U.S. patent application number 09/829203 was filed with the patent office on 2002-04-25 for 1,2-dihydro-2-oxoquinoline derivatives.
Invention is credited to Chaki, Shigeyuki, Gotoh, Makoto, Kumagai, Toshihito, Nagamine, Masashi, Nakazato, Atsuro, Okubo, Taketoshi, Tomisawa, Kazuyuki, Yoshida, Masanori.
Application Number | 20020049323 09/829203 |
Document ID | / |
Family ID | 18256057 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020049323 |
Kind Code |
A1 |
Nakazato, Atsuro ; et
al. |
April 25, 2002 |
1,2-Dihydro-2-oxoquinoline derivatives
Abstract
A 1,2-dihydro-2-oxoquinoline derivative represented by the
formula: 1 wherein Ar is a pyridyl group or a group represented by
the formula: 2 (wherein X.sup.3 and X.sup.4 are the same or
different, and are each a hydrogen atom, a halogen atom, a
C.sub.1-5 alkyl group, a C.sub.1-5 alkoxy group, a hydroxyl group
or a trifluoromethyl group), Y is a nitrogen atom, CH or C(OH),
R.sup.1 and R.sup.2 are the same or different, and are each a
hydrogen atom, a C.sub.1-10 alkyl group, a C.sub.3-15 alkoxyalkyl
group or a C.sub.3-15 alkylaminoalkyl group or R.sup.1 and R.sup.2
taken together with the nitrogen atom to which they are attached
form a cyclic amino group, X.sup.1 and X.sup.2 are the same or
different, and are each a hydrogen atom, a C.sub.1-5 alkyl group, a
C.sub.1-5 alkoxy group or a halogen atom, or X.sup.1 and X.sup.2
taken together form an alkylenedioxy group, and n is an integer of
1 to 3; or a pharmaceutically acceptable salt thereof.
Inventors: |
Nakazato, Atsuro; (Tokyo,
JP) ; Okubo, Taketoshi; (Tokyo, JP) ; Kumagai,
Toshihito; (Tokyo, JP) ; Chaki, Shigeyuki;
(Tokyo, JP) ; Tomisawa, Kazuyuki; (Tokyo, JP)
; Nagamine, Masashi; (Nara, JP) ; Gotoh,
Makoto; (Osaka, JP) ; Yoshida, Masanori;
(Osaka, JP) |
Correspondence
Address: |
LORUSSO & LOUD
3137 Mount Vernon Avenue
Alexandria
VA
22305
US
|
Family ID: |
18256057 |
Appl. No.: |
09/829203 |
Filed: |
April 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09829203 |
Apr 10, 2001 |
|
|
|
09555568 |
Jun 1, 2000 |
|
|
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Current U.S.
Class: |
544/354 ;
546/156 |
Current CPC
Class: |
C07D 401/06 20130101;
C07D 215/54 20130101; C07D 241/44 20130101 |
Class at
Publication: |
544/354 ;
546/156 |
International
Class: |
C07D 215/36; C07D
241/36 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 3, 1997 |
JP |
332539/1997 |
Claims
1. A 1,2-dihydro-2-oxoquinoline compound represented by the
formula: 10wherein Ar is a pyridyl group or a group represented by
the formula: 11(wherein X.sup.3 and X.sup.4 are the same or
different, and are each a hydrogen atom, a halogen atom, a
C.sub.1-5 alkyl group, a C.sub.1-5 alkoxy group, a hydroxyl group
or a trifluoromethyl group), Y is a nitrogen atom, R.sup.1 and
R.sup.2 are the same or different, and are each a hydrogen atom, a
C.sub.1-10 alkyl group, a C.sub.3-15 alkoxyalkyl group or a
C.sub.3-15 alkylaminoalkyl group, or R.sup.1 and R.sup.2 taken
together with the nitrogen atom to which they are attached form a
cyclic amino group, X.sup.1 and X.sup.2 are the same or different,
and are each a hydrogen atom, a C.sub.1-5 alkyl group, a C.sub.1-5
alkoxy group or a halogen atom, or X.sup.1 and X.sup.2 taken
together form an alkylenedioxy group, and n is an integer of 1 to
3; or a pharmaceutically acceptable salt thereof.
