Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-09
2003-05-06
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S066000
Reexamination Certificate
active
06559161
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel pyrido[2,3,4-k,l]acridine compounds. The invention also relates to their use in the treatment of cancers and processes for preparing them.
DESCRIPTION OF PRIOR ART
The polycyclic aromatic alkaloids based on the pyrido[2,3,4-k,l]acridine skeleton are a growing class of ascidian metabolites that often exhibit a variety of interesting biological properties, including antitumour activity, as reviewed by Molinksy (1993), Álvarez and Joule (1992), Álvarez et al (1991) and Groundwater and Munawar (1998). As examples of these alkaloids, there are described: norsegoline (Rudi et al, 1988), varamines (Molinsky and Ireland, 1989), Iissoclins (Searle and Molinsky, 1994), diplamine (McDonald et al, 1994; Chryulu and McKee, 1989), isobutyramide (Molinksy, 1993), cystodytins (Kobayashi wt al, 1988 and 1991), and pantherinine (Kim et al, 1993). The structures of these compounds are shown below.
Biological studies on pyridoacridines are severely limited due to their very low availability from natural sources, and therefore the study of their mechanism of action and the establishment of reliable structure-activity relationships requires the development of efficient synthetic routes.
SUMMARY OF INVENTION
The present inventors have developed an efficient process for producing compounds containing the pyrido[2,3,4-k,l]acridine skeleton in a small number of steps from commonly available starting materials. Furthermore, the novel compounds produced by the process exhibit activity against a wide variety of mammalian cancer cell lines.
Therefore, in a first aspect, the invention provides compounds of formula (I):
wherein:
R
1
represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a hydroxy group, an alkoxy group having from 1 to 6 carbon atoms, a halogen atom, a nitro group, an amino group, a monoalkylamino group wherein the alkyl moiety has from 1 to 6 carbon atoms, a dialkylamino group wherein each alkyl moiety may be the same or different and each has from 1 to 6 carbon atoms, a monoalkoxyamino group wherein the alkoxy moiety has from 1 to 6 carbon atoms, a dialkoxyamino group wherein each alkoxy moiety may be the same or different and each has from 1 to 6 carbon atoms, an alkanoylamino group having from 1 to 20 carbon atoms or an alkanesulfonylamino group having from 1 to 6 carbon atoms;
R
2
represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; and
R
3
represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms;
and pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides a pharmaceutical composition containing as an active ingredient a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
In a third aspect, the invention provides a method for treating a mammal affected by a malignant tumour sensitive to a compound of formula (I) as defined above, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined above.
In a fourth aspect, the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of malignant tumours.
In a fifth aspect, the invention provides a method for preparing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, described in more detail hereinafter.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The compounds of formula (I) above are defined in more detail below.
The alkyl group may be a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. Of these groups, alkyl groups having from 1 to 4 carbon atoms are preferred, particularly the methyl and ethyl groups, and the methyl group is especially preferred.
The alkoxy group comprises an oxygen atom substituted by a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as those described and exemplified above. As examples of such groups, there may be mentioned the methyoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups. Alkoxy groups having from 1 to 4 carbon atoms are preferred, and the methoxy and ethoxy groups are especially preferred.
The monoalkylamino group comprises an amino group which is substituted by an alkyl group having 1 to 6 carbon atoms such as those described and exemplified above. As examples of such groups there may be mentioned the methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentylamino and hexylamino groups. Monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms are preferred.
The dialkylamino group comprises an amino group which is substituted by two alkyl group having 1 to 6 carbon atoms such as those described and exemplified above. The alkyl groups may be the same or different, but are preferably the same. As examples of such groups there may be mentioned the dimethylamino, diethylamino, N-methylethylamino, diisopropylamino, dibutylamino, dipentylamino and dihexylamino. Dialkylamino groups wherein each alkyl group has from 1 to 4 carbon atoms are preferred.
The monoalkoxyamino group comprises an amino group which is substituted by an alkoxy group having 1 to 6 carbon atoms such as those described and exemplified above. The dialkoxyamino group comprises an amino group which is substituted by two alkoxy group having 1 to 6 carbon atoms such as those described and exemplified above. The alkoxy groups may be the same or different, but are preferably the same.
The alkanoylamino group comprises an amino group which is substituted by an alkanoyl group having from 1 to 20 carbon atoms, examples of which include the formyl, acetyl, propanoyl, butanoyl, pentanoyl, 2,2-dimethylpropanoyl (pivaolyl), hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl (lauroyl), tetradecanoyl (myristoyl), hexadecanoyl (palmitoyl), octadecanoyl (stearoyl) and icoscanoyl (arachidoyl) groups. Of the alkanoylamino groups, those groups having from 1 to 6 carbon atoms, particularly from 1 to 4 carbon atoms, are preferred, and the formylamino and acetylamino groups are especially preferred.
The alkanesulfonylamino group comprises an amino group which is substituted by an alkanesulfonyl group, of which the alkyl part is a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as those described and exemplified above. Examples of suitable alkanesulfonylamino groups include the methanesulfonylamino, ethanesulfonylamino, propanesulfonylamino, butanesulfonylamino, pentanesulfonylamino and hexanesulfonylamino groups. Of these groups, alkanesulfonylamino groups having from 1 to 4 atoms, especially the methanesulfonylamino and ethanesulfonylamino groups, are preferred.
The compounds of the present invention contain a basic nitrogen atom, and may therefore form salts by addition with an acid. There is no particular restriction on the nature of such salts, provided that, when the salt is used for therapeutic purposes, it must be pharmaceutically acceptable, ie the salt must be about as active, more active, or not unduly less active than the free base compound, and about as toxic, less toxic or not unduly more toxic than the free base compound. However, when the salt is used for non-therapeutic purposes (eg as an intermediate in the production of further compounds) even this restriction does not apply. Examples of such salts include salts of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; salts of alkanesulfonic acids such
Alvarez Mercedes
Feliu Lidia
Fernandez-Puentes Jose Luis
Garcia Gravalos Dolores
Aulakh C. S.
Fish & Richardson P.C.
Universidad de Barcelona
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