Pyridone derivatives

 

(57) Abstract:

Usage: in medicine as an anesthetic. The inventive products: pyridone derivatives of formula (I) or E-COOC2H5and G-CH2Y, Y-phenyl or benzo//Tien-4-yl, or E and G taken together form a group where R is H, Y is phenyl, triptoreline, 3,4-acid; 3,4-dichlorophenyl or benzo//Tien-4-yl, R1and R2form together with the nitrogen atom to which they are attached, pyrrolidinyl And-carbocyclic radical or a group-CH(B)-CH2-B - phenyl or isopropyl. Reagent 1: compound of formula (II) Reagent 2: CH2=CH-COOC2H5. Reagent 3: Y-CH(R)-COM, where M is hydroxyl or halogen. Reaction conditions: inert organic solvent

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connection 1 and connection 2. table 1.

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity.

According to the invention pyridone derivatives correspond to the following formula:

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in which the E is a radical COOOC2H5and G is a group CH2-Y, in which Y is phenyl, 3,4-dimethoxyaniline, 4-trifloromethyl, 3,4-dichlor the ora R is a hydrogen atom;

Y is phenyl, 4-cryptomerioides, 3,4-dimethoxyaniline, 3,4-dichloraniline, or benzo//Tien-4-ilen radical;

b)

in which Y is phenyl, 4-trifloromethyl, 3,4-dimethoxyaniline, 3,4-dichloraniline or benzo//Tien-4-ilen radical;

in)

in which R is hydrogen, benzyl, methyl, ethyl, or 2-propanaminium radical, Y is phenyl, 4-trifloromethyl, 3,4-dimethoxyaniline, 3,4-dichloraniline or benzo//Tien-4-ilen radical,

A is a carbocyclic radical or a group

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which means phenyl or isopropyl;

R1and R2form together with the nitrogen atom to which they are attached, pyrrolidinyl.

These compounds may be in the form of possible isomers, racemates, enantiomers and diastereoisomers, as well as in the form of their salts.

Salts with organic or inorganic acids of the compounds of formula (I) can for example be a salt formed with the following acids: hydrochloric, Hydrobromic, idiscovered, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoic, maleic, Shmarinov, succinates, winnipeger, methansulfonate, econsultancy, propanesulfonate such alkylsulfonate acid, as, for example, methanesulfonate: acid alpha ethicality acid, such rimonabantonline acid as benzosulfonate, and aridiculous acid, such as sulfonic paratroopa acid.

Basic salts can serve as salts of sodium, potassium, lithium, calcium, magnesium or ammonium, and salts with organic bases such as methylamine, Propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, three (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methylglucamine.

When a represents a group of the products of formula (I) can be represented by one of the following forms:

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When a represents a substituted radical cycloalkyl, preference is given to those products, the substituents are in the TRANS position.

Among the compounds of formula (I) include in particular those which correspond to formula (IA)

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in which A, R1and R2defined above and the group

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is

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where Y has Vesennie above, and R is hydrogen.

Compounds according to the invention exhibit high affinity for these receptors, in particular, to Kappa receptors, and can be used as analgesic agents.

The compounds of formula (I) according to the invention can be obtained in the following way.

Aminosidine formula (II)

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where A, , are the values specified above for A, R1and R2or the same values, in which the reaction of a protected group, is subjected to the interaction with the acrylic ester of General formula (III)

CH2CH COOC2H5< / BR>
to obtain condensation products of the formula (IV)

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where A' have the above meaning, which is subjected to interaction with the compound of the formula (V)

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where R' has the meanings indicated above for R, or the same values, in which the reaction of a protected group, Y' has the values specified above for Y, or the same values, in which the reaction of a protected group, and M stands for hydroxyl or halogen atom, to obtain the compounds of formula (VI)

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where A', R' and Y' have the above values, and if R' means hydrogen, removing the protective group and get the compounds of formula (Ib), then with high q/BR> where A', R' and Y' have the above meanings, and if R' means hydrogen, removing the possible protective groups and receive compound of formula (IA1), corresponding to formula (IA);

then either the compound of formula (VII) in which R' means a hydrogen, or a compound of formula 1A1(if necessary), subject to: or reduction reaction of exopoli in the gamma position to the nitrogen atom with obtaining the compounds of formula (VIII)

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where A', and Y' have the above values, and if these values correspond to the values A,R1, R2and Y receive the target compound of formula (IA2), corresponding to formula (IA)

or of reduction reaction by catalytic hydrogenation of the same exopoli with obtaining the compounds of formula (IX)

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where A', and Y' have the above significance, and if these values correspond to the values A, R1, R2and Y, we obtain the connection formula 1A3corresponding to formula (IA),

and then (if necessary), the compound of formula (IX) or (IA3treated with a strong base to obtain the corresponding anion, which is subjected to the action of a reagent able to instill radical R', and R' has a value, yasamut the above values, and R' is benzyl, methyl, ethyl or 2-properly radical, and if A', and Y' have the values A, R1, R2and Y, we obtain the connection formula (IA4), corresponding to formula (IA),

either the compound of formula (VII) in which R' or R is different from hydrogen, is subjected to the action of the recovery agent exopoli to obtain the compounds of formula (X), or which corresponds to the compound of formula (IA4or he is transferred to a compound of formula (IA4removing any protective groups

the compounds of formula (I) translate, if necessary, in salt or isolated in the form of possible isomers, racemates, enantiomers and diastereoisomers.

The preferred conditions of implementation of the method is the following:

the condensation reaction of a diamine of the formula (II) with acrylic ester of the formula (III) can be carried out in an inert solvent, such as ethanol, methanol or butanol: the first solution can be cooled to a temperature of about 10oC, then by shaking, bring to room temperature at which the product of formula (IV);

during the reaction to obtain the amide of formula (VI), the acylation of the secondary amine of the formula (IV) can be bacneteventstate, or cyclohexylcarbodiimide, or by using an acid halide of the formula (V), where M represents a halogen atom, such as chlorine atom: reaction usually happens in such an organic solvent, such as tetrahydrofuran or in such a chlorinated solvent, such as methylene chloride with stirring at room temperature conditions;

the cyclization reaction of the compounds of formula (VI) to compounds of formula (VII) can be carried out in an alkaline medium, for example in the presence of sodium hydride or potassium, or alcoholate, for example tert.the butyl sodium or potassium hydroxide in an organic solvent, such as tetrahydrofuran, toluene or ether. Reaction medium can in the beginning to slightly cool before 12 15oC, then bring to room temperature or heated with reflux;

the reduction of compounds of formula (VII) or (1A1) to the compounds of formula (VIII) or (1A2) can be carried out, for example, by transformation of the oxo-group in the compound of formula (VII) in hydrazono using a reagent such as, for example, arylsulfonamides, for example, para-toluene-sulfonylhydrazide in such an organic solvent as, for example, acetic acid, or an alcohol, e.g. methanol or ethanol in the face-to-face hydrazone, for example, using sodium alcoholate or potassium, for example, ethylate sodium, or methylate or butyl sodium or potassium;

the reaction is carried out in such gidrauxilirovanne solvent, as, for example, hot ethylene glycol at a temperature of about 120 160oC;

the reduction of compounds of formula (VIII) or (1A2) to the compounds of formula (IX) or (IA3can be performed, for example, by catalytic hydrogenation of the ethylene group in the presence of such hydrogen acid, such as hydrochloric acid or Hydrobromic acid: the reaction is carried out in alcohol, such as ethanol, acetic acid or complex acid ester, such as ethyl acetate, platinum oxide at room temperature.

