Derivatives 7-[3-[4-(6-toranzo[d]isoxazol-3-yl)piperidine - 1-yl]propoxy]-chromen-4-it, the method of production thereof, pharmaceutical composition for the inhibition of d2-,5-ht2aand h1receptors and method of inhibition of d2-,5-ht2aand h1receptors in the treatment of psychosis and schizophrenia

 

(57) Abstract:

The invention relates to new derivatives 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -chromen-4-it formula I, where R is hydrogen, Cho, CH2OR2or COOH; R1means alkyl containing from 1 to 4 carbon atoms, provided that one of substituents R and R1is hydrogen, and their pharmaceutically acceptable salts, intended for use in the treatment of psychosis and schizophrenia, as well as to a method for producing these compounds, pharmaceutical compositions and method of inhibiting D2-, 5-HT2aand H1receptors in the treatment of psychosis and schizophrenia. The technical result is to provide new compounds used in medicine as a drug. 4 C. and 3 h. p. F.-ly, 3 PL.

The technical field to which the invention relates

The invention relates to chemical products, in particular derivatives 7-[3-[4-(6-toranzo[d] isoxazol-3-yl) piperidine-1-yl] propoxy] -chromen-4-it and their salts, which can be used in the pharmaceutical industry in the manufacture of tools for the treatment of psychosis and schizophrenia.

Art

In Pat is their action. Known compounds act on the D2and 5-HT2Areceptors, which is typical for psychotropic drugs. However, to date there are no publications about H1-antihistamine action of the compounds known from the prior patents.

The invention

The present invention relates to a derivative 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -chromen-4-it General formula (I)

< / BR>
where R is hydrogen, Cho, CH2OR2or COOH; R1means hydrogen or CH2HE and R2means alkyl containing from 1 to 4 carbon atoms, provided that one of substituents R and R1is hydrogen, and their pharmaceutically acceptable additive salts.

Compounds according to the present invention are new and they are obtained by interaction of 2- (or 3-substituted 7-(3-holodramas)-4H-1-benzopyran-4-it General formula (II), where R and R1defined for formula (I), X is a halogen, preferably chlorine or bromine, with 6-fluoro-3-(4-piperidinyl)-benzo[d] isoxazol (III) in accordance with scheme 1 in the presence of a base, which is selected from carbonates or bicarbonates of alkali or alkaline earth metals and catalyt is containing a series of solvent, chosen from N, N-dimethylformamide, acetonitrile, or etc.

< / BR>
According to another method, compound (I, R= CHO, R1= H) and (I, R= CH2OR2, R1= H) can be obtained, respectively, by oxidation or alkylation 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -3-hydroxymethyl) -chromen-4-it (see the application for the grant of a patent Spain 9600323). The oxidation is usually carried out in the presence of oxalicacid and dimethyl sulfoxide in a halogenated solvent, preferably dichloromethane. The alkylation is usually carried out using the appropriate alcohol R2-OH (IV), where R2previously defined for formula (I), in an acidic medium at the boiling temperature of the reaction mixture. Of the new compounds of the formula (I) can get their salts by adding an appropriate acid using known methods of organic chemistry.

The properties of the compounds according to the present invention differ from the compounds described in the aforementioned patents. Indeed, applicants found that compounds of General formula (I) possess, in addition to the strong effect on the D2and 5-HT2Areceptors, which is characteristic of psychotropic drugs, strong action on H1-re the/SUB>-antihistamine effect of the compounds known from the prior patents.

Information confirming the possibility of use of the invention

Specific binding to receptors D2, 5-HT2Aand H1investigated, as described below.

D2receptors: membrane fraction, corresponding to 20 mg striatum (the striatum) rats, incubated in 2 nm solution of radioactive spiperone ([3N] spiperone), which is used as a specific ligand, Tris-Hcl buffer solution at 35oC and pH 7.4 for 20 minutes Then determine non-specific binding by adding its spiperone in micromolar concentrations. The value of the IC50(the concentration at which there is 50% inhibition) is calculated by the degree of inhibition of specific binding, defined at Appendix 11 different concentrations of the test compounds. After incubation the sample is filtered through a glass fiber filter and washed three times with buffer solution of Tris-HCl. Associated with the receptor radioactivity retained on the membrane and is determined using a liquid scintillation counter.

