Phenanthridinium derivatives

Details Phenanthridinium derivatives Phenanthridinium derivatives

1999-05-20

2001-02-13

Aulakh, Charanjit S. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S041000, C546S042000, C546S045000, C546S050000, C546S051000, C546S058000, C514S280000, C514S283000

Reexamination Certificate

active

06187783

ABSTRACT:

This application is a 371 of PCT/JP97/04252, filed Nov. 21, 1997, now WO 98/23614 published Apr. 06, 1998.
FIELD OF THE INVENTION
The present invention relates to a novel phenanthridinium derivative which has an antitumor activity and is expected to be effective as a medicine, and pharmaceutical use thereof.
BACKGROUND ART
Alkylating agents, metabolic antagonists, antibiotics, plant alkaloids, etc. are currently used in chemotherapy for patients with cancer.
2,3-(Methylenedioxy)-5-methyl-7-hydroxy-8-methoxy-benzo[c]phenanthridinium chloride or iodide reported in Chem. Pharm. Bull., 33, 1763 is known to exhibit an antitumor activity (Japanese Patent KOKAI Nos. 2-243628 and 3-184916). Benzo[c]phenanthridinium derivertive and its antitumor activity are also reported in Japanese Patent KOKAI No. 5-208959.
Malignant tumor has a diversity of characteristics. Moreover, use of these antitumor agents causes resistance thereto. It is thus desired to develop a new antitumor agent.
DISCLOSURE OF THE INVENTION
The present inventors have found a novel phenanthridinium derivative having a structure formed by linking the nitrogen atom at the 5-position with the carbon atom at the 6-position through aliphatic hydrocarbon chains adjacent thereto and also found that the new phenanthridinium derivative exhibits an antitumor activity and is resistant to chemical reduction and to biological metabolic reactions. These properties of the phenanthridinium derivative are found to be extremely advantageous for applying the same to a medicine, and the present invention was accomplished thereby.
That is, the present invention relates to a novel phenanthridinium derivative represented by general formula (A):
wherein
R
1
is a substituted or unsubstituted lower aliphatic hydrocarbon group;
R is an aliphatic hydrocarbon chain having 2 to 6 carbon atoms which may optionally be substituted with a substituent selected from the group consisting of a lower alkyl group, a halogen and a hydroxy group;
each of Y and Z independently represents a hydrogen, a hydroxy or a lower alkoxy group; or Y and Z are combined together to form methylenedioxy or a phenyl ring; and,
X
−
is an acid residue or a hydrogen acid residue.
The present invention further relates to a novel phenanthridinium derivative represented by general formula (B):
wherein
R
1
is a substituted or unsubstituted lower aliphatic hydrocarbon group;
R is a lower aliphatic hydrocarbon chain having 2 to 6 carbon atoms which may optionally be substituted with a substituent selected from the group consisting of a lower alkyl group, a halogen and hydroxy group;
each of Y and Z independently represents a hydrogen, a hydroxy or a lower alkoxy group; or Y and Z are combined together to form methylenedioxy or a phenyl ring.
The present invention further relates to a pharmaceutical composition comprising as an active ingredient the compound represented by general formula (A) or (B) together with a pharmacologically acceptable carrier.
The present invention further relates to an antitumor agent comprising as an active ingredient the compound represented by general formula (A) or (B) together with a pharmacologically acceptable carrier.
The present invention further relates to the compound represented by general formula (A) or (B) for use in the pharmaceutical composition as an active ingredient.
The present invention further relates to use of the compound represented by general formula (A) or (B) in the production of a pharmaceutical composition for the treatment or prevention of tumor.
The present invention further relates to a method for the treatment or prevention of tumor which comprises administering to human the compound represented by general formula (A) or (B) at an effective dose.
BEST MODE FOR CARRYING OUT THE INVENTION
