a linear or branched alkyl or acyl radical each containing up to 3 carbon atoms, their isomeric forms and their salts.

Very particularly preferred compounds of the formula (III-I) according to the invention are,

wherein:

R⁴²represents imidazolyl, oxazolyl, thiazolyl or oxadiazolyl, which radicals may optionally be substituted up to 2 times by identical or different substituents being ethoxycarbonyl, phenyl, methyl or ethyl, where the alkyl radical may in turn be substituted by hydroxy, chloro, ethoxycarbonyl, oxycarbonylmethyl or methoxy,

R⁴³and R⁴⁴Taken together, including the double bond,represents phenyl, which may be optionally substituted by nitro,

A³represents phenyl or pyrimidinyl substituted by fluorine, their isomeric forms and their salts.

The invention also relates to a method for producing compounds of the general formula (III-I) according to the invention, characterised in that [ A3]]Reacting a compound of the formula (III-II)

Wherein

R⁴²、R⁴³And R⁴⁴Having the above-mentioned meanings, with compounds of the general formula (III-III)

D³-CH₂-A³(III-III)

Wherein

A³Has the meaning of the above-mentioned formula,

D³represents trifluoromethanesulfonate or halogen, preferably bromine,

the reaction in an inert solvent can be carried out, if desired, in the presence of a base,

alternatively, [ B3]]Reacting a compound of the formula (III-IV)

Wherein

A³、R⁴⁴And R⁴⁴Has the meaning of the above-mentioned formula,

L³represents a group-SnR⁵⁵R⁵⁶R⁵⁷、ZnR⁵⁸Iodine, bromine or trifluoromethanesulfonate,

wherein

R⁵⁵、R⁵⁶And R⁵⁷Identical or different, each represents a linear or branched alkyl radical containing upto 4 carbon atoms,

R⁵⁸represents a halogen, and is characterized in that,

with compounds of the general formula (III-V)

R⁴²-T³(III-V)

Wherein

R⁴²Utensil for cleaning buttockHas the meaning of the above-mentioned formula,

and the number of the first and second electrodes,

when L is³＝SnR⁵⁵R⁵⁶R⁵⁷Or ZnR⁵⁸When the temperature of the water is higher than the set temperature,

T³represents trifluoromethanesulfonate or halogen, preferably bromine,

and is

When L is³When the compound is iodine, bromine or trifluoromethanesulfonate,

T³represents a group SnR^55’R^56’R^57’、ZnR^58’Or BR⁵⁹R⁶⁰，

Wherein R is^55’、R^56’、R^57’And R^58’Having the above-mentioned R⁵⁵、R⁵⁶、R⁵⁷And R⁵⁸And the same or different from these groups,

R⁵⁹and R⁶⁰Identical or different, each represents a hydroxyl group, an aryloxy group having 6 to 10 carbon atoms or a straight-chain or branched alkyl or alkoxy group each having up to 5 carbon atoms, or together form a 5-or 6-membered carbocyclic ring,

the palladium-catalyzed reaction is carried out in an inert solvent,or [ C3]]When in use

When the temperature of the water is higher than the set temperature,

wherein

R⁶¹Denotes straight-chain or branched alkyl containing up to 4 carbon atoms,

reacting a compound of the formula (III-VI)

Wherein A is³，R⁴³And R⁴⁴Having the above-mentioned meanings, with diazo compounds of the general formula (III-VII)

Wherein

R⁶²Denotes straight-chain or branched alkyl containing up to 4 carbon atoms,

in the presence of copper salts or rhodium salts to give compounds of the general formula (III-Ia)

Wherein

A³，R⁴³、R⁴⁴And R⁶²Having the above meaning, [ D3]]When in useWhen a compound of the formula (III-VIII) is used

Wherein A is³，R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

or by reaction with a compound of the formula (III-IX)

In NaOCO-CH₃Direct reaction in N-methylpyrrolidine system to compounds of the general formula (III-Ib),

wherein

R⁴³、R⁴⁴And A³Has the meaning of the above-mentioned formula,

then acetyl is removed in methanol under the action of potassium hydroxide,

alternatively, the first and second electrodes may be,

the compound of the formula (III-X) is first prepared by reacting a compound of the formula (III-VIII) with a compound of the formula (III-IX)

Wherein

R⁴³、R⁴⁴And A³Has the meaning of the above-mentioned formula,

then preparing hydroxymethyl compound under the action of potassium hydroxide,

then, if necessary, the methylol compound is converted into the corresponding alkoxy compound by alkylation by a conventional method,

alternatively, [ E3]Reacting a compound of the formula (III-XI)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

with a compound of the formula (III-XII),

to obtain the compounds of the general formulas (III-XIII)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

then subjected to a Retro-Diels-Alder reaction (see J. org. chem., 1988, 58, 3387-90),

alternatively, [ F3]Reacting a compound of the formula (III-XIV)

Wherein

A³、R⁴³And R⁴⁴Having the above-mentioned meanings, with compounds of the general formula (III-XV)

Br-CH₂-CO-R⁶³(III-XV)

Wherein

R⁶³Represents a linear or branched alkyl or alkoxycarbonyl group each containing up to 4 carbon atoms, in an inert solvent to give a compound of the formula (III-Ic)

Wherein

A³、R⁴³、R⁴⁴And R⁶³Having the above-mentioned meanings (see oxazole compounds (Oxazoles), J.Wiley/New York, 1986, page 11/12),

for the case of esters (R)⁶³＝CO₂-(C₁-C₄Alkyl)), by a reduction reaction by a conventional method to produce the corresponding methylol compound, or [ G3]]When in use

When the temperature of the water is higher than the set temperature,

reacting a carboxylic acid of the formula (III-XVI)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

first converted into a compound of the formula (III-XVII) with hydrazine hydrate

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

then, reacted with a compound of the formula (III-XVIII)

Cl-CO-CH₂-Cl (III-XVIII) to give the compound of formula (III-XIX)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

then cyclizing under the action of phosphorus oxychloride to generate the compound with the general formula (III-Id)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

also, as described above, -CH₂-OH-substituted compounds from the corresponding-CH₂-O-CO-CH₃Preparation of substituted compounds (see Arzn. Forsch.45(1995)10, 1074-1078), or

[H3]When R is⁴²When a group of the formula is represented,

wherein

R⁶⁴Represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

R⁶⁵including the heterocyclic radicals R listed above⁴²Within the meaning of the sub (Unter) substituent(s), compounds of the general formula (III-XX)

Wherein

A³、R⁴³、R⁴⁴、R⁶⁴And R⁶⁵Has the meaning of the above-mentioned formula,

with PPh₃/I₂In the presence of a base, preferably triethylamine, or [ I3]When R is⁴⁵When a group of the formula is represented,

wherein a3 has the abovementioned meaning, compounds of the general formula (III-XXI)

Wherein A is³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

R⁶⁶having the above-mentioned R⁶⁴And the same or different therefrom,

or first reduced by conventional methods to the corresponding compounds of the formulae (III-XXII)

followed by oxidation to prepare compounds of the formula (III-XXIII)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

alternatively, the compounds of the formulae (III-XXI) are converted directly into compounds of the formulae (III-XXIII) by reduction,

subsequently, it is reacted with a1, 2-or 1, 3-dihydroxy compound by a conventional method,or [ J3]When R is⁴²When a group of the formula is represented,

wherein

R⁶⁷Having the above-mentioned R⁶⁵And the same or different thereto, compounds of the general formulae (III-XXIV)

Wherein

R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

qrepresents hydrogen or a group-CH₂-A³And is

R⁶⁸Represents halogen or a linear or branched alkoxy group containing up to 4 carbon atoms, preferably chlorine, methoxy or ethoxy,

with a compound of the formula (III-XXV),

wherein

R⁶⁷Has the meaning of the above-mentioned formula,

if desired in the presence of a base, and, when Q ═ H, subsequently reacting the product with formula a³-CH₂A compound of the formula-Br (III-XXVI) in which A has the abovementioned meaning, orReacting a compound of the formula (III-XXVII)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

with a compound of the formula (III-XXVIII),

R^67’-CO-R^68’(III-XXVIII)

wherein

R^67’Having R⁶⁷The above-mentioned meaning of and the same or different from it,

R^68’having R⁶⁸The above-mentioned meaning of and the same or different from it,

if desired, the reaction is carried out in the presence of a base,

for the group-S (O)_c3NR⁵⁰R⁵¹and-S (O)_c3’NR^50’R^51’Starting from the unsubstituted compound of the general formula (III-I), the compound is first reacted with thionyl chloride and subsequently with an amine,

and, R can be changed or introducedby a conventional method if necessary⁴²、R⁴³、R⁴⁴And/or A³The substituents listed below are preferably prepared by reduction, oxidation, cleavage of protecting groups and/or nucleophilic substitution.

Can be used forThe process of the present invention is illustrated by the following reaction equation.

Suitable solvents in the individual steps of the process [ A3]are inert organic solvents which do not change under the reaction conditions. The solvent includes ethers such as diethyl ether or tetrahydrofuran; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions; nitromethane; dimethylformamide; acetone; acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Particular preference is given to tetrahydrofuran, toluene or dimethylformamide.

Bases which can be used in the process of the invention are inorganic or organic bases. These bases include and are preferably alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as barium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; or alkali metal or alkaline earth metal alkoxides, for example sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide; or organic amines (trialkyl (C)₁-C₆) Amines), such as triethylamine; or heterocyclic compounds, e.g. 1, 4-diazabicyclo [2.2.2]Octane (DABCO), 1, 8-diazabicyclo [5.4.0]]Non-7-ene (DBU), pyridine, diaminopyridine, N-methylpyrrolidone, methylpiperidine or morpholine. Alkali metals such as sodium and hydrides thereof such as sodium hydride can also be used as the base. Preference is given to sodium and potassium carbonate, triethylamine, sodium hydride and N-methylpyrrolidone.

The amount of base used is 1 to 5mol, preferably 1 to 3mol, per mol of the compound of the formula (III-II).

Suitable solvents for the individual steps of process [ B3]are inert organic solvents which do not change under the reaction conditions. The solvent includes ethers such as diethyl ether or tetrahydrofuran, DME or dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions; nitromethane; dimethylformamide; acetone; acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Particular preference is given to tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane.

Suitable solvents for the process [ C3]are the abovementioned partial solvents, with particular preference being given to benzene.

Suitable metal salts are copper salts or rhodium (II) salts, e.g. CuOTf, Cu (acac)₂And Rh (OAc)₂. Copper acetylacetonate is preferred.

The amount of salt used is a catalytic amount.

The process [ D3]according to the invention is carried out with one of the above-mentioned cyclic amine bases, preferably with N-methylpyrrolidone, at from 100 ℃ to 200 ℃, preferably at 150 ℃.

The process [ E3]according to the invention is carried out at from 150 ℃ to 210 ℃ and preferably at 195 ℃.

The process [ F3]according to the invention is generally carried out in one of the above-mentioned ethers, preferably in tetrahydrofuran at reflux temperature.

The reaction from the free methyl hydroxyl group to the corresponding methyl alkoxy compound is carried out in a conventional manner by alkylation with an alkyl halide, preferably an alkyl iodide, in the presence of one of the bases mentioned above, preferably sodium hydride.

The compounds of the formulae (III-III), (III-V), (III-VI), (III-VII), (III-VIII), (III-IX), (III-XI), (III-XII), (III-XIV), (III-XVI) and (ITI-XVIII) are known or can be prepared by customary methods.

Of the compounds of the formula (III-II), some are known and can be prepared by a process in which compounds of the formula (III-XXXIX) are reacted

Wherein

R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

L^3’having the above-mentioned L³And the same or different therefrom,

the reaction with the compounds of the formulae (III-V) is carried out analogously to the process [ B3]described above.

Some compounds of the formula (III-IV) are known and novel in the case of stannyl and can be prepared, for example, by a process in which a compound of the formula (III-IVa) is reacted

Wherein

R⁴³、R⁴⁴And A³Has the meaning of the above-mentioned formula,

L^3″represents triflate or halogen, preferably iodine,

with compounds of the general formula (III-XXX)

(SnR⁵⁵R⁵⁶R⁵⁷)₂(III-XXX)

Wherein

R⁵⁵、R⁵⁶And R⁵⁷Has the meaning of the above-mentioned formula,

the reaction was carried out under palladium catalysis as described above.

The compounds of the formulae (III-IVa) and (III-XXX) are known or can be prepared by customary methods.

In some cases, the compounds of the formulae (III-X), (III-XIII), (III-XVII) and (III-XIX) are novel and can be prepared, for example, by the methods described above.

The procedure [ H3]was carried out by conventional methods, in particular according to the description in P.Wipf, CP.Miller, J.Organischen Chemie, 1993, 58, 3604, C.S.Moody et al, synthetic letters (Synlett)1996, page 825.

Some compounds of the general formula (III-XX) are known or can be prepared by reacting the corresponding amides with α -diazo- β -keto ester under catalysis of rhodium salts (cf. C.S. Moody et al, synthetic letters 1996, p.825).

Process [ I3]was carried out by a conventional method for preparing acetals. The reduction step will be described in detail below.

The compounds of the formulae (III-XXI), (III-XXII) and (III-XXIII) are known in some cases and novel substances, and can be prepared by the above-described methods.

The procedure [ I3]was performed analogously to that described in s.chim and h.j.shirie, journal of heterocyclic chemistry (j.heterocyclic. chem.)1989, 26, 125 and journal of pharmaceutical chemistry (j.med. chem.)1990, 33, 113.

Some of the compounds of the formulae (III-XXIV) and (III-XXV) are known or can be prepared by customary methods.

The compounds of the formulae (III-XXVI) are known in some cases and are novel and can be prepared from the corresponding cyano-substituted compounds and hydroxylamine hydrochloride. If desired, a base, preferably sodium methoxide in methanol, may be used in the reaction.

The compounds of the formulae (III-XXVII) are known or can be prepared by customary methods.

Processes [ H3]- [ J3]are generally carried out at reflux temperatures from 0 ℃ to atmospheric pressure.

When present, the formula-S (O)_c3NR⁵⁰R⁵¹and-S (O)_c3’NR^50’R^51’When the radical (b) is used, the corresponding unsubstituted compound is first reacted with thionyl chloride. And then reacted with an amine in an ether as described above, preferably dioxane. When c3 is 2, the oxidation reaction is subsequently carried out by conventional methods. The reaction is usually carried out at 0 ℃ to 70 ℃ under normal pressure.

Wherein R is⁴²Compounds of embodiment III of the present invention representing oxazolyl groups of the formula (III-XXVIII)

Wherein Y and Z have the following meanings, are preferably prepared by a novel process described below, which can be used as a general method for preparing compounds of this type.

The invention therefore also relates to a process for the preparation of oxazole compounds of the general formulae (III-XXIX),

wherein

X and Y are the same or different and each represents an aliphatic, alicyclic, araliphatic, aromatic and heterocyclic group which may be optionally substituted, including a saturated, unsaturated or aromatic monocyclic heterocyclic or polycyclic heterocyclic group, a carboxyl group, an acyl group, an alkoxy group, an alkoxycarbonyl group or a cyano group, or represents hydrogen, wherein the aromatic and heterocyclic groups may be substituted with one or more substituents selected from the group consisting of:

halogen, formyl, acyl, carboxyl, hydroxyl, alkoxy, aryloxy, acyloxy, optionally substituted amino, amido, aminocarbonyl, alkoxycarbonyl, nitro, cyano, phenyl and alkyl which may be substituted with one or more substituents selected from halogen, hydroxyl, amino, carboxyl, acyl, alkoxy, alkoxycarbonyl, and heterocyclic and phenyl which may in turn be substituted with one or more substituents selected from: amino, mercapto, hydroxy, formyl, carboxy, acyl, alkylthio, alkoxyacyl, alkoxy, alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl and alkyl, which groups may optionally be substituted by hydroxy, carboxy, acyl, alkoxy or alkoxycarbonyl,

wherein the aliphatic, cycloaliphatic and araliphatic radicals may be substituted by one or more substituents selected from the group consisting of: fluorine, hydroxyl, alkoxy, aryloxy, acyloxy, alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl and acyl,

z is selected from the following groups:

hydroxy, alkoxy, arylalkoxy optionally substituted by alkyl and/or halogen, aryloxy optionally substituted by alkyl and/or halogen, aroyloxy, acyloxy, alkylthio, arylthio optionally substituted by alkyl and/or halogen,Diacylimino or a group of formula (III-XXX)

Wherein Y and X have the above-mentioned meanings,

characterized in that an amide of the formula (III-XXXI)

In which Y and X have the abovementioned meanings and Hal represents chlorine or bromine, with the formula M1⁺Z^-Or M2²⁺(Z^-)₂Wherein M1 is an alkali metal, M2 is an alkaline earth metal, and Z is as defined above.

