Title of Invention

NONSTEROIDAL ANTIINFLAMMATORIES

Abstract N/A
Full Text FORM 2
THE PATENTS ACT 1970
(39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13)
NONSTEROIDAL ANTIINFLAMMATORIES
SCHERING AKTIENGESELLSCHAFT, a German company, of D-13342 Berlin T Germany.



The following specification particularly describes the invention and the manner in which it is to be performed:


WO 00/325B4

PCT/EP99/09754

Nonsteroidal Antiinflammatory Agents
This invention relates to the use of nonsteroidal compounds for the production of pharmaceutical agents that have an antiinflammatory activity as well as the nonsteroidal compounds themselves.
In addition to a large number of steroid compounds, which bind well to the glucocorticoid receptor and have an antiinflammatory action (glucocorticoids), nonsteroidal compounds are known that namely bind to the glucocorticoid receptor, for which to date no inflammatory suppression has been shown, however [cf. Nature Medicin 4 £1998} 92, Mol. Pharmacol, 52 (1997) 571]. In addition, nonsteroidal compounds were described that are derived from steroidal compounds, have an affinity to the glucocorticoid receptor and probably have an antiinflammatory action that is mediated by the receptor [J. Med. Chem, 36, 3278-3285], In animal experiments, however, these compounds did not show any advantages relative to steroidal glucocorticoids, i.e., it was- not possible to separate the antiinflammatory action from the metabolic effects, e,g., suppression of the suprarenal function.
Nonsteroidal compounds have now been found that bind well to the glucocorticoid receptor and, mediated by this bond, produce a suppression of inflammation. In the animal experiment, these compounds show a clear dissociation between antiinflammatory and

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metabolic actions and are therefore superior both to the previously described steroidal glucocorticoids and the nonsteroidal glucocorticoids,
Compounds that are suitable according to this invention for the production of pharmaceutical agents that have an antiinflammatory action are the nonsteroidal compounds of general formula I

in which
R1 and R2 are the same or different and stand for a hydrogen
atom, a C;-C5 alkyl groupH or, together with the C-atom
of the chain, stand for a ring with a total of 3-7-
linksH
R3 stands for a C1-C5 alkyl group or a partially or
completely fluorinated C1-C5 alkyl groupH
A stands for the group

(the dashed line means the interface site), in which R6 means a hydrogen atom, a C1-C5 alkyl group, a C1-C10 acyl

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group, a C3-C|0 carbalkoxyalkyl group, a C2-c5 cyanoalkyl group, a C3-C10 unsubstituted or substituted allyl group, a C3-Cl0 unsubstituted or substituted propargyl group, a CE-C5 alkoxyalkyl group, a C2-C5 alkyl group that is partially or completely substituted by fluorine atoms,
R5 to R& are the same or different from one another and are selected from hydrogen or halogen atoms or C1-C5 alkoxy groups, and R* and'R5 together mean a heterocyclic ring, which in addition to the oxygen atom optionally can contain at least one other heteroatom from the group of oxygen, nitrogen, sulfur, with a total of 5-7 links, B stands for a carbonyl group or a CE2 group, and Ar stands for a ring system, selected from the group of general partial formulas 2-5,


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in which
radicals X3a, X3b, X*, X6, x7 (in partial formulas 2 and 3)
and Y1, Y5, Y7, and Ya fin partial formulas 4 and 5) are the game or different and are selected from hydrogen atoms, C^-Cj alkyl groups, partially or completely fluorinated C]-C5 alkyl groups,
and, moreover,, radicals x4, X6, X7 {in partial formulas 2 and 3) or Ys, Y7f Y* tin partial formulas 4 and 5) are selected from the halogen atoms, hydroxy groups, Cj-Cg alkoxy groups or Cj-C, alkanoyloxy groups, and if B stands for a CH2 group, the physiologically compatible salts of the compounds of general formula 1 with acids.
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 separately present stereoisomers are part of the subject of this invention.
The substituents that are defined as groups in the compounds of general formula I can have the meanings below in each case.
The C.-C alkyl groups can readily be a methyl-, ethyl-, n-propyl-, iso-propyl-, n~, iso-, or tert-butyl group or an n-

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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. Fluorine, chlorine or bromine is preferred here.
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-C5 alkyl group, the perfluorinated, above-mentioned alkyl groups, and of the latter mainly the tritluoromethyl group or pentafluoroethyl group, are considered, and 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 is considered.
For example, a carboxymethyl, tert-butoxymethyl or ethoxymethyl group cart stand for the C3-Cl0 carbalkoxyalkyl group,-the first two mentioned groups are preferred. The information on the C-atoms relates to the C-atoms that are contained overall in the carbalkoxyalkyl group.
As representatives of the C2-Cs cyanoalkyl group, cyanomethyl and 1- and 2-cyanoethyl can be mentioned; cyanomethyl is preferred.
The C3-C]0 allyl group is preferably an unsubstituted allyl group; in the case of a substituted allyl group, for example, 1-methylallyl, 1,1-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylallylH 3,3-dimethylallyl, cinnamyl and 3-cyclohexylallyl can be mentioned.

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An unsubstituted propargyl, a methylpropargyl, 3-methylpropargyl, 3-phenylpropargyl or 3-cyclohexylpropargyl group is the typical representative of a C3-C10Propargyl group,- the unsubstituted propargyl group is preferred.
For example, methoxymethyl, ethoxymethyl or 2 -methoxyethyl can stand for C2-C5 alkoxyalkyl.
Representatives of a C2-C5 alkoxy group are selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2 ,2-dimethylpropoxy or 3-methylbutoxy groups. A methoxy or ethoxy group is preferred.
C1-C3 perfluoroalkoxy groups are the corresponding perfluorinated radicals of the C1-C5 alkoxy groups above.
As C.-C5 alkyl groups for the etherification of hydroxy groups, the above-mentioned alkyl groups are suitable; primarily a methyl or ethyl group. As a C1-C5 alkanoyl group for the esterification of hydroxy groups, a formyl, acetyl, propionyl, butyrylr iso-butyryl, valeryl or iso-valeryl or pivaloyl group is considered, preferably an acetyl group.
As a C;-C10 acyl group for the esterification of hydroxy groups, for example, the above-mentioned alkanoyl groups, preferably in turn an acetyl group or a benzoyl, toluoyl, phenyl acetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl group, can be mentioned.
As a CrC5 alkanoyloxy group for x\ X6, X7, Y\ Y5, Y7 or Ya, a fozrmyloxy, acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy or iso-valeryloxy group is considered, preferably an acetoxy group.

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If the compounds of general formula I (B = -CH2-) are present as salts, this can be, for example, in the form of hydrochloride, sulfate, nitrate, maleate, fumarate, tartrate or benzoate.
If the compounds according to the invention are present B.S racemic mixtures, they can be separated into the pure, optically active norms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the racemic mixtures can be separated into the pure isomers by chromatography on a carrier material that is itself optically active (CHIRALPAK ADCBJ) . It is also possible to esterify the free hydroxy group in a racemic compound oz general formula I with an optically active acid and to separate the diastereoisomer esters that are obtained by fractionated crystallization or by chromatography and to saponify the separated esters in each case to form the optically pure isomers. As an optically active acid, for example, mandelic acid, campfrorsulfonic acid or tartaric acid can be used.
Preferred according to this invention are those compounds of general formula I, in which:
R1 and R2 are the same or different and stand for a hydrogen
atom, a methyl or ethyl group; also together with the
C-atom of the chain, R1 and R? stand for a cyclopropyl
ring, and/or
Rz stands for a C1-Cs perfluoroalkyl group, and/or

A stands for the group

{the dashed line means the interface site), in which
RA means a hydrogen atomH a methyl, ethyl, propyl or 2-propyl group, an acetyl group, a methoxy-, ethoxy-or tert-butoxycarbonyl group, a cyanomethyl group, a 2-cyanoethyl group, an allyl group, a propargyl group, a methoxymethyl-, methoxyethyl- or ethoxyethyl group, a mono-, di- or trifluoromethyl group, a pentafluoroethyl or nonafluorobutyl group, R5 to R3 in one or two positions mean fluorine or
chlorine atoms and in the remaining positions mean hydrogen atoms, or
R' and R5 together with incorporation of phenyl-ring atoms 2 and 3 mean a furan, a dihydrofuran or a 2,3-dihydro-l, 4-dioxine ring, and R*, P.7 and Re mean hydrogen atoms, Xia stands for a hydrogen atom or a methyl group, ox

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X3a and xSb are the same or different and stand for a
hydrogen atom or a methyl group, X4, X6 and X7 are the same or different and,
independently of one another, stand for a hydrogen atom or a fluorine atom or a chlorine atom, and/or
Y4 stands for a methyl, ethyl, propyl, 2-propyl or
trifluoromethyl group and/or Y5, Y7 and Ya are the same or different and,
independently of one another, stand for a hydrogen atom or a fluorine atom or a chlorine atom, and the other substituents all have the meanings that are indicated in formula I.
In addition, the use of those compounds of general formula I in which Ar stands for a ring system of partial formula 2 or 5 is preferred.
The use of the compounds that are mentioned below is especially preferred according to the invention:
5-{2-Hydroxy-3-[1-(2-methoxyphenyl)-cyclopropylj-2-trifluoromethyl-propionylamina}-phthalide
5-{3- [1- (5-fluoro-2-methoxyphenyl)-cyclopropyl]-2 -hydroxy-2-trifluoromethy1-propionylamino}-phthalide
5- {2-hydroxy-4- (2-methoxyphenyl} -4 -methyl-2 -trifluoiromethyl-valeroylamino]-phthalide
5- {3- [1- f5-fluoro-2-hydroxyphenyl) -cyclopropyl) -2-hydxoxy-2-trifluoromethyl-propionylamino)-phthalide

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5- [4- (5-fluoro-2-hydroxyphenyl]-2-hydroxy-4-methyl-2-brifluoromethyl-valeroylamino} -phthalide
5- [4- (S-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide
4-bromo-5-[4-(5-fluoro-2-hydtoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide
4-bromo-5-[4-(3-bromo-5-fluoro-2-hydroxyphenyl)- 2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide
6-{3- (i- (5-fluoro-2-hydroxyphenyl)-cyclopropyl] -2-hydroxy-2-trifluoromethyl-propionylamino}-4-methyl-2,3-benzoxazin-l-one
5- [4- [5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2, 3-benzoxazin-l-one
6- [4- {5-fluoro-2-hydroxyphenyl) -2-hydroxy-4 -methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2 , 3-benzoxazin-l-one
5-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-trifluoromethyl-valeroylaminol -4-ethyl-2 r 3-benzoxszin-l-one
6-14-(S-fluoro-2-methoxyphenyl)-2-hydroxy-4~methyl-2-trifluoromethyl-pentylamino]-4-methyl-2, 3-benzoxazin-l-one
€- [4- (5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -4-methyl-2, 3-benzoxazin-l-one
6- [4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2,3-benzoxazin-l-one
6- [4- (4-broma-2-methoxyphenyl)-2-hydroxys-methyl-2 -trifluoromethyl-pentylamino] -4-methyl-2,3-benzoxazin-l-one.
In addition, the use of the compounds that are known from Tables 3 to 6 is preferred.

