Pharmaceutical compositions and their uses
View Patent ↗The present invention relates to compositions comprising 1,2-dihydropiridin-2-one compounds and an immunoregulatory or anti-inflammatory agent. The compositions are useful for the prevention or the treatment of neurodegenerative diseases, for example demyelinating disorders.
1. A pharmaceutical composition comprising
I) a compound represented by the following formula or a salt thereof:
wherein,
Q indicates O;
R 1 indicates X 1 -A 1 ;
R 2 indicates X 2 -A 2 ;
R 3 indicates hydrogen;
R 4 indicates X 3 -A 3 ; and
R 5 indicates hydrogen,
wherein X 1 , X 2 , and X 3 each indicates a single bond and A 1 , A 2 , and A 3 are the same as or different from each other and each indicates a C 6-14 aromatic hydrocarbocyclic group or a 5 to 14 membered aromatic heterocyclic group, wherein each of A 1 , A 2 , and A 3 is optionally substituted with a hydroxyl group, a halogen atom, an amino group, or a nitrile group; and
II) β-interferon.
2. A composition as claimed in claim 1 , wherein the compound is one or more of:
3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one, 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one, 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one, 3-(2-cyanophenyl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one, 3-(2-cyanophenyl)-1-(3-pyridyl)-5-(2-pyrinidinyl)-1,2-dihydropyridin-2-one, 3-(2-fluoropyridin-3-yl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one, and 3-(2-cyanopyridin-3-yl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one.
3. A composition, as claimed in claim 1 , wherein the β-interferon is IFN-beta-1a or IFN-beta-1b.
4. A composition, as claimed in claim 3 , wherein the IFN-beta-1a is Rebif or Avonex and the IFN-beta-1b is Betaseron or Betaferon.
5. A pharmaceutical composition for the treatment of a demyelinating disorder comprising a therapeutically effective amount of a composition for treating said demyelinating disorder according to claim 1 in combination with a pharmaceutically acceptable carrier or excipient.
6. The pharmaceutical composition according to claim 5 , wherein the demyelinating disorder is encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV-myelopathy, HTLV-myelopathy, progressive multifocal leucoencephalopathy, or a secondary demyelinating disorder.
7. The pharmaceutical composition as claimed in claim 6 , wherein the demyelinating disorder is a secondary demyelinating disease which is CNS lupus erythematodes, polyarteritis nodosa, Sjoegren's syndrome, sarcoid granuloma or isolated cerebral vasculitis.
8. A method for the treatment of a demyelinating disorder, the method comprising administering to a patient a composition as claimed in claim 1 .
9. A method for the treatment of a demyelinating disorder, the method comprising administering to a patient a composition comprising
I) a compound represented by the following formula or a salt thereof:
wherein, Q indicates O; R 1 indicates X 1 -A 1 ; R 2 indicates X 2 -A 2 ; R 3 indicates hydrogen; R 4 indicates X 3 -A 3 ; and R 5 indicates hydrogen, wherein X 1 , X 2 , and X 3 each indicates a single bond and A 1 , A 2 , and A 3 are the same as or different from each other and each indicates a C 6-14 aromatic hydrocarbocyclic group or a 5 to 14 membered aromatic heterocyclic group, wherein each of A 1 , A 2 , and A 3 is optionally substituted with a hydroxyl group, a halogen atom, an amino group, or a nitrile group; and
II) β-interferon
wherein the compound and the β-interferon are administered separately, simultaneously or sequentially.
10. A kit comprising, a first container comprising
a compound represented by the following formula or a salt thereof:
wherein, Q indicates O; R 1 indicates X 1 -A 1 ; R 2 indicates X 2 -A 2 ; R 3 indicates hydrogen; R 4 indicates X 3 -A 3 ; and R 5 indicates hydrogen, wherein X 1 , X 2 , and X 3 each indicates a single bond and A 1 , A 2 , and A 3 are the same as or different from each other and each indicates a C 6-14 aromatic hydrocarbocyclic group or a 5 to 14 membered aromatic heterocyclic group, wherein each of A 1 , A 2 , and A 3 is optionally substituted with a hydroxyl group, a halogen atom, an amino group, or a nitrile group, and
a second container comprising β-interferon,
optionally with instructions for use.
11. A kit comprising:
a first container comprising therein a compound represented by the following formula or a salt thereof:
wherein,
Q indicates O;
R 1 indicates X 1 -A 1 ;
R 2 indicates X 2 -A 2 ;
R 3 indicates hydrogen;
R 4 indicates X 3 -A 3 ; and
R 5 indicates hydrogen,
wherein X 1 , X 2 , and X 3 each indicates a single bond and A 1 , A 2 , and A 3 are the same as or different from each other and each indicates a C 6-14 aromatic hydrocarbocyclic group or a 5 to 14 membered aromatic heterocyclic group, wherein each of A 1 , A 2 , and A 3 is optionally substituted with a hydroxyl group, a halogen atom, an amino group, or a nitrile group; and
a second container comprising therein β-interferon,
optionally with instructions for use,
wherein one or both of the first container and the second container further comprise a pharmaceutically acceptable carrier or excipient.
12. A kit, as claimed in claim 10 , for use in the treatment of a demyelinating disorder.
13. A kit, as claimed in claim 10 , wherein the compound and the β-interferon, are administered separately, simultaneously, or sequentially.
14. A pharmaceutical composition comprising:
3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one or a salt thereof;
β-interferon; and
at least one pharmaceutically acceptable carrier or excipient.
15. The pharmaceutical composition of claim 14 , wherein 3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one or a salt thereof and β-interferon are formulated for separate, simultaneous, or sequential administration.
16. A method of treating a demyelinating disorder which comprises administering to a patient in need thereof a pharmaceutically effective amount of a composition of claim 14 or 15 .
17. The method of claim 16 , wherein 3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one or a salt thereof and β-interferon are administered sequentially.
18. A composition as claimed in claim 1 , wherein the compound and the immunoregulatory or anti-inflammatory agent are for separate, simultaneous, or sequential administration.
19. A combination comprising:
3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one or a salt thereof; and
β-interferon.
20. The combination of claim 19 , wherein 3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one or a salt thereof and β-interferon are for separate, simultaneous, or sequential administration.
21. The method of claim 8 , wherein the demyelinating disorder is encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Bane syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV-myelopathy, HTLV-myelopathy, progressive multifocal leucoencephalopathy, or a secondary demyelinating disorder.
22. The method of claim 8 , wherein the demyelinating disorder is a secondary demyelinating disease which is CNS lupus erythematodes, polyarteritis nodosa, Sjoegren's syndrome, sarcoid granuloma or isolated cerebral vasculitis.