Antagonism of human formyl peptide receptor for treatment of disease
AssigneeNikan Pharmaceuticals, LLC
InventorJohn D. Benson
Life of this patent
Estimating the term…
Abstract
The present invention is directed to modulators of eosinophilic and neutrophilic function and the use of such modulators for treatment of eosinophil-associated and neutrophil-associated diseases.
Claims46
A cyclosporine H derivative of formula I:
- and pharmaceutically acceptable salts and solvates thereof, wherein
- R1 is
- R2 is C1-C6 alkyl, C3-C6 cycloalkyl, or hydroxy-C1-C6 alkyl;
- R4, R5 and R11 are independently C1-C6 alkyl or C3-C6 cycloalkyl;
- R8 is C1-C6 alkyl, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl;
- R12, R13, R14 and R15 are independently H or methyl;
- R21 is H, methyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or phenyl;
- R23 is H or C1-C6 alkyl;
- R24 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, —NHR21, hydroxy or C1-C6 alkoxy;
- R25 is C1-C6 alkyl;
- wherein R21, R24 and R25 are optionally substituted one or more times with —OH, —CHO, or —CO2H;
- and
- wherein any two adjacent carbon atoms of R21, R22, R24 and R25, together with an oxygen atom, may form an epoxide;
- R22, R26, R27, R28 and R29 are independently H, halogen, cyano, nitro, methyl, C1-C6 alkyl, C2-C6 alkenyl, —OR30, —C(O)R30, —OC(O)R30, —C(O)OR30, —S(O)R30, —SO2R30, —SO3R30, —OSO2R30, —OSO3R30, —PO2R30R31, —OPO2 R30R31, —PO3 R30R31, —OPO3 R30R31, —N(R30)R31, —C(O)N(R30)R31, —C(O)NR30NR31SO2R32, —C(O)NR30SO2R32, —C(O)NR30CN, —SO2N(R30)R31, —SO2N(R30)R31, —NR32C(O)R30, —NR32C(O)OR30 or —NR32C(O)N(R30)R31;
- or R26 and R27 are together —O—;
- or R28 and R27 together, or R22 and R26 together, are independently —O—;
- or R22 and R29 together are —O—;
- or R28, together with the carbon to which it is bonded, is —C(═O)R30, —CO2R30, —CH2OR30, —CH2OC(O)R30, —CH(OR30)2, —C(O)N(R30R31), —C(═NR31)R30, —C(═NOR31)R30, or —C(═NNR31)R30;
- provided that at least one pair of R27 and R28, R26 and R27, or R22 and R26 do not form a ring;
- and
- R30, R31 and R32 are each independently —H or an optionally substituted aliphatic, cycloaliphatic, benzyl, or aryl, or —N(R30)R31 together is an optionally substituted heterocyclic group, or —CH(OR30)2 together is a cyclic acetal group.
2-6. (canceled)
A cyclosporine H derivative of formula I:
- and pharmaceutically acceptable salts and solvates thereof, wherein
- R1 is CH(OH)CH(CH3)CH2CH2R17R18;
- wherein:
- R17 is —CHCHCH2CH2—, —CHCHCH2C(O)—, —(CH2)4— or —(CH2)3C(O)—;
- and
- R18 is OH, O—C1-C6 alkyl, OC(O)—C1-C6 alkyl, NH2, NH—C1-C6 alkyl or NHC(O)—C1-C6 alkyl;
- R2 is C1-C6 alkyl, C3-C6 cycloalkyl, or hydroxy-C1-C6 alkyl;
- R4, R5 and R11 are independently C1-C6 alkyl or C3-C6 cycloalkyl;
- R8 is C1-C6 alkyl, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl;
- R12, R13, R14 and R15 are independently H or methyl.
8-14. (canceled)
16-19. (canceled)
A method of treating a subject suffering from an eosinophil-associated disease, comprising administering a therapeutically effective amount of cyclosporine H or dihydro cyclosporine H, such that said subject is treated.
25-27. (canceled)
29-32. (canceled)
(canceled)
A method for decreasing eosinophil mobilization in a subject, comprising administering to said subject an effective amount of cyclosporine H or dihydro cyclosporine H, such that eosinophil mobilization in said subject is decreased.
36-39. (canceled)
A method for decreasing the level of circulating eosinophils in a subject, comprising administering to said subject cyclosporine H or dihydro cyclosporine H in an amount sufficient to decrease said level of circulating eosinophils in said subject.
42-45. (canceled)
47-51. (canceled)
A method for decreasing the accumulation of eosinophils at sites associated with a disease related to increased eosinophilic function or decreasing localized eosinophil cell numbers in a subject, comprising administering to said subject a therapeutically effective amount of cyclosporine H or dihydro cyclosporine H, such that the accumulation of eosinophils at sites associated with a disease related to increased eosinophilic function or localized eosinophil cell numbers in said subject is decreased.
53-60. (canceled)
A method of treating a subject suffering from a chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective amount of a formyl peptide receptor (FPR) antagonist, such that said subject is treated.
63-64. (canceled)
A method of treating a subject suffering from a chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective amount of cyclosporine H, dihydro cyclosporine H, or pharmaceutically acceptable salts and solvates thereof, such that said subject is treated.
(canceled)
A method of treating a subject suffering from emphysema, comprising administering a therapeutically effective amount of a formyl peptide receptor (FPR) antagonist, such that said subject is treated.
69-70. (canceled)
A method of treating a subject suffering from emphysema, comprising administering a therapeutically effective amount of cyclosporine H or dihydrocyclosporine H, such that said subject is treated.
A method of treating a subject suffering from an inflammatory disease, comprising administering a therapeutically effective amount of a formyl peptide receptor (FPR) antagonist, such that said subject is treated.
75-76. (canceled)
A method of treating a subject suffering from an inflammatory disease, comprising administering a therapeutically effective amount of dihydro cyclosporine H, or pharmaceutically acceptable salts and solvates thereof, such that said subject is treated.
79-82. (canceled)
A method of treating a subject suffering from an inflammatory disease, comprising administering a therapeutically effective amount of dihydrocyclosporine H.
Dependencies are inferred from the claim text.