In the specific examples of the above definitions containing substituents within their scope, reference is made to the corresponding meanings in the explanations given above for the compounds of embodiment III of the invention.

In a preferred embodiment of the process, the oxazole compounds of the present invention wherein X is a group of the formula in formulas (III-XXIX) above are prepared

Wherein

R⁴³、R⁴⁴And A³As defined above, Y is alkyl or phenyl optionally substituted with alkyl or halogen.

Examples of oxazole compounds which can be obtained by the above-mentioned preparation methods are: 2, 4-dimethyl-5-methoxymethyl-oxazole, 2-ethyl-5-methoxymethyl-oxazole, 2-isopropyl-4-ethyl-5-ethoxymethyl-oxazole, 2-cyclopropyl-4-hexyl-5-isopropoxy-methyl-oxazole, 2-phenyl-4-methyl-5-methoxymethyl-oxazole, 2- (m-trifluoromethyl-phenyl) -4-methyl-5-butoxymethyl-oxazole, 4-methyl-5-methoxymethyl-2- (m-trifluoromethyl-phenyl) -oxazole, 2-phenyl-4-methyl-5-phenoxymethyl-oxazole, m-trifluoromethyl-phenyl-oxazole, m-trifluoromethyl-oxazole, n-methyl-5-ethoxymethyl-oxazole, m-trifluoromethyl-oxazole, m-methyl-5-ethoxymethyl-oxazole, m-trifluoromethyl-5-ethoxymethyl-oxazole, m, 2- (2-chloro-6-fluorophenyl) -4-methyl-5-p-tert-butylphenoxymethyl-oxazole, 2, 4-dimethyl-5-acetoxymethyl-oxazole, 2, 4-dimethyl-5- (3-heptylcarbonyloxy) methyl-oxazole, 2-phenyl-4-methyl-5-acetoxymethyl-oxazole, 2- (1-benzylidazol-3-yl) -5-hydroxymethyl-4-methyl-oxazole, 5-acetoxymethyl-2- (1-benzylidazol-3-yl) -4-methyl-oxazole, 2- (1-benzylidazol-3-yl) -5-methoxymethyl-4-oxazole -methyl-oxazole, 2- [1- (2-fluorobenzyl) indazol-3-yl]-5-hydroxymethyl-4-methyl-oxazole, 2- [1- (2-fluorobenzyl) indazol-3-yl]-5-methoxymethyl-4-methyl-oxazole, 2- [1- (2-fluorobenzyl) indazol-3-yl]-4-methyl-5- (N-phthalimidomethyl) -oxazole, 4-ethyl-2- [1- (2-fluorobenzyl) indazol-3-yl]-5-hydroxymethyl-oxazole, 2-phenyl-4-ethyl-5-benzoyloxymethyl-oxazole, 2-phenyl-4-methyl-5-methylmercaptomethyl-oxazole, bis [ (2-phenyl-4-methyl-oxazol-5-yl) methyl]disulfide and 2-phenyl-4-methyl-5-N-phthalimidomethyl-oxazole.

The preparation of the oxazole compounds of the present invention can be accomplished, for example, by reacting an amide compound with a compound of the formula M1 according to reaction formula (a)⁺Z^-Or M2²⁺(Z^-)₂The compound of (1):

or M2^2-(Z^-)₂→

Or M2Hal₂+ZH

Compound M1⁺Z^-In (b), M1 is an alkali metal selected from, for example, lithium (Li), sodium (Na) or potassium (K), preferably sodium or potassium. Mention may be made of the formula M1⁺Z^-Is an alkoxide, such as sodium methoxide, sodium butoxide or potassium tert-butoxide; phenolates such as sodium phenolate and sodium 4-tert-butyl-phenolate; carboxylates such as sodium or potassium acetate, lithium butyrate, sodium benzoate and sodium 2, 6-difluorobenzoate; phthalimide salts such as potassium phthalimide and sodium phthalimide; hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; mercaptides, such as the sodium salt of methyl mercaptan or thiophene; and Na₂S₂Thereby producing a disulfide of the formula

Compound M2²⁺(Z^-)₂M2 in (a) is an alkaline earth metal selected from, for example, magnesium or calcium.

The reaction of equation (a) is carried out in a solvent at a temperature of about 20 ℃ to 200 ℃. Suitable solvents are polar compounds such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, N-methyl-epsilon-caprolactam and dimethylsulfoxide, and compounds of the formula Z-H can also be used as solvents, for example the reaction of amides with sodium methoxide can be carried out successfully in methanol. Preferably, an alkaline adjuvant such as potassium carbonate or cesium carbonate is additionally added. The resulting oxazole compound can be isolated by: after removing the insoluble salts by filtration, the solvent is removed by distillation, if necessary, and the oxazole compound is extracted from the crude product with a suitable solvent, for example, a hydrocarbon such as cyclohexane or toluene, or a chlorinated hydrocarbon such as dichloromethane or chlorobenzene, or an ester such as ethyl acetate or ether, to which water is added to remove the water-soluble product. The crude product can be purified by conventional methods, for example by distillation or recrystallization or chromatography.

The amide compound used as a starting material can be produced by a known method, for example, from a compound of formula a, b or c.

a: hal ═ Cl or Br; l is^v＝NH₂b: hal ═ Cl or Br; l is^vOH c: hal ═ Cl or Br; l is^vCl or Bf

Starting from the amine of formula a, the amine of formula (XXXI) is formed by known methods by reaction with a corresponding acylating agent such as an acid halide, ester or acid.

Starting from the compounds of the formula b or c, the amide is formed in a known manner by reaction with a nitrile in the presence of a strong acid.

The amides corresponding to formula a can be obtained, for example, by hydrolysis under acidic conditions from amides which can be obtained in a known manner by the Ritter reaction from alkyl halides of the formulae b and c or allyl alcohol. The amines can also be prepared from the corresponding allyl halides of formula c by reaction with the corresponding substituted phthalimides followed by hydrolysis by allylnucleophilic substitution reaction with, for example, phthalimide salts.

The compounds of the formula b are readily prepared in a known manner from simple starting materials in a two-step reaction according to reaction equations (b) and (c):

the compounds of the formula c are prepared in a known manner, for example by addition of carbon tetrachloride or carbon tetrabromide to the corresponding olefin compounds by free-radical-initiated addition reaction with subsequent elimination of hydrogen halide, see reaction equation (d):

the invention also relates to the use of a compound of the general formula (III-I)/(III-Ia) according to the invention in combination with an organic nitrate and an NO donor.

The invention also relates to the use of compounds that inhibit cyclic guanosine monophosphate (cGMP) cleavage. In particular with inhibitors of phosphodiesterase 1, 2 and 5 (named according to Beavo and Reifnyder (1990) TIPS11, page 150-155). The compounds of the invention have increased effects and their desired pharmacological effects are enhanced by these inhibitors.

The compounds of the general formula (III-I)/(III-Id) according to the invention show an unpredictable, valuable range of pharmacological effects.

The compounds of the general formula (III-I)/(III-Id) according to the present invention cause vascular relaxation/inhibit platelet aggregation and lower blood pressure, and also increase coronary blood flow. This effect is mediated by direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. In addition, the compounds of the present invention also potentiate the action of substances having a cGMP level-increasing activity, such as EDRF (endothelial derived relaxin), NO donor, hematoporphyrin IX, arachidonic acid or phenylhydrazine derivative.

TABLE A

Example No. 2	Percentage increase in cGMP
Example No. 2	Percentage increase in cGMP	III-71	315
III-73	＞1000	III-71	315
III-73	＞1000	III-74	114
III-75	＞1000	III-74	114
III-75	＞1000	III-76	397
III-77	＞1000	III-76	397
III-77	＞1000	III-78	223

Example No. 2	Percentage increase in cGMP
Example No. 2	Percentage increase in cGMP	III-79	124
III-80	＞1000	III-79	124
III-80	＞1000	III-81	110
III-82	455	III-81	110
III-82	455	III-87	268
III-91	479	III-87	268
III-91	479	III-92	319
III-93	271	III-92	319

In vitro vascular relaxation

After several control cycles, the substances to be observed were observed in each case at increasing doses and compared with the level of contraction initially obtained in the last time. From this, the concentration (IC) required to reduce the level of the control value to 50% was calculated₅₀). The standard volume used was 5. mu.l.

TABLE B

Example No. 2	Aorta IC₅₀
Example No. 2	Aorta IC₅₀	III-71	5μM
III-73	9.4μM	III-71	5μM
III-73	9.4μM	III-75	2.2μM
III-76	7.4μM	III-75	2.2μM
III-76	7.4μM	III-77	8.3μM
III-78	10μM	III-77	8.3μM
III-78	10μM	III-79	13μM
III-80	3.6μM	III-79	13μM
III-80	3.6μM	III-81	12μM
III-82	15μM	III-81	12μM
III-82	15μM	III-87	19μM
III-88	7.1μM	III-87	19μM
III-88	7.1μM	III-90	4.1μM
III-95	2.4μM	III-90	4.1μM

Blood pressure measurement for anesthetized rats

Male Wistar rats weighing 300-350g were anesthetized with thiopental (100mg/kg i.p.). After performing tracheotomy, a catheter was inserted into the femoral artery to measure blood pressure. Various doses of the test substance in a suspension in tylose solution were administered orally using a gastric tube. Inhibition of platelet aggregation in vitro

For the study, 445. mu.l of PRP and 5. mu.l of the active compound solution were preincubated in a 37 ℃ water bath. Platelet aggregation was then measured in an agglutination meter at 37 ℃ using nephelometry. For this purpose, 50. mu.l of collagen, an aggregation-inducing agent, are added to the previously incubated samples and the change in optical density is recorded. For quantitative evaluation, the maximum agglutination was determined and the percentage inhibition compared to the control was calculated therefrom.

Table D

Example No. 2	IC₅₀(μg/ml)
Example No. 2	IC₅₀(μg/ml)	III-71	50
III-72	1	III-71	50

The compounds of embodiment III described in the present invention are also active compounds against diseases of the central nervous system which are characterized by impairment of the NO/cGMP system. In particular, they are suitable for eliminating cognitive impairment, improving cognitive and memory functions and for the treatment of alzheimer's disease. They are also suitable for the treatment of disorders of the central nervous system, such as anxiety, stress and depression, sexual dysfunction of central nervous origin and sleep disorders, pathological disorders for the regulation of food and additive substance intake.

They are also suitable for preventing and combating cerebral infarctions (cerebral stroke), such as the consequences of stroke, cerebral ischemia and craniocerebral injury. The compounds of the invention are also useful against pain.

The invention encompasses pharmaceutical preparations which comprise one or more compounds of the invention or consist exclusively of one or more active compounds of the invention, in addition to a non-toxic and inert pharmaceutically acceptable carrier, and processes for the preparation of these preparations.

In general, to achieve the desired effect, it has proven advantageous in human and veterinary medicine to administer the active compound or compounds according to the invention in a total amount of from about 0.5 to about 500, preferably from 5 to 100, mg/kg of body weight per 24 hours, if appropriate in divided doses. A single dose preferably contains from about 1 to about 80, in particular from 3 to 30, mg/kg of body weight of one or more active compounds according to the invention. IV

According to embodiment IV, the invention relates to 1-benzyl-3- (substituted heteroaryl) -fused pyrazole derivatives of the general formula (IV-I) and their isomeric forms and salts,

wherein

A⁴Represents a phenyl group, optionally substituted up to 3 times with identical or different substituents selected from: halogen, hydroxy, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each containing up to 6 carbon atoms,

R⁶⁹represents a group of the formula

Or

Wherein

R⁷²Is represented by the formula-CH (OH) -CH₃Or a linear or branched alkyl group containing from 2 to 6 carbon atoms which may be substituted once or twice by hydroxy or by a linear or branched alkoxy group containing up to 4 carbon atoms, or

Represents formyl, straight-chain or containing up to 6 carbon atomsBranched acyl, nitro, OR straight OR branched alkyl of up to 6 carbon atoms, the latter being substituted by amino, azido OR by the formula-OR⁷³Is substituted with a group(b) of (a),

wherein

R⁷³Represents a straight or branched chain acyl group containing up to 5 carbon atoms or a compound of formula-SiR⁷⁴R⁷⁵R⁷⁶、

or-CH₂-OR⁷⁹Group (d) of

Wherein

R⁷⁴、R⁷⁵And R⁷⁶Identical or different, denotes an aryl radical having 6 to 10 carbon atoms or a linear or branched alkyl radical having up to 6 carbon atoms,

R⁷⁸represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms,

and is

R⁷⁹Represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

or

R⁷²Represents a group of the formula

or-S (O)_c4NR³²R³³

Wherein

R⁸⁰Represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

R⁸¹represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

a4 represents a number of 1, 2 or 3,

b4 and b 4', which are identical or different, represent a number 0, 1, 2 or 3,

c4 represents a number of 1 or 2, and

R⁸²and R⁸³Identical or different, represents hydrogen or a linear or branched alkyl radical having up to 10 carbon atoms, which alkyl radical is optionally substituted by a cycloalkyl radical having 3 to 8 carbon atoms or by an aryl radicalhaving 6 to 10 carbon atoms, which in turn may be substituted by halogen,

or

Represents an aryl group having 6 to 10 carbon atoms, which aryl group may optionally be substituted by halogen, or

Represents a cycloalkyl group having 3 to 7 carbon atoms, or

R⁸²And R⁸³Together with the chlorine atom, form a 5-to 7-membered saturated heterocyclic ring, which may optionally contain a further oxygen atom or a group-NR⁸⁴，

Wherein

R⁸⁴Represents hydrogen, a linear or branched alkyl radical containing up to 4 carbon atoms or a radical of formula

or

R⁷²Is represented by the formula-CH₂-OR⁸⁵The group of (a) or (b),

wherein

R⁸⁵Represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms, R⁷⁰And R⁷¹Together form a radical of the formula

Or

Wherein

R⁸⁶Represents hydrogen, halogen, hydroxyl, nitro, amino, trifluoromethyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, or is of the formula-S (O)_c4’NR^82’R^83’Wherein c 4', R^82’And R^83’With c4, R mentioned above⁸²And R⁸³The radicals have the same meaning and are identical to or different from these radicals,

provided that only A is present⁴Is represented by cyano, nitro, trifluoromethyl, azido, carboxyl or a group containing toPhenyl substituted by straight-chain or branched alkoxycarbonyl of up to 6 carbon atoms or at least twice by the radicals listed above, or R⁸⁶Represents nitro, amino, trifluoromethyl or represents formula-S (O)_c4NR^82’R^83’When a group of (1) is presentR in the case of a phenyl ring and in the position directly adjacent to the heteroatom⁷²Can represent formula-CH₂-OR⁸⁵A group.

The compounds of the general formula (IV-I) according to the invention can also be present in the form of their salts. Mention may generally be made herein of salts with inorganic or organic bases or acids.

In embodiment IV of the invention, physiologically acceptable salts are preferred. Physiologically acceptable salts may be salts of the substances of the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, fumaric acid, maleic acid or benzoic acid.