5-HT2Areceptors: th ketanserina ([3H] ketanserin), which is used as a specific ligand, Tris-Hcl buffer solution at 35oC and pH 7.4 for 30 minutes Then determine non-specific binding by adding its mianserin at a concentration of 5 μm. The value of the IC50(the concentration at which there is 50% inhibition) is calculated by the degree of inhibition of specific binding, defined at Appendix 11 different concentrations of the test compounds. After incubation the sample is filtered through a glass fiber filter and washed three times with buffer solution of Tris-HCl. Associated with the receptor radioactivity retained on the membrane and is determined using a liquid scintillation counter.

H1receptors: determination of the activity carried out by incubation of the membranes of cerebellar marine back in the presence or absence of test compounds in 1 nm solution of [3N] -pyrilamine used as a specific marker, 25oC for 60 minutes Associated radioactivity is separated by filtration (Whatman GF/B) on the collector Brandel cell Harvester. The number associated with the receptor of radioactivity retained on the filter set is concentratie 1 micron.

The results of biochemical studies, presented in the form of values IC50(molar concentration) for D2and 5-HT2Areceptors compared with the compound according to example 2', described in Spanish patent application 9600323, and with standard haloperidol are summarized in table 1 and the results for N1-receptor compared with the compound according to example 2', described in the patent Spain 9600323, and with standard prometazina are summarized in table 2.

Based on the data of table 1 it can be concluded that the compounds according to the present invention, obtained as described in examples 1 and 2, shown as ligands D2and 5-HT2Areceptors stronger action than the compound according to example 2' Spanish application 9600323. The ratio of D2/5-HT2Aindicates that all connections activity exceeds standard haloperidol, the result indicates reduced risk of extrapyramidal effects.

Similarly, based on the data of table 2 it can be concluded that the compounds according to the present invention, obtained as described in examples 3 and 6, are as ligands N1-receptor stronger effect than the is the efficiency of the compounds according to example 3 above, than the activity of the standard prometazina.

Compounds according to the present invention was compared with the compound according to example 2' Spanish application 9600323 through tests used in the field of pharmacology animals, namely, the inhibitory action initiated by apomorphine behavior "up on the grid" (P. Protais et al: "Psychopharmacology", 50, 1-6, 1976). To perform this experiment were used male Swiss mice weighing 22-24, one week before the experiment, animals kept indoors at 20-22oWith the cyclical nature of dark light 12/12 h with free access to food and water. For 2 h before the experiment, animals are placed in individual cages without access to food. Then at the time of the experiment 0 test animals injected medication or 0.25% agar. After 60 min, animals injected subcutaneous apomorphine dose of 1 mg/kg and even after 70 min estimate the behavior of animals. Two additional assessments are conducted at intervals of 10 minutes

To assess the behavior of each animal is placed on the bottom of a small rectangular box (117,54,5 cm). Wall boxes are made from translucent methacrylate in addition to the one side surface (width 7.5 cm), which is a 3 mm provolochnogo, 2 = two feet on the floor, 4 = four paws on the grid. If the animal takes several positions within 2 min of observation, recording the time spent by the animal in each position in seconds. Finally, calculate an average value. At the same time appreciate the cataleptic activity of the compounds administered to the rats by oral, and Express it in the form of the effective dose 50% (ED50).

The results, presented in the form of inhibitory dose 50% (ID50(mg/kg) on the test of "up on the grid and ED50(mg/kg) on catalepsy test, summarized in table 3. This table shows also therapeutic index (TI), which is a measure of the safe use of the investigated compounds.

Based on the data of table 3 it can be concluded that the compounds according to the present invention, obtained as described in examples 3 and 6 have a higher therapeutic index than the compound according to example 2' Spanish application 9600323 and the standard haloperidol, which confirms the advantage to reduce the risk of extrapyramidal effects at therapeutic doses.

Compounds according to the present invention can be used as a psychotropic medium spans daily dose is from 1 to 500 mg, preferably from 2 to 50 mg, inclusive. Normal forms for oral administration of the compounds as psychotropic drugs are solutions, tablets, coated tablet, capsule, granules, syrups, etc., Compounds according to the present invention can also be used as antihistamine drugs for Allergy treatment by oral administration, injection or administration by rectal, and the daily dose is from 1 to 500 mg, preferably from 2 to 150 mg, inclusive. Normal forms for oral administration of these compounds for the treatment of allergies are solutions, tablets, coated tablet, capsule, granules, syrups, etc., Compounds used as anti-allergic agents, you can also enter in the form of a composition for external use, such as an ointment, lotion, powder, etc., at concentrations from 0.5 to 5%, preferably from 1 to 2%, inclusive.

