DE102005017301A1 - Substituted chroman derivatives, process for their preparation and their use as anti-inflammatory agents - Google Patents

Abstract

The invention relates to poly-substituted heterocyclic compounds of general formula (I), DOLLAR F1 process for their preparation and their use as anti-inflammatory agents.

Description

introduction

The This invention relates to substituted chroman derivatives, to processes for their use Production and its use as an anti-inflammatory.

From the prior art ( DE 100 38 639 WO 03/082827 and WO 02/10143) disclose open-chain nonsteroidal anti-inflammatory drugs. 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 is further non-steroidal anti-inflammatory provided.

Short description of invention

worin
R¹ und R² unabhängig voneinander ein Wasserstoffatom, eine Hydroxy-Gruppe, ein Halogenatom, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkylgruppe, eine (C₁-C₁₀)-Alkoxygruppe, eine (C₁-C₁₀)-Alkylthiogruppe, eine (C₁-C₅)-Perfluoralkylgruppe, eine Cyanogruppe, eine Nitrogruppe, oder eine -NR⁹R^9a-Gruppe sind,
oder R¹ und R² zusammen eine Gruppe ausgewählt aus den Gruppen -O-(CH₂)_n-O-, -O-(CH₂)_n-CH₂-, -O-CH=CH-, -(CH₂)_n+2-,-NH-(CH₂)_n+1-, -N(C₁-C₃-alkyl)-(CH₂)_n+1-, und -NH-N=CH- bilden,
wobei n = 1 oder 2 ist und die endständigen Sauerstoffatome und/oder Kohlenstoffatome und/oder Stickstoffatome mit direkt benachbarten Ring-Kohlenstoffatomen verknüpft sind,
R¹¹ ein Wasserstoffatom, eine Hydroxy-Gruppe, ein Halogenatom, eine Cyanogruppe, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkylgruppe, eine (C₁-C₁₀)-Alkoxygruppe, eine (C₁-C₁₀)-Alkylthiogruppe, oder eine (C₁-C₅)- Perfluoralkylgruppe ist,
R¹² ein Wasserstoffatom, eine Hydroxygruppe, ein Halogenatom, eine Cyanogruppe, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkylgruppe, oder eine (C₁-C₁₀)-Alkoxygruppe ist,
R³ eine gegebenenfalls durch 1 bis 3 Hydroxygruppen, 1 bis 3 Halogenatome, und/oder 1 bis 3 (C₁-C₅)-Alkoxygruppen substituierte (C₁-C₁₀)-Alkylgruppe,
eine gegebenenfalls substituierte (C₃-C₇)-Cycloalkylgruppe,
eine gegebenenfalls substituierte Heterocyclylgruppe,
eine gegebenenfalls substituierte Arylgruppe, oder
eine gegebenenfalls durch eine oder mehrere Gruppen, die unabhängig voneinander ausgewählt sind aus
(C₁-C₅)-Alkylgruppen, die selbst gegebenenfalls substituiert sein können durch 1 bis 3 Hydroxy- oder 1 bis 3 -COOR¹³ -Gruppen,
(C₁-C₅)-Alkoxygruppen,
Halogenatomen, Hydroxygruppen, -NR⁹R^9a-Gruppen, (C₁-C₅)-Perfluoralkylgruppen, Nitrogruppen, Thiolgruppen, Sulfoxylgruppen, Sulfonsäuregruppen, Sulfonamidgruppen, Sulfonimingruppen, Cyanogruppen oder -(CO)-(C₁-C₅)-Alkylgruppen, und
Exomethylengruppen
substituierte, gegebenenfalls 1 bis 4 Stickstoffatome und/oder 1 bis 2 Sauerstoffatome und/oder 1 bis 2 Schwefelatome und/oder 1 bis 2 Ketogruppen enthaltende mono- oder bizyklische Heteroarylgruppe ist, wobei diese Gruppe über eine beliebige Position mit dem Stickstoffatom verknüpft ist und gegebenenfalls an einer oder mehreren Stellen hydriert sein kann,
R^3a ein Wasserstoffatom, eine Cyanogruppe oder eine gegebenenfalls substituierte (C₁-C₅)-Alkylgruppe ist;
R⁴, R⁵, R⁶ und R^6a unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, eine Hydroxygruppe, eine -NR⁹R^9a-Gruppe, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkylgruppe, eine (C₁-C₁₀)-Alkoxygruppe oder eine (C₁-C₁₀)-Alkylthiogruppe sind,
R⁹ und R^9a unabhängig voneinander ein Wasserstoffatom, eine (C₁-C₅)-Alkylgruppe oder eine -(CO)-(C₁-C₅)-Alkylgruppe sind,
R¹⁰ eine (C₁-C₁₀)-Alkylgruppe oder eine -(CO)-(C₁-C₁₀)-Alkylgruppe bedeutet,
R¹³ ein Wasserstoffatom oder eine (C₁-C₅)-Alkylgruppe bedeutet,
R¹⁴ ein Wasserstoffatom, ein Fluoratom oder eine teilweise oder vollständig fluorierte (C₁-C₅)-Alkylgruppe bedeutet, und
Y eine Methylengruppe, ein Sauerstoffatom, ein Schwefelatom, eine -S(O)_n-Gruppe (wobei n = 1 oder 2), eine -S(O)(NR¹³)-Gruppe, eine -NH-Gruppe oder eine -NR¹⁰-Gruppe bedeutet;
in der Form eines beliebigen Stereoisomeren oder eines Gemisches von Stereoisomeren; oder als pharmakologisch unbedenkliches Salz oder Derivat.The present invention relates to compounds of the general formula (I),

wherein
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 ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, a (C ₁ -C ₁₀ ) Alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group, a nitro group, or an -NR ⁹ R ^9a group,
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 + 1} -, -N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} -, and -NH-N = CH- form,
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,
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 is a (C ₁ -C ₅ ) -perfluoroalkyl group,
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} a (C ₁ -C ₁₀ ) -alkyl group which is optionally substituted by 1 to 3 hydroxyl groups, 1 to 3 halogen atoms and / or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups,
an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group,
an optionally substituted heterocyclyl group,
an optionally substituted aryl group, or
one optionally substituted by one or more groups selected independently of each other
(C ₁ -C ₅ ) -alkyl groups which may themselves be optionally substituted by 1 to 3 hydroxy or 1 to 3 -COOR ¹³ groups,
(C ₁ -C ₅ ) -alkoxy groups,
Halogen atoms, hydroxy groups, -NR ⁹ R ^9a groups, (C ₁ -C ₅ ) perfluoroalkyl groups, nitro groups, thiol groups groups, sulfoxylic groups, sulfonic acid groups, sulfonamide groups, sulfonimine groups, cyano groups or - (CO) - (C ₁ -C ₅ ) -alkyl groups, and
exomethylene
is substituted, optionally 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, said group being linked via any position with the nitrogen atom and optionally can be hydrogenated at one or more sites,
R ^{3a is} a hydrogen atom, a cyano group or an optionally substituted (C ₁ -C ₅ ) alkyl group;
R ⁴ , R ⁵ , R ⁶ and R ^6a are each independently hydrogen, halogen, hydroxy, -NR ⁹ R ^9a , optionally substituted (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) -alkoxy group or a (C ₁ -C ₁₀ ) -alkylthio group,
R ⁹ and R ^{9a are} independently of one another a hydrogen atom, a (C ₁ -C ₅ ) -alkyl group or a - (CO) - (C ₁ -C ₅ ) -alkyl group,
R ^{10 is} a (C ₁ -C ₁₀ ) -alkyl group or a - (CO) - (C ₁ -C ₁₀ ) -alkyl group,
R ^{13 represents} a hydrogen atom or a (C ₁ -C ₅ ) -alkyl group,
R ^{14 represents} a hydrogen atom, a fluorine atom or a partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, and
Y is a methylene group, an oxygen atom, a sulfur atom, an -S (O) _n group (where n = 1 or 2), an -S (O) (NR ¹³ ) group, an -NH group or an -NR ¹⁰ group means;
in the form of any stereoisomer or mixture of stereoisomers; or as a pharmacologically acceptable salt or derivative.

The The present invention further relates to methods of preparation of compounds of general formula (I) as described herein.

Farther the present invention relates to pharmaceutical compositions, which one or more compounds of the general formula (I) in combination with one or more pharmaceutical carrier or Excipients include.

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

worin die Substituenten R¹ bis R¹⁴ und Y die oben genannten Bedeutungen haben, sowie die Verwendung dieser Verbindungen zur Darstellung von Verbindungen der allgemeinen Formel (I), wie oben definiert.The present invention furthermore relates to compounds of the general formula (II)

wherein the substituents R ¹ to R ¹⁴ and Y have the abovementioned meanings, and the use of these compounds for the preparation of compounds of general formula (I), as defined above.

Detailed description of the invention

definitions

The Designation 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, No nyl, decyl and their 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 , (C ₁ -C ₅ ) alkoxy groups, halogen atoms, -NR ⁹ R ^9a , a partially or fully fluorinated (C ₁ -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 partial or completely fluorinated alkyl group, for example, the following partially or Completely fluorinated groups: 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 while optionally used in the synthesis, are commercially available, or the published syntheses of the corresponding reagents belong to State of the art, or published syntheses can be applied analogously.

The alkoxy groups mentioned in the definitions of general formula (I) may be straight-chain or branched and may be, 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 C ₁ -C ₃ -, C ₁ -C ₈ -, and C ₁ -C ₁₀ 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. C ₁ -C ₅ -alkylthio groups are preferred. A methylthio or ethylthio group is particularly preferred.

The Alkoxy and alkylthio groups described above can be used their alkyl groups carry the same substituents, the above already for the alkyl groups have been described in general. Preferred substituents for alkoxy and alkylthio groups are independent selected from each other 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 H ₅ ) ₂ , -NH ( C ₃ H ₇ ), -N (C ₃ H ₇ ) ₂ , -NH (C ₄ H ₉ ), -N (C ₄ H ₉ ) ₂ , -NH (C ₅ H ₁₁ ), -N (C ₅ H ₁₁ ) 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 H ₁₁ ,

The (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, 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 alkylidene or Exoalkylidengruppe is a group having 1 to 10 Kohenstoffatomen to understand, which is bound via an exodo double bond to the system (ring or chain). Preference is given to (C ₁ -C ₅ ) - and (C ₁ -C ₃ ) alkylidene, particular preference is given to exomethylene.

The Heterocyclyl group is one containing one or more heteroatoms, cyclic, non-aromatic group and may, for example, pyrrolidine, Imidazolidine, pyrazolidine, piperidine. Also perhydroquinoline and perhydroisoquinoline to the heterocyclyl groups according to the invention.

Suitable substituents for heterocyclyl and heteroaryl groups are, for example, substituents from the following group: optionally substituted C ₁ -C ₅ -alkyl group, hydroxy, (C ₁ -C ₅ ) -alkoxy, -NR ⁹ R ^9a , 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 sen.

aryl groups in the context of the invention are aromatic or partially aromatic carbocyclic Groups of 6 to 14 carbon atoms containing a ring, e.g. Phenyl or phenylene or more condensed rings such as e.g. naphthyl or anthranyl. Exemplary are 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 convenient point resulting in a stable compound by one or more of hydroxy, halogen, optionally C ₁ -C ₅ alkyl substituted by 1 to 3 hydroxy or COOR ¹³ groups, C C ₁ -C ₅ alkoxy, cyano, -CF ₃ , and nitro.

The Aryl groups can be partially hydrogenated and then additionally or alternatively to the listed above Substituents also carry keto and / or Exoalkyliden. In part hydrogenated phenyl is e.g. Cyclohexadienyl, cyclohexenyl, cyclohexyl to understand. A partially hydrogenated substituted naphthalene system is, for example, 1-tetralone or 2-tetralone.

