CA2305458C - Nonsteroidal (hetero) cyclically-substituted acylanilides with mixed gestagenic and androgenic activity - Google Patents

Nonsteroidal (hetero) cyclically-substituted acylanilides with mixed gestagenic and androgenic activity Download PDF

Info

Publication number
CA2305458C
CA2305458C CA002305458A CA2305458A CA2305458C CA 2305458 C CA2305458 C CA 2305458C CA 002305458 A CA002305458 A CA 002305458A CA 2305458 A CA2305458 A CA 2305458A CA 2305458 C CA2305458 C CA 2305458C
Authority
CA
Canada
Prior art keywords
hydroxy
methyl
trifluoromethyl
valeroylamino
phthalide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA002305458A
Other languages
French (fr)
Other versions
CA2305458A1 (en
Inventor
Manfred Lehmann
Klaus Schollkopf
Peter Strehlke
Nikolaus Heinrich
Karl-Heinrich Fritzemeier
Hans-Peter Muhn
Rolf Krattenmacher
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=7831567&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2305458(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Schering AG filed Critical Schering AG
Publication of CA2305458A1 publication Critical patent/CA2305458A1/en
Application granted granted Critical
Publication of CA2305458C publication Critical patent/CA2305458C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention relates to non-steroidal gestagens of the general formula I (See formula I) in which: R1 and R2 are the same or different and each stands for a hydrogen atom, a C1-C5 alkyl group or a halogen atom, or R1 and R2 together with the C-atom of the chain form a 3- to 7-membered ring; R3 stands for a C1-C5 alkyl group, or a partially or completely fluorinated C1-C5 alkyl group; A stands for an optionally substituted monocyclic or bicyclic, carbocylic or heterocyclic, aromatic ring, an ester group - COOR4, an alkenyl group -CR5=CR6R7, an alkynyl group -C.ident.CR5, or for a partially or completely fluorinated C1-C5 alkyl group; B stands for a carbonyl group or a CH2 group; and Ar is a ring system. The novel compounds display a strong affinity to the gestagen receptor. They can be used on their own or in combination with estrogens in contraceptive preparations. They can also be used for treatment of endometriosis. They can be used with estrogens in preparations for the treatment of gynaecological disorders, premenstrual symptoms and in substitution therapy. Their androgenic activity enables them to be used for male birth control, male HRT and to treat andrological disease agents.

