WO2000021954A1

WO2000021954A1 - Novel heterocyclyl-methyl-substituted pyrazoles

Info

Publication number: WO2000021954A1
Application number: PCT/EP1999/007202
Authority: WO
Inventors: Achim Feurer; Alexander Straub; Chantal FÜRSTNER; Johannes-Peter Stasch; Elisabeth Perzborn; Joachim Hütter; Klaus Dembowsky
Original assignee: Bayer Aktiengesellschaft
Priority date: 1998-10-09
Filing date: 1999-09-29
Publication date: 2000-04-20
Also published as: CA2346698A1; EP1119566A1; DE19846514A1; AU6330099A; JP2002527435A

Abstract

The invention relates to novel heterocyclyl-methyl-substituted pyrazole derivatives, to methods for producing them and to their use as medicaments, especially as medicaments for treating cardiovascular diseases.

Description

New heterocyclyl-methyl-substituted pyrazoles

The present invention relates to new heterocyclyl-methyl-substituted pyrazole derivatives, ner processes for their preparation and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.

It is already known that 1-benzyl-3-aryl-fused pyrazole derivatives inhibit platelet aggregation (cf. EP 667 345 AI).

The present invention relates to new heterocyclyl-methyl-substituted pyrazoles of the general formula (I)

in which

R ^{1 represents} a 6-membered aromatic heterocycle with up to 3 nitrogen atoms, which may be up to 2 times identical or different by hydrogen, formyl, carboxyl, hydroxy, mercapto, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl, each with up to to

6 carbon atoms, Νitro, cyano, azido, halogen, phenyl and / or by a group of the formula

-ΝR ⁴ R ⁵

is substituted, wherein R ⁴ and R ^{5 are} identical or different and are hydrogen or straight-chain or branched acyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which may be by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl, each having up to 5 carbon atoms,

or

R ⁴ and R ⁵ together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle which may optionally additionally contain an oxygen or sulfur atom or a radical of the formula -NR ⁶ ,

wherein

R ^{6 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

and / or is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in turn is substituted by hydroxy, amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino each having up to 5 carbon atoms or by a radical of the formula - OR ⁷ can be substituted,

wherein

R ⁷ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR ⁸ R ⁹ R ¹⁰ , woπn

R ⁸ , R ⁹ and R ^{! 0 are the} same or different and are aryl with 6 to 10 carbon atoms or alkyl with up to 6 carbon atoms,

and / or optionally by a radical of the formula

or S (0) NR ¹² R ¹³

is substituted, wherein

b and b 'are the same or different and represent a number 0, 1, 2 or 3,

a represents a number 1, 2 or 3,

R ¹¹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

c represents a number 1 or 2 and

R ¹² and R ^{13 are the} same or different and is hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally by cycloalkyl

3 to 8 carbon atoms or by aryl with 6 to 10 carbon atoms lenstoffatomen is substituted, which in turn can be substituted by halogen or

Aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or

Cycloalkyl having 3 to 7 carbon atoms

or

R ¹² and R ¹³ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which can optionally contain a further oxygen atom or a radical -NR ¹⁴ ,

wherein

R ^{14 is} hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

means

or benzyl or phenyl, where the ring systems are optionally substituted by halogen,

and the 6-membered aromatic heterocycle R ¹ , which contains up to 3 nitrogen atoms, 1 to 3 times the same or different

(A) straight-chain or branched alkyl having 7 to 20 carbon atoms, straight-chain or branched alkenyl having up to 20 carbon atoms and 1 to 2 double bonds, straight-chain or branched alkynyl having up to 20 carbon atoms and 1 to 2 triple bonds,

where alkenyl or alkynyl have a double or triple bond at the point of attachment to the heterocycle R ¹ ,

Cycloalkoxy with 3 to 14 carbon atoms, or optionally substituted aryl with 6 to 10 carbon atoms,

where the alkyl, alkenyl, alkynyl, cycloalkoxy and aryl radicals mentioned are in turn optionally and in the case of aryl = phenyl optionally substituted by formyl, carboxyl, hydroxy,

Mercaptyl, nitro, cyano, azido, halogen, straight-chain, branched or cyclic alkyl, acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl each having up to 6 carbon atoms, by aryl having 6 to 10 carbon atoms, which may be by halogen, alkyl, alkoxy in each case 1 to 6 carbon atoms is substituted by 5- to 6-membered hetaryl, with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which is optionally substituted by halogen, alkyl, alkoxy each having 1 to 6 carbon atoms is substituted,

and or through a group of formula

-NR ^a aRτ> b '

wherein

R ^a and R ^{b are} identical or different and are hydrogen or straight-chain or branched acyl having up to 10 carbon atoms, cyclic acyl having 3 to 8 carbon atoms, straight-chain or branched alkyl having up to 10 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, where appropriate by

Hydroxy, amino, monoalkylamino, dialkylamino or substituted by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 5 carbon atoms,

or

R ^a and R together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle, which may be by

Hydroxy is substituted and which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^C ,

wherein R ° is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

and / or by a group of the formula

-OR ^d

wherein

R ^d denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR ^e R ^f R ⁸ ,

wherein

R ^e , R ^f and R ^{8 are the} same or different and are aryl with 6 to 10 carbon atoms or alkyl with up to 6 carbon atoms,

and or

(B) is substituted by a 3- to 14-membered heterocyclic ring which can be saturated or unsaturated and contains 1 to 4 heteroatoms from the series N, O, S, SO, SO ₂ and optionally by

Halogen, phenyl, cyano, alkyl, alkoxy each having 1 to 6 carbon atoms, -NR ^h R,

in which R ^h and R ^{1 may be the} same or different and denote hydrogen, straight-chain, branched or cyclic alkyl or acyl having up to 6 carbon atoms

or

R ^h and R together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^J ,

wherein

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

and or

(C) is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is imperative by one or more of the following groups

Formyl, mercaptyl, nitro, cyano, cyclic acyl with 3 to 14 carbon atoms, straight-chain or branched acyl with 6 to 14

Carbon atoms, alkoxy with 6 to 14 carbon atoms, acylamino with 6 to 14 carbon atoms, alkoxycarbonyl with 6 to 14 carbon atoms, alkylthio with up to 14 carbon atoms, cyclic alkyl with 3 to 14 carbon atoms, phenyl, which may be by Halogen, alkyl of up to 6 carbon atoms or alkoxy of up to 6 carbon atoms;

5- to 6-membered hetaryl with 1 to 3 heteroatoms from the N series,

O, S, SO, SO ₂ , which is optionally substituted by halogen, alkyl having up to 6 carbon atoms or alkoxy having up to 6 carbon atoms;

-NR ^k R ', where one of the radicals R ^k and R ¹ can be hydrogen and the other or both independently of one another are straight-chain or branched acyl having up to 10 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms or R ^k and R ¹ together form a 3- to 7-membered saturated or partially unsaturated heterocycle with the nitrogen atom, which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^m ,

wherein

R ^{m is} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, is substituted;

and or

(D) is substituted by alkoxy with up to 6 carbon atoms, which in turn is substituted,

by hydroxy, -NR ⁿ R °, where R ⁿ and R ° are the same or different

Can be hydrogen or straight-chain, branched or cyclic alkyl or acyl, each having up to 6 carbon atoms, or R ⁿ and R ° together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle, which counteracts optionally also contains an oxygen or sulfur atom or a radical of the formula -NR ^P ,

woπn

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

and or

(E) by halogen-substituted acyl having up to 14 carbon atoms, acyloxy having up to 14 carbon atoms, arylthio having 6 to 10 carbon atoms, the aryl radical optionally being substituted by halogen, alkyl, alkoxyl each having 1 to 6 carbon atoms; Heteroarylthio, with 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which is optionally substituted by halogen, straight-chain or branched alkyl or alkoxy with 1 to 6 carbon atoms, is substituted ,

and or

(F) by a residue of the formula

-SO ₂ R ^q or -SOR ^{r is} substituted,

in which

R ^q and R ^r straight-chain or branched alkyl having 1 to 10 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms, Aryl with 6 to 10 carbon atoms, which is optionally substituted by halogen, alkyl with 1 to 6 carbon atoms or alkoxy with 1 to 6 carbon atoms, or 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which if necessary by

Halogen, straight-chain or branched alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms is substituted

and or

(G) is substituted by a radical -SO ₃ H

and or

(H) is substituted by a radical -CON = C (NH ₂ ) ₂ or -C = NH (NH ₂ )

and or

(I) is substituted by a -CONR ^s R radical

in which

R ^s and R * may be the same or different and denote hydrogen, straight-chain or branched alkyl having 1 to 14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms,

said alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxy, Amino, straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 6 carbon atoms,

Aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, straight-chain or branched alkyl having 1 to

6 carbon atoms, cycloalkyl with 3 to 14 carbon atoms, alkoxy with 1 to 6 carbon atoms,

or 5- to 6-membered heterocyclyl with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which optionally by

Halogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms, alkoxy having 1 to 6 carbon atoms,

are substituted,

and or

R ^s and R * are aryl having 6 to 10 carbon atoms, which may be halogen, straight-chain or branched

Alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 14 carbon atoms, alkoxy with 1 to 6 carbon atoms is substituted, and / or

R ^s and R ¹ 3- to 10-membered saturated, partially unsaturated or completely unsaturated heterocyclyl with 1 to 5 heteroatoms from the series N, O, S; SO, SO ₂ , which may be halogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms. atoms, alkoxy is substituted with 1 to 6 carbon atoms,

and or

R ^s and R together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^U ,

in which

R ^{u is} hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms,

and or

(J) is substituted by a radical of the formula - R,

in which

R ^v and R ^{w can be the} same or different and straight-chain or branched acyl with 7 to 14 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, -SO ₂ alkyl with 1 to 4 carbon atoms, hydroxymethyl, hydroxyethyl,

Alkoxycarbonyl with up to 5 carbon atoms, alkoxyalkyl with a total of up to 8 carbon atoms, acyloxymethyl with up to 6 carbon atoms in the acyl radical (preferably pivaloyloxymethyl) or the following radicals

R ^x -O-CH (Ry) -O-CO-

mean,

wherein

R ^x and RY are identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

m represents a number 0, 1 or 2 and R ^z denotes straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

or one of the radicals R ^v and R ^{w can} optionally be hydrogen,

and or

(K) is substituted by a radical of the formula -PO (OR) (OR ')

in which

R and R 'represent the same or different straight-chain, branched or cyclic alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms or benzyl,

R ² and R ³ , including the double bond, form a phenyl ring which may be up to 3 times identical or different through formyl,

Mercaptyl, carboxyl, hydroxy, amino, straight-chain or branched acyl, alkylthio, alkoxy, alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which are in turn substituted by Hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each having up to 5 carbon atoms, can be substituted, or optionally substituted by a group of the formula -S (O) _c. NR ^{12 '} R ^13' , where c ' R ¹² and R ^{13 have} the meaning of c, R ¹² and R ¹³ given above and are identical or different with this,

A represents phenyl or a 5- to 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms from the series S, N and / or O, which is optionally up to 3 times identical or different by mercaptyl, Hydroxy, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted can in turn be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,

and / or is substituted by a group of the formula - (CO) _d -NR ¹⁵ R ¹⁶ ,

wherein

d represents a number 0 or 1,

R ¹⁵ and R ^{16 are} identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl, each having up to 5 carbon atoms,

their isomeric forms and salts and their N-oxides.

