AU8021198A - Non-steroidal (hetero) cyclically substituted acylanilides with mixed gestagen and androgen activity - Google Patents

Description

WO 98/54159 PCT/EP98/03242 NONSTEROIDAL (HETERO) CYCLICALLY-SUBSTITUTED ACYLANILIDES WITH MIXED GESTAGENIC AND ANDROGENIC ACTIVITY This invention relates to nonsteroidal compounds, which have a high gestagenic activitV. In addition to a large number of steroid compounds with gestagenic action, gestagens that are not steroids are also known (for example from EP 0 253 500 B1 and WO 94/01412, cf. J. Med. Chem. 38 (1995) 4878). This invention describes the compounds of general formula [ Ri R2HO R3 H A B Ar in which

R

1 and R 2 are the same or different and stand for a hydrogen atom, a C 1

-C

5 alkyl group or a halogen atom, and also together with the C-atom of the chain stand for a ring with a total of 3-7 links, R, stands for a C 1

-C

5 alkyl group or a partially or completely fluorinated C 1

-C

5 alkyl group, C3~RA/

I

2 A stands for a monocyclic or bicyclic aromatic ring that is optionally substituted by one or more radicals, selected from halogen atoms, C 1

-C

5 alkyl groups, C 2

-C

5 alkenyl groups -CR 5

=CR

6

R

1 , whereby R 5 ,

R

6 and R 7 are the same or different and, independently of one another, mean hydrogen atoms or C 1

-C

5 alkyl groups; hydroxy groups; hydroxy groups that carry a C 1 -Cio acyl group, a C 3

-C

10 carbalkoxyalkyl group, a C 2

-C

5 cyanoalkyl group, a

C

3 -Cio unsubstituted or substituted allyl group, a

C

3

-C

1 o unsubstituted or substituted propargyl group, a C 2

-C

5 alkoxyalkyl group, a C 1 -C. alkyl group that is partially or completely substituted by fluorine atoms; the cyano or nitro group, C 1 C5 alkoxy groups,

CI-C

5 alkylthio groups, mono- or disubstituted

C

1 -CIO amino groups or partially or completely fluorinated

C

1

-C

5 alkyl groups, for an ester group -COOR 4 , whereby R 4 means a C 1

-C

5 alkyl group, for an alkenyl group -CR 5

=CR

6 R7, whereby R', R 6 and R' are the same or different, and, independently of one another, mean hydrogen atoms, halogen atoms, aryl radicals or C 1

-C

5 alkyl groups, for an alkinyl group -C-CR 5 , whereby R 5 means a hydrogen atom or a CI-C 5 alkyl group, for a partially or completely fluorinated CI-C 5 alkyl group,,

OY

B stands for a carbonyl group or a CH 2 group, and Ar stands for a ring system, selected from the group of general partial formulas 2-11, 4 x 3a X4 X4 N NO N\ \N 0Z S X6 N t6 N X N x x X7 X7 X7 2 3 4 X4 3b X 3 a X4 X3b

X

3 a x4 X 3 b 3a X6 6 6 X7 0 7 0 5 6 7

Y

5 y 4 Y 5 y 4 Y 5 Y N 7 0 8 Y Y O Y8 8 0 0 8- 9 10 5 y 4 N S7 NR 5 Y8 0 11 in which radicals X 3 a, X 4 , X 6 , X 7 (in partial formula 2) , X 4 , X 6 , X 7 (in partial formulas 3 and 4) , X 3 a, X 3 b, X 4 , X 6 , X7 (in partial formulas 5, 6 and 7) or Y 4 , Y 5 , y 7 y 8 (in partial formulas 8, 9, 10 and 11) are the same or different and are selected from hydrogen atoms, C 1

-C

5 alkyl groups, which in addition can contain a hydroxy group that is optionally etherified with a C,-C 5 alkyl group or esterified with a C 1

-C

5 alkanoyl group, partially or completely fluorinated C 1

-C

5 alkyl groups, C 2

-C

5 alkenyl groups -CR5=CR 6 R7, whereby R 5 , R 6 , and R 7 have the above-mentioned meaning, alkinyl groups -C=CR 5 , whereby R 5 has the above mentioned meaning, radicals X 3 a and X 3 b also together with the C-atom of benzocondensed ring system 5, 6 or 7 can form a ring with a total of 3-7 links, and moreover, radicals X 4 , X 6 , X 7 (in partial formulas 2, 3, 4, 5, 6 and 7) or Y4', Y 5 , Y 7 , Y 8 (in partial formulas 8, 9, 10 and 11) are selected from halogen atoms, hydroxy groups, C,-C 5 alkoxy groups or C 1

-C

5 alkanoyloxy groups, also if B in general formula I stands for a CH 2 group, Ar in addition stands for a phenyl radical of general partial formula 12, R. 12 in which R 9 and R 1 O are the same or different and mean a cyano group, a nitro group, a halogen atom, a C,-C 5 alkyl group, a Cl-C5 alkoxy group, a partially or completely fluorinated C,-C 5 alkyl group, a Ci-C 5 alkylthio group, a C 1 -C, alkylsulfinyl group or a

C,-C

5 alkylsulfonyl group, and if B stands for a CH 2 group, the physiologically compatible salts of the compounds of general formula I with acids. The compounds according to the invention are distinguished from the known nonsteroidal compounds with gestagenic action by the substitution pattern on the aryl radical that is on the right in general formula I. In the compounds that are present here, Ar is a benzocondensed, bicyclic ring system, while in the structures that are known from EP 0 253 500 B1 and that can be considered as the closest compounds, a phenyl radical that is substituted in one, two or three places is at this point. The compounds of general formula I according to the invention can be present as different stereoisomers because of the presence of asymmetry centers. Both the racemates and the stereoisomers that are detached are part of the subject of this invention.

6 The substituents that are defined as groups in the compounds of general formula I can have the following meanings in each case.

C

1

-C

5 Alkyl groups can readily be a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl group or an n-pentyl, 2,2 dimethylpropyl or 3-methylbutyl group. A methyl or ethyl group is preferred. A fluorine, chlorine, bromine or iodine atom can stand for a halogen atom. Here, fluorine, chlorine or bromine is preferred. If RI and R 2 together with the C-atom of the chain form a 3- to 7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred. For a partially or completely fluorinated C 1

-C

5 alkyl group, the perfluorinated alkyl groups that appear above and of the latter mainly the trifluoromethyl group or pentafluoroethyl group as well as partially fluorinated alkyl groups, for example, the 5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3 heptafluoropentyl group, are considered. As a C 2 -C. alkenyl group, for example, a vinyl-, allyl- or 2,3-dimethyl-2-propenyl group can appear; if aromatic compound A is substituted with an alkenyl group, preferably it is a vinyl group. For example, a carboxymethyl, tert-butoxymethyl or ethoxymethyl group can stand for the C 2

-C

5 carbalkoxyalkyl group; the first two groups that are mentioned above are preferred. LU), r ..

7 As representatives of the C 2

-C

5 cyanoalkyl group, cyanomethyl and 1- and 2-cyanoethyl can be mentioned; cyanomethyl is preferred. The C 3

-C

0 allyl group is preferably an unsubstituted allyl group; in the case of a substituted allyl group, for example, 1 methylallyl, 1,1-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylallyl, 3,3-dimethylallyl, cinnamyl and 3 cyclohexylallyl can be mentioned. An unsubstituted propargyl group, a methylpropargyl group, 3-methylpropargyl group, 3-phenylpropargyl group or 3 cyclohexylpropargyl group are typical representatives of a C3-C1O propargyl group; the unsubstituted propargyl group is preferred. For example, methoxymethyl, ethoxymethyl or 2-methoxyethyl can stand for C 2

-C

5 alkoxyalkyl. Representatives of a C 1

-C

5 alkoxy group are selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, tert-butoxy groups or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy groups. A methoxy or ethoxy group is preferred. C,-C, Perfluoroalkoxy groups are the corresponding perfluorinated radicals of the C,-C, alkoxy groups above. Monocyclic or bicyclic aromatic ring A, which can be substituted, is a carbocyclic or heterocyclic aryl radical. In the first case, this is, for example, a phenyl or naphthyl radical, preferably a phenyl radical. As a heterocyclic radical, for example, a monocyclic heterocyclic radical can be, for example, the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,

RA.

8 pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, specifically all possible isomers relative to the positions of the heteroatoms. The thienyl radical is preferred as heteroaryl radical A. For R 4 , a methyl, ethyl, n- or iso-propyl group is preferred as a C 1

-C

5 alkyl group in ester group -COOR 4 . As a C,-C, alkyl group for etherification of hydroxy groups, the above-mentioned alkyl groups are suitable, primarily a methyl or ethyl group. As a C-C, alkanoyl group for esterification of hydroxy groups, a formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or iso-valeryl or pivaloyl group is suitable, preferably an acetyl group. As a C 1

-C

1 O acyl group for esterification of hydroxy groups, for example, the above-mentioned alkanoyl groups, preferably in turn an acetyl group or a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl group can be mentioned. If X 3 8 and X 3 b together with. the C-atom of the benzocondensed ring system form a 3- to 7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred. As a C,-C 5 alkanoyloxy group for X 4 , X 6 , X 7 , Y 4 , Y 5 , y 7 or Y', a formyloxy, acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy or isovaleryloxy group is suitable, preferably an acetoxy group.

9 The above-mentioned C 1

-C

5 alkyl groups can stand for C 1

-C

5 alkyl within the C 1 -C. alkylthio, C 1 -C. alkylsulfinyl or C 1 -C. alkylsulfonyl group. If the compounds of general formula I (B = -CH 2 ) are present as salts, this can be in the form of, for example, hydrochloride, sulfate, nitrate, tartrate or benzoate. If the compounds according to the invention are present as racemic mixtures, they can be separated into pure, optically active forms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the racemic mixtures can be separated by chromatography into pure isomers on an optically active carrier material (CHIRALPAK ADR)) It is also possible to esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereoisomeric esters that are obtained by fractionated crystallization or by chromatography, and to saponify the separate esters in each case into the optically pure isomers. For example, mandelic acid, camphorsulfonic acid or tartaric acid can be used as optically active acid. Preferred according to this invention are those compounds of general formula I, in which: R1 and R 2 are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring, and/or

R

3 stands for a C1-Cs perfluoroalkyl group, and/or RA4/ 0Z 7xj 10 A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals, selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, a (CH2)n group (n=3,4,5), which with 2 adjacent C atoms of aromatic compound A forms a ring with n+2 links and can contain unsaturations; vinyl groups, hydroxy groups, methoxy groups, ethoxy groups, and/or either X" stands for a hydrogen atom or a C-Cs alkyl group, or

X"

3 a and X 3 b are the same or different and stand for a hydrogen atom or a C1-Cs alkyl group and/or

X

4 , X 6 and X 7 are the same or different, and stand for, independently of one another, a hydrogen atom or a halogen atom, and/or Y 4 stands for a C 1

-C

5 alkyl group or a C 1

-C

5 perfluoroalkyl group, and/or

Y

5 , Y 7 and Y 8 are the same or different and, independently of one another, stand for a hydrogen atom or a halogen atom, and the other substituents all have the meanings that are indicated in Formula 1. In addition, those compounds of general formula I in which Ar stands for a ring system of partial formula 6, 7, 10 or 11 are preferred.

11 The compounds that are mentioned below are especially preferred according to the 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 valeroylamino] -phthalide, 5- [2- (hydroxy-4- (4-methoxyphenyl) -4-methyl-2 trifluoromethyl-valeroylamino] -phthalide, 5- [2-hydroxy-4- (2-hydroxyphenyl) -4-methyl-2-trifluoromethyl valeroylaminol -phthalide, 5- [4- (2-f luorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino] -phthalide, 5- [4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino] -phthalide, 5- [4- (4-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino]-phthalide, 5- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl 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, 'T RA)4 12 5- [4- (4-cyanophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino] -phthalide, 5- [4- (3,4-dimethyiphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeroylamino] -phthalide, 5- [4- (3,5-dimethylphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeroylamino] -phthalide, 5- [2-hydroxy-4- (2-methoxy-5-methylphenyl) -4-methyl-2 trifluaromethyl -valeroylaminol -phthalide, 5- [4- (5-chloro-2 -hydroxyphenyl) -2 -hydroxy-4-methyl-2 trifluoromethyl -valeroylamino] -phthalide, 5- [4- (5 -fluoro-2 -hydroxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeroylamino] -phthalide, 5- [2-hydroxy-4- (2-hydroxy-5-methylphenyl) -4-rnethyl-2 trifluoromethyl-valeroylamino] -phthalide, 5- [4- (5-f luoro-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-f luoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl -valeroylamino] -phthalide, 5- (2-hydroxy-4-phenyl-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 trifluorornethyl-valeroylamino] -phthalide, 27 1.3 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) phthalide, 5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl pentylamino) -phthalide, 5- [4- (4-f luorophenyl) -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, 5- [4- (3 -fluoro-4-hydroxyphenyl) -2 -hydroxy-4-methyl-2 trifluoromethyl-valeroylamino] -phthalide, 5- [4- (3-f luorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino] -phthalide, 6- (3-hydroxy-3-rnethyl-1-butinyl) -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-trifluoromethyl pentylamino) -2, 3-benzoxazin-1-one, 4-ethyl-6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2 trifluorornethyl-valeroylamino) -2, 3-benzoxazin-l-one, 6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl valeroylamino] -4-methyl-2, 3-benzoxazin-1-one, 5-- R

