RU2067979C1 - Derivative of aminobenzoic acid or its pharmaceutically acceptable salt - Google Patents

Abstract

FIELD: organic chemistry, pharmaceutical industry. SUBSTANCE: desired product has formula

where R¹ is cyanoalkyl, substituted or unsubstituted cycloalkyl, halogenated lower alkyl, alkynyl or tetrahydro-4H-pyran, R² is amino or acyl amino group, R³ is halogen, X is -NH- group, Z is =N-CH₃ or (CH₃)O. Suitable derivative of benzoic acid is used as reagent 1, amino derivative of bicyclo[3.2.1]octane is used as reagent 2. Reaction is carried out in aqueous solution of sodium hydroxide in the presence of pyridine at room temperature. EFFECT: improves quality of desired product. 4 tbl

Description

 The present invention relates to derivatives of aminobenzoic acid, especially to derivatives of aminobenzoic acid, useful as medicines, and to a process for their preparation.

 The number of patients with unidentified complaints, such as a full sensation of abdominal cavity, heartburn, nausea and vomiting, among patients with gastrointestinal diseases has recently been steadily increasing and currently reaches 60% or higher.

 Most of these unidentified (undiagnosed) complaints are caused by a functional abnormality of the digestive tract. For example, it is known that patients with epigastric unidentified complaints, such as chronic gastritis, are in a condition characterized by delayed gastric emptying, while patients with hypogastric unidentified complaints, such as irritable bowel syndrome (or mucous colitis), including as The main symptoms are abnormal emptying and abdominal pain, are in a state of intestinal hyperkinesis.

 It is recognized that stress and anxiety are the cause of any unidentified complaints, and in this sense, an unidentified complaint is one of the modern diseases.

 Dopamine antagonists, muscle-acting agents for regulating smooth muscle movement and acetylcholine release accelerators are currently used to alleviate the aforementioned gastrointestinal unidentified complaints. However, dopamine antagonists cause strong negative reactions, such as parkinsonism, so they should be used with great care, muscle-acting agents to regulate smooth muscle movement cause negative reactions such as excessive constipation, and acetylcholine release accelerators act ineffectively as antiemetic or antiphobic sedatives, and thus are unsatisfactory.

 Under these circumstances, the present inventors conducted studies to develop agents that are effective in treating all types of patients with gastrointestinal unidentified or vague complaints, without causing any strong negative reactions, and exhibit depressive activity against anxiety or fear that almost always appears as one of the causative factors of such patients.

As a result of these studies, it was concluded that the above requirements can be fulfilled with the help of a drug that exhibits both serotonin antagonism (hereinafter abbreviated “5HT ₃ ”) and the activity of accelerating the release of acetylcholine (hereinafter abbreviated “ACh”) . Therefore, further studies were carried out in order to find a compound having both types of activity with a well-balanced ratio of activities, and it was found that this goal can be achieved using the aminobenzoic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof. The present invention was created based on these findings.

 Although aminobenzoic acid derivatives useful as medicaments have been described in UK Patent Publication A N1593146 (1981) by Beecham Group Ltd. published July 15, 1981 N2125398 (1984). Sandon AG, Sandonpatent GMBH and Sandots A, published March 7, 1984 and N2205095 (1988) Bristol-Myers Squibb Co. and Bristol Myers Co. published November 30, 1989, US Pat. N4797406 (1985) Sandots Patent-GMBH and Sandots A, published March 19, 1991 European Patent Publication A N189002 (1986) Sandots AG, published July 30, 1986 N220011 (1987) by Beach Group Pls. published April 29, 1987, and N302699 (1989) Fordonal CA and Walton CA published February 8, 1989 and a UK patent publication N 2169292 (1988) Sandots-Ltd. Published September 21, 1988, the compounds of the present invention differ from them in chemical structure.

где A атом кислорода,
R¹ представляет собой цианоалкил, замещенный или незамещенный циклоалкилалкил, галоидзамещенный низший алкил, алкинил или тетрагидро-4Н-пиран,
R² представляет амино- или алкиламиногруппу,
R³ представляет атом галогена,
X представляет группу -NH-, Z представляет собой группуN-CH₃.The compound of the present invention is an aminobenzoic acid derivative represented by the following general formulas, or a pharmacologically acceptable salt thereof:

where A is an oxygen atom,
R ¹ represents cyanoalkyl, substituted or unsubstituted cycloalkylalkyl, halo substituted lower alkyl, alkynyl or tetrahydro-4H-pyran,
R ² represents an amino or alkylamino group,
R ³ represents a halogen atom,
X represents a group —NH—, Z represents a group N — CH ₃ .

 The pharmacologically acceptable salt of the present invention includes inorganic acid salts such as hydrochloride, bromohydrate, sulfate and phosphate, organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate, and amino acid salts such as arginate, asparaginate and glutamate .

 Further, the aminobenzoic acid derivatives of the present invention can form metal salts, such as the sodium, potassium, calcium or magnesium salt, or may be present in the form of a hydrate. Pharmacologically acceptable salts of the present invention include these metal salts and hydrates.

 Although the compound of the present invention may be present as geometric isomers or optical isomers, it is not necessary to say that the present invention includes all isomers.

 Experimental Example 1

 Antagonism against 2-methylserotonin-induced contraction or ileum systole.

This experiment was carried out according to the method of the authors Sangeret al. (see Eur. J. Pharmacol. 159, 113 124 (1989)). The non-terminal portion of the ileum of the male Hartley guinea pig was suspended in a Krebs-Hensleit solution (37 ^° C.) using a load of 0.5 g at the end of the ileum, and a gaseous mixture comprising 95% oxygen and 5% carbon dioxide was passed through the solution. Iliac contraction was determined isometrically. After leaving the ileum, the ileum was standing for one or more hours without stabilization, a solution of the test compound was added to the solution and after 30 minutes 2-methylserotonin was non-cumulatively added. The pA2 value was calculated based on a shift to the right of the dose-response curve of the contraction caused by 2-methylserotonin induced by the test compound according to the method of Possumet al. (see A.cn. Int. Pharmacodyn. 143, 299 (1963)). BRL 24682 was used as a control in this experiment. The results are given in table 1.

 Experimental Example 2

 Activity against vomiting of a hound dog caused by cisplatin.

 Hounds dogs weighing 7-12 kg were used. 3 mg / kg cisplatin (Sigma product) (1 mg / kg saline) was administered to each dog through the vein of the forefoot. One hour after the administration of cisplatin, the control group was injected with physiological saline (0.2 ml / kg), the test group of dogs was injected with a solution of the test compound in physiological saline, each dog through a vein of another forepaw. The vomiting frequency observed over the 5-hour period from the moment of cisplatin administration was recorded, and the degree of inhibition of the test compound was calculated by the following formula.

 The results are given in table 2.

Экспериментальный пример 3.

Experimental Example 3

 Activity to promote (induce) gastric emptying function.

 This experiment was conducted according to the method of Decktoret al. (see Eur. J. Pharmacol. 147, 313 316 (1988)). Male Fscher rats (weight: 160-180 g) were kept hungry for 18 hours before each rat was orally given 3 ml of experimental food, including methyl cellulose, beef broth, casein, sugar and corn starch. One hour after the feed was administered, the stomach was completely removed from each rat. The degree of gastric emptying was calculated based on the weight of the experimental food remaining in the stomach. The degree of induction of gastric emptying function was determined by comparing the degree of gastric emptying in the treated rats with the degree of control rats that were not given any of the test compounds. Each test compound was administered orally one hour before the administration of the test feed. As a control in this experiment, BP 24682 was used.

 The results are given in table 3.

 Experimental Example 4

 The effect of increasing contraction of the ileum of the guinea pig caused by stimulation in an electric field.

This experiment was carried out according to the method of Sangeret al. (see Br. J. Pharmacol. 91, 77 89 (1987)). The longitudinal muscle of the non-terminal ileum of the guinea pig was separated and vertically suspended in a solution (37 ^° C) in a Magnus tube when a load of 0.5 g was applied to the end of the muscle. A mixed gas was passed through the solution, including 98% oxygen and 5% carbon dioxide. Muscle contraction was determined isometrically. In order to cause muscle contraction, stimulation in the electric field was applied to the muscle using a platinum electrode once every 10 seconds. The contraction was caused by the release of acetylcholine. After the muscle stabilized, a solution of the test compound was cumulatively added to the Magnus tube at a 10 minute interval. The effect of the test compound is presented as a percentage based on the initial reduction. The minimum concentration of each test compound at which an increase was detected in the contraction due to the release of acetylcholine is shown in Table 4.

From the results of the above pharmacological experiments, it can be understood that the compounds of the present invention have 5-HT ₃ antagonism and ACh excretion activity and, therefore, are effective in terms of their ability to induce gastrointestinal functions such as gastric emptying and are useful as antiemetics funds.

Accordingly, the compound of the present invention acts as an accelerator of 5-HT ₃ antagonism and ACh secretion, which is why it is useful as a medicine based on these activities.

Acetylcholine release acceleration activity is based on the 5-HT ₄ antagonistic activity of the compound of the present invention.

