THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE

• US 20180194802A1
• Filed: 11/10/2017
• Published: 07/12/2018
• Est. Priority Date: 01/19/2012
• Status: Active Grant

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Popovici-Muller, Janeta, Lemieux, Rene M., Travins, Jeremy, Cai, Zhenwei, Cui, Dawei, Zhou, Ding
• Granted Patent: US 10,640,534 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 205/08 with one oxygen atom directly attached in position 2, e.g. beta-lactams
• CPC Class Codes: C07D 207/26 2-Pyrrolidones
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07K 5/06078 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N

Abstract

Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein:

2. The compound of claim 1, wherein:

R¹ is C₄-C₆ carbocyclyl optionally substituted with one to three R⁷ groups;

each R² and R³ is independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R⁷ groups;

R⁴ is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R⁷ groups;

ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R⁵ groups;

each R⁵ and R⁷ is independently halo;

—

CF₃;

—

CN;

—

OR⁶;

—

N(R⁶)₂;

—

C(O)C₁-C₄ alkyl;

C₁-C₄ haloalkyl;

C₁-C₄ alkyl optionally substituted with —

OR⁶ or —

N(R⁶)₂;

—

O—

C₁-C₄ alkyl optionally substituted with halo, —

OR⁶ or —

N(R⁶)₂;

—

SO₂N(R⁶)₂;

—

S(O)—

C_1-4 alkyl;

—

SO₂(C₁-C₄ alkyl);

—

NR⁶SO₂R⁶;

C₃-C₅ carbocyclyl optionally substituted with one or two R⁶ groups;

—

O—

(C₃-C₆ carbocyclyl optionally substituted with one or two R⁶ groups);

5-6 membered heteroaryl;

—

C₁-C₄ alkyl-C(O)O—

C₁-C₄ alkyl;

or —

C(O)O—

C₁-C₄ alkyl;

or

each R⁶ is independently H or C₁-C₄ alkyl.

3. The compound of claim 1, wherein each R² and R³ is independently aryl optionally substituted with one to three R⁷ groups.

4. The compound of claim 1 having formula II-a,

5. The compound of claim 1, wherein R¹ is C₄ or C₆ cycloalkyl optionally substituted with one to two R⁷ groups and R⁷ associated with R¹ is halo.

6. The compound of claim 5, wherein R¹ is

7. The compound of claim 5, wherein ring A is:

8. The compound of claim 7, wherein ring A is:

9. The compound of claim 7, wherein R⁴ is aryl or heteroaryl, each aryl or heteroaryl is optionally substituted with one to three R⁷ groups.

10. The compound of claim 9, wherein R⁴ is:

11. The compound of claim 10, wherein R⁴ is:

12. The compound of claim 1 wherein the compound is selected from any one of compounds from Table 1.

13. A pharmaceutical composition comprising a compound of claim 1;

and a pharmaceutically acceptable carrier.

14. The composition of claim 13, further comprising a second therapeutic agent useful in the treatment of cancer.

15. 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 13.

16. The method of claim 15, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.

17. The method of claim 15, 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.

18. The method of claim 17, further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of cancer.

19. A method of making a compound of structural formula (A) or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein:

20. The method of claim 19 wherein the Buchwald conditions comprise the use of a palladium catalyst, a ligand and a base in an organic solvent.

21. The method of claim 20 wherein the solvent is dioxane, the palladium catalyst is Pd₂(dba)₃, the ligand is Xphos and the base is cesium carbonate.

22. A method of making a compound of structural formula (B) or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof,

23. The method of claim 22 wherein the Ugi coupling takes place in a solvent.

24. The method of claim 23 wherein the solvent is methanol.