Combinations for the treatment of immunoinflammatory disorders
AssigneeCombinatoRx, Incorporated
InventorsCurtis Keith, Alexis Borisy, Grant Zimmerman, Edward Roydon Jost-Price, Palaniyandi Manivasakam, Nicole Hurst, Michael A. Foley
Life of this patent
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Abstract
The invention features a method for treating a patient having an immunoinflammatory disorder, by administering to the patient (i) a tetra-substituted pyrimidopyrimidine, and (ii) a corticosteroid simultaneously or within 14 days of each other in amounts sufficient to reduce or inhibit immunoinflammation.
Claims36
A method for treating a patient who has an immunoinflammatory disorder or is at risk for developing an immunoinflammatory disorder, said method comprising administering to said patient:
- (a) a corticosteroid;
- and
- (b) a compound having the formula:
- 6
- wherein each Z and each Z′ is, independently, N, O, C,
- 7
- wherein when Z or Z′ is O or
- 8
- then p=1,
- when Z or Z′ is N,
- 9
- then p=2,
- when Z or Z′ is C, then p=3;
- each R1 is, independently, X, OH, N-alkyl, a branched or unbranched alkyl group having 1 to 20 carbon atoms, a heterocycle, or, when p>1, two R1 groups from a common Z or Z′ atom, in combination with each other, represent —(CY2)k—, wherein k is an integer between 4 and 6, inclusive;
- each X is, independently, Y, CY3, C(CY3)3, CY2CY3, (CY2)1-5OY, CnY2n−1, wherein
- n=3-7 inclusively;
- and
- each Y is independently:
- H, F, Cl, Br, or I,
- wherein said compound and said corticosteroid are administered simultaneously or within 14 days of each other, in amounts and for a duration sufficient to treat said patient.
A pharmaceutical composition comprising
- (i) a corticosteroid;
- (ii) a compound having the formula:
- 10
- wherein each Z and each Z′ is, independently, N, O, C,
- 11
- wherein when Z or Z′ is O or
- 12
- then p=1,
- when Z or Z′ is N,
- 13
- then p=2,
- when Z or Z′ is C, then p=3;
- each R1 is, independently, X, OH, N-alkyl, a branched or unbranched alkyl group having 1 to 20 carbon atoms, a heterocycle, or, when p>1, two R1 groups from a common Z or Z′ atom, in combination with each other, represent —(CY2)k—, wherein k is an integer between 4 and 6, inclusive;
- each X is, independently, Y, CY3, C(CY3)3, CY2CY3, (CY2)1-5OY, CnY2n−1, wherein
- n=3-7 inclusively;
- and
- each Y is independently:
- H, F, Cl, Br, or I;
- and
- (iii) a pharmaceutically acceptable excipient.
A pharmaceutical pack comprising
- (i) a corticosteroid;
- and
- (ii) a compound having the formula:
- 14
- wherein each Z and each Z′ is, independently, N, O, C,
- 15
- wherein when Z or Z′ is O or
- 16
- then p=1,
- when Z or Z′ is N,
- 17
- then p=2,
- when Z or Z′ is C, then p=3;
- each R1 is, independently, X, OH, N-alkyl, a branched or unbranched alkyl group having 1 to 20 carbon atoms, a heterocycle, or, when p>1, two R1 groups from a common Z or Z′ atom, in combination with each other, represent —(CY2)k—, wherein k is an integer between 4 and 6, inclusive;
- each X is, independently, Y, CY3, C(CY3)3, CY2CY3, (CY2)1-5OY, CnY2n−1, wherein
- n=3-7 inclusively;
- and
- each Y is independently:
- H, F, Cl, Br, or I.
A method for treating a patient who has an immunoinflammatory disorder or is at risk for developing an immunoinflammatory disorder, said method comprising administering to said patient:
- (a) two or more corticosteroids;
- and
- (b) a compound having the formula:
- 18
- wherein each Z and each Z′ is, independently, N, O, C,
- 19
- wherein when Z or Z′ is O or
- 20
- then p=1,
- when Z or Z′ is N,
- 21
- then p=2,
- when Z or Z′ is C, then p=3;
- each R1 is, independently, X, OH, N-alkyl, a branched or unbranched alkyl group having 1 to 20 carbon atoms, a heterocycle, or, when p>1, two R1 groups from a common Z or Z′ atom, in combination with each other, represent —(CY2)k—, wherein k is an integer between 4 and 6, inclusive;
- each X is, independently, Y, CY3, C(CY3)3, CY2CY3, (CY2)1-5OY, CnY2n−1, wherein
- n=3-7 inclusively;
- and
- each Y is independently:
- H, F, Cl, Br, or I;
- wherein each of said compound and said two or more corticosteroids are administered in amounts sufficient to treat said patient.
A method for identifying combinations of compounds useful for treating a patient having an immunoinflammatory disorder, said method comprising the steps of:
- (a) contacting immune cells in vitro with (i) a first compound selected from the group consisting of dipyridamole, fludrocortisone, and prednisolone, and (ii) a candidate compound;
- and
- (b) determining whether the combination of said first compound and said candidate compound reduces TNFα levels in said immune cells relative to immune cells contacted with said first compound but not contacted with said candidate compound, or peripheral blood mononuclear cells contacted with said candidate compound but not with said first compound, wherein a reduction of said TNFα levels identifies said combination as a combination that is useful for treating a patient having an immunoinflammatory disorder.
A method for treating a patient who has an immunoinflammatory disorder or is at risk for developing an immunoinflammatory disorder, said method comprising administering to said patient (i) dipyridimole and (ii) prednisolone or fludricortisone within one hour of each other in amounts and for a duration sufficient to treat said patient.
Dependencies are inferred from the claim text.