If the compounds of the invention carry free carboxyl groups, physiologically acceptable salts may also be their metal or ammonium salts. Particularly preferred salts are, for example, the sodium, potassium, magnesium or calcium salts, and also the ammonium salts from ammonia or organic amines, such as ethylamine, di-or triethylamine, di-or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

Preferred compounds ofthe general formula (IV-I) according to the invention are the following compounds and their isomeric forms and salts:

wherein

A⁴Represents phenyl, which may be optionally substituted up to 3 times by the same or different substituents selected from: fluorine, chlorine, bromine, hydroxyl, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each of which contains up to 5 carbon atoms,

R⁶⁹represents a group of the formula

Or

Wherein

R⁷²Is represented by the formula-CH (OH) -CH₃Or a linear or branched alkyl group having 2 to 4 carbon atoms, afterWhich may be substituted once or twice by hydroxy or by straight-chain or branched alkoxy having up to 3 carbon atomsOr is or

Representing formyl, straight-chain OR branched acyl having up to 4 carbon atoms, nitro OR straight-chain OR branched alkyl having up to 4 carbon atoms, which may be substituted by amino, azido OR a group of the formula-OR⁷³Is substituted with a group (b) of (a),

wherein

R⁷³Represents a linear or branched acyl group containing up to 4 carbon atoms or a compound of formula-Si (CH)₃)₂C(CH₃)₃，or-CH₂-OR⁷⁹The group of (a) or (b),

wherein

and is

R⁷⁹Represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms,

or

R⁷²Represents a group of the formula

Or

Wherein

R⁸⁰Represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms,

R⁸¹represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms, and

a4 represents a number of 1 or 2,

or

R⁷²Is represented by the formula-CH₂-OR⁸⁵The group of (a) or (b),

wherein

R⁸⁵Represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms,

R⁷⁰and R⁷¹Together form a radical of the formula

Or

Wherein

R⁸⁶Represents hydrogen, fluorine, chlorine, bromine, hydroxyl, nitro, amino, trifluoromethyl or straight-chain or branched alkyl or alkoxy each containing up to 3 carbon atoms,

provided that only A is present⁴Represents phenyl which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or

R⁸⁶R in the case of a phenyl ring and in the position directly adjacent to the heteroatom when representing nitro, amino or trifluoromethyl⁷²Can represent formula-CH₂-OR⁸⁵A group.

Particularly preferred compounds of the general formula (IV-I) according to the invention are the following compounds and isomeric forms and salts thereof:

wherein

A⁴Represents phenyl, which may be optionally substituted up to 3 times by the same or different substituents selected from: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each containing up to 3 carbon atoms,

R⁶⁹represents a group of the formula

Or

Wherein

R⁷²Is represented by the formula-CH (OH) -CH₃Or a linear or branched alkyl group containing 2 to 4 carbon atoms, which may be substituted once or twice by hydroxy, methyl or methoxy, or

Representing a formyl group, a straight-chain OR branched acyl group having up to 3 carbon atoms, a nitro group, OR a straight-chain OR branched alkyl group having up to 3 carbon atoms, which may be substituted by an amino group, an azido group OR a group of formula-OR⁷³Is substituted with a group (b) of (a),

wherein

R⁷³Represents a linear or branched acyl group containing up to 3 carbon atoms or a compound of formula-Si (CH)₃)₂C(CH₃)₃，

or-CH₂-OR⁷⁹The group of (a) or (b),

wherein

R⁷⁸Represents hydrogen or a methyl group,

and is

or

R⁷²Represents a group of the formulaOr

Wherein

R⁸¹represents hydrogen or methyl, and

a4 represents a number 1 or 2, or

R⁷²Are the same or different and represent formula-CH₂-OR⁸⁵The group of (a) or (b),

wherein

R⁸⁵Represents hydrogen or a methyl group,

R⁷⁰and R⁷¹Together form a radical of the formula

Or

Wherein

R⁸⁶Represents hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, amino, hydroxyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,

provided that only A is present⁴Represents phenyl which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or R⁸⁶R in the case of a phenyl ring and in the position directly adjacent to the heteroatom when representing nitro, amino or trifluoromethyl⁷²Can representformula-CH₂-OR⁸⁵A group.

wherein

A⁴Represents phenyl, which may be optionally substituted up to 2 times by the same or different substituents selected from: fluorine, chlorine, methyl, methoxy, cyano, nitro, trifluoromethyl or trifluoromethoxy,

R⁷⁰and R⁷¹Together, including the double bond, form a phenyl ring, which may optionally be substituted with nitro, fluoro, amino or methoxy,

provided that only A is present⁴Represents phenyl which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or R⁸⁶R in the case of a phenyl ring and in the position directly adjacent to the heteroatom when representing nitro, amino or trifluoromethyl⁷²Can represent formula-CH₂-OR⁸⁵A group.

The invention also relates to a process for the preparation of compounds of the general formula (IV-I), characterized in that [ A4]]In which A is⁴Compounds of the general formula (VI-II) having the abovementioned meanings

H₂N-NH-CH₂-A⁴(IV-II)

By reaction with R⁶⁹、R⁷⁰And R⁷¹Compounds of the general formula (IV-III) having the abovementioned meanings

In an inert solvent, if desired in the presenceof an acid, into which⁴、R⁶⁹、R⁷⁰And R⁷¹Compounds of the general formulae (IV-IV) having the abovementioned meanings and subsequent oxidation and cyclization of the products with lead tetraacetate/boron trifluoride etherate,

or [ B4]]In which R is⁶⁹、R⁷⁰And R⁷¹Compounds of the general formula (IV-V) having the abovementioned meanings

And wherein A⁴Has the above meaning and D⁴Represents trifluoromethanesulfonate or halogen, preferablyThe bromine compounds of the general formulae (IV-VI) are reacted in an inert solvent, if desired in the presence of a base,

D⁴-CH₂-A⁴(IV-VI)

or [ C4]]Reacting a compound of the formula (IV-VII)

Wherein

A⁴、R⁷⁰And R⁷¹Have the above meanings, and

L⁴is represented by the formula-SnR⁸⁷R⁸⁸R⁸⁹、ZnR⁹⁰Iodine or trifluoromethanesulfonate ester

Wherein R is⁸⁷、R⁸⁸And R⁸⁹Identical or different and denotes straight-chain or branched alkyl having up to 4 carbon atoms, and

R⁹⁰represents a halogen, and is characterized in that,

carrying out palladium catalytic reaction with compounds of general formulas (IV-VIII) in an inert solvent,

R⁶⁹-T⁴(VI-VIII)

wherein R is⁶⁹Has the meaning described above, and

at L⁴＝SnR⁸⁷R⁸⁸R⁸⁹Or ZnR⁹⁰In the case of (a) in (b),

T⁴represents trifluoromethanesulfonate or represents halogen, preferably bromine, and

at L⁴In the case of iodine or triflate,

T⁴is represented by the formula SnR^87’R^88’R^89’、ZnR^90’Or BR⁹¹R⁹²，

Wherein

R^87’、R^88’、R^89’And R^90’Having the above-mentioned R⁸⁷、R⁸⁸、R⁸⁹And R⁹⁰And the same or different from them

And is

R⁹¹And R⁹²Identical or different, represents hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5-or 6-membered carbocyclic ring,

or

[D4]In which R is⁷²In the case of an alkyl group having 2 to 6 carbon atoms substituted twice with a hydroxyl group,

in which A is⁴、R⁷⁰And R⁷¹Compounds of the general formula (IV-Ia) having the above-mentioned meanings

By a Wittig reaction in (C)₆H₅)₃P^_-CH₂ ^_In the system is converted into R⁷⁰、R⁷¹And A⁴The compounds of the general formulae (IV-IX) having the abovementioned meanings, with subsequent introduction of the hydroxyl function by means of osmium tetroxide,

and if desired, at R⁶⁹、R⁷⁰、R⁷¹And/or A⁴The substituents listed below may be converted or introduced using conventional methods, preferably using reduction, oxidation, cleavage of protecting groups and/or nucleophilic substitution methods.

The method of the present invention can be illustrated by way of example by the following equation:

suitable solvents for the steps of process [ A4]are generally inert organic solvents which do not change under the reaction conditions. They include ethers such as diethyl ether, dimethoxyethane or tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; alcohols, such as methanol, ethanol or propanol; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum ether fractions; nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. Mixtures of these solvents may also be employed. Ethanol and THF are preferably used in the first step of the process [ A4], and methylene chloride is preferably used for the cyclization reaction.

The reaction is generally carried out at from 0 to 150 ℃ and preferably at from +20 to +110 ℃.

The reaction can be carried out under normal pressure, under increased pressure and under reduced pressure (for example, 0.5 to 5 bar). Usually at atmospheric pressure.

Suitable carboxylic acids are generally carboxylic acids, such as acetic acid, toluenesulfonic acid, sulfuric acid or hydrochloric acid. Acetic acid is preferred.

Suitable solvents for the steps of process [ B4]are generally inert organic solvents which do not change under the reaction conditions. They include ethers such as diethyl ether or tetrahydrofuran; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum ether fractions; nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. Mixtures of these solvents may also be employed. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be used in the process of the invention are generally inorganic or organic bases. These preferably include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkaline earth metal carbonates, such as calcium carbonate; or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methylate, sodium or potassium ethylate or potassium tert-butylate; or an organic amine (trialkyl (C)₁-C₆) Amines), such as triethylamine; or heterocyclic compounds, e.g. 1, 4-diazabicyclo [2.2.2]Octane (DABCO), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. Alkali metals, such as sodium and hydrides thereof, such as sodium hydride, can also be used as bases. Sodium carbonate, potassium carbonate, triethylamine and sodium hydride are preferred.

The amount of the base to be used is 1 to 5 moles, preferably 1 to 3 moles, per mole of the compound of the general formula (II).

Suitable solvents for processes [ C4]and [ D4]are generally inert organic solvents which do not change under the reaction conditions. They include ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum ether fractions; nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. Mixtures of these solvents may also be employed. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

Suitable palladium compounds in the present description are typically PdCl₂((C₆H₅)₃)₂Bis (dibenzylacetone) palladium (Pd (dba))₂) [1, 1' -bis- (diphenylphosphino) ferrocene]Palladium (II) chloride (Pd (dppf) Cl₂) Or Pd (P (C)₆H₅)₃)₄。Pd(P(C₆H₅)₃)₄Is preferred.

The compounds of the formulae (IV-II), (IV-III), (IV-VI) and (IV-VIII) are known or can be prepared by customary methods.

The general formulae (IV-IV) are known in some cases or can be prepared as described above.

The compounds of the general formulae (IV-V) areknown in some cases and can be prepared by the following methods: similar to the method [ C4]]Reacting a compound of the formula (IV-IX)

Wherein

R⁷⁰And R⁷¹Has the meaning of the above-mentioned formula,

and is

L^4’Having the above-mentioned L⁴And may be the same as or different from it,

with the general formula (IV-VIII).

The compounds of the formulae (IV-VII) are known in some cases but are novel in the case of stannyl and can be prepared in this case by the following process: as mentioned above, the compounds of the general formula (IV-VIIa)

Wherein

R⁷⁰、R⁷¹And A has the meaning indicated above, and,

and is

L^4″Represents triflate or halogen, preferably iodine,

and wherein R⁸⁷、R⁸⁸And R⁸⁹The compounds of the general formula (IV-X) having the abovementioned meaning are reacted in the presence of palladium catalysts.

(SnR⁸⁷R⁸⁸R⁸⁹)₂(IV-X)

The compounds of the formulae (IV-VIIa), (IV-IX) and (IV-X) are known or can be prepared by customary methods.

The compounds of the general formulae (IV-IX) are novel and can be prepared by the processes described above.

The reduction is generally carried out with reducing agents, preferably those which are suitable for reducing carbonyl groups to hydroxyl compounds. Particularly suitable reduction reactions herein are carried out with metal hydrides or complex metal hydrides in an inert solvent, if desired in the presence of trialkylboranes. The reduction reaction is preferably carried out using a complex metal hydride such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylbohydride, diisobutylaluminum hydride or lithium aluminum hydride. The reduction is particularly preferably carried out with diisobutylaluminum hydride and sodium borohydride.

The reducing agent is generally used in an amount of 1 to 6 moles, preferably 1 to 4 moles, per mole of the compound to be reduced.

The reduction is generally carried out at a temperature of-78 ℃ to +50 ℃, preferably-78 ℃ to 0 ℃, in the case of DIBAH, 0 ℃, at room temperature under NaBH₄In the case of (2), particular preference is given to carrying out at-78 ℃ in each case depending on the choice of reducing agent and solvent.

The reduction reaction is generally carried out under normal pressure, and may be carried out under increased pressure or reduced pressure. At the group-S (O)_c4R⁸¹R⁸²and-S (O)_c4’R^81’R^82’In the case of (2), the corresponding unsubstituted compound of the formula (IV-I) is first reacted with thionyl chloride. The reaction with the amine in one of the above-mentioned ethers, preferably dioxane, is carried out in the next step. In the case of c4 ═ 2, oxidation was subsequently carried out by conventional methods. The reaction is carried out at 0 ℃ to 70 ℃ under normal pressure.

Cleavage of the protecting group is carried out in one of the above-mentioned alcohols and/or tetrahydrofuran or acetone, preferably methanol/tetrahydrofuran, in the presence of hydrochloric acid, trifluoroacetic acid or toluenesulfonic acid at from 0 to70 ℃, preferably at room temperature and at normal pressure.

The compounds of the formula (IV-Ic) are novel compounds and can be prepared as described in methods [ A4]to [ C4].

The invention also relates to combinations of compounds of the general formulae (IV-I) and (IV-Ia) with organic nitrates (or salts) and NO donors.

The organic nitrates and NO donors in the context of the present invention are generally substances which exhibit their therapeutic action by releasing NO or NO-like compounds. Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.

The invention also relates to the use of compounds that inhibit cyclic guanosine (cGMP) cleavage. In particular with inhibitors of phosphodiesterase 1, 2 and 5 (named according to Beavo and Reifsnyder (1990) TIPS11, page 150-155). The compounds of the invention have increased effects and their desired pharmacological effects are enhanced by these inhibitors.

The compounds of the general formulae (IV-I) and (IV-Ia) exhibit an unpredictable, valuable range of pharmacological effects.

The compounds of the general formulae (IV-I) and (IV-Ia) of the present invention cause vascular relaxation/inhibit platelet aggregation and lower blood pressure, and also increase coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and by an increase in intracellular cGMP. The compounds of the invention also potentiate the action of substances with elevated cGMP levels, such as EDRF (endothelial derived relaxin), NO donors, hematoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

They are therefore useful in the treatment of cardiovascular diseases, such as hypertension and myocardial insufficiency, stable and unstable angina pectoris and peripheral and cardiovascular diseases and arrhythmias, in the treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transient and sudden ischaemia and peripheral circulatory disorders; for the prevention of restenosis, such as post-thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA) and bypass angioplasty restenosis; and for the treatment of arteriosclerosis and genitourinary disorders, such as prostatic hypertrophy, erectile dysfunction and incontinence.

Stimulation of soluble guanylate cyclase in primary endothelial cells

Primary endothelial cells were isolated from porcine aorta by treatment with collagenase solution. Then, the culture was carried out in a medium until fusion was achieved. For ease of observation, cells were plated, seeded in cell culture dishes, and subcultured until confluent. To stimulate endothelial guanylate cyclase, the medium was aspirated, the cells were washed once with Ringer solution and incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP, 1. mu.M). Thereafter, the test substance (final concentration of 1. mu.M) was pipetted onto the cells. At the end of the 10 min incubation period, the buffer was aspirated off and the cells were lysed at-20 ℃ for 16 h. Intracellular cGMP was then measured by radioimmunoassay.

