JP2002241379A - 3-oxadiazolylquinoxaline derivative - Google Patents

Abstract

(57) [Problem] To provide a compound having a selective high affinity for a benzodiazepine receptor. SOLUTION: A 3-oxadiazolylquinoxaline derivative represented by the following chemical formula (1). Embedded image (Where Het represents an oxadiazolyl group, R ₁ represents a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group,
R ₂ is a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an acyl group, a substituted or unsubstituted benzoyl group, or the like; R ₃
Represents a hydrogen atom, a halogen atom, a lower alkoxy group or the like. [Effect] The compound of the present invention has a selective high affinity for benzodiazepine receptors and is therefore useful as a benzodiazepine receptor agonist.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention is useful as a medicine,
In particular, the present invention relates to a novel 3-oxadiazolylquinoxaline derivative having a selective affinity for a benzodiazepine receptor and its use as a medicament.

[0002]

BACKGROUND OF THE INVENTION Benzodiazepine (BZP) compounds represented by diazepam have anxiolytic activity and were initially developed as anxiolytics. In addition to anxiolytic activity, anticonvulsant activity, sedation and hypnotic activity. Since then, these compounds have been widely applied clinically as 1) anxiolytics, 2) hypnotic (sleeping) drugs, 3) muscle relaxants, and 4) antiepileptic drugs.

The main pharmacological actions of BZP compounds are 1) habituation, 2) hypnosis, 3) central muscle relaxation, 4) anticonvulsant, etc. These pharmacological actions are independent of each other. It is not to be manifested by a mechanism of action but to be attributed to a closely related neuropharmacological mechanism. BZP
The systemic compound still has many problems to be improved such as side effects such as light-headedness, drowsiness, muscle relaxation or cognitive ability, and decreased reflex motor ability, and tolerance and dependence formation.

Since the latter half of the 1970's, research on the pharmacological action of BZP compounds has provided a foothold for elucidation of the mechanism of action. One is the enhancement of the central nervous system γ-aminobutyric acid (GABA) nervous signal transduction mechanism by BZP compounds by BZP compounds, and the other is the enhancement of BZP-specific binding sites (BZP receptors). Together with the discovery, it is a demonstration of a functional communication mechanism between the BZP and GABA receptors in the brain. Based on these research results, BZ
It has been almost established that the GABAergic neuronal signal transduction mechanism is involved in the pharmacological action of P-type compounds.

The above-mentioned side effects of the BZP compound,
For the purpose of solving various problems to be improved, such as resistance and dependency formation, research and development of non-BZP-based compounds which are different in chemical structure from benzodiazepine but function similarly in action mechanism are being conducted. These compounds, including these compounds, have been summarized as benzodiazepine receptor agonists. As such non-BZP compounds, for example, compounds represented by the following chemical formulas 2 and 3 are known.

The compound shown in Chemical formula 2 is a compound of Journal of Medicinal C (Journal of Medicinal C).
hemistry), Vol. 34, page 2060 (1991).

[0007]

Embedded image (Wherein, R _a is a hydrogen atom, R _{b to} R _d are methyl groups, etc.
And R _e represents a methoxy group and the like. )

The compound shown in Chemical formula 3 is disclosed in JP-A-6-19.
No. 2258 and JP-A-7-10874.

[0009]

Embedded image

[0010] However, a compound having the same selective high affinity for the benzodiazepine receptor and exhibiting the opposite effect has been found among the non-BZP compounds [Braestrup. C et al., Neuropharmacol., 22, 1451-1457
(1983)]. The administration of these compounds exerts pharmacological effects such as enhancement of convulsions, induction of anxiety, and enhancement of muscle tone. For this reason, a group of BZP compounds as conventional anxiolytics was called an agonist, and a group of compounds having the opposite pharmacological action was called an inverse agonist.

With the discovery of inverse agonists, intensive studies have been conducted on the relationship between the intrinsic activity of compounds that bind to benzodiazepine receptors (BZP receptors) and their pharmacological actions. Affinity) compounds can be agonists (further sub-classified into full agonists and partial agonists), inverse agonists (further sub-classified into full inverse agonists and partial inverse agonists), depending on the mode of modification of complex function or the intrinsic activity of the compound Classified as antagonists. Agonists act to enhance the coupling function between GABA receptor and Cl ion channel by selectively binding to BZP receptor, and increase Cl ion influx into cells by increasing the frequency of Cl ion channel opening and closing. And suppress the cell activity by increasing the intracellular negative charge. Inverse agonists reduce this coupling function, that is, Cl
It acts in the direction of decreasing the frequency of opening and closing of ion channels, reduces the inflow of Cl ions into cells, and enhances cell activity by increasing the intracellular negative charge (enhancing cell excitability). Antagonists by themselves do not alter the coupling function and inhibit agonist binding to the BZP receptor.

