BG64212B1 - Nonsteroid (hetero) cyclic substituted acylanylides of mixed gestagenous and androgenous activity - Google Patents

Abstract

The nonsteroid gestagens can be used individually or in combination with estrogens in contraceptive preparations, in the treatment of endometriosis, as well as of gynaecological distrurbances. The compounds can find also application in the treatment of premenstrual complaints and in substitution treatment. Their androgenous activity makes them suitable for controlling the male fertility, in male hormonosubstituting therapy (HRT) and in the treatment of andrological syndromes. They have the general formula where R1 & R2 are the same or different and mean hydrogen atom, C1-5 alkyl group or halogen atom or together with C-atom of the chain form a total of 3-7 member ring; R3 means C1-5 alkyl group or completely or partially fluorized C1-5 alkyl group; A means optionally substituted mono- or bicyclic aromatic ring, ester group -COOR4, alkenyl group -CR5=CR6R7, alkynyl group -C CR5 or partially or completely fluorized C1-5 alkyl group. B is carbonyl or CH2 group and Ar is a ring system selected from the following group of general partial formulae in case that B in the general formula I means CH2 group, Ar can mean phenyl residue with general partial formula The new compounds have very high affinity to the gestagen receptor. 33 claims

Description

Technical field

The invention relates to non-steroidal compounds which exhibit high gestagenic activity.

BACKGROUND OF THE INVENTION

In addition to a large number of steroid compounds with gestagenic activity, non-steroidal gestagens are also known (e.g., EP 0 243 500 B1 and WO 94/01413; see also J.Med. Chem., 38, (1995) 4878).

SUMMARY OF THE INVENTION

The invention relates to compounds of general formula I

(I) in which

R ¹ and R ² are the same or different and represent a hydrogen atom, a C ₁₅ alkyl group or a halogen atom or together with the C atom of the chain form a 3-7 membered ring together;

R ³ represents a C 1-6 alkyl group or a fully or partially fluorinated Ο _μ5 alkyl group;

A means optionally having one or more residues selected from halogen atoms, a C ₁₃ alkyl group, a C ₁₅ alkenyl group -CR 1 CRTU, wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently represent hydrogen or A C _1-5 alkyl group, a hydroxyl group, hydroxyl groups bearing a C _1-6 alkyl group; _1O allyl group, C ₃₁₀ carboxyalkyl group, C ₂₃ cyanoalkyl group, C ₃₁₀ unsubstituted or substituted allyl group, C _{3 0} unsubstituted or substituted propargyl group, C ₂ . ₃ alkoxyalkyl group, completely or partially substituted by fluorine atoms C _{| 3} alkyl group, with cyano or nitro group,

C _1-3 alkoxy groups, C ₁₃ alkylthio groups, mono or disubstituted C ₁₁₀ amine groups or partially or fully fluorinated C 1-6 alkyl groups, substituted mono- or bicyclic carbocyclic or heterocyclic aromatic ring;

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

in which the residues X ^3a , X ⁴ , X ⁶ , X ⁷ (in partial formulas 2), X ⁴ , X ⁶ , X ⁷ , (in partial formulas 3 and 4), X ^3a , X ³ , X ⁴ , X ⁶ , X ⁷ (in partial formulas 5, 6, and 7) or Υ ⁴ , Υ ⁵ , Y ⁷ , Y ⁸ (in partial formulas 8, 9, 10 and 11) may be the same or different and are selected from hydrogen atoms , C15 alkyl groups, which may optionally further comprise a C15 alkyl group, esterified or a C15 alkanoyl group, an esterified hydroxyl group, partially or fully fluorinated C1-3 alkyl groups, C2 3 alkenyl groups -CR ⁵ = CR ⁶ R ⁷ , wherein R ^6, R ⁶ and R ⁷ have the meaning given n an upper matter alkynyl groups -C = CR ^4, wherein R ⁵ has the above meaning, the radicals X ^3a and X ^zy can furthermore, together with the C-atom of the benzofused ring system 5, 6 or 7 to form a 3 - 7-membered ring as well as residues X ⁴ , X ⁶ , X ⁷ (in partial formulas 2, 3, 4, 5, 6 and 7) or Υ ⁴ , Υ ⁵ , Υ ⁷ , Y ⁸ (partial formulas 8, 9 , 10 and 11) may be halogen atoms, hydroxyl groups, alkoxy groups, C 1-5 alkanoyloxy groups, and in the case that B represents a CH ₂ group, the physiologically tolerable salts of the compounds of general formula I with acids.

The compounds of the invention differ from the known non-steroidal compounds with gestagenic activity by the substituent in the acyl moiety of formula (I) standing to the right. , have at this point a single, double or triple substituted phenyl residue.

The compounds of the invention of general formula I, due to the presence of asymmetric centers, may exist as different stereoisomers. Both racemates and separated stereoisomers are encompassed within the scope of the invention.

Defined as groups of substituents in the compounds of general formula I may have the following meanings.

The C ₁₅ alkyl groups are methyl, ethyl, η-propyl, isopropyl, η-, iso-, tert-butyl or n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl. The methyl and ethyl groups are preferred.

The halogen atoms may be fluorine, chlorine, bromine or iodine.

Fluorine, chlorine or bromine are preferred.

When R ¹ and R ² together with the C-atom of the chain form a 3-7 membered ring, this may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. A cyclopropyl ring is preferred.

Partially or wholly fluorinated C ₁₅ alkyl group refers to perfluorinated alkyl groups, the alkyl moiety having the above meanings, of which trifluoromethyl or pentafluoroethyl group is preferred. For partially fluorinated alkyl groups, 5,5,5,4,4-pentafluoropentyl or 5,5,5,4,4,3,3heptafluoropentyl group is meant.

Such as C _2-5 alkenyl groups may be, for example, a vinyl, allyl or 2,3-dimethyl-2-propenyl group; if the aromatic A is substituted with an alkenyl group then it is preferably a vinyl group.

The ₁₃ carboxyalkyl group may for example be a carboxymethyl, tert-butoxymethyl or ethoxymethyl group, the first two being preferred.

Representatives of a C _2-5 cyanoalkyl group are cyanomethyl and 1- and 2-cyanoethyl; cyanomethyl is preferred.

The ₃₁₀ allyl group is preferably an unsubstituted allyl group; in the case of a substituted allyl group, it is meant 1-methylallyl, 1,1-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylallyl, 3,3-dimethylallyl, cinnamyl and 3-cyclohexylallyl.

The unsubstituted propargyl group, methylpropargyl, 3-methylpropargyl, 3-phenylpropargyl or 3-cyclohexylpropargyl are the representatives of C ₃ . ₀ propargyl group, preferably an unsubstituted propargyl group.

C _2-5 alkoxyalkyl may, for example, be methoxymethyl, ethoxymethyl or 2-methoxyethyl.

Representatives of the C ₁₃ alkoxy group are the methoxy, ethoxy, n-propoxy, iso-propoxy, η-, iso-, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy group. Methoxy or ethoxy groups are preferred.

With _b5 perfluoroalkoxy groups are the corresponding perfluorinated moieties described above with _K alkoxy groups.

The mono or bicyclic aromatic ring A which may be substituted is a carbocyclic or heterocyclic aryl moiety.

In the first case, it concerns, for example, a phenyl or naphthyl moiety, preferably a phenyl moiety.

Heterocyclic residue may for example be monocyclic heterocyclic residue, such as thienyl, furyl, pyrrolidone, pyrazolyl, pyridyl, pyrazinyl, pyridyl, pyrazolyl, it in all possible isomeric forms with respect to the position of the heteroatoms. The thienyl moiety is preferred as the heteroaryl moiety A.

The C ₁₅ alkyl group for the esterification of hydroxyl groups refers to the said alkyl groups, preferably a methyl or ethyl group.

The C _1-3 alkanoyl group for the esterification of hydroxyl groups refers to the formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or isovaleryl groups, preferably the acetyl group.

Like with,. _{The 10} acyl group for esterification of hydroxyl groups refers to said alkanoyl groups, again preferably an acetyl group or benzoyl, toluyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl group.

When X ³ and X ³ together with the C-atom of the benzocondensed ring system form

A 3-7 membered ring, i.e. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. A cyclopropyl ring is preferred.

Such as C, _ ₃ alkanoyloxy group for X ^4, X ^6, X ^7, Υ ^4, Υ ^5, Y ⁷ and Y ⁸ are given the formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy or iso-valeryloxy group, the preferred is the acetoxy group.

As C _i-5 alkyl being C _b5 alkylsulfinyl or C ₁₅ alkilslufonilovite groups may be mentioned C _yz alkyl groups.

If the compounds of general formula I (B = -CH ₂ -) are in the form of salts, they may be hydrochlorides, sulfates, nitrates, tartrates or benzoates.

When the compounds of the invention are in the form of racemic mixtures, they can be separated into optically active forms by known methods. For example, racemic mixtures can be separated by chromatography on an optically active carrier material (Chiralpak AD ^R ) of pure isomers. It is also possible for the free hydroxyl groups in the racemic compound of general formula I to be esterified with optically active acid and the resulting diastereoisomeric esters separated by fractional crystallization or by chromatography and the individual esters saponified to optically pure isomers. For example, almond acid, camphorsulfonic acid or tartaric acid may be used as optically active acids.

According to the invention preferred compounds of general formula I are those in which:

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

R ³ is a C _[3 perfluoroalkyl group and / or A is optionally mono-optionally substituted with fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, vinyl, hydroxyl groups, methoxy groups, ethoxyl groups, substituted benzoyl or naphthalenes, naphthalenes or naphthalenes; thiophene ring and / or or

X ³ = hydrogen or a C _{| An} alkyl group or

X ³ 'and X ³ may be the same or different and represent hydrogen or a C ₁₅ alkyl group and / or

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

Y ⁴ represents C _{| A 5} alkyl group or a perfluoroalkyl group and / or

Υ ⁵ , Y ⁷ and Y ⁸ are the same or different and independently represent a hydrogen or a halogen atom and all other substituents in formula I have the indicated meanings.

In addition, compounds of general formula I are preferred in which the substituent Ar represents a ring system of partial formula 6, 7, 10 or 11.

Particularly preferred compounds of the invention are the following:

4-bromo-5- (2-hydroxy-4-methyl-4-phenyl-

2-Trifluoromethyl-valeroylamino) -phthalide;

6-bromo-5- (2-hydroxy-4-methyl-4-phenyl2-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-Fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide;

5- [4- (4-chlorophenyl) -2-hydroxy-4-methyl2-trifluoromethyl-valeroylamino] -phthalide;

5- [4- (4-bromophenyl) -2-hydroxy-4-methyl2-trifluoromethyl-valeroylamino] -phthalide;

5- [2-hydroxy-4-methyl-4- (4-toluyl) -2-trifluoromethyl-valeroylamino] -phthalide;

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

5- [4- (4-cyanophenyl) -2-hydroxy-4-methyl2-trifluoromethyl-valeroylamino] -phthalide;

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

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

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

5- [4- (5-Chloro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide;

5- [4- (5-Fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide;

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

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

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

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

5- (2-hydroxy-4-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-trifluoromethyl-valeroylamino] phthalide;

5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide;

5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-pentylamino] -phthalide;

5- [4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide;

5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] phthalide;

6- acetyl-5- (2-hydroxy-4-methyl-4-phenyl2-trifluoromethyl-valeroylamino] -phthalide;

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

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

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

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

6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-

2.3-benzoxazin-1-one;

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

6- [4- (4-bromophenyl) -2-hydroxy-4-methyl2-trifluoromethyl-valeroylamino] -4-ethyl-2,3-benzoxazin-1-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-1-one;

- (4-nitro-3-trifluoromethylanilino) -4-phenyl-2-trifluoromethyl-2-pentanol;

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

5- [2-hydroxy-3- (1-phenyl-cyclopropyl) 6

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-Fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide;

In addition, the compounds of Tables 7 to 15 are preferred.

