Title: Certain 1,3-disubstituted isoquinoline derivatives
Abstract: Condensed pyridine compounds represented by formula (I): ##STR1##wherein: R.sup.1 and R.sup.3 are, independently, hydrogen, lower alkyl, or lower alkoxy; R.sup.2 represent an amino substituent; ring A is a benzene ring, pyridine ring, thiophene ring, or furan ring; and B represents a substituent containing a ring structure. Also, pharmaceutically acceptable salt and hydrates thereof. These compounds are clinically useful medicaments having serotonin antagonism, and in particular, for treating, ameliorating, or preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
Patent Number: 6,875,761 Issued on 04/05/2005 to Ueno, et al.
| Inventors:
|
Ueno; Kohshi (Ibaraki, JP);
Sasaki; Atsushi (Ibaraki, JP);
Kawano; Koki (Ibaraki, JP);
Okabe; Tadashi (Ibaraki, JP);
Kitazawa; Noritaka (Ibaraki, JP);
Takahashi; Keiko (Ibaraki, JP);
Yamamoto; Noboru (Ibaraki, JP);
Suzuki; Yuichi (Ibaraki, JP);
Matsunaga; Manabu (Ibaraki, JP);
Kubota; Atsuhiko (Tsuchiura, JP)
|
| Assignee:
|
Eisai Co., Ltd. (Tokyo, JP)
|
| Appl. No.:
|
796673 |
| Filed:
|
March 10, 2004 |
Foreign Application Priority Data
| Current U.S. Class: |
514/183; 514/253.03; 514/307; 514/309; 514/310; 514/300; 544/358; 544/363; 546/139; 546/143; 546/18; 546/113 |
| Intern'l Class: |
A61K 031//33; A61K 031//47; A61K 031//49.5; C07D 241//04; C07D 217//00 |
| Field of Search: |
514/183,307,253.05,309,310,300
544/358,363
546/139,143,18,113
|
References Cited [Referenced By]
U.S. Patent Documents
| 3857944 | Dec., 1974 | Simpson et al. | 514/253.
|
| 4942163 | Jul., 1990 | Behrens | 514/309.
|
| Foreign Patent Documents |
| 438 308 | Jun., 1967 | CH.
| |
| 2 314 985 | Oct., 1974 | DE.
| |
| 2268524 | Nov., 1975 | FR.
| |
| 1 545 767 | May., 1979 | GB.
| |
| 1545767 | May., 1979 | GB.
| |
| 56-92871 | Jul., 1981 | JP.
| |
| 8002119 | Oct., 1980 | NL.
| |
Other References
Chemical Abstract DN 94:174912, also cited as NL 8002113, dated Oct. 1980.*
Chemical Abstract DN85:160167, also cited asFR 2268524, dated Nov. 1975.*
Chemical Abstract DN 69:35972, also cited as CH 438308, dated Dec. 1967.*
Nair M.D., Chemical Abstract DN 77:164414, also cityed as Indian J. Chem.
10/4,337-40(1972).
|
Primary Examiner: Raymond; Richard L.
Assistant Examiner: Patel; Sudhaker B.
Attorney, Agent or Firm: Birch, Stewart, Kolasch & Birch, LLP
Parent Case Text
This application is a divisional of application Ser. No. 09/852,850, filed
May 11, 2001 now U.S. Pat. No. 6,790,844, which is a divisional of Ser.
No. 09/509,778, filed on Mar. 31, 2000 (now U.S. Pat. No. 6,340,759B1) and
for which priority is claimed under 35 U.S.C. .sctn.120. Application Ser.
No. 09/509,778 is the national phase under 35 U.S.C. .sctn.371 of PCT
International Application No. PCT/JP98/04465 filed on Oct. 2, 1998. The
entire contents of each of the above-identified applications is hereby
incorporated by reference. This application also claims priority under 35
U.S.C. .sctn.119 to Application Ser. No. 9-284290 filed in Japan on Oct.
2, 1997.
Claims
What is claimed is:
1. A compound represented by the following formula, its pharmaceutically
acceptable salt or hydrates thereof
##STR654##
wherein,
ring A represents a pyridine ring;
R.sup.1 represents a hydrogen atom, a halogen atom, a lower alkyl group or
a lower alkoxyl group;
R.sup.2 represents a 1-R.sup.4 -piperazin-4-yl group;
R.sup.4 represents a hydrogen atom, a lower alkyl group, a hydroxy lower
alkyl group, a halogenated lower alkyl group, a lower cycloalkyl group, an
aryl group, an aralkyl group, a 1-piperidyl group, an alkenyl group, a
cyano lower alkyl group, a carbamoyl lower alkyl group, a lower acyl
group, an aromatic acyl group, a lower alkoxyl carbonyl group, an
aryloxycarbonyl group or an aralkyloxycarbonyl group;
n represents 0 or an integer of 1 to 6; and
B represents an optionally substituted aryl group, an optionally
substituted aralkyloxy group, an aryl(hydroxy)alkyl group, an aromatic
acyl amino group, an arylsulfonylamino group, a lower alkoxyl
arylsulfonylamino group, a hydroxy lower alkoxyl styryl group, a lower
alkoxy aryloxy group, a 4-phenylpiperidin-1-yl group, a
4-pyridylpiperidin-1-yl group, an arylalkenyl group, an arylalkynyl group,
an aromatic acyl alkynyl group, an optionally N-substituted amino lower
alkyl group, an optionally substituted arylamino group, an optionally
substituted aralkylamino group or a group selected from the groups
represented by the following formulae:
##STR655##
wherein p represents 0 or an integer of 1 to 6;
R.sup.13, R.sup.14, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, R.sup.25, R.sup.27 and R.sup.29
independently represent a hydrogen atom, a halogen atom, a hydroxyl group,
a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a
hydroxy lower alkoxy group or tetrahydropyranyl group;
R.sup.24 represents a hydrogen atom or a lower alkyl group;
R.sup.26 represents a hydrogen atom or a hydroxy lower alkyl group;
R.sup.28 represents a hydrogen atom or a lower alkyl group;
R.sup.30 represents a hydrogen atom, a lower alkyl group; a lower alkoxy
group, a hydroxy lower alkyl group or a hydroxy lower alkoxy group;
W represents sulfur atom or oxygen atom; and
the bond represented by the following formula:
-----
is a single or double bond.