2. A 1,2-dihydro-2-oxoquinoline compound represented by the
formula: 12wherein Ar is a pyridyl group or a group represented by
the formula: 13(wherein X.sup.3 and X.sup.4 are the same or
different, and are each a hydrogen atom, a halogen atom, a
C.sub.1-5 alkyl group, a C.sub.1-5 alkoxy group, a hydroxyl group
or a trifluoromethyl group), Y is a nitrogen atom, R.sup.1 and
R.sup.2 are the same or different, and are each a C.sub.1-10 alkyl
group, a C.sub.3-15 alkoxyalkyl group or a C.sub.3-15
alkylaminoalkyl group, or R.sup.1 and R.sup.2 taken together with
the nitrogen atom to which they are attached form a cyclic amino
group, X.sup.1 and X.sup.2 are the same or different, and are each
a hydrogen atom, a C.sub.1-5 alkyl group, a C.sub.1-5 alkoxy group
or a halogen atom, or X.sup.1 and X.sup.2 taken together form an
alkylenedioxy group, and n is an integer of 1 to 3; or a
pharmaceutically acceptable salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to compounds having a high
affinity for mitochondrial diazepam binding inhibitor receptor
(MDR).
BACKGROUND ART
[0002] Benzodiazepine (BZ) receptors which are an acting site of
anti-anxiety drugs are classified into 2 subtypes of central
benzodiazepine receptor (CBR) located on GABA.sub.A
receptor/chloride channel complex and MDR located on the central
nervous system (glial cells) or adrenal glands (Clin.
Neuropharmacol., 16, 401-417 (1993)). Recently, CBR agonists of
which representative is diazepam are widely used as anti-anxiety
drugs. However, since CBR agonists act directly on GABA.sub.A
receptor/chloride channel complex, they cause an anti-anxiety
action together with side-effects such as excessive sedation or
psychic dependence. On the other hand, since MDR agonists act
indirectly on GABA.sub.A receptor/chloride channel complex via
synthesis of neurosteroids such as endogenous neuroactive steroids
(endogenous anti-anxiety substances), they cause an anti-anxiety
action, but do not cause side-effects such as psychic dependence or
excessive sedation (J. Pharmacol. Exp. Ther., 267, 462-471, 1993;
ibid., 265, 649-656, 1993).
[0003] Accordingly, there is a need of the development of
therapeutic agents for diseases (obsessive disorders, panic
disorders) on which the previous BZs do not have a satisfactorily
therapeutic effect, and development of MDR agonists as anti-anxiety
drugs which alleviate the side-effects as recognized in the
previous BZs.
[0004] Furthermore, the compounds which act on MDR, in view of
acting on GABA.sub.A receptors, have a possibility of use as
therapeutical agents of sleeping disorders, epilepsy, dyskinesia
accompanied by muscle rigidity, feeding disorders, circulation
disorders, recognition and learning disability or drug dependence
(Progress in Neurobiology, 38, 379-395, 1992, ibid., 49, 73-97,
1996; J. Neurochem., 58, 1589-1601; Neuropharmacol., 30, 1435-1440,
1991). In addition, these compounds, in view of the physiological
functions of MDR, have a possibility of use as therapeutic agents
of cancer (Biochimica et Biophysica Acta, 1241, 453-470, 1995),
lipid metabolism abnormality (Eur. J. Pharmacol., 294, 601-607,
1995), schizophrenia (Neuropharmacology, 35, 1075-1079, 1996),
cerebral infarction (J. Neurosci., 15, 5263-5274, 1995), AIDS
(Abstracts of the fifth international conference on AIDS, p. 458,
1989), Alzheimer's disease (Alzheimer Dis. Assoc. Disotd., 2,
331-336, 1988) or Huntington chorea (Brain Res., 248, 396-401,
1982).
[0005] Among the compounds having affinity for MDR, there are
indole compounds disclosed in Japanese Translation of PCT
publication (Kohyo) No. 6-501030.
DISCLOSURE OF THE INVENTION
[0006] As a result of extensive researches about compounds having a
high affinity for MDR, the present inventors have, found that the
specific 1,2-dihydro-2-oxoquinoline derivatives meet the above
object, thus the present invention has been accomplished. As stated
above, while the indole compounds having an affinity for MDR are
known, there are not reported 1,2-dihydro-2-oxoquinoline
derivatives of the present invention which have an affinity for
MDR.
