MXPA98000620A - (r) -5-bromo-n- (1-ethyl-4-methylhexahidro-1h-1,4-diazepin-6-il) -2-metoxy-6-methylamin-3-pyridincarboxamide, process for preparation of the same and pharmaceutical composition containing such compue - Google Patents

Abstract

This invention describes a compound to which is expressed by the following formula (I), or physiologically acceptable acid addition salts thereof. The claimed compound exhibits excellent antiemetic effect on the basis of its potent antagonistic activity for the serotonin S3 receptor and dopamine D2, and is useful for the treatment or prophylaxis of various gastrointestinal symptoms which are associated with various diseases and drug administration.

Description

w -5-TOGMO, W. n -CTTt.- -MBrnt.mpcAHTPB -? tt-? .nTiwaPTM.fi.

FOR PREPARATION OF THE SAME AND PHARMACEUTICAL COMPOSITION. THAT FLOATS SUCH COMPOSITE TECHNICAL FIELD This invention relates to novel (R) -5-bromo-N- (1-ethyl-4-methyl-exahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide which shows potent antagonistic activities for serotonin S3 (which will be mentioned below as 5-HT3) and dopamine D2 receptor; with processes to prepare it; and with a pharmaceutical composition containing such compound.

AmBcaDBpESJS- on application for Japanese patent open to the public (KOKAI) KOKAI number 92959/1993 broadly describes a class of compounds represented by the formula (A) below: REF: 26651 [wherein Rx and R2 may be the same or different, and each means a hydrogen atom, lower alkyl or a substituted lower alkyl group, etc. R3 may be the same or different and each means a hydrogen atom or lower alkyl, etc. R5 can be the same or different and each means a hydrogen atom, a halogen atom, lower alkoxy, amino, a mono- or di-substituted amino group, etc. Het means a monocyclic heteroaryl or dichyclic heteroaryl different from the 1H-indazolyl group, q is 0, 1 or 2, s is 1, 2 or 3, B means -CXNR6 (CH2) r-, etc., in which R6 is a hydrogen atom or lower alkyl, etc., X means an oxygen or sulfur atom and r is 0, 1, 2, or 3, m is 1, 2, 3 or 4, and n is 1, 2 or 3], and also The case in which Het can be pyridyl is described. Meanwhile, a single specific compound in which Het is a 3-pyridyl group and which is described in the specification is one of Example 37, represented by the following formula: This compound of Example 37 differs clearly in the structure of the compound of the present invention which is expressed by the formula (I) presented below. In the first compound, the 3-pyridyl group is unsubstituted and the 4-position of hexahydro-lH-1,4-diazepine is substituted with methyl. Such a KOKAI gazette, furthermore, discloses that the compounds of the above formula (A) are serotonin S3 (5-HT3) receptor antagonists and are useful for therapeutic and prophylactic treatment of anorexia, nausea, emesis, abdominal satiety and the like accompanying acute and chronic gastritis, and diseases such as gastric and duodenal ulcers; or of nausea or emesis that presents with administration of antitumor agents, radioactive irradiation and motion sickness. The gazette, however, does not mention the antagonism to the dopamine D2 receptor. In addition, WO93 / 08186 describes a group of compounds represented by the formula (B) below: [wherein R x means C 1-6 alkoxy, C 3-8 cycloalkoxy or C 3-8 cycloalkyl) alkoxy. R 2 is set for hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or amino which may be substituted with 1 or 2 C 1 alkyl; R3 is set for hydrogen, halogen or C1_6 alkyl; L is 0 or NH; and Z is established for the di-azacyclic or azadicyclic side chain], which teaches that the compounds are useful for therapeutic or prophylactic treatment of pain, emesis, central nervous system disorders and gastrointestinal disorders, as 5-HT3 antagonists. Such WO93 / 08186 mentions, as one of the suitable examples of the diazacyclic side chain Z, EP-A-358903 belongs to the patent family of the KOKAI patent application mentioned above KOKAI number 92959/93, but does not contain a description specific for a compound having a diazacyclic side chain which is covered by the general formula (A) as above. Therefore, O93 / 08186 does not suggest in any way the compound of the present invention. On the other hand, domperidone [chemical name: 5-chloro-l- [1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl] -1 , 3-dihydro-2H-benzimidazol-2-one; cf. eg. Merck Index, llava edition 3412 (1989)] which is a dopamine receptor antagonist agent D2 is effective in alleviating the emesis that accompanies the various problems of the digestive system and which accompanies the cold syndrome in children, but shows only an insufficient effect on the emesis that is presented by administration of antitumor agents such as cisplatin. Recently, as a drug which can selectively inhibit in large quantities the emesis that occurs with the administration of antitumor agents, serotonin S3 receptor antagonist agents have been developed, and currently such antiemetic agents as granisetron hydrochloride [chemical name] : endo-1-methyl-N- (9-methyl-9-azabicyclo- [3.3.1] non-3-yl) -1H-indazole-3-carboxamide hydrochloride; cf. eg., Merck Index, llava edition 4443 (1989)], ondansetron hydrochloride [chemical name: # 1,2, 3, 9-tetrahydro-9-methyl-3- [(2-methyl-lH-imidazole-) hydrochloride] 1-yl) methyl] -4H-carbazol-4-one; cf. eg, Merck Index, llava edition 6802 (1989)] and azasetron hydrochloride [chemical name: (±) -N-1-azabicyclo- [2.2.2] oct-3-yl-6-chloro-3 hydrochloride, 4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-8-carboxamide; cf. eg, Drugs of the Future. 111 (3), 206-211 (1993)] which. They are used clinically. However, the clinical application of these serotonin S3 receptor antagonists is limited to emesis, which occurs mainly during the administration of antitumor agents. In addition, it is mentioned that they only have an insufficient effect in late emesis.

