EP1828189A1 - Substituted pteridines for treating inflammatory diseases - Google Patents

Abstract

The invention relates to novel pteridines, which are suitable for treating respiratory tract or gastro-intestinal complaints or diseases, inflammatory diseases of the joints, skin, or eyes, diseases of the peripheral or central nervous system, or carcinomas. The invention also relates to pharmaceutical compositions containing said compounds.

Description

 SUBSTITUTED PTERIDINE FOR THE TREATMENT OF INFLAMMATORY DISEASES

The invention relates to novel pteridines which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases,

Inflammatory diseases of the joints, the skin or the eyes,

Diseases of the peripheral or central nervous system or

• cancers, as well as pharmaceutical compositions containing these compounds.

STATE OF THE ART

Pteridines are known as drugs with antiproliferative action from the prior art. Merz et al. describe in the Journal of Medicinal Chemistry 1998, 41, 4733-4743 the preparation of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and derivatives thereof, which are free of positional isomers. It has been shown that the compounds produced can inhibit the growth of tumor cells. In DE 3540952 2-piperazino-pteridines are described, which are substituted in the 6-position with a halogen atom selected from a fluorine, chlorine or bromine atom. These compounds were shown to inhibit the activity of tumor cells and human platelets in vitro. DE 3323932 discloses 2-piperazino-pteridines which carry in the 4-position a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group. These compounds were shown to inhibit the activity of tumor cells and human platelets in vitro. In DE 3445298 pteridines are described with a large number of unter¬ different substituents in the 2-, 4-, 6- and 7-position, wherein compounds having a 2-piperazino group on the pteridine skeleton are suitable as inhibitors for tumor growth and antithrombotic have metastasis-inhibiting properties. Tri- and tetrasubstituted pteridine derivatives are disclosed in US Pat. No. 2,940,972, disclosing in general terms that these pteridines have valuable pharmacological properties, namely coronary dilatory, sedative, antipyretic and analgesic effects. The phosphodiesterase 4 inhibitors known in the art are known to induce side effects such as nausea and vomiting (Doherty, 1999, Curr. Op. Chem. Biol., Aug. 3, (4): 466-73). The substances named in this invention are particularly preferably suitable for the treatment of said diseases since they are used in an animal model for nausea and vomiting (S. Murinus, Yamamoto K. et al., Physiol. Behav., 2004, Oct. 30, 83 ( 1), 151-6) do not trigger these side effects.

The object of the present invention is to provide novel compounds which are suitable for the prevention or treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, the skin or the eyes, disorders of the peripheral or central nervous system, or cancers, in particular those compounds characterized by less side effects, especially emesis and nausea.

DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that pteridines of the formula I are suitable for the treatment of inflammatory diseases. The present invention therefore relates to compounds of the formula 1

wherein

R ^{1 is} a saturated or unsaturated, five-, six- or seven-membered heterocyclic ring which may contain one nitrogen atom and one further atom selected from the group consisting of nitrogen, sulfur and oxygen;

R ^{2 is} a five, six or seven membered heterocyclic ring

Nitrogen atom and another atom selected from the group consisting of nitrogen, sulfur and oxygen may contain;

R ^{3 is} a group of the formula 1a, wherein

A is a monocyclic heterocyclic ring or a bicyclic ring optionally containing one or more heteroatoms; X NR ^{3 2} , 0, S;

YC _1-4 -alkylene substituted with one or more R ³³ m 0, 1, 2;

R ^{3 1 are} each independently of one another C _1-4 -alkyl, aryl, COOR ^{3 1 1} , CONR ^{3 1 1} R ^{3 1 2} , CN, NR ^{3 1 1} R ^{3 1 2} , NHCOR ^{3 1 1} , OR ^{3 1 1} , OC _1-4 -haloalkyl, SO ₂ R ^{3 1 1} , SO ₂ NH ₂ ,

Halogen, C _1-6 haloalkyl, C _1- 6 alkyl-CONH _2, OC _1-6 alkyl-NH _2, OC _3-6 cycloalkyl, OC _1-4 alkylene-C _3-6 - cycloalkyl;

R ^{3 is 1} H, C _1-4 alkyl; R ^{3 1 2} H, C _1-4 alkyl; or

R ^{3 1} forms together with two atoms of A a 5 or 6-membered carbocyclic ring or a 5 or 6-membered heterocyclic ring which may contain one or more oxygen or nitrogen atoms;

R ^{32 is} H ₁ C _1-6 alkyl;

R ^{33 are} each, independently of one another, C _1-6 -alkyl, C _1-6 -alkyl-OH, C _3-6 -cycloalkyl,

C ₃ - ₆ cycloalkyl-OH, O-C _1-6 -alkyl, COOH, COO- C _1-6 -alkyl, CONH _2; R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 4, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein R ^{1 is} a saturated or unsaturated, five- or six-membered heterocyclic ring which may contain one nitrogen atom and one further atom selected from the group consisting of nitrogen and sulfur;