 The compound of the present invention is effective against various diseases, and specific examples of diseases include irritable bowel syndrome, peptic esophagitis, nausea, vomiting, abdominal pain and bloating caused by chronic gastritis, gastroptosis, gastric post-resection syndrome or the like, gastrointestinal symptoms and gastrointestinal failure represented by diseases caused by the administration of anticancer agents or irritation during irradiation, anxiety, migraine, memory loss syndrome yati.

 In addition, the compound of the present invention is less toxic and highly safe, thus being also valuable in this sense.

 When the compounds obtained in the following Examples 4 and 43 were each administered orally to rats for one week at a dose of up to 30 mg / kg, there was no evidence of toxicity.

 Further, when the above two compounds were administered each to beagle dogs, no toxicity of up to 1.5 mg / kg was manifested.

 The compound of the present invention is prescribed as a therapeutic and prophylactic agent for the above diseases in the form of tablets, powders, granules, capsules, syrups and inhaled preparations. Although its dose varies markedly depending on the degree of symptoms, age and type of disease, the dose for an adult per day is about 0.01 to 1000 mg, preferably 0.1 to 500 mg, more preferably 0.1 to 100 mg, which can be prescribed in the form of one to several servings per day.

 When the compound of the present invention is administered as an injection, the dose is usually 1 3000 μg-kg, preferably about 3 to 1000 μg / kg.

 The preparations according to the present invention are prepared using conventional carriers by conventional methods.

 More specifically, a solid oral preparation according to the present invention is prepared by adding an excipient and, if necessary, a binder, disintegrant, lubricant, coloring agent and / or flavoring agent to the active ingredient to form the resulting mixture into tablets, coated tablets, granules, powders or capsules in conventional ways.

 Examples of excipients include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silica, examples of binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, acacia gum, trigacanth, gelatin, shellac, hydroxypropyl cellulose nitroxypropyl cellulose nitroxypropyl cellulose nitroxypropyl cellulose nitrate and pectin, examples of lubricants include magnesium stearate, talc, polyethylene glycol, silicon dioxide and hardened vegetable oil, examples of coloring agents include and allowed authoritative bodies as pharmaceutical additives, and examples of corrigents include powder, cocoa, mint herb, aromatic powder, mentha oil, borneol and powdered cinnamon bark. Of course, tablets and granules may be suitably coated with sugar, gelatin or the like, if necessary.

 An injection preparation according to the present invention is prepared by adding a pH regulator, buffer, stabilizer and / or solubilizing agent to the desired active ingredient and converting the mixture into an injection preparation for subcutaneous, intramuscular or intravenous administration using a conventional process.

 Examples.

 Now will be described examples according to the present invention, although the present invention is not limited to them.

 In the examples, Me represents a methyl group and Ac an acetyl group. /// 2 Example A.

Трифенилфосфин (146,4 г) растворялся в тетрагидрофуране (500 мл). К полученному раствору при -65^oC в струе азота, постепенно, по каплям, в указанном порядке добавлялись диэтилазокарбоксилат (97,2 г), 3-пентин-2-ол (33,2 г) и раствор метил-4-ацетоамидо-5-хлорсалицилата (80 г) в тетрагидрофуране (1,4 л). Температура реакционной смеси поднималась до комнатной температуры, и реакционная смесь перемешивалась в течение ночи при комнатной температуре. Растворитель удалялся при пониженном давлении. Остаток растворялся в этилацетате (200 мл) и по каплям при перемешивании добавлялся п-гексан (1: 3 л). Кристаллы, осажденные таким образом, отфильтровывались и фильтрат концентрировался в вакууме. Остаток очищался с помощью хроматографии на колонке через силикагель, давая 74,3 г целевого соединения.Methyl 4-acetoamido-5-chloro-2- (3-pentin-2-yl) oxy benzoate

Triphenylphosphine (146.4 g) was dissolved in tetrahydrofuran (500 ml). To the resulting solution at -65 ^° C in a stream of nitrogen, diethylazocarboxylate (97.2 g), 3-pentin-2-ol (33.2 g) and a solution of methyl-4-acetoamido- were gradually added dropwise in this order. 5-chlorosalicylate (80 g) in tetrahydrofuran (1.4 L). The temperature of the reaction mixture rose to room temperature, and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 ml) and p-hexane (1: 3 L) was added dropwise with stirring. The crystals thus precipitated were filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography through silica gel, giving 74.3 g of the target compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm

 1.65 (d, J 5.5 Hz, 3H), 1.82 (d, J 2.0 Hz, 3H), 2.26 (s, 3H), 3.86 (s, 3H), 4, 85, 4.94 (m. 1H), 7.72 (br s. 1H), 7.88 (s, 1H), 8.46 (s, 1H).

 Example B.

К суспензии метил 4-ацетоамидо-5-хлор-2-(3-фенил-2-ил)-окси бензоата (73,3 г) в метаноле (700 мл), по каплям, при 0^oC добавлялась серная кислота (73 мл). Температура реакционной смеси поднималась до комнатной температуры. После того, как реакционная смесь перемешивалась в течение ночи при комнатной температуре, реакционная смесь выливалась в насыщенный водный раствор бикарбоната натрия (5 л), постепенно. Кристаллы, осажденные таким образом, удалялись с помощью фильтрования, промывались водой и сушились, давая 66,5 г целевого соединения в виде бесцветных кристаллов.Methyl 4-amino-5-chloro-2 - {(3-pentin-2-yl)} hydroxy benzoate

To a suspension of methyl 4-acetoamido-5-chloro-2- (3-phenyl-2-yl) -oxy benzoate (73.3 g) in methanol (700 ml), sulfuric acid (73) was added dropwise at 0 ^° C. ml). The temperature of the reaction mixture rose to room temperature. After the reaction mixture was stirred overnight at room temperature, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (5 L), gradually. The crystals thus precipitated were removed by filtration, washed with water and dried, to give 66.5 g of the target compound as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm.

 1.66 (d, J 6.5 Hz, 3H), 1.81 (d, J 2.0 Hz, 3H), 3.81 (s, 3H), 4.41 (br s. 2H), 4.70 4.78 (m, 1H), 6.53 (s, 1H), 7.82 (s, 1H).

 Example C.

К суспензии метил 4-амино-5-хлор-2-(3-пентин-2-ил)-окси бензоата (56,0 г) в метаноле (1,3 л) добавлялся водный 5 норм. раствор гидроокиси натрия (140 мл). Получающаяся в результате смесь перемешивалась в течение 6 часов при 50^oC и затем 3 дня при комнатной температуре. К полученной смеси добавлялась вода (1 л) с последующим подкислением 2 норм. соляной кислотой. Кристаллы, полученные таким образом, удалялись с помощью фильтрования, промывались водой и сушились, давая 51,5 г целевого соединения в виде бесцветных кристаллов.4-amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoic acid

To a suspension of methyl 4-amino-5-chloro-2- (3-pentin-2-yl) -oxy benzoate (56.0 g) in methanol (1.3 L) was added aqueous 5 norms. sodium hydroxide solution (140 ml). The resulting mixture was stirred for 6 hours at 50 ^° C. and then for 3 days at room temperature. Water (1 L) was added to the resulting mixture, followed by acidification of 2 norms. hydrochloric acid. The crystals thus obtained were removed by filtration, washed with water and dried, giving 51.5 g of the target compound as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm

1.50 (d. J 6.50 Hz, 3H), 1.79 (d, J 2.0 Hz, 3H), 4.81, 4.84 (m. 1H), 6.07 (br s , 2H), 6.53 (s, 1H), 7.56 (s, 1H). Mp 114 116 ^o C.

 Example D.

(±)-4-амино-5-хлор-2-{ (3-пентин-2-ил)окси} бензойная кислота (15,2 г) растворялась в этаноле (105 мл) и к полученному раствору при комнатной температуре добавлялся раствор (+)-дегидроабиэтиламина (17,1 г) в этаноле (15 мл). Получающаяся в результате смесь отстаивалась на столе в течение 2 часов. Кристаллы, полученные таким образом, удалялись с помощью фильтрования и перемешивались небольшим количеством этанола. Затем кристаллы растворялись в водном 1 норм. растворе гидроокиси натрия и проводилось экстрагирование дихлорметаном. Водная фаза подкислялась концентрированной соляной кислотой, затем экстрагировалась хлороформом. Органическая фаза сушилась и концентрировалась в вакууме, давая 4,23 г белых кристаллов.(S) -4-amino-5-chloro-2 - {(3-pentin-2-yl) oxy} benzoic acid

(±) -4-amino-5-chloro-2- {(3-pentin-2-yl) oxy} benzoic acid (15.2 g) was dissolved in ethanol (105 ml) and a solution was added to the resulting solution at room temperature (+) - dehydroabiethylamine (17.1 g) in ethanol (15 ml). The resulting mixture settled on the table for 2 hours. The crystals thus obtained were removed by filtration and stirred with a small amount of ethanol. Then the crystals were dissolved in aqueous 1 norms. sodium hydroxide solution and extraction was carried out with dichloromethane. The aqueous phase was acidified with concentrated hydrochloric acid, then extracted with chloroform. The organic phase was dried and concentrated in vacuo to give 4.23 g of white crystals.