Therefore, although there are effective drugs for a specific type of emesis, an antiemetic agent of a wide range of application that can strongly inhibit emesis induced by various causes has not yet been developed. Therefore there is a demand for the development of an antiemetic agent that has a broad spectrum.

DESCRIPTION OF THE INVENTION In the process of our series of research work regarding potent and selective antagonists for serotonin S3 receptor, we considered that a substance which shows dopamine D2 receptor antagonist activity, in addition to the serotonin S3 receptor antagonist activity would be effective for emesis induced by various causes, and synthesized amounts of hexahydro-lH-1,4-diazepine derivatives in order to impart an antagonistic activity to the dopamine D2 receptor to antagonist activity and to the serotonin S3 receptor, and this research was carried out . Accordingly, it has now been discovered that (R) -5-bromo-N- (l-ethyl-4-methylhexahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3 -pyridine-carboxamide, which is expressed by the following formula (I) it satisfies the objective and has broad-spectrum antiemetic effects. Therefore, the present invention provides (R) -5-bromo-N- (l-ethyl-4-methylhexahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3- pyridinecarboxamide of the formula (I) above, and their physiologically acceptable addition salts. The invention provides, in addition, a method for preparing such a compound. The invention also provides pharmaceutical preparations containing such a compound. Additionally, the invention provides an intermediate product for preparing such compound. As physiologically acceptable acid addition salts of the compound of formula (I), for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; and the organic acid salts such as oxolate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate and methanesulfonate. In the compound of formula (I) and the physiologically acceptable acid addition salts thereof may be present in the form of hydrates and / or solvates, and these hydrates and / or solvates are also included in the compounds of the present invention. The compound of the present invention can be prepared, for example, by reacting the compound of formula (II) below or a reactive derivative thereof with a compound of formula (III) below.

As reactive derivatives of the compound of formula (II), for example, there can be named lower alkyl esters (in particular methyl ester), active esters, acid anhydrides, acid halides (in particular, acid chloride), etc. Specific examples of active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester and N-hydroxysuccinimide ester. As acid anhydrides, symmetrical acid anhydrides and mixed acid anhydrides can be used. Examples of mixed acid anhydride include those with alkyl chloroformates such as ethyl chloroformate, isobutyl chloroformate and the like; Aralkyl chloroformates such as benzyl chloroformate; those with aryl chloroformate such as phenyl chloroformate; and those with alkanoic acids such as isovaleric acid, pivalic acid and the like. When the compound of formula (II) is used per se, as the starting material, the above reaction can be carried out in the presence of a condensing agent such as N, N '-dicyclohexylcarbodiimide, l-ethyl-3- hydrochloride ( 3-dimethylaminopropyl) carbodiimide, N, N'-carbonyldiimidazole, N, N'-carbonyldisuccinimide, l-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline, diphenylphosphorylazide, propanephosphonic anhydride, benzotriazol-1-yloxy-tris (dimethylamino) hexafluorophosphate ) phosphonium and the like.

The reaction of the compound of formula (II) or a reactive derivative thereof with the compound of formula (III) is carried out in the presence or absence of a solvent. Useful solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; esters such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; alcohols such as ethanol and isopropanol, ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethisulfoxide, ethylene glycol, water and the like. These solvents can be used each alone or in combination of more than one class. If necessary, the reaction can be carried out in the presence of a base. Examples of useful bases on such occasion include alkaline hydroxide such as sodium hydroxide and potassium hydroxide; alkaline carbonate such as sodium carbonate and potassium carbonate; alkaline acid carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate; and an organic base such as triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine. Suitable reaction temperatures are usually within a range of from about -30 ° C to about 200 ° C, preferably from about -10 ° C to about 150 ° C. The compound of formula (III) can be supplied to the reaction system in a proportion usually of 1-3 moles, preferably 1-1.5 moles per mole of compound of formula (II) or a reactive derivative thereof. Meanwhile, it is also possible to use a large excess if the individual occasion requires it, to leave the function also as a base. The compound of formula (II) to be used as the starting material can be prepared by the steps indicated in reaction scheme 1 below. The specific conditions for each of the steps are shown later in reference example 1.

REACTION SCHEME 1 (IV) (V) (VI) (VII) (VIII) (IX) Stage 6 (ID In the above formulas, Rx means a linear or branched C1-6 group. The compound of formula (III) which is also used as the starting material is a novel compound not described in the literature available up to now and can be prepared, for example by the steps indicated in reaction scheme 2 below. The specific conditions for each of the steps are shown later in Example 2.

