Anti-tubulin acting arylpyrrol, arylfuran and arylthiophene derivatives, method for the preparation thereof and for the use thereof as an antimitotic

1. A compound represented by following formula I:

in which:

Z represents N, O or S,

R1, R3, R4, R5 and R6 represent independently of one another an atom of hydrogen, an atom of fluorine, a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group, a C 2 -C 12 linear or branched alkenyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B represents

a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6 linear or branched alkyl group, a C 1 -C 6 linear or branched alkoxy group, a NH 2 group, a NO 2 group, a CN group, a COOH group, a C 1 -C 6 linear or branched CO 2 (alkyl) group, a CONH 2 group, a C 1 -C 6 linear or branched CONH(alkyl) group, a C 1 -C 6 linear or branched CON(alkyl) 2 group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3 group, an OSO 2 CF 3 group;

a naphthyl group;

an anthracenyl group;

a 9H-fluorenyl group possibly substituted at position 9 by one or two C 1 -C 12 linear or branched alkyl groups;

an anisyl group or a pyridinyl group;

R2 represents H, a C 1 -C 12 linear or branched alkyl group, a phenyl group, a benzyl group, a C 1 -C 6 linear or branched CO 2 (alkyl) group, a CO 2 (benzyl) group, a C 3 -C 6 linear or branched CO 2 (alkenyl) group, a tosyl group, a mesyl group, a 9-fluorenylmethoxycarbonyl (FMOC) group, a NH 2 group or a C 1 -C 6 linear or branched NH(alkyl) group, a C 1 -C 6 linear or branched N(alkyl) 2 group, NH tertiobutyloxycarbonyl, NHCO 2 CH 2 phenyl or R2 is absent when Z represents O or S;

X represents a C 1 -C 12 linear or branched alkyl group, a C 1 -C 12 linear or branched hydroxyalkyl group or a C 1 -C 12 linear or branched aminoalkyl group;

A represents a CH group, a nitrogen atom or a NL + group in which L represents a C 1 -C 12 linear or branched alkyl group;

Y represents an atom of hydrogen, a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group, an OH group, a CN group, a N 3 group, a C 1 -C 12 linear or branched alkoxy group, a C 1 -C 12 linear or branched hydroxyalkyl group, a C 1 -C 12 linear or branched aminoalkyl group, N 2 + , a NZ1-NHZ2, NH—NZ1Z2 or NZ1Z2 group in which Z1 and Z2 represent independently of one another an atom of hydrogen, a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group, a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6 linear or branched alkyl group, a C 1 -C 6 linear or branched alkoxy group, a NH 2 group, a CN group, a COOH group, a C 1 -C 6 linear or branched CO 2 (alkyl) group, a CONH 2 group, a C 1 -C 6 linear or branched CONH(alkyl) group, a C 1 -C 6 linear or branched CON(alkyl) 2 group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3 group, an OSO 2 CF 3 group, a benzyl group, an anisyl group, a pyridinyl group, C(O)—W, C(S)—W or C(NH)—W in which

W represents a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group, a C 1 -C 12 linear or branched alkoxy group, a C 1 -C 12 linear or branched alkylthio group or NQQ1 in which

Q and Q1 represent independently of one another an atom of hydrogen, a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group or CH(M)CO 2 M1 in which

M and M1 represent independently of one another a hydrogen atom, a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group, a C 2 -C 12 linear or branched alkenyl group, a phenyl group, a benzyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B is as defined above,

with the exception of the following formulas:

2. A compound according to claim 1 in which Z represents N.

3. A compound according to claim 1 in which A represents the group CH.

4. A compound according to claim 1 in which Y represents a NH 2 group or an atom of hydrogen.

5. A compound according to claim 1 in which X represents a C 1 -C 12 linear or branched alkyl group.

6. A compound according to claim 1 wherein said compound is selected from the group consisting of:

7. A method of preparing compounds according to claim 1 comprising the steps of:

a) synthesizing a pyrrolylalkylcarbinole, furanylalkylcarbinole or thiophenylalkylcarbinole unit of following formula II:

in which Z, X, R1 and R4 are as defined in claim 1 and GP represents a nitrogen protective group when Z represents N, or is absent when Z represents O or S, and

b) functionalizing the pyrrolylalkylcarbinole, furanylalkylcarbinole, or thiophenylalkylcarbinole unit by introducing an aryl or heteroaryl unit at position 3 of the pyrrole, furan or thiophene ring.

