Derivatives of 2,3-dihydropyrano[2,3-b]pyridine or its salt, the method of obtaining 2-aminomethyl-2,3-dihydropyrano(2,3-b) pyridine as starting substances for obtaining derivatives of 2,3-dihydropyrano[2,3-b]pyridine and method thereof

 

(57) Abstract:

Usage: in medicine as a serotonin receptors. The inventive product derivatives of 2,3-dihydropyrano [2,3 b] pyridine F.-ly (I), where A lower alkylene and R a hydrogen atom or a group where A has the above meaning, or their salts. Reagent 1: 2-aminomethyl-2,3-dihydropyrano (2,3 - b) pyridine f-ly II. Reagent 2: compound f-ly where L deleted group and A has the above meaning. Process conditions: if necessary in the presence of a base and of a reaction accelerator, in an inert solvent, followed if necessary by alkylation and selection of the target product in free form or in salt form. 2 aminomethyl-2,3-dihydropyrano(2,3 b) pyridine was prepared as follows: reagent 1 connection F.-ly (IV), where T is a halogen atom. Reagent 2: phthalimide potassium. Process conditions: inert solvent in the atmosphere of inert gas. Reagent 3: connection F.-ly (V) Reagent 4: 2-aminoethanol or hydrazinehydrate. The affinity of compounds f-ly I respect receptor NT shown in the results of studies on membrane preparations obtained from calf Amonov horns. As radioactive labeled ligand was used 3H-serotonin. Ki=what properties, in particular, derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula

< / BR>
(I) where a lower alkylene;

R is a hydrogen atom or a group

A

or their salts.

In General can be called a salt with inorganic or organic acids.

Preferred physiologically tolerated salt.

Physiologically tolerated salts of derivatives of 2,3-dihydropyrano[2,3-b] pyridine can be salts with mineral acids, carboxylic acids or sulphonic acids. Particularly suitable are, for example, salts with hydrochloric acid, methanesulfonic acid, econsultancy acid, toluensulfonate acid, benzosulfimide acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid.

Within the above definition of heterocycle usually means a 5-7 membered aromatic ring, which, as the heteroatoms may contain oxygen, sulfur and/or nitrogen and which may be precondensation further aromatizes the 1-2 nitrogen atom and, if necessary, benzododecinium. As a particularly preferred heteroaryl can be called: thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, hinely, ethanolic, ginossar, hinely, thiazolyl, benzothiazolyl, isothiazolin, oxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl and indolyl.

A further object of the invention is a method of obtaining the proposed compounds of formula I, namely, that the amine of the formula

< / BR>
(II) is subjected to interaction with the compound of the formula

L-A

(III) where a has the abovementioned meanings and L is a typical removable group, such as bromine, chlorine, iodine, tosyl or mesyl, preferably bromine, in an inert solvent, if necessary in the presence of a base and of a reaction accelerator, followed if necessary by alkylation to produce compounds in which R does not mean a hydrogen atom.

As solvents it is possible to use water or common organic solvents, which are inert under the reaction conditions. To them, preferably belong alcohols, such as methanol, ethanol, propanol or isopropanol, or ethers, such as, for example, a simple diethyl ether, dioxane, tetrahydrofuran, is h, or amides, such as dimethylformamide or triamide hexamethylphosphoric acid, or dimethyl sulfoxide, acetonitrile, complex ethyl ester acetic acid, or halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloride or hydrocarbon, or pyridine, picoline or N-methylpiperidine. In addition, you can use a mixture of these solvents. Preferably use dimethylformamide.

As a reason suitable the usual inorganic or organic bases. To them, preferably belong to the alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, or carbonates of alkali metals, such as sodium carbonate or potassium, or an alkali metal alcoholate, such as, for example, methanolate sodium or potassium, or ethanolate sodium or potassium, or organic amines, such as triethylamine, picoline or N-methylpiperidine, or amides, such as sodium amide or diisopropylamide lithium, or ORGANOMETALLIC compounds, such as, for example, utility or finality. Preferably using triethylamine. When this base is used in the amount of 1-5 moles, preferably 1-2 moles, per mole of the compounds of General formula III. Compounds of General) 1-1,5-fold excess compared to the amount of the compounds of formula II.

