SK160999A3 - Non-steroidal (hetero) cyclically substituted acylanilides with mixed gestagen and androgen activity - Google Patents

Abstract

The invention relates to non-steroidal gestagens of general formula (I), wherein R<1> and R<2> are the same or different and stand for a hydrogen atom, a C1-C5 alkyl group or a halogen atom, or together with the C atom of the chain stand for a ring with 3-7 units, R<3> means a C1-C5 alkyl group or a partially or fully fluorinated C1-C5 alkyl group, A stands for an optionally substituted mono or bi-cyclic aromatic ring, an ester group -COOR<4>, an alkenyl group -CR<5>=CR<6>R<7>, an alkinyl group -CCR<5> or for a partially or fully fluorinated C1-C5 alkyl group, B means a carbonyl group or a CH2 group and Ar is a ring system selected from the group of general partial formulae (2-11). When B represents a CH2 group in general formula (I), Ar additionally means a phenyl radical of partial general formula (12). The novel compounds display a very strong affinity to the gestagen receptor. They can be used on their own or in combination with oestrogen's in contraceptive preparations. They can also be used in the treatment of endometriosis. They can be used with oestrogen's in preparations for the treatment of gynaecological disorders. They can also be used to treat pre-menstrual complaints and in substitution therapy. Their androgen activity enables them to be used for male fertility control, male HRT and to treat andrological syndromes.

Description

Technical field

The invention relates to non-steroidal compounds having a high gestagenic activity and to a process for their preparation.

BACKGROUND OF THE INVENTION

In addition to a large number of steroid compounds with a sgestagenic effect, non-steroid progestogens are known (for example, from EP 0 253 500 B1 and WO 94/01412, see J: Med. Chem. 38 (1995) 4878).

SUMMARY OF THE INVENTION

The present invention provides non-steroidal (hetero) cyclically substituted acylanilides of formula I

Ar in which

R ¹ and R ² are the same or different and represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a halogen atom and, together with the carbon atom of the chain, a ring having a total of 3 to 7 members,

R ³ represents an alkyl group having 1 to 5 carbon atoms or a partially or fully fluorinated alkyl group having 1 to 5 carbon atoms,

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A represents a monocyclic or bicyclic aromatic ring, optionally substituted with one or more radicals selected from the group consisting of halogen atoms, alkyl groups of 1 to 5 carbon atoms, aalkenyl groups of 2 to 5 carbon atoms, CR ⁵ = CR ⁶ R ⁷ , wherein: R ⁵ , R ⁶ and R ⁷ are the same or different and independently of one another are hydrogen atoms or alkyl groups of 1 to 5 carbon atoms, furthermore hydroxy groups, hydroxy groups bearing an acyl group of 1 to 10 carbon atoms, carboxyalkyl group of 3 to 5 carbon atoms C 2 -C 5 cyanalkyl, C 2 -C 5 unsubstituted or substituted C 3 -C 10 allyl, C 3 -C 10 unsubstituted or substituted propargyl, C 2 -C 5 alkoxyalkyl and partially or totally fluorine substituted C1-C5alkyl; further include cyano or nitro, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, C 1 -C 10 monosubstituted or disubstituted amino, or partially or fully fluorinated C 1 -C 5 alkyl, a group -COOR ⁴ wherein R ⁴ represents an alkyl group having 1 to 5 carbon atoms, the alkenyl group -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently of one another are hydrogen atoms, halogen atoms, aryl radicals or alkyl groups of 1 to 5 carbon atoms, alkynyl group -C = CR ⁵ , wherein R ⁵ represents a hydrogen atom or alkyl group of 1 to 5 carbon atoms, or partially or fully fluorinated alkyl groups of 1 to 5 carbon atoms carbon atoms,

B represents a carbonyl group or a CH2 group and

Ar represents a ring system selected from the group of general formulas 2 to 11

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6 7

31342 / ktorých in which residues X ^3a , X ⁴ , X ⁶ , X ⁷ (in sub-formula 2), X ⁴ , X ⁶ , X ⁷ (in sub-formulas 3 and 4), X ^3a , X ^3b , X ⁴ , X ⁶ , X ⁷ (in sub-formulas 5, 6 and 7) or Y ⁴ , Y ⁵ , Y ⁷ and Y ⁸ (in sub-formulas 8, 9, 10 and 11) are the same or different and are selected from the group consisting of hydrogen atoms, alkyl groups of 1 to 5 carbon atoms, which may additionally contain a hydroxyl group, etherified with an alkyl group of 1 to 5 carbon atoms or esterified with an alkanoyl group of 1 to 5 carbon atoms, partially or fully fluorinated alkyl groups of 1 to 5 carbon atoms , (C 2 -C 5) alkenyl groups -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, and alkynyl groups -C ⁵ CR ⁵ , wherein R ⁵ is as defined above, residues X ^3a and X ^3b can furthermore form with the carbon atom of the benzocondensed ring 5, 6 and 7 a total ring of 3 to 7 members, as well as also the radicals X ^4, X ⁶ and X ⁷ (in partial formulas 2, 3,4, 5, 6 and 7) or the Y ^4, Y ^5, Y ⁷ and Y ⁸ (in partial formulas 8, 9, 10 and 11) selected from the group consisting of halogen atoms, hydroxy groups, alkoxy groups of 1 to 5 carbon atoms, and furthermore in case B in formula I is CH 2, Ar is additionally a phenyl radical of formula 12

wherein R ⁹ and R ¹⁰ are the same or different and are cyano, nitro, halogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, partially or fully fluorinated C 1 -C 5 alkyl, alkylthio of 1 to 5 carbon atoms, alkylsuifinylovú having 1 to 5 carbon atoms or an alkylsulfonyl group, as well as in case B is _CH2, physiologically acceptable salts of the compounds of formula I with acids.

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The compounds of the present invention differ from the known non-steroidal compounds having a gestagenic action of the variable-residue substitution pattern standing to the right in formula I. For the compounds present herein, Ar is a benzo-fused bicyclic ring system, whereas for compounds resulting from EP 0 253 500 B1 occur as the closest similar structures at this site at one, two or three times the substituted phenyl moiety.

The compounds of the formula I according to the invention can be present as different stereoisomers due to the presence of more asymmetric centers. Both racemates and separately occurring stereoisomers are within the scope of the present invention.

As groups defined by substituents in the compounds of formula I, they may in each case have the following meanings.

C 1 -C 5 alkyl groups can be at least one methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl groups. Methyl or ethyl is preferred.

The halogen atom may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

When R ¹ and R ² together with the carbon atom of the chain form a 3- to 7-membered ring, it is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, a cyclopropyl ring is preferred.

Partially or fully fluorinated alkyl groups having from 1 to 5 carbon atoms include the abovementioned perfluorinated alkyl groups, in particular trifluoromethyl or pentafluoroethyl, as well as partially fluorinated alkyl groups, for example 5,5,4,4,3,3heptafluoropentyl.

C 2 -C 5 alkenyl groups include, for example, vinyl, allyl or 2,3-dimethyl-2-propenyl; in the case where the aromatic A is substituted by an alkenyl group, it is preferably a vinyl group.

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C 2 -C 5 carbalkoxyalkyl may be, for example, carboxymethyl, tert-butoxymethyl or ethoxymethyl, preferably both.

Representatives of cyanomethyl having 2 to 5 carbon atoms include cyanomethyl, 1-cyanethyl and 2-cyanethyl, with cyanomethyl being preferred.

The C 3 -C 10 allyl group is preferably an unsubstituted allyl group; examples of substituted allyl groups include 1-methylallyl, 1,1-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylallyl, 3,3-dimethylallyl, cinnamyl and 3cyclohexylallyl.

Representatives of the propargyl group having 3 to 10 carbon atoms include unsubstituted propargyl, 3-methylpropargyl, 3-phenylpropargyl or 3-cyclohexylpropargyl. An unsubstituted propargyl group is preferred.

C 2 -C 5 alkoxyalkyl may, for example, be methoxymethyl, ethoxymethyl or 2-methoxyethyl.

Representatives of C 1 -C 5 alkoxy may be selected from the group consisting of methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, 2,2-dimethyl-3-propyl. Preferred are methoxy and ethoxy.

C 1 -C 5 perfluoroalkoxy groups are perfluorinated radicals corresponding to the above alkoxy groups.

The monocyclic or bicyclic aromatic ring A, which may be substituted, is a carbocyclic or heterocyclic aryl radical.

In the first instance, it is, for example, a phenyl or naphthyl radical, preferably a phenyl radical.

As the heterocyclic radical, for example, a monocyclic radical such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrolinyl, imidazolinyl,

31342 / H pyrazolinyl, thiazolinyl, triazolyl and tetrazolyl moieties and all possible isomers with respect to the position of the heteroatoms. As heteroaryl radical A, a thienyl radical is preferred.

In the -COOR ⁴ ester group, a methyl, ethyl, n-propyl or isopropyl group is preferred for R ⁴ as an alkyl group having 1 to 5 carbon atoms.

Suitable alkyl groups having 1 to 5 carbon atoms for the etherification of the hydroxyl groups which may be mentioned are the above-mentioned alkyl groups, in particular the methyl and ethyl groups.

Suitable alkanoyl groups having 1 to 5 carbon atoms for the esterification of hydroxyl groups are, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl, preferably acetyl.

Suitable acyl groups having 1 to 10 carbon atoms for the esterification of hydroxyl groups are, for example, the abovementioned alkanoyl groups, preferably again acetyl, or benzoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl.

When X ^3a and X ^3b together with the carbon atom form a benzo-fused ring system of 3 to 7 ring members, it is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, preferably a cyclopropyl ring.

Suitable alkanoyloxy groups X ⁴ , X ⁶ , X ⁷ , Y ⁴ , Y ⁵ , Y ⁷ or Y ⁸ are formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy or isovaleryloxy, preferably acetyl.

C 1 -C 5 alkylthio, C 1 -C 5 alkylthio, C 1 -C 5 alkylsulfinyl or C 1 -C 5 alkylsulfonyl include the abovementioned C 1 -C 5 alkyl groups. .

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Where the compounds of formula I (B = CH ₂ -) are present as salts, this may be in the form of the hydrochloride, sulfate, nitrate, tartrate or benzoate.

When the compounds of formula (I) of the present invention are present as racemic mixtures, they can be resolved by means of methods known to those skilled in the art to separate racemates into pure optically active forms. For example, racemic mixtures can be separated into pure isomers by chromatography on an optically active carrier material (Chiralpak AD ^R ). It is also possible to esterify the free hydroxy group in the racemic compound of formula I with an optically active acid and to separate the diastereomeric esters obtained by fractional crystallization or to saponify the resolved esters to optically pure isomers. As the optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid may be used.

Preferably, according to the present invention, those compounds of formula I are those in which:

R ¹ and R ² are the same or different and represent a hydrogen atom, a methyl group, an ethyl group or, together with the carbon atom of the chain, a cyclopropyl ring, and / or

R ³ is a C 1 -C 5 perfluoroalkyl group, and / or A is a benzene, naphthalene or thiophene ring optionally substituted with one or more radicals selected from the group consisting of fluorine, chlorine or bromine atoms, methyl groups, ethyl groups, (CH 2) _n , wherein n = 3, 4, 5, which, with two adjacent carbon atoms of the aromatics A, form a ring with n + 2 members and may contain unsaturated bonds, vinyl groups, hydroxy groups, methoxy groups and ethoxy groups, and / or

X ^3a represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or

X ^3a and X ^3b are the same or different and represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and / or

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X ⁴ , X ⁶ and X ⁷ are the same or different and are independently hydrogen or halogen, and / or

Y ⁴ represents an alkyl group having 1 to 5 carbon atoms or a perfluoroalkyl group having 1 to 5 carbon atoms, and / or

Y ⁵ , Y ⁷ and Y ⁸ are the same or different and independently of one another are hydrogen or halogen, and the other substituents have all the meanings given in formula I.

Further preferred are those compounds of formula I in which Ar is a ring system of formula 6, 7, 10 or 11.

The following compounds are particularly preferred according to the present invention:

4-Bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide,

6-bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) phthalide,

5- (2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino) -phthalide, 5- [2-hydroxy-4- (3-methoxyphenyl) -4-methyl-2-trifluoromethyl-4-phenyl -valeroylaminojftalid.

5- [2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide,

5- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-4-phenyl-valeroylaminojftalid,

5- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide,

5- [4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide,

5- [4- (4-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide,

5- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide,

5- [2-hydroxy-4-methyl-4- (4-tolyl) -2-trifluoromethyl-valeroylamino] -phthalide, 5- [2-hydroxy-4-methyl-4- (3-tolyl) -2- trifluoromethyl-valeroylamino] -phthalide, 5- [4- (4-cyanophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (3,4-dimethylphenyl) -2- hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- (4- (3,5-dimethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

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5- [2-hydroxy-4- (2-methoxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- [4- (5-chloro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- [2-hydroxy-4- (2-hydroxy-5-nnetylfenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- [4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- [4- (2-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- [4- (3-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- (2-Hydroxy-4-methyl-2-trifluoromethyl-valeroylamino) -phthalide _I

5- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- [4- (5-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide,

5- (2-Hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide ₁

5- (2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino) -phthalide,

5. [4- (4-fl _u-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide,

5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino] phthalide,

6-acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) phthalide _I, 5- [4- (3-fluoro-4-hydroxyphenyl) -2-hydroxy-4-nnetyl 2-trifluórmetyf-pentylamino] -phthalide,

5- [4- (3-Fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide,

6- (3-hydroxy-3-methyl-1-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino) -phthalide,

6- (2-hydroxy-4-nnetyl-4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl-2 3benzoxazin _I-1-one,

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6- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -4-trifluoromethyl-2,3-benzoxazin-1-one,

4-ethyl-6- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) 2,3-benzoxazin-1-one,

4-ethyl-6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -2 3benzoxazin _1-1-one,

6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2,3-benzoxazin-l-one,

4-ethyl-6- [2-hydroxy-4-methyl-4- (4-methylphenyl) -2-trifluoromethyl-valeroylamino] -2,3benzoxazin-1-one,

6- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valéroyalmino] -2,3benzoxanin-1-one,

4-ethyl-6- [4- (fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylaminol-2,3-benzoxazin-1-one,

6- [4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2,3-benzoxazin-1-one,

1- (4-nitro-3-trifluoromethylanilino) ^and 4-phenyl-2-trifluoromethyl-2-pentanol, _l

1- (4-Nitro-3-trifluoromethylanilino) -4-phenyl-2-trifluoromethyl-2-pentanol ₁

5- (2-hydroxy-4 ₁ 4-dimethyl-2-trifluoromethyl-5-hexenoylamino) phthalide ₁

5- [2-hydroxy-3- (1-phenyl-cyclopropyl) -2-trifluoromethyl-propionylamino] -phthalide

5- [2-hydroxy-3- (1-phenyl-cyclobutyl) -2-trifluoromethyl-propionylamino] -phthalide,

5- [2-hydroxy-3- (1-phenyl-cyclohexyl) -2-trifluoromethyl-propionylamino] -phthalide,

6- (2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one _l of 5- [4- (3-chloro-4-methoxyphenyl) -2 hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide.