/

14 4-ethyl-6-[2-hydroxy-4-methyl-4- (4-methylphenyl) -2 trifluoromethyl-valeroylamino]-2,3-benzoxaz in-i-one, 6-[4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino] -4-ethyl-2, 3-benzoxazin-1-one, 4-ethyl-6-[4- (5-f luoro-2-methoxyphenyl) -2-hydroxy-4-methyl 2-trifluoromethyl-valeroylamino]-2, 3-benzoxazin-1-one, 6-[4- (5-f luoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeroylamino]-4-methyl-2, 3-benzoxazin-1-one, 1- (4-nitro-3-trifluoromethylanilino) -4-phenyl-2 trifluoromethyl-2-pentanol, 1-(4-nitro-3-trifluoromethylanilino) -4-phenyl-2 trifluoromethyl-2-pentanol, 5-(2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5 hexenoylamino) -phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclopropyl)-2-trifluoromethyl propionylamino)-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclobutyl)-2-trifluoromethyl propionylamino]-phthalide, 5-[2-hydroxy-3- (1-phenyl-cyclohexyl) -2-trifluoromethyl propionylamino]-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. In addition, the compounds that are known from Tables 7 to 15 are preferred. P11 15 All above-mentioned compounds are especially preferred in the form of the optical antipodes or the separate diastereomers. In the gestagen receptor binding test on the gestagenic action using cytosol from rabbit uterus homogenate and from 3

H

progesterone as a reference substance, the new compounds show a strong to very strong affinity to the gestagen receptor (see Table 1). In addition to their gestagenic action, which is pronounced to different degrees depending on the compound of general formula I that is considered, the new compounds are also distinguished by a more or less strongly pronounced affinity to the androgen receptor. The androgen receptor binding test on androgenic action was carried out using cytosol that consists of rat prostate homogenate and 3 H-methyltrienolone as a reference substance. The new compounds are thus represented relative to the gestagenic compounds from EP 0 253 500 B1 as compounds with a quite novel mix profile, which consists of gestagenic action and androgenic action. For the compounds of general formula I according to the invention, in this case all three of the cases that are possible below are found, which based on the competition factors on progesterone receptor (KFprog) and androgen receptor (KFAndro) are classified within the scope of this invention as follows: 16 Table 1 Example No. Structure Competition Factor (Reference Substance 3

H

Progesterone) HO CF 3 17 ,CFa 0 (Flash point 141 1420) () 2.0 0

NO

2 (Flash point 161 0 C) 65 3HCF 3 0.17 0 0 HO CF 104 3 0.1 0 - 0 0 106 -H3CF 0.55 - I N 0 ()EP 0 253 500 Bl, Example 2 1) Compounds with stronger gestagenic action and less pronounced androgenic action (KFprog < 1 and KFAndro 5); 2) Compounds with stronger androgenic action and less pronounced gestagenic action (KFAndrO < 5 and KFprog > 1); 3) Compounds with pronounced gestagenic action and pronounced androgenic action (KFprog < 1 and KFAndrO < 5). Depending on their classification according to 1), 2) or 3), the new compounds according to the invention can be used for different medical or pharmaceutical purposes. In the case of the compounds that are classified under 1) with stronger gestagenic action and less pronounced androgenic action, these are very effective gestagens, which, like the already numerous known gestagenic compounds, are suitable for preserving pregnancies in the case of parenteral administration and in the case of oral administration. In combination with an estrogen, combination preparations are obtained that can be used for contraception and for the treatment of menopausal symptoms. Based on their high gestagenic action, the new compounds of general formula I that are classified under 1) can be used, for example, alone or in combination with estrogens in contraceptive preparations. However, all other possible uses that are known for gestagens are now open to these new compounds (see, e.g., "Kontrazeption mit Hormonen [Contraception with Hormones]," Hans Dieter Taubert and Herbert Kuhl, Georg Thieme Verlag Stuttgart New York, 1995). Suitable dosages can be determined as a matter of routine, e.g., by determining the bioequivalency, for example in the R\ RAZ,1 18 pregnancy-maintenance test, relative to a known gestagen for a specific use, for example an amount that is bioequivalent to 30 to 150 pg of levonorgestrel for contraception. The dosage of the compounds according to the invention under 1) in contraceptive preparations is preferably to be 0.01 to 2 mg per day. The gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations. The daily dose is preferably administered once. As estrogens, all natural and synthetic compounds that are known as estrogenically active are suitable. As natural estrogens, these are especially estradiol and also its longer-acting esters, such as valerate, etc. or estriol. Preferably, however, synthetic estrogens such as ethinylestradiol, 14a,17a-ethano-1,3,5(10)-estratriene-3,17@-diol (WO 88/01275), 14c,17a-ethano-1,3,5(10)-estratriene-3,16a,170 triol (WO 91/08219) or the 15,15-dialkyl derivatives of the estradiol, and of these especially 15,15-dimethylestradiol (WO 95/04070) can be mentioned. As a synthetic estrogen, ethinylestradiol is preferred. Also, the estratrien-3-amidosulfonates that have become known recently (WO 96/05216 and WO 96/05217), derived from estradiol or ethinylestradiol, which are distinguished by low hepatic estrogeneity, are suitable as estrogens for common use with the compounds of general formula I that are classified under 1). Finally, the 14a,15a-methylene steroids from the estrane series, especially the 14a,15a-methylene-17a-estradiol as well as corresponding 3-amidosulfonate derivatives can be mentioned. SRAZ/ LuW.ii The estrogen is administered in an amount that corresponds to that of 0.01 to 0.05 mg of ethinylestradiol. The new compounds of general formula I that are classified under 1) can also be used in preparations for treatment of gynecological disorders and for substitution therapy. Because of their advantageous profile of action, these compounds according to the invention are especially well suited for treatment of premenstrual symptoms, such as headaches, depression, water retention and mastodynia. The daily dose in the treatment of premenstrual symptoms is approximately 1 to 20 mg. Analogously to what is already known for other gestagens, the new compounds can also be used for treating endometrioses. Finally, these new compounds can also be used as gestagenic components in the compositions for female birth control that have recently become known and that are distinguished by the additional use of a competitive progesterone antagonist (H. B. Croxatto and A. M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. by Runnebaum, Rabe & Kiesel - Vol. 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group - 1991, page 245; WO 93/17686, WO 93/21927, US-Pat. 5,521,166). The dosage lies in the range that is already indicated, and the formulation can be carried out as in conventional OC preparations. The administration of the additional, competitive progesterone antagonist can in this case also be performed sequentially. Those compounds of the general formula, which are to be categorized as above under 2) or 3), i.e., compounds that always

R

have a strong androgenic action (androgenic gestagens), can be used for the production of pharmaceutical preparations for male birth control. Currently, in several WHO studies, the contraceptive action of a combination that consists of an orally administered gestagen (Depot-medroxy progesterone acetate, levonorgestrel ester, cyproterone acetate) is tested on men with a parenterally administered androgen (testosterone oenanthate). By contrast, birth control in men is possible with these compounds in one dosage form, specifically an oral dosage form or a dosage form that is to be administered transdermally. In addition, the compounds according to the invention with androgenic action can be used with older males for male HRT (Hormone Replacement Therapy). Those compounds of general formula I, which can more likely be classified under 2), i.e., compounds with mainly androgenic action and weaker gestagenic action, can be used for male hormone therapy. Preparations for treating a hypergonadism or for treating male infertility and disturbances of potency can be produced with them. For male birth control and for treating the above-mentioned androgenic disease agents, the compounds according to the invention are used in the dosages that are equivalent in action to the testosterone oenanthate amounts that are used in the WHO studies or to the dosages that are already in androgen therapy of compounds used. Amounts that are equivalent in action are those amounts that, in the test on androgenic action on the seminal vesicles

R

21 and/or prostate of the rat (Hershberger Test), achieve comparable action. For HRT in man, to date a substitution dose of approximately 10 mg/day of testosterone oenanthate is used. For male birth control studies that are performed by the WHO, different testosterone esters (oenanthate, bucyclate, undecanoate) are used in the range of approximately 10-30 mg/day. At this point it should be pointed out that the transitions between 1), 2) and 3), as regards the correlation according to the invention of various indications with these varying mix profiles 1), 2) and 3), are smooth. The compounds that more likely lie on the edge of the indicated KF areas based on their KFPro, and/or KFAfdro, can easily be used also for the indications that are assigned to the adjacent mix profile. The compounds of general formula I also partially show actions on the glucocorticoid and/or mineral corticoid receptor. The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, by the active ingredient, optionally in combination with an estrogen, being processed with the vehicles that are commonly used in galenicals, diluents, optionally flavoring correctives, etc., and conveyed in the desired form of administration. For the preferred oral administration, especially tablets, coated tablets, capsules, pills, suspensions or solutions are suitable. For parenteral administration, especially oily solutions, such as, for example, solutions in sesame oil, castor oil and tonseed oil, are suitable. To increase solubility, 22 solubilizers, such as, for example, benzyl benzoate or benzyl alcohol, can be added. The compounds of general formula I can also be administered continuously by an intrauterine release system (intrauterine system = IUS; e.g., MIRENA(R); the release rate of the active compound(s) is selected in this case in such a way that the dose that is released daily lies within the already indicated dosage range. It is also possible to incorporate the substances according to the invention in a transdermal system and thus to administer them transdermally. The compounds of general formula I according to the invention can be produced as described below.

LU

23 Production Process 1. A carbonyl compound of general formula II R1 R2 H A B Ar II in which A, B, Ar, R' and R 2 have the meaning that is indicated in formula I, is reacted with a compound o.f general formula CnF 2 nn,-SiR 3 , in which R 3 has the meaning that is indicated in general formula 1, in the presence of a catalyst or with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, to a compound of formula I. As catalysts, fluoride salts or basic compounds such as alkali carbonates are suitable (J. Amer. Chem. Soc. 111, 393 (1989)). 2. A compound of general formula III R1 R2HO R3 4 FG A B III in which A, B, R1, R 2 and R 3 have the meaning that is indicated in formula 1 and FG means a leaving group, is reacted with a compound Ar-NH--R, whereby R" means a hydrogen atom or a C 1

-C

5 acyl group, and Ar has the meaning that is indicated in general formula I, whereby optionally then radical R" is cleaved off to RAL9 ain a compound of formula I. In this case, the compound of

LU

24 general formula III optionally can be formed only as an intermediate product, e.g., this can be an acid chloride that is formed as an intermediate product from a corresponding carboxylic acid. As leaving groups, for example, a chlorine or bromine atom or the tosylate radical can be mentioned. 3. A compound of general formula IV R1 R2 R3 0 A IV in which A, R', R 2 and R 3 have the meaning that is indicated in formula I, is reacted with a compound of formula Ar-NH-R", whereby R" and Ar have the above-indicated meanings, whereby optionally then radical R" is cleaved off, to obtain a compound of formula I with B in the meaning of a CH 2 group. 4. A compound of formula I, which in radical A or in radical Ar contains the grouping aryl-X, whereby "aryl" represents an isocyclic or heterocyclic aromatic compound that corresponds to the definitions that are given for formula I and X means a bromine or iodine atom or the group -O-SO 2 R , in which R means .a C 1

-C

5 perfluoroalkyl group, is reacted under metal catalysis to compound aryl-R 13 according to processes that are known in the art with a compound of formula R1 3 -Y, whereby R represents an optionally substituted aryl, ethenyl or ethinyl radical and Y represents a hydrogen atom (J. Org. Chem. 43, 2947 ) 978) ), group B (0-R1 4

)

2 (J. Org. Chem. 58, 2201 (1993)) or L 'u 25 Sn(R 5

)

3 (J. Org. Chem. 52, 422 (1987)) with R 14 and R1 5 meaning a phenyl radical or C 1

-C

5 alkyl and R 4 also represents hydrogen, Mg-halogen or an alkali metal atom. 5. In a compound of formula I, which contains an alkoxy or acyloxy substituent in A or Ar, the OH group is released, and optionally etherified or esterified in another reaction or, after conversion into a 1-phenyl-5-tetrazolylether, is completely eliminated by hydrogenation (J. Amer. Chem. Soc. 88, 4271 (1966)). Of all the foregoing process variants, 1. and 2. are suitable for the production of all compounds that fall under general formula I. Compounds of general formula I can be produced with the third variant, in which B stands for a -CH 2 group. Using the fourth and fifth process variants, functionalizations of already existing compounds of general formula I can be undertaken. Compounds that were produced according to one of the processes above and in which A is an optionally substituted aromatic ring optionally can be selectively substituted in this aromatic radical according to known processes. Examples of these processes are the catalytic hydrogenation of multiple bonds, nitration and halogenation. The starting materials that are used in the examples are produced as follows: AL/ 7 A4 26 Production of Starting Materials 4-Methyl-4-phenyl-2-oxovaleric acid A Grignard solution that is produced from 26.4 g of magnesium and 162 ml of 2-methyl-2-phenyl-1-chloropropane in 150 ml of diethyl ether was added in drops to 600 ml of oxalic acid diethyl ester at -30 0 C. After 2 hours at room temperature, it was added to ammonium chloride solution, extracted with diethyl ether, dried (Na 2

SO

4 ) and distilled in fractionated form; 84 g of ethyl ester (boiling point 115-120 0 C/0.03 hPa), which is dissolved in 1 1 of methanol, is obtained, mixed with 500 ml of 1m sodium hydroxide and stirred for 1.5 hours at room temperature. After the methanol is evaporated in a vacuum, the residue is dispersed between water and diethyl ether, the aqueous phase is acidified with hydrochloric acid and extracted with diethyl ether. After concentration by evaporation, 57 g of 4 methyl-4-phenyl-2-oxovaleric acid is obtained as a thick oil. 4,4-Dimethyl-2-oxo-5-hexenoic acid 36 g of 3,3-dimethyl-4-pentenoic acid is obtained as an oil from 50 g of 3,3-dimethyl-4-pentenoic acid methyl ester by saponification with 10% potassium hydroxide solution. By stirring with thionyl chloride (20 hours, room temperature), the acid chloride is obtained, boiling point 59 0 C/30 hPa. 16 g of it is stirred with 15 g of trimethylsilylcyanide and 0.16 g of zinc iodide for 4 days. After distillation, 13 g of 4,4-dimethyl-2 oxo-5-hexenoic acid nitrile, boiling point 75-85 0 C/30 hPa, is iRAL ained. 2 g of it is saturated with 0.6 ml of methanol in 13