 These crystals were dissolved in ethyl acetate (70 ml), and (S) - (-) - naphthylethylamine (2.67 ml) was added to the resulting solution. The mixture thus obtained was settled on the table for 1 hour. The crystals thus obtained were removed by filtration and washed with a small amount of ethyl acetate. Then the crystals were dissolved in 1 norm. hydrochloric acid and extraction was carried out with chloroform. The organic phase was dried and concentrated in vacuo, yielding 2.38 g of white crystals.

 Subsequently, these crystals were again dissolved in ethyl acetate (45 ml), and (S) - (-) - naphthylethylamine (1.41 ml) was added to the resulting solution. The mixture thus obtained was settled on the table for 1 hour. The crystals thus precipitated were removed by filtration and washed with a small amount of ethyl acetate. Then the crystals were dissolved in 1 norm. hydrochloric acid and extraction was carried out with chloroform. The organic phase was dried and concentrated in vacuo to give 1.50 g (99.6%) of the target compound as white crystals.

 Example 1

400 мг 4-Амино-5-хлор-2-(3-пентин-2-ил)окси бензойной кислоты и 400 мг эндо-3-амино-8-метил-8-азабицикло[3.2.1]октана растворялись в 20 мл пиридина с последующим добавлением 0,38 мл 5 норм. водного раствора гидроокиси натрия при перемешивании при комнатной температуре. Полученная смесь перемешивалась в течение 10 минут с последующим добавлением 650 мг 1,3-дициклогексилкарбодиимида. Полученная смесь перемешивалась при комнатной температуре в течение 8 часов с последующим добавлением 30 мл воды. Получающаяся в результате смесь фильтровалась для удаления нерастворимых веществ и фильтрат подщелачивался водным раствором гидроокиси натрия и экстрагировался хлороформом. Органическая фаза сушилась над безводным сульфатом магния и перегонялась для удаления растворителя. Остаток очищался с помощью хроматографии через силикагель (10% метанол/хлороформ), давая 450 мг целевого соединения в виде белых кристаллов.Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) - {(3-pentin2-yl) oxy} benzamide

400 mg of 4-amino-5-chloro-2- (3-pentin-2-yl) oxybenzoic acid and 400 mg of endo-3-amino-8-methyl-8-azabicyclo [3.2.1] octane were dissolved in 20 ml pyridine followed by the addition of 0.38 ml of 5 norms. aqueous sodium hydroxide solution with stirring at room temperature. The resulting mixture was stirred for 10 minutes, followed by the addition of 650 mg of 1,3-dicyclohexylcarbodiimide. The resulting mixture was stirred at room temperature for 8 hours, followed by the addition of 30 ml of water. The resulting mixture was filtered to remove insoluble matter, and the filtrate was made basic with an aqueous solution of sodium hydroxide and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by chromatography through silica gel (10% methanol / chloroform) to give 450 mg of the target compound as white crystals.

¹ H-NMR (400 MHz, d ₆ -DMMSO) δ ppm 1.56, 1.65 (m, 5H), 1.75, 1.85 (ms, 5H), 1.95, 2.13 (m, 4H), 2.18 (s, 3H), 3, 00, 3.13 (m, 2H), 3.93, 4.00 (m, 1H), 5.05, 5.13 (m, 1H), 5.89 (br s, 2H), 6, 59 (s, 1H), 7.70 (s, 1H), 8.87 (d, J 6.0 Hz, 1H).

Mp 173 175 ^o C.

 Example 2

450 мг эндо-4-амино-5-хлор-N-8-метил-(8-азабицикло(3.2.1)окт-3-)-ил-2- (3-пентин-2-ил)окси} бензамида растворялось в 5 мл этанола с последующим добавлением этанольной соляной кислоты и диэтилового эфира в указанном порядке. Осажденная таким образом соль удалялась с помощью фильтрования. Получалось 320 мг целевого соединения в виде бледно-желтых кристаллов.Endo-4-amino-5-chloro-N- [8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2 - {(3-pentin-2-yl) oxy} benzamide hydrochloride

450 mg endo-4-amino-5-chloro-N-8-methyl- (8-azabicyclo (3.2.1) oct-3 -) - yl-2- (3-pentin-2-yl) oxy} benzamide was dissolved in 5 ml of ethanol, followed by the addition of ethanol hydrochloric acid and diethyl ether in this order. The salt thus precipitated was removed by filtration. The result was 320 mg of the target compound as pale yellow crystals.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm 1.60 (d, J 6.5 Hz, 3H), 1.82 (d. J 2.0 Hz, 3H), 1.98 2.48 (m, 8H), 2.64 (d, J 6 , 0 Hz, 5H), 3.75 3.98 (m 2H), 3.95 4.05 (m 1 H), 5.05 5.13 (m 1 H), 5.95 (br s , 2H), 6.6 (s, 1H), 7.63 (s. 1H), 7.92 (d. J 5.0 Hz, 1H).

 Example 3

 (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl) -2- (3-pentin-2-yl) oxy} benzamide.

 (+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (3-pentin-2-yl) oxy} benzamide .

800 мг рацемической модификации соединения, полученного в примере 2, подвергалось жидкостной хроматографии высокой разрешающей способности (HPLC) с использованием хиральной колонки (продукт фирмы Дайцел Кемикал Индастриз, Лтд. Хиралцел Од) и растворителя в подвижной фазе (этанол:гексан:триэтиламин 20:80:0,1), давая 370 мг (-)-изомера и 300 мг (+)-изомера; (-)-изомер ¹H-ЯМР (400 МГц, CDСl₃) δ млн. дол.

800 mg of the racemic modification of the compound obtained in Example 2 was subjected to high-resolution liquid chromatography (HPLC) using a chiral column (product of Deicel Chemical Industries, Ltd. Chiralcel Od) and a solvent in the mobile phase (ethanol: hexane: triethylamine 20:80 : 0.1), yielding 370 mg of the (-) isomer and 300 mg of the (+) isomer; (-) - isomer ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm.

 1.68 1.83 (m. 5H), 1.84 (d. J 3.0 Hz, 3H), 1.85 1.95 (m, 3H), 2.05 2.15 (m, 2H) 2.20 2.29 (m 2H), 2.30 (s, 3H), 3.11 3.18 (m, 2H), 4.17 4.25 (m, 1H), 4.35 ( br s, 2H), 4.93 (sq. J, 3.0 Hz, 7.0 Hz, 1H), 6.46 (s, 1H), 7.98 (d, J 5.5 Hz, 1H), 8.09 (s, 1H).

(+) - isomer ¹ H-NMR (400 MHz, CDCl ₃ ) d mln.

 1.66 1.79 (m, 5H), 1.84 (d. J 3.0 Hz, 3H), 1.85 1.94 (m. 2H), 2.06 2.15 (m. 2H) , 2.20 2.3 (m, 2H), 2.32 (s, 3H), 3.10 3.18 (m 2H), 4.16 4.24 (m, 1H), 4.93 ( sq. sq., J 3.0 Hz, 7.0 Hz, 1 H), 6.46 (s, 1 H), 7.98 (d. 5.5 Hz, 1 H), 8.08 (s, 1 H) .

Mp 144 145 ^o C.

 Example 4

1,85 г (-)-эндо-4-Амино-5-хлор-N-(8-метил-8-азабицикло(3.2.1)-окт-3-ил)-2- (3-пентин-2-ил)окси}бензамида растворялось в 9 мл этанола с последующим добавлением 2,46 мл 2 норм. соляной кислоты и 90 мл воды в указанном порядке. Полученная смесь подвергалась сушке вымораживанием, давая 1,99 г целевого гидрохлорида (-)-изомера.(-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo- (3.2.1) oct-3-yl) -2- (3-pentin-2-yl) oxy} benzamide hydrochloride

1.85 g (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl) -2- (3-pentin-2- il) oxy} benzamide was dissolved in 9 ml of ethanol, followed by the addition of 2.46 ml of 2 norms. hydrochloric acid and 90 ml of water in the indicated order. The resulting mixture was freeze dried to give 1.99 g of the desired hydrochloride of the (-) - isomer.

Mz m / z (FAB): 376 (M ⁺ +1 ¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm 1.62 (d. J 6.5 Hz, 3H), 1.84 (d. J 2.0 Hz, 3H), 2.03 - 2.45 (m. 8H), 2.67 (d. J 5.1 Hz, 3H), 3.82 3.91 (m, 2H) ), 4.00 4.05 (m, 1H), 5.10, 5.14 (m, 1H), 5.96 (br s, 2H), 6.63 (s. 1H), 7.66 ( p. 1H), 7.93 (d. J 5.0 Hz, 1H, 9.92 (s. 1H).

 Examples 5 to 19.

 The following compounds were obtained by a method similar to the method of example 1.

