Racemic or optically active perhydro-1h-pyrido(1,2 - a) pyrazine or their pharmaceutically acceptable salts and method of production thereof

 

(57) Abstract:

Use: medicine for the treatment of psychotic diseases. The inventive products: perhydro-1H-pyrido-[1,2-a] pyrazine formula (1) or their salts, where L and X are taken separately, where X is H, L - R(CH2)mCO., or L and X, taken together, are groups of formula (2 - 7), R - /C3-C7-cycloalkyl, phenyl or norbornyl, R1, R2and R3- H or CH3Y is O or S, Y1- CH2or S, Y2and Y3- H or Y2and Y3are taken together to represent (CH2)gZ is H or Cl, m = 0, 1, 2 or 3, n = 1, 2, 3 or 4, p = 1 or 2, g = 3, 4, or 5, --- indicates communication or lack of communication. Reagent 1: compound of formula (8), where Y and n are defined above, D - nucleophilic tsepliaeva group. Reagent 2 : L-NH(X), in the case when L and X form together with the nitrogen atom derivative of piperidine. Reaction conditions: inert organic solvent. 7 C. and 32 C. p. F.-ly. 3 table.

The present invention relates to some of perhydro-IH-pyrido[1,2-a] pyrazines described by formula (1) and defined below; to pharmaceutical compositions and methods of treatment of psychotic diseases with their help; and to some of the intermediate compounds used in them is whether CH and Larepresents one of the radicals of the group, including the pyrazole, triazole tetrazol or cyclic imide, have useful antibiotically activity, as indicated Bright and prolonged operation in the International application PCT N WO 90/08144.

Describes a series of compounds possessing neuroleptic activity, which are used in the treatment of psychotic diseases. They include derivatives of piperidine derivatives of the formula

< / BR>
where t denotes 1 or 2, Ar represents naphthyl, or one of various bicyclic heteroaryl groups, including benzisothiazol, and Xband Ybtogether with the accession of the phenyl ring form a similar bicyclic heteroaryl group (Lowe III et al. US Patent 4831031); and the compounds of formula

< / BR>
where Q is some bicyclic heteroaryl group, Alk is Alcantara and X represents O, S, NH or substituted NH (Kennis et al. US Patent 4957916).

The present invention refers to both the racemic and optically active perhydro-IH-pyrido[1,2-a] pyrazines formula

< / BR>
or their pharmaceutically acceptable additive salts of the acid,

where

L and H are taken separately, where X is H and L is R(CH2)mCO.,

or L and X taken together are

< / BR>
R about who appoints hydrogen or CH3;

Y is O or S;

Y1is CH2or S;

Y2and Y3denote hydrogen, or Y2and Y3taken together and are (CH2)q;

Z is H or Cl;

m is 0, 1, 2 or 3;

n has a value of 1, 2, 3 or 4;

p has the value 1 or 2;

q has a value of 3, 4 or 5;

means a connection or no connection.

In these compounds the group is attached in the 7 - or 8-position of perioperative ring system may be either in CIS or in TRANS position with respect to 9a-hydrogen. When the Deputy is 8-position, which is associated with the ease of acquisition and are usually more active, preferred are compounds, mainly having the substituent in the 8-position and 9a-hydrogen in the TRANS configuration relative to each other, or, in other words, 8 and 9a-hydrogens are CIS with respect to each other. Preferred values of Y and Z are oxygen and hydrogen. When L and X are taken separately, the preferred value of X is hydrogen and the preferred value of L is R(CH2)mCO, where R is phenyl or (C3-C6) cycloalkyl and m has a value of 1 or 2. When L and X are taken together, predmosti Y1is CH2, p is 1 and Y2and Y3together.

As apparent to any expert in this field, the compounds according to the present invention may exist in racemic and optically active form. Compounds in which hydrogen Deputy located in the 7-position is TRANS with respect to 9a-hydrogen, and having the absolute stereochemical formula

< / BR>
usually more active than the enantiomers (mirror images). In the formula (1a) stereochemical structure is always, without exception, will be 9aS, while the stereochemical structure in the 7-position will be different, depending on the exact values of n, L and X. However, when n has a value of 2 in the formula (1a), the stereochemical structure will invariably 7S.

The present invention also relates to intermediate products for the synthesis of compounds of formula (I) described by the following formula:

< / BR>
where the first alternative B is a (C1-C3)alkoxycarbonyl and X1is C O; or second alternative, X1is CH2and B is HOCH2.

The present invention is easy to implement, there are a number of different techniques, which are Dov is but a widely used source products are the compounds of formula

< / BR>
where n and Y are defined above and D is a nucleophilic capable of substitution group such as chlorine, bromine or methansulfonate. Last, the so-called esters nelfinavir, are preferred because they are easily formed from the corresponding alcohol, the receipt of which is illustrated in detail below. When the obtained product of formula (I) is L and X are taken together, this method is preferred because the required nucleophilic capable of substitution groups are usually readily available. When L and X are taken together to form an imide or cyclic sulfonamide, the preferred reagents are anionic derivatives of the corresponding imides, for example

< / BR>
When L and X are taken together to originate from simple piperidinol derivative, such as

< / BR>
usually use the free amine, preferring its corresponding anionic form. Such nucleophilic substitution reaction is usually carried out with an excess of one of the reagents in order to make this reaction is second order with a supplier within a reasonable period of time. Usually an excess of the most available reagent, which in this case is usually the anion imine or amine. Reactory to neutralize the molar equivalent of acid, formed as a side product. This may be amine reagent or a stronger base, relative to nucleophilic base, such as triethylamine or 2,6-lutidine. Nucleophilic substitution is carried out usually in a reaction-inert solvent, preferably such that a relatively polar, in order to dissolve the reactants and to provide faster response. Temperature is not the decisive factor, but usually it above the level of room so as to promote a reasonable quick speed of response, but should not be so high as to promote undesirable side reactions and decomposition.

The alcohols used in the preparative method, easily accessible from the corresponding esters of CIS - and TRANS-piperidinecarboxylic acids, as described in detail in the examples below. Such alcohols are capable of separation by formation of diastereomeric esters with optically active acids. These esters are usually isolated, for example, known chromatographic methods. Divided diastereomers hydrolyzing esters to give the desired optically active alcohol.

All clinically effective antipsychotic agents inhibit the adherence SS is tan standard antipsychotic substances interact with a wide range of neurotransmitter receptors their ability to block D-2 binding is the only activity that shows a high degree of correlation with their clinical oral dosage (Creese et al. Sciences, 192: 481 483, 1976). I believe that the clinical effect is the result of mesolimulus-mesocortical attacks on forebrain, specific inhibition of dopamine hypersensitivity induced by the increasing density of the receptor, as shown in studies of post-mortem brain of patients with schizophrenia (Lee et al. Nature, 274: 897, 1978).

The ability of these compounds of formula (I) to substitute for the binding of D-2 receptors was determined according to the standard technique radioligand homogenate binding, as indicated below. Adult rat line Sprague-Dawley (3 test) were decapitated, the brain quickly separated and caudafe-putamen was dissected. The tissue is homogenized in 50 volumes of ice-cold 50 mm Tris-HCl buffer containing 100 mm NaCl and mm MgCl2and brought up to a pH of 7.2. This mixture twice was centrifuged at 20000 x g for 15 min each time, emergent product each time was discarded and the pellet suspended in fresh buffer prior to homogenization. The final pellet is again suspended in buffer to a concentration of 5.6 mg/ml Cushnie concentrations of the studied drugs. Other tubes contained only buffer /"full"/ or saturated concentration /+/butaclamol /10mm "empty"/. Tube /final volume of 1.0 ml were incubated at 37oC for 15 min, then rapidly filtered under vacuum through a filter with glass fibers and washed with 12 ml of ice-cold buffer harvester cells Brandela. The filters were then separated and counted in a scintillation counter using 5 ml of scintillation fluid Beckman Readysafe. The resulting calculations are then used to determine the IC50or extrapolated concentrations of the studied drugs for inhibition of binding in half for each tested compound. /Method Leysen et al. Biochemical Pharuacology, 27: 307-316 /1978/.

Antipsychotic activity of these compounds is also shown on neuroleptic activity using methods basic standard techniques. One method of adult rat line Sprague-Dawley pre-treated with appropriate doses of the test compounds by subcutaneous injection. Half an hour later, all rats administered intragastrically 1 mg/kg of apomorphine hydrochloride, dissolved in 0.1% solution of ascorbate. Rats have behavioral factor, according to the following swieca in the cell, 2, intermittent snorting wheezing behavior, 3= long snorting with intermittent movements of the mouth and 4 long licking and chewing movements. Connection with neuroleptic activity will be lower complete a standard assessment of groups subjected to processing by the drug, relative to untreated control rats, depending on their /connections/ antagonistic forces impact on the dopamine receptor.

The biological activity of the compounds of the present invention makes them useful for the treatment of psychotic disorders in people. For example, these compounds are used in the treatment of psychotic disorders schizophrenic type, in particular the compounds are useful for treating or improving symptoms such as anxiety, agitation, excessive aggressiveness, stress, and social or emotional withdrawal in psychotic patients.

The compound of formula (1) or its pharmaceutically acceptable salt is administered to patients both individually and in combination with pharmaceutically acceptable carriers or diluents, in a pharmaceutical composition, in accordance with generally accepted pharmaceutical practice. These compounds designate is offered by the introduction. In addition, pharmaceutical compositions comprising the compound of formula (1) or its pharmaceutically acceptable salt, the weight ratio of active ingredient to carrier will be normal from 1:6 to 2:1, and preferably 1:4 to 1:1. However, in some cases, the selected value depends on the solubility of the active component, the required dosage and the specific treatment method.

For oral use of neuroleptic agent of the present invention compounds are assigned, for example, in the form of tablets or capsules, or in the form of aqueous solutions or suspensions. In the case of tablets for oral use media that can be used include lactose and corn starch, can be added to lubricating agents such as magnesium stearate. For oral administration in the form of capsules used diluents are lactose and dried corn starch. When you need water suspension for oral administration, the active ingredient may be connected with emulsifying or suspendresume agents. If desirable, may be added some sweetening or flavouring agents. For intramuscular and intravenous administration can be prig. For internal use is controlled by the concentration of total solutions for isotonic drug.

When the agent of the present invention is used to treat psychotic illnesses in humans, the daily dosage is usually determined by a physician. However, the dosage will vary depending on the age, weight and individual susceptibility of the patient, and the extent of the patient's symptoms. However, in most examples, an effective amount for the treatment of psychotic diseases will be your daily dose of from about 1 to 500 mg, preferably about 5 to 100 mg, in single or divided doses, orally or parenterally. In some cases it may be necessary to use dosage and above these limitations.

The following examples are provided solely for the purpose of further illustration. The nomenclature used here, including a designation of the relative stereochemistry /R*S*/ absolute stereochemistry /R, S/, is in accordance with Rigaudi et al. IUPAC Nomenclature of Organic Chemistry, 1979 Edition, Pergamon Press, New York.