The mono- or bicyclic heteroaryl may optionally 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, contain a maximum of 2 sulfur atoms and / or a maximum of 2 keto groups could be. Any subcombination of these groups is possible. The heteroaryl group may be hydrogenated at one or more sites.

monocyclic Heteroaryl groups can for example, 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.

bicyclic Heteroaryl groups can for example, phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, Dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, Isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzo [b] thienyl, Benzo [c] thienyl, pyrazolo [1,5-a] pyridyl, benzimidazolyl, dihydroisoquinolinyl, Dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl Quinolinyl, isoquinolinyl, quinolonyl, isoquinolone, quinazolinyl, Quinoxalinyl, cinnolinyl, phthalazinyl, dihydrophthalazinyl, 1,7- or 1,8-naphthyridinyl, coumarinyl, isocumarinyl, indolizinyl, Isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, Furanopyrazinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, Dihydrofuranopyrimidinyl, Dihydrofuranopyrazinyl, Dihydrofuranopyridazinyl, Dihydrobenzofuranyl be.

When the heteroaryl groups are partially or completely hydrogenated, compounds of the general formula (I) in which R ^{3 is} tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridine-4 are included -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] benzoxazin-4-onyl, 3,4-dihydrobenz [1,4] oxazin-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, 2,3-1,2,3,4-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 hydroxyl groups or 1 to 3 -COOR ¹³ groups, C ₁ -C ₅ -alkoxy groups, halogen atoms, and / or exomethylene groups. 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.

Optionally required 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 Gree See, 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 group (eg, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, tetrahydropyranyl groups).

The Compounds of the invention of the general formula (I) by the presence of asymmetric centers as stereoisomers available. The subject of the present invention are all possible ones Diastereomers both as racemates, as well as in enantiomerically pure Shape. The term stereoisomers also includes all possible ones Diastereomers and regioisomers and tautomers (e.g., keto-enol tautomers) in which the stereoisomers of the invention can be present which are therefore also the subject of the invention.

The Compounds of the invention can also in the form of salts with pharmacologically acceptable anions are present, for example in the form of the hydrochloride, sulfate, Nitrates, phosphates, pivalates, maleates, fumarates, tartrates, Benzoates, mesylates, citrates or succinates.

Also pharmacologically acceptable derivatives or prodrugs of the compounds of general formula (I) are encompassed by the invention. As derivatives or prodrugs are, for example, esters, ethers or amides of Compounds of general formula (I) or other compounds referred to in the organism to compounds of the general formula (I) metabolize. Suitable compounds are, for example, in Hans Bundgaard (ed.), Design of Prodrugs, Elsevier, Amsterdam 1985, listed.

Bevorzucgte embodiments

A 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 ₁₀ ) -alkyl group, a C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₁₀ ) alkylthio, (C ₁ -C ₅ ) perfluoroalkyl, cyano, nitro, or -NR ⁹ R ^9a .

A preferred group of compounds of general formula (I) those compounds in which Y is an oxygen atom, a sulfur atom or a methylene group.

Another preferred group of compounds of the general formula (I) are those compounds in which R ^{3 represents} an optionally substituted aryl or heteroaryl group. A more preferred group of compounds of general formula (I) are those compounds in which R ^{3 represents} an optionally substituted aryl or heteroaryl group selected from the group consisting of naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl , Dihydroisoquinolinyl, thiophthalidyl, benzofuranyl-benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, chromanyl, isochromanyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl , 1,7- or 1,8-naphthyridinyl, pyrazolo [1,5-a] pyridyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group.

Another preferred group of compounds of the general formula (I) are those compounds in which R ^{3a is} a hydrogen atom or a (C ₁ -C ₅ ) -alkyl group.

Another preferred group of compounds of the general formula (I) are those compounds in which R ⁴ , R ⁵ , R ⁶ , and R ^6a independently of one another represent a hydrogen atom, a halogen atom or an optionally substituted (C ₁ -C ₁₀ ) -alkyl group mean.

Another preferred group of compounds of the general formula (I) are those compounds in which R ¹ and R ² independently of one another represent a hydrogen atom, 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 the substituents R ¹¹ and R ¹² each represent a hydrogen atom.

Another preferred group of compounds of the general formula (I) are those compounds in which the substituent R ^{14 represents} a fluorine atom or a trifluoromethyl group.

A particularly preferred group of compounds of the general formula (I) are those compounds in which R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ^6a independently of one another represent a hydrogen atom, a halogen atom or an optionally substituted (C ₁ -C ₁₀ ) alkyl group, Y represents an oxygen atom, a sulfur atom or a methylene group, R ^{3a is} a hydrogen atom or a (C ₁ -C ₅ ) alkyl group, R ¹¹ and R ¹² each represent a hydrogen atom, R ^{14 is} a fluorine atom or a trifluoromethyl group, and R ^{3 represents} an optionally substituted aryl or heteroaryl group selected from the group consisting of naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzofuranyl, benzoxazinonyl -, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naph thyridinyl, pyrazolo [1,5-a] pyridyl, dihydroindolonyl, chromanyl, isochromanyl, dihydroisoindolonyl, benzimidazole or indolyl.

each more possible Combination of the above subgroups and the preferred specified substituents with their general and / or special Meanings are also included in the present invention to watch.

biological activity

The anti-inflammatory effect of the compounds of the general formula (I) is induced in animal experiment by testing in the croton oil inflammation in the rat and mouse (J. Exp. Med. (1995), 182, 99-108). For this the animals become croton oil in ethanolic solution applied topically to the ears. The test substances are simultaneously or two hours before the croton oil also applied topically or systemically. After 16-24 hours are the ear weight as a measure of inflammatory edema, the peroxidase as a measure of immigration of granulocytes and elastase activity as a measure of immigration of neutrophils Granulocytes measured. The compounds of general formula (I) inhibit both topical and systemic in this test Application the three above-mentioned inflammatory parameters.

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 used for the binding assays. In comparison to the reference substance [ ³ H] -dexamethasone, the substances show a high affinity for GR. Thus, for the compound from Example 1, an IC ₅₀ (GR) = 20 nM and IC ₅₀ (PR)> 1 μM and for the compound from Example 2 an IC ₅₀ (GR) = 30 nM and IC ₅₀ (PR)> 1 μM ,

When essential, molecular mechanism for the anti-inflammatory Effect of glucocorticoids becomes GR mediated inhibition Transcription of cytokines, adhesion molecules, enzymes and other pro - inflammatory Factors considered. This inhibition is caused by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B, causes (to the overview see Cato ACB and Wade E, BioEssays 18, 371-378 1996).

The Compounds of the invention of general formula (I) inhibit those produced by lipopolysaccharide (LPS) triggered Secretion of the cytokine IL-8 in the human monocyte cell line THP -1. The concentration of cytokines was in the supernatant by means of commercial available ELISA kits determined.

A the most common undesirable Effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoids: Immunology, Pharmacology and Therapy Guidelines, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998]. reason therefor is the stimulation of gluconeogenesis in the liver by induction the one for this responsible enzymes and free amino acids resulting from the degradation of Proteins (catabolic effect of glucocorticoids) arise. One key enzyme the catabolic metabolism in the liver is the tyrosine aminotransferase (DID). The activity This enzyme can be determined photometrically from liver homogenates and represents a good measure of the unwanted Metabolic effects of glucocorticoids TAT induction animals are 8 hours after administration of the test substances killed removed the liver and measured the TAT activity in the homogenate. The Compounds of the general formula (I) induce in this test in doses in which they are anti-inflammatory, not or only to a small extent the tyrosine aminotransferase.

medical indications

• (i) Lungenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Chronisch obstruktive Lungenerkrankungen jeglicher Genese, vor allem Asthma bronchiale – Bronchitis unterschiedlicher Genese – Adult respiratory distress syndrome (ARDS) – Bronchiectasis – Alle Formen der restriktiven Lungenerkrankungen, vor allem allergische Alveolitis, – Alle Formen des Lungenödems, vor allem toxisches Lungenödem, z.B. Bestrahlungs-Pneumonitis – Sarkoidosen und Granulomatosen, insbesondere Morbus Boeck
• (ii) Rheumatische Erkrankungen/Autoimmunerkrankungen/Gelenkerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Alle Formen rheumatischer Erkrankungen, insbesondere rheumatoide Arthritis, akutes rheumatisches Fieber, Polymyalgia rheumatica, Morbus Behcet – Reaktive Arthritis – Entzündliche Weichteilerkrankungen sonstiger Genese – Arthritische Symtome bei degenerativen Gelenkerkrankungen (Arthrosen) – Traumatische Arthritiden – Vitiligo – Kollagenosen jeglicher Genese, z.B. systemischer Lupus erythematodes, Sklerodermie, Polymyositis, Dermatomyositis- Sjögren-Syndrom, Still-Syndrom, Felty-Syndrom – Sarkoidosen und Granulomatosen – - Rheumatische Weichteilerkrankungen
• (iii) Allergien oder pseudoallerg. Erkrankungen, die mit entzündlichen, und/oder proliferativen Prozessen einhergehen: – Alle Formen allergischer Reaktionen, z.B. Quincke Ödem, Heuschnupfen, Insektenstich, allergische Reaktionen auf Arzneimittel, Blutderivate, Kontrastmittel etc., Anaphylaktischer Schock, Urtikaria, allergische und irritative Kontakdermatitis, allergische Gefäßerkrankungen – Vasculitis allergica
• (iv) Gefäßentzündungen (Vaskulitiden) – Panarterütis nodosa, Arteriitis temporalis, Erythema nodosum – Polyarteritis nodosa – Wegner Granulomatose – Giant cell arteriitis
• (v) Dermatologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Atopische Dermatitis (vor allem bei Kindern) – Sämtliche Ekzemformen wie z.B. atopisches Ekzem (v.a. bei Kindern) – Exantheme jedweder Genese oder Dermatosen – Psoriasis und Parapsoriasis-Formenkreis – Pityriasis rubra pilaris – Erythematöse Erkrankungen, ausgelöst durch unterschiedlichen Noxen, z.B. Strahlen, Chemikalien, Verbrennungen etc. – Bullöse Dermatosen wie z.B. autoimune Pemphigus vulgaris, bullöses Pemphigoid – Erkrankungen des lichenoiden Formenkreises, – Pruritus (z.B. allergischer Genese) – Seborrhoisches Ekzem – Rosacea-Formenkreis – Pemphigus vulgaris – Erythema exsudativum multiforme – Balanitis – Vulvitis – Manifestation von Gefäßerkrankungen – Haarausfall wie Alopecia areata – Cutane Lymphome – Parapsoriasis
• (vi) Nierenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Nephrotisches Syndrom – Alle Nephritiden, z.B. Glomenulonephritis
• (vii) Lebererkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – akuter Leberzellzerfall – akute Hepatitis unterschiedlicher Genese, z.B. viral, toxisch, arzneimittelinduziert – chronisch aggressive und/oder chronisch intermittierende Hepatitis
• (viii) Gastrointestinale Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – regionale Enteritis (Morbus Crohn) – Colitis Ulcerosa – Gastritis – Refluxoesophagitis – Gastroenteritiden anderer Genese, z.B. einheimische Sprue
• (ix) Proktologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Analekzem – Fissuren – Hämorrhoiden – idiopathische Proktitis
• (x) Augenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – allergische Keratitis, Uveitis, Iritis, – Konjunktivitis – Blepharitis – Neuritis nervi optici – Chorioditis – Ophtalmia sympathica
• (xi) Erkrankungen des Hals-Nasen-Ohren-Bereiches, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – allergische Rhinitis, Heuschnupfen – Otitis externa, z.B. bedingt durch Kontaktexem, Infektion etc. – Otitis media
• (xii) Neurologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Hirnödem, vor allem Tumor-bedingtes Hirnödem – Multiple Sklerose – akute Encephalomyelitis – Meningitis – verschieden Formen von Krampfanfällen, z.B. BNS-Krämpfe – Akute Rückenmarksverletzung – Schlaganfall
• (xiii) Bluterkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen wie z.B.: – Erworbene hämolytische Anämie – Idopathische Thrombocytopenia
• (xiv) Tumorerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen wie z.B.: – Akute lymphatische Leukämie – Maligne Lymphome – Lymphogranulomatosen – Lymphosarkome – Ausgedehnte Metastasierungen, vor allem bei Mamma- Bronchial- und Prostatakarzinom
• (xv) Endokrine Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen wie z.B.: – Endokrine Orbitopathie – Thyreotoxische Krise – Thyreoiditis de Quervain – Hashimoto Thyreoiditis – Morbus Basedow – Endokrine Ophthalmopathy – Granulomatous thyroiditis – Struma lymphomatosa – Grave Krankheit
• (xvi) Organ- und Gewebstransplantationen, Graft-versus-host-disease(xvii) Schwere Schockzustände, z.B anaphylaktischer Schock, systemic inflammatory response syndrome (SIRS)
• (xviii)Substitutionstherapie bei: – angeborene primäre Nebenniereninsuffizienz, z.B. kongenitales adrenogenitales Syndrom – erworbene primäre Nebenniereninsuffizienz, z.B. Morbus Addison, autoimmune Adrenalitits, postinfektiös, Tumoren, Metastasen etc. – angeboren sekundäre Nebenniereninsuffizienz, z.B. kongenitaler Hypopitutitarismus – erworbene sekundäre Nebenniereninsuffizienz, z.B. postinfektiös, Tumoren etc.
• (xix) Emesis, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – z.B. in Kombination mit einem 5-HT3-Antagonisten bei Zytostika – bedingten Erbrechen.
• (xx) Schmerzen bei entzündlicher Genese, z.B. Lumbago
• (xxi) Endometriose
• (xxii) Verschiedene Erkrankungen.