[0007] The present invention is directed to a
1,2-dihydro-2-oxoquinoline derivative represented by Formula [I]:
3
[0008] wherein Ar is a pyridyl group or a group represented by the
formula: 4
[0009] (wherein X.sup.3 and X.sup.4 are the same or different, and
are each a hydrogen atom, a halogen atom, a C.sub.1-5 alkyl group,
a C.sub.1-5 alkoxy group, a hydroxyl group or a trifluoromethyl
group), Y is a nitrogen atom or CH, R.sup.1 and R.sup.2 are the
same or different, and are each a hydrogen atom, a C.sub.1-10 alkyl
group, a C.sub.3-15 alkoxyalkyl group or a C.sub.3-15
alkylaminoalkyl group, or R.sup.1 and R.sup.2 taken together with
the nitrogen atom to which they are attached form a cyclic amino
group, X.sup.1 and X.sup.2 are the same or different, and are each
a hydrogen atom, a C.sub.1-5 alkyl group, a C.sub.1-5 alkoxy group
or a halogen atom, or X.sup.1 and X.sup.2 taken together form an
alkylenedioxy group, and n is an integer of 1 to 3, provided that Y
is other than CH when all of R.sup.1, R.sup.2, X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are hydrogen atoms; or a pharmaceutically
acceptable salt thereof.
[0010] In the present invention, the halogen atom for X.sup.3 and
X.sup.4 refers to a fluorine atom, a chlorine atom, a bromine atom
or an iodine atom. The C.sub.1-5 alkyl group for X.sup.3 and
X.sup.4 refers to a straight or branched alkyl group, and examples
thereof are a methyl group, an ethyl group, a propyl group and an
isopropyl group. The C.sub.1-5 alkoxy group for X.sup.3 and X.sup.4
refers to a straight or branched alkoxy group, and examples thereof
are a methoxy group and an ethoxy group. The C.sub.1-10 alkyl group
for R.sup.1 and R.sup.2 refers to a straight, branched or cyclic
alkyl group, and examples thereof are a methyl group, an ethyl
group, a propyl group, an isopropyl group, a cyclopropyl group, a
butyl group, an isobutyl group, a cyclobutyl group, a
cyclopropylmethyl group, a pentyl group, an isopentyl group, a
cyclopentyl group, a cyclobutylmethyl group, a 1-ethylpropyl group,
a hexyl group, an isohexyl group, a cyclohexyl group, a
cyclopentylmethyl group, a 1-ethylbutyl group, a heptyl group, an
isoheptyl group, a cyclohexylmethyl group, an octyl group, a nonyl
group and a decyl group. The C.sub.3-15 alkoxyalkyl group for
R.sup.1 and R.sup.2 refers to a straight, branched or cyclic
C.sub.1-13 alkoxy-C.sub.2-14 alkyl group, and examples thereof are
a methoxyethyl group, a methoxypropyl group, a methoxybutyl group,
an ethoxyethyl group, an ethoxypropyl group, an ethoxybutyl group,
an ethoxypentyl group, an ethoxyhexyl group, an ethoxyheptyl group,
a propoxyethyl group, a propoxypropyl group, a propoxybutyl group,
an isopropoxyethyl group and a cyclopropylmethoxyethyl group. The
C.sub.3-15 alkylaminoalkyl group for R.sup.1 and R.sup.2 refers to
a straight, branched or cyclic C.sub.1-13 alkylamino-C.sub.2-14
alkyl group, and examples thereof are a methylaminoethyl group, a
dimethylaminoethyl group, a methylaminopropyl group, a
dimethylaminopropyl group, a methylaminobutyl group, an
ethylaminoethyl group, an ethylaminopropyl group, an
ethylaminobutyl group, an ethylaminopentyl group, an
ethylaminohexyl group, an ethylaminoheptyl group, an
ethylaminooctyl group, a propylaminoethyl group, a
propylaminopropyl group, a propylaminobutyl group, an
isopropylaminoethyl group, a cyclopropylmethylaminoethyl group and
a pyrrolidinoethyl group. Examples of the cyclic amino group which
is formed by R.sup.1, R.sup.2 and the nitrogen atom to which they
are attached are a pyrrolidino group, a piperidino group, a
homopiperidino group, a morpholino group, a piperazino group, an
N-methylpiperazino group and a 3,5-dimethylpiperazino group. The
C.sub.1-5 alkyl group for X.sup.1 and X.sup.2 refers to a straight,
branched or cyclic alkyl group, and examples thereof are a methyl
group, an ethyl group, a propyl group, an isopropyl group, a butyl
group, an isobutyl group and a pentyl group. The C.sub.1-5 alkoxy
group for X.sup.1 and X.sup.2 refers to a straight, branched or
cyclic alkoxy group, and examples thereof are a methoxy group, an
ethoxy group, a propoxy group, an isopropoxy group, a butoxy group,
an isobutoxy group, a cyclopropylmethoxy group, a pentoxy group and
an isopentoxy group. The halogen atom for X.sup.1 and X.sup.2
refers to a fluorine atom, a chlorine atom, a bromine atom or an
iodine atom. Examples of the C.sub.1-5 alkylenedioxy group which is
formed by X.sup.1 and X.sup.2 taken together are a methylenedioxy
group, an ethylenedioxy group and an n-propylenedioxy group. In
addtion, examples of the pharmaceutically acceptable salt in the
present invention are salts with mineral acids such as sulfuric
acid, hydrochloric acid or phosphoric acid, or salts with organic
acids such as acetic acid, oxalic acid, lactic acid, tartaric acid,
fumaric acid, maleic acid, methanesulfonic acid or benzenesulfonic
acid.
