Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-12
2004-09-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C512S014000, C512S014000, C512S014000, C512S014000, C512S014000, C512S014000, C544S224000, C544S238000, C544S295000, C544S296000, C544S333000, C544S357000, C544S405000, C544S406000, C546S262000, C546S264000, C546S334000
Reexamination Certificate
active
06787546
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel heterocyclic compounds or salts thereof, which are useful as a medicine.
BACKGROUND ART
Heterocyclic compounds of the formula below have been known to be useful as anticancer agent (WO95/027699).
wherein A is optionally substituted heteroaryl or its oxide, B is optionally substituted ethenylene, D is optionally substituted phenylene, G is optionally substituted phenyl and R
0
is hydrogen, acetyl, optionally substituted alkyl or optionally substituted alkenyl.
It has also been known that (E)-4-(2-(2-(N-(4-methoxy-benzenesulfonyl) amino)phenyl)ethenyl)pyridine 1-oxide (hereinafter, referred to as “Compound A”) has a potent growth inhibition activity on cancer cells, and that (E)-4-(2-(2-(N-(4-acetyl-N-(4-methoxy-benzenesulfonyl)amino)phenyl)ethenyl)pyridine 1-oxide (hereinafter, referred to as “Compound B”) has an anticancer activity with low toxicity. Accordingly, the Compounds A and B have been expected to be promising drugs for oral administration in the treatment of various malignant tumors such as lung cancer, breast cancer, gastrointestinal cancer, prostate cancer, blood cancer and the like.
Although Compounds A and B are suited for oral administration, they can hardly been used in a liquid form for intravenous injection or the like because of extremely low solubility in injectable solutions.
The absorptiveness of anticancer agents, when administered orally, sometimes varies depending on individuals; and hence intravenous administration is mainly employed for the treatment of cancer from the viewpoint of reliability, accuracy and safety. The intravenous injection is convenient when a patient is unable to accept the oral administration. Under the conditions, anticancer agents useful as an injection have been demanded in the field of clinical medicine.
DISCLOSURE OF THE INVENTION
The purpose of the present invention is to provide novel compounds having a potent anticancer activity which are water-soluble and injectable.
The present inventors have synthesized and investigated into various compounds, during which they found that compounds of the formula [I] below are water-soluble and have extremely high anticancer activity among them, and thus completed the present invention.
The present invention relates to the following (1)-(10).
(1) A compound of the formula [I] or a salt thereof:
A—B—D—E [1]
wherein
A is optionally substituted heteroaryl or its oxide;
B is optionally substituted ethenylene;
D is optionally substituted phenylene; and
E is a group of the formula:
wherein G is optionally substituted phenyl; and R is optionally substituted heteroaryl or heteroarylmethyl, or a group of the formula:
wherein n is an integer of 1 to 5; R
5
and R
6
are same or different and independently selected from the group consisting of hydrogen, C
1
—C
6
alkyl, hydroxyalkyl, aminoalkyl; or R
5
and R
6
taken together with the adjacent nitrogen atom may form a 5- to 7-membered cyclic amino group for —NR
5
(R
6
) which may optionally be substituted and, in addition to the nitrogen atom, may optionally comprise an oxygen, sulfur or nitrogen atom as a ring-composing member.
(2) The compound of the formula [I] mentioned in the above (1) or a salt thereof, wherein A is 4-pyridyl or 1-oxido-4-pyridyl; B is ethenylene; D is optionally substituted phenylene; and E is the group of the formula:
wherein R and G are the same as defined in claim
1
.
(3) The compound of the formula [I] mentioned in the above (1) or a salt thereof, wherein A is 4-pyridyl or 1-oxido-4-pyridyl; B is ethenylene; D is optionally substituted phenylene; E is the group of the formula:
wherein G is optionally substituted phenyl and R is the group of the formula:
wherein n, R
5
and R
6
are the same as defined in claim
1
.
