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Definitions

• the present invention relates to the use of non-steroidal compounds for the production of medicaments for the treatment of inflammation, selected compounds and their production processes.
• non-steroidal compounds In addition to a large number of steroid compounds that bind well to the glucocorticoid receptor and have an anti-inflammatory effect (glucocorticoids), non-steroidal compounds are known that bind to the glucocorticoid receptor, but for which no anti-inflammatory effect has so far been shown [cf. Nature Medicin 4 (1998) 92, Mol. Pharmacol. 52 (1997) 571]. Furthermore, non-steroidal compounds have been described which are derived from steroidal compounds, have affinity for the glucocorticoid receptor and are likely to have an anti-inflammatory effect mediated by receptors [J. Med. Chem. 36, (1993), 3278-3285]. However, these compounds showed no advantages over steroidal glucocorticoids in animal experiments, i.e. the anti-inflammatory effects of metabolic effects, e.g. Suppression of adrenal function to separate.
• non-steroidal compounds which have a high gestagenic activity.
• the document states that some of the compounds claimed also have activity on the glucocorticoid and / or mineral corticoid receptor.
• no connections are specifically mentioned in this context, nor are test results disclosed.
• Compounds which have selectivity with regard to the effects mentioned are advantageous in terms of industrial applicability.
• phenol derivatives which have an active dissociation between the anti-inflammatory activity and the undesirable metabolic side effects are known as non-steroidal anti-inflammatory agents.
• the object was therefore to provide new non-steroidal anti-inflammatories which show at least as good or better dissociation of action than the compounds of the prior art.
• Nonsteroidal compounds have now been found which bind well to the glucocorticoid receptor and, through this binding, bring about an anti-inflammatory effect. In the experiment, these compounds show significantly better or at least equally good dissociations of effects between anti-inflammatory and undesirable effects and are superior to the previously described, non-steroidal glucocorticoids or at least have an equally good effect.
• R and R are the same or different and represent a hydrogen atom, a C 5 -C 5 alkyl group or, together with the C atom of the chain, a ring with a total of 3-7 links, R represents a straight-chain or branched C 1 -C 5 -alkyl group or a straight-chain or branched, partially or completely fluorinated O, -C 5 alkyl group,
• R 4 to R 8 are identical or different from one another and are a hydrogen atom, a halogen atom, a cyano group, a nitro group, a COOR 9 group, where R 9 is a hydrogen atom, a straight-chain or branched
• Ci-C ⁇ alkyl group or a benzyl group a CONR 10 group, where R 10 represents a hydrogen atom or a straight-chain or branched C 1 -C 5 alkyl group, an NHR 11 group where R 11 represents a hydrogen atom, a straight-chain or branched Ci-Cs-alkyl group, a straight-chain or branched partially or fully fluorinated C ⁇ -C 5 alkyl group, a C1-C5-acyl group, a -S ( 2 - (C ⁇ -C 5 ) alkyl group or an optionally by halogen or a C ⁇ -C 5 alkyl group substituted -SO 2 phenyl group, a straight-chain or branched Ci-C ⁇ -alkyl group, a straight-chain or branched C 2 -C 5 alkenyl group, a straight-chain or branched C2-C5-alkynyl group, a straight-chain or branched , partially or
• Mean acyl group, an aryl radical or a heteroaryl radical, R 4 and R 5 together with the two carbon atoms of ring A represent a saturated or unsaturated carbocyclic ring with a total of 5-7 members, Ar represents a ring system selected from the group of general sub-formulas 1 or 2,
• radicals X 3a , X 3b , X 4 , X 6 , X ? (in sub-formula 1) and Y 4 , Y 5 , Y 7 , Y 8 (in sub-formula 2) are the same or different and represent a hydrogen atom, a straight-chain or branched C, -C 5 -alkyl group, or a straight-chain or branched, partially or fully fluorinated C, -C 5 alkyl group, the radicals X, X.