[0011] The compound of Formula [I] can be prepared by the following
general preparation methods 1 to 3. In the following reaction
formulae, Ar, Y, R.sup.1, R.sup.2, X.sup.1, X.sup.2 and n are as
defined above, Y.sup.1 is a nitrogen atom or CH, R.sup.3 and
R.sup.4 are the same or different, and are each a C.sub.1-5 alkyl
group or a benzyl group, and X.sup.5 is a chlorine atom, a bromine
atom or an iodine atom. 5
[0012] Step (A): A 1,2-dihydro-2-oxoguinolinecarboxylate ester
derivative (1) can be reacted with an arylalkyl halide derivative
(2) in an inert solvent, if necessary, by using a phase transfer
catalyst in the presence of a base to give a
1-arylalkyl-1,2-dihydro-2-oxoquinolinecarborboxylate ester
derivative (3).
[0013] Examples of the inert solvent are alcohols (e.g. methanol or
ethanol), ethers (e.g. 1,2-dimethoxyethane or tetrahydrofuran),
hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g.
chloroform or dichloromethane), acetonitrile,
N,N-dimethylformamide, water and a mixture thereof. Examples of the
phase transfer catalyst are quaternary ammonium salts (e.g.
benzyltriethyl ammonium bromide) and crown ethers (e.g.
18-crown-6-ether). Examples of the base are inorganic bases (e.g.
potassium carbonate, sodium hydroxide, sodium hydride or metallic
sodium) and alcoholates (e.g. potassium t-butoxide or sodium
ethoxide).
[0014] Step (B): The
1-arylalkyl-1,2-dihydro-2-oxoquinolinecarborboxylate ester
derivative (3) is hydrolyzed with a base or an acid in an inert
solvent to give a 1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic
acid derivative (4).
[0015] Examples of the inert solvent are alcohols (e.g. methanol or
ethanol), ketones (e.g. acetone), ethers (e.g. 1,2-dimethoxyethane
or tetrahydrofuran), hydrocarbons (e.g. toluene or benzene),
halogenide solvents (e.g. chloroform or dichloromethane),
acetonitrile, N,N-dimethylformamide and a mixture of these solvents
with water. Examples of the base are inorganic bases (e.g.
potassium carbonate, sodium carbonate, potassium hydroxide or
sodium hydroxide). Examples of the acid are hydrochloric acid,
sulfuric acid and phosphoric acid.
[0016] Step (C): The compound (6) of the present invention can be
synthesized from the
1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic acid derivative
(4) via the acid halide or mixed acid anhydride thereof.
[0017] The acid halide includes an acid chloride and an acid
bromide, and for example, they can be obtained by reacting a
halogenating agent (e.g. thionyl chloride, thionyl bromide, oxalyl
chloride, carbon tetrachloride-triphenylphosphine or carbon
tetrabromide-triphenylphosphin- e) in an inert solvent. Examples of
the above inert solvent are ethers (e.g. tetrahydrofuran),
hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g.
chloroform or dichloromethane), acetonitrile and
N,N-dimethylformamide.
[0018] The mixed acid anhydride includes an anhydride of a
carboxylic acid with a carbonic acid, and for example, it can be
obtained by reacting a halocarbonate ester (e.g. ethyl
chlorocarbonate or isobutyl chlorocarbonate) in the presence of an
organic base (e.g. triethylamine, diisopropylethylamine,
N-methylmorpholine or pyridine) or an inorganic base (e.g. sodium
hydride) in an inert solvent. Examples of the inert solvent are
ethers (e.g. tetrahydrofuran), hydrocarbons (e.g. toluene or
benzene), halogenide solvents (e.g. chloroform or dichloromethane),
acetonitrile and N,N-dimethylformamide.
[0019] The compound (6) of the present invention can be also
obtained by the reaction of the
1-arylalkyl-1,2-dihydro-2-oxoquinolinecarboxylic acid derivative
together with a condensing agent and an amine (5) in an inert
solvent.