[0012] As described above, the BZP receptor is interposed between the GABA receptor and the Cl ion channel, and is recognized as a molecular unit forming a complex with them. Recently, it has been revealed that there are at least three subtypes of this BZP receptor, ω ₁ , ω ₂ and ω ₃ , respectively.
Named the receptor. ω ₁ receptor is the expression of sedation and sleep action and anti-anxiety effects, ω ₂ receptors on the muscle relaxant action,
omega ₃ receptors have been suggested to be involved deeply in the pharmacological effects and development of tolerance, such as antianginal heart action. Conventional BZP compounds are believed to express its pharmacological effects by binding to omega ₁ and omega ₂ receptors.

In general, as an index for predicting the intrinsic activity of a compound that binds to a BZP receptor, the BZP receptor affinity ratio (GABA ratio) in the presence and absence of GABA is known. In the relationship between intrinsic activity and GABA ratio, GAB
Those with an A ratio exceeding 1 are agonists, and those with a GABA ratio of 1
Are classified as antagonists, and those with a GABA ratio of less than 1 as inverse agonists. Most of the conventional BZP-based compounds such as the compounds shown in Chemical formulas 2 and 3 have a GABA ratio exceeding 1 and have an intrinsic activity as an agonist. Conversely, a compound having a GABA ratio of less than 1 and having properties as an inverse agonist is, for example, a compound represented by the following chemical formula (4).

[0014]

Embedded image

The β-carboline derivative shown in Chemical formula 4 is Pr
oc. Natl. Acad. Sci. USA 1980, 77 , 2288 (Braestrup.
C, etc., Proceeding of the National Academy of Scie
nces of the United States of America).

On the other hand, many studies have been made on the relationship between the intrinsic activity and the pharmacological effect. As mentioned above, BZP agonists are used as anxiolytics, drugs for sleep disorders (sleep inducers) and drugs for epilepsy. used. However, it is well known not only in animals but also in humans that the administration of BZP agonists has an amnesic effect as another effect. Therefore, the reverse effect of the BZP inverse agonist on the effect of inducing amnesia, ie, the anti-amnesic effect,
Brain activation is expected. In addition, the activity of acetylcholine, which has an important role in cognitive function, is reduced by the agonist and increased by the inverse agonist. Therefore, among the inverse agonists, those having an anti-memory impairment effect are expected. Therefore, BZP inverse agonists are expected as brain stimulants and therapeutic agents for memory disorders such as senile dementia, cerebrovascular and Alzheimer-type dementia.

The compound of the present invention represented by the following general formula (I) showing a selective high affinity for the benzodiazepine receptor has not yet been reported.

[0018]

SUMMARY OF THE INVENTION The present invention relates to a novel 3-oxadiazolyl quinoxaline derivative represented by the following general formula (I) which is useful as a medicine, in particular, has a selective high affinity for a benzodiazepine receptor, and its use as a medicine. About use.

[0019]

Embedded image (Wherein Het represents an oxadiazolyl group, R ₁ represents a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, R ₂ represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an acyl group, a substituted or unsubstituted benzoyl group, an amino group, A mono- or di-lower alkylamino group, a lower alkoxycarbonylmethyloxy group, a mono- or di-lower alkylaminocarbonylmethyloxy group or a substituted or unsubstituted benzyloxy group, and R ₃ represents a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group; Group, halogen atom or lower alkoxy group Taste.)

[0020]

DETAILED DESCRIPTION OF THE INVENTION The present inventors have studied a non-benzodiazepine compound having an affinity for a benzodiazepine receptor in the brain and found that a 3-oxadiazolylquinoxalin derivative represented by the above general formula (I) is a benzodiazepine derivative. Having a selective high affinity for the (BZP) receptor,
Being useful as a benzodiazepine receptor agonist,
Moreover, the combination of the substituents R ₁ and R ₂ (R ₃ )
BZP agonist and BZP agonist
It has been found that some have properties as a ZP inverse agonist.

The compound of the present invention is represented by the general formula (I). Preferred compounds are those represented by the formula (I) wherein R ₁ is C ₁
-C ₃ alkyl group, C ₃ -C ₄ cycloalkyl group, C ₂
A C ₃ -C ₃ alkenyl group or a substituted or unsubstituted heteroaryl group, R ₂ is a hydrogen atom, a C ₁ -C ₃ alkyl group, a halogen atom or a C ₁ -C ₃ alkoxy group, and R ₃ is a hydrogen atom Compounds. More preferred compounds include the following compounds.

3- (3-methyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one, 3- (3-ethyl-1,2,4-oxadiazole- 5-yl) quinoxalin-2 (1H) -one, 3-
(3-propyl-1,2,4-oxadiazole-5
Il) quinoxalin-2 (1H) -one, 6-chloro-
3- (3-methyl-1,2,4-oxadiazole-5
-Yl) quinoxalin-2 (1H) -one, 6-chloro-3- (3-ethyl-1,2,4-oxadiazole-
5-yl) quinoxalin-2 (1H) -one, 6-fluoro-3- (3-ethyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one, 6-
Methoxy-3- (3-ethyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one,
3- [3- (3-pyridyl) -1,2,4-oxadiazol-5-yl] quinolin-2 (1H) -one, 3-
(3-cyclopropyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one, 3-
(5-methyl-1,2,4-oxadiazol-3-yl) quinoxalin-2 (1H) -one, 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) Quinoxalin-2 (1H) -one, 3- (5-ethyl-1,2,4-oxadiazol-3-yl) quinoxalin-2 (1H) -one

In the present specification, "lower" of lower alkyl and lower alkoxy means a straight or branched carbon chain having 1 to 6 carbon atoms, and "lower" of cyclo lower alkyl means It means a carbon chain having 3 to 6 carbon atoms.
Lower alkenyl and lower alkynyl have 2 to 6 carbon atoms.
Having two straight or branched carbon chains, such as allyl, 1-propenyl, propargyl, 2-methyl-
And a 1-ethynyl group. An acyl group has 1 carbon atom.
Acyl having up to 6 straight or branched carbon chains. An aryl group is a phenyl group or a naphthyl group, and a heteroaryl group is a 5- to 6-membered ring group containing 1 to 3 hetero atoms, such as a furyl group, a thienyl group, a pyridyl group, an isoxazolyl group, which are the same or different. And the hetero atom is a nitrogen atom, an oxygen atom, or a sulfur atom. Preferred substituents of the substituted aryl group or the substituted heteroaryl group include 1 to 3 halogen atoms, C ₁ -C
Examples include a ₃ alkyl group or a C ₁ -C ₃ alkoxy group.

The compound of the present invention can be produced by the following production methods 1 to 4.

(Production method 1) The following general formula (Ia)

[0026]

Embedded image (In the formula, R ₁ , R ₂ and R ₃ are the same as described above.)

Alternatively, the following general formula (Ib):

[0028]

Embedded image (Wherein R ₁ , R ₂ and R ₃ are the same as those described above) wherein R ₁ is a group other than a lower alkoxy group.

[0029]

Embedded image (In the formula, R ₁ ′ means the same group as R _{1 described} above except for a lower alkoxy group, and R ₂ and R ₃ are the same as described above.)

Alternatively, the following formula (III)

[0031]

Embedded image (Wherein, R ₁ ′ represents the same group as R _{1 described} above except for a lower alkoxy group, and R ₂ and R ₃ have the same meaning as described above.) Can be.

This ring closure reaction may be carried out using a dehydrating agent, but is usually carried out by heating in a suitable solvent which does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, and N, N-dimethylformamide. These solvents alone,
Alternatively, two or more kinds are used in combination. The reaction temperature varies depending on the type of the starting compound used and the like.
° C, preferably 80 to 120 ° C.

(Production Method 2) In the compound of the present invention represented by the general formula (Ia), the compound wherein R ₁ is a lower alkoxy group is represented by the following formula (IV)

[0034]

Embedded image (Wherein, R ₁ "represents a lower alkoxy group, and R ₂ and R ₃ are the same as those described above), for example, in Journal of Heterocyclic Chemistry (Jou
rnal of Heterocyclic Chemistry) 18 p. 1197 (1981)
Can be produced by reacting hydroxylamine according to the method described in (1).

This reaction is usually carried out in a suitable solvent, such as alcohols such as methanol and ethanol;
Water. The reaction temperature varies depending on the type of the starting compound used and the like, but is usually 50 to 90 ° C.

(Production Method 3) In the compound of the present invention represented by the general formula (Ib), the compound wherein R ₁ is a lower alkoxy group is represented by the following formula (V)

[0037]

Embedded image (Wherein R ₁ represents a lower alkoxy group, and R ₂ and R ₃ are the same as described above), for example, according to the method described in Synthesis, page 843 (1986). And subjecting it to an intramolecular ring closure reaction.

This ring closure reaction is usually carried out by heating in a suitable solvent, and examples of the solvent include aromatic hydrocarbons such as benzene, xylene and toluene, and ethers such as tetrahydrofuran and dioxane. The reaction temperature varies depending on the type of the starting compound used, and the like.
Usually, it is 50 to 150 ° C, preferably 80 to 120 ° C.

(Production method 4) The following general formula (Ic)

[0040]

Embedded image (Wherein, R _1, R ₂ and R ₃ are the same. Supra) compounds of the present invention represented by the following formula (VI)

[0041]

Embedded image (Wherein R ₁ , R ₂ and R ₃ are the same as described above). The compound can be produced by intramolecular ring closure.

This ring closure reaction may be carried out using a dehydrating agent, but is usually carried out by heating in a suitable solvent which does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, and N, N-dimethylformamide. These solvents are used alone or in combination of two or more. The reaction temperature varies depending on the type of the starting compound used, etc.
The temperature is 50 ° C, preferably 80 to 120 ° C.

The ring-closing reaction may be carried out according to the method described in JP-A-6-192258, in a suitable solvent that does not affect the reaction, with a trivalent phosphorus compound such as triphenylphosphine and a dialkylazodicarboxylic acid. It can be carried out in the presence of an acid ester. The reaction temperature varies depending on the type of the starting compound used and the like, but is usually 0 to 110 ° C, preferably 0 to 60 ° C.

Formula (I) produced by the above production methods 1 to 4
The compound of the present invention represented by is isolated and purified by a conventional method such as chromatography, recrystallization, and reprecipitation.

Next, a method for producing a starting compound of the compound of the present invention will be described.

Compound of formula (II) used in the above-mentioned production method 1
(II) can be produced by the method shown in the following reaction formula (Formula 14).

[0047]

Embedded image (In the Scheme, R ₁ 'is a supra than lower alkoxy group R ₁
It means the same groups as, R ₂ and R ₃ are as defined supra. )

The compound (1) or its reactive derivative at the carboxyl group is reacted with various amidoximes (2) under ordinary amidation reaction conditions to produce the compound (II) of the formula (II).

The compound of the formula (III) used in the production method 1
Can be produced by the method shown in the following reaction formula (Formula 15).

[0050]

Embedded image (In the Scheme, R ₁ 'is a supra than lower alkoxy group R ₁
And R ₂ and R ₃ are the same as described above. )

The compound (3) is reacted with hydroxylamine in a usual manner to give a compound (4), which is then reacted with a reactive derivative at a carboxyl group in the presence of a base to obtain a compound of the formula (I
Compound (III) of II) can be produced.

The compound of the formula (IV) used in the above-mentioned production method 2 can be produced, for example, by the method shown in the following reaction formula (Chemical Formula 16) according to the method described in JP-A-7-10874. it can.

[0053]

Embedded image (In the reaction formula, R ₁ "represents a lower alkoxy group, and R ₂ and R ₃ are the same as described above.)

Compound (1) or its reactive derivative at the carboxyl group is reacted with an alkali metal thiocyanate in a suitable solvent to give compound (13), which is then subjected to alcoholysis to give compound (IV) of formula (IV) Can be manufactured.

The compound of the formula (V) used in the above-mentioned production method 3 can be produced by the method shown in the following reaction formula (Formula 17).

[0056]

Embedded image (In the reaction formula, R ₁ "represents a lower alkoxy group, and R ₂ and R ₃ are the same as described above.)

The compound (8) is reduced with a reducing agent such as sodium borohydride, tetrabutylammonium borohydride, lithium aluminum hydride in a suitable solvent which does not affect the reaction to give a compound (14). Oxidation with active manganese dioxide in a solvent gives compound (15).

Compound (15) was reacted with hydroxylamine under the usual oximation conditions to give compound (16).
For example, the compound (17) is obtained by reacting with N-chlorosuccinimide according to the method described in Journal of Organic Chemistry, Vol. 45, page 3916 (1980).

Compound (17) may, for example, be synthesized (Synt
hesis) According to the method described in page 102 (1979), sodium azide is reacted in a suitable solvent to give compound (18).
Then, it is represented by XCOR ₁ "(X represents a halogen atom and R ₁ " represents a lower alkoxy group) in a suitable solvent according to the method described in Synthesis, page 843 (1986). After reacting the compound to give compound (19), it can be reacted with triphenylphosphine to produce compound (V) of formula (V).

The compound of the formula (VI) used in the above-mentioned production method 4 can be produced by the method shown in the following reaction formula (formula 18).

[0061]

Embedded image (In the reaction formula, R ₁ , R ₂ and R ₃ are the same as described above.)

The compound (1) or its reactive derivative at the carboxyl group is reacted with a hydrazide (5) represented by R ₁ CONHNH ₂ (R ₁ is the same as described above) under ordinary amidation reaction conditions. The compound of (VI) can be produced.

The compound (VI) of the formula (VI) is a compound (1)
Alternatively, the reactive derivative at the carboxyl group is reacted with hydrazine under ordinary amidation reaction conditions, and then the reactive derivative at the carboxyl group represented by R ₁ COOH (R ₁ is the same as described above) is reacted. It can also be produced by a two-step reaction.

Further, a method for producing the starting compound of the compound of the present invention will be described.

The compound (1) used in the above reaction formula (Chemical formula 14 or 16) is, for example,
Heterocyclic chemistry vol.13, p.427 (197
According to the method described in 6) or the following reaction formula (Chemical Formula 1)
It can be manufactured by the method shown in 9).