TABLE A percentage increase in cGMP IV-136>1000 IV-138324 IV-139723 IV-140619 IV-143>1000 IV-153341 IV-148978 IV-164289 IV-165256 IV-171926 IV-175473 IV-179921 in vitro vascular relaxation

Table B example aorta IC₅₀(μm)IV-136 7.2IV-139 12IV-140 12-17IV-153 9.1IV-148 6.7IV-164 12IV-165 29 IV-16618 IV-1718.7 IV-17511 IV-17911 blood pressure measurement of anesthetized rats

Male Wistar rats weighing 300-350g were anesthetized with thiopental (100mg/kg i.p.). After performing tracheotomy, a catheter was inserted into the femoral artery to measure blood pressure. Various doses of the test substance in a suspension in tylose solution were administered orally using a gastric tube.

The invention encompasses pharmaceutical preparations which comprise one or more compounds of the invention in addition to a non-toxic and inert pharmaceutically suitable carrier or which consist exclusively of one or more active compounds of the invention, and processes for the preparation of these preparations. Inhibition of platelet aggregation in vitro

For the study, 445. mu.l of PRP and 5. mu.l of the active compound solution were preincubated in a 37 ℃ water bath. Platelet aggregation was then determined in an aggregometer (aggregometer) by nephelometry at 37 ℃. For this purpose, 50. mu.l of collagen, an aggregation-inducing agent, are added to the previously incubated samples and the change in optical density is recorded. For quantitative evaluation, the maximum agglutination was determined and the percentage inhibition compared to the control was calculated therefrom.

TABLE C example No. IC₅₀(μg/ml)IV-136 30

The compounds of embodiment IV described in the present invention are also active compounds against diseases of the central nervous system which are characterized by impairment of the NO/cGMP system. In particular, they are suitable for eliminating cognitive impairment, improving cognitive and memory functions and for the treatment of alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system, such as anxiety, tension and depression, pathological disorders of food and addictive substance intake of the central nervous system.

They are also suitable for the prevention and combating of cerebral infarct events (cerebral stroke), such as stroke, cerebral ischemia and consequences of craniocerebral injury. The compounds of the invention are also useful against pain.

The therapeutically active compound should preferably be present in the above mentioned pharmaceutical preparations in an amount of 0.1-99.5%, preferably about 0.5-95% by weight of the total mixture.

In general, to achieve the desired effect, it has proven advantageous in human and veterinary medicine to administer the active compound or compounds according to the invention in a total amount of from about 0.5 to about 500, preferably from 5 to 100, mg/kg of body weight per 24 hours, if appropriate in divided doses. A single dose preferably contains from about 1 to about 80, in particular from 3 to 30, mg/kg of body weight of one or more active compounds according to the invention.Starting Compounds example I of the invention 1A5- (1, 3-Dioxido-2-yl) -2-tributylstannyl-furan

200ml of sec-butyllithium (1.3M in cyclohexane, 260mmol) are added dropwise over the course of 20 minutes at-70 ℃ to a solution of 34.4g of 2- (2-furyl) -1, 3-dioxane (224mmol, obtainable from furfural and propane-1, 3-diol) in 320ml ofTHF.The solution was warmed to-20 ℃ and held for 30 minutes, then re-cooled to-78 ℃. A solution of 60.8ml of tributylstannyl chloride in 160ml of THF is added dropwise over 30 minutes, after which the mixture is allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, and the residue is distilled to give (b.p.)_0.8180 deg.c). 93g of product are obtained. Example I/2A3- (5- (1, 3-dioxan-2-yl) furan-2-yl) indazole

10g (41mmol) of 3-iodoindazole (U.Wrzeciono et al, Pharmazie 1979, 34, 20) are dissolved in 125ml of DMF under argon, 0.7g of Pd (PPh3)4 are added and the mixture is driedThe mixture was stirred for 15 minutes. 19.4g (43.9mmol)2- (5-tributylstannyl-2-furyl) -1, 3-dioxane were added and the mixture was stirred at 100 ℃ for 2 hours. The solvent was evaporated in vacuo and the residue was chromatographed over silica gel using toluene and a toluene/ethyl acetate mixture as eluent. 10g (90.3% of theory) of 3(2- (5- (1, 3-dioxan-2-yl) furanyl) indazole R are obtained_f(SiO₂Toluene/ethyl acetate 4: 1: 0.1MS (ESI/POS): 271(82, M + H), 213(100), 157(10) embodiment II of the invention example II/3A2- (1, 3-dioxan-2-yl) -6-trimethylstannyl pyridine

2g (8.19mmol) of 2- (1, 3-dioxane-2-yl) -6-bromopyridine (R) from 6-bromo-2-pyridinecarboxaldehyde (inorganic chemistry (Inorg. chem.)1971, 10, 2474) and 1, 3-propanediol were initially introduced at-80 ℃_f(SiO₂Ethyl acetate): 0.67) was added to 50ml of diethyl ether, followed by addition of 3.6ml of a 2.5N N-butyllithium solution in hexane. The mixture is stirred at-80 ℃ for 30 minutes and 1.8g of trimethylstannyl chloride in 5ml of diethyl ether are added. The mixture was first stirred at-80 ℃ and then returned to-30 ℃. Poured into water, extracted with ethyl acetate, the organic phase dried over sodium sulfate and the solvent evaporated in vacuo. The product (1.1g) was used in the next reaction without purification. R_f(SiO₂Ethyl acetate): 0.2MS (CI): 330(80, M + H), 166(100) examples II/4a3- (6- (1,3-dioxane-2-yl) -2-pyridyl) indazoles

60mg of Pd (PPh) are added at room temperature under an argon atmosphere₃)₄To a solution of 0.82g (3.35mmol) of 3-iodoindazole in 10ml DMF was added and the mixture was stirred for 15 minutes. 1.1g (3.35mmol)2- (1, 3-dioxan-2-yl) -6-trimethylstannyl pyridine are added and stirred at 100 ℃ for 4 hours. It was then evaporated in vacuo and the residue was chromatographed on silica gel. 300mg (32% of theory) of oil are obtained. MS (CI/NH)₃): 283(100, M + H). EXAMPLE II/5A 3-iodoindazole

58.1g of iodine (229mmol) are added portionwise to a suspension of 25.6g of indazole (217mmol) in a solution of 625ml of methanol and 625ml of 2N sodium hydroxide over 1 hour. After the mixture was stirred at room temperature for 3 days, 75ml of concentrated hydrochloric acid were added under ice cooling, the mixture was acidified with 2N hydrochloric acid and a 20% strength sodium thiosulfate pentahydrate solution was added until the color of iodine disappeared. The precipitate was separated off by suction filtration, washed to neutrality with water and dried in a vacuum oven at 50 ℃. For further purification, the solid was added to methanol. Undissolved constituents were filtered off and the filtrate was evaporated to dryness on a rotary evaporator, the product thus obtained being an off-white solid. Yield: 52.6g (quantitative) R_fThe value: 0.63 (silica; cyclohexane/ethyl acetate 1: 1) melting Point: 137 deg.CExample II/6A 1-benzyl-iodoindazole

1.49g of 95% pure sodium hydride (59.0mmol) are added portionwise under argon to a solution of 12.0g (49.2mmol) of 3-iodoindazole in 100ml of anhydrous tetrahydrofuran. After the mixture was stirred at room temperature for 45 minutes, 7.02ml (59.0mmol) of benzyl bromide was added dropwise. The mixture was stirred at room temperature overnight, then diethyl ether and water were added. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness with a rotary evaporator. The excess benzyl bromide was separated off by bulb tube distillation. The residue of the distillation is the product in oily form and subsequently crystallizes. Yield: 15.4g (94% of theory) of R_fThe value: 078 (silica gel; cyclohexane/ethyl acetate 1: 1) melting Point: example II/7A 1-benzyl-3-trimethylstannyl indazole at 54 ℃

800g of 1-benzyl-3-iodoindazole (24.0mmol), 23.7g (72.0mmol) of hexamethylditin and 2.00g of Pd (PPh) under argon atmosphere₃)₄(7.2 mol%) was heated to reflux in 240ml of 1, 4-dioxane overnight. The mixture was allowed to cool to room temperature and 72ml of 1M potassium fluoride solution was addedThe solution was stirred with 200ml of ethyl acetate for 30 minutes. After filtering off the precipitate with celite, the organic phase of the filtrate is washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is removed with a rotary evaporator. The residue is stirred with n-pentane, the precipitate is filtered off with suction and dried in vacuo at 50 ℃ to give the product in the form of a white solid. Yield: 6.05g (68%; purity: 88% (by GC)) R_fThe value: 0.47(silica; cyclohexane/ethyl acetate 10: 1) melting Point: 122 ℃ MS-EI: 372(Sn, M)⁺23), 357(Sn, 56), 207(100), 165(Sn, 61), 91(68). Ph-phenyl Et-ethyl Me-methyl EE-ethyl acetate H-hexane PE-petroleum ether MeOH-methanol E-diethyl ether DMF-dimethylformamide Ac-acetyl KOH-potassium hydroxide NMP-N-methylpyrrolidone embodiment III of the present invention example III/8a 1-benzyl-3-iodoindazole

A solution of 2.99g iodoindazole (12.25mmol) in 10ml THF was added dropwise to a suspension of 515mg NaH (60% oil dispersion, 12.88mmol) in 20ml THF. After 15 minutes, 1.55ml of benzyl bromide was added. After 6 hours at room temperature and 3 hours at 40 ℃, water was added to the reaction mixture, and extraction was performed with diethyl ether. The organic phase was dried over sodium sulfate and concentrated. By chromatography (SiO)₂(ii) a Petroleum ether: ethyl acetate 9: 1) to give 3.351g of a viscous oil which solidified under vacuum. Melting point: r at 51.5-52.5 DEG C_f0.38 (Hexane/EtOAc 3: 1) example III/9A 1-benzyl-3-cyanoindazole

420mg of NaH (60% oil dispersion, 10.3mmol) are dispersedTo a mixture of 1.0g of 3-cyanoindazole (7.0mmol) and 1.7ml of benzyl bromide (14.0mmol) in 6ml of THF was added in portions, and the mixture was stirred at room temperature for 15 hours. The reaction was stopped by adding 2 drops of water, the mixture was concentrated and the residue was chromatographed (SiO)₂(ii) a Petroleum ether: ethyl acetate 3: 1). 1.3g of a solid was obtained. Melting point: example III/10A 1-benzyl-3-trimethylstannyl indazole at 91 deg.C

1.67g of 1-benzyl-3-iodoindazole (5.00mmol), 4.95g of hexamethylditin (15.0mmol)and 530mg of Pd (PPh)₃)₄(10 mol%) was heated to reflux in 50ml of anhydrous 1, 4-dioxane overnight. The mixture was allowed to cool to room temperature, 15ml of 1M potassium fluoride solution and 50ml of ethyl acetate were added and stirred for 30 minutes. After filtering off the precipitate, the organic phase of the filtrate is washed with water, dried over magnesium sulfate and the solvent is removed with a rotary evaporator. The residue was dried under vacuum at 50 ℃ to give the product as a white solid which was used in the next reaction without further purification. Yield: 78% R_fThe value: 0.32 (silica; cyclohexane/ethyl acetate 16: 1) MS-EI: 372(Sn, M)⁺23), 357(Sn, 56), 207(100), 165(Sn, 61), 91(68), embodiment IV of the invention example IV/11A5- (1, 3-dioxan-2-yl) -2-tributylstannyl-furan

200ml of sec-butyllithium (1.3M in cyclohexane, 260mmol) are added dropwise over the course of 20 minutes at-70 ℃ to a solution of 34.4g of 2- (2-furyl) -1, 3-dioxane (224mmol, obtainable from furfural and propane-1, 3-diol) in 320ml of THF. Warming the solution to-20 deg.CAnd held for 30 minutes and then cooled again to-78 ℃. A solution of 60.8ml of tributylstannyl chloride in 160ml of THF is added dropwise over 30 minutes, after which the mixture is allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, and the residue is distilled to give (b.p.)_0.8180 deg.c). 93g of product are obtained. Example IV/12A3- (5- (1, 3-Dioxolan-2-yl) furan-2-yl) indazole

10g (41mmol) of 3-iodoindazole (U.Wrzeciono et al, Pharmazie 1979, 34, 20) are dissolved in 125ml of DMF under argon, 0.7g of Pd (PPh3)4 are added and the mixtureis stirred for 15 minutes. 19.4g (43.9mmol)2- (5-tributylstannyl-2-furyl) -1, 3-dioxolane are added and the mixture is stirred for 2 hours at 100 ℃. The solvent was evaporated in vacuo and the residue was chromatographed over silica gel using toluene and a toluene/ethyl acetate mixture as eluent. 10g (90.3% of theory) of 3- (2- (5- (1, 3-dioxolan-2-yl) furanyl) indazole R are obtained_f(SiO₂Toluene/ethyl acetate 4: 1): 0.1 preparation example embodiment I of this invention example I/13- (5- (1, 3-dioxan-2-yl) furan-2-yl) -1- (4-picolyl) indazole

A solution of 2g (7.41mmol) of 3- (5- (1, 3-dioxan-2-yl) furan-2-yl) indazole in 10ml of DMF is added under argon to a suspension of 355mg NaH (60% paraffin dispersion) in 10ml of DMF and the mixture is stirred at room temperature for 1 hour. Then, 1.46g of 4-pyridylmethyl chloride hydrochloride was added, followed by 355mg of NaH (60% paraffin dispersion). The mixture is stirred at room temperature for 1 hour and then at 100 ℃ for 1 hour, poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel using a toluene/ethyl acetate mixture as eluent to give 1g (37% of theory) of an oil. R_f(SiO₂Ethyl acetate): 0.25 example I/23- (5-formyl-2-furyl) -1- (4-picolyl) indazole

1g (2.77mmol) of 3- (5- (1, 3-dioxan-2-yl) furan-2-yl) -1- (4-picolyl) indazole is dissolved in 10ml of acetone, and 20ml of 50% strength acetic acid are added. The mixture was boiled for 1 hour, added to water, extracted with ethyl acetate, the organic phase was dried over sodium sulfate and evaporatedEvaporation in air gave 0.8g (95.3% of theory) of an oil. R_f(SiO₂Ethyl acetate): 0.25 example I/33- (2- (5-Hydroxyl)Methyl furyl)) -1- (4-picolyl) indazole

0.4g (1.3mmol) of 3- (5-formyl-2-furyl) -1- (4-picolyl) indazole are suspended in 20ml of propanol and 0.4g of NaBH is added at 0 DEG.C₄. After stirring the mixture at room temperature for 1 hour, the clear solution is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel using a toluene/ethyl acetate mixture as eluent. 200mg (50% of theory) of crystals are obtained. Melting point: 183 ℃ R_f(SiO₂Ethyl acetate): 0.14

The compounds listed in tables I/1, I/2 and I/3 can be prepared analogously as described in examples I/1, I/2 and I/3.Table I/1:

table I/1: continuously for

Table I/1: continuously for

mp ℃ -melting point (. degree.C.)Table I/2:

ethyl acetate/MeOH/T toluene amount: number of partsTable I/3:table I/3: continuously for

Ethyl acetate, H, hexane, C, cyclohexaneEXAMPLES OF THE INVENTION example II/341-BENZYL-3- (6- (1, 3-DIOXYCHEXACYL-2-YL) -2-PYRIDINYL) INDAZOLE

580mg of NaH (60% strength paraffin dispersion) were slowly added to a solution of 3.7g (13.1mmol) of 3- (6- (1, 3-dioxane-2-yl) -2-pyridyl) indazole in THF under argon. After the mixture was stirred for 30 minutes, 1.71ml of benzyl bromide was added, followed by stirring in the chamberStir for 1 hour with warming. The mixture is poured into water, extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel eluting with an ethyl acetate/toluene mixture to give 1.52g (31% of theory) of an oil. R_f(SiO₂Ethyl acetate): 0.3MS 372(100, M +1) example II/351-benzyl-3- (6-formyl-2-pyridinyl) indazole

