WO2006108713A2 - 1-amino-1, 2,3,4-tetrahydro-naphthaline-2-ol derivates as anti-inflammatory agents - Google Patents

Abstract

The invention relates to poly-substituted tetrahydronaphtalene derivatives of formula (I) and to a method for the production and the use thereof in the form of antiphlogistics.

Description

 tetrahydronaphthalene,

Process for their preparation and their use as anti-inflammatory agents

introduction

The invention relates to tetrahydronaphthalene derivatives, processes for their preparation and their use as anti-inflammatory agents.

Open-chain nonsteroidal anti-inflammatory agents are known from the prior art (DE 100 38 639 and WO 02/10143). These compounds show in the experiment Wirkdissoziationen between anti-inflammatory and undesirable metabolic effects and are superior to the previously described nonsteroidal glucocorticoids or at least have an equally good effect.

In the present invention, other nonsteroidal anti-inflammatory agents are provided.

Brief description of the invention

The present invention relates to compounds of the general formula (I),

wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted _(C1-CK)) - alkyl group, a (CRCI ₀₎ alkoxy, (Ci-Cio) alkylthio group, a (C1-C5) - perfluoroalkyl group, a cyano group, a nitro group, or a -NR ⁹ R ^9a group, or R ¹ and R ² together are a group selected from the groups

-CKCHz) _n -O-, -O- (CHz) _n -CHz-, -O-CH = CH-, - (CH ₂ ) _{n +} 2 -, - NH- (CH ₂ ) _{n +} r, -N (CrC 3 -alkylHCH2) n ₊ i-, and -NH-N = CH- form, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms with directly adjacent

Ring carbon atoms are linked,

R ^{11 is} a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C 1 -C 10) -alkyl group, a (C 1 -C 10) -alkoxy group, a (C ₁ -C 10) -alkylthio group, or a (Ci-C ₅ ) - Perfluoralkylgruppe is,

R ^{12 is} a hydrogen atom, a hydroxy group, a halogen atom, a

Cyano group, an optionally substituted (C 1 -C 10) -alkyl group, or a (C 1 -C 10) -alkoxy group,

R ^{3 is} optionally substituted by 1 to 3 hydroxy groups, 1 to 3 halogen atoms, and / or 1 to 3 (Ci-Cs) alkoxy substituted

(C ₁ -C 10) -alkyl group, an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, optionally one or more groups independently selected from one another

(C 1 -C ₅ ) -alkyl groups which themselves may optionally be substituted by 1 to 3 hydroxyl or 1 to 3 -COOR ¹³ groups, (C 1 -C ₅ ) -alkoxy groups,

Halogen atoms, hydroxy groups, -NR ⁹ R ^9a groups, and exomethylene groups is substituted mono- or bicyclic heteroaryl group containing 1 to 4 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms and / or 1 to 2 keto groups, this group being linked via any position with the group X and optionally can be hydrogenated at one or more sites,

R ^{4 is} a hydroxy group, an -OR ¹⁰ group or an -O (CO) R ¹⁰ group,

R ^{6 is} a hydrogen atom, a halogen atom, or an optionally substituted (C 1 -C 10) -alkyl group, R ⁷ and R ⁸ are each independently a hydrogen atom, a halogen atom, an optionally substituted (C 1 -C 10) -alkyl group, a cyano group, together (C ₁ -C ₄ ) -alkylidene group or, together with the carbon atom of the tetrahydronaphthalene system, an optionally substituted (C ₃ -C ₆ ) -cycloalkyl ring; or

R ⁶ and R ⁷ together form a fused five- to eight-membered saturated or unsaturated carbo or heterocycle, optionally substituted by 1 to 2 keto groups, 1 to 2 (C _r C ₅ ) -alkyl groups, 1 to 2 (C _r C ₅ ) - alkoxy groups, and / or 1 to 4 halogen atoms substituted form; or

R ¹ and R ⁸ together form an annelated five- to eight-membered saturated or unsaturated carbocycle or heterocycle optionally substituted by 1 to 2 keto groups, 1 to 2 (-C ₅₎ -alkyl groups, 1 to 2 (C _r C ₅₎ - alkoxy groups, and / or 1 to 4 halogen atoms is substituted; R ⁹ and R ^9a are each independently a hydrogen atom, a (C ₁ -C ₅ ) -

Are alkyl group or - (CO) - (dC ₅ ) -alkyl,

R ^{10 represents} a (C 1 -C 10) -alkyl group or any desired hydroxy-protecting group,

R ^{13 is} a hydrogen atom or a (C 1 -C ₅ ) -alkyl group, and X is a bond or a group -C (OO) -, -C (SS) -, -C (OO) -NH-, -C ( = S) -

NH-, -S (O) _m - (where m = 1 or 2), -C (= O) -O-, -C (= S) -O- or a group - (CH ₂ ) _P - ( where p = 1, 2 or 3), where, when X contains a carbonyl or thiocarbonyl function, this function is linked to the group -NH- in the general formula (I), in the form of any stereoisomer or mixture of stereoisomers; or as a pharmacologically acceptable salt or derivative.

The present invention further relates to processes for the preparation of compounds of general formula (I) ₁ as described herein. Furthermore, the present invention relates to pharmaceutical compositions comprising one or more compounds of the general formula (I) in combination with one or more pharmaceutical carriers or excipients.

The present invention also relates to the use of the compounds of general formula (I) for the preparation of pharmaceutical compositions having anti-inflammatory activity.

The present invention additionally relates to compounds of the general formula (II)

wherein the substituents R ¹ to R ^{12 have} the meanings given above, and the use of these compounds for the preparation of compounds of general formula (I).

The present invention additionally relates to compounds of the general formula (IV)

wherein the substituents R ¹ to R ^{12 have} the meanings given above, and the use of these compounds for the preparation of compounds of general formula (I). Detailed description of the invention

definitions

The term halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom.

The alkyl groups mentioned in the definitions of the general formula (I) may be straight-chain or branched and may be, for example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, and the hexyl, heptyl, nonyl, decyl group and their random branched derivatives. Preferred are alkyl groups containing 1 to 10, 1 to 8, or 1 to 5 carbon atoms. A methyl or ethyl group is particularly preferred.

