JP2008535889A - Substituted chroman derivatives, methods for their preparation and their use as anti-inflammatory agents - Google Patents

Abstract

The present invention relates to a novel polysubstituted heterocyclic compound of general formula (I), a process for its preparation and its use in an anti-inflammatory form.

Description

The present invention relates to substituted chroman derivatives, methods for their preparation and their use as anti-inflammatory agents.
Ring-opening non-steroidal anti-inflammatory agents are known in the art (DE 100 38 639, WO 03/082827 and WO 02/10143). These compounds show experimental separation between anti-inflammatory and undesired metabolic effects and are superior or at least better than the non-steroidal glucocorticoids described to date.
The present invention further provides non-steroidal anti-inflammatory agents.

Brief description of the invention:
The present invention relates to the following general formula (I):

[Wherein, R ¹ and R ² are independently of each other a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, (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 a —NR ⁹ R ^9a group, or
R ¹ and R ² together represent -0- (CH ₂ ) _n -O-, -0- (CH ₂ ) _n -CH _2- , -0-CH = CH-,-(CH ₂ ) _{n + 2 -, - NH- (} CH 2) n + 1 -, -N (C1-C 3 - alkyl) - a and -NH-n = CH- are selected from the group - (CH _{2) n + 1} Wherein n is 1 or 2, and the terminal oxygen atom and / or carbon atom and / or nitrogen atom is directly bonded to an adjacent ring atom;

R ¹¹ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) - an alkylthio group, or a (C ₁ -C ₅₎ - a 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 optionally substituted by ₁ to 3 hydroxy groups, 1 to 3 halogen atoms, and / or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups (C ₁ -C ₁₀ ) -Alkyl group, optionally substituted (C ₃ -C ₇ ) -cycloalkyl group, optionally substituted heterocyclyl group, optionally substituted aryl group, or optionally substituted by one or more substitution values. A monocyclic or bicyclic heteroaryl group, wherein said substituent can itself optionally be substituted by 1 to 3 hydroxy or 1 to 3 -COOR ¹³ groups (C _1- C ₅ ) -alkyl group, (C ₁ -C ₅ ) -alkoxy group, halogen atom, hydroxy group, —NR ⁹ R ^9a group, (C ₁ -C ₅ ) -perfluoroalkyl group, nitro group, thiol group, sulfoxyl Group, sulfonic acid group, sulfonamido group, sulfonimine group, cyano group, or-(CO)-(C ₁ -C ₅₎ - alkyl groups, and is selected from the exomethylene group from each other independently and optionally, 1 to 4 nitrogen atoms, and / or 1 to 2 oxygen atoms and / or 1 to 2, Comprising 1 sulfur atom and / or 1 to 2 keto groups, which group is bonded to the nitrogen atom at any position and is optionally hydrogenated at one or more positions. Get

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 a hydrogen atom, a halogen atom, a hydroxy group, an NR ⁹ R ^9a group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, ( C ₁ -C ₁₀ ) -alkoxy group or (C ₁ -C ₁₀ ) -alkylthio group,
R ⁹ and R ^9a are each 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 is a hydrogen atom, a fluorine atom, or a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group;
Y is a methylene group, oxygen atom, sulfur atom, —S (O) n (where n = 1 or 2), —S (O) (NR ¹³ ) group, —NH group, or —NR ¹⁰ group. A compound in the form of any stereoisomer or mixture of stereoisomers; or a pharmacologically acceptable salt or derivative thereof.

The invention further relates to a process for the preparation of compounds of general formula (I) as described herein.
The present invention further relates to pharmaceutical compositions comprising one or more compounds of general formula (I) and one or more pharmaceutical carriers or excipients.
The invention further relates to the use of a compound of general formula (I) for the manufacture of a pharmaceutical composition having an anti-inflammatory effect.

The present invention further includes the following general formula (II):

[Wherein R ^{1 to} R ¹⁴ and Y have the above-mentioned meanings], and the use of these compounds for the preparation of compounds of general formula (I) as described above Related.

Detailed description of the invention:
Definition :
The term halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. A fluorine, chlorine or bromine atom is preferred.
The alkyl group referred to in the definition of general formula (I) can be straight-chain or branched and can be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl or n-pentyl, 2,2, -dimethylpropyl, 2-methylbutyl or 3-methylbutyl groups, and hexyl, heptyl, nonyl, decyl groups and derivatives thereof branched by any means. Particularly preferred are alkyl groups comprising 1 to 10, 1 to 8, or 1 to 5 carbon atoms.

The alkyl group is optionally hydroxy, cyano, nitro, —COOR ¹³ , (C ₁ -C ₅ ) -alkoxy, halogen atom, —NR ⁹ R ^9a , partially or fully fluorinated ( It can be substituted by 1 to 5, preferably 1 to 3 groups independently selected from C ₁ -C ₃ ) -alkyl groups. The alkyl group can 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. . Fluorine atoms, hydroxy, methoxy and / or cyano groups represent a particularly preferred subgroup of substituents.
1-3 hydroxy and / or 1-3 COOR ¹³ groups are a particularly preferred group of substituents for alkyl groups. Hydroxy groups are particularly preferred in this regard.

  Examples of suitable partially or fully fluorinated alkyl groups are the following partially or fully fluorinated groups: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1 -Difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl. Of these, a trifluoromethyl group or a pentafluoroethyl group is preferred. Fully fluorinated groups are also referred to as perfluoroalkyl groups. Reagents that are optionally used during the synthesis can be purchased, or published methods of synthesis of the corresponding reagents belong to the prior art, or published methods of synthesis can be applied as well.

The alkoxy groups mentioned in the definition of general formula (I) are straight-chain or branched and are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n- Represents a pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy, or 3-methylbutoxy group; 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.

Alkylthio groups mentioned in the definition of general formula (I) are linear or branched and are methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio or n- Represents a pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio, or 3-methylbutylthio group; C ₁ -C ₅ -alkyl groups are preferred. A methylthio or ethylthio group is particularly preferred.

The alkoxy and alkylthio groups can have the same substituents on them as generally described above for alkyl groups. Preferred substituents for alkoxy and alkylthio groups are independently selected from halogen (especially fluorine and / or chlorine), hydroxy and cyano.
The substituent --NR ⁹ R ^9a is, for example, --NH ₂ , --NH (CH ₃ ), --N (CH ₃ ) ₂ , --NH (C ₂ H ₅ ), --N (C ₂ Hs) ₂ , --NH ( C ₃ H ₇ ), -N (C ₃ H ₇ ) 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 means.

(C ₃ -C ₇ ) -cycloalkyl group is a hydroxy group, a halogen atom (C ₁ -C ₅ ) -alkyl group, (C ₁ -C ₅ ) -alkoxy group, NR ⁹ R ^9a group, COOR ¹³ group, A saturated cyclic group optionally substituted with one or more groups selected from CHO, cyano and having 3 to 7 ring carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, It means methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.

An alkylidene or exoalkylidene group means a group having 1 to 10 carbon atoms attached to the system (ring or chain) through an exo double bond. (C ₁ -C ₅ )-and (C ₁ -C ₃ ) -alkylidene are preferred, and exomethylene is particularly preferred.
A heterocyclyl group is a cyclic non-aromatic group comprising one or more heteroatoms and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine. Perhydroquinoline and perhydroisoquinoline are also included in the heterocyclyl group of the present invention.

Examples of suitable substituents for heterocyclyl and heteroaryl groups are substituents from the following groups: optionally substituted (C ₁ -C ₅ ) -alkyl groups, hydroxy, (C ₁ -C ₅ ) -Alkoxy, -NR ⁹ R ^9a , halogen, cyano, -COOR ¹³ , -CHO. The substituent may optionally also be attached to the nitrogen atom of the heterocyclyl or heteroaryl group; N-oxides are also included in this definition.

The aryl group in the present invention is an aromatic or partially aromatic carbocyclic group having 6 to 14 carbon atoms, such as phenyl or phenylene, or many fused rings such as naphthyl, having one ring. Or anthranyl. Examples that may be mentioned are phenyl, naphthyl, tetralinyl, anthranyl, indanyl and indenyl. Optionally substituted phenyl and naphthyl groups are preferred.
Aryl groups, hydroxy, halogen, C ¹ -C optionally substituted by 1-3 hydroxy groups or COOR ^{13 5} - alkyl, or C ¹ -C ⁵ - alkoxy, cyano, from -CF ₃ and nitro One or more groups can be substituted at any position leading to the appropriate compound.

  The aryl group can be partially hydrogenated and then can further carry keto and / or exoalkylidene as an alternative to the above substitutions. Partially hydrogenated phenyl means for example cyclohexadienyl, cyclohexenyl or cyclohexyl. A partially hydrogenated, substituted naphthalene system is, for example, 1-tetralone or 2-tetralone.

The monocyclic or bicyclic heteroaryl group optionally comprises 1 to 9 groups selected from a nitrogen atom, an oxygen atom, a sulfur atom or a keto group, of which a maximum of 4 nitrogen atoms There can be up to 2 oxygen atoms, up to 2 sulfur atoms and / or up to 2 keto groups.
Any subcombination of these groups is possible. A heteroaryl group can be hydrogenated at one or more positions.

  Monocyclic heteroaryl groups include, for example, pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, 1H- and 4H-pyrazole, 1H- And 2M-pyrrole, oxazole, thiazole, furazane, 1H- and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.

  Bicyclic heteroaryl groups are, for example, phthalidyl, thiofuralidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indronyl, dihydroindronyl, isoindolonyl, dihydroindronyl, benzofuranyl, benzo [b] Thienyl, benzo [c] thienyl, pyrazolo [1,5-a] pyridyl, benzimidazolyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinyl, quinolinyl, isoquinolinyl, quinolonyl, Isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, dihydrophthalazinyl, 1,7- or 1,8-naphthyridinyl, coumarinyl, isocoumarinyl, indolizinyl, isobenzofuranyl , Azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzo It may be a furanyl group.