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All of the above-mentioned compounds are preferably used in the form of the optical antipodes or the separate diastereomers.-
Nonsteroidal compounds as such with a mixed profile that consists of gestagenic and androgenic activity in different manifestations are already the subject of PCT Application PCT/EP3S/03242 that was filed on June 2, 1998 (priority; Hay 30, 1991, DE 197 23 722.3). The compounds of general formula I that are to be used according to this patent application for the production of pharmaceutical agents with antiinflammatory action fall within the scope of the general formula that is contained in PCT Application PCT/EP98/03242.
The compounds of general formula I that are cited by name below specifically fall within the scope of the general formula that is contained in the non-prepublished PCT Application PCT/EP98/03242, but are not previously described by name there. They are thus novel and also meet the patenting requirement of inventive activity because of the antiinflammatory action that is dissociated from metabolic effects and that was found for the first time in nonsteroidal compounds. These compounds as such are therefore also part of the subject of this invention.
5-{3- [1- {5-Fluoro-2-methoxyphenyl) - cyclopropyl} -2-hydroxy-2-trifluoromethyl-propionylamino]-phthalide
5-{3- [1- (5-fluoro-2-hydroxyphenyl) -cyclopropyl] -2-hydroxy-2 -trifluoromethyl-propionylamino}-phthalide
4~bromo-5- [4- {5-fluoro-2-hydrotyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide

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4-bromo-5-(4-(3-bromo-5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide
6- {3- [1- (5-fluoro-2-hydroxyphenyl)-cyclopropyl]-2-hydroxy-2-txif luaromethyl-propiGnylamino} -4 -methyl-2 , 3 -benzoxasin-l-one
G-[2-hydroxy-4-(2-hydroxyphenyl]-4-methyl-2-trifluoromethyl-valeroylamino]-4-ethyl-2,3-benzoxazin-l-one
S- [4- (4-bromo-2-methoxyphenyl) -2-hydi:oxy-4-methyl-2-trifluoromethy 1-pentylamino] -4-methyl-2 , 3 -benzoxazin-1-one
5- (3- [1- t5-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino} -phthalide
6- [2-hydroxy-4- (S-fluoro-2-methoxyphenyl) -4-inethyl-2-trifluoromethy1-pentylamino}-4-methyl-2,3-benzoxazin-1-one
5-(3- [1- (5-fluoro-2-hydroxyphenyl)-cyclopropyl)-2-hydroxy-2-trifluoromethyl-propionylami.no) -phthalide
6-{3- [1- (5-fluoro-2-hydroxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino)-4-methyl-2, 3-benzoxazin-1-one (-)-4-bromo-5-[4-fS-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide
(-)-4-bromo-S-[4-f3-bromo-5-fluoro-2-hydroxyphenylJ-2-hydroxy-4-rnethyl-2-trifluoroniethyl-pentylamino) -phthalide
5-[2-hydroxy-4-{5-isopropyl-2-methoxyphenyl) -4-methyl-2 -trifluoromethyl-valeroylamino]-phthalide
5- 12-hydroxy-4-[2-methoxy-5-propyl-phenyl)-4-methyl-2-trifluoromethyl-valeroylamina] -phthalide
5- [2-hydroxy-4-(2-benzyloxy-5-fluorophenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

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5- [2-hydroxy-4- [2-difluoromethoxy-5-fluorophenyl) -4-methyl-2-trifluorotnethyl-valeroylamino) -phthalide
5- [2-hydroxy-4- {5-fluoro-2-methoxymethoxy-phenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
5- [2-hydroxy-4- (2-etboxymethoxy-5-fluorophenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
5-{ |2-hydroxy-4-(5-fluoro-2-(2-methoxyethoxy)-phenyl]-4-methyl-2-trifluoromethyl-valeroylamino} -phthalide
Pharmacological Data
In the glucocorticoid receptor (GR) binding test with use of cytosol preparations that consist of the thymus homogenates of rats and of [JH]-dexamethasone as a reference substance, the
compounds of formula I show a high to very high affinity to GR,
In addition, in the gestagen receptor binding test, these compounds show affinities for the gestagen receptor with cytosol preparations from rabbit uterus homogenates and [3H]-progesterone being used as reference substances.
In addition, in the mineral corticoid receptor (MR) binding test, these compounds show affinities for MR with cytosol preparations from rat hippocampi and [JHJ-aldosterone being used as reference substances.
As an essential molecular mechanism for the antiinflammatory action of glucocorticoids, the inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors that are mediated by the GR can be seen. This inhibition is produced by an interaction of the GR with other transcription

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factors, e.g., AP-1 and NF-kappa-B (for a survey, see Cato, A. C. B., and Wade, E.r Bio2ssays 13, 371-378, 1996) .
The compounds of general formula I according to the invention inhibit the secretion of the cytokine IL-B that is triggered by lipopolysaccharide [LPSJ in human monocyte cell line THP-l. The concentration of the cytokines was determined in the supernatant with use of commercially available ELISA kits.
The antiinflammatory actions of the compounds of general formula I were tested in the animal experiment by testing in the croton oil-induced inflammation in rats and mice. In this .connection, croton oil in eth&nolic solution was administered topically to the animals' ears. The test substances were also administered topically or systemically simultaneously with or two hours before the croton oil. After 16-24 hours, the ear weight was measured as a measurement for the inflammatory edema, the peroxidase activity was measured as a measurement for the invasions of granuloctyes, an& the elastase activity was measured as a measurement for the invasions of neutrophilic granuloctyes. In this test, the compounds of general formula I inhibit the three above-mentioned inflammation parameters both after topical administration and after systemic administration.
One of the most frequent undesirable effects of a glucocorticoid therapy is the so-called "steroid diabetes" [cf, Hats, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien [Glucocorticoids; Immunological Bases, Pharmacology and Therapy Guidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 199S] . The

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reason for this is the stimulation of the gluconeogenesis in the liver by induction of the enzymes that are responsible for this effect and by free amino acids that develop from the degradation of proteins [catabolic action of glucocorticoids]. A key enzyme of the catabolic metabolism in the liver is the tyrosinamino transferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good measurement of the undesirable metabolic actions of the glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after the test substances are administered, the livers are removed, and the TAT activity in the homogenate is measured. In this test, at doses at which they have an antiinflammatory action, the compounds of general formula I induce little or no tyrosinamino transferase.
Since the substances of the general formula also have a high affinity to the progesterone receptor, the new compounds were tested for their gestagenic action in the animal experiment. For this purpose, the pregnancy-maintenance test was performed on ovariectomized rats. In this respect, female rats are covered and undergo ovariectomy under anesthesia on day eight of the pregnancy two hours after substance administration. On days S to 14 of the pregnancy, the animals are treated daily with the test substances, and on day 15, the animals are sacrificed, and the number of living and dead fetuses per animal is determined. In the case of empty uteri, the number of implantation sites is determined by staining with 10% ammonium sulfide solution. The new compounds of formula I resulted in little or no maintenance

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of pregnancy up to a dose of 500 /ig per kg of body weight. If the daily dose is increased to about 10 jmg per kg of body weight, a weakened gestagenic action can be observed. Because of this .action, the substances cannot be used as gestagens with a typical spectrum of action.
In summary, the new compounds of general formula I compared to the previously used steroidal glucocorticoids have the following properties:
nonsteroidal structure (i.e., the substances are also effective in patients who, because of an allergic reaction to the steroid basic structures of conventional glucocorticoids, are no longer accessible to the latter for therapy [of. Lutz, M.E., el-Azhary R,A., Mayo Clin. Proc. 72, 1141-1144, 1997] approximately as good antiinflammatory action with less metabolic action
weak gestagenic action, despite the high affinity to the progesterone receptor.
Indications
Because of their antiinflammatory action and additional antiallergic, immunosuppressive and antiproliferative actions, the compounds of general formula I according to the invention can be used as medications for treatment or prophylaxis of the following pathologic conditions in mammals and humans: In this

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case, the term "DISEASE" stands for the following indications:
[i] Lung diseases, which accompany inflammatoryH allergic and/or proliferative processes:
Chronically obstructive lung diseases of any origin, mainly bronchial asthma bronchitis of different origins
all forms of restrictive lung diseases, mainly allergic alveolitis,
all forms of pulmonary edema, mainly toxic pulmonary edema
sarcoidoses and granulomatoses, especially Boeck's disease [ii) Rheumatic diseases/auto-immune diseases/degenerative joint diseases, which accompany inflammatory, allergic and/or proliferative processes:
All forms of rheumatic diseases, especially rheumatoid
arthritis, acute rheumatic fever, polymyalgia
rheumatica
reactive arthritis
inflammatory soft-tissue diseases of other origins
arthritic symptoms in degenerative joint diseases
(arthroses)
traumatic arthritides
collagen diseases of any origins, e.g., systemic lupus
erythematodes, sclerodermia, polymyositis,

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dermatomyositis, Sjogren's syndrome, Still syndrome, Felty's syndrome (iii) Allergies, which accompany inflammatory, allergic and/or proliferative processes:
All forms of allergic reactions, e.g,, Quincke's edema, hay fever, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc. , anaphylactic shock, urticaria, contact dermatitis (iv) Vascular inflammations {vasculitis)
Polyarteritis nodosa, temporal arteritis, erythema nodosum fv) Dermatological diseases, which accompany inflammatory, allergic and/or proliferative processes:
Atopic dermatitis (mainly in children)
psoriasis
pityriasis rubra pilans
erythematous diseases, triggered by different noxae,
e.g., radiation, chemicals, burns, etc.
bullous dermatoses
diseases of the lichenoid group
itching (e.g., of allergic origins)
seborrheal eczema
rosacea
pemphigus vulgaris
erythema exudativum multiforme
balanitis