R ^{2 is} a five- or six-membered heterocyclic ring which may contain one or two nitrogen atoms;

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ^{1 is} a saturated or unsaturated, five- or six-membered heterocyclic ring containing one nitrogen atom and optionally one further sulfur atom;

R ^{2 is} a six-membered heterocyclic ring containing two nitrogen atoms;

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ^{3 is} a group of formula 1a wherein

A is a monocyclic heterocyclic ring or a bicyclic ring optionally containing one, two or three heteroatoms; X NR ^{3 2} , 0, S;

YC _1-4 -alkylene substituted with one or more R ³³ m 0, 1, 2; R ^{3 1 are} each independently of one another C _1-4 -alkyl, aryl, COOR ^{3.1 .1} , CONR ^{3 1 1} R ^{3 1 2} , CN, NR ^{3 1 1} R ^{3 1 2} , NHCOR ^{3 1 1} , OR ^{3 1 1} , OC _1-4 haloalkyl, SO ₂ R ^{3 1 1,} SO ₂ NH _2, halogen, C ₁ _ ₆ haloalkyl, C ₁ _ ₆ alkyl-CONH _2, O-C ₁ _ ₆ alkyl-NH _2, OC _{3 -6-} cycloalkyl, OC _{1 -4} -alkylene-C _3-6 -cycloalkyl;

R ^{3 is 1} H, C _1-4 alkyl; R ^{3 1 2} H, C _1-4 alkyl;

R ^{3 2} H, C _1-6 alkyl;

R ³³ are each independently C _1-e alkyl, _C1-6 alkyl-OH, C _3-6 cycloalkyl,

C _3-6 -cycloalkyl-OH, O-C _1-6 -alkyl, COOH, COO-C _1-6 -alkyl, CONH ₂ ; R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 4, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ³ is a group of the general formula 1 a, in which

A is a five, six or seven membered heterocyclic, aromatic or nonaromatic ring, or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms, optionally containing one, two or three heteroatoms;

X NR ^{3 2} , O, S;

YC _1-4 -alkylene substituted with one or more R ³³ m 0, 1 or 2; R ^{3 1 are} each independently of one another C _1-4 -alkyl, aryl, COOR ^{3 1 1} , CONR ^{3 1 1} R ^{3 1 2} , CN, NR ^{3 1 1} R ^{3 1 2} , NHCOR ^{3 1 1} , OR ^{3 1 1} , OC _1-4 haloalkyl, SO ₂ R ^{3 1 1} , SO ₂ NH ₂ , halogen;

R ^{3 1 1} H, C _1-6 alkyl;

R ^{3 1 2} H, C _1-6 alkyl;

R ^{32 is} H, C _1-6 alkyl;

R ³³ are each independently C _1-6 alkyl, C _1-6 alkyl-OH, C ₃ - ₆ -cycloalkyl, O- C _1-6 -alkyl, COOH, COO-C _1-β alkyl, CONH ₂ ;

R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ³ is a group of the general formula 1 a, in which

A is a five, six or seven membered heterocyclic, aromatic or nonaromatic ring containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur; or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms optionally containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ³² , O, S;

YC ₁ _ ₂ -alkylene substituted with one or more R ³³ m O, 1 or 2; R ^{3 1 are} each independently of one another C _1-4 -alkyl, aryl, COOH, C _1-4

CONH ₂ , CN, NH ₂ , NHCO-C _1-4 -alkyl, OH, OC _1-4 -alkyl, OC _1-4 -haloalkyl,

SO ₂ -C _1-4 -alkyl ₁ SO ₂ NH _2, halogen; R ^{32 is} H, C _1-4 alkyl; R ³³ is H, C _1-4 alkyl, C _1-4 alkyl-OH, C ₃ - ₆ cycloalkyl, OC _1-4 alkyl, COOH,

COO-C _1-4 alkyl, CONH ₂ ; R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ³ is a group of general formula 1a wherein

A is a five, six or seven membered heterocyclic aromatic ring containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur; or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms optionally containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ^{3 2} , O, S;

YC ₁ _ ₂ -alkylene substituted with one or more R ³³ m O, 1 or 2;

R ^{3 1 are} each independently of one another methyl, ethyl, propyl, Ph, COOH,

COOMe, CONH ₂ , CN, NH ₂ , NHCOMe, OH, OMe, OEt, OCF ₃ , OCHF ₂ , SO ₂ Me, SO ₂ NH ₂ , F, Cl, Br; R ^{32 is} H ₁ C _1-4 alkyl;

R ^{33 is} H, methyl, ethyl, propyl, butyl, CH ₂ OH, CH ₂ CH ₂ OH, C (CH ₂ ) ₂ OH,

