Hexa-cyclic compound

Details Hexa-cyclic compound Hexa-cyclic compound

1995-05-26

2002-06-18

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S041000, C544S125000, C514S233200

Reexamination Certificate

active

06407115

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel compound having an antitumor activity and a process for preparing this compound.
2. Description of the Background
Camptothecin is a penta-cyclic alkaloid isolated from barks, roots, fruits, or leaves of camptotheca acuminata. This compound is known to exhibit an antitumor activity because of its capability of inhibiting nucleic acid synthesis. According to the results of clinical tests conducted in the United States, however, the compound was found to have a problem in view of safety, and its research and development as a medicine have been discontinued. Thereafter, research on derivatives of camptothecin possessing better activity and reduced toxicity has been undertaken worldwide. However, no report has surfaced so far on the derivative with satisfactory clinical results.
The scarce solubility of camptothecin in water is another problem of this compound in administering it as a medicine. A method of opening the lactone ring and converting it into the sodium carbonate is known as one of the means for making camptothecin water-soluble. The product obtained by this method, however, exhibits a very reduced antitumor activity. The development of a water-soluble camptothecin derivative with the lactone ring being retained as is has therefore been desired.
The present inventors have conducted extensive studies for the purpose of obtaining camptothecin derivatives with more excellent activity and higher safety, as well as excellent characteristics required for a drug to be administered, and found that hexa-cyclic compounds obtained by the addition of a water-soluble ring to camptothecin had characteristics superior to camptothecin. This finding has led to the completion of this invention.
SUMMARY OF THE INVENTION
Accordingly, an object of this invention is to provide a hexa-cyclic compound represented by the following general formula:
wherein R
1
and R
2
individually represent a hydrogen atom, a hydroxyl group, a C
1-6
alkyl group (“C
1-6
alkyl group means an alkyl group having 1 to 6 carbon atoms. Hereinafter defined in the same manner.) which may contain a halogen manner.) which may contain a halogen atom, a nitro or cyano group, a C
1-6
alkenyl group, a C
1-6
alkynyl group, a C
1-6
alkoxyl group, a C
1-6
aminoalkoxyl group, a halogen atom, a nitro group, a cyano group, a mercapto group, a alkylthio group, an amino group which may contain a protective group, a C
1-6
aminoalkyl groups which may contain a protective group or a C
1-6
alkyl group at the amino-position, a C
1-6
aminoalkylamino group which may contain a protective group or a C
1-6
alkyl group at the amino-position, a C
1-6
alkyl group with a heterocyclic ring which may contain a C
1-6
alkyl, C
1-6
alkoxyl, amino, halogeno, nitro, or cyano group, a carbonyl with a-heterocyclic ring which may contain a C
1-6
alkyl, C
1-6
alkoxyl, amino, halogeno, nitro, or cyano group, a C
1-6
alkylamino group with a heterocyclic ring which may contain C
1-6
alkyl, C
1-6
alkoxyl, amino (which may contain a protective group), halogeno, nitro, cyano or a protective group, an amino-heterocyclic group which may contain a protective group or a C
1-6
alkyl group at the nitrogen atom of the heterocyclic ring moiety or at the amino position, a heterocyclic-amino group which may contain a protective group or a C
1-6
alkyl group at the nitrogen atom of the heterocyclic ring moiety or at the amino position, or a carbamoyl group which may contain a protective group or a C
1-6
alkyl group; R
3
represents a C
1-6
alkyl group; R
4
represents an amino group which may contain a protective group, a quaternary trialkyl ammonium such as —N
+
(CH
3
)
3
, a C
1-6
alkylamino group which may contain a protective group, a C
1-6
aminoalkyl group which may contain a protective group, a C
1-6