REACTION SCHEME 2 (XIX) (lll) In. the above formulas Et, means an ethyl group, Z1 means an amino protecting group such as a tert-butoxycarbonyl group, a triphenylmethyl group and an acetyl group; Z2 means a benzyloxycarbonyl group which is optionally substituted with a chlorine atom, a bromine, methoxy or nitro atom; R 2 means a hydrogen atom, a halogen atom, C 1-3 alkyl or C 1 alkoxy; and R, _ has the meaning indicated previously. The compound of formula (III) above can be obtained as an acid addition salt based on the production method used in each individual occasion. As such, for example, the aforementioned physiologically acceptable acid addition salts can be named. More specifically, salts of inorganic acid such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; and organic acid salts such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate and methanesulfonate. According to the method of preparing the compound of formula (I), the configuration of the compound of formula (III) of one of the starting materials in the compound of formula (I) produced in this way is retained intact.

The compound of formula (I) as formed by the above preparation method can be isolated and purified by conventional techniques such as chromatography, recrystallization, reprecipitation or the like. The compound of formula (I) and that of formula (III) can be obtained in the form of free base or acid addition salt based on the reaction and processing conditions used. The acid addition salt can be converted to a free base by conventional methods, for example, by a treatment with a base such as an alkali carbonate and alkali hydroxide. Meanwhile, the free base can lead to the acid addition salt by treatment with a desired acid, according to conventional methods. The following are the pharmacological test results of the compound of the invention and the control compounds identified below to explain the pharmacological activities characteristic for the compound of this invention: (1) domperidone a selective dopamine D2 receptor antagonist which has been used clinically as an antiemetic agent or to improve gastrointestinal motility; (2) ondansetron hydrochloride, a selective serotonin S3 receptor antagonist which has been used clinically as an antiemetic at the moment of administering an antitumor drug; (3) granisetron hydrochloride, a selective serotonin S3 receptor antagonist which has been used clinically as an antiemetic at the moment of administering an antitumor drug; (4) Metoclopramide hydrochloride, a medication which has been used throughout the world as an antiemetic or agent that improves gastrointestinal motility [chemical name; 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide dihydrochloride monohydrate; cf. eg. , Merck Index, llava edition 6063 (1989)].

A. Antagonist activities of dopamine D2 receptor and serotonin S3 receptor Test example 1: Activities of dopamine D2 receptor binding and serotonin S3 receptor binding (in vitro receptor binding assay) The dopamine D2 receptor and serotonin S3 receptor binding assays were carried out following the methods of I. Créese, et al. al., [E ?? r_. ? . Pharmacol .. 4, 337 (1977)] and S. J. Peoutka and A. Hamik EiiE-il-Pharmacc-1. , IASL, 297 (1988)], respectively. Raw or untreated rat brain synaptosome fractions are prepared as samples of receptor and [3 H] spiperone (D2) and [3 H] quipazine (S3), as labeled ligands. A buffer solution containing each of the receptor and labeled ligand samples (final volume: 1 ml) is incubated for a prescribed period, in the presence of one of the test compounds at various concentration levels, and subsequently the radioactive ligand bound to the receptor on a filter using a cell harvester (Brandel Co.) and the radioactivity in each filter is determined with a liquid scintillation counter to determine the total amount bound to the receptor. The unit amount is specifically calculated by subtracting the non-specific bound amount from the total bound amount, the non-specific bound amount is that amount bound under the presence of an excessive amount of unlabeled ligand [spiperone (D2) and [3H] quipazine (S3)] which is measured concurrently. The concentration level of the test compound at which the specific binding of labeled ligand (IC 50 value) is inhibited by 50% is calculated with probit analysis. The results are shown in Table 1.

Test Example 2 Inhibitory effect in the von Bezold-Jarisch reflex (antiserotonin activity S3) This test is carried out following the method of Fozard, et al., [Cf. ah- Pharmac.olosy. 326. 36-44 (1984)]. They are anesthetized with urethane (1.5 g / kg, intraperitoneal) male ister rats weighing 250-350 g and placed on their back. The electrocardiogram (electrode II) and the heart rate of the animals are recorded in an ink oscillograph by means of a biophysical amplifier and a pulse rate tachometer, respectively. When 2-methylserotonin is administered (5-HT3 agonist) of a dose of 10-30 μg / kg intravenously, the heart rate decreases transiently (von Bezold-Jarisch reflex). A fixed amount of 2-methylserotonin is repeatedly administered at 15 minute intervals until stable responses are obtained, and then the test compound is administered intravenously, 3 minutes before the administration of 2-methylserotonin. The speed of. inhibition of the von Bezold-Jarisch reflex after administration of the test compound by response before administration, and the effective dose of the test compound causing 50% inhibition (ED50 value) is determined by probit analysis. The results are shown in table 1 below.

TABLE 1 As is clear from the results indicated in Table 1 above, the compound of Example 1 shows more dopamine D2 receptor binding activity equivalent to that of domperidone which is a selective dopamine D2 receptor antagonist, as well as a strong activity of serotonin S3 receptor binding exceeding that of ondansetron hydrochloride and granisetron hydrochloride which are known selective antagonists of serotonin S3 receptor. In addition, for the inhibition of the von Bezold-Jarisch reflex, the compound of the invention has an excellent effect compared to ondansetron hydrochloride. As an antiemetic agent showing binding activity to both serotonin S3 and dopamine D2 receptors, metoclopramide hydrochloride is known. However, its binding activity to both receptors is much weaker than that of the compound of Example 1. Therefore, the compound of the invention has potent antagonistic activity for both serotonin S3 and dopamine D2 receptors, and is a highly promising antiemetic agent of broad spectrum to inhibit emesis induced by various causes.

B. Antiemetic effects Test Example 3: Inhibitory effect on emesis induced by apomorphine Three to four Beagle dogs (body weight: 8-15 kg) were used to examine the inhibitory effect of the test compounds on eomssis induced by apomorphine.

This test is commonly carried out as a method to detect dopamine blocker. The prescribed dose of a test compound was administered orally to each of the test animals and dissolved or suspended in 0.5% tragacanth solution and two hours later administered with apomorphine hydrochloride (0.3 mg / kg) per subcutaneous solution in the spine. The number of induced episodes was counted in the next 1 hour and the rate of inhibition was calculated by comparing the number of emetic episodes of the groups of test dogs with those of the control group, and the effective dose of each test compound was determined. to inhibit emesis by 50% (ED50 value) by probit analysis. Results are shown in table 2.

Test Example 4: Effect on emesis induced by cisplatin in ferrets Male ferrets (Marshall Lab., United States) weighing approximately 1 kg were used. For intravenous injection, a cannula was implanted in the cervical vein under anesthesia with pertobarbital, 3-4 days in advance before the experiment. Each test group was prescribed a dose of a test compound dissolved or suspended in a 0.5% tragacanth solution and administered orally, and 30 minutes later it was administered intravenously through the cisplatin cannula (Sigma) 10 mg / kg (physiological saline, 3 ml / kg). The number of. emetic episodes induced in the following 3 hours and was administered as the inhibition rate of the test compound. The effective doses of the test compounds to inhibit emesis by 50% (ED50 values) determined by probit analysis are indicated in Table 2.

Test Example 5: Effect of emesis induced by cisplatin in dogs Four to five dogs (body weight: 10-12 kg) were used to examine the inhibitory effect of test compounds on emesis induced by cisplatin. Each test group is prescribed a dose of a test compound dissolved or suspended in a 0.5% tragacanth solution and administered orally, 30 minutes later cisplatin (Sigma), 3 mg / kg (physiological saline, 3 ml / kg). The number of hermetic episodes is recorded in the next 5 hours after the administration of cisplatin to calculate the rate of each of the test compounds, and the effective dose (ED50 value) is determined to inhibit emesis by 50%, by probit analysis The results are indicated in table 2 below.

TABLE 2 As is evident from the results shown in Table 2, the compound of Example 1 shows excellent inhibitory effect on apomorphine-induced emesis based on antagonism of the dopamine D2 receptor with certainty, although its effect is not equal to that of domperidone which is a selective dopamine D2 receptor antagonist. In addition, a particularly remarkable effect, the compound shows a powerful inhibitory effect on emesis induced by cisplatin based on its antagonism to the serotonin S3 receptor, of a level approximately equivalent to that of ondansetron hydrochloride which is a selective receptor antagonist of serotonin S3. These results suggest that the compound of Example 1 possess a broad spectrum of antiemetic effect, due to its excellent property which concurrently shows potent antagonistic activities for the serotonin S3 receptor and dopamine D2, in a good balance. In addition, the compound of Example 1 shows a stronger antiemetic effect than metoclopramide hydrochloride which has weak binding activity to both serotonin S3 and dopamine D2 receptors. In particular, it shows a much stronger inhibitory effect on emesis induced by cisplatin, which clearly shows a significant difference in the effect of metoclopramide hydrochloride to be added. c. Effect on the central system Test Example 6: Inhibitory effect of the exploratory activity Male mice (5 per group, strain Std-ddy, weighing 20-25 g) are used as test animals, each of which is administered orally with a test compound which is dissolved or suspended in a solution of 0.5% tragacanth and after 2 hours of administration are placed in a test cage (23 x 35 x 30 cm) in an Animex activity meter (Farad Co.). The exploratory activity is counted for each mouse in the next 3 minutes. The mean scores of exploratory activities (counts / 3 minutes) are compared by group of mice tested with that of a control group to calculate the inhibition rate, and the effective dose (ED50 value) of each test compound is determined for 50 % inhibition by probit analysis. The ED 50 values of the compound of Example 1 and of metoclopramide hydrochloride are 48.5 mg / kg and 22.4 mg / kg, respectively, indicating that the former has a weaker central inhibitory effect. As evident from the above test results, the compound of formula (I) and the physiologically acceptable acid addition salts thereof show excellent antiemetic effects on the basis of their potent serotonin S3 receptor and dopamine D2 receptor antagonist activities , and are useful for the treatment or prophylaxis of various gastrointestinal symptoms which are associated with various diseases and drug administration, as broad spectrum antiemetic agents. More specifically, they are useful for the treatment or prophylaxis of nausea, emesis, anorexia, abdominal satiety, upper abdominal discomfort, abdominal pain, heartburn, belching and the like which usually accompany diseases such as acute and chronic gastritis, esophageal reflux, ulcer gastric and duodenal, gastric neurosis, gastroptosis, post-gastreptomy syndrome, scleroderma, diabetes, esophageal and biliary duct disorders, periodic vomiting and upper respiratory tract infections. They are also useful for the treatment and prophylaxis of, for example, irritable bowel syndrome, constipation and diarrhea in infants. In addition, they can be used for the treatment or prophylaxis of nausea or emesis induced by administration of antitumor agents or preparations of levodopa, or morphine which is a narcotic analgesic, or at the time of radioactive irradiation. In addition, they can be used for the treatment or prophylaxis of intoxication with additive drugs (morphine, nicotine, amphetamine and similar) and as an antipsychotic or anxiolytic agent. The compound of formula (I) and the physiologically acceptable acid addition salts thereof can be administered orally, non-parenterally or intrarectally. Although the clinical dose varies with factors such as the class of compound, route of administration, severity of the disease and age of the patient, when used as an antiemetic, for example, normally an adequate dose varies between 0.01-10 mg / kg / day, preferably 0.1-3 mg / kg / day. When used as an antipsychotic agent, a suitable dose range is usually 3-50 mg / kg / day, preferably 5-30 mg / kg / day.