Cyclopropyl, COOH, COOMe, COOEt, COOPr CONH ₂ , OMe, OEt, OPr; R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ³ is a group of general formula 1a wherein A contains a five, six or seven membered heterocyclic aromatic ring containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur; or an aromatic or non-aromatic bicyclic ring consisting of eight, nine or ten atoms, optionally one, two or three

Heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ^{3 2} , O, S; YC ₁ _ ₂ -alkylene substituted with one or more R ³³ m O, 1 or 2;

R ^{3 1 are} each independently methyl, / so-propyl, terf-butyl;

OMe, OEt, F, Cl, Br, CN, R ³² is H;

R ^{33 is} H, methyl, / so-propyl, tert-butyl, cyclopropyl, CH ₂ OH, CH ₂ CH ₂ OH,

C (CH ₂ ) ₂ OH, COOH, COOMe, CONH ₂ , OMe, and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ³ is a group of the general formula 1 a, in which

A is a five, six or seven membered heterocyclic aromatic ring containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur; or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms optionally containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ^{3 2} , O, S;

YC _1-2 -alkylene substituted with one or more R ³³ m 0, 1 or 2;

R ^{3 1 is} methyl, / so-propyl, tert-butyl; ^R32 H, methyl; R ³³ H, methyl;

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ^{3 is} a group of general formula 1 a, wherein A is a five- or six-membered heterocyclic aromatic ring containing one or two heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur; or an aromatic or nonaromatic bicyclic ring consisting of nine or ten atoms, optionally containing one or two heteroatoms, independently of one another, selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ^{3 2} , 0; YC _1-2 -alkylene, optionally substituted with one or more R ³³ m 0, 1, 2;

R ^{3 1 is} methyl, R ^{32 is} H, R ^{3 is 3} H,

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Preferred are the above compounds of formula 1 wherein

R ^{3 is} a group of general formula 1 a, wherein

A thiophenyl, furanyl, pyrazole, pyridinyl, isoxazole, thiazole, benzimidazole,

Benzo [b] thiophene, 2,3-dihydrobenzo [1,4] dioxin, 1,2,3,4-tetrahydronaphthalene, oxazole; X NR ^{3 2} , 0;

YC _1-2 -alkylene, optionally substituted with one or more R ^{3 3} m 0, 1, 2;

R ^{3 1} methyl, R ^{3 2} H, R ^{3 3} H, and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Especially preferred are the above compounds of formula 1 wherein

R ^{3 is} a radical selected from the group consisting of

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

USED GUIDES AND DEFINITIONS

In the context of this application, in the definition of possible substituents, these can also be represented in the form of a structural formula. An asterisk ( ^* ) in the structural formula of the substituent is understood to be the point of attachment to the remainder of the molecule. For example, the residues N-piperidinyl (I), 4-piperidinyl (II), 2-ToIyI (IM), 3-ToIyI (IV) and 4-ToIyI (V) are shown as follows:

If there is no star ( ^* ) in the structural formula of the substituent, then each hydrogen atom can be removed from the substituent and the valence liberated thereby serves as a binding site to the remainder of a molecule. For example, VI may have the meaning of 2-ToIyI, 3-ToIyI, 4-ToIyI and benzyl.

By pharmacologically acceptable acid addition salts are meant for example those salts which are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydro Oxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

The term "C _1-6 -alkyl" (including those which are part of other groups) is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms and branched and unbranched alkyl groups having 1 to 10 by the term "C _1-4 -alkyl" 4 carbon atoms understood. Preference is given to alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, / so-pentyl, neo-pentyl or hexyl. Optionally, the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise specified, the definitions of propyl, butyl, pentyl and hexyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and tert-butyl, etc.

The term "C _1-4 -alkylene" (including those which are part of other radicals) are understood as meaning branched and unbranched alkylene groups having 1 to 4 carbon atoms. For example: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene or 1, 2-dimethylethylene. Unless otherwise stated, the definitions propylene and butylene include all conceivable isomeric forms of the respective radicals of the same carbon number. For example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene. Should the carbon chain be substituted by a radical which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring having 3, 4, 5 or 6 carbon atoms, the following examples of the rings are included:

The term "C _3-6 -cycloalkyl" (including those which are part of other groups) means cyclic alkyl groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. So far not otherwise described, the cyclic alkyl groups may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

Halogen is in the context of the present invention for fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.

The term "C _1-6 haloalkyl" (including those which are part of other radicals) is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms which are substituted by one or more halogen atoms. By the term "C _1-4 -alkyl" is meant branched and unbranched alkyl groups having from 1 to 4 carbon atoms which are substituted by one or more halogen atoms. Preferred are alkyl groups having 1 to 4 carbon atoms. For example: CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ .

The term "aryl" (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms. For example: phenyl or naphthyl, more preferably aryl is phenyl. Unless otherwise stated, the aromatics may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, / so-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term "heterocyclic rings" or "Het" are meant five-, six- or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, in which case the ring via a carbon atom or, if present, via a nitrogen atom to be linked to the molecule. As examples of five-, six- or seven-membered, saturated or unsaturated heterocyclic rings, mention is made:

Unless otherwise stated, a heterocyclic ring may be provided with a keto group. As an example for this are called.

or a bicyclic ring optionally containing one or more heteroatoms

By the term "bicyclic rings" is meant eight-, nine- or ten-membered bicyclic rings which may optionally contain one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. The ring may be linked to the molecule via a carbon atom of the ring or, if present, via a nitrogen atom of the ring. An example of a bicyclic ring is given by:

As an example of a bicyclic ring which may contain one or more, preferably one, two or three, heteroatoms are called pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, Benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

EXAMPLES

The compounds according to the invention can be prepared by methods known per se from the literature, as described, for example, in DE 3540952. In addition, the following two-step method is applied to the compound 5 shown below.

Compound 5 - Step 1: 0.093 ml (0.986 mmol) of thiophenemethanol and 55 mg (1.375 mmol) of sodium hydride are introduced into 5 ml of tetrahydrofuran, stirred at room temperature for 0.5 hours. It is then cooled to ⁰ ° C. and 300 mg (0.985 mmol) of 2,6,7-trichloro-4-pyrrolidin-1-yl-pteridine are added. The reaction mixture is stirred for 16 hours at room temperature, then treated with water and extracted with dichloromethane. The organic phase is washed with water, dried and evaporated to dryness. Yield: 327 mg (= 87% of theory)

Compound 5 - Alternative Step 1: 8.21 ml (16.42 mmol) of 2 M lithium diisopropylamide solution are initially charged in 100 ml of tetrahydrofuran, and 1.55 ml (16.44 mmol) of thiophenemethanol are added. It is stirred for 0.1 hours at room temperature, then cooled to -1 O ⁰ C. 5.00 g (16.42 mmol) of 2,6,7-trichloro-4-pyrrolidin-1-yl-pteridine are added, then stirred for 2 hours at this temperature and for 16 hours at room temperature. After further addition of 0.5 eq thiophene methoxide (deprotonation with lithium diisopropylamide in tetrahydrofuran) is stirred for 2 hours at room temperature. Then, the reaction mixture is mixed with 800 ml of water, the

Distilled off tetrahydrofuran. The aqueous residue is extracted with dichloromethane / methanol 9: 1, the organic phase washed with water, dried and evaporated to dryness. The residue is purified by chromatography and crystallized from diethyl ether. Yield: 1, 82 g (= 29% of theory)

Compound 5 - Step 2: 347 mg (0.908 mmol) of 2,6-dichloro-4-pyrrolidin-1-yl-7- (thiophen-3-ylmethoxy) -pteridine are dissolved in 20 ml of dioxane, 0.225 ml (1.29 g mmol) of diisopropylethylamine and 280 mg (3.25 mmol) of piperazine dissolved in dioxane. The reaction mixture is stirred for 16 hours at 8O ⁰ C, then evaporated. The residue is purified by chromatography. Yield: 163 mg (= 42% of theory)

Example 28: i-Thiophen-3-yl-cyclopropanol: 1.37 ml (10.00 mmol) of ethylthiophene-3-carboxylate and 0.29 ml (1.00 mmol) of titanium tetra-isopropyloxide are placed in 5 ml of diethyl ether , 21, 20 ml (21, 20 mmol) of ethyl magnesium bromide (Grignard reagent in tetrahydrofuran) in 15 ml of diethyl ether added dropwise within 1 hour, the temperature of 2O ⁰ C should not exceed. The reaction mixture is stirred for 1.5 hours, then hydrolyzed with 10% sulfuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.330 g (24% of theory)

EXAMPLE 30: i -Furan-2-yl-cyclopropanol: 2.50 g (17.66 mmol) of furan-2-carbocyclic ethyl ester and 0.52 ml (1.77 mmol) of titanium tetra-isopropyloxide are dissolved in 56 ml of diethyl ether submitted, 12.48 ml (37.44 mmol) of ethyl magnesium bromide (Grignard reagent in tetrahydrofuran) in 28 ml of diethyl ether added dropwise within 1 hour, the temperature of 2O ⁰ C should not exceed. The reaction mixture is stirred for 1.5 hours, then hydrolyzed with 180 ml of 10% sulfuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.650 g (30% of theory)