When the heteroaryl group is partially or fully hydrogenated, the present invention includes compounds of general formula (I) wherein R ³ is: tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl , Piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridine-4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl, chromanyl, isochromanyl, thiochromanyl, decahydroquinolinyl, tetrahydro Quinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinoline-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4- Dihydro-2H-benz [1,4] xazinyl, 1,2-dihydro [1,3] benzoxazine-4-onyl, 3, 4-dihydrobenz [1,4] oxazine-4-onyl, 3,4-dihydro-2H-benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydro Quinoxalinyl, 1H-cinnoline-4-onyl, 3H-quinazoline-4-onyl, 1H-quinazoline-4-onyl, 3,4-dihydro-1H-quinoxalin-2-onyl, 2,3-1,2 , 3,4-tetrahydro [1,5] naphthyridinyl, dihydro-1H- [1,5] naphthyridyl, 1H- [1,5] naphthylid-4-onyl, 5,6,7,8-tetrahydro-1H-naphthyridine -4-onyl, 1,2-dihydropyrido [3,2-d] [1,3] oxazine-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.

A mono- or bicyclic heteroaryl group is optionally a C ₁ -C ₅ -alkyl group optionally substituted by 1 to 3 hydroxy groups or 1 to 3 -COOR ¹³ groups, or C _1- It can be substituted by one or more substituents selected from C ₅ -alkoxy groups, halogen atoms, and / or exomethylene groups. Substituents can optionally also be attached directly to heteroatoms (eg, nitrogen atoms) if possible. The present invention also includes N-oxides.

Where appropriate, suitable hydroxy protecting groups that are necessary are all conventional hydroxy protecting groups known to those skilled in the art, in particular silyl ethers or esters of C ₁ -C ₁₀ organic acids, C ₁ -C ₅ ethers, Benzyl ether or benzyl ester. Conventional hydroxy protecting groups are described in detail in TW Greene, PGM Wuts “Protective Groups in Organic Synthesis”, 2nd E ditione, John Wiley & Sons, 1991. The protecting group is preferably an alkyl-, aryl- or mixed alkylaryl-substituted silyl group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or a triisopropylsilyl group (TIPS), or another standard hydroxy protecting group such as a methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl or tetrahydropyranyl group.

The compounds of the invention of general formula (I) can exist as stereoisomers due to the presence of asymmetric centers. The present invention relates to all possible diastereomers as racemate and in mirror image pure form. The term stereoisomer also includes all possible diastereomers and positional isomers and tautomers (eg, keto-enal tautomers), where diastereomers of the present invention exist, Thus, the present invention relates to this as well.
The compounds of the present invention may also be in the form of salts with pharmacologically acceptable anions, such as hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate. It can be present in the form of an acid salt, mesylate, citrate or oxalate.

  The present invention also encompasses pharmacologically suitable derivatives or prodrugs of the compounds of general formula (I). Derivatives or prodrugs refer, for example, to compounds of general formula (I), or to compounds of general formula (I), esters, ethers or amides of other compounds that are metabolized in the body. Suitable compounds are listed, for example, in Hans Bundgaard (Herausg.), Design of Prodrugs, Elsevier, Amsterdam 1985.

Preferred embodiment :
A subgroup of the compounds of the invention of general formula (I) is that R ¹ and R ² are independently of each other a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group , (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) -alkylthio group, (C ₁ -C ₅ ) -perfluoroalkyl group, cyano group, nitro group, or —NR ⁹ R ^9a group. Those compounds.
A preferred group of compounds of general formula (I) are those compounds wherein Y is an oxygen atom, a sulfur atom or a methylene group.

A further preferred group of compounds of the general formula (I) are those compounds wherein R ³ is based on optionally substituted aryl or heteroaryl. A more preferred group of compounds of general formula (I) are aryl or heteroaryl groups in which R ³ is optionally substituted, preferably naphthyl, phthalidyl, isoindolyl, dihydroidyl, dihydroisoindolyl, dihydroisoquinolyl. Nyl, thiophthalidyl, benzofuranyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, chromanyl, isochromanyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-pyrazolyl Those compounds selected from the group consisting of [1,5-a] pyridyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole and indolyl groups.

A further preferred group of compounds of the general formula (I) are those compounds wherein R ^3a is a hydrogen atom or a (C ₁ -C ₅ ) -alkyl group.
A further preferred group of compounds of the general formula (I) are R ⁴ , R ⁵ , R ⁶ and R ^6a , independently of one another, a hydrogen atom, a halogen atom or an optionally substituted (C ₁ -C ₁₀ ) -alkyl Those compounds that are groups.

A further preferred group of compounds of the general formula (I) are those in which R ¹ and R ² are, independently of one another, a hydrogen atom, a halogen atom or an optionally substituted (C ₁ -C ₁₀ ) -alkyl group A compound.
A further preferred group of compounds of the general formula (I) are those compounds in which the substituents R ¹¹ and R ¹² are in each case a hydrogen atom.
A further preferred group of compounds of the general formula (I) are those compounds in which the substituent R ¹⁴ is a fluorine atom or a trifluoromethyl group.

A particularly preferred group of compounds of the general formula (I) is that R ¹ , R ² , R ⁴ , R ⁶ and R ^6a are independently of one another substituted with a hydrogen atom, a halogen atom or optionally substituted (C ₁ -C ₁₀ ) -Alkyl group, Y is an oxygen atom, sulfur atom or methylene group, R ^3a is a hydrogen atom or (C ₁ -C ₅ ) -alkyl group, and R ¹¹ and R ¹² are each hydrogen. An atom, R ¹⁴ is a fluorine atom or a trifluoromethyl group, and R ³ is an optionally substituted aryl or heteroaryl group, preferably naphthyl, phthalidyl, isoindolyl, dihydroidyl, dihydroisoindolyl , Dihydroisoquinolinyl, thiophthalidyl, benzofuranyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, chromanyl, isochromanyl, indazo Benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, pyrazolo- [1,5-a] pyridyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole and indolyl groups Those compounds selected from the group consisting of:

  Any additional possible combinations of the above subgroups and substituents indicated as being preferred by their general and / or specific meaning are to be considered as embraced by the present invention.

Biological activity :
The anti-inflammatory effect of compounds of general formula I has been tested in animal experiments by testing in haze oil-induced inflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). For this purpose, a haze oil solution in ethanol was administered locally to the animal's ear. Test substances were also administered locally or systemically at the same time as or after 2 hours of administration of the haze oil. After 16-24 hours, ear weight was measured as a dose for inflammatory edema, peroxidase activity as a dose for granulocyte migration, and elastase activity as a dose for neutrophil granulocyte migration. In this test, the compounds of general formula I inhibit three of the above inflammatory parameters after local and systemic and systemic administration.

The binding of substances to glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is produced recombinantly. Tested with the help of different receptors. A cytosolic preparation of Sf9 cells infected with a recombinant baculovirus encoding GR is used for binding studies. Compared to the control substance [ ³ H] -dexamethasone, the substance shows a very high affinity for GR. Thus, IC ₅₀ (GR) = 20 nM and IC ₅₀ (PR)> 1 μM are measured for the compound from Example 1 and IC ₅₀ (GR) = 30 nM and IC ₅₀ (PR)> 1 μM are from Example 2. Measured for compounds.

GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is regarded as an essential molecular mechanism for the anti-inflammatory effects of glucocorticoids. This inhibition is generated by the interaction of GR with other transcription factors such as AP-1 and NF-κ-B (for an overview see Cato, ACB and Wade E, BioEssays 18,371-378 1996 ).
The compounds of general formula I according to the invention inhibit the secretion of cytokine IL-8 induced by lipopolysaccharide (LPS) in the human monocyte cell line THP-1. Cytokine concentrations were determined in the supernatant by a commercially available ELISA kit.

  One of the most undesirable effects of glucocorticoid treatment is the so-called “steroid diabetes” (see Hatz, HJ, Glucocorticoide: Immun allogische Grundlagen, Pharmak all ogie und Therapierichtlinien, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998) . The reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible for this and by free amino acids produced from protein degradation (glucocorticoid catabolism). The key enzyme of catabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme is determined spectrophotometrically from liver homogenates and provides a good measure for the undesired metabolic effects of glucocorticoids. For measurement of TAT induction, animals are sacrificed 8 hours after administration of the test substance, the liver is removed, and TAT activity in the homogenate is measured. In this test, compounds of general formula I induce little or no tyrosine aminotransferase at doses where they have anti-inflammatory activity.

Medical symptoms :
Based on their anti-inflammatory and also anti-allergenic, immunosuppressive and anti-proliferative effects, the compounds of general formula I according to the invention can be used for the treatment or prevention of the following pathological conditions in patients, especially mammals and preferably humans: As used herein, the term “disease” refers to the following symptoms:

(I) Lung diseases associated with inflammation, allergies and / or proliferative processes:
-Chronic obstructive pulmonary disease of any origin, mainly bronchial asthma;
-Bronchitis of different origin;
-All forms of restrictive lung disease, mainly allergic alveolitis;
-All forms of pulmonary edema, mainly toxic pulmonary edema;
-Sarcoidosis and granulomatosis, especially Beck's disease;

(Ii) rheumatic diseases / autoimmune diseases / joint diseases associated with inflammation, allergies and / or proliferative processes:
-All forms of rheumatic disease, in particular rheumatoid arthritis, acute rheumatic fever, rheumatic polymyalgia;
-Reactive arthritis;
-Inflammatory parenchyma disease of other origins;
-Joint inflammation symptoms in the case of osteoarthritis (arthropathy);
-Traumatic arthritis;
-Collagen disease of any origin, such as systemic extematodes, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, Still's syndrome, Felty syndrome;

(Iii) allergies associated with inflammatory and / or proliferative processes:
-All forms of allergic reactions such as angioedema, hay fever, insect bites, pharmaceutical agents, blood derivatives, contrast media, etc., hypersensitivity shock, urticaria, contact dermatitis;
(Iv) Vascular inflammation (vasculitis):
-Panarteritis nodules, temporal arteritis, erythematous erythema;

(V) Dermatological disorders associated with inflammation, allergies and / or proliferative processes:
-Atopic dermatitis (mainly in children);
-Psoriasis;
-Pore red rash;
-Erythematous diseases induced by different toxicities such as radiation, chemicals, burns, etc .;
-Bullous skin disease;
-Diseases of lichenoid groups;
-Itching (eg of allergic origin);
-Seborrheic edema;
-Shusa;
-Pemphigus vulgaris;
-Erythematous exudative polymorphs;
-Balanitis;
-Vulvitis;
-Hair loss, eg alopecia area;
-Alopecia areata;
-Cutaneous T-cell lymphoma;

