US 6,720,427 B2 · Thiazole derivatives

Abstract

The invention provides compounds of formula 1 wherein R1, R3, and R4 are as defined, and their pharmaceutically acceptable salts. Compounds of formula 1 are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula 1 for treating diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission are described. Also described are pharmaceutical compositions and methods comprising compounds of formula 1 for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.

A compound of the formula

wherein R1 is a straight chain or branched (C2-C8)alkyl, a straight chain or branched (C2-C8)alkenyl, a straight chain or branched (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14) aryl, (5-14 membered) heteroaryl, or ABN-;
and wherein R1 is optionally substituted with from one to six substituents R5 independently selected from F, Cl, Br, I, nitro, cyano, —CF3, —NR7R8, —NR7C(═O)R8, —NR7C(═O)OR8, —NR7C(═O)NR8R9, —NR7S(═O)2R8, —NR7S(═O)2NR8R9, —OR7, —OC(═O)R7, —OC(═O)OR7, —C(═O)OR7, —C(═O)R7, —C(═O)NR7R8, —OC(═O)NR7R8, —OC(═O)SR7, —SR7, —S(═O)R7, —S(═O)2R7, —S(═O)2NR7R8, and R7;
A and B are each independently selected from straight or branched (C1-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8)alkynyl, (C3-C6)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, and (5-11 membered) heterocycloalkyl;
or A and B may be connected to form a 3-8 membered heterocyclic ring optionally containing one or two double bonds and optionally containing one or two further hetero atoms selected independently from O, S, and N;
and A and B, or the heterocyclic ring formed thereby, can be optionally independently substituted with from one to six substituents R5 independently selected from F, Cl, Br, I, nitro, cyano, —CF3, —NR7R8, —NR7C(═O)R8, —NR7C(═O)OR8, —NR7C(═O)NR8R9, —NR7S(═O)2R8, —NR7S(═O)2NR8R9, —OR7, —OC(═O)R7, —OC(═O)OR7, —C(═O)OR7, —C(═O)R7, —C(═O)NR7R8, —OC(═O)NR7R8, —OC(═O)SR7, —SR7, —S(═O)R7, —S(═O)2R7, —S(═O)2NR7R8, and R7;
R3 is —C(═O)NR9—, —C(═O)O—, —C(═O)(CR10R11)n—, or —(CR10R11)n—;
R4 is a straight chain or a branched (C1-C8)alkyl, a straight chain or a branched (C2-C8)alkenyl, a straight chain or branched (C2-C8 alkynyl), (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, or (5-14 membered) heteroaryl;
and wherein R4 is optionally substituted with from one to three substituents R6 independently selected from F, Cl, Br, I, nitro, cyano, —CF3, —NR7R8, —NR7C(═O)R8, —NR7C(═O)OR8, —NR7C(═O)NR8R9, —NR7S(═O)2R8,—NR7S(═O)2NR8R9, —OR7, —OC(═O)R7, —OC(═O)OR7, —C(═O)OR7, —C(═O)R7, —C(═O)NR7R8, —OC(═O)NR7R8, —OC(═O)SR7, —SR7, —S(═O)R7, —S(═O)2R7, —S(═O)2NR7R8, or R7;
each R7, R8, and R9 is independently selected from H, straight chain or branched (C1-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl), (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, and (5-14 membered) heteroaryl, wherein R7, R8, and R9 are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO2, —CN, —CF3, —NR10R11, —NR10C(═O)R11, —NR10C(═O)OR11, —NR10C(═O)NR11R12, —NR10S(═O)2R11, —NR10S(═O)2NR11R12, —OR10, OC(═O)R10, —OC(═O)OR10, —OC(═O)NR10R11, —OC(═O)SR10, —SR10, —S(═O)R10, —S(═O)2R10, —S(═O)2NR10R11, —C(═O)R10, —C(═O)OR10, —C(═O)NR10R11, and R10;
or, when R7 and R8 are as in NR7R8, they may instead optionally be connected to form with the nitrogen of NR7R8 to which they are attached a heterocycloalkyl moiety of from three to seven ring members, said heterocycloalkyl moiety optionally comprising one or two further heteroatoms independently selected from N, O, and S;
each R10, R11, and R12 is independently selected from H, straight chain or branched (C1-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl), (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, and (5-14 membered) heteroaryl, wherein R10, R11, and R12 are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO2, —CN, —CF3, —NR13R14, —NR13C(═O)R14, —NR13C(═O)OR14, —NR13C(═O)NR14R15, —NR13S(═O)2R14, —NR13S(═O)2NR14R15, —OR13, —OC(═O)R13, —OC(═O)OR13, —OC(═O)NR13R14, —OC(═O)SR13, —SR13, —S(═O)R13, —S(═O)2R13, —S(═O)2NR13R14, —C(═O)R13, —C(═O)OR13, —C(═O)NR13R14, and R13;
each R13, R14, and R15 is independently selected from H, straight chain or branched (C1-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl), (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, and (5-14 membered) heteroaryl, wherein R13, R14, and R15 are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO2, —CN, —CF3, —NR16R17, —NR16C(═O)R17, —NR16C(═O)OR17, —NR16C(═O)NR17R18, —NR16S(═O)2R17, —NR16S(═O)2NR17R18, —OR16, —OC(═O)R16, —OC(═O)OR16, —OC(═O)NR16R17, —OC(═O)SR16, —SR16, —S(═O)R16, —S(═O)2R16, —S(═O)2NR16R17, —C(═O)R16, —C(═O)OR16, —C(═O)NR16R17, and R16;
each R16, R17, and R18 is independently selected from H, straight chain or branched (C1-C8)alkyl, straight chain or branched (C2-C8)alkenyl, straight chain or branched (C2-C8 alkynyl), (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl, and (5-14 membered) heteroaryl;
n is 0, 1, 2, or 3;
wherein R10 and R11 in —C(═O)(CR10R11)n— and —(CR10R11)n— are for each iteration of n defined independently as recited above;
or a pharmaceutically acceptable salt thereof.

13 more elements

Thiazole derivatives

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Thiazole derivatives

Life of this patent

Abstract

Claims24