SK284943B6 - Non-steroidal (hetero) cyclically substituted acylanilides with mixed gestagen and androgen activity and process for their preparation - Google Patents

Abstract

Non-steroidal (hetero) cyclically substituted acylanilides of general formula (I), wherein R1 and R2 are the same or different and stand for a hydrogen atom, a C1-C5 alkyl group, a halogen atom or together with the C atom of the chain stand for a ring with 3-7 units, R3 optionally means fluorinated C1-C5 alkyl group, A stands for an optionally substituted mono or bi-cyclic aromatic ring, B means a carbonyl group or a -CH2- group, Ar is a ring system more specified in the claims and process for their preparation.

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 steroidal compounds having a gestagenic effect, non-steroid gestagens 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 (heterojicyclically substituted acylanilides of formula (I))

R 'F »HO R ³

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, carbocyclic or heterocyclic 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 ⁵ 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 , (C 3 -C 10) carboxyalkyl, (C 2 -C 5) cyanalkyl, (C 3 -C 10) unsubstituted or substituted allyl, (C 3 -C 10) unsubstituted or substituted propargyl, (C 2 -C 5) alkoxyalkyl atoms and partially or completely by fluorine substitution C 1 -C 5 alkyl, further include cyano or nitro, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, mono- or disubstituted C 1 -C 10 amino or partially or fully fluorinated alkyl groups 1 to 5 carbon atoms

B represents a carbonyl group or a CH ₂ group and Ar represents a ring system selected from the group of general formulas (2) to (11)

t ⁹ )

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, aalkenyl groups of 2 to 5 carbon atoms -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above and alkynyl groups -C = CR ⁵ wherein R ⁵ is as defined above, the radicals X ^3a and X ^3b may further form with the carbon atom of the benzocondensed ring 5, 6 and 7 a ring having a total of 3 to 7 carbon atoms. enmi, 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, hydroxy, alkoxy of 1 to 5 carbon atoms, or alkanoyl of 1 to 5 carbon atoms, as well as when B is CH ₂ , the physiologically acceptable acid addition salts of the compounds of formula (I).

The compounds of the present invention differ from the known non-steroidal compounds having a gestagenic effect by a substitution formula in the aryl moiety, standing to the right in formula (I). For the compounds present herein, Ar is a benzo-fused bicyclic ring system, whereas for the compounds resulting from EP 0 253 500 B1, the phenyl moiety substituted one, two or three times at this point occurs as the closest similar structure.

The compounds of formula (I) of the present invention may exist as different stereoisomers due to the presence of multiple 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 (1), they may in each case have the following meanings.

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In the case of alkyl groups having 1 to 5 carbon atoms, it may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl. 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, for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, a cyclopropyl ring is preferred.

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

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.

C 2 -C 5 carbalkoxyalkyl may be, for example, carboxymethyl, tert-butoxymethyl or ethoxymethyl, both of which are preferred.

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 3-cyclohexylallyl.

Representative of the C3 -C10 propargyl group 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, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, 2,2-dimethylprop

3-methylbutoxy. 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 a phenyl or naphthyl radical, preferably a phenyl radical.

As the heterocyclic moiety, for example, a monocyclic moiety such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrolinyl, pyriazinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl, pyrazolyl, pyrazol that is, all possible isomers with respect to the position of the heteroatoms. As heteroaryl radical A, a thienyl radical is preferred.

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

Suitable alkanoyl groups having 1 to 5 carbon atoms for the esterification of hydroxyl groups are 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 alkanoyl groups mentioned, 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 1, Y ⁴ , Y ⁵ , Y ⁷ or Y ⁸ are formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy or isovaleryloxy, preferably acetyl.

The alkyl groups having 1 to 5 carbon atoms in the alkylthio group having 1 to 5 carbon atoms, the alkylsulfinyl group having 1 to 5 carbon atoms or the alkylsulfonyl group having 1 to 5 carbon atoms, are those alkyl groups having 1 to 5 carbon atoms.

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

When the compounds of formula (I) according to the present invention are present as racemic mixtures, they can be resolved into pure optically active forms by methods known to those skilled in the art. 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 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 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 a cyclopropyl ring together with the carbon atom of the chain, and / or R ³ represents a perfluoroalkyl group having 1 to 5 carbon atoms, and / or

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, vinyl groups, hydroxy groups, methoxy groups and ethoxy groups, and / or either

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

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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

X ⁴ , X ⁶ and X ⁷ are the same or different and independently of one another represent a hydrogen atom or a halogen atom, 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 are independently hydrogen or halogen, and the other substituents have all the meanings given in formula (I).

Further preferred are those compounds of formula (1) in which Ar is a ring system of sub-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-valeroylamino-phthalide, 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-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 5- [4- (4-Bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide, 5- [2-hydroxy-2-trifluoromethyl-4-phenyl-valeroylamino] -phthalide 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-dimethyls) (phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino-phthalide, 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-valeroylaminoj-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-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, 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, 5- (2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino) -phthalide, 5- [4- (4-fluorophenyl)] -2-hydroxy-4-methyl-2-trifluoromethyl-pentylaminoj-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,

5- [4- (3-fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylaminoj-phthalide,

5- [4- (3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentylamino] phthalide,

6- (3-hydroxy-3-methyl-1-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide, 6- (2-hydroxy-4-methyl) -4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one; 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-trifluoromethylpentylamino) -2,3-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-methoxy-phenyl) -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] -2,3-benzoxazin-1-one, 6- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -2,3-benzoxanin-1-one,

4-Ethyl-6- [4- (fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylaminol-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,

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

5- [2-hydroxy-3- (1-phenyl-cyclopropyl) -2-trifluoromethyl--propion-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;

5- [4- (3-ch1ór-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylaminoj-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).

Thus, the novel compounds present themselves as an entirely 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 general formula (I) here are, for all three of the following, which are in the present invention are classified by a competition factor for the progesterone receptor (KF _Prog) and androgen receptor ^(Ki _{ar! D. O} j as shown in Table 1.

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Table 1

Pr. structure Competition factor (p'ov litu’H-Pnignwrtn) C) 1 17 (mp 141-142'C) j 0 ^ NO _a (·) T U 2.0 (tt. 181 ° C) 1) 0 ^ NO- 65 in J r 00:17 Y 104 ť A 0.1 AJ ABOUT 106 HOCFj yS 0.55 J C XJ 1 ' 0

O EP 0253 500 B1. Example 2

1) Compounds with stronger gestagenic and less pronounced androgenic effect (KF _prog ) <1 and KF _andro > 5)

2) Compounds with stronger androgenic and less pronounced gestagenic action (KF _prog )> 1 and KFandro ^< 5)

3) Compounds with pronounced gestagenic and pronounced androgenic activity (KF _prog ) <1 and KF _mdro <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.

Compounds classified under 1) with a stronger gestagenic and less pronounced androgenic effect are very potent gestagens which, like many known gestagenic compounds, are suitable for maintaining 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.

Because of their high gestagenic activity, the novel compounds of formula (I), classified in (1), alone or in combination with estrogens, can be used in contraceptive preparations. However, all other uses known 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 means, for example by determining bioequivalence, for example in a pregnancy maintenance test as compared to 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.

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 cstriol.

However, synthetic estrogens such as ethynyl estradiol, 14α, 17α-ethano1-1,3,5- (10) estratriene-3,17β-ο1 (WO 88/01275), 14a, 17a, -ethanol-1, 14a, 17a, 17a-ethano, 3,5- (10) estratriene-3,16α, β-triol (WO 91/08219) or 15,15-dialkyl estradiol derivatives and in particular 15,15-dimethylestradiol (WO 95/04070). Of the synthetic tarragens, 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-methylene steroids 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), can 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 may also be used as progestogenic components in newly published female fertility control products, characterized by the additional use of competitive progesterone antagonists (HB Croxatto and AM Salvatierra, Female Contraception and Small Advances in Gynecological and Obstetric Research Šerieš, Parthenon Publishing Group - 1991 245: WO 93/17686, WO 93/21927, U.S. Pat. No. 5,521,166).

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

The compounds of formula (I) which are included in (2) or (3), i.e. compounds which in any case have a strong androgenic effect (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 (depot-medroxyprogesterone acetate, levonogestrelester, 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 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 for the treatment of hypergonadism or for the treatment of male infertility and potency disorders.

In order to control male fertility and to treat the above-mentioned disease pattern, the compounds according to the invention are used in dosages which are in effect equivalent to the amounts used in the WHO studies of testosterononate used, or doses already used in 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).

For men, HRT has so far used a dose of approximately 10 mg / day of testostrononanthate.

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 blend profiles 1), 2) and 3) are movable. For such compounds, which by virtue of their KF _prog and / or KF _an . _{The drugs} are on the edge of said KF region, it is possible to consider without further indication the associated effect profile.

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

The formulation of the pharmaceutical preparations 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, if appropriate, taste correcting 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 an intramatemic release system (IntraUterineSystem = 1US; for example MIRNE); the release rate of the active compound or compounds is selected so that the daily release dose lies within said dosage area. 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 present invention of formula (I) may be prepared as follows.

The present invention further provides a process for the preparation of compounds of formula (1), which comprises:

1. react the carbonyl compound of the general formula (II)

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

R ³ - SiMe ₃ , wherein R ³ is as defined in formula (I), and me represents a methyl group in the presence of a catalyst, or with an alkyl metal compound, for example a Grignard reagent or an alkyl lithium compound, to a compound of formula (I). Suitable catalysts are fluoride salts or basic compounds such as 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 , wherein R ^{11 is} hydrogen or C 1 -C 5 acyl, and Ar is as defined in formula (I), optionally leaving the R ¹¹ residue to form a compound of formula (I). The compound of formula (III) may optionally be formed as an intermediate, for example it may be the intermediate acid chloride formed from the corresponding carboxylic acid. Cleavable groups include, for example, a chlorine or bromine atom or a toxylate radical; or be

3. reacting a compound of formula (IV)

R ¹ r ² R ³

wherein A, R ¹ , R ² and R ^{3 are} as defined in formula (I), with a compound of formula

Ar-NH-R, wherein R ¹¹ and Ar are as hereinbefore defined, optionally leaving R ^{11 to} cleave to give 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 represents a perfluoroalkyl group having 1 to 5 carbon atoms, is reacted in a known manner with a compound of the formula

R ¹³ -Y, wherein R ¹³ is an optionally substituted aryl ethenyl or ethynyl radical and Y is a hydrogen atom (J. Org. Chem. 43, 2947 (1978)), group B (OR ¹⁴ ) 2 (J. Org. Chem. 58, 2201 (1993)), or Sn (R ^l5) 3 (J. Org. Chem. 52, 422 (1987), in which R ¹⁴ and R ¹⁵ represent a phenyl radical or alkyl having 1 to 5 carbon atoms, and R ¹⁴ also a hydrogen atom, an Mg-halogen or an alkali metal atom, with metal catalysts for the compound Aryl-R ¹³ ;

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5. in the compound of formula (I) which contains alkoxysubstituted or acyloxysubstituted substituents in A or Ar, liberates the OH group and optionally etherifies or esterifies it by further reaction, or completely eliminates it by hydrogenation after conversion to 1-phenyl-5-tetrazolyl ether (J) Amer Chem Soc., 88, 4271 (1966).

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

If desired, compounds which have been produced according to any one of the above processes 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.

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

The Grignard solution, made from 26.4 g magnesium and 162 ml 2-methyl-2-phenyl-1-chloropropane in 150 ml diethyl ether, was 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 1 l of methanol, mixed 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 (b.p. 75-85 ° C). / 30 hPa). 2 g of this material are saturated with hydrogen chloride gas with 0.6 ml of methanol in 13 ml of hexane 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

1.3 ml of 3N sodium hydroxide gives 0.32 g of 4,4-dimethyl-2-oxo-5-hexenoic acid as a yellowish liquid.

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 moles) 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-phenyl-cyclobutylcarbaldehyde. 3 g of this substance is dissolved in 10 ml of tetrahydrofuran and added dropwise at 0 ° C to the 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 mono-sulfuric acid. Extraction with diethyl ether, drying over anhydrous sodium sulfate and evaporation gave 0.89 g of 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid as a yellowish oil.

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

16.7 g of 2-methoxyphenylacetonitrile, 158 ml of lithium triisopropylamide (bipolar solution) and 46.7 ml of 1.2 dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric triamide are reacted with one another in accordance with J. Org. Chem. 40 (1975) 3497. 5.6 g of 1- (2-methoxyphenyl) cyclopropylcarbonitrile (bp 104-115 ° C / 10 Pa) are obtained, which are reacted further as described for 3- (1-Phenyl-cyclobutyl) -2-oxopropionic acid to give 3- [1- (2-methoxyphenyl) cyclopropyl] -2-oxopropionic acid as an oil.

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 the table are obtained. second

Table 2

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Pr. n Z (* H) 1.1. (° C) 1 3-F oil 1 2-C1 60-63 1 4-C1 oil 1 2-Br 49-54 1 3-Br oil 1 2,4-Cl ₂ 185-190 1 3-OCH ₃ oil 1 3-CFj oil 3 oil 3 _4-CH3 50-61 4 4-OCH ₃ oil

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 Annalen) are slowly added. 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran, after which the mixture was stirred at -70 ° C for one hour 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 sodium sulphate and evaporated. Chromatography on silica gel using hexane / ethyl acetate (97: 3) yields 63 mg of 4- (3-methoxyphenyl) -4-methyl-2-oxo-valeric acid methyl ester, which is mixed with 1 ml of potassium hydroxide in methanol (10 ml). %). 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 acetate phase was combined, dried over anhydrous sodium sulfate 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

Grignard reagent was 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, gave 9.5 g of 2-hydroxy-4-methyl-4 ethyl ester. phenyl-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. After evaporation of the solvent, 3.2 g of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid are obtained in the form of a colorless crystalline substance (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 after stirring at room temperature for 40 hours, the mixture is added to ice-cold water. 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) afforded 1 g of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (mp 38-39). C).

1.9 g of 4- (5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester was refluxed for 2 hours with 40 ml of potassium hydroxide solution in methanol (10%). ). 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).

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

Analogously as described, a mixture of 2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4- (2-thienyl) -2 is obtained. trifluoromethyl

-valeric acid and 2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeric acid (9: 1) (m.p. 150-151 ° C).

The acids listed in Table 3 below are prepared analogously.

