JPH04208267A - New heterocyclic compound and drug composition containing the same compound - Google Patents

Abstract

NEW MATERIAL:A cycloheptimidazole compound shown by formula I [R<1> is H, lower alkyl or benzoyl; Z is single bond, lower alkylene or CONH-(CH2)a (a is 0, 1 or 2); X is group shown by formula II (b and c are 0, >=1, etc., to satisfy b+c=3), group shown by formula III (R<3> is halogenated benzyl), etc.] or a salt thereof. USE:Having 5-HT3 acceptor antagonism, useful as sthenia agent of digestive tube motion function to improve discharge delay of gastric contents, antiemetic drug, antianxiety agent, antipsychotic agent, antiarrhythmic agent, etc. PREPARATION:A compound shown by formula TV is reacted with a compound shown by formula V optionally in an alcoholic solvent at 10-100 deg.C for 1-60 hours to give a compound shown by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to novel cyclohebutoimidazole compounds, pharmacologically acceptable salts or optically active forms thereof, and human-use or This article relates to novel pharmaceuticals for animals, and more specifically, to stimulate and improve gastric motility to treat delayed gastric emptying.
A drug that improves and treats emptying, gastric and esophageal reflux, flatulence, indigestion, and gastric ulcers, as well as a cell growth inhibitor that has anti-nausea, anti-vomiting and nausea activity, and is used in motion sickness, motion sickness, cancer treatment, etc. Improves nausea and vomiting caused by radiation, etc.
Medications to treat, as well as prevention and treatment of anxiety, hallucinations, delusions, psychosis, schizophrenia, migraines, cluster complex headaches, trigeminal neuralgia, and other psychiatric and neurological disorders of the central nervous system and peripheral nervous system. Regarding medicine.

[Prior art and problems to be solved by the invention] Japanese Patent Application Laid-Open No. 56-125384 (U.S. Patent No. 4.258.
No. 188) discloses a method for producing 2-(1-piperazinyl)cyclo/\butoimidazole derivatives and their use as therapeutic agents for hypertension. In addition, the present inventors have found that some compounds of 2-(l-piperazinyl)cyclohebutoimidazole derivatives have psychotropic activity, that is, antipsychotic activity, especially antidepressant activity, and have shown that they have been found to have antipsychotic activity, especially antidepressant activity, etc. A patent application was filed for a new medical use of the therapeutic agent (Japanese Patent Application Laid-Open No. 60-260516). Further, JP-A-64-3172 discloses cyclohebutoimidazole derivatives having anti-inflammatory and analgesic effects.

On the other hand, recently the tetrahydrocarbazolone derivative GR
Compounds such as 38032F or benzamide derivatives such as Zacopride and BRL24924 have been investigated as 5-HT3 receptor antagonists, and their antiemetic activity, gastric motility promoting effect, as well as anxiolytic and antipsychotic effects have been demonstrated, and clinical research has been conducted. (19 Monkovic: Dr.
ugs of the future, 14.44
．． 1989 and J, R.

Fozard; Trends in Pharmac
ol, Sci, 8.44.1987).

The present inventors will continue to search for compounds that have a different chemical structure from the above-mentioned compounds, have an antiemetic effect, activate gastrointestinal motility, and improve gastrointestinal function.
We conducted extensive research thinking that we could develop a highly safe drug with new characteristics not found in the above compounds, and discovered that a specific cyclohebutoimidazole compound was found to have 5H
The present invention was completed based on the discovery that it has T3 receptor antagonistic activity and biological activity that meets the above objectives.

[Means to solve the problem]

1 The present invention is based on the general formula (1) [wherein R1 represents a hydrogen atom, a lower alkyl group, or a benzoyl group, and Z represents a single bond, a lower alkylene group, or -
CONH-(CH2)- (a is the number 0, ■ or 2), X is the following formula (b and C are the number 0 or an integer greater than or equal to 1 that satisfies b0C=3 or 4, The ring is a lower alkyl group, which may be mono- or tetrasubstituted, and the ring member nitrogen atom may be substituted with a lower alkyl group, a benzyl group, a halogenated phenoxyalkyl group, or a halogenated benzyl group, and any two (R3 is a halogenated benzyl group), (R3 is a halogenated benzyl group) ), n (d is a number of 0 or 1, the ring may be substituted with an amino group), halogenated phenyl group, (Y represents 10- or 18O2-, the ring is a halogen atom) (R' and R5 each independently represent a hydrogen atom or a lower alkyl group)] or a pharmacologically acceptable salt thereof.

The present invention further provides a pharmaceutical composition containing a cyclohebutoimidazole compound represented by the general formula [1j or a pharmacologically acceptable salt thereof as an active ingredient.