The inventive compounds of the general formula (I) can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, Νaphthalenedisulfonic acid, acetic acid. 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 according to the invention which have a free carboxyl group. For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, and 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 according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

In the context of the present invention, the substituents generally have the following meaning:

Depending on the substituents listed above, alkyl having up to 20 carbon atoms generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodeyl, eicosyl.

Depending on the substituents listed above, alkenyl having up to 20 carbon atoms generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably one or two, double bonds. For example, allyl, propenyl, Isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl, isooctenyl.

Depending on the substituents listed above, alkynyl generally represents a straight-chain or branched hydrocarbon radical with 2 to

20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.

Depending on the substituents listed above, acyl with up to 10 carbon atoms generally represents straight-chain or branched lower alkyl having 1 to 9 carbon atoms which are bonded via a carbonyl group. Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Depending on the substituents listed above, alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 14 carbon atoms which is bonded via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy. The

Terms "alkoxy" and "alkyloxy" are used synonymously.

Alkoxycarbonyl can, for example, by the formula

- C - O alkyl

II O are shown.

Alkyl stands for a straight-chain or branched hydrocarbon radical with 1 to 13 carbon atoms. For example, the following alkoxy carbo- called onyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.

Aromatic, saturated and unsaturated heterocycles in the context of the invention, depending on the substituents listed above, generally represent a 3- to 10-membered or 5- to 6-membered heterocycle which has up to 4

Contain heteroatoms from the series S, N and / or O and which can optionally also be bonded via a nitrogen atom. Examples include: pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, pyrimidyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, morpholinyl or piperidyl. Hetaryl stands for an aromatic heterocyclic radical.

Cycloalkoxy in the context of the invention is an alkoxy radical whose hydrocarbon radical is a cycloalkyl radical. The cycloalkyl radical generally has up to 8 carbon atoms. Examples include: cyclopropyloxy and cyclohexyloxy. The terms "cycloalkoxy" and "cycloalkyloxy" are used synonymously.

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

R ¹ for a radical of the formula stands,

which may be up to 2-fold identical or different through hydrogen, formyl, carboxyl, hydroxy, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl and / or are substituted by a group of the formula -NR ⁴ R ⁵ ,

wherein

R ⁴ and R ^{5 are} identical or different and denote hydrogen or straight-chain or branched acyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which may be by hydroxyl, amino or by straight-chain or branched alkoxy having up to 3 carbon atoms is substituted, or

R ⁴ and R ⁵ together with the nitrogen atom represent a morpholine ring or a radical of the formulas

-N NH, -N N-CH- or form

and / or are substituted by straight-chain or branched alkyl having up to 5 carbon atoms, which in turn is substituted by hydroxy, amino, fluorine,

Carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or Acylamino each having up to 4 carbon atoms or can be substituted by a radical of the formula -OR ⁷ ,

wherein

R ⁷ denotes straight-chain or branched acyl having up to 4 carbon atoms,

and / or optionally by a radical of the formula

0— - CCHH ₂ , p O—— ((CCHH ₂ Λ) _b CCHH ₃

- CH _{2 ε} ooddeerr

Ö (CH ^• ₂ _y) _b b. ^, C- "H" ₃ - OR ¹¹

are substituted, wherein

b and b 'are the same or different and represent a number 0, 1, 2 or 3,

a represents a number 1, 2 or 3,

R ¹¹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

and the 6-membered aromatic heterocycles listed above under R ^{1 are} identical to or different from one to three times

(A) straight-chain or branched alkyl having 7 to 14 carbon atoms, straight-chain or branched alkenyl having up to 14 carbon atoms with a double bond, straight-chain or branched alkynyl having up to 14 carbon atoms and a triple bond, where alkenyl or alkynyl have a double or triple bond at the point of attachment to the heterocycle R ¹ ,

Cycloalkyloxy with 3 to 8 carbon atoms, or substituted phenyl are substituted,

where the alkyl, alkenyl, alkynyl and cycloalkyloxy radicals in turn are optionally substituted and the phenyl radical is necessarily substituted by carboxyl, hydroxyl, mercaptyl, nitro, cyano,

Azido, fluorine, chlorine, bromine, straight-chain, branched or cyclic alkyl, acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl, each having up to 6 carbon atoms, by aryl having 6 to 10 carbon atoms, which is optionally by fluorine, chlorine, bromine, alkyl , Alkoxy is substituted with 1 to 6 carbon atoms in each case, by 5- to 6-membered hetaryl, with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, bromine, alkyl, alkoxy each with 1 to 6 carbon atoms is substituted,

and or

through a group of formula

wherein

R ^a and R ^{b are the} same or different and are hydrogen or straight-chain or branched acyl with up to 6 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, straight means chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, these being optionally by

Hydroxy, amino, monoalkylamino, dialkylamino or substituted by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms,

or

R and R ^b together with the nitrogen atom form a 3- to 7-membered saturated heterocycle,

which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^C ,

wherein

R ^{c is} hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms.

and / or by a group of the formula

-OR ^d

wherein

R ^{d means} straight-chain or branched acyl with up to 4 carbon atoms, and or

(B) are substituted by a 3- to 8-membered heterocyclic ring which can be saturated or unsaturated and contain 1 to 4 heteroatoms from the series N, O, S and optionally by

Fluorine, chlorine, bromine, phenyl, cyano, alkyl, alkoxy each having 1 to 6 carbon atoms, -NR ^h R,

in which

R ^h and R may be the same or different and denote hydrogen, straight-chain, branched or cyclic alkyl or acyl having up to 4 carbon atoms

or

R ^h and R together with the nitrogen atom form a 3- to 7-membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula

-NR ^j contains

woπn

and or (C) are substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is imperative by one or more of the following groups

Mercaptyl, nitro, cyano, cyclic acyl with 3 to 8 carbon atoms, straight-chain or branched acyl with 6 to 10 carbon atoms, alkoxy with 6 to 10 carbon atoms, acylamino with 6 to 10 carbon atoms, alkoxycarbonyl with 6 to 10 carbon atoms, alkylthio with up to 10 Carbon atoms, cyclic alkyl having 3 to 8 carbon atoms,

Phenyl, which is optionally by

Fluorine, chlorine, bromine, alkyl with up to 6 carbon atoms or alkoxy with up to 6 carbon atoms; 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which may be replaced by fluorine, chlorine, bromine, alkyl with up to 6

Carbon atoms or alkoxy is substituted with 1 to 6 carbon atoms;

-NR ^k R ', where one of the radicals R ^k and R ¹ can be hydrogen and the other or both independently represent straight-chain or branched acyl having up to 6 carbon atoms, cyclic alkyl having 3 to 8 carbon atoms or R ^k and R ¹ together form a 3- to 7-membered saturated heterocycle with the nitrogen atom, which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^m ,

wherein

R ^m denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

is substituted, and or

(D) are substituted by alkoxy with up to 6 carbon atoms, which in turn is substituted by

Hydroxy, -NR ⁿ R °, where R ⁿ and R ° may be the same or different hydrogen or straight-chain, branched or cyclic alkyl or acyl each having up to 5 carbon atoms, or R ⁿ and R ° together with the nitrogen atom are a 3- to 7th form a membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^P ,

woπn

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

and or

(E) by halogen-substituted acyl with up to 10 carbon atoms,

Acyloxy with up to 10 carbon atoms, arylthio with 6 to 10

Carbon atoms, the aryl radical being optionally fluorine,

Chlorine, bromine, alkyl, alkoxyl each having 1 to 6 carbon atoms, heteroarylthio, with 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O or S, which is optionally by fluorine, chlorine, bromine, straight-chain or branched alkyl or alkoxy with 1 to 6 carbon atoms is substituted,

are substituted and / or (F) by a residue of the formula

-SO ₂ R ^q or -SOR ^{r are} substituted,

in which

R ^q and R ^r straight-chain or branched alkyl having 1 to 6 carbon atoms, cyclic alkyl having 3 to 8 carbon atoms,

Aryl having 6 to 10 carbon atoms, which may be by

Fluorine, chlorine, bromine, alkyl with 1 to 6 carbon atoms or alkoxy with 1 to 6 carbon atoms, or 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine , Bromine, straight-chain or branched alkyl with

1 to 4 carbon atoms or alkoxy is substituted by 1 to 4 carbon atoms

and or

(G) are substituted by a radical -SO ₃ H

and or

(I) are substituted by a radical -CONR ^s R '

in which

R ^s and R ^{l may be the} same or different and are hydrogen, straight-chain or branched alkyl having 1 to 10 carbon atoms. atoms or cycloalkyl having 3 to 8 carbon atoms,

said alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxy,

Amino, straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 5 carbon atoms,

Aryl with 6 to 10 carbon atoms, which may be fluorine, chlorine, bromine, straight-chain or branched

Alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkoxy with 1 to 6 carbon atoms;

or 5- to 6-membered heterocyclyl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy 1 to 6 carbon atoms is substituted,

are substituted,

and or

^s and R ^{1 are} aryl having 6 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,

and or R ^s and R * are 3- to 8-membered saturated heterocyclyl having 1 to 3 heteroatoms from the series N, O, S; which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,

and or

R ^s and R 'together with the nitrogen atom form a 3- to 7-membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^U ,

in which

(J) are substituted by a radical of the formula -NRH

in which

R ^v and R ^{w can be the} same or different and straight-chain or branched acyl with 7 to 10 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, -SO ₂ alkyl with 1 to 4 carbon atoms, hydroxymethyl, hydroxyethyl, alkoxycarbonyl with up to 5 carbon atoms , Alkoxyalkyl with a total of up to 8 carbon atoms, acyloxymethyl with up to 6 carbon atoms in the acyl radical (preferably pivaloyloxymethyl) or the following radicals

R ^x -O-CH (Ry) -O-CO-,

mean,

wherein

R ^x and Ry are the same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms m represents a number 0, 1 or 2 and

R ^z denotes straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl,

or one of the radicals R ^v and R ^{w can} optionally be hydrogen,

(K) are substituted by a radical of the formula -PO (OR) (OR ')

in which

R and R 'are the same or different straight-chain, branched or cyclic alkyl having up to 6 carbon atoms or aryl

6 to 10 carbon atoms or benzyl,

R ² and R ³ , including the double bond, form a phenyl ring which may be up to 3 times the same or different by formyl, carboxyl, hydroxy, amino, straight-chain or branched acyl, alkoxy, or

Alkoxycarbonyl, each with up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl with up to 5 carbon atoms, which in turn are substituted by hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or Alkoxycarbonyl can each be substituted with up to 4 carbon atoms,

A for phenyl or for tetrahydropyranyl, furyl, tetrahydrofuryl, morpholinyl,

Pyrimidyl, piperazinyl or pyridyl, which is optionally up to 2 times identical or different by hydroxy, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl in each case 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 is substituted by hydroxy, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each with up to 4 Carbon atoms can be substituted

and / or are substituted by a group of the formula - (CO) _d -NR ¹⁵ R ¹⁶ ,

wherein

a number means 0 or 1,

R ' ⁵ and R ^{16 are the} same or different and are hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,

their isomeric forms and salts and their N-oxides.

Compounds of the general formula (I) in which

R ¹ for a radical of the formula

or stands

where the listed 6-membered aromatic heterocycles R ¹ , optionally up to 2 times the same or different by hydrogen, formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl in each case up to 4 carbon atoms, methylamino, amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms which are in turn substituted by hydroxy, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl, Acylamino can each be substituted with up to 3 carbon atoms,

and / or optionally by a radical of the formula

-N / ^{~ "} λ N-CH- -

are substituted,

and the 6-membered aromatic heterocycles listed above under R ¹ 1 to 3 times, identically or differently by

(A) straight-chain or branched alkyl having 7 to 10 carbon atoms, straight-chain or branched alkenyl having up to 6 carbon atoms and a double bond, straight-chain or branched alkynyl having up to 6 carbon atoms and a triple bond,

where alkenyl or alkynyl have their double or triple bond at the point of attachment to the heterocycle R ¹ ,

Cycloalkyloxy with 3 to 6 carbon atoms, substituted phenyl are substituted, the alkyl-, alkenyl-, alkynyl- and cycloalkyloxy-

Residues in turn, if necessary, and the phenyl residue is necessarily substituted by carboxyl, hydroxy, cyano, fluorine, chlorine, straight chain, branched or cyclic alkyl, acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl, each having up to 3 carbon atoms, by phenyl, which is optionally substituted by fluorine, chlorine, alkyl, alkoxy each having 1 to 4 carbon atoms, by 5- to 6-membered hetaryl, with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, alkyl, alkoxy each having 1 to 4 carbon atoms,

and or

through a group of formula

-NR ^a anRb

woπn

R ^a and R ^{b are} identical or different and are hydrogen or straight-chain or branched acyl having up to 4 carbon atoms, cyclic acyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, where appropriate by

or R ^a and R ^b together with the nitrogen atom form a heterocycle of the formula

-N O

-N NH

or

form

and / or by a group of the formula

-OR ^d

wherein

R ^d straight-chain or branched acyl with up to 3 carbon atoms

and or

(B) are substituted by a 5- to 6-membered heterocyclic ring, which can be saturated or unsaturated and contains 1 to 4 heteroatoms from the series N, O, S and optionally by

Fluorine, chlorine, phenyl, cyano, alkyl, alkoxy each having 1 to 4 carbon atoms, -NR ^h R, in which

R ^h and R may be the same or different and denote hydrogen, straight-chain, branched or cyclic alkyl or acyl having up to 3 carbon atoms

or

R ^h and R together with the nitrogen atom represent a radical of the formula

-N

or

form and / or

(C) are substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is imperative by one or more of the following groups

Cyano, cyclic acyl with 3 to 6 carbon atoms, alkylthio with up to 6 carbon atoms, cyclic alkyl with 3 to 14 carbon atoms, phenyl, which may be by Fluorine, chlorine, alkyl with up to 4 carbon atoms or

Alkoxy is substituted with up to 4 carbon atoms;

5- to 6-membered hetaryl with 1 to 3 heteroatoms from the N series,

O, S, which is optionally substituted by fluorine, chlorine, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms,

-NR ^k R ', where one of the radicals R ^k and R ¹ can be hydrogen and the other or both independently represent straight-chain or branched acyl having up to 4 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms or R ^k and R ¹ together with the nitrogen atom a heterocycle of the formula

-N NH

or

form

and or

(D) are substituted by alkoxy with up to 4 carbon atoms, which in turn is substituted by

Hydroxy, -NR ⁿ R °, where R ⁿ and R ° may be the same or different hydrogen or straight-chain, branched or cyclic alkyl or acyl each having up to 4 carbon atoms or R ⁿ and R ° together with the nitrogen atom form a heterocycle of the formula -N

-N NH

or

-N NCH

form

and or

(E) by halogen-substituted acyl with up to 6 carbon atoms,

Acyloxy with up to 6 carbon atoms or phenylthio, the

Phenyl radical is optionally substituted by fluorine, chlorine, alkyl, alkoxy each having 1 to 4 carbon atoms; Heteroarylthio with 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl or alkoxy having 1 to 4 carbon atoms; are substituted,

and or

(F) by a residue of the formula

-SO ₂ R ^q or -SOR ^{r are} substituted

in which R ^q and R ^r straight-chain or branched alkyl having 1 to 3 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms,

Phenyl, which is optionally substituted by fluorine, chlorine, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 3 carbon atoms, or 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by

Fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms is substituted,

and or

(G) are substituted by a radical -SO ₃ H

and or

(I) are substituted by a -CONR ^s R radical,

in which

R ^s and R 'may be the same or different and denote hydrogen, straight-chain or branched alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

said alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino, straight-chain or branched alkoxy, acyl or

Alkoxycarbonyl, each with up to 4 carbon atoms, Phenyl which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms;

or by 5- to 6-membered heterocyclyl having 1 to 3 heteroatoms from the series N, O, S, which may be fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms,

Alkoxy is substituted with 1 to 4 carbon atoms,

are substituted,

and or

R ^s and R * are phenyl which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms,

and or

R ^s and R * are 3- to 6-membered saturated heterocyclyl having 1 to 3 heteroatoms from the series N, O, S; which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms,

and or R ^s and R together with the nitrogen atom form a group of the formula

-N O

-N NH

or

form

and or

(J) are substituted by a radical of the formula -NR ^V R ^W

in which

R ^v and R ^{w can be the} same or different and hydroxymethyl,

Hydroxyethyl, SO ₂ alkyl having 1 to 4 carbon atoms,

R ^x -O-CH (Ry) -O-CO-

mean,

in which

R ^x and Ry can be the same or different and represent hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,

10 R ^z for straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl, cyclohexyl or aryl and m represents a number 0, 1 or 2 and

or one of the radicals R ^v and R ^{w can} optionally be hydrogen,

and or

(K) are substituted by a radical of the formula -PO (OR) (OR ')

in which

R and R 'are the same or different straight-chain, branched or cyclic alkyl having up to 4 carbon atoms or phenyl or benzyl,

R ² and R ³ , including the double bond, form a phenyl ring which may be identical or different up to 2 times through formyl, carboxyl, hydroxy, amino, straight-chain or 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 are substituted, which in turn can be substituted by hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,

A represents phenyl or tetrahydropyranyl, tetrahydrofuryl, furyl or pyridyl, which may optionally be up to 2 times identical or different by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, 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 are substituted, that can in turn be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,

wherein

d represents a number 0 or 1,

R ¹⁵ and R ^{16 are} identical or different and are hydrogen or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,

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

Compounds of the general formula (I) in which

R ¹ for a radical of the formula

wherein the pyrimidyl radical listed above may be up to 2 times identical or different by methyl, ethyl, isopropyl, fluorine, amino, cyano, methoxy, chlorine, hydroxymethyl or by a radical of the formula

is substituted,

and the above-mentioned pyrimidyl radical R ¹ 1- to 3-fold identical or different by a radical of the formula -SO2CH3 or by a radical of the formula -PO (OH) ₂ , -PO (OMe) ₂ , -PO (OEt) ₂ or -PO (O ⁱ Pr) _{2 is} substituted,

R ² and R ^{3 together} with the double bond form a phenyl ring and

A represents phenyl, which is optionally substituted by fluorine or cyano

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

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

[A] compounds of the general formula (II)

in which

R, R and R have the meaning given above, with compounds of the general formula (III)

D-CH ₂ -A (III)

in which

A has the meaning given above,

and

D represents triflate or halogen, preferably chlorine or bromine,

in inert solvents, if appropriate in the presence of a base,

or

[B] Compounds of the general formula (IV)

in which

A, R and R have the meaning given above,

and L represents a radical of the formula -SnR ¹ TTR ¹⁹ , ZnR ^2U , iodine or triflate,

wherein

R ¹⁷ , R ¹⁸ and R ^{19 are} identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms,

and

R ^{20 represents} halogen,

with compounds of the general formula (V)

R'-T (V)

in which

R ^{1 has} the meaning given above,

and

in the case L = SnR "R ¹⁸ R ¹⁹ or ZnR

T represents triflate or halogen, preferably chlorine or bromine,

and

in the case L = iodine or triflate

T represents a radical of the formula SnR ¹⁷ R ¹⁸ R ¹⁹ , ZnR ²⁰ or BR ^2, R ²² , woπn

R ^{17 '} , R ^18' , R '^9' and R ^{20 'have} the abovementioned meaning of R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ and are the same or different with this,

R ²¹ and R ^{22 are the} same or different and are hydroxy, aryloxy having 6 to 10 carbon atoms or straight-chain or branched

Are alkyl or alkoxy each having up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,

implemented in a palladium-catalyzed reaction in inert solvents,

[C] amidines of the general formula (VI)

in which

A, R ² and R ^{3 have} the meaning given above,

with enamines of the general formula (VII)

in which

R ^{r represents} one of the above-mentioned substituents of the 6-membered aromatic heterocycle R ¹

and

represents a suitable leaving group such as dimethylamino or hydroxyl,

implements

and optionally the substituents listed under R ¹ , R ² , R ³ and / or A are varied or introduced by customary methods, preferably by reduction, oxidation, removal of protective groups and / or by nucleophilic substitution.