• X (in sub-formula 1) or Y, Y, Y (in sub-formula 2) are also the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a C.-, C- 5 alkoxy group or a CC 5 alkanoyloxy group mean, and their racemates or stereoisomers present separately, and optionally their physiologically tolerable salts.
• the compounds of general formula I according to the invention can exist as different stereoisomers due to the presence of asymmetry centers. Both the racemates and the separately present stereoisomers belong to the subject of the present invention.
• a particular subject of the present invention are the isomers which rotate the plane of polarized light in such a way that they are referred to as (+) compounds.
• the substituents defined as groups or radicals in the compounds of the general formula I can each have the following meanings.
• the d-Cs-alkyl groups R 1 , R 2 , R 3 , R 4 , R 5 , R 12 , X n , Y ° can be straight-chain or branched and for a methyl, ethyl, n-propyl, iso- Propyl, n-butyl, isobutyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group.
• a methyl or ethyl group is preferred.
• R 1 and R 2 together with the carbon atom of the chain form a 3-7 membered ring, this can optionally be substituted by 1-2 oxygen atoms and for example a cyclopropyl, butyl, pentyl hexyl or heptyl ring , his.
• the partially or fully fluorinated alkyl groups mentioned above are suitable.
• the trifluoromethyl group and the pentafluoroethyl group are preferred.
• the substituents of the phenyl ring A can independently of one another have the meanings defined in the claims, such as a hydrogen atom, a halogen atom, a cyano group, a nitro group, an NHR 1 group where R 11 is a hydrogen atom, a straight-chain or branched dC ⁇ alkyl group, a straight-chain one or branched partially or fully fluorinated d-Cs-alkyl group, a Ci-C ⁇ -acyl group, a
• R 4 and R 5 together with the two carbon atoms of ring A can mean a saturated or unsaturated carbocyclic ring with a total of 5-7 members, such as, for example, indane, naphthalene, tetrahydronaphthalene, benzocycloheptane.
• An object of the invention is the use of the compounds of the general formula I in which R 4 to R 8 are identical or different from one another and are a hydrogen atom, a halogen atom, a cyano group, a nitro group, a COOR 9 group where R 9 is a hydrogen atom, a straight-chain or branched C 1 -C 5 -alkyl group or a benzyl group, a CONR 10 group, where R 10 represents a hydrogen atom or a straight-chain or branched C 1 -C 5 -alkyl group, an NHR 11 group, where R 11 represents a Hydrogen atom, a straight-chain or branched C 1 -C 5 -alkyl group, a straight-chain or branched partially or completely fluorinated C 1 -C 5 -alkyl group, a Ci-Cs-acyl group, a -SO 2 - (-C-Cs) alkyl group or an optionally by halogen or a Ci
• halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom.
• a fluorine, chlorine or bromine atom is preferred.
• a C ⁇ -Cs alkenyl group there are, for example, a vinyl, 2-substituted vinyl group, 1-propenyl, 2-propenyl, 2- or 3-substituted 2- Propenyl group, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-methyl-1-butenyl, 2 -Methyl-1-butenyl, 3-methyl-1-butenyl group into consideration.
• the alkenyl groups which carry the double bond in the 1- or 2-position are preferred.
• the methyl or the ethyl group are particularly suitable as substituents for the vinyl group or the propenyl group.
• a C2-C 5 alkynyl group is, for example, an ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-methyl-1-butynyl, 4-methyl-1-butynyl or 1-pentynyl group understood.
• the alkynyl groups which have a triple bond in the 1- or 2-position are preferred.
• Ci-Cs-acyl group means, for example, a formyl, acetyl, propionyl, n-butyroyl, 2-methylpropionyl, n-valeroyl, 2-methylbutyroyl, 3-methylbutyroyl or a pivaloyl group.
• a sulfonyl (C -Cs) alkyl group R 11 means , for example, a methylsulfonyl or an ethylsulfonyl group.
