CZ2001333A3 - Substituted pyrazole derivatives, process of their preparation, medicaments in which they are comprised and their use - Google Patents

Abstract

The present invention relates to substituted pyrazole derivatives, condensed with six-membered heterocyclic rings of the formula I in which the substituents have the meanings as disclosed in the specification, the method for their manufacture, and the pharmaceuticals substances containing and using them, in particular as pharmaceuticals for treatment of cardiovascular diseases, hypertonia, thromboembolic diseases, ischemia and sexual dysfunction.

Description

Substituted pyrazole derivatives, process for their preparation, medicaments containing them and their use

Technical field

The invention relates to substituted pyrazole derivatives fused with six-membered heterocyclic rings, to a process for their preparation, to medicaments containing them and to their use, in particular as medicaments for the treatment of cardiovascular diseases.

BACKGROUND OF THE INVENTION

It is known that 1-benzyl-3- (substituted heteroaryl) -condensed pyrazole derivatives inhibit thrombocyte aggregation (see EP 667 345 A1).

WO 98/16233 discloses the use of 1-benzyl-3- (substituted heteroaryl) -condensated pyrazole derivatives for the treatment of special diseases of the cardiovascular and central nervous systems.

WO 98/16507 discloses heterocyclylmethyl-substituted pyrazole derivatives and their use in the treatment of cardiovascular diseases.

WO 98/23619 also discloses substituted pyrazole derivatives for the treatment of cardiovascular diseases.

SUMMARY OF THE INVENTION

The present invention provides substituted pyrazole derivatives of formula (I)

in which

R ¹ represents a saturated or aromatic 5- or 6-membered heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, which may be bonded via a nitrogen atom and which is optionally up to two times the same or differently substituted by a radical from group (i) hydrogen, amino, azido, formyl, mercaptyl, carboxyl, hydroxy, straight or branched acyl, alkoxy, alkylthio or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight or branched or straight or branched alkyl of up to 6 carbon atoms, which itself may be substituted by hydroxy, amino, azido, carboxyl, straight or branched

an acyl, alkoxy, alkoxycarbonyl or acylamino group each having up to 5 carbon atoms or a radical of the formula -OR 4, where r 4 denotes a straight or branched acyl group having up to 5 carbon atoms, and / or is substituted by a radical of the formula

OR denotes o-CH ₂ O (CH ₂ ) _b -y I.

OCH ₂ (CH ₂ ) _and O (CH ₂ ) _b 'or -S (O) -Nr 5 r 7, wherein a, bab' are the same or are 0, 1, 2 or 3,

R @ 1 denotes a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, c denotes the number 1 or 2, and

R 6 and R 6 are the same or different and denote a hydrogen atom or a straight or branched alkyl group of up to 10 carbon atoms which is optionally substituted by a cycloalkyl group of 3 to 8 carbon atoms or an aryl group of 6 to 10 carbon atoms be substituted with a halogen atom,

or denotes an aryl group having 6 to 10 carbon atoms optionally substituted by a halogen atom, or denotes a cycloalkyl group having 3 to carbon atoms, or

R and R together with the nitrogen atom form a 5- to 7-membered saturated heterocycle, which may optionally contain an additional oxygen atom or a radical of formula

Q

-NR, wherein

O

R 0 represents a hydrogen atom, a straight or branched alkyl group having up to 4 carbon atoms or a radical of formula

a benzyl or phenyl group, wherein the ring systems are optionally substituted with halogen, and at least one radical of group (ii), comprising a 3- to 8-membered ring which may be saturated, unsaturated or partially unsaturated, contains 1 to 4 heteroatoms from the group consisting of N, O , S, SO, and SO2 and may also be bonded through nitrogen, with imidazolyl, imidazolinyl, imidazolidinyl, morpholine, piperidine, piperazine, pyrrolidine, triazolyl, pyrrole, thiomorpholine, S-oxothiomorpholine and S, S-dioxothiomorpholine morpholine optionally substituted one or more times by a 5- or 6-membered ring containing two oxygen atoms as ring members and forming a bicyclic unit or a di-unit with a 3- to 8-membered ring and / or a hydroxy, cyano, straight or branched alkyl, acyl or alkoxycarbones The alkyl, acyl and alkoxycarbonyl groups may be substituted by hydroxy, amino, halogen, carboxy or a straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino group of up to 5 carbon atoms each and an aryl ring of up to 5 carbon atoms. 6 to 10 carbon atoms, which is substituted by a straight or branched alkyl group of up to 4 carbon atoms, and an alkenyl group of 2 to 10 carbon atoms, an alkynyl group of 2 to 10 carbon atoms, an alkyl group of 7 to 20 carbon atoms. optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxy, straight or branched acyl, alkoxy, alkoxy or alkoxycarbones Or 5 OR ⁴ , wherein

R ⁴ denotes a straight or branched acyl group of up to 5 carbon atoms, and an alkyl group of 1 to 6 carbon atoms which is substituted one to three times with an aryl, heteroaryl, halogen, cyano, dialkylamino, alkylamino or cycloalkyl group, and acyl a group which is substituted by a halogen atom, in particular a fluorine atom, an acyloxy group, an arylthio group or a heteroarylthio group, and a group -NO or radicals of the formulas SO4H or -SCOjR4, where d denotes 1 or 2 and denotes a straight or branched up to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms or a saturated or unsaturated 5- to 6-membered heterocycle with up to 3 heteroatoms for sulfur, nitrogen and / or oxygen groups, wherein the ring systems may be optionally substituted with halogen or straight or a branched alkyl or alkoxy group in each case having up to 4 carbon atoms, and a radical of formula ΡΟ (ΟΚ ^ θ) (OR ^^), whereby

R ¹⁰ and R ¹¹ are the same or different and denote a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms or a benzyl group, and an oxycycloalkyl group 3 to 8 ring members or radicals of the formulas -CON = C (NH ₂ ) ₂ , -C = NH (NH ₂ ), -NH-C (= NH) NH ₂ or (CO) _e NR ¹² R ¹³ , where e represents 0 or 1 a

R and R are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 14 carbon atoms, a cycloalkyl group of 3 to 14 carbon atoms, an aryl group of 6 to 10 carbon atoms or a saturated or unsaturated three to ten membered ring 5 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, said radicals may be substituted by an aryl group of 6 to 10 carbon atoms, a heterocyclyl group, a cycloalkyl group of 3 to 7 carbon atoms, a hydroxy group, an amino group or a straight or branched alkoxy, acyl or alkoxycarbonyl a group of up to 6 carbon atoms, in each case where e = 1,

R ²² _and may also, with the inclusion of the nitrogen atom to which they are attached, form a 5- or 6-membered ring with up to 3 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, which may optionally be up to three times substituted by hydroxy or alkyl or alkoxy; carbon atoms, and if e = 0,

-ι o -ι α, _v

R @ 1 and R @ ² may also be a straight, branched or cyclic acyl group of up to 14 carbon atoms, a hydroxyalkyl, a straight or branched alkoxycarbonyl or alkoxyalkyl group of up to 6 carbon atoms or a radical -SC2R2; branched alkyl having up to 4 carbon atoms, ¹³ and / or R ^12, and R is also radicals of the formulas

wherein _and R 6 _and R 18 _and £ R31 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, g is 0, 1 or 2 and

R represents a phenyl group, a straight or branched alkyl group having up to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, with the proviso that when e = 0, not 19, R and R simultaneously represent a hydrogen atom, or

R1 denotes a purine radical which may optionally be up to three times substituted by halogen, azido, cyano, hydroxy, amino, alkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms, alkyl of up to 5 carbon atoms and / or alkoxy of up to 5 carbon atoms,

3

R a comprises a six membered saturated or aromatic heterocycle with up to 3 heteroatoms selected from the group consisting of nitrogen, sulfur and / or oxygen, which may optionally be up to three times the same or differently substituted with a formyl, carboxy group, including a double bond 444 44 444 hydroxy, mercaptyl, straight or branched chain acyl, alkylthio or alkoxycarbonyl group each having up to 6 carbon atoms, nitro, cyano, halogen or straight or branched alkyl or alkoxy group each having up to 6 carbon atoms substituted with hydroxy, amino, carboxy, straight or branched chain acyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms each, and / or optionally substituted by the formula -NR ³³ R ³³ , α α α

R and R are the same or different and denote a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms, or

2

R denotes a hydrogen atom and α α

R represents an acyl group, and / or may be optionally substituted by a phenyl group, which may itself be substituted up to twice equally or differently with a halogen atom or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms, and / or is optionally substituted with N = CH-NR ³⁴ R ³⁵ , wherein

R ³⁴ and R ³³ are the same or different and denote a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 6 carbon atoms, and

A denotes a 5- or 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen or phenyl optionally substituted up to three times equally or differently with amino, mercaptyl, hydroxy, formyl, carboxy, straight or branched acyl, alkylthio, alkyloxyacyl, alkoxyacyl, alkoxyacyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight or branched alkyl having up to 6 carbon atoms it may itself be substituted by hydroxy, carboxy, straight or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and / or substituted by a group of the formula - (CO), where h denotes 0 or 1 and

-2 from -i * 7

R ^J and R ^{JD /} are identical or different and denote hydrogen cable set, frenylovou, benzyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms and their isomeric forms and salts.

Preferred according to the present invention are substituted pyrazole derivatives of the general formula I in which:

R1 denotes a saturated or aromatic five-membered six-membered heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen which may be bonded via a nitrogen atom and which is optionally up to two times the same or differently substituted by a radical from group (i) , amino, azido, formyl, mercaptyl, carboxyl, hydroxy, straight or branched acyl, alkoxy, alkylthio or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight or branched chain having up to 6 carbon atoms, which itself can be substituted by hydroxy, amino, azido, carboxyl, straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino, each having up to 5 carbon atoms or a radical of the formula -OR 4, wherein

R 6 represents a straight or branched acyl group of up to 5 carbon atoms, and / or is substituted by a radical of the formula

Ο ·

CH,

O (CH

2'b and _7- (CH ₂ )

2'ao (chj; ^-N - ^{R 5} wherein a, bab 'are the same or different and denotes 0, 1, 2 or 3 and denotes a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, and at least one radical of group (ii), comprising a 3- to 8-membered ring which may be saturated, unsaturated or partially unsaturated, contains 1 to 4 heteroatoms from the group consisting of N, O, S, SO and SO ₂ and may also be bonded via nitrogen, in particular Preferred is imidazolyl, imidazolinyl, imidazolidinyl, morpholine, piperidine, piperazine, pyrrolidine, triazolyl, pyrrole, thiomorpholine, S-oxothiomorpholine and S, S-dioxothiomorpholine ring, and which is optionally one or more times substituted with a five-membered or six-membered atom, as ring members and with a three to eight membered ring form a bicyclic unit or spiro unit, and / or h 15-hydroxy, cyano, straight- or di-hydroxy;

a branched alkyl, acyl or alkoxycarbonyl group of up to 6 carbon atoms each, the alkyl, acyl and alkoxycarbonyl group being substituted by a hydroxy, amino, halogen, carboxy or straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino group in each case , and an aryl ring of 6 to 10 carbon atoms which is substituted by a straight or branched alkyl group of up to 4 carbon atoms and an alkenyl group of 2 to 10 carbon atoms, an alkynyl group of 2 to 10 carbon atoms, an alkyl group of 7 to 20 carbon atoms carbon atoms optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxy, straight or branched acyl, alkoxy, alkoxycarboxy a bonyl or acylamino group each having up to 5 carbon atoms or an OR4 radical, wherein

R ^ denotes a straight or branched acyl group of up to 5 carbon atoms, and an alkyl group of 1 to 6 carbon atoms which is substituted one to three times with an aryl, heteroaryl, halogen, cyano, dialkylamino, alkylamino or cycloalkyl group, and acyl a group which is substituted by a halogen atom, in particular a fluorine atom, an acyloxy group, an arylthio group or a heteroarylthio group, and a group -NO or radicals of the formulas SO4H or wherein d is 1 or 2 and

R ^ denotes a straight or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a saturated or unsaturated 5- to 6-membered heterocycle having up to 3 heteroatoms for sulfur, nitrogen and / or oxygen, wherein the ring systems may be optionally substituted by halogen or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms each, and the remainder of the formula PO (OR 4 ®) (OR ^{4 4} ), wherein

R ^ -θ R and R ⁴⁴ jsou are the same or different and denote a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms or a benzyl group, and oxycycloalkyl a group having from 3 to 8 ring members or radicals of the formulas -CON = C (NH 2) 2, -C = NH (NH ₂ ), -NH-C (= NH) NH ₂ or (CO) _e NR ¹² R ¹³ , wherein e denotes 0 or 1 and

-i o 13

R and R are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 14 carbon atoms, a cycloalkyl group of 3 to 14 carbon atoms, an aryl group of 6 to 10 carbon atoms or a saturated or unsaturated three to ten membered ring 5 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, said radicals being optionally substituted by an aryl group of 6 to 10 carbon atoms, a heterocyclyl group, a cycloalkyl group of 3 to 7 carbon atoms, a hydroxy group, an amino group or a straight or branched alkoxy, acyl or alkoxycarbonyl having up to 6 carbon atoms, in each case if e = 1, 7

R and R may also, with the inclusion of the nitrogen atom to which they are attached, form a 5- or 6-membered ring with up to 3 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, which may optionally be up to three times substituted by hydroxy or alkyl or alkoxy in each case up to 8 carbon atoms, and if e = 0,

R @ 1 and R @ 2 may also be a straight, branched or cyclic acyl group of up to 14 carbon atoms, a hydroxyalkyl, straight or branched alkoxycarbonyl or alkoxyalkyl group of up to 6 carbon atoms or the radical -SC (R),

R ³ denotes a straight or branched alkyl group having up to 4 carbon atoms, and / or

13

R and R are also radicals of the formulas

R

About • · · ·

whereas

And R 16 and R 16 are the same or different and denote a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, g denotes 0, 1 or 2 and

7

R represents a phenyl group, a straight or branched alkyl group having up to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, with the proviso that when e = 0, R and R do not simultaneously represent a hydrogen atom, or

R1 denotes a purine radical which may optionally be up to three times substituted by halogen, azido, cyano, hydroxy, amino, alkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms, alkyl of up to 5 carbon atoms and / or alkoxy of up to 5 carbon atoms,

9

R and R ^J include a fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl radical, which may optionally be up to two times the same or differently substituted by a formyl, carboxy, hydroxy, mercaptyl, straight or branched acyl, alkylthio or alkoxycarbonyl group in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine or bromine, or a straight or branched alkyl or alkoxy group of up to 5 carbon atoms each of which may themselves be substituted by hydroxy, amino, carboxy, straight or branched acyl, alkoxy or alkoxycarbonyl having up to 4 carbon atoms in each case, and / or the aforementioned heterocyclic rings optionally substituted by a α α fall of the formula -NR R, wherein:

R and R are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, or

-2 O

R denotes a hydrogen atom and α α

R is a formyl group, and / or the abovementioned fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl rings optionally substituted with a phenyl group, which may itself be substituted by a fluorine, chlorine or bromine atom, or a straight or branched alkyl or alkoxy group each having up to 4 carbon atoms and

A denotes thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl group, which may optionally be up to two times the same or differently substituted by hydroxy, formyl, carboxy, straight or branched acyl, alkylthio-, alkoxy-, alkyloxyacyl, a group each having up to 4 carbon atoms or a fluorine, chlorine or bromine atom,

and isomeric forms and salts thereof.

