JPH10203987A - Agent containing (r)-1-ethyl-4-methylhexahydro-1h-1,4-diazepine derivative as active component and effective for suppressing vomition induced by morphine-like agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an agent effective for suppressing the vomition caused by the administration of a morphine-like agent such as morphine by using an (R)-1-ethyl-4-methylhexahydro-1H-1,4-diazepine derivative as a component. SOLUTION: This agent contains a compound of the formula (Ar is 5-bromo-2- methoxy-6-methylamino-3-pyridyl or 5-chloro-2-methoxy-4-methylaminophenyl) as an active component. The compound of the formula has strong antagonistic action on the receptors of both serotonin S3 (5-HT3 ) and dopamine D2 , exhibits excellent suppressing action on morphine-induced vomition, exerts weak central suppressing action and is useful for the treatment and prevention of nausea and vomition caused by the administration of a morphine-like agent for suppressing the pain of cancer. The compound of the formula is compounded in an amount of 0.1-70wt.% and formed in the form of a drug for oral administration, parental administration or rectal infusion. The administration rate is 0.01-10mg/kg/day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to serotonin S ₃
(R) -1-ethyl-4-methylhexahydro-1H-1,4-diazepine derivative showing potent antagonism at both (5-HT ₃ ) and dopamine D ₂ receptors, more specifically 5
(R) having a bromo-2-methoxy-6-methylamino-3-pyridinecarboxamide moiety or a 5-chloro-2-methoxy-4-methylaminobenzamide moiety
1-ethyl-4-methylhexahydro-1H-1,4-
The present invention relates to a morphine-like drug-induced emesis suppressant containing a diazepine derivative as an active ingredient.

[0002]

2. Description of the Related Art JP-A-5-92959 discloses

[0003]

Embedded image

[Wherein, R ₁ and R ₂ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkyl group having a substituent, etc., and R ₃ is the same or different and each represents a hydrogen atom, R ₅ is the same or different and each represents a hydrogen atom, a halogen atom, a lower alkoxy group, an amino group, a mono-substituted or di-substituted amino group, etc., and Het is a monocyclic heteroaryl group or A bicyclic heteroaryl other than a 1H-indazolyl group, q
Represents 0, 1 or 2, s represents 1, 2 or 3,
B represents —CXNR ₆ (CH ₂ ) r— or the like, wherein R ₆ represents a hydrogen atom, a lower alkyl group, etc., X represents an oxygen atom or a sulfur atom, and r represents 0, 1, 2, or Or 3
M represents 1, 2, 3 or 4, and n represents 1, 2,
Or 3. ]

The compound represented by the formula is serotonin S ₃ (5-
HT ₃ ) antagonizes the receptor and causes anorexia, nausea, vomiting, abdominal distension, etc. in diseases such as acute / chronic gastritis, gastric / duodenal ulcers, or nausea or vomiting such as sickness, etc. Although it is described that it can be used for the treatment and prevention of morphine, no description is given of its inhibitory effect on vomiting induced by morphine-like drugs.

Japanese Patent Publication No. 7-500590 discloses the following chemical formula 4.

[0007]

Embedded image

Wherein R ₁ is C _1-6 alkoxy, C _3-8
Cycloalkoxy or C _3-8 cycloalkyl C _1-4 alkoxy; R ₂ is hydrogen, halo, C _1-6 alkyl, C _1-6
Alkoxy or optionally substituted by one or two C _1-6 alkylamino; R ₃ is hydrogen, halo or C _1-6 alkyl; L is O or NH; and Z is di - azacyclic Or an azabicyclic side chain. )

And a compound described as a 5-HT ₃ antagonist that can be used in the treatment or prevention of pain, vomiting, central nervous system disorders and gastrointestinal disorders. ing.

[0010] The above-mentioned Japanese Patent Application Laid-Open No. 5-92959 further describes the same clinical use of the compound represented by the following chemical formula 5 as with the compound represented by the chemical formula 3 above.

[0011]

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(Wherein R ₁ ′ represents a lower alkyl group;
R ₂ ′ represents a hydrogen atom, a lower alkyl group and the like, R ₇ ′ represents a lower alkoxy group and the like, and R ₅₂ represents an amino group, a methylamino group, a dimethylamino group and the like. )

Japanese Patent Application Laid-Open No. 1-117860 describes that a compound represented by the following formula 6 has a gastrointestinal function enhancing action and is useful as an antiemetic or gastrointestinal enhancer. There is no description of an inhibitory effect on vomiting induced by morphine-like drugs.

[0014]

Embedded image

Wherein R ₁ represents a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group;
₂ represents a hydroxyl group, means an alkoxy group, R ₃ denotes an amino group, disubstituted amino group, or an acylamino group, R ₄
Represents a halogen atom, or R ₃ and R ₄ may be taken together to form —NH—N ＝ N—, R ₅ represents a hydrogen atom, a lower alkyl group, and X represents a single bond or means a lower alkylene group, Y is a single bond, -CH ₂ -, -
NR _6- (R ₆ represents a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group or the like) and the like, n represents 0 or 1, and a broken line represents n when Y is -CH ₂ -and n
When 0 is 0 means an optionally present double bond. However, when (i) Y is a single bond, n means 0, and (ii) when Y is -O-, n means 1.
(Iii) when Y is a single bond or —CH ₂ —, R ₁ represents an unsubstituted or substituted aryl (lower) alkyl group; and (iv) when n is 0, X represents a lower alkylene group. I do. ]

Japanese Patent Application Laid-Open No. 4-210970 discloses that a compound represented by the following formula 7 has a strong 5-HT ₃ receptor antagonistic action and a strong dopamine D ₂ receptor antagonistic action, and Although described as useful, there is no description of any inhibitory effect on vomiting induced by morphine-like drugs.

