DE10330358A1 - New arylalkanol derivatives used for treating e.g. respiratory diseases, joint diseases, vascular inflammations, skin disorders, kidney and liver diseases and neurological diseases - Google Patents

Abstract

Arylalkanol derivatives (I) are new. Arylalkanol derivatives of formula A-C(R 1>)(R 2>)-CH 2-C(OH)(R 3>)-B'-NH-Q (I) and their isomers and salts are new, except for phthalazinone derivatives. A : aryl, benzyl or phenethyl (all optionally substituted by at least 1 1-5C alkyl, 1-5C alkoxy, 1-5C alkylthio, 1-5C perfluoroalkyl, halo, OH, CN, NO 2, O(CH 2) n, O(CH 2) nCH 2, OCH=CH, (CH 2) n+2 or NR 4>R 5>); n : 1 or 2; R 4>, R 5> : H, 1-5C alkyl or 2-6C alkanoyl; R 1>, R 2> : H, Me or Et, or R 1> + R 2> : 3-6C cycloalkane; R 3> : 1-8C alkyl (optionally substituted by at least 1 halo, OH or 1-3C alkoxy), optionally fluorinated 1-3C alkyl or 2-6C alkenyl, 2-6C alkynyl, 3-8C cycloalkyl, 3-7C heterocyclyl, aryl, heteroaryl, (1-8C)alkyl(3-8C)cycloalkyl, (1-8C alkyl)aryl or (1-8C alkyl)heteroaryl (all optionally substituted); B' : CH 2, CHMe, CHEt or CO, and Q : quinazolinyl, quinoxalinyl, cinnolinyl, indazolyl, phthalazinyl, naphthyridinyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl (all optionally substituted by at least 1 1-5C alkyl, 1-5C alkoxy, 1-5C alkylthio, 1-5C perfluoroalkyl, halo, OH, CN, NO 2 or NR 4>R 5>). An independent claim is also included for the preparation of (I). ACTIVITY : Antiinflammatory; Antiallergic; Immunosuppressive; Antiasthmatic; Antirheumatic; Antiarthritic; Dermatological; Antipsoriatic; Antipruritic; Cytostatic; Nephrotropic; Hepatotropic; Antiulcer; Vasotropic; Ophthalmological; Cerebroprotective; Neuroprotective; Thyromimetic; Antiemetic; Analgesic; Gastrointestinal-Gen.; Auditory; Hemostatic; Endocrine-Gen. MECHANISM OF ACTION : Glucocorticoid receptor (GR) ligand. In a GR binding assay, results showed that 4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(2-methyl-5-quinazolinylamino)-2-trifluoromethyl-2-pentanol (Ia) exhibited an IC 50 value of 1.8 nM.

Description

The Invention relates to heterocyclic substituted pentanol derivatives, in particular by quinazoline, quinoxaline, cinnoline, indazole, phthalazine, Naphthyridine and benzothiazole substituted pentanol derivatives, process for their preparation and their use as anti-inflammatory agents.

bekannt, wobei der Ar-Rest Phthalide, Thiophthalide, Benzoxazinone oder Phthalazinone umfaßt. Diese Verbindungen zeigen im Experiment Wirkdissoziationen zwischen antiinflammatorischen und unerwünschten metabolischen Wirkungen und sind den bisher beschriebenen, nichtsteroidalen Glucocorticoiden überlegen oder weisen zumindest eine ebenso gute Wirkung auf.From the state of the art DE 100 38 639 A1 and WO02 / 10143 A1 are anti-inflammatory agents of the general formula

wherein the Ar moiety comprises phthalides, thiophthalides, benzoxazinones or phthalazinones. These compounds show in the experiment Wirkdissoziationen between anti-inflammatory and undesirable metabolic effects and are superior to the previously described nonsteroidal glucocorticoids or at least have an equally good effect.

The selectivity of the prior art compounds over the other steroid receptors but still in need of improvement.

Therefore It was an object of the present invention to provide compounds available their selectivity across from the other steroid receptors is improved.

These Problem is solved by the compounds according to the claims.

worin
A für eine Aryl-, eine Benzyl- oder eine Phenethylgruppe steht, wobei die Aryl-, Benzyl- oder Phenethylgruppe gegebenenfalls substituiert sein kann durch einen oder mehrere Reste aus der Gruppe C₁-C₅-Alkyl, C₁-C₅-Alkoxy, C₁-C₅-Alkylthio, C₁-C₅-Perfluoralkyl, Halogen, Hydroxy, Cyano, Nitro, -O-(CH₂)_n-O-, -O-(CH₂)_n-CH₂-, -O-CH=CH-, -(CH₂)_n+2-
wobei n = 1 oder 2 ist und die endständigen Sauerstoffatome und/oder Kohlenstoffatome mit direkt benachbarten Ring-Kohlenstoffatomen verknüpft sind,
oder NR⁴R⁵,
wobei R⁴ und R⁵ unabhängig voneinander Wasserstoff, C₁-C₅-Alkyl oder (CO)-C₁-C₅-Alkyl sein können,
R¹ und R² unabhängig voneinander ein Wasserstoffatom, eine Methyl- oder Ethylgruppe oder gemeinsam mit dem Kohlenstoffatom der Kette einen C₃-C₆-Cycloalkylring,
R³ eine C₁-C₃-Alkylgruppe oder eine gegebenenfalls teilweise oder vollständig fluorierte C₁-C₃-Alkylgruppe,
B eine gegebenenfalls durch eine Methyl- oder Ethylgruppe substituierte Methylengruppe oder eine Carbonylgruppe und
Q eine über eine beliebige Position verknüpfte Chinazolinyl-, Chinoxalinyl-, Cinnolinyl-, Indazo-, Phthalazinyl-, Naphthyridinyl- oder Benzothiazolinylgruppe,
die gegebenenfalls substituiert sein kann durch einen oder mehrere Reste aus der Gruppe C₁-C₅-Alkyl, C₁-C₅-Alkoxy, C₁-C₅-Alkylthio, C₁-C₅-Perfluoralkyl, Halogen, Hydroxy, Cyano, Nitro, NR⁴R⁵,
wobei R⁴ und R⁵ unabhängig voneinander Wasserstoff, C₁-C₅-Alkyl oder (CO)-C₁-C₅-Alkyl sein können,
oder deren N-Oxide bedeutet
sowie deren Racemate oder getrennt vorliegenden Stereoisomeren, und gegebenenfalls deren physiologisch verträgliche Salze.The present invention therefore relates to compounds of general formula I.

wherein
A is an aryl, a benzyl or a phenethyl group, where the aryl, benzyl or phenethyl group may optionally be substituted by one or more radicals from the group C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy , C ₁ -C ₅ -alkylthio, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -
where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms,
or NR ⁴ R ⁵ ,
where R ⁴ and R ⁵ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl,
R ¹ and R ² independently of one another represent a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the chain, a C ₃ -C ₆ -cycloalkyl ring,
R ^{3 is} a C ₁ -C ₃ -alkyl group or an optionally partially or completely fluorinated C ₁ -C ₃ -alkyl group,
B is an optionally substituted by a methyl or ethyl group methylene group or a carbonyl group and
Q is a quinazolinyl, quinoxalinyl, cinnolinyl, indazo, phthalazinyl, naphthyridinyl or benzothiazolinyl group linked via an arbitrary position,
which may optionally be substituted by one or more radicals from the group C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, C ₁ -C ₅ perfluoroalkyl, halogen, hydroxy, cyano , Nitro, NR ⁴ R ⁵ ,
where R ⁴ and R ⁵ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl,
or their N-oxides
as well as their racemates or separately present stereoisomers, and optionally their physiologically acceptable salts.

A Aryl group includes Phenyl and naphthyl. Phenyl is preferred.

The substituted aryl, benzyl or phenethyl groups on the ring 1-3 substituents, preferably 2 substituents.

The following Substitution patterns on the ring A are a special subject of the Invention: 2,5-disubstituted phenyl derivatives and 2,4-disubstituted Phenyl derivatives.

Especially preferred are 2,4- and 2,5-disubstituted phenyl derivatives which substituted by a hydroxy or alkoxy group and a halogen atom are.

The C ₁ -C ₅ -alkyl groups in A, R ³ , R ⁴ , and R ⁵ may be straight-chain or branched and may be methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, Butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A methyl or ethyl group is preferred.

For a partially or completely fluorinated C ₁ -C ₃ -alkyl group, the following are partially or completely fluorinated groups: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1- Trifluoroethyl, tetrafluoroethyl, pentafluoroethyl. Of these, preferred are the trifluoromethyl or the pentafluoroethyl group.

The alkyl radicals R ¹ and R ² together with the carbon atom of the chain can form a 3 to 6-membered ring.

The C ₁ -C ₅ alkoxy groups in A and Q may be straight-chain or branched and may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy. A methoxy or ethoxy group is preferred.

The C ₁ -C ₅ -alkylthio groups in A and Q may be straight-chain or branched and may be methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. A methylthio or ethylthio group is preferred.

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

The NR ⁴ R ⁵ group can be, for example, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , N (H) (CO) CH ₃ , N (CH ₃ ) (CO) CH ₃ , N [( CO) CH ₃ ] ₂ , N (H) CO ₂ CH ₃ , N (CH ₃ ) CO ₂ CH ₃ , N (CO ₂ CH ₃ ) ₂ .

As alkyl radicals R ⁴ and R ⁵ , C ₁ -C ₃ -alkyl are preferred.

As the acyl radicals R ⁴ and R ⁵ , (CO) -C ₁ -C ₃ -alkyl are preferred.

For the rest B is the unsubstituted methylene group and the carbonyl group prefers.