Particularly preferred according to the present invention are substituted pyrazole derivatives of the general formula I in which:

R1 represents a pyrimidine radical which is optionally up to two times the same or differently substituted by a radical from the group (i) comprising a hydrogen atom, an amino group, a hydroxyl group, an alkoxycarbonyl alkoxycarbonyl group of up to 3 carbon atoms each, a cyano group or a halogen atom; ), comprising a 5- to 6-membered ring which may be saturated, unsaturated or partially unsaturated, contains 1 to 3 heteroatoms selected from the group consisting of N, O, S, SO and SO2 and may also be bonded through nitrogen, with imidazolyl, imidazolinyl being particularly preferred , imidazolidinyl, morpholine, piperidine, piperazine, pyrrolidine, triazolyl, pyrrole and thiomorpholine ring and which is optionally mono- or poly-substituted by a five-membered ring containing two oxygen atoms as ring members and forming a bicyclic unit with a 3- to 8-membered ring a unit, such as 1,4-dioxa-8-azaspiro [4.5] decane and 1,5-dioxa-9-aza. Spiro [5.5] undecane radical and / or hydroxy, cyano, straight or branched alkyl, acyl or alkoxycarbonyl of up to 3 carbon atoms each, alkyl, acyl and the alkoxycarbonyl group may be substituted by a hydroxy, amino, halogen, carboxy or straight or branched acyl or alkoxy group of up to 3 carbon atoms each, and a tolyl radical, or an alkyl group of 7 carbon atoms optionally substituted by cyano and alkyl (C až-C 5) group which is substituted one to three times with halogen, cyano, aryl and acyloxy, and -NO or radicals of formula -SfOj ^R, where d is 1 or 2; and

R represents straight-chain or branched alkyl having 1 to 4 carbon atoms, aryl having 6 carbon atoms or thienyl, and a radical of the formula PO (OR ² 0) (OR ^12), are identical or different and denote pří24 • · ·

m or a branched alkyl group having up to 3 carbon atoms, and radicals of the formula -NH-C (= NH) NH 2 or (CO) _e NR ¹² R ¹² , where e is 0 or 1; and

O 1 Q

R and R are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 4 carbon atoms or a cycloalkyl group of 3 carbon atoms, said radicals being optionally substituted by an aryl group of 6 carbon atoms, furyl, cycloalkyl 3 carbon atoms, a hydroxy group or a straight alkoxy group of up to 2 carbon atoms, and if e = 1,

R and R may also, with the inclusion of the nitrogen atom to which they are attached, form a 5- or 6-membered ring with up to 2 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, which may optionally be up to twice substituted by hydroxy or methyl, and e = 0, may also represent a direct acyl group with up to 14 carbon atoms, and / or

with the proviso denotes _and R 3 in the case that e = 0 simultaneously hydrogen, nenebo

R1 denotes a purine residue which may optionally be up to twice substituted by a halogen atom, an azido group, an amino group, an alkylamino group having up to 4 carbon atoms and / or a methyl group, o

R ^J and R forms, including the double bond pyridinyl or pyrimidinyl ring, and

A represents a phenyl or pyrimidyl group optionally substituted by a fluorine, chlorine or bromine atom, and isomeric forms and salts thereof.

Particularly preferred according to the present invention are

also substituted pyrazole derivatives of the general formula I in which

R1 denotes the remainder of the formula

in which

R 'denotes an amino group,

R '' denotes a substituted morpholine, piperidine, piperazine, pyrrolidine, triazolyl or thiomorpholine group and

R '' denotes a hydrogen atom or an amino group.

Very particularly preferred according to the present invention are substituted pyrazole derivatives of the general formula I in which R '' represents a morpholinyl group.

The compounds of the formula I according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids can be mentioned.

Physiologically acceptable salts are preferred within the scope of the present invention. Physiologically acceptable salts of the compounds of the present invention may be salts of the compounds of the present invention.

of the present invention with mineral acids 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, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid , maleic acid or benzoic acid.

Physiologically acceptable salts may also be metal or ammonium salts of the compounds of the present invention having a free carboxyl group. Particularly preferred are, for example, the sodium, potassium, magnesium or calcium salts as well as ammonium salts derived from ammonia or organic amines, such as ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds of the present invention may exist in stereoisomeric forms that exist either as an image and a mirror image (enantiomers) or not as an image and a mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to the corresponding mixtures thereof. Like the diastereomers, the racemic forms can be resolved into stereoisomerically uniform components in a known manner.

In the present invention, unless otherwise indicated, substituents generally have the following meanings:

• 4 4 · · · J · t · 444 · t 4 · 4 · 4 · 4 · 4 · 4 · 4

4444444 4 4 »43« · *

Alkyl is generally a straight or branched chain hydrocarbon radical having 1 to 20 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, decyl, dodecyl or eicosyl.

Alkenyl is generally a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms and having one or more, preferably one or two, double bonds. Examples include allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl or isooctenyl.

An alkynyl group is generally a straight or branched hydrocarbon radical having 2 to 20 carbon atoms and having one or more, preferably one or two, triple bonds. For example, ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl may be mentioned.

An acyl group is generally a straight or branched low alkyl group having 1 to 9 carbon atoms, which is linked via a carbonyl group. Examples are acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Alkoxy generally denotes a straight or branched hydrocarbon radical having from 1 to 14 carbon atoms bonded via an oxygen atom. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy may be mentioned.

9 9 9 9 9 9 12

9

Isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy. The terms alkoxy and alkyloxy are synonyms.

Alkoxyalkyl generally denotes an alkyl radical of up to 8 carbon atoms, which is substituted by an alkoxy group of up to 8 carbon atoms.

For example, a non-carbonyl group may be represented by the formula

O = C-O-alkyl

Alkyl is generally a straight or branched hydrocarbon radical having 1 to 13 carbon atoms. For example, the following alkoxycarbonyl radicals may be mentioned: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

A cycloalkyl group generally denotes a cyclic hydrocarbon ring having from 3 to 8 carbon atoms. Preferred are cyclopropyl, cyclopentyl and cyclohexyl, examples of which are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the context of the present invention, a cycloalkoxy group denotes an alkoxy radical whose hydrocarbon radical is a cycloalkyl radical. The cycloalkyl radical generally has up to 8 carbon atoms. Examples which may be mentioned are cyclopropyloxy and cyclohexyloxy. The terms cycloalkoxy and cycloalkyloxy are synonymous.

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

In the context of the present invention, halogen represents fluorine, chlorine, bromine and iodine.

Heterocycle denotes, in the context of the present invention, a generally saturated, unsaturated or aromatic 3- to 10-membered, for example 5- or 6-membered heterocycle, which may contain up to three heteroatoms from the group consisting of sulfur, nitrogen and / or oxygen and which in the case of a nitrogen atom . Examples are oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolidinyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3-triazolyl, thiazolyl, piperazol, oxazolyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl, oxazolyl, imidazolyl, imidazolyl group. Thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl are preferred. The term heteroaryl refers to an aromatic heterocyclic radical.

The present invention further provides a process for the preparation of substituted pyrazole derivatives of formula (I), wherein compounds of formula (II) are converted, depending on the different meanings of the above heterocycles and R 1 [A].

R @ 4 D (II), in which it has the meaning given above and denotes the radicals of the formulas

O

II

CN or C1-C4-CN represents an alkyl group having 1 to 4 carbon atoms, by reaction with compounds of the formula III a-ch ₂ nh-nh ₂ (iii), in which A is as defined above, in inert solvents, optionally in the presence of a base, to compounds of formula IV or IVa

H ₂ C — A

H ₂ CA

H ₂ N.

(N) h ₂ n ^ n.

NC (IVa) in which A and R ^{1 are} as defined above, and in the case of compounds of formula IVa,

cyclized with carboxylic acids, nitriles, formamides or guanidinium salts, and in the case of compounds of formula IV cyclized with 1,3-dicarbonyl derivatives, their salts, tautomers, enol ethers or enamines, in the presence of acids and optionally under the influence of microwave radiation, or

2 [B] when R and R together form a pyrazine ring, the compounds of formula IV are first converted by nitrosation to compounds of formula V

In which, in the second formula (VI), A and R 6 have the meanings given above, a step is carried out by reduction to produce compounds of the general formula wherein

(VI) as hereinbefore defined and then cyclized using 1,2-dicarbonyl compounds

or [C] reacting compounds of formula VII

Wherein A, R, and R are as defined above, and

L denotes a radical of the formula -SnR ^^ R ^^ R ^^,

9

ZnR, iodo, bromo or triflate, wherein r39, r40 _and r41 are the same or different and denote a straight or branched alkyl group having up to 4 carbon atoms and

9

R is halogen, with compounds of formula VIII

R ¹ - T (VIII) in which R has the abovementioned meaning, and if L = SnR39R40R41 ZNR ⁴ H and

T represents a triflate group or a halogen atom, preferably a bromine atom, and, when L = iodine, bromine or triflate,

T represents a radical of the formula SnR ⁴ R 41, Zn R ⁴ or

BR43 ^R44, wherein R39, β ⁴ θ, r ^{4 4} ^ 1 are are as defined above for R ^^ R ^ O ^ and R ^ and R are identical or different and '44' for

R and R are the same or different and are hydroxy, aryloxy of 6 to 10 carbon atoms or a straight or branched alkyl or alkoxy group of up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring in a palladium catalysed reaction in inert solvents, optionally in the presence of a base, or [D] when R 1 is an optionally substituted pyrimidine residue, amidines of formula IX are reacted

(IX),

Q in which A, R and R are as defined above, for example with compounds of formula X, Xa, Xb or Xc

AlkOOCk COOAlk ALkOOC.

.CN

R ¹ '(Xb) wherein

R ^r (Xc)

R1 represents an optionally substituted cycloalkyl radical, as defined by R1,

Alk denotes a straight or branched alkyl group having up to 8 carbon atoms, preferably up to 4 carbon atoms, and

Z represents amino, alkylamino of up to 7 carbon atoms, dialkylamino of up to 7 carbon atoms, nitrogen-bonded piperidine or morpholine, hydroxy, alkoxy of up to 7 carbon atoms, acyloxy of up to 7 carbon atoms or aroyloxy of 6 to 10 carbon atoms and, in the case of the groups -S (O) _c Nr 6r 7 _and -S (O) _c > NR b R 6, when starting from unsubstituted compounds of the general formula I, they are first reacted with thionyl chloride and in the second step with the corresponding amines, and optionally with the substituents mentioned under X, Y, R ¹ ,

R ² , R ² and / or A are varied or introduced by conventional methods, preferably by acylation of free amino or hydroxy groups, chlorination, catalytic hydrogenation, reduction, oxidation, cleavage of protecting groups and / or nucleophilic substitution.

For example, the process of the present invention can be illustrated by the following reaction scheme.

Method [A]

About • · · · · ·

Γ »

Method [C]

Pd (PPh ₃ ) ₂ CI ₂ ¹

Method [D]

Na ₂ CO ₃

Amidin

HCI-Salz

nh ₄ ci% *

\

SO ₂ Me

3

The heterocycles mentioned under R and R may also be introduced by reaction of appropriately substituted compounds according to other known heterocyclic syntheses.

Suitable solvents for the individual process steps [A] and [B] are inert organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, tetrahydrofuran, dimethyl ether and dioxane, alcohols such as methanol and ethyl alcohol, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichlorethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

In general, inorganic or organic bases can be used as bases in the process 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, alkali metal or alkaline earth metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butylate, or organic amines (trialkyl (C 1 -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 or hydrides thereof such as sodium hydride as bases. Sodium and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is used in the reaction of the compounds of the formula II with the compounds of the formula III in an amount of 1 to 5 mol, preferably 1 to 3 mol, based on 1 mol of the compound of the formula II.

The reaction of compounds of formula II with compounds of formula III is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably 20 ° C to 110 ° C.

This reaction can be carried out under normal, elevated levels.

or reduced pressure, for example 0.05 to 0.5 MPa. In general, working at normal pressure.

Proton acids are generally suitable as acids for the cyclization reaction optionally carried out in the process of the present invention. These preferably include inorganic acids such as hydrochloric or sulfuric acid, or organic carboxylic acids having 1 to 6 carbon atoms, optionally substituted by fluorine, chlorine and / or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or acid propionic acid, or sulfonic acids with alkyl radicals of 1 to 4 carbon atoms or aryl radicals, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or thioureasulfonic acid.

The catalytic hydrogenation reaction optionally performed during the process of the present invention can generally be carried out with hydrogen in water or in inert organic solvents such as alcohols, ethers, halogenated hydrocarbons or mixtures thereof using catalysts such as Raney nickel, palladium, palladium on charcoal or platinum, or hydrides or boranes in inert solvents, optionally in the presence of catalysts.

The chlorination reactions, optionally carried out during the process according to the invention, are carried out in general by means of customary chlorinating agents, such as PCl2.

PCl2, POCl2 or elemental chlorine. POCl 3 is preferred in the present invention.