1.52g (4.1mmol) of 1-benzyl-3- (6- (1, 3-dioxan-2-yl) -2-pyridyl) indazole are dissolved in 10ml of acetone, and 20ml of acetic acid of 50% strength are added. The mixture is stirred for 3 hours at 50 ℃, poured into water and extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel using a toluene/ethyl acetate mixture to give 180mg (14% of theory) of an oil. R_f(SiO₂Toluene/ethyl acetate): 0.7 MS (CI/NH)₃): 314(100, M + H) example II/361-benzyl-3- (6-hydroxymethyl-2-pyridyl) indazole

180mg (0.57mmol) of 1-benzyl-3. (6-formyl-2-pyridinyl) indazole are suspended in 20ml of propanol and 180mg of NaBH are added slowly₄. After stirring the mixture at room temperature for 30 minutes, the clear solution is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel using a toluene/ethyl acetate mixture as eluent to give 120mg (66% of theory) of crystals. Melting point: r at 75 DEG C_f(SiO₂Ethyl acetate): 0.15MS (CI, NH)₃): 316(100, M + H) example II/37 l-benzyl-3- (2-pyrimidinyl) indazole

200mg of 1-benzyl-3-trimethylstannylalndazole (crude, 70% purity by GC), 35mg of 2-chloropyrimidine (0.30mmol) and 29mg of Pd (PPh) under argon₃)₄(0.025mmol) was heated to reflux in 2.5ml of toluene overnight. Cooling the mixture to room temperature, adding saturated ammonium chloride solution, and adding ethyl acetateAnd (5) extracting with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed with a rotary evaporator. Purifying by chromatography on alumina using cyclohexane/ethyl acetate (gradient 10: 1-1: 1) as eluent. Yield: 80mg (93%) R_f: 0.67 (alumina, cyclohexane/ethyl acetate 10: 1) melting Point: MS-EI at 154 ℃: 286 (M)⁺Examples II/381-benzyl-3- (4, 5-dimethyl-2-pyrimidinyl) indazole

640mg of 1-benzyl-3-trimethylstannylalndazole (1.72mmol) and 212mg of 2-chloro-4, 5-dimethylpyrimidine were added under argon^*(1.49mmol) and 72mg (0.10mmol)Pd(PPh₃)₂Cl₂(5.8 mol%) was heated to reflux in 20ml of toluene overnight. The mixture was cooled to room temperature, saturated ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed with a rotary evaporator. Purifying by chromatography on silica gel with cyclohexane/ethyl acetate (gradient 10: 1-1: 1) as eluent. Yield: 239mg (51% of theory) of R_f: 0.33 (silica gel, cyclohexane/ethyl acetate 1: 1) melting Point: 119 deg.C^*Sugasawa et al, Yakugaku Zasshi, 71, 1951, 1345, 1348; chemical abstracts (Chem, Abstr.), 1952, 8034.

The compound examples listed in tables II/1, II/2 and II/3 can be prepared analogously as described in examples II/34-38:

TABLE II/1

TABLE II/1-continuation

TABLE II/1-continuation

TABLE II/1-continuation

TABLE II/2

TABLE II/2-continuation

EE: ethyl acetate Cy: cyclohexaneEXAMPLES embodiment III of the present invention example III/691-benzyl-3- (1-methylimidazol-2-yl) -indazole

2.50g of 1-benzyl-3-iodoindazole (7.48mmol), 3.33g of 1-methyl-2-tributylstannyl imidazole (8.98mmol) (K.Gare, K.Undheim et al, actachem.Scand.1993, 47, 57) and 432mg of tetrakis-triphenylphosphine palladium (0.37mmol) are heated in 10ml of DMF at 80 ℃ for 2 days under argon. After cooling, water was added to the mixture, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. Chromatography (SiO)₂；CH₂Cl₂MeOH 100: 1) to give 2.40g of an oil. MS: (CI, NH)₃)：289(M+H⁺100) example III/702- (1-Benzylindazol-3-yl) -oxazole-5-carboxylic acid ethyl ester

Ethyl diazopyruvate (250mg, 1.76mmol) (T.Ohsumi) was added over 4 hours&H.Neunhofer, tetrahedra (Tetrahedron)1992, 48, 5227) was added dropwise to a reflux of 600mg of 1-benzyl-3-cyanoindazole (2.57mmol) and 0.8mg of copper (II) acetylacetonate (3mmol) in 1ml of benzene. After this time, the reaction mixture was heated to reflux for a further 15 minutes, cooled and evaporated in vacuo. The residue is chromatographed (SiO)₂(ii) a Cyclohexane to ethyl acetate 3: 1). 67mg of a yellow oil are obtained. R_f0.11 (cyclohexane/ethyl acetate 3: 1) example III/711-benzyl-3- (5-hydroxymethyl oxazol-2-yl) -indazole

18mg of lithium aluminium hydride (0.47mmol) are added to a solution of 67mg of 2- (1-benzylindazol-3-yl) -oxazole-5-carboxylic acid ethyl ester in 2ml of diethyl ether at 0 ℃. After 3 hours at 0 ℃, the reaction mixture was stirred at room temperature for 24 hours, then water was added and extracted 3 times with ether. The organic phase was dried over sodium sulfate and concentrated. After chromatography (SiO)₂(ii) a Cyclohexane and ethyl acetate 2: 1-3: 2) to obtain 12mg of a white solid. R_f0.12 (hexane/ethyl acetate 1: 1). Example III/722- (1-Benzylindazol-3-yl) -thiazole-4-carboxylic acid ethyl ester

148mg of 1-benzyl-3-trimethylstannylalndazole (0.399mmol), 86mg of 2-bromothiazole-4-carboxylic acid ethyl ester (0.364mmmol) (Erlenmeyer et al, Helv. Chim. acta 1942 (25)) 1073, and 42mg of Pd (PPh) under argon₃)₄Stirred in 2ml DMF at 80 ℃ for 2 days. After cooling, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. After chromatography (SiO)₂(ii) a Petroleum ether: ethyl acetate 3: 1) to yield 75mg (52%) of a white solid. R_fMelting point 0.31 (hexane/ethyl acetate 3: 1): 95-96 ℃.

The compounds listed in Table III/1 can be prepared analogously to the description given above:

table III/1.

H: has already gotAn alkane E: ethyl acetate

The compounds listed in Table III/2 can be prepared analogously to the description given above or can be used as described in [ A3]]～[G3]The process variants described below are obtained from the corresponding indazole derivatives:or

(indazole-CO is used hereinafter)₂H. indazole-CO-Cl or indazole-CO-NH₂Representation).Table III/2:

table III/2: continuously forTable III/2: continuously for

Table III/2: continuously forTableIII/2: continuously for

Table III/2: continuously forTable III/2: continuously for

TABLE III/2-continuation

[]In the formulaTable III/3:table III/3: continuously for

Table III/3: continuously for

Table III/3: continuously for

Table III/3: continuously for

Table III/3: continuously for

Table III/3: continuously for

Table III/3: continuously for

Preparation of oxazolyl compounds of the formulae III to XXIX and wherein R⁴²Method examples according to the invention for the preparation of compounds representing groups of the formulae III to XXVIII

In the description of the following experiments, the retention time R is, unless otherwise stated_fWas measured on silica gel TLC. H-hexane, EE-ethyl acetate. Method example 1

A mixture of 10g of3- (m-trifluoromethylbenzoylamino) -1, 1-dichlorobut-1-ene, 5.1g of sodium methoxide and 35ml of dimethylacetamide was stirred at 25 ℃ overnight, 50ml of water was then added, and the mixture was extracted several times with dichloromethane. The dichloromethane phase is separated off, dried over sodium sulfate and filtered, and the solvent is removed in a vacuum rotary evaporator. The residue obtained is distilled to give 7.3g of 4-methyl-5-methoxymethyl-2- (m-trifluoromethylphenyl) -oxazole (boiling point range 96-100 ℃ C./0.2 mbar). Preparation method using 1, 1-dichloro-3- (m-trifluoromethylbenzamido) -but-1-ene step 1:

a mixture of 615g of 1, 1, 1, 3-tetrachlorobutane (obtained by initiating the addition reaction of carbon tetrachloride and propylene from the free radicals), 13.3g of tetrabutylammonium bromide and 138.2g of sodium hydroxide in 390ml of water was stirred well at room temperature for 24 hours. 2L of water are then added, the two phases are separated and the organic phase is dried over sodium sulfate. 1, 1, 3-trichlorobut-1-ene and 1, 1, 1-trichlorobut-2-ene (492g, boiling range 45-50 ℃ C./20 mbar) were obtained by distillation of the crude product.Step 2:

210g of 1, 1, 3-trichloro-but-1-ene and 1, 1, 1-trichloro-but-2-ene and 52ml of anhydrous hydrocyanic acid are metered simultaneously into a solution of 38g of water in 568g of concentrated sulfuric acid over 1 hour while stirring. Then, 78ml of hydrocyanic acid were added thereto over 2 hours. After 2 hours of reaction, excess hydrocyanic acid was distilled off. The reaction mixture was made basic with 20% strength sodium hydroxide solution and the crude product (195g) was isolated by extraction with dichloromethane.

The crude product is mixed with 950ml of half-concentrated hydrochloric acid with stirring and the mixture is heated at boiling temperature under reflux condensation. After 24 hours, the mixture was cooled and extracted with dichloromethane to remove a small amount of by-products. The aqueous phase was concentrated to dryness on a rotary evaporator. Then, a semi-concentrated sodium hydroxide solution was added and the mixture was stirred to adjust the pH to 9. The separated amine is separated off and distilled. 156g of 3-amino-1, 1-dichloro-but-1-ene having a boiling point of 45-50 ℃ C./18 mbar are obtained. And 3, step 3:

a solution of 26.9g of m-trifluoromethylbenzoyl chloride in 25ml of methylene chloride was added dropwise to a mixture of 21.0g of 3-amino-1, 1-dichloro-but-1-ene, 35ml of methylene chloride and 15.9g of sodium carbonate in 45ml of water over 30 minutes while cooling with ice and with sufficient stirring. After 1 hour of reaction, the two phases were separated. The organic phase was concentrated to give 39.0g of 2, 2-dichloro-3- (m-trifluoromethylbenzoylamino) -but-1-ene.Method example 2

A mixture of 1, 1-dichloro-4- (m-trifluoromethylbenzamido) -but-1-ene, 4.2g of sodium butoxide and 35ml of dimethylformamide was heated at 100 ℃ for 7 hours with stirring. After the reaction was complete, the mixture was worked up analogously to example 1. The crude product obtained is distilled in vacuo to give 6.4g of 5-butyloxymethyl-4-methyl-2- (m-trifluoromethylphenyl) -oxazole (boiling point range 106 ℃ C./0.2 mbar). Method example 3

1.8g of 3-acetylamino-1, 1-dichlorobut-1-ene and 1.0g of sodium methoxide were heated under reflux in 20ml of methanol at the boiling temperature for 24 hours. After this time, the methanol was distilled off, the residue was taken up in 5ml of water and 30ml of dichloromethane, the organic phase was separated and distilled in vacuo. 0.9g of 2, 4-dimethyl-5-methoxymethyl-oxazole having a boiling point of 54 ℃ C./20 mbar was obtained. Method example 4

7g of 3- (2-chloro-6-fluoro)Benzoylamino) -1, 1-dichloro-but-1-ene, 11.7g of sodium 4-tert-butylphenolate and 100ml of N-methylpyrrolidone were heated and stirred at 100 ℃ for 8 hours. The solvent was distilled off, the residue was taken up in water and dichloromethane, the organic phase was separated, dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product was purified by chromatography. 5.1g of 2- (2-chloro-6-fluorophenyl) -4-methyl-5- (4-tert-butylphenoxymethyl) -oxazole were obtained.Method example 5

5g of 3-benzoylamino-1, 1-dichlorobut-1-ene, 36g of sodium acetate and 500ml of N-methylpyrrolidone were heated and stirred at 150 ℃ for 36 hours. The crude product was then isolated in a manner analogous to that described in example 4. Vacuum distillation gave 35g of 5-acetoxymethyl-4-methyl-2-phenyloxazole (boiling point range 89-91/0.1 mbar). Method example 6

To a solution of 15mg of 3- (1-benzylidazole-3-carboxamido) -1, 1-dichlorobut-1-ene (40. mu. mol) in 20. mu. l N-methylpyrrolidone was added 80. mu.l of 1M NaOH under argon and the mixture was heated at 55 ℃ for 1 hour. Cooled and 0.8ml of water and 8ml of ethyl acetate are added. The organic phase is concentrated and the residue is purified by preparative TLC (SiO)₂). 9.9mg (77%) of 2- (1-benzylindazol-3-yl) -5-hydroxymethyl-4-methyloxazole (m.p. 127) are obtained. MS (DC 1/NH)₃)：320(100，MH⁺).R_f: 0.17 (H: EE 1: 1). Method example 7

(in this example, the amide intermediate was prepared in situ from formula 3a and the acid chloride.)

500mg of 1-benzylindazole-3-carbonyl chloride (1.847mmol), 260mg of 3-amino-1, 1-dichlorobut-1-ene (1.847mmol) and 318mg of sodium acetate (3.88mmol) are stirred in 4ml of N-methylpyrrolidone at 150 ℃ under argon atmosphere for 5 days. The crude mixture was cooled, water was added, and extracted several times with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated, and the residue is chromatographed (SiO)₂Petroleum ether/ethyl acetate 3: 1). Two products were isolated:1, 1-dichloro-3- (1-benzylindazole-3-carboxamido) -but-1-ene (410mg, 59%) R_f: 0.26 (H: EE 3: 1) and 5-acetoxymethyl-2- (1-benzylindazol-3-yl) -4-methyloxazole (160mg, 24%). MS (DCl/NH)₃)：362(100，MH⁺).R_f: 0.17 (H: EE 3: 1). Method example 8

100mg of 3- (1-benzylindazole-3-carboxamido) -1, 1-dichloro-but-1-ene (0.267mmol) and 29mg of sodium methoxide were heated overnight at 100 ℃ under argon atmosphere with 0.5ml of N-methylpyrrolidone. The mixture was cooled and subjected to column chromatography (SiO)₂Cyclohexane to ethyl acetate 3: 1). 35.9mg (40%) 2- (1-benzylindazol-3-yl) -5-methoxymethyl-4-methyloxazole was isolated as a yellow oil. MS (DCl/NH)₃)：334(100，MH⁺).R_f：0.67(CH₂Cl₂MeOH 100: 5) method example 9

730mg of 1, 1-dichloro-3- [1- (2-fluorobenzyl) indazole-3-carboxamido]-but-1-ene(1.86mmol) and 3.75ml of 1N NaOH (3.75mmol) in 7.4ml of N-methylpyrrolidone were stirred at 50 ℃ under argon overnight. After cooling, the mixture was poured into icewater and the precipitated product was filtered off and dried. Finally, by column chromatography (SiO)₂Cyclohexane: ethyl acetate 2: 1). 375mg (60%) of 2- [1- (2-fluorobenzyl) indazol-3-yl are obtained as white crystals]-5-hydroxymethyl-4-methyloxazole. Melting point: MS (ESI-POSITIVE) at 144 ℃: 338(100, MH)⁺).R_f：0.20(H∶EE 1∶1)。

1, 1-dichloro-3- [1- (2-fluorobenzyl) indazole-3-carboxamido]-but-1-ene was prepared as follows: mu.l pyridine was added to a solution of 400mg 1- (2-fluorobenzyl) -indazole-3-carbonyl chloride (1.385mmol) and 200mg 3-amino-1, 1-dichloro-but-1-ene in 1.5ml THF and the mixture was stirred at room temperature for 3 hours. Then water and ethyl acetate were added. The organic phase was dried over sodium sulfate and concentrated. To obtain a crude product of 1, 1-dichloro-3- [1- (2-fluorobenzyl) indazole-3-carboxamido]But-1-ene, pure enough to be used directly in the next reaction by TLC identification。R_f: 0.32 (H: EE 3: 1). Method example 10

