Aminoacetonitrile and method of production thereof

 

(57) Abstract:

The invention relates to physiologically active compounds and relates amidoalkylation, and the method of their derivation. Describes new connections - aminoacetonitrile General formula (1) ANH(CH2)nONO2where a is a residue of acetic acid, substituted nicotinoylureas, n = 2; or a residue of propionic acid, substituted nicotinoylureas, n = 2; or the balance of butyric acid, substituted nicotinoylureas, n = 3; or a residue Caproic acid, substituted nicotinoylureas, n = 2; or a residue of acetic acid, substituted isonicotinamide; n = 2; or a residue of propionic acid, substituted isonicotinamide, n = 2; or the balance of butyric acid, substituted isonicotinamide, n = 2; or the balance of Caproic acid, substituted isonicotinamide, n = 2; or a group-O2DOWN2CH2NHC(CH2)3NHC(O)PyC(O)NH(CH2)3C(O), n = 2, where PY is pyridine substituted in positions 2 and 6, the compounds have koronrodilatatia effect and have lower toxicity relative to caloric animals, in comparison with analogues of the compounds of formula (1) can be COI is. 2 S. p. f-crystals.

The invention relates to amidoalkylation, which are physiologically active substances possessing koronrodilatatia effect, in addition, they can be used as starting compounds for synthesis on the basis of complexes of platinum, palladium and other metals, as, for example, in the works of B. S. Fedorov, N. And.Golovin, M. A. Fadeev A. B. Eremeev, V. C. Arakcheev, Century, Strukov, B. C. Cedars, Century, Shilov, R. F. mills, and L. O. atovmian. Synthesis and crystal structure of 2-nitroacetanilide and its complex with PdCl2. Izvestiya an. A series of chemical, 1998, No. 3, 527-530; I. L. Eremenko, I. L. Golubnichy, S. E. Nefedov, A. A. Sidorov, D. A. Nesterenko, N. P. Konovalov, L. M. Volkova, L. T. Eremenko. Synthesis, structure and antimetastatic activity of the complex trans-[Pt(C5H4C(O)NHC2H4ONO2)2Cl2] . WPI. An. Ser. chem., 1997, 1672. Specifically, the present invention relates to amidoalkylation formulas (1)

ANH(CH2)nONO2,

where A is the residue of acetic acid, substituted nicotinoylureas, n = 2; or a residue of propionic acid, substituted nicotinoylureas, n = 2; or the balance of butyric acid, substituted nicotinoylureas, n = 3; or staticcodeanalysisrule, n = 2; or a residue of propionic acid, substituted isonicotinamide, n = 2; or the balance of butyric acid, substituted isonicotinamide, n = 2; or the balance of Caproic acid, substituted isonicotinamide, n = 2; or A group - O2NOCH2CH2NHC(O)(CH2)3NHC(O)PyC(O)NH(CH2)3C(O), n = 2, where Py is pyridine substituted in positions 2 and 6.

Known for high cardiac activity nitroglycerin [Ginevich A. I., Corehalova N. A. Cardiac glycosides. The positive and negotive aspects of application Ginevich A. I., Corehalova N. A., Euv. J. Chim. Pharmacol., 1989, 31, 247] , which, treating of polynuclear alcohols, widely used in practice for unloading of the heart and improve coronary circulation. However, it has a high toxicity in relation to caloric animals, LD50for it is 108 mg/kg

The closest in chemical structure to the proposed compounds is N-(2-nitroxyethyl)nicotinamide (commercial name of nicorandil, SIGMET), which is currently considered as the most effective treatment for angina and heart failure [K. Sakai, Am. J. Cardiology, 1989, 63, 2j - 10j]. However, nicorandil has a sufficiently high toxicity towards theplot the th invention is the development of new amidoalkylation formula (1), which have less toxicity in relation to caloric animals. This creates the prerequisites for their use as physiologically active substances with koronrodilatatia effect. In addition, the compounds of formula (1) can be used as starting compounds for synthesis on the basis of complexes of platinum, palladium and other metals.

Another aim of the invention is to develop a method of producing amidoalkylation formula (1).

Proposed connection are new in the literature are not described not described and the way they are received.

This goal is achieved by the method lies in the fact that ethyl ester aminocarbonyl acid is exposed to the acid chloride pyridineboronic acid, followed by separation of the resulting ethyl ester N-pyridinedicarboxylic acid and processing its aminoalcohols, then the resulting amideast formula (2)

ANH(CH2)nOH,

where A is the residue of acetic acid, substituted nicotinamidase, n = 2; or a residue of propionic acid, substituted nicotinoylureas, n = 2; or the balance of butyric acid, substituted nicotinoylureas, n = 3; or osteocutaneous, n = 2; or a residue of propionic acid, substituted isonicotinamide, n = 2; or the balance of butyric acid, substituted isonicotinamide, n = 2; or the balance of Caproic acid, substituted isonicotinamide, n = 2; or A group - O2NOCH2CH2NHC(O)(CH2)3NHC(O)PyC(O)NH(CH2)3C(O), n = 2, where Py is pyridine substituted in positions 2 and 6;

nitrous nitrious agent, followed by separation of the target product.

Thus the necessary and sufficient conditions for this reaction are: a) the use of ethyl esters aminocarbonyl acids and anhydrides pyridinecarboxylic acids in the form of hydrochloride; b) the process of interaction of ethyl esters aminocarbonyl acid anhydrides pyridineboronic acid in stoichiometric amounts; C) carrying out the process of nitration of amidopirina environment conc. nitric acid or its solution in an organic solvent type dichloroethane and so on; d) isolation of the target product immediately after dilution of the reaction mixture with water, or after prior neutralization.

The invention is characterized by the following examples.

Example 1.RA - aminobutyric acid and of 3.65 g of acid chloride of isonicotinic acid was added at room temperature 7-8 ml of triethylamine. The reaction mixture was stirred for 1 hour, adding water and a few drops of conc. HCl. The aqueous layer was separated, saturated KCl was added 20 ml of ethyl acetate and neutralized with soda. The ethyl acetate was separated, and the aqueous solution was extracted with an additional 20 ml of ethyl acetate. The combined extracts were dried over MgSO4; after the distillation of the ethyl acetate under reduced pressure obtained 4.3 g of ethyl ester of N-isonicotinoyl--aminobutyric acid, so pl. 63-65oC.

A mixture of 4.3 g of ethyl ester of N-isonicotinoyl - - aminobutyric acid and 10 ml of aminoethanol was heated for 4-6 hours, then drove away under reduced pressure, the excess aminoethanol, the residue was recrystallized from isopropanol. Received 3,98 g of N-(2-oxyethyl)amide NI-isonicotinoyl - - aminobutyric acid, so pl. 130-132oC.

The mixture 3,98 g of N-(2-oxyethyl)amide NI-isonicotinoyl- - aminobutyric acid and 7.2 ml of HNO3was stirred at 0 to 10oC for 1-1 .5 hours. The reaction mixture was poured into 50 ml ice water, neutralized with sodium bicarbonate, saturated KCl and were extracted with ethyl acetate (CH ml); the combined extracts vasoselective upon standing in the refrigerator secretaryshall. Beige crystals, so PL 88-89oC (from dichloromethane). Found (%): C 48,46; H 5,24; N 18,73. C12H16N4O5. Calculated (%): C 48,65; H Of 5.40; N 18,92. IR spectrum , cm-1: 765 (NO2); 895 (O-NO2); 1025 (C-O); 1265, 1310 (C-N); 1280, 1635 (ONO2); 1555, 1610 (C-C, C-N from Py); 1670 (C=O); 1555, 3300 (NH); 2855, 2935 (CH2). PMR spectrum (DMSO-d6, , M. D., J, Hz): 8,75 (ush.T., H, NH,3JNH-CH= 6,1); 8,72 (ush.T., 2H2JH(2)-H(3)=2JH(6) H(5)= 6,4); 8,09 [ush. so, JNH-CH= 6,1 (CH2C(O)NH]; 7,74 (d, 2H,2JH(3)-H(2)=2JH(5) H(6)= 6,4); 4,51 (t, 2H,3JCH-CH= 5,1 (CH2CH2O); 3,37 (D. T., 2H, 3JNH-CH= 7,0,3JCH-CH= 7,0 (NHCH2CH2O); 3,34 (ush.D. T., 2H 3JNH-CH= 7,0,3JCH-CH= 7,0 (NHCH2CH2CH2); 2,11 (m, 2H, CH2CH2CH2CO) of 1.80 (m, 2H, CH2CH2CH2).

Example 2. N-(2-nitroxyethyl)amide NI-isonicotinamide acid. The synthesis was performed analogously to example 1. Of 3.7 g of the hydrochloride of ethyl ether aminouksusnoy acid and 3.75 g of acid chloride of isonicotinic acid obtained 5.35 g of N-(2-nitroxyethyl)amide NI-isonicotinamide acid, so pl. 99-101oC. Found (%): C 44,51; H To 4.23; N 20,67. C10H12N4O5. Calculated (%): C 44,78; H 4,47; N To 20.88. IR SPECT is, 265, 3390 (NH). PMR spectrum (DMSO-d6, , M. D., J, Hz): 9,02 (ush.T., H,3JNH-CH= 6,1) (PyC(O)NH); 8,69 (ush.D., 2H2JH(2)-H(3)=2JH(6) H(5)= 6,4); 8,16 (ush.T., H,3JNH-CH= 6,1 (CH2C(O)NH); 7,74 (d, 2H, 2JH(3)-H(2)=2JH(5) H(6)= 6,4); of 4.54 (t, 2H,3JCH-CH= 5,1 (CH2CH2ONO2); the 3.89 (d, 2H,3JCH-NH= 6,1 (NHCH2CO) 3,44 (D. T., 2H,3JCH-NH= 6,0,2JCH-CH= 5,2 (NHCH2CH2ONO2).

Example 3. N-(2-nitroxyethyl)amide NI-isonicotinoyl--aminopropionic acid.

The synthesis was performed analogously to example 1. From 4.1 g of the hydrochloride of ethyl ether - aminopropionic acid and 3.75 g of acid chloride of isonicotinic acid obtained of 3.46 g of N-(2-nitroxyethyl)amide NI-isonicotinoyl - aminopropionic acid, so pl. 95-97oC. Found (%): C 46,62; H To 4.81; N 19,64. C11H14N4O5. Calculated (%): C, 46.81 / Bbl; H 5,00; N 19,85. IR spectrum , cm-1: 760 (NO2); 842 (CH from Py); 880 (O-NO2); 1015, 1125 (C=O); 1285, 1630 (ONO2); 1554, 1596, 1617 (C-C and C-N from Py); 1540, 3305 (NH), 2935 (CH2). PMR spectrum (DMSO-d6, , M. D., J, Hz): 8,75 (ush.T., H,3JNH-CH= 6,1) (PyC(O)NH); 8,72 (ush. D. , 2H,2JH(2)-H(3)=2JH(6) H(5)= 6,4; 8,21 (ush.T., H, 3JNH-CH= 6,1 (CH2C(O)NH); 7,74 (d, 2H,2JH(3)-H(2NH-CH = 7,0,3JCH-CH= 7,0 (NH-CH2CH2ONO2); 2,39 (t, 2H,3JCH-NH= 6,4 (NHCH2CO).

Example 4. N-(2-nitroxyethyl)amide NI-isonicotinoyl - - aminocaproic acid.

The synthesis was performed analogously to example 1. From 4,85 g of the hydrochloride of ethyl ether - aminocaproic acid and 3.75 g of acid chloride of isonicotinic acid obtained 6,55 g of N-(2-nitroxyethyl)amide NI-isonicotinoyl--aminocaproic acid, so pl. 66-68oC. Found (%): C 51,42; H 5,96; N 17,01. C14H20N4O5. Calculated (%): C 51,79; H 6,16; N 17,26. IR spectrum , cm-1: 755 (NO2); 850 (CH from Py); 875 (O-NO2); 1070 (C-O); 1255, 1300 (C-N); 1280, 1650 (ONO2); 1410, 1508 (C-C, C-N from Py); 1670 (C=O); 1545, 3325 (NH); 2865, 2940 (CH2). PMR spectrum (DMSO-d6, , M. D., J, Hz): 8,73 (ush.T., H,3JNH-CH= 6,1 PyCONH); 8,73 (ush.D., 2H 2JH(2)-H(3)=2JH(6) H(5)= 6,4); 8,03 (ush. so , H,3JNH-CH= 6,1 (CH2CONH); 7,74 (d, 2H,2JH(3)-H(2)=2JH(5) H(6)= 6,4); 4,51 (t, 2H,3JCH-CH= 5.1 (CH2CH2ONO2); 3,37 (D. T., 2H,3JCH-NH=3JCH-CH= 7,0 (NHCH2CH2ONO2); 3,24 (ush.D. t, 2H,3JCH-NH=3JCH-NH= 7,0 (PyCONHCH2CH2); 2,13 (ush.m, 2H, CH2CH2CO) 1,30 (ush.m, 6H, CH2CH2CH2CH2I-nicotinoyl- - aminobutyric acid, so pl. 90-92oC. Found (%): C, 48.38 Per; H 5,17; N 18,77. C12H16N4O5. Calculated (%): C 48,65; H Of 5.40; N 18,92. IR spectrum , cm-1: 705, 835 (CH from Py); 750 (NO2); 885 (O-NO2); 1025 (C-O); 1277, 1630 (ONO2); 1315 (C-N); 1420, 1480, 1590, 1610 (C-C and C-N from Py); 1545 and 3275 (NH); 1655 (C=O); 2860, 2925, 2965, 3080 (CH2).

Example 6. N, NIBis(2-nitroxyethyl)butyramide pyridine-2,6 - dicarboxylic acid. The synthesis was performed analogously to example 1. Out of 2.72 g of the hydrochloride of ethyl ether - aminobutyric acid and 1.9 g of dichlorohydrin pyridine-2,6-dicarboxylic acid obtained 1.66 g of N,NIbis(2-nitroxyethyl)butyramide pyridine-2,6-dicarboxylic acid, so pl. 117-119oC. Found (%): C 43,25; H 5,32; N 16,54. C19H27N7O102H2O. Calculated (%): C 43,37; H 5,72; N 16,86. PMR-spectrum (CD3CN, , M. D.): 3,82 (D. T., 2, CH2NH); 4.72 in (t, 2H, CH2ONO2); 8,12 (D. D., H, CH4); TO 8.25 (2H, CH3,5); 8,58 (2H, NH).

Example 7. N-(2-nitroxyethyl)amide NI-nicotinamidase acid. The synthesis was performed analogously to example 1. Of 3.7 g of the hydrochloride of ethyl ether aminouksusnoy acid Oh acid, so pl. 97-99oC. Found (%): C 44,63; H 4.09 To; N 20,61. C10H12N4O5. Calculated (%): C 44,72; H 4,47; N To 20.88. IR spectrum , cm-1: 705, 845 (CH from Py); 745 (NO2); 835 (O-NO2); 1030 (C-O); 1280, 1615, 1640 (ONO2); 1320 (C-N); 1405, 1470 (C-C, C-N from Py); 1665 (C=O); 1550, 1560, 3300, 3345 (NH); 2850, 2925 (CH2). PMR spectrum (DMSO-d6, , M. D.): 9,02 (C, H, CH2); 8,90 (doctor d, H, CH5); 8,67 (ush. d, H, CH6); 8,20 (D. t, H, CH4); 8,64 (ush.t, H, PyC(O)NHCH2; of 7.48 (ush.t, H, NHCH2CH2ONO2); a 4.53 (t, 2H, CH2CH2ONO2); 3,90 (s, H2O); 3,50 (D. t, 2H, PyCOCH2); of 2.50 (t, 2H, NHCH2CO).

Example 8. N-(2-nitroxyethyl)amide NI-nicotinoyl - - aminopropionic acid.

The synthesis was performed analogously to example 1. From 4.1 g of the hydrochloride of ethyl ether - aminopropionic acid and 3.75 g of nicotinic acid chloride of the acid obtained 3,86 g of N-(2-nitroxyethyl)amide NI-nicotinoyl- - aminopropionic acid, so pl. 102-104oC. Found (%): C 46,59; H To 4.73; N 19,61. C11H14N4O5. Calculated (%): C, 46.81 / Bbl; H 5,00; N 19,85. IR spectrum , cm-1: 700 (CH from Py); 745 (NO2); 885 (O-NO2); 1030 (C-O); 1210, 1315 (C-N); 1280, 1630 (ONO2); 1420, 1480, 1595 (C-C and C-N from Py); 1660 (C=O); 1555, 3335 (NH); 2935 (CH2). PMR spectrum (DMSO-d6, , M. D.): 9,0 (ush.C, H, CH2); 8,67 (ush.d, H, CH6); at 8.60 (ush.t, H, PyC(O)NHCH2); t, 2H, NHCH2CH2ONO2); 3,42 (D. t, 2H, PyCONHCH2CH2); 2.40 a (t, 2H, NHCH2CH2CO).

Example 9. N-(2-nitroxyethyl)amide NI-nicotinoyl - - aminocaproic acid.

The synthesis was performed analogously to example 1. From 4,85 g of the hydrochloride of ethyl ether - aminocaproic acid and 3.75 g of nicotinic acid chloride of the acid obtained 6.2 g of N-(2-nitroxyethyl)amide NI-nicotinoyl- - -aminocaproic acid, so pl. 74-76oC. Found (%): C 51,58; H 5,94; N 17,01. C14H20N4O5. Calculated (%): C 51,79; H 6,16; N 17,26. IR spectrum , cm-1: 705, 870 (CH from Py); 750 (NO2); 885 (O-NO2); 1030 (C-O); 1280, 1630 (ONO2); 1420, 1480, 1610 (C-C, C-N from Py); 1649, 1658 (C=O); 1550, 3285 (NH); 2935 (CH2). PMR-spectrum (CD3CN, , M. D., J, M. D.): 8,96 (doctor d, H, J = 0,7; 2,3; CH2); 8,68 (doctor d, H, J = 1,6; 4,8; CH6); 8,11 (D. D. d, H, J = 1,7; 2,3; 7,9; CH4); 7,42 (D. D. d, H, J = 0,7; 4,8; 7,9; CH5); 7,42 (ush.C, H, PyCONH); 6,30 (ush.C, H, CH2CONH); 4,50 (t, 2H, J = 5,3; CH2CO) 3,47 (D. T., 2H, J = 5,3; 5,3; NHCH2CH2O); 3,35 (D. T. , 2H, J = 6,7; 6,7; NHCH2CH2CH2); and 2.14 (t, 2H, J = 7,3; CH2CO) was 1.58 (m, 4H, CH2CH2CH2CH2CH2); to 1.37 (m, 2H, CH2CH2CH2CH2CH2).

Example 10. N-(3-nitrosopropane)amide NI-nicotinoyl - - aminobutyric acid.

Centigrades salt of the acid chloride of nicotinic acid and 1.68 g of 3-aminopropanol-1 obtained 2,48 g of N-(3-nitrosopropane)amide NI-nicotinoyl- - aminobutyric acid, so pl. 92-93oC. Found (%): C 50,12; H 5,54; N 17,87. C13H18N4O5. Calculated (%): C 50,32; H Of 5.81; N 18,06. PMR spectrum (DMSO-d6, , M. D.): 1,78 (Queen, 4H, CH2CH2CH2ONO2); of 2.50 (m, 2H, NHCH2CH2CH2CO) to 4.52 (t, 2H, CH2ONO2); 3,22 (D. t, 2H, NHCH2); a 7.85 and 8,58 (ush.t, 2H, NH); of 7.48 (doctor d, H, CH5); 8,16 (D. t, H, CH4); 9,00 (C, H, CH2).

Thus, the proposed method of obtaining compounds of formula (1) can achieve the goal of the invention and to obtain previously unknown aminoacetonitrile that significantly extend the range of compounds based on amidoalkylation and can be used as a physiologically active substances with koronrodilatatia effect and low toxicity. For example, the percentage of ischemia to the zone of necrosis for N-(2-nitroxyethyl)amide NI-nicotinoyl- - aminopropionic acid is 37,4% with an error of 4.2%, and for N-(2-nitroxyethyl)amide NI-nicotinamidase acid - 38,4% with an error of 5.3%.

Tests for General toxicity was performed by intraperitoneal administration of the drug in water or 15% alcohol white mice weighing 20, the test Results showed, Thu and data allow us to classify the claimed connection to the discharge of toxic substances in relation to caloric animals.

1. Aminoacetonitrile formula 1

ANH(CH2)nONO2,

where A is the residue of acetic acid, substituted nicotinoylureas; n = 2; or a residue of propionic acid, substituted nicotinoylureas, n = 2; or the balance of butyric acid, substituted nicotinoylureas, n = 3; or a residue Caproic acid, substituted nicotinoylureas, n = 2; or a residue of acetic acid, substituted isonicotinamide, n = 2; or a residue of propionic acid, substituted isonicotinamide, n = 2; or the balance of butyric acid, substituted isonicotinamide, n = 2; or the balance of Caproic acid, substituted isonicotinamide, n = 2; or A group O2NOCH2CH2NHC(O)(CH2)3NHC(O)PyC(O)NH(CH2)3C(O), n = 2, where Py is pyridine substituted in positions 2 and 6.

2. The method of producing amidoalkylation formula 1

ANH(CH2)nONO2,

where A is the residue of acetic acid, substituted nicotinoylureas, n = 2; or a residue of propionic acid, substituted nicotinoylureas, n = 2; or the balance of butyric acid, substituted nicotinoylureas, n = 3; or a residue Caproic acid, substituted nicotinoylureas, n = 2; or the major isonicotinamide, n = 2; or the balance of butyric acid, substituted isonicotinamide, n = 2; or the balance of Caproic acid, substituted isonicotinamide, n = 2; or A group O2NOCH2CH2NHC(O)(CH2)3NHC(O)PyC(O)NH(CH2)3C(O), n = 2, where Py is pyridine substituted in positions 2 and 6,

characterized in that the ethyl ester aminocarbonyl acid is exposed to the acid chloride pyridineboronic acid, followed by separation of the resulting ethyl ester N-pyridinedicarboxylic acid and processing its aminoalcohols, then the resulting amideast formula

ANH(CH2)nOH2,

where A is the specified values when n = 2 or 3,

nitrous nitrous agent, followed by separation of the target product.

 

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2 cl

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should correct hemostasis disorders intra-operationally due to introducing fraxiparine about 40-80 min against the onset of operation along with intravenous injection of mexidol, by drops at the dosage of about 5-6 mg/kg patient's body weight dissolved in 400 ml 0.9%-NaCl solution at the rate of 60 drops/min. The present innovation enables to create the peak of fraxiparine and mexidol concentrations at traumatic stage of operation that enables to correct hemostasiological disorders during operative interference and at early post-operational period due to combined action of preparations onto different links of hemostasis.

EFFECT: higher efficiency and accuracy of correction.

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with treating acute anterior and posterior ischemic optic neuropathy due to introducing vasodilators and anticoagulants as caffeine, halidor, dicinon in complex therapy in hospital for 10 d. Moreover, it is necessary to perform parabulbar introduction of 0.3 ml dexasone, 0.2 ml caffeine, 0.3 ml emoxipin successively, fractionally every 20 min once daily in combination with daily intramuscular injections once daily of 2.0 ml dicinon and 1.0 ml halidor and intravenous injection of haemodesum by drops per 200.0 ml on the 1st, 3d and 5th d of therapy. Also, it is necessary to carry out 5 seances of hirudotherapy for temple area every other day under coagulogram control. Then one should introduce milgamma, dicinon and nootropil at age-dependent dosages for 1 mo ambulatorily. The innovation provides complex improvement of microcirculation and metabolicocular and cerebral processes, regeneration of nervous tissue and reconstruction of optic nerve's conductivity at decreased frequency of therapeutic side effects.

EFFECT: higher efficiency of therapy.

2 ex, 1 tbl

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