RU2007147940A - Polycyclic oxadiazoles or isoxazoles and their use as ligands of the S1P receptor - Google Patents

Abstract

1. The compound of formula I! ! where or X is —N = and Y is —O—; or X is —O— and Y is! -N =; or X is CH and Y is O; ! R1 is substituted biphenylyl, 4-phenoxyphenyl or 4- (phenyl C1-4 alkoxy) phenyl, wherein at least one of the phenyl groups is monosubstituted; phenyl substituted with one or more substituents selected from the group consisting of halogen, nitrile, C1-8 alkyl, haloC1-8 alkyl, C1-8 alkoxy,! halo C1-8 alkoxy group, C1-8 alkoxy-C1-8 alkoxy group, C1-8 alkyl-C1-8 alkoxy group,! C1-8 alkyl-halo C1-8 alkoxy group, halo C1-8 alkyl-C1-8 alkoxy group, halo C1-8 alkyl halo C1-8 alkoxy group, halo C1-8 alkoxy-C1-8 alkoxy group, C1-8 alkoxy halo C1-8 alkoxy group, haloC1-8 alkoxy group, haloC1-8 alkoxy group 8alkoxy-C1-8alkyl, haloC1-8alkoxy-C1-8alkyl, C1-8alkoxy-haloC1-8alkyl, haloC1-8alkoxy-haloC1-8alkyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl! C3-6cycloalkyl-C1-4alkyl, C3-6cycloalkyl-C1-8 alkoxy, C3-6cycloalkyloxy, phenyl-C1-4alkoxy and heterocyclyl-C1-4alkoxy; or substituted 5- or 6-membered heteroaryl; ! R2 is C1-6alkyl optionally substituted with halogen, OH, NH2, C1-4alkoxy or C1-4alkylcarbonyloxy; an amino group; carboxyl group; sulfamoyl; carbamoyl; or HN-CO-C1-4 alkyl; or ! R2 is R3-R4-COOH or R3-R4-CONR5R6,! where R3 is SO2-NH; SO2-N (C1-4alkyl); CO-NH; CO-H (C1-4alkyl); ! CH2-O; NH-CO; or N (C1-4 alkyl) CO; and R4 is C1-6 alkylene, optionally interrupted by O, S or C = CH2, or optionally substituted phenylene or! C3-6cycloalkylene; and each of R5 and R6, independently, is hydrogen or C1-6 alkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic radical

Claims (9)