[0066]

Embedded image (In the Scheme, R ₂ and R ₃ identical supra.)

The compound (3) used in the above-mentioned reaction formula (Formula 15) can be obtained, for example, from Journal of the American Chemical Society, Vol. 73, p. 3246 (1).
951) and Journal of Organic Chemistry, Vol. 37, p. 2498 (1972), according to the method shown in the following reaction formula (Chemical Formula 20).

[0068]

Embedded image (In the reaction formula, R ₂ and R ₃ are the same as described above.)

[0069]

[Effects] The pharmacological test methods and results of representative compounds of the present invention will be described below, and the characteristics of the action of the compounds of the present invention will be described.

Test Example 1 Benzodiazepine receptor binding test:

Life Science No. 20
A benzodiazepine receptor binding test was performed according to the method described in Vol. 2101 (1977).

The crude synaptosome membrane fraction prepared from the brain of Wistar rats aged 7 to 8 weeks was purified from a mixture containing 118 mM sodium chloride, 4.8 mM potassium chloride, 1.28 mM calcium chloride and 1.2 mM magnesium sulfate.
It was suspended (1 g wet weight of brain / 20 ml) in a mM Tris-HCl buffer (pH 7.4) to prepare a receptor membrane standard. [ ³ H] diazepam was used as a labeling ligand.

A test compound having a known concentration in each test tube, [ ³ H]
Diazepam (final concentration 1.5 nM), a receptor membrane standard and the above buffer were added to make a reaction solution (total volume 1 ml), and the reaction was started by the addition of the membrane standard. After incubation at 0 ° C. for 20 minutes, the labeled ligand bound to the receptor was suction-filtered on a Whatman GF / B glass fiber filter using a cell harvester (manufactured by Brandel) to stop the reaction. The plate was washed three times with 5 ml of a 50 mM Tris-HCl buffer (pH 7.7). Next, the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. In addition, the amount of binding in the presence of 1 μM diazepam measured at the same time was regarded as the amount of non-specific binding, and this was subtracted from the total amount of binding to determine the amount of specific binding. Furthermore, the concentration at which the test compound inhibits the specific binding of the labeled ligand by 50% (IC ₅₀
Value) was calculated by the probit method. The results are shown in Tables 1 and 2.

[0074]

[Table 1]

[0075]

[Table 2]

Test Example 2 Benzodiazepine ω ₁ and ω ₂ receptor binding test and GABA ratio:

The Journal of Pharmacology and Experimental Therapeutics (Jo
rnal of Pharmacology and Experimental Therapeutic
s) according to the method described in 253 vol 334 (1990), benzodiazepine (BZP) omega ₁ and omega ₂ receptor binding test and GABA ratio (GABA presence and B in the absence
ZP receptor affinity ratio) was calculated.

The crude synaptosome membrane fraction prepared from the cerebellum and spinal cord of 7-8 week old male Wistar rats was purified by
20 mM sodium chloride, 5 mM potassium chloride, 2 mM
5 containing calcium chloride and 1 mM magnesium sulfate
Suspension (1 g) in 0 mM Tris-HCl buffer (pH 7.4)
(Wet weight / 40 ml) to obtain membrane samples of ω1 and ω2 receptors, respectively. [ ³ H] flumazenil was used as a labeling ligand in both binding tests.

A test compound having a known concentration in each test tube, [ ³ H]
Flumazenil (omega ₁ final concentration 0.3nM For receptor binding studies, in the case of omega ₂ receptor binding assay final concentration 1n
M), a receptor membrane standard, either bicuculline or GABA (final concentration 100 μM) and the above buffer were added to make a reaction solution (total volume 1 ml), and the reaction was started by adding the membrane standard. After incubation at 37 ° C. for 30 minutes, the labeled ligand bound to the receptor was suction-filtered on a Whatman GF / B glass fiber filter using a cell harvester (manufactured by Brandel) to stop the reaction. -Hydrochloric acid buffer (pH 7.7)
Washed 3 times with 5 ml. Subsequently, the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. In addition, the amount of binding in the presence of 10 μM flunitrazepam measured at the same time is defined as the non-specific binding amount,
This was subtracted from the total binding to determine the specific binding. Next, the concentration at which the test compound inhibited the specific binding of the labeled ligand by 50% (IC ₅₀ value) was calculated by the probit method. Moreover, it obtains a GABA presence and absence ratio IC ₅₀ values in (bicuculline presence) (IC ₅₀ / bicuculline IC ₅₀ for the presence of GABA presence), GA
The BA ratio was used. The results are shown in Tables 3 to 5.

[0080]

[Table 3]

[0081]

[Table 4]

[0082]

[Table 5]

Test Example 3 Pentylenetetrazole-induced seizure enhancement test

Benzodiazepine receptor inverse agonists are known to enhance the convulsions of various convulsants [Progress in Neuro-Psychopharmacology and Biologics
logical Psychiatry, Vol. 12, p. 951 (1988)]. Therefore, the pentylenetetrazole-induced seizure enhancing effect of some compounds having a GABA ratio of 1 or less was examined.

DdY male mouse (body weight: 22 to 25 g)
Five animals were orally administered the compound of Example 12 (20 mg / kg), and 15 minutes later, pentylenetetrazole (70 mg / kg) was administered subcutaneously at a dose that did not induce tonic convulsions alone. Immediately after that, it was observed for 30 minutes whether tonic extension spasms of the hind limbs occurred. As a result, a seizure enhancing effect was observed in 5 out of 5 animals. Similarly, when the compound of Example 25 (10 mg / kg) was orally administered, a spasm enhancing effect was observed in 6 out of 15 animals.

As shown in the above test results, the compounds of the present invention have selective high affinity for benzodiazepine receptors and are useful as benzodiazepine receptor agonists. In addition, some of the compounds of the present invention have a property as a BZP agonist and a compound as a BZP inverse agonist in intrinsic activity using a GABA ratio as an index. The compound of the present invention having properties as an inverse agonist is expected to be a clinical application completely different from an agonist, for example, a brain activator, a therapeutic agent for memory disorders such as senile dementia and Alzheimer's disease.

[0087]

[Method of using the compound of the present invention as a medicine] When the compound of the present invention is used as a benzodiazepine receptor agonist, it may be administered orally, parenterally or rectally, but oral administration is preferred. Dosage includes administration method, patient symptom / age, treatment form (prevention or treatment)
Although it varies depending on the like, it is usually 0.01 to 10 mg / kg / day, preferably 0.02 to 5 mg / kg / day.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextrin, starch,
Sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resin,
Methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, Examples include sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, liquid paraffin, white petrolatum, nonionic surfactant, propylene glycol, water and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injections and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of injections, it is prepared by dissolving a physiologically acceptable acid addition salt of the compound (I) of the present invention in water, but may be dissolved in an isotonic agent if necessary. Further, a pH adjuster, a buffer and a preservative may be added.

These preparations contain the compound of the present invention in an amount of 0.0
It can be contained at a rate of 1% or more, preferably 0.05 to 70%. These formulations may also contain other therapeutically active ingredients.

[0091]

EXAMPLES The compounds of the present invention will be specifically described below with reference to Reference Examples and Examples. In addition, the symbol in a table | surface means each following substituent. Me: methyl group; Et: ethyl group; n-Pr: n-propyl group; iso-Pr: isopropyl group; c-Pr: cyclopropyl group; Ph: phenyl group.

Reference Example 1 Production of 1,2-dihydro-2-oxo-3-quinoxalinecarboxylic acid:

(1) To a mixture of 10.8 g of o-phenylenediamine and 200 ml of ethanol was added 17.4 g of diethyl ketomalonate, and the mixture was refluxed under heating for 2 hours. The reaction solution was cooled on ice, and the precipitated crystals were collected by filtration to give a colorless solid of 1,2-dihydro-
18. ethyl 2-oxo-3-quinoxalinecarboxylate;
3 g were obtained.

(2) A mixed solution of 10 g of the above ester and 150 ml of a 10% aqueous hydrochloric acid solution was heated under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration and washed with water to give 8.2 g of the title compound.

Reference Example 2 Production of 1,2-dihydro-2-oxo-3-quinoxalinecarbonitrile:

(1) To a mixture of 10.8 g of o-phenylenediamine in 200 ml of ethanol, an aqueous solution of 23.1 g of diethyl sodium oxalyl acetate in 150 ml of water and 7 ml of acetic acid were added, and the mixture was heated under reflux for 30 minutes. The reaction was cooled on ice,
The precipitated crystals were collected by filtration and dried to obtain 10.3 g of 2-ethoxycarbonylmethylene-2oxo-1,2,3,4-tetrahydroquinoxaline as a colorless solid.

(2) 7 g of the above solid and 0.9 g of trichloroacetic acid
3.9 g of isopentyl nitrite was added dropwise to a suspension of g of acetic acid in 150 ml, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried. After the filtrate was concentrated to dryness under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration, dried, and combined with the above crystals to obtain ethyl acetate.
5.7 g of-(1,2-dihydro-2-oxo-3-quinoxalyl) hydroxyiminoacetate were obtained.

(3) To a suspension of 20 g of the above solid, 40.2 g of triphenylphosphine and 27 g of triethylamine in 500 ml of tetrahydrofuran, 26.7 g of diethyl azodicarboxylate was added dropwise with stirring under ice cooling. After the addition, the mixture was stirred at room temperature for 1 hour. After adding a small amount of water to the reaction solution, the reaction solution was concentrated to dryness under reduced pressure. Isopropanol was added to the residue, and the crystals were collected by filtration to obtain 18 g of 3-ethoxycarbonylisoxazolo [4,5-b] quinoxaline.

