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US 12,606,520 B2Granted
Calpain-2 inhibitor compounds and methods of treatment
AssigneeWestern University of Health Sciences
InventorMichel Baudry
Life of this patent
Estimating the term…
Abstract
Compounds of Formula (I) or (X) are provided including for treatment of disorders such as a disorder or symptom associated with neuronal cell death. In one aspect, compounds which are selective inhibitors of calpain-2 are provided. Preferred compounds can be useful to treat acute neurodegeneration.
Claims31
A compound of the following Formula (I),
- wherein A is carbocyclic aryl, or heteroaryl
- R1 is a non-hydrogen substituent;
- n is an integer of from 0 (where the ring A is unsubstituted) to the value permitted by the valence of A;
- L1 and L2 are each the same or different optionally substituted alkylene having 1 to 6 carbons;
- R2 is non-hydrogen substituent,
- R4 and R5 are independently hydrogen, or unsubstituted C1-C6 alkyl such as methyl;
- and
- pharmaceutically acceptable salts thereof.
5 more elements
A compound of the following Formula (X),
- wherein:
- A is C1-C6 alkyl, carboxyl (—C(O)O—), aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
- B is carbocyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
- L1 is a bond, or substituted or unsubstituted C1-C6 alkylene,
- L2 is a bond, substituted or unsubstituted C1-C6 alkylene, or —S(O)2—,
- Each R1 is independently C1-C6 alkyl, halogen, cyano, nitro, C1-C6 alkoxy, aryl, heterocycloaryl, heterocycloalkyl, —C(O)(CH2)mN(Ra)(Rb), —O(CH2)mN(Ra)(R), —CONH(CH2)mN(Ra)(Rb), —C(O)NH—CH(Rc)(Rd), —C(O)OCH(R)(Rd), —(CH2)mN(Ra)(R), —(CH2)mN(Ra)C(O)Rb, —(CH2)mN(Ra)C(O)ORb, —O(CH2)mRc, —O(CH2)mOH, —S(O)2Rb, or —O(Ph)X;
- R2 is unsubstituted C1-C6 alkyl;
- Each R6 is independently C1-C6 alkyl, halogen, cyano, nitro, C1-C6 alkoxy, aryl, heterocycloaryl, heterocycloalkyl —C(O)(CH2)mN(Ra)(Rb), —O(CH2)mN(Ra)(R), —CONH(CH2)mN(Ra)(Rb), —C(O)NH—CH(Rc)(Rd), —C(O)OCH(R)(Rd), —(CH2)mN(Ra)(R), —(CH2)mN(Ra)C(O)Rb, —(CH2)mN(Ra)C(O)ORb, —O(CH2)mRc, —O(CH2)mOH, or —O(Ph)X;
- Two R6 together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl;
- Ra, Rb, Rc, and Rd are independently hydrogen, C1-C6 alkyl that may be optionally substituted with halogen, —OH, amine, or unsubstituted C3-6 cycloalkyl;
- X is halogen;
- n is independently an integer from 0 to 12;
- m is independently an integer from 0 to 6;
- k is independently an integer from 0 to 12;
- and pharmaceutically acceptable salts thereof.
12 more elements
A compound has the following Formula (XIII),
- wherein:
- Each R1 is independently C1-C6 alkyl, halogen, cyano, nitro, C1-C6 alkoxy, aryl, heterocycloaryl, heterocycloalkyl, —C(O)(CH2)mN(Ra)(Rb), —O(CH2)mN(Ra)(Rb), —CONH(CH2)mN(Ra)(Rb), —C(O)NH—CH(Rc)(Rd), —C(O)OCH(R)(Rd), —(CH2)mN(Ra)(R), —(CH2)mN(Ra)C(O)Rb, —(CH2)mN(Ra)C(O)ORb, —O(CH2)mRc, —O(CH2)mOH, —S(O)2Rb, or —O(Ph)X;
- R2 is unsubstituted C1-C6 alkyl;
- Each R6 is independently C1-C6 alkyl, halogen, cyano, nitro, C1-C6 alkoxy, aryl, heterocycloaryl, heterocycloalkyl —C(O)(CH2)mN(Ra)(Rb), —O(CH2)mN(Ra)(R), —CONH(CH2)mN(Ra)(Rb), —C(O)NH—CH(Rc)(Rd), —C(O)OCH(R)(Rd), —(CH2)mN(Ra)(R), —(CH2)mN(Ra)C(O)Rb, —(CH2)mN(Ra)C(O)ORb, —O(CH2)mRc, —O(CH2)mOH, or —O(Ph)X;
- Two R6 together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl;
- Ra, Rb, Rc, and Rd are independently hydrogen, C1-C6 alkyl that may be optionally substituted with halogen, —OH, amine, or unsubstituted C3-6 cycloalkyl;
- X is halogen;
- n is independently an integer from 0 to 5;
- m is independently an integer from 0 to 6;
- k is independently an integer from 0 to 5;
- p is independently an integer from 0 to 6;
- and pharmaceutically acceptable salts thereof;
- and pharmaceutically acceptable salts thereof.
10 more elements
A compound has the following Formula (XIV),
- wherein:
- Each R1 is independently C1-C6 alkyl, halogen, cyano, nitro, C1-C6 alkoxy, aryl, heterocycloaryl, heterocycloalkyl, —C(O)(CH2)mN(Ra)(Rb), —O(CH2)mN(Ra)(Rb), —CONH(CH2)mN(Ra)(Rb), —C(O)NH—CH(Rc)(Rd), —C(O)OCH(R)(Rd), —(CH2)mN(Ra)(Rb), —(CH2)mN(Ra)C(O)Rb, —(CH2)mN(Ra)C(O)ORb, —O(CH2)mRc, —O(CH2)mOH, —S(O)2Rb, or —O(Ph)X;
- R2 is unsubstituted C1-C6 alkyl;
- Each R6 is independently C1-C6 alkyl, halogen, cyano, nitro, C1-C6 alkoxy, aryl, heterocycloaryl, heterocycloalkyl —C(O)(CH2)mN(Ra)(Rb), —O(CH2)mN(Ra)(Rb), —CONH(CH2)mN(Ra)(Rb), —C(O)NH—CH(Rc)(Rd), —C(O)OCH(R)(Rd), —(CH2)mN(Ra)(Rb), —(CH2)mN(Ra)C(O)Rb, —(CH2)mN(Ra)C(O)ORb, —O(CH2)mRc, —O(CH2)mOH, or —O(Ph)X;
- Two R6 together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl;
- Ra, Rb, Rc, and Rd are independently hydrogen, C1-C6 alkyl that may be optionally substituted with halogen, —OH, amine, or unsubstituted C3-6 cycloalkyl;
- X is halogen;
- n is independently an integer from 0 to 5;
- m is independently an integer from 0 to 6;
- k is independently an integer from 0 to 5;
- p is independently an integer from 0 to 6;
- and pharmaceutically acceptable salts thereof.
9 more elements
Dependencies are inferred from the claim text.