Table 3

FROM (H) 1.1. (° C) From the ^4-CH, 136-138 z ³ = z ⁴ = ch ₃ 115-117 z ³ = z ⁵ = ch ₃ 118 Z ⁴ = Br 131-132 Z ⁴ = C1 133-135 Z ⁴ = F 140-141 z ² = and ₃ 98-99 of ⁴ = och ₃ 129-130 Z ² -Z ⁵ -OCH 3 136-137 z ² = och 3, z ⁵ = ch 3 106-107 z ² = and ₃ , z ⁴ = f 103 -106 z ² = and ₃ , z ⁵ = f 102-104 z ⁴ = and ₃ , z ² = f 122-124 z ⁴ = and ₃ , z ³ = f 108-109 z ² = and ₃ , Z ⁵ = C1 103-105 Z ³ / Z ⁴ = (CH ₂ ) ₃ 118-119 Z ³ / Z ⁴ = -CH = CH-CH = CH- 137 Z ² = OCH ₃ , Z ⁴ = Br 115-116 Z ² = Br, Z = _OCH3 ⁴ 122-124 z ⁴ = c ₆ h ₅ 162-163 Z ² = OCH 3, Z ⁴ = CH (CH 3) ₂ 137-138

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

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

Heating the ethyl ester of 4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric, tributylvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine-palladium-II-chloride in dimethylformamide to 120 ° C to give 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-vinylphenyl) -valeric acid ethyl ester, 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, tributyl-1-ethoxyvinyltin, tri-otolylphosphine and bis-tri-o-tolylphosphine-palladium ethyl ester -L-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-ethyl ester -o-tolylphosphine-palladium-II-chloride 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. After saponification, the title compound is obtained as a foam.

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

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

SK 284843 B6

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

Prepared from 4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeric 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-4- (4-methoxyphenyl) -4-methyl-2-trifluoromethylvaleric acid ethyl ester with 4 ml of 100% nitric acid in 12 ml of trifluoroacetic acid for 1 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 tetrachloride. 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 ethyl ester thus obtained

4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeric was stirred with 8.6 ml of 1 M sodium hydroxide in ethyl alcohol / water (2: 1, v / v) and stirred for 3 hours at room temperature. After the addition of water, it is extracted with diethyl ether, the aqueous phase is acidified with 1 m 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 are 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 above 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 above 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 above in the form of an oily substance.

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

It is obtained analogously to that described in the previous example (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 embodiment in the form of an oily substance.

3- (1-Phenylcaclopentyl) -pyruvic acid

It is obtained in an analogous manner to that described in the previous embodiment from 1-phenylcyclopentanol by reaction with ethyl 2-trimethylsilyloxyacrylic acid 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-phenyl-valeric acid ethyl ester are dissolved in 40 ml of tetrahydrofuran and treated at -78 ° C with 3.6 ml of trifluoromethyl-trimethylsilane 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, evaporated and distilled on a bead column. 4.4 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valveric acid ethyl ester (boiling point 95 DEG-100 DEG C./0.04 hPa) are obtained.

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. It is obtained as follows

4.1 g of 4-phenyl-2-trifluoromethyl-1,2-pentadiol (b.p. 120 ° C / 0.04 hPa).

4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentadiol in 30 ml of pyridine are mixed with 3.8 g of acid chloride at 0 ° C.

4-toluenesulfonic acid. 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-trifluoromethylpentyl) 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 ° C) and [2-hydroxy-4- ( 2-methoxy-5-fluór10

4-Toluenesulfonic acid phenyl) -4-methyl-2-trifluoromethylpentyl] ester (m.p. 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 was mixed with 35 mg of sodium hydride (80% in mineral oil) at 0 ° C. 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 g 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 to 90 ° C. Heat for 2 hours at 95 ° C, filter, acidify the filtrate with hydrochloric acid and extract 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 was washed with potassium bicarbonate solution, dried over anhydrous sodium sulfate, and the ethyl acetate phase was evaporated, yielding 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 2 hours at 60 ° C, the mixture is stirred five times with diethyl ether and the ether phase is evaporated. 4.1 g of 4-bromo-5-aminophthalide are obtained as a residue (m.p. 176-180 ° C).

6-bromo-5-aminophthal id

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

Boiling with ethanol gives a mixture of 2-bromo-6-ethoxycarbonyl-3-nitro-benzoic acid and 3-bromo-6-ethoxycarbonyl-4-nitro-benzoic 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 is suspended in 7 ml of acetonitrile, cooled to -35 ° C and treated dropwise with

1.5 g of said 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 to 30 ml of thionyl chloride. 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 ° C) are obtained.

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 ammonia (33%), heated to 60 ° C. After 2 hours at 60 ° C, the mixture is stirred five times with 200 ml of diethyl ether, the diethyl ether phase is evaporated and the residue is crystallized from hexane. It is obtained as follows

3.1 g of 4-amino-2-bromo-benzoic acid allylamide (m.p. 115-117 ° C).

g 4-amino-2-bromo-benzoic acid allylamide,

5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid are refluxed for 1.5 hours with a water separator. The solution was then diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with potassium carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from hexane. 13.4 g of N-allyl-2-bromo-4- (2,5-dimethylpyrrol-1-yl) -benzamide (m.p. 136 DEG-138 DEG C.) are obtained.

g of N-allyl-2-bromo-4- (2,5-dimethylpyrrol-1-yl) -benzamide in 100 ml of dimethoxyethane is mixed with -70 ° C with

14.2 ml of 1.4 M butyllithium in hexane and, after 30 minutes at -70 ° C, 1.63 ml of crotonaldehyde are added. 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 is diluted with water, extracted with ethyl acetate, washed with potassium carbonate solution, dried over sodium sulphate and evaporated. The residue obtained after chromatography on silica gel using hexane / ethyl acetate (98: 2) gives 1.1 g of crystalline 5- (2,5-dimethylpyrol-1-yl) -3- (1-propenyl) -phthalide (mp 91-95). C).

1.1 g of 5- (2,5-dimethylpyrrol-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) is heated to 120 ° C for 24 hours. The solvent is then distilled off, the residue is 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). to 130 ° C).

The phthalides listed in Table 4 are obtained analogously.

Table 4

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x ^3a / x ^3b 1.1. (° C ch ₃ / h 152-156 ch ₃ / ch ₃ 94-97 c ₂ h ₅ / h 137-140 c ₂ h ₅ / c ₂ h ₅ 95-96 ch = ch ₂ / h 89-93 - (CH ₂ ) 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 for 20 minutes at -3 ° C to 3 ° C, 228 mg of 4-bromo-5-aminophthalide are added and stirred for 1.5 hours at 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-valeroyl-amino) -phthalide, the compounds shown in Tables 5 and 6 are obtained.

Table 5

from

Pr. FROM Z ^ H 1.1. (° C) Z ² = 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-phenylcyclopropyl) acid. -2-oxo-propionic (mp 132-138 ^° C).

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-valoyl-amino) -phthalide, from 5-aminophthalide and 3- (1-phenylcyclobutyl) acid. -2-oxo-propionic (mp 142-146 ° C).

5- (3- (1-Phenyl-cyclohexyl) -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-phenylcyclohexyl) acid. -2-oxo-propionic acid (mp 120-123 ° C).

The compounds listed in Table 6 were also prepared.

Table 6

from

Pr. n Z (* H) 1.1. (° 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-Cl ₂ 135-138 1 3-OCH 140-153 1 3-CF ₃ 166-170 3 140-144 3 _4-CH3 oil 4 4-OCH ₃ 129-130

SK 284843 B6

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-valcroylamino) -phthalide from 6-amino-4-methyl-2,3-benzoxazine- 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- (l-phenyl-cyclohexyl) -2-oxo-propionylamino] -4-methyl-2,3-benzoxazin-l-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 an acid

3- (1-phenyl-cyclohexyl) -2-oxo-propionic (m.p. 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

The title compound was prepared in analogy to the example described above 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 (m.p. 148-150 ° C).

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) acid. (methoxyphenyl) -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) -acid. (methoxyphenyl) -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-valeroylamino) -phthalide using 5-aminophthalide and 3- (1-phenyl-cyclopentyl) - Of 2-oxo-propionic (mp 140-144 ° C).

6- [4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeroyl-amino] -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-valeroylamino) -phthalide using 4-ethyl-2,3-benzoxazin-1- 4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid (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 for the production of 4-bromo-aminophthalide. 56.4 g of acid are obtained

4-nitro-2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -benzoic acid.

