JPH045288A - Homopiperazine compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I{R is lower alkyl; R1 is H, halogen, lower alkyl, nitro, cyano, etc.; X is group shown by formula II or formula III [R2 and R3 are H or lower alkyl; R4 is H, halogen, nitro or amino; R5 is H lower alkyl. (substituted) aryl lower alkyl]}. EXAMPLE:N- (1-Benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl) -5-bromo-2,3- dihydrobenzo [b] furan-7-carboxamide. USE:A serotonin 3 (5-HR3) antagonist. PREPARATION:A compound (reactive derivative) shown by the formula X-COOH is reacted with a compound shown by formula IV optionally in a solvent such as benzene preferably at - 10 to 150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides serotonin 3 (5-HT3) as a medicine.
) relates to homopiperazine compounds useful as antagonists.

In the 1960s, 4-amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide [-ship name metoclopramide; see for example Merck Index, 10th edition, 6019 (1983)] was introduced in the 1960s. Various substituted benzoic acid amide derivatives and heterocyclic carboxylic acid amide derivatives have been synthesized and their pharmacological properties have been studied (for example, in JP-A No. No. 52-83737,
80-123485 and US Pat. No. 4,207,327).

On the other hand, MrJL-72222, which selectively antagonizes the serotonin M receptor, was reported in the late 1970s (Japanese Unexamined Patent Publication No.
8-978) and IC5205-930 (see Japanese Unexamined Patent Publication No. 59-3Ei675).
serotonin M receptor has been classified as serotonin 3 receptor), and several serotonin 3 receptor antagonists have been discovered (for example, JP-A-61-275276, JP-A-62-209077, JP-A-62- (See No. 252764)
. These compounds are not only effective against anticancer drug-induced nausea and vomiting, migraine, and arrhythmia, but also against schizophrenia, anxiety, and dependence on alcohol, nicotine, and narcotics (see JP-A-1-31729). It is also reported to be effective.

The present invention provides a novel homopiperazine compound having excellent serotonin 3 (5-HT3) antagonistic activity.

General formula (1) [wherein R means a lower alkyl group, R, is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group,
It means a nitro group, a cyan group or a trifluoromethyl group.

X means a group represented by, where R2 and R3 are the same or different and mean a hydrogen atom or a lower alkyl group,
R4 means a hydrogen atom, a halogen atom, a nitro group or an amino group, and R5 means a hydrogen atom, a lower alkyl group, or an unsubstituted or substituted aryl (lower) alkyl group. ] It is related with the homopiperazine compound or its acid addition salt represented by these.

The addition salt of the compound represented by formula (1) is preferably a physiologically acceptable salt. acid salt,
and oxalates, maleates, fumarates, lactates,
Examples include organic acid salts such as malate, citrate, tartrate, benzoate, and methanesulfonate.

Since the compounds of formula (I) have at least one asymmetric carbon atom, stereoisomers, mixtures and racemates thereof are included in the compounds of the invention. Furthermore, since Compound (I) can exist as a hydrate, the hydrate is also included in the compounds of the present invention.

Terms used in this specification will be explained below.

"Lower" means 1 to 6 carbon atoms unless otherwise specified. The "lower alkyl group" may be chain-like or branched-chain, and specifically, methyl.

Examples include ethyl, propyl, isopropyl, butyl and the like. "Lower alkoxy group" specifically refers to methoxy,
Examples include ethoxy, propoxy, butoxy and the like. “Halogen atom J is fluorine.

means a chlorine, bromine or iodine atom. Examples of the aryl moiety include phenyl, naphthyl, and the like. "Unsubstituted or substituted aryl (lower) alkyl group" refers to an aryl moiety having 1 to 3 halogen atoms, lower alkyl group, trifluoromethyl group, hydroxy group, or lower alkoxy group.

It means one substituted with a cyano group, an amino group or a nitro group, and specific examples thereof include benzyl, 2-fluorobenzyl, 3-methylbenzyl, 4-methoxybenzyl and the like.

Specific examples of the compound represented by formula (I) include (1) N
-(1-benzyl-4-methylhexahydro-IH-1
,4-diazepin-6-yl)-5-bromo-2,3-
Dihydrobenzo[blfuran-7-carboxamide.

(2) N-[1-(3-methylbenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]
-5-Bromo-2,3-dihydrobenzo[b]lfuran 7-carboxamide.

(3) N-[1-(4-methylbenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]
-5-bromo-2,3-dihydrobenzo[blfuran-
7-Carboxamide.

(4) N-[1-(3-fluorobenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-5-bromo-2,3-dihydrobenzo[b]lfuran 7 - Carboxamides.

(5) N-[1-(4-fluorobenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-5-bromo-2,3-dihydrobenzo[b]lfuran 7 - Carboxamides.

(6) N-[1-(3-)lifluoromethylbenzyl)
-4-methylhexahydro-LH-1,4-diazepin-6-yl]-5-bromo-2,3-dihydrobenzo[
b] lfuran 7-carboxamide.

(7) N-(1-benzyl-4-methylhexahydro-
IH-1,4-diazepin-6-yl)-2,3-dihydrobenzo[blfuran-7-carboxamide.

(8) N-[1-(3-methylbenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]
-2,3-dihydrobenzo[b]lfuran 7-carboxamide.

(9) N-(1-benzyl-4-methylhexahydro-
IH-1,4-diazepin-6-yl)-5-nitro-
2,3-dihydrobenzo[b-cotlan-7-carboxamide.

(10) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl)-5-chloro-2,3-dihydrobenzo[b]lfuran 7-carboxamide.

(11) N-[1-(3-methylbenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-5-chloro-2,3-dihydrobenzo[b]lfuran 7 - Carboxamides.

(12) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl)-2-methyl-2,3-dihydrobenzo[b]lfuran 7-carboxamide.

(+3)N-(1-benzyl-4-ethylhexahydro-IH-1,4-diazepin-6-yl)-2-methyl-2,3-dihydrobenzo[bl furan-7-carboxamide.

(14) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl)-2,2-dimethyl-2,3-dihydrobenzo[b]lfuran 7-carboxamide.

(15) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl)=2-ethyl-2,3-dihydrobenzo[b]lfuran 7-carboxamide.

(16) N-[1-(3-fluorobenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-2-methyl-2,3-dihydrobenzo[b]lfuran 7 - Carboxamides.

(17) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl)-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-
1,4-penzoxazine-8-carboxamide.

(18) N-[1-(4-fluorobenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-6-chloro-3,4-dihydro-4-methyl-3
-Oxo-2H-1,4-benzoxazine-8-carboxamide.

(19) N-[1-(3-fluorobenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-6-chloro-3,4-dihydro-4-methyl-3
-Oxo-2H-1,4-benzoxazine-8-carboxamide.

(20) N-[+-(2-fluorobenzyl)-4-methylhexahydro-LH-1,4-diazepin-6-yl]-6-chloro-3,4-dihydro-4-methyl-3
-Oxo-2H-1,4-benzoxazine-8-carboxamide.

(21) N-[1-(4-chlorobenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-6-chloro-3,4-dihydro-4-methyl-3-
Oxo-2H-1,4-benzoxazine-8-carboxamide.

(22) N-[1-(4-methylbenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-6-chloro-3,4-dihydro-4-methyl-3-
Oxo-2H-1,4-benzoxazine-8-carboxamide.

(23) N-[1-(3-methylbenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-6-chloro-3,4-dihydro-4-methyl-3-
Oxo-2H-1,4-benzoxazine-8-carboxamide.

(24) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl)-6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo -2H-1,4-benzoxazine-8-carboxamide.

(25) N-(1-benzyl-4-methylhexahydro-LH-1,4-diazepin-6-yl]-6-bromo-3,4-dihydro-4-methyl-3-oxo-2H-
1,4-Benzoxazine-8-carboxamide.

(26) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl]-6-bromo-3,4-dihydro-3,4-dimethyl-3-oxo-
2H-1,4-benzoxazine-8-carboxamide.

(27) N-(1-benzyl-4-methylhexahydro-IH-1,4-diazepin-6-yl)-6-bromo-3,4-dihydro-2,2,4-trimethyl-3-oxo -2H-1,4-benzoxazine-8-carboxamide.

(28) N-[1-(4-methoxybenzyl)-4-methylhexahydro-IH-1,4-diazepin-6-yl]-6-bromo-3,4-dihydro-2,2,4- )
riftyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide and (29)N-[1-(4-cyanobenzyl)-4-methylhexahydro-IH-1,4-diazepine-6- yl]-6-chloro-2-ethyl-3゜4-dihydro-4-
Methyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide is mentioned.

(Hereinafter, blank spaces) Compound (I) of the present invention can be produced, for example, by the following method.

A compound represented by the following general formula (II) -COOH (II) (wherein, X means the same as defined above) or a reactive derivative thereof; have the same meanings as above.) It can be produced by reacting with a compound represented by:

Examples of reactive derivatives of the compound of formula (II) include lower alkyl esters, active esters, acid anhydrides, acid halides, especially acid chlorides, and the like. Specific examples of active esters include p-nitrophenyl ester,
2,4.5-) Licrophenyl ester, pentachlorophenyl ester, cyan methyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenztriazole ester, N-hydroxy-5-norbornene-2 ,3-
Dicarboximide ester, N-hydroxypiperidine ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-hydroxy-4,5-
Examples include dichlorophenyl ester, 2-hydroxypyridine ester, 2-pyridylthiol ester, and the like. As the acid anhydride, a symmetrical mixed acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl chlorocarbonate, and an aralkyl chloride carbonate such as benzyl chlorocarbonate. Mixed acid anhydrides with aryl chlorocarbonates such as phenyl chlorocarbonate, mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid, and the like.

Also, dicyclohexylcarbodiimide, 1-ethyl-
The reaction can also be carried out in the presence of a condensing agent such as 3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. can. Dicyclohexylcarbodiimide or 1 as condensing agent
When using -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, N-hydroxysuccinimide, 1-hydroxybenztriazole, 3- Hydroxy-4-oxo-3,4-dihydro-1,2,3-benztriazine, N-hydroxy-
5-norbornene-2,3-dicarboximide or the like may be added and reacted.

A compound of formula (II) or a reactive derivative thereof and a compound of formula (III)
) with the compound is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of raw material compound, etc., and examples include aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether,
Ethers such as tetrahydrofuran and dioxane,
Examples include halogenated hydrocarbons such as methylene chloride and chloroform, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol, and water, and these solvents may be used alone or in combination of two or more. The reaction using the acid halide of formula (II) used as Alkali carbonates such as potassium or triethylamine, tributylamine, diisopropylethylamine.

Examples include organic bases such as N-methylmorpholine, which can also serve as an excess amount of the compound of formula (III).The reaction temperature varies depending on the type of raw material compound used, but is usually about -30°C to about 200'C1 is preferably about -10°C to about 150°C.

Incidentally, when groups involved in the reaction are present in the structure of the compound of formula (TI) or (III), it is desirable to protect these groups according to a conventional method and remove them after 5 reactions.

The raw material compound (l1l) can be produced by the method shown in Reference Example 1 or a method similar thereto, and can be obtained by hydrolysis if necessary.

Compound (I) produced by the above production method is isolated and purified by conventional methods such as chromatography, recrystallization, and reprecipitation.

The compound of formula (1) can be obtained in the form of a free base or an acid addition salt depending on the selection of raw material compounds, reaction and treatment conditions, etc. Acid addition salts can be converted to the free base in a conventional manner, eg, by treatment with a base such as an alkali carbonate or an alkali hydroxide. on the other hand.

The free base can be converted into an acid addition salt by treatment with various acids according to conventional methods.

The compound of formula (I) and its physiologically acceptable acid addition salts are antagonists of serotonin 3 (5-HT 3) receptors and are effective against acute and chronic gastritis, gastric and duodenal ulcers, gastric neuropathy, and gastroptosis. For the treatment and prevention of anorexia, nausea, vomiting, abdominal bloating, etc. in diseases such as esophageal and biliary tract diseases,
It can be used to treat and prevent urinary tract disorders and diarrhea and constipation such as irritable bowel syndrome or carcinoid syndrome.

Furthermore, it can be used during the administration of anticancer drugs such as cisplatin, during radiation irradiation, and for the treatment and prevention of nausea or vomiting caused by motion sickness such as motion sickness. Also.

It can be used for the treatment and prevention of cluster headache 9 migraine and trigeminal pain, as well as anxiety, pain and psychotic disorders such as schizophrenia or schizophrenia, dementia, sensory disorders, stress-related psychosis. disease, heart disease (e.g. arrhythmia, angina pectoris), obesity, pulmonary embolism.

It can also be used to treat rhinitis or serotonin-induced nasal disorders, insomnia, or pain. Addictive drugs (alcohol, morphine, nicotine.

It can also be used to treat and prevent addiction to amphetamines, etc. The route of administration may be oral, parenteral or rectal. The dosage varies depending on the type of compound, administration method, patient's symptoms and age, etc., but is usually in the range of 0.0001 to 20 mg/kg/day, preferably 0.001 to 5 mg/kg/day. However, it is also possible to use it beyond this range at the discretion of the doctor.

When the compound of formula (1) or a salt thereof is used for the above-mentioned pharmaceutical purposes, it is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. As a pharmaceutical carrier, a substance commonly used in the pharmaceutical field and which does not react with the compound of formula (1) or its salt is used. Specifically, for example, citric acid and glutamic acid.

Glycine, lactose, inositol, glucose, mannitol, dextrin, sorbitol, cyclodextrin, starch, white sugar, methyl paraoxybenzoate, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxylic acid Methylcellulose calcium, ion exchange resin, methylcellulose.

Gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light silicic anhydride, magnesium stearate.

Talc, tragacanth, bentonite, vegum.

Carboxy vinyl polymer, titanium oxide, sodium chloride, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, ethanol, benzyl alcohol, hydroxylated Examples include sodium, hydrochloric acid, water and the like. Dosage forms include tablets, capsules, and granules.

Examples include fine granules, powders, syrups, suspensions, injections, and halves. These formulations are prepared according to conventional methods.

In the case of a liquid preparation, it may be dissolved or suspended in water or other suitable medium before use, and tablets, granules, and fine granules may be coated by a well-known method. . These formulations may also contain other therapeutically valuable ingredients. Reference examples and examples are given below to further illustrate the present invention; Examples of, but not limited to, compound identification include elemental analysis, mass spectra, and IR spectra.

The analysis was conducted using UV spectra, NMR spectra, etc. In Examples and Reference Examples, the solvent in parentheses indicated at melting point means a recrystallization solvent.

Furthermore, in the following Reference Examples and Examples, the following abbreviations may be used to simplify the description.

Ph: phenyl group J: bond constant S knee doublet d: doublet dd: double doublet t: triplet m: multiplet 11L 6-acetylamino-1-benzyl-4-methylhexahydro- Production of IH-1,4-diazepine: He1v, Gbitn, Acta, 45.2383~
2402 (1962) was dissolved in 8 ml of acetonitrile, 3.3 g of sodium azide was added, and the mixture was heated under reflux for 2 hours. Insoluble matter was removed by filtration, and the filtrate was distilled off under reduced pressure. The residue was dissolved in toluene IO [1all and 70% hydrogenated bis(
10.4 g of a toluene solution of sodium (2-methoxyethoxy)aluminum is added little by little, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice water, and a 48% aqueous sodium hydroxide solution is added. The aqueous layer was extracted with toluene, combined with the organic layer, and dried over anhydrous magnesium sulfate.
Add 5.2 g of acetic anhydride to this and stir at room temperature for 2 hours. The reaction mixture was washed with a 48% aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 5.4 g of oil are obtained. The residue was purified by silica gel column chromatography and eluted with chloroform-methanol (20:1) to obtain the oily target product 1.
Obtain Ogfe.

"H-NMR spectrum (CDCl2.δppm)
: 1.85 (311, s.

-COCH-), 2.35 (311,s, -N
CL), 3.4B, 3.72 (each In, each d.

Each J=13Hz, -CIIIs=Ph), 3.
98 (IH,m, -GOIf[J-), 6.35
(IH.

d, -COQ-), 7.30 (5L at,
-CLCaHa) Container■ -UN-(1-benzyl-4-methylhexahydro-IH-
1,4-diazepin-6-yl)-5-bromo-2,3
-Dihydrobenzo[b]l Furan 7-carboxamide production: 5-but0-E-2,3-dihydrobenzo[b]l Furan 7-carboxylic acid, 8oomg notluene 2oIIl■
Add 0.9 ml of thionyl chloride to the suspension and reflux for 2.5 hours. After cooling, the solvent and excess thionyl chloride are distilled off under reduced pressure to obtain a crude acid chloride. Dissolve this in chloroform 20111 and add 6-amino-1-benzyl-4
-Methylhexahydro-IH-1,4-diazepine 89
A solution of 0 mg in 10 ml of chloroform is added dropwise. After stirring at room temperature for 3.5 hours, the reaction mixture was washed with a 10% aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to obtain 1.24 g of an oil. Recrystallize this from acetone to obtain the desired product (300%)
Get mg.

Melting point llOoC”H-NMR spectrum (CDC1a, 8 pPID
): 2.41(3H,S, -NCH3),
2.47-2.92 (OH, m), 2.98-3
．． 16 (2B, m).

3, 28 (2H,t, J=8Hz, -0CE[2
CH2-), 3.69 (2H,s, 4CH,P
h), 4.28-4.45 (Ill, m, -C
ON[C! i-), 4.75 (2H,t, J=
8Hz.

-0C11,CH2-), 7.16-7, 42 (O
H, o+), 7.98-8.04 (IL m)
.

8, 35 (IH, d, J=8Hz, -CONH-
) Fire-1 N-(1-benzyl-4-methylhexahydro-IH-
1,4-diazepin-6-yl)-5-nitro-2,3
-Preparation of dihydrobenzo[blfuran-7-carboxamide: 5-nitro-2 instead of 5-bromo-2,3-dihydrobenzo[b]lfuran-7-carboxylic acid in Example 1
, 3-dihydrobenzo[b]lfuran-7-carboxylic acid and the same reaction and treatment as in Example 1 to obtain the desired product.

Melting point 142-143°C (acetone-chloroform)
'H-NMR spectrum (ClICl3.δppm)
: 2.42(3H,S, -NCH3), 2.
47-2.95 (6H, m), 2.97-3.1
6 (2L m).

3.39 (2H, t, J=8Hz, -01J2CE1.
-), 3.69 (2H, S, -NCH, Ph), 4.
28-4.46 (Ill, m, -CONIIIC
H-), 4.92 (2fl, t, J=8Hz
.

-0CHzCli2-), 7.15-7.39 (
5H, m), 8.14-8.20 (llllI,
m).

8.37 (IH, d, J=8Hz, -CONH-), 8
．． 85 (1fI, d, J = 2.5Hz) Kyotane-1 N-(1-benzyl-4-methylhexahydro-IH-
Preparation of 1,4-diazepin-6-yl)-2°3-dihydrobenzo[blfuran-7-carboxamide: 5-bromo-2,3-dihydrobenzo[b]lfuran 7-carboxylic acid in Example 1 Using 2,3-dihydrobenzo[blfuran-7-carboxylic acid instead of 2,3-dihydrobenzo[bl], the reaction and treatment were carried out in the same manner as in Example 1 to obtain a crude target product. This is subjected to silica gel column chromatography and purified by elution with acetone to obtain the desired product. This is treated with oxalic acid to obtain the target oxalate 0.25 hydrate.

Melting point 72-76°C (ethanol-diethyl ether)
1H-NMR spectrum (DMSO-d, δppm)
: 2.75(3111,s, -NCR,),
2.72-3. Old (3H, m), 3.26 (3
H, t, J=8Hz.

-0CH2CHX-), 3.14-3.53 (5
H, m), 3.7Ei (2■, dd.

-MCIlzPh), 4.29-4.45 (Il
l, ts, -CONHCH-), 4.75 (211
,t.

J=8Hz, -0CH2C112-), 6.98
(IH, t, J=7Hz), 7.20-7.4
7 (OH, m), 7.65 (IH, d, J=7
flz), 8.34 (11,d, J=8Hz.

-CONH-) 夾胤桝-1 N-(1-Benzyl-4-methylhexahydro-IH-
1,4-diazepin-6-yl)-6-chloro-3,4
-dihydro-4-methyl-3-oxo-2H-1,4-
Preparation of benzoxazine-8-lupoxamide: 6-chloro-3,4-dihydro-4-methyl-3-oxo-28-1,4-benzoxazine 8-carboxylic acid 2
．． After heating and refluxing 0 g of thionyl chloride and 511 Ill of thionyl chloride for 1.5 hours, excess thionyl chloride was distilled off under reduced pressure. Toluene was added to the residue and evaporated under reduced pressure to completely remove thionyl chloride. The residue was dissolved in 100 rnl of chloroform, and the solution was added dropwise to 50 ml of a chloroform solution containing 2.0 g of 6-amino-1-benzyl-4-methylhexahydro-IH-1,4-diazepine and 3.3 g of triethylamine under water cooling. . After stirring the reaction solution at room temperature for 3 hours, washing with water,
Dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography to obtain 2.9 g of the desired product as an oil. This is treated with oxalic acid to obtain the target product, 1.5-oxalate/0.5-hydrate.

Melting point 167-169°C (methanol) H-NMR
Spectrum (DMSO-d, δppm): 2.80
(3H,s, -NCH,) , 3.25 [3H,
s, -N (CI13) C0-1, 3,77 (2H
,s.

-MCIlzPh), 4.39 (ill, 11
1. -CON anal H-), 4.75 (2H, s.

-0CR,C0-), 8.59 (IL d, J
=811z, -CONH-) Patent applicant: Dainippon Pharmaceutical Co., Ltd. Agent: Yushibe Tsuboi

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R means a lower alkyl group, R_1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, It means a cyano group or a trifluoromethyl group, and X means a group represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where R_2 and R_3
are the same or different and mean a hydrogen atom or a lower alkyl group, R_4 means a hydrogen atom, a halogen atom, a nitro group or an amino group, and R_5 means a hydrogen atom, a lower alkyl group,
It means an aryl (lower) alkyl group that is unsubstituted or has a substituent. ] A homopiperazine compound or an acid addition salt thereof.