The reduction of compounds of formula (VIII) to the compound of formula (IX) may be carried out under the action of a mixed hydride such as sodium borohydride, in an organic solvent, for example in a lower alcohol, mainly in ethanol.

As a strong base, it is preferable to use an alcoholate of an alkali metal, such as tributyltin sodium.

As the reagent is able to instill the radical R of the compound of formula (IX) or the em to be mesilate, mostly toilet. The halide may be chloride, bromide or iodide.

The recovery of the carbonyl group in the compound of formula (VII), where R or R' is different from a hydrogen atom, is carried out in the same conditions, which were defined above to obtain compounds of formula (VIII).

In the compounds of formula (V), (VI), (VII), (VIII), (IX) and (X) different reactive groups that may be protected by suitable protective groups are, for example, hydroxide radicals, acyl, free carboxy or amino, monoalkylamines.

Below as an example is an incomplete list of protective reactionary groups:

the hydroxy group can be protected by radicals of trimethylsilyl, dihydropyran, benzyl, methoxy or methoxymethyl;

the amino group can be protected by radicals of trityl, benzyl, tert.butoxycarbonyl, phthalimido or other radicals known in the chemistry of peptides, such groups atilov, as, for example, the formyl group can be protected, for example, in the form of cyclic or acyclic ketals such as dimethyl - or diethylacetal or atlantoaxial;

the carboxy group can be protected, in the form of esters formed with easily flake the s.

The removal of these protective groups is carried out under normal conditions, namely under conditions of acidic hydrolysis using acids such as, for example, hydrochloric acid, benzoylthiourea or paratroopa sulfonic, formic or triperoxonane.

Group phthalimido removed by hydrazine.

The following examples illustrate the formation of compounds:

Example 1. TRANS.(t)-3-{[2(1-pyrrolidinyl)cyclohexyl]-[(3,4 - dichlorophenyl)acetyl]amino}ethylpropane

Stage A: TRANS. (t)-3-[(2- (1-pyrrolidinyl)cyclohexyl]amino]ethylpropane.

To a solution of 8.4 g of 2-(1-pyrrolidinyl) cyclohexanone 50 cm3ethanol, cooled to +10oC add for 30 min 5.4 cm3ethyl acrylate, dissolved in 50 cm3of ethanol. The solution is stirred for 6 h at room temperature. Is evaporated to dryness, collect 12.7 g of product for use in this form at a later stage.

The spectrum of IR (CHCL3)

1726 cm-1< / BR>
-NH 3260 cm1-< / BR>
NMR (CDCL3)

COOC2H5< / BR>
2,52 Axial

of 0.95 to 3.0 Other protons

Stage B: Trance, (t)-3-{[2-(1 - pyrrolidinyl)cyclohexyl]-(3,4-dichlorophenyl)acetyl]amino}ethylpropane

The mixture 10,65 g 3.4 dihl is for 1 h at room temperature. Within 10 min add 12,65 g of the solution of the amine obtained in stage A, 70 cm3anhydride tetrahydrofuran. Stirred for 5 h at room temperature. Extracted with ethyl acetate, washed it first 120 cm3a saturated solution of sodium bicarbonate, then 2 times 70 cm3water, dried and concentrated to dryness under reduced pressure. The balance in 22 g chromatographies on silica (eluent: ethyl acetate/triethylamine (97-3). Get to 17.6 g of the desired product for use in this form at a later stage:

Range IR

1725 cm-1Region ether

1730 cm-1Tertiary amide

Example 2. TRANS. ()-3-(3,4 - dichlorophenyl)-1-[2-(1-pyrrolidinyl)cyclohexyl]2.4 piperidine and its hydrochloride.

a) Obtaining grounds For suspension of 2.4 g of the hydrate of sodium (in the form of 50-aqueous liquid oil) and 100 cm3anhydrous tetrahydrofuran (THF), stirred at 0 added dropwise within 15 min at 0/+5oC solution 15,14 g of the compound obtained in example 1, in 50 cm3anhydrous tetrahydrofuran. Stirred for 1 h 45 min, then the medium is brought to room temperature, then stirred for further 2 h at room temperature (observed hydrogen gas) then contentroot 2 times 100 cm3sulphuric ether and acidified with aqueous phase 5 cm3of acetic acid. Then add 2.5 g of potassium carbonate, stirred at room temperature to obtain crystals, which are drained, washed with 3 times 20 cm3water, then 3 times 20 cm3ether, then dried product under reduced pressure at 50oC. Gain of 11.75 g of target compound in the form of the base.

So pl. 133oC.

The spectrum of IR (Nujol). Adsorption of OH/NH

Absorption

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Absorption 1603 cm-1(F, complex)

Aromatic compounds

b) Obtaining hydrochloride

1,756 g obtained above base is dissolved in hot 10 cm3ethanol 95, filtered light insoluble fraction, rinsed 3 times with 1 cm3boiling ethanol 95 and add 1 cm35,75 N hydrochloric ethanol. Cooled to 20oC and stirred for 1 h wring out, washed with 2 times 1 cm3ethanol 95, 2 times 1 cm3ethanol 100 and 3 times 5 cm3the ether. After drying under reduced pressure at 70oC get 1,484 g of target compound. So pl. > 260oC.

Analysis of C21H26CL2H2O2HCl

Calculated C 56,58; H 6,10; N6,28; Cl 23,28

Found, C 56,5; H is

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1.2 to 2.2 Other protons

Example 3. TRANS. ()-3-(3,4-dichlorophenyl)-5,6-dihydro-1-[2-(1-pyrrolidinyl)cyclohexyl]-2(1H)-pyridinone and its fumarate.

Stage A: TRANS()-2-[3-(3,4-dichlorophenyl)-2-oxo-1-[2-(2-pyrrolidinyl)cyclohexyl] -1,2,5,6-tetrahydro-4-pyridyl] -hydrazide of 4-methylbenzenesulfonic acid.

A mixture of 5 g of the base obtained in example 2, 2,95 g paratoluenesulfonyl and 25 cm3acetic acid is stirred for 4 h at room temperature. Then add in the reaction medium 150 cm3water saturated with sodium chloride, then 50 cm3sulfuric ether, stirred for 2 h at room temperature. Drained, washed with 20 cm3a saturated solution of sodium chloride and 5 cm3sulfuric ether, then with 15% potassium carbonate solution, water and ether. Dried under reduced pressure at 20oC and obtain 6.25 g of the desired product. So pl. 200oC, which in this form is used at a later stage.

The spectrum of IR (CHCl3)

-SO21336 1165 cm-1< / BR>
/C = O 1627 cm-1< / BR>
Region C C 1601, 1545, 1490, 1474 cm-1< / BR>
C N C-NH 3360 cm-1complex

Stage B: (TRANS. ()-3-(3,4 - dichlorophenyl)-5,6-dihydro-1-[2-(1-pyrrol 28 cm3ethanol 100 for 30 min at 20 - 35oC, then heated to 60oC and add 5,64 g of the product obtained at stage A, and 22 cm3of ethylene glycol. Distil ethanol at normal pressure, then heated for 30 min to 160oC in the reaction medium to full gas emissions. Cooled at 20oC and extracted with methylene chloride, dried, filtered and concentrated to dryness under reduced pressure, collecting of 3.78 g of the product as the base. Chromatographic on silica get 1,319 g base (eluent: ethyl acetate/0.5% triethylamine)

b) Receiving fumarata

0,63 g of the product obtained after chromatography, dissolved in 5 cm3ethanol, added 248 mg of fumarovoi acid and heated under reflux. Press at 20oC, washed 3 times with 0.5 cm3ethanol, then 3 times with ether, 5 cm3. After drying receive 0,681 g of the desired product. So pl. 202o.

