JPH04208283A - New heterocyclic compound and pharmaceutical composition containing the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [group of formula II is formula III (R<1>, R<2>, R<7> and R<8> are H or lower alkyl; R<3> to R<6> are H, lower alkyl, etc.; R<3> and R<4> or R<5> and R<6> may be bonded with each other to form an oxo group; X is H, amino, etc.) or formula IV (R<12> is H, hydroxyl, etc.; a is 1 or 2); R<9> to R<11> are H, halogen, etc.; when X is H, formyl, etc., at least one of R<1> to R<11> is not H] or its pharmacologically permissible salt. EXAMPLE:The compound of formula V. USE:A therapeutic agent for dyspepsia, gastric ulcer, etc. PREPARATION:The objective compound can be produced by reacting a compound of formula VI with a compound of formula VII in a solvent, hydrolyzing the product with an acid and then neutralizing with an alkali and reacting the resultant compound of formula VIII with an alkyl halide in the presence of an acid acceptor in a reaction solvent.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to novel cycloheptoimidazole compounds, their pharmacologically acceptable salts or optically active forms, and human-use or It relates to a new drug for animals, and more specifically, it stimulates and enhances gastric motility, thereby slowing 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. Symptoms and vomiting caused by irradiation with radiation, etc. - 5 = Medications to improve and treat vomiting, as well as anxiety, hallucinations, delusions,
It relates to medicines for preventing and treating mental and neurological disorders of the central nervous system and peripheral nervous system, such as chronic illness, schizophrenia, migraines, cluster complex headaches, and trigeminal neuralgia.

[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 a 2-(1-piperazinyl)noclohep-imidabul derivative and its use as a therapeutic agent for hypertension. In addition, the present inventors have found that some of the above-mentioned 2-(1-piperazinyl)cycloheptoimidazole derivatives have psychotropic activity, that is, antipsychotic activity, particularly antidepressant activity, etc., and have found that some compounds have psychotropic activity, that is, antipsychotic activity, especially antidepressant activity, etc. Filed a patent application for a new medicinal use of medicine (Japanese Patent Application Laid-Open No. 60-260516)
. Further, JP-A-64-3172 discloses cycloheptoimidazole derivatives having anti-inflammatory and analgesic effects.

On the other hand, recently, tetrahydrocarbazolone derivatives
Compounds such as R38032F or henzamide derivatives such as sacopride, BRL24924, or 5-HT3
It was investigated as a receptor antagonist, and its anti-emetic activity, gastric motility-promoting effect, as well as its anxiolytic and anti-schizophrenic effects were clarified.
Clinical research is also progressing (1. Monkovic; D
rugs of the future, shellfish, 44.
1989 and J, R.

Fozard; Trends in Pharmac
ol, Sci, 8.44°+987).

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 carried out intensive research thinking that we could develop a highly safe drug with new characteristics not found in the above compounds, and found that a specific cyclohebutoimidazole compound
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]

In the present invention, general 2 and R8 independently represent a hydrogen atom or a lower alkyl group, and R3, R4, R5 and R6 independently represent a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group. group, aminocarbonyl group or lower alkylamino lower alkyl group, or R3
and R4 or R5 and R6 may be bonded to each other to form an oxo(20) group, and X is a hydrogen atom, an amino group, a formyl group, a lower alkylaminocarbonyl group, a lower alkyl group, a diphenylmethyl group ( (one or both phenyl rings may be substituted with a halogen atom), a lower alkylsulfonyl group, a phenylsulfonyl group, a halogenated phenylthio group, a phenylthiocarbonyl group, or -(CI+2), -R"(R" is an amino group, a lower alkylamino group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a group optionally substituted with a halogen atom or a lower alkylcarbonylamino group, a halogenated benzoyl group, a phenoxy lower alkyl group carbonyl group, aminocarbonyl group, halokenated phenylaminocarbonyl group, (R" represents a lower alkyl group), a is a number of 1 or 2, b is an integer of 1 to 4, and C is a number of 0 or 1. , R12 represents a hydrogen atom, a hydroxyl group, a lower alkyl group, an amino lower alkyl group, an elementary atom, a lower alkyl group, or a lower alkylcarbonyl group) or a piperidino group, and R9, Rlo and R1+ are independent of each other. represents a hydrogen atom, a halogen atom, a nitroso group, a lower alkyl group, an amine group, a lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonylamino group, or a piperazino group, or RIO and R11 are connected. -CH= CH-CH= CH- may be formed, provided that when X is a hydrogen atom, formyl group, lower alkyl group or lower alkoxycarbonyl group, at least one of R1 to R1+ is a non-hydrogen atom. A cyclohebutoimidazole compound or a pharmacologically acceptable salt thereof.

The present invention further provides a pharmaceutical composition containing a cyclohebutoimidazole compound represented by Formula I or a pharmacologically acceptable salt thereof as an active ingredient.

In the general formula (I) that specifies the cyclohebutoimidazole compound of the present invention, the lower alkyl group may be linear or branched, and preferably has 1 to 6 carbon atoms. Specific examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, 5eC-butyl, 1-butyl, t-butyl, n-pentyl, 1-pentyl, neopentyl, and isomers of One example is hexyl.

In lower alkoxy, lower alkylthio groups, lower alkylamino groups, lower alkoxycarbonyl groups, lower alkylaminocarbonyl groups, lower alkylsulfonyl groups, the alkyl moiety thereof preferably has 1 carbon atom.
~6, and may be linear or branched.

Lower alkoxy groups include methoxy, ethoxy, n-
Examples include propoxy, i-propoxy, n-butoxy, 1-butoxy, 5ec-butoxy, and isomer pentyloxy. Examples of the lower alkylthio group correspond to these alkoxy groups, such as methylthio, ethylthio, n- or 1-propylthio, rr-1i- or 5ec-butylthio.

Examples of lower alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- or i-propoxycarbonyl, n-1i-1sec- or t-butoxycarbonyl.

Examples of lower alkylamino groups include methylamino, ethylamino, n-propylamino, i-propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino, and butylamino. .

Examples of the lower alkylamino lower alkyl group include methylaminomethyl, methylaminoethyl, methylaminopropyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, methylethylaminoethyl, and methylbutylaminoethyl.

Lower alkylaminocarbonyl groups include methylaminocarbonyl, ethylaminocarbonyl, n- or l
Mention may be made of -propylaminocarbonyl, n-11-1SeC- or t-butylaminocarbonyl, as well as the corresponding dialkylaminocarbonyl.

Examples of the lower alkylcarbonyl group include methylcarbonyl, ethylcarbonyl, n- or 1-propylcarbonyl, n-11-15eC- or t-butylcarbonyl.

Lower alkylcarbonylamino groups include methylcarbonylamino, ethylcarbonylamino, n- or l
-propylcarbonylamino, n-11-1sec= or t-butylcarbonylamino, and the nitrogen atom thereof may be substituted with a lower alkyl group.

Examples of the amino lower alkyl group include aminomethyl, aminoethyl, aminopropyl, and aminobutyl, with aminomethyl and aminoethyl being preferred.

Examples of the lower alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, n- or i-propylsulfonyl, n-11-1sec- or t-butylsulfonyl.

Examples of halokene atoms include fluorine, chlorine, bromine, and iodine. In halogenated phenyl, hendiyl, phenoxy, phenylthio, etc., the Hensen ring may have one or several identical or different halo-ken atoms.

Examples of the phenoxy lower alkyl group include phenoxymethyl group, phenoxymethyl group, and phenoxyprobyl group.

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

(Margin below essence) Table 1 pH 14 // // Hydrochloride 13 // // // //
Hydrochloride 26
Hydrochloride 3Q // // // //
Hydrochloride -+ 17- 66 Dihydrochloride 7Q
// // // // Hydrochloride 74 Hydrochloride 78
〃〃 Hydrochloride 134///
/// Hydrochloride 138 ” ”
Hydrochloride 154
Hydrochloride ■3 1513 // // // //
Hydrochloride 162 〃〃
Hydrochloride 166
Hydrochloride 170〃 Hydrochloride 174 〃〃 Hydrochloride 113 178 〃” Hydrochloride 182〃〃 Hydrochloride 113
6// l/ // Hydrochloride 19Q////// Hydrochloride 194
〃” Hydrochloride 198/
///// Hydrochloride 202〃〃
Hydrochloride 206
Hydrochloride 210″″
Hydrochloride 214 // //'
// Hydrochloride 218〃〃
Hydrochloride 222////l/
Hydrochloride 226//////
Hydrochloride ■3 230 ” ”
Hydrochloride 234〃〃 Hydrochloride 233////// Hydrochloride 242
″ ″ Hydrochloride +13 244 ″ ″ ・ Hydrochloride 246 〃 〃
Maleate 25
0 〃 〃
Maleate 254
/////
Maleate 258/
/ // // Hydrochloride 262////l/ Hydrochloride 266//
//// Hydrochloride 270〃〃
Hydrochloride -29 = Shi■3 274〃〃 Hydrochloride 278
〃 ~ Hydrochloride 282
hydrochloride 286
／／ ／／ ／／
Hydrochloride = 30- 290 〃'' Hydrochloride 297 〃〃 Tartrate 301 〃 〃
〃 p-Toluenesulfonate 3Q
5////ll Sulfate 310″
″ Hydrochloride 314〃〃
Hydrochloride 318//////
Hydrochloride 322/)//l/
Dihydrochloride 326// // l/
Dihydrochloride 33Q//////
Maleate 502
Dihydrochloride 5Q6//////
Hydrochloride 518〃
Dihydrochloride 522//Ill/ Dihydrochloride 526////// Hydrochloride-34
= 530 Hydrochloride 5
34////// Hydrochloride 538
The dihydrochloride compound represented by the formula CI) can be produced, for example, by the method described below.

Manufacturing method A m (2) (3) R.

Manufacturing method B: p“ Manufacturing method C Manufacturing method.

Manufacturing method E In the manufacturing method, the reaction between compounds (1) and (2) is carried out using an acid scavenger such as potassium carbonate in an amount of 0.8 to 3.0 mol, preferably 1.0 mol, per 1 mol of compound (1). ~2.0
molar amount of a solvent such as a mixed solvent of acetone and water (acetone/water molar ratio -20 to 1, preferably 15 to 1)
3) under reflux for 1 to 10 hours, preferably 2 to 7 hours, thereby producing compound (3). In the reaction between the obtained compound (3) and thiourea, an acid scavenger such as thorium methoxide is added in an amount of 0.8 to 2.0 mol, preferably 1.0 to 1 mol, per 1 mol of compound (3). .6 mol present in a solvent such as methanol, ethanol, dichloromethane or acetonitrile at 20-80°C, preferably 40-70°C for 1-20 hours, preferably 3-10
Time is done. Next, a methylating agent such as methyl iodide is added in an amount of 1 to 6 mol, preferably 1.0 mol, per 1 mol of compound (3).
When 3 to 4 moles are added and reacted at 20 to 5°C for 1 to 20 hours, preferably 3 to 10 hours, a compound is produced. The reaction between compound (4) and amine (5) can be carried out without a solvent if they are mutually dissolved under the reaction conditions, but is usually carried out in a solvent. As the solvent, alcohols, particularly n-butanol, n-amyl alcohol, n-hexyl alcohol, etc. are preferably used. This reaction is carried out at 80-170°C, preferably 100-150°C, and
The reaction is carried out for 20 hours, preferably 2 to 10 hours, and the desired compound (6) is produced.

You can also react in the same way.

In production method B, the reaction between the amine (5) and methylthioamidine sulfate is preferably carried out in water at room temperature for 2 to 40 hours.
The reaction is carried out for ~30 hours, thereby producing compound (7). Next, compound (7) and compound (3) were combined into compound (
0.8 to 2.0 mol per 1 mol of 3), preferably 1.
The desired compound (6) can be obtained by reacting in a solvent, preferably an alcohol such as methanol or ethanol, in the presence of 0 to 1.6 mol of an acid scavenger such as strium methoxide. Also in this production method, amine (5)
Pyrrole, piperidine, thiomorpholine, etc. can be used instead.

In production method C, the reaction of compounds (8) and (9) can be carried out under the same conditions as the reaction of compounds (4) and (5) in production method A. Compound (11) is obtained by hydrolyzing the obtained compound QO) with an acid such as hydrochloric acid and then neutralizing with an alkali such as sodium hydroxide. Next, compound (11) and alkyl halide were added to 1 of compound (11).
0.8 to 3.0 moles, preferably 1.0 to 2.0 moles.
in the presence of an acid scavenger such as 0 mol of sodium hydroxide in a reaction solvent such as dimethylformamide, dimethyl sulfoxide at 20-100°C, preferably 30-80°C,
When reacting for 2 to 20 hours, preferably 4 to 10 hours, compound (12) is obtained.

In the production method, the reaction between compound (9) and methylthioamidine sulfate can be carried out under the same conditions as the reaction between compound (5) and methylthioamidine sulfate in production method B. The obtained compound (1) is reacted with compound (3) in the same manner to form compound α0, and the following treatment is carried out in the same manner as in production method C.

In production method E, the reaction between compound (14) and alkyl halide can be carried out in the same manner as in production method C, and compound (
151 is obtained.

= 41- When the compound of the general formula [■] has an asymmetric carbon atom, it is usually obtained as a racemate, and is separated into optically active forms by an optical resolution method that avoids diastereomeric salt formation with an optically active acid. I can do it.

Naturally, it is also possible to synthesize optically active compound (I) from optically active starting compounds.

Pharmaceutically acceptable salts of the compound of general formula [■] 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, phthalene Salts formed from acids that form non-toxic acid addition salts containing pharmacologically acceptable anions such as sulfonate salts and their hydrates, and quaternary ammonium salts and their hydrates. Included. These salts may be formed during the synthetic route or may be obtained by reacting the free compounds with the acids mentioned above.

-42= According to the research conducted by the present inventors, the compound of general formula CI) of the present invention is a gastrointestinal motility enhancer that has 5-HT3 receptor antagonistic activity and improves delayed gastric emptying. It has been revealed that it is useful as an antiemetic, an anxiolytic, a schizophrenia treatment, a migraine treatment, a visceral pain treatment, an antiarrhythmic agent, and a respiratory disease treatment.

Compounds of general formula CI) are usually used in the form of pharmaceutical compositions and can be administered by various routes such as oral, subcutaneous, intramuscular, intravenous, intranasal, percutaneous and rectal routes.

The present invention encompasses pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of general formula CI) or a pharmacologically acceptable salt thereof as defined above as active ingredient. Pharmaceutically acceptable salts include, for example, the acid addition salts and quaternary annimoum 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 papules, soft and hard serums. It can be in the form of chin capsules, herbal medicines and sterile packaged powders. Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, microcrystalline cellulose, gum arabic, calcium phosphate, algine-1.
, calcium silicate, microcrystalline cellulose, polyhinylpyrrolidone, gum tragacanth, seratin, syrup, methylcellulose, carboxymethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert polymers, Water or mineral oil.

Either solid or liquid compositions may contain fillers, binders, lubricants, wetting agents, disintegrating agents, emulsifying and suspending agents, preservatives, sweetening agents, or flavoring agents. 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 and the like. 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 will generally contain (1,001 to 500 mg, preferably 0.005 to 250 mg) per unit dosage form.
Contains active ingredients.

Compounds of general formula CI) 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.

Compounds of general formula CI) may be effective gastric motility enhancers, antiemetics, anxiolytics, antipsychotics, antiarrhythmics, etc. on their own or, if necessary, in combination with one or more other equivalent agents. Can also be administered in combination.

The production and biological activity of the compound of general formula [■] of the present invention will be explained in more detail below with reference to a series of Examples, Reference Examples, and Experimental Examples, but the present invention is not limited thereto. do not have. Furthermore, in the following examples of pharmaceutical compositions, one or more compounds of the general formula CI) are used as active ingredients.

〔Example〕

Synthesis of compounds of the invention.

Example IA Synthesis of compounds Nα153 and 154 according to Preparation A Tropolone (compound of formula (1) where R=H) 75.0 g
(0,614 mol), 480 g of acetone, 48 g of water, 127.2 g (0,922 mol) of potassium carbonate and 77,/I[H (0,614 mol) of dimethyl sulfate were prepared in a 1p equipped with a thermometer and a stirring blade. The mixture was placed in a flask and refluxed for 8 hours. The reaction mixture was then poured into 500 mj of water,
Extract twice with 500 ynl of dichloromethane and concentrate the dichloromethane layer to obtain tropolone methyl ether as an oil with 78,5[! (Yield 90.4%, based on tropolone) was obtained.

Tropolone methyl ether 20.0 g (0,147
mol) in 150 mj of ethanol, 31.2 g of 28% sodium methoxide methanol solution (0,16
2 mol) and 12.3 g (0,162 mol) of thiourea were added, and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, 24.1 g (0.170 mol) of methyl iodide was added, and the mixture was refluxed for 2 hours.

The reaction mixture was concentrated using an evaporator, and the residue was separated by silica gel column chromatography (developed with ethyl acetate).
g (yield 50.2%, based on 1-robon methyl ether)
Obtained.

2-methylthiocyclohebutoimidazole 1.00g (
0,0057 mol) and 0.5 2-methylpiperazine
7 g (0,0057 mol) were refluxed in 5 ml of n-amyl alcohol for 6 hours. The reaction mixture was concentrated and the residue was treated with silica gel chromatography (developed with dichloromethane methanol-5.1) to give 2-(2-methylpiperazino)-cycloheptoimidazole (compound Nα153) of the following formula as an oil. 0.50g
(0,0022 mol, yield 38%) was obtained. The obtained oil was dissolved in 5 ml of acetonitrile, and 0.2 ml of concentrated hydrochloric acid was added.
2 g (0,0022 mol) was added at room temperature and stirred for 30 minutes.

The reaction mixture is concentrated, the residue is washed with 10 ml of hexane, filtered and dried to give the hydrochloride salt of compound Na153,
That is, 049 g of compound Nα154 was obtained as yellow crystals. Melting point 170°C0 The compound of the present invention synthesized in the same manner as this method was
Shown in the table. In this table, Yl represents the yield of the free compound based on 2-methylthione clohebutoimidazole (4), and Y2 represents the yield of the salt based on the free compound (both moles: 96).

(Margin below essentials) Table 2 (1) Table 2 (2) Table 2 (3) Table 2 (4) Table 2 (5) Table 2 (6) Table 2 (7) Example 2A Synthesis of compounds Nα153 and Nα154 by production method B 2
-Methylpiperazine 25.0 g (0,250 mol)
and 34.8 g of 2-methylthioamidine sulfate (
0,250 mol) was stirred in 150 ml of water at room temperature for 48 hours, and then concentrated using an evaporator. 50 ml of acetone was added to the residue to crystallize it, which was filtered and dried to obtain 32.9 g (yield: 69%) of the compound of the following formula as white crystals. Melting point 105°C0 This guanidine sulfate 10.0g (0,0524 mol)
, tropolone methyl ether 6,41g (0,0471
mol) and 8,17 g (0,0942 mol) of 28% sodium methoxide methanol solution in 40 t of ethanol.
Refluxed in nl for 9 hours. The reaction mixture was concentrated in an evaporator, the residue was poured with 50 ml of water and extracted twice with 100 rnl of dichloromethane each time. The dichloromethane layer was concentrated using an evaporator, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol-5:1).
When treated with
32 mol, yield 49.4%) was obtained. The obtained oil was dissolved in 50 ml of acetonitrile, and 2.34 g of concentrated hydrochloric acid was added.
(0,0232 mol) was added at room temperature and stirred for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in 100 m hexane (
! Washing with
．． 1g was obtained.

Melting point 170°C0 Example 3A Optically active compound Nα162 Matsumoto et al. method (J, λled, Chem, +990
．． 33.1645-1656) from (±)-2-methylpiperazine and L-(+)-tartaric acid to (R)-
(-)-2-Methylpiperazine was synthesized and the same procedure as in Example 2 was performed using this optically pure 2-methylpiperazine to obtain an optically active compound Nn162.

[α] o = +31.8° (C = 0.5, H2O).

Example 4A Synthesis of optically active compound Nα166 Optically active (S)-(+)-2 was synthesized in the same manner as in Example 3A, except from ±)-2-methylpiperazine and (D)-(-)-tartaric acid. - Using methylpiperazine, optically active compound Nα166 was obtained.

[α], = −37,5 (C = 0, H2O).

Table 3 shows compounds of the present invention synthesized in a similar manner to the above method. Yl and Y2 in this table have the above meanings.

(Leaving space below unfaithfulness) Table 3 (1) Table 3 (2) Table 3 (3) Table 3 (4) Table 3 (5) Table 3 (6) Table 3 (7) Example 5A Synthesis of compounds Na13 and 14 according to Preparation C 2-methylthiocyclohebutoimidazole (see Example IA)
5.00 g (0,0284 mol) and 3.24 g (0,0284 mol) of 1-formylpiperazine were refluxed in n-amyl alcohol for 5 hours. The residue was treated with silica gel column chromatography (developed with dichloromethane methanol 10:I) to give 3.87 g (yield 5696) of 2-(4-formylpiperazino)-cyclohebutoimidazole of the following formula as yellow crystals.
The resulting compound was added to 20yn of concentrated hydrochloric acid (70 °C
After heating for 3 hours, it was concentrated, and the residue was adjusted to pH 9 by adding 30% sodium hydroxide, and dichloromethane 50%
yn7! It was extracted. The extract was concentrated using an evaporator, and the residue was washed with cyclohexane to obtain 1.93 g (yield: 57%) of 2-piperazinocyclohebutoimidazole of the following formula as an oil.

2-piperazinocycloheptoimidazole thus obtained 1. Dissolve OOg (0,0047 mol) in 10 ml of dimethyl sulfoxide and add 0.24 g of thorium hydroxide.
(0,0061 mol) was added and stirred at room temperature for 20 minutes.

This mixture was then added to chloromethoxymethane (CH3QC
H2CI) 0.49g (0,0061 mol) was added,
After stirring for 5 hours, the reaction mixture was poured into 20 ml of water,
Extracted twice with dichloromethane for 30 d each. After concentrating the dichloromethane layer using an evaporator, the residue was treated with silica gel column chromatography (developed with dichloromethane methanol-5.1) to obtain the compound Nα of the following formula.
0.71 g (yield 5996.2-piperazinocyclohebutoimidazole standard) of 13 was obtained as an oily substance. Dissolve this oil in acetonitrile and add 0.28 g of concentrated hydrochloric acid.
(0,0028 mol) was added at room temperature and stirred for 30 minutes. The reaction mixture was concentrated, the residue was washed with 10 ml of hexane, filtered and dried to give 0.67 g of the hydrochloride of compound Nα13, i.e. compound Nα14, as yellow crystals.
(yield 82%, based on compound Nα13) was obtained.

Melting point 249-2517C0 Similar to this method, the compounds shown in Table 4 were obtained. Yl and Y2 in the table have the above meanings.

(Margins below the essence) Table 4 (1) Table 4 (2) Table 4 (3) Table 4 (4) Table 4 (5) Table 4 (6) Example 6A Compound Nα13 1 by manufacturing method - 5.0 Og (0,0439 mol) of formylpiperazino and 6.09 g (0,0439 mol) of 2-methylthioamidine sulfate
, 0439 mol) was stirred with 100 ml of water at room temperature for 36 hours.

The reaction mixture was concentrated using an evaporator, 50 ynl of acetone was added to the residue, and the resulting crystals were filtered and dried to obtain 7.29 g (yield: 81%) of the compound of the following formula as white crystals. Melting point 95°C8 3.00 g (0,0146 mol) of this crystal, 2.82 g (0,01 mol) of 28% sodium methoxide methanol solution
47 mol) and 1.90 g of tropolone methyl ether
(0,0140 mol) was refluxed in 30 ml of ethanol for 6 hours. The reaction mixture was then concentrated in an evaporator and the residue was poured into 20 ml of water and 30 ml each of dichloromethane.
The dichloromethane layer was concentrated using an evaporator, and the residue was treated with silica gel column chromatography (developed with dichloromethane/methanol = 101). Imidazole as yellow crystals 1yb2g
(yield: 45%). Melting point: 128°C8 Using this formyl compound, the following procedure was carried out in the same manner as in Example 5A,
Compounds Na13 and 14 were prepared.

Similar to this method, the compounds shown in Table 5 were obtained. Yl and Y2 in the table have the above meanings.

(Leaving space below essentials) Table 5 (1) Table 5 (2) Example 7A Synthesis of compounds Nα213 and 214 by Production Method E In the methoxymethylation step of Example 5A, 2-piperazinocycloimidazole was replaced with 2 - (2-methylpiperazino)-cyclohebutoimidazole (compound Nα1
53 (see Examples IA and 2A) and substituting ethyl bromide for chloromethoxymethane, 2-(1-ethyl-2-methylpiperazino)-cyclohebutoimidazole of the formula Obtained as an oil.

Similar to this method, the compounds shown in Table 6 were prepared. Yl and Y2 in the table have the above meanings.

When the compound of the general formula [■] has an asymmetric carbon atom, it is usually obtained as a racemate and can be resolved into optically active forms by a common optically active resolution method.

Table 6 (1) Table 6 (2) Table 6 (3) Table 6 (4) (Essential bottom margin) Example IB A tablet containing 10 ■ of active ingredients is manufactured as follows. .

Active ingredients per tablet: 10 mg corn starch 55 mg crystalline cellulose 35 mg polyvinylpyrrolidone 5 mg (as a 10% aqueous solution) carboxymethylcellulose/calcium 10 mg magnesium stearate 4 ■ Talc
1 mg total 120 ■ Pass 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, tablets each weighing 120 mg are produced by a tablet machine.

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

Active ingredients per tablet: 200mg corn starch 50mg crystalline cellulose 42mg light silicic anhydride
7■Magnesium stearate
1 mg total 300 mg Pass the above ingredients through an 80 mesh sieve and mix thoroughly. The resulting powder is compressed to produce tablets weighing 300 mg.

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

Active ingredients per sublingual tablet: 2.5 mg Mannitol 56.5 mg Hydroxypropyl methylcellulose 5.0 ■ Magnesium stearate 1.5 ■ Total 65.5
Remove mg magnesium stearate (pass the above ingredients 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.

(Margins below essence) Active ingredients 0.5mg lactose 98.5mg magnesium stearate 1. Omg total 10
0.0 mg Combine the above ingredients and pass through an 80 mesh sieve to mix thoroughly. Fill capsules with 100 mg of the obtained powder.

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

Active ingredients per capsule 100mg corn starch 40mg lactose
5mg Magnesium Stearate 5mg Total 150■ Combine the above ingredients and pass through an 80 mesh sieve to mix thoroughly. The obtained powder is filled into capsules in an amount of 150 mg each.

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

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

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
Add dilute hydrochloric acid to pH 3.5 Sodium chloride injection Total appropriate amount: 1 mj Example 8B An ampoule injection containing 50 ml of active ingredient is produced as follows.

Active ingredient per ampoule 50 mg Sodium chloride 1.8 mg Distilled water for injection Quantity Total 2 ml Example 9B A syrup containing 5 mg of 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 yne Appropriate amounts of buffering agents, coloring agents, flavoring agents, and preservatives can be added as necessary.

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

Active ingredient 10 parts g or 100 μg
Benzalkonium chloride 0.1 mg Physiological saline 0.6 mg or 0.9 mρ Distilled water appropriate amount Total 1.0 mg The resulting solution is filtered through a 0.2 μm filter and filled into a spray pump or gelatinized. Soak the sponge in the filtrate.

Example 11B A suspended aerosol containing 20 cm of active ingredient is prepared as follows.

Active ingredients 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 brought into solution. Mixed. This suspension is metered into an aluminum aerosol bed and dichlorocyfluoromethane is pressure packed into this bed.

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

10 parts of ammonium polyacrylate are dissolved in 60 parts of water. Meanwhile, add 2 parts of glycerin siglycidyl ether to 10 parts of water.
Dissolve while heating. Furthermore, in the other hand, dissolve 10 parts of polyethylene glycol (Grade 400, 10 parts of water, and 1 part of active ingredient) with stirring. Next, while stirring the aqueous solution of ammonium polyacrylate, add an aqueous solution of glycerin diglycyl ether and an aqueous solution of polyethylene glycol containing the active ingredient. Add and mix the drug-containing hydrogel solution,
The active ingredient is applied to a flexible plastic film at a concentration of 0.5 mg per square centimeter, the surface is covered with release paper, and the product is cut into 35 square centimeters to prepare a formulation.

Example 13B An adhesive patch containing 10 cm of active ingredient 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, crosslinking was carried out at 25°C for 24 hours, a release film was attached to the adhesive interface, and this was further cut into 35 square centimeters to prepare a preparation.

Regarding the biological activity of the compound of general formula (I) used in the present invention, in vitro and 1 nviv 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 the general formula [■] on ardiac slowing) and the accompanying reduction in blood pressure was investigated by varying the dosage.

Furthermore, the inhibitory effect of the compound of general formula CI) on tachycardia induced by 5-HT was also investigated using atrial specimens isolated from rabbits. Furthermore, using gastric strip specimens extracted from guinea pigs, that is, gastric fundus circular muscle specimens or longitudinal muscle specimens of the small intestine, we investigated the potentiating effect of the compound of the general formula [■] on contractions induced by electrical stimulation. .

Next, before giving a methylcellulose solution containing phenol red as a test meal to fasted rats, the test drug was administered to examine its ability to enhance gastric emptying. In dogs, strain gauges (Star Medical:
F-0813) 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 administering cholera toxin to mice or 5-HTP (a precursor of 5-+ (T))
We investigated whether functional abnormalities such as increased gastrointestinal motility induced by the administration of liptophan) were suppressed by the test drug of general formula CI).

Furthermore, vomiting induced by 5-FU, cisplatin, cyclophosphamide, doxorubicin, CLISO4, or apomorphine was induced in dogs, and the suppressive and inhibiting effects of the test drug on vomiting were investigated. In addition, the antiemetic effect of the general formula [■] was investigated using animals such as ferrets and Suncus instead of dogs.

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] B-, J reflection Fozard et al. (Fozard, JRand Ho5
t, M: Br1tishJ, Pharmacol,
77; 520.1982), the effect on the B-J reflex was investigated. That is, urethane (1.2 g/k
g i,p,) Blood pressure and heart rate of anesthetized rats were recorded by polygraph. 40mg of serotonin (5-HT) for rats
After confirming that stable reflex bradycardia occurred after administering 5-t/kg intravenously, the test drug was administered intravenously, and 5 minutes later, 40 mg/kg of 5-t (T) was administered again. The suppression rate was determined by comparing the reflex bradycardia with the response before administration of the test drug.

If the test drug was insoluble in water and could only be administered intravenously, it was administered intraperitoneally 20 minutes before 5-HT administration. The results are shown in Table 7.

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-Henselei solution (Krebs-Henselei I) to which 2 μM atropine was added in advance
The right atrium specimen was suspended in a Magnus tube filled with 5-HT, and 8 μg/yn (!) of 5-HT was added to induce tachycardia. The test drug was added to the Magnus tube 5 minutes before 5-HT administration. The suppressive effect of 5-HT on tachycardia was determined.The results are shown in Table 7.

Experimental Example 3 Guinea pig isolated gastric strip specimen Bachheit, KHet al.
: , J, circle 1arm.

Pharmacol, 37; 664, 1985), the stomach of a Hartley guinea pig that had been fasted for 24 hours was removed, and a longitudinal muscle specimen of the small incision was prepared and suspended in a Magnus tube. When the contraction of the anterior strip caused by electrical stimulation stabilized, the test drug was added, and the effect of enhancing contractile force was observed. The results are shown in Table 7.

Experimental Example 4 Rat gastric emptying capacity A 1.5% methylcellulose suspension containing 0.05% phenol red was orally administered to Wistar rats that had been 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. For the measurement of phenol red, 0.1N Na was added to the excised 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 8.

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 9.

Experimental Example 6 Gastric movement in anesthetized dog An adult mongrel (8-13 kg) was anesthetized by intravenous administration of bendoparbital 30 μ/kg, and after laparotomy, contraction movements in the direction of the circular muscle could be recorded on the serosa surface of the dorsal court. Yoni Strain Gauge (Star Medical: F-0813
) was sewn on. The animals were left for 30 minutes or more after the surgery, and after gastric spontaneous movements were recorded, the test drug was intravenously administered to examine the effects on gastric spontaneous movements. In this experiment, the compound Nα1
4.86.145.154 and 170 showed a promoting effect on gastric spontaneous motility, whereas 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 1O.

(Blank below the essence) ot 10B Table 8: Rat gastric emptying capacity (1) Table 8: Rat gastric emptying capacity (2) +17 Table 9: Sunkusisplatin vomiting 1B Table 10: Mouse acute toxicity (1) Chapter 10 Table Mouse Acute Toxicity (2) As is clear from the results of the above experimental example, - Formula (I)
The compounds include existing metoclopramide, cisplatin′,
BRL24924.1cs205-930, GR3B0
32F.

It has excellent pharmacological effects that are equal to or greater than MDL72222 and the like.

Therefore, the compounds of the general formula CI) according to the invention are characterized by their 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 gastric insufficiency, ischemic bowel disease, obesity, irritable bowel syndrome (ICS)
), 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.

Also, during the administration of anticancer drugs such as cisplatin, cyclophosphamide, doxorubicin, and 5-FU, which have cell-killing effects, and when irradiating the chest, abdomen, and other parts of the body with radiation, X-rays, and neutrons, or when the stomach It can be used as an antiemetic to suppress nausea and vomiting as a result of depression, migraines, indigestion, ulcers, etc. Furthermore, it can be used as a gastric emptying promoter for radiological examinations and the like.

In the cardiovascular system, it can prevent and treat arrhythmia, vascular spasm, etc. 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 nasal diseases such as rhinitis and serotonin-induced nasal diseases.
Can be treated. In the central nervous system and peripheral nervous system,
Prevention and treatment of anxiety, hallucinations, delusions, chronic illness, and schizophrenia, or drug withdrawal/discontinuation syndrome from dependence-inducing drugs 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, trigeminal neuralgia, and the like.

The compound of general formula CI) of the present invention is useful as a prophylactic, 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 C 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 medicine.

〔Effect of the invention〕

It was revealed that the compound of general formula (I) of the present invention has excellent pharmacological activity as shown in Experimental Examples 1 to 6 and Tables 7 and 8. Furthermore, the toxicity of the compounds of the present invention is generally weak as shown in Tables 7 and 10 of Experimental Examples. The compound of general formula (I) 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. That is expected.

Procedural amendment

Claims (2)

[Claims] (1) General formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] [In the formula, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Mathematical formula, There are chemical formulas, tables, etc. Showing the group of ▼,
R^1, R^2, R^7 and R^8 independently represent a hydrogen atom or a lower alkyl group, R^3, R^
4, R^5 and R^6 are each independently a hydrogen atom,
It represents a lower alkyl group, carboxyl group, lower alkoxycarbonyl group, aminocarbonyl group or lower alkylamino lower alkyl group, or R^3 and R^4 or R^5 and R^6 are bonded to each other to form oxo (=0 ) group; ), lower alkylsulfonyl group, phenylsulfonyl group, halogenated phenylthio group, phenoxythiocarbonyl group, or -
(CH_2)_b-R^1^3 {R^1^3 is an amino group, a lower alkylamino group, a lower alkoxy group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a halogen atom, or a lower alkylcarbonylamino group. Phenoxy group that may be substituted, ▲Mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. , tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 indicates a lower alkyl group) , a is a number of 1 or 2, b is an integer of 1 to 4, c is a number of 0 or 1, R^1^2 is a hydrogen atom, a hydroxyl group, a lower alkyl group, an amino lower alkyl group, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^1^3 and R^1^4 each independently represent a hydrogen atom, a lower alkyl group, or a lower alkylcarbonyl group) or a piperidino group, R^ 9
, R^1^0 and R^1^1 each independently represent a hydrogen atom, a halogen atom, a nitroso group, a lower alkyl group, an amino group, a lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl represents an amino group or a piperazino group, or R^1^0 and R
^1^1 may be linked to form -CH=CH-CH=CH-, provided that when X is a hydrogen atom, formyl group, lower alkyl group or lower alkoxycarbonyl group, R^1~ At least one of R^1^1 represents a group other than a hydrogen atom] or a pharmacologically acceptable salt thereof. (2) A pharmaceutical composition containing a cycloheptoimidazole compound represented by general formula I or a pharmacologically acceptable salt thereof as an active ingredient.