Example 31: 1-thiophen-2-yl-cyclopropanol: 2.00 ml (14.88 mmol) of ethylthiophene-2-carboxylate and 0.44 ml (1.45 mmol) of titanium tetra-isopropyloxide are introduced in 56 ml of diethyl ether, 10.51 ml (31. 54 mmol) of ethylmagnesum bromide (Grignard reagent in tetrahydrofuran) in 28 ml of diethyl ether are added dropwise within 1 hour, during which the temperature should not exceed 20.degree. The reaction mixture is stirred for 1.5 hours, then hydrolyzed with 180 ml of 10% sulfuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.300 g (14% of theory) EXAMPLE 33: i -Furan-3-yl-cyclopropanol: 2.50 g (17.84 mmol) of furan-3-carboxylic acid ethyl ester and 0.53 ml (1.82 mmol) of titanium tetra-isopropyloxide are placed in 56 ml of diethyl ether , 12.61 ml (37.82 mmol) of ethyl magnesium bromide (Grignard reagent in tetrahydrofuran) in 28 ml of diethyl ether is added dropwise within 1 hour, the temperature should not exceed 2O ° C. The reaction mixture is stirred for 1.5 hours, then hydrolyzed with 180 ml of 10% sulfuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 1.05 g (47% of theory)

EXAMPLE 24 Thiazol-2-yl-methanol: 0.20 ml (2.28 mmol) of 2-thiazolecarboxaldehyde are initially charged in 10 ml of ethanol, and 0.172 g (4.55 mmol) of sodium borohydride are added. The reaction mixture is stirred for 16 hours under reflux, then evaporated. The residue is extracted with water and ethyl acetate, and the organic phase is washed with water. The combined aqueous phases are saturated with sodium chloride and extracted with ethyl acetate. The resulting organic phase is dried and evaporated to dryness. Yield: 0.146 g (= 56% of theory)

EXAMPLE 34 Isoxazol-3-yl-methanol: 0.039 g (1.03 mmol) of sodium borohydride are dissolved in 4 ml of tetrahydrofuran and 0.13 ml of methanol, while cooling with ice at 0 ° -5 ° C., a solution of 0.100 g (1, 03 mmol) of isoxazole-3-carbaldehyde in 6 ml of tetrahydrofuran was added dropwise. The reaction mixture is stirred for 16 hours at room temperature, then evaporated. The residue is extracted with water and ethyl acetate. The organic phase is washed with sodium chloride solution, dried and evaporated to dryness. Yield: 0.110 g (> 100% of theory)

PRECURSORS

Precursors for the synthesis of the compounds of formula 1 according to the invention are generally available commercially. However, the precursor for preparing the compound 17 must be provided separately. Precursor for compound 17: thiazol-2-yl-methanol: 0.20 ml (2.28 mmol) of 2-thiazole-carboxaldehyde are initially charged at room temperature in 10 ml of ethanol, 172 mg (4.55 mmol) of sodium borohydride are added and then 16 Stirred under reflux for hours. Then the reaction mixture is evaporated, the residue extracted with water and ethyl acetate. The water phase is saturated with sodium chloride, again with

Extracted ethyl acetate. The resulting organic phase is dried and evaporated to dryness. Yield: 146 mg (= 56% of theory)

Below are exemplified compounds that can be represented by one of the synthetic routes shown above.

INDICATIONS

As has been found, the compounds of formula 1 are characterized by a variety of possible applications in the therapeutic field. Worth mentioning are those applications for which the compounds of formula 1 according to the invention can preferably be used as a PDE4 inhibitor due to their pharmaceutical activity. Examples include his respiratory or gastrointestinal diseases or disorders, inflammatory diseases of the joints, the skin or the eyes, cancers, as well as diseases of the peripheral or central nervous system. Preference is given here to the prevention and treatment of respiratory or lung diseases, which are associated with increased mucus production, inflammation and / or obstructive diseases of the respiratory tract. Examples include his, acute, allergic or chronic bronchitis, chronic obstructive pulmonary disease (COPD), cough, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmers ^' disease, hyperrespiratory airways, infectious bronchitis or pneumonitis, pediatric asthma, bronchiectasis, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), bronchial edema, pulmonary edema, bronchitis, pneumonia or interstitial pneumonia caused by various causes such as aspiration, inhalation of toxic gases or bronchitis, pneumonia or interstitial pneumonia caused by heart failure, Radiation, chemotherapy cystic fibrosis or cystic fibrosis, alphal-antitrypsin deficiency.

Likewise preferred is the treatment of inflammatory diseases of the gastrointestinal tract. Examples of this are its called, acute or chronic inflammatory changes in gallbladder inflammation, Crohn's disease, ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitis cystica profunda, pneumatosis cystoides intestinales, diseases of the bile ducts and gallbladder, e.g. Gallstones and conglomerates for the treatment of inflammatory diseases of the joints such as rheumatoid arthritis or inflammatory diseases of the skin and eyes.