Of the Rest Q can over each ring carbon atom may be linked to the (NH) group of the chain. Preferred are for Quinazoline ring, quinoxaline ring, cinnoline ring and phthalazine ring the 5- and 8-position, for the naphthyridine ring the 3- and 5-position and for the indazole and the benzothiazole ring the 7- and the 4-position.

The Compounds of the invention of general formula I can by the presence of asymmetric centers as distinct Stereoisomers are present. Both the racemates and the separate present stereoisomers belong to the subject of the present invention.

One special subject of the present invention with regard to their potency are the separately present stereoisomers, i. (+) - enantiomer and (-) - enantiomers.

The processes for preparing the compounds of WO98 / 54159, WO00 / 32584 and WO02 / 10143 can also be used for the preparation of the compounds of the invention. For the attachment of characteristic of the compounds of the invention benzothiazole quinazoline, quinoxaline, cinnoline, indazole, phthalazine, 1,7- and 1,8-Naphthyridinruppe the following steps can A1) for B = CO

An α-keto acid of the general formula (II) in which A, R ¹ and R ^{2 have} the meanings given for formula (I) is reacted with aminobenzothiazole, aminoquinazoline, aminoquinoxaline, aminocinnoline, aminoindazole or aminophthalazine derivative (Q-NH ₂ ) the α-ketoamide (III), wherein A, R ¹ and R ^{2 have} the abovementioned meaning, converted in the manner known in the art. For example, using dehydrating coupling reagents as known from peptide chemistry, eg dicyclohexylcarbodiimide, or by first converting the acid into an acid chloride, eg with thionyl chloride or POCl ₃ and subsequent reaction with Q-NH _2, the α-ketoamide (III) receive.

wobei R³ die oben angegebene Bedeutung hat und R⁶ eine C₁-C₅-Alkylgruppe bezeichnet, wobei die drei R⁶-Gruppen nicht gleich sein müssen, in Gegenwart eines Katalysators, z.B. Fluorid-Salzen oder Basen, wie etwa Alkalicarbonaten (J. Am. Chem. Soc. 1989, 111, 393), zur Titelverbindung (I) umgesetzt. A2 für B=CO

Compound (III) is reacted either with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, or by reaction with compound (IV),

where R ^{3 has} the abovementioned meaning and R ⁶ denotes a C ₁ -C ₅ -alkyl group, where the three R ⁶ groups do not have to be identical, in the presence of a catalyst, for example fluoride salts or bases, such as alkali metal carbonates (J. Chem. Soc., 1989, 111, 393) to give the title compound (I). A2 for B = CO

worin A, R¹ und R² wie oben beschrieben definiert sind und R⁷ C₁-C₄-Alkyl ist, nach den üblichen Methoden, z.B. mit Thionylchlorid in Methanol oder Ethanol oder mit Methyliodid und Alkalicarbonat, verestert werden und in Analogie zur Reaktionsfolge A1) von (III) in (I) in Verbindung (VI) umgewandelt werden.Alternatively, α-ketoacids (II) can also be converted into compounds (V),

wherein A, R ¹ and R ² are defined as described above and R ^{7 is} C ₁ -C ₄ alkyl, are esterified by conventional methods, for example with thionyl chloride in methanol or ethanol or with methyl iodide and alkali metal carbonate, and in analogy to the reaction sequence A1) from (III) to (I) in compound (VI).

• a) Eine Verbindung der allgemeinen Formel (VII) oder (VIII),
  
  worin A, B und R¹, R² und R³ die oben angegebene Bedeutung haben und LG eine beliebige Fluchtgruppe wie Halogenid oder Sulfonat bedeutet, wird mit einer Verbindung der allgemeinen Formel (IX) oder (X)
  
  worin R⁹ ein Wasserstoffatom, eine C₁-C₅-Azylgruppe oder Alkoxy- oder Aryloxycarbonylgruppe bedeutet und Q die oben angegebene Bedeutung hat, umgesetzt, wobei der Rest R⁹ abgespalten oder ein intermediär gebildetes Oxazolidinon (vgl. z.B. S.J. Brickner, D.K. Hutchinson, M.R. Barbachyn, P.R. Manninen, D.A. Ulanowicz, S.A. Garmon, K.C. Grega, S.K. Hendges, D.S. Toops, C.W. Ford, G.E. Zurenko J. Med. Chem. 1996, 39, 673) beispielsweise mit wäßrigen Alkalihydroxiden gespalten wird, um zur Titelverbindung (I) zu gelangen.
• b) Ein anderer Weg besteht darin, Verbindungen der Formel (VII) oder (VIII) mit Stickstoffnucleophilen, beispielsweise Azid-Salzen oder Ammoniak umzusetzen, wobei sich im ersten Falle eine Reduktion in der dem Fachmann bekannten Weise, z.B. mit komplexen Hydridreagenzien, wie Lithiumaluminiumhydrid, oder durch eine Übergangsmetall-katalysierte Hydrogenolyse anschließt, um zu Verbindungen der Formel (XI) zu gelangen.
  
  Den Resten R¹-R³, A und B kommt die gleiche Bedeutung wie oben angegeben zu.
• c) Verbindung (XI) kann unter Basenkatalyse, z.B. in Gegenwart tertiärer Aminbasen oder Alkalicarbonaten oder -hydroxiden, oder unter Übergangsmetallkatalyse, z.B. Palladiumkatalyse (J.P. Wolfe, S. Wagaw, J.-F. Marcoux, S.L. Buchwald Acc. Chem. Res. 1998, 31, 805; J.F. Hartwig Acc. Chem. Res. 1998, 31, 852), mit einem halogenierten Chinazolin, Chinoxalin, Cinnolin, Indazol, Phthalazin, Naphthyridin oder Benzothiazol in die Titelverbindung (I) übergeführt werden.
• d) Schließlich läßt sich die Titelverbindung (I) auch durch reduktive Aminierung einer Verbindung der Formel (XII) mir Q-NH₂ synthetisieren, wobei z.B Natriumcyanoborhydrid, Natriumtriacetoxyborhydrid oder Wasserstoff unter Palladium Katalyse als Reduktionsmittel in Betracht kommen.

The ester is saponified under standard conditions, such as aqueous alkali hydroxide solution, to the acid (VI; R ⁷ = H). This is converted to the title compound (I) for coupling with an aminoquinazoline, aminoquinoxaline, aminocinnoline, aminoindazole, aminophthalazine, aminonaphthyridine and aminobenzothiazole using a common activating reagent, for example thionyl chloride, optionally in the presence of a catalyst such as dimethylaminopyridine. B) for B = an optionally substituted by methyl or ethyl methylene group

• a) a compound of the general formula (VII) or (VIII)
  
  wherein A, B and R ¹ , R ² and R ³ are as defined above and LG is any leaving group such as halide or sulfonate, is reacted with a compound of general formula (IX) or (X)
  
  wherein R ^{9 represents} a hydrogen atom, a C ₁ -C ₅ -acyl group or alkoxy- or aryloxycarbonyl group and Q has the abovementioned meaning, wherein the residue R ^{9 is} cleaved off or an intermediately formed oxazolidinone (cf., for example, SJ Brickner, DK Hutchinson , MR Barbachyn, PR Manninen, DA Ulanowicz, SA Garmon, KC Grega, SK Hendges, DS Toops, CW Ford, GE Zurenko J. Med. Chem. 1996, 39, 673), for example, with aqueous alkali metal hydroxides to give the title compound ( I) to arrive.
• b) Another way is to react compounds of formula (VII) or (VIII) with nitrogen nucleophiles, for example, azide salts or ammonia, wherein in the first case a reduction in the manner known in the art, for example with complex hydride reagents, such as lithium aluminum hydride , or by a transition metal-catalyzed hydrogenolysis followed to obtain compounds of formula (XI).
  
  The radicals R ¹ -R ³ , A and B have the same meaning as stated above.
• c) Compound (XI) can be subjected to base catalysis, for example in the presence of tertiary amine bases or alkali metal carbonates or hydroxides, or under transition metal catalysis, for example palladium catalysis (JP Wolfe, S. Wagaw, J.-F. Marcoux, SL Buchwald Acc. Chem. 1998, 31, 805; JF Hartwig Acc. Chem. Res. 1998, 31, 852), with a halogenated quinazoline, quinoxaline, cinnoline, indazole, phthalazine, naphthyridine or benzothiazole are converted into the title compound (I).
• d) Finally, the title compound (I) can also be synthesized by reductive amination of a compound of the formula (XII) with Q-NH ₂ , for example sodium cyanoborohydride, sodium triacetoxyborohydride or hydrogen under palladium catalysis being suitable as the reducing agent.

R ^{8 represents} methyl or ethyl according to the substituents defined for the methylene group in B.

in the Trap, that the Compounds of general formula I may be present as salts this for example in the form of the hydrochloride, sulfate, nitrate, Phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, Citrate or succinate.

If the compounds according to the invention are present as racemic mixtures, they can be separated into the pure optically active forms by methods of racemate resolution which are familiar to the person skilled in the art. For example, the racemic mixtures can be separated into the pure isomers by chromatography on an even optically active carrier material (CHIRALPAK AD ^®). It is also possible to esterify the free hydroxy group in a racemic compound of the general formula I with an optically active acid and to separate the resulting diastereoisomeric esters by fractional crystallization or chromatography and to saponify the separated esters respectively to the optically pure isomers. As the optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.

The binding of the substances to the glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is checked using recombinant receptors. Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are used for the binding assays. In comparison to the reference substance [ ³ H] -dexamethasone, the substances show a high to very high affinity for GR.

