PDE4B inhibitors and uses therefor
1 Assignment
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Accused Products
Abstract
Compounds active on phosphodiesterase PDE4B are provided. Also provided herewith are compositions useful for treatment of PDE4B-mediated diseases or conditions, and methods for the use thereof.
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Citations
51 Claims
- 1. A compound having the chemical structure
- 9. A compound having the chemical structure
- 16. A compound having structure
- 23. A compound having the chemical structure
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30. A method for treating a human patient suffering from or at risk of a disease or condition for which PDE4B modulation provides a therapeutic benefit, said method comprising
administering to said patient an effective amount of a PDE4B modulator having a chemical structure of wherein: -
X is selected from the group consisting of O, S, and Nk7;
R1, R2, R4, R5, R7, R9 and R10 are independently selected from the group consisting of hydrogen, acyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl, provided, however, that R1 and R2, or R4 and R5, or R9 and R10, or R2 and R3 can combine to form an optionally substituted heterocycle;
R3 is selected from the group consisting of cyano, nitro, —
C(Z)R8, —
S(O2)NR9R10, —
S(O2)R11, and optionally substituted lower alkyl;
Y and Z are independently selected from the group consisting of O and S;
R6 and R8 are selected from the group consisting of, hydroxy, alkoxy, thioalkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and optionally substituted heterocycle; and
R11 is independently selected from the group consisting of hydroxy, alkoxy, thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl. - View Dependent Claims (31, 32)
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33. A method for treating a human patient suffering from or at risk of a disease or condition for which PDE4B modulation provides a therapeutic benefit, said method comprising
administering to said patient an effective amount of a PDE4B modulator having a chemical structure of wherein: -
X is selected from the group consisting of S, O, and NR15;
R12 is selected from the group consisting of hydrogen, —
OR16, —
SR16, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R13 is selected from the group consisting of —
OR16, —
SR16, and optionally substituted amine;
R14 is selected from the group consisting of-OR16, —
SR16, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —
C(Z)R19, —
C(Z)NR20R21, —
S(O2)NR20R21, and —
S(O2)R22;
R15 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —
C(Z)R19, —
C(Z)NR20R21, —
S(O2)NR20R21, and —
S(O2)R22;
R16 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and —
C(Z)R19;
Z is selected from the group consisting of O and S;
R19 is selected from the group consisting of hydroxy, alkoxy, thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
R20 and R21 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl, or R20 and R20 may combine to form a 5-7 membered carbocyclic or heterocyclic ring; and
R22 is selected from the group consisting of hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl. - View Dependent Claims (34, 35)
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36. A method for treating a human patient suffering from or at risk of a disease or condition for which PDE4B modulation provides a therapeutic benefit, said method comprising
administering to said patient an effective amount of a PDE4B modulator having a chemical structure of wherein R23 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; - or
R23 can combine with R26, (R25)m or both R26 and (R25)m,to form a 5-7 membered optionally substituted carbocyclic ring system or an optionally substituted heterocyclic ring system;
R24 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
provided, however, that if R24 is substituted aryl, then said aryl substitution is not substituted isopropyl;
if R24 is optionally substituted lower alkenyl, then any double bond of R24 is removed from the sulfonyl S to which R24 is bonded by at least two bonds; and
if R24 is optionally substituted lower alkynyl, then any triple bond of R24 is removed from the sulfonyl S to which R24 is bonded by at least two bonds;
R25, if present, is optionally substituted lower alkylene;
R26 is an optionally substituted carbocyclic or an optionally substituted heterocyclic structure having 3-14 ring atoms, wherein when R26 is aryl, then the substitution of R26, if present, is not substituted isopropyl.;
m is 0-3. - View Dependent Claims (37, 38)
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42. A method for optimizing ligands specific for PDE4B, said method comprising:
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identifying a compound that binds to a plurality of phosphodiesterases; and
determining whether a derivative of said compound has greater specificity for PDE4B than said compound. - View Dependent Claims (43, 44, 45, 46, 47)
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48. A modified compound, said compound comprising:
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a PDE4B binding compound, and a linker moiety attached thereto at an energetically allowed site for binding of said modified compound to PDE4B. - View Dependent Claims (49, 50, 51)
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Specification