• sulfonylphenyl group R 11 which is optionally substituted by halogen or a Ci-Cs-alkyl group
• the free valence of the sulfonyl group is attached to the nitrogen atom of the NHR 11 group.
• Aryl means a phenyl group or a substituted phenyl group
• Halogen atoms which are cyano, nitro,
• Ci-Cs alkoxy amino, hydroxyl, carboxy and Ci-Cs alkanoyl groups, branched and unbranched C 5 -C 5 alkyl groups, branched and unbranched Ci-Cs alkyl groups, which can be partially or completely fluorinated, in Question.
• Heteroaryl comprises aromatic heterocyclic 5- and 6-rings, the ring 1-3 further heteroatoms from the group oxygen, nitrogen, or sulfur can contain. Heterocyclic five-membered rings are preferred. Furyl, thienyl, pyridyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl may be mentioned in particular.
• the heteroaryl groups can optionally be substituted by branched and unbranched Ci-Cs-alkyl groups, branched and unbranched Ci-Cs-alkyl groups which can be fluorinated and / or halogen atoms.
• hydroxyl groups possible for the radicals X ⁇ , Y ° can optionally be present as ethers or esters, which are defined below:
• alkyl groups in particular a methyl or ethyl group, are suitable as the Ci-Cs-alkyl group for etherifying hydroxy groups.
• a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or iso-valeryl or pivaloyl group, preferably an acetyl group, are suitable as the CrC 5 alkanoyl group for the esterification of hydroxyl groups.
• alkanoyl groups preferably again an acetyl group, or a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl group may be mentioned, for example, as the Ci-Cs-acyl group for the esterification of hydroxy groups.
• the d-Cs-alkanoyloxy group for X 4 , X 6 > X 7 , Y 4 , Y 5 , Y 7 or Y 8 is a formyloxy, acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy or iso -Valeryloxy distr into consideration, preferably an acetoxy group.
• Non-steroidal compounds as such with a mixed profile of gestagenic and androgenic activity in different forms are already the subject of WO 98/54159.
• the compounds of the general formula I according to claim 1 to be used according to the present patent application for the preparation of medicaments with anti-inflammatory activity fall within the scope of the general formula contained in WO 98/54159, but are not preferred there as a group or disclosed directly as compounds. They are thus new and, because of the anti-inflammatory effect found for them, dissociated from undesirable metabolic or other effects, also meet the patenting requirement of the inventive step.
• Undesired effects / effects in the sense of the present invention are metabolic effects or bonds to other steroid receptors.
• the present invention relates to the following compounds.
• (+) 6- [4- (Indan-4'-yl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] -4-methyl-2,3-benzoxazin-1-one 6- [4- (5th -Fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] -4-methyl-2,3-benzoxazin-1 -one
• (+) - 6- [4- (2,5-Difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] -4-methyl-2,3-benzoxazin-1 -one 6- [4- (2nd , 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] -4-methyl-2,3-benzoxazin-1 -one
• (+) - 6- [4- (4-Fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroyl] amino-4-methyl-2,3-benzoxazin-1- on 6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroyl] amino-4-methyl-2,3-benzoxazin-1-one
• (+) - 6- [3- ⁇ 1- (2-Chloro-4-fluorophenyl) cyclobutyl ⁇ -2-hydroxy-2-trifluoromethylpropionyl] amino-4-methyl-2,3-benzoxazin-1- on 6- [3- ⁇ 1- (2-chloro-5-fluorophenyl) cyclopropyl ⁇ -2-hydroxy-2-trifluoromethylpropionyl] - amino-4-methyl-2,3-benzoxazin-1-one
• (+) - 6- [3- ⁇ 1- (2-Chloro-5-fluorophenyl) cyclobutyl ⁇ -2-hydroxy-2-trifluoromethylpropionyl] amino-4-methyl-2,3-benzoxazin-1- on 6- [3- ⁇ 1- (2,4-dichlorophenyl) cyclopropyl ⁇ -2-hydroxy-2-trifluoromethylpropionyl] - amino-4-methyl-2,3-benzoxazin-1-one