(Vi) renal disease associated with inflammation, allergies and / or proliferative processes:
-Nephrotic syndrome;
-All nephritis;
(Vii) Liver disease associated with inflammation, allergies and / or proliferative processes:
-Acute hepatocyte degradation;
Different origins such as viruses, toxicity, pharmaceutical agents-induced acute hepatitis;
-Chronic aggressive hepatitis and / or chronic intermittent hepatitis;

(Viii) Gastrointestinal diseases associated with inflammation, allergies and / or proliferative processes:
-Localized enteritis (Crohn's disease);
-Ulcerative colitis;
-Gastritis;
-Reflux esophagitis;
-Other origins such as gastroenteritis of the inherent sprue;

(Ix) Rectal diseases attached by inflammation, allergy and / or proliferative processes:
-Anal edema;
-Cracks;
− 痔 痔;
-Idiopathic proctitis;

(X) Ocular diseases associated with inflammation, allergies and / or proliferative processes:
-Allergic keratitis, uveitis, iritis;
-Conjunctivitis;
-Blepharitis;
-Optic neuritis;
-Choroiditis;
-Sympathetic ophthalmitis;

(Xi) diseases of the ear-nose-throat region associated with inflammation, allergies and / or proliferative processes:
-Allergic rhinitis, hay fever;
-Otitis externa caused by contact dermatitis, infection, etc .;
-Otitis media;

(Xii) neurological diseases associated with inflammation, allergies and / or proliferative processes;
-Cerebral edema, mainly tumor-induced cerebral edema;
-Multiple sclerosis;
-Acute meningitis;
-Meningitis;
-Various forms of convulsions, such as infantile occipital convulsions;

(Xiii) blood diseases associated with inflammation, allergies and / or proliferative processes:
-Acquired hemolytic anemia;
-Idiopathic thrombocytopenia;

(Xiv) tumor diseases associated with inflammation, allergies and / or proliferation processes:
-Acute lymphoblastic leukemia;
-Malignant lymphoma;
-Lymphogranulomatosis;
-Lymphosarcoma;
-Intensive metastases mainly in breast, bronchial and prostate cancer;

(Xv) Endocrine diseases associated with inflammation, allergies and / or proliferative processes:
-Endocrine orbital disease;
-Thyroid crisis;
-De Kervan thyroiditis;
-Hashimoto thyroiditis;
-Basedow's disease;

(Xvi) organ and tissue transplantation, versus host graft disease;
(Xvii) Severe shock conditions such as hypersensitivity shock, systemic inflammatory response syndrome (SIRS);
(Xviii) vomiting associated with inflammation, allergies and / or proliferative processes:
-In combination with a 5-HT3 antagonist in vomiting e.g. induced by cell growth inhibition;
(Xix) pain of inflammatory origin, eg back pain;

(Xx) Replacement therapy for:
Congenital-secondary adrenal insufficiency, eg congenital adrenal syndrome;
-Acquired-secondary adrenal dysfunction, such as Addison's disease, autoimmune adrenalitis, post-infectious tumor, metastasis, etc.
Congenital secondary adrenal insufficiency, eg congenital hypopituitarism;
-Acquired secondary adrenal insufficiency, such as post-infectious tumors, etc.

Agents comprising stereoisomers of general formula I exhibit specific efficacy against the following diseases:
1. Embryonic disease 2. Rheumatic diseases / autoimmune diseases Skin disease 4. 4. Degenerative joint disease Vascular inflammation Anti-host graft disease 7. 7. Severe state of shock 8. Vomiting associated with inflammation, allergies and / or proliferative processes Inflammation-related pain

  Furthermore, the compounds of general formula I according to the invention can be used for the treatment and prevention of additional pathological conditions not mentioned above, where synthetic glucocorticoids are used (in this regard, Hatz, HJ , Glucocorticoide: see Immun allogische Grundlagen, Pharmak all ogie und Therapierichtlinien, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998).

All the above mentioned indications are described in more detail in Hatz, HJ, Glucocorticoide: Immun all ogische Grundlagen, Pharmak all ogie und Therapierichtlinien, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998.
Appropriate doses for therapeutic effects in the above pathological conditions will vary and will be treated, eg, the ability of the compound of general formula (I), disease (eg, height, weight, sex, etc.), mode of administration and treatment Depends on the nature and severity of the condition to be treated and its use as a prophylactic or therapeutic agent.
The present invention relates to the use of a compound of the invention for the manufacture of a pharmaceutical composition.

The present invention further provides the following:
(I) a compound of the invention of the general formula (I) for the manufacture of a pharmaceutical composition for the treatment or prevention of inflammatory processes and in particular for the treatment of diseases (as defined above), or thereof One use of the mixture
(ii) including administering a pharmaceutically effective amount of a compound of general formula (I) to a patient in need of such treatment, preferably a mammal, especially a human, to reduce or inhibit a disease or condition. Methods for the treatment or prevention of inflammatory processes, and in particular for the treatment of diseases (as defined above);
(Iii) one of the compounds of the invention or a mixture thereof and, if appropriate, at least one pharmaceutical excipient, which has an anti-inflammatory effect, in particular for the treatment of diseases (as defined above) A pharmaceutical composition comprising a carrier.

  In general, satisfactory results can be expected in animals if the daily dose comprises a compound of the invention in the range of 1 μg to 100,000 μg per kg body weight. For larger animals, such as humans, recommended daily doses range from 1 μg to 100,000 μg per kg body weight. A dose of 10-30,000 μg per kg body weight is preferred, and a dose of 10-10,000 μg per kg body weight is more preferred. For example, this dose is suitably administered more than once per day. For treatment of acute shock (eg, hypersensitive shock), a single dose can be given that is significantly greater than the doses mentioned above.

Pharmaceutical products based on the new compounds include carrier substances, fillers, substances that affect degradation, binders, humectants, lubricants, adsorbents, diluents, flavor modifiers, colorants commonly used in pharmaceutical techniques. , Etc. are carried out by means known in the art and converted into the desired dosage form. In this case, see Remingt on's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Penns Il vania (1980).
For oral administration, especially tablets, coated tablets, capsules, pills, powders, granules, fragrances, suspensions, emulsions or solutions are suitable.

For parenteral administration, injection and infusion are possible.
For intra-articular injection, correspondingly prepared crystalline suspensions can be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (eg, in the form of enemas), and ointments for systemic and local treatment.

For new pulmonary administration of compounds, the compounds can be used in the form of aerosols and inhalants.
For topical administration to the eye, outer ear, middle ear, nasal cavity and sinuses, the novel compounds can be used as drops, ointments and tinctures in the corresponding pharmaceutical formulations.
For topical application, formulations in gels, ointments, fat ointments, creams, pastes, powders, suspensions, emulsions and solutions are possible. The dosage of the compounds of general formula I should be 0.01% to 20% in these formulations in order to achieve a sufficient pharmacological action.

The present invention also comprises a compound of general formula I according to the present invention as a therapeutically active ingredient. In addition, the compounds of general formula I according to the invention are part of the invention as therapeutically active ingredients together with pharmaceutically compatible and acceptable excipients and / or carriers.
The compounds of the invention of general formula (I) can also be formulated and / or administered in combination with further active ingredients, where appropriate.

    Thus, the present invention also relates to a combination therapy or a combined composition, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I) or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising a salt is administered simultaneously with one or more pharmaceutical agents (optionally in the same composition) or sequentially with said pharmaceutical agent to treat one of the above pathological conditions Is done. For example, for the treatment of rheumatoid arthritis, osteoarthritis, CPOD (chronic obstructive pulmonary disease), asthma or allergic rhinitis, the compound of formula (I) of the present invention is one for the treatment of such conditions. Or it can be combined with a plurality of pharmaceutical agents. When such a combination is administered by inhalation, the pharmaceutical agents to be combined can be selected from the following list:

PDE4 inhibitors, including inhibitors of PDE4D isoforms;
A selective β.

Muscari receptor antagonists (eg M1, M2 or M3 antagonists, eg more selective M3 antagonists), eg ipratropium bromide, tiotripium bromide, oxitropium bromide, pirenzepine or telenzepine:
• A chemokine receptor function modulator (eg, a CCR1 receptor antagonist); or • An inhibitor of p38 kinase function.

  With respect to another subject of the invention, such a combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat COPD, asthma or allergic rhinitis and It can also be administered orally, by inhalation or orally in combination with xanthine (eg aminophylline or theophylline).

Preparation method :
The compounds of the invention of the general formula (I) can be obtained by various means. The preparation methods described below form part of the present invention.
Unless otherwise stated, the substituents used in the following methods have the same meaning as defined in the section “Short Description of the Invention”, eg the section “Detailed Description of the Invention”.

In general, compounds of general formula (I) are prepared by reaction of an aldehyde of general formula (II) with an amine of general formula R ³ —NH ₂ and subsequent reduction of the resulting imine. The order of the reactions is summarized in the following scheme.

Scheme 1 : Reaction of a compound of general formula (II) to obtain a compound of general formula (I) :

The compounds of general formula (II) used in this order are obtained by the various methods of the present invention.
Method A: Preparation of compounds of general formula (II) from compounds of general formula (IX) through intermediate (III A) :
In the first step of Method A, a compound of general formula (IX) (wherein R is preferably a C ₁ -C ₅ -alkyl group) is reacted to give a compound of 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.

Scheme 2 : Preparation of compounds of general formula (VIII) :

When R ^3a in the compound of general formula (VIII) is a hydrogen atom, the reaction occurs by reduction, for example by catalytic hydrogenation of compound (IX) with elemental hydrogen over a suitable metal catalyst. A compound of general formula (VIII) (wherein R ^3a is a cyano or alkyl group) reacts a compound of general formula (IX) with a cyanide ion or an organometallic alkyl compound (eg, an organic copper compound). Can be obtained. Those methods are known in the art.

  In the next step, the carboxylic acid ester of the general formula (VIII) obtained by this means is converted into an alcohol of the general formula (VII) by a method known in the art using a suitable reducing agent (eg hydrogenation). Reduced by lithium aluminum) (Scheme 3).

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

  Aldehydes of general formula (VI) are obtained by careful oxidation of alcohols of general formula (VII) by methods known in the art (Scheme 4):

Scheme 4 : Preparation of compounds of general formula (VI) :

The aldehyde of the general formula (VI) is reacted with a suitable organometallic reagent M-CF ₂ R ¹⁴ , thus allowing the introduction of the group —CF ₂ R ¹⁴ into the molecule (Scheme 5), where M is an electrophilic leaving group. Examples of suitable organometallic reagents are 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). On the other hand, organolithium or organomagnesium compounds can also be used to introduce the group CF ₂ R ¹⁴ . In this case, an alcohol of the general formula (V) is obtained.