 Example 5

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол. 1,03 (т. J 8 Гц, 3Н, 1,52 (т. J 12,0 Гц, 2Н), 1,68 1,74 (м. 2Н), 1,84 2,12 (м. 6Н), 2,14 (с. 3Н), 3,03 (шир. с. 2Н), 3,93 4,02 (м. 1Н), 4,94 (т. J 4,0 Гц, 1Н), 5,94 (с. 2Н), 6,60 (с, 1Н), 7,67 (с. 1Н), 7,78 (д. J 6,0 Гц, 1Н).Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl-2- (1-pentin-3-yl) oxy} benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm. 1.03 (t. J 8 Hz, 3H, 1.52 (t. J 12.0 Hz, 2H), 1.68 1.74 (m. 2H), 1.84 2.12 (m. 6H) 2.14 (s. 3H), 3.03 (br s. 2H), 3.93 4.02 (m. 1H), 4.94 (t. J 4.0 Hz, 1H), 5, 94 (s. 2H), 6.60 (s, 1H), 7.67 (s. 1H), 7.78 (d. J 6.0 Hz, 1H).

Mp 182 184 ^o C.

 Example 6

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол. 1,50 1,70 (м. 2Н), 1,75 1,90 (м. 2Н), 1,03 2,13 (м, 4Н), 2,22 (с, 3Н), 3,10 3,20 (м. 2Н), 3,81 (т. J 2 Гц, 1Н), 3,94 4,01 (м. 1Н), 4,88 (д. J 2 Гц, 2Н), 5,99 (шир.с. 2Н), 6,52 (с. 1Н), 7,67 (с. 1Н), 7,99 (д. J 5 Гц, 1Н).Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2-propargyloxybenzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm 1.50 1.70 (m 2H), 1.75 1.90 (m 2H), 1.03 2.13 (m, 4H), 2.22 (s, 3H), 3.10 3, 20 (m. 2H), 3.81 (t. J 2 Hz, 1H), 3.94 4.01 (m. 1H), 4.88 (d. J 2 Hz, 2H), 5.99 (broad S.p. 2H), 6.52 (s. 1H), 7.67 (s. 1H), 7.99 (d. J 5 Hz, 1H).

 Example 7

¹H-ЯМР (400 МГц, d₆DMСО) δ млн.дол. 1,51 1,58 (м. 2Н), 1,75 1,83 (м. 2Н), 1,84 (т. J 2,5 Гц, 3Н), 1,95 2,10 (м. 4Н), 2,15 (с. 3Н), 3,00 3,03 (м. 2Н), 3,96 3,98 (м. 1Н), 4,82 (кв. J 2,5 Гц, 2Н), 5,97 (с. 2Н), 6,50 (с. 1Н), 7,69 (с. 1Н), 8,06 (д. J 7 Гц, 1Н).Endo-4-amino-2- (2-butynyloxy) -5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ DMSO) δ ppm. 1.51 1.58 (m. 2H), 1.75 1.83 (m. 2H), 1.84 (t. J 2.5 Hz, 3H), 1.95 2.10 (m. 4H) 2.15 (s. 3H), 3.00 3.03 (m. 2H), 3.96 3.98 (m. 1H), 4.82 (q. J 2.5 Hz, 2H), 5 97 (s. 2H), 6.50 (s. 1H), 7.69 (s. 1H), 8.06 (d. J 7 Hz, 1H).

Mp 188 191 ^o C.

 Example 8

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол. 1,58 1,68 (м. 2Н), 1,71 (т. J 2,5 Гц, 3Н), 1,73 1,80 (м. 2Н), 1,90 2,10 (м. 4Н, 2,66 (т.кв. J 6,6, 2,5 Гц, 2Н), 3,00 3,10 (м. 2Н), 3,95 3,97 (м. 1Н), 4,12 (т. J 6,5 Гц, 2Н), 5,90 (с. 2Н), 6,49 (с. 1Н), 7,70 (с. 1Н), 7,90 (д. J 6,5 Гц, 1Н).Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2-3-pentynyloxy benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm 1.58 1.68 (m. 2H), 1.71 (t. J 2.5 Hz, 3H), 1.73 1.80 (m. 2H), 1.90 2.10 (m. 4H, 2.66 (i.e., J 6.6, 2.5 Hz, 2H), 3.00 3.10 (m 2H), 3.95 3.97 (m 1H), 4.12 (t J 6.5 Hz, 2H), 5.90 (s. 2H), 6.49 (s. 1H), 7.70 (s. 1H), 7.90 (d. 6.5 Hz, 1H )

 Example 9

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-3- {(3-butyn-2-yl) oxy)} -5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-5-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.52 1.60 (m, 2H), 1.64 (d.J. 6.5 Hz, 3H), 1.71 1.78 (m. 2H), 1.95 2.08 (m. 4H) 2.13 (s. 3H), 2.97 3.03 (m. 2H), 3.70 (d. J 3.0 Hz, 1H), 3.93 3.99 (m. 1H), 5 14 (d.c. J 3.0, 6.5 Hz, 1H), 5.97 (br s, 2H), 6.59 (s. 1H), 7.78 (s. 1H), 7 81 (d. J 6.5 Hz, 1H).

 Example 10

¹H-ЯМР (400 МГц, CDСl₃) δ млн.дол.Endo-4-amino-5-chloro-2 - {(4-heptin-3-yl) oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm.

 1.10 (t. J 8.0 Hz, 3H), 1.12 (t. J 8.0 Hz, 3H), 1.71 2.31 (m. 12H), 2.32 (s. 3H) , 3.16 (br s, 2H), 4.20 (dd. J 4.0, 11.0 Hz, 1H), 4.35 (br s, 2H), 4.73 4.78 (m . 1H), 6.43 (s. 1H), 7.98 (br.s. 1H), 8.09 (s. 1H).

 Example 11

¹H-ЯМР (400 МГц, CDСl₃) δ млн.дол.Endo-4-amino-5-chloro-2 - {(4-heptin-2-yl) oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm.

1.10 (t. J 7.5 Hz, 3H), 1.52 (d. J 6.0 Hz, 3H), 1.74 1.92 (m. 6H), 2.08 2.18 (m .3H), 2.26 2.34 (m. 1H), 2.33 (s. 3H), 2.52 (A ₂ BCX type, J 2.5; 7.5; 16.0 Hz, 1H) 2.64 (A ₂ BX type, J 2.5; 2.5; 16.0 Hz, 1H), 3.20 (br.s. 2H), 4.16 4.24 (m. 1H), 4.33 (br.s. 2H), 4.52 4.63 (m. 1H), 6.32 (s. 1H), 7.96 (br.s. 1H), 8.10 (s. 1H) )

 Example 12

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-2 - {(2-hexin-4-yl) oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.02 (t. J 7.5 Hz, 3H), 1.50 1.63 (m. 2H), 1.70 1.80 (m. 2H), 1.83 (d. J 2.0 Hz , 3H), 1.85 2.13 (m. 6H), 2.16 (s. 3H), 3.00 3.10 (m. 2H), 3.91 4.00 (m. 1H), 4 88 4.94 (m 1H), 5.92 (br.s. 2H), 6.58 (s. 1H), 7.68 (s. 1H), 7.85 (d. J 6.0 Hz, 1H).

 Example 13

¹H-ЯМР (400 МГц, d₆-DMСО+CDСl₃) δ млн. дол.Endo-4-amino-5-chloro-2 - {(3-hexin-2-yl) oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO + CDCl ₃ ) δ ppm

 1.02 (t. J 7.5 Hz, 3H), 1.55 1.65 (m. 5H), 1.73 1.85 (m. 2H), 1.95 2.10 (m. 4H) 2.15 2.23 (m 5H), 3.00 3.13 (m 2E), 3.93 4.00 (m 1 H), 5.12 (q, J 6.5; 2.0 Hz, 1H), 5.93 (br s, 2H), 6.59 (s. 1H), 7.69 (s. 1H), 7.89 (d. J 6.0 Hz, 1H )

Mp 144 145 ^o C.

 Example 14

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-5-chloro-2- {(1-hexin-3-yl) oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 0.93 (t. J 7.5 Hz, 3H), 1.40 -1.60 (m. 4H), 1.65 1.75 (m. 2H), 1.80 2.22 (m. 6H) ), 2.15 (s. 3H), 3.00 (br.s. 2H), 3.70 (s. 1H), 3.90 4.00 (m. 1H), 4.95 (t. J 4.0 Hz, 1H), 5.94 (br.s. 2H), 6.60 (s. 1H), 7.69 (s. 1H), 7.76 (d. J 6.0 Hz, 1H )

 Example 15

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-5-chloro-2- (2-fluoroethoxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.50 1.60 (m, 2H), 1.62 1.75 (m, 2H), 1.90, 2.18 (m. 4H), 2.13 (s. 3H), 2.98 3, 03 (m. 2H), 3.95 4.00 (m. 1H), 4.25 4.28 (m. 1H), 4.32 4.35 (m. 1H), 4.75 4.77 ( m. 1H), 4.88 4.90 (m. 1H), 5.92 (br s, 2H), 6.55 (s. 1H), 7.68 (s. 1H), 7.77 ( d. J 7.0 Hz, 1H).