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 was 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 ethyl alcohol and 50 ml of water. The reaction mixture is then diluted with water and the crystals are filtered off with suction. After drying, it is obtained

3.5 e of 6-amino-4-methyl-2,3-benzoxazin-1-one (m.p. 291-296 ° C).

6-amino-4-ethyl-2,3-benzoxazin-l-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 Bol. Sci. Fac. Chim. Ind. Bologna, 22, 33, 36, 37 (1964).

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

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

SK 284843 B6

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-11-2-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)).

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

350 mg of 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide were dissolved under argon in 15 ml of dimethylformamide by cooling with ice and mixed with 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

It was produced analogously to that described in Example 1 of

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 (mp 205-210 ° C) .

Example 3

5- (2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino) phthalide

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

Example 4

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

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

Example 5

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

Prepared in analogy 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 (mp 153-157 ° C) ).

Analogously to Example 1, the compounds listed in Table 7 were prepared.

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

Table 7

Pr. n FROM (*) 1.1. (° C) Isomerism 6 1 168-175 racemate 7 1 172-179 (+) - enantiomer 8 1 172-179 (-) - enantiomer of 9 1 3-F 155-158 racemate 10 1 2-C1 192-194 racemate 11 1 4-C1 148-154 racemate 12 1 4-C1 174-176 (+) - enantiomer 13 1 4-C1 173-175 (-) - enantiomer of 14 1 2-Br 163-165 racemate 15 1 3-Br 189-191 racemate 16 1 2,4-Clj 216-218 racemate 17 1 2-OCH 200 - 208 (-) - Enantiornér 18 1 2-OCH ₃ 195-208 (-) - enantiomer of 19 1 3-OCH ₃ 225-228 racemate

SK 284843 B6

20 1 3-CFj 152-163 racemate 21 2 182-188 racemate 22 2 187-192 (+) - enantiomer 23 2 188-192 (-) - enantiomer of 24 3 106-112 (+) - enantiomer 25 3 _4-CH3 179-183 racemate 26 4 165 -171 racemate 27 4 170-174 (+) - enantiomer 28 4 170-174 (-) - enantiomer of

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

Table 8

about

Pr. n 1.1. (° C) Isomerism 29 1 78-84 racemate 30 1 227-235 (+) - enantiomer 31 230-239 (-) - enantiomer of 32 2 174-184 racemate 33 4 185-187 racemate 34 4 90-97 (+) - enantiomer 35 4 90-96 (-) - enantiomer of

Table 9

Pr. of ⁿ (* H) 1.1. (° C) 36 Z ² = I amorphous. 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 was 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 over sodium sulphate and evaporated. After chromatography on silica gel (hexane / ethyl acetate 1: 1), 39 mg of 6- (2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one is obtained ( mp 173-175 ° C).

Example 41 (method 2)

5- (2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -flalid

500 mg of 2-hydroxy-4-phenyl-2-trifluoromethylvaleric 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 at 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 anhydrous 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

SK 284843 B6

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-benzoxazine-1- (mp 172-173 ° C).

Analogously to Example 41, the compounds listed in the following Table 10 were prepared.

Table 10

3b

Pr. R ² W X ⁿ (* H) Z ⁿ (* H) 1.1. (° C) Isomerism resp. m _d (c = 0.5) 43 H ABOUT X ^3a / X ^3b = H / CH ₃ 175-185 Diast.-Gem. 44 H ABOUT X ^3a = H, X ^ib = CH ₃ 175-178 -22.5 45 H ABOUT X ^3a = H, X ^ib = CH ₃ 210-213 -74 46 H 0 X ^3a = CH ₃ , X ^3b = H 210-213 -69.5 47 H 0 X ^3a = CH ₃ , X ³ H 175-179 -21.5 48 H 0 X ^3a = C ₂ H ₅ 169-174 49 H 0 X ^3a = CH = CH ₂ 162-174 50 H 0 X ^3a = CH = CH ₂ -CH ₃ 160-162 51 H 0 X ^3a = CF ₃ 156-166 52 H 0 X ^3a = X ^Jb = CH 160-171 53 H 0 X ^3a = X ^3b = C ₂ H ₅ 172-176 54 H 0 X ^3a + X ^3b = (CH ₂ ) ₄ 168-170 55 H 0 X ⁴ = Br 180-185 56 CH, 0 159-162 57 CH 0 X ⁴ = Br 187-194 58 CH 0 Z ² = CH ₃ 155-156 racemate 59 CH 0 Z ² = CH 3 148-149 (+) - form 60 CH 0 Z ² = CH 3 145-146 (-) - form 61 CH 0 Z ⁴ = CH 3 189-190

Pr. R ² w X OH) FROM (H) 1.1. (° C) Isomerism resp. m _d (c = 0.5) 62 CH 0 Z ³ = Z ⁴ = CH ₃ 206-207 racemate 63 CH 0 Z ³ = Z ⁴ = CH 3 207 - 209 (+) - form 64 CH 0 Z ³ = Z ⁴ = CH 3 207 - 209 (-) - form 65 CH 0 Z ³ = Z ⁵ = CH 3 154 racemate 66 CH 0 Z ³ = Z ⁵ = CH 3 188-189 (+) - form 67 CH 0 z '= z ³ = ch. 188 (-) - form 68 CH 0 Z ³ -Z ⁴ - (CH ₂ ). 171-173 69 CH, 0 Z ³ / Z ⁴ = -CH = CH- CH = CH- 218-219 70 CH 0 z ⁴ = f 177-178 71 CH 0 Z ⁴ = C1 184-185 72 CH, 0 Z ⁴ = Br 177-179 73 CH ABOUT Z ² = OCH ₃ 134-135 racemate 74 CH ABOUT of ⁴ = och ₃ 183-184 75 CH ABOUT z ² = z ⁵ = and ₃ 145 76 CH ABOUT Z ² = OCH 3, Z ⁵ = CH 3 126-127 racemate 77 CH ABOUT of ^2-OCH ,, Z ⁵ = CH 169-170 (+) - form 78 CH ABOUT Z ² = OCH 3, Z ^? = CH 169 (-) - form 79 CH ABOUT Z ² = OCH 3, z ⁴ = f 180-181 80 CH ABOUT z ² = and ₃ , z ⁵ = f 140-141 81 CH ABOUT z ⁴ = and ₃ , z ² -f 207 82 CH ABOUT z ⁴ = and ₃ , z ³ = f 178- 179 83 CH ABOUT z ² = and ₃ , Z ³ = C1 141 racemate 84 CH ABOUT Z ² = OCH 3, Z ⁵ = Cl 106-108 + 105.5 (1)

SK 284843 B6

Pr. R ² W X (* H) of ⁿ (* H) 1.1. (° C) Isomers and w _D (c = 0.5) 85 CH, ABOUT z ² = and ₃₎ z ⁵ = ci 105-207 -97 (1) 86 H with 189-191 87 CH, with 173-175 88 H ch ₂ 161-162 89 H O-CH ₂ 192-195 90 CH, ABOUT of ⁴ = ch = ch ₂ 190-192 racemate 91 CH ₃ ABOUT z ⁴ = cn 230 -233 racemate 92 CH, ABOUT of ⁴ = coch, 174-176 racemate 93 CH, 0 of ⁴ = conh ₂ 130- 1332 racemate 94 CH, 0 Z ² = OCH _3i Z ⁴ = Br 144-145 racemate 95 CH, 0 Z ² = OCH ₃ , Z ⁴ = Br 176-177 (+) - enantiomer 96 CH, 0 Z ² = OCH ₃ , Z ⁴ = Br 177-178 -139.6 97 CH, 0 Z ² = Br, Z ⁴ = OCH 197-198 racemate 98 CH, 0 z ² = and ₃ , z ⁴ = cn 135-136 racemate 99 CH, 0 z ³ = no ₂ , z ⁴ = OCH 202-206 racemate 100 CH, 0 Z ² = COCH 3, Z ⁴ = CH (CH 2) 2 135 racemate 101 ch ₃ 0 Z ³ = COCH ³ , z ⁴ = and ₃ 213-214 racemate