In general formulas (A) and (B) in the present invention, the lower aliphatic hydrocarbon group includes for example an alkyl group having 1 to 5 carbon atoms and an alkenylmethyl group having 3 to 5 carbon atoms. Examples of such an alkyl group having 1 to 5 carbon atoms are methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, etc. Examples of the alkenylmethyl group having 3 to 5 carbon atoms are allyl, 2-butenyl, 3-methyl-2-butenyl, etc. These lower aliphatic hydrocarbon groups may optionally be substituted, and examples of such substituents are a hydroxy group, a C
1
-C
5
alkoxy group, a C
1
-C
5
alkoxycarbonyl group, an acetyl group, a halogen, a carbamoyl group or a phenyl group optionally substituted with a methoxy group.
Specific examples of the aliphatic hydrocarbon group which may be substituted or unsubstituted are methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, 2-hydroxypropyl, allyl, 2-butenyl, 3-methyl-2-butenyl, methoxycarbonylmethyl, isopropoxycarbonylmethyl, carbamoylmethyl, benzyl, 4-methoxyphenylmethyl, fluoromethyl, trifluoromethyl, etc. Particularly preferred are methyl, ethyl, allyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, carbamoylmethyl and trifluoromethyl.
The aliphatic hydrocarbon chain having 2 to 6 carbon atoms in general formulas (A) and (B) of the present invention, which may be substituted with a substituent selected from the group consisting of a lower alkyl group, a halogen and a hydroxy group, refers to, e.g., a substituted or unsubstituted polymethylene group having 2 to 6 carbon atoms. The lower alkyl group as the substituent of the aliphatic hydrocarbon chain is a alkyl group having 1 to 5 carbon atoms which is exemplified by methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, etc. Preferred examples of the substituent are methyl and ethyl. Examples of the halogen atom are fluorine, chlorine, bromine and iodine.
Specifically, the aliphatic hydrocarbon chain having 2 to 6 carbon atoms, which may be substituted or unsubstituted, refers to —CH
2
CH
2
—, —CH
2
CH
2
CH
2
—, —CH
2
CH(CH
3
)CH
2
—, —CH
2
C(CH
3
)
2
CH
2
—, —CH
2
CH(OH)CH
2
—, —CH
2
CHFCH
2
—, —CH
2
CF
2
CH
2
—, —CH
2
CHClCH
2
—, —CH
2
CH
2
CH
2
CH
2
—, —CH
2
CH
2
CH
2
CH
2
CH
2
—, —CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
—, etc. Particularly preferred is an unsubstituted polymethylene chain having carbon atoms 3 to 4, such as —CH
2
CH
2
CH
2
— or —CH
2
CH
2
CH
2
CH
2
—.
In general formulas (A) and (B) of the present invention, examples of the lower alkoxy group is an alkoxy group having 1 to 5 carbon atoms such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, etc., preferably an alkoxy group having 1 to 3 carbon atoms such as methoxy, ethoxy, n-propoxy or i-propoxy.
The acid residue of X
−
in general formula (A) of the present invention means an acid residue that forms a normal salt, e.g., X
−
is a halogen ion such as a chloride, bromide, iodide or fluoride ion, or a sulfate, nitrate or p-toluenesulfonate ion. The hydrogen acid residue means an acid reside that forms a hydrogen acid salt. The hydrogen acid residue contains 1 or 2 hydrogen atoms and is exemplified by a hydrogensulfate ion, a dihydrogenphosphate ion, etc. Among them, a chloride ion and a hydrogensulfate ion are particularly preferred.
In the present invention, preferred examples of the compounds are those of general formulas (A) and (B) wherein R
1
is methyl, ethyl, allyl, 2-hydroxyethyl, 2-methoxyethyl, 2-acetoxyethyl, carbamoylmethyl or trifluoromethyl, R is an unsubstituted polymethylene chain having 3 to 4 carbon atoms, and Y and Z are combined together to represent methylenedioxy or to form a phenyl ring.
The compounds represented by general formula (A) may be prepared by the following processes, which are classified into two types. Each process is explained below.
1. Synthesis of the compound represented by general formula (A) wherein R
1
represents methyl (hereinafter referred to as synthesis of type 1 in general formula (A)):
(a) The compound of general formula (A) wherein R
1
is methyl can be synthesized by the following reaction scheme 1.
Reaction scheme 1:
In the starting compounds of general formula (1), Y and Z have the same significance as defined in gen

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