Novel stabilized activated derivatives of carbamic acid, their process of preparation and their use for the preparation of ureas

Compounds of the formula (III bis)

• 66
• in which
• “n” is a whole number greater than or equal to 1,
• “i” is a whole number varying from 2 to n+1,
• the Y group can be or contain:
• 1/ a pseudopeptide
• 2/ an amino acid residue or a chain of amino acids comprising 1 to 10 residues,
• 3/ a GP group which can be:
• a protective group selected from:
• a hydrogen atom, an oxycarbonyl (ROCO), acyl, alkyl, aryl, urea, phthalimide (with R1=Ø), biotin, O2 (with R1=Ø) group,
• or such that the “GP-N” entity forms an “NH2+” entity,
• the groups R1 and Ri can each represent independently from each other:
• a hydrogen, a halogen, the protected or unprotected side chain of an amino acid selected from natural and synthetic amino acids, a (C1-C20) alkyl group substituted or not, an alkyl group whose cyclic structure contains 5 to 20 carbon atoms, a group ORa, NH2, OH, —COORa, —CONHRa, —CONH2, —CH2COORa, —CH2CONHRa, —CH2CONH2,
• Ra representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl having 1 to 20 carbon atoms group, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms,
• the X group represents a group conferring on the compound of formula (III bis) a structure of an activated derivative of carbamic acid, which X group is from a compound selected particularly from phenols, if desired substituted with at least one nitro or at least one halogen, or hydroxylamine derivatives, or hydroxy-1,2,3-benzotriazole, 1-oxo-2-hydroxydihydrobenzotriazine (HODhbt), 7-aza-1-hydroxy-benzotriazole (HOAt), 4-aza-1-hydroxybenzotriazole (4-HOAt), imidazole and tetrazole,
• the R1 and Ri groups can also form a cycle,
• provided that the compound of formula (III bis) is different from the following compounds in which:
• n=2, GP=Boc, R1=isobutyl, R2=R3=H, X=4-nitrophenol
• n=2, GP=Boc, R1=benzyl, R2=R3=H, X=4-nitrophenol
• n=2, GP=Boc, R1=CH2-p-C6H4Ot-Bu, R2=R3=H, X=4-nitrophenol
• n=2, GP=Boc, R1=H, R2=R3=H, X=4-nitrophenol

Compounds of the formula (IV)

• 70
• in which
• “n” is a whole number greater than or equal to 1,
• “i” is a whole number varying from 2 to n+1,
• the Y group can be or contain:
• 1/ a pseudopeptide
• 2/ an amino acid residue or a chain of amino acids comprising 1 to 10 residues
• 3/ a GP which can be:
• a protective group selected from:
• a hydrogen atom, an oxycarbonyl (ROCO), acyl, alkyl, aryl, urea, phthalimide (with R1=Ø), biotin, O2 (with R1=Ø) group,
• or such that the “GP-N” entity forms an “NH2+” entity,
• the groups R1 and Ri can each represent independently from each other:
• hydrogen, halogen, protected or unprotected side chain of an amino acid selected from natural or synthetic amino acids, a (C1-C20) alkyl group substituted or not, an aryl group, whose cyclic structure contains 5 to 20 carbon atoms, an ORa, NH2, OH, —COORa, —CONHRa, —CONH2, —CH2COORa, —CH2CONHRa, —CH2CONH2 group,
• Ra representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl having 1 to 20 carbon atoms group, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms,
• the groups R1 and Ri can also form a cycle,
• provided that the compound of formula (IV) is different from the compounds in which:
• n=1, GP=Boc or benzyloxycarbonyle, R1=Ø
• n=2, GP=phtalimide, R1=Ø, R3=benzyle, R2=H
• n=2, GP=phtalimide, R1=Ø, R3=methyle, R2=H
• n=2, GP=phtalimide, R1=Ø, R3=H, R2=H
• n=2, GP=phtalimide, R1=Ø, R3=CH2i-Pr, R2=H
• n=2, GP=phtalimide, R1=Ø, R3=CH2COOt-Bu, R2=H
• n=2, GP=phtalimide, R1=Ø, R3=CH2 CH2 CH2 CH2NHBoc, R2=H
• n=2, GP=phtalimide, R1=Ø, R3=CH2CH2CH2NHCNH (N-Mtr), R2=H, (Mtr=4-methoxy-2,3,6-trimethyl-benzenesulphonyle)
• n=2, GP=Boc, R1=benzyle, R2=R3=H
• n=2, GP=Boc, R1=i-Bu, R2=R3=H
• n=2, GP=Boc, R1=H, R2=R3=H

Compounds of formula (VII)

• 74
• in which
• “n” is a whole number greater than or equal to 1,
• “i” is a whole number varying from 2 to n+1,
• the Y group can be or contain:
• 1/ a pseudopeptide
• 2/ an amino acid residue or a chain of amino acids comprising 1 to 10 residues
• 3/ a GP group which can be:
• a protective group selected from:
• oxycarbonyl (ROCO), acyl, alkyl, aryl, urea, phthalimide (with R1=Ø), biotin, O2 (with R1=Ø),
• or such that the “GP-N” entity forms an “NH2+” entity,
• the groups R1 and Ri can each represent independently of each other:
• hydrogen, halogen, the protected or unprotected side chain of an amino acid selected from natural and synthetic amino acids, a (C1-C20) alkyl group, substituted or not, an aryl group, whose cyclic structure contains 5 to 20 carbon atoms, an ORa, NH2, OH, —COORa, —CONHRa, —CONH2, —CH2COORa, —CH2CONHRa, —CH2CONH2 group,
• Ra represents an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl group having 1 to 20 carbon atoms, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms,
• the group B can be either N-W′ or O,
• the groups W and W′ can be or contain:
• A/ hydrogen
• B/ a pseudopeptide
• C/ an amino acid residue or a chain of amino acid residues comprising 1 to 10 residues
• the groups R1 and Ri can also form a cycle,
• provided that the compounds of the following formulas are excluded:
• 75
• provided that the compound of formula (VII) is different from the analogs of the peptide Tyr-Gly-Gly-Phe-Leu-OH, containing one or several derivatives as defined below mimicking the side chain of amino acids present in the peptide and permitting the introduction of one or several urea linkages, which is to say that the compound of formula (VII) is different from the following compounds:
• 76
• in which R represents hydroxybenzyl, a hydrogen atom, a benzyl group, or an isobutyl group,
• and provided that the compound of formula (VII) is different from:
• 77

Compounds of formula (VIII)

• 81
• in which
• W′ can be or contain:
• A/ hydrogen,
• B/ a (C1-C20) alkyl group, substituted or not,
• C/ an aryl group, whose cyclic structure contains 5 to 20 carbon atoms,
• D/ a protected or unprotected side chain of amino acids selected from proteinogenic and non-proteinogenic amino acids and in the case of proline, W′=—CH2—CH2—CH2—CH(COOR)—,
• E/ an amino acid residue or a chain of amino acid residues comprising 1 to 10 residues,
• Ri and R′i represent independently of each other a hydrogen atom, a halogen, the protected or unprotected side chain of an amino acid selected from natural and synthetic amino acids, a (C1-C20) alkyl group, substituted or not, or an aryl group,
• B is a nitrogen atom or an oxygen atom,
• ai, a′i, bi-1 and bi represent interatomic bonds that can be single or double,
• the group Y′ can be or contain:
• I/ a (C1-C20) alkyl group, substituted or not,
• II/ an aryl group
• III/ a pseudopeptide
• the Y group can be or contain:
• I/ a (C1-C20) alkyl group, substituted or not
• II/ an aryl group
• III/ a pseudopeptide
• IV/ or form with B an amino acid residue or a chain of amino acid residues comprising 1 to 10 residues, the acid function of the amino acid residue or of the chain of amino acid residues being fixed on the group NY′,
• V/ or form with B a urea oligomer comprising 1 to 10 residues, the carbonyl function of the urea residue being fixed on the group NY′.

Compounds of formula (VIII bis)

• 83
• in which:
• the total number of atoms forming the cycle is greater than six,
• “n” is a whole number greater than or equal to 1,
• “i” is a whole number varying from 2 to n+1,
• the R1, Ri and Rn+2 groups can each represent independently of each other:
• a hydrogen, a halogen, the protected or unprotected side chain of an amino acid selected from natural and synthetic amino acids, a (C1-C20) alkyl group, substituted or not, an aryl group, whose cyclic structure contains 5 to 20 carbon atoms, an ORa, NH2, OH, —COORa, —CONHRa, —CONH2, —CH2COORa, —CH2CONHRa, —CH2CONH2 group,
• Ra representing an allyl, benzyl, t-butyl, fluorenylmethyl, alkyl group having 1 to 20 carbon atoms, or an aryl group whose cyclic structure contains 5 to 20 carbon atoms,
• the groups R1 and R1 can also form a cycle,
• the group Y can be or contain:
• 1/ a (C1-C20) alkyl group, substituted or not
• II/ an aryl group
• III/ a pseudopeptide
• IV/ or forming with B an amino acid residue or a chain of amino acid residues comprising 1 to 10 residues, the acid function of the amino acid residue or of the chain of amino acid residues being fixed on the group NR1,
• the group B can be either N-W′ or O,
• the group W′ can be or contain:
• A/ hydrogen,
• B/ a (C1-C20) alkyl group, substituted or not,
• C/ an aryl group, whose cyclic structure contains 5 to 20 carbon atoms,
• D/ a protected or unprotected side chain of amino acids selected from proteinogenic and non-proteinogenic amino
• acids and in the case of praline, W′=—CH2—CH2—CH2—CH(COOR)—
• E/ an amino acid residue or a chain of amino acid residues comprising 1 to 10 residues.