US 5,349,061 A · O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity

Abstract

O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroaryl-macrolides of the general structural Formula I: ##STR1## have been prepared from suitable precursors by alkylation and/or arylation at C-3" and/or C-4" of the cyclohexyl ring. These macrolide immunosuppressants are useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.

A compound selected from the group consisting of:

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-pyridyl) -2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethox y-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3, 10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-pyridyl) -2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13 ,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3, 10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(2-thienyl) -2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethox y-13,19,21,27-tetramethyl-11,28 -dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-thienyl) -2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethox y-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(2-thienyl) -2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13 ,19,21,27-tetramethyl-11,28 -dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
-17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-thienyl) -2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13 ,19,21,27-tetramethyl-11,28 -dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -2-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-di methoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
-17Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -3-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-di methoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(benzothien -5-yl)-2"'-hydzoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-di methoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -6-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,23-dim ethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -2-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimeth oxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -3-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,23-dimetho xy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -5-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,23-dimetho xy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(benzothien -6-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimeth oxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -2-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-di methoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -3-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-di methoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-( 4"-(2"'-(benzofuran -5-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-di methoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -6-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-di methoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -2-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimeth oxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -3-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimeth oxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -5-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimeth oxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -6-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimeth oxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
or a pharmaceutically acceptable salt thereof.

20 more elements

O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity

Life of this patent

O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity

Life of this patent

Abstract

Claims1