5′-nucleotidase inhibitors and therapeutic uses thereof

Abstract

The subject matter of the present invention is compounds which have a 6-aminopurine backbone corresponding to formula (I): in which R.sub.1, R.sub.2, R.sub.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.sub.3, for use in the treatment of cancer. ##STR00001##

Claims

1. A compound which has a 6-aminopurine backbone, characterized in that it has the formula: ##STR00021## wherein R.sub.1 and R.sub.2, which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, —NH.sub.2, —NHR.sub.9, —NR.sub.9R′.sub.9, —NHCOR.sub.9, —N(COR.sub.9)(COR′.sub.9), —CF.sub.3, halogen, —OH, —OR.sub.9, —SH or —SR.sub.9, with R.sub.9 and R′.sub.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.sub.7 and N.sub.9 of the purine, and is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, halogen, —(CH.sub.2).sub.n—OR.sub.5, —(CH.sub.2).sub.n1—O—(CH.sub.2).sub.n2R.sub.5, —(CH.sub.2).sub.n′—COOR.sub.5 or —(CH.sub.2)n-P(═O)(OR.sub.6)(OR.sub.7), where: n, n.sub.1 and n.sub.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.sub.5 is hydrogen, alkyl, alkenyl, alkynyl, aryl or —COR.sub.9, R.sub.6 and R.sub.7, which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, an organic cation or a metal cation, X is a divalent radical chosen from C═O, C═S, C═NR.sub.8 and SO.sub.2, where: R.sub.8 is hydrogen, alkyl, alkenyl, alkynyl, —OH or —OR.sub.9, Y has the same meaning as R.sub.5, Ar is a biphenyl, R.sub.3 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —NH.sub.2, —NHR.sub.9, —NR.sub.9R′.sub.9, —OH, —OR.sub.9, aryloxy, —OCH.sub.2C.sub.6H.sub.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.sub.4, where: R.sub.4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, —(CH.sub.2).sub.n—OR.sub.5, —(CH.sub.2).sub.n1—O—(CH.sub.2).sub.n2R.sub.5, —(CH.sub.2).sub.n—COOR.sub.5 or —(CH.sub.2).sub.n—P(═O)(OR.sub.6R.sub.7), R.sub.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.sub.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.sub.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.sub.4 chosen from hydrogen and —(CH.sub.2).sub.n—P(═O)(OR.sub.6)(OR.sub.7) as defined in claim 1.

4. The compound as claimed in claim 1 wherein: R.sub.1 is hydrogen, (—NH.sub.2), (—NHR.sub.9), (—NR.sub.9R′.sub.9), (—NHCOR.sub.9), or (—N(COR.sub.9)(COR′.sub.9)), R.sub.2 is hydrogen, benzyl or phenyl, Z is hydrogen, benzyl, phenyl, —(CH.sub.2).sub.n—OR.sub.5, —(CH.sub.2).sub.n1—O—(CH.sub.2).sub.n2R.sub.5, —(CH.sub.2).sub.n′—COOR.sub.5 or —(CH.sub.2).sub.n—P(═O)(OR.sub.6)(OR.sub.7) where: n, n.sub.1, n.sub.2 and n′, which may be identical or different, are, independently of one another, an integer equal to 1 or 2, R.sub.5 is hydrogen, ethyl, acetyl (—COCH.sub.3) or phenyl, R.sub.6 and R.sub.7, which may be identical or different, are, independently of one another, hydrogen, methyl, ethyl, a sodium cation (Na.sup.+) or a lithium cation (Li+), X is C═O or SO.sub.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.sub.4—(N.sub.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): ##STR00022## wherein R.sub.1 and R.sub.2, which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, —NH.sub.2, —NHR.sub.9, —NR.sub.9R′.sub.9, —NHCOR.sub.9, —N(COR.sub.9)(COR′.sub.9), —CF.sub.3, halogen, —OH, —OR.sub.9, —SH or —SR.sub.9, with R.sub.9 and R′.sub.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.sub.7 and N.sub.9 of the purine, and is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, halogen, —(CH.sub.2).sub.n—OR.sub.5, —(CH.sub.2).sub.n1—O—(CH.sub.2).sub.n2R.sub.5, —(CH.sub.2).sub.n′—COOR.sub.5 or —(CH.sub.2)n-P(═O)(OR.sub.6)(OR.sub.7), where: n, n.sub.1 and n.sub.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.sub.5 is hydrogen, alkyl, alkenyl, alkynyl, aryl or —COR.sub.9, R.sub.6 and R.sub.7, which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, an organic cation or a metal cation, X is a divalent radical chosen from C═O, C═S, C═NR.sub.8 and SO.sub.2, where: R.sub.8 is hydrogen, alkyl, alkenyl, alkynyl —OH or —OR.sub.9, Y has the same R.sub.5, Ar is a biphenyl or a naphthyl, R.sub.3 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —NH.sub.2, —NHR.sub.9, —NR.sub.9R′.sub.9, —OH, —OR.sub.9, aryloxy, —OCH.sub.2C.sub.6H.sub.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.sub.4, where: R.sub.4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, —(CH.sub.2).sub.n—OR.sub.5, —(CH.sub.2).sub.n1—O—O—CH.sub.2).sub.n2R.sub.5, —(CH.sub.2).sub.n—COOR.sub.5 or —CH.sub.2).sub.n—P(═O)(OR.sub.6R.sub.7), R.sub.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-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.sub.4—(N.sub.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, 9H-purin-6-ylnaphthalene-1-carboxamide, 9H-purin-6-ylnaphthalene-2-carboxamide, (naphthalene-1-carbonylamino-9H-purin-6-yl)methylphosphonic acid, (naphthalene-2-carbonylamino-9H-purin-6-yl)methylphosphonic acid, 9H-purin-6-yl-[1,1′-biphenyl]-4-sulfonamide, and mixtures thereof.

8. The method of claim 6 wherein said method inhibits at least one 5′-nucleotidase chosen from cytosolic 5′-nucleotidase II (cN-II), cytosolic 5′-nucleotidase IA (cN-IA), cytosolic 5′-nucleotidase IB (cN-IB), cytosolic 5′-nucleotidase IMA (cN-IIIA), cytosolic 5′-nucleotidase NIB (cN-IIIB), ecto-5′-nucleotidase (eN, CD73), cytosolic 5′(3′)-deoxynucleotidase (cdN) and mitochondrial 5′(3′)-deoxynucleotidase (mdN).

9. The method of claim 6, wherein administration of said compound is combined with at least one nucleoside analog and/or at least one nucleobase analog.

10. The method of claim 9, wherein: the nucleoside analog is chosen from cladribine, fludarabine, clofarabine, cytarabine, gemcitabine, nelarabine, floxuridine and pentostatin, the nucleobase analog is chosen from fluorouracil, 6-mercaptopurine and 6-thioguanosine.

11. A composition comprising: at least one compound of formula (I): ##STR00023## wherein R.sub.1 and R.sub.2, which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, —NH.sub.2, —NHR.sub.9, —NR.sub.9R′.sub.9, —NHCOR.sub.9, —N(COR.sub.9)(COR′.sub.9), —CF.sub.3, halogen, —OH, —OR.sub.9, —SH or —SR.sub.9, with R.sub.9 and R′.sub.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.sub.7 and N.sub.9 of the purine, and is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, halogen, —(CH.sub.2).sub.2—OR.sub.5, —(CH.sub.2).sub.n1—O—(CH.sub.2).sub.n2R.sub.5—(CH.sub.2).sub.n′—COOR.sub.5 or −(CH.sub.2)n-P(═O)(OR.sub.6)(OR.sub.7), where: n, n.sub.1 and n.sub.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.sub.5 is hydrogen, alkyl, alkenyl, alkynyl, aryl or —COR.sub.9, R.sub.6 and R.sub.7, which may be identical or different, are, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, an organic cation or a metal cation, X is a divalent radical chosen from C═O, C═S, C═NR.sub.8 and SO.sub.2, where: R.sub.8 is hydrogen, alkyl, alkenyl, alkynyl, —OH or —OR.sub.9, Y has the same R.sub.5, Ar is a biphenyl or a naphthyl, R.sub.3 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —NH.sub.2, —NHR.sub.9, —NR.sub.9R′.sub.9, —OH, —OR.sub.9, aryloxy, —OCH.sub.2C.sub.6H.sub.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.sub.4, where: R.sub.4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, —COR.sub.9, —(CH.sub.2).sub.n—OR.sub.5, —(CH.sub.2).sub.n1—O—CH.sub.2).sub.n2R.sub.5, —(CH.sub.2).sub.n—COOR.sub.5 or —(CH.sub.2).sub.n—P(═O)(OR.sub.6R.sub.7), R.sub.3 being bonded to Ar in the ortho, meta or para position, X being bonded to Ar in the ortho, meta or para position, in combination with: at least one nucleoside analog chosen from cladribine, fludarabine, clofarabine cytarabine, gemcitabine, nelarabine, floxuridine and pentostatin, and/or at least one nucleobase analog chosen from fluorouracil, 6-mercaptopurine and 6-thioguanosine, and optionally at least one pharmaceutically acceptable excipient.

12. The composition as claimed in claim 11, wherein the compound of formula (I) 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-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.sub.4—(N.sub.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, 9H-purin-6-ylnaphthalene-1-carboxamide, 9H-purin-6-ylnaphthalene-2-carboxamide, (naphthalene-1-carbonylamino-9H-purin-6-yl)methylphosphonic acid, (naphthalene-2-carbonylamino-9H-purin-6-yl)methylphosphonic acid, 9H-purin-6-yl-[1,1′-biphenyl]-4-sulfonamide, and mixtures thereof.

13. The method of claim 6, wherein said composition is administered simultaneously, separately or sequentially with administration of an additional therapy.

14. The method of claim 6, wherein the cancer is: solid tumors, or acute hemopathies, chronic myeloproliferative syndromes or chronic lymphoproliferative syndromes, chronic lymphoid leukemia, hairy cell lymphoma or multiple myeloma.

Description

(1) FIG. 1 illustrates the general synthesis scheme for the compounds of formula (I), wherein R.sub.1, R.sub.2, X, Y, Z, Ar and R.sub.3 are as previously defined. The compound of formula (III) is as previously defined.

(2) FIGS. 2 and 3 exemplify the appropriation of a compound of formula (III) wherein Ar represents a biphenyl.

(3) More particularly, FIGS. 2a and 2b exemplify two possible synthesis routes for preparing a compound of formula (III), wherein the biphenyl is substituted on one of its rings with a substituent R.sub.3 and on its other ring with a substituent COOR.sub.11. In FIG. 3, the biphenyl is substituted on one of its rings with a substituent R.sub.3 and on its other ring with a substituent COOH.

(4) FIG. 4 illustrates a process for preparing various compounds of formula (I) wherein Y═H, X═(C═O) or SO.sub.2, and Ar=biphenyl or naphthyl optionally substituted with a substituent R.sub.3, with R.sub.1, R.sub.2, Z and R.sub.3 as previously defined.

(5) More particularly, FIGS. 4a and 4b exemplify the preparation of a compound (I) of the invention wherein Y═H and X═(C═O) and Ar=biphenyl.

(6) FIG. 4c exemplifies a process for preparing compounds (I) wherein Y═H, X═SO.sub.2 and Ar=biphenyl.

(7) FIG. 4d exemplifies a process for preparing compounds (I) wherein Y═H, X═(C═O) and Ar=naphthyl.

(8) FIG. 5 illustrates the survival of B6D2F1 mice having received L1210 cells and treated with: cyclodextrins alone (.square-solid.), fludarabine (100 mg/kg) (.circle-solid.), compound (2) of the invention alone (3.94 mg/kg) (.box-tangle-solidup.) or in combination with fludarabine (100 mg/kg) (Δ), compound (2) of the invention alone (7.89 mg/kg) (.diamond-solid.) or in combination with fludarabine 100 mg/kg (⋄).

(9) FIG. 6 illustrates the percentage of Annexin V labeling for cells of CLL (FIG. 6A) and AML (FIG. 6B) patients, incubated with the presence of DMSO, of fludarabine (10 μM), of cytarabine (100 μM) or of compound (2) of the invention (100 μM).

Example 1: Illustration of 33 Compounds Corresponding to Formula (I) Defined Above

(10) Tables 1 to 4 below exemplify 33 compounds of formula (I) synthesized by the inventors, and denoted respectively (1) to (33) in the subsequent text.

(11) In compounds (1) to (18) of table 1:

(12) R.sub.1═R.sub.2═Y═Z═H, X═(C═O) (carbonyl) and Ar=biphenyl, said biphenyl possibly being substituted with a substituent R.sub.3, said substituent R.sub.3 being chosen from hydrogen, pyrrole or imidazole, said imidazole being optionally substituted with a substituent R.sub.4.

(13) The chemical name of compounds (1) to (18) is respectively the following: 9H-purin-6-yl-[1,1′-biphenyl]-2-carboxamide (1), 9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide (2), 9H-purin-6-yl-[1,1′-biphenyl]-4-carboxamide (3), 9H-purin-6-yl-[1,1′-biphenyl]-3′-N-pyrrole-2-carboxamide (4), 9H-purin-6-yl-[1,1′-biphenyl]-4′-N-pyrrole-2-carboxamide (5), 9H-purin-6-yl-[1,1′-biphenyl]-3′-N-pyrrole-3-carboxamide (6), 9H-purin-6-yl-[1,1′-biphenyl]-4′-N-pyrrole-3-carboxamide (7), 9H-purin-6-yl-[1,1′-biphenyl]-3′-N-pyrrole-4-carboxamide (8), 9H-purin-6-yl-[1,1′-biphenyl]-4′-N-pyrrole-4-carboxamide (9), 9H-purin-6-yl-[1,1′-biphenyl]-3′-N-imidazole-2-carboxamide (10), 9H-purin-6-yl-[1,1′-biphenyl]-4′-N-imidazole-2-carboxamide (11), 9H-purin-6-yl-[1,1′-biphenyl]-3′-N-imidazole-3-carboxamide (12), 9H-purin-6-yl-[1,1′-biphenyl]-4′-N-imidazole-3-carboxamide (13), 9H-purin-6-yl-[1,1′-biphenyl]-3′-C.sub.4-imidazole-2-carboxamide (14), 9H-purin-6-yl-[1,1′-biphenyl]-4′-C.sub.4-imidazole-2-carboxamide (15), 9H-purin-6-yl-[1,1′-biphenyl]-3′-C.sub.4-imidazole-3-carboxamide (16), 9H-purin-6-yl-[1,1′-biphenyl]-4′-C.sub.4-imidazole-3-carboxamide (17), 9H-purin-6-yl-[1,1′-biphenyl]-4′-C.sub.4—(N.sub.1-ethoxyphosphinylmethyl)imidazole-3-carboxamide (18).

(14) The orientation indicated in table 1 (ortho, meta or para) respectively for the —NH—(C═O)— group and for the R.sub.3 group relates to the position of each of these groups relative to the biphenyl.

(15) TABLE-US-00001 TABLE 1 —NH—(C═O)— Compounds (I) orientation R.sub.3/orientation R.sub.4 Numbers ortho —H / (1) meta —H / (2) para —H / (3) ortho meta / (4) ortho para / (5) meta meta / (6) meta para / (7) para 0 meta / (8) para para / (9) ortho meta / (10) ortho para / (11) meta meta / (12) meta para / (13) ortho meta —H (14) ortho para —H (15) meta meta —H (16) meta para —H (17) meta 0 meta —CH.sub.2—P(═O)(ONa)OEt) (18)

(16) In compounds (19) to (28) of table 2:

(17) R.sub.1═R.sub.2═Y═H, X═(C═O) (carbonyl), and Ar=unsubstituted biphenyl.

(18) The chemical name of compounds (19) to (28) is respectively the following: 7-(phenylmethyl)-7H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide (19), 9-(phenylmethyl)-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide (20), 7-[(phenylmethoxy)methyl]-7H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide (21), 9-[(phenylmethoxy)methyl]-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide (22), 9-[2-(acetyloxy)ethyl]-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide (23), 9-(2-hydroxyethyl)-9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide (24), ethyl 2-[(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]acetate (25), 2-[(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]acetate (26), diethyl [(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]methylphosphonate (27), [(1,1′-biphenyl)-3-carbonylamino-9H-purin-6-yl]methylphosphonic acid (28).

(19) The orientation of the —NH—(C═O)— group indicated (ortho, meta or para) relates to the position of said group relative to the biphenyl.

(20) TABLE-US-00002 TABLE 2 —NH—(C═O)— Compounds (I) Z orientation Numbers —CH.sub.2Ph (N.sub.7) meta (19) —CH.sub.2Ph (N.sub.9) meta (20) —CH.sub.2—O—CH.sub.2Ph (N.sub.7) meta (21) —CH.sub.2—O—CH.sub.2Ph (N.sub.9) meta (22) —(CH.sub.2).sub.2—O—Ac (N.sub.9) meta (23) —(CH.sub.2).sub.2—OH (N.sub.9) meta (24) —CH.sub.2—COOEt (N.sub.9) meta (25) —CH.sub.2—COOH (N.sub.9) meta (26) —CH.sub.2—P(═O)(OEt).sub.2 (N.sub.9) meta (27) —CH.sub.2—P(═O)(OH).sub.2 (N.sub.9) meta (28)

(21) N.sub.7 or N.sub.9 indicate the position of the substituent Z on the nitrogen respectively in position 7 or 9 of the aminopurine compound (I).

(22) In compounds (29) to (32) of table 3:

(23) R.sub.1═R.sub.2═Y═H, X═(C═O) (carbonyl), and Ar=unsubstituted naphthyl.

(24) The definition of Z is indicated in table 3 for each of compounds (29) to (32).

(25) The chemical name of compounds (29) to (32) is respectively the following: 9H-purin-6-yl-naphthalene-1-carboxamide (29), 9H-purin-6-yl-naphthalene-2-carboxamide (30), (naphthalene-1-carbonylamino-9H-purin-6-yl)methylphosphonic acid (31), (naphthalene-2-carbonylamino-9H-purin-6-yl)methylphosphonic acid (32).

(26) The orientation of the —NH—(C═O)— group indicated (1 or 2) in table 3 relates to the position of said group relative to the naphthyl.

(27) TABLE-US-00003 TABLE 3 —NH— (C═O)— Compounds (I) Z orientation Numbers H 1 (29) H 2 (30) —CH.sub.2—P(═O)(OH).sub.2 (N.sub.9) 1 (31) —CH.sub.2—P(═O)(OH).sub.2 (N.sub.9) 2 (32)

(28) In compound (33) of table 4:

(29) R.sub.1═R.sub.2═Y═H, X═(SO.sub.2) (sulfonyl), and Ar=unsubstituted biphenyl.

(30) The chemical name of compound (33) is the following: 9H-purin-6-yl-[1,1′-biphenyl]-4-sulfonamide (33).

(31) TABLE-US-00004 TABLE 4 —NH—(SO.sub.2)— Compound (I) Z orientation Number H para (33)

(32) The orientation of the —NH—(SO.sub.2)— group indicated (para) in table 4 relates to the position of said group relative to the biphenyl.

Example 2: Synthesis of Compounds of Formula (I)

(33) FIG. 1 is a synthesis scheme which recaps and generalizes all of the steps described below.

(34) Synthesis of the Compounds of Formula (I) Wherein Y═H, X═(C═O) or SO.sub.2, and Ar=Biphenyl or Naphthyl Optionally Substituted with a Substituent R.sub.3.

(35) 1) Preparation of the biphenyl compound of formula (III) wherein R.sub.10═COOR.sub.11 (FIGS. 2a and 2b).

(36) According to the definition of the substituents R.sub.3 or R.sub.10, those skilled in the art will adjust the experimental conditions described below.

(37) Synthesis of the Compound (III) Wherein Ar=Biphenyl (FIG. 2a)

(38) Pd(PPh.sub.3).sub.4 (tetrakis (triphenylphosphine)palladium) (0.1 eq.), DMF (dimethylformamide) and phenyl bromide substituted with an R.sub.3 (1 eq.) (FIG. 2a) are added, under an argon atmosphere, to a three-necked round-bottomed flask.

(39) Potassium carbonate K.sub.2CO.sub.3 (3 eq.) and the corresponding ethoxycarbonyl benzeneboronic derivative (1.7 eq.) are then successively added. The mixture is stirred under argon at 100° C., until thin layer chromatography (TLC) reveals that the starting product has been consumed. The mixture is cooled to ambient temperature, and diluted with water and the product is extracted with ethyl acetate (EtOAc). The combined organic phases are washed with brine, dried over sodium sulfate (Na.sub.2SO.sub.4) and filtered. The solvent is eliminated under vacuum and the residue is purified by silica gel column chromatography, elution being carried out for example with a dichloromethane/methanol mixture (DCM/MeOH: 100/0 to 95/5), to give the expected methyl ester or ethyl ester compound (III) in the form of an oil (FIG. 2a).

(40) Synthesis of the Compound (III) Wherein Ar=Biphenyl (FIG. 2b)

(41) Pd.sub.2(dba).sub.3 (tris(dibenzylideneacetone)dipalladium) (0.1 eq.), DMF (dimethylformamide) and methyl or ethyl benzoate bromide (1 eq.) (FIG. 2b) are added, under an argon atmosphere, to a three-necked round-bottomed flask.

(42) Potassium carbonate K.sub.2CO.sub.3 (3 eq.) and the benzeneboronic derivative substituted with an R.sub.3 (1.2 eq.) are then successively added. The mixture is stirred under argon at 100° C., until thin layer chromatography (TLC) reveals that the starting product has been consumed. The mixture is cooled to ambient temperature, diluted with water, and neutralized by adding a hydrochloric acid solution (1M) and the product is extracted with ethyl acetate (EtOAc). The combined organic phases are washed with brine, dried over sodium sulfate (Na.sub.2SO.sub.4) and filtered. The solvent is eliminated under vacuum and the residue is purified by silica gel column chromatography, elution being carried out for example with a petroleum ether/dichloromethane mixture (PE/DCM: 100/0 to 20/80), to give the expected methyl ester or ethyl ester compound (III) in the form of an oil (FIG. 2b).

(43) 2) Preparation of the Biphenyl Compound (III) Wherein R.sub.10═COOH (FIG. 3).

(44) A solution of sodium hydroxide (2M NaOH) in water is added dropwise to a solution or suspension of the methyl or ethyl ester compound (III) as obtained in the previous step (point 1) above) in a 1,4-dioxane/ethanol mixture (2/1, v/v). The mixture is stirred at 50° C. until TLC reveals that the reaction is complete. An aqueous hydrochloric acid solution (1M HCl) is then added until the pH is equal to 3, and the mixture is extracted with EtOAc. The combined organic faces are washed with brine, dried over Na.sub.2SO.sub.4 and filtered. The solvent is eliminated under vacuum and the residue is purified by silica gel column chromatography, elution being carried out for example with DCM/MeOH (100/0 to 90/10) to give the expected carboxylic acid compound (III) in the form of a white powder (FIG. 3).

(45) 3) Preparation of a Compound of Formula (I) Wherein Y═H, X═CO and Ar=Biphenyl (FIGS. 4a and 4b).

(46) According to the definition of the substituents R.sub.1, R.sub.2, Z and R.sub.3, those skilled in the art will choose the starting products and will if necessary adjust the experimental conditions described below.

(47) Synthesis of the Compound (I) as Exemplified in FIG. 4a

(48) An appropriate coupling reagent, for instance a carbonyl diimidazole/dimethylaminopyridine mixture (CDI (2 eq.)/DMAP (0.2 eq.)), is added to a solution, with stirring, of the carboxylic acid compound (III) (1 eq.) as obtained in the previous step (point 2) above) in DMF at ambient temperature. After 5 minutes, the 2-aminopurine derivative (2 eq.) of formula (II) is added and the mixture is stirred at 100° C. until the end of the reaction. The solvent is then eliminated under vacuum and the residue is purified by silica gel column chromatography, elution being carried out for example with a DCM/MeOH mixture (100/0 to 90/10) to give the compound of formula (I) of the invention with Y═H and X═CO (FIG. 4a).

(49) Synthesis of the Compound (I) as Exemplified in FIG. 4b

(50) The desired commercial acid chloride compound (III) (1 eq.) is added to a solution, with stirring, of a 2-aminopurine derivative (1.25 eq) of formula (II) in pyridine at ambient temperature. The reaction mixture is stirred at 100° C. until the end of the reaction. The solvent is then eliminated under vacuum and the residue is purified by silica gel column chromatography, elution being carried out for example with DCM/MeOH (100/0 to 90/10) to give the expected compound (I°) (FIG. 4b).

(51) 4) Preparation of a Compound of Formula (I) Wherein Y═H, X═SO.sub.2 and Ar=Biphenyl (FIG. 4c)

(52) The desired commercial sulfuryl chloride compound (III) (1 eq.) is added to a solution, with stirring, of a 2-aminopurine derivative (1.25 eq.) of formula (II) in pyridine at ambient temperature. The reaction mixture is stirred at 100° C. until the end of the reaction. The solvent is then eliminated under vacuum and the residue is purified by silica gel column chromatography, elution being carried out for example with DCM/MeOH (100/0 to 90/10) to give the expected compound (I°) (FIG. 4c).

(53) 5) Preparation of a Compound of Formula (I) Wherein Y═H, X═CO and Ar=Naphthyl (FIG. 4d)

(54) The desired commercial acid chloride compound (III) (with Ar=naphthyl, see FIG. 4d) (1 eq.) is added to a solution, with stirring, of a 2-aminopurine derivative (1.25 eq.) of formula (II) in pyridine at ambient temperature. The reaction mixture is stirred at 100° C. until the end of the reaction. The solvent is then eliminated under vacuum and the residue is purified by silica gel column chromatography, elution being carried out for example with DCM/MeOH (100/0 to 90/10) to give the expected compound (I°) (FIG. 4d).

Example 3: Determination of the Inhibitory Properties and Cytotoxic Activities of the Compounds (I) of the Invention

(55) The inhibitory properties of the compounds (I) of the invention were determined with respect to the purified recombinant target enzyme cN-II (determination of the inhibition of the 5′-nucleotidase activity).

(56) The cytotoxic activities of the compounds of the invention were evaluated in various tumor cell lines (determination of the IC.sub.50).

(57) A selection of these biological data is presented hereinafter and relates to the compounds (I) of the invention for which an inhibitory activity was measured in vitro but also in cell culture: cytotoxic effect and/or effect of synergy with one of the anticancer molecules chosen from cladribine, fludarabine, clofarabine, cytarabine, gemcitabine, nelarabine, floxuridine or pentostatin (namely nucleoside analogs).

(58) The abbreviations used signify:

(59) cN-II: cytosolic 5′-nucleotidase II,

(60) RL: Human follicular lymphoma cell line used for the cytotoxicity tests (other lines such as CCRF-CEM and MDA-MB-231 were also tested for certain compounds (I) of the invention),

(61) Synergy MTT: test for evaluating the cell survival inhibition synergy between the cN-II-inhibiting compounds (I) of the invention and the known anticancer agent (namely a cytotoxic nucleoside analog chosen from cladribine, fludarabine, clofarabine, cytarabine, gemcitabine, nelarabine, floxuridine or pentostatin).

(62) The MTT test described hereinafter makes it possible to evaluate whether the effect is:

(63) 1) “additive” in nature: independent effects of the compounds (I) of the invention (cN-II inhibitors) and of the known anticancer agents,

(64) 2) “antagonistic” in nature: opposite effects of the compounds (I) of the invention and of the known anticancer agents;

(65) 3) “synergistic” in nature: potentiating effect on the known anticancer agent by the cN-II-inhibiting compound (I) of the invention.

(66) It is this third point (synergistic effect) which is investigated in the following text.

(67) Experimental Procedure of the cN-II Inhibition Test:

(68) The activity of cN-II is measured in vitro by following the appearance of the inorganic phosphate produced during the enzymatic reaction. The purified recombinant cN-II enzyme is used in the presence of its preferential substrate, inosine 5′-monophosphate (IMP). During the hydrolysis reaction, inosine and inorganic phosphate are produced from the IMP. This phosphate is then assayed by means of a colorimetric method using Malachite green (kit sold by the company Gentaur): the reading of absorbence at 630 nm makes it possible to quantify the inorganic phosphate.

(69) The same experiment is carried out in the presence of the 5′-nucleotidase-inhibiting compounds (I) of the invention (concentration range from 0 to 2 mM). This “broad” screening test makes it possible to determine the percentage inhibition of cN-II by the compounds (I) in the range of concentrations studied.

(70) Experimental Conditions:

(71) The reagents used are: 50 mM imidazole buffer, pH=6.5, 500 mM NaCl and 10 mM MgCl.sub.2. The enzyme (cN-II) concentration is 0.1 μM and the IMP concentration is 100 μM.

(72) An incubation at 37° C. is carried out for 2 to 5 minutes and then stopped by adding the Malachite green reagent which contains a strong acid. A phosphate concentration range is performed in parallel in order to quantify the phosphate produced during the reaction.

(73) For the compounds of the invention which demonstrated a strong inhibition with this first test, a second inhibition test is carried out by measuring the enzymatic kinetics. This longer test makes it possible to characterize the mode of inhibition and to determine the inhibition constant (Ki).

(74) Experimental Procedure of the “Synergy MTT” Test:

(75) For the tests of synergy between the cN-II-inhibiting compounds (I) and the cytotoxic nucleoside analogs, the cells are seeded into 96-well plates containing varied concentrations of the inhibitor (I) alone, of the nucleoside analog alone or of a mixture of the two compounds at a constant ratio (close to the ratio of the IC.sub.50 values for each compound alone). After 72 h of incubation, the living cells are quantified using the MTT reagent.

(76) The inhibitory concentration 50 (IC.sub.50) and the combination index (CI.sub.95) are calculated with the CompuSyn software 1.0 (ComboSyn, Inc., USA).

(77) The IC.sub.50 corresponds to the concentration of a compound which allows 50% survival of the cells.

(78) The CI.sub.95 is calculated according to the method of Chou and Talalay.sup.3 with a formula which takes into account the concentrations of the two compounds and the fraction affected at these concentrations (i.e. the dead cells). CI.sub.95 values below 0.9 indicate synergy between the two compounds, values between 0.9 and 1.1 indicate additivity, and values above 1.1 indicate antagonism according to the customs in the literature.sup.4 and the software manual (Compusyn user's guide). This method is the reference method in the evaluation of interactions between molecules.sup.3; 5; 6; 7.

(79) Table 5 below groups together all of the experimental data obtained regarding the inhibitory activity of about twenty compounds of formula (I) of the invention.

(80) TABLE-US-00005 TABLE 5 Comp.(I) Inhibition RL cancer line tested cN-II in vitro K.sub.i Inhibition strength IC.sub.50 (N°) (200 μM) (mM) (Strong/Medium/Weak) (μM) Synergy MTT  (1) 17 n.d.* W/70% inh. at 1 mM 165 Additive with cladribine  (5) 87 +/− 3% n.d. S  51 Additive with cladribine  (4) 69 +/− 9 n.a. S  25 Additive with cladribine (11)  0% n.d. W/42% inh. at 0.8 mM  51 Antagonistic with cladribine & clofarabine Additive with fludarabine (15)  0% n.d. W/58% inh. at 0.8 mM 107 n.d. (10) 13% n.d. W/25% inh. at 0.8 mM 168 +/− 56 n.d. (14)  7-40% n.d. W/not reproducible 215 +/− 13 n.d.  (6) 56 +/− 13% 1.53 S  11 +/−4 Antagonistic with cladribine, clofarabine, fludarabine  (7) 28% n.d. M n.d n.d.  (2) 60 +/− 5% 0.8 S/competitive  25 Synergy with cladribine & clofarabine (13) 10% n.d. W 203 n.d. (12) 39 +/− 11% n.d. W  34 Synergy with cladribine & clofarabine Antagonistic with fludarabine (16) 47 +/− 12% n.d. W  53 Synergy with clofarabine Antagonistic with fludarabine (17) 21 +/− 10% n.d. W  5 Synergy with clofarabine Antagonistic with fludarabine (19) 68 +/− 15% n.d. S  60 Synergy with cladribine & fludarabine (20) 58 +/−19% n.d. S  51 Antagonistic with cladribine & clofarabine Synergy with fludarabine (22) 43 +/− 7% n.d. M 188 +/− 33 n.d. (21) 50 +/− 2% n.d. M  36 +/− 5 Synergy with cladribine & clofarabine Additive with fludarabine  (3) 60 +/− 5% 0.8 S/competitive 128 n.d.  (9)  0% n.d. No effect/Insoluble  98 Synergy with cladribine Antagonistic with fludarabine (29) 40 +/− 10% n.d. M 130 n.d. (30) 35 +/− 10% n.d. M  58 n.d. (31) 10% n.d. W 250 n.d. (32) 10% n.d. W 145 n.d. (33) 70 +/− 5% n.d. S 195 n.d. *n.d.: not determined; n.a.: not applicable since compound insoluble in the reaction buffer.

(81) Conclusion

(82) Compounds (2), (9), (12), (16), (17), (19), (20) and (21) show a synergistic effect with at least one of the three anticancer agents of the prior art.

(83) Compounds (2), (4), (6), (12), (17) and (21) also show intrinsic cytotoxic activity on the cell model used, with IC.sub.50 values of about a few micromolar to a few tens of micromolar.

Example 4: Evaluation of the In Vivo Antitumor Activity and Ex Vivo Cytotoxic Activity of a Compound of the Invention

(84) The antitumor properties of compound (2) of the invention, namely 9H-purin-6-yl-[1,1′-biphenyl]-3-carboxamide, were determined in a syngeneic model of an intraperitoneal tumor in mice.

(85) Experimental Procedure of the In Vivo Evaluation:

(86) In order to obtain solutions of compound (2) at concentrations compatible with the in vivo evaluations, compound (2) is solubilized at 10 mM using 2,6-diO-methyl-beta-cyclodextrins. L1210 murine leukemia cells (1 million) are injected into the intraperitoneal cavity of four-week-old B6D2F1 mice (three mice per group) on day 1, and the mice are treated on days 2, 4, 7, 9 and 11 with fludarabine (100 mg/kg), compound (2) (7.89 mg/kg or 3.94 mg/kg), a combination of fludarabine and compound (2) or a solution of cyclodextrins alone. The survival of the mice is used as final point of the experiment (see FIG. 5).

(87) Conclusion:

(88) An increase in the dose of compound (2) from 3.94 to 7.89 mg/kg makes it possible to prolong the survival of the mice, indicating a dose-effect in this range.

(89) The combination between compound (2), in particular at 7.89 mg/kg, and fludarabine at 100 mg/kg makes it possible to prolong the survival of the mice compared with fludarabine alone, indicating a potentiating effect of this combination.

(90) Experimental Procedure of the Ex Vivo Evaluation:

(91) Peripheral blood was recovered from patients suffering from chronic lymphoblastic leukemia (LLC) or from acute myeloid leukemia (AML) in heparinized tubes. After lysis of the red blood cells, the blood is incubated for 24 hours in the presence of DMSO, of 10 μM fludarabine, of 100 μM cytarabine or of 100 μM compound (2) of the invention, before determination of the induction of apoptosis and of cell death with the Annexin V and propidium iodide labels by flow cytometry. The cells having experienced an effect of the incubations are labeled with Annexin V alone or with propidium iodide (see FIG. 6).

(92) Conclusion:

(93) All the CLL examples are more sensitive to incubation with 100 μM of compound (2) of the invention than to incubation with 10 μM of fludarabine (65.3% compared with 45.8%), thereby indicating good cytotoxicity of compound (2) for these cells.

(94) For the AML samples, two out of five are more sensitive to 100 μM of compound (2) than to 100 μM of cytarabine, with a mean over the five samples in favor of cytarabine (44.5% compared with 38.6%).

General Conclusion

(95) The originality of the invention is based on the nature of the pharmacological target (cytosolic and non-membrane). No intracellular (cytosolic) 5′-nucleotidase inhibitor is to date described in the treatment of human pathological conditions.

(96) The hitherto unpublished combination of the compounds of the invention, which are 5′-nucleotidase inhibitors, and in particular cN-II inhibitors, with cytotoxic nucleoside analogs which are known at the current time, makes it possible to increase the efficacy of this drug class via several mechanisms: (1) via intrinsic inhibition of cN-II inducing a mechanism of apoptosis; (2) by increasing the intracellular concentration of the phosphorylated (nucleotide) forms of the nucleoside analog, which forms are responsible for its antiproliferative activity; (3) by making it possible to respond to certain mechanisms of cell resistance associated with the overexpression of cN-II.

LITERATURE REFERENCES

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