Isoxazoline derivative and a process for the preparation thereof

An isoxazoline derivative of the formula (I)

• in which,
• R and R′ each independently represents hydrogen, simple alkyl chain (—SAC), simple cycloalkyl (—SCAC), aromatic (—Ar), or simple alkyl chain substituted with aromatic (—SAC—Ar);
• R1 represents —SAC, —SCAC, —Ar, or —SAC—Ar, or represents side chain of amino acids, or —(CH2)nCOOZ (in which n is 1 or 2, and Z is hydrogen, —SAC, —Ar, or —SCAC);
• R3 represents —SAC, —SCAC, —Ar, or —SAC—Ar, or represents side chain of amino acids;
• R2 represents —SAC, —SCAC, —Ar, or —SAC—Ar, or represents a non-hydrogen side chain of amino acids, or represents —(CH2)p(O)mR5 (in which R5=—SAC, —SCAC, —Ar, —SAC—Ar;
• p=0, 1 or 2;
• and m=0 or 1), or —(CH2)qOC(═O)R6 (in which R6=—SAC, —SCAC, —Ar, —SAC—Ar;
• and q=1 or 2);
• R4 represents
• a) amino acid residue in which {circle around (1)} the carboxyl group attached to the chiral carbon of amino acid is bound to the amine group to form an amide bond, {circle around (2)} the chiral carbon of amino acid has either R or S configuration, {circle around (3)} the amino group attached to the chiral carbon of amino acid is protected by formyl, acetyl, propyl, cyclopropylcarbonyl, butyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, or cyclopropylaminocarbonyl, or the amino group may be replaced with a hydrogen atom, and {circle around (4)} the carboxyl group in the side chain may form an ester group with —SAC or —SCAC,
• b) —C(′O)R7 (in which R7=—SAC, —SCAC, —Ar, —SAC—Ar), —CO2R8 (in which R8=hydrogen or R7), —C(═O)NR8R8, —SOR7, or —C(═O)CH═CH—Ar, or
• c) —(C═O)—L—CO2R8, in which L represents a divalent (=capable of double substitution) linker selected from a group consisting of C1-6 alkyl, C3-8 cycloalkyl, furan, thiophene, diazole (1,2 or 1,3), triazole (1,2,3 or 1,3,4), tetrazole, oxazole, isoxazole, thiazole, isothiazole, diazine, (1,2 or 1,3 or 1,4), triazine, —Ph(—R9)— (in which R9=H, F, Cl, Br, I, CHO, OH, OCH3, CF3, OCF3, CN, C(═O)Me), tetrahydrofuran, tetrahydrothiophene, 1,4-dioxane, —CH═C(R10)— (in which R10=H, methyl, ethyl), —CH═CHCH(R10)—, —CH2C(═O)CH2—, and —C(═O)CH2CH2—
• in cases where R1 and the adjacent R′, and/or R3 and the adjacent R are connected to each other to form a cyclic compound, R1—R′ or R3—R together represents —(CH2)n—, —(CH2)n—O—(CH2)m—, or —(CH2)n—NR13—(CH2)m— (in which n+m<9, R13=—SAC, —SCAC, —Ar, —SAC—Ar, —C(O)—SAC, —C(═O)—SCAC, ′C(═O)—Ar, or —C(═O)—SAC—Ar;
• X represents —CN, —CHO, —C(═O)R14 (in which R14=—SAC, —SCAC, —Ar, —SAC—Ar, —CHN2), —C(═O)OR15 (in which R15=—SAC, —SCAC, —Ar, or —SAC—Ar), —CONR16R17 (in which R16 and R17 each represents —H, —SAC, —O—SAC, —SCAC, —Ar, or —SAC—Ar), —C(═O)CH2O(C═O)Ar″ (in which A″=2,6-disubstituted phenyl with F, Cl, Br, I, or CH3), —C(═O)CH2OR18 (in which R18 represents —SAC, —SCAC, —Ar, or —SAC—Ar), or —C(═O)CH2OC(═O)R19 (in which R19=—SAC, —SCAC, —Ar, or —SAC—Ar), or
• X represents —COCH2—W, wherein W represents —N2, —F, —Cl, —Br, —I, —NR20R21 or —SR22 (in which R20, R21 and R22 each independently represents —SAC, —SCAC, —Ar, or —SAC—Ar or R20 and R21 are connected to form a cyclic compound) or W represents
• in which Y represents —OH, OR23 (in which R23=—SAC, or —SCAC), —C(═O)R24 (in which R24=—H, —SAC, or —SCAC), —F, —Cl, —Br, —I, —CN, —NC, —N3, —CO2H, —CF3, —CO2R25 (in which R25=—SAC, or —SCAC), —C(═O)NHR26 (in which R26=—SAC, or —SCAC), and —C(═O)NR27R28 (in which R27, R28=—SAC, or —SCAC) and can be mono-or poly-substituted at its maximum regardless of the order and the kinds, the pharmaceutically acceptable salts, the esters and the stereochemically isomeric forms thereof.