JP2969679B2 - Thienocycloheptapyridazine compounds and their pharmaceutical uses - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to thienocycloheptapyridazine compounds which are novel and useful as pharmaceuticals, and their pharmaceutical uses.

[Problems to be solved by the prior art and the invention]

BACKGROUND ART Benzodiazepine (BZP) derivatives represented by diazepam have been used as anti-anxiety drugs or therapeutic drugs for sleep disorders since ancient times. Due to recent pharmacological studies, BZ
It was found that a receptor having specific affinity for the P derivative exists in the central nervous system. [Science, vol. 198, 849 (197
7)]. Since then, a lot of research has been done, including BZP derivatives
A compound (BZP agonist) having a structure different from BZP and exhibiting high affinity for the BZP receptor and exhibiting a BZP-like action,
A compound that shows high affinity to the BZP receptor but has a pharmacological action opposite to that of BZP (BZP inverse agonist) and does not show any pharmacological action by itself despite its high affinity to the BZP receptor, Agonist or inverse
Research and development of compounds (BZP antagonists) that exhibit an action that antagonizes the action of an agonist [Advanc
e in Drug Research, vol. 14, 165 (1985)].

BZP derivatives used as anxiolytics have sedative action, muscle relaxant action, anticonvulsant action, etc. in addition to anxiolytic action, and often have side effects such as light-headedness, drowsiness, etc. Research on non-BZP compounds has been actively pursued with the aim of developing active anxiolytics, but none has been satisfactory.

In recent years, the amnesic-inducing effects of BZP agonists have become known [Nature, vol. 321, 864 (1986)], and the possibility of antagonists that antagonize the effect and inverse agonists that exhibit the opposite effect as brain function activators. There have been reports suggesting that (Trends in Neuroscien
ces, vol. 11, 13 (1988)].

By the way, U.S. Patent No. 4602019 describes 2,4,4a, 5-tetrahydro-7 having a cardiotonic effect and an antihypertensive effect.
-(1H-imidazol-1-yl) -3H-indeno [1,
2-c] pyridazin-3-one and the like, as well as the Journal of Medicinal Chemistry (J. Med.
Chem.), Vol. 24, p. 830 (1981) discloses compounds such as 2- (4-chlorophenyl) benzothiopyrano [4,3-c] pyrazol-3-one having an immunosuppressive action and the like. I have.

[Means for solving the problem]

The present inventors have found that BZPs having a non-BZP skeleton useful as pharmaceuticals
With the aim of developing agonists, inverse agonists or antagonists, intensive studies were conducted to provide effective compounds and medicaments.

 The above object is achieved by the present invention described below.

That is, the first invention is a general formula Wherein R is hydrogen, halogen or C _1-4 alkyl, Ar
Is aryl, heteroaryl, or aryl having at least one halogen, C _1-4 alkyl, C _1-4 alkoxy, nitro, amino, hydroxy, trifluoromethyl, C _2-5 alkanoylamino, or Heteroaryl, the bond between the 4 and 4a positions Represents a single bond or a double bond. The present invention provides a thienocycloheptapyridazine compound represented by the following formula:

Another object of the present invention is to provide a pharmaceutical composition comprising the thienocycloheptapyridazine compound represented by the general formula (I).

When each symbol in the general formula (I) and each of the following general formulas is described by definition, halogen means chlorine, bromine, fluorine and the like, and C _1-4 alkyl means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Tertiary butyl and the like, C _1-4 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy and the like, and C _2-5 alkanoylamino is acetylamino, propionylamino, butyrylamino, Pivaloylamino and the like; aryl is phenyl, naphthyl and the like; heteroaryl is 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 3- or 4-pyrazolyl, 1- or 2-imidazolyl, 2- , 4- or 5
-Pyrimidinyl, 3-, 4- or 5-pyridazinyl, 2
A 5-membered ring such as-, 4- or 5-benzimidazolyl, 6
A membered ring or a fused ring thereof having 1 to 3 (preferably 1 to 2) heteroatoms (for example, nitrogen, oxygen, and sulfur) is shown.

