Pyrrolydenemethyl-derivatives and process for their preparation

A compound selected from:

• 4-methoxy-5-{›5-(undec-10-en-1-yl)-2H-pyrrol-2-ylidene!methyl}-2,2'-bi-1H-p yrrole;
• 4-ethoxy-5-›(5-decyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-ethoxy-5-›(5-dodecyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-ethoxy-5-›(3,5-nonamethylene-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrro le;
• 4-ethoxy-5-›(5-undecyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-propoxy-5-›(5-undecyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-ethoxy-5-{›5-(undec-10-en-1-yl)-2H-pyrrol-2-ylidene!methyl}-2,2'-bi-1H-py rrole;
• 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-1H-pyrrole;
• 4-undecyloxy-5-›(5-undecyl-2H-pyrrol-2-ylidene) methyl!-2,2'-bi-1H-pyrrole;
• 4-benzyloxy-5-›(5-undecyl-2H-pyrrol-2-ylidene) methyl!-2,2'-bi-1H-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-1H-pyrrole;
• 4-methoxy-5-›(5-tridecyl-2H-pyrrol-2-ylidene) methyl!-2,2'-bi-1H-pyrrole;
• 4-ethoxy-5-›(5-tridecyl-2H-pyrrol-2-ylidene) methyl!-2,2'-bi-1H-pyrrole;
• 4-butoxy-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-1H-pyrrole;
• 4-methoxy-5-››5-(5-phenoxy-pent-1-yl)-2H-pyrrol-2-ylidene!methyl!-2,2'-bi-1 H-pyrrole;
• 4-ethoxy-5-››5-(5-phenoxy-pent-1-yl)-2H-pyrrol-2-ylidene!methyl!-2,2'-bi-1H -pyrrole;
• 4-butoxy-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 -1H-pyrrole;
• 4-methoxy-5-››5-(6-fluoro-hex-1-yl)-2H-pyrrol-2-ylidene!methyl!-2,2'-bi-1H- pyrrole;
• 4-methoxy-5-››5-(6-hydoxy-hex-1-yl)-2H-pyrrol-2-ylidene!methyl!-2,2'-bi-1H- pyrrole;
• 4-methoxy-5-››5-(5-morpholinecarboxamido-pent-1-yl)-2H-pyrrol-2-ylidene!met hyl!-2,2'-bi-1H-pyrrole;
• and
• 4-methoxy-5-››5-(7-cyano-hept-1-yl)-2H-pyrrol-2-ylidene!methyl!-2,2'-bi-1H- pyrrole;
• and the pharmaceutically acceptable salts thereof.
• 4.

A parmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and as an active principle a compound of formula (IB) ##STR18## wherein R'.sub.1 represents hydrogen, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl and aryloxy;

• R'.sub.2 represents hydrogen, C.sub.1 -C.sub.6 alkyl, cyano, carboxy or (C.sub.1 -C.sub.6 alkoxy)carbonyl;
• R'.sub.3 represents halogen, hydroxy or (C.sub.1 -C.sub.11 alkoxy unsubstituted or substituted by phenyl;
• R'.sub.4 represents hydrogen, C.sub.1 -C.sub.6 alkyl or phenyl;
• each of R'.sub.5 and R'.sub.6 independently represents hydrogen, C.sub.2 -C.sub.20 alkanoyl, C.sub.3 -C.sub.20 alkenoyl, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, (C.sub.3 -C.sub.4 alkenyl)carbamoyl, aralklcarbamoyl, arylcarbamoyl and --CONR.sub.c R.sub.d in which each of R.sub.c and R.sub.d independently is hydrogen or C.sub.1 -C.sub.6 alkyl or R.sub.c and R.sub.d, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring;
• or
• two of R'.sub.4, R'.sub.5 and R'.sub.6 taken together form a C.sub.4 -C.sub.12 polymethylene chain, which is unsubstituted or substituted by a C.sub.1 -C.sub.12 alkyl, by a C.sub.2 -C.sub.12 alkenyl or by a C.sub.1 -C.sub.12 alkylidene group, wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by a substituent chosen from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, aryloxy and aryl;
• the remaining one being hydrogen or C.sub.1 -C.sub.12 alkyl;
• or a pharmaceutically acceptable salt thereof;
• and wherein
• when at the same time R'.sub.3 is methoxy and R'.sub.1, R'.sub.2, R'.sub.4 and R'.sub.5 are hydrogen, then R'.sub.6 is other than n-nonyl or n-undecyl;
• and wherein
• when at the same time R'.sub.3 is methoxy and R'.sub.1, R'.sub.2 and R'.sub.5 are hydrogen, then R'.sub.4 and R'.sub.6, taken together, are other than an .alpha.-ethyl-nonamethylene chain;
• and wherein
• when it the same time R'.sub.3 is methoxy, R'.sub.6 is methyl and R'.sub.1, R'.sub.2 and R'.sub.4 are hydrogen, then R'.sub.5 is other than n-pentyl;
• and wherein
• when at the same time R'.sub.3 is methoxy and R'.sub.1, R'.sub.2 and R'.sub.4 are hydrogen, then R'.sub.5 and R'.sub.6, taken together, are other than an .alpha.-butyl-heptamethylene chain;
• and wherein
• when at the same time R'.sub.3 is hydroxy, R'.sub.1, R'.sub.2 and R'.sub.4 are hydrogen and R'.sub.6 is methyl, then R'.sub.5 is other than n-pentyl;
• and wherein
• when at the same time R'.sub.3 is methoxy, R'.sub.1 and R'.sub.2 are hydrogen and R'.sub.6 is methyl, then R'.sub.4 and R'.sub.5, taken together, are other than an .alpha.-methyltetramethylene chain,
• or a pharmaceutically acceptable salt thereof.

A method of treating a mammal in need of an immunomodulating agent, said method comprising administering to said mammal an effective amount of a compound of formula (IC) ##STR19## wherein R".sub.1 represents hydrogen, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl and aryloxy;

• R".sub.2 represents hydrogen, C.sub.1 -C.sub.6 alkyl, cyano, carboxy or (C.sub.1 -C.sub.6 alkoxy)carbonyl;
• R".sub.3 represents halogen, hydroxy or C.sub.1 -C.sub.11 alkoxy unsubstituted or substituted by phenyl;
• R".sub.4 represents hydrogen, C.sub.1 -C.sub.6 alkyl or phenyl;
• each of R".sub.5 and R".sub.6 independently represents hydrogen, C.sub.2 -C.sub.20 alkanoyl, C.sub.3 -C.sub.20 alkenoyl, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, (C.sub.3 -C.sub.4 alkenyl)carbamoyl, aralkyl-carbamoyl, arylcarbamoyl and --CONR.sub.c R.sub.d in which each of R.sub.c and R.sub.d independently is hydrogen or C.sub.1 -C.sub.6 alkyl or R.sub.c and R.sub.d, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring;
• or
• two of R".sub.4, R".sub.5 and R".sub.6 taken together form a C.sub.4 -C.sub.12 polymethylene chain, which is unsubstituted or substituted by a C.sub.1 -C.sub.12 alkyl, by a C.sub.2 -C.sub.12 alkenyl or by a C.sub.1 -C.sub.12 alkylidene group, wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by a substituent chosen from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, aryloxy and aryl;
• the remaining one being hydrogen or C.sub.1 -C.sub.12 alkyl;
• or a pharmaceutically acceptable salt thereof;
• and wherein
• when at the same time R".sub.3 is methoxy and R".sub.1, R".sub.2, R".sub.4 and R".sub.5 are hydrogen, then R".sub.6 is other than n-undecyl;
• and wherein
• when at the same time R".sub.3 is methoxy and R".sub.1, R".sub.2 and R".sub.5 are hydrogen, then R".sub.4 and R".sub.6, taken together, are other than an .alpha.-ethyl-nonamethylene chain;
• and wherein
• when at the same time R".sub.3 is methoxy and R".sub.1, R".sub.2 and R".sub.4 are hydrogen, then R".sub.5 and R".sub.6, taken together, are other than an .alpha.-butyl-heptamethylene chain.

