Patent EA-001356-B1 (EA)
Title: Diglycosylated 1,2-diols as mimetics of sialyl-lewis x and sialyl-lewis a
Inventor: KOLB HARTMUTH CHRISTIAN
IPC: A61P35/00
Filed: 1996-06-26
Abstract: 1. A compound of the formula I   in which: X is the residue of a non-glycosidic aliphatic 1,2-diol; R1 is a group of the formula III   R2 is hydrogen, C1-C12alkyl or C6 aryl; R3 is hydrogen or My; R4 is  R3 is C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C1aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, which are unsubstituted or substituted  by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)R34, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; where R31 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl; Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl; y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal; wherein and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)R34, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, including its physiologically tolerated salts of said compound. 2. A compound according to claim 1, wherein X is a linear or branched C2-C20-alkylene, -alkenylene, C3-C12-cycloalkylene, -cycloalkenylene, C3-C11-heterocycloalkylene or -heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-. 3. A compound as claimed in claim 1, wherein X is the residue of a 1,2-diol corresponding to formula II:   in which R5 and R6 are, independently of one another, hydrogen, C1-C12alkyI, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl; or R5 and R6 are, together with the -CH-CH- group, C3-C12cycloalkylene, C3-C12-cycloalkenylene, C2-C11heterocycloalkylene and C3-C11heterocycloalkenylene with heteroatoms selected from the group -O-, -S- and -N-; where alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)OR31, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7 C10 heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11araIkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, Ci-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. 4. A compound according to claim 3, wherein R5 and R6  (a) are unsubstituted or substituted by C1-C12alkyl or C1-C12alkoxy; (b) are, together with the group -CH-CH-, a 5- to 8-membered carbocycle; (c) are, together with the group -CH-CH-, a 5- to 8-membered heterocarbocycle; (d) are, independently of one another, hydrogen, unsubstituted C1-C12alkyl or C1-C12alkyl which is substituted by a substituent selected from the group consisting of -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C3-C12cycloalkyl, C,-C6alkoxy, phenyloxy and benzyloxy; unsubstituted C3-C12cycloalkyl or C3-C12cycloalkyl which is substituted by a substituent selected from the group consisting of -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C1-C6alkyl, C1-C6alk- oxy, phenyloxy and benzyloxy; C6-C10aryl which is unsubstituted or substituted by -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C1-C6alkyl or C1-C6alkoxy; C3-C9heteroaryl with 1 or 2 hetero atoms selected from the group consisting of oxygen and nitrogen atoms; or C7-C12aralkyl which is unsubstituted or substituted by -C(O)ORs1, -OC(O)Rs4, -C(O)ONa or -C(O)OK, primary amino, secondary amino, C1-C6alkyl or C1-C6alkoxy; (e) are, together with the group -CH-CH-, a 5- to 12-membered carbocycle or 5- or 6-membered heterocarbocycle with a hetero atom selected from the group consisting of oxygen and nitrogen atoms; or (f) are, together with the -CH-CH- group, C3-C12cycloalkylene, C4-C12cycloalkenylene, C2-C11heterocycloalkylene or C3-C11heterocycloalkenylene with hetero atoms selected from the group of -O-, -S- and -N-; where cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7 C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide, where Rs1 is hydrogen, My, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, Rs4 is hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C13cycloalkyl, C2-C11heterocycloalkyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl or C6-C10heteroaralkyl, and Rs2 and R20 are hydrogen, C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11-heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C11aralkyl, C6-C10heteroaralkyl, C8-C11-aralkenyl or C7-C10heteroaralkenyl, and alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkyloxy, heteroaralkyl, aralkenyl and heteroaralkenyl in turn are unsubstituted or substituted by one of the abovementioned substituents; and y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal. 5. A compound according to claim 4, wherein R5 and R6 are, together with the -CH-CHgroup, C3-C12cycloalkylene or C2-C11heterocycloalkylene with nitrogen as hetero atom; where cycloalkylene and heterocycloalkylene are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, C(O)ORs1, OC(O)Rs4, C(O)Rs2, NR8R9, C1-C12alkyl, R8C(O)(NH)p N(R9)-, -C(O)(NH)pNR8R9, R8S(O)2(NH)pN(R9)-; R8R40NC(O)(NH)pN(R9)-, R8OC(O)(NH)pN(R9)-, -OC(O)(NH)pNR8R9, and R10-SO2-, in which R8, R9, R10 and R40 are, independently of one another, hydrogen, OH, C1-C12alkyl, C1-C12alkenyl, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C5-C9heteroaryl, C7-C16aralkyl, C8-C16aralkenyl with C2-C6alkenylene and C6-C10aryl, C6-C15heteroaralkyl, C6-C15heteroaralkenyl, or di-C6-C10aryl-C1-C6-alkyl, which are unsubstituted or substituted by one or more substituents selected from the group consisting of OH, halogen, C(O)ORs1, OC(O)Rs4, C(O)Rs2, nitro, NH2, cyano, SO3My, OSO3My, NR20SO3My, C1-C12alkyl, C2-C12alkenyl, C1-C12alkoxy, C3-C12cycloalkyl, C3-C12cycloalkenyl, C2-C11heterocycloalkyl, C2-C11heterocycloalkenyl, C6-C10aryl, C6-C10aryloxy, C5-C9heteroaryl, C5-C9heteroaryloxy, C7-C11aralkyl, C7-C11aralkyloxy, C6-C10heteroaralkyl, C8-C11aralkenyl, C7-C10heteroaralkenyl, primary amino, secondary amino, sulfonyl, sulfonamide, carbamide, carbamate, sulfonhydrazide, carbhydrazide, carbohydroxamic acid and aminocarbonylamide; Rs1 is hydrogen, My