(1) The optically active compounds reported in Table 10 are separated analogously to Example 88 (2) In methyl alcohol (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 carrier (Chiralpak AD ^R , Daicel) using hexane / 2-propyl alcohol / ethyl alcohol (900: 25: 25, v / v) to give 200 mg of racemate mg (- I-forms (mp 136-137 ° C), and _D = -194.8 ° (c = 0.5 in chloroform), mg (+) - forms (mp 135-136 ° C), and _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-valeroylaminoj-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-trifluoromethyl-valeroylamino] -phthalide (mp 166 ° C), α _D = + 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), ( +) - 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) gave 266 mg of 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide (m.p. 110 ° C).

Analogously to Example 104, the compounds in Table 11 were obtained.

Table 11

SK 284843 B6

Pr. R ² W FROM" (H) 1.1. (° C) Isomerism resp. ^{I ''} 'D (c = 0.5) (2) 105 H ABOUT 110 racemate 106 H 0 123 -18.6 107 H 0 123 -18.4 108 ch ₃ 0 139-140 racemate 109 CH ₃ 0 159-160 + 12.0 (4) 110 ch ₃ 0 160-161 12.5 (4) 111 CH ₃ 0 z ⁴ = f 148-149 racemate 112 ch ₃ 0 z ⁴ = f 162-164 +9.0 113 ch ₃ 0 z ⁴ = f 162-164 -6.7 114 ch ₃ 0 z ² = and ₃ , z ^l f 148-149 115 H ch ₂ 161-162 116 H och ₂ _ 127-128

1) The optically active compounds listed in Table 11 are separated analogously to Example 102

2) In methyl alcohol

3) Formation of 1-isochromanone

4) In chloroform

Example 117

4-ethyl-6- (2-hydroxy-4-phenyl-2-trifluoromethyl-pcntylamino) -2,3-benzoxazin-l-one

This compound was obtained analogously to Example 104 from 151 mg of 6-acetamido-4-ethyl-2,3-benzoxazin-2-one, 208 mg of (2-hydroxy-4-phenyl-2-trifluoromethylpentyl). 4-toluenesulfonic acid ester and 36 mg of sodium hydride (mp 161-163 ° C).

Example 118 1- (4-Nitro-3-trifluoromethylanilino) -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-l-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) 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 under argon. , 25 mg of bis-triphenylphosphmpalladium-II-chloride. After refluxing for a few hours, an additional 30 mg of 2-methyl-3-butin-2-ol was added 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-triphenylphosphor palladium-II-chloride in 4 ml of toluene under an argon atmosphere. After refluxing for 5 hours, 45 mg of bis-triphenylphosphine-palladium-II-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 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.

Table 12

SK 284843 B6

Pr. X » (H) FROM (H) mp CC) 121 X ^ ij CHC i 22 X ° -CH-CH 3 191-197 123 χό = 160-163 12- 1X-- CeC-CH-OH 2 OS-211 125 X ₆ -C ₆ Hj 160-IO3 126 OH - Xn = 157-I5S 12 ' XT-CeHaOCHjW 125-127 123 Z 3 -CH <H, 178-180 129 WS-CzHsC) 152-153 130 Z - '= Crh («) 220

t j 1 Z ^with CN 112 132 of ⁴ -ch-ch ₂ 190-192 133 Z ^ COCH} (-) 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-phthalide valeroylaminoj

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 a temperature of 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 sulphate 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) was obtained. 139-140 ° C).

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

Table 13

Pr. B of ⁿ (* H) 1.1. (° C) Isomerism resp. W _D (c = 0.5) 135 C-O z ^{1 2} = oh 222-224 136 c = o z ⁴ = oh 228-230 137 c = o of ² -of ⁵ -oh 265-267 138 c = o z ² = oh, z ⁵ = ch ₃ 215-217 racemate 139 c = o z ² = oh, z ⁵ = ch ₃ 173-174 (-) - form 140 c = o z ² = oh, z ⁵ = ch ₃ 173-174 (-) - form 141 c = o z ² = oh, z ⁴ = f 240-242 142 c = o Z ² = OH, Z ⁵ = F 201 -202 143 c = o z ² = OH, Z ² = f 242-243 144 c = o z ² = oh, Z ⁵ -C 1 220-221 145 ch ₂ z ² = oh, z ⁵ = f 156-157 racemate 146 ch ₂ z ² = oh, z ⁵ = f 157-159 +23.5 147 ch ₂ z ² = oh, z ⁵ = f 157-159 -18.7 148 c = o Z ² = OH, Z ⁴ = Br 224-226 racemate 149 c = o z ³ = no ₂ , z ⁴ = oh 167-169 racemate 150 c = o z ³ = ci, z ⁴ = oh 168 -169 racemate 151 c = o Z ³ = Br, Z ⁴ = OH 105 racemate

1) The optically active compounds listed in Table 13 are separated analogously to Example 102

2) In methyl alcohol

SK 284843 B6

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 -trifluoromethyl-valeroylamino-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 the 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-trifluoromethyl-valeroyalmino] -phthalide (m.p. 157 ° C) are obtained.

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

Example 153

The compound is obtained analogously to the previous example from 57 mg of 5- [2-hydroxy-4- (2-hydroxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide (mp 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).

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-methyl-2-trifluoromethyl-valeroylamino] -phthalide in 1 ml of dimethylformamide was stirred with 28 mg of potassium carbonate and 50 mg of ethyl iodide for 24 hours at 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 the solvent is evaporated off 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.

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

Table 14

Pr. R 1.1. (° C) Izoméria prip. m _d (c = 0.5) 155 CH _{(CH3) 2} 153-154 racemate 156 ch ₂ ch = ch ₂ 152 racemate 157 ch ₂ ch = ch ₂ 187-189 racemate 158 CH ₂ CN 170-172 racemate 159 CH ₂ COOC (CH ₃ ) ₃ 145 racemate 160 CH ₂ COOC (CH ₃ ) ₃ 143 -131.5 161 CO ₂ (CH ₃ ) ₃ 142-143 (+) - form

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-trifluoromethyl-valcroylamino-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, dried 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-vaieroylaminoj-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 listed in the following Table 15 were prepared in this manner.

