| CPC A01N 1/0226 (2013.01) [A61K 31/138 (2013.01); A61K 31/40 (2013.01); A61K 31/44 (2013.01); C07C 211/03 (2013.01); C07D 207/04 (2013.01); C07D 207/18 (2013.01); C07D 207/30 (2013.01); C07D 211/04 (2013.01); C07D 213/04 (2013.01)] | 21 Claims |
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1. A method for reducing or delaying cellular damage that occurs during ex vivo storage of a transplantable whole or partial organ or tissue, the method comprising
(i) contacting the whole or partial organ or tissue ex vivo with a composition comprising an amount of a sigma 1 receptor (S1R) agonist compound effective in reducing or delaying cellular damage of said transplantable whole or partial organ or tissue during ex vivo storage and a physiologically acceptable solution suitable for ex vivo organ preservation,
(ii) maintaining the transplantable whole or partial organ or tissue ex vivo in said composition before transplantation,
wherein the transplantable whole or partial organ or tissue is maintained at a temperature of from 0° C. to 10° C., and
wherein the S1R agonist compound has the following formula I′:
 wherein
Q1 is H, halogen, pseudo-halogen, C(1-4) alkyl optionally substituted with 1, 2, 3 or 4 halogen(s), C(1-3) alkoxy, C(6-10) aryl, optionally substituted with 1, 2, 3 or 4 halogen(s),
Q2 is H, halogen, pseudo-halogen or C(1-3) alkoxy,
X is O, CH2, ethylene or carbonyl (CO), amide or not present,
or X has the formula
 wherein R6 is selected from the group consisting of a hydroxyl, substituted or unsubstituted C(1-6) alkyl, C(1-6) alkoxy, or C(1-6) alkoxyalkyl, and C(5-10) aryl,
or X has the formula
 wherein W is —CH— or carbonyl (—CO—) or W is not present, and
R6 and R6′ are independently substituted or unsubstituted C(1-6) alkyl, C(1-6) alkyloxy, C(1-6) alkoxyalkyl, C(1-6) alkyloxy carbonyl, or at least one of R6 and R6′ is a C(5-10) aryl,
or R6 and R6′ together form a C(4-7) cycloalkyl,
or X has the formula
 wherein R6 is selected from a substituted or unsubstituted C(1-6) alkyl, C(1-6) alkoxy, or C(5-10) aryl,
Y is CH, N or O, —O—CH2—CH2—O— or not present
wherein
if Y is O then R4 is not present,
if Y is N then R4 is H, or a C(1-3) alkyl or C(1-3) alkenyl, or R4 and R1 together with Y, N and the carbon atoms between them form a C(5-7) heterocyclic ring,
if Y is CH then R4 is selected from a H, substituted or unsubstituted C(1-4) alkyl, C(1-4) alkoxy and C(5-10) aryl, or R4 and R1 together with Y, N and the carbon atoms between them form a C(5-7) heterocyclic ring,
R3 is selected from H, a substituted or unsubstituted C(1-6) alkyl, C(1-6) alkoxy, C(5-10) aryl, or
R3 and the —X—Y—C2- alkyl moiety, via R6, may form a saturated or partially unsaturated 6 to 8 membered cycloalkyl or 6 to 8 membered heterocycloalkyl comprising 0 to 3 heteroatom(s), or
R3 and the —X—Y—C2- alkyl moiety, via R6, may form a substituted or unsubstituted C(7-14) polycyclic aryl or C(7-14) polycyclic heteroaryl or C(7-14) cycloalkylaryl, or
R3 and the —Y—C2- alkyl moiety, via R4, may form a saturated or partially unsaturated 6 to 8 membered cycloalkyl or 6 to 8 membered heterocycloalkyl comprising 0 to 3 heteroatom, or an alkylaryl,
R5 is H, C(1-3) alkyl or C(1-3) alkyloxy or
R5 and R6 together with carbon atoms which they are attached to form a 3, 4, 5 or 6 membered saturated or unsaturated ring, said ring optionally comprising a heteroatom,
R1 and R2 are independently H or a C(1-6) alkyl, or
R1 and R2 form a 5 or 6 membered, saturated or unsaturated ring,
said ring optionally comprising a heteroatom, or
said ring being optionally a substituted or unsubstituted piperidine ring, or
R1 is a C(2-4) alkylene and together with Y and N and the carbon atoms between Y and N form a heterocyclic ring, and
R2 is a C(1-6) alkyl, C(5-10) aryl or C(7-10) aralkyl,
or R2 is a C(2-4) alkylene and together with the N form a heterocyclic ring,
or a pharmaceutically acceptable salt thereof.
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