Description

CA 02305458 2005-02-14 1 NONSTEROIDAL (HETERO) CYCLICALLY-SUBSTITUTED ACYLANILIDES WITH MIXED GESTAGENIC AND ANDROGENIC ACTIVITY This invention relates to nonsteroidal compounds, which have a high gestagenic activity. In addition to a large number of steroid compounds with gestagenic action, gestagens that are not steroids are also known (for example from EP 0 253 500 B1 and WO 94/01412, cf. J. Med. Chem 38 (1995) 4878). This invention describes compounds of general formula I (I) Ri R-' HO R; H N A B~ ~Ar in which: R1 and R2 are the same or different and each stands for a hydrogen atom, a C1-CS alkyl group or a halogen atom, or R1 and R2 together with the C-atom of the chain form a 3- to 7-membered ring; R3 stands for a C1-C5 alkyl group, or a partially or completely fluorinated C1-CS alkyl group; CA 02305458 2006-03-30 2 A stands for a monocyclic or bicyclic, carbocylic or heterocyclic, aromatic ring that is optionally substituted by one or more radicals selected from: halogen atoms; C1-CS alkyl groups; alkenyl groups of the formula CRS=CR6R' (wherein RS, R6 and R' are the same or different and, independently of one another, are each hydrogen atoms or C1-CS alkyl groups); hydroxyl groups; hydroxyl groups that carry a C1-Clo acyl group, a C3-Clo carbalkoxyalkyl group, a CZ-C5 cyanoalkyl group, a C3-Clo unsubstituted or substituted allyl group, a C3-Clo unsubstituted or substituted propargyl group, a CZ-CS alkoxyalkyl group, or a C1-CS alkyl group that is partially or completely substituted by fluorine atoms; cyano groups; vitro groups; C1-CS alkoxy groups; C1-C5 alkylthio groups; mono- or di-substituted C1-Clo amino groups; and partially or completely fluorinated C1-C5 alkyl groups; or A may also stand for: an ester group -COOR4 in which R4 is a C1-CS alkyl group; an alkenyl group of the formula -CRS=CR6~R'~ (wherein RS~, R6~ and R'~ are the same or different, and independently of one another, are each hydrogen atoms, halogen atoms, aryl radicals or C1-CS alkyl groups); an alkynyl group of the formula -C=CRS in which RS is a hydrogen atom or a C1-CS alkyl group; or a partially or completely fluorinated C1-CS alkyl group; B stands for a carbonyl group or a CHZ group; and Ar stands for a ring system, selected from the group of partial general formulas 2 through 11: CA 02305458 2005-02-14 3 X4 X3a 4 X N\ 6 \ ~ ~N / ~N X N x6 ~ N S X7 X~ 3a 3a 7 Y 5 Y4 Y 5 Y4 \ \ ~N 1 y '~ Y O Y8 O Y8 O 9 Y 5 Y4 \ ~N Y7 i NR5 Y8 D 11 in which: radicals X3a, X9, X6, X' (in partial formula 2) , X9, X6, X' (in partial formulas 3 and 4), X3a, X3b, Xq, X6, X' (in partial formulas 5, 6 and 7) or Yq, Y5, Y' and Y8 (in partial formulas 8, 9, 10 and 11) are each the same or CA 02305458 2005-02-14 4 different and are selected from: hydrogen atoms; C1-C5 alkyl groups, which in addition may contain a hydroxy group that is optionally etherified with a C1-C5 alkyl group or esterified with a C1-CS alkanoyl group; partially or completely fluorinated C1-CS alkyl groups; alkenyl groups of the formula -CRS=CR6R' (wherein RS, R6 and R' are the same or different and, independently of one another, are each hydrogen atoms or C1-CS alkyl groups); and alkynyl groups of the formula -C=CRS in which RS is a hydrogen atom or a C1-CS alkyl group; or radicals X3a and X3b together with the C-atom of the benzocondensed ring system of partial formula 5, 6 or 7 can form a 3- to 7-membered ring; or radicals XQ, X6, X', (in partial formulas 2, 3, 4, 5, 6 and 7) or Y4, YS, Y', YB (in partial formulas 8, 9, and 11) are selected from: halogen atoms; hydroxy groups; C1-CS alkoxy groups; and C1-C5 alkanoyloxy groups; and, if B in general formula I is a CH2 group, Ar also can be a phenyl radical of partial general formula 12 R9 Rio 92 in which: R9 and R1.degree. are the same or different and each mean a cyano group, a nitro group, a halogen atom, a C1-C5 alkyl group, a partially or completely fluorinated C1-CS alkyl group, a C1-CS alkylthio group, a C1-C5 alkylsulfinyl group or a C1-CS alkylsulfonyl group; or, if B stands for a CH2 group, a physiologically-compatible salt of a compound of formula I. CA 02305458 2005-02-03 The compounds according to thEa invention are distinguished from the known nonsteroidal compounds with gestagenic action by the substitution pattern on the aryl radical that is on the right in general formula I. In the compounds that are present here, Ar is a benzocondensed, bicyclic ring system, while in the structures that are known from EP C~ 253 500 B1 and that can be considered as the closest compounds., a phenyl radical that is substituted in one, two or three places is at this point. The compounds of general formula I according to the invention can be present as different stereoisomers because of the presence of asymmetry centers. Both the racemates and the stereoisomers that are detached are part of the subject of this invention. CA 02305458 2000-04-OS 6 The substituents that are defined as groups in the compounds of general formula I can have the following meanings in each case. C1-CS Alkyl groups can readily be a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl group or an n-pentyl, 2,2- dimethylpropyl or 3-methylbutyl group. A methyl or ethyl group is preferred. A fluorine, chlorine, bromine or iodine atom can stand for a halogen atom. Here, fluorine, chlorine or bromine is preferred. If R1 and RZ together with the C-atom of the chain form a 3- to 7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred. For a partially or completely fluorinated C1-CS alkyl group, the perfluorinated alkyl groups that appear above and of the latter mainly the trifluoromethyl group or pentafluoroethyl group as well as partially fluorinated alkyl groups, for example, the 5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3- heptafluoropentyl group, are considered. As a C2-CS alkenyl group, for example, a vinyl-, allyl- or 2,3-dimethyl-2-propenyl group can appear; if aromatic compound A is substituted with an alkenyl group, preferably it is a vinyl group. For example, a carboxymethyl, tert-butoxymethyl or ethoxymethyl group can stand for the CZ-C5 carbalkoxyalkyl group; the first two groups that are mentioned above are preferred. CA 02305458 2000-04-OS 7 As representatives of the C2-C5 cyanoalkyl group, cyanomethyl and 1- and 2-cyanoethyl can be mentioned; cyanomethyl is preferred. The C3-Coo allyl group is preferably an unsubstituted allyl group; in the case of a substituted allyl group, for example, 1- methylallyl, l,l-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylallyl, 3,3-dimethylallyl, cinnamyl and 3- cyclohexylallyl can be mentioned. An unsubstituted propargyl group, a methylpropargyl group, 3-methylpropargyl group, 3-phenylpropargyl group or 3- cyclohexylpropargyl group are typical representatives of a C~-Coo propargyl group; the unsubstituted propargyl group is preferred. For example, methoxymethyl, ethoxymethyl or 2-methoxyethyl can stand. for C2-CS alkoxyalkyl. . . Representatives of a C~-C5 alkoxy group are selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, tent-butoxy groups or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy groups. A methoxy or ethoxy group is preferred. C~-C5 Perfluoroalkoxy groups are the corresponding perfluorinated radicals of the C~-CS alkoxy groups above. Monocyclic or bicyclic aromatic ring A, which can be substituted, is a carbocyclic or heterocyclic aryl radical. In the first case, this is, for example, a phenyl or naphthyl radical, preferably a phenyl radical. As a heterocyclic radical, for example, a monocyclic heterocyclic radical can be, for example, the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, CA 02305458 2000-04-OS 8 pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, specifically all possible isomers relative to the positions of the heteroatoms. The thienyl radical is preferred as heteroaryl radical A. For R4, a methyl, ethyl, n- or iso-propyl group is preferred as a C~-CS alkyl group in ester group -COOR4. As a C~-C5 alkyl group for etherification of hydroxy groups, the above-mentioned alkyl groups are suitable, primarily a methyl or ethyl group. As a C~-C5 alkanoyl group for esterification of hydroxy groups, a formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or iso-valeryl or pivaloyl group is suitable, preferably an acetyl group. As a C~-Coo acyl group for esterification of hydroxy groups, for example, the above-mentioned alkanoyl groups, preferably in turn an acetyl group or a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl group can be mentioned. If X38 and X3b together with. the C-atom of the benzocondensed ring system form a 3- to 7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred. As a C~-C5 alkanoyloxy group for X4, X6, X~, Y4, Y5, Y~ or Y8, a formyloxy, acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy or isovaleryloxy group is suitable, preferably an acetoxy group. CA 02305458 2000-04-OS 9 The above-mentioned C1-CS alkyl groups can stand for C1-CS alkyl within the C1-CS alkylthio, C1-CS alkylsulfinyl or C1-C5 alkylsulfonyl group. If the compounds of general formula I (B = -CHZ) are present as salts, this can be in the form of, for example, hydrochloride, sulfate, nitrate, tartrate or benzoate. If the compounds according to the invention are present as racemic mixtures, they can be separated into pure, optically active forms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the racemic mixtures can be separated by chromatography into pure isomers on an optically active carrier material (CHIRALPAK AD~R~). It is also possible to esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and. to separate the diastereoisomeric esters that are obtained by fractionated crystallization or by chromatography, and to saponify the separate esters in each case into the optically pure isomers. For example, mandelic acid, camphorsulfonic acid or tartaric acid can be used as optically active acid. Preferred according to this invention are those compounds of general formula I, in which: R1 and RZ are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring, and/or R' stands for a C1-CS perfluoroalkyl group, and/or CA 02305458 2000-04-OS A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals, selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, a ( CHZ ) n group ( n=3 , 4 , 5 ) , whi ch with 2 adj acent C atoms of aromatic compound A forms a ring with n+2 links and can contain unsaturations; vinyl groups, hydroxy groups, methoxy groups, ethoxy groups, and/or either X3a stands for a hydrogen atom or a C1-CS alkyl group, or X3a and X3b are the same or different and stand for a hydrogen atom or a Cl-CS alkyl group and/or X4, X6 and X' are the same or different, and stand for, independently of one another, a hydrogen atom or a halogen atom, and/or Y4 stands for a C1-CS alkyl group or a C1-CS perfluoroalkyl group, and/or Y5, Y' and YB are the same or different and, independently of one another, stand for a hydrogen atom or a halogen atom, and the other substituents all have the meanings that are indicated in Formula 1. In addition, those compounds of general formula I in which Ar stands for a ring system of partial formula 6, 7, 10 or 11 are preferred. CA 02305458 2000-04-OS 11 The compounds that are mentioned below are especially preferred according to the invention: 4-Bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide, 6-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide, 5-(2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl- valeroylamino)-phthalide, 5-[2-hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethyl- valeroylamino]-phthalide, 5-[2-(hydroxy-4-(4-methoxyphenyl)-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-trifluoromethyl- 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-tolyl)-2-trifluoromethyl- valeroylamino]-phthalide, 5-[2-hydroxy-4-methyl-4-(3-tolyl)-2-trifluoromethyl- valeroylamino]-phthalide, CA 02305458 2000-04-OS 12 5-[4-(4-cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeroylamino]-phthalide, 5-[4-(3,4-dimethylphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(3,5-dimethylphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[2-hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-(4-(5-chloro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-(4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[2-hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2- 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, CA 02305458 2000-04-OS 13 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-phenyl-2-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-butinyl)-5-(2-hydroxy-4-methyl-4- phenyl-2-trifluoromethyl-valeroylamino)-phthalide, 6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-4-methyl-2,3-benzoxazin-1-one, 6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-4-trifluoromethyl-2,3-benzoxazin-1-one, 4-ethyl-6-(2-hydroxy-4-phenyl-2-trifluoromethyl- pentylamino)-2,3-benzoxazin-1-one, 4-ethyl-6-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2- 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, CA 02305458 2000-04-OS 14 4-ethyl-6-[2-hydroxy-4-methyl-4-(4-methylphenyl)-2- trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one, 6-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeroylamino]-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-vitro-3-trifluoromethylanilino)-4-phenyl-2- trifluoromethyl-2-pentanol, 1-(4-vitro-3-trifluoromethylanilino)-4-phenyl-2- trifluoromethyl-2-pentanol, 5-(2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5- hexenoylamino)-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclopropyl)-2-trifluoromethyl- propionylamino]-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclobutyl)-2-trifluoromethyl- propionylamino]-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclohexyl)-2-trifluoromethyl- propionylamino]-phthalide, 6-(2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino)-4-methyl- 2,3-benzoxazin-1-one, 5-[4-(3-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide. In addition, the compounds that are known from Tables 7 to 15 are preferred. CA 02305458 2000-04-OS All above-mentioned compounds are especially preferred in the form of the optical antipodes or the separate diastereomers. In the gestagen receptor binding test on the gestagenic action using cytosol from rabbit uterus homogenate and from 3H- progesterone as a reference substance, the new compounds show a strong to very strong affinity to the gestagen receptor (see Table 1) . In addition to their gestagenic action, which is pronounced to different degrees depending on the compound of general formula I that is considered, the new compounds are also distinguished by a more or less strongly pronounced affinity to the androgen receptor. The androgen receptor binding test on androgenic action was carried out using cytosol that consists of rat prostate homogenate and 'H-methyltrienolone as a reference substance. The new compounds are thus represented relative to the gestagenic compounds from EP 0 253 500 B1 as compounds with a quite novel mix profile, which consists of gestagenic action and androgenic action. For the compounds of general formula I according to the invention, in this case all three of the cases that are possible below are found, which based on the competition factors on progesterone receptor (KFPro9) and androgen receptor (KFAnazo) are classified within the scope of this invention as follows: .. CA 02305458 2005-02-03 16 Table 1 Example No. Structure Competition Factor (Reference Substance ~i- Progesterone) ( ) 1~ HO CF3 H N\ ~ Fs I O Flash ( point 141- 142.degree.) (*~ 2 . 0 HO CFl H N~ ~ CF3 ~I O N02 (Flash point 161.degree.C) 65 0.17 HO CF3 N 0 a o.1 HO CFg \~ 'H ~N~~ I O n 0 HO CF3 H / N / I \N I O ~ _O O 0.55 () EP 0 253 500 B1, Example 2 CA 02305458 2000-04-OS 17 1) Compounds with stronger gestagenic action and less pronounced androgenic action (KFPro9 < 1 and KFAnaro > 5) ; 2) Compounds with stronger androgenic action and less pronounced gestagenic action (KFAnaro < 5 and KFProg > 1) ; 3) Compounds with pronounced gestagenic action and pronounced androgenic action (KFProg < 1 arid KFAnaro < 5) . Depending on their classification according to 1), 2) or 3), the new compounds according to the invention can be used for different medical or pharmaceutical purposes. In the case of the compounds that are classified under 1) with stronger gestagenic action and less pronounced androgenic action, these are very effective gestagens, which, like the already numerous known gestagenic compounds, are suitable for preserving pregnancies in the case of parenteral administration and in the case of oral administration. In combination with an estrogen, combination preparations are obtained that can be used for contraception and for the treatment of menopausal symptoms. Based on their high gestagenic action, the new compounds of general formula I that are classified under 1) can be used, for example, alone or in combination with estrogens in contraceptive preparations. However, all other possible uses that are known for gestagens are now open to these new compounds (see, e.g., "Kontrazeption mit Hormonen [Contraception with Hormones]," Hans- Dieter Taubert and Herbert Kuhl, Georg Thieme Verlag Stuttgart - New York, 1995). Suitable dosages can be determined as a matter of routine, e.g., by determining the bioequivalency, for example in the CA 02305458 2000-04-OS 18 pregnancy-maintenance test, relative to a known gestagen for a specific use, for example an amount that is bioequivalent to 30 to 150 ~g of levonorgestrel for contraception. The dosage of the compounds according to the invention under 1) in contraceptive preparations is preferably to be 0.01 to 2 mg per day. The gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations. The daily dose is preferably administered once. As estrogens, all natural and synthetic compounds that are known as estrogenically active ire suitable. As natural estrogens, these are especially estradiol and also its longer-acting esters, such as valerate, etc. or estriol. Preferably, however, synthetic estrogens such as ethinylestradiol, 14a,17a-ethano-1,3,5(10)-estratriene-3,17-diol (WO 88/01275), 14a,17a-ethano-1,3,5(10)-estratriene-3,16a,17R- triol (WO 91/08219) or the 15,15-dialkyl derivatives of the estradiol, and of these especially 15,15-dimethylestradiol (WO 95/04070) can be mentioned. As a synthetic estrogen, ethinylestradiol is preferred. Also, the estratrien-3-amidosulfonates that have become known recently (WO 96/05216 and WO 96/05217), derived from estradiol or ethinylestradiol, which are distinguished by.low hepatic estrogeneity, are suitable as estrogens for common use with the compounds of general formula I that are classified under 1). Finally, the 14a,15a-methylene steroids from the estrane series, especially the 14a,15a-methylene-17a-estradiol as well as the corresponding 3-amidosulfonate derivatives can be mentioned. CA 02305458 2000-04-OS 19 The estrogen is administered in an amount that corresponds to that of 0.01 to 0.05 mg of ethinylestradiol. The new compounds of general formula I that are classified under 1) can also be used in preparations for treatment of gynecological disorders and for substitution therapy. Because of their advantageous profile of action, these compounds according to the invention are especially well suited for treatment of premenstrual symptoms, such as headaches, depression, water retention and mastodynia. The daily dose in the treatment of premenstrual symptoms is approximately 1 to 20 mg. Analogously to what is already known for other gestagens, the new compounds can also be used for treating endometrioses. Finally, these new compounds can also be used as gestagenic components in the compositions for female birth control that have recently become known and that are distinguished by the additional use of a competitive progesterone antagonist (H. B. Croxatto and A. M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. by Runnebaum, Rabe & Kiesel - Vol. 