Example 1

Racemic dimethyl TRANS-1-(2-phthalimido)-ethyl/piperidin to 1.5, in primary forms

Well peremeci is tons of dimethyl ether hydrochloride /280 g 1.18 mol/ methylene chloride /4,5 l/ add a constant flow of a solution of 2-phthalimidomethyl triphala /417 g of 1.29 mol/ methylene chloride /3 l/ over a 3-hour period. The organic layer is separated and the aqueous extracted with fresh methylene chloride /3 l/. The combined organic extracts washed with water /3 l/, then brine /3 l/, dried over anhydrous magnesium sulfate and finally concentrated in vacuo to a solid residue. The rest is grinded into powder by boiling under reflux in ether /3 l/ under vigorous stirring for 15 minutes After cooling to room temperature the solution was poured into hexane /3 l/ and the resulting mixture stirred for 18 hours Obtained colorless precipitate is collected by filtration, and the cake remaining on the filter, washed with hexane /1 l/. Drying in vacuo gives 437,3 g /yield of 99.1%/ specified in the title compounds as a colorless solid product. TCX Rf (ethyl acetate/methylene chloride 1:1 by volume, spray iodoplatinate) of 0.5.

Example 2

Racemic method (7R*, 9aS*) 4, 6, 7, 8, 9a-hexahydro-2H,3H-pyrido/1,2-a/-pyrazin-1-one-7-carboxylate

To a well stirred suspension specified in the header of the example 1 composition /194 g, 0.52 mol/ me in temperature. Add methylene chloride /2 l/ and the resulting mixture was vigorously stirred for 1 h the Resulting white precipitate is filtered off, and before you pulverize the cake on the filter is washed with methylene chloride /1 l/. Concentration of the filtrate in vacuo gives a colorless precipitate, which granularit and then vigorously stirred while boiling under reflux in methylene chloride /3 l/ 10 minutes, the Cooled mixture is filtered and the obtained filtrate was concentrated in vacuo to obtain specified in the connection header /output 89,4 g, 81.6 per cent/ in the form of solid ivory, TCX Pf (methylene chloride/methanol 9:1 by volume; spray iodoplatinate) 0,38.

Example 3

Racemic /7R*, 9aS*/-perhydro-7-(hydroxymethyl)-1H-pyrido-[1,2-a] pyrazin

To a stirred suspension of amidoamine specified in the title of the example 2 /244 g, 1.15 mol/ in anhydrous tetrahydrofuran (THF /THF, 5,5 l/ added dropwise in a stream of nitrogen 1.0 M solution of sociallyengaged /2,33 l, 2,33 mol/ maintaining the temperature of the reaction mixture below 40oC. the mixture is Then refluxed for 18 hours, After careful adding dropwise water /90 ml/ reaction (cooling to room comperemedia within 1 hour Insoluble inorganic salt is separated by filtration, and the obtained filtrate was concentrated in vacuo and get a light yellow solid residue /output 179,4 g, 90.6% of/ sufficiently pure for use in the next stage without additional purification. TCX Rf (methylene chloride/methanol/concentrated aqueous ammonia 3 1 0.1 volume; the spray iodoplatinate) 0,19.

Example 4

Racemic /7R*, 9aS*/-2- (benzo[d] isoxazol-3-yl)-perhydro-7-(hydroxymethyl)-1H-pyrido[1,2-a]pyrazin

Stir the solution spirtuality specified in the header of the example 3 /179,4 g, 1.05 mol, 3-chloro-1,2-benzo[d]isoxazol /194,2 g of 1.26 mol/ and 1,8-diazabicyclo/5,4,0/undec-7-ene /DBU, 197,9 g of 1.30 mol/ pyridine /400 ml/ heated under 100oC for 18 h After cooling to 35oC add water /3 l/, methylene chloride /2.5 l/, and finally saturated aqueous solution of sodium carbonate /2 l/, and the resulting biphasic mixture was vigorously stirred for 3 hours Reddish-brown solid precipitate formed during the stirring, filtered, the cake on the filter is washed first with water and then hexane /1 l each/ before drying in vacuum. Kneading powder of the whole sample /216 g/ isopropyl alcohol /630 ml/ s posleduuschego reddish-brown powder, pure enough for use in the next stage without additional purification. TCX Rf (methylene chloride/methanol 9 1 by volume; spray iodoplatinate) 0,50.13C NMR (CDCl3) Delta(164.0, 161.1, 129.5, 122.3, 122.1, 116.2, 110.5, 66.3, 60.3, 58.7, 54.3, 53.7, 48.3, 39.1, 29.0, 26.7.

Example 5

Racemic (7R*, 9aS*)-2-(benzo[d] isoxazol-3-yl)-perhydro-7-(methanesulfonylaminoethyl)-1H-pyrido[1,2-a]pyrazin

To cold /5oC/ and stirred suspension of the alcohol that is specified in the header of the example 4 /154,0 g 0.54 mol) and triethylamine /81,76 ml, to 59.6 g, 0,589 mol/ methylene chloride /3 l/ added dropwise a solution of methanesulfonamide /43,55 ml, 64,5 g, 0,563 mol/ methylene chloride /350 ml/ for more than 30 min. Monitoring with TLC (methylene chloride/methanol 9:1 by volume; spray iodoplatinate) of the reaction mixture after an additional half-hour of mixing indicates not full completion of the reaction. Completely, the reaction is carried out within 1/2 hour after adding the second portion of triethylamine /8,23 ml, 6.0 g, 59,3 mmol/ methanesulfonanilide /4,32 ml, 6.4 g, 55,9 mmol/ added dropwise in a solution of methylene chloride /20 ml/. Add water /3 l/ and methylene chloride /1.5 l/ and the biphasic mixture was vigorously stirred before section shall stricty then combine, washed with brine /double 2 liter portions/ and dried over anhydrous sodium sulfate. Concentration in vacuo gives a reddish-brown solid product /178,0 g, 90.2% for exit/ TCX Rf (methylene chloride/methanol 9:1 by volume; spray iodoplatinate): 0,24. MC m/z 365,1 (M, C17H23N3O4S).

13C NMR (CDCl3) Delta 164.0, 160.9, 129.6, 122.4, 122.1, 116.0, 110.5, 71.9, 59.9, 57.7, 54.0, 53.3, 48.1, 37.4, 35.9, 28.4, 26.2.

Example 6

Racemic (7S*, 9S*)-2-(benzo[d] isostasy-3-yl)-7-(cyanomethyl)perhydro-IH-pyrido/1,2-a/pyrazin

Stir the solution nelfinavir specified in the header of example 5 /177,5 g, 0,486 mol and sodium cyanide /35,7 g, advanced 0.729 mol in N,N-dimethylformamide /3.0 l/ heated at 110oC for 18 hours the Solvent is removed in vacuo, the obtained reddish-brown solid residue is dissolved in water methylenchloride /2.5 l each/ two-phase mixture, the pH of the mixture mix well set 10 /saturated aqueous solution of sodium carbonate/. Then the layers are separated and the aqueous phase is extracted with portions of fresh methylene chloride /1.5 l/. The combined organic extracts washed with brine /two 1-liter servings/, dried over anhydrous sodium sulfate and concentrate in vacuumatic/hexane 1 1 by volume; the spray iodoplatinate) 0,20.

13C (CDCl3) Delta 164.0, 161. 129.6, 122.4, 122.0, 117.9, 116.0, 110.5, 59.9, 59.5, 53.9, 53.3, 48.1, 32.9, 29.6, 28.7, 22.1. This product is 7.9 and the hydrogens still trance.

In the same way mesilate product specified in the header of the example 24, is converted into the corresponding nitrile, racemic /7R*, 9S*/-2-(benzo[d] isoxazol-3-yl)-7-(3-cyanopropyl)perhydro-IH-pyrido[1,2-a]pyrazin also have 7 and 9a hydrogens in position trance.

Example 7

Racemic /7S*, 9S*/-7-(2-amino-ethyl)-2-(benzo [d] isoxazol-3-yl)perhydro-IH-pyrido[1,2-a]pyrazin

To stir the nitrile specified in the header of example 6, /136,9 g, 0,462 mol/ in anhydrous tetrahydrofuran /3.5 l/ added dropwise 1.0 M solution of sociallyengaged /LAG/ tetrahydrofuran /693 ml, 0,693 mol for 1 h, the Reaction mixture is boiled with a back boiler for 6 h, then stirred at room temperature for 18 h and finally repay careful adding dropwise water/tetrahydrofuran (26 ml and 30 ml, respectively), 15% aqueous sodium hydroxide solution /26 ml/ and water /80 ml/. The mixture is stirred for 0.5 hours Add anhydrous sodium sulphate /400 g/ and the inorganic salts filtered off. from the filtrate, the resulting solution was concentrated in vacuo to obtain presents in the title compound as a yellow solid product /output 131,9 g, 95%/. TCX Rf (methylene chloride/methanol/concentrated aqueous ammonia 9 1 0.1 volume; the spray iplatinum):0,28.

13C NMR/CDCl3/ Delta 164.0, 161.1, 129.4, 122.2, 122.1, 116.2, 110.4, 61.7, 60.2, 54.2, 53.8, 48.3, 39.7, 38.7, 33.9, 30.7, 29.4.

In the same way 3-cyanopropionic the product of the preceding example is converted into the corresponding 4-aminobutyrate, which is inversely converted into the corresponding kidnie derived by the methods of examples 10 to 12.

Example 8

Optically active /7S, 9aS/-7-(2-amino-ethyl)-2-(benzo[d]isoxazol-3-yl)perhydro-IH-pyrido[1,2-a]pyrazin

Racemic amine specified in the header of example 7 /131, 5mm g, 0,438 mol dissolved in ethanol /2.4 l/ boiling under reflux. Add -/+/- almond acid /66.6 g, 0,438 mol/, obtaining a clear solution, which is allowed to cool and leave at room temperature for 18 hours Colourless crystalline precipitate is filtered, the cake washed twice with portions of 300 ml of diethyl ether. Drying in vacuo gives of 92.6 g of colorless crystal /partially destroyed/ salt so pl.-suspension, which is filtered off after allow it to cool to room temperature. Washed cake on the filter with two 300 ml portions of diethyl ether, and then drying in vacuo gives to 75.6 g of colorless crystalline salt: so pl. 214 217oC, which is then subjected to optical separation and allocation 2S, 9aS /-/ -enantiomer in the form of its salt -/+/- almond acid. Again the whole sample is refluxed in ethanol (1.0 l) for 0.5 h, cooled to room temperature and left for 18 h filtration with subsequent leaching of the cakes on the filter with ether and drying in vacuo give to 66.3 g of colorless crystals; so pl. 216 218oC. Just described procedure crystallization using 1 l of ethanol as a solvent for crystallization are repeated five times to obtain 45,1 g divided salt -/+/- almond acid 7S, 9aS-/-/-enantiomer; so pl. 223 224oC. the Entire sample is dissolved in a biphasic mixture of methylene chloride (2.5 l) / water (1.4 l) to bring the pH to 9 (saturated aqueous solution of sodium carbonate). The layers are separated and the aqueous portion extracted with 2 l of fresh methylene chloride. Concentration in vacuum dried with anhydrous sodium sulfate combined organic extracts Yes the de colorless amorphous product. []2D0-8,65o(to 3.73, methylene chloride).13C NMR /CDCl3/ Delta identical specified for the racemic amine.