The acylations of the free amino or hydroxy groups, optionally performed during the process of the present invention, can be carried out by conventional methods known to those skilled in the art. For example, the corresponding free amino or hydroxy groups can be converted by reaction with an acid halide, preferably acid chloride, or acid anhydride, in the presence of a base such as sodium hydride, pyridine or dimethylaminopyridine, in a solvent such as tetrahydrofuran or dichloromethane to the corresponding amides or esters. , or by reaction with a sulfonyl halide, preferably a sulfonyl chloride, to the corresponding sulfonamides or sulfonic acid esters.

The oxidation of thioether groups to sulfoxide groups or sulfone groups, optionally carried out during the process of the present invention, can be carried out by conventional methods known to those skilled in the art. For example, such oxidations can be carried out with m-chloroperoxybenzoic acid (MCPBA) in a solvent such as dichloromethane.

Nucleophilic substitutions and Vilsmeier reactions, optionally performed during the process of the present invention, are carried out by conventional methods known to those skilled in the art.

The nitrosation of the compounds of the formula IV to the compounds of the formula V mentioned in the first step of the process [Β] can be carried out according to the protocol of P. G. Baraldi et al., Synthesis 1984, 148.

The reductions, optionally carried out during the process according to the invention, are carried out in general by means of conventional reducing agents, preferably those suitable for the reduction of carbonyl compounds to hydroxy compounds. Ob-

Particularly suitable in this connection is reduction with metal hydrides or complex metal hydrides in inert solvents, optionally in the presence of a trialkylborane. Reduction with complex metal hydrides, such as, for example, lithium borate, sodium borate, potassium borate, zinc borate, lithium trialkyl borohydride, diisobutylaluminum hydride or lithium aluminum hydride is preferred. Very particularly preferably, the reduction is carried out with 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 reduced compound.

The reductions optionally carried out during the process according to the invention are generally carried out at a temperature in the range of -78 ° C to 50 ° C, preferably -78 ° C to 0 ° C for DIBAH and 0 ° C to room temperature for NaBH 4.

The reductions, optionally carried out during the process according to the invention, are generally carried out under normal pressure. However, it is also possible to operate at elevated or reduced pressure.

The compounds of formulas II and III are known per se or can be prepared by conventional methods (see, for example, J. Hromath et al., Monatsh. Chem. 1976, 107, 233).

The compounds of the general formulas (IV), (IVa), (V) and (VI) are known in part and can be prepared as described above.

Suitable solvents for process [C] are inert organic solvents which, under the given reaction conditions, are

Φ Φ · · · · · φ «• φφφ φφφ · φ φ does not change. Patří these include ethers such as diethyl ether, tetrahydrofuran, dimethyl ether and dioxane, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, carbon tetrachloride,

1,2-dichlorethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction of compounds of formula VII with compounds of formula VIII is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably 20 ° C to 110 ° C.

This reaction may be carried out under normal, elevated or reduced pressure, for example 0.05 to 0.5 MPa. In general, working at normal pressure.

PdCl 2 (P (C 1 H 3) 3) 2 is generally suitable as the palladium compounds in the present invention. palladium-bis-dibenzylideneacetone (Pd (dba) 2), [1,1'-bis- (diphenylphosphino) ferrocene] palladium (II) chloride (Pd (dppf) Cl 2) or Pd (P (C ₆ H ₅ )) ₃ ) 4. Preference is given to Pd (P (C ₆ H _{5) 3), fourth}

The compounds of formula (VII) are known per se or can be produced by methods known per se (see, for example, K. Kirschke: Houben-Veyl, Methoden der Organischen Chemie, Thieme-Verlag Stuttgart, 4th Ed., Volume E8b, Part 2, 399-763 especially with regard to pyrazolopyridines: CR Hardy in AR Katritzky (Hrsg.), Adv. Het. Chem. 1984, 36, 304-409, especially with regard to pyrazolopyrimidines: H. H. Elgandi ······· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (Et al., Adv. Het. Chem. 1987, 41,319-376). The preparation of the corresponding halopyrazolo [3,4-b] pyrimidines and organotin pyrazolo [3,4-b] pyrimidines of the formula VII is described in WO 98/23619 and can be carried out analogously also for the corresponding triflate and organo-zinc compounds of the formula VII.

The compounds of formula (VIII) are known and are obtainable by conventional methods (see, for example, MG Hoffmann et al. In: Houben-Veyl, Methoden der organischen Chemie, 4th Ed., Volume E9b, Part 1, pp. 1-249; A. Veissenberger et al., The Chemistry of Heterocyclic Compounds Pyrimidines, 1962, 16; ibid 1970, 16, Suppl. 1, ibid 1985, 16, Suppl. 2, ibid 1994, 52).

Process [D] is carried out at a temperature in the range of 80 ° C to 120 ° C, preferably 100 ° C to 110 ° C or at reflux temperature.

Reagents of formula X, Xa, Xb, or Xc may function as solvents. however, the reaction may also be carried out in other suitable solvents, such as toluene, methanol or dichloromethane. Low boiling solvents such as dichloromethane can be distilled off during the reaction.

Process [D] can be carried out at normal, elevated or reduced pressure, for example 0.05 to 0.5 MPa. In general, working at normal pressure.

The reaction can be carried out either in one step or via open-chain compounds such as, for example.

It can be carried out under vacuum and can be carried out without the addition of the solvents mentioned above.

with both the base and the acid or amidines of the formula (IX), the compounds of the formula (XI) may be prepared in which they have:

(Xi), first reacted in ethers with trifluoroacetic anhydride (TFAA) and in the presence of bases to give compounds of formula (XII)

CN (ΧΠ), ·· 0 ··· 99 t «» »

A, R ² and R ³ as defined above, is then prepared with sodium methanolate compound of formula XIII diisocyanates having

(XIII),

A, R ² and R ³ as defined above, in a subsequent step by reaction with ammonium chloride and glacial acetic acid in alcohol is converted to the corresponding amidine HCl salt of formula XIV

(XIV)

3 in which A, R and R are as defined above, and in the last step they are reacted with bases, preferably potassium carbonate or an alkali metal alcoholate such as sodium ethanolate.

Suitable solvents for the reaction of compounds of formula XI to compounds of formula XII are ethers such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethylformamide.

and dioxane. Tetrahydrofuran is preferred.

Organic bases (trialkyl (C1-C6) -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, dimethylaminopyridine, methylpiperidine or morpholine, pyridine being preferred.

The reaction is carried out at a temperature in the range of 0 ° C to 40 ° C, preferably at room temperature.

The reaction may be carried out at normal, elevated or reduced pressure, for example 0.05 to 0.5 MPa. In general, working at normal pressure.

The amide of formula XI can be obtained by saponification of the corresponding ester starting compound with a base to an acid, converting it to an acid chloride by conventional methods, for example using SOCl 2 or POCl 2, followed by reaction with ammonia.

The elimination of water from the amide of the formula XI to the nitrile of the formula XII can be carried out with all conventional water-removing agents. Trifluoroacetic anhydride (TFAA) is preferred according to the present invention.

The conversion of the nitrile of the formula XII to the iminoether of the formula XIII can be carried out both in an acidic medium, for example with a mixture of hydrogen chloride and an alcohol, as well as in a basic medium, for example with a mixture of methanol and sodium methylate. It is usually carried out at a temperature between 0 ° C and 40 ° C, for example at room temperature.

• · ····

Suitable solvents for the reaction of the compounds of the formula XIII to the compounds of the formula XIV are alcohols such as methanol or ethyl alcohol, preferably methanol.

The reaction is carried out at a temperature in the range of 0 ° C to 40 ° C, preferably at room temperature.

The reaction may be carried out at normal, elevated or reduced pressure, for example 0.05 to 0.5 MPa. In general, working at normal pressure.

Suitable bases for the liberation of compounds of formula IX from compounds of formula XIV are inorganic or organic bases. 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, and alkali alcoholates metals such as sodium methoxide. Sodium carbonate and sodium methoxide are preferred.

Pyrimidine ring formation is accomplished by conventional methods (see, for example, MG Hoffmann et al. In: Houben-Veyl, Methoden der Organischen Chemie, 4th Ed., Volume E9b, Part 1, pp. 1-249; A. Veissenberger et al. , The Chemistry of Heterocyclic Compounds - Pyrimidines, 1962, 16; ibid 1970, 16 Suppl.1, ibid 1985, 16, Suppl.2, ibid 1994, 52).

In this connection, the iminoethers of the general formula can be used

XIII and these, for example, react with a suitable enamine. However, the iminoether can also first be converted with the aid of ammonia or its salts into the corresponding amidine and reacted as the free base of formula IX or as a salt of formula XIV with enamines, acetals, enol ethers, aldehydes, enolates, malonitrilesters or malondinitriles.

The enamines optionally used in this reaction can be prepared, for example, from C-H-acidic compounds, such as acetonitrile derivatives, by known methods by reaction with dimethylformamide derivatives, such as bis (dimethylamino) -tert-butoxymethane, dialkoxy-dialkylamino-methanene.

Compounds of formula XI may be prepared by reacting compounds of formula XV H ₅ C ₂ o // a

CN (XV)

The ONs are converted with compounds of formula XVI

A - CH ₂ -NH-NH ₂ (XVI) in ethers, preferably dioxane and trifluoroacetic acid, to compounds of formula XVII

Ί

H ₂ ^{N 4 N} N

(XVII)

CO ₂ C ₂ H _{5 is} then reacted with compounds of formula XVIII

Z - CH = CH - CHO (XVIII), in which Z is as defined above, especially denotes the group -N (CH ₂ ) 2, in inert solvents, preferably dioxane, to produce compounds of formula XIX

and mixed with ammonia in methanol in the final step.

Instead of the sodium salt of the enolate XV, enol ethers, ketones or enamines may also be used.

If desired, the reaction of compounds of formulas XV and XVI to XVII can also be carried out via intermediates of formulas A and B

AND

at room temperature.

··· «·· ·· · 999 · 9 *

Compounds of formula (X) may be prepared by reacting with formula (XX) or (XXa), for example, compounds of formula [Alk ₂ N] ₂ -CH-OAlk '(XX)

Alk ₂ N - CH - [OAlk '] ₂ (XXa) in which

Alk and Alk 'are the same or different and denote a straight or branched alkyl group having up to 5 carbon atoms, with compounds of formula XXI

R ¹ '- CH ₂ - CN (XXI),' 1 wherein R represents the cycloalkyl radical mentioned in R 1.

Compounds of formulas XX, XXa and XXI are known or can be prepared by conventional methods.

Compounds of formulas XII, XIII, XIV, XV, XVI,

XVII, XVIII and XIX are partially new and can be produced as described above.

The parimidine residue may be formed using a reagent of formula Xa, which is available, for example, as follows:

Compounds of formula (XXII)

in which R má is as defined above and Alk is an alkyl group of up to 4 carbon atoms, is converted by ammonia in suitable solvents, preferably alcohols such as methanol, at a temperature in the range of 0 ° C to 40 ° C, preferably at room temperature to compounds of formula XXIII

H ₂ NCC

wherein R is as defined above, and these are then reacted via water-withdrawing agents such as Burgess reagent, POCl2, P2O5, SOCl2, trifluoroacetic anhydride / pyridine by conventional methods.

When using a Burgess reagent, the reaction is preferably carried out in inert solvents such as ethers or chlorinated hydrocarbons. Examples include dichloromethane and tetrahydrofuran. Preferably a 1: 2 mixture of said solvents is used. The reaction is carried out at a temperature in the range of 0 ° C to 40 ° C, preferably at room temperature.

Compounds of formula XXII are known and / or are readily available to those skilled in the art.

Compounds of formula X are partially subject to keto-53

-enol-tautomerism, for example

The pyrimidine residue can be a compound of formula Xa as follows:

can also be created using which is, for example, available

Compounds of formula XXIIa

AlkOOC. .COOAlk

Wherein R is as defined above and Alk is an alkyl group having up to 4 carbon atoms, is converted by ammonia in suitable solvents, preferably alcohols such as methanol, at a temperature in the range of 0 ° C to 40 ° C, preferably at room temperature, to compounds of formula XXIHa h ₂ night ^ ^ conh ₂ (XXIIIa)

Ϊ 'in which R has the abovementioned meaning, and these are followed by customary methods react despite dehydrating agent such as Burgess-reagent POCl ^,? 2θ5' SOC1 _2, trifluoroacetic anhydride / pyridine.

When using a Burgess reagent, the reaction is preferably carried out in inert solvents such as ethers or chlorinated hydrocarbons. Examples include dichloromethane and tetrahydrofuran. Preferably a 1: 2 mixture of said solvents is used. The reaction is carried out at a temperature in the range of 0 ° C to 40 ° C, preferably at room temperature.

Compounds of formula XXIIa are known and / or are readily available to those skilled in the art.

Where typical protective groups are used in the derivatisation reaction, they are generally cleaved in one of the abovementioned alcohols and / or tetrahydrofuran or acetone, preferably a mixture of methanol and tetrahydrofuran, in the presence of hydrochloric acid, trifluoroacetic acid or toluenesulfonic acid at a temperature in the range of 0 ° C to 70 ° C, preferably at room temperature and under normal pressure.

The compounds of the formula I according to the invention exhibit an unpredictable valuable spectrum of pharmacological action.

The compounds of the present invention of formula (I) cause vascular reaxization, inhibition of thrombocyte aggregation and lowering of blood pressure, as well as an increase in coronary blood flow. These effects are mediated through direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. In addition, compounds of the present invention of Formula I potentiate the effect of cGMP elevating agents such as Endothelium derived relaxing factor (EDRF), NO-donors, protoporphyrin IX, ara55 quidonic acid, or phenylhydrazine derivatives.

Thus, the compounds may be used in medicaments for the treatment of cardiovascular diseases such as high blood pressure and cardiac insufficiency, stable and instable angina pectoris, peripheral and cardiovascular diseases, arrhythmias, thromboembolic diseases and ischemia such as myocardial infarction, stroke, transistoric and ischemic attacks, peripheral blood circulation disorders, restenosis inhibition, such as after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, as well as for the treatment of arterioscleric diseases, urinary disorders, asthmatic diseases such as prostatahypertrophy, erectile dysfunction, female sexual dysfunction and incontinence.

The compounds of the formula I according to the invention are also active substances for the treatment of diseases in the central nervous system which are characterized by disorders of the NO / cGMP system. They are particularly suitable for eliminating congnitive deficits, improving learning and memory performance, and for treating Alzheimer's disease. They are also suitable for the treatment of central nervous system diseases such as states of fear, tension and depression, central nervous system-induced sexual dysfunction and sleep disorders, as well as for the control of eating and eating disorders.