2. A compound represented by the following formula, its pharmaceutically
acceptable salt or hydrates thereof
##STR656##
wherein,
ring A represents a pyridine ring;
R.sup.1 represents a hydrogen atom, a halogen atom, a lower alkyl group or
a lower alkoxy group;
R.sup.2 represents a 1-R.sup.4 -piperazin-4-yl group;
R.sup.4 represents a hydrogen atom, a lower alkyl group, a hydroxy lower
alkyl group, a halogenated lower alkyl group, a lower cycloalkyl group, an
aryl group, an aralkyl group, a 1-piperidyl group, an alkenyl group, a
cyano lower alkyl group, a carbamoyl lower alkyl group, a lower acyl
group, an aromatic acyl group, a lower alkoxyl carbonyl group, a
aryloxycarbonyl group or an aralkyloxycarbonyl group;
n represents 0 or an integer of 1 to 6; and
B represents a group selected from the groups represented by the following
formulae:
##STR657##
wherein z represents 0 or 1;
Q represents a nitrogen atom or a methine group;
R.sup.7, R.sup.8 and R.sup.9 are the same as or different from each other
and each represents a hydrogen atom, a halogen atom, a hydroxy group, a
lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower
alkoxy group, a lower thioalkoxyl group, a hydroxy lower thioalkoxyl
group, an arylthio group, a heteroarylthio group, a
heteroaryl(hydroxy)alkyl group, a halogenated lower alkyl group, a hydroxy
lower alkyl group, a dihydroxy lower alkyl group, a halogenated (hydroxy)
lower alkyl group, a hydroxyalkenyl group, a hydroxyalkynyl group, a
hydroxy lower cycloalkenyl group, a lower alkoxy(hydroxy)alkyl group, a
lower alkoxy(hydroxy)alkoxy group, a lower alkoxyalkyl group, a lower
alkoxyalkoxy group, a lower thioalkoxyalkoxy group, a lower
alkylsulfonylalkoxy group, a hydroxy lower alkoxy group, a dihydroxy lower
alkoxy group, a hydroxy lower alkylalkoxy group, a hydroxyimino lower
alkyl group, a lower cyclalkyl (hydroxy) alkyl group, an aralkyl group, a
hydroxyaralkyl group, a cyano group, a cyano lower alkyl group, an amide
group, an N-lower alkylamide group, an N-lower cyclalkylamide group, an
N,N-di lower alkylamide group, an N-hydroxy lower alkylamide group, an
N-hydroxy lower alkyl-N-lower alkylamide group, an N-arylamide group, a
cyclic aminocarbonyl group, a carbamoyl group, an N-lower alkyl carbamoyl
group, an N,N-di lower alkyl carbamoyl group, an aminosulfonyl group, a
cyclic aminosulfonyl group, an N-lower alkylaminosulfonyl group, an
N-lower cycloalkylaminosulfonyl group, an N,N-di lower alkylaminosulfonyl
group, an N-hydroxy lower alkylaminosulfonyl group an N-lower
alkoxyalkylaminosulfonyl group, an N-halogenated lower alkylsulfonyl
group, a pyrrolidinylsulfonyl group, a lower alkylsulfonylaminoalkyl
group, an N-lower alkylaminosulfonylalkyl group, an N,N-di lower
alkylaminosulfonylalkyl group, a lower acyl group, a lower acylalkyl
group, a lower cycloalkyl(hydroxy)methyl group, a tetrahydropyranyl group,
a hydroxytetrahydropyranyl group, a hydroxy lower alkyltetrahydropyranyl
group, a lower acylaminoalkyl group, a (thiazol-2-yl)hydroxymethyl group,
a di(thiazol-2-yl)hydroxymethyl group, a lower alkylsulfonyl group, a
lower alkoxyalkylsulfonyl group, a hydroxy lower alkylsulfonyl group, a
lower alkylsulfonylalkyl group, an N-lower alkylamidealkyl group, an aryl
group, an aralkyl group, a heteroaryl group, a heteroaryl lower alkyl
group, a heteroaryl lower alkoxy group, a heteroarylsulfonyl group, a
4-morpholinylsulfonyl group, a 4-oxythiomorpholinylsulfonyl group, a
4-dioxythiomorpholinylsulfonyl group, a 4-morpholinylsulfonyl group, a
hydroxy lower cycloalkyl group, a hydroxy lower cycloalkyloxy group, a
hydroxycycloalkenyl group, a halogenated hydroxy lower alkyl group, a
4-hydroxypiperidyl group, a 4-lower alkoxypiperidyl group, an
.omega.,.omega.-lower alkylenedioxyalkyl group, an .omega.,.omega.-lower
alkylenedioxyalkoxy group, a lower cycloalkylhydroxymethyl group, an
aryloxy group, an arylaminosulfonyl group, amino group, a lower alkylamino
group, a di lower alkylamino group, a hydroxy lower alkylamino group, a
lower acylamino group, a hydroxy lower acylamino group, a lower
alkylsulfonylamino group, a pyridyl lower alkoxy group, a lower
alkylpyridylalkoxy group, a lower alkoxyhydroxyalkoxy group, a lower
thioalkoxyalkoxy group, a lower alkylsulfonylalkoxy group, an N-lower
alkylcarbamoyl group, an N,N-di lower alkylcarbamoyl group, an N-hydroxy
lower alkylcarbamoyl group, an N-hydroxy lower alkyl-N-lower
alkylcarbamoyl group, a halogenated lower alkoxy group, a cyano lower
alkoxy group, a hydroxy lower cyclalkoxy group, trifluoromethyl group, a
trifluoromethoxy group, an amino lower alkoxy group, an N-lower alkyl
aminoalkoxy group, an N,N-di lower alkylaminoalkoxy group, a lower
acylalkoxy group, a lower acylaminoalkoxy group, a (1,3-dioxolanyl) lower
alkyl group, a (1,3-dioxolanyl) lower alkoxy group, an amido lower alkoxy
group, a 4-(hydroxyalkyl)tetrahydropyran-4-yl group, a
2,3-dihydrobenzofuranyl group, a 2-hydroxy-2-alkyl-2,3-dihydrobenzofuranyl
group, an indanonyl group, a hydroxyindanyl group, an imidazolyl lower
alkoxy group, a succinimide group or a 2-oxazolidon-3-yl group;
furthermore, R.sup.7 represents a hydrogen atom, while R.sup.8 and R.sup.9
form a cyclopentanone ring, a hydroxycyclopentane ring, a
hydroxylalkylcyclopentane ring, a cyclohexanone ring, hydroxycyclohexane
ring, a hydroxyalkylcyclohexane ring, a
2-hydroxymethyl-2-methylcyclopentanone ring, a 1,2-ethylenedioxy ring or a
methylenedioxy ring;
m or p represents 0 or an integer of 1 to 6;
R.sup.10 and R.sup.12 independently represent a hydrogen atom, a halogen
atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a
hydroxy lower alkyl group, a hydroxy lower alkoxy group or a
tetrahydropyranyl group;
R.sup.11 represents a hydrogen atom, a halogen atom, a hydroxy group, a
lower alkyl group or a lower alkoxy group;
W represents sulfur atom or oxygen atom; and
the bond represented by the following formula: {character pullout}
is a trans or cis bond.
3. The compound as claimed in one of claims 1 and 2, wherein R.sup.1 is a
hydrogen atom.
4. The compound as claimed in one of claims 1 and 2, wherein R.sup.4 is
ethyl.
5. The compound as claimed in one of claims 1 and 2, wherein B is phenyl,
pyridyl, phenyloxy, or pyridyloxy, each of which may be substituted by up
to three substituents selected from the group consisting of halogen atoms,
lower alkoxy groups, halogenated lower alkyl groups, hydroxy lower alkyl
groups, dihydroxy lower alkyl groups, lower alkoxy(hydroxy)alkyl groups,
lower alkoxy(hydroxy)alkoxy groups, lower alkoxyalkyl groups, lower
alkoxyalkoxy groups, hydroxy lower alkoxy groups, dihydroxy lower alkoxy
groups, lower cycloalkyl (hydroxy) alkyl groups, cyano groups, N-lower
alkylaminosulfonyl groups, N-lower cycloalkylaminosulfonyl groups, lower
acylalkyl groups, hydroxytetrahydropyranyl groups, lower acylaminoalkyl
groups, 4-morpholinylsulfonyl groups, hydroxy lower cycloalkyl groups
.omega.,.omega.-lower alkylenedioxyalkoxy groups, hydroxy lower acylamino
groups, lower alkylsulfonylamino groups, halogenated lower alkoxy groups,
cyano lower alkoxy groups, N,N-di lower alkylaminoalkoxy groups, and lower
acylalkoxy groups.
6. The compound as claimed in one of claims 1 and 2, wherein B is phenyl,
pyridyl, phenyloxy, or pyridyloxy, each of which may be substituted by up
to three substituents selected from the group consisting of lower
alkoxy(hydroxy)alkoxy groups, lower alkoxyalkoxy groups, hydroxy lower
alkoxy groups, and dihydroxy lower alkoxy groups.
7. A pharmaceutical composition which comprises a pharmaceutically
effective dose of the compound as claimed in claim 1 or 2, its
pharmaceutically acceptable salt or hydrates thereof, and pharmaceutically
acceptable carriers.
8. A method for treating spastic paralysis or for ameliorating myotonia,
which comprising the step of administering to a patient a pharmaceutically
effective dose of the compound as claimed in claim 1 or 2, its
pharmaceutically acceptable salt or hydrates thereof.
Description
FIELD OF THE INVENTION
The present invention relates to a clinically useful medicament having a
serotonin antagonism, in particular, that for treating, ameliorating and
preventing spastic paralysis or central muscle relaxants for ameliorating
myotonia.
