Imidazo[4,5-b]pyridine Derivatives 121

Imidazo[4,5=b]pyridine Derivatives of Potential Tuberculostatic Activity Part 1: Synthesis and Quantitative Structure-Activity Relationships

Ludwik Bukowski and Roman Kaliszan

Department of Organic Chemistry and Department of Biopharmaceutics and Pharmacodynamics, Medical Academy, 80-41 6 Gdahrk. Poland

Received December 22,1989

New derivatives of imidazo[4,5-b]pyridine and 9Hdipyrido-[l,2-~:3’,2’- djimidazole were synthesized. Antibacterial activity against Mycobucterium tuberculosis of selected compounds was detennined. These data were com- bined with the corresponding bioactivity data previously generated for two other series of imidazo[4,5-b]pyridines. Analysis of Quantitative Structure- Activity Relationships [QSAR] was carried out using nonempirical structural descriptors. Hydrophobicity of the agents studied was found decisive for their activity. A QSAR equation was derived allowing rational design of active derivatives.

Imldam[4,5-b]pyridin-Derjvate mit miiglicherweise tuberkulostatischer Wirkung. - Teil 1: Synthese und quantitative Struktur-Wirkung-Baie- hung

Neue lmidazo[4,5-b]pyridine und 9H-Dipyrido[ 1.2-u:3’,2’-~imidazole wur- den hergestellt und die antibakterielle Wirkung ausgesuchter Verbindungen gegen Mycobacteriwn ruberculosis wurde bestimmt. Die entspr. Daten wur- den mit Bioaktiviatsdaten in Beziehung gesetzt, die bereits ftir zwei andere Reihen von Imidazo[4,5-b]pyridinen ermittelt wurden. Eine Quantitative Struktur-Aktivi~~-Relation (QSAR) wurde unter Venvendung nicht-empiri- scher Strukturmerkmale errechnet. Die hydrophoben Eigenschaften der un- tersuchten Strukturen enviesen sich als entscheidend fur ihre Wirkung. Eine QSARGIeichung wurde abgeleitet. die eine rationelle Entwicklung aktiver Verbindungen erlaubt.

Among the derivatives of 2-~yanomethylimidazo[4,5- blpyridine several agents of marked activity against Myco- bacterium tuberculosis were found’*2). Thus, it seemed in- teresting to enlarge the series of structures in order to study quantitative relationships between chemical structure and antibacterial activity of imidazo[4,5-b]pyridines. Having representative sets of 2-cyanomethylimidazo[4,5-b]pyridine derivatives and l-methyl-lH-2-cyanomethylimidazo[4,5- blpyridine derivatives‘3) we completed the series by synthe- sizing new 3-methyl-3H-2-cyanomethylimidazo[4,5-b]py- ridine derivatives.

QSAR studies of tuberculostatic agents were started by Seydel et a1.3). These authors related antibacterial activity against Mycobacterium tuberculosis in a series of isonice tinic acid hydrazide derivatives to their chromatographic data and pKa values. A similar situation has been observed in the case of the in vitro tuberculostatic activity of pyrazine carbothioamide derivatives4) and 2-cyanomethylbenzimida- zole derivatives’). Here, too, thin-layer chromatographic data from the liquid parafftdwater system gave satisfactory correlation with bioactivity when used together with spec- troscopic data related to polarity and thus to the ionization ability of individual derivatives. Also Weisser et ~ 1 . 6 ; ~ ) in their studies of thiobenzamide derivatives obtained QSAR equations using chromatographic and spectroscopic parame- ters for structure characterization.

The above mentioned QSAR studies have a common fea- ture in that the description of antibacterial activity is per- formed in terms of empirical structural parameters. The QSAR equations allowing rational design of active struc- tures should contain nonempirical structural descriptors, i.e.

the parameters which can be determined basing exclusively on the structural formulas of the agents. In this work we attempted to derive QSAR employing nonempirical structu- ral descriptors having in mind a rationally guided synthesis of potential tuberculostatic agents.

Synthesis

The starting material for our syntheses was 3-methyl-3H- 2-cyanomethylimidazo[4,5-b]pyridine (1). The compound was obtained by reaction of 3-amino-2-methylaminopy- ridine with ethyl cyanoacetate.

With compound 1 reactions of the CN group and of the methylene moiety were camed out. Taking advantage of applied methods’*2) compounds 3-21 were prepared [Scheme 11. Antibacterial activity against Mycobucterium tuberculosis of the majority of the synthesized derivatives was determined.

It was found2) that 1 -methyl-1H-2-cyanomethyl-imidazo [4,5-b]pyridine easily reacts with ethyl cyanoacetate for- ming derivatives of SH-dipyrido[ I ,2a:3’ ,2’-d]imidazole. Here, the reaction of 1 with ethylcyanoacetate led for the first time to the isomeric system of gH-dipyrido[ 1,2-a:3’,2’- dlimidazole 22 [Scheme 21. Of the two possible structures of this compound the more likely seems to be 22a. Forma- tion of 22a may be explained by the reaction of cyano- ketene [formed from ethyl cyanoacetate]’) with the 1.3- dinucleophilic center of compound 1.

Derivatives of 9H-dipyrido[ 1,2-a:3’,2’-~imidazole were also obtained by a reaction of 1 with ethyl a-cyanopropion- ate 23 and with diethyl malonate 24.

Arch. Pharni. (Weinheim) 324.121-127 (1991) OVCH Verlagsgesellschaft mhH. D-6940 Weinheim. 1991 fl365-6233/91/0202-0121 $3.50 + .2Sm

122 Bukowski and Kaliszan

20

CH3 4-10

Scheme 1

Comp R

4 -CONH2

5 -CSNH2 6

7

B

9

10

As compounds 22 and 23 are formed in a reaction of two nitrile-type substrates the question arises which CN group does not take part in the reaction. The answer seems to be provided by mass spectra of 22 and 23 in which the frag- ment ion at m/z = 170 [C9HbN4] is present. The precise mass of this ion is 170.05918, calculated value = 170.05920. This means that the CN group in compounds 22 and 23 originates from 3-methyl-3H-2-cyanomethylimidazo[4,5-b]pyridine 1.

Physical characteristics and tuberculostalic activity of the compounds under consideration: Tab. 1.

Structural Analysis

Along with the newly synthetized 3-methyl-3H-2-cyano- methylimidazo[4,5-b]pyridine derivatives (Scheme 1 ) in QSAR studies were included the reported'*2) derivatives of

Comp R'

11, 15 -phony1

12, 16 -3.4-dimethoxyphenyl 13, 17 14, 18

-4- hydroxy - 3- methoxyphenyl

-4-diethylaminophenyl

2-cyanomethylimidazo[4,5-b]pyridine and l-methyl-lH-2- cyanomethylimidazo[4,5-b]pyridine. Structures belonging to the two later groups are presented in Fig. 1. Altogether a total number of 29 structures was considered.

Of several nonempirical structural parameters determined, the meaningful for bioactivity description appeared hydro- phobicity parameter, Xf, as calculated by the fragmental method of';Hansch and Leo'). The method of calculation of & is illustrated in Fig. 2 and the corresponding numerical data are compiled in Tab. 2.

Another nonempirical structural descriptor, which was found significant for the antibacterial activity description, was an indicator variable Q. This variable was assigned value 1 in the case of derivatives possessing a methyl sub- stituent at the imidazole-N. Otherwise, the variable was equal zero.

Arch. Phorm. (Weinheini) 324. 121-127 (1991)

Imidazo[4,5-h]pyridine Derivatives

Scheme 2

J L a 22 b

I

CH,-$H-COOR

1 + i AH3 cN

I 23

24

Antibacterial Activity

Minimum concentrations [MIC, yg/ml] of the compounds, inhibiting growth of a standard strain H37Rv of Mycobacte- rium tuberculosis, were determined in the Institute of Tuberculosis in Warsaw as described"! Determinations were performed in Youmans fluid medium containing 10% of bovine serum. The MIC is the minimum concentration of the series: 2000, 10o0, 500, 250, 125, 62.5, 31.2, 15.6, and 7.8 pg/ml, at which the growth of bacteries is completely inhibited. For QSAR analysis the value log l/MIC was taken. For respective numerical data cf. Tab. 2.

In QSAR studies the activity against the strain H37Rv was considered. It should be mentioned that MIC data deter- mined for a limited set of derivatives against the ethambu- tol-, ethionamide-, isonicotinhydrazide- and rifampicin-re- sistant strains of Mycobacterium tuberculosis are closely parallel to the H37Rv data.

QSAR Analysis

The "best" QSAR equation formed, which describes anti- bacterial activity in vitro against Mycobacrerium tubercu- losis, H37Rv has the following form:

0.2609/ M. 1926/ B n = 29; s = 0.2335; R2 = 0.8780; p <

Where g is the number of compounds used to derive the regression equation; s is standard deviation from regression; & is multiple correlation coefficient; and p is significance level. The numbers in parenthesis denote 95% confidence limits.

The parameter Ef reflecting hydrophobicity of the agents studied is significant in Eqn. 1 at the p c l o 9 significance

log l/MIC = -0.7671/ M.2229/ +0.2985/ M.0465/ Zf -

123

level. The indicator variable Q is also a significant structu- ral descriptor - its significance level in Eqn. 1 is p = 0.005. Both two structural variables used here are nearly completely orthogonal as their intercomelation is only R = 0.0257. Thus, the parameters Cf and D may be used together in a multi-parameter regression equation.

The prevailing importance of hydrophobicity for the anti- bacterial activity of imidazo[4,5-b]pyridine derivatives may be illustrated by the high correlation coefficient [& = 0.91661 of the one-parameter regression equation log l/MIC versus Cf. An analogous relationship log l/MIC against Q is characterized by the correlation coefficient as low as R = 0.1709. Nevertheless, an introduction of the D parameter in Eqn. 1 is statistically justified.

Fig. 1: Derivatives of 2-cyanomethylimidazo [4.5-h1 pyridine (35-43) and I-methyl-I-H-2-cyanomethylimidazo [4,5-b] pyridine (25-34) considered in QSAR studies.

WJ I

25-34 ti

35-43

Cornp. No

25. 35

26, 36

27, 37

38

28

29

30

31, 39

32, 40

33

34. 41

42

43

-CHz-CSNH,

-CH2-C(NOH)NH2

-CH,CONHNHz

-CHz-CONHN=CH

,XHS

-CHz-CONHN=CH *CHI

-CHz-CO-NHNmCH

-cH2-coNHN-cH -JJJ

-C(CSNH+CH -&CHI

-C(CSNH)-CH

-C(CSNH2)4X

-C(CSNH~)-CH -Q

Arch. Pharni. (Wrinhrini) 324. 121-127 (1991)

124 Bukowski and Kaliszan

Fig. 2: Example calculations of hydrophobicity parameter 4. Methyl3-methyI-3H-2-iniidazo[4J-b]pyridineacetate (3)

3f& + 3e . + 2Pi& + %<.. + fCH8 + 2f, + f.s. + - - - 3/0.35/+ 3/0.44/+ 21-1.1: + I-0.56f + D89f + 210.20/ + I-0.79f + + fNHa 4- f m + 2F/4 + 5fb + fc6& + 2% + 2fm3 + 1-1.541 + /Ob43/ + 21-0.55/+ 5/-0.121 + /1.44/ + 21-0.611 + 2jQ.89/+ i 2fWH3/ = c f + 2/-0.121 = -0.98

Where: ar - aromatic; underlined - fused in aromatic ring; F/J - unsaturated; b - single bond in chain; C6H3 - trisubstituted phenyl.

Analysing Eqn. 1 one can conclude that an increasing hy- drophobicity of the agents studied leads to their increasing in v i m antibacterial activity (lower MIC). Such an observa- tion can be rationalized in terms of affinity of the com- pounds towards the highly lipophilic bacterial cell wall.

Interesting is the effect of substitution in the imidazole ring of the agents on bioactivity. The presence or absence of the methyl substituent in the system studied is reflected by the parameter D.

Negative sign at the 12 coefficient in Eqn. 1 means that methyl substitution in the heterocyclic system decreases antibacterial activity as compared to unsubstituted analogs. On the other hand, it should be noted here that the methyl substituent provides a positive input to hydrophobicity and thus to bioactivity. It may be concluded then that the steric and/or electronic effects caused by methyl substitution op- pose the effects resulting from increasing lipophilicity.

The molecular descriptors in Eqn 1. are easily determined from simple structural formulas of the agents. Thus, new congeners can be designed and their predicted activity cal- culated. Certainly, hydrophobicity of imidazo[4,5-b]py- ridine derivatives cannot be increased indefinitely. Taking in mind preparative problems and solubility limitations the most reasonable compromise should be synthesis of agents of hydrophobicity ranging from 0.5 to 1 .O units of &.

Experimental Part

Mp. (uncorrected): Boetius apparatus - IR spectra: Specord 75 spectro- photometer, KBr pellets. - 'H-NMR spectra: 80 MHz Tesla 478, HMDSO as ext. standard. - MS spectra: LKS 9000 S apparatus. - Elementary ana- lyses: Department of Physical Chemistry, Medical Academy, Gdafsk

3-Methyl-3H-2-cyanomethylimidazo[4S-h]pyridine (1)

3-Amino-2-methylaminopyridine (0.02 mol) and ethyl cyanoacetate (0.03 rnol) were heated at 180-185'C with stirring for 20 min. The precipi- tate obtained after cooling was washed with ether and recrystallized. IR (cm-I): 2260 (C=N). 'H-NMR (CDC13) 6 (ppm) = 3.78 (s, 3H), 4.00 (s. 2H), 7.03-7.25 (m, IH), 7.88-8.00 (d, J = 6 Hz, IH), 8.27-8.37 (d, J = 4 Hz, IH). - MS [70eV, m/z (%)I: 172 (100, M"), 171 (25). 132 (29). 105 (lo), 104 (14). 79 (20). 78 (15),64 (12). 52 (1 I) , 51 (1 1).

A solution of nitrile 1 (0.01 mol) in 50 ml of CH3OH was saturated with dry HCl at room temp. for 6 h. Then, the mixture was cooled in ice-water, made alkaline with NaHC03 solution and extracted with CHCi3. The chlo- roform layer was dried (MgS04) and after evaporation of the solvent the residue was recrystallized. IR (cm-I): 1710 (C=O), 1210 (C-0-C).

When the reaction was carried out under reflux instead of ester 3.2.3-di- methylimidazo[4,5-b]pyridine 2 was isolated. Mp. (from benzene 112- 114'C) was in accord with lit. ' I ) . 'H-NMR (CDC13) 6 (ppm) = 2.5 (s, 3H), 3.7 (s, 3H), 7.07-7.25 (m, IH), 7.87-8.00 (d, J = 8 Hz. IH), 8.28-8.37 (d, J = 6Hz. 1H).

3-MethyI-3H-2-iniidaio[4~-h]pyridineacetaniide (4)

Method a: Ester 3 (1 g, 0.006 mol) was mixed with CH3OH saturated with NH3 at O'C (15 ml) and left overnight. The precipitated solid was filtered off and recrystallized.

Method b: The solution of 1 (0.5 g, 0.003 mol) in 7 ml of conc. H2S04 was left at room temp. for 24 h. Then the mixture was poured into a sniall amount of ice and made alkaline with conc. NH40H. The precipitated solid was filtered off and recrystallized. - IR (cm-I): 1680; 1640 (CONH2).

3-Methyl-3 H -2- imidozo[4.5-h]pyridineacetamide mime (6) To a solution of nitrile 1 (0.003 mol) in CH30H (5 ml) a freshly prepared

aqueous solution of NH20H.HCI (0.003 mol) and Na2C03 (0.003 mol) was added and the mixture was refluxed for 20 min. After cooling, the precipi- tate was filtered off and recrystallized. IR (cm-'): 1670 (C=N).

3-Methyl-3H-2-imidazo[45-h]pyridineaceticacidhydra~ide (7)

A solution of ester 3 (0.005 mol) in CH30H (10 ml) was refluxed for a few min with a small excess of 100% hydrazine hydrate. After cooling the solid product was filtered off and purified by recrystallization. - IR (cm-I): 3300,3190 (NH2); 1620 ( C S ) .

3-Methyl-3H-2-imidazo[4,5-b~pyridineacetic acid hydrazide hydrazones 8-10

Equimolar amounts of hydrazide 7 and veratraldehyde. vaniline or 2-fu- ralaldehyde were refluxed for 10-20 min respectively in CzHsOH. The solid was filtered off and recrystallized.

3-Methyl-3H-2(a-cyano-~-arylvinyl)imidazo[4,S-b]pyridines 11-14

To 0.01 mol of nitrile 1 in absol. CzH50H (20 ml) 0.01 mol of the appropriate aldehyde and several drops of piperidine were added. The mix- ture was refluxed for 1-2 h. After cooling the precipitated solid was filtered off and recrystallized. IR spectra of 11-14 show the C=N group in the 2200 cm-' region.

3-Methyl-3H-2-(3-iniinocoumaritiyl)imidazo[4J-b]pyridi1~e (19); 3-Methyl-3H-2-[3-(2-aminochinolyl)~imi~zo[45-h]pyridine (21)

19 and 20 were obtained from 1 and salicylaldehyde 19 or 2-aminoben- zaldehyde (211 as described for comp. 11-14. 19 IR (cm-'): 3210; 3060 2940; 1650 1590 1210 990 900: 740. - MS

[70 eV, m/z (%)I: 277 (15). 276 (M". 64), 275 (29). 260 (21). 259 (100). 248 (6). 133 (8). 78 (7). 39 (6). 21: IR (cm"): 3450 3300; 3150: 3060,2910 1605: 1480 1290 720. -

MS [70 eV, m/z (%)I: 276 (20). 275 (M+', 100). 274 (77). 259 (19). 247 (10),246(11), 138(10),79(5),78(5).

3-Methyl-3H-2-(3-coumari1~yl)imida:~[4J-h]p?;ridine (20)

To a mixture of 5 ml DMFIHzO (1: 1) 0.3 g (0.001 mol) of comp. 19 was added and refluxed for 2 h. The precipitate obtained after cooling was

Arrh. Pharm. (Weinheim) 324. 121-127 (1991 1

Imidazo[4,5-b]pyridine Derivatives

Table 1: Physical data and tuberculostatic activity of compounds 1-24

Comp. itip./OC/ Yield 1:ol.formula Analysis T u b e r c u l o s t a t i c a c t i v i t y i i I C pg/ml Eecryst. s 01. 7c hl .wt . calcd/found liycobacteriuru :

C 11 N 1f37nv 109x 193=

125

I

3

4

5

6

7

8

9

10

11

i2

13

14

15

16

17

18

19

20

2 1

22

23

24

146-148 B

95-97 C

218-220 1y

198-200 T7

221-223 Dh!F/\V

223-226 E t

205-237 imF/q

245-247 Dh?/i i

193-195 D W / W

214-216 D!@/\?

135-187 t t

138-190 iy

118- 1 2 0 DhP/%

186-188 I

190-192 T

188-190 v

186-188 TV

214-216 DW/ ?

DWP8 259-261

200-202 E t

312-314 DMF/W

356-350 ULF/ 4

344-347 DS.F/d

58

7 0

63

74

58

60

71

73

60

70

72

70

70

54

53

53

52

80

70

54

62

40

5 2

CgIigK4

172.2

10HilNJ02 205.2

9H10N40 190.2

CgBI0S4S

206.2

C9HllN50 205.2

cg911h'50

205.2

C18'f19N503 353.3

17H17N503 339.3

c14"13N502 283.2

C16xx12N4 260.3

18ii16N402 320.3

17H14N402 306.3

20i12 1'5 331.4

c161114K4s 294.3

C18H18N402S 354.3

171116N402S 340.3

C20H23N5S 365.4

c 161112~40

276.3

161iilN302 277.3

C16H13N5 275.3

c 2n9x5 o 239.2

C l 3 l I 1 ~ ~ 5 0

253.2

CI2iL$i4O2 243.2

62. 7? 62.46

58.53 58.76

56.53 56.67

52 .42 52.24

52.67 52.71

52.67 52.62

61.18 61.29

60.17 60.12

59.35 59.41

73.83 73.62

67.48 67.16

66.65 G6.48

72.48 72.51

65.29 65.16

61.61 61.64

59.99 59.84

65.73 65.77

69.55 69.41

69.30 69.08

69.80 69.60

60.24 59.93

Gl.66 6 1 . 5 L

60.00 5 9 . 8 3

4.68 4.55

5.40 5.35

5.30 5.45

4.99 4.87

5.40 5.36

5.40 5.31

5.42 5.32

5.05 4.86

4.63 4.58

4.65 4.60

5.03 5.12

4.61 4.36

6.39 6.28

4.80 4.70

5.12 4.85

4.74 4.86

6.34 6.17

4.38 4.32

4.00 3.91

4.76 4.53

3.79 3.66

4 . 3 9 4.16

3.36 3 . 24

32.54 32.6i

20.48

29.46

27.17

34.13

34.13

19.82

20.64

24.72

21.53

17.49

18.29

21.13

19.04

15.81

16.46

19.17

20.28

15.16

25.44

2s. 2 a 29.15

27.66 27.42.

23.33 23.06

31 16

500 500

250 250

250 250

500 125

500 250

31

3 1

16

31

16

16

8

16

62

500

250

300

250

250

62

62

62

62

Sovent: B - benzene. C - cyclohexane, Et - CzHsOH, DMF- dimethylformamide, W - H20. 'Bacterial strain isolated from patiens resistant against isonicotinhydrazide, ethambutol and rifampicine.

Bacterial strain isolated from patiens succeptible towards isonicotinhydrazide. ethambutol and rifampicine. xx

Arch. Pharm. (weitzheim) 324.121-127 (1991)

126

l o g l/hlIC

Obsd I C a l c d x'

Bukowski and Kaliszan

Table 2: Bioactivity and structural data for imidazo[4,5-b]pyridine derivatives

Hydrophobi - I n d i c a t o r c i t y v a r i a b l e

f D

Com- pound N O

5 6 7 8 9 10 I5 16 17 18 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

S t r u c t u r a l p a r a m e t e r s A c t i v i t y aga ins t Mycobacter iuru t u b e r c u l o s i s 11, ~ Rv

31.2 500 250 250 500 500

31.2 31.2 15.6 31.2 31.2

I000 250 500 500 250 31.2 15.6 15.6 15.6 125 250 250 250 7.8 15.6 31.2 31.2 31.2

-1.494 -2.699 -2.398 -2.398 -2.699 -2.699 -1.494 -1.494 -1.193 -1.494 -1.494 -3.000 -2.398 -2.699 -2.699 -2.398 -1.494 -1.193 -1.193 -1.193 -2.097 -2.398 -2.398 -2.398 -0.892 -1.193 -1.494 -1.494 -1.494

-1.601 -2.714 -2.586 -2.419 -2 -598 -2.523 -1.279 -1.320 -1.500 -1.371 -1.601 -2.714 -2.586 -2.419 -2.598 -2.523 -1.320 -1.500 -1.371 -1.279 -1.537 -2.651 -2.522 -2.313 -1.257 -1.436 -1.215 -1.361 -1.567

C a l c u l a t e d from Eqn.1

filtered off and recrystallized. - IR (cm-I): 2960 1710; 1290; 990. - MS [70 eV, m/z (%)I: 278 (22), 277 (M", 97), 276 (IOO), 249 (40), 248 (17). 220 (26),79(14),78(10),51 (11).

3-Merhyl-3H-2-imidazo[4.5-h]pyridineerhanethioamide (5); 3-Meth~l-3H-2-(cl-carbothioaniide-~-a~lvi1iyl)iniidazo[4,5-b]pyridines 15-18

To a solution of 1 or 11-14 (0.01 mol) in C2HsOH (1.14) or pyridine (11-13), N(CZH& (0.1 mol) was added and the mixture was saturated with H2S for 1-3 h and then left overnight. The precipitated solid was separated by filtration and purified by recrystallization.

7-Amin0-9-methyl-5-0,~0-9H-dipyrido[l.2-a:3' 2'-d]iniida:ole-R- carbonitrile (22)

7-Amino-6,9-dimethyl-5-0~0-9H-dipyrido[ I .2-a:3' 2' -d]iniida:ole& carbonitrile (23)

7-H~dro~-9-1~iethyl-5-~.~0-9H-dip?.rir[ I .2-a:3' 2' -d]iniidn:ole-R. carbonirrilc (24)

-1.92 -5.65 -5.22 -4.66 -5.26 -5.01 -0.84 -0.98 -1.58 -1.15 -1.92 -5.65 -5.22 -4.66 -5.26 -5.01 -0.98 -1.58 -1.15 -0.84 -2.58 -6.31 -5.88 -5.18 -1.64 -2.24 -1.50 -1.99 -2.68

1 1 1 1 1 I 1 1 I 1 I 1 1 1 1 1 1

1 1 I

0 0 0

0 0 0

0 0

0

0.002 mol of nitrile 1 and 0.01 mol of ethyl cyanoacetate. ethyl u-cyano- propionate or diethyl malonate were heated with stirring for 1-2 h at 180- 185'C. After cooling the solid was washed with CH3OH and purified by recrystallization.

2 2 IR (cm-l): 3360; 3080 2950 2200 (CGN): 1650 1520: 14S0 1395; 1290; 995. - 'H-NMR (TFA) 6 (ppm) = 4.23 (s, 3H). 6.51 (s, IH), 7.50- 7.66 (m, IH), 8.62-8.75 (m. 2H). - MS [70 eV, m/z (%)I: 240 (15). 239 (M", 57). 211 (10). 200 (13), 199 (IOO), 172 (10). 171 (20). 170 (8). 103 (11),79(12),78(12),28(17). 23 IR (cm-I): 3420 3150; 2930; 2200 (C=N): 1650 1530 1490: 1395;

910 760. - 'H-NMR (TFA) 6 (ppm) = 2.32 (s, 3H), 4.40 (s, 3H). 7.67-7.90 (m, IH), 8.85-9.02 (m. 2H). - MS [70 eV, mlz (lo)]: 254 (13). 253 (M'., 60). 224 (23). 199 (100). 172 (9), 171 (28). 170 (5). 149 (37). 103 (25). 91 (27). 78 (20).

2 4 IR (cm'l): 3300-2800.2200 (C=N): 1620: 1580 1520: 1W. 1210 990 800. - 'H-NMR (TFA) 6 (ppm) = 4.30 (s, 3H). 6.50 (s, IH). 7.69-7.87 (m, lH),8.52-8.60(d,J=6Hz, lH).9.38-9.47(d.J=7Hz. lH).-MS[70 eV. m/z (lo)]: 241 (14). 240 (M+'. 100). 212 (22). 21 I (12). 199 (47). 198 (73). 171 (26). 170(44), 143 (10). 103(22). 94(13).

Arch. Pharni. (WeinheiniJ 3-74. 121-127 (1991)

Imidazo[4,5-b]pyridine Derivatives

References

1

2 3

4

5

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[ Ph7741

Arch. Pharnr. (Weinheini) 324. 121-1-17 (1991)