136mg of 1, 1-dichloro-3- [1- (2-fluorobenzyl) indazole-3-carboxamido]But-1-ene (0.267mmol) and 47mg of sodium methoxide were stirred in 0.6ml of N-methylpyrrolidone at 100 ℃ under argon overnight. The mixture was cooled and subjected to column chromatography (SiO)₂) And (5) directly purifying. 24mg (20%) of 2- [1- (2-fluorobenzyl) indazol-3-yl are isolated as a yellow oil]-5-methoxymethyl-4-methyloxazole. Melting point: MS (ESI-POSITIVE) at 86-88 ℃: 374(65, M + Na)⁺)，352(100，MH⁺).R_f：0.18(CH₂Cl₂∶MeOH 100∶1)。Method example 11

136mg of 1, 1-dichloro-3- [1- (2-fluorobenzyl) indazole-3-carboxamido]But-1-ene (0.267mmol) and 164mg of potassium phthalimide were stirred in 0.6ml of N-methylpyrrolidone at 150 ℃ overnight under an argon atmosphere. The N-methylpyrrolidone is evacuated at 60 ℃ under high vacuum and the residue is chromatographed (SiO)₂Cyclohexane/ethyl acetate 2: 1). This gave 48.5mg (36%) of 2[1- (2-fluorobenzyl) indazol-3-yl as yellow crystals]-4-methyl-5- (N-phthaloylaminomethyl) -oxazole. Melting point: 175 ℃ and 177 ℃. MS (ESI-POSITIVE): 467(100, MH)⁺).R_f：0.64(CH₂Cl₂MeOH 100: 1). Method example 12

1.05g of 1, 1-dichloro-3- [1- (2-fluorobenzyl) indazole-3-carboxamido]Pent-1-ene (2.58mmol) and 5.20 ml of 1N NaOH (5.20mmol) are stirred in 15ml of N-methylpyrrolidone at 50 ℃ for 2 days under argon. After cooling, the mixture was poured into ice water and extracted several times with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated (N-methylpyrrolidone is removed under high vacuum). The residue was purified by column chromatography (alumina, cyclohexane/ethyl acetate 2: 1). 470mg (52%) of 5-ethyl-2- [1- (2-fluorobenzyl) indazol-3-yl as white crystals are obtained]-5-hydroxymethyl-oxazole. Melting point: 137-139 ℃. MS (ESI-POSITIVE): 352(100, MH)⁺).R_f: 0.08 (alumina, cyclohexane: EE 2: 1).Preparation of embodiment IV of the invention example IV/1341- (2-cyanobenzyl) -3- (5- (1, 3-dioxolan-2-yl) furan-2-yl) -indazole

A solution of 2g (7.41mmol) of 3- (5- (1, 3-dioxolan-2-yl) -furan-2-yl) indazole in 10ml of DMF is added under argon to a suspension of 355mg of NaH (60% paraffin dispersion) in 10ml of DMF and the mixture is stirred at room temperature for 1 hour. Then 1.5g of 2-cyanobenzyl bromide was added. The mixture is stirred for 30 minutes at 100 ℃, poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel using a toluene/ethyl acetate mixture as eluent to give 2.1g (73.5% of theory) of an oil. R_f(SiO₂Toluene/ethyl acetate 1: 1): 0.63. example IV/1351- (2-cyanobenzyl) -3- (5-formyl-2-furyl) -indazole

2.1g (5.5mmol) of 1- (2-cyanobenzyl) -3- (5- (1, 3-dioxolan-2-yl) furan-2-yl) -indazole are dissolved in 20ml of acetone, and 40ml of 50% strength acetic acid are added. The mixture is boiled for 1 hour, poured into water, extracted with ethyl acetate, the organic phase is washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo to yield 1.61g (89% of theory) of a solid. Melting point: 137 ℃ R_f(SiO₂Toluene/ethyl acetate 4: 1): 0.4 example IV/1361- (2-cyanobenzyl) -3- (5-hydroxymethylfuran-2-yl) -indazole

0.8g (2.44mmol) of 1- (2-cyanobenzyl) -3- (5-formyl-2-furyl) -indazole are suspended in 50ml of propanol and 0.8g of NaBH is added slowly at 0 ℃₄. After stirring the mixture at room temperature for 1 hour, the clear solution is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated in vacuo, and the residue is chromatographed on silica gel using a toluene/ethyl acetate mixture as eluent to give 600mg (theoretical amount) of75%) crystallized. Melting point: 147 ℃ R_f(SiO₂Toluene/ethyl acetate 1: 1): 0.52 example IV/1371-benzyl-3- [5- (1, 3-dioxolan-2-yl) -furan-2-yl]-indazoles

661mg of 5- (1, 3-dioxolan-2-yl) -2-tributylstannyl-furan (1.54mmol) (M.Yamamoto, H.Izukawa, M.Saiki, K.Yamada, J.chem.Soc.chem.Comm.1988, 560), 431.5mg of 1-benzyl-3-iodoindazole (1.29mmol) and 90mg of tetrakistriphenylphosphine palladium (0.078mmol) were heated in 2.5ml of DMF at 80 ℃ for 10 h under argon. After cooling, water was added to the mixture, which was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. By chromatography (SiO)₂Petroleum ether: ethyl acetate 9: 1) to yield 381.3mg of a viscous oil. R_f: 0.16 (Hexane/EtOAc 3: 1) EXAMPLE IV/1381-benzyl-3- (5-formylfuran-2-yl) -indazole

336mg of 1-benzyl-3- [5- (1, 3-dioxolan-2-yl) -furan-2-yl]-indazole (0.97mmol) and crystalline p-toluenesulfonic acid are heated under reflux in 5ml acetone and 0.3ml water for 20 hours. Thereafter, 40ml of diethyl ether was added to the reaction mixture. Small amount of sodium chloride for organic phaseThe solution was washed, dried over sodium sulfate and concentrated. The residue slowly crystallized. The crystals were washed with a little ether and dried under vacuum: 210.4 mg. R_f: 0.24 (Hexane/EtOAc 3: 1) melting point: example IV/1391- [5- (1-benzylindazol-3-yl) furan-2-yl]97-99 deg.C]Ethanol

300L MeLi solution (1.6M in ether; 0.480mmol) was added dropwise to a solution of 1-benzyl-3- (5-formylfuran-2-yl) -indazole (134.1mg, 0.44mmol) in 3ml THF, cooled to-78 deg.C. After 10 minutes, an aqueous ammonium chloride solution was added to the mixture and extracted with ether. The organic phase is washed with sodium chloride solution, dried over sodium sulfate and concentrated. By chromatography (SiO)₂(ii) a Petroleum ether: ethyl acetate 2: 1) to give 133mg of a viscous oil. R_f: 0.11 (Hexane/EtOAc 3: 1) MS (CI)，NH₃)：319(M+H⁺Example IV/1403- (5-acetylfuran-2-yl) -1-benzyl-indazole

Reacting 1- [5- (1-benzyl indazol-3-yl) -furan-2-yl]Ethanol (51.2 mg; 0.160mmol) and 250mg MnO₂(2.9mmol) in 2ml chloroform under heating and refluxing. After 12 hours, a further 250mg of MnO were added₂. After a further 12 hours, the mixture is filtered through kieselguhr, the filtrate is concentrated and the residue is chromatographed (SiO)₂Petroleum ether: ethyl acetate 3: 1) gave 29.8mg of a pale yellow solid. R_f: 0.21 (Hexane/EtOAc 3: 1) melting point: example IV/1413- (5-azidomethylfuran-2-yl) -1-benzyl-indazole 99-100 deg.C

195.1mg of 1-benzyl-3- (5-hydroxymethylfuran-2-yl) -indazole (0.64mmol) (Kuo S. -C., Yu Lee F., Teng C. -M.EP0667345A 1), 252mg of triphenylphosphine (0.96mmol) and 60.3mg of sodium azide (0.93mmol) were dissolved in 2.5ml of DMF. 308.4mg of carbon tetrabromide were added, and the resulting mixture was stirred at room temperature for 20 hours. Adding 5mlAfter water, extraction was performed with ethyl acetate. The organic phase is washed with sodium chloride solution, dried over sodium sulfate and concentrated. By chromatography (SiO)₂Cyclohexane: ethyl acetate 2: 1) gave 206.7mg of a viscous oil which subsequently solidified slowly. R_f: 0.63 (Hexane/EtOAc 1: 1) melting Point 51-52 deg.C example IV/1423- (5-Aminomethylfuran-2-yl) -1-benzyl-indazole

121.5mg of 3- (5-azidomethylfuran-2-yl) -1-benzyl-indazole (0.369mmol) and 102mg of triphenylphosphine (0.389mmol) are stirred in 1ml of THF for 3.5 h. Then 10. mu.l of water was added. After 24 hours, diethyl ether and 0.3M aqueous hydrochloric acid were added to the mixture. The solid is filtered off, the aqueous phase is made alkaline with 2M sodium argon oxide andextracted with diethyl ether. The organic phase is washed with a small amount of water and then with sodium chloride solution, dried over sodium sulfate and concentrated. 79.9mg of yellow oil were obtained.Example IV/1431-benzyl-3- (5-nitrofuran-2-yl) -indazole

800mg of 5-nitrofuran-2-ylphenylketone benzylhydrazone (mixture of E + Z, 2.49mmol) are dissolved in 35ml of dichloromethane. 1.99g of lead tetraacetate (4.49mmol) and 15.6ml of BF were mixed₃Etherate (50% in ether, 62mmol) was added and the mixture was heated to reflux for 1 hour. After cooling, the reaction mixture is poured into ice, the organic phase is separated, washed with 0.2M sodium hydroxide solution and then with water, dried over sodium sulfate and concentrated. Chromatography gave 140mg of yellow crystals. R_f: 0.20 (petroleum ether/ethyl acetate 10: 1) melting Point: 148 + 151 deg.C (decomposition)

In analogy to the example description given above, the compounds summarized in tables IV/1, IV/2, IV/3, IV/4 and IV/5 were prepared.Table IV/1:table IV/1: continuously for

Table IV/1: continuously forTable IV/1: continuously for

Table IV/1: continuously forTable IV/1: continuously for

Table IV/2:

table IV/2: continuously for

Table IV/3:

table IV/4:table IV/5:

table IV/5: continuously forTable IV/5: continuously forTable IV/5: continuously for

Table IV/5: continuously for

Table IV/5: continuously forTABLE IV/5-continuation

^*EE ═ ethyl acetate

H-hexane

P ═ petroleum ether

Toluene (T ═ toluene)

Claims

1. Heterocyclylmethyl-substituted pyrazole derivatives of the general formula (I-I) and the isomeric forms, salts and N-oxides thereof:

wherein:

R⁵，R⁶and R⁷Are identical to each otherOr different, each represents an aryl group having 6 to 10 carbon atoms or an alkyl group having up to 6 carbon atoms, and/or is substituted by a group of the formula

or-S (O)_c1NR⁹R¹⁰Wherein

a1 represents a number of 1, 2 or 3,

c1 represents a number of 1 or 2,

R⁹and R¹⁰The same or different, each represents hydrogen or a linear or branched alkyl group containing up to 10 carbon atoms, which alkyl group may optionally be substituted by a cycloalkyl group containing 3 to 8 carbon atoms or an aryl group containing 6 to 10 carbon atoms, which groups in turn may be substituted by halogens, or R⁹And R¹⁰Represents an aryl group containing 6 to 10 carbon atoms, which may optionally be substituted by halogen, or,

R⁹and R¹⁰Represents a cycloalkyl group having 3 to 7 carbon atoms, or,

Wherein

R²and R³Including the double bond, form a 5-membered heteroaromatic ring or phenyl ring containing one heteroatom selected from S, N and/or O, which heteroaromatic ring or phenyl ring may optionally be substituted up to 3 times by identical or different substituents selected from formyl, carboxyl, hydroxyl, amino, each containing up to 6 carbon atomsStraight-chain or branched acyl, alkoxy or alkoxycarbonyl, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each having up to 5 carbon atoms,

and/or optionally of the formula-S (O)_c1’NR^9’R^10’Wherein c 1', R^9’And R¹⁰' having the above-mentioned c1, R⁹And R¹⁰And the same or different therefrom,

A¹represents a 5-6 membered aromatic or saturated heterocyclic ring containing up to 3 heteroatoms selected from S, N and/or O, which heterocyclic ring may optionallybe substituted up to 3 times by identical or different substituents selected from mercapto, hydroxy, formyl, carboxy, each containing up to 6 carbon atomsIs selected from the group consisting of straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each having up to 5 carbon atoms,

wherein:

d1 represents a number of 0 or 1,

2. The compound of formula (I-I) according to claim 1, wherein:

R¹represents furyl, pyrrolyl, thienyl or phenyl, which radicals may optionally be substituted up to 2 times by identical or different substituents being formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkyl having in each case up to 5 carbon atomsOxycarbonyl, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl OR a linear OR branched alkyl group having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, linear OR branched acyl, alkoxy, alkoxycarbonyl OR acylamino having in each case up to 4 carbon atoms OR by the formula-OR⁴Is substituted with a group (b) of (a),

wherein:

and/or substituted by groups of the formula

Or

Wherein

a1 represents a number of 1, 2 or 3,

R²and R³Including the double bond, form a furyl, thienyl or phenyl ring, which may optionally be substituted up to 3 times by the same or different substituent, which is formylA radical, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,

A¹represents tetrahydropyranyl, thienyl, furanyl, tetrahydrofuranyl, pyrazinyl, morpholinyl, pyrimidinyl, pyridazinyl or pyridinyl, which groups may optionally be substituted up to 2 times by identical or different substituents from the group consisting of hydroxy, formyl, carboxy, straight-chain or branched acyl having up to 4 carbon atoms each, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms each, which groups in turn may be substituted by hydroxy, carboxy, straight-chain or branched alkyl having up to 4 carbon atoms eachAcyl, alkoxy or alkoxycarbonyl, or a pharmaceutically acceptable salt thereof,

wherein:

d1 represents a number of 0 or 1,

R¹²and R¹³Identical or different, each represents hydrogen, phenyl, benzyl or a straight-chain or branched alkyl or acyl radical each having up to 4 carbon atoms, their isomeric forms, their salts and their N-oxides.

3. The compound of the general formula (I-I) according to claim 1,

wherein:

R¹denotes furyl, pyrrolyl, thienyl or phenyl, which are optionally substituted up to 2 times by identical or different substituents, such as formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 4 carbon atoms in each case or by straight-chain or branched alkyl having up to 4 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having up to 3 carbon atoms in each case,

and/or substituted by groups of the formulaOr

Wherein

a1 represents a number of 1 or 2,

R⁸represents hydrogen or a methyl group,

R²and R³Including the double bond, to form a furyl, thienyl or phenyl ring, which may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in turn may be substituted byhydroxyl, amino, carboxyl, in each case up to 3 carbon atomsLinear or branched acyl, alkoxy or alkoxycarbonyl substitution of carbon atoms,

A¹represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl or pyridinyl, which may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, straight-chain or branched acyl having up to 3 carbon atoms each, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 3 carbon atoms each, which may in turn be substituted by hydroxyl, carboxyl, straight-chain or branched acyl having up to 3 carbon atoms each, alkoxy or alkoxycarbonyl,

wherein:

d1 represents a number of 0 or 1,

R¹²and R¹³Identical or different, each represents hydrogen or a linear or branched alkyl or acyl radical, each containing up to 3 carbon atoms, their isomeric forms, their salts and their N-oxides.