(4) A mixture of 2.43 g of the above solid and a 5% aqueous sodium hydroxide solution (20 ml) was stirred at room temperature for 2 hours. After cooling with ice, the reaction solution was acidified with 1N aqueous hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crude crystals were washed with water and isopropanol to obtain 1.6 g of the title compound.

Reference Example 3 Production of 1,2-dihydro-2-oxo-3-quinoxalinamide oxime: 6.96 g of sodium carbonate in water (5
013 ml) to the solution under ice cooling.
g was added. This is converted to 1,2-dihydro-2-oxo-3
Quinoxaline carbonitrile 15 g ethanol 30
The mixture was added to 0 ml of the suspension, and heated under reflux for 5 hours. After evaporating the solvent under reduced pressure, water was added to the residue and the crystals were collected by filtration. After washing with water, washing with isopropanol gave the title compound 10.4 as a colorless solid.
g was obtained.

Reference Example 4 Production of N'-acetyl-1,2-dihydro-2-oxo-quinoxaline carbohydrazide: 1,2-dihydro-
2-oxo-3-quinoxalinecarboxylic acid (0.95
g) and N, N'-carbonyldiimidazole (1.22
g) N, N-dimethylformamide (DMF; 10 m
The solution of 1) was heated and stirred at 70 ° C. for 3 hours. Then, 0.55 g of acetohydrazide was added to the reaction solution, and
The mixture was heated and stirred for an hour. After evaporating the solvent under reduced pressure, isopropanol was added to the residue and the crystals were collected by filtration to give the title compound (1.06 g)
I got

Example 1 3- (3-methyl-1,2,4-oxadiazole-5
Preparation of -yl) quinoxalin-2 (1H) -one:

0.95 g (5 mmol) of 1,2-dihydro-2-oxo-3-quinoxalinecarboxylic acid and N,
A solution of 1.22 g (7.5 mmol) of N′-carbonyldiimidazole in 50 ml of DMF was heated and stirred at 60 ° C. for 3 hours. Then, 0.56 g (7.5 mmol) of acetamidooxime was added to the solution, and 1.5
Stirred for hours. Furthermore, the solution was heated and stirred at 130 ° C. for 3 hours, and then concentrated to dryness under reduced pressure. Isopropanol was added to the residue, and the crystals were collected by filtration. The obtained crystals were subjected to silica gel column chromatography, and chloroform-
After elution and purification with methanol (100: 1), recrystallization from ethanol gave 0.6 g of the title compound as a colorless solid.
(52.6% yield). Mp 254-255 ° C.

Using the corresponding starting compounds, the compounds of Examples 2 to 23 were obtained in the same manner as in Example 1. These compounds are shown in Tables 6 to 8.

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[0106]

[Table 6]

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[Table 7]

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[Table 8]

Example 24 3- (5-Methyl-1,2,4-oxadiazole-3
Preparation of -yl) quinoxalin-2 (1H) -one:

(1) 1,2-dihydro-2-oxo-3-
1.02 g (5 mmol) of quinoxaline amide oxime
0.59 g (7.5 mmol) of acetyl chloride was added dropwise to a suspension of potassium carbonate and 1.14 g (8.25 mmol) of methyl carbonate in methyl ethyl ketone under ice-cooling and stirring. After the addition, the mixture was stirred at room temperature overnight. The solvent was concentrated to dryness under reduced pressure. Water was added to the residue, and the precipitated crystals were collected by filtration, washed with water, washed with isopropanol and dried to obtain 0.98 g of a colorless solid. Used for the next reaction without further purification.

(2) 0.98 g of the above solid in 50 ml of DMF
Was heated and stirred at 130 ° C. for 3 hours. After the reaction solution was concentrated to dryness under reduced pressure, the residue was subjected to silica gel column chromatography to give chloroform-methanol (10%).
0: 1), and recrystallized from ethanol to give 0.44 g of the title compound as a colorless solid (yield 38.6).
%). 289-291 ° C.

The compounds of Examples 25 to 28 were obtained in the same manner as in Example 24, using the corresponding starting compounds.
Table 9 shows these compounds.

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[Table 9]

Example 29 Preparation of 3- (1,2,4-oxadiazol-3-yl) quinoxalin-2 (1H) -one

Boron trifluoride ether complex (0.22 m
To 1) under ice-cooling, 1,2-dihydro-2-oxo-3-quinoxalinamide oxime (1.02 g) of ethyl orthoformate (10 ml) was added dropwise. After the reaction solution was heated to reflux for 1 hour, the solvent was distilled off under reduced pressure. Water was added to the residue, and the crystals were collected by filtration. The obtained crude crystals were subjected to medium pressure column chromatography (Diaion CHP-20P) to elute the solvent.
After purification, recrystallization from methanol gave the title compound. Mp 290-292 ° C.

