JP3087763B2 - Novel heterocyclic compound and pharmaceutical composition containing the same - Google Patents

Description

The present invention relates to a novel cycloheptimidazole compound,
The present invention relates to a pharmacologically acceptable salt or an optically active substance thereof, and a novel medicine for humans or animals containing these compounds, and more specifically, to stimulate and enhance gastric motility. Due to delayed or emptying of the stomach, gastric and esophageal reflux, flatulence, indigestion, medicine to improve and treat gastric ulcer, etc., or has anti-nausea, anti-cancer vomiting and nausea activity, motion sickness, motion sickness, Cell growth inhibitors in cancer treatment, etc., drugs to improve and treat nausea and vomiting caused by irradiation with radiation, etc., and further anxiety, hallucinations, delusions, mania,
Prevents central nervous system and peripheral nervous system psychiatric / neurological disorders such as schizophrenia, migraine, clustered complex headache, trigeminal neuralgia, etc.
It relates to the medicament to be treated.

[Problems to be solved by conventional technology and invention]

JP-A-56-125384 (corresponding to U.S. Pat. No. 4,258,188) discloses a method for producing a 2- (1-piperazinyl) cycloheptoimidazole derivative and its use as a therapeutic agent for hypertension. I have. In addition, the present inventors have found a psychotropic effect, that is, an antipsychotic effect, particularly an antidepressant activity, in some of the 2- (1-piperazinyl) cycloheptimidazole derivatives, and the present invention relates to a therapeutic agent for mammalian psychosis. We applied for a patent for a new medical use (JP-A-60-260516). JP-A-64-31
No. 72 discloses a cycloheptimidazole derivative having an anti-inflammatory action and an analgesic action.

On the other hand, recently a tetrahydrocarbazolone derivative GR
38032F or Zako Pride benzamide derivatives, compounds such as BRL24924, is currently being discussed as a 5-HT ₃ receptor antagonists, anti-emetic activity, gastric prokinetic activity, further anti-anxiety, anti-schizophrenia activity is revealed, Clinical research is also ongoing (I. Monkovic; Drugs of the future, 14 , 44,198
9 and JRFozard; Trends in Pharmacol. Sci., 8 , 44, 1
987).

The present inventors are compounds having a different chemical structure from the above compounds, have an antiemetic effect, activate gastrointestinal motility,
If we continue to search for a compound that has a function to improve the function of the digestive tract, we will develop a highly safe drug that has new features not found in the above compound. Of the cycloheptimidazole compound is 5
-HT ₃ receptors have antagonism, found to have a biological activity which matches the above-mentioned object, the present invention has been completed.

[Means for solving the problem]

1 The present invention relates to a compound of the general formula I Wherein R ¹ represents a hydrogen atom, a lower alkyl group or a benzoyl group, and Z is a single bond, a lower alkylene group or -CO
NH- (CH ₂ ) _a- (a is a number of 0, 1 or 2);
X is the following formula (B and C are a number of 0 or an integer of 1 or more that satisfies b + C = 3 or 4, the ring is a lower alkyl group, which may be mono- or tetra-substituted, and the ring member nitrogen atom is a lower alkyl group; It may be substituted by a benzyl group, a halogenated phenoxyalkyl group or a halogenated benzyl group, and any two ring carbon atoms or any one ring carbon atom and a ring nitrogen atom have 1 to 1 carbon atoms. 3 may be bonded by a linear lower alkylene group). (R ³ represents a benzyl halide group), (D is a number of 0 or 1, and the ring may be substituted with an amino group), a halogenated phenyl group, (Y is Or -SO _2- , wherein the ring may be substituted with a halogen atom), (R ⁴ and R ⁵ each independently represent a hydrogen atom or a lower alkyl group)] or a pharmacologically acceptable salt thereof.

The present invention is further a pharmaceutical composition containing, as an active ingredient, the cycloheptoimidazole compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof.

In the general formula [I] for specifying the cycloheptoimidazole compound of the present invention, specifically, R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a lower group such as an isobutyl group. Examples include an alkyl group and a benzoyl group.

Specific examples of Z include a single bond, a methylene group, an ethylene group, a propylene group which may be branched, a lower alkylene group such as a butylene group which may be branched, and -CONH (C
H ₂ ) _a- (a is 0, 1 or 2).

x has the above-mentioned meaning, and the following can be individually mentioned.