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group - 1991, page 245; WO 93/17686, WO 93/21927, US-Pat. 5,521,166). The dosage lies in the range that is already indicated, and the formulation can be carried out as in conventional OC- preparations. The administration of the additional, competitive progesterone antagonist can in this case also be performed sequentially. Those compounds of the general formula, which are to be categorized as above under 2) or 3), i.e., compounds that always CA 02305458 2000-04-OS have a strong androgenic action (androgenic gestagens), can be used for the production of pharmaceutical preparations for male birth control. Currently, in several WHO studies, the contraceptive action of a combination that consists of an orally administered gestagen (Depot-medroxy progesterone acetate, levonorgestrel ester, cyproterone acetate) is tested on men with a parenterally administered androgen (testosterone oenanthate). By contrast, birth control in men is possible with these compounds in one dosage form, specifically an oral dosage form or a dosage form that is to be administered transdermally. In addition, the compounds according to the invention with androgenic action can be used with older males for male HRT (Hormone Replacement Therapy). Those compounds of general formula I, which can more likely be classified under 2), i.e., compounds with mainly androgenic action and weaker gestagenic action, can be used for male hormone therapy. Preparations for treating a hypergonadism or for treating male infertility and disturbances of potency can be produced with them. For male birth control and for treating the above-mentioned androgenic disease agents, the compounds according to the invention are used in the dosages that are equivalent in action to the testosterone oenanthate amounts that are used in the WHO studies or to the dosages that are already in androgen therapy of compounds used. Amounts that are equivalent in action are those amounts that, in the test on androgenic action on the seminal vesicles CA 02305458 2000-04-OS 21 and/or prostate of the rat (Hershberger Test), achieve comparable action. For HRT in man, to date a substitution dose of approximately mg/day of testosterone oenanthate is used. For male birth control studies that are performed by the WHO, different testosterone esters (oenanthate, bucyclate, undecanoate) are used in the range of approximately 10-30 mg/day. At this point it should be pointed out that the transitions between 1), 2) and 3), as regards the correlation according to the invention of various indications with these varying mix profiles 1), 2) and 3), are smooth. The compounds that more likely lie on the edge of the indicated KF areas based on their KFPIOg and/or KFpndro. can easily be used also for the indications that are assigned to the adjacent mix profile. The compounds of general formula I also partially show actions on the glucocorticoid and/or mineral corticoid receptor. The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, by the active ingredient, optionally in combination with an estrogen, being processed with the vehicles that are commonly used in galenicals, diluents, optionally flavoring correctives, etc., and conveyed in the desired form of administration. For the preferred oral administration, especially tablets, coated tablets, capsules, pills, suspensions or solutions are suitable. For parenteral administration, especially oily solutions, such as, for example, solutions in sesame oil, castor oil and cottonseed oil, are suitable. To increase solubility, CA 02305458 2000-04-OS 22 solubilizers, such as, for example, benzyl benzoate or benzyl alcohol, can be added. The compounds of general formula I can also be administered continuously by an intrauterine release system (intrauterine system = IUS; e.g., MIRENA~R'); the release rate of the active compounds) is selected in this case in such a way that the dose that is released daily lies within the already indicated dosage range. It is also possible to incorporate the substances according to the invention in a transdermal system and thus to . administer them transdermally. The compounds of general formula I according to the invention can be produced as described below. i I CA 02305458 2005-02-03 23 Production Process 1. A carbonyl compound of general formula II O H N A B~~ ~Ar II in which A, B, Ar, R1 and R2 have th~~ meaning that is indicated in formula I, is reacted with trifluoromethyl- trimethyl silane or trimethyl-pentaf:luoroethyl silane, in the presence of a catalyst or with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, to a compound of formula I. As catalyst:>, fluoride salts or basic compounds such as alkali carbonates are suitable (J. Amer. Chem. Soc. 111, 393 (1989)). 2. A compound of general formula III R1 R2 HO R3 rFG A III in which A, B, R1, RZ and R3 have the meaning that is indicated in formula 1 and FG means a leaving group, is reacted with a compound Ar-NH-R11, whereby R11 means a hydrogen atom or a C,-CS acyl group, and Ar has the meaning that is indicated in general formula I, whereby optionally then radical R'1 is cleaved off to obtain a compound of formula I. In this case, the compound of .. CA 02305458 2005-02-03 24 general formula III optionally can be formed only as an intermediate product, e.g., this can be an acid chloride that is formed as an intermediate product from a corresponding carboxylic acid. As leaving groups, for example,. a chlorine, bromine or iodine atom, a tosylate or mesylate radical or a C1-C9 perfluoroalkylsulfonyloxy radical. 3. A compound of general formula IV R~ R2 R3 O A IV in which A, R', RZ and R3 have the meaning that is indicated in formula I, is reacted with a compound of formula Ar-NH-R1', whereby R1' and Ar have the above-indicated meanings, whereby optionally then radical R'1 is cleaved off, to obtain a compound of formula I with B in the meaning of a CHZ group. 4. A compound of formula I, which in radical A or in radical Ar contains the grouping aryl-X, whereby "aryl" represents an isocyclic or heterocyclic aromatic compound that corresponds to the definitions that are given for formula I and X means a bromine or iodine atom or the group -O-SOZR'z, in which R'z means.a C1-CS perfluoroalkyl group, is reacted under metal catalysis to compound aryl-R'3 according to processes that are known in the art with a compound of formula R"-Y, whereby R'' represents an optionally substituted aryl, ethenyl or ethinyl radical and Y represents a hydrogen atom (J. Org. Chem. 43, 2947 (1978)), group B (O-R'a)= (J. Org. Ch~.degree.m. 58, 2201 (1993)) or CA 02305458 2000-04-OS Sn(R15)3 (J. Org. Chem. 52, 422 (1987) ) with R19 and R15 meaning a phenyl radical or Cl-CS alkyl and R'9 also represents hydrogen, Mg-halogen or an alkali metal atom. 5. In a compound of formula I, which contains an alkoxy or acyloxy substituent in A or Ar, the OH group is released, and optionally etherified or esterified in another reaction or, after conversion into a 1-phenyl-5-tetrazolylether, is completely eliminated by hydrogenation (J. Amer. Chem. Soc. 88, 4271 (1966) ) . Of all the foregoing process variants, 1. and 2. are suitable for the production of all compounds that fall under general formula I. Compounds of general formula I can be produced with the third variant, in which B stands for a -CHZ group. Using the fourth and fifth process variants, functionalizations of already existing compounds of general formula I can be undertaken. Compounds that were produced according to one of the processes above and in which A is an optionally substituted aromatic ring optionally can be selectively substituted in this aromatic radical according to known processes. Examples of these processes are the catalytic hydrogenation of multiple bonds, nitration and halogenation. The starting materials that are used in the examples are produced as follows: CA 02305458 2000-04-OS 26 Production of Starting Materials 4-Methyl-4-phenyl-2-oxovaleric acid A Grignard solution that is produced from 26.4 g of magnesium and 162 ml of 2-methyl-2-phenyl-1-chloropropane in 150 ml of diethyl ether was added in drops to 600 ml of oxalic acid diethyl ester at -30.degree.C. After 2 hours at room temperature, it was added to ammonium chloride solution, extracted with diethyl ether, dried (Na2S0q) and distilled in fractionated form; 84 g of ethyl ester (boiling point 115-120.degree.C/0.03 hPa), which is dissolved in 1 1 of methanol, is obtained, mixed with 500 ml of lm sodium hydroxide and stirred for 1.5 hours at room temperature. After the methanol is evaporated in a vacuum, the residue is dispersed between water and diethyl ether, the aqueous phase is acidified with hydrochloric acid and extracted with diethyl ether. After concentration by evaporation, 57 g of 4- methyl-4-phenyl-2-oxovaleric acid is obtained as a thick oil. 4,4-Dimethyl-2-oxo-5-hexenoic acid 36 g of 3,3-dimethyl-4-pentenoic acid is obtained as an oil from 50 g of 3,3-dimethyl-4-pentenoic acid methyl ester by saponification with 10% potassium hydroxide solution. By stirring with thionyl chloride (20 hours, room temperature), the acid chloride is obtained, boiling point 59.degree.C/30 hPa. 16 g of it is stirred with 15 g of trimethylsilylcyanide and 0.16 g of zinc iodide for 4 days. After distillation, 13 g of 4,4-dimethyl-2- oxo-5-hexenoic acid nitrile, boiling point 75-85.degree.C/30 hPa, is obtained. 2 g of it is saturated with 0.6 ml of methanol in 13 CA 02305458 2000-04-OS 27 ml of hexane while being cooled with ice with hydrochloric-acid gas, and it is mixed for 2 hours with water. From the hexane phase, after drying (Na2S09) and concentration by evaporation, 0.558 g of 4,4-dimethyl-2-oxo-5-hexenoic acid methyl ester, boiling point 48.degree.C/0.003 hPa, is obtained. 0.535 g of it is saponified with 1.3 ml of 3N sodium hydroxide solution, whereby 0.32 g of 4,4-dimethyl-2-oxo-5-hexenoic acid is obtained as a yellowish liquid. 3-(1-Phenyl-cyclobutyl)-2-oxo-propionic acid g of 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminum hydride in toluene (1.2 molar) at -72 to -69.degree.C. After 4 hours at -75.degree.C, 30 ml of ethyl acetate is added in drops. After heating to room temperature, additional ethyl acetate and water are added. It is filtered on diatomaceous earth, the organic phase is separated, dried (Na2S04) and concentrated by evaporation. After chromatography on silica gel (hexane with 0-10% ethyl acetate), 7.6 g of 1-phenyl-cyclobutanecarbaldehyde is obtained. 3 g of it is dissolved in 10 ml of tetrahydrofuran and added in drops at 0.degree.C to a solution, in which previously 5 g of triethyl-2- ethoxyphosphonoacetate in 70 ml of tetrahydrofuran was mixed at 0.degree.C with 10.3 ml of a 2 molar solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene. After hours at room temperature, water is added, it is extracted with ethyl acetate, dried (Na2S09) and concentrated by evaporation. 2 g of this crude product is saponified with 28 ml of 1N sodium hydroxide solution. 1.32 g of the acid, which is CA 02305458 2000-04-OS 28 heated for 20 hours to 90.degree.C with 25 ml of 1 molar sulfuric acid while being stirred vigorously, is obtained. After extraction with ether, drying (Na2S04) and concentration by evaporation, 0.89 g of 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid is obtained as a yellowish oil. 3-(1-(2-Methoxyphenyl)-cyclopropyl]-2-oxo-propionic acid Corresponding to J. Org. Chem. 40 (1975) 3497, 16.7 g of 2- methoxyphenylacetonitrile, 158 ml of lithium diisopropylamide (2 molar solution) and 46.7 ml of 1,2-dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric acid triamide were reacted with one another. 5.6 g of 1-(2-methoxyphenyl)- cyclopropyl-carbonitrile, boiling point 104-115.degree.C/0.1 mbar, which was further reacted as described for 3-(1-phenyl-cyclobutyl)-2- oxo-propionic acid, was obtained. 3-[1-(2-Methoxyphenyl)- cyclopropyl]-2-oxo-propionic acid is thus obtained as an oil. The acids that are described in Table 2 were obtained analogously to the process that is described for 3-(1-phenyl- cyclobutyl)-2-oxo-propionic acid and for 3-[1-(2-methoxyphenyl)- cyclopropyl]-2-oxo-propionic acid. CA 02305458 2000-04-OS 29 Table 2 ~CHz)n O Z ~ ~COOH Z4 ~ ~ 6 ~Z Z Example n Z" Flash Point H) (oC) 1 3-F oil 1 2-C1 60-63 1 4-C1 oil 1 2-Br 49-54 1 3-Br oil 1 2,4-C1 185-190 1 3-OCH oil 1 3-CF oil 3 oil 3 4-CH 50-61 4 4-OCH oil CA 02305458 2000-04-OS 3-(1-Phenyl-cyclopropyl)-2-oxo-propionic acid is obtained analogously to the process that is described for 3- (1-phenyl-cyclobutyl)-2-oxo-propionic acid. 3-(1-Phenyl-cyclohexyl)-2-oxo-propionic acid is obtained analogously to the process that is described for 3- (1-phenyl-cyclobutyl)-2-oxo-propionic acid. 4-(3-Methoxyphenyl)-4-methyl-2-oxo-valeric acid 4.2 ml of a 0.6 m solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran is mixed at -70.degree.C with 257 mg of copper bromide-dimethylsulfide complex and then stirred at -40.degree.C for 20 minutes. It is cooled again to -70.degree.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 [Liebigs Annals] 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran are slowly added. It is stirred for one hour at -70.degree.C and then heated to room temperature. Then, 2N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethane. After 200 mg of tetrabutylammonium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethane phase is dried (Na2S09) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (97:3), 63 mg of 4-(3-methoxyphenyl)-4- methyl-2-oxo-valeric acid-methyl ester, which is mixed with 1 ml CA 02305458 2000-04-OS 31 of potassium hydroxide in methanol (10%), is obtained. After 45 minutes, it is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase is dried (Na2S09) and concentrated by evaporation. 50 mg of 4-(3-methoxyphenyl)-4- methyl-2-oxo-valeric acid is obtained. 2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid The Grignard reagent is produced from 1.5 g of magnesium and g of 2-methyl-2-phenylpropyl chloride in 100 ml of diethyl ether, which, after reaction with 10 g of trifluoropyruvic acid ethyl ester, yields 9.5 g of 2-hydroxy-4-methyl-4-phenyl-2- trifluoromethyl-valeric acid ethyl ester, boiling point 90.degree.C/0.045 hPa. 7.5 g of the ethyl ester is refluxed with 100 ml of potassium hydroxide in methanol (10%) for 18 hours. After concentration by evaporation in a vacuum, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified with 2N hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation, 3.2 g of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeric acid is obtained as colorless crystals, boiling point 124-126.degree.C. CA 02305458 2000-04-OS 32 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeric acid 1.3 g of anhydrous zinc chloride and 13.2 g of granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methallyl bromide for 30 minutes. Then, the solution of 25 g of methallyl bromide and 17 g of trifluoropyruvic acid ethyl ester in 80 ml of tetrahydrofuran is added in drops at boiling heat over 2 hours, and boiled for another hour. Then, while being cooled with ice, saturated ammonium chloride solution and 300 ml of ethyl acetate are added, stirred for 30 minutes at 0.degree.C, and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water. The solvent is dried (Na2S04) and concentrated by evaporation, and the residue is distilled in a vacuum. 17.6 g of 2-hydroxy-4-methylene-2-trifluoromethyl- valeric acid ethyl ester, boiling point 48.degree.C/1 hPa, is obtained. 0.8 g of anhydrous aluminum chloride is added to 5 ml of 4- fluoranisole and 0.9 g of 2-hydroxy-4-methylene-2- trifluoromethyl-valeric acid ethyl ester. After 40 hours of stirring at room temperature, it is added to ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 1N hydrochloric acid and water, dried (NazS09) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (1:1), 1 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeric acid ethyl ester, melting point 38-39.degree.C, is obtained. CA 02305458 2000-04-OS 1.9 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeric acid ethyl ester is refluxed with 40 ml of potassium hydroxide in methanol (10a) for 2 hours. After the solvent is concentrated by evaporation in a vacuum, water is added, it is extracted with hexane, and the separated water phase is acidified with 6N hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate phase is washed with water, dried (NaZS04) and concentrated by evaporation. The residue is crystallized from hexane. 1.55 g of 4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, flash point 102-104.degree.C, is obtained. 2-Hydroxy-4-methyl-4-(2-thienyl)-2-trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4-(3-thienyl)-2-trifluoromethyl-valeric acid The mixture of 2-hydroxy-4-methyl-4-(2-thienyl)-2- trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4-(3- thienyl)-2-trifluoromethyl-valeric acid (9:1), flash point 150- 151.degree.C, was produced analogously. The acids of Table 1 were produced analogously. Table 3 Z2 CH~CHsOH CFA Z3 \~ ~ ~COOH Z~Z g _5 CA 02305458 2000-04-OS . 34 Z Melting Point j ( #H) (C) ZQ CH3 136-138 - Z3 ZQ - CH3 115-117 - Z3 ZS - CH3 118 - Z9 Br 131-132 - ZQ Cl 133-135 - Zq F 140-141 - ZZ OCH3 9g-99 - Zq OCH3 129-130 - Zz Z5 - OCH3 136-137 - ZZ OCH3, - CH3 106-107 - ZS ZZ OCH3, - F 103-106 - Z' ZZ OCH3, - F 102-104 - ZS Z4 OCH3, - F 122-124 - ZZ Z4 OCH3, - F 108-109 - Z3 ZZ OCH3, - C1 103-105 - ZS Z3/Z4- (CH2) 118-119 3 Z3/Z9- -CH=CH-CH=CH- 137 ZZ OCH3, - Br 115-116 - Z9 ZZ Br, Z4 OCH3, 122-124 - - Z4 CsHs 162-163 - ZZ OCH3, - CH (CH3) 2 137-138 - Zg By conversion according to standard processes, other acids are obtained from the acids above or their precursors: 2-Hydroxy-4-methyl-2-trifluoromethyl-4-(4-vinylphenyl)-valeric acid By heating 4-(4-bromophenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeric acid ethyl ester, tributylvinyltin, tri- CA 02305458 2000-04-OS o-tolylphosphine and bis-tri-o-tolylphosphine-palladium(II) chloride in dimethylformamide to 120.degree.C, 2-hydroxy-4-methyl-2- trifluoromethyl-4-(4-vinylphenyl)-valeric acid ethyl ester is obtained, which provides the title compound, melting point 73- 74.degree.C, by alkaline saponification. 4-(4-Acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid analogously to the compound above of 4-(4-bromophenyl)-2-hydroxy- 4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1- ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o- tolylphosphine-palladium-II-chloride in dimethylformamide to 120.degree.C and then acid hydrolysis of the enol ether and alkaline saponification, melting point 158-162.degree.C. 4-(4-Acetyl-3-methoxypheayl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeric acid analogously to the compound above of 4-(4-bromo-3-methoxyphenyl)- 2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1-ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o- tolylphosphine-palladium-II-chloride in dimethylformamide to 120.degree.C, oil. 4-(4-Cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid from 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeric acid ethyl ester, zinc cyanide and tetrakis- CA 02305458 2000-04-OS 36 triphenylphosphine-palladium in dimethylformamide at 140.degree.C. After saponification, the title acid is obtained as a foam. 4-(4-Carbamoylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeric acid is obtained by treating the ethyl ester of the acid above with hydrogen peroxide and saponification, melting point 244-245.degree.C. 4-(4-C~rano-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeric acid from 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140.degree.C. After saponification, the title acid is obtained as an amorphous powder. 4-(3-Bromo-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeric acid from 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl- valeric acid ethyl ester by bromation with N-bromosuccinimide in dimethylformamide at 0.degree.C and subsequent saponification. Melting point 94- 96.degree.C . CA 02305458 2000-04-OS 37 2-Hydroxy-4-methyl-4-(3-nitro-4-methoxyphenyl)-2-trifluoromethyl- valeric acid This compound is obtained by reaction of 2.5 g of 2-hydroxy- 4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid ethyl ester with 4 ml of 100% nitric acid in 12 ml of trifluoroacetic acid for one hour at 0.degree.C, melting point 79-80.degree.C. 4-(4-Iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid 3.2 g of 4-iodo-2-methoxybenzoic acid-methyl ester in 10 ml of diethyl ether is added to 24.2 mmol of methylmagnesium bromide in 23 ml of diethyl ether. After 20 hours, ammonium chloride solution is added, the ether phase is separated, dried and concentrated by evaporation. 2.4 g of the residue is dissolved in 10 ml of dichloromethane, mixed with 714 mg of 2- trimethylsilyloxy-acrylic acid-ethyl ester, cooled to -70.degree.C and mixed with 0.27 ml of tin(IV) chloride. After 15 minutes, the solution is added to potassium carbonate solution. After extraction with diethyl ether, the organic phase is washed with water, dried and concentrated by evaporation. 