Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-26
2004-11-23
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S153000, C544S183000, C544S284000, C544S235000
Reexamination Certificate
active
06821987
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to quinoline derivatives and quinazoline derivatives which have antitumor activity. More particularly, the present invention relates to quinoline derivatives and quinazoline derivatives which are therapeutically effective for diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.
2. Background Art
WO 97/17329, Japanese Patent Laid-Open No. 328782/1997, and WO 00/43366 describe quinoline derivatives and quinazoline derivatives having antitumor activity. They, however, do not disclose the compounds of the present invention.
SUMMARY OF THE INVENTION
The present inventors have found that a group of azolyl-containing quinoline derivatives and quinazoline derivatives have potent antitumor activity.
An object of the present invention is to provide compounds having potent antitumor activity.
According to the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein
X and Z each independently represent CH or N;
Y represents O or S;
R
1
, R
2
, and R
3
, which may be the same or different, represent a hydrogen atom, C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyl, C
2-6
alkynyl, nitro, or amino and the C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyl, and C
2-6
alkynyl groups are optionally substituted by a halogen atom; hydroxyl; C
1-4
alkyl; C
1-4
alkoxycarbonyl; amino on which one or two hydrogen atoms are optionally substituted by C
1-4
alkyl optionally substituted by hydroxyl or C
1-4
alkoxy; group R
12
R
13
N—C(═O)—O— wherein R
12
and R
13
, which may be the same or different, represent a hydrogen atom or C
1-4
alkyl optionally substituted by hydroxyl or C
1-4
alkoxy; or group R
14
—(S)
m
— wherein R
14
represents a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group optionally substituted by C
1-4
alkyl and m is 0 or 1;
R
4
represents a hydrogen atom;
R
5
, R
6
, R
7
, and R
8
, which may be the same or different, represent a hydrogen atom, a halogen atom, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylthio, trifluoromethyl, nitro, or amino;
R
9
and R
10
, which may be the same or different, represent a hydrogen atom, C
1-6
alkyl, or C
1-4
alkylcarbonyl and the alkyl portion of the C
1-6
alkyl or C
1-4
alkylcarbonyl group is optionally substituted by a halogen atom; C
1-4
alkoxy; amino optionally substituted by C
1-4
alkyl optionally substituted by C
1-4
alkoxy; or a saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic group; and
R
11
represents azolyl on which one or more hydrogen atoms are optionally substituted by a halogen atom; C
1-4
alkyl; C
1-4
alkoxy; C
1-4
alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C
1-4
alkyl group(s) which may be the same or different; C
1-4
alkoxycarbonyl C
1-4
alkyl, C
1-4
alkylcarbonyl, or C
3-5
cyclic alkyl.
The compounds according to the present invention are therapeutically effective for diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.
DETAILED DESCRIPTION OF THE INVENTION
Compound
The terms “C
1-6
alkyl” and “C
1-6
alkoxy” as used herein as a group or a part of a group respectively mean straight chain or branched chain alkyl and alkoxy having 1 to 6, preferably 1 to 4 carbon atoms.
The terms “C
2-6
alkenyl” and “C
2-6
alkynyl” as used herein as a group or a part of a group respectively mean straight chain or branched chain alkenyl and alkynyl having 2 to 6, preferably 1 to 4 carbon atoms.
Examples of C
1-6
alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.
Examples of C
1-6
alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
Examples of C
2-6
alkenyl include allyl, butenyl, pentenyl, and hexenyl.
Examples of C
2-6
alkynyl include 2-propenyl, butynyl, pentynyl, and hexynyl.
Examples of C
3-5
cyclic alkyl include cyclopropyl and cyclopentyl.
The term “halogen atom” means a fluorine, chlorine, bromine, or iodine atom.
The saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic ring is preferably a five- to seven-membered, more preferably five- or six-membered, saturated or unsaturated carbocyclic or heterocyclic ring.