Furthermore, they are also suitable for regulating blood flow to the brain and are thus an effective means of treating migraines.

They are also suitable for the prophylaxis and treatment of the consequences of cerebral infarction (Apoplexia cerebri), such as cases of stroke, cerebral ischemia and trauma following brain damage. Likewise, the compounds of the present invention can be used for the treatment of pain conditions.

To this end, the compounds of the present invention have antiflamatorial effects and can therefore be used as anti-inflammatory agents.

In addition, the invention includes the combination of compounds of the present invention of formula I with organic nitrates and NO-donors.

Organic nitrates and NO-donors in the context of the present invention are generally substances which exert their therapeutic effect through the release of NO or NO-type, respectively.

Preferred are sodium nitroprusside (SNP), nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1.

In addition, the present invention encompasses a combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are especially inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beava and Reifsynder (1990) TIPS 11, pp. 150-155. These inhibitors potentiate the effect of the compounds of the present invention and increase the desired pharmacological effect.

The following assays were performed to determine cardiovascular effects: In vitro assays on isolated enzyme and cells of vascular origin examined the guanylate cyclase-dependent effect of cGMP formation with and without NO-donor. Anti-aggregatoric properties are shown on collagen-stimulated human thrombocytes. The vascular-relaxing effect is determined on phenylephrine precontracted rabbit aorta rings. Blood pressure reducing effect is tested in narcotized and awake rats.

Stimulation of recombinant soluble guanyl cyclase in vitro

Stimulation assays for recombinant soluble guanyl cyclase and compounds of the present invention with and without NO-donors are performed according to the method detailed in the application: M. Hoenicka, Ε. Becker M., H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer, and J.-P. Stasch: Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 system: stimulation by YC-1, nitric oxide, and carbon dioxide. J. Mol. Med 77: 14-23 (1999). The results are shown in Figure 1.

Stimulation of soluble guanylate cyclase in primary endothelial cells

Primary endothelial cells are isolated from porcine aorta by treatment with collagenase solution. The cells are then cultured in culture medium at 37 ° C / 5% CO 2 until confluence is achieved. For assays, cells are passaged, plated in 24-well cell culture plates and subcultured until confluency (~ 2 x 10 6 cells / well). To stimulate endothelial guanylate cyclase, the culture medium is aspirated and the cells are washed once with Ringer's solution. After removing the Ringer's solution, the cells are incubated in stimulation buffer with or without NO-donor (sodium nitroprusside, SNP or DEA / NO, 1 gm) for a period of time. · ·················································· minutes at 37 ° C / 5% CO 2 · Then test substances (final concentration 1 μΜ) are pipetted to the cells. After a 10 minute incubation period, the buffer solution is aspirated and 4 ° C stop buffer is added to the cells. The cells are then lysed for 16 hours at -20 ° C. Finally, the liquid containing intracellular cGMP is collected and the cGMP concentration is determined using the cGMP-SPA system (Amersham Buchler, Braunschweig). The results are shown in Tables 1 and 2 below.

Table 1

Stimulation of soluble guanylate cyclase in primary endothelial cells

ex 16 (μΜ) cGMP (pmol) 0 1.7 0.1 5.1 0.3 13.2 1 1.0 20.8 3.0 34.5 10 47.7

Table

Stimulation of soluble guanylate cyclase in primary endothelial cells with 3- (4,6-diamino-5-N-morpholinopyrimidin-2-yl) -1- (2-fluorobenzyl) -4-pyrazolo [3,4-b] pyridine (Example 16) )

Example increase of cGMP concentration (%) 1 > 1000 2 > 1000 1 > 1000 6 600 13 > 1000 14 > 1000

Blood vessels relaxing effect in vitro

The rabbits are killed by a blow to the back of the neck and bled. The aorta is removed and the adherent tissue is removed. The isolated rabbit aorta 1.5 mm wide rings are individually preloaded into a 5 ml organ bath with carbon dioxide gassed with KrebsHeseleite solution (mM): NaCl: 119; KCl: 4.8; CaCl ₂ x 2 H ₂ 0: 1; MgSO ₄ x 7 H ₂ 0: 1.4; KH ₂ PO _4: 1.2; NaHCO ₃ : 25; glucose: 10 at 37 ° C.

The contraction force is determined by Staham UC2-Zellen, amplified and A / D-Vandler (DAS-1802 HC, Keithley Instruments Munchen) is digitized and parallel-registered on a line chart recorder. To achieve contraction, phenylephrine is added cumulatively to the bath at increasing concentrations. After several control cycles, the test substance is added at increasing dose in each additional embodiment and the contraction achieved is compared with the contraction level achieved in the last embodiment. From this, the concentration required to reduce the control value by 50% (IC ₅₀ ) is calculated. · The standard application volume is 5 μΐ, the proportion of DMSO in the bath solution is 0.1%. The results are shown in Table 3 below

Table 3

Blood vessels relaxing effect in vitro

Example IC ₅₀ [µM] 1 0.23 3 0.38 * » □ 0.4 5 0.24 7 3.4 13 0.41 16 0.2 21 0.67 22nd 0.68 23 0.54 24 0.35 25 0.79 26 1 27 Mar: 0.18 28 0.22

• · · · · ·

31 0.53 32 0,5S - * 0.62 35 i, ⁸ 71 0.7 73 0.69 77 0.76 78 9.5 79 4.1

Measurement of blood pressure in narcotized rats

Male Vistar rats weighing 300-350 g are anesthetized with thiopental (100 mg / kg ip). Following tracheotomy, a blood pressure catheter is inserted into the femoral artery. Test substances are administered orally in Transcutol, Cremophor EL, H ₂ 0 (10% / 20% / 70%) in a volume of 1 ml / kg. The results are shown in Table 4 below

Table 4

Ex. dose (mg / kg p.o.) max. pressure drop (mm Hg) 16 0.3 21 16 1.0 35

Effect on mean blood pressure of alert, spontaneously hypertensive rats

Blood pressure is measured continuously for 24 h in spontaneous hypertonic, 200-250 g heavy, freely moving female rats (MOL: SPRD). To this end, the animals were implanted with chronic Druckaufnehmer (Data Sciences Inc., St. Paul, MN, USA) in the descending abdominal aorta under the renal aorta and fixed in the abdominal cavity with the associated transmitter.

Animals were individually housed in type III cages, which were positioned at individual receiving stations and subjected to a 12-hour light / dark rhythm. Water and feed were freely available.

To obtain data, blood pressure was registered in each rat every 5 minutes for 10 seconds. The measurement points were unified for a period of 15 minutes and the average value was calculated from these values.

The test compounds were dissolved in a mixture of transcutol (10%), cremophor (20%) and water (70%) and were administered orally via a esophagus probe at a volume of 2 ml / kg body weight. Test doses ranged from 0.3 to 30 mg / kg body weight. The results are shown in the attached Fig. 2.

Inhibition of thrombocyte aggregation in vitro

Blood of healthy individuals of both sexes is used to determine thrombocyte aggregation. As anticoagulants, you will get into and out of your life. one part of a 3.8% aqueous sodium citrate solution is mixed with 9 parts of blood. The blood is centrifuged at 900 rpm for 20 minutes. The pH of the platelet-enriched plasma is adjusted to 6.5 with an ACD (sodium citrate / citric acid / glucose) solution. The thrombocytes are then centrifuged and taken up in buffer and centrifuged again. The thrombocyte precipitate is taken up in the buffer and then mixed with 2 mmol / l calcium chloride.

To measure aggregation, an aliquot of the thrombocyte suspension is incubated with the test substance for 10 minutes at 37 ° C. Thrombocyte aggregation is then induced by the addition of collagene in an aggregometer and detected by a turbidometric method (Born, G.V.R., J. Physiol. (London), 168, 178-195, 1963) at 37 ° C. The results are shown in Table 5.

Table 5

Ex. C. ΙΟ ₅₀ (μΜ) 16 0.06

Erection measurement supporting guanylate cyclase stimulator efficacy

In order to achieve a complete and lasting erection, the cavernous artery and the overall architecture of corpus cavernosum, which is a network of smooth muscles and collagen connective tissue, must be maximally dilated so that Corpus cavernosum is completely · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Filled with blood (Anderson K.-E. and Vágner G., Physiology of Penile Erection Physiological Reviews 75, 191-236 (1995), Meinhardt V, Kropmann RF, Vermeig P, Lycclama A, Nigelholt and Zwartendijk J, The Influence of Medication on Erectile Dysfunction, Int J of Impotence Res. , 17-26 (1997) Smooth muscle relaxation is mediated by NO, which is released by sexual stimulation of nonadrenal, non-choline nerve fibers in endothelial cells of the blood vessels of Corpus cavernosum, NO activates guanylate cyclase, resulting in increased cGMP resulting in smooth muscle dilation orpus cavernosum, and thus for erection, vigilant rabbits are used to test the efficacy of the compounds of the present invention. The rabbits were chosen because the neurophysiology, hemodynamics, and contraction and smooth muscle contraction of corpus cavernosum relaxation in rabbits and humans are very similar (Meyer MF, Taher, Krah, Staubesand J, Becker AJ, Kircher, Jonas U.). Forsmann VG, Stief ChG, Intracarvenous Application of SIN-1 in Rabbit and: Functional and Toxcological Results Annals Urol., 27, 179-182 (1993), Taub HC, Lerner SE, Melman A., Christ GJ, Relationship between contraction and relaxation in human and rabbit corpus cavernosum, Urology 42, 698-671, (1993).

Method

Adult male chinchillla rabbits weighing 3 to 5 kg, upon delivery, adapt for a few days to stand alone.

They have free access to water and can feed for two hours a day. Animals are maintained at day / night rhythm for 10/14 hours (light from 8 hours) at a temperature in the range of 22-24 ° C.

Animals are weighed prior to the start of the experiment. For intravenous «4 · 4 ··» ^»Μ Λ» ··

1 *! 4 · 4 »4 4 4« 444 «444» 444

444 444 44 444 44

For nasal application, the compounds of the present invention are dissolved in a mixture of transcutol (Gattefosse GmbH) diluted with 20% cremophor (BAASF) and water in a ratio of 3: 7. Sodium nitroprusside is dissolved in 0.9% sodium chloride. The substances are injected at 0.5 ml / kg into the ear vein at the doses indicated in the table. For oral administration, the test substances are dissolved in a mixture of glycerol, water and polyethylene glycol (6: 10: 9.69) and administered at the dosages listed in the table at a volume of 1 ml / kg using an oesophageal probe.

The action of guanylate cyclase stimulators is enhanced by NO-donors. This was demonstrated by an additional dose of sodium nitroprusside.

Sodium nitroprusside was injected at a dose of 0.2 mg / kg simultaneously with the compound of the present invention into the ear vein. When the compound of the present invention was administered orally, these animals were injected with nitroprusside 30 minutes after the oral dose into the ear vein. Appropriate controls were performed with solvent and nitroprusside alone.

Under resting conditions the rabbit penis is not visible and is fully covered by the skin. The erection is evaluated by measuring the length of the protruding penis with a caliper. The measurements are taken 5, 10, 15, 30, 45, 60, 120 and 180 minutes after application of the substance. The effect is calculated as the product of the length of the hair of the uncovered penis in millimeters and the duration of the erection in minutes.

Intravenous injection of sodium nitroprusside causes an erection lasting about 10 minutes (110 [mm x min]).

• 4 · 4 4 4 4 4 4

The present invention includes pharmaceutical compositions comprising, in addition to non-toxic, inert, pharmaceutically acceptable carriers, one or more compounds of the present invention of formula (I), as well as a process for making such compositions.

The active compounds can also be present in one or more of the above-mentioned carriers in microencapsulated form.

The therapeutically active compounds of formula I should be present in the above pharmaceutical compositions in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, based on the total composition.

In addition to the compounds of the present invention of formula (I), the above pharmaceutical compositions may also contain other pharmaceutically active substances.

In general, it has proven advantageous in both human and veterinary medicine to administer the active ingredient (s) in a total amount of about 0.5 to about 500 mg / kg body weight per 24 hours, preferably 5 to 100 mg / kg, to achieve the desired results. kg of body weight, optionally in the form of multiple individual doses. A single dose comprises the active compound (s) of the present invention in an amount of about 1 to about 80 mg / kg body weight, especially 3 to 30 mg / kg.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows stimulation of soluble guanylate cyclase by 3- (4,6-diamino-5-N-morpholino-2-pyrimidinyl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine (example 16) in the presence of different NO concentrations.

Figure 2 shows the effect of 3- (4,6-diamino-5-N-morpholino-2-pyrimidinyl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine (Example 16) ) for the mean blood pressure of alert, spontaneously hypertensive rats.

The present invention is illustrated in more detail by the following non-limiting examples. Unless otherwise indicated, the amounts refer to% by weight.

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations are used in the following examples:

RT = room temperature

EE = ethyl acetate

MCPBA = m-chloroperoxybenzoic acid

BABA = n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6 (50: 9: 25: 15; org. Phase)

The following mobile phases are used for thin layer chromatography:

TI El: toluene-ethyl acetate (1: 1) ·················

TI EtOHl : toluene - ethyl alcohol (1 1) Cl El: cyclohexane - ethyl acetate (1 1) Cl E2: cyclohexane - ethyl acetate (1 2)

Starting compounds

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

R

To a solution of N, N-dimethylformamide dimethylacetal (5.95 g, 50.0 mmol) in absolute methanol (25 mL) was added 2-substituted acetonitrile derivative (50.0 mol) with water cooling and stirred at room temperature for one hour.

Sulfone; The precipitate is filtered off with suction and dried under high vacuum.

Phosphonic acid ester: The solution is first evaporated at 40 ° C and 200 kPa pressure on a rotary evaporator and then freed from methanol at room temperature under high vacuum.

Ex. Edukt Product yield mp 1 H NMR IA N S CN II O Kío NC 0 N— 88% 128 [deg.] C 2A 1! 0 0 ^ / V_ _o NC o 99% 1 H-NMR (400 MHz, CDCl ₃ ), δ = 1.34 (t, 6H, CH ₃ ), 3.12 (s, 3K, NCH ₃ ), 3.31 (s, 3H, NCH ₃ ), 4.07 (m, 4H) , CH ₂ ), 7.20 (d, 1H, Olefin CH).