Further preferred are compounds resulting from the following Tables 7 to 15.

All of said compounds are particularly preferred in the form of optical antipodes or separated diastereomers.

In the Gestagen Receptor Binding Assay for Gestagenic Effect Using Hare Uterine Cytosol and ³ H-Progesterone as a Reference, the new compounds show strong to very strong affinity for Gestagen receptors (see Table 1).

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Thus, the novel compounds present themselves as a completely new compound activity profile that combines the gestagenic and androgenic activity in contrast to the gestagenic compounds of EP 0 253 500 B1.

For the compounds of the formula I according to the invention, all three of the following cases which have been classified according to the competitive factors at the progesterone receptors (KF _prog ) and the androgen receptors (KF _an dro) in the following manner are given in the table below. first

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Table 1

. Pr. structure competition factor (comparative substance). ^ K-ProgesiCTDu ') C) ($ 4.141-142 ^e ) In ° Xo, 17 (*) Cf.i. 151 ° C) M ^Ó ^ NO, 2.0 65 \ ίΓ% about 0.17 104 1% ^c · ^ I C0 o UO> 11 0 OJ 106 HO Cr. ,, i Y <Ä V 'H H ib ¹ · i ii 0 0.55 and

(*) EP 0 253 500 B1, Example 2

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1) Compounds with stronger progestogenic and less pronounced androgenic UCink (KFprog) 1 3 KFandro 5)

2) Compounds with stronger androgenic and less pronounced gestagenic effect (KF _P r _O g)> 1 and KF _an dro <5)

3) Compounds with marked gestagenic and marked androgenic effect (KF p _ro g) <1 and KF andro <5)

Depending on their classification according to 1), 2) or 3), the novel compounds of the present invention can be used for various medical or pharmaceutical purposes.

The compounds classified under 1), with a stronger gestagenic and less pronounced androgenic effect, are very effective gestagens which, like many known gestagenic compounds, are suitable for the maintenance of pregnancy in both parenteral and oral administration.

In combination with estrogen, combination preparations can be obtained which can be used for contraception and for treating climacteric problems.

Owing to their high gestagenic activity, the novel compounds of the formula I, classified in paragraph 1), alone or in combination with the cicrogens in contraceptive preparations, can be used. However, all other applications known to date for gestagens are also open to these new compounds (see, for example, "Contrazeption mit Hormonen", Hans Dieter Taubert and Herbert Kuhl, Georg Thieme Verlag Stuttgart-New York, 1995).

Appropriate dosages may be ascertained by conventional methods, for example by determining bioequivalence, for example in a pregnancy maintenance test compared to a known gestagen to determine use, for example an amount that is bioequivalent to 30 to 150 pg levonorgestrel for contraception.

The dosage of the compounds of the present invention, classified in paragraph 1), in contraceptives should preferably be 0.01 to 2 mg per day.

Gestagenic and estrogenic active ingredient components are preferably administered orally in contraceptive preparations. The daily dose is preferably a single dose.

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Suitable estrogens are all natural and synthetic known compounds known as estrogens.

Natural estrogens include, in particular, estradiol, as well as its further esters, such as valerate and the like, or estriol.

However, synthetic estrogens such as ethynyl estradiol, 14α, 17α-ethanol-1,3,5- (10) estratriene-3,17β-diol (WO 88/01275), 14α, 17α, -ethanol-1, but not particularly preferred, may be mentioned. 3,5- (10) estratriene-3,16a, 17β-triol (WO 91/08219) or 15,15-dialkyl estradiol derivatives and in particular 15,15-dimethylestradiol (WO 95/04070). Of the synthetic tarragons, ethynyl estradiol is preferred.

Also the short-known estratriene-3-amidosulfonates (WO 96/05126 and WO 96/05217), derived from estradiol or ethinyl estradiol, which are characterized by low hapathic estrogenicity, are suitable for use with the compounds of the present invention, classified in paragraph 1).

Finally, 14a, 15a-methylensteroids of the various series, in particular 14a, 15a-methylene-17a-estradiol, as well as the corresponding 3-amidosulfonate derivatives can be contemplated.

The estrogen is applied in an amount corresponding to 0.01 to 0.05 mg of ethinyl estradiol.

The compounds of formula I, classified in paragraph 1), may also be used in preparations for the treatment of gynecological disorders and for substitution therapy. Because of their good profile of action, the compounds of the present invention are particularly well suited for the treatment of premenstrual problems such as headaches, depressive states, water retention and mastodynia. The daily dose for treating premenstrual problems is about 1 to 20 mg.

Analogously, as is known for other gestagens, the novel compounds can also serve to treat endometriosis.

Finally, the novel compounds can also be used as progestogenic components in the newly published female fertility control products which are characterized by the additional use of competitive progesterone antagonists (H.B. Croxatto and A.M. Salvatierra, Female Contraception and Small Advances in

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".with

Gynecological and Obstetric Research Serias, Parthenon Publishing Group 1991, p. 245; WO 93/17686, WO 93/21927, U.S. Pat. 5,521,166).

The dosage lies within the stated range, the formulation can be used as with conventional OC preparations. The application of additional competitive progesterone antagonists can also be carried out sequentially.

The compounds of formula (i) above which are included in (2) or (3) above, i.e. compounds which in any case have a strong androgenic action (androgenic gestagens), can be used for the production of preparations for controlling male fertility.

In several WHO studies, the contraceptive effect of a combination of orally administered gestagen (depotmedroxyprogesterone acetate, levonogestrel-ester, cyproterone acetate) with parenterally administered androgen (testosterone monantate) is being tested in men.

In contrast, fertility control in men in a single administration form, orally or transdermally, is possible with the present compounds.

In addition, the compounds of the present invention with androgenic activity can be used in older men for male HRT (Hormone Replacement Therapy).

Such compounds of the formula I which can be classified in the aforementioned paragraph 2), i.e. compounds with predominantly androgenic and weaker gestagenic action, can be used for male hormone therapy. With them, preparations can be made to treat hypergonadism or to treat male infertility and potency disorders.

To control male fertility and to treat the aforementioned disease pattern, the compounds of the present invention are used in doses equivalent in effect to the amounts used in the WHO trials of testosterone monohydrate or those already used in the androgen therapy of the compounds used.

In effect equivalent amounts are those which achieve a comparable effect in the androgenic effect on the seminal vesicle and / or rat prostate (Hershberger test).

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For men, HRT is currently using a dose of approximately 10 mg / day testosterone monanthate.

For the WHO male fertility control study presented herein, various testosterone esters (monantate, bucyclate, undecanoate) are used in an amount of about 10 to 30 mg per day.

At this point, it should be pointed out that the transitions between 1), 2) and 3) with respect to the different indications to these different mixed profiles 1), 2) and 3) are movable. For such compounds which, by virtue of their KF _prog and / or KF _an dro, are on the edge of said KF region, the indications assigned to the adjacent effect profile can also be considered without further consideration.

In part, the compounds of the formula I also exhibit effects on glucocorticoid and / or mineralocorticoid receptors.

The formulation of the pharmaceutical compositions based on the novel compounds is carried out in a manner known per se by treating the active ingredient, optionally in combination with an estrogen, with carrier substances, diluents and, optionally, taste correction agents usable in galenics and converting them into the desired dosage form. .

Tablets, coated tablets, capsules, pills or solutions are particularly suitable for the preferred oral dosage form.

Oil solutions, such as solutions in sesame oil, castor oil and cottonseed oil, are particularly suitable for parenteral dosage forms. Diluents, such as benzyl benzoate or benzyl alcohol, may be added to increase solubility.

The compounds of formula I may be administered continuously via the intramaterial release system (IntraUterine System = IUS; for example, MIRENA®); the release rate of the active compound or compounds is selected so that the daily release dose lies within the aforementioned dosage range. It is also possible to incorporate the compounds of the present invention into the transdermal system and thus to apply them transdermally.

The compounds of the formula I according to the invention can be prepared as follows.

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The present invention further provides a process for the preparation of compounds of the formula I which comprises:

1. reacting a carbonyl compound of formula II

Ar in which A, B, Ar, R ¹ and R ^{2 have the} meanings given in formula I, with a compound of the general formula

Wherein R ³ has the meaning given in formula I, in the presence of a catalyst, or an alkyl metal compound, for example with a Grignard reagent or an alkyllithium compound, to a compound of formula I. Suitable catalysts are fluoride salts or basic compounds such as are alkali metal carbonates (J. Amer. Chem. Soc. 111, 393 (1989));

2. reacting a compound of formula III

in which A, B, R ¹ , R ² and R ^{3 are} as defined in formula I and FG is a leaving group, with a compound of the formula

Ar-NH-R ¹¹

31342 / H wherein R ¹¹ is H or acyl having 1 to 5 carbon atoms and Ar is as defined in formula I wherein the radical R ¹¹ optionally cleaved off to arrive at compounds of the formula I. Compounds of formula III it can optionally be formed as an intermediate, for example it can be an intermediate acid chloride formed from the corresponding carboxylic acid. Cleavable groups include, for example, a chlorine or bromine atom or a toxylate radical; or reacting a compound of formula IV

In which A, R ¹ , R ² and R ³ in formula I are as defined above, with a compound of formula

Ar-NH-R ¹¹ , wherein R ¹¹ and Ar are as hereinbefore defined, optionally removing R ¹¹ to form a compound of formula I wherein B is CH 2; or be

4. A compound of formula I which contains an Aryl-X group in A or Ar, wherein "Aryl" is an isocyclic or heterocyclic aromatic, as defined in formula I, and X is a bromine or iodine atom, or -O-SO ₂ R ¹² , wherein R ¹² is a C 1 -C 5 perfluoroalkyl group, is reacted in a known manner with a compound of the formula

R ¹³ -Y

31342 / H wherein R ¹³ is an optionally substituted aryl ethenyl or ethynyl radical and Y is a hydrogen atom (J. Org. Chem. 43, 2947 (1978)), B (OR ¹⁴ ) 2 (J. Org. Chem. 58, 2201 (1993)) or Sn (R ¹⁵ ) 3 (J. Org. Chem. 52, 422 (1987) in which R ¹⁴ and R ¹⁵ represent a phenyl radical or an alkyl group having 1 to 5 carbon atoms and R ¹⁴ also hydrogen atom, Mg-halogen or an alkali metal atom, with metal catalysts for the compound Aryl-R ¹³ ;

5. In a compound of formula I which contains alkoxy or acyloxy substituents in A or Ar, the OH group is liberated and optionally etherified or esterified by further reaction or is completely eliminated by hydrogenation after conversion to 1-phenyl-5-tetrazolyl ether (J. Amer. Chem. Soc., 88, 4271 (1966).

Of the above process variants, process 1 and process 2 are suitable for the preparation of all the compounds of formula (I).

By way of variant 3, compounds of formula (I) wherein B is -CH 2 - are obtainable.

By means of process variants 4 and 5, functionalizations can be carried out on the compounds of the formula I already obtained.

If desired, compounds which have been produced according to any of the above methods and in which A is an optionally substituted aromatic ring can be selectively substituted on that aromatic ring by known methods. Examples of such methods include catalytic hydrogenation of multiple bonds and halogenation.

DETAILED DESCRIPTION OF THE INVENTION

Production of starting materials

The starting materials used in the following examples are prepared by the following methods.

31342 / H

4-Methyl-1-phenyl-2-oxovaleric acid

A Grignard solution made from 26.4 g magnesium and 162 ml 2-methyl-2-phenyl-1-chloropropane in 150 ml diethyl ether is added dropwise to 600 ml diethyl oxalate at -30 ° C. After 2 hours at room temperature, the mixture is added to ammonium chloride solution, extracted with diethyl ether, dried over anhydrous sodium sulphate and distilled in fractionation to give 84 g of ethyl ester (b.p. 115-120 ° C / 0.03 hPa). which is dissolved in 11 ml of methanol, treated with 500 ml of 1 m sodium hydroxide and stirred for 1.5 hours at room temperature. After evaporation of the methanol in vacuo, the residue is partitioned between water and diethyl ether, the aqueous phase is acidified with hydrochloric acid and extracted with diethyl ether. Evaporation gave 57 g of 4-methyl-4-phenyl-2-oxovaleric acid as a thick oil.

