RU2008132810A - MTOR INHIBITOR COMBINATION AND ANTIFOLATE COMPOUND - Google Patents

Abstract

1. A combination comprising an mTOR inhibitor and an antifolate compound. ! 2. A pharmaceutical composition comprising an mTOR inhibitor and an antifolate compound in combination with a pharmaceutically acceptable excipient. ! 3. A pharmaceutical package comprising an mTOR inhibitor and an anti-folate compound, together with instructions for combined administration. ! 4. Pharmaceutical packaging comprising an mTOR inhibitor along with instructions for combined administration with an anti-folate compound. ! 5. Pharmaceutical packaging comprising an anti-folate compound along with instructions for combined administration with an mTOR inhibitor. ! 6. A method of treating disorders that are mediated by mTOR and / or thymidylate synthetase, comprising administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with an antifolate compound, either sequentially or simultaneously. ! 7. The use of a combination, pharmaceutical combination, pharmaceutical composition or pharmaceutical package according to one of claims 1 to 5, to obtain a medicinal product for use in the method according to claim 6. ! 8. A method of obtaining a medicinal product for use in the method according to claim 6, including either! a) combining, for example, mixing an mTOR inhibitor and an antifolate compound with a pharmaceutically acceptable excipient, or! b) combining, for example, mixing an mTOR inhibitor with a pharmaceutically acceptable excipient to obtain a COMP 1 pharmaceutical composition, and combining, for example, mixing an antifolate compound with a pharmaceutically acceptable excipient, to obtain a COMP 2 pharmaceutical composition, and either! (i) comb

Claims (14)

1. A combination comprising an mTOR inhibitor and an antifolate compound. 2. A pharmaceutical composition comprising an mTOR inhibitor and an antifolate compound in combination with a pharmaceutically acceptable excipient. 3. A pharmaceutical package comprising an mTOR inhibitor and an anti-folate compound, together with instructions for combined administration. 4. Pharmaceutical packaging comprising an mTOR inhibitor along with instructions for combined administration with an anti-folate compound. 5. Pharmaceutical packaging comprising an anti-folate compound along with instructions for combined administration with an mTOR inhibitor. 6. A method of treating disorders that are mediated by mTOR and / or thymidylate synthetase, comprising administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with an antifolate compound, either sequentially or simultaneously. 7. The use of a combination, pharmaceutical combination, pharmaceutical composition or pharmaceutical package according to one of claims 1 to 5, to obtain a medicinal product for use in the method according to claim 6. 8. A method of obtaining a medicinal product for use in the method according to claim 6, including either a) combining, for example, mixing an mTOR inhibitor and an antifolate compound with a pharmaceutically acceptable excipient, or b) combining, for example, mixing an mTOR inhibitor with a pharmaceutically acceptable excipient to obtain a COMP 1 pharmaceutical composition, and combining, for example, mixing an antifolate compound with a pharmaceutically acceptable excipient, to obtain a COMP 2 pharmaceutical composition, and either (i) combining the pharmaceutical composition COMP 1 and the pharmaceutical composition COMP 2 in one package, or (ii) a separate package of the COMP 1 pharmaceutical composition and the COMP 2 pharmaceutical composition, but with the addition of instructions for the combined administration of the COMP 1 pharmaceutical composition and the COMP 2 pharmaceutical composition to each package. 9. The combination of the present invention, method or use provided by the present invention, comprising, in addition to the combination of an mTOR inhibitor with an anti-folate compound, at least one other drug substance. 10. The combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical packaging, method or use according to one of claims 1 to 9, in which the mTOR inhibitor is rapamycin, 40-O- (2-hydroxyethyl) -rapamycin, 32-deoxorapamycin, 16- pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-yyloxy-32 (S or R) -dihydrorapamycin, 16-pent-2-ynyloxy-32 (8 or R) -dihydro-40-O- (2 -hydroxyethyl) -rapamycin, 40- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoate] -rapamycin (also designated CCI779), 40-epi- (tetrazolyl) -rapamycin (also designated ABT578), the so-called rapalogin, n example, AP23573, the compound that is described under the name TAFA-93, or a compound disclosed under the name biolimus. 11. The combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical package, method or use of claim 10, wherein the mTOR inhibitor is 40-O- (2-hydroxyethyl) -rapamycin. 12. The combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical packaging, method or use according to one of claims 1 to 11, in which the anti-folate compound is a compound of the formula

wherein R ₁ is —OH or —NH ₂ , R ₃ is 1,4-phenylene or 1,3-phenylene unsubstituted or substituted with chlorine, fluorine, methyl, methoxy or trifluoromethyl, thienediyl or furandiyl, unsubstituted or substituted with chlorine, fluorine, methyl, methoxy or trifluoromethyl, cyclohexanediyl, or alkanediyl, R ₄ is hydrogen, methyl, or hydroxymethyl, and R ₅ is hydrogen, an alkyl of 1-6 carbon atoms, or an amino group, in free form or in the form of a pharmaceutically acceptable salt, optionally in the form of a solvate. 13. The combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical packaging, method or use according to item 12, in which the antifolate compound is permethrexide of the formula

14. The combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical packaging, method or use according to item 13, in which permethrexide is presented in the form of disodium salt heptahydrate.