4-amino-5-chloro-2,3-dihydro-n-[1-(3-methoxypropyl)-4 - piperidinyl]-7-benzofuroxan or its pharmaceutically acceptable acid additive salt, methods of its production, pharmaceutical composition and method of reception

 

(57) Abstract:

Describes the new compound 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl] -7-benzofuroxan or its pharmaceutically acceptable acid additive salt, manifesting interceptions properties. Also describes pharmaceutical compositions containing these new compounds, methods of making the compounds and compositions and their use as pharmaceuticals, in particular in the treatment of conditions, including reduced peristalsis. 5 c. and 8 C.p. f-crystals, 3 tables.

This invention relates to a new production benzamide and pharmaceutically acceptable acid additive salts, pharmaceutical compositions containing these compounds, methods of producing these compounds and compositions and their use as pharmaceuticals, in particular, in the treatment of conditions, including weakened peristalsis of the intestines, especially the colon.

In our European patent application (EP) 0 389037-A, published on September 26, 1990, disclosed derivatives of N-(3-hydroxy-4 - piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran) carboxamide as having your the disclosed derivatives of N-(4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide, also have properties that stimulate peristalsis of the gastrointestinal tract.

The connection that is the subject of this application, differs from them in that it demonstrates the superior interceptions properties.

This invention relates to the compound of the formula

(I)

and its pharmaceutically acceptable acid additive salts.

The chemical name of the compounds of formula (I) is 4-amino-5 - chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7 - benzofuroxan.

Assumes pharmaceutically acceptable acid additive salt, mentioned here above, include forms of therapeutically active non-toxic acid additive salts which the compounds of formula (1) can form. The latter can conveniently be obtained by processing forms the Foundation of such a suitable acid. Suitable acids include, for example, inorganic acids such as kaleidostone acid, e.g. hydrochloric or Hydrobromic acid, sulfuric, nitric; phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanesulfonate, p - toluensulfonate, ciclamino, salicylic, p - aminosalicylic, AMOVA and similar acids. Used here previously, the term "additive salt" also includes a solvate, which is able to form compounds of formula (1), and their salts. These are solvate, for example, hydrates, alcoholate, and the like. On the contrary, the salt form can be converted by treatment with alkali in the form of a free base. Further, the term "compounds of formula (1)" means a compound of formula (1), as well as its pharmaceutically acceptable acid salt additive, unless otherwise indicated.

Interesting compounds of formula (1) are acid additive salts, which are formed by processing forms the Foundation of the compounds of formula (1) kaleidostone acids or butandiol acid.

Preferred compounds of formula (1) are monohydrochloride 4-amino-5-chloro-2,3-dihydro-N-[1- (3-methoxypropyl)- 4-piperidinyl]-7-benzoperoxide and butanedioate 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4 - piperidinyl]-7-benzoperoxide (1:1).

The compounds of formula (I) can be obtained in accordance with the methods described in the European patents EP-0 389037-A and EP-0 445862-A. which you can select from the reaction mixture and, if you continue to be clean in accordance with generally known in this field techniques, such as, for example, extraction, distillation, crystallization, rubbing and chromatography.

The compounds of formula (I) can be obtained N-alkylation of the intermediate compounds of formula (II) alkylating reagent of formula (III), where W is a suitable leaving group such as halogen, for example chlorine; or sulfonyloxy leaving group, for example, methansulfonate (mesilate) or p-toluensulfonate (toilet) in an inert towards the reaction solvent, such as a dipolar aprotic solvent, e.g. dimethylformamide, in the presence of a suitable base such as e.g. triethylamine. To increase the reaction rate can also add a suitable catalyst, such as potassium iodide.

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The compound of formula (I) can also be obtained by the reaction of N-acylation of carboxylic acids of the formula (IV) or its reaction - nesposobnogo intermediate product and an amine of the formula (Y). The reaction of N-acylation can be carried out by mixing the two reagents in a reaction inert solvent such as chlorinated hydrocarbons, for example chloroform or aromatic hydrocarbons the area or getting them mentioned in EP-O 389037-A and EP-O 445862.