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vulvitis
hair loss, such as alopecia areata
cutaneous T-cell lymphoma (vi) Nephropathies, which accompany inflammatory, allergic and/or proliferative processes:
Nephrotic syndrome
all nephritides (vii) Liver diseases, which accompany inflammatory, allergic and/or proliferative processes:
Acute liver cell decomposition
acute hepatitis of different origins, e.g., vitally-,
topically- or pharmaceutical agent-induced
chronically aggressive and/or chronically intermittent
hepatitis (viii) Gastrointestinal diseases, which accompany inflammatory, allergic and/or proliferative processes;
Regional enteritis [Crohn's disease)
ulcerative colitis
gastritis
reflux esophagitis
gastroenteritides of other origins, e.g., native sprue fix} Proctc-logical diseases, which accompany inflammatory, allergic and/or proliferative processes: Anal eczema
fissures hemorrhoids idiopathic proctitis

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Ex) Eye diseases, which accompany inflammatory, allergic and/or proliferative processes:
Allergic keratitis, uveitis, iritis conjunctivitis blepharitis optic neuritis chorioiditis sympathetic ophthalmia {xi] Diseases of the ear-nose-throat area, which accompany inflammatory, allergic and/or proliferative processes: Allergic rhinitis, hay fever
otitis externa, e.g., caused by contact dermatitis, infection, etc. otitis media (xii) Neurological diseases, which accompany inflammatory, allergic and/or proliferative processes:
Cerebral edema, mainly tumor-induced cerebral edema multiple sclerosis acute encephalomyelitis meningitis
different forms of convulsions, e.g., infantile nodding spasms (xiii) Blood diseases, which accompany inflammatory, allergic and/or proliferative processes:
Acquired hemolytic anemia idiopathic thrombocytopenia

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[xiv) Tumor diseases, which accompany inflammatory, allergic and/or proliferative processes:
Acute lymphatic leukemia malignant lymphoma lymphogranulomatoses lymphosarcoma
extensive metastases, mainly in breast, bronchial and prostate cancers [xv] Endocrine diseases, which accompany inflammatory, allergic and/or proliferative processes; Endocrine orbitopathy thyrotoxic crisis . de Quervain's thyroiditis Hashimoto's thyroiditis hyperthyroidism (xvi) Organ and tissue transplants, graft-versus-host disease (xvii) Severe shock conditions, e.g., anaphylactic shock, systemic inflammatory response syndrome (SIRS) (xviii) Substitution therapy, with:
innate primary suprarenal insufficiency, e.g,,
congenital adrenogenital syndrome
acquired primary suprarenal insufficiency, e.g.,
Addison's disease, autoimmune adrenalitis, meta-
infective, tumors, metastases, etc.
innate secondary suprarenal insufficiency, e,g.,
congenital hypopituitarism

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acquired secondary suprarenal insufficiency., e.g.,
meta-infective, tumors, etc. {xix) Emesis, which accompanies inflammatory, allergic and/at proliferative processes;
e.g., in combination with a 5-HT -antagonist in
cytostatic-agent-induced vomiting. (xx) Pain of inflammatory origin, e.g., lumbago.
The compounds of general formula 1 according to the invention can also be used for therapy and prophylaxis of
additional pathologic conditions that are not mentioned above, for which synthetic glucocorticoids are now used (see in this connection Hatzr H. J,, Glucocorticoids: Immunologische Grundlagen, Pharmacologic und Therapierichtlinien,
Wissenschaftliche "Verlagsgesellschaft mbH, Stuttgart, 1998]. All previously mentioned indications (i) to (xx) are
de-scribed in detail in Hats, H. J,, Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1S98.
For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose is different, and it depends on, for example, the active strength of the compound of general formula I, the host, the type of administration and the type and severity of the conditions that are to be treated, as well as the use as prophylactic agent or therapeutic agent.

In addition,'the invention provides
(i) the use of one of the compounds of the invention according to formula I or its mixture for the production of a medication for treating a DISEASE;
(ii) a process for treating a DISEASE, and said process
comprises an administration of an amount of compound according to the invention, whereby the amount suppresses the disease and whereby the amount of compound is given to a patient who requires such a medication;
{iii) a pharmaceutical composition for treating a DISEASE, and said treatment comprises one of the compounds according to the invention or its mixture and at least one pharmaceutical adjuvant and/or vehicle. In general, satisfactory results are to be expected in animals when the daily doses comprise a range of 1 fig to 100,000 pq of the compound according to the invention per kg of body weight. In larger mammals, for example humans, a recommended daily dose lies in the range of 1 /ig to 100,000 jig per kg of body weight. Preferred is a dose of 10 to 30,000 fiq per kg of body weight, more preferably a dose of 10 to 10,000 ;*g per kg of body weight. For example, this dose is suitably administered several times daily. For treating acute shock [e.g., anaphylactic shock), individual doses can be given that lie considerably above the above-mentioned doses.
The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the

24
art by the active ingredient being processed with the vehicles, fillers, substances that influence decomposition, binding agents, humectants, lubricants, absorbents, diluents, flavoring correctives, staining agents, etc, that are commonly used in galenicals and converted into the desired form of administration, in this case, reference is to be made to Remington's Pharmaceutical Science, 15th Ed Mack Publishing Company, East Pennsylvania (1980),
For oral administration, especially tablets, coated tablets, capsules, pills, powders, granulates, lozenges, suspensions, emulsions or solutions are suitable.
For parenteral administration, injection and infusion preparations are possible.
For intra-articular injection, correspondingly prepared crystal suspensions can be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
For rectal administration, the new compounds can be used in the form of suppositories, capsules, solutions {e.g., in the form of enemas) and ointments, both for systemic and for local therapy.
For pulmonary administration of the new compounds, the latter can be used in the form of aerosols and inhalants.
For local application to eyes, outer ear channels, middle ear, nasal cavities, and paranasal sinuses, the new compounds can

25
be used as drops, ointments and tinctures in corresponding pharmaceutical preparations.
For topical application, formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds o£ general formula I should be 0.01%-2o% in these preparations to achieve an adequate pharmacological action.
The invention also comprises the compounds o£ general formula I according to the invention as therapeutic active ingredients. In addition, the compounds of general formula I according to the 'invention are part of the invention as therapeutic active ingredients together with pharmaceutically compatible and acceptable adjuvants and vehicles. The invention also comprises a pharmaceutical composition that contains one of the pharmaceutically active compounds according to the invention or mixture thereof and a pharmaceutically compatible salt or pharmaceutically compatible adjuvants and vehicles.
In particular, the following compounds show an especially effective pharmaceutical action. In this case, the second compound is the preferred one in the groups' 14- (5-Fluoro-^-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino)-phthalide
5- [4-f5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide
6- [4- i5-fluoro-2-methoxyphenyl) -2-hydroxy-4 -methyl-2 -trifluoromethyl-valeroylamino] -4-methyl-2 , 3 -benzoxazin- l-one

26
6- [4- E4-bromo-2-methoxyphenyl) -2-hydroxy-4 -methyl -2 -trifluoromethyl-valetoylamino]-4-methyl-2,3-benzoxazin-l-one
S- (4-(5-fluoro-2-hydroxyphenyl)- 2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2f 3-bensoxazin-l-one

27
Examples:
The compounds of general formula I according to the invention can be produced as described below:
Production Process
(1} . A carbonyl compound of general formula II

in which A, B, Ar, R.1 and R2 have the meaning that is indicated in formula I, is reacted to form a compound of formula I with a compound of general formula CnF .-SiR3, in which R3 has the meaning that is indicated in general formula Ir in the presence of a crystals or with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl. As a catalyst, fluoride salts or basic compounds such as alkali carbonates are suitable (j. Am. Chem. Soc. Ill, 393 C19S5)) .
(2) . A compound of general formula III

in which A, B, R*, Rz and R3 have the meaning that is indicated in formula I and FG means a leaving group, is reacted with a compound Ar-NH-R9, whereby R9 means a hydrogen atom or a C1-C5

29
acyl group and Ar has the meaning that is indicated in general formula I, whereby optionally then radical R9 is cleaved off to obtain a compound of formula I. In this case, the compound of general formula III can optionally be formed only as an intermediate product, e.g., it can be an acid chloride that is formed as an intermediate product from a corresponding carboxylic acid. As leaving groups, for example, a fluorine, chlorine or bromine atom or the tosylate radical can be mentioned. (3). A compound of general formula IV

in which A, Rl, R2 and R3 have the meaning that is indicated in
formula I, is reacted in a solvent or without a solvent with a compound of formula Ar-NH-R5, whereby R9 and Ar have the meanings that are indicated under 2, whereby optionally then radical R9 is cleaved off to obtain a compound of formula I with 8 in- the meaning of a CH? group.
(4) A compound of formula I, in which R4, means "a hydrogen atomH is reacted with a suitable reagent to obtain compounds with radicals R* in additional meanings that are indicated for formula I. Examples of this are the etherification or esterification of a corresponding hydroxy1 compound.

29
Of the process variants above, 1. and 2. are suitable for the production of all compounds that fall under general formula I.
With the third variant, compounds of general formula I can be produced, in which
B stands for a CH3 group.
Optionally, compounds that were produced according to one of the above processes and in which A is an optionally substituted aromatic ring can be substituted selectively 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: Production of the starting Materials
3- [1- (2-Methoxyphenyl)-cyclopropyl] -2-oxo-propionic acid
Corresponding to J. Org. Chem. 40 (1975) 3497, 16.7 g of 2-
methoxyphenylacetonitrile, 15a ml of lithium triisopropylamide t3 molar solution) and 46.7 ml of 1,2-cychloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric acid triamide are reacted with one another. 5.6 g ot 1-[2-methoxyphenyl)-cyclopropyl-carbonitrile, boiling point 104-115°C/0.1 mbar, which is further reacted as described for 3 -(1-phenyl-cyclobutyl)-2 -oxo-propionic acid is obtained. 3-[1-(2-Methoxyphenyl)-cyclopropyll-2-oxo-propionic acid is thus obtained as an oil.