Optical resolution of racemic //-Amin to the present 7S,9aS-/-/-Amin confirmed by a comparative study19F NMR their chiral amide derived Moser with respective derivatives 7R, 9aR-/+/- pairs (the product of example 9). A separate study of crystalline diffraction of X-rays of a specified derivative amide of Moser set identical stereochemistry presented in the header of the example 9 and the real products.

Example 9

Optically active /7R, 9aR/-7-(2-amino-ethyl) -2-(benzo[d]isoxazol-3-yl)perhydro-IH-pyrido[1,2-a]pyrazin

The solution specified in the header of example 7 racemic amine /1.40 g, 3,79 mmol/ R -/-/- almond acid /577 mg, 3,79 mmol/ ethanol /24 ml/ leave to stand at room temperature for 18 h, during this time formed a heavy crystalline mass. Crystalline solid mass is filtered, washed with diethyl ether and dried in vacuum /270 mg/. The entire sample was dissolved in hot ethanol /5 ml/. The solution was concentrated in vacuo to a volume of 4 ml and left to stand at with diethyl ether and dried in vacuum to obtain salt R-/-/-almond acid presents 7R,9aR-/+/-amine, 107 mg /output of 12.5%/; so pl. 218 222oC; []2D019,6o(c 0,56, methanol).

The entire sample is dissolved in a mix well methylenchloride /water (8 ml and 4 ml, respectively) mixed with establishing a pH of 9.5 (saturated aqueous solution of sodium carbonate). The separated organic extract was washed with an equal volume of water, dried /waterless sodium sulfate/ and concentrated in vacuo to obtain separated programalso Amin /51 ml, 7.3% of the total output of/ in the form of a colorless amorphous solid product. TCX Rf (methylene chloride/methanol/ concentrated aqueous ammonia solution 9 1 0.1 volume; the spray iodoplatinate) 0,28; []2D0+ 7,86o(from 1.22, methylene chloride).

Example 10

The aggregate method AND

Racemic /7S*, 9aS*/-2-(benzo[d] isoxazol-3-yl)-perhydro-7-(2-(3,3-tetramethyleneglutaric)-ethyl)-1H-pyrido[1,2-a]pyrazin

A mixture containing racemic amine specified in the header of example 7, /465 mg, 1.54 mol/ and 3.3-tetramethyleneglutaric aldehyde /290 mg, 1.70 mmol, Aldrich Chemical Co/. In xylene (6 ml, the level of boiling 139 - 144oC)intensively refluxed for 18 hours Xylene solution was carefully decanted from the insoluble resin, education xylene portion concentrated in vacuo to an oil /0.65 g/. Flash chromatography of the entire sample (20 g of silica gel, 32 63 mesh; elution first with ethyl acetate / hexane 1:1; the reduction of the amount of hexane in an eluting system in the process of chromatography was carried out, resulting in the elution of pure ethyl acetate at the end) gives specified in the header connection /exit 75 mg, 10.8% of/ in the form of a colorless amorphous solid product. TCX Rf (elution with ethyl acetate, potassium permanganate spray): 0,25.

Example 11

The aggregate method B

Racemic /7S*, 9aS*/2 -(benzo[d]isoxazol-3-yl)-perhydro-7-(2-(3,3-trimethylenediamine)-ethyl)-1H-pyrido[1,2-a]pyrazin

A mixture containing racemic amine (example 7 /98 mg, 0,326 mmol/ and 3.3-tetramethyleneglutaric anhydride /55 mg, 0,359 mmol/ "xylenes" (4,0 ml, the level of boiling 139 144oC), stirred and heated at 150oC for 15 minutes Xylene solvent carefully removed in vacuum /is significant foaming/ raw nellysimonova intermediate product, Cyclotimia in the form of an amber solid product. Spend dehydrate cyclization of the entire sample in acetic anhydride /1.0 ml/ by heating the reaction mixture at 100 110oC for 2.5 hours, the Concentration of the mixture in vchodove connection: so pl. 163,9 165,3oC 13C NMR (CDCl3) Delta 171.7, 164.0, 161.0, 129.5, 122.2(2), 116.0, 110.5, 61.3, 60.2, 54.2, 53.7, 48.2, 44.9, 37.4, 35.1, 34.7, 31.1, 32.1, 30.4, 29.3, 14.7.

Example 12.

The aggregate method B

Optically active /7S, 9aS/-2-(benzo[d]isoxazol-3-yl)perhydro-7-(2-3,3-tetramethyleneglutaric)-ethyl)-1H-pyrido[1,2-a] pyrazin

A mixture containing 7S, 9aS(- (-) -amine specified in the header of example 8, /1,53 g 5,09 mmol/ and 3.3-tetramethyleneglutaric anhydride /0,94 g, 5,59 mmol, Aldrich Chemical Co/ xylenes /60 ml, the level of boiling 139 - 144oC/ is stirred and heated at 150oC for 15 minutes Xylenes carefully removed in vacuum /is significant foaming/ raw nellysimonova amide acid as an amber solid product [TCX Rf (methylene chloride/ methanol 9:1 by volume; spray iodoplatinate) 0,45] pure enough to receive imide without purification. The entire sample is stirred and heated in acetic anhydride /42 ml/ 100 - 110oC for 2.5 h, the Reaction mixture was concentrated in vacuo to obtain a solid residue, which is crushed in a well-stirred mixture of methylene chloride/water /60 ml and 50 ml, respectively/ when establishing a pH of 9.5 /saturated aqueous solution of sodium carbonate/. The phases are separated and the aqueous fekih extracts give a yellow solid product. Flash chromatography of the entire sample (30 g of silica gel, 32 63 mesh); elution first with methylene chloride then add methanol to increase the polarity of the eluting system to methylene chloride/methanol in the end equal to 97:3 by volume gives pure (TCX control in various eluting systems; potassium permanganate spray) product specified in the header, in the form of a colorless amorphous solid product /yield 1.40 g, 61% /. []2D04,6o/c 2,3, methylene chloride/. TCX Rf /acetate, potassium permanganate spray/: 0,25. HPM S m/z 450.2639 (M, C26H34O3N4).13NMR (CDCl3Delta 172.1, 164.0, 161.1, 129.5, 122.2(2), 116.2, 110.5, 61.3, 60.2, 54.2, 53.7, 48.2, 44.9, 39.5, 37.5, 37.4, 34.2, 32.6, 30.4, 29.3, 24.2.

230 mg of a sample of amorphous product is crystallized twice from isopropanol /2 ml servings/ receiving 150 mg /output 65,2%/ colorless crystals; so pl. 157 158oC. Spectroscopic properties and optical rotation of amorphous and crystalline material are identical. Enantioselective, quantitative study of high resolution liquid chromatography /BRGH/ was carried out using chiral column type AGP (1-glycoprotein) (mobile phase: 0.01 M aqueous potassium dihydrophosphate/dimethylocta what they study optical purity specified in the header of the product is 95%

Example 13

Salt nelfinavir

69,6 mg /0,154 mmol/ amorphous specified in the header of example 12 dissolved in ethyl acetate /1 ml/. Add methansulfonate acid /16,6 mg, 0,170 mmol; 98% Aldrich Chemical Co/, the resulting solution is stirred 2 h at room temperature, during which the formation of heavy crystalline mass. The product is filtered, washed with diethyl ether and dried in vacuum to obtain monomethylamine salt of the product specified in the header of example 12, in the form of colorless needles, 54 mg /output 63,9% /; so pl. 211 212oC []2D03,7o/ /c 2,1, methylene chloride/,13C NMR /CDCl3/Delta 172.5, 164.2, 159.7, 130.2, 123.1, 121.4, 115.3, 110.7, 61.4, 59.6, 52.3, 56.5, 45.7, 44.6, 39.6, 37.5, 36.6, 31.4, 31.1, 28.6, 26.1, 24.2.

The experiment is repeated with a large number of sample /468 mg, 1.04 mmol/ receiving identical crystalline product /500 mg/ 88% yield.

Optical purity of this monomethylamine salt determined by the quantitative enantioselective research URGH described in example 12, and is 98%

Example 14

Optically active /7R, 9aR/-2-(benzo[d]isoxazol-3-yl)perhydro-7-(2-(3,3-tetramethyleneglutaric)ethyl)-1H-pyrido[1,2-a]pyrazin

The method described in example 12, Leamy in the form of a colorless amorphous solid product. TCX Rf /acetate, potassium permanganate spray/: 0,25. []2D0+ 3,63o/o 0,77, methylene chloride/. Optical purity is defined as 95% by studies using enantiomeric URGH as described in example 12.

Example 15

Racemic /7S*, 9aS*/-2-(benzo[d] isoxazol-3-yl)-perhydro-7-(2-(cyclohexyloxycarbonyloxy)-ethyl-1H-pyrido[1,2-a]pyrazin

To a well stirred solution cyclohexyloxy acid /35 mg, 0.25 mmol, Aldrich Chemical Co./ in anhydrous methylene chloride /2 ml/ add 1-hydroxybenzotriazole (37 mg, 0.25 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methods-p-toluensulfonate (145 mg, 0.34 mmol, Aldrich Chemical Co.) and Amin specified in the header of example 7, (51 mg, 0,17 mmol) and the resulting mixture was stirred at room temperature for 18 hours the Solvent is removed in vacuum, the residue is crushed in a well-stirred mixture of methylene chloride/water (10 ml each) when establishing pH 9 (saturated aqueous solution of sodium carbonate). The separated organic phase was concentrated in vacuo to a solid product. Flash chromatography of the entire sample (2.0 silica gel, 32 63 mesh; elution with methylene chloride/methanol 97:3 by volume) gives specified in the title compound in the form of becanada.com potassium): 0,40. HRMS m/z 424.2854 (M, C25H36O2N4).

Example 16

Racemic /7S*, 9aS*/-2-(benzo[d]isoxazol-3-yl)perhydro-7-(2-anolamine)-ethyl)-1H - pyrido[1,2-a]pyrazin

The solution containing the amine indicated in the header of example 7, /100 mg, 0.33 mmol), triethylamine /0,051 ml, 37,2 mg, 0,37 mg/ DL and 2-trailhead /0,039 ml of 53.5 mg, and 0.37 mmol, Aldrich Chemical Co/, in anhydrous methylene chloride /5.0 ml/ was stirred at room temperature for 1 h Add an equal quantity of water, the pH of the well-mixed mixture set 9.5 /aqueous saturated solution of sodium carbonate/. The phases are separated and the aqueous portion extracted with an equal volume of fresh methylene chloride. The combined organic extracts washed with water /10 ml, dried /waterless sodium sulfate/ and concentrated in vacuo to a solid product. Flash chromatography of the entire sample /3.8 g of silica gel, 32 63 mesh; elution with ethyl acetate/ network specified in the title compound as a colourless solid product, 16,8 mg /output 12,3%/. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,51. HPM 410.1759 corresponds to the mass ion C22H26N4O2S.