BACKGROUND OF THE INVENTION
Myotonia, which seriously restrains daily life, is induced by any of a
number of factors or a combination thereof, for example,
cervico-omo-brachial syndromes accompanying stiffness or pain in the neck,
shoulder, arm, lumbar and dorsal skeletal muscles due to abnormal posture,
fatigue, changes in the backbone with ageing etc., shoulder periarthritis
accompanying inflammation in the tissues constituting the shoulder joint
due to charges in the shoulder joint caused by trauma, etc., and spastic
paralysis wherein accelerated limb muscle tonus hinders voluntary
movements.
In particular, spastic paralysis is a disease which accompanies limb muscle
tonus, stiffening, walking difficulty, etc. and thus seriously restrains
daily life.
PRIOR ART
It has been a practice to treat these diseases mainly with the use of
medicaments. At the present stage, central muscle relaxants or peripheral
muscle relaxants are administered to patients with these diseases.
Particular examples of used central muscle relaxants include Tolperisone
hydrochloride, Baclofen, Tizanidine hydrochloride, Chlorzoxazone and
Diazepam.
On the other hand, particular examples of used peripheral muscle relaxants
include suxamethoniun chloride, Pancuronium bromide and dantrolene sodium.
Central muscle relaxants act selectively on the central nervous system so
as to relax muscles. Therefore, it is expected that those action on the
upper center would exhibit a more potent muscle relaxant effect. However,
there arise at the same time some problems including extrapyramidal
symptoms and neurologic manifestations such as sleepiness, sluggishness
and atony. Namely, there has been known hitherto no medicament capable of
achieving well-balanced principal action and side effects.
Diazepam, which is inherently a minor tranquilizer, is efficacious against
diseases accompanying metal symptoms such as anxiety, tension and
depression. However, its effect is too potent to merely ameliorate
myotonia. With the use of diazepam, therefore, spastic paralysis can be
relieved but there arise some problems such as dizziness.
On the other hand, suxamethonium chloride and Pancuronium bromide which are
peripheral muscle relaxants are marketed exclusively as injections, which
makes the chronic administration thereof difficult.
Dantrolene sodium is processed into injections and preparations for oral
use and has a relatively potent muscle relaxant effect. However, it
suffers from problems of having only a low margin of safety and frequently
induced muscular atony. Accordingly, it is difficult for those other than
medical specialists to administer this medicine.
As discussed above, there has been known hitherto no medicaments for
treating and ameliorating myotonia in spastic paralysis etc., which is
clinically useful and has a high safety.
DISCLOSURE OF THE INVENTION
Under these circumstances, the present inventors have conducted extensive
studies to develop medicaments for treating, ameliorating and preventing
spastic paralysis or central muscle relaxants which have a potent effect
of ameliorating myotonia while sustaining a high safety and newly paid
their attention to compounds having a serotonin antagonism. As a result,
they have successfully found that a novel condensed pyridine compound
represented by the following formula or a pharmacologically acceptable
salt thereof has an excellent central muscle relaxant effect and a high
safety and thus makes it possible to solve the above problems, thus
completing the present invention.
Accordingly, the present invention aims at providing clinically useful
novel medicaments which have well-balanced principal action and side
effects and make it possible to overcome the problem encountering in the
prior art that those acting on the upper center would exhibit a more
potent muscle relaxant effect but at the same time suffer from problems
including extrapyramidal symptoms and neurologic manisfestations such as
sleepiness, sluggishness and weakness.
Because of the anti-serotonin effect, it is expected that the condensed
pyridine compound of the present invention is moreover useable in
preventing, treating and ameliorating depression, emotional disorders,
schizophrenia, sleep disturbance, anxiety, spinal cord injury, thrombosis,
hypertension, brain circulatory disturbances, peripheral circulatory
disturbances, drug addition, etc.
In addition to the condensed pyridine compound, the present invention
provides medicinal composition which comprises a pharmaceutically
effective dose of the condensed pyridine compound, its pharmaceutically
acceptable salt or hydrates thereof and pharmaceutically acceptable
carriers. Further, it provides an agent for treating, ameliorating or
preventing diseases against which serontonin antagonism is efficacious, an
agent for treating, ameliorating or preventing spastic paralysis and a
muscle relaxant, which comprise the above-mentioned active ingredient.
Further, it provides a treating, ameliorating or prophylactic agent
comprising the above-mentioned effective ingredient for diseases for which
the serotonin antagonism is efficacious or, a therapeutic, ameliorating
and prophylactic agents or spastic paralysis and a muscle relaxation
agent.
Furthermore, it provides a method for treating diseases against which the
serotonin antagonism is efficacious or spastic paralysis, or ameliorating
myotonia, which comprising the step of administering a pharmacologically
effective dose of the condensed pyridine compound, its pharmacologically
acceptable salt or hydrates thereof to a patient. Additionally, it
provides the use of the effective ingedient for producing the
above-mentioned medicaments.
Herein, the condensed pyridine compound (I) of the present invention is
represented by the following formula:
##STR2##
wherein, ring A represents benzene ring, pyridine ring, thiophene ring or
furan ring;
R.sup.1 represents hydrogen atom, halogen atom, a lower alkyl group or a
lower alkoxyl group;
R.sup.2 represents 4-morpholinyl group, 1-imidazolyl group, 1-lower alkyl
homopiperazin-4-yl group or any one selected from the groups represented
by the following formulae:
##STR3##
(wherein, T represents nitrogen atom or methine group;
R.sup.1 represents hydrogen atom, halogen atom, a lower alkyl group or a
lower alkoxyl group;
R.sup.4 represents hydrogen atom, a lower alkyl group, a hydroxy lower
alkyl group, a halogenated lower alkyl group, a lower cycloalkyl group, an
aryl group, an aralkyl group, 1-piperidyl group, an alkenyl group, a cyano
lower alkyl group, a carbamoyl lower alkyl group, a lower acyl group, an
aromatic acyl group, a lower alkoxyl carbonyl group, an aryloxycarbonyl
group or an aralkyloxycarbonyl group;
R.sup.5 and R.sup.6 are the same as or different from each other and each
represents hydrogen atom, a lower alkyl group, a di lower alkyl aminoalkyl
group, an optionally substituted heteroaryl lower alkyl group);
n represents 0 or an integer of 1 to 6; and
B represents an optionally substituted aryl group, an optionally
substituted heteroaryl group, an optionally substituted aralkyloxy group,
an aryl (hydroxy) alkyl group, an aromatic acyl amino group, an
arylsulfonylamino group, a lower alkoxyl arylsulfonylamino group, a
hydroxy lower alkoxyl styryl group, a lower alkoxyl aryloxy group,