SK 284843 B6

Table 15

Pr. R ⁵ in of ⁿ (* H) B Y ⁿ OH) 1.1. (° C) Isomers and ^[α] D (c = 0.5) (2) 163 H 0 c = o Y ⁴ = CH 3 165 -166 racemate 164 H 0 c = o y ⁴ = c ₂ h ₅ 159-160 racemate 165 ch ₃ 0 c = o Y ⁴ = CH 3 185 +162 166 CH 0 c = o Y ⁴ = CH 3 184-185 -182 167 CH 0 c = o y ⁴ = c ₂ h ₅ 148-153 racemate 168 CH 0 c = o y ⁴ = c ₂ h ₅ 159-160 +173 169 CH 0 c = o y ⁴ = c ₂ h ₅ 159-160 -175 170 CH 0 Z ^{1 2} = OCH 3 c = o Y ⁴ = CH 3 161 -163 racemate 171 CH 0 Z ² = OCH 3 c = o Y ⁴ = CH 3 173 -175 -54.7 (4) 172 CH 0 Z ² = OCH 3 c = o Y ⁴ = CH 3 173 -175 +52.2 173 CH 0 Z ² = OCH 3 c = o y ⁴ = c ₂ h ₅ 164 racemate 174 CH 0 Z ² = OCH 3 c = o y ⁴ = c ₂ h ₅ 190-191 (+) - form 175 CH 0 Z ² = OCH 3 c = o y ⁴ = c ₂ h ₅ 190-191 -161.3 (CHCl 3) 176 CH 0 Z ² = OCH 3, z ⁵ = f c = o Y ⁴ -CH 2 165 racemate 177 CH 0 Z ² = OCH 3, z ⁵ = f c = o Y ⁴ = CH 3 188-189 (-) - form 178 CH 0 Z ² = OCH 3, z ⁵ = f c = o Y ⁴ = CH 3 187-188 -132.8 (CHCl 3) 179 CH 0 Z ² = OCH 3, z ⁵ = f c = o y ⁴ = c ₂ h ₅ 126-128 racemate 180 CH 0 Z ⁵ = OCH _b Z ⁵ = F c = o y ⁴ = c ₂ h ₅ 170-171 -147.4 181 CH 0 z ² = and ₃ , z ⁵ = f c = o y ⁴ = c ₂ h ₅ 171 (+) - form 182 CH 0 z ^; -och ₃ , Z ⁵ = C1 c = o Y ⁴ = CH 3 182-184 racemate 183 CH 0 Z ² = OCH 3, Z ⁵ = C1 c = o Y ⁴ = CH 3 198-199 (+) - form 184 CH 0 Z ² = OCH 3, Z ⁵ = C1 c = o Y ⁴ = CH 3 197-198 -90.2 185 CH 0 Z ² = OCH 3, Z ⁴ = Br c = o Y ⁴ = CH 3 206-207 racemate

Pr. R ² in of ⁿ (* H) B γη (H) 1.1. (° C) Isomerism resp. m _d (c = 0.5) 186 CH 0 Z ² = OCH 3, Z ⁴ = Br C-O Y ⁴ = CH 3 194-198 (-) - form 187 CH 0 Z ² = OCH 3, Z ⁴ = Br C-O Y ⁴ = CH 3 196-198 -122.2 (CHCl 3) 188 CH 0 of ⁴ = ch ₃ C-O Y ⁴ = CH 3 222-223 racemate 189 CH 0 of ⁴ = ch ₃ C-O y ⁴ = c ₂ h ₅ 187-188 racemate 190 CH 0 of ⁴ = ch ₃ C ~ H y ⁴ -c ₂ h ₅ 160 -63.7 191 CH 0 Z ⁴ = CH 3 C-O y ⁴ = c ₂ h ₅ 160 (+) - form 192 CH ABOUT z ⁴ = f c = o Y ⁴ = CH 3 188-190 racemate 193 CH ABOUT Z ⁴ = Br c = o y ⁴ = ch ₃ 219-220 racemate 194 CH ABOUT Z ⁴ = Br c = o Y ⁴ = CH 3 231 -233 -49.3 195 CH ABOUT Z ⁴ = Br c = o Y '= CH, 231 -233 (+) - form 196 CH ABOUT c = o y ⁴ = ch ₃ 175-183 197 CH NH C-0 Y ⁴ = CH 3 198 CH NCH ₃ c = o Y ⁴ = CH 3 199 CH ABOUT z ² = oh, z ⁵ = f c = o Y ⁴ = CH 3 234-236 racemate 200 CH ABOUT z ² = oh, z ⁵ = f c = o Y ⁴ = CH 3 232-234 (-) - form 201 CH ABOUT z ² = oh, z ⁵ = f c = o Y ⁴ = CH 3 232-234 -34.1 202 CH 0 Z ² = OH, Z ⁴ = Br c = o Y ⁴ = CH 3 248-250 racemate 203 CH 0 z-no ₂ , z ⁴ = and ₃ c = o Y ⁴ = CH 3 215-217 racemate 204 H 0 ch ₂ Y ⁴ = CH 3 148-149 racemate 205 CH 0 ch ₂ Y ⁴ = CH 3 132-133 racemate 206 CH about ch ₂ y ⁴ = c, h ₃ 121-122 racemate

1) The optically active compounds reported in Table 15 are divided analogously to Example 102

2) In methyl alcohol

SK 284843 B6

Example 207

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

This compound was obtained analogously to Example 41 from 2-hydroxy-4-phenyl-2-trifluoromethylvaleric acid and 5-aminobenz [1.2.5] oxadiazole (m.p. 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-trifluoromethylvaleric acid and 5-amino-benzo [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-trifluoromethylvaleric acid and 6-amino-1-methyl-benzotriazole (m.p. 194-196 ° C).

Claims (33)

