Substituted in the ring of 2-amino-1,2,3,4-tetrahydronaphthalene or 3-aminopropane


C07C225/20 - having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton

 

(57) Abstract:

The invention provides a new intermediate compounds used to obtain substituted in the ring of 2-amino-1,2,3,4 of tetrahydronaphthalenes and 3-aminopropanol exhibiting binding activity against receptor 1A and serotonin. 2 C.p. f-crystals, 1 table.

In the past few years, it became apparent that the serotonin-(5-oxitriptan, abbreviated as 5-HT) released by presynaptic cells that are directly or indirectly linked to some near physiological phenomena, including appetite, memory, depression, thermoregulation, sleep, sexual behavior, fear, hallucinatory behavior (Glennon, R. A. J. Med. Chem. 30, 1 (1987).

It was established the existence of multiple types of 5-HT receptors. These receptors have been classified as 5-HT1-, 5-HT2and 5-HT3receptors, with the first of these receptors are further divided into subclasses 5-HT1A, 5-HT1B, 5-HT1Cand 5-HT1D.

It has been shown that some 2-amino-1,2,3,4-Tetra-gidronavtov (2 - aminotetraline) and 3-aminopropane have binding ability of 5-HT1A-receptor. The application for the European patent N 385658, published September 9, 1 is AMI, the sulfoxidov and sulfones. These compounds are also described as having the binding ability of 5-HT1A-receptor. Another class of 2-aminotetraline described in the application for the European patent N 343830, published on 29 November 1989, These compounds have piperazinyl or homopiperazine part of the molecule in the second position and in contrast to previous tetraline show inhibition of re-uptake of serotonin in contrast to the binding capacity of the receptor of serotonin. In the application for the European patent N 399982, published on November 28, 1990, describes 2-aminotetraline with other substituents in the 8-th position 5 - or 6-membered aryl which may contain one or two heteroatoms selected among nitrogen, oxygen or sulfur. In the international application under the patent cooperation Treaty N 090/15047, published December 13, 1990, describes 2-aminotetraline, substituted at any of positions 5, 6, 7 or 8, among others, Deputy Het. Het is described as a pentabasic heterocyclic ring containing nitrogen, carbon, and in some cases oxygen.

Currently opened class of compounds, which due to their exceptional 5-HT1Aactivity is very useful in the treatment of, for example, RAS is sabreena provides a new, intermediate, used to get substituted in the ring of 2-amino-1,2,3,4-tetrahydronaphthalenes and 3-aminopropanol with in the 8th position of tetrahydronaphthalene and in the 5th position chromane particular isoxazol-3-ilen, or isoxazol-5-ilen Deputy.

The compounds exhibit partially affinity and antagonism against 5-HT1A-receptor.

More specifically, this invention relates to compounds of the formula

< / BR>
in which R represents a C1-C4-alkyl;

R1C1-C4-alkyl;

X is-CH2- or-O-;

Q means

< / BR>
where each Rameans independently hydrogen, C1-C4alkyl or C1-4alkoxy.

In the above formulas, the term "C1-C4-alkyl" means a straight or branched alkyl chain having from one to four carbon atoms. Such C1-C4-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The compound of the invention is used to obtain compounds containing aromatic heterocyclic ring having the formula

< / BR>
Preferably the aromatic heterocyclic ring is unsubstituted what ucture replaced by any of the groups, selected from C1-C4-alkyl, C1-C4-alkoxy, C1-C4-thioalkyl, hydroxy, amino, cyano or phenyl.

Multiple substitution is included in the scope of the invention. So, both carbon atom can be substituted as described previously. However, preferably, if there is a substitution in the ring when the ring is one-deputizing.

The term "C1-C4-alkyl" has the meaning as defined previously.

The term "C1-C4-alkoxy" means any one of the group comprising methoxy substituents, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. The term "C1-C4-thioalkyl" means any of the methylthio, ethylthio, h-propylthio, isopropylthio, h-butylthio, isobutyric, verbality and tert-butylthiourea.

Although all of the compounds according to the invention is useful as an intermediate for producing compounds used for treatment of various disorders, because of their ability to modulate the function of 5-HT1A-receptor in mammals, however, some compounds are preferred.

Thus, R and R1preferably are both C1-C4-alkyl and more preferably OEM invention:

2 ethylamino-8-(1-oxo-3-(dimethylamino)-prop-2-enyl)-1,2,3,4 - tetrahydronaphthalen,

2-(di-n-propylamino)-8-(1-oxo-2-methoxy-3-(dimethylamino)-prop - 2-enyl)-1,2,3,4-tetrahydronaphthalen,

3-(DIN-propylamino)-5-(tert-butoxycarbonylmethyl)-chroman,

3-(di-n-propylamino)-5-(1-oxo-2-methyl-3-(dimethylamino)-prop-2 - enyl)-chroman etc.

Compounds according to the invention can be obtained by methods well-known experts in this field. Compounds in which X represents-CH2- can be synthesized using 8-bromo-2-tetralone. 8-Bromo-tetralone then subjected to reductive aminating the desired amine to give the desired intermediate compound 2-amino-8-brometalia. Intermediate 8-bromoadenosine then used in a variety of reactions to obtain the compounds according to the invention.

