THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

• US 20170057994A1
• Filed: 11/09/2016
• Published: 03/02/2017
• Est. Priority Date: 07/25/2013
• Status: Abandoned Application

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Lemieux, Rene M., Popovici-Muller, Janeta, Travins, Jeremy M., Cai, Zhenwei, Cui, Dawei, Zhou, Ding
• Application Number:
  US15/347,407
• Publication Number:
  US 20170057994A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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, which is selected from any one of the 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.