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

In the gestagen receptor binding test for gestagenic action using cytosyl of rabbit uterine homogenate and using ³ H-progesterone as a comparator, the new compounds show strong to very strong affinity for the gestagen receptor (see Table 1).

Example No. structure competency factor (with respect to ³ Nprogesterone) (*) (mp 141 - 142 ° C) 17 (*) (mp 161 ° C) BUT CF _S cVoC 2.0 65 0.17 104 0 0.1 106 . HO CF ₃ ο 0.55

In addition to its gestagenic activity, which is differently expressed in the various compounds of general formula I, the new compounds also have a greater or less pronounced affinity for the androgen receptor. The androgen receptor binding test for androgen action was performed using the rat cytosol prostate homogenate and using ³ H-methyltrienol as a comparator.

The novel compounds are thus distinguished from the gestagenic compounds of EP 0253 500 B1 with a completely new mixed profile that is composed of gestagenic and androgenic activity.

For the compounds of the invention of general formula I, all three possible cases are concerned, which, based on the competitive factors of the progesterone receptor (KF _Pr0I ) and the androgen receptor (KF _Andro ), ^are classified within the scope of the present invention as follows:

Table 1 hj * · '· (*) EP Ο 253 500 Bl, Example 2

1) Compounds with a strong gestagenic and less pronounced androgenic action (KF _Prog <1HKF _Andro >5);

2) Compounds with a strong androgenic and less pronounced gestagenic action (KF _Andro <5 and KF _Prof >1);

3) Compounds with highly gestagenic and highly androgenic action (KF _Proi <1 ^and KF _Proi > 5).

According to the classification according to 1), 2) or 3), the new compounds of the invention may find application for various medical or pharmaceutical purposes.

When classified under 1) compounds with high gestagenic activity and less pronounced androgenic action, many active gestagens are present, and as already known numerous gestagenic compounds, are suitable for retention in pregnancy by parenteral and oral administration.

In combination with estrogen, combination preparations are prepared that can be used as contraceptives and for the treatment of menopausal complaints.

Due to the high gestagenic activity, the new, under 1) classified compounds of general formula I, for example, alone or in combination with estrogen preparations, can be used as contraceptives. However, with all other known gestagenic agents, new uses may be employed (see, for example, "Kontrazeption mit Hormonen", Hans-Dieter Taubert und Herbert Kuhl, Georg Thieme Verlag Stuttgart - New York, 1995).

Appropriate dosages can be determined according to the experience of one of skill in the art, for example by determining bioequivalence, for example in a pregnancy retention test for a known gestagen for a particular application, for example an amount equivalent to 30 to 150 mg of levonorgestrel as a contraceptive.

The dosage of the compounds of the invention below 1) for contraceptives should preferably be 0.01 to 2 mg per day.

Gestagenic and estrogenic active substances are mainly used together with oral contraceptives. The daily dose is mostly given once.

Estrogens are all known natural or synthetic estrogenic compounds.

As natural estrogens, these are especially estradiol as well as its longer-acting ester such as valerate and others or estriol.

However, synthetic estrogens such as ethinylestradiol, 14a, 17a, -etano-1,3,5 (10) -estratriene-3,17P-diol (WO 88/01275), 14a, 17a-ethano-1,3 should be mentioned above , 5 (10) estatriene-3,16a, 17β-triol (WO 91/08219) or 15,15-dialkyl estradiol derivatives, and in particular 15,15-dimethylestradiol (WO 95/04070). Of synthetic estrogens, ethinylestradiol is preferred. Recently known estratriene-3-amidosulfonates (WO 96 / -5216 and WO 96/05217), derivatives of estradiol or ethinylestradiol, which are characterized by low hepatic estogenity, are also suitable for use as estrogens together with the compounds classified under 1) of general formula I. Finally, reference is made to 14a, 15a-methylene steroids of the estranic order, in particular 14a, 15a-methylene-17a-estradiol, and the corresponding

3-amidosulfonate porous.

Estrogen is administered in an amount corresponding to 0.01 to 0.05 mg of ethinylestradiol.

The new compounds of general formula (I) can also be used in preparations for the treatment of gynecological disorders and for replacement therapy. Due to their favorable activity profile, these compounds of the invention are particularly suitable for the treatment of premenstrual complaints such as headache, depressed mood, water retention and mastodynia. The daily dose for the treatment of premenstrual complaints is about 1 to 20 mg.

Similar to other progestogens, new compounds can also be used in the treatment of endometriosis.

The novel compounds may also participate as components of the recently known compositions for female fertility control, which are characterized by the additional use of a competitive (competitive) progesterone antagonist (HBCroxatto and AMSalvatierra in Female Contraception and Male Fertility Regulation, ed. By Runnebaum, Rabe & Kiesel - Vol 2. Advances in Gynecolodical and

Obstrtric Research Series, Parthenon Publishing Group - 1991, p. 245; WO 93/17686, WO 93/21927, US Patent 5 521 166).

The dosage is within the limits given above, the formulation may be as with conventional OS preparations. The administration of additional competitive progesterone antagonists may also be administered sequentially.

Those compounds of general formula I that are classified under 2) or 3), i.e. compounds, which in any case have a strong androgenic action (androgenic gestagens), can be used in the preparation of pharmaceutical preparations for male fertility control.

The contraceptive activity of a combination of an orally administered gestagen (depo-medroxyprogesterone acetate, levonorgestrel ester, cyproteron acetate) with parenterally administered androgen (testosterononan-20 trate) in men is currently being studied in a number of 15 WHO studies.

In contrast to the above compounds of the invention, it is possible for the male fertility control to be performed by oral or transdermal administration of a dosage form.

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

The compounds of general formula I, which are to be classified rather as 2), i. compounds with predominantly androgenic and lesser gestagenic activity can be used for 35 male hormonal therapy. They can be used to treat hypergonadism or treat male infertility and potency disorders.

In male fertility control and for the treatment of these androgenic diseases, the compounds of the invention are administered at dosages equivalent in effect to the testosterone-nontantate amounts used in the WHO studies, respectively, to 45 doses of the already used androgenic compounds.

Equivalent in action are those which, in the test for androgenic action of the semen sac and / or prostate of the rat (Hershberger test), show comparable activity.

To date, a replacement dose of approximately 10 mg / day of testosterononanth has been used in male HRT.

Various testosterone esters (Oeanthat, Bucyclat, Undecanoat) are used in the WHO fertility control studies in men, ranging from approximately 10 to 30 mg / day.

It should be noted here that the arrangement according to the invention of groups 1), 2) and 3) has no clearly distinguishable boundaries and overflow into each other. Those compounds, which, based on their KF _{Pro (} and / or KFA _ndro, are rather at the boundary of the said KF bands, can also be used for indications in the adjacent mixed profile.

The compounds of general formula I also partially show activity on the glucocorticoid and / or mineralocorticoid receptor.

The formulation of the pharmaceutical preparations based on the compounds is carried out in a known manner by mixing the active substance, optionally in combination with estrogen, with the carriers used in the galenic, diluents, optionally flavor enhancers, etc. and forming in the desired form. application.

Preferably for oral administration, the preparations are tablets, dragees, capsules, pills, suspensions or solutions. ®

For parenteral administration, particularly suitable oil solutions are, for example, solutions in sesame oil, castor oil and cottonseed oil. Solubility intermediates such as benzyl benzoate or benzyl alcohol may be used to increase solubility.

The compounds of formula I can also be administered continuously via a built-in release system (Intra Uterine System = IUS; e.g. MIRENA ^R ). The rate of release of the active compound (s) is chosen so that the daily release rate meets the dosage limits already indicated. It is also possible that the substances of the invention are incorporated into the transdermal system and thus administered through the skin.

The compounds of the invention of general formula I can be prepared in the following ways.

Method of preparation

A carbonyl compound of general formula II

R »R2 Ο Η .ΧλΑ.

II in which A, Β, Ar, R ¹ and R ² have the meanings given in Formula I, is reacted with a compound of the general formula R ³ - SiMe ₃ in which R ³ has the meanings given in Formula I in the presence of a catalyst or reacts with an alkyl metal compound, for example, a Grignard reagent or a lithium alkyl compound, to give a compound of formula I. Fluoride salts or alkali compounds such as alkali carbonates can be used as a catalyst (J.Amer. Chem. Soc. Ill, 393 (199)) .

2. A compound of general formula III

Ri R2QHR3 / 9 ·

III in which A, B, R ¹ , R ² and R ³ have the meanings given in formula I, and FG is a leaving group, reacted with compound Ar NH-R in which R represents a hydrogen atom or C | _{5 is} an acyl group, and Ar has the meanings given in formula I, optionally thereafter leaving the residue R to yield a compound of general formula I. The compound of general formula III may then only be formed as an intermediate. for example, it may be an intermediate acid chloride formed from the corresponding carboxylic acid. As leaving group, for example, chlorine or bromine or a tosylate moiety are considered.

3. A compound of general formula IV

R ¹ R2 R ³

IV in which A, R ¹ , R ² and R ³ have the meanings given in formula I, is reacted with a compound of formula Ar-NH-R in which R has the above meanings, and optionally thereafter the residue R ¹¹ is cleaves to yield a compound of general formula I wherein B is a -CH ₂ group.

A compound of formula I, wherein residue A or residue Ar contains the aryl-X group, wherein "aryl" means an isocyclic or heterocyclic aromatic radical corresponding to the definitions given in formula I, and X represents bromine or iodine, or the group -O-SO ₂ R ¹² in which R ¹² represents a C 13 perfluoroalkyl group is reacted in a known manner with a compound of formula R ¹³ - Y, in which R ¹³ represents an optionally substituted aryl, ethenyl or ethynyl moiety and Y is hydrogen, den atom (J. Org. Chem., 43, 2947 (1978)), group B (OR ¹⁴ ) 2 (J. Org. Chem., 58, 2201 (1993)) or Sn (R ^{, 5} ) 3 (J. Organ Chem., 52, 422 (1987)) in which R ¹⁴ and R ¹⁵ denote a phenyl moiety or a C 1-5 alkyl group and R ¹⁴ may also denote a hydrogen, Mg-halogen or alkali metal atom, under the action of a metal catalyst, to give the aryl compound -R ¹³ .

5. In a compound of formula I in which the A or Ar site has an alkoxy or acyloxy substituent, the OH group is released and optionally subsequently converted to ether or ester or, after conversion to 1-phenyl 5-tetrazolylether, by hydrogenation completely eliminated (J.Amer. Chem. Soc. 88, 4271 (1966)).

Of the embodiments described, the preparation methods 1 and 2 are suitable for the preparation of all compounds falling under the general formula I.

In Option 3, compounds of the general Formula I in which B is a -CH ₂ group can be prepared.

By the variants 4 and 5 of the production methods steps can be taken to functionalize already existing compounds of general formula I.