LU

ml of hexane while being cooled with ice with hydrochloric-acid gas, and it is mixed for 2 hours with water. From the hexane phase, after drying (Na 2

SO

4 ) and concentration by evaporation, 0.558 g of 4,4-dimethyl-2-oxo-5-hexenoic acid methyl ester, boiling point 48 0 C/0.003 hPa, is obtained. 0.535 g of it is saponified with 1.3 ml of 3N sodium hydroxide solution, whereby 0.32 g of 4,4-dimethyl-2-oxo-5-hexenoic acid is obtained as a yellowish liquid. 3-(1-Phenyl-cyclobutyl)-2-oxo-propionic acid 10 g of 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminum hydride in toluene (1.2 molar) at -72 to -69 0 C. After 4 hours at -75 0 C, 30 ml of ethyl acetate is added in drops. After heating to room temperature, additional ethyl acetate and water are added. It is filtered on diatomaceous earth, the organic phase is separated, dried (Na 2

SO

4 ) and concentrated by evaporation. After chromatography on silica gel (hexane with 0-10% ethyl acetate), 7.6 g of 1-phenyl-cyclobutanecarbaldehyde is obtained. 3 g of it is dissolved in 10 ml of tetrahydrofuran and added in drops at 0 0 C to a solution, in which previously 5 g of triethyl-2 ethoxyphosphonoacetate in 70 ml of tetrahydrofuran was mixed at 0 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 is added, it is extracted with ethyl acetate, dried (Na 2

SO

4 ) and concentrated by evaporation. 2 g of this crude product is saponified with 28 ml of 1N sodium hydroxide solution. 1.32 g of the acid, which is :1,A4 28 heated for 20 hours to 90 0 C with 25 ml of 1 molar sulfuric acid while being stirred vigorously, is obtained. After extraction with ether, drying (Na 2

SO

4 ) and concentration by evaporation, 0.89 g of 3-(l-phenyl-cyclobutyl)-2-oxo-propionic acid is obtained as a yellowish oil. 3-[l- (2-Methoxyphenyl) -cyclopropyl] -2-oxo-propionic acid Corresponding to J. Org. Chem. 40 (1975) 3497, 16.7 g of 2 methoxyphenylacetonitrile, 158 ml of lithium diisopropylamide (2 molar solution) and 46.7 ml of 1,2-dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric acid triamide were reacted with one another. 5.6 g of 1-(2-methoxyphenyl) cyclopropyl-carbonitrile, boiling point 104-115 0 C/0 .1 mbar, which was further reacted as described for 3-(l-phenyl-cyclobutyl)-2 oxo-propionic acid, was obtained. 3- [1- (2-Methoxyphenyl) cyclopropyl]-2-oxo-propionic acid is thus obtained as an oil. The acids that are described in Table 2 were obtained analogously to the process that is described for 3-(1-phenyl cyclobutyl) -2-oxo-propionic acid and for 3- [l- (2-methoxyphenyl) cyclopropyl] -2-oxo-propionic acid.

RAL,

1 Table 2

(CH

2 )n 0 Z 3 COOH z Z5 Example n 2" Flash Point (* H) (*C) 1 3-F oil 1 2-Cl 60-63 1 4-Cl oil 1 2-Br 49-54 1 3-Br oil 1 2,4-Cl, 185-190 1 3-OCH3 oil 3-CF3 oil 3 oil 3 4-CH4 50-61 4 4-OCH, oil Lu 30 3- (1-Phenyl-cyclopropyl) -2-oxo-propionic acid is obtained analogously to the process that is described for 3 (1-phenyl-cyclobutyl)-2-oxo-propionic acid. 3- (1-Phenyl-cyclohexyl) -2-oxo-propionic acid is obtained analogously to the process that is described for 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 is mixed at -70 0 C with 257 mg of copper bromide-dimethylsulfide complex and then stirred at -40 0 C for 20 minutes. It is cooled again to -70 0 C, and 0.33 ml of 1,3 dimethyl-tetrahydro-2-lH-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs Annalen [Liebigs Annals] 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran are slowly added. It is stirred for one hour at -70 0 C and then heated to room temperature. Then, 2N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethane. After 200 mg of tetrabutylammonium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethane phase is dried (Na 2

SO

4 ) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (97:3), 63 mg of 4-(3-methoxyphenyl)-4 methyl-2-oxo-valeric acid-methyl ester, which is mixed with 1 ml A4 LU .31 of potassium hydroxide in methanol (10%), is obtained. After 45 minutes, it is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase is dried (Na 2

SO

4 ) and concentrated by evaporation. 50 mg of 4-(3-methoxyphenyl)-4 methyl-2-oxo-valeric acid is obtained. 2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid The Grignard reagent is produced 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 trifluoropyruvic acid ethyl ester, yields 9.5 g of 2-hydroxy-4-methyl-4-phenyl-2 trifluoromethyl-valeric acid ethyl ester, boiling point 90 0 C/0.045 hPa. 7.5 g of the ethyl ester is refluxed with 100 ml of potassium hydroxide in methanol (10%) for 18 hours. After concentration by evaporation in a vacuum, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified with 2N hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation, 3.2 g of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid is obtained as colorless crystals, boiling point 124-126 0 C. &RA4, LuC.

4- (5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeric acid 1.3 g of anhydrous zinc chloride and 13.2 g of granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methallyl bromide for 30 minutes. Then, the solution of 25 g of methallyl bromide and 17 g of trifluoropyruvic acid ethyl ester in 80 ml of tetrahydrofuran is added in drops at boiling heat over 2 hours, and boiled for another hour. Then, while being cooled with ice, saturated ammonium chloride solution and 300 ml of ethyl acetate are added, stirred for 30 minutes at 0 0 C, and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water. The solvent is dried (Na 2

SO

4 ) and concentrated by evaporation, and the residue is distilled in a vacuum. 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl valeric acid ethyl ester, boiling point 48 0 C/1 hPa, is obtained. 0.8 g of anhydrous aluminum chloride is added to 5 ml of 4 fluoranisole and 0.9 g of 2-hydroxy-4-methylene-2 trifluoromethyl-valeric acid ethyl ester. After 40 hours of stirring at room temperature, it is added to ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 1N hydrochloric acid and water, dried (Na 2

SO

4 ) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (1:1), 1 g of 4- (5-f luoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeric acid ethyl ester, melting point 38-39 0 C, is obtained.

1.9 g of 4-(5-fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeric acid ethyl ester is refluxed with 40 ml of potassium hydroxide in methanol (10%) for 2 hours. After the solvent is concentrated by evaporation in a vacuum, water is added, it is extracted with hexane, and the separated water phase is acidified with 6N hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate phase is washed with water, dried (Na 2

SO

4 ) and concentrated by evaporation. The residue is crystallized from hexane. 1.55 g of 4-(5-fluoro-2 methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, flash point 102-104 0 C, is obtained. 2-Hydroxy-4-methyl-4-(2-thienyl)-2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeric acid The mixture of 2-hydroxy-4-methyl-4-(2-thienyl)-2 trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4-(3 thienyl)-2-trifluoromethyl-valeric acid (9:1), flash point 150 151 0 C, was produced analogously. The acids of Table 1 were produced analogously. Table 3

Z

2

CH

3

CH

3 OH CF 3 3 Z COOH 4 / 6 Z Z Z5 34 Zn Melting Point (#H) (OC) Z = CH 3 136-138 Z = Z' = CH 3 115-117

Z

3 = Z 5 = CH 3 118 Z = Br 131-132 Z4 = Cl 133-135

Z

4 = F 140-141 Z2 = OCH3 98-99 Z' = OCH 3 129-130 Z2 = Z OCH3 136-137 Z = OCH 3 , Z 5 = CH 3 106-107 Z2 = OCH 3 , Z 4 = F 103-106 Z2 = OCH3, Z' = F 102-104 Z4 = OCH 3 , Z 2 = F 122-124 Z4 = OCH 3 , Z 3 = F 108-109 Z2 = OCH3, Z' Cl 103-105 Z3/ZI = (CH 2 ) 3 118-119

Z

3

/Z

4 = -CH=CH-CH=CH- 137 2 4 Z = OCH 3 , Z = Br 115-116 Z2 = Br, Z 4 = OCH 3 , 122-124 Z' = C 6

H

5 162-163 Z2 = OCH3, Z' = CH (CH 3

)

2 137-138 By conversion according to standard processes, other acids are obtained from the acids above or their precursors: 2-Hydroxy-4-methyl-2-trifluoromethyl-4- (4-vinylphenyl) -valeric acid By heating 4- (4-bromophenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeric acid ethyl ester, tributylvinyltin, tri RA4> 35 o-tolylphosphine and bis-tri-o- tolylphosphine-palladium(II) chloride in dimethylformamide to 120 0 C, 2-hydroxy-4-methyl-2 trifluoromethyl-4-(4-vinylphenyl)-valeric acid ethyl ester is obtained, which provides the title compound, melting point 73 74'C, by alkaline saponification. 4- (4-Acetylphenyl) - 2 -hydroxy-4-methyl-2-trifluoromethyl-valeric acid analogously to the compound above of 4-(4-bromophenyl)-2-hydroxy 4 -methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1 ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o tolylphosphine-palladium-II-chloride in dimethylformamide to 120 0 C and then acid hydrolysis of the enol ether and alkaline saponification, melting point 158-162 0 C. 4- (4-Acetyl-3-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeric acid analogously to the compound above of 4-(4-bromo-3-methoxyphenyl) 2 -hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-l-ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o tolylphosphine-palladium-II-chloride in dimethylformamide to 120-C, oil. 4- (4-Cyanophenyl) - 2 -hydroxy-4-methyl-2-trifluoromethyl-valeric acid from 4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeric acid ethyl ester, zinc cyanide and tetrakis

RA,

36 triphenylphosphine-palladium in dimethylformamide at 140 0 C. After saponification, the title acid is obtained as a foam. 4- (4-Carbamoylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeric acid is obtained by treating the ethyl ester of the acid above with hydrogen peroxide and saponification, melting point 244-245 0 C. 4- (4-Cyano-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeric acid from 4- (4-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140 0 C. After saponification, the title acid is obtained as an amorphous powder. 4- (3-Bromo-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeric acid from 2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl valeric acid ethyl ester by bromation with N-bromosuccinimide in dimethylformamide at 0 0 C and subsequent saponification. Melting point 94-96"C.

LU

37 2-Hydroxy-4-methyl-4- (3-nitro-4-methoxyphenyl) -2-trifluoromethyl valeric acid This compound is obtained by reaction of 2.5 g of 2-hydroxy 4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeric acid ethyl ester with 4 ml of 100% nitric acid in 12 ml of trifluoroacetic acid for one hour at 0 0 C, melting point 79-80 0 C. 4- (4-Iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid 3.2 g of 4-iodo-2-methoxybenzoic acid-methyl ester in 10 ml of diethyl ether is added to 24.2 mmol of methylmagnesium bromide in 23 ml of diethyl ether. After 20 hours, ammonium chloride solution is added, the ether phase is separated, dried and concentrated by evaporation. 2.4 g of the residue is dissolved in 10 ml of dichloromethane, mixed with 714 mg of 2 trimethylsilyloxy-acrylic acid-ethyl ester, cooled to -70 0 C and mixed with 0.27 ml of tin(IV) chloride. After 15 minutes, the solution is added to potassium carbonate solution. After extraction with diethyl ether, the organic phase is washed with water, dried and concentrated by evaporation. 500 mg of the 4 (4-iodo-2-methoxyphenyl-4-methyl-2-oxo-valeric acid ethyl ester that is thus obtained is stirred with 8.6 ml of 1 M sodium hydroxide in ethanol/water (2:1, v/v) for 3 hours at room temperature. After adding water, it is extracted with diethyl ether, the water phase is acidified with 1 m hydrochloric acid and extracted with diethyl ether. After drying and concentration by evaporation, 410 mg of 4- (4-iodo-2-methoxyphenyl) -4-methyl-2 , o-valeric acid is obtained as a yellowish oil.

R

38 4- (3-Chlorophenyl) -4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above of amorphous powder. 4- (3-Bromophenyl) -4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above of an amorphous powder. 4- (2-Iodophenyl) -4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above as an amorphous powder. 4- (3-Iodophenyl) -4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above of an amorphous powder. 4- (4-Iodophenyl) -4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above as an oil. 4- (5-Fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above, melting point 58-60 0 C. 4- (4-Bromo-2-methoxyphenyl) -2-oxo-valeric acid is obtained analogously to the embodiment above as an oil.