• (+) - 6- [3- ⁇ 1- (2,4-dichlorophenyl) cyclopropyl ⁇ -2-hydroxy-2-trifluoromethylpropionyl] - amino-4-methyl-2,3-benzoxazin-1 -one
• (+) - 6- [3- ⁇ 1- (2,5-difluorophenyl) cyclopropyl ⁇ -2-hydroxy-2-trifluoromethylpropionylamino] -4-methyl-2,3-benzoxazin-1-one 6- [ 3- ⁇ 1 - (2,3,5-Thfluorophenyl) cyclopropyl ⁇ -2-hydroxy-2-trifluoromethylpropionylamino] -4-methyl-2,3-benzoxazin-1-one
• (+) - 6- [3- ⁇ 1- (2,3,5-Trifluorophenyl) cyclobutyl ⁇ -2-hydroxy-2-trifluoromethylpropionylamino] -4-methyl-2,3-benzoxazin-1-one 6 - [3- ⁇ 1- (2-bromophenyl) -cyclopropyl ⁇ -2-hydroxy-2-trifluormethylpropionylamino] -
• (+) - 6- [4- (2-Bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] -4-methyl-2,3-benzoxazin-1-one 6- [4- (2,3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylcaproylamino] -4-methyl-2,3-benzoxazin-1-one
• a special aspect of the present invention are the 2,3-benzoxazin-1-ones listed above.
• Another aspect of the present invention are the compounds listed above, whose 2,3-benzoxazin-1-one bears a methyl group in the 3-position.
• the compounds of the general formula I are present as salts, this can be, for example, in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
• the compounds according to the invention can be separated into the pure, optically active forms by methods of racemate separation familiar to the person skilled in the art.
• the racemic mixtures can be chromatographed Separate into the pure isomers on a self-optically active carrier material (CHIRALPAK AD®).
• CHIRALPAK AD® self-optically active carrier material
• esterify the free hydroxyl group in a racemic compound of the general formula I with an optically active acid and to separate the resulting diastereoisomeric esters by fractional crystallization or chromatographically and to saponify the separated esters to give the optically pure isomers.
• mandelic acid, camphorsulfonic acid or tartaric acid can be used as the optically active acid.
• compounds which have been prepared by one of the processes below and in which A is a substituted aromatic ring can be selectively substituted on this aromatic radical by known processes. Examples of this process are the catalytic hydrogenation of multiple bonds, nitration and halogenation. Halogen and nitro substitutions also offer the possibility of further modifications.
• aryl bromides can be reacted with boron, tin or zinc reagents with palladium catalysis in the manner known to those skilled in the art.
• Nitro compounds can be reduced to aniline derivatives, for example hydrogenolytically, or with metals such as. eg iron or zinc. After diazotization, the aniline derivatives can be reacted in a known manner, for example in the sense of Sandmeyer reactions.
• R 1 and R 2 have the meanings given in formula I is either optionally esterified with a compound of the general formula (R 12 ) 3 SiR 3 (III)
• R 3 has the meaning given in the general formula I and R 12 represents a Ci-Cs-alkyl group, in the presence of a catalyst or with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, to give a compound of the formula IV
• R 13 represents a hydrogen atom or a C1-C5 acyl group and Ar has the meaning given in the general formula I, reacted, the radical R 13 then being split off to give a
• R 13 represents a hydrogen atom or a C 5 -C 5 acyl group and Ar has the meaning given in the general formula I, optionally after activation of the acid function by, for example, conversion into the acid chloride, the radical R 13 then being split off in any order and with a compound of the general formula III
• R 13 represents a hydrogen atom or a CrC 5 acyl group and Ar has the meaning given in the general formula I, reacted, the radical R 13 then being split off in order to arrive at a compound of the formula I.