Examples of saturated or unsaturated three- to seven-membered carbocyclic or heterocyclic rings include phenyl, cycloheptyl, cyclohexyl, and cyclopentyl.
The saturated or unsaturated three- to seven-membered heterocyclic ring contains one or more hetero-atoms selected from oxygen, nitrogen, and sulfur atoms. The term “hetero-atom” used herein means an oxygen, nitrogen, or sulfur atom. Examples of saturated or unsaturated three- to seven-membered heterocyclic groups include pyridyl, piperidino, piperazino, morpholino, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolidinyl, and pyrazolyl.
The term “azolyl” as used herein means a five-membered saturated or unsaturated heterocyclic group containing two or more hetro-atoms, as ring atoms, selected from the group consisting of nitrogen, sulfur, and oxygen atoms, wherein at least one of the hetero-atoms is a nitrogen atom.
R
1
preferably represents a hydrogen atom.
The C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyl, and C
2-6
alkynyl groups, which may be represented by R
1
, R
2
, and R
3
, are optionally substituted by group R
14
—(S)m—.
The carbocyclic or heterocyclic group, which may be represented by R
14
, preferably represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group. The carbocyclic group more preferably represents phenyl. The heterocyclic group more preferably represents a saturated or unsaturated five-membered heterocyclic group containing one to four nitrogen atoms or a saturated or unsaturated six-membered heterocyclic group containing one or two hetero-atoms selected from nitrogen and oxygen atoms. More specifically, the hetero-atom constituting the six-membered heterocyclic group may be one nitrogen atom and one oxygen atom, or one or two nitrogen atoms.
When m is 0 (zero), —(S)m — represents a bond.
A substituted C
1-6
alkoxy group, which may be represented by R
1
, R
2
, and R
3
, preferably represents group R
31
—(CH
2
)p—O— wherein R
31
represents a halogen atom; hydroxyl; C
1-4
alkoxy; C
1-4
alkoxycarbonyl; amino on which one or two hydrogen atoms each are optionally substituted by C
1-4
alkyl optionally substituted by hydroxyl or C
1-4
alkoxy; group R
12
R
13
N—C(═O)—O— wherein R
12
and R
13
are as defined in formula (I); or group R
14
—(S)m— wherein R
14
is as defined in formula (I), and p is an integer of 1 to 6, preferably 1 to 4, more preferably 1 or 2.
R
2
and R
3
preferably represent C
1-4
alkoxy, more preferably methoxy.
X preferably represents N or CH, and Z preferably represents CH.
Preferably, at least one of R
5
, R
6
, R
7
, and R
8
represents a halogen atom.
Preferably, at least one of R
5
, R
6
, R
7
, and R
8
represents a chlorine or fluorine atom.
Preferably, at least one of R
5
, R
6
, R
7
, and R
8
represents C
1-4
alkyl.
Preferably, at least one of R
5
, R
6
, R
7
, and R
8
represents C
1-4
alkoxy.
Preferably, at least one of R
5
, R
6
, R
7
, and R
8
represents C
1-4
alkylthio, trifluoromethyl, nitro, or amino.
Preferably, R
5
and R
6
represent a halogen atom, more preferably a chlorine or fluorine atom, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylthio, trifluoromethyl, nitro, or amino, and R
7
and R
8
represent a hydrogen atom.
R
1
and R
10
preferably represent a hydrogen atom.
R
11
preferably represents group (i):
wherein Q represents O, S, or NH, and R
22
and R
23
, which may be the same or different, represent a hydrogen atom; a halogen atom; C
1-4
alkyl; C
1-4
alkoxy; C
1-4
alkylthio; trifluoromethyl; nitro; amino on which one or two hydrogen atoms are optionally substituted by C
1-4
alkyl
Fujiwara Yasunari
Hasegawa Kazumasa
Isoe Toshiyuki
Kubo Kazuo
Nagao Rika
Berch Mark L.
Habte Kahsay
Kirin Beer Kabushiki Kaisha
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