In addition, the quinazolines, quinoxalines, cinnolines, indazoles, phthalazines, naphthyridines, and benzothiazoles of formula (I) described herein exhibit high selectivity for the glucocorticoid receptor. For example, example 2 shows the following profile: IC ₅₀ (GR) = 1.8 nM; IC ₅₀ (MR), IC ₅₀ (PR), IC ₅₀ (AR)> 1 μM.

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

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

The anti-inflammatory activity of the compounds of the general formula I was tested in animal experiments by testing in the croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108). For this purpose, the animals were topically applied croton oil in ethanolic solution to the ears. The test substances were also applied topically or systemically simultaneously or two hours before the croton oil. After 16-24 hours, ear weight was measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocytic immigration, and elastase activity as a measure of neutrophil granulocyte immigration. The compounds of general formula I hem In this test, both after topical and after systemic administration, the three above-mentioned inflammation parameters.

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

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

Because of their anti-inflammatory and additional anti-allergic, immunosuppressive and anti-proliferative action, the compounds of the general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans: The term "DISEASE" stands for the following indications:

• (i) Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes: - Chronic obstructive pulmonary diseases of all origins, especially bronchial asthma - Bronchitis of various origins - All forms of restrictive lung diseases, especially allergic alveolitis, - All forms of pulmonary edema, especially toxic pulmonary edema - sarcoidosis and granulomatosis, in particular Boeck's disease
• (ii) Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes: - All forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica - Reactive arthritis - Inflammatory soft tissue diseases of other genesis - Arthritic symptoms degenerative joint diseases (arthrosis) - Traumatic arthritis - collagenosis of any genesis, eg systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis - Sjögren syndrome, still syndrome, Felty syndrome
• (iii) Allergies associated with inflammatory and / or proliferative processes: All forms of allergic reactions, eg, edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis
• (iv) vasculitis - panarteritis nodosa, temporal arteritis, erythema nodosum
• (v) Dermatological disorders associated with inflammatory, allergic and / or proliferative processes: - atopic dermatitis (especially in children) - psoriasis - pityriasis rubra pilaris - erythematous diseases caused by different noxae, eg radiation, chemicals, burns etc. - Bullous dermatoses - Diseases of the lichenoid type, - Pruritus (eg allergic origin) - Seborrheic dermatitis - Rosacea - Pemphigus vulgaris - Erythema exudativum multiforme - Balanitis - Vulvitis - Hair loss such as alopecia areata - Cutaneous T-cell lymphoma
• (vi) kidney disease associated with inflammatory, allergic and / or proliferative processes: - nephrotic syndrome - all nephritides
• (vii) liver disease associated with inflammatory, allergic and / or proliferative processes: acute hepatic cell disintegration acute hepatitis of various causes, eg viral, toxic, drug-induced, chronic aggressive and / or chronic intermittent hepatitis
• (viii) Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes: - regional enteritis (Crohn's disease) - ulcerative colitis - gastritis - reflux esophagitis - gastroenteritis of other genesis, eg native sprue
• (ix) proctological diseases associated with inflammatory, allergic and / or proliferative processes: - anal eczema - fissures - hemorrhoids - idiopathic proctitis
• (x) ocular diseases associated with inflammatory, allergic and / or proliferative processes: - allergic keratitis, uveitis, iritis, - conjunctivitis - blepharitis - neuritis nervi optici - choroiditis - ophthalmia sympathica
• (xi) diseases of the ear, nose and throat, which are associated with inflammatory, allergic and / or proliferative processes: - allergic rhinitis, hay fever - otitis externa, eg due to contact xem, infection, etc. - otitis media
• (xii) Neurological diseases associated with inflammatory, allergic and / or proliferative processes: - brain edema, especially tumor-related cerebral edema - multiple sclerosis - acute encephalomyelitis - meningitis - various forms of seizures, eg BNS cramps
• (xiii) Blood disorders associated with inflammatory, allergic and / or proliferative processes: - Acquired hemolytic anemia - Idopathic thrombocytopenia
• (xiv) tumors associated with inflammatory, allergic and / or proliferative processes: - acute lymphoblastic leukemia - malignant lymphoma - lymphogranulomatosis - lymphosarcoma - extensive metastases, especially in breast, bronchial and prostate cancers
• (xv) Endocrine disorders associated with inflammatory, allergic and / or proliferative processes: - endocrine orbitopathy - thyrotoxic crisis - thyreitis de Quervain - Hashimoto's thyroiditis - Graves' disease
• (xvi) Organ and tissue transplants, graft-versus-host disease (xvii) Severe shock states, eg, anaphylactic shock, systemic inflammatory response syndrome (SIRS)
• (xviii) Substitution therapy in: - congenital primary adrenal insufficiency, eg congenital adrenogenital syndrome - acquired primary adrenal insufficiency, eg Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc. - congenital secondary adrenal insufficiency, eg congenital hypopitotitarism - acquired adrenal insufficiency, eg post-infectious, Tumors etc.
• (xix) Emesis associated with inflammatory, allergic and / or proliferative processes: - eg in combination with a 5-HT3 antagonist in cytostatic - induced vomiting.
• (xx) Pain in inflammatory genesis, eg lumbago

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

All The aforementioned indications (i) to (xx) are described in detail in Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998.

For the therapeutic Effects in the above disease states is the appropriate dose different and depends for example, the potency the compound of general formula I, the host, the route of administration and the nature and severity of the conditions to be treated, as well as from use as a prophylactic or therapeutic.

• (i) die Verwendung eines der erfindungsgemäßen Verbindung gemäß Formel I oder deren Gemisch zur Herstellung eines Medikaments zur Behandlung von einer ERKRANKUNG;
• (ii) ein Verfahren zur Behandlung von einer ERKRANKUNG, welches Verfahren eine Verabreichung einer Verbindungsmenge gemäß der Erfindung umfaßt, wobei die Menge die Krankheit unterdrückt, und wobei die Verbindungsmenge einem Patienten gegeben wird, der ein solches Medikament benötigt;
• (iii) eine pharmazeutische Zusammensetzung zur Behandlung von einer ERKRANKUNG, welche Behandlung eines der erfindungsgemäßen Verbindungen oder deren Gemisch und wenigstens einen pharmazeutischen Hilfs- und/oder Trägerstoff umfaßt.

The invention further provides

• (i) the use of one of the compounds of the invention of formula I or a mixture thereof for the manufacture of a medicament for the treatment of a DISEASE;
• (ii) a method of treating a DISEASE, which method comprises administering a compounding amount according to the invention, wherein the amount suppresses the disease, and wherein the compounding amount is given to a patient in need of such a drug;
• (iii) a pharmaceutical composition for the treatment of a DISEASE, which comprises treatment of one of the compounds of the invention or their mixture and at least one pharmaceutical excipient and / or carrier.

in the In general, satisfactory results can be expected in animals when the daily Doses a range of 1 μg up to 100,000 μg the compound of the invention per kg of body weight include. For larger mammals, for example, to humans, is a recommended daily dose in the range of 1 μg up to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg of body weight, more preferred a dose of 10 to 10,000 μg per kg of body weight. For example, this dose is conveniently administered several times a day. For the treatment of acute shock (e.g., anaphylactic shock) can Single doses are given that are well above the above doses lie. (Are the cans correct?)

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

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

For the parenteral Application injection and infusion preparations are possible.

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

For intramuscular injection can aqueous and oily injection solutions or suspensions and entprechende Depotpräparationen use.

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

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

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

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

The Invention also the compounds of the invention the general formula I as a therapeutic agent. Farther belongs to the invention, the compounds of the invention the general formula I as a therapeutic agent together with pharmaceutically acceptable and acceptable excipients and carriers.

Also comprises The invention relates to a pharmaceutical composition containing one of the pharmaceutically active compounds of the formula of the invention I or mixtures thereof or their pharmaceutically acceptable Salt or its pharmaceutically acceptable salts and pharmaceutically compatible Excipients and carriers contains.

The The following examples serve to illustrate the invention without limit them to it to want. The syntheses of key precursors in the context of the experimental part are not already disclosed the technique, and can for example from WO 98/54159, (WO 00/32584) or WO 02/10143 be removed.

Experimental part

example 1

4-(5-Fluor-2-methoxyphenyl)-4-methyl-1-(phthalazin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (phthalazin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

4- (5-Fluoro-2-methoxy-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal 0.81 ml (8.67 mmol) of oxalyl chloride are cooled to -60 ° C. in 15 ml of dichloromethane and mixed with 1.6 ml of 22.6 mmol) of dimethyl sulfoxide in 10 ml of dichloromethane. After 15 minutes, 1.0 g (3.22 mmol) of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-trifluoromethyl-pentane-1,2-diol (WO 00/32584) in 10 ml of dichloromethane is added and the mixture is stirred for one hour at -60 ° C. 4.1 ml (29 mmol) of triethylamine are added and the mixture is allowed to warm to RT over 30 min. It is poured into 50 ml of water and extracted with CH ₂ Cl ₂ . The combined organic extracts are washed with saturated NaCl solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Chromatography on silica gel with hexane-ethyl acetate (0-30%) gives 600 mg of the product.

'H-NMR (CDCl _3); δ = 1.38 (s, 3H), 1.47 (s, 3H), 2.23 (d, 1H), 3.36 (d, 1H), 3.86 (s, 3H), 6.77 (dd, 1H), 6.87 (dd, 1H) , 6.91 (ddd, 1H), 9.05 (s, 1H).

