Patent EA-000925-B1 (EA)
Title: Synergistic immunosuppressant composition containing a 2,2"-bi-1h-pyrrole compound
Inventor: FERRARI MARIO
IPC: A61K31/4025
Filed: 1997-09-02
Abstract: 1. A product containing: (a) an immunosuppressant agent (A) and (b) at least one immunosuppressant 2,2'-bi-lH-pyrrole compound (B) having the following formula (I)   wherein R1 is hydrogen, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents, which are the same or different, chosen independently from halogen, C1-C6 lkoxy, hydroxy, aryl and aryloxy;  R2 is hydrogen, C1-5C6 alkyl, cyano, carboxy or (C1-C6 alkoxy)carbonyl; R3 is halogen, hydroxy or C1-C11 alkoxy unsubstituted or substituted by phenyl; R4 is hydrogen, C1-C6 alkyl or phenyl; each of R5 and R6, which are the same or different, is independently hydrogen, C2-C20 alkanoyl, C3-C20, alkenoyl, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups are unsubstituted or substituted by 1 to 3 substituents, which are the same or different, chosen independently from halogen, C1-C6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C1-C6 alkoxy)carbonyl, (C3-C4 alkenyl)carbamoyl, aralkylcarbamoyl, arylcarbamoyl and CONRcRd in which each of Rc and Rd, which are the same or different, is independently hydrogen or C1-C6 alkyl or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; or two of R4, R45 and R6, taken together, form a C4-C12 polymethylene chain, which is unsubstituted or substituted by a C1-C12 alkyl, by a C2-C12 alkenyl or by a C1-C12 alkylidene group, wherein the alkyl, alkenyl and alkylidene groups is in turn unsubstituted or substituted by a substituent chosen from halogen, Cl-Cy alkoxy, hydroxy, cyano, carboxy, (C,-C6 alkoxy)carbonyl, aryloxy and aryl; the remaining one being hydrogen or C1 -C12 alkyl; or a pharmaceutically acceptable salt thereof; in amounts to produce a superadditive immunosuppressant effect, as a combined preparation for simultaneous, separate or sequential use in immunosuppressant therapy. 2. A product according to claim 1, wherein the immunosuppressant agent (A) is selected from: (a) cyclosporin A, cyclosporin C; (b) FK506; (c) azathioprine; (d) methotrexate; (e) rapamycin; (f) mycophenolate mofetil; and (g) an immunosuppressant glucocorticoid, such as prednisone or dexamethasone; or is a mixture of two or more thereof. 3. A product according to claim 1, wherein the immunosuppressant agent (A) is selected from cyclosporin A, azathioprine, prednisone, dexametasone and mycophenolate mofetil. 4. A product according to claim 1, wherein the immunosuppressant agent (A) is cyclosporin A. 5. A product according to claim 1, wherein in the immunosuppressant compound (B) of formula (I) R1 is hydrogen or C1-C20 alkyl; R2 and R5 are hydrogen; R3 is hydroxy or C1-C11 alkoxy unsubstituted or substituted by phenyl; R4 is hydrogen or C1-C4 alkyl; R6 is hydrogen, C1-C14 alkyl or C2-C14d alkenyl, wherein the alkyl and the alkenyl groups are unsubstituted or substituted by a substituent chosen from halogen, C1-C4 alkoxy, hydroxy, phenyl, phenoxy and cyano; or R5 and R6, taken together, form a C4-C12 polymethylene chain, which is unsubstituted or substituted by C1-C6 alkyl, C3-C6 alkenyl or a C1-C8 alkylidene group, wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by halogen, C1-C4 alkoxy, hydroxy, cyano, phenoxy or phenyl. 6. A product according to claim 1, wherein the immunosuppressant compound (B) in selected from: 4-methoxy-5-{[5-(undec-10-en-l-yl)-2H-pyrrol-2-ylidene]methyl}-2,2'-bi-lH-pyrrole; 4-ethoxy-5-[(5-decyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH- pyrrole; 4-ethoxy-5-[(5-dodecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-ethoxy-5-[(3,5-nonamethylene-2H-pyrrol-2-ylidene)methyl]2,2'-bi-lH-pyrrole; 4-ethoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-propoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-butoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-ethoxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-decyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-pentadecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-1H-pyrrole; 4-metoxy-5-[(5-heptyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-phenethyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-1H-pyrrole; 4-methoxy-5-([5-(5-carboxy-pent-l-yl)-2H-pyrrol-2-ylidene]methyl)-2,2'-bi-1H-pyrrole; 