The compounds of formula (I) possess excellent stimulating peristalsis properties. In particular, these compounds of formula (I) exhibit a significant increase peristalsis effect on small and large intestines. In other words, these compounds of formula (I) have interceptions properties. These properties are confirmed by pharmacological examples described herein below. These compounds of formula (I) increase neadrenergicheskoy neholinergichesky (NANH) excitation and pushing fecal formations (balls) from the colon. In addition to stated they accelerate gastric emptying and contractility of the small intestine and have a facilitating effect on cholinergic nerves. Such compounds are devoid of 5-HT2or 5-HT3-receptor antagonistic properties. In addition, these compounds also exhibit activity in vivo, as evidenced by tests "Telemetry registration peristalsis shell or colon cancer in in the minds of dogs."

Because of their useful interceptions reinforcing the connection properties that are the subject of the invention can be prepared in various forms for the purposes waerenga connection in the form of a base or an acid additive salt as the active ingredient is combined in intimate mixture with a pharmaceutically acceptable carrier, which can take many many forms depending on the form of preparation desired for administration. Data pharmaceutical compositions are desirable in the form of a unit dose, preferably suitable for administration orally, rectally or via parenteral injection. For example, upon receipt of the compositions in oral dosage form to use conventional pharmaceutical environment, such as for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja tools and the like in the case of powders, pills, capsules and tablets. Due to ease their introduction of tablets and capsules represent the most favorable oral form of a unit dose, in which case, obviously, use solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes, at least in the most part, sterile water, though, to facilitate the dissolution, you can include other ingredients. Can be obtained, for example, injectable solutions, in which the carrier includes the dummy suspension, in the case which can be used in suitable liquid media, suspendresume tools and the like. In the compositions suitable for transdermal administration, the carrier optionally includes a tool that improves the penetration and/or a suitable wetting means, optionally in combination in small proportions with suitable additives of any nature, which does not have a significant detrimental effects on the skin. These supplements can facilitate the introduction into the skin and/or may be useful in obtaining the desired compositions. These compositions can be entered in different ways, for example in the form of a transdermal patch, in the form of applying patches and ointments.

Particularly beneficial to prepare the above-mentioned pharmaceutical compositions in the form of a unit dose for ease of administration and uniformity of dosage. Form of unit doses used in the description and the claims, refers to discrete units suitable as unit doses, each unit contains a defined quantity of active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dozirovannym, wafers, injectable solutions or suspensions, forms a volume of a teaspoon, tablespoon, and the like, and separated multiple doses.

Because of its ability to stimulate intestinal peristalsis and, in particular, the ability to increase peristalsis of the colon, the compounds of the invention are useful for normalization or improvement of the passage of contents through the intestine in subjects suffering from symptoms associated with impaired peristalsis, such as decreased peristalsis of the intestine and colon or decreased motility in combination with delayed gastric emptying.

Because of the usefulness of the compounds of the present invention provides a method of treating warm-blooded animals, including humans, suffering from impaired peristalsis of the intestinal system, such as, for example, a higher, pseudoprobability, intestinal atony, postoperative intestinal atony, irritable bowel syndrome (srtc) induced drug slow the passage of contents through the intestine. In particular, there is provided a method of treatment of disorders of peristalsis of the colon. Connections can also be used to facilitate cleaning of the colon, stimuliruyuscyego intestine (the large or small intestine) the amount of the compounds of formula (I) warm-blooded animals, including humans. Therefore, provided the use of compounds of formula (I) as a drug and, in particular, the use of the compounds of formula (I) for the manufacture of a medicinal product for treating conditions involving impaired peristalsis or violated the passage of contents through the small and large intestines.

In General it is assumed that therapeutically effective amount is about 0.001 mg/kg to about 10 mg/kg body weight, preferably from about 0.02 mg/kg to about 5 mg/kg of body weight. The treatment method may also include the introduction of the active ingredient according to the scheme of introduction from two to four times a day.

Experimental part

Example 1

4-Amino-5-chloro-2,3-dihydro-7-benzofuranol acid (0.05 mol) (the receipt of which is described in EP-O 389037-A) suspended in trichloromethane (135 ml) and was cooled to 5oC. is added dropwise at a temperature below 10oC was added N, N-diethylethanamine (0.05 mol). Was added dropwise ethylchloride (0.05 mol) and the reaction mixture was stirred for 40 min, keeping the temperature below 10oC. Developed is trichlormethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 minutes and the Mixture was washed with water (50 ml). The precipitate was separated by filtration through a glass filter and washed with water and CHCl3. The filtrate was divided into layers. The separated organic layer was washed with water (50 ml) and 50% NaOH solution (1 ml), dried, filtered and the solvent evaporated. The residue was stirred in 2-propanol (100 ml). The mixture was acidified with a mixture of HCl/2-propanol (7.2 ml of 5.29 n). The mixture was stirred in section 16 h at room temperature and the resulting precipitate was separated by filtration, washed with 2-propanol (15 ml) and dried (vacuum; 50oC) receiving of 12.6 g (62%) of monohydrochloride 4-amino-5 - chloro-2,3-dihydro-N-[1-(C-methoxypropyl)4-piperidinyl] -7 - benzoperoxide (connection 1).

Example 2

A mixture of 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl) -7-benzoperoxide (0.01 mol), 1-chloro-3-methoxypropane (0.012 mol), N,N-diethylethanamine (2.1 ml) and K1 (a catalytic amount) in N,N-dimethylformamide (75 ml) was stirred overnight at 50oC. the Reaction mixture was cooled. The solvent is evaporated. The residue was purified column chromatography on silica gel (eluent: CHCl3/(CH3HE/NH3), 97/3). Pure fractions were collected and the solvent evaporated. panel. The residue was separated by filtration and dried (vacuum; 80oC) to give 1.40 g (35%) of monohydrochloride 4-amino-5 - chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl] -7 - benzoperoxide (connection 1).

Example 3

The reaction in the stream of N2. 4-Amino-5-chloro-2,3-dihydro-7-benzofuranol acid (0.18 mol) was dissolved in tetrahydrofuran (360 ml) and the solution was stirred and cooled to 3oC. In one portion was added 1,1'-carbonylbis-1H-imidazole (9,18 mol) and cooling was stopped. The mixture was stirred for 75 minutes (the mixture became homogeneous after 30 min). Was added dropwise a solution of 1-(3-methoxypropyl)-4-piperidylamine (0.18 mol) in tetrahydrofuran (90 ml) (exothermic temperature of the reaction was increased from 23 to 27oC). The reaction mixture was stirred for 24 h was Added 1,1'- carbonylbis-1H-imidazole (of 0.0125 mol) and the reaction mixture was stirred for 75 minutes was Added 1-(3 - methoxypropyl)-4-piperidylamine (of 0.0125 mol) in 10 ml THF). The resulting reaction mixture was stirred for 3 h at room temperature, then for 2.5 hours at the boiling temperature under reflux. Then the mixture was stirred for 13 h, leaving it to cool to room temperature and the observed washed with water, then dried (vacuum; 30oC) receiving a 62.9 g (95%) of the monohydrate of 4-amino-5-chloro-2,3-dihydro-N-[1- (3-methoxypropyl)-4 - piperidinyl]-7-benzoperoxide; so pl. 90,7oC (compound 2).

Example 4

Connection (2) (5 g, 0,0129 mol) was dissolved in hot ethanol (25 ml). Solution was added (+)-(S)-lactic acid (1.45 g, 0,0135 mol) in ethanol (10 ml). With continuous stirring crystallization started at 23oC. the Mixture was stirred for 24 hours the Precipitate was separated by filtration, washed with ethanol (2 ml), then dried (vacuum; 55oC; 72 h) to give 3.7 g (62%) salt (1: 1) 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4 - piperidinyl]-7-benzoperoxide and (+)-(S)-2-hydroxypropanoic acid; so pl. 170,4oC (compound 3).

Connection (2) (5 g, 0,0129 mol) was dissolved in a hot mixture of ethanol (35 ml)/water (3.5 ml). Added phosphoric acid (0,929 ml), which almost immediately led to crystallization. The mixture was stirred for 24 h at 23oC. the Precipitate was separated by filtration, washed with ethanol (2 ml), then dried (vacuum; 55oC; 72 h), receiving by 5.87 g (97,7%) salt (1:1) 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4 - piperidinyl]-7-benzoperoxide and phosphoric acid; so pl. 259,6oC (compound 4).

oC. the Precipitate was separated by filtration, washed with ethanol (2 ml), then dried (vacuum; 55oC; 72 hours) to give 5.4 g (93,3%) of the hydrobromide of 4-amino-5-chloro-2,3-dihydro-N- [1-(3-methoxypropyl)-4-piperidinyl] -7-benzoperoxide (1:1); so pl. 280,1oC (compound 5).

Connection (2) (5 g, 0,0129 mol) was dissolved in hot ethanol (25 ml). Solution was added succinic acid (1.6 g) in a mixture of ethanol (10 ml)/water (3.5 ml). Rubbing along the walls led to crystallization. The mixture was stirred for 24 h at 23oC. the Precipitate was separated by filtration, washed with ethanol (2 ml), then dried (vacuum; 55oC; 72 hours) to give 5.7 g (91%) of butanedioate 4-amino-5-chloro-2,3-dihydro-N-[1-(3 - methoxypropyl)-4-piperidinyl] -7-benzoperoxide (1:1); so pl. 197,2oC (compound 6).

Example 5

Connection (2) (5 g, 0,0129 mol) was dissolved in ethanol (35 ml). Was added water (3.5 ml). Was added dropwise sulfuric acid (0.75 ml). The mixture was stirred for 24 h at 22oC. the Precipitate was separated by filtration, washed with ethanol (2 ml), then dried (vacuum; 55-60oC; 72 h), receiving of 6.1 g (101%) of sulfate, 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4 - piperidinyl] -7-ethanol (35 ml). Was added water (3.5 ml). Was added dropwise methane acid (0,88 ml). The mixture was stirred, then dried (vacuum; 55-60oC; 72 h) to give 6 g (100%) salt 4-amino - 5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl] -7 - benzoperoxide and methanesulfonate (1:1); so pl. 286oC (compound 8).

Connection (2) (5 g, 0,0129 mol) was dissolved in isobutyl ketone (35 ml) at 60-65oC. was added dropwise acetic acid (0.8 ml) (the temperature rose to 75oC). Adding almost immediately led to the deposition. The mixture was left to cool to room temperature. The mixture was stirred for 20 hours the Precipitate was separated by filtration, washed with ethanol (2 ml), then dried (vacuum; 55-60oC; 72 h) to give 5.5 g (99%) salt 4-amino-5-chloro-2,3-dihydro-N-[1- (3-methoxypropyl)-4-piperidinyl]-7-benzoperoxide and acetic acid (1:1); so pl. 156,1oC (compound 9).

The drugs examples

Example 6

Stimulation neadrenergicheskoy neholinergichesky artificially induced relaxation of nerves with subsequent reduction. Relaxation was medieaval through the mediator, different from norepinephrine, nitric oxide, or ATP. The reduction was medieaval through the transmitter that is different from acetylchol the next by decapitation. The ascending colon was removed and the cavity was purified by repeated washing with a solution of De Jalon. After careful dissection of the mesentery of the ascending colon was divided into segments of length 3 see Each segment was placed vertically in an organic bath (tub) containing 100 ml De Jalon. Organic bath maintained at a 37.5oC and filled with a mixture of 95% oxygen and 5% carbon dioxide. For block-and muscarinic receptors in the solution were added phentolamine (10-6M), propanol (310-7M) and atropine (310-7M). The reduction was measured isometrically. The drug is repeatedly stretched to obtain a basal tension of 40 mn and left to stabilize for at least 45-60 minutes To obtain the maximum reduction in the solution bath was added histamine (310-5M). Transmural stimulation caused along the length of the strips of the colon by means of two platinum electrodes, the anode threaded through the cavity of the colon, the cathode was in the bath solution. The drug was initiated rectangular wave pulses (9, 1 MS/pulse) for 10 s every 5 min at different frequencies. Electrical stimulation resulted in relaxation (=ON-response), followed immediately by a reduction (=OFF-otvetyi followed by three stimulation at 1.5 Hz to obtain a submaximal contraction. Then, in the liquid bath was added a test compound and again both stimulus (0,4 Hz and 1.5 Hz) was repeated three times. At a concentration of 310-7M test compound induced an increase of the OFF - response to 100% of the initial value.

Example 7

Guinea pigs Dunkin-Harley either sex (350, without starvation) were killed by cervical shift followed by decapitation. The ascending colon is cut at a distance of 5 cm from the rectum, cut and ligated to a length of 40 cm and freed from adherent tissue. When in the colon there were at least 10 balls, tissue was transferred to a glass beaker containing 200 ml of Krebs-Henseleit, saturated with a mixture of 95% oxygen and 5% carbon dioxide and maintained at 37oC. the Solution contained either a pure solvent or the test compound. Push the beads were counted and removed from the solution every 5 min for a maximum period of 60 minutes

Cumulative number of balls dislodged from the colon in each moment, expressed as a percentage of the total number of balls present in a colon at the beginning of the experiment. Deposited curves response time by plotting to the ation of the present compounds 310-9M 80% of the initial number of balls was removed within 10 minutes

Example 8

Coaxial stimulation of the ileum of the Guinea pig

Guinea pigs Dunkin Harley both sexes (weight 500 g) were killed by cervical shift followed by decapitation. The terminal ileum was separated and washed heated and saturated oxygen solution of Krebs-Henseleit. Non-end segments of the intact ileum length 4.5 cm Guinea pigs vertically hung with preload of 1 g in 100 ml of Krebs-Henseleit (37,5oC) saturated with a mixture of 95% O2and 5% CO2. Transmural stimulation caused along the length of the segment of the ileum by means of two platinum electrodes, the anode threaded through the cavity of the ileum, the cathode was in the bath solution. The drug was filed by a rectangular stimulus [1 MS; 0.1 Hz; submaximal response (current, resulting in 80% of the maximum response)] from the programmable stimulator. Reduction was measured isometrically. During the stabilization period of 30 min, the strips several times stretched to a tension of 2 g in order to obtain the tension of the stationary state 1, Before electrical stimulation p is ainali when sirmixalot current to determine the maximum amplitude of the responses in the form of muscle contractions. When responses were stable, gave a submaximal stimulation to obtain 80% of the maximum response up until a response the muscle contractions were constant for at least 15 minutes, after which the liquid bath was added a single dose of the test compound. The amplitude response of muscle contractions in 5 min after injection of the test compounds is compared with the amplitude before the introduction of the test compounds. This compound showed higher amplitude response of muscle contractions by more than 5% at concentrations of 3, 10-9M

Compounds according to the invention were subjected to a screening test for toxicity in rats. This test involves an injection to rats of the test compounds at a dose of 40 mg/kg None of the tested compounds did not show any signs of acute toxicity at the tested dose. All connections, proposed according to the invention, had the indicator LD50more than 40 mg/kg

Below, the applicants cite evidence to demonstrate the unexpected superior interceptions properties of the compounds of the present invention in comparison with the connection 107 PR is that the data below clearly indicate the superior properties of these compounds, on what basis is it claimed the proposal may be deemed patentable selective invention with regard to EP-0445862.

Connection 107 EP-0445862 (for brevity "the connection 107") represented by the formula

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Connection 1 of the present invention obtained in example 2, represented by formula

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Connection 1 and connection 107 are subjected to different periods of time the test is called "Fecal pellet propulsion in the guinea-pig colon descendens (Propolice or pushing fecal balls in the descending colon of the Guinea pig"). Using this test measured the rate of emptying from the fecal balls colon and demonstrates the effect of increasing contractility or peristalsis of the colon. A detailed description of this test shown in example 7 in the description to this application. The results obtained in this test are shown in table 1.

From the data in table 1 shows that the percentage of popped fecal balls in 10 min is higher for the connection 1 of the present invention in comparison with the connection 107, which confirms the superior properties enhance contractility exhibited by compounds of this is Pete called "Telemetric recording of the motility of the colon in the fasted conscious dog" ("Telemetry registration peristalsis of the colon contained on the famine in the consciousness of the dog"). With this experience evaluate the effect of test compounds on the motility of the colon using visual observation of defecation on unrestrained contained in hunger and in the mind of the dog.

The results of this test are shown below in tables 2 and 3.

As you can see from the results presented in tables 2 and 3, the effect on peristalsis of the colon as in the proximal and in the distal part of the colon is much more pronounced for compounds 1, than for the connection 107. Data, stimulating enhanced motility properties connection 1, result in a higher number of cases of bowel movements during the observation period after administration of the compounds 1 in comparison with the number of bowel movements after injection of compound 107.

Whereas in General all of the above studies, which show the results shown in tables 1, 2 and 3, applicants believe that these results clearly demonstrate the superior and unexpected properties connection 1 pending application, which is manifested in increased motility compared with the connection 107, described in EP-0445862.

Next is that, if the examiner considers it necessary, may be added to the description to this application.

Examples of compositions

The following ready preparative forms are typical examples of pharmaceutical compositions in the form of unit dosages suitable for systemic and topical introduction warm-blooded animal in accordance with the present invention.

Example 9: Solutions for oral administration

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioate acid and thereafter 20 g of compound 1. The latter solution is combined with the remaining part of the first solution, and thereto is added to 12 l of 1,2, 3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of sodium saccharin dissolved in 0.5 l of water and added 2 ml of raspberry and 2 ml of gooseberry family essences. The latter solution is combined with the first, water is added in the amount necessary up to a volume of 20 l, obtaining a solution for oral administration, containing 5 mg of compound 1 teaspoon (5 ml). The resulting solution fill in appropriate containers.

Example 10: Capsules

20 g of compound 1, 6 g of lauryl sodium, 56 g Alchymist solution subsequently fill 1000 suitable hardened gelatin capsules, each of which includes 20 mg of compound 1.

Example 11: Tablets, film-coated

Obtain core tablets

A mixture of 100 g of compound 1, 570 g lactose and 200 g starch mix well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 120 g of polyvinylpyrrolidone (Kollindon-90 KRabout 200 ml of water. Mix the wet powder is sifted through a sieve, dried, and sift again. Then add 100 g microcrystalline cellulose (AvicelR) and 15 g hydrogenated vegetable oil (SterotexR). All is mixed well and compressed into tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose (Methocel 60 HGR) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel SDRR) in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first, and then added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated ink suspension (Opaspray K-1-2109R), and all homogenized. Core tablets cover obtained is propyl)-4-piperidinyl]-7-benzofuroxan formula I

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or its pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, which represents monohydrochloride 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl] -7-benzoperoxide.

3. Connection on p. 1, which represents butanedioate 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl] -7-benzoperoxide (1:1).

4. Pharmaceutical composition having enterokinase properties, including pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of paragraphs.1-3.

5. A method of obtaining a pharmaceutical composition according to p. 4, according to which a therapeutically effective amount of a compound according to any one of paragraphs.1-3 thoroughly mixed with a pharmaceutically acceptable carrier.

6. The compound according to any one of paragraphs.1-3, with enterokinase properties.

7. The compound according to any one of paragraphs.1-3, with the ability to accelerate the passage of contents through the intestine.

8. The method of obtaining compounds under item 1 or 2, in which the intermediate product of formula II

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N-alkylate alkylating reagent of formula III

CH3-O-(CH2)3-W
and, if desired, the compound of the formula I is converted into a therapeutically active non-toxic acid additive salt, or conversely, an acid additive salt is converted into the free base using lye.

9. The method of obtaining compounds under item 1 or 2, in which the amine of the formula V N-acelerou carboxylic acid of formula IV

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and, if desired, the compound of the formula I is converted into a therapeutically active non-toxic acid additive salt, or conversely, an acid additive salt is converted into the form of the free base with alkali.

 

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The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and method of production thereof
The invention relates to medicine, namely to addiction

The invention relates to compounds of formula I and their pharmaceutically acceptable salts, where the substituent R represents a halogen - C1-C8-alkyl, halogen - (C2-C8alkenyl, halogen - C2-C8-quinil or halogen - C1-C8-alkyl, substituted hydroxy or C1-C8-alkoxygroup; R1represents a hydrogen atom, halogen atom or C1-C8-alkoxygroup; or R and R1together with the two carbon atoms common to the benzene ring, form a condensed C4-C6-cycloalkyl, where one carbon atom is optionally replaced by oxygen atom, and where one or two carbon atoms optionally have up to five substituents selected from a halogen atom, a C1-C6-alkyl and halogen - (C1-C6-alkyl; X represents a C1-C6-alkoxy-, halogen - C1-C6-alkoxy, fenoxaprop or halogen atom; and Ar represents a phenyl group optionally substituted by a halogen atom

The invention relates to the transdermal administration of drugs

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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