.RAL,<

3- (1-Phenylcyclopentyl) -pyruvic acid is obtained analogously to the embodiment above of 1 phenylcyclopentanol with 2-trimethylsilyloxy-acrylic acid-ethyl ester and tin(IV) chloride as an oil. 4-Toluenesulfonic acid- (2-hydroxy-4-phenyl-2-trifluoromethyl pentyl) ester A Grignard solution, to which 15 ml of oxalic acid diethyl ester is added at -30 0 C within 30 minutes, is prepared from 2.6 g of magnesium chips and 15 ml of 2-phenyl-l-chloropropane in diethyl ether. It is stirred for one hour at -20 0 C and for 2 hours at 0 0 C, and then mixed with saturated ammonium chloride solution. The diethyl ether phase is separated, dried (Na 2

SO

4 ) and concentrated by evaporation and distilled in a vacuum. 17.7 g of 2-oxo-4-phenylvaleric acid ethyl ester, boiling point 98 100)C/0.03 hPa, is obtained. 4.4 g of 2-oxo-4-phenylvaleric acid ethyl ester is dissolved in 40 ml of tetrahydrofuran and mixed at -78'C with 3.6 ml of trifluoromethyl-trimethylsilane and 2 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran. After 24 hours at -78 0 C, another 20 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran is added. It is stirred for 1.5 hours at 0 0 C, ethyl acetate and saturated common salt solution are added, the organic phase is separated, and it is washed with saturated common salt solution and water. Then, it is dried (Na 2

SO

4 ) and concentrated by evaporation and distilled on a bulb tube. 4.4 g 40 of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 95-100 0 C/0.04 hPa, is obtained. 4.35 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester is dissolved in 100 ml of diethyl ether and stirred with 1.3 g of lithium aluminum hydride for one hour at 0 0 C and for 16 hours at room temperature. A little water is added while being cooled, and it is stirred for one hour. The diethyl ether phase is separated, dried (Na 2

SO

4 ) and concentrated by evaporation and distilled on a bulb tube. 4.1 g of 4-phenyl-2 trifluoromethyl-1,2-pentanediol, boiling point 120 0 C/0.04 hPa, is obtained. 4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol in 30 ml of pyridine is mixed at 0 0 C with 3.8 g of 4-toluenesulfonic acid chloride. After 16 hours at 0 0 C, it is concentrated by evaporation in a vacuum, mixed with ethyl acetate, washed with water, dried (Na 2

SO

4 ) and concentrated by evaporation. By crystallization from ethyl acetate/hexane, 4.9 g of 4 toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl pentyl)ester, melting point 95-96 0 C, is obtained. Analogously, 4-toluenesulfonic acid-(2-hydroxy-4-methyl-4 phenyl-2-trifluoromethyl-pentyl)ester, melting point 78 0 C, is obtained. Analogously, 4-toluenesulfonic acid-[4-(4-fluorophenyl)-2 hydroxy-4-methyl-2-trifluoromethyl-pentyl]ester, melting point 80-81"C, and 4-toluenesulfonic acid- [2-hydroxy-4- (2-methoxy-5 fluorophenyl)-4-methyl-2-trifluoromethyl-pentyl]ester, melting point 93-95 0 C, were produced. U! 1-)' 41 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 is mixed at 0 0 C with 35 mg of sodium hydride (80% in mineral oil). After one hour at 0 0 C, it is diluted with water and extracted with dichloromethane. The dichloromethane phase is washed with water, dried (Na 2

SO

4 ) and concentrated by evaporation. The residue is distilled. 200 mg of 2-(2-phenylpropyl)-2 trifluoromethyl-oxiran, boiling point 110 0 C/1 hPa, is obtained. 4-Bromo-5-aminophthalide 23 g of 3-bromo-4-nitro-1,2-xylene is suspended in 200 ml of pyridine and 600 ml of water and mixed at 60 0 C in portions with 260 g of potassium permanganate, whereby the temperature rises to 90 0 C. It is heated for 2 more hours to 95 0 C, filtered, the filtrate is acidified with hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation, 27 g of 3-bromo-4-nitrophthalic acid is obtained. 12 g of acid is heated for 15 minutes to 220 0 C and then distilled on a bulb tube. At 0.03 hPa, 10 g of 3-bromo-4 nitrophthalic acid anhydride is distilled. The anhydride is dissolved in 120 ml of dimethylformamide and is slowly mixed at 0 0 C with 78.8 ml of a 0.5 M solution of sodium borohydride in dimethylformamide. After 3 hours at 0 0 C, 2N hydrochloric acid is carefully added, and it is extracted with ethyl acetate. After washing with potassium bicarbonate solution, drying (Na 2

SO

4 ) and concentration by evaporation of the

LU!

42 ethyl acetate phase, 6.6 g of 4-bromo-5-nitrophthalide is obtained. 6.6 g of 4-bromo-5-nitrophthalide is dissolved in 45 ml of ethanol and added in drops to a mixture of 65 g of iron(II) sulfate, 220 ml of water and 65 ml of ammonia (33%) that is heated to 60'C and stirred well. After 2 hours at 60 0 C, the mixture is absorptively precipitated five times with 200 ml of diethyl ether. The diethyl ether phases are concentrated by evaporation. As a residue, 4.1 g of 4-bromo-5-aminophthalide is obtained, melting point 176-180 0 C. 6-Bromo-5-aminophthalide 4-Bromo-5-nitrophthalic acid anhydride is produced analogously to the process of 4-bromo-5-nitro-1,2-xylene that is described above. By boiling with ethanol, a mixture of 2-bromo-6 ethoxycarbonyl-3-nitrobenzoic acid and 3-bromo-2-ethoxycarbonyl 4-nitrobenzoic acid is obtained from the above. 1.2 ml of oxalyl chloride is carefully added in drops to 7.2 ml of a 0.66 m solution of dimethylformamide in dichloromethane at 0 0 C. The solution is stirred for 1 hour at 0 0 C and for 5 minutes at room temperature. After concentration by evaporation in a vacuum, the residue is suspended in 7 ml of acetonitrile, cooled to -35'C and mixed drop by drop with 1.5 g of the ester mixture. After one hour at the same temperature, it is cooled to -70 0 C, and 2.4 ml of a 2 m solution of sodium borohydride in dimethylformamide is added in drops. It is stirred for 20 hours AL room temperature, water is added, alkalized with potassium carbonate and extracted with diethyl ether. The diethyl ether phase is dried (Na 2

SO

4 ) and concentrated by evaporation. A mixture of 5-bromo-6-nitrophthalide and 6-bromo-5-nitrophthalide, which is separated on silica gel with hexane/ethyl acetate (95:5), is obtained. The reduction to aminophthalide is carried out as described above. 6-Bromo-5-aminophthalide, melting point 235-241 0 C, is obtained. 5-Amino-3-(1-propenyl)-phthalide 5 g of 2-bromo-4-nitrobenzoic acid is converted into acid chloride, which is dissolved in 50 ml of tetrahydrofuran and added in drops to 3 ml of allylamine in 20 ml of tetrahydrofuran, by 2 hours of boiling with 30 ml of thionyl chloride and distilling-off of excess thionyl chloride. After 20 hours at room temperature, it is dispersed between 1N hydrochloric acid and ethyl acetate, the ethyl acetate phase is washed with water, dried (Na 2

SO

4 ) and concentrated by evaporation. The residue is crystallized with hexane. 5.6 g of 2-bromo-4-nitrobenzoic acid allylamide, melting point 98-100 0 C, is obtained. This material is dissolved in 35 ml of ethanol and added in drops to a mixture of 50 g of iron(II) sulfate, 170 ml of water and 50 ml of ammonia (33%) that is heated to 60 0 C and stirred well. After 2 hours at 60'C, the mixture is absorptively precipitated 5 times with 200 ml of diethyl ether, the diethyl ether phases are concentrated by evaporation, and the residue is crystallized with hexane. 3.1 g of 4-amino-2-bromo-benzoic acid llylamide, melting point 115-117 0 C, is obtained. RALL

'Y"

11 g of 4-amino-2-bromobenzoic acid-allylamide, 5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid are refluxed for 1.5 hours with a water separator. Then, the solution is diluted with ethyl acetate, washed with 1N hydrochloric acid and then with potassium carbonate solution, dried (Na 2

SO

4 ) and concentrated by evaporation. The residue is crystallized with hexane. 13.4 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl) benzamide, melting point 136-138 0 C, is obtained. 3 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl)-benzamide in 100 ml of dimethoxyethane is mixed at -70 0 C with 14.2 ml of 1.4 M butyllithium in hexane. After 30 minutes at -70 0 C, 1.63 ml of crotonaldehyde is added. The solution is allowed to heat to room temperature, stirred for another 20 hours, 50 ml of 50% acetic acid is added and heated for 6 hours to 60 0 C. Then, it is diluted with water, extracted with ethyl acetate, the ethyl acetate phase is washed with potassium carbonate solution. The ethyl acetate phase is dried (Na 2

SO

4 ) and concentrated by evaporation. After chromatography on silica gel with hexane ethyl acetate (98:2), the residue produces 1.1 g of crystalline 5-(2,5-dimethylpyrrol-1-yl)-3-(1-propenyl)-phthalide, melting point 91-95 0 C. 1.1 g of 5-(2,5-dimethylpyrrol-1-yl)-3-(l-propenyl) phthalide, 8.56 g of hydroxylamine-hydrochloride and 4.58 g of potassium hydroxide in 75 ml of ethanol/water (16:6.8, vv) are heated for 24 hours at 120 0 C. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na 2

SO

4 ) and concentrated by evaporation and chromatographed on silica gel. 640 mg of 5

LU

amino-3- (1-propenyl) -phthalide, melting point 125-130 0 C, is obtained with dichloromethane/methanol (99:1). The phthalides of Table 4 are obtained analogously. Table 4 x 3b

H

2 N 0

X

3 a/X 3 b Melting Point [ 0 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 (CH2) 4- 105-110

LU

-M V 4-Bromo-5- ( 4 -methyl-2-oxo-4-phenyl-valeroylamino) -phthalide 412 mg of 4 -methyl-4-phenyl-2-oxovaleric acid is dissolved in 10 ml of dimethylacetamide and mixed under argon at -8 0 C with 261 mg of thionyl chloride. After 20 minutes of stirring at -3 to +3 0 C, 228 mg of 4-bromo-5-aminophthalide is added. It is stirred for 1.5 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na 2

SO

4 ) and after the solvent is concentrated by evaporation and after treatment with diethyl ether, 360 mg of 4 bromo-5- ( 4 -methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, melting point 150-152 0 C, is obtained. Analogously to the production of 4-bromo-5-(4-methyl-2-oxo 4-phenyl-valeroylamino)-phthalide, the compounds of Tables 5 and 6 are obtained. CLR RA4/ 47 Table 5 ZI O Z3H 4 06 50 Z Example Z"I Melting Point Z H (*C) Z= I 205-207 Z= Cl 170-171 Z3 = Br 168-169 3 Z = I 155-157 5- [3- (1-Phenyl-cyclopropyl) -2-oxo-propionylamino] -phthalide was obtained analogously to the process that is described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5-aminophthalide and 3- (1-phenyl-cyclopropyl) -2-oxo propionic acid, melting point 132-138 0 C. 5- [3- (1-Phenyl-cyclobutyl) -2-oxo-propionylamino] -phthalide was obtained analogously to the process that is described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5-aminophthalide and 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid, melting point 142-146 0 C. RAL/U

LU

48 5- [3- (1-Phenyl-cyclohexyl) -2-oxo-propionylamino] -phthalide was obtained analogously to the process that is described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5-aminophthalide and 3- (1-phenyl-cyclohexyl) -2-oxo-propionic acid, melting point 120-123 0 C. The compounds of Table 6 were also produced:

;RAL/,

1

LVO(U

49 Table 6 Z2 (CH )n 0 3 H 0 Z4 Z 6 N 5 z Example n Z" Melting Point (o H) (*C) 1 3-F 142-146 1 2-Cl 148-151 1 4-Cl 161-170 1 2-Br 172-178 1 3-Br 152-159 1 2,4-C1 2 135-138 1 3-OCH 3 140-153 1 3-CF 3 166-170 3 140-144 3 4-CH 3 oil 4 4 -OCH 3 129-130 0 50 6- [3- (1-Phenyl-cyclopropyl) -2-oxo-propionylamino] -4-methyl-2,3 benzoxazin-1-one was obtained analogously to the process described for 4-bromo-5 (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 6-amino-4 methyl-2,3-benzoxazin-l-one and 3- (1-phenyl-cyclopropyl) -2-oxo propionic acid, melting point 197-200 0 C. 6- [3- (1-Phenyl-cyclobutyl) -2-oxo-propionylamino] -4-methyl-2,3 benzoxazin-1-on was obtained analogously to 6- [3- (1-phenyl-cyclopropyl) -2-oxo propionylamino]-4-methyl-2,3-benzoxazin-l-one with use of 3-(1 phenyl-cyclobutyl)-2-oxo-propionic acid, melting point 155-156 0 C. 6- [3- (1-Phenyl-cyclohexyl) -2-oxo-propionylamino] -4-methyl-2,3 benzoxazin-1-one was obtained analogously to 6- [3- (1-phenyl-cyclopropyl) -2-oxo propionylamino)-4-methyl-2,3-benzoxazin-l-one with use of 3-(1 phenyl-cyclohexyl) -2-oxo-propionic acid, melting point 132-134 0 C. 5- (4,4-Dimethyl-2-oxo-5-hexenoylamino) -phthalide was obtained analogously to the process that is described for 4 bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5 aminophthalide and 4,4-dimethyl-2-oxo-5-hexenoic acid, melting point 103-104 0 C. '2:,A 51 6-Bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide Analogously to the example above, 1.7 g of 6-bromo-5- (4 methyl-2-oxo-4-phenyl-valeroylamino) -phthalide is obtained from 2.0 g of 4-methyl-4-phenyl-2-oxovaleric acid and 1.11 g of 6 bromo-5-aminophthalide with 1.27 g of thionyl chloride in 60 ml of dimethylacetamide, melting point 148-150 0 C. 5- [4- (4-Iodo-2-methoxyhenyl) -4-methyl-2-oxo-valeroylamino) phthalide was obtained analogously to the process that is described for 4 bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5 aminophthalide and 4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxo valeric acid as a foam. 5- [4- (4-Iodophenyl) -4-methyl-2-oxo-valeroylamino) -phthalide was obtained analogously to the process that is described for 4 bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5 aminophthalide and 4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid as an oil. 5- [4- (3-Iodophenyl) -4-methyl-2-oxo-valeroylamino) -phthalide was obtained analogously to the process that is described for 4 bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5 aminophthalide and 4- (3-iodophenyl) -4-methyl-2-oxo-valeric acid, melting point 160-161 0 C. IN I 52 5- [4- (4-Bromo-2-methoxyhenyl) -2-oxo-valeroylamino) -phthalide was obtained analogously to the process that is described for 4 bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5 aminophthalide and 4- (4-bromo-2-methoxyphenyl) -2-oxo-valeric acid, melting point 136-14 0 0C. 5- [3- (1-Phenyl-cyclopentyl) -2-oxo-propionylamino] -phthalide was obtained analogously to the process that is described for 4 bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 5 aminophthalide and 3-(1-phenyl-cyclopentyl)-2-oxo-propionic acid, melting point 140-144 0 C. 6- [4- (5-Fluoro-2-methoxyhenyl) -4-methyl-2-oxo-valeroylamino) -4 methyl-2, 3 -benzoxazin-1-one was obtained analogously to the process that is described for 4 bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 4 methyl-2,3-benzoxazin-l-one and 4- (5-f luoro-2-methoxyphenyl) -4 methyl-2-oxo-valeric acid, melting point 171-173 0 C. 6- [4- (5-Fluoro-2-methoxyhenyl) -4-methyl-2-oxo-valeroylamino) -4 ethyl-2,3-benzoxazin-1-one was obtained analogously to the process that is described for 4 bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 4 ethyl-2,3-benzoxazin-l-one and 4- (5-f luoro-2-methoxyphenyl) -4 methyl-2-oxo-valeric acid, melting point 157-158 0

C.