4-phenylpiperidin-1-yl group, 4-pyridylpiperidin-1-yl group, an optionally
substituted arylalkenyl group, an optionally substituted arylalkynyl
group, an optinally substituted heteroarylalkenyl group, an optionally
substituted heteroarylalkynyl group, an aromatic acyl alkynyl group, an
optionally N-substituted amino lower alkyl group, an optionally
substituted arylamino group, an optionally substituted aralykylamino group
or any one selected from the groups represented by the following formulae:
##STR4##
##STR5##
(wherein z represents 0 or 1;
Q represents nitrogen atom or methine group;
R.sup.7, R.sup.8 are R.sup.9 are the same as or different from each other
and each represents hydrogen atom, halogen atom, hydroxyl group, a lower
alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy
group, a lower thioalkoxyl group, a hydroxy lower thioalkoxyl group, an
arylthio group, a heteroarylthio group, a heteroaryl (hydroxy) alkyl
group, a halogenated lower alkyl group, a hydroxy lower alkyl group, a
dihydroxy lower alkyl group, a halogenated (hydroxy) lower alkyl group, a
hydroxyalkenyl group, a hydroxyalkynyl group, a hydroxy lower cycloalkenyl
group, a lower alkoxy (hydroxy) alkyl group, a lower alkoxy (hydroxy)
alkoxy group, a lower alkoxyalkyl group, a lower alkoxyalkyl group, a
lower thioalkoxyalkoxy group, a lower alkylsulfonylakoxy group, a hydroxy
lower alkoxy group, a dihydroxy lower alkoxy group, a hydroxy lower
alkylalkoxy group, a hydroxyamino lower alkyl group, a lower cycloalkyl
(hydroxyl) alkyl group, an aralkyl group, a hydroxyaralkyl group, cyano
group, a cyano lower alkyl group, amide group (carbamoyl group), an
N-lower alkylamide group, an N-lowre cycloalkylamide group, an N,N-di
lower alkylamide group, an N-hydroxy lower alkylamide group, an N-hydroxy
lower alkyl-N-lower alkylamide group, an N-arylamide group, cyclic
aminocarbonyl group, carbamoyl group, an N-lower alkyl carbamoyl group, an
N,N-di lower alkyl carbamoyl group, aminosulfonyl group, cyclic
aminosulfonyl group, an N-lower alkylaminosulfonyl group, an N-lower
cycloalkylaminosulfonyl group, an N,N-di lower alkylaminosulfonyl group,
an N-hydroxy lower alkylaminosulfonyl group, an N-lower
alkoxyalkylaminosulfonyl group, an N-halogenated lower alkylsulfonyl
group, pyrrolidinylsulfonyl group, a lower alkylsulfonylaminoalkyl group,
an N-lower alkylaminosulfonylalkyl group, an N,N-di lower
alkylaminosulfonylalkyl group, a lower acyl group, a lower acylalkyl
group, a lower cycloalkyl (hydroxy) methyl group, tetrahydropyranol group,
hydroxytetrahydropyranyl group, a hydroxy lower alkyltetrahydropyranyl
group, a lower acylaminoalkyl group. (thiazol-2-yl)hydroxymethyl group, di
(thiazol-2-yl)hydroxymethyl group, a lower alkylsulfonyl group, a lower
alkoxyalkylsulfonyl group, a hydroxy lower alkylsulfonyl group, a lower
alkylsulfonyl group, an N-lower alkylamidealkyl group, an aryl group, an
aralkyl group, a heteroaryl group, a heteroaryl lower alkyl group, a
heteroaryl lower alkoxy group, a heteroarylsulfonyl group,
4-morpholinylsulfonyl group, 4-oxythiomorpholinylsulfonyl group,
4-dioxythiomorpholinylsulfonyl group, 4-morpholinylsulfonyl group, a
hydroxy lower cycloalkyl group, a hydroxy lower cycloalkyloxy group, a
hydroxycycloalkenyl group, a halogenatedhydroxy lower alkyl group,
4-hydroxypiperidyl group, a 4-lower alkoxypiperidyl group, an
.omega.,.omega.-lower alkylenedioxyalkyl group, an .omega.,.omega.-lower
alkylenedioxyalkoxy group, a lower cycloalkylhydroxymethyl group, an
aryloxy group, an arylaminosulfonyl group, amino group, a lower alkylamino
group, a di lower alkylamino group, a hydroxy lower alkylamino group, a
lower acylamino group, a hydroxy lower acylamino group, a lower
alkylsulfonylamino group, a pyridyl lower alkoxygroup, a lower
alkylpyridylalkoxy group, a lower alkoxyhydroxyalkoxy group, a lower
thioalkoxyalkoxy group, a lower alkylsulfonylalkoxy group, an N-lower
alkylcarbamoyl group, an N,N-di lower alkylcarbamoyl group, an N-hydroxy
lower alkylcarbamoyl group, an N-hydroxy lower alkyl-N-lower
alkylcarbamoyl group, a halogenated lower alkoxy group, a cyano lower
alkoxy group, a hydroxy lower cycloalkoxy group, trifluoromethyl group,
trifluoromethoxy group, an amino lower alkoxy group, an N-lower alkyl
aminoalkoxy group, an N,N-di lower alkylaminoalkoxy group, a lower
acylalkoxy group, a lower acylaminoalkoxy group, a (1,3-dioxolanyl) lower
alkyl group, a (1,3-dioxolanyl) lower alkoxyl group, an amide lower alkoxy
group, a 4-(hydroxyalkyl)tetrahydropyran-4-yl group,
2,3-dihydrobenzofuranyl group, a 2-hydroxy-2-alkyl-2,3-dihydrobenzofuranyl
group, indanonyl group, hydroxyindanyl group, an imidazolyl lower alkoxyl
group, succinimide group or 2-oxazolidon-3-yl group;
furthermore, R.sup.7 represents hydrogen atom, while R.sup.8 and R.sup.9
form cyclopentanone ring, hydroxycyclopentane ring, a
hydroxyalkylcyclopentane ring, cyclohexanone ring, hydroxycyclohexane
ring, a hydroxyalkylcyclohexane ring,
2-hydroxymethyl-2-methylcyclopentanone ring, 1,2-ethylenedioxy ring or
methylenedioxy ring;
m or p represent 0 or an integer of 1 to 6;
R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.25,
R.sup.27 and R.sup.29 independently represent hydrogen atom, halogen atom,
hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower
alkyl group, a hydroxy lower alkoxy group or tetrahydropyranyl group;
R.sup.11 represents hydrogen atom, halogen atom, hydroxy group, a lower
alkyl group or a lower alkoxy group;
R.sup.24 represent hydrogen atom or a lower alkyl group;
R.sup.26 represent hydrogen atom or a hydroxy lower alkyl group;
R.sup.28 represent hydrogen atom or a lower alkyl group;
R.sup.30 represents hydrogen atom, a lower alkyl group, a lower alkoxy
group, a hydroxy lower alkyl group or a hydroxy lower alkoxy group;
W represent sulfur atom or oxygen atom;
the bond represented by the following formula:
-----
represent a single or double bond; and
the bond represented by the following formula:
{character pullout}
represent trans or cis bond.).
Among these condensed pyridine compounds, the condensed pyridine compound
(II) represented by the following formula is more preferable:
##STR6##
wherein, ring A represents benzene ring, thiophene ring or furan ring;
R.sup.1 represents hydrogen atom, halogen atom, a lower alkyl group or a
lower alkoxy group;
R.sup.2 represents 4-morpholinyl group, 1-imidazolyl group, a 1-lower
alkylhomopiperazin-4-yl group or any one selected from the groups
represented by the following formulae:
##STR7##
(wherein, T represents nitrogen atom or methine group;
R.sup.4 represents hydrogen atom, a lower alkyl group, a hydroxy lower
alkyl group, a halogenated lower alkyl group, a lower cycloalkyl group, an
aryl group, an aralkyl group, 1-piperidyl group, an alkenyl group, a cyano
lower alkyl group, a carbamoyl lower alkyl group, a lower acyl group, an
aromatic acyl group, a lower alkoxy carbonyl group, an aryloxycarbonyl
group or an aralkyloxycarbonyl group; and
R.sup.5 and R.sup.6 are the same as or different from each other and each
represents hydrogen atom, a lower alkyl group, a di lower alkylaminoalkyl
group, an optionally substituted heteroaryl lower alkyl group.);
n represents 0 or an integer of 1 to 6; and
B represents an optionally substituted aryl group, an optionally
substituted heteroaryl group, an optionally substituted aralkyloxy group,