The above-mentioned alkyl groups may be optionally substituted by 1 to 5, preferably 1 to 3, groups independently selected from hydroxy, cyano, nitro, -COOR ¹³ , dC ₅ alkoxy groups, halogen, -NR ⁹ R ^9a , and a partially or fully fluorinated Ci-C ₃ alkyl group. The alkyl groups may preferably be substituted by 1 to 3 halogen atoms and / or 1 to 3 hydroxy and / or 1 to 3 cyano and / or 1 to 3 -COOR ¹³ groups. A particularly preferred subgroup of substituents are fluorine atom, hydroxy-methoxy and / or cyano groups.

Another preferred group of substituents for the alkyl groups are 1 to 3 hydroxy and / or 1 to 3 -COOR ¹³ groups. Particularly preferred are the hydroxy groups.

For a partially or fully fluorinated alkyl group, for example, the following partially or completely fluorinated groups are contemplated:

Fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1, 1-difluoroethyl, 1, 2

Difluoroethyl, 1, 1, 1-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl. Of these, preferred are the trifluoromethyl or the pentafluoroethyl group. The fully fluorinated

Group is also called perfluoroalkyl group. The reagents that may be used during the synthesis are commercially available or have been published

Syntheses of the corresponding reagents belong to the prior art, or published syntheses can be applied analogously.

The alkenyl groups have at least one C = C double bond and may be straight-chain or branched. Alkenyl groups having 2 to 8 carbon atoms are preferred. The alkynyl groups have at least one C≡C triple bond and may be straight-chain or branched. Preferred are alkynyl groups having 2 to 8 carbon atoms.

The alkoxy groups mentioned in the definitions of general formula (I) can be straight-chain or branched and are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy. C ₁ -C ₅ - and CrC ₃ -, Ci-C ₈ -, and CrClio alkoxy groups are preferred. A methoxy or ethoxy group is particularly preferred. The alkylthio groups mentioned in the definitions of general formula (I) may be straight-chain or branched and may be, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. CrC ₅ alkylthio groups are preferred. A methylthio or ethylthio group is particularly preferred.

The alkoxy and alkylthio groups described above may bear on their alkyl groups the same substituents as described above for the alkyl groups in general. Preferred substituents for alkoxy and alkylthio groups are independently selected from halogen (especially fluorine and / or chlorine), hydroxy and cyano.

The substituent -NR ⁹ R ^{9a is} , for example, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -NH (C ₂ H ₅ ), -N (C ₂ Hs) ₂ , -NH (C ₃ H ₇ ), -N (C ₃ H ₇ J ₂ , -NH (C ₄ H ₉ ), -N (C ₄ Hg) ₂ , -NH (C ₅ H ₁₁ ), -N (C ₅ Hn) ₂ , -NH (CO) CH ₃ , -NH (CO) C ₂ H ₅ , -NH (CO) C ₃ H ₇ , -NH (CO) C ₄ H ₉ , -NH (CO) C ₅ Hn. C ₃ -C ₇ ) -cycloalkyl group means one optionally represented by one or more groups selected from hydroxy groups, halogen atoms, (C ₁ -C ₅ ) -alkyl groups, (C ₁ -C ₅ ) -alkoxy groups, -NR ⁹ R ^9a groups, -COOR ¹³ groups , -CHO, and cyano, substituted saturated cyclic group having 3 to 7 ring carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.

As the alkylidene or Exoalkylidengruppe is to be understood a group having 1 to 10 carbon atoms, which is bound via an exodo double bond to the system (ring or chain). Preference is given to (C ₁ -C ₅ ) - and (CrC ₃ ) alkylidene, particular preference is given to exomethylene. The heterocyclyl group is a cyclic, non-aromatic group containing one or more heteroatoms and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine. Perhydroquinoline and perhydroisoquinoline also belong to the heterocyclyl groups according to the invention. Suitable substituents for heterocyclyl and heteroaryl groups, for example substituents from the following group: Cr, optionally substituted C ₅ alkyl, hydroxy, C ₁ -C ₅ -alkoxy, -NR ⁹ R ^9, halogen, cyano, -COOR ^13, - CHO. The substituents may optionally also be bonded to the nitrogen atom of the heterocyclyl or heteroaryl group; N-oxides are also included in the definition.

Aryl groups within the meaning of the invention are aromatic or partially aromatic carbocyclic groups having from 6 to 14 carbon atoms which contain a ring, such as e.g. Phenyl or phenylene or more condensed rings such as e.g. Naphthyl or anthranyl. Examples include phenyl, naphthyl, tetralinyl, anthranyl, indanyl, and indenyl. The optionally substituted phenyl group and the naphthyl group are preferred.

The aryl groups may be substituted at any suitable point leading to a stable compound by one or more radicals selected from the group hydroxy, halogen, optionally substituted by 1 to 3 hydroxy or -COOR ¹³ groups substituted Ci-Cs-alkyl, CrC ₅ Alkoxy, cyano, -CF ₃ , and nitro.

The aryl groups may be partially hydrogenated and then additionally or alternatively to the abovementioned substituents also carry keto and / or Exoalkylidengruppen. Among partially hydrogenated phenyl, e.g. To understand cyclohexadienyl, cyclohexenyl, cyclohexyl. A partially hydrogenated substituted naphthalene system is, for example, 1-tetralone or 2-tetralone.

A (C 1 -C ₈ ) alkylaryl group is an aryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C 1 -C 6 -alkyl unit (as defined above).

A (C ₂ -C ₈ ) alkenylaryl group is an aryl group as already described above which is linked to the ring system via a straight-chain or branched (C ₂ -C ₈ ) -alkenyl unit (as defined above).

A (C ₂ -C ₆ ) alkynylaryl group is an aryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C ₂ -C ₈ ) -alkynyl unit (as defined above). The mono- or bicyclic heteroaryl group may optionally contain 1 to 9 groups selected from nitrogen atoms, oxygen atoms, sulfur atoms or keto groups, of which a maximum of 4 nitrogen atoms, a maximum of 2 oxygen atoms, a maximum of 2 sulfur atoms and / or a maximum of 2 keto groups may be included. Any subcombination of these groups is possible. The heteroaryl group may be hydrogenated at one or more sites.