(4) The compound mentioned in the above (3) or a salt thereof, wherein R
5
and R
6
are same or different and independently selected from the group consisting of hydrogen, C
1
—C
6
alkyl; or R
5
and R
6
taken together with the adjacent nitrogen atom may form an optionally substituted 5- to 6-membered cyclic amino group for —NR
5
(R
6
).
(5) The compound of the formula [I] mentioned in the above (1) or a salt thereof, wherein A is 4-pyridyl or 1-oxido-4-pyridyl; B is ethenylene; D is phenylene; and E is a group of the formula:
wherein G is optionally substituted phenyl; and R is optionally substituted 5- to 6-membered heteroaryl or heteroarylmethyl.
(6) The salt mentioned in the above (1), wherein the salt is hydrochloride.
(7) A pharmaceutical composition comprising a compound of the formula [1] in the above-mentioned (1) or a salt thereof as an active ingredient.
(8) The pharmaceutical composition of the above-mentioned (7) which is in a form of injection.
(9) An anticancer agent comprising a compound of the formula [I] in the above-mentioned (1) or a salt thereof as an active ingredient.
(10) The anticancer agent of the above-mentioned (9) which is in a form of injection.
The structural feature of the compound of the present invention is that phenyl in the stilbazole nucleus carries an aminoacylamino group, or a heteroaroylamino group or a heteroaroylaminomethyl group containing nitrogen atom.
The compound having the above structural feature is a novel compound never documented heretofore. The compound of the present invention has a superior anticancer activity with a low toxic potential.
The present invention will hereinafter be described in detail.
Terms herein used to show various substituents are defined below.
Examples of “phenylene” group include 1,2-phenylene, 1,3-phenylene and 1,4-phenylene. The phenylene group may have one or two substituents at an arbitrary position(s), examples of which include hydroxy, halogen, amino, C
1
—C
6
alkyl and C
1
—C
6
alkoxy. Among others, optionally substituted 1,2-phenylene, especially non-substituted 1,2-phenylene, is preferred.
The ethenylene group may have a substituent(s) at each carbon atom, examples of which include cyano, bromo and C
1
—C
6
alkyl. Among others, optionally substituted ethenylene, especially non-substituted ethenylene, is preferred.
The term “heteroaryl” refers to a 5- to 6-membered heteroaryl group having one to two nitrogen atoms as the ring-composing member. The heteroaryl group optionally has one or two substituents at an arbitrary position(s), examples of which include halogen, C
1
—C
6
alkyl, C
1
—C
6
alkoxy, hydroxy and C
1
—C
6
aminoalkyl. The heteroaryl for A includes 6-membered heteroaryl, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl and pyrazinyl. Among others, non-substituted 4-pyridyl is preferred. The heteroaryl for R includes a 5- to 6-membered one, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-imidazolyl, 2-imidazolyl and 4-imidazolyl.
The term “alkyl” refers to a straight or branched alkyl group of 1-6 carbons, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, and the like. Among others, C
1
—C
3
alkyl, especially methyl is preferred.
The alkyl moiety of “hydroxyalkyl” and “aminoalkyl” is as defined above.
Examples of “cyclic amino” include, for example, pyrrolidin-1-yl, piperidino, hexamethylenimino, tetrahydropyridin-1-yl, octahydroazosin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholino and thiomorpholino. The cyclic amino may have one or two substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl and a heterocyclic group having a nitrogen atom, at any position. Among others, non-substituted pyrrolidin-1-yl, piperidino, morpholino as well as piperazin-1-yl substituted with pyridyl are preferred.
Examples of “halogen” include fluorine, chlorine, bromine, iodine and the like.
The “phenyl” group may have one or two substituents, for example, hydroxy or C
1
—C
6
alkoxy. Among others,
Aoki Tomiyoshi
Suzuki Toshiyuki
Greenberg & Traurig, LLP
Nippon Shinyaku Co. Ltd.
Raymond Richard L.
Rzucidlo Eugene C.
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