If desired, compounds prepared according to any one of the variants and in which A is an optionally substituted aromatic ring can be selectively substituted in this aromatic ring in a known manner. Examples of such methods are catalytic hydrogenation of unsaturated bonds, nitration and halogenation.

The starting materials used in the examples are prepared as follows.

Examples of carrying out the invention

Preparation of starting compounds

4-Metal-4-phenyl-2-oxovaleric acid

Grignard solution obtained from 26.4 g of magnesium and 162 ml of 2-methyl-2-phenyl-1-chloropropane in 150 ml of diethyl ether was added dropwise to 600 ml of oxalic acid diethyl ester at -30 ° C. After 2 h at room temperature, the reaction mixture was poured onto an ammonium chloride solution, extracted with diethyl ether, dried over sodium sulfate and fractionally distilled. 84 g of ethyl ester (mp 115-120 ° C / 0.03 hPa) are obtained. It was dissolved in 1 L of methanol, 500 ml of 1 M sodium hydroxide was added and stirred at room temperature for 1.5 h. After evaporation of the methanol under ₂ θ vacuum, the residue was partitioned between water and diethyl ether, the aqueous phase was acidified with hydrochloric acid and extracted with diethyl ether. After distillation was obtained 57 g of 4-methyl-4fenil-2-oxovaleric acid in the format ₂ j mat thick oil.

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

From 50 g of 3,3-dimethyl-4- βθ pentenoic acid methyl ester by saponification with 10% potassium base 36 g of 3,3-dimethyl-4-pentenoic acid are obtained in the form of an oil. Stirring with thionyl chloride (20 h at room temperature) afforded the acid chloride. Mp 59 ° C / 30 hPa. 16 g of it with 15 g of trimethylsilyl cyanide and 0.16 g of zinc iodide were stirred for 4 days. Distillation gave 13 g of 4,4-dimethyl-2-oxo-5-hexanoic acid nitrile, b.p. 75-85 ° C / ₄ θ 30 hPa. 2 g of it with 0.6 ml of methanol in 13 mJ hexane were cooled with ice with hydrogen chloride gas and water was added after 2 hours. From the hexane phase is obtained after drying over sodium sulfate and concentrating 0.588 g of 4,4-dimethyl-2-oxo-5-hexanoic acid methyl ester, m.p. 48 ° C / 0.003 hPa. From this, 0.535 g was saponified with 1.3 ml of 3 N sodium hydroxide to give 0.32 g of 4,4-dimethyl-2-oxo-5 hexanoic acid as a yellowish liquid.

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

To 10 g of 1-phenyl-cyclobutanecarbonyl dissolved in 70 ml of toluene was added 56 ml of diisobutylaluminum hydride in toluene (1.2 molar solution) at -72 to -69 ° C. After 4 h at -75 ° C, 30 ml of ethyl acetate were added dropwise. It is warmed to room temperature and new amounts of ethyl acetate and water are added. It was filtered through kieselguhr, the organic phase was separated, dried over sodium sulfate and concentrated. Chromatography on silica gel (hexane with 0-10% ethyl acetate) afforded 7.6 g of 1-phenyl-cyclobutanecarbaldehyde. 3 g of it was dissolved in 10 ml of tetrahydrofuran and at 0 ° C was added dropwise to a solution previously prepared from 5 g of triethyl-2ethoxyphosphonacetate in 70 ml of tetrahydrofuran and at 0 ° C 10.3 ml of a 2 molar solution of lithium diisopropylamide were added. tetrahydrofuran / heptane / ethylbenzene. After 20 h at room temperature, water was added, extracted with ethyl acetate, dried over sodium sulfate and concentrated. 2 g of this crude product is saponified with 28 ml of 1 N sodium hydroxide solution. 1.32 g of the acid is obtained which is heated with vigorous stirring for 20 hours at 90 ° C with 25 ml of 1 molar sulfuric acid solution. After extraction with ether, drying over sodium sulfate and concentration, 0.89 g (3-1-phenyl-) is obtained. cyclobutyl) -2-oxo-propionic acid as a yellowish oil.

3- [1- (2-Methoxyphenyl-cyclopropyl) -2-oxo-acetic acid

According to J. Org. Chem. 40 (1975) 3497

16.7 g of 2-methoxyphenylacetonitrile, 158 ml of lithium triisopropylamide (2 molar solution) and

46.7 ml of 1,2-dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric acid triamide are reacted with each other. 5.6 g of 1- (2-methoxyphenyl) -cyclopropyl-carbonitrile are obtained, b.p. 104-115 ° C / 0.1 mbar, which is further developed as described for 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid. 3- [1- (2-Methoxyphenyl-cyclopropyl] -2-oxo-propionic acid is obtained as an oil.

The acids described in Table 2 were prepared analogously to the methods described for the preparation of 3- (1-phenylcyclobutyl) -2-oxopropionic acid and 3- [1- (2-methoxyphenyl-cyclopropyl] -2-oxopropionic acid.

Table 2.

Z ⁵

an example η Ζ ^η (* Η) T.T. (° C) 1 3-F butter 1 2-CI 60-63 1 4-CI butter 1 2-Nr 49-54 1 3-Nr butter 1 2,4-CI ₂ 185 - 190 1 3-OCH ₃ butter 3 3-CF 3 butter 3 butter 3 4-CH ₃ 50-61 4 4-OCH ₃ butter

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

Prepared analogously to the process for the preparation of 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid.

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

Prepared analogously to the process for the preparation of 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid.

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

To 4.2 ml of a solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran at -70 ° C was added 257 mg of copper bromide-dimethylsulfide complex and then stirred at -40 ° C for 20 min. It was cooled again to -70 ° C and 0.33 ml of 1.3 dimethyl-tetrahydro-2-1H-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs Annalen 1974 slowly added) , 477) and 0.71 ml trimethylchlorosilane in 3.5 ml tetrahydrofuran. It was stirred for 1 h at -70 ° C and allowed to warm to room temperature. Then 2 N hydrochloric acid and ethyl acetate were added, the ethyl acetate phase was separated, concentrated and the residue was dissolved in 5 in dichloromethane. After the addition of 200 mg of tetrabutylammonium fluoride, it was left at room temperature for 1 hour, washed with water, and the dichloromethane phase was dried over sodium sulfate and concentrated. Chromatography on silica gel eluting with hexane / ethyl acetate (97: 3) afforded 63 mg of 4- (3-methoxyphenyl) -4-methyl-2-oxo-valeric acid methyl ester. To it was added 1 ml of potassium hydroxide in methanol (10%). It was concentrated, the residue was dissolved in water and extracted with diethyl ether. The aqueous phase was acidified with 6 N hydrochloric acid and extracted with diethyl ether. The ether phase was dried over sodium sulfate and concentrated. 50 mg of 4- (3-methoxyphenyl) -4-methyl-2-oxo-valeric acid are obtained.

2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid

From magnesium 1.5 and 10 g of 2-methyl-2-phenylpropyl chloride in 100 ml of diethyl ether, a Grignard reagent is obtained which, upon reaction with 10 g of trifluorobenzic acid ethyl ester, yields 9.5 g of 2-hydroxy-4-methyl-4-phenyl- 2-Trifluoromethyl valeric acid. Since 90 ° C / 0.045 hPa.

7.5 g of ethyl ester was refluxed with 100 ml of potassium hydroxide in methanol (10%) for 18 h. After concentration in vacuo, the residue was dissolved in water and extracted with diethyl ether. The aqueous phase was acidified with 2 hydrochloric acid and extracted with diethyl ether. Concentration of the solvent gave 3.2 g of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid. M.P. 124-126 ° C.

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

1.3 g of anhydrous zinc chloride and 13.2 g of manganese grains in 100 ml of THF were refluxed with 0.2 ml of methyl bromide for 30 min. Then, a solution of 25 g of methyl bromide and 17 g of ethyl trifluorobenzic acid ethyl ester in 80 ml of THF was added under reflux for 2 h and refluxed for 1 h. Saturated ammonium chloride solution and 300 ml ethyl acetate were added under ice-cooling, stirred for 30 min at 0 ° C, and the separated ethyl acetate phase was washed with saturated ammonium chloride solution and three times with water. The solvent was dried over sodium sulfate and evaporated. The residue was distilled in vacuo to give 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester, m.p. 48 ° C / 1 hPa.

To 5 ml of 4-fluoroanisole and 0.9 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester was added 0.8 g of anhydrous aluminum chloride. After stirring at room temperature for 40 h, it was poured onto ice-cold 2 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with 1 N hydrochloric acid, dried over sodium sulfate and concentrated. Chromatography on silica gel eluting with hexane / ethyl acetate (1: 1) afforded 1 g of 4- (5-fluoro-2 ¹ θ methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester with mp 38-39 ° C.

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

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

In a similar manner, a mixture of 2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl-valeric acid and 2-hydroxy-4methyl-4- (3-thienyl-2-trifluoromethyl-valeric acid ( 9: 1) mp 150-151 ° C.

The acids of Table 3 were prepared analogously.

Table 3.

2?

Z (* H) mp (C) - 136 - 138 Z ^J = Z * = CH3 115 - 117 ζ ³ = ζ® = Ch ₃ 118 z ⁴ = Br 131 - 132 2 * ^ 75 133-135 - 140 - 141 2 ^g = OCH ₃ 98-99 ζ ⁴ = OCH ₃ 129 - 130

Ζ ^π (# H) mp HS) z ² = z ³ = 0CH ₃ 136 - 137 Ζ ² = OCH31 Ζ ⁵ = CH3 106 - 107 Ζ ² = OCH3, Z ⁴ = F 103 - 106 Z ² = OCH ₃ , Z ³ = F 102 - 104 Z ⁴ = OCH ₃₁ Z ² = F 122 - 124 By ⁴ FOCFVF ^ F 108 - 109 ζ ² = basic ₃₁ ζ ⁸ = α 103 105 Ζ ³ / Ζ ⁴ = (CHg) s 118 - 119 Ζ ³ / Ζ * = -CH = CH-CH = CH- 137 Ζ ² = OCH3, Ζ ⁴ = Br 115 - 116 Ζ ² = Br, Ζ ⁴ = OCHg 122 - 124 ζ ⁴ = C ₆ H ₅ 162 - 163 Ζ ² = OCH31 Ζ ⁴ = CH (CH3) 2 137 - 138

Other acids from the above acids or their intermediates are obtained by conversion to standard methods.

2-hydroxy-4-methyl-2-trifluoromethyl-4 (4-vinylphenyl) valerian xxelin. By heating 4- (4- (bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl vinyltin, trio-toluylphosphine and bis-tri-o-toluylphosphine-palladium-1-chloride by heating dimethylformamide at 120 ° C yields 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-vinylphenyl) -valeric acid ethyl ester which, upon alkaline saponification, gives the title compound, mp 73-74 ° S.

4- (4-acetylphenyl) -2-hydroxy-4-methyltrifluoromethyl-valeric acid

Analogous to the above 4- (4-bromophenyl) 2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1-ethoxyvinyltin, tri-o-toluylphosphine and bis-tri-o -toluylphosphine palladium-N-chloride in dimethylformamide at 120 ° C and subsequent acid hydrolysis in enolether and alkaline saponification to give the title compound, m.p. Mp 159-162 ° C.

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

Analogously to the above compound of 4- (4-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1-ethoxyvinyltin, tri-o-toluylphosphine and Bis-tri o-toluylphosphine-palladium-N-chloride in dimethylformamide at 120 ° C gave the title compound as an oil.