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

[A] or [B]

Me ₆ Sn ₂ (3eq), Pd (PP) ₃ ) ₄

[C]:

Inert organic solvents which do not change under the reaction conditions are suitable as solvents for the individual steps of processes [A], [B] and [C].

These include ethers such as diethyl ether or tetrahydrofuran, DME, dioxane, alcohols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible to mix the

Use solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane is particularly preferred.

In general, inorganic or organic bases can be used as bases for the processes according to the invention. 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 methoxide, sodium or potassium ethanolate or potassium tert .butylate, or organic amines (trialkyl (C _r C ₆ ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4. 0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to use alkali metals such as sodium and their hydrides such as sodium hydride as bases. Sodium and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is used in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, based on 1 mol of the compound of the general formula (II).

The reaction is generally carried out in a temperature range from 0 ° C. to 150 ° C., preferably from + 20 ° C. to + 110 ° C. The reaction can be carried out under normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure.

Protonic acids are generally suitable as acids for the cyclization. These preferably include inorganic acids such as hydrochloric acid or sulfuric acid, or organic carboxylic acids with 1-6 C atoms, optionally substituted by fluorine, chlorine and / or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulfonic acids with -C ^ alkyl radicals or aryl residues such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

The catalytic hydrogenation can generally be carried out using hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium,

Palladium on charcoal or platinum, or with hydrides or boranes in inert solvents, optionally in the presence of a catalyst.

The chlorination is generally carried out using the customary chlorinating agents, for example PC1 ₃ , PC1 ₅ , POCl ₃ or elemental chlorine. Is preferred within the

Invention POCl ₃ .

In the event that the residues of the formulas -S (O) _c NR ¹ R ¹³ and -S (O) _c .NR ^{12 '} R ^13' are to be introduced, the corresponding unsubstituted precursors are first reacted with thionyl chloride. In a further step the implementation takes place with the

Amines in one of the ethers listed above, preferably dioxane. In the case of c = 2, an oxidation is then carried out using customary methods. The reactions take place in a temperature range from 0 ° C to 70 ° C and normal pressure. The nucleophilic substitutions and Vilsmeier reactions are carried out according to the usual published methods.

The reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of carbonyl to hydroxy compounds. Reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane, is particularly suitable. The reduction is preferably carried out using complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminum hydride. The reduction is very particularly preferably carried out using diisobutylaluminum hydride and sodium borohydride.

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

The reduction generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C. in the case of the DIBAH, from 0 ° C. to room temperature in the case of the NaBH ₄

The reduction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.

Particularly suitable solvents for process [B] are: ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible Use mixtures of solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is generally carried out in a temperature range from 0 ° C. to 150 ° C., preferably from 110 ° C. to 150 ° C.

The reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.

PdCl ₂ (P (C ₆ H ₅ ) ₃ ) ₂ , palladium-bis-dibenzylidene acetone (Pd (dba) ₂ ), [l, l'-bis (diphenylphosphino) ferrocene are generally suitable as palladium compounds in the context of the present invention ] -Palladium (II) chloride (Pd (dppf) Cl ₂ ) or Pd (P (C ₆ H ₅ ) ₃ ) ₄ . Pd (P (C ₆ H ₅ ) ₃ ) ₄ is preferred.

The compounds of the general formula (IV) are known and customary

Methods can be produced.

Process [C] takes place in a temperature range from 55 ° C to 120 ° C, preferably at 80 ° C.

In process [C] either the free amidine base is used. In this case, the enamines act as solvents. Or the amidines are reacted in the form of their salts, preferably hydrochlorides, in the presence of a base, preferably sodium methoxide or potassium tert-butoxide in alcohols, preferably methanol or tert-butanol.

The use of the enols is reacted with the free amidine base in an inert solvent, preferably toluene.

The process [C] can be carried out at normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure. The amidines of the general formula (VI) are new and therefore a further subject of the invention. They can be prepared by using the compounds of the general formula (VIII)

in which

A, R ² and R ^{3 have} the meaning given above,

with sodium methoxide to give compounds of the general formula (IX)

in which

A, R ² and R ^{3 have} the meaning given above,

implemented in a next step by reaction with NH ₄ C1 and glacial acetic acid in alcohols in the corresponding amidine HCl salt of the general formula (X)

in which A, R ² and R ^{3 have} the meaning given above,

transferred and in a last step mixed with bases, preferably sodium carbonate.

The conversion of the nitrile into the imino ether can be carried out in acid, e.g. with HCl / alcohol mixtures as in basic such as e.g. with methanol sodium methanolate.

The pyrimidine is prepared by customary methods.

Here you can start from the imino ether and e.g. implement with a suitable enamine. However, the imino ether can also first be converted into an amidine using ammonia or its salts, and this can be reacted with enamines either as a free base or as a salt.

Instead of the enamines of formula (VII), other aldehyde equivalents such as e.g. Acetals, aminals, enol ethers, aldehydes or enols can be used.

The enamines can e.g. from C-H-acidic compounds such as acetonitrile derivatives by known methods by reaction with dimethylformamide derivatives such as e.g. Bis (dimethylamino) tert-butoxymethane, dialkoxy-dialkylamino-methanes can be produced.

Alcohols such as methanol or ethanol are suitable as solvents for the reaction of the compounds of the general formulas (IX) -> (X). Methanol is preferred.

The reaction takes place in a temperature range from 0 ° C to 40 ° C, preferably at room temperature. The reaction can be carried out at normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure.

Inorganic or organic bases are suitable as bases for the release of the free amidine bases from the hydrochlorides (X). These include, for example, 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, alkali alcoholates such as potassium tert-butoxide. Sodium carbonate and potassium tert-butoxide are preferred.

The reaction takes place in a temperature range from 0 ° C to 40 ° C, preferably at room temperature.

The compounds of general formula (VII) are new and can be prepared by using the compounds of formula (XI)

with compounds of the formula (XII)

Q ¹ - CH ₂ - CN

(XII)

wherein Q 'represents one of the substituents of R ¹ described above,

implemented at temperatures of 80 to 120 ° C.

The compounds of the general formulas (XI) and (XII) are known and can be prepared by customary methods.

The compounds of general formulas (IX) and (X) are new and can be prepared as described above.

The compounds of the formula (VIII) can be prepared by reacting the corresponding 3-cyanoindazoles with compounds of the general formula (XIII)

Bf,

(XIII)

in which

A has the meaning given above,

in inert solvents, preferably with tetrahydrofuran in the presence of a base, preferably sodium hydride.

The compounds of the general formula (XIII) are known or can be prepared by customary methods.

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

The compounds of the general formula (I) according to the invention lead to vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure as well as an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. In addition, the compounds of the general formula (I) according to the invention enhance the action of substances which increase the cGMP level, such as EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

They can therefore be used in medicines for the treatment of cardiovascular diseases such as, for example, for the treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic disorders and ischemia such as myocardial infarction, stroke, transistoric and Ischemic attacks, peripheral circulatory disorders, prevention of restenoses such as after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneously transluminal coronary angioplasties (PTCA), bypass and for the treatment of arteriosclerosis and diseases of the genitourinary system such as prostate erectile dysfunction, female prostate hypertrophy Dysfunction and incontinence are used.

In addition, the invention comprises the combination of the invention

Compounds of the general formula (I) with organic nitrates and NO donors.

Organic nitrates and NO donors in the context of the invention are generally substances which are therapeutic via the release of NO or NO species

Make an impact. Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.

The invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are in particular

Inhibitors of phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and Reif snyder (1990) TiPS 11 pp. 150 to 155. These inhibitors potentiate the activity of the compound according to the invention and increase the desired pharmacological effect.

The following investigations were carried out to determine the cardiovascular effects: In in vitro investigations on cells of vascular origin, the influence on the guanylate cyclase-dependent cGMP formation was examined with and without NO donor. The anti-aggregatory properties have been demonstrated on human platelets stimulated with collagen. The vasodilatory effect was determined on rabbit aortic rings precontracted with phenylephrine. The hypotensive effects were examined in anesthetized and awake rats.

