DD280110A1 - PROCESS FOR THE PREPARATION OF 1.2.4-TRIAZOLO / 1.5-A / PYRIDINE-8-CARBONITRILES - Google Patents

Abstract

The invention relates to a process for the preparation of 1,2,4-triazolo & 1,5-a! Pyridine-8-carbonitriles, which can be used in principle in the therapy of cardiovascular diseases due to their positive inotropic activity. According to the invention, 2-imino-2H-pyridin-1-amines are reacted with carboxylic acids, carboxylic acid esters or nitriles to give 1,2,4-triazolo & 1,5-a! Pyridine-8-carbonitriles of the general formula I. The invention can be used in the chemical and pharmaceutical industries. Formula I

Description

CN

with the meaning given for R and R ¹ or RR ¹ with a carboxylic acid ester of the general formula III

R ² -COOR ³ III

with the explanation given for R ² and in the R ³ alkyl or aryl! means, or with a carboxylic acid of general formula IV

R ² -COOH IV

with the meaning given for R ² or with a nitrile of the general formula V

R ² -CN V

is reacted with the meaning given for R ² in an organic solvent or in an excess of the carboxylic acid ester of the general formula III or the carboxylic acid of the general formula IV.

2. The method according to claim 1, characterized in that an aliphatic alcohol, such as, for example, ethanol, isopropanol or n-butanol, or acetonitrile or dimethylformamide is used as the organic solvent.

Field of application of the invention

The invention relates to a process for the preparation of 1,2,4-triazolo | 1.5-a] pyridine-8-carbonitrilone. Such compounds have a positive inotropic activity and are therefore suitable in principle for use in the therapy of cardiovascular diseases.

Characteristic of the known state of the art

It is known that 1,2,4-triazolo [1 .B-alpyridine-e-carbonitriles by reacting 8-Cyanoadiazolo (3.2-ajpyridiniumsalzen with cyanamide (GV Bo''d, SRDando: J. Chem. Soc. C 3873 (1971)) or of 1-amino-3-cyanopyrid-2-ones with carboxylic acid amides (RCPhadke, DWRangnekar: Synthesis 860 (1986)) Both methods do not give unsubstituted 5-position I ^ .A- Triazololines.o-alpyridine-e-carbonitriles and also do not permit 2-carbalkoxy,

To synthesize 2-cyanomethyl- or 2-trifluoromethyl-1,2,4-triazolo [1,5-a] pyridine-8-carbonitriles. The former method also has the disadvantage that hard to access starting compounds must be used. Furthermore, it is known that 1-aminopyridinium iodide with trifluoroacetonitrile (R.E. Banks, S.M. Hitchen: J. Fluorine Chem. 15, 179 [198O], Chein. Abstr. 93,95180r [198O]) or 1,2-diaminopyridinium iodide with trifluoroacetic anhydride (REBanks, SM Hitchen: J. Fluorine Chem. 20, 373 [19821, Chem. Abstr. 97, 109934m [1982)] to 2-trifluoromethyl-1,2,4-triazolo [ Let 1.5-a | pyridine react. In addition to the fact that very expensive reagents are required, no 2-trifluoromethyl-1,2,4-triazolo [1,5-a] pyridine-8-carbonitriles can be prepared by both methods. Particularly disadvantageous proves the former method, which provides difficult separable product mixtures.

It is further known that compounds having a 1,2-diaminopyridine structure react with carboxylic acid derivatives to give 1,2,4-triazolo [1,5-3] pyridines (KTPotts, HRBurton, J.Bathacharyya: J. Org. Chem. 31,260 [1966); T. O'kamoto, M. Heirobe, Y. Tamai, E. Yabe: Chem. Pharm. Bull. 14, 506 [1966]; C. Casagrande, A. lnvernizzi: Farmaco, Ed, Sci. 27.101 [1972J, Chem. Abstr. 76, 1266873 [1972]; K. Kubo, N.Itoh, I.Sohzu, Y. Isomura, H.Honma: Jap. Pat., 79.05.996, Chem. Abstr. 91, 57007 [19791; S.Suzue: Jap. Pat. 79.39.094, Chem. Abstr. 91,91646 [1979]; T.lrikura, S. Suzuue: U.S. Pat. 4,202,977, Chem. Abstr. 94, 4021 w [1981]; T.lrikura, S.Suzue · DE-OS 2,905,823, Chem. Abstr. 94, 121541b [1981]; Kanebo Ltd .: Jap. Pat. 81.63.983, Chem. Abstr. 95, 203964b [1981]; Kyorin Pharmaceutical Co., Ltd .: Franz. Pat. 2,450,259, Chem. Abstr. 97,72373z [1982]; A. McKillop, A.Henderson, P.S. Ray, C. Avendano, E.G. Molinero: Tetrahedron Letters 23,3357 (1982); Kyorin Pharmaceutical Co., Ltd .: Jap. Pat. 82,206,684, Chem. Abstr. 98, 160725s [1983]).

In addition, it is known that 1,2,4-triazolo [1,5-a-pyridines both antivirole (H. Berner, H. Reinshagen: Monatsh. Chem. 106, 1059 [1975]), and analgesic, antipyretic, antiphlogistic (K. Kubo, N. Itoh, I.Sohzu, Y. Isomura, H. Honma: Jap. Pat., 79.05.996, Chem. Abstr., 91, 57007, [1979]) and, in particular, antihypertensive (S. Suzuue: Jap. Pat. 79.39 Chem. Abstr. 91,91646 [19791; T.Irikura, S. Suzuue: US Pat. 4,202,977, Chem. Abstr. 94, 4021 w [1981]; 1.Irikura, S. Suzuue: DE OS 2,905,823, Chem. Abstr. 94, 121541b [1981]; Kyorin Pharmaceutical Co., Ltd .: Franz. Pat. 2,450,259, Chem. Abstr. 97,72373z [1982]; Kyorin Pharmaceutical Co., Ltd .: Jap. Pat. 82,206,684, Chem. Abstr. 98, 160725s [1983]).

Object of the invention

The aim of the invention is to provide an economically advantageous, preparatively simple and easily accessible Ausgangsverbindunqen based method for the synthesis of 5-unsubstituted 1,2,4-triazolo [1.5-a] pyridine-8-carbonitrile, which is used for the treatment of cardiovascular diseases appear appropriate.

Explanation of the essence of the invention

The object of the invention is to develop a process for preparing 1,2,4-triazolo (1,5-a) pyridine-8-carbonitriles which is unsubstituted in the 5-position and which starts from easily accessible starting compounds, requires the shortest possible reaction times and only one process step and it allows to isolate the final products without expensive separation operations.

According to the invention, this object is achieved in that 1,2,4-triazolo [1 .S-alpyridine-8-carbonitrile of the general formula I,

CN

in the R and R ^{1 are} identical or different hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or RR 'together a tri-, tetra-, penta-, hexa- or decamethylene bridge or a benzo-fused alkenylene bridge and R ² carbalkoxy, cyanomethyl or Trifluormethvl, are prepared by reacting a 2-lmino-2H-pyridin-1-amine of the general formula II

CN with the meaning given for R and R ¹ or RR ¹ with a carboxylic acid ester of the general formula III

R ² -COOR ³ III

with the explanation given for R ² and in which R ^{3 is} alkyl or aryl, or with a carboxylic acid of general formula IV

R ² -COOH IV

with the meaning given for R ² or with a nitrile of the general formula V

R * -CN V

with the meaning given for R ² in an organic solvent or in an excess of the carboxylic acid ester of the general formula III or the carboxylic acid of the general formula IV. The solvent used is an aliphatic alcohol, such as, for example, ethanol, isopropanol or n-butanol, or Acetonitrile or dimethylformamide used.

The teaching according to the invention makes it possible to make the 1,2,4-triazolo [1,5-a] pyridine-8-carbonitriles of the general formula I in a simple manner, accessible in short reaction times in only one process step and without expensive separation operations, with easily preparable starting compounds be used.

The products of general formula I according to the invention are new. Surprisingly, they have a positive inotropic activity, wherein the peripheral blood pressure is practically not affected, which was not expected in the prior art. Thereafter, of 1,2,4-triazolo [1.5-a] pyridines with respect to the cardiovascular system, only their pronounced antihypertensive effect known.

embodiments example 1

The 1,2,4-triazolo [1 .B-alpyridine-S-carbonitriles of the general formula I prepared according to the various variants are summarized in Table 1.

option A

A mixture of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II, 20 mmol of ethyl cyanoacetate and 20 ml of ethanol is refluxed for 1 hour. After cooling, the precipitated end product of general formula I (R ² = CH ₂ CN) is filtered off with suction, washed with ethanol, dried in air and recrystallized.

Variant B

Analogous to A, however, instead of ethanol, 20 ml of n-butanol are used as solvent.

Variant C

Analogous to A, however, 20 ml of acetonitrile are used as the solvent instead of ethanol.

Variant D

Analogous to A, but instead of Cyanessigsäureethylester 20mmol Cyanessigsäurephenylester be used.

Variant E

Analogously to A, however, instead of ethyl cyanoacetate, 20 mmol of malononitrile are used.

Variant F

A mixture of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II and 10 ml of diethyl oxalate is refluxed for 15 minutes. After cooling, the precipitated end product of the general formula I (R ² = COOC ₂ Hs), as described for A, is isolated and purified.

Variant G

A mixture of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II, 20 mmol of diethyl oxalate and 20 ml of isopropanol is refluxed for 1 hour. After cooling, the precipitated end product of general formula I (R ² = COOC ₂ H ₅ ), as described for A, is isolated and purified.

Variant H

Analogously to G, however, 10 ml of dimethylformamide are used as solvent instead of isopropanol and the reaction time is reduced to 30 minutes. After cooling, the reaction solution is diluted with 25 ml of ethanol. The end product of the general formula I (R ² = COOC ₂ H ₅ ) is isolated and purified after completion of the crystallization as described for A.

Variant I

15 mmol of trifluoroacetic acid ethyl ester are added dropwise to a suspension of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II in 25 ml of n-butanol with stirring at room temperature. After a total of two hours of stirring, the reaction mixture is diluted with 25 ml of cyclohexane and completes the crystallization by storing the mixture for several hours in the refrigerator. The precipitated end product of general formula I (R ² = CF ₃ ) is filtered off with suction, washed with n-Buumul, dried in air and recrystallized.

Variant J

A solution of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II in 10 ml of trifluoroacetic acid is refluxed for 30 minutes. After cooling, the reaction solution is diluted with 50 ml of water. The precipitated Endproduk 'of the general formula I (R ² = CF ₃ ) is filtered off, washed with 50% aqueous ethanol, dried in air and recrystallized.

Example 2

The test of the 1.2.4-triazolo (1.5-aJpyridin-8-carbonitrile of the general formula I on positive inotropic activity was carried out according to the following method:

The experiments were carried out on anesthetized beagle dogs (2mg / kg morphine i.m. as premedication, 30mg / kg pentobarbital i.v., 0.02mg / kg / min phenobarbital sodium i.v. as continuous infusion) of both sexes of the VEB Jenapharm breed.

The test substances were dissolved in propylene glycol and applied in a volume of 0.1 ml / kg in increasing dosages at intervals of 10 minutes by means of a Flexüle in the saphenous vein saphena. A tip catheter (W 121, VEB Meßgerätewerk Zwönitz) was inserted into the left ventricle via the artery femoralis dextra for intraventricular pressure measurement. The measure of the positive inotropic effect was the percentage increase in the maximum rate of pressure increase in the left ventricle (dp / dt _ma , in Torr / s). The peripheral blood pressure was detected in the femoral artery via a plastic catheter (Charriere 7) with an external electromechanical pressure transducer (W 102). The ECG (standard leads) was

With needle electrodes removed from the extremities and registered synchronously to the ventricular pressure curve, the peripheral blood pressure and the electronically differentiated ventricular pressure curve on an electrocardiograph 6 NEK-4. The measured values for two compounds of the general formula I are summarized in Tables 2, 3 and 4 and have been compared with amrinone as a reference substance.

Table 1 Prepared 1,2,4-triazolo [1.5-a] pyridine-8-carbonitriles of the general formula I.

R - (CHj) ₃ - R ¹ R ² Ausb./% F./"C No. CH ₃ H CH ₂ CN variant Recryst. la - (CH ₂ I ₃ - 80 / A 215 to 216.5 71 / B n-butanol - (CH ₂ I ₃ - 74 / C 66 / D , CH ₃ - (CH ₂ I ₄ - H COOC ₂ H ₅ 69 / E ib 68 / F 224-226 - (CH ₂ I ₅ - 48 / G acetic acid CH ₃ H CF ₃ 51 / H ic -C = CH-CH = CH-CH = C- (CH ₂ I ₂ 99 / I 110-112 (CH ₃ I ₂ CHCH ₂ H CH ₂ CN 73 / J n-butanol id 4-CH ₃ OC ₆ H ₄ 77 / A 204.5 to 206.5 4-CH ₃ OC ₆ H ₄ -CH ₂ H CH ₂ CN n-butanol Ie Thien-2-yl 77 / A 215-217 C ₂ H ₅ CH ₃ CH ₂ CN acetic acid If 66 / A 124-126 CH ₂ CN water ig 91 / A 170-171 COOC ₂ H ₅ n-butanol lh 58 / F 238-240 (Zers.) CF ₃ acetic acid ii 83 / I 125-126 CH ₂ CN n-butanol ii 88 / A 172 to 174.5 CH ₂ CN n-butanol Ik 89 / A 171-172 CH ₂ CN n-butanol Il 94 / A 228-229 H CH ₂ CN n-butanol in the 86 / A 277-280 (Zers.) H CH ₂ CN acetic acid Ir, 87 / A from 270 Zers. acetic acid

Table 2 Percent change in cardiac contractility (dp / dt _m ") in beagle dogs (n = 3) after iv bolus application of compounds of general formula I compared to amrinone

amrinone Compound I a Compound Ij x ± s χ ± s x ± s output values 2 600 ± 1100 4000 ± 1200 5 260 ± 1 630 (Torr / s) Dose (mg / kg) x% ± s x% ± s x% ± s 0.2 18 ± 7 0.5 27 ± 13 11 ± 4 0.6 27 ± 6 1.0 45 + 21 11 ± 4 2.0 66 ± 25 48 ± 20 13 ± I 5.0 84 ± 42 29 ± 11 6.0 75 ± 28 ED5o (mol / kg) ⁶ : 1-10 " ⁶ 8.8 x 10 " ⁶ 4.3 x 10 " ⁵ relative effectiveness 1.0 0.7 0.2

η = number of animals

x ± s = mean with standard deviation

x% ± s = percentage change to baseline with standard deviation.g

Table 3 Pr ocentual change in systolic peripheral blood pressure (P ₁ ) in Beagle dogs (n = 3) after iv Bclusapplikation of compounds of general formula I compared to amrinone

amrinone Compound I a Compound I] x ± s x ± s x ± s output values 153 ± 24 195 ± 26 152 ± 33 (Torr) Dose (mg / kg) x% ± s x% ± s x% ± s 0.2 -2 ± 3 0.5 5 ± 8 0.6 -4 ± 6 1.0 0 ± 3 6 ± 2 2.0 - 1 ± 18 -4 ± 6 6 ± 6 5.0 -30 ± 25 7 ± 7 6.0 -4 + 2

η = number of animals

x ± s = mean with standard deviation

χ% s = percentage change to baseline with standard deviation

Table 4 Percent Change in Diastolic Peripheral Blood Pressure (Pd) in Beagle Dogs (n = 3) After i. v. Bolus application of compounds of the general formula I in comparison with amrinone

amrinone Compound I a Compound Ij x + s x ± s x ± s output values 86 ± 19 128 ± 25 113 + 26 (Torr) Dose (mg / kg) x% ± s ~ + ~) ± s x% + s 0.2 -i ± 2 0.5 -2 ± 15 0.6 -2 ± 6 1.0 -20 ± 7 1 ± 2 2.0 -12 ± 21 - 2 ± 11 3 + 2 5.0 -38 ± 21 1 ± 2 6.0 -9 + 1

η = number of animals

x ± s = mean with standard deviation

x% + s = Percentage change to the initial value with S'.ndard deviation

Claims (1)

Ί. Process for the preparation of 1,2,4-triazolo [1,5-a] pyridine-8-carbonitriles of general formula I, in the R and R ^{1 are} identical or different hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or RR ¹ together a tri-, tetra-, penta-, hexa- or decamethylene bridge or a benzo-fused alkenylene bridge and R ² carbalkoxy, cyanomethyl or trifluoromethyl, characterized in that a 2-imino-2H-pyridin-1-amine of the general 3n formula II