JPH05230057A - Optically active indazole-3-carboxamide derivative and antiemetic agent containing the same as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new compound having antagonistic action on serotonin 3 (5-HT2) receptors and useful as an antiemetic agent. CONSTITUTION:(-)-N-[1-Methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazep in-6- yl)-1H-indazole-3-carboxamide (salt). This compound is obtained by converting (S)-(-)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid into an acid chloride with thionyl chloride, then reacting the resultant compound with 6-amino-1-methyl-4-(3- methylbenzyl)hexahydro-1H-1,4-diazepine, subjecting the mixture of the two kinds of diastereomers to medium-pressure column chromatography using silica gel eluting the mixture with ethyl acetate, providing oily (+)-N-[1-methyl-4-(3- methylbenzyl)hexahydro-1H-1,4-diazepin-6-yl]-alpha-methoxy-alpha- trifluoromethylphenylacetamide, hydrolyzing the obtained compound with a concentrated hydrochloric acid and reacting the prepared hydrolyzate with 1H-indazole-3-carboxylic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION INDUSTRIAL FIELD The present invention relates to a novel indazole-3-carboxamide derivatives useful as antiemetic having antagonism of serotonin 3 (5-HT ₃₎ receptors. To prior art late 1970s reported serotonin M receptor selectively桔抗MDL-72222 [JP 58-978, Trends in Pharmaceutical Sciences, 8 , 44 (1987) Reference and ICS 20 5- Since the discovery of 930 [JP 59-36675, Trends in Pharmaceutical Sciences, 8 , 44 (1987)], the number of serotonin M receptors (currently classified as serotonin 3 receptors), how many Such serotonin 3 receptor blockers have been found (see, for example, JP-A Nos. 61-275276, 62-209077 and 62-252764).

These compounds are effective not only for anti-cancer drug-induced nausea and vomiting, migraine, arrhythmia, etc., but also for schizophrenia, anxiety, or addiction to alcohol, nicotine, narcotics, etc. [JP-A-1-31729, Eur. J. Pharmcol., 151 , 159 (1988)] is also effective.

 JP-A-2-256670 discloses N- [1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepine-6 represented by the following formula, which has a strong serotonin triblock effect. -Yl] -1H-indazole-3-carboxamide (hereinafter referred to as compound A) is disclosed.

Compound A has an asymmetric carbon atom at the 6-position of the homopiperazine ring, and can be obtained as a racemate by a conventional production method. DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present inventor has optically resolved Compound A to obtain its optically active substance, the (−) isomer [hereinafter referred to as Compound (−) A] and the (+) isomer [hereinafter Compound ( +) A]] was obtained. Surprisingly, compound (-) A showed a greater in vitro serotonin 3 (5-HT ₃ ) receptor blocking activity than compound (+) A [receptor binding inhibitory activity and isolated ileal serotonin 3 (5). -HT ₃ ) induced contraction inhibitory effect] is 100-170 times stronger, and 5-HT ₃ receptor blockade in vivo (von Bezold Jarisch reflex inhibitory effect) is 400 times stronger and vomiting inhibitory effect is also 300 times stronger. The inventors have found that the above is strong and completed the present invention. Effect invention means and invention, there is provided an optically active form of the compound A (-) - N- [1- methyl-4- (3-methylbenzyl) hexane Sahidoro-1H-1,4-diazepine -6-yl] -1H-indazole-3-carboxamide [compound (-) A] or a salt thereof and an antiemetic agent containing the same as an active ingredient.

 Examples of the salt of the compound (-) A of the present invention include physiologically acceptable salts, for example, inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate. Salts and organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and the like can be mentioned.

 In addition, since the compound (-) A of the present invention may exist as a hydrate and a solvate, these hydrates and solvates are also included in the compound of the present invention.

 The compound (-) A of the present invention can be produced by the method described in Examples. That is, (S)-(−)-α-methoxy-α-trifluoromethylphenylacetic acid was converted to an acid chloride with thionyl chloride, and 6-amino-1-methyl-4- (3-methylbenzyl) hexahydro was added to the acid chloride. -1H-1,4-diazepine was reacted, and the obtained mixture of two diastereomers was subjected to medium pressure column chromatography using silica gel, eluting with ethyl acetate, and eluting first ( (Low polarity) oily (+)-N- [1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepine-6-yl] -α-methoxy-α-trifluoro Obtain methylphenylacetamide. This is hydrolyzed with concentrated hydrochloric acid to obtain oily (+)-6-amino-1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepine, which is disclosed in JP-A-2-256670. Compound (-) A of the present invention can be produced by reacting 1H-indazole-3-carboxylic acid in the presence of N, N'-carbonyldiimidazole according to the method (a) described in 1. above.