53 6-Amino-4-methyl-2,3-benzoxazin-1-one 60 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 1 of toluene with a water separator until water is no longer produced. The solution is washed with potassium bicarbonate, dried (Na 2

SO

4 ) and concentrated by evaporation. 71.7 g of the crystalline ketal is obtained from pentane. The latter is oxidized in 1.5 1 of pyridine and 4.5 1 of water with 350 g of potassium permanganate, as described above in the production of 4-bromo-5-aminophthalide. 56.4 g of 4-nitro-2 (2,5,5-trimethyl-1,3-dioxan-2-yl)-benzoic acid is obtained. 52 g of the acid is hydrogenated in 500 ml of methanol and 500 ml of ethyl acetate with 10 g of palladium/carbon (10%). 45.5 g of the crystalline amino compound is obtained from pentane. 10 g of the amine is refluxed with 100 ml of concentrated hydrochloric acid for 2 hours. The solvent is concentrated by evaporation in a vacuum, and the residue is refluxed with 15.7 g of hydroxylamine hydrochloride, 8.4 g of potassium hydroxide, 120 ml of ethanol and 50 ml of water for 12 hours. It is diluted with water, and the crystals are suctioned off. After drying, 3.5 g of 6-amino-4-methyl-2,3-benzoxazin-l-one, melting point 291-296"C, is obtained. 6-Amino-4 -ethyl-2 ,3-benzoxazin-1-one is obtained analogously from 2-methyl-5-nitropropiophenone, melting point 89-93 0 C. -1 A L1 54 6-Amino-1-methyl-1H-benzotriazole is described in Heterocycles 36, 259 (1993). 5-Amino-benz[1,2,5]oxadiazole is described in Boll. Sci. Fac. Chim. Ind. Bologna, 22, 33, 36, 37 (1964). 5-Amino-benz [1,2,5] thiazole is described in J. Heterocycl. Chem. 11, 777 (1974). 5-Amino-1-indanone is described in J. Org. Chem. 27, 70 (1962). 6-Amino-1,2,3 ,4-tetrahydro-1-naphthalinone is described in J. Org. Chem. 27, 70 (1962). 6-Amino-3,4-dihydro-1H-2-benzopyran-1-one is produced by catalytic hydrogenation (palladium/carbon) in ethanol from the corresponding nitro compound (Canad. J. Chem. 61, 2643 (1983) The examples below are used for a more detailed explanation of the invention. Other compounds can be produced by using homologous/analogous reagents. The required starting compounds are described above under "Starting Compounds." Example 1 (Process 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 is dissolved under argon in 15 ml of dimethylformamide and mixed with 0.77 ml of trifluoromethyltrimethylsilane and 350 mg of cesium carbonate while being cooled with ice. After 3 hours of stirring at room temperature, 5 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and some drops of water are added and stirred for one hour at room temperature. After 100 ml of water is added, it is extracted with ethyl acetate, the organic phase is dried (Na 2

SO

4 ) and concentrated by evaporation. 250 mg of 4-bromo-5- (2-hydroxy-4-methyl-4-phenyl-2 trifluoromethyl-valeroylamino) -phthalide, melting point 187 194'C, is obtained. Example 2 6-Bromo-5- ( 2 -hydroxy-4-methyl-4-phenyl-2- trifluoromethyl valeroylamino) -phthalide is obtained analogously to Example 1 from 1.6 g of 6-bromo-5-(4 methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, 3.5 ml of trifluoromethyltrimethylsilane and 1.6 g of cesium carbonate, melting point 205-210 0 C. cIRA, 3 IvL Example 3 5- (2-Hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino) phthalide is obtained analogously to Example 1 from 20 mg of 5-(4-methyl-2 oxo-4-phenyl-valeroylamino)-phthalide, 0.1 ml of trimethyl pentafluoroethylsilane and 20 mg of cesium carbonate, melting point 187-189 0 C. Example 4 5- [2-Hydroxy-4 - (3 -methoxyphenyl) -4-methyl-2-trifluoromethyl valeroylamino]-phthalide is obtained analogously to Example 1 from 30 mg of 5-[4-(3 methoxyphenyl)-4-methyl-2-oxo-valeroylamino]-phthalide, 0.13 ml of trifluoromethyltrimethylsilane and 30 mg of cesium carbonate, melting point 173-178 0 C. Example 5 5- (2-Hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino) phthalide is obtained analogously to Example 1 from 200 mg of 5-(4,4 dimethyl-2-oxo-5-hexenoylamino)-phthalide, 0.22 ml of trifluoromethyl-trimethylsilane and 258 mg of cesium carbonate, melting point 153-157 0 C. The compounds of Table 7 are obtained analogously to Example 1. Rz Table 7 2 OH CF3 6 0 (CH2)n H N _ 0 4 6N z Example n Z" Melting Isomerism (# H) Point (*C) 6 1 168-175 racemate 7 1 172-179 (+)-enantiomer 8 1 172-179 (-)-enantiomer 9 1 3-F 155-158 racemate 10 1 2-Cl 192-194 racemate 11 1 4-Cl 148-154 racemate 12 1 4-Cl 174-176 (+)-enantiomer 13 1 4-Cl 173-175 (-)-enantiomer 14 1 2-Br 163-165 racemate 15 1 3-Br 189-191 racemate 16 1 2, 4-C1 2 216-218 racemate 17 1 2-OCH 3 200-208 (+)-enantiomer 18 1 2-OCH 3 195-208 (-)-enantiomer 19 1 3-OCH 3 225-228 racemate 20 1 3-CF 3 152-163 racemate 21 2 182-188 racemate 22 2 _ 187-192 (+) -enantiomer 23 2 188-192 (-) -enantiomer R;> Liu J 0 24 3 106-112 (+) -enantiomer 25 3 4-CH 3 179-183 racemate 26 4 165-171 racemate 27 4 170-174 (+)-enantiomer 28 4 170-174 (-)-enantiomer If 6-amino-4-methylbenzoxazinone instead of the aminophthalide is used in Example 1, the compounds that are listed in Table 8 are obtained. Table 8

(CH

2 )n OH CF 3 H N 0 0 Example n Melting Point Isomerism (*C) 29 1 78-84 racemate 30 1 227-235 (+)-enantiomer 31 230-239 (-)-enantiomer 32 2 174-184 racemate 33 4 185-187 racemate 34 4 90-97 (+)-enantiomer 35 4 90-96 (-)-enantiomer , I'- RRAA 1-NN' 59 Table 9 2 Z 3O C F 30 3 z 5 0 Example Z" Melting Point (# H) (*C) 36 Z2 = I amorphous 37 z 3 = Cl 174 38 Z 3 = Br 182-183 39 Z = I 190-191 Example 40 6- (2-Hydroxy-2,4-dimethyl4-phenyl-valeroylamino) -4-methyl-2,3 benzoxazin-l-one 72 mg of 6-(4-methyl4-phenyl-2-oxo-valeroylamino)-4-methyl 2,3-benzoxazin-l-one in 4 ml of tetrahydrofuran is mixed with 3 ml of methylmagnesium bromide (3 mol) at 0 0 C. After 30 minutes, ammonium chloride solution is added, the organic phase is separated, dried and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 1:1), 39 mg of 6- (2-hydroxy-2,4-dimethyl4-phenyl-valeroylamino) -4-methyl-2, 3 benzoxazin-l-one, melting point 173-175 0 C, is obtained. I RA4LU LU zC., 60 Example 41 (Process 2) 5- (2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide 500 mg of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid (Eur. Apple. 0 253 500 (Imperial Chemical Industries)) in 10 ml of dimethylacetamide is mixed at -15'C with 0.14 ml of thionyl chloride. After 3 hours of stirring at -15 0 C, 600 mg of 5 aminophthalide (solid) is added. The solution is stirred for 2 hours at -15 0 C and then left for 18 hours at room temperature, then mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na 2

SO

4 ) and concentrated by evaporation. The residue is stirred with diethyl ether and suctioned off. 290 mg of 5-(2-hydroxy-4-phenyl-2 trifluoromethyl-valeroylamino)-phthalide, melting point 166 168 0 C, is obtained. Example 42 6- (2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl 2,3-benzoxazin-1-one is obtained analogously to Example 41 from 784 mg of 2-hydroxy-4 phenyl-2-trifluoromethyl-valeric acid in 17 ml of dimethylacetamide and 500 mg of 6-amino-4-methyl-2,3-benzoxazin 1-one, melting point 172-173 0 C. The compounds that are presented in Table 10 are produced analogously to Example 41: LU4, 61 TABLE 10 2 2 z X7 0 Example R 2w nZ Melting Iso (,,H) (*H) point merism (OC) or [at] ID (c=0 .5) ____ ___ __ ____ _ _ ___ ___(2) 43 H 0 X 3a/ X 3 b= H 175-185 Diast. _____/ CH 3 _____mixture 44 H 0 x 3 a =H, 175-178 +22.5 3a 45 H 0o ~= H, 210-213 -74 3a 46 H 0 x~= CH 3 , 210-213 -69.5 X3b= 47 H 0 X 3a= CH 3 , 175-179 -21.5 X3b= 48 H 0 X 3 a =C2H 5 _____169-174_____ 49 H 0 X 3 a= CH= 162-174 ____ ____ ____ ____ ____ ____ CH 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ 50 H 0 X 3 a= CH= 160-162 ____ ___ ___ ____ ____ ___ CH 2

-CH

3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ 51 H 0 Xa= CF 3 _____156-166 52 H 0 x~a= X 3 b= 160-171 ____ ____ ____ ____ ____ ____ CH 3 _ _ _ _ _ 53 H 0 X a=X~b 172-176 54 H 0 X 3 a +X3b_ 168-170 _______ ___ ___ _______ (CH,)_ _ _ _ _ _ _ _ _ _ _ _ 62 55 H 0 X 4 =Br _____180-185 ____ 56 CH 3 0 ____ 159-162 57 CH 3 0 X 4 =Br ____ 187-194 ____ 58 CH 3 0 Z 2

=CH

3 155-156 race ____ ________ ____mate 59 CH 3 0 Z 2 = CH 3 148-149 (+) _______f form 60 CH 3 0 Z 2 = CH 3 145-146 (-) 61 CH 3 0 _____Z 4

=CH

3 189-190 _____ i lRA //N~ 63 Table 10 (Continuation) Example R2 W X" Z" Melting Iso (#H) (OH) point merism (OC) or [a]D (c=0.5) (2) 62 CH 3 0 Z3=Z4= 206-207 race

CH

3 mate 63 CH 3 0 Z3=z4= 207-209 (+)

CH

3 form 64 CH 3 0 Z3=z4= 207-209 (-)

CH

3 form 65 CH 3 0 Z3=Z5= 154 race

CH

3 mate 66 CH 3 0 Z 3 =ZS= 188-189 (+)

CH

3 form 67 CH 3 0 Z 3

=Z

5 = 188

CH

3 form 68 CH 3 0 Z3/Z4= 171-173

(CH

2 ) 3 69 CH 3 0 z3/Z4= 218-219

-CH=CH

CH=CH

70 CH 3 0 Z 4 =F 177-178 71 CH 3 0 Z 4 =Cl 184-185 72 CH 3 0 Z 4 =Br 177-179 2 73 CH 3 0 Z =OCH 3 134-135 race mate 74 CH 3 0 Z 4

=OCH

3 183-184 75 CH 3 0 Z2=ZS= 145 OCH3 76 CH 3 0 Z 2

=OCH

3 , 126-127 race

Z

5

=CH

3 mate 77 CH 3 0 Z 2

=OCH

3 , 169-170 (+)

Z=CH

3 form 78 CH 3 0 Z 2

=OCH

3 , 169 Z =CH 3 form RA4 64 79 CH 3 0 Z 2

=OCH

3 , 180-181 IZ4= 80 CH 3 0 Z 2

=OCH

3 , 140-141 Z'=F Table 10 (Continuation) Example R2 W X" Z" Melting Iso (+H) (+H) point merism (OC) or [a]D (c=0.5) (2) 81 CH 3 0 Z"=OCH 3 , 207

Z

2 =F 82 CH 3 0 Z 4

=OCH

3 , 178-179

Z

3 =F 83 CH 3 0 Z 2

=OCH

3 , 141 race

Z

5 =Cl mate 84 CH 3 0 Z 2

=OCH

3 , 106-108 +105.5

Z

5 =Cl (1) 85 CH 3 0 Z 2

=OCH

3 , 105-207 -97 (1)

Z

5 =Cl 86 H S 189-191 87 CH 3 S 173-175 88 H CH 2 161-162 89 H O-CH 2 192-195 (3) 90 CH 3 0 Z 4 =CH= 190-192 race