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

4- (4-Bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, zinc cyanide, and tetrakis-triphenylphosphine-palladium in dimethylformamide at 120 ° C and subsequent hydrolysis to give the title compound .

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

It is obtained by treating the ethyl ester of the above acid with hydrogen peroxide and saponifying it. M.P. Mp 244-245 ° C.

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

It is obtained 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 ° C. After saponification, the title compound is obtained as an amorphous powder.

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

It is obtained from 2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeric acid ethyl ester by bromination with N-bromosuccinimide in dimethylformamide at 0 ° C and subsequent saponification. M.P. 94-96 ° C.

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

This compound is obtained by reacting 2.5 g of 2-hydroxy-4- (4-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeric acid ethyl ester with 4 in 100% nitric 5 acid in 12 ml of trifluoroacetic acid over 1 h at 0 ° C. M.P. 79-80 ° C.

4- (4-Iodine-2-methoxyphenyl) -4 ~ methyl-2-oxovaleric acid

To 24.2 mmol of methylmagnesium bromide in 23 ml of 10 diethyl ether was added 3.2 g of methyl ester of

4-Iodine-2-methoxybenzoic acid in 10 ml of diethyl ether. After 20 h, ammonium chloride solution was added, the ether phase was separated, dried and concentrated. The resulting residue 15 (2.4 g) was dissolved in dichloromethane and 714 mg of 2-trimethylsilyloxyacrylic acid ethyl ester was added. Cool to -70 ° C and add 0.27 ml of tin (IV) chloride. After 15 minutes, the solution was poured into a solution of potassium carbonate. After extraction with diethyl ether, the organic phase is washed with water, dried and concentrated. 500 mg of 4- (4-iodide-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid ethyl ester thus obtained together with 8.6 ml of 1 M 25 sodium hydroxide in ethanol / water (2: 1, v / v) stirred for 3 h at room temperature. After the addition of water, it was extracted with diethyl ether, the aqueous phase was acidified with 1M hydrochloric acid and extracted with diethyl 30 ether. Drying and concentration gave 410 mg of 4- (4-iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid as a yellow oil.

4- (3-Chlorophenyl) -4-methyl-2-oxo-valeric acid 35

Obtained analogously to the method described above and is an amorphous powder.

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

Obtained analogously to the method described above and is an amorphous powder.

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

Obtained analogously to the method described above and is an amorphous powder. 45

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

Obtained analogously to the method described above and is an amorphous powder.

4- (4-Iodophenyl) -4-methyl-2-oxo-valeria-50-new acid

Obtained analogously to the method described above and is an oil.

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

Obtained analogously to the method described above with m.p. 58-60 ° C.

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

Obtained analogously to the above example and is an oil.

3- (1-Phenylcyclopentyl) -benzoic acid Prepared in analogy to the above example of 1-phenylcyclopentanol ethyl ester with 2-trimethylsilyloxy-acrylic acid and tin (IV) chloride as an oil.

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

From 2.6 g of magnesium chips with 15 ml of 2-phenyl-1-chloropropane in diethyl ether a Grignard solution was obtained to which 15 ml of oxalic acid diethyl ester was added over 30 min at -30 ° C. It is stirred for 1 h at -20 ° C and 2 h at 0 ° C and then a saturated solution of ammonium chloride is added. The diethyl ether phase was separated, dried over sodium sulfate and concentrated. It is distilled in vacuo. 17.7 g of 2-oxo-4-phenyl valeric acid ethyl ester are obtained, m.p. 98-100 ° C / 0.03 LPa.

4.4 g of 2-oxo-4-phenyl valeric acid ethyl ester was dissolved in 40 ml of tetrahydrofuran and 3.6 ml of trifluoromethyl-trimethylsilane and 2 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran were added at -78 ° C. After 24 h at -78 ° C, new 20 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran was added. It was stirred for 1.5 h at 0 ° C, ethyl acetate and saturated sodium chloride solution were added, the organic phase was separated and washed with saturated sodium chloride solution and water. It was dried over sodium sulfate and concentrated by distillation on a spherical apparatus. 4.4 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester are obtained, m.p. 95-100 ° C / 0.04 bPa.

4.35 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester was dissolved in 100 ml of diethyl ether and stirred at 0 ° C for 1 h with 1.3 g of lithium aluminum hydride and 16 h at room temperature. Under cooling, a little water was added and stirred for 1 h. The diethyl ether phase was separated, dried over sodium sulfate, concentrated and distilled on a spherical apparatus. 4.1 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol are obtained, b.p. 120 ° C / 0.04 bPa.

4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol in 30 ml of pyridine are mixed at 0 ° C with 3.8 g of 4-toluenesulfonic acid chloride. After 16 h at 0 ° C it was concentrated in vacuo, ethyl acetate was added, washed with water, dried with sodium sulfate and concentrated. Crystallization from ethyl acetate / hexane gave 4.9 g of 4-toluenesulfonic acid (2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl) ester. M.P. 95-96 ° C.

Analogously, the 4-toluenesulfonic acid 2-hydroxy-4methyl-4-phenyl-2-trifluoromethyl-pentyl ester was obtained, mp 78 ° C.

The 4-toluenesulfonic acid [4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentyl] ester of m.p. 80-81 ° C and [2-hydroxy-4- (2-methoxy-

4-Toluenesulfonic acid 5-fluorophenyl) -4-methyl-2-trifluoromethylpentyl ester, m.p. 93-95 ° C.

2- (2-phenylpropyl) -2-trifluoromethyl-oxane

35 mg of sodium hydride (80% in mineral oil) was added to 400 mg (2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl ester of 4-toluenesulfonic acid in 5 ml of dimethylformamide) at 0 ° C. The mixture is diluted with water and extracted with dichloromethane, the dichloromethane phase is washed with water, dried over sodium sulfate and concentrated, the residue distilled to give 200 mg of 2- (2-phenylpropyl-2-trifluoromethyl-oxane) with mp. k. 110 ° C / 1 hPa.

4-Bromo-5-aminophthalide g 3-bromo-4-nitro-1,2-xylene is suspended in 200 ml of pyridine and 600 ml of water and 260 g of potassium permanganate are added portionwise at 60 ° C, at which temperature rises to 90 "C. The mixture is heated at 95 ° C for 2 hours, filtered, the filtrate is acidified with hydrochloric acid and extracted with diethyl ether. Concentration of the solvent gave 27 g of 3-bromo-4-nitrophthalic acid.

g of this acid was heated at 220 ° C for 15 min and then distilled into a spherical apparatus. At 0.03 hPa, 10 g of 3-bromo-4-nitrophthalic acid anhydride were distilled.

The anhydride was dissolved in 120 ml of dimethylformamide and slowly added at 0 ° C to 78.8 ml of 0.5 molar sodium borohydride solution in dimethylformamide. After 3 h at 0 ° C, 2N hydrochloric acid was carefully added and extracted with ethyl acetate. Washing with potassium bicarbonate solution, drying over sodium sulfate and concentration of the ethyl acetate phase gave 6.6 g of 4-bromo-

5-nitrophthalide.

6.6 g of 4-bromo-5-nitrophthalide was dissolved in 45 ml of ethanol and added dropwise to 60 ° C with a mixture of 65 g of iron-N-sulfate, 220 ml of water and 65 ml of ammonia (33%) under vigorous stirring. . After 2 h at 60 ° C, the mixture was stirred five times with 200 ml of diethyl ether each. The ether phases are concentrated. The residue was obtained 4.1 g of 4bromo-5-aminophthalide, m.p. 176-180 ° C.

6-bromo-5-aminophthalide

4-Bromo-5-nitrophthalic acid anhydride was prepared analogously to the previous example of 4-bromo-5-nitro-1,2-xylene.

Boiling with ethanol yields a mixture of 2-bromo-6-ethoxycarbonyl-3-nitrobenzoic acid and 3-bromo-2-ethoxycarbonyl-

4- nitro-benzoic acid.

1.2 ml of oxalyl chloride were carefully added to a 7.2 ml 0.66 M solution of dimethylformamide in dichloromethane at 0 ° C. The solution was stirred for 1 h at 0 ° C and for 5 min at room temperature. After concentration in vacuo, the residue was suspended in 7 ml of acetonitrile, cooled to -35 &lt; 0 &gt; C and 1.5 g of an ester mixture were added thereto. After 1 h, the temperature was cooled to -70 ° C and a 2 M solution of sodium borohydride in dimethylformamide was added dropwise. Stirred for 20 h at room temperature. The diethyl ether phase was dried over sodium sulfate and concentrated. A mixture of

5- bromo-6-nitrophthalide and 6-bromo-5-nitrophthalide, which were separated with hexane / ethyl acetate (95: 5).

The reduction of the aminophthalide is carried out as described above. 6 Bromo-5-aminophthalide is obtained, m.p. Mp 235-241 ° C.

5-Amino-3- (1-propenyl) -phthalide 2-bromo-4-nitrobenzoic acid was refluxed for 2 hours with 30 ml of thionyl chloride and the distillation of excess thionyl chloride was converted to acid chloride, which dissolved in 50 ml. tetrahydrofuran was added dropwise to 3 ml of allylamine in 20 ml of tetrahydrofuran. After 20 h at room temperature, the reaction mixture was partitioned between 1N hydrochloric acid and ethyl acetate, the ethyl acetate phase was washed with water, dried over sodium sulfate and concentrated. The residue was crystallized from hexane. 5.6 g of 2bromo-4-nitrobenzoyl allamide are obtained, m.p. 98-1 ° C. 5 This material was dissolved in 35 ml of ethanol and added dropwise to a 60 ° C mixture of 50 g of iron-N-sulfate, 170 ml of water and 50 ml of ammonia (33%) under vigorous stirring. After 2 h at 60 ° C, the mixture was stirred five times with 10 200 ml of diethyl ether each. The ether phases were concentrated and the residue was crystallized from hexane. 3.1 g of allylamide and 4-amino-2-bromo-benzoic acid are obtained, m.p. 115-117 ° C.

g of 4-amino-2-bromo-benzo-15-ene allylamide, 5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid were refluxed for 1.5 h. The solution was then diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with potassium carbonate solution, dried over sodium sulfate and concentrated. The residue was crystallized from hexane. 13.4 g of b) -allyl-2-bromo-4- (2,5-dimethylpyrrol-1-yl) -benzamide are obtained, m.p. 136-138 ° C. 25

To 3 g of N-allyl-2-bromo-4- (2,5-dimethylpyrrol-1-yl) -benzamide in 100 ml of dimethoxyethane were added at -70 ° C 14.2 ml of 1,4 M butyllithium in hexane. After 30 min, 1.63 ml of crotonaldehyde was added at -70 ° C. The solution was allowed to warm to room temperature, stirred for a further 20 h, 50 ml of 50% acetic acid was added and heated at 60 ° C for 6 h. It is then diluted with water, extracted with ethyl acetate and the ethyl acetate phase washed with a solution of potassium carbonate. The ethyl acetate phase was dried over sodium sulfate and concentrated. The residue after chromatography on silica gel and eluting with hexanethyl acetate (98: 2) gave 1.1 g of crystalline 5- (2,5-dimethylpyrrol-1-yl) -3- (1-propenyl) -phthalide, m.p. 91-95 ° C.