Stimulation of soluble guanylate cyclase in primary endothelial cells

Primary endothelial cells were removed from pig aortas by treatment with

Collagenase solution isolated. The cells were then cultured in culture medium at 37 ° C./5% CO ₂ until confluence was reached. For the investigations, the cells were passaged, sown in 24-well cell culture plates and subcultivated until they reached confluence (~ 2 × 10 ⁵ cells / well). The culture medium was aspirated to stimulate endothelial guanylate cyclase and the cells were washed once with Ringer's solution. After removing the Ringer's solution, the cells were incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP or DEA NO 1 μM) for 10 minutes at 37 ° C./5% CO ₂ . The test substances (final concentration 1 μM) were then pipetted into the cells and incubated for a further 10 minutes. After the incubation period, the buffer solution was aspirated and 4 ° C stop buffer was added to the cells. The cells were then lysed at -20 ° C for 16 hours. The supernatants containing the intracellular cGMP were then removed and the cGMP concentrations were determined by the cGMP-SPA system (Amersham Buchler, Braunschweig). Vascular relaxant effect in vitro

Rabbits are anesthetized and bled by the blow of the neck. The aorta is removed, adherent tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths at 37 ° C, carbogen gassers

Krebs-Henseleit solution with the following composition (mM): NaCl: 119; KC1: 4.8; CaCl ₂ x 2 H ₂ O: 1; MgSO ₄ x 7 H ₂ O; 1.4; KH ₂ PO ₄ : 1.2; _NaHCO3: 25; Glucose: 10. The contraction force is recorded with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich) and recorded in parallel on a line recorder. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is examined in increasing doses in each subsequent run and the level of the contraction is compared with the level of the contraction reached in the last previous run. From this the concentration is calculated which is required to reduce the level of the control value by 50% (IC ₅₀ ). The standard application volume is 5 μl, the DMSO content in the bath solution corresponds to 0.1%.

The compounds of the examples in this radical IC ₅ o values of <10 uM.

Blood pressure measurements on anesthetized rats

Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg i.p.). After tracheotomy, a catheter for measuring blood pressure is inserted into the femoral artery. The substances to be tested are in

Transcutol, Cremophor EL, H ₂ O (10% / 20% / 70%) administered orally in a volume of 1 ml / kg. Effect on mean blood pressure in conscious, spontaneously hypertensive rats

Continuous blood pressure measurements over 24 hours were carried out on spontaneously hypertonic 200-250 g free-moving female rats (MOL: SPRD). For this purpose, the animals were chronically implanted with pressure transducers (Data Sciences Inc., St. Paul, MN, USA) in the descending abdominal aorta below the renal artery and the associated transmitter was fixed in the abdominal cavity.

The animals were housed individually in Type III cages positioned on the individual recipient stations and were adapted to a 12 hour light / dark rhythm. Water and feed were freely available.

To collect data, the blood pressure of each rat was recorded every 5 minutes for 10 seconds. The measuring points were combined for a period of 15 minutes and the mean value was calculated from these values.

The test compounds were dissolved in a mixture of Transcutol (10%), Cremophor (20%), H ₂ O (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight. The test doses were between 0.3 - 30 mg / kg body weight.

Inhibition of platelet aggregation in vitro

Blood from healthy volunteers of both sexes was used to determine platelet aggregation. 9 parts of blood were added to one part of 3.8% sodium citrate solution as an anticoagulant. The blood was centrifuged at 900 rpm for 20 min. The pH of the platelet-rich plasma obtained was adjusted to pH 6.5 using ACD solution (sodium citrate / citric acid / glucose). The platelets were then centrifuged off and taken up in buffer and centrifuged again. The platelet precipitate was taken up in buffer and 2 mmol / 1 CaCl 2 were additionally added.

For the aggregation measurements, aliquots of the platelet suspension with the test substance were incubated at 37 ° C. for 10 min. The aggregation was then triggered by adding collagen in an aggregometer and determined using the turbidometric method according to Born (Born, GN.R., J. Physiol. (London), 168, 178-195, 1963) at 37 ° C.

The compounds of the general described in the present invention

Formula (I) also represents active substances for combating diseases in the central nervous system which are characterized by disorders of the ΝO / cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory and for treating Alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system such as

Anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, stimulants and addictive substances.

The active ingredients are also suitable for regulating cerebral blood flow and are therefore effective means of combating migraines.

They are also suitable for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and cranial-brain trauma. The compounds of the general

Formula (I) can be used to combat painful conditions.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the compounds of the general formula (I) according to the invention and processes for the preparation of these preparations. The active ingredient can optionally also be in microencapsulated form in one or more of the above-mentioned carriers.

The therapeutically active compounds of the general formula (I) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

In addition to the compounds of the general formula (I) according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight.

Examples of starting compounds

Example 1A 1- (2-fluorobenzyl) -3-cyanindazole

12.0 g (83.9 mmol) of 3-cyanindazole were dissolved under argon in 100 ml of abs. THF dissolved and 20.6 g (109 mmol) of 2-fluorobenzyl bromide added. 2.55 g (100 mmol) of sodium hydride (95%) were added in portions with ice cooling. After stirring overnight at room temperature, the mixture was concentrated to about a quarter of the volume on a rotary evaporator and H ₂ O and ethyl acetate were added. The aqueous phase was extracted again with ethyl acetate. Drying the combined organic phases over MgSO ₄ and distilling off the solvent on a rotary evaporator gave the product.

Yield: 19.5 g (93%)

Rf value: 0.69 (silica gel; cyclohexane / ethyl acetate 1: 1)

Example 2A

1 - (2-fluorobenzyl) indazole-3 amidinium chloride

One from 190 mg (8.26 mmol) and 30 ml abs. Methanol-prepared sodium methoxide solution was added to a solution of 20.0 g (79.9 mmol) of l- (2-fluorobenzyl) -3-cyanoindazole in 200 ml of methanol and the mixture was stirred at 40 ° C. for 22 h. After adding 0.46 ml of acetic acid and 4.30 g of NH 4 Cl, the mixture was stirred at 40 ° C. for a further 24 h and the mixture was then evaporated to dryness on a rotary evaporator. Taking up the residue in acetone and suctioning off the remaining precipitate provided the product in the form of a light beige powder after drying in a high vacuum.

Yield: 20.5 g (84%) m.p .:> 230 ° C

MS-EI: m / z (%) = 268 (31, M ⁺ free base), 251 (15), 109 (100).

General instructions for the preparation of 2-substituted 3-dimethylaminoacrylonitriles

To a solution of 5.95 g (50.0 mmol) of N, N-dimethylformamide dimethylacetal in 25 ml abs. 50.0 mmol of 2-substituted acetonitrile derivative are added to methanol with water cooling and the mixture is stirred at room temperature for 1 h. Sulfones: The precipitate is filtered off and dried in a high vacuum.

Phosphonic acid ester: The solution is first freed from the methanol at 40 ° C. and 20 mbar on a rotary evaporator, then at room temperature in a high vacuum.

Example 3A

Educt product yield mp.

Example 3B

Educt product yield 'H-NMR

4:07 (m, 4H, CH _2), 7.20 (d, 1H, olefin CH). Output connection 4A

1 - (2-fluorobenzyl) -3-iodindazole

20.0 g (82.0 mmol) 3-iodoindazole were in argon in 200 ml abs. THF solved. 2.49 g (97.6 mmol) of sodium hydride (95%) was added and the mixture was stirred at room temperature for 45 min. After adding 18.6 g (98.4 mmol) of 2-fluorobenzyl bromide and stirring overnight at room temperature, the mixture was mixed with ethyl acetate and sat. NaCl solution added. The organic phase was washed with water, dried over MgSO4 and then evaporated to dryness on a rotary evaporator.

Yield: 29.0 g (100%, purity according to GC: 80%)

R _f value: 0.78 (silica gel; cyclohexane / ethyl acetate 1: 1)

Output connection 5A

1 - (2-fluorobenzyl) -3 - (trimethylstannyl) indazole

23.6 g (67.0 mmol) of l- (2-fluorobenzyl) -3-iodindazole, 66.4 g of hexamethyldizm (203 mmol) and 8.00 g of Pd (PPh ₃ ) ₄ were in an argon atmosphere in 680 ml 1.4- Dioxane heated under reflux overnight. The mixture, cooled to room temperature, was extracted with 200 ml of 1M aqueous KF solution and with ethyl acetate. The organic phase was dried over MgSO ₄ and then evaporated to dryness on a rotary evaporator. The purification was carried out in 3 portions by chromatography on silica gel (cyclohexane / ethyl acetate 50: 1).

Yield: 16.6 g (64%, purity of the 3 batches according to GC: 79-94%, remainder:

PPh ₃ ) R _f value: 0.95 (silica gel; cyclohexane / ethyl acetate 1: 1) mp: 71 ° C

Output connection 6A

4-amino-2-chloro yrimidine-5-carboxamide

1.00 g of 2,4-dichloropyrimidine-5-carboxylic acid chloride (4.73 mmol) was dissolved in 10 ml of 1,4-dioxane under argon and ammonia was passed in for 15 minutes at 10 ° C. After two days at room temperature, the precipitate became suction filtered, washed with a little water and dried in a high vacuum.

Yield: 700 mg (86%)

R _r value: 0.06 (silica gel; cyclohexane / ethyl acetate 1: 1)

MS-EI: m / z (%) = 172 (100, Cl, M ⁺ ), 156 (71, Cl), 137 (22), 120 (28), 68 (31). Manufacturing examples

example 1

3 - [4-Amino-5- (2-pyridyl) -2-pyrimidyl] -1 - (2-fluorobenzyl) indazole

Under argon, 350 mg (2.00 mmol) sodium methoxide solution (30%, in methanol) with 5 ml abs. Methanol and 610 mg (2.00 mmol) of l- (2-fluorobenzyl) indazol-3-amidinium chloride were added. After stirring for 5 minutes at room temperature, 346 mg (6.00 mol) of 2- (2-pyridyl) -3-dimethylaminoacrylonitrile were added and the mixture was heated under reflux overnight. After cooling to room temperature, the precipitate was filtered off and stirred in pentane. Sucking off the precipitate again and drying in a high vacuum provided the product in the form of a bright solid.

Yield: 315 mg (40%)

MS-EI: mz (%) - 396 (100, M ⁺ ), 395 (49), 301 (28), 109 (28). Example 2

3- [4-Amino-5-methanesulfonyl-2-pyrimidyl] -1- (2-fluorobenzyl) indazole

304 mg (1.00 mmol) l- (2-fluorobenzyl) indazole-3-amidinium chloride, 174 mg (1.00 mmol) 2-methanesulfonyl-3-dimethylaminoacrylonitrile (can be prepared analogously to Example 3A with 2-methanesulfonylacetonitrile as starting compound), 5 ml of tert-butanol and 123 mg (1.20 mmol) of potassium tert-butoxide were stirred at 80 ° C. overnight. The resulting precipitate was filtered off, with water and

Washed pentane and dried under high vacuum.