4,4-Dimethyl-2-oxo-5-hexenoic acid

From 50 g of 3,3-dimethyl-4-pentenoic acid methyl ester saponified with 10% potassium hydroxide, 36 g of 3,3-dimethyl-4-pentenoic acid is obtained as an oily liquid. Stirring with thionyl chloride (20 hours at room temperature) gave the acid chloride (bp 59 ° C / 30 hPa). 16 g of this material are mixed with 15 g of trimethylsilyl cyanide and 0.16 g of zinc iodide for 4 days and after distillation, 13 g of 4,4-dimethyl-2-oxo-5-hexanoic acid nitrile is obtained (boiling point 75-85 ° C / 30 ° F). hPa). 2 g of this material are saturated with HCl (0.6 ml) in hexane (13 ml) under ice-cooling and mixed with water after 2 hours. After drying over anhydrous sodium sulfate and evaporation, 0.558 g of 4,4-dimethyl-2-oxo-5-hexenoic acid methyl ester (boiling point 48 ° C / 0.003 hPa) is obtained from the hexane phase. 0.535 g of this substance are saponified with 1.3 ml of 3 N sodium hydroxide to give 0.32 g of 4,4-dimethyl-2-oxo-5-hexenoic acid as a yellowish liquid.

31342 / H

3- (1-Phenyl-cyclobutyl) -2-oxo-propionic acid 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminium hydride in toluene (1.2 molar) at -72 ° C. to -69 ° C. After 4 hours at -75 ° C, 30 ml of ethyl acetate are added dropwise. After warming to room temperature, additional ethyl acetate and water were added, after which the mixture was filtered through diatomaceous earth, the organic phase was separated, dried over anhydrous sodium sulphate and evaporated. Chromatography on silica gel (hexane with 0-10% ethyl acetate) gave 7.6 g of 1-phenylcyclobutylcarbaldehyde. 3 g of this material is dissolved in 10 ml of tetrahydrofuran and added dropwise at 0 ° C to a solution obtained by mixing 5 g of triethyl 2-ethoxyphosphonoacetate in 70 ml of tetrahydrofuran at 0 ° C with 10.3 ml of a 2 molar solution of lithium diisopropylamide in tetrahydrofuran. / heptane / ethylbenzene. After 20 hours at room temperature, water was added, extracted with ethyl acetate, the extract was separated, dried over anhydrous sodium sulfate and evaporated. 2 g of this crude product are saponified with 28 ml of 1 N sodium hydroxide. 1.32 g of acid are obtained, which is heated to 90 DEG C. for 20 hours with vigorous stirring with 25 ml of 1 molar sulfuric acid. After extraction with diethyl ether, drying over sodium sulphate and evaporation, 0.89 g of 3- Of (1-phenylcyclobutyl) -2-oxo-propionic acid in the form of a yellowish oily color.

3- [1- (2-Methoxy-phenyl) -cyclopropyl] -2-oxo-propionic acid

16.7 g of 2-methoxyphenylacetonitrile, 158 ml of lithium triisopropylamide (two molar solution) and 46.7 ml of 1.2 dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric triamide are reacted with each other in accordance with J. Org. Chem. 40 (1975) 3497. 5.6 g of 1- (2-methoxyphenyl) -cyclopropyl-carbonitrile (b.p. 104-115 ° C / 10 Pa) are obtained, which are reacted further as described for 3- ( 1-phenyl-cyclobutyl) -2-oxopropionate. 3- [1- (2-Methoxyphenyl) cyclopropyl] -2-oxo-propionic acid is obtained as an oil.

31342 / H

Analogously to that described for the preparation of 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid and 3- [1- (2-methoxyphenyl) -cyclopropyl] -2-oxo-propionic acid, the acids listed in Table 2 are obtained.

Table 2

COOH

Pr. ' n FROM" (S) m.p.. (° C) I 3-F oil 1 2-Cl 60-63 1 4-Cl oil l 2-Br 4 $ -54 1 3-Br oil 1 2.4-C b 185-190 1 3-OCH ₃ oil 1 3-CF3 oil J oil J 4-CK3 50-61 4 4-OCK3 oil

31342 / H

3- (1-Phenyl-cyclopropyl) -2-oxo-propionic acid

The title compound is obtained analogously to that described for the preparation of 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid.

3- (1-Phenyl-cyclohexyl) -2-oxo-propionic acid

The title compound is obtained analogously to that described for the preparation of 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid.

4- (3-Methoxyphenyl) -4-methyl-2-oxo-valeric acid

4.2 ml of a 0.6 m solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran was mixed with copper (I) bromide / dimethylsulfide complex at -70 ° C and then stirred at -10 ° C for 20 minutes. Then the mixture is recooled to -70 ° C and 0.33 ml of 1,3-dimethyltetrahydro-2-1H-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs) are slowly added. Annalen 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran, after which the mixture was stirred for one hour at -70 ° C and warmed to room temperature. Then, 2 N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, evaporated and the residue is dissolved in 5 ml of dichloromethane. After addition of 200 mg of tetrabutylammonium fluoride, the mixture is left for one hour at room temperature, then washed with water, the dichloromethane phase is separated, dried over anhydrous sodium sulphate and evaporated. After chromatography on silica gel using hexane / ethyl acetate (97; 3) 63 mg of methyl 4- (3-methoxyphenyl) -4-methyl-2-oxo-valeric acid are obtained, which is mixed with 1 ml of potassium hydroxide in methanol (10%). After 45 minutes the mixture was evaporated, the residue was dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6 N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase was combined, dried over anhydrous sulfate

31342 / H sodium and evaporated. 50 mg of 4- (3-methoxyphenyl) -4-methyl-2-oxo-valeric acid are obtained.

2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleric acid

A Grignard reagent is prepared from 1.5 g of magnesium and 10 g of 2-methyl-2-phenylpropyl chloride in 100 ml of diethyl ether, which, after reaction with 10 g of trifluoropyruvate, gives 9.5 g of 2-hydroxy-4-methyl-4-phenyl ethyl ester. -2-trifluoromethyl-valeric (b.p. 90 ° C / 0.045 hPa).

7.5 g of the ethyl ester are refluxed for 18 hours with 100 ml of a solution of potassium hydroxide in methanol (10%). After concentration in vacuo, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase was acidified with 2N hydrochloric acid and extracted with diethyl ether. Evaporation of the solvent gave 3.2 g of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid as a colorless crystalline solid (m.p. 124-126 ° C).

4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid

1.3 g of anhydrous zinc chloride and 13.2 granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methalyl bromide for 30 minutes. A solution of 25 g of metalyl bromide and 17 g of trifluoropyruvic acid ethyl ester in 80 ml of tetrahydrofuran is then added dropwise over 2 hours while boiling and boiling for a further hour. Saturated ammonium chloride solution and 300 ml ethyl acetate were then added under ice-cooling, stirred for 30 minutes at 0 ° C and the separated ethyl acetate phase was washed with saturated ammonium chloride solution and three times with water. The organic phase is dried over sodium sulphate and evaporated and the residue is distilled under vacuum. 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester (boiling point 48 ° C / 1 hPa) are obtained.

To 5 ml of 4-fluoroanisole and 0.9 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester is added 0.8 g of anhydrous aluminum chloride and 40 ml

31342 / H of stirring at room temperature was added to ice-cold 2 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 1 N hydrochloric acid and water, dried over sodium sulphate and evaporated. Chromatography on silica gel using hexane / ethyl acetate (1: 1) gave 1 g of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleric acid ethyl ester (m.p. 38-39 ° C). .

1.9 g of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester was refluxed with 40 ml of potassium hydroxide solution in methanol (10%) for 2 hours. After evaporation of the solvent in vacuo, water is added, extracted with hexane and the separated aqueous phase is acidified with 6 N hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate phase is washed with water, dried over sodium sulphate and evaporated. The residue is crystallized from hexane to give 1.55 g of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid (m.p. 102-104 ° C).

2-Hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethylvaleric acid and 2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeric acid.

Analogously to the above, a mixture of 2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl-valeric acid is obtained. and 2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeric acid (9: 1) (mp 150-151 °).

The acids listed in Table 3 are prepared analogously.

Table 3

31342 / H

for * Mp. (®Η) (° C) Z ^ CKs 13o-138 Z ^ Z ⁴ CK ₃ 115-117 Z ³ = Z ⁵ = CH ₅ US Z = Br 131-132 Z ^ ci 133-135

31342 / H

Conversion by standard methods yields additional acids from the above acids or their precursors:

2-Hydroxy-4-methyl-2-trifluoromethyl-4- (4-vinylphenyl) -valeric acid

Heating of ethyl 4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, tributylvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine palladium-11-chloride in dimethylformamide to 120 ° C gives ethyl 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-vinylphenyl) valerate, which affords the title compound by alkaline saponification (mp 73-74 ° C).

4- (4-Acetylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid

Prepared in analogy to the preceding compound from 4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1 ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o- tolylphosphine-palladium-11-chloride in dimethylformamide by heating to 120 ° C followed by acid hydrolysis of the enol ether and alkaline saponification (mp 158-162 ° C).

4- (4-Acetyl-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid

Prepared in analogy to the preceding compound from 4- (4-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, tributyl-1-ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o ethyl ester -tolylphosphine-palladium-11-chloride i, I in dimethylformamide by heating to 120 ° C (oily liquid)

4- (4-Cyanophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid

Prepared from ethyl 4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, zinc cyanide and tetrakis-triphenylphosphine palladium in dimethylformamide at 140 ° C. foam.

31342 / H

4- (4-Cyrbamoylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid

It is obtained by treating the ethyl ester of the above acid with hydrogen peroxide and saponification (m.p. 244-245 ° C).

4- (4-Cyano-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid

Prepared from 4- (4-methoxyphenyl) -4-methyl-2-trifluoromethylvaleric acid ethyl ester by bromination with N-bromosuccinimide in dimethylformamide at 0 ° C followed by saponification (m.p. 94-96 ° C).

2-Hydroxy-4-methyl-4- (3-nitro-4-methoxyphenyl) -2-trifluoromethyl-valeric acid

This compound is obtained by reacting 2.5 g of 2-hydroxy-4I (4-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeric acid ethyl ester with 4 ml of 100% nitric acid in 12 ml of trifluoroacetic acid for one hour at 0 °. C (mp 79-80 ° C).

4- (4-Iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid

To 24.2 mmol of methylmagnesium bromide in 23 ml of diethyl ether is added 3.2 g of methyl 4-iodo-2-methoxybenzoate in 10 ml of diethyl ether. After 20 hours, ammonium chloride solution is added, the ether phase is separated, dried and evaporated. 2.4 g of the residue obtained are dissolved in 10 ml of dichloromethane, mixed with 714 mg of 2-trimethylsilyloxyacrylic acid ethyl ester, cooled to -70 DEG C. and treated with 0.27 ml of tin (II) chloride. After 15 minutes, this solution was added to a potassium carbonate solution. After extraction with diethyl ether, the organic phase is washed with water, dried and evaporated. 500 mg of the 4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid ethyl ester thus obtained are stirred with 8.6 ml of 1 M sodium hydroxide in ethyl alcohol / water (2: 1, v / v). volume) and stirred for 3 hours at room temperature. After addition of water, it is extracted

31342 / H with diethyl ether, the aqueous phase was acidified with 1m hydrochloric acid and extracted with diethyl ether. After drying and evaporation, 410 mg of 4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid was obtained as a yellowish oil.

4- (3-Chloro-phenyl) -4-methyl-2-oxo-valeric acid

It is obtained in an analogous manner to that described above in the form of an amorphous powder.

4- (3-Bromophenyl) -4-methyl-2-oxo-valeric acid

It is obtained in an analogous manner to that described above in the form of an amorphous powder.

4- (2-Iodophenyl) -4-methyl-2-oxo-valeric acid

It is obtained in an analogous manner to that described in the previous embodiment in the form of an amorphous powder.

4- (3-Iodophenyl) -4-methyl-2-oxo-valeric acid

It is obtained in an analogous manner to that described in the previous embodiment in the form of an amorphous powder.

4- (4-Iodophenyl) -4-methyl-2-oxo-valeric acid

It is obtained in an analogous manner to that described in the previous example in the form of an oily substance.

4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid

31342 / H

It is obtained in an analogous manner to that described in the previous embodiment (m.p. 58-60 ° C).

4- (4-Bromo-2-methoxyphenyl) -2-oxo-valeric acid

It is obtained in an analogous manner to that described in the previous example in the form of an oily substance.

3- (1-Phenylcaclopentyl) -pyruvic acid

It is obtained in an analogous manner to that described in the preceding example from 1-phenylcyclopentanol by reaction with 2-trimethylsilylloxyacrylic acid ethyl ester and tin (II) chloride as an oily substance.

4-Toluenesulfonic acid (2-hydroxy-4-phenyl-2-trifluoromethylpentyl) ester

Grignard reagent was prepared from 2.6 g of magnesium shavings and 15 ml of 2-phenyl-1-chloropropane in diethyl ether, to which 15 ml of oxalic acid diethyl ester was added over 30 minutes at 30 ° C. The reaction mixture was stirred for 1 hour at -20 ° C and for 2 hours at 0 ° C and then treated with saturated ammonium chloride solution. The diethyl ether phase is separated, dried over sodium sulphate, evaporated and distilled in vacuo. 17.7 g of 2-oxo-4-phenyl-valeric acid ethyl ester (b.p. 98-100 ° C / 0.03 hPa) are obtained.

4.4 g of 2-oxo-4-phenylvalerate are dissolved in 40 ml of tetrahydrofuran and treated at -78 DEG C. with 3.6 ml of trifluoromethyltrimethylsilane and 2 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 24 hours at -78 ° C, an additional 20 mL of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. The reaction mixture is stirred for

1.5 hours at 0 ° C, ethyl acetate and saturated sodium chloride solution are added, the organic phase is separated and washed with saturated sodium chloride solution and water. It is then dried over anhydrous sodium sulphate,

31342 / H was evaporated and distilled on a bead column. 4.4 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester (boiling point 95 DEG-100 DEG C./0.04 hPa) are obtained.

I

4.35 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester are dissolved in 100 ml of diethyl ether, 1.3 g of lithium aluminum hydride are added at 0 DEG C. and stirred at 0 DEG C. for one hour and for 16 hours at room temperature. While cooling, a small amount of water is added, stirred for one hour, the diethyl ether phase is separated, dried over sodium sulphate, evaporated and distilled on a bead column. 4.1 g of 4-phenyl-2-trifluoromethyl-1,2-pentadiol (boiling point 120 DEG C./0.04 hPa) are obtained.