A 5-›2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole compound having the following formula (I) ##STR24## wherein R.sub.1 represents hydrogen, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl and aryloxy;

• R.sub.2 represents hydrogen, C.sub.1 -C.sub.6 alkyl, cyano, carboxy or (C.sub.1 -C.sub.6 alkoxy)carbonyl;
• R.sub.3 represents halogen, hydroxy or C.sub.1 -C.sub.11 alkoxy unsubstituted or substituted by phenyl;
• R.sub.4 represents hydrogen, C.sub.1 -C.sub.6 alkyl or phenyl;
• each of R.sub.5 and R.sub.6 independently represents hydrogen, C.sub.2 -C.sub.20 alkanoyl, C.sub.3 -C.sub.20 alkenoyl, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, (C.sub.3 -C.sub.4 alkenyl)carbamoyl, aralkyl-carbamoyl, arylcarbamoyl and --CONR.sub.c R.sub.d in which each of R.sub.c and R.sub.d independently is hydrogen or C.sub.1 -C.sub.6 alkyl or R.sub.c and R.sub.d, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring;
• or two of R.sub.4, R.sub.5 and R.sub.6 taken together form a C.sub.4 -C.sub.12 polymethylene chain, which is unsubstituted or substituted by a C.sub.1 -C.sub.12 alkyl, by a C.sub.2 -C.sub.12 alkenyl or by a C.sub.1 -C.sub.12 alkylidene group, wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by a substituent chosen from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, aryloxy and aryl;
• the remaining one being hydrogen or C.sub.1 -C.sub.12 alkyl;
• or a pharmaceutically acceptable salt thereof;
• and wherein
• when at the same time R.sub.3 is methoxy and R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are hydrogen, then R.sub.6 is other than hydrogen, C.sub.1 -C.sub.9 alkyl, undecyl or dodecyl;
• and wherein
• when at the same time R.sub.3 is methoxy and R.sub.1, R.sub.2, R.sub.4 and R.sub.6 are hydrogen, then R.sub.5 is other than n-undecyl;
• and wherein
• when at the same time R.sub.3 is methoxy, and R.sub.1 and R.sub.2 are hydrogen, and R.sub.4 and R.sub.6 are methyl, then R.sub.5 is other than hydrogen or alkyl;
• and wherein
• when at the same time R.sub.3 is methoxy and R.sub.1, R.sub.2 and R.sub.5, are hydrogen, then R.sub.4 and R.sub.6, taken together, are other than an .alpha.-alkyl-nonamethylene, .alpha.-ethyl-alkylene, or .alpha.-butylheptamethylene chain;
• and wherein
• when at the same time R.sub.3 is methoxy, R.sub.6 is methyl and R.sub.1, R.sub.2 and R.sub.4 are hydrogen, then R.sub.5 is other than alkyl;
• and wherein
• when at the same time R.sub.3 is methoxy and R.sub.1, R.sub.2 and R.sub.4 are hydrogen, then R.sub.5 and R.sub.6, taken together, are other than .alpha.-butyl-alkylmethylene or .alpha.-alkyl-heptamethylene chain;
• or R.sub.5 being methyl, then R.sub.6 is other than n-pentyl;
• or R.sub.5 being ethyl, then R.sub.6 is other than n-butyl;
• and wherein
• when at the same time R.sub.3 is hydroxy, R.sub.1, R.sub.2 and R.sub.4 are hydrogen and R.sub.6 is methyl, then R.sub.5 is other than alkyl;
• and wherein
• when at the same time R.sub.3 is methoxy, R.sub.1 and R.sub.2 are hydrogen and R.sub.6 is methyl, then R.sub.4 and R.sub.5, taken together, are other than an .alpha.-methyl-tetra-methylene or .beta.-methyl-tetramethylene chain;
• or R.sub.4 being n-propyl, then R.sub.5 is other than n-heptyl;
• and wherein
• when at the same time R.sub.1 and R.sub.2 are hydrogen, R.sub.3 is methoxy, R.sub.5 is ethyl and R.sub.6 is methyl, R.sub.4 is other than alkyl;
• and wherein
• when at the same time R.sub.1 and R.sub.2 are hydrogen, R.sub.3 is methoxy, R.sub.4 is methyl and R.sub.5 is ethyl, R.sub.6 is other than C.sub.2 -C.sub.9 alkyl;
• and wherein
• when at the same time R.sub.3 is methoxy R.sub.1, R.sub.2, and R.sub.4 are hydrogen, and R.sub.5 is pentyl, then R.sub.6 is other than C.sub.2 -C.sub.9 alkyl;
• when at the same time R.sub.3 is hydroxy R.sub.1, R.sub.2, and R.sub.4 are hydrogen, and R.sub.5 is C.sub.5 H.sub.11, then R.sub.6 is other than C.sub.2 -C.sub.9 alkyl;
• when at the same time R.sub.3 is methoxy R.sub.1, R.sub.2, and R.sub.4 are hydrogen, and R.sub.5 is (CH.sub.2).sub.5 --Me, then R.sub.6 is other than C.sub.2 -C.sub.9 alkyl;
• when at the same time R.sub.3 is methoxy R.sub.1, R.sub.2, and R.sub.4 are hydrogen, and R.sub.5 is n-heptyl, then R.sub.6 is other than C.sub.2 -C.sub.9 alkyl;
• when at the same time R.sub.3 is methoxy R.sub.1, R.sub.2, and R.sub.4 are hydrogen, and R.sub.5 is (CH.sub.2).sub.10 --Me, then R.sub.6 is other than C.sub.2 -C.sub.9 alkyl.