Example 3A

3- (dimethylamino) -2-N-morpholinacrylonitrile

8.13 g (64.5 mmol) of morpholinoacetonitrile and 13.3 ml (64.5 mmol) of tert-butoxy-bis (dimethylamino) methane were stirred overnight at 80 ° C. The reaction mixture was then cooled to room temperature, concentrated on a rotary evaporator and finally distilled in vacuo.

Yield: 11.0 g (94%) (cis- and trans-isomer)

Boiling point: 119 ° C / 0,8 kPa • · · ·

Example 4A

3- (dimethylamino) -2-N-thiomorpholinacrylonitrile

N

6.65 g (46.8 mmol) of N-thiomorpholinacetonitrile (Vise, LD et al., J. Med. Chem., 19, 1974, 1232-1234) and 9.70 ml (47.0 mmol) of tert-butoxy -bis (dimethylamino) methane was stirred overnight at 80 ° C. The reaction mixture was then cooled to room temperature, concentrated on a rotary evaporator and finally distilled in vacuo.

Yield: 9.98 g (88% based on pure content, cis- and trans-isomers)

Boiling point: 96 ° C / 0.8 kPa

Example 5A

3-Dimethylamino-2-methylsulfonylacrylic acid ethyl ester

6.65 g (40 mmol) of methanesulfonyl acid ethyl ester · · · · · · · · · · · ·

acetic acid and 5.72 g (48 mmol) of N, N-dimethylformamide dimethyl acetal 1 were heated at 85 ° C overnight. The solution is then evaporated on a rotary evaporator, the solid is triturated with cyclohexane and filtered off with suction.

Yield: 8.36 g (94.5%).

Example 6A

Acid diamide

2- (4-methylpiperazine) malonic acid

1.00 g (5.52 mmol) of 2-bromomalonic acid diamide (Backes, Vest and Vhiteley, J. Chem. Soc. 1921, 119, 359),

0.61 g (6.10 mmol) of N-methylpiperazine and 1.15 g (8.29 mmol) of potassium carbonate are combined in 10 ml of acetonitrile and the reaction mixture is heated at 50 ° C overnight. The mixture was filtered and the solid was digested with boiling ethanol and filtered off with suction. The filtrate was evaporated on a rotary evaporator and the product was further reacted in crude form.

Yield: 1.14 g (crude yield) Rf (SiO ₂ , BABA): 0.06

Example 7A

2- (4-Acetylpiperazine) malonic acid diamide

9 «9999 9 · · · 9 9 · · · 9

6.16 g (25.8 mmol) of 2-bromomalonic acid diethyl ester, 3.63 g (28.3 mmol) of N-acetylpiperazine and 5.34 g (38.6 mmol) of potassium carbonate are mixed with 100 ml of acetonitrile and heated. at 28 ° C for 28 hours. The reaction mixture is then cooled, taken up in 50 ml of ethyl acetate and washed with water. The organic phase is separated, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator. The yield of crude product is 8.57 g. 7 g of this product are dissolved in 70 ml of a solution of ammonia in methanol and stirred for 90 hours at room temperature. The solid is filtered off with suction, washed with methanol and dried.

Yield: 2.76 g (49.6%).

Example 8A

2- (4-methylpiperazine) malondinitrile

O

About

441 mg (2.04 mmol) of the 2- (4-methylpiperazine) malonic acid diamide of Example 6A was dissolved in 20 mL of tetrahydrofuran: dichloromethane (3: 1). A total of 1.70 (7.15 mmol) of Burgess reagent was added in three equal portions at 30 minute intervals. After an additional thirty minutes, the reaction mixture is directly chromatographed on silica gel using ethyl acetate as the eluent.

Yield: 233 mg (69.4%)

Rf (Si0 _2, EE): 0.22

Analogously to Examples 6A to 8A, compounds were prepared

NCk XN

R

- Ex. R yield (% of theory) is based on malondiamide Rf (SiO ₂ ) 9A ό 80.2 0.72 (EE) 10A 1 ( ^CH 3 O čh ₃ 38.1 0.66 EE 11A 'V ^l h σ 36.5 0.69 (EE) 12A Λ with 81.6 0.75 (EE) 13A A h ₃ co ch ₃ 73.9 0.69 EE

• ·

Ex. R yield (% of theory) is based on malondiamide Rf (SiO ₂ ) 14A ó N cAch ₃ 42.9 0.33 (EE) 15A 0 in 35.2 0.65 EE 16A at 52.5 0.33 (EE) 17A 47.6 0.70 18A Φ CN 13.4 0.68 EE

The preparation of 2-N-morpholino-malondinitrile, 2- (Ν, Ν-dimethylamino) malondinitrile and 2- (Ν, N-diethylamino) malondinitrile is carried out according to H. Gold and O. Bayer, Chem. Ber. 1961, 94, 2594.

The preparation of 2- (1,3-thiazol-2-yl) -malononitrile was carried out according to Yamanaka, H .; Ohby, S. and Sakamota T., Heterocycles, 1990, 31, 1115.

Example 19A

2- (5-methyl-1,3,4-thiadiazol-2-yl) -malononitrile

400 mg (10.0 mmol) of sodium hydride (60% suspension in oil) were suspended in 40 ml of tetrahydrofuran under argon. Malondinitrile (661 mg, 10.0 mmol) in tetrahydrofuran (10 mL) was added dropwise and the reaction was stirred for 15 min before a solution of 2-methyl-5-methylsulfonyl-1 (891 mg, 5.0 mmol) was added dropwise. 3,4-thiadiazole in 10 ml tetrahydrofuran. The reaction mixture was heated to 50 ° C, stirred overnight, cooled and concentrated on a rotary evaporator. The residue is dissolved in water and the pH is adjusted to 3 with hydrochloric acid. This gives a brown solid which is filtered off and dried in vacuo.

Yield: 714 mg (87%).

Mp: 210 ° C (dec.).

Example 20A

5-Amino-1- (2-fluorobenzyl) -1H-pyrazole-3-carboxylic acid ethyl ester

• ·

100 g (0.613 mol) of the sodium salt of ethyl cyanopyruvate (prepared analogously to Borsch and Manteuffel, Liebigs Ann. 1934, 512, 97) are mixed with 111.75 g (75 g) of nitrogen with good stirring under argon. ml, 0.98 mol) of trifluoroacetic acid and stirred for 10 minutes, a large part of the starting material being dissolved. Add 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine and boil overnight. After cooling, the precipitated sodium trifluoroacetate crystals are sucked off, washed with dioxane and the solution is further reacted as crude.

Example 21A

1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid ethyl ester

• ·

The above solution of Example 20A was mixed with 61.25 mL (60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 mL (83.88 g, 0.736 mol) of trifluoroacetic acid and boiled under an argon atmosphere for 3 days. The solvent is evaporated in vacuo, the residue is taken up in water and extracted three times with 1 L of ethyl acetate each time. The organic phases are combined, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator. The residue is chromatographed on 2.5 kg of silica gel and eluted with a 4: 1 toluene / toluene-ethyl acetate gradient.

Yield: 91.6 g (49.9% over two degrees) Mp: 85 Noc: 2 ° C Rf (SiO ₂ , T1E1) : 0,83 Example 1 and d 22A

1- (2-Fluorobenzyl) -4-pyrazolo [3,4-b] pyridine-3-carboxamide

The ester of Example 21A (10.18 g, 34 mmol) is introduced into 150 ml of ammonia at 0-10 ° C saturated methanol, the reaction mixture is stirred for two days at

at room temperature and then concentrated in vacuo.

Rf _(SiO2, T1E1): 0.33

Example 23A

3-Cyano-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

36.1 g (133 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamide from Example 22A are dissolved in 330 ml of tetrahydrofuran and mixed with 27 g (341 mmol). ) pyridine. Trifluoroacetic anhydride (47.76 mL, 71.66 g, 341 mmol) was then added over 10 minutes, increasing the temperature to 40 ° C. The reaction mixture was stirred overnight at room temperature, then added to 1 liter of water and extracted three times with 0.5 L of ethyl acetate each time. The organic phase was washed with saturated sodium bicarbonate solution and 1N HCl, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator.

Yield: 33.7 g (100%)

Mp: 81 ° C

Rf _(SiO2, T1E1): 0.74

Example 24A

1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidic acid methyl ester

Dissolve 30.37 g (562 mmol) of sodium methylate in 1.5 L of methanol and add 36.45 g (144.5 mmol) of 3-cyano-1- (2-fluorobenzyl) -ΙΗ-pyrazolo [3,4] -b] pyridine from Example 23A, stirred for 2 hours at room temperature, and the resulting solution was used directly in the next step.

Example 25A

1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine

• ·

The above solution of (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidic acid methyl ester from Example 24A in methanol was mixed with 33.76 g (32.19 mL, 562 mmol) of glacial acetic acid. and 9.28 g (173 mmol) of ammonium chloride and stirred at reflux overnight.

The solvent was evaporated in vacuo, the residue was triturated with acetone and the precipitated solid was filtered off with suction. It is taken up in 2 liters of water, mixed with stirring with 31.8 g of sodium carbonate and extracted three times with a total of 1 liter of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulphate and evaporated in vacuo.

Yield: 27.5 g (76.4% over two steps)

Mp: 86 ° C

Rf _(SiO2, TlEtOHl): 0.08

Manufacturing examples

Example 1

3- (4-Amino-5-methylsulfonyl-pyrimidin-2-yl) -1- (2-fluoro-benzyl) -1H-pyrazolo [3,4-b] pyridine

g (7.42 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine from Example 25A, 1.39 g (7 mmol)

3- (dimethylamino) -2- (methylsulfonyl) -2-propenenitrile (which is obtainable analogously to Example ΙΑ), 0.79 ml (7 mmol) piperidine and 200 ml isoamyl alcohol are stirred for 12 h at 110 ° C. Deň: 32 ° C. After cooling, the precipitated crystals are filtered off with suction and washed with diethyl ether.

0.94 g (31.8%) of the title compound is obtained.

Mp: 272 ° C

Rf (Si0 _2, EE): 0.72

The following are produced analogously:

444444 · * 44 44 4

44 «···· · · · ······ 4 · · · 4 4 ·· ···· ·

44 ·· · ·· • 444444 44 4 4 · <4 4 ··

Ex. R mp [° C] Rf (SiO ₂ ) yield 2 CH3CH2CH2SO2- 254 0.86 (EE) 30 (CH ₃ ) 2CHSO ₂ - 268 0.82 (EE) 31.6 4 (CH ₃ ) ₃ C-SO ₂ - > 280 0.23 (T1E1) 25.4 5 [(CH ₃ ) ₂ CHO] ₂ PO- 190 0.19 (T2E1) 10.8 - 6 -conh ₂ 215 0.25 T1E1 9.6 7 -SO 2 - (2-thienyl) 275 0.47 (T1E1) 11.5 8 -ch ₂ cf ₃ 181 14.4 9 PhSO ₂ - 279 0.51 (T2E1) 29.2 10 PhSO- 218 0.26 (T2E1) 19.4 11 - (CH ₂ ) ₅ CN 107 0.21 (EE) 18 12 - (CH ₂ ) 7 CN 147 0.36 EE 13.5 13 -CH2CH2-CN 201 0.2 (T4EtOHl) 12

The corresponding 3-dimethylaminoacrylonitriles having the corresponding R-substituent at the 2-position, which are reacted with the amidine of Example 25A as starting compounds of Examples 2-13 can be prepared analogously to Examples 1A and 3A.

Example 14

3- [5-Cyano-4- (4-methyl-phenyl) -pyrimidin-2-yl] -1- (2-fluoro-benzyl) -1H-pyrazolo [3,4-b] pyridine

• ♦ 0 0 0 t 0 0 00

00 »

200 mg (0.74 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine from Example 25A, 171 mg (0.8 mmol) of (dimethylamino) -2- ( 4-methylbenzoyl) -2-propenenitrile (which is obtainable analogously to Example 1), 0.68 mg (0.8 mmol) of piperidine and 20 ml of 2-pentanol are stirred for 12 hours at 110 ° C. After cooling, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel. 217 mg (69.5%) of the title compound are obtained.

Mp: 229 ° C

Example 15

3- (4,6-Diamino-5-benzyl-pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

200 mg (0.74 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine from Example 25A, 125 mg (0.8 mmol) of 2-benzylmalodinitrile (obtainable from malodinitrile) and benzyl bromide with a base such as potassium carbonate), 0.68 mg (0.8 mmol) of piperidine and 20 mL of 2-pentanol were stirred at 110 ° C for h. After cooling, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel. 165 mg (52.2%) of the title compound are obtained.

Mp: 193 ° C

Example 16

3- (4,6-Diamino-5-N-morpholinopyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

200 mg (0.74 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine from Example 25A and 400 mg (2.65 mmol) of 2-N-morpholino-malondinitrile (synthesis) see H. Gold and 0. Bayer, Chem. Ber. 1961, 94, 2594) are heated at 105 ° C under vacuum for 12 hours. The solid residue was dissolved in dimethylformamide, silica gel was added and the solvent was evaporated in vacuo. After chromatography, 222 mg (71.1%) of the title compound are obtained.