[0017]

Embedded image

Wherein R ₁ represents a hydrogen atom or a lower alkyl group, R ₂ represents

[0019]

Embedded image

Here, B represents a linear lower alkylene group, A represents -CO-, etc., R ₁₀ represents a hydrogen atom or a halogen atom, and R ₃ represents a hydroxyl group, a lower alkoxy group or the like. R ₄ represents a hydrogen atom, a halogen atom, etc., R ₅ represents an amino group, a mono- or di-lower alkylamino group, etc., R ₆ represents a hydrogen atom, a halogen atom, etc., and R ₇ represents a hydrogen atom, means a lower alkoxy group, R ₈ is a hydrogen atom, a lower alkyl group, R ₉
Represents a hydrogen atom, a lower alkyl group or the like, and n represents 1, 2 or 3. )

[0021]

SUMMARY OF THE INVENTION Domperidone, a dopamine D ₂ receptor antagonist [chemical name: 5-chloro-1-
[1- [3- (2,3-dihydro-2-oxo-1H-
Benzimidazol-1-yl) propyl] -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one; for example, Merck Index, 11th edition, 3412
(1989) is effective for vomiting associated with various gastrointestinal symptoms and vomiting associated with upper respiratory tract infection in children, but has a sufficient effect on vomiting that occurs when administering anticancer drugs such as cisplatin. I can't say.

Accordingly, a serotonin S ₃ receptor antagonist has been developed as a drug that selectively and strongly suppresses vomiting that occurs when an anticancer drug is administered. Currently, granisetron hydrochloride [chemical name: endo-1-methyl-N- (9- Methyl-9-azabicyclo [3.3.1] non-3-yl) -1H-indazole-3-carboxamide hydrochloride; for example, MerckI
ndex, 11th edition, 4443 (1989)], ondansetron hydrochloride [chemical name: 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazole-1-
Yl) methyl] -4H-carbazol-4-one hydrochloride; see, for example, MerckIndex, 11th edition, 6802 (1989)], and azasetron hydrochloride [chemical name: (±) -N-1
-Azabicyclo [2.2.2] oct-3-yl-6
Chloro-3,4-dihydro-4-methyl-3-oxo-
2H-1,4-benzoxazine-8-carboxamide hydrochloride; for example, Drugs of the Future, 18 (3), 206-2
11 (1993)]. However, the clinical application of these serotonin S ₃ receptor antagonists is mainly limited to vomiting that occurs upon administration of anticancer drugs and the like.

On the other hand, in the treatment of cancer, not only vomiting that occurs when an anticancer drug is administered, but also persistent physical pain at the end of cancer afflicts the patient. For this reason, morphine preparations are frequently used to relieve cancer pain in cancer patients, but morphine has many gastrointestinal and central nervous system side effects, which pose a major problem in pain treatment associated with cancer treatment. ing. In particular, as a side effect of morphine, side effects of gastrointestinal symptoms such as nausea, vomiting and constipation are high, and metoclopramide [chemical name: 4-amino-
5-chloro-N- [2- (diethylamino) ethyl]-
2-methoxybenzamide dihydrochloride monohydrate; see, for example, Merck Index, 11th edition, 6063 (1989)], haloperidol [chemical name: 4- [4- (4-chlorophenyl)
-4-hydroxy-1-piperidinyl] -1- (4-fluorophenyl) -1-butanone; for example, Merck Inde
x, 12th edition, 4629 (1996)], and antiemetic agents such as domperidone described above have been used. However, the efficacy of these drugs is not sufficient, and the development of an even better antiemetic has been desired.

[0024]

The present inventors have developed a potent and selective serotonin S ₃ receptor antagonist and dopamine D
_In a series of researches on substances having both ₂ receptor antagonism, the following formula (I)

[0025]

Embedded image (In the formula, Ar means a 5-bromo-2-methoxy-6-methylamino-3-pyridyl group or a 5-chloro-2-methoxy-4-methylaminophenyl group.)

As a result of examining various antiemetic effects of the (R) -1-ethyl-4-methylhexahydro-1H-1,4-diazepine derivative represented by the following formula, a compound represented by the formula (I) was obtained. The present inventors have found that they have a particularly strong inhibitory effect on vomiting induced by morphine-like drugs represented by morphine, and completed the present invention.

According to the present invention, (R) -1-ethyl-4-methylhexahydro-1H-
An agent for suppressing morphine-like drug-induced emesis comprising a 1,4-diazepine derivative and a physiologically acceptable acid addition salt thereof as an active ingredient is provided.

Examples of the physiologically acceptable acid addition salts of the compound represented by the formula (I) include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate. Acid salts,
And organic acid salts such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate and methanesulfonate.

The compound of formula (I) and the physiologically acceptable acid addition salts thereof may exist as hydrates and / or solvates, and these hydrates and / or solvates are also present. Included in the compounds according to the invention.