The invention is illustrated below by the following examples.

Example 1: 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -3-formylamino-4-one

A solution of 3 ml (42 mmol) of DMSO in 10 ml of dichloromethane are added dropwise to a solution of 2 ml (23 mmol) of oxalicacid in 35 ml of dry dichloromethane, the OHL is given 5 g (11 mmol) 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -3-(hydroxymethyl)chromen-4-it (Spanish patent application ES 9600323) and stirred for another 30 min at -70oC. and Then added dropwise 15 ml (107 mol) of triethylamine, stirred overnight, leaving the reaction mixture to gradually warm to room temperature. When cooled to -20oTo the reaction mixture are added 50 ml of water, the mixture is allowed to warm to room temperature, the organic phase is decanted, dried over sodium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica gel. Upon elution of the column with a mixture l3: CH3HE (98: 2, vol. : about. ) get 2,12 g 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -3-formylamino-4-one with a yield of 43%, so pl. 163-165oC.

IR-spectrum (KBr): 1691, 1652, 1619, 1441 cm-1.

The NMR spectrum (CDCl3): 2,10 (m, 6 H), of 2.20 (m, 2 H), 2,60 (t, 2 H), 3,10 (m, 3 H), 4,19 (t, 2 H), of 6.96 (d, 1 H), 7,05 (m, 2 H), from 7.24 (dd, 1 H), of 7.69 (dd, 1 H), 8,19 (d, 1 H), of 8.47 (s, 1 H), 10,37 (s, 1 H).

Example 2: hydrochloride 7-[3-[4-(6-torbenson[d] isoxazol-3-yl) piperidine-1-yl] propoxy] -4-oxoprost-3-carboxylic acid.

A mixture of 0.87 g (3 mmol) 7 (3 chloropropoxy)-4-oxoprost-3-carboxylic acid, 0.7 g (3 mmol) of the hydrochloride of 6-fluoro-3-(4-piperidinyl)benzo[d] isoxazol to 0.85 g (6 mmol) of anhydrous potassium carbonate and catalytic amounts of potassium iodide in 25 ml of N, N-dimethylformamide is heated at 89-90o

IR-spectrum: 3100-3700, 1698, 1616, 1447, 1384, 1165, 1121 cm-1.

NMR-spectrum (DMSO): 2,13 (m 6N), is 2.30 (m, 2H), piperidine-2Haand-6Ha, and 3.16 (d+m, 3H, piperidine-2He, -4H, -6Ne), 4,10 (t, J= 6 Hz, 2H, O-CH2), to 6.67 (s, 1H, 8-H), 6,79 (d, J= 8.7 Hz, 1 H, 6-H), 7,10 (td, J= 8.4 and 2.1 Hz, 1 H, benzisoxazol-5H), 7,27 (dd, J= 8.4 and 2.1 Hz, 1H, benzisoxazol-7H), 7,79 (dd, J= 8.4 and 5.4 Hz, 1H, benzisoxazol-4H), of 7.97 (d, J= 8.7 Hz, 1H, -5H), 9,86 (s, 1H, 2-H).

Example 3: hydrochloride 7-[3-[4-(6-Formoso[d] isoxazol-3-yl) piperidine-1-yl] propoxy] -3-methoxymethyl-chromen-4-it.

A solution of 2 g (4.4 mmol) 7-[3-[4-(6-ferebant[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -3-(hydroxymethyl)-chromen-4-she's in 20 ml of 2 M HCl in methanol is heated under reflux for 2 hours the Solvent is evaporated, the residue is dissolved in dichloromethane and washed with saturated solution of CO3HNa. The organic phase is evaporated, the residue is dissolved in acetonitrile this obtain 0.75 g of the hydrochloride 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -3-methoxymethyl-chromen-4-it, the output is 34%, so pl. 219-221oC.

IR-spectrum (KBr): 1659, 1615, 1443, 1273, 1244 cm-1.