CH

2 mate 91 CH 3 0 Z 4 =CN 230-233 race mate 92 CH 3 0 Z 4

=COCH

3 174-176 race mate 93 CH 3 0 Z 4

=CONH

2 130-132 race I _mate 94 CH 3 0 Z2 =OCH 3 , 144-145 race

Z

4 =Br mate Lit/ 65 95 CH 3 0 Z 2

=OCH

3 , 176-177 (+) Z 4 =Br enanti omer 96 CH 3 0 Z2 =OCH 3 , 177-178 -139.6

Z

4 =Br 97 CH 3 0 Z 2 =Br, 197-198 race

Z

4

=OCH

3 mate 98 CH 3 0 Z 2

=OCH

3 , 135-136 race

Z

4 =CN mate 99 CH 3 0 Z 3 =N0 2 , 202-206 race

Z

4 =0CH 3 mate 100 CH 3 0 Z 2

=COCH

3 135 race

Z

4 =CH mate

(CH

3

)

2 101 CH 3 0 Z 3

=COCH

3 213-214 race

Z

4 =0CH 3 I mate (1) The optically active compounds that are presented in Table 10 were separated analogously to Example 88. (2) In methanol. (3) Formation of a 1-isochromanone. Example 102 (+) and (-) 5- [2-Hydroxy-4-methyl-4- (2-methoxyphenyl) -2 trifluoromethyl-valeroylamino] -phthalide The enantiomer mixture of Example 73 is separated by chromatography on chiral carrier material (CHIRALPAK AD(R), DAICEL Company) with hexane/2-propanol/ethanol (900:25:25, vvv). Thus, from 200 mg of racemate, there are obtained 73 mg of (-)-form, melting point 136-137 0 C, [aoD = -194.80 (c = 0.5 in chloroform), 59 mg of (+)-form, melting point 135-136 0 C, [aoD = +192.20 (c \RAL 0.5 in chloroform). LU ,u) 66 Example 103 5- [2-Hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl valeroylamino] -phthalide and 5- [2-Hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl valeroylamino] -phthalide The mixture of 2-hydroxy-4-methyl-4- (2-thienyl) -2 trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4- (3 thienyl)-2-trifluoromethyl-valeric acid (9:1) was reacted with 5 aminophthalide analogously to Example 41. After the position isomers are separated by chromatography and after the racemates are separated analogously to Example 102, there are obtained (+) -5- [2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl valeroylamino] -phthalide, melting point 166 0 C, aD = +163.60 (c 0.5 in chloroform), (-)-5-[2-hydroxy-4-methyl-4-(2-thienyl)-2 trifluoromethyl-valeroylamino] -phthalide, melting point 166 0 C, aD = -160.80 (c = 0.5 in chloroform), (+)-5-[2-hydroxy-4-methyl-4 (3-thienyl) -2-trifluoromethyl-valeroylamino] -phthalide, melting point 135'C and (-)-5-[2-hydroxy-4-methyl-4-(3-thienyl)-2 trifluoromethyl-valeroylamino] -phthalide, melting point 135 0 C. Example 104 (Process 3) 5- (2-Hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide 760 mg of 5-acetamido-phthalide in 20 ml of dimethylformamide is mixed at 0 0 C with 144 mg of sodium hydride (80% in mineral oil), and, after 20 minutes, with 800 mg of 4 luenesulfonic acid- (2-hydroxy-4-phenyl-2-trifluoromethyl Lu 67 pentyl) -ester. After 16 hours at 60'C, the solvent is concentrated by evaporation in a vacuum, the residue is dissolved in ethyl acetate, washed with water, dried (Na 2

SO

4 ) and concentrated by evaporation. After chromatography on silica gel with cyclohexane/ethyl acetate (2:1), 266 mg of 5-(2-hydroxy-4 phenyl-2-trifluoromethyl-pentylamino) -phthalide, melting point 110 0 C, is obtained. The compounds of Table 11 are obtained analogously to Example 104. Table 11 Z2 CH R2W OH CF3 2 H Z3 ZN N W Z5 0 Example R2 W Z" Melting Iso (+H) point merism (OC) or [a]D (c=0 .5) (2) 105 H 0 110 race mate 106 H 0 123 +18.6 107 H 0 123 -18.4 108 CH 3 0 139-140 race mate ~RA4, 68 109 CH 3 0 159-160 +12.0 (4) 110 CH 3 0 160-161 -12.5 (4) 111 CH 3 0 z4 = F 148-149 race mate 112 CH 3 0 z4 = F 162-164 +9.0 113 CH 3 0 z = F 162-164 -6.7 114 CH 3 0 Z2 = OCH 3 , Z' = F 148-149 115 H CH 2 161-162 116 H OCH 2 127-128 (3) (1) The optically active compounds that are presented in Table 11 were separated analogously to Example 102. (2) In methanol (3) Formation of a 1-isochromanone. (4) In chloroform. Example 117 4-Ethyl-6- (2-hydroxy-4-phenyl-2-trifluoromethyl -pentylamino) -2,3 benzoxazin-1-one The compound is obtained analogously to Example 104 from 151 mg of 6-acetamido-4-ethyl-2,3-benzoxazin-2-one, 208 mg of 4 toluenesulfonic acid- (2-hydroxy-4-phenyl-2-trifluoromethyl pentyl)ester and 36 mg of sodium hydride, melting point 161 163 0 C. Example 118 1- (4-Nitro-3-trifluoromethylanilino) -4-phenyl-2-trifluoromethyl 2-pentanol 100 mg of 4-nitro-3-trifluoromethylacetanilide in 2 ml of RAL - ethylformamide is mixed at 0 0 C with 12 mg of sodium hydride T0 T70 69 (80% in mineral oil) and, after 20 minutes, with 150 mg of 2-(2 phenylpropyl)-2-trifluoromethyl-oxiran. It is stirred for 16 hours at 60 0 C, diluted with water and extracted with ethyl acetate. After washing with water, the ethyl acetate phase is dried (Na 2

SO

4 ) and concentrated by evaporation. 80 mg of N- (2 hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroyl) -4-nitro-3 trifluoromethylaniline, melting point 119-120 0 C, is obtained. After racemate separation analogously to Example 102, there are obtained the (-)-form, [C]D = ~49.6 (c = 0.5 in chloroform), the (+)-form, [a]D = +48.80 (c = 0.5 in chloroform) . Example 119 (Process 4) 6- (3-Hydroxy-3-methyl-1-butinyl) -5- (2-hydroxy-4-methyl-4-phenyl 2- trifluoromethyl -valeroylamino) -phthalide 150 mg of the bromine compound of Example 2 is 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 under argon with 0.25 mg of bis triphenylphosphine-palladium-II-chloride. After 5 hours of reflux boiling, another 30 mg of 2-methyl-3-butin-2-ol is added, and it is refluxed for 20 hours. It is diluted with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na 2

SO

4 ) and concentrated by evaporation. The crude product is chromatographed on silica gel. With cyclohexane/ethyl acetate (1:1), 60 mg of crystalline 6-(3-hydroxy-3-methyl-l-butinyl)-5

LU

70

(

2 -hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) phthalide, melting point 162-168 0 C, is obtained. Example 120 6-Acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl valeroylamino) -phthalide 100 mg of the bromine compound of Example 2 is dissolved together with 95 mg of tributyl-(l-ethoxyvinyl)-tin and 8 mg of bis-triphenylphosphine-palladium-II-chloride in 4 ml of toluene under argon. After 5 hours of reflux boiling, another 45 mg of bis-triphenylphosphine-palladium-II-chloride is added, and it is refluxed for 20 hours. 1N hydrochloric acid is added and extracted with ethyl acetate. The ethyl acetate phase is dried (Na 2

SO

4 ) and concentrated by evaporation. The crude product is stirred in 3 ml of tetrahydrofuran and 3 ml of 2N hydrochloric acid for 2 days at room temperature. It is mixed with water and extracted with ethyl acetate. After washing with water, it is dried (Na 2

SO

4 ) and concentrated by evaporation. The residue is pulverized with diethyl ether/pentane, and 21 mg of crystalline 6-acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl valeroylamino)-phthalide, melting point 195-199 0 C, is obtained. The compounds of Table 12 are obtained analogously to Examples 119 and 120. , ; RAZ,/

LU.

71 Table 12 Z2 CH 3 CH3 OH CF 3 X4 Z H z N 00 z Z O Z5 X7 O Example Xn Z" Melting Point (H) (+H) (*C) 121

X

4

=CH=CH

2 foam 122

X

6

=CH=CH

2 191-197 123 X =C (OC 2

H

5 ) =CH 2 160-163 124

X

6 =C= C-CH 2 OH 208-2.11 125

X

6

=C

6

H

5 160-163 126 157-158 X6= 127

X

6

=C

6

H

4 0CH 3 (p-) 125-127 128

Z

3

=CH=CH

2 178-180 129

Z

3

=C

2

H

5 (*) 152-153 130

Z

3

=COCH

3 () 220 131

Z

3 =CN 112 132

Z

4

=CH=CH

2 190-192 133

Z

4

=COCH

3 (") 205-207 ( ) Obtained from the vinyl compound by catalytic hydrogenation. ( ) Obtained from the enol ether by mild acidic hydrolysis.

72 Example 134 (Process 5) 5- [4- (3-Fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-4-2 trifluoromethyl-valeroylamino] -phthalide 132 mg of 5-[ 4

-(

3 -fluoro-4-methoxyphenyl)-2-hydroxy-4 methyl-4-2-trifluoromethyl-valeroylamino) -phthalide (Example 82) is dissolved in 15 ml of dichloromethane and mixed at 0 0 C with 1.2 ml of a 1 M solution of boron tribromide in dichloromethane. After 16 hours at 0 0 C, ice, ethyl acetate and potassium bicarbonate are added to the mixture, and the ethyl acetate phase is separated, dried (Na:SO 4 ) and concentrated by evaporation. 120 mg of 5- [4- ( 3 -fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-4-2 trifluoromethyl-valeroylamino] -phthalide, melting point 139 140'C, is obtained from ethyl acetate/diisopropyl ether/hexane. The compounds that are presented in Table 13 are obtained analogously to Example 86. Table 13 Z 2 HO CF 3 Z 3 B ,N 4 /6 LZ Z 73 Example B Z" Melting Isomerism (+H) Point or (*C) [a]J _(c=0.5) (2) 135 C=O Z2=OH 222-224 136 C=O

Z

4 =OH 228-230 137 C=O

Z

2 =Z'=OH 265-267 138 C=O Z 2 =OH, 215-217 racemate Z5=CH 3 139 C=O Z 2 =OH, 173-174 (+) -form

Z

5

=CH

3 140 C=O Z 2 =OH, 173-174 (-)-form Z5=CH 3 141 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 4 =OH, Z 2 =F 242-243 144 C=O Z 2 =OH, Z 5 =Cl 220-221 145

CH

2 Z2 =OH, Z 5 =F 156-157 racemate 146

CH

2 Z2 =OH, Z 5 =F 157-159 +23.5 147

CH

2 Z'=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 =N0 2 , 167-169 racemate Z4 =OH 150 C=O Z 3 =Cl, Z 4 =OH 168-169 racemate 151 C=O Z 3 =Br, Z 4 =OH 105 racemate (1) The optically active compounds that are presented in Table 13 were separated analogously to Example 102. (2) In methanol. LU

C)

Example 152 5- [4- (3-Fluorophenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl valeroylamino] -phthalide 66 mg of (3-fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-4-2 trifluoromethyl-valeroylamino]-phthalide is stirred with 126 mg of potassium carbonate and 108 mg of 5-chloro-lphenyl-lH tetrazole in 3 ml of dimethylformamide for 16 hours. Then, the dimethylformamide is distilled off in .a vacuum, and the residue is dispersed between 1N hydrochloric acid and ethyl acetate. After washing with water, the ethyl acetate phase is dried (Na 2

SO

4 ) and concentrated by evaporation, and the residue is chromatographed on silica gel with hexane/ethyl acetate (1:1). The product is hydrogenated in 10 ml of methanol with 30 mg of palladium/carbon (10%). After the catalyst is removed and the solvent is concentrated by evaporation, the product is chromatographed on silica gel with hexane/ethyl acetate (1:1). 49 mg of 5- [4- (3-f luorophenyl) -2-hydroxy-4-methyl-4-2 trifluoromethyl-valeroylamino]-phthalide, melting point 157 0 C, is obtained. By racemate cleavage analogously to Example 102, the (+) form is obtained with melting point 140-141 0 C, and the (-)-form is obtained with melting point 141 0 C. ,-RA41

C.,

Example 153 5-[2-Hydroxy-4-methyl-4-(3-tolyl)-2-trifluoromethyl valeroylamino]-phthalide The compound is produced analogously to the example above from 57 mg of 5-[2-hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl 2-trifluoromethyl-valeroylamino]-phthalide, melting point 152 153 0 C. By racemate cleavage analogously to Example 102, the (+) form is obtained with melting point 148-149 0 C, and the (-)-form is obtained with melting point 145-146 0 C. Example 154 5-[4-(5-Fluoro-2-ethoxyphenyl)-2-hydroxy-4-methyl-4-2 trifluoromethyl-valeroylamino]-phthalide 44 mg of 5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl 4

-

2 -trifluoromethyl-valeroylamino]-phthalide is stirred in 1 ml of dimethylformamide with 28 mg of potassium carbonate and 50 mg of ethyl iodide for 24 hours at room temperature. It is then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na 2

SO

4 ) and after the solvent is concentrated by evaporation, 35 mg of 5-[4-(5-fluoro-2 ethoxyphenyl)-2-hydroxy-4-methyl-4-2-trifluoromethyl valeroylamino]-phthalide, melting point 108 0 C, is obtained. The compounds of Table 14 were produced analogously to Example 154.