(B and c have the aforementioned meanings) Can be mentioned. These rings may be mono- to tetrasubstituted by lower alkyl groups described by the R ^1, a lower alkyl group wherein a hydrogen atom bound to a ring member nitrogen atom described in the R ^1, benzyl, fluoro Phenoxymethyl, fluorophenoxyethyl, fluorophenoxypropyl, chlorophenoxymethyl, chlorophenoxyethyl, chlorophenoxypropyl, bromophenoxymethyl, bromophenoxyethyl, bromophenoxypropyl, etc., halogenated phenoxyalkyl, fluorobenzyl, chlorobenzyl, bromo It may be substituted by a halogenated benzyl group such as benzyl.

In these rings, those in which any two ring carbon atoms or any one ring carbon atom and a ring nitrogen atom are bonded by a linear lower alkylene group having 1 to 3 carbon atoms include: And the like.

As R ³ in, specific examples include the above-mentioned benzyl halide group.

And the amino group may be substituted on the cyclohexyl ring.

Specific examples of the halogenated phenyl group include fluorophenyl, chlorophenyl, and bromophenyl.

And a halogen atom such as fluorine, chlorine or bromine may be substituted on the benzene ring.

R ⁴ and R ⁵ in each independently represent a hydrogen atom or a lower alkyl group described for R ¹ .

Examples of the compound of the general formula [I] include the compounds shown in Table 1.

The compound represented by the general formula [I] can be produced, for example, by the following method. N in the following reaction formula is 0
The numbers 4 to 4, Me represents a methyl group, Ph represents a phenyl group, and other symbols have the above-mentioned meanings.

In the production method A, the reaction between the compounds (1) and (2) is generally carried out at a molar ratio of (1) / (2) = 0.7 to 3.0, preferably 1.0.
~ 2.0, 20 ~ 170 ° C, preferably 1 ~ 20 at a temperature of 50 ~ 150 ° C
The reaction is preferably performed for 3 to 10 hours, thereby producing the compound (3). A solvent can be used for this reaction, if necessary. As the solvent, alcohol solvents, particularly n-butanol, n-amyl alcohol, n-hexyl alcohol and the like are preferable.

In the production method B, the reaction of the compound (4) with the compound (1) is generally carried out at a molar ratio of (4) / (1) = 0.3 to 2.0, preferably 0.5.
The reaction is carried out at a temperature of 1.01.0, 10〜100 ° C., preferably 20〜80 ° C. for 16060 hours, preferably 44040 hours, whereby the compound (5) is formed. Then, the compounds (5) and (6) are generally treated with a molar ratio of (5) / (6) = 0.7 to 3.0, preferably 1.0.
When the reaction is carried out at 10 to 120 ° C., preferably 20 to 80 ° C. for 1 to 20 hours, preferably 3 to 10 hours, at 2.0 to 2.0, for example, in the presence of an acid scavenger such as sodium methoxide, compound (3) is formed. . A solvent can be used for this reaction, if necessary, and the solvent is preferably an alcoholic solvent, particularly methanol, ethanol, n-propanol, i-propanol, or the like.

In the production method C, the reaction between the compounds (6) and (7) can be carried out in the same manner as the reaction between the compounds (5) and (6) in the production method B, whereby the compound (8) is produced. Next, the reaction between the compounds (8) and (9) is generally carried out using (8) /
The molar ratio of (9) is 0.5 to 2.0, preferably 0.7 to 1.5, and is preferably 10 to 10 in the presence of an acid scavenger such as triethylamine.
The reaction can be performed at a temperature of 0 ° C., preferably 20 to 80 ° C., for 1 to 20 hours, preferably 2 to 10 hours, to produce compound (10).
A solvent can be used for this reaction as necessary, and examples of the solvent include alcohols such as methanol and ethanol, acetonitrile, dichloromethane and the like. The reaction between the obtained compound (10) and (1) is generally carried out at a molar ratio of (10) / (1) = 0.3 to 2.0, preferably 0.5 to 1.5.
In the presence of an acid scavenger such as potassium carbonate
The reaction can be carried out at a temperature of up to 120 ° C. for a period of 1 to 20 hours, preferably 3 to 10 hours. A solvent can be used for this reaction as necessary, and examples of the solvent include alcohols such as methanol and ethanol, acetonitrile, dichloromethane and the like.

In the production method D, the reaction between the compounds (8) and (12) is generally carried out by a molar ratio of (8) / (12) = 0.5 to 2.0, preferably 0.7.
The reaction is carried out at 10 to 100 ° C., preferably 20 to 80 ° C. for 1 to 10 hours, preferably 2 to 8 hours in the presence of an acid scavenger such as triethylamine, thereby producing the compound (13). For this reaction, a solvent can be used if necessary. Examples of the solvent include ethers such as tetrahydrofuran and halogenated hydrocarbons such as cyclomethane.

When the compound of the formula [I] has an asymmetric carbon atom, it is usually obtained as a racemate, and can be separated into optically active compounds by an optical resolution method such as diastereomeric salification with an optically active acid. Naturally, it is also possible to synthesize an optically active compound from an optically active raw material compound.

The pharmacologically acceptable salts of the compound of the general formula [I] of the present invention include, for example, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate , Maleate, fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, sugar, methanesulfonate, p-toluenesulfonate, naphthalenesulfonic acid Salts formed from acids which form non-toxic acid addition salts containing pharmacologically acceptable anions such as salts and their hydrates and quaternary ammonium salts and their hydrates are included. You. These salts may be formed in a synthetic route, or may be obtained by reacting a free compound with the above-mentioned acid.

According to the study of the present inventors, the compound of the general formula [I] of the present invention has a 5-HT ₃ receptor antagonistic activity and improves gastrointestinal motility enhancer which improves the delay of gastric emptying, It has been revealed that it is useful as an antiemetic, anxiolytic, schizophrenia treatment, migraine treatment, visceral pain treatment, antiarrhythmic, and respiratory disease treatment.

The compound of the formula [I] is generally used in the form of a pharmaceutical composition, and can be administered by various routes such as oral, subcutaneous, intramuscular, intravenous, intranasal, percutaneous penetration and rectal route.

The present invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmacologically acceptable salts include the aforementioned, for example, acid addition salts and quaternary ammonium salts.

Compositions of the present invention include, for example, tablets, capsules, powders, granules, troches, cachets, elixirs, emulsions, emulsions,
It can be in the form of syrups, suspensions, aerosols, ointments, sterile injectable solutions, molded vaps, soft and hard gelatin capsules, suppositories and sterile packaged powders. Examples of pharmacologically acceptable carriers include lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, acacia, calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, tragacanth gum, gelatin, syrup,
Methylcellulose, carboxymethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate,
Inert polymers, such as water or mineral oil.

Whether fixed or liquid compositions, fillers, binders,
Lubricants, wetting agents, disintegrants, emulsions and suspensions, preservatives,
It may contain sweeteners or fragrances. The compositions can also be disposed such that the active ingredient is released rapidly, conjunctively or delayed after administration to the patient.

For oral administration, the compounds of general formula [I] are mixed with carriers and diluents and made into tablets, capsules and the like. For parenteral administration, the active ingredient is dissolved in 10% dextrose in water, isotonic saline, sterile water, or a similar liquid and is administered via intravenous infusion or injection, or vial or intramuscular injection. Sealed in ampoule. Advantageously, solubilizing agents, local anesthetics, preservatives and / or buffers can also be included in the solvent. To increase stability, the composition can be lyophilized after injection into a vial or ampoule. Other cases of parenteral administration include formulations administered nasally as aerosols, sprays, inhalants and the like. In addition, preparations which are administered transdermally as ointments and cataplasms are also included. In this case, a molded vap or tape is advantageous.

The compositions generally comprise from 0.001 to 5 per unit dosage form.
It contains 00 mg, preferably 0.005 to 250 mg, of the active ingredient.

The compounds of general formula [I] are effective over a wide dosage range. For example, the daily dose is usually 0.0001mg
in the range of / kg to 50mg / kg. The actual amount of the compound to be administered will be determined by a physician, depending on the compound to be administered and on the age, weight, response, severity of the condition, the route of administration, etc. of the individual patient. Therefore, the above dosage ranges do not limit the scope of the invention. The number of daily doses is usually 1 to 6 times, preferably 1 to 4 times.

The compounds of the general formula [I] can themselves be effective gastric motility enhancers, antiemetic agents, anxiolytics, antipsychotics, antiarrhythmic agents, etc., but if necessary one or more other active compounds It can also be administered in combination with drugs.

The production and biological activity of the compound of the general formula [I] of the present invention will be described in more detail below with reference to a series of Examples, Reference Examples and Experimental Examples, but the present invention is not limited thereto. . In the examples of the pharmaceutical composition shown below, one or several compounds of the general formula [I] are used as the active ingredient.

〔Example〕

Synthesis of Compounds of the Invention: Example 1A Synthesis of Compounds Nos. 1009 and 1010 by Preparation Method A 3-aminoquinuclidine [R ¹ =, n = 0, X = 2.00 g (0.0159 mol) of 2-methylthiocycloheptimidazole [compound of formula (2)] 2.79 g (0.0159 mol) of n-amino alcohol 2
Refluxed in 0 ml for 5 hours. After concentrating the reaction mixture with an evaporator and treating it by silica gel column chromatography (developed with dichloromethane: methanol = 4: 1), the following formula is obtained. 0.76 g (yield 19%) of compound No. 1009 was obtained. Dissolve 0.76 g of this compound in 5 ml of acetonitrile, 0.31 g of concentrated hydrochloric acid
Was added and stirred at room temperature for 30 minutes. Concentrate the reaction mixture,
Wash with 20 ml of ether, filter and dry to give compound N
o. 1009 hydrochloride, that is, 0.44 g (yield 51%) of compound No. 1010 was obtained as yellow crystals. Melting point 295-298 [deg.] C (decomposition).

Table 2 shows compounds of the present invention synthesized in the same manner as in this method. In this table, Y ₁ represents the yield of the free compound based on 2-methylcycloheptoimidazole, and Y ₂ represents the yield of the salt based on the free compound (all in mol%).

Example 2A Synthesis of Compound No. 1009 by Production Method B 3-Aminoquinuclidine 2.00 g (0.0159 mol), 2-aminoquinuclidine
Methylthioamidine sulfate [compound of formula (4)] 2.21 g
(0.0159 mol) and 20 ml of water are charged together and
After stirring for an hour, the mixture was concentrated with an evaporator. The residue was crystallized by adding 20 ml of acetone, filtered and dried, the following formula: 4.42 g of the compound was obtained. Then 2.42 g of this compound was added to 28
To the mixture were added 2.15 g of a methanol solution of 1.5% sodium methoxide, 1.51 g of tropolone methyl ether and 20 ml of ethanol, and the mixture was refluxed for 3 hours. The reaction mixture was extracted with dichloromethane, the dichloromethane layer was concentrated, and the concentrate was subjected to silica gel chromatography (dichloromethane: methanol = 4: 4).
Compound No. 1009 0.31g
(Yield 11%) was obtained.

Compounds shown in Table 3 were synthesized in the same manner as in this method. Y ₁ and Y ₂ in the table have the above-mentioned meaning.

Example 3A Synthesis of Compound Nos. 1065 and 1066 by Preparation C Tropolone methyl ether 5.00 g (0.0386 mol), guanidine sulfate 3.79 g (0.0368 mol), 28% sodium methoxide methanol solution 7.10 g (0.0368 mol) and ethanol 30 ml Charged together and refluxed for 5 hours. The reaction mixture was poured into 100 ml of water and extracted twice with 200 ml each of dichloromethane. The dichloromethane layer was concentrated, and the residue was dissolved in 30 ml of dichloromethane, and 4.70 g of phenyl chlorocarbonate was added thereto.
(0.0300 mol), and the mixture was stirred at room temperature for 3 hours. 30 ml of water was added to the reaction mixture, the dichloromethane layer was concentrated, and the concentrate was washed with hexane. Was obtained as yellow crystals of 3.13 g (yield: 40%) of cycloheptimidazole-2-phenylcarbamate. Melting point 2
23-225 ° C.

3.13 g of the obtained compound was dissolved in 20 ml of dichloromethane, and 4.64 g of a 28% sodium methoxide methanol solution was dissolved.
(0.0240 mol) and 1.51 g of 3-aminoquinuclidine
(0.0120 mol) were charged together and stirred for 5 hours. The reaction mixture was poured into 30 ml of water, and the dichloromethane layer was concentrated.
The residue was treated by silica gel column chromatography (developed with dichloromethane: methanol = 3: 1) to give the following formula Compound No. 1065 as yellow crystals (1.44 g, yield 40.3%)
Obtained. 280-283 ° C. When this compound was converted to a hydrochloride in the same manner as in Example 1A, compound No. 1066 was obtained in a yield of 72%. Melting point> 300 ° C.

Table 4 shows the compounds of the present invention synthesized in the same manner as in this method. In the formula, Y ₁ and Y ₂ have the meaning described above.

Example 4A Synthesis of Compound No. 1085 by Production Method D The 2-aminocycloheptoimidazole [compound of formula (8)] required as a starting material can be synthesized in the same manner as in Example 1, section 1. 2.00 g (0.0138 mol) of this compound
Was dissolved in dichloromethane (20 ml) and triethylamine (2.79) was dissolved.
g (0.0276 mole) and benzoyl chloride 1.94 g (0.01
38 mol) and refluxed for 3 hours. The reaction solution was poured into 10 ml of water, and the dichloromethane layer was concentrated by an evaporator.
When processed by silica gel column chromatography (developed with ethyl acetate), the following formula is obtained. Of Compound No. 1085 was obtained as yellow crystals (yield: 38%). Mp 148-150 ° C.

Compounds shown in Table 5 were synthesized in the same manner as in this method.

Example 1B A tablet containing 10 mg of active ingredient is prepared as follows.

Per tablet Active ingredient 10mg Maize starch 55mg Crystalline cellulose 35mg Polyvinylpyrrolidone 5mg (as 10% aqueous solution) Carboxymethylcellulose calcium 10mg Magnesium stearate 4mg Talc 1mg Total 120mg Pass active ingredient, starch and crystalline cellulose through 80 mesh sieve and completely Mix. The obtained powder is mixed with a polyvinylpyrrolidone solution, granulated, and passed through an 18-mesh sieve. The granules thus produced are dried at 50-60 ° C. and sized again with an 18 mesh sieve. The carboxymethylcellulose calcium and magnesium stearate and talc, previously sieved through a 80 mesh screen, are added to the granules and mixed, after which tablets are weighed 120 mg each with a tablet machine.

Example 2B A tablet containing 200 mg of the active organism is prepared as follows.

Active ingredient per tablet 200mg Corn starch 50mg Microcrystalline cellulose 42mg Light silicic anhydride 7mg Magnesium stearate 1mg Total 300mg The above ingredients are thoroughly mixed through 80 mesh sieve. The resulting powder is compression molded to produce tablets weighing 300 mg.

Example 3B A sublingual tablet containing 2.5 mg of the active ingredient is prepared as follows.

Active ingredient 2.5 mg per sublingual tablet Mannitol 56.5 mg Hydroxypropyl methylcellulose 5.0 mg Magnesium stearate 1.5 mg Total 65.5 mg The above ingredients except magnesium stearate are thoroughly mixed through an 80 mesh sieve. Add an appropriate volume of pure water and granulate the powder. After drying, the powder is sieved and mixed with magnesium stearate and compressed into tablets using suitable punches.

Example 4B A capsule containing 0.5 mg of active ingredient is prepared as follows.

Active ingredient per capsule 0.5mg Lactose 98.5mg Magnesium stearate 1.0mg Total 100.0mg Combine the above ingredients, pass through 80 mesh sieve and mix thoroughly. The resulting powder is filled into capsules in 100 mg increments.

Example 5B A capsule containing 100 mg of active ingredient is prepared as follows.

Active ingredient per capsule 100mg Corn starch 40mg Lactose 5mg Magnesium stearate 5mg Total 150mg Combine the above ingredients, pass through 80 mesh sieve and mix thoroughly. The obtained powder is filled into capsules 150 mg at a time.

Example 6B A vial ready-to-use injection containing 5 mg of active ingredient is prepared as follows.

 When using 5 mg of active ingredient / 50 mg of mannitol per vial, dissolve in 1 ml of distilled water for injection and use.

Example 7B An ampoule containing an ampoule containing 100 μg or 500 μg of the active ingredient is produced as follows.

Example 8B Injectable ampoule containing 50 mg of active ingredient is prepared as follows.

Active ingredient per ampoule 50 mg Sodium chloride 1.8 mg Distilled water for injection qs 2 ml Example 9B A syrup containing 5 mg of active ingredient is prepared as follows.

Active ingredient per 1 unit 5 mg Sucrose 2.5 g Glycerin 0.5 g Distilled water Appropriate amount 5.0 mL A buffer, a colorant, a flavoring agent, and a preservative can be added as needed.

Example 10B A nasal composition containing 10 μg or 10 μg of the active ingredient is prepared as follows.

Active ingredient 10 μg or 100 μg Benzalkonium chloride 0.1 mg Saline 0.6 ml or 0.9 ml Distilled water qs 1.0 ml Filter the resulting solution through a 0.2 μm filter and fill into nasal spray pump or gelatin Soak the sponge with the filtrate.

Example 11B A suspension aerosol containing 20 mg of active ingredient is prepared as follows.

Active ingredient per can 20 mg Oleic acid 4 mg Trichlorofluoromethane 4.5 g Dichlorodifluoromethane 12.5 g Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C. and the active ingredient is mixed into the solution. The suspension is weighed into an aluminum aerosol can and dichlorodifluoromethane is pressurized into the can.

Example 12B An adhesive patch preparation containing 17.5 mg of the active ingredient is prepared as follows.

Dissolve 10 parts of ammonium polyacrylate in 60 parts of water. On the other hand, 2 parts of glycerin diglycidyl ether are dissolved in 10 parts of water while heating. On the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water and 1 part of the active ingredient are stirred and dissolved. Then, while stirring the aqueous solution of ammonium polyacrylate, the aqueous solution of the drug-containing gel was added and mixed with the aqueous solution of glycerin diglycidyl ether and the aqueous solution of the active component of polyethylene glycol. mg, and the surface is covered with release paper and cut into 35 square centimeters to make a formulation.

Example 13B An adhesive patch containing 10 mg of the active ingredient is produced as follows.

100 parts of sodium polyacrylate, 100 parts of glycerin,
150 parts of water, trialpoxypropyl isocyanurate 0.2
Parts, ethanol 100 parts, isopropyl myristate 25
Parts, 25 parts of propylene glycol and 15 parts of the active ingredient were prepared as a mixed aqueous sol solution. Next, this sol solution was applied to a nonwoven fabric surface of a composite film composed of a rayon nonwoven fabric and a polyethylene film to a thickness of 100 μm to form a drug-containing pressure-sensitive adhesive layer. The content of auxiliary release substances (isopropyl myristate and propylene glycol) contained in this layer was about 20% by weight. Thereafter, crosslinking was performed at 25 ° C. for 24 hours, a release film was bonded to the adhesive interface, and this was further treated for 35 hours.
The product is cut into square centimeters.

In vitro and in vivo tests were performed on the biological activity of the compound of the general formula [I] used in the present invention as follows.

In anaesthetized rats, early with reflex vagal stimulation, the von Besold-Jarlish reflex (hereinafter BJ reflex) induced by a rapid bolus intravenous injection of 5-HT (20-50 μg / kg). The inhibitory effect of the compound of the general formula [I] on the acute abrupt cardiac slowing and the accompanying decrease in blood pressure was studied at different doses.

In addition, the inhibitory effect of the compound of the general formula [I] on the tachycardia induced by 5-HT was examined using atrial specimens extracted from rabbits. Furthermore, the effect of the compound of the general formula [I] on the contraction induced by electrical stimulation was examined using a stomach strip specimen isolated from a guinea pig, that is, a fundus stromal muscle specimen or a crustal longitudinal muscle specimen.

Next, the test drug was administered to fasted rats before giving a methylcellulose solution containing phenol red as a test meal, and the ability to enhance gastric emptying was examined. In dogs, a strain gauge (Star Medical: F-081S) was sewn to the body of the stomach, and the activity of the test drug on gastric motility was examined under light anesthesia or awakening.

Furthermore, dysfunctions such as secretory diarrhea induced by giving cholera toxin to mice, or increased gastrointestinal motility induced by administering 5-HTP which is a precursor of 5-HT to mice are represented by the general formula [ The extent of inhibition by the test drug [I] was examined.

Using dogs, 5-FU, cisplatin, cyclophosphamide, doxorubicin, CuSO ₄ or apomorphine-induced vomiting was induced, and the suppressive / inhibitory effects of the test drug on vomiting were examined. In addition, animals such as ferrets and sunkus were used instead of dogs, and the antiemetic effect of the general formula [I] was examined.

On the other hand, the inhibitory effect of the test drug on arrhythmias induced by using norepinephrine in anesthetized rats was also examined. Further, the analgesic activity, anti-anxiety activity, anti-schizophrenia activity and the like of the test drug were also tested in experimental animals. That is, the mice were placed under stressful conditions, dosed with the test compound, and normalization of access-oriented social behavior was observed. Improvement and antagonism to rhinitis, reflex action of pulmonary function, etc. were also studied.

Experimental Example 1 BJ Reflection Fozard et al. (Fozard, JR and Host, M: British J. Pha
rmacol. 77: 520, 1982), and the effect on BJ reflection was examined. That is, the blood pressure and heart rate of urethane (1.2 g / kg ip) anesthetized rats were recorded in a polygraph. After intravenously administering 40 μg / kg of serotonin (5-HT) to rats, it was confirmed that stable reflex bradycardia was generated, and then the test drug was intravenously administered, and 5 minutes later, 40 μg / kg of 5-HT was again administered. Was compared with the response before administration of the test drug to determine the inhibition rate. When the test drug was insoluble in water and could not be administered intravenously, it was administered intraperitoneally 20 minutes before 5HT administration. Table 6 shows the results.

Experimental example 2 Rabbit extirpated right atrium specimen The heart of a rabbit anesthetized with pentobarbital was extirpated,
A right atrial specimen was prepared. A right atrium specimen was suspended in a Magnus tube filled with Krebs-Henzeleit solution pre-added with 2 μM of atropine, and 5-HT 8 μg / ml.
Was added to cause tachycardia. The test drug was added to the Magnus tube 5 minutes before 5-HT administration, and the inhibitory effect of 5-HT on tachycardia was determined. Table 6 shows the results.

Experimental Example 3 Guinea pig extirpated gastric strip specimen Bachheit et al. (Bachheit, KH et al: J. Pharm. Pharma
Col. 37; 664, 1985), the stomach of a Hartley-type guinea pig that had been fasted for 24 hours was excised, and a small bay longitudinal muscle sample was prepared and suspended in a Magnus tube. When the contraction of the gastric strip caused by electrical stimulation is stabilized, the test drug is added,
The effect of enhancing the contractile force was observed. Table 6 shows the results.

Experimental Example 4 Rat Gastric Evacuation Capability To a Wistar rat fasted for 24 hours, a 1.5% methylcellulose suspension containing 0.05% phenol red was orally administered as a test meal, and 15 minutes later, the stomach was removed and remained in the stomach. The residual stomach content was determined by measuring the phenol red content. Phenol red was measured by adding 0.1N NaOH to the stomach, crushing with a polytron, deproteinizing with trichloroacetic acid, and
It was made alkaline by 0.5N NaOH and measured by measuring the absorbance at 560 nm. The gastric excretion rate (GER) is calculated by the following formula using the absorbance of the gastric residue of the animal immediately after test meal administration (zero-hour animal) and the absorbance of the gastric residue of the test drug-administered animal. Was. Table 7 shows the results.

Experimental Example 5 Sunks-cisplatin vomiting A venous cannula for drug administration was implanted in the jugular vein of Sunks (27-38 g) under ether anesthesia 12 hours before the start of the experiment. The experiment was performed by administering the test drug subcutaneously to the back, 30 minutes later, administering 40 mg / kg of cisplatin from an implanted venous cannula, and recording the number of vomiting during 2 hours. Table 8 shows the results.

Experimental Example 6 Stomach motility of anesthetized dog Anesthetized mongrel dog (8-13 kg) was intravenously administered with pentobarbital 30 mg / kg, and after laparotomy, contraction movement in the direction of the circular muscle could be recorded on the serosa surface of the stomach vestibule. Was sewn with a strain gauge (Star Medical: F-081S). After 30 minutes or more after the operation, the spontaneous stomach movement was recorded, and then the test drug was intravenously administered to examine the effect on the stomach spontaneous movement. In this experiment, compounds Nos. 1001, 1006 and 1010 showed a stimulatory effect on gastric locomotor activity, whereas control GR38032F did not.

Experimental Example 7 Acute Acute Toxicity A test drug was intraperitoneally administered to 2 to 5 male ddY mice of 5 weeks of age, and the general symptoms were observed according to the multifaceted observation method of Irwin. The presence or absence was checked. Table 9 shows the results.

As is clear from the results of the above experimental examples, the compound of the general formula (I) has an excellent or better pharmacological effect as compared with existing metoclopramide, cysupride, BRL24924, ICS205-930, GR38032F, MDL72222 and the like. Having.

Therefore, the compound of the general formula [I] of the present invention
Various diseases caused by overstimulation of receptors each organ below based on antagonism against HT ₃ receptor, condition being treated, can be applied to improve. Organs include the gastrointestinal system, cardiovascular system, respiratory system, central nervous system, peripheral nervous system, and the like.

In the gastrointestinal system, by stimulating and enhancing gastrointestinal motility, gastric peristalsis decreases, delays gastric emptying and emptying, gastric and esophageal reflux, flatulence, indigestion, gastric ulcer, diabetic gastric insufficiency, Ischemic bowel disease, obesity, irritable bowel syndrome (IC
S), It can improve and treat pain in various parts of the abdomen due to bloating of the colon due to ICS, various visceral pains, gastrointestinal pain such as after surgery or childbirth, or abdominal cramps, and gastrointestinal dysmotility. Cisplatin having a cell killing effect,
When administering anticancer drugs such as scrophosphamide, doxorubicin, 5-FU, and radiation, X-rays, chests such as neutron rays,
When irradiating the abdomen or other parts of the body or stomach depression,
It can be used as an antiemetic or the like to suppress nausea and vomiting as a result of migraine, dyspepsia, ulcers and the like.
Further, it can be used as a gastric emptying accelerator for radiological examinations and the like.

In the cardiovascular system, arrhythmia, vasospasm and the like can be prevented and treated. In the respiratory system, diseases in the bronchi and lungs, for example, pulmonary emboli such as miliary, respiratory hypofunction, rhinitis, and serotonin-induced nasal diseases can be prevented and treated. The central nervous system and peripheral nervous system prevent anxiety, hallucinations, delusions, mania, schizophrenia, etc.
Treatment or psychostimulants, opiates, alcohol,
Drug withdrawal / interruption syndrome from dependence inducers such as nicotine, improvement / treatment of withdrawal symptoms, prevention / reduction of dependence progression, and prevention / treatment of migraine, clustered complex headache, trigeminal neuralgia, etc. Can be used as a medicament.

The compound of the general formula [I] of the present invention is useful as an agent for preventing or ameliorating the above-mentioned diseases, but is not limited thereto. Further, when a toxicity test of the compound of the general formula [I] of the present invention was conducted, it was found that the compound was weak in toxicity and could be used as a safe drug.

〔The invention's effect〕

The compounds of the general formula [I] of the present invention were prepared in Experimental Examples 1 to 6
And as shown in Tables 6 to 8, it was revealed to have excellent pharmacological activity. The toxicity of the compounds of the present invention is generally weak as shown in Experimental Example 7 and Table 9. The compound of the general formula (I) of the present invention is generally considered to be a highly safe drug having high activity and low toxicity, and is suitably used as an agent for preventing, ameliorating and treating the above-mentioned various diseases. Is expected.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/496 A61K 31/496 31/5377 31/5377 A61P 1/08 A61P 1/08 1/14 1/14 9/06 9 / 06 11/00 11/00 25/06 25/06 25/18 25/18 25/22 25/22 C07D 401/12 C07D 401/12 403/12 403/12 413/12 413/12 451/04 451 / 04 451/14 451/14 453/02 453/02 471/08 471/08 (72) Inventor Ikuo Tomino 6-1-2 Waki, Waki-machi, Kuga-gun, Yamaguchi Prefecture Inside Mitsui Petrochemical Industry Co., Ltd. (72 ) Inventor Noriaki Kihara 61-2, Waki, Waki-machi, Kuga-gun, Yamaguchi Prefecture Inside Mitsui Petrochemical Industry Co., Ltd. (72) Inventor Joji Kamiya 2141 Togo, Mobara City, Chiba Prefecture (72) Inventor Hitoshi Sakano Mobara City, Chiba Prefecture Togo 2142 (72) Inventor Akihiro Kotanibe 2142 Togo, Mobara-shi, Chiba Prefecture (72) Inventor Mie Nakamura 1471, Shibahara, Chonan-cho, Nagao-gun, Chiba Prefecture (72) (In Japanese) Kaori Torimori 1-103, Hagiwara-cho, Mobara-shi, Chiba (72) Inventor Akira Awaya 1541, Yabe-cho, Totsuka-ku, Yokohama-shi, Kanagawa (56) References JP-A 64-3172 (JP, A) (58) Survey Field (Int. Cl. ⁷ , DB name) C07D 235/02 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula I Wherein R ¹ represents a hydrogen atom, a lower alkyl group or a benzoyl group, and Z is a single bond, a lower alkylene group or -CO
NH- (CH ₂ ) _a- (a is a number of 0, 1 or 2);
X is the following formula (B and c are a number of 0 or an integer of 1 or more that satisfies b + c = 3 or 4, the ring is a lower alkyl group, which may be mono- or tetra-substituted, and a ring member nitrogen atom is a lower alkyl group; It may be substituted by a benzyl group, a halogenated phenoxyalkyl group or a halogenated benzyl group, and any two ring carbon atoms or any one ring carbon atom and a ring nitrogen atom have 1 to 1 carbon atoms. 3 may be bonded by a linear lower alkylene group). (R ³ represents a benzyl halide group), (D is a number of 0 or 1, and the ring may be substituted with an amino group), a halogenated phenyl group, (Y is Or -SO _2- , wherein the ring may be substituted with a halogen atom), (R ⁴ and R ⁵ each independently represent a hydrogen atom or a lower alkyl group)] or a pharmacologically acceptable salt thereof. 2. A 5-HT ₃ receptor antagonist comprising, as an active ingredient, a cycloheptoimidazole compound represented by the general formula [I] or a pharmacologically acceptable salt thereof.