an aryl (hydroxy)alkyl group, an aromaticacylamino group, an
arylsulfonylamino group, a lower alkoxyarylsufonylamino group, a hydroxy
lower alkoxystyryl group, a lower alkoxyaryloxy group,
4-phenylpiperidin-1-yl group, 4-pyridylpiperidin-1-yl group, an optionally
substituted arylalkenyl group, an optionally substituted arylalkynyl
group, an optionally substituted heteroarylalkenyl group, an optionally
substituted heteroarylalkynyl group, an aromaticacylalkynyl group, an
optionally N-substituted amino lower alkyl group, an optionally
substituted arylamino group, an optionally substituted aralkylamino group
or any one selected from the groups represented by the following formulae:
##STR8##
##STR9##
(wherein, z represents 0 or 1;
Q represents nitrogen atom or methine group;
R.sup.7, R.sup.8 and R.sup.9 are the same as or different from each other
and each represents hydrogen atom, halogen atom, hydroxy group, a lower
alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy
group, a lower thioalkoxy group, a hydroxy lower thioalkoxy group, an
arylthio group, a heteroarylthio group, a heteroaryl(hydroxy)alkyl group,
a halogenated lower alkyl group, a hydroxy lower alkyl group, a dihydroxy
lower alkyl group, a halogenated(hydroxy) lower alkyl group, a
hydroxyalkenyl group, a hydroxyalkynyl group, a hydroxy lower cycloalkenyl
group, a lower alkoxy(hydroxy)alkyl group, a lower alkoxy(hydroxy) alkoxy
group, a lower alkoxyalkyl group, a lower alkoxyalkoxy group, a lower
thioalkoxyalkoxy group, a lower alkyl sulfonylalkoxy group, a hydroxy
lower alkoxy group, a dihydroxy lower alkoxy group, a hydroxy lower
alkylakoxy group, a hydroxyimino lower alkyl group, a lower cycloalkyl
(hydroxy) alkyl group, an aralkyl group, a hydroxyaralkyl group, cyano
group, an cyano lower alkyl group, amide group (carbamoyl group), an
N-lower alkyl amide group, an N-lower cycloalkyl amide group, an N,N-di
lower alkyl amide group, an N-hydroxy lower alkyl amide group, an
N-hydroxy lower alkyl-N-lower alkyl amide group, an N-arylamide group, a
cyclic amino carbonyl group, carbamoyl group, an N-lower alkyl carbamoyl
group, an N,N-di-lower alkyl carbamoyl group, aminosulfonyl group, a
cyclic amino sulfonyl group, an N-lower alkyl aminosulfonyl group, an
N-lower cycloalkylaminosulfonyl group, an N,N-di lower alkyl aminosulfonyl
group, an N-hydroxy lower alkylaminosulfonyl group, an N-lower
alkoxyalkylaminosulfonyl group, an N-halogenated lower alkylsulfonyl
group, pyrrolidinylsulfonyl group, a lower alkylsulfonylaminoalkyl group,
an N-lower alkylaminosulfonylalkyl group, an N,N-di lower
alkylaminosulfonylalkyl group, a lower acyl group, a lower acylalkyl
group, a lower cycloalkyl (hydroxy)methyl group, tetrahydropyranyl group,
hydroxytetrahydropyranyl group, a hydroxy lower alkyltetrahydropyranyl
group, a lower acylaminoalkyl group, (thiazol-2-yl)hydroxymethyl group,
di(thiazol-2-yl)hydroxymethyl group, a lower alkylsulfonyl group, a lower
alkoxyalkylsulfonyl group, a hydroxy lower alkyl sulfonyl group, a lower
alkyl sulfonylalkyl group, an N-lower alkyl amidealkyl group, an aryl
group, an aralkyl group, a heteroaryl group, a heteroaryl lower alkyl
group, a heteroaryl lower alkoxy group, a heteroarylsulfonyl group,
4-morpholinylsulfonyl group, 4-oxythiomorpholinylsulfonyl group,
4-dioxythiomorpholinylsulfonyl group, 4-morpholinylsulfonyl group, a
hydroxy lower cycloalkyl group, a hydroxy lower cycloalkyloxy group, a
hydroxycycloalkenyl group, a halogenated hydroxy lower alkyl group,
4-hydroxypiperidyl group, a 4-lower alkoxy piperidyl group, an
.omega.,.omega.-lower alkylene dioxyalkyl group, an .omega.,.omega.-lower
alkylene dioxylalkoxy group, a lower cycloalkyl hydroxymethyl group, an
aryloxy group, an arylaminosulfonyl group, amino group, a lower alkylamino
group, a di lower alkylamino group, a hydroxy lower alkylamino group, a
lower acylamino group, a hydroxy lower acylamino group, a lower
alkylsulfonylamino group, a pyridyl lower alkoxy group, a lower
alkylpyridylalkoxy group, a lower alkoxyhydroxyalkoxy group, a lower
thioalkoxyalkoxy group, a lower alkylsulfonylalkoxy group, an N-lower
alkylcarbamoyl group, an N,N-di lower alkylcarbamoyl group, an N-hydroxy
lower alkylcarbamoyl group, an N-hydroxy lower alkyl-N-lower
alkylcarbamoyl group, a halogenated lower alkoxy group, a cyano lower
alkoxy group, a hydroxy lower cycloalkoxy group, trifluoromethyl group,
trifluoromethoxy group, an amino lower alkoxy group, an N-lower alkyl
aminoalkoxy group, an N,N-di lower alkylaminoalkoxy group, a lower
acylalkoxy group, a lower acylaminoalkoxy group, a (1,3-dioxolanyl) lower
alkyl group, a (1,3-dioxolanyl) lower alkoxy group, an amide lower alkoxy
group, a 4-(hydroxyalkyl)tetrahydropyran-4-yl group,
2,3-dihydrobenzofuranyl group, a 2-hydroxy-2-alkyl-2,3-dihydrobenzofuranyl
group, indanonyl group, hydroxyindanyl group, an imidazolyl lower alkoxy
group, succinimide group or 2-oxazolidon-3-yl group;
furthermore, R.sup.7 represents hydrogen atom, while R.sup.8 and R.sup.9
may form cyclopentanon ring, hydroxycyclopentane ring, a
hydroxyalkylcyclopentane ring, cyclohexanone ring, hydroxycyclohexane
ring, a hydroxyalkylcyclohexane ring,
2-hydroxymethyl-2-methylcyclopentanone ring, 1,2-ethylenedioxy ring or
methylenedioxy ring;
m or p represents 0 or an integer of 1 to 6;
R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.25,
R.sup.27 and R.sup.29 independently represent hydrogen atom, halogen atom,
hydroxy group, a lower alkyl group, a lower alkoxy group, a hydroxy lower
alkyl group, a hydroxy lower alkoxy group or tetrahydropyranyl group;
the concrete examples of the heteroaryl group include 4-morpholinyl group,
2,6-dimethyl-4-morpholinyl group, 4-thiomorpholinyl group,
4-oxythiomorpholinyl group, 4-dioxythiomorpholinyl group, 1,3-dioxanyl
group, 1,4-dioxanyl group, tetrahydrofuranyl group, dihydropyranyl group,
4,4-ethylenedioxypiperidin-1-yl group, 4-hydroxypiperidin-1-yl group,
4-methoxypiperidin-1-yl group, 4-acetylpiperazin-1-yl group, a 4-hydroxy
lower alkyl piperidin-1-yl group and the like;
the concrete examples of the heteroaryl lower alkyl group include
4-morpholinylmethyl group, 4-thiomorpholinylmethyl group, a
(tetrahydropyran-4-yl) lower alkyl group, pyridylmethyl group and the
like;
R.sup.11 represents hydrogen atom, halogen atom, hydroxy group, a lower
alkyl group or a lower alkoxy group;
R.sup.24 represents hydrogen atom or a lower alkyl group;
R.sup.26 represents hydrogen atom or a hydroxy lower alkyl group;
R.sup.28 represents hydrogen atom or a lower alkyl group;
R.sup.30 represents hydrogen atom or a lower alkyl group, a lower alkoxy
group, a hydroxy lower alkyl group or a hydroxy lower alkoxy group;
W represents sulfur atom or oxygen atom;
the bond represented by the following formula:
-----
represents a single or double bond; and
the bond represented by the following formula:
{character pullout}
represents trans or bis bond.).
More specifically, the condensed pyridine compound of the present invention
preferably include the condensed pyridine compounds represented by the
following formulae:
##STR10##
##STR11##
##STR12##
wherein R.sup.31 has the same meaning as that of the above R.sup.1,
R.sup.32 has the same meaning as that of the above R.sup.2 and R.sup.33
has the same meaning as that of the above B, respectively.