Example 30 3- (5-methyl-1,3,4-oxadiazole-2
Preparation of -yl) quinoxalin-2 (1H) -one:

(1) 1,2-dihydro-2-oxo-3-
0.95 g (5 mmol) of quinoxalinecarboxylic acid and 1.22 g of N, N'-carbonyldiimidazole (7.
(5 mmol) in 50 ml of DMF was heated and stirred at 60 ° C. for 3 hours. Then, 0.56 g (7.5 mmol) of acetohydrazide was added to the solution, and 1.5
Stirred for hours. The reaction solution was concentrated to dryness under reduced pressure. Isopropanol was added to the residue, the crystals were collected by filtration, and then recrystallized to give N′-acetyl-1,2-dihydro-2 as a colorless solid.
-Oxo-3-quinoxaline carbohydrazide 1.06
g (86.1% yield). Melting point> 290 ° C.

(2) A solution of 0.74 g (3 mmol) of the above compound, 1.57 g (6 mmol) of triphenylphosphine and 1.06 g (10.5 mmol) of triethylamine in 50 ml of anhydrous tetrahydrofuran was stirred under ice-cooling with azodicarboxylic acid. A solution of 1.04 g (6 mmol) of diethyl acidate in 5 ml of anhydrous tetrahydrofuran was added dropwise. After stirring at room temperature for 3 hours, a small amount of water was added, and the mixture was concentrated to dryness under reduced pressure. Isopropanol was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 0.26 g (yield 38%) of the title compound as a colorless solid. Melting point> 29
0 ° C.

The compounds of Examples 31 to 37 were obtained in the same manner as in Example 30 using the corresponding starting compounds.
These compounds are shown in Table 10.

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[Table 10]

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Makoto Oka 17-26 Takadacho, Ibaraki-shi, Osaka F-term (reference) 4C063 AA01 AA03 BB01 CC58 CC92 DD12 DD34 DD58 EE01 4C086 AA01 AA02 AA03 BC71 GA02 GA04 GA07 GA08 GA09 MA01 MA04 NA14 ZA05 ZA06 ZA23 ZA29 ZA94 ZC42

Claims (5)

[Claims] [Claim 1] (Wherein Het represents an oxadiazolyl group, R ₁ represents a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, R ₂ represents a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, an acyl group, a substituted or unsubstituted benzoyl group, an amino group, A mono- or di-lower alkylamino group, a lower alkoxycarbonylmethyloxy group, a mono- or di-lower alkylaminocarbonylmethyloxy group or a substituted or unsubstituted benzyloxy group, and R ₃ represents a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group; Group, halogen atom or lower alkoxy group 3-oxadiazolylthio Lucino quinoxaline derivative represented by the taste.). 2. R ₁ is a C ₁ -C ₃ alkyl group, C ₃ -C _3
4 cycloalkyl, C ₂ -C ₃ alkenyl group, a substituted or unsubstituted heteroaryl group, R ₂ is a hydrogen atom, C ₁ -C ₃ alkyl group, a halogen atom or C ₁ ~
C ₃ alkoxy group, 3-oxadiazolylthio Lucino quinoxaline derivative according to claim 1, wherein R ₃ is a hydrogen atom. 3. 3- (3-methyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one, 3- (3-ethyl-1,2,4-oxadi) Azol-5-yl) quinoxalin-2 (1H) -one, 3-
(3-propyl-1,2,4-oxadiazole-5
Il) quinoxalin-2 (1H) -one, 6-chloro-
3- (3-methyl-1,2,4-oxadiazole-5
-Yl) quinoxalin-2 (1H) -one, 6-chloro-3- (3-ethyl-1,2,4-oxadiazole-
5-yl) quinoxalin-2 (1H) -one, 6-fluoro-3- (3-ethyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one, 6-
Methoxy-3- (3-ethyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one,
3- [3- (3-pyridyl) -1,2,4-oxadiazol-5-yl] quinolin-2 (1H) -one, 3-
(3-cyclopropyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one, 3-
(5-methyl-1,2,4-oxadiazol-3-yl) quinoxalin-2 (1H) -one, 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) Quinoxalin-2 (1H) -one and 3- (5-
Any one of 3-oxadiazolylquinoxaline derivatives selected from ethyl-1,2,4-oxadiazol-3-yl) quinoxalin-2 (1H) -one. 4. A composition for a drug acting on a benzodiazepine receptor, comprising the compound according to claim 1 and a physiologically acceptable additive. 5. A benzodiazepine receptor agonist comprising the compound according to any one of claims 1 to 3 as an active ingredient.