Phenylpyrrolic compounds used as drugs, their preparation and ap

Details Phenylpyrrolic compounds used as drugs, their preparation and ap Phenylpyrrolic compounds used as drugs, their preparation and ap

1991-04-01

1993-02-23

Lee, Mary C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514423, 514312, 546157, 548517, 548532, 548537, A61K 3140, C07D21516, C07D20730

Patent

active

051890550

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new phenylpyrrole compounds, to their preparation and to their application as an active principle, especially as a drug having antimitotic activity.
The object of the present invention is to propose new compounds which are of use in combating cancer cells, disclosed initially by their reactivity towards tubulin and then by a demonstration of their antimitotic properties.
Tubulin is a cell protein with a molecular weight of the order of 110,000 to 120,000 daltons, consisting of two closely associated subunits, .alpha. and .beta.. It constitutes a basic component whose assembly in helicoid form permits the construction of complex macromolecular structures commonly known as microtubules. The latter are encountered in practically all eukaryotic cells and are used in the formation of many cytoplasmic structures: mitotic spindle, centrioles, flagellae, axonemes, neurotubules, etc. Microtubules thus have fundamental roles, not yet all enumerated, in the life of the cell (division, motility, transport, growth, etc.). The assembling of tubulin is a reversible dynamic mechanism subject to a regulation which has not at present been elucidated.
After extraction of the protein (from pig brain), it is possible to monitor in vitro its assembling and dismantling behaviour under the effect of varying different physicochemical parameters:
- polymerization in the form of microtubules following a temperature rise to 37.degree. C.; promoted by the presence of GTP, polycations, glycerol, etc.
- depolymerization caused by a low temperature (4.degree. C.) and promoted by Ca.sup.2+ ions, excess GTP, etc.
A number of natural substances are capable of binding to specific tubulin receptor sites. They inhibit its polymerization (colchicine, vinblastine, vincristine, podophyllotoxin, etc.) or its depolymerization (taxol, rhazinilam) and can cause its spiralization (vinblastine).
The present invention has been directed towards substances exhibiting biaryl character, capable of interacting with tubulin and hence exhibiting activity as a mitotic spindle poison. To this end, compounds containing a phenylpyrrole skeleton have been synthesized.
The compounds which are the subject of the present invention correspond to the general formula I ##STR1## in which - R.sub.1, R.sub.2 and R.sub.3, independently of one another, are represented by:
(1) - H
(2) - C.sub.1-6 alkyl, ##STR2## in which A.sub.1 and A.sub.2, independently of one another, represent: (a) - H atom at the 5-position of the pyrrole ring, ##STR3## in which B represents: - phenyl(C.sub.1-4 alkoxy), at the 5-position of the pyrrole ring.
(1) - 5- or 6-membered heterocycloalkyl(C.sub.1-4 alkyl), ##STR4## in which Y represents: (a) - C.sub.1-4 alkoxy
The present invention also relates to the preparation of the compounds represented by the general formula I. This preparation process is characterized in that a nitrostyrene of formula II is reacted. [sic] ##STR5## in which: the NO.sub.2 group is situated at the 2'- or 3'-position, with an alkyl isocyanoacetate of formula III
The reaction is carried out according to the method of Barton and Zard permitting the formation of pyrroles from aliphatic or aromatic nitroalkenes, in a THF/absolute tert-butanol (2:1) mixture at a temperature of 40.degree.-50.degree. C. The starting point of the reaction is the Michael type addition of an .alpha.-isocyanoacetate to the nitrostyrene in the presence of a base, in this case DBU.
The nitrostyrene used is prepared beforehand by the condensation of nitroethane with the corresponding nitrobenzaldehyde according to a Knoevenagel reaction.
From the nitrostyrenes, access is hence gained directly or via a simple functional conversion to the phenylpyrroles which are the subject of the present invention.
Thus, in the case where the compound I' is obtained ##STR6## it is converted to other compounds represented by the general formula I according to one or more of the following conversions:
(1) - simultaneous reduction of the nitro group of the aromatic ring and the ester function o

REFERENCES:
CA 112:76858n Novel dimerization . . . pyrroles, Mukherjee et al, 1989, p. 768.
CA 113:115077z Preparation . . . agents, Thal et al., 1990, p. 671.

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