Patent EA-003299-B1 (EA)
Title: Non-steroidal inflammation inhibitors
Inventor: LEHMANN MAHFRED
IPC: C07D265/02
Filed: 1999-11-29
Abstract: 1. Use of at least one compound of general formula I for the production of pharmaceutical agents that have an antiinflammatory action in which R<1> and R<2> are the same or different and stand for a hydrogen atom, a C1-C5 alkyl group, or, together with the C-atom of the chain, stand for a ring with a total of 3-7 links, R<3> stands for a C1-C5 alkyl group or a partially or completely fluorinated C1-C5 alkyl group, A stands for the group (the dashed line means the interface site), in which R<4> means a hydrogen atom, a C1-C5 alkyl group, a C1-C10 acyl group, a C3-C10 carbalkoxyalkyl group, a C2-C5 cyanoalkyl group, a C3-C10 unsubstituted or substituted allyl group, a C3-C10 unsubstituted or substituted propargyl group, a C2-C5 alkoxyalkyl group, a C1-C5 alkyl group that is partially or completely substituted by fluorine atoms, R<5> to R<8> are the same or different from one another and are selected from hydrogen or halogen atoms and C1-C5 alkoxy groups, and R4 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 CH2 group, and Ar stands for a cyclic system, selected from the group of formulas 2-5, in which radicals X<3a>, X<3b>, X<4>, X<6>, X<7> (in partial formulas 2 and 3) and Y<4>, Y<5>, Y<7>, and Y<8> (in partial formulas 4 and 5) are the same or different and are selected from the group of hydrogen atoms, C1-C5 alkyl groups, partially or completely fluorinated C1-C5 alkyl groups, and, moreover, radicals X<4>, X<6>, X<7> (in partial formulas 2 and 3) or Y<5>, Y<7>, Y<8> (in partial formulas 4 and 5) are selected from the group containing halogen atoms, hydroxy groups, C1-C5 alkoxy groups or C1-C5 alkanoyloxy groups, and if B stands for a CH<2> 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 1 for the production of pharmaceutical agents for treatment of at least one of the following 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, (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) Transplant diseases, (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 presented in different stereoisomers. 4. Use of the compounds of general formula I according to claim 1 or 2 in the form of separately presented stereoisomers, if the compound can be present in different stereoisomers. 5. Use according to claim 1, 2, 3 or 4, characterized in that the C1-C5 alkyl group(s) in the compound of general formula I is (are) selected from the group of. methyl, ethyl, n-propyl, 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 Y<5>, Y<7>, Y<8> is selected from the group containing fluorine, chlorine or bromine. 7. Use according to claim 1, 2, 3 or 4, wherein R<1> and R<2> together with the C-atom of the chain form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. 8. Use according to claim 1, 2, 3 or 4, wherein 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 C1-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 C1-C5 alkyl group. 10. Use according to claim 1, 2, 3 or 4, wherein a carboxymethyl, tert-butoxymethyl or ethoxymethyl group stands for a C3-C10 carbalkoxyalkyl group. 11. Use according to claim 1, 2, 3 or 4, wherein a cyanomethyl group, 1- or 2-cyanoethyl group stands for a C2-C5 cyanoalkyl group. 12. Use according to claim 1, 2, 3 or 4, wherein an unsubstituted allyl group, a 1-methylallyl, 1,1-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylallyl, 3,3-dimethylallyl, cinnamyl and 3-cyclohexylallyl group stands for a C3-C10 allyl group. 13. Use according to claim 1, 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 C3-C10 propargyl group. 14. Use according to claim 1, 2, 3 or 4, wherein a methoxymethyl group, ethoxymethyl group or 2-methoxyethyl 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-, iso- or tert-butoxy- or n-pentoxy-, 2,2-dimethylpropoxy- or 3-methylbutoxy group stands for a C1-C5 alkoxy group. 16. Use according to claim 1, 2, 3 or 4, wherein a perfluorinated methoxy-, ethoxy-, n-propoxy-, iso-propoxy-, n-, iso-, tert-butoxy-, n-pentoxy-, 2,2-dimethylpropoxy- or 3-methylbutoxy group stands for a C1-C5 perfluoroalkoxy group. 17. Use according to claim 1, 2, 3, or 4, wherein a formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or isovaleryl or pivaloyl group stands for a C1-C5 alkanoyl group. 18. Use according to claim 1, 2, 3, or 4, wherein a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl groups stands for a C1-C10 acyl group. 19. Use according to claim 1, 2, 3 or 4, wherein a formyloxy-, acetoxy-, propionyloxy-, butyryloxy-, isobutyryloxy-, valeryloxy- or isovaleryloxy- group stands for a C1-C5 alkanoyloxy group for X<4>, X<6>, X<7>, Y<4>, Y<5>, Y<7> or Y<8>. 20. Use according to claim 1, 2, 3 or 4, wherein if the compounds of general formula I (B = -CH2-) are presented as salts, they are presented in the form of hydrochloride, sulfate, nitrate, maleate, fumarate, tartrate or benzoate. 21. Use according to claim 1 or 2, wherein a compound of general formula I is used, in which R<1> and R<2> 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 R<3> stands for a C1-C5 perfluoroalkyl group, and/or A stands for the group (the dashed line means the interface site), in which R<4> means a hydrogen atom, a methyl, ethyl, propyl or 2-propyl group, an acetyl group, a methoxy-, ethoxy- or tert-butoxycarbonyl group, a cyanomethyl or 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, R<5> to R<8> in one or two positions mean fluorine or chlorine atoms and in the remaining positions mean hydrogen atoms, or R<4> and R<5> together with incorporation of 2 and 3 phenyl-ring atoms mean a furan, a dihydrofuran or a 2, 3-dihydro-1, 4-dioxine ring, and R<6>, R<7> and R<8> mean hydrogen atoms, X<3a> stands for a hydrogen atom or a methyl group, or X<3a> and X<3b> are the same or different and stand for a hydrogen atom or a methyl group, X<4>, X<6> and X<7> 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 Y<4> stands for a methyl, ethyl, propyl, 2-propyl or trifluoromethyl group and/or Y<5>, Y<7> and Y<8> are the same or different and, independently of one another, stand for a hydrogen atom or a 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 that is selected from 5-{2-hydroxy-3-[1-(2-methoxyphenyl)-cyclopropyl]-2-trifluoromethylpropionylamino}phthalide; 5-{3-[1-(5-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethylpropionylamino}phthalide; 5-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethylvaleroylamino]phthalide; 5-{3-[1-(5-fluoro-2-hydroxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethylpropionylamino}phthalide; 5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide; 5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]phthalide; 4-bromo-5-[4-(5-fluoro-2-hydroxyphenyyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]phthalide; 4-bromo-5-[4-(3-bromo-5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]phthalide; 6-{3-[1-(5-fluoro-2-hydroxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one; 6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one; 6-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one; 6-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-4-ethyl-2,3-benzoxazin-1-one; 6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]-4-methyl-2,3-benzoxazin-1-one; 6-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]-4-methyl-2,3-benzoxazin-1-one; 6-[4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one; 6-[4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]-4-methyl-2,3-benzoxazin-1-one, and in addition, all compounds from Tables 3-6 as well as in Examples 85 and 86. 24. Compounds of general formula I