Analysis of C21H26Cl2N2O, (C4H4O4)

Calculated C 57,14; H of 5.68; N 4,94; Cl 12,49

Found, C 57,1; H 5,9; N 4,9; 12,5 Cl

NMR CDCl3(250 MHz)

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2.25 kg 2,80 7H, CH2in alpha N pyrrolidine

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0.8 to 1.9 Other protons

Example 4. TRANS. ()-3-)-3-(3,4- dichlorophenyl)-1-[2-(1-pyrrolidinyl)cyclohexyl]-2-piperidine (isomer A) and its fumarate

To a solution of 5,61 g of compound obtained in stage In example 3, 112 cm3ethanol 100 and 11.2 cm237% hydrochloric acid is added 0.56 g 80-tion of platinum oxide is added and stirred in a hydrogen atmosphere (at a pressure in 1835 mbar) for 4 h 30 min (just absorb 4173 cm3hydrogen). Filter the catalyst and the filtrate is evaporated to dryness under reduced pressure. The remainder absorb 10 cm3water and 50 cm3ethyl acetate, alkalinized with excess sodium carbonate and decanted, the aqueous phase is re-extracted with 30 cm3ethyl acetate, the organic extracts are washed with salt water, dried, filtered and dried to dryness under reduced pressure. The residue (05,45 g) chromatographic on silica (eluent: ethyl acetate with 0.5 triethylamine (highlighting isomer A), then the ethyl acetate with 1 then 2 of triethylamine for isomer B). So, get isomer And 2,452, So pl. 109oC isomer In 2,359.

The product of example 4: hydrochloride isomer Century

2,359 g obtained above isomer B was dissolved in 2 cm3ethanol, add 4 cm3hydrochloric ethanol 1,68 N (pH 1). Drained, washed first with Ethan at +5/+10oC, then sulfuric ether. After drying poluchaetsya, collect 1,498 g of the desired product So pl. >260oC.

Analysis of C21H28Cl2N2O, HCl

Calculated C for 58.4; H 6,77; N 6,48; Cl 24,63

Found, C, A 58.6; H, 6.7; In N Of 6.6; Cl 24,5.

NMR CDCl3(250 MHz)

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< / BR>
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of 1.0 to 2.2 other protons.

The product of example 5: (isomer A). fumarate of isomer A.

2,452 g of the isomer And dissolved in hot 10 cm3ethanol, add 865 mg of fumarovoi acid. Heated to reflux, then cooled to 20oC, wring out, washed with ethanol, then ether. Get 2,638 g of the desired product. So pl. 153oC.

Analysis of C21H28Cl2N2O, H4C4O4< / BR>
Calculated C 58,71; H of 6.31; N 5,48; Cl 13,86

Found, C, a 58.6; H 6,4; N 5,6; 14,0 Cl

NMR CDCl3MHz)

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< / BR>
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1,07 to 2.2 Other protons

Example 6. TRANS.()-3-{[[3,4 - acid)acetyl]-[2-(1-pyrrolidinyl)cyclohexyl]amino}propanoate ethyl.

The operation is done as at stage B of example 1 from 16,67 g of compound obtained in stage a of example 1 with the use of 14.12 g of 3,4-dimethoxyphenylacetic acid and 11,67 g carbonyldiimidazole. After chromatography receive (eluent: ethyl acetate with 1% triethylamine) 23,69 g and ether 1724 cm-1< / BR>
C O amide 1625 cm-1< / BR>
Aromatic compounds 1592 cm-1type 1514 cm-1< / BR>
Example 7. TRANS. (+->)-3-(3,4-acid)-1- [2-(1-pyrrolidinyl)cyclohexyl]-2,4-piperidinedione. The operation is carried out in the same manner as in example 2, but as the initial substance use and 5.2 g of the product obtained in example 6. After evaporation under reduced pressure to obtain dry extract, which is extracted with a saturated solution of sodium chloride, squeezed, washed in hexane and dried under reduced pressure.

Get 3,638 g of the desired product. So pl. 260oC.

The product is condensed with tetrahydrofuran, then it is dissolved in a mixture of methylenechloride (7 -3), filtered on clasele and evaporated under reduced pressure.

Get 2,935 g of the desired product. So pl. 260oC.

The spectrum of IR (Nujol)

Region absorption OH/NH

1640 cm-1Weak absorption

1583 cm-1< / BR>
1534 cm-1(EP) Area of aromatic compounds

1516 cm-1(max)

The product in this form is used for the subsequent stage.

Example 8. [TRANS.()]-5,6-dihydro-3-(3,4-acid)-1- [2-(1-pyrrolidinyl)cyclohexyl]2,(1H)-pyridinone.

Stage A: [Terpyridine.

The operation is carried out as in stage A of example 3, but as the source of the substance take to 11.61 g of the product obtained as in example 7, and using 7.2 g of paratoluenesulfonyl and get 16,27 g of the desired product (So pl. 95 200oC), which is used in this form at a later stage.

After recrystallization 205 mg of the crude product from ethanol, to obtain 92 mg of the product so pl. 238 240oC.

The spectrum of IR (CHCl3)

C-NH - 3340 cm-1(complex)

1628 cm-1< / BR>
Region conjugated systems 1601 cm-1< / BR>
+ The type of the aromatic compounds 1516 cm-11495 cm-1< / BR>
-SO2< / BR>
Stage B: (TRANS.()]-5,6-dihydro-3-(3,4-acid)-1- [2-(1-pyrrolidinyl)cyclohexyl]2(1H)-pyridinone

The operation is carried out as in stage B of example 3, but as the initial substance use 16,42 g of the product obtained above in stage A, as well as use of 1.99 g of sodium and 60 cm3of ethylene glycol. Get 12,83 g of the desired product used in this form for the following example.

Example 9. [(1 alpha, 2 beta)()]-3-(3,4-acid)-1- [2-(1-pyrrolidinyl)cyclohexyl]-2-piperidine (isomer A and isomer B) and oxalate isomer B.

The operation was performed as in example 4, but in the NT: the first methylenchloride (95 5), then (90 10)), to 7.84 g of isomer A and 2.8 g of isomer B, 2.8 g of isomer B is thickened in 8 cm3sulfuric ether. Get 0,538 g of the product. So pl. 188 191oC. the Filtrate is again chromatographic and obtain 1.85 g of residue which combines with the above 0,538 g for cooking fumarata in ethanol, then it is crystallized in isopropanol. On the basis of 1,419 g fumarata, obtained above, in the reaction with sodium bicarbonate and sodium carbonate receive the base. Dry extract of 1.050 g dissolved in tetrahydrofuran at 50oC where add 423 mg of anhydrous oxalic acid, is heated with reflux. Press at 20oC, washed in tetrahydrofuran, and then in ethanol. Receive 987 mg of product, which is recrystallized in tetrahydrofuran with 5% water, after azeotropic removal of water, wring out and get 964 mg of the desired product. So pl. 192 196oC.

Analysis of C23H34N2O3C2H2O

Calculated C 63,01; H to 7.61; N 5,88

Found, C 62,7; H 7,7; N 5,8.