4. The compound of the general formula (I-I) according to claim 1,

wherein:

A¹is furyl, pyridyl, pyrimidinyl, pyridazinyl, thienyl, tetrahydrofuranOr tetrahydropyranyl, which groups may optionally be substituted by chlorine, bromine, methoxy, methoxycarbonyl or carboxyl, their isomeric forms, salts and N-oxides thereof.

5. Preparation of the compound of claim 1A process for the preparation of a compound of formula (I-I), characterized in that [ A1]]Reacting a compound of the general formula (I-II)

Wherein

R¹、R²And R³Having the above-mentioned meanings, with compounds of the general formula (I-III)

D¹-CH₂-A¹(I-III)

Wherein

A¹Has the meaning of the above-mentioned formula,

D¹represents trifluoromethanesulfonate or halogen, preferably bromine,

Wherein

A¹、R²And R³Has the meaning of the above-mentioned formula,

L¹represents a group-SnR¹⁴R¹⁵R¹⁶、ZnR¹⁷Iodine or a triflate ester of an acid,

wherein

R¹⁷represents halogen, with a compound of the general formula (I-V)

R¹-T¹(I-V)

Wherein

R¹Has the meaning of the above-mentioned formula,

and the number of the first and second electrodes,

T¹represents trifluoromethanesulfonate or halogen, preferably bromine, and

when L is¹Iodine or triflateWhen the temperature of the water is higher than the set temperature,

T¹represents a group SnR^14’R^15’R^16’、ZnR^17’Or BR¹⁸R¹⁹，

R¹⁸and R¹⁹Identical or different, each represents hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5-or 6-membered carbocyclic ring, are reacted in an inert solvent, in a palladium-catalyzed manner,

and for the group-S (O)_c1ANR⁹R¹⁰and-S (O)_c1’NR^9’R^10’Starting from the unsubstituted compound of the general formula (I-I), the compound is first reacted with thionyl chloride and subsequently with an amine,

6. A medicament containing at least one compound of the general formula (I-I) according to claim 1.

7. Pharmaceutical preparation containing at least one compound of the general formula (I-I) according to claim 1 and at least one organic nitrate (or salt) or NO donor.

8. Pharmaceutical preparations containing at least one compound of the general formula (I-I) according to claim 1 and at least one compound which inhibits the cleavage of cyclic guanylic acid (cGMP).

9. Use of a compound of general formula (I-I) according to claim 1 for the preparation of a medicament for the treatment of cardiovascular diseases.

10. Use of a compound of general formula (I-I) according to claim 1 for the preparation of a medicament for the prevention and combating of the consequences of cerebral infarct events (cerebral stroke) such as stroke, cerebral ischemia and cranio-cerebral trauma.

11. 1-heterocyclyl-methyl-substituted pyrazoles of general formula (II-I) and their isomeric forms, salts and N-oxides,

wherein:

R²⁰denotes a 6-membered heteroaromatic ring containing up to 3 nitrogen atoms, which may optionally be substituted up to 3 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, mercapto, straight-chain or branched acyl,alkoxy, alkylthio or alkoxycarbonyl each containing up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl and/or a group of the formula

-NR²³R²⁴

Wherein

R²³And R²⁴Identical or different, each represents hydrogen or a linear or branched acyl group having up to 6 carbon atoms or a linear or branched alkyl group having up to 6 carbon atoms, which groups may optionally be substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino or linear or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 5 carbon atoms,

or

R²²And R²⁴Together with the nitrogen atom, form a 3-7 membered saturated or partially saturated heterocyclic ring, which may optionally contain an oxygen or sulfur atom or a compound of formula-NR²⁵The group of (a) or (b),

wherein

R²⁵Represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

and/or by straight chains containing up to 6 carbon atomsOR branched alkyl which in turn may be substituted by hydroxy, amino, halogen, carboxy, straight OR branched acyl, alkoxy, alkoxycarbonyl OR acylamino each containing up to 5 carbon atoms, OR by the formula-OR²⁶Is substituted with a group (b) of (a),

wherein

R²⁷、R²⁸And R²⁹Identical or different, each represents an aryl group having 6 to 10carbon atoms or an alkyl group having up to 6 carbon atoms, and/or is optionally substituted by a group of the formula

or-S (O)_c2NR³¹R³²

Wherein

a2 represents a number of 1, 2 or 3,

c2 represents a number of 1 or 2,

R³¹and R³²Identical or different, each represents hydrogen or a linear or branched alkyl radical having up to 10 carbon atoms, which may optionally be substituted by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen, or,

R³¹and R³²Represents a cycloalkyl group having 3 to 7 carbon atoms, or,

Wherein

A²represents phenyl or a 5-to 6-membered aromatic or saturated heterocyclic ring containing up to 3 heteroatoms from the group S, N and/or O, which phenyl and heterocyclic ring may optionally be substituted up to 3 times by identical or different substituents from the group consisting of mercapto, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl each containing up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl each containing up to 6 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each containing up to 5 carbon atoms,

wherein:

d2 represents a number of 0 or 1,

12. The compound of claim 11 of the formula (II-I)

Wherein:

R²⁰represents a group of the formula

Or

These radicals may optionally be substituted up to 3 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, straight-chain or branched acyl having up to 5 carbon atoms, alkoxy or alkoxycarbonyl, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl and/or-NR²³R²⁴The group of (a) or (b),

wherein

and/OR by a linear OR branched alkyl radical having up to 5 carbon atoms, which in turn may be substituted by hydroxyl, amino, fluorine, carboxyl, linear OR branched acyl, alkoxy, alkoxycarbonyl OR acylamino each having up to 4 carbon atoms, OR of the formula-OR²⁶Is substituted by a group of (1), wherein

R²⁶Represents a straight-chain or branched acyl group containing up to 4 carbon atoms and/or is optionally substituted by a group of the formula

Or

Wherein

a2 represents a number of 1, 2 or 3,

R²¹and R²²Including the double bond, to form a furyl, thienyl or phenyl ring, which groups may optionally be substituted up to 3 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which groups in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms,

wherein:

d2 represents a number of 0 or 1,

R³⁴and R³⁵Identical or different, each represents hydrogen, phenyl, benzyl or a straight-chain or branched alkyl or acyl radical each having up to 4 carbon atoms, their isomeric forms, their salts and their N-oxides.

13. The compound of claim 11, of the general formula (II-I),

wherein:

R²⁰represents a group of the formulaOr

Wherein the ring system may optionally be substituted up to 3 times by identical or different substituents being formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, methylamino, amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms each, which in turn may be substituted by hydroxy, carboxy, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having up to 3 carbon atoms each, and/or by a group of the formulaOr

R²¹And R²²Including the double bond, to form a furyl, thienyl or phenyl ring, which may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl,straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,

A²represents phenyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl or pyridinyl, which groups may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxy, straight-chain or branched acyl having up to 3 carbon atoms each, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluoro, nitrogen, bromo, nitro, cyano, trifluoromethyl or represents a group containing up to 3 carbon atomsLinear or branched alkyl which may in turn be substituted by hydroxyl, carboxyl, linear or branched acyl each containing up to 3 carbon atoms, alkoxy or alkoxycarbonyl,

wherein:

d2 represents a number of 0 or 1,

R³⁴and R³⁵Identical or different, each represents hydrogen or a linear or branched alkyl or acyl radical, each containing up to 3 carbon atoms, their isomeric forms, their salts and their N-oxides.

14. The compound of claim 11, of the general formula (II-I),

wherein:

R²⁰represents a group of the formula

Or

Wherein the above heterocyclic ring system may be optionally substituted up to 3 times by the same or different substituent(s) methyl, fluoro, formyl, amino, cyano, methoxy, methoxycarbonyl, methylamino, chloro or a group of formula-NH- (CH)₂)₂-OH，

Or

R²¹And R²²Including the double bond, to form a benzene ring,

A²represents phenyl optionally substituted by fluorine or cyano, its isomeric forms, salts and N-oxides thereof.

15. A process for the preparation of compounds of the general formula (II-I) according to claim 1, characterized in that [ A2]]Reacting a compound of the formula (II-II)

Wherein

R²⁰、R²¹And R²²Has the meaning of the above-mentioned formula,

with compounds of the general formula (II-III)

D²-CH₂-A²(II-III)

Wherein

A²Has the meaning of the above-mentioned formula,

D²represents trifluoromethanesulfonate or halogen, preferably bromine,

in an inert solvent, if desired in the presence of a base, or [ B2]Reacting a compound of the formula (II-IV)

Wherein

A²、R²¹And R²²Has the meaning of the above-mentioned formula,

wherein

R³⁹represents a halogen, and is characterized in that,with compounds of the general formula (II-V)

R²⁰-T²(II-V)

Wherein

R²⁰Has the meaning of the above-mentioned formula,

and the number of the first and second electrodes,

T²represents trifluoromethanesulfonate or halogen, preferably bromine,

and is

When L is²When the compound is iodine or trifluoromethanesulfonate,

T²represents a group SnR^36’R^37’R^38’、ZnR^39’Or BR⁴⁰R⁴¹，

the palladium-catalyzed reaction is carried out in an inert solvent,

for the group-S (O)_c2NR³¹R³²and-S (O)_c2’NR^31’R^32’Starting from the unsubstituted compound of the formula (II-I), the compound is first reacted with thionyl chloride and subsequently with an amine, and R can be changed or introduced by customary methods, if desired²⁰、R²¹、R²²And/or A²The substituents listed below are preferably prepared by reduction, oxidation, cleavage of protecting groups and/or nucleophilic substitution.

16. A medicament containing at least one compound of the general formula (II-I) according to claim 11.

17. Pharmaceutical preparation containing at least one compound of the general formula (II-I) according to claim 11 and at least one organic nitrate (or salt) or NO donor.

18. Pharmaceutical preparations containing at least one compound of the general formula (II-I) according to claim 11 and at least one compound which inhibits the cleavage of cyclic guanylic acid (cGMP).

19. Use of a compound of general formula (II-I) according to claim 11 for the preparation of a medicament for the treatment of cardiovascular diseases.

20. Use of a compound of general formula (II-I) according to claim 11 for the preparation of a medicament for the prevention and combating of the consequences of cerebral infarct events (cerebral stroke) such as stroke, cerebral ischemia and cranio-cerebral trauma.

21. 3-heterocyclyl-substituted pyrazole derivatives of the general formula (III-I), their isomeric forms and their salts

Wherein:

wherein

wherein:

R⁴⁶，R⁴⁷and R⁴⁸Identical or different, each represents an aryl radical having 6 to 10 carbon atoms or an alkyl radical having up to 6 carbon atoms,

and/or substituted by groups of the formula

Or

-S(O)_c3NR⁵⁰R⁵¹

Wherein

a3, b3 and b 3' each represent a number 0, 1, 2 or 3,

c3 represents a number of 1 or 2,

Represents a cycloalkyl group having 3 to 7 carbon atoms, or,

wherein

R⁵²Denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

R⁴³and R⁴⁴Including the double bond, to form a 5-membered heteroaromatic ring or phenyl ring containing one heteroatom selected from S, N and/or O, which heteroaromatic ring or phenyl ring may optionally be substituted up to 3 times by identical or different substituents selected from formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms each, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 5 carbon atoms each,

and/or optionally of the formula-S (O)_c3’NR^50’R^51’Is substituted by a group ofIn c 3' and R^50’And R^51’Having the above-mentioned c3 and R⁵⁰And R⁵¹And the same or different therefrom,

A³denotes a 5-to 6-membered aromatic or saturated heterocycle containing up to 3 heteroatoms from the group S, N and/or O or a phenyl group, which may optionally be substituted up to 3 times by identical or different substituents from the group consisting of amino, mercapto, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl each containing up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl each containing up to 6 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each containing up to 5 carbon atoms,

wherein:

d3 represents a number of 0 or 1,

22. The compound of formula (III-I) according to claim 21,

wherein:

R⁴²represents imidazolyl, oxazolyl, thiazolyl, 1, 2, 3-triazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyranyl or morpholinyl, which radicals may optionally be substituted up to 2 times by identical or different substituents being formyl, trifluoromethyl, phenyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having up to 5 carbon atoms in each case, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which radicals in turn may be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched alkyl having up to 4 carbon atoms in each caseAcyl, alkoxy, alkoxycarbonyl OR amido substituted OR substituted by a group of formula-OR⁴⁵Is substituted with a group (b) of (a),

wherein:

and/or substituted by groups of the formula

Or

Wherein

a3 represents a number 0, 1, 2 or 3,

A³represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, pyrimidinyl, phenyl, morpholinyl, pyridazinyl or pyridinyl, which groups may optionally be substituted up to 2 times by identical or different substituents from the group consisting of hydroxy, formyl, carboxy, straight or branched chain acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl, fluoro, chloro, bromo, nitro, cyano, trifluoromethyl or straight or branched chain alkyl having up to 4 carbon atomsWhich in turn may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each containing up to 4 carbon atoms,

wherein:

d3 represents a number of 0 or 1,

R⁵³and R⁵⁴Identical or different, each represents hydrogen, phenyl, benzyl or a linear or branched alkyl or acyl radical each having up to 4 carbon atoms, their isomeric forms and their salts.

23. The compound of formula (III-I) according to claim 21,

wherein:

R⁴²represents imidazolyl, oxazolyl, oxadiazolyl or thiazolyl, which are optionally substituted up to 2 times by identical or different substituents being formyl, trifluoromethyl, phenyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in turn may be substituted by hydroxy, fluorine, chlorine, trifluoromethyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms or by the formula-O-CO-CH₃Is substituted with a group (b) of (a),

and/or substituted by groups of the formulaOr

Wherein

a3 represents a number 0, 1 or 2,

R⁴⁹represents hydrogen or a methyl group,

R⁴³and R⁴⁴Including the double bond, to form furyl, thienyl or phenyl, which may optionally be substituted up to 2 times by identical or different substituents from the group consisting of formyl, carboxyl, hydroxyl, amino, straight-chain or branched having in each case up to 4 carbon atomsAcyl, alkoxy or alkoxycarbonyl, nitro, cyano, fluorine, chlorine, phenyl or a linear or branched alkyl radical having up to 3 carbon atoms, which in turn may be substituted by hydroxyl, amino, carboxyl, linear or branched acyl, alkoxy or alkoxycarbonyl, each having up to 3 carbon atoms,

A³represents tetrahydropyranyl, phenyl, thienyl or pyridyl, which groups may optionally be substituted up to 2 times by the same or different substituents selected from formyl, carboxy, straight or branched acyl, alkylthio, alkoxyacyl each containing up to 3 carbon atomsA radical, alkoxy or alkoxycarbonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or a linear or branched alkyl radical having up to 3 carbon atoms, which in turn may be substituted by hydroxyl, carboxyl, linear or branched acyl radicals each having up to 3 carbon atoms, alkoxy or alkoxycarbonyl,

wherein:

d3 represents a number of 0 or 1,

24. The compound of formula (III-I) according to claim 21,

wherein:

R⁴³and R⁴⁴Taken together, including the double bond, represents a phenyl group, which may be optionally substituted with a nitro group,

A³represents phenyl or pyrimidinyl substituted by fluorine, iso-orStructural forms and salts thereof.