1. The compound of formula I

, where or X is —N = and Y is —O—; or X is —O— and Y is -N =; or X is CH and Y is O; R ₁ is substituted biphenylyl, 4-phenoxyphenyl or 4- (phenylC _1-4 alkoxy) phenyl, wherein at least one of the phenyl groups is monosubstituted; phenyl substituted with one or more substituents selected from the group consisting of halogen, nitrile, C _1-8 alkyl, haloC _1-8 alkyl, C _1-8 alkoxy group, haloC _1-8 alkoxy group, C _1-8 alkoxy-C _1-8 alkoxy group, C _1-8 alkyl-C _1-8 alkoxy group, C _1-8 alkyl-haloC _1-8 alkoxy group, haloC _1-8 alkyl-C _1-8 alkoxy group, haloC _1-8 alkyl-haloC _1-8 alkoxy group, haloC _1-8 alkoxy-C _1-8 alkoxy group, C _{1 -8} alkoxy-haloC _1-8 alkoxy group, haloC _1-8 alkoxy-haloC _1-8 alkoxy group, C _1-8 alkoxy-C _1-8 alkyl, haloC _1-8 alkoxy-C _1-8 alkyl, C _1-8 alkoxy-haloC _1-8 alkyl, haloC _1-8 alkoxy-haloC _1-8 alkyl, C _2-6 alkenyloxy group, C _2-6 alkynyloxy group, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, C _3-6 cycloalkyl-C _1-8 alkoxy, C _3-6 cycloalkyloxy, phenyl-C _1-4 alkoxy and heterocyclyl C _1-4 alkoxy; or substituted 5- or 6-membered heteroaryl; R ₂ is C _1-6 alkyl optionally substituted with halogen, OH, NH ₂ , C _1-4 alkoxy, or C _1-4 alkylcarbonyloxy; an amino group; carboxyl group; sulfamoyl; carbamoyl; or HN-CO-C _1-4 alkyl; or R ₂ is R ₃ —R ₄ —COOH or R ₃ —R ₄ —CONR ₅ R ₆ , where R ₃ is SO ₂ —NH; SO ₂ -N (C _1-4 alkyl); CO-NH; CO-H (C _1-4 alkyl); CH ₂ -O; NH-CO; or N (C _1-4 alkyl) CO; and R ₄ is C _1-6 alkylene, optionally interrupted O, S or C = CH ₂ , or optionally substituted phenylene or C _3-6 cycloalkylene; and each of R ₅ and R ₆ , independently, is hydrogen or C _1-6 alkyl, or R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocyclic residue, and ring A may be optionally substituted, with the proviso that when Y is O, X is —N═ or —CH═, and R ₂ is SO ₂ NH — R ₄ —COOH, where R ₄ is branched C _1-6 alkylene, then i. R ₁ is other than phenyl or monosubstituted with halogen, C _1-8 alkyl, With _1-8 alkoxy, haloC _1-8 alkyl or haloC _1-8 alkoxy, or disubstituted with one or two substituents selected from halogen, C _1-8 alkyl and C _1-8 alkoxy; or ii. R ₁ is other than monosubstituted thienyl or furyl; or its physiologically hydrolyzable derivative, its salt, hydrate and / or solvate. 2. The compound according to claim 1, where R ₁ denotes substituted biphenylyl, 4-phenoxyphenyl or 4- (phenylC _1-4 alkoxy) phenyl, where at least one of the phenyl groups is monosubstituted. 3. The compound according to claim 1 or 2, wherein R ₂ is C _1-6 alkyl optionally substituted with halogen, OH, NH ₂ , C _1-4 alkoxy, or C _1-4 alkylcarbonyloxy; an amino group; carboxyl group; sulfamoyl; carbamoyl; or NM-CO-C _1-4 alkyl. 4. The method of obtaining the compounds of formula I according to claim 1, which consists in the fact that a) to obtain a compound of formula I, where X is —N═ and Y is O and R ₂ is as defined above, a compound of formula II

, where ring A and R _{2 are} indicated according to claim 1, react with a compound of formula III

, where R _{1 is} designated by definition above, or its functional derivative; or b) to obtain a compound of formula I, where X is —N═ and Y is O and R ₂ is R ₃ —R ₄ —COOH or R ₃ —R ₄ —CONR ₅ R ₆ , where R ₃ is NH — CO or N (C _1-4 alkyl) CO and R ₄ , R ₅ and R _{6 are} designated according to claim 1, the compound of formula IV

, where R ₁ and ring A are designated according to claim 1 and R ' ₂ is NH ₂ or NH (C _1-4 alkyl), is reacted with an acylating agent or a subsequent Sandmeyer reaction; or c) to obtain a compound of formula I, where Y is —N═ and X is O, cyclization is carried out in the presence of, for example, a Burgess reagent, a compound of formula V

where R ₁ , R ₂ and ring A are designated according to claim 1; or g) to obtain a compound of formula I, where Y is O and X is CH, a compound of formula VI

, where R ₁ designated according to claim 1, is introduced into the reaction with the compound of formula VII

, where R ₂ designated according to claim 1; or d) the compound of formula I is converted to another compound of formula I, and the resulting compound of formula I is again converted to its free form or to its salt form, and, if necessary, the compound of formula I obtained in free form is converted to the desired salt form or vice versa. 5. The compound of formula I according to one of claims 1 to 3 or its pharmaceutically acceptable salt for use as a medicine. 6. A pharmaceutical composition comprising a compound of formula I according to one of claims 1 to 3, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier. 7. The compound of formula I according to one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition used for the prophylaxis or treatment of diseases or diseases mediated by lymphocytes. 8. A pharmaceutical combination comprising a) a first agent, which is a compound of formula I according to one of claims 1 to 3, in free form or in the form of a pharmaceutically acceptable salt, and b) at least one co-agent, which is an immunosuppressant, immunomodulator, anti-inflammatory, chemotherapeutic or anti-infective agent. 9. A method for the prevention or treatment of disorders or diseases mediated by lymphocytes, which consists in administering to a patient in need of such treatment an effective amount of a compound of formula I according to one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.