4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentadiol in 30 ml of pyridine are mixed with 3.8 g of 4-toluenesulfonic acid chloride at 0 ° C. After 16 hours at 0 ° C, the reaction mixture was evaporated in vacuo, treated with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated. Crystallization from ethyl acetate-hexane gave 4.9 g of 4-toluenesulfonic acid (2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl) -ester (m.p. 95-96 ° C).

Analogously there is obtained 4-toluenesulfonic acid (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentyl) ester (m.p. 78 ° C).

Analogously there is obtained 4-toluenesulfonic acid [(4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentyl] ester (mp 80-81 ^e C) and [2-hydroxy-4- (2-methoxy-5)]. 4-Toluenesulfonic acid-4-methyl-2-trifluoromethyl-pentyl] -ester (mp 93-95 ° C).

2- (2-phenylpropyl) -2-trifluoromethyl-oxiran

400 mg of 4-toluenesulfonic acid (2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl) -ester in 5 ml of dimethylformamide are mixed with 35 mg at 0 ° C.

31342 / H sodium hydride (80% in mineral oil). After one hour at 0 ° C, the mixture was diluted with water and extracted with dichloromethane. The dichloromethane phase is washed with water, dried over sodium sulphate, evaporated and the residue is distilled. 200 mg of 2- (2-phenylpropyl) -2-trifluoromethyl-oxirane (boiling point 110 ° C / 1 hPa) is obtained.

4-Bromo-5-aminophthalide 3-Bromo-4-nitro-1,2-xylene is suspended in 200 ml of pyridine and 600 ml of water and mixed in portions with 260 g of potassium permanganate at 60 ° C as the temperature rises The mixture was heated at 95 ° C for 2 hours, filtered, acidified with hydrochloric acid and extracted with diethyl ether. After evaporation of the solvent, 27 g of 3-bromo-4-nitrophthalic acid is obtained.

g of this acid was heated to 220 ° C for 15 minutes and then distilled on a bead column. At 0.03 hPa 10 g of 3-bromo-4-nitrophthalic anhydride is distilled.

This anhydride is dissolved in 120 ml of dimethylformamide and slowly mixed with 78.8 ml of a 0.5 M solution of sodium borohydride in dimethylformamide at 0 ° C. After 3 hours at 0 ° C, 2 N acetic acid was carefully added. The extract is washed with potassium hydrogen carbonate solution, dried over sodium sulphate and the ethyl acetate phase is evaporated to give 6.6 g of 4-bromo-5-nitrophthalide.

6.6 g of 4-bromo-5-nitrophthalide are dissolved in 45 ml of ethyl alcohol and added dropwise to a well-stirred mixture of 65 g of ferrous sulfate, 220 ml of water and 65 ml of ammonia (33%), heated to 60 ° C. After stirring at 60 ° C for 5 hours, the mixture was stirred five times with diethyl ether and the ether phase was evaporated. 4.1 g of 4-bromo-5-aminophthalide are obtained as a residue (m.p. 176-180 ° C).

31342 / H

6-bromo-5-amino-

4-Bromo-5-nitrophthalic anhydride is prepared analogously to 4-bromo-5-nitro-1,2-xylene as described above.

Boiling with ethanol gives a mixture of 2-bromo-6-ethoxycarbonyl-3-nitro-benzoic acid and 3-bromo-6-ethoxycarbonyl-4-nitrobenzoic acid from this anhydride.

To a 7.2 ml of a 0.66 m solution of dimethylformamide in dichloromethane at 0 ° C was carefully added dropwise 1.2 ml of oxalyl chloride and the solution was stirred for 1 hour at 0 ° C and for 5 minutes at room temperature. After evaporation in vacuo, the residue obtained is suspended in 7 ml of acetonitrile, cooled to 35 ° C and treated dropwise with 1.5 g of the above ester mixture. After one hour at this temperature, the reaction mixture was cooled to -70 ° C and 2.4 ml of a 2m solution of sodium borohydride in dimethylformamide was added dropwise. The mixture was stirred for 20 hours at room temperature, water was added, basified with potassium carbonate and extracted with diethyl ether. The diethyl ether phase was dried over anhydrous sodium sulfate and evaporated to give a mixture of 5-bromo-6-nitrophthalide and 6-bromo-5-nitrophthalide which was separated on silica gel using hexane / ethyl acetate (95: 5).

The reduction to aminophthalide is carried out as described above. 6-Bromo-5-aminophthalide is obtained (m.p. 235-241 ° C).

5-Amino-3- (1-propenyl) -phthalide 2-bromo-4-nitrobenzoic acid with boiling for 2 hours is converted to the acid chloride, which is dissolved in 50 ml of tetrahydrofuran and then added dropwise, followed by distilling off the remaining thionyl chloride. to 3 ml of allylamine in 20 ml of tetrahydrofuran. After 20 hours at room temperature, it is partitioned between 1N hydrochloric acid and ethyl acetate, the ethyl acetate phase is washed with water, dried over sodium sulphate and evaporated. The residue is crystallized from hexane. 5.6 g of 2-bromo-4-nitrobenzoic acid allylamide (m.p. 98-100 DEG C.) are obtained.

31342 / H

This material was dissolved in 35 mL of ethyl alcohol and added dropwise to a well stirred mixture of 50 g of ferrous sulfate, 170 mL of water and 50 mL of ammoniac (33%), heated to 60 ° C. After 2 hours at 60 ° C It is stirred with 200 ml of diethyl ether, the diethyl ether phase is evaporated and the residue is crystallized from hexane. 3.1 g of 4-amino-2-bromobenzoic acid allylamide (m.p. 115 DEG-117 DEG C.) are obtained.

g of 4-amino-2-bromo-benzoic acid allylamide, 5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid are refluxed with a water separator for 1.5 hours. The solution is then diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with potassium carbonate solution, dried over sodium sulphate and concentrated. The residue is crystallized from hexane. This gives 13.4 g of N-allyl-2-bromo-4- ₍₂ '5-dimethyl-pyrrol-1-yl) benzamide (mp 136 to 138 ° C).

g of N-allyl-2-bromo-4- (2,5-dimethylpyrrol-1-yl) -benzamide in 100 ml of dimethoxyethane is mixed with 14.2 ml of 1,4 M butyllithium in hexane at -70 ° C and after 30 minutes 1.63 ml of crotonaldehyde are added at -70 ° C. The reaction solution was allowed to warm to room temperature, stirred for an additional 20 hours, 50 ml of 50% acetic acid was added and heated at 60 ° C for 6 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, ethyl ester phase. Wash with potassium carbonate solution, dry over anhydrous sodium sulphate and evaporate. The residue is chromatographed on silica gel with hexane / ethyl acetate (98: 2) to give 1.1 g of crystalline S-N, N-dimethylpyrrol-1-yl-S-N-propenyl-phthalide (m.p. 91-95 ° C).

1.1 g of 5- (2,5-dimethylpyrol-1-yl) -3- (1-propenyl) -phthalide, 8.56 g of hydroxylamine hydrochloride and 4.58 g of potassium hydroxide in 75 ml of a mixture of ethanol and water (16 g). (6.8) was heated at 120 ° C for 24 hours. The solvent was then distilled off, the residue was mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried over anhydrous sodium sulphate, evaporated and the residue is chromatographed on silica gel using dichloromethane / methanol (99: 1) to give 640 mg of 5-amino-3- (1-propenyl) -phthalide (mp 125-130). ° C).

The phthalides listed in Table 4 are obtained analogously.

31342 / H

Table 4

X3 / X3B mP ' [° C] CH ;, / E 152-156 CH ;, / CH; 94-97 OJ C ₂ K ₅ / K 137-140 C2 ^{H5 / C2E5} 95-96 CH CKI / E M 89-93 - <CK2) of 4- 105-110

4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) phthalide

412 mg of 4-methyl-4-phenyl-2-oxovaleric acid was dissolved in 10 ml of dimethylacetamide and treated with 261 mg of thionyl chloride under argon at -8 ° C. After stirring at -3 ° C to 3 ° C for 20 minutes, 228 mg of 4-bromo-5-aminophthalide was added. and stirred for 1.5 hours at room temperature

Room temperature. The reaction mixture is then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried over anhydrous sodium sulphate and, after evaporation of the solvent and treatment with diethyl ether, 360 mg of 4-bromo-5- (4-methyl-2-oxo) is obtained. -4-phenyl-valeroylamino) -phthalide (mp 150-152 ° C).

Analogously to the preparation of 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, the compounds shown in Tables 5 and 6 are obtained.

31342 / H

Table 5

Pr. FROM mp Z? H CQ Z- = I 205-207 Z ³ = C1 170-171 Z ³ = Br 168-169 W ³ = I 155-157

5- [3- (1-phenyl-cyclopropyl) -2-oxo-propionylamino] -phthalide

The title compound is prepared according to the method described for the preparation of 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide, from 5-aminophthalide and 3- (1-phenyl- cyclopropyl) -2-oxo-propionic acid methyl ester (mp 132 to 138 ^and C).

¹

5- (3- (1-Phenyl-cyclobutyl) -2-oxo-propionylamino] -phthalide

The title compound is prepared according to the method described for the preparation of 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide, from 5-aminophthalide and 3- (1-phenyl- cyclobutyl) -2-oxo-propionic (mp 142-146 ° C).

31342 / H

5- [3- (1-Phenyl-cyclohexyl) -2-oxo-propylamino] -phthalide

The title compound is prepared according to the method described for the preparation of 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide, from 5-aminophthalide and 3- (1-phenyl- cyclohexyl) -2-oxo-propionic (mp 120-123 ° C).

The compounds listed in Table 6 were also prepared.

pr. n FROM mp (S) (° C) 1 3-F 142-146 1 2-C1 148-151 1 4-C1 161-170 1 2-Br 172-178 • 1 3-Br 152-159 1 2,4-Cb 135-138 1 3-OCH ₃ 140-153 1 • j-Crj 166-170 · * J 140-144 R J 4-CH3 oil 4 4-OCH3 129-130

31342 / H

6- [3- (1-phenyl-cyclopropyl) -2-oxo-propionylamino] -4-methyl-2,3-benzoxazin-1-one

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide from 6-amino-4-methyl-2,3-benzoxazin-1-one and 3- (1-phenyl-cyclopropyl) -2-oxo-propionic acid (mp 197-200 ° C).

6- [3- (1-phenyl-cyclobutyl) -2-oxo-propionylamino] -4-methyl-2,3-benzoxazin-1-one.

The title compound is prepared analogously to that described for 6- [3- (1-phenyl-cyclopropyl) -2-oxo-propiolamino] -4-methyl-2,3-benzoxazin-1-one using 3- (1- phenyl-cyclobutyl) -2-oxo-propionic (mp 155-156 ° C).

6- [3- (1-phenyl-cyclohexyl) -2-oxo--propion-4-methyl-2,3-benzoxazin-1-one

The title compound is prepared analogously to that described for 6- [3- (1-phenyl-cyclopropyl) -2-oxo-propionyl-amino] -4-methyl-2,3-benzoxazin-1-one using 3- ( 1-phenyl-cyclohexyl) -2-oxo-propionic (mp 132-134 ° C).

5- (4,4-Dimethyl-2-oxo-5-hexenoylamino) -phthalide

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide using 5-aminophthalide and 4,4-dimethyl-2-oxo- 5-hexene (mp 103-104 ° C).

6-Bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide m.p.

! ''

The title compound was prepared in analogy to the above example from 2.0 g of 4-methyl-4-phenyl-2-oxovaleric acid and 1.11 g of 6-bromo-5-amino) -phthalide using 1.27 g of thionyl chloride in 60 ml of dimethylacetamide and 1.7 g of 6-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) phthalide (mp 148-150 ° C).

31342 / H

5- [4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeroylamino] -phthalide

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide using 5-aminophthalide and 4- (4-iodo-2-methoxyphenyl) acid. 4-Methyl-2-oxo-valeric foam.

5- [4- (4-iodophenyl) -4-methyl-2-oxo-valeroylamino] -phthalide

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide using 5-aminophthalide and 4- (4-iodophenyl) -4- methyl 2-oxo-valeric oil.

5- [4- (3-iodophenyl) -4-methyl-2-oxo-valeroylamino] -phthalide

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide using 5-aminophthalide and 4- (3-iodophenyl) -4- methyl 2-oxo-valeric (mp 160-161 ° C).

5- [4- (4-bromo-2-methoxyphenyl) -2-oxo-valeroylamino] -phthalide

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide using 5-aminophthalide and 4- (4-bromo-2-methoxyphenyl) acid. -2-oxo-valeric (mp 160-161 ° C),

5- [3- (1-phenyl-cyclopentyl) -2-oxo-propionylamino] -phthalide

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide using 5-aminophthalide and 3- (1-phenyl-cyclopentyl) - Of 2-oxo-propionic (mp 140-144 ° C).

31342 / H

6- [4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeroylamino] -4-methyl-2,3-benzoxazin-1-one

The title compound is prepared analogously to that described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroyl-amino) -phthalide using 4-ethyl-2,3-benzoxazin-1-one and an acid 4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeric (mp 157-158 ° C).

6-amino-4-methyl-2,3-benzoxazin-1-one g of 2-methyl-5-nitroacetophenone, 38.5 g of 2,2-dimethyl-1,3-propanediol and 6 g of p-toluenesulfonic acid are boiled in 1 L of toluene under a water separator until the end of water evolution. The solution was washed with potassium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated. 71.7 g of crystalline ketal are obtained from pentane.

