Pseudopeptide compounds having an inhibiting activity with respect to paths activated by proteins with active tyrosine kinase activity and pharmaceutical compositions containing same

Pseudopeptide compound corresponding to general formula II:

• 4
• wherein:
• P denotes a protecting group or a hydrogen atom,
• R3 denotes a straight chain or branched C1 to C4 alkyl group or an alkylcycloalkyl group having a C3 to C6 cycloalkyl,
• R4 and/or R5 denote
• a hydrogen,
• a straight chain or branched C1 to C6 alkyl group
• a C1 to C6 arylalkyl group wherein aryl denotes a phenyl or naphtyl nucleus optionally substituted by one or more hydroxyl groups, or
• an aminohexanoic chain followed by the sequences RQIKIWFQNRRMKWKK, IRQPKIWFPNRRKPWKK, Cys-S-S-Cys-RQIKIWFQNRRMKWKK and Cys-S-S-Cys-IRQPKIWFPNRRKPWKK, derived from Antennapedia, and the phenylmethyl group substituted by P1′ is a precursor of a group selected from the group consisting of:
• a phenylmethyl radical wherein the phenyl nucleus is substituted in the para position by a phosphate, phosphonomethyl, phosphonomonofluoromethyl or phosphonodifluoromethyl radical or
• a naphtylmethyl radical which may be substituted in the 4 position by a phosphate, phosphonomethyl, phosphonomono- or phosphonodifluoromethyl radical,
• each of these radicals also being optionally substituted by one or more substituents selected from the group consisting of C1 to C4 alkyl or C1 to C4 alkoxy groups and/or one or more halogen atoms,
• and the phenylmethyl group substituted by P2′ is a precursor of a group selected from the group consisting of:
• a phenylmethyl or naphtylmethyl or cyclohexylmethyl radical, 2- or 3-pyridinylmethyl, substituted at the para or meta position of the ring by a phosphate, C1 to C2 phosphonoalkyl group, phosphonomonofluoromethyl, phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-(dicarboxy)ethyl, 2-malonyloxy, 5-tetrazolyl or 5-tetrazolylmethyl radical or
• a radical alkyl of the type (CH2)n (wherein n=3 or 4) substituted in end position by a phosphate group, C1 to C2 phosphonoalkyl, preferably phosphonomonofluoromethyl and phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-malonyloxy, 2-dicarboxyethyl, 5-tetrazolyl or 5-tetrazolylmethyl radical and the pharmaceutically acceptable salts thereof.

A pharmaceutical composition containing as active ingredient at least one compound selected from the group consisting of:

• mAZ-pTyr-(αMe)pTyr-Asn-N H2
• mAZ-pTyr-(αMe)pTyr-Asn-Aha-Antennapedia
• mAZ-Pmp-(αMe)pTyr-Asn-NH2
• mAZ-pTyr-(αMe)Phe(COOH)-Asn-NH2
• mAZ-pTyr-(αMe)Phe(CH2—COOH)-Asn-NH2.
• mAZ-pTyr-(αMe)Pmp-Asn-N H2
• mAZ-pTyr-(αMe)F2Pmp-Asn-N H2
• mAZ-pTyr-(αMe)Phe(PO3H2)-Asn-NH2
• mAZ-pTyr-(αMe)Phe(PO3H2)-Asn-Aha-Antennapedia

A method of preparing a pharmaceutical composition intended for the treatment of diseases connected with proliferative processes, cancers and/or metastases comprising combining excipients with a compound of general formula I

• 5
• wherein:
• P denotes a protecting group or a hydrogen atom,
• R1 denotes
• a phenylmethyl radical wherein the phenyl nucleus is substituted in the para position by a phosphate, phosphonomethyl, phosphonomonofluoromethyl or phosphonodifluoromethyl radical or
• a naphtylmethyl radical which may be substituted in the 4 position by a phosphate, phosphonomethyl, phosphonomono- or phosphonodifluoromethyl radical,
• each of these radicals also being optionally substituted by one or more substituents selected from among the C1 to C4 alkyl or C1 to C4 alkoxy groups and/or one or more halogen atoms,
• R2 denotes:
• a phenylmethyl or naphtylmethyl or cyclohexylmethyl radical, 2- or 3-pyridinylmethyl, substituted at the para or meta position of the ring by a phosphate, C1 to C2 phosphonoalkyl group, phosphonomonofluoromethyl, phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-(dicarboxy)ethyl, 2-malonyloxy, 5-tetrazolyl or 5-tetrazolylmethyl radical or
• a radical alkyl of the type (CH2)n (wherein n=3 or 4) substituted in end position by a phosphate group, C1 to C2 phosphonoalkyl, preferably phosphonomonofluoromethyl and phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-malonyloxy, 2-dicarboxyethyl, 5-tetrazolyl or 5-tetrazolylmethyl radical,
• R3 denotes a straight chain or branched C1 to C4 alkyl group or an alkylcycloalkyl group having a C3 to C6 cycloalkyl,
• R4 and/or R5 denote
• a hydrogen,
• a straight chain or branched C1 to C6 alkyl group
• a C1 to C6 arylalkyl group wherein aryl denotes a phenyl or naphtyl nucleus optionally substituted by one or more hydroxyl groups, or
• an aminohexanoic chain followed by the sequences RQIKIWFQNRRMKWKK, IRQPKIWFPNRRKPWKK, Cys-S-S-Cys-RQIKIWFQNRRMKWKK and Cys-S-S-Cys-IRQPKIWFPNRRKPWKK derived from Antennapedia and pharmaceutically acceptable salts thereof.

A method of preparing a pharmaceutical composition intended for the treatment of diseases connected with proliferative processes, cancers and/or metastases comprising combining excipients with a compound selected from the group consisting of:

• mAZ-pTyr-(αMe)pTyr-Asn-NH2
• mAZ-pTyr-(αMe)pTyr-Asn-Aha-Antennapedia
• mAZ-Pmp-(αMe)pTyr-Asn-NH2
• mAZ-pTyr-(αMe)Phe(COOH)-Asn-NH2
• mAZ-pTyr-(αMe)Phe(CH2—COOH)-Asn-NH2.
• mAZ-pTyr-(αMe)Pmp-Asn-NH2
• mAZ-pTyr-(αMe)F2Pmp-Asn-NH2
• mAZ-pTyr-(αMe)Phe(PO3H2)-Asn-NH2
• mAZ-pTyr-(αMe)Phe(PO3H2)-Asn-Aha-Antennapedia.

A method of preparing a pharmaceutical composition intended for the treatment of diseases connected with proliferative processes, cancers and/or metastases comprising combining excipients with a compound of general formula II

• 6
• wherein:
• P denotes a protecting group or a hydrogen atom,
• R3 denotes a straight chain or branched C1 to C4 alkyl group or an alkylcycloalkyl group having a C3 to C6 cycloalkyl.
• R4 and/or R5 denote
• a hydrogen,
• a straight chain or branched C1 to C6 alkyl group
• a C1 to C6 arylalkyl group wherein aryl denotes a phenyl or naphtyl nucleus optionally substituted by one or more hydroxyl groups, or
• an aminohexanoic chain followed by the sequences RQIKIWFQNRRMKWKK, IRQPKIWFPNRRKPWKK, Cys-S-S-Cys-RQIKIWFQNRRMKWKK and Cys-S-S-Cys-IRQPKIWFPNRRKPWKK, derived from Antennapedia,
• and the phenylmethyl group substituted by P1′ is a precursor of a group selected from the group consisting of:
• a phenylmethyl radical wherein the phenyl nucleus is substituted in the para position by a phosphate, phosphonomethyl, phosphonomonofluoromethyl or phosphonodifluoromethyl radical or
• a naphtylmethyl radical which may be substituted in the 4 position by a phosphate, phosphonomethyl, phosphonomono- or phosphonodifluoromethyl radical,
• each of these radicals also being optionally substituted by one or more substituents selected from the group consisting of C1 to C4 alkyl or C1 to C4 alkoxy groups and/or one or more halogen atoms,
• and the phenylmethyl group substituted by P2′ is a precursor of a group selected from the group consisting of:
• a phenylmethyl or naphtylmethyl or cyclohexylmethyl radical, 2- or 3-pyridinylmethyl, substituted at the para or meta position of the ring by a phosphate, C1 to C2 phosphonoalkyl group, phosphonomonofluoromethyl, phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-(dicarboxy)ethyl, 2-malonyloxy, 5-tetrazolyl or 5-tetrazolylmethyl radical or
• a radical alkyl of the type (CH2)n (wherein n=3 or 4) substituted in end position by a phosphate group, C1 to C2 phosphonoalkyl, preferably phosphonomonofluoromethyl and phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-malonyloxy, 2-dicarboxyethyl, 5-tetrazolyl or 5-tetrazolylmethyl radical and the pharmaceutically acceptable salts thereof.

A method for the treatment of cancers, metastases and/or diseases connected with proliferative processes comprising administering to a patient in need of such treatment a therapeutically efficient amount of a compound comprising a pseudopeptide corresponding to general formula I

• 7
• wherein:
• P denotes a protecting group or a hydrogen atom,
• R1 denotes
• a phenylmethyl radical wherein the phenyl nucleus is substituted in the para position by a phosphate, phosphonomethyl, phosphonomonofluoromethyl or phosphonodifluoromethyl radical or
• a naphtylmethyl radical which may be substituted in the 4 position by a phosphate, phosphonomethyl, phosphonomono- or phosphonodifluoromethyl radical, each of these radicals also being optionally substituted by one or more substituents selected from among the C1 to C4 alkyl or C1 to C4 alkoxy groups and/or one or more halogen atoms,
• R2 denotes:
• a phenylmethyl or naphtylmethyl or cyclohexylmethyl radical, 2- or 3-pyridinylmethyl, substituted at the para or meta position of the ring by a phosphate, C1 to C2 phosphonoalkyl group, phosphonomonofluoromethyl, phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-(dicarboxy)ethyl, 2-malonyloxy, 5-tetrazolyl or 5-tetrazolylmethyl radical or
• a radical alkyl of the type (CH2)n (wherein n=3 or 4) substituted in end position by a phosphate group, C1 to C2 phosphonoalkyl, preferably phosphonomonofluoromethyl and phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-malonyloxy, 2-dicarboxyethyl, 5-tetrazolyl or 5-tetrazolylmethyl radical,
• R3 denotes a straight chain or branched C1 to C4 alkyl group or an alkylcycloalkyl group having a C3 to C6 cycloalkyl.
• R4 and/or R5 denote
• a hydrogen,
• a straight chain or branched C1 to C6 alkyl group
• a C1 to C6 arylalkyl group wherein aryl denotes a phenyl or naphtyl nucleus optionally substituted by one or more hydroxyl groups, or an aminohexanoic chain followed by the sequences RQIKIWFQNRRMKWKK, IRQPKIWFPNRRKPWKK, Cys-S-S-Cys-RQIKIWFQNRRMKWKK and Cys-S-S-Cys-IRQPKIWFPNRRKPWKK derived from Antennapedia and pharmaceutically acceptable salts thereof.

A method for the treatment of cancers, metastases and/or diseases connected with proliferative processes comprising administering to a patient in need of such treatment a therapeutically efficient amount of a compound from the group consisting of:

• m-AZ-pTyr-(αMe)pTyr-Asn-NH2
• mAZ-pTyr-(αMe)pTyr-Asn-Aha-Antennapedia
• mAZ-Pmp-(αMe)pTyr-Asn-NH2
• mAZ-pTyr-(αMe)Phe(COOH)-Asn-NH2
• mAZ-pTyr-(αMe)Phe(CH2—COOH)-Asn-NH2.
• mAZ-pTyr-(αMe)Pmp-Asn-NH2
• mAZ-pTyr-(αMe)F2Pmp-Asn-NH2
• mAZ-pTyr-(αMe)Phe(PO3H2)-Asn-NH2
• mAZ-pTyr-(αMe)Phe(PO3H2)-Asn-Aha-Antennapedia

A method for the treatment of cancers, metastases and/or diseases connected with proliferative processes comprising administering to a patient in need of such treatment a therapeutically efficient amount of a compound comprising a pseudopeptide compound corresponding to general formula II:

• 8
• wherein:
• P denotes a protecting group or a hydrogen atom,
• R3 denotes a straight chain or branched C1 to C4 alkyl group or an alkylcycloalkyl group having a C3 to C6 cycloalkyl.
• R4 and/or R5 denote
• a hydrogen,
• a straight chain or branched C1 to C6 alkyl group
• a C1 to C6 arylalkyl group wherein aryl denotes a phenyl or naphtyl nucleus optionally substituted by one or more hydroxyl groups, or
• an aminohexanoic chain followed by the sequences RQIKIWFQNRRMKWKK, IRQPKIWFPNRRKPWKK, Cys-S-S-Cys-RQIKIWFQNRRMKWKK and Cys-S-S-Cys-IRQPKIWFPNRRKPWKK, derived from Antennapedia,
• and the phenylmethyl group substituted by P1′ is a precursor of a group selected from the group consisting of:
• a phenylmethyl radical wherein the phenyl nucleus is substituted in the para position by a phosphate, phosphonomethyl, phosphonomonofluoromethyl or phosphonodifluoromethyl radical or
• a naphtylmethyl radical which may be substituted in the 4 position by a phosphate, phosphonomethyl, phosphonomono- or phosphonodifluoromethyl radical,
• each of these radicals also being optionally substituted by one or more substituents selected from the group consisting of C1 to C4 alkyl or C1 to C4 alkoxy groups and/or one or more halogen atoms,
• and the phenylmethyl group substituted by P2′ is a precursor of a group selected from the group consisting of:
• a phenylmethyl or naphtylmethyl or cyclohexylmethyl radical, 2- or 3-pyridinylmethyl, substituted at the para or meta position of the ring by a phosphate, C1 to C2 phosphonoalkyl group, phosphonomonofluoromethyl, phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-(dicarboxy)ethyl, 2-malonyloxy, 5-tetrazolyl or 5-tetrazolylmethyl radical or
• a radical alkyl of the type (CH2)n (wherein n=3 or 4) substituted in end position by a phosphate group, C1 to C2 phosphonoalkyl, preferably phosphonomonofluoromethyl and phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-malonyloxy, 2-dicarboxyethyl, 5-tetrazolyl or 5-tetrazolylmethyl radical and the pharmaceutically acceptable salts thereof.

An automatable process for evaluating, in a high throughput test, the affinity of a compound comprising a pseudopeptide corresponding to general formula I

• 9
• wherein:
• P denotes a protecting group or a hydrogen atom,
• R1 denotes
• a phenylmethyl radical wherein the phenyl nucleus is substituted in the para position by a phosphate, phosphonomethyl, phosphonomonofluoromethyl or phosphonodifluoromethyl radical or
• a naphtylmethyl radical which may be substituted in the 4 position by a phosphate, phosphonomethyl, phosphonomono- or phosphonodifluoromethyl radical, each of these radicals also being optionally substituted by one or more substituents selected from among the C1 to C4 alkyl or C1 to C4 alkoxy groups and/or one or more halogen atoms,
• R2 denotes:
• a phenylmethyl or naphtylmethyl or cyclohexylmethyl radical, 2- or 3-pyridinylmethyl, substituted at the para or meta position of the ring by a phosphate, C1 to C2 phosphonoalkyl group, phosphonomonofluoromethyl, phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-(dicarboxy)ethyl, 2-malonyloxy, 5-tetrazolyl or 5-tetrazolylmethyl radical or
• a radical alkyl of the type (CH2)n (wherein n=3 or 4) substituted in end position by a phosphate group, C1 to C2 phosphonoalkyl, preferably phosphonomonofluoromethyl and phosphonodifluoromethyl, phosphonate, phosphinate, sulfonate, sulfonomethyl, carboxylate, carboxymethyl, carboxymethyloxy, malonyl, 2-malonyloxy, 2-dicarboxyethyl, 5-tetrazolyl or 5-tetrazolylmethyl radical,
• R3 denotes a straight chain or branched C1 to C4 alkyl group or an alkylcycloalkyl group having a C3 to C6 cycloalkyl,
• R4 and/or R5 denote
• a hydrogen,
• a straight chain or branched C1 to C6 alkyl group
• a C1 to C6 arylalkyl group wherein aryl denotes a phenyl or naphtyl nucleus optionally substituted by one or more hydroxyl groups, or an aminohexanoic chain followed by the sequences RQIKIWFQNRRMKWKK, IRQPKIWFPNRRKPWKK, Cys-S-S-Cys-RQIKIWFQNRRMKWKK and Cys-S-S-Cys-IRQPKIWFPNRRKPWKK derived from Antennapedia and pharmaceutically acceptable salts thereof for Grb2, wherein said compound is made to compete with the peptide biotine Aha-PSpYVNVQN for Grb2 in an ELISA test.