Examples of monocyclic heteroaryl groups include pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, 1H- and 4H-pyrazole, 1H- and 2H-pyrrole, Oxazole, thiazole, furazane, 1H- and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.

For example, cyclic heteroaryl groups include phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzo [b] thienyl, Benzo [c] thienyl, benzimidazolyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, Dihydrophthalazinyl, 1, 7- or 1, 8-naphthyridinyl, coumarinyl, iso-cumarinyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, pyrazolo [1, 5] a] be pyridinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl.

When the heteroaryl groups are partially or fully hydrogenated, compounds of the general formula (I) wherein R ^{3 is} tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridine 4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl, chromanyl, isochromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl , Tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro-2H-benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazine-4-onyl, 3,4-dihydrobenz [1,4] oxazine-4 -onyl, 3,4-dihydro-2H-benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-onyl, 3H- Quinazolin-4-onyl, 1H-quinazolin-4-onyl, 3,4-dihydro-1H-quinoxaline-2-onyl,

2,3-1,3,3,4-Tetrahydro [1,5] naphthyridinyl, dihydro-1H- [1,5] naphthyridyl, 1H- [1,5] -naphthyrid-4-onyl, 5,6 , 7,8-tetrahydro-1H-naphthyridin-4-onyl, 1, 2-dihydropyrido [3,2-d] [1,3] oxazin-4-onyl, octahydro-1H-indolyl, 2,3- Dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1,3-dihydro-2H-isoindolyl, 1, 2-dihydroindazolyl, 1H-pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1H pyrrolo [2,3-b] pyridyl, 2,2-dihydro-1H-pyrrolo [2,3-b] pyridin-3-onyl, to the present invention. The mono- or bicyclic heteroaryl group may optionally be substituted by one or more substituents selected from C 1 ^-C ₅ -alkyl groups ^optionally substituted by 1 to 3 hydroxy groups or 1 to 3 -COOR ^{1 15} groups, C 1 -C ₅ -alkoxy groups, halogen atoms, and / or exomethylene groups be substituted. The substituents may, if possible, optionally also be bonded directly to the heteroatom (eg on the nitrogen atom). N-oxides are also part of the present invention.

A (d-CeJalkylheteroaryl group is a heteroaryl group as already described above, which is linked to the ring system via a straight-chain or branched (CrCβJ-alkyl unit (as defined above).

A (C ₂ -C ₈ ) alkenyl heteroaryl group is a heteroaryl group as already described above which is linked to the ring system via a straight-chain or branched (C ₂ -C 6) -alkenyl unit (as defined above).

A (C ₂ -C ₈ ) alkynylheteroaryl group is a heteroaryl group, as already described above, which is linked to the ring system via a straight-chain or branched (C ₂ -C 6) -alkynyl unit (as defined above).

A (C 1 -C 6) alkyl heterocyclyl group is a heterocyclyl group as already described above which is linked to the ring system via a straight-chain or branched (C 1 -C 6) -alkyl moiety (as defined above). A (C ₂ -C 6) alkenyl heterocyclyl group is a heterocyclyl group as already described above, which is linked to the ring system via a straight-chain or branched (C ₂ -C ₈ ) -alkenyl unit (as defined above).

Suitable hydroxy protecting groups are all customary hydroxy protecting groups known to the person skilled in the art, in particular silyl ethers or esters of organic C ₁ -C ₁₀ -acids, C ₁ -C ₅ ethers, benzyl ethers or benzyl esters. The usual hydroxy protecting groups are described in detail in TW Greene, PGM Wut's Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, 1991). The protecting groups are preferably alkyl, aryl or mixed alkylaryl-substituted silyl groups, for example the trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or Triisopropylsilyl groups (TIPS) or other common hydroxy protecting groups (eg, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, tetrahydropyranyl groups).

The compounds of the general formula (I) according to the invention can be present as stereoisomers due to the presence of asymmetric centers. The present invention relates to all possible diastereomers both as racemates, as well as in enantiomerically pure form. The term stereoisomers also encompasses all possible diastereomers and regioisomers and tautomers (eg keto-enol tautomers) in which the stereoisomers according to the invention can be present, which are therefore also the subject of the invention. The compounds according to the invention can also be present in the form of salts with pharmacologically acceptable anions, for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.

Also pharmacologically acceptable derivatives or prodrugs of the compounds of general formula (I) are encompassed by the invention. As derivatives or prodrugs, for example, esters, ethers or amides of the compounds of the general

Formula (I) or other compounds referred to in the organism

Metabolize compounds of general formula (I). Suitable compounds are listed, for example, in Hans Bundgaard (Ed.), Design of Prodrugs, Elsevier, Amsterdam 1985.

Preferred embodiments

A subgroup of compounds of the general formula (I) according to the invention are those compounds in which R ⁷ and R ⁸ independently of one another represent a hydrogen atom, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a cyano group, together a (CrC -ιo) alkylidene group or together with the carbon atom of the tetrahydronaphthalene an optionally substituted (C ₃ -C ₆ ) cycloalkyl ring.

Another subgroup of compounds of the general formula (I) according to the invention are those compounds in which R ⁶ and R ⁷ together have a fused five- to eight-membered saturated or unsaturated carbo or heterocycle which is optionally substituted by 1 to 2 keto groups, 1 to 2 ( C ₁ -C ₅ ) - alkyl groups, 1 to 2 (dC ₅ ) alkoxy groups, and / or 1 to 4 halogen atoms substituted form.

A further subgroup of compounds of the general formula (I) are those compounds in which R ¹ and R ⁸ together form an annelated five- to eight-membered saturated or unsaturated carbocycle or heterocycle optionally substituted by 1 to 2 keto groups, 1 to 2 ( Ci-C ₅ ) - alkyl groups, 1 to 2 (Ci-CsJ-alkoxy groups, and / or 1 to 4 halogen atoms substituted form. Another subgroup of compounds of the general formula (I) according to the invention are those compounds in which R ¹ and R ^2, independently of one another, are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 4) -alkyl group, a (C 1 -Cio) - Alkoxy group, a (Ci-C-ιo) -alkylthio group, a (CrC ₅ ) - perfluoroalkyl group, a cyano group, a nitro group, or a -NR ⁹ R ^9a group.

Another subgroup of compounds of the general formula (I) according to the invention are those compounds in which or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) n-CH ₂ -, -O-CH = CH-, - (CH ₂ ) n ₊ 2 -, - NH- (CH ₂ ) n ₊ i-, -N (C 1 -C 3 -alkyl) - (CH ₂ ) n ₊ i - form, and -NH-N = CH-, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are linked to directly adjacent ring carbon atoms.

A preferred group of compounds of general formula (I) are those compounds in which X is a bond or a group -C (= O) -, -C (= O) -NH-, -SO ₂ - or -CH ₂ - is.

Another preferred group of compounds of the general formula (I) are those compounds in which R ^{4 is} a hydroxy group or an -OR ¹⁰ group. Particularly preferred are those compounds in which R ^{4 is} a hydroxy group.

Another preferred group of compounds of the general formula (I) are those compounds in which R ^{6 is} a hydrogen atom.

Another preferred group of compounds of the general formula (I) are those compounds in which R ^{6 is} a halogen atom or an optionally substituted (C 1 -C 10) -alkyl group.

Another preferred group of compounds of the general formula (I) are those compounds in which R ^{7 represents} a halogen atom or an optionally substituted methyl or ethyl group.

Another preferred group of compounds of the general formula (I) are those compounds in which R ⁷ and R ⁸ each represent a methyl group, or together with the carbon atom of the tetrahydronaphthalene system form a cyclopropyl group. Particularly preferred are the compounds in which R ⁷ and R ⁸ each represent a methyl group.

Another preferred group of compounds of the general formula (I) are those compounds in which R ^{3 is} an optionally substituted aryl or Heteroaryl group means. Particular preference is given here to those compounds in which the aryl or heteroaryl group is selected from the group consisting of naphthyl, benzofuranyi, pyrazolo [1, 5-a] pyridinyl, phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, Benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, chromanyl, isochromanyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl. Particularly preferred are the groups pyrimidinyl and naphthyl. Another preferred group of compounds of the general formula (I) are those compounds in which the substituents R ¹¹ and R ¹² each represent a hydrogen atom.

A particularly preferred group of compounds of the general formula (I) as defined above are those compounds in which R ¹ , R ² , R ¹¹ , and R ¹² independently of one another represent a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted (CrCi _O ) Alkyl group, or a (Ci-Cio) alkoxy group, R ^{3 represents} an optionally substituted aryl or heteroaryl group, R ^{4 represents} a hydroxy group, an -OR ¹⁰ group or an -O (CO) R ¹⁰ group, R ^{6 represents} a hydrogen atom, a halogen atom or an optionally substituted (C 1 -C 10) -alkyl group, R ⁷ and R ⁸ independently of one another an optionally substituted (C 1 -C 10) -alkyl group, together a (C 1 -C 10) -alkylidene group or together with the carbon atom of the tetrahydronaphthalene system denote an optionally substituted (C ₃ -C ₆ ) -cycloalkyl ring, R ¹⁰ denotes a (C ₁ -C ¹⁰ -ιι) -alkyl group, and X denotes a bond or a group -C (= O) - , -C (= O) -NH-, -S ( O) _m - (where m is 1 or 2), or - (CH ₂ ) _p - (where p is 1, 2 or 3).

A very particularly preferred group of compounds of the general formula (I) as defined above are those compounds in which R ¹ , R ² , R ¹¹ , and R ¹² independently of one another represent a hydrogen atom, a halogen atom, or a (C 1 -C 10) -alkoxy group , R ^{3 is} an optionally substituted pyrimidinyl, naphthyl or quinolinyl group, R ^{4 is} a hydroxy group, R ^{6 is} a hydrogen atom, R ⁷ and R ^{8 are} independently an optionally substituted (C-ι-Cio) alkyl group, especially methyl , mean, and X means a bond. Any further possible combination of the abovementioned subgroups and the substituents given as preferred having their general and / or special meanings is likewise to be regarded as covered by the present invention. production method

The compounds of the general formula (I) according to the invention can be obtained in various ways. The manufacturing methods described below also form part of the present invention. Unless otherwise indicated, the substituents used in the process descriptions below have the same meaning as described in the "Brief Description of the Invention" section above, including the definitions given in the "Detailed Description of the Invention" section.

The compounds according to the invention are prepared by firstly generating amino compounds of the general formula (II),

which can be converted by various further reactions to compounds of general formula (I). The synthesis of the amines of the general formula (II) is described in detail below.

A process according to the invention (Process A) is characterized in that a compound of the general formula (II) is reacted by reacting with a compound selected from compounds of the general formulas R ³ -X-Nu (where Nu represents a nucleofugic group), R ³ - N = C = O or R ³ -N = C = S, and optionally subsequent replacement of a carbonyl oxygen atom with sulfur by methods known in the art, to give a compound of general formula (I).

The optional substitution of a carbonyl oxygen atom for sulfur mentioned in the above-described process is known in the art and can be achieved, for example, by reaction with Lawesson's reagent or phosphorus pentasulfide.

As nucleofuge groups Nu used in the method described above

Compound R ³ -X-Nu, for example, halogen atoms or leaving groups such as the acetate, tosylate, mesylate or triflate are suitable. The compounds R ³ -X- Nu thus belong, for example, to the classes of the carboxylic acid, sulfonic acid, or sulfinic acid halides or the mixed anhydrides of these acids, as well as to the esters of cnioroformic acid, of toluenesulfonic acid, of methylsulfonic acid and of trifluoromethylsulfonic acid. In the process A described above, when the group X has the meaning of a bond, the nucleofugic group is a halogen atom (preferably a bromine or iodine atom). In this case, the reaction is conducted under copper catalysis.

A further process according to the invention (process B) for the preparation of compounds of the general formula (I) comprises reacting a compound of the general formula (II) as described above with a compound of the general formula R ³ -CHO and the resulting imine is reduced.

A further process according to the invention (process C) for the preparation of compounds of the general formula (I) comprises reacting a compound of the general formula (II) as described above with phosgene or thiophosgene and subsequently forming the resulting isocyanate or isothiocyanate is reacted with compounds of general formula R ³ -OH or R ³ -NH ₂ to give a compound of general formula (I).

Compounds of the general formula (II) can be obtained by a process in which the 1-tetralone derivatives (V) known in the prior art are converted by selective oxidation into the 2-hydroxy-1-tetralone derivatives of the general formula (IV) which are subsequently converted into the corresponding oximes (III) and catalytically reduced with hydrogen, whereby the compounds of the general formula (II) are obtained, in which the substituent R ^{4 is} a hydroxy group. The reaction sequence is shown below in Scheme 1. The conditions for the individual process steps are familiar to the person skilled in the art.

The tetralone derivatives of the general formula (V) can be obtained, for example, analogously to the processes described in WO 03/082827 and WO 2005/003098.

SCHEME 1: Preparation of compounds of general formula (II)

(V) (IV)

(M)

(III)

Biological activity

The anti-inflammatory activity of the compounds of general formula (I) is tested in animal experiments by testing in croton oil-induced inflammation in rat and mouse (J. Exp. Med. (1995), 182, 99-108). For this purpose, the animals are topically applied croton oil in ethanolic solution to the ears. The test substances are also applied topically or systemically simultaneously or two hours before the croton oil. After 16-24 hours, ear weights are measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocytic immigration, and elastase activity as a measure of neutrophil granulocyte immigration. The compounds of the general formula (I) inhibit the three abovementioned inflammatory parameters in this test both after topical and after systemic administration. The binding of the substances to the glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is checked using recombinant receptors. Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are reported for the Bonding studies used. In comparison with the reference substance [ ³ H] -dexamethasone, the substances show a high affinity for GR.

As a major molecular mechanism for the anti-inflammatory effect of glucocorticoids, the GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes, and other pro-inflammatory factors is considered. This inhibition is mediated by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B (for review see Cato ACB and Wade E, BioEssays 18, 371-378 1996).

The compounds of the general formula (I) according to the invention inhibit the lipopolysaccharide (LPS) -derived secretion of the cytokine IL-8 in the human monocyte cell THP-1. The concentration of cytokines was determined in the supernatant by means of commercially available ELISA kits.

One of the most common adverse effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason for this is the stimulation of gluconeogenesis in the liver by induction of the responsible enzymes and by free amino acids, which arise from the degradation of proteins (catabolic effect of glucocorticoids). A key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good measure of the undesired metabolic effects of the glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after administration of the test substances, the liver removed and the TAT activity in the Homogenate measured. The compounds of the general formula (I) do not or only to a limited extent induce the tyrosine aminotransferase in doses in which they have an antiinflammatory effect in this test.

Medical indications

Because of their anti-inflammatory and additional anti-allergic, immunosuppressive and anti-proliferative action, the compounds of the general formula (I) according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in patients, in particular mammals and preferably humans: The term "DISEASE" refers to the following indications: (i) lung diseases associated with inflammatory, allergic and / or proliferative processes:

- Chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma

- Bronchitis of different origin

- All forms of restrictive lung diseases, especially allergic alveolitis,

- All forms of pulmonary edema, especially toxic pulmonary edema - sarcoidosis and granulomatosis, in particular Boeck's disease

(ii) Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes:

All forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica

- Reactive arthritis

- Inflammatory soft tissue diseases of other causes

- Arthritic symptoms in degenerative joint disease (arthrosis)

- Traumatic arthritis - collagenosis of any genesis, e.g. systemic lupus erythematosus,

Scleroderma, polymyositis, dermatomyositis-Sjögren syndrome, still syndrome, Felty syndrome

(iii) allergies associated with inflammatory and / or proliferative processes:

All forms of allergic reactions, e.g. Quincke edema, hay fever,

Insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis

(iv) Vasculitis

- Panarteritis nodosa, temporal arteritis, erythema nodosum

(v) Dermatological disorders associated with inflammatory, allergic and / or proliferative processes: - Atopic dermatitis (especially in children)

- psoriasis

- Pityriasis rubra pilaris

Erythematous diseases triggered by different noxae, e.g. Blasting, chemicals, burns etc.

- Bull's-eye dermatoses

- diseases of the lichenoid type,

- pruritus (eg allergic genesis)

- Seborrheic dermatitis - Rosacea

- Pemphigus vulgaris

- Erythema exudative. multiforme

- balanitis

- vulvitis - hair loss like alopecia areata

- Cutaneous T - cell lymphomas

(vi) kidney disease associated with inflammatory, allergic and / or proliferative processes:

- Nephrotic syndrome - All nephritis

(vii) liver disease associated with inflammatory, allergic and / or proliferative processes:

- Acute liver cell decay

acute hepatitis of different origins, e.g. viral, toxic, drug-induced - chronic aggressive and / or chronic intermittent hepatitis

(viii) Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes:

- regional enteritis (Crohn's disease)

- Ulcerative colitis - Gastritis - reflux oesophagitis

- Gastroenteritides of other genesis, e.g. native sprue

(ix) proctological diseases associated with inflammatory, allergic and / or proliferative processes:

- Anal eczema

- fissures

- Hemorrhoids

- idiopathic proctitis

(x) eye diseases associated with inflammatory, allergic and / or proliferative processes:

- allergic keratitis, uveitis, iritis,

- conjunctivitis

- Blepharitis

- Neuritis nervi optici - Chorioditis

- Ophtalmia sympathica

(xi) diseases of the ear, nose and throat, which are associated with inflammatory, allergic and / or proliferative processes:

allergic rhinitis, hay fever, otitis externa, e.g. due to contact problems, infection etc.

- Otitis media

(xii) neurological disorders associated with inflammatory, allergic and / or proliferative processes:

- Cerebral edema, especially tumor-related cerebral edema - multiple sclerosis

- Acute encephalomyelitis

- Meningitis

- various forms of seizures, eg BNS cramps (xiii) Blood disorders associated with inflammatory, allergic and / or proliferative processes:

- Acquired hemolytic anemia

- Idopathic thrombocytopenia

(xiv) tumors associated with inflammatory, allergic and / or proliferative processes:

- Acute lymphocytic leukemia

- Malignant lymphomas

- Lymphogranulomatoses - Lymphosarcomas

- Extensive metastases, especially in breast, bronchial and prostate cancers

(xv) Endocrine disorders associated with inflammatory, allergic and / or proliferative processes: - endocrine orbitopathy

- Thyrotoxic crisis

- Thyreoiditis de Quervain

- Hashimoto's thyroiditis

- Graves' disease

(xvi) Organ and tissue transplants, graft-versus-host disease

(xvii) Severe shock states, such as anaphylactic shock, systemic inflammatory response syndrome (SIRS)

(xviii) emesis associated with inflammatory, allergic and / or proliferative processes:

- e.g. in combination with a 5-HT3 antagonist in cytostatic - related

Vomit.