25. A process for the preparation of compounds of the general formula (III-I) according to claim 21, characterized in that [ a3]]Reacting a compound of the formula (III-II)

Wherein

R⁴²、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

with compounds of the general formula (III-III)

D³-CH₂-A³(III-III)

Wherein

A³Has the meaning of the above-mentioned formula,

D³represents trifluoromethanesulfonate or halogen, preferably bromine,

in an inert solvent, if desired in the presence of a base, or [ B3]Reacting a compound of the formula (III-IV)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

wherein

R⁵⁵、R⁵⁶And R⁵⁷Identical or different, each represents a linear or branched alkyl radical containing up to 4 carbon atoms,

R⁵⁸represents halogen, with a compound of the general formula (III-V)

R⁴²-T³(III-V)

Wherein

R⁴²Has the meaning of the above-mentioned formula,

and the number of the first and second electrodes,

T³represents trifluoromethanesulfonate or halogen, preferably bromine,

and is

When L is³When the compound is iodine, bromine or trifluoromethanesulfonate,

T³represents a group SnR^55’R^56’R^57’、ZnR^58’Or BR⁵⁹R⁶⁰，

R⁵⁹and R⁶⁰Identical or different, each represents a hydroxyl group, an aryloxy group having 6 to 10 carbon atoms or a linear or branched alkyl or alkoxy group each having up to 5 carbon atoms, or together form a 5-or 6-membered carbocyclic ring, the palladium-catalyzed reaction being carried out in an inert solvent, or [ C3]]When in use

Time of flight

Wherein

R⁶¹Representing a linear or branched alkyl radical containing up to 4 carbon atoms, compounds of the general formulae (III-VI)

with diazo compounds of the general formula (III-VII)

Wherein

R⁶²Denotes straight-chain or branched alkyl containing up to 4 carbon atoms,

Wherein

A³，R⁴³、R⁴⁴And R⁶²Having the above meaning, [ D3]]When in useTime of flight

Reacting a compound of the formula (III-VIII)

or by reaction with a compound of the formula (III-IX)

wherein

R⁴³、R⁴⁴And A³Has the meaning of the above-mentioned formula,

then acetyl is removed in methanol under the action of potassium hydroxide,

alternatively, the first and second electrodes may be,

Wherein

R⁴³、R⁴⁴And A³Has the meaning of the above-mentioned formula,

then preparing hydroxymethyl compound under the action of potassium hydroxide,

the methylol compound is then converted to the phase by conventional alkylation methods if desiredThe corresponding alkoxy compound, or, [ E3]]Reacting a compound of the formula (III-XI)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

with a compound of the formula (III-XII),

to obtain the compounds of the general formulas (III-XIII)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

then carrying out Retro-Diels-Alder reaction on the mixture,

alternatively, [ F3]Reacting a compound of the formula (III-XIV)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

with compounds of the general formula (III-XV)

Br-CH₂-CO-R⁶³(III-XV)

Wherein

R⁶³Denotes straight-chain or branched alkyl or alkoxycarbonyl radicals each containing up to 4 carbon atoms,

in an inert solvent to form the compound of the general formula (III-Ic)

Wherein

A³、R⁴³、R⁴⁴And R⁶³Has the meaning of the above-mentioned formula,

for the case of esters (R)⁶³＝CO₂-(C₁-C₄Alkyl)), by a reduction reaction by a conventional method to produce the corresponding methylol compound, or [ G3]]When in useWhen a carboxylic acid of the general formula (III-XVI) is used

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

then, reacted with a compound of the formula (III-XVIII)

Cl-CO-CH₂-Cl (III-XVIII)

To obtain the compound of the general formula (III-XIX)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

also, as described above, -CH₂-OH-substituted compounds from the corresponding-CH₂-O-CO-CH₃Preparation of substituted compounds, or [ H3]When R is⁴²When a group of the formula is represented,

wherein

R⁶⁵including the heterocyclic radicals R listed above⁴²Within the meaning of the sub-substituents of (a), compounds of the general formula (III-XX)

Wherein

with PPh₃/I₂In the presence of a base, preferably triethylamine,

or[I3]When R is⁴⁵When a group of the formula is represented,

wherein a3 has the meaning given above,

reacting a compound of the formula (III-XXI)

R⁶⁶having the above-mentioned R⁶⁴And the same or different therefrom,

followed by oxidation to prepare compounds of the formula (III-XXIII)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

subsequently, it is reacted with a1, 2-or 1, 3-dihydroxy compound by conventional methods, or [ J3]]When R is⁴²When a group of the formula is represented,

wherein

Wherein

R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

q represents hydrogen or a group-CH₂-A³And is

with a compound of the formula (III-XXV),

wherein

R⁶⁷Has the meaning of the above-mentioned formula,

if desired in the presence of a base, and, when Q ═ H, subsequently reacting the product with formula a³-CH₂A compound of the formula-Br (III-XXVI) in which A has the abovementioned meaning, or

Reacting a compound of the formula (III-XXVII)

Wherein

A³、R⁴³And R⁴⁴Has the meaning of the above-mentioned formula,

with a compound of the formula (III-XXVIII),

R^67’-CO-R^68’(III-XXVIII)

wherein

if desired, the reaction is carried out in the presence of a base,

and, R can be changed or introduced by a conventional method if necessary⁴²、R⁴³、R⁴⁴And/or A³The substituents listed below are preferably prepared by reduction, oxidation, cleavage of protecting groups and/or nucleophilic substitution.

26. A process for the preparation of oxazole compounds of the general formulae (III-XXIX),

wherein

X and Y are identical or different and each represents an optionally substituted aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic radical, including saturated, unsaturated or aromatic monocyclic or polycyclic heterocyclic radicals, carboxyl, acyl, alkoxy, alkoxycarbonyl or cyano radicals, or represents hydrogen, where the aromatic and heterocyclic radicals may be substituted by one or more substituents selected from the group consisting of:

halogen, formyl, acyl, carboxyl, hydroxyl, alkoxy, aryloxy, acyloxy, amino optionally substituted with alkyl, amido, aminocarbonyl, alkoxycarbonyl, nitro, cyano, phenyl and alkyl, which alkyl may be substituted with one or more substituents selected from halogen, hydroxyl, amino, carboxyl, acyl, alkoxy, alkoxycarbonyl, and heterocycle and phenyl, which heterocycle and phenyl may in turn be substituted with one or more substituents selected from: amino, mercapto, hydroxy, formyl, carboxy, acyl, alkylthio, alkoxyacyl, alkoxy, alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl and alkyl, which groups may optionally be substituted by hydroxy, carboxy, acyl, alkoxy or alkoxycarbonyl,

wherein the aliphatic, cycloaliphatic and araliphatic radicals may be substituted by one or more substituents selected from the group consisting of: fluorine, hydroxyl, alkoxy, aryloxy, acyloxy, alkyl substituted amino, amido, aminocarbonyl, alkoxycarbonyl and acyl, and Z is selected from the group consisting of:

hydroxy, alkoxy, arylalkoxy optionally substituted by alkyl and/or halogen, aryloxy optionally substituted by alkyl and/or halogen, aroyloxy, acyloxy, alkylthio, arylthio optionally substituted by alkyl and/or halogen, diacylimino or a radical of formula (III-XXX)

Wherein Y and X have the abovementioned meanings, characterized in that amides of the formula (III-XXXI)Wherein Y and X have the above-mentioned meaningsHal represents chlorine or bromine, with the formula M1⁺Z^-Or M2²⁺(Z^-)₂Wherein M1 is an alkali metal, M2 is an alkaline earth metal, and Z is as defined above.

27. The process of claim 26 for the preparation of oxazole compounds wherein in the above formulas (III-XXIX) X is a group of the formula

Wherein

R⁴³、R⁴⁴And A³As defined in claim 21, Y is alkyl or phenyl optionally substituted with alkyl or halogen.

28. The process of claim 26 or 27, wherein the reaction is carried out in a solvent at a temperature of about 20 ℃ to 200 ℃.

29. A medicament containing at least one compound of the general formula (III-I) according to claim 21.

30. Pharmaceutical preparation containing at least one compound of the general formula (III-I) according to claim 21 and at least one organic nitrate (or salt) or NO donor.

31. Pharmaceutical preparations containing at least one compound of the general formula (III-I) according to claim 21 and at least one compound which inhibits the cleavage of cyclic guanylic acid (cGMP).

32. Use of a compound of general formula (III-I) according to claim 21 for the preparation of a medicament for the treatment of cardiovascular diseases.

33. Use of a compound of general formula (III-I) according to claim 21 for the preparation of a medicament for the prevention and combating of the consequences of cerebral infarct events (cerebral stroke) such as stroke, cerebral ischemia and cranio-cerebral trauma.

34. General formula (VII)1-benzyl-3- (substituted heteroaryl) -fused pyrazole derivatives of (IV-I) and their isomeric forms and salts

Wherein

R⁶⁹represents a group of the formula

Or

Wherein

Representing formyl, straight-chain OR branched acyl having up to 6 carbon atoms, nitro, OR straight-chain OR branched alkyl having up to 6 carbon atoms, which may be substituted by amino, azido OR a group of formula-OR⁷³Is substituted with a group (b) of (a),

wherein

or-CH₂-OR⁷⁹Group (d) of

Wherein

and is

R⁷⁹Represents hydrogen or a linearor branched alkyl group containing up to 4 carbon atoms,or

R⁷²Represents a group of the formulaor-S (O)_c4NR⁸²R⁸³

Wherein

a4 represents a number of 1, 2 or 3,

b4 and b 4', which are identical or different, represent a number 0, 1, 2 or 3,

c4 represents a number of 1 or 2, and

R⁸²and R⁸³Identical or different, represents hydrogen or a linear or branched alkyl radical having up to 10 carbon atoms, which alkyl radical may optionally be substituted by a cycloalkyl radical having 3 to 8 carbon atoms or by an aryl radical having 6 to 10 carbon atoms, which in turn may be substituted by halogen,

or

Represents an aryl group having 6 to 10 carbon atoms, which may optionally be substituted by halogen, or represents a cycloalkyl group having 3 to 7 carbon atoms, or

R⁸²And R⁸³Together with the nitrogen atom, form a 5-to 7-membered saturated heterocyclic ring, which may optionally contain a further oxygen atom or a group-NR⁸⁴，

Wherein

Or represents benzyl or phenyl, wherein the ringsystem may optionally be substituted by halogen,

or

R⁷²Is represented by the formula-CH₂-OR⁸⁵The group of (a) or (b),

wherein

R⁷⁰and R⁷¹Together form a radical of the formula

Or

Wherein

provided that only A is present⁴Represents phenyl which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or R⁸⁶Represents nitro, amino, trifluoromethyl or represents formula-S (O)_c4NR^82’R^83’In the case of a phenyl ring and in the position directly adjacent to the heteroatom⁷²Can represent formula-CH₂-OR⁸⁵A group.

35. The compound of formula (IV-I) according to claim 34,

wherein

R⁶⁹represents a group of the formula

Or

Wherein

R⁷²Is represented by the formula-CH (OH) -CH₃Or straight or branched chain containing 2-4 carbon atomsAlkyl which may be substituted once or twice by hydroxy or by straight-chain or branched alkoxy having up to 3 carbon atoms, or

Representing formyl, straight-chain OR branched acyl having up to 4 carbon atoms, nitro OR straight-chain OR branched alkyl having up to 4 carbon atoms, which may be substituted by amino, azido OR a group of the formula-OR⁷³Is substituted by a group of (1), wherein

R⁷³Represents a straight or branched chain acyl group containing up to 4 carbon atoms or the formula-Si(CH₃)₂C(CH₃)₃ or-CH₂-OR⁷⁹The group of (a) or (b),

wherein

and is

or

R⁷²Represents a group of the formula

Or

Wherein

a4 represents a number 1 or 2, or

R⁷²Is represented by the formula-CH₂-OR⁸⁵The group of (a) or (b),

wherein

R⁷⁰and R⁷¹Together form a radical of the formula

Or

Wherein

R⁸⁶Represents hydrogen, fluorine, chlorine, bromine, hydroxyl, nitro, amino, trifluoromethyl or a linear or branched alkyl or alkoxy group having up to 3 carbon atoms,

as well as their isomeric forms and salts thereof,

36. The compound of claim 34, of the general formula (IV-I),

wherein

A⁴Represents a phenyl group, optionally substituted up to 3 times with identical or different substituents selected from: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each containing up to 3 carbon atoms,

R⁶⁹represents a group of the formula

Or

Wherein

Representing formyl, straight-chain OR branched acyl having up to 3 carbon atoms, nitro OR straight-chain OR branched alkyl having up to 3 carbon atoms, the latter being substituted by amino, azido OR a radical of formula-OR⁷³Is substituted with a group (b) of (a),

wherein

R⁷³Denotes straight-chain or branched acyl having up to 3 carbon atoms orIn the form of a pin-Si(CH₃)₂C(CH₃)₃，

or-CH₂-OR⁷⁹The group of (a) or (b),

wherein

R⁷⁸Represents hydrogen or a methyl group,

and is

R⁷⁹Represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms, or

R⁷²Represents a group of the formula

Or

Wherein

R⁸¹represents hydrogen or methyl, and

a4 represents a number 1 or 2, or

R⁷²Same or different and represent formula-CH₂-OR⁸⁵The group of (a) or (b),

wherein

R⁸⁵Represents hydrogen or a methyl group,

R⁷⁰and R⁷¹Together form a radical of the formulaOr

Wherein

R⁸⁶Represents hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, amino, hydroxy or each ofStraight or branched alkyl or alkoxy of up to 3 carbon atoms,

as well as their isomeric forms and salts thereof,

provided that only A is present⁴Represents phenyl which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or R⁸⁶Represents nitro, ammoniaOr trifluoromethyl, R in the case of a phenyl ring and in the position directly adjacent to a heteroatom⁷²Can represent formula-CH₂-OR⁸⁵A group.

37. The compound of claim 34, of the general formula (IV-I),

wherein

A⁴Represents a phenyl group, optionally substituted up to 2 times with identical or different substituents selected from: fluorine, chlorine, methyl, methoxy, cyano, nitro, trifluoromethyl or trifluoromethoxy,

R⁷⁰and R⁷¹Including double bonds, together form a phenyl ring, which is optionally substituted with nitro, fluoro, amino or methoxy,

38. A process for the preparation of a compound of the general formula (IV-I), characterized in that [ A4]]In which A is⁴Compounds of the general formula (VI-II) having the abovementioned meanings

H₂N-NH-CH₂-A⁴(IV-II)

In an inert solvent, if desired in the presence of an acid, into which⁴、R⁶⁹、R⁷⁰And R⁷¹Compounds of the general formulae (IV-IV) having the abovementioned meanings and subsequent oxidation and cyclization of the products with lead tetraacetate/boron trifluoride etherate,

or

[B4]In which R is⁶⁹、R⁷⁰And R⁷¹Compounds of the general formula (IV-V) having the abovementioned meanings

And wherein A⁴Has the above meaning and D⁴The compounds of the formulae (IV-VI) which represent trifluoromethanesulphonates or halogens, preferably bromine, are reacted in an inert solvent, if desired in the presence of a base,

D⁴-CH₂-A⁴(IV-VI) or [ C4]Reacting a compound of the formula (IV-VII)

Wherein

A⁴、R⁷⁰And R⁷¹Have the above meanings, and

R⁹⁰represents a halogen, and is characterized in that,

R⁶⁹-T⁴(VI-VIII)

wherein R is⁶⁹Has the meaning described above, and

at L⁴＝SnR⁸⁷R⁸⁸R⁸⁹Or ZnR⁹⁰When the temperature of the water is higher than the set temperature,

at L⁴When the compound is iodine or trifluoromethanesulfonate,

Wherein

And is

or

and if desired, at R⁶⁹、R⁷⁰、R⁷¹And/or A⁴The substituents listed below may be converted or introduced by conventional methods, preferably by reduction, oxidation, cleavage of protecting groups and/or nucleophilic substitution.

39. A medicament containing at least one compound of the general formula (IV-I) according to claim 34.

40. Pharmaceutical preparation containing at least one compound of the general formula (IV-I) according to claim 34 and at least one organic nitrate (or salt) or NO donor.

41. Pharmaceutical preparations containing at least one compound of the general formula (IV-I) according to claim 34 and at least one compound which inhibits the cleavage of cyclic guanylic acid (cGMP).

42. Use of a compound of general formula (IV-I) according to claim 34 for the preparation of a medicament for the treatment of cardiovascular diseases.

43. Use of a compound of general formula (IV-I) according to claim 34 for the preparation of a medicament for the prevention and combating of the consequences of cerebral infarct events (cerebral stroke) such as stroke, cerebral ischemia and cranio-cerebral trauma.