On account 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 Term "DISEASE" for the following indications:

• (i) Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes: - Chronic obstructive pulmonary diseases of all origins, especially bronchial asthma - Bronchitis of various origins - Adult respiratory distress syndrome (ARDS) - Bronchiectasis - All forms of restrictive lung disease, pre all allergic alveolitis, - all forms of pulmonary edema, especially toxic pulmonary edema, eg radiation pneumonitis - sarcoids 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, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, Behcet's disease - reactive arthritis - inflammatory soft tissue diseases of other origin - Arthritic symptoms in degenerative joint diseases (arthritis) - Traumatic arthritis - Vitiligo - Collagenosis of any genesis, eg systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis - Sjögren syndrome, Still's syndrome, Felty's syndrome - sarcoids and granulomatoses - - Rheumatic soft tissue diseases
• (iii) allergies or pseudoallerg. Diseases associated with inflammatory and / or proliferative processes: - All forms of allergic reactions, eg Quincke's edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, allergic and irritative contact dermatitis, allergic vascular disease - Vasculitis allergica
• (iv) Vasculitides - Panarterutis nodosa, temporal arteritis, erythema nodosum - polyarteritis nodosa - Wegner granulomatosis - giant cell arteriitis
• (v) Dermatological disorders associated with inflammatory, allergic and / or proliferative processes: - Atopic dermatitis (especially in children) - All forms of eczema such as atopic dermatitis (especially in children) - Rarities of any genesis or dermatoses - Psoriasis and parapsoriasis Formkreis - Pityriasis rubra pilaris - Erythematous diseases, caused by different noxious agents, eg radiation, chemicals, burns, etc. - Bullous dermatoses such as autoimmune pemphigus vulgaris, bullous pemphigoid - Diseases of the lichenoid form, - Pruritus (eg allergic genesis) - Seborrheic dermatitis - Rosacea type - Pemphigus vulgaris - Erythema multiforme - Balanitis - Vulvitis - Manifestation of vascular diseases - Hair loss such as alopecia areata - Cutaneous Lymphoma - Parapsoriasis
• (vi) kidney disease associated with inflammatory, allergic and / or proliferative processes: - nephrotic syndrome - all nephritides, eg, glomenulonephritis
• (vii) liver disease associated with inflammatory, allergic and / or proliferative processes: acute hepatic cell disintegration acute hepatitis of various causes, eg 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 esophagitis - gastroenteritis of other genesis, eg native sprue
• (ix) proctological diseases associated with inflammatory, allergic and / or proliferative processes: - anal eczema - fissures - hemorrhoids - idiopathic proctitis
• (x) ocular diseases associated with inflammatory, allergic and / or proliferative processes: - allergic keratitis, uveitis, iritis, - conjunctivitis - blepharitis - neuritis nervi optici - choroiditis - ophthalmia 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, eg due to contact xem, infection, etc. - otitis media
• (xii) Neurological disorders associated with inflammatory, allergic and / or proliferative processes: - brain edema, especially tumor-related cerebral edema - multiple sclerosis - acute encephalomyelitis - meningitis - various forms of seizures, eg BNS cramps - acute spinal cord injury - stroke
• (xiii) Blood disorders associated with inflammatory, allergic and / or proliferative processes such as: - Acquired hemolytic anemia - Idopathic thrombocytopenia
• (xiv) tumors associated with inflammatory, allergic and / or proliferative processes such as: - acute lymphoblastic leukemia - malignant lymphoma - lymphogranulomatosis - lymphosarcoma - extensive metastases, especially in breast, bronchial and prostate cancers
• (xv) endocrine disorders associated with inflammatory, allergic and / or proliferative processes such as: - endocrine orbitopathy - Thyrotoxic crisis - Thyreoiditis de Quervain - Hashimoto's thyroiditis - Graves' disease - Endocrine ophthalmopathy - Granulomatous thyroiditis - Struma lymphomatosa - Grave disease
• (xvi) Organ and tissue transplants, graft-versus-host disease (xvii) Severe shock states, eg, anaphylactic shock, systemic inflammatory response syndrome (SIRS)
• (xviii) replacement therapy in: - congenital primary adrenal insufficiency, eg congenital adrenogenital syndrome - acquired primary adrenal insufficiency, eg Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases etc. - congenital secondary adrenal insufficiency, eg congenital hypopitotitarism - acquired adrenal insufficiency, eg post-infectious, Tumors etc.
• (xix) Emesis associated with inflammatory, allergic and / or proliferative processes: - eg in combination with a 5-HT3 antagonist in cytostatic - induced vomiting.
• (xx) Pain in inflammatory genesis, eg lumbago
• (xxi) Endometriosis
• (xxii) Various diseases.

Furthermore can the compounds of the invention of the general formula (I) for the therapy and prophylaxis of others Unmentioned disease states are used for today synthetic glucocorticoids are used (see Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998).

All previously mentioned indications are described in detail in Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998th

For the therapeutic Effect on the above disease states, the appropriate dose is different and hang for example, the potency the compound of general formula (I), the patient (e.g., size, weight, Sex, etc.), the mode of administration and the type and the Severity of the conditions to be treated, and use as a prophylactic or therapeutic.

The The invention relates to the use of the claimed compounds for the preparation of a pharmaceutical composition.

• (i) die Verwendung einer der erfindungsgemäßen Verbindungen der allgemeinen Formel (I) oder deren Gemisch zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung oder Vorbeugung von entzündlichen Prozessen, und insbesondere zur Behandlung einer ERKRANKUNG (wie oben definiert);
• (ii) ein Verfahren zur Behandlung oder Vorbeugung von entzündlichen Prozessen, insbesondere zur Behandlung einer ERKRANKUNG (wie oben definiert), welches Verfahren eine Verabreichung einer pharmazeutisch wirksamen Menge einer Verbindung der allgemeinen Formel (I) umfaßt, wobei die Menge die Krankheit oder die Symptome erleichtert oder unterdrückt, und wobei die Verbindung einem Patienten, vorzugsweise einem Säugetier, insbesondere einem Menschen, gegeben wird, der eine solche Behandlung benötigt;
• (iii) eine pharmazeutische Zusammensetzung zur Entzündungshemmung, insbesondere zur Behandlung einer ERKRANKUNG (wie oben definiert), wobei die Zusammensetzung eine der erfindungsgemäßen Verbindungen oder deren Gemisch und gegebenenfalls wenigstens einen pharmazeutischen Hilfs- und/oder Trägerstoff umfaßt.

The invention further provides

• (i) the use of one of the compounds of the general formula (I) according to the invention or a mixture thereof 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) wherein the amount is 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 acute shock (eg anaphylactic Shock) single doses can be given, which are well above the above doses.

The Formulation of pharmaceutical preparations based on the new Compounds are carried out in a conventional manner by the active ingredient with those used in galenics Excipients fillers, Regulators, binders, humectants, lubricants, Absorbents, diluents, Taste Correctives, Colorants etc., processed and in the desired Transferred application form. there is on Remington's Pharmaceutical Science, 15th ed Mack Publishing Company, East Pennsylvania (1980).

For the oral In particular, tablets, dragees, capsules, pills, Powders, granules, lozenges, suspensions, emulsions or solutions in Question.

For the parenteral Application injection and infusion preparations are possible.

For intra-articular injection can appropriately prepared crystal suspensions are used.

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

For the rectal Application can the new compounds in the form of suppositories, capsules, solutions (e.g. in the form of clysters) and ointments both to the systemic, as well used for local therapy.

to pulmonary application of the new compounds may be in the form of aerosols and inhalants.

For the local Application to eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses can the new compounds as drops, ointments, tinctures and gels be used in appropriate pharmaceutical preparations.

For the topical Application are formulations in gels, ointments, greases, creams, Pastes, powders, suspensions, emulsions and solutions possible. The dosage of the compounds of the general formula (I) should be 0.01% -20% in these preparations, to achieve a sufficient pharmacological effect.

The Invention also includes the compounds of the invention of the general Formula (I) as a therapeutic agent. Furthermore belongs to the invention the compounds of the invention the general formula (I) as a therapeutic agent together with one or more pharmaceutically acceptable and acceptable excipients and / or carriers.

The Compounds of the invention of the general formula (I) optionally also formulated in combination with other active ingredients and / or administered.

production method

The Compounds of the invention of the general formula (I) are accessible in various ways. The manufacturing processes described below also form a part of the present invention.

Provided Unless otherwise specified, those used in the process descriptions below have Substituents have the same meaning as above in the section "Short Description of the invention ", including the in the section "Detailed Description of the invention "indicated Definitions.

In general, compounds of the general formula (I) are prepared by reacting aldehydes of the general formula (II) with amines of the general formula R ³ -NH ₂ and subsequent reduction of the imines obtained thereby. The reaction sequence is summarized in Scheme 1 below.

Scheme 1: Reaction of compounds of general formula (II) to compounds of general formula (I)

The compounds of the general formula used in this sequence (II) are accessible by various methods according to the invention.

Method A: Presentation of compounds of general formula (II) of compounds of general formula (IX) the intermediate (IIIA).

In the first step of process A compounds represents by the general formula (IX) in which R is preferably a C ₁ -C _S alkyl group, to give compounds of the general formula (VIII) (Scheme 2). Compounds of general formula (IX) are known in the art and can be prepared by methods known to those skilled in the art.

SCHEMA 2: Preparation of compounds of the general formula (VIII)

If R ^3a in the compounds of the general formula (VIII) represents a hydrogen atom, the reaction is carried out by reduction, for example, by catalytic hydrogenation of the compound (IX) with elemental hydrogen over suitable metal catalysts. Compounds of the general formula (VIII) in which R ^{3a represents} a cyano or alkyl group are obtainable by reacting compounds of the general formula (IX) with cyanide ions or organometallic alkyl compounds (for example copper-organic compounds). These methods are known in the art.

in the next Step are the resulting carboxylic acid esters of the general formula (VIII) with a suitable reducing agent (e.g., lithium aluminum hydride) according to processes known in the art to alcohols of the general Formula (VII) reduced (Scheme 3).

