Naphthalimidobenzamide derivatives

Details Naphthalimidobenzamide derivatives Naphthalimidobenzamide derivatives

2000-03-03

2001-10-09

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S232800, C514S292000, C514S296000, C544S126000, C544S361000, C546S099000, C546S087000

Reexamination Certificate

active

06300331

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel naphthalimidobenzamide derivatives which have high affinity with DNA, have useful biological activity and are usable for the treatment of various diseases such as malignant tumor.
1. Background Art
In recent days, genetic information of various organisms including human being has been revealed vigorously. Pharmaceuticals having strong interaction with a specific region of a gene, thereby exhibiting their pharmacological action have increased their utility as a remedy having a high target orientation.
There is a strong demand for the development of a pharmaceutical which has particularly high affinity with DNA and exhibits excellent remedial effects for diseases such as malignant tumor.
2. Disclosure of the Invention
The present inventors have carried out an extensive investigation with a view to attaining the above-described object. As a result, it has been found that a novel naphthalimidobenzamide derivative represented by the below-descried formula (1) has high affinity with DNA, exhibits excellent anti-tumor activity and is therefore useful as a medicament such as a remedy for a malignant tumor or the like, leading to the completion of the present invention.
The present invention provides a naphthalimidobenzamide derivative represented by the following formula (1):
wherein,
R
1
represents a hydrogen atom, a nitro group, a hydroxyl group, an amino group, a halogen atom, a cyano group, a carboxyl group, a carbamoyl group, an uleyl group, an alkyl group, a trihalogenoalkyl group, an alkoxy group, an alkylamino group, a dialkylamino group, an acyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group, an alkylureyl group or an alkoxycarbonylamino group;
R
2
represents a hydrogen atom or an alkyl group;
l stands for an integer of 1 to 3;
A
1
represents a linear or branched alkylene group which may be interrupted by —N(R
3
)— (R
3
representing a hydrogen atom or an alkyl group), —O—, —S—, —C(═O)NH—, —NHC(═O)—, —S(═O)— or —S(═O)
2
—,
X
1
represents an aryl or heteroaryl group, an aryldicarbonylimino or heteroaryldicarbonylimino group, an arylamino or heteroarylamino group, an arylcarbonylamino or heteroarylcarbonylamino group, an arylcarbamoyl or heteroarylcarbamoyl group, an aryloxy or heteroaryloxy group, an arylthio or heteroarylthio group, an arylsulfinyl or heteroarylsulfinyl group, or an arylsulfonyl or heteroarylsulfonyl group (the above-described aryl or heteroaryl group may have a substituent); and
Y represents a hydrogen atom or —C(═O)N(R
4
)—A
2
—X
2
(R
4
representing a hydrogen atom or an alkyl group and A
2
representing a linear or branched alkylene group which may be interrupted by —N(R
5
)— (R
5
representing a hydrogen atom or an alkyl group), —O—, —S—, —C(═O)NH—, —NHC(═O)—, —S(═O)— or —S(═O)
2
—, X
2
representing a hydrogen atom, an aryl group, a heterocyclic group, an aryldicarbonylimino or heteroaryldicarbonylimino group, an arylamino or heteroarylamino group, an arylcarbonylamino or heteroarylcarbonylamino group, an arylcarbamoyl or heteroarylcarbamoyl group, an aryloxy or heteroaryloxy group, an arylthio or heteroarylthio group, an arylsulfinyl or heteroarylsulfinyl group, or an arylsulfonyl or heteroarylsulfonyl group (the aryl or heteroaryl or heterocyclic group may have a substituent), or R
4
, A
2
and X
2
may form, together with a nitrogen atom adjacent thereto, a nitrogen-containing heterocyclic ring which may have a substituent)], or a salt thereof; or a preparation process thereof.
The present invention also provides a pharmaceutical comprising, as an effective ingredient, a compound represented by the above-described formula (1) or salt thereof.
The present invention further provides a pharmaceutical composition comprising a compound represented by the above-described formula (1) or salt thereof and a pharmaceutically acceptable carrier. The present invention further provides the use of a compound represented by the above-described formula (1) or salt thereof as a pharmaceutical.
The present invention further provides a process for treating a malignant tumor, which comprises administering a compound represented by the above-described formula (1) or salt thereof.
Although compounds having a naphthalimidobenzamide skeleton are described in, for example, DE 2446533, DE 2436032, DE 2460390 and DE 2606904 and Japanese Patent Application Laid-Open No. HEI 7-234530, they are evidently different from the compounds of the formula (1) in structure and moreover, the above-described literature does not include any description of their pharmacological action.
BEST MODES FOR CARRYING OUT THE INVENTION
Described specifically, each group defined by R
1
, R
2
, R
3
, R
4
, R
5
, A
1
, A
2
, X
1
, X
2
and Y in the compounds represented by the above-described formula (1) and another group or symbol described herein are as follows:
In the compounds represented by the above-described formula (1), l pieces of R
1
s may exist on any position on the naphthalimide group and they may be the same or different. Among them, preferred positions are 3-position, 4-position, 5-position and 6-position. l stands for an integer of 1 to 3, preferably 1 or 2.
R
1
represents a hydrogen atom, a nitro group, a hydroxyl group, an amino group, a halogen atom, a cyano group, a carboxyl group, a carbamoyl group, an ureyl group, an alkyl group, a trihalogenoalkyl group, an alkoxy group, an alkylamino group, a dialkylamino group, an acyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group, an alkylureyl group or an alkoxycarbonylamino group.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.
As the alkyl group, C
1-6
alkyl groups are preferred. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl groups.
As the trihalogenoalkyl group, trihalogenomethyl groups are preferred. Specific examples include trifluoromethyl and trichloromethyl groups.
As the alkoxy group, C
1-6
alkoxy groups are preferred. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
As the mono- or di-alkylamino group, mono- or di(C
1-6
alkyl)amino groups are preferred. Specific examples include methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di-n-propylamino, isopropylamino, diisopropylamino, n-butylamino, di-n-butylamino, isobutylamino, diisobutylamino, sec-butylamino, di-sec-butylamino, tert-butylamino, di-tert-butylamino, pentylamino, dipentylamino, hexylamino and dihexylamino groups.
As the acyl group, C
1-6
acyl groups are preferred. Specific examples include formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl, hexanoyl and pivaloyl groups.
As the alkylcarbamoyl group, C
1-6
alkylcarbamoyl groups are preferred. Specific examples include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl and hexylcarbamoyl groups.
As the dialkylcarbamoyl group, di(C
1-6
alkyl)carbamoyl groups are preferred. Specific examples include dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl, di-n-propylcarbamoyl, diisopropylcarbamoyl, di-n-butylcarbamoyl, diisobutylcarbamoyl, di-sec-butylcarbamoyl, di-tert-butylcarbamoyl, dipentylcarbamoyl and dihexylcarbamoyl groups.
As the acylamino group, C
1-6
acylamino groups are preferred. Specific examples include formylamino, acetylamino, propionylamino, butyrylamino, 2-methylpropionylamino, pivaloylamino, pentanoylamino, 3-methylbutyrylamino and hexanoylamino groups.
As the alkylureyl group, C
1-6
alkylureyl groups are preferred. Specific examples include methylureyl, ethylureyl, n-propylureyl, isopropylureyl, n-butylureyl, isobutylureyl, sec-butylureyl, tert-butylureyl, pentylureyl and hexylureyl groups.
As the alkoxycarbonylamino group, C
1-6
alkoxycarbonylamino groups are preferred. Specific examples i

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