1.1 g of 5- (2,5-dimethylpyrrol-1-yl) -3- (1-propenyl) -phthalide, 8.56 g of hydroxylamine hydrochloride and 4.58 g of potassium hydroxide in 75 ml of ethanol / water (16: 6 , 8 v / v) are heated for 24 h at 120 ° C. The solvent was distilled off, the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate phase was dried over sodium sulfate, concentrated and chromatographed on silica gel. It was eluted with dichloromethane / methanol (99: 1) to give 640 mg

5-amino-3- (1-propenyl) phthalide, m.p. 125130 ° C.

The phthalides of Table 4 were similarly prepared.

Table 4. *

χ ^ω / x ³⁶ M.P. SS) sn77n 152 - 156 dream ₃ / dream ₃ 94-97 _{5 g} of n / n 137-140 s ₂ n ₅ / s ₂ n ₅ 95 - 96 CH = CH ₂ / N 89-95 - (CIS) ₄ - 105 - 110

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

412 mg of 4-methyl-4-phenyl-2-oxovaleric acid was dissolved in 10 ml of dimethylacetamide and 261 mg of thionyl chloride was added to argon at -8 ° C. After stirring for 20 hours at -3 to + 3 ° C, 228 mg of 4-bromo-5-aminophthalide was added. It was stirred for 1.5 h at room temperature, water was added and extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate and after evaporation of the solvent and treatment with diethyl ether gave 360 mg of 4bromo-5 - ( 4-methyl-2-oxo-4-phenyl-valeroyl

but) -phthalide, m.p. 150-152 ° C.

Similar to the production of 4-bromo-

5- (4-Methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, the compounds of Tables 5 and 6 were prepared.

Table 5.

Example Z (* H) Τ. τ. (“0 Z ² = 1 205 - 207 Z ³ = Cl 170 - 171 Ζ ³ = Nr 168-169 Z ³ = 1 155 - 157

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

In analogy to the procedure described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) phthalide from 5-aminophthalide and 3- (phenyl-cyclopropyl) -2-oxo-propionic acid, the compound is obtained the title. M.P. 132-138 ° C.

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

In analogy to the method described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) phthalide from 5-aminophthalide and 3- (phenyl-cyclobuZ2-yl) -2-oxo-propionic acid, the compound is obtained from the title. M.P. 142-146 ° C.

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

In the same manner as the 4-bro25 mo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) phthalide of 5-aminophthalide and 3- (phenyl-cyclohexyl) -2-oxopropionic acid, the compound was prepared from the title. M.P. 120-123 ° C.

In the same way the compounds of Table 6 are obtained.

Table 6.

Example η Ζ ^η (* Η) Τ. τ. ft) 1 3-F 142 - 146 1 2-CI 148-151 1 4-CI 161 - 170 1 2-Βγ 172 - 178 1 3-Βγ 152-159 1 135 - 138 1 3-θθΗ ₃ 140 - 153 1 3-CF ₃ 166 - 170 3 140 144 3 4-CH ₃ butter 4 4-OCH ₃ 129 - 130

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

Prepared analogously to 4-bromo-5 (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide from 6-amino-4-methyl-2,3-benzoxazin-1-one and 5

3- (1-Phenyl-cyclopropyl) -2-oxo-propionic acid. M.P. Mp 197-100 ° C.

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

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

3- (1-Phenyl-cyclobutyl) -2-oxo-propionic acid. M.P. Mp 155-156 ° C.

6- (3- (1-Phenyl-cyclohexyl) -2-oxo-pro-15-pionylamino] -4-methyl-2,3-benzoxazin-1-one

Prepared analogously to 6- (3- (1-phenyl-cyclopropyl) -2-oxo-propionylamino] -4methyl-2,3-benzoxazin-1-one using

3- (1-Phenyl-cyclohexyl) -2-oxo-propionic acid 20. M.P. 132-134 ° C.

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

Prepared by the procedure described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -25 phthalide of 5-aminophthalide and 4,4-dimethyl-2-oxo-5-hexanoic acid .

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

Similar to the previous example of 2.0 g 30

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 is obtained

1.6 g of 6-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, m.p. Mp 148-150 ° C. 35

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

Obtained analogously to the descriptions for

4-Bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide process from 5-aminophthalide and 4- (4-40 iodine-2-methoxyphenyl) -4-methyl-2-oxo- valeric acid. Obtained in the form of a foam.

5- [4- (4-Iodophenyl) -4-methyl-2-oxo-valeroylamino] -phthalide 45

Obtained analogously to the descriptions for

4-Bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide process from 5-aminophthalide and 4- (4-iodophenyl) -4-methyl-2-oxo-valeric acid. Represents oil. 50

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

Obtained analogously to the 5-aminophthalide and 4- (3-iodophenyl) -4-methyl-2-oxo 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide method -Valeric acid. M.P. 160-161 ° C.

5- [4- (4-Bromo-2-methoxyphenyl) -2-oxaleroylamino] -phthalide

Obtained analogously to the 5-aminophthalide and 4- (4-bromo-2-methoxyphenyl) -2-oxo methods described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide -Valeric acid. M.P. 136-140 ° C.

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

Obtained analogously to the 5-aminophthalide and 3- (1-phenyl-cyclopentyl) -2-oxopropionate method described for 4-bromo-4- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide acid. M.P. 140-144 ° C.

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

Obtained analogously to the 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide method described in 4-methyl-2,3-benzoxazin-1-one and 4- (5- fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid. M.P. 171-173 ° C.

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

Prepared analogously to the 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide method described in 4-ethyl-2,3-benzoxazin-1-one and 4- (5- fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid. M.P. Mp 157-158 ° C.

6-amino-4-methyl-2,3-benzoxazin-1-one g 2-methyl-5-nitroacetophenone, 38.5 g of 2,2-dimethyl-1,3-propanediol and 6 g of p-toluenesulfonic acid in 1 1 toluene is boiled with a water separator until no more water is released. The solution was washed with potassium carbonate, dried over sodium sulfate and evaporated. Pentane gave 71.7 g of crystalline ketal. This compound was oxidized to 1.5 l of pyridine and 4.5 l of water with 350 g of potassium permanganate as described above to give 4-bromo-5-aminophthalide. It turns out

56.4 g of 4-nitro-2- (2,5,5-trimethyl-1,3-dioxan2-yl) -benzoic acid.

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

g of the amine with 100 ml of concentrated hydrochloric acid was refluxed for 2 h. The solvent was evaporated in vacuo and the residue was boiled with 15.7 g of hydroxylamine hydrochloride, 8.4 g of potassium hydroxide, 120 ml of ethanol and 50 ml of water for 12 h. It is diluted with water and the crystals are filtered off. After drying, 3.5 g of 6-amino-4-methyl-2,3-benzoxazin-1-one are obtained. M.P. 291-296 ° C.

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

Prepared analogously to 2-methyl-5nitropropiophenone. M.P. 89-93 ° C.

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

The preparation method is described in Heterocycles 36, 259 (1993).

5-amino-benz [1.2.5] oxadiazole

The method is described in Boll. Sci. Fac. Chim. Ind. Bologna, 22, 33, 36.37 (1964).

5-amino-benz [1.2.5] thiadiazole

The method is described in J. Heterocycl. Chem. 11, 777 (1974).

5-amino-1-indanone

The method is described in J. Org. Chem., 27, 70, (1962).

6- Amino-1,2,3,4-tetrahydro-1-naphthalinone The method is described in J. Org. Chem., 27,

70, (1962).

6-amino-3,4-dihydro-1H-2-benzopyran-1-one Prepared by catalytic hydrogenation (palladium on carbon) in ethanol from the corresponding nitro compound (Canad. J. Chem. 61, 2643 (1983)).

The following examples serve to illustrate the invention. Other compounds may be prepared using homologous or analogous reagents. The necessary starting compounds are described in the preceding examples as "starting compounds".

Example 1 (Method 1).

4-bromo-5- (2-hydroxy-4-methyl-4-phenyl2-trifluoromethyl-valeroylamino) -phthalide

350 mg of 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide were dissolved in 15 ml of dimethylformamide under argon and 0.77 ml of trifluoromethyl-trimethylsilane were added under ice-cooling. 350 mg of cesium carbonate. After stirring at room temperature for 3 hours, a 1 M solution of 5 tetrabutylammonium fluoride in tetrahydrofuran and a few drops of water was added in 5 ml and stirred at room temperature for 1 hour. After the addition of 100 ml of water, it was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and evaporated 10 times. 250 mg of 4-bromo-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino) -phthalide are obtained, m.p. 187-194 ⁰ p.

Example 2.

6-bromo-5- (2-hydroxy-4-methyl-4-phenyl15 2-trifluoromethyl-valeroylamino) -phthalide

Obtained analogously to Example 1 of

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. M.P. Mp 20 205-210 ° C.

Example 3.

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

Obtained analogously to Example 1 from 25 20 mg of 5- (4-methyl-2-oxo-4-phenyl-valeroylamino) -phthalide, 0.1 ml of trimethyl-pentafluoroethylsilane and 20 mg of cesium carbonate. M.P. 187-189 ° C.

Example 4.

5- [2-hydroxy-4- (3-methoxyphenyl) -4- (330 methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide

Obtained analogously to Example 1 from 30 mg of 5- [4- (3-methoxyphenyl) -4-methyl-2-oxaleroylamino] phthalide, 0.13 ml of trifluoromethylethyltrimethylsilane and 30 mg of cesium carbonate. M.P. 173-178 ° C.

Example 5.

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

Obtained analogously to Example 1 of

200 mg of 5- (4,4-dimethyl-2-oxo-5-hexanoylamino) -phthalide, 0.22 ml of trifluoromethyl-trimethylsilane and 258 mg of cesium carbonate. M.P. Mp 153-157 ° C.

Analogously to Example 1, 45 compounds of Table 7 were obtained.

Table 7.

Example P. Z ⁿ (0 H) TTTS) isomerism 6 1 168 - 175 the racemate 7 1 172 - 179 (+) - enantiomer 8 1 172 - 179 (-) - Enantiomer 9 1 3-F 155 - 158 the racemate 10 1 2-CI 192 - 194 the racemate 11 1 4-CI 148-154 the racemate 12 1 4-CI 174 - 176 (+) - enantiomer 13 1 4-CI 173 - 175 (-) - Enantiomer 14 1 2-Br 163 - 165 the racemate 15 1 C-Br 189 - 191 the racemate 16 1 2C £ 216 - 218 the racemate 17 1 2-OCH ₃ 200 - 208 (+) - enantiomer 18 1 2-OCH ₃ 195 - 208 (-) - Enantiomer 19 1 3-OCH ₃ 225 - 228 the racemate 20 1 3-CF of 152 - 163 the racemate 21 2 182 - 188 the racemate 22 2 187 - 192 (+) - enantiomer 23 2 188 - 192 (-) - Enantiomer 24 3 106 - 112 (+) - enantiomer 25 3 4-CH ₃ 179 - 183 the racemate 26 4 165 - 171 the racemate 27 4 170 - 174 (+) - enantiomer 28 4 170 - 174 (-) - Enantiomer

If Example 1 used 6-amino-4-methylbenzoxazinone instead of aminophthalide, then the compounds described in Table 8 were obtained.

Table 8.

Example η —- isomerism 29 1 78-84 the racemate 30 1 227 - 23 & (+) - enantiomer 31 4 230 - 239 (-) - Enantiomer 32 έ 174 - 184 the racemate 33 4 185 - 187 the racemate 34 4 90-97 (+) - enantiomer 35 4 90-96 () * Enantiomer

Table 9.