[0020] The condensing agent refers to a conventional amidating
reagent such as, for example, diphenylphosphoryl azide, diethyl
cyanophosphate, carbonyldiimidazole or carbodiimides of which
representatives are N,N'-dicyclohexylcarbodiimide and
N-ethyl-N'-dimethylaminopropylcarbodiim- ide hydrochloride.
Examples of the inert solvent are ethers (e.g. 1,2-dimethoxyethane
or tetrahydrofuran), hydrocarbons (e.g. toluene or benzene),
halogenide solvents (e.g. chloroform or dichloromethane),
acetonitrile and N,N-dimethylformamide. In this reaction, if
necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole,
3-hydroxy-4-oxo-3,4-dihydro- -1,2,3-benzotriazine, etc. can be
added as an activating agent. 6
[0021] A 1,2-dihydro-2-oxoquinolinecarboxylic acid derivative (7)
is amidated according to Step (C) to give a compound (8) of the
present invention, which is then subjected to 1-arylalkylation
according to Step (A) to give a compound (6) of the present
invention. 7
[0022] Step (D): An isatoic anhydride derivative (9) Is reacted
with a malonate ester (10) in an inert solvent in the presence of a
base to give a 4-hydroxy-1,2-dihydro-2-oxoquinolinecarboxylate
ester derivative (11).
[0023] Examples of the inert solvent are alcohols (e.g. methanol or
ethanol), ethers (e.g.-1,2-dimethoxyethane or tetrahydrofuran),
hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g.
chloroform or dichloromethane), acetonitrile,
N,N-dimethylformamide, water and a mixture thereof. The base
includes inorganic bases (e.g. potassium carbonate, sodium
hydroxide, sodium hydride or metallic sodium) or alcoholates (e.g.
potassium t-butoxide or sodium ethoxide).
[0024] Step (E): The
4-hydroxy-1,2-dihydro-2-oxoquinolinecarboxylate ester derivative
(11) can be reacted with an amine derivative (5) in an inert
solvent to give a compound (12) of the present invention.
[0025] Examples of the inert solvent are alcohols (e.g. methanol or
ethanol), ethers (e.g. 1,2-dimethoxyethane or tetrahydrofuran),
hydrocarbons (e.g. toluene or benzene), halogenide solvents (e.g.
chloroform or dichloromethane), acetonitrile,
N,N-dimethylformamide, water and a mixture thereof.
INDUSTRIAL APPLICABILITY
[0026] The compounds of the present invention have a high affinity
for MDR, and therefore they are useful as therapeutic or preventive
drugs of central diseases such as anxiety, related diseases
thereto, depression, epilepsy, sleeping disorders, recognition and
learning disability or schizophrenia, dyskinesia accompanied by
muscle rigidity, feeding disorders, circulation disorders, drug
dependence, cancer, lipid metabolism abnormality, cerebral
infarction, AIDS, Alzheimer's disease or Huntington chorea.
BEST MODE OF CARRYING OUT THE INVENTION
[0027] The present invention is illustrated in more detail by
showing the following examples and an experiment.
EXAMPLE 1
[0028] (1) Preparation of
N,N-dihexyl-1-benzyl-1,2-dihydro-2-oxoquinoxalin-
e-3-carboxamide
[0029] A solution of 3.90 g of ethyl
1,2-dihydro-2-oxoquinoxaline-3-carbox- ylate in 25 ml of
N,N-dimethylformamide was added dropwise to a suspension of 0.79 g
of 60% sodium hydride/oil in 10 ml of N,N-dimethylformamide at room
temperature over 30 minutes. After stirring at room temperature for
30 minutes, 3.36 g of benzyl bromide was added dropwise over 10
minutes, followed by stirring at room temperature overnight. The
reaction mixture was concentrated under reduced pressure. The
residue, after addition of ethyl acetate, was washed with water, 1
N hydrochloric acid, a saturated aqueous sodium bicarbonate
solution and a saturated aqueous sodium chloride solution, and
dried over anhydrous sodium sulfate. After removal of the drying
agent by filtration, the filtrate was concentrated under reduced
pressure. The residue was purified by chromatography (silica gel;
Wakogel C200 (manufactured by Wako Pure Chemicals), developing
solvent; hexane-ethyl acetate=10:1-2:1) and recrystallized from
ethyl acetate-hexane to give 3.77 g of ethyl
1-benzyl-1,2-dihydro-2-oxoquinoxal- ine-3-carboxylate.
