Method for preparing 3,6-diazahomoadamantane

FIELD: organic chemistry, chemical technology, virology.

SUBSTANCE: invention relates to a new method for synthesis of a novel compound - 3,6-diazahomoadamantane of the formula: . Compounds of 3,6-diazahomoadamantane class possess an antiviral effect comparable with antiviral effect of aminoadamantane, elicit strychnine-like activity and show bactericidal, fungicide and algicidal properties and can be used as an antiviral preparation. Method for synthesis of 3,6-diazahomoadamantane involves interaction of 1-phenylthio-3,6-diazahomoadamantane-9-one with 65-66% hydrazine hydrate at boiling to form 1-phenylthio-3,6-diazahomoadamantane-9-one hydrazone that is subjected for reduction in Kizhner-Wolf reaction by alloying with alkali and then 1-phenylthio-3,6-diazahomoadamantane is desulfurized with Raney nickel in isopropyl alcohol at boiling.

EFFECT: improved method of synthesis.

2 cl, 1 ex

 

The invention relates to the field of organic chemistry, and specifically the way to obtain 3,6-deazaguanosine, which has the following structure:

Connection class 3,6-deazaguanosine possess antiviral activity comparable with antiviral action aminoadamantana, show tehnikoy.udobnoe activity, and also have bactericidal, fungicidal and algicidal properties.

A method of obtaining 1-alkyl - and 1-aryl-3,6-deazaguanosine recovery of the corresponding hydrazones at a temperature of 220-240°in the presence of alkali to the reaction of Kirzner-wolf [A.I. Kuznetsov, IGOR Vladimirov, Serov T.M., Moskovkin, AS Heterodonty and their derivatives. 17. Recovery 3,6-diazepamandmyths on Kizaru-wolf. // CHC. - 1992. No. 5 - S-657.]. However, in the conditions of this reaction hydrazone 3,6-deazaguanosine without substituents at the nodal positions becomes asin. The presence of volumetric substituents in the molecule deazaguanosine reduces the biological activity of the substance.

The technical object of the present invention to provide an accessible method for the synthesis of 3,6-deazaguanosine without substituents at the nodal positions.

The technical result of the proposed achievement is that 1 phenylthio-3,6-dosagemedicament the-9-he, which is obtained by the known method [A.I. Kuznetsov, IGOR Vladimirov, Basargin E.B. and other Heteroaromatic and their

R=Me, Et, Pr, Ph

derivatives. II. Synthesis of 3,6-diazepamandmyths-9-it and its derivatives with substituents at the nodal positions. // CHC. - 1990. No. 5. - S.675-680.] when heated phenylthiazole with tetramethylenedisulfotetramine in boiling isopropyl alcohol in the presence of acetic acid as catalyst, in turn hydrazone 1 phenylthio-3,6-diazepamandmyths-9-it is boiling in 65-66%wage hydrazinehydrate, which is then subjected to recovery 1 phenylthio-3,6-diazepamandmyths by the reaction of Kirzner-wolf by fusion with alkali, and the resulting 1-phenylthio-3,6-diazepamandmyths desulfurized Raney Nickel in boiling isopropyl alcohol. Output 3.6-deazaguanosine was 76%. The synthesis is carried out according to the following scheme:

Example 1

1 phenylthio-3,6-diazepamandmyths-9-he

A solution of 3.66 g (21.78 mmol) tetramethylenedisulfotetramine and 3.27 ml (54.45 mmol) of acetic acid in 30 ml of isopropyl alcohol was heated to 60°C. Then was added 3.61 g (21.78 mmol) phenylthiourea and stirred at room temperature for 1 h the Solvent was evaporated in vacuum. The reaction mass was treated with hot heptane (3×100 ml, the extractant was evaporated in vacuum. After recrystallization from heptane received 2 g 1 phenylthio-3,6-diazepamandmyths-9-it. Yield 35%. TPL133-134°C. IR spectrum, νcm-1: 1695 (CO), 1600 (arene).1H-NMR Spectrum, δ, ppm: 3.02 m (4H, NCH2CH2N); 3.55-3.25 m (8H, NCH2C,2J=14.0 Hz); 0.80 USS (1H, CH); 7.45 d, 7.12 d (C6H5). Mass spectrum, m/z (IRel., %): 274[M+]

Hydrazone 1 phenylthio-3,6-diazepamandmyths-9-it

Was heated at the boil for 3 hours, a solution of 2.37 g (8.64 mmol) of 1-thiophenyl-3,6-diazepamandmyths-9-she's in 40 ml of 66%aqueous solution of hydrazine hydrate is added. Was cooled to 0°deposited precipitate was filtered. After recrystallization from isopropyl alcohol received 2 g of the hydrazone of 1-thiophenyl-3,6-diazepamandmyths-9-it. Yield 80%. TPL189-190°C. IR spectrum, νcm-1: 3300, 1560 (NH), 1680 (C=N), 1600 (arene).1H-NMR Spectrum, δ, ppm: 2.98 m (4H, NCH2CH2N); 3.52-2.75 m (8H, NCH2C,2J=14.0 Hz); 5.20 USS (NH2); 1.90 USS(1H, CH), 7.55 d, 7.35 d (C6H5). Mass spectrum, m/z (IRel., %): 288[M+]

1 phenylthio-3,6-diazepamandmyths 13

Floated 2 h at 220-240°thoroughly mixed With a mixture of 1.90 g (6.59 mmol) of hydrazone 1 phenylthio-3,6-diazepamandmyths-9-she and 1.75 g of powdery potassium hydroxide. The cooled alloy was extracted with diethyl ether (2×25 ml), the solvent drove in the Aquum. After recrystallization from heptane received 1.30 g of 1-phenylthio-3,6-deazaguanosine. Yield 76%. TPL87-89°C. IR spectrum, νcm-1: 1600 (arene).1H-NMR Spectrum, δ, ppm: 3.00 m (4H, NCH2CH2N); 3.35-2.60 m (8H, NCH2C,2J=14.0 Hz); 1.85 ush. s (1H, CH); 1.25 (2 H, CH2). Mass spectrum, m/z (IRel., %): 260[M+]

3,6-Diazepamandmyths

To a solution of 0.40 g (2.33 mmol) of 1-phenylthio-3,6-deazaguanosine in 20 ml of isopropyl alcohol was added 2 g of freshly prepared Raney Nickel and the mixture is boiled for 20 hours, further adding every 7 h 2 g of Raney Nickel. The catalyst was filtered off, washed with isopropyl alcohol, the filtrate was evaporated in vacuum. After recrystallization from heptane was obtained 0.18 g of 3,6-deazaguanosine. Yield 76% (per 1 phenylthio-3,6-diazepamandmyths). TPL250-251°C.

1H-NMR Spectrum, δ. ppm: 3.12 m (4H, NCH2CH2N); 3.42 d, 2.80 (8H, CCH2N2J=14.0 Hz); 1.85 USS (1H, CH), 1.30 (2H, CH2).13C-NMR spectrum, δ, ppm: 29.79 (1,8), at 34.07 (C-8), 57.27 (5, 4), 62.37 (-2, 7, 10, 11). Mass spectrum, m/z (IRel., %): 152 [M+](97), 108 (97), 95 (66), 85 (30), 72 (17), 60 (45), 55 (57), 57 (100), 42 (65). Elemental analysis: calculated, % With at 71.05, N 10.52, 18.52 N, found, % 71.09, N. 10.50, N 18.50.

The identity of the compounds was confirmed by a combination of mass spectrometry, IR,1H-NMR-13C-NMR spectroscopy, and the e element analysis.

Thus, this method allows to obtain 3,6-diazepamandmyths without substituents at the nodal positions, which can be used as an antiviral drug.

The way to obtain 3,6-deazaguanosine, which consists in the interaction of 1-phenylthio-3,6-diazepamandmyths-9-she 65-66% hydrazinehydrate at boiling with the formation of hydrazone 1 phenylthio-3,6-diazepamandmyths-9-it, which is subjected to recovery by the reaction of Kirzner-wolf by fusion with alkali, and the resulting 1-phenylthio-3,6-diazepamandmyths desulfurized Raney Nickel in boiling isopropyl alcohol.



 

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where

R1represents optionally protected or modified iminomethylene group, optionally protected or modified hydroxymethylene group; and

R4is-H; or

R1and R4together form a group of the formula (IV), (V), (VI) or (VII):

R5represents-H or-IT;

R7represents-och3and R8is HE, or R7and R8together form a group-O-CH2-O-;

R14aand R14bthey are both-H or one is-H and the other represents-OH, -och3or-och2CH3or R14aand R14btogether form ketogroup; and R15

and derivatives of 21-cyanocobalamine formula (XVIb):

The invention also relates to new compounds:

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FIELD: organic chemistry, chemical technology, virology.

SUBSTANCE: invention relates to a new method for synthesis of a novel compound - 3,6-diazahomoadamantane of the formula: . Compounds of 3,6-diazahomoadamantane class possess an antiviral effect comparable with antiviral effect of aminoadamantane, elicit strychnine-like activity and show bactericidal, fungicide and algicidal properties and can be used as an antiviral preparation. Method for synthesis of 3,6-diazahomoadamantane involves interaction of 1-phenylthio-3,6-diazahomoadamantane-9-one with 65-66% hydrazine hydrate at boiling to form 1-phenylthio-3,6-diazahomoadamantane-9-one hydrazone that is subjected for reduction in Kizhner-Wolf reaction by alloying with alkali and then 1-phenylthio-3,6-diazahomoadamantane is desulfurized with Raney nickel in isopropyl alcohol at boiling.

EFFECT: improved method of synthesis.

2 cl, 1 ex

FIELD: medicine, chemical-pharmaceutical industry, chemical technology.

SUBSTANCE: invention relates to using biologically active derivatives of ajmaline possessing anti-arrhythmic effect. Method for synthesis of N4-propylajmalinium salts with carboxylic acids is carried out by neutralization of N4-propylajmalinium hydroxide with equivalent amount of carboxylic acid in homogenous phase. The end substance is isolated by distillation of solvent with the yield of salts 97-99%. Method provides preparing acetate, l-lactate, hydrooxalate, hydromalonate, hydrosuccinate, hydroglutarate, l-hydrotartrate, hydrocitrate, salicylate and p-aminobenzoate. Stable solution of N4-propylajmalinium hydromalonate in water for injection of a medicinal agent comprises sodium metabisulfite as antioxidant, 5-30 mg/ml of N4-propylajmalinium hydromalonate, ascorbic acid as antioxidant taken in the effective amounts. Preferably, stable solution of N4-propylajmalinium hydromalonate comprises 10 mg of N4-propylajmalinium hydromalonate/ml of solution, 0.20 wt.-% of sodium metabisulfite and 0.05 wt.-% of ascorbic acid as measured for solution of N4-propylajmalinium hydromalonate. Invention provides the development stable aqueous compositions of N4-propylajmalinium salts for injection of medicinal agent by selection of antioxidants.

EFFECT: improved preparing method.

7 cl, 5 tbl, 5 ex

FIELD: chemistry.

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10 cl, 91 ex, 22 tbl

FIELD: medicine, pharmaceutics.

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16 cl, 98 ex

FIELD: pharmacology.

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14 cl, 60 tbl, 15 ex

FIELD: medicine, pharmaceutics.

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41 cl, 11 dwg, 162 ex

FIELD: chemistry.

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EFFECT: improved method.

13 cl, 4 ex

FIELD: medicine, pharmaceutics.

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EFFECT: invention refers to the compounds of formula (I) possessing an activity modulating α7 nicotinic acetylcholine receptors, α4β2 nicotinic acetylcholine receptors or both subtypes of α7 and α4β2 nicotinic acetylcholine receptors, the based pharmaceutical composition and methods of treating with using them.

18 cl, 1 tbl, 113 ex

FIELD: medicine, pharmaceutics.

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EFFECT: using pharmaceutical composition containing a crystalline monohydrate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3,3,1,13,7]decane dihydrocitrate having high stability and poor moisture absorption.

3 cl, 9 dwg, 6 ex

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