Likewise preferred is the treatment of cancer. Exemplary of this are called all forms of acute and chronic leukemias such as, acute lymphoblastic and acute myeloid leukemia, chronic lymphocytic and chronic myeloid leukemia, as well as bone tumors such as osteosarcoma and as well as all types of gliomas such as oligodendroglioma and glioblastoma.

Preference is furthermore given to the prevention and treatment of diseases of the peripheral or central nervous system. Examples include depression, bipolar or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis, or acute and chronic pain conditions Injuries to the brain caused by stroke, hypoxia or traumatic brain injury.

More particularly, the present invention relates to the use of compounds of formula 1 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory organs, including the lung, such as allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma.

Most preferred is the use of the compounds of formula 1 for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma.

Also preferred is the use of the compounds of formula 1 for the treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as brain damage caused by stroke, hypoxia or craniocerebral trauma.

An outstanding aspect of the present invention is the reduced profile of side effects. In the context of the invention, this is understood as being able to administer a dose of a pharmaceutical composition without inducing vomiting in the patient, preferably nausea, particularly preferably malaise. Most preferably, administration of a therapeutically effective amount of substance without inducing emesis or nausea is at any stage of the disease process.

COMBINATIONS The compounds of the formula 1 can be used alone or in combination with other active compounds of the formula 1 according to the invention. If appropriate, the compounds of the formula 1 can also be used in combination with other pharmaceutically active compounds. Preferred active substances are those which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 Kinase inhibitors or two or three combinations thereof, such as combinations of betamimetics with corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,

Anticholinergics with betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,

Corticosteroids with PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists - PDE4 inhibitors with EGFR inhibitors or LTD4 antagonists

EGFR inhibitors with LTD4 antagonists.

Also, the combinations of three active ingredients each one of the o.g. Classes of compounds is part of the invention.

PRESENTATIONS

A further aspect of the invention is medicaments for the treatment of respiratory diseases which contain one or more of the abovementioned pteridines of the formula 1 which are used in combination with one or more additional active substances selected from the group of betamimetics, anticholinergics, corticosteroids, PI3-kinase inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines or PAF antagonists, preferably betamimetics, anticholinergics or corticosteroids are used together or sequentially, for simultaneous, sequential or separate administration.

Suitable application forms are, for example, tablets, capsules, solutions, juices, emulsions or inhalable powders or aerosols. In this case, the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50% by weight of the total composition, ie in amounts sufficient to achieve the dosage range given below.

Oral administration may be in the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension. In the case of an inhalative administration, the active substance combination can be carried out as a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.

Therefore, pharmaceutical formulations are preferably characterized by the content of one or more compounds of formula 1 according to the above preferred embodiments.

It is particularly preferred if the compounds of the formula 1 are administered orally, it is particularly preferred if the administration takes place once or twice daily. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract. You can also use suspension aids or Thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

The capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules. Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

As adjuvants there may be mentioned, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), excipients such as e.g. ground natural minerals (eg kaolins, clays, talc, chalk) ground synthetic minerals (eg fumed silica and silicates), sugars (eg pipe, milk and dextrose) emulsifiers (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg Magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

In the case of oral administration, of course, the tablets may also contain additives other than those mentioned. Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.

It is likewise preferred if the compounds of the formula 1 are administered by inhalation, it being particularly preferred if the administration is carried out once or twice daily. For this purpose, the compounds of formula 1 must be provided in inhaled dosage forms. Inhalable forms of administration include inhalable powders, propellant-containing metered dose inhalers or propellant-free inhalable solutions Consider, which may be present in admixture with conventional physiologically acceptable excipients.

In the context of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions. The administration forms which can be used in the context of the present invention will be described in detail in the following part of the description.

Inhalation powders The compounds of the formula 1 are in a mixture with physiologically acceptable

The following physiologically acceptable excipients may be used to prepare the inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and polysaccharides (eg dextrans), polyalcohols (eg sorbitol, Mannitol, XyNt), salts (eg sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Preferably, mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. Lactose, most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention. Process for the preparation of the inhalable powders according to the invention by grinding and

Micronization as well as final mixing of the ingredients are known in the art.

Propellant-containing inhalation aerosols The propellant-containing aerosols which can be used in the context of the use according to the invention

Inhalation aerosols may contain 1 in propellant gas or in dispersed form. The propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and hydrogen halides such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof. The under the Propellant-containing inhalable aerosols which can be used according to the invention may also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusting agents. All of these ingredients are known in the art.

LPG-free inhalation solutions

The use according to the invention of compounds of the formula 1 is preferably carried out for the preparation of propellant-free inhalable solutions and inhalable suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water only or it may be a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids. To adjust this pH, acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferable. Optionally, mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid.

Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.