4-methoxy-5-{[5-(5-carboxy-pent-l-yl)-2H-pyrrol-2-ylidene]methyl)-2,2'-bi-1H-pyrrole methylester; 4-methoxy-5-[4,5,6,7-tetrahydro-2H-indol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(4-hexyl-4,5,6,7-tetrahydro-2H-indol-2-ylidene) methyl]-2,2'-bi-lH-pyrrole; 4-ethoxy-5-{[5- (undec-10-en-l-yl)-2H-pyrrol-2-ylidene]methyl}-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene) methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(4-hexyl-5-methyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-methyl-4-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-nonyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-methyl-4-pentyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-isopropoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-1H-pyrrole; 4-amyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-undecyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-benzyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene) methyl]-2,2'-bi-lH-pyrrole; 4-benzyloxy-5-[(2H-pyrrol-2-ylidene)methyl]-2,2'-bi-1H-pyrrole; 4-undecyloxy-5-[(2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-tridecyl-2H-pyrrol-2-ylidene)methyl]-2,2-bi-lH-pyrrole; 4-ethoxy-5-[(5-tridecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-buthoxy-5-[(5-tridecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-1H-pyrrole; 4-benzyloxy-5-[(5-tridecyl-2H-pyrrol-2-ylidene)methyl]-2,2-bi-lH-pyrrole; 4-methoxy-5-[[5-(5-phenoxy-pent-1-yl)-2H-pyrrol-2-ylidene] methyl]-2,2'-bi-lH-pyrrole; 4-ethoxy-5-[[5-(5-phenoxy-pent-1-yl)-2H-pyrrol-2-ylidene]methyl]-2,2'-bi-lH-pyrrole; 4-buthoxy-5-[[5-(5-phenoxy-pent-1-yl)-2H-pyrrol-2-ylidene]methyl]-2,2'-bi-1H-pyrrole; 4-benzyloxy-5-[[5-(5-phenoxy-pent-1-yl)-2H-pyrrol-2-ylidene]methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[[5-(6-fluoro-hex-1-yl)-2H-pyrrol-2-ylidene]methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[[5-(6-hydoxy-hex-1-yl)-2H-pyrrol-2-ylidene]methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[[5-(5-morpholinecarboxamido-pent-l-yl)-2H-pyrrol-2-ylidene]methyl]-2,2'-bi-lH-pyrrole;and 4-methoxy-5-[[5-(7-cyano-hept-l-yl)-2H-pyrrol-2-ylidene] methyl]-2,2'-bi-lH-pyrrole; or is a pharmaceutically acceptable salts thereof. 7. A product according to claim 1, wherein the immunosuppressant compound (B) is selected from: 4-ethoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-methoxy-5-[(5-tridecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-ethoxy-5-[(5-tridecyl-2H-pyrrol-2-ylidene)methyl]-2,2'-bi-lH-pyrrole; 4-buthoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]2,2'-bi-lH-pyrrole; and 4-benzyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidenejmethyl]-2,2'-bi-lH-pyrrole; or is a pharmaceutically acceptable salts thereof. 8. A product according to claim 1, wherein the amount of each of agent (A) and compound (B) is from 5 to 85% of its therapeutically effective amount when given alone. 9. A pharmaceutical composition for use in immunosuppressant therapy in mammals, including humans, comprising: (a) an immunosuppressant agent (A) in a pharmaceutically acceptable carrier and/or excipient, and (b) at least one immunosuppressive 2,2'-bi-lH-pyrrole compound (B) of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier and/or excipient, in amounts to produce a superadditive immunosuppresant effect. 10. A pharmaceutically composition according to claim 9, wherein the amount of each of agent (A) and compound (B) is from 5 to 85% of its therapeutically effective amount when given alone. 11. An immunosuppressant therapy method for use in mammals, including humans, in need thereof, the method comprising administering to said mammal (a) an immunosuppressant agent (A) and (b) at least one immunosuppressant 2,2'-bi-lH-pyrrole compound (B) of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to produce a superadditive immunosuppressive effect. 12. A method for lowering the side effects caused by immunosuppressant therapy in mammals, including humans, in need thereof, the method comprising administering to said mammal a combination preparation comprising (a) an immunosuppressant agent (A) and (b) at last one 2,2'-bi-lH-pyrrole immunosuppressive compound (B) of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, in a quantity effective to produce a superadditive immunosuppressive effect.