NMR-spectrum (Dl3CD3D): to 2.25 (m, 2H), 2,50 (m, 2H), 2,90 (m, 2H), 3,05 (m, 2H), 3,35 (m, 2H), 3,48 (s, 3H) of 3.60 (m, 1H), 3,80 (d, 2H), 4,20 (m, 2H), 4,39 (s, 2H), 6.90 to (d, 1H), 6,97 (d, 1H), 7,16 (td, 1H), 7,66 (dd, 1H), of 7.95 (s, 1H), 8,10 (d, 1H), to 8.20 (dd, 1H).

Example 4: 7-hydroxy-2-(hydroxymethyl)-chromen-4-one

3 g of sodium borohydride added in several portions to a suspension of 5 g (21 mmol) of ethyl 7-hydroxy-4-oxo-chroman-2-carboxylate and 5 g (45 mmol) of anhydrous calcium chloride in 100 ml of absolute ethanol, cooled to 0oC, and the mixture is stirred at room temperature for 16 hours Then add 1 g of sodium borohydride and stirred for further 2 hours, the Reaction mixture was suspended in 200 ml of water and slowly acidified with HCl. The precipitate is filtered off, washed with water and dried in vacuum, thus obtain 2.7 g of 7-hydroxy-2-(hydroxymethyl)-chromen-4-it is in the form of solid, yield 66%, so pl. 250-252oC.

IR-spectrum (KBr): 2700-3500, 1650, 1634, 1570, 1458, 1326, 1250, 1101 cm-1.

NMR spectrum (d6-DMSO): 3,50 (s, usher. , 2H, HE) and 4.40 (s, 2H, CH2HE, of 6.20 (s, 1H, 3-H), PC 6.82 (d, J= 2.4 Hz, 1H, 8-H), 6,92 (dd, J= 8.7 and 2.4 Hz, 1H, 6-H), 7,86 (d, J= 8,7, 1H, 5-H).

Example 5: 7-(3-chloropropoxy)-2-(hydroxymethyl)-chromen-4-one

A mixture of 6 g (31 monata of potassium in 100 ml of acetone and 25 ml of N, N-dimethylformamide is heated under reflux for 16 hours, the Reaction mixture was poured into 100 ml of water and extracted with 100 ml of ethyl acetate. The organic extracts are washed with two portions of 100 ml of water, dried over sodium sulfate and evaporated in vacuum. The resulting residue is suspended in 25 ml of ethyl ether, filtered and dried in a vacuum, you get to 4.2 g of 7-(3-chloropropoxy) -2- (hydroxymethyl) -chromen-4-it, the yield is 50%, so pl. 110-112oC.

IR-spectrum (KBr): 2600-3500, 1651, 1628, 1592, 1448, 1246, 1099 cm-1.

The NMR spectrum (CDCl3): 3,76 (t, J= 6 Hz, 2H, CH2C1), of 4.16 (t, J= 6 Hz, 2 H, O-CH2), 6,44 (s, 1H, 3-H), 6,78 (d, J= 2.1 Hz, 1H, 8-H), 6.90 to (dd, J= 8.7 and 2.1 Hz, 1H, 6-H), to 7.99 (d, J= 8.7 Hz, 1H, 5-H).

Example 6: hydrochloride 7-[3-[4-(6-toranzo[d] isoxazol-3-yl) piperidine-1-yl] propoxy] -2-(hydroxymethyl) chromen-4-it.

A mixture of 3 g (11 mmol) of the compound obtained according to example 5, 2,88 g (11 mmol) of the hydrochloride of 6-fluoro-3-(4-piperidinyl)-benzo[d] isoxazol, 2.16 g (26 mmol) of sodium bicarbonate and catalytic amounts of potassium iodide in 80 ml of acetonitrile is heated under reflux for 48 hours the Mixture is cooled, poured into 100 ml of water and extracted with 100 ml of chloroform. The chloroform layer is washed with water, dried over sodium sulfate and upari the[d] isoxazol-3-yl) piperidine-1-yl] propoxy] -2-(hydroxymethyl) -chromen-4-it, yield 40%.

NMR-spectrum (Dl3): of 2.0-2.2 (m, 8H), 3,10 (d+m, 3H), piperidine-2He-The 4H and 6He), of 4.13 (t,J = 6.6 Hz,2H,O-CH2-CH2-CH2), 6,41 (s, 1H, 3-H), 6.89 in (d, J= 2.1 Hz, 1H, 8-H) 6,94 (dd, J= 8.7 and 2.1 Hz, 1H, 6-H), 7,07 (td, J= 8.7 and 2.4 Hz, 1H, benzisoxazol-5H), 7,25 (dd, J= 8.7 and 2.4 Hz, 1 H, benzisoxazol-7H), 7,71 (dd, J= 8,7 and 5.1 Hz, 1H, benzisoxazol-4H), of 8.04 (d, J= 8.7 Hz, 1H, 5-H).