Scheme 5 : Preparation of compounds of general formula (V) :

  Ketones of general formula (IV) are obtained by oxidation of alcohols of general formula (V) using methods known in the art (eg using Dess-Martin periodinane as the oxidative system) (Scheme 6) .

Scheme 6 : Preparation of compounds of general formula (IV) :

  The ketone of general formula (IV) is then converted to its corresponding cyanohydrin of general formula (III A) (Scheme 7). Suitable reagents are, for example, calcium or copper cyanide or trimethylsilyl cyanide. According to the reagent used, R in the general formula (III A) is a hydrogen atom or a trimethylsilyl group.

Scheme 7 : Preparation of compounds of general formula (III A) :

  A cyanohydrin of general formula (III A), if appropriate, is converted to an aldehyde of general formula (II) by removal of the trimethylsilyl group and by a suitable reducing agent (eg diisobutylaluminum hydride) (Scheme 8). .

Scheme 8 : Preparation of compound of general formula (II) from compound of general formula (III A) :

Method B: Preparation of compounds of general formula (II) from compounds of general formula (IX) through intermediate (III B) :
The synthesis of precursor compounds of general formulas (VII), (VII), (VI), (V) and (IV) proceeds in method B as in method A.
The aldehyde of general formula (IV) is then converted to an unsaturated alcohol of general formula (III B) with a suitable organometallic reagent (eg, a Grignard compound such as vinylmagnesium bromide) (Scheme 9). .

Scheme 9 : Preparation of compounds of general formula (III B) :

  Compounds of general formula (II) are obtained by oxidizing double bonds in compounds of general formula (III B) (for example with ozone or transition metal oxides such as osmium tetroxide followed by suitable oxidation By decomposition with an agent such as sodium periodate (Scheme 10).

Scheme 10 : Preparation of compounds of general formula (II) from compounds of general formula (III B) :

Method C: Preparation of compounds of general formula (II) from compounds of general formula (XIII) :
A compound of general formula (II) is obtained from a compound of general formula (XIII) known in the art from the latter, and the general formula R ¹⁴ CF ₂ —C (═O) —CO ₂ R (where R Is preferably a C ₁ -C ₅ -alkyl group) and is reacted with an α-ketoester of the general formula (XII), optionally catalyzed by a chiral-Lewis acid in the final reaction. A compound is obtained (Scheme II).

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

  Diols of general formula (XI) are obtained from compounds of general formula (XII) by reducing the ester functionality by methods known to those skilled in the art (eg with lithium aluminum hydride) (Scheme 12) .

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

  This diol (XI) can be converted to a compound of general formula (X) by reduction of double bonds (eg, by catalytic hydrogenation with elemental hydrogen over a suitable metal catalyst) (Scheme 13).

Scheme 13 : Preparation of compounds of general formula (X) :

Aldehydes of the general formula (II) (wherein the substituents R ^3a and R ⁴ have a hydrogen atom) are obtained from those diols of the general formula (X) by oxidizing the terminal hydroxy group (scheme) 14).

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

As an alternative to the reaction sequence shown above for Method C, an ester of general formula (XII) can also be reduced to its corresponding aldehyde, which is directly coupled with a primary amine of general formula R ³ —NH ₂ . Can be reacted. Subsequently, the isolated double bond present in the right ring of the compound is hydrogenated with an appropriate reducing agent. This alternative sequence also results in compounds of general formula (I), wherein the substituents R ^3a and R ⁴ have the meaning of hydrogen atoms.

Synthesis 1: Preparation of compound of general formula (VII) :
A. 2- (chroman-4-yl) ethanol :
2.27 g ethyl (2-chroman-4-yl) acetate (J. Med. Chem. 44, (2001), pp. 1085-1098) together with 800 mg lithium aluminum hydride in 50 ml THF at 0 ° C Stir for 2 hours. Saturated ammonium chloride solution and ethyl acetate are added to the mixture and then filtered through porous diatomaceous earth. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine and dried over sodium sulfate. 1.9 g of 2- (chroman-4-yl) ethanol is obtained as a crude crop.
¹ H-NMR (CDCI ₃ ): δ = 1.72-1.90 (m, 2H), 2.0-2.2 (m, 2H), 2.96-3.09 (m, 1 H), 3.80 (t, 2H), 4.13-4.25 ( m, 2H), 6.79 (d, 1 H), 6.87 (t, 1 H), 7.10 (t, 1 H), 7.14 (d, 1 H).

B. 2- (4-Methylchroman-4-yl) ethanol :
11.5 ml of methylmagnesium chloride solution (3.3 M in THF) was added to 7.3 g of ethyl E / Z- (chroman-4-ylidene) acetate (J. Med. Chem. 44, 55 ml of THF at 0 ° C). (2001), pp. 1085-1098), 100 mg of copper (I) chloride and 5.1 ml of chlorotrimethylsilane, slowly adding the temperature always below 5 ° C. The mixture is stirred for 1 hour at 0 ° C. and 10 hours at room temperature. Saturated ammonium chloride solution is added to the mixture and then extracted with ether. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated under vacuum. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90: 10) yields ethyl 2- (4-methylchroman-4-yl) acetate as a crude product.

This is mixed with 1 g of lithium aluminum hydride in 50 ml of THF at 0 ° C. and stirred at 0 ° C. for 1.5 hours. The mixture is carefully added to the ammonium chloride solution and diluted with ethyl acetate. It is filtered through porous diatomaceous earth and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium acetate and concentrated under vacuum. 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 (CDCI ₃ ): δ = 1.36 (s, 3H), 1.74 (dd di H), 1.91-2.11 (m, 3H), 3.57-3.75 (m, 2H), 4.10-4.28 (m, 2H ), 6.79 (d, 1 H) ₁ 6.89 (t, 1 H), 7.08 (t, 1 H), 7.22 (d, 1 H).

C. The following can be prepared analogously by the methods described:
2- (6-methylchroman-4-yl) -ethanol;
2- (7-methylchroman-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-tetrahydronaphthalin-1-yl) -ethanol;
2- (2-methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanol;

2- (4-methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanol;
2- (5-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanol;
2- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanol;
2- (6-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanol;
2- (6-Fluoro-1,2,3,4-tetrahydronaphthalin-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: Preparation of compound of general formula (VI) :
A. 2- (chroman-4-yl) ethanal :
1.7 ml DMSO in 25.0 ml dichloromethane is added to 1 ml oxalyl chloride in 25.0 ml dichloromethane at -78 ° C. After 5 minutes, 1.9 g of 2- (chroman-4-yl) ethanol is added dropwise at −78 ° C. in 25.0 ml of dichloromethane. After 15 minutes, 7 ml of triethylamine is added and the mixture is slowly warmed to RT. It is washed with water, brine, 1% sulfuric acid and saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. 1.81 g of the title compound are obtained as a yellow oil.
¹ H-NMR (CDCI ₃ ): δ = 1.73-1.86 (m, 1 H) ₁ 2.11-2.28 (m, 1 H), 2.75 (dd, 1 H), 2.93 (dd, 1 H), 3.43-3.56 (m, 1 H), 4.11-4.25 (m, 2H), 6.81 (d, 1 H), 6.87 (t, 1 H), 7.03-7.17 (m, 2H), 9.88 (s, IH).

B. 2- (4-Methylchroman-4-yl) ethanal :
1.0 ml DMSO in 25.0 ml dichloromethane is added to 0.58 ml oxalyl chloride in 25.0 ml dichloromethane at −78 ° C. After 5 minutes, 1.2 g of 2- (methylchroman-4-yl) ethanol is added dropwise at −78 ° C. in 25.0 ml of dichloromethane. After 15 minutes, 4 ml of triethylamine is added and the mixture is slowly warmed to RT. It is washed with water, brine, 1% sulfuric acid and saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90: 10) yields 970 mg of 2- (4-methylchroman-4-yl) ethanal as a colorless oil.

¹ H-NMR (CDCI ₃ ): δ = 1.48 (s, 3H), 1.92 (ddd, 1 H), 2.12 (ddd, 1 H), 2.59 (dd, 1 H), 2.69 (dd, 1 H), 4.11-4.29 (m, 2H), 6.83 (d, 1 H), 6.92 (t, 1 H), 7.12 (t, 1 H), 7.23 (d, 1 H), 9.66 (s, 1 H).

C. The following can be prepared analogously by the methods described:
2- (6-Methylchroman-4-yl) -ethanal;
2- (7-methylchroman-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-tetrahydronaphthalin-1-yl) -ethanal;
2- (2-methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanal;

2- (4-Methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanal;
2- (5-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanal;
2- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanal;
2- (6-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -ethanal;
2- (6-Fluoro-1,2,3,4-tetrahydronaphthalin-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: Preparation of compound of general formula (V) :
A. 2- (chroman-4-yl) -1-trifluoromethylethanol :
2 ml of tetrabutylammonium fluoride solution (1M in THF) was added to a solution of 1.8 g 2- (chroman-4-yl) ethanal and 4.6 ml trifluoromethyltrimethylsilane in 60 ml THF at 0 ° C. Add to solution and stir for 1 hour. With the spatula tip, solid tetrabutylammonium fluoride is added once more and water is added. The mixture is extracted with ethyl acetate and the organic phase is washed with brine and dried over sodium sulfate. Chromatography on silica gel (hexane / ethyl acetate 95: 5 → 90: 10) gives 2.1 g of 2- (chroman-4-yl) -1-trifluoromethylethanol as a mixture of diastereomers. .
¹ H-NMR (CDCI ₃ , selected signal): δ = 1.76-1.97 (m, 2H), 1.98-2.34 (m, 2H), 3.08-3.25 (m, 1 H), 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-trifluoromethylethanol :
0.87 ml tetrabutylammonium fluoride solution (1M in THF) was added to 870 mg 2- (4-methylchroman-4-yl) ethanal and 2 ml trifluoromethyltrimethyl in 30 ml THF at 0 ° C. Add to solution of silane and stir for 1 hour. With the spatula tip, solid tetrabutylammonium fluoride is added once more and water is added. The mixture is extracted with ethyl acetate and the organic phase is washed with brine and dried over sodium sulfate. 1.2 g of 2- (4-methylchroman-4-yl) -1-trifluoromethylethanol are obtained as a brown oil (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.34 (s, 3H), 1.35 (s, 3H), 1.68 (ddd, 1 H), 1.78 (ddd, 1 H), 1.85 (dd, 1 H), 1.90-2.04 (m), 2.05-2.14 (m), 2.31 (ddd, 1 H), 3.73-3.83 (m, 1 H), 3.97-4.22 (m), 6.77 (d, 1 H, Diastereomer. A + B), 6.80-6.87 (m, 1 H, diastereomer. A + B), 7.0-7.1 (m), 7.17-7.21 (m).