500 mg of the 4- (4-iodo-2-methoxyphenyl-4-methyl-2-oxo-valeric acid ethyl ester that is thus obtained is stirred with 8.6 ml of 1 M sodium hydroxide in ethanol/water (2:1, v/v) for 3 hours at room temperature. After adding water, it is extracted with diethyl ether, the water phase is acidified with 1 m hydrochloric acid and extracted with diethyl ether. After drying and concentration by evaporation, 410 mg of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2- oxo-valeric acid is obtained as a yellowish oil. CA 02305458 2000-04-OS 38 4-(3-Chlorophenyl)-4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above of amorphous powder. 4-(3-Bromophenyl)-4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above of an amorphous powder. 4-(2-Iodophenyl)-4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above as an amorphous powder. 4-(3-Iodophenyl)-4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above of an amorphous powder. 4-(4-Iodophenyl)-4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above as an oil. 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained analogously to the embodiment above, melting point 58-60.degree.C. 4-(4-Bromo-2-methoxyphenyl)-2-oxo-valeric acid is obtained analogously to the embodiment above as an oil. CA 02305458 2000-04-OS 39 3-(1-Phenylcyclopentyl)-pyruvic acid is obtained analogously to the embodiment above of 1- phenylcyclopentanol with 2-trimethylsilyloxy-acrylic acid-ethyl ester and tin(IV) chloride as an oil. 4-Toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl- pentyl) ester A Grignard solution, to which 15 ml of oxalic acid diethyl ester is added at -30.degree.C within 30 minutes, is prepared from 2.6 g of magnesium chips and 15 ml of 2-phenyl-1-chloropropane in diethyl ether. It is stirred for one hour at -20.degree.C and for 2 hours at 0.degree.C, and then mixed with saturated ammonium chloride solution. The diethyl ether phase is separated, dried (Na2S09) and concentrated by evaporation and distilled in a vacuum. 17.7 g of 2-oxo-4-phenylvaleric acid ethyl ester, boiling point 98- 100.degree.C/0.03 hPa, is obtained. 4.4 g of 2-oxo-4-phenylvaleric acid ethyl ester is dissolved in 40 ml of tetrahydrofuran and mixed at -78.degree.C with 3.6 ml of trifluoromethyl-trimethylsilane and 2 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran. After 24 hours at -78.degree.C, another 20 ml of 1 M tetrabutylammonium fluoride in tetrahydrofuran is added. It is stirred for 1.5 hours at 0.degree.C, ethyl acetate and saturated common salt solution are added, the organic phase is separated, and it is washed with saturated common salt solution and water. Then, it is dried (Na2S0q) and concentrated by evaporation and distilled on a bulb tube. 4.4 g CA 02305458 2000-04-OS of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 95-100.degree.C/0.04 hPa, is obtained. 4.35 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester is dissolved in 100 ml of diethyl ether and stirred with 1.3 g of lithium aluminum hydride for one hour at 0.degree.C and for 16 hours at room temperature. A little water is added while being cooled, and it is stirred for one hour. The diethyl ether phase is separated, dried (Na2S04) and concentrated by evaporation and distilled on a bulb tube. 4.1 g of 4-phenyl-2- trifluoromethyl-1,2-pentanediol, boiling point 120.degree.C/0.04 hPa, is obtained. 4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol in 30 ml of pyridine is mixed at 0.degree.C with 3.8 g of 4-toluenesulfonic acid chloride. After 16 hours at 0.degree.C, it is concentrated by evaporation in a vacuum, mixed with ethyl acetate, washed with water, dried (Na2S04) and concentrated by evaporation. By crystallization from ethyl acetate/hexane, 4.9 g of 4- toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl- pentyl)ester, melting point 95-96.degree.C, is obtained. Analogously, 4-toluenesulfonic acid-(2-hydroxy-4-methyl-4- phenyl-2-trifluoromethyl-pentyl)ester, melting point 78.degree.C, is obtained. Analogously, 4-toluenesulfonic acid-[4-(4-fluorophenyl)-2- hydroxy-4-methyl-2-trifluoromethyl-pentyl]ester, melting point 80-81.degree.C, and 4-toluenesulfonic acid-[2-hydroxy-4-(2-methoxy-5- fluorophenyl)-4-methyl-2-trifluoromethyl-pentyl]ester, melting point 93-95.degree.C, were produced. CA 02305458 2000-04-OS 41 2-(2-Phenylpropyl)-2-trifluoromethyl-oxiran 400 mg of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2- trifluoromethyl-pentyl)ester in 5 ml of dimethylformamide is mixed at 0.degree.C with 35 mg of sodium hydride (80% in mineral oil). After one hour at 0.degree.C, it is diluted with water and extracted with dichloromethane. The dichloromethane phase is washed with water, dried (Na2S09) and concentrated by evaporation. The residue is distilled. 200 mg of 2-(2-phenylpropyl)-2- trifluoromethyl-oxiran, boiling point 110.degree.C/1 hPa, is obtained. 4-Bromo-5-aminophthalide 23 g of 3-bromo-4-nitro-1,2-xylene is suspended in 200 ml of pyridine and 600 ml of water and mixed at 60.degree.C in portions with 260 g of potassium permanganate, whereby the temperature rises to 90.degree.C. It is heated for 2 more hours to 95.degree.C, filtered, the filtrate is acidified with hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation, 27 g of 3-bromo-4-nitrophthalic acid is obtained. 12 g of acid is heated for 15 minutes to 220.degree.C and then distilled on a bulb tube. At 0.03 hPa, 10 g of 3-bromo-4- nitrophthalic acid anhydride is distilled. The anhydride is dissolved in 120 ml of dimethylformamide and is slowly mixed at 0.degree.C with 78.8 ml of a 0.5 M solution of sodium borohydride in dimethylformamide. After 3 hours at 0.degree.C, 2N hydrochloric acid is carefully added, and it is extracted with ethyl acetate. After washing with potassium bicarbonate solution, drying (Na~S09) and concentration by evaporation of the CA 02305458 2000-04-OS 42 ethyl acetate phase, 6.6 g of 4-bromo-5-nitrophthalide is obtained. 6.6 g of 4-bromo-5-nitrophthalide is dissolved in 45 ml of ethanol and added in drops to a mixture of 65 g of iron(II) sulfate, 220 ml of water and 65 ml of ammonia (33 0 ) that is heated to 60.degree.C and stirred well. After 2 hours at 60.degree.C, the mixture is absorptively precipitated five times with 200 ml of diethyl ether. The diethyl ether phases are concentrated by evaporation. As a residue, 4.1 g of 4-bromo-5-aminophthalide is obtained, melting point 176-180.degree.C. 6-Bromo-5-aminophthalide 4-Bromo-5-nitrophthalic acid anhydride is produced analogously to the process of 4-bromo-5-nitro-1,2-xylene that is described above. By boiling with ethanol, a mixture of 2-bromo-6- ethoxycarbonyl-3-nitrobenzoic acid and 3-bromo-2-ethoxycarbonyl- 4-nitrobenzoic acid is obtained from the above. 1.2 ml of oxalyl chloride is carefully added in drops to 7.2 ml of a 0.66 m solution of dimethylformamide in dichloromethane at 0.degree.C. The solution is stirred for 1 hour at 0.degree.C and for 5 minutes at room temperature. After concentration by evaporation in a vacuum, the residue is suspended in 7 ml of acetonitrile, cooled to -35.degree.C and mixed drop by drop with 1.5 g of the ester mixture. After one hour at the same temperature, it is cooled to -70.degree.C, and 2.4 ml of a 2 m solution of sodium borohydride in dimethylformamide is added in drops. It is stirred for 20 hours at room temperature, water is added, alkalized with potassium CA 02305458 2000-04-OS 43 carbonate and extracted with diethyl ether. The diethyl ether phase is dried (NazS04) and concentrated by evaporation. A mixture of 5-bromo-6-nitrophthalide and 6-bromo-5-nitrophthalide, which is separated on silica gel with hexane/ethyl acetate (95:5), is obtained. The reduction to aminophthalide is carried out as described above. 6-Bromo-5-aminophthalide, melting point 235-241.degree.C, is obtained. 5-Amino-3-(1-propenyl)-phthalide g of 2-bromo-4-nitrobenzoic acid is converted into acid chloride, which is dissolved in 50 ml of tetrahydrofuran and added in drops to 3 ml of allylamine in 20 ml of tetrahydrofuran, by 2 hours of boiling with 30 ml of thionyl chloride and distilling-off of excess thionyl chloride. After 20 hours at room temperature, it is dispersed between 1N hydrochloric acid and ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2S0q) and concentrated by evaporation. The residue is crystallized with hexane. 5.6 g of 2-bromo-4-nitrobenzoic acid- allylamide, melting point 98-100.degree.C, is obtained. This material is dissolved in 35 ml of ethanol and added in drops to a mixture of 50 g of iron(II) sulfate, 170 ml of water and 50 ml of ammonia (33%) that is heated to 60.degree.C and stirred well. After 2 hours at 60.degree.C, the mixture is absorptively precipitated 5 times with 200 ml of diethyl ether, the diethyl ether phases are concentrated by evaporation, and the residue is crystallized with hexane. 3.1 g of 4-amino-2-bromo-benzoic acid- allylamide, melting point 115-117.degree.C, is obtained. CA 02305458 2000-04-OS 44 11 g of 4-amino-2-bromobenzoic acid-allylamide, 5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid are refluxed for 1.5 hours with a water separator. Then, the solution is diluted with ethyl acetate, washed with 1N hydrochloric acid and then with potassium carbonate solution, dried (Na2S09) and concentrated by evaporation. The residue is crystallized with hexane. 13.4 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl)- benzamide, melting point 136-138.degree.C, is obtained. 3 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl)-benzamide in 100 ml of dimethoxyethane is mixed at -70.degree.C with 14.2 ml of 1.4 M butyllithium in hexane. After 30 minutes at -70.degree.C, 1.63 ml of crotonaldehyde is added. The solution is allowed to heat to room temperature, stirred for another 20 hours, 50 ml of 50~ acetic acid is added and heated for 6 hours to 60.degree.C. Then, it is diluted with water, extracted with ethyl acetate, the ethyl acetate phase is washed with potassium carbonate solution. The ethyl acetate phase is dried (Na2S04) and concentrated by evaporation. After chromatography on silica gel with hexane ethyl acetate (98:2), the residue produces 1.1 g of crystalline 5-(2,5-dimethylpyrrol-1-yl)-3-(1-propenyl)-phthalide, melting point 91-95.degree.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, w) are heated for 24 hours at 120.degree.C. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na2S09) and concentrated by evaporation and chromatographed on silica gel. 640 mg of 5- CA 02305458 2000-04-OS amino-3-(1-propenyl)-phthalide, melting point 125-130.degree.C, is obtained with dichloromethane/methanol (99:1). The phthalides of Table 4 are obtained analogously. Table 4 3b X HZN \ O O X3a/X3b Melting Point [C] CH3/H 152-156 CH3/CH3 94-97 CzHs/H 137-140 CzHs/ CzHs 95 - 9 6 CH=CHz/H 89-93 - (CHz) 4- 105-110 CA 02305458 2000-04-OS - 46 4-Bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide 412 mg of 4-methyl-4-phenyl-2-oxovaleric acid is dissolved in 10 ml of dimethylacetamide and mixed under argon at -8.degree.C with 261 mg of thionyl chloride. After 20 minutes of stirring at -3 to +3.degree.C, 228 mg of 4-bromo-5-aminophthalide is added. It is stirred for 1.5 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (NaZS09) and after the solvent is concentrated by evaporation and after treatment with diethyl ether, 360 mg of 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide, melting point 150-152.degree.C, is obtained. Analogously to the production of 4-bromo-5-(4-methyl-2-oxo- 4-phenyl-valeroylamino)-phthalide, the compounds of Tables 5 and 6 are obtained. CA 02305458 2000-04-OS 47 Table 5 Z2 Z3 N w 0 Z 0 Z Example Z" Melting Point Z ~ H (C) ZZ - I 205-207 Z3 - Cl 170-171 Z3 - Br 168-169 Z3 - I 155-157 5-[3-(1-Phenyl-cyclopropyl)-2-oxo-propionylamino]-phthalide was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclopropyl)-2-oxo- propionic acid, melting point 132-138.degree.C. 5-[3-(1-Phenyl-cyclobutyl)-2-oxo-propionylamino]-phthalide was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, melting point 142-146.degree.C. CA 02305458 2000-04-OS 48 5-(3-(1-Phenyl-cyclohexyl)-2-oxo-propionylamino]-phthalide was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclohexyl)-2-oxo-propionic acid, melting point 120-123.degree.C. The compounds of Table 6 were also produced: CA 02305458 2000-04-OS 49 Table 6 2 Z(CHz)n O 3 H Z \ N ~ \ 0 Z4 ~ / 6 IO / ~Z \ 0 Z Example n Zn Melting Point H) (C) 1 3-F 142-146 1 2-C1 148-151 1 4-C1 161-170 1 2-Br 172-178 1 3-Br 152-159 1 2,4-C12 135-138 1 3-OCHj 140-153 1 3-CF3 166-170 I 3 140-144 3 4-CH, oil 4 4-OCH3 129-130 CA 02305458 2000-04-OS 6-[3-(1-Phenyl-cyclopropyl)-2-oxo-propionylamino]-4-methyl-2,3- benzoxazin-1-one was obtained analogously to the process described for 4-bromo-5- (4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 6-amino-4- methyl-2,3-benzoxazin-1-one and 3-(1-phenyl-cyclopropyl)-2-oxo- propionic acid, melting point 197-200.degree.C. 6-[3-(1-Phenyl-cyclobutyl)-2-oxo-propionylamino]-4-methyl-2,3- benzoxazin-1-on was obtained analogously to 6-[3-(1-phenyl-cyclopropyl)-2-oxo- propionylamino]-4-methyl-2,3-benzoxazin-1-one with use of 3-(1- phenyl-cyclobutyl)-2-oxo-propionic acid, melting point 155-156.degree.C. 6-[3-(1-Phenyl-cyclohexyl)-2-oxo-propionylamino]-4-methyl-2,3- benzoxazin-1-one was obtained analogously to 6-[3-(1-phenyl-cyclopropyl)-2-oxo- propionylamino]-4-methyl-2,3-benzoxazin-1-one with use of 3-(1- phenyl-cyclohexyl)-2-oxo-propionic acid, melting point 132-134.degree.C. 5-(4,4-Dimethyl-2-oxo-5-hexenoylamino)-phthalide was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5- aminophthalide and 4,4-dimethyl-2-oxo-5-hexenoic acid, melting point 103 -104.degree.C . CA 02305458 2000-04-OS 51 6-Bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide Analogously to the example above, 1.7 g of 6-bromo-5-(4- methyl-2-oxo-4-phenyl-valeroylamino)-phthalide is obtained from 2.0 g of 4-methyl-4-phenyl-2-oxovaleric acid and 1.11 g of 6- bromo-5-aminophthalide with 1.27 g of thionyl chloride in 60 ml of dimethylacetamide, melting point 148-150.degree.C. 5-[4-(4-Iodo-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)- phthalide was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5- aminophthalide and 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo- valeric acid as a foam. 5-[4-(4-Iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5- aminophthalide and 4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid as an oil. 5-[4-(3-Iodophenyl)-4-methyl-2-oxo-valeroylamino)-phthalide was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5- aminophthalide and 4-(3-iodophenyl)-4-methyl-2-oxo-valeric acid, melting point 160-161.degree.C. CA 02305458 2000-04-OS 52 5-[4-(4-Bromo-2-methoxyhenyl)-2-oxo-valeroylamino)-phthalide was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5- aminophthalide and 4-(4-bromo-2-methoxyphenyl)-2-oxo-valeric acid, melting point 136-140.degree.C. 5-[3-(1-Phenyl-cyclopentyl)-2-oxo-propionylamino]-phthalide was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5- aminophthalide and 3-(1-phenyl-cyclopentyl)-2-oxo-propionic acid, melting point 140-144.degree.C. 6-[4-(5-Fluoro-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)-4- methyl-2,3-benzoxazin-1-one was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 4- methyl-2,3-benzoxazin-1-one and 4-(5-fluoro-2-methoxyphenyl)-4- methyl-2-oxo-valeric acid, melting point 171-173.degree.C. 6-[4-(5-Fluoro-2-methoxyhenyl)-4-methyl-2-oxo-valeroylamino)-4- ethyl-2,3-benzoxazin-1-one was obtained analogously to the process that is described for 4- bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 4- ethyl-2,3-benzoxazin-1-one and 4-(5-fluoro-2-methoxyphenyl)-4- methyl-2-oxo-valeric acid, melting point 157-158.degree.C. CA 02305458 2000-04-OS 53 6-Amino-4-methyl-2,3-benzoxazin-1-one 60 g of 2-methyl-5-nitroacetophenone, 38.5 g of 2,2- dimethyl-1,3-propanediol and 6 g of p-toluenesulfonic acid are boiled in 1 1 of toluene with a water separator until water is no longer produced. The solution is washed with potassium bicarbonate, dried (Na2S09) and concentrated by evaporation. 71.7 g of the crystalline ketal is obtained from pentane. The latter is oxidized in 1.5 1 of pyridine and 4.5 1 of water with 350 g of potassium permanganate, as described above in the production of 4-bromo-5-aminophthalide. 56.4 g of 4-nitro-2- (2,5,5-trimethyl-1,3-dioxan-2-yl)-benzoic acid is obtained. 52 g of the acid is hydrogenated in 500 ml of methanol and 500 ml of ethyl acetate with 10 g of palladium/carbon (10%). 45.5 g of the crystalline amino compound is obtained from pentane. g of the amine is refluxed with 100 ml of concentrated hydrochloric acid for 2 hours. The solvent is concentrated by evaporation in a vacuum, and the residue is refluxed with 15.7 g of hydroxylamine hydrochloride, 8.4 g of potassium hydroxide, 120 ml of ethanol and 50 ml of water for 12 hours. It is diluted with water, and the crystals are suctioned off. After drying, 3.5 g of 6-amino-4-methyl-2,3-benzoxazin-1-one, melting point 291-296.degree.C, is obtained. 6-Amino-4-ethyl-2,3-benzoxazin-1-one is obtained analogously from 2-methyl-5-nitropropiophenone, melting point 89-93.degree.C. CA 02305458 2000-04-OS 54 6-Amino-1-methyl-1H-benzotriazole is described in Heterocycles 36, 259 (1993). 5-Amino-benz[1,2,5]oxadiazole is described in Boll. Sci. Fac. Chim. Ind. Bologna, 22, 33, 36, 37 (1964) . 5-Amino-benz[1,2,5]thiazole is described in J. Heterocycl. Chem. 11, 777 (1974). 5-Amino-1-indanone is described in J. Org. Chem. 27, 70 (1962). 6-Amino-1,2,3~4-tetrahydro-1-naphthalinone is described in J. Org. Chem. 27, 70 (1962). 6-Amino-3,4-dihydro-1H-2-benzopyran-1-one is produced by catalytic hydrogenation (palladium/carbon) in ethanol from the corresponding nitro compound (Canad. J. Chem. 61, 2643 (1983) . The examples below are used for a more detailed explanation of the invention. Other compounds can be produced by using homologous/analogous reagents. The required starting compounds are described above under "Starting Compounds." CA 02305458 2000-04-OS Example 1 (Process 1) 4-Bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide 350 mg of 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)- phthalide is dissolved under argon in 15 ml of dimethylformamide and mixed with 0.77 ml of trifluoromethyltrimethylsilane and 350 mg of cesium carbonate while being cooled with ice. After 3 hours of stirring at room temperature, 5 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and some drops of water are added and stirred for one hour at room temperature. After 100 ml of water is added, it is extracted with ethyl acetate, the organic phase is dried (Na2S04) and concentrated by evaporation. 