Example 17

Racemic /7R*, 9aS*/-2-(benzo[d]isoxazol 0.11 mmol/ add to a well stirred suspension of sodium hydride (4.4 mg of 60% dispersion in mineral oil sodium hydride; of 2.64 mg, 0.11 mmol of sodium hydride) in anhydrous dimethylformamide /DMF, 0.5 ml/. The reaction mixture was stirred under heating at 60oC in nitrogen atmosphere for 20 minutes a Solution of nelfinavir specified in the header of example 5 /20 mg, 0.55 mmol/ in anhydrous DMF /1.0 ml/ add to the mixture and the resulting mixture was stirred at 100oC for 6 hours the Solvent is removed in vacuum and the residue is crushed in a well-stirred mixture of methylene chloride, water (15 ml each) with fixed pH 10 (saturated aqueous solution of sodium carbonate). The organic phase is separated, treated with activated charcoal and filtered, dried /waterless sodium sulfate/ and finally concentrated in vacuo to a colorless amorphous product. Crystallization of the entire sample from isopropanol gives 13.2 mg /exit 55%/ specified in the connection header; so pl. 208 209oC. theorm 436.2466 corresponds to the mass ion C25H32N4O3.

Example 18

Racemic /7R*, 9aS*/-7-(azidomethyl)-2-(benzo[d] isoxazol-3-yl)perhydro-1H-pyrido[1,2-a]pyrazin

A mixture containing mesilate specified in the header of example 5 /473 mg, 1,29 mmol/ and sodium azide /170 mg, 2.58 mmol/ in anhydrous N,N-dimethylformamide /5.0 ml/, peremeshivaniya then crushed in a well-stirred mixture of methylene chloride/water (20 ml each) with the pH of 11.5 (saturated aqueous solution of sodium carbonate). The organic phase is separated, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain specified in the header of the product (in which 7 - 9a-hydrogen atoms are in TRANS) as a light yellow amorphous product /370 mg, entrance to 91.2%/. TCX Rf (ethyl acetate/methanol/concentrated aqueous ammonia solution 9:2:0.2 to volume; potassium permanganate spray): 0,78.

In the same way (8R*, 9aS*)-8-(methanesulfonylaminoethyl) specified in the header of example 39, is converted into the corresponding (8R*, 9aS*)-8-(aminomethyl) derivative, in which 8 and 9a-hydrogen atoms are in CIS.

Example 19

Racemic (7S*, 9aS*)-7-(aminomethyl)-2-(benzo[d] isoxazol-3-yl)perhydro-1H-pyrido[1,2-a]pyrazin

A solution of azide specified in the header of example 18, a mixture of ethanol/methanol (2 ml and 1 ml, respectively) hydronaut in a Parr apparatus (50 psi, 26 mg of the catalyst is 5% palladium on coal) for 2.5 hours, the Catalyst is filtered off under nitrogen atmosphere, the resulting filtrate was concentrated in vacuo to obtain specified in the header of the product in the form of a colorless amorphous solid product (yield 50 mg, 99%). TCX Rf (ethyl acetate/methanol/concentrated aqueous ammonia solution 9:2:0,2 is .6, 54.2, 53.7, 48.2, 46.4, 39.6, 29.0, 28.2.

In the same way the corresponding 8-(azidomethyl)derivative is converted into the corresponding 8-(aminomethyl)is derived.

Example 20

Racemic (7R*, 9aS*)-2-(benzo[d] isoxazol-3-)-perhydro-7-((3,3-tetramethyleneglutaric)-methyl)-1H-pyrido[1,2-a]pyrazin

The mixture containing the amine indicated in the header of example 19 (31 mg, 0.11 mmol) and 3,3-tetramethyleneglutaric anhydride (20 mg, 0.12 mmol, Aldrich Chemical Co. ) in xylenes (1.0 ml, the level of boiling 139 144oC) stirred under heating at 105oC for 10 min After cooling to room temperature, the xylenes carefully removed in vacuum (accompanied by considerable foaming) to obtain the intermediate nellysimonova acid amide as a colourless solid product [TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,39] which is used to obtain imide without additional purification. The entire sample was stirred at 105oC in acetic anhydride (2.0 ml) for 3 hours, the Excess acetic anhydride is removed in vacuo to obtain a solid residue, which is then crushed in a well-stirred mixture of methylene chloride/methanol (10 ml and 5 ml, respectively) when setting is concentrated in vacuo to a solid product (33 mg). Flash chromatography of the entire sample (550 mg of silica gel, 32 63 mesh; elution first with methylene chloride and then increasing the polarity of the eluting system by adding methanol to the final relationship methylene chloride/methanol 98:2 by volume) to obtain specified in the header of the product in the form of a colorless amorphous solid product (yield of 16.4 mg, 34.8 per cent). TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,42. HRMS m/z 436.2466 (M, C25H32O3N4.13NMR (CDCl3) Delta 172.4, 164.0, 161.1, 129.5, 122.2, 122.1, 116.2, 110.5, 60.0, 59.6, 54.3, 53.7, 48.2, 44.9, 42.8, 39.4, 37.7, 35.9, 29.1, 28.4, 24.3.

A sample of pure amorphous product is easily crystallized from isopropanol (so pl. 208 -209oC). The crystalline product is identical in all respects to the product obtained by the method described in example 17.

Example 21

Racemic (7S*, 9aS*)-7-(cyclohexylmethyl-3-yl)-carbonylmethyl)-2-(benzo[d]isoxazol-3 - yl)perhydro-1H-pyrido[1,2-a]pyrazin

To a well stirred mixture cyclohexyloxy acid (23 mg, 0.16 mmol, Aldrich Chemical Co. ) in anhydrous methylene chloride (1 ml) was added 1-hydroxybenzotriazole (25 mg, 0.16 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methods-p-methanesulfonate (100 mg, 0.25 IMO is the atur within 18 PM The solvent is removed in vacuo, and the residue is crushed in a well-stirred mixture of methylene chloride/methanol (10 ml each) when setting the pH to 9 (saturated aqueous solution of sodium carbonate). The separated organic phase was concentrated in vacuo to a solid product. Flash chromatography of the entire sample (2.0 g silica gel, 32 63 mesh; elution with ethyl acetate: methanol 9:1 by volume) to obtain specified in the header of the product in the form of a colorless amorphous solid product, 10 mg (yield of 19.5%). TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,43. HRMS 410.2684 corresponds to the mass ion C24H34N4O2.

Example 22

Racemic (7S*, 9aS*)-2-(benzo [d]isoxazol-3-yl)-7-(4-(4-perbenzoic)piperidinomethyl)-perhydro-1H - pyrido[1,2-a]pyrazin

To a solution of 4-(p-perbenzoic)piperidine (1169 mg, 0,058 mmol) isobutyl ketone (0.2 ml) is added sodium carbonate (15.2 mg, 0.14 mmol), potassium iodide (1 mg) and the solution nelfinavir specified in the header of example 5 (21 mg, 0,058 mmol) isobutyl ketone (0.3 ml) and the resulting mixture is refluxed for 4 hours the Solvent is removed in vacuum and the residue is crushed in a well-stirred mixture of methylene chloride/methanol (the om. The combined organic extracts are treated with activated charcoal, dried (anhydrous sodium sulfate) and concentrated in vacuo to a colorless solid product. Crystallization of the entire sample from isopropanol gives presents in the title compound, 13.9 mg, yield of 56.7% so pl. 179 -181oC. TCX Rf (methylenchlorid/methanol 9: 1 by volume; potassium permanganate spray): 0,17.

Example 23

Racemic (7S*, 9aS*)-2-(benzo [d]isoxazol-3-yl(perhydro-7-(2,2-di(methoxycarbonyl)-ethyl)-1H-pyrido[1,2-a]pyrazin

To a solution of diethylmalonate (2,054 g of 15.5 mmol) in anhydrous N,N-dimethylformamide (80 ml) is added sodium hydride (0,77 g of 60% suspension of sodium hydride in mineral oil; 462 mg, and 19.3 mmol of sodium hydride) and the mixture is heated at 55oC for 1 h Add mesilate product specified in the header of example 5 (5,44 g, 14.9 mmol) and the resulting mixture was stirred under heating at 100oC for 42 hours the Solvent is removed in vacuo, the remaining solid residue is ground up in a well-stirred two-phase mixture of methylene chloride/saturated aqueous bicarbonate (150 ml each, pH 8.9). The organic phase is separated, well washed with equal volumes of water and brine, dried dilacerate. Then add hexane to the turbidity of the solution. After standing for 3 h at room temperature crystallizes specified in the header of the product (2,60 g, yield of 43.5% so pl. 134 138oC. TCX Rf (ethyl acetate; potassium permanganate spray): 0,36.

Example 24

Racemic (7S*, 9aS*)-2-(benzo[d] isoxazol-3-yl)perhydro-7-(3-(methanesulfonate)- propyl)-1H-pyrido[1,2-a]pyrazin

Diethylmalonate specified in the header of example 23, (0.65 g, of 1.62 mol) boil vigorously with a back boiler in concentrated hydrochloric acid for 3 hours the pH of the reaction mixture (cooled to room temperature) is set equal to 6.8 by adding dropwise a 10% aqueous lithium hydroxide. Concentrating the mixture in vacuo gives an intermediate solid crude lithium salt of racemic (7S*, 9aS*)-7-(2-carboxymethyl)perhydro-2-(benzo[d] isoxazol-3-yl)perhydro-1H-pyrido[1,2-a] pyrazine. The entire sample is stirred for 18 h in methanol concentrated sulfuric acid (7,0 and 0.12 ml, respectively). Concentration in vacuo gives an oily residue which is dissolved in a biphasic mixture of ethyl acetate/saturated aqueous bicarbonate (25 ml each; pH 7.8). The organic phase is separated and concentrated in Vacu the house and finally methylenchlorid/methanol 97:3 by volume) to obtain the corresponding pure methyl ester (0,23 g, output 41,8%) as a colourless oil. TCX Rf (ethyl acetate; potassium permanganate spray): 0,20.13NMR (CDCl3) Delta 174.0, 164.0, 161.0, 129.5, 122.3, 122.1, 116.1, 110.5, 61.3, 60.2, 54.1, 53.7, 51.6, 48.2, 35.6, 31.5, 30.2, 29.5, 29.2.