More specifically, the condensed pyridine compound of the present invention
preferably includes the following ones:
(1) 3-(4-benzyloxybutyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(2) 1-(1-methylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(3) 1-(1-methylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(4) 1-(4-ethylpiperazin-1-yl)-3-(4-trifluoromethylphenyl)isoquinoline,
(5) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-fluoropropyl)phenyl]isoquinoline,
(6) 1-(4-ethylpiperazin-1-yl)-3-(2-hydroxyphenyl)isoquinoline,
(7) 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline,
(8) 1-(4-ethylpiperazin-1-yl)-3-(2-methoxyphenyl)isoquinoline,
(9) 1-(4-ethylpiperazin-1-yl)-3-(3-methoxyphenyl)isoquinoline,
(10) 1-(4-ethylpiperazin-1-yl)-3-(4-methoxyphenyl)isoquinoline,
(11) 3-(2,3-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(12) 3-(2,4-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(13) 3-(2,5-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(14) 3-(3,4-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(15) 3-(3,5-dimethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(16) 1-(4-ethylpiperazin-1-yl)-3-(2,4,5-trimethoxyphenyl)isoquinoline,
(17) 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxymethylphenyl)isoquinoline,
(18) 3-[2-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(19) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxypropyl)phenyl]isoquinoline,
(20) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)phenyl]isoquinoline,
(21) 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxybutyl)phenyl]isoquinoline,
(22) 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxybutyl)phenyl]isoquinoline,
(23) 3-[4-(4-hydroxybutyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(24)
3-[4-(1,3-dihydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(25)
3-[4-(1,3-dihydroxy-3-methylbutyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquin
oline,
(26)
3-[4-(3-hydroxy-1-methoxybutyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoli
ne,
(27)
1-(1-ethylpiperazin-4-yl)-3-[4-(3-hydroxy-1-fluoropropyl)phenyl]isoquinoli
ne,
(28)
1-(4-ethylpiperazin-1-yl)-3-[4-(4-hydroxymethyl-3-fluoro)phenyl]isoquinoli
ne,
(29)
1-(4-ethylpiperazin-1-yl)-3-[3-fluoro-4-(1-hydroxypropyl)phenyl]isoquinoli
ne,
(30)
3-[3-chloro-4-(3-hydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoli
ne,
(31)
3-[3-carboxamide-4-(3-hydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoqu
inoline,
(32)
3-[3-cyano-4-(3-hydroxypropyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinolin
e,
(33)
1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)-3-methoxyphenyl]isoquinol
ine,
(34)
3-[3-(3-hydroxypropyl)-4-methoxyphenyl]-1-(4-ethylpiperazin-1-yl)isoquinol
ine,
(35)
3-[3-(4-hydroxybutyl)-4-methoxyphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoli
ne,
(36) 1-[4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(37)
3-[3,4-(2-dihydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(38)
3-[3,5-(2-dihydroxyethyoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(39)
3-[3-chloro-4-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoli
ne,
(40)
3-[3-methyl-4-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoli
ne,
(41)
3-[3-isopropyl-4-(2-hydroxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquin
oline,
(42) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxyethoxy)phenyl]isoquinoline,
(43)
3-[3,4-(2-dimethoxyethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(44)
3-[4-(2-hydroxyethoxy)methylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(45) 1-(4-ethylpiperazin-1-yl)-3-[4-(2-fluoroethoxy)phenyl]isoquinoline,
(46) 3-(3,4-methylenedioxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(47) 1-(1-ethylpiperazin-4-yl)-3-(4-acetonyloxyphenyl)isoquinoline,
(48) 3-[4-(3-aminopropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(49)
1-(4-ethylpiperazin-1-yl)-3-[4-(2-dimethylaminoethoxy)phenyl]isoquinoline,
(50)
3-[4-(3-acetamidepropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(51) 3-(4-cyanomethoxyphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(52) 3-[4-(2-cyanoethoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(53) 3-[4-(3-cyanopropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(54)
3-[4-(3-methylthiopropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(55)
3-[4-(3-methylsulfonpropoxy)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(56)
3-[4-[2-(1-imidazonyl)ethoxy]phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(57)
3-{4-[3-(4-pyridyl)propoxy]phenyl}-1-(4-ethylpiperazin-1-yl)isoquinoline,
(58)
3-{4-[2-(2-methylpyridin-5-yl)ethoxy]phenyl}-1-(4-ethylpiperazin-1yl)isoqi
noline,
(59) 1-(1-ethylpiperazin-4-yl)-3-[4-(N-ethylcarbamyl)phenyl]isoquinoline,
(60)
(Z)-1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyiminomethylphenyl)isoquinoline,
(61)
(E)-1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyiminomethylphenyl)isoquinoline,
(62) 3-(4-cyanophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(63) 1-(4-ethylpiperazin-1-yl)-3-(4-N-propylaminocarbonylphenyl)
isoquinolin,
(64)
3-[4-(4-hydroxy-1-cyclohexen-1-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquin
oline,
(65) 3-(4-aminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(66) 3-[4-(N,N-dimethylamino)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(67)
3-[4-(2-hydroxyethyl)aminophenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(68) 3-(4-acetamidephenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(69) 3-(4-ethylcarbonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(70) 3-(4-propylcarbonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(71) 3-(4-ethylsulfonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(72) 3-(4-propylsulfonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(73) 3-(4-butylsulfonylaminophenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(74) 3-(4-sulfonamidephenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(75) 3-[(4-morpholinyl)
sulfonylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(76) 3-[(4-thiomorpholinyl)
sulfonylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(77) 3-[(1,1-dioxythiomorpholinyl)
sulfonylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(78)
3-(4-ethylsulfonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(79)
3-(4-ethylsulfonylaminoethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(80)
3-(4-ethylaminosulfonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(81)
3-(4-propylaminosulfonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinolin
e,
(82)
3-[4-N,N-diethylamino)sulfonylmethylphenyl]-1-(4-ethylpiperazin-1-yl)isoqu
inoline,
(83)
3-[4-(tetrahydropyran-4-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(84)
3-[4-(5,6-dihydro-2H-pyran-4-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinol
ine,
(85)
3-(4-ethylcarbonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(86)
3-(4-propylcarbonylaminoethylphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(87)
3-(4-ethylaminocarbonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(88)
3-(4-propylaminocarbonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinolin
e,
(89)
3-(4-butylaminocarbonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(90)
3-(4-methylsulfonylmethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(91)
3-(3-chloro-4-ethylsulfonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)iso
quinoline,
(92)
3-(3-chloro-4-propylsulfonylaminomethylphenyl)-1-(4-ethylpiperazin-1-yl)is
oquinoline,
(93) 3-(4-morpholinymethylphenyl)-1-(4-ethylpiperazin-1-yl) isoquinone,
(94)
3-(4-thiomorpholinymethylphenyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(95) 3-[4-(3-oxazolidionone)phenyl]-1-(4-ethylpiperazin-1yl)isoquinoline,
(96)
3-[4-(4,4-ethylenedioxypiperidin-1-yl)phenyl]-1-(4-ethylpiperazin-1-yl)iso
quinoline,
(97)
1-(4-ethylpiperazin-1-yl)-3-[4-(4-hydroxypiperidin-1-yl)phenyl]isoquinolin
e,
(98)
1-(4-ethylpiperazin-1-yl)-3-[4-[4-methoxypiperidin-1-yl)phenyl]isoquinolin
e,
(99)
3-[2-(4-acetylpiperazin-1-yl)pyridin-5-yl]-1-(4-ethylpiperazin-1-yl)isoqui
noline,
(100)
3-[4-(4-acetylpiperazin-1-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(101) 3-(2-methoxybenzyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(102)
3-(.alpha.-methyl-(4-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinoline
,
(103)
3-[.alpha.-hydroxy-(2-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinolin
e,
(104)
3-[.alpha.-hydroxy-(4-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinolin
e,
(105) 3-[.alpha.-methyl-.sup..alpha.