Scheme 3: Preparation of compounds of general formula (VII)

By careful oxidation of the alcohols of the general formula (VII) by methods known in the art, the aldehydes of the general formula (VI) are obtained (Scheme 4): Scheme 4: Preparation of compounds of the general formula (VI)

The aldehydes of the general formula (VI) can be reacted with suitable organometallic reagents M-CF ₂ R ¹⁴ , whereby the group -CF ₂ R ¹⁴ can be introduced into the molecule (Scheme 5), wherein M represents an electrophilic leaving group. Suitable organometallic reagents are, for example, compounds of the general formula C _n F _{2n + 1} -Si (CH ₃ ) ₃ in the presence of a catalyst. Suitable catalysts in this process step are fluoride salts or basic compounds such as alkali metal carbonates (J. Am. Chem. Soc., 1989, 111, 393). Alternatively, lithium or organomagnesium compounds can be used to introduce the group -CF ₂ R ¹⁴ . In this case, the alcohols of the general formula (V) are obtained.

SCHEME 5: Preparation of compounds of the general formula (V)

By Oxidation of the alcohols of the general formula (V) with in the state of Technique known methods (e.g., with Dess-Martin Periodinan as Oxidizing agent) are ketones of the general formula (IV) accessible (Scheme 6).

SCHEME 6: Preparation of compounds of the general formula (IV)

The Ketones of the general formula (IV) are subsequently in the corresponding cyanohydrins of general formula (IIIA) transferred (Scheme 7). Suitable reagents for this purpose are, for example, potassium, sodium or copper cyanide, or trimethylsilyl cyanide. Corresponding the reagent used R in the general formula (IIIA) a hydrogen atom or a trimethylsilyl group.

SCHEME 7: Preparation of compounds of the general formula (IIIA)

The Cyanohydrins of the general formula (IIIA) are then - optionally after removal of the trimethylsilyl group - with a suitable reducing agent (e.g., diisobutylaluminum hydride) into the aldehydes of the general Formula (II) (Scheme 8th).

Scheme 8: Preparation of compounds of general formula (II) from compounds of general formula (IIIA)

Method B: Presentation of compounds of general formula (II) of compounds of general formula (IX) the intermediate (IIIB)

The Synthesis of precursor compounds of the general formulas (VIII), (VII), (VI), (V) and (IV) is included Method B as in Method A.

Of the Aldehyde of the general formula (IV) is subsequently with a suitable organometallic reagent (e.g., a Grignard compound, such as. Vinylmagnesium bromide) to an unsaturated alcohol of the general Formula (IIIB) (Scheme 9).

SCHEME 9: Preparation of compounds of general formula (IIIB)

By Oxidation of the double bond in the compounds of general Formula (IIIB) (e.g., by ozone or by transition metal oxides, e.g. Osmiumtetraoxid with subsequent Cleavage using a suitable oxidizing agent such as e.g. Sodium periodate) Compounds of general formula (II) are obtained (Scheme 10).

Scheme 10: Preparation of compounds of the general formula (II) from compounds of the general formula (IIIB)

Method C: Presentation of compounds of general formula (II) of compounds of general formula (XIII)

For the preparation of compounds of the general formula (II) from the compounds of the general formula (XIII) known in the prior art, these are first reacted with α-keto acid esters of the general formula R ¹⁴ CF ₂ -C (OO) -CO ₂ R (where R is preferably a C ₁ -C ₅ alkyl group) with catalysis with - optionally chiral - Lewis acids in an ene reaction to give compounds of general formula (XII) (Scheme 11).

SCHEME 11: Preparation of compounds of general formula (XII)

By Reduction of the ester function according to known in the art Process (eg, by means of lithium aluminum hydride) is from the compound of the general formula (XII) the diol of the general formula (XI) accessible (Scheme 12).

SCHEME 12: Preparation of compounds of general formula (XI)

This Diol (XI) can be prepared by reducing the double bond (e.g., by catalytic Hydrogenation with elemental hydrogen on suitable metal catalysts) be converted into a compound of general formula (X) (Scheme 13).

SCHEME 13: Preparation of compounds of the general formula (X)

By oxidation of the terminal hydroxyl group can be obtained from these diols of the general formula (X) such aldehydes of the general formula (II) in which the substituents R ^3a and R ⁴ in the compounds of general formulas (I) and (II) is the meaning have a hydrogen atom (Scheme 14).

Scheme 14: Preparation of compounds of general formula (II) from compounds of general formula (X)

Alternatively to the reaction sequence given above for process C, esters of the general formula (XII) can also be reduced to the corresponding aldehydes which can be reacted directly with the primary amines of the general formula R ³ -NH ₂ . Subsequently, the isolated in the right ring of the compound double bond is hydrogenated with suitable reducing agents. This alternative sequence also gives compounds of the general formula (I) in which the substituents R ^3a and R ^{4 have} the meaning of a hydrogen atom.

Synthesis 1: Representation of compounds of general formula (VII)

A. 2- (chroman-4-yl) -ethanol:

At 0 ° C., 2.27 g of 2- (chroman-4-yl) -acetic acid ethyl ester (J. Med. Chem. 44, (2001), pp. 1085-1098) are stirred with 800 mg of lithium aluminum hydride in 50 ml of THF for 2 hours. The mixture is mixed with saturated ammonium chloride solution and with ethyl acetate and filtered through diatomaceous earth. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine and dried with sodium sulfate. This gives 1.9 g of 2- (chroman-4-yl) ethanol as crude yield.
¹ H-NMR (CDCl _3): δ = 1.72-1.90 (m, 2H), 2.0-2.2 (m, 2H), 2.96-3.09 (m, 1H), 3.80 (t, 2H), 4:13 to 4:25 (m , 2H), 6.79 (d, 1H), 6.87 (t, 1H), 7.10 (t, 1H), 7.14 (d, 1H).

B. 2- (4-methylchroman-4-yl) -ethanol:

7.3 g E / Z- (chroman-4-ylidene) -acetic acid ethyl ester (J. Med. Chem. 44, (2001), pp. 1085-1098), 100 mg of copper (I) chloride and 5.1 ml of chlorotrimethylsilane in 55 ml of THF become slow at 0 ° C with 11.5 ml of methylmagnesium chloride solution [3.3 M in THF), so that the temperature always stays below 5 ° C. It will be one more Hour at 0 ° C and stirred for 10 hours at room temperature. The approach becomes more saturated Ammonium chloride solution and extracted with ether. The combined organic phases are washed with brine, dried with sodium sulfate and in vacuo concentrated. After chromatography on silica gel (hexane / ethyl acetate 100: 0 -> 90:10) gives 2- (4-methyl-chroman-4-yl) -acetic acid ethyl ester as a crude product. This is dissolved in 50 ml of THF at 0 ° C with 1 g of lithium aluminum hydride and 1.5 hours at 0 ° C touched. The mixture is carefully added to saturated ammonium chloride solution and diluted with ethyl acetate. It is filtered through diatomaceous earth and the aqueous phase with ethyl acetate extracted. The combined organic phases are washed with brine, dried with sodium sulfate and concentrated in vacuo.

After chromatography on silica gel (hexane / ethyl acetate 100: 0 -> 60:40) gives 1.2 g of 2- (4-methylchroman-4-yl) ethanol as a colorless oil.
¹ H NMR (CDCl _3): δ = 1:36 (s, 3H), 1.74 (ddd, 1H), 1.91-2.11 (m, 3H), 3.57-3.75 (m, 2H), 4:10 to 4:28 (m, 2H ), 6.79 (d, 1H), 6.89 (t, 1H), 7.08 (t, 1H), 7.22 (d, 1H).

C. It is also possible to prepare by the processes described:
2- (6-methylchroman-4-yl) -ethanol
2- (7-methyl-chroman-4-yl) -ethanol
2- (6-fluorochroman-4-yl) -ethanol
2- (6-methoxychroman-4-yl) -ethanol
2- (7-methoxychroman-4-yl) -ethanol
2- (1,2,3,4-tetrahydronaphthalen-1-yl) ethanol
2- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) ethanol
2- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) ethanol
2- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) ethanol
2- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) ethanol
2- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) ethanol
2- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) ethanol
2- (thiochroman-4-yl) ethanol:
2- (4-methylthiochroman-4-yl) -ethanol
2- (4-ethylchroman-4-yl) -ethanol
2- (4-propylchroman-4-yl) -ethanol

Synthesis 2: Representation of compounds of general formula (VI)

A. 2- (chroman-4-yl) ethanal:

1 ml of oxalyl chloride in 25.0 ml of dichloromethane are mixed at -78 ° C. with 1.7 ml of DMSO in 25.0 ml of dichloromethane. After 5 min. 1.9 g of 2- (chroman-4-yl) -ethanol in 25.0 ml of dichloromethane are added dropwise at -78 ° C. After 15 min. is added 7 ml of triethylamine and slowly warmed to RT. It is mixed with water, brine, 1% sulfuric acid and sat. Washed sodium bicarbonate solution, dried with sodium sulfate and concentrated in vacuo. 1.81 g of the title compound are obtained as a yellow oil.
¹ H-NMR (CDCl _3): δ = 1.73-1.86 (m, 1H), 2:11 to 2:28 (m, 1H), 2.75 (dd, 1H), 2.93 (dd, 1H), 3:43 to 3:56 (m, 1H ), 4.11-4.25 (m, 2H), 6.81 (d, 1H), 6.87 (t, 1H), 7.03-7.17 (m, 2H), 9.88 (s, 1H).

B. 2- (4-methylchroman-4-yl) ethanal:

0.58 ml of oxalyl chloride in 25.0 ml of dichloromethane are mixed at -78 ° C. with 1.0 ml of DMSO in 25.0 ml of dichloromethane. After 5 min. 1.2 g of 2- (4-methylchroman-4-yl) ethanol in 25.0 ml of dichloromethane are added dropwise at -78 ° C. After 15 min. is added 4 ml of triethylamine and slowly warmed to room temperature. It is mixed with water, brine, 1% sulfuric acid and sat. Washed sodium bicarbonate solution, dried with sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90:10) gives 970 mg of 2- (4-methylchroman-4-yl) -ethanal as a colorless oil.
¹ N-NMR (CDCl _3): δ = 1:48 (s, 3H), 1.92 (ddd, 1H), 2.12 (ddd, 1H), 2:59 (dd, 1H), 2.69 (dd, 1H), 4:11 to 4:29 ( m, 2H), 6.83 (d, 1H), 6.92 (t, 1H), 7.12 (t, 1H), 7.23 (d, 1H), 9.66 (s, 1H).

