Substituted 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:

Usage: as a selective agonist relative to the 5-ht1a-receptor. The inventive product-substituted 2-amino-1,2,3,4-tetrahydronaphthalene or 3-aminopropane f-ly 1, where R and R2-(C1-C4)alkyl, (C3-C4)alkenyl; X-CH2O; A-C(O) CH(OH; R2-(C1-C6) alkyl or phenyl, optionally substituted by halogen or alkoxy; cyclo(C3-C7) alkyl. Reagent 1: compound f-ly 1, where R2A=Br. Reagent 2: R2COZ, where Z-Hal, H, OH, and other reaction Conditions: in the presence of n-utility with subsequent oxidation.

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2 S. p. f-crystals, 1 table.

With neurotransmitters-serotonin (5-hydroxytryptamine and 5-HT)is associated directly or indirectly a number of physiological phenomena, including appetite, memory, thermoregulation, sleep, sexual behavior, depression, anxiety, and hallucinations (Glennon, R. A. J. Med. Chem. , 1 (1987)).

There are many types of 5-HT receptors, which are divided into 5-HT1-, 5-HT2and 5-HT3receptors, and the first type is further divided into subclasses 5-HT1A, 5-HT1B; 5-HT1Cand 5-HT1D.

Some 2-amino-1,2,3,4-tetrahydronaphthalene (2-aminotetraline) and 3-aminka the e in the 8-position to the formyl, the cyano, halogen, hydroxymethyl, carboxamido group, carboxyl or alkoxycarbonyl. These compounds are described as having high affinity to 5-HT1A-receptor, 2-aminotetraline, bearing in position 8 Deputy-formyl (among other substituents). In addition, other known 2-aminotetraline substituted in the 8-position and 3-aminopropane substituted in 5-position, where the substituents are sulfides, sulfoxidov and sulfones. These compounds, as described, also have affinity to 5-HT1Athe receptor.

Know of any other class 2-aminotetraline. The described connections are in the 2-position of the rest of the piperazinil or homopiperazine, differ from those of tetraline, do not show affinity for serotonin receptors, but, on the contrary, tend to re-capture of a serotonin. Opened an additional class of compounds, which due to their agonistic activity towards 5-HT1Areceptors, useful in the treatment of, for example, sexual dysfunction, anxiety, depression, disorders of consciousness, vomiting, misuse of drugs, high blood pressure, excessive secretion of acid, eating disorders such as anorexia and forced obsessive behaviour is necromany, being selective agonists relative to 5-HT1Athe receptor.

The aim of the invention is a compound of the formula

(I) where R1-C4-alkyl or alkenyl3-4;

R1alkyl WITH1-4or alkenyl3-4;

X-CH2- or-0-;

R2alkyl WITH1-C6, alkyl WITH1-C6,

substituted by halogen or alkoxy WITH1-C4phenyl, phenyl substituted by halogen or alkoxy WITH1-C4phenyl (C1-C4) alkyl, or cycloalkyl3-C7;

and pharmaceutically acceptable salts joining with acids.

In the above formulas, the term alkyl WITH1-C4denotes a straight or branched alkyl chain comprising from one to four carbon atoms. Such alkyl groups WITH1-C4represent methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The term alkoxy-group1-C4means any of the groups: methoxy, n-propoxy; isopropoxy; n-butoxy; isobutoxy-, tert-butoxy - and second-butoxy.

The term cycloalkyl3-C7denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptylamine to the alkyl group WITH1-C4. Examples of such groups are benzyl, phenylethyl, -methylbenzyl, 3-phenylpropyl-naphthylmethyl-naphthylmethyl, 4-phenylbutyl etc.

The term of alkenyl2-C4denotes a straight or branched hydrocarbon chain containing from two to four carbon atoms and includes one double bond. This definition includes groups: vinyl, 1-methylvinyl, 2-methylvinyl, allyl, 2-butenyl, 3-butenyl, 1-butenyl, 1-methylallyl, 2-methylallyl etc.

For the purposes of the invention specifically determined that the concept of alkenyl3-C4denotes allyl, 2-butenyl, 3-butenyl and 2-methylallyl.

Although all of the compounds according to this invention are useful for the treatment of various disorders due to their ability to activate 5-HT1Areceptors, some of them are preferred.

Another compound of the invention is a compound of the formula

(II)

which in itself is active, and in this case it is mainly used as an intermediate product in the synthesis of compounds of General formula (I). In the formula (II) X, R and R1have the meanings given above, R2-(C1-C6) alkyl, phenyl, phenyl substituted by halogen or (C1
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Each of these compounds exist in the form of individual d-and l-stereoisomers, as well as racemic mixtures of such isomers. Accordingly, the compounds according to the invention include not only the dl-racemates, but also their optically active d - and l-isomers.

The invention includes pharmaceutically acceptable salts of accession with the acid compounds defined by formula (I).

Compounds according to the invention, because they are amines, have the main character and in accordance with this interact with a number of mineral and organic acids with the formation of pharmaceutically acceptable salts of accession. Due to the fact that the free amines of the compounds according to the invention at room temperature are, as a rule, oil is preferable to make available amines to their corresponding pharmaceutically acceptable salt of joining with acids that facilitates the handling and use, since the latter at room temperature are usually solids.

To obtain such salts typically used mineral acids such as hydrochloric, bromate as maleic, fumaric, paratoluenesulfonyl, methansulfonate acid, oxalic acid, para-bromophenyl-sulfonic, carbonic acid, succinic, citric acid, benzoic acid, acetic acid, etc. Thus, examples of pharmaceutically acceptable salts are sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, monohydratefast, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propenal, decanoate, kaprilat, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, salt sabatinovka acid, fumarate, maleate, Butin-1,4-diet, hexyne-1,6-diet, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, ecological, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, tartrate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, salt almond acid, etc. are Preferred salts joining with acids are salts with mineral acids such as hydrochloric and Hydrobromic acid, and also salts of organic acids, such as maleic.

In addition, some of these salts can form salt is retina.

The following connections are additionally illustrate the compounds included in the invention:

2-(Di-p-propylamino)-8-acetyl-1,2,3,4-tetrahydronaphthalen;

2-(Di-p-propylamino)-8-( -dimethylbutyryl)-1,2,2,4-tetrahydronaphthalen;

2 ethylamino-8-benzoyl-1,2,3,4-Tetra - hydronephrosis;

2-(N-methyl-N-benzylamino)-8-isobut-RIL-1,2,3,4 - tetrahydronaphthalen;

2 diallylamine-8-phenylacetyl-1,2,3,4-tetrahydronaphthalen;

2 diethylamino-8-(p-methoxybenzoyl)-1,2,3,4-tetrahydronaphthalen;

2-(Di-p-propylamino)-8-TRIFLUOROACETYL-1,2,3,4-tetrahydronaphthalen;

2 benzylamino-8-heptanoyl-1,2,3,4-those-traditonally;

2-(Di-p-propylamino)-8-( -methylpropionyl)-1,2,3,4-tetrahydronaphthalen;

2-dimethylamino-8-cyclohexylcarbonyl-Nile-1,2,3,4-tetrahydronaphthalen;

2-(Dicyclopentadiene)-8-( -clobetasol)-1,2,3,4 - tetrahydronaphthalen;

2-(Di-p-propylamino)-8-(p-chlorophenyl-acetyl)-thio-1,2,3,4 - tetrahydronaphthalen;

2 ethylamino-8-propionyl 1,2,3,4-tet-raidernation;

2-p-butylamino-8-( , -dimethylpropionic)-1,2,3,4-tetrahydronaphthalen;

2-(Di-p-propylamino)-8-[-(4'-methoxy - phenyl)-propionyl]-1,2,3,3 - tetrahydronaphthalen;

3-(Di-p-propylamino)-5-acetyl-chroman etc.

Compounds according to the invention preferably receive cher the traveler in the desired intermediate product 2-amino-8-brotherhood. The obtained 8-bromo-intermediate is then subjected to treatment to obtain the desired connection, directly or via an appropriate connection, in which group at position 8 is an R2CH(OH)-.

These reactions proceed according to the following schema:

And synthesis of 8-bromo-2-tetralone;

In the reductive amination;

With the replacement of the bromine-substitute through the processing of lithium;

D transformation of the carbonyl-derived in connection according to the invention.

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Replacement of the bromo-substituent through the processing of lithium

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The transformation of the carbonyl-derived

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8-Bromo-2-tetralone represent an intermediate, which after reductive amination and treatment appropriate reagent in the presence of organolithium compounds give compounds according to the invention. For example, in the case when the reaction involves the use of aldehyde, the resulting product, although in itself active, represents an intermediate of formula (II) to obtain the final product. In cases where the reaction involves the use of ester, its product is the finished product.

Tetralone can be obtained by any of the way around the ring by phenylacetylcarbinol and ethylene in the presence of aluminium chloride.

The resulting tetralone by a simple reductive amination using the selected amine, turn 2-amino-8-bromo-1,2,3,4-tetrahydronaphthalen, which can serve as intermediate product for the synthesis of compounds according to this connection. First, the tetralone is introduced into the reaction with the amine with the appropriate education, enamine, which is then reduced with sodium borohydride resulting in tetrahydronaphthalen.

2-amino-8-bromo-1,2,3,4-tetrahedronal-Talin can be used to obtain the compounds according to the invention by receiving laisteridge intermediate by reaction with alkyllithium, preferably n-butyllithium.

Active litiisoderzhashchego intermediate is then treated with an appropriate carbonyl compound with obtaining either directly ketone, or its source. Thus, treatment of 8-Li-tetraline connection R2COZ, where Z is halogen, alkoxy, hydroxy, aryloxy, -S-(C1-C3-alkyl), -OCO2R,

NN-O-N-N

and so on, leads to the formation of the desired ketone.

In contrast, treatment of 8-licitation carbon dioxide and processing then received carboxylate organolithium sodyeistvii 8-licitation with the appropriate aldehyde to obtain the alcohol of formula (II), which is then oxidized to the ketone.

Mentioned alcohol can also be obtained by adding a suitable ORGANOMETALLIC reagent (R2M, where M is Li, MgW, ZnW, etc., and W the corresponding halide) to 8-formyl-2-aminotetralin. The latter is obtained by adding 8-lithium-2-aminotetralin to dimethylformamide and treating the resulting product with water.

Alternatively, you can first block of 8-bromo-2-tetralone and turn bromosalicylic to the corresponding ketone. Received 8-acyl-2-tetralone after deprotection expose recovery aminating receiving the connection according to the invention.

When carrying out the above reactions can be replaced 8-limitation on the appropriate Grignard reagent to provide the desired product.

Compounds according to this invention, in which X represents oxygen, can be obtained by reductive amination and replacement of the bromo-substituent, but using 5-bromo-3-chromanone. The latter can be obtained from m-Bromphenol through a series of reactions. In short, the process m-Bromphenol allylbromide in the presence of potassium carbonate, resulting in a gain allyl ester 3-bromo-phenyl. The ether is converted into 2-b converted into ethyl ester of 2-allyl-3-(carboxymethoxy) bromine benzol. After oxidation with ozone and subsequent restorative treatment, allyl group in turn formylmethylene Deputy, which is then oxidized with Jones reagent to carboxymethyl, so that the end product is the ethyl ester of (2-carboxymethyl-3-bromo)phenoxyalkanoic acid. Partial ester turn in diethyl ether with ethanol and gaseous hydrogen chloride. In the presence of tert-butoxide potassium diethyl ether cyclist, receiving a mixture of 4-etoxycarbonyl-5-bromo-3-chromanone and 2-etoxycarbonyl-5-bromo-3-chromanone. After heating in the presence of acid, the latter is transformed into 5-bromo-3-chromanone.

Alternatively, an improved synthesis of 5-bromo-3-chromanone includes a sequence of reactions, as initial substances for which use of ethyl ether (2-allyl-3-carboxymethoxy)bromine benzol, bramasol oxidized by ozone, after receiving treatment dimethylthiophenol ethyl ester (2-formylmethyl-3-carboxymethoxy)bromobenzo-La. Formylmethylene Deputy oxidized later in carboxymethyl using Jones reagent, and the end product is (2-bromo-6-ethoxycarbonylmethoxy) pelota, then the received disutility ether cyclist in the presence of tert-butoxide potassium, receiving 4-t-butoxycarbonyl-5-bromo-3-chromanone. Then otscheplaut tert-butoxycarbonyl the group using triperoxonane acid, resulting get the desired 5-bromo-3-chromanone. Optically active isomers of the racemic mixtures according to the invention are also considered part of this invention. Such optically active isomers can be obtained from their respective optically active precursors by the described methods or by separation of racemic mixtures. The separation can be carried out in the presence of the release agent, using chromatography or re-crystallization. Useful separating agents are, in particular, d - and l-tartaric acid, d - and l-ditawarkannya acid, etc.

One particularly useful methods for obtaining optically active isomers of the compounds according to the invention is carried out through the synthesis of 8-substituted-2-tetralone, 5-substituted-3-chromanone or 5-substituted-3-thiochroman. Any of these intermediate can be subjected to reductive alkylation of optically active-phenethylamine, then divide the mixture diaster the way they substituted optically active 2-amino-1,2,3,4-tetrahydronaphthalen, 3-aminopropan or 3-aminothiophene.

To remove the rest of Venetia requires relatively strict conditions that may cause a violation of the integrity of the core molecules tetraline, chromane or thiochroman. It was found that the cleavage can be much easier and more efficient way, requiring removal of only mild conditions, using specific p-nitro-phenethylamine.

The removal of the remainder of the p-nitro-Venetia is provided by the recovery of the p-nitro group and subsequent solvolysis in the presence of acid, the obtained p-amino-ventilago balance. To restore the nitro-group you can use various remedial agents, including, for example, trichloride titanium, sociallyengaged or a mixture of zinc/acetic acid or catalytic hydrogenation. Solvolytic cleavage occurs while processing monohydrochloride (or other salts of monobasic acid) product recovery by water or alcohol at room temperature or, in some cases when high. A particularly convenient method of removing the residue of the p-nitro-Venetia is the hydrogenation of monohydrochloride amine in methanol over platinum catalyst.

Sineni according to the invention. It was found that 8-poslednie compounds in optically active form cannot be obtained by conventional methods, while the above-described method using p-nitro-phenethylamine allows it.

The compounds used as starting material for the synthesis of compounds according to the invention are known and can be easily obtained by standard methods. Moreover, each of the sequence of reactions used to obtain the compounds according to the invention, includes a well-known reaction.

Pharmaceutically acceptable salts of joining with acids are usually obtained by a reaction between 1,2,3,4-tetrahydronaphthalene, chroman, sulfoxide thiochroman according to the invention with an equimolar or excess amount of acid. Typically, the reagents are combined in a common solvent such as diethyl ether or benzene, and from the solution by conventional precipitated salt for approximately the period of time from one hour to 10 days, after which it can be separated by filtering.

Compounds according to the invention and methods for their synthesis are illustrated in the following examples.

P R I m e R 1. Getting 2-di-p-propylamino-8-pentanoyl-1,2,3,4 - tetrahydronaphthalene in the form of oxalate.

To the-utility (3.5 mmol, 3.0 ml, 1.2 M solution in hexane). The reaction mixture was stirred at -78aboutC for 45 min, and then added n-pentanol (of 0.41 ml, 3.9 ml). After stirring for 5 min at -78aboutTo the reaction mixture was warmed up to room temperature and poured into dilute HCl solution. The resulting solution was washed once with ether and the separated ether layer. The aqueous layer was podslushivaet solution of NH4OH and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated, obtaining 0.95 g of crude product.

Cleaning Express chromatography on silica gel using a mixture of ether:hexane 1:1 with traces of NH4OH gave 0.68 g of the product MS(FD):m/e 317.

To a solution of 2-di-n-propylamino-8-(1'-hydroxy-1-pentyl)-1,2,3,4 - tetrahydronaphthalene (0,63 g 2.0 mmol) in methylene chloride (50 ml) was added chlorproma pyridinium (0.9 g, 4.0 mmol) and molecular sieves 4A (30 g). The reaction mixture was stirred at room temperature for 1.5 h, after which the reaction was suspended by the addition of methanol (50 ml). Added ether to until the reaction mixture became dull, and then brought her in the short column with silica gel and was suirable ether. Eluent was concentrated. Elution of the column was continued 10% solution m is obyvali through celite. The filtrate was combined with the crude product obtained after elution with ether, and concentrated. Purification of this material on a column of silica gel to expressrotary with a mixture of 1:3 ether:hexane containing traces of NH4OH, give 240 mg of the compounds. MS(FD):m/e 315. Got oxalate and crystallized from a mixture of ethyl acetate/hexane, gave 165 g of white crystals, so pl. 107-108,5aboutC.

Elemental analysis.

Calculated With 68,12; N To 8.70; N 3,45.

Found, 67,85; N 8,67; N 3,41.

P R I m m e R 2. Getting 2-di-n-propylamino-8-TRIFLUOROACETYL-1,2,3,4-tetrahed-ronfalin in the form of the hydrobromide.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in 10 ml of THF, and cooled the mixture to -78aboutWith, then added 2.2 ml of n-utility (1.6 M solution in hexane). Stirred the reaction mixture at -78aboutWith over 40 minutes Added ethyltryptamine (0,42 ml, 3.5 mmol) and the mixture left to warm to room temperature, then poured it into the water, brought the pH to 12 and was extracted with a mixture of methylene chloride. The extract was dried over sodium sulfate and boiled away to balance 1,1,

The residue was subjected to purification on a column of silica gel, which was suirable a mixture of hexa mg of the mixture, which then was subjected to purification using processing on a column of silica gel. The appropriate fractions obtained after the second chromatographic purification, combined with pure fractions from the first chromatographic purification, receiving 240 mg of product. The product was converted to the hydrobromide and recrystallization salt from a mixture of ethyl acetate and hexane, resulting in received 150 mg of the above compound in the form of a solid reddish-brown color with so pl. 142-144aboutC.

Elemental analysis.

Calculated With 52,95; N 6,17; N 3,43.

Found, 53,19; N Between 6.08; N 3,35.

P R I m e R 3. Getting 2-di-p-propylamino-8-propionyl 1,2,3,4-tetrahedron-Talina in the form of oxalate.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (8.5 g, a 27.4 mmol) in 80 ml THF and cooled the solution to -78aboutWith, then added 25.7 mm n-utility (1.6 M solution in hexane). Stirred the mixture at -78aboutC for one hour, then added 2.4 ml (from 32.9 mmol) of propionic aldehyde. The mixture was warmed up to room temperature, then poured into water and was extracted with methylene chloride. The extract was dried over sodium sulfate and boiled away, which gave 9.1 g of yellow oil.

The oil was placed in colon. Combined appropriate fractions, having 6.5 g (82,0%) of 2-di-n-propylamino-8-(1'-hydroxypropyl)-1,2,3,4-tetrahydronaphthalene in the form of a clear oil.

The resulting product was dissolved in 250 ml of methylene chloride and to the solution was added 17.0 g (78,6 mmol) Harrogate pyridinium (XXII) and 30 g of molecular sieves 4. Stirred the mixture for 3 h at room temperature, then added 250 ml of ether and celite. The mixture was poured into a short column with silica gel and was suirable ether. Added methanol to dissolve the brown sludge precipitated after addition the reaction mixture of ether. The material introduced into the column and was suirable 10% methanol in methylene chloride. Eluent was concentrated, having a brown oil, which was further subjected to purification using column chromatography, using hexane:ether composition 2: 1, and then clean the ether as solvent. Combined fractions containing the target product, and concentrate, which gave 4.7 g of product. Got oxalate, which took 2.5 g of this material, three recrystallization it from a mixture of ethanol/ether, and the product was received in the form of a white solid (1.5 g, so pl. of 114.5-115aboutC).

Elemental analysis.

Calculated With 66,82; N 8,29; N 3,71.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (5.0 g, 16,1 mmol) in 50 ml THF and cooled the mixture to -78aboutWith, and then added to 21.0 ml of n-utility (0.92 M solution in hexane). Stirred the mixture for 30 min and added to 1.85 ml (21,0 mmol) Butyraldehyde. The mixture was left to warm to room temperature and was stirred overnight, then poured it in the water and was extracted with methylene chloride. The extract was dried over sodium sulfate and boiled away, gaining 6.4 g of residue. The residue was placed in a column with silica gel and was suirable a mixture of 2% methanol in methylene chloride containing environments ammonium hydroxide. Combined appropriate fractions, gave 4.8 g of 2-di-p-propylamino-8-(1'-hydroxybutyl)-1,2,3,4-tetrahydronaphthalene in the form of a thick oil.

Oil (4.0 g, 13,2 mmol) was dissolved in 200 ml of methylene chloride and added molecular sieves 4 (30 g). Shuffled mixture was added 10.0 g (46.2 mmol) XXII. Continued to stir the mixture for 3 h at room temperature, after which it was poured into a pad of silica gel and was suirable successively with ether and 3% solution of methanol in methylene chloride containing a trace of ammonium hydroxide, highlighting the product as a brown oil.

The oil was placed in to the Oia. Combined appropriate fractions, receiving the oil, which, when dissolved in ether gave a brown precipitate. The precipitate was separated by filtration and the filtrate is boiled away, having received 3.0 g of light brown oil, which represents the free base specified in the connection name.

Turned one gram of the obtained oil in the hydrobromide, which was recrystallization from the mixture and ethyl acetate, giving 0.9 g mentioned in the title compound as tan crystals with so pl. 122-123aboutC. After repeated recrystallization allocated 750 mg of the product so pl. 125-126,5aboutC.

Elemental analysis.

Calculated With 62,82; N 8,43; N 3,66.

Found, With 63,09; N By 8.22; N 3,66.

P R I m e R 5. Getting 2-di-p-propylamino-8-(-methylpropionyl)- 1,2,3,4-tetrahydronaphthalene in the form of the hydrobromide.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in 10 ml THF and cooled the solution to -78aboutWith, then added 3.5 ml (1.0 M solution in hexane) n-utillity. After 30 min, to the mixture was added 0,41 ml (3.5 mmol) of methylisobutyl, the mixture was stirred at -10aboutC for 30 min, and then poured into 10% aqueous hydrochloric acid solution, washed with ether, and raised the PE the result to 0.72 g of residue.

The residue was placed in a column with silica gel and was suirable successively with a mixture of 4: 1 hexane and ether containing a trace of ammonium hydroxide, and then with a mixture of 3: 1 hexane and ether containing a trace of ammonium hydroxide. Combined appropriate fractions, gave 190 mg of the free base named in the title compound.

The connection was turned into a salt of Hydrobromic acid, and after recrystallization from ethyl acetate received 80 mg of the compounds in the form of red-brown crystals with so pl. 175-176,5aboutC.

Elemental analysis.

Calculated C 62,82; N 8,43; N 3,66.

Found, 62,54; N 8,53 N 3,44.

P R I m e R 6. Getting 2-di-p-propylamino-8-( -methylbutyryl)- 1,2,3,4-tetrahydronaphthalene in the form of the hydrobromide.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in 10 ml THF and cooled the mixture to -78aboutWith, then added 3.5 ml of n-utility (1.0 M solution in hexane). After 30 min added of 0.53 ml (3.5 mmol) of utilizability, then the mixture was heated to -10aboutC and kept at this temperature for 30 minutes the mixture is Then poured into dilute acid, washed with ether and brought the pH up to 10. The mixture was extracted with methylene chloride, dried of extras who eat and suirable successively with a mixture of 4: 1 hexane and ether, containing traces of ammonium hydroxide, and then with a mixture of 3: 1 hexane and ether containing a trace of ammonium hydroxide. Combined appropriate fractions, which gave 50 mg of the free base specified in the connection name.

Turned free base in a hydrobromide, which recrystallize from a mixture of ethyl acetate and hexane, obtaining 30 mg specified in the connection name in the form of a reddish-brown powder with so pl. 131-132aboutC.

Elemental analysis.

Calculated, 63,63; N 8,64; N 3,53.

Found, 63,35; N 8,42; N 3,83.

P R I m e R 7. Getting 2-di-p-propylamino-8-dimethylpropionic - 1,2,3,4-tetrahydronaphthalene in the form of the hydrobromide.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 32 mmol) in 20 ml of THF and cooled the solution to -78aboutWith, then added the 4.7 ml of n-utility (0,82 M solution in hexane). Stirred the mixture for 30 min at -78aboutWith, and then added to 0.56 ml (4.2 mmol) of methyltrimethoxysilane. The mixture was left to warm to room temperature, then poured into water and was extracted with methylene chloride. The extract was dried over sodium sulfate and boiled away, having obtained 1.6 g of residue.

The residue was placed in a column with silica gel and suirable 140 mg free base specified in the connection name.

Turned free base in a hydrobromide, which then recrystallization from methanol/ethyl acetate and obtained 80 mg of target compound with so pl. 157-158aboutC.

Elemental analysis.

Calculated, 63,63; N 8,65; N 3,53.

Found, 63,39. N 8,46; N 3,43.

P R I m e R 8. Getting 2-di-p-propylamino-8-cyclohexanecarbonyl-1,2,3,4-te trihydroxyflavone in the form of oxalate.

Method A.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in 10 ml THF and cooled the solution to -78aboutWith, and then added to 2.8 ml of n-utility (1.27 M solution in hexane). Stirred the mixture at -78aboutC for 45 min, then added a 0.59 ml (3.5 mmol) of ethylcyclohexylamine. The mixture was left to warm to room temperature and then poured into 10% hydrochloric acid, washed with ether, brought the pH to 10 by adding ammonium hydroxide, and was extracted with methylene chloride. The extract was dried over sodium sulfate and boiled away, which gave 0.8 g of residue.

The residue was placed in a column with silica gel and was suirable mixture 3:1 hexane and ether containing a trace of ammonium hydroxide. Combined appropriate fractions, gave 0.36 g of the target is the thief of 8-bromo-2-di-p-propylamino-1,2,3,4-tetrahedron-Talina (1.0 g, 3.2 mmol) in THF (10 ml) at -78aboutC, and stirred the solution for 45 minutes Added cyclohexanecarboxaldehyde (of 0.47 ml, 3.9 mmol). The reaction mixture was stirred at -78aboutC for 5 min, heated to room temperature, poured into dilute aqueous HCl and washed with ether. He parselocale water layer NH4OH and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated, giving 1.1 g of crude product. Dissolve the crude product in methylene chloride (50 ml) and added molecular sieves and chlorproma pyridinium (1.4 g, 6.4 mmol), was stirred reaction mixture at room temperature for 2 hours was Added methanol (50 ml) and the reaction mixture was concentrated to a paste-like state. The paste was dissolved in methylene chloride (50 ml) and added enough ether to obtain a turbid solution. The resulting material was added to silikagelevye cushion and suirable ether.

Silicagel pillow was suirable 10% solution of methanol in methylene chloride and concentrated eluent, obtaining an oily residue. This material was washed with methanol and filtered through celite. The filtrate was combined with the ether solution obtained as described above and concentrated filtered through Florisil. Concentrated filtrate receiving 560 mg of oil, which was subjected to purification Express chromatography on silica gel using a mixture of 3:1 hexane and ether containing traces of NH4OH, as a solvent. Combined appropriate fractions, and concentrate, which gave 350 mg of the desired compound. Got oxalate, which was led from a mixture of ethyl acetate/hexane, gave 370 mg of a white solid with so pl. of 98.5-100aboutC.

Elemental analysis.

Calculated With 69,58; N 8,64; N 3,25.

Found, 69,28; N 8,87; N 3,00.

P R I m e R 9. Getting 2-di-p-propylamino-8-benzoyl-1,2,3,4 - tetrahydronaphthalene as tosilata.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in 20 ml of THF and cooled the solution to -78aboutWith, then added 3.0 ml of n-utility (1.6 M solution in hexane). Stirred the mixture at -78aboutC for one hour, after which was added 0.5 ml (4.8 mmol) of benzaldehyde. Continued stirring for 15 min, left the mixture to warm to room temperature and then poured into water and was extracted with methylene chloride. Dry the extract over sodium sulfate, which gave 1.4 g of a yellow oil.

Put the butter in a column sisie faction, obtaining 0.9 g of 2-di-n-propylamino-8-( -hydroxybenzyl)-1,2,3,4-tetrahydronaphthalene.

Dissolved described product (or 0.83 g, 2.5 mmol) in 50 ml of methylene chloride and added to a solution of about 1 g of molecular sieves, and then 1.9 g (8.6 mmol) XXII. Stirred the mixture for 2 h, then diluted it with ether and poured into a column with silica gel. The column was suirable ether, and then with a mixture of 10% methanol and methylene chloride. Combined fractions and the residue was dissolved in methanol; the solution was filtered through a nozzle celite. The filtrate is boiled away and put the rest in a column Florisil, which was suirable mixture 2:1 of hexane and ether. Combined appropriate fractions, gave 0.5 g of the free base of the target compound.

Turned free base in toilet, which has recrystallization from a mixture of acetone and ether, receiving 125 mg of target compound in the form of a white powder with so pl. 148,5-149aboutC.

Elemental analysis.

Calculated C 70,97; N. Of 7.35; N Was 2.76.

Found, 71,18; N 7,27; N Is 2.74.

P R I m e R 10. Getting 2-di-p-propylamino-8-(n-chlorobenzene)- 1,2,3,4-tetrahydronaphthalene.

Dissolved 2-di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in 10 ml THF and cooled the solution to -78GNSO -78aboutWith, and then added with 680 mg (1.5 equivalents) of 4-chloro-benzaldehyde in THF. Stirred the mixture for 15 min at -78aboutWith, then left to warm to room temperature. Poured the mixture into 10% aqueous hydrochloric acid solution, washed with ether, brought the pH to 10 by adding ammonium hydroxide, and was extracted with methylene chloride. Dry the extract over sodium sulfate and boiled away, obtaining 1.5 g of residue.

Put the remainder in a column with silica gel and was suirable mixture 1:1 of hexane and ethyl acetate containing a trace of ammonium hydroxide. Combined appropriate fractions, gave 1.3 g mostly pure 2-di-p-propylamino-8-(-hydroxy-4'-chloro - benzyl)-1,2,3,4 - tetrahydronaphthalene.

Dissolved described product (3.2 mmol) in 50 ml of methylene chloride and added 30 g of molecular sieves 4, and then 1.4 g (6.4 mmol) XXII. Stirred the mixture for one hour, then diluted with ether and poured on siliciano pillow, which was then washed with ether, the filtrate is boiled away. Washed silica gel with a mixture of 10% methanol and methylene chloride, the obtained filtrate is boiled away and the residue was dissolved in methanol and twice it was filtered. This filtrate was combined with the ether filtrate, the mixture was placed in a column with silicagel the shares, that gave 0.3 g of the target compound.

MS(FD):m/e 369.

P R I m e R 11. Getting 2-di-p-propylamino-8-(O-perbenzoic)- 1,2,3,4-tetrahydronaphthalene in the form of a salt of para-toluensulfonate acid.

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g, up 3.22 mmol) in THF (25 ml), the solution was cooled to -78aboutWith and added to 2.5 ml of n-utility (1.27 M solution in hexane). After soaking for one hour added orthoferrosilite (0,38 ml, up 3.22 mmol). The mixture was stirred for 10 min at -78aboutS, after which the reaction was suspended, adding water at -78aboutC. the Reaction mixture was poured into dilute HCl solution and was extracted with methylene chloride, parselocale water layer NaOH and was extracted with methylene chloride. Dried primary extract (Na2SO4) and concentrated, receiving 200 mg of residue, which according to NMR data did not contain the target product. The extract was acidified material was dried (Na2SO4) and concentrated, obtaining 2.0 g of residue. Purification of the resulting material using a column of rapid chromatography on silica gel using as solvent a mixture of 1:1 ether and hexane containing a trace of ammonium hydroxide, gave the free base of the target soy is stallization from a mixture of ethyl acetate/ether received 118 mg of the target compound with so pl. 107-109aboutC.

Elemental analysis.

Calculated With 68,55; N 6,90; N 2,66.

Found, 68,41; N 7,02; N 2,65.

P R I m e R 12. Getting oxalate 2-di-p-propylamino-8-(methoxyacetyl)-1,2,3,4-tetrahydronaphthalene.

Method a:

Dissolved 2-di-p-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalen (5.0 g, 16,1 mmol) in 25 ml THF and cooled the solution to -78aboutWith, then added 3,22 ml n-utility (1M solution in hexane). The mixture was stirred at -78aboutC for 1.5 h, the Solution was transferred via cannula into a solution of methylmetacrylate (7,05 ml, 160 mmol) in THF at -78aboutC. Stirred the reaction mixture at room temperature overnight, poured into a solution of NaHCO3and was extracted with CH2Cl2. The extract was dried (Na2SO4) and concentrated, obtaining 6.8 g of crude product.

Then the resulting material was placed in a chromatographic column and suirable product using a 4% solution of methanol in methylene chloride containing a trace of ammonium hydroxide. Combined appropriate fractions, gave 1.4 g of the target compound.

Got oxalate, three recrystallize from ethyl acetate, resulting in salt as a white powder with so pl. 118< utility (1.2 M solution in hexane, 2,8 ml, 3.4 mmol) to a solution of 8-bromo-2-di-p-propylamino-1,2,3,4-tetrahydronaphthyl - Lin (1 g, up 3.22 mmol) in THF (50 ml) at -78aboutC. After 1.5 h was added a solution of chloride trimethylamine (1.3 g, 2.0 mmol) in THF (20 ml). The reaction mixture was left to warm to room temperature, stirred at room temperature overnight, poured into water and was extracted with methylene chloride. Dried extract (Na2SO4) and concentrated, obtaining the crude product. Purification by chromatography using methanol:methylene chloride 1:10 gave 1.2 g of the desired product, which is then directly used in the next stage.

b) 2-Di-p-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalen.

Added bis-triphenylphosphine dichloride (120 mg) to a solution of 2-dipropylamino-8-tributylstannyl-1,2,3,4-Tetra - gerenation (500 mg, of 1.27 mmol) in benzene (20 ml). Added methoxyacetanilide (1.5 ml, 1.77 g, 16.5 mmol). Stirred the reaction mixture at room temperature overnight and was then heated for 5 h under reflux. Poured the reaction mixture into water and was extracted with methylene chloride. Dried extract (MgSO4) and concentrated, receiving 800 mg of crude product. Cleaning chromatographically-1,2,3,4-tetrahydronaphthyl - Lin.

P R I m e p 13. Getting 2-Di-p-propylamino-8-acetyl-1,2,3,4 - tetrahydronaphthalene.

Method a:

Added a solution of n-utility (1.6 M in hexane, to 15.1 ml, and 24.2 mmol) to a solution of 8-bromo-2-di-p-propylamino-1,2,3,4-tetrahed-ronfalin (5.0 g, 16,1 mmol) in THF (50 ml) at -78aboutAnd stirred the reaction mixture for one hour at -78aboutC. Through the reaction mixture at -78aboutWith was barbotirovany gaseous carbon dioxide to the disappearance appeared dark purple color. Added motility (1.4 M solution in ether, 23 ml). Stirred the reaction mixture at -78aboutC for 30 min, and then warmed to room temperature. Was stirred for 10 min at room temperature, after which disappeared pink color. Added 10 ml metallice, and the reaction mixture is again acquired a pink color. After 15 min the pink color disappeared, and added 10 ml of a solution metallicy. The reaction mixture is poured on ice, acidified with hydrochloric acid and was extracted with ether. He parselocale aqueous layer was extracted with methylene chloride. Dried primary extract (Na2SO4) and concentrated receiving, 3.8 g of crude product. Cleaning Express chromatography on silica gel with the new connection in the form of a yellow oil (2.7 g, 61%).

Prepared salt of maleic acid and recrystallize from methanol/ethyl acetate/hexane, gave maleate with so pl. 115-116aboutC.

Elemental analysis.

Calculated With 67,84; N. Of 8.04; N 3,60.

Found, With 68,07; N 8,02; N 3,55.

It is possible to prepare, on the contrary, the salt of hydrochloric acid. Crystallization from a mixture of ethanol/ether gave the hydrochloride as colorless crystals with so pl. 124-125aboutC.

Elemental analysis:

Calculated With 69,77; N 9,11; N To 4.52.

Found, 69,91; N 9,20; N 4,53.

Method B.

Added n-utility (1.6 M solution in hexane, of 60.5 ml, to 96.8 mmol) to a solution of 8-bromo-2-di-p-propylamino-1,2,3,4-tetrahed-ronfalin (20,0 g, and 64.5 mmol) in THF (200 ml) at -78aboutAnd stirred the reaction mixture at -78aboutC for one hour. Added acetaldehyde (4.3 ml, 77.4 mmol) and left the mixture to warm to room temperature. Poured the reaction mixture into water, parselocale with ammonium hydroxide and extracted with methylene chloride. Dried extract (Na2SO4) and concentrated, obtaining 21,4 g yellow oil.

To a solution of the yellow oil in methylene chloride (800 ml) was added molecular sieves with pore size of 4 (30 g) and the Added methanol and filtered the reaction mixture through the nozzle celite. The filtrate was concentrated and subjected to chromatographic purification on florile, using as solvent a mixture of hexane:ether 2:1. Combined appropriate fractions, gave 6.8 g of the desired product. From the obtained after filtration through celite, the solids were prepared by suspension in 10% solution of methanol in methylene chloride, which was subjected to purification using column chromatography on Florisil, using as solvent a 10% solution of methanol in methylene chloride. Combined fractions which contained the product, and concentrate, having a residue containing a small amount of methylene chloride. To this residue was added ether to until the solution became slightly turbid. The solution is poured onto a bed of silica gel and was suirable ether. The resulting material was combined with the product from the initial filtrate and concentrated, obtaining the ketone as a pale brown oil (9,9 g).

P R I m e R 14. Preparation of 2-di-n-propylamino-8-(3-phenylpropionyl)-1,2,3,4-tetrahydronaphthalene hydrochloride.

To a solution of 8-bromo-2-dipropylenetriamine (2.0 g, 6.4 mmol) in anhydrous tetrahydrofuran (300 ml) at -78aboutWas added a solution of n-utility in hexane is dipropionate (1.73 g, 12,89 mmol) in anhydrous tetrahydrofuran (40 ml). The resulting solution was stirred at -78aboutC for 5 min and then was heated to room temperature. The solution was poured into water and was extracted with a solution of 1:3 isopropanol/methylene chloride. The extract was dried and evaporated in vacuum with the torching of 3.2 g of yellow oil. This oil was dissolved in acetone solution (100 ml) and MN2SO4(40 ml). Slowly at room temperature was introduced Jones reagent (4.5 ml) under stirring. The resulting solution was stirred at room temperature for 45 min, cooled with isopropanol, increased basicity IN NaOH solution and then extracted with a solution of 1: 3 isopropanol/methylene chloride. The extract was dehydrated (Na2SO4) and evaporated in vacuo to obtain 2.9 g of brown oil. Cleaning method flashmemory [25% Et O AC in hexane (NH4OH)] gives 632 mg of oily product. The hydrochloride salt was obtained and recrystallized from Et O Ac/hexane to yield 119 mg of the titled product as a white crystalline solid with a melting point of 87-88aboutC.

MS(ED):m/e 363.

IH NMR (CDCl3) free base: = 7,83 (m, 1H), 7,25 (m, 7H), 3,60 is 2.80 (m, 11N), 2,20-of 1.80 (m, 5H), 1,6 is but WITH 75,06; N TO 8.57; N 3,50.

Found, 74,79; N To 8.57; N 3,55.

P R I m e R 15. Preparation of 2-Di-p-propylamino-8-(4-phenylbutyl)-1,2,3,4 - tetrahydronaphthalene.

To a solution of 8-bromo-2-dipropylenetriamine (2.1 g, 6.7 mmol) in anhydrous tetrahydrofuran (300 ml) at -78aboutWas added a solution of n-utility in hexane (1.12m, 9,04 ml, 10,12 mmol). The resulting solution was stirred 15 min, then was slowly introduced 4-phenylbutyraldehyde (2.0 g, 13.5 mmol) in anhydrous tetrahydrofuran (40 ml). The solution was poured into water and extracted with a solution of 1: 3 isopropanol/methylene chloride. The extract was dehydrated (Na2SO4) and evaporated under vacuum obtaining of 3.46 g of a yellow oil. Cleaning method flash chromatography [5-10% MeOH in CH2Cl2(NH4OH)] give 2.14 g of oily product. This oil was dissolved in acetone solution (100 ml) and MN2SO4(21 ml). Reagent Johnson (2.4 ml) was slowly introduced at room temperature under stirring. The resulting solution was stirred at room temperature for 45 min, cooled with isopropanol, increased basicity IN NaOH solution and then was extracted with a solution of 1:3 isopropanol/methylene chloride. The extract was dehydrated (Na2SO4) and evaporated in vacuum to a hollow substance in the form of oil product.

MS (FD): m/e 377.

1H NMR (CDCl3): 7,30 (m, 3H), 7,10 (m, 5H), 3,0-2,4 (m, N), 2.0 (m, 2H), 1,5 (m, 6N), 1,25 (s, 1H), 0.6 a (t, 6N).

Elemental analysis for C26H35NO

Calculated With 82,71; S 9,34; N 3,71.

Found, 82,45; N 9,40; N 3,82.

P R I m e R 16. Preparation of 2-di-n-propylamino-8-(5-phenylpentane)-1,2,3,4-tetrahydronaphthalene hydrobromide.To a solution of 8-bromo-2-dipropylenetriamine (1.0 g, 3.2 mmol) in anhydrous tetrahydrofuran (90 ml) at -78aboutWas added a solution of p-utility in hexane (1.2 M, 5.4 ml, 6.4 mmol). The resulting solution was subjected to stirring for 15 min, then was slowly introduced 5-phenylpentane (0.74 g, of 4.57 mmol) in anhydrous tetrahydrofuran (40 ml). The resulting solution was subjected to stirring at -78aboutC for 50 min, and then warmed to room temperature. The solution is poured into water and was extracted with a solution of 1:3 isopropanol/methylene chloride. The extract was dried and evaporated obtaining of 1.37 g of a yellow oil. Cleaning method flash chromatography [5% MeOH in CH2Cl2(NH4OH)] give 252 mg of the oil product. This oil was dissolved in a solution of acetone (75 ml) and 2M H2SO4(2.5 ml). When stirring was slowly introduced the Jones reagent (0,32 ml) is the temperature, chilled with isopropanol, the basicity is increased IN NaOH solution and then extracted with a solution of 3:1 isopropanol/methylene chloride. The extract was dried (Na2SO4) and dehydrated by vacuum to obtain 193 mg of oil. The hydrobromide salt was obtained and recrystallized from Et O Ac/hexane to yield 60 mg of the titled product as a white crystalline solid.

The melting point of 100-102aboutC.

MS(FD): m/e 391.

1H NMR (CDCl3): 7,20 (m, 8H), 2,9 (m, 6N), to 2.65 (t, 2H), 2,45 (m, 4H), 2,10-1,6 (m, 6N), 1,50 (m, 4H), 1,25 (m, 1H), 0,90 (t, 6N).

Elemental analysis for C27H37NOHBr

Calculated With 68,63; N 8,11; N 2,96.

Found, 68,37; N. Of 8.25; N To 3.02.

P R I m e R 17. Preparation of 5-acetyl-3-di-p-Propylenediamine

A. Ethyl (2-amyl-3-bromophenoxy)acetate.

To a solution of 2-allyl-3-bromophenol (15.2 g, and 71.4 mmol) in acetonitrile (350 ml) was added ethyl CHLOROACETATE (9.6 g, 78.5 per mmol), potassium carbonate (19.7 g, 143 mmol). The reaction mixture was stirred at 60aboutC for 66 hours, the Reaction mixture was filtered and evaporated in vacuo to obtain the crude product as light yellow oil. Cleaning method flash chromatography (1:1) hexane/diethyl ether) D6,00 (m, 1H), 5,02 (m, 2H), with 4.64 (s, 2H), 4,27 (K, 2N), to 3.67 (d, 2H), of 1.30 (t, 3H).

b. Ethyl (3-bromo-2-formylmethylene)acetate

A solution of 16.6 g (of 55.5 mmol) of the intermediate obtained above was cooled in pure ethanol (500 ml) at -78aboutWith, and then the reaction mixture was barbotirovany ozone, after 20 min the solution became light blue, and all source materials were consumed (TCS 1:1 hexane/ether). The reaction mixture was gradually heated to room temperature. At this point, the colorless solid was precipitate and was again cooled to -78aboutC. was added dropwise dimethyl sulfide (7.3 ml, 100 mmol) and the reaction mixture was warmed gradually to room temperature. Volatile components were removed by vacuum to obtain 18.3 g of the above compound as a pale yellow oil.

1H NMR (CDCl3): = to 9.70 (s, 1H), 7,25 (d, 1H), 7,11 (t, 1H), 6,74 (d, 1H), to 4.62 (s, 2H), 4,22 (K, 2N), of 4.00 (s, 2H), 1.26 in (t, 3H).

C. Ethyl (3-bromo-2-(Carbo-t-butoxymethyl)phenoxy)acetate.

To a solution of the product obtained in example b (approximately 55 mmol) in acetone was added Jones reagent until a permanent bright orange color. There was obtained a dark-green solid, while gradually to the mixture was diluted with water and then extracted with ether. The ether extract was washed with water and extracted with saturated aqueous sodium bicarbonate solution. The acidity of an aqueous extract increased hydrochloric acid and was extracted with a solution of 3:1 chloroform/isopropanol. Mixed organic extracts were washed with brine, dehydrated (Na2SO4) and then evaporated in vacuum to obtain 12.3 g of the corresponding carboxylic acid as a yellow viscous oil.

IR (film): 1739, 1755 cm-1.

MS (FD): m/e 318(100), 316(90).

1H NMR (CDCl3): 7,26 (d, 1H), 7,12 (t, 1H), 6.75 in (d, 1H), of 4.66 (s, 2H), 4,25 (K, 2N), Android 4.04 (s, 2H), of 1.29 (t, 3H).

To a solution of 10.7 g (33.8 mmol) prepared above carboxylic acid t-butyl acetate (160 ml) at 10aboutWas added dropwise concentrated sulfuric acid (9.7 ml) at a rate sufficient to maintain the temperature below 10aboutC. the Reaction mixture was stirred at 10aboutC for 2 h, then poured into a slurry of ice water and NaHCO3and then were extracted with methylene chloride. The extract was dried and evaporated to obtain 9.0 g of the named compound as a viscous light yellow oil.

d. 5-bromo-4-t-butoxycarbonyl-3-chromanone.

A solution of 9.0 g,g, 48.2 mmol) in tetrahydrofuran (275 ml) at room temperature. Dark red solution was poured on ice and added to a dilute HCl solution to establish a pH of the reaction solution to pH equal to 6. Weakly acidic solution was then extracted with ether. The organic extract was washed with saturated salt solution, dried (Na2SO4) and evaporated in vacuo to obtain 6.2 g of the named compound as a viscous orange oil.

E. 5-bromo-3-chromanone.

A solution of 5 g of the product obtained above in example d in triperoxonane acid (75 ml) was stirred at room temperature for 1 h Volatiles from the reaction solution were removed by vacuum. The residue was dissolved in ether, washed with a solution of NaHCO3dried (Na2SO4) and evaporated with the formation of 2.54 g of orange glass. Cleaning method flash chromatography (1:1 hexane/ether) gives 1,76 g of these compounds in the air of an orange oil.

1H NMR (CDCl3): = to 7.32 (d, 1H), 7,12 (t, 1H), 7,02 (d, 1H), to 4.41 (s, 2H), 3,69 (s, 1H).

f. 5-bromo-3-dipropylamino.

To a solution of 620 mg of the compound prepared in example e, in toluene (20 ml) was added dipropylamine (0.7 ml, 6 mmol) and p-colorcollection the mixture was cooled to room temperature and evaporated in vacuum to obtain a dark red-orange precipitate. The residue was dissolved in tetrahydrofuran (40 ml) to which was then added cyanoborohydride sodium (400 mg, 6.4 mmol). The resulting solution was saturated with HCl. The resulting reaction mixture was stirred for 18 h at room temperature and then was poured into 15% aqueous sodium hydroxide solution (100 ml). This solution was vigorously stirred for 2 h, and then was extracted with ether. The organic extract was dried (Na2SO4) and evaporated in vacuo to precipitate. This precipitate was suspended in 10% hydrochloric acid, and then washed with ether. Was increased basicity of the aqueous layer with a solution of concentrated ammonium hydroxide and then was extracted with dichloromethane. The organic layer was washed with saturated saline solution, dehydrated (Na2SO4) and then evaporated in vacuum to obtain a light yellow oil. Cleaning method flash chromatography [4:1 hexane/diethyl ether (NH4OH)] give 420 mg of the above compound as a colourless oil.

1H NMR (CDCl3): 7,16 (d, 1H), 6,98 (t, 1H), 6,80 (d, 1H), 4,28 (m, 1H), 3,78 (t, 1H), 3,17 (m,1H), 2,93 (m, 1H), to 2.67 (m, 1H), 2,53 (t, 4H), 1,49 (sextet, 4H), of 0.91 (t, 6N).

g. 5-(1-hydroxyethyl)-3-dipropylamino.

To a solution of 4.95 g of soy is in hexane (1.35 M, 15.3 ml of 20.6 mmol). The resulting solution was stirred at -78aboutC for 20 min and was added acetaldehyde (1.8 ml, 1.4 g of 31.8 mmol). The resulting reaction mixture was stirred at -78aboutC for 30 min and at room temperature for 30 minutes Then the mixture was poured into water and extracted with 1: 3 isopropanol/methylene chloride solution. The extract was dehydrated (Na2SO4) and evaporated in vacuo to obtain a yellow oil. Cleaning method flash chromatography [1: 1 ether/hexane (NH4OH)] gives 4.1 g of the named product as a pale yellow oil.

1H NMR (CDCl3): 7,20-7,10 (m, 2H), 6,77 (s, 1H), 5,17-to 5.03 (m, 1H), 4,33-4.26 deaths (m,1H), 3,78 (t, 1H), 3.25 to of 3.12 (m,1H), 3,05 at 2.45 (m, 6N), 1,77 was 1.43 (m, 8H), of 0.95 (t, 6N).

h. 5-acetyl-dipropylamine.

Reagent John (5 ml) was added to a solution of 4.1 g of the compound prepared in paragraph g, in acetone (200 ml), 2N sulfuric acid was introduced slowly enough that the temperature of the reaction solution did not exceed 30aboutC. gradually Introducing sulfuric acid reacting solution was stirred for 1 h at room temperature, cooled by the addition of isopropanol (2 ml), increased the basicity of a solution of NaOH and then was extracted with a solution of 1:3 isopropanol/methylene chloride. EII network of 3.48 g of the named compound as a yellow oil.

1H NMR (CDCl3): to 7.32 (d,1H), 7,18 (t, 1H), 6,98 (d,1H), 4,29 (d, 1H), 3,88-with 3.79 (m, 1H), 3,16 are 2.98 (m, 3H), at 2.59 (s, 3H), 2,60 is 2.43 (m, 4H), 1,55-of 1.40 (m, 4H), 0,89 (t, 6N).

P R I m e R 18. Preparation of 2-di cyclopropanemethylamine-8 - acetyl-1,2,3,4-tetrahydronaphthalene.

A. 2 Di cyclopropanemethylamine-8-bromo-1,2,3,4-tetrahydronaphthalen.

A solution of 8-bromo-tetralone (9.0 g, 40 mmol), Dicyclopentadiene (10 g, 80 mmol) and p-toluensulfonate (0,1 EC. 4 mmol, 760 mg) in toluene (200 ml) was heated under reflux for 5 h, water was collected in the trap Dean-stark. The reaction solution was then evaporated in vacuo and the resulting residue was added to a tetrahydrofuran (200 ml) and NaCNBH3(50 mmol, 3 g) was introduced. Added gaseous HCl until saturation of the reaction solution. Then the solution was stirred at room temperature overnight, poured into ice-cold water and increased the basicity of the NaOH solution. The resulting solution was extracted CH2Cl2the extract was dehydrated (Na2SO4) and then evaporated in vacuum to obtain a brown oil. This oil was dissolved in tetrahydrofuran (200 ml) was added triethylamine (25 ml). The resulting solution was heated under reflux and filtered through a layer of ground is the group of 11.8 g of the crude titled compound as oil. Purification of this substance by the method of flash chromatography [2:1 ether/hexane (NH4OH)] gives 8.6 g of the named product as a yellow oil.

1H NMR (CDCl3): = 7,4 (d, 1H), 7,03 (d, 1H), 6,98 (t, 1H), 3,42 be 3.29 (m, 1H), 3,16-3,00 (m, 1H), 3.00 and-2,78 (m, 2H), 2,78 is 2.44 (m, 5H), 2,15-of 1.97 (m, 1H), 1,67-of 1.45 (m, 1H), 1.04 million-0.87 (m, 2H), 0,64-of 0.48 (m, 4H), 0,28-0,10 (m, 4H).

MS(FD): m/e 333 (100 M+, 335 (97, M+)

Elemental analysis for C18H24NBr

Calculated With 64,67; N 7,24; N 4,19.

Found, 64,47; N To 7.32; N 4,28.

b. 2 Dicyclopentadiene-8-(1-hydroxyethyl)-1,2,3,4-tetrahydronaphthalen.

A solution of n-utility in hexane (1.37 M, 5,65 ml, 7.7 mmol) was added to a solution of 2.0 g (6,45 mmol) of the compound prepared in paragraph a, in tetrahydrofuran at -78aboutC. Then the resulting solution was mixed at -78aboutC for 20 min and introduced acetaldehyde (12 mmol, 530 mg). After stirring at -78aboutC for 10 min the reaction solution was heated to room temperature, poured into water and then extracted CH2Cl2. The extract was dehydrated (Na2SO4) and evaporated in vacuo to obtain 2.3 g of orange oil. Purification of this oil by the method of flash chromatography [2:1 ether/hexane (NH4OH)] gave 1,53 g of the named product.

aboutC. the resulting solution was stirred at room temperature for 20 min and then cooled by the addition of isopropanol (0.5 ml). The resulting green precipitate was filtered, and the filtrate is introduced into the water. The aqueous solution was extracted with a solution of 1:3 isopropanol/chloroform, the basicity is increased by the NaOH solution, then extraction of CH2Cl2. Mixed organic layers were filtered through brownmillerite, washed with water, dried (Na2SO4) and evaporated to obtain 1.5 g of a gray oil. This oil was purified by the method of flash chromatography [5% methanol in CH2Cl2(NH4OH)] to obtain 1.2 g of a yellow oil. Further purification by the method of flash chromatography [4:1 ether/hexane (NH4OH)] gives 1.0 g of the named product.

1H NMR (CDCl3): = of 7.48 (d, 1H), 7.24 to 7,16 (m, 1H), 3,35-3,18 (m, 1H), 3,16-3,03 (m, 1H), 3,03-2,84 (m, 3H), 2,64 is 2.46 (m, 3H), 2.57 m (s, 3H), 2,16-of 1.95 (m, 1H), 1,75-of 1.55 (m, 2H), 1,02-0,88 (m, 2H), 0,57 of 0.47 (m, 4H), is 0.22 to 0.08 (m, 4H).

P R I m e R 19. Obtaining hydrochloride 2-diallylamine-8-acetyl - 1,2,3,4-tetrahydronaphthalene.

A. 2 Diallylamine-8-bromo-1,2,3,4-tatata p-toluenesulfonic acid (0.1 EQ. 1.4 g) in toluene is heated at the boiling 5 h, and the water collected in the trap Dean-stark. The reaction solution was concentrated in tetrahydrofuran (200 ml) and add Na(CN)BH3(79,92 mmol, 5,022 g). In the reaction solution is passed gaseous hydrogen chloride until saturation of the solution. The solution was stirred at room temperature overnight, poured into ice-cold water and add NaOH until an alkaline reaction. The resulting solution is extracted with CH2Cl2the extract is dried Na2SO4and concentrated in vacuo to obtain a brown oil. The oil was dissolved in tetrahydrofuran (150 ml) and add triethylamine (50 ml). The resulting solution is heated to boiling, cooled and filtered through a bed of basic alumina. The alumina is washed several times with diethyl ether. The combined filtrates concentrated to obtain 16,083 g of the crude product in the form of a black, viscous substance. Purification of the crude product flash chromatography (10% ethyl acetate in hexane (NH4OH) gives 14,118 g 2 diallylamine-8-bromo-1,2,3,4-tetrahydronaphthalene.

b. 2 Diallylamine-8-(1-hydroxyethyl)-1,2,3,4-tetrahydronaphthalen.

A solution of n-utility in hexane (1,515 M, 22,82 ml, 34,57 mmol) are added to a solution of 7.0 the solution stirred at -78aboutC for 10 min and added acetaldehyde (46,1 mmol, 2,03 g). After stirring at -78aboutC for 105 min, the reaction solution is heated to room temperature, poured into water and extracted with a mixture of chloroform/isopropanol 3:1. The extract is dried and concentrated in vacuo to obtain 7,615 g of a brownish-yellow oil. Purification of the oil flash chromatography (5% methanol in CH2Cl2gives 6,024 g 2 diallylamine-8-(1-hydroxyethyl)-1,2,3,4-tetrahydro-naphthalene.

C. 2-Diallylamine-8-acetyl-1,2,3,4-tetrahydronaphthalene hydrochloride.

The Jones reagent (8,31 ml) are added to a solution 6,024 g (22,28 mmol) of the compound obtained in stage b, in the mixture of acetone (200 ml) and 2 M sulfuric acid (68 ml) with a sufficiently slow rate to maintain the temperature of the reaction solution below 30aboutC. the Resulting mixture was stirred at room temperature until until thin layer chromatography shows that the reaction close to completion, and is decomposed by the addition of isopropanol (2 ml). The resulting solution lead to alkaline pH by adding NaOH solution and extracted with a solution of isopropanol/chloroform 1:3. The extract is dried Na2SO4and concentrate to obtain 7,196 g yellow oil. This oil cleansing is astonaut in methanol and added 3.8 g of 1 N hydrochloric acid with stirring. The resulting solution was concentrated in vacuo with the formation of a white foam, which was dissolved in methanol while heating. Once fully foam will dissolve, add ethyl acetate, resulting in a slow precipitation of a white granular solid. The precipitate was separated by filtration and receive 981 mg 2 diallylamine-8-acetyl-1,2,3,4-tetrahydronaphthalene of hydrochloride.

So pl. 131-133aboutC.

Analysis calculated for C18H23NO HCl.

Calculated With 70,69; N To $ 7.91; N 4,58.

Found, 70,49; N 7,89; N 4,50.

P R I m e R 20. Getting 2-dimethylamino-8-(o-methoxybenzoyl)-1,2,3,4 - tetrahydronaphthalene of hydrochloride.

A. 2-Dimethylamino-8-(-hydroxy-2-methoxybenzoyl)-1,2,3,4 - tetrahydronaphthalen.

A solution of n-utility in hexane (1.42 M, 14,54 ml, 20,65 mmol) are added to a solution of 3.5 g (13,77 mmol) of 2-dimethylamino-8-bromo-1, 2,3,4-tetrahydronaphthalene in tetrahydrofuran (300 ml) at -78aboutC. the Solution was stirred at -78aboutC for 10 min and add on-anisaldehyde (27,54 mmol, 3.75 g). After stirring at -78aboutC for 60 min the reaction solution warmed to room temperature, poured into water and extracted with a mixture of chloroform/isopropanol 3:1. The extract is dried Na2society flash chromatography (10% methanol in CH2Cl2(N4OH) network of 2.54 g of 2-dimethylamino-8-(-hydroxy-2-methoxybenzyl)-1,2,3,4-tet - raidernation in the form of a white solid connections.

b. 2-Dimethylamino-8-(o-methoxybenzoyl)-1,2,3,4-tetrahydronaphthalene hydrochloride.

The Jones reagent (3.0 ml) are added to a solution of 2.54 g of compound obtained in stage a, in a mixture of acetone (100 ml) and 2 M measuring acid (24,48 ml) at a speed slow enough to maintain the temperature of the reaction solution below 30aboutC. the Resulting solution was stirred at room temperature until until thin layer chromatography shows that the reaction close to completion, and is decomposed by the addition of isopropanol (2 ml). The resulting solution was poured into water and lead to alkaline by adding NaOH solution. The alkaline solution is extracted with a mixture of isopropanol/chloroform 1:3, dried Na2SO4and concentrated in vacuo to obtain 2,599 g of the crude product. The crude product is purified flash chromatography (5% methanol in HCH2Cl2(NH4OH) obtaining 1,781 g yellow oil. The oil is dissolved in methanol and added 5.8 ml of 1N hydrochloric acid with stirring. The resulting solution was concentrated in vacuo to education berprestasi to deposition (after ultrasonic treatment) of a white precipitate. The precipitate are filtered and obtain 1.48 g of 2-dimethylamino-8-(o-methoxybenzoyl)1,2,3,4 - tetrahydronaphthalene of hydrochloride. So pl. 170-172aboutC.

Analysis calculated for C20H23NO2HCl.

Calculated C 69,45; N. Of 6.99; N 4,05.

Found, From 69.20; H 7,08; N 4,07.

As noted above, the compounds of formula I according to this invention have affinity to the receptor 5-HT. Therefore, another embodiment of the invention is a method of providing agonistic effect in relation to the receptors 5-HT1Aconsisting in the introduction to the needy in mammals pharmaceutically effective amount of the compounds according to the invention.

The concept of a pharmaceutically effective amount represents the number of compounds according to this invention, the ability to communicate 1A-receptors of serotonin. The specific dose of a compound used according to the invention should be determined by specific circumstances, including, for example, input connection method of use and the condition of the patient. A typical daily dose, usually contains about 0.01 to 20 mg/kg of active compound. The preferred daily dose is about 0.05-10 mg/kg, and in iterally, subcutaneous, intravenous, intramuscular, rectal, as well as in the nose or through the skin. Special features of the compounds according to this invention is their extremely high selectivity in terms of agonistic actions for 1A-serotonin receptors in relation to other serotonin receptors.

It is shown that a number of physiological functions are exposed to serotonergic neutral systems of the brain. It is expected that the compounds according to the invention have the ability to treat in mammals a number of conditions and disorders, mediators which are 5-HT receptors, such as sexual disorders, eating disorders, depression, alcoholism, pain, anxiety, Smoking, and senile dementia. Therefore, the invention also provides methods of treating the above disorders, the effectiveness of which is determined by agonistic effect on 5-HT-receptors in mammals.

The following is a description of the experiments the aim of which was to demonstrate the ability of compounds according to the invention to act agonistically on 1A serotonin receptors. General method described in Wong et. al. J. Neutral Transm. 71:207-218 (1988).

The male rats Sprague-Dawley (weight 110-150 g) from Harlan Industri killed by decapitate. Quickly he removed the brains and cut the cortical layer at 4aboutC.

Homogenized brain tissue of 0.32 M sucrose. After centrifugation at 1000 x g for 10 min, and then at 17000 x g for 20 min was separated fraction crude synaptosomal tissue. Prepared suspension of the mass in 100 volumes of 50 mm Tris-HCl, pH 7.4, thermostatically her at 37aboutC for 10 min, and subjected to centrifugation at 50000 g for 10 minutes, the Process was repeated, and the resulting centrifugation mass prepared suspension in ice Tris-HCl, 50 mm, pH 7.4, using a method of fixing a radio-ligands have been identified by site-specific marked containing tritium 8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydro-naphthalene (3H-8-OH-DPAT), a 5-HT1A-receptors.

Commit (3H-8-OH-DPAT) was performed according to previously described method (Wond et. al. J. Neutral Transm, 64:251-269 (1985). Synaptic membranes, separated from corticales layer, thermostatically at 37aboutC for 10 min in a mixture of 2 ml of 50 mm Tris-HCl, pH 7.4:10 M of pargyline; 0.6 mm ascorbic acid, and 0.4 nm3N-8-CH-DPAT; and from 1 to 1000 nm of the test compound. Fixation was ended by filtering samples through filters from Steklovolokno ntilation fluid PCS (Amersham/Searle). Radioactivity was measured using scintillation spectrometer for liquids. In some samples also included its 8-OH-DPAT (10 M) with the aim of establishing a non-specific fixation. Specific fixation3H-8-OH-DPAT was determined by the difference between the radioactivity in the absence and in the presence of 10 M of the planned 8-OH-DPAT.

The results of the evaluation of various compounds according to this invention is shown in the table: the first column indicates the number of the example of the evaluated compounds; the following six structure of the tested compounds, the following column form salts of the test compounds, in the last column the number of the test compounds, expressed in nanomolar concentration required to inhibit 50% fixation 3H-8-OH-DPAT (in the table it refers to as IC50).

1. Substituted 2-amino-1,2,3,4-tetrahydronaphthalene or 3-aminopropane General formula

< / BR>
where R is C1-C4-alkyl, C3-C4alkenyl;

R1C1-C4-alkyl, C3-C4alkenyl;

X-CH2O;

R2C1-C6-alkyl, C1-C6-alkyl substituted by halogen or C1-C4-alkoxy, phenyl, phenyl substituted by halogen or C1-C4and islote-additive salt.

2. Substituted 2-amino-1,2,3,4-tetrahydronaphthalene or 3-aminopropane General formula

< / BR>
where R is C1-C4-alkyl, C3-C4alkenyl;

R1C1-C4-alkyl, C3-C4alkenyl;

X-CH2O;

R2C1-C6-alkyl, phenyl, phenyl substituted by halogen or C1-C4-alkoxygroup, phenyl-C1-C4-alkyl; cyclo-C3-C7-alkyl.

 

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