 Example 16

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-2- (3-cyanopropoxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.52 1.59 (m 2H), 1.65 1.74 (m 2H), 1.95 2.15 (m 6H), 2.13 (s. 3H), 2.66 (t .J 7.0 Hz, 2H), 2.97 3.02 (m. 2H), 3.94 3.99 (m. 1H), 4.14 (t. J 6.0 Hz, 2H), 5 90 (br s, 2H), 6.50 (s. 1H), 7.66 (s. 1H), 7.80 (d. J 7.0 Hz, 1H).

 Example 17

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-2- (1-cyclopentylethoxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.18 1.35 (m. 5H), 1.43 1.65 (m. 6H), 1.66 1.83 (m. 4H), 1.93 - 2.23 (m. 8H), 3 01.13.13 (m 2H), 3.93 4.00 (m 1H), 4.22 4.31 (m 1H), 5.84 (s. 2H), 6.56 (s. 1H), 7.70 (s. 1H), 7.96 (d. J 5.5 Hz, 1H).

 Example 18

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl) -2-tetrahydro-4H-pyran-4-hydroxybenzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.53 1.80 (m 6H), 1.93 2.13 (m 6H), 2.17 (s. 3H), 3.00 3.13 (m 2H), 3.38 -3 48 (m. 2H), 3.88 3.98 (m. 3H), 4.51 4.61 (m. 1H), 5.85 (br.s. 2H), 6.62 (s. 1H ), 7.68 (s, 1H), 7.85 (d. J, 6.0 Hz, 1H).

 Example 19

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-5-chloro-2- (4-methoxycyclohexyloxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.20 1.35 (m, 1H), 1.43 1.68 (m. 4H), 1.69 1.81 (m. 3H), 1.82 - 1.91 (m. 1H), 1 95 2.25 (m 10H), 3.23 (s. 3H), 3.26 3.36 (m 2n), 3.39 3.50 (m 1H), 3.91 4.00 (m. 1H), 4.30 4.43 (m. 1H), 5.83 (br.s. 2H), 6.57 (s. 1H), 7.68 (s. 1H), 7.85 (d. J 5.0 Hz, 1H).

 Examples 20 to 34.

 The following compounds were obtained in a manner analogous to that presented in example 2.

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Example 20
Endo-4-amino-5-chloro-n- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- {(1-pentin-3-yl) oxy} benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.02 (t. J 8 Hz, 3H), 1.82 2.12 (m. 6H), 2.21 2.24 (m. 2H), 2.40 2.44 (m. 2H), 2 62 (d. J 6.0 Hz, 3H), 3.72 (s. 2H), 3.82 (br.s. 2H), 3.93 4.03 (m. 1H), 4.93 ( t. J 4.0 Hz, 1H), 6.62 (s. 1H), 7.60 (s. 1H), 7.86 (d. J 5.0 Hz, 1H).

MC m / z (FAB), 376 (M ⁺ +1.

 Example 21

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2-propargyloxybenzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.90 2.10 (m 2H), 2.11 2.30 (m 4H), 2.41 2.53 (m 2H), 2.63 (s. 3H), 3.72 (t .J 2.0 Hz, 1H), 3.78 3.85 (m, 2H), 3.94 4.03 (m, 1H), 4.86 (d. J 2.0 Hz, 1H), 6 01 (br s, 2H), 6.53 (s. 1H), 7.62 (s. 1H), 8.00 (d. J 5.0 Hz, 1H).

Mp 242 245 ^o C.

 Example 22

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-2- (2-butynyloxy) -5-chloro (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.86 (br s, 3H), 2.00 2.06 (m, 2H), 2.15 2.31 (m, 4H), 2.36 2.45 (m, 2H), 2.65 (s. 3H), 3.80 3.88 (m. 2H), 3.96 4.04 (m. 1H), 4.8 (br s. 2H), 6.00 (br s. 2H) ), 6.50 (s. 1H), 7.63 (s. 1H), 8.05 (d. J, 7.0 Hz, 1H).

MC m / z (FAB), 362 (M ⁺ +1.

Mp 263 265 ^o C.

 Example 23

¹H-ЯМР (400 Мгц, d₆-DMСО) δ млн. дол.Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (3-pentynyloxy) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.74 (t. 2.5 Hz, 3H), 2.06 2.15 (m. 2H), 2.20 2.30 (m. 4H), 2.38 - 2.46 (m. 2H) 2.64 2.73 (m. 5H), 3.80 3.93 (m. 2H), 3.95 4.03 (m. 1H), 4.10 (t. J 6.5 Hz, 2H) ), 6.52 (s. 1H), 7.65 (see. 1H), 7.93 (d. 7.0 Hz, 1H).

MC m / z (FAB), 376 (M ⁺ +1).

 Example 24

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-2- {(3-butyn-2-yl) oxy} -5-chloro-N- (8-methyl-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.63 (d. J 6.5 Hz, 3H), 1.97 2.30 (m. 6H), 2.46 2.57 (m. 2H), 2.61 (d. J 5.0 Hz , 3H), 3.71 (d. J 3.0 Hz, 1H), 3.78 3.85 (m. 2H), 3.95 4.00 (m. 1H), 4.68 (br s , 2H), 5.12 (d.c. J 3.0, 6.5 Hz, 1H), 6.62 (s. 1H), 7.61 (s. 1H), 7.88 (d. J 6.0 Hz, 1H), 10.68 (br s. 1H).

MC m / z (FAB), 362 (M ⁺ +1).

Mp 154 158 ^o C.

 Example 25

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-2 - [(4-heptin-3-yl) oxy] -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 0.98 1.08 (m. 6H), 1.78 2.30 (m. 10H), 2.50 2.58 (m. 2H), 2.63 (d. J 5.0 Hz, 3H) 3.83 (br s. 2H), 3.93 4.00 (m. 1H), 4.90 4.96 (m. 1H), 6.63 (s. 1H), 7.64 (s) . 1H), 7.94 (br s. 1H).

 Example 26

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-2- {(4-heptin-2-yl) oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 0.99 (t. J 7.5 Hz, 3H), 1.40 (d. J 4.0 Hz, 3H), 2.00 2.16 (m 6H), 2.18 2.30 (m .2H), 2.40 2.54 (m. 2H), 2.57 2.66 (m. 2H), 2.63 (d. J 5.0 Hz, 3H), 3.84 (br s , 2H), 3.94 3.99 (m. 1H), 4.53 4.62 (m. 1H), 6.56 (s. 1H), 7.66 (s. 1H), 7.92 ( d. J 5.0 Hz, 1H), 10.40 (br s. 1H).

 Example 27

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-5-chloro-2- {(2-hexin-4-yl) -oxy)} hydrochloride} - N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.01 (t. J 7.5 Hz, 3H), 1.84 (d. J 2.0 Hz, 3H), 1.85 2.10 (m. 6H), 2.23 2.33 (m .2H), 2.39 2.50 (m. 2H), 2.65 (d. J 6.0 Hz, 3H), 3.81 3.88 (m. 2H), 3.96 4.04 ( m. 1H), 4.88 4.95 (m. 1H), 5.95 (br s. 2H), 6.61 (s. 1H), 7.63 (s. 1H), 7.92 ( d. J 6.0 Hz, 1H).

Mp 137 141 ^o C.

 Example 28

¹H-ЯМР 400 МГц, d₆-DMСO) δ млн. дол.Endo-4-amino-5-chloro-2 hydrochloride - {(3-hexin-2-yl) -oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR 400 MHz, d ₆ -DMCO) δ ppm

 1.04 (t. J 7.6 Hz, 3H), 1.60 (d. J 6.5 Hz, 3H), 1.98 2.33 (m. 8H), 2.38 2.58 (m .2H), 2.65 (d. J 5.0 Hz, 3H), 3.80 3.90 (m. 2H), 3.96 4.04 (m. 1H), 5.11 (sq. T J 6.5, 2.0 Hz, 1H), 5.98 (br.s. 2H), 6.61 (s. 1H), 7.64 (s. 1H), 7.94 (d. J 5.0 Hz, 1H).

Mp 134 136 ^o C.

 Example 29

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Hydrochloride-endo-4-amino-5-chloro-2- {(1-hexin-3-yl) oxy} -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 0.93 (t. J 7.5 Hz, 3H), 1.42 1.55 (m. 2H), 1.67 2.15 (m. 6H), 2.20 2.30 (m. 2H) 2.40 2.50 (m. 2H), 2.63 (d. J 5.0 Hz, 3H), 3.70 (s. 1H), 3.78 3.85 (m. 2H), 3 95 4.02 (m. 1H), 4.96 (t. J 4.0 Hz, 1H), 5.20 (br.s. 2H), 6.62 (s. 1H), 7.60 ( p. 1H), 7.82 (d. J 6.0 Hz, 1H).

MC m / z (FAB), 390 (M ⁺ +1).

Mp 138 140 ^o C.

 Example 30

¹H-ЯМР (400 МГц, d₆-DMСО), δ млн.дол.Endo-4-amino-5-chloro-2- (2-fluoroethoxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO), δ ppm.