In the general formula [1] specifying the cyclohebutoimidazole compound of the present invention, R1 specifically includes a hydrogen atom, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, etc. and benzoyl group.

Specifically, Z includes a single bond, a lower alkylene group such as a methylene group, an ethylene group, an optionally branched propylene group, an optionally branched butylene group, and -CONH(C
H2)-(a is 0, ■ or 2).

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

The following can be mentioned as examples of "having". These rings may be mono- or tetra-substituted with the lower alkyl group described for R1 above, and the hydrogen atom bonded to the ring member nitrogen atom is
Lower alkyl groups, benzyl groups, fluorophenoxymethyl, fluorophenoxyethyl, fluorophenoxypropyl, chlorophenoxymethyl, chlorophenoxyethyl, chlorophenoxypropyl, bromophenoxymethyl, bromophenoxyethyl, bromophenoxypropyl, and other halogenated phenoxy It may be substituted with an alkyl group, a halogenated benzyl group such as a fluorobenzyl group, chlorobenzyl, or bromobenzyl.

In these rings, any two ring member carbon atoms or any one ring member carbon atom and ring member nitrogen atom have a carbon number of 1
Examples of those bonded by the linear lower alkylene group of ~3 include the above-mentioned halogenated benzyl group.

may be replaced.

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

Examples include lower alkyl groups.

- Examples of compounds of the formula CI) include the compounds shown in Table 1.

(Margins below this page) Table 1 1006 Dihydrochloride 101O Hydrochloride 1o18 Trihydrobromide 1026 "I Dihydrochloride 1030 Dihydrochloride 1034 Dihydrochloride 1038" Dihydrochloride■042〃〃 Hydrochloride 1046 〃〃 Dihydrochloride 1050〃〃
Hydrochloride 1054 ” 〃 Dihydrochloride 1058 〃〃 Hydrochloride 1062〃〃
Dihydrochloride 1066H〃 Hydrochloride 1070H〃 Hydrochloride 1074
H” Hydrochloride 1078, H Hydrochloride 1097 C2H6CH2CH2NH2-1098
〃〃 Dihydrochloride 1101 HCH2CH2N(CH2)!
-1105HCH2CH2N(C2H6)2 -
1109 CH, CH2CH, NHCH, -111
0〃, // Hydrochloride 1113 HN(CH3)2 -111
4〃〃 Hydrochloride 1117 HCH2CH2NH2-1118〃
Hydrochloride 1121 HCH2CH2NH2H5-1122
N 〃 Hydrochloride 1125 C
Ha CH2CH2N(C2Hs)2 -11
26 〃〃 Hydrochloride 1129 C2
H6CH2CH2N(C2H5)2 -1130
〃〃 Hydrochloride 1133 HCH2CH2NH2N (C2Hs)
2-1134〃〃 Hydrochloride 1137 H(CHx)4N(CzHs)2-1
138〃〃 Hydrochloride 1154 ” ” Dihydrochloride 1
158 Dihydrobromide 1162 Dihydrochloride 1166 Hydrobromide 1170 Dihydrochloride 1174
The hydrochloride compound represented by general formula (I) can be produced, for example, by the following method. In the reaction formula below, n is 0 to
The number 4, Me represents a methyl group, ph represents a phenyl group, and the other symbols have the above-mentioned meanings.

(Margins below this page) Manufacturing method A: (1) f2) Manufacturing method B: Manufacturing method C: Manufacturing method D = In manufacturing method A, the reaction of compounds (1) and (2) is generally performed at a molar ratio of (1)/(2). =0.7-3.0 preferably 1.0-2.0.20-170°C preferably 50-1
The reaction is carried out at a temperature of 50° C. for 1 to 20 hours, preferably 3 to 10 hours, thereby producing compound (3). A solvent may be used in this reaction if necessary, and preferred examples of the solvent include alcoholic solvents, particularly n-butanol, n-amyl alcohol, n-hexyl alcohol, and the like.

In production method B, the reaction between compound (4) and (1) is generally carried out at a molar ratio of (4)/(1) = 0.3 to 2.0, preferably 0.5 to 1.10 to 100°C. is 20-80
C. for 1 to 60 hours, preferably 4 to 40 hours, thereby producing compound (5). Then, compounds (5) and (6) are mixed, -generally in the molar ratio of (5)/(6)=
0.7-3.0 preferably 1.0-2.0, e.g. 10-3.0 in the presence of an acid scavenger such as sodium methoxide.
Compound (3) is produced by reacting at 120°C, preferably 20-80°C, for 1-20 hours, preferably 3-10 hours. A solvent may be used in this reaction if necessary, and preferred solvents include alcoholic solvents, particularly methanol, ethanol, n-propanol, i-propanol, and the like.

In production method C, the reaction of compounds (6) and (7) can be carried out in the same manner as the reaction of compounds (5) and (6) in production method B, thereby producing compound (8). Then, the reaction between compounds (8) and (9) is generally (8)/(9
) molar ratio = 0.5 to 2.0 preferably 0.7 to 1.5
at a temperature of 10 to 100°C, preferably 20 to 80°C, for 1 to 20 hours, preferably 2 to 10 hours, in the presence of an acid scavenger such as triethylamine,
Compound αO) is produced. A solvent can be used in this reaction if necessary, and examples of the solvent include alcohols such as methanol and ethanol, acetonide, dichloromethane, and the like. Obtained compound (io)
The reaction between (1) and (1) is generally performed using the molar ratio αO)/(1) =
0.3 to 2.0 preferably 0.5 to 1.5, for example 10 to 120° in the presence of an acid scavenger such as potassium carbonate.
The reaction can be carried out for 1 to 20 hours, preferably for 3 to 10 hours, and thereby the compound αυ is obtained. A solvent may be used in this reaction if necessary, and examples of the solvent include alcohols such as methanol and ethanol, acetonitrile, and dichloromethane.

In the manufacturing process, the reaction between compound (8) and 0x is generally carried out at a molar ratio of (8)/Q2 = 0.5 to 2.0, preferably 0
．． 7 to 1.5, 10 to 100°C, preferably 20 to 80°C, in the presence of an acid scavenger such as triethylamine.
The reaction is carried out for 1 to 10 hours, preferably for 2 to 8 hours, thereby producing compound α East. A solvent can be used in this reaction if necessary, and examples of the solvent include ethers such as tetrahydrofuran, and halogenated hydrocarbons such as dichloromethane.

When the compound of general formula (I) has an asymmetric carbon atom, it is usually obtained as a racemate, and can be separated into optically active forms by an optical resolution method such as diastereomeric salt formation with an optically active acid.

Naturally, it is also possible to synthesize optically active compounds from optically active raw material compounds.

Pharmaceutically acceptable salts of the compound of 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, saccharate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate Salts formed from acids that form non-toxic acid addition salts containing pharmacologically acceptable anions such as salts and hydrates thereof and quaternary ammonium salts and hydrates thereof are included. Ru. These salts may be generated during the synthetic route, but they can also be obtained by reacting the free compound with the above-mentioned acid.

According to the research conducted by the present inventors, the compound of the general formula CI) of the present invention has a 5-HTs receptor antagonistic effect and is a gastrointestinal motility enhancer and an antiemetic agent that improves delayed gastric emptying. It has been revealed that it is useful as an anxiolytic agent, a schizophrenia treatment agent, a migraine treatment agent, a visceral pain treatment agent, an antiarrhythmic agent, and a respiratory disease treatment agent.
The compounds of general formula CI) are usually used in the form of pharmaceutical compositions and can be administered by various routes, such as orally, subcutaneously, intramuscularly, intravenously (intranasally, percutaneously and rectally).

The present invention encompasses pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound of general formula (I) or a pharmacologically acceptable salt thereof as described above as an active ingredient. Pharmaceutically acceptable salts include, for example, the acid addition salts and quaternary ammonium salts described above.

The compositions of the invention can be used, for example, in tablets, capsules, powders, granules, troches, cachets, elixirs, emulsions, emulsions, syrups, suspensions, aerosols, ointments, sterile injectable solutions, molded bags, soft and hard gelatin. It can be in the form of capsules, herbal medicines and sterile packaged powders. Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic, calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, gum tragacanth, gelatin. , syrup, methylcellulose, carboxymethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert polymers, water or mineral oil.

Both fixed and liquid compositions may contain fillers, binders, lubricants, wetting agents, disintegrants, emulsifying and suspending agents, preservatives, sweetening or flavoring agents, and the like. The compositions can also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

For oral administration, the compound of formula [■] is mixed with carriers and diluents and put into the form of tablets, capsules, etc. For parenteral administration, the active ingredient is dissolved in 10% aqueous dextrose, isotonic saline, sterile water, or similar liquid and placed in a vial or for administration by intravenous infusion or injection, or by intramuscular injection. sealed in an ampoule.

Advantageously, solubilizing agents, local anesthetics, preservatives and/or buffering agents may also be included in the vehicle. To increase stability, the composition can also be lyophilized after filling into vials or ampoules. Other examples of parenteral administration include formulations administered nasally as aerosols, sprays, inhalants, and the like. Also included are preparations administered transdermally as ointments and poultices.

In this case, molded poultices or tapes are advantageous.

The compositions generally contain from 0.001 to 500 mg, preferably from 0.005 to 250 mg per unit dosage form.
Contains active ingredients.

Compounds of general formula (I) are effective over a wide dosage range. For example, the dosage per day is usually 0.000
It ranges from 1 mg/kg to 50 mg/kg.

The actual amount of compound administered will be determined by the physician depending on the compound being administered and on the age, weight, response, and severity of the patient's symptoms, route of administration, etc. of the individual patient. Therefore, the above dosage ranges are not intended to limit the scope of the invention. - The number of doses per day is usually 1 to 6 times, preferably 1 to 6 times per day.
~4 times is appropriate.

The compounds of general formula (I) can be effective propulsive agents, antiemetics, anxiolytics, antipsychotics, antiarrhythmics, etc. by themselves, but if necessary they can be combined with one or more other equivalent agents. It can also be administered in combination with drugs.

The preparation and biological activity of the compound of general formula CI) of the present invention will be explained in more detail below by a series of Examples, Reference Examples and Experimental Examples, but the present invention is not limited thereto. Furthermore, in the following examples of pharmaceutical compositions, one or more compounds of general formula (I) are used as the active ingredient.

〔Example〕

Synthesis of compounds of the invention: Example IA Synthesis of compounds Nα 1009 and 1010 according to Preparation A 3-aminoquinuclidine (R1-H, n=0, X-mol) and 2-methylthiocyclohebutoimidazole [
Compound of formula (2)) 2.79g (0°0159 mol)
was refluxed in 20 ml of n-amyl alcohol for 5 hours.

After concentrating the reaction mixture using an evaporator, it was treated with silica gel column chromatography (developed with dichloromethane:methanol-4=1) to obtain the compound Nα1.
0.76 g (yield 19%) of 009 was obtained. 0.76 g of this compound was dissolved in 5 ml of acetonitrile, 0.31 g of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, washed with 201 nl of ether, filtered and dried to give 0.44 g of compound Nα1009 hydrochloride, i.e. compound Nα1010 as yellow crystals (51% yield).
) obtained. Melting point 295-298°C (decomposed).

The compound of the present invention synthesized in a similar manner to this method was
Shown in the table. In this table, Y represents the yield of the free compound based on 2-methylcyclohebutoimidazole, and Y2 represents the yield of the salt based on the free compound (both in mol %).

Table 2 (2) Table 2 (3) Table 2 (4) Table 2 (5) Table 2 (6) Table 2 (7) Table 2 (8) Table 2 (9) 2 Table (10) Table 2 (11) Example 2 Synthesis of compound Nα1009 according to production method B 2.00 g (0,0159 mol) of 3-aminoquinuglydine, 2-methylthioamidine sulfate [compound of formula (4) )2.21g(
0.0159 mol) and 20 rnl of water were charged together, stirred at room temperature for 50 hours, and then concentrated using an evaporator. The residue was crystallized by adding 20 ml of acetone, filtered and dried to obtain 4.42 g of the compound of the following formula. Next, this compound 2.
42g of 28% sodium methoxide methanol solution 2
．． 15g, l-ropolone methyl ether 1.51
g and 20 g of ethanol were added, and the mixture was refluxed for 3 hours. The reaction mixture was extracted with dichloromethane, the dichloromethane layer was concentrated, and the concentrate was treated with silica gel chromatography (developed with dichloromethane:methanol-4:1) to obtain 0.31 g of compound Nα1009 (yield 11%).
) obtained.

Similar to this method, the compounds shown in Table 3 were synthesized. Y and ¥2 in the table have the above meanings.

(Leaving space below main text) Table 3 Example 3A Synthesis of compounds N111065 and 1066 by production method C Tropolone methyl ether 5.00 g (0,0368
mol), guanidine sulfate 3.97 g (0,0368 mol), 28% sodium methoxide methanol solution 7.1
0g (0,0368 mol) and 30'ml ethanol
were added together and refluxed for 5 hours. Add 10 parts of the reaction mixture to 10 parts of water.
0 ml and extracted twice with 200 ml each of dichloromethane. The dichloromethane layer was concentrated, and the residue was dissolved in 3o7T11 of dichloromethane. 4.70 g (0.0300 mol) of phenyl chlorocarbonate was added thereto, and the mixture was stirred at room temperature for 3 hours. 30ml of water was added to the reaction mixture, the dichloromethane layer was concentrated, and the concentrate was washed with hexane to obtain 3.13g (yield: 4o%) of cyclohebutoimidazole-2-phenylcarbamate of the following formula as yellow crystals. . Melting point: 223-225°c0 3.13g of the obtained compound was added to 20ynl of dichloromethane.
4.64 g (0,0240 mol) of 28% sodium methoxide methanol solution and 1.51 g (0,0120 mol) of 3-aminoquinuclidine were added together and stirred for 5 hours. Pour the reaction mixture into 30ml of water,
The dichloromethane layer was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=
3:1 expansion), the compound Nα1 of the formula
065 as yellow crystals 1.44g (yield 40.3%)
Obtained. Melting point: 280-283°C. This compound is converted into a hydrochloride salt in the same manner as in Example IA, resulting in the compound Nα106
6 was obtained in 72% yield. Melting point>300℃.

The compound of the present invention synthesized in the same manner as this method was
Shown in the table. Y and Y2 in the formula have the above meanings.

(Margins below this page) Table 4 (1) Table 4 (2) (Margins below this page) Example 4A Compound N (2-aminocyclohebutoimidazole [formula (8
) can be synthesized in the same manner as in Section 1 of Example 3A. 2.00 g (0,0138 mol) of this compound was dissolved in 20 ml of dichloromethane, 2.79 g (0,0276 mol) of triethylamine and 1.94 g (0,0138 mol) of benzoyl chloride were added, and the mixture was refluxed for 3 hours. The reaction solution was poured into 10 ml of water, the dichloromethane layer was concentrated using an evaporator, and then treated with silica gel column chromatography (developed with ethyl acetate) to obtain 1.31 g (yield 38%) of the compound Nα1085 of the following formula as yellow crystals. It was done. Melting point: 148-150°C0 Compounds shown in Table 5 were synthesized in a similar manner to this method.

Table 5 Example IB Tablets containing the active ingredient IO■ are manufactured as follows.

Active ingredients per tablet: 10 mg Corn starch 55 ■ Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 5 mg (as a 10% aqueous solution) Carboxymethyl cellulose/calcium lO ■ Magnesium stearate 4 ■ Talc
1 ■ Total 120 ■ Pass the active ingredient, starch and microcrystalline cellulose through an 80 mesh sieve and mix thoroughly. The obtained powder is mixed with a polyvinylpyrrolidone solution and granulated, and then passed through an 18-mesh sieve. The granules produced in this way are
Dry at 0°C and sieve again using an 18-mesh sieve. Calcium carboxymethyl cellulose and magnesium stearate and talc, previously sieved through an 80 mesh sieve, are added to the granules and, after mixing, are produced in a tablet machine into tablets each weighing 120 square centimeters.

Example 2B Tablets containing 200 mg of active ingredient are manufactured as follows.

Active ingredients per tablet: 200 ■ Corn starch 50 ■ Crystalline cellulose
42mg light silicic anhydride
7mg magnesium stearate
1) Total of 300 mg Pass the above ingredients through an 80 mesh sieve and mix thoroughly. The resulting powder is compression molded to produce tablets weighing 300 square meters.

Example 3B Sublingual tablets containing 2.5 μ of active ingredient are manufactured as follows.

Active ingredients per sublingual tablet: 2.5mg mannitol 56.5mg hydroxypropyl methylcellulose 5.0mg magnesium stearate], 5mg total 65
．． 5) Pass the above ingredients except magnesium stearate through an 80 mesh sieve and mix thoroughly. Add 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 a suitable punch.

Example 4B Capsules containing 0.5 μ of active ingredient are prepared as follows.

(Margin below essence) Active ingredient per capsule: 0.5■Lactose
98.5 ■Magnesium stearate 1. Omg total 100.0■ Combine the above ingredients and pass through an 80 mesh sieve to mix thoroughly. Fill 100 square capsules of the obtained powder.

Example 5B Capsules containing 100 ml of active ingredient are prepared as follows.

Active ingredients per capsule: 100 ■ Corn starch 40 ■ Lactose
5■Magnesium stearate 5■Total 150■ Mix the above ingredients and pass through an 80 mesh sieve to mix thoroughly. Fill 150 square capsules of the obtained powder.

Example 6B A ready-to-dissolve injection in a vial containing 5 cm of active ingredient is prepared as follows.

Active ingredient per vial: 5 ■ Mannitol 50 ■ When using, 1 portion of distilled water for injection
Dissolve and use 7nl.

Example 7B Ampoule injections containing 100 μg or 500 μg of active ingredient are produced as follows.

100 μg or 500 μg of active ingredient per ampoule
g Add dilute hydrochloric acid to pH 3.5 Sodium chloride injection Appropriate amount total 11 Example 8B An ampoule injection containing 50 ml of active ingredient is prepared as follows.

Active ingredient per ampoule 50 ■ Sodium chloride 1.8 ■ Distilled water for injections Total quantity 2 mj' Example 9B A syrup containing 5 ■ active ingredient is prepared as follows.

Active ingredient per dosage unit: 5mg sucrose
2.5g glycerin
0.5g distilled water
Appropriate amount total: 5.0 rnl Appropriate amounts of buffering agents, coloring agents, flavoring agents, and preservatives can be added as necessary.

Example 10B A composition containing 10 μg or 100 μg of active ingredient is prepared as follows.

Active ingredient 10μg or 100μg
Benzalkonium chloride 0.1 mg Physiological saline 0.6 ml or 0.9 mj' Distilled water appropriate amount Total 1.0 ml Filter the resulting solution with a 0.2 μm filter and fill it into a spray pump, or gelatin Soak a shaped sponge with the filtrate.

Example 1IB A suspended aerosol containing 20 μ of active ingredient is prepared as follows.

Active ingredients per can 20 ■ Oleic acid 4 ■ Trichlorofluoromethane 4.5 g Dichlorodifluoromethane 12.5 g Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C, and activated Mix the ingredients into the solution. This suspension is metered into an aluminum aerosol bed and cyclodifluoromethane is pressure packed into this bed.

Example 12B An adhesive patch containing 17.5 μ of active ingredient is produced as follows.

10 parts of ammonium polyacrylate are dissolved in 60 parts of water. Meanwhile, add 2 parts of glycerin diglycidyl ether to 10 parts of water.
Dissolve while heating. On the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water, and 1 part of the active ingredient were dissolved with stirring. Next, while stirring the aqueous solution of ammonium polyacrylate, an aqueous solution of glycerin diglycidyl ether and an aqueous solution containing an active ingredient of polyethylene glycol were added and mixed, and a drug-containing hydrogel solution was applied to a flexible plastic film in which the amount of active ingredient was 0 per square centimeter. .5 cm, cover the surface with release paper and cut into 35 square centimeters to prepare the preparation.

Example 13B An adhesive patch containing the active ingredient IO is prepared as follows.

100 parts of sodium polyacrylate, 100 parts of glycerin
A mixed aqueous sol solution containing 150 parts of water, 0.2 parts of triepoxypropyl isocyanurate, 100 parts of ethanol, 25 parts of isopropyl myristate, 25 parts of propylene glycol, and 15 parts of the active ingredient was prepared.

Next, this sol solution was applied to a thickness of 100 μm on the nonwoven surface of a composite film consisting of a rayon nonwoven fabric and a polyethylene film to form a drug-containing adhesive layer. The content of release aids (isopropyl myristate and propylene glycol) contained in this layer was approximately 20% by weight. Thereafter, it is crosslinked at 25° C. for 24 hours, a release film is attached to the adhesive interface, and this is further cut into 35 square centimeters to prepare a preparation.

Regarding the biological activity of the compound of general formula [■] used in the present invention, in vitro and 1nvjv tests were conducted as follows.
o test was conducted.

In anesthetized rats, 5-HT (20-50 μg/
The initial rapid reflex bradycardia (initial abrupt c
The inhibitory effect of the compound of general formula (I) on ardiac slowing) and the concomitant reduction in blood pressure was investigated by varying the dosage.

Furthermore, the inhibitory effect of the compound of general formula (I) on 5-HT-induced tachycardia was also investigated using atrial specimens isolated from rabbits. Furthermore, the enhancing effect of the compound of the general formula [■] on contraction induced by electrical stimulation was investigated using gastric strip specimens extracted from guinea pigs, ie, gastric fundus circular muscle specimens or longitudinal muscle specimens of the curvature minor.

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

Furthermore, secretory diarrhea induced by giving cholera toxin to mice;
Alternatively, examine to what extent functional abnormalities such as increased gastrointestinal motility induced by administration of 5-HTP, a precursor of 5-HT, to mice are suppressed by the test drug of formula [1]. did.

Furthermore, vomiting induced by 5-FU, cisplatin, cyclophosphamide, doxorubicin, CuSO4, or apomorphine was induced in dogs, and the suppressing/preventing effects of the test drug on vomiting were investigated. Furthermore, instead of dogs, animals such as ferrets and sunkus were used to examine the antiemetic effect of -formula CI).

On the other hand, the inhibitory effect of the test drug on arrhythmia induced using norepinephrine in anesthetized rats was also investigated. Furthermore, the analgesic activity, anxiolytic activity, antischizophrenia activity, etc. of the test drug were also tested in experimental animals. Specifically, mice were placed under stressful conditions, administered a test compound, and normalization of approach-oriented social behavior was observed. We also investigated the improvement and antagonism of rhinitis, reflex effects of reduced lung function, etc.

Experimental Example I B-J Reflection Fozard, JRand Ho5t
, M: Br1tishJ, Pharmacol;
77; 520.1982), the effect on the B-J reflex was investigated. That is, urethane (1.2 g/kg
i, P,) Blood pressure and heart rate of anesthetized rats were recorded by polygraph. Serotonin (5-HT) 40mg/ for rats
After confirming that stable reflex bradycardia occurred after administering 5-HT kg intravenously, the test drug was administered intravenously, and 5 minutes later, 5-HT 40 mg/kg was administered again. The inhibition rate was determined by comparing the response with the response before administration of the test drug. In addition, if the test drug is insoluble in water and cannot be administered intravenously,
- Administered intraperitoneally 20 minutes before HT administration. The result is the 6th
Shown in the table.

Experimental Example 2 Right Atrium Extracted from a Rabbit The heart of a rabbit anesthetized with bendoparbital was removed to prepare a right atrium. Krebs-Henseleit solution (Krebs-Henseleit solution) to which 2 μM atropine was added in advance
suspend the right atrial specimen in a Magnus tube filled with
Tachycardia was induced by adding 8 μg/lnl of 5-HT.

The test drug was added to the Magnus tube 5 minutes before the administration of 5-HT.
- The inhibitory effect of HT on tachycardia was determined. Experimental example 3
Guinea pig pre-excision strip specimen Bachheit, KHet al.
: J, Pharm.

The stomach of a Hartley guinea pig that had been fasted for 24 hours was removed according to the method of Pharmacol., 37; 664, 1985), and a longitudinal muscle specimen of the small incision was prepared and suspended in a Magnus tube. When the contraction of the gastric strips caused by electrical stimulation became stable, the test drug was added, and the effect of increasing contractile force was observed. The results are shown in Table 6.

° Experimental Example 4 Rat gastric emptying capacity A 1.5% methylcellulose suspension containing 0.05% phenol red was orally administered to Wistar rats fasted for 24 hours as a test meal, and 15 minutes later, the stomachs were removed. The amount of residual gastric contents was determined by measuring the content of phenol red remaining in the stomach. To measure phenol red, add O, IN Na to the removed stomach.
Add OH, crush with a polytron, remove protein with trichloroacetic acid, and make alkaline with 0.5N NaOH.
This was done by measuring absorbance at 560 nm. The gastric emptying rate (GER) is calculated using the following formula using the absorbance of the gastric contents residue of the animal immediately after administration of the test meal (time zero animal) and the absorbance of the gastric contents residue of the test drug-administered animal. Ta. The results are shown in Table 7.

Experimental Example 5 A venous cannula for drug administration was implanted into the jugular vein of a Suncus (27-38 g) under ether anesthesia 12 hours before the start of the Suncussisplatin emesis experiment. The experiment was conducted by administering the test drug subcutaneously to the back, and 30 minutes later administering cisplatin (40 μg/kg) through an implanted intravenous cannula, and recording the number of vomitings over a 2-hour period. The results are shown in Table 8.

Experimental Example 6 Anesthetizing gastric movement An adult mongrel dog (8-13 kg) was anesthetized with an intravenous administration of bendoparbital 30 μ/kg, and after laparotomy, contractile movements in the direction of the circular muscle were recorded on the serosa surface of the antrum of the stomach. Strain gauge (Star Medical: F-081S)
) was sewn. The test drug was left for 30 minutes or more after the surgery, and after gastric spontaneous movement was recorded, the test drug was administered intravenously to examine its effect on gastric spontaneous movement. In this experiment, the compound Na1
001.2006 and 2010 showed a promoting effect on spontaneous gastric movements, while the control GR38032F did not show this effect.

Experimental Example 7 Mouse Acute Toxicity The test drug was intraperitoneally administered to 2 to 5 5-week-old ddY male mice, general symptoms were observed according to Irwin's multifaceted observation method, and mortality was determined within 24 hours after administration. I checked to see if it existed. The results are shown in Table 9.

(Margins below essence) Table 7: Rat gastric emptying capacity *P<0.05 Table 8: Sunkusisplatin emesis mean + S, E,
* P < 0.05 Table 9: Mouse Acute Toxicity As is clear from the results of the above experimental examples, - Formula CI)
The compound is the existing metoclopramide, cisplatin, B
RL24924, IC3205-930, GR3803
Compared to 2F, MDL 72222, etc., it has excellent pharmacological effects that are equal to or greater than those of 2F and MDL 72222.

Therefore, the compound of general formula [1) of the present invention has its 5-H
Based on its antagonistic effect on T3 receptors, it can be applied to the treatment and improvement of various diseases and symptoms caused by overstimulation of receptors in the following organs. Examples of organs include the gastrointestinal system, cardiovascular system, respiratory system, central nervous system, and peripheral nervous system.

In the gastrointestinal system, by stimulating and increasing gastrointestinal motility, it slows gastric emptying and emptying due to decreased gastric motility.
Stomach/esophageal reflux, flatulence, indigestion, gastric ulcer, diabetic renal failure, ischemic bowel disease, obesity, irritable bowel syndrome (IC3)
), it can improve and treat pain in various parts of the abdomen due to colon distention associated with IC3, various visceral pains, after surgery or childbirth, gastrointestinal pain such as abdominal spasm, and gastrointestinal motility disorders.

In addition, when administering anticancer drugs such as cisplatin, cyclophorosphamide, doxorubicin, and 5-FIJ, which have cell-killing effects, and when irradiating the chest, abdomen, and other parts of the body with radiation, X-rays, and neutron beams, Alternatively, it can be used as an antiemetic to suppress nausea and vomiting as a result of gastric stasis, migraine, indigestion, ulcers, and the like. Furthermore, it can be used as a gastric emptying promoter for radiological examinations and the like.

In the cardiovascular system, arrhythmia, vascular spasm, etc. can be prevented and treated. In the respiratory system, diseases in the bronchus and lungs, such as pulmonary emboli such as miliary emboli, reflex effects of decreased lung function,
Prevents and prevents nasal diseases such as rhinitis and serotonin-induced pancreatic disease.
Can be treated. In the central nervous system and peripheral nervous system,
Prevention and treatment of anxiety, hallucinations, delusions, chronic illnesses, schizophrenia, etc., drug withdrawal/discontinuation syndrome from addictive inducers such as psychostimulants, opiates, alcohol, and nicotine;
Improving and treating withdrawal symptoms, preventing and reducing the progression of dependence,
Furthermore, it can be used as a medicine for the prevention and treatment of migraine, cluster complex headache, and trigeminal neuralgia.

The compound of general formula (I) of the present invention is useful as a preventive, ameliorating or therapeutic agent for the above-mentioned diseases, and the diseases to which it can be applied are not limited to these. Furthermore, the general formula of the present invention (
When the compound I) was tested for toxicity, it was found that its toxicity was low and it could be used as a safe drug.

〔Effect of the invention〕

The compound of general formula CI] of the present invention was found to have excellent pharmacological activity as shown in Experimental Examples 1 to 6 and Tables 6 to 8. Furthermore, the toxicity of the compounds of the present invention is generally weak, as shown in Experimental Example 7 and Table 9. The compound of general formula CI) of the present invention is thus generally considered to be a highly active, lowly toxic, and highly safe drug, and is suitably used as a prophylactic, ameliorating, or therapeutic agent for the various diseases mentioned above. It is expected.

Claims (2)

[Claims] (1) General formula I ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ [I] [In the formula, R^1 represents a hydrogen atom, a lower alkyl group, or a benzoyl group, and Z represents a single bond, a lower alkylene group, or -CONH -(CH_2)_a-(a is 0, 1 or 2
), and X is the following formula ▲ Numerical formula, chemical formula, table, etc. , may be mono- or tetrasubstituted, and the ring member nitrogen atom may be substituted with a lower alkyl group, benzyl group, halogenated phenoxyalkyl group, or halogenated benzyl group, and any two ring member carbon atoms Alternatively, any one ring member carbon atom and ring member nitrogen atom may be bonded by a linear lower alkylene group having 1 to 3 carbon atoms), ▲Mathematical formulas, chemical formulas, tables, etc.▼ (R^3 indicates a halogenated benzyl group), ▲Mathematical formulas, chemical formulas, tables, etc.▼ (d is a number of 0 or 1, and the ring may be substituted with an amino group), halogenated phenyl group, ▲Mathematical formula , chemical formulas, tables, etc. ▼ (Y is ▲ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or -SO
(R^4 and R^5 each independently represent a hydrogen atom or a lower alkyl group)] A cycloheptoimidazole compound represented by or a pharmacologically acceptable salt thereof. (2) A pharmaceutical composition containing a cycloheptoimidazole compound represented by the general formula [I] or a pharmacologically acceptable salt thereof as an active ingredient.