Indian Journal of Chemistry Vol. 43B, June 2004, pp. 1314- 1319

Synthesis and antimicrobial activity of new polyfunctionally substituted pyridines and their fused derivatives

Abdel-Zaher A Elassar

Chemistry Department , Faculty of Science, Helwan University, Ain Helwan, Cairo, Egypt E··mail : aelassar@yahoo.com

Received 26 February 2003; accepted (revised) 22 December 2003

Ethyl pyruvate (EP) on reacting with malononitrile or isothiocyanates gives the pyridine derivati ves 5 and 9a , b , respecti vely. Chalcone deri vati ve of EP reacts with malononitrile to yield the pyran derivative which in turn IS transformed into pyridine derivative 14. Reactivity of 5 and 9a towards di fferent organic reagents has been investigated . Antimicrobial activity of some newly synthesized pyridines is also reported.

IPC: Int.CI,7 211/00, 213/00, A 61 P 31104, 31110

The observed anti-HIV activity of pyridine compounds or their fused derivatives recently stimul ated extensive interest in the synthesis and chemi stry of these compounds. 1-4 Moreover, polyfunctionall y substituted pyridines are important because of their optical properties 5,6 and biological acti vity,7 which depends mainly on the nature and position of the substituents. These include anti­convul sant activity,8 antihi staminic agents,9 and cardiovascular di sorder treatment. 10, II An enormous number of preparation approaches proposed for poly­functi onally substituted pyridines have al so been reported. 12·18 Despite thi s, to the best of our knowledge, the reacti vity of EP in such reactions has never been investigated . As a part of our biological chemi stry program, samples of polysubstituted pyridines were required and thus the reactivity of EP towards di fferent organic reagents was inves tigated . The obtained pyridines were used as starting materi als for the synthesis of condensed and substituted pyridine systems.

Results and Discussion Ethyl pyruvate 1 reacted with malononitrile e ither

in basic or ac idic medium to give pyridine derivati ve 5 or ylidene deri vati ve 3. The latter compound was ru led out based on the mass spec tra, which shows ml z 328 (67%, M+) and agrees with the molecular formul a C16H16N40 4. In additi on to 'H NMR spectra which show a singlet at 8 8.2 1 ppm fo r pyridine-H. 13C NMR spectra show the pyrid ine carbons, two ester carbonyl groups, two cyano groups, e thyle nic

carbons, methylene and methyl groups at expected positions (ej Experimental). Further, the geometrical shape of compound 5, (2Z)-structure , was establi shed based on the NOE difference measurements which reveal the presence of methyl group and pyridine-H in one direction. Furthermore, IR spectrum shows amino, cyano and carbonyl groups at 3459, 33 12, 2217, 2220 and 1738, 1722 cm· l

, respective ly. The reaction product 5 was be lieved to be formed by reacting 1 with malononitrile to give the non-i solated ylidene deri vati ve 3 . The latter was d imeri zed under reaction conditions through the addi tion of acti ve methyl group in the compound 3 to the cyano group in another molecule to give the intermedi ate 4 . Intermediate 4 readily cycli zed via addi tion of amino group to cyano group giving the final iso lated product 5 (ej Scheme I).

Acti ve methyl group in compound 1 reacts readil y with phenyl isothiocyanate or benzoyl isothiocyanate fo llowed by treating with malononitrile in situ under basic conditions to give the aminopyridines 9a, b . The structure of the reacti on product was be li eved to be fo rmed via addi tion of methyl group to the isothiocyanate functi on affording the intermedi ate 6. Malononitril e was condensed, in situ, with the intermedi ate 6 to afford ylidene deri vati ve 7 , whi ch was cycli zed to 8 . Under reaction conditi ons the non iso lated intermedi ate 8 was rearranged to give the final isolated aminopyridine deri vati ves 9a,b . A lkylation of amino group in compound 9 seemed to be necessary, thi s may be due to the observed biologica l acti vity for N,N-dimethylamino group.

ELASSAR el al.: SYNTHESIS OF POL YFUNCTIONALLY SUBSTITUTED PYRIDINES 1315

Scheme I

NC CN

II ------l.~ I II ~ I 10 RNCS RNH 0 R:rJ(H

M~C02El S~C02El S C02El

1 6a: R=Ph 7

b: R=COPh

9c: R=Ph 9a: R=Ph 8 b: R=COPh

Scheme II

Thus, 9a reacted readily with methyl iodide in the presence of potassium carbonate to give N,N­dimethylaminopyridine derivative 9c (ef Scheme II). The structure of 9a, b was established based on elemental and spectral data. IR spectra of compound 9a reveals the presence of amino, cyano and carbonyl groups at 3440,3310, 2216 and 1739 cm- I. While that of 9c shows only cyano and carbonyl groups at 2220 and 1737 cm· l

. In addition to IH NMR, which shows the pyridinic proton at -8.3 1 ppm and other protons at expected positions .