-hydroxy-(4-methoxybenzyl)]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(106) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxyphenethyl)isoquinoline,
(107)
1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethoxy)phenethyl]isoquinoline,
(108)
1-(1-ethylpiperazin-4-yl)-3-[3-(2-hydroxyethoxy)phenethyl]isoquinoline,
(109)
1-(1-ethylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenethyl]isoquinoline,
(110)
1-(1-ethylpiperazin-4-yl)-3-[3-[2-(2-hydroxyethoxy)phenyl]propyl]isoquinol
ine,
(111) 3-(2-methoxyphenylcarbonyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(112) 3-(4-methoxyphenylcarbonyl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(113) 3-(4-methoxyindan-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(114) 3-(6-methoxyindan-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(115)
3-[4-(2-hydroxyethoxy)indan-1-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(116)
3-(8-methoxy-1,2-dihydronaphthalen-4-yl)-1-(4-ethylpiperazin-1-yl)isoquino
line,
(117)
3-(7-methoxy-1,2-dihydronaphthalen-4-yl)-1-(4-ethylpiperazin-1-yl)isoquino
line,
(118)
3-(6-methoxy-1,2-dihydronaphthalen-4-yl)-1-(4-ethylpiperazin-1-yl)isoquino
line,
(119)
3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(4-ethylpiperazin-1yl)is
oquinoline,
(120)
3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(4-ethylpiperazin-1-yl)i
soquinoline,
(121)
3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(4-ethylpiperazin-1-yl)i
soquinoline,
(122)
3-(3-hydroxymethylchroman-6-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(123) 1-(4-ethylpiperazin-1-yl)-3-(2-pyridyl)isoquinoline,
(124)
1-(4-ethylpiperazin-4-yl)-3-[5-(2-hydroxyethoxy)pyridin-2-yl]isoquinoline,
(125)
1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethoxy)pyridin-5-yl]isoquinoline,
(126)
1-(1-ethylpiperazin-4-yl)-3-[2-(2-methoxyethoxy)pyridin-5-yl]isoquinoline,
(127)
1-(1-ethylpiperazin-4-yl)-3-[5-(2-methoxyethoxy)pyridin-2-yl]isoquinoline,
(128)
3-(2-propylcarbonylaminopyridin-5-yl)-1-(4-ethylpiperazin-1-yl)isoquinolin
e,
(129)
3-[2-methylsulfonylpyridin)-5-yl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(130)
3-[2-ethylsulfonylpyridin)-5-yl)-1-(4-ethylpiperazin-1-yl)isoquinoline,
(131) 1-(1-ethylpiperazin-4-yl)-3-(2-butylpyridin-5-yl)isoquinoline,
(132)
1-(1-ethylpiperazin-4-yl)-3-[5-(3-fluoropropyl)pyridin-2-yl)isoquinoline,
(133)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-fluoropropyl)pyridin-5-yl]isoquinoline,
(134)
1-(1-ethylpiperazin-4-yl)-3-[5-(3-hydroxypropyl)pyridin-2-yl]isoquinoline,
(135)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-hydroxypropyl)pyridin-5-yl]isoquinoline,
(136)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-hydroxybutyl)pyridin-5-yl]isoquinoline,
(137)
1-(1-ethylpiperazin-4-yl)-3-[2-(4-hydroxybutyl)pyridin-5-yl]isoquinoline,
(138)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-hydroxy-3-methylbutyl)pyridin-5-yl]isoqu
inoline,
(139)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-methoxypropyl)pyridin-5-yl)isoquinoline,
(140)
1-(1-ethylpiperazin-4-yl)-3-[3-(3-methoxypropyl)pyridin-5-yl)isoquinoline,
(141)
1-(1-ethylpiperazin-4-yl)-3-[5-(3-methoxypropyl)pyridin-2-yl)isoquinoline,
(142)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-ethoxypropyl)pyridin-5-yl]isoquinoline,
(143)
1-(1-ethylpiperazin-4-yl)-3-[2-[3-(2-propoxy)propyl]pyridin-5-yl]isoquinol
ine,
(144)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-methoxybutyl)pyridin-5-yl]isoquinoline,
(145)
1-(1-ethylpiperazin-4-yl)-3-{2-[2-(2-hydroxy-2-cyclohexyl)ethynyl]pyridin-
4-yl}isoquinoline,
(146)
1-(1-ethylpiperazin-4-yl)-3-[2-(1-butyn-1-yl)pyridin-5yl]isoquinoline,
(147)
1-(4-ethylpiperazin-1-yl)-3-[2-(morpholin-4-yl)pyridin-5-yl]isoquinoline,
(148)
1-(4-ethylpiperazin-1-yl)-3-[5-(morpholin-4-yl)pyridin-2-yl]isoquinoline,
(149)
3-[2-(2,6-dimethylmorpholin-4-yl)pyridin-5-yl]-1-(4-ethylpiperazin-1-yl)is
oquinoline,
(150)
1-(4-ethylpiperazin-1-yl)-3-[2-thiomorpholin-4-yl)pyridin-5-yl]isoquinolin
e,
(151)
1-(4-ethylpiperazin-1-yl)-3-[2(S-oxythiomorpholin-4-yl)pyridin-5-yl]isoqui
noline,
(152)
1-(4-ethylpiperazin-1-yl)-3-[2-(4-hydroxypiperidin-1-yl)pyridin-5-yl]isoqu
inoline,
(153)
1-(4-ethylpiperazin-1-yl)-3-[2-(4-methoxypiperidin-1-yl)pyridin-5-yl]isoqu
inoline,
(154)
1-(4-ethylpiperazin-1-yl)-3-[2-(4-hydroxymethylpiperidin-1-yl)pyridin-5-yl
]isoquinoline,
(155)
3-[2-(5,6-dihydro-2H-pyran-4-yl)pyridin-5-yl]-1-(4-ethylpiperazin-1-yl)iso
quinoline,
(156)
3-[2-(tetrahydropyran-4-yl)pyridin-5-yl]-1-(4-ethylpiperazin-1-yl)isoquino
line,
(157)
3-[4-[3-(3-pyridyl)propoxy]phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(158) 1-(1-ethylpiperazin-4-yl)-3-(1-phenylpiperazin-4-yl)isoquinoline,
(159) 1-(1-ethylpiperazin-4-yl)-3-[1-(2-pyridyl)
piperazin-4-yl]isoquinoline,
(160) 3-[4-(4-morpholinyl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(161)
1-(1-ethylpiperazin-4-yl)-3-(2-hydroxymethylthiophen-4-yl)isoquinoline,
(162)
1-(1-ethylpiperazin-4-yl)-3-(2-hydroxymethylthiophen-5-yl)isoquinoline,
(163)
1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethyl)thiophen-5-yl]isoquinoline,
(164)
1-(1-ethylpiperazin-4-yl)-3-[2-(1-hydroxypropyl)thiophen-4-yl]isoquinoline
,
(165)
1-(1-ethylpiperazin-4-yl)-3-[2-(1-hydroxypropyl)thiophen-5-yl)isoquinoline
,
(166) 3-[2-(tetrahydropyran-4-yl)
thiophen-5-yl]-1-(4-ethylpiperazin-1yl)isoquinoline,
(167)
1-(1-ethylpiperazin-4-yl)-3-[4-methyl-5-(2-hydroxyethyl)thiazol-2-yl]isoqu
inoline,
(168)
1-(1-ethylpiperazin-4-yl)-3-(2-hydroxymethylthiazol-5-yl)isoquinoline,
(169)
1-(1-ethylpiperazin-4-yl)-3-[1-(2-hydroxyethyl)pyrazol-3-yl]isoquinoline,
(170)
1-(1-ethylpiperazin-4-yl)-3-[(1-hydroxypropyl)thiazol-5-yl]isoquinoline,
(171)
1-(1-ethylpiperaziin-4-yl)-3-[2-(3-hydroxypropyl)thiazol-5-yl]isoquinoline
,
(172)
1-(1-ethylpiperazin-4-yl)-3-[2-(3-methoxypropyl)thiazol-5-yl]isoquinoline,
(173)
1-(1-ethylpiperazin-4-yl)-3-[2-(4-morpholinyl)thiazol-5-yl]isoquinoline,
(174)
3-(2-propylcarbonylaminopyrimidin-5-yl)-1-(4-ethylpiperazin-1-yl)isoquinol
ine,
(175)