8. A method according to claim 7 wherein X represents (CH 2 ) 3 , and wherein step a) consists of the cyclodehydration of unsaturated β-γ aminoketones of following formula III:

in which Z, R1, R4 and GP are as defined in claim 7 in order to obtain the product of following formula IV:

in which Z, R1, R4 and GP are as defined in claim 7 ,

followed by the introduction of the alcohol function by hydroboration-oxidation of the product of formula IV in order to obtain the product of formula II as defined in claim 7 .

9. A method according to claim 7 wherein R2, R3, R4, R5 and R6 represent an atom of hydrogen, Y represents a NH 2 group, A represents a CH group, X represents (CH 2 ) 3 and Z represents N, wherein step b) consists of:

a palladium-catalyzed Suzuki-Miyaura cross-coupling of the compound of formula II, in which R4 represents an atom of hydrogen, X represents (CH 2 ) 3 , Z represents N and GP represents a nitrogen protective group, and of 2-triazene boronic acid in order to obtain a compound of following formula V:

in which GP represents a nitrogen protective group,

deprotection of the triazene function in order to obtain the group of following formula VI:

in which GP represents a nitrogen protective group,

specific deprotection of protective group GP in order to obtain the compound of formula I in which R2, R3, R4, R5 and R6 represent an atom of hydrogen, Y represents a NH 2 group, A represents a CH group, X represents (CH 2 ) 3 , and Z represents N.

10. A pharmaceutical composition comprising a compound according to claim 1 or a compound selected from the group consisting of:

and a pharmaceutically acceptable excipient.

11. A compound of formula V:

in which GP represents a nitrogen protective group and R1 represents an atom of hydrogen, an atom of fluorine, a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group, a C 2 -C 12 linear or branched alkenyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B represents a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6 linear or branched alkyl group, a C 1 -C 6 linear or branched alkoxy group, a NH 2 group, a NO 2 group, a CN group, a COOH group, a C 1 -C 6 linear or branched CO 2 (alkyl) group, a CONH 2 group, a C 1 -C 6 linear or branched CONH(alkyl) group, a C 1 -C 6 linear or branched CON(alkyl) 2 group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3 group, an OSO 2 CF 3 group; a naphthyl group; an anthracenyl group; a 9H-fluorenyl group possibly substituted at position 9 by one or two C 1 -C 12 linear or branched alkyl groups; an anisyl group or a pyridinyl group.

12. A compound of formula VI:

in which GP represents a nitrogen protective group and R1 represents an atom of hydrogen, an atom of fluorine, a C 1 -C 12 linear or branched alkyl group, a C 3 -C 12 cycloalkyl group, a C 2 -C 12 linear or branched alkenyl group, a CH 2 —B or CH 2 —CH 2 —B group in which B represents a phenyl group possibly substituted by one or more groups chosen among a C 1 -C 6 linear or branched alkyl group, a C 1 -C 6 linear or branched alkoxy group, a NH 2 group, a NO 2 group, a CN group, a COOH group, a C 1 -C 6 linear or branched CO 2 (alkyl) group, a CONH 2 group, a C 1 -C 6 linear or branched CONH(alkyl) group, a C 1 -C 6 linear or branched CON(alkyl) 2 group, a Cl atom, a Br atom, an I atom, an OH group, a COCF 3 group, an OSO 2 CF 3 group; a naphthyl group; an anthracenyl group; a 9H-fluorenyl group possibly substituted at position 9 by one or two C 1 -C 12 linear or branched alkyl groups; an anisyl group or a pyridinyl group.