Jimer 2 ^L (# H) TTTS) 36 ζ ² = ι amorphous 37 174 38 T = Br 182 -183 39 2 ³ = 1 190 - 191

Example 40

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

To 72 ml of 6- (4-methyl-4-phenyl-2-oxo-valeroylamino) -4-methyl-2,3-benzoxazin-1-one in 4 ml of tetrahydrofuran was added 3 ml of methylmagnesium bromide (3 molar) at 0 ° C. After 30 min ammonium chloride solution was added, the organic phase was separated, dried and evaporated. Chromatography on silica gel (hexane / ethyl acetate 1: 1) gave 39 mg of 6- (2-hydroxy-2,4-dimethyl-phenyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-one, m.p. 173-175 ° C.

Example 41 (Method 2).

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

To 500 mg of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid (Eur. Anm. 0 253 500 (Imperial Chemical Industries) in 10 ml of dimethylacetamide at -15 ° C was added

0.14 ml of thionyl chloride. After stirring at -15 ° C for 3 h, 600 mg of 5-aminophthalide 20 (solid) was added. The solution was stirred for 2 h at -15 ° C and left for 18 h at room temperature. Water was then added and extracted with ethyl acetate. The ethyl acetate phase was dried over sodium sulfate and evaporated. The residue was taken up in diethyl ether and filtered. 290 mg of 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -phthalide are obtained, m.p. Mp 166-168 ° C. Example 42.

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

Prepared 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-benzoxy55-sazin-1-one. M.P. 172-173 ° C.

The compounds of Table 10 were prepared analogously to Example 41.

Table 10.

at- mayor Fr W Χ ^η (# Η) Ζ ^η (* H) Melting point (° C) isomerism, respectively [a] _o (c = 0.5) (2) 43 Η 0 X ^3d / X ^3b = H / CH ₃ 175-185 diast. a mixture 44 Η 0 _X 3a ₌ n _X 3b _{= CH3} 175-178 + 22.5 45 Η 0 X ° * = H, χΛ- _{= 0Η3} 210-213 -74 46 Η 0 X ^3tt = CH _3t X ^3b = H 210-213 -69.5 47 Η 0 X ^3a = CH ₃ , Χ ^ = Η 175-179 -21.5 48 Η 0 χ ° “= s _g n ₅ 169-174 49 Η 0 x ^3x = CH = CH ₂ 162-174 50 Η 0 X = CH = CH ₂ - CH ₃ 160-162 51 Η 0 X ^3a = CF ₃ 156-166 52 Η ό CH »X ^x = CH ₃ 160-171 53 Η 0 χ ^3α = X ^3b = C ₂ H ₅ 172-176 54 Η 0 X ^3d + X ^3b = (CH ₂ ) ₄ 168-170 55 Η 0 180-185 56 dream ₃ 0 159-162 57 CH ₃ 0 Χ * Ξ ~ Βτ 187-194 58 dream ₃ 0 Ζ ² = CH3 155-156 the racemate 59 dream ₃ 0 ζ ² = dream ₃ 148-149 (+) - form 60 CH ₃ 0 Ζ ² = CH ₃ 145-146 (-) - form

at- mayor R ² W X ⁿ (# H) Ζ ^π (* H) T. t. (° C) isomerism, resp. [a] _o (c = 0.5) (2) 61 CH ₃ 0 ζ ⁴ = dream ₃ 189-190 62 CH ₃ 0 Ζ ³ = Ζ ⁴ = dream ₃ 206-207 the racemate 63 CH ₃ 0 Ζ ³ = Ζ ⁴ = CH ₃ 207-209 (+) - form 64 dream ₃ 0 Ζ ³ = Ζ ⁴ = dream ₃ 207-209 (-) - form 65 dream ₃ 0 ζ ³ = ζ ⁵ = dream ₃ 154 the racemate 66 CH ₃ 0 ζ ³ = ζ ³ = dream ₃ 188-189 (+) - form 67 CH ₃ 0 ζ ² = ζ ⁵ = dream ₃ 188 (-) - form 68 dream ₃ 0 Z ³ / Z ⁴ = (CH ₂ ) ₃ 171-173 69 CH ₃ 0 z ³ / z ⁴ = CH = CHC = CH- 218-219 70 dream ₃ 0 177-178 71 CH ₃ 0 Ζ * Ξϋϊ 184-185 72 CH ₃ 0 Ζ * ΞΒ} 177-179 73 dream ₃ 0 Z ² = OCH ₃ 134-135 the racemate 74 dream ₃ 0 ζ ⁴ = base ₃ 183-184 75 CH ₃ 0 Ζ ² = Ζ ⁵ = base ₃ 145 76 dream ₃ 0 Ζ ² = OCH ζ ⁵ = CH ₃ 126-127 the racemate 77 dream ₃ 0 ζ ² = OCH ₃ ζ ⁵ = Option ₃ 169-170 (+) - form 78 dream ₃ 0 ζ ² = bas 3 ζ ⁵ = ch 3 169 (-) - form 79 CH ₃ 0 Z ² = OCH ₃ Z ⁴ = F 180-181 80 CH ₃ 0 Z ² = OCH ₃ Z ⁵ = 'F 140-141

an example R W X ⁿ (# H) Z ⁿ (* H) Τ. τ. (° C) isomerism, respectively [a] _o (¢ = 0.5) (2) 81 dream ₃ 0 Z ⁴ = OCH ₃ Z ² = F 207 82 dream ₃ 0 Z ⁴ = OCH ₃ Z ³ = F 178-179 83 dream ₃ 0 Z ² = OCH ₃ Z ⁵ = CI 141 the racemate 84 SN ₃ 0 Z ² = OCH ₃ Z ⁵ = CI 106-108 +105.5 (1) 85 dream ₃ 0 Z ² = OCH ₃ Z ⁵ = CI 105-207 -97 (1) 86 n S 189-191 87 CH ₃ S 173-175 88 n dream ₂ 161-162 89 n 0 - dream ₂ (3) 192-195 90 CH ₃ 0 with ⁴ = ch = ch ₂ 190-192 the racemate 91 CH3 0 Z * = CN 230-233 the racemate 92 dream ₃ 0 Z ⁴ = COCH ₃ 174-176 the racemate 93 dream ₃ 0 with ⁴ = conh ₂ 130-132 94 dream ₃ 0 Z ² = OCH ₃ Z ⁴ = Art 144-145 the racemate 95 dream ₃ 0 Z ² = OCH ₃ Z ⁴ = Art 176-177 (+) - enantiomer 96 CH ₃ 0 Z ² = OCH ₃ Z ⁴ = Art 177-178 -139.6 97 CH ₃ 0 Z * = Nr 197-198 the racemate

an example Ft W X ⁿ (* H) Z (# H) Τ. τ, and ° C) isomerism, respectively [a] _o (c = 0.5) (2) Z ⁴ = OCH ₃ 98 0 “T-OsnG z⁴= cn 135-136 the racemate 99 SIG 0 ζ ³ = νο ₂ Z ⁴ = OCH ₃ 202-206 the racemate 100 W Z ² = O CH ₃ = CH (CH 3) ₂ 135 the racemate 101 CH3 0 : ³ = cos ³ Z ⁴ = OCH 3 213-214 the racemate

(1) The optically active compounds of Table 10 were separated analogously to Example 88.

(2) in methanol (3) formation of 1-isochromanone. Example 102

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

The enantiomeric mixture of Example 73 was separated by chromatography on a chiral support material (Chiralpak AD, Fa Daicel) with hexane / 2-propanol / ethanol (900: 25: 25 v / v). Or 200 mg of racemate are obtained:

mg (-) - form with m.p. 136-137 (R), [α] = 194.8 (c = 0.5 in chloroform), mg (+) - m.p. 135-136 C, [a] = + 192.2 (c = 0.5 in chloroform).

Example 103

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

A mixture of 2-hydroxy-4-methyl-4- (2-thienyl) -2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeric acid (9: 1) converted to 5-aminophthalide analogously to Example 41. After chromatographic separation of the position 20 isomers and separation of the racemates, analogously to Example 102, the following were obtained:

(+) 5- [2-Hydroxy-4-methyl-4- (2-thienyl) 2-trifluoromethyl-valeroylamino] phthalide, m.p.

166 (C) = + 163.6 (c = 0.5 in chloroform), (-) 5- [2-hydroxy-4-methyl-4- (2-thienyl) 2-trifluoromethyl-valeroylamino] phthalide with m.p. .t. 166 (C) = -160.8 (c = 0.5 in chloroform), (+) 5- [2-hydroxy-4-methyl-4- (3-thienyl) -23θ trifluoromethyl-valeroylamino] phthalene mp. t. 135 C and (-) 5- [2-hydroxy-4-methyl-4- (3-thienyl) -2-trifluoromethyl-valeroylamino] phthalide, m.p. 135 p.

Example 104 (Method 3).

5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide

To 760 mg of 5-acetamido-phthalide in 20 ml of dimethylformamide were added at 0 ^and C 144 mg of sodium hydride (80% in mineral oil) and after 20 min 800 mg (2-hydroxy-4-phenyl-240 trifluoromethyl-pentyl) ester of 4-toluenesulfonic acid. After 16 h at 60 ^and C, the solvent was distilled off in vacuo, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and evaporated. Chromatography on silica gel with cyclohexane / ethyl acetate (2: 1) afforded 266 mg of 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide, m.p. 110 ° C.

The compounds of Table 11 were prepared analogously to Example 104.

Table 11.

at- mayor FT W Z (* H) t T. № isomerism, respectively [a] _o (c = 0.5) (2) 105 N. 0 110 the racemate 106 N. 0 123 +18.6 107 n 0 123 -18.4 108 CH ₃ 0 139-140 the racemate 109 TNG 0 159-160 +12.0 (4) 110 CH3 0 160-161 -12.5 (4) 111 CH3 0 Z ⁴ = F 148-149 the racemate 112 Tng 0 z ⁴ = f 162-164 +9.0 113 CH3 0 z ⁴ = f 162-164 -6.7 114 CH3 0 Z ² = OCH ₃ , Z ° = F 148-149 115 n dream ₂ 161-162 116 n OCH3 (3) 127-128

(1) The optically active compounds of Table 11 were separated analogously to Example 102;

(2) in methanol;

(3) formation of 1-isochromanone;

(4) in chloroform.

Example 117.

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

The compound was prepared analogously to Example 104 of 151 mg of 6-acetamido-4-ethyl-2,3-benzoxazin-2-one, 208 mg (2-hydroxy-4-phenyl2-trifluoromethyl-pentyl) 4-toluenesulfonic acid ester and 36 mg sodium hydride. M.P. 161-163 ° C.

Example 118.

1- (4-Nitro-3-trifluoromethylanilino) -4- 50 phenyl-2-trifluoromethyl-2-pentanol

To 100 ml of 4-nitro-3-trifluoromethyl35 cetanylide in 2 ml of dimethylformamide at 0 ° C was added 12 mg of sodium hydride (80% in mineral oil) and after 20 minutes 150 mg of 2- (2-phenylpropyl) -2-trifluoromethyl-oxane. It was stirred for 16 h at 60 ° C, diluted with water and extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over sodium sulfate and evaporated. 80 mg of N (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroyl) -4-nitro-3-trifluoromethylaniline m.p. 119-120 ° C.