Mp: 261 ° C

Rf: (EE): 0.2

- 85 Produced in analogy

Example R yield Rf (SiO ₂ ) 17 (from 25A and 2- (1H-1,2,4-triazolyl) -malonic acid diethyl ester) (according to Ex. 7A)) N ^ N HO ^ Y ^ OH N 29.5 0.32 (BABA) 18 (from 25A and 10A) N ^ N ^CH = 11.9 0.36 (BABA) 19 Dec (from 25A and 2-acetamidocyanacetic acid ethyl ester N ^ N ° γ ^Ν ch ₃ 12.9 0.61 (BABA) 20 May (from 25A and 2-N-pyrrolmalonic acid diethyl ester) "AND- O 15.2 0.63 (EE)

· · · · · · · · · · · ·

Example R yield (% of theory) Rf (SiO ₂ ) 21 (from 25A and 8A) Ú ₂ Ν ^ Υ ^ ^ΝΗ 2 ú N ch ₃ 82.7 0.06 (BABA) 22nd (of 25A and hydroxyimino- malononitrile, sodium salt) <N o ^x 1,8 0.50 (EE) 23 (from 25A and 12A) N ^ N Η, Ν '^^ ΝΗ, at WITH 43.3 0.85 (BABA) 24 (from 25A and 13A) N ^ N h ₂ n ^ V ^ nh ₂ Λ h ₃ c ^ o ^ ch ₃ 72.4 0.72 (BABA) 25 (of 25A and 2-N-dimethylaminomalondinitrile) (Synthesis vgl. Chem. Ber. 1961, , 2594)) 1 'H ₂ N'N 4 ^NH 2 H ₃ C' ^N 'CH ₃ 41.6 0.53 (BABA)

and

Example R yield (% of theory) Rf (SiO 2) 26 (from 25A and 2-N-diethylaminomalondinitrile) (Syntesa vgl. Chem. Ber. 1961, 94, 2594)) nAn 1 1 ' AND 58.4 0.75 (BABA) 27 Mar: (from 25A and 14A) A * h ₂ nY ^ h ₂ µ H ₃ C ^ O 52.3 0.27 (BABA) 28 (from 25A and 9A) Λ KnYM Ν 0 54.8 0.65 (BABA) 29 (from 25A and 15A) | N Η ₂ νΑ | Α _ΝΗ2 0 v 55.1 0.48 (BABA) 30 (from 25Δ and 16A) N ^ N ^H 2 ^N-NH S U N 2 H ₃ C '° ^ crude product O.OS (BABA)

• · · ·

Example R yield (% of theory) Rf (SiO ₂ ) 31 (from 25A and 17A) N 2 N k A ^H 2 ^N 1 4 ^NH 2 9 cAo k * 1 ~ -I 0.50 (EE) 32 (from 25A and 18A) N ^ N h ₂ nS ^ nh ₂ . 0 CN 97.7 0.53 (BABA) 33 (from 25A and 2- (thiazol-2-yl) malondinitrile (synthesis: Heterocycles, 1990, 31, 1115) \ = J 22.1 0., S5 (BABA) 34 (from 25A and 19A) N ^ N ^H 2 ^N ^ V ^ ^NH 2 N ^ S \ / N = ech ₃ 1,2 0.63 BABA

9 · · · «« «« fl fl fl fl fl. Fl

Example R yield (% of theory) Rf (SiO ₂ ) 35 (of 25A and 2-methyl- sulfonyl- malondi- nitrile) N ^ N O = S = O '1 ch ₃ 1.1.3 0.90 (BABA)

Example 36

3- (4,6-bis (trifluoromethyl) pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

mg (19 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine from Example 25A and 42 mg (20 mmol)

1,1,1,5,5,5-hexafluoroacetylacetone was held at 110 ° C for 5 hours. Chromatography gave 33 mg (40.3%) of the title compound.

Mp: 109 ° C

Rf: (Tol): 0.35

Example 37

3- (5-ethoxycarbonyl-4-trifluoromethyl-pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

Cl

600 mg of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamidine hydrochloride (obtainable from the amidine of Example 25A by reaction with HCl) is stirred in 30 ml of methanol with 106 mg of sodium methoxide and mixed with 472 mg (1.96 mmol) of 3-ethoxy-2-trifluoroacetyl-acrylic acid ethyl ester. After stirring for 12 hours, the precipitate was filtered off with suction and washed with diethyl ether. 249 mg (27.5%) of the title compound are obtained as crystals.

Mp: 174 ° C

Rf: _SiO2 T1E1: 0.76

Example 38

4-Amino-2- (1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl} -pyrimidine-5-phosphonic acid diethyl ester:

2.44 g (9.00 mmol) of the amidine of Example 25A and 3.71 g (16.0 mmol) of 1-cyano-1- (dimethylamino) methylene-methanephosphonic acid diethyl ester (Aboujaoude, Elie Elia; Collignon, Noel; Savignac (Philippe, Tetrahedron, 41, 1985, 427-434) is well mixed, sonicated for 5 minutes and then stirred overnight at 100 ° C under vacuum in a diaphragm pump. The reaction mixture was cooled to room temperature, stirred hot with methanol, and the insoluble components were removed by filtration. The filtrate is concentrated and the residue is chromatographed on silica gel (C → C: E 1: 1-> E).

Yield: 638 mg (16%)

Mp: 185 ° C

R _f: 0.09 (C: E 1: 1)

Example

3- (4-Amino-5-N-morpholin-pyrimidin-2-yl) -1- (2-fluoro-benzyl) -4-pyrazolo [3,4-b] pyridine

CN

1.00 g (3.72 mmol) of the amidine of Example 25A and 2.00 g (11.0 mmol) of the 3- (dimethylamino) -2-morpholino-acrylonitrile of Example 3A are mixed well, sonicated for 5 minutes. and then stirred under vacuum at 120 ° C overnight. The reaction mixture was cooled to room temperature, stirred with tert-butyl methyl ether, and the precipitate formed was filtered off with suction and chromatographed on silica gel (C: E 100: 1 → C: E 1: 1).

Yield: 262 mg (17%).

Mp: 205 ° C

R _f 0.05 (C: E 1: 1)

Example 40

3- (4-Amino-5-N-thiomorpholin-pyrimidin-2-yl) -1- (2-fluoro-benzyl) -4-pyrazolo [3,4-b] pyridine

5.00 g (18.6 mmol) of amidine from Example 25A and 9.98 g (50.7 mmol) of 3- (dimethylamino) -2-thiomorpholinacrylonitrile from Example 4A were mixed well, sonicated for 5 minutes and then was stirred overnight under vacuum at 100 ° C. The reaction mixture was cooled to room temperature, stirred with tert-butyl methyl ether, and the precipitate formed was filtered off with suction.

Yield: 1.43 g (18%)

Mp:> 205 ° C

R _f: 0.06 (C: EE 1: 1)

Example 41

3- (4-Hydroxy-5- (methylsulfonyl) -pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

H, N

The amidine of Example 25A (2.32 g, 8.61 mmol) and the enamine of Example 5A (5.71 g, 25.8 mmol) were mixed and heated in an open vessel at 100-105 ° C for 4 hours. The residue obtained is cooled, digested with toluene, filtered and washed with toluene.

Yield: 1.16 g (33.6%)

Rf _(SiO2, EA) = 0.23

Example 42

3- (6-chloro-8-methyl-9H-purin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

650 mg (1.65 mmol) of hydroxypyrimidine of Example 19 are taken up in 3 ml of phosphorus oxytrichloride, two drops of Ν, Ν-dimethylaniline are added and the solution is heated under reflux for 3 hours. The reaction mixture was then cooled and evaporated on a rotary evaporator. The residue is taken up in ethyl acetate, carefully washed with saturated sodium bicarbonate solution, dried and evaporated on a rotary evaporator. The crude product obtained is further reacted.

Yield: 580 mg (89.1%) R f (SiO ₂ , EE): 0.21

The following compounds were prepared analogously to Example 42:

F

R

Ex. Edukt Product yield (% of theor.) Rf (SiO 2) 43 O O i n: L . N ^ N '"""and 59.6 0.70 (EE) 44 N ^ N HO ^ Y ^ OH at O O nestano- dowry (crude product) O.64 (C1E1) 45 N ^ N o - - - ch ch ₃ N ^ N Ο '-''Ό ch ₃ 21.4 0.44 (0 E2)

The starting material of Example 43 was prepared as the compound of Example 17. The starting material of Example 44 was prepared as the compound of Example 20. The starting material of Example 45 was produced as the compound of Example 41.

• ·

Example 46

3- (5-ethyl-4- (2-hydroxyethylaminocarbonyl) pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

70.0 mg (0.179 mmol) of methyl ester (produced from Example 25A and 4- (dimethylamino) -3-ethyl-2-oxo-3-butenoic acid methyl ester analogously to Example 36) at 109.3 mg ( 1.78 mmol) of amine and stirred for 3 hours at 60 ° C. Dichloromethane was then added and washed once with 0.5 N hydrochloric acid solution. The organic phase is dried over anhydrous magnesium sulphate and evaporated in vacuo.

Yield: 30.6 mg (40.7%)

Rf _(SiO2, E) 0.31

They are prepared analogously by reaction with the corresponding amines:

F

H ₃ C

Example R yield Rf (SiO 2) 47 —N \ H 36.0 0.48 (C1E2) 48 —N \ _ Q 13.2 0.20 (C1E2) 49 \ X CH, CH N ^3, crude product 0.12 (C1E2) 50 CH, / - (\ _ ch ₃ 22.0 « 0.37 (C1E2) 51 -O crude product 0.42 (E) 52 —1 H -QH 22.8 0.05 (C1E2) 53 N 0 CH ₃ H crude product 0.37 (C1E2) 54 ΤΌ crude product 0.61 (C1E2) 55 87.0 0.65 (C1E2) 56 Tkl 57.7 0.66 (C1E2) 57 -NH, 86.9 0.26 (C1E2)

························································ 9 9 9 9 9 99 9 9 9

Amines useful as starting compounds are commercially available or are readily prepared by those skilled in the art by conventional methods such as those described by J. Mark, Advanced Organic Chemistry, 3 ed., Viley, 1985, p.1153.

Example 58

3- (4- (4,5-dihydro-4-imidazol-2-yl) -5-ethyl-pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

Dissolve 68.9 mg (1.15 mmol) of ethylenediamine in 10 mL of toluene and add 0.60 mL (1.15 mmol) at 0 ° C.

M solution of trimethylaluminum in toluene and the reaction mixture was stirred for 2 hours at room temperature. 155 mg (0.38 mmol) of ethyl ester (made from the compound of Example 25A and ethyl 4- (dimethylamino) -3-ethyl-2-oxo-3-butenoate, analogously to Example 36) are then added. The reaction mixture is stirred for 5 days at 75 ° C, cooled, washed with sodium potassium tartrate solution and the aqueous phase is extracted with dichloromethane. The organic phases were combined, dried over magnesium sulphate, treated with 500 mg of silica gel and evaporated on a rotary evaporator.

For purification, it was chromatographed on 10 g of silica99 gel (0.040-0.063 mm) using an ethyl acetate to ethyl acetate / methanol 9: 1 system as eluent.

Yield: 75.0 mg (49%).

Rf _(SiO2, C1E1): 0.04

Example 59

- [5-ethyl-4- (1H-imidazol-2-yl) -pyrimidin-2-yl] -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

mg (0.15 mmol) of the dihydroimidazole of Example 58 and 100 mg of palladium on carbon (10%) in 5 ml of toluene were heated to reflux. After 6 days, the reaction mixture was filtered and the solvent was evaporated in vacuo.

The material is chromatographed on 8 g of silica gel (0.040-0.063 mm) using cyclohexane / ethyl acetate 2: 1 to 1: 2 as eluent.

Yield: 8.8 mg (14.3%)

Rf _(SiO2, C1E2): 0.24

Example 60

3- (5-ethyl-4- (1H-imidazol-1-yl) -pyrimidin-2-yl) -1- (2 *)

100 ALIGN!

(fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

N mg (0.16 mmol) of chloro compound (made from Example 25A and 2-formylbutanoic acid ethyl ester analogously to Example 36 followed by reaction with phosphorus oxytrichloride analogously to Example 42) and 22.2 mg (0) (33 mmol) of imidazole was dissolved in 5 ml of dimethylformamide and treated with 33.8 mg (0.24 mmol) of potassium carbonate, followed by stirring at 100 ° C overnight. The reaction mixture was then cooled, diluted with ethyl acetate and washed twice with water. The organic phase was separated, dried over anhydrous magnesium sulphate and evaporated in vacuo.

Yield: 47.4 mg (72.7%).

Analogously to Example 60, the following compounds were prepared by reaction with the corresponding amines:

• ···

- 101

Example R ¹ R ² yield Rf (SiO ₂ ) 61 (from ex. 45) SO ₂ CH ₃ 'ΛΛ —N 0 79.3 0.58 (E) 62 (from ex. 45) Sat ₂ ch ₃ H 58.3 0.34 (Cl E2) 63 (from ex. 45) Sat ₂ ch ₃ 1 H 29.0 0.43 (C1E2) 64 (see example 60) ch ₂ ch ₃ ^ N ^ CH ₃ ¹³ H 25.6 0.18 (C1E2) 65 (see example 60) ch, ch ₃ ,! H 11.4 0.11 (C1E2) 66 (see example 60) ch ₂ ch ₃ -0 crude product 0.36 (Cl E2) 67 (see example 60) ch ₂ ch ₃ / - \ —N 0 IN-/ crude product 0.22 (C1E2) 6S (see example 60) ch ₂ ch ₃ -Ό crude product 0.14 (C1E2) í 69 (see example 60) ch ₂ ch ₃ H NH ₂ 7.7 j 0.03 (C1E2) 70 (see example 60) ch ₂ ch ₃ ch ₃ 8.8 0.30 (CIE2)

• · ··················

102

Examples 71-79

The chloro group of the compounds of Examples 42 to 45 can be reduced by known methods using ammonium formate and palladium on carbon or exchanged by reaction with nucleophiles such as azidanion, ammonia, amines or methanol. The azido group so introduced can be reduced by sodium dithionite itself. The following compounds are obtained in this way:

R

Example R yield (% of theory) Rf (SiO 2) 71 (ex. 42) N ^ N ll · ij η-ν'Τ> = N h ₃ c 53.7 0.25 (EE) 72 (ex. 42) N ^ N h-n (N) = N h ₃ c 26, S 0.69 (BABA)

103 ·· «··· • · · ♦ · · · · ·

Example R yield f% theory) Rf (SiO ₂ ) 73 (ex. 42) N ^ N) = N h ₃ c 13, S 0.61 (BABA) 74 (ex. 42) N ^ N h- _n ^{/ L} V ^ n ^ ^x ^ ch ₃ ) = NH h ₃ c crude product 0.78 (BABA) 75 (from ex. 44) Η, Ν- ^ ψ ^ ΟΙ O crude product 0.53 (BABA) 76 (from ex. 44) ? ^h 3 i ch ₃ xVv Η Ν H O crude product 0.77 (EE) 77 (ex. 43) N ^ N C 1 - ^ y ^ NH ₂ & 9.8 78 (ex. 43) N ^ N XX Η, ΟΟ'γ ^ ΝΗ, N- ⁴ ' 10.6 0.73 (BABA) 79 (from Ex. 43) N ^ N ^H 2 ^N-NH ₂ S .N. ^N // ⁴ ' 18.9 0.29 (EE)

ftft · ··· ft · · ··················································

104 · · · · · · · · · · · · ·

Example 80

3- (4-Diacetylamino-5-ethyl-pyrimidin-2-yl) -1- (2-fluoro-benzyl) -4-pyrazolo [3,4-b] pyridine

50.0 mg (0.14 mmol) of the amine (obtainable analogously to Example 60 by reaction of the chlorine compound described herein with ammonia and optionally sodium azide followed by reduction with sodium dithionite) is dissolved in dichloromethane and mixed with 33.8 mg. (0.43 mmol) of acetyl chloride and 68.1 mg (0.86 mmol) of pyridine. The solution was stirred for 4 hours at room temperature, washed once with 1 N HCl and then with saturated NaHCO 3 solution. The organic phase was separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The material was chromatographed on silica gel (0.040-0.063 mm) for purification using cyclohexane / ethyl acetate 1: 1 as eluent.