• the compound of the general formula VI can optionally also be formed only as an intermediate product which, if desired, can be isolated or can also be produced only in situ. for example, it can be an acid chloride formed intermediately from a corresponding carboxylic acid. For example, a fluorine, chlorine or bromine atom or, if no intermediate acid chloride is formed, the mesylate residue or tosylate residue may be mentioned as escape groups.
• glucocorticoid receptor The binding of the substances to the glucocorticoid receptor (GR) is checked with the aid of a recombinantly produced receptor. Cytosol preparations from Sf9 cells which had been infected with recombinant baculoviruses which code for the GR are used for the binding studies. Compared to the reference substance [ 3 H] -dexamethasone, the substances show a high to very high affinity for GR.
• these compounds show affinities for MR in the mineral corticqid receptor (MR) binding test using cytosol preparations from Sf9 cells which were infected with baculoviruses coding for the MR and with [ 3 H] aldosterone as reference substance.
• MR mineral corticqid receptor
• GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is regarded as an essential molecular mechanism for the anti-inflammatory effect of glucocorticoids. This inhibition is caused by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa- B, (for an overview see Cato, AGB and Wade E, BioEssays 18, 371-378 1996).
• the compounds of the general formula I according to the invention inhibit the secretion of the cytokine IL-8 triggered by lipopolysacchard (LPS) in the human monocyte cell line THP-1.
• LPS lipopolysacchard
• the concentration of the cytokines in the supernatant was determined using commercially available ELISA kits.
• the anti-inflammatory activity of the compounds of the general formula I were tested in animal experiments by testing in croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108).
• croton oil was applied topically to the ears in ethanolic solution.
• the test substances were also applied topically or systemically at the same time or two hours before the croton oil.
• the ear weight as a measure of the inflammatory edema
• the peroxidase activity as a measure of the immigration of granulocytes
• the Elastase activity measured as a measure of the immigration of neutrophil granulocytes.
• the compounds of the general formula I inhibit the three above-mentioned inflammation parameters in this test both after topical and after systemic application.
• glucocorticoid therapy One of the most common undesirable effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Immunological basics, pharmacology and therapy guidelines, Horschafliche Verlagsgesellschaft mbH, Stuttgart, 1998].
• the reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible for this and by free amino acids that result from the breakdown of proteins (catabolic effect of the glucocorticoids).
• a key enzyme of the catabolic metabolism in the liver is tyrosine aminotranferase (TAT).
• TAT tyrosine aminotranferase
• the activity of this enzyme can be determined photometrically from liver homogenates and is a good measure of the undesirable metabolic effects of the glucocorticoids.
• the animals are sacrificed 8 hours after the administration of the test substances, the liver is removed and the TAT activity in the Homogenate measured.
• the compounds of the general formula I do not induce the tyrosine aminotransferase, or do so only to a small extent, in which they are anti-inflammatory.
• the new compounds of general formula I have the following properties compared to the steroidal glucocorticoids used hitherto:
• Non-steroidal structure ie the substances are still effective in patients who, due to an allergic reaction to the steroid basic structures of conventional glucocorticoids, are no longer accessible to them with therapy (cf.Lutz, ME, el-Azhary RA, Mayo Clin. Proc. 72 , 1141-1144, 1997), similarly good anti-inflammatory activity with low metabolic activity
• the compounds of general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans:
• the term “DISEASE” stands for the following indications:
• Lung diseases that are associated with inflammatory, allergic and / or proliferative processes - Chronic obstructive lung diseases of any genesis, especially
• Kidney diseases associated with inflammatory, allergic and / or proliferative processes are associated with inflammatory, allergic and / or proliferative processes:
• liver diseases associated with inflammatory, allergic and / or proliferative processes are included in the liver diseases associated with inflammatory, allergic and / or proliferative processes.
• acute hepatitis of various origins e.g. viral, toxic, drug-induced - chronically aggressive and / or chronically intermittent hepatitis
• Gastroenteritis of a different origin e.g. indigenous sprue (ix) proctological diseases associated with inflammatory, allergic and / or proliferative processes:
• Severe shock conditions e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
• SIRS systemic inflammatory response syndrome
• adrenal insufficiency e.g. Addison's disease, autoimmune adrenalitis, post-infectious, tumors, metastases etc.