Following separation of the racemate according to Example 102, the following were obtained:

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

Example 119 (Method 4).

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

150 mg of the compound of Example 2 together with 30 mg of 2-methyl-3-butin-2-ol, 0.24 mg of copper-1-iodide and 0.9 mg of triphenylphosphine were dissolved in 1.5 ml of pyridine and in atmosphere 0.25 mg of bis-triphenylphosphine-palladium-N-chloride was added to argon. After refluxing for 5 h, new 30 mg of 2-methyl-3-butin-2-ol was added and refluxed for 20 h. It is diluted with water and extracted with ethyl acetate. The ethyl acetate phase was dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel, eluting with cyclohexane / ethyl acetate (1: 1). 60 mg of crystalline 6- (3-hydroxy-3-methyl-1-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl2-trifluoromethyl-valeroylamino) -phthalide are obtained. Mp 162-168 ° C.

Example 120.

6-acetyl-5- (2-hydroxy-4-methyl-4-phenyl2-trifluoromethyl-valeroyl) -phthalide

100 mg of the bromo compound of Example 2 together with 95 mg of tributyl- (1-ethoxyvinyl) -tin and 8 mg of bis-triphenylphosphine-palladium-5-di-N-chloride were dissolved in 4 ml of toluene under argon. After 5 h reflux, new 45 mg of bis-triphenylphosphine-palladium-II-chloride were added and refluxed for another 20 h. 1N chloro 10 hydrochloric acid was added and extracted with ethyl acetate. The ethyl acetate phase was dried over sodium sulfate and evaporated. The crude product was stirred in 3 ml of tetrahydrofuran and 3 ml of 2N hydrochloric acid for 2 days at room temperature. Water was added and extracted with ethyl acetate. After washing with water, it is dried over sodium sulfate and evaporated. The residue was triturated with diethyl ether / pentane to give 21 mg of crystalline 6-acetyl-5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroyl) -phthalide, m.p. Mp 195-199 ° C.

In analogy to Examples 119 and 120, the compounds of Table 12 were prepared.

Table 12.

Example X (* H) Z (* H) τ. T. co 121 x ⁴ = CH = CH ₂ foam 122 x ° = CH = CH ₂ 191 - 197 123 .X ^e = C (0C _g H5) = CH ₂ 160 - 163 124 X ⁶ = C = C-CH ₂ OH 208 - 211 125 x ° = c ₆ n ₅ 160 - 163 126 II «O <X ' 157 - 158 127 X ^and = C ₆ H ₄ OCH ₃ (p-) 125 - 127 128 z ³ = CH = CH ₂ 178 - 180 129 Z ³ = c ₂ n ₅ (*) 152 - 153 130 z ³ = cOCh ₃ (**) 220 131 Ζ * ΞϋΝ 112 132 ζ ⁴ = He = dream _g 190 - 192 133 Z ⁴ = COCH ₃ (** j 205 - 207

(*) is obtained by catalytic hydrogenation of the vinyl compound (· *) is obtained by soft acid hydrolysis of the enoleter.

Example 134 (Method 5). 5

5- [4- (3-Fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] -phthalate

132 mg of 5- [4- (3-fluoro-4-hydroxyphenyl) 2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] -phthalate (Example 82) was dissolved in 15 ml of dichloromethane and at 0 ° C. added 1.2 ml of a 1M solution of bortribromide in dichloromethane. After 16 h at 0 ° C, a mixture of ice, ethyl acetate and potassium carbonate was added and the ethyl acetate phase was separated, dried over sodium sulfate and evaporated. Ethyl acetate / diisopropylether / hexane afforded 120 mg of 5- [4- (3-fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] -phthalate, m.p. 139-140®C.

The compounds of Table 13 were prepared in analogy to Example 86.

Table 13.

an example IN Z ⁿ (# H) TTTCj isomerism, CbOTB. [a] _D (c = 0.5) (2) 135 c = o z ² = he 222 - 224 136 c = o z ⁴ = he 228 - 230 137 0 = 0 Z ² = Z ⁹ = OH 265 - 267 138 c = o Z ² = OH, Z ³ = CH ₃ 215 - 217 the racemate 139 c = o Z ² = OH, Z ³ = CH ₃ 173 - 174 (+) - form 140 c = o Z ² = OH, Z ³ = CH ₃ 173 - 174 (-) - form 141 c = o Z ² = OH, Z ⁴ = F 240 - 242 142 c = o Z ² = OH, Z ³ = F 201 202 143 c = o Z ⁴ = OH, Z ² = F 242 - 243 144 0 = 0 Z ² = OH, Z ⁵ = Cl 220 - 221 145 the dream of _Mr Z ² = OH, Z ⁵ = F 156 - 157 the racemate 146 the dream of _Mr Z ² = OH, Z ° = F 157 - 159 + 23.5 147 dream ₂ Z ² = OH, Z ^a = F 157 - 159 -18.7 148 c = o Z ² = OH, Z ⁴ = Br 224 - 226 the racemate 149 0 = 0 z ³ = no ₂ , Ζ ** = OH 167-169 the racemate 150 0 = 0 2 ^J = CI, 'r = OH 108 - 1 & the racemate 151 z ³ = XT ¹ »oh 105 the racemate

(1) The optically active compounds of Table 13 were separated analogously to Example 102.

(2) In methanol.

Example 152.

5- [4- (3-Fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalene ml (3-fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl- valeroylamino-phthalide with 126 mg potassium carbonate and 108 mg 5-chloro-1-phenyl-1H-tetrazole in 3 ml dimethylformamide was stirred for 16 h. The dimethylformamide was then distilled in vacuo and the residue partitioned between 1N hydrochloric acid and ethyl acetate. After washing with water, the ethyl acetate phase is dried over sodium sulfate and distilled off, the residue being chromatographed on silica gel with eluent hexane / ethyl acetate (1: 1). The product was hydrogenated in 10 ml of methanol with 30 mg palladium on carbon (10%). After removal of the catalyst and distillation of the solvent, the residue was chromatographed on silica gel with eluent hexane / ethyl acetate (1: 1). 49 mg of 5- [4- (3-fluorophenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] -phthalide, m.p. 157 ° C.

Separating the racemate analogously to Example 102 gave the (+) form with m.p.

140-141 ° C and the (-) - form, m.p. 141 ° C.

Example 153.

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

The compound was prepared analogously to the previous example of 57 mg of 5- [2-hydroxy-4 (2-hydroxy-5-methyl phenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide. M.P. Mp 152-153 ° C.

Separating the racemate analogously to Example 102 gave the (+) form with m.p. 148-149 ° C and (-) - form with m.p. 145-146 ° C.

Example 154.

5- [4- (5-Fluoro-3-ethoxyphenyl) -2-hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] -phthalide mg 5- [4- (5-fluoro-3-hydroxyphenyl) 2 -hydroxy-4-methyl-4-2-trifluoromethyl-valeroylamino] phthalide in 1 ml of dimethylformamide, 28 mg of potassium carbonate and 50 mg of ethyl iodide were stirred for 20 h at room temperature. Water was added, extracted with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate and evaporation of the solvent gave 35 mg of 5- [4- (5-fluoro25 3-ethoxyphenyl) -2-hydroxy-4- methyl-4-2-trifluoromethyl-valeroylamino] -phthalide, m.p. 108 ° C.

In analogy to Example 154, the compounds of Table 14 were prepared.

Table 14.

Example R ...... t: t co isomerism, respectively, [a] _o (0 = 0.5) (2) 155 CH (CH3) ₂ 154 - 154 the racemate 156 0H ₂ CH = CH ₂ 152 the racemate 157 SSCH = US 187 - 189 the racemate 1b8 CH ₂ Cl 1 / U - '1/2 —Draw— 159 CH ₂ SOOS (CH 3) ₃ 145 the racemate 160 CH _g SOOO (CH 3) ₃ 143 -131.5 161 CH ₂ SOOS (CH 3) ₃ 142 - 143 (+) - form

Example 162.

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

4- methyl-2-trifluoromethyl-valeroylamino] -phthalide in 1.5 ml of methanol and 20 mg of N-chlorosuccinimide were stirred for 5 h. The mixture was partitioned into ice water, sodium bicarbonate solution and ethyl acetate, the ethyl acetate phase was separated, dried and evaporated. That is how it happens

5- [4- (3-Chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide which, after recrystallization from isopropyl ether, melts at 189-191 ° C.

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

It is obtained from 5- [4- (3-chloro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide by cleavage of the ether according to Example 134. 105 ° C.

According to the method described above, the 2,3-benzoxazine and phthalosinone derivatives of Table 15 are obtained.

an example Ft V Ζ ^η (# Η) B Y ⁿ (# H) Τ. τ. (° C) isomerism, respectively [a] _o (¢ = 0.5) (2) 163 N. 0 c = o Y ⁴ = CH ₃ 165-166 the racemate 164 N. ό c = o Y ⁴ = C ₂ H ₅ 159-160 the racemate 165 CH3 0 c = o Y ⁴ = CH 3 185 +162 166 CH ₃ 0 c = o y ⁴ = CH ₃ 184-185 -182 167 W 0 c = o Y ⁴ = C ₂ H ₅ 148-153 the racemate 168 CH ₃ 0 c = o Y ⁴ = C ₂ H ₅ 159-160 +173 169 SN ₃ 0 c = o Y ⁴ = C 2 H ₅ 159-160 -175 170 CH ₃ 0 Z ^z = OCH ₃ c = o Y ⁴ = CH 3 161-163 the racemate 171 CH3 ό Z ² = OCH ₃ c = o Y ⁴ = CH 3 173-175 -54.7 (3) 172 W 0 Z ^z = OCH ₃ c = o Y ⁴ = Ch ₃ 173-175 +52.2 173 CH ₃ 0 Z ² = OCH ₃ c = o Y ⁴ = C ₂ H ₅ 164 the racemate 174 CH3 0 Z ^z = OCH ₃ c = o Y ⁴ = C ₂ H ₅ 190-191 (+) - form 175 W 0 Z ² = OCH ₃ c = o Y ⁴ = C ₂ H ₅ 190-191 -161.3 (CHCI3) 176 W 0 Z ^z = OCH ₃ z ⁵ = f c = o Y ⁴ = CH ₃ 165 the racemate 177 CH ₃ 0 Z ² = OCH ₃ z ⁵ = f c = o Y ⁴ = CH 3 188-189 (+) - form 178 CH ₃ 0 z ² = och ₃ z ⁵ = f c = o Y ⁴ = CH 3 187-188 -132.8 (CHC1 ₃ )