(xix) Pain with inflammatory genesis, eg lumbago (xx) replacement therapy in:

- congenital primary adrenal insufficiency, e.g. Congenital adrenogenital syndrome

Acquired primary adrenal insufficiency, e.g. Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc.

- congenital secondary adrenal insufficiency, e.g. congenital hypopitotitarism

Acquired secondary adrenal insufficiency, e.g. postinfectious, tumors etc ..

Particularly effective are drugs containing stereoisomers of the general formula Ia in the following diseases:

1. lung diseases

2. rheumatic diseases / autoimmune diseases

3. dermatological diseases

4. degenerative joint diseases 5. vascular inflammation

6. graft versus host disease

Severe shock states

8. Emesis associated with inflammatory, allergic and / or proliferative processes 9. Inflammatory pain.

In addition, the compounds of the general formula (I) according to the invention can be used for the therapy and prophylaxis of other disease states not mentioned above, for which synthetic glucocorticoids are used today (see Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH , Stuttgart, 1998).

All of the aforementioned indications are described in detail in Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998. For the therapeutic effect in the above-mentioned disease states, the appropriate dose is different and depends, for example, on the potency of the Compound of general formula (I), the patient (eg size, weight, sex, etc.), the mode of administration and the nature and severity of the conditions to be treated, as well as the use as a prophylactic or therapeutic agent. The invention relates to the use of the claimed compounds for the preparation of a pharmaceutical composition.

The invention further provides

(i) the use of one of the compounds of the general invention

Formula (I) or its mixture for the preparation of a pharmaceutical composition for the treatment or prevention of inflammatory

Processes, and in particular for the treatment of a DISEASE (as defined above);

(ii) a method for the treatment or prevention of inflammatory processes, in particular for the treatment of a DISEASE (as defined above), which method comprises administering a pharmaceutically effective amount of a compound of general formula (I), said amount being the disease or symptoms relieved or suppressed, and wherein the compound is given to a patient, preferably a mammal, especially a human, in need of such treatment;

(Iii) a pharmaceutical composition for anti-inflammatory, in particular for the treatment of a DISEASE (as defined above), wherein the composition comprises one of the compounds according to the invention or their mixture and optionally at least one pharmaceutical excipient and / or carrier.

In general, satisfactory results are expected in animals when the daily doses range from 1 μg to 100,000 μg of the compound of the invention per kg of body weight. For larger mammals, such as humans, a recommended daily dose is in the range of 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg body weight, more preferably a dose of 10 to 10,000 μg per kg body weight. For example, this dose is conveniently administered several times a day. For the treatment of an acute shock (eg anaphylactic shock) single doses may be given that are well above the doses mentioned above. The formulation of the pharmaceutical compositions based on the new compounds is carried out in a conventional manner by the active ingredient with the commonly used in Gaienik carriers, Füiistoffen, Zerfaiisbeeinflussern, binders, humectants, lubricants, absorbents, thinners, flavoring agents, colorants, etc. , processed and converted into the desired application form. Reference may be made to Remington ^'s Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).

For oral administration in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions in question.

For parenteral administration, injection and infusion preparations are possible.

For intraarticular injection appropriately prepared crystal suspensions may be used.

For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy.

For pulmonary administration of the new compounds, these can be used in the form of aerosols and inhalants.

For local application to the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses, the new compounds may be used as drops, ointments, tinctures and gels in appropriate pharmaceutical preparations. For topical application, formulations in gels, ointments, greases, creams, pastes, powders, suspensions, emulsions and solutions are possible. The dosage of the compounds of general formula (I) should be 0.01% - 20% in these preparations in order to achieve a sufficient pharmacological effect. The invention likewise encompasses the compounds of the general formula (I) according to the invention as therapeutic active ingredient. Furthermore, the invention compounds of the general formula (I) according to the invention as a therapeutic agent together with one or more pharmaceutically acceptable and acceptable excipients and / or carriers. If appropriate, the compounds of the general formula (I) according to the invention may also be formulated and / or administered in combination with further active compounds.

The invention therefore also relates to combination therapies or combined compositions wherein a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, is administered either simultaneously (optionally in the same composition) or sequentially together with one or more medicaments for the treatment of any of the above-mentioned conditions. For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD (chronic obstructive pulmonary disease), asthma or allergic rhinitis, a compound of general formula (I) of the present invention may be combined with one or more medicaments for the treatment of such a condition. Where such a combination is administered by inhalation, the drug to be combined may be selected from the following list:

A PDE4 inhibitor including an isoform PDE4D inhibitor;

• a selective ß.sub2. Adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol,

Salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;

A muscarinic receptor antagonist (for example an M1, M2 or M3 antagonist, such as a selective M3 antagonist) such as, for example, ipratropium bromide, tiotropium bromide, oxitropium bromide,

Pirenzepine or telenzepin;

• a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); or

• an inhibitor of p38 kinase function.

For another object of the present invention, such a combination with a compound of the general formula (I) or a pharmaceutically acceptable salt thereof is used for the treatment of COPD, asthma or allergic rhinitis and may be administered by inhalation or orally in combination with xanthine (such as aminophylline or theophylline), which may also be administered by inhalation or orally.

Examples

Preparation of 4,4-dimethyl-1-pyrimidin-5-ylamino-1,2,3,4-tetrahydronaphthalene-2-ol

5,5-dimethyl-dihydrofuran-2-one (J. Am. Chem. Soc., 1947, 69, 2322-2324), 4,4-dimethyl-3,4-dihydro-2H-naphthalene-1-one (J. Chem. Soc., 1947, 69, 2322-2324) and 2-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (J. Org. Chem. 1184-1190) are prepared according to the literature.