1. Non-steroid (hetero) cyclically substituted acylanilides of formula (I) R ¹ R HO R ³ 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 carbocyclic or heterocyclic 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, alkenyl groups of 2 to 5 carbon atoms, groups -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 an acyl having 1 to 5 carbon atoms, further hydroxy groups, hydroxy, bearing the acyl group having 1 to 10 carbon atoms, (C 3 -C 10) carboxyalkyl, (C 2 -C 5) cyanalkyl, unsubstituted or substituted (C 3 -C 10) allyl, (C 3 -C 10) unsubstituted or substituted propargyl, (C 2 -C 5) alkoxyalkyl; partially or fully fluorine substituted al (C 1 -C 5) -alkyl, further comprising cyano or nitro, C 1 -C 5 -alkoxy, C 1 -C 5 -alkylthio, mono- or di-substituted C 1 -C 10 -amino or partially or fully fluorinated C 1 -C 5 -alkyl; 1 to 5 carbon atoms, B represents a carbonyl group or CH groups, and Ar represents a ring system selected from the group of general formulas (2) to (11) wherein the radicals X ^3a , X ⁴ , X ⁶ , X ⁷ (in partial) (4), X ⁴ , X ⁶ , X ⁷ (in sub-formulas (3) and (4)), X ^3a , X ^3b , X ⁴ , X ^s , 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 having 1 to 5 carbon atoms which may additionally contain a hydroxyl group; esterified by alkyl of 1 to 5 carbon atoms or an esterified alkanoyl group having 1 to 5 carbon atoms, partially or fully fluorinated alkyl group having 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 as defined above and alkynyl groups -OCR ⁵ wherein R ⁵ is as defined above, the radicals X ^3a and X ^3b may further form with the carbon atom of the benzo fused ring (of formula (5), (6) or (7)) ring having a total of 3 to 7 members, as well as also the radicals X ^4, X ⁶ and X ⁷ in the 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, C 1 -C 5 alkoxy or alkanoyloxy groups with 1 to 5 carbon atoms, and in the case where B is CH ₂ , physiologically acceptable salts of the compounds of formula (I) with acids. Acylanilides according to claim 1 of the general 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 (1), in which SK 284843 B6 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 cyclopropyl ring. Acylanilides according to claim 1, in which R ³ represents a perfluoroalkyl group having 1 to 5 carbon atoms. 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, vinyl, hydroxy, methoxy or ethoxy groups. Acylanilides according to claim 1 of the general formula (I) in which X ^3a represents a hydrogen atom or an alkyl group 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. 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. The acylanilides according to claim 1 of the general formula (I), in which Y ⁴ represents an alkyl group having 1 to 5 carbon atoms or a perfluoroalkyl group having 1 to 5 carbon atoms. 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. 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, ethyl, vinyl, hydroxy, methoxy and ctoxy groups and either 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, 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 are independently hydrogen or halogen, and the other substituents have all the meanings given in formula (I). Acylanilides according to claim 1 of the general formula (I), in which Ar represents a ring system of the partial formula (6). Acylanilides according to claim 1 of the general formula (I), in which Ar represents a ring system of the partial formula (7). The acylanilides according to claim 1 of the general formula (I), in which Ar represents a ring system of the partial formula (10). Acylanilides according to claim 1 of the general formula (I), in which Ar represents a ring system of the partial formula (11). 16. The acylanilides according to 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 -valeroylamino-phthalide, 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-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, 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-dimethyl) phenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino-phthalide, 5- [2-hydroxy-4- (2-methoxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalid 5- [4- (5-chloro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -halide, 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-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (3-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- (2-hydroxy-4) 5- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- [4- (5-chloro-2-methyl-2-trifluoromethyl-valeroylamino) -phthalide] -methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide, 5- (2-hydroxy-4- methyl-2-trifluoroacetic methyl-pentylamino) -phthalide, 5- [4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide, 5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide, 6-Acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide. SK 284843 B6 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-trifluoromethyl-valeroylamino) -phthalide, 6- (2-hydroxy-4-methyl) 4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl-2,3-benzoxazin-l-one, 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-l-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-valeroylamino] -4-methyl-2,3-benzoxazin-1-one, 4-ethyl-6- [2-hydroxy-4-methyl-4- (4-methylphenyl) -2-Trifluoromethyl-valeroylamino] -2,3-benzoxazin-1-one, 6- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -2,3-benzoxazine - i-one, 4-ethyl-6- [4- (fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -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, 5- (2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino) -phthalide, 5- [2-hydroxy-3- (l-phenyl-cyclopropyl) -2-trifluoromethyl-propionylamino] -phthalide, 5- [2-hydroxy-3- (l-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. 18. The acylanilides according to claim 1, which are compounds of the formula TI Z (* H) Isomerism 1 racemate 1 (+) - enantiomer 1 (-) - enantiomer of 1 3-F racemate 1 2-C1 racemate 1 4-C1 racemate 1 4-C1 (+) - enantiomer 1 4-C1 (-) - enantiomer of 1 2-Br racemate 1 3-Br racemate 1 2,4-Cl ₂ racemate 1 2-OCH ₃ (+) - enantiomer 1 2-OCH (-) - enantiomer of 1 3-OCH ₃ racemate 1 3-CF ₃ racemate 2 racemate 2 (+) - enantiomer 2 (-) - enantiomer of 3 (-) - enantiomer of 3 _4-CH3 racemate 4 racemate 4 (+) - enantiomer 4 (-) - enantiomer of The acylanilides according to claim 1, which are compounds of formula n Isomerism 1 racemate 1 (+) - enantiomer (-) - enantiomer of 2 racemate 4 racemate 4 (+) - enantiomer 4 (-) - enantiomer of SK 284843 B6 20. Acylanilides according to claim 1, which are compounds of the formula FROM Z2-1 Z ^ Sr Z ³ -I The acylanilides according to claim 1, which are compounds of formula R ² W x ⁿ (* H) Z ”(* H) Isomerism H 0 X ^3a / X ^3b = H / CH ₃ Diast.