JPH0570456A - Benzoxazine compound - Google Patents

Abstract

PURPOSE:To obtain a new compound, having excellent and sustained release antagonistic action on serotonin recceptors and useful as a medicine. CONSTITUTION:6-Chloro-2,2,4-trimethyl-N-(9-methyl-9-azabicyclo[3.3.1] non-3- yl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide, its stereoiso and salts thereof. The above-mentioned compound is obtained by reacting 6-chloro-2,2,4- trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid with 9-methyl-9- azabicyclo[3.3.1]nonan-3-amine. The resultant compound is useful for treating disease in digestive organs such as dyspepsia, nausia, emesis, diarrhea, indefinite complaint of digestive organs or irritable bowel syndrome, diseases in central nervous systems such as dementia, depressaive symptoms, anxiety or neuropathy, abuse of medicines, substance dependence, etc.

Description

Detailed Description of the Invention

[0001]

The present invention has pharmacological activity,
The present invention relates to a novel benzoxazine compound useful as a medicine, its stereoisomers and pharmaceutically acceptable salts thereof.

[0002]

PRIOR ART AND PROBLEM TO BE SOLVED BY THE INVENTION One of the serotonin (5-HT) receptor subtypes, 5
It has been confirmed that the -HT ₃ receptor exists in the sensory nervous system, the autonomic nervous system and the like, and is also distributed in the central nervous system. As the whole picture of this 5-HT ₃ receptor becomes clear, it is suggested that the clinical application of the antagonist is wide ranging from peripheral to central. This compound showing an antagonistic action on the 5-HT ₃ receptor is used for treating disorders such as depressive symptoms, anxiety, psychosis or dementia in the central nervous system, and indigestion, nausea, vomiting and diarrhea in the digestive tract system. It is known to be useful for prevention and treatment of digestive system diseases such as digestive system indefinite complaints and irritable bowel syndrome, and for reduction or treatment of addiction caused by drug abuse. As the 5-HT ₃ receptor blocker, 1H-indole-3-carboxylic acid 3α-tropanyl ester (tropisetron), 1,2,3,9-tetrahydro-9-methyl-3-[(2 -Methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (ondansetron), endo-1-methyl-N- (9-methyl-9-azabicyclo [3.3.1]] Non-3-yl)-
1H-indazole-3-carboxamide (granisetron) and the like are known. Also, US Pat. No. 4,89
No. 2,872, No. 4,933,445, No. 4,9
No. 35,511 discloses 2H-1,4-benzoxazinecarboxamide compounds showing 5-HT ₃ receptor antagonistic activity. An object of the present invention is to provide a compound having a superior and long-lasting antagonistic action on the 5-HT ₃ receptor.

[0003]

The present invention provides 6-chloro-2,2,4, which has a superior and long-lasting antagonism of 5-HT ₃ receptors and is useful as a medicine. -Trimethyl-N- (9-methyl-9-azabicyclo [3.
3.1] Non-3-yl) -3,4-dihydro-2H-
It relates to 1,4-benzoxazine-8-carboxamide, its stereoisomer or a pharmaceutically acceptable salt thereof. The compound of the present invention is 6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (hereinafter, also referred to as carboxylic acid compound) or its reactivity. It is produced by reacting the derivative with 9-methyl-9-azabicyclo [3.3.1] nonan-3-amine (hereinafter, also referred to as amine compound) or a stereoisomer thereof. (A) When using a free carboxylic acid, the reaction is dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halide (phosphorus trichloride, phosphorus oxychloride, etc.), diethylchlorophosphite, o-phenylenechlorophosphite,
It is carried out in an inert solvent in the presence of a condensing agent such as ethyldichlorophosphite, under cooling, at room temperature or under heating.
The amine compound may be reacted with phosphorus halide in an inert solvent in advance and then condensed with the carboxylic acid compound. For example, when the phosphorus halide is phosphorus trichloride, the amine compound is preliminarily about 1/2
After reacting mol of phosphorus trichloride in an active solvent in the presence of a tertiary base such as triethylamine, pyridine and N, N-dimethylaniline under cooling or at room temperature, the carboxylic acid compound is allowed to react with the carboxylic acid compound at room temperature or The reaction is carried out under heating, preferably under heating under reflux. (B) When an acid halide such as acid chloride or acid bromide is used as the reactive derivative of the carboxylic acid compound, the reaction is carried out in an inert solvent with triethylamine, pyridine, N, N
-In the presence of a tertiary base such as dimethylaniline under cooling or at room temperature, or in the presence of an alkali such as sodium hydroxide, potassium hydroxide in water under cooling or at room temperature. (C) As a reactive derivative of a carboxylic acid compound, a symmetrical acid anhydride or a mixed acid such as an alkyl carbonic acid mixed acid anhydride, an alkyl phosphoric acid mixed acid anhydride, an alkyl phosphorous acid mixed acid anhydride, and a sulfuric acid mixed acid anhydride. When an anhydride is used, the reaction is triethylamine, pyridine, N, N- in an inert solvent.
It is carried out in the presence of a tertiary base such as dimethylaniline or N-methylmorpholine, under cooling, at room temperature or under heating. (D) When an active amide such as acid imidazolide, acid pyrrolidide, or 2,4-dimethylpyrazolidide is used as the reactive derivative of the carboxylic acid compound, the reaction is carried out in an inert solvent at room temperature or under heating. (E) When an ester such as methyl ester, ethyl ester, p-nitrophenyl ester or p-chlorophenyl ester is used as the reactive derivative of the carboxylic acid compound, the reaction is carried out with an inert solvent (the amine compound is used in excess to serve as the solvent. It can be carried out at room temperature or under heating, preferably under heating under reflux. As the inert solvent used in each of the above condensation reactions, benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, diethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, hexamethylphosphoric triamide, diethylene glycol, When the carboxylic acid compound is a reactive derivative, such as dimethylformamide, ethyl acetate or the like, or a mixed solvent thereof, it is appropriately selected depending on its type. Carboxylic acid compounds include, for example, synthesis
(Synthesis) 6-chloro-2,2 produced according to the method described in 1979, page 541 or according to the method described in US Pat. No. 4,892,872.
-Dimethyl-3-oxo-3,4-dihydro-2H-
6-chloro-obtained by reducing 1,4-benzoxazine-8-carboxylic acid ester (ethyl ester etc.) with sodium borohydride-3 borondifluoride diethyl ether complex in an inert solvent such as tetrahydrofuran. 2,2-Dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid is esterified with an alcohol (methanol, etc.), and then the ester compound is added in the presence of a base (potassium carbonate, triethylamine, etc.). , Methylating agents (methyl halides such as methyl chloride and methyl iodide, dimethyl sulfate, etc.)
Is obtained, and then alkali hydrolysis is carried out. The compound obtained by the present invention has a stereoisomer (endo-exo form) derived from a crosslinked amine,
In the present invention, it is preferable to obtain the desired stereoisomer by selecting the starting amine compound. The compounds of the present invention may be combined with pharmaceutically acceptable acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, maleate, fumarate, tartrate and the like. can do.

When the compound of the present invention is used as a medicine,
It is usually mixed with additives such as pharmaceutically acceptable carriers, excipients and diluents, and safely administered to patients in the form of tablets (including sugar-coated tablets and film-coated tablets), granules, powders, injections, etc. It The dose may vary depending on the patient's symptoms, body weight, age, etc., but usually, in the case of oral administration, it is about 0.1 to 50 mg / kg per day for an adult, and this may be administered once or in several divided doses. preferable.

[0005]

The compound of the present invention exhibits an excellent and long-lasting 5-HT ₃ receptor antagonistic action. 5 of the compounds of the present invention
-HT ₃ receptor antagonism is induced by intravenous administration of 5-HT to rats, and von Besault-Jarish reflex (JRFozard, Naunyn-Schmiedebergs Arch. Ph.
armacol. 326, 36 (1984)), and [ ³ H] -for the 5-HT ₃ receptor.
It is shown by the specific binding test of granisetron. The compound of the present invention is used for the prevention and treatment of digestive system diseases such as dyspepsia, delayed gastric emptying, diarrhea, digestive system indefinite complaint, irritable bowel syndrome, peptic ulcer and / or migraine,
Cluster headache, arrhythmia or nausea, vomiting, especially nausea or vomiting induced by the administration of anticancer agents, nausea or vomiting induced by radiation therapy, or dementia, depressive symptoms,
Anxiety, central nervous system disorders such as psychosis, treatment of substance abuse and substance dependence, or abnormal behavior such as dyskinesia, old age or cerebrovascular disorder and excitability associated with alcoholism, aggression, emotional disorder etc. Useful for treatment.

[0006]

EXAMPLES The present invention will be described in detail below with reference to reference examples and examples, but the present invention is not limited thereto.

Reference Example 1 6-chloro-2,2-dimethyl-3,4-dihydro-2
A mixture of H-1,4-benzoxazine-8-carboxylic acid, methanol and concentrated sulfuric acid is heated to reflux with stirring.
The reaction solution is cooled and the precipitated crystals are collected by filtration, washed with methanol and dried to give 6-chloro-2,2-dimethyl-
3,4-dihydro-2H-1,4-benzoxazine-
Methyl 8-carboxylate is obtained. Reference Example 2 6-chloro-2,2-dimethyl-3,4-dihydro-2
Methyl iodide is added to a solution of methyl H-1,4-benzoxazine-8-carboxylate and potassium carbonate in dimethylformamide under cooling and stirring, and the mixture is heated and stirred. The reaction solution was added to water, the insoluble matter was filtered off, washed with water and dried to give 6-
Chloro-2,2,4-trimethyl-3,4-dihydro-
Methyl 2H-1,4-benzoxazine-8-carboxylate is obtained. Reference Example 3 Methyl 6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate and sodium hydroxide were dissolved in a mixed solvent of methanol and water and heated. Stir. Add the reaction mixture to water,
Add concentrated hydrochloric acid. The insoluble matter is collected by filtration, washed with water and dried to obtain 6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid. Melting point 172-174 ° C

Example 1 1.12 g of 6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid was dissolved in 30 ml of ethyl acetate to give triethylamine 1 .23 ml was added. -10 to 5 ° C in this solution
While cooling, 0.53 g of pivaloyl chloride is added dropwise. After stirring at the same temperature for 15 minutes, endo-8-methyl-9-azabicyclo [3.3.1] nonan-3-amine (0.68 g) was added at -10 to 5 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture obtained is washed with water, dried over magnesium sulfate and then concentrated. Ethanol hydrochloric acid was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol, and the melting point was 262 ° C.
(Decomposition) endo-6-chloro-2,2,4-trimethyl-N- (9-methyl-9-azabicyclo [3.3.
1] non-3-yl) -3,4-dihydro-2H-1,
4-benzoxazine-8-carboxamide hydrochloride is obtained as white crystals.

Formulation Example 1 Compound of Example 1 10.0 mg Lactose 30.0 mg Corn starch 19.8 mg Crystalline cellulose 28.0 mg Talc 2.0 mg Magnesium stearate 0.2 mg Total amount 90.0 mg Compound of Example 1 and lactose , Corn starch and crystalline cellulose are mixed, a part of corn starch is kneaded and granulated as a paste solution, and dried at 50 ° C. for 3 hours. The dried product is passed through a 24-mesh sieve, talc and magnesium stearate are added, and a tablet having a diameter of 6.0 mm is produced on a rotary tableting machine to produce a tablet of 90 mg per tablet. Next, this tablet is coated with hydroxypropylmethylcellulose and titanium oxide as a film coating base at 5 mg per tablet. Formulation Example 2 Compound of Example 1 5.0 mg Sodium chloride 18.0 mg Distilled water for injection Total 2.0 ml Sodium chloride was dissolved in about 80 parts of distilled water for injection,
Then, the compound of Example 1 was added and dissolved, and the whole amount (100
Part). After filtration using a membrane filter (0.2 μm), fill an ampoule of 2 ml in volume and 115 ° C.
It is manufactured by sterilizing for 30 minutes.

[0010]

EFFECTS OF THE INVENTION Pharmacological test 1: Specific binding test of [ ³ H] -granisetron to 5-HT ₃ receptor Using [ ³ H] -granisetron as a labeling compound, Biochemical Pharmacology (Biochem.
l.), 38, 1693-1695 (1984).
The experiment was performed by the method of Nelson and Thomas et al. Control [ ³ H] -granisetron 5-
The inhibitory constant (Ki value) was determined by graphically determining the 50% inhibitory concentration (IC ₅₀ ) of the compound of the present invention with respect to the specific binding amount to the HT ₃ receptor, and the Ki of the compound of Example 1 was determined.
The value was 0.019 nM.

Pharmacological test 2: Antagonism of Von Bezold-Jarish reflex Naunyn-Schmiedebergs Arch. Pharmacol. 326
Volume, page 36 (1984), Fozard
5-HT of the compound of the present invention using as an index the antagonism of von Besold-Jarish reflex induced by serotonin in rats anesthetized according to the method of
₃ Receptor blocking effect was evaluated. Male Wistar rats weighing 350 to 450 g were anesthetized by intraperitoneal administration of urethane 1.25 g / kg, and an intravenous cannula was inserted into the left external jugular vein and a blood pressure and heart rate measuring cannula was inserted into the left femoral artery. The antagonistic effect of the compound of the present invention (intravenous administration, 5 minutes pretreatment) on reflex bradycardia induced by intravenous administration of serotonin 20 μg / kg was examined to find that the maximum activity was 5%.
When the dose required for 0% antagonism (ED ₅₀ ) was calculated,
It was 0.24 μg / kg. Next, the compounds of the present invention were administered to serotonin intravenously at 14, 30, 45, 60 and 1
20 minutes before intravenous administration, antagonism against von Besault-Jarish reflex was measured by the same method as above to determine an effective dose (ED ₅₀ ). The results are summarized in Table 1.

[0012]

[Table 1] Table 1 ──────────────────────────────────── ED ₅₀ (μg / kg) Test compound ────────────────────────── 5 minutes 15 minutes 30 minutes 45 minutes 60 minutes 120 minutes ─────────── ────────────────────────── 0.24 0.15 0.11 0.10 0.11 0.12 Compound of Example 1 ───────────── ─────────────────────── (In the table, the time (minutes) indicates the dosing interval between the test compound and serotonin.)

The compound of Example 1 was orally (300 mg / kg) or intraperitoneally (100 mg) administered to ddy mice.
/ Kg), no abnormality was observed for 5 days.

The compounds of the present invention, their stereoisomers, and their pharmaceutically acceptable salts are excellent and durable.
-HT ₃ receptors have antagonistic activity, useful as pharmaceuticals.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/535 ACP AEN (72) Inventor Ryuhei Ikezawa Ryohei Ikezawa, Yoshitomi-cho, Chikomi-gun, Fukuoka 955 Address Yoshi Tomi Pharmaceutical Co., Ltd. Central Research Laboratory

Claims (1)

[Claims] 1. 6-Chloro-2,2,4-trimethyl-
N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide, its stereoisomer or their Pharmaceutically acceptable salts.