Small-molecule modulators of Trp-p8 activity
View Patent ↗Provided are small-molecule Trp-p8 modulators, including Trp-p8 agonists and Trp-p8 antagonists, and compositions comprising small-molecule Trp-p8 agonists as well as methods for identifying and characterizing novel small-molecule Trp-p8 modulators and methods for decreasing viability and/or inhibiting growth of Trp-p8 expressing cells, methods for activating Trp-p8-mediated cation influx, methods for stimulating apoptosis and/or necrosis, and related methods for the treatment of diseases, including cancers such as lung, breast, colon, and/or prostate cancers as well as other diseases, such as benign prostatic hyperplasia, that are associated with Trp-p8 expression.
1. A method for treatment of benign prostatic hyperplasia (BPH), an enlarged prostate, acute urinary retention, or symptoms thereof or reducing prostate size in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I-B:
wherein
R 1 is selected from H, alkyl, heteroalkyl, aryl, and arylalkyl;
R 2a is selected from aryl, alkyl, heteroalkyl, and arylalkyl;
R 3 is selected from alkyl, heteroalkyl, and arylalkyl;
R 4 is selected from H, alkyl, heteroalkyl, and arylalkyl; and
R 3 and R 4 together with the nitrogen group form an aliphatic amine;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein R 1 is H.
3. The method of claim 1 wherein R 3 is alkyl, heteroalkyl or arylalkyl, each of which has 1, 2, 3, 4, 5, or 6 carbons.
4. The method of claim 3 wherein R 3 is selected from methylene, ethylene, propylene, and butylene.
5. The method of claim 1 wherein R 4 is selected from H and methyl.
6. The method of claim 1 wherein R 2a is a group selected from phenyl, furan, methylpyrrole, methylbenzoate, aminophenyl, hydroxyphenyl, cyanophenyl, and methoxyphenyl.
7. The method of claim 1 wherein the moiety:
is selected from the group consisting of 2-(2-amino-ethyl)-5-furan-2-yl-2H-pyrazol-3-yl, 2-(2-amino-propyl)-5-phenyl-2H-pyrazol-3-yl, 2-(2-amino-ethyl)-5-phenyl-2H-pyrazol-3-yl, 2-(2-amino-ethyl)-5-(1-methyl-1H-pyrrol-2-yl)-2H-pyrazol-3-yl, 2-(2-amino-propyl)-5-phenyl-2H-pyrazol-3-yl, 2-(2-amino-ethyl)-5-(4-amino-phenyl)-2H-pyrazol-3-yl, 2-(2-amino-ethyl)-5-(4-hydroxy-phenyl)-2H-pyrazol-3-yl, 2-(2-methylamino-ethyl)-5-phenyl-2H-pyrazol-3-yl, 2-(2-amino-propyl)-5-phenyl-2H-pyrazol-3-yl, 2-(2-amino-ethyl)-5-(3-cyano-phenyl)-2H-pyrazol-3-yl, 2-(2-amino-ethyl)-5-(3-methoxy-phenyl)-2H-pyrazol-3-yl, 4-{1-(2-Amino-ethyl)-1H-pyrazol-3-yl}-benzoic acid methyl ester, 2-(2-amino-ethyl)-5-(3-amino-phenyl)-2H-pyrazol-3-yl, and 2-(2-amino-ethyl)-5-(3-hydroxy-phenyl)-2H-pyrazol-3-yl.
8. A method of claim 1 , said method further comprising administration of one or more benign prostatic hyperplasia (BPH) therapeutic agents in combination with the compound of formula I.
9. The method of claim 8 wherein said combination is administered simultaneously.
10. The method of claim 8 wherein said mammal is a human.
11. A method of preparing a pharmaceutical composition useful for treating benign prostatic hyperplasia (BPH), comprising mixing a compound of Formula I-B:
wherein
R 1 is selected from H, alkyl, heteroalkyl, aryl, and arylalkyl;
R 2a is selected from aryl, alkyl, heteroalkyl, and arylalkyl;
R 3 is selected from alkyl, heteroalkyl, and arylalkyl;
R 4 is selected from H, alkyl, heteroalkyl, and arylalkyl; and
R 3 and R 4 together with the nitrogen group form an aliphatic amine;
or a pharmaceutically acceptable salt thereof,
with a pharmaceutically acceptable carrier or agent.