Compounds according to the invention, in which X represents oxygen, receive as described above, but using 5-substituted 3-chromanone. This molecule can be obtained by a sequence of reactions, starting with meta-Bromphenol. Briefly, meta Bromphenol treated with methyl-allyl in the presence of potassium carbonate to obtain a simple allyl-3-pomperaug ether. the rum Chloroacetic acid is converted to ethyl ester of 2-allyl-3-(carboxymethoxy)-bromine benzol. In the oxidation with ozone and subsequent treatment in the reducing conditions of the allyl group pay in Famil-methyl Deputy, which is then oxidized further by using Jones reagent in carboxymethyl Deputy, with the resulting product is the ethyl ester of (2-carboxymethyl-3-bromo)-phenoxyalkanoic acid. The carboxylic acid group of this compound atrificial tert-butyl acetate and concentrated sulfuric acid with obtaining the ethyl ester of 3-bromo-2-(Carbo-tert-butoxymethyl)-phenoxyalkanoic acid. In the presence of potassium tert - butylate complex fluids cyclized with the formation of 4-tert-butoxycarbonyl-5-bromo-3-chromanone. Under stirring at room temperature in the presence of acid, the latter is transformed into 5-bromo-3-chromanone.

Compounds according to the invention can be obtained a number of common reactions. The General scheme of the reactions below. Group Raand Rchave the following meanings:

Rarepresents hydrogen, C1-C4-alkyl; O(C1-C4-alkyl);

Rchydrogen or C1-C4-alkyl.

< / BR>
Compounds according to the invention have asymmetric carbon, to depict what dinani exists in the form of a separate d-and l-stereoisomers, and as a racemic mixture of such isomers.

Such optically active isomers can be obtained from their respective optically active precursors.

One particularly useful method for obtaining optically active isomers is carried out according to the invention through the 8-substituted-2-tetralone or 5-substituted-Z-chromanone. Any of these intermediate products can be reductive alkylated optically active-phenethylamine, after which the resulting mixture of diastereomers separated by a known method, such as chromatography. Banding a-fenetylline part of the molecule gives respectively substituted, optically active 2-amino-1,2,3,4-tetrahydronaphthalen or C-aminochrome. Conditions required to remove fenetylline part, relatively hard and can lead to violation of the integrity of the core molecules tetraline and Romana. It was found that the cleavage can be more easy and effective way that requires only mild conditions removal, if an individual used phenethylamine is para-nitro - a-phenethylamine.

The separation of para-nitro - a-fenetylline part of the molecules reach the recovery of para-nitro group to further sour PPI can be achieved by numerous reducing agents, including, for example, titanium trichloride, alumoweld lithium or a mixture of the zinc-acetic acid, or by catalytic hydrogenation. Solvolytic cleavage occurs when hydrochloric salt (or other monobasic salt) product recovery are processed with water or alcohol at room temperature or in some cases at elevated temperatures. Particularly suitable condition for removal of para-nitro - a-fenetylline part is the hydrogenation of monochloride amine in methanol over platinum catalyst.

As mentioned above, the compounds are useful as intermediates for producing compounds according to the invention, are the corresponding 8-brometalia. It was found that 8-bromoaniline in its optically active form, it is impossible to obtain using traditional methodology, while they can be obtained using the method described above, with the use of para-nitro-phenethylamine.

Compounds employed as initial starting materials in the synthesis of compounds according to the invention are widely known and easily synthesized by standard methods, typically used by experts in this field.

A solution of n-utility (1.6 M in hexane, 15,1 ml and 24.2 mmole) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (5.0 g, 16,1 mmole) in tetrahydrofuran (50 ml) at -78oC, and the reaction mixture was stirred at -78oC 1 h After the reaction mixture was barbotirovany gaseous carbon dioxide at -78oC until the disappearance of the resulting dark purple coloring. Was added methyl lithium (1.4 M in ether, 23 ml). The reaction mixture was stirred at -78oC for 30 min and warmed up to room temperature. The reaction was stirred an additional 10 min at room temperature, and during this time I lost a pink coloration. Added an additional 10 ml metallice, and the reaction mixture was again acquired a pink color. After 15 min the pink color disappeared and added an additional 10 ml metallicy. The reaction mixture was poured on ice, acidified with hydrochloric acid and was extracted with ether. The aqueous layer was podslushivaet and was extracted with methylene chloride. The basic extracts were dried (sodium sulfate), concentrated and obtained 3.8 g of product. Purification flashamature on silica gel with Mino-8-acetyl-1,2,3,4-tetrahydronaphthalen in the form of a yellow oil (2.7 g, 61%).

Example 2. Getting 2-di-n-propylamino-8-(tert-butoxycarbonyl-acetyl)- 1,2,3,4-tetrahydronaphthalene.