C. It is also possible to prepare by the methods described above:
2- (6-methylchroman-4-yl) ethanal
2- (7-methyl-chroman-4-yl) ethanal
2- (6-fluorochroman-4-yl) ethanal
2- (6-methoxychroman-4-yl) ethanal
2- (7-methoxychroman-4-yl) ethanal
2- (1,2,3,4-tetrahydronaphthalen-1-yl) ethanal
2- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) ethanal
2- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) ethanal
2- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) ethanal
2- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) ethanal
2- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) ethanal
2- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) ethanal
2- (thiochroman-4-yl) ethanal
2- (4-methylthiochroman-4-yl) ethanal
2- (4-ethylchroman-4-yl) ethanal
2- (4-propylchroman-4-yl) ethanal

Synthesis 3: Representation of compounds of general formula (V)

A. 2- (Chroman-4-yl) -1-trifluoromethyl-ethanol:

A solution of 1.8 g of 2- (chroman-4-yl) -ethanal and 4.6 ml of trifluoromethyltrimethylsilane in 60 ml of THF are added at 0 ° C. with 2 ml of tetrabutylammonium fluoride solution (1M in THF) and stirred for 1 hour. It is again added a spatula tip solid tetrabutylammonium and mixed with water. It is extracted with ethyl acetate, the organic phase washed with brine and dried with sodium sulfate. Chromatography on silica gel (hexane / ethyl acetate 95: 5 → 90:10) gives 2.1 g of 2- (chroman-4-yl) -1-trifluoromethyl-ethanol as a mixture of diastereomers.
¹ N-NMR (CDCl ₃ , selected signals): δ = 1.76-1.97 (m, 2H), 1.98-2.34 (m, 2H), 3.08-3.25 (m, 1H), 4.03-4.35 (m, 3H), 6.88-6.95 (m, 2H), 7.06-7.21 (m, 2H).

B. 2- (4-methylchroman-4-yl) -1-trifluoromethyl-ethanol:

A solution of 870 mg of 2- (4-methylchroman-4-yl) ethanal and 2 ml of trifluoromethyltrimethylsilane in 30 ml of THF at 0 ° C with 0.87 ml of tetrabutylammonium fluoride solution (1M in THF) and stirred for 1 hour. It is again added a spatula tip solid tetrabutylammonium fluoride and treated with water. It is extracted with ethyl acetate, the organic phase washed with brine and dried with sodium sulfate. This gives 1.2 g of 2- (4-methylchroman-4-yl) -1-trifluoromethyl-ethanol as a brown oil (mixture of diastereomers).
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.34 (s, 3H), 1.35 (s, 3H), 1.68 (ddd, 1H), 1.78 (ddd, 1H), 1.85 (dd, 1H), 1.90 -2.04 (m), 2.05-2.14 (m), 2.31 (ddd, 1H), 3.73-3.83 (m, 1H), 3.97-4.22 (m), 6.77 (d, 1H, Diaster.A + B), 6.80 -6.87 (m, 1H, Diaster.A + B), 7.0-7.1 (m), 7.17-7.21 (m).

C. Also, processes described above can be prepared:
2- (6-methylchroman-4-yl) -1-trifluoromethyl-ethanol
2- (7-methyl-chroman-4-yl) -1-trifluoromethyl-ethanol
2- (6-fluorochroman-4-yl) -1-trifluoromethyl-ethanol
2- (6-methoxychroman-4-yl) -1-trifluoromethyl-ethanol
2- (7-methoxychroman-4-yl) -1-trifluoromethyl-ethanol
2- (1,2,3,4-tetrahydronaphthalen-1-yl) -1-ethanol-trifluoromethyl
2- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -1-trifluoromethyl-ethanol
2- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -1-trifluoromethyl-ethanol
2- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -1-trifluoromethyl-ethanol
2- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -1-trifluoromethyl--ethanol
2- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -1-pentafluoroethyl-ethanol
2- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) -1-trifluoromethyl-ethanol
2- (thiochroman-4-yl) -1-trifluoromethyl-ethanol:
2- (4-methylthiochroman-4-yl) -1-trifluoromethyl-ethanol
2- (4-ethylchroman-4-yl) -1-trifluoromethyl-ethanol
2- (4-propylchroman-4-yl) -1-trifluoromethyl-ethanol

Synthesis 4: Representation of compounds of general formula (IV)

A. 3- (Chroman-4-yl) -1,1,1-trifluoropropan-2-one:

54.0 g of Dess-Martin Periodinan in 650 ml of dichloromethane are treated at room temperature with a solution of 9.0 g of 2- (chroman-4-yl) -1-trifluoromethyl-ethanol in 65 ml of dichloromethane and stirred for 10 hours. The approach is with ges. Sodium bicarbonate solution, diluted with diethyl ether and with sodium thiosulfate solution for 30 min. touched. The organic phase is separated and washed with water. It is dried with sodium sulfate and concentrated in vacuo. This gives 7.95 g of 3- (chroman-4-yl) -1,1,1-trifluoropropan-2-one.
¹ H-NMR (CDCl _3): δ = 1.62-1.77 (m, 1H), 2:08 to 2:22 (m, 1H), 2.94 (dd, 1H), 3.11 (dd, 1H), 3:39 to 3:50 (m, 1H ), 4.02-4.20 (m, 2H), 6.75 (d, 1H), 6.81 (t, 1H), 6.97 (d, 1H), 7.05 (t, 1H).

B. 3- (4-Methylchroman-4-yl) -1,1,1-trifluoropropan-2-one:

7.8 g of Dess-Martin periodinane in 100 ml of dichloromethane are added at 0 ° C with a solution of 1.2 g of 2- (chroman-4-yl) -1-trifluoromethyl-ethanol in 20 ml of dichloromethane and stirred at 0 ° C for 1 hour. Of the Approach is with ges. Sodium bicarbonate solution, diluted with diethyl ether and with sodium thiosulfate solution for 30 min. touched. The organic phase is separated and washed with water. It is dried with sodium sulfate and concentrated in vacuo. This gives 1.1 g of 3- (4-methylchroman-4-yl) -1,1,1-trifluoropropan-2-one as a brown oil.
¹ H-NMR (CDCl _3): δ = 1:50 (s, 3H), 2.0 (ddd, 1H), 2.25 (ddd, 1H), 3.10 (s, 2H), 4:10 to 4:28 (m, 2H), 6.83 ( d, 1H), 6.90 (t, 1H), 7.13 (t, 1H), 7.18 (d, 1H).

C. Also, processes described above can be prepared:
2- (6-methylchroman-4-yl) -1,1,1-trifluoropropan-2-one
2- (7-methylchroman-4-yl) -1,1,1-trifluoropropan-2-one
2- (6-fluorochroman-4-yl) -1,1,1-trifluoropropan-2-one
2- (6-methoxychroman-4-yl) -1,1,1-trifluoropropan-2-one
2- (7-methoxychroman-4-yl) -1,1,1-trifluoropropan-2-one
2- (1,2,3,4-tetrahydronaphthalen-1-yl) -1,1,1-trifluoropropan-2-one
2- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -1,1,1-trifluoropropan-2-one
2- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -1,1,1-trifluoropropan-2-one
2- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -1,1,1-trifluoropropan-2-one
2- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -1,1,1-trifluoropropan-2-one
4- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -1,1,1,2,2-pentafluorobutane-3-one
2- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) -1,1,1-trifluoropropan-2-one
2- (4-methylthiochroman-4-yl) -1,1,1-trifluoropropan-2-one
2- (4-ethylchroman-4-yl) -1,1,1-trifluoropropan-2-one
2- (4-propylchroman-4-yl) -1,1,1-trifluoropropan-2-one

Synthesis 5: Representation of compounds of general formula (IIIA)

3- (chroman-4-yl) -2-trifluoromethyl-2-trimethylsilyloxy-propionitrile

140 mg 3- (chroman-4-yl) -1,1,1-trifluoropropan-2-one in 2.5 ml of dichloromethane are added at room temperature with 124 mg of trimethylsilyl cyanide and stirred for 4 hours (J. Med. Chem. 2003, (46), pp. 2494-2501). The approach is on Add water and extracted with ethyl acetate. The combined organic phases washed with brine, dried with sodium sulfate and concentrated in vacuo. You get 204 mg of the title compound as an oil.

Synthesis 6: Representation of compounds of general formula (II) of compounds of general formula (IIIA)

3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde

204 mg of 3- (chroman-4-yl) -2-trifluoromethyl-2-trimethylsilyloxy-propionitrile in 5 ml of toluene at -70 ° C with 0.4 ml of DIBAL-H solution (1.5 M in toluene) and 4 hours at - 70 ° C stirred. After addition of 1 ml of ethyl acetate, the mixture is warmed to room temperature, treated with 1M sulfuric acid and stirred for 10 hours. The batch is diluted with water, extracted with ethyl acetate, the combined organic phases washed with brine, dried with sodium sulfate and concentrated in vacuo. The remaining oil is taken up in 1 ml of THF, treated with tetrabutylammonium fluoride solution [1M in THF] and stirred for 6 hours at room temperature. It is added water, extracted with ethyl acetate, washed with brine, dried and concentrated in vacuo. 124 mg of the title compound are obtained as an orange-colored oil.
MS (ei): M ⁺ = 274

Synthesis 7: Representation of compounds of the general formula (IIIB)

A. 1- (Chroman-4-y-yl) -2-trifluoromethyl-3-buten-2-ol:

A solution of 7.4 g of 3- (chroman-4-yl) -1,1,1-trifluoropropan-2-one in 75 ml of THF is added at room temperature to 33.3 ml of vinylmagnesium bromide solution [1H in THF] at room temperature. It is stirred for 4 hours at room temperature and then sat. Ammonium chloride solution given. The batch is extracted with ethyl acetate and the combined organic phases are washed with brine, dried with sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90:10) gives 7.0 g of 1- (chroman-4-yl) -2-trifluoromethyl-3-buten-2-ol as a yellow oil (mixture of diastereomers). ,
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.8-1.9 (m), 1.97 (dd, 1H), 2.01-2.37 (m), 2.93-3.03 (m, 1H), 3.03-3.12 (m, 1H), 4.05-4.27 (m), 5.53 (d, 1H), 5.58-5.70 (m, 3H), 5.97-6.17 (m, 2H), 6.73-6.94 (m, 4H), 7.02 (d, 1H), 7.04-7.13 (m, 2H), 7.21 (d, 1H).

B. 1- (4-Methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol:

A solution of 1.1 g of 3- (4-methylchroman-4-yl) -1,1,1-trifluoropropan-2-one in 30 ml of THF is added at room temperature to 9.2 ml of vinylmagnesium bromide solution [1H in THF] at room temperature. It is stirred for 5 hours at room temperature and then sat. Ammonium chloride solution given. The batch is extracted with ethyl acetate and the combined organic phases are washed with brine, dried with sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 95: 5) gives 930 g of 1- (4-methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol as an oil.
MS (ei): M ⁺ = 286

C. Also, processes described above can be prepared:
1- (6-methyl-chroman-4-yl) -2-trifluoromethyl-3-buten-2-ol
1- (7-methyl-chroman-4-yl) -2-trifluoromethyl-3-buten-2-ol
1- (6-fluorochroman-4-yl) -2-trifluoromethyl-3-buten-2-ol
1- (6-methoxychroman-4-yl) -2-trifluorrriethyl-3-buten-2-ol
1- (7-methoxychroman-4-yl) -2-trifluoromethyl-3-buten-2-ol
1- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-3-buten-2-ol
1- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-3-buten-2-ol
1- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-3-buten-2-ol
1- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-3-buten-2-ol
1- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-3-buten-2-ol
1- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-pentafluoroethyl-3-buten-2-ol
1- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-3-buten-2-ol
1- (4-methylthiochroman-4-yl) -2-trifluoromethyl-3-buten-2-ol
1- (4-ethylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol
1- (4-propylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol

Synthesis 8: Presentation of compounds of general formula (II) of compounds of general formula (IIIB)

A. 3- (Chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde:

In a solution of 7.0 g of 1- (chroman-4-yl) -2-trifluoromethyl-3-buten-2-ol in 450 ml of dichloromethane and 120 ml of methanol at -70 ° C ozone is introduced until the solution a assumes blue coloring. Then argon is passed through the solution for one minute, mixed with 3.6 ml Dimethylsulfld and stirred at -70 ° C for one hour. It is slowly warmed to room temperature and stirred for a further 10 hours. The batch is added to water and extracted with dichloromethane. The combined organic phases are dried and concentrated in vacuo. This gives 6.6 g of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde as a yellow oil.
MS (ei): M ⁺ = 274

B. 2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propionaldehyde:

In a solution of 900 mg of 1- (4-methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol in 56 ml of dichloromethane and 14 ml of methanol ozone is introduced at -70 ° C until the Solution takes a blue dye. Then argon is passed through the solution for one minute, mixed with 0.42 ml of dimethyl sulfide and stirred for an hour at -70 ° C. It is slowly warmed to room temperature and stirred for a further 10 hours. The batch is added to water and extracted with dichloromethane. The combined organic phases are dried and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 96: 4) gives 330 mg of 2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propionaldehyde as a yellow oil (mixture of diastereomers) ,
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.38 (s, 3H, diast. A), 1.43 (s, 3H, diast. B), 1.57-1.65 (m, 2H), 1.81 (ddd, 1H ), 2.13 (ddd, 1H), 2.37 (d, 1H, Diaster B), 2.45-2.60 (m), 2.83 (d, 1H, Diaster B), 3.69 (s, 1H, Diaster A), 3.86 (s, 1H, diast. B), 3.97 (dd, 1H, diast. B), 4.08-4.35 (m), 6.78-6.84 (m, 1H, diast. A + B), 6.88-6.95 (m, 1H ), 7.07-7.21 (m), 7.23-7.30 (m), 8.88 (s, 1H, Diaster.B), 9.56 (s, 1H, Diaster A).

