PI3K/AKT/mTOR inhibitors and pharmaceutical uses thereof

Patent metadata

Field	Value
Publication number	US-9656984-B2
Application number	US-201415025086-A
Country	US
Kind code	B2
Filing date	Sep 24, 2014
Priority date	Sep 25, 2013
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

The invention relates to new PI3K/AKT/m TOR inhibitors and their use for the prevention and/or the treatment of a disease selected from the group consisting of: inflammatory diseases, autoimmune diseases, neurodegenerative diseases, cancers, transplant rejection, diseases characterized by a premature aging and tuberous sclerosis.

First claim

The invention claimed is:

1. A compound having one of the following formulae:

or its pharmaceutically acceptable salts, hydrates or hydrated salts or its polymorphic crystalline structures, racemates, diastereomers or enantiomers.

2. The compound according to claim 1 , having the following formula:

or its pharmaceutically acceptable salts, hydrates or hydrated salts or its polymorphic crystalline structures, racemates, diastereomers or enantiomers.

3. A method of treatment of a disease selected from the group consisting of: inflammatory diseases, autoimmune diseases, neurodegenerative diseases, cancers, transplant rejection and diseases characterized by a premature aging comprising administering a pharmaceutical acceptable amount of a compound of formula (I) as defined in claim 1 to a patient in need thereof.

4. The method according to claim 3 , wherein the disease is selected among cancers.

5. The method according to claim 4 , wherein the cancer is breast cancer.

6. A method of treatment of tuberous sclerosis comprising administering a pharmaceutical acceptable amount of a compound having formula (I):

wherein:
X is O or S;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of:

H, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, OH, a fluorine atom, a bromine atom, a iodine atom, O(C 1 -C 10 )alkylene-NHCO(C 1 -C 10 )alkylene-(C 5 -C 10 )heterocycloalkyl and O(C 1 -C 10 )alkylene-NH—CS—NH—R″ with R″ being:

wherein:
R 2 and R 3 may form together with the carbon atoms to which R 2 and R 3 are attached to form a (C 6 -C 10 )aryl group; and
R″ and the (C 5 -C 10 )heterocycloalkyl are optionally substituted by at least one substituent selected from OH and ═O;
EWG is chosen selected from the group consisting of:

NO 2 , CHO, COR, CN, CN—OH, CONHR, CONRR′ and COOR; R and R′ being independently from each other chosen from (C 1 -C 10 )alkyl groups;
R 5 is a (C 6 -C 10 )aryl, a (C 5 -C 10 )heteroaryl group, a (C 3 -C 10 )cycloalkyl or a (C 3 -C 10 )heterocycloalkyl group; said aryl and heteroaryl being optionally substituted by at least one substituent independently chosen from halogen, (C 1 -C 10 )alkoxyl and nitro;

R 5 being different from the group:

and wherein when EWG is COOMe, one of R 1 , R 2 , R 3 or R 4 is different from H;
and provided that the compound of formula (I) is not:

or its pharmaceutically acceptable salts, hydrates or hydrated salts or its polymorphic crystalline structures, racemates, diastereomers or enantiomers to a patient in need thereof.

7. The method of claim 6 , wherein EWG is NO 2 or CHO.

8. The method of claim 6 , wherein R 1 is H.

9. The method of claim 6 , wherein R 2 is H, (C 2 -C 10 )alkynyl, Br, F, I, OH, O(C 1 -C 10 )alkylene-NHCO(C 1 -C 10 )alkylene-(C 5 -C 10 )heterocycloalkyl or O(C 1 -C 10 )alkylene-NH—CS—NH—R″ with R″ being:

wherein:
R″ and the (C 5 -C 10 )heterocycloalkyl group are optionally substituted by OH or ═O;
or R 2 forms with R 3 together with the carbon atoms to which R 2 and R 3 are attached to form a (C 6 -C 10 )aryl.

10. The method of claim 6 , wherein R 3 is H, (C 1 -C 10 )alkoxyl or R 3 forms with R 2 together with the carbon atoms to which R 3 and R 2 are attached to form a (C 6 -C 10 )aryl.

11. The method of claim 6 , wherein R 4 is H, halogen or (C 1 -C 10 )alkoxyl.

12. The method of claim 6 , wherein R 5 is a possibly substituted phenyl or a tetrahydropyranyl group.

13. A compound having the following formula (i):

wherein X is O or S and Ri is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, OH, a fluorine atom, a bromine atom and a iodine atom;

or its pharmaceutically acceptable salts, hydrates or hydrated salts or its polymorphic crystalline structures, racemates, diastereomers or enantiomers.

14. The compound according to claim 13 , where Ri is selected from the group consisting of H, a fluorine atom, a bromine atom or a iodine atom.

Assignees

• Univ Rennes
• Centre Nat Rech Scient
• Inst Nat De La Sante Et De La Rech Medicale (Inserm)

Inventors

• Jean Mickael
• Fouque Amélie
• Legembre Patrick
• Van De Weghe Pierre

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D311/60 Primary

  with aryl radicals attached in position 2 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title