Methods of treating bone mass diseases
The present invention provides methods and therapeutic agents for lowering or increasing serum serotonin levels in a patient in order to increase or decrease bone mass, respectively. In preferred embodiments, the patient is known to have, or to be at risk for, a low bone mass disease such as osteoporosis and the agents are TPH1 inhibitors or serotonin receptor antagonists.
1. A method of treating osteoporosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a TPH1 inhibitor that lowers the level of peripheral serotonin in the patient;
where the TPH1 inhibitor is selected from the group consisting of:
and pharmaceutically acceptable salts thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond (i.e., A is directly bound to D), —O—, —S—, —C(O)—, —C(R4)═, ═C(R 4 )—, —C(R 3 R 4 )—, —C(R 4 )═C(R 4 )—, —C≡C—, —N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —C(R 3 R 4 )N(R 5 )—, —N(R 5 )C(R 3 R 4 )—, —ONC(R 3 )—, —C(R 3 )NO—, —C(R 3 R 4 )O—, —OC(R 3 R 4 )—, —S(O 2 )—, —S(O 2 )N(R 5 )—, —N(R 5 )S(O 2 )—, —C(R 3 R 4 )S(O 2 )—, or —S(O 2 )C(R 3 R 4 )—; D is optionally substituted aryl or heterocycle; R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R 5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3; and
and pharmaceutically acceptable salts thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond (i.e., A is directly bound to D), —O—, —S—, —C(O)—, —C(R4)═, ═C(R 4 )—, —C(R 3 R 4 )—, —C(R 4 )═C(R 4 )—, —C≡C—, —N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —C(R 3 R 4 )N(R 5 )—, —N(R 5 )C(R 3 R 4 )—, —ONC(R 3 )—, —C(R 3 )NO—, —C(R 3 R 4 )O—, —OC(R 3 R 4 )—, —S(O 2 )—, —S(O 2 )N(R 5 )—, —N(R 5 )S(O 2 )—, —C(R 3 R 4 )S(O 2 )—, or —S(O 2 )C(R 3 R 4 )—; D is optionally substituted aryl or heterocycle; E is optionally substituted aryl or heterocycle; R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R 5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
2. The method of claim 1 where the agent is selected from the group consisting of:
and pharmaceutically acceptable salts thereof; and
and pharmaceutically acceptable salts thereof.