Co-solvents and / or further auxiliaries can be added to the propellant-free inhalable solutions which can be used in the context of the inventive use. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. By auxiliaries and additives is meant in this context any pharmacologically acceptable substance which is not an active ingredient but which can be formulated together with the active ingredient (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy. The auxiliaries and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives that ensure or prolong the useful life of the finished drug formulation, flavorings, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonants. Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins found in the human organism. Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.

For the above-described forms of treatment, ready-to-use packs of a medicament for the treatment of respiratory disorders, including an enclosed description containing, for example, the words respiratory disease, COPD or asthma, a pteridine and one or more combination partners selected from the group described above, are provided.

Claims

Compounds of the formula 1,

wherein

R ^{1 is} a saturated or unsaturated, five, six or seven membered heterocyclic ring which may contain one nitrogen atom and another atom selected from the group consisting of nitrogen, sulfur and oxygen;

R ^{2 is} a five, six or seven membered heterocyclic ring which may contain one nitrogen atom and another atom selected from the group consisting of nitrogen, sulfur and oxygen;

R ^{3 is} a group of the formula 1 a,

wherein

A is a monocyclic heterocyclic ring or a bicyclic ring optionally containing one or more heteroatoms; X NR ^{3 2} , 0, S;

YC _1-4 -alkylene substituted with one or more R ³³ m 0, 1, 2;

R ^{3 1 are} each independently of one another C _1-4 -alkyl, aryl, COOR ^{3 1 1} , CONR ^{3 1 1} R ^{3 1 2} , CN, NR ^{3 1 1} R ^{3 1 2} , NHCOR ^{3 1 1} , OR ^{3 1 1} ,

O-C _1-4 -haloalkyl, SO ₂ R ^{3 1 1} , SO ₂ NH ₂ , halogen, C _1-6 -haloalkyl, C _1-6 -alkyl-CONH ₂ , OC _1-6 -alkyl-NH _2, OC ₃ - ₆ -cycloalkyl, O-C _1-4 -alkylene- C _3-6 -cycloalkyl;

R ^{3 is 1} H, C _1-4 alkyl; R ^{3 1 2} H, C _1-4 alkyl; or

R ^{3 1} together with two atoms of A forms a 5 or 6-membered carbocyclic ring or a 5 or 6-membered heterocyclic ring of one or more oxygen or

May contain nitrogen atoms;

R ^{32 is} H, C _1-6 alkyl;

R ³³ are each independently C _1-6 alkyl, C _1-6 alkyl-OH, C _1-6 cycloalkyl, C ₃ - ₆ cycloalkyl-OH, OC _1-6 alkyl, COOH, COO-C _{1 -6-} alkyl, CONH ₂ ;

R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 4, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

2. Compounds of formula 1, according to claim 1, wherein

R ^{1 is} a saturated or unsaturated, five- or six-membered heterocyclic ring which may contain a nitrogen atom and another atom selected from the group consisting of nitrogen and sulfur;

R ^{2 is} a five- or six-membered heterocyclic ring which may contain one or two nitrogen atoms;

and pharmacologically acceptable salt, diastereomers, enantiomers,

Racemates, hydrates or solvates thereof.

3. Compounds of formula 1, according to claim 1 or 2, wherein R ^{1 is} a saturated or unsaturated, five- or six-membered heterocyclic ring containing one nitrogen atom and optionally one further sulfur atom;

R ^{2 is} a six-membered heterocyclic ring containing two nitrogen atoms;

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

4. Compounds of formula 1, according to any one of claims 1 to 3, wherein

R ³ is a group of general formula 1a wherein

A is a five, six or seven membered heterocyclic, aromatic or nonaromatic ring, or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms, optionally containing one, two or three heteroatoms;

X NR ^{3 2} , O, S;

YC _1-4 -alkylene substituted with one or more R ³³ m 0, 1 or 2;

R ^{3 1} are each independently CI_ ₄ alkyl, aryl, COOR ^{3 1 1,} CONR ¹ R ^{3 1 3 1 2,} CN, NR ^{3 1 1 1 2} R ^3, NHCOR ^{3 1 1 3 1} OR ^1, OC _{1 -4} haloalkyl, SO ₂ R ^{3 1 1} , SO ₂ NH ₂ , halogen;

R ^{3 1 1} H, C _1-6 alkyl;

R ^{3 1 2} H, C _1-6 alkyl;

R ^{3.2 is} H, C _1-6 -alkyl; R ^{33 are} each, independently of one another, C _1-6 -alkyl, C _1-6 -alkyl-OH,

C ₃ - ₆ cycloalkyl, OC _1-6 alkyl, COOH, COO-C _1-6 alkyl, CONH _2;

R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

Compounds of formula 1, according to any one of claims 1 to 4, wherein

R ³ is a group of the general formula 1 a, in which

A is a five, six or seven membered heterocyclic, aromatic or nonaromatic ring, one, two or three