To a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydro-naphthalene (1.0 g, up 3.22 mmole) in tetrahydrofuran (50 ml) at -78oC solution was added n-utility in hexane (1.1 M, 4.4 ml, 1.5 equivalents). The reaction mixture was stirred at -78oC 1 h after the reaction mixture was barbotirovany gaseous carbon dioxide. The resulting mixture was heated to room temperature. After removal of volatile components from the reaction mixture brown oil was poured into water and washed with ether. The organic phase was decanted, and the aqueous layer was concentrated and dissolved in methanol. After the solution was passed gaseous hydrogen chloride and the reaction mixture was heated under reflux for 3 hours After cooling, the reaction mixture was poured into water (50 ml), was podslushivaet using acidic sodium carbonate (aqueous) and extracted with ether. The ether extract was dried over magnesium sulfate, concentrated and received 1.0 g of black oil. Purification flashamature through the column, elwira a mixture of hexane-ethyl acetate in the ratio of 4:1, received 440 mg of 2-di-n-propylamino-8-(methoxycarbonyl)-1,2,3,4-tetrahydronaphtyl the 8oC. the LDA solution was heated to -20oC for 30 min and again cooled to -78oC before the addition of 2.83 ml (20,96 mmol) tert-butyl acetate. After 10 passages were added 440 mg (1,47 mmole) of 2-di-n-propylamino-8-methoxycarbonyl - 1,2,3,4-tetrahydronaphthalene in 20 ml of dry tetrahydrofuran. The reaction mixture was heated to room temperature and was stirred for three days.

The resulting mixture was poured into water (50 ml) and was extracted with dichloromethane (three times 50 ml). The extract was dried (magnesium sulfate), concentrated and received 1.8 g of oil. Cleaning thin-layer column chromatography with elution 10% methanol in dichloromethane gave 160 mg of 2-di propylamino-8-(tert-butoxycarbonylmethyl)-1,2,3,4 - tetrahydronaphthalen in the form of a yellow oil.

Example 3. Obtaining a salt of maleic acid, 2-di-n-cuts-but-8-(isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene.

A solution of 2-di-n-propylamino-8-acetyl-1,2,3,4-tetrahydronaphthalene (0.3 g, 1.1 mmole), obtained as described in example 1, and Tris-(dimethylamino)-methane (0.32 g, 2.2 mmole) in toluene was heated under reflux 5 h and at a temperature of 60oC for 18 h was Added an additional aliquot quantity of Tris-(dimethylamino)-methane (0.16 g, 1.1 mmole) and the reaction mixture p-8-[1-oxo-3- (dimethylamino)-prop-2-enyl] -1,2,3,4-tetrahydronaphthalen (0.39 g) as a viscous orange oil.

Hydroxylamine hydrochloride (0.32 g, 4.6 mmole) was added to a solution of 2-di-n-propylamino-8-[1-oxo-3-(dimethylamino)-prop-2-enyl]- 1,2,3,4-tetrahydronaphthalene (0.75 g, to 2.29 mmole) in acetic acid (5 ml) and the reaction mixture was stirred at room temperature. The reaction mixture was concentrated and the residue was dissolved in water. The solution was made basic by addition of concentrated ammonium chloride solution and was extracted with ether. The extract was washed with brine, dried with sodium sulfate, concentrated and received a viscous pale-orange oil. Formed salt of maleic acid. Crystallization from a mixture of ethanol-ether was obtained target compound indicated in the title of example, in the form of off-white crystals (0.24 g), melting point of 136-138oC. Recrystallization of this salt from ethanol was obtained colorless crystals (155 mg), melting point 139-141oC.

Elemental analysis:

Calculated C 66,65, H 7,29, N 6,76

Found, C 66,86; H 7,33; N 6,79.

Example 4. 2-di-n-propylamino-8-(5-gidroksiapatita-Z-yl)-1,2,3,4 - tetrahydronaphthalen.

2-di-n-propylamino-8-(Trat-butoxycarbonylmethyl)-1,2,3,4 - tetrahydronaphthalen (obtained as described in example 2), (1.0 g, 3.3 mmole) was dissolved in 25 ml of methanol. It is time to relax a temperature of 48 hours The solution was filtered to remove unused hydroxylamine hydrochloride. The mixture was concentrated and three times recrystallized from methanol-ethyl acetate. Allocated 30 mg of target compound.

Analysis mass spectroscopy (RD) showed sophisticated mass 314.

Example 5. Obtaining a salt of maleic acid, 2-di-n-propylamino-8- (4-methylisoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene.

A) Obtaining 2-di-n-propylamino-8-propionyl 1,2,3,4-tetrahydronaphthalene.

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (8.5 g, a 27.4 mmole) was dissolved in 80 ml of tetrahydrofuran and cooled to -78oC, after which was added 25.7 mm n-utility (1.6 M in hexane). The mixture was stirred at -78oC for one hour, after which was added 2.4 ml (32,9 mmole) propionamide guide. The mixture was heated to room temperature, then poured into water and was extracted with methylene chloride. The extract was dried over sodium sulfate, evaporated and got to 9.1 g of yellow oil.