As used herein, the term "morphine-like drug" refers to a drug used in the treatment of pain and antitussives such as cancer diseases in the clinic. For example, morphine, a narcotic analgesic, is used.
Ethyl morphine, synthetic narcotic analgesic pethidine, non-narcotic analgesics pentazocine, eptazosin, buprenorphine, codeine, an antitussive that is a related compound of morphine,
Dihydrocodeine and the physiologically acceptable acid addition salts of these compounds are mentioned. Physiologically acceptable acid addition salts include the same as those mentioned above for the compounds of formula (I). The morphine-like drugs used clinically are, specifically, morphine hydrochloride, morphine sulfate, buprenorphine hydrochloride, pethidine hydrochloride, epazosin hydrobromide, codeine phosphate, typical examples of which are morphine hydrochloride and buprenorphine hydrochloride. Is mentioned. As for morphine, there are various dosage forms called morphine preparations. Specifically, morphine is used as morphine hydrochloride powder, morphine hydrochloride tablets, morphine sulfate release tablets, morphine hydrochloride injection, and morphine hydrochloride suppository. .

The scope of the compound of the formula (I) includes the compounds represented by the following formulas (10) and (11), and physiologically acceptable salts thereof.

[0032]

Embedded image

(R) -5-bromo-N- (1-ethyl-
4-methylhexahydro-1H-1,4-diazepine-
6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide and

[0034]

Embedded image

(R) -5-chloro-N- (1-ethyl-
4-methylhexahydro-1H-1,4-diazepine-
6-yl) -2-methoxy-4-methylaminobenzamide.

The compound of the formula (I) is, for example, represented by the following formula (I
I)

[0037]

Embedded image Ar-COOH (II)

(Wherein Ar has the same meaning as described above) or a reactive derivative thereof represented by the following formula (III):

[0039]

Embedded image

The compound can be produced by reacting with the compound represented by the following formula. Production examples 1 and 2 described below show specific production methods.

The starting compound of the formula (II) in which Ar is a 5-bromo-2-methoxy-6-methylamino-3-pyridyl group can be produced, for example, by the process shown in the following chemical formula (14). Example 1 shows specific conditions of each step.

[0042]

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(Wherein R ₁ is a linear or branched C _1-
It means a C ₆ alkyl group. The compounds of formula (II) in which Ar is a 5-chloro-2-methoxy-4-methylaminophenyl group can be prepared by methods known per se,
For example, it can be produced by the method described in J. Med. Chem., 24 , 1224-1230 (1981) or a method analogous thereto. Further, the compound of the formula (III) used as a starting material can be produced, for example, by the process shown in the following chemical formula 15, and Reference Example 2 described below shows specific conditions of each process.

[0044]

Embedded image

Wherein Et represents an ethyl group, and Z ₁ represents
tert-butoxycarbonyl group, triphenylmethyl group,
An amino-protecting group such as an acetyl group; Z ₂ represents a chlorine atom, a bromine atom, a benzyloxycarbonyl group optionally substituted by methoxy or nitro, and R ₂ represents a hydrogen atom, a halogen atom, Atoms, C ₁ -C ₃
Means an alkyl group or a C ₁ -C ₃ alkoxy group, R ₁
Has the above-mentioned meaning. )

According to the above process for preparing the compound of formula (I), the configuration of the compound of formula (III) as the starting material is retained in the product of formula (I).

The compound of the formula (I) produced by the above-mentioned production method can be isolated and purified by a conventional method such as chromatography, recrystallization and reprecipitation.

The compound of the formula (I) and the compound of the formula (III) can be obtained in the form of a free base or an acid addition salt depending on reaction and treatment conditions. The acid addition salt can be converted to a free base by a conventional method, for example, treatment with a base such as alkali carbonate or alkali hydroxide, while the free base can be converted to a free base by treatment with various acids according to a conventional method. It can lead to acid addition salts.

[0049]

The results of pharmacological tests of the compound of formula (I) (compounds of Preparation Examples 1 and 2 described below) and the following control compounds are shown below, and the characteristics of the pharmacological action of the compound of formula (I) are shown below. explain.

(1) Domperidone: a selective dopamine D ₂ receptor antagonist used clinically as an antiemetic or gastrointestinal tract function improving agent. (2) Ondansetron hydrochloride: A selective serotonin S ₃ receptor antagonist used clinically when an anticancer drug is administered as an antiemetic. (3) Haloperidol: an antipsychotic agent that has a strong dopamine D ₂ receptor inhibitory activity and is used clinically. (4) Metoclopramide hydrochloride: a drug used clinically as an antiemetic or gastrointestinal tract function improving agent.

A. Dopamine D ₂ receptor and serotonin
Test Example 1 for Action on S ₃ Receptor 1 : Dopamine D ₂ receptor binding action and serotonin S ₃ receptor binding action (in vitro receptor binding assay) Creese, I. et al. [Eur. J. Pharmacol., 46 , 337 ( 1977)] and Peroutka, SJ and Hamik, A. [Eur. J. Pharm
acol., 148 , 297 (1988)], dopamine D ₂ and serotonin S ₃ receptor binding tests, respectively. Crude synaptosome membrane fraction prepared from rat brain was used as a receptor specimen, and [ ³ H] spiperone (D ₂ ) and [ ³ H] keypazine (S ₃ ) were used as labeling ligands. After incubating the receptor specimen and a buffer containing each labeled ligand (final volume: 1 ml) for a certain period of time in the presence of various concentrations of the test compound, the radioligand bound to the receptor was removed from the cell harvester (Brandel).
And separated on the filter. The radioactivity on the filter was measured with a liquid scintillation counter to determine the total amount of binding. Simultaneously measured unlabeled ligands [Spiperone (D ₂ ) and [ ³ H] Kipazine (S
₃ ) The amount of binding in the presence of excess of
This was subtracted from the total binding to determine the specific binding. Test compound 50% specific binding of labeled ligand
The inhibitory concentration (IC ₅₀ value) was calculated by the probit method. The results are shown in Table 1 below.

Test Example 2 : von Bezold-Jarisch reflex inhibitory action (anti-serotonin S ₃ action) This test was performed according to the method of Fozard et al. [Arch. Pharmacology, 326 ,
36-44 (1984)]. Male Wistar rats (body weight 250-350 g) were anesthetized with urethane (1.5 g / kg, intraperitoneal) and fixed in a dorsal position. Electrocardiogram (second lead)
Was derived and the heart rate was recorded on an oscilloscope via a heart rate tachometer. Intravenous administration of 2-methylserotonin (a serotonin S ₃ agonist) at 10-30 μg / kg results in a transient decrease in heart rate, ie, von Bezold
-Jarisch reflection occurs. A fixed amount of 2-methylserotonin was repeatedly administered at 15-minute intervals, and after a stable reaction was obtained, the test compound was intravenously administered 3 minutes before 2-methylserotonin administration. Test compounds were calculated inhibition of the reaction after the administration to the reaction prior to the administration, 50% inhibiting effective amount (ED ₅₀ value) was determined by probit method. The results are shown in Table 1 below.

[0053]

[Table 1]

As is clear from the results shown in Table 1 above,
The compound of Production Example 1 has a dopamine D ₂ receptor binding action superior to or better than domperidone known as a selective dopamine D ₂ receptor antagonist, and a selective serotonin S ₃
It has a potent serotonin S ₃ receptor binding action that surpasses ondansetron hydrochloride known as a receptor antagonist, and has an excellent action comparable to ondansetron hydrochloride in von Bezold-Jarisch reflex suppression action. Have.
Further, the compound of Production Example 2 also has an excellent action similarly to the compound of Production Example 1. In addition, metoclopramide hydrochloride is known as an antiemetic agent having a binding action to both serotonin S ₃ and dopamine D ₂ receptor, but the binding action to both receptors is smaller than that of the compounds of Production Examples 1 and 2. Is much weaker.

B. Control Test Example For a吐作 3: Using Morphine-induced inhibitory effect one group 5-15 beagle dogs against vomiting (weighing 10 to 13 kg), were investigated the inhibitory effect of the test compound on emesis induced by morphine hydrochloride. A predetermined dose of a test compound dissolved or suspended in a 0.5% tragacanth solution is intravenously administered (i.
v.) or oral administration (po), and 15 for intravenous administration
One minute later, in the case of oral administration, one hour later, morphine hydrochloride (3 mg / kg) was subcutaneously injected into the back, and then the number of vomiting was counted over one hour. Vomiting number of test compound administration group was calculated percent inhibition compared to that of the control group, 50% inhibiting effective amount (ED ₅₀ value) was determined by probit method. The results are shown in Table 2 below.

[0056]

[Table 2] ^* : Not measured

As is clear from the results shown in Table 2 above,
The compound of Production Example 1 showed a potent inhibitory effect on morphine hydrochloride-induced vomiting by intravenous administration and oral administration, and its efficacy was about twice that of haloperidol and about 10 times that of metoclopramide hydrochloride.

The results of various emetic suppression tests are shown below,
5 shows that the compounds of Production Example 1 and Production Example 2 are compounds having an antiemetic action with a similar profile.

Test Example 4 : Inhibitory effect on apomorphine-induced vomiting Using 3 to 4 beagle dogs (body weight: 8 to 15 kg) per group, the inhibitory effect of a test compound on apomorphine-induced vomiting was examined. This test is commonly used as a method for detecting dopamine blockers. A prescribed dose of the test compound dissolved or suspended in a 0.5% tragacanth solution was orally administered, and 2 hours later, apomorphine hydrochloride (0.3 mg / kg) was injected subcutaneously into the back, and then the number of vomits was counted for 1 hour. Vomiting number of test compound administration group was calculated percent inhibition compared to that of the control group, 50% inhibiting effective amount (ED ₅₀ value) was determined by probit method. The results are shown in Table 3 below.

Test Example 5 : Effect of ferret on cisplatin-induced vomiting A male ferret (Marshall, USA) weighing about 1 kg was used. For intravenous administration, the jugular vein was cannulated under pentobarbital anesthesia 3-4 days before the experiment. The test group was orally administered a predetermined dose of a test compound dissolved or suspended in a 0.5% tragacanth solution, and 30 minutes later, 10 mg / kg of cisplatin (manufactured by Sigma) (3 ml / kg of physiological saline)
Was administered intravenously via a cannula. The number of vomits induced during 3 hours after administration of cisplatin was recorded to calculate the inhibition rate of the test compound.
The effective amount (ED ₅₀ value) for% inhibition was determined. The results are shown in Table 3 below.

Test Example 6 : Effect on Canine Cisplatin-Induced Vomiting Using 4 to 5 beagle dogs (body weight: 10 to 12 kg) in a group, the inhibitory effect of a test compound on cisplatin-induced vomiting was examined. To the test group, a predetermined dose of the test compound dissolved or suspended in a 0.5% tragacanth solution was orally administered, and 30 minutes later, 3 mg / kg of cisplatin (manufactured by Sigma) (3 ml / kg of physiological saline) was intravenously injected. Was administered. The number of vomits induced during 5 hours after the administration of cisplatin was recorded to calculate the inhibition rate of the test compound.
The effective amount (ED ₅₀ value) for% inhibition was determined. The results are shown in Table 3 below.

[0062]

[Table 3] ^* : Not measured

As is clear from the results shown in Table 3 above,
The compounds of Production Example 1 and Production Example 2 exhibited strong antiemetic effects, and their action profiles were similar. That is, the compound of Production Example 1 and the compound of Production Example 2
_In apomorphine-induced vomiting based on ₂ receptor antagonism, it does not reach domperidone, which is a selective dopamine D ₂ receptor antagonist, but shows an excellent inhibitory effect,
Furthermore, remarkably, in cisplatin-induced emesis based on the serotonin S ₃ receptor antagonistic action, the compound exhibited a potent inhibitory action almost equivalent to that of ondansetron hydrochloride, which is a selective serotonin S ₃ receptor antagonist.

The compounds of Production Examples 1 and 2 were
It shows a stronger antiemetic effect than metoclopramide hydrochloride, which shows a weak binding effect on both receptors of serotonin S ₃ and dopamine D ₂ , and in particular shows a much stronger inhibitory effect on cisplatin-induced emesis, and the effect is clearly different. Was seen.

C. Test Example 7 for Central Action : Inhibitory Action for Exploratory Behavior Five Std-ddY male mice (20 to 25 g in weight) were used in each group. A test compound dissolved or suspended in a 0.5% tragacanth solution was orally administered, and two hours later, mice were individually animalized.
Ex-momentum measurement device (manufactured by Farad) Measurement cage (23 × 35
× 30 cm), and the amount of exploratory activity for 3 minutes was measured. The average value of the amount of exploratory activity (count / 3 minutes) in the test compound administration group was determined, the inhibition rate was calculated in comparison with that in the control group, and the effective dose (ED ₅₀ value) of 50% inhibition was determined by the probit method. .

The ED ₅₀ values of the compound of Production Example 1, the compound of Production Example 2, and metoclopramide hydrochloride were 48.5 mg /
kg, 83.9 mg / kg and 22.4 mg / kg, indicating that the compounds of Production Examples 1 and 2 had a weaker central inhibitory effect than metoclopramide hydrochloride.

As is evident from the above test results, the compound of the formula (I) which has a strong serotonin S ₃ and dopamine D ₂ receptor antagonistic action and exhibits an emesis suppressing action based on these receptor antagonistic actions, and its physiologically active substance Is an acid addition salt that is acceptable for morphine-induced vomiting,
The compound of formula (I) and its physiologically acceptable acid addition salts have a weak central nervous system and have a weak central nervous system. It can be used for treatment or prevention.

The route of administration of the compound of formula (I) and the physiologically acceptable acid addition salt thereof may be any of oral administration, parenteral administration and rectal administration. It varies depending on the administration method, the patient's symptoms and age, etc., but is usually 0.01 to 10 mg / kg / day, preferably 0.1 to 3 mg / kg.
A range of mg / kg / day is appropriate.

When the compound of the formula (I) or a physiologically acceptable acid addition salt is used for the above-mentioned medicinal purposes, the compound is usually
It is administered in the form of a preparation prepared by mixing with a preparation carrier. As the carrier for the preparation, a non-toxic substance which is commonly used in the field of the preparation and does not react with the compound of the present invention is used. Specifically, for example, citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol,
Dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose Calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, Talc, tragacanth, bentonite, veegum, carboki Vinyl polymer, titanium oxide, 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, sodium chloride, sodium hydroxide, Hydrochloric acid, water and the like.

Examples of the dosage form include tablets, orally disintegrating tablets, capsules, granules, powders, syrups, suspensions, patches, injections, suppositories and the like. These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method.

These preparations can contain the compound of formula (I) or a physiologically acceptable acid addition salt thereof in a proportion of 0.01% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically valuable components.

[0072]

Production Examples The production method of the compound of the formula (I) will be specifically described below with reference to Reference Examples and Production Examples. The identification of compounds is based on elemental analysis values, mass spectra, IR spectra, NMR
The measurement was performed based on spectra and the like.

In the following Reference Examples and Production Examples,
The following abbreviations may be used to simplify the description.

J: coupling constant, s: singlet, d: doublet, t: triplet, m: multiplet, br-s: wide singlet, ee: enantiomeric excess.

Reference Example 1 Production of 5-bromo-2-methoxy-6-methylamino-3-pyridinecarboxylic acid:

(1) 2,6-difluoropyridine 50
g in 200 ml of tetrahydrofuran.
6 M n-butyllithium tetrahydrofuran solution 326
ml was added dropwise. After stirring at the same temperature for 1 hour, a lump of 29 g of dry ice was added little by little to the reaction solution. Then, after stirring at the same temperature for 30 minutes, the temperature is raised to about 5 ° C.
ml was added. The reaction solution was washed twice with ethyl acetate, the aqueous layer was adjusted to pH 3 with concentrated hydrochloric acid, and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration and recrystallized from diethyl ether-n-hexane to give 2,6-difluoro-3-pyridinecarboxylic acid 6
3 g were obtained. 170-171 ° C

(2) 63 g of the above product, methanol 7
A mixture of 00 ml and 5 ml of concentrated sulfuric acid was heated under reflux for 20 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ice water.
Extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform to obtain methyl 2,6-difluoro-3-pyridinecarboxylate (64 g) as an oil.

(3) 38 g of ethanol 5
72 g of ethanol solution of 20% methylamine in 00 ml solution
Was added dropwise at -20 ° C to -25 ° C. After stirring at the same temperature for 5 hours, the temperature was raised to room temperature, and the reaction solution was concentrated under reduced pressure. Ice water was added to the concentrated solution, and the precipitated solid was collected by filtration, washed with water, dried, and then treated with diethyl ether-n-hexane (2:
The mixture was recrystallized from 3) to obtain 15.7 g of methyl 2-fluoro-6-methylamino-3-pyridinecarboxylate.
156-159 ° C

(4) 15.7 g of the above product in methanol
To the 400 ml solution was added 19.1 g of potassium tert-butoxyside, and the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, and an aqueous solution of sodium hydrogen carbonate was added to the residue. The precipitated solid was collected by filtration, washed with water, dried and dried.
16.3 g of methyl methoxy-6-methylamino-3-pyridinecarboxylate was obtained. Melting point 120-122 ° C (n
-Recrystallized from hexane-diethyl ether)

(5) 7.0 g of N-bromosuccinimide was added to a solution of 7.3 g of the above product in 70 ml of dimethylformamide.
And heated at 80 ° C. for 4 hours. Ice water is added to the reaction solution,
The precipitated solid is collected by filtration, washed with water and dried, and then dried.
9.8 g of methyl-bromo-2-methoxy-6-methylamino-3-pyridinecarboxylate were obtained. Melting point 136 ~
138 ° C (recrystallized from n-hexane-diethyl ether)

(6) An aqueous solution containing 3.1 g of sodium hydroxide in 100 ml of a methanol solution of 20 g of the above product 200
Then, the mixture was heated and refluxed for 1.5 hours. After cooling, methanol was distilled off under reduced pressure, and the mixture was acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried to obtain the desired product 18.
9 g were obtained. 224-225 ° C

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm):
2.92 (3H, d, J = 5Hz), 3.88 (3H, s), 7.08 (1H, d, J = 5
Hz), 7.98 (1H, s), 12.08 (1H, s)

Reference Example 2 Preparation of (R) -6-amino-1-ethyl-4-methylhexahydro-1H-1,4-diazepine:

(1) N'-methyl-N- (3-methylbenzyl) ethylenediamine 1602 g of chloroform 12
Under ice cooling, a solution of 2180 g of di-tert-butyl dicarbonate in 3500 ml of chloroform was added dropwise to the 00 ml solution. After stirring at room temperature for 18 hours, the reaction solution was distilled off under reduced pressure, toluene and ice water were added to the residue, and a 10% aqueous citric acid solution was added dropwise at an internal temperature of 4 ° C. or lower under ice cooling to make the aqueous layer acidic. . The fractionated toluene layer was extracted with water, and the obtained aqueous layer was combined with an acidic aqueous solution, and washed with toluene. The aqueous layer was made alkaline with a 48% aqueous sodium hydroxide solution and then re-extracted with toluene. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give N'-tert-
1860 g of butoxycarbonyl-N'-methyl-N- (3-methylbenzyl) ethylenediamine was obtained as an oil.

(2) 50 g of the above product and (S) -2-
Mix 53 g of methoxycarbonyl-1-benzyloxycarbonylaziridine and stir at 80 ° C. for 20 hours to obtain crude (R) -2- (benzyloxycarbonyl) amino-3
-[N- [2- [N '-(tert-butoxycarbonyl)
-N'-methylamino] ethyl] -N- (3-methylbenzyl)] methyl aminopropionate was obtained.

(3) To the above crude product was added 750 ml of a 10% ethanol solution of hydrogen chloride, and the mixture was stirred at 30 to 40 ° C. for 2 hours. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was washed with water.
It was dissolved in 500 ml, and the aqueous layer was washed with diethyl ether. The aqueous layer was neutralized with sodium bicarbonate and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crude (R) -2- (benzyloxycarbonyl) amino-3- [N- (2-methylaminoethyl) -N- (3 -Methylbenzyl)] 79 g of methyl aminopropionate was obtained. A part of the product was converted into oxalate and recrystallized from ethanol-diethyl ether to obtain the oxalate of the above methyl ester. 185-190 ° C

(4) The above crude methyl ester 39
g was dissolved in 70 ml of ethanol, 70 ml of a 2N aqueous sodium hydroxide solution was added dropwise at 0 ° C to 10 ° C, and the mixture was stirred at room temperature for 16 hours. Ethanol was distilled off under reduced pressure, the aqueous solution was adjusted to pH 8 with concentrated hydrochloric acid, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crude (R) -2- (benzyloxycarbonyl).
Amino-3- [N- (2-methylaminoethyl) -N-
(3-methylbenzyl)] aminopropionic acid 36.4 g
I got A part of the product was purified to obtain crystals. Melting point 1
70-175 ° C

(5) 36.4 g of the above crude product was dissolved in 180 ml of methylene chloride, and 18.2 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was dissolved.
Was added and stirred at room temperature for 20 hours. After the reaction solution was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether-n-hexane to give (S) -3- (benzyloxycarbonyl) amino-1.
-Methyl-4- (3-methylbenzyl) hexahydro-
22 g of 2-oxo-1,4-diazepine were obtained. Melting point
70-71 ° C

(6) 18.0 g of 1-chloroethyl chlorocarbonate was added to a solution of 40.8 g of the above product in 400 ml of methylene chloride.
Was added dropwise and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, 400 ml of methanol was added to the residue, and the mixture was heated under reflux for 1 hour. After methanol was distilled off under reduced pressure, water was added to the residue, and the residue was washed with diethyl ether. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with chloroform.
After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crude (S) -3- (benzyloxycarbonyl) amino-1-methylhexahydro-2-oxo-
1,4-Diazepine was obtained.

(7) Methanol 6 is added to the above crude product.
00 ml and 21.2 g of triethylamine, and 11.6 g of an aqueous 80% acetaldehyde solution under ice-cooling.
Stirred for hours. Then, 3.97 g of sodium borohydride was added little by little at the same temperature, and the mixture was stirred under ice cooling for 1 hour and further at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (15: 1) to give (S) -3.
-(Benzyloxycarbonyl) amino-5-ethyl-
28 g of 1-methylhexahydro-2-oxo-1,4-diazepine was obtained as an oil.

(8) To 28 g of the above product, 140 ml of a 48% aqueous solution of hydrobromic acid was added, and the mixture was heated with stirring at 60 ° C. for 2 hours.
After cooling, the reaction solution was washed twice with diethyl ether, the aqueous layer was made alkaline with potassium carbonate, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give (S) -3-amino-5-ethyl-
19 g of 1-methylhexahydro-2-oxo-1,4-diazepine was obtained as an oil.

(9) To a solution of 23 g of the above product in 300 ml of tetrahydrofuran was added dropwise 1000 ml of a 1M borane-tetrahydrofuran solution under ice-cooling, followed by stirring at room temperature for 16 hours. Under ice cooling, 500 ml of 1N hydrochloric acid was added, and the mixture was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, the residue was washed twice with diethyl ether, the aqueous layer was made alkaline with potassium carbonate, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 19 g of the desired product as an oil.

Reference Example 3 Production of (S) -6-amino-1-ethyl-4-methylhexahydro-1H-1,4-diazepine:

Reference Example 2 (R) -2-methoxycarbonyl-1-benzyloxycarbonylaziridine was used in place of (S) -2-methoxycarbonyl-1-benzyloxycarbonylaziridine in (2). 2)
Reaction and treatment were carried out in the same manner as in (9) to obtain the desired product.

Production Example 1 (R) -5-bromo-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-
Preparation of 2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate:

(1) 5-bromo-2-methoxy-6
18.0 g of methylamino-3-pyridinecarboxylic acid, N,
A mixture of 11.7 g of N'-carbonyldiimidazole and 50 ml of dimethylformamide was stirred at room temperature for 8 hours. 13.0 g of (R) -6-amino-1-ethyl-4-methylhexahydro-1H-1,4-diazepine was added to the mixture, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and a 2N aqueous sodium hydroxide solution was added thereto.
Extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with a mixed solution of chloroform-methanol (15: 1), and recrystallized from diethyl ether to give (R) -5-bromo-N
-(1-ethyl-4-methylhexahydro-1H-1,
4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide 1/4 hydrate
19.6 g was obtained. 52-55 ° C

The compound showed a retention time of 23.6 minutes by high performance liquid chromatography (HPLC) under the following conditions, and the optical purity was 99% ee or more.

[HPLC conditions] HPLC column: CHIRALPAK AS (manufactured by Daicel Chemical Industries, Ltd.); inner diameter 4.6 mm × 250 mm, mobile phase: n-hexane-ethanol-diethylamine (940: 30: 2), flow rate: 0.8 ml / Min, temperature: 25 ° C, detection: UV 254 nm.

(2) The above product (19 g) was treated with fumaric acid to give a difumarate, and recrystallized from ethanol to obtain the desired product (23 g). 152-155 ° C

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm):
1.02 (3H, t, J = 7Hz), 2.43 (3H, s), 2.5-3.0 (10H,
m), 2.93 (3H, d, J = 5Hz), 3.98 (3H, s), 4.14 (1H,
m), 6.60 (4H, s), 6.99 (1H, d, J = 5Hz), 8.09 (1H,
s), 8.48 (1H, d, J = 8Hz), 12.80 (2H, br-s)

Reference Example 4 (S) -5-bromo-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-
Preparation of 2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate:

(1) (R)-in Production Example 1 (1)
6-amino-1-ethyl-4-methylhexahydro-1
(S) -6-amino-1-ethyl-4-methylhexahydro-1H-1,4 instead of H-1,4-diazepine
(S) -5-Bromo-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepine-6-reacted and treated in the same manner as in Production Example 1 (1) using -diazepine. Yl) -2-Methoxy-6-methylamino-3-pyridinecarboxamide monohydrate was obtained. Melting point 67-68 ° C
(Recrystallized from diethyl ether-petroleum ether)

The compound was obtained under the same conditions as in Production Example 1 by HPL
C showed a retention time of 27.5 minutes, and the optical purity was 99% ee or more.

(2) The above product was treated with fumaric acid to give a difumarate, which was recrystallized from ethanol to obtain the desired product. 152-155 ° C

Production Example 2- (R) -5-chloro-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-
Preparation of 2-methoxy-4-methylaminobenzamide dimaleate:

(1) 5-chloro-2-methoxy-4-
6.9 g of methylaminobenzoic acid, (R) -6-amino-1
A mixture of 5.0 g of -ethyl-4-methylhexahydro-1H-1,4-diazepine, 6.2 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 100 ml of methylene chloride was stirred at room temperature for 4 hours. did. The reaction solution was washed successively with an aqueous sodium hydroxide solution, water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with a mixture of chloroform and methanol (10: 1).
After purification, (R) -5-chloro-N- (1-ethyl-4-
Methylhexahydro-1H-1,4-diazepine-6
Yl) -2-methoxy-4-methylaminobenzamide
9.6 g were obtained as an oil.

The compound showed a retention time of 24.6 minutes by high performance liquid chromatography (HPLC) under the following conditions, and had an optical purity of 99% ee or more. [HPLC conditions] HPLC column: CHIRALPAK AS (manufactured by Daicel Chemical Industries, Ltd.); 4.6 mm × 250 mm, mobile phase: n-hexane-ethanol-diethylamine (940: 60: 2), flow rate: 0.8 ml / min, temperature : 25 ° C, detection: UV 254 nm.

(2) 9.6 g of the above product was treated with maleic acid to give a maleate salt, and recrystallized from a mixed solution of methanol and isopropanol to obtain 11 g of the desired product. Melting point 161-162 ° C

Reference Example 5-(S) -5-chloro-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-
Preparation of 2-methoxy-4-methylaminobenzamide:

Production Example 2 (R) -6-amino-1-ethyl-4-methylhexahydro-1H-1,
Using (S) -6-amino-1-ethyl-4-methylhexahydro-1H-1,4-diazepine instead of 4-diazepine, the reaction and treatment were carried out in the same manner as in Production Example 2 (1) to give (S) ) -5-Chloro-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-
2-methoxy-4-methylaminobenzamide was obtained.

The compound was obtained under the same conditions as in Production Example 2 by HPL
C showed a retention time of 28.0 minutes, and the optical purity was 99% ee or more.

Formulation Example 1 : Production of tablets (5 mg tablets) (R) -5-bromo-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-
2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate (5 g), lactose (80 g), corn starch (30 g), crystalline cellulose (25 g),
Hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g), and magnesium stearate (1.3 g)
g).

The above components are mixed and granulated by a conventional method, and the mixture is tableted at 145 mg per tablet to produce 1000 tablets.

Formulation Example 2 : Preparation of powder (1% powder ) (R) -5-bromo-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-
2-methoxy-6-methylamino-3-pyridinecarboxamide difumarate (10 g), lactose (960 g), hydroxypropylcellulose (25 g), and light anhydrous silicic acid (5 g).

After mixing the above components by a conventional method, a powder is prepared.

Formulation Example 3 : Production of injection (0.5% injection)

[0117]

[Table 4] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ · (R) -5-bromo-N- (1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate (10 g) sorbitol (100 g) ・ Water for injection (appropriate amount) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ total volume 2000 ml ━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

(R) -5-bromo-N- (1-ethyl-
4-methylhexahydro-1H-1,4-diazepine-
6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate and sorbitol are dissolved in a part of the water for injection, and the whole is prepared by adding the remaining water for injection. This solution is passed through a membrane filter (0.
22 μm), fill the filtrate into 2 ml ampules, which is then sterilized at 121 ° C. for 20 minutes.

[0119]

As described above, the compound represented by the formula (I) and a physiologically acceptable acid addition salt thereof can strongly suppress nausea and vomiting caused by administration of a morphine-like drug such as morphine. Can be.

Claims (3)

[Claims] [Claim 1] (Wherein, Ar represents a 5-bromo-2-methoxy-6-methylamino-3-pyridyl group or a 5-chloro-2-methoxy-4-methylaminophenyl group). -1-ethyl-4-methylhexahydro-1H
A morphine-like drug-induced emesis suppressant comprising a 1,4-diazepine derivative or a physiologically acceptable acid addition salt thereof as an active ingredient. 2. The following chemical formula 2 (R) -5-bromo-N- (1-ethyl-4)
-Methylhexahydro-1H-1,4-diazepine-6
-Yl) -2-Methoxy-6-methylamino-3-pyridinecarboxamide or a physiologically acceptable acid addition salt thereof as an active ingredient. 3. The antiemetic agent according to claim 1, wherein the morphine-like agent that induces vomiting is morphine or buprenorphine or a physiologically acceptable acid addition salt thereof.