alkylaminoalkyl group which may contain a protective group, a sulfonic acid group, or a carboxyl group; Z represents an oxygen atom, a sulfur atom, CR
5
R
6
, wherein R
5
and R
6
individually represent a hydrogen atom or a C
1-6
alkyl, or N—R
7
, wherein R
7
stands for a hydrogen atom, a C
1-6
alkyl. group, a C
1-6
aminoalkyl group which may contain a protective group, a C
1-6
aminoalkyl group which may contain a protective group, a C
1-6
alkylaminoalkyl group which may contain a protective group, or a protective group for the amino group; and m and n individually represent 0, 1 or 2.
Other objects, features and advantages of the invention will hereinafter become more readily apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
Preferred examples of groups represented by R
1
or R
2
in formula (I) are C
1-3
alkyl, C
1-3
alkenyl, hydroxymethyl, hydroxyl, C
1-3
alkoxyl, halogen, nitro, amino, C
1-3
alkylamino, cyano-C
1-3
alkyl, aminomethyl, dimethylhydrazino, morpholine-1-yl, piperidine-1-yl, and the like.
Ethyl group and the like are given as preferable groups for R
3
.
Amino group, C
1-6
alkylamino, amino-C
1-6
alkyl, C
1-6
alkylamino-C
1-6
alkyl groups are given as preferred groups for R
4
. Among these, especially preferable are methylamino, dimethylamino, aminomethyl, ethylamino, diethylamino, aminoethyl, methylaminomethyl, dimethylaminomethyl, hydroxy ethylamino and the like.
When substituent R
4
and substituent R
1
or R
2
of compound (I) are suitably selected, the compound possesses sufficient water-solubility and a suitable degree of lipophilicity, and thus exhibits excellent properties. The lipophilicity is a parameter of cell membrane permeability of the compound, and the improved cell membrane permeability promises cytotoxicity against cancerous cells.
Examples of preferable combination of R
4
, R
1
and R
2
include such that:
R
4
is NH
2
, NHCH
3
or N(CH
3
)
2
, and
R
1
or R
2
is CH
3
or C
2
H
5
Among them, most preferred is a combination where R
4
is NH
2
, R
1
is 4-methyl and R
5
is 5-fluoro.
When R
4
is NH
2
, and R
1
or R
2
is OH, only an insufficient cell membrane permeability is obtained, and therefore, it is preferred that the compound be converted to a pro-drug, in other words, the OH group is converted to —O—Y or —O—CO—Y. Here, Y is amino, dialkylamino, dialkylaminoalkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,. heterocyclic group which may contain one or more C
1-6
alkyl, C
1-6
alkoxyl, amino, halogeno, nitro or cyano group, or alkyl group with heterocyclic ring which may contain one or more C
1-6
alkyl, C
1-6
alkoxyl, amino, halogeno, nitro or cyano groups.
A quaternary-trialkyl ammonium such as —N
+
(CH
3
)
3
is also preferred as R
4
.
Methylene group, oxygen atom, sulfur atom, imino(—NH—), alkylimino(—N(alkyl)—), and the like are given as preferable groups represented by Z.
As preferred protective groups for amino group, given are formyl, acetyll, trithyl, tert-butoxycarbonyl, benzyl, p-methoxybenzyloxycarbonyl, and the like.
Given as preferred examples for heterocyclic groups are 4-7 membered rings having one or more nitrogen atoms which may contain one or more oxygen atoms or sulfur atoms, such as azetidine, piperazine, morpholine, pyrrolidine, piperidine, imiazole, thiazole, oxazole, pyridine, and the like. Among them, those having 5 or 6 membered rings such as pyrrolidine, piperidine, piperazine, morpholine and the like are especially preferred.
Among the compounds of formula (I), those having a six-membered ring for the A-ring, which are represented by the following formula (IA) is particularly preferable.
Furthermore, among the compounds of formula (I), those in which the asymmetric carbon at 9 position of the F-ring takes the S-type configuration are preferable from the aspect of medicinal activity.
The compounds of the present invention can be prepared according to the process exemplified by the following reaction scheme.
According to the above process scheme, an aminoketone compound (2) and a pyranoindolizine compound (3) are condensed by the Friedlaender reaction to produce the compound (I).
Aminoketone compound

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