Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-24
2000-04-25
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546208, A61K 31445
Patent
active
060544686
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with the compound 1-(1H-pyrrol-2-ylmethyl)-2-piperidone for use as a medicine, in particular for use as an agent for reducing excessive directional cell migration (as in metastasis); and with pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the title compound as an active ingredient.
The present invention is concerned with the compound 1-(1H-pyrrol-2-ylmethyl)-2-piperidone of formula (I) ##STR1## and the pharmaceutically acceptable acid addition salts thereof for use as a medicine.
The base compound 1-(1H-pyrrol-2-ylmethyl)-2-piperidone is known from J. Med. Chem., 1992, 35 (3), 552-8 for use as an intermediate in the manufacture of antipsychotic agents. Hitherto, the compound was not known to have pharmacological activity.
Pharmaceutically acceptable acid addition salts are novel and comprise the therapeutically active, non-toxic salt forms obtained by treating a base form with an acid such as, for example, an inorganic acid, e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid ; or an organic acid, e.g. acetic, propanoic, hydroxyacetic, lactic, pyruvic, malonic, succinic, maleic, fumaric, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic acid. The compound of formula (I) is preferably in the base form for use as a medicine.
The compound 1-(1H-pyrrol-2-ylmethyl)-2-piperidone can conveniently be prepared by condensing 1H-pyrrol-2-carboxaldehyde with methyl 5-aminopentanoate to the corresponding imine, and then reducing the imine to the secondary amine which will cyclize to the title compound. The first condensation step can be performed in any aprotic solvent, in the presence of a dehydrating agent, optionally in the presence of an acid or base. Suitable aprotic solvents are, for example, halogenated hydrocarbons such as di- and trichloromethane. Suitable dehydrating agents are, for example, 50 nm molecular sieves, anhydrous salts such as anhydrous copper sulphate. Acid and base catalysts which can be used are, for example, p-toluenesulfonic acid and triethylamine.
The reduction-cyclization step can be performed by catalytically hydrogenating the imine compound at room temperature in an appropriate solvent. Suitable catalysts are platinum oxide, platinum-on-charcoal and palladium-on-charcoal. Appropriate solvents are alcohols, in particular ethanol, esters, e.g. ethyl acetate, ethers, e.g. tetrahydrofuran.
In UK Patent Application No. 9510944.3 filed Jun. 1, 1995 and in PCT/EP96/02311 (published as WO-96/38555 on Dec. 12, 1996) which claims priority of said UK Patent Application and which was filed concommittantly with the priority application of the instant patent application, there are described processes for the identification of compounds which inhibit or enhance the direction of cell migration, and the use of such compounds in the regulation of directional cell migration. The patent applications referred to elucidate the key role of the UNC-53 protein in the control of directional cell migration. Increased UNC-53 protein activity was found to be proportional to increased growth cone extension in the correct direction of cell migration. Inhibitors and enhancers of the unc-53 gene or the UNC-53 protein were predicted to affect the cell motility; inhibitors thus have utility in--amongst other disorders and diseases--oncology, in particular in metastasis.
Unexpectedly, the compound 1-(1H-pyrrol-2-ylmethyl)-2-piperidone has now been identified as an inhibitor of directional cell migration in assays as disclosed in the patent applications referred to above. One such assay is described in more detail in the experimental part hereunder, and the results of said assay are in addition summarized in FIG. 1. In FIG. 1, the black blocks refer to a wild-type N4 mouse neuroblastoma cell line and the hatched blocks to a transfected N4 cell line overexpressing the UNC-53 protein (cell-line deposited under LMBP Accession No. 1549CB at the Belgian Coordinated C
REFERENCES:
Bogaert et al. "Vertebrate homologues of C elegans UNC-53 Protein . . . " Derwent abst. 1998--362411, 1998.
Pyrrole Mannich Bases as Potential Antipsychotic Agents, J. Med. Chem. 1992, 552-558; vol. 35. No. 3 pp. 352-358.
Geerts Hugo Alfons Gabriel
Geysen Johan Jozef Gustave Hendrik
Kukla Michael Joseph
Appollina Mary A.
Chang Ceila
Janssen Pharmaceutica N.V.
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