[0030] (2) To 2.00 g of ethyl
1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carb- oxylate were added 10
ml of ethanol and 20 ml of 10% aqueous sodium hydroxide solution,
followed by stirring at room temperature for an hour. To the
reaction solution was added dropwise 3 N hydrochloric acid to make
acidic (pH=3.0), and the precipitated crystals were collected by
filtration and washed with water and diethyl ether to give 1.73 g
of 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid.
[0031] (3) In 30 ml of tetrahydrofuran were dissolved 0.50 g of
1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid and 0.87 ml
of triethylamine, and after cooling to -40.degree. C., 0.19 ml of
ethyl chlorocarbonate was added dropwise over 5 minutes. After
stirring at -40.degree. C. for 10 minutes, 0.46 ml of dihexylamine
was added dropwise over 5 minutes. After stirring at -40.degree. C.
for an hour, the temperature was raised to room temperature over an
hour, followed by stirring at room temperature overnight. The
reaction mixture was concentrated under reduced pressure, and the
residue, after addition of ethyl acetate, was washed with water, IN
hydrochloric acid, a saturated aqueous sodium bicarbonate solution
and a saturated aqueous sodium chloride solution, and dried over
anhydrous sodium sulfate. After removal of the drying agent by
filtration, the filtrate was concentrated under reduced pressure.
The residue was purified by chromatography (silica gel; Wakogel
C200 (manufactured by Wako Pure Chemicals), developing solvent;
chloroform) and recrystallized from hexane to give 0.53 g of
N,N-dihexyl-l-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxamide.
[0032] The structures and physical property data of the present
compound and the compounds prepared similarly are shown in Tables 1
and 2.
EXAMPLE 2
[0033] Preparation of
N,N-dihexyl-1-(3-picolyl)-1,2-dihydro-2-oxoquinoline-
-3-carboxamide
[0034] (1) In a mixture of 50 ml of tetrahydrofuran and 250 ml of
N,N-dimethylformamide were dissolved 9.46 g of
1,2-dihydro-2-oxoquinoline- -3-carboxylic acid and 5.06 g of
N-methylmorpholine, and after cooling to -15.degree. C., 6.83 g of
isobutyl chlorocarbonate was added dropwise over 10 minutes. After
stirring at -15.degree. C. for 10 minutes, 9.73 g of dihexylamine
was added dropwise over 5 minutes. After stirring at -15.degree. C.
for 4 hours and then at room temperature overnight, the reaction
mixture was concentrated under reduced pressure, and the residue,
after addition of ethyl acetate, was washed with water, 1N
hydrochloric acid, a saturated aqueous sodium bicarbonate solution
and a saturated aqueous sodium chloride solution, and dried over
anhydrous sodium sulfate. After removal of the drying agent by
filtration, the filtrate was concentrated under reduced pressure.
The residue was recrystallized from hexane to give 13.51 g of
N,N-dihexyl-1,2-dihydro-2-o- xoquinoline-3-carboxamide.
[0035] (2) To a solution of 1.01 g of
N,N-dihexyl-1,2-dihydro-2-oxoquinoli- ne-3-carboxamide in 13 ml of
N,N-dimethylformamide was added 136 mg of 60% sodium hydride/oil,
followed by stirring at room temperature for an hour. To the
reaction solution was added 434 mg of 3-picolyl chloride, followed
by stirring at room temperature for 4 hours. The reaction mixture
was poured into water and extracted with ethyl acetate, and the
extract was washed with water, a saturated aqueous sodium
bicarbonate solution and a saturated aqueous sodium chloride
solution, and dried over anhydrous sodium sulfate. After removal of
the drying agent by filtration, the filtrate was concentrated under
reduced pressure. The residue was purified by chromatography
(silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals),
developing solvent; hexane-ethyl acetate=7:13-1:19) and
recrystallized from ethyl acetate to give 0.47 g of
N,N-dihexyl-1-(3-picolyl)-1,2-dihydro-2-oxoquinoline-3-carboxamide.
[0036] The structures and physical property data of the present
compound and the compounds prepared similarly are shown in Tables 1
and 2.
