Nitrates alcohols containing amide, dinitromethane and nitroamine group, the method of production thereof, 3- (acylaminoalkyl)-tetrahydro-1,3-oksazolov and - oxazine, the method of production thereof

 

(57) Abstract:

The invention relates to new nitrates alcohols of General formula (I), where R', R", n, m are presented in the claims, the way they are received by means of nitration of 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazino. Also offers new intermediate compound is 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazine General formula (II) wherein R', R", n, m are specified in the claims, and the way they are received. The invention can be used in medical practice for the creation of medicines, for example, cardiovascular. 4 C. and 3 h.p. f-crystals, 2 PL.

R C(O)N(R") and(CH2)nC(NO2)2CH2N(NO2)(CH2)mONO2(I)

The invention relates to the field of new chemicals and for nitrates alcohols of General formula (I)

R C(O)N(R") and(CH2)nC(NO2)2CH2N(NO2)(CH2)mONO2(I)

where R'=-CH3, R ' =-CH2OH, n=1, m=2; (1)

R'=-CH3, R"=H, n=1, m=2; (2)

R'=-CH3, R ' =-CH2OH, n=2, m=2; (3)

R'=-CH3, R"=H, n=2, m=2; (4)

R'=-CH3, R ' =-CH2OH, n=1, m=3; (5)

R'=-CH3, R"=H, n=1, m=3; (6)

< / BR>
which can be ispolzovaniya)-tetrahydro-1,3-oksazolov and - oxazino - intermediates in the synthesis of compounds of formula (I) and the method of their derivation.

The proposed compounds of formula (I) contain in their molecules amide, dinitromethane, nitramine and nitrate groups. This combination of groups in the molecules of a substance is new, and so close structural analogs of known compounds, they have not.

As similar to destination can be selected N-(2-nitroxyethyl)nicotinamide, which is a modern highly effective the cardiovascular agent (Lieberman, S. C. , L. Yakhontov N., Chem.-Pharm. journal, 1988, 1046).

The task of the technical solution is the synthesis of previously unknown nitrates alcohols containing amide, dinitromethane and nitramino group, namely the compounds of formula (I), which can be used to create medicines, for example, cardiovascular, and how they are received. The problem is solved proposed by the compounds of General formula (I) and the way they are received.

The most widely used method of obtaining nitrates alcohols (nitroethanol) is the nitration of alcohols with nitric acid or its mixture with sulfuric acid (E. Y. Orlov, Chemistry Jenia nitrates alcohols of the formula (I), because the corresponding alcohols is unknown. Our attempts at getting them failed.

In this regard, we have developed a method of obtaining nitrates alcohols of the formula (I), consisting in the nitration of 3-(acylaminoalkyl)tetrahydro-1,3-oksazolov and-oxazino General formula (II) at a temperature of 0-60oWith the dilution of the reaction mixture with water and separation of the product by filtration.

Distinctive features of the method are:

1) use as nitroamine compounds 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazino General formula (II),

2) use as nitrouse means of nitric acid concentration of 90-100%, taken in an amount of 2.5 to 5.0.h. 1 wt.h. microimage substances; use of acid concentration less than 90% leads to a significant lowering of the yield of the product;

3) use as nitrouse means a mixture of nitric and sulfuric acids at their volumetric ratio of 1:(1-3), changing the balance in one direction or another leads to a decrease in product yield,

4) use as nitrouse means a mixture of nitric acid and methylene chloride in a volume ratio of 1:(1-7), the increase in the ratio above 1: 7 leads to "ptx2">

The reaction of nitration tetrahydro-1,3-oksazolov and-oxazino was not previously known.