To 70 mg (0.48 mmol) of 5-aminophthalazine (IA Shaikh, F. Johnson, AP Grollman J. Med. Chem. 1986, 26, 1329-1340) in 2 ml of acetic acid, 200 mg (0.65 mmol) of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal in 5 ml of toluene. The reaction solution is heated for 6 hours to reflux with removal of water and refluxed for a further 4 hours on molecular sieve (4 A). The solvent is removed in vacuo and residues of acetic acid are removed by azeotropic codistillation with toluene. After chromatography on silica gel with hexane-ethyl acetate (0-70%) are 40 mg

4- (5-Fluoro-2-methoxyphenyl) -4-methyl-1- (phthalazin-5-ylmino) -2- (trifluoromethyl) -pentan-2-ol. To 10 mg of imine in 10 ml of ethyl acetate and 1 ml of triethylamine are added 20 mg of palladium on carbon and shaken for 2 h under a hydrogen atmosphere at atmospheric pressure. The solution is freed by filtration from the catalyst and evaporated. After chromatography on silica gel with hexane-ethyl acetate (0-70%) 4 mg of the desired product are obtained 'H-NMR (CDCl ₃ ); δ = 1.44 (s, 3H), 1.66 (s, 3H), 2.07 (d, 1H), 3.07 (d, 1H), 3.16 (d, 1H), 3.24 (d, 1H), 3.85 (s, 3H) , 6.42 (d, 1H), 6.76 (m, 2H), 7.11 (dd, 1H), 7.30 (d, 1H), 7.66 (dd, 1H), 9.38 (s, 1H), 9.48 (s, 1H).

Example 2

4-(5-Fluor-2-methoxyphenyl)-4-methyl-1-(2-methychinazolin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methychinazolin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

5-Amino-2-methychinazolin

12.7 g (mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (MT Bogert, VJ Chambers J. Org. Chem. 1905, 649-658) and 37.5 g of phosphorus pentachloride are dissolved in 75 ml of phosphoryl chloride over 20 Heated under reflux for hours. After cooling, pour into sat. NaHCO ₃ solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. This gives 14 g of 4-chloro-2-methyl-5-nitroquinazoline, of which 4.5 g (20.2 mmol) are dissolved in 225 ml of ethyl acetate and 22.5 ml of triethylamine. 2 g of palladium on carbon are added and the mixture is stirred with ice-cooling for 4 hours under a hydrogen atmosphere at atmospheric pressure. The solution is freed by filtration through Celite from the catalyst, washing with 200 ml of ethanol, and evaporated. Chromatography on silica gel with ethyl acetate-ethanol (0-10%) gives 530 mg of the product. 'H-NMR (CDCl _3); δ = 2.87 (s, 3H), 4.52 (br, 2H), 6.77 (d, 1H), 7.33 (d, 1H), 7.65 (t, 1H), 9.40 (s, 1H).

180 mg (0.48 mmol) of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 50 mg of 5-amino-2-methyyninazoline are dissolved in 20 ml of dichloroethane and 2 ml Acetic acid with continuous slow removal of the solvent over 5 hours concentrated to 5 ml. The residual solvent is removed in vacuo and residues of acetic acid are removed by azeotropic codistillation with toluene. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 58 mg of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methyquinazolin-5-ylmino) -2- (trifluoromethyl) -pentan-2-ol obtained. To the imine in 10 ml of ethyl acetate and 1 ml of triethylamine are added 20 mg of palladium on carbon and shaken for 2 h under a hydrogen atmosphere at atmospheric pressure. The solution is freed by filtration from the catalyst and evaporated. Take up in 5 ml of chloroform and add 200 mg of activated manganese dioxide and stir for 30 min. It is filtered through Celite and concentrated in vacuo. Chromatography on silica gel with hexane-ethyl acetate (0-70%) gives 22 mg of the product. 'H-NMR (CDCl _3); δ = 1.47 (s, 3H), 1.56 (s, 3H), 2.38 (d, 1H), 2.77 (d, 1H), 2.83 (s, 3H), 3.16 (dd, 1H), 3.33 (dd, 1H), 3.85 (s, 3H), 4.70 (br, 1H), 6.05 (d, 1H), 6.77 (dd, 1H), 6.88 (ddd, 1H), 7.09 (dd, 1H), 7.24 (d, 1H), 7.56 (t, 1H), 9.16 (s, 1H).

Example 3

4-(5-Fluor-2-hydroxyphenyl)-4-methyl-2-methychinazolin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-hydroxyphenyl) -4-methyl-2-methychinazolin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

103 mg (0.23 mmol) of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methynoquinazolin-5-ylamino) -2- (trifluoromethyl) -pentan-2-ol in 10 ml of CH ₂ Cl ₂ is added at 0 ° C with 5 ml of 1M boron tribromide-CH ₂ Cl ₂ solution. After 10 h, a further 5 ml of 1M boron tribromide CH ₂ Cl ₂ solution are added and the mixture is poured into saturated NaHCO ₃ after 72 h at room temperature, stirred for 20 minutes and extracted with CH ₂ Cl ₂ . The combined organic extracts are washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Chromatography with hexane-2-propanol (0-20%) on silica gel provides 80 mg of the product.

'H-NMR (CDCl _3); δ = 1.51 (s, 3H), 1.58 (s, 3H), 2.37 (d, 1H), 2.81 (s, 3H), 2.91 (d, 1H), 3.25 (dd, 1H), 3.43 (dd, 1H) , 5.05 (br., 1H), 6.20 (d, 1H), 6.54 (dd, 1H), 6.69 (m, 1H), 7.05 (dd, 1H), 7.23 (d, 1H), 7.59 (d, 1H) , 7.58 (d, 1H), 8.32 (d, 1H), 8.68 (d, 1H).

Example 4

4-(2,5-Difluorphenyl)-4-methyl-1-(2-methylchinazolin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (2,5-difluorophenyl) -4-methyl-1- (2-methylquinazolin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

4- (2,5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal

5.4 g (15.5 mmol) of ethyl 4- (2,5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerate (WO 02/10143) are dissolved in diethyl ether at 0 ° C. and treated with 1.76 g of (20) within 20 min. 46.5 mmol) of lithium aluminum hydride. Stir at RT for 4 h, carefully add enough saturated NaHCO ₃ solution until no gas evolution is observed. The mixture is diluted with ethyl acetate, stirred for a further 15 minutes and then the precipitate formed is filtered off. It is concentrated and chromatographed on silica gel with hexane / ethyl acetate (50%). This gives 2.45 g of 2,5-difluorophenyl) -4-methyl-2-trifluoromethyl-pentane-1,2-diol as a pale yellowish crystallizing oil. 800 mg (2.8 mmol) of 4- (2,5-difluorophenyl) -4-methyl-2-trifluoromethyl-pentane-1,2-diol are introduced into 20 ml of dichloromethane and added at 0 ° C 9.5 ml of DMSO and 1.95 ml of triethylamine , The solution is slowly mixed with 1.34 g (8.4 mmol) of SO ₃ -pyridine complex and stirred at 0 ° C for 2 h. The mixture is between ges. Distributed ammonium chloride solution and MTBE, the phases were separated and the aqueous phase extracted with MTBE. The combined organic phases are washed with water and sat. NaCl solution and dried with NaSO ₄ . It is concentrated and chromatographed on silica gel with hexane / ethyl acetate (30%). This gives 710 mg of the desired product. ¹ H-NMR (CDCl _3): δ = 1:41 (s, 3H), 1:48 (s, 3H), 2:39 (d, 2H), 3:02 (d, 1H), 3.61 (s, 1H), 6.84-7.18 ( m, 3H), 9.23 (s, 1H).

240 mg (0.84 mmol) of 4- (2,5-difluoro-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 200 mg (1.26 mmol) of 5-amino-2-methyl-quinazoline are initially analogous to Example 2 implemented. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 80 mg of 4- (2,5-difluorophenyl) -4-methyl-1- (2-methylquinazolin-5-ylmino) -2- (trifluoromethyl) - pentan-2-ol, which are taken up in ethyl acetate / ethanol 1: 1 and hydrogenated with 10 mg of palladium catalyst (10% on activated carbon) under a hydrogen atmosphere (1 atm). After 5 hours at RT, the catalyst is filtered off with suction and the filtrate is concentrated. The residue is taken up in chloroform again and reacted analogously to Example 2 with manganese dioxide. After chromatographic purification, 15 mg of the desired product are obtained as a red-brown film. MS (ESI): 440 (M + H); ¹ H-NMR (CDCl ₃ ): δ = 1.48 (s, 3H), 1.62 (s, 3H), 2.29 (d, 1H), 2.61 (d, 1H), 2.79 (s, 3H), 3.19-3.35 ( m, 2H), 3.61 (s, 1H), 4.69-4.73 (m, 1H), 6.00 (d, 1H), 6.83-6.91 (m, 2H), 7.08-7.14 (m, 1H), 7.23 (d, 1H), 7.52 (dd, 1H), 9.14 (d, 1H).

Example 5

4-(5-Fluor-2-methoxyphenyl)-4-methyl-1-(2-methylbenzothiazol-7-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methyl-benzothiazol-7-ylamino) -2- (trifluoromethyl) pentan-2-ol

200 mg (0.65 mmol) of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanal and 126 mg (0.77 mmol) of 7-amino-2-methylbenzothiazole (Libeer et al., Bull.Soc.Chim.Belg., 1971; 80; 43-47) are heated to 125 ° C in 8 ml of acetic acid for 5 hours. After cooling to room temperature, 214 mg (1.01 mmol) of sodium triacetoxyborohydride are added and the mixture is stirred for 16 h. After adding a further 100 mg (0.47 mmol) of sodium triacetoxyborohydride and stirring for 2 hours, toluene is added and concentrated in vacuo. The residue is taken up in ethyl acetate, the organic phase with sat. Sodium bicarbonate and sat. Sodium chloride solution and dried over sodium sulfate. Chromatography on silica gel with hexane-ethyl acetate (0-50%) gives 221 mg of the product. 'H-NMR (CDCl _3); δ = 1.45 (s, 3H), 1.58 (s, 3H), 2.25 (d, 1H), 2.78 (d, 1H), 2.82 (s, 3H), 3.14 (s, 1H), 3.16 (dd, 1H) , 3.28 (dd, 1H), 3.48 (dd, 1H), 3.84 (s, 3H), 4.23 (d, 1H), 5.97 (d, 1H), 6.82 (dd, 1H), 6.96 (ddd, 1H), 7.15 (dd, 1H), 7.21 (t, 1H), 7.42 (d, 1H).