A. 2-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one;

0.87 g (5.0 mmol) of 4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one was dissolved in 20 ml of THF under argon, cooled to -74 ⁰ C and then 15.2 ml (0.5 M in toluene, 7.6 mmol) Kalum-bis- (trimethylsilyl) amide solution was added dropwise at -74 to -71.5 ⁰ C to 30 and stirred at -74 ⁰ C min. 2.3 g (7.6 mmol) of [(8,8-dichlorcamphoryl) sulfonyl] oxaziridine were dissolved in 30 ml of THF and added dropwise at -74 to -68 ⁰ C to the reaction solution, while the reaction mixture turned dark red. The reaction was stirred 75 min at -74 ⁰ C. For workup, the reaction mixture was carefully mixed with saturated sodium bicarbonate solution and then extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered off and concentrated in vacuo. This gave 3.07 g of a viscous yellow oil as crude product, which was purified by column chromatography with ethyl acetate / hexane: 539 mg (57%) of a pale yellow, viscous oil.

¹ H-NMR (300 MHz, CDCl ₃ ): δ / ppm = 1.46 (s, 6H), 2.05 (dd, 1H), 2.30 (dd, 1H), 3.74 (s, 1H), 4.60 (dd , 1 H), 7.34 (t, 1 H), 7.44 (d, 1 H), 7.58 (t, 1 H), 8.00 (d, 1 H).

B. 2-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime: 525 mg (2.76 mmol) 2-hydroxy-4,4-dimethyl-3,4-dihydro- 2H-naphthalen-1-one were dissolved in 10 ml of pyridine, cooled to -14 ⁰ C and 348 mg (5:53 mmol) of hydroxylamine - Added hydrochloride, slowly warmed to room temperature and stirred for 48 h. For workup, pyridine was distilled off on a rotary evaporator, the residue with 20 ml of saturated sodium chloride solution and 20 ml of citric acid solution (10%) and extracted three times with 30 ml of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered off and concentrated. This gave 608 mg of crude product, which was purified by column chromatography with hexane / ethyl acetate: 402 mg (71%) of colorless viscous oil.

¹ H-NMR (300 MHz, CDCl ₃ ): δ / ppm = 1.23 (s, 3H), 1.44 (s, 3H), 1.86 (dd, 1H), 2.09 (dd, 1H), 5.21 (dd, 1H), 7.21-7.27 (m, 1H), 7.37-7.39 (m, 2H), 7.82 (d, 1H).

C. 1-Amino-4.4-dimethyl-1, 2.3.4-tetrahydro-naphthalen-2-ol: 381 mg (1.86 mmol) 2-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalene 1-on oxime was dissolved in 45 ml of methanol, treated with 78 mg of palladium on activated carbon (10%) and with 0.6 ml of concentrated hydrochloric acid. The flask was evacuated several times, purged with hydrogen and then stirred under hydrogen at room temperature for 6 hours. For workup, the catalyst was filtered through Celite, washed with methanol, the filtrate was treated with 5 ml of saturated sodium bicarbonate solution and concentrated on a rotary evaporator. The residue was treated with saturated sodium bicarbonate solution and ethyl acetate and the organic phase was separated off. The aqueous phase was back-extracted twice with ethyl acetate. The combined organic phases were washed with sodium chloride solution, dried over sodium sulfate, filtered off and concentrated under reduced pressure: 320 mg (90%) of product.

¹ H-NMR (300 MHz, CDCl ₃ ): δ / ppm = 1.30-1.35 (m, 3H), 1.40 (s, 3H), 1.76-2.05 (m, 2H), 2.24 (bs, 3H), 3.63 4.09 (m, 2H), 7.18 - 7.53 (m, 3H), 7.49 - 7.53 (m, 1H).

D. 4.4-Dimethyl-1-pyrimidin-5-ylamino-1,2,3,4-tetrahydronaphthalene-2-ol:

57 mg (0.30 mmol) of 1-amino-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene-2-ol, 32 mg (0.20 mmol) of 5-bromopyridine, 3.8 mg (0.02 mmol) of copper iodide, 7.73 mg (0.04 mmol) of N, N-diethyl-2-hydroxybenzamide and 84.9 mg (0.4 mmol) of potassium phosphate were weighed into a microwave vessel, purged with argon, then 150 .mu.l of DMF was added, the vessel closed and at 90 for 21 h ⁰ C stirred. For work-up the reaction mixture was cooled to room temperature, treated with 2 ml of ethyl acetate, added 0.5 ml (33%) of ammonium hydroxide solution and 5 ml of water. It was extracted twice with ethyl acetate, the combined organic phases, washed with sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. 97 mg of crude product were purified by column chromatography (column material: amine phase, ethyl acetate): 31 mg (58%). Preparative HPLC gave the desired product.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ / ppm = 1.29 (s, 3H), 1.34 (s, 3H), 1.77-1.87 (m, 2H), 3.87 (bs, 1H), 4.42 (t, 1H), 5.00 (d, 1H), 6.47 (d, 1H), 7.14 (t, 1H), 7.22 - 7.24 (m, 2H), 7.38 (d, 1H), 8.18 ( s, 2H), 8.33 (s, 1H).

According to the above-mentioned instructions, the following compounds are also obtained in an analogous manner:

4,4-dimethyl-7-methoxy-1-pyrimidin-5-ylamino-1,2,3,4-tetrahydronaphthalene-2-ol,

8-fluoro-4,4-dimethyl-5-methoxy-1-pyrimidin-5-ylamino-1,2,3,4-tetrahydronaphthalene-2-ol,

4,4-dimethyl-1-naphth-1-ylamino-1,2,3,4-tetrahydronaphthalene-2-ol, and 4,4-dimethyl-1-quinolin-5-ylamino-i, 2,3 , 4-tetrahydro-naphthalene-2-ol.