C. Also, processes described above can be prepared:
2-hydroxy-3- (6-methyl-chroman-4-yl) -2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (7-methyl-chroman-4-yl) -2-trifluoromethyl-propionaldehyde
3- (6-fluorochroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (6-methoxychroman-4-yl) -2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (7-methoxychroman-4-yl) -2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propionaldehyde
3- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-pentafluoroethyl-propionaldehyde
3- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propionaldehyde
3- (4-ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde
2-hydroxy-3- (4-propylchroman-4-yl) -2-trifluoromethyl-propionaldehyde

Synthesis 9: Presentation of compounds of general formula (XIII)

4-Methylenthiochroman:

79.9 ml of n-butyllithium solution [1.6 M in hexane] are added dropwise at -10 ° C. to a solution of 40.9 g of methyltriphenylphosphonium bromide in 470 ml of THF. It is stirred for a further 45 minutes and then added 18.8 g of thiochroman-4-one. The mixture is mixed with a further 330 ml of THF and stirred for 1 hour at room temperature. The preparation is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried with sodium sulfate and concentrated in vacuo. After chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90:10), 11.7 g of 4-methylenethiochromane are obtained as an oil.
¹ H-NMR (CDCl _3): δ = 2.8-2.9 (m, 2H), 3:03 to 3:13 (m, 2H), 4.98 (s, 1H), 5.5 (s, 1H), 6.98-7.08 (m, 1H ), 7.08-7.17 (m, 2H), 7.54 (d, 1H).

Synthesis 10: Presentation of compounds of the general formula (XII)

A. Ethyl 2-hydroxy-3 - [(2H) thiochromen-4-yl) -2-trifluoromethyl-propionate:

A solution of 1.3 ml of titanium tetraethylate in 10 ml of toluene is treated at room temperature with 3.54 g of binaphthol and stirred for one hour. To this solution is added a solution of 10 g of 4-methylenethiochroman in 60 ml of toluene and 15 ml of trifluoropyruvate. The reaction solution is stirred at 120 ° C. for 3 hours and at room temperature for a further 10 hours. The reaction solution is diluted with water and ethyl acetate and filtered through diatomaceous earth. The organic phase is washed with brine, dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel (hexane / ethyl acetate 100: 0 -> 90:10) receives ma 19.8 g of 2-hydroxy-3 - [(2H) thiochromen-4-yl] -2-trifluoromethyl-propionic acid ethyl ester as a brown oil.
¹ H-NMR (CDCl _3): δ = 1.19 (t, 3H), 3:03 (d, 1H), 3.17 (dd, 1H), 3.30 (dd, 1H), 3.81 (s, 1H), 3.87-3.97 ( m, 1H), 4.09-4.18 (m, 1H), 6.10 (t, 1H), 7.07-7.18 (m, 2H), 7.30 (d, 1H), 7.42 (d, 1H).

B. 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) -propionic acid ethyl ester

20 g (307 mmol) of zinc dust and 710 mg (2.5 mmol) of lead (II) chloride suspended in 200 ml of THF and at room temperature 11.2 ml (100 mmol) of dibromomethane was added. One stirs another 60 minutes and 33 ml (33 mmol) of a 1 M titanium (IV) chloride solution is added dropwise Dichloromethane over 40 minutes with ice cooling to. After one hour at room temperature 4.4 g (30 mmol) Chroman-4-on was added in several portions, with the Reaction to 30 ° C heated. Man stirs another 3 hours at room temperature. It is diluted with diethyl ether and The reaction mixture is carefully poured onto a mixture of 4 M hydrochloric acid and Given ice cream. The phases are separated, extracted with diethyl ether, washes with water, dried over sodium sulfate and remove the solvent. The crude product is purified by column chromatography on silica gel (hexane / isopropyl ether 0-20%) to give 2.75 g 4-methylene-chroman.

To 170 mg (0.60 mmol) of 1,1'-bi-2-naphthol are added 0.60 ml (0.3 mmol) of a 0.5 M titanium tetraisopropylate solution in toluene and the red solution is stirred for 2 hours at room temperature. 1.0 g (6.8 mmol) of 4-methylene-chroman and 2.3 (13.6 mmol) of ethyl trifluoropyrate are added and the mixture is heated to 110 ° C. over 2 hours. After cooling, column chromatography on silica gel (He xan / ethyl acetate 20%) to give 1.15 g of ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate.

Synthesis 11: Presentation of compounds of general formula (XI)

1,2-dihydroxy-3 - [(2H) thiochromen-4-yl] -2-trifluoromethyl-propane:

At 0 ° C, 8.7 g of lithium aluminum hydride are added to a solution of 19.0 g of 2-hydroxy-3 - [(2H) thiochromen-4-yl] -2-trifluoro-ethyl-propionic acid ethyl ester in 500 ml of THF and it is at 0 ° for 2 hours C and stirred for 1 hour at room temperature. The approach is carefully with ges. Ammonium chloride solution and extracted with ethyl acetate. The combined organic phases Weden washed with water and brine, dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel (hexane / ethyl acetate 100: 0 -> 80:20) gives 11 g of 1,2-dihydroxy-3 - [(2H) thiochromen-4-yl] -2-trifluoromethyl-propane as a colorless oil.
¹ N-NMR (CDCl _3): δ = 2.86 (d, 1H), 3:02 to 3:11 (m, 2H), 3:23 to 3:33 (m, 2H), 3.54-3.70 (m, 2H), 6.13 (t, 1H ), 7.11-7.21 (m, 2H), 7.35 (d, 1H), 7.46 (d, 1H).

Synthesis 12: Representation of compounds of general formula (X)

1,2-dihydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propane:

9 g of 1,2-dihydroxy-3 - [(2H) thiochromen-4-yl] -2-trifluoromethyl-propane in 130 ml of ethanol are mixed with 9 g of Raney nickel and stirred in an autoclave under a hydrogen atmosphere at 50 bar for 2 hours , Again, 9 g of Raney nickel are added and further reacted for 5 hours with hydrogen at 50 bar. The mixture is filtered off with suction through diatomaceous earth and concentrated in vacuo. This gives 8.1 g of 1,2-dihydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propane as a yellow oil (mixture of diastereomers).
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.92 (dd, 1H), 1.95-2.07 (m), 2.18 (dd, 1H), 2.40-2.53 (m, 2H), 2.97-3.08 (m, 2H), 3.20-3.31 (m, 2H), 3.32-3.40 (m, 2H), 3.61 (t, 2H), 3.90 (d, 1H), 3.96 (d, 1H), 7.01-7.08 (m), 7.09 -7.20 (m).

Synthesis 13: Presentation of compounds of general formula (II) of compounds of general formula (X)

2-hydroxy-3-thiochroman-4-yl) -2-trifluoromethyl-propionaldehyde:

2.4 ml of oxalyl chloride in 240 ml of dichloromethane are added at -78 ° C. with 4.6 ml of DMSO in 80 ml of dichloromethane. After 5 min. 1,2-dihydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propane in 80 ml of dichloromethane are added dropwise at -78 ° C. After 15 min. is added 22.8 ml of triethylamine and slowly warmed to room temperature. It is dried with water and brine, with sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 85:15) gives 4.0 g of 2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propionaldehyde as a yellow oil (mixture of diastereomers).
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.75-1.93 (m), 1.95-2.03 (m), 2.12-2.28 (m), 2.60 (dd, 1H), 2.81-2.90 (m, 2H) , 2.95-3.02 (m), 3.03-3.18 (m), 6.84-7.10 (m), 9.12 (s, 1H, Diaster. A), 9.66 (s, 1H, Diaster. B).

Synthesis 14: Presentation of imines from compounds of the general formula (II)

A. 5- [3- (Chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -quinoline 2 [1H] -one:

To a solution of 600 mg of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde and 386 mg of 5-aminoquinoline-2 [1H] -one in 22 ml of toluene is added 0.76 ml of titanium tetraisopropoxylate and allowed to stand for 4 hours heated to 110 ° C. The approach is on ges. Sodium carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane 100%, dichloromethane / isopropanol 100: 0 → 95: 5) gives 275 mg of 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -quinoline 2 [1H] -one as a beige foam (mixture of diastereomers).
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.76-1.85 (m), 2.02-2.12 (m), 2.13-2.22 (m), 2.27 (d, 1H), 2.31 (d, 1H), 2.40 -2.48 (m), 2.61 (d, 1H, Diaster A + B), 2.93-3.01 (m, 1H, Diaster A), 3.22-3.31 (m, 1H, Diaster B), 4.10-4.18 (m ), 4.22-4.29 (m), 4.87 (bs, 1H, Diaster A), 5.02 (bs, 1H, Diaster B), 6.64 (d, 1H, Diaster B), 6.72 (d, 1H, Diaster. A), 6.73-6.84 (m), 6.88-7.00 (m), 7.06-7.17 (m), 7.24-7.31 (m), 7.37-7.42 (m), 7.45-7.54 (m), 8.06-8.18 (m ), 12.43 (bs, 1H, Diaster A + B).

B. 5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-progylideneamino] -quinoline 2 [1H] -one:

A solution of 300 mg of 3- (4-methylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde and 160 mg of 5-aminoquinolin-2 [1H] -one in 10 ml of toluene are admixed with 1.1 ml of titanium tetraisopropoxylate and Heated to 110 ° C for 6 hours. The approach is on ges. Sodium hydrogen carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 0: 100) gives 300 mg of 5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -quinoline 2 [1H ] -on as a foam (mixture of diastereomers).
¹ H NMR (CDCl ₃ , selected signals): δ = 1.41 (s, 3H, Diaster A), 1.46 (s, 3H, Diaster B), 1.65-1.77 (m, 1H, Diaster A), 1.81 -1.94 (m, 1H, Diaster.B), 2.3-2.4 (m, 1H, Diaster.B), 2.43 (d, 1H, Diaster A + B), 2.61 (d, 1H, Diaster B), 2.61 -2.73 (m, 2H, Diaster B), 2.87 (d, 1H, Diaster A), 3.98-4.27 (m), 4.31-4.41 (m, 1H, Diaster B), 4.82 (bs, 1H, Diatsre B), 5.0 (bs, 1H, Diaster A), 5.93 (d, 1H, Diaster A), 6.49 (d, 1H, Diaster A), 6.58 (d, 1H, Diaster B), 6.72 (d. d, 1H, Diaster A), 6.74-6.93 (m), 7.03 (t, 1H, Diaster B), 7.2-7.34 (m), 7.38-7.50 (m, 2H, Diaster B), 8.0 (s , 1H, Diaster.B), 8.05 (d, 1H, Diaster A), 8.13 (d, 1H, Diaster B), 12.65 (bs, 1H, Diaster A + B).