250 mg of 4-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2- trifluoromethyl-valeroylamino)-phthalide, melting point 187- 194.degree.C, is obtained. Example 2 6-Bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide is obtained analogously to Example 1 from 1.6 g of 6-bromo-5-(4- methyl-2-oxo-4-phenyl-valeroylamino)-phthalide, 3.5 ml of trifluoromethyltrimethylsilane and 1.6 g of cesium carbonate, melting point 205-210.degree.C. CA 02305458 2000-04-OS 56 Example 3 5-(2-Hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino)- phthalide is obtained analogously to Example 1 from 20 mg of 5-(4-methyl-2- oxo-4-phenyl-valeroylamino)-phthalide, 0.1 ml of trimethyl- pentafluoroethylsilane and 20 mg of cesium carbonate, melting point 187-189.degree.C. Example 4 5-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethyl- valeroylamino]-phthalide is obtained analogously to Example 1 from 30 mg of 5-[4-(3- methoxyphenyl)-4-methyl-2-oxo-valeroylamino]-phthalide, 0.13 ml of trifluoromethyltrimethylsilane and 30 mg of cesium carbonate, melting point 173-178.degree.C. Example 5 5-(2-Hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino)- phthalide is obtained analogously to Example 1 from 200 mg of 5-(4,4- dimethyl-2-oxo-5-hexenoylamino)-phthalide, 0.22 ml of trifluoromethyl-trimethylsilane and 258 mg of cesium carbonate, melting point 153-157.degree.C. The compounds of Table 7 are obtained analogously to Example 1. CA 02305458 2000-04-OS 57 Table 7 2 OH CFa (CHz)n N _ w v 4 ~ / g p I / O Z 'Z O Zg Example n Zn Melting Isomerism H) Point (C) 6 1 168-175 racemate 7 1 172-179 (+)-enantiomer 8 1 172-179 (-)-enantiomer 9 1 3-F 155-158 racemate 1 2-C1 192-194 racemate 11 1 4-Cl 148-154 racemate 12 1 4-Cl 174-176 (+)-enantiomer 13 1 4-C1 173-175 (-)-enantiomer 14 1 2-Br 163-165 racemate 1 3-Br 189-191 racemate 16 1 2,4-Clz 216-218 racemate 17 1 2-OCH3 200-208 (+)-enantiomer 18 1 2-OCH3 195-208 (-)-enantiomer 19 1 3-OCH3 225-228 racemate 1 3-CF3 152-163 racemate 21 2 182-188 racemate 22 2 187-192 (+)-enantiomer 23 2 188-192 (-)-enantiomer CA 02305458 2000-04-OS 58 24 3 106-112 (+)-enantiomer 25 3 4-CH3 179-183 racemate 26 4 165-171 racemate 27 4 170-174 (+)-enantiomer 28 4 170-174 (-)-enantiomer If 6-amino-4-methylbenzoxazinone instead of the aminophthalide is used in Example l, the compounds that are listed in Table 8 are obtained. Table 8 (CHZ)n OH CFA I / ~- 1~ I \ wN % O O Example n Melting Point Isomerism (~C) 29 1 78-84 racemate 30 1 227-235 (+)-enantiomer 31 230-239 (-)-enantiomer 32 2 174-184 racemate 33 4 185-187 racemate 34 4 90-97 (+)-enantiomer ~' 35 4 90-96 (-)-enantiomer CA 02305458 2000-04-OS 59 Table 9 2 Z O CFA Z3 \ ~ \ ~O 4 / g O / Z ~ ~Z - O Z Example Zn Melting Point ( # H) (C) 3 6 ZZ - I amor hous 37 Z3 - Cl 174 38 Z3 - Br 182-183 39 Z3 - I 190-191 Example 40 6-(2-Hydroxy-2,4-dimethyl4-phenyl-valeroylamino)-4-methyl-2,3- benzoxazin-1-one 72 mg of 6-(4-methyl4-phenyl-2-oxo-valeroylamino)-4-methyl- 2,3-benzoxazin-1-one in 4 ml of tetrahydrofuran is mixed with 3 ml of methylmagnesium bromide (3 mol) at 0.degree.C. After 30 minutes, ammonium chloride solution is added, the organic phase is separated, dried and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 1:1), 39 mg of 6-(2-hydroxy-2,4-dimethyl4-phenyl-valeroylamino)-4-methyl-2,3- benzoxazin-1-one, melting point 173-175.degree.C, is obtained. CA 02305458 2000-04-OS Example 41 (Process 2) 5-(2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide 500 mg of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid (Eur. Appl. 0 253 500 (Imperial Chemical Industries)) in 10 ml of dimethylacetamide is mixed at -15.degree.C with 0.14 ml of thionyl chloride. After 3 hours of stirring at -15.degree.C, 600 mg of 5- aminophthalide (solid) is added. The solution is stirred for 2 hours at -15.degree.C and then left for 18 hours at room temperature, then mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (NazSOq) and concentrated by evaporation. The residue is stirred with diethyl ether and suctioned off. 290 mg of 5-(2-hydroxy-4-phenyl-2- trifluoromethyl-valeroylamino)-phthalide, melting point 166- 168.degree.C, is obtained. Example 42 6-(2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)-4-methyl- 2,3-benzoxazin-1-one is obtained analogously to Example 41 from 784 mg of 2-hydroxy-4- phenyl-2-trifluoromethyl-valeric acid in 17 ml of dimethylacetamide and 500 mg of 6-amino-4-methyl-2,3-benzoxazin- 1-one, melting point 172-173.degree.C. The compounds that are presented in Table 10 are produced analogously to Example 41: CA 02305458 2000-04-OS 61 TABLE 10 2 2 3b CH, R CF3 OH Z3 \ N 4 ~ / g 10 E X Example R2 W X Zn Melting Iso- ( ~H) (#H) point merism (C) or (a) o (c=0.5) (2) 43 H 0 X3/X3b=H . 175-185 Diast . /CH3 mixture 44 H O X3a=H, 175-178 +22.5 X3b=CH3 45 H 0 X3a=H, 210-213 -74 X3b=CH3 46 H O X3=CH3, 210-213 -69.5 X3b=H 47 H 0 X3'=CH3, 175-179 -21.5 X3b=H 48 H 0 X3a=C2H5 169-174 49 H 0 X3a=CH= 162-174 CH~ 50 H O X3'=CH= 160-162 CH2 - CH, 51 H 0 X3a=CF3 156-166 2 H O X3a=X3b- 16 0 -171 CH3 53 H 0 X''=X'~- 172-176 CZHS I 54 H 0 X3a+X3b- 16 8 -17 0 (CH~) CA 02305458 2000-04-OS 62 55 H O XQ=Br 180-185 56 CH~ 0 159-162 57 CH3 O Xq=Br 187-194 58 CH3 O ZZ=CH3 155-156 race- mate I 59 CH3 O ZZ=CH3 148-149 (+) - f o rm 60 CH3 O ZZ=CH3 145-146 (-)- form 61 CH3 O Z4=CH3 189-190 CA 02305458 2000-04-OS 63 Table 10 (Continuation) Example Rz W X Z Melting Iso- (#H) (#H) point merism (C) or Ial n (C=0.5) (2) 62 CH3 O Z3=Z4= 206-207 race- CH3 mate 63 CH3 O Z3=Zq= 207-209 (+) - CH, form 64 CH3 0 Z3=Zq= 207-209 (-) - CH3 form 65 CH3 O Z3=ZS= 154 race- CH3 mate 66 CH3 0 Z3=ZS= 188-189 (+) - CH3 form 67 CH3 0 Z3=ZS= 188 ( _ ) - CH3 form 68 CH3 0 Z3/Zq= 171-173 (CHZ) 3 69 CH3 O Z3/Z9= 218-219 -CH=CH- CH=CH- 70 CH3 O Z9=F 177-178 71 CH3 O Z9=C1 184-185 72 CH3 0 Z9=Br 177-179 73 CH3 0 Zz=OCH3 134-135 race- mate 74 CH3 0 ZQ=OCH3 183-184 75 CH3 O ZZ=ZS= 145 OCH3 76 CH3 O Z2=OCH3, 126-127 race- I ZS=CH3 mate 77 CH3 0 ZZ=OCH3, 169-170 (+) - ZS=CH3 form 78 CH3 0 Z2=OCH3, 169 (-) - ZS=CH3 form CA 02305458 2000-04-OS 64 79 CH3 0 Z2=OCH3, 180-181 Z4=F 80 CH3 O ZZ=OCH3, 140-141 ZS=F Table 10 (Continuation) Example Rz W Xn Zn Melting Iso- (~H) (#H) point merism (~C) Or ~a~ D (c=0.5) (2) 81 CH3 O Z9=OCH3, 207 ZZ=F 82 CHj 0 Z4=OCH3, 178-179 Z3=F 83 CH3 O ZZ=OCH3, 141 race- ZS=Cl mate 84 CH3 0 ZZ=OCH3, 106-108 +105.5 ZS=C1 ( 1 ) 85 CH3 0 Zz=OCH3, 105-207 -97 (1) ZS=C1 86 H S 189-191 87 CH3 S 173-175 88 H CHZ 161-162 89 H 0-CHZ 192-195 (3) 90 CH3 0 Z9=CH= 190-192 race- CHZ mat a 91 CH3 0 Z4=CN 230-233 race- mate 92 CH3 0 Z4=COCH3 174-176 race- mate 93 CH3 O Z9=CONHZ 130-132 race- mate 94 CHj O ZZ=OCH3, 144-145 race- Z'=Br mate CA 02305458 2000-04-OS 95 CH3 O ZZ=OCHj, 176-177 (+) - Zq=Br enanti- omer 96 CH3 0 ZZ=OCH3, 177-178 -139.6 Z9=Br 97 CH3 O ZZ=Br, 197-198 race- Z9=OCH3 mate 98 CH3 O Zz=OCH3, 135-136 race- Z9=CN mate 99 CH3 0 Z3=NOZ, 202-206 race- Z9=OCH3 mate 100 CH3 0 Zz=COCH3 135 race- Z'=CH mate (CHg) 2 101 CH3 0 Z3=COCH3 213-214 race- Z9=OCH3 mate (1) The optically active compounds that are presented in Table 10 were separated analogously to Example 88. (2) In methanol. (3) Formation of a 1-isochromanone. Example 102 (+) and (-) 5-[2-Hydroxy-4-methyl-4-(2-methoxyphenyl)-2- trifluoromethyl-valeroylamino]-phthalide The enantiomer mixture of Example 73 is separated by chromatography on chiral carrier material (CHIRALPAK AD~R~, DAICEL Company) with hexane/2-propanol/ethanol (900:25:25, vvv). Thus, from 200 mg of racemate, there are obtained 73 mg of (-) -form, melting point 136-137.degree.C, [a]D = -194.8.degree. (c - 0.5 in chloroform), 59 mg of (+) -form, melting point 135-136.degree.C, [a] D = +192 .2.degree. (c - 0.5 in chloroform). CA 02305458 2000-04-OS 66 Example 103 5-[2-Hydroxy-4-methyl-4-(2-thienyl)-2-trifluoromethyl- valeroylamino]-phthalide and 5-[2-Hydroxy-4-methyl-4-(3-thienyl)-2-trifluoromethyl- valeroylamino]-phthalide The mixture of 2-hydroxy-4-methyl-4-(2-thienyl)-2- trifluoromethyl-valeric acid and 2-hydroxy-4-methyl-4-(3- thienyl)-2-trifluoromethyl-valeric acid (9:1) was reacted with 5- aminophthalide analogously to Example 41. After the position isomers are separated by chromatography and after the racemates are separated analogously to Example 102, there are obtained (+)-5-[2-hydroxy-4-methyl-4-(2-thienyl)-2-trifluoromethyl- valeroylamino] -phthalide, .melting point 166.degree.C, aD = +163.6.degree. (c = 0.5 in chloroform), (-)-5-[2-hydroxy-4-methyl-4-(2-thienyl)-2- trifluoromethyl-valeroylamino]-phthalide, melting point 166.degree.C, aD - -160.8.degree. (c = 0.5 in chloroform), (+)-5-[2-hydroxy-4-methyl-4- (3-thienyl)-2-trifluoromethyl-valeroylamino)-phthalide, melting point 135.degree.C and (-)-5-[2-hydroxy-4-methyl-4-(3-thienyl)-2- trifluoromethyl-valeroylamino]-phthalide, melting point 135.degree.C. Example 104 (Process 3) 5-(2-Hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-phthalide 760 mg of 5-acetamido-phthalide in 20 ml of dimethylformamide is mixed at 0.degree.C with 144 mg of sodium hydride (80% in mineral oil), and, after 20 minutes, with 800 mg of 4- toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl- CA 02305458 2000-04-OS 67 pentyl)-ester. After 16 hours at 60.degree.C, the solvent is concentrated by evaporation in a vacuum, the residue is dissolved in ethyl acetate, washed with water, dried (Na2S04) and concentrated by evaporation. After chromatography on silica gel with cyclohexane/ethyl acetate (2:1), 266 mg of 5-(2-hydroxy-4- phenyl-2-trifluoromethyl-pentylamino)-phthalide, melting point 110.degree.C, is obtained. The compounds of Table 11 are obtained analogously to Example 104. Table 11 H N W O Z.degree. Example RZ W Zn Melting Iso- (#H) point merism (C) or LaID (C=0.5) (2) 105 H 0 110 race- mate 106 H 0 123 +18.6 107 H O 123 -18.4 108 CH3 O 139-140 race- mate CA 02305458 2000-04-OS 68 109 CH3 0 159-160 +12.0 (4) 110 CH3 O 160-161 -12.5 (4) 111 CH3 O ZQ - F 148-149 race- mate 112 CH3 O Zq - F 162-164 +9.0 113 CH3 0 Z' - F 162-164 -6.7 114 CH3 O ZZ - OCH3, ZS - 148-149 F 115 H CHZ 161-162 116 H OCHZ 127-128 (3) (1) The optically active compounds that are presented in Table 11 were separated analogously to Example 102. (2) In methanol (3) Formation of a 1-isochromanone. (4) In chloroform. Example 117 4-Ethyl-6-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-2,3- benzoxazin-1-one The compound is obtained analogously to Example 104 from 151 mg of 6-acetamido-4-ethyl-2,3-benzoxazin-2-one, 208 mg of 4- toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl- pentyl)ester and 36 mg of sodium hydride, melting point 161- 163.degree.C. Example 118 1-(4-Nitro-3-trifluoromethylanilino)-4-phenyl-2-trifluoromethyl- 2-pentanol 100 mg of 4-nitro-3-trifluoromethylacetanilide in 2 ml of dimethylformamide is mixed at 0.degree.C with 12 mg of sodium hydride CA 02305458 2000-04-OS 69 (80.degree.s in mineral oil) and, after 20 minutes, with 150 mg of 2-(2- phenylpropyl)-2-trifluoromethyl-oxiran. It is stirred for 16 hours at 60.degree.C, diluted with water and extracted with ethyl acetate. After washing with water, the ethyl acetate phase is dried (Na2S09) and concentrated by evaporation. 80 mg of N-(2- hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroyl)-4-nitro-3- trifluoromethylaniline, melting point 119-120.degree.C, is obtained. After racemate separation analogously to Example 102, there are obtained the ( - ) - form, [a] D = -4 9 . 6.degree. ( c = 0 . 5 in chloroform) , the (+) -form, [a] D = +48 .8.degree. (c = 0 .5 in chloroform) . Example 119 (Process 4) 6-(3-Hydroxy-3-methyl-1-butiayl)-5-(2-hydroxy-4-methyl-4-phenyl- 2-trifluoromethyl-valeroylamino)-phthalide 150 mg of the bromine compound of Example 2 is dissolved together with 30 mg of 2-methyl-3-butin-2-ol, 0.24 mg of copper(I) iodide and 0.9 mg of triphenylphosphine in 1.5 ml of pyridine and mixed under argon with 0.25 mg of bis- triphenylphosphine-palladium-II-chloride. After 5 hours of reflux boiling, another 30 mg of 2-methyl-3-butin-2-of is added, and it is refluxed for 20 hours. It is diluted with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na2S0q) and concentrated by evaporation. The crude product is chromatographed on silica gel. With cyclohexane/ethyl acetate (1:1), 60 mg of crystalline 6-(3-hydroxy-3-methyl-1-butinyl)-5- CA 02305458 2000-04-OS (2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)- phthalide, melting point 162-168.degree.C, is obtained. Example 120 6-Acetyl-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide 100 mg of the bromine compound of Example 2 is dissolved together with 95 mg of tributyl-(1-ethoxyvinyl)-tin and 8 mg of bis-triphenylphosphine-palladium-II-chloride in 4 ml of toluene under argon. After 5 hours of reflux boiling, another 45 mg of bis-triphenylphosphine-palladium-II-chloride is added, and it is refluxed for 20 hours. 1N hydrochloric acid is added and extracted with ethyl acetate. The ethyl acetate phase is dried (NaZS04) and concentrated by evaporation. The crude product is stirred in 3 ml of tetrahydrofuran and 3 ml of 2N hydrochloric acid for 2 days at room temperature. It is mixed with water and extracted with ethyl acetate. After washing with water, it is dried (Na2S09) and concentrated by evaporation. The residue is pulverized with diethyl ether/pentane, and 21 mg of crystalline 6-acetyl-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide, melting point 195-199.degree.C, is obtained. The compounds of Table 12 are obtained analogously to Examples 119 and 120. CA 02305458 2000-04-OS / 1 Table 12 Z2 CH~CH~ OH CFA Xa Z3 N / ~ ~ ~ \ O Z ~Z s X / ZS X~ O Example X Z Melting Point CC) 121 Xq=CH=CH2 foam 122 X6=CH=CHz 191-197 123 X6=C (OCzHS) 160-163 =CH2 124 X6=C=C-CHZOH 208-211 125, X6=C6Hs 160-163 126 157-158 X6= 127 X6=C6HqOCH3 (p-) 125-127 128 Z''=CH=CHz 178 -18 0 129 Z'=CZHS (a) 152-153 130 Z'=COCH3 ('') 220 131 Z'=CN 112 132 Z4=CH=CHZ 190-192 133 ~ Z4=COCH3 ('a) 205-207 v i .....~-umv.u itVm t-11C VlLly1 (.:UIII~J~L1I1Q Dy catalytic hydrogenation. (;') Obtained from the enol ether by mild acidic hydrolysis. CA 02305458 2000-04-OS 72 Example 134 (Process 5) 5-[4-(3-Fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-4-2- trifluoromethyl-valeroylamino]-phthalide 132 mg of 5-[4-(3-fluoro-4-methoxyphenyl)-2-hydroxy-4- methyl-4-2-trifluoromethyl-valeroylamino]-phthalide (Example 82) is dissolved in 15 ml of dichloromethane and mixed at 0.degree.C with 1.2 ml of a 1 M solution of boron tribromide in dichloromethane. After 16 hours at 0.degree.C, ice, ethyl acetate and potassium bicarbonate are added to the mixture, and the ethyl acetate phase is separated, dried (Na.S04) and concentrated by evaporation. 120 mg of 5-[4-(3-fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-4-2- trifluoromethyl-valeroylamino]-phthalide, melting point 139- 140.degree.C, is obtained from ethyl acetate/diisopropyl ether/hexane. The compounds that are presented in Table 13 are obtained analogously to Example 86. Table 13 Z2 HO CF3 Z3 ~ _ g~N w O 4 ~ / 6 / Z ~ 'Z \o ~5 CA 02305458 2000-04-OS Example H Zn Melting Isomerism (~H) Point or (c) tal D (c=0.5)(2) 135 C=O Zz=OH 222-224 136 C=O Z9=OH 228-230 137 C=0 ZZ=Zs=OH 265-267 138 C=O Z2=OH, 215-217 racemate Zs=CHs 139 C=O Z2=OH, 173-174 (+)-form Z s=CH3 140 C=O Z2=OH, 173-174 (-) -form Zs=CH3 141 C=0 ZZ=OH, Zq=F 240-242 142 C=O ~ ZZ=OH, Zs=F 201-202 143 C=O ZQ=OH, Z2=F 242-243 144 C=0 ZZ=OH, Zs=C1 220-221 145 CHZ Z2=OH, Zs=F 156-157 racemate 146 CHz ZZ=OH, Zs=F 157-159 +23.5 147 CH2 ZZ=OH, Zs=F 157-159 -18.7 148 C=0 ZZ=OH, Zq=Br 224-226 racemate 149 C=0 Z3=NO2, - 167-169 racemate Z9=OH 150 C=0 Z3=C1, Z4=OH 168-169 racemate 151 C=0 Z3=Br, Zq=OH 105 racemate (1) The optically active compounds that are presented in Table 13 were separated analogously to Example 102. (2) In methanol. CA 02305458 2000-04-OS 74 Example 152 5-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-4-2-trifluoromethyl- valeroylamino]-phthalide 66 mg of (3-fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-4-2- trifluoromethyl-valeroylamino)-phthalide is stirred with 126 mg of potassium carbonate and 108 mg of 5-chloro-lphenyl-1H- tetrazole in 3 ml of dimethylformamide for 16 hours. Then, the dimethylformamide is distilled off in.a vacuum, and the residue is dispersed between 1N hydrochloric acid and ethyl acetate. After washing with water, the ethyl acetate phase is dried (Na2S04) and concentrated by evaporation, and the residue is chromatographed on silica gel with hexane/ethyl acetate (1:1). The product is hydrogenated in 10 ml of methanol with 30 mg of palladium/carbon (10%). After the catalyst is removed and the solvent is concentrated by evaporation, the product is chromatographed on silica gel with hexane/ethyl acetate (1:1). 49 mg of 5-[4-(3-fluorophenyl)-2-hydroxy-4-methyl-4-2- trifluoromethyl-valeroylamino)-phthalide, melting point 157.degree.C, is obtained. By racemate cleavage analogously to Example 102, the (+)- form is obtained with melting point 140-141.degree.C, and the (-)-form is obtained with melting point 141.degree.C. CA 02305458 2000-04-OS Example 153 5-[2-Hydroxy-4-methyl-4-(3-tolyl)-2-trifluoromethyl- valeroylamino]-phthalide The compound is produced analogously to the example above from 57 mg of 5-[2-hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl- 2-trifluoromethyl-valeroylamino]-phthalide, melting point 152- 153.degree.C. By racemate cleavage analogously to Example 102, the (+)- form is obtained with melting point 148-149.degree.C, and the (-)-form is obtained with melting point 145-146.degree.C. Example 154 5-[4-(5-Fluoro-2-ethoxyphenyl)-2-hydroxy-4-methyl-4-2- trifluoromethyl-valeroylamino]-phthalide 44 mg of 5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl- 4-2-trifluoromethyl-valeroylamino]-phthalide is stirred in 1 ml of dimethylformamide with 28 mg of potassium carbonate and 50 mg of ethyl iodide for 24 hours at room temperature. It is then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2S09) and after the solvent is concentrated by evaporation, 35 mg of 5-[4-(5-fluoro-2- ethoxyphenyl)-2-hydroxy-4-methyl-4-2-trifluoromethyl- valeroylamino]-phthalide, melting point 108.degree.C, is obtained. The compounds of Table 14 were produced analogously to Example 154. CA 02305458 2000-04-OS 76 Table 14 OR OH CF3 H N O F O Example R Melting Point Isomerism or (C) (a] D (c=0.5) (2) 155 CH(CH3)~ 153-154 r acemate 156 CHZCH=CHZ 152 racemate 157 CHZCH=CHZ 187-189 racemate 158 CHZCN 170-172 racemate 159 CHzCOOC(CH3)3 145 racemate 160 CHZCOOC (CH3) 143 -131.5 I s 161 CH2COOC (CH3) 142-143 (+) -form 3 Example 162 5-[4-(3-Chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide 22 mg of 5-[2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide is stirred in 1.5 ml of methanol with 20 mg of N-chlorosuccinimide. The mixture is then dispersed in ice water, sodium bicarbonate solution and ethyl acetate, the ethyl acetate pahse is dried, and it is concentrated by evaporation. 20 mg of 5-[4-(3-bromo-4-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide, CA 02305458 2000-04-OS 77 which melts at 189-191.degree.C after recrystallization from isopropylether, is obtained. 5-[4-(3-Chloro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide is obtained from 5-[4-(3-chloro-4-methoxyphenyl)-2-hydroxy-4- methyl-2-trifluoromethyl-valeroylamino]-phthalide by ether cleavage analogously to Example 134, Melting point 105.degree.C. The 2,3-benzoxazinone and phthalazinone derivatives of Table 15 were produced according to the above-mentioned process. Table 15 Z2 CHI R2H0 CFA Y 5 Y 4 Z3 H \ BiN \ ~ N Z / Z6 ~, ~ / V ZS Y$ O CA 02305458 2000-04-OS 78 Example R2 V Zn B 'Y" Melting Iso- (#H) (#H) point merism (C) or talD (c=0.5) (2) 163 H 0 C=O Y9=CH3 165-166 race- mate 164 H O C=O Yq=CZHS 159-160 race- mate 165 CH3 0 C=0 Y9=CH3 185 +162 166 CHj 0 C=O Y9=CH3 184-185 -182 167 CH3 O C=0 Y4=CZHS 148-153 race- mate 168 CH3 0 C=0 Y9=CZHS 159-160 +173 169 CH3 O C=0 Y9=CzHs 159-160 -175 CA 02305458 2000-04-OS 79 Example R2 V Zn B Y" Melting Iso- (#H) (#H) point merism (c) or fa]D (c=0.5) (2) 170 CH3 O ZZ=OCH3 C=O YQ=CH3 161-163 race- mate 171 CH3 O Zz=OCH3 C=O YQ=CH3 173-175 -54.7 (4) 172 CH3 0 ZZ=OCH3 C=O Y9=CH3 173-175 +52.2 173 CH3 0 ZZ=OCH3 C=0 Y'=C2H5 164 race- materia 1e 174 CH3 0 ZZ=OCH3 C=O Y4=CZHS 19 0 -191( + ) - form 175 CH3 O ZZ=OCH3 C=0 Y9=CZHS 190-191 -161.3 (CHC13) 176 CH3 0 ZZ=OCH3, C=0 Yq=CH3 165 race- ZS=F mate 17 7 CH3 0 ZZ=OCH3 C=O Y4=CH3 18 8 -18 ( + ) - , 9 ZS=F form 178 CH3 0 Zz=OH3, C=0 Y4=CH3 187-188 -132 8 ZS=F . (CHC13) 179 CH3 O Z2=OH3, C=0 Yq=CZHS 126-128 race- ZS=F mate 18 0 CH3 O ZZ=OCH3 C=O Y'=CZHS 17 0 -171-14 7 , 4 ZS=F . 181 CH3 0 ZZ=OCH3 C=0 Y4=CZHS 171 ( + ) - , ZS=F form 182 CH3 O Zz=OCH3, C=0 Yq=CH3 182-184 race- ZS=C1 mate 183 CH3 0 ZZ=OCH3, C=O Y4=CH3 198-199 (+) - ZS=C1 form 184 CH3 O ZZ=OCH3, C=0 Y4=CH3 197-198 -90 2 ZS=CZ . 185 CH3 O ZZ=OCH3, C=0 Yq=CH3 206-207 race- ZQ=Br mate 186 CH3 0 ZZ=OCH3, C=O Y'=CH3 194-198 (+) - ZQ=Br form CA 02305458 2000-04-OS 187 CH3 O Z2=OCH3, C=O YQ=CH3 196-198 -122.2 ZQ=Br (CHC1,) ' 188 CHI 0 Z9=CH, C=0 Yq=CH3 222-223 race- mate 189 CH3 0 ZQ=CH3 C=O YQ=CZHS 187-188 race- mate 190 CH3 O Z9=CH3 C=O Yq=C~HS 160 -63.7 191 CH3 0 ZQ=CH3 C=0 YQ=CZHS 160 (+) - f o rm 192 CH3 0 Zq=F C=0 Y4=CH, 188-190 race- mate 193 CH3 O ZQ=Br C=O Yq=CH3 219-220 race- mate 194 CHI 0 Z'=Br C=O YQ=CH3 231-233 -49.3 195 CH3 0 Zq=Br C=O Yq=CH3 231-233 (-) - f orm 196 CH, 0 C=0 Y'=CF, 175-183 197 CH3 NH C=O Yq=CH3 198 CH3 NCH3 C=0 Y9=CH3 199 CH3 0 ZZ=OH, C=0 YQ=CH3 234-236 race- ZS=F mate 200 CH3 O Z2=OH, C=O Yq=CH3 232-234 (-) - ZS=F form 201 CH3 0 ZZ=OH, C=0 YQ=CH3 232-234 -34.1 ZS=F 202 CH, 0 ZZ=OH, C=0 q=CHI 248-250 race- Y Zq=Br mate 203 CH3 O Z3=NO2, C=0 YQ=CH3 215-217 race- Zq=OCH3 mate 204 H O CHz Yq=CH; 148-149 race- mate 205 CH3 O CH2 Y"=CH3 132-133 race- mate ~~ 206 CH3 0 CHZ Yq=CZHS 121-122 race- mate (1) The optically active compounds that are presented in Table 15 were separated analogously to Example 102. (2) In methanol. CA 02305458 2000-04-OS 81 Example 207 5-(2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)- benz[1,2,5]oxadiazole The compound was obtained from 2-hydroxy-4-phenyl-2- trifluoromethyl-valeric acid and 5-amino- benz[1,2,5]oxadiazole analogously to Example 41. Melting point 192.degree.C. Example 208 5-(2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamiao)- benzo(1,2,5]thiadiazole The compound was obtained from 2-hydroxy-4-phenyl-2- trifluoromethyl-valeric acid and 5-amino- benzo[1,2,5]thiadiazole analogously to Example 41. Melting point 166-167.degree.C. Example 209 6-(2-Hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)-1 methyl-benzotriazole The compound was obtained from 2-hydroxy-4-phenyl-2 trifluoromethyl-valeric acid and 6-amino-1-methyl benzotriazole analogously to Example 41. Melting point 194-196.degree.C.

