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Pharmaceutical Chemistry Journal

Vol. 32, No. 6, 1998

1-AMINO-4-(5-ARYLOXAZOL-2-YL)-I,3-BUTADIENES: SYNTHESIS AND STUDY OF SPECTRAL AND PHARMACOLOGICAL PROPERTIES
D. A. Maiboroda, l E. V. Babaev, 2 and L. V. Goncharenko z

Translated from Khimiko-Farmatsevticheskii Zhumal, Vol. 32, No. 6, pp. 24- 28, June, 1998.
Original article submitted July 29, 1997.

Recently we have reported [1] that reaction with piperidine leads to opening of the pyridine ring in the 2-phenyloxazolo[3, 2-a]pyridinium (Ia) cation with the formation of 1(piperid- l-yl)-4-(5-pheuyloxazol-2-yl)- IE,3E-butadiene (IIa). It was also found that the p-nitrophenyl-substituted cation (Ib) may be converted, depending on the reaction conditions, into bothlE,3E (lib) and 1E,3Z (IIib) stereomers [2]. The formation ofdienes of the latter type is rather unusual for reactions involving secondary amines. Indeed, a related system of bridged azolopyridinium compounds [3, 4] features only the IE,3E isomers; the IE,3Z configuration can be obtained only using alkaline amine salts. The purpose of this work was to study the possibility of synthesizing the 1E,3Z stereomers of 1-amino-4-(azol-2yl)butadienes (III- V), using reactions of cations Ib - If with free secondary amines, and to investigate the spectral and pharmacological properties of the synthesized compounds. Experiments showed that the treatment of salts Ib-If (Table 1) with cyclic secondary amines leads to compounds representing (by the data of mass spectrometry and elemental analysis) 1 : 1 adducts between the initial heterocyclic system and the secondary amines. Their IR spectra (Table 2) exhibit absorption bands in the region of 1630- 1620 cm-t characteristic of the conjugated dienes, while the 13C NMR spectra
I Moscow State University, Moscow, Russia. 2 All-Russia Scientific Center for Safety Testing of Biologically Active Substances, Ministry of Health of the Russian Federation, Staraya Kupavna, Moscow Region, Russia.

(Table 3) are missing the signals of tertiary and quaternary aliphatic carbon atoms.

'

rl
lla, llb, lie, lif

(Y)
R
-

N "

ClO 4 Ia-lf

X

N

a:X=O,R=H;
b: X = O, R = 4-NO2; c: X = O, R = 3-NO2; d: X = S, R = 4-NO2; e: X = NMe, R = 4-NO2; f.- X = O, R = Br. Y = CH 2 (II, III); CH2CH 2 (IV); O (V).

This evidence is sufficient to classify the synthesized compounds as products resulting from opening of the six-mere-

TABLE 1. Characteristics of Azolopyridinium Salts lc- le
Cornpound Ic ld le** M.p., °C 201-202 249-250 235 -236 IH NMR spectrum in CF3COOH: ~, ppm and J, Hz Yield, Empirical formula % (s,3-H) (d, 5-H) (dd,6-H) (dd, 7-I-I)(d, 8-H) 2-aryl 68 75 70 CI3H9CIN207 C13H9CIN206S CI4HI2CIN306 8.87 8.38 8.16 9.00 8.66 8.64 7.95* 7.36* 7.56 8.53* 7.69 8.08 8.23 7.91" 7.91 8.88, 8.51, 8.33, 7.90 7.90-7.82, 7.45-7.38 8.51 -8.45, 7.85-7.78

J56 6.4 6.6 7.0

J67 7.8 7.5 7.1

J78 9.0 9.1 9.3

.[ Overlap with the signal from 2-aryl substituent. 6(N-CH3) = 4.00 ppm.

310
0091 - 150X/98/3206-0310520.00 o 1999 Kluwer Academic/Plenum Publishers


1-Amino-d-(5-aryloxazol-2-yl)-l,3-butadienes: Synthesis And Study of Spectral Properties

311

TABLE 2. Characteristics of l-Amino-4-(5-arylazol-2-yl)butadienes Compound M.p., °C -" 179 - 180"" 160- 161"" 147- 148 193 - 194 120- 121 128 - 129 162 - 163 148- 150 Yield, % 67 88 81 96 62 68 81 47 70 Empirical formula, -" - "" -'* CI9H21N303 CI7HITN304 CIsH|9N303 CIsHI9N302S CI9H22N402 CIsHIgBrN20 Mass spectrum:

m/z (Irwin,%)

IR spectrum: Vc=0 cm - I (nujol mulls) 1628 1640, 1625 1622 1625 1623 1630 1625 1630 1628 268 259 259 260 259 277 270 258 240

UV spectrum (CHCI3): ~'max, nm (log e)

lla lib lIlb lVb Vb lIlc llld lie lIf

280 (34) 325 (62) 325 (63) 339 (63) 327 (40) 325 (47) 341 (24) 338 (17) 360/358 276/274

M +, 196 (100) M +, 241 (100), 195 (63) M+, 241 (I00), 195 (65) M +, 241 (100), 195 (39) M +, 241 (100), 195 (57) M +, 241 (100), 195 (23) M Â, 257 (100), 211 (40) M Â, 254 (100), 208 (38) (46/40) M +, (94/100), 195 (12)

(3.99), (3.80), (4.46), (4.00), (3.94), (4.23), (4.03), (3.96), (3.97),

281 287 287 350 335 400 360 352 287

(4.05), (3.80), (4.41), (4.35), (4.26), (4.37) (4.15), (4.25), (4.15),

382 350 346 475 439

(4.38) (4.32), 462 (4.36) (4.88), 464 (4.88) (4.33) (4.34)

483 (4.42) 454 (4.25) 391 (4.47)

" [1l. "" [2].

bered cycle of the initial cations with the formation of a butadiene system (lie, IIf, IIIc, IIId, IVb, and Vb). Previously we have demoustrated that the isomer formed at room temperature has a 1E,3Z configuration, while the same reaction at a higher temperature leads to the IE,3E isomer (configurations of the 1E,3E and 1E,3Z isomers IIb and IIIb were assigned on the basis of their NOESY spectra) [2]. The results of our quantum-chemical MNDO calculations [5] of the heats of formation of the isomeric butadienes IIb (AHr= 49.54 kcal/mole) and IIIb (AHf= 55.15 kcal/mole) showed evidence of a somewhat greater thermodynamic stability of the IE,3E stereomer lib. Therefore, we may expect that reactions proceeding under the kinetically controlled conditions will yield the 1E,3Zstereomers (similar to butadiene IIIb), whereas the process under more rigid conditions (thermodynamic control) would favor the formation of IE,3E isomers. Indeed, it was established that a short-term treatment of perchlorates Ib-Id with cyclic secondary amines at room temperature leads to the 1E,3Z stereomers IIIc, IIId, IVb, and Vb. The IH NMR spectra of these compounds (Table 4) in the region of signals from butadiene protons are virtually identical to the spectrum of established IE,3Zisomer mb and differ from the the spectrum of the IE,3Eisomer IIb (Table 5). It should be noted that the opening ofa pyridine fragment with 1E,3Zstereomer (IIId) formation under mild conditions was also observed for 2-(4-nitrophenyl)thiazolo[3,2-a]pyridinium (Id) (according to the published data, the products of room-temperature interactions between 3-(4-bromophenyl)thiazolo[3,2-apyridinium and secondary amines were assigned the structure of adducts with bridging 8a-carbon atom [3]). Replacement of the oxygen atom in compound Ib by the MeN group increases the stability of the system with respect to the cycle opening. Indeed, in contrast to the oxa and thia

TABLE3. Chemical Shifts (8, ppm) in the 13C NMR Spectra (CDCI3) of l-Amino-4-(5-arylazol-2-yl)- 1,3-butadienes

pound lla

Corn- CpC 3
(CH) 148.08, 139.35 148.41, · 140.78 146.88, 137.22 148.28, 139.75 150.14, 140.11 150.31, 140.22

C'2'C4 C5(C) C6(cH) C7' Cs'
(CH) 104.37, 98.01 103.01, 97.50 104.04, 98.47 104.03, 97.90 98.98, 96.77 98.07, 95.92 163.78 123.65

C-R(C) 149.19, 129.05, 127.84 146.64, 146.02, 134.29 136.97, 130.73, 126.33 148.17, 128.09, 121.25 146.13, 146.00, 134.32 146.08, 145.91, 134.40

(CH)

C~ I

.7..~'C I (,t~ti2) 49.79, 25.75, 24.58 49.59, 25.38, 24.07 49.44, 25.21, 24.12 49.93, 25.78, 24.58 49.70, 25.36, 24.06 54.04, 28.85, 27.50, 27.18 66.07, 50.37 49.72, 25.38, 24.11 49.78, 25.36, 24.05

124.65, 123.88 124.39 123.39 127.38, 124.13 132.28, 125.38 124.38, 123.37 124.39, 123.25

llb

165.26

127.38

lle*

151.55

130.08

llf

164.09

124.37

Illb

165.15

127.34

lVb

165.46

127.37

Vb

150.35, 140.10 149.86, 139.25

98.73, 96.82 99.51, 96.73

165.07

127.36

lllc

164.53

129.72

146.22, 146.03, 134.35 148.67, 146.11, 130.16 138.74, 138.60, 126.96

124.40, 123.38 128.76, 125.26, 121.55, l 17.87 125.96, 124.36

llld

150.33, 141:08

107.80, 96.86

146.03

137.59

* 8(N-CH3) = 31.43 ppm.


312

D.A. Maiboroda et al.

analogs, l-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridinium perchlorate (Ie) remained unchanged under the action of piperidine at room temperature. Treatment under more rigid conditions (boiling in acetonitrile) led to the formation of the 1E,3E isomer IIe. Thus, it is practically impossible to obtain a IE,3Z stereomer under kinetic control in this system. Previously we have demonstrated that a reaction of 2phenyloxazolo[3,2-a]pyridinium perchlorate (Ia) with piperidine at 20°C leads to the formation of only 1E,3E-butadiene isomer (IIa) [1]. A similar result was obtained upon opening of a salt of 2-(bromophenyl)oxazolo[3,2-apyridinium (If), whereby only the 1E,3E isomer IIf was isolated from the reaction mixture. The absence of the IE,3Z isomer among the products in these systems can be explained by certain features of the treatment of reaction mixtures. In both cases, the primary reaction products have the form of a viscous amorphous mass and require additional chromatographic purification, during which a transformation of the IE,3Z butadienes into thermodynamically more stable 1E,3E isomers is not excluded. In the crystalline state, the 1E,3Z-butadienes IIIc, IIId, IVb, and Vb are sufficiently stable with respect to the stereoizomerization process. At the same time, the 1E,3Zisomers in solution are slowly transformed into the IE,3E isomers. For example, the IH NMR spectrum of the initially pure IE,3Z isomer IIIb in CDCI3, measured after a l-day storage of the solution at room temperature, shows evidence of the appearante of IIb with the IIIb /IIb isomer ratio of approximately 3 : 1. Moreover, even an increase in the time of the reaction mixture stirring from 0.5 - 1 to 3 -4 h during the synthesis of compound IIIb results, according to the IH NMR spectrum,

in the formation of a significant amount of the IE,3E isomer lib. Butadienes IIb, IIIb, IIId, IIIe, IVb, and Vb, containing p-nitrophenyl substituents, have the form of almost absolutely black fine-crystalline powders, while their solutions in benzene and chloroform have a crimson-red color. The electronic absorption spectra (Table 2) contain two intense (log e > 4) absorption bands in the visible range ()~x = 330-350 and 440-480 nm). In contrast, butadiene IIa, IIf, and IIIc have an orange color and their spectra contain a single absorption band in the visible range at 380-400 nm. We may suggest that the second, longwave absorption band in the spectra of compounds containing p-nitrophenyl groups is due to the intmmolecular charge transfer:
O--

Oo

This substitution is apparently impossible for the isomeric m-nitrophenyl-substituted butadiene IIIc; accordingly, the corresponding absorption band is missing from the UV spectrum of this compound. An interesting feature is observed in the mass spectra of IIa, lib, IIe, IIf, IIIb-IIId, IVb, and Vb: each of these contains only three peaks with the relative intensity exceeding

TABLE 4. Chemical Shifts (8, ppm) in the IH NMR Spectra (CDCI3) of Compound llIb* IVb Vb lilt llld 6.65-6.40 m 6.78 (d, 1H), 6.60 - 6.30 (m, 2I-I) 6.71-6.46 m 6.64-6.38 m 6.63 (d, 1H), 6.51 - 6.32 (m, 2H) (3H, dien¢) (IH, diene) 5.70-5.57 m 5.52 d 5.80-5.70 m 5.70-5.57 m 6.00 d

l-Amino.4.(5-arylazol-2-yl)-lE,3Z-butadienes
(41-I, azolyl) 7.56 7.49 7.58 7.46 8.04 (4H, 2-aryl) 8.28-8.19, 7.75-7.66 8.30- 8.20, 7.76 - 7.66 8.30-8.15, 7.80-7.68 8.41, 8.05, 7.84, 7.51 8.28 - 8.15, 7.70- 7.57 1-diaikylamino 3.4 - 3.2 (4H), 1.7 - 1.5 (6I-0 3.5 - 3.3 (4H), 1.9- !.5 (8H) 3.8 - 3.6 (4H), 3.4 - 3.2 (41-I) 3.3-3.1 (4H), 1.7-1.5 (6H) 3.3 -3.1 (4H), !.7- 1.5 (6H)

* For IH NMR spectrum measured in C6D6 see [2].

TABLE 5. Chemical Shifts (~5,ppm) and Spin-Spin Coupling Constants (J, Hz) in the IH NMR Spectra (CDCI3) of l-Amino-4-(5-arylazol-2-yl)-lE,3E-butadienes
Com o

pound lla[l] lib* lle** Ilf

(d, I-H) (dd, 2-H) (dd, 3-H) (d, 4-H) (s, Hazolyl) 6.53 6.59 6.48 6.54 5.31 5.34 5.36 5.31 7.21 7.30 7.33 7.21 5.97 5.98 5.98 5.92 7.25 7.49 7.22 7.26

(Haryt) 7.64-7.59,7.41-7.35 8.30 - 8.20, 7.78 - 7.68 8.32 - 8.20, 7.57 - 7.45 7.54 - 7.46

J12 13.1 13.0 13.0 13.0

J23 11.2 11.5 11.4 11.3

J34 15.2 15.5 14.9 15.2

(Hdialkytamino) 3.2 -3.0 (4H), 1.7-1.5 (6H) 3.3 - 3.1 (4H), 1.7 - 1.5 (6H) 3.2 - 3.0 (4H), 1.7- 1.5 (6H) 3.2 - 3.0 (4H), 1.7 - 1.5 (6H)

* For IH NMR spectrum measured in C6D6 see [2]. ** ~5(N--CH3) = 3.61 ppm.


l-Amino-4-(5-aryloxazol-2-yl)-l,3-butadienes: Synthesis And Study of Spectral Properties

313

10% (M +, 20-60%; [M+-NR2], 100%; and [M+-NRz-R], 20- 60%; here, NR2 is the secondary amine fragment and R is the substituent in the benzene ring). The most intense peak corresponds to fragments formed upon splitting of the secondary amine fragment NR 2 from the initial molecule. We may suggest that these fragments represent a stable aromatic system, 2-arylazolo[3,2-apytidinium cation, which may account for the absence of intense peaks corresponding to further decomposition. A potential pharmacological activity of compounds IIb, IIIb - IIId, IVb, and Vb was estimated using a computer program PASS 4.2 (Prediction of Activity Spectrum for a Substance) [6], which is capable of predicting some types of activity of a given compound upon analysis of its structural formula. The prognosis is based on the structure-activity relationships established by analysis of the data for more than 10,000compounds forming the learning sample set. The PASS system either predicts the possible type of pharmacological activity or indicates a possible mechanism of the biological action. The activity prognosis has the form of a probability of the corresponding manifestations or their absence, since the learning sample set contains data on both definitely active and definitely inactive compounds. As an example, we will consider the prognosis for the spectrum of pharmacological activity of compound III (Table 6). The data are sufficiently representative for the entire seties, since the substances have very similar structures. An analysis of the prognosis suggests the possible antimicrobial activity of compounds of the series studied. The experimental investigation showed that compounds IIb, IIIbIIId, IVb, and Vb exhibited weak antibacterial activity with respect to both the Gram-positive and Gram-negative species. The minimum bacteriostatic concentration for the compounds studied is 100-200 lag/ml. The further search in the series of compounds with analogous structures will probably reveal more active agents. There is also a sufficiently high probability that the compounds studied have the properties of reversible inhibitors of the monoamine oxidase (MAO). However, this is accompanied with a relatively high probability of carcinogen and mutagen manifestations. This circumstance hinders using substances of the series studied as potential neurotropic agents. EXPERIMENTAL CHEMICAL PART The IR spectra were measured on an UR-20 spectrophotometer (Germany) using samples prepared as nujol mulls. The UV spectra were recorded with a Varian K325 instrument. The IH NMR spectra were measured on the Bruker M-400 and AC-200 spectrometers with TMS as the internal standard. The course of the reactions was monitored by TLC on Silufol UV-254 plates. The chromatographic separations were effected with the aid of Silpearl columns. The data of elemental analyses agree with the results of calculations according to the empirical formulas.

2-Aryloxazolo- and thiazolo[3,2-alpyridinium perchlorates (Ib-Id). To a solution of 0.106 mole of substituted phenacyl bromide in 100-150 ml acetonitrile was added 10 rnl (12.03 g, 0.106 mole) of 2-chloropyridine and the mixture was boiled for 18- 22 h. The precipitated crystals were filtered and washed with acetonitrile (2 x (1 - 2) ml) to obtain: (a) 2-chloro-l-(4-nitrophenacyl)pyridinium bromide; yield, 54%; m.p., 202- 203°C (decomp.); Ct3HIoBrCIN203; (b) 2-¢hloro-l-(3-nitrophenacyl)pyridinium bromide; yield, 51%; m.p., 191- 192°C (decomp.); CI3HIoBrCIN203. To 2-chloro-l-phenacylpyridinium salt (2 g) dissolved at 60-70°C in 20-30 ml of the EtOH-H20 mixture (1: 1) was added with stirring 20 ml of a saturated aqueous NaHCO3 solution. The mixture was kept at this temperature for 5 - 10 min and allowed to cool The precipitate was filtered to obtain (a) 1-(4-nitrophenacyl}-2-pyridone; yield, 80%; m.p., 234 - 235°C (reported m.p., 236 - 238°C [7]); IR spectrum (Vc=o, cm-I): 1711, 1665; Ct3HIoN204; Co) 1-(3nitrophenaeyl)-2-pyridone; yield, 92%; m.p., 167-168°C; IR spectrum (Vc=o, cm- 1): 171 I, 1667; Ct3Hl0N204. To 2-ehloro-1-(4-nitrophenacyl)pyridinium salt (2 g) dissolved at 40-50°C in 15 ml of the EtOH-H20 mixture (1 : 1) was added dropwise with stirring 2 ml of a 20% aqueous Na2S solution until precipitation ceases (in excess of the latter reagent, the precipitate partly dissolves and the solution acquires a dark-red color). The mixture was kept at this tem-

TABLE 6. Spectrum of Pharmacological Activity Predicted for Compound

IIIb by PASS 4.2 Program Activity type Antimicrobial Carcinogenic Reversible MAO inhibitor Antihelminthic Antifungal Antihypoxic Dopaminergic receptor stimulator Antitrichomonacidal Mutagenic Antituberculous Myorelaxant MAO inhibitor Antiallergic H2-histamine receptor blocking Antiviral Antiprotozoal Reversible acetylcholinesterase inhibitor Antispirochetal Antiparkinsonic Immunomodulator Antiandronogenic Probability, % active 78 75 71 63 60 52 41 35 40 36 36 30 30 21 34 24 27 23 32 31 24 inactive 1 5 3 4 3 14 9 5 12 13 15 17 17 9 23 13 17 14 27 26 23


314

D.A. Maiboroda et ai.

perature for 5 - 10 min and allowed to cool. The precipitate was filtered to obtain 1-(4-nitrophenaeyl)-2-thiopyridone; yield, 74%; m.p., 194- 195°C; IR spectrum (Vc=o, cm- i): 1719; CI3HIoNzO3S. N-substituted pyridone or thiopyfidone (1 g) was carefully dissolved in 2 ml of concentrated H2SO4 and the solution was allowed to stand overnight. Then was added 50100 ml of water and the mixture was heated to 60-80°C and, if necessary, filtered hot. To the filtrate was added 5 ml of 70% HCIO4. The resulting precipitate was recrystallized from the EtOH - H20 mixture (1 : 1) to obtain perchlorates Ib -Id. Characteristics of salts Ic and Id, perchlorate Ib were described previously [2].

EXPERIMENTAL BIOLOGICAL PART The bacteriostatic activity of compounds lib, IIIb- IIId, IVb, and Vb was studied at the Laboratory of Antibacterial Preparations (All-Russia Scientific Center for Safety Testing of Biologically Active Substances) by the method of double serial dilutions in a liquid nutrient medium (meat-infusion broth). The test cultures were Gram-positive St. aureus ATCC 6538 and Gram-negative E. coli ATCC 25922 species at a concentration of 2.5 x 105 cells/ml. ACKNOWLEDGMENTS one of the authors (E. V. B.) gratefully acknowledges the support from the Russian Foundation for Basic Research (project No. 96-03-32935), the Center for Fundamental Natural Sciences (project No. 95-0.9.4-222), and the Volkswagen- Stiftung foundation. REFERENCES 1. E. V. Babaev, K. Yu. Pasichnichenko, and D. A. Maiboroda, Khim. GeterotsiM. Soedin., No. 3, 397-402 (1997). 2. E. V. Babaev, A. V. EfLmOV,D. A. Maiboroda, and IC Jug, LiebigsAnnalen (Eur. J. Org. Chem.), No. 1, 193 - 196 (1998). 3. G. Hajos and A. Messmer, J. Heterocy¢l. Chem., 21, 809-811 (1984). 4. A. Messmer, G. Hajos, and G. Timari, Tetrahedron, 48, 8451 8458 (1992). 5. M. J. S. Dewar and W. Thiel, J. Am. Chem. Soc., 99, 48994907 (1977). 6. D. A. Filimonov and V. V. Poroikov, Bioactive Compounds Design: Possibilities for Industrial Use, BIOS Scientific Publishers Ltd., Oxford (1996), pp. 47- 56. 7. U. M. Teotino, L. Polo-Friz, A. Gandini, and D. D. Bella, Farmaco Ed. Sci., 17, 988-999 (1962); Chem. Abstr., 64, 9676h (1966). 8. E. S. Hand and W. W. Paudler, Tetrahedron, 38, 49- 55 (1982). 9. C. K. Bradsher and M. F. Zinn, J. Heterocycl. Chem., 4, 66 - 70 (1967). 10. E. V. Babaev, A. V. Efimov, and D. A. Maiboroda, Khim. Geterotsikl. Soedin.,No. 8, 1104- 1111 (1995).

1-Methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridinium perehlorate (le). To 2g (8.37mmole) of 2-(4-nitrophenyl)imidazo[1,2-a]pyridine [8] was added 8ml (84 re_mole) of freshly distilled dimethylsulfate and the mixture was heated for 2 - 3 h on a water bath. The resulting homogeneous mixture was cooled and shaken with 50 ml ether and the ether solution was decanted. To the residue was added I00 ml water, and the mixture was heated to 80°C and filtered hot. To the filtrate was added 10 ml of 70% HCIO4, and the precipitate was re,crystallized from the EtOH-1-120 mixture (1 : 1) to obtain perchlorates Ie (Table 1). Perehlorate If was obtained as described in [9, 10]. Butadienes IIf, IIIb- Hid, IVb, and Vb (Table 2). To 0.2 g of the corresponding 2-arylazolopyridinium perchlorate was added 1 ml piperidine, hexamethyleneimine, or morpholine and the mixture was stirred for 0.5 - 1 h at room temperature. Then was added 50- 100 ml water. The precipitate was filtered, washed with water, and dried in air. Compound IIf was additionally purified by chromatography on a short column filled with silica gel and eluted with ether. Butadienes IIb and lie (Table 2). To a solution of 0.2 g of the corresponding 2-arylazolopyridinium perchlorate in 5 - 10 ml acetonitrile was added 0.5 ml amine and the mixture was boiled with reflux for 2 - 3 h and cooled. Then was added 50-100ml water. The precipitate was filtered, washed several times with water, and dried in air.