Claims

claims 1. compounds of the general forms! (I)

wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C 4) -alkoxy group, a (C ₁ -C 4) -alkylthio group, a (C ₁ -C 4) radical ₅ ) - perfluoroalkyl group, a cyano group, a nitro group, or a -NR ⁹ R ^9a group, or R ¹ and R ² together are a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, - NH- (CH ₂ ) _{n + 1} -, -N (Ci-C ₃ -alkylHCH ₂ ) n ₊ i-, and -NH-N = CH-, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms with directly adjacent Ring carbon atoms are linked, R ¹¹ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (CRCI _O) -alkyl group, a (CrCio) alkoxy group, a (CrCio) -alkylthio group, or a _(Ci-C5) - perfluoroalkyl group is R ^{12 is} a hydrogen atom, a hydroxy group, a halogen atom, a Cyano group, an optionally substituted (Ci-Ci _O ) alkyl group, or a (CrC-ιo) alkoxy group, R ^{3 is} optionally substituted by 1 to 3 hydroxy groups, 1 to 3 halogen atoms, and / or 1 to 3 (Ci-Cs) alkoxy substituted (C _r Cio) alkyl, an optionally substituted (C ₃ -C ₇₎ cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, optionally substituted by one or more groups independently selected from (C 1 -C ₅ ) -alkyl groups which may themselves be optionally substituted by 1 to 3 hydroxy or 1 to 3 -COOR ¹³ -Groups, (CrC ₅ ) -alkoxy groups, Halogen atoms, hydroxy groups, -NR ⁹ R ^9a groups, and Exomethylengruppen substituted, 1 to 4 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms and / or 1 to 2 keto groups containing mono- or bicyclic heteroaryl group, wherein this group is linked via any position with the group X and may optionally be hydrogenated at one or more sites, R ^{4 is} a hydroxy group, an -OR ¹⁰ group or an -O (CO) R ¹⁰ group, R ^{6 is} a hydrogen atom, a halogen atom, or an optionally substituted (Ci-Cio) alkyl group, R ⁷ and R ^{8 are} independently a hydrogen atom, a halogen atom, an optionally substituted (CrC-ιo) alkyl group, a cyano group, together (C ₁ -C ₄ ) -alkylidene group or, together with the carbon atom of the tetrahydronaphthalene system, an optionally substituted (C ₃ -C ₆ ) -cycloalkyl ring; or R ⁶ and R ⁷ together form an annelated five- to eight-membered saturated or unsaturated carbocycle or heterocycle optionally substituted by 1 to 2 keto groups, 1 to 2 (-C ₅₎ -alkyl groups, 1 to 2 _(Ci-C5) - alkoxy groups and / or 1 to 4 halogen atoms is substituted; or R ¹ and R ⁸ together form a fused five to eight membered saturated or unsaturated carbo or heterocycle, optionally substituted by 1 to 2 keto groups, 1 to 2 (Ci-C ₅ ) -alkyl groups, 1 to 2 (CrC ₅ ) - alkoxy groups, and / or 1 to 4 halogen atoms substituted form; R ⁹ and R ^9a are independently a hydrogen atom, a (-C ₅₎ - alkyl group or - (CO) - (CrC ₅₎ alkyl, R ¹⁰ is a (CrCio) alkyl group or any hydroxyl-protecting group, R ^{13 represents} a hydrogen atom or a (C 1 -C ₅ ) -alkyl group, and X is a bond or a group -C (OO) -, -C (SS) -, -C (OO) -NH-, -C (SS) -NH-, -S (O) _m - ( where m = 1 or 2), -C (= O) -O-, -C (= S) -O- or a group - (CH ₂ ) _P - (where p = 1, 2 or 3), where if X is a Carbonyl or thiocarbonyl function, this function being bonded to the group -NH- in general formula (I), in the form of any stereoisomer or mixture of stereoisomers; or as a pharmacologically acceptable salt or derivative. 2. Compounds according to claim 1, wherein X is a bond or group -C (O) -, -C (= O) -NH-, -SO ₂ - or -CH ₂ -. 3. Compounds according to claim 1 or 2, wherein R ^{4 is} a hydroxy group or a group -OR ¹⁰ . 4. Compounds according to one of the preceding claims, wherein R ^{6 is} a hydrogen atom. 5. Compounds according to one of the preceding claims, wherein R ⁷ and R ⁸ each represent a methyl group, or together with the carbon atom of the tetrahydronaphthalene system form a cyclopropyl group. 6. Compounds according to one of the preceding claims, wherein R ^{3 represents} an optionally substituted aryl or heteroaryl group. 7. A compound according to claim 6, wherein the aryl or heteroaryl group is selected from the group consisting of optionally substituted naphthyl, Benzofuranyi-, Pyrazoiofi .δ-ajpyridinyi-, phenyi, phthalidyl, isoindolyl, dihydroindolyl, Dihydroisoindolyl-, Dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, Quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromanyl, isochromanyl, phthalazinyl, 1, 7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl groups. 8. Compounds according to one of the preceding claims for the preparation of a medicament. 9. Use of a compound according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment or prevention of inflammatory processes. A method for treating or preventing inflammatory processes in a patient, characterized in that a patient in need of such treatment or prevention is administered a pharmaceutically effective amount of a compound of general formula (I) according to any one of claims 1 to 7. 11. Pharmaceutical preparations containing at least one compound according to any one of claims 1 to 7 and one or more pharmaceutically acceptable carriers and / or excipients. 12. A process for preparing a compound of general formula (I) according to any one of claims 1 to 7, characterized in that a compound of general formula (II)

(II) a) by reaction with a compound selected from compounds of the general formulas R ³ -X-Nu (wherein Nu represents a nucleofuge group), R ³ -N = C = O or R ³ -N = C = S, and optionally subsequent Substitution of a carbonyl oxygen atom to sulfur, to a compound of general formula (I) is reacted, or b) reacted with a compound of general formula R ³ -CHO and the resulting imine is reduced, or c) is reacted with phosgene or thiophosgene, and the resulting isocyanate or isothiocyanate is subsequently reacted with compounds of the general formula R ³ -OH or R ³ -NH ₂ to give a compound of the general formula (I); where the substituents R ¹ to R ¹² and X have the meanings given in claims 1 to 7. 13. Compounds of the general formula (II)

where the substituents R ¹ to R ^{12 have} the meanings given in claims 1 to 7. 14. Use of compounds of the general formula (II) as described in claim 13 for the preparation of compounds of the general formula (I) according to one of claims 1 to 7. 15. Compounds of the general formula (IV),

where the substituents R ¹ to R ^{12 have} the meanings given in claims 1 to 7. 16. Use of compounds of general formula (IV) as described in claim 15 for the preparation of compounds of general formula (I) according to one of claims 1 to 7.