 1.94-2.23 (m. 6H), 2.40 2.52 (m. 2H), 2.62 (br.s. 3H), 3.72 3.85 (m. 2H), 3, 94 4.04 (m. 1H), 4.26 4.29 (m. 1H), 4.33 4.37 (m. 1H), 4.74 4.78 (m. 1H), 4.87 4 90 (m. 1H), 6.04 (br.s. 2H), 6.51 (s. 1H), 7.67 (s. 1H), 7.95 (t. J 7.0 Hz, 1H )

Mp 260,262 ^o C.

 Example 31

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Endo-4-amino-5-chloro-2- (3-cyclopropoxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-8-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 2.03 2.13 (m, 6H), 2.22 2.27 (m, 2H), 2.38 2.46 (m, 2H), 2.64 (d.J, 5.4 Hz, 3H) 2.68 (t. J 7.5 Hz, 2H), 3.82 (m. 2H), 3.94 4.00 (m. 1H), 4.12 (t. J 6.8 Hz, 2H) ), 5.93 (br s. 2H), 6.52 (s. 1H), 7.56 (s. 1H), 7.88 (d. 4.8 Hz, 1H), 10.14 ( br.s. 1H).

MC m / z (FAB), 377 (M ⁺ + H) ⁺ .

Mp 130 132 ^o C.

 Example 32

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-2- (1-cyclopentylethoxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.16 1.33 (m. 5H), 1.43 1.65 (m. 4H), 1.66 1.80 (m. 2H), 1.88 - 2.08 (m. 4H), 2 10 2.18 (m. 1H), 2.20 2.35 (m. 2H), 2.38 2.65 (m. 5H), 3.79 3.86 (m. 2H), 3.95 4.01 (m 1H), 4.23 4.31 (m 1H), 6.59 (s. 1H), 7.65 (s. 1H), 7.98 (d. J 5.0 Hz) , 1H), 10.55 (br.s. 1H).

Mp 154 156 ^o C.

 Example 33

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl) -2- (tetrahydro-4-pyran-4-hydroxy) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.55 1.68 (m, 2H), 2.01 2.12 (m. 6H), 2.23 2.30 (m. 2H), 2.35 - 2.45 (m. 2H), 2 64 (d. J 5.0 Hz, 3H), 3.38 3.48 (m, 2H), 3.80 3.87 (m. 2H), 3.89 4.00 (m. 3H), 4.50 4.59 (m. 1H), 5.88 (br.s. 2H), 6.63 (s. 1H), 7.61 (s. 1H), 7.90 (d. J 6, 0 Hz, 1H).

Mp 226 228 ^o C.

 Example 34

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Endo-4-amino-5-chloro-2- (4-methoxycyclohexyloxy) -N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.20 1.30 (m. 1H), 1.38 1.58 (m. 2H), 1.80 1.75 (m. 1H), 1.80 1.90 (m. 1H), 1, 95 2.15 (m. 7H), 2.20 2.30 (m. 2H), 2.35 2.45 (m. 2H), 2.63 (s. 3H), 3.14 3.20 ( m. 1H), 3.23 (s. 3H), 3.80 3.88 (m. 2H), 3.93 4.00 (m. 1H), 4.28 4.40 (m. 1H), 5.86 (br s. 2H), 6.58 (s. 1H), 7.61 (s. 1H), 7.91 (d. J 5.0 Hz, 1H).

 Example 35

 (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl) - 2- {(1-pentin-3-yl) oxy }benzamide.

Названные в заголовке соединения получались по способу, аналогичному способу примера 3.(+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl) - 2- {(1-pentin-3-yl) oxy }benzamide

The title compounds were obtained by a method similar to that of Example 3.

(-) isomer
Mp 179 182 ^o C
(+) isomer
Mp 183 184 ^o C.

 Examples 36 to 38.

 The following compounds were obtained by a method similar to that of example 4.

 Example 36

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн.дол.Hydrochloride (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (3-pentin-2-yl) oxy} benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.60 (d. J 6.5 Hz, 3H), 1.82 (d. J 2.0 Hz, 3H), 1.95 2.09 (m 2H), 2.10 2.17 (m .2H), 2.23 2.32 (m. 2H), 2.33 2.45 (m. 2H), 2.65 (d. J 5.0 Hz, 3H), 3.82 3.86 ( m. 2H), 3.98 4.03 (m. 1H), 5.06 5.14 (m. 1H), 5.98 (br s. 2H), 6.60 (s. 1H), 7 63 (s. 1H); 7.92 (d. J 5.0 Hz, 1H).

MC m / z (FAB), 376 (M ⁺ +1).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ 97.25 ^° (c 1.09, MeOH).

 Example 37

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.Hydrochloride (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (1-pentin-3-yl) oxy} benzamide

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.02 (t. J 8.0 Hz, 3H), 1.82 2.12 (m. 6H), 2.21 2.24 (m. 2H), 2.40 2.44 (m. 2H) 2.62 (d. J 6.0 Hz, 3H), 3.72 (s. 2H), 3.82 (br.s. 2H), 3.93 4.03 (m. 1H), 4, 93 (t. J 4.0 Hz, 1H), 6.62 (s. 1H), 7.60 (s. 1H), 7.86 (d. J 5.0 Hz, 1H).

MC m / z (FAB), 376 (M ⁺ +1).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -74.55 ^° (c 1.12, MeOH).

Mp 144 147 ^o C.

 Example 38

¹H-ЯМР (400 МГц, d₆-DMСО) δ млн. дол.(+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl-2- (1-pentin-3-yl) oxy} benzamide hydrochloride

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.02 (t. J 8.0 Hz, 3H), 1.82 2.12 (m. 6H), 2.21 2.24 (m. 2H), 2.40 2.44 (m. 2H) 2.62 (d. J 6.0 Hz, 3H), 3.72 (s. 2H), 3.82 (br.s. 2H), 3.93 4.03 (m. 1H), 4, 93 (t. J 4.0 Hz, 1H), 6.62 (s. 1H), 7.60 (s. 1H), 7.86 (d. J 5.0 Hz, 1H).

MC m / z (FAB), 376 (M ⁺ +1).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ 76.36 ^° (c 1.10, MeOH).

Mp 146 148 ^o C.

 Example 39

10 г 4-амино-5-хлор-2-{ (4-пентин-2-ил)окси} бензойной кислоты и 10 г эндо-3-амино-8-метил-8-азабицикло(3.2.1)октана растворялись в 50 мл пиридина с последующим добавлением 9,4 мл 5 норм. водного раствора гидроокиси натрия и 16,1 г дициклогексилкарболиимида в данном порядке. Полученная смесь перемешивалась при комнатной температуре на протяжении ночи с последующим добавлением воды. Осажденные нерастворимые вещества отфильтровывались, и полученный фильтрат подщелачивался 5 норм. водным раствором гидроокиси натрия и экстрагировался хлороформом. Органическая фаза промывалась насыщенным водным раствором обычной соли, сушилась над безводным сульфатом магния и концентрировалась в вакууме. Остаток очищался с помощью хроматографии на силикагельной колонке (10% метанол/хлороформ), давая 10,7 г целевого соединения в виде бесцветных кристаллов.Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) -oct-3-yl) -2- (4-pentin-2-yl) oxy} benzamide

10 g of 4-amino-5-chloro-2- {(4-pentin-2-yl) oxy} benzoic acid and 10 g of endo-3-amino-8-methyl-8-azabicyclo (3.2.1) octane were dissolved in 50 ml of pyridine, followed by the addition of 9.4 ml of 5 norms. an aqueous solution of sodium hydroxide and 16.1 g of dicyclohexylcarbolyimide in this order. The resulting mixture was stirred at room temperature overnight, followed by the addition of water. Precipitated insoluble substances were filtered off, and the resulting filtrate was basified with 5 norms. aqueous sodium hydroxide solution and was extracted with chloroform. The organic phase was washed with a saturated aqueous solution of ordinary salt, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (10% methanol / chloroform), to give 10.7 g of the target compound as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ), δ ppm

1.54 (d. J 6.0 Hz, 3H), 1.74 1.88 (m. 4H), 2.01 2.13 (m. 3H), 2.21 2.30 (m. 2H) 2.30 (s. 3H), 2.58 (A ₂ BX type, J 3.0; 7.0; 17.0 Hz, 1H), 2.58 (A ₂ BX type, J 3.0; 5.0; 17.0 Hz, 1H), 3.13 3.19 (m 2H), 4.18 4.23 (m 1H), 4.31 4.38 (br s. 2H), 4.60 4.69 (m, 1H), 6.32 (s. 1H), 7.89 (d. J, 3.0 Hz, 1H), 8.10 (s. 1H).

Mp 208 209 ^o C.

 Example 40

130 мг эндо-4-амино-5-хлор-N-(8-метил-8-азабицикло(3.2.1)окт-3-ил)-2- (4-пентин-2-ил)окси} бензамида растворялось в 2 мл этанола. Полученный раствор подкислялся добавлением 20% смеси соляная кислота/этанол при охлаждении льдом с последующим добавлением диэтилового эфира. Выпавшие таким образом в осадок кристаллы выделялись фильтрованием и сушились, давая 140 мг целевого соединения в виде бесцветных кристаллов.Endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- ((4-pentin-2-yl) oxy) benzamide hydrochloride

130 mg of endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (4-pentin-2-yl) oxy} benzamide was dissolved in 2 ml of ethanol. The resulting solution was acidified by the addition of a 20% hydrochloric acid / ethanol mixture under ice cooling, followed by diethyl ether. The crystals thus precipitated were isolated by filtration and dried, to give 140 mg of the target compound as colorless crystals.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.41 (d. J 6.0 Hz, 3H), 2.03 2.14 (m. 4H), 2.21 2.29 (m. 2H), 2.40 2.53 (m. 2H) 2.60 2.68 (m. 5H), 3.01 (t. J 3.0 Hz, 1H), 3.80 - 3.85 (m. 2H), 3.98 4.00 (m. 1H), 4.60 4.66 (m, 1H), 6.57 (s. 1H), 7.67 (s. 1H), 7.86 (d. J 3.0 Hz, 1H).

Mp 139 141 ^o C.

 Example 41

1,65 г рацемической модификации соединения подвергалось жидкостной хроматографии высокой разрешающей способности с использованием хиральной колонки (продукт Дайцел Кемикал Индастриз, Лтд. Хирацел Од) и растворителя в подвижной фазе (этанол: гексан:триэтиламин 20:80:0,1), давая 480 мг (+)-изомера и 450 мг (-)-изомера.(+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (4-pentin-2-yl) oxy} benzamide
(-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (4-pentin-2-yl) oxy} benzamide

1.65 g of the racemic modification of the compound was subjected to high-resolution liquid chromatography using a chiral column (product of Deicel Chemical Industries, Ltd. Hiracel Od) and a solvent in the mobile phase (ethanol: hexane: triethylamine 20: 80: 0.1), giving 480 mg (+) - isomer and 450 mg (-) - isomer.

(+) - ¹ H-NMR isomer (400 MHz, CDCl ₃ ) δ ppm.

1.54 (d. J 6.0 Hz, 3H), 1.71 1.83 (m. 4H), 2.01 2.13 (m. 3H), 2.21 2.30 (m. 2H) 2.30 (s. 3H), 2.58 (A ₂ BX type, J 3.0 Hz, 7.0; 17.0 Hz, 1H), 2.68 (A ₂ BX type, J 3.0 ; 5.0; 17.0 Hz, 1H), 3.13 3.19 (m. 2H), 4.18 4.23 (m. 1H), 4.35 (br s. 2H), 4, 64 (i.e., J 6.0; 6.0 Hz, 1H), 6.32 (s. 1H), 7.89 (d. 5.5 Hz, 1H), 8.10 (s. 1H )

(-) - isomer ¹ H-NMR (400 MHz, CDCl ₃ ) d mln.

1.54 (d. J 6.0 Hz, 3H), 1.71 1.88 (m. 4H), 2.05 2.15 (m. 2H), 2.20 2.30 (m. 2H) 2.30 (s. 3H), 2.58 (A ₂ BX type, J 3.0, 7.0; 17.0 Hz, 1H), 2.68 (A ₂ BX type, J 3.0; 5.0; 17.0 Hz, 1H), 3.13 3.19 (m 2H), 4.15 4.24 (m 1 H), 4.33 (br s. 2H), 4.64 (i.e., J 6.0; 6.0 Hz, 1H), 6.32 (s. 1H), 7.89 (d. 5.5 Hz, 1H), 8.11 (s. 1H).

 Example 42

309 мг (+)-эндо-4-амино-5-хлор-(8-метил-8-азабицикло(3.2.1)окт-3-ил)-3-((3-пентин-2-ил)оксо)бензамида растворялось в 1,5 мл этанола с последующим добавлением 0,411 мл 2 норм. соляной кислоты и 15 мл воды в указанном порядке. Полученная смесь подвергалась сушке вымораживанием, давая 333 г хлоргидрата (+)-изомера.(+) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (4-pentin-2-yl) oxo} benzamide hydrochloride

309 mg (+) - endo-4-amino-5-chloro- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -3 - ((3-pentin-2-yl) oxo) benzamide was dissolved in 1.5 ml of ethanol, followed by the addition of 0.411 ml of 2 norms. hydrochloric acid and 15 ml of water in the indicated order. The resulting mixture was freeze dried to give 333 g of the hydrochloride (+) - isomer.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.44 (d. J 6.5 Hz, 3H), 2.07 2.17 (m. 4H), 2.26 2.37 (m. 2H), 2.38 2.43 (m. 2H) 2.65 2.71 (m. 5H), 3.00 (t. J 2.5 Hz, 1H), 3.82 - 3.93 (m. 2H), 4.01 4.05 (m. 1H), 4.65 (t.v. J 6.0; 6.0 Hz, 1H), 5.91 (br s. 2H), 6.59 (s. 1H), 7.69 (s. 1H), 7.88 (d. J 5.0 Hz, 1H), 9.87 (s. 1H).

MC m / z (FAB), 376 (M ⁺ +1).

Целевое соединение получалось по способу, аналогичному способу примера 42.Example 43
(-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo) - (3.2.1) oct-3-yl-2 - ((4-pentin-2-yl) oxy ) benzamide hydrochloride

The target compound was obtained in a manner analogous to the method of example 42.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.42 (d. J 6.0 Hz, 3H), 2.04 2.13 (m. 4H), 2.23 2.27 (m. 2H), 2.35 2.43 (m. 2H) 2.62 2.67 (m. 5H), 3.01 (t. J 3.0 Hz, 1H), 3.80 - 3.84 (m. 2H), 3.96 4.00 (m. 1H), 4.64 (t.K. J 6.0 Hz, 1H), 6.57 (s. 1H), 7.66 (s. 1H), 7.87 (d. J 5.0 Hz, 1H).

MC m / z (FAB), 376 (M ⁺ +1).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -8.88 ^° (c 1.07, MeOH).

 Example 44

260 мг 4-ацетамидо-2-(3-бутинилокси)-5-хлор-бензойной кислоты и 216 мг эндо-3-амино-8-метил-8-азабицикло(3.2.1)-октана растворялись в 5 мл пиридина с последующим добавлением 0,2 мл 5 норм. водного раствора гидроокиси натрия и 300 мг (1,3-дициклогексилкарбодиимида в данном порядке. Полученная смесь перемешивалась при комнатной температуре на протяжении ночи с последующим добавлением воды. Нерастворимые вещества, осажденные таким образом, отфильтровывались, и фильтр подщелачивался водным раствором гидроокиси натрия и экстрагировался хлороформом. Органическая фаза промывалась насыщенным водным раствором обычной соли, сушилась над безводным сульфатом магния и концентрировалась в вакууме. Остаток очищался с помощью хроматографии на силикагельной колонке (10% метанол/хлороформ), давая 130 мг целевого соединения в виде бесцветных кристаллов.Endo-4-Acetamido-2- (3-butynyloxy) -5-chloro-N-8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

260 mg of 4-acetamido-2- (3-butynyloxy) -5-chloro-benzoic acid and 216 mg of endo-3-amino-8-methyl-8-azabicyclo (3.2.1) octane were dissolved in 5 ml of pyridine followed by adding 0.2 ml of 5 norms. an aqueous solution of sodium hydroxide and 300 mg (1,3-dicyclohexylcarbodiimide in this order. The resulting mixture was stirred at room temperature overnight, followed by the addition of water. The insoluble matter thus precipitated was filtered off, and the filter was made basic with an aqueous solution of sodium hydroxide and extracted with chloroform The organic phase was washed with a saturated aqueous solution of ordinary salt, dried over anhydrous magnesium sulfate and concentrated in vacuo. raffia on a silica gel column (10% methanol / chloroform) to give 130 mg of the title compound as colorless crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm.

 1.85 1.93 (m, 2H), 2.06 (t. J 3.0 Hz, 1H), 2.13, 2.18 (m. 2H), 2.27 (s. 3H), 2, 30 2.38 (m. 4H), 2.78 (d.t. J 3.0; 7.0 Hz, 2H), 3.20 - 3.28 (m. 4H), 4.20 4.26 (m. 1H), 4.35 (t. J 7.0 Hz, 2H), 7.75 7.78 (m. 1H), 8.05 8.9 (m. 1H), 8.23 (s . 1H), 8.33 (s. 1H).

 Example 45

130 мг эндо-4-ацетамидо-2-(3-бутинилокси)-5-хлор-N-(8-метил-8-азабицикло (3.2.1)окт-3-ил)бензамида растворялось в 5 мл метанола с последующим добавлением раствора 200 мг гидроокиси натрия в 1 мл воды. Полученная смесь перемешивалась при комнатной температуре на протяжении ночи. Кристаллы, осажденные в реакционной системе, выделялись с помощью фильтрования, промывались водой и сушились, давая 120 мг целевого соединения в виде бесцветных кристаллов.Endo-4-amino-2- (3-butynyloxy) -5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide

130 mg of endo-4-acetamido-2- (3-butynyloxy) -5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide was dissolved in 5 ml of methanol, followed by the addition of a solution of 200 mg of sodium hydroxide in 1 ml of water. The resulting mixture was stirred at room temperature overnight. The crystals precipitated in the reaction system were isolated by filtration, washed with water and dried, giving 120 mg of the target compound as colorless crystals.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 1.58 1.64 (m 2H), 1.70 1.75 (m 2H), 1.94 2.09 (m 4H), 2.12 (s. 3H), 2.72 (d tm J 3.0; 7.0 Hz, 2H), 2.96 3.02 (m 3H), 3.27 3.32 (m 2H), 3.92 3.96 (m 1H ), 4.17 (t. J 7.0 Hz, 2H), 5.88 5.92 (m, 2H), 6.50 (s. 1H), 7.70 (s. 1H), 7.88 (d. J 7.0 Hz, 1H).

 Example 46

20 мг эндо-4-амино-2-(3-бутинилокси)-5-хлор-N-(8-метил-8-азабицикло (3.2.1)окт-3-ил)бензамида растворялось в смеси, включающей 1 мл этанола и 7 мл воды, с последующим добавлением 28 мкл 2 норм. водного раствора соляной кислоты. Полученная смесь подвергалась сушке вымораживанием, давая 20 мг целевого соединения в виде бесцветных кристаллов.Endo-4-amino-2- (3-butynyloxy) -5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide hydrochloride

20 mg of endo-4-amino-2- (3-butynyloxy) -5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) benzamide was dissolved in a mixture comprising 1 ml of ethanol and 7 ml of water, followed by the addition of 28 μl of 2 norms. aqueous hydrochloric acid. The resulting mixture was freeze dried to give 20 mg of the target compound as colorless crystals.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm

 2.06 2.15 (m. 4H), 2.23 2.30 (m. 2H), 2.31 2.40 (m. 2H), 2.65 (s. 3H), 2.69 (d mp J 3.0; 7.0 Hz, 2H), 3.01 (t. J 3.0 Hz, 1H), 3.81 - 3.86 (m 2H), 3.96 4.01 (m. 1H), 4.15 (t. 7.0 Hz, 2H), 6.51 (s. 1H), 7.65 (s. 1H), 7.91 (d. J 7.0 Hz, 1H).

MC m / z (FAB), 362 (M ⁺ ++).

Mp 226 229 ^o C.

 Example 47

300 мг (S)-(-)-эндо-4-амино-5-хлор-N-(8-метил-8-азабицикло(3.2.1)окт-3-ил)-2- (3-пентин-2-ил)окси}бензамида растворялось в 2 мл этанола с последующим добавлением 0,1 мл метилиодида при комнатной температуре. После перемешивания полученного раствора в течение четырех часов осажденные кристаллы отделялись фильтрованием, промывались дважды небольшим количеством холодного этанола и сушились, давая 257 мг целевого соединения в виде белых кристаллов.(S) -endo-4-amino-5-chloro-N- (8,8-dimethyl-8-azoniabicyclo (3.2.1) oct-3-yl) -2- (3-pentin-2-yl) oxy } benzamide iodide

300 mg (S) - (-) - endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (3-pentin-2 -yl) oxy} benzamide was dissolved in 2 ml of ethanol, followed by the addition of 0.1 ml of methyl iodide at room temperature. After stirring the resulting solution for four hours, the precipitated crystals were separated by filtration, washed twice with a small amount of cold ethanol and dried, giving 257 mg of the target compound as white crystals.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

1.59 1.60 (d. 3H), 1.82 1.83 (d. 3H), 1.90 1.96 (m. 2H), 2.16 - 2.20 (d. 2H), 2 38 2.42 (m. 2H), 2.50 2.59 (m. 2H), 3.01 (s. 3H), 3.12 (s. 3H), 3.84 (br s. 2H) ), 4.10 4.16 (dd. 1H), 5.03 5.11 (m, 1H), 5.99 (s. 2H), 6.60 (s. 1H), 7.62 (s. 1H), 7.92-7.95 (d. 1H). MC m / z (FAB), 390 (M ⁺ ).

Mp 195 ^o C (div.).

 Example 48

1,13 г (S)-эндо-4-амино-5-хлор-N-(8-метил-8-азабицикло(3.2.1)окт-3-ил)-2-{ (3-пентин-2-ил)окси} бензамида растворялось в 50 мл дихлорметана с последующим добавлением 0,81 г м-хлорнадбензойной кислоты при охлаждении льдом. Полученный раствор перемешивался в течение получаса. После завершения реакции реакционная смесь, полученная таким образом, промывалась насыщенным водным раствором бикарбоната натрия и насыщенным водным раствором обыкновенной соли в указанном порядке, сушилась над сульфатом магния. После того, как растворитель выпаривался, остаток обрабатывался диизопропиловым эфиром, давая 0,40 г целевого соединения.(S) -endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (3-pentin-2-yl) oxy} benzamide 8-oxide

1.13 g of (S) -endo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- {(3-pentin-2- il) oxy} benzamide was dissolved in 50 ml of dichloromethane, followed by the addition of 0.81 g of m-chloroperbenzoic acid under ice-cooling. The resulting solution was stirred for half an hour. After completion of the reaction, the reaction mixture thus obtained was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of ordinary salt in this order, dried over magnesium sulfate. After the solvent was evaporated, the residue was treated with diisopropyl ether to give 0.40 g of the target compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm

 1.65 1.67 (2 x d, J 6.5 Hz, 3H), 1.83 1.84 (2 x d, J 1.5 Hz, 3H), 1.90 2.40 (m. 6H ), 2.47 2.57 (m. 1H), 2.79 2.86 (m. 1H), 3.27, 3.30 (s. X 2, 3H), 3.43, 3.66 ( 2 x m. 2H), 4.30 (m. 1H), 4.41; 4.45 (2 x br s. 2H), 4.88 (m. 1H), 6.42, 6.43 (s. X 2, 1H), 3.08; 8.10 (2 x s. 1H), 8.00; 8.14 (- x with a broad d. J 6.5 Hz, 1H).

MC m / z (FAB), 392 (M ⁺ +1).

 Example 49

Целевое соединение получалось из экзо-3-аминотропана и (S)-4-амино-5-хлор-2-{ (3-пентин-2-ил)окси} бензойной кислоты по способу, аналогичному способу примера 1.(S) -enzo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (3-pentin-2-yl) oxy} benzamide

The target compound was obtained from exo-3-aminotropan and (S) -4-amino-5-chloro-2- {(3-pentin-2-yl) oxy} benzoic acid in a manner analogous to the method of example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm

 1.68 (d. J 6.5 Hz, 3H), 1.83 (d. J 2.0 Hz, 3H), 1.73 1.88 (m. 4H), 1.92 2.02 (m .2H), 2.05 2.14 (m. 2H), 2.38 (s. 3H), 3.32 (m. 2H), 4.32 (m. 1H), 4.42 (br s .2H), 4.75 4.83 (m. 1H), 6.48 (s. 1H), 7.64 (br.J. 5.0 Hz, 1H), 8.01 (s, 1H) .

MC m / z (FAB), 376 (M ⁺ +1).

 Example 50

Целевое соединение получалось по способу, аналогичному способу примера 2.(S) -exo-4-amino-5-chloro-N- (8-methyl-8-azabicyclo (3.2.1) oct-3-yl) -2- (3-pentin-2-yl) oxy} hydrochloride} benzamide

The target compound was obtained in a manner analogous to the method of example 2.

¹ H-NMR (400 MHz, d ₆ -DMCO) δ ppm.

 1.63 (d. J 6.5 Hz, 3H), 1.81 (d. J 1.5 Hz, 3H), 1.88 2.25 (m. 8H), 2.61 (d. J 6 , 0 Hz, 3H), 3.85 (m. 2H), 4.21 (m. 1H), 4.98 (m. 1H), 6.59 (s. 1H), 7.64 (d.J 5.5 Hz, 1H), 7.65 (s. 1H), 10.94 (br.s. 1H).

MC m / z (FAB), 376 (M ⁺ +1).

 Although the invention has been described in the manner described above, it should be apparent that various modifications may be made to it. Such variations should not be considered a departure from the idea and scope of the invention, and all such modifications as are obvious to specialists in this field are intended to be included in the scope of the following claims. TTT1 TTT2

Claims (6)

1. Derived aminobenzoic acid of the General formula

where is oxygen;
R ¹ cyanoalkyl, substituted or unsubstituted cycloalkylalkyl, halo substituted lower alkyl, alkynyl or tetrahydro-4H-pyran;
R ^{2 is an} amino or acylamino group;
R ^{3 is} halogen;
X group —NH—;
Z group N CH ₃ , N (CH ₃ ) _{2 or} NO (CH ₃ ),
or a pharmaceutically acceptable salt thereof.  2. The compound according to claim 1, characterized in that it is a racemic mixture or a pharmacologically acceptable salt thereof.  3. The compound according to claim 1, characterized in that it is a (+) isomer or its pharmacologically acceptable salt.  4. The compound according to claim 1, characterized in that it is a (-) isomer or its pharmacologically acceptable salt. 5. The compound according to claim 1, characterized in that it contains oxygen, R ¹ alkynyl, R ² amino, R ³ chlorine, Z group N CH ₃ , or a pharmacologically acceptable salt thereof.  6. The compound according to claim 1, having activity to accelerate the release of acetylcholine and antagonistic activity to serotonin.

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