Example 6

4-(5-Fluor-2-hydroxyphenyl)-4-methyl-1-(2-methylbenzothiazol-7-ylamino)-2-(trifluormethyl)pentan-2-ol

4- (5-fluoro-2-hydroxyphenyl) -4-methyl-1- (2-methyl-benzothiazol-7-ylamino) -2- (trifluoromethyl) pentan-2-ol

Analogously to Example 3, 150 mg (0.13 mmol) of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methylbenzothiazol-7-ylamino) -2- (trifluoromethyl) -pentan-2-ol in 15 ml of CH ₂ Cl ₂ with 6.8 ml of 1M boron tribromide-CH ₂ Cl ₂ solution. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 102 mg of the product are obtained. ¹ H-NMR (CDCl _3); δ = 1.50 (s, 3H), 1.59 (s, 3H), 2.31 (d, 1H), 2.79 (d, 1H), 2.80 (s, 3H), 3.27 (m, 2H), 3.40 (dd, 1H) , 3.54 (dd, 1H), 6.02 (d, 1H), 6.11 (br, 1H), 6.65 (dd, 1H), 6.82 (ddd, 1H), 7.12 (dd, 1H), 7.18 (t, 1H) , 7.40 (d, 1H).

Example 7

1-(Chinoxalin-5-ylamino)-4-(5-fluor-2-methoxyphenyl)-4-methyl-2-(trifluormethyl)-pentan-2-ol

1- (quinoxaline-5-ylamino) -4- (5-fluoro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentan-2-ol

To 80 mg (0.55 mmol) of 5-aminoquinoxaline (Salon, V. Milata, N. Pronayova, J. Lesko Monatsh. Chem. 2000, 131, 293-299) in 2 ml of acetic acid are added 140 mg (0.46 mmol) of 4 - (5-Fluoro-2-methoxy-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal, dissolved in 5 ml of dichloroethane. The reaction solution is refluxed for 5 hours on molecular sieve (4 A). The mixture is partitioned between water and dichloromethane and extracted (CH ₂ Cl ₂ ). The combined organic phases are washed (saturated NaCl solution), dried (Na ₂ SO ₄ ) and concentrated. Chromatographic purification on silica gel with hexane / ethyl acetate (0-50%) gives 82 mg of 1- (quinoxalin-5-ylmino) -4- (5-fluoro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentane-2-ol in 3 ml Methanol was added and mixed with 100 ul of acetic acid and 10 mg (0.26 mmol) of NaBH ₄ . The reaction mixture is stirred for 2 days at RT, two additional 10 mg NaBH _{4 are} added twice. The mixture is partitioned between water and dichloromethane and extracted (CH ₂ Cl ₂ ). The combined organic phases are washed (saturated NaCl solution), dried (Na ₂ SO ₄ ) and concentrated. The crude product is purified by chromatography on silica gel with hexane / ethyl acetate (10-50%). 40 mg of the desired product are obtained, which can be recrystallised from hexane / diethyl ether. MS (ESI): 438 (M + H); ¹ H-NMR (CDCl ₃ ): δ = 1.46 (s, 3H), 1.61 (s, 3H), 2.26 (d, 1H), 2.80 (d, 1H), 2.99 (s, 1H), 3.22-3.49 ( m, 3H), 3.85 (s, 3H), 6.07 (d, 1H), 6.81 (dd, 1H), 6.91-6.99 (m, 1H), 7.19 (dd, 1H), 7.36 (dd, 1H), 7.46 (d, 1H), 8.61 (d, 1H), 8.80 (d, 1H).

Example 8

1-(Chinoxalin-5-ylamino)-4-(5-fluor-2-hydroxyphenyl)-4-methyl-2-(trifluormethyl)-pentan-2-ol

1- (quinoxaline-5-ylamino) -4- (5-fluoro-2-hydroxyphenyl) -4-methyl-2- (trifluoromethyl) pentan-2-ol

Analogously to Example 3, 30 mg (68 μmol) of 1- (quinoxaline-5-ylamino) -4- (5-fluoro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) -pentan-2-ol are dissolved reacted in 3 ml of dichloromethane with 3 ml of boron tribromide solution (1M in CH ₂ Cl ₂ ) and stirred at RT for 24 h. The mixture is between ethyl acetate and sat. NaHCO ₃ solution and extracted with ethyl acetate. The combined organic phases are washed (saturated NaCl solution), dried (Na ₂ SO ₄ ) and concentrated. The crude product is purified by chromatography on silica gel with hexane / ethyl acetate (20%). 15 mg of the desired product are obtained. MS (ESI): 424 (M + H); ¹ H-NMR (CDCl _3): δ = 1:46 (s, 3H), 1:53 (s, 3H), 2.28 (d, 1H), 2:58 (d, 1H), 2.97 (br, 1H), 3:30 to 3:56 ( m, 1H), 6.18 (d, 1H), 6.56 (dd, 1H), 6.76-6.83 (m, 1H), 7.15 (dd, 1H), 7.36 (d, 1H), 7.46 (d, 1H), 8.65 (d, 1H), 8.83 (d, 1H).

Example 9

α-[(Chinoxalin-5-ylamino)methyl]-1-(2-chlor-5-fluorphenyl)-α-(trifluormethyl) cyclobutanethanol

α - [(quinoxaline-5-ylamino) methyl] -1- (2-chloro-5-fluorophenyl) -α- (trifluoromethyl) cyclobutaneethanol

1- (2-Chloro-5-fluorophenyl) -β-hydroxy-β- (trifluoromethyl) cyclobutane propanal 3.1 g (8.7 mmol) of 1- (2-chloro-5-fluorophenyl) -β-hydroxy-β- (trifluoromethyl) cyclobutanopropionic acid ethyl ester (WO 02/10143) are reacted analogously to Example 4 with 990 mg (26.1 mmol) of lithium aluminum hydride. This gives 1.80 g of 1- (2-chloro-5-fluorophenyl) -β- (hydroxy) -β- (trifluoromethyl) cyclobutanopropanol as a pale yellowish oil. In 20 ml of dichloromethane are placed 493 .mu.l (2.56 mmol) of oxalyl chloride. At -75 ° C., 802 μl (11.3 mmol) of DMSO are stirred in and, after 15 min, a solution of 800 mg (2.56 mmol) of the 1 - [(chloro-5-fluorophenyl) -β- (hydroxy) -β- (trifluoromethyl) cyclobutanopropanol in 10 ml of dichloromethane. After a further 15 minutes, 2.20 ml (15.8 mmol) of triethylamine are added dropwise and the mixture is stirred at -60 ° C. for 30 minutes and at 0 ° C. for 30 minutes. The reaction is stopped by adding water, the phases are separated and extracted with dichloromethane. The combined organic phases are washed with water and sat. NaCl solution and dried with NaSO ₄ . It is concentrated and chromatographed on silica gel with hexane / ethyl acetate (30%). This gives 810 mg of the desired product. MS (Cl): 342 (M + NH _4); ¹ H-NMR (CDCl _3): δ = 1.74-1.92 (m, 1H), 2.00-2.70 (m, 5H), 2.86 (d, 1H), 3.19 (d, 1H), 3:52 (s, 1H), 6.79-6.93 (m, 1H), 7.10-7.24 (m, 2H), 8.94 (s, 1H).

To 325 mg (0.96 mmol) of 5-aminoquinoxaline (Salon, V. Milata, N. Pronayova, J. Lesko Monatsh. Chem. 2000, 131, 293-299) in 3 ml of acetic acid are added 200 mg (0.64 mmol) of 1 - [2-chloro-5-fluorophenyl) -β-hydroxy-β- (trifluoromethyl) cyclobutanpropanal in 2 ml of toluene and stirred for 24 h at RT. The solution is partitioned between toluene and water, the aqueous phase extracted with toluene, the combined organic phases with sat. NaCl solution, dried (Na ₂ SO ₄ ) and the solvent removed. The crude α - [(quinoxa lin-5-ylimino) methyl] -1- (2-chloro-5-fluorophenyl) -α- (trifluoromethyl) cyclobutanethanol is taken up in methanol / acetic acid 1: 1 and admixed with 100 mg (2.66 mmol) NaBH ₄ . After stirring for 6 hours at RT, the reaction is stopped by adding sat. Quenched NH ₄ Cl solution and diluted the mixture with dichloromethane. After extraction with dichloromethane, the combined organic phases are washed (saturated NaCl solution), dried (Na ₂ SO ₄ ) and the solvents are removed. 280 mg of product are obtained as a dark red resin which can be crystallized from hexane / diethyl ether. MS (ESI): 454 (M + H).