Yield: 33.2 mg (53.5%)

Rf _(SiO2, C1E2): 0.41

103 ·· · «··»

• tt tt

Example 81

3- [4- (2-Benzoyloxymethyl-benzoylamino) -5-ethyl-pyrimidin-2-yl] -1- (2-fluoro-benzyl) -1H-pyrazolo [3,4-b] pyridine

H-C mg (0.23 mmol) of sodium hydride (60% suspension in oil) was suspended in 1 ml of tetrahydrofuran at room temperature. A solution of 40 mg (0.11 mmol) of an amine (see Example 80) with 0.8 mL of tetrahydrofuran was added followed by a solution of 34.7 mg (0.13 mmol) of 2- (benzoyloxymethyl) benzoyl chloride. After 30 minutes, 5 ml (0.12 mmol) of sodium hydride (60%) and 14 mg (0.05 mmol) of the above acid chloride were added again. After one hour, the reaction mixture was treated with water, extracted

106 with ethyl acetate, the organic phase is washed with 1 M hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. The material was crystallized from cyclohexane / ethyl acetate.

Yield: 25 mg (37.1%)

Rf _(SiO2, C1E1): 0.50

Example 82

3- (4-Acetoxy-5-ethyl-pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine;

3- (3-Acetyl-5-ethyl-pyrimidin-4-one-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

O

Xach H, CO CH ₃

73.8 mg (0.21 mmol) of the hydroxypyrimidine compound (prepared from Example 25A and 2-formylbutanoic acid ethyl ester analogously to Example 36) were dissolved in 2 mL of dichloromethane and mixed

27.9 mg (0.27 mmol) of triethylamine and 25.9 mg (0.25 mmol) of acetic anhydride. The solution was stirred for three

107 hours at room temperature, then taken up in ethyl acetate, washed with water and the aqueous phase extracted once with ethyl acetate. The combined organic phases are washed twice more with water, dried over anhydrous magnesium sulphate and evaporated on a rotary evaporator.

Yield: 42.0 mg (50.8%)

Rf (Si0 _2, C1E2): 0.5

Example 83

3- (5-ethyl-4- (methylsulfinyl) -pyrimidin-2-yl) -1- (2-fluoro-benzyl) -1H-pyrazolo [3,4-b] pyridine and

3- (5-ethyl-4- (methylsulfonyl) pyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

45.2 mg (0.12 mmol) of methylthioether (produced from Example 60 of the chloro compound used by reaction with sodium methanethiolate in toluene) and 30.8 mg (0.18 mmol) of MCPBA in 2 mL of dichloromethane are stirred at 0 ° C. After three hours, the reaction mixture is treated with sodium bicarbonate solution and ethyl acetate, the organic phase is separated, dried and evaporated on a rotary evaporator.

The material is chromatographed on 8 g of silica gel (0.040-0.063 mm) using cyclohexane / ethyl acetate 1: 1 to 1: 4 as eluent.

• · · · · · · · · · · · · · · · ·

- 108

B: Yield: 36.0 mg (76.4%) Rf (SiO ₂ , ClE ₂ ): 0.057

C: Yield: 7.1 mg (14.5%) Rf (Si0 _2, C1E2): 0.79

Example 84

3- (4,6-diamino-5-N-4-oxothiomorpholinopyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine;

3- (4,6-Diamino-5-N-4,4-dioxothiomorpholinopyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

230 mg (0.53 mmol) of thiomorpholine of Example 23 and 130 mg (0.53 mmol) of MCPBA were stirred in 5 mL of dichloromethane at 0 MCPBA. After 30 minutes, the same amount of MCPBA was added again. After 1.5 hours, the reaction mixture was treated with silica gel and evaporated. The material is chromatographed on silica gel 60 (0.040-0.063 mm) using cyclohexane / ethyl acetate for purification.

B: Yield: 86 mg (36.1%) Rf (SiO ₂ , BABA): 0.18

C: Yield: 14 mg (5.7%) Rf _(SiO2, BABA): 0.41.

Claims (17)