Hi gh reactivity of methyl group in compound 1 prompted LI S to block via condensation with aromatic aldehyde. Thus, compound 1 readily reacted with /11-

nitrobcnzaldehyde in basic medium to give the chalcone derivative 10, which agrees (mp and spectra) with that reported from the ring openning of oxazine derivatives .19 Malononitrile reacted with 10 in ethanolic piperidene to give the 4-H pyran derivative 13 or ylidene derivative 15. Compound 15 was ruled

out based on the elemental analysis and spectral data . Compound 13 was believed to be formed via addition of active methylene in malononitrile to the double bond in compound 10 to give the non-isolated intermediates 11 . The enolic form 12 cyclized to give the final isolated product, 4H-pyran derivative 13. Transformation of 13 to the target ring system, pyridine 14 took place by heating in a mixture of acetic acid/ammonium acetate mixture in a si milar manner to that reported earlier 18,20·22 (ef Scheme III).

Reactivity of the prepared pyridines is investigated towards nucleophilic reagents to prepare hetero­aromatic substituted and fused pyridines. Thus, pyridine derivative 5 reacted with hydrazine hydrate and aromatic amines 17a, b to give 18 and 20 a,b, respectively. The reaction mechanism was believed to proceed via elimination of ethanol to give the intermediates 16 and 19, followed by cyclization under reaction conditions to give the isolated products 18 and 20a, b, respectively. The reaction products 18 and 20a, b were established based on 13C NMR spectra which reveal the absence of the ethylenic carbons in compound 5 and the appearance of the pyridazine and pyrrole carbons, respective ly at expected positions (ef Scheme IV).

On the other hand , pyridine derivative 9a reacted with hydrazine hydrate in ethanolic solution to give the diaminopyridopyridazinone derivative 22. This may be proceeded through the elimination of ethanol to give hydrazide derivative 21 followed by addition of cyano group to give 22. The reaction product was confirmed on the basis of the IR spectra which reveal the absence of CN group, in addition to IH NMR spectra which show the absence of ethyl ester protons (ef Scheme V).

1316

5

INDIAN J. CHEM. , SEC B, JUNE 2004

16

RNH2

17a: R=Ph NH

b: 2_pYridY~2 .

9a

CN N7

Me I ~ C02Et

0:: CN

INHR 19

Scheme IV

21

Scheme V

N-N H

18

20a: R=Ph b: 2-pyridyl

22

CN

Pyridinethione 9a reacted with aromatic amines 17a, b to give pyrro]opyridine derivatives 23a, b . The reaction procJuct was readily established based on the I H NMR spectra which reveal the absence of ethyl ester protons and IR spectra which reveal the presence of amide carbonyl at - 1670 cm- I and the absence of

cyano group (ef Scheme VI).

Antimicrobial activity The various biological activities of pyridines and

fused pyridines promoted our attention to study the antimicrobial activities of some newl y synthesized

ELASSAR et al.: SYNTHESIS OF POLY FUNCTIONALLY SUBSTITUTED PYRIDINES 1317

:erNH2

CN PhN

S C02Et +

9a

:a=<lN NH2 NH

NR RNH2 ~s

17a,b 23 a: R=Ph

b: R= 2-Pyridyl

Scheme VI

products. The bactericidal and antifungal activities were studied . Thus, compounds 9c and 18 are the most active against So aureus, while compounds 13 and 23a have shown activity against B. subtilis. Both the compounds 9c and 13 have shown severe effect against E. coli and B. cereus, respecti vely. Antifungal study reveals that 9c and 20a is the most active against A. niger. Minimum inhibitory concentration (MIC) data of various compounds showed a slight to moderate effect with the tested microorgani sms. Running control with pure DMSO only has shown no effect. The data in Table I show that most of the tested compounds are effective.

Experimental Section All melting points are uncorrected . IR spectra were

recorded in KBr on a Shimadzu 408 IR spectro­photometer. 'H NMR and I3C NMR spectra on a Vari an EM-390 