Heteroatoms independently selected from

Group consisting of oxygen, nitrogen and sulfur, contains; or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms optionally containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ^{3 2} , 0, S;

YC _1-2 -alkylene substituted with one or more R ³³ m O, 1 or 2;

R ^{3 1 are} each independently of one another C _1-4 -alkyl, aryl, COOH, COO-C _1-4 -alkyl, CONH ₂ , CN, NH ₂ , NHCO-C _1-4 -alkyl, OH,

OC _1-4 alkyl, OC _1-4 haloalkyl, SO ₂ C _1-4 alkyl, SO ₂ NH ₂ , halogen; R ^{32 is} H, C _1-4 -alkyl; R ³³ is H, C _1-4 alkyl, d_ ₄ alkyl-0H, C ₃ - ₆ cycloalkyl, OC _1-4 alkyl, COOH,

COO-C _1-4 alkyl, CONH ₂ ; R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring with 3,

5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

6. Compounds of formula 1, according to any one of claims 1 to 5, wherein

R ³ is a group of the general formula 1 a, in which

A is a five, six or seven membered heterocyclic aromatic ring containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur; or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms optionally containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ³² , O, S;

YC _1-2 -alkylene substituted with one or more R ³³ m 0, 1 or 2;

R ^{3 1 are} each independently methyl, ethyl, propyl, Ph, COOH, COOMe, CONH ₂ , CN, NH ₂ , NHCOMe, OH, OMe, OEt, OCF ₃ , OCHF ₂ , SO ₂ Me, SO ₂ NH ₂ , F , Cl, Br;

R ^{32 is} H, C _1-4 alkyl;

R ^{33 is} H, methyl, ethyl, propyl, butyl, CH ₂ OH, CH ₂ CH ₂ OH, C (CH ₂ ) ₂ OH,

Cyclopropyl, COOH, COOMe, COOEt, COOPr, CONH ₂ , OMe, OEt, OPr; R ³³ together with one or two carbon atoms of Y forms a carbocyclic ring having 3, 5 or 6 carbon atoms

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

7. Compounds of formula 1, according to any one of claims 1 to 6, wherein

R ³ is a group of the general formula 1 a, in which

A is a five, six or seven membered heterocyclic aromatic ring containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur; or an aromatic or nonaromatic bicyclic ring consisting of eight, nine or ten atoms optionally containing one, two or three heteroatoms independently of one another selected from the group consisting of oxygen, nitrogen and sulfur;

X NR ^{3 2} , O, S;

YC _1-2 -alkylene substituted with one or more R ³³ m 0, 1 or 2;

R ^{3 1 is} methyl, iso-propyl, tert-butyl;

^R32 H, methyl; R ³³ H, methyl;

and pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.

8. Compounds of formula 1, according to any one of claims 1 to 7, wherein R ^{3 is} a group of general formula 1 a, wherein

A thiophenyl, furanyl, pyrazole, pyridinyl, isoxazole, thiazole,

Benzimidazole, benzo [b] thiophene, 2,3-dihydrobenzo [1,4] dioxin, 1,2,3,4-tetrahydronaphthalene, oxazole;

X NR ^{3 2} , 0;

YC _1-2 -alkylene, optionally substituted with one or more R ³³ m 0, 1, 2;

R ^{3 1} methyl, R ³² H, R ³³ H,

and pharmacologically acceptable salt, diastereomers, enantiomers,

Racemates, hydrates or solvates thereof.

9. Compounds according to any one of claims 1 to 8 as a medicament.

Use of compounds according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of diseases which can be treated by inhibition of the PDE4 enzyme.

11. Use of compounds according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of respiratory or gastrointestinal disorders or diseases, as well as inflammatory diseases of the joints, skin or eyes, cancers, as well as diseases of the peripheral or central nervous system ,

12. Use of compounds according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention and treatment of respiratory or lung diseases, which are associated with increased mucus production, inflammation and / or obstructive diseases of the respiratory tract.

13. Use of compounds according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of inflammatory diseases of the gastrointestinal tract.

14. Use of compounds according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of inflammatory and obstructive diseases such as COPD, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis.

Use of compounds according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention and treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic

Depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis, or acute and chronic pain and brain damage caused by stroke, hypoxia or traumatic brain injury.

16. Use of compounds according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of cancers such as acute and chronic leukemias, acute lymphoblastic and acute myeloid leukemia, chronic lymphocytic and chronic myeloid leukemia, and

Bone tumors such as osteosarcoma and all types of gliomas such as oligodendroglioma and glioblastoma.

17. Use, according to any one of claims 9 to 16, wherein side effects of the treatment are reduced.

Use according to any one of claims 9 to 16, wherein the reduced side effects are selected from the group consisting of emesis and nausea.