30
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 SO ml of tetrahydrofuran is added in drops at boiling heat over two hours and boiled for another hour. Then, saturated ammonium chloride solution and 300 ml of ethyl acetate are added while being cooled with ice, stirred for 30 minutes at G°C, and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times with water. The solvent is dried [Na2SO4] 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 4S°C/l hPaf is obtained, O.B g of anhydrous aluminum chloride is added to 5 ml of 4-fluoroanisole 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 IN hydrochloric acid and water, dried (Na2S04) , and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (1:1), 1 g of 4- (5-fluaro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, flash point 3S-39°C, is obtained.

31
1.9 g of 4-f5-fluoro-2-methoxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester is refluxed with 40 ml of potassium hydroxide in methanol (10%) for 2 hours. After the solvent is concentrated by evaporation in a vacuum, water is added, extracted with hexane, and the separated water phase is acidified with SN hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2SO4) , 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 1Q2-104°C, is obtained.
The acids of Table 1 were produced analogously.
Table 1



J4

By conversion according to standard processes, additional
acids ate obtained from the acids above or from their precursors:
4- (4-Cyano-2-methoxyphenyl) -2-hydroxy-4-methyl-2 -trifluoromethyl-valeric acid
Ths title compound is obtained from 4- [4-bromo-2-methoxyphenyl) -2-hydroxy-4-Tnethyl-2-tri£luoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in clime thy Iformamide at 1400C. After saponification, the title acid is obtained as an amorphous powder.

33
4- f4-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 dichlorometbane, mixed with 714 mg of 2-trimethylsilyloxy-acrylic acid-ethyl ester cooled to -70°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 e.6 ml of 1 M sodium hydroxide in ethanol/water (2:1H v/v) for 3 hours at room temperature. After water is added, 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.
4- (5-Fluoro-2-methoxyphenyl} -4-methyl-2-oxo-valeric acid
is obtained analogously to the embodiment above, flash point 53-
6 0°C.
4-(4-Bromo-2-methoxyphenyl)-2-oxo-valeric acid
is obtained analogously to the embodiment above as an oil.

4- (2, 3-Dihydro-7-benzofuranyl) -4-methyl-2 -oxo-valeric acid
1.69 g of 1- (2,3-dihydro-7-benzofuranyl) -i-methyl-ethanol is obtained in the usual way from 1.7 g of 2r3-dihydro-benzofuran-7-carboxylic acid methyl ester in 35 ml of diethyl ether and 7 ml of a 3 molar solution of methyl magnesium chloride in tetrahydrofuran. This product is reacted analogously to the process that is described for 4-[4-iodo-2-methoxyphenyl}-4-methyl-2-oxo-valeric acid. i.B g of the title compound is obtained as a yellow-brown oil.
4- (3-Chloro-2-methoxyp) -2-oxo-valeric acid
S.2 ml of methyl iodide is added to 10 g of 3- chlorosalicylic acid and 18 g of potassium carbonate in 88 ml of dimethylformamide, and the mixture is stirred overnight. It is diluted with water, extracted with ethyl acetate, the organic phase is dried (Na2S06) and concentrated hy evaporation. The residue is distilled on a bulb tube. 10 g of 3-chloro-2-methoxybenzoic acid methyl ester is obtained, boiling point 100°C/0.17 mbar.
This ester is reacted analogously to the process that is described for 4 - l4-iodo-2-methoxyphenyl) -4 -methyl-2-oxo-valeric acid, 3 g of the title compound is obtained as a light yellow oil.
4- ( 6-Fluoro-2-methoxyphenyl) -2-oxo-valeric acid
IB g of the title compound is obtained as a light yellow oil from IS g of 6-fluorosalicylic acid analogously to the process

35
that is described for 4-{3-chloro-2-methoxyphenyl]-2-oxo-valeric acid.
4-Toluenesulfonic acid- [4- (5-fluoro-2 -mathoxyphenyl) -2-hydroxyzine thyl-2-trifluoromethyl-pentyl) -ester
810 mg of 4-(S-fluoro-2'methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid is reduced in 20 ml of ether with 190 mg of lithium-aluminum hydride. After aqueous sodium bicarbonate solution is added, the ether phase is separated, dried (Na2S04) , concentrated by evaporation, and the residue is distilled on a bulb tube. 700 mg of 2-hydroxy-4-[5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-pentanol, which is dissolved in 7 ml of pyridine and is mixed at 0°C with 440 mg of 4-toluenesulfonic acid chloride, is obtained. After 2 days at 0°C, it is concentrated by evaporation in a vacuum, dispersed between 1 H hydrochloric acid and ethyl acetate, the ethyl acetate phase is washed several times with l M hydrochloric acid, dried (NazS04) , and concentrated by evaporation. The title compound is thus obtained, flash point 93-940C.
4-Toluenesulfonic acid- [4- (5-fluoro-2-methoxy-phenyl) -2-hydroxy-2-trifluoromethyl-pentyl]-ester
is produced analogously to the previous instructions, flash point 43-500C.

36
2- [2- (5-Fluoro-2-methoxyphenyl) -2 -methyl-propyl 1 -2-trifluoromethyl-oxiran
3-S g of 2-hydroxy-4- (5-fluoro-2-methoxyphenyl ) -4-methyl-2-trifluoromethyl-pentanol and 3.45 g of triphenylphosphine are dissolved in SO ml of tetrahydrofuran and mixed in 3 portions at 0°C with 2.5 ml of azodicarboxylic acid-diethyl" ester. After one hour at 0QC, it is stirred for 16 more hours at room temperature, then refluxed for 7 hours and again stirred for 48 hours at room temperature. After concentration by evaporation, a hexane-isopropyl ether mixture is added, filtered, and the filtrate is chromatographed on silica gel. The product that is eluted with hexane/ethyl acetate is distilled on a bulb tube, boiling point 1000C/O.5 mbar.
_ 2- [2- (4-Bromo-2-methoxyphenyl) -2-methyl-propyl] -2-trifluoromethyl-oxiran
is obtained analogously to the example above, boiling point 120°C/O.04 mbar.
4 –Bromo- 5 -amiuophthalide
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°C in portions with 260 g of potassium permanganate, whereby the temperature increases to 90°C. It is heated for 2 more hours to 95°C, filtered, the filtrate is acidified with hydrochloric acid and extracted with diethyl ether. After concentration by evaporation of the solvent, 27 g of 3-bromo-4-nitrophthalic acid is obtained.

37
12 g of the acid is heated for 15 minutes to 220°C, and then it is 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 slowly mixed at 0°C with 78 . 3 ml of a 0.5 M solution of sodium borohydride in dimethylformamide. After three hours at 00C, 2N hydrochloric acid is carefully added and extracted with ethyl acetate. After washing with potassium bicarbonate solution, drying [Na2SO4] , and concentration by evaporation of the ethyl acetate phase, 6-6 g of 4-bromo-5-nitrophthalide is obtained.
6.6 g of 4-bromo-S-nitrophthalide is dissolved in 45 ml of ethanol and added in drops to a mixture of 65 g of iron (II) sulfate, 220 ml of water and 65 ml of ammonia (33*) that is heated to 60°C and thoroughly stirred. After 2 hours at 60°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, flash point l76-180QC.
6-Bromo-5-aminophthalide
4-Bromo-5-nitrophthalic acid anhydride is produced analogously to the above-described process from 4-bromo-5-nitro-1,2-xylene.
By boiling with ethanol, a mixture of 2-bromo-6-ethoxycarbonyl-3-nitro-benzoic acid and 3-bromo-2-ethoxycarbonyl-4-nitro-benzoic acid is obtained from the above.

38
1,2 ml of oxalyl chloride is carefully added in drops at 0°C to 7,2 ml of a 0.66 m solution of dimethylformamide in dichloromethane. The solution is stirred for I hour at 0°C and for 5 minutes at room temperature. After concentration by evaporation in a vacuum, the residue is suspended in 7 ml of acetonitrile, cooled to -35°C and mixed drop by drop with 1.5 g of the ester mixture. After one hour at the same temperature, it is cooled to -700C, 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 carbonate and extracted with diethyl ether. The diethyl ether phase is dried (Na2SO4) and concentrated by evaporation. A mixture of 5-bromo-6-nitrophthalide and 6-broma-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 is obtained, flash point 235-241°C,
The phthalides of Table 2 are obtained analogously.
Table 2
I I b


39

5 -Ace t amido-phthalide
3 g of 5-amino-phthalide, 10 ml of acetic anhydride and 30 ml of tetrahydrofuran are refluxed for i hour. The crystals that are precipitated after cooling are suctioned off and washed with isopropyl ether. 3.3 g. of the title compound is obtained, flash point > 300°C,
6-Amino-4-methyl-2,3-bensoxazin-1-one
60 g of 2-methyl-5-nitroacetophenone, 33.5 g of 2,2-dimethyl-1, 3-propanediol and 6 g of p-toluenesulfonic acid are boiled in i 1 of toluene with a water separator until water is no longer produced. The solution is washed with potassium bicarbonate, dried (Na2SO4) , 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.

40
52 g ot the acid is hydrogenated in 500 ml of methanol and 500 ml of ethyl acetate with 10 g of palladium/carbon (10%). 45.5 g of the crystalline amino compound is obtained from pentane.
10 g of the amine is refluxed with 100 ml of concentrated hydrochloric acid for 2 hours. The solvent is concentrated by evaporation in a vacuum, and the residue is refined 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-2H3-benzoxazin-l-one is obtained, flash point 29l-296°C,
6-Amino-4-ethyl-2,3-benzoxazin-l-one
is obtained analogously from 2-methyl-5-nitropropiophenone, flash
point B9-930C.
6-Acetamido-4-methyl-2,3-benzoxazin-l-one
This compound is obtained analogously to the 5-acetamido-phthalide from 6-amino-4-methyl-2,3-benzoxazin-1-one, refluxed only for 6 days, and then water is added and extracted with ethyl acetate. After drying and concentration by evaporation of the solvent, the title compound is obtained as crystals, flash point 223-229°C.