;RA

1 Table 14 OR OH CF 3 H N K0 0 F 0 Example R Melting Point Isomerism or (*C) ['] " (c=0.5) (2) 155 CH (CH 3 ) 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 (CH3 3 145 racemate 160

CH

2

COOC_(CH

3 ) 3 143 -131.5 161

CH

2 COOC (CH 3 ) 3 142-143 * (+)-form Example 162 5- [4- ( 3 -Chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeroylamino] -phthalide 22 mg of 5- [2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2 trifluoromethyl-valeroylamino]-phthalide is stirred in 1.5 ml of methanol with 20 mg of N-chlorosuccinimide. The mixture is then dispersed in ice water, sodium bicarbonate solution and ethyl acetate, the ethyl acetate pahse is dried, and it is concentrated by evaporation. 20 mg of 5-[ 4 -(3-bromo-4-methoxyphenyl)-2 hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide, LU ArrC which melts at 189-191 0 C after recrystallization from isopropylether, is obtained. 5- [4- (3-Chloro-4-hydroxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethyl-valeroylamino] -phthalide is obtained from 5- [4- (3-chloro-4-methoxyphenyl) -2-hydroxy-4 methyl-2-trifluoromethyl-valeroylaminol-phthalide by ether cleavage analogously to Example 134, Melting point 105 0 C. The 2,3-benzoxazinone and phthalazinone derivatives of Table 15 were produced according to the above-mentioned process. Table 15

Z

2

CH

3 R2HOCF y 5 y 4 Z3 Z Z8 V ZSy8 0

RA

Example R2 V Z" B Y" Melting Iso (+H) (wH) point merism (*C) or [Cf] D, (c=O.5) (2) 163 H 0 C=0 Y 4

=CH

3 165-166 race mate 164 H 0 C=O Y 4

=C

2 H 159-160 race mate 165 CH 3 0 C=0 Y 4

=CH

3 185 +162 166 CH 3 0 C=O Y 4

=CH

3 184-185 -182 167 CH 3 0 C=0 Y 4

=C

2

H

5 148-153 race ... __ mate 168 CH 3 0 C=0 Y 4

=C

2 Hs 159-160 +173 169 CH 3 0 C=0 Y 4

=C

2 H, 159-160 -175

;;RAZ/

Example R 2 V Z" B Y" Melting Iso (*H) (oH) point merism (*C) or [cx] (c=O.5) (2) 170 CH 3 0 Z 2

=OCH

3 C=O Y 4

=CH

3 161-163 race mate 171 CH 3 0 Z 2

=OCH

3 C=O Y 4

=CH

3 173-175 -54.7 (4) 172 CH 3 0 Z 2

=OCH

3 C=o Y 4

=CH

3 173-175 +52.2 173 CH 3 0 Z 2

=OCH

3 C=0 Y 4

=C

2

H

5 164 race materia le 174 CH 3 0 Z 2

=OCH

3 C=0 Y 4

=C

2

H

5 190-191 (+) form 175 CH 3 0 Z 2

=OCH

3 C=0 Y 4

=C

2

H

5 190-191 -161.3 1 (CHC1 3 ) 176 CH 3 0 Z 2

=OCH

3 , C=0 Y 4

=CH

3 165 race

Z

5 =F mate 177 CH 3 0 Z 2

=OCH

3 , C=0 Y 4

=CH

3 188-189 (+) I Z 5 =F form 178 CH 3 0 Z 2 =0H 3 , C=0 Y 4

=CH

3 187-188 -132.8

Z

5 =F (CHC1 3 ) 179 CH 3 0 Z 2 =0H 3 , C=0 Y 4

=C

2

H

5 126-128 race Z =F mate 180 CH 3 0 Z2=0CH 3 , C=0 Y 4

=C

2

H

5 170-171 -147.4 _ _ _ _Z 5 =F 181 CH 3 0 Z 2 =0CH 3 , C=0 Y 4

=C

2

H

5 171 (+) I Zs=F form 182 CH 3 0 Z 2 =0CH 3 , C=0 Y 4

=CH

3 182-184 race Z =Cl mate 183 CH 3 0 Z 2

=OCH

3 , C=0 Y 4

=CH

3 198-199 (+) __ Z 5 =C1 form 184 CH 3 0 Z 2

=OCH

3 , C=O Y 4

=CH

3 197-198 -90.2 Z =C1 185 CH 3 0 Z 2

=OCH

3 , C=0 Y 4

=CH

3 206-207 race

I_._Z

4 =Br I I I mate 186 CH 3 0 Z 2

=OCH

3 , C=0 Y 4

=CH

3 194-198 (+) Z 4 =Br form -7~ 80 187 CH 3 0 Z 2

=OCH

3 , C=O Y 4

=CH

3 196-198 -122.2

Z

4 =Br (CHC1) 188 CH 3 0 Z 4

=CH

3 C=O Y 4

=CH

3 222-223 race mate 189 CH 3 0 Z 4

=CH

3 C=O Y 4

=C

2

H

5 187-188 race mate 190 CH 3 0 Z 4

=CH

3 C=0 Y 4

=C

2

H

5 160 -63.7 191 CH 3 0 Z 4

=CH

3 C=O Y 4

=C

2 H 160 form 192 CH3 0 Z 4 =F C=0 Y 4

=CH

3 188-190 race mate 193 CH 3 0 Z 4 =Br C=0 Y 4

=CH

3 219-220 race I_ mate 194 CH 3 0 Z 4 =Br C=0 Y 4 =CH, 231-233 -49.3 195 CH 3 0 Z 4 =Br C=0 Y 4

=CH

3 231-233 (-) form 196 CH3 0 C=O Y 4

=CF

3 175-183 197 CH 3 NH C=O Y 4

=CH

3 198 CH 3

NCH

3 C=0 Y 4

=CH

3 199 CH 3 0 Z 2 =0H, C=0 Y 4

=CH

3 234-236 race I Z'=F mate 200 CH 3 0 Z 2 =OH, C=0 Y 4

=CH

3 232-234 (-) Z =F form 201 CH 3 0 Z 2 =OH, C=0 Y 4

=CH

3 232-234 -34.1 I_ _ Z 5 =F 202 CH 3 0 Z 2 =OH, C=0 Y 4

=CH

3 248-250 race

Z

4 =Br mate 203 CH 3 0 Z3=N0 2 , C=0 Y 4

=CH

3 215-217 race

Z

4 =0CH 3 mate 204 H 0 CH 2

Y

4

=CH

3 148-149 race I _mate 205 CH 3 0 CH 2

Y

4

=CH

3 132-133 race mate 206 CH 3 0 CH 2

Y

4

=C

2 H 121-122 race _ 1 _ 1_ 1 1 mate (1) The optically active compounds that are presented in Table 15 were separated analogously to Example 102. (2) In methanol. ST R&

Claims (33)