-Gem. H 0 X ^3a = H, X ^3b = CH ₃ (+) - form H 0 X ^3a = H, X ^3b = CH ₃ (-) - form H 0 X ^3a = CH ₃ , X ^ib = H (+) - form H 0 X ^3a = CH ₃ , X ^3b = H (-) - form H 0 X ^3a = C ₂ H ₅ H 0 X ^3a = CH = CH ₂ H 0 X ^3a = CH = CH ₂ -CH ₃ H 0 X ^3a = CF ₃ H 0 _X 3a _{= X} 3b ₌ cH ₃ H 0 X ^{, a} = X ^3b = C ₂ H ₅ H 0 X ^3a = X ^3b = (CH ₂ ) ₄ H about X ⁴ = Br CH 0 CH 0 X ⁴ = Br CH 0 z ² = ch ₃ racemate CH ₃ 0 Z ² = CH 3 (+) - form CH 0 Z ² = CH 3 (-) - form CH 0 Z ² = CH 3 R ² w X (* H) FROM (H) Isomerism CH 0 Z ³ = Z ⁴ = CH 3 racemate CH 0 Z ³ = Z ⁴ = CH 3 (+) - form CH 0 Z ³ = Z ⁴ = CH 3 (-) - form CH 0 Z ³ -Z ⁵ -CH racemate CH 0 Z ³ = Z ⁵ = CH 3 (+) - form CH 0 Z ³ = Z ⁵ = CH 3 (-) - form CH 0 Z ³ / Z ⁴ = (CH ₂ ) j CH 0 of ³ / of ⁴ = -ch = chch = ch- CH 0 z ⁴ = f CH 0 Z ⁴ = CI CH, 0 Z ⁴ = Br CH ABOUT z ² = and ₃ racemate CH 0 of ⁴ - OCHj CH 0 Z ² = Z ⁵ = OCH 3 CH 0 z ² = och 3, z ^s = ch 3 racemate CH 0 z ² = och 3, z ⁵ = ch 3 (+) - form CH 0 Z ² = OCH 3, Z 2 CH 3 (-) - form SK 284843 B6 CH 0 z ² -och ,, z ⁴ = f CH 0 z ² = and, z ⁵ = f CH 0 Z ⁴ = OCH 3, z ² = f CH 0 Z ⁴ = OCH ³ , z ³ = f CH 0 Z ² = OCH 3, z ⁵ = ci racemate CH 0 z ² = and ₃ , z ⁵ = ci (+) - form R ² w X (H) Z ⁿ (* H) Isomerism CH 0 Z ² = OCH 3, Z -C 1 (-) - form H with CH WITH H ch ₂ H O-CH, (2) CH ₃ 0 of ⁴ = ch = ch ₂ racemate CH 0 z ⁴ = cn racemate CH, 0 Z ⁴ = COCH 3 racemate CH ₃ 0 of ⁴ = conh. racemate CH 0 Z ² = OCH 3, Z ⁴ -Br racemate CH 0 Z ² = OCH 3, Z ⁴ = Br (+) - enantiomer CH 0 Z ² = OCH 3, Z ⁴ = Br (-) - form CH 0 Z ² = Br, Z ⁴ = OCH 3 racemate CH 0 z'-OCH 3, Z ⁴ = CN racemate CH 0 Z ³ = NO _2j Z ⁴ = OCH 3 racemate CH ABOUT Z ² = COCH 3, Z ⁴ = CH (CH 3) ₂ racemate CH 0 Z ³ = COCH ³ , Z ⁴ -OCH 3 racemate The acylanilides according to claim 1, which are compounds of the formula R ² W Z ⁿ (* H) Isomerism H 0 racemate H 0 (+) - form H 0 (-) - form CH about racemate CH 0 (+) - form CH 0 (-) - form CH 0 F ^ F racemate CH 0 Z ⁴ = F (-) - form CH 0 z ⁴ = f (-) - form CH 0 Z ² = OCH 3, z ⁵ = f H CH, H OCH ₂ (2) The acylanilides according to claim 1 of formula (1) which are compounds of formula SK 284843 B6 X (#H) FROM (/ R) X-CH-CKZ X O-CH-CHI X ^s = C (OC ₂ H 5) = CH 2 ^No X-C »C-CH ₂ OH X ^ C _é H _ä CH x M _Delta X = C5H4OCH5 (P ·) From ³ -CH-CH ₂ 2- = Ct H3 Z ³ - COCH Z ³ - CN Z4 = CH = CH _: Z ⁴ = COCH ₂ 24. The acylanilides according to claim 1, which are compounds of the formula B Z (* H) Isomerism C-O z ² = oh c = o z ⁴ = oh c = o z ² = z ⁵ = oh C-O z ² = oh, z ^: = ch racemate C-O z ² = oh, z ⁵ = ch ₃ (+) - form c = o z ² = oh, z ⁵ = ch ₃ (-) - form c = o z ² = oh, z ⁴ = f c = o z ² = oh, z ⁵ = f c = o z ⁴ = oh, z ² = f c = o z ² = oh, z ^: = ci CH ₂ z ² = oh, z ⁵ = f racemate ch ₂ z ² = oh. z ⁵ = f (+) - form ch ₂ z ² = oh, z ⁵ = f (-) - form c = o Z ² = OH, Z ⁴ = Br racemate c = o z ³ = no ₂ , z ⁴ = oh racemate c = o Z ³ = C1, z ⁴ = oh racemate c = o Z ³ = Br, Z ⁴ = OH racemate SK 284843 B6 25. The acylanilides according to claim 1, which are compounds of the formula R Isomerism CH _{(CH3) 2} racemate ch ₂ ch = ch ₂ racemate ch ₂ ch = ch ₂ racemate ch ₂ cn racemate CH ₂ COOC (CH ₃ ) ₃ racemate CH ₂ COOC (CH ₃ ) ₃ (-) - form CH ₂ COOC (CH ₃ ) ₃ (+) - form 26. Acylanilides according to claim 1, which are compounds of the formula R ² IN of ⁿ (* H) B Y (* H) Isomerism H 0 c = o y ⁴ = ch ₃ racemate H 0 c = o y ⁴ = c, h ₅ racemate ch ₃ 0 c = o y ⁴ -ch ₃ (+) - form ch ₃ 0 c = o y ⁴ = ch ₃ (-) - form ch ₃ 0 c = o y ⁴ = c ₂ h ₅ racemate ch ₃ 0 c = o y ⁴ = c ₂ h ₅ (+) - form ch ₃ 0 c = o y ⁴ = c ₂ h ₅ (-) - form ch ₃ 0 z ² = och, c = o y ⁴ = ch. racemate ch ₃ 0 z ² = and ₃ c = o y ⁴ = ch. (-) - form CH, 0 z ² = och, c = o y ⁴ = ch ' (+) - form ch ₃ 0 z ² = och, c = o y ⁴ = c ₂ h ₅ racemate ch ₃ 0 z ² = och, c = o y ⁴ -c ₂ h ₅ (+) - form CH, 0 z ² = och, c = o y ⁴ = c, h ₅ (-) - form CH, 0 z ² = and ₃ , z ⁵ = f c = o y ⁴ = ch ₃ racemate CH, 0 z ² = and ₃ , z ⁵ = f c = o y ⁴ = ch. (+) - form CH, 0 z ² = and ₃ , z ⁵ = f c = o y ⁴ = ch ₃ (-) - form CH, 0 z ² = and ₃ , z ⁵ = f c = o y ⁴ = c ₂ h ₅ racemate ch ₃ 0 of ^2- z 'of ⁵ = f c = o y ⁴ = c ₂ h ₅ (-) - form ch ₃ 0 z ² = and ₃ , z ⁵ = f c = o y ⁴ = c ₂ h ₅ (+) - form ch ₃ 0 z ² = and ₃ , z ⁵ = ci c = o y ⁴ = ch ₃ racemate ch. 0 z ² = and 'Z ⁵ = C1 c = o y ⁴ = ch (+) - form ch ₃ 0 z ² = and ₃ , Z ⁵ = C1 c = o y ⁴ = ch ₃ (-) - form CH, 0 Z ² = OCH ₃ , Z ⁴ = Br c = o y ⁴ = ch racemate R ² IN FROM (H) B Y ⁿ (* H) Isomerism CH, 0 Z ² = OCH ₃ , Z ⁴ = Br C-O y ⁴ = ch (+) - form CH, 0 Z ² = OCH ₃ , Z ⁴ = Br C-O y ⁴ ch, (-) - form ch ₃ 0 z ⁴ = ch, C-O y ⁴ = ch racemate CH, 0 z ⁴ = ch, C-O y ⁴ = c ₂ h ₅ racemate CH, 0 of ⁴ = ch ₃ C-O y ⁴ = c ₂ h ₅ (-) - form CH, 0 of ⁴ = ch ₃ C-O y ⁴ = c ₂ h ₅ (+) - form CH, 0 z ⁴ = f C-O y ⁴ = ch racemate ch ₃ 0 Z ⁴ = Br C-O y ⁴ = ch racemate CH, 0 Z ⁴ = Br C-O y ⁴ = ch. (-) - form SK 284843 Β6 CH 0 Z ⁴ = Br C-O y ⁴ = ch ₃ (+) - form CH ₃ 0 C-O y ⁴ = ch ₃ CH ₃ NH C-O y ⁴ = ch ₃ CH < NCH ₃ C-0 y ⁴ = ch ₃ CH ₃ 0 z ² = oh, z ⁵ = f c = o y ⁴ = ch ₃ racemate ch ₃ 0 z ² = oh, z ⁵ = f c = o y ⁴ = ch ₃ (+) - form ch ₃ 0 z ² = oh, z ⁵ = f c = o y ⁴ = ch ₃ (-) - form ch ₃ 0 Z ² = OH, Z ⁴ = Br c = o y ⁴ = ch ₃ racemate ch ₃ 0 of ³ = no2, of ⁴ = och3 c = o y ⁴ = ch ₃ racemate H 0 ch ₂ y ⁴ = ch ₃ racemate CH ₃ ABOUT ch ₂ y ⁴ = ch ₃ racemate ch ₃ 0 ch ₂ y ⁴ = c ₂ h ₅ racemate 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. A process for preparing acylanilides of formula (I) R 'R ² HO ^R ' in which A, B, Ar, R ^1, R ² and R ^{3 are} as defined in claim 1, characterized in that the carbonyl compound of the general formula (II) in which they have A, B, Ar, R ¹ and R ^{2 are as} defined in formula (I), with a compound of formula R ³ -SiMe ₃ , wherein R ³ is as defined in formula (I) and Me represents a methyl group, in the presence of a catalyst, or with an alkyl metal compound, for example a Grignard reagent or an alkyl lithium compound, to a compound of formula (I). 30. The process of claim 29 wherein the catalyst is an alkali metal fluoride salt or carbonate. A process for the preparation of acylanilides of the general formula (I) R ^{r 2} be R ³ in which A, B, Ar, R ^1, R ² and R ³ in Claim 1 above, characterized by 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 represents a leaving group, with a compound of the general formula Ar-NH-R ¹¹ wherein R ^{11 is} hydrogen or C 1 -C 5 alkanoyl and Ar has the meanings given in formula (I), optionally removing the radical R ¹¹ . A process according to claim 31, wherein the leaving groups in formula (III) are chlorine, bromine or iodine, tosylate or mesylate or perfluoroalkylsulfonyloxy of 1 to 4 carbon atoms. A process according to claim 32, wherein the compound of formula (III) is an acid chloride, an intermediate formed from the corresponding carboxylic acid. 34. Preparation of Compounds of Formula (I) R ² R ³ be R in which A, Ar, R ^1, R ² and R ³ in Claim 1 above and B is -CH ₂ -, wherein by reacting a compound of formula (IV) wherein A, R ¹ , R ² and R ^{3 have the} meanings given in formula (I) with a compound of the formula ^Ar-NH-R11, in which ^R11 and Ar in Claim 23 above, wherein the optionally then radical ^R11 is cleaved off. End of document