This ketal is oxidized in 1.5 L of pyridine and 4.5 L of water with 350 g of potassium permanganate as described above for the production of 4-bromaminophthalide. 56.4 g of 4-nitro-2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -benzoic acid are obtained.

g of this acid was hydrogenated in 500 ml of methanol and 500 ml of ethyl acetate using 10 g of palladium on carbon (10%). 45.5 g of crystalline amino compound are obtained from pentane.

g of the amine is refluxed in 100 ml of concentrated hydrochloric acid for 2 hours. The solvent was then evaporated in vacuo (and the residue was refluxed for 12 hours with 15.7 g of hydroxylamine hydrochloride, 8.4 g of potassium hydroxide, 120 ml of ethanol and 50 ml of water. The reaction mixture was diluted with water and the crystals were After drying, 3.5 g of 6-amino-4-methyl-2,3-benzoxazin-1-one (mp 291-296 ° C) is obtained.

31342 / H

6-Amino-4-ethyl-2,3-benzoxazin-1-one

The title compound is obtained analogously using 2-methyl-5-nitrophenone (m.p. 89-93 ° C).

6-amino-1-methyl-1H-benzotriazole

Described in Heterocycles 36, 259 (1993).

5-amino-benz [1,2,5] oxadiazole

Described in Boli. Sci. Fac. Chim. Ind. Bologna, 22, 33, 36, 37 (1964).

5-amino-benz [1,2,5] thiadiazol

Described in J. Heterocycl. Chem. 11, 777 (1974).

5-amino-1-indanone

Described in J. Org. Chem. 27, 70 (1962).

6-amino-1,2,3,4-tetrahydro-1-naphthalenone

Described in J. Org. Chem. 27, 70 (1962).

6-amino-3,4-dihydro-1H-2-benzopyran-1-one

It is produced by catalytic hydrogenation (palladium / carbon) in ethyl alcohol from the corresponding nitro compound (Canad. J. Chem. 61,2643 (1983)).

'I

The following examples serve to illustrate the invention in more detail. Other compounds can be made using homologous / analogous reagents. The necessary starting compounds are described above.

Example 1 (method 1)

4-bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) phthalide

31342 / H

350 mg of 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide was dissolved under argon in 15 ml of dimethylformamide by cooling with ice and a mixture of 0.77 ml of trifluoromethyltrimethylsilane and 350 mg of cesium carbonate. After stirring at room temperature for 3 hours, 5 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and a few drops of water are added and stirred for one hour at room temperature. After addition of 100 ml of water, the mixture is extracted with ethyl acetate, the organic phase is separated, dried over sodium sulphate and evaporated. 250 mg of 4-bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide (m.p. 187-194 ° C) are obtained.

Example 2

6-bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) phthalide

Prepared in analogy to Example 1 from 1.6 g of 6-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, 3.5 ml of trifluoromethyl-trimethylsilane and

1.6 g of cesium carbonate (m.p. 205-210 ° C).

Example 3

5- (2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroyl-amino) phthalide

Prepared in analogy to Example 1 from 20 mg of 5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, 0.1 ml of trimethylpentafluoroenilylsilane and 20 mg of cesium carbonate (mp 187-189 ° C) .

Example 4

5- [2-hydroxy-4- (3-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide

31342 / H

Prepared in analogy to Example 1 from 30 mg of 5- [4- (3-methoxyphenyl) -4-methyl-2-oxo-valeroylamino) -phthalide, 0.13 ml of trifluoromethyltrimethylsilane and 30 mg of cesium carbonate.

Example 5

5- (2-hydroxy-4 ₁ 4-dimethyl-2-trifluoromethyl-5-hexenoylamino) phthalide

It was prepared analogously to Example 1 from 200 mg of 5- (4,4-dimethyl-2-oxo-hexenoylamino) -phthalide, 0.22 ml of trifluoromethyl-trimethylsilane and 258 mg of cesium carbonate (m.p. 153-157 ° C).

The compounds listed in Table 7 were prepared analogously to Example 1.

Table 7

31342 / H

Pr. ' n FROM' (~ C) mp TO isomers 6 1 168-175 racemate 7 1 172-179 (- ^ - Enanncmér WITH 1 172-179 (J-Esanticmér C 1 3-F 155-158 racemate 10 1 2-C1 192-194 RACAM ii 1 4-Cl 143-154 Racsma: 12 1 λ 4-C1 174-176 (-) - Enardiomér 13 l 4-Cl 173-175 (-) - enantiomer of 14 I 2-Br 163-165 9 Racsmat 15 1 3-Br 189-191 Racsmat ló 1 2,4-Cl ₂ 2I6-21S RACAM 17 T 2-OCH 1 200-20S (-) - E: 'antiO'.Tier

31342 / H

When 6-amino-4 methylbenzoxazinone is used in Example 1 instead of aminophthalide, the compounds shown in Table 8 are obtained.

Table 8

'Pr. n mp CC) Isomerism 29 I 78-84 Racsmaŕ 30 1 227-235 (+> Enanxicmér 31 230-239 (-) - Enanx Omer 32 2 174-184 Racsmái 4 185-187 Racsnát 34 4 90-97 (+) - Enantioir.ér 35 4 T 90-96 (-) - Enanr: om r ^

31342 / H

Table 9

Pr. FROM* (* E) mP · (° C) 36 Z ² = I amor-f 37 Z ³ = C1 174 38 Z ³ = Br 182-183 39 W ³ = I 190-191

Example 40

6- (2-Hydroxy-2,4-dimethyl-4-phenyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one mg 6- (4-methyl-4-phenyl-2-oxo-valeroylamino) 4-Methyl-2,3-benzoxazin-1-one in 4 ml of tetrahydrofuran is mixed with 3 ml of methylmagnesium bromide (3 M) at 0 ° C. After 30 minutes ammonium chloride solution is added, the organic phase is separated, dried anhydrous sodium sulfate and evaporated. Chromatography on silica gel (hexane / ethyl acetate 1: 1) yielded 39 mg of 6- (2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one (mp 173). to 175 ° C).

31342 / H

Example 41 (method 2)

5- (2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide

500 mg of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid (EP A1 0 253 500 (Imperial Chemical Industries)) in 10 ml of diethyl acetamide are mixed with 0.14 ml of thionyl chloride at -15 ° C and after stirring for three hours 600 mg of solid 5-aminophthalide is added at this temperature. The solution was stirred for 2 hours at -15 ° C and then left for 18 hours at room temperature, then treated with water and extracted with ethyl acetate. The ethyl acetate phase is separated, dried over sodium sulphate and evaporated. The residue is stirred with diethyl ether and filtered off with suction. 290 mg of 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide (m.p. 166-168 ° C) are obtained.

Example 42

6- (2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one

Prepared in analogy to Example 41 from 784 mg of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid in 17 ml of dimethylacetamide and 500 mg of 6-amino-4-methyl-2,3-benzoxazin-1-one (mp 172-173 ° C).

The compounds listed in the following Table 10 were prepared analogously to Example 41.

31342ΛΊ

Pr. R ² W X ^Q (-K) FROM" (H) mp (° C) Isomerism or WD (c = 0.5) (21 43 The 0 X3a / x3b-K / CK3 175-185 DIAS Gcm. XI r v n 0 X ^3a = E. X ^3b = CK ₃ 175-178 -22.5 xs The 0 X3-K.x3b »CH ₃ 210-213 -74 46 i ^K 0 _X 3a = CH 3 ° C 210-213 -69.5 47 The 0 XJ £ = CE-, X ^3b = E * f 175-179 -21.5 48 The 0 X - '' = C2K5 169-174 and 4S H 0 X 3a = CH = CE ₂ 162-174 50 The 0 X3 = CE = CH7- CH ;, 160-162 51 The 0 X3a = CF ;, 156-166 52 E 0 _X 3a _{with X} 3ces CH ;, 160-171 <*? 10 E 0 _X 3a = _X 3b- c ₂ H ₅ 172-176 54 at 0 X3a ^ x3b »(CH2) ₄ 168-170 30 E 0 X · ¹ = Br ISO-185 56 CE ;, 0 159-162 3 / CH ;, 0 X- = Br j 1 1 Í 187-154 | 1 58 CE ;. 0 Z ² = CE; j 1 155-15 «) i T RACS: w w ch ₃ 0 Z- = CH ;, 14S-149 (-) - FONR. 50 CE ;, 0 Z = CH; 145-146 (-) - Fonn 51 CH ;, 0 From the CE ^ ;, 189-190

31342 / H

Table 10 (continued)

Pr. R W x ° (= H) Z ⁿ (= H) mP ' (° C) Isomerism resp. Wd (c = 0.5) S2 CH; 0 Z 2 Z 2 CH; 206-207 Racsmát 53 CH ;, 0 Z ² = Z-CH ;, 207-209 (-) '- FONR. 54 CH ;, 0 Z ² = Z ⁴ = CH; 207-209 (-) - Fcrm A A WW CH; 0 Z 3 = z == CEJ 154 RACAM 56 CH ;, 0 Z ^: '= Z == CH; 18S-1S9 (-) - Fcnr. 57 CH; 0 Z - = Z = CH ^; 133 (-) - Forum A A CC CH ;, ⁰ Z ² / Z ⁴ = (CH 2); 171-173 A A «· W CH; 0 Z ³ / Z ~ = -CH = CHCK = CH- 213-219 70 CH; 0 Z-F 177-173 71 CH; 0 Z 1 = C 1 1S4-1S5 72 CH ;, 0 Z '= är 177-179 73 CH; 0 Z ² = OCH; 134-135 Rac: ~ ya: 74 CH, * 0 Z ⁴ = OCK- l33-184 w * 1 c CH; 0 Z ² = Z- = OCH; 145 75 CH; 0 Z = OCH3; Z = CH; 126-127 Rac; -át 77 CH; 0 Z- = OCH; ,, Z- = CH; 169-170 (-) - Forr. £ 7 CH; 0 Z = OCH; Z ^: = CH ;, 169 (-) - Forre

50 CK ₃ ⁰ Z = OCH2; Z2-F 140-14 ' 31 CH; ABOUT OCH., Z ² = F 207 82 CH; ABOUT Z ^ = OCH3; Z ² = F 17S-I79 23 CH; 0 Z- = OCH ;, Z- = Cl 141 Racarr.át 34 CH; 0 Z- = OCH; Z- = Cl 106-108 -105.5 mm (1)

31342 / H

Table 10 (continued)

Pr. R ² W X ⁿ (®K) Z ⁿ (= H) mp (° C) Izoméria prip. body (c = 0.5) 25 CH3 0 Ζ ² = ΟΟΗ ₃ Ζ ³ = Cl 105-207 -97 d) 86 E with 189-191 87 · CH. * with 173-175 88 H CK ₂ 161-162 8S The 0-CH 2 (3) 192-195

90 CE3 0 Z '= ch = ch ₂ 190-192 Racsrná: 91 CK3 0 Z ⁴ = CN 230-233 Racsná: 92 CH; 0 Z ⁴ = COCH; 174-176 Racsxá 93 CE3 0 Z ⁴ = conh ₂ 130-132 Raciľr.ŕ. 94 CE3 0 Z-OCH; Z ⁴ = Er 144.U5 Rac: m £: 95 CH ;, 0 Z = OCH; = Z ⁴ = - 176-177 1 -) - E.-ir. :: orr.er 96 CH; θ Z = OCH; Z ⁴ = Br 177. 73 -135.6 97 CH; 0 Z = 5 R, Z ⁴ = _OCH3 197-198 Rac: -. £: 98 CH; 0 Z = OCH; Z ⁴ = CN 135-136 Racsmác 99 CK3 0 of ³ = no ₂ . z- = och ₃ 202-206 Racimo 100 CH; 0 Z ² = COCH 2, Z ⁴ = CK (CH 3) 2 135 Racľľľáá:, 101 CH; 0 Z ³ ® COCE ;, Z ⁴ OCK3 213-214 Racsrr.át

31342 / H (1) The optically active compounds shown in Table 10 are separated analogously to Example 88 (2) in methanol (3) Formation of 1-isochromanone.

Example 102 (+) and (-) 5- [2-hydroxy-4-methyl-4- (2-methoxyphenyl) -2-trifluoromethyl-valeroylamino] phthalide

The mixture of enantiomers of Example 73 was separated by chromatography on a chiral support material (Chiralpak AD ^R , Daicel) using hexane / 2-propyl alcohol / ethyl alcohol (900: 25: 25, v / v) to give 200 mg of the racemate (-) - forms (mp 136-137 ° C), α d = -194.8 ° (c = 0.5 in chloroform), mg (+) - forms (mp 135-136 ° C), α d = + 192.2 "( c = 0.5 in chloroform),

Example 103

5- [2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl-valeroylamino] -phthalide and 5- [2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl valeroylamino] phthalide

A mixture of 2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl- (3-thienyl) -2-trifluoromethyl-valeric acid (9: 1) is added. was reacted analogously to Example 41 with 5-aminophthalide and chromatographic resolution of the positional isomers and racemate resolution of Example 102 gave (+) - 5- [2-hydroxy-4-methyl-4- (2-thienyl) - 2-trifluoromethylvaleroylamino-phthalide (mp 166 ° C), <xd = +163.6 "(c = 0.5 in chloroform), (-) - 5- [2-hydroxy-4-methyl-4- (2- thienyl) -2-trifluoromethyl-valeroylamino] -phthalide (mp 166 ° C), and _D = -160.8 ° (c = 0.5 in chloroform),

31342 / H (+) - 5- [2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeroylamino] -phthalide (mp 135 ° C) and (-) - 5- [2- hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeroylamino] -phthalide (mp 135 ° C).

Example 104 (method 3)

5- [2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino] -phthalide

760 mg of 5-acetamido-phthalide in 20 ml of dimethylformamide are mixed with 144 mg of sodium hydride (80% in mineral oil) at 0 ° C and after 20 minutes with 800 mg of (2-hydroxy-4-phenyl-2-trifluoromethyl-). pentyl) 4-toluenesulfonic acid ester. After 16 hours at 60 ° C, the solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated. Chromatography on silica gel using cyclohexane / ethyl acetate (2: 1) yielded 266 mg of 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide (m.p. 110 ° C).