Hydrochloride: the Obtained product is dissolved in a mixture of chloroform: methanol (3: 1) and precipitated by adding the solution model HC1 in methanol, thus obtain 1.4 g of the hydrochloride 7-[3-[4-(6-toranzo [d] isoxazol-3-yl) piperidine-1-yl] propoxy] -2-(hydroxymethyl) -chromen-4-it is in the form of a solid substance, so pl. 248-251oC.

IR-spectrum (KBr): 3300, 2500, 1648, 1603, 1439, 1329, 1122, 1094 cm-1.

Example 7: 0.025% of the composition for injection

The composition of 1 ampoule

The compound according to example 3 0.5 mg

Methyl p-hydroxybenzoate - 1.0 mg

Propyl p-hydroxybenzoate - 0.1 mg

Bidistilled water to Bring up to 2.0 ml

Example 8: composition of 0.1% solution for oral administration

The composition per 100 ml

The compound according to example 3 to 100 mg

Methyl p-hydroxybenzoate - 135 mg

Propyl p-hydroxybenzoate 15 mg

Sorbitol 70% - 20 mg

Saccharin sodium 50 mg

Apelsin 1 mg of active connections

The composition of 1 tablet

The compound according to example 3 - 1.0 mg

Corn starch - 32.4 mg

Talc - 4.5 mg

Hydrogenated castor oil 1.5 mg

Lactose - To 150.0 mg

Example 10: composition of tablets containing 5 mg of active connections

The composition of 1 tablet

The compound according to example 3 - 5.0 mg

Corn starch - to 43.2 mg

Talc - 6.0 mg

Hydrogenated castor oil - 2,0 mg

Lactose - Up to 200.0 mg

Example 11: composition of tablets containing 10 mg of active connections

Composition the composition of 1 tablet

The compound according to example 3 10.0 mg

Corn starch - 40,0 mg

Sodium dodecyl sulfate - 0.50 mg

Corn starch (pre-gelatinizing) - 8,00 mg

Magnesium stearate - of 1.20 mg

Lactose - Up 240,00 mg

Example 12: composition of 1% topical cream

The composition of 100g

The compound according to example 3 and 1.0 g

Isopropyl myristate - 9.00 g

Cetosteatil alcohol - 6,00 g

Propylene glycol - 3.00 g

Polyglycolic ether fatty acids - 5,00 g

Decroly ester of oleic acid - 6,00 g

Flavor - 0,30 g

Methyl p-hydroxybenzoate - 0.15 g

About g

The specialist should be clear that the examples used as illustrations and should not limit the scope of the invention, involving various variants and modifications and is presented in the following claims.

1. Derivatives 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] chromen-4-it formula I

< / BR>
where R is hydrogen, Cho, CH2OR2or COOH;

R1means hydrogen or CH2IT;

R2means alkyl containing from 1 to 4 carbon atoms, provided that one of substituents R and R1is hydrogen,

and their pharmaceutically acceptable salts.

2. The compounds of formula I on p. 1, wherein R is Cho, CH2OR2or COOH and R1means hydrogen or R is hydrogen and R1means of CH2HE.

3. The compounds of formula I on p. 1, characterized in that these compounds and their pharmaceutically acceptable salt additive designed for use in the treatment of psychosis and schizophrenia.

4. The compounds of formula I under item 1 or 2, characterized in that they are intended for the preparation of pharmaceutical compositions for the treatment of psychosis and shiz the ditch, containing an effective amount of the compounds of formula I under item 1 or 2, or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

6. The method of inhibition of D2-, 5-HT2Aand H1receptors in the treatment of psychosis and schizophrenia by introducing an effective amount of the compounds of formula I under item 1 or 2, or its pharmaceutically acceptable salt additive.

7. Method of producing compounds of the formula I or their salts, namely, that involves the interaction of the intermediate compounds of formula II

< / BR>
where R and R1defined for formula I;

X is halogen, preferably chlorine or bromine,

intermediate compounds of formula III

< / BR>
to obtain the compounds of formula I with the further optional treatment of the corresponding acid to obtain their pharmaceutically acceptable salts.

 

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