C. 5- [2-Hydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propylideneamino-quinoline 2 [1H] -one:

To a solution of 700 mg of 2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propionaldehyde and 386 mg of 5-aminoquinoline-2 [1H] -one in 20 ml of toluene is added 2.6 ml of titanium tetraisopropoxylate and allowed to stand for 4 hours heated to 110 ° C. The approach is on ges. Sodium hydrogen carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane 100%, dichloromethane / isopropanol 100: 0 → 96: 4) gives 600 mg of 5- [2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propylideneamino] -quinoline 2 [1H] -one as a foam (mixture of diastereomers).
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.81-2.08 (m), 2.11-2.22 (m), 2.30-2.46 (m), 2.56 (dd, 1H), 2.87-2.96 (m), 3.01 -3.40 (m), 4.93 (s, 1H, Diaster.A + B), 6.28 (d, 1H), 6.69 (d, 1H), 6.77 (d, 1H, Diaster.A + B), 6.86 (d, 1H), 6.99 (t, 1H), 7.01-7.11 (m), 7.13 (d, 1H), 7.18-7.27 (m), 7.31-7.43 (m), 7.74 (s, 1H), 8.08 (s, 1H ), 8.10 (d, 1H), 8.18 (d, 1H), 12.01 (bs, 1H, Diaster. A + B).

D. 5- (3- (Chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino-phthalazine-1 [2H] -one:

A solution of 600 mg of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde and 384 mg of 5-aminophthalazin-1 [2H] -one in 22 ml of toluene is treated with 0.76 ml of titanium tetraisopropoxylate and treated for 7 hours heated to 110 ° C. The approach is on ges. Sodium hydrogen carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane 100%, dichloromethane / isopropanol 100: 0 → 95: 5) gives 818 mg of 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -phthalazine -1 [2H] -one as yellow foam (mixture of diastereomers).
¹ H-NMR (CDCl ₃ , selected signals): δ = 1.80-1.93 (m), 2.03-2.22 (m), 2.32 (d, 1H), 2.38 (d, 1H), 2.46 (d, 1H), 2.58 -2.68 (m), 2.97-3.05 (m, 1H), 3.26-3.36 (m), 4.10-4.21 (m), 4.22-4.29 (m), 4.76 (s, 1H, Diaster A), 4.89 (s , 1H, Diaster.B), 6.82-6.83 (m), 6.86-7.0 (m), 7.03-7.18 (m), 7.21 (d, 1H, Diaster A), 7.70-7.81 (m), 8.06 (s , 1H, Diaster.B), 8.14 (s, 1H, Diaster A), 8.33-8.55 (m). 10.47 (bs, 1H, Diaster A + B).

E. 5- [3- (Chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -8-fluoro-2-methylquinazoline:

A solution of 250 mg of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propionaldehyde and 180 mg of 5-amino-8-fluoro-2-methylquinazoline in 10 ml of toluene is treated with 0.31 ml of titanium tetraisopropoxylate and 6 Hours heated to 110 ° C. The approach is on ges. Sodium hydrogen carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (dichloromethane / methanol 100: 0 → 60:40) gives 191 mg of 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -8-fluoro-2 Methylquinazoline as orange-colored foam (mixture of diastereomers).
¹ H-NMR (CDCl _3): δ = 1.80-1.92 (m, 1H), 2:02 to 2:22 (m), 2:33 (d, 1H), 2:38 (d, 1H) 2.46 (d, 1H), 2.63 ( dd, 1H), 2.98 (s, 3H, Diaster.A + B), 3.27-3.38 (m), 4.09-4.18 (m), 4.23-4.30 (m), 4.79 (s, 1H, Diaster.A), 4.91 (s, 1H, Diaster.B), 6.71-6.78 (m), 6.79-6.87 (m), 6.89-6.97 (m), 7.03-7.13 (m), 7.47-7.57 (m), 8.09 (s, 1H, Diaster. B), 8.18 (s, 1H, Diaster. A).

F. Also can be made:
5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -2-methylquinazoline
4- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] indazole
4- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -1,3-dihydro-indol-2-one
5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -2-methyl-isoquinolin-1-one
5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] iso chromen-1-one
5- [2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] -one phthalazin-1 [2H]
5- [2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline
5- [2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline
4- [2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] indazole
5- [2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] iso chromen-1-one
5- [2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] iso chromen-1-one
4- [2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propylideneamino] indazole
5- [2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propylideneamino] phthalazine-1 [2H] -one
8-fluoro-5- [2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methyl-quinazoline
4- [2-hydroxy-3- (6-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] indazole
5- [2-hydroxy-3- (6-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline
4- [2-hydroxy-3- (7-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] indazole
5- [2-hydroxy-3- (7-methyl-chroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline
5- [3- (6-fluorochroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -2-methylquinazoline
5- [3- (6-fluorochroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] phthalazine-1 [2H] -one
5- [3- (6-fluorochroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] iso chromen-1-one
5- [2-hydroxy-3- (6-methoxychroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline
5- [2-hydroxy-3- (7-methoxychroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline
5- [2-Hydroxy-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propylideneamino] -chinolin2 [1H] -one
5- [2-Hydroxy-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propylideneamino] -2-methyichinolin
8-fluoro-5- [2-hydroxy-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline
5- [2-hydroxy-3- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline
5- [2-hydroxy-3- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline
5- [2-hydroxy-3- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propylideneamino] -2-methyl-iso-quinolin-1-one
5- [3- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -2-methyl-iso-quinolin-1-one
5- [2-hydroxy-3- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-pentafluoroethyl-propylideneamino] -chinolin2 [1H] -one
5- [3- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -chinolin2 [1H] -one
5- [2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluotmethyl-propylideneamino] quinolin-2 -one [1H]
5- [2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline
5- [2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline
5- [3- (4-ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -2-methylquinoline
5- [3- (4-ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylidenaminoj-quinoline-2 [1H] -one
5- [3- (4-ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] phthalazine-1 [2H] -one
5- [2-hydroxy-3- (4-propylchroman-4-yl) -2-trifluoromethyl-propylideneamino] quinolin-2 [1H] -one

Compounds of the general Formula (I)

Example 1:

5 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyll-amino} quinolin-2 [1 H] -one:

To a solution of 15 mg of 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -quinolin2 [1H] -one in 1.5 ml of methanol and 0.3 ml of glacial acetic acid, 31 mg of sodium cyanoborohydride are added at room temperature and it is stirred for 3.5 hours. The approach is on ges. Sodium hydrogen carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (dichloromethane / methanol 100: 0 → 60:40) gives 12 mg of 5 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] -amino} -quinoline -2 [1H] -one as a yellow foam (mixture of diastereomers).
¹ H-NMR (CDCl ₃ , selected signals): δ = 2.0-2.13 (m), 2.13-2.21 (m), 3.17-3.27 (m, 1H), 3.55 (s, 1H), 3.63 (s, 1H) , 4.01-4.13 (m, 2H), 6.49 (d, 1H), 6.58 (t, 1H, DiS. A + B), 6.62-6.79 (m, 3H), 6.99 (t, 1H, Diaster A + B ) 7.06 (d, 1H), 7.10 (d, 1H), 7.30-7.39 (m, 1H, Diaster A + B), 8.12 (d, 1H, Diaster A + B).

Example 2, 3, 4 and 5:

5 - {[2-Hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one, diastereomer A, (+) enantiomer:

5 - {[2-Hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one, diastereomer B, (-) - enantiomer:

5 - {[2-Hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one, diastereomer A, (-) - Enantiomer:

5 - {[2-Hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one, diastereomer B, (+) enantiomer:

To a solution of 50 mg of 5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -quinolin2 [1H] -one in 4.8 ml of methanol and 1.0 ml of glacial acetic acid at room temperature 100 Sodium cyanoborohydride is added and it is stirred for 3.5 hours. The approach is on ges. Sodium hydrogen carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. HPLC chromatography (Chiralpak AD-H, hexane / ethanol 95: 5 → 50:50) gives 1 mg of 5 - {[2-hydroxy-3- (4-methylchroman-4-yl) -2- trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one (fraction 1: diastereomer A, (+) - enantiomer), 5 mg of 5 - {[2-hydroxy-3- (4-methylchroman-4 -yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one (fraction 2: diastereomer B, (-) - enantiomer), 7 mg 5 - {[2-hydroxy-3- (4 -methyl-chroman-4-yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one (fraction 3: diastereomer A, (-) - enantiomer), and 8 mg of 5 - {[2 -Hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one (fraction 4: diastereomer B, (+) - enantiomer), respectively as colorless foams.
Example 2 (fraction 1): ¹ H NMR (CD ₃ OD): δ = 1.54 (s, 3H), 1.87 (ddd, 1H), 2.17 (d, 1H), 2.22 (d, 1H), 2.37 (ddd , 1H), 3.42 (d, 1H), 3.52 (d, 1H), 4.11 (ddd, 1H), 4.22 (ddd, 1H), 6.33 (d, 1H), 6.47 (d, 1H), 6.66 (dd, 1H), 6.78 (t, 1H), 7.0 (dt, 1H), 7.27-7.33 (m, 2H), 8.0 (d, 1H).
Example 3 (Group 2): ¹ H-NMR (CD ₃ OD): δ = 1:40 (s, 3H), 1.68-1.76 (m, 1H), 2.15 (d, 1H), 2:53 (d, 1H), 2.85 (d, 1H), 2.87-2.97 (m, 1H), 3.06 (d, 1H), 4.02-4.11 (m, 1H), 4.20-4.27 (m, 1H), 5.74 (d, 1H), 6.44 (i.e. , 1H), 6.59 (d, 1H), 6.7 (d, 1H), 6.88 (t, 1H), 7.04 (t, 1H), 7.15 (t, 1H), 7.36 (d, 1H), 7.96 (d, 1H).
Example 4 (Group 3): ¹ H-NMR (CD ₃ OD): δ = 1:54 (s, 3H), 1.87 (ddd, 1H), 2.17 (d, 1H), 2.22 (d, 1H), 2:37 (ddd , 1H), 3.42 (d, 1H), 3.52 (d, 1H), 4.11 (ddd, 1H), 4.22 (ddd, 1H), 6.33 (d, 1H), 6.47 (d, 1H), 6.66 (dd, 1H), 6.78 (t, 1H), 7.0 (dt, 1H), 7.27-7.33 (m, 2H), 8.0 (d, 1H).
Example 5 (Group 4): ¹ H-NMR (CD ₃ OD): δ = 1:40 (s, 3H), 1.68-1.76 (m, 1H), 2.15 (d, 1H), 2:53 (d, 1H), 2.85 (d, 1H), 2.87-2.97 (m, 1H), 3.06 (d, 1H), 4.02-4.11 (m, 1H), 4.20-4.27 (m, 1H), 5.74 (d, 1H), 6.44 (i.e. , 1H), 6.59 (d, 1H), 6.7 (d, 1H), 6.88 (t, 1H), 7.04 (t, 1H), 7.15 (t, 1H), 7.36 (d, 1H), 7.96 (d, 1H).