Another task solutions are the new 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazine General formula (II)

< / BR>
where R'=-CH3, R"=H, n=1, m=2; (9)

R'=-CH3, R"=H, n=2, m=2; (10)

R'=-CH3, R"=H, n=1, m=3; (11)

< / BR>
and development of the method of their derivation. These compounds are intermediate materials for the production of nitrates of the formula (I), many other compounds, such as various derivatives of N-substituted aminoalcohols. In addition, they are of independent interest as potential biologically active substances (H. Hellmann, G. Opitz, - Aminoalkylierung, 1960, Verlag Chemie, GMBH, S. 15-16).

The most common way of obtaining tetrahydro-1,3-oksazolov and-oxazino based on the reaction of aminomethylpyridine, which involves two components: amerosport and formaldehyde. In this way cannot be obtained substances containing fragments that must be present in molecules (ibid, S. 16-19), compounds of formula (I) (amide and dinitroethylene group). Well-known private way to obtain tetrahydro-1,3-oxazino (but not-oksazolov), also based on the reaction of aminomethylpyridine (D. montrealbuy, formaldehyde and a primary amine, also it is impossible to obtain substances with the desired fragments of the molecule (amide and dinitroethylene groups).

The developed method consists in carrying out the interaction of three components - acylaminopenicillin (acedcommand, H-acid), formaldehyde and amerosport. The process is carried out in aqueous or aqueous-alcoholic medium at room temperature, the product is removed by filtration or extraction.

1 Acetamido-2,2-dinitro-3-(tetrahydro-1',3'-oxazol-3'-yl)propane (9).

To a suspension 14,16 g 1 atsetamino-2,2-dinitroethane in 40 ml of H2O under stirring and cooling to 10 to 14oWith added dropwise a solution of 4.9 g of 2-aminoethanol in 10 ml of H2O. Then at a temperature of 17-20oWith added dropwise 16 ml of 30% aqueous formalin. The exposure at 18-22oWith 4 hours. Cooled the mass to 2oC, the precipitate was filtered, washed it with ice water, dried and recrystallize. The output of 15.1 g (72% of theoretical.), so pl. 114-115oWith (CCl4with CHCl3). Found: C 36,5, H 5,38, N Is 21.3%. C8H14N4O6. Calculated: C 36,64, H 5,38, N 21,37%.

1 Acetamido-3,3-dinitro-4-(tetrahydro-1',3'-oxazol-3'-yl)butane (10).

To a suspension 1,91 g 1 atsetamino-3,3-dinitro the 2-aminoethanol in 2 ml of H2O and a solution of 2 ml of 30% aqueous formaldehyde solution in 2 ml of H2A. Exposure at 20-25oC for 5 hours. Separated the organic layer and the aqueous was extracted with CH2Cl2. The combined extract was washed with water, dried over MgSO4and activated carbon. After removal of solvent received 2,34 g (84,8% of theoretical. ) oily substances, n20D1,5002. Found: C, 39.2 And H 6,3, N Of 20.3%. C9H16N4O6. Calculated: C 39,13, H Of 5.84, N To 20.28%.

1 Acetamido-2,2-dinitro-3-(tetrahydro-1',3'-oxazin-3'-yl)propane (11).

To a solution of 3.54 g of 1-atsetamino-2,2-dinitroethane in 7 ml of CH3OH while stirring and cooling to 10 to 14oC was added dropwise a solution of 1.5 g of 3-aminopropanol in 7 ml of H2O and a solution of 4 ml of 30% aqueous formaldehyde solution in 4 ml of H2A. Exposure at 18-22oC 4 hours. Cooled the mass to 2oC, the precipitate was filtered, washed it with ice water, dried, recrystallize. The output of 4.2 g (76% of theoretical.), so pl. 144-145oC (with decomp.) (from dichloromethane to ethyl acetate). Found: C To 39.4, H 6,1, N 20,5%. C9H16N4O6. Calculated: C 39,13, H Of 5.84, N To 20.28%.

Compounds (12) and (13) was obtained in the same way. In Table. 1 shows a so pl., output, IR and PMR spectra of compounds (9-13).

6-(N-Hydroxymethylamino)-3,5,5-trinitro-3-usahec> the added portions 1 g of compound (9) was mixed with 10o1-2 hours. Poured the mixture into the ice, the precipitate was filtered, washed with water, dried, recrystallize. The output of 0.4-0.5 g (28-35% of theoretical.), so pl. 114-115oC (with decomp.) (from dichloromethane). Found: C 25,9, H 3,8, N 23,7%. C7H12N6O10. Calculated: C 24,71, H Of 3.56, N 24,70%.

6 Acetamino-3,5,5-trinitro-3-azahexane-1 (2).

To 3-9 ml H2SO4(d=1,83) under stirring at room temperature was added 1 g of compound (9). To the obtained solution when cooled to 0-4oWith added dropwise 3 ml of HNO3(d=1,51), heated up to 60oWith and kept at this temperature for 30 minutes, Cooled, poured into ice. The precipitated product was dissolved in CH2Cl2the solution was washed with water, removed the solvent, the residue was recrystallize from dichloroethane. The output of 0.26-0.31 g (20-24% of theoretical.), so pl. 124-125oC (with decomp.). Found: C 25,0, H 3,9, N 23,7%. C7H12N6O10. Calculated: C 24,71, H Of 3.56, N 24,7%.

7-(N-Hydroxymethylamino)-3,5,5-trinitro-3-azaleptinum-1 (3).

To 35 ml of HNO3(d=1,51) with stirring and cooled to 0-4oWith added dropwise a solution of 5,52 g of compound (10) in 35-250 ml of CH2Cl2. Extract with 10oFrom 3-6 hours. Valeriana organic layer, he recrystallize from 90% CH3OH. The output of 3.6-4.0 g (47-52% of theory. ), so pl. 102-103oC (with decomp.). Found: C 27,7, H 4.2, N 22,6%, C9H16N6O11. Calculated: C 28,13, H 4,20, N 21,87%.

Other nitrates were obtained similarly. In table.2 shows so pl., output, IR and PMR spectra of compounds (1-8).

For compounds (1-5, 7) defined acute toxicity on gray mice in the laboratory of experimental cancer chemotherapy IHFC wounds. These compounds have LD50in the interval 410-820 mg/kg

Compounds (1, 2, 4) were studied by cardiac activity at the Russian scientific center for security biologically active substances of the Ministry of health by introducing a dose of a substance to white rats, which was provoked myocardial infarction with subsequent determination of the zone of necrosis (in % to the area of ischemia). Analyte (1, 2, 4) showed the following values, respectively:

48,44,9%, 40,34,6%, 39,00,89%

For N-(2-nitroxyethyl)nicotinamide, selected as similar in purpose, this value is 425,4% value LD50=475 mg/kg), i.e., the proposed substances showed cardiac activity at the same high level.

Thus, the claimed resh intermediate compounds for the synthesis of target compounds, a new method to produce these intermediate compounds and the positive effect of target compounds lies in their high cardiac activity.

1. Nitrates alcohols containing amide, dinitromethane and nitroamine group, of General formula I

R C(O)N(R") and(CH2)nC(NO2)2CH2N(NO2)(CH2)mONO2< / BR>
where R' = -CH3, R ' = - CH2OH, n = 1, m = 2; (1)

R' = -CH3, R" = H, n = 1, m = 2; (2)

R' = -CH3, R ' = - CH2OH, n = 2, m = 2; (3)

R' = -CH3, R" = H, n = 2, m = 2; (4)

R' = -CH3, R ' = - CH2OH, n = 1, m = 3; (5)

R' = -CH3, R" = H, n = 1, m = 3; (6)

< / BR>
2. The method of obtaining nitrates alcohols of the General formula I

R C(O)N(R") and(CH2)nC(NO2)2CH2N(NO2)(CH2)mONO2< / BR>
where R' = -CH3, R ' = - CH2OH, n = 1, m = 2; (1)

R' = -CH3, R" = H, n = 1, m = 2; (2)

R' = -CH3, R ' = - CH2OH, n = 2, m = 2; (3)

R' = -CH3, R" = H, n = 2, m = 2; (4)

R' = -CH3, R ' = - CH2OH, n = 1, m = 3; (5)

R' = -CH3, R" = H, n = 1, m = 3; (6)

< / BR>
by nitration, characterized in that act nitrouse tool 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazine at 0 - 60oC, followed by dilution of the reaction mass woeste nitric acid concentration of 90 100% in the amount of 2,5 - 5,0 about. including 1 wt.h. microimage substances.

4. The method according to p. 2, characterized in that as nitrouse tools use a mixture of nitric and sulfuric acid in a volume ratio of 1 : (1 - 3).

5. The method according to p. 2, characterized in that as nitrouse tools use a mixture of nitric acid with methylene chloride in a volume ratio of 1 : (1 - 7).

6. 3-(Acylaminoalkyl)-tetrahydro-1,3-oksazolov and oxazine General formula II

< / BR>
where R' = -CH3, R" = H, n = 1, m = 2; (9)

R' = -CH3, R" = H, n = 2, m = 2; (10)

R' = -CH3, R" = H, n = 1, m = 3; (11)

< / BR>
7. The method of obtaining 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazino General formula II

< / BR>
where R' = -CH3, R" = H, n = 1, m = 2; (9)

R' = -CH3, R" = H, n = 2, m = 2; (10)

R' = -CH3, R" = H, n = 1, m = 3; (11)

< / BR>
by the reaction of aminomethylpyridine, characterized in that the reaction is administered three components: H-acid (in the form of acylaminopenicillin), formaldehyde and aminoplast.

 

Same patents:

The invention relates to a new method of obtaining derivatives taxane General formula

< / BR>
which have valuable protivoanemicakimi and antitumor properties

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them
The invention relates to a derivative of succinic acid, which are physiologically active substances possessing koronrodilatatia effect, in addition, they can be used as components of explosive compounds and powders

The invention relates to physiologically active compounds and relates to derivatives of succinic acid, specifically nitrate N-alkanolamines or imides, method of production thereof, and also N-alkanolamines or imides

The invention relates to a new derivative of cyclohexanol, of the formula:

,

which can find application in medical practice as coronelismo, cardiotonic and antihypoxic tools

The invention relates to organic chemistry, specifically to the derivatives of nitroglycerin, namely alkoxycyanobiphenyl General formula

-H2O-CHH2OR having cardiotonic activity that involves their use in medical practice

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

The invention relates to a new compound - monoethanolammonium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid f-crystals (I), which is antioxidant and anti-ischemic activity and may find application in medicine

The invention relates to medicine, the inhibitor of intimal hypertrophy, containing as the active ingredient oxindole derivative represented by formula I, or its salt, where R represents a hydrogen atom, phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a phenyl group, which may be substituted, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a hydrogen atom, a lower alkyl group, benzyl group or benzosulfimide group which may be substituted, or acyl group,axially group, lower alkoxycarbonyl group, phenylcarbamoyl group which may be substituted, or triptorelin group represents CH or N; n represents an integer from 0 to 4, inclusive, that indicates the number of substituents and double dotted/solid line represents a simple bond or double bond, which has an excellent inhibitory action against intimal hypertrophy, and used as an agent for prevention (treatment) attenuation of proliferative vascular diseases such as restenosis after RTSA, arteriosclerosis, peripheral embolism and angia, use oxendolone derived to obtain an inhibitor of intimal hypertrophy, compositions for inhibiting intimal hypertrophy and method of prevention and treatment of intimal hypertrophy

The invention relates to medicine, particularly cardiology, and for slowing the progression of corneoscleral

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

The invention relates to pharmacology, in particular ORGANOMETALLIC compounds possessing biological activity, which can find application in drug development for the prevention and treatment of coronary heart disease

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them
Up!