Example 10

4-(5-Fluor-2-methoxyphenyl)-4-methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methyl-1,8-naphthyridin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

1-amino-4- (5-fluoro-2-methoxyphenyl) -4-methyl-2- (trifluormefhyl) propan-2-ol

1.0 g (3.4 mmol) of 2- [2- (5-fluoro-2-methoxyphenyl-2-methylpropyl] -2- (trifluoromethyl) oxirane (WO 00/32584) in 68 ml of THF are mixed with 1.1 g of sodium azide and 180 mg of ammonium chloride The mixture is concentrated by evaporation, concentrated with ether, washed with water, dried (Na ₂ SO ₄ ) and concentrated by evaporation Chromatography on silica gel with hexane-ethyl acetate (0-15%). provides 950 mg of 1-azido-4- (5-fluoro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) propan-2-ol, which are dissolved in 29 ml of THF and treated portionwise with 270 mg at 0 ° C After 1 h, the reaction is treated with ethyl acetate and water and filtered through Celite, the ethyl acetate phase is dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 920 mg of amine.

¹ H-NMR (CDCl _3): δ = 1.4 (s, 3H), 1.5 (s, 3H), 2.15 (d, 1H), 2:45 (d, 1H), 2:55 (d, 1H), 2.75 (d, 1H), 2.80 (m), 3.8 (s, 3H), 6.8 (dd, 1H), 6.9 (td, 1H), 7.05 (dd, 1H) 202 mg (1.13 mmol) of 5-chloro-2-methylnaphthyridine (EV Brown, J. Org. Chem. 1965, 1607-1609) are added to 350 mg (1.13 mmol) of 1-amino-4- (5-fluoro-2-methoxyphenyl) -4-methyl-2- (trifluoromethyl) pentane-2-ol and 128 mg (1.13 mmol) of DABCO. It is heated to 150 ° C for 1.5 h. Chromatography of the cooled melt on silica gel with dichloromethane / methanol (0-10%) gives 385 mg of the desired product. 'H-NMR (CDCl _3); δ = 1.46 (s, 3H), 1.58 (s, 3H), 2.45 (d, 1H), 2.68 (s, 3H), 2.72 (d, 1H), 3.20 (d, 1H), 3.38 (d, 1H) , 3.83 (s, 3H), 5.86 (d, 1H), 6.77 (dd, 1H), 6.92 (ddd, 1H), 7.08 (dd, 1H), 7.11 (d, 1H), 7.71 (d, 1H), 8.50 (d, 1H).

Example 11

4-(5-Fluor-2-hydroxyphenyl)-4-methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-hydroxyphenyl) -4-methyl-1- (2-methyl-1,8-naphthyridin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

Analogously to Example 3, mg (0.13 mmol) of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methyl-1,8-naphthyridin-5-ylamino) -2- (trifluoromethyl) - pentan-2-ol in 15 ml CH ₂ Cl ₂ with 1M boron tribromide CH ₂ Cl ₂ solution. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 102 mg of the product are obtained. ¹ H-NMR (CDCl _3); δ = 1.50 (s, 3H), 1.59 (s, 3H), 2.31 (d, 1H), 2.79 (d, 1H), 2.80 (s, 3H), 3.27 (m, 2H), 3.40 (dd, 1H) , 3.54 (dd, 1H), 6.02 (d, 1H), 6.11 (br, 1H), 6.65 (dd, 1H), 6.82 (ddd, 1H), 7.12 (dd, 1H), 7.18 (t, 1H) , 7. (d, 1H).

Example 12

1-(Cinnolin-5-ylamino)-4-(5-fluor-2-hydroxyphenyl)-4-methyl-2-(trifluormethyl)-pentan-2-ol

1- (cinnoline-5-ylamino) -4- (5-fluoro-2-hydroxyphenyl) -4-methyl-2- (trifluoromethyl) pentan-2-ol

240 mg (0.78 mmol) of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 170 mg (1.17 mmol) of 5-aminocinnoline (JR Elkins, EV Brown J Heterocycl Chem., 1968, 639-646) are dissolved in 10 ml of dichloroethane. Add 1 ml of acetic acid and 30 mg of powdered molecular sieve (4 A), and reflux for 6 h over molecular sieve (4 A). The reaction mixture is partitioned between dichloromethane and water, the phases are separated, the aqueous phase is extracted with CH ₂ Cl ₂ , and the combined organic phases are washed with sat. NaHCO ₃ solution and sat. NaCl solution and dried with Na ₂ SO ₄ . It is concentrated and chromatographed on silica gel with hexane / ethyl acetate (20 to 50%). This gives 70 mg of 1- (cinnolin-5-ylimino) -4- (5-fluoro-2-hydroxyphenyl) -4-methyl-2- (trifluoromethyl) -pentan-2-ol, of which 30 mg are taken up in THF and with 10 mg (0.16 mmol) of sodium cyanoborohydride and 100 ul of acetic acid are added. After stirring for 6 h, partition between water and CH ₂ Cl ₂ and separate the phases. The aqueous phase is extracted with CH ₂ Cl ₂ , the combined organic phases with sat. NaCl solution and dried with Na ₂ SO ₄ . It is concentrated, the residue is taken up in chloroform again, a spatula tip of activated manganese dioxide is added and the mixture is stirred at RT for 2 h. Then the manganese dioxide is filtered off and the filtrate is concentrated. The crude product is chromatographed on silica gel with hexane / ethyl acetate (20 to 50%). 3.3 mg of the desired product are obtained as a red film. MS (ESI): 438 (M + H); ¹ H-NMR (CDCl ₃ ): δ = 1.48 (s, 3H), 1.53 (s, 3H), 2.59 (dd, 2H), 3.13 (s, 1H), 3.24 (dd, 1H), 3.37 (dd, 1H), 3.89 (s, 3H), 4.80-4.84 (m, 1H), 6.47 (d, 1H), 6.83 (dd, 1H), 6.91-6.99 (m, 1H), 7.05 (dd, 1H), 7.76 -7.87 (m, 2H), 8.11 (d, 1H), 9.08 (d, 1H).

Example 13

4-(5-Fluor-2-methoxyphenyl)-4-methyl-1-(8-fluor-2-methylchinazolin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (8-fluoro-2-methylquinazolin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

5 amino-8-fluoro-2-methylquinazoline

To a solution of 3.35 g (20.25 mmol) of chloral hydrate and 21.27 g (149.7 mmol) of sodium sulfate in 72 ml of water is a 50 ° C warm solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of water and 1.6 ml conc. hydrochloric acid (37%), which was previously stirred at this temperature for 1 h. Man stirs another 30 min at RT and heated after the addition of 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water over 45 min at 125 ° C and keeps them Temperature for 5 min. After cooling and another hour is the fancy light brown precipitate filtered off, washed with water and dried. You get 3.0g (15.0 mmol) of the hydroxylimine as an intermediate, the portionwise in 15 ml conc. sulfuric acid be solved at 60 ° C. After complete The addition is heated at 80 ° C for 2 hours and at 90 ° C for 4 hours. Allow to cool and pouring the solution on 100g of ice. It is extracted with ethyl acetate, the organic phase is washed with Water, dries Sodium sulfate and concentrated. After chromatography on silica gel with Hexane-ethyl acetate (0-45%), 1.2 g (7.1 mmol) of the 4,7-difluoroisatin receive. To Isatin in 30 ml of a 1 molar sodium hydroxide solution over 10 min Dripped 1.8 ml of a 30% hydrogen peroxide solution. After 2 hours stir at RT is at 0 ° C chilled and 5 ml of 4 molar hydrochloric acid are added and 50 ml Diluted with water. you extracted with ethyl acetate, dried over sodium sulfate, concentrated and receives so quantitatively 1.27 g of the 3,6-difluoroanthranilic acid, which without further purification is implemented.

The 3,6-difluoroanthranilic acid is heated to 100 ° C. in 8 ml of acetic anhydride for 45 minutes. After cooling, the resulting acetic acid and excess acetic anhydride is azeotroped with toluene in the Va removed. The residue is concentrated with ice cooling with 40 ml of a 25% ammonia solution and stirred for 72 hours. Dilute with water and acidify with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and concentrated. The 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one obtained in this way and 6 g of phosphorus pentachloride are heated to 125 ° C. over 20 h in 20 ml of phosphoryl chloride. After cooling, pour into sat. NaHCO ₃ solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. This gives quantitatively 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which are dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine. 600 mg of palladium on carbon are added and the mixture is shaken for 2 h (480 ml of hydrogen uptake) under a hydrogen atmosphere at atmospheric pressure. The solution is freed from the catalyst by filtration through Celite, washing with 100 ml of ethanol, and evaporated. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline are obtained. To 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6 in 10 ml of DMF are added 890 mg (13.7 mmol) of sodium azide and the mixture is heated for 8 h 125 ° C. The solvent is removed in vacuo and chromatographed on silica gel with ethyl acetate to give 52 mg of product. ¹ H-NMR (CDCl _3); δ = 2.92 (s, 3H), 4.31 (br., 2H), 6.67 (dd, 1H), 7.38 (dd, 1H), 9.37 (s, 1H).

To 200 mg (0.48 mmol) of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 40 mg (0.23 mmol) of 5-amino-8-fluoro-2- Methylquinazoline are added in dichloroethane 50 mg of sodium acetate, 0.05 ml of trifluoroacetic acid and 0.1 ml of acetic acid. The mixture is heated under reflux and removed after 4 hours, the solvent in vacuo with the addition of toluene. Chromatography on silica gel with hexane-ethyl acetate (0-70%) gives 58 mg of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (8-fluoro-2-methylquinazolin-5-ylmino) -2 - (trifluoromethyl) -pentan-2-ol obtained. To the imine in 10 ml of ethyl acetate and 1 ml of triethylamine are added 20 mg of palladium on carbon and shaken for 1 h under a Wassestoffatmosphäre at atmospheric pressure. The solution is freed by filtration from the catalyst and evaporated. Take up in 5 ml of chloroform and add 200 mg of activated manganese dioxide and stir for 30 min. It is filtered through Celite and concentrated in vacuo. Chromatography on silica gel with hexane-ethyl acetate (0-70%) gives 12 mg of the product. 'H-NMR (CDCl _3); δ = 1.46 (s, 3H), 1.55 (s, 3H), 2.37 (d, 1H), 2.76 (d, 1H), 2.90 (s, 3H), 3.13 (dd, 1H), 3.27 (dd, 1H), 3.85 (s, 3H), 4.50 (br, 1H), 5.94 (dd, 1H), 6.77 (dd, 1H), 6.91 (ddd, 1H), 7.08 (dd, 1H), 7.30 (dd, 1H), 9.16 (s, 1H).

