Patent ID: 6653345
Filing Date: 2003-11-25
Classification: A61K,C07D

Abstract:
A method of inhibiting mammalian Câ€”C chemokine synthesis comprising delivering an effective amount of a prostaglandin I2 derivative to a Câ€”C chemokine synthesis pathway, wherein the prostaglandin I2 derivative is a 4,8-inter-m-phenylene prostaglandin I2 derivative represented by the following formula, or a pharmacologically acceptable salt thereof: wherein R1 represents the following: (A) COOR2 wherein R2 is: 1) hydrogen or a pharmacologically acceptable cation; 2) straight chain alkyl having 1 to 12 carbon atoms, or branched alkyl having 3 to 14 carbon atoms; 3) â€”Zâ€”R3 wherein Z is a valence bond or straight chain or branched alkylene represented by CtH2t wherein t represents an integer of 1 to 6, and P3 represents cycloalkyl having 3 to 12 carbon atoms or substituted cycloalkyl having 3 to 12 carbon atoms and 1 to 3 substituents R4 each of which is hydrogen or alkyl having 1 to 5 carbon atoms; 4) â€”(CH2CH2O)nCH3 wherein n is an integer of 1 to 5; 5) â€”Zâ€”Ar1 wherein Z is defined above, and Ar1 is phenyl, &agr;-naphthyl, &bgr;-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, &agr;-furyl, &bgr;-furyl, &agr;-thienyl, &bgr;-thienyl or substituted phenyl (wherein a substituent is at least one of chlorine, fluorine, iodine, trifluoromethyl, alkyl having 1 to 4 carbon atoms, nitro, cyano, methoxy, phenyl, phenoxy, p-acetoamidobenzamide, â€”CH&boxH;Nâ€”NHâ€”C(&boxH;O)â€”NH2), â€”NHâ€”C(&boxH;O)Ph, â€”NHâ€”C(&boxH;O)â€”CH3 and â€”NHâ€”C(&boxH;O)â€”NH2); 6) â€”CtH2tCOOR4 wherein CtH2t and R4 are defined above; 7) â€”CtH2tN(R4)2 wherein â€”CtH2t and R4 are defined above; 8) â€”CH(R5)â€”C(&boxH;O)â€”R6 wherein R5 is hydrogen or benzoyl, and R6 is phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl; 9) â€”CpH2pâ€”Wâ€”R7 wherein W is â€”CH&boxH;CHâ€”, â€”CH&boxH;CR7 or â€”Câ‰¡Câ€”, and R7 is hydrogen or straight chain or branched alkyl or aralkyl having 1 to 30 carbon atoms, and p is an integer of 1 to 5; or 10) â€”CH(CH2OR8)2 wherein R8 is alkyl or acyl having 1 to 30 carbon atoms; (B) â€”CH2OH; (C) â€”C(&boxH;O)N(R9)2 wherein R9 is hydrogen, straight chain alkyl having 1 to 12 carbon atoms, branched alkyl having 3 to 12 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, cycloalkylalkylene having 4 to 13 carbon atoms, phenyl, substituted phenyl (wherein the substituent is defined in (A) (5)), aralkyl having 7 to 12 carbon atoms, or â€”SO2R10 wherein R10 is alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, phenyl, substituted phenyl (the substituent is defined in (A) (5)), or aralkyl having 7 to 12 carbon atoms, two R9 groups may be the same or different, and when one of the R9 groups is â€”SO2R10, the other R9 is not â€”SO2R10; or (D) â€”CH2OTHP (THP is a tetrahydropyranyl group); A is the following: 1) â€”(CH2)mâ€”; 2) â€”CH&boxH;CHâ€”CH2â€”; 3) â€”CH2â€”CH&boxH;CHâ€”; 4) â€”CH2â€”Oâ€”CH2â€”; 5) â€”CH&boxH;CHâ€”; 6) â€”Oâ€”CH2â€”; or 7) â€”(â‰¡Câ€”; wherein m represents an integer of 1 to 3; D is hydrogen, alkyl having 1 to 4 carbon atoms, chlorine, bromine, fluorine, formyl, methoxy or nitro; G is â€”Xâ€”C(R11)(R12)OR13 wherein R11 is hydrogen, alkyl having 1 to 4 carbon atoms; R13 is hydrogen, acyl having 1 to 14 carbon atoms, aroyl having 6 to 15 carbon atoms, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxythienyl, or t-butyl; X is the following; 1) â€”CH2â€”CH2â€”; 2) â€”CH&boxH;CHâ€”; or 3) â€”Câ‰¡Câ€”; and R12 is the following; 1) straight chain alkyl having 1 to 12 carbon atoms, or branched alkyl having 3 to 14 carbon atoms; 2) â€”Zâ€”Ar2 wherein Z is defined above, and Ar2 represents phenyl, &agr;-naphthyl, &bgr;-naphthyl, or phenyl substituted by at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, alkyl having 1 to 4 carbon atoms, nitro, cyano, methoxy, phenyl or phenoxy; 3) â€”CtH2tOR14 wherein CtC2t is defined above, and R14 represents straight chain alkyl having 1 to 6 carbon atoms, branched alkyl having 3 to 6 carbon atoms, phenyl, phenyl substituted by at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, alkyl having 1 to 4 carbon atoms, nitro, cyano, phenyl or phenoxy, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted by 1 to 4 straight chain alkyl groups having 1 to 4 carbon atoms; 4) â€”Zâ€”R3 wherein Z and R3 are defined above; 5) â€”CtH2tâ€”CH&boxH;C(R15)R16 wherein CtH2t is defined above, and R15 and R16 each represent hydrogen, methyl, ethyl, propyl, or butyl; or 6) â€”CuH2uâ€”Câ‰¡Câ€”R17 wherein u is an integer of 1 to 7, CuH2u represents straight chain or branched alkyl, and R17 represents straight chain alkyl having 1 to 6 carbon atoms; E is hydrogen or â€”OR18 wherein R18 represents acyl having 1 to 12 carbon atoms, aroyl having 7 to 15 carbon atoms, or R2 (wherein R2 is defined above); and the formula represents a d, l or dl form.