C. The following can be prepared analogously by the above method:
2- (6-methylchroman-4-yl) -1-trifluoromethyl-ethanol;
2- (7-methylchroman-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-trifluoromethyl-ethanol;
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-trifluoromethylethanol;
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: Preparation of compounds of general formula (IV) :
A. 3- (chroman-4-yl) -1,1,1-trifluoropropan-2-one :
54.0 g Dess-Martin periodinane in 650 ml dichloromethane was mixed with a solution of 9.0 g 2- (chroman-4-yl) -1-trifluoromethylethanol in 65 ml dichloromethane at room temperature and for 10 hours. Stir. The mixture is mixed with saturated sodium bicarbonate solution, diluted with diethyl ether and stirred with sodium thiosulfate solution for 30 minutes. The organic phase is separated and washed with water. It is dried over sodium sulfate and concentrated under vacuum. 7.95 g of 3- (chroman-4-yl) -1,1,1-trifluoropropan-2-one are obtained.

¹ H-NMR (CDCI ₃ ): δ = 1.62-1.77 (m, 1 H), 2.08-2.22 (m, 1 H), 2.94 (dd, 1 H), 3.11 (dd, 1 H), 3.39-3.50 (m, 1 H), 4.02-4.20 (m, 2H), 6.75 (d, 1 H), 6.81 (t, 1 H), 6.97 (d, 1 H), 7.05 (t, 1 H).

B. 3- (4-Methylchroman-4-yl) -1,1,1-trifluoropropan-2-one :
7.8 g Dess-Martin periodinane in 100 ml dichloromethane is mixed at 0 ° C. with a solution of 1.2 g 2- (chroman-4-yl) -1-trifluoromethylethanol in 20 ml dichloromethane and 0 ° C. For 1 hour. The mixture is mixed with saturated sodium bicarbonate solution, diluted with diethyl ether and stirred with sodium thiosulfate solution for 30 minutes. The organic phase is separated and washed with water. It is dried over sodium sulfate and concentrated under vacuum. 1.1 g of 3- (4-methylchroman-4-yl) -1,1,1-trifluoropropan-2-one are obtained.
¹ H-NMR (CDCI ₃ ): δ = 1.50 (s, 3H), 2.0 (dd di H) ₁ 2.25 (dd di H), 3.10 (s, 2H), 4.10-4.28 (m, 2H), 6.83 ( d, 1 H), 6.90 (t, 1 H), 7.13 (t, 1 H), 7.18 (d, 1 H).

C. The following can be prepared analogously by the above method:
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-pentafluorobutan-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: Preparation of compounds of general formula (III A) :
3- (chroman-4-yl) -2-trifluoromethyl-2-trimethylsilyloxy-propionitrile :
140 mg of 3- (chroman-4-yl) -1,1,1-trifluoropropan-2-one in 2.5 ml of dichloromethane is mixed with 124 mg of trimethylsilyl cyanide at room temperature and stirred for 4 hours. (J. Med. Chem. 2003, (46), pp. 2494-2501). The mixture is added to water and extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated under vacuum. 204 mg of the title compound are obtained as an oil.

Synthesis 6: Preparation of compound of general formula (II) from compound of general formula (III A) :
3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropionaldehyde :
0.4 ml of diBAL-H solution (1.5 M in toluene) was added to 204 mg of 3- (chroman-4-yl) -2-trifluoromethyl-2-trimethylsilyloxypro in 5 ml of toluene at -70 ° C. Add to the pionitrile and stir the mixture at -70 ° C for 4 hours. Following the addition of 1 ml of ethyl acetate, warm to room temperature, add 1 M sulfuric acid and stir for 210 hours. The mixture is diluted with water and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and dried under vacuum. The remaining oil is taken up in 1 ml of THF, mixed with tetrabutylammonium fluoride solution (1M in THF) and stirred at room temperature for 6 hours. Add water followed by extraction with ethyl acetate, wash with brine and concentrate under vacuum. 124 mg of the title compound are obtained as an orange oil.
MS (ei): M + = 274

Synthesis 7: Preparation of compound of general formula (III B) :
A. 1- (chroman-4-yl) -2-trifluoromethyl-3-buten-2-ol :
A solution of 7.4 g 3- (chroman-4-yl) -1,1,1-trifluoropropan-2-one in 75 ml THF is added to 33.3 ml vinylmagnesium bromide solution (1M in THF). Add at room temperature. The mixture is stirred at room temperature for 4 hours and then added to saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated under vacuum. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90: 10) gave 7.0 g of 1- (chroman-4-yl) -2-trifluoromethyl-3-buten-2-ol. Obtained as a yellow oil (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.8-1.9 (m), 1.97 (dd, 1 H), 2.01-2.37 (m), 2.93-3.03 (m, 1 H), 3.03- 3.12 (m, 1 H), 4.05-4.27 (m), 5.53 (d, 1 H), 5.58-5.70 (m, 3H), 5.97-6.17 (m, 2H), 6.73-6.94 (m, 4H) ₁ 7.02 (d, 1 H), 7.04-7.13 (m, 2H), 7.21 (d, 1 H).

B. 1- (4-Methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol :
A solution of 1.1 g 3- (4-methylchroman-4-yl) -1,1,1-trifluoropropan-2-one in 30 ml THF was added to 9.2 ml vinylmagnesium bromide solution (in THF, To 1M) at room temperature. The mixture is stirred at room temperature for 5 hours and then added to saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated under vacuum. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90: 10) gave 930 mg of 1- (4-methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol Is obtained as an oil.
MS (ei): M + = 286

C. The following can be prepared analogously by the above method:
1- (6-methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol;
1- (7-methylchroman-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-trifluoromethyl-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: Preparation of compound of general formula (II) from compound of general formula (III B) :
A. 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropionaldehyde :
Ozone was dissolved in a solution of 7.0 g 1- (chroman-4-yl) -2-trifluoromethyl-3-buten-2-ol in 450 ml dichloromethane and 120 ml methanol at -70 ° C. Pass until it turns blue. Argon is then passed through the solution for 1 minute, 3.6 ml of dimethyl sulfide is added, and the mixture is stirred at -70 ° C for 1 hour. It is slowly warmed to room temperature and then stirred for 10 hours. The mixture is added to water and extracted with dichloromethane. The combined organic phases are dried and concentrated under vacuum. 6.6 g of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropionaldehyde is obtained as a yellow oil.
MS (ei): M + = 274.

B. 2-Hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropionaldehyde :
Ozone was dissolved in a solution of 900 mg 1- (4-methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol in 56 ml dichloromethane and 14 ml methanol at -70 ° C. Pass until the solution turns blue. Argon is then passed through the solution for 1 minute, 0.42 ml of dimethyl sulfide is added, and the mixture is stirred at -70 ° C for 1 hour. It is slowly warmed to room temperature and then stirred for 10 hours. The mixture is added to water and extracted with dichloromethane. The combined organic phases are dried and concentrated under vacuum. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90: 10) gave 330 mg of 2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropionaldehyde. Obtained as a yellow oil (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.38 (s, 3H, diastereomer. A) ₁ 1.43 (s, 3H, diastereomer. B), 1.57-1.65 (m, 2H) , 1.81 (ddd, 1 H), 2.13 (ddd, 1 H), 2.37 (d, 1 H, diastereomer. B), 2.45-2.60 (m), 2.83 (d, 1 H, diastereomer. B ), 3.69 (s, 1 H, diastereomer. A), 3.86 (s, 1 H, diastereomer. B), 3.97 (dd, 1 H, diastereomer. B), 4.08-4.35 (m) , 6.78-6.84 (m, 1 H, diastereomer. A + B), 6.88-6.95 (m, 1 H), 7.07-7.21 (m), 7.23-7.30 (m), 8.88 (s, 1 H, Diastereomers. B), 9.56 (s, 1 H, diastereomers. A).

C. The following can be prepared analogously by the above method:
2-hydroxy-3- (6-methylchroman-4-yl) -2-trifluoromethyl-propionaldehyde;
2-hydroxy-3- (7-methylchroman-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: Preparation of compound of general formula (XIII) :
4-Methylenethiochroman :
79.9 ml of n-butyllithium solution (1.6 M in hexane) is added dropwise to a solution of 40.9 g of methylphenylphosphonium bromide in 470 ml of THF at −10 ° C. The mixture is stirred for an additional 45 minutes and then 18.8 g thiochroman-4-one is added. The mixture is further mixed with 330 ml of THF and stirred at room temperature for 1 hour. The mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over sodium sulfate and encephaloma under vacuum. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90: 10) gives 11.7 g of 4-methylenethiochroman as an oil.
¹ H-NMR (CDCI ₃ ): δ = 2.8-2.9 (m, 2H) ₁ 3.03-3.13 (m, 2H), 4.98 (s, 1 H), 5.5 (s, 1 H), 6.98-7.08 (m , 1 H), 7.08-7.17 (m, 2H), 7.54 (d, 1 H).

Synthesis 10: Preparation of compounds of general formula (XII) :
A. Ethyl 2-hydroxy-3-[(2H) thiochromen-4-yl] -2-trifluoromethylpropionate :
3.54 g of binaphthol is added to a solution of 1.3 ml of titanium tetraethoxide in 10 ml of toluene at room temperature and stirred for 1 hour. A solution of 10 g 4-methylenethiochroman in 60 ml toluene and 15 ml trifluoropyruvate is added to this solution. 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 porous diatomaceous earth. The organic phase is washed with brine and dried over sodium sulfate. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90: 10) gave 19.8 g of ethyl 2-hydroxy-3-[(2H) thiochromen-4-yl] -2-trifluoromethylpropio The nate is obtained as a brown oil.