Example 6:

5 - {[2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propyl] amino} quinolin-2 [1 H] -one:

To a solution of 50 mg of 5- [2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propylideneamino] -quinolin2 [1H] -one in 4.8 ml of methanol and 1.0 ml of glacial acetic acid at room temperature 100 mg of sodium cyanoborohydride and it is stirred for 1 hour. The approach is on ges. Sodium hydrogen carbonate solution, extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated in vacuo. This gives 44 mg of 5 - {[2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propyl] -amino} -quinolin-2 [1H] -one as a yellow foam (mixture of diastereomers) ,
¹ H-NMR (CHCl ₃ , selected signals): δ = 1.80-1.92 (m), 2.07-2.12 (m), 2.18 (dd, 1H), 2.30 (dd, 1H), 2.32-2.40 (m, 1H) , 2.88-2.95 (m), 3.05-3.18 (m), 3.20-3.31 (m), 3.31-3.38 (m), 3.42 (dd, 1H), 4.11-4.23 (m), 6.17 (d, 1H), 6.22 (d, 1H), 6.44 (t, 1H), 6.54 (d, 1H), 6.60 (d, 1H), 6.85-7.20 (m), 7.51-7.57 (m), 11.25-11.44 (bd, 1H, Diaster, A + B).

Example 7:

3- (chroman-4-yl) -1 - [(2-methyl-quinolin-S-yl) amino] -2- (trifluoromethyl) propan-2-ol

A. Take 1.15 g of ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate in 30 ml of diethyl ether and cool to -5 ° C. 275 mg (7.2 mmol) of lithium aluminum hydride are added in portions over 10 minutes. The mixture is stirred for 2 hours at this temperature and poured into saturated ammonium chloride solution. The suspension is filtered through Celite, rinsing thoroughly with ethyl acetate. The phases of the filtrate are separated and it is extracted again with ethyl acetate. It is washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. Chromatographic purification on silica gel (hexane / ethyl acetate 25-33%) yields 620 mg of 3- (2H-chromene-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal. ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 3.06 (d, 1H), 3.26 (d, 1H), 3.89 (s, 1H), 4.67 (dd, 1H), 4.70 (dd, 1H), 5.74 (t, 1H), 6.80 (d, 1H) , 6.93 (t, 1H), 7.15 (t, 1H), 7.21 (d, 1H), 9.63 (s, 1H).

B. To 245 mg (0.9 mmol) of 3- (2H-chromene-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal and 150 mg (0.95 mol) of 5-amino-8-methylquinoline in 10 ml of toluene Add 0.4 ml (2.0 mmol) of titanium tetraethylate and the mixture is allowed to stand for 2 hours at 100 ° C heated. After cooling pouring one on water and stir fiercely after. The suspension is filtered through celite while thoroughly with Ethyl acetate is washed. The phases of the filtrate are separated and it is extracted again with ethyl acetate. It is dried over sodium sulfate and remove the solvent in a vacuum. After chromatographic purification on silica gel (hexane / ethyl acetate 50%) 180 mg of 3- (2H-chromen-4-yl) -1 - [(2-methylquinolin-5-yl) -imino] -2- (trifluoromethyl) -propan-2-ol. 90 mg of the imine thus obtained are taken up in 4 ml of methanol and at 0 ° C cooled. you Add 25 mg (0.66 mmol) of sodium borohydride and drip dropwise 2 hours on saturated Ammonium chloride solution and stir violently. It is extracted several times with ethyl acetate, washed with saturated Sodium chloride solution, dries over Sodium sulfate and removes the solvent in a vacuum. The column chromatographic Separation on silica gel (hexane / ethyl acetate 50%) yields 80 mg of 3- (2H-chromene-4-yl) -1 - [(2-methylquinolin-5-yl) amino] -2- (trifluoromethyl) propane-2-one. oil.

C. 30 mg of 3- (2H-chromene-4-yl) -1 - [(2-methylquinolin-5-yl) amino] -2- (trifluoromethyl) -propan-2-ol are taken up in 8 ml of methanol and after addition of 10 mg of palladium on carbon (10%), the suspension is shaken for 2 hours under a hydrogen atmosphere at atmospheric pressure. The mixture is filtered through celite while rinsing thoroughly with methanol. The solvent is removed in vacuo and, after purification by chromatography on silica gel (hexane / ethyl acetate 50%), 12 mg of the title compound are obtained as a mixture of diastereomers.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 2.05-2.37 (m, 4H), 2.74 (s, 3H), 3.24-3.32 (m, 1H), 3.51 (dd, 0.5H), 3.50 (dd, 1H), 3.61-3.72 (m, 1.5H ), 4.21 (m, 2H), 4.45 (br, 1H), 6.70 (dd, 0.5H), 6.75 (dd, 0.5H), 6.78-6.88 (m, 2H), 7.08-7.13 (m, 1.5H) , 7.18 (d, 0.5H), 7.27 (d, 1H), 7.53-7.56 (m, 2H), 8.04 (d, 0.5H), 8.06 (d, 0.5H).

Also can be made to the above described rules:
3- (chroman-4-yl) -1- (2-methylquinolin-5-ylamino) -2-trtfluormethyl-propan-2-ol
5 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} phthalazin-1 [2H] -one
5 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -8-fluoro-2-methylquinazoline
5 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -2-methylquinazoline
4 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -indazole
4 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -1,3-dihydro-indol-2-one
5 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] -amino} -2-methyl-iso-quinolin-1-one
5 - {[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -iso-chromene-1-one
5 - {[2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} phthalazin-1 [2H] -one
5 - {[2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinoline
5 - {[2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinazoline
4 - {[2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -indazole
5 - {[2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -iso-chromene-1-one
5 - {[2-hydroxy-3- (4-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -iso-chromene-1-one
4 - {[2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propyl] amino} -indazole
5 - {[2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propyl] amino} -one phthalazin-1 [2H]
8-fluoro-5 - {[2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinazoline
4 - {[2-hydroxy-3- (6-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -indazole
5 - {[2-hydroxy-3- (6-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinoline
4 - {[2-hydroxy-3- (7-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -indazole
5 - {[2-hydroxy-3- (7-methyl-chroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinazoline
5 - {[3- (6-fluorochroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -2-methylquinazoline
5 - {[3- (6-fluorochroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} phthalazin-1 [2H] -one
5 - {[3 (6-fluorochroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -iso-chromene-1-one
5 - {[2-hydroxy-3- (6-methoxychroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinazoline
5 - {[2-hydroxy-3- (7-methoxychroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinazoline
5 - {[2-hydroxy-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propyl] amino} -chinolin2 [1H] -one
5 - {[2-hydroxy-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinoline
8-fluoro-5 - {[2-hydroxy-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinazoline
5 - {[2-hydroxy-3- (2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinoline
5 - {[2-hydroxy-3- (4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinoline
5 - {[2-hydroxy-3- (5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-trifluoromethyl-propyl] -amino} -2-methyl-iso-quinoline-1- on
5 - {[3- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) -2-hydroxy-2-trifluoromethyl-propyl] -amino} -2-methyl-iso-quinolin 1-one
5 - {[2-hydroxy-3- (6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -2-pentafluoroethyl-propyl] amino} -chinolin2 [1H] -one
5 - {[3- (6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -chinolin2 [1H] -one
5 - {[2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propyl] amino} quinoline-2 [1H] -one
5 - {[2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinazoline
5 - {[2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propyl] amino} -2-methylquinoline
5 - {[3- (4-ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} -2-methylquinoline
5 - {[3- (4-ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} quinoline-2 [1H] -one
5 - {[3- (4-ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} phthalazin-1 [2H] -one
5 - {[2-hydroxy-3- (4-propylchroman-4-yl) -2-trifluoromethyl-propyl] amino} quinoline-2 [1H] -one

Claims (13)

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 (C ₁ -C ₁₀ ) alkyl group, a (C ₁ -C ₁₀ ) alkoxy group, a (C ₁ -C ₁₀ ) Alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group, a nitro group, or an -NR ⁹ R ^9a group, or R ¹ and R ² together form a group selected from the group -O- (CH ₂ ) _{n is} -O-, -O- (CH ₂ ) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, - NH- (CH ₂ ) _{n + 1} -, Form -N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} -, and -NH-N = CH-, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms 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 (C ₁ -C ₅ ) -perfluoroalkyl group, R ^{12 is} a hydrogen a is 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} an optionally substituted by 1 to 3 hydroxy groups, 1 to 3 Halogen atoms, and / or (C ₁ -C ₅ ) -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, or an 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, (C ₁ -C ₅ ) alkoxy groups, halogen atoms, hydroxy groups, -NR ⁹ R ^9a groups, (C ₁ -C ₅ ) perfluoroalkyl groups, nitro groups, thiol groups, sulfoxyl groups, sulfonic acid groups, sulfonamide groups, sulfonimine groups , Cyano groups or - (CO) - (C ₁ -C ₅ ) -alkyl groups, and Exomethylengruppen substituted, optionally 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, which group is linked via any position with the nitrogen atom and may optionally be hydrogenated at one or more sites, R ^3a Is hydrogen atom, a cyano group or an optionally substituted (C ₁ -C ₅ ) alkyl group; R ⁴ , R ⁵ , R ⁶ and R ^6a are each independently hydrogen, halogen, hydroxy, -NR ⁹ R ^9a , optionally substituted (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) -alkoxy group or a (C ₁ -C ₁₀ ) -alkylthio group, R ⁹ and R ^{9a are} independently a hydrogen atom, a (C ₁ -C ₅ ) -alkyl group or a - (CO) - (C ₁ -C ₅ ) Alkyl group, R ^{10 is} a (C ₁ -C ₁₀ ) alkyl group or a - (CO) - (C ₁ -C ₁₀ ) alkyl group, R ^{13 is} a hydrogen atom or a (C ₁ -C ₅ ) alkyl group R ^{14 represents} a hydrogen atom, a fluorine atom or a partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, and Y represents a methylene group, an oxygen atom, a sulfur atom, an -S (O) _n group (where n = 1 or 2), an -S (O) (NR ¹³ ) group, an -NH group or an -NR ¹⁰ group; in the form of any stereoisomer or mixture of stereoisomers; or as a pharmacologically acceptable salt or derivative. Compounds according to claim 1, wherein Y is an oxygen atom, a sulfur atom or a methylene group represents. Compounds according to claim 1 or 2, wherein R ^{3 represents} an optionally substituted aryl or heteroaryl group, preferably selected from the group consisting of naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzofuranyl, Benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, chromanyl, isochromanyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7 or 1,8 Naphthyridinyl, pyrazolo [1,5-a] pyridyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole and indolyl groups. Compounds according to any one of the preceding claims, wherein R ^{3a is} a hydrogen atom or a (C ₁ -C ₅ ) -alkyl group. Compounds according to any one of the preceding claims, wherein R ⁴ , R ⁵ , R ⁶ , and R ^6a independently represent a hydrogen atom, a halogen atom or an optionally substituted (C ₁ -C ₁₀ ) alkyl group. Compounds according to any one of the preceding claims, wherein R ^{14 represents} a fluorine atom or a trifluoromethyl group. Compounds according to a of the preceding claims for the manufacture of a medicament. Use of a compound according to any one of claims 1 to 6 for the preparation of a pharmaceutical composition for treatment or prevention of inflammatory Processes. Method of treatment or prevention of inflammatory Processes in a patient, characterized in that a Patient in need of such treatment or prevention pharmaceutically effective amount of a compound of the general formula (I) according to one the claims 1 to 6 is administered. Pharmaceutical preparations containing at least a connection according to a the claims 1 to 6 and one or more pharmaceutically acceptable carrier and / or Excipients. Process for the preparation of compounds according to one of Claims 1 to 6, characterized in that a compound of the general formula (II)

is reacted with an amine of the general formula R ³ -NH ₂ and the resulting imine is reduced to a compound of general formula (I), wherein the substituents R ¹ to R ¹⁴ and Y have the meanings mentioned in claims 1 to 6. Compounds of the general formula (II)

where the substituents R ¹ to R ¹⁴ and Y have the meanings mentioned in claims 1 to 6. Use of compounds of the general formula (II) as defined in claim 12 for the preparation of compounds of general formula (I) according to a the claims 1 to 6.