To apply the compound of formula (I) or the physiologically acceptable acid addition salts thereof to medical uses as above, they are usually administered in the form of preparations formulated for mixing with known carriers for pharmaceutical preparations. As the carriers, those commonly used in the spherical preparation field are used which are not reactive with the compound of the present invention and are non-toxic. Specific examples of such carriers include citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch., sucrose, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropylstarch, calcium carboxymethylcellulose, ion exchange resins, methylcellulose, gelatin, gum arabic, pullulan , hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light silicic anhydride, magnesium stearate, talc, tragacanth, bentonite, beegum, carboxyvinyl polymer, titanium dioxide, fatty acid ester sorbitan, sodium lauryl sulfate, glycerin, fatty acid glycerides, purified lanolin, glycerogelatine, polysorbate, macrogol, vegetable oil, wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide, hydrochloric acid and water. As applicable forms of preparation, tablets, capsules, granules, powders, syrup, suspension, injections and suppositories can be mentioned. These preparations can be prepared following known and conventional methods. Liquid preparations can take a form which is dissolved or suspended in water or other suitable medium immediately prior to administration. The tablets and granules can be coated by a well-known method per se. These preparations may contain at least 0.01%, preferably 0.1-70% of the compound of formula (I) or a physiologically acceptable acid addition salt thereof. These preparations may additionally contain therapeutically useful or additional components. In the following the present invention is explained more specifically with reference to the reference examples and working examples, it being understood that the invention is not limited in any way to these examples. The identification of the formed compounds can be carried out by means such as elemental analysis, mass spectrum, IR spectrum and NMR spectrum. In the following reference examples, and working examples, the following abbreviations can be used to simplify the description: J: coupling constant s: singlet d: doublet t: triplet m: multiplet sa: broad singlet ee: enantiomeric excess Reference Example 1 Preparation of 5-bromo-2-methoxy-6-methyl-amino-3-pyridinecarboxylic acid (1) 50 g of 2,6-difluoropyridine are dissolved in 200 ml of tetrahydrofuran and 326 ml of a 1.6 M n-butyllithium tetrahydrofuran solution are added to the solution at -70 ° C, followed by stirring for a period of hour at the same temperature. 29 g of blocks of dry ice are added to the reaction mixture little by little, followed by stirring for 30 minutes at the same temperature. As the temperature increases by approximately 5 ° C, 500 ml of ice water are added. The reaction mixture is washed twice with ethyl acetate and the aqueous layer is adjusted to pH 3 with concentrated hydrochloric acid. The aqueous layer is subsequently extracted with chloroform. The extract is washed with saturated saline, water, dried over magnesium sulfate, and the solvent is concentrated under reduced pressure. The crystalline precipitate is collected by filtration and recrystallized from diethyl ether-n-hexane to provide 63 g of 2,6-difluoro-3-pyridinecarboxylic acid (mp 170-171 ° C). (2) A mixture of 63 g of the above product, 700 ml of methanol and 5 ml of concentrated sulfuric acid is heated under reflux for 20 hours. After evaporating the solvent under reduced pressure, the residue is diluted with water and ice and extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on a silica gel column, eluted with chloroform and purified to provide 64 g of methyl 2,6-difluoro-3-pyridinecarboxylate as an oil. (3) To 500 ml of an ethanol solution containing 38 g of the above product, 72 g of a solution of 20% methylamine in ethanol are added dropwise at -20 ° C to -25 ° C. The mixture is stirred for 5 h at the same temperature, after which the temperature is increased to room temperature. The reaction mixture is concentrated under reduced pressure. Water with ice is added to the condensate and the precipitate is collected by filtration, washed with water, dried and recrystallized from diethyl ether-n-hexane (2: 3). Therefore, 15.7 g of methyl 2-fluoro-6-methylamino-3-pyridinecarboxylate are obtained (mp 156-159 ° C). (4) To 400 ml of a methanol solution containing 15.7 g of the above product, 19.1 g of potassium tert-butoxide are added and heated under reflux for 3 hours. After cooling, the reaction mixture is concentrated under reduced pressure and an aqueous solution of sodium hydrogen carbonate is added to the residue. The precipitate is then collected by filtration, washed with water and dried to provide 16.3 g of methyl 2-methoxy-6-methylamino-3-pyridinecarboxylate (mp 120-122 ° C, recrystallized from n-hexane-ether diethyl). (5) To 70 ml of a dimethylformamide solution containing 7.3 g of the above product is added 7.0 g of N-bromosuccinimide at 80 ° C for 4 hours. Water with ice is added to the liquid reaction and in this way the precipitate is collected by filtration, washed with water and dried to provide 9.8 g of methyl 5-bromo-2-methoxy-6-methylamino-3-pyridinecarboxylate ( mp 136-138 ° C, recrystallized from n-hexane-diethyl ether). (6) To 100 ml of a methanol solution containing 20 g of the above product, add 200 ml of an aqueous solution containing 3.1 g of sodium hydroxide, followed by 1.5 hours of heating under reflux. After allowing to cool, methanol is evaporated under reduced pressure and the residue is acidified with concentrated hydrochloric acid. The solid precipitated in this way is collected by filtration, washed with water and dried to give 18.9 g of the objective product (mp 224-225 ° C). Spectrum of *? NMR (DMSO-d6, d ppm): 2.92 (3H, d, J = 5 Hz), 2.88 (3H, s), 7.08 (1H, d, J = 5 Hz), 7.98 (1H, s), 12.08 ( 1H, s).