EXAMPLE 3
[0037] Preparation of
N,N-dihexyl-1-benzyl-4-hydroxy-1,2-dihydro-2-oxoquin-
oline-3-carboxamide
[0038] (1) In a solution of 4.50 g of diethyl malonate in 20 ml of
N,N-dimethylformamide was gradually added 1.10 g of 62.4% sodium
hydride at room temperature, and stirring was continued at room
temperature until hydrogen evolution ceased. The reaction solution
was heated to 80.degree. C., and a solution of 6.70 g of
N-benzylisatoic anhydride in 20 ml of N,N-dimethylformamide was
added dropwise. After the addition, the reaction mixture was
stirred under heating at 120.degree. C. for 7 hours. After cooling
to room temperature, the reaction mixture was poured into ice water
and washed with ethyl acetate. The aqueous phase was made acidic
with 1 N hydrochlorid acid, and extracted with ethyl acetate. The
organic phase was washed with a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate. After removal
of the drying agent by filtration, the filtrate was concentrated
under reduced pressure. The residue was crystallized from ethanol
to give 5.88 g of ethyl
1-benzyl-4-hydroxy-1,2-dihydro-2-oxoquinoline-3-carboxylate.
[0039] (2) A mixture of 0.30 g of ethyl
1-benzyl-4-hydroxy-1,2-dihydro-2-o- xoquinoline-3-carboxylate and 2
ml of dihexylamine was stirred under heating at 130.degree. C. for
2 hours. After cooling to room temperature, to the reaction
solution were added chloroform and 1 N hydrochloric acid, and the
separated organic phase was washed with 1 N hydrochloric acid and
water. The organic phase was dried over anhydrous magnesium
sulfate. After removal of the drying agent by filtration, the
filtrate was concentrated under reduced pressure. The residue was
purified by chromatography ((silica gel; Merk silica gel 230-4000
mesh (Merk Co.), developing solvent; chloroform) and allowed to
stand for crystallization to give 0.36 g of
N,N-dihexyl-l-benzyl-4-hydroxy-1,2-dihydro-2-oxoquinoli-
ne-3-carboxamide.
[0040] The structures and physical property data of the present
compound and the compounds prepared similarly are shown in Table
2.
1TABLE 1 8 Comp.*.sup.1 Exp.*.sup.2 m.p. (Recry.sol.*.sup.3) No.
No. R.sup.1 R.sup.2 X.sup.1 X.sup.2 Y n Ar (.degree. C.) 01 1 H H H
H CH 1 Ph 229.0 .about. 231.0 (CH.sub.2Cl.sub.2/Hex) 02 1 Me H H H
CH 1 Ph 177.0 .about. 177.5 (AcOEt/Hex) 03 1 Me Me H H CH 1 Ph
219.0 .about. 220.0 (AcOEt) 04 1 n-Pr n-Pr H H CH 1 Ph 135.0
.about. 136.0 (AcOEt/Hex) 05 1 n-Hex n-Hex H H CH 1 Ph 118.5
.about. 120.0 (AcOEt/Hex) 06 1 n-Dec n-Dec H H CH 1 Ph 78.5 .about.
80.0 (AcOEt/Hex) 07 1 (CH.sub.3).sub.2N(CH.sub.2).sub.3
(CH.sub.3).sub.2N(CH.sub.2).sub.3 H H CH 1 Ph 84.0 .about. 86.0
(Hex) 08 1 (CH.sub.2CHMe).sub.2NH*.sup.4 H H CH 1 Ph 199.5 .about.
201.0 (Hex) 09 2 n-Hex n-Hex H H CH 1 2-F--Ph 93.0 .about. 94.0
(standing*.sup.5) 10 2 n-Hex n-Hex H H CH 1 2-Cl--Ph 108.5 .about.
109.0 (standing*.sup.5) 11 2 n-Hex n-Hex H H CH 1 4-Cl--Ph 150.0
.about. 151.0 (standing*.sup.5) 12 2 n-Hex n-Hex H H CH 1 2-Br--Ph
115.5 .about. 116.5 (standing*.sup.5) 13 2 n-Hex n-Hex H H CH 1
4-Me--Ph 145.0 .about. 146.0 (IPE) 14 2 n-Hex n-Hex H H CH 1
2-MeO--Ph 99.0 .about. 100.0 (standing*.sup.5) 15 2 n-Hex n-Hex H H
CH 1 3-MeO--Ph 107.5 .about. 108.0 (standing*.sup.5)
*.sup.1Compound number *.sup.2Example number used for synthesis of
the compound. *.sup.3Recrystallization solvent: CH.sub.2Cl.sub.2 =
dichloromethane, Hex = hexane, AcOEt = ethyl acetate, IPE =
diisopropyl ether. *.sup.4a 3,5-dimethylpyperazino group.
*.sup.5Crystallization by purification by chromatography on a
silica gel column, drying and standing In R.sup.1, R.sup.2 and Ar,
n-Hex is an n-hexyl group, n-Dec is an n-decyl group, n-Pr is an
n-propyl group and Ph is a phenyl group.