• congenital secondary adrenal insufficiency e.g. congenital
• the suitable dose for the therapeutic effects in the abovementioned disease states is different and depends, for example, on the potency of the compound of the general formula I, the host, the mode of administration and the type and severity of the conditions to be treated, and the use as a prophylactic or therapeutic agent.
• the invention further provides
• Compounds or their mixture and at least one pharmaceutical auxiliary and / or carrier comprises.
• the daily doses comprise a range from 1 ⁇ g to 100,000 ⁇ g of the compound according to the invention per kg of body weight.
• a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg body weight.
• a dose of 10 to 30,000 ⁇ g per kg body weight is preferred, more preferably a dose of 10 to 10,000 ⁇ g per kg body weight.
• this dose is conveniently administered several times a day.
• acute shock e.g. anaphylactic shock
• single doses can be given that are clearly above the doses mentioned above.
• the pharmaceutical preparations based on the new compounds are formulated in a manner known per se by processing the active substance with the carrier substances, fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc. customary in galenics and converted into the desired application form. It is made to Remington's Pharmaceutical Science, 15 tn ed. Mack Publishing Company, pointing East Pennsylvania (1980).
• Tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions are particularly suitable for oral administration.
• Appropriately prepared crystal suspensions can be used for intra-articular injection.
• Aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used for intramuscular injection.
• the new compounds in the form of suppositories, capsules, solutions (for example in the form of clysms) and ointments can be used both for systemic and for local therapy.
• the pulmonary application of the new compounds can be used in the form of aerosols and inhalants.
• the new compounds can be used as drops, ointments and tinctures in appropriate pharmaceutical preparations for local use on the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses.
• formulations in gels, ointments, fatty ointments, creams, pastes, powder, milk and tinctures are possible.
• the dosage of the compounds of the general formula I should be 0.01% to 20% in these preparations in order to achieve a sufficient pharmacological effect.
• the invention also encompasses the compounds of general formula I according to the invention as therapeutic active ingredients.
• the invention furthermore relates to the compounds of the general formula I according to the invention as a therapeutic active substance together with pharmaceutically acceptable and acceptable excipients and carriers.
• the invention also comprises a pharmaceutical composition which contains one of the pharmaceutically active compounds according to the invention or a mixture thereof and a pharmaceutically acceptable salt or pharmaceutically acceptable excipients and carriers.
• a solution of 8.04 ml of 2-diethylphosphono-2-ethoxyacetic acid ethyl ester in 40 ml of tetrahydrofuran is mixed with ice cooling within 16 minutes with 16.5 ml of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane toluene and 30 minutes at 0 ° C stirred.
• a solution of 5.2 g of 2- (5-fluor-2-methylphenyI) -2-methylpropionaldehyde in 30 ml of tetrahydrofuran is added dropwise at 0 ° C. within 30 minutes.
• 6- [4- (5-Fluoro-2-methylphenyl) -4-methyl-2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one was analogous to 5- [4- (5-fluoro 2-methylphenyl) -4-methyl-2-oxovaleroylamino] phthalide using 4- (5-fluoro-2-methylphenyl) -4- methyl-2-oxovaleric acid and 6-amino-2,3-benzoxazin-1-one obtained, mp. 186 ° C.
• 6- [4- (2-Chloro-5-fluorophenyl) -4-methyl-2-oxovaIeroylamino] -4-methyl-2,3-benzoxazin-1-one becomes analogous to 5- [4- (5-fluor -2-methylphenyl) -4-methyl-2-oxovaleroylaminojphthalide obtained from 4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxovaleric acid and 6-amino-2,3-benzoxazin-1-one, mp . 198-199 ° C.
