THERAPEUTIC COMPOUNDS AND COMPOSITIONS

• US 20150299115A1
• Filed: 10/11/2013
• Published: 10/22/2015
• Est. Priority Date: 10/15/2012
• Status: Active Grant

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Popovici-Muller, Janeta, Salituro, Francesco G., Saunders, Jeffrey O., Travins, Jeremy, Yan, Shunqi
• Granted Patent: US 10,202,339 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4406 only substituted in position 3, e.g. zimeldine nicotinic acid A61K31/455
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 311/44 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 267/10 : not condensed with other rings
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 309/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links

Abstract

Provided are aryl sulfonamide diarylurea derivative compounds that are inhibitors of mutant isocitrate dehydrogenase 1/2 (IDH 1/2), useful for treating cancer. Also provided are methods of treating cancer comprising administering to a subject in need thereof a compound described herein. Cancers that are treatable by the compounds of the invention are glioblastoma, myelodysplastic syndrome, myeloproliferative neoplasm, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, and non-Hodgkin'"'"'s lymphoma (NHL).

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt or hydrate thereof:

2. The compound of claim 1, wherein the compound is a compound of Formula (II):

3. The compound of claim 1, wherein the compound is a compound of Formula (III):

4. The compound of claim 1, wherein the compound is a compound of Formula (IV):

5. The compound of claim 1, wherein the compound is selected from Table 1.

6. The compound of claim 1, wherein the compound is selected from Table 2.

7. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier.

8. The composition of claim 7, further comprising a second therapeutic agent useful in the treatment of cancer.

9. A method of treating a cancer characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α

-ketoglutarate to R(−

)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim 7.

10. The method of claim 9, wherein the IDH2 mutation is an IDH2 R140Q or R172K mutation.

11. The method of claim 10, wherein the IDH2 mutation is an IDH2 R140Q mutation.

12. The method of claim 11, wherein the cancer is selected from glioblastoma (or glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas or angioimmunoblastic non-Hodgkin'"'"'s lymphoma (NHL).

13. A method of treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α

-ketoglutarate to R(−

)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim 7.

14. The method of claim 13, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.

15. The method of claim 14, wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer in a patient.

16. The method of claim 9, further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of cancer.