an example Ft V Z (# H) B Y ⁿ (# H) Τ. τ. (° C) isomerism, respectively [a] _o (c = 0.5) (2) 179 dream ₃ 0 Z ² = OCH ₃ z ⁵ = f c = o Y ⁴ = C ₂ H ₅ 126-128 the racemate 180 CH3 0 Z ² = OCH ₃ Z ⁵ = F 0 = 0 Y ^ h ₈ 170-171 -147.4 181 CH ₃ 0 Z ² = OCH ₃ Z ⁵ = F c = o Y '= c ₂ H ₆ 171 (+) - form 182 CH ₃ 0 Z ² = OCH ₃ Z ⁵ = CI c = o y ⁴ = CH ₃ 182-184 the racemate 183 CH ₃ 0 Z ² = OCH ₃ Z ⁵ = CI 0 = 0 Y ⁴ = CH ₃ 198-199 (+) - form 184 dream ₃ 0 Z ² = OCH ₃ Z ⁵ = CI 0 = 0 Y ⁴ = CH ₃ 197-198 -90.2 185 dream ₃ 0 ^r Z ² = 0CH ₃ Z ⁴ = Art 0 = 0 Y ⁴ - CH ₃ 206-207 the racemate 186 dream ₃ 0 Z ² = OCH ₃ Z ⁴ = Art 0 = 0 Y ⁴ = CH ₃ 194-198 (+) - form 187 CH ₃ 0 Z ² = OCH ₃ Z ⁴ = Art c = o Y ⁴ = CH ₃ 196-198 -122.2 (SNAU 188 dream ₃ 0 Z ⁴ = CH ₃ 0 = 0 Y ⁴ = CH ₃ 222-223 the racemate 189 dream ₃ 0 Z ⁴ = CH ₃ 0 = 0 Y ⁴ = C ₂ H ₅ 187-188 the racemate 190 dream ₃ 0 Z ⁴ = CH ₃ c = o Y ⁴ = C ₂ H ₅ 160 -63.7 191 CH ₃ 0 Z ⁴ = CH ₃ c = o Y ⁴ = C ₂ H ₅ 160 (+) - form 192 dream ₃ 0 Z ⁴ = F c = o Y ⁴ = CH ₃ 188-190 the racemate 193 dream ₃ 0 Z * = Nr 0 = 0 Y ⁴ = CH ₃ 219-220 the racemate 194 dream ₃ 0 ? = Br c = o Y ⁴ = CH ₃ 231-233 -49.3 195 dream ₃ 0 Ζ'Ξβί 0 = 0 Y ⁴ = CH ₃ 231-233 (+) - form 196 dream ₃ 0 c = o Y ⁴ = CF ₃ 175-183

an example R ^{1 2} V Ζ ^π (* Η) B Y (* H) Τ. τ. (° C) isomerism, respectively [a] _o (c = 0.5) (2) 197 dream ₃ NH c = o y ⁴ = CH ₃ 198 CH ₃ N-dream ₃ c = o Y ⁴ = CH ₃ 199 SN ₃ 0 Ζ ² = ΟΗ, with ⁵ = f c = o Y ⁴ = CH ₃ 234-236 the racemate 200 CH ₃ 0 Z ² = OH, z ⁵ = f c = o Y ⁴ = CH ₃ 232-234 (+) - form 201 dream ₃ 0 Z ² = OH, z ⁵ = f c = o y ⁴ = CH ₃ 232-234 -34.1 202 CH ₃ 0 z ² = oh, Z ⁴ = Br c = o Y ⁴ = CH ₃ 248-250 the racemate 203 CH ₃ 0 z ³ = no2, Z ⁴ = OCH3 ¢ = 0 y ⁴ = CH ₃ 215-217 the racemate 204 n 0 CH ₂ Y ⁴ = CH ₃ 148-149 the racemate 205 CH3 0 CH ₂ Y ⁴ = CH 3 132-133 the racemate 206 CIS 0 CH ₂ Y ⁴ = c ₂ H ₅ 121-122 the racemate

(1) The optically active compounds of Table 15 were separated analogously to Example 102 (2) in methanol

Example 207.

5- (2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -benz [1.2.5] oxadiazole

The compound was prepared analogously to Example 41 from 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid and 5-aminobenz [1.2.5] oxadiazole. M.P. 192 ° C.

Example 208.

5- (2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino) -benz [1.2.5] thiadiazole

The compound was prepared analogously to Example 41 from 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid and 5-aminobenz [1.2.5] thiadiazole. M.P. 166-167 “p.

Example 209.

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

The compound was prepared analogously to Example 41 from 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid and 6-amino-1-methyl-benzotriazole. M.P. 194-196 ° C.

Claims (18)

Claims Compounds of general formula (I) wherein R ¹ and R ² are the same or different and represent a hydrogen atom, a C _1-5 alkyl group or a halogen atom or together with the C-atom of the chain form a 3-7 membered ring together; R ³ represents a C 1-6 alkyl group or a fully or partially fluorinated C ₁₅ alkyl group; A means optionally having one or more residues selected from halogen atoms, a C ₁₅ alkyl group, a C ₁₅ alkenyl group - CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently one of the another means hydrogen or a C _1-5 alkyl group, a hydroxyl group, hydroxyl groups bearing a C ₁₁₀ acyl group, C ₃ . ₁₀ carbalkoxy alkyl group, C ₂ . ₅ cyanoalkyl group, C _{3 0} unsubstituted or substituted allyl group, C ₃₁₀ unsubstituted or substituted propargyl group, C ₂₅ alkoxyalkyl group, wholly or partially substituted with fluorine atoms C ₁₅ alkyl group, with cyan or nitro group, C ₁₅ alkoxy groups, alkylthio groups, mono or disubstituted C ,. ₁₀ amine groups or partially or fully fluorinated C _1-5 alkyl groups substituted by a mono- or bicyclic, carbocyclic or heterocyclic aromatic ring, 5 B represents a carbonyl or CH ₂ group, and Ar means a ring system selected from the group of general partial formulas 2 through 11: 5 6 7 in which the residues X ^3a , X ⁴ , X ⁶ , X ⁷ (in the roxyl group, partially or wholly the fluo · partial formula 2), X ⁴ , X ⁶ , X ⁷ (in the partial formulas 3 and 4), X ^3a , X ^3b , X ⁴ , X ⁶ , X ⁷ (in partial formulas 5, 6 and 7) or Y ⁴ , Y ^s , Υ ⁷ , Y ⁸ (in partial formulas 8, 9, 10 and 11) can be identical or different and selected from hydrogen atoms, C ₁₅ alkyl groups, which may optionally further comprise a C ₁₅ alkyl group esterified or a C ₁₅ alkanoyl group esterified hydrogenated C ₁₅ alkyl groups, C ₂ . ₅ alkenyl groups -CR ^ CR * ^ ⁷ , wherein R ⁵ , R ⁶ and R ⁷ have the above meaning, alkynyl groups -C = CR ⁵ in which R ^J has the above meaning, residues X ^3a and X ^h may further, together with the C-atom of the benzocondensed ring system 5, 6 or 7, form a 3-7 membered ring as well as residues X ⁴ , X ⁶ , X ⁷ (in partial formulas 2, 3, 4, 5, 6 and 7) or Y ⁴ , Υ ⁵ , Υ ⁷ , Y ⁸ (in partial formulas 8,9, 10 and 11) may be halogen atoms, hydroxyl groups, C _{| 5} alkoxy groups or C ₁₃ alkanoyl groups, and the physiologically acceptable salts of the compounds of general formula I with acids. Compounds of general formula I according to claim 1 in the form of racemates or mixtures of diastereomers. Compounds of general formula I according to claim 1 in the form of separated optical isomers. Compounds of general formula I according to claim 1, wherein R ¹ and R ² are the same or different and represent a hydrogen atom, a methyl or ethyl group or together with the C-atom of the chain form a general cyclopropyl ring. Compounds of general formula I according to claim 1, wherein R ³ is a C ₁₃ perfluoroalkyl group. Compounds of general formula I according to claim 1, wherein A represents optionally one or more residues selected from among fluorine, chlorine, bromine atoms, metal groups, ethyl groups, vinyl groups, hydroxy groups, methoxy groups, ethoxy groups substituted benzene, naphthalene or thiophene ring. Compounds of general formula I according to claim 1, wherein X ³ represents hydrogen or a C _1-4 alkyl group. Compounds of general formula I according to claim 1, wherein X ³ ° and X ³ are the same or different and represent hydrogen or a C _1-5 alkyl group. Compounds of general formula I according to claim 1, wherein X ⁴ , X ⁶ and X ⁷ are the same or different and independently represent a hydrogen or halogen atom. Compounds of general formula I according to claim 1, wherein Y ⁴ is a C _1-5 alkyl group or a C ₁₃ perfluoroalkyl group. Compounds of general formula I according to claim 1, wherein Υ ⁵ , Y ⁷ and Y ⁸ are the same or different and independently represent a hydrogen or halogen atom. Compounds of general formula I according to claim 1, wherein R ¹ and R ² are the same or different and represent a hydrogen atom, a methyl or ethyl group or together with the chain atom form a general cyclopropyl ring, R ³ means a C ₁₃ perfluoroalkyl group , A means optionally with one or more residues selected from fluorine, chlorine, bromine atoms, metal, ethyl groups, vinyl groups, hydroxy, methoxy, ethoxy groups substituted benzene, naphthalene or thiophene ring and / or X ³ "is hydrogen or C | _3 alkyl, or X ³ and X are the same ^zy or different and represent hydrogen or a C13 alkyl group, X ^4, X ⁶ and X ⁷ are the same or different and independently of one another represent hydrogen or halogen or Y ⁴ is C _yz alkyl group or C _b5 perfluoroalkyl group, Υ ^3, Y ⁷ and Y ⁸ are the same or different and independently represent hydrogen or halogen, and all other substituents in formula I have the meanings indicated therein. Compounds of general formula I according to claim 1, wherein Ar represents a ring system of partial formula 6. Compounds of general formula I according to claim 1, wherein Ar represents a ring system of partial formula 7. Compounds of general formula I according to claim 1, wherein Ar represents a ring system of partial formula 10. Compounds of general formula I according to claim 1, wherein Ar represents a ring system of partial formula 11. Compounds of general formula I according to claim 1, namely: 4-bromo-5- (2-hydroxy-4-methyl-4-phenyl2-trifluoromethyl-valeroylamino) -phthalide; 6-bromo-5- (2-hydroxy-4-methyl-4-phenyl2-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-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-toluyl) -2-trifluoromethyl-valeroylamino] -phthalide; 5- [2-hydroxy-4-methyl-4- (3-toluyl) -2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (4-cyanophenyl) -2-hydroxy-4-methyl2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (3,4-dimethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (3,5-dimethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [2-hydroxy-4- (2-methoxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (5-Chloro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (5-Fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [2-hydroxy-4- (2-hydroxy-5-methylphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (5-Fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (3-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- (2-hydroxy-4-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-trifluoromethyl-valeroylamino] phthalide; 5- (2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide; 5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-pentylamino) -phthalide; 5- [4- (4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide; 5- [4- (5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] phthalide; 6- acetyl-5- (2-hydroxy-4-methyl-4-phenyl2-trifluoromethyl-valeroylamino) -phthalide; 5- [4- (3-Fluoro-4-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 5- [4- (3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; 6- (3-hydroxy-3-methyl-1-butynyl) -5- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino] -phthalide; 6- (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl-2,3-benzoxazin-1-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-trifluoromethyl-valeroylamino] -2,3-benzoxazin-1-one; 6- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl- 2.3-benzoxazin-1-one; 4-ethyl-6- [2-hydroxy-4-methyl-4- (4-methylphenyl) -2-trifluoromethyl-valeroylamino] -2,3-benzoxazin-1-one; 6- [4- (4-bromophenyl) -2-hydroxy-4-methyl2-trifluoromethyl-valeroylamino] -4-ethyl-2,3-benzoxazin-1-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-1-one; 1- (4-nitro-3-trifluoromethylanilino) -4-phenyl-2-trifluoromethyl-2-pentanol; 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-fluoro-4-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide; Compounds of general formula I according to claim 1, namely: