Use of Sigma-1 receptor agonist compounds
The present invention is directed to compositions and methods for the prevention, inhibition, and/or treatment of progressive fibrosis present in various fibroproliferative disorders. In particular, embodiments of the present invention relate to the use of Sigma-1 receptor agonists for use in the treatment or prevention of progressive fibrosis characterized by the overproliferation of ECM producing cells, e.g. myofibroblasts and by the excessive deposition of ECM components in a medical or disease condition. Preferred Sigma-1-receptor agonists are disclosed.
1. A method for the treatment of progressive fibrosis of the kidney or lung of a subject, said method comprising administering to the subject an S1R agonist compound in an effective amount sufficient for controlling, reversing or inhibiting progressive fibrosis by reversing or inhibiting fibrotic remodeling of the extracellular matrix, and
wherein said S1R agonist compound has the following formula II:
wherein
Q 1 is a Cl or F or a methyl-halogen selected from CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , or a methoxy,
Q 2 is H, Cl or F,
R 6 is selected from a substituted or unsubstituted C(1-6) alkyl, C(1-6) alkoxy, C(1-6) alkoxy C(1-6) alkyl, C(5-10) aryl,
Y is CH or O, wherein
if Y is O then R 4 is not present,
if Y is CH then R 4 is H, methyl or ethyl,
R 3 is H, methyl or ethyl, or R 3 and R 4 together with the —Y—C2 alkyl moiety which they are attached to, may form a saturated or partially unsaturated cyclic group comprising 0 to 2 heteroatom(s) or R 4 and R 3 together form a C(2-4) alkyl bridge,
R 1 and R 2 are independently H, methyl or ethyl,
or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1 wherein the subject is suffering in progressive fibrosis and has a fibroproliferative disorder, said disorder being selected from the group consisting of renal diseases and lung diseases.
3. The method according to claim 1 wherein the organ affected by progressive fibrosis is the kidney, and the fibroproliferative disorder is a renal disease.
4. The method according to claim 1 wherein
Q 1 is a methyl-halogen selected from CHF 2 , CF 3 , CHCl 2 or CCl 3 ,
Q 2 is H,
R 6 is selected from a substituted or unsubstituted C(1-6) alkoxyalkyl (or C(1-6) dialkyl-ether) or C(1-2) alkoxy C(2-5) alkyl,
Y is CH or O, wherein
if Y is O then R 4 is not present,
if Y is CH then R 4 is H, methyl or ethyl,
R 3 is H or methyl.
5. The method according to claim 4 wherein said compound is fluvoxamine.
6. A method for the treatment of progressive fibrosis in a tissue of a subject wherein said tissue is a tissue in the kidney or in the lung of said subject, said method comprising administering to the kidney of said subject an S1R agonist compound in an effective amount sufficient for controlling, reversing or inhibiting progressive fibrosis,
wherein said S1R agonist compound has the following formula II:
wherein
Q 1 is a Cl or F or a methyl-halogen selected from CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , or a methoxy,
Q 2 is H, Cl or F,
R 6 is selected from a substituted or unsubstituted C(1-6) alkyl, C(1-6) alkoxy, C(1-6) alkoxy C(1-6) alkyl, C(5-10) aryl,
Y is CH or O, wherein
if Y is O then R 4 is not present,
if Y is CH then R 4 is H, methyl or ethyl,
R 3 is H, methyl or ethyl, or R 3 and R 4 together with the —Y—C2 alkyl moiety which they are attached to, may form a saturated or partially unsaturated cyclic group comprising 0 to 2 heteroatom(s) or R 4 and R 3 together form a C(2-4) alkyl bridge,
R 1 and R 2 are independently H, methyl or ethyl,
or a pharmaceutically acceptable salt thereof.
7. The method according to claim 6 wherein progressive fibrosis is treated by preventing, reversing or inhibiting fibrotic remodeling of the extracellular matrix in the kidney of said subject.
8. The method according to claim 6 wherein the subject is suffering in progressive fibrosis and has a fibroproliferative disorder, said disorder being a renal disease.
9. A method for the treatment of progressive fibrosis in a tissue of a subject by reversing or inhibiting fibrotic remodeling of the extracellular matrix, wherein said tissue is a progressively fibrotic tissue, wherein the tissue is a kidney tissue or a lung tissue,
said method comprising administering to the subject an S1R agonist compound in an effective amount sufficient for reversing or inhibiting fibrotic remodeling of the extracellular matrix,
said S1R agonist compound for use having the following formula II:
wherein
Q 1 is a Cl or F or a methyl-halogen selected from CH 2 F, CHF 2 CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , or a methoxy
Q 2 is H, Cl or F,
R 6 is selected from a substituted or unsubstituted C(1-6) alkyl, C(1-6) alkoxy, C(1-6) alkoxy C(1-6) alkyl, C(5-10) aryl,
Y is CH or O, wherein
if Y is O then R 4 is not present,
if Y is CH then R 4 is H, methyl or ethyl,
R 3 is H, methyl or ethyl, or R 3 and R 4 together with the —Y—C2 alkyl moiety which they are attached to, may form a saturated or partially unsaturated cyclic group comprising 0 to 2 heteroatom(s) or R 4 and R 3 together form a C(2-4) alkyl bridge,
R 1 and R 2 are independently H, methyl or ethyl,
or a pharmaceutically acceptable salt thereof.
10. The method according to claim 9 wherein said compound is fluvoxamine.
11. The method according to claim 10 wherein the subject is suffering from progressive fibrosis is affecting the kidney or the lung and the subject has a fibroproliferative disorder which is a renal disease or a lung disease.
12. The method according to claim 1 wherein R 6 is selected from a substituted or unsubstituted C(1-4) alkyl, C(1-4) alkoxy, C(1-6) alkoxyalkyl (or C(1-6) dialkylether) or C(5-7) aryl.
13. The method according to claim 9 wherein the subject is suffering from progressive fibrosis affecting the kidney or the lung and the subject has a fibroproliferative disorder which is a renal disease or a lung disease.