Example 1 Preparation of (R) -5-bromo-N- (1-ethyl-4-methylhexahydro-lH-difumarate, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide: (1) A liquid mixture of 18.0 g of 5-bromo-2-methoxy-6 acid is stirred for 8 hours at room temperature. -methylamino-3-pyridinecarboxylic acid, 11.7 g of N, N'-carbonyldiimidazole and 50 ml of dimethylformamide. To the reaction mixture is added 13.0 g of (R) -6-amino-1-ethyl-4-methylhexahydro-1H-1,4-diazepine, followed by stirring for 15 hours at room temperature. The reaction mixture is concentrated under reduced pressure, and to which is added an aqueous 2N sodium hydroxide solution, followed by extraction with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on a silica gel column, eluted and purified with chloroform-methanol (15: 1) and recrystallized from diethyl ether to provide 19.6 g of the 1/4 hydrate of (R) -5. -bromo-N- (l-ethyl-4-methylhexahydro-lH-1,4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide (mp 52-55 ° C). This compound shows a retention time of 23.6 minutes in high performance liquid chromatography (CLAP) carried out under the conditions specified below, and has an optical purity of at least 99% ee.

[CLAP conditions] CLAP column: CHIRALPAK AS (Daicel Chemical Industries) inner diameter: 4.6 mm x 250 mm mobile phase: n - hexane - ethanol - diethyl sheet (940: 30: 2) regime: 0.8 ml / min temperature: 25 ° C detection : UV 254 nm (2) Treat 19 g of the above product with fumaric acid to convert it to difumarate and recrystallize from methanol to provide 23 g of the objective product (mp 152-155 ° C). Spectrum * -H NMR (DMSO-d6, d ppm): 1.02 (3H, t, J = 7 Hz), 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 = 5 Hz), 8.09 (1H, s), 8.48 (1H, d, J = 8 Hz), 12.80 (2H, broad s).

Reference Example 2 Preparation of (S) -5-bromo-N- (1-ethyl-4-methylhexahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3- difumarate pyridinecarboxamide: (1) The reaction and processing of Example 1 (1) is repeated except that (R) -6-amino-1-ethyl-4-methylhexahydro-1H-1,4-diazepine is substituted with (S) -6- amino-l-ethyl-4-methylhexahydro-lH-l, 4-diazepine and the monohydrate of (S) -5-bromo-N- (l-ethyl-4-methylhexahydro-lH-l, 4-diazepin- 6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide (mp 67-68 ° C, recrystallized from diethyl ether-petroleum ether). The compound shows a retention time of 27.5 minutes in CLAP under the same conditions as those indicated in Example 1, and has an optical purity of at least 99% ee. (2) The product formed in the above is treated with fumaric acid and converted to difumarate, which recrystallizes from ethanol to provide the objective product (mp 152-155 ° C).