Claims (44)

  1. 82 The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 1. A compound of formula I <IMG> in which: R1 and R2 are the same or different and each stands for a hydrogen atom, a C1-C5 alkyl group or a halogen atom, or R1 and R2 together with the C-atom of the chain form a 3- to 7-membered ring; R3 stands for a C1-C5 alkyl group, or a partially or completely fluorinated C1-C5 alkyl group; A stands for a monocyclic or bicyclic, carbocylic or heterocyclic, aromatic ring that is optionally substituted by one or more radicals selected from: halogen atoms; C1-C5 alkyl groups; alkenyl groups of the formula -CR5=CR6R7 (wherein R5, R6 and R7 are the same or different and, independently of one another, are each hydrogen atoms or C1-C5 alkyl groups); hydroxyl groups; hydroxyl groups that carry a C1-C10 acyl group, a C3-C10 carbalkoxyalkyl group, a C2-C5 cyanoalkyl group, a C3-C10 unsubstituted or substituted allyl group, a C3-C10 unsubstituted or substituted propargyl group, a C2-C5 alkoxyalkyl group, or a C1-C5 alkyl group that is partially or completely substituted by fluorine atoms; cyano groups; nitro groups: C1-C5 alkoxy groups; C1-C5 alkylthio groups; mono- or di-substituted C1-C10 amino groups; and partially or completely fluorinated C1-C5 alkyl groups; 83 A may also stand for: an ester group -COOR4 in which R9 is a C1-C5 alkyl group; an alkenyl group of the formula -CR5'=CR6'R7' (wherein R5', R6' and R7' are the same or different, and independently of one another, are each hydrogen atoms, halogen atoms, aryl radicals or C1-C5 alkyl groups); an alkynyl group of the formula -C.ident.CR5 in which R5 is a hydrogen atom or a C1-C5 alkyl group; or a partially or completely fluorinated C1-C5 alkyl group; B stands for a carbonyl group or a CH2 group; and Ar stands for a ring system, selected from the group of partial general formulas 2 through 11: <IMG> in which: radicals X3a, X4, X6, X7 (in partial formula 2), X4, X6, X7 (in partial formulas 3 and 4) , X3a, X3b, X4, X6, X7 (in partial formulas 5, 6 and 7) or Y4, Y5, Y7 and Y8 (in partial formulas 8, 9, 10 and 11) are each the same or different and are selected from: hydrogen atoms; C1-C5 84 alkyl groups, which in addition may contain a hydroxy group that is optionally etherified with a C1-C5 alkyl group or esterified with a C1-C5 alkanoyl group; partially or completely fluorinated C1-C5 alkyl groups; alkenyl groups of the formula -CR5=CR6R7 (wherein R5, R6 and R7 are the same or different and, independently of one another, are each hydrogen atoms or C1-C5 alkyl groups); and alkynyl groups of the formula -C.ident.CR5 in which R5 is a hydrogen atom or a C1-C5 alkyl group; or radicals X3a and X3b together with the C-atom of the benzocondensed ring system of partial formula 5, 6 or 7 can form a 3- to 7-membered ring; or radicals X4, X6, X7, (in partial formulas 2, 3, 4, 5, 6 and 7) or Y4, Y5, Y7, Y8 (in partial formulas 8, 9, and 11) are selected from: halogen atoms; hydroxy groups; C1-C5 alkoxy groups; and C1-C5 alkanoyloxy groups; and, if B in general formula I is a CH2 group, Ar also can be a phenyl radical of partial general formula 12 <IMG> in which: R9 and R10 are the same or different and each mean a cyano group, a nitro group, a halogen atom, a C1-C5 alkyl group, a partially or completely fluorinated C1-C5 alkyl group, a C1-C5 alkylthio group, a C1-C5 alkylsulfinyl group or a C1-C5 alkylsulfonyl group; or, if B stands for a CH2 group, a physiologically-compatible salt of a compound of formula I.
  2. 2. A compound according to claim 1, wherein B is a carbonyl 85 group or a CH2 group, and Ar is a ring system selected from the group of partial general formulas 2 through 11.
  3. 3. A compound according to claim 1 or 2, wherein the compound is in the form of a racemate or diastereomer mixture.
  4. 4. A compound according to claim 1 or 2, wherein the compound is in the form of a separate optical isomer.
  5. 5. A compound according to any one of claims 1 to 4, wherein R1 and R2 are the same or different, and each stands for a hydrogen atom, methyl or ethyl, or R1 and R2 together with the C-atom to which they are attached form a cyclopropyl ring.
  6. 6. A compound according to any one of claims 1 to 5, wherein R3 stands for a C1-C5 perfluoroalkyl group.
  7. 7. A compound according to any one of claims 2 to 6, wherein A stands for a benzene, naphthalene or thiophene ring, which in each case optionally is substituted by one or more radicals selected from: fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, vinyl groups, hydroxy groups, methoxy groups and ethoxy groups.
  8. 8. A compound according to any one of claims 1 to 6, wherein said monocyclic or bicyclic heteroaromatic ring of substituent A is thienyl, furyl, pyranol, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, 86 pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl or tetrazolyl.
  9. 9. A compound according to any one of claims 1 to 8, wherein X3a stands for a hydrogen atom or a C1 -C5 alkyl group.
  10. 10. A compound according to any one of claims 1 to 8, wherein X3a and X3b are the same or different and each stands for a hydrogen atom or a C1-C5 alkyl group.
  11. 11. A compound according to any one of claims 1 to 10, wherein X4, X6 and X7 are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom.
  12. 12. A compound according to any one of claims 1 to 11, wherein Y4 stands for a C1-C5 alkyl group or a C1-C5 perfluoroalkyl group.
  13. 13. A compound according to any one of claims 1 to 12, wherein Y5, Y7 and Y8 are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom.
  14. 14. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 2.
  15. 15. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 3. 87
  16. 16. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 4.
  17. 17. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 5.
  18. 18. A compound according to any one of claims 1 to 13, in which Ar stands for w ring system of partial general formula 6.
  19. 19. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 7.
  20. 20. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 8.
  21. 21. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 9.
  22. 22. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 10. 88
  23. 23. A compound according to any one of claims 1 to 13, in which Ar stands for a ring system of partial general formula 11.
  24. 24. A compound of general formulae I according to claim 1, wherein the compound is one of: 4-Bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide, 6-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-phthalide, 5-(2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl- valeroylamino)-phthalide, 5-[2-hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethyl- valeroylamino)-phthalide, 5-[2-(hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl- valeroylamino]-phthalide, 5-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-trifluoromethyl- valeroylamino]-phthalide, 5-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeroylamino]-phthalide, 5-[4-(4-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, 89 5-[2-hydroxy-4-methyl-4-(4-tolyl)-2-trifluoromethyl- valeroylamino]-phthalide, 5-[2-hydroxy-4-methyl-4-(3-tolyl)-2-trifluoromethyl- valeroylamino]-phthalide, 5-[4-(4-cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeroylamino]-phthalide, 5-[4-(3,4-dimethylphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(3,5-dimethylphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[2-hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(5-chloro-2-hydroxyphenyl]-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[2-hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide, 5-[4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2- 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, 90 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-phenyl-2-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-butinyl)-5-(2-hydroxy-4-methyl-4- phenyl-2-trifluoromethyl-valeroylamino)-phthalide, 6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-4-methyl-2,3-benzoxazin-1-one, 6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl- valeroylamino)-4-trifluoromethyl-2,3-benzoxazin-1-one, 4-ethyl-6-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)- 2,3-benzoxazin-1-one, 4-ethyl-6-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2- 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, 91 4-ethyl-6-[2-hydroxy-4-methyl-4-(4-methylphenyl)-2- trifluoromethyl-valeroylamino]-2,3-benzoxazin-1-one, 6-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl- valeroylamino]-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, 5-(2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino)- phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclopropyl)-2-trifluoromethyl- propionylamino]-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclobutyl)-2-trifluoromethyl- propionylamino]-phthalide, 5-[2-hydroxy-3-(1-phenyl-cyclohexyl)-2-trifluoromethyl- propionylamino]-phthalide, 6-(2-hydroxy-2,4-dimethyl-4-phenyl-valeroylamino)-4-methyl- 2,3-benzoxazin-1-one, 5-[4-(3-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethyl-valeroylamino]-phthalide. 92
  25. 25. A compound of general formula I according to claim 1, wherein the compound is one of: <IMG> n Z a Isomerism ( # H) 1 racemate 1 (+)-enantiomer 1 (-)-enantiomer 1 3-F racemate 1 2-Cl racemate 1 4-Cl racemate 1 4-Cl (+)-enantiomer 1 4-Cl (-)-enantiomer 1 2-Br racemate 1 3-Br racemate 1 2,4-Cl2 racemate 1 2-OCH3 (+)-enantiomer 1 2-OCH3 (-)-enantiomer 1 3-OCH3 racemate 1 3-CF3 racemate 2 racemate 2 (+)-enantiomer 2 (-)-enantiomer 3 (+)-enantiomer 3 4-CH3 racemate 4 racemate 93 4 (+) -enantiomer 4 (-) -enantiomer
  26. 26. A compound of the general formula I according to claim 1, wherein the compound is one of: <IMG> 94
  27. 27. A compound of the general formula I according to claim 1, wherein the compound is one of: <IMG> Zn (.noteq. H) Z2 = I Z3 = Cl Z3 = Br Z3 = I
  28. 28. A compound of the general formula I according to claim 1, wherein the compound is one of: <IMG> 95 <IMG> 96 <IMG> 97 <IMG>
  29. 29. A compound of the general formula I according to claim 1, wherein the compound is one of: <IMG> 98 <IMG>
  30. 30. A compound of the general formula I according to claim 1, wherein the compound is one of: <IMG> 99 <IMG>
  31. 31. A compound of the general formula I according to claim 1, wherein the compound is one of: <IMG> 100 <IMG>
  32. 32. A compound of the general formula I according to claim 1, wherein the compound is one of: <IMG> 101 <IMG>
  33. 33. A compound of the general formula I according to claim l, wherein the compound is one of: <IMG> 102 <IMG> 103 <IMG>
  34. 34. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 33, and a pharmaceutically-compatible carrier.
  35. 35. Use of a compound according too any one of claims 1 to 33, for the production of a pharmaceutical composition for contraception, or for treating menopausal symptoms or preserving pregnancy.
  36. 36. Use a pharmaceutically-effective amount of a compound according to any one of claims 1 to 33, for contraception, or for treating menopausal symptoms or preserving pregnancy in a patient in need of such treatment.
  37. 37. A process for the preparation of a compound as defined in any one of claims 1 to 33, comprising reacting a carbonyl compound of formula II <IMG> 104 in which A, B, Ar, R1, R2 and R3 have the meanings that are defined in the said one claim with trifluoromethyl-trimethyl silane or trimethyl- pentafluoroethyl silane, in the presence of a catalyst or with an alkyl metal compound, to produce the said compound.
  38. 38. A process as defined in claim 37, in which R3 is CF3 or C2F5.
  39. 39. A process according to claim 37 or 38, wherein the catalyst is a fluoride salt or an alkali carbonate.
  40. 40. A process according to claim 37 or 38, wherein the alkyl metal compound is a Grignard reagent or a lithium alkyl compound.
  41. 41. A process for the preparation of a compound as defined in any one of claims 1 to 33, comprising reacting a compound of formula III <IMG> in which A, B, R1, R2 and R3 have the meanings that are defined in the said one claim, and FG means a leaving group with a compound Ar-NH-R11, wherein R11 is a hydrogen atom or a C1-C5 alkanoyl group and Ar has the meaning defined in the said one claim, and optionally then cleaving off radical R11. 105
  42. 42. A process according to claim 41, wherein the leaving group FG is a chlorine, bromine or iodine atom, a tosylate or mesylate radical, or a C1-C4 perfluoroalkylsulfonyloxy radical.
  43. 43. A process according to claim 42, wherein the compound of formula III is an acid chloride that is formed as an intermediate product from the corresponding carboxylic acid.
  44. 44. A process for the preparation of a compound as defined in any one of claims 1 to 33, in which A, Ar, R1, R2 and R3 have the meanings that are defined in the said one claim and B is a -CH2 group, comprising reacting a compound of a formula IV <IMG> in which A, R1, R2 and R3 have the above-mentioned meanings, with a compound formula Ar-NH-R11, wherein R11 is a hydrogen atom or a C1-C5 alkanoyl group and Ar has the meaning defined in the said one claim, and optionally then cleaving off radical R11.
CA002305458A 1997-05-30 1998-06-02 Nonsteroidal (hetero) cyclically-substituted acylanilides with mixed gestagenic and androgenic activity Expired - Fee Related CA2305458C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19723722A DE19723722A1 (en) 1997-05-30 1997-05-30 Nonsteroidal progestogens
DE19723722.3 1997-05-30
PCT/EP1998/003242 WO1998054159A1 (en) 1997-05-30 1998-06-02 Non-steroidal (hetero) cyclically substituted acylanilides with mixed gestagen and androgen activity