3-[2-(5,6-dihydro-2H-pyran-4-yl)thiophen-4-yl]-1-(4-ethylpiperazin-1-yl)is
oquinoline,
(176)
3-[2-(5,6-dihydro-2H-pyran-4-yl)thiophen-5-yl]-1-(4-ethylpiperazin-1-yl)is
oquinoline,
(177) 1-(1-ethylpiperazin-4-yl)-3-(phenylethynyl)isoquinoline,
(178) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxyphenyl)ethynylisoquinoline,
(179) 1-(1-ethylpiperazin-4-yl)-3-(2-pyridyl)ethynylisoquinoline,
(180)
3-[3-(4-morpholinyl)-1-propynl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(181) 1-(1-ethylpiperazin-4-yl)-3-(3-phenyl-1-propynyl)isoquinoline,
(182) 1-(1-ethylpiperazin-4-yl)-3-(4-phenyl-1-butynyl)isoquinoline,
(183)
1-(1-ethylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenylethynyl]isoquinoline
,
(184) 1-(1-ethylpiperazin-4-yl)-3-benzoylethynylisoquinoline,
(185) 1-(1-ethylpiperazin-4-yl)-3-(2,4-dimethoxyphenylethynyl)isoquinoline,
(186)
1-(1-ethylpiperazin-4-yl)-3-[3-(3-methoxypropyl)-5-pyridyl]ethynylisoquino
line,
(187)
1-(1-ethylpiperazin-4-yl)-3-[2-(2-hydroxyethoxy)phenyl]ethynylisoquinoline
,
(188)
1-(1-ethylpiperazin-4-yl)-3-[3-(2-hydroxyethoxy)-2-pyridyl]ethynylisoquino
line,
(189) 1-(1-ethylpiperazin-4-yl)-3-(trans-2-phenylethenyl)isoquinoline,
(190)
1-(1-ethylpiperazin-4-yl)-3-[trans-2-(4-methoxyphenyl)ethenyl]isoquinoline
,
(191)
1-(1-ethylpiperazin-4-yl)-3-[cis-2-(4-methoxyphenyl)ethenyl]isoquinoline,
(192)
1-(1-ethylpiperazin-4-yl)-3-(cis-1-methyl-2-phenylethenyl)isoquinoline,
(193)
1-(1-ethylpiperazin-4-yl)-3-(trans-1-methyl-2-phenylethyenyl)isoquinoline,
(194)
1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-hydroxyethoxyphenyl)ethenyl]isoqui
noline,
(195)
1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-methoxyphenyl)ethenyl]isoquinoline
,
(196)
1-(1-ethylpiperazin-4-yl)-3-(trans-2-methyl-2-phenylethen-1-yl)isoquinolin
e,
(197)
1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-fluorophenyl)ethenyl]isoquinoline,
(198)
1-(1-ethylpiperazin-4-yl)-3-[(E)-4-(2-hydroxyethoxy)styryl]isoquinoline,
(199)
1-(1-ethylpiperazin-4-yl)-3-{trans-2-[3-(2-hydroxyethoxy)phenyl]ethenyl}is
oquinoline,
(200)
3-{(E)-2-[2-(4-morpholinyl)pyridin-5-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)
isoquinoline,
(201)
3-[(E)-2-(4-methylsulfonylphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)isoquin
oline,
(202)
3-[(E)-2-(2-methylsulfonylphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)isoquin
oline,
(203)
3-[(E)-2-(4-methylsulfonylmethylphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)i
soquinoline,
(204)
3-{(E)-2-(3-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoqui
noline,
(205)
3-{(E)-2-[4-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperazin-1-yl)isoqui
noline,
(206)
3-{(E)-2-methyl-2-[4-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperaziin-1
-yl)isoquinoline,
(207)
3-{(E)-2-methyl-2-[3-(4-morpholinyl)phenyl]ethenyl}-1-(4-ethylpiperazin-1-
yl)isoquinoline,
(208)
3-[(E)-2-methoxymethyl-2-phenylethenyl]-1-(4-ethylpiperazin-1-yl)isoquinol
ine,
(209) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(2-pyridyl)ethenyl]isoquinoline,
(210) 1-(1-ethylpiperazin-4-yl)-3-[trans-2-(4-pyridyl)ethenyl]isoquinoline,
(211)
1-(1-ethylpiperazin-4-yl)-3-[3-(2-methoxy)phenyl-2-propenyl]isoquinoline,
(212)
1-(1-ethylpiperazin-4-yl)-3-[3-(2-hydroxyethoxy)phenyl-1-propenyl]isoquino
line,
(213)
3-{(E)-2-[2-(4-morpholinyl)pyridin-5-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)
isoquinoline,
(214)
3-{(E)-2-[3-(4-morpholinyl)pyridazin-6-yl]ethenyl}-1-(4-ethylpiperazin-1-y
l)isoquinoline,
(215)
3-{(E)-2-[4-(4-morpholinyl)pyrimidin-6-yl]ethenyl}-1-(4-ethylpiperazin-1-y
l)isoquinoline,
(216)
3-{(E)-2-[2-(4-morpholinyl)pyrazin-6-yl]ethenyl}-1-(4-ethylpiperazin-1-yl)
isoquinoline,
(217) 3-[1-(4-methoxyphenyl)ethenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline,
(218) 1-(1-ethylpiperazin-4-yl)-N-phenyl-3-isoquinolinecarboxamide,
(219) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxyanilinomethyl)isoquinoline,
(220) 1-(1-ethylpiperazin-4-yl)-3-(4-methoxybenzylamino)isoquinoline,
(221) 1-(1-ethylpiperazin-4-yl)-4-methoxy-3-(4-methoxyphenyl)isoquinoline,
(222) 1-(1-ethylpiperazin-4-yl)-5-methyl-3-(4-methoxyphenyl)isoquinoline,
(223)
1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)phenyl]-6-fluoroisoquinoli
ne,
(224) 1-(1-ethylpiperazin-4-yl)-6-fluoro-3-(4-methoxyphenyl)isoquinoline,
(225) 1-(1-ethylpiperazin-4-yl)-6-methyl-3-(4-methoxyphenyl)isoquinoline,
(226)
1-(4-ethylpiperazin-1-yl)-6-methoxy-3-(4-trifluoromethylphenyl)isoquinolin
e,
(227) 1-(4-ethylpiperazin-1-yl)-6-methoxy-3-(4-methoxyphenyl)isoquinoline,
(228) 1-(1-ethylpiperazin-4-yl)-7-methyl-3-(4-methoxyphenyl)isoquinoline,
(229) 1-(4-ethylpiperazin-1-yl)-7-fluoro-3-(4-methoxyphenyl)isoquinoline,
(230)
1-(4-ethylpiperazin-1-yl)-3-[4-(2-hydroxyethoxy)phenyl]-7-fluoroisoquinoli
ne,
(231) 1-(4-ethylpiperazin-1-yl)-7-methoxy-3-phenylisoquinoline,
(232) 1-(4-ethylpiperazin-1-yl)-7-methoxy-3-(2-methoxyphenyl)isoquinoline,
(233) 1-(1-ethylpiperazin-4-yl)-8-fluoro-3-(4-methoxyphenyl)isoquinoline,
(234)
1-(1-ethylpiperazin-4-yl)-8-fluoro-3-[4-(2-hydroxyethoxy)phenyl]isoquinoli
ne,
(235) 1-(1-ethylpiperazin-4-yl)-8-methoxy-3-(4-methoxyphenyl)isoquinoline,
(236) 1-(1-propylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(237) 1-(1-propylpiperazin-4-yl)-3-[4-(2-hydroxyethoxy)phenyl]isoquinoline,
(238) 1-(1-isopropylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(239) 1-(1-cyclopropylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(240) 1-(1-allylpiperazin-4-yl)-3-(4-methoxyphenyl)isoquinoline,
(241) 1-[1-(2-fluoroethyl)piperazin-4-yl]-3-(4-methoxyphenyl)isoquinoline,
(242) 1-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(4-methoxyphenyl)isoquinoline,
(243)
1-(4-ethylsulfonylaminomethylphenyl)-1-[4-(2-hydroxyethyl)piperazin-1-yl]i
soquinoline,
(244) 8-(4-ethylpiperazin-1-yl)-6-(4-methoxyphenyl)pyrido[2,3-c]pyridine,
(245)
8-(1-ethylpiperazin-4-yl)-6-[4-(2-hydroxyethoxy)phenyl]-1,7-naphthyridine,
(246)
8-(1-ethylpiperazin-4-yl)-6-[4-[(S)-2-hydroxypropoxy]phenyl]-1,7-naphthyri
dine,
(247)