Yield: 215 mg (54%)

MS-EI: m / z (%) = 397 (60, M +), 302 (30), 109 (100).

Example 3

3- [4-Amino-5- (2-pyridylsulfonyl) -2-pyrimidyl] -1- (2-fluorobenzyl) indazole

304 mg (1.00 mmol) of l- (2-fluorobenzyl) indazole-3-amidinium chloride, 237 mg (1.00 mmol) of 2- (2-pyridylsulfonyl) -3-dimethylaminoacrylonitrile, 5 ml of tert-butanol and 123 mg (1.20 mmol) potassium tert-butoxide were stirred at 80 ° C. overnight. The resulting precipitate was suction filtered and applied to silica gel. The product was isolated by chromatography on silica gel (cyclohexane / ethyl acetate 20: 1 → 1: 1 → 0: 100).

Yield: 120 mg (26%)

MS-EI: m / z (%) = 460 (18, M ⁺ ), 396 (47), 395 (47), 287 (30), 109 (100).

Example 4

4-Amino-2- [1- (2-fluorobenzyl) indazol-3-yl] pyrimidin-5-phosphonic acid diethyl ester

609 mg (2.00 mmol) l- (2-fluorobenzyl) indazole-3-amidinium chloride, 464 mg (2.00 mmol) 1-cyano-1 - (dimethylamono) methylene-methanephosphonic acid diethyl ester (can be prepared analogously to Example 3b 2- (diethoxyphosphoryl) acetonitrile), 10 ml of tert-butanol and 246 g (2.40 mmol) of potassium tert-butanolate were stirred at 80 ° C. overnight. The mixture was drawn up on silica gel and the product was isolated by chromatography on silica gel (cyclohexane / ethyl acetate 30: 1 → 1: 1).

Yield: 167 mg (18%)

M.p .: 152 ° C

MS-EI: m / z (%) - 445 (100, M ⁺ ), 109 (91).

Example 5

4-Amino-2- [1- (2-fluorobenzyl) indazol-3-yl] pyrimidine-5-phosphonic acid diisopropyl ester

304 mg (1.00 mmol) of l- (2-fluorobenzyl) indazole-3-amidinium chloride, 260 mg (1.00 mmol) of 1-cyano-1 - (dimethylamino) methylene-methanephosphonic acid diisopropyl ester, 5 ml of tert-butanol and 123 mg (1.20 mmol) of potassium tert-butoxide were stirred at 80 ° C. overnight. The mixture was drawn up on silica gel and the product was isolated by chromatography on silica gel (cyclohexane / ethyl acetate 20: 1 - 1: 1).

Yield: 171 mg (35%) mp: 182 ° C

MS-EI: m / z (%) = 483 (44, M ⁺ ), 109 (100). Example 6

4-Amino-2- [1- (2-fluorobenzyl) indazol-3-yl] pyrimidine-5-carboxamide

638 mg (1.64 mmol) l- (2-fluorobenzyl) -3- (trimethylstannyl) indazole 282 mg, (1.64 mmol) 4-amino-2-chloropyrimidine-5-carboxamide and 69.0 mg (0. 10 mmol) of Pd (PPh ₃ ) ₂ Cl ₂ were stirred under argon in 17 ml of DMF at 150 ° C. overnight. The mixture, cooled to room temperature, was mixed with water and extracted with ethyl acetate. The organic phase dried over MgSO _{4 was} coated on silica gel and chromatographed (cyclohexane / ethyl acetate 50: 1 - 1: 1 → 0: 100), a product-containing fraction being isolated at R = 0.06, which was further by preparative HPLC was cleaned.

Yield: 42 mg (7.1%)

R _r value: 0.06 (silica gel; cyclohexane / ethyl acetate 1: 1)

MS-EI: m / z (%) = 362 (100, M ⁺ ), 267 (25), 109 (81).

Claims

1. Heterocyclyl-methyl-substituted pyrazoles of the general formula (I)

in which

R ^{1 stands} for a 6-membered aromatic heterocycle with up to 3 nitrogen atoms, which may be up to 2 times the same or different by hydrogen, formyl, carboxyl, hydroxyl, mercapto, straight-chain or branched acyl, alkoxy, alkylthio or Alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl and / or by a group of the formula

-NR ⁴ R ⁵

is substituted, wherein

R ⁴ and R ^{5 are} identical or different and are hydrogen or straight-chain or branched acyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which may be by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino or by straight-chain or branched alkoxy, acyl or

Alkoxycarbonyl is substituted with up to 5 carbon atoms in each case, or

wherein

R ^{6 is} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms.

and / or is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in turn is substituted by hydroxy,

Amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino each having up to 5 carbon atoms or can be substituted by a radical of the formula -OR ⁷ ,

wherein

R ⁷ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR ⁸ R ⁹ R ¹⁰ ,

wherein

R ⁸ , R ⁹ and R ^{10 are the} same or different and are aryl with 6 to 10 carbon atoms or alkyl with up to 6 carbon atoms, and / or optionally by a radical of the formula

is substituted, wherein

b and b 'are the same or different and represent a number 0, 1, 2 or 3,

10 a represents a number 1, 2 or 3,

R ⁿ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

15 c denotes a number 1 or 2 and

R ¹² and R ^{13 are the} same or different and are hydrogen or straight-chain or branched alkyl with up to 10

Carbon atoms means that if necessary

20 cycloalkyl having 3 to 8 carbon atoms or by

Aryl is substituted with 6 to 10 carbon atoms, which in turn can be substituted by halogen or

25 aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or Cycloalkyl having 3 to 7 carbon atoms

or

wherein

means

where the alkyl, alkenyl, alkynyl, cycloalkoxy and aryl radicals in turn are optionally and, in the case of aryl = phenyl, necessarily substituted by formyl, carboxyl, hydroxyl, mercaptyl, nitro, cyano, azido, halogen, straight-chain, branched or cyclic alkyl, acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl each having up to 6 carbon atoms, by aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, alkyl, alkoxy each having 1 to 6 carbon atoms, by 5- to 6- membered hetaryl, with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which optionally by Halogen, alkyl, alkoxy each having 1 to 6 carbon atoms,

and or

through a group of formula

-NR a ^a τRyb '

10 where

R ^a and R ^{b are the} same or different and are hydrogen or straight-chain or branched acyl having up to 10 carbon atoms, cyclic acyl having 3 to 8 carbon atoms, straight-chain or branched alkyl having up to 10 carbon atoms or cycloalkyl having 3 to 14 carbon atoms , where appropriate by

20 hydroxy, amino, monoalkylamino, dialkylamino or substituted by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 5 carbon atoms,

25 or

R ^a and R together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle, which may be by Hydroxy is substituted and which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^C ,

wherein

R ^c denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

and / or by a group of the formula

-OR ^d

wherein

R ^d denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR ^e R ^f R ^g ,

wherein

and or

(B) is substituted by a 3- to 14-membered heterocyclic ring, which may be saturated or unsaturated, and 1 to 4 Contains heteroatoms from the series N, O, S, SO, SO ₂ and optionally through

in which

R ^h and R ^{1 may be the} same or different and denote hydrogen, straight-chain, branched or cyclic alkyl or acyl having up to 6 carbon atoms

or

wherein

and or

(C) is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is imperative by one or more of the following groups Formyl, mercaptyl, nitro, cyano, cyclic acyl with 3 to 14 carbon atoms, straight-chain or branched acyl with 6 to 14 carbon atoms, alkoxy with 6 to 14 carbon atoms, acylamino with 6 to 14 carbon atoms, 5 alkoxycarbonyl with 6 to 14 carbon atoms, alkylthio with up to 14 carbon atoms, cyclic alkyl with 3 to 14 carbon atoms, phenyl, which may be by

Halogen, alkyl with up to 6 carbon atoms or

10 alkoxy is substituted with up to 6 carbon atoms;

5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which is optionally substituted by halogen, alkyl having up to 6 carbon atoms or alkoxy having up to 6 carbon atoms;

15 -NR ^k R ', where one of the radicals R ^k and R' can be hydrogen and the other or both independently of one another are straight-chain or branched acyl having up to 10 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms or R ^k and R ¹ together with the nitrogen atom

20 a 3- to 7-membered saturated or partially unsaturated

Form heterocycle, which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^m ,

25 where

30 is substituted; and or

by hydroxy, -NR ⁿ R °, where R ⁿ and R ° may be the same or different hydrogen or straight-chain, branched or cyclic alkyl or acyl each having up to 6 carbon atoms or R ⁿ and R ° together with the nitrogen atom are a 3 to Form 7-membered saturated or partially unsaturated heterocycle, which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^P ,

wherein

and or

(E) by halogen-substituted acyl having up to 14 carbon atoms, acyloxy having up to 14 carbon atoms, arylthio having 6 to 10 carbon atoms, the aryl radical optionally being halogen, alkyl, alkoxyl each having 1 to 6

Carbon atoms is substituted; Heteroarylthio, with 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which is optionally substituted by halogen, straight-chain or branched alkyl or alkoxy having 1 to 6 carbon atoms , and or

(F) by a residue of the formula

-SO ₂ R ^q or -SOR ^{r is} substituted,

in which

R ^q and R ^r straight-chain or branched alkyl having 1 to 10 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms,

Aryl with 6 to 10 carbon atoms, which is optionally substituted by halogen, alkyl with 1 to 6 carbon atoms or alkoxy with 1 to 6 carbon atoms, or 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which if necessary by

Halogen, straight-chain or branched alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4

Carbon atoms is substituted

and or

(G) is substituted by a radical -SO ₃ H

and or

(H) is substituted by a radical -CON = C (NH ₂ ) ₂ or -C = NH (NH ₂ ) and or

(I) is substituted by a radical -CONR ^s R '

in which

R ^s and R 'may be the same or different and denote hydrogen, straight-chain or branched alkyl having 1 to 14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms,

said alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino, straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 6 carbon atoms,

Aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms, alkoxy having 1 to 6 carbon atoms,

or 5- to 6-membered heterocyclyl having 1 to 3 heteroatoms from the series N, O, S, SO, SO ₂ , which may be halogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms, alkoxy is substituted with 1 to 6 carbon atoms,

are substituted, and or

R ^s and R * mean aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms, alkoxy having 1 to 6 carbon atoms, and / or

10

R ^s and R * 3- to 10-membered saturated, partially unsaturated or completely unsaturated heterocyclyl with 1 to 5 heteroatoms from the series N, O, S; SO, SO ₂ , which may be halogen, 15 straight-chain or branched alkyl having 1 to 6

Carbon atoms, cycloalkyl with 3 to 14 carbon atoms, alkoxy with 1 to 6 carbon atoms,

20 and / or

R ^s and R 'together with the nitrogen atom are a 3- to 7-membered saturated or partially unsaturated

Form heterocycle, which may be an additional one

25 oxygen or sulfur atom or a residue of

Contains formula -NR ^U ,

in which R ^{u is} hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms,

and or

(J) is substituted by a radical of the formula -NR,

in which

R ^v and R ^{w can be the} same or different and straight-chain or branched acyl with 7 to 14 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, -SO ₂ alkyl with 1 to 4 carbon atoms, hydroxymethyl, hydroxyethyl, alkoxycarbonyl with up to 5 carbon atoms, alkoxyalkyl with a total of up to 8 carbon atoms, acyloxymethyl with up to 6 carbon atoms in the acyl radical (preferably pivaloyloxymethyl or the following radicals

R ^x -O-CH (Ry) -O-CO-

mean,

woπn

R ^x and R are identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

m represents a number 0, 1 or 2 and

R ^z denotes straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

or one of the radicals R ^v and R ^{w can} optionally be hydrogen,

and or (K) is substituted by a radical of the formula -PO (OR) (OR ')

in which

R ² and R ³ , including the double bond, form a phenyl ring which may be up to 3 times the same or different through formyl, mercaptyl, carboxyl, hydroxy, amino, straight-chain or branched acyl, alkylthio, alkoxy, alkoxycarbonyl, each having up to 6 carbon atoms , Nitro, cyano, azido,

Halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms are substituted, which in turn can be substituted by hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, or optionally by a group of the formula -S (O) _c .NR ¹² R ^{13 are} substituted, in which c ', R ¹² and R ^{13' have} the meaning of c, R ¹² and R ¹³ given above and are identical or different with this,

A for phenyl or a 5- to 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms from the

Row S, N and / or O is optionally up to 3 times the same or different by mercaptyl, hydroxy, formyl, carboxyl, straight-chain or branched acyl, alkylthio,

Alkyloxyacyl, alkoxy or alkoxycarbonyl, each with up to

6 carbon atoms, nitro, cyano, trifluoromethyl, azido, Halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms is substituted, which in turn can be substituted by hydroxy, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each having up to 5 carbon atoms,

and / or is substituted by a group of the formula - (CO) _d -NR ^{, 5} R ¹⁶ ,

wherein

d represents a number 0 or 1,

their isomeric forms and salts and their N-oxides.

Compounds according to claim 1 of the general formula (I), in which

R ¹ for a radical of the formula

or stands

optionally up to 2 times the same or different by hydrogen, formyl, carboxyl, hydroxy, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each with up to 5 Carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl and / or are substituted by a group of the formula -NR ⁴ R ⁵ ,

wherein

R ⁴ and R ^{5 are} identical or different and are hydrogen or straight-chain or branched acyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which may be by hydroxyl, amino or by straight-chain or branched

Alkoxy is substituted with up to 3 carbon atoms, or

R ⁴ and R ⁵ together with the nitrogen atom represent a morpholine ring or a radical of the formula

-N _{\ /} N-CH 3- form

and / or by straight-chain or branched alkyl with up to 5

Are substituted carbon atoms, which in turn are replaced by hydroxy, amino, fluorine, carboxyl, straight-chain or branched acyl,

Alkoxy, alkoxycarbonyl or acylamino each having up to 4 carbon atoms or can be substituted by a radical of the formula -OR ⁷ ,

wherein

R ⁷ denotes straight-chain or branched acyl having up to 4 carbon atoms, and / or optionally by a radical of the formula

ooddeerr

are substituted, wherein

b and b 'are the same or different and represent a number 0, 1, 2 or 3,

a is a number 1,

2 or 3 means

R "is hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

and the 6-membered aromatic listed above under R ¹

Heterocycles 1 to 3 times the same or different

(A) straight-chain or branched alkyl having 7 to 14 carbon atoms, straight-chain or branched alkenyl having up to 14 carbon atoms with a double bond, straight-chain or branched alkynyl having up to 14 carbon atoms and a triple bond,

Cycloalkyloxy with 3 to 8 carbon atoms, or substituted phenyl are substituted,

the alkyl, alkenyl, alkynyl and cycloalkyloxy radicals mentioned in turn optionally and the phenyl radical

5 are necessarily substituted by carboxyl, hydroxy,

Mercaptyl, nitro, cyano, azido, fluorine, chlorine, bromine, straight-chain, branched or cyclic alkyl, acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl, each with up to 6 carbon atoms,

10 by aryl with 6 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, alkyl, alkoxy each having 1 to 6 carbon atoms, by 5- to 6-membered hetaryl, with 1 to 3 heteroatoms from the series N, O , S, which may be replaced by fluorine, chlorine,

15 bromine, alkyl, alkoxy, each having 1 to 6 carbon atoms, is substituted,

and or

20 by a group of the formula

-NR ^a R ^b

wherein

25

R ^a and R ^{b are the} same or different and are hydrogen or straight-chain or branched acyl having up to 6 carbon atoms, cyclic acyl having 3 to 6 carbon atoms, straight-chain or branched alkyl 30 having up to 6 carbon atoms or cycloalkyl having 3 means up to 8 carbon atoms, where appropriate by

or

10

R ^a and R ^b together with the nitrogen atom form a 3- to 7-membered saturated heterocycle,

woπn

20 R ^c hydrogen or straight-chain or branched

Means alkyl with up to 3 carbon atoms,

and / or by a group of the formula

25 -OR ^d

wherein

R ^d denotes straight-chain or branched acyl having up to 4 carbon atoms, and or

in which

or

R ^h and R together with the nitrogen atom form a 3- to 7-membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^j ,

wherein

Mercaptyl, nitro, cyano, cyclic acyl with 3 to 8 carbon atoms, straight-chain or branched acyl with 6 to 10 carbon atoms, alkoxy with 6 to 10 carbon atoms, acylamino with 6 to 10 carbon atoms, alkoxycarbonyl with 6 to 10 carbon atoms, alkylthio with up to 10 Carbon atoms, cyclic alkyl having 3 to 8 carbon atoms, phenyl, which may be by

Fluorine, chlorine, bromine, alkyl with up to 6 carbon atoms or alkoxy with up to 6 carbon atoms;

5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, bromine, alkyl having up to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; -NR ^k R ', where one of the radicals R ^k and R ¹ can be hydrogen and the other or both independently represent straight-chain or branched acyl having up to 6 carbon atoms, cyclic alkyl having 3 to 8 carbon atoms or R ^k and R ¹ together form a 3- to 7-membered saturated heterocycle with the nitrogen atom, which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^m ,

wherein R ^m denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

is substituted,

and or

Hydroxy, -NR ⁿ R °, where R "and R ° may be the same or different hydrogen or straight-chain, branched or cyclic alkyl or acyl each having up to 5 carbon atoms or R ⁿ and R ° together with the nitrogen atom are a 3- to 7th form a membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^P ,

woπn

and or

(E) by halogen-substituted acyl having up to 10 carbon atoms, acyloxy having up to 10 carbon atoms, arylthio having 6 to 10 carbon atoms, the aryl radical optionally being substituted by fluorine, chlorine, bromine, alkyl, alkoxyl each having 1 to 6 carbon atoms, hetero - arylthio, with 5- to 6-membered hetaryl with 1 to 3 hetero- atoms from the series N, O or S, which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl or alkoxy having 1 to 6 carbon atoms,

are substituted and / or

(F) by a residue of the formula

-SO ₂ R ^q or -SOR ^{r are} substituted,

in which

Aryl with 6 to 10 carbon atoms, which may be fluorine, chlorine, bromine, alkyl with 1 to 6 carbon atoms or alkoxy with 1 to 6

Carbon atoms is substituted, or 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which optionally by

Fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms is substituted

and or

(G) are substituted by a radical -SO ₃ H and or

(I) are substituted by a radical -CONR ^s R '

in which

R ^s and R may be the same or different and denote hydrogen, straight-chain or branched alkyl having 1 to 10 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,

said alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxy, amino, straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 5 carbon atoms,

Aryl having 6 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 5 carbon atoms,

Cycloalkyl with 3 to 8 carbon atoms, alkoxy with 1 to 6 carbon atoms;

are substituted, and or

R ^s and R ^{l are} aryl having 6 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,

10 and / or

R ^s and R * 3- to 8-membered saturated heterocyclyl with 1 to

3 mean heteroatoms from the series N, O, S;

15 which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,

20 and / or

R ^s and R together with the nitrogen atom form a 3- to 7-membered saturated heterocycle which

25 additionally contains an oxygen or sulfur atom or a radical of the formula -NR ^U ,

in which

30 R ^{u is} hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms, (J) are substituted by a radical of the formula -NR ^V R ^W

in which

R ^v and R ^{w can be the} same or different and straight-chain or branched acyl with 7 to 10 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, -SO ₂ alkyl with 1 to 4 carbons

10 atoms of matter, hydroxymethyl, hydroxyethyl, alkoxycarbonyl with up to 5 carbon atoms, alkoxyalkyl with a total of up to 8 carbon atoms, acyloxymethyl with up to 6 carbon atoms in the acyl radical (preferably pivaloyloxymethyl) or the following radicals

15

R ^x -O-CH (Ry) -O-CO-

mean,

wherein

R ^x and Ry are the same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms

10 m denotes a number 0, 1 or 2 and

15 or one of the radicals R ^v and R ^{w can} optionally be hydrogen, (K) are substituted by a radical of the formula -PO (OR) (OR ')

in which

R and R 'are the same or different straight-chain, branched or cyclic alkyl having up to 6 carbon atoms or aryl having 6 to 10 carbon atoms or benzyl,

R ² and R ³ , including the double bond, form a phenyl ring which may be up to 3 times the same or different by 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 are substituted, which in turn can be substituted by hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms ,

A for phenyl or for tetrahydropyranyl, furyl, tetrahydrofuryl,

Morpholinyl, pyrimidyl, piperazinyl or pyridyl, which is optionally up to 2 times the same or different by hydroxy, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, 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 can be substituted by hydroxy, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, and / or are substituted by a group of the formula - (CO) _d -NR ¹⁵ R ¹⁶ ,

wherein

d represents a number 0 or 1,

R ¹⁵ and R ^{16 are} identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,

their isomeric forms and salts and their N-oxides.