Publications (2)

Publication Number Publication Date
CA2305458A1 CA2305458A1 (en) 1998-12-03
CA2305458C true CA2305458C (en) 2007-05-01

Family

ID=7831567

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002305458A Expired - Fee Related CA2305458C (en) 1997-05-30 1998-06-02 Nonsteroidal (hetero) cyclically-substituted acylanilides with mixed gestagenic and androgenic activity

Country Status (30)

Country Link
EP (1) EP0986545B1 (en)
JP (1) JP2002502385A (en)
KR (1) KR100536870B1 (en)
CN (1) CN100445272C (en)
AR (1) AR011480A1 (en)
AT (1) ATE286035T1 (en)
AU (1) AU747083C (en)
BG (1) BG64212B1 (en)
BR (1) BR9809703A (en)
CA (1) CA2305458C (en)
CZ (1) CZ296377B6 (en)
DE (2) DE19723722A1 (en)
EA (1) EA004306B1 (en)
EE (1) EE04492B1 (en)
ES (1) ES2234121T3 (en)
HR (1) HRP980289B1 (en)
HU (1) HUP0002126A3 (en)
ID (1) ID23499A (en)
IL (2) IL133195A0 (en)
IS (1) IS2498B (en)
NO (1) NO325076B1 (en)
NZ (1) NZ501359A (en)
PL (1) PL197887B1 (en)
PT (1) PT986545E (en)
SK (1) SK284943B6 (en)
TR (1) TR199902924T2 (en)
TW (1) TW577882B (en)
UA (1) UA64752C2 (en)
WO (1) WO1998054159A1 (en)
ZA (1) ZA984655B (en)