PATENT CLAIMS 109 Substituted pyrazole derivatives of the general formula I CH — A in which R1 represents a saturated or aromatic 5- or 6-membered heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, which may be bonded via a nitrogen atom and which is optionally up to two times the same or differently substituted by a radical from group (i) atom, amino, azido, formyl, mercaptyl, carboxyl, hydroxy, straight or branched acyl, alkoxy, alkylthio or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight or branched alkyl groups of up to 6 carbon atoms, which may itself be substituted by hydroxy, amino, azido, carboxyl, straight or branched An acyl, alkoxy, alkoxycarbonyl or acylamino group of up to 5 carbon atoms or a radical of the formula -OR 4, wherein: R 1 represents a straight or branched acyl group of up to 5 carbon atoms, and / or is substituted by a radical of the formula O-ch ₂ o (ch ₂ )> - - (|. X _ OCH ₂ - (CH ₂ ) _and O (CH ₂ ) _b N. OR "or -S (0) -NR ^ R ^, where a, bab 'are the same or different and denotes 0, 1, 2, or 3, R 6 denotes a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, c denotes 1 or 2 and r 6 and R 6 are the same or different and denote a hydrogen atom or a straight or branched alkyl group of up to 10 carbon atoms optionally substituted with cycloalkyl of 3 to 8 carbon atoms or aryl of 6 to 10 carbon atoms, which in itself may be substituted by halogen, - 111 or represents an aryl group having 6 to 10 carbon atoms, which is optionally substituted by a halogen atom, or represents a cycloalkyl group having 3 to 10 carbon atoms; Or 7 R ⁶ and R ⁷ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle, which may optionally contain an additional oxygen atom or a radical of the formula -NR, wherein: Q R represents a hydrogen atom, a straight or branched alkyl group of up to 4 carbon atoms, or a radical of the formula benzyl or phenyl, the ring systems being optionally substituted with halogen, and at least one radical of (ii) comprising a three to eight membered ring which may be saturated, unsaturated or partially unsaturated, contains 1 to 4 heteroatoms selected from the group consisting of N, O, S, SO and SO ₂ and may also be bonded through nitrogen, with imidazolyl, imidazolinyl, imidazolidinyl being particularly preferred. - 112 morpholine, piperidine, piperazine, pyrrolidine, triazolyl, pyrrole, thiomorpholine, S-oxothiomorpholine and S, S-dioxothiomorpholine ring optionally substituted one or more times by a 5- or 6-membered ring containing two oxygen atoms as ring members and with a three-membered ring to 8-membered rings form a bicyclic unit or spiro unit and / or a hydroxy, cyano, straight or branched alkyl, acyl or alkoxycarbonyl group of up to 6 carbon atoms each of which the alkyl, acyl and alkoxycarbonyl group may be substituted by hydroxy, amino, carbox, carbox or a linear or branched acyl, alkoxy, alkoxycarbonyl or acylamine group of up to 5 carbon atoms each, and an aryl ring of 6 to 10 carbon atoms which is substituted by a straight or branched alkyl group of up to 4 carbon atoms and alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkyl of 7 to 20 carbon atoms. optionally substituted by aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxy, straight or branched acyl, alkoxy, alkoxycarbones; - a 113 or acylamino group each having up to 5 carbon atoms or the remainder of the RMM '*, R ^ denotes a straight or branched acyl group of up to 5 carbon atoms, and an alkyl group of 1 to 6 carbon atoms which is substituted one to three times with an aryl, heteroaryl, halogen, cyano, dialkylamino, alkylamino or cycloalkyl group, and acyl a group which is substituted by a halogen atom, in particular a fluorine atom, an acyloxy group, an arylthio group or a heteroarylthio group, and a -NO group or a radical of formula SO4H or -SOOjjR4, where d is 1 or 2 and R ^ denotes a straight or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms or a saturated or unsaturated 5- to 6-membered heterocycle having up to 3 heteroatoms for sulfur-containing groups, nitrogen and / or oxygen, wherein the ring systems may be optionally substituted with a halogen or a straight or branched alkyl or alkoxy group with - 114 in each case up to 4 carbon atoms, and the remainder of the formula ΡΟ (ΟΡ ² θ) (OR ¹¹ ), R ¹⁰ and R ¹¹ are the same or different and denote a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms or a benzyl group, and an oxycycloalkyl group 3 to 8 ring members or radicals of the formulas -CON = C (NH ₂ ) ₂ > -C = NH (NH ₂ ), -NH-C (= NH) NH ₂ or (CO) _e NR ¹² R ¹³ , where e represents 0 or 1 a -19 13 R ^x and R are the same or different and denote a hydrogen atom, a straight or branched alkyl group of up to 14 carbon atoms, a cycloalkyl group of 3 to 14 carbon atoms, an aryl group of 6 to 10 carbon atoms or a saturated or unsaturated three to ten membered ring up to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said radicals may be substituted by an aryl group of 6 to 10 carbon atoms, a heterocyclyl group, a cycloalkyl group of 3 to 7 carbon atoms, a hydroxy group, an amino group or a straight 115 or a branched alkoxy, acyl or alkoxycarbonyl group each having up to 6 carbon atoms, and when e = 1, R ²² _and R ²³ may also, with the inclusion of the nitrogen atom to which they are attached, form a 5- or 6-membered ring with up to 3 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, which may optionally be up to three times substituted by hydroxy or alkyl or alkoxy. up to 8 carbon atoms, and if e = 0, 19 13 R and R may also stand for straight, branched or cyclic acyl group having up to 14 carbon atoms, hydroxyalkyl, straight-chain or branched alkoxycarbonyl or alkoxyalkyl each having up to 6 carbon atoms or a radical -SO-R ^24, wherein R ³⁴ denotes a straight or branched alkyl group having up to 4 carbon atoms, and / or R ¹² and R ¹³ also denote radicals of the formulas - 116 - OR ¹⁵ O 0 ' - ^r r C-R ¹⁷ O R ²⁶ -O-CH (R ²⁷ ) -O-CO 117 in addition R ³ and R ^ and R ^ _and f R31 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, represents the number 0, 1 or 2 and denote phenyl, straight-chain or branched alkyl having up to 6 carbon atoms or a 3 to 8 carbon cycloalkyl group, with the proviso that when e = 0, not 12 13 R and R simultaneously represent a hydrogen atom, or R @ ¹ denotes a purine radical which may be optionally up to three times substituted by halogen, azido, cyano, hydroxy, amino, alkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms, alkyl of up to 5 carbon atoms and / or alkoxysku ········································· 118 pins with up to 5 carbon atoms, 2 3 R and R include a six membered saturated or aromatic heterocycle with up to 3 heteroatoms selected from the group consisting of nitrogen, sulfur and / or oxygen, which may optionally be up to three times the same or differently substituted with a formyl, carboxy, hydroxy, mercaptyl, straight or branched acyl, alkylthio or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, halogen or straight or branched alkyl or alkoxy of up to 6 carbon atoms each of which may themselves be substituted by hydroxy, amino, carboxy, straight or branched chain acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, and / or is optionally substituted with the group -NR ² R 33, wherein r 32 _and r 33 are the same or different and denote a hydrogen atom or a straight or branched alkyl group having up to 6 carbon or atoms R represents a hydrogen atom and r33 represents an acyl group, and / or may be optionally substituted by a phenyl group, which itself may be substituted up to two times the same or differently by a halogen atom or a direct one, or - 119 branched alkyl or alkoxy of up to 6 carbon atoms, and / or is optionally substituted with the formula -N = CH-NR ³⁴ R ³⁵ , wherein: R ³⁴ and R ³³ are the same or different and denote a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 6 carbon atoms, and A denotes a 5- or 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen or phenyl optionally substituted up to three times the same or differently with amino, mercaptyl, hydroxy, formyl, carboxy, straight or branched acyl, alkylthio, alkyloxyacyl, alkoxyacyl, alkoxyacyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight or branched alkyl having up to 6 carbon atoms it may itself be substituted by hydroxy, carboxy, straight or branched acyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms each, and / or substituted by the formula - (CO) _h -NR ³⁶ R ³⁷ , the number being 0 or 1 a 120 «2 (Z 2 7 R ¹⁰ and R ¹⁰ 'are the same or different and denote a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl or acyl group of up to 5 carbon atoms each, and their isomeric forms and salts. The substituted pyrazole derivatives according to claim 1, in which R represents a saturated or aromatic five-membered six-membered heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen which may be attached via a nitrogen atom and which is optionally up to two times the same or differently substituted with , amino, azido, formyl, mercaptyl, carboxyl, hydroxy, straight or branched acyl, alkoxy, alkylthio or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight or branched chain having up to 6 carbon atoms, which itself can be substituted by hydroxy, amino, azido, carboxyl, straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino, each having up to 5 carbon atoms or a radical of the formula -OR 4, wherein 121 R ⁴ represents a straight or branched acyl group of up to 5 carbon atoms, and / or is substituted by a radical of the formula O-CH ₂ O (CH ₂ ) _b - (I '( OCH ₂ - (CH ₂ ) ₃ O (CH ₂ ) _b 'N. 5 OR where a, bab 'are the same or different and denotes 0, 1, 2 or 3 and R ³ represents a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, and at least one radical of group (ii) comprising a three to eight membered ring which may be saturated, unsaturated or partially unsaturated contains 1 to 4 heteroatoms from the group including N, O, S, SO and SO ₂ and may also be bonded through nitrogen, with imidazolyl, imidazolinyl, imidazolidinyl, morpholine, piperidine, piperazine, pyrrolidine, triazolyl, pyrrole, thiomorpholine, S-oxothiomorpholine and S, S particularly preferred. -dioxothiomorpholine ring and which is optionally one, or 9 · 9 ··· - 122 -. · ··· .. :::. :: • 9 Multiple substituted by a 5- or 6-membered ring containing two oxygen atoms as ring members and with a 3- to 8-membered ring constituting a bicyclic unit or spiro unit and / or a hydroxy, cyano, straight or branched alkyl, acyl group or an alkoxycarbonyl group having up to 6 carbon atoms each, the alkyl, acyl and alkoxycarbonyl group being substituted by hydroxy, amino, halogen, carboxy or a straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino group each having up to 5 carbon atoms, (C až-C 10) alkyl group substituted with straight or branched (C 4-C 4) alkyl and (C a-C alk) alkenyl, (C až-C alk) alkynyl, (C až-C 20) alkyl group j e optionally substituted with aryl, heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamino, hydroxy, amino, azido, carboxy, straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino, in each case OR ⁴ , wherein R ⁴ denotes a straight or branched acyl group The group consisting of up to 5 carbon atoms and 1 to 6 carbon atoms substituted one to three times by aryl, heteroaryl, halogen, cyano, dialkylamino, alkylamino or cycloalkyl, and acyl substituted by an atom halogen, in particular fluorine, acyloxy, arylthio or heteroarylthio, and -NO or the radicals SO4H or -5 (O) ^ 9, where d is 1 or 2 and R ^ represents a straight or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms or a saturated or unsaturated 5- to 6-membered heterocycle having up to 3 heteroatoms for sulfur, nitrogen and / or oxygen, wherein the ring systems may be optionally substituted by halogen or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms each, and the remainder of the formula PO (OR ¹¹ ) (OR ¹¹ ), wherein: - 124 R- ^θ and R stejné^ nebo are the same or different and denote a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms or a benzyl group, and a 3- to 8-ring oxycycloalkyl group or radicals of the formulas -CON = C (NH ₂ ) ₂ > -C = NH (NH ₂ ), -NH-C (= NH) NH ₂ or (CO) _e NR ¹² R ¹³ , where e is 0 or 1 and 19 11 R and R are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 14 carbon atoms, a cycloalkyl group of 3 to 14 carbon atoms, an aryl group of 6 to 10 carbon atoms or a saturated or unsaturated 3 to 10 membered ring 5 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, said radicals being optionally substituted by an aryl group having 6 to 10 carbon atoms, a heterocyclyl group, a cycloalkyl group having 3 to 7 carbon atoms, a hydroxy group, an amino group or a straight or branched alkoxy, acyl or alkoxycarbonyl having up to 6 carbon atoms in each case, 125 and, if e = 1, R ²² and R ²³ may also, with the inclusion of the nitrogen atom to which they are attached, form a 5- or 6-membered ring with up to 3 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, which may optionally be up to three times substituted by hydroxy or alkyl or alkoxy. up to 8 carbon atoms, and if e = 0, 19 13 R and R may also be a straight, branched or cyclic acyl group of up to 14 carbon atoms, a hydroxyalkyl, a straight or branched alkoxycarbonyl or alkoxyalkyl group of up to 6 carbon atoms, or a radical of -SO ₂ R ³⁴ , denoting a straight or branched alkyl group with and / or n12-n13 also denotes radicals of the formulas - 126 • 4 * 4 * «« • 444 · · · · · «· * ¹ • • *« <4 4 * Λ · ·· »4 ·· ο ο ^R16 15, 0 '· · · · · · · · · · · 127 wherein _a r 16 _and r 18 r 31 are the same or different and denote a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, g denotes 0, 1 or 2 and 1 7 R represents a phenyl group, a straight or branched alkyl group having up to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, with the proviso that when e = 0, no123 R and R simultaneously represent a hydrogen atom, or R1 denotes a purine radical which may optionally be up to three times substituted by halogen, azido, cyano, hydroxy, amino, alkylamino of up to 5 carbon atoms, dialkylamino of up to 5 carbon atoms, alkyl of up to 5 carbon atoms and / or alkoxy of up to 5 carbon atoms, R and R include a fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl moiety, which may optionally be up to two times the same or differently substituted by a formyl, carboxy group, including a double bond. · * 128 hydroxy, mercaptyl, straight or branched acyl, alkylthio or alkoxycarbonyl of up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine or bromine, or straight or branched alkyl or alkoxy of up to 5 carbon atoms which may themselves be substituted by hydroxy, amino, carboxy, straight or branched acyl, alkoxy or alkoxycarbonyl of up to 4 carbon atoms, and / or the abovementioned heterocyclic rings are optionally substituted by a group of the formula -NR R ', R ^J and R ^J are the same or different and denote a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, or -i o R is hydrogen and -i a R represents a formyl group, and / or the abovementioned fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl rings optionally substituted by a phenyl group, which itself may be substituted by a fluorine, chlorine or bromine atom, or a straight or branched alkyl or alkoxy group each having up to 4 carbon atoms and A denotes thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl 129 are optionally substituted up to two times the same or differently by hydroxy, formyl, carboxy, straight or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl of up to 4 carbon atoms or fluorine, chlorine or bromine and their isomeric groups forms and salts. The substituted pyrazole derivatives according to claim 1, in which R ⁴ represents a pyrimidine radical which is optionally up to two times the same or differently substituted by a radical from the group (i) comprising a hydrogen atom, an amino group, a hydroxyl group, an alkoxycarbonyl alkoxycarbonyl group of up to 3 carbon atoms each, a cyano group or a halogen atom; ii), comprising a 5- to 6-membered ring, which may be saturated, unsaturated or partially unsaturated, contains 1 to 3 heteroatoms from the group consisting of N, O, S, SO and SO ₂ and may also be bonded through nitrogen, imidazolyl being particularly preferred , an imidazolinyl, imidazolidinyl, morpholine, piperidine, piperazine, pyrrolidine, triazolyl, pyrrole and thiomorpholine ring, and which is optionally one or more times a substituent. - 130 bold five-membered ring containing two oxygen atoms as ring members and with a three to eight membered ring forms a bicyclic unit or spiro unit such as 1,4-dioxa-8-azaspiro [4.5] decane and 1,5-dioxa-9 -azaspiro [5.5] undecane radical, and / or hydroxy, cyano, straight or branched alkyl, acyl or alkoxycarbonyl of up to 3 carbon atoms each, the alkyl, acyl and alkoxycarbonyl groups being substituted by hydroxy, amino, halogen or carboxy a straight or branched acyl or alkoxy group of up to 3 carbon atoms each, and a tolyl radical, or an alkyl group of 7 carbon atoms optionally substituted by cyano and an alkyl group of 1 to 5 carbon atoms which is substituted one to three times by an atom halogen, cyano, aryl and acyloxy, and -NO n or the radicals of the formulas -5 (0) ^ β ^, wherein d is 1 or 2 and denotes a straight or branched alkyl group having 1 to 4 carbon atoms, an aryl group having 6 carbon atoms, or 131 is a thienyl group, and a residue of formula PO (OR 2 R 3) (OrU), wherein R 4 O and r H are the same or different and denote a straight or branched alkyl group having up to 3 carbon atoms, and the radicals -NH-C (= NH) NH 2 or (CO) _c NR 6 R 13, where e is 0 or 1 and R and R are the same or different and represent a hydrogen atom, a straight or branched alkyl group of up to 4 carbon atoms or a cycloalkyl group of 3 carbon atoms, said radicals being optionally substituted by an aryl group of 6 carbon atoms, furyl, cycloalkyl 3 carbon atoms, a hydroxy group or a straight alkoxy group of up to 2 carbon atoms, and if e = 1, 19 11 R and R may also, with the inclusion of the nitrogen atom to which they are attached, form a 5- or 6-membered ring with up to 2 heteroatoms from the group consisting of nitrogen, oxygen and sulfur, which may optionally be up to twice substituted by hydroxy; 132 with a methyl group, and if e = 0, R ¹ and R ¹ may also represent a direct acyl group of up to 14 carbon atoms, and / or with this measure, R ¹ and R ^{11 means} that when e = 0, the hydrogen atom is non-contiguous, or R @ ¹ denotes a purine radical, which may optionally be up to twice substituted by a halogen atom, an azido group, an amino group, an alkylamino group having up to 4 carbon atoms and / or a methyl group, R 2 and R 2, including the double bond, form a pyridyl or pyrimidinyl ring and denote a phenyl or pyrimidyl group which are: 133 optionally substituted with a fluorine, chlorine or bromine atom, and their isomeric forms and salts thereof. Substituted pyrazole derivatives according to claims 1 to 3 of the general formula I, in which R ¹ denotes a radical of the formula in which R 'denotes an amino group, R '' denotes a substituted morpholine, piperidine, piperazine, pyrrolidine, triazolyl or thiomorpholine group and R '' denotes a hydrogen atom or an amino group. 5. A compound according to claim 4, in which R &apos; is a morpholinyl group. 6. A process for the preparation of the substituted pyrazole derivatives of the general formula I according to claim 1, characterized in that, according to claim 1, the process is carried out 134 of about 9 different meanings of the above-mentioned heterocycles R and R [A] will convert the compounds of formula II R ¹ -D (II), wherein R ^{3 is} as defined above and denotes radicals of the formulas CN, O .. © or jj Na C ^Z © 'CN represents alkyl having 1 to 4 carbon atoms, by reaction with compounds of formula III (III) in which A has the abovementioned meaning, and-CH ₂ -NH-NH _2, in inert solvents, if appropriate in the presence of a base, to compounds of formula IV or IVa H ₂ C —A H 'C-A OF , H ₂ N N_ (IV) a R '(IVa) 135 in which A and as defined above, and in the case of compounds of formula IVa, are then cyclized with carboxylic acids, nitriles, formamides or guanidinium salts, and in the case of compounds of formula IV, are cyclized with 1,3-dicarbonyl derivatives, their salts , tautomers, enol ethers or enamines, in the presence of acids and optionally under the action of microwave radiation, or [B] when R and R together form a pyrazine ring, the compounds of formula IV are first converted by nitrosation to compounds of formula V in which in a second step, the compounds of formula (VI) are reduced by reduction, H, N \ h ···· · · * · # · ♦ · · · » 136 in which A and R are as defined above, and then cyclized using 1,2-dicarbonyl compounds, preferably an aqueous solution glyoxal, or [C], reacting compounds of formula VII ch ₂ -a Wherein A, R and R are as defined above and L denotes a radical of the formula -SnR ³⁹ R ⁴ ®r ⁴ l ZnR, iodine, bromine or triflate, wherein R ³⁹ , r 40 _and R 41 are the same or different and denote a straight or branched alkyl group having up to 4 carbon atoms and R ⁴² represents a halogen atom with compounds of formula VIII R ¹ - Τ (VIII), in which R ^{2 is} as defined above, and when L = SnR ³⁹ R ⁴⁰ R ⁴¹ or ZnR ⁴² , 137 • · · · T represents a triethylate group or a halogen atom, preferably a bromine atom, and when L = iodine, bromine or triflate, T represents a radical of the formula Sn R ³ R ⁴ R ⁴ R ⁴ , Zn R ⁴³ or BR ⁴³ 'R ⁴⁴ '; R ³ , R ⁴⁰ , R ⁴ -, - and R ⁴³ have the meanings given above for R ³ , R ⁴ , R ⁴⁴ and R ⁴³ and are the same or different with and R ³ and R ³ are the same or different and denote hydroxy, aryloxy of 6 to 10 carbon atoms or a straight or branched alkyl or alkoxy group of up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring in palladium catalysed reaction in inert solvents , optionally in the presence of a base, or [D], when R ^ is an optionally substituted pyrimidine residue, the amidines of formula IX are reacted. 138 in which they have A, R ² and R ^{3 are} as defined above, for example with compounds of formula X, Xa, Xb or Xc AlkOCOCX / CN AlkOOC. .COOAlk (Xb) R ¹ (Xc) wherein R is an optionally substituted cycloalkyl radical as defined in R ⁴ , Alk denotes a straight or branched alkyl group having up to 8 carbon atoms, preferably up to 4 carbon atoms, and Z is amino, alkylamino of up to 7 carbon atoms, dialkylamino of up to 7 carbon atoms, nitrogen-bonded piperidine or morpholine, hydroxy, alkoxy of up to 7 carbon atoms, acyloxy of up to 7 carbon atoms or aroyloxy of 6 to 10 carbon atoms , 139 and in the case of the groups -S (O) _C NR 6 R 6 and -S (O) _c > Nr 6 R 6; starting from unsubstituted compounds of the formula I, they are first reacted with thionyl chloride and in the second step with the corresponding amines, and optionally with the substituents mentioned under X, Y, R1, R, R and / or A, are varied or introduced by conventional methods, preferably by acylation of free amino or hydroxy groups, chlorination, catalytic hydrogenation, reduction, oxidation, deprotection and / or nucleophilic substitution. A medicament comprising at least one substituted pyrazole derivative of the formula I according to claim 1. A process for the manufacture of medicaments, characterized in that at least one compound of the formula I according to claim 1 is converted, if appropriate with customary auxiliaries and additives, into a suitable dosage form. A medicament comprising at least one substituted pyrazole derivative of the formula I according to claim 1 in combination with organic nitrates or NO-donors. 10. A medicament comprising at least one substituted pyrazole derivative of the formula I as defined in 140e of claim 1 in combination with compounds that inhibit the degradation of cyclic guanosine monophosphate. Use of substituted pyrazole derivatives of the general formula I according to claim 1 for the manufacture of medicaments. Use of the substituted pyrazole derivatives of the general formula I according to claim 1 for the manufacture of medicaments for the treatment of cardiovascular diseases. Use of the substituted pyrazole derivatives of the general formula I according to claim 1 for the manufacture of a medicament for the treatment of hypertonia. Use of the substituted pyrazole derivatives of the general formula I according to claim 1 for the manufacture of medicaments for the treatment of thromboembolic diseases and ischemia. Use of substituted pyrazole derivatives of the general formula I according to claim 1 for the manufacture of medicaments for the treatment of sexual dysfunctions. Use of the substituted pyrazole derivatives of the general formula I according to claim 1 for the manufacture of medicaments with antiflammatory properties. Use according to any one of claims 11 to 16, wherein the compounds of the formula I according to claim 1 are used in combination with organic nitrates or NO-donors or in combination with compounds which inhibit the degradation of cyclic guanosine monophosphates.