 The starting compound 6-amino-1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepine can be produced by the method described in Reference Example 1.

 Compound (+) A can be similarly produced by the method described in Examples using (R)-(+)-α-methoxy-α-trifluorophenylacetic acid.

 The compound (-) A of the present invention produced by the above method is isolated and purified by a conventional method such as chromatography, recrystallization and reprecipitation.

 Further, the compound (-) A can be obtained in the form of a free base or an acid addition salt depending on the selection of the starting compound, the reaction / treatment conditions and the like. The acid addition salt can be converted into a free base by a conventional method, for example, by treating with a base such as alkali carbonate or alkali hydroxide.

On the other hand, the free base can be converted into an acid addition salt by treating it with various acids according to a conventional method.

 The pharmacological actions of the compound (-) A of the present invention, such as serotonin 3 receptor anti-inflammatory action, will be described below.

Test Example 1 Von Bezold-Jarisch Reflex Inhibitory Action (Serotonin 3 Receptor Blocking Action) This test was conducted according to the method of Fozard et al. [Arch. Pharmacology, 326, 36-44 (1984)].

SD male rats (body weight 300-400 g) were anesthetized with urethane (1.5 g / kg, intraperitoneal) and fixed in the dorsal position.

An electrocardiogram (2nd lead) was derived and the heart rate was recorded in ink on an oscillograph via a heart rate tachometer. Intravenous administration of 2-methyl serotonin (5-HT ₃ agonist) at 30 μg / kg causes a transient decrease in heart rate, that is, the von Bezold-Jarisch reflex. A fixed amount of 2-methylserotonin was repeatedly administered at 15-minute intervals, and after a stable reaction was obtained, the test compound (1 μg / kg) was intravenously administered 3 minutes before the administration of 2-methylserotonin. The inhibition rate of the test compound was calculated from the following formula.

The ID ₅₀ values calculated from the results of the inhibition rate are shown in Table 1.

Test Example 2 5-HT-induced contraction-suppressing action of isolated ileum (serotonin 3 receptor blocker action) Male Hartley guinea pigs (body weight 300-550 g) were killed by bruising the head and the terminal ileum was removed and left An ileal specimen with a length of 3 cm was prepared. The specimen was suspended in a 10 ml mug tube and filled with nutrient solution (37 ° C) saturated with 95% oxygen and 5% carbon dioxide. A load of 1 g was applied to the sample. Contraction was induced by adding 1 × 10 ^-5 M serotonin in the presence of 0.2 μM methysergide. The test compound at each concentration was added 3 minutes before the addition of serotonin. The drug efficacy was calculated by calculating the ID ₅₀ value from the inhibition rate of the reaction before the test compound was added to the reaction before the test compound was added, and the results are shown in Table 2.

Test Example 3 Rat brain synapse membrane 50HT ₃ receptor binding blocking activity (serotonin 3 receptor blocking activity) Peroutka and Hamik [see Eur. J. PHarmacol., 1 47 , 298 (1988)] were partially modified. Then, a binding test was conducted. A crude synaptic membrane prepared from rat frontal cortex was used as a receptor specimen, and [ ³ H] keeperdin was used as a labeled ligand. The crude synaptic membrane was treated with Triton X. After incubating a buffer solution (final volume: 1 ml) containing the receptor sample and the labeled ligand in the presence of various concentrations of the test compound for a certain period of time, the labeled ligand bound to the receptor was applied to the cell harvester (Brandell). Used to separate on filter. The radioactivity on the filter was measured with a liquid scintillation counter to determine the total amount of binding. In addition, the amount of binding in the presence of excess unlabeled ligand [granisetron] measured at the same time was defined as the amount of nonspecific binding, and the specific binding amount was determined by subtracting from this total binding amount. The concentration at which the test compound inhibits the specific binding of the labeled ligand by 50% (IC ₅₀ ) was calculated by the probit method, and the results are shown in Table 3.

Test Example 4 Cisplatin-induced emesis suppressing action A male ferret (Marshall, USA) having a body weight of about 1 kg was used. For intravenous administration, the jugular vein was cannulated under pentobarbital anesthesia 3-4 days prior to the experiment. Physiological saline (2 ml / kg) was used as a control group, and each dose of the test compound was used as an experimental group. Cisplatin (Sigma) 10 mg / kg (physiological saline 3 ml / kg) 30 minutes before and 45 minutes after the intravenous administration. Intravenous administration twice a minute. The latency from the administration of cisplatin to the onset of vomiting and the number of emesis induced within 3 hours after the administration of cisplatin were recorded.

The results are shown in Table 4.

Test Example 5 Mouse Acute Toxicity On the other hand, as an acute toxicity test, Std-ddY strain mice (25 to 30 g) were used, and the test compound dissolved in physiological saline was intravenously administered, and the presence or absence of death was observed for 7 days after the administration. It was observed and the LD ₅₀ value was calculated.

 The results are shown in Table 5.

As is clear from the above test results, compound (−) A and its physiologically acceptable acid addition salts are potent antagonists of serotonin 3 (5-HT ₃ ) receptors and are associated with acute and chronic gastritis. , Treatment and prevention of anorexia, nausea, vomiting, abdominal bloating, etc. in diseases such as gastric / duodenal ulcer, gastric neuropathy, gastric ptosis, etc., and diarrhea / biliary tract disorders, urinary tract disorders, and irritable bowel It can be used for the treatment and prevention of diarrhea and constipation such as syndrome or carcinoid syndrome. Furthermore, it can be used for the treatment and prevention of nausea or vomiting of motion sickness such as motion sickness at the time of administration of an anti-cancer agent such as cisplatin and at the time of radiation irradiation. It can also be used for the treatment and prevention of cluster headache, migraine and trigeminal neuralgia, and also for psychotic disorders such as anxiety, distress and schizophrenia or mania, dementia, cognitive impairment, stress-related. It can also be used to treat mental disorders, heart disorders (eg arrhythmias, angina), obesity, pulmonary embolism, rhinitis or serotonin-induced nasal disorders, insomnia or pain. It can also be used for the treatment and prevention of addiction to addictive drugs (alcohol, morphine, nicotine, amphetamine, etc.). The route of administration may be oral, parenteral or rectal.

The dose varies depending on the type of compound, administration method, patient's symptoms, age, etc., but is usually 0.0001 to 10 mg.
/ Kg / day, preferably 0.001 to 2 mg / kg / day. However, it is possible to use beyond this range at the discretion of the doctor.

 When the compound (-) A or a salt thereof is used in the above-mentioned medicinal use, it is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. As the pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and which does not react with the compound (-) A or a salt thereof is used. Specifically, for example, citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextrin, sorbit, cyclodextrin, starch, sucrose, methyl paraoxybenzoate, magnesium aluminometasilicate, synthetic aluminum silicate, Crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl cellulose calcium, ion exchange resin, methyl cellulose, gelatin, gum arabic, pullulan, hydroxy propyl cellulose, low-substituted hydroxy propyl cellulose, hydroxy propyl methyl cellulose, polyvinyl. Pyrrolidone, Polyvinyl alcohol, Light anhydrous silicic acid, Magnesium stearate, Talc, Tragant, Bentonite, Bee System, carboxyvinyl 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 acetate Examples include rucor, sodium hydroxide, hydrochloric acid and water. Dosage forms include tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections and suppositories. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or other appropriate medium before use. Tablets, granules and fine granules may be coated by a known method. These formulations may also contain other therapeutically valuable ingredients.

 In order to describe the present invention more specifically, reference examples and examples will be given below, but the present invention is not limited to these examples. The compound was identified by elemental analysis, mass spectrum, IR spectrum, UV spectrum, NMR spectrum and the like.

 Further, the following abbreviations may be used for simplification of description in the following examples and reference examples.

Ph: Phenyl group J: Binding constant s: Singlet d: Doublet m: Multiplet Br: Broad Example (-)-N- [1-methyl-4- (3-methylbenzyl) hexahydro-1H-1 , 4-Diazepin-6-yl] -1H-indazole-3-carboxamide: (1) 10 g of (S)-(−)-α-methoxy-α-trifluoromethylphenylacetic acid was added to thionyl chloride. Add to 100 ml and heat to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, 200 ml of dichloromethane and 13.6 ml of pyridine were added to the residue, and 6-amino-1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepine was added under ice cooling. Add 11 g dropwise and stir at room temperature for 2 hours. The reaction solution is washed with water and 1N hydrochloric acid in this order, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting mixture of two diastereomers was subjected to medium-pressure column chromatography using silica gel and eluted with ethyl acetate to elute (low polarity) oily (+)-N- [1]. 3.5 g of -methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepine-6-yl] -α-methoxy-α-trifluoromethylphenylacetamide are obtained.

Mass spectrum m / z: 449 (M ⁺ ) ¹ H-NMR spectrum (CDCl ₃ , δ ppm): 2.32 (3H, s, -CH ₂ C ₆ H ₄ C H ₃ ), 2.37 (3H, s,- NC H ₃ ), 2.4-3.0 (8H, m), 3.45 (3H, s, -OC H ₃ ), 3.42 (1H, d, J = 12Hz, -C H ₂ C ₆ H ₄ CH ₃ ), 3.55 ( 1H, d, J = 12Hz, -C H ₂ C ₆ H ₄ CH ₃ ), 4.12 (1H, m, -CONHC H- ), 7.0-7.2 (4H, m, -CH ₂ C ₆ H ₄ CH ₃ ) , 7.3-7.5 (5H, m, -CH ₂ C ₆ H ₅ ), 7.84 (1H, d, J = 7Hz, -CON H- ). ¹⁹ F-NMR spectrum (CDCl ₃ , δ ppm):-
70.02. (2) The above compound (3.0 g) is added to concentrated hydrochloric acid (250 ml), the mixture is heated under reflux for 72 hours, and then the solvent is distilled off under reduced pressure.

To the residue was added 10% sodium hydroxide, the mixture was extracted with dichloromethane, dried, and the solvent was distilled off under reduced pressure to obtain oily (+)-6-amino-1-methyl-4- (3-methylbenzyl). 2.4 g of hexahydro-1H-1,4-diazepine are obtained.

(3) To an N, N-dimethylformamide solution (20 ml) containing 1.2 g of 1H-indazole-3-carboxylic acid, 1.2 g of N, N'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 2 hours. 2.4 g of the above compound is added to the reaction solution and stirred for 8 hours. The reaction solution is washed with water and a 10% aqueous sodium hydroxide solution in this order, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The crystallized solid obtained is recrystallized from acetone to obtain 1.2 g of the desired product.

Melting point 163-164 ° C. Mass spectrum m / z: 337 (M ⁺ ). ¹ H-NMR spectrum (CDCl ₃ , δppm): 2.30 (3H, s, -CH ₂ C ₆ H ₄ C H ₃ ), 2.60 (3H, s,- NC H ₃ ), 2.5-2.8 (8H, m), 3.63 (2H, s, -C H ₂ C ₆ H ₄ CH ₃ ), 4.55 (1H, m.-CONHC H- ), 6.95-7.50 (7H, m), 8.42 (1H, d, J = 9Hz, 4-H), 8.90 (1H, m, -CON H- ), 13.8 (1H, br, 1-H). (4) 1.0 g of the above object Is dissolved in 20 ml of ethanol, 1.4 g of a 30% hydrochloric acid-ethanol mixed solution is added, and the precipitated crystals are collected by filtration and dried to obtain 1.0 g of the desired dihydrochloride.

Melting point 248-249 ° C. Reference Example 1 Preparation of 6-amino-1-methyl-4- (3-methylbenzil) hexahydro-1H-1,4-diazepine: (1) Helv. Chim. Acta, 45 , 2383 ~ 2402 (1962). 6.1 g of 2-chloromethyl-1-benzyl-4-methylpiperazine synthesized according to the method described is dissolved in 60 ml of acetonitrile, 3.3 g of sodium azide is added, and the mixture is heated under reflux for 2 hours.

The insoluble matter is filtered off and the filtrate is evaporated under reduced pressure.

The residue is dissolved in 100 ml of toluene, and 10.4 g of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene under ice-cooling is added little by little, followed by stirring at room temperature for 3 hours. Pour the reaction mixture into ice water and add a 48% aqueous sodium hydroxide solution. The aqueous layer is extracted with toluene, combined with the organic layer, dried over anhydrous magnesium sulfate, 5.2 g of anhydrous acetic acid is added, and the mixture is stirred at room temperature for 2 hours. The reaction solution was washed with 48% aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 5.4 g of an oily product. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1) and purified to give oily 6-acetylamino-1-benzyl-4-methylhexahydro-1H-1,4-diazepine 1.0. get g.

¹ H-NMR spectrum _{(CDCl 3, δ ppm):} 1.85 (3H, s, -COC H 3), 2.35 (3H, s, -NC H 3), 3.46, 3.72 ( each 1H, each d, each J = 13Hz, -C H ₂ Ph), 3.98 (1H, m.-CONHC H- ), 6.35 (1H, d, -CON H- ), 7.30 (5H, m, -CH ₂ C ₆ H ₅ ). (2 ) 20 g of the above compound is dissolved in 400 ml of ethanol and 70 ml of acetic acid, 2.0 g of 10% palladium carbon is added as a catalyst, and hydrogenation is carried out under heating and atmospheric pressure. After absorbing a calculated amount of hydrogen, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 30 g of oily 6-acetylamino-1-methylhexahydro-1H-1,4-diazepine acetate.

(3) A mixture consisting of 3.0 g of the above compound, 3.5 g of 3-methylbenzyl chloride, 17 g of anhydrous potassium carbonate, 0.1 g of sodium iodide and 200 ml of methyl ethyl ketone is heated under reflux for 16 hours. The insoluble matter is filtered off, and the filtrate is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (20: 1), and oily 6-acetylamino-1-methyl-4- (3-methylbenzyl) hexahydro- 1.5 g of 1H-1,4-diazepine are obtained. ¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.86 (3H, s, -COC H ₃ ), 2.34 (3H, s, -CH ₂ C ₆ H ₄ C H ₃ ), 2.36 (3H, s,- NC H ₃ ), 3.43,3.67 (each 1H, each d, each J = 12Hz, -C H ₂ C ₆ H ₄ CH ₃ ), 3.97 (1H, m, -CONHC H- ), 6.45 (1H, d, -CON H- ), 7.0-7.4 (4H, m, -CH ₂ C ₆ H ₄ CH ₃ ). (4) Dissolve 1.8 g of the above compound in 20 ml of 10% hydrochloric acid and heat under reflux for 2 hours. After cooling to room temperature, the mixture is made alkaline with an aqueous sodium hydroxide solution, extracted with chloroform, the chloroform layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.5 g of the oily target substance. Reference Example 2 Preparation of (+)-N- [1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepin-6-yl] -1H-indazole-3-carboxamide: ( R)-(+)-α-methoxy-α-trifluoromethylphenylacetic acid and 6-amino-1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepine. By reacting and treating in the same manner as in Example (1), (-)-N- [1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepin-6-yl]- α-Methoxy-α-trifluoromethylphenylacetamide is obtained.

 The above compound is reacted and treated in the same manner as in Example (2), and then 1H-indazole-3-carboxylic acid is reacted and treated in the same manner as in Example (3) to obtain the desired product.

The desired product is reacted and treated in the same manner as in Example (4) to obtain the desired dihydrochloride. Agent example 1 (-) N- [1-Methyl-4- (3-methylbenzil) hexahydro-1H-1,4-diazepin-6-yl] -1H-indazole-3-carboxamide dihydrochloride injection in appropriate amount Dissolve in water, add citric acid and sorbitol to dissolve, then adjust the pH value to 4.5 with sodium hydroxide, and add water for injection to adjust the total volume. The solution is filtered through a membrane filter (0.22 μm), the filtrate is filled into 2 ml ampoules and then it is sterilized at 120 ° C. for 20 minutes. Formulation Example 2 Per 1000 tablets (-)-N- [1-methyl-4- (3-methylbenzil) hexahydro-1H-1,4-diazepin-6-yl] -1H-indazole-3-carboxamide. Dihydrochloride ……………… 10g Lactose ………………………………………… 76.5g Corn starch ……………… 28g Crystalline cellulose ………………………… 25g Hydroxypropyl Cellulose: 3.5 g Light anhydrous silicic acid: 0.7 g Magnesium stearate: 1.3 g The above ingredients were mixed and granulated by a conventional method, and then tableted at 145 mg per tablet, Produce 1000 tablets. Formulation Example 3 Per 1000 capsules (-)-N- [1-methyl-4- (3-methylbenzil) hexahydro-1H-1,4-diazepin-6-yl] -1H-indazole-3-carboxamide. Dihydrochloride ……………… 10g Lactose …………………………………… 190g Corn starch ……………… 22g Hydroxypropylcellulose …… 3.5g Light anhydrous silicic acid ………… ………… 1.8g Magnesium stearate ………… 2.7g By the usual method, the above ingredients are mixed and granulated, and then filled into 1000 capsules. Formulation Example 4 Per 1000 g (-)-N- [1-methyl-4- (3-methylbenzyl) hexahydro-1H-1,4-diazepin-6-yl] -1H-indazole-3-carboxamide.2 Hydrochloride ……………… 20g Lactose …………………………………… 950g Hydroxypropylcellulose …… 25g Light anhydrous silicic acid ……………… 5g After mixing the ingredients, make into a granule.

Claims (4)

[Claims] 1. (-)-N- [1-Methyl-4- (3-
(Methylbenzyl) hexahydro-1H-1,4-diazepin-6-yl] -1H-indazole-3-carboxamide or a salt thereof. 2. (-)-N- [1-Methyl-4- (3-
(Methylbenzyl) hexahydro-1H-1,4-diazepin-6-yl] -1H-indazole-3-carboxamide dihydrochloride. 3. An antiemetic agent comprising the compound according to claim 1 or a salt thereof as an active ingredient. 4. An antiemetic agent containing the compound according to claim (2) as an active ingredient.