Analogously to Example 104, the compounds in the table are obtained

11th

31342 / H

Table 11

Pr. R ^{1 2 3} w FROM" (= C) tt ( ^e ) Isomerism resp. (CJD (0 = 0.5) 10 = H d ° 110 Racsmat 10c The 0 | 123 -1S.6 107 H 0 123 -18.4 · 108 CH; 0 139-1-0 Racsxat 10S ch ₃ 0 159-160 -12.0 mm (4) 110 CE; 0 160-161 -12.5 mm (4) 111 CH; 0 z ⁴ = f 143-149 Racsmát 112 CH; 0 Z ^ F 162-164 ^ 9.0 113 CH; 0 Z ^ F 162-164 -6.7 4 4 4 1 1 ** CH; 0 Z ² = OCH-., Z == F 148-149 115 H CH ₂ 161-162 116 K IOCH-, | (3) 1 127-128

(1) The optically active compounds listed in Table 11 are analogous to those described in Example 102 (2) In methanol (3) Formation of 1-isochromanone (4) In chloroform

31342 / H

Example 117

4-ethyl-6- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) 2,3-benzoxazin-1-one

The title compound was obtained in analogy to Example 104 from 151 mg of 6-acetamido-4-ethyl-2,3-benzoxazin-2-one, 208 mg of (2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)-ester Of 4-toluenesulfonic acid and 36 mg of sodium hydride (mp 161-163 ° C).

Example 118

1- (4-nitro-3-trifluómnetylanilino) -4-phenyl-2-trifluoromethyl-2-pentanol

100 mg of 4-nitro-3-trifluoromethyl acetanilide in 2 ml of dimethylformamide was treated with 12 mg of sodium hydride (80% in mineral oil) at 0 ° C and after 20 minutes 150 mg of 2- (2-phenylpropyl) -2-trifluoromethyl oxirane. The reaction mixture was stirred for 16 hours at 60 ° C, diluted with water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over sodium sulphate and evaporated. 80 mg of N- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroyl) -4-nitro-3-trifluoromethylaniline are obtained (m.p. 119-120 ° C).

(-) - form [α] _D = - 49.6 ° (c = 0.5 in chloroform), (+) - form [α] _D = + 48.8 ° (c = 0.5 in chloroform),

Example 119 (method 4)

6- (3-hydroxy-3-methyl-1-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl-2-trifluómľietylvaleroylamino) phthalide

150 mg of the bromo compound of Example 2 are dissolved together with 30 mg of 2-methyl-3-butin-2-ol, 0.24 mg of copper (I) iodide and 0.9 mg of triphenylphosphine in 1.5 ml of pyridine and mixed with 0.25 under argon. mg bis-triphenylphosphine palladium-11-chloride. After refluxing for five hours, add

31342 / H additional 30 mg of 2-methyl-3-butin-2-ol and the reaction mixture was refluxed for 20 hours. It is then diluted with water and extracted with ethyl acetate, the ethyl acetate phase is separated, dried over sodium sulphate and evaporated. The crude product is chromatographed on silica gel using cyclohexane / ethyl acetate (1: 1) to give 60 mg of crystalline 6- (3-hydroxy-3-methyl-1-butynyl) -5- (2-hydroxy-4-methyl-4- phenyl-1-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide (mp 162-168 ° C).

Example 120

6-acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) phthalide

100 mg of the bromo compound of Example 2 are dissolved together with 95 mg of tributyl- (1-ethoxyvinyl) -tin and 8 mg of bis-triphenylphosphine-palladium-11-chloride in 4 ml of toluene under an argon atmosphere. After refluxing for five hours, 45 mg of bis-triphenylphosphine-palladium-11-chloride are added and refluxed for a further 20 hours. Then, 1 N hydrochloric acid is added, extracted with ethyl acetate, the ethyl acetate phase is separated, dried over anhydrous sodium sulphate and evaporated. The crude product is stirred in 3 ml of tetrahydrofuran and 3 ml of 2 N hydrochloric acid for 2 days at room temperature, mixed with water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over anhydrous sodium sulphate and concentrated. The residue is triturated with a mixture of diethyl ether and pentane to give 21 mg of crystalline 6-acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide (mp 195-199 ° C). ₍ .

Analogously to Examples 119 to 120, the compounds shown in Table 12 are obtained.

31342 / H

Table 12

Pr. X ⁿ (-H) FROM" (H) mp (° C) 121 X = CH-CPb and p and 122 X ⁶ = CK-CK · 191-197 123 X 6 = C (OC ₂ H 5) -CE 2 160-163 124 X 0 = CsC-CrbOK 208-211 125 X ^O = C ₆ C ₃ 160-163 126 OH x s-CT 157-153 127 PG-C ^ OCH ^ TP) 125-127 123 S ^3-CH = CE ₂ 130 17? 129 Z3-C ₂ K ₅ 152-153 i 30 Z - '= COCK ;, _(') 220

31342 / H

131 Z ³ = CN 112 132 of ⁴ »ch = ch ₂ 190-192 133 Z ⁴ = COCH ₃ 205-207

(*) Obtained by catalytic hydrogenation from a vinyl compound (**) Obtained by gentle acid hydrolysis from enol ether.

Example 134 (method 5)

5- [4- (3-fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] -phthalide

132 mg of 5- [4- (3-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-4- (2-trifluoromethyl) valeroylamino] phthalide (Example 82) was dissolved in 15 mL of dichloromethane at 0 ° C was mixed with 1.2 mL of a 1 M solution of boron tribromide in dichloromethane. After 16 hours at 0 ° C, ice, ethyl acetate and potassium bicarbonate are added to the mixture, the ethyl acetate phase is separated, dried over anhydrous sodium sulfate and evaporated. From a mixture of ethyl acetate, diisopropyl ether and hexane, 120 mg of 5- [4- (3-fluoro-4-hydroxy-phenyl) -2-hydroxy-4-methyl-4- (2-trifluoromethyl) -valeroylamino] -phthalide (tt 139) was obtained. to 140 ° C).

Analogously to Example 86, the compounds shown in Table 13 are obtained.

31342 / H

Table 13

• Pr. B .Z ⁿ • (H) mp PC) Isomerism resp. JcId (c = 0.5i) 135 WHAT Z = OH ^ 77.77.1 136 OO Z = OH 228-230 137 OO z ² = z ⁵ = oh 265-267 138 what Z ² = OH. Z = Cr>. 215-217 racemate: 13S what Z ² = OE. of ⁵ = ch ₃ 173-174 (-) - FONR. 14Q WHAT Z ² = OH. Z = CK ₃ 173-174 (-) - Fonn 141 WHAT Z ² = OH. Z ⁴ »F 240-242 142 WHAT Z ² = OK. Z ⁵ = F 201-202 143 WHAT Z 2 = OH, Z ² = F 242-243 144 WHAT z ² = oh, Z = C1 220-221 145 ch ₂ Z ² = OH. Z ⁵ = F 156-157 racemate 146 CK ₂ Z ² = OH. Z- = F 157-159 1 +23.5 147 CK ₂ Z ² = OK. Z5 = r 157-159 -18.7 143 WHAT ² = ΟΗ Ζ, Ζ = ⁴ Βγ 224-226 Racema't 149 WHAT Z ³ = no ₂ . z = OH 167-169 Racema't 150 WHAT . Z ³ = Cl. Z = OH 168-169 racemate 151 WHAT Z ³ = Br. Z-OH 105 Rac Entities

31342 / H (1) The optically active compounds listed in Table 13 are subdivided in analogy to Example 102 (2) in methanol.

Example 152

5- [4- (3-Fluorophenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino-phthalide mg (3-fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-4-2 -trifluoromethylvaleroylamino-phthalide was stirred with 126 mg of potassium carbonate and 108 mg of 5-chloro-1-phenyl-1H-tetrazole in 3 ml of dimethylformamide for 16 hours, after which dimethylformamide was distilled off in vacuo and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. . The ethyl acetate phase is washed with water, dried over sodium sulphate and evaporated and the residue is chromatographed on silica gel using hexane / ethyl acetate (1: 1). The product was hydrogenated in 10 mL of methanol using 30 mL of palladium on carbon (10%). After removal of the catalyst and evaporation of the solvent, the product is chromatographed on silica gel using hexane / ethyl acetate (1: 1). 49 mg of 5- [4- (3-fluorophenyl) -2-hydroxy-4-methyl-4-2-trifluoromethylvaleroyalmino-phthalide (m.p. 157 ° C) are obtained.

Resolution of the racemate analogously to Example 102 yields the (+) - form (mp. 140-141 ° C) and the (-) - form (mp. 141 ° C).

Example 153 i

I

5- [2-hydroxy-4-methyl-4- (3-tolyl) -2-trifluoromethyl-valeroylamino] -phthalide

The compound was obtained analogously to the previous example from 57 mg of 5- [2-hydroxy-4- (2-hydroxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide (m.p. 152-153 ° C).

Resolution of the racemate analogously to Example 102 yields the (+) - form (m.p. 148-149 ° C) and the (-) - form (mp 145-146 ° C).

31342 / H

Example 154

5- [4- (5-fluoro-2-ethoxyphenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] phthalide mg 5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy- 4-Methyl-4-2-trifluoromethylvaleroylamino-phthalide was stirred in 1 ml of DMF with 28 mg of potassium carbonate and 50 mg of ethyl iodide for 24 hours at room temperature. Then, the reaction mixture is mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried over anhydrous sodium sulphate and the solvent is evaporated to give 35 mg of 5- [4- (5-fluoro-2-ethoxyphenyl) -2-hydroxy -4-methyl-4-2-trifluoromethyl-valeroylamino-phthalide (mp 108 ° C).

Analogously to Example 154, the compounds listed in Table 14 are obtained.

Table 14

Pr. R mp (° C) Isomerism resp. [C] q (c = 0.5) 155 CE (CK ₃ ) ₂ 153-154 Racsmat 15O ch ₂ ch = ce ₂ 152 Racsmat 157 ce ₂ ch = ck ₂ 187-189 Racsmat 158 ce ₂ cn 170-172 racemate 159 CE ₂ COOC (CE ₃ ) ₂ 145 Raccmát 160 CO ₂ COOC (CE ₃ ) ₃ 143 -131.5 161 CE ₂ COOC (CH ₃ ) ₃ 142-143 (+) - form

31342 / H

Example 162

5- [4- (3-chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] phthalide mg 5- [2-hydroxy-4- (4-methoxyphenyl) -4-methyl- 2-Trifluoromethylvaleroylamino] -phthalide is stirred in 1.5 ml of methanol with 20 mg of N-chlorosuccinimide for 5 hours, after which the mixture is poured into a mixture of ice water, sodium bicarbonate solution and ethyl acetate, the ethyl acetate phase is separated and dried over anhydrous sodium sulfate. and evaporated. 20 mg of 5- [4- (3-bromo-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide is obtained, which is recrystallized from isopropyl ether (mp 189-191 ° C). .

5- [4- (3-chloro-4-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide

This compound is obtained from 5- [4- (3-chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide by cleavage of ether (m.p. 105 ° C).

The 2,3-benzoxazinone and phthalazinone derivatives shown in Table 15 are prepared as described above.

Z ² CCl R ² 'HO CF ₃ -3 i

T a b u l a 15

1 Pr. R ² 1 in Z ⁿ (= H) B γη (= H) mp CC) Isomeric Φ ^Γ · I =] d (c = 0.5) (2) 163 E 0 C-O Y ⁴ = ce ₃ 165-166 racemate 164 H 0 C-O y ⁴ »c ₂ h ₅ 159-160 RACAM 165 CK ₃ 0 C-O Y ^ CH 185 +162 166 ch ₃ 0 C-O Y ⁴ = ch ₃ 184-185 -182 167 ch ₃ 0 C = C y ⁴ »c ₂ h ₅ 148-153 racemate 168 CK ₃ 0 C-O y ⁴ = c ₂ h ₅ 159-160 +173 1 ŕft n C = O 1 Y ⁴ = OH; 159-160 -175

Table 15 (continued)

Pr. R IN FROM" ( »H) B yn (= C) (° C) Isomer PC. (ELD (c-0.5) 170 * « 0 Z ² = OCH; C-O Y ⁴ = CC} 161-163 Rscsmác 171 c «1 ^J 0 Z- = OCH ;, C-O Y @ CK; 173-175 5-.7 (4) 172 CK} 0 Z = ₃ WHAT Y ⁴ = CE 173-175 173 CK ;, 0 Z ² = OCH ;, WHAT Y ^ prowl 164 Ric = ~ methacrylate 174 CH ;, 0 Z ² = OCH; WHAT Y ⁴ -C ₂ K < 190-191 (-) - FONR. 175 CK; 0 iZ ² = OCK- WHAT Y ~ = c ₂ h ₅ 190-191 - 1.3 (CHCI) j CH ;, ⁰ Z-OCH ^2}, F = 2 C-O v4 ₌ rr · 4 Ui. R 1O5 '* Kzc: —ac i 77 CH ;. 0 Z ² = OCH 2, Z = F WHAT Y @ CK} 188-139 (-1-Forrr. 173 CH; 0 Z ² = OCH 2 Z 2 -F WHAT Y ⁴ -CH ;, 187-1SS ' -132.3 (CHCI}) 179 CH; 0 Z ² = OCH 2; Z ⁵ = F what Y ^ C-H, and 126-123 _ * · ratchets ISO CK ₅ 0 Z ² = OCH 2; Z ⁵ = F c = o Y ⁴ »C2Kj 170-171 1 1 • i — t IS1 CH ;, 0 Z ² = OCH; what Y 1 = C ₂ Hf 171 (-) - Fcnr. 132 CH ;, 0 Z ² = OCH}, Z == Cl what Y ⁴ = CH. w 182-134 Racsmas IS3 CH, • 0 Z ² = OCH; Z ² = Cl what Y ^ CE ;, 19S-199 I-i-Fom 184 CH ;, about From ² »OCH ,, Z-Cl what Y = CH; 197-198 -90.2 185 CH ;, 0 Z ² = OCH}, Z = Br what y ⁴ = ch ₃ 206-207 Racsmát 186 ru. " '• j about Z = OCH3; Z '= Er what Y ⁴ = CE 194-198 (-) - Fom 187 CH ;. 0 Z ² = OCH ,, Z ⁴ »Er what Y ⁴ »CH} 196-198 -122.2 fCKCi}) 183 CH ;, 0 Z CH} c = o Y ⁴ »CK} Racsna: 139 CH ;. about From ^4-CH ;. what Y = ⁴ C2K5 IS7-1SS Racexít 190 CH ;, 0 Z = CH 2. what Y '= C; H 5 160 -Ó3.7 191 CK ;. ° Z ~ = CK ;, what Y '= C2K5 160 (-) - FONR. 192 CH ;. ⁰ Z ⁴ = F what Y- = CH} l88-190