Compounds according to claim 1 of the general formula (I), in which

R for a residue of the formula

where the listed 6-membered aromatic heterocycles R ¹ , optionally up to 2 times the same or different by hydrogen, formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, methylamino, amino, fluorine, chlorine, bromine, Cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms are substituted, which in turn is substituted by hydroxy, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl, Acylamino can each be substituted with up to 3 carbon atoms,

and or optionally by a radical of the formula

,

are substituted,

and the 6-membered aromatic heterocycles listed above under R ¹ 1- to 3-fold, identically or differently

Cycloalkyloxy with 3 to 6 carbon atoms, substituted phenyl are substituted, the alkyl, alkenyl, alkynyl and cycloalkyloxy radicals mentioned in turn optionally being substituted and the phenyl radical being substituted by carboxyl, hydroxy, cyano, fluorine, chlorine, straight-chain, branched or cyclic alkyl, Acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl, each having up to 3 carbon atoms, by phenyl, which is optionally substituted by fluorine, chlorine, alkyl, alkoxy each having 1 to 4 carbon atoms, by 5- to 6-membered hetaryl, with 1 up to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, alkyl, alkoxy each having 1 to 4 carbon atoms,

10 and / or

through a group of formula

15 -NR ^a aRr> b '

wherein

R ^a and R ^{b are the} same or different and is hydrogen or 20 straight-chain or branched acyl having up to 4 carbon atoms, cyclic acyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, where this if necessary through

Hydroxy, amino, monoalkylamino, dialkylamino or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl, each having up to 5 carbon atoms, or

R ^a and R ^b together with the nitrogen atom form a heterocycle of the formula

-N O

-N NH

or

-N NCH-

Form \ _ / ³

and / or by a group of the formula

-OR ^d

woπn

R ^d straight-chain or branched acyl with up to 3 carbon atoms

and or

(B) are substituted by a 5- to 6-membered heterocyclic ring, which may be saturated or unsaturated, and 1 to Contains 4 heteroatoms from the series N, O, S and optionally through

Fluorine, chlorine, phenyl, cyano, alkyl, alkoxy each having 1 to 4 carbon atoms, -NR ^h R,

in which

R ^h and R can be the same or different and hydrogen, straight-chain, branched or cyclic

Alkyl or acyl with up to 3 carbon atoms

or

R ^h and R together with the nitrogen atom represent a radical of the formula

-N O

or

form

Cyano, cyclic acyl with 3 to 6 carbon atoms, alkylthio with up to 6 carbon atoms, cyclic alkyl with 3 to 14 carbon atoms, phenyl, which may be by

Fluorine, chlorine, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms; 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms,

-N O

-N NH

or

form and or

Hydroxy, -NR ⁿ R °, where R ⁿ and R ° are the same or different

Hydrogen or straight chain, branched or cyclic

Alkyl or acyl, each having up to 4 carbon atoms, or R ⁿ and R ° together with the nitrogen atom are a heterocycle of the formula

-N

or

form

and or

(E) by halogen-substituted acyl having up to 6 carbon atoms, acyloxy having up to 6 carbon atoms or phenylthio, the phenyl radical optionally being fluorine, chlorine,

Alkyl, alkoxy each having 1 to 4 carbon atoms; Heteroarylthio with 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which may be fluorine, chlorine, straight-chain or branched alkyl or Alkoxy is substituted with 1 to 4 carbon atoms; are substituted,

and or

(F) by a residue of the formula

-SO ₂ R ^q or -SOR ^{r are} substituted

in which

R ^q and R ^r straight-chain or branched alkyl having 1 to 3 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms,

and or

(G) are substituted by a radical -SO ₃ H

and or

(I) are substituted by a -CONR ^s R radical, in which

R ^s and R can be the same or different and hydrogen, straight-chain or branched alkyl with 1 to

6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

the said alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxy, amino, straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms,

15 phenyl, which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms;

20 or by 5- to 6-membered heterocyclyl having 1 to 3 heteroatoms from the series N, O, S, which may be substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cyclo-

25 alkyl with 3 to 6 carbon atoms, alkoxy with 1 to

4 carbon atoms is substituted,

are substituted,

30 and / or R ^s and R * are phenyl, which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms 5,

and or

R ^s and R * are 3- to 6-membered saturated heterocyclyl having 1 to 10 3 heteroatoms from the series N, O, S; which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms,

15 and / or

R ^s and R 'together with the nitrogen atom form a group of the formula

-N NH

or

form

and or (J) are substituted by a radical of the formula -NRH "

in which

R ^v and R ^{w can be the} same or different and hydroxymethyl, hydroxyethyl, SO ₂ alkyl with 1 to 4 carbon atoms, alkoxycarbonyl with up to 5 carbon atoms, alkoxyalkyl with a total of up to 8 carbon atoms, acyloxymethyl with up to 6 carbon atoms in the acyl radical (preferred Pivaloyloxy-methyl) or the following radicals

R ^x -O-CH (Ry) -O-CO-,

mean,

in which

R ^z for straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl, cyclohexyl or aryl and

m represents a number 0, 1 or 2 and

or one of the radicals R ^v and R ^{w can} optionally be hydrogen,

and or

(K) are substituted by a radical of the formula -PO (OR) (OR ')

in which R and R 'are the same or different straight-chain, branched or cyclic alkyl having up to 4 carbon atoms or phenyl or benzyl,

R ² and R ³ , including the double bond, form a phenyl ring which may be up to 2 times identical or different by formyl, carboxyl, hydroxy, amino, straight-chain or 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 are substituted, which in turn can be substituted by hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,

A for phenyl or for tetrahydropyranyl, tetrahydrofuryl, furyl or

Pyridyl stands, optionally up to 2 times the same or different by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl, each with up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in turn can be substituted by hydroxy, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,

wherein

a number means 0 or 1, R ¹⁵ and R ^{16 are} identical or different and are hydrogen or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,

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

4. Compounds according to claim 1 of the general formula (I), in which

R ¹ for a radical of the formula

where the pyrimidyl radical listed above may be up to 2 times identical or different by methyl, ethyl, isopropyl, fluorine, amino, cyano, methoxy, chlorine, hydroxymethyl or by a radical of

formula

- N O or -N S

is substituted,

and the pyrimidyl radical R ¹ listed above is 1 to 3 times identical or different by a radical of the formula -SO CH ₃ or by a radical of the formula -PO (OH) ₂ , -PO (OMe) ₂ , -PO (OEt) ₂ or -PO (O ⁱ Pr) _{2 is} substituted, R ² and R ^{3 together} with the double bond form a phenyl ring and

A represents phenyl which is optionally substituted by fluorine or cyano

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

5. A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that

[A] compounds of the general formula (II)

in which

R ¹ , R ² and R ^{3 have} the meaning given above,

with compounds of the general formula (III)

D-CH ₂ -A (III)

in which

has the meaning given above,

and D represents triflate or halogen, preferably chlorine or bromine,

in inert solvents, if appropriate in the presence of a base,

or

[B] Compounds of the general formula (IV)

in which

A, R ² and R ^{3 have} the meaning given above,

and

L represents a radical of the formula -SnR R ¹⁸ R ¹⁹ , ZnR ²⁰ , iodine or triflate,

wherein

R ¹⁷ , R ¹⁸ and R ^{19 are} identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms, and

R ^{20 represents} halogen,

with compounds of the general formula (V)

R'-T (V)

in which

R ^{1 has} the meaning given above,

and

in the case L = SnR ^{, 7} R ¹⁸ R ¹⁹ or ZnR ²⁰

T for triflate or for halogen, preferably for chlorine or

Bromine stands,

and

in the case L = iodine or triflate

T represents a radical of the formula SnR ¹⁷ R ^{18 '} R ^19' , ZnR ^{20 '} or BR ²¹ R ²² ,

wherein R ^{17 '} , R ^18' , R ^{19 '} and R ^{20' have} the meaning given above for R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ and are the same or different with this,

R ²¹ and R ^{22 are the} same or different and are hydroxyl, aryloxy with 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy each with up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,

implemented in a palladium-catalyzed reaction in inert solvents,

[C] amidines of the general formula (VI)

in which

A, R ² and R ^{3 have} the meaning given above,

with enamines of the general formula (VII)

in which

R ^{1 represents} one of the above-mentioned substituents of the 6-membered aromatic heterocycle R ¹

and

represents a suitable leaving group such as dimethylamino or hydroxyl,

implements

and optionally the substituents listed under R ¹ , R ² , R ³ and / or A by conventional methods, preferably by reduction, oxidation, removal of protective groups and / or by nucleophilic

Substitution varies or introduces.

6. Medicament containing at least one compound of general formula (I) according to claim 1.

7. Medicament preparations containing a combination of at least one compound of the general formula (I) according to Claim 1 and at least one organic nitrate or an NO donor.

8. Medicinal preparations containing a combination of at least one

A compound of general formula (I) according to claim 1 and compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP).

9. Use of compounds of general formula (I) according to claim

1 for the manufacture of pharmaceuticals.

10. Use according to claim 9 for the manufacture of medicaments for the treatment of cardiovascular diseases.

11. Use according to one of claims 9 or 10 in the manufacture of medicaments for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and traumatic brain injury.