• Example 2 was obtained analogously to Example 1 from 6- [4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxovaleroylamino] -2,3-benzoxazin-1-one, mp. 201-203 ° C.
• the enantiomer mixture from Example 3 is separated by chromatography on a chiral support material (CHIRALPAK AD®, DAICEL) with hexane / ethanol (19: 1, vv). The following is obtained from 190 mg of racemate:
• 2- (3-fluorophenyl) -2-methylpropionitrile Analogously to the process described for 2- (5-fluoro-2-methylphenyl) -2-methylpropionitrile, 2- (3-fluorophenyl) -2-methylpropionitrile is synthesized, b.p. 102-103 ° C70.029 hPa.
• ethyl 4- (3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerate are dissolved in 20 ml of trifluoroacetic acid and at 0 ° C with 0.84 ml of 100 percent. Nitric acid added. After 3 hours at 0 ° C. and 16 hours at room temperature, the mixture is poured onto ice, the crystals are filtered off with suction, washed with water and dried. By recrystallization from hexane, 2.5 g of ethyl 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerate, mp. 66-67 ° C., are obtained. After chromatography on silica gel with hexane, the mother liquor
• Ethyl acetate (8: 1) as the first fraction a further 500 mg of 4- (5-fluor-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleric acid ethyl ester and as the second fraction 800 mg of 4- (3-fluoro- 4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleric acid ethyl ester as an oil.
• Example 4 is obtained analogously to Example 4 from 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleric acid and 6-amino-2,3-benzoxazin-1-one, mp. 208-210 ° C.
• Example 4 is obtained analogously to Example 4 from 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleric acid and 5-aminophthalide, mp. 188-189 ° C.
• Example 4 is obtained analogously to Example 4 from 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleric acid and 6-amino-2,3-benzoxazin-1-one, mp. 236-237 ° C.
• Triethylamine added at 0 ° C. After 10 min at room temp. become 10.6 mL
• the combined extracts are dried (Na2SO 4 ) and i. Vak. concentrated.
• the residue is taken up in 8 mL DMF and treated with 0.42 mL (6.8 mmol) methyl iodide and 2.21 g (6.8 mmol) cesium carbonate. After 5 h at room temp. the mixture is diluted with 600 mL MTBE, with 10 percent. Sulfuric acid and sat. Washed NaCI, dried (Na 2 S0 4 ) and i. Vak. concentrated. Column chromatography on silica gel with hexane-ethyl acetate yields 0.9 g of product.
• the mixture is diluted with 150 mL MTBE, with a solution of 1.2 g NaHCOs and 4.0 g Na 2 S ⁇ 3 in 50 mL water, sat. NaHCO 3 and sat. Washed NaCI, dried (Na 2 SO 4 ) and i. Vak. concentrated.
• the residue 250 mg is taken up in 16 mL THF-EtOH (1: 1) and mixed with 3.9 mL (3.9 mmol) of a 1 M sodium hydroxide solution. After 30 minutes, the batch is i. Vak. concentrated, diluted with 20 mL water and washed with MTBE. The aqueous phase is with 10 percent.
• the enantiomer mixture from Example 9 is separated by chromatography on a chiral support material (CHIRALPAK AD®, DAICEL) with hexane / ethanol (95: 5, vv). The following is obtained from 830 mg of racemate:
• Ethyl 2-hydroxy-4-methyl-4- (4-trifluoromethylphenyl) valerate 1.72 g (6.0 mmol) ethyl 4-methyl-4- (4-trifluomethylphenyl) -2-pentenoate are dissolved in ethyl acetate in the presence of 0.17 g 10 proc. Palladium / activated carbon catalyst stirred for 15 h in a hydrogen atmosphere (1 atm). The mixture is filtered through Celite and i. Vak. concentrated: 1.72 g of 4-methyl-4- (4-trifluomethylphenyl) valeric acid ethyl ester. 0.57 g (2.0 mmol) of this is dissolved in 7 mL THF and at -78 ° C with 5.6 mL (2.8 mmol)
• Example 13 is a by-product of the synthesis of Example 12.