[0041]
2TABLE 2 9 Comp.*.sup.1 Exp.*2 m.p. (Recry.sol.*.sup.3) No. No.
R.sup.1 R.sup.2 X.sup.1 X.sup.2 Y n Ar (.degree. C.) 16 2 n-Hex
n-Hex H H CH 1 2,5-(MeO).sub.2--Ph 124.0 .about. 124.5 (standing
*.sup.4) 17 2 n-Hex n-Hex H H CH 1 3,5-(MeO).sub.2--Ph 94.5 .about.
95.5 (standing *.sup.4) 18 2 n-Hex n-Hex H H CH 1 2-Py 98.5 .about.
99.0 (AcOEt) 19 2 n-Hex n-Hex H H CH 1 3-Py 123.0 .about. 123.5
(AcOEt) 20 2 n-Hex n-Hex H H CH 1 4-Py 107.5 .about. 108.0 (AcOEt)
21 2 n-Hex n-Hex H H CH 2 Ph 75.0 .about. 77.0 (Hex) 22 1 n-Hex
n-Hex 6-Cl H CH 1 Ph 145.0 .about. 146.0 (AcOEt/Hex) 23 1 n-Hex
n-Hex 7-Cl H CH 1 Ph 119.0 .about. 119.5 (AcOEt/Hex) 24 1 n-Hex
n-Hex OCH.sub.2O*.sup.5 CH 1 Ph 123.0 .about. 124.0 (AcOEt/Hex) 25
1 n-Hex n-Hex 6-OMe 7-OMe CH 1 Ph 122.5 .about. 123.5 (AcOEt/Hex)
26 3 n-Hex n-Hex H H COH 1 Ph 106.0 .about. 108.0 (standing*.sup.4)
27 1 n-Hex n-Hex H H N 1 Ph 53.5 .about. 55.5 (Hex) *.sup.1Compound
number *.sup.2Example number used for synthesis of the compound.
*.sup.3Recrystallization solvent: Hex = hexane, AcOEt = ethyl
acetate. *.sup.4Crystallization by purification by chromatography
on a silica gel column, drying and standing *.sup.5a
6,7-methylenedioxy group. In R.sup.1, R.sup.2 and Ar, n-Hex is an
n-hexyl group, Py is a pyridyl group and Ph is a phenyl group.
[0042] Experiment [MDR Receptor Binding Assay]
[0043] Crude mitochondria fractions prepared from rat cerebral
cortex were used as a receptor sample, and [.sup.3H]PK11195 was
used as a [.sup.3H]-labeled ligand.
[0044] A binding assay using the [.sup.3H]-labeled ligand was
carried out according to the following method as described in
Journal of Pharmacology and Experimental Therapeutics, 262,
971(1992).
[0045] Preparation of Receptor Sample: Rat cerebral cortex was
homogenized using a Teflon-coated homogenizer in a 10 mM HEPES
buffer (pH 7.4) containing 0.32 M sucrose in ten volumes of the wet
weight. The homogenate was centrifuged at 900.times. g for 10
minutes, and the resulting supernatant was centrifuged at
9,000.times. g for 10 minutes. The precipitate was suspended in a
HEPES buffer to give a protein concentration of 1 mg/ml, and
centrifuged at 12,000.times. g for 10 minutes. The resulting
precipitate was suspended in a 50 mM HEPES buffer (pH 7.4) to give
a crude mitochondria fraction.
[0046] MDR Binding Assay: Mitochondria sample (1.0 mg protein/ml),
[.sup.3H]PK11195 (2 nM) and the test drug were reacted at 4.degree.
C. for 90 minutes.
[0047] After completion of the reaction, the reaction mixture was
filtered with suction through a glass filter (GF/B) treated with
0.3% polyethyleneimine, and the radioactivity on the filter was
measured by a liquid scintillation spectrometer.
[0048] The binding at the reaction in the presence of 10 .mu.M
PK11195 was defined as non-specific binding of [.sup.3H]PK11195,
and the difference between total binding and non-specific binding
was defined as specific binding. A fixed concentration of
[.sup.3H]PK11195 (2 nM) was reacted with varied concentrations of
the test drug under the above-mentioned conditions to give an
inhibition curve, and the concentration (IC.sub.50) of the test
drug to exhibit 50% inhibition of [.sup.3H]PK11195 binding was
measured by the inhibition curve, and results are shown in Table
3.
3 TABLE 3 Compound No. MDR IC.sub.50 (nM) 04 1.71 05 0.159 06 53.4
18 0.404 19 0.368 20 0.192 21 6.58 23 0.132
* * * * *