Patent IL-132363-A (IL)
Title: Kappa agonist compounds for use in the prevention or treatment of pruritus and anti-pruritic pharmaceutical formulations containing them
IPC: A61K31/22
Filed: 1998-06-19
Abstract: A compound or a pharmaceutically acceptable salt thereof of the formula wherein n is 0-1; R is unsubstituted phenyl or phenyl substituted with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, hydroxy, -O-CO-NH2-, -O-CO-NHalkyl, -O-CO- N(alkyl)2, C1-6 alkoxy, trifluoromethyl, C1-4 alkoxy-C1-4 alkyloxy, carboxy- C1-4 alkyloxy, nitrile, nitro and amino; or mono or dialkyl amino, amide, sulfonamide, carboxamide; or mono or disubstituted carboxamide, ureido, or mono and di-alkylsubstituted ureido; or R represents an alkyl or cycloalkyl group having up to 7 carbon atoms, wherein the cycloalkyl moiety, where present, can be optionally substituted by one or more subsitutents selected from the group consisting of hydroxy, amino, amidino, guanidino, aminocarbonyl, carboxy, C1-6 alkoxy, (C1-6 alkoxy) carbonyl, (C3-6 alkenyloxy) carbonyl, (C3-6 alkynyloxy) carbonyl, C1-6 alkanoyloxy, C1-6 alkylsulfide, C1-6 alkylsulfoxide, C1-6 alkylsulfone, C1-6 (monoalkylamino) carbonyl, C1-6 acylamino, C1-6 acylmethylamino and C1-6 monoalkylamino; or R represents the group -B-R7 in which B represnts -CH2-, 3671 כ" ז בשבט התשס" ד - February 19, 2004 CH(CH3)- or a single bond and R7 represents an optionally substituted C6-10 carbocyclic aryl group with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, hydroxy, -O-CO-NH2, -O-CO-NHalkyl, -O-CO-N(alkyl)2, C1-6 alkoxy, trifluoromethyl, C1-4 - alkoxy- C1-4 alkyloxy, carboxy-C1-4 alkyloxy, nitrile, nitro and amino; or mono or dialkyl amino, amide, sulfonamide, carboxamide; mono or disubstituted carboxamide ureido; and mono or di-alkylsubstituted ureido; or R represents the group -D-R8 in which D represents a single bond, -CH2-, -CH(CH3)-, CH2O-, -CH(CH3)O-, -CH2-S, -CH2NH- or -CH(CH3)NH- and R8 represents a 4-6 membered heterocyclic ring containing up to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the heterocyclic ring optionally being substituted on nitrogen or sulfur by oxygen or on nitrogen by hydroxy or C1-3 alkyl and/or the ring optionally being substituted on carbon by one or more substituents selected from the group consisting of amino, hydroxy, thio (and their tautomers), cyano, halogen, C1-3 alkoxy, C1-3 monoalkylamino, C1-3 acylamino, C1-3 acylmethylamino, and C1-3 alkylthio; R1 and R2 are independently selected from the group consisting of H, C1-6 alkyl, C3-5 alkenyl, C3-5 alkynyl, and C4-7 cycloalkylalkyl group; or R2 can be taken together wth R1 and the nitrogen to which they are attached to form a heterocyclic ring which may optionally contain a further heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, said heterocyclic ring selected from the group consisting of 1-azetidinyl and 1-pyrrolidinyl said 1-pyrrolidinyl optionally substituted at the 3-position by OH, -CH2OH, tri (C1-C6 alkyl) silyloxy, acyloxy, C1-6 alkyl, C1-6 alkoxy or C1-6 alkanoyloxy; 1-piperazinyl optionally subsitued at the 4-position by alkyl of 1 to 3 carbon atoms; 1-morpholino; 2, 5-dihydro-1H- pyrrol-1-yl; 3-azabicyclo [3.1.0] hexan- 3-yl;' or 3-azabicyclo [3.2.0] heptan-3-yl; R3 represents hydrogen, C1-7 alkyl, -CH2-phenyl or htereocyclic wherein the phenyl or heterocyclic groups may be substituted with one to three substituents selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy and methoxycarbonyl; mono-, di- or tri- halomethyl; cyano; COR9, CH=NOR10, OR10, SR10, CH2CN, CH2OR10, CH2SR10, CH2S(O)R10, CH2S(O)2R10, CH2N(R10) R11, CH2(R10), CH2NR10OH, CH2N(COR10) OH, CH2NR10COR11, CH2NR10S(O)2R11, or CH2OCOR10, wherein R9 is hydrogen, hydroxy, amino, NHOH, NHOCH3, pyridylamino, NHN(CH3)2, C1-4 alkoxy, benzyloxy, C1-4 alkylamino, di-C1-4 alkylamino, C1-4 alkyl or C1-4 alkylthio; R10 and R11 are each hydrogen, C1-4 alkyl, C1-4 alkoxy or C7-11 phenylalkyl), or OR12, wherein R12 is hydrogen, C1-4 alkyl or a hydroxy protecting group; X represents -CO-, or