Preferred compounds of the present invention include 2- (4-chlorophenyl) -9-methyl-2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [ 1,2-
c] pyridazin-3-one, 2- (4-methylphenyl) -9-methyl-2,4,4a, 5,
6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 2-phenyl-9-methyl-2,4,4a, 5, 6,7-Hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-
c] pyridazin-3-one, 2- (4-methoxyphenyl) -9-methyl-2,4,4a,
5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 2- (4-chlorophenyl) -2,5,6, 7-tetrahydro-9-methyl-3H-thieno [2 ', 3': 6.7] cyclohepta [1,2-c] pyridazin-3-one, 2- (4-chlorophenyl) -2,4,4a, 5,6,7-Hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2
-C] pyridazin-3-one, 2- (6-chloro-2-pyridyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 2- (4-methylphenyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] Cyclohepta [1,2
-C] pyridazin-3-one, 2- (4-methoxyphenyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,
2-c] pyridazin-3-one, 9-bromo-2- (4-chlorophenyl) -2,4,4a, 5,
6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 9-bromo-2- (4-methoxyphenyl) -2,4 , 4a,
5,6,7-hexahydro-3H-thieno [2 ', 3': 6.7] cyclohepta [1,2-c] pyridazin-3-one, 9-bromo-2- (4-chlorophenyl) -2, 5,6,7−
And compounds such as tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one.

The compound of the general formula (I) has the general formula (Wherein R is as defined above) and a hydrazine derivative represented by the general formula Ar-NHNH ₂ (III) (where Ar is as defined above) or an acid addition thereof General formula obtained by reacting with salt (Wherein the symbols have the same meanings as described above).

The reaction is carried out in a suitable solvent, for example, an alcoholic solvent such as methanol, ethanol or propanol, benzene,
The reaction proceeds by heating and refluxing for 5 to 20 hours in a solvent that does not inhibit the reaction, such as toluene, to give compounds of general formulas (I) and (IV).

When the hydrazine derivative of the general formula (III) is an acid addition salt, the reaction is carried out in the presence of a deacidifying agent (such as sodium acetate, potassium acetate, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, pyridine and triethylamine).

When the compound of the general formula (IV) is obtained, 5
By heating and refluxing for 1010 hours, the compound of the general formula (I) can be obtained.

In the general formula (I), the compound in which the bond between the 4-position and the 4-a position is a double bond is 1- to 1.5-fold molar amount of the compound having a single bond at 20 to 60 ° C. in an acetic acid solvent. [Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 14, p. 262 (1971)], or a compound whose binding site is a single bond and sodium-
It can also be synthesized by a method of reacting with m-nitrobenzenesulfonate (Bachmann method, British Patent No. 1168291).

The compound of the general formula (I) thus produced can be isolated and purified by a conventional method such as column chromatography and recrystallization.

The compound of the general formula (II) in the present invention is a novel compound which has not been described in the literature. (Wherein R has the same meaning as defined above). To a compound of the general formula (V) or an acid addition salt of the compound represented by the formula
A quaternary ammonium compound is obtained by holding for a period of time, which is reacted with potassium cyanide or sodium cyanide in aqueous methanol at 30 to 50 ° C. for 4 to 10 hours to obtain a compound of the general formula Wherein R is as defined above, and then the compound of the formula (VI) is added to acetic acid and concentrated hydrochloric acid, and the mixture is refluxed for 5 to 12 hours.

For reference, typical examples of the compound of the general formula (II) are shown together with physical constants.

◎ 2-methyl-4-oxo-5,6,7,8-tetrahydro-4
H-cyclohepta [b] thiophen-5-acetic acid, melting point 15
5.5-157.5 ° C ◎ 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophen-5-acetic acid, melting point 130-131 ° C ◎ 2-bromo-4-oxo-5,6,7 , 8-Tetrahydro-4H-cyclohepta [b] thiophen-5-acetic acid, melting point
129-131 ° C. [Action / Effect] The compound of the general formula (I) of the present invention is
It shows a high affinity of 0 ^-8 to 10 ^-9 mol, and has an antagonistic effect on chemical convulsants such as bicuculline and pentylenetetrazole. In addition, it has the effect of suppressing amnesia induced by electroconvulsive shock.