The reaction mixture containing the methyl ester (23 mg, 0.07 mmol) and sociallyengaged (0,167 ml of 1.0 M solution in tetrahydrofuran; 0,17 mmol of sociallyengaged) in anhydrous tetrahydrofuran (0.5 ml) is refluxed for 4 hours the Reaction is cooled to room temperature and quenched with a solution of methanol (7 drops) and tetrahydrofuran (5 ml). The inorganic part is filtered off and the filtrate was concentrated in vacuo to obtain the corresponding alcohol product, racemic (7S*, 9aS*)-2-(benzo[d] isoxazol-3-yl)perhydro-7-(3-(hydroxypropyl)-1H-pyrido[1,2-a]pyrazine in the form of a colorless amorphous solid product (to 15.9 mg, yield 75,4). TCX Rf (methylene chloride/methanol 9: 1 by volume; potassium permanganate spray): 0,35.13NMR CD3OD)Delta 165.1, 162.2, 131.2, 123.8, 123.7, 116.9, 111.0, 63.0, 62.5, 61.7, 55.0, 54.3, 48.9, 36.7, 31.6, 31.4, 30.6, 29.9.

Example 25

Racemic (7R*, 9aS*-2-(6-chlorobenzo[d]-isoxazol-3-yl)perhydro-7-(hydroxymethyl)-1H - pyrido[1,2-a]pyrazin.

According to the method of example 4 alcohol-amioka product (206 mg, output 53,8%) allocated in the form of a pale yellow amorphous solid product. This product 7 - 9a-hydrogens are TRANS. TCX Rf methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,41.13NMR (CDCl3) Delta 164.2, 160.6, 136.1, 123.3, 122.8, 114.9, 110.8, 65.9, 60.2, 58.7, 54.1, 53.4, 48.0, 39.0, 28.8, 26.7.

Example 26

Racemic (7R*, 9aS*)-2-(6-chlorobenzo[d]isoxazol-3-yl)perhydro-7-((3,3 - tetramethyleneglutaric)methyl)-1H-pyrido[1,2-a]pyrazin

By way of examples 5 and 17 alcohol-amine product specified in the header of example 25 (66 mg, 0,165 mmol) converts specified in the header of the product (13,7 mg, yield 17.6%) and isolated in the form of a colorless solid product. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,64.13NMR (CDCl3) Delta 172.4, 164.4, 160.9, 136.0, 123.2, 122.7, 115.1, 110.8, 59.9, 59.5, 54.2, 53.6, 48.2, 44.9, 42.8, 39.4, 37.7, 35.9, 29.0, 28.3, 24.3.

Example 27

Racemic (7S*, 9aS*)-2-(6-chlorobenzo[d]isoxazol-3-yl)perhydro-7-(hydroxymethyl)-1H-pyrido[1,2-a]pyrazin

According to the method of example 4 racemic (7S*,9aS*)-7-(hydroxymethyl)perhydro-1H-pyrido[1,2]pyrazin (300 mg, of 1.76 mmol), also called CIS-7-hydroxymethyl-2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a] pyrazin, derived from dimethyl CIS-p is benzo[d]isoxazol transform specified in the title compound (369 mg, yield 65%) and was isolated as a colorless solid product. In this product, 7 - and 9-positions are CIS-shows specification 7S, 9aS-stereochemistry. TCX Rf (metalachlor/methanol 9: 1 by volume; potassium permanganate spray): 0,30.13NMR (CDCl3) Delta 164.3, 160.5, 136.1, 123.3, 122.7, 114.9, 110.8, 67.6, 60.1, 58.2, 54.1, 53.6, 48.3, 34.4, 26.9, 26.3.

Example 28

Racemic (7S*, 9aS*)-2-(6-chlorobenzo[d]isoxazol-3-yl)perhydro-7-((3,3 - tetrahydrobiopterine)methyl)-1H-pyrido[1,2-a]pyrazin

According to the methods of examples 5 and 7 transform specified in the header of example 26 product (13,8 mg, 0.04 mmol) in specified in the header of this example, compound (20 mg, 100%) allocated in the form of a colorless foam. TCX Rf (methylene chloride/methanol 9: 1 by volume; spray permanganate potassium): 0,73.13NMR (CDCl3) Delta 172.5, 164.4, 160.8, 136.0, 123.1, 122.8, 115.1, 110.8, 60.4, 58.5, 54.1, 53.6, 48.2, 45.1, 41.5, 39.4, 37.6, 32.9, 25.0, 24.8, 24.3.

Example 29

Racemic (7R*, 9aS*)-2-(benzo[d] isothiazol-2-yl)-perhydro-7-(hydroxymethyl)-1H-pyrido[1,2-a]pyrazin

A mixture containing Mixable products for preparing 4 below (230 mg, 1.38 mmol), 3,2-chloro-1,2-benzothiazole (280 mg, 2,78 mmol) and potassium iodide (20 mg) in isoamyl alcohol (5.0 ml) is boiled with reverse holodilnik.ru the entire sample (20 g of silica gel, 32 64 mesh; elution with ethyl acetate/methanol 15:2 by volume) to give 49 mg (17%) specified in the header of the product (derived ether TRANS piperidine-2,5-in primary forms and therefore have a 7 - 9a-hydrogen substituents and TRANS) as a colorless amorphous solid product. TCX Rf (methylene chloride/methanol 9: 1 by volume; potassium permanganate spray): 0,28. MS m/Z 365.1 (M, C17H23N3O4S).13NMR (CDCl3) Delta 141.8, 133.0, 132.0, 127.8, 126.7, 116.8, 110.0, 66.0, 61.8, 61.6, 58.4, 55.9, 55.6, 39.0, 28.8, 26.6.

Example 30

Racemic (7S*, 9aS*)-2-(benzo[d] isothiazol-3-yl)-perhydro-7-(hydroxymethyl)-1H-pyrido[1,2-a]pyrazin

A mixture of racemic (7S*,9aS*)-7-(hydroxymethyl)perhydro-1H-pyrido[1,2-a] pyrazin [also called CIS-(7-hydroxymethyl)perhydro-1H-pyrido[1,2-a] pyrazin] obtained according to Preparation 5 from page 28 wyrezyserowany international application N WO 90/08144 (1,62 g of 9.56 mmol) and isoamyl alcohol (8.0 ml) is refluxed for 18 hours Add methylene chloride (100 ml) and the mixture is filtered. The filtrate is concentrated in vacuo to an oil. Flash chromatography of the entire sample (30 g of silica gel, 32 64 mesh; elution first with ethyl acetate and finally with ethyl acetate/methanol 9:1 by volume) gives the uke is 1 by volume; the potassium permanganate spray): 0,3413NMR (CDCl3) Delta 142.9, 133.5, 132.8, 127.8, 126.7, 116.7, 109.8, 65.6, 61.8, 61.6, 57.1, 56.0, 55.6, 34.7, 25.9, 25.8.

Example 31

Racemic (7R*, 9aS*)-2- (benzyloxycarbonyl)-perhydro-7-(hydroxymethyl)-1H-pyrido[1,2-a]pyrazin

To the solution specified in the header of the example 3 product (640 mg, 3,76 mmol) in acetone/water (6.3 ml and 2.2 ml, respectively) is added dropwise over several minutes to a solution of benzylbromide (and 0.61 ml, 729 mg, 4,27 mmol) in acetone (2 ml), maintaining the pH of the mixture equal to 9.5, by introducing dropwise a saturated aqueous solution of sodium carbonate. After completion of addition, the reaction stirred for 5 min at room temperature. The solvent acetone is removed in vacuo, add ethyl acetate (60 ml) and water (30 ml) and the pH of the mixture mix well set equal to 9.5 (sodium carbonate). The separated organic phase is dried (anhydrous sodium sulfate) and concentrated in vacuo to an oil (940 mg). Flash chromatography of the entire sample /10 g of silica gel, 32 63 mesh, elution first with ethyl acetate (100 mg), followed by ethyl acetate/methanol (100 ml, 97: 3 by volume) and finally with ethyl acetate/methanol (200 ml, 90:10 by volume)/network specified in the procurement of the product in the form of colourless malamar 32

Racemic (7R*, 9aS*)-2-(benzyloxycarbonyl)-perhydro-7-((3,3-tetrahydrobiopterine)methyl)-1H-pyrido[1,2-a]pyrazin

To a chilled (5oC) and mix well to a solution of N-carboxymethylcysteine intermediate from example 31 (0,164 mg, 1.07 mmol) in methylene chloride (7 ml) is added dropwise methanesulfonanilide (0,087 ml, 1.13 mmol). The reaction mixture was stirred 15 min at room temperature. Add methylene chloride (10 ml) and water (15 ml) and the pH of the mixture mix well set equal to 9.5 (1 N. aqueous sodium carbonate). The organic phase is separated, washed three times with equal volumes of water, dried (anhydrous sodium sulfate) and concentrated in vacuo to obtain the intermediate mutilator. The entire sample was dissolved in anhydrous N, N-dimethylformamide (DMF), 2.0 ml) and the resulting solution was added to DMF solution (3.0 ml) sodium 3,3-tetramethyleneglutaric obtained from sodium hydride (47 mg, 60% dispersion of sodium hydride in mineral oil was 28.2 mg, 1.18 mmol of sodium hydride) and 3,3-tetramethylene of glutarimide (198 mg, 1.18 mmol, Aldrich Chemical Co.). The mixture is stirred and heated at 90oC for 19 hours Concentrated in vacuo to an oil which is dissolved in a good stir this mixture is hydrated extract is stirred with fresh equal to the volume of the portion of ethyl acetate establishing pH 8.5 (saturated aqueous solution of sodium carbonate). The separated organic phase is concentrated in vacuo to an oil. A study using NMR shows that the desired product contains a mixture of 3,3-tetramethylene of glutarimide that separate additional processing (methylene chloride/water, 30 ml each, with the establishment of the pH to 9.0 with sodium carbonate). Concentration in vacuum dried dry sodium sulfate the organic extract gives specified in the title compound as a colourless oil, 230 mg (yield 47.9 per cent). TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,60.

Example 33

Racemic (7R*, 9S*)-7-((3,3 - tetramethyleneglutaric)methyl)perhydro-1H-pyrido[1,2-a]pyrazin

The solution specified in the header of example 32 product (230 mg, 0.51 mmol) in a mixture of ethanol/methanol (10 ml and 2 ml, respectively) hydronaut apparatus Parra (hydrogen pressure of 50 psig above 110 mg of the catalyst 20% of hydroxide palladium on coal) within 2 hours the Catalyst is filtered off under nitrogen atmosphere and the resulting filtrate was concentrated in vacuo to obtain specified in the procurement of product as colorless viscous oil, 150 mg (yield 92%).

Example 34

Racemic (7R*, 9aS*)-2-(benzo[d] isoxazol-3-yl)-perhydro-7-((3,3-tetrame is (90 mg, 0.28 mmol), 3-chloro-1,2-benzothiazole (for 95.2 mg, 0,56 mmol) and sodium carbonate (60 mg, 0,56 mmol) in isoamyl alcohol (1.0 ml) is stirred and heated at 110oC for 1 h the Mixture is cooled to 50oC, add an additional 3-chlorobenzotriazol (95; 2 mg of 0.56 mmol). The reaction is then stirred and heated at 120oC for 3 hours After cooling to room temperature, add methylene chloride (10 ml) and the resulting mixture is filtered, the filtrate concentrated in vacuo to an oil. Flash chromatography of the entire sample (3 g silica gel, 32 63 mesh, elution first with ethyl acetate/hexane, then ethyl acetate and finally with ethyl acetate/methanol/ kontsentrirovannym water ammonia 9:2:0.1 volume) gives specified in title product as an amorphous solid, 25 mg (yield of 19.7%). TCX Rf (ethyl acetate/hexane 9:1 by volume):0,18.

Example 35

Racemic dimethyl

CIS-1-(cyanomethyl)piperidine-2,4-in primary forms

A mixture containing specified in the header of preparation 5 dimethyl ether dicarboxylic acid (12.4 g, 61,6 mmol), bromoacetonitrile (5,15 ml, 8,87 mg, 73,9 mmol), anhydrous sodium carbonate (26 mg, 0.25 mol) and potassium iodide (1.73 g, 10.4 mol) in the mixture (283 ml) is stirred and boiled with reverse holdout in a well-stirred mixture of methylene chloride/water (200 ml and 100 ml, respectively). The layers are separated and the aqueous portion extracted twice 100 ml of fresh methylene chloride. The organic extracts are combined dried (anhydrous sodium sulfate) and concentrated in vacuo to obtain specified in the title compound as a viscous oil in quantitative yield (14.8 g). TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,78.13NMR (CDCl3) Delta 173.7, 171.8, 114.1, 62.1, 52.4, 51.9, 51.5, 43.3, 39.8, 31.7, 27.4.

Example 36

Racemic methyl (8R*, 9aS*)-4, 6, 7, 8, 9, 9a-hexahydro-2H,3H-pyrido[1,2-a]-pyrazin-1-one-8-carboxylate

A solution of the product specified in the header of example 35 (14,80 g of 61.6 mmol) in a mixture of methanol/ethyl acetate (250 ml and 100 ml, respectively) hydronaut apparatus Parra (hydrogen pressure of 50 psig, 25,2 g of the catalyst of the Raney Nickel) for 18 h at room temperature. The catalyst is filtered off, the filtrate concentrated in vacuo to an amorphous solid product. Crystallization of the entire sample from isopropyl alcohol gives specified in the header connection (to 5.21 g, yield and 39.9%) as a colourless crystalline product, so pl. 185 186oC. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,3.13NMR (CDCl3) Delta 174.8, 170.6, 64.ro-1H-pyrido[1,2-a]pyrazin

According to the method of example 3 aminoether product specified in the header of example 36 (95, 231 g, 24.6 mmol) restore obtaining specified in the header of amerosport (33,3 g, yield 81%) allocated in the form of a colorless amorphous solid product. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,3.13NMR (CDCl)3) Delta 67.8, 60.4, 54.8, 54.7, 51.3, 38.3, 32.8, 30.3, 28.5.

Example 38

Racemic (8R*, 9aS*)-2-(benzo[d] isoxazol-3-yl)-perhydro-8-(hydroxymethyl)-1H-pyrido[1,2-a]pyrazin

The mixture containing aminoplast specified in the header of example 37, (20,0 g, 117 mmol), 3-chloro-1,2-benzisoxazol (36,1 g, 235 mmol) and 1,8-diazabicyclo [5,4,0] under-7-ene (DBU, 25.4 g, 25 ml, 167 mmol) in 2,6-lutidine (19.6 ml) is stirred and heated at 140oC for 18 hours Add DBU (25.4 g, 5 ml, 167 mmol) and 2,6 - lutidine and the reaction mixture was stirred at 140oC for an additional 7 hours the Solvent is removed in vacuo, and the residue is extracted in a well-stirred mixture of methylene chloride/water (200 ml each). Chilled water part twice extracted with 50 ml of fresh methylene chloride. The combined organic extracts washed three times with equal volumes of water, dried (anhydrous sodium sulfate) and conc is their methylenchlorid/methanol 9:1 by volume) gives specified in the header of the connection (in which 8 - and 9-hydrogen substituents are CIS) as an amorphous solid product, 15.7 g, yield of 46.7% TCX Rf (ethyl acetate methanol 15,2 by volume; potassium permanganate spray): 018,3.13NMR (CDCl3) Delta 163.9, 160.9, 129.6, 122.3, 122.2, 116.0, 110.4, 67.3, 59.6, 55.0, 53.7, 53.6, 48.1, 38.1, 32.5, 28.4.

Example 39

Racemic (8R*, 9aS*)-2-(benzo[d] isoxazol-3-yl)-perhydro-8-(methanesulfonate-methyl)-1H-pyrido[1,2-a]pyrazin

According to the method of example 5 N-benzisoxazoles alcohol of example 38 (15.7 g, 5.46 mmol) is converted into the corresponding mesilate specified in the header, (19 g, yield 95%) allocated in the form of a pale yellow amorphous solid product. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,53.13NMR (CDCl3) Delta 163.8, 160.9, 129.5, 122.3, 122.1, 115.9, 110.3, 73.6, 58.9, 54.3, 53.7, 53.6, 48.2, 37.2, 35.3, 31.9, 28.0.

Example 40

Racemic (8R*, 9aS*)-2-(Benzo[d] isoxazol-3-yl)-8-(cyanomethyl)perhydro-1H-pyrido[1,2-a]pyrazin

A mixture containing mesilate specified in the procurement of example 39, (2.0 g, vs. 5.47 mmol) and sodium cyanide (805 mg, 16.4 mmol) in N,N-dimethylformamide (32 ml) is stirred and heated at 100oC for 18 hours the Solvent is removed in vacuum and the residue is dissolved in a well-stirred mixture of methylene chloride/methanol (150 ml each) when establishing a pH of 9.5 (6N. an aqueous solution of carbonate is adicheskie extracts dried (anhydrous sodium sulfate) and concentrated in vacuo to a pale yellow amorphous solid product (1,53 g). Crystallization of the entire sample from isopropyl alcohol gives specified in the header connection 707 mg, yield 43,6% so pl. 164 166oC.13NMR (CDCl3) Delta 164.0, 160.9, 129.6, 122.4, 122.1, 118.2, 116.0, 110.5, 59.1, 54.6, 53.6, 53.5, 48.3, 35.1, 32.8, 31.3, 24.2.

Example 41

Racemic (8R*, 9aS*)-8-(2-amino-ethyl)-2-(benzo[d] isoxazol-3-yl)perhydro-1H-pyrido[1,2-a]pyrazin

According to the method of example 7 nitrile specified in the header of example 40, (700 mg, 2.36 mmol) to restore specified in the header of the product (610 g, yield 86%) allocated in the form of a yellow oil. TCX Rf (ethyl acetate/methanol/concentrated aqueous ammonia 1:1:0.15 in volume; the potassium permanganate spray): 0,3.

Example 42

Racemic (8R*, 9aS*)-2-(benzo[d] isoxazol-3-yl)perhydro-8-(2,2-di(methoxycarbonyl)ethyl)-1H-pyrido[1,2-a]pyrazin

By way of example 23 mesilate specified in the header of example 39, (19,0 g, 52 mmol) is converted into dimethylaminomethyl the product specified in the header (7,80 g, yield 37%) allocated in the form of a viscous yellow oil. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,54.

Example 43

Racemic (8R*, 9aS*)-2-(benzo[d]isoxazol-3-yl)perhydro-8-(3-hydroxypropyl)-1H-pyrido[1,2-a]pirsc) is converted into a real alcohol, specified in the header (0.95 g, yield 18.8 percent), is allocated in the form of a viscous yellow oil. TCX Rf (ethyl acetate/methanol/concentrated aqueous ammonia 1:1: 0.15 in volume; the potassium permanganate spray): 0,64.

Example 44

Racemic (8R*, 9aS*)-2-(benzo [d] isoxazol-3-yl)perhydro-8-(3-(methanesulfonate)-propyl)-1H-pyrido [1,2-a]pyrazin

According to the method of example 5 alcohol specified in the header of example 43, (0,85 g, a 3.01 mmol) converts specified in the header of the product (0,89 g, 75% yield) emitted in the form of a yellow oil. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,50.

Final imide-substituted products (with 8 - and 9-and hydrogen atoms CIS) is obtained by reaction of nelfinavir with the appropriate imide sodium by way of example 17.

Example 45

Racemic (7S*, 9aS*)-2-(benzo [d] isoxazol-3-yl)perhydro-7-(hydroxymethyl)-1H-pyrido[1,2-a]pyrazin

A mixture containing racemic (7S*, 9aS*)-7-(hydroxymethyl)perhydro-1H-pyrido[1,2-a]pyrazin (see example 27; 500 mg of 2.93 mmol), 3-chloro-1,2-benzisoxazol (890 mg, 5,86 mmol) and 1,8-diazabicyclo[5,4,0]under-7-ene (DBU, 446 g, 0,438 ml of 2.83 mmol) in 2,6-lutidine (0.5 ml) is stirred and heated at 145oC for 18 hours the Solvent filtrowa and the solvent evaporated in vacuo to a dark brown residue. Flash chromatography of the entire sample (20 g of silica gel, 32 63 mesh; elution with ethyl acetate/methanol 95:5 by volume) to give 350 mg (41.7 per cent) specified in the connection header (in which 7 - 9a-hydrogen substituents remain in CIS) as a colorless amorphous solid product. HRMS m/Z 287.1639 (M, C16H21N3O2).13NMR (CDCl3) Delta 164.0, 161.0, 129.5, 122.3, 122.1, 116.1, 110.5, 67.5, 60.2, 58.2, 54.2, 53.7, 48.3, 34.4, 26.9, 26.3.

Example 46

Racemic (7S*9a*)-2- (benzo[d] isoxazol-3-yl)perhydro-7-(methanesulfonate)-methyl)-1H - pyrido[1,2-a]pyrazin

According to the method of example 5 alcohol specified in the header of example 45, (8.0 g, 27.8 mmol) is converted into the specified header mesylate derived (to 9.57 g, the yield was 94.2%) allocated in the form of a yellow amorphous solid product. TCX Rf (methylene chloride/methanol 9:1 by volume; spraying potassium permanganate): 0,76.13NMR (CDCl3Delta 163.9, 161.0, 129.5, 122.3, 122.2, 116.1, 110.4, 71.1, 60.2, 55.7, 54.0, 53.6, 48.3, 37.1, 33.4, 24.7, 24.2.

Example 47

Racemic (7R*, 9aS*)-2-(benzo[d]isoxazol-3-yl)-7-(cyanomethyl)perhydro-1H-pyrido[1,2 - a]pyrazin

According to the method of example 6 mesilate specified in the header of example 46 (3,39 g, 9.28 are mmol) is converted into the nitrile specified in the header (1.5 g, yield of 54.5%) allocated to Leah): 0,72.13NMR (CDCl3) Delta 163.9, 161.0, 129.5, 122.3, 122.1, 119.7, 116.1, 110.4, 60.1, 59.4, 53.9, 53.6, 48.3, 31.2, 26.8, 24.1, 19.5.

Example 48

Racemic (7R*, 9aS*)-2-(aminoethyl)-2-(benzo[d] isoxazol-3-yl)perhydro-1H-pyrido[1,2-a]pyrazin

According to the method of example 7 nitrile specified in the header of example 47, (1.50 g, of 5.06 mmol) to restore specified in the title amine (1,34 g, yield 88,2%) allocated in the form of a yellow viscous oil. TCX Rf (ethyl acetate/methanol/concentrated aqueous ammonia 1:1:0.15 in volume; the potassium permanganate spray) 0,20.

Final imide-substituted products with 7 - 9a-hydrogen atoms of Cys, obtained by reaction of an amine with the anhydride of a suitable acid to the method of examples 10 to 12.

Example 49

Racemic (7R*, 9aS*)-2-(benzo[d] isoxazol-3-yl)perhydro-7-(2,2-di(methoxycarbonyl)ethyl)-1H-pyrido[1,2-a]pyrazin

By way of example 23 mesilate specified in the header of example 46, (to 9.57 g, 26 mmol) is converted into dimethylaminonaphthalene the product specified in the header (6,54 g, yield 61,5%), emitted as light yellow oil. TCX Rf (methylene chloride/methanol 9:1 by volume; potassium permanganate spray): 0,67.13NMR (CDCl3) Delta 170.1, 169.9, 163.9, 161.1, 129.4, 122.2(2), 116.2, 110.4, 60.5, 58.7, 54.2, 53.6, 52.5, 50.1, 48.2, 31.3,�oxypropyl)-1H-pyrido[1,2-a]pyrazin

By way of example 24 diethylmalonate product specified in the header of example 49 (6,54, 16 mmol) is converted into the specified header alcohol (897 mg, yield 17.7%) and emitted as light yellow amorphous solid product. TCX Rf (ethyl acetate/methanol/concentrated aqueous ammonia 1:1:0.15 in volume; the potassium permanganate spray): 0,71.

Example 51

Racemic (7R*, 9aS*)-2-(benzo[d]isoxazol-3-yl)-7-(3-(methanesulfonate)-propyl)-1H - pyrido[1,2-a]pyrazin

According to the method of example 5 alcohol specified in the header of example 50, (897 mg, 2,85 mmol) is converted into the specified header mesilate (1,02 g, yield 90,5%) allocated in the form of a yellow viscous oil, TCX Rf (ethyl acetate; potassium permanganate spray): 0,35.

Example 52

Using the methods of obtaining from the previous examples, additional CIS-7-substituted compounds of the formula

< / BR>
receive, as follows (see tab. 1).

Example 53

Using the methods of obtaining from the previous examples, additional TRANS-7-substituted compounds of the formula

< / BR>
receive the following way (table. 2).

Example 54

Using the methods of obtaining from the previous examples, additional CIS-8-substituted compounds of formulas is l/piperidine-2-carboxylic acid

Mix dimethyl CIS-piperidine-2,5, in primary forms /20 g 0,077 mol, salicylic aldehyde /3 ml, about 0.014 mol/ and acetic acid /200 ml, and refluxed for 24 hours the Mixture is cooled and evaporated in vacuo to a thick oil. The residue is placed in 300 ml of isopropyl alcohol and again evaporated to 200 ml, and the product begins to precipitate. After granulating for 2 h specified in the header, the product is filtered and dried in air emitting 9,20 g; so pl. 184oC/softening 191 200oC /Razlog./).1H-NMR (CDCl3, 300 MHz/ Delta: to 3.73 /c, 3H/, 3,62 /septet, 2H/, 3,15 /t, 1H/, 2,90,/m 1H/, 2,30 /m, 2H/, 1,74 /m, 2H/.

Crude CIS-5-/methoxycarbonyl/piperidine-2-carboxylic acid, contain some amount of TRANS-isomer, 4.52 g, was isolated by the process of evaporation of the mother liquor. Product return process instead of dimethyl CIS-piperidine-2,5-in primary forms.

Replacement salallaho of the aldehyde benzaldehyde gives the same products, but the desired equilibrium mixture of CIS and TRANS acids is achieved more slowly.

Preparation of 2

3:1 Mixture of TRANS and CIS-5-/methoxycarbonyl/piperidine-2-carboxylic acid

Mix dimethyl CIS-piperidine-2,5, in primary forms/112 g of 0.56 mol/ salicyl C for 60 hours The mixture is cooled, evaporated in vacuo to a thick oil, which crystallizes of 61.7 g /59% / specified in the header of the product by evaporation of 800 ml of isopropyl alcohol. The composition of the product determined1H-NMR /D2O, 300 MHz/ peak when 3,13 ppm /t, 1H, J 14,5 Hz/ identified as TRANS, and peak at to 3.33 ppm /DD, IH/identified as CIS.

Preparation of 3

Dimethyl TRANS-piperidine-2,5-hydrochloride in primary forms

Method AND

The mixture obtained in the preceding preparation /15,1 g, 0.08 mol, suspended in 200 ml of methanol and stirred under N2at 0, 5oC. for 5 minutes is added dropwise thionyl chloride /7,35 ml, 0.1 mol/. After 30 min the mixture is heated to room temperature and after 1 h and refluxed for 6 hours While cooling from the reaction mixture crystallizes specified in the header of the product /6.8 g/. The second and third parts /5.3g and 0.63 g/ target product is obtained by the process of evaporation of the mother liquor to a small volume and dilution with 200 ml of isopropyl alcohol. The total yield of the product specified in the header, is 67% so pl. 207 209oC.

Calculated: C 45,48; H 6,79; N Of 5.89.

Found: C 45,34; H 6,55; N Of 5.82.

Dimethyl CIS-piperidine-2,5, in primary forms, you is use.

Method B

The same method specified in the header of preparation 1 product is converted into a product that is listed in the header above.

Preparation of 4

70: 30 Mixture of racemic /7S*, 9aS*/-7-(hydroxymethyl)perhydro-IH-pyrido[1,2-a] pyrazine and racemic /7R*, 9aS*/-7-(hydroxymethyl)- perhydro-1H-pyrido[1,2-a]pyrazine

The methods described in preparations 1-4 on pages 26 and 27 of the international patent application N WO 90/08144, dimethyl pyridine-2,5, in primary forms converted into a mixture of racemic 1-copersito-1H-pyrido[1,2-a]pyrazin-7-carboxylates in the form of oil / i.e., without separation "CIS" or (7S*, 9aS*)-isomer/. Recovery LiAIH4this mixture under preparation 5 on pages 28 WO specified 90/08144 network specified in the header of the product with almost quantitative yield. The composition of the product determine 300 MHz1H-NMR.

Preparation of 5

Racemic dimethyl CIS-pyridine-2,4-in primary forms

A solution of pyridine-2,4-dicarboxylic acid dimethyl ester /148,5 g, 0.76 to mol/ ethyl acetate /1.5 l/ hydronaut at room temperature in the apparatus Parra /50 psig pressure of hydrogen above 4.0 g of a catalyst of platinum oxide/ within 18 hours the Catalyst is filtered off and the filtrate is concentrated is estwenno/ when establishing a pH of 9.5 /sodium carbonate/. The layers are separated and the aqueous portion is extracted twice with portions of 1 l of fresh methylene chloride. The combined organic extracts dried /waterless sodium sulfate/ and evaporated in vacuo to a viscous yellow oil. The above procedure is repeated in the same quantities and specified in the header of the product of two cycles unite /290,1 g, yield 94.7% of/. TCX Rf (methylene chloride/methanol 9: 1 by volume; potassium permanganate spray): 0,36 /Rf source dimethyl ether in the same system: 0,82/.

Preparation of 6

Dimethyl CIS-N-(2-(phthalimido)ethyl)-piperidine-2,5-in primary forms

Method A.

Dissolve 12.0 g /45,6 mmol/ phthalimido acetaldehyde of diethylacetal /Aldrich Chemical Co. Inc./ in 36 ml of acetic acid and 1.34 ml of concentrated HCl is heated at 45 50oC for 2 hours, After cooling the solution to 20oC add the remaining 9.08 g of dimethyl CIS-piperidine-2,5-in primary forms and continue stirring for another 30 min at 20 25oC. the Obtained light orange solution was treated in the same way 12,08 g /57 mmol/ Na (OAc)3BH for more than 30 min, followed by additional stirring for 30 min at 30-35oC. the Solution is cooled to 20oC and diluted with 120 mg of H2R and 120 ml of CH2Cl2to follow the th bicarbonate. Replacement of CH2Cl236 ml of EtOH, followed by addition of 100 ml of hexane for crystallization of the solid product which is left to granulomatosa overnight at a temperature of 20 25oC. Filtration and drying of this solid product gives 13.5 g /79,4/ specified in the header of the product in the form of a solid, melting at 97 100oC.

Method B.

Stir a mixture of 70 ml of CH2CI2, 9,8 g /51 mmol/ N-/2-hydroxyethyl/phtalimide and 6.1 ml /0.52 mmol/ 2,6-lutidine is cooled to -4oC. Maintaining the temperature below 15oC add anhydride triftormetilfullerenov acid /8,9 ml of 0.53 mmol/ slowly over 1 h the resulting mixture was stirred at 15 to 20oC for 1.25 h, then washed with 40 ml of H2O, 40 ml of 2 N. NCI and 40 ml of H2O obtaining the solution of N//2-triplelux/ethyl/phtalimide. When 20 25oC in a separate reaction vessel was placed 50 ml of CH2CI2, 55 H2O and 10.6 /0.1 mol/ Na2CO3. After stirring for 15 min dimethyl CIS-piperidin to 2.5, in primary forms /11.9 g, 50 mmol/ above the reagent are combined and the mixture is stirred for 1.25 h at 20 25oC. the Organic layer is separated, washed with 30 ml of water and displace CH2Cl2to the connection. After mixing and granulation for 1 h at 0 to 5oC specified in the header of the product produce by filtration, 16.7 g; so pl. 98 100oC.

Method

To a well stirred two-phase mixture of sodium carbonate /500 g, 4,72 mmol/ water /3 l/ and CIS-2,5-piperidine in primary forms of dimethyl ether /240 g, 1.18 mmol/ methylene chloride /4,5 l/ constant stream add a solution of 2-phthalimidomethyl triphala /417 g of 1.29 mol/ methylene chloride /3 years/ period of time more than 3 hours the Organic layer was separated and the aqueous layer was extracted with fresh methylene chloride /3 l/. The combined organic extracts washed with water /3 l/, then brine /3 l/, dried over anhydrous magnesium sulfate and finally concentrated in vacuo to a solid product. The rest is ground up into a powder by boiling under reflux in ether /3 l/ under vigorous stirring for 15 minutes After cooling to room temperature the solution was poured into hexane /3 l/ and the resulting mixture stirred for 18 hours Specified in the header of the product collected by filtration.

Preparation of 7

Methyl /7C*, 9aS*/-4,6,7,8,9,9 a-hexahydro-2H, 3H-pyrido[1,2-a]pyrazin-1-one-7-carboxylate

A mixture of 240 ml of methanol, 16.6 g /44 m is>C for 17 hours the mixture is Then diluted with 200 ml of CH2Cl2, granularit for 1 h and side deemed allocate filtration with washing 75 ml of CH2Cl2. The combined filtrate and wash liquor evaporated to 225 ml by distillation and CH2Cl2/methanol replacing isopropyl alcohol to a final volume of 200 ml After slow cooling from the 50oC to 8oC during 2-hour period specified in the header of the product, 9.2 grams, isolated by filtration. The entire product was then purified by recrystallization from CH2Cl2obtaining 7,45 cleaned specified in the header of the product, identical to the product specified in the header of preparation 4 visititing WO 90/08144, Bright et al.

1. Racemic or optically active perhydro-1H-pyrido(1,2-a) pyrazine General formula I

< / BR>
or their pharmaceutically acceptable salts accession acid,

where L and X are taken separately, where X N and L R (CH2)mCO

or L and X, taken together, are

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R3WITH7-cycloalkyl, phenyl or norbornyl; R1, R2and R3each independently hydrogen or CH3;

Y is O or S;

Y1CH2or S;

Y2and Y3vodr 1 or 2;

q 3, 4, or 5;

_ _ _ means a connection or no connection.

2. Connection on p. 1, in which the group is attached in the 7-position with perioperative ring system.

3. Connection on p. 2, in which Y is O and Z is N.

4. Connection on p. 3, in which X N.

5. Connection on p. 4, in which a hydrogen substituent in the 7-position with perioperative cyclic system is in the TRANS position in relation to 9a-hydrogen.

6. Connection on p. 5, in which R3WITH7- cycloalkyl or phenyl; m is 0 or 1.

7. Connection on p. 5, in which n is 2 and R cyclopentyl, cyclohexyl or cycloheptyl.

8. Connection on p. 4, in which a hydrogen substituent in the 7-position with perioperative cyclic system is in the CIS-position relative to the 9a-hydrogen.

9. Connection on p. 8, in which m is 0 or 1; n 2; R3- C6-cycloalkyl or phenyl.

10. Connection on p. 9, in which m is 0; R cyclopentyl.

11 Connection on p. 9, in which m is 0; R cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl.

12. Connection on p. 3, in which L and X, taken together,

< / BR>
13. Connection on p. 12, in which a hydrogen substituent in the 7-position of Badinerie on p. 13, in which n is 1 or 2; p is 1; Y1- CH2; Y2and Y3together.

15. Connection on p. 14, in which n is 1; q 4.

16. Connection on p. 14, in which n is 2; q is 3 or 4.

17. Connection on p. 12, in which a hydrogen substituent in the 7-position with perioperative cyclic system is in the CIS-position relative to the 9a-hydrogen.

18. Connection on p. 17, in which n and p are each equal to 2.

19. Connection on p. 3, in which L and X, taken together,

< / BR>
20. Connection on p. 19, in which --- indicates no connection; R1, R2and R3each N.

21. Connection on p. 20, in which n is 2; the substituent in the 7-position with perioperative cyclic system is in the TRANS position in relation to 9a-hydrogen.

22. Connection on p. 1, in which the group

< / BR>
attached at the 8-position with perioperative ring system and is located in the TRANS-position relative to the 9a-hydrogen;

Z N;

Y 0.

23. Connection on p. 22, in which X N.

24. Connection on p. 22, in which L and X, taken together,

< / BR>
25. Connection on p. 24,

in which n is 2;

p 1;

q 4;

Y1CH2;

Y2and Y3taken together the. 6, with 7S, 9aS stereochemistry.

28. Racemic or optically active perhydro-1H-pyrido(1,2-a)pyrazin formula

< / BR>
where Z is H or Cl;

Z1NH2BUT, OSO2R5N3or SP;

R5WITH1WITH5-alkyl;

n 1, 2, or 3.

29. Connection on p. 28, in which Z N.

30. Connection on p. 29, in which n is 2; Deputy Z1-(CH2)n- located in the 7-position with perioperative cyclic system.

31. Connection on p. 30, in which Z1NH2.

32. Connection on p. 31, in which Z1NH2; hydrogen substituent in the 7-position is TRANS-position relative to the 9a-hydrogen.

33. Connection on p. 32, which is optically active.

34. Connection on p. 33, with 7S 9S stereochemistry.

35. Perhydro-1H-pyrido(1,2-a)pyrazine stereochemical formulas

< / BR>
where1WITH3-alkoxycarbonyl and X1C=O or B - NON2and X1CH2.

36. Perhydro-1H-pyrido(1,2-a)pyrazin formula

< / BR>
37. Racemic dimethyl CIS-1-(nanometer)piperidine-2,4-in primary forms.

38. The method of obtaining racemic or optically active perhydro-1H-pyrido (1,2 - a) pirati the/SUB>WITH7-cycloalkyl, phenyl or norbornyl;

R1, R2and R3each independently hydrogen or CH3;

Y is O or S;

Y1CH2or S

Y2and Y3hydrogen or Y2and Y3taken together, the group (CH2)q;

Z is H or Cl;

m 0, 1, 2 or 3;

n 1, 2, 3 or 4;

p is 1 or 2;

q 3, 4, or 5;

_ _ _ refers to the communication or lack of communication,

characterized in that the compound of General formula II

< / BR>
where Y, Z and n have the specified values; (D nucleophilic tsepliaeva group,

subjected to interaction with nitrogen-containing heterocyclic compound of General formula III

in the case when L and X form together with the nitrogen atom derived piperidine, or with anionic derivative of compound III

in the case when L and X together with the nitrogen atom form an amide or cyclic sulfonamide, in an inert solvent.

39. The method according to p. 38, characterized in that is used as a compound of the formula II in which D is chlorine, bromine or methanesulfonylaminoethyl.

 

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FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I): where: R1 stands for either hydrogen atom, or direct or branched (C1-C7)alkyl; R2 stands for either direct or branched (C1-C7)alkyl, or (C3-C7)cycloalkyl, or (C3-C7)cycloalkyl(C1-C3)alkyl; X stands for hydrogen atom or halogen; R3 stands for either hydrogen atom, or one or more sibstitutes chosen from halogen atoms and following groups: trifluoromethyl, direct or branched (C1-C6)alkyl, (C1-C6)alkoxyl, or group of general formula NR4R5 where R4 and R5 stand for hydrogen atom; as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

10 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel method for obtaining (±)N-[1-(4-fluorophenyl)-2-(1-ethylpiperidin-4-yl)ethyl]-4-nitrobenzamide, corresponding to structural formula (I) or its pharmaceutically acceptable salts. Method mainly relates to hydrochloride of formula (I) compound (niferidil hydrochloride). Niferidil hydrochloride is used as medication for treatment of atrial fibrillation in people. In accordance with claimed method formula (I) compound is obtained by interaction of ethyl ether of 4-fluorobenzoic acid with 4-picoline in tetrahydrofurane in presence of catalyst or condensing means with obtaining 1-(4-fluorophenyl)-2-(4-pyridyl)ethanol. It is preferable to use sodium bis(trimethylsilyl)amide as condensing agent in amount 1-2 moles per a mole of 4-fluorobenzoate. Obtained compound is alkylated with ethylhalogenide with obtaining respective pyridinium salt. The latter is subjected to catalytic reduction with hydrogen in presence of palladium or platinum catalyst with addition of concentrated hydrochloric acid for obtaining 2-(1-ethylpiperidin-4-yl)-1-(4-fluorophenyl)ethanol of formula (II) which is subjected to reductive amination with obtaining [2-(1-ethylpiperidin-4-yl)-1-(4-fluorophenyl)-ethyl]amine, with further interaction of the latter with acid chloride of 4-nitrobenzoic acid with obtaining (±)N-[1-(4-fluorophenyl)-2-(1-ethylpiperidin-4-yl)ethyl]-4-nitrobenzamide of formula (I) in free form or in form of its pharmaceutically acceptable salt. Formula (II) compound is a novel intermediate compound.

EFFECT: method makes it possible to simplify and cheapen the process due to reduction of number of stages, as well as to improve quantity of obtained target product to 99,6% by HPLC data.

5 cl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel 1,2,3-tris-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]-propane trichlorides of the general formula:

wherein at -X+ as -N+R1RR, R1 = R2 mean hydrogen atom (H), R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e (the general degree of oxypropylation) = 49,b + d + f (the general degree of oxyethylation) = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 55, b + d + f = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 90, b + d + f = 27; at -X+ as -N+R1R2R3, R1 = R2 means H, R3 means phenyl, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means phenyl, a + c + e = 90, b + d + f = 27; at -X+ as , a + c + e = 80, b + d + f = 24; at -X+ as , a + c + e = 90, b + d + f =27. Also, invention relates to a method for synthesis of these compounds. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]-propane of the formula:

wherein a + c + e = 49-90, b + d + f = 0-27 with monochloroacetic acid in the presence of acidic catalyst, in boiling organic solvent medium with azeotropic removal of water formed and the following treatment of synthesized reaction product in polar solvent medium at heating with amino-compounds of the formula: NR1R2R3 wherein R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, phenyl, or morpholine of the formula:

in the following mole ratios of reagents - propane hydroxyl derivative : monochloroacetic acid : amino-compound or morpholine = 1:(3.0-3.2):(3.0-3.2), respectively. New compounds show the bactericidal and fungicide activity and properties of demulsifying agents for petroleum emulsions.

EFFECT: improved method of synthesis, valuable properties of compounds.

7 cl, 3 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel [(heterylonio)-methylcarbonyloxypoly(alkyleneoxy)]-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]propane trichlorides of the general formula: wherein: at X+ = Y+ means X+ means -N+R1R2R3 wherein R1 = R2 means hydrogen atom (H); R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e (total degree of oxypropylation) = 49; b + d + f (total degree of oxyethylation) = 9; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 9; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0, and to a method for their synthesis. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]propane of the formula: wherein a + c + e = 55; b + d + f = 0-10 with monochloroacetic acid in the presence of acid catalysts, in organic solvent medium and with azeotropic removal of formed water and the following treatment at heating of the synthesized reaction productwith a mixture of morpholine and aliphatic amine in the molar ratio of reagents - hydroxyl derivative of propane: monochloroacetic acid : morpholine : aliphatic amine = 1:(3.0-3.2):(1.0-2.1):(1.0-2.1), respectively and wherein the total amount of morpholine and aliphatic amine is 3.0-3.2 mole. Novel compounds possess emulsifying properties for aqueous-bitumen and aqueous-mazut emulsions.

EFFECT: improved method of synthesis, valuable properties of compounds.

6 cl, 2 tbl, 8 ex

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

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