41
5- [4- (4-Iodo-2 -methoxyphenyl) -4-methyl-2-oxo-valeroylamino) -phthalide
1.7 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is dissolved in 25 ml of dimethyl acetamide and mixed under argon at -8QC with 0.37 ml of thionyl chloride. After 20 minutes Of stirring at -3 to + 3°C, 700 mg of 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 [Na2S04), and after the solvent is concentrated by evaporation and after chromatography of the crude product on silica gel with hexane/ethyl acetate (60:20), 1.5 g of 5-[4-U-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamino)-phthalide is obtained as a foam.
5- [4- 4-Bramo-2-methoxyphenYl) -4-methyl-2-oxo-valeroylamino) -
phthalide
was obtained from 5-aminophthalide and 4-t4-bromo-2-
methoxyphenyl)-4-methyl-2-oxo-valeric acid analogously to the
process that is described for 5-[4-{4-iodo-2-methoxyphenyl)-4-
methyl-2-oxo-valeroylamino] -phthalide , flash point 13 6-1400C .
5-[4- {3-Chloro-2 -methoxyphenyl} –4-methyl-2-oxo-valeroylamino -phthalide
was obtained as a beige-colored foam from B-aminophthalide and 4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid analogously to the process that is described for 5-[4-E4-iodo-2-
methoxyphenyl}-4-methyl-2-oxo-valeroylamino)-phthalide.

42
5- [4- [6-Fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeroylamino) -
phthalide
was obtained from 5-aminophthalide and 4-(6-fluoro-2-
methoxyphenyl) -4-methyl-2-oxo-valeric acid analogously to the
process that is described for 5-(4-(4-iodo-2-methoxyphenyl)-4-
methyl-2-axo-valeroylamino)-phthalide, flash point 175-179°C
5-{3- [1- (2-Methoxyphenyl) -cyclopropyl] -2 -oxo-propionylamino}-
phthalide
was obtained from 5-aminophthalide and 3-II-(2-methaxyphenyl)-
cyclopropyl]-2-oxo-propionic acid analogously to the process that
is described for 5-[4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-
valeroylamino)-phthalide, flash point 190-202°C
5-{3- [l- (5-Fluoro-2-methoxyphenyl) -cyclopropyl] -2-oxo-
propionylamino}-phthalide
was obtained from 5-aminophthalide and 3 -[1-(5-fluoro-2-
methoxyphenyl)-cyclopropyl]-2-oxo-propionic acid analogously to the process that is described for 5-[4-(4-iodo-2-methoxyphenyl)-4'-methyl-2-OXO-valeroylamino) -phthalide, flash point 190-1930C,
5- [4- (2,3 -Dihydro-7-benzofuranyl) -4-methyl-2-oxo-valetoylamino] -
phthalide
was obtained as a white foam from 5-aminophthalide and 4-(2,3-dihydro-7-benzofuranyl) -4-methyl-2-oxo-valeric acid analogously to the process that is described for 5 -[4 -{4-iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeroylamino) -phthalide.

43
6- [4- (5-Fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeroylamino] -4-methyl-2, 3-benzoxazin-l-one
was obtained from 6-amino-4-methyl-2, 3-benzoxazin-l-one and 4- (5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid analogously to the process that is described for 5-[4-E4-iodo-2-methoxyphenyl)--4-methyl-2-oxo-valeroylamino) -phthalide, flash point 171-173°C.
4-Ethyl-6- [4- (5-fluoro-2-methoxyphenyl) -4-methyl-2 -oxo-valeroylamino)-2,3-benzoxazin-l-one
was obtained from 6-amino-4-ethyl-2,3-benzoxazin-i-one and 4-(S-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid analogously to the process that is described for 5-[4-{4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamina)-phthalide, flash point 157-1580C.
6- [4- (6-Fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeroylajni.no] -4 -methyl-2,3-benzoxazin-l-one
was obtained from 6-amino-4-methyl-2 , 3-benzoxazin-l-one and 4- [6-fluoro-2-methoxyphenyl) -4-methyl-2-oxo-valeric acid analogously to the process that is described for 5-[4-(4-iodo-2-methoxyphenyl}-4-methyl-2-oxo-valeroylamino)-phthalide, flash point 17B-1810C.

S- Tl- (S-Fluoro-2-methoxyphenyl) -cyclopropyl] -2 -oxo-propionyl amino] -4 -methyl- 2 , 3-benzoxazin-l-one
was obtained from G-amino-4~-methyl-2f 3-benzoxazin-l-one and 3-[l-C5-f luoro-2-methoxyphenyl) -cyclopropyl] -2-oxo-propionic acid analogously to the process that is described, for 5-[4-(4-iodo-2-methoxyphenyl) -4-methyl-2-oxo-valeroylamino) -phthalide, flash point 222-227°C,
6- [4- (2,3-Bibydro-7-benzofuranyl) -4-methyl-2-oxo-valeroylamino] -4-methyl-2 , 3-benzoxazin-l-one
was obtained from 6-amino-4-methyl-2, 3-benzoxazin-l-one and 4-[2, 3-dihydro-7-benzofuranyl} -4-methyl-2 -oxo-valeric acid analogously to the process that is described for 5- [4-U-iodo-2-methoxyphenyl) j4-methyl-2-oxo-valeroylamino) -phthalide, flash point 171-177°C.
The examples below are used for a more detailed explanation of the invention. Additional compounds can be produced by using homologous/analogous reagents. The necessary starting compounds axe described above under "Starting Compounds."

Example 1 (Process 1)
5-{2-Hydroxy-3- [1- (2~methoxyphenyl) -cyclopropyl] -2-trifluoromethyl-propionyland.no}-phthalide
500 mg of 5-{3-[1-[2-methoxyphenyl]-cyclopropyl] -2-oxo-propionylamino}-phthalide is dissolved under argon in IS ml of dimethylformamide and mixed with 0.77 ml of trifluoromethyl-trimethylsilane and 500 mg of cesium carbonate while being cooled with ice. After 18 hours of stirring at room temperature, 5 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and a few drops of water are added and stirred for one hour at room temperature. After 100 ml of water is added, it is extracted with ethyl acetate, the organic phase is dried (Na2S04), and concentrated by evaporation. The crude product is chromatographed on silica gel. With hexane/ethyl acetate (B0:20), the title compound is obtained in a pure state.
The enantiomer mixture is separated by chromatography on chiral support medium tCHlRALPAX AD(R), DAICEL Company) with hexane/2-propanol/ethanol (900: 25; 2 5, wvj . There is thus obtained
( + ) -Enantiomer with flash point 2D0-20B°C, [a] D 4-106.9° {c = 0.5, CHC13)
(-}-Enantiomer with flash point l95-20a°C, [a] D -104.9° [c = 0.5, CHCl3)

46
Example 2
5- (3- [l- t5-Fluoro-2-methoxyphenyl) - eye lo propyl] -2-hydxoxy-2-trifluoromethyl-propionylamino}-phthalide
is obtained from 5- {3- [1- E5-fluoro-2-methoxyphenyl) -cyclopropyl] -2-oxo-propionylamino)-phthalide analogously to Example 1, flash point 170~1790C (racemate).
Example 3 (Process 2)
5- [2-Hydroxy-4- [2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
100 mg of 2-hydroxy-4-t2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid is mixed in 5 ml of
dimethylacetamide at 0°C with 0.23 ml of thionyl chloride. After 30 minutes of stirring at 0°C, 390 mg of 5-aminophthalide in 2 ml of dimethylacetamide is added, and the mixture is stirred for another 4 hours at this temperature. Then, ice water is added, extracted with ethyl acetate, and after drying {Na3S04) , the crude product is chromatographed on silica gel. With hexane/ethyl acetate [50:50), the title compound is obtained in a crystalline state, flash point 134-1350C.
After racemate separation, there are obtained (+)-Enantiomer with flash point 135-136*C, [tfJD +lS2,2a fc=l> CHC15},
(-)-Enantiomer with flash point 136-137°C, [a]& -194,e° (c -1, CHC13) .
The compounds of Table 3 are obtained analogously.

- Table 3




4B

(1) The optically active compounds that are presented in the table were separated analogously to Example 1. Unless otherwise indicated, the measurement was made in methanol.
If 6-amino-4-methyl-2,3-benzoxazin-l-one or 6-amino-4-ethyl-2, 3-benzoxasin-l-one is used in Example 3 instead of 5-aminophthalide, the examples that are listed in Table 4 are
obtained.






50

(1) The optically active compounds that are presented in the table were separated analogously to Example 1. Unless otherwise indicated, the measurement was made in methanol-

51
Example 4 2
5- [2-Hydroxy-4- (5-£luoro-2-methoxyphenyl) -4-methyl-2-
trifluoromethyl-pentylamino]-phthalide
688 mg of 5-acamidophthalide in 15 ml of dimethylformamide is mixed under argon at 0°C with 108 mg of an 8"0% sodium hydride/oil suspension. After 10 minutes of stirring at this temperature, 55G mg of 4-toluenesulfonic acid-[2-hydroxy-4-[5-fluoro-2-methoxyphenyl)-2-trifluoromethyl-pentyl}-ester is added. After 16 hours of stirring at 600C, it is added to 1 M hydrochloric acid, neutralised with potassium carbonate, and extracted with ethyl acetate, After drying (Na2SO4) , the crude product is chromatography on silica gel. With hexane/ethyl acetate (60:40), the title compound is obtained in a crystalline state, flash point 148-149°C.
Example 43
6- [2 -Hydroxy-4- (5-fluoro-2-methoxyphenyl) -4-methyl-2-trifluoromethyl-pentylamino] -4-methyl-2 , 3 -benzoxazin-l-one
584 mg of 2-[2-(S-fluoro-2-methoxyphenyl)-2-methyl-propyl}-2-trifluoromethyl-oxiran. 2S2 mg of 6-amino-4-methyl-2,3-benzoxazin-1-one and 1 ml of 1,3-dimethyl-3,4,5, 6-tetrahydro-2 [1H}-pyrimidinone are heated to 120°C for 6 hours. After 1 ml
of tetrahydrofuran is added, it is chromatographed on silica gel, and the title compound is eluted with hexane/ethyl acetate/tstrahydrofuran [55:4G:5), flash point 178-1790C.