31342 / H

Table 15 (continued)

193 CH ;, 0 Z = Br C-O Y ⁴ = CH; 219-220 RACAM: 194 CH; 0 br c = o Y ⁴ CH; 231-233 -jo 3 195 CH; 0 Z ^ Br c = o Y ⁴ CH; 231-233 (-) - Fonn 196 CH; 0 c = o Y ^ CF; I75-IS3 197 CH; KK c = o Y ⁴ 'CH; 19S · CH. • rf KCE; c = o Y = CH; 199 · CH. • rf ABOUT Z = OH. Z ⁵ = F c = o Y ⁴ CH; 23t * Z j c RACAM 200 CH; 0 Z = OH. Z ⁵ = r c = o Y ⁴ CH; 232-234 (-) - Fcm 201 CH; 0 Z = OH. Z * = F c = o Y ⁴ CK; 232-234 -34.1 202 CH; ⁰ Z = OH. Z = Br c = o v4 ₌ «. ·, •> rf * · t 24S-25U 1 Raccnát 202 CH; 0 Z- = ΚΟί. Z ”= OCH; c = o Y ⁴ = CH; 2 i 5-2 b Racarr.át 204 H ⁰ CH; Y ⁴ - CH $ 145-14 Racarnac 205 CH; 0 CH; Y ⁴ CH; 132-133 Racan 206 · CH: 0 CH; Y ⁴ = C; K ₅ 121-122 1 Racssiat

(1) The optically active compounds listed in Table 13 are separated analogously to Example 102 (2) In methanol.

31342 H

Example 207

5- (2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) benzo [1,2,5] oxadiazole

This compound is obtained analogously to Example 41 from 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid and 5-aminobenz [1.2.5] oxadiazole (mp 192 ° C).

Example 208

5- (2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -benzo [1.2.5] thiadiazole

This compound was obtained analogously to Example 41 from 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid and 5-aminobenzo [1.2.5] thiadiazole (m.p. 166-167 ° C).

Example 209

6- (2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -1-methyl-benzotriazole

This compound was obtained analogously to Example 41 from 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid and 6-amino-1-methylbenzotriazole (m.p. 194-196 ° C).

Claims (34)

