5′-nucleotidase inhibitors and therapeutic uses thereof

Patent metadata

Field	Value
Publication number	US-9783541-B2
Application number	US-201415023911-A
Country	US
Kind code	B2
Filing date	Sep 29, 2014
Priority date	Oct 1, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The subject matter of the present invention is compounds which have a 6-aminopurine backbone corresponding to formula (I): in which R 1 , R 2 , R 3 , X, Y and Z are as defined in any one of claims 1 to 5 , and Ar is a biphenyl or a naphthyl which may be substituted with R 3 , for use in the treatment of cancer.

First claim

The invention claimed is:

1. A compound which has a 6-aminopurine backbone, characterized in that it has the formula:

wherein R 1 and R 2 , which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , —NH 2 , —NHR 9 , —NR 9 R′ 9 , —NHCOR 9 , —N(COR 9 )(COR′ 9 ), —CF 3 , halogen, —OH, —OR 9 , —SH or —SR 9 ,
with R 9 and R′ 9 , which may be identical or different, are, independently of one another, alkyl, alkenyl, alkynyl or aryl,
Z is on either of the positions N 7 and N 9 of the purine, and is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , halogen, —(CH 2 ) n —OR 5 , —(CH 2 ) n1 —O—(CH 2 ) n2 R 5 , —(CH 2 ) n ′—COOR 5 or —(CH 2 )n-P(═O)(OR 6 )(OR 7 ), where:
n, n 1 and n 2 , which may be identical or different, are, independently of one another, an integer ranging from 1 to 10 and n′ an integer ranging from 0 to 10,
R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl or —COR 9 ,
R 6 and R 7 , which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , an organic cation or a metal cation,
X is a divalent radical chosen from C═O, C═S, C═NR 8 and SO 2 , where:
R 8 is hydrogen, alkyl, alkenyl, alkynyl, —OH or —OR 9 ,
Y has the same meaning as R 5 ,
Ar is a biphenyl,
R 3 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —NH 2 , —NHR 9 , —NR 9 R′ 9 , —OH, —OR 9 , aryloxy, —OCH 2 C 6 H 5 ; a 5-membered or 6-membered aromatic or nonaromatic heterocycle comprising one or more heteroatoms chosen from N, O and S, said 5-membered or 6-membered heterocycle also possibly being substituted with a substituent R 4 , where:
R 4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , —(CH 2 ) n —OR 5 , —(CH 2 ) n1 —O—(CH 2 ) n2 R 5 , —(CH 2 ) n —COOR 5 or —(CH 2 ) n —P(═O)(OR 6 R 7 ),
R 3 being bonded to Ar in the ortho, meta or para position,
X being bonded to Ar in the ortho, meta or para position,
with the exception of the compound 9H-purin-6-yl-[1,1′-biphenyl]-4-carboxamide.

2. The compound as claimed in claim 1 , wherein the substituent R 3 is a hydrogen or a 5-membered or 6-membered aromatic or nonaromatic heterocycle comprising one or more heteroatoms chosen from N, O and S, said heterocycle possibly being substituted with a substituent R 4 as defined in claim 1 .

3. The compound as claimed in claim 1 wherein the 5-membered heterocycle is a pyrrole or an imidazole, said pyrrole or imidazole possibly being substituted with a substituent R 4 chosen from hydrogen and —(CH 2 ) n —P(═O)(OR 6 )(OR 7 ) as defined in claim 1 .

4. The compound as claimed in claim 1 wherein:
R 1 is hydrogen, (—NH 2 ), (—NHR 9 ), (—NR 9 R′ 9 ), (—NHCOR 9 ), or (—N(COR 9 )(COR′ 9 )),
R 2 is hydrogen, benzyl or phenyl,
Z is hydrogen, benzyl, phenyl, —(CH 2 ) n —OR 5 , —(CH 2 ) n1 —O—(CH 2 ) n2 R 5 , —(CH 2 ) n ′—COOR 5 or —(CH 2 ) n —P(═O)(OR 6 )(OR 7 ) where:
n, n 1 , n 2 and n′, which may be identical or different, are, independently of one another, an integer equal to 1 or 2,
R 5 is hydrogen, ethyl, acetyl (—COCH 3 ) or phenyl,
R 6 and R 7 , which may be identical or different, are, independently of one another, hydrogen, methyl, ethyl, a sodium cation (Na + ) or a lithium cation (Li+),
X is C═O or SO 2 ,
Y is hydrogen.