52
Example 44
5-{3- [1- (5-Fluoro-2-hydroxyphenyl) -cyclopropyl] -2-hydroxy-2-trifluoromethyl-propionylamino}-phthalide
225 mg of 5-{3- [1-{5-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino}-phthalide is mixed in 4.5 ml of dichloromethane at 0°C with 2-48 ml of a 1 molar solution of boron tribromide in dichlorometh.ane. After 3 hours of stirring at 0°C, the mixture is added to water, extracted with ethyl acetate, the organic phase is dried (Na3S04) and concentrated by evaporation. After the residue is triturated with hexane, the- title compound is obtained in crystalline form, flash point 196-1990C
Example 4 5
6- {3- [1- (5-Fluoro-2-hydxoxyphenyl) -cyclopropyl] -2-hydroxy-2-trifluoxomethyl-propionylamiao}-4-methyl-2, 3-benzoxazin-l-one is obtained from 6- {3- [1-(5-fluoro-2-methoxyphenyl}-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino}-4-methyl-2 , 3-benzoxazin-1-one analogously to 5-{3-[l-(S-fluoro-2-hydroxyphenyl) -cyclopropyl] -2-hydroxy-2-trifluoromethyl-propionylamino}-phthalide, flash point 23S-244°C.
Example 4 6
6- [2-Hydroxy-4 - [5-fluoro-2-hydroxyphenyl) -4 -methyl-2-trifluoromethyl-valeroylamino] -4 -methyl -2 , 3-benzoxazin-l-one is obtained from 6- (2-hydroxy-4-[2-fluoro-2-methoxyphenyl)-4 -
rnethyl-2-trifluoromethyl-valeroylamino} -4-methyl-2 , 3-benzoxazin-

53
1-one analogously to 5-{3-[1-(5-fluoro-2-hydroxyphenyl)-
cyclopropyl] -2-hydroxy-a-trifluoromethyl-propionylamino}-
phthalide, flash point 234-2360C,
(-f)-Enantiomer, flash point 23Q-234°C, [a]Q +34° (c = 0.5) (-)-Enantiomer, 'flash point 230-232°C, [a]a -34.1° [c =
0-51 -
Example 47
6- [2-Hydroxy-4- (2-hydroxyphenyl) -4-rnethyl-2-trifluoromethyl-valeroylamino]~4-ethyl-2,3-benaoxazin-1-one
is obtained from 6- [2-hydroxy-4- {2-methoxyphenyl) -4-methyl-2-triflruoromethyl-valeroylamino) -4-ethyl-2 , 3-benzoxazin-l-one analogously to 5-{3- [l- [5-fluoro-2-hydroxyphenyl) -cyclopropyll -2-hydroxy-2-trifluoromethyl-propionylamino}-phthslider flash point 164°C, .
( + )-Enantiomex with flash point 191-192°C, [α]D +161.5° (c = 0.5, CHCl3)
(-)-Enantiomer with flash point 190-1910C, [a] a -161.3° Mc = 0.5, CHCl3)
The examples of Tables 5A and 5B are obtained analogously.


54



Il '.'

(1) The optically active compounds that are presented in the table were separated analogously to Example 1. Unless otherwise indicated, the measurement was made in methanol.
Table 5B



56

(1) The optically active compounds that are presented in the table were separated analogously to Example 1. Unless otherwise indicated, the measurement was made in methanol,
Example 70 (Process 5)
5- [4- (2-Ethoxy-5-fluorophenyl),-2-hydroxy-4-methyl-2-
trifluoromethyl-valeroylamino] -phthalide
44 mg of 5-[4-[5-f luoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-4 -2-trifluoromethyl-valeroyl-amino] -phthalide is stirred in l ml of dimethylformamide with 28 mg of potassium carbonate and SO 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 (Na2S04) , and after the solvent is concentrated by evaporation, 35 mg of 5- [4 - (2-ethoxy-S-fluorophenyl) -i -hydro-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide is obtained, flash point l08°C

■-" "Y
The compounds of Table 6 were produced analogously to the example above.
Table 6




SB

(1) The optically active compounds that are presented in the table were separated analogously to Example 1. Unless otherwise indicated, the measurement was made in methanol.
Example 33
(-) -4-Bromo-5- [4- (5-fluoro-2-hydroxyphenyl) -2 -hydroxy-4 -methyl-2-trlfluoromethyl-pentylamino] -phthalide
55 mg of (-)-5-[4-{5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide is mixed under nitrogen in 1 ml of dimethylformamide at 2°C with 18 mg of N-bromosuccinimide. After 2 hours at this temperature, it is diluted with 20 ml of ethyl acetate, extracted with water, and the organic phase is dried (Ma2S04) and concentrated by evaporation. With chromatography on silica gel, the title compound is fluted in. crystalline form with hexane/ethyl acetate (4:1), flash point 22S-2320C

52
Example 84
(-) -4-Bromo-5- [4- (3-bromo-5-f luoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -phthalide
If 44 mg of N-bromosuccinimide is used in the preceding example on 100 mg of t-1 -5- (4 - [5-fluoro-2-hydroxyphenyl} -2 -hydroxy-4-methyl-2 -trifluoromethyl-pentylamino] -phthalide r the title compound is obtained in crystalline form after chromatography on silica gel with hexane/ethyl acetate (7:3), flash point 144-14G*C.
Example 85
5- [4- (2,3-Dihydro-7-benzofiuranYl-2-hydroxy-4-jnethyl-2-trifluoromethyl-pentaiioyl-amino] -phthalide is obtained from 5- [4- (2,3-dihydro-7-benzofuranyl-4-methyl-2-oxo-
pentane-amino]-phthalide analogously to Example 1, flash point 182-185°C.
Example B 6
6- [4- (2,3-Dihydro-7-benzofuranyl-2-hydroxy-4-inethyl-2-trifluorometfayl-pentanoyl-amino] -4-methyl-2, 3-benzoxazin-l-one is obtained from 6- [4- {2 ;3-dihydro-7-benzofulranyl-4 -methyl-2-oxo-
pentanoyl-amino}-l-methyl-2,3-benzoxazin-l-one analogously to
Example l, flash point 2l5-2200C.

60
Pharmacological Examples
In the glucocorticoid receptor (GR)-binding test with use of cytosol preparations that consist of the thymus homogenates of rats and of 10 nM of [3H] -dexamethasone as a reference substance (cf. Lefebvre et al. J. Steroid Biochem, 33, 557-563, 1989)r the compounds of formula l show a high to very high affinity to the GR (see Table),
Table of GR-Values

"e" corresponds to the base of natural logarithms.
The compounds that are mentioned in the table are the following especially preferred compounds:
i : 5- [4- (5-Fluroao-2-hydroxphenyl] -2-hydroxy-4-methyl-2 -trifluoromethyl-valeroylamino]-phthaliae

61
ii; 5- (4- (5-Fluoro-2-hydroxyphenyl)- 2-hydroxy-4-methyl-2-trifluoromethyl-pentylanri.no}-phthalide
iii: 6- [4- (5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2 r 3-benzoxazin-i-one
iv: 6- [4- [4-Bromo-2-methoxyphenyD -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2,3-benzoxazin-i-one
v: 6- [4- [5-Fluoro-2-hydi:oxyphenyl) -2-hydroxy-4 -methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2, 3-benzoxazin-i-one
The compounds of general formula I according to the invention inhibit the secretion of cytokine 1L-S in human monocyte cell line THP-l that is triggered by lipopolysaccharide (LPS) . The concentration of the cytokines was determined in the supernatant by means of commercially available ELISA kits (cf. Welksr et al., Int. Arch. Allergy Immunol., 109, 110-115, 1996}. At a concentration of 1 ^M, the compounds show a maximum inhibition of cytokine secretion by 50-80%,
The antiinflammatory actions of the compounds of general formula I were tested in the animal experiment by testing in the croton oil-induced inflammation in rats and mice (cf. Tubaro et al, Agents Actions, 17„ 347-349, 1985) h In this respect, croton oil in an ethanolic solution was administered topically to the ears in the animals. The .test substances were also topically or systemically administered simultaneously or two hours before the croton oil. After 16-24 hours, the ear weight was measured as a measurement for the inflammatory edema, the peroxidase activity was measured as a measurement for the invasions of granuloctyes,

62
and the elastase activity was measured as a measurement for the invasions of neutrophilic granuloctyes. in this test, the compounds of general formula I inhibit the three above-mentioned inflammation parameters both after topical administration and after systemic administration.
To measure the TAT induction, the animals are sacrificed 6 hours after the test substances are administered, the livers are removed, and the TAT activity in the homogenate is measured (of. Diamandstone et al. Anal. Biochemistry, 16, 395-401, 1966). At a dose of 10-30 mg/kg of body weight, the compounds inhibited the ear inflammation by about 50-30% and induced in this dose range the tyros_inamino transferase in the liver of the animals by 1-4 times the starting value. Since the substances of the general formula also have a high affinity to the progesterone receptor, the new compounds were tested for their gestagenic action in the animal experiment. For this purpose, the pregnancy-maintenance test was performed on ovariectomized rats (cf. Neumann et al. Arzneim- Forsch. (Drug Res.), 34, 296-318, 1984). In this respect, female rats are covered and undergo ovariectomy under anesthesia on day eight of the pregnancy two hours after substance administration. On days 8-14 of the pregnancy, the animals are treated daily with the test substances, and on day 15, the animals are sacrificed, and the number, of living and dead fetuses per animal is determined. In the case of empty uteri, the number of implantation sites is .determined by staining with 10% ammonium sulfide solution. The new compounds of formula I resulted in little or no maintenance of pregnancy up to a dose of

63
500 μg per kg of body weight. In dosages of up to 500 μg/kg of body weight, the new compounds" of general formula I had little to no gestagenic action; in increasing the daily (Hose to 10 mg per kg of body weight, a reduced gestagenic action was to be observed.
In particular the following compounds show an especially effective pharmaceutical action:
5-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-rnethyl-2-trifluoromethyl-valeroylarnino] -phthalide
5- [4- (5-f luoro-2-hydroxyphenyl} - 2-hydroxys-methyl-2-trifluoromethyl-pentylamino] -phthalide
6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2,3-benzoxazin-l-one
6- 14- (4-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylartiino] -4-methyl-2,3-benzoxazin-l-one
5-[4-[5-fluoro-2-hydroxyphenyl)-2-hydroxy-4~methyl-2-trifluorottiethyl-valeroylamino] -4-methyl-2,3-benzoxasin-l-one,
Because of their antiinflammatory action and additional antiallergic, immunosuppressive and antiproliferative actions, the compounds of general formula I according to the invention can be used as medications for treatment or prophylaxis of the following pathologic conditions in mammals and humans: In this case, the term "DISEASE" stands for the following indications:

61
Indications:
(i) Lung diseases
(ii) Rheumatic diseases/auto-immune
diseases/degenerative joint diseases (iii) Allergies
(iv} Vascular inflammations (vasculitis) (v) Dermatological diseases
(vi) Nephropathies
(vii) Liver diseases
(viii) Gastrointestinal diseases
(ix) Proctological diseases
(x) Eye diseases
(xi} Diseases of the ear-nose-throat area
(xii) Neurological diseases
(xiii) Blood diseases
(xiv) Tumor diseases
[xv) Endocrine diseases
(xvi) Transplants
[xvii) Severe shock conditions
[xviii} Substitution therapy" with suprarenal insufficiency
(xix) Emesis
(xx) Pain of inflammatory origin (e.g,, lumbago).
The compounds of general formula I according to the invention can also be used for therapy and prophylaxis of additional pathologic conditions that are not mentioned above, for which synthetic glucocorticoids are now used (see in this

65
connection Hat a, H- J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998}
For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose is different, and it depends on, for example, the active strength of the compound of general formula I, the host, the type of administration, and the type and severity of the conditions that are to be treated, as well as the use as prophylactic agent or therapeutic agent.

66
Claims:
1. Use of at least one compound of general formula I for the production, of pharmaceutical agents that have an antiinflammatory action

in which
R1 and R2 are the same or different and stand for a hydrogen atom, a C^-C^ alkyl group, orr together with the C-atom of the chain, stand for a ring with a total of 2-7 links, R5 stands for a C,-C^ alkyl group or a partially or
completely fluorinated Ck-C5 alkyl group,
A stands for the group


67
(the dashed line means the interface site)r in which R^ means a hydrogen atom, a ci"G5 alkyl group, a C,-C10 acyl group, a Cj-C1G carbalkoxyalfcyl group, a C2-C^ cyanoalkyl group, a Cj-Cl0 unsubstituted or substituted allyl group, a C3-C1Q unsubstituted or substituted propargyl group, a C^-c^ alkoxyalkyl group, a C,-C5 alkyl group that is partially or completely substituted by fluorine atoms,
_R5 to Rfl are the same or different from one another and are selected from hydrogen or halogen atoms or C.-cg alkoxy groups, and R' and R5 together mean a heterocyclic ring, which in addition to the oxygen atom optionally can contain at least one other heteroatom from the group of oxygen, nitrogen, sulfur, with a total of 5-1 links, B stands for a carbonyl group or a CH3 group, and Ar stands for a ring system, selected from the group of general-partial .formulas 2-5,


-33

in which
radicals Xla, X3h,X4, X6, X7 (in partial formulas 2 and 3) and Y4, Y*. Y7, and Y* (in partial formulas 4 and 5) are the same or different and are selected from hydrogen atoms, C|_c5 alkyl groups, partially or completely fluorinated C,-C5 alkyl groups,
and, moreover, radicals X4, X6, Xr (in partial formulas 2 and 3) or Y5, Y7, Ya (in partial formulas 4 and 5], are selected from the halogen atoms, hydroxy groups, C^Cj alkoxy groups or Cfc-C5 alkanoyloxy groups, and if B stands for a CH? group, the physiologically compatible salts of the compounds of general formula I with acids.
2. Use of at least one compound of general formula I according to claim l for the production of pharmaceutical agents for treatment of at least one of the diseases that for the most part accompany inflammatory, allergic and/or proliferative processes:
(i) Lung diseases
(ii) Rheumatic diseases/auto-immune
diseases/degenerative joint diseases

69
(iii) Allergies
(iv) Vascular inflammations (vasculitis)
(v) Dermatological diseases
(vi) Nephropathies
(vii) Liver diseases
(viii) Gastrointestinal diseases
(ix} Proctologics diseases
(x) Eye diseases
(xi) Diseases of the ear-nose-throat area
(xii) Neurological diseases
(xiii) Blood diseases
(xiv) Tumor diseases
(xv) Endocrine diseases
(xvi) Transplants
[xvii] Severe shock conditions
(xviii) Substitution therapy with suprarenal insufficiency
(xix) Emesis
(xx) Pain of inflammatory origin (e.g,, lumbago).
3. Use of the compounds of general formula I according to claim 1 or 2 in racemate form, if the compound can be present in different stereoisomers.
4. Use of the compounds of general formula I according to claim i or 2 in the form of separately present stereoisomers, if the compound can be present in different stereoisomers.
5. Use according to claim 1, 2, 3 or 4, characterized in that the Cj-C5 alkyl group(s) in the compound of general formula I is Care) selected from the group of methyl, ethyl, n-propyl.

70
iso-propyl, n-, iso- or tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl radicals.
6. Use according to claim 1, 2, 3 or 4, wherein halogen atom Y5r Y7, YB is selected from fluorine, chlorine or bromine.
7. Use according to claim l, 2, 3 or .4, wherein R1 and Rz together with the C-atom of the chain form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
0. Use according to claim 1, 2, 3 or 4, wherein a perfluorinated methyl, ethyl„ n-propyl, iso-propyl, n-, iso- or tert-butyl, n-pentyl, 2,2~dimethylpropyl or 3-methylbutyl group stands for a completely fluorinated C.-C5 alkyl group.
9. Use according to claim 1, 2, 3 or 4, wherein the
5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3-
heptafluoropentyl group stands for a partially fluorinated C..-C.
alkyl group.
10. Use according to claim 1, 2, 3 or 4, wherein a Carboxymethyl, tert-butoxymethyl or ethoxmethyl group stands for a C3-C]D carbalkoxyalkyl group.
11. Use according to claim 1, 2, 3 or 4, wherein a Cyanomethyl group, i- or 2-cyanoethyl group stands for a C2-C^ cyanoalkyl group.
13, Use according to claim 1, 2, 3 or 4, wherein an unsubstituted allyl group, a 1-methylallyl, l,l-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylsllyl, 3,3-dimethylallyl, dynamic and 3-cyclohexylallyl group stands for a C3-C10 allyl group..

71
13. Use according to claim lH 2, 3 or 4, wherein an
unsubstituted propargyl group, a methylpropargyl group, 3-
methylpropargyl group, 3-phenylpropargyl group or 3-
cyclohexylpropargyl group stands for a Cj-C^ propargyl group.
14. Use according to claim l, 2, 3 or 4, wherein a
methoxymethyl group, ethaxymethyl group or 2 - methoxyethy1 group
stands for a C2-C5 alkoxyalkyl group.
15. Use according to claim 1, 2., 3 or 4, wherein a methoxy, ethoxy, n-propoxy, iso~propoxy, n-P iso- or tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy group stands for a C,-C5 alkoxy group.
16. Use according to claim 1, 1, 3 or 4, wherein a perfluorinated methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-or tert-butoxy, or n-pentoxy, 2,2-dimethylpropoxy, or 3-methylbutoxy group stands for a C1-C5 perfluoroalkoxy group.
17. Use according to claim l,-2, 3, or 4, wherein a formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or iso-valeryl or pivaloyl group stands for a C,-C. alkanoyl group.
IB. Use according to claim 1, 2, 3, or 4, wherein a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl groups stands for a c1-C5 acyl group.
19. Use according to claim 1, 2, 3 or 4, wherein a formyloxy, acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy or isovaleryloxy group stands for a C1-C3 alkanoyloxy group for x\ Xb, X7, Y\ Y5r Y7 or Yfl.
20. Use according to claim 1, 2, 3 ox 4, wherein if the compounds of general formula X {B - -CH-2-) are present as salts,

72
they are present in the form of hydrochloride, sulfate, nitrate, maleate, fumarate, tartrate or benzoate.
21- Use according to claim l or 2, wherein a compound of general formula I is used, in which
R1 and R1 are the same or different and stand for a hydrogen .atom, a methyl or ethyl group .or together with the C-atom of the chain stand for a cyclopropyl ring, and/or R3 stands for a Ci~cs perfluoroalkyl group, and/or A stands for the group

{the dashed line means the interface site)(
in which
R* means a hydrogen atom, a methyl, ethyl, propyl or 2-propyl group, an acetyl group, a methoxy, ethoxy or tert-butoxycarbonyl group, a cyanomethyl group, a 2-cyanoethyl group, an allyl group, a propargyl group, a methoxymethyl, methoxyethyl or ethoxyethyl group, a mono-, di- or trifluoromethyl group, a pentafluoroethyl or nonafluorobutyl group,

73
R5 to Ra in one or two positions mean fluorine or
chlorine atoms and in the remaining positions mean hydrogen atoms, or
R4 and R5 together with incorporation of phenyl-ring atoms 2 and 3 mean a furan, a dihydrofuran or a 2,3-dihydro-l,4-dioxine ring, and R6r R7 and Rs mean hydrogen atoms, X3B stands for a hydrogen atom or a methyl group, or X3* and X3b are the same or different and stand for a
hydrogen .atom or a methyl group, X1, X6 and X7 are the same or different and,
independently of one another, stand for a hydrogen atom or a fluorine atom or a chlorine atom, and/or Y1 . stands for a methyl, ethyl, propyl, 2-propyl or
trifluoromethyl group and/or Y5, Y7 and Y8 are the same or different and,
independently of one another, stand for a hydrogen atom or a fluorine atom or a. chlorine atom, and the other substituents have the meanings that are indicated in formula I.
22. use according to claim 1 or 2, wherein a compound of general formula I is used, in which Ar stands for a ring system of partial formula 2 or 5.
23. use of at least one compound according to claim 1 or 2