¹ H-NMR (CDCI ₃ ): δ = 1.19 (t, 3H), 3.03 (d, 1 H), 3.17 (dd, 1 H) ₁ 3.30 (dd, 1 H), 3.81 (s, 1 H), 3.87-3.97 (m, 1 H), 4.09-4.18 (m, 1 H), 6.10 (t, 1 H), 7.07-7.18 (m, 2H) ₁ 7.30 (d, 1 H), 7.42 (d, 1 H).

B. Ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate :
20 g (307 mm) zinc dust and 710 mg (2.5 mmol) lead (II) chloride are suspended in 200 ml THF and 11.2 ml (100 mmol) dibromomethane is added at room temperature. The mixture is stirred for a further 60 minutes and 33 ml (33 mmol) of a 1M solution of titanium (IV) chloride in dichloromethane are added dropwise over 40 minutes while cooling on ice. After 1 hour, 4.4 g (30 mmol) of solid chroman-4-one is added in portions at room temperature and the reaction is warmed to -30.degree. The mixture is stirred at room temperature for a further 3 hours. It is diluted with diethyl ether and the reaction mixture is carefully added to a mixture of 4M hydrochloric acid and ice. The phases are separated and subsequently extracted with diethyl ether, washed with water, dried over sodium sulfate and the solvent is removed. The crude product is purified by column chromatography on silica gel (hexane / isopropyl ether 0-20%) to give 2.75 g of 4-methylenechroman.

  0.60 ml (0.3 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene is added to 170 mg (0.60 mmol) of 1,1′-bi-2-naphthol and the red solution is stirred at room temperature for 24 hours. Stir for hours. 1.0 g (6.8 mmol) 4-methylenechroman and 2.3 g (13.6 mmol) ethyl trifluoropyruvate are added and the mixture is heated at 110 ° C. for 2 hours. Immediately after cooling, purification by column chromatography on silica gel (hexane / ethyl acetate 0-20%) yielded 1.15 g of ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- ( Trifluoromethyl) propionate is obtained.

Synthesis 11: Preparation of compounds of general formula (XI) :
1,2-dihydroxy-3-[(2H) thiochromen-4-yl] -2-trifluoromethylpropane :
8.7 g lithium aluminum hydride into a solution of 19.0 g ethyl 2-hydroxy-3-[(2H) thiochromen-4-yl] -2-trifluoromethylpropionate in 500 ml THF at 0 ° C. And the mixture is stirred for 2 hours at 0 ° C. and 1 hour at room temperature. The mixture is carefully mixed with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over sodium sulfate and concentrated under vacuum. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 80: 20) gave 11 g of 1,2-dihydroxy-3-[(2H) thiochromen-4-yl] -2-trifluoromethylpropane. To be obtained as a colorless oil.
¹ H-NMR (CDCI ₃ ): δ = 2.86 (d, 1 H), 3.02-3.11 (m, 2H), 3.23-3.33 (m, 2H), 3.54-3.70 (m, 2H), 6.13 (t, 1 H), 7.11-7.21 (m, 2H), 7.35 (d, 1 H), 7.46 (d, 1 H).

Synthesis 12: Preparation of compounds of general formula (X) :
1,2-dihydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropane :
9 g 1,2-dihydroxy-3-[(2H) thiochromen-4-yl] -2-trifluoromethylpropane in 130 ml ethanol is mixed with 9 g Raney nickel and in an autoclave at 50 bar for 2 hours. Stir under a hydrogen atmosphere. 9 g of Raney nickel are added again and the reaction with hydrogen at 50 bar is continued for 5 hours. The mixture is filtered by suction through porous diatomaceous earth and concentrated under vacuum. 8.1 g of 1,2-dihydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropane are obtained as a yellow oil (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.92 (dd, 1 H), 1.95-2.07 (m), 2.18 (dd, 1 H), 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 (diH), 3.96 (diH), 7.01-7.08 (m) , 7.09-7.20 (m).

Synthesis 13: Preparation of compound of general formula (II) from compound of general formula (X) :
2-Hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropanaldehyde :
4.6 ml DMSO in 80 ml dichloromethane is added to 2.4 ml oxalyl chloride in 240 ml dichloromethane at -78 ° C. After 5 minutes, 1.2 g of 1,2-dihydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropane is added dropwise at −78 ° C. in 80 ml of dichloromethane. After 15 minutes, 22.8 ml of triethylamine is added and the mixture is slowly warmed to RT. It is washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 85: 15) converted 4.0 g of 2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropanaldehyde into yellow Obtained as an oil (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.75-1.93 (m), 1.95-2.03 (m), 2.12-2.28 (m), 2.60 (dd, 1 H), 2.81-2.90 (m , 2H), 2.95-3.02 (m), 3.03-3.18 (m), 6.84-7.10 (m), 9.12 (s, 1 H, diastereomer. A), 9.66 (s, 1 H, diastereomer. B).

Example 14: Preparation of an imine from a compound of general formula (II) :
A. 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropylideneamino] quinolin-2 [1H] -one :
0.76 ml of titanium tetraisopropoxide is added to 600 mg of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropionaldehyde and 386 mg of 5-aminoquinoline-2 [1H] in 22 ml of toluene. Add to ON solution and heat the mixture at 110 ° C. for 4 hours. The mixture is added to saturated sodium carbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane 100%, dichloromethane / isopropanol 100: 0 → 95: 5) gave 275 mg of 5- [3- (chroman-4-yl) -2-hydroxy-trifluoromethylpropylideneamino The quinolin-2 [1H] -one is obtained as a beige foam (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.76-1.85 (m), 2.02-2.12 (m), 2.13-2.22 (m), 2.27 (d, 1 H), 2.31 (d, 1 H), 2.40-2.48 (m), 2.61 (d, 1 H, diaster. A + B), 2.93-3.01 (m. 1 H _: diastereomer. A), 3.22-3.31 (m, IH, di Stereomers.B), 4.10-4.18 (m), 4.22-4.29 (m), 4.87 (bs, 1 H, diastereomers. A), 5.02 (bs, 1 H, diastereomers. B), 6.64 ( d, 1 H, diastereomer. B), 6.72 (d, 1 H, diastereomer. 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, 1 H, diastereomer. A + B).

B. 5- [2-Hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropylideneamino] quinolin-2 [1H] -one :
1.1 ml titanium tetraisopropoxide in 300 ml 3- (4-methylchroman-4-yl) -2-hydroxy-2-trifluoromethylpropionaldehyde and 160 mg 5-aminoquinoline-2 in 10 ml toluene Add to the solution of [1H] -one and heat the mixture at 110 ° C. for 6 hours. The mixture is added to saturated sodium bicarbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 0: 100) gave 300 mg of 5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropylene. Ridenamino] quinolin-2 [1H] -one is obtained as a foam (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.41 (s, 3H, diastereomer. A), 1.46 (s, 3H, diastereomer. B), 1.65-1.77 (m, 1 H A), 1.81-1.94 (m, 1 H, diastereomer. B), 2.3-2.4 (m, 1 H, diastereomer. B), 2.43 (d, 1 H, diastereomer A + B), 2.61 (d, 1 H, diastereomer. B), 2.61-2.73 (m, 2H, diastereomer. B), 2.87 (d, 1 H, diastereomer. A), 3.98 -4.27 (m), 4.31-4.41 (m, 1 H, diastereomer. B), 4.82 (bs, 1 H ₁ diastereomer. B), 5.0 (bs, 1 H, diastereomer. A), 5.93 (d, 1 H, diastereomer. A), 6.49 (d, 1 H, diastereomer. A), 6.58 (d, 1 H, diastereomer. B), 6.72 (d, 1 H, diastereomer Stereomers. A), 6.74-6.93 (m), 7.03 (t, 1 H, diastereomer. B), 7.2-7.34 (m), 7.38-7.50 (m, 2H, diastereomer. B), 8.0 (s, 1 H, diastereomer. B), 8.05 (d, 1 H, diastereomer. A), 8.13 (d, 1 H, diastereomer. B), 12.65 (bs, 1 H, diastereomer. A + B).

C. 5- [2-Hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropylideneamino] quinolin-2 [1H] -one :
2.6 ml of titanium tetraisopropoxide is added to 700 mg of 2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropionaldehyde and 386 mg of 5-aminoquinoline-2 [1H] in 20 ml of toluene. Add to ON solution and heat the mixture at 110 ° C. for 4 hours. The mixture is added to saturated sodium bicarbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane 100%, dichloromethane / isopropanol 100: 0 → 96: 4) gave 600 mg of 5- [2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropylene. Ridenamino] quinolin-2 [1H] -one is obtained as a foam (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.81-2.08 (m), 2.11-2.22 (m), 2.30-2.46 (m), 2.56 (dd, 1 H), 2.87-2.96 (m ), 3.01-3.40 (m), 4.93 (s, 1 H, diastereomer. A + B), 6.28 (d, 1 H), 6.69 (d, 1 H), 6.77 (d, 1 H, diastereomer A + B), 6.86 (d, 1 H), 6.99 (t, 1 H), 7.01-7.11 (m), 7.13 (d, 1 H), 7.18-7.27 (m), 7.31-7.43 (m ), 7.74 (s, 1 H), 8.08 (s, 1 H), 8.10 (d, 1 H), 8.18 (d, 1 H), 12.01 (bs, 1 H, diastereomers. A + B).

D. 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropylideneamino] phthalazin-1 [2H] -one :
0.76 ml of titanium tetraisopropoxide was added to 600 mg of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropionaldehyde and 384 mg of 5-aminophthalazine-1 [2H in 22 ml of toluene. ] -One is added to the solution and the mixture is heated at 110 ° C. for 7 hours. The mixture is added to saturated sodium bicarbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane 100%, dichloromethane / isopropanol 100: 0 → 95: 5) gave 818 mg of 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropylene. Ridenamino] phthalazin-1 [2H] -one is obtained as a yellow foam (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 1.80-1.93 (m), 2.03-2.22 (m), 2.32 (d, 1 H), 2.38 (d, 1 H), 2.46 (d, 1 H), 2.58-2.68 (m), 2.97-3.05 (m, 1 H), 3.26-3.36 (m), 4.10- 4.21 (m), 4.22-4.29 (m), 4.76 (s, 1 H ₁ Dia Stereomers. A), 4.89 (s, 1 H, diastereomers. B), 6.82-6.83 (m), 6.86-7.0 (m), 7.03-7.18 (m), 7.21 (d, 1 H, diastereomers A), 7.70-7.81 (m), 8.06 (s, 1 H, diastereomer. B), 8.14 (s, 1 H, diastereomer. A), 8.33-8.55 (m). 10.47 (bs , 1H _, diastereomer. A + B).