As the reaction accelerator is usually used iodides of alkali metals, preferably sodium iodide or potassium, in an amount of 0.01-0.5 mol, preferably 0.01 to 0.1 mol per mol of compound of General formula III.

The reaction is usually carried out at a temperature of 0-150aboutC, preferably at temperatures from room temperature up to 80aboutC.

The reaction is usually carried out at atmospheric pressure. However, the reaction can be also carried out at elevated or reduced pressure (for example, at a pressure of 0.5 to 3 bar).

The alkylation is usually carried out in an environment of one of the abovementioned solvents, preferably in a medium of dimethylformamide, when 0-158aboutC, preferably at a temperature from room temperature to 100aboutC.

As alkylating tools you can use, for example, alkylhalogenide with 1-8 carbon atoms in the alkyl part, esters of sulfonic acids or substituted or unsubstituted diallylsulfide with 1-6 carbon atoms in each alkyl part, or vallalat with 6-10 carbon atoms in each aryl part, preferably methyliodide, ester p-toluenesulfonic acid or dimethylsulfate.

Compounds of General formula II are new and they can vet the bromine and/or chlorine, or a mixture of (T-Br, T-CL) is subjected to interaction with phthalimide potassium in an inert solvent and in the protective gas atmosphere and the obtained compound of General formula

< / BR>
(V) is subjected to interaction with 2-aminoethanol or hydrazinehydrate to release aminophenol.

As a solvent for reactions performed with phthalimido and potassium 2-aminoethanol fit the above solvents, preferably toluene, and dimethylformamide. The solvent can also be used reagent 2-aminoethanol, which in this case is used in excess.

The reactions take place at a temperature of 50-150aboutWith, preferably 60-120aboutC and atmospheric pressure.

Compounds of General formula III are well known.

Compounds of General formula V are novel and can be obtained by the above method.

Compounds of General formula VI are new and you can get them due to the fact that the compound of General formula

< / BR>
(VI) is subjected to bromirovanii, preferably elemental bromine, in the environment of one of the abovementioned solvents, preferably in an environment of methylene chloride, and the obtained compound of General formula

Compounds of General formula VII are also new.

Compounds of General formula VI are new. You can get them due to the fact that the compound of General formula

< / BR>
(VIII) is subjected to conventional chlorination chlorination agents, preferably with thionyl chloride, in an environment of one of the foregoing solvents, preferably dichloromethane, with subsequent recovery of activated copper zinc in the environment of one of the abovementioned solvents, preferably methanol, or hydride presence of TBT in the environment of a hydrocarbon, preferably toluene.

The chlorination reaction and recovery usually takes place at 0-120aboutAnd atmospheric pressure.

Compounds of General formula VIII are also new. They can be obtained, for example, due to the fact that known from the literature 2-methoxypyridine-3-carbaldehyde or its substituted derivative is subjected to interaction with allylbromide and aluminum in the presence of mercury chloride (II) in the environment of one of the abovementioned ethers, preferably tetrahydrofuran. The reaction is usually carried out at temperatures from -60 to +50aboutC, preferably from -60 to +25aboutC, and at atmospheric pressure.

The proposed compounds exhibit vacation or a trip Wi similar in structure to the compounds they are more selective in respect of the receptor 5-HT1Apartly antagonistic effect on serotonin and fewer side effects. They are agonistic, partial agonistic and antagonistic action on the serotonin receptor compared to similar in structure to the compounds they show greater therapeutic range.

Thus, the proposed vysokoreaktsionnye ligands of the receptor serotonin 1 represent active compounds for combating diseases which are characterized by impaired serotoninergen system, in particular with the participation of receptors that have a high affinity to 5-oxitriptan (serotonin); 5-HT1). Therefore, they are suitable for the treatment of diseases of the Central nervous system, such as, for example, state of fear, stress and depression caused by Central nervous system disorders, sexual dysfunctions and disorders of sleep and ingestion of food products. In addition, they are suitable for the treatment of conscious deficits, to improve the ability to study and stimulate memory function, as well as for the treatment of Alzheimer's disease. In addition, the new compounds are also suitable for modulation of the cardiovascular system. They also vozdeistviiu. In addition, the new compounds are also suitable for the prevention and combat the effects of cerebral infarctions, such as stroke, traumatic brain injury, cerebral ischemia, and related subsequent processes. The new compounds can also be used to treat diseases of the intestinal tract that are caused by violations serotoninergen system, and carbohydrate balance.