The oil was introduced into a column with silica gel and was suirable a mixture of 3% methanol in methylene chloride containing a trace of ammonium hydroxide. The desired fractions were combined and obtained 6.5 g (82%) of 2-di-n-propylamino-8-(1-oksipropil)-1,2,3,4-tetrahydronaphthalene in the 17.0 g (78,7 mmole) Harrogate pyridinium with molecular sieves and the Mixture was stirred 3 h at room temperature, after which was added 250 ml of ether and celite. The mixture was put into a short column of silica gel and was suirable ether. Added methanol to dissolve the brown sludge, which knocked out by adding ether to the reaction mixture. This material was injected into the column and was suirable 10% methanol in methylene chloride. Eluent was concentrated and received a brown oil which was further purified column chromatography, using as solvent a mixture of hexane-ether in the ratio 2:1, then clean the air. The fractions containing the product were combined, concentrated and obtained 4.7 g of 2-di-n-propylamino-8 - propionyl 1,2,3,4-tetrahydronaphthalene.

B) Formation of ring 4-methyl-isoxazol-5-yl.

2-Di-N-propylamino-8-propionyl 1,2,3,4-tetrahydronaphthalen (1.5 g, 5.2 mmole) was dissolved in 50 ml of toluene and was added 2.2 ml of Tris-(dimethylamino)- methane. The mixture was heated at 80oC, leaving for the night. The mixture is then evaporated and the residue was dissolved in acetic acid. Added hydroxylamine hydrochloride (730 mg, of 10.4 mmole) and the mixture was left overnight with stirring at room temperature. The mixture was poured into water, have established pH 11 with ammonium hydroxide and the resulting mixture was extracted with methylene chloride. The extract was dried listed with a mixture of hexane-ether in the ratio 2: 1, when this ether contained traces of ammonium hydroxide. Appropriate fractions were combined and received 1.0 g (61,3%) of free base of the target compound.

50 mg of the free base into a salt of maleic acid, recrystallized from a mixture of ethanol-ether and obtained 55 mg of white crystals, melting point 118oC.

Elemental analysis for C24H32N2O5.

Calculated C 67,27; H 7,53; N 6,54

Found, C 66,99; H 7,60; N 6,35.

Example 6. Getting 2-di-n-propylamino-8-(4-utilization-5-yl)- 1,2,3,4-tetrahydronaphthalene.

A) Obtaining 2-di-n-propylamino-8 butyryl-1,2,3,4-tetrahydronaphthalene.

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (5.0 g, 16,1 mmole) was dissolved in 50 ml of tetrahydrofuran and the mixture was cooled to -78oC, then added to 21.0 ml of n-utility (0.92 M in hexane). The mixture was stirred 30 min and added to 1.85 ml (21,0 mmol) butyric aldehyde. The mixture was heated to room temperature and left overnight under stirring, after which it was poured into water and was extracted with methylene chloride. The extract was dried over sodium sulfate, evaporated and obtained 6.4 g of residue. The residue was introduced into a column of silica gel and was suirable a mixture of 2% metanode-n-propyl-amino-8-(1'-hydroxybutyl) -1,2,3,4-tetrahydronaphthalene in the form of a viscous oil.

Oil (4.0 g, 13.2 mmole) was dissolved in 200 ml of methylene chloride was added molecular sieves (30 g). The mixture was stirred and added 10.0 g (46,2 mmole) Harrogate pyridinium; the stirring was continued for 3 h at room temperature, after which the mixture was poured in a layer of silica gel and consistently suirable ether and 3% methanol in methylene chloride containing a trace of ammonium hydroxide, and provided the product as a brown oil.

The oil was placed in a column of silica gel and was suirable a mixture of 3% methanol in methylene chloride containing a trace of ammonium hydroxide. Appropriate fractions were combined and received the oil, which, being dissolved in ether, caused the formation of a brown precipitate. The precipitate was removed by filtration, the filtrate evaporated and obtained 3.0 g of 2-di-n-propylamino-8-Buti-RIL-1,2,3,4-tetrahydronaphthalene in the form of a light brown oil.

B) Formation of ring 4-ethyl-isoxazol-5-yl.

Tert-butyl sodium (0,82 g, 7.3 mmole) suspended in 100 ml of tetrahydrofuran. To the mixture was added ethyl ester of formic acid (1.0 g, 13.3 mmole) and 2-di-n-cuts-but-8-butyryl-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.3 mmole). The resulting mixture was left overnight under stirring at room temperature is possible solids. The resulting mixture having a pH of 6.0, was stirred at room temperature for 20 h, after which it was poured into water and was set to pH 12 with ammonium hydroxide. Then the mixture was extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated. The residue was dissolved in 100 ml of toluene was added 100 mg of para-toluenesulfonic acid. Then the mixture was heated under reflux for 1.5 h then poured into water and was extracted with methylene chloride. Extract methylene chloride was dried over sodium sulfate and evaporated.

The residue was introduced into a column with silica gel and was suirable a mixture of hexane-ether in the ratio 2:1, and the ether contained traces of ammonium hydroxide. The appropriate fractions were collected and obtained 0.9 g of target compound indicated in the title of the example. Mass spectrum (FD): 327 (100).

