Mitochondrial activity inhibitors targeting tumoral metabolism

Patent metadata

Field	Value
Publication number	US-12371402-B2
Application number	US-201917297439-A
Country	US
Kind code	B2
Filing date	Nov 28, 2019
Priority date	Nov 28, 2018
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

The invention relates to compounds of formula (I) as follows: (I) wherein X 1 and X 2 , identical or different, are NR 5 or a sulfur atom, Y is a group (C 1 -C 10 )alkanediyl, Ar 1 and Ar 2 , identical or different, are an aryl group optionally substituted by one or several groups selected from a halogen atom, a (C 1 -C 6 ) alkyl, —OR 1 , —NR 1 R 2 and —COOR 3 ′ with R 1 and R 2 , independently of each other, are a hydrogen atom, a (C- 1 -C 6 ) alkyl group or a —COR 3 group, R 3 and R 4 ′ independently of each other, are a hydrogen atom or a (C 1 -C 6 ) alkyl group, and R 5 is a hydrogen atom or a (C 1 -C 6 )alkyl group, or a pharmaceutically acceptable salt and/or solvate thereof, in particular for use in cancer treatment.

First claim

The invention claimed is:

1. A method for treating a cancer comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as follows:

wherein
X 1 and X 2 , identical or different, are NR 5 or a sulfur atom, and at least one of X 1 and X 2 is a sulfur atom,
Y is a group (C 1 -C 10 ) alkanediyl,
Ar 1 and Ar 2 , identical or different, are each a naphthyl group optionally substituted by one or several groups selected from a halogen atom, a (C 1 -C 6 ) alkyl, —OR 1 , —NR 1 R 2 and —COOR 3 ,
with R 1 and R 2 , independently of each other, are a hydrogen atom, a (C 1 -C 6 ) alkyl group or
a —COR 4 group,
R 3 and R 4 , independently of each other, are a hydrogen atom or a (C 1 -C 6 ) alkyl group, and
R 5 is a hydrogen atom or a (C 1 -C 6 ) alkyl group,

or a pharmaceutically acceptable salt and/or solvate thereof.

2. The method according to claim 1 , wherein Y is a group —(CH 2 ) n — and n is an integer between 1 and 10.

3. The method according to claim 1 , wherein X 1 and X 2 are a sulfur atom.

4. The method according to claim 1 , wherein Ar 1 and Ar 2 are identical.

5. The method according to claim 1 , wherein Ar 1 and/or Ar 2 is an unsubstituted naphthyl group.

6. The method according to claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

and the pharmaceutically acceptable salts and solvates thereof.

7. The method according to claim 1 , wherein the cancer is selected from the group consisting of haematological cancers, lung cancers, cervix cancers, prostate cancer, melanoma and neuroendocrine tumors.

8. The method according to claim 1 , wherein the cancer is a LKB-1 gene-deficient cancer.

9. A method for treating a cancer comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 and at least one pharmaceutically acceptable excipient.

10. The method according to claim 9 , wherein the cancer is selected from the group consisting of haematological cancers, lung cancers, cervix cancers, prostate cancer, melanoma and neuroendocrine tumors.

11. The method according to claim 9 , wherein the cancer is a LKB-1 gene-deficient cancer.

12. A method for inhibiting mitochondrial complex I, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as follows:

wherein
X 1 and X 2 , identical or different, are NR 5 or a sulfur atom, and at least one of X 1 and X 2 is a sulfur atom,
Y is a group (C 1 -C 10 ) alkanediyl,
Ar 1 and Ar 2 , identical or different, are each a naphthyl group optionally substituted by one or several groups selected from a halogen atom, a (C 1 -C 6 ) alkyl, —OR 1 , —NR 1 R 2 and —COOR 3 ,
with R 1 and R 2 , independently of each other, are a hydrogen atom, a (C 1 -C 6 ) alkyl group or a —COR 4 group,
R 3 and R 4 , independently of each other, are a hydrogen atom or a (C 1 -C 6 ) alkyl group, and
R 5 is a hydrogen atom or a (C 1 -C 6 ) alkyl group,

or a pharmaceutically acceptable salt and/or solvate thereof or a composition comprising said compound of formula (I) and at least one pharmaceutically acceptable excipient.

13. A compound selected from the group consisting of:

and the pharmaceutically acceptable salts and solvates thereof.

Assignees

• Centre Leon Berard
• Centre Nat Rech Scient
• Univ Claude Bernard Lyon
• Inst Nat Sante Rech Med
• Univ Grenoble Alpes
• Univ Caen

Inventors

• Billaud Marc
• Prudent Renaud
• Cordier-Bussat Martine
• Fontaine Eric
• Dallemagne Patrick
• Suzanne Peggy
• Rault Sylvain

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07C335/32 Primary

  having sulfur atoms of isothiourea groups bound to acyclic carbon atoms · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/155 Primary

  Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) · CPC title