The pharmacological action of the compound of the present invention will be described below together with experimental methods.

Experimental Example 1 Substitution ability for benzodiazepine Specific benzodiazepine receptor binding test
Life Science, Vol. 20, 2101 (1977)
Was carried out according to the method described in (1).

The crude synaptosome fraction was isolated from the cerebral cortex of male Wistar rats 9 to 10 weeks old, suspended in 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM sodium chloride and 5 mM potassium chloride, and used for experiments. Was.

Next, several concentrations of the test compound and tritiated diazepam (final concentration 2 nM) were added to the synaptosome suspension,
Incubated at 0 ° C for 20 minutes. The suspension was then filtered through a Whatman GF / B glass fiber filter, the filter was washed with the above buffer, and the radioactivity remaining on the filter was measured with a liquid scintillation counter.

The specific binding amount was a value obtained by subtracting the binding amount obtained in the presence of 10 ^-6 M non-radioactive diazepam from the total binding amount.

According to the above test methods, the binding ability of the compound of the present invention to the benzodiazepine receptor is evaluated by the ability to displace tritiated diazepam from its binding site, and is represented by a Ki value (nM).

 Table 1 shows the test results.

Experimental Example 2 Anti-bicuculline Action An anti-bicuculline action test was carried out according to the method of Life Science, Vol. 21, p. 1779 (1977).

Male ddY mice weighing 20 to 28 g were used as 7 to 14 mice per group. One hour after the test compound was orally administered, (+)
Bicuculline (0.6 mg / kg) was intravenously administered, and the presence or absence of tonic extension convulsions within 5 minutes was examined. The 50% effective concentration (ED ₅₀ ) value was determined. The ED ₅₀ of the compounds of Examples 1 and 5 was determined. The values were 8.1 mg / kg and 9.8 mg / kg, respectively.

Experimental Example 3 Effect on experimental amnesia (amnesia) Using male ddY mice as a group of 20 mice, the effect on learning and memory of amnesia-loaded mice was evaluated using a step-through passive avoidance response as an index. investigated. Amnesia-loaded animals were created by loading an electroconvulsive shock (ECS) immediately after the acquisition trial, and the retention test was performed 24 hours after the acquisition trial. Test compounds were administered intraperitoneally (ip) 30 minutes prior to the acquisition trial.

As a result, the compound of Example 4 significantly prolonged the reaction latency at the time of trial of the retention test from 2.5 mg / kg (ip), and showed the effect of improving amnesia.

Experimental Example 4 Acute Toxicity When 300 mg / kg of the compound of Example 4 was intraperitoneally administered to 5 male ddY mice per group, no death was observed until 5 days after administration. 1000 mg / k
When g was orally administered, no deaths were observed for 5 days after the administration.

As is apparent from various pharmacological studies including the above experiments, the compound of the general formula (I) of the present invention has a high affinity for the BZP receptor, such as bicuculline and pentylenetetrazole. Is useful as an anxiolytic because it has an antagonistic effect on chemical convulsants, but has little effect on somatic functions such as muscle relaxation. Alternatively, because it has the effect of suppressing amnesia induced by electroconvulsive shock, amnesia treatment drug, brain function activator,
It is useful as an anti-dementia drug and the like. It is also useful as a neutralizer (antidote) for overdose or poisoning of existing anti-drugs such as diazepam.

When the compound of the general formula (I) of the present invention is used as a medicament, the compound is mixed with a therapeutically effective amount of a compound and appropriate pharmacologically acceptable excipients, carriers, diluents and the like. , Capsules, granules, syrups, injections, suppositories or powders. For example, in the case of oral administration, the dose is usually about 5 to 500 mg per day for an adult, and it can be administered once or divided into several times.

〔Example〕

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 2-methyl-4-oxo-5,6,7,8-tetrahydro-4
2.5 g of H-cyclohepta [b] thiophen-5-acetic acid and 1.95 g of 4-chlorophenylhydrazine in 50 ml of toluene
The suspension is heated at reflux for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethanol to give 2- (4-chlorophenyl) -9-methyl-2,4,4a, 5,6,7 having a melting point of 119 to 121 ° C. -Hexahydro-3H-thieno [2 ',
2.7 g of 3 ': 6,7] cyclohepta [1,2-c] pyridazin-3-one are obtained.

Example 2 A reaction and treatment were carried out in the same manner using 4-methylhydrazine instead of 4-chlorophenylhydrazine used in Example 1, to obtain 2-methylhydrazine having a melting point of 117 to 119 ° C.
(4-methylphenyl) -9-methyl-2,4,4a, 5,6,7-
Hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one is obtained.

Example 3 A reaction and treatment were conducted in the same manner using phenylhydrazine instead of 4-chlorophenylhydrazine used in Example 1, to obtain 2-phenyl-9-methyl-2,4 having a melting point of 102 to 103 ° C. , 4a, 5,6,7-Hexahydro-3H-
Thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one is obtained.

Example 4 When 4-methoxyphenylhydrazine was used instead of 4-chlorophenylhydrazine used in Example 1 to carry out the reaction and treatment in the same manner, the melting point was 136-13.
8.5 (C) 2- (4-methoxyphenyl) -9-methyl-
2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3':
6,7] cyclohepta [1,2-c] pyridazin-3-one is obtained.

Example 5 2- (4-chlorophenyl) -9-methyl-2,4,4a,
To a solution of 3.6 g of 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one in 30 ml of acetic acid at 40 ° C. with stirring, was added bromine. Add 0.6 ml, 40 ~ 4
Incubate at 5 ° C for 30 minutes. The reaction solution is poured into water, and the precipitated oil is collected by decantation. This crude product was subjected to silica gel column chromatography. From the part eluted from chloroform, 2- (4-chlorophenyl) -2,5,6,7-tetrahydro-9-methyl-3H-, having a melting point of 149.5 to 151 ° C, was obtained. 1.27 g of thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one are obtained.

Example 6 A suspension of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophen-5-acetic acid (2.0 g) and 4-chlorophenylhydrazine (1.6 g) in ethanol (40 ml) was heated to reflux for 8 hours. After cooling, the reaction solution was concentrated under reduced pressure, and ethanol was distilled off. The residue was dissolved in acetic acid (40 ml), and the mixture was heated under reflux for 2 hours. Acetic acid is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography. Crystals obtained from the fraction eluted with chloroform were recrystallized from a mixed solvent of chloroform-ethanol to give 2- (4-chlorophenyl) -2,4,4a, 5,5 as light brown crystals having a melting point of 156 to 158 ° C. 6,7−
2.0 g of hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one are obtained.

By the same method as described above, for example, the following compound is obtained.

Example 7 2- (6-chloro-2-pyridyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] Example 8 2- (4-Methylphenyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7 Cyclohepta [1,
2-c] pyridazin-3-one, melting point 105-107 ° C Example 9 2- (4-methoxyphenyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3' : 6,7] cyclohepta [1,2-c] pyridazin-3-one, melting point 135-137 ° C. Example 10 9-bromo-2- (4-chlorophenyl) -2,4,4a,
5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, melting point 129
~ 131 ° C Example 11 9-Bromo-2- (4-methoxyphenyl) -2,4,4
a, 5,6,7-Hexahydro-3H-thieno [2 ', 3': 6,7]
Cyclohepta [1,2-c] pyridazin-3-one, melting point 1
39-141 ° C Example 12 9-bromo-2- (4-chlorophenyl) -2,4,4a,
To a solution of 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one (2.5 g) in acetic acid (40 ml) at 40 ° C. with stirring was added bromine. 1.1 g of a 5 ml solution of acetic acid are added in 10 minutes. React at 40-50 ° C for 20 minutes and pour into ice water. The precipitated crystals are collected by filtration, washed with water, dissolved in chloroform, and subjected to silica gel column chromatography. Crystals obtained from the fraction eluted from chloroform were recrystallized from a mixed solvent of ethanol-chloroform.
As white crystals at 143 to 144 ° C, 9-bromo-2- (4-
1.5 g of (chlorophenyl) -2,5,6,7-tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one are obtained.

The compounds shown in the following table are obtained in the same manner as in the above examples.

Pharmaceutical Formulation Example The tablet containing 10 mg of the compound of the general formula (I) of the present invention is:
It is prepared according to the following formula.

Compound of the formula (I) 10.0 mg Lactose 58.5 mg Corn starch 25.0 mg Crystalline cellulose 20.0 mg Polyvinylpyrrolidone K-30 2.0 mg Talc 4.0 mg Magnesium stearate 0.5 mg 120.0 mg The compound of the formula (I) is pulverized with an atomizer, Fine powder having an average particle diameter of 10 μm or less, lactose, corn starch and crystalline cellulose are sufficiently mixed in a kneading machine, and kneaded using a polyvinylpyrrolidone paste solution. Pass the kneaded material through a 200 mesh sieve, dry at 50 ℃,
Pass through a 24-mesh sieve. Mix talc and magnesium stearate and use a 8 mm diameter punch to weigh 120.0
mg tablets are obtained. These tablets can be sugar-coated or film-coated if necessary.

Continuation of the front page (56) References JP-A-2-9866 (JP, A) JP-A-1-228969 (JP, A) European Publication 308515 (EP, A1) (58) Fields investigated (Int. ⁶ , DB name) C07D 495/04 A61K 31/50 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] (1) General formula Wherein R is hydrogen, halogen or C _1-4 alkyl, Ar
Is aryl, heteroaryl, or aryl having at least one halogen, C _1-4 alkyl, C _1-4 alkoxy, nitro, amino, hydroxy, trifluoromethyl, C _2-5 alkanoylamino, or Heteroaryl, the bond between the 4 and 4a positions Represents a single bond or a double bond. ) A thienocycloheptapyridazine compound represented by the formula: (2) 2- (4-chlorophenyl) -9-methyl-2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ',
3 ': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 2- (4-methylphenyl) -9-methyl-2,4,4a, 5,
6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 2-phenyl-9-methyl-2,4,4a, 5, 6,7-Hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-
c] pyridazin-3-one, 2- (4-methoxyphenyl) -9-methyl-2,4,4a,
5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 2- (4-chlorophenyl) -2,5,6, 7-tetrahydro-9-methyl-3H-thieno [2 ', 3': 6.7] cyclohepta [1,2-c] pyridazin-3-one, 2- (4-chlorophenyl) -2,4,4a, 5,6,7-Hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2
-C] pyridazin-3-one, 2- (6-chloro-2-pyridyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 2- (4-methylphenyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] Cyclohepta [1,2
-C] pyridazin-3-one, 2- (4-methoxyphenyl) -2,4,4a, 5,6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,
2-c] pyridazin-3-one, 9-bromo-2- (4-chlorophenyl) -2,4,4a, 5,
6,7-hexahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one, 9-bromo-2- (4-methoxyphenyl) -2,4 , 4a,
5,6,7-hexahydro-3H-thieno [2 ', 3': 6.7] cyclohepta [1,2-c] pyridazin-3-one, 9-bromo-2- (4-chlorophenyl) -2, 5,6,7−
The compound according to claim 1, wherein the compound is selected from the group consisting of tetrahydro-3H-thieno [2 ', 3': 6,7] cyclohepta [1,2-c] pyridazin-3-one. (3) An anxiolytic comprising the compound according to (1) or (2) as an active ingredient. 4. A therapeutic agent for amnesia, a brain function activating agent or an anti-dementia agent comprising the compound according to claim 1 or 2 as an active ingredient.