Example 2 Preparation of (R) -6-amino-l-ethyl-4-methyl-hexahydro-lH-1,4-diazepine: (1) To a mixture of 1200 ml of chloroform and 1602 g of N '-methyl-N- (3-methylbenzyl) ethylenediamine is added dropwise under ice cooling a mixture of 3500 ml of a chloroform solution and 2180 g of dicarbonate of diterbutyl. After stirring, the reaction mixture for 18 hours at room temperature, this reaction mixture is concentrated to dryness under reduced pressure. When adding toluene and water with ice to the residue, an aqueous solution of 10% citric acid is added dropwise under cooling, with ice, to maintain the temperature inside the solution at no more than 4 ° C. By this method, the aqueous layer becomes acidic. The toluene layer is separated and extracted with water. The aqueous layer obtained in this way is combined with the aqueous acidic solution and washed with toluene. The aqueous layer is made alkaline with a 48% aqueous solution of sodium hydroxide and re-extracted with toluene. The extract is washed with water and with saturated saline, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure affords 1860 g of N "-tert-butoxycarbonyl-N '-methyl-N- (3-methylbenzyl) ethylenediamine as an oily product. (2.) 50 g of the above product are mixed with 53 g of (S) -2-methoxycarbonyl-1-benzyloxycarbonylaziridine and stirred at 80 ° C for 20 hours. Based on this, (R) -2- (benzyloxycarbonyl) amino-3- [N- [2- [N 1 - (tert-butoxycarbonyl) -N '-methylamino] ethyl] -N- (3-methylbenzyl) - Raw or untreated aminopropionate. (3) To the above untreated product is added 750 ml of 10% hydrogen chloride in an ethanol solution and stirred for 2 hours at 30-40 ° C. The insoluble material is removed by filtration, the solvent is evaporated under reduced pressure and the residue is dissolved in 500 ml of water. The aqueous layer is washed with diethyl ether, neutralized with sodium hydrogen carbonate and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to provide 79 g of (R) -2- (benzyloxycarbonyl) amino-3- [N- (2-methylaminoethyl) -N- (3-methylbenzyl) ) untreated methyl aminopropionate. A part of the product is converted to a form of the corresponding oxalate which recrystallizes from ethanol-diethyl ether to provide an oxalate of the methyl ester: m.p. 185-190 ° C. (4) 39 g of the above untreated methyl ester are dissolved in 70 ml of ethanol, and 70 ml of a 2N aqueous sodium hydroxide solution are added dropwise at 0 ° C-10 ° C followed by stirring. 16 hours at room temperature. Evaporation of ethanol under reduced pressure, the aqueous solution is adjusted to pH 8 with concentrated hydrochloric acid and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to provide 36.4 g of (R) -2- (benzyloxycarbonyl) -amino-3- [N- (2-ethylaminoethyl) -N- (3 -methylbenzyl)] aminopropionic untreated. A part of the product is purified to provide a crystalline product having a melting point of 170-175 ° C. (5) To a solution of 36.4 g of the above untreated product in 180 ml of methylene chloride are added 18.2 g of l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, followed by stirring for 20 hours at room temperature . The reaction mixture is washed with water, dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure and the residue is recrystallized from diethyl ether n-hexane to provide 22 g of (S) -3- (benzyloxycarbonyl amino-1-methyl-4- (3-methylbenzyl) hexahydro-2-oxo-l, -diazepine (mp) 70-71 ° C). (6J To a mixture of 400 ml of methylene chloride and 40.8 g of the above product is added dropwise 18.0 g of 1-chloroethyl chloroformate, followed by stirring for 3 hours at room temperature.The solvent is evaporated under reduced pressure and add to the residue 400 ml of methanol, followed by heating for 1 hour, under reflux.After evaporation of methanol under reduced pressure water is added to the residue which is subsequently washed with diethyl ether.The aqueous layer becomes alkaline with a solution aqueous sodium hydroxide solution and extracted with chloroform.The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated therein under reduced pressure to give (S) -3- (benzyloxycarbonyl) amino-1-methylhexahydro-2 -oxo-1, 4-diazepine untreated. (7) To the above untreated product are added 600 ml of methanol and 21.2 g of triethylamine, and 11.6 g of an 80% aqueous solution of acetaldehyde are further added, under ice-cooling, followed by stirring for 2 hours. Subsequently 3.97 g of sodium borohydride are added in portions at the same temperature and the mixture is stirred for one hour under cooling with ice and for 16 hours subsequent to room temperature. After evaporating the solvent under reduced pressure, the residue is extracted with chloroform. The extract is washed with saturated saline, water, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (15: 1) to provide 28 g of (S) -3- (benzyloxycarbonyl) amino-5-ethyl-1-methylhexahydro- 2-oxo-l, 4-diazepine as an oil. (8) To 28 g of the previous product are added 140 ml of an aqueous solution of hydrobromic acid at 48%, followed by heating for 2 hours under stirring at 60 ° C. After cooling, the reaction mixture is washed with diethyl ether twice and the aqueous layer is made alkaline with potassium carbonate and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure affords 19 g of (S) -3-amino-5-ethyl-1-methylhexahydro-2-oxo-l, 4-diazepine as an oily product. (9) To 300 ml of a tetrahydrofuran solution containing 23 g of the above product is added dropwise 1000 ml of a 1M borane-tetrahydrofuran solution, followed by stirring for 16 hours at room temperature. Subsequently, 500 ml of 1N hydrochloric acid are added under cooling with ice and the mixture is heated for 1 hour under reflux. After allowing the mixture to cool, the solvent is evaporated under reduced pressure and the residue is washed twice with diethyl ether and the aqueous layers are made alkaline with potassium carbonate and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure produces 19 g of the objective product as an oil.

Reference Example 3 Preparation of (S) -6-amino-l-ethyl-4-methyl-hexahydro-lH-1,4-diazepine: The objective compound is obtained by carrying out the reactions processing in a manner similar to that of Example 2 (2) - (9), except that the (S) -2-methoxycarbonyl-1-benzyloxycarbonylaziridine used in step (2) ) is substituted with (R) -2-methyl-1-ylcarbonyl-1-benzyloxycarbonylaziridine.

Formulation Example 1: Preparation of tablets (5 mg tablets) (R) -5-bromo-n- (l-ethyl-4-methylhexahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino difumarate -3-pyridinecarboxamide 5 g Lactose 80 g Corn starch 30 g Crystalline cellulose 25 g Hydroxypropyl cellulose 3 g Light silicic anhydride 0.7 g Magnesium stearate 1.3 g By following conventionally, the above components are mixed, granulated tabletted in 1000 tablets, each weighing 145 mg.

Formulation Example 2 Powder preparation (1% powder) (R) -5-Bromo-N- (l-ethyl-4-methylhexahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide difumarate 10 g Lactose 960 g Hydroxypropylcellulose 25 g Light silicic anhydride 5 g The components are mixed processed in a conventional manner, to a powder preparation.

Formulation example 3: Injection preparation (0.5% injection) (R) -5-bromo-N- (l-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl) -2-methoxy-6-methylamino difumarate -3-pyridinecarboxamide 10 g Sorbitol 100 g Water for injection an adequate amount Total 2000 ml It dissolves (R) -5-bromo-N- (l-ethyl-4-methylhexahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide sorbitol in one part of water for injection then the rest of the liquid for injection is added until it constitutes the total amount of 2000 ml. This solution is filtered through a membrane filter (0.22 μm). The filtrate is supplied as a filler in 2 ml bottles sterilized at 121 ° C for 20 minutes.

ISLTRI &L.

As explained above, the compound of the present invention, as presented by the formula (I) its physiologically acceptable acid addition salts show excellent antiemetic effect on the basis of its powerful antagonistic activity for serotonin S3 receptor dopamine. D2, are useful as antiemetic agents for the treatment or prophylaxis of various gastrointestinal symptoms which are related to various diseases drug administration. More specifically, they are useful for the treatment or prophylaxis of nausea, emesis, anorexia, abdominal satiety, upper abdominal discomfort, abdominal pain, heartburn, belching the like which often accompany diseases such as acute chronic gastritis, esophageal reflux , gastric duodenal ulcer, gastric neoris, gastroptosis, post-gastreptomy syndrome, scleroderma, diabetes, esophageal biliary duct disorders, periodic puerile vomiting upper respiratory tract infections. They are also useful for the treatment prophylaxis of, for example, irritable bowel syndrome, constipation diarrhea in infants. In addition, they can be used for the treatment prophylaxis of nausea or emesis induced by administration of antitumor agents or preparations of levodopa, or morphine, which is a narcotic analgesic, or at the time of radioactive irradiation. In addition, they can be used as antipsychotic or anxiolytic agents. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, property is claimed as contained in the following:

Claims (8)

1. (R) -5-bromo-N- (l-ethyl-4-methylhexahydro-lH-l, 4-diazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide, characterized in that it is expressed by the formula (I) below or the physiologically acceptable acid addition salts thereof.

2. A method for the preparation of a compound according to claim 1, characterized in that it comprises reacting a compound of formula (II) below or a reactive derivative thereof, with a compound of formula (III) below and, if necessary, converting the resulting product in the form of a free base to a corresponding physiologically acceptable acid addition salt.

3. A medicament characterized by containing the compound of formula (I) according to claim 1 or a physiologically acceptable acid addition salt thereof.

4. An antiemetic agent, characterized in that it contains the compound of formula (I) according to claim 1 or a physiologically acceptable acid addition salt thereof, as an effective ingredient.

5. A pharmaceutical composition, characterized in that it comprises the compound of formula (I) according to claim 1 or a physiologically acceptable acid addition salt thereof, and a carrier, for medical preparations.

6. A method for treating nausea or emesis, characterized in that it comprises administering an effective amount of the compound of formula (I) according to claim 1, or a physiologically acceptable acid addition salt thereof to a patient suffering from nausea or emesis.

7. The use of the compound of formula (I) according to claim 1 or its physiologically acceptable acid addition salt thereof, characterized in that it is used to treat a patient suffering from nausea or emesis or for the prophylactic treatment against nausea or emesis

8. ^ (R) -6-Amino-l-ethyl-4-methylhexahydro-lH-1,4-diazepine, characterized in that it is expressed by the following formula (III) or the acid addition salts thereof. This invention describes a compound which is expressed by the following formula (I): or physiologically acceptable acid addition salts thereof. The claimed compound exhibits excellent antiemetic effect on the basis of its potent antagonistic activity for the serotonin S3 receptor and dopamine D2, and is useful for the treatment or prophylaxis of various gastrointestinal symptoms which are associated with various diseases and drug administration.