• 1 H-NMR (CDCIs), ⁇ (ppm) 1.41 (s, 3H), 1.44 (s, 3H), 2.44 (d, 1H), 2.60 (s, 3H), 2.80 (br. S, 1H ), 2.89 (d, 1 H), 6.53 (dd, 1 H), 6.92 (m, 2H), 7.66 (dd, 1 H), 8.24 (d, 1 H), 8.35 (d, 1 H), 8.70 (br.s, 1 H).
• 2- (5-fluoro-2-methylphenyl) -2-methylpropionaldehyde is obtained as a colorless oil, bp 80 ° C / 0.05 hPa.
• the enantiomer mixture from Example 14 is separated by chromatography on a chiral support material (CHIRALPAK AD®, DAICEL) with hexane / ethanol (19: 1, v). The following is obtained from 100 mg of racemate:
• 6- [4-Methyl-4- (3-methyl-2-nitrophenyl) -2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one is analogous to 5- [4- (5-fluoro- 2-methylphenyl) -4-methyl-2-oxovaleroylamino] phthalide obtained from 4-methyl-4- (3-methyl-2-nitrophenyl) -2-oxovaleric acid and 6-amino-2,3-benzoxazin-1-one, mp . 184-187 ° C.
• Example 18 was obtained analogously to Example 1 from 6- [4-methyl-4- (3-methyl-2-nitrophenyl) -2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1 -one, mp 201- 203 ° C.
• Example 18
• Example 22 is obtained analogously to Example 20 from 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] phthalide, mp. 125 ° C.
• Example 22 is obtained analogously to Example 20 from 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] phthalide, mp. 125 ° C.
• Example 22 is obtained analogously to Example 20 from 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] phthalide, mp. 125 ° C.
• Example 22 is obtained analogously to Example 20 from 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] phthalide, mp. 125 ° C.
• the enantiomer mixture from Example 23 is separated by chromatography on a chiral support material (CHIRALPAK AD®, DAICEL) with hexane / ethanol (93: 7, vv).
• Example 25 is analogous to Example 24 starting from the corresponding (-) - 6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] - 4-methyl-2, 3-benzoxazin-1-one produced.
• the enantiomer mixture from Example 28 is separated by chromatography on a chiral support material (CHIRALPAK AD®, DAICEL) with hexane / ethanol (9: 1, vv).
• a chiral support material CHIRALPAK AD®, DAICEL
• the following is obtained from 300 mg of racemate: (-) - 6- ⁇ 3- [4- (2-Chloro-5-fluorophenyl) tetrahydropyran-4-yl] -2-hydroxy-2-trifluoromethylpropionylamino ⁇ -4-methyl-2,3-benzoxazin-1 - on as the first fraction 129 mg, mp.
• the potency of the anti-inflammatory is determined by inhibiting the secretion of the cytokine IL-8 in a cell test.
• the compounds of the general formula I according to the invention inhibit the secretion of the cytokine IL-8 triggered by lipopolysacchard (LPS) in the human monocyte cell line THP-1.
• LPS lipopolysacchard
• the concentration of the cytokines in the supernatant was determined using commercially available ELISA kits.
• the compounds of formula 1 show a high to very high potency and effectiveness in inhibition (see Table 10).
• the anti-inflammatory activity of the compounds of the general formula I were tested in animal experiments in croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108).
• croton oil was applied topically to the ears in ethanolic solution.
• the test substances were applied systemically two hours before the croton oil. After 16-24 hours, the ear weight was measured as a measure of the inflammatory edema.
• the compounds of formula 1 show a comparable and sometimes stronger inhibition of the inflammation induced by croton oil to the standard (prednisolone) (see Table 11).
• TAT tyrosine aminotranferase
• the induction factor stands for the corresponding n-fold increase in tyrosine aminotranferase enzyme activity in treated animals compared to untreated animals.

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