Thiosemicarbazones inhibitors of lysophosphatidic acid acyltransferase and uses thereof

Patent metadata

Field	Value
Publication number	US-9622993-B2
Application number	US-201515302640-A
Country	US
Kind code	B2
Filing date	Apr 7, 2015
Priority date	Apr 7, 2014
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

Lysophosphatidic acid acyltransferase-beta (LPAAT-β) catalyzes the production of phosphatidic acid (PA) from lysophosphatidic acid (LPA). The lipid cofactor PA contributes to the activation of c-Raf, BRAF, mTOR and PKC-ζ. LPAAT-β expression is a prognostic factor in gynecologic malignancies and is being investigated as a therapeutic target in a variety of tumor types. A class of thiosemicarbazones was identified as inhibitors of LPAAT-β from a screen of a library of small molecules. A focused library of thiosemicarbazones derivatives was prepared and led to the development of compounds which potently inhibit LPAAT-β and inhibit the growth of MiaPaCa2 human pancreatic cancer cells.

First claim

What is claimed is:

1. A compound having Formula I,

wherein,
R 1 is F, Cl, Br, CF 3 , or C 1-5 alkyl, or C 2-5 alkenyl,
R 2 is H or optionally substituted C 1-6 alkyl or phenyl; and
n is 1, 2, 3, 4 or 5; and
each R 3 is, independent of any other, F, Cl, Br, OH, CN, NH 2 , optionally substituted C 1-8 alkyl, C 1-8 alkenyl, OC 1 -C 8 alkyl, OC 2-8 alkenyl, NHC 1 -C 8 alkyl, NHC 2 -C 8 alkenyl, C 5-6 cycloalkyl, phenyl, COC 1-8 alkyl, COC 5-6 cycloalkyl, or CO phenyl; CONHC 1-8 alkyl, CONHC 5-6 cycloalkyl, or CONHphenyl; or R 2 and R 3 can form a fused aryl or heteroaryl;
wherein optional substituents are selected from F, Cl, Br, OH, CN, C 1-8 alkyl, OC 1-8 alkyl, phenyl, CN, C 1-4 haloalkyl, or a pharmaceutical acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is a C 2-4 alkyl.

3. The compound of claim 1 , wherein R 1 is propenyl.

4. The compound of claim 1 , wherein R 2 is H.

5. The compound of claim 1 , wherein R 2 is methyl.

6. The compound of claim 1 , wherein n is 2.

7. The compound of claim 1 , wherein n is 3.

8. The compound of claim 1 , wherein n is 2 and each R 3 is chosen from F, Cl, Br, and CN.

9. The compound of claim 1 , wherein the compound inhibits LPAAT-β.

10. A method of treating cancer in a subject, comprising: administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.

11. The method of claim 10 , wherein the cancer is pancreatic cancer.

12. The method of claim 10 , wherein the compound is administered with an anti-cancer agent.

13. The method of claim 10 , wherein the cancer is colon cancer.

14. The method of claim 10 , wherein the subject is also administered regorafenib.

15. A method of treating obesity in a subject, comprising: administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.

Assignees

• H Lee Moffitt Cancer Ct & Res

Inventors

• Springett Gregory
• Sebti Said M
• Lawrence Nicholas J

Classifications

• C07C337/08

  the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones · CPC title

• A61K31/175 Primary

  having the group [IMAGE cpc-sch-A61K-0950.gif] , >N—C(O)—N=N— or[IMAGE cpc-sch-A61K-0951.gif] , e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof · CPC title

• A61K31/4412

  having oxo groups directly attached to the heterocyclic ring · CPC title