The following data illustrate the high affinity of the new compounds in the receptor 5-HT1. Thus, the connection Primero has TOi= 1,0 nmol/L. These data represent the results of studies on membrane preparations obtained from calf Amonov horns. At the same time as the radioactive labeled ligand was used3H-serotonin.

The object of the invention is also pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable excipients and carriers, contain one or more compounds of General formula I, or which consist of one or more compounds of formula I as the active substance, and the method of obtaining these drugs. In these preparations the active substance formula compounds of the formula I, the pharmaceutical preparations can also contain other pharmaceutical active substances.

The pharmaceutical preparations can be obtained in a known manner by known methods, for example, with the aid (s) or carrier (s).

In General to achieve the desired result, it is advantageous to apply the active(s) substance(s) of formula I in the total amount of about 0.1 to 100 μg/kg, preferably in total PR IMEMO 1-50 μg/kg of body weight per 24 hours, if necessary, in some individual doses.

However, if necessary it may be appropriate to deviate from the specified number, namely depending on the type and weight of the subject to treatment of the patient, the individual behavior of the patient regarding medications, the type and degree of the disease, type of drug and villas and torque or gaps villas tools.

The following examples illustrate how to obtain the original compounds.

P R I m e R 1. 3-(1-hydroxy-but-3-EN-1-yl)-2-methoxypyridine

< / BR>
of 29.9 g (1.1 g-atom) of aluminum shavings and 100 mg of mercury chloride (II) is suspended in 300 ml of dry tetrahydrofuran in an argon atmosphere. Heated to 40aboutWith and slowly add drops of 1-2 ml 214,0 g (1.77 mol) of allylbromide in 250 ml of dry tetrahydrofuran. The temperature rises to about 50aboutS. aboutC. Additionally stirred at 60aboutC for one hour, the solution is cooled to a temperature of 60aboutWith and add drops at this temperature to 112.4 g (0.765 mol) 2-methoxypyridine-3-carbaldehyde in 250 ml of dry tetrahydrofuran. Optionally stirred at a temperature of 0aboutC for one hour and at 20aboutC for 2 hours and Then cooling drops add 500 ml of saturated solution of ammonium chloride, optionally stirred for 0.5 h, filtered and the filtrate concentrated in vacuum. The residue is absorbed in a complex ethyl ester acetic acid, washed with water and dried over sodium sulfate. Get 136,1 g of light yellow oil, which is subjected to fractional distillation. Output 110,9 g (81% of theory).

So Kip. 91-100aboutC/0.5 mm RT.article.

P R I m m e R 2. 3-(1-chloro-but-3-EN-1-yl)-2-methoxypyridine

< / BR>
of 56.5 g (0.32 mol) of the compound of example 1 in 400 ml of dry dichloromethane is stirred with 277 ml (3.8 mol) of thionyl chloride at 20-30aboutWith during the night. Then in a vacuum produced by using water-jet pump, at 20-30aboutTo remove dichloromethane and unreacted thionyl chloride. The residue is partitioned between dichloromethane and aqueous saturated sodium bicarbonate solution. Org is as oil. Yield 94% of theory.

P R I m e R 3. 2-(but-3-EN-1-yl)2-methoxypyridine

< / BR>
118,5 g (0.54 mol) of the compound of example 2 in 1000 ml of dry methanol is stirred from 71.4 g of zinc (activated copper) and boiled for 2 hours the Precipitate is filtered off and the filtrate evaporated in vacuum. By fractional distillation of the residue gain of 20.0 g of the above compound with so Kip. 96aboutC/20 mm RT.article Exit 23% of theory.

P R I m e R 4. 3-(3,4-dibromo-buta-1-yl)-2-methoxypyridine

< / BR>
14.4 g (88 mmol) of bromine in 30 ml of dry dichloromethane drops added under stirring to a solution of 14.0 g (88 mmol) of the compound of example 3 in 70 ml of dry dichloromethane at 20-30aboutC. After the expiration of 15 min, the reaction mixture is mixed with cold saturated sodium bicarbonate solution, add a few ml of a solution of sodium sulfite and share phase. The dichloromethane phase is dried and evaporated in vacuum. of 28.1 g of dry above-mentioned compound is obtained as oil.

Output 100% of theory.

P R I m e R s 5,6. (2-Bromo-methyl)-2,3-dihydropyrano(2,3-b)pyridine (example 5).

and (2-chloro-methyl)-2,3-dihydropyrano- (2,3-b)pyridine (example 6)

< / BR>
of 28.1 g (88 mmol) of the crude compound of example 4 in 212 ml of 5% hydrochloric acid is boiled with paramashiva is. Then the aqueous phase is alkalinized by adding sodium carbonate solution and extracted with dichloromethane. By this phase evaporation in vacuum is to obtain 15.0 g of crystalline product containing the compounds of examples 5,6 in the ratio of 12:5

A yield of about 79% of theory.

P R I m e R 7. 2-phthalimidomethyl-2,3-dihydropyrano (2,3-b)pyridine

15,0 (70 mmol) of a mixture of compounds of examples 5, 6 (the ratio of 12: 5) and 16.0 g (86 mmol) of phthalimide potassium in 150 ml of dimethylformamide is heated to 100aboutWith under stirring in nitrogen atmosphere for 20 hours and Then the dimethylformamide is distilled off in vacuum and the residue partitioned between dichloromethane and water. Get 24,0 g of crystals with a melting point 152-158aboutC.

NMR (DCl3); 1.70 to 2,00 (m, 1H); 2,00-of 2.20 (m, 1H); 2,80-2,90 (m, 2H); 3,80-3,95 and 4.10-4.25 in (system AB, 2H); 4,50 with 4.65 (m, 1H); 6.75 in-6,90 (m, 1H); 7,30-7,40 (m, 1H); 7,65-7,80 (m, 2H); 7,80-to 7.95 (m, 2H) and 8.00-8,10 (m, 1H) hours/million Yield: about 100% of theory.

P R I m e R 8. 2-Aminomethyl-2,3-dihydropyrano(2,3-b)pyridine

< / BR>
3.2 g (11 mmol) of the compound of example 7 and 9.2 g (150 mmol) of 2-aminoethanol heated in nitrogen atmosphere up to 80aboutC. after 5 min, cooled and the reaction mixture was partitioned between 70 ml of toluene and 92 ml of 4% aqueous solution of sodium chloride. Then the phases are separated and the aq g of the above compound as a pale yellow oil.

Yield 94% of theory.

NMR (DCl3): 1,73-of 1.85 (m, 1H); 1.93 and is 2.00 (m, 3H, 2H; exchange as a result of the additive D2O); 2,74-2,95 (m), as well as 2,96 (quasi d, 4H); 4.09 to 4,18 (m, 1H); for 6.81-6,86 (m, 1H); 7,35-7,37 (m, 1H) and 8,04-with 8.05 (m, 1H) h/million

P R I m e R s 9, 10. 2-N-bis-(4-butylboronic)-aminomethyl-2,3-dihydropyrano- [2,3-b]pyridine (example 9)

and 2-N-(4-butylboronic)-aminomethyl-2,3-dihydropyrano (2,3-b)pyridine (example 10)

NH-(CH2)4- 2.1 g (11 mmol) of the compound of example 8, 3.5 g (11 mmol) of 4-bromoethylamine, 1.1 g (11 mmol) of triethylamine and 10 mg of sodium iodide in 10 ml of dimethylformamide was stirred at 60aboutC for 9 h in argon atmosphere. The dimethylformamide is distilled off at 40aboutC and a pressure of 0.01 mm RT. Art. the Residue partitioned between water and dichloromethane and the phases are separated. The organic phase is alkalinized 0.1 N. sodium hydroxide, washed with water, and then dried over sodium sulfate and evaporated. Obtain 4.0 g of a light yellow oil, which chromatographic on 200 g of silica gel using as eluent a mixture of toluene and complex ethyl ester acetic acid (gradient). Obtain 0.7 g of 2-N-bis-(4-butylboronic)-aminomethyl-2,3-dihydropyran (2,3-b)pyridine.

Output 10% theory.

NMR (DCl3): 1,54 of 1.86 (m, N); 2,19-of 2.34 (m, 1H); 2,54-of 2.86 (m,5 alkalinized 0.1 N. hydrokit sodium and shaken out with dichloromethane. Then dichloromethane extracts are washed with water, dried over sodium sulfate and evaporated. 1.2 g of residue chromatographic on 60 g of silica gel using as eluent a mixture of toluene and complex ethyl ester of acetic acid in a volume ratio of 1:1. Obtain 0.2 g of 2-N-(4-butylboronic)-aminomethyl-2,3-dihydropyrano(2,3-b)pyridine.

5% of theory.

NMR (DCl3): 1,62-2,05 (m, 6N); 2,74 is 3.40 (m, 7H); 3,76-3,82 (m, 2H); 4,32-4,00 (m, 1H); 6,80-6,85 (m, 1H); of 7.36-7,39 (m, 1H); 7,79-to 7.93 (m, 3H) and 8,02-with 8.05 (m, 2H) hours/million

P R I m e R 11. Hydrochloride of 2-N-bis-(4-butylboronic)-aminomethyl-2,3-dihydro - pyrano-(2,3-b)pyridine

HCl

0.7 g of the compound of example 1 dissolved in 100 ml of simple Dyatlovo ether and acidified to pH 4-5 1 M ethereal hydrochloric acid. Obtain 0.5 g of the above compound as an amorphous salt.

WITH31H34N4O7S2x 2HCl

Designed With 52,32; N 5,10; N 7,87.

Found, 52,1-53,5; N 5,01-5,02, N 7,88-7,97.

P R I m e R 12. Hydrochloride of 2-N-(4-butylboronic)-aminomethyl-2,3-dihydropyrano- (2,3-b)-pyridine

HCl

0.2 g of the compound of example 10 is dissolved in 50 ml simple diethyl ether and acidified to pH 4-5 1 M APIRG crystalline salts of the above compounds with a melting point of 42-50aboutC. NMR (DCl3/DMSO-d6): characteristic signals 4.6 and 4.8 (broad m, 3H 2); 7,0 7,1 (m, 1H); 7,7 7,8 (m, 1H); 7,9 8,1 (m, 4H); 8,2 8,3 (m, 1H), and to 9.3 and 9.5 (m, 1H) hours/million

1. Derivatives of 2,3-dihydropyrano [2,3-b] pyridine of General formula

< / BR>
where a lower alkylene;

R is hydrogen or a group

< / BR>
where a has the specified value,

or their salts.

2. Derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula

< / BR>
where a lower alkylene;

R is hydrogen or a group

< / BR>
where a has the specified value,

and their salts, are active against serotonin receptors.

3. The method of obtaining derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula

< / BR>
where a lower alkylene;

R is hydrogen or a group

< / BR>
where a has the specified value,

or their salts, characterized in that the compound of the formula

< / BR>
subjected to interaction with the compound of General formula

< / BR>
where a is the specified value;

L delete group

in inert solvents, if necessary, in the presence of a base and of a reaction accelerator, followed, if necessary, by alkylation and selection of the target product in free form or in salt form.

< the derivatives of 2,3-dihydropyrano[2,3-b]pyridine by p. 1.

5. The method of obtaining 2-aminomethyl-2,3-dihydropyrano[2,3-b]pyridine of the formula

< / BR>
characterized in that the compound of General formula

< / BR>
where T is halogen,

or a mixture of T different halogen atoms), is subjected to the interaction with phthalimide potassium in an inert solvent and in the atmosphere of inert gas, and the obtained compound of the formula

< / BR>
subjected to interaction with 2-aminoethanol or hydrazinehydrate.

 

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