A 5-›2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole compound having the following formula (I) ##STR25## wherein R.sub.1 represents hydrogen, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl and aryloxy;

• R.sub.2 represents hydrogen, C.sub.1 -C.sub.6 alkyl, cyano, carboxy or (C.sub.1 -C.sub.6 alkoxy)carbonyl;
• R.sub.3 represents C.sub.1 -C.sub.11 alkoxy substituted by phenyl;
• R.sub.4 represents hydrogen, C.sub.1 -C.sub.6 alkyl or phenyl;
• each of R.sub.5 and R.sub.6 independently represents hydrogen, C.sub.2 -C.sub.20 alkanoyl, C.sub.3 -C.sub.20 alkenoyl, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, (C.sub.3 -C.sub.4 alkenyl)carbamoyl, aralkyl-carbamoyl, arylcarbamoyl and --CONR.sub.c R.sub.d in which each of R.sub.c and R.sub.d independently is hydrogen or C.sub.1 -C.sub.6 alkyl or R.sub.c and R.sub.d, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring;
• or two of R.sub.4, R.sub.5 and R.sub.6 taken together form a C.sub.4 -C.sub.12 polymethylene chain, which is unsubstituted or substituted by a C.sub.1 -C.sub.12 alkyl, by a C.sub.2 -C.sub.12 alkenyl or by a C.sub.1 -C.sub.12 alkylidene group, wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by a substituent chosen from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, aryloxy and aryl;
• the remaining one being hydrogen or C.sub.1 -C.sub.2 alkyl;
• or a pharmaceutically acceptable salt thereof.

A method of treating a mammal in need of an immunomodulating agent, said method comprising administering to said mammal an effective amount of a compound selected from the group consisting of:

• 4-ethoxy-5-›(5-undecyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-methoxy-5-›(5-tridecyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-ethoxy-5-›(5-tridecyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-butoxy-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-1H-pyrrole;
• 4-methoxy-5-›(5-decyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• 4-methoxy-5-›(5-pentadecyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole;
• and
• 4-methoxy-5-›(5-phenethyl-2H-pyrrol-2-ylidene)methyl!-2,2'-bi-1H-pyrrole,
• and salts of said compounds.