Example 10. ((1 alpha, 2 beta)()-3-(3,4-acid)-1- [2-(1-pyrrolidinyl)cyclohexyl]-2-piperidine (isomer A) and its hydrochloride.

3,566 g of isomer A obtained in example 9, thicken in 10 cm3sulfuric ether with refl is. 1.6 g product obtained above is dissolved in 4 cm4ethanol 100, add 0.4 cm36,6 n hydrochloric solution of ethanol. Drained, washed with ethanol and ether, get 1,326 g of the desired product. So pl. 193oC.

Analysis of C23H34N2O3HCl

Calculated C 65,31; H a 8.34; N 6,62; Cl scored 8.38

Found, C 65,3; H 8,4; N Is 6.4; Cl 8,5.

Example 11. (S)-3[[(3,4-dichlorophenyl)acetyl] [1-phenyl-2-(1-pyrrolidinyl) ethyl amino ethylpropane.

Stage A. (S)-3-[[(1-phenyl-2-(1-pyrrolidinyl)ethyl]amino] ethylpropane and his dichlorhydrate.

The operation is carried out as in stage A of example 1, but as educt take 16,19 g (S)-alpha-phenyl-1-pyrrolidineethanol and 11 cm3ethyl acrylate. Stirred for 40 h at 20/22oC. Evaporated to dryness and receive 22,08 g crude product as a base.

Obtaining hydrochloride: 22,08 g crude product is dissolved in 200 cm3ethanol 100 and add, at 20oC, 25 cm36,6 n hydrochloric solution of ethanol. Drained, washed with ethanol, then with ether, and after drying at 60oC under reduced pressure, get 22,22 g of the desired product. So pl. 245 250oC.

alphaD19o51 (c 1% H2O).

Stack in stage B of example 1, but the original substance is 22,22 g of the hydrochloride obtained above on A stage with 16.3 g (3,4-dichloride-acetic acid and 12,89 g carbonyldiimidazole. Get 30,48 g of the desired product, which is used in this form at a later stage.

Example 12. (1S)-3-(3,4-dichlorophenyl)-1-[1-phenyl-2-(1-pyrrolidinyl)ethyl] -2,4-piperidinedione.

The operation was performed as in example 2, but the original product is 28.6 g of the product obtained in example 11, using 3,3 g of sodium hydride. Get 24,74 g of the desired product, which is used in this form for the next example. So pl. 110 115oC crystallized diethyl ether.

Example 13. (S)-3-(3,4-dichlorophenyl)-5,6-dihydro-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-2(1H)-pyridinone and its fumarate. Stage A. (S)-2-[3-(3,4-dichlorophenyl)-2-oxo-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl] -1,2,5,6-tetrahydro-4-pyridyl]-hydrazine 4-methylbenzenesulfonic acid

The operation is carried out as in stage A of example 3, but the original substance is 30 g of the product obtained in example 12 and 14 g of steam-toluensulfonate. Stirred for 5 h and evaporated acetic acid under reduced pressure. Alkalinized to pH 9 in the presence of 12.5 g of sodium carbonate. Extracted with methylene chloride, dried, Phil stage.

(alpha)D(purified product) + 64,5 1,5oC (c 1% in methanol).

Stage B: (S)-3-(3,4-dichlorophenyl)-5,6-dihydro- [1-phenyl-2-(1-pyrrolidinyl)ethyl]-2(1H)-pyridinone and its fumarate

The operation is done as at stage B of example 3, but the original substance is 39 g of the product obtained above in stage A, using 6,05 g of sodium and 250 cm3of ethylene glycol. Get 22,33 g of the desired product as the base.

Getting fumarata. 22,17 g of product obtained above are dissolved in 65 cm3hot ethanol 100 and added 6.4 g of fumaric acid. Heated at 60oC to dissolve, then cooled and press at 20oC, washed with ice cold ethanol, then ether. Get 15,64 g of the desired product, So pl. 162o164oC.

Obtaining reasons: 6,9 g of the product obtained above are dissolved in 100 cm3ethyl acetate and 40 cm3aqueous 10% sodium carbonate solution. Decanted and again extracted with ethyl acetate, dried, filtered and distil to dryness under reduced pressure, gain of 5.4 g of the product as the base, which is used in this form for the next example, the analytical sample fumarata was prepared by recrystallization 500 g fumarata VoC + 2 (c 1% in methanol).

Analysis of C23H34ON2Cl2C4H4O4< / BR>
Calculated C 61,02; H 5,31; N 5,27; Cl 13,34

Found, C 61,0; H 5,1; N 5,2; 13,5 Cl.

Example 14, (1S)-3-(3,4-dichlorophenyl)-1-[1-phenyl-2-(1-pyrrolidinyl)ethyl] -2-piperidine (isomer A and isomer B) and maleate isomer A.

1-St way the Operation was performed as in example 4, but the original product are of 5.4 g of the compound obtained in example 13, using 0.6 g of 80% platinum oxide, and hydronaut under a pressure of 1500 mbar, absorbing 400 cm3hydrogen, and get 5,81 N. of the desired product, which chromatographic on silica (eluent: ethyl acetate with 2% triethylamine). Get 0,975 g of the desired product isomer A and of 1.80 g of isomer B.

Getting maleate, 901 g crude product (isomer A) was dissolved in 6 cm3ethyl acetate, add 251 mg of maleic acid and heated to 60oC. is Cooled to 20oC for 1 h, drained, washed with ethyl acetate and ether. Gain of 1.02 g of the desired product. So pl. 140o- 141oC.

(alpha)D+ 118oC + 2o(c 1% in methanol).

Analysis of C23H24Cl2H2O, C4H4O4< / BR>
Calculated C 60,79; H 5,67; N 5,25; Cl to 13.29

Found, C 61,1; H 5,6; N5 to 7.40 (m) 7H

H-aromatic compound

1.62 to 3,37 16 other protons.

the 2nd way. a 3.01 g of the product obtained in example 13, was dissolved in 30 cm3ethanol, add 0.6 g of sodium borohydride and stirred for 6 hours Add 2 cm3water, maintaining a temperature of 20 25oC add 1 cm3acetic acid ( pH 6), remove the solvents under reduced pressure, remove the remainder of the 20 th aqueous solution of sodium carbonate, then extracted in the presence of ethyl acetate. Dried and concentrated to dryness under reduced pressure. Obtain 3.1 g of the desired product, which is used in this form.

Chromatography on silica 615 mg of the product allows to obtain 380 mg of isomer A and 229 mg of isomer B.

Example 15. Fumarate (1S)-3-(3,4-dichlorophenyl)-1- [1-Phenyl-2-(1-pyrrolidinyl)ethyl]-2-piperazinone (isomer B).

Dissolve to 1.75 g of the product obtained in example 14 (isomer B), 8 cm3isopropanol and add 400 mg of fumaric acid, heated to dissolve, cooled to 20oC, wring out, washed first with isopropanol and 5oC, then ether. Get of 1.594 g of product, which kristallisera 6 cm3ethanol 100.

Get 1.197 g of the desired product. So pl. d) 7,27 (d) Aromatic compounds

3,74 m

6,11 (dd, j 10 and 6)/CH-C6H5< / BR>
of 7.25 to 7.45 (m) 6H aromatic compounds

1,79 up to 3.33 16 other protons

Example 16. (S)-3-[[(4-triptoreline)acetyl] -[1-phenyl-2- (1-pyrrolidinyl)ethyl]-ethylpropane

The operation is carried out in the same way as in stage B of example 1, using 5.31g 4-triftormetilfullerenov acid, 4,22 g carbonyldiimidazole and 7,27 g dichlorhydrate (S)-3-[[(1-phenyl)-2- (1-pyrrolidinyl)ethyl]amino]ethylpropane, which is obtained by the same method as in stage A of example 11, maintaining the reaction medium stirring for 20 h at room temperature.

After chromatography on silica (eluent: ethyl acetate), gain of 9.8 g of the desired product

(alpha)D+ 89,5oC2o(c 1, methanol).

Example 17. (1S)-3-(4-trichoroethylene)-1-[1-phenyl-2-(1-pyrrolidinyl)ethyl] -2,4-piperidinedione. The operation is performed in the same manner as in example 2, but the original product is 9,42 g of the product obtained in example 16, using of 1.15 g of sodium hydride. Get a 9.35 g of the desired product, which in this form is used in the following example.

Example 18. (S)-3-(4-triptoreline)-5,6-dihydro-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-2]-1,2,5,6-tetrahydro-4-pyridyl]-hydrazide of 4 - methylbenzenesulfonic acid

The operation is performed in the same way as in stage A of example 13, but the starting material is a 9.35 g of the product obtained in example 17 and a 4.86 g of para-toluensulfonate get 15,16 g of the desired product, which is used in this form in the next stage.

Stage b (S)-3-(4-triptoreline)-5,6-digiteo-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-2(1H)-pyridinone and its fumarate

The operation is performed in the same way as in stage B of example 3, but the original substance is 15,16 g of the product obtained at stage A, using 2.1 g of sodium and 85 cm3of ethylene glycol. After chromatography on silica (eluent: ethyl acetate) get to 4.17 g of the desired product as the base.

The operation is performed in the same manner as in example 13, but the source product is 201 mg of the obtained base and 60 mg of fumaric acid, obtain 116 mg of the desired fumarata. So pl. 198o200oC.

(alpha)D+ 93,5oC3o(c 0.5% dimethylformamide).

Analysis of C24H25F3N2O, C4H4O4< / BR>
Calculated C 63,39; H 5,51; N 5,28; F 10,08. Found, C 63,1; H 5,4; 5,4 N; F 10,7.

Example 19. (S)-1-[1-phenyl-2-(1-pyrrolidinyl)ethyl]-3- [(4-triptoreline)phenyl]-2-piperidine (isomer A and room temperature at 40 cm3ethanol in the presence of 0.79 g of sodium borohydride.

Add 8 cm3a mixture of acetic acid and water (1 1) has a neutral effect. The solvent is removed under reduced pressure, extract the residue with 50 cm3ethyl acetate, 30 cm320 aqueous sodium carbonate and 20 cm3water.

The reaction mixture is stirred, decanted, extracted with ethyl acetate, dried, remove the solvents under reduced pressure and obtain 4.15 g of crude product, which chromatographic on silica (eluent: ethyl acetate with 2 of triethylamine). Get 2,07 g of isomer A. T. pl. 126 128oC and 1.2 g of isomer B.

Getting fumarata isomer A. 1,59 g of the isomer And dissolved in 5 cm3ethanol, add 443 mg fumaric acid, filter the solution and concentrate to dryness under reduced pressure. Carry out crystallization, diluted with 10 cm31,2-dimethoxyethane, squeezed and rinsed with ether. Dried under reduced pressure at 80oC and collect 998 mg of crude product.

After recrystallization 953 mg of the product in ethyl acetate, receive 528 mg of the desired product. So pl. 176 178oC.

(alpha)D+ 73oC 2,5o(c 0.5 N2O).

< / BR> Found, C Of 60.8; H 5,6; N 4,7; F 9,9.

Example 20. Fumarate (S)-1-[1-phenyl-2-(1-pyrrolidinyl) ethyl]-3[(4-triptoreline)phenyl]-2-piperazinone (isomer a and isomer B) and the fumarate of isomer B.

of 1.16 g of isomer B in the form of the base obtained in example 19 was dissolved in 2 cm3ethanol, add 333 mg of fumaric acid and heated with relief until dissolved. Cooled to room temperature, press the formed crystals, wash them first in a mixture of ethanol-ether, then ether. Dried at 80oC under reduced pressure and receive 989 mg of the desired product. So pl. 168 170oC.

(alpha)D+ 150oC 3.5o(c 0,5% H2O)

Analysis of C24H27F3N2O, C4H4O4< / BR>
Calculated C 63,15; H by 5.87; N 5,26; F 10,70

Found, C a 62.9; H 5,8; N 5.3; F 10,6

Example 21. (S)-3-{[(3,4-dichlorophenyl)acetyl]-1-[2-methyl-1- [(1-pyrrolidinyl)methyl] propyl]-amino}ethylpropane.

Stage A. (S)-3-[[2-methyl-1-[(1-pyrrolidinyl)methyl] propyl] -amino] ethylpropane.

The operation is performed in the same way as on the stage As in example 1, using 18,24 g 2-methyl-1-[(1-pyrrolidinyl)methyl]-Propylamine and 15.1 cm3ethyl acrylate. Obtain 29 g of the desired product.

(alpha)D+ 43,5ropyl]amino}ethylpropane

The operation is performed in the same way as in stage B of example 1, but the starting material is of 28.7 g of 3,4-dichlorophenylamino acid, 27,52 g of the product obtained at stage a and 22,7 g carbonyldiimidazole. Get to 57.2 g of crude product which is purified by chromatography on silica (item: ethyl acetate methanol (95 5)) and get of 39.2 g of the desired product.

(alpha)D+ 26,5o1.5o(c 0.8, methanol).

Obtaining 2-methyl-1-((1-pyrrolidinyl)methyl)Propylamine used as the starting material in example 21.

Stage A: 1-[methyl 3-(S)-2-[[(phenylmethoxy)carbonyl] -amino]butanoyl]pyrrolidin

At room temperature mix of 32.6 g of 3-methyl (S)-2- [[(phenylmethoxy)carbonyl] amino]butanoyl, 20 g of hydrated hydroxybenzotriazole in 326 cm3of methylene chloride, cooled to 0oC and added dropwise within 20 min of ice-cold solution containing 30 g dicyclohexylcarbodiimide 128 cm3of methyl chloride. Stirred for 1 h at 0/+5oC added dropwise within 10 min 15 cm3pyrrolidine and stirred for 20 hours allowing you to restore to room temperature. Filtered, rinsed in methylene chloride, then with ether and concentrated to dryness under reduced Yes the,88 g of the desired product, which in this form is used in the next stage.

(alpha)D-6o1o(c 1% in methanol).

Stage b 1-((S)-2-amino-3-methylbutanoyl)pyrrolidin

A mixture containing 42,88 g of the product obtained at stage a, gidrogenit in 1880 mbar for 3 hours at 429 cm3hydrochloric acid in the presence 4,22 g of the active angle from 10 palladium. Filtered, the filtrate is concentrated under reduced pressure. Carry out crystallization, removing the remainder of the 50 cm3ethyl acetate, press the crystals of the desired product in the form of hydrochloride, is dissolved in 15 cm3water and add 25 cm3sodium lye. Get 19,79 g of the desired product, which is used in this form in the next stage.

(alpha)D+35,5o2,5o(c 0.3, methanol)

Stage C. 2-methyl-1-((1-pyrrolidinyl)methyl)Propylamine B 400 cm3of tetrahydrofuran, cooled to -10oC enter of 8.2 g of hydride lithium aluminium, is then added dropwise within 20 minutes, the solution containing 19,79 g of the product obtained at stage B 100 cm3of tetrahydrofuran, cooled to -5/-8oC. Stirred for 2 h 30 min, maintaining the temperature 0/+5oC add 30 cm320% aqueous solution of sodium carbonate, then gennym pressure and get 17,37 g of the desired product, which in this form is used for the subsequent synthesis step.

(alpha)D+45,5o1,5o(c 1% in methanol)

Example 22. (S)-3-(3,4-dichlorophenyl)-1-[2-methyl-1- [(1-pyrrolidinyl)methyl] propyl]2,4-piperidinedione

The operation is performed in the same manner as in example 2, but the original product is 16,71 g of the product obtained in example 21 using 2.76 g of sodium hydride. Get 13,37 g of the desired product, which is used in this form for the following example.

(alpha)D+23o1,5o(c 1% in methanol)

Example 23. (S)-3-(3,4-dichlorophenyl)-5,6-dihydro-1- [2-methyl-1-[(1-pyrrolidinyl) methyl] propyl]-2(1H)-piperidine.

Stage A, (S)-2-3-(3,4-dichlorophenyl)-2-oxo-1-[2-methyl-1- [(1-pyrrolidinyl) methyl] propyl]-1,2,5,6-tetrahydro-4-pyridyl]hydrazide 4-methylbenzenesulfonic acid

The operation is performed in the same way as on stage And in example 13, but the original substance is 11,85 g of the product obtained in example 22, and of 7.70 g of p-toluensulfonate and get 18,09 g of the desired product, which in this form is used for the next stage.

Stage b (S)-3-(3,4-dichlorophenyl)-5,6-dihydro-1-[2-metal-1- [(1-pyrrolidinyl)methyl] propyl] -2 (1H)-piperidine Operation is performed in the same way, h is s and 130 cm3of ethylene glycol. After chromatography on silica (item: ethyl acetate with 2% triethylamine) get 11,24 g of the desired product in the form of base

The operation is carried out in the same manner as in example 13, the original substance is 11,24 g the base and 3.57 g of fumaric acid, receive 17 g fumarata. So pl. 166 168oC.

Getting established: 17 g of the product obtained above, absorb 100 cm3ethyl acetate and 20 cm3water and slowly add 2.5 g of sodium carbonate. Mix, decanted, Astrovirus with ethyl acetate, washed with salt water, dried and remove the solvents under reduced pressure. Get 5,54 g of the desired product as the base.

(alpha)D+7,5o1o(c 1% methanol)

Example 24. (S)-3-(3,4-dichlorophenyl)-1-[2-methyl-1-[(1-pyrrolidinyl) methyl] propyl]-2-piperidine isomer a And isomer B and maleate isomer A.

The operation is performed in the same manner as in example 19, the original substance is 3.25 g of the base obtained in example 23 and 0.77 g of sodium borohydride and get 3,17 g crude product. After chromatography obtain 1.44 g of isomer a and of 1.37 g of isomer B.

Getting maleate isomer A: 1.55 g of isomer a, obtained as described the effect the crystallization, drained, rinsed in ethanol, then ether and obtain 1.85 g of the desired product.

(alpha)D+ 81o2o(c 0.5 dimethylformamide).

Analysis

Calculated C 57,72 H 6,46 N 5,61 Cl 14,20

Found, C 58,0, H 6,5; 5,6; Cl14,1

Example 25. Maleate (S)-3-(3,4-dichlorophenyl)-1-[2-methyl-1- [(1-pyrrolidinyl)methyl]propyl]-2-piperazinone, isomer B.

Dissolve by heating of 1.46 g of isomer B, obtained in example 24, in the solution containing 486 mg of Melitopol acid in 5 cm3ethyl acetate.

Carry out crystallization, press the formed crystals, rinsed in ethyl acetate, then ether and dried under reduced pressure at 80oC. Obtain 1.77 g of the desired maleate.

(alpha)D-60,5o2,5o(0.5 dimethylformamide)

Analysis

Calculated C 51,72 H 6,46 N 5,61 Cl 14,20

Found, C 57,7; H 6,4; N 5,4; Cl 13,8

Example 26. (S)-3-phenylacetyl-[1-phenyl-2-(1-pyrrolidinyl)ethylamino] -ethylpropane.

The operation is performed in the same way as in stage B of example 11, but using of 3.54 g of phenylacetic acid, 4,22 g carbonyldiimidazole and 7,27 g dichlorhydrate (S)-3- [phenyl-acetyl[1-phenyl-2-(1-pyrrolidinyl) ethyl]amino]ethylpropane obtained in the same way that Nele chromatography on silica (eluent: ethyl acetate) get 8,15 g of the desired product.

(alpha)D+ 96,52o(c 1% in methanol).

Example 27. (S)-3-phenyl-1-[1-phenyl-2-(1-pyrrolidinyl) ethyl]-2,4-piperidinedione.

The operation is performed in the same manner as in example 2, but the original substance is 7,955 g of the product obtained in example 26 and 1.12 g of sodium hydride.

Get 6,70 g of the desired product which is used in this form in the following example.

Example 28. (S)-3-phenyl-5,6-dihydro-1-[1-phenyl-2-(1-pyrrolidinyl) ethyl] -2(1H)-pyridinone.

Stage A. (S)-3-phenyl-2-oxo-1-[[1-phenyl-2-(1-pyrrolidinyl) ethyl] -1,2,5,6-tetrahydro-4-pyridyl]-hydrazide 4-methylbenzenesulfonic acid

The operation is performed in the same way as on stage And in example 13, but the original substance is 6,70 g of the product obtained in example 27 and 4.50 g of n-polyacrilonitrile and get the 10.40 g of the desired product, which is used in this form for the next stage.

Stage b (S)-3-phenyl-5,6-dihydro-1-[1-phenyl-2-(1-pyrrolidinyl) ethyl] 2(1H)-pyridinone

The operation is performed in the same way as in stage B of example 3, but the original substance is the 10.40 g of the product obtained above in stage A, 2.0 g of sodium and 80 cm3of ethylene glycol. After crystallization in isopropyl ether get 2,75 g ishmail-1-[1-phenyl-2-(1-pyrrolidinyl) ethyl] -2-piperidine (isomer A, the isomer In and fumarate of isomer A).

The operation is performed in the same manner as in example 19, but the original substance is 2.66 g of the product obtained in example 28 and 0.62 g of sodium borohydride. Obtain 2.7 g of crude product. After chromatography Recuperat of 1.59 g of isomer Century

Getting fumarata isomer A.

The operation is performed in the same manner as in example 19, the original substance is 1.55 g of isomer As prepared above and 568 mg of fumaric acid. Obtain 1.92 g of the desired fumarata. So pl. 191 193oC.

(alpha)D+ 94,52o(c 1 dimethylformamide).

Analysis

Designed, 69,81; H 6,94; N 6,03

Found, C is 69.7; H 7,0; N 6,0

Example 30. Fumarate (S)-3-phenyl-1-[1-phenyl-2-(1-pyrrolidinyl) ethyl] -2-piperazinone, isomer Century

The operation is performed in the same manner as in example 20, the original substance is 9,81 mg of isomer B obtained in example 29 and 325 mg of fumaric acid. Obtain 1.07 g of the desired fumarata. So pl. 200o- 202oC.

(alpha)D+ 116o2o(c 1 dimethylformaldehyde).

Analysis

Calculated C 69,81; H 6,94; N 6,03

Found, c 69,5; H 7,0; N 6,0

Example 31. (S)-3-[(benzo(C)Tien-4-yl)acetyl]-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl-amino]ethylpropyl ssnoi acid, 4,22 g carbonyldiimidazole and 7,27 g dichlorhydrate (S)-3-[-1-phenyl-2-(1-pyrrolidinyl)ethyl amino]ethylpropane obtained both on stage And in example 11, the reaction medium is then stirred for 20 h at room temperature.

After chromatography on silica (eluent: ethyl acetate) get to 9.66 g of the desired product.

(alpha)D79o2o(1 methanol).

Example 32. (S)-3-[benzo(b)Tien-4-yl]-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl] -2,4-piperidinedione.

The operation is performed in the same manner as in example 2, but the original substance is used for 9.47 g of the product obtained in example 31, with the use of 1.15 g of sodium hydride. Get 10,45 g of the desired product, which in this form is used in the following example.

Example 33. (S)-3-(benzo(b)Tien-4-yl)5,6-dihydro-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-2(1H)-pyridinone and its fumarate.

Stage A. (S)-2-[3-(benzo(b)Tien-4-yl)-2-oxo-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl] -1,2,5,6-tetrahydro-4-pyridyl] -hydrazyl 4-methyl-benzosulfimide acid

The operation is carried out in the same way as on stage And in example 13, the original substance is 10,45 g of the product obtained in example 32 and a 4.86 g of p. toluensulfonate get 15,03 g of the desired product, Conil-2-(1-pyrrolidinyl)ethyl]-2 (1H)-pyridinone and its fumarate.

The operation is performed in the same way as in stage B of example 3, but the original substance is 15,03 g of the product obtained above in stage A, 2.16 g of sodium and 85 cm3of ethylene glycol. After chromatography on silica (eluent: ethyl acetate) get 8,29 g of the desired product in the form of a Foundation. Following the method used in example 13 to obtain fumarata, but on the basis of compared to 8.26 g of the obtained base and 2.5 g of fumaric acid, receive 6,82 g of the desired fumarata. So pl. 194 195oC.

The receiving base. to 5.66 g fumarata, obtained above, is placed in a 20 cm3water and add 30 cm3aqueous solution with 20 sodium carbonate and 100 cm3ethyl acetate. Mix, decanted, extracted with ethyl acetate, dried and concentrated to dryness under reduced pressure 4.94 g of the desired product Recuperat a base, and in this form used for the following example.

Example 34. (S)-3-(benzo(b)Tien-4-yl)-1- [1-phenyl-2-(1-pyrrolidinyl)ethyl] -2-piperidine (isomer a And isomer b and the fumarate of isomer A).

The operation is performed in the same manner as in example 19, but it is 4.93 g of the product obtained in example 33 and 3 times in 1 g of sodium borohydride. Get 5,23 g crude product. After chromatography them the same way as in example 19, but according to 2.55 g of isomer As obtained above and 823 mg of fumaric acid. Receive and 2.79 g of the desired fumarata. So pl. 234 - 238oC.

(alpha)D+1102o(c 1 dimethylformamide).

Analysis

Calculated C 66,90; H is 6.19; N 5,38; C 6,16

Found, C 67,0; H 6,2; N 5.3; S 6,2

Example 35. Fumarate (S)-3-(benzo(b)Tien-4-yl)-1-[-phenyl-2- (1-pyrrolidinyl)ethyl]-2-piperidine (isomer B).

The operation is performed in the same manner as in example 20, but the original substance is 1.98 g of isomer B prepared in example 34 and 628 mg of fumaric acid. Get to 1.38 g of the desired fumarata. So pl. 195 - 197oC.

(alpha)D+1102o(c 1 dimethylformamide).

Analysis

Calculated C 66,90; H is 6.19; N 5,38; S 6,16

Found, C 67,0; H 6,2; N 5.3; S 6,2

Example 36. (S)-3-(3,4-dichlobenil)-3-methyl-1-[1-phenyl-2- (1-pyrrolidinyl) ethyl]-2-piperidine (isomer A isomer B and maleate isomer A).

2.67 g of crude (S)-3-(3,4-dichlorophenyl)-1-[-phenyl-2-(1-pyrrolidinyl) ethyl] -2-piperidine obtained in example 14, is cooled to -20oC 40 cm3Of tetrahydrofuran and added to 1.16 g of tert butyl potassium, then the solution pereshivayut for 1 h at -8 2oC. is Cooled to -15oC add 0.6 cm3under the conditions, then peremeshivaya, extracted with ethyl acetate, dried and concentrated to dryness under reduced pressure. To give 2.83 g of the crude product in the form of a Foundation that chromatographic on silica (eluent: ethyl acetate/n-hexane (9-1), then the ethyl acetate with 1% triethylamine). Get 0,996 g of isomer A and 1,307 g of isomer B.

Maleate isomer A. 947 g of isomer A and 304 mg of maleic acid are dissolved, gently stirring, 4 cm3ethyl acetate. Filter, add to the filtrate 3 cm3ethanol, crystallized, wring out the crystals, rinsed in ethyl acetate and ether, dried at 70oC under reduced pressure and receive 823 g of the desired maleate. So pl. 136 138oC.

(alpha)D+60,5 1,5o(c 1, methanol).

Analysis

Calculated C 61,43; H of 5.89; N 5,12; Cl to 12.95

Found, C 61,6;H 6,0; N 5,1; Cl 12,8.

Example 37. Fumarate (S)-3-(3,4-dichlorophenyl)-3-methyl-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-2-piperazinone (isomer B).

1.24 g of isomer B obtained in example 36 was dissolved, gently stirring, 5 cm3Ethanol, added 370 mg of fumaric acid and heated under reflex until dissolved. Cooled, crystallized, wring out the crystals, propulsive their first in ethanol, then ether, and dried at 70+ 1252o(c 1, methanol).

Analysis

Calculated C 61,43; H of 5.89; N 5,12; Cl 12,95 Found, C is 61.5; H 5,8; 5,0 N; Cl 12,8

Example 38. (1S)-3-(3,4-dichlorophenyl)-3-ethyl-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-2-piperidine (isomer B isomer A and methanesulfonate isomer B).

The operation is performed in the same manner as in example 36, but the starting material is 2 g of the product obtained in example 14, 0.87 g of trebuchet potassium and 0.6 cm3ethyliodide. Obtain 2.1 g of the crude product in the form of a Foundation that chromatographic on silica (eluent: ethyl acetate/methylene chloride (58-15). Gain of 1.05 g of isomer A and 0.87 g of isomer B.

Thicken 0.87 g of isomer B of 4 cm3a mixture of isopropyl ether/n-hexane (1-), press the crystallized product is dried and receive 0,567 g of the desired product isomer B. T. pl. 113 -114oC.

Getting methansulfonate isomer B. 542 mg of isomer B are dissolved at room temperature in 2 cm3ethanol and 0.7 cm3an ethanol solution methanesulfonic acid (2M), crystallized, diluted 1 cm3ethyl ester, wring out and dry the crystals under reduced pressure at 70oC. Obtain 268 mg of the desired methansulfonate. So pl. 207 209oC.

(alpha)D+ 1072o(c 1, methanol).

1,05 g of isomer A obtained in example 38, thicken 4 cm3isopropyl ether at room temperature, press the crystals rinsed H-hexane, and dried under reduced pressure. Receive 599 g of crystallized product in the form of a Foundation. So pl. 123 124oC. the Operation is performed in the same manner as in example 37, the original substance is 587 mg of the base and 168 mg of fumaric acid. Receive 559 mg of the desired fumarata. So pl. 148 150oC.

(alpha)D+ 46,51,5o(c 1, methanol).

Analysis

Calculated C 62,02; H 6,10; N 4,99; Cl 12,63

Found, C 61,9; H 6,1; N 4,8; Cl 12,9

Example 40. (1S)-3-(3,4-dichlorophenylethyl)-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-2-piperidine (isomer B isomer A and fumarate of isomer B).

The operation is performed in the same manner as in example 36, but the original substance is 2.76 g of the product obtained in example 14, and 0.98 g of tert butyl potassium and 1.2 cm3brombenzene. Get up 3.22 g of the desired product in the form of a Foundation. After chromatography on silica (alue: ethyl acetate-methylene chloride (75 15), receive 668 mg of isomer A and 533 mg of isomer B.

Getting fumarata isomer B. the Operation is performed in the same manner as in example 37, the original substance is 455 mg of isomer B, RAS is>
C.

(alpha)D+ 57,51,5o(c 1 dimethylformamide).

Analysis

Calculated C 65,49; H of 5.82; N 4,99; Cl 11,37

Found, C 65,3; H 5,9; N 4,5; Cl 11,3

Example 41. Hydrochloride (1S)3-3-(3,4-dichlorophenyl)-3-phenylmethyl-1- [1-phenyl-2-(1-pyrrolidinyl)ethyl]-2-piperazinone (isomer A).

462 mg of the isomer A obtained in example 40, dissolved in 4.5 cm3ethanol at room temperature and add 0.5 cm3an ethanol solution chlorotalonil acid 6,6 N. Crystallized, wring out and dry the crystals at 80oC under reduced pressure and obtain 340 mg of the desired hydrochloride. So pl. 206 208oC.

(alpha)D+ 415o(c 1 dimethylformamide).

Analysis

Calculated C 66,24; H 6,11; N 5,11; Cl 19,55

Found, C 66,0; H 6,2; N 5,1; Cl 19,2

Example 42. (1S)-3-(3,4-dichlorophenyl) -1- [1-phenyl-2-(1-pyrrolidinyl)ethyl] -3-(2-propenyl) -2 - piperidine (isomer A isomer B and methanesulfonate isomer A).

The operation is performed in the same manner as in example 36, but the starting material is a 2.01 g of the product obtained in example 14, 0.9 g of tert.the butyl potassium and 0.65 cm3allylbromide. Obtain 2.28 g of crude desired product as a Foundation. After chromatography on silica (eluent: ethyl acetate/Meiling carried out in the same way, as in example 38, but the original substance is 806 mg of isomer A and 1 cm3an ethanol solution methanesulfonic acid (2M) and receive 628 mg of the desired methansulfonate. So pl. 171 172oC.

(alpha)D+ 411,5o(c dimethylformamide).

Analysis

Calculated C 58,58; H Is 6.19; N Is 5.06; S 5,79; Cl 12,81.

Found, C 58,7; H 6,3; N 5,2; S 5,7; Cl 12,8.

Example 43. Methanesulfonate (1S)-3-(3,4-dichlorophenyl)-1-[1-phenyl-2- (1-pyrrolidinyl)ethyl]-3-(2-propenyl)-2-piperazinone (isomer B).

The operation is performed in the same manner as in example 38, but the original substance is 913 mg of isomer B obtained in example 42 and 1.2 cm3an ethanol solution methanesulfonic acid (2M) and get a 780 g of the desired methansulfonate. So pl. 239 241oC.

(alpha)D+ 922o(c 1 dimethylformamide).

Analysis

Calculated C 58,58; H is 6.19; N Is 5.06; S 5,79; Cl 12,81

Found, C of 58.9; H 6,3; N 5,1; S To 5.8; Cl 12,6

Examples of the pharmaceutical composition.

Example 44. Get pills, corresponding to the following formula:

The product from example 5 To 200 mg

Filler Up to 800 mg

(filler elements: lactose, talc, starch, magnesium stearate)

Example 45. Get the solution for intramuscular injection, ACC/BR> Pharmacological research.

1). Binding to opiate receptors in vitro.

Use of membrane residue, conserved at -30oC (approximately 30 days) and obtained from the brain of Wistar rats.

Sediment resuspendable in buffer solution Tris pH 7,72 cm3fraction of the distributor in vitro for hemolysis and added 93H-ethylketocyclazocine 1 nM and analyzed product. Initially, the product was tested at a concentration of 5 10-6M (three times). If the tested product displaces more than 50% of the radioactivity specifically bound to the receptor, it is tested again at 7 different doses to determine the dose that inhibits 50 radioactivity specifically bound to the receptor. Thus determined by the inhibitory concentration 50 Nonspecific binding is determined by adding the product known under the name of U-50488 H (Lahti et al. 1982, Life Sci. 31, 2257) of 10-5M (three times). The product is incubated at 25oC for 40 min, immersed in an ice bath at 0oC (for 5 min), filtered under vacuum, washed with Tris buffer solution pH of 7.7 and count the radioactivity in the presence of scintillating solution Trition. The results expr the military in nM, necessary to offset 50 specific radioactivity associated with the investigated receptor.

Issleduemyi the product of example Cl50in nM

8 9

7 0,2

4 22

2). Antiarrhythmic effect observed in rats.

Male rats weighing 300 to 350 g, shot intraperitoneally the introduction of 1.20 g/kg of urethane, produce a tracheotomy and translate them into artificial respiration (40 50 dowani 3 ml/min).

Needles are inserted subcutaneously thus, to record the electrocardiogram rats signal derivation DII.

The analyzed products are administered intravenously. After 5 min after injection via the jugular vein injected with 10 µg/min aconitine and measure the time of occurrence of cardiac arrhythmias. The results are expressed in percentage increase in time of occurrence of cardiac arrhythmias in comparison to the control animals and taking into account the dose of investigational product.

The results presented in the table show that the products according to the invention have excellent anti-arrhythmic properties.

Pyridone derivatives of the formula

< / BR>
where E is the radical SOOS2H5and G band of CH2-Y, where Y is phenyl, 3,4-dimethoxy, form a group

< / BR>
where R is hydrogen;

Y is phenyl, 4-triftormyetil, 3,4-dimethoxyaniline, 3,4-dichloraniline or benzo(b)Tien-4-ilen radical,

< / BR>
where Y is phenyl, 4-triftormyetil, 3,4-dimethoxyaniline, 3,4-dichloraniline or benzo(b)Tien-4-ilen radical,

< / BR>
where R is hydrogen, benzyl, methyl, ethyl or 2-properly radical;

Y is phenyl, 4-triftormyetil, 3,4-dimethoxyaniline, 3,4-dichloraniline or benzo(b)Tien-4-ilen radical;

And carbocyclic radical or group

< / BR>
where phenyl or isopropyl;

R1and R2form together with the nitrogen atom to which they are attached, pyrrolidinyl.

 

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The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

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The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

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< / BR>
where a group

< / BR>
where m and n are independent of each other represent 1 or 2,

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< / BR>
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R2hydrogen, alkoxy 1 to 4 carbon atoms or alkyl with 1 to 4 carbon atoms,

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