Example 14

4-(5-Fluor-2-hydroxyoxyphenyl)-4-methyl-1-(8-fluor-2-methylchinazolin-5-ylamino)-2-(trifluormethyl)-pentan-2-ol

4- (5-fluoro-2-hydroxyoxyphenyl) -4-methyl-1- (8-fluoro-2-methylquinazolin-5-ylamino) -2- (trifluoromethyl) pentan-2-ol

Analogously to Example 3, 20 mg (43 μmol) of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (8-fluoro-2-methylquinazolin-5-ylamino) -2- (trifluoromethyl) pentane 2-ol in 4 ml of CH ₂ Cl ₂ with 2 ml of 1M boron tribromide-CH ₂ Cl ₂ solution. After chromatography on silica gel with hexane / 2-propanol (10%), 17 mg of the product are obtained. 'H-NMR (CDCl _3); δ = 1.50 (s, 3H), 1.57 (s, 3H), 2.35 (d, 1H), 2.86 (s, 3H), 2.90 (d, 1H), 3.21 (dd, 1H), 3.36 (dd, 1H), 4.72 (br, 1H), 6.08 (dd, 1H), 6.54 (dd, 1H), 6.68 (ddd, 1H), 7.03 (dd, 1H), 7.33 (dd, 1H), 9.19 (s, 1H).

Example 15

N-(2-Methylchinazolin-5-yl)-4-(5-fluor-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluormethyl)pentansäureamid

N- (2-methylquinazolin-5-yl) -4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanamide

104 mg (0.41 mmol) of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-oxopentanoic acid (WO 00/32584) and 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline in 2 ml of DMF at RT under argon with 102 mg (4.49 mmol) dicyclohexylcarbodiimide. The mixture is stirred for 3 hours at room temperature, the reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is washed with water and dried (Na ₂ SO ₄ ). Chromatography on silica gel with hexane-ethyl acetate (0-70%) gives 64.9 mg of N- (2-methylquinazolin-5-yl) -4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-oxopentanoic acid amide, which are dissolved in 2.2 ml of DMF and cooled to 0 ° C. The solution is mixed with 0.18 ml of (trifluoromethyl) trimethylsilane and 243 mg of cesium carbonate and stirred for 6 hours at room temperature. Water is added, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. The concentrated intermediate is taken up in 2 ml of THF and 100 μl of a 1 M solution of tetrabutylammonium fluoride are added. The mixture is stirred for 30 minutes, water is added, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. Chromatography on silica gel with hexane-ethyl acetate (0-65%) gives 14.7 mg of product. 'H-NMR (CDCl _3); δ = 1.44 (s, 3H), 1.46 (s, 3H), 2.85 (d, 1H), 2.91 (s, 1H), 3.04 (d, 1H), 3.89 (s, 3H), 4.18 (s, 1H) , 6.77 (m, 2H), 6.94 (dd, 1H), 7.79 (d, 1H), 7.86 (t, 1H), 8.05 (d, 1H), 9.08 (s, 1H), 9.12 (s, 1H).

Example 16

4-(5-Fluor-2-methoxyphenyl)-1-(1H-indazol-4-ylamino)-4-methyl-2-(trifluormethyl)pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -1- (1H-indazol-4-ylamino) -4-methyl-2- (trifluoromethyl) pentan-2-ol

154 mg of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 80 mg of 1H-indazol-4-ylamine (v. Auwers Chem. Ber., 1920, 53 , 1213) are dissolved in 10 ml of toluene and 1.5 ml of acetic acid and stirred for 16 hours at room temperature. It is treated with ethyl acetate and sodium bicarbonate solution, the ethyl acetate phase washed twice with sodium bicarbonate solution, dried over sodium sulfate and concentrated. Chromatography on silica gel with hexane / ethyl acetate (1.5 + 1) gives 172 mg of 4- (5-fluoro-2-methoxyphenyl) -1- (1H-indazol-4-ylmino) -4-methyl-2- (trifluoromethyl) pentane -2-ol obtained. MS (EI ⁺ ): 423/424.

148 mg of imine are dissolved in 5 ml of methanol and 0.5 ml of acetic acid, combined with 60 mg Natriuncyanoborhydrid, stirred for 2 hours at 0 ° C and 6 hours at room temperature. It is treated with ethyl acetate and sodium bicarbonate solution, the ethyl acetate phase washed twice with sodium bicarbonate solution, dried and concentrated. Chromatography on silica gel with hexane / ethyl acetate (1.5 + 1) yields 130 mg of 4- (5-fluoro-2-methoxyphenyl) -1- (1H-indazol-4-ylamino) -4-methyl-2- (trifluoromethyl) pentane -2-ol obtained. MS (EI ⁺ ): 425/426, 1 H NMR (CDCl ₃ ); δ = 1.45 (s, 3H), 1.58 (s, 3H), 2.27 (d, 1H), 2.78 (d, 1H), 3.18 (d, 1H), 3.35 (d, 1H),), 3.85 ( s, 3H), 5.67 (d, 1H), 6.83 (dd, 1H), 6.85 (d, 1H), 6.95 (ddd, 1H), 7.12 (dd, 1H), 7.15 (dd, 1H), 7.86 (br , 1H).

Example 17

4-(5-Fluor-2-hydroxyphenyl)-1-(1H-indazol-4-ylamino)-4-methyl-2-(trifluormethyl)pentan-2-ol

4- (5-fluoro-2-hydroxyphenyl) -1- (1H-indazol-4-ylamino) -4-methyl-2- (trifluoromethyl) pentan-2-ol

Analogously to Example 3, 127 mg of 4- (5-fluoro-2-methoxyphenyl) -1- (1H-indazol-4-ylamino) -4-methyl-2- (trifluoromethyl) -pentan-2-ol are mixed with 10 ml of 1M boron tribromide -CH ₂ Cl ₂ solution implemented. After chromatography on silica gel with hexane / ethyl acetate (40%), 60 mg of 4- (5-fluoro-2-hydroxyphenyl) -1- (1H-indazol-4-ylamino) -4-methyl-2- (trifluoromethyl) pentane 2-ol obtained. Mp: 164-165 ° C, MS (EI ⁺ ): 411/412 'H-NMR (D6-DMSO); δ = 1.37 (s, 3H), 1.55 (s, 3H), 1.92 (d, 1H), 2.92 (dd, 1H), 3.03-3.18 (2H), 5.16 (t (br), 1H), 5.58 (i.e. , 1H), 5.82 (s, 1H), 6.65 (d, 1H), 6.81 (dd, 1H), 6.85 (ddd, 1H), 6.95 (dd, 1H), 7.00 (dd, 1H), 7.97 (s, 1H), 9.75 (s, 1H), 12.7 (s, 1H)

Example 18

4-(5-Fluor-2-methoxyphenyl)-4-methyl-1-(1-methyl-1H-indazol-4-ylamino)-2-(trifluormethyl)pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (1-methyl-1H-indazol-4-ylamino) -2- (trifluoromethyl) pentan-2-ol

154 mg of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 91 mg of 1-methyl-1H-indazol-4-ylamine (Sureau Chimia, 1961, 15, 195) are converted into 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (1-methyl-1H-indazol-4-ylmino) -2- (trifluoromethyl) pentane as described in Example 15. 2-ol reacted with MS (EI ⁺ ): 437/438 and further with sodium cyanoborohydride to give 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (1-methyl-1H-indazol-4-ylamino) - 2- (trifluoromethyl) pentan-2-ol reduced. MS (EI ^+): 439/440, 'H-NMR (CDCl _3); δ = 1.46 (s, 3H), 1.59 (s, 3H), 2.27 (d, 1H), 2.77 (d, 1H), 3.05-3.20 (3H), 3.38 (d, 1H), 3.82 (s, 3H) , 4.00 (s, 3H), 5.60 (d, 1H), 6.75 (d, 1H), 6.84 (dd, 1H), 6.95 (ddd, 1H), 7.12 (dd, 1H), 7.16 (dd, 1H), 7.75 (s, 1H).