PATENT CLAIMS Non-steroid (hetero) cyclically substituted acylanilides of the general formula I in which R ¹ and R ² are the same or different and represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a halogen atom and, together with the carbon atom of the chain, a ring having a total of 3 to 7 members, R ³ represents an alkyl group having 1 to 5 carbon atoms or a partially or fully fluorinated alkyl group having 1 to 5 carbon atoms, A represents a monocyclic or bicyclic aromatic ring, optionally substituted by one or more radicals selected from the group consisting of halogen atoms, alkyl groups of 1 to 5 carbon atoms, alkenyl groups of 2 to 5 carbon atoms, CR ⁵ = CR ⁶ R ⁷ , wherein R ^5, R ⁶ and R ⁷ are the same or different and are independently hydrogen atoms or alkyl groups of 1 to 5 ¹ carbon atoms, further hydroxy groups, the hydroxy groups of which carry an acyl group having 1 to 10 carbon atoms, a carboxyalkyl group having 3 C-C ky ky cyanalkyl, C až-C nes nes unsubstituted or substituted aryl, C a-C až nes prop unsubstituted or substituted propargyl, C až-C alko alkoxyalkyl, partially or wholly fluorine substituted alkyl having 1 to 5 carbons atoms 31342 / H cyano or nitro, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, C 1 -C 5 alkylthio, mono- or disubstituted C 1 -C 10 amino or partially or fully fluorinated alkyl groups up to 5 carbon atoms, an ester group -COOR ⁴ wherein R ⁴ represents an alkyl group having 1 to 5 carbon atoms, an alkenyl group -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently of one another, hydrogen atoms, halogen atoms, aryl radicals or alkyl radicals of 1 to 5 carbon atoms, an alkynyl group -CsCR ^5, wherein R ⁵ represents hydrogen or alkyl having 1 to 5 carbon atoms, or a partially or completely fluorinated alkyl group of 1 to 5 carbon atoms, B represents a carbonyl group or a CH2 group and Ar is a ring system selected from the group of general formulas 2 to 11 3b 3a 31342 / H in which residues X ^3a , X ⁴ , X ⁶ , X ⁷ (in sub-formula 2), X ⁴ , X ⁶ , X ⁷ (in sub-formulas 3 and 4), X ^3a , X ^3b , X ⁴ , X ⁶ , X ⁷ (in sub-formulas 5, 6 and 7) or Y ⁴ , Y ⁵ , Y ⁷ and Y ⁸ (in sub-formulas 8, 9, 10 and 11) are the same or different and are selected from the group consisting of hydrogen atoms, alkyl groups of 1 to 5 carbon atoms which may additionally contain a hydroxyl group, an etherified alkyl group of 1 to 5 carbon atoms or an esterified alkanoyl group of 1 to 5 carbon atoms, partially or fully fluorinated alkyl groups of 1 to 5 carbon atoms , (C 2 -C 5) alkenyl groups -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, and alkynyl groups -C ⁵ CR ⁵ , wherein R ⁵ is as defined above, residues X ^3a and X ^3b can further form a 5, 6 or 7 ring with c and, in addition, the residues X ⁴ , X ⁶ and X ⁷ in sub-formulas 2, 3, 4, 5, 6 and 7 or Y ⁴ , Y ⁵ , Y ⁷ and Y ⁸ in sub-formulas 8 , 9, 10 and 11 selected from the group consisting of halogen atoms, hydroxy groups, (C 1 -C 5) alkoxy or (C 1 -C 5) alkanoyloxy groups, In addition, in case B in formula I is CH 2, Ar is additionally a phenyl radical of formula 12. !! While R ⁹ and R ¹⁰ are the same or different and are cyano, nitro, halogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, partially or fully fluorinated C 1 -C 5 alkyl, (C 1 -C 5) alkylthio, (C 1 -C 5) alkylsulfinyl or alkylsulfonyl, and, when B is CH 2, the physiologically acceptable acid addition salts of the compounds of the formula (I). Acylanilides according to claim 1 of the formula I in the form of a racemate or a mixture of diastereomers. Acylanilides according to claim 1 of the formula I in the form of separated optical isomers. Acylanilides according to claim 1 of the general formula I in which R ¹ and R ² are the same or different and represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the chain represent a cycliopropyl ring. 5. Compounds of claim 1 of formula I, wherein R ³ is a perfluoroalkyl group having 1 to 5 carbon atoms. The acylanilides according to claim 1 of the general formula I in which A represents a benzene, naphthalene or thiophene ring optionally substituted by one or more radicals selected from the group consisting of fluorine, chlorine or bromine atoms, methyl, ethyl, (CH ₂ ) _n groups, wherein n = 3, 4 and 5 which with two adjacent carbon atoms of aromatic A form a ring with n + 2 members and may contain 31342.Ή ΊΟ unsaturated bonds, vinyl, hydroxy, methoxy or ethoxy. 7. Compounds of claim 1 of formula I, wherein X ³ represent hydrogen or alkyl having 1 to 5 carbon atoms. Acylanilides according to claim 1 of the general formula I in which X ^3a and X ^3b are the same or different and represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. The acylanilides according to claim 1 of the general formula I in which X ⁴ , X ⁶ and X ⁷ are the same or different and independently of one another are hydrogen or halogen. 10. Compounds of claim 1 of formula I, wherein Y ⁴ is alkyl having 1 to 5 carbon atoms or perfluoroalkyl having 1 to 5 carbon atoms. The acylanilides according to claim 1 of the general formula I in which Y ⁵ , Y ⁷ and Y ⁸ are the same or different and independently of one another are hydrogen or halogen. The acylanilides according to claim 1 of the general formula I in which R ¹ and R ² are the same or different and represent a hydrogen atom, a methyl group, an ethyl group or, together with the carbon atom of the chain, a cyclopropyl ring. R ³ represents a perfluoroalkyl group having 1 to 5 carbon atoms, A represents a benzene, naphthalene or thiophene ring optionally substituted by one or more radicals selected from the group consisting of fluorine, chlorine or bromine atoms, methyl groups, ethyl groups, (CH 2) _n groups, wherein n = 3,4, 5 which, with two adjacent carbon atoms of the aromatics A, form a ring with n + 2 members and may contain unsaturated bonds of vinyl, hydroxy, methoxy and ethoxy groups and either X ^3a represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or 31342 · H X ^3a and X ^3b are the same or different and represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, X ⁴ , X ⁶ and X ⁷ are the same or different and independently of one another are hydrogen, Y ⁴ represents an alkyl group having 1 to 5 carbon atoms or a perfluoroalkyl group having 1 to 5 carbon atoms, Y ⁵ , Y ⁷ and Y ⁸ are the same or different and independently of one another are hydrogen or halogen, and the other substituents have all the meanings given in formula I. The acylanilides according to claim 1 of the general formula I in which Ar represents a ring system of partial formula 6. 14. The compound of claim 1 wherein Ar is a ring system of Formula 7. 15. The compound of claim 1 wherein Ar is a ring system of Formula 10. 16. A compound according to claim 1, wherein Ar is a ring system of formula 11. 17. The acylanilides of claim 1 which are: 4-Bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide, 6-bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl) valeroylamino) phthalide, 5- (2-Hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino) -phthalide, 5- [2-hydroxy-4- (3-methoxyphenyl) -4-methyl-2-trifluoromethyl-4-phenyl-valeroylaminoftalid, 5- [2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide, 5- [2-hydroxy-4- (2-methoxy-phenyl / ^-4-me ethyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide, 5- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide, 5- [4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide, 5_ [4- (4-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide, 31342.Ή 5- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valéroyalmino] phthalide, 5- [2-Hydroxy-4-methyl-4- (4-tolyl) -2-trifluoromethyl-valeroylamino] -phthalide ₁ S-P-hydroxy ^ -methyl-is-trifluoromethyl-tolylJ ^ valeiOylaminoj-phthalide, 5- [4- (4-cyanophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (3,4-dimethyl-phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] _-phthalide) 5- [4- (3-dimetyifenyf _l 5) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide _l 5- [2-hydroxy-4- (2-methoxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (5-chloro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [2-hydroxy-4- (2-hydroxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (2-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluómnetyl-valeroylamino] -phthalide, 5- [4- (3-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- (2-Hydroxy-4-methyl-2-trifluoromethyl-valeroylamino) -phthalide _I 5- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (5-chloro-2-methoxyphenyl) -2-hydroxy-4-methyl- 2-Trifluoromethyl-valeroylamino] phthalide, 5- (2-Hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide ₁ 5- (2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino) -phthalide, 5- [4- (4-Fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide ₁ 5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino] phthalide, 6-Acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide ₁ 31342 / H 5- [4- (3-fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide, 5- (4- (3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide, 6- (3-hydroxy-3-methyl-1-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino) -phthalide, 6- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-όπ, 6- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -4-trifluoromethyl-2,3-benzoxazin-1-one, 4-ethyl-6- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -2 _L 3-benzoxazin-1-one, 4-ethyl-6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino-2,3-benzoxazin-1-one, 6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylannino] -4-methyl-2,3-benzoxazin-1-one, 4-ethyl-6- [2-hydroxy-4-methyl-4- (4-methylphenyl) -2-trifluoromethyl-valeroylamino] -2,3benzoxazin-1-one, 6- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylannÍno] -, 2,3-benzoxazin-1-one, 4-ethyl-6- [4- (fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] -2,3-benzoxazin-1-one, 6- [4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2,3-benzoxazin-1-one, 1- (4-nitro-3-trifluoromethylanilino) -4-phenyl-2-trifluoromethyl-2-pentanol, 1- (4-nitro-3-trifluoromethylanilino) -4-phenyl-2-trifluoromethyl-2-pentanol, 5- (2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylanine) -phthalide, 5- [2-hydroxy-3- (1-phenyl-cyclopropyl) -2-trifluoromethyl-propionylamino] -phthalide, 5- [2-hydroxy-3- (1-phenyl-cyclobutyl) -2-trifluoromethyl-propionylamino] -phthalide, 5- [2-hydroxy-3- (1-phenyl-cyclohexyl) -2-trifluoromethyl-propionyl-amino] -phthalide, 6- (2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one; 5- [4- (3-chloro-4-methoxyphenyl) -2] hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide. 31342 / H 18. The acylanilides of claim 1 which are compounds of formula n from* (-H) .. Isomerism 1 Racsmát 1 (+) - Enannomér 1 (J-Enanriomer 1 3-F Racsnat 1 2-C1 Racsmát 1 4-0 Racsmát 1 4-C1 (+) - enantiomer 1 4-0 (J-Enaníiomer 1 2-Br Racsmát 1 3-Br Racsmát 1 2,4-CH Racsmát 31342 H .y l 2-OCE3 (+) - enantiomer 1 2-OCE3 (-) - Eaaniiamér 1 3-OCE3 Racsmat and 3-CF3 Rac Mac 2 Racsmát 0 (+) - Eaandotnér 2 (-) - enantiomer of J (-) - Enannomér J 4-CB3 Racsmát 4 racemate 4 (-) - Enar.ciomér .1 -T (-) - Enantiorncr 31342 / H 19. The acylanilides according to claim 1, which are. compounds of formula n Isomerism 1 RACAM 1 (+) - enantiomers of (-) - Enanriomer 2 RACAM 4 RACAM 4 (-R) -Enaniiomér X • T (-) - Eaarniomér 20. The acylanilides of claim 1 which are compounds of formula 31342Ή Z (= H) Z- = I Z ³ = Cl Z - '= Br W ³ = I 21. The acylanilides of claim 1 which are compounds of formula R W x ⁿ (= H) _Z n (= H) Isomerism " in r. 0 X 3 / X3B = E / CKI; M Diasi.-Gem. U at 0 X ^3a = H. X ³ ° = CE3 (+) - Fonn The 0 X ³ = X ³ ° E = _CH, (-) - Fom r * • * 0 X ^3a = CH ₃ X ^3b -K (-) - form U h · 0 X 3 = ^{3 b} = C cE3.X (-) - form n 0 X = ³ C2E5 31342. H H 0 X 3a = CK = CH ₂ H 0 X 3a = CH = CH-> CH; ; K 0 X3a = CF; The 0 χ3α X3B = _C = H; The 0 χ3α X3B = c = ₂ to ₅ H 0 X3a_ χ3ο =, _{CH2> 4} H 0 X ⁴ = Br CK ₃ 0 CH ;, 0 X ⁴ = Br CH; 0 Z = CE. Racsmát CH; 0 Z- = CK; (-) - FONR. CH; ⁰ 1 Z = CH; (-) - Fcm CH; 0 Z = CH; R 2 W . \ N (= C) FROM" (· Κ) isomers CH; 0 =3 = Ζ ^ CH; Racamai CH ;, 0 Z ^ Z = CH; (-) - Fcnn ch ₃ ⁰ Z 3 = Z ⁴ = CH; (-> FONR. CK; 0 Z 3 = Z ⁵ = CH; Racsnia: CH; 0 Z 3 = Z 5 = CE; (-) - Forum CH; 0 Z 3 = Z == CK, | ' 1 (-> Fora CH; 0 Z ³ / Z ⁴ = (CH ₂ ); CK; 0 Z ³ / Z ⁴ = -CH-CKCH = CK- CK; 0 Z ⁴ »F CK; 0 Z ⁴ = C1 CK; 0 Z ⁴ = Br CK; 0 Z = OCH; Racsmat 31342 / H j CH ;, r 0 Z ⁴ = OCH; • CH ;, 0 Z ² = Z 5 = OCH ₃ ch ₃ 0 Z ² = OCK ₃ , Z ⁵ = CH; Racsmát ch ₃ 0 Z ² = OCK; Z ⁵ = CH; H -) - Fonn ch ₃ 0 Z ² = OCH ;, Z 2 = CK; (-) - form ch ₃ 0 Z ² = OCH 2, Z 2 F CK ₃ 0 Z ^2e OCH ₃ , 2 P = F CK ₃ 0 Z ⁴ = OCH 2, Z ² = F CH ;, about Z ⁴ ® OCH; ,, Z- ' ^s F í CH ;, θ, Z = _OCH3 .Z ^5-Cl Racsmát CK ₃ 0 Z = OCH; Z = C1 ^ (J -) - Fonn R W X ⁿ (-H) FROM" (= H) Isomerism CK ₃ 0 Z = _OCH3 .Z ^5-Cl (-) - form H with CK ₃ with ¹ H CH; H O-CH (3) R ² w X ⁿ -H) FROM" (= ΕΊ Isomerism CK ₃ 0 From ^4-CH = CH; Racsmát CH; 0 z ⁴ = cn Racsmát CH; 0 Z ⁴ = COCH; Racsmát CH; 0 Z ⁴ = CONH; Racsmát - Ch>. 0 Z ² = OCH,. Z ~ = Er Racsmát 31342.Ή CH ₃ 0 Z = OCH _3, Z ⁴ = Br (+) - enantiomer CH3 0 Z = OCH _3, Z ⁴ = Br (-) - form CK-. * 0 From the ² "Br, Z = _OCH3 ⁴ Racsmat ch ₃ 0 Z ² = _OCH3, Z ⁴ 'CN Racsmat ch ₃ 0. z = no ₂ . of ⁴ = och ₃ Racsmat ch ₃ 0 Z - COCH ₃ , Z ⁴ 'CH (CH ₃ ) ₂ Racsmat ch ₃ 0 T? = CO ₃ , Z ⁴ "OCH 3 Racsmat The acylanilides of claim 1, which are compounds of formula | R ² I I i w ZQ ( 'H); Isomerism ' The 0 Racsmat The 0 (-) - form The 0 (-) - form CK ₃ 0 Racsmat CK ₃ 0 (-) - Forľn CEt * 0 (-) - Farm 31342.Ή CH; ⁰ Z ⁴ = F Racsmát CK; 1 0 z ⁴ = f (-) - Fonn CH Cr * 3 o o _Z 4 = F Z- = OCH;, z 5 = F (-) - Fonn ¼ A A CH ₂ at A · OCH d (3) The acylanilides of claim 1, which are compounds of formula X ° (-K) Z ⁿ ("K) x * -ch «ce ₂ CH = CH ₂ X ⁶ = C (OC ₂ K ₅ ) = CK ₂ * X 0 = CsC-CH ₂ OK x ⁶ = c ₆ h ₅ °> X6-C ₆ H ₄ OCK ₃ IT 31342 / H Z ³ = CK = CK ₂ Z ³ = C ₂ K ₅ Z ³ = COCH 3 Z ³ = CN From ⁴ »ch = ck ₂ Z = ⁴ COCK3 24. The acylanilides of claim 1 which are compounds of formula 31342.Ή B Z ⁿ (-H) Isomerism C-O Z ² = OK c = o Z ⁴ »OK c = o Z ² = Z ⁵ = OK c = o Z ² = OK. Z5 = CK ₃ Racsmat c = o Z2 = OK. Z ³ ® CK _; . (-) - form c = o Z2 = OK. Z- = CH ;, (-) - form c = o Z2 = OK. Z ⁴ ® F c = o Z2 = OK, Z ⁵ = F c = o Z ⁴ = OK. Z ² = F c = o Z2 = OE.Z ⁵ ®C1 Cr> Z 2 = OE, Z ⁵ = F Racsmat CK ₂ Z ² = OK, Z ⁵ ® F (4 -) - Fonn ck ₂ Z ² = ok.z ⁵ = f (-) - Fonn c = o Z ² = OE, Z ⁴ = Br Racsmat c = o Z ³ = NO- ?, Z ⁴ = OK Racsmat c = o Z ³ = Cl, Z ⁴ ® OK Racsmat c = o Z ³ = Er, Z ⁴ ® OH Racsmat 25. The acylanilides of claim 1, which are compounds of formula 31342., H R Isomerism CH (CH ₂ ) ₂ Racsmat CE7CH = CK7 Racsmát CH ₂ CE = CH ₂ Racsmat ce ₂ cn Racsmát CE ₂ COOC (CH 2); Racsmat CH ₂ COOC (CH 2); (-> Form CO ₂ COOC (CH 2) ₃  (+) - form 26. The acylanilides of claim 1, which are compounds of formula R ² IN of ⁿ (= H) .B γη ( 'H) .Izoméria H 0 C-O Y = CH; Racsmái H 0 C-O y ⁴ = c-, e ₅ Racsmat ch ₃ 0 C-O Y ⁴ = CE; (+) - form ch ₃ 0 c = o Y = CH; (-) - form CH; 0 c = o y ^{4 =} c ₂ h ₅ Racsmat CE; 0 c = o ^{y 4} = C ₂ H ₅ (-) - form CH; 0 c = o y ⁴ = C ₂ H ₅ (-) - form 31342 / H R 2 in Z ⁿ (* H) B γη ( 'H) Isomerism CK ₃ 0 z ² = oc ₃ C-O Y ⁴ = ce ₃ Racsmát ch ₃ 0 z ² = oc ₃ C-O Y ⁴ = ce ₃ (-) - Fonn ce ₃ 0 z- = oc ₃ C-O y ⁴ = ce ₃ (+) - Fonn ch ₃ 0 z- = oc ₃ C-O y ⁴ = c-> h <·· a * ✓ Racsmat ce ₃ 0 z ² = oc ₃ · C-O Υ * -Ο> Κ < a · w (+) - form CK ₃ 0 Z ² = OCH 3 c = o Y ⁴ = c ₂ e ₅ (-) - Farm ch ₃ 0 Z ² = oc ₃ , z ⁵ = f c = o y ⁴ = ch ₃ Racsmát CK ₃ 0 z ² = and ₃ , z ⁵ »f c = o y ⁴ = ce ₃ (+) - Farm CK ₃ 0 Z ² = OCH :. Z ⁵ = f c = o Y ^ CEs (-) - Fonn ch ₃ 0 z ² = oc ₃ , z ⁵ = f c = o y ⁴ = c ₂ e ₅ Racsmát ch ₃ 0 Z = OCE ₃ , z 5 = F c = o Y ⁴ - C ₂ E ₅ (-) - form ch ₃ 0 Z = _OCH3, Z ⁵ = F c = o y ⁴ - c ₂ h ₅ (-) - form ch ₃ 0 z ² = oc ₃ , z ⁵ = C1 c = o Y ^ CEs Racsmát ch ₃ 0 Z ² = oc ₃ , Z ⁵ = C1 c = o Y ⁴ = ch ₃ (+) - form ch ₃ 0 Z = OCE ₃ , z 5 = Cl C-O Y ^ EC's (-) - form ce ₃ 0 Z ² = OCH: Z ⁴ Br c = o Y ⁴ - CE: Racsmát i CK ₃ 0 Z ² = OCH :. Z ⁴ = Br c = o Y ⁴ = CH: a * (-) - form CH: 0 Z ² = OCH: Z ⁴ Br C-Q 1 1 Y ⁴ = ce ₃ (-) - Fonn CK ₃ j 0 From ⁴ ^ CH: c = o CE: about* Racsma't CF 'u n J 0 From ⁴ ^ ₃ c = o Y ⁴ = c ₂ e ₅ Racsmát ch ₃ i 0 z ^ = ce ₃ c = o Y ⁴ ^ c ₂ h ₅ (-) - form CH: 0 z ^d = ce ₃ c = o y ⁴ ^ c ₂ h ₅ (+) - form ce ₃ 0 Z ^ F c = o y ⁴ = ce ₃ Racsmát ce ₃ 0 Z ⁴ = Br c = o y- = ce ₃ Racsmát ce ₃ 1 0 Z ⁴ = Br c = o y- = ce ₃ '-) - form 31342 / H CH3 ⁰ Z ⁴ = Br WHAT Y ^ CH (+) - form CHt 0 WHAT y ⁴ = cf ₃ CK3 NH WHAT Y ^ CH CK3 n CK 3 WHAT Y ^4-CH ₃ CK3 ABOUT Z ² = OH. Z ⁵ = F WHAT Y ⁴ ® CH ;, Racsmát CE3 0 Z ² = OH, Z ⁵ = F WHAT Y ^4-CH ₃ (+) - form CK3 0 Z = OH. Z ⁵ «= F WHAT y ⁴ = ch ₃ (-) - form CH ;, 0 Z ² = OH. Z ⁴ = Br WHAT Y ⁴ ® CK3 Racsmát CH ;, 0 Z ³ = NO 0, Z ⁴ = OCH 3 WHAT Y ⁴ = CC ₅ Racsmát H 0 CH; Y = CH; Racsmát CH ;. 0 CH; Y ^ EC; Racsmát CH ;, 0 CH; Y ^ C ^ - Racsmát 31342 / H 27. A pharmaceutical composition comprising at least one acylanilide of formula I according to claim 1 and a pharmaceutically acceptable carrier. Use of the acylanilides of the general formula I according to claim 1 for the production of pharmaceutical preparations. 29. A process for the preparation of acylanilides of the formula I Ar wherein A, B, Ar, R ^{1 are} characterized by formula (II) R ² and R ³ in Claim 1 above, characterized in that reacting a carbonyl compound Π in which A, B, Ar, R ¹ and R ^{2 have the} meanings given in formula I, with a compound of the general formula Wherein R ³ has the meaning given in formula I, I in the presence of a catalyst, or an alkyl metal compound, for example a Grignard reagent or an alkyllite compound, to a compound of formula I. 30. The process according to claim 29, wherein the catalyst is an alkali metal fluoride salt or carbonate. 31. A process for the preparation of acylanilides of the formula I 31342 / H wherein A, B, Ar, R ¹ , R ² and R ^{3 are} as defined in claim 1, characterized in that a compound of formula III is reacted FG in which A, B, R ^1, R ² and R ³ as defined in formula I and FG is a leaving group, with a compound of formula Ar-NH-R ¹¹ wherein R ^{11 is} hydrogen or C 1 -C 5 alkanoyl and Ar is as defined in formula I, optionally leaving the residue R ¹¹ cleaved. A process according to claim 31, wherein the leaving groups in formula III are a chlorine, bromine or iodine atom, a tosylate or mesylate radical or a perfluoroalkyisulfonyloxy radical having 1 to 4 carbon atoms. 33. The process of claim 32, wherein the compound of formula III is an acid chloride intermediate formed from the corresponding carboxylic acid. A process for the preparation of acylanilides of the formula I 31342 / H in which A, Ar, R ^1, R ² and R ³ in Claim 1 above and B is -CH ₂ - | characterized in that a compound of formula IV in which A, R ¹ , R ² and R ^{3 have the} meanings given in formula I is reacted with a compound of the formula Ar-NH-R ¹¹ 'wherein R ¹¹ and Ar are as defined in claim 23, optionally removing the residue R ¹¹ thereafter.