E. 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropylideneamino] -8-fluoro-2-methylquinazoline :
0.31 ml of titanium tetraisopropoxide is added to 250 mg of 3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropionaldehyde and 180 mg of 5-amino-8-fluoro-methyl in 10 ml of toluene. Add to the solution of quinazoline and heat the mixture at 110 ° C. for 6 hours. The mixture is added to saturated sodium bicarbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (dichloromethane / methanol 100: 0 → 60: 40) gave 191 mg of 5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethylpropylideneamino]- 8-Fluoro-2-methylquinazoline is obtained as an orange foam (mixture of diastereomers).

¹ H-NMR (CDCI ₃ ): δ = 1.80-1.92 (m, 1 H), 2.02-2.22 (m), 2.33 (d, 1 H), 2.38 (d, 1 H), 2.46 (d, 1 H ), 2.63 (dd, 1 H), 2.98 (s, 3H, diastereomer. A + B), 3.27-3.38 (m), 4.09-4.18 (m), 4.23-4.30 (m), 4.79 (s, 1 H _, diastereomer. A), 4.91 (s, 1 H, diastereomer. B) ₁ 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, 1 H _, diastereomer. B) ₁ 8.18 (s, 1 H _, diastereomer. A).

C. The following can be prepared analogously by the above method:
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-dihydroindol-2-one;
5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -2-methyl-iso-quinolin-1-one;
5- [3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -iso-chromen-1-one;
5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -phthalazin-1 [2H] -one;

5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline;
5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline;
4- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -indazole;
5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -iso-chromen-1-one;
5- [2-hydroxy-3- (4-methylchroman-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] -phthalazin-1 [2H] -one;
8-fluoro-5- [2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline;
4- [2-hydroxy-3- (6-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -indazole;
5- [2-hydroxy-3- (6-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline;
4- [2-hydroxy-3- (7-methylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -indazole;
5- [2-hydroxy-3- (7-methylchroman-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] -phthalazin-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-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propylideneamino] -quinolin 2 [1 H] -one;

5- [2-hydroxy-3- (1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline;
8-fluoro-5- [2-hydroxy-3- (1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinazoline;
5- [2-hydroxy-3- (2-methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline;
5- [2-hydroxy-3- (4-methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propylideneamino] -2-methylquinoline;
5- [2-Hydroxy-3- (5-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propylideneamino] -2-methyl-iso-quinoline-1 -on;
5- [3- (5,7-Dimethyl-1,2,3,4-tetrahydronaphthalin-1-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -2-methyl-iso-quinoline -1-one;

5- [2-Hydroxy-3- (6-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -2-pentafluoroethyl-propylideneamino] -quinolin-2 [1 H] -one ;
5- [3- (6-Fluoro-1,2,3,4-tetrahydronaphthalin-1-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -quinolin-2 [1 H] -one ;
5- [2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propylideneamino] -quinolin-2 [1 H] -one;
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-propylideneamino] -quinolin-2 [1 H] -one;
5- [3- (4-Ethylchroman-4-yl) -2-hydroxy-2-trifluoromethyl-propylideneamino] -phthalazin-1 [2H] -one;
5- [2-Hydroxy-3- (4-propylchroman-4-yl) -2-trifluoromethyl-propylideneamino] -quinolin-2 [1 H] -one.

Compounds of general formula (i) :
Example 1 : 5-{[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino} quinolin-2 [1H] -one :
31 mg of sodium cyanoborohydride was dissolved in 15 ml 5- [3- [chroman-4-yl] -2-hydroxy-2-trifluoromethylpropylene in 1.5 ml methanol and 0.3 m glacial acetic acid at room temperature. Add to the solution of denamino] quinolin-2 [1H] -one and stir the mixture for 3.5 hours. The mixture is added to saturated sodium bicarbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (dichloromethane / methanol 100: 0 → 60: 40) gave 12 mg of 5-{[3- (chroman-4-yl) -2-hydroxy-2-trifluoromethyl-propyl] amino } Quinolin-2 [1H] -one is obtained as a yellow foam (mixture of diastereomers).

¹ H-NMR (CDCI ₃ , selected signal): δ = 2.0-2.13 (m), 2.13-2.21 (m), 3.17-3.27 (m, 1 H), 3.55 (s, 1 H), 3.63 ( s, 1 H), 4.01-4.13 (m, 2H), 6.49 (d, 1 H), 6.58 (t, 1 H, diastereomer. A + B), 6.62-6.79 (m, 3H), 6.99 ( t, 1 H, diastereomer. A + B), 7.06 (d, 1 H), 7.10 (d, 1 H), 7.30-7.39 (m, 1 H ₁ diastereomer. A + B), 8.12 ( d, 1H, diastereomer. A + B).

Examples 2, 3, 5 and 5 :
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one, diastereomer A, (+) enantiomer ;
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one, diastereomer B, (−) enantiomer ;
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one, diastereomer A, (−) enantiomer ;
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one, diastereomer B, (+) enantiomer :

  100 mg sodium cyanoborohydride was added to 50 mg 5- [2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl in 4.8 ml methanol and 1.0 ml glacial acetic acid at room temperature. To the solution of propylideneamino] quinolin-2 [1H] -one and the mixture is stirred for 3.5 hours. The mixture is added to saturated sodium bicarbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. HPLC chromatography (Chiralpack AD-H, hexane / ethanol 95: 5 → 50: 50) gives the following compounds:

  1 mg of 5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one (fraction 1; diastereomer A, (+) Enantiomer) 5 mg of 5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one (fraction Min 2; diastereomer B, (-) enantiomer), 7 mg 5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethylpropyl] amino} quinoline- 2 [1H] -one (fraction 3; diastereomer A, (−) enantiomer), and 8 mg of 5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2- Trifluoromethylpropyl] amino} quinolin-2 [1H] -one (fraction 4; Dias Reoma B, (+) enantiomer).

Example 2 (fraction 1) : ¹ H-NMR (CD ₃ OD): δ = 1.54 (s, 3H) ₁ 1.87 (ddd, 1 H), 2.17 (d, 1 H), 2.22 (d, 1 H) , 2.37 (ddd, 1 H), 3.42 (d, 1 H), 3.52 (d, 1 H), 4.11 (ddd, 1 H), 4.22 (ddd, 1 H), 6.33 (d, 1 H), 6.47 (d, 1 H), 6.66 (dd, 1 H), 6.78 (t, 1 H), 7.0 (dt, 1 H), 7.27-7.33 (m, 2H), 8.0 (d, 1 H).
Example 3 (fraction 2) : ¹ H-NMR (CD ₃ OD): δ = 1.40 (s, 3H), 1.68-1.76 (m, 1 H), 2.15 (d, 1 H), 2.53 (d, 1 H), 2.85 (d, 1 H), 2.87-2.97 (m, 1 H), 3.06 (d, 1 H), 4.02-4.11 (m, 1 H), 4.20-4.27 (m, 1 H), 5.74 (d, 1 H), 6.44 (d, 1 H), 6.59 (d, 1 H), 6.7 (d, 1 H), 6.88 (t, 1 H), 7.04 (t, 1 H), 7.15 (t , 1 H), 7.36 (d, 1 H), 7.96 (d, 1 H).

Example 4 (fraction 3) : ¹ H-NMR (CD ₃ OD): δ = 1.54 (s, 3H), 1.87 (ddd, 1 H) ₁ 2.17 (d, 1 H) ₁ 2.22 (d, 1 H) ₁ 2.37 (ddd, 1 H) ₁ 3.42 (d, 1 H) ₁ 3.52 (d, 1 H), 4.11 (ddd, 1 H), 4.22 (dd di H), 6.33 (d, 1 H), 6.47 ( Di H) ₁ 6.66 (dd, 1 H), 6.78 (t, 1 H), 7.0 (dt, 1 H) ₁ 7.27-7.33 (m, 2H), 8.0 (d, 1 H).
Example 5 (fraction 4) : ¹ H-NMR (CD ₃ OD): δ = 1.40 (s, 3H), 1.68-1.76 (m, 1 H), 2.15 (d, 1 H) ₁ 2.53 (d, 1 H), 2.85 (d, 1 H) ₁ 2.87-2.97 (m, 1 H), 3.06 (d, 1 H) ₁ 4.02-4.11 (m, 1 H), 4.20-4.27 (m, 1 H), 5.74 (d, 1 H), 6.44 (d, 1 H), 6.59 (d, 1 H) ₁ 6.7 (d, 1 H), 6.88 (t, 1 H), 7.04 (t, 1 H), 7.15 (t , 1 H), 7.36 (d, 1 H), 7.96 (d, 1 H).

Example 6 : 5-{[2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one :
100 mg sodium cyanoborohydride in 50 ml of 5- [2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropylideneamino in 4.8 ml methanol and 1.0 ml glacial acetic acid at room temperature Add to the solution of quinolin-2 [1H] -one and stir the mixture for 1 hour. The mixture is added to saturated sodium bicarbonate solution and extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. 44 mg of 5-{[2-hydroxy-3- (thiochroman-4-yl) -2-trifluoromethylpropyl] amino} quinolin-2 [1H] -one as a yellow foam (mixture of diastereomers) Get as.

¹ H-NMR (CHCI ₃ , selected signal): δ = 1.80-1.92 (m), 2.07-2.12 (m), 2.18 (dd, 1 H) ₁ 2.30 (dd, 1 H) ₁ 2.32-2.40 ( m, 1 H), 2.88-2.95 (m), 3.05-3.18 (m), 3.20-3.31 (m), 3.31-3.38 (m), 3.42 (dd, 1 H) ₁ 4.11-4.23 (m), 6.17 (d, 1 H), 6.22 (d, 1 H) ₁ 6.44 (t, 1 H), 6.54 (d, 1 H), 6.60 (d, 1 H), 6.85-7.20 (m), 7.51-7.57 ( m), 11.25-11.44 (bd, 1 H ₁ diastereomer. A + B).