1. 2. Compounds of general formula I according to claim 1 in the form of the racemate or diastereozer mixture.
2. 3. Compounds of general formula I according to claim 1 in the form of separate optical isomers.
3. 4. Compounds of general formula I according to claim 1, characterized in that RI and R 2 are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring.
4. 5. Compounds of general formula I according to claim 1, wherein R 3 stands for a C 1 -C, perfluoroalkyl group.
5. 6. Compounds of general formula I according to claim 1, wherein A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals, selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, a (CH 2 )n group (n=3,4,5), which with 2 adjacent C atoms of aromatic compound A forms a ring with n+2 links and can contain unsaturations; vinyl groups, hydroxy groups, methoxy groups, and ethoxy groups.
6. 7. Compounds of general formula I according to claim 1, wherein X 3 " stands for a hydrogen atom or a C 1 -C 5 alkyl group.
7. 8. Compounds of general formula I according to claim 1, wherein X3" and X3b are the same or different and stand for a hydrogen atom or a CI-C. alkyl group.
8. 9. Compounds of general formula I according to claim 1, wherein X 4 , X 6 and X 7 are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom. (the next page is 87)
9. 10. Compounds of general formula I according to claim 1, wherein Y 4 stands for a C 1 -C. alkyl group or a Cl-Cs perfluoroalkyl group.
10. 11. Compounds of general formula I according to claim 1, wherein Y', Y' and Y' are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom.
11. 12. Compounds of general formula I according to claim 1, wherein R1 and R 2 are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring, and R 3 stands for a C 1 -C 5 perfluoroalkyl group, A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals, selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, a (CH 2 )n group (n=3,4,5), which with 2 adjacent C atoms of aromatic compound A forms a ring with n+2 links and can contain unsaturations; vinyl groups, hydroxy groups, methoxy groups, and ethoxy groups; and either X 3 a stands for a hydrogen atom or a CI-C. alkyl group, or x 3a and X 3 , are the same or different and stand for a hydrogen atom or a Cl-C. alkyl group and X 4 , X 6 and X 7 are the same or different, and stand for, independently of one another, a hydrogen atom or a halogen atom, or Y 4 stands for a C 1 -C 5 alkyl group or a C 1 -C 5 perfluoroalkyl group, and Y 5 , Y 7 and Y 8 are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom, and the other substituents all have the meanings that are indicated in Formula 1.
12. 13. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 6.
13. 14. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 7.
14. 15. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 10.
15. 16. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 11.
16. 17. Compounds of general formula I according to claim 1, namely 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 valeroylamino) -phthalide, 5- [2- (hydroxy-4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl valeroylamino] -phthalide, 5- [2-hydroxy-4- (2-hydroxyphenyl) -4-methyl-2-trifluoromethyl valeroylamino) -phthalide, 5- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino) -phthalide, 5- [4- (4-f luorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino) -phthalide, 5- [4- (4-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino -phthalide, 5- [4- (4-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino] -phthalide, & RA 5- [2-hydroxy-4-methYl-4- (4-tolyl) -2-trifluoromethyl valeroylamino] -phthalide, 5- [2-hydroxy-4-methyl-4- (3-tolyl)-2-trifluorotnethyl valeroylamino] -phthalide, 5- [4- (4-cyanophenyl) -2-hydroxy-4-methyl-2-trif1uoromethyl valeroylamino] -phthalide, 5- [4- (3,4-ditnethylphelyl) -2-hydroxy-4-mfethyl-2 trifluoromethyl-valeroylainl-phthalide, 5- [4- (3,5-dirnethylphel) -2-hydroxy-4-mfethYl-2 trifluoromethy1-valeroylanino] -phthalide, 5- [2-hydroxy-4- (2-methoxy-5-mfethYlphelyl) -4-methyl-2 trifluoromethy-vaeroylamino] -phthalide, 5- [4- (5- chloro-2 -hydroxyphenyl) -2 -hydroxy-4-mrethyl-2 trifluoromethy-valeroylanino] -phthalide, 5- [4- (5-f luoro-2-hydroxyphel)-2-hydroxy-4-mfethy)l-2 trifluoromethYl-valeroylamino] -phthalide, 5- [2-hydroxy-4 -(2 -hydroxy-5-methYlphelyl) -4-methyl-2 trifluoromethyl-valeroylanino] -phthalide, 5- [4- (5-fluoro-2-methoxyphel) -2-hydroxy-4-methyl-2 trifluoromethyl-valeroylanino] -phthalide, 5- [4- (2-fluoro-4-nethoxyphel) -2-hydroxy-4-mfethyl-2 trifluoromethy-valeroylamnil-phthalide, 5- [4- (3-f luoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2 trifluoromethy-vaeroylaino] -phthalide, 5- ( 2 -hydroxy-4-phefyly1>trif1uoromethyl-valeroylamino) phthalide, 5- [2-hydroxy-4- (2-methoxyphelYl) -4-methy1-2-trif1uoromfethyl valeroylanino] -phthalide, 5- [4- (5- chloro-2 -methoxyphenyl) -2 -hydroxy-4-methyl-2 trifluoromethyl-valeroylamil]-phthalide, 5- ( 2 -hydroxy-4-phefl2-trif1uoromfethy1-Petylamino) phthalide, 5- (-yrx--ehl4phnl2tilooehl pentylamino) -phthalide, 5- [4- (4-f luoropheny-2-hydroxy-4-methyl-2-trif1uoromethyl pentylamino] -phthalide, 5- [4- (5-f luoro-2-hydroxyphelYl) -2-hydroxy-4-mfethyl-2 trifluoromethyl-peltylamil]-phthalide, 6-acetyl-5- (2-hydroxy-4-methy14-phefl12-trifluoromethyl valeroylamino) -phthalide, 5- [4- (3 -fluoro-4-hydroxyphelYl) -2-hydroxy-4-mfethyl-2 trifluoromethyl -valeroylaminl-phthalide, 5- [4- (3-f luorophenyl) -2-hydroxy-4-methyl-2-trif1uoromethyl valeroylaminl-phthalide, 6- (3-hydroxy-3-methyl-1-butiyl) -5- (2-hydroxy-4-methyl-4 phenyl-2-trifluoromTethy1-valeroylamino) -phthalide, valeroylamino) -4-methyl-2, 3-benzoxazin--ofle, 6- (2-hydroxy-4-methy14-phefl12-trif1uoromethyl valeroylamino) -4-trifluoromethyl-2, 3-benzoxazil-ofle, 4-ethyl-6- ( 2 -hydroxy-4-phel-2-trif1uoromfethyl1pentylamino) 2, 3-benzoxazil-ofle, 4-ethyl-6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2 trifluorotnethyl-valeroylamil]-2, 3-benzoxazil-ofle, 6- [2-hydroxy-4- (2-methoxyphelyl) -4-methyl-2-trifluoromfethyl valeroylaminl-4-methyl-2, 3-benzoxazin--ofle, 3 , ' R 4-ethyl-6-[2-hydroxy-4-methyl- 4 -(4-methylphenyl)-2 trifluoromethyl-valeroylamino]-2,3-benzoxazin-l-one, 6-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino]-4-ethyl-2,3-benzoxazin-l-one, 4-ethyl-6-[4-(5-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-l-one, 1-( 4 -nitro-3-trifluoromethylanilino)-4-phenyl-2 trifluoromethyl-2-pentanol, 1-( 4 -nitro-3-trifluoromethylanilino)-4-phenyl-2 trifluoromethyl-2-pentanol, 5-(2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino) phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclopropyl)-2-trifluoromethyl propionylamino]-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclobutyl)-2-trifluoromethyl propionylamino]-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclohexyl)-2-trifluoromethyl propionylamino]-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.
17. 18. Compounds of general formula I according to claim 1, namely the compounds 92 2 3 (CH2)n OH CFa Z4 !: 6 0 Z 5 0 n Zn Isomerism (4 H) 1 racemate 1 _ _(+) -enantiomer 1 (-) ~-enantiomer 1 3-F racemate 1 2-Cl racemate 1 4-Cl racemate 1 4-Cl (+)-enantiomer 1 4-Cl (-)-enantiomer 1 2-Br racemate 1 3-Br racemate 1 2,4-Cl 2 racemate 1 2-OCH 3 (+)-enantiomer 1 2-OCH 3 (-)-enantiomer 1 3-OCH 3 racemate 1 3-CF 3 racemate 2 racemate 2 (+)-enantiomer 2 (-) -enantiomer 3 (+) -enantiomer 3 4-CH 3 racemate 4 _ racemate 93 4 (+) -enantiomer 4 (-) -enantiomer
18. 19. Compounds of the general formula according to claim 1, namely the compounds (CH 2 )n OH CF 3 0N 0 n Isomerism 1 racemate 1 (+)-enantiomer (-)-enantiomer 2 racemate 4 racemate 4 (+)-enantiomer 4 (-)-enantiomer PA7 94
19. 20. Compounds of the general formula according to claim 1, namely the compounds Z2_ 3 0 CFa z Y 0 4 6O Zn (+ H) Z2 Z3= Cl Z3= Br Z3 I
20. 21. Compounds of the general formula according to claim 1, namely the compounds 2 24 3a 3b Z3H w 4 6 0 6 / Z 5 X7 0 -- 6 95 R 2 W rn z' Isomerism (* H) (H)I H 0 X 3 a/X 3 b =H/CH 3 Diast. -Gem. H 0 X 3 a=H, X 3 b=CH 3 ___()-form H 0 X 3 a=H, X 3 b= CH 3 ____()-form H 0 X 3 a=CH 3 , X 3 b=H -___ (+form H 0 X 3 a= CH 3 , X 3 b=H (- -form H 0 X 3 a= C 2 H 5 _______ H 0 x 3 a= CH=CH 2 ____ H 0 X 3 a= CH=CH 2 -CH 3 ___ H 0 X 3 a=CF 3 ____ H 0 X 3 a=X 3 b= CH 3 H 0 X 3 a=x 3 b= C 2 H 5 __________ H 0 x 3 a= 3 b= (CH 2 ) 4 ___ H 0 X 4 =Br____ CH 3 0__ __ CH 3 0 X 4 =Br CH 3 0 Z 2 =CH 3 racemate CH 3 0 __ _ _ _ _ _ _ _ _ _ _ _ _ _ Z 2 =CH 3 (+)-form CH 3 0 __ _ _ _ _ _ _ _ _ _ _ _ _ _ Z 2 =CH 3 (-) -form CH 3 0 Z 4 =CH 3 _______ '& RA~, 96 R 2 ~ w x isomerism CH 3 0 Z'= Z'=CH 3 racemat e CH 3 0 (+Z=C 3 9) -form CH 3 0 Z 3 =Z 4 = CH 3 (-) -form CH 3 0 z 3 =Z 5 = CH 3 rac emat e CH 3 0 Z = Z 5 =CH 3 (+) -form CH 3 0 Z 3 =Z 5 = CH 3 (-) -form CH 3 0 Z 3 /Z 1 4 = (CH 2 ) 3 CH 3 0 z 3 /Z= -CH=CH-CH=CH-________ CH 3 0 Z =F1_________ CH 3 0 Z 4 =Br CH 3 0 Z'=OC 3 r CH 3 0 2 =OCH 3 ,ZCH racemate CH 3 0 Z =OCH 3 ,Z=H(- -fr CH 3 0 Z 2 =ZOCH 3 ZF CH 3 0 Z 2 = OCH 3 , Z 5 =F _____(+)-form_ CH 3 0 Z2 =OCH 3 , Z5 =F CH 3 0 Z 4 =OCH 3 , Z =F ________ CE 3 0 2 =OCH 3 , Z 5 =C1 racemate CH 3 0 Z 2 =OCH 3 , Z 5 =C1 (+) -form R AZ/ 97 R 2 W xnZ Isomerism CH; 0 Z=CZ 5 =C()form H S _ _ _ H CH? _ _ _ _ _ _ _ _ _ _ _ H 10 CH, (3) _____ _____________ ___ R 2 w X nIsomerism __ __ __ ( H) (0 H) _ _ _ _ _ _ FP. 0 Z'= CH =CH, racemate CH.; 0 _ Z 4 =CN racemate C3 0 Z4= COCH, racemate CHI 0 Z4= CONH, racemate CH; 0 - Z = OCH, f Z 4 = Br racemate CH 3 0 Z2 OCH 3 , Z 4 = Br (+)-enantiomer CH - Z 2 OCH-4, Z 4 =Br ()fr CH. 0 Z = Br, Z 4 = OCH, racemate CH; 0 Z2= OCH, Z' - C racemrate CH; 0 3= NO, Z= C. racemate CH. 0 - - Z = COCH3 r Z 4 = CH (CH,~), racemate ICa _ 0 Z3= CCH, Z 4 = OCHI racemate
21. 22. Compounds of the general formula according to claim 1 namely the compounds 3- H Z5 0 R 2 w n Isomerism (0 H) H 0 racemate H 0 (+)-form H 0 (-)-form CH 0 racemate CH 0 (+) -form CH 0 (-)-form H 0 Z F racemate 0H O Z = F (+) -f orm 0 = F (-) -form CH 3 0 Z 2 =OCH 3 , L H, 0Z4 F (+)-form_ _ _ _ _ Z 5 = F H CH 2 H OCH2 (3) 1
22. 23. Compounds of the general formula according to claim 1, namely the compounds 2 CH 3 CH. OH CF 3 X4 H Z3 N z Z6 Ox ; a \~e R4X Z5 X7 0 -0R K.44 (* H) (*~ H) X'=CH=CH X 6 =CH=CH X 6 =C (OCH,) =CH, X 6 =C=C-CH,0H X6=C H; x 6 = X =CH4OCHz (p-) Z 3 =CH=CH? Z3=CH Z 3=COCH Z3=CN Z''=CH=CH, Z''=COCHI
23. 24. Compounds of the general formula according to claim 1, namely the compounds Z 2 HO CF 3 Z 3 B ' N 4 6 z 5 B Zn Isomerism (*_H) C=O Z 2 =OH C=O Z 4 =OH C=O Z 2 =Z 5 =OH C=O Z 2 =OH, Z 5 =CH, racemate C=O Z 2 =0H, Z 5 =CH, (+) -form C=O Z 2 =0H, Z 5 =CH, (-) -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 5 =Cl CH, Z 2 =OH, Zs=F racemate CH, Z 2 =OH, Z 5 =F _f CH, Z 2 =OH, Z5=F _ f C=o Z 2 =OH, Z4=Br racemate C=o Z 3 =NO,, Z 4 =OH racemate C=O z 3 =Cl, Z4=OH racemate C=O Z 3 =Br, Z 4 =OH racemate
24. 25. Compounds of the general formula according to claim 1, namely the compounds OR OH CF 3 H ON 0O F0 R A 4 R Isomerism CH (CHO) racemate C=CH=C, racemate CH,CHaCH, racemate CH,CN racemate CHCOOC(CH.,) racemate CHCOOC (CH )(-) -form CH,COOC (CH.)', (+) -form
25. 26. Compounds of the general formula according to claim 1, namely the compounds Z 2 CH 3 R 2 HO CF 3 Y 5 y 4 H B N N I I V ZZ6 Y Z 5 8 0 R 2 V Z" B Yn Isomerism (+H) (* H) H 0 C=O Y 4 =CH; racemate H 0 C=0 Y 4 =CHs racemate CH 0 C=0 Y 4 =CH; (+) -form CH 0 C=0 Y 4 =CH4 (-)-form CH 0 _ C=O Y 4 =C,H, racemate CH 0 C=0 Y 4 =CH, _ +) -form CH O _C0 (-)-form LUJ R2 V Z'n B ynisomerism (H) ___ (H) _____ CE 3 0a Z 2 =OCH 3 C=O Y 4 =CH 3 racemate CH 3 0 Z 2 =OCE 3 C=0 y 4 =CH 3 (-)-foarm CH 3 0 Z 2 =OCH 3 C=0 Y 4 = CE 3 (+) -form CH 3 0 Z 2 =OCH 3 C=0 y 4 =C 2 H 5 racemat e CH 3 0 2 =OCH 3 C=O y 4 = C 2 H 5 (+) -form CE 3 0 Z 2 =OCH 3 -C=O Y 4 =C 2 Hg (-)-foarm CE 3 0 Z 2 =0 CH 3 , Z 5 =F C=O Y 4 =CH 3 racemate CH 3 0 Z 2 =0OCH 3 , Z 5 =F C=0 y 4 = CH 3 (+) -form CH 3 0 Z 2 =OCH 3 , Z 5 = F C=0 y 4 =CH 3 (-)-foarm CE 3 0 2 =0CE 3 , Z 5 =F C=O y 4 = C 2 E 5 racemate CH 3 0 Z 2 =0CH 3 , Z 5=F C=0 y 4 =C 2 H 5 (-)-foarm CH 3 0 z 2 =0CH 3 1 Z 5 =F C=0 Y 4 = C 2 H5 (+) -form CE 3 0 Z 2 = OCE 3 , Z 5 =C1 C=O Y 4 = CH 3 racemate CE 3 0 Z 2 =OCH 3 , Z 5 =C1 C=0 Y 4 =CH 3 (+) -form CH 3 0 2 =0CH 3 , Z 5 =cJ. C=0 y 4 = CH 3 (-)-form CE 3 0 Z 2 =OCH 3 , Z 4 =Br C=O Y 4 =CH 3 racemate CE 3 10 Z 2 =0CE 3 , Z 4 =Br C=0 Y 4 = CE 3 (+) -form CE 3 0 2 =OCH 3 , Z 4 =Br C=O Y 4 = CH 3 (-)-foarm CE 3 0 Z 4 =CE 3 C=0 Y 4 =CH 3 racemate CE 3 0 Z 4 =CH 3 C=O jy 4 =C 2 H 5 racemate CE 3 0 Z 4 =CH 3 C=0 Y 4 C 2 H 5 (-)-foarm CE 3 0 Z 4 =CE 3 C=0 Y 4 =C 2 E 5 (+) -form CE 3 0 Z 4 =F C=0 y 4 = CE 3 racemate CH 3 0 Z 4 =Br C=0 Y 4 =CH 3 racemate CE 3 0 Z 4 =Br C=0 y 4 = CE 3 (-)-foarm CE 3 0 Z 4 =Br C=0 y 4 =CF 3 (+) -form CE 3 0 __________C=0 Y 4 =CF 3 CE 3 NEH _________ C=0 Y= CE 3 ______ CE 3 NCH 3 C=0 Y 4 =CH 3 ______ CE 3 0 Z=OH, Z 5 =F C=0 Y =CE 3 racemate CH0 2 =OE, Z F C=0 y 4 =CHE 3 (+) -form L') CH 3 0 Z=OH, Z'=F C=O Y 4 =CH 3 (-)-form CH 3 0 Z 2=OH, Z =Br C=O Y 4 =CH 3 racemate CH 3 0 Z 3 =NO 2 , Z 4 =OCH 3 C=0 Y 4 =CH 3 racemate H 0 CH 2 Y 4 =CH 3 racemate CH 3 0 CH 2 Y 4 =CH 3 racemate CH 3 0 CH 2 Y 4 =C 2 H 5 racemate
26. 27. Pharmaceutical preparations that contain at least one compound of general formula I according to claim 1 as well as a pharmaceutically compatible vehicle.
27. 28. Use of the compounds of general-formula I according to claim 1 for the production of pharmaceutical preparations.
28. 29. Process for the production of compounds of general formula I RI R2HO R3 H A B Ar in which A, B, Ar, R1, R 2 and R 3 have the meaning that is indicated in claim 1, wherein a carbonyl compound of general formula II R 2 H A B Ar II in which A, B, Ar, R 1 and R 2 have the meaning that is indicated in formula I, is reacted with a compound of general formula CnF 2 r -SiR 3 , in which R 3 has the meaning that is indicated in general formula 1, in the presence of a catalyst or with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, to a compound of general formula I.
29. 30. Process according to claim 29, wherein the catalyst is a fluoride salt or an alkali carbonate.
30. 31. Process for the production of compounds of general formula I R1 HO R3 H A B Ar in which A, B, Ar, R 1 , R 2 and R 3 have the meaning that is indicated in claim 1, wherein a compound of general formula III R1 R2HO R3 A B FG III in which A, B, R 1 , R 2 and R 3 have the meaning that is indicated in general formula 1 and FG means a leaving group, is reacted with a compound of formula Ar-NH-R 11 , whereby R 11 means a hydrogen atom LA, or a C 1 -C 5 alkanoyl group, and Ar has the meaning that is indicated in general formula I, and optionally then radical R 11 is cleaved off.
31. 32. Process according to claim 31, wherein leaving group FG in connection with general formula III is a chlorine, bromine or iodine atom, a tosylate or mesylate radical or a Cl-C4 perfluoroalkylsulfonyloxy radical.
32. 33. Process according to claim 32, wherein the compound of general formula III is an acid chloride that is formed as an intermediate product from the corresponding carboxylic acid.
33. 34. Process for the production of compounds of general formula I RI HO R3 H A V B N in which A, Ar, R 1 , R 2 and R 3 have the meaning that is indicated in claim 1, and B means a -CH 2 group, wherein a compound of general formula IV R1 R2 R3 A IV IRA4, in which A, R 1 , R 2 and R 3 have the meaning that is indicated in formula I, is reacted with a compound of formula Ar-NH-R", whereby R 11 and Ar have the meanings that are indicated in claim 23, and optionally then radical R" is cleaved off.