Example 19

4-(5-Fluor-2-hydroxyphenyl)-4-methyl-1-(1-methyl-1H-indazol-4-ylamino)-2-(trifluormethyl)pentan-2-ol

4- (5-fluoro-2-hydroxyphenyl) -4-methyl-1- (1-methyl-1H-indazol-4-ylamino) -2- (trifluoromethyl) pentan-2-ol

84 mg of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (1-methyl-1H-indazol-4-ylamino) -2- (trifluoromethyl) -pentan-2-ol 22 are prepared analogously to Example 3 Obtained mg of 4- (5-fluoro-2-hydroxyphenyl) -4-methyl-1- (1-methyl-1H-indazol-4-ylamino) -2- (trifluoromethyl) -pentan-2-ol. M.p .: 193-194 ° C, MS (EI ⁺ ): 425/426, 1H-NMR (D6-DMSO); δ = 1.40 (s, 3H), 1.53 (s, 3H), 1.91 (d, 1H), 2.95 (dd, 1H), 3.09-3.20 (2H), 3.90 (s, 3H), 5.26 (t (br) , 1H),), 5.62 (d, 1H), 5.83 (s, 1H), 6.73 (d, 1H), 6.80 (dd, 1H), 6.85 (ddd, 1H), 6.99-7.05 (2H), 7.93 ( s, 1H), 9.75 (s, 1H)

Example 20

4-(5-Fluor-2-methoxyphenyl)-4-methyl-1-(2-methyl-2H-indazol-4-ylamino)-2-(trifluormethyl)pentan-2-ol

4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methyl-2H-indazol-4-ylamino) -2- (trifluoromethyl) pentan-2-ol

154 mg of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanal and 91 mg of 2-methyl-2H-indazol-4-ylamine (Sureau Chimia, 1961, 15, 195) are prepared as described in Example 15 to give 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methyl-2H-indazol-4-ylmino) -4-methyl-2- ( trifluoromethyl) pentan-2-ol [m.p .: 92-94 ° C, MS (EI ⁺ ): 437/438] and further with sodium cyanoborohydride to give 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1 - (2-methyl-2H-indazol-4-ylamino) -2- (trifluoromethyl) pentan-2-ol reduced. MS (EI ^+): 439/440, 'H-NMR (CDCl _3); δ = 1.47 (s, 3H), 1.56 (s, 3H), 2.30 (d, 1H), 2.75 (d, 1H), 3.14 (d, 1H), 3.29 (d (br), 1H), 3.33 (s (br), 1H), 3.75 (s (br), 1H), 3.85 (s, 3H), 4.15 (s, 3H), 5.55 (d, 1H), 6.86 (d, 1H), 6.95-7.07 (2H ), 7.10 (dd, 1H), 7.15 (dd, 1H), 7.66 (s, 1H)

Example 21

4-(5-Fluor-2-hydroxyphenyl)-4-methyl-1-(2-methyl-2H-indazol-4-ylamino)-2-(trifluormethyl)pentan-2-ol

4- (5-fluoro-2-hydroxyphenyl) -4-methyl-1- (2-methyl-2H-indazol-4-ylamino) -2- (trifluoromethyl) pentan-2-ol

132 mg of 4- (5-fluoro-2-methoxyphenyl) -4-methyl-1- (2-methyl-2H-indazol-4-ylamino) -2- (trifluoromethyl) -pentan-2-ol 100 are obtained analogously to Example 3 mg of 4- (5-fluoro-2-hydroxyphenyl) -4-methyl-1- (2-methyl-2H-indazol-4-ylamino) -2- (trifluoromethyl) -pentan-2-ol, m.p .: 182 ° C , MS (EI ⁺ ): 425/426, 1 H-NMR (D6-DMSO); δ = 1.40 (s, 3H), 1.55 (s, 3H), 1.93 (d, 1H), 2.89 (dd, 1H), 3.05-3.17 (2H), 4.07 (s, 3H), 5.00 (t (br) , 1H), 5.38 (d, 1H), 5.85 (s, 1H), 6.72-6.90 (4H), 6.99 (dd, 1H), 8.16 (s, 1H), 9.73 (s, 1H)

Example 22

4-(2 5-Difluorphenyl)-1-(1H-indazol-4-ylamino)-4-methyl-2-(trifluormethyl)pentan-2-ol

4- (2-5-Difluorophenyl) -1- (1H-indazol-4-ylamino) -4-methyl-2- (trifluoromethyl) -pentan-2-ol

207 mg (0.73 mmol) of 4- (2,5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanal with 150 mg (1.10 mmol) of 1H-indazol-4-ylamine (v. Auwers Chem. Ber., 1920, 53, 1213). 110 mg of 4- (2,5-difluorophenyl) -1- (1H-indazol-4-ylmino) -4-methyl-2- (trifluoromethyl) -pentan-2-ol are obtained. 50 mg (0.12 mmol) thereof are reduced analogously to Example 7 with 27 mg (0.72 mmol) NaBH ₄ . Chromatography on silica gel with hexane / ethyl acetate (20-30%) gives 18 mg of the desired product.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.48 (s, 3H), 1.62 (s, 3H), 2.27 (d, 1H), 2.52 (d, 1H), 3.23-3.38 (m, 2H) , 5.67 (d, 1H), 6.83-7.01 (m, 3H), 7.08-7.18 (m, 2H), 7.89 (s, 1H)

Example 23

4-(4-Brom-2-methoxyphenyl)-2-hydroxy-N-(1H-indazol-4-yl)-4-methyl-2-(trifluormethyl)pentansäureamid

4- (4-bromo-2-methoxyphenyl) -2-hydroxy-N- (1H-indazol-4-yl) -4-methyl-2- (trifluoromethyl) pentanamide

122 mg of 4-dimethylaminopyridine are dissolved in the heat in 3 ml of sulfolane ^®, cooled to room temperature and combined with 0.0525 ml of thionyl chloride. After 45 minutes at room temperature, 192 mg of 4- (4-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) pentanoic acid (WO 98/54159) are added and stirred again at room temperature for 45 minutes. It is mixed with 90 mg of 1H-indazol-4-ylamine (v. Auwers Chem. Ber., 1920, 53, 1213), heated for 1 hour at 80 ° C and combined with sodium bicarbonate solution and ethyl acetate. The ethyl acetate phase is washed four times with water, dried and concentrated. After chromatography on silica gel with hexane / ethyl acetate (50%), 150 mg of 4- (4-bromo-2-methoxyphenyl) -2-hydroxy-N- (1H-indazol-4-yl) -4-methyl-2- ( trifluoromethyl) pentanoic acid amide. MS (EI ⁺ ): 499/501 'H-NMR (D6-DMSO); δ = 1.38 (s, 3H), 1.50 (s, 3H), 2.17 (d, 1H), 3.10 (d, 1H), 3.83 (s, 3H), 6.65 (dd, 1H), 6.97 (d, 1H) , 7.03 (d, 1H), 7.08 (s, 1H), 7.10 (d, 1H), 7.27 (dd, 1H), 7.31 (d, 1H), 7.92 (s, 1H), 9.45 (s, 1H), 13.1 (s, 1H)

Example 24

4-(4-Brom-2-hydroxyphenyl)-2-hydroxy-N-(1H-indazol-4-yl)-4-methyl-2-(trifluormethyl)pentansäureamid

4- (4-bromo-2-hydroxyphenyl) -2-hydroxy-N- (1H-indazol-4-yl) -4-methyl-2- (trifluoromethyl) pentanamide

100 mg of 4- (4-bromo-2-methoxyphenyl) -2-hydroxy-N- (1H-indazol-4-yl) -4-methyl-2- (trifluoromethyl) -pentanoic acid amide are prepared as in Example 3 using 55 mg of 4- (4- 4-bromo-2-hydroxyphenyl) -2-hydroxy-N- (1H-indazol-4-yl) -4-methyl-2- (trifluoromethyl) pentanoic acid amide. MS (EI ⁺ ): 485/487, 'H-NMR (D6-DMSO); δ = 1.42 (s, 3H), 1.48 (s, 3H), 2.23 (d, 1H), 3.15 (d, 1H), 6.54 (dd, 1H), 6.83 (d, 1H), 6.95 (d, 1H) , 7.00 (s, 1H), 7.10 (d, 1H), 7.25 (dd, 1H), 7.30 (d, 1H), 7.95 (s, 1H), 9.61 (s, 1H), 9.95 (s, 1H), 13.12 (s, 1H)

Claims (8)

Compounds of the general formula I

A is an aryl, a benzyl or a phenethyl group, where the aryl, benzyl or phenethyl group may optionally be substituted by one or more radicals from the group C ₁ -C ₅ -alkyl, C ₁ -C ₅ - Alkoxy, C ₁ -C ₅ -alkylthio, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH ₂ - , -O-CH = CH-, - (CH ₂ ) _{n + 2} - where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms, or NR ⁴ R ⁵ , where R ⁴ and R ⁵ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl, R ¹ and R ² independently of one another represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom the chain is a C ₃ -C ₆ -cycloalkyl ring, R ^{3 is} a C ₁ -C ₃ -alkyl group or an optionally partially or completely fluorinated C ₁ -C ₃ -alkyl group, B is optionally a methyl or ethyl group e is a substituted methylene group or a carbonyl group and Q is a quinazolinyl, quinoxalinyl, cinnolinyl, indazolyl, phthalazinyl, naphthyridinyl or benzothiazolinyl group linked via an arbitrary position, which may optionally be substituted by one or more radicals from the group C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, C ₁ -C ₅ - perfluoroalkyl, halogen, hydroxy, cyano, nitro, NR ⁴ R ⁵ , wherein R ⁴ and R ^{5 are} independently hydrogen , C ₁ -C ₅ alkyl or (CO) -C ₁ -C ₅ alkyl, or their N-oxides and their racemates or separately present stereoisomers, and optionally their physiologically acceptable salts. Compounds according to claim 1 characterized in that Q is a benzothiazole linked via any position, Quinazolinyl, quinoxalinyl, cinnolinyl, indazolyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl group. Compounds according to the preceding claims, characterized in that A is a substituted by a hydroxy group or a C ₁ -C ₅ alkoxy group and a halogen atom phenyl. Compounds according to the preceding claims characterized in that they are the (+) - enantiomers. Compounds according to the preceding claims characterized in that they are the (-) - enantiomers Pharmaceutical preparations containing at least a compound according to any one of the preceding claims or their mixtures and pharmaceutically acceptable excipients and carriers. Use of the compounds according to claim 1 for the preparation of medicines. Use of the compounds according to claim 1 for the preparation a medicine for the treatment of inflammatory diseases.