Families Citing this family (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19856475A1 (en) 1998-11-27 2000-05-31 Schering Ag Nonsteroidal anti-inflammatories
DE10038639A1 (en) 2000-07-28 2002-02-21 Schering Ag New and known N-aryl 2-hydroxy-omega-arylalkanamide derivatives, useful e.g. for treating inflammatory diseases such as rheumatism
DE10346940B3 (en) * 2003-10-06 2005-06-16 Schering Ag Substituted pentanols, their use for the preparation of medicaments, in particular anti-inflammatories and pharmaceutical compositions containing them
AU2002219218A1 (en) * 2000-12-28 2002-07-16 Schering Ag Method for screening for progesterone receptor isoform-specific ligands
AU2003202216A1 (en) * 2002-01-14 2003-07-30 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical formulations containing them and uses thereof
EP1344776A1 (en) * 2002-03-11 2003-09-17 Schering Aktiengesellschaft 5- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -phtalide and 6- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -4-methyl-2,3-benzoxazin-1-one derivatives with progesterone receptor modulating activity for use in fertility control, hormone replacement therapy and the treatment of gynecological disorders
PL372490A1 (en) * 2002-03-11 2005-07-25 Schering Aktiengesellschaft 5-{2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino}-phtalide and related compounds with progesterone receptor modulating activity for use in fertility control and hormone replacement therapy
WO2003082787A1 (en) 2002-03-26 2003-10-09 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
CA2478156C (en) 2002-03-26 2011-02-15 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
DE10215316C1 (en) * 2002-04-02 2003-12-18 Schering Ag Quinoline and isoquinoline derivatives, a pharmaceutical agent and their use as anti-inflammatory agents
US7186864B2 (en) 2002-05-29 2007-03-06 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7074806B2 (en) 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
JP2006504678A (en) 2002-08-21 2006-02-09 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Glucocorticoid mimetics, process for producing the same, pharmaceutical composition thereof, and use thereof
WO2004019935A1 (en) 2002-08-29 2004-03-11 Boehringer Ingelheim Pharmaceuticals, Inc. -3 (sulfonamidoethyl) -indole derivaties for use as glucocorticoid mimetics in the treatment of inflammatory, allergic and proliferative diseases
EP1562906A4 (en) * 2002-10-15 2009-12-02 Univ Tennessee Res Foundation SELECTIVE ANDROGEN RECEPTOR HETEROCYCLIC MODULATORS AND METHODS OF USE THEREOF
DE10261874A1 (en) * 2002-12-20 2004-07-08 Schering Ag Nonsteroidal anti-inflammatories
CA2512257A1 (en) 2003-01-03 2004-07-29 Boehringer Ingelheim Pharmaceuticals, Inc. 1-propanol and 1-propylamine derivatives and their use as glucocorticoid ligands
US20040224992A1 (en) * 2003-02-27 2004-11-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
EA200600148A1 (en) * 2003-07-01 2006-08-25 Шеринг Акциенгезельшафт HETEROCYCLICALLY SUBSTITUTED DERIVATIVES OF PENTANOL, METHOD OF THEIR RECOVERY AND THEIR APPLICATION AS INFLAMMATION INHIBITORS
GB0316290D0 (en) 2003-07-11 2003-08-13 Glaxo Group Ltd Novel compounds
UY28526A1 (en) 2003-09-24 2005-04-29 Boehringer Ingelheim Pharma GLUCOCORTICOID MIMETICS, METHODS OF PREPARATION PHARMACEUTICAL COMPOSITIONS AND USES OF THE SAME
US7507843B2 (en) 2003-10-16 2009-03-24 Boehringer Ingelheim Pharmaceuticals, Inc. Stereoselective synthesis of certain trifluoromethyl-substituted alcohols
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
PE20060272A1 (en) 2004-05-24 2006-05-22 Glaxo Group Ltd (2R, 3R, 4S, 5R, 2'R, 3'R, 4'S, 5'S) -2.2 '- {TRANS-1,4-CYCLOHEXANODIYLBIS- [IMINO (2 - {[2- (1-METHYL- 1H-IMIDAZOL-4-IL) ETHYL] AMINO} -9H-PURIN-6,9-DIYL)]} BIS [5- (2-ETHYL-2H-TETRAZOLE-5-IL) TETRAHYDRO-3,4-FURANODIOL] AS AN A2A AGONIST
TWI307630B (en) 2004-07-01 2009-03-21 Glaxo Group Ltd Immunoglobulins
DE102004062182B4 (en) * 2004-12-20 2007-06-06 Bayer Schering Pharma Ag Transdermal patch with progesterone A-specific ligands (PRASL) as active ingredient
CA2592514A1 (en) 2004-12-27 2006-07-06 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
EP1841780B1 (en) 2005-01-10 2011-07-27 Glaxo Group Limited Androstane 17-alpha-carbonate derivatives for use in the treatment of allergic and inflammatory conditions
JPWO2006083030A1 (en) * 2005-02-04 2008-06-26 味の素株式会社 Fatty acid production method and fatty acid salt crystals
MY145343A (en) 2005-03-25 2012-01-31 Glaxo Group Ltd Novel compounds
PE20061193A1 (en) 2005-03-25 2006-12-02 Glaxo Group Ltd DERIVATIVES OF 3,4-DIHYDROPYRIMIDO [4,5-d] PYRIMIDIN-2- [1H] -0NA AS KINASE INHIBITORS p38
DE102005017326A1 (en) * 2005-04-14 2007-03-29 Schering Ag Tetrahydronaphthalene derivatives, process for their preparation and their use as anti-inflammatory agents
DE102005030294A1 (en) * 2005-06-24 2007-01-04 Schering Ag Nonsteroidal progesterone receptor modulators
DE102005030293A1 (en) * 2005-06-24 2007-01-04 Schering Ag Use of nonsteroidal progesterone receptor modulators
US7408060B2 (en) 2005-06-24 2008-08-05 Schering Ag Nonsteroidal progesterone receptor modulators
GB0514809D0 (en) 2005-07-19 2005-08-24 Glaxo Group Ltd Compounds
WO2007065828A1 (en) 2005-12-09 2007-06-14 F. Hoffmann-La Roche Ag Glucocorticoid receptor modulators as antiinflammatory agents
PE20071068A1 (en) 2005-12-20 2007-12-13 Glaxo Group Ltd 3- (4 - {[4- (4 - {[3- (3,3-DIMETHYL-1-PIPERIDINYL) PROPYL] OXY} PHENYL) -1-PIPERIDINYL] CARBONYL} -1-NAPHTHALENYL) PROPANOIC OR PROPENOIC ACID, SALTS OF THE SAME, AS ANTAGONISTS OF THE H1 AND H3 RECEPTORS
MX2008013411A (en) 2006-04-20 2008-11-04 Glaxo Group Ltd Novel compounds.
GB0611587D0 (en) 2006-06-12 2006-07-19 Glaxo Group Ltd Novel compounds
AU2007329548A1 (en) 2006-12-06 2008-06-12 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
UY30805A1 (en) * 2006-12-21 2008-07-31 Bayer Schering Pharma Ag NON-STEROID MODULATORS OF PROGESTERONE RECEPTORS
UY30815A1 (en) * 2006-12-21 2008-07-31 Bayer Schering Pharma Ag NON-STEROID MODULATORS OF THE PROGESTERONE RECEIVER
DE102007049630A1 (en) 2007-10-11 2009-10-29 Bayer Schering Pharma Aktiengesellschaft New amide compounds used for therapy and/or prophylaxis of gynecological diseases e.g. endometriosis, for female fertility control and female hormone replacement therapy
DE102007023614A1 (en) 2007-05-21 2008-11-27 Bayer Schering Pharma Aktiengesellschaft New amide compounds used for treatment of gynecological diseases e.g. endometriosis, for female fertility control and female hormone replacement therapy, has general formula
JP5090773B2 (en) 2006-12-26 2012-12-05 国立大学法人東京工業大学 Method for producing optically active fluorinated carbonyl-ene product
PE20081889A1 (en) 2007-03-23 2009-03-05 Smithkline Beecham Corp INDOL CARBOXAMIDES AS INHIBITORS OF IKK2
DE102007032800A1 (en) 2007-07-10 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
DE102007058747A1 (en) 2007-12-05 2009-06-10 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
EP2070909A1 (en) * 2007-12-15 2009-06-17 Bayer Schering Pharma AG Non-steroidal progesterone receptor modulators
MX2010012814A (en) 2008-05-23 2010-12-20 Amira Pharmaceuticals Inc 5-lipoxygenase-activating protein inhibitor.
ES2383246T3 (en) 2008-06-05 2012-06-19 Glaxo Group Limited 4-amino-indazoles
US8163743B2 (en) 2008-06-05 2012-04-24 GlaxoGroupLimited 4-carboxamide indazole derivatives useful as inhibitors of PI3-kinases
EP2300472B1 (en) 2008-06-06 2012-01-18 Boehringer Ingelheim International GmbH Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2010094643A1 (en) 2009-02-17 2010-08-26 Glaxo Group Limited Quinoline derivatives and their uses for rhinitis and urticaria
JP5656880B2 (en) 2009-03-09 2015-01-21 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ 4-oxadiazol-2-yl-indazole as an inhibitor of PI3 kinase
WO2010102968A1 (en) 2009-03-10 2010-09-16 Glaxo Group Limited Indole derivatives as ikk2 inhibitors
EP2408769A1 (en) 2009-03-17 2012-01-25 Glaxo Group Limited Pyrimidine derivatives used as itk inhibitors
EP2408458A1 (en) 2009-03-19 2012-01-25 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 (STAT6) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP2408916A2 (en) 2009-03-19 2012-01-25 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF CONNECTIVE TISSUE GROWTH FACTOR (CTGF) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20120029054A1 (en) 2009-03-19 2012-02-02 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of GATA Binding Protein 3 (GATA3) Gene Expression Using Short Intefering Nucleic Acid (siNA)
JP2012520684A (en) 2009-03-19 2012-09-10 メルク・シャープ・エンド・ドーム・コーポレイション RNA interference-mediated inhibition of BTBandCNChomology1 (basic leucine zipper transcription factor 1) (Bach1) gene expression using small interfering nucleic acids (siNA)
WO2010111497A2 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE INTERCELLULAR ADHESION MOLECULE 1 (ICAM-1)GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
JP2012521760A (en) 2009-03-27 2012-09-20 メルク・シャープ・エンド・ドーム・コーポレイション RNA interference-mediated inhibition of apoptosis signal-regulated kinase 1 (ASK1) gene expression using small interfering nucleic acids (siNA)
WO2010111471A2 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP2411520A2 (en) 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE THYMIC STROMAL LYMPHOPOIETIN (TSLP) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP2411018A2 (en) 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE NERVE GROWTH FACTOR BETA CHAIN (NGFß) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (SINA)
EP2421834A1 (en) 2009-04-24 2012-02-29 Glaxo Group Limited Pyrazole and triazole carboxamides as crac channel inhibitors
AR076373A1 (en) 2009-04-24 2011-06-08 Glaxo Group Ltd N-PIRAZOLIL CARBOXAMIDS AS CALCIUM CHANNEL INHIBITORS
LT2899191T (en) 2009-04-30 2017-10-25 Glaxo Group Limited Oxazole substituted indazoles as pi3-kinase inhibitors
JP2013512880A (en) 2009-12-03 2013-04-18 グラクソ グループ リミテッド Indazole derivatives as PI3-kinase inhibitors
WO2011067364A1 (en) 2009-12-03 2011-06-09 Glaxo Group Limited Novel compounds
WO2011067365A1 (en) 2009-12-03 2011-06-09 Glaxo Group Limited Benzpyrazole derivatives as inhibitors of p13 kinases
EP3020393B1 (en) 2009-12-16 2020-10-07 3M Innovative Properties Company Formulations and methods for controlling mdi particle size delivery
WO2011110575A1 (en) 2010-03-11 2011-09-15 Glaxo Group Limited Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases
GB201007203D0 (en) 2010-04-29 2010-06-16 Glaxo Group Ltd Novel compounds
US9326987B2 (en) 2010-09-08 2016-05-03 Glaxo Group Limited Indazole derivatives for use in the treatment of influenza virus infection
RS54286B1 (en) 2010-09-08 2016-02-29 Glaxosmithkline Intellectual Property Development Limited POLYMORPHS AND SALTS N- [5- [4- (5 - {[(2R, 6S) -2,6-DIMETHYL-4-MORPHOLINYL] METHYL} -1,3-OXAZOL-2-yl) -1H-INDAZZOL- 6-IL] -2 (methyloxy) -3-pyridinyl] -methanesulfonamide
WO2012035055A1 (en) 2010-09-17 2012-03-22 Glaxo Group Limited Novel compounds
EP2630127A1 (en) 2010-10-21 2013-08-28 Glaxo Group Limited Pyrazole compounds acting against allergic, inflammatory and immune disorders
US9156791B2 (en) 2010-10-21 2015-10-13 Glaxo Group Limited Pyrazole compounds acting against allergic, immune and inflammatory conditions
GB201018124D0 (en) 2010-10-27 2010-12-08 Glaxo Group Ltd Polymorphs and salts
GB201104153D0 (en) 2011-03-11 2011-04-27 Glaxo Group Ltd Novel compounds
EP2683716A1 (en) 2011-03-11 2014-01-15 Glaxo Group Limited Pyrido[3,4-b]pyrazine derivatives as syk inhibitors
KR20160060100A (en) 2013-09-22 2016-05-27 칼리토르 사이언시즈, 엘엘씨 Substituted aminopyrimidine compounds and methods of use
RU2016112268A (en) 2013-10-17 2017-11-22 Глаксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед PI3K inhibitor for the treatment of respiratory disease
WO2015055691A1 (en) 2013-10-17 2015-04-23 Glaxosmithkline Intellectual Property Development Limited Pi3k inhibitor for treatment of respiratory disease
WO2015148867A1 (en) 2014-03-28 2015-10-01 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
US20170100385A1 (en) 2014-05-12 2017-04-13 Glaxosmithkline Intellectual Property (No. 2) Limited Pharmaceutical compositions comprising danirixin for treating infectious diseases
JP2018527362A (en) 2015-09-11 2018-09-20 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Substituted heteroaryl compounds and methods of use
GB201602527D0 (en) 2016-02-12 2016-03-30 Glaxosmithkline Ip Dev Ltd Chemical compounds
US20190161480A1 (en) 2016-08-08 2019-05-30 Glaxosmithkline Intellectual Property Development Limited Chemical Compounds
GB201706102D0 (en) 2017-04-18 2017-05-31 Glaxosmithkline Ip Dev Ltd Chemical compounds
GB201712081D0 (en) 2017-07-27 2017-09-13 Glaxosmithkline Ip Dev Ltd Chemical compounds
EP3569228A1 (en) * 2018-05-17 2019-11-20 Association pour la recherche à l'IGBMC (ARI) Non-steroidal selective glucocorticoid receptor agonistic modulators (segrams) and uses thereof
WO2019099311A1 (en) 2017-11-19 2019-05-23 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
KR102737185B1 (en) 2018-01-20 2024-12-05 선샤인 레이크 파르마 컴퍼니 리미티드 Substituted aminopyrimidine compounds and methods of use thereof
WO2021191875A1 (en) 2020-03-26 2021-09-30 Glaxosmithkline Intellectual Property Development Limited Cathepsin inhibitors for preventing or treating viral infections
CR20230007A (en) * 2020-06-12 2023-06-01 Shanghai Jemincare Pharmaceuticals Co Ltd Phthalazinone compound, and preparation method therefor and medical use thereof
CN114605308B (en) * 2022-03-18 2023-12-19 阜新孚隆宝医药科技有限公司 Preparation method of azabicyclo medicine intermediate of Pa Luo Weide and intermediate

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4191775A (en) * 1977-12-15 1980-03-04 Imperial Chemical Industries Limited Amide derivatives
NZ197008A (en) * 1980-05-22 1984-10-19 Ici Ltd Acylanilide derivatives and pharmaceutical compositions
JPS5789048A (en) * 1980-11-20 1982-06-03 Nat Jutaku Kenzai Independent pilar with cover
CA1261835A (en) * 1984-08-20 1989-09-26 Masaaki Toda (fused) benz(thio)amides
GB8617653D0 (en) * 1986-07-18 1986-08-28 Ici Plc Amide derivatives
GB8617652D0 (en) * 1986-07-18 1986-08-28 Ici Plc Acylanilide derivatives
HUT68424A (en) * 1992-07-01 1995-06-28 Ortho Pharma Corp Novel 1-arylsulphonyl-, -arylcarbonyl- and 1-arylphosphonyl-3-phenyl-1,4,5,6-tetrahydro-pyridazines

Also Published As

Publication number Publication date
BG64212B1 (en) 2004-05-31
IL133195A0 (en) 2001-03-19
EA004306B1 (en) 2004-02-26
NZ501359A (en) 2001-11-30
TW577882B (en) 2004-03-01
SK284943B6 (en) 2006-02-02
AU747083C (en) 2004-01-29
CZ296377B6 (en) 2006-03-15
EA199900989A1 (en) 2000-08-28
JP2002502385A (en) 2002-01-22
WO1998054159A1 (en) 1998-12-03
BG103903A (en) 2000-04-28
CA2305458A1 (en) 1998-12-03
EP0986545A1 (en) 2000-03-22
AU8021198A (en) 1998-12-30
KR100536870B1 (en) 2005-12-16
CZ425799A3 (en) 2000-04-12
HRP980289B1 (en) 2005-08-31
AR011480A1 (en) 2000-08-16
NO325076B1 (en) 2008-01-28
DE19723722A1 (en) 1998-12-10
BR9809703A (en) 2000-07-11
IL133195A (en) 2007-07-24
EP0986545B1 (en) 2004-12-29
KR20010013123A (en) 2001-02-26
UA64752C2 (en) 2004-03-15
EE9900548A (en) 2000-06-15
TR199902924T2 (en) 2000-02-21
PL197887B1 (en) 2008-05-30
DE59812452D1 (en) 2005-02-03
SK160999A3 (en) 2000-07-11
HUP0002126A3 (en) 2002-12-28
ES2234121T3 (en) 2005-06-16
NO995845D0 (en) 1999-11-29
IS2498B (en) 2009-02-15
IS5241A (en) 1999-11-09
EE04492B1 (en) 2005-06-15
ATE286035T1 (en) 2005-01-15
ZA984655B (en) 1999-03-16
AU747083B2 (en) 2002-05-09
PT986545E (en) 2005-04-29
CN1258286A (en) 2000-06-28
NO995845L (en) 2000-01-27
HUP0002126A2 (en) 2001-06-28
CN100445272C (en) 2008-12-24
HRP980289A2 (en) 1999-02-28
ID23499A (en) 2000-04-27
PL337088A1 (en) 2000-07-31

Similar Documents

Publication Publication Date Title
CA2305458C (en) Nonsteroidal (hetero) cyclically-substituted acylanilides with mixed gestagenic and androgenic activity
US6245804B1 (en) Nonsteroidal gestagens
JPH0753725B2 (en) 4H-1-benzopyran-4-one derivative and its salt, their production method and anti-inflammatory agent containing them
IL143393A (en) Nonsteroidal antiinflammatories
CA2415847C (en) Aminoalkylbenzoyl-benzofuran or benzothiophene derivatives, method for preparing same and compositions containing same
FI80691B (en) FOERFARANDE FOER FRAMSTAELLNING AV BENSOTIOFENER OCH BENSOFURANER MED ANTIALLERGISK AKTIVITET.
ITMI20010385A1 (en) METHOD FOR THE PREPARATION OF CITALOPRAM
CA1330562C (en) Benzothiophenes having antiallergic activity and both novel and other selected benzothiophenes having activity for treating acute respiratory distress syndrome
JPH0510347B2 (en)
JPS6212214B2 (en)
US4690945A (en) Process for the preparation of 5&#39;-substituted 2-(3&#39;-thienyl)propionic acids
US4246281A (en) Pharmacologically active acenaphthene derivatives
US4223035A (en) Treating prostate hypertrophy with 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidines
Floutz Consideration Reactions of Phthalaldehydic Acid. II.
Crenshaw et al. Potential antifertility agents. 5. 2, 3-Diphenyl-1-(N-methyl-N-propargyl) aminoindenes
US3546252A (en) Dimethyl oxa-steroids
Horning et al. Aromatization Studies. VI. Aminobiphenyls and Naphthylamines
US4183944A (en) Thienothienylcarbonyl-phenylalkanoic acids and derivatives thereof
PL59726B1 (en)

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed