Racemic and optical active derivatives of tetralin and 7-hydroxytyramine

 

(57) Abstract:

Usage: in medicine. The inventive product is a derivative of tetralin f-ly: R-CH2-O-tetralin-(YY')-CH-R'where R is 2 - pyridyl, 2-chinolin, R'-C1-C3-alkyl, Y and Y'together form a carbonyl group or individually Y is hydrogen, Y'-hydroxyl derivatives of 7-hydroxy-tetralone. table 1.

The present invention relates to substituted tetralins, 7 hydroxytyramine and close to them compounds of formula (1) below, which are due to the inhibition of 5-lipoxygenase enzyme and/or blocking leukotriene receptors are useful for the prevention or treatment of asthma, arrhythmia, psoriasis, ulcers, myocardial infarction and related pathological States in mammals. The present invention also concerns pharmaceutical compositions and intermediates used for the synthesis of the above compounds of formula (1).

Craft and al. in U.S. patent No. 4 661 596 describe the connection that represents disubstituted naphthalenes, dihydronaphthalene or tetraline having the formula:

< / BR>
in which the dotted lines represent possible double bonds, Rais a 2-pyrid who was Salil or 1-alkyl-2-benzimidazolyl, and Rbis gidroksilnuyu, lower alkoxy or perfluoroalkyl. As the compounds of the present invention, these compounds inhibit lipoxygenase enzyme and antagonizing action of leukotriene D4 and therefore useful for the prevention and treatment of asthma. Used in this description of chemical nomenclature corresponds to the nomenclature adopted by the International Union of pure and applied chemistry, "Nomenclature of organic chemistry, 1979 Edition. "Pergamon Press, new York, 1979

The present invention relates to racemic or optically active compounds having the structural formula:

(1)

in which

n is 1; X represents CH2; X'represents CH2; Y and Y'taken together form a carbonyl group, or Y and Y'taken separately, Y is hydrogen and Y'is gidroksilnuyu; Z represents CH2; Z'represents CH; R represents 2-pyridyl or 2-chinolin; and R'is a (C1C3)alkyl.

Given the ease of obtaining and valuable biological activity, preferred are the compounds of formula (1), in which the fight C2or C3alkyl. Most preferred are racemic or optically active compounds having the relative stereochemical formula:

< / BR>
especially those of racemic or optically active compounds of the formula (II) or (III) in which X and X1each represents CH2R represents 2-pyridyl or 2-chinolin and R1represents n-propyl, and a pair of optically active enantiomeric compounds of the formula (III) in which X and X1each represents CH2, R represents a 2-chinolin and R1represents n-propyl.

The present invention also describes pharmaceutical compositions for use in mammals animals, which contain the compound of formula (I) and a pharmaceutically acceptable carrier; and a method of inhibiting 5-lipoxygenase enzyme and/or blocking leukotriene D4 receptors in mammals animals to prevent or treat asthma (especially in men), arthritis, psoriasis, ulcers of the gastrointestinal tract or myocardial infarction.

Finally, the present invention relates to a valuable intermediate compounds of the structural formula:

in which n, X, Z and ZPU, or Y2and Y3taken separately, Y2represents hydrogen and Y3represents a hydroxy-group; and Rarepresents a hydroxy-group.

The present invention is practically feasible.

The compounds of formula (1) in which Y + Y'carbonyl, or Y is N and Y'HE is a, and X1represents CH2regardless of whether they are geometric (CIS-TRANS) or optical isomers, obtained by chemical transformations shown in schemes 1 and 2, in which n, X, Z, Z1R and R1defined above. Below are discussed in detail various chemical transformations on these schemes, as well as chemical transformations required to obtain the compounds of formula (1) with different values and Y, Y'and X1and methods of separation of CIS-TRANS and optical isomers.

The condensation according to the scheme 1 is usually made with a phenolic group in protected form, as shown, and the metal is the preferred protecting group. According to preferred conditions uses a molar excess of the desired aldehyde and a molar excess of a secondary amine, the education raminosoa intermediate compounds.

< / BR>
< / BR>
This reaction is usually carried out in inert to the implementation of the mixture solvent, and particularly suitable solvent for this purpose are the lower alcohols, such as methanol. The temperature conditions of this chemical transformations are not critical, they usually range from 0 to 70oC, and is particularly suitable room temperature.

The term "inert to the reaction medium solvent" mean a solvent which does not react with the starting substances, chemicals, intermediate products or final products in such a way as to adversely affect the yield of the desired product.

C-Alkylation according to the scheme 1, is performed by the first transformation of the ketone (A) in its lithium salt, usually in situ, by affecting mainly one molar equivalent of a strong spatial difficult grounds, such as diisopropylamide lithium, usually carried out at low temperature (for example, about -40 ° to -80oC, typically at a bath temperature of dry ice-acetone). This salt, in turn, is subjected to the interaction with the alkylating reagent, preferably highly reactional already at a higher temperature (for example, from about 0 to 40oC). The last specified reagents conveniently introduced into a cold solution of lithium salt, and temperature allow to rise to room as reaction. The reaction of obtaining salt and alkylation is usually carried out in the same inert to the reaction mixture solvent (e.g. tetrahydrofuran). For specialists in this area should be clear that any free hydroxy or carboxypropyl in the alkylating reagent should be in a protected form.

Conversion using catalytic hydrogenation (dibenzylamine, enter H2in a double bond) according to schemes 1 and 2 are carried out under normal conditions, usually inert to the reaction mixture the solvent, and preferably used as the noble metal catalyst, and under conditions of moderate temperature (for example, from about 0 to 70oC and under hydrogen pressure (for example, under a pressure of about 1 to 10 atmospheres). Although in some cases it may be desirable higher pressure indicated moderate pressure allow the use of much lower labor costs and less expensive equipment.

Suitable for a given t is ez media and also known for their catalytic compounds such as oxides, chlorides, etc. Examples of suitable catalysts carriers are carbon, silicon dioxide, barium sulphate. The catalysts can be prepared directly in the workflow conditions by pre-restoration of suitable salts of catalytic compounds.

Examples of preferred catalysts are 5% palladi coal, 5% platinum on charcoal, 5% rhodium on charcoal, platinum chloride, palladium chloride, platinum oxide and the oxide of ruthenium.

The most preferred catalyst according to the invention is palladium on coal. Suitable solvents for the hydrogenation process are the lower alkanols, ethyl acetate and tetrahydrofuran.

Simple methyl ester [compound of formula (C)] according to scheme 1 are released with the formation of the corresponding phenol derivative is also generally accepted ways; for example, they are released with concentrated NVG or VVG3.

Phenol alkylation as shown in scheme 2, is a normal reaction of nucleophilic substitution.

This reaction is usually carried out in the presence of aqueous by-product HX2).

In those substrates that contain aliphatic alcohol group (for example, compound IV, in which Y2represents N and Y3is a HE), are commonly used bases of sufficient strength to transformations of this group in the anion, in a quantity not more than sufficient to turn more acidic phenol in salt. When any of these reagents contains a group with acidity, similar to or greater than the acidity of the compounds nucleophilic substitution, it is also potentially involved in the process of the group is welcomed to enter in a protected form (for example, heteroaromatic phenolic group as methoxy - or benzyloxy, the carboxyl group in the form of a complex with methyl or benzyl ether removed by hydrolysis or hydrogenolysis according to the described examples).

These nucleophilic substitution reaction is carried out in inert to the reaction medium solvent, preferably such that it has less acidity than displacing phenol, alcohol or mercaptan. Most preferred are polar aprotic solvents such as dimethylformamide or acetone, usually with malarine is satisfactory temperature in the range of about from 10 to 70oC, and the most desirable room temperature. According to one preferred options, phenol, alcohol or mercaptan irreversibly converted to the anion by using a base such as sodium hydride. According to other preferred options, as the base used FOR2CO3in the presence of NaI; or used Cs2CO3in the presence of CsI.

The reaction of the "recovery" according to the scheme 2 requires recovery of the ketone to the secondary alcohol, for which there are a number of reagents selective action. When there are no other groups that are recoverable using LiAlH4(such as a carboxy - or ethoxycarbonyl), this reagent is well suited for this purpose. On the other hand, when there are such groups, as a reducing reagent is preferred NaBH4. In any case hydride recovery are normally inert to the reaction mixture solvent (such as tetrahydrofuran in the case of LiAlH4, methanol or a combination of methanol/tetrahydrofuran in the case of NaBH4). In any case, the temperature is not critical, usually quite satisfactory temperature in the range from 0 to 50oWith, and placed a mixture of CIS - and TRANS-isomers (as illustrated by the formulas (II) and (III), and when this hydride recovery is usually observed this result. If a particularly desirable one of these isomers, typically defined such conditions recovery, which favor the formation of the desired isomer. For example, the restoration of NaBH4in the presence of cesium chloride tends to favour the formation of the CIS isomer. Catalytic hydrogenation is usually desirable way to recovery, and, as a rule, it is carried out under conditions that are somewhat more stringent than those described above (e.g., longer, higher content of catalyst, higher temperatures and/or pressure).

The hydrogenation is carried out preferably in such substrates, as

(V)

which contain no other easy gidriruemyi group. The Pd/C catalyst favors the formation of the CIS isomer. However, as a result of changing conditions and replacement of the catalyst of this trend can be modified and even reversed.

When, according to this invention, are formed and CIS-and TRANS-isomer at the same time, they usually can be divided standard chemical methods (for example by izbirateli (IV), in which Y and Y1or Y2and Y3form a carbonyl group, contain an asymmetric carbon atom in the alpha position, which is adjacent to the carbonyl group, and, therefore, are racemic compounds capable of division into optically active enantiomers by, for example, conversion of the racemate then reduced to diastereoisomeric salts with optically active acid, which are usually able to be separated by fractional crystallization.

As a possible option, if the substrate contains a carboxyl group, formed partial diastereoisomeric salts with optically active organic amine. Optical activity can coil the use of optically active reagent at this stage, resulting in an asymmetric carbon atom, for example in the use of optically active catalyst type catalyst Wilkinson, or a noble metal deposited on optically active media, when carrying out the hydrogenation. Optically active ketones can also be obtained by conventional re-oxidation of optically active alcohol, described in the next paragraph, for example, by oxidation Jones is Aut a hydrogen and Y1(or Y3) is a HE, contain two asymmetric carbon atom, corresponding to the two racemates and four optically active compounds. One of these racemates is above CIS-isomer and the other is the TRANS-isomer. Each of these racemates are capable of division into a pair of enantiomers through diastereoisomeric salt, as explained in detail above. However, it is desirable to convert this racemic alcohol in the appropriate diastereoisomeric esters or urethanes formed with optically active acid or isocyanate. Such derivative compounds with covalent links usually are subjected to various methods of separation (e.g., chromatography), different from the mode of separation diastereoisomeric salts.

These diastereoisomeric esters are formed from alcohols and optically active acids by standard methods, are usually ways, including activation of the acid, for example the acid chloride, mixed anhydride with alkylphosphonate, or dehydrative agent combinations, such as dicyclohexylcarbodiimide.

Preferred optical active acid in this case is S-O-acetylindole acid. They hydrolyzed the conventional ways, for example, aqueous acid or aqueous base, and the resulting optically active enantiomeric alcohols.

Proletarienne esters of this invention are obtained by methods similar to the methods used for the synthesis of esters, as described above. Esters with alpha-amino acids, including natural L-amino acids, usually obtained from the appropriate amino acids in which the alpha-amino group, group Deputy NH2or NH (e.g., lysine, ornithine, arginine, histidine, tryptophan), hydroxy-group (serine, homoserine, threonine, tyrosine), mercaptopropyl (cysteine) and carboxypropyl (glutamic acid, aspartic acid) are in protected form (for example N-benzyloxycarbonyl, O - and S-benzyl) that are normally removed by catalytic hydrogenation in the next stage. Similarly, in the case of esters with primary or secondary aminosalicylate these acids will form a paired connection with the protected amino groups. Such protection is, of course, is not mandatory in the case of acids containing a tertiary aminosalicyclic. And finally, carboxy substituted esters are best obtained from bretania, it is known that arachidonic acid is metabolized in mammals animals in two different ways, one of which leads to the formation of prostaglandins and thromboxanes, and the other leads to various oxidation products, called leukotrienes, which are designated by an alphanumeric combination, for example B4, C4 and D4. The first stage of this oxidative pathway is the oxidation of arachidonic acid under the influence of 5-lipoxygenase enzyme, the enzyme that normally inhibited by compounds /1/, corresponding to this invention, thus blocking the synthesis of all leukotrienes. He as such provides a mechanism to use these compounds for treating or preventing asthma (when LTC4 and LTD4 are mediators of inflammation), arthritis (when LTB4 is a mediator of inflammation), psoriasis (when LTB4 is a mediator), ulcers (when LTC4 and LTD4 are mediators) and myocardial infarction (when LTB4 is a mediator). The increase of this inhibiting the enzyme activity is manifested in the ordinary ability of these compounds to anlagenservice leukotriene D4 (that is, to block receptors LTD4). Typically, the data connection antagonizing also leukotrien B4. Informediary formula (1) in the "in vitro" is determined by the following test. Cells RBL-1 stored in the form of a monolayer, are grown for 1 or 2 days in tissue culture in a basic medium (Eagle) with salt Earl plus 15% fetal bovine serum, supplemented with antibiotic (antimycotic solution (GIBCO). Cells once rinsed with RPMI 1640 (GIBCO) and re-suspendered in RPMI 1640 plus 1 micromolar glutathione to the cell density of 1 x 10 cells/ml 0.5 ml of this cell suspension is incubated at 30>198>C together with 0,001 ml dimethanesulfonate solution medicine for 10 minutes. The reaction begins when the simultaneous input of 0.005 ml (14C) arachidonic acid in ethanol and 0.002 ml A in dimethyl sulfoxide to obtain a final concentration respectively 5.0 and 7.6 micromol. After incubation for 5 minutes at a temperature of 30oThe reaction is terminated by the input of 0.27 ml of acetonitrile/acetic acid (100/0,3) and this environment is clarified by centrifugation. Is the analysis of the distribution of the product through the injection of 0.2 ml Svetlanova surface layer from the centrifuge column liquid chromatography high resolution. Separation of radioactive products is carried out in a radial column of ARTS CN (internal diameter 5 mm, Waters) with ispolzovat from 35 to 70% for 15 minutes at 1 ml/min Quantification is performed using the recording device Berthold radioactivity has a built-in integrator and a cell volume of 0.2 ml Omniplan 2.4 ml/min (NEN) with a column for the thread. Total individual dose for each product is calculated as a percentage of total doses and then compared with the average control values. These results are expressed as the percentage of suppression and are expressed in the form of curves, depending on the logarithm of the concentration of the drug. Values 1C50determined graphically (see table).

For compounds known from U.S. patent 4 661 596 value 1C50inhibition of the enzyme lipoxygenase 50 micromol that approximately 5 to 10 times less than the activity exhibited by the compounds of the present invention.

Conducted testing of leukotriene receptor 4 (LTD4) determining the ability of the compound to compete with radiolucency LTD4 for specific points of LTD4 receptor on lung membranes of the Guinea pig. In this test, Guinea pigs at the age of 3 to 4 weeks acclimatized under standard conditions for 3 days, after which they would wordplays. The final age of the pigs was 24 31 d is Ali cavity of the thorax and lung were removed, washed in 50 mmol. buffer Tris (pH 7.0) and placed in pure buffer solution. In this and in all subsequent operations, all tissue and buffer solutions were kept on ice during preparation, and all operations centrifugation was carried out at a temperature of 4oC. Tissue of bronchi and connective tissue is removed from the lungs. This tissue was weighed and placed in 50 ml polycarbonate tubes with buffer solution in a ratio of 1 g tissue/3 ml buffer solution. The fabric was gomogenizirovannykh through the device of Tissuemizer of Tekman at full speed for 30 seconds and centrifugals in a rotating device Sovall SS-34 speed 3250 rpm for 15 minutes. The surface layer was centrifugals with a speed of 1900 rpm for 10 minutes. The obtained compacted sediment was again suspenderbelt in buffer solution using a homogenizer Tissuemizer with an average speed of (item 75) for 10 seconds. This new suspension was again centrifugals speed 19000 rpm for 10 minutes. The resulting precipitate was again suspenderbelt using device Tissuemizer with low speed (position 50) for 10 seconds in 1 ml of buffer solution on g is of the aliquot into polypropylene tubes and stored at -70oC. In a polystyrene test tube was introduced the following components:

(1) 25 μl of one of the following:

A. dimethyl Sulfoxide (to determine total binding).

Century 1 micromol.LTD4 (to determine non-specific binding).

C. 30 nanomol 100 micromol compounds in dimethyl sulfoxide.

(2) 0,025 ml 3H-LTD4 (with specific activity of 30 to 60 Ci/mmol) in 50 mmol Tris buffer (pH 7.0) + 10 micromol L-cysteine (12000 15000 CPM/0,025 ml).

(3) 0.2 ml of the diluted membrane preparation (1 Mg/ml) (the drug was diluted in 50 micromol. buffer solution of Tris + MgCl2so in 200 microl. protein concentration was achieved MgCl210 micromol).

These reaction tubes were incubated at 25oC for 30 minutes. In each tube was injected with 4 ml of cold buffer solution of Tris + 10 micromol MgCl2. The content they were quickly filtered through a filter Whatman GF/C separation device Yeda. The filter were washed three times in four milliliters of buffer solution of Tris-MgCl2. This filter is transferred into scintillation vials. In a vial was introduced ultravioleta scintillation fluid. The vial was closed and subjected to a swirl motion and subjected to detection is>/BR>SB (X NSB)/(TB NSB)

where X cpm counts per minute of the sample;

NSB cpm counts per minute of nonspecific binding;

TV CPM counts per minute of the total binding.

The percentage of specific binding represented graphically as a function of the concentration of the compound. 1C50is the concentration at which is 50% of SB. Ki is calculated according to the following formula:

Ki (IC50)/[1+(L/Kd)]

where L is the concentration of the injected ligand (micromol) CPM I/CPM 1 micromol 3H-LTD4;

d 1 micromol (the dissociation constant).

Human neutrophilic leukocytes are used to measure competition test molecules with (3H)-LB4 to bind LTB4 receptor. In this test, the neutrophils were separated from heparinized human peripheral blood (usually 100 ml) using a gradient Hypagye-Ficoll (density 1,095 g/ml). To re-suspension of the cells used balanced salt solution Hank (HBSS) containing 0.1 g/100 ml bovine serum albumin (HBSS BSA). This one-step process Hypague-Ficoll gives high-purity population of the neutrophil (more than 95%). Cell viability is determined by dye exclusion Trypanosoma blue (must be more than 95%), and fu (85% positive). Exposed to the test compounds dissolved in dimethyl sulfoxide to a concentration of 100 micromol. These solutions are diluted 500 times with HBSS-BSA. 100 micromolar concentration of the drug is achieved by entering the dilution of sample in aliquot (0.5 ml) into the reaction tube. Prepared a series of dilute solutions of 1 3 and 1 5 (adopted), and lukwata (0.5 ml) of these diluted solutions is introduced into the incubation tube. In borosilicate test tubes (12 x 75 mm) is introduced (3H) LTBA/NEN: specific radioactivity of more than 180 CI/mmol; 0,005 ml in absolute ethanol). Then put 0.5 ml of drug solution (see above). The binding reaction becomes infected by the addition of 0.5 ml ice the neutrophil cell density (5 x 106cells/ml) and continues at a temperature of 4oC for 30 minutes. The incubation is terminated by rapid filtration through a filter Whatman GF/C glass with separation of free from bound radioactive labeled ligand. These filters are washed three times with chilled ice HBSS, dried, placed in 4 ml ultrapoor and exposed display. Total binding is defined as CPM, present on the filter (cell associated), when radioactiv the mini-linking is obtained by incubation of cells with radioactively labeled ligand plus 1 micromol. aradioactive labeled LTB4. Specific binding is the total binding CPM, adjusted for non-specific binding CPM. Each tube is corrected for nonspecific binding. Point premaxillae offset radioactive labeled ligand are determined by graphical analysis of the semi-log curve of the percentage of specific binding (in the absence of any competitor) depending on concentration.

For the evaluation of compounds of formula (1) in the "in vivo" they are tested by the so-called analysis on mortality PAF.

Materials for testing.

Mouse: male species CD1, all about the same weight (about 26 g), 12 pieces per group.

The media dispensing medications, administered orally: EES (5% ethanol, 5% emulphor, 90% saline). Kept at room temperature.

Medications: for routine screening dose of 50 mg/kg 20 mg drug dissolved in 4 ml of EES using ultrasonic treatment in an ultrasonic bath or grinding in the grinding device Ten Broech for dissolving medication, if necessary. If the solubility is still a problem, Lakers 2.5 mg/ml bovine serum albumin (BSA, Sigma A 4378) and 0.05 mg/ml propranolol (Sigma H 0884). Daily prepared fresh batch and aged at room temperature. Factor activation of promocao (F): prepared 10 micromol. the main solution by dissolving 1 mn PAF (Calbiochem 429460) of 0.18 ml of ethanol. This solution is kept at -20oC and diluted in medium-to-day use. The concentration used PAF is regulated so that when you enter a dose of 0.1 ml/10 g body womersley about 80% of the untreated control organisms. It is usually 0,028 g/kg (dilute basic solution 1 to 2034). The solution is prepared in glass containers and can be used with glass syringes for minimizing the adhesion PAF. He is aged at room temperature. Positive control: Use finedon in the amount of 25 mg/kg (approximate dose ED50).

Method.

45 minutes before the injection of PAF mice treated by oral input medicines in an amount of 0.1 ml/10 g body. After a 35-40 minute they are placed under the influence of a heating lamp to extend the tail vein for injection of PAF. PAF is administered by intravenous injection in an amount of 0.1 ml/10 g body weight, and death usually to the control results. Due to the fact that this analysis is sensitive to endogenous catecholamines (e.g., protection of mice beta - agonists), to address this potential problem, use propranolol. It also helps if the mouse acclimatise to room conditions prior to testing, and if the room noise and temperatures remain moderate and permanent. The distance from the heating lamp must be installed so that the vasodilatation occurred without creating visible stress in mice. Fasting mice should be excluded.

The variations.

1. The time for oral dosing can be changed.

2. An intravenous dosage of medication possible through joint injection drugs and PAF in the same amount and in the same media as described above. For co-injection of PAF is prepared in double concentration from the desired concentration in saline with BSA and propanolol, as described above, and the drug is prepared in double concentration from the desired concentration in the same medium. Both drugs are mixed in equal volumes immediately before injection.

For use for the prevention or treatment of asthma, arthritis, psoriasis and ulcers W is ingibiruet 5-lipoxygenase and/or blocking leukotriene receptor approximately 0.5 to 50 mg/kg/day in single or divided daily doses. A more preferred dose limit is 2 to 20 mg/kg/day, although in some cases the doctor may need a dose beyond these. The preferred method of drug administration is oral, but in some cases, the preferred parenteral input (e.g., intramuscular, intravenous, intradermal, for example in cases where the absorption of drugs via oral input is reduced under the influence of the disease or when the patient is unable to swallow the medicine.

Compounds corresponding to this invention, are normally introduced in the form of pharmaceutical compositions comprising at least one of the compounds of formula (1), together with a pharmaceutically suitable carrier or diluent. Such compositions are usually prepared well-known manner using solid or liquid carriers or diluents, as is customary for the appropriate input method: oral input the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders, etc., and for parenteral input in the form of injection solutions or suspensions, etc.

6-(2-Chinolin)methoxy-4-chromanone.

A mixture of 6-hydroxy-4-chromanone (10.0 g, 0,0609 mol), 2-chloromethylpyridine (11.9 g, 0,0670 mol), sodium iodide (109 g, 0,0670 mole), potassium carbonate (25,3 g, 0,183 mole) and acetone (200 ml) is heated under reflux overnight in an atmosphere of N2. After 17 hours the mixture becomes lighter and analysis by thin layer chromatography (10% ethyl acetate) CH2Cl2shows the complete transformation of the raw product in a slightly less polar product. The mixture is cooled, filtered and the filtrate concentrated in vacuo. The residual product concentration dissolved in ethyl acetate (400 ml), washed with H2O and brine, dried over MgSO4and concentrated in vacuo to a dark brown oil. After purification in a column of silica gel with elution with a mixture of 10% ethyl acetate (CH2Cl2) gives the desired product in the form of a whitish solid, 15.3 g (82%), melting point 112 114oC; analysis by thin-layer chromatography (ethyl acetate:CH2Cl2in the ratio 1:9), Rf of 0.30.

Example 2.

3-Oxymethylene-6-(2-chinolin)methoxy-4-chromanone.

Into a solution of the desired product of the preceding example (7,00 g, 0,0229 mol) and ist 2.2 g (0,0458 mole) 50% sodium hydride in mineral oil. Yellowish-green mixture was stirred at room temperature for 5 minutes, then add 2 drops of ethanol to initiate the reaction. Within 5 minutes, the mixture turns into a red-orange emitting gas and is slightly exothermic. This mixture was stirred at room temperature for 1 hour, after which, according to the analysis by thin layer chromatography (5% CH3OH/CH2Cl2), the source material is fully converted to a more polar product. This reaction mixture is poured into 400 ml ice water, the pH is brought to 5 by 2 normal HCl, and it is extracted with ethyl acetate (500 ml). The organic layer is washed with water and brine, dried over MgSO4and concentrated in vacuo to education pasty yellow solid. After repeated stirring with hexane to remove mineral oil is obtained the desired product with a yield of 85% thin layer chromatography (CH3OH CH2Cl21:19), Rf 0.40 in.

Example 3.

3-Diazo-6-(2-chinolin)methoxy-4-chromanone.

In the solution of the final product of the preceding example (of 7.60 g, is 0.023 mol) and dry triethylamine (6.4 ml, 0,046 mol) in dry CH22Cl2(25 ml). The reaction mixture is slowly heated to room temperature overnight with stirring. After 18 hours, as shown by thin layer chromatography (20% ethyl acetate (CH2CLl2) there is a complete disappearance of starting material and formation of a less polar product. This mixture is processed 1 normal NaOH (100 ml) and stirred for 10 minutes. After treatment with saline layers are separated and the organic layer is diluted with 200 ml of ethyl acetate. Then the methylene chloride is removed in vacuo. An ethyl acetate residual product is washed with water and brine, dried over MgSO4and concentrated in vacuo, and the result is the final desired product as a dark yellow solid, 6 g (90%); analysis by thin-layer chromatography (ethyl acetate: CH2Cl21:4), Rf 0,27.

Example 4.

3 Cyclohexyloxy-6-(2-chinolin)methoxy-4-chromanone.

In the suspension of the final product of the preceding example (1.50 g, a 4.53 mol) and cyclohexanol (1.7 ml, and 16.4 mmole) in dry toluene (25 ml) at a temperature of 70oWith injected 5 mg dimer of rhodium acetate (2-shaft). During the reaction rapidly excreted N2and mix with the education of the less polar product and the presence of only traces of starting material. The reaction mixture is concentrated in vacuum. The residual product is dissolved in ethyl acetate (100 ml), washed with water and brine, dried over MgSO4and concentrated in vacuo to education oil amber color. After chromatographic separation in a column of silica gel with elution with a mixture of 10% ethyl acetate (CH2Cl2it turns out the desired product as a yellow precipitate, 0,59 g (32%); analysis by thin-layer chromatography (ethyl acetate:CH2Cl2in the ratio 1:4) Rf 0,68. IR spectrum (KBr) 2940, 1700, 1490 cm-1mass spectrum (m/e) 403, 1780 (M+). Carrying out the process in the same way, but using artilleryman instead of cyclohexanol is obtained 3-octylthio-6-(2-chinolin)methoxy-4-chromanone.

Example 5.

CIS and TRANS-3-cyclohexyloxy-6-(2-chinolin)methoxy-4-chromanol.

In the solution of the final product of the preceding example (580 mg, of 1.44 mol) in methanol (30 ml) at a temperature of 0 to 5oC enter 56 mg (1,45 mmole) sodium borohydride. The reaction mixture is heated to room temperature with stirring. After 1 hour, as shown by thin layer chromatography (20% ethyl acetate) CH2Cl2), there is a complete conversion of starting material with the image is dissolved in ethyl acetate, washed with water and brine, dried over MgSO4and concentrated in vacuo, and the result is a yellow-white solid. After separation in a chromatographic column on silica gel with elution with a mixture of 20% ethyl acetate (CH2Cl2end of the less polar CIS-product as a yellow foam (450 g) and the more polar end of the TRANS-product as a pale yellow oil (30 mg). The total yield of 82% of the CIS-isomer precrystallization from toluene-hexane to education 417 mg yellow-white needle crystals, melting point 127 130oC, and the TRANS-isomer is mixed with hexane education 11 mg of a white solid, melting point 63 65oC.

CIS-isomer. Range IR (KBR) 1500, 2940 cm-1.

Mass spectrum (m/e) 405, 1922 (M+).

Elementary analysis.

Calculated by the formula C25H27NO4.

C, 74,05; H, OF 6.71; N, 3,45%

Found: C, 74,07; H, 6,69; N, 3,38%

The TRANS-isomer. IR spectrum (KBR) 1495, 2940 cm-1.

Mass spectrum (m/e) 405, 1980 (M+).

In the implementation process in the same way 3-attitional previous example becomes a mixture of CIS - and TRANS-3-octylthio-6-(2-chinolin> By processes in the same manner as described in example 4, the final product of example 3 (1.12 g) and isopropyl alcohol into the connection, which, after chromatographic separation gives the desired end product, 1.48 g (81% ), with a melting point 85oC; analysis by thin-layer chromatography (ethyl acetate:CH2Cl2in the ratio 1:9), Rf of 0.35.

Example 7.

CIS - and TRANS-3-(1-methylethoxy)-6-(2-chinolin)methoxy-4-chromanol.

By processes in the same manner as in example 5, the end product of the preceding example (1,38 g) is transformed into the desired final compounds after their chromatographic separation.

CIS-isomer. 1.19 g (86% ), melting point 116 118oC, less polar. IR spectrum (KBr) 1490 cm-1. Mass spectrum (m/e) 365, 1360 (M+).

Elementary analysis.

Calculated according to the formula: C22H23NO4< / BR>
C, 72,31; H, 6,34; N, 3,83%

Found: C, 71,95; H,6,01, N,3,76%

The TRANS-isomer. 0.09 g, melting point 102 103oC, more polar. IR spectrum (KBR) 1500 cm-1. Mass spectrum (m/e) 365, 1360 (M+).

Example 8.

2-Butyl-3,4-dihydro-7-methoxy-1(2H)-naphtalene.

In solution (at a temperature of -78< 2,5 Mol n-utillity slowly injected (within 15 minutes) a solution of 5.00 g (28,4 mmole) of 3,4-dihydro-7-methoxy-1(2H)-naftalina in 10 ml of tetrahydrofuran. The reaction mixture is stirred for 10 minutes at a temperature of -78oC. This cooling bath is then replaced by a bath of ice-water (with a temperature of 0oC), and then quickly enter 3.98 ml (35 mmol) of n-butylidene. Then enter hexamethylphosphoramide (10.4 ml, 60 mmol) and the resulting solution was stirred at 25oC for 2 hours. This reaction mixture is introduced into a mixture of 200 ml of saturated ammonium chloride with 300 ml of a simple ester. The organic layer is separated, washed with saturated ammonium chloride (200 ml), saturated sodium chloride (200 ml), dried over magnesium sulfate and evaporated with the formation of oil, which is purified in a chromatography column on silica gel (250 g) with elution with a mixture of 5% ether-hexane, and the result is 1.6 g (24%) of the desired final product in the form of oil. Range1H-NMR (COCl3) Delta (ppm): 0,92 (Shir.T. CH3), 1,1 2,7(m N), 2,87 (m, CH2), 3,80 (OCH3), a 7.0(m, 2ArH) and 7,41(D. J 2 Hz, ArH).

Example 9.

2-Butyl-3,4-dihydro-7-hydroxy-1(2H)-naphtalene.

A mixture of 19.1 g (82,4 mmole) of the final product from the previous example in 77 ml of glacial acetic acid and 77 ml of concentrated Hydrobromic acid is heated with education is cooled, introduced into 1 liter of a mixture of ice-water and extracted three times with simple ether in portions of 200 ml. United ethereal extracts are washed with 1 liter of water and 500 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to obtain an oil, which solidifies on standing, and the result of 17.2 g (96%) of the final desired product, which precrystallization of a mixture of simple ether-hexane; melting point of the product 55 58oC; IR spectrum (l3) 3352, 3580, 1671 cm-1.

Range1H-NMR (CDCl3) Delta (ppm): 0,90(m, CH3), 1,1-2,7 (m N); 2,90 (m, CH2and 7.1 (m, 2ArH) and 7.75 (Shir.with. 1ArH).

Elementary analysis.

Calculated according to the formula: C14H18O2: C 77,03; H, 8,31%

Found: C, 77,25; H, 8,25%

Example 10.

2-Butyl-3,4-dihydro-7-(2-chinolin)-methoxy-1(2H)-naphtalene.

A mixture of 4.35 g (20.0 mmol) of the final product of the preceding example, 4,27 g (20 mmol) of the hydrochloride of 2-chloromethylpyridine, 16.3 g (50 mmol) of cesium carbonate and 200 mg (0,769 mmole) of cesium iodide in 43 ml of acetone is heated under reflux for 21 hours. The reaction mixture is cooled, diluted with 43 ml of a simple ether and filtered. The filtrate typowanie dichloromethane, and the result is a desired end product in the form of oil (of 5.55 g). This purified oil is crystallized by stirring with hexane, and the result is 3,22 g (45%) of crystalline product, melting point 49 51oC.

Mass spectrum (m/e 359 (M+), 303, 142 and 115. The spectrum of IR (l3) 1670, 1600, 1568 cm-1.

Range1H-NMR (DCl3) Delta (ppm): 0,90 (m, CH3), 1,1 2,7(m N), 2,85 (m, CH2), 5,34 (S. OCH2) and 7.1 to 8.2 (m AGN).

Elementary analysis.

Calculated according to the formula: C24H25NO2:

C, 80,18; H, 7,01; N, 3,90%

Found: C, 80,44; H,7,08; N, 3,76%

Example 11. CIS - and TRANS-2-butyl-1,2,3,4-Tetra-hydro-7-(2-chinolin)methoxy-1-naphthol.

In solution (oC) a 2.00 g (5,57 mmole) of the final product of the preceding example in 40 ml of methanol is injected 1.26 g sodium borohydride. The reaction mixture is stirred for 2 hours at ABOUToC and then concentrated in a rotary evaporator apparatus. The residual product concentration is dissolved in a mixture of simple ether and saturated NaCl. The organic layer is dried over magnesium sulfate and evaporated to education oil, which is purified in column liquid chromatography modest dalam the order of 1.0 g (50%) of the CIS isomer and 770 mg (38%), TRANS-isomer, both in the form of oil. Both isomer crystallized from a mixture of simple ether/hexane.

CIS-isomer. The melting temperature of 78.5 80oC. Mass spectrum (me) 361 (M+), 342, 286, 143, 142 and 115. The spectrum of IR (NSDP3) 3590, 3400, 1609, 1600, 1572 cm-1.

Range1H-NMR (DCl3, 300 MHz) Delta (ppm): 0,89(t J 7 Hz, CH3), 1,2 1,7(m N), 2,55 2,82 (m, CH2), 4,53 (D. J 4.0 Hz, CH), 4,73 (HE), 5,33 (C. CH2O), 6,85 (D. D. J 8, 2 Hz, ArH), 6,98 (m, ArH), 7,49(D. D. J 8, 8 Hz, AGN), 7.62mm(D. J 8 Hz,ArH), 7,68 (D. D. J 8, 8 GS ArH), to 7.77 (D. J 8 Hz, AGN).

Elementary analysis.

Calculated according to the formula: C24H27NO2:

C, 79,74; H, 7,53; N, A 3.87%

Found: C, 79,44; H, 7,42; N, 3,81%

The TRANS-isomer. Melting point 70 72oC. Mass spectrum (m/e 361 (M+, 286, 143, 142 and 115. IR spectrum (l3) 3580, 3435, 1605, 1600, 1575 cm-1.

Range1H-NMR (CDCl3, 300MHz) Delta (ppm): 0,87 (so J 8 Hz, CH3), 1,1 1,8 (m, 8H), of 1.97 (m, 1H), 2,66 (m, CH2), 4,32 (so J 6,98 Hz, CH), 5,33 (S. och2), 6,83 (D. D. J 8, 2 Hz, ArH), of 6.96 (D. J 8 Hz, ArH), 7,15 (D. J 2 Hz, ArH), 7,49 (D. D. J 8, 8 Hz, ArH), 7,63 (D. J 8 Hz, ArH), 7,66 (D. D. 8; 8 Hz, ArH), to 7.77 (D. J 8 Hz, ArH), 8,03 (D. J 8 Hz, ArH), 8,13 (D. J 8 Hz, ArH).

Elementary analysis.

Calculated according to the formula: C24H27NO2:

C, 79,74; H, 7,53; N, A 3.87%

Found:-1-naphthyl-R-O-acetylindole.

In solution (OoC) 764 mg (2.12 mmole) of TRANS-isomer of the final product of the preceding example, 493 mg (2,54 mmole) of (R/-(-)-O-acetylindole acid and 305 mg (2.5 mmole) of 4-(N,N-dimethylamino) pyridine in 4 ml of dichloromethane added 480 mg (2,32 mmole) dicyclohexylcarbodiimide. After 5 minutes the reaction mixture is heated and stirred at 25oC for 3 hours. The formed precipitate is removed by filtration and the filtrate evaporated with the formation of oil, which is purified by liquid chromatography moderate pressure on silica gel with elution with a mixture of 20 to 50% ether-hexane, and the resulting products a and B. Each of them is crystallized from a mixture of simple ether-hexane, and the result is 436 g (39%) diastereoisomer and 466 mg (41%) of diastereoisomer Century

Diastereoisomer A. melting point 94 94oC; range1H-NMR (CDCl3), 300 MHz, δ (ppm): 0,86 (t J 7 Hz, CH3), 1,1 2,1 (m N), 2,18 (C. CH3CO) to 2.66 (m, CH2), to 4.98 (painting AB, co2), 5,75 (D. J 6 Hz, CH), 5,88 (C. CH), 6,34 (D. J 2 Hz, ArH), 6,77 (D. D. J 8, 2 Hz, ArH), 6,93 (D. J 8 Hz, ArH), and 7.1 to 7.6 (m, 7 ArH), 7,71 (D. D. J 8, 8 Hz, ArH), 7,81 (D. J 8 Hz, ArH), 8,07 (D. J 8 Hz, ArH), and 8.16 (D. J 8 Hz, ArH).

Diastereoisomer Century melting point 70 81oC. SUB>), 5,31 (picture AB; co2), 5,77 (D. J 6 Hz, CH), by 5.87 (C. CH), 6,85 (D. D. J 8.2 Hz, ArH); 6,93 (D. J 2 Hz, ArH)- 6,95 (D. J 8 Hz, ArH), and 7.3 (m, 2 ArH) was 7.45 (m, 2 ArH), to 7.67 (m, 2 ArH), 7,79 (D. J 8 Hz, ArH), 8,05 (D. J 8 Hz, ArH) and 8,15 (D. J 8 Hz, ArH).

Example 13.

(-)-TRANS-2-Butyl-1,2,3,4-tetrahydro-7-(2-chinolin)methoxy-1-naphthol.

A mixture of 405 mg (0.75 mmole) of diastereoisomer And from the previous example and 832 mg (6,03 mmole) of anhydrous potassium carbonate in 6.25 ml of methanol, and 6.25 ml of tetrahydrofuran and 1.5 ml of water is stirred for 15 hours at a temperature of 25oC. This reaction mixture is then introduced into 100 ml saturated sodium chloride and extracted three times with simple ether portions 30 ml. United ethereal extracts are dried over magnesium sulfate and evaporated to education oils. This oil is crystallized from a mixture of simple ether-hexane, and the result is 160 mg (59%) of the desired final product, melting point 59 61oC.

()2D0= -26,3(CH3OH, c 0,001). Range1H-NMR (DCl3, 300 MHz) Delta (ppm): 0,89 (t J 7 Hz, CH3, 1,1 2,1 (m N), 2,68 (m, CH2), 4,33 (D. D. J 6, 6 Hz, CH), are 5.36 (S. OCH2), 6,83 (D. D. J 8 and 2 Hz, ArH), 6,97 (D. J 8 Hz, ArH), 7,17 (D. J 2 Hz, ArH), 7,50 (D. D. J 8; 8 Hz, ArH), 7,65 (D. J 8 Hz, ArH), 7,69 (D. D. J 8 Hz, ArH), 7,79 (D. J 8 Hz, ArH), 8,04 (doctor who aftol.

By processes in the same way as described in the previous example, diastereoisomer Century, the product of example 13 (0,46 g) is transformed into the desired final crystallized product of 0.13 g (54%), melting point 58 - 59oC.

()2D0= +23,6(CH3HE=0,001). Range1H-NMR identical to the spectrum of (-)-isomer of the previous example.

Example 15.

2-Butyl-3,4-dihydro-7-(2-pyridyl)-methoxy-1(2H)-naphtalene.

Carrying out the process in the same manner as in example 10, the end product of example 9 (5,70 g, 34.3 mmole) and the hydrochloride of 2-picolylamine (5,63 g, 34.3 mmole) turn into this desired connection, 4,37 g (41%), melting point 56 60oC. Mass spectrum (m/e 309 (M+), 253, 93 and 92. The spectrum of IR (l3) 1677, 1608, 1594, 1573 cm-1. Range1H-NMR (CDCl3) Delta (ppm): 0,98 (m, CH3, 1,1 2,7 (m N), 2,96 (m, CH2's , 5.25 (C. CH2O), 7,05 of 7.9 (m, 6 ArH) and 8.3 (Shir. D. J 6 Hz, ArH).

Elementary analysis. Calculated according to the formula: C20H23NO2:

C, 77,64; H, 7,49; N, 4,35%

Found: C, 77,93; N, 7,42; N, 4,50%

Example 16.

CIS - and TRANS-2-Butyl-1,2,3,4-tetrahydro-7-(2-pyridyl)methoxy-1-naphthol

Carrying out the process in the same manner as in example 1 CIS-isomer. 0.96 g (42%), melting point 101 103oC; less polar. Mass spectrum (m/e 311 (M+), 236, 199, 94, 93 and 92.

IR-spectrum (l3) 3592, 1610, 1594, 1574 cm-1. Range1H-NMR (CDCl3, 300 MHz) Delta (ppm): 0,87 (m, CH3, 1,1 1,9 (m N), 2,5 2,8 (m, CH2), 4,51 (Shir. C. CH), 5,13 (C. CH2O) 6,80 (D. J 8 Hz, ArH), 6,91 (Shir.with. ArH), 6,97 (Shir. D. J 8 Hz, ArH), 7,14 (D. D. J 8, 8 Hz, ArH), 7,44 (D. J 8 Hz, ArH), 7,63 (D. D. J 8; 8 Hz, ArH) and 8,51 (D. J 5 Hz, ArH).

Elementary analysis.

Calculated according to the formula: C20J25NO2:

C, 77,14; H, 8,09; N 4,50.

Found: C, 77,31; H 7,94; N, 4,46%

The TRANS-isomer. 1.12 g (49%), melting point 62 64oC; more polar. Mass spectrum (m/e 311 (M+), 292, 236, 199, 94, 93 and 92. IR Spectrum (l3) 3584, 3414, 1609, 1594, 1574 cm-1. Range1H-NMR (CDCL3, 300 MHz) Delta (ppm): 0,89 (m, CH3), 1,1 2,1 (m N), to 2.67 (m, CH2), 4,32 (Shir.with. CH), 5,15 (S. OCH2), 6,79 (D. D. J 8, 2 Hz, ArH), of 6.96 (D. J 8 Hz, ArH), 7,11 (D. J 2 Hz, ArH), 7,17 (D. D. J 8, 8 Hz, ArH), of 7.48 (D. J 8 Hz, ArH), 7,66 (D. D. J 8, 8 Hz, ArH) and 8,53 (D. J 5 Hz, ArH).

Example 17.

3-Isopropyl-6-benzyloxy-4-Hormann.

Carrying out the procedure of example 8, 6-benzyloxy-4-Hormann and isopropylated turns into this desired product.

Example 18.

3-Isopropyl-6-oxime) in the presence of 1 g of 5% Pd/C at room temperature in 200 ml of CH3HE and 100 ml of tetrahydrofuran up until not consumed odnokolernyh equivalent to N2. The catalyst is recovered by filtration over diatomaceous earth and the final product is recovered by evaporation of the filtrate to dryness.

Example 19.

3-Isopropyl-6-(2-chinolin)-methoxy-4-chromanone.

Carrying out the procedure in the same manner as in example 1, the product of the previous example, turn into this desired connection.

Example 20.

CIS - and TRANS-3-isopropyl-6-(2-chinolin)methoxy-5-chromanol.

Carrying out the procedure in the same manner as in example 5, the product from the previous example make this a desirable product.

Example 21.

Carrying out the procedure according to example 1 or example 10, using a suitable substituted chlorochilon heterocyclic compound instead of 2-chloromethylpyridine, the final product of example 9 is transformed into the following additional products: 2-Butyl-3,4-dihydro-7-(3-pyridyl)methoxy-1(2H)-naphtalene; 2-butyl-3,4-dihydro-7-(4-pyridyl)methoxy-1-(2H)-naphtalene; 2-butyl-3,4-dihydro-7-(2-pyrazinyl)methoxy-1(2H)-naphthaline; 2-butyl-3,4-dihydro-7-(6-fluoro-2-chinolin)methoxy-1(2H)-naphtalene; 2-butyl-3,4-dihydro-7-(2-benzodiaz Natalini)methoxy-1(2H)-naphtalene.

Carrying out the procedure according to the method of example 11, these compounds are converted into the corresponding CIS - and TRANS-2-butyl-1,2,3,4-tetrahydro-7-(substituted)methoxy-1-naphthol.

Example 22.

3-Pentylidene-6-(2-chinolin)methoxy-4-chromanone.

The mixture 0,112 mole of end product from example 1 and 0,169 mol of Pentanes in 100 ml of methanol at a temperature of 25oC add a 14.1 ml (0,169 mole) of pyrrolidine. The resulting solution was stirred for 60 hours at a temperature of 25oC, cooled to 0oC and filtered and the result is the target compound.

Using this procedure, the corresponding aldehyde instead of Pentanes receive the following products: 3-(2-Cyclopentylacetyl)-6-(2-chinolin)methoxy-4-chromanone; 3-(2-ethoxypropionate)-6-(2-chinolin)methoxy-4-chromanone; and 3-(4-ethoxycarbonylbutyl)-6-(2-chinolin)-methoxy-4-chromanone.

Example 23.

3 Pentyl-6-(2-chinolin)methoxy-4-chromanone.

A mixture of 25.2 g of the final product of the preceding example and 2 g of 5% Pd/C(50%) H2O in 1 liter of ethyl acetate is subjected to hydrogenation at 35 psi (2,45 ATM) up until not consumed 1 molar equivalent of N2(about 18 hours). The reaction mixture is filtered through diatomaceous earth with those who nd the desired product.

Carrying out the procedure in the same way that other products of the preceding example are converted to the following products: 3-(2-Cyclopentylmethyl)-6-(2-chinolin)methoxy-4-chromanone; 3-(3-ethoxypropan)-6-(2-chinolin)methoxy-4-chromanone; and 3-(4-methoxycarbonyl)butyl-6-(2-chinolin)methoxy-4-chromanone.

Carrying out the procedure in the same manner as in example 11, the products of this example are subject to further transformation into the corresponding CIS - and TRANS-2-(substituted)-6-(2-chinolin)methoxy-4-chromanol.

Example 24.

3-(4-Carboxybutyl)-6-(2-chinolin)-methoxy-4-chromanone.

To a solution of 630 mg of substituted 4-(methoxycarbonyl)-bootrom product of the preceding example in 100 ml of methanol and 25 ml of tetrahydrofuran, add 10 ml of 5-normal NaOH. The reaction mixture is heated on a steam bath for 10 minutes. Volatiles evaporated in vacuo, and the residual product evaporation is dissolved in water and acidified with diluted HCl until the pH=5. The precipitation of the final desired product is recovered by filtration and dried in the air.

Example 25.

CIS-3-(4-Carboxybutyl)-6-(2-chinolin)methoxy-4-chromanol.

During the process of hydrogenation according to example 18, but 2 the final product of the preceding example is converted to final product of this example.

Example 26.

7-Benzyloxy-3,4-dihydro-4-(cyclopentyl)methoxy-1-benzoxazin-(2H)-he.

In a solution of 1.5 g (cyclopentyl)methanol in 50 ml of tetrahydrofuran enter 720 mg of 50% sodium hydride. After stirring up until almost fully evaporates H2(about 30 minutes), is introduced a solution of 4.5 g of crude 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxazin-5-(2H)-she. The reaction mixture was stirred at room temperature for 5 hours. The tetrahydrofuran is evaporated in vacuo, and the residual product is evaporated, dissolved in ethyl acetate and washed with water. An ethyl acetate layer is dried over sodium sulfate and evaporated in vacuo, and the result is the desired target compound.

Example 27.

3,4-Dihydro-7-hydroxy-4-(cyclopentyl)methoxy-1-benzoxazin-5-(2H)-he.

A mixture of 2 g of the product of the preceding example, 200 mg of 10% Pd/C and 50 ml of methanol is subjected to hydrogenation in shaking the Parr apparatus at 50 psig (3.5 ATM) for 2.5 hours. The catalyst is removed by filtration, the filtrate is evaporated in vacuum and the result is a final product is aridra-4-(cyclopentyl)methoxy-1-benzoxazin,7-diol.

In a solution of 3.5 g of the product of the preceding example in 100 ml of tetrahydrofuran is administered 1 g of lithium hydride-aluminum. The reaction mixture was stirred at room temperature for 15 minutes, then quickly cooled with water, acidified to pH=4 with diluted hydrochloric acid and extracted with ethyl acetate. An ethyl acetate layer is dried over sodium sulfate and evaporated in vacuo, and the result is a mixture of end products, which is separated in the chromatographic column on silica gel with elution with a mixture of dichloromethane/simple ether.

Example 29.

()-TRANS-2,3,4,5-Tetrahydro-4-(cyclopentyl/-methoxy-7- (2-chinolin)methoxy-1-benzoxazin-5-ol.

To a solution of 840 mg of the TRANS-isomer of the final product of the preceding example in 25 ml of dimethylformamide add 154 mg of 50% NaH. After stirring for 20 minutes introduce 570 mg of 2-chloromethylpyridine. The reaction mixture was stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. An ethyl acetate layer is dried over sodium sulfate and evaporated in vacuum and the result is the desired target compound. Similarly is obtained the corresponding CIS-product.

2Cl2(25 ml) at a temperature of 0oC enter 125 mg (0.57 mmole) meta-chlormadinone acid. The reaction mixture was stirred at 0oC for 2 hours, then diluted with CH2Cl2(50 70 ml), washed with saturated NaHCO3N2Oh, brine, dried over Na2SO4and concentrated in vacuum and the result is a desired end product.

Example 31.

3-(octanesulfonyl)-6-(2-chinolin)methoxy-4-chromanone.

In a partial solution of 3-(octylthio) of the product of example 4 (1.20 mmole) in 50 ml of hot methanol injected a solution of KHSO3(2.20 g, to 3.58 mmole) in N2(20 ml). The reaction mixture was stirred at room temperature for 30 minutes, then diluted with H2(200 ml) and ethyl acetate (250 ml). The organic layer is washed 2 x N2O and brine, dried over Na2SO4and Argonauts to dryness, and the result is a desired end product.

Example 32.

7,8-Dihydro-7-methyl-3-(2-chinolin)methoxy-5(6N)-hinolan.

Carrying out the procedure according to example 1, 7, 8-dihydro-3-hydroxy-7-methyl-5(6N)-hinolan and 2-chlormethine into the final desired product with a yield of 67% temperature plow,8-dihydro-7-methyl-3-(2-chinolin)methoxy-5(6N)-hinolan.

Carrying out the procedure according to method 8, the end product of the preceding example is converted into the desired end product of this example.

Example 34.

CIS - and TRANS-6-butyl-7,8-dihydro-7-methyl-3-(2-chinolin)methoxy-5(6N)-hinolan.

Carrying out the procedure according to example 2, the final product of the preceding example is converted to the mixture of end products of this example. This product is a mixture of 6,7-CIS and 6,7-TRANS-isomers, although it is not excluded the possibility that this product includes one of these isomers.

Example 35.

CIS-6-Butyl-5,6,7,8-tetrahydro-C - and TRANS-7-methyl-3-(2-chinolin)methoxy-r-5-ginola and TRANS-6-Butyl-5,6,7,8-tetrahydro-and TRANS-7-methyl-3-(2-chinolin)methoxy-r-5-ginola.

Carrying out the procedure according to example 5, the product of the preceding example is converted into the desired end products of this example, the names of which are given under the existing nomenclature of the International Union of pure and applied chemistry (IUPAC Nomenclature of Organic Chemistry, 1979. Ed. page 477 478). Each of these products is a mixture of two compounds, one of which is 7-methyl group CIS(C) relative to (r) to 5-exigrep and the other is 7-methyl group TRANS (t or the other of these C-7 or t-7 isomers.

Example 36.

6(8H)-Oxymethylene-7-methyl-3-(2-chinolin)methoxy-5(7H)-hinolan.

Carrying out the procedure according to example 2, the final product of example 61 into the final desired product of this example with a yield of 99% analysis by thin layer chromatography (CH2Cl2ethanol 19 1) Rf of 0.6.

Example 37.

8(8H)-Diazo-7-methyl-3-(2-chinolin)-methoxy-5(7H)-hinolan.

Carrying out the procedure according to example 3, the end product of the preceding example is converted to final desired product of this example with a yield of 99% analysis by thin layer chromatography (CH2Cl2the ethanol in the ratio of 19 to 1) Rf 0.25 in.

Example 38.

CIS - and TRANS-7,8-Dihydro-7-methyl-6-pentoxil-3-(2-chinolin)methoxy-5(6N)-hinolan.

(See example 34 for explanations of the composition of the re-isomer).

Carrying out the procedure according to example 4, the end product of the preceding example and pentanol turn into a mixture of end products of this example.

Example 39.

5,6,7,8-Tetrahydro-CIS - and TRANS-7-methyl-6-phenoxy-3-(2-chinolin)methoxy-r-5-chinolin and 5,6,7,8-tetrahydro-CIS - and TRANS-7-methyl-t-6-phenoxy-3-(2-chinolin)methoxy-r-5-chinolin.

(See example 35 for explanation of nomencl the sample into the final products of this example.

Example 40.

CIS-3-Cyclohexyloxy-6-(2-chinolin)-methoxy-4-chromanol-N, N - dimethylglycine.

CIS-isomer of the final product of example 5 (0.22 mmole) was dissolved in CH2Cl2(3 ml). Then the solution is added sequentially 4-(Dimethylamino)-pyridine (0,043 g, 0.35 mmole), N,N-dimethylglycinamide (0,038 g of 0.26 mmole) and dicyclohexylcarbodiimide (0,050 g of 0.26 mmole) and the mixture stirred for 18 hours. The reaction mixture is abruptly cooled by an equal volume of water and a byproduct of cyclohexylamine is removed by filtration. The organic layer in the filtrate is separated, washed with saturated NaHCO3, water and brine, dried over Na2SO4and Argonauts to obtain the final product of this example. In the same way are obtained the corresponding esters of glycinate of the TRANS-isomer of the final product of example 11, and the final products of examples 7, 11, 13, 14, and 16.

Example 41.

Dichlorhydrate CIS-3-cyclohexyloxy-6-(2-chinolin)methoxy-4-chromanol-N,N - dimethylglycine.

The final product of the preceding example (0.10 g, 0,19 mmole) dissolved in 5 ml of absolute ethanol, add value (0.475) ml (value (0.475) mmole) of 1-normal hydrochloric acid and the mixture OYe compound of this example.

Example 42.

Dichlorhydrate TRANS-2-butyl-1,2,3,4-tetrahydro-7-(2-chinolin)methoxy-1-naphthyl-4 - piperidineacetate.

To a solution of 935 mg (to 4.52 mmole) of the hydrochloride of 4-piperidinemethanol acid, 733 mg (6.02 mmole) of 4-(N, N-dimethylamino)pyridine and 1.36 g (of 3.77 mmole) of TRANS-isomer of the final product of example 11 in 7.5 ml of CH2Cl2at a temperature of 0oC add 852 mg (4,14 mmole) dicyclohexylcarbodiimide. The reaction mixture is stirred for 15 hours at a temperature of 25oC, then filtered and the filtrate evaporated to dryness. The obtained residual product is digested, dissolved in 100 ml of ethanol. Enter 1 normal hydrochloric acid (7,54 ml) and the reaction mixture is concentrated to dryness in a rotary evaporation apparatus, and the result is the final product of this example.

Example 43.

3,4-Dihydro-7-(2-chinolin)methoxy-1(2H)-naphtalene.

Carrying out the procedure of example 10, out of 5.00 g (30.9 mmol) of 7-hydroxy-3,4-dihydro-1(2H)naftalina and to 9.91 g (46.3 mmole) of chlorhidrate 2-chloromethylpyridine obtain 3.5 g (37%) of the final desired compound.

Mass spectrum (m/e 303 (M+; 286, 274, 142 and 115.

Range1H-NMR (DCl3, 300 MHz), δ (h/min): 2,08 (m, 2H), 2,60 rH), 8,07 (D. J 8 Hz, ArH) and 8.16 (D. J 8 Hz, ArH).

Example 44.

Carrying out the procedure according to example 22, using the appropriate aldehyde as a starting reagent, the final product of the previous example, make the following connections: 2(4H)-Hexylidene-7-(2-chinolin)methoxy-1(3H)-naphtalene; 2(4H)-cyclopentylmethyl-7-(2-chinolin)methoxy-1(3H)-naphtalene; and 2(4H)-(2,2-deformation)-7-(2-chinolin)-methoxy-1(3H)-naphtalene.

Example 45.

Carrying out the procedure according to example 23, the products of the previous examples make the following connections:

3,4-Dihydro-2-hexyl-7-(2-chinolin)methoxy-1(2H)-naphtalene;

3,4-dihydro-2-cyclopentylmethyl-7-(2-chinolin)-methoxy-1(2H)-naphtalene; and

3,4-dihydro-2-(2,2-deformaty)-7-(2-chinolin)-methoxy-1(2H)-naphtalene.

Example 46.

Carrying out the procedure according to example 5, the products of the previous example, make the following connections:

CIS - and TRANS-1,2,3,4-tetrahydro-2-hexyl-7-(2-chinolin)methoxy-1-naphthol;

CIS - and TRANS-1,2,3,4-tetrahydro-2-cyclopentylmethyl-7-(2-chinolin)- methoxy-1-naphthol; and

CIS - and TRANS-1,2,3,4-tetrahydro-2-(2,2-deformaty)-7-(2-chinolin)methoxy-1-naphthol.

Example 47.

2-Butylidene-6-methoxy-1-Indien.

Example 48.

2-Butyl-6-methoxy-1-indanone.

Carrying out the procedure according to example 18, the final product from the previous example into the final desired compound of this example.

Example 49.

2-Butyl-6-hydroxy-1-indanone.

Carrying out the procedure according to the method of obtaining the drug 3, as described below, 8.00 g (31,7 mmole) of the final product of the preceding example is converted to the target compound of this example.

Example 50.

2-Butyl-6-(2-chinolin)methoxy-1-indanone.

Carrying out the procedure according to example 10, 14.7 mmole the final product of the preceding example and 4,80 g (22.4 mmole) of the hydrochloride of 2-chloromethylpyridine become the final link 4-picolylamine, according to this procedure are respectively 2-butyl-6-(2-, 3 - and 4-pyridyl)-methoxy-1-indanone.

Example 51.

CIS - and TRANS-2-butyl-6-(2-chinolin)methoxy-1-indanol.

Carrying out the procedure according to example 5, the end product of the preceding example is converted into the final products of this example.

Example 52.

3-Pentylidene-6-methoxy-1-(para-toluensulfonyl)-2,3-dihydro(1H)-chinoline.

Carrying out the procedure of example 22, 25,0 g (75.5 mmol) of 6-methoxy-1-toluensulfonyl-2,3-dihydro-4(1H)Hinayana (J. Am. Chem.Soc. Vol. 71, R. 1901, 1949 and 9.7 g (113 mmol) of pentanal turn in the final product of this example.

Example 53.

6-Methoxy-1-(para-toluensulfonyl)-3-pentyl-2,3-dihydro-4(1H)- chinoline.

Carrying out the procedure according to example 23, the product of the preceding example is converted into the final product of this example.

Example 54.

6-Hydroxy-3-pentyl-2,3-dihydro-4(1H)quinoline.

A mixture of 10 g of the final product of the preceding example in 35 ml of acetic acid and 35 ml of concentrated NVG heated under reflux for 8 hours, after which it is introduced into a mixture of ice-water, and the resulting precipitates the final product of this example In the solution 8,66 mmol end product of the preceding example in 13 ml of pyridine is slowly injected 1,65 g (8,66 mmol) paratoluenesulfonyl. The reaction mixture is stirred for 1 hour, then is introduced into 200 ml of 1 normal Hcl and extracted with ethyl acetate. The organic layer is washed with fresh 1 - normal HCl and then saturated NaCl, dried over MgSO4and Argonauts, and the result is a desired end product.

Example 56.

Carrying out the procedure according to examples 1 or 10, the end product of the preceding example communicates with a suitable heterotrimetallic and the result is the corresponding 6-(2-chinolin, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-honokalani, 2-pyrimidinyl, 6-fluoro-2-chinolin, 5-fluoro-2-benzothiazolyl and 1-phthalazine)methoxy derivatives. These compounds, in turn, gidrolizuyutza (1 g) by heating under reflux for 8 to 9 hours in a mixture of 7.5 ml of acetic acid and 4 ml of concentrated HCl, followed by dilution with an equal volume of water, bringing the pH to 8.0 by means of 6 - normal NaOH and extraction with CH2Cl2. The organic layer is dried over MgSO4and Argonauts, and the result is the desired ketone products:

2,3-Dihydro-3-pentyl-6-(2-chinolin)methoxy-4-(1H)-hinolan;

2,3-dihydro-3-pentyl-6-(2-pyridyl)methoxy-4-(1H)-hinolan;

2,3-dighiero-3-pentyl-6-(2-honokalani)methoxy-4(1H)-hinolan;

2,3-dihydro-3-pentyl-6-(2-pyrimidinyl)methoxy-4(1H)-hinolan;

2,3-dihydro-3-pentyl-6-(6-fluoro-2-chinolin)-methoxy-4(1H)-hinolan;

2,3-dihydro-3-pentyl-6-(5-fluoro-2-benzothiazolyl)-methoxy-4(1H)-hinolan;

and 2,3-dihydro-3-pentyl-6-(1-phthalazine)methoxy-4(1H)-hinolan.

Example 57.

Carrying out the procedure according to example 5, the products of the preceding example is converted into the corresponding CIS - and TRANS-1,2,3,4-tetrahydro-3-pentyl-6-(substituted)methoxy-4-quinolones.

Example 58.

3-Butyl-6-(2-chinolin)methoxytyramine-4-one

Through successive stages according to examples 8 to 10, 7-methoxytyramine-4-one is converted to final product of this example.

Example 59.

CIS - and TRANS-3-butyl-6-(2-chinolin)-methoxytyramine-4-one-1-oxide.

In a solution of 30 mmol of the final product of the preceding example in 100 ml of CH2Cl2at a temperature of from -5 to 9oC slowly introducing 31 mmol meta-chlormadinone acid. The mixture was stirred until until starch-KI test paper does not become negative (a few hours), and then quickly cooled in 100 ml of water. The organic layer is separated, washed with saturated NaHCO3dried over MgSO4and distillate what adansonii acid and carrying out the reaction for a longer period of time (16 hours) at room temperature, get the appropriate sulfon (1,1-dioxide).

Example 60.

Carrying out the procedure according to example 5, the end products of the previous three examples are converted to corresponding CIS - and TRANS-thiochroman-4-Ola.

Example 61.

7,8-Dihydro-7-methyl-3-(2-chinolin)-methoxy-5(6N)-hinolan.

Carrying out the procedure according to example 1, 7,8-dihydro-3-hydroxy-7-methyl-5(6N)-hinolan and 2-chlormethine turn into the final product of this example with the release of 67% melting point 141 - 144oC. Mass spectrum (m/e) calculated: 318, 1365; found: 318, 1325.

Receiving 1.

4-(2-Cyanoethoxy)anisole.

4-Methoxyphenol (248 g), KOH (5.6 g) and Acrylonitrile (397 ml) dissolved in 1 liter of tert-butanol and heated with stirring at a temperature of 75oC for 5 hours. The mixture is then cooled to room temperature and Argonauts in vacuum to the formation of the solid residual product that is re-suspended in simple ether, and insoluble materials are removed by filtration. The latter are dissolved in 2 l of ethyl acetate, washed sequentially 1 l each of the following agents: water, saturated NaHCO3and saturated NaCl, dried over MgSO4and p is SS="ptx2">

Getting 2.

6-Methoxy-4-chromanone.

The final product of the preceding example (199 g) is mixed with 240 ml of N2Oh, and 480 ml of concentrated Hcl and heated under reflux overnight. The reaction mixture is cooled to room temperature and the solids are removed by filtration. The latter are dissolved in 2 l of ethyl acetate, washed with 200 ml water, dried over MgSO4and is distilled over under vacuum, and the result is the intermediate product 3-(4-methoxyphenoxy)propionic acid, 195 g, melting point 105 107oC. the Latter is introduced into 600 ml of hot mixed polyphosphoric acid supported at a temperature of 75oC, and the mixture is stirred for 2 hours. The temperature rises to maximum 89oC for the first half hour, then reduced to a temperature bath of 75oC. the Reaction mixture is quickly cooled in 3.2 liters of ice and water and extracted with 1.2 l of ethyl acetate. The organic extract was successively washed (600 ml each) with water, saturated NaHCO3and saturated NaCl, dried over MgSO4and Argonauts to education 180 g of solid products, which are dissolved in 400 ml of CH2CL2processed their precrystallization simple isopropyl ether with the formation of the purified final product, 120 g, melting point 46 48oC, which is identical to the industrial product.

Getting 3.

6-Hydroxy-4-chromanone.

A solution of 36 g of the product of the previous example to obtain the drug in 290 ml of acetic acid and 290 ml of 48% Hydrobromic acid is heated under reflux for 3 hours. The reaction mixture is cooled and Argonauts in vacuum before the formation of the crude product, which was diluted with water (6 l), cooled to a temperature of 0 to 5oC, and the final product is recovered by filtration of 25.7 g (80%), melting point 133 - 136oC. If desired, this product is optionally purified by passing through a chromatographic column filled with silica gel, using a mixture of ethyl acetate/hexane as eluent.

Getting 4.

A mixture of 25 g of the product of the previous example to obtain the drug, with 26.5 g of benzyl bromide and 28 g of potassium carbonate in 150 ml of acetone is heated under reflux during the night. The reaction mixture is cooled and filtered to remove potassium carbonate. The filtrate is evaporated, and the residual product is evaporated, dissolved in ethyl acetate and washed with water. An ethyl acetate layer is dried over which recristallization from methylene chloride/hexane, and the result is 29 g of the final desired product, melting point 107 108oC.

Range1H-NMR (acetone-d6) Delta (ppm): 2,7 (so 2N), 4,4 (t 2H), 5,08 (C. 2H), 7,2 7,5 (m, 3H).

Getting 5.

3-Oxymethylene-6-benzyloxy-4-chromanone.

In the solution 172,5 g of the product of the previous example, the preparation of the drug in 1.7 l of toluene containing 168 ml of ethylformate and 3.5 ml of ethanol, impose separate portions 66 g of a 50% aqueous sodium hydrate. The reaction mixture was stirred at room temperature for 1 hour, then poured into 1.5 liters of a mixture of ice water and acidified to pH=4 with diluted hydrochloric acid. The aqueous layer was extracted with several portions of ethyl acetate. The organic layers are mixed, dried over sodium sulfate and evaporated in vacuum and the resulting crude product, which is mixed with hexane to remove hydride oil. The product crystallizes in the excerpt, the melting point of the product 82 85oC.

Getting 6.

3-Diazo-6-benzyloxy-4-chromanone.

The solution was 35.3 g of the final product of the previous example to obtain the drug in 250 ml of dichloromethane containing 25,2 g triethylamine enter the reaction mixture is heated to room temperature and stirred over night. The reaction mixture is washed with water, dried over sodium sulfate and evaporated in vacuum and the resulting crude product that is purified in a chromatography column on silica gel with elution with dichloromethane, and the result is 21 g of product, melting point 100 103oC.

Range 1H-NMR (DCl3) Delta (ppm): 5,02 (D. J 4, 2H), 6,7 7,5 (m, 10H).

Getting 7.

4-(4-Methoxyphenoxy)butyric acid.

4-Methoxyphenyl introduced into the solution NaOC2H5prepared by dissolving 2.3 g of Na in 50 ml of ethanol. After 5 minutes you enter gamma-butyrolactone and the mixture is heated under reflux during the night. Ethanol Argonauts, and the residual product of the distillation is heated at 155oC overnight, then cooled, diluted with water and acidified to pH=3 with diluted hydrochloric acid. This product is recovered by filtration, is obtained 19.5 g of product with a melting point of 103 - 104oC.

Getting 8.

3-4-Dihydro-7-methoxy-1-benzoxazepin-5(2H)-he

34 g of the product of the previous example to obtain the drug dissolved in 300 ml of polyphosphoric acid is heated at 100oC in which e is obtained as crude product. This crude product is purified by distillation, the boiling point of the product 100oC at 0.5 mm

9.

3,4-Dihydro-7-hydroxy-1-benzoxazin-5-(2H)-he.

The mixture 19,23 g of the final product of the previous example to obtain the drug, 95 ml of 48% Hydrobromic acid and 95 ml of acetic acid are heated under reflux for 4 hours. The reaction mixture is cooled and evaporated in vacuo, and the resulting crude product that is purified in a chromatography column on silica gel, elution with dichloromethane, and the result is of 8.3 g of the final product, with a melting point of 116 120oC.

Range1H-NMR (CDCl3) Delta (ppm): 2,0 of 2.45 (m, 2H), 2.95 points (so J 7, 2H), 4,20 (so J 7, 2H), 6,8 7,1 (m, 3H), 7,4 (C. 1H).

10.

7-Benzyloxy-3,4-dihydro-1-benzoxazepin-5(2H)-he.

A mixture of 6.5 g of the product of the previous example to obtain the drug, a 4.3 ml of benzyl bromide, 6.3 g of potassium carbonate and 40 ml of acetone are heated with stirring under reflux overnight. The reaction mixture is cooled and filtered to remove inorganic substances. The filtrate is evaporated in vacuo, and the residual product cypriani harivamsa in vacuum, and the result is a crude product which is purified by recrystallization from a simple isopropyl ether, and the result is a 8.4 g of the final product with a melting point of 62 63oC.

Receipt 11.

7-Benzyloxy-4-bromo-3,4-dihydro-1-benzoxazin-5/2H/he.

In a solution of 6.3 g of the final product of the previous example to obtain the drug in 25 ml acetic acid is added a solution 3,76 g of bromine in 25 ml of acetic acid. The reaction mixture is stirred for 3 minutes, and the volatile matter is distilled over under vacuum before the formation of the residual product is dissolved in ethyl acetate and washed with water. An ethyl acetate layer is dried and evaporated, and the result is of 8.2 g of product which is used without purification in the next stage.

Getting 12.

3-Bromo-6-methoxy-4-hinolan

To a solution of 6-methoxy-4-chromanone (35 g) in a simple ethyl ether (1.6 l) at a temperature of 5 to 10oC injected dropwise within 30 minutes to 10.6 ml of bromine. The mixture was stirred at 5 to 10oC for 30 minutes and then heated to room temperature. After 2 hours, as shown in the analysis by thin layer chromatography (CH2Cl2), proishodila water (1 l), saturated NaHCO3(500 ml) and brine (500 ml), dried over MgSO4and evaporated in vacuo to education yellow solid. The crude product is purified in a chromatography column on silica gel (using the evaporative chromatography) using 2.4 kg of fine silica gel with elution with a gradient system consisting of hexane-dichloromethane in the ratio of 3:1, then the system composed of hexane-dichloromethane in the ratio of 2:1 and finally, the system 30% hexane-dichloromethane. The result is a final desired product as a yellow solid with a yield of 80%

13.

1-Amino-5-methylcyclohex-1-EN-3-one.

5-Methyl-1,3-cyclohexandione (40 g, of 0.32 mol) dissolved in 500 ml of benzene at 70oC. the Solution was heated under reflux for 2 hours, during which time via the reaction mixture is passed in the form of bubbles NH3and the resulting water is collected in the trap Dean and stark. The mixture is then cooled to 0oC and the final product is removed by filtration, the yield of 39.8 g; melting point 165 169oC.

Range1H-NMR (dimethylsulfoxide-d6) Delta (ppm): 0,98 (C. 3H), 1,6 OF 1.88 (2H), 2,14 OF 2.38 (2H), 3,14 3,6 (1H), 4 is malonamide sodium (Org.Synth.Coll. Volume 4, page 844; 42,4 g,269 mole) dissolved in 200 ml of dimethylformamide, and the resulting solution was dried over molecular sieves type 4A, is extracted by filtering 100 ml of the same solvent as rinsing. To the United filtrate and the rinse is added pyridine (91 ml, 89 g of 1.13 mol) and the mixture cooled to -5oC. is Introduced dropwise chloride tosyl (53 g, 0,277 mol) in 200 ml of dimethylformamide, while the temperature is maintained at -5 to -8oC, and the reaction mixture is heated to room temperature. The final product of the previous example to obtain the drug (33.6 g, 0,270 mole), dissolved by heating in 200 ml of dimethylformamide and put in a steady stream directed into the reaction mixture which is then stirred for 18 hours at room temperature, then put into 2 liters of a mixture of ice-water and extracted (2 x 1 l) with ethyl acetate. The organic layers are mixed, dried over MgSO4and distills, and the result is the final desired product, 33 g (61% with a melting point 64 67oC).

Get 15.

3-Amino-7,8-dihidro-7-methyl-5(6N)-hinolan.

The final product of the previous example to obtain the product (27 g) is introduced into the flask Parra 250 MDA (H2) 50 psi (3.5 bar) for 2 hours at room temperature. The catalyst is removed by filtration over diatomaceous earth and the filtrate concentrated to dryness. The remaining brown solid product is then subjected to evaporation chromatography by first dissolving in CH3OH, with the introduction of 50 ml of dry silica gel with grains 32 63 μm and concentration to dryness. The resulting product is then introduced into the column chromatography evaporative 30 cm x 15 cm silica gel, through which are passed a 1% triethylamine in CH2Cl2isopropanol (19:1). The column is eluted with the same solvent system. Contains the average product fractions are collected and distills with the formation of the final desired product. Issa-spectrum (m/e) calculated: 176, 0950; found: 176, 0944; analysis by thin layer chromatography (19:1, CH2Cl2C2H5OH), Rf of 0.32.

Getting 16.

7,8-Dihydro-7-methyl-5(6N)-chinolin-6-disneycartoon.

The final product of the previous example to obtain the drug (15,26 g) at room temperature is placed in a 500 ml 3-necked flask equipped with a mechanical stirrer, addition funnel and the outlet tube is positioned with the rear l, then the reaction mixture turned into a clear deep red solution. Then the last is cooled to 0oC, and during this time the solution deposited some amount of solids. To this suspension, with a still temperature of 0oC, is added 5,98 g NaNO2in 35 ml of N2About dropwise within 5 to 10 minutes, and the resulting mixture was stirred at 0oC for 30 minutes. To this mixture, which is still at a temperature of 0oC, is added 15,24 ml HPF6(60 weight. in N2within 5 minutes. Immediately formed a light brown precipitate. Upon termination of this add intense peremeshivanie lasts for 10 to 15 minutes. The obtained solid product is filtered, washed with 2 x 25 ml of cold N2O, 2 x 25 ml simple ether and then dried in vacuo overnight over R2ABOUT5and the result is 25,62 g (89%) of the final desired product, melting point 175 176,5oC.

Getting 17.

7,8-Dihydro-3-hydroxy-7-methyl-5(6N)-hinolan.

The final product of the preceding example (25,62 g) is introduced in the form of a portion of 0.5 g in 500 ml of boiling 5% H2SO4during this time (in this case 2.5 hours), which isclinical for 40 minutes, then cooled to 0oC and pH by up to 6 by 6-normal NaOH (in this case requires 160 ml). The reaction mixture is extracted with ethyl acetate 3 x 250 ml At the first extraction of the emulsion is broken by filtering through diatomaceous earth. The organic extracts combined, dried over MgSO4, distills before the formation of solids, and residual product of the distillation is dissolved in CH3OH, stirred with silica gel, Argonauts and subjected to evaporative chromatography, as in the previous example, using as eluent CH2Cl2-isopropanol (19: 1), and the result is the final desired product, 9.2 grams (67%), with a melting point 210,5 212oC.

Getting 18.

3-Benzyloxy-7,8-dihydro-7-methyl-5(6N)-hinolan.

Carrying out the procedure of example obtaining the drug 4, the product of the previous example to obtain the drug turn in the final desired product of this example with the release of 78% with a melting point 80,5 8105oC. Mass spectrum (m/e) calculated: 267, 1259; found: 267, 1261.

Getting 19.

2-Chloromethyloxirane.

2-Methylphenoxy (8,94 g) is mixed with 50 ml of CCL4and 6.5 g of NaObratno funnel, so that Cl2was barbotirovat very slowly. This procedure is continued for 1 hour, and then the reaction mixture alagaesia 20oC in an ice bath and is distributed between the solution saturated NaHCO3and simple ether. The ether is separated, dried over MnSO4and concentrated to dryness. The residual product concentration immediately passed through an evaporation column (20 cm) filled with silica gel particle size of 32 to 63 μm (column diameter 8 cm) using as eluent a mixture of simple ether hexane in a ratio of 1 to 1. After passing 1 l of going 250 ml fractions. Fraction 3 50 are mixed and concentrated, and the result is 2.58 g (23% ) of final product as a yellow solid; analysis by thin-layer chromatography (ethyl acetate CH2Cl2in the ratio of 3 7), Rf of 0.65. Range1H-NMR (CDCl3) Delta (ppm): 4,86 (C. 2H), 7,74 for 7.78 (m, 2H), 8,02 is 8.16 (m, 2H), 9,01 (m, 1H).

20.

2-Bromo-3,4-dihydro-7-methoxy-1(2H)-naphtalene.

To a solution of 25 g (0,142 mole) of 7-methoxy-3,4-dihydro-1(2H)-naftalina in 1 l of simple ether at a temperature of 10oC is added dropwise (maintaining the temperature of the reaction mixture is about 10oC (of 37.9 g (0,237 say who compete crystallizes from a simple ester, and the result of 31.6 g (87%) of the final compounds of this example, the melting point 79 80oC.

Mass spectrum (m/e) 256 and 254 (M+, 174, 173, 148, 131, 120, 115 103. IR Spectrum (l3) 1680, 1610 cm-1.

range1H-NMR (DCl3) Delta (ppm): 2,2 2,7 (m, 2H), 2,9 3,5 (m, 2H), 3,95 (S. OCH3), 4,78 (so J= 4 Hz, ADHD), 7,0 - 7,4 (m AGN) and 7,58 (Shir.with. ArH).

Elementary analysis.

Calculated according to the formula: C11H11BrO21/2 H2O:

C, 50,89; H, 4,46%

Found: C, 50,71; N, 4,36.

Getting 21.

6-Benzyloxy-3-methylene-4-chromanone.

A solution of 9.2 g of 6-benzyloxy-4-chromanone, dimethylamine hydrochloride and 1.3 g of paraformaldehyde in 100 ml of acetic acid is heated on a steam bath for five hours. Volatile products is distilled over under vacuum, and the residual product of the distillation is purified on silica gel with elution CH2Cl2and the result is 3.7 g of product, Rf (CH2Cl2) of 0.5. Range1H-NMR (CDCl3) Delta (ppm): 4,85 (S. 2N), of 5.05 (C. 2H), 5,55 (C. 1H), 6.30-in (C. 1H), 6,80 of 7.60 (m, 8H).

Getting 22.

3-Bromo-2-(bromomethyl)-6-methylpyridine and 3-bromo-6-(bromomethyl)-2-methylpyridin.

In a round bottom flask of 25 ml, equipped with metalloid, to 4.5 ml of carbon tetrachloride and 10 mg (0.04 mmole) of benzoyl peroxide. The resulting mixture is heated during the night. Analysis by thin-layer chromatography carried out at this point, shows that the source material is still present, and add 0.7 g (3.9 mmole) of N-bromosuccinimide, and the reaction mixture is heated under reflux for 4 hours. The precipitate is filtered and washed with 2 x 50 ml CCL4(hot). The filtrate is concentrated until the formation of the oil, and then the crude product is purified using the evaporative chromatography on silica gel (200 g) using as eluent a mixture of hexane CH2Cl2in the ratio of 3 to 1, and the result is the two specified end connection corresponding to this example, with the release of 218 mg (11%) of 2-(bromomethyl) derived and 285 mg (14%) 6-bromomethyl) derived; analysis by thin-layer chromatography (hexane - CH2Cl2in the ratio 3:1), Rf 0,07 and Rf of 0.13, respectively.

2-(Bromomethyl)is derived.

Range1H-NMR (Dimethylsulfoxide-d6(Delta (ppm): 7,99 (D. J 7.8 Hz), (1H), 7,19 (D. J 7.8 Hz, 1H), 4,71 (C. 2H), 2,46 (C. 3H).

6-(Bromomethyl) is derived.

Range1H 1. Racemic and optically active derivatives of tetralin General formula

< / BR>
where R is 2-pyridyl, 2-chinolin; R1(C1-C3)- alkyl; Y and Y1taken together form a carbonyl group or, taken separately, Y is hydrogen, Y1-hydroxyl.

2. Derivatives of 7-hydroxytyramine General formula II

where R1, Y, Y are the specified values.

 

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FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to derivatives of platinum tetrachloride and to a method for their preparing also. Invention proposes compounds of the formula PtCl4 x 2 Li wherein Li represents N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotine hydroxamic acid, or isonicotine hydroxamic acid. Also, invention proposes a method for preparing these compounds that involves interaction of pyridine carboxylic acid nitroxyethylamides or hydroxamic acids, or their hydrochlorides with potassium hexachloroplatinate followed by isolation of the end product. Invention provides synthesis of the unknown early chelate platinum compounds that are physiologically active substances and can be used in medicinal practice instead cisplatin as effective anti-metastatic medicinal agents with low toxicity.

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

2 cl, 3 ex

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