Example 7 : 3- (chroman-4-yl) -1-[(2-methylquinolin-5-yl) amino] -2- (trifluoromethyl) propan-2-ol :
A. 1.15 g of ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate is taken up in 30 ml of diethyl ether and cooled to -5 ° C. 275 mg (7.2 mmol) of solid lithium aluminum hydride is added in portions over 10 minutes. The mixture is stirred at this temperature for 2 hours and poured into saturated ammonium chloride solution. The suspension is filtered through celite and washed thoroughly with ethyl acetate. The filtrate phases are separated and the ethyl acetate extraction is repeated. Wash with saturated sodium chloride solution and dry over sodium sulfate, followed by removal of the solvent under vacuum. Chromatographic purification on silica gel (hexane / ethyl acetate 25-33%) gave 620 mg of 3- (chroman-4-yl) -1-[(2-methylquinolin-5-yl) amino] -2- ( Trifluoromethyl) propan-2-ol is obtained.

¹ H-NMR (300 MHz, CDCI ₃ ); δ = 3.06 (d, 1 H), 3.26 (d, 1 H), 3.89 (s, 1 H), 4.67 (dd, 1 H), 4.70 (dd, 1 H), 5.74 (t, 1 H), 6.80 (d, 1 H), 6.93 (t, 1 H), 7.15 (t, 1 H), 7.21 (d, 1 H), 9.63 (s, 1 H ).

B. 0.4 ml (2.0 ml) of titanium tetraethoxide in 245 mg (0.9 mmol) of 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) in 10 ml of toluene Propanal and 150 mg (0.95 mol) of 5-amino-8-methylquinoline are added and the mixture is heated at 100 ° C. for 2 hours. After cooling, it is poured into water and stirred vigorously. The suspension is filtered through celite and washed thoroughly with ethyl acetate. The filtrate phases are separated and the ethyl acetate extraction is repeated. Dry over sodium sulfate and subsequently remove the solvent under vacuum. Chromatographic purification on silica gel (hexane / ethyl acetate 50%) gave 180 mg of 3- (2H-chroman-4-yl) -1-[(2-methylquinolin-5-yl) imino] -2- ( Trifluoromethyl) propan-2-ol is obtained.

  90 mg of imine obtained in this way is taken up in 4 ml of methanol and cooled to 0 ° C. 25 mg (0.66 mmol) of solid sodium borohydride are added, followed after 2 hours by pouring into saturated ammonium chloride solution and stirring vigorously. Extract several times with ethyl acetate, wash with saturated ammonium chloride solution and dry over sodium sulfate, followed by removal of the solvent under vacuum. Separation by column chromatography on silica gel (hexane / ethyl acetate 50%) gave 80 mg of 3- (2H-chroman-4-yl) -1-[(2-methylquinolin-5-yl) amino] 2- (Trifluoromethyl) propan-2-ol is obtained.

C. 30 mg of 3- (2H-chroman-4-yl) -1-[(2-methylquinolin-5-yl) amino] -2- (trifluoromethyl) propan-2-ol in 8 ml of methanol And after addition of 10 mg palladium on carbon (10%), the suspension is shaken under atmospheric pressure for 2 hours. The mixture is filtered through celite and washed 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, CDCI ₃ ); δ = 2.05-2.37 (m, 4H), 2.74 (s, 3H), 3.24-3.32 (m, 1 H), 3.51 (dd, 0.5H), 3.50 ( dd, 1 H), 3.61-3.72 (m, 1.5H), 4.21 (m, 2H), 4.45 (br, 1 H), 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, 1 H), 7.53-7.56 (m, 2H), 8.04 (d, 0.5H), 8.06 (d, 0.5H).

The following compounds are prepared analogously by the above method:
3- (chroman-4-yl) -1- (2-methylquinolin-5-ylamino) -2-trifluoromethyl-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-dihydroindol-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-chromen-1-one;
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -phthalazin-1 [2H] -one;
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinoline;
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinazoline;
4-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -indazole;

5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -iso-chromen-1-one;
5-{[2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -iso-chromen-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} -phthalazin-1 [2H] -one;
8-fluoro-5-{[2-hydroxy-3- (4-thiochroman-4-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinazoline;
4-{[2-hydroxy-3- (6-methylchroman-4-yl) -2-trifluoromethylpropyl] -amino} -indazole;

5-{[2-hydroxy-3- (6-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinoline;
4-{[2-hydroxy-3- (7-methylchroman-4-yl) -2-trifluoromethyl-propyl] -amino} -indazole;
5-{[2-hydroxy-3- (7-methylchroman-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} -isochromen-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-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propyl] -amino} -quinolin 2 [1 H] -one;
5-{[2-hydroxy-3- (1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinoline;
8-fluoro-5-{[2-hydroxy-3- (1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinazoline;
5-{[2-hydroxy-3- (2-methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinoline;

5-{[2-hydroxy-3- (4-methyl-1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propyl] -amino} -2-methylquinoline;
5-{[2-Hydroxy-3- (5-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -2-trifluoromethyl-propyl] -amino} -2-methyl-iso-quinoline -1 -on;
5-{[3- (5,7-dimethyl-1,2,3,4-tetrahydronaphthalin-1-yl) -2-hydroxy-2-trifluoromethyl-propyl] -amino} -2-methyl-iso -Quinolin-1-one;
5-{[2-hydroxy-3- (6-methoxy-1,2,3,4-tetrahydronaphthalin-1-yl) -2-pentafluoroethyl-propyl] -amino} -quinoline 2 [1 H]- on;
5-{[3- (6-Fluoro-1,2,3,4-tetrahydronaphthalin-1-yl) -2-hydroxy-2-trifluoromethyl-propyl] -amino} -quinoline 2 [1 H]- on;
5-{[2-hydroxy-3- (4-methylthiochroman-4-yl) -2-trifluoromethyl-propyl] -amino} quinolin-2 [1 H] -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} -quinolin-2 [1 H] -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} -quinolin-2 [1 H] -one.

Claims (13)

The following general formula (I):

[Wherein, R ¹ and R ² are independently of each other a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, (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 a —NR ⁹ R ^9a group, or
R ¹ and R ² together represent -0- (CH ₂ ) _n -O-, -0- (CH ₂ ) _n -CH _2- , -0-CH = CH-,-(CH ₂ ) _{n + 2 -, - NH- (} CH 2) n + 1 -, -N (C1-C 3 - alkyl) - a and -NH-n = CH- are selected from the group - (CH _{2) n + 1} Wherein n is 1 or 2, and the terminal oxygen atom and / or carbon atom and / or nitrogen atom is directly bonded to an adjacent ring atom;
R ¹¹ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, (C ₁ -C ₁₀ ) -alkoxy group, (C ₁ -C ₁₀ ) - an alkylthio group, or a (C ₁ -C ₅₎ - a 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 optionally substituted by ₁ to 3 hydroxy groups, 1 to 3 halogen atoms and / or 1 to 3 (C ₁ -C ₅ ) -alkoxy groups (C ₁ -C ₁₀ ). - alkyl group, optionally substituted (C ₃ -C ₇₎ -, optionally substituted with a cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group or one or more substituents, A monocyclic or bicyclic heteroaryl group, wherein said substituent can itself optionally be substituted by 1 to 3 hydroxy or 1 to 3 —COOR ¹³ groups (C ₁ -C ₅ ). -Alkyl group, (C ₁ -C ₅ ) -alkoxy group, halogen atom, hydroxy group, -NR ⁹ R ^9a group, (C ₁ -C ₅ ) -perfluoroalkyl group, nitro group, thiol group, sulfoxyl group, sulfone acid group, a sulfonamide group, a sulfonic imine group, a cyano group, or _{- (CO) - (C 1} -C 5) An alkyl group and an exomethylene group selected independently of one another, and optionally 1 to 4 nitrogen atoms, and / or 1 to 2 oxygen atoms, and / or 1 to 2 sulfur atoms, And / or comprises 1 to 2 keto groups, which groups can be attached to the nitrogen atom at any position and possibly optionally hydrogenated at one or more positions;
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 a hydrogen atom, a halogen atom, a hydroxy group, an NR ⁹ R ^9a group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, ( C ₁ -C ₁₀ ) -alkoxy group or (C ₁ -C ₁₀ ) -alkylthio group,
R ⁹ and R ^9a are each 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 is a hydrogen atom, a fluorine atom, or a partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group;
Y is a methylene group, oxygen atom, sulfur atom, —S (O) n (where n = 1 or 2), —S (O) (NR ¹³ ) group, —NH group, or —NR ¹⁰ group. is there]
A compound in the form of any stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt or derivative thereof.   The compound according to claim 1, wherein Y is an oxygen, sulfur or methylene group. R ³ is an optionally substituted aryl or heteroaryl group, preferably naphthyl, phthalidyl, isoindolyl, dihydroidyl, 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, dihydroindronyl A compound according to claim 1 or 2 selected from the group consisting of, dihydroisoindolonyl, benzimidazole and indolyl groups. The compound according to any one of claims 1 to 3, wherein R ^3a is a hydrogen atom or a (C ₁ -C ₅ ) -alkyl group. R ⁴ , R ⁵ , R ⁶ and R ^6a are each independently a hydrogen atom, a halogen atom or an optionally substituted (C ₁ -C ₁₀ ) -alkyl group. The described compound. The compound according to any one of claims 1 to 5, wherein R ¹⁴ is a fluorine atom or a trifluoromethyl group.   Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament.   Use of a compound according to any one of claims 1 to 6 for the manufacture of a pharmaceutical composition for the treatment or prevention of inflammatory processes.   A method for the treatment or prevention of an inflammatory process in a patient, wherein a pharmaceutically effective amount of a compound of formula (I) according to any one of claims 1 to 6 requires such treatment or prevention. To be administered to a patient.   A pharmaceutical product comprising at least one compound according to any one of claims 1 to 6 and one or more pharmaceutically acceptable carriers and / or excipients. It is a preparation method of the compound of any one of Claims 1-6, Comprising: The following formula (II):

Wherein R ^{1 to} R ¹⁴ and Y have the meanings specified in claims 1 to 6 are reacted with an amine of the formula R ³ —NH ₂ and the resulting imine Wherein is reduced to a compound of general formula (I). Formula (II) below:

[Wherein R ^{1 to} R ¹⁴ and Y have the meanings specified in claims 1 to 6].   Use of a compound of general formula (II) according to claim 12 for the preparation of a compound of general formula (I) according to any one of claims 1-6.