5. The compound as claimed in claim 1 selected from the group consisting of:
9H-purin-6-yl-[1,1′-biphenyl]-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-N-pyrrole-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-N-pyrrole-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-N-pyrrole-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-N-pyrrole-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-N-pyrrole-4-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-N-pyrrole-4-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-N-imidazole-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-N-imidazole-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-N-imidazole-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-N-imidazole-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-C4-imidazole-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-C4-imidazole-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-C4-imidazole-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-C4-imidazole-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-4′-C 4 —(N 1 -ethoxyphosphinylmethyl)imidazole-3-carboxamide,
7-(phenylmethyl)-7H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
9-(phenylmethyl)-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
7-[(phenylmethoxy)methyl]-7H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
9-[(phenylmethoxy)methyl]-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
9-[2-(acetyloxy)ethyl]-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
9-(2-hydroxyethyl)-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
ethyl 2-[(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]acetate,
2-[(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]acetic acid,
diethyl [(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]methylphosphonate,
[(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]methylphosphonic acid,
and mixtures thereof.

6. A method for the treatment of cancer comprising administering to a subject that has cancer a compound which has a 6-aminopurine backbone, wherein said compound has formula (I):

wherein
R 1 and R 2 , which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , —NH 2 , —NHR 9 , —NR 9 R′ 9 , —NHCOR 9 , —N(COR 9 )(COR′ 9 ), —CF 3 , halogen, —OH, —OR 9 , —SH or —SR 9 ,
with R 9 and R′ 9 , which may be identical or different, are, independently of one another, alkyl, alkenyl, alkynyl or aryl,
Z is on either of the positions N 7 and N 9 of the purine, and is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , halogen, —(CH 2 ) n —OR 5 , —(CH 2 ) n1 —O—(CH 2 ) n2 R 5 , —(CH 2 ) n ′—COOR 5 or —(CH 2 )n-P(═O)(OR 6 )(OR 7 ), where:
n, n 1 and n 2 , which may be identical or different, are, independently of one another, an integer ranging from 1 to 10 and n′ an integer ranging from 0 to 10,
R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl or —COR 9 ,
R 6 and R 7 , which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , an organic cation or a metal cation,
X is a divalent radical chosen from C═O, C═S, C═NR 8 and SO 2 , where:
R 8 is hydrogen, alkyl, alkenyl, alkynyl —OH or —OR 9 ,
Y has the same R 5 ,
Ar is a biphenyl or a naphthyl,
R 3 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —NH 2 , —NHR 9 , —NR 9 R′ 9 , —OH, —OR 9 , aryloxy, —OCH 2 C 6 H 5 ; a 5-membered or 6-membered aromatic or nonaromatic heterocycle comprising one or more heteroatoms chosen from N, O and S, said 5-membered or 6-membered heterocycle also possibly being substituted with a substituent R 4 , where:
R 4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR 9 , —(CH 2 ) n —OR 5 , —(CH 2 ) n1 —O—O—CH 2 ) n2 R 5 , —(CH 2 ) n —COOR 5 or —CH 2 ) n —P(═O)(OR 6 R 7 ),
R 3 being bonded to Ar in the ortho, meta or para position,
X being bonded to Ar in the ortho, meta or para position.

7. The method as claimed in claim 6 , wherein said compound is chosen from the group:
9H-purin-6-yl-[1,1′-biphenyl]-2-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide,
9H-purin-6-yl-[1,1′-biphenyl]-3′-N-

Assignees

• Centre Nat De La Rech Scientifique-Cnrs
• Hospices Civils Lyon
• Ecole Normale Superieure Lyon
• Univ Claude Bernard Lyon
• Univ De Montpellier 1

Inventors

• Chaloin Laurent
• Peyrottes Suzanne
• Lionne Corinne
• Marton Zsuzsanna
• Egron David
• Guillon Remi
• Perigaud Christian
• Dumontet Charles
• Jordheim Lars Petter
• Krimm Isabelle

Classifications

• C07F9/65616

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title

• A61K31/708

  having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title