74
that is selected from
5-{2-Hydroxy-3- [1- (2-methoxyphenyl) -cyclopropyl] -2-trifluoromethyl-propionylamino} -phthalide
5-(3- [1- (5-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino}-phthalide
5- [2-hydroxy-4- (2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
5-{3- [1-(5-£luoro-2-hydroxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylaTnino}-phthalide
5- [4- [5-fluGro-2-hydrGxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -phthalide
5- [4- (5-fluoro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide
4-bromo-5-(4-[5-fluoro-2-hydroxyphenyl}-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide
4-bromo-5- {4- E3-bromo-5-fluoro-2-hydroxyphenyl] - 2-hydroxyzine thyl-2 -trifluoromethyl-pentylamino] -phthalide
6-{3- II-(5-fluoro-2-hydroxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino}-4-methyl-2,3-benzoxazin-1-one
6- 14- {5-fluoro-a-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoEomethyl-valeroylami.no] -4-methyl-2,3-benzoxazin-l-one
6- [4- (5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl~2-trifluoromethyl-yaleroylamino]-4-methyl-2,3-benzoxa^in-l-one
G- [2-hydroxy-4- (2-hydroxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-4-ethyl-2,3-ben.zoxaziii-l-one
S- [4- (S-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino] -4-methyl-2,3-ben£oxazin-i-one

75

6- [4- (5-£luoro-2-hydroxyphenyl) -2 -hydroxy-4 -methyl-2 -trifluoromethyl-pentylamino] -4-methyl-2,3-benzoxazin-l-one
6-14- (4-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -4-methyl-2, 3-benzoxazin-l-one
24.6- [4- t4-bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluororaethyl-pentylamino] -4-methyl-2, 3-benzoxazin-l-one, and in addition all compounds from Tables 2-S as well as in Examples B5 and Q6.
Compounds of general formula I according to claim 1, namely
5-{3- [l- (5-Fluaro-2-methoxyphenyl) -cyclopropylj -2-hydraxy-2-trifluoromethyl-propionylamino}-phthalide
S-{3- II- (5-fluoro-2-hydroxyphenyl) -cyclopropyl] -2 -hydroxy-2-trifluoromethyl-propionylamino}-phthalide
4-bromo-5- [4- [S-fluoro-2-hydroxyphenyl} -2-hydroxy-4 -methyl-2-trifluoromethyl-pentylamino] -phthalide
4-bromo-5- [4-|3-bromo-5-fluoro-2-hydroxyphenyl)-2 -hydroxy-4-methyl-2-trifluoromethyl-pentylamino)-phthalide
6- {2- [i- (5-fluoro-2~hydroxyphenyll -cyclopropyl] -2-hydroxy-2-trifluoramethyl-propionylamino}-4-methyl-2,3-benzoxazin-l-one
6- [2-hydroxy-4- {2-hydroxyphenyl) -4 -methyl-2-trifluoromethyl-valeroylamino]-4-ethyl-2,3-benzoxazin-I-one
6- [4- (4-bromo-2-methoxyphenyl) -2-hydroxyJ4-methyl-2-trifluoromethyl-pentylamino] -4 -methyl-2 , 3-benzoxazin-l-one
5- {3- [1- (5-fluoro-2-methoxyphenyl] -cyclopropyl] -2-hydroxy-2-trifluoromethyl-propionylamino}-phthalide

76
6- (2-hydroxy-4- (5-f luoro-2-methoxyphenyl) -4-methyl-2-trifluoromethyl-pentylamino] -4-methyl-2,3-benzoxazin-l-one
5- {3- [l- (5-fluoro-2-hydroxyphenyl) -cyclopropyl] -2-hydroxy-a-trifluoromethyl-propionylamino}-phthalide
6- {3- (1- (5-f luoro-2-hydroxyphenyl} -cyclopropyl}~2-hydroxy-2-trifluoromethyl-propionylamino}-4-methyl-2, 3-benzoxazin-l-one
(-) -4-bromo-5- [4- [5-fluoro-2-hydroxyphenyl} -2-hydroxy-4-Tnethyl-2-trifluQromethyl-peutylaniino] -phthalide
(_} -4-bromo-5- 14- (3-bromo-5-fluoro-2-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentyl amino] -phthalide
5- [2-hydro-4- [5-isopropyl-2-methoxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
5- (2-hydroxy-4- (2-methoxy-5-propyl-phenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
5-[2-hydroxy-4-(2-benzyloxy-S-fluorophenyl)-4-methyl-2-trixluoromethyl-valeroylamino] -phthalide
5- [2-hydroxy-4- £2-difluoromethoxy-5-fluorophenyl) -4 - methyl trif luoromethyl-valeroylamino] -phthalide
5- [2-hydroxy-4- f 5-f luoro-2-methoxymethoxy-phenyl) -4 -methyl-2-trifluoromethyl-valeroylaminol-phthalide
5-[2-hydroxy-4-(2-ethoxymethoxy-S-fluorophenyl}-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
5-{[2-hydroxy-4-[5-fluoro-2-f2-methoxyethoxy)-phenyl]-4-me thy 1^,2-trif luoromethyl-valeroylamino (-phthalide
25. Pharmaceutical preparations that contain at least one compound according to claim 24, as well as a pharmaceutically compatible vehicle.

26 Use of at least one compound according to claim 24 for the production of pharmaceutical agents.
27 Use of at least one compound substantially as herein described with-reference to the foregoing examples.
28 Pharmaceutical preparation substantially as herein described with reference to the foregoing examples. _
29 Dated this27th day of April, 2005,



Documents:

341-MUMNP-2005-ABSTRACT 3-7-2008.pdf

341-MUMNP-2005-ABSTRACT(18-12-2008).pdf

341-MUMNP-2005-ABSTRACT(28-4-2005).pdf

341-MUMNP-2005-ABSTRACT(AMENDED)-(18-12-2008).pdf

341-MUMNP-2005-ABSTRACT(AMENDED)-(3-7-2008).pdf

341-MUMNP-2005-ABSTRACT(GRANTED)-(29-5-2009).pdf

341-MUMNP-2005-CANCELLED PAGES 3-7-2008.pdf

341-MUMNP-2005-CANCELLED PAGES(18-12-2008).pdf

341-MUMNP-2005-CLAIMS 3-7-2008.pdf

341-MUMNP-2005-CLAIMS(18-12-2008).pdf

341-MUMNP-2005-CLAIMS(28-4-2005).pdf

341-MUMNP-2005-CLAIMS(AMENDED)-(18-12-2008).pdf

341-MUMNP-2005-CLAIMS(AMENDED)-(3-7-2008).pdf

341-MUMNP-2005-CLAIMS(GRANTED)-(29-5-2009).pdf

341-mumnp-2005-claims.doc

341-mumnp-2005-claims.pdf

341-MUMNP-2005-CORRESPONDENCE 3-7-2008.pdf

341-MUMNP-2005-CORRESPONDENCE(18-12-2008).pdf

341-MUMNP-2005-CORRESPONDENCE(25-5-2009).pdf

341-MUMNP-2005-CORRESPONDENCE(IPO)-(1-7-2009).pdf

341-mumnp-2005-correspondence-received.pdf

341-MUMNP-2005-DECLARATION 3-7-2008.pdf

341-mumnp-2005-descripiton (complete).pdf

341-MUMNP-2005-DESCRIPTION(COMPLETE) 3-7-2008.pdf

341-MUMNP-2005-DESCRIPTION(COMPLETE)-(28-4-2005).pdf

341-MUMNP-2005-DESCRIPTION(GRANTED)-(29-5-2009).pdf

341-MUMNP-2005-FORM 1 3-7-2008.pdf

341-MUMNP-2005-FORM 1(2) 28-4-2005.pdf

341-MUMNP-2005-FORM 1(28-4-2005).pdf

341-mumnp-2005-form 13(25-5-2009).pdf

341-MUMNP-2005-FORM 13(3-7-2008).pdf

341-MUMNP-2005-FORM 18(28-10-2005).pdf

341-MUMNP-2005-FORM 2(COMPLETE)-(28-4-2005).pdf

341-MUMNP-2005-FORM 2(GRANTED)-(29-5-2009).pdf

341-MUMNP-2005-FORM 2(TITLE PAGE) 3-7-2008.pdf

341-MUMNP-2005-FORM 2(TITLE PAGE)-(COMPLETE)-(28-4-2005).pdf

341-MUMNP-2005-FORM 2(TITLE PAGE)-(GRANTED)-(29-5-2009).pdf

341-MUMNP-2005-FORM 3 3-7-2008.pdf

341-MUMNP-2005-FORM 3(28-4-2005).pdf

341-mumnp-2005-form-1.pdf

341-mumnp-2005-form-18.pdf

341-mumnp-2005-form-2.doc

341-mumnp-2005-form-2.pdf

341-mumnp-2005-form-3.pdf

341-mumnp-2005-form-5.pdf

341-mumnp-2005-form-pct-ib-304.pdf

341-MUMNP-2005-PETITION UNDER RULE 137 3-7-2008.pdf

341-MUMNP-2005-PETITION UNDER RULE 138 3-7-2008.pdf

341-MUMNP-2005-POWER OF ATTORNEY 3-7-2008.pdf

341-MUMNP-2005-POWER OF AUTHORITY(13-1-2006).pdf

341-MUMNP-2005-SPECIFICATION(AMENDED)-(3-7-2008).pdf

341-MUMNP-2005-WO INTERNATIONAL PUBLICATION REPORT(28-4-2005).pdf


Patent Number 234466
Indian Patent Application Number 341/MUMNP/2005
PG Journal Number 28/2009
Publication Date 10-Jul-2009
Grant Date 29-May-2009
Date of Filing 28-Apr-2005
Name of Patentee SCHERING AKTIENGESELLSCHAFT
Applicant Address D-13324 Berlin
Inventors:
# Inventor's Name Inventor's Address
1 MANFRED LEHMANN Lutherstrasse 13, D-12305 Berlin
2 KONRAD KROLIKIEWICZ Ehrenpreisweg 33, D-12357 Berlin
3 WERNER SKUBALLA Mattersbue=rger Weg 12, D-13465 Berlin
4 PETER STREHLKE Bilssestrasse 56, D-10713 Berlin
5 FRANK KALBRENNER Blissestrasse 56, D-10713 Berlin
6 ROLAND EKERDT Vierrutenberg 47, D-13469 Berlin
7 CLAUDIA GIESEN Hakenfelder Strasse 8C, D-13587Berlin
PCT International Classification Number C07D307/88
PCT International Application Number PCT/EP99/09754
PCT International Filing date 1999-11-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 198 56 475.9 1998-11-27 Germany