Example 7. Obtaining a salt of maleic acid 2-DIN-Propylamine-8- (3-marked isoxazol-5-yl)-1,2,3,4-tetrahydronaphthalene.

Tert-butyl potassium (450 mg, 4.0 mmole) suspended in tetrahydrofuran was added 0.7 ml (7.3 mmole ethyl acetate and 0.5 g (1.8 mmole) of 2-di-n-propylamino-8-acetyl-1,2, 3,4-tetrahydronaphthalene (obtained as described in example 5) in tetrahydrofuran. The total number of used tetrahydrofuran SOS is 640 mg (9.2 mmole) of hydroxylamine hydrochloride. Then the reaction mixture was stirred at room temperature for 64 hours the Mixture was poured into water and was set to pH 12 with ammonium hydroxide. Then the mixture was extracted with a mixture of chloroform and isopropyl alcohol in the ratio of 3:1. The extract was dried over sodium sulfate, evaporated and received 450 mg of a solid product. The solid was dissolved in toluene, was added a small amount of para-toluenesulfonic acid and the mixture was heated under reflux for 2 hours Then the mixture was poured into water, have established pH 12 with ammonium hydroxide and the mixture was extracted with methylene chloride. Extract methylene chloride was dried over sodium sulfate, evaporated and received 390 mg of a brown oil.

Oil was injected into the column with silica and suirable a mixture of 2% methanol in methylene chloride containing a trace of ammonium hydroxide. The desired fractions were collected and received 210 mg (35% of the free base of a compound indicated in the title example}

The compound was converted to the salt of maleic acid, which was recrystallized from a mixture of ethanol and ether and received 200 mg of target compound, melting point output reached 125.5-127,5oC. Mass spectrum (FD): 313 (100).

Calculated C 67,27; H 7,53; N 6,54

Elemental analysis for C24Hamino-8-(4-method kiitokset-5-yl)-1,2,3,4-tetrahydronaphthalene.

2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (5.0 g, 16,1 mmole) was dissolved in 25 ml of tetrahydrofuran and cooled to -78oC, and then added 3,22 ml n-utility (1 M in hexane). The mixture was stirred at -78oC an hour and a half. The resulting solution was transferred via cannula into a solution of methyl ester methoxybutanol acid (7.5 ml, 160 mmol) in tetrahydrofuran at -78oC. the Reaction mixture was left under stirring at room temperature overnight, then poured into a solution of acid sodium carbonate and was extracted with chloroform. The extract was dried (sodium sulfate), concentrated and obtained 6.3 g of the crude product.

Then the material was placed in a column for chromatography and suirable using 4% methanol in methylene chloride containing a trace of ammonium hydroxide. Appropriate fractions were combined and obtained 1.4 g of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene.

A solution of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene (1.0 g) and Tris-(dimethylamino)-methane (1.5 ml) in toluene (25 ml) was heated under reflux for 1.5 hours the Reaction mixture was concentrated and obtained crude 2-di-n-propylamino-8-(1-oxo-2-methoxy-3- (dimethylamino)-prop-2-enyl)-1,2,3,4-tet is,3,4-tetrahydronaphthalene (1.1 g) in methanol was added hydroxylamine hydrochloride (1.2 g) and the reaction mixture was left overnight under stirring at room temperature. The reaction mixture was concentrated and the residue was dissolved in toluene. Added a para-toluensulfonate (660 mg) to the resulting solution and the reaction mixture was heated under reflux for 2 hours the Reaction mixture was concentrated, and the residue was dissolved in a mixture of water and methylene chloride. This mixture was poured into sodium bicarbonate solution and the resulting mixture was extracted with methylene chloride. The extract was dried with magnesium sulfate, concentrated and the obtained oil (600 mg). Purification by thin-layer chromatography, using as solvent a mixture of ether-hexane in the ratio of 1: 1 was obtained 160 mg of the free base of the target compound indicated in the title of the example. Salt of hydrochloric acid were then obtained. Recrystallization from methanol-ether gave the target compound as white crystals (86 mg). So pl. 178oC.

Calculated C 58,68; H 7,14 N 6,84

Found, C 58,88; H Of 7.23; N 6,60.

Example 9. Getting C-di-n-propylamino-5-(isoxazol-5-yl)chroman.

A) Obtaining C-di-n-propylamino-5-brahaman

A solution of Z-keto-5-brahaman (45 mmol, 10,33 g), dipropylamine (90 mmol, 9.0 g) and p-toluensulfonate acid (4.5 mmole, 850 g) in 200 ml of toluene is heated to boiling with reverse kolodzie remove the trap by Dean stark and concentrate the reaction solution, getting a brown oil.

This oil is dissolved in tetrahydrofuran, and then add to 3.38 g (54 mmole) of laborgerate sodium. Then the reaction solution bubbled with gaseous hydrogen chloride with such speed, that the solution temperature did not exceed 45oC. When the color of the reaction solution begins to brighten, the addition of hydrogen chloride ceased. After this solution was stirred at room temperature for 2 days.

After 2 days, the reaction solution is alkalinized using sodium hydroxide solution, and then the alkaline solution is extracted with methylene chloride. The extract is dried over sodium sulfate and then concentrated in vacuo, obtaining an orange oil. This oil is dissolved in a solution consisting of 200 ml of tetrahydrofuran and 45 ml of triethylamine. The resulting solution was heated to boiling under reflux, maintaining this temperature for 30 min, cooled to room temperature and then stirred at room temperature for 3 days. After 3 days the reaction mixture was filtered through basic alumina, and the filtrate was concentrated in vacuo, receiving and 15.3 g of orange oil. This oil is cleaned by a chromatography method with mgnovennogo above in connection name.

B) Obtaining 3-di-n-propylamino-5-(1-oxetan)chromane.

To a cold (-78oC) to a solution of 4.95 g (15.9 mmole) obtained above compound in 200 ml of tetrahydrofuran, add and 15.3 ml (to 20.6 mmole) of 1.35 M solution of n-utility in hexane, the resulting solution was stirred at -78oC for 20 min, and then added 1.4 g (of 31.8 mmole) of acetaldehyde. The resulting solution was stirred at -78oC for 30 min, warmed to room temperature and then stirred at room temperature for another 30 minutes after this time the reaction solution was poured into water and the resulting aqueous solution is extracted with a solution of the following composition: isopropanol/chloroform 1:3. The extract is dried over sodium sulfate and then concentrated in vacuo, receiving a yellow oil. This oil is cleaned by a chromatography method with instant evaporation, using as eluent a mixture of 1:1 diethyl ether/hexane (NH4OH and obtaining 4.1 g of the above in the title compound as a pale yellow oil.

C) Obtaining C-di-n-propylamino-5-acetylproline

To a solution of 4.1 g (of 14.8 mmole) obtained above in connection 120 ml of acetone, add 40 ml of 2M solution of sulfuric acid and 5 ml of Jones reagent (Jones Reagent), Jones reagent, and the solution swor left to stir at room temperature for 1 h After 1 h the reaction is quenched by adding isopropanol, and alkalinized reaction solution using sodium hydroxide solution. This alkaline solution is extracted with a solution of the following composition: isopropanol/chloroform 1:3. The extract is dried over sodium sulfate and concentrated in vacuo, getting to 7.32 g of yellow oil. This oil is cleaned by a chromatography method with instant evaporation, using as eluent a mixture of 1:3 diethyl ether/hexane (NH4OH), and receiving of 3.48 g of the above in the title compound as a pale yellow oil.

D) Obtaining 3-di-n-propylamino-5-(isoxazol-5-yl)chroman-hydrobromide.

A solution of 500 mg (1,81 mmole) obtained above compounds and 540 mg (5,43 mmole) of Tris(dimethylamino) methane in 20 ml of toluene is heated to boiling under reflux and stirred at this temperature for 2 h After 2 h the reaction solution was diluted with diluted sodium hydroxide solution and then extracted with a solution of the following composition: isopropanol/chloroform 1: 3. The obtained extract is dried over sodium sulfate and then concentrated in vacuo, receiving a dark yellow oil.

This oil is dissolved in 10 ml of acetic acid and added 480 mg solid gidroxinimesoulid the p was concentrated in vacuo, getting 543 mg orange oil. This oil is cleaned by a chromatography method with instant evaporation, using as eluent a mixture of 1:1 diethyl ether/hexane (NH4OH and getting 482 mg of colorless oil.

This oil is dissolved in diethyl ether and the resulting solution was treated with Hydrobromic acid, getting white sticky precipitate. The precipitate is recovered and recrystallized from a mixture of ethyl acetate/hexane, getting 460 mg specified in the title of a white solid. So pl. 171-173oC. MS(FD): 300(100), 301(15)

Calculated C 56,70; H is 6.61; N 7,35

Found, C 56,71; H 6,56; N 7,54.

As noted above, compounds derived from intermediate compounds according to the invention have a binding receptor 5-HT1Aability.

It has been shown that various physiological functions are subject to the effects of serotonergic nervous system of the brain.

As such compounds, obtained from the intermediate according to the invention, able to heal in mammals different States and disorders arising from the mediation of 5-HT receptors, such as sexual disorders, hypertension, appetite disorders, depression, alcoholism, pain, senile with the s treatment of the aforementioned disorders in the above doses for exposure to receptors 5-oxitriptan in mammals.

Was conducted the following experiment shows the ability of the compounds according to the invention to bind receptors 1A-serotonin. Areas specifically marked, labeled with tritium 8-hydroxy-2 - dipropylamino-1,2,3,4-tetrahydronaphthalene (3H-8-OH-DRATHA), were identified as receptors 5-HT1A. This General procedure is presented Wongetal J. Neural. Transm. 71:207-218 (1988).

Male rats Sprague-Dawley (weight 110-150 g) from Harlan Industries (Cumberland, JN) were fed Purina Chow on the needs of the last three days before being used in the research. Rats were killed by decapitation. The brain was rapidly removed and dissected in the cerebral cortex at 4oC.

Brain tissue is homogenized in of 0.32 M sucrose. After centrifugation at 1000g for 10 min and then at 17000g for 20 min was deposited crude synaptosomal fraction. Sediment suspended in 100 volumes of 50 mm Tris-HCl, pH of 7.4, incubated at 37oC for 10 min and centrifuged at 50000g for 10 minutes, the Process was repeated and the final precipitate suspended in ice 50-Molina buffer Tris-HCl with a pH of 7.4.

The binding of labeled tritium-8-hydroxy-2-dipropylamino-1,2,3,4 - tetrahydronaphthalene was carried out by previously described method (Wond et al. J. Neural. Transm. 64: 251-269 the e 10 min in 2 ml of 50 mmol Tris-HCl at a pH of 7.4, 10 mmol of pargyline, 0.6 mmole of ascorbic acid, 5 mmol of calcium chloride, 2-on-namosh labeled with tritium 8-hydroxy-2-dipropylamino-1,2,3,4 - tetrahydronaphthalene and 0.1-1000 nolah test connection. The binding was finished by filtering the samples at reduced pressure through a glass fiber filter (CFB). The filters twice washed with 5 ml ice buffer and placed in scintillation vessels with 10 ml of scintillation fluid PCS (Amesham/Searle). Radioactivity was measured by liquid scintillation spectrometer. In some samples also included its tritium-8-hydroxy-2-di-propyl-amino-1,2,3,4-tetrahydronaphthalen at a concentration of 10 micromol to obtain nonspecific binding. Specific binding of labeled tritium-8-hydroxy-2-dipropylamino-1,2, 3,4-tetrahydronaphthalene was defined as the difference between the radioactivity bound in the absence and in the presence of 10 micromol unlabeled 8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene.

Compounds according to the invention were tested on their effect in vivo at levels 5-oxindoles acid (5-HIAA) in the brain and levels of serum corticosterone. Male rats Sprague-Dawley, weighing 150-200 g, were administered subcutaneously or orally with aqueous solutions of the test Ali to clot and then centrifuged to separate the serum. The concentration of corticosterone in the serum was determined spectrofluorometrically method Salama (Solem, J. H. Brinek-Johnsen, T. Scand. J. Clin. Inwesr. (Suppl. 80), 17,1, (]965).

Whole brain decapitated rats were rapidly removed, frozen on dry ice and kept at -15oC. concentration of 5-oxindoles acid (5-HIAA) were measured by liquid chromatography with electrochemical registration, as described Fuller, R. W. Snoddy, H. D. Perry, K. W., Life Sci. 40, 1021 (1987).

The results of tests of various compounds according to the invention are presented in the table. In the table the first column represents the number of examples of the test compounds, in the second column presents the number of test compounds are expressed in nanomolar concentration required for inhibition of binding of labeled tritium-8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene 50% expressed as inhibiting 50% concentration (IN50), in the third column presents the minimum effective dose (MED) test compounds introduced subcutaneously, to lower levels of 5-HIAA in the brain and the fourth column presents the minimum effective dose of the test compound, is introduced subcutaneously, need to increase levels kortiko-sterone seven in the ring of 2-amino-1,2,3,4-tetrahydronaphthalene or 3-aminopropane General formula

< / BR>
where R1-4alkyl; R1- C1-4alkyl;

X CH2- or-O-;

Q is

< / BR>
each Raindependently hydrogen, C1-4alkyl or C1-4alkoxy.

2. Connection on p. 1, in which Rapredstavljaet hydrogen.

3. Connection on p. 2, which is a 2-di-n-propylamino-8-[1-oxo-3-(dimethylamino)-prop-2-enyl]-1,2,3,4-tetrahydronaphthalen.

 

Same patents:

The invention relates to new chemical compounds with valuable properties, in particular to piperidinylmethyl derived chromane General formula (I)

< / BR>
where A is hydrogen or lower alkoxy,

E is hydrogen, hydroxyl, phenyl or piperidyl,

G phenyl not substituted or substituted with halogen and/or trifluoromethyl, fenoxaprop substituted by trifluoromethyl, benzyl, substituted phenylcarbinol, aminocarbonyl,

provided that E does not mean hydrogen or hydroxide, when G is phenyl, and their salts with inorganic acids

The invention relates to new derivatives chromane with activity open To ion channels

)6-cyano-3,4-dihydro-2,2 - dimethyl-trans - 4-(2-oxo-1-pyrrolidinyl) -2h-1-benzopyran-3-ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining derived benzopyran representing () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-pyrrolidinyl)-2H - 1-benzopyran-3-ol of the formula VI

known as Cromakalim (DRL 34 915)

The invention relates to new derivatives of benzopyran that have protivogipertenzin activity and can be used in the treatment and prevention of cardiovascular diseases

) 6-cyano-3,4-dihydro-2,2 - dimethyl - trans-4- (2 - hydroxy-1 - pyrrolidinyl) -2h-1 - benzopyran-3 - ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo - 1-1-pyrrolidinyl)-2H-1-benzopyran-3-ol formula

(I) known as Cromakalim

The invention relates to new 8-carbonylation 2-aminotetraline, their enantiomers and salts, processes for their preparation, pharmaceutical preparations on their basis and use of such compounds in therapy

FIELD: pharmacology.

SUBSTANCE: invention relates to new arylcycloalkylamines of the general formula

. In the general formula (I), R1, R2 are H, linear or branched alkyl (C1-C4), linear or branched alkoxy (C1-C4), halogen; Y is -CH2-O-CH2-, - (CH2)n-, where n: 1-3; X is -CO-NH-(CH2)6-, -CO-(CH2)k-, -CH2-NH-(CH2)6-, -CH(CH3)-NH-(CH2)6-, -(CO)p-(CHR5)m, where p, m-: 0, 1, k: 2, 4-7, R5: H, linear alkyl C1-C5; R3, R4 are H, linear alkyl C1-C4, -CH2-C≡CH, -(CH2)2-O-(CH2)2-NH2, cyclopropyl, cyclopropylmethyl; 4-pyridinyl, an amino acid residue of a proteinogenic acyclic or aromatic α-amino acids, γ-aminobutyric acid, ε-aminocaproic acid, β-alanine; -CHR6-CH2-OR7, where R6: H or a linear or branched alkyl C1-C4, benzyl, R7: H, linear alkyl C1-C4, or R3, R4 together with the nitrogen to which they are attached, form a pyrrolidine, 2-(hydroxymethyl) pyrolidine, 4-aminopyridinium ring; G is (C1-C4) carboxylic acid, methanesulfonic acid or a mineral acid or water. As an acyclic or aromatic α-amino acid residue, they contain a proteinogenic α-amino acid residue. As (C1-C4) carboxylic acid, they contain at least one compound from the group consisting of acetic, fumaric, succinic, tartaric, malic and maleic acids. As a mineral acid, they contain at least one compound from the group consisting of hydrochloric, phosphoric, sulfuric acids. The preferred compounds are arylcycloalkylamine derivatives of the general formula , wherein Y: -CH2-O-CH2-, -(CH2)2-. The invention also relates to a pharmaceutical composition which can be a combination of arylcycloalkylamine derivatives and at least one substance from the group comprising levodopa, palmitoyle ethanolamide, N-(2-aminoethyl) palmitamide hydrochloride, rasagiline, risperidone, toloxaton, quetiapine, gamma-aminobutyric acid, sodium valproate, amitriptyline, clomepramine, fluoxetine, paroxetine, sertraline, phenylephrine, dexamethasone, prednisolone. The composition may be in the form of a tablet, capsule, pellet, powder for preparation of a solution for enteral administration, a solution for parenteral administration, a powder for preparation of a solution for parenteral administration.

EFFECT: neuroprotective, analgesic and antidepressant action.

11 cl, 13 tbl, 96 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tocopherol, tocotrienol and other derivatives of chroman of the general formula (1): wherein X is taken among the group comprising oxygen and nitrogen atoms; Y is taken among the group comprising oxygen, nitrogen and sulfur atoms wherein if Y represents oxygen or nitrogen atom then n = 1 and if Y represents sulfur atom then n = 0; R1 represents residue of carboxylic acid, carboxamide, ester, alcohol, amine or sulfate; R2 represents methyl; R3 represents methyl; R4 represents methyl; R5 is taken among the group comprising alkyl, alkenyl, alkynyl, carboxyl and ester residue wherein if Y represents nitrogen atom then indicated nitrogen atom is replaced with group R6 wherein R6 represents hydrogen atom or methyl wherein if X represents oxygen atom, Y represents oxygen atom and R5 represents phytyl then R1 doesn't mean butanoic acid. Also, invention relates to a pharmaceutical composition based on these compounds, a method for treatment of cellular-proliferative disease and a method for induction of cells apoptosis. Invention provides preparing new compounds possessing the proliferative effect.

EFFECT: valuable medicinal properties of compounds.

36 cl, 4 tbl, 19 dwg, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the given invention, there is offered a method for preparing a compound of formula , where Y is specified of CH3, CH2OH, CH2CH2OH, CH2Br and Br; involving the stages: (1) reaction of the compound of formula where OX represents hydroxy or O-M+ where M+ represents cation chosen of Li+, Na+ and K+ and Y is such as specified above; with trans-cynnamaldehyde , with a secondary amine compound added; then (2) acid treatment of a product from the previous stage to prepare a compound of formula (I). The aforesaid method can be used for preparing tolterodine and fezoterodine which are effective in treating the hyperactive urinary bladder. There are also declared compounds of formulae V, VI and VII.

EFFECT: development of the effective method for preparing the compound.

25 cl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing methyl 1 -[3-(cyclohexylcarbamoyl)-2-oxochroman-4-yl]cyclopentanecarboxylate of formula (1) which consists in boiling 1-bromcyclopentanecarboxylic acid methyl ester with zinc and 2-oxo-2H-chromen-3-carboxylic acid cyclohexylamide in the medium of benzol - ethylacetate - hexamethylphosphorotriamide (10:5:1) for 4 hours.

EFFECT: produced compound is novel and possesses analgesic action.

1 tbl, 2 ex

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