Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-21
2001-06-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S241000, C514S273000, C544S106000, C544S198000, C544S199000, C544S209000, C544S324000, C544S325000
Reexamination Certificate
active
06251900
ABSTRACT:
TECHNICAL FIELD
The present invention relates to heterocyclic compounds in which s-triazine or pyrimidine is substituted with benzimidazole and morpholine and which are represented by the Appearanceula (I) or pharmaceutically acceptable acid addition salts thereof and antitumor agents containing the heterocyclic compounds as effective components:
wherein X and Y respectively represent nitrogen atom or one of them represents nitrogen atom and the other represents C—R
7
wherein R
7
represents hydrogen or halogen atom; R
1
, R
2
, R
4
, R
5
and R
6
represent hydrogen atom or C
1
-C
6
alkyl; R
3
represents morpholino (which may be substituted with one or two C
1
-C
6
alkyl, trifluoromethyl, hydroxymethyl, monohalogenomethyl or —CH
2
NR
8
R
9
wherein R
8
represents hydrogen atom or C
1
-C
6
alkyl and Rg represents hydrogen atom, C
1
-C
6
alkoxycarbonyl or benzyl), piperidino (which may be substituted with hydroxy, acetoxy, oxo, ethylenedioxy or amino C
1
-C
6
alkyl), piperazinyl (which may be substituted with C
1
-C
6
alkyl), thiomorpholino, benzimidazolyl, cyano or —NR
10
R
11
wherein R
10
and R
11
represent hydrogen atom, C
1
-C
6
alkyl, hydroxy C
1
-C
6
alkyl or morpholino C
1
-C
6
alkyl.
BACKGROUND ART
s-Triazine (1,3,5-triazine) and pyrimidine derivatives have been researched in the fields of synthetic resins, synthetic fibers, dyes and agricultural chemicals and a number of such compounds have been synthesized. In the field of pharmaceuticals, researches have been made with respect to antitumor, anti-inflammatory, analgesic and antispasmodic activities. Especially, hexamethylmelamine (HMM) is well-known, which has been developed as analogue of antitumor agent triethylenemelamine (TEM) [B. L. Johnson et al. Cancer, 42: 2157-2161(1978)].
TEM is known as alkylating agent and is an s-triazine derivative having cytotoxic antitumor activity. HMM has been marketed in Europe under the indications for the treatment of ovarian and small cell lung cancers, and its action on solid cancers have attractive.
Among the s-triazine derivatives, imidazolyl-s-triazine derivatives are well-known which exhibit cytotoxic and selective aromatase inhibiting activities and have been proposed as medicine for estrogen-dependent diseases such as endometriosis, multicystic ovarium, mastosis, endometrium carcinoma and breast cancer (PCT publication WO93/17009).
However, there is still room for improvement on HMM with respect to its antitumor spectrum and intensity of antitumor activities against solid cancers. As to imidazolyl-s-triazine derivatives, they are limitative in application since they exhibit considerably higher aromatase inhibitory activities than their cytotoxic activities and application of them to cancerous patients other than those who suffer from estrogen-dependent diseases may lead to development of secondary effects such as menstrual disorders due to lack of estrogen. There are still, therefore, strong demands on medicines with no aromatase inhibitory activities and effective for solid cancers.
DISCLOSURE OF THE INVENTION
In order to expand antitumor spectrum of and increase antitumor activities of HMM, we, the inventors, carried out intensive studies on s-triazine and pyrimidine derivatives to surprisingly find out that heterocyclic compounds with substitution of benzimidazole and morpholine and represented by the Formula I exhibit by far strong antitumor activities with no aromatase inhibitory activities in comparison with the conventional s-triazine and pyrimidine derivatives, thus accomplishing the present invention.
The terms used for definition of letters in the Formula I, by which the heterocyclic compounds of the invention are represented, will be defined and exemplified in the following.
The term “C
1
-C
6
” refers to a group having 1 to 6 carbon atoms unless otherwise indicated.
The “C
1
-C
6
alkyl group” refers to a straight- or branched-chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or n-hexyl.
The “amino C
1
-C
6
alkyl group” refers to the above-mentioned “C
1
-C
6
alkyl group” with amino group coupled to any of the carbon atoms.
The “hydroxy C
1
-C
6
alkyl” refers to the above-mentioned “C
1
-C
6
alkyl” with any of the carbon atoms coupled to hydroxy group.
The “morpholino C
1
-C
6
alkyl” refers to the above-mentioned “C
1
-C
6
alkyl” with any of the carbon atoms coupled to morpholino group.
The “C
1
-C
6
alkoxy” refers to a straight- or branched-chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy or the like.
The “halogen atom” may be fluorine, chlorine, bromine or iodine atom.
The compounds according to the present invention may be as follows, though the present invention is not limited to these compounds.
2-(benzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine
2-(2-methylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine
2-(5,6-dimethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine
4,6-dimorpholino-2-(2,5,6-trimethylbenzimidazol-1-yl)-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(cis-2,6-dimethylmorpholino)-6-morpholino-1,3,5-triazine
4-(cis-2,6-dimethylmorpholino)-2-(2-methylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(trans-2,6-dimethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(2-methylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(2-ethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(2-chloromethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(2-fluoromethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(2-hydroxymethylmorpholino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-morpholino-6-(2-trifluoromethyl-morpholino)-1,3,5-triazine
2-(benzimidazol-1-yl)-4,6-bis(cis-2,6-dimethylmorpholino)-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-(cis-2,6-dimethylmorpholino)-1,3,5-triazine
4,6-bis(cis-2,6-dimethylmorpholino)-2-(2,5,6-trimethyl-benzimidazol-1-yl)-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-(cis-2,6-dimethylmorpholino)-1,3,5-triazine
2-(benzimidazol-1-yl)-4-[2-(tert-butoxycarbonyl-aminomethyl)morpholino]-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-[2-(N-benzyl-N-methylamino-methyl)morpholino]-6-morpholino-1,3,5-triazine
2-(2-aminomethylmorpholino)-4-(benzimidazol-1-yl)-6-morpholino-1,3,5-triazine
4-(cis-2,6-dimethylmorpholino)-2-(2-methylbenzimidazol-1-yl)-6-thiomorpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-morpholino-6-piperidino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(4-hydroxypiperidino)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-morpholino-6-(4-oxopiperidino)-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(3-hydroxypiperidino)-6-morpholino-1,3,5-triazine
2-(4-acetoxypiperidino)-4-(benzimidazol-1-yl)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-[3-(4-tert-butoxycarbonylaminobutyl)piperidino]-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-morpholino-6-(piperazin-1-yl)-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(4-methylpiperazin-1-yl)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-cyano-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-dimethylamino-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-[N-(2-hydroxyethyl)-N-methylamino]-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-[N,N-di(2-hydroxyethyl)amino]-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(N-ethyl-N-2-morpholinoethyl)amino-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(N-butyl-N-2-morpholinoethyl)amino-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-morpholino-6-thiomorpholino-1,3,5-triazine
2,4-di(benzimidazol-1-yl)-6-morpholino-1,3,5-triazine
2-(benzimidazol-1-yl)-4-(1,4-dioxa-8-azaspyro[4,5]dekan-8-yl)-6-morpholino-1,3,5-triazine
2-(be
Inaba Masahiro
Kawashima Seiichiro
Matsuno Toshiyuki
Watanabe Tetsuo
Yaguchi Shinichi
Balasubramanian Venkataraman
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Raymond Richard L.
Zenyaku Kogyo Kabushiki Kaisha
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