Patent EA-001913-B1 (EA)
Title: Pharmaceutical compounds
Inventor: AL-AWAR RIMA S
IPC: A61K31/395
Filed: 1997-08-29
Abstract: 1. A compound of Formula I   wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, NR<51>R<52>, COR<52>, OR<53>, and Ar' of formula   R<51> is selected from the group consisting of hydrogen and (C1-C3)-alkyl; R<52> is selected from the group consisting of hydrogen and (C1-C3)-alkyl; R<53> is selected from the group consisting of (C1-C12)-alkyl; R<54> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, (C1-C6)-alkyl-(R<57>' R<57>'' R<57>'''), simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4-(tert-butyldimethylsiloxy)benzyltriphenylphosophonium, COOR<57>, PO3H, SO3H, SO2R<58>, N(R<59>)R<60>, NHOR<61>, NHCHR<61>', CN, NO2, halogen, OR<62>, CH2(O)R<62>', -CH2OC(O)R<95>, CH2N(R<96>)R<96>', COR<100>, ((C1-C6)-alkyl)OR<100>,   and SR<63>; R<95> is selected from the group consisting of -R<98>NH3; R<96> and R<96>' are each independently selected from the group consisting of hydrogen and (C1-C6)-alkyl, -R<97>NH3, and -R<99>NR<99>'R<99>''; R<97> is selected from the group consisting of (C1-C6)-alkyl; R<98> is selected from the group consisting of (C1-C6)-alkyl; R<99> is (C1-C6)-alkyl; R<99>' and R<99>'' are each independently selected from the group consisting of hydrogen and (C1-C6)-alkyl; R<100> is selected from the group consisting of hydrogen, and Si(R<101>R<102>R<103>); R<101> is (C1-C6)-alkyl; R<102> is (C1-C6)-alkyl; R<103> is (C1-C6)-alkyl; R<104> is selected from the group consisting of C(O)(C1-C6)-alkyl-N(R<106>)(R<59>)R<60>, C(O)(C1-C6)-alkyl-N', fused bicyclic, and NHR<105>N(R<106>)(R<59>)R<60>; R<105> is selected from the group consisting of C(O)(C1-C6)-alkyl, (C1-C6)-alkyl; R<106> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, C(O)OR<107>; R<107> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, CR<108>R<109>R<110>; R<108> is selected from the group consisting of hydrogen and (C1-C6)-alkyl; R<109> is selected from the group consisting of hydrogen and (C1-C6)-alkyl; R<110> is selected from the group consisting of hydrogen and (C1-C6)-alkyl; R<111> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, and C(O)OR<107>; R<55> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, C(R<57>'R<57>''R<57>'''), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR<57>, PO3H, SO3H, SO2R<58>, NR<59>R<60>, NHOR<61>, NHCHR<61>', CN, NO2, halogen, OR<62>, and SR<63>; R<56> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, C(R<57>'R<57>''R<57>'''), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR<57>, PO3H, SO3H, SO2R<58>, NR<59>R<60>, NHOR<61>, NHCHR<61>', (C1-C6)-alkyl-NR<59>R<60>, CN, NO2, halogen, OR<104>, CR<104>, OR<62> , and SR<63>; R<57> is selected from the group consisting of hydrogen and (C1-C12)-alkyl; R<57>' is selected from the group consisting of hydrogen, halogen, and (C1-C12)-alkyl; R<57>'' is selected from the group consisting of hydrogen, halogen, and (C1-C12)-alkyl; R<57>''' is selected from the group consisting of hydrogen, halogen, and (C1-C12)-alkyl; R<58> is selected from the group consisting of hydrogen and (C1-C12)-alkyl; R<59> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluoromethoxycarbonyl (FMOC); R<60> is selected from the group consisting of hydrogen and (C1-C6)-alkyl; R<61> is selected from the group consisting of hydrogen, OR<64>, CH2NHR<65>, NHR<65>' and fluoromethoxycarbonyl (FMOC); R<61>' is selected from the group consisting of hydrogen, OR<64>, CH2NHR<65>, NHR<65>' and fluoromethoxycarbonyl (FMOC); R<62> is selected from hydrogen, and (C1-C6)-alkyl; R<62>' is selected from hydrogen, OH, OR<62>, and (C1-C6)-alkyl; R<63> is selected from hydrogen and (C1-C6)-alkyl; R<64> is selected from the group consisting of hydrogen, (C1-C6)-alkyl, CH2NR<66>R<67>; R<65> is selected from the group consisting of hydrogen and (C1-C6)-alkyl, NH2, and fluoromethoxycarbonyl (FMOC); R<65>' is selected from the group consisting of hydrogen and (C1-C6)-alkyl, NH2, and fluoromethoxycarbonyl (FMOC); R<66> is selected from the group consisting of hydrogen and (C1-C6)-alkyl and fluoromethoxycarbonyl (FMOC); R<67> is selected from the group consisting of hydrogen and (C1-C6)-alkyl; R<1> and R<2> are each independently selected from the group consisting of halogen, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, phosphate, OR<31>, SR<31>, NR<31>, OH, SH, NR<92>, R<93>, NR<94>, and NH2; R<92>, R<93>, and R<94> are each independently selected from the group consisting of (C1-C6)-alkyl; provided that one selected from the group consisting of R<1> and R<2> is selected from the group consisting of OR<31>, SR<31>, NR<31>, OH, and SH; or R<1> and R<2> may be taken together with C-18 and C-19 to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, a cyclopropyl ring or mono-(C1-C6)-alkyl-phosphate ring; or R<1> and R<2> may be taken together to form a second bond between C-18 and C-19; R<3> is a C1-6 alkyl group; R<4> is H or OH; R<5> is H or OH; R<4> and R<5> may be taken together to form a second bond between C13 and C14; R<6> is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (C1-C6)-alkyl, (C3-C8)-cycloalkyl, substituted (C3-C8)-cycloalkyl, substituted (C1-C6)-alkyl, a group of the formula III'   and a group of the formula III'':   R<7> is selected from the group consisting of NR<51>R<52>, R<53>NR<51>R<52>, OR<53>, H and a C1-6 alkyl group; R<51> and R<52> are independently selected from the group consisting of (C1-C3)-alkyl; R<53> is (C1-C3)-alkyl; R<8> is H or a C1-6alkyl group; or R<7> and R<8> can form a cyclopropyl ring; R<9> is selected from the group consisting of H, a C1-6alkyl group, unsaturated C1-6-alkyl, C1-6-alkyl-(C3-C5)--cycloalkyl, and benzyl; R<10> is H or a C1-6 alkyl group; R<11> is selected from the group consisting of hydrogen, OH, C1-6 alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R<14> is selected from the group consisting of hydrogen and C1-6 alkyl; R<15>, R<16>, and R<17> are each independently selected from the group consisting of hydrogen, OR<18>, halo, NR<18>'R<19>', NO2, OPO3H2, OR<19>-phenyl, SCH2-phenyl, CONH2, CO2H, PO3H2, SO2R<23>, and ZZ; R<18> is selected from the group consisting of hydrogen, aryl, (C1-C6)-alkyl, C(O)R<90> and fluoromethoxycarbonyl (FMOC); R<18>' is selected from the group consisting of hydrogen, (C1-C6)-alkyl and C(O)R<90>'; R<19> is (C1-C6)-alkyl, C(O)R<90>'' and fluoromethoxycarbonyl (FMOC); R<19>' is selected from the group consisting of hydrogen, (C1-C6)-alkyl, and C(O)R<90>''', R<90>, R<90>', R<90>'', and R<90>''' are each independently selected from the group consisting of hydrogen, (C1-C6)-alkyl, OR<91> and aryl; R<91>' is selected from the group consisting of (C1-C6)-alkyl, aryl, and hydrogen; R<23> is selected from the group consisting of hydrogen and (C1-C3)-alkyl; R<30> is hydrogen or (C1-C6)-alkyl; or R<30> may be taken together with the N at C-11 to form a three to seven membered cyclic ring; R<31> is selected from the group consisting of (C1-C12)-alkyl, R<32>; R<32> is selected from the group consisting of amino acid, carbohydrate, amino sugar, (saccharide)q, C(O)R<33>, and   R<33> is selected from the group consisting of R<37>R<38>, R<38>, R<37>N; (R<20>')R<38>, R<37>N(R<20>')(C1-C6)-alkyl-C(O)R<38>, R<37>N(R<20>')C(O)R<38>, and R<37>O-(C1-C6)-alkyl-O-(C1-C6)-alkyl-O-(C1-C6)-alkyl-O-(C1-C6)-alkyl and R<37>(NR<18>'R<20>')R<38>; R<20>' is selected from the group consisting of hydrogen, (C1-C6)-alkyl, and -CO2R<21>'; R<21>' is selected from the group consisting of hydrogen and (C1-C6)-alkyl; R<34> is (C1-C4)-alkyl; R<35> is hydrogen or (C1-C3)-alkyl; R<36> is hydrogen, OH, halo, (C1-C3)-alkyl, OR<34>, NO2, NH2 and heteroaromatic; R<37> is (C1-C6)-alkyl; R<38> is COOR<39>,  , NH2, (NR<18>'R<20>'), heterocyclic, heteroaromatic, OH, (C1-C6)-alkyl, and amino acid; R<39> is H or (C1-C6)-alkyl; R<40>, R<41>, and R<42> are each independently selected from the group consisting of hydrogen, OR<43>, halo, NH2, NO2, OPO(OR<46>)2, -OR<44>-phenyl, and R<45>; R<43> is (C1-C6)-alkyl; R<44> is (C1-C6)-alkyl; R<45> is selected from the group consisting of a unsubstituted simple aromatic group and a substituted simple aromatic group; R<46> is selected from the group consisting of H, Na, (C1-C6)-alkyl and -C(CH3)3; R<50> is hydrogen or   n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; q is 2, 3, or 4; X is selected from the group consisting of O, C, S, NH and alkylamino; Y is selected from the group consisting of C, O, NH, S, SO, SO2 and alkylamino; Z is selected from the group consisting of -(CH2)n-, -(CH2)p-O-(CH2)m- and (C3-C5)-cycloalkyl; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof; provided that if R<1> is selected from the group consisting of halogen, OH, OR<31>, SH, amino, monoalkylamino, dialkylamino, trialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate and phosphate, and R<2> is selected from the group consisting of OH, NH2, NR<31> and SH or <1>R and R<2> together form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, a cyclopropyl ring, or monoalkylphosphate ring, or R<1> and R<2> together form a second bond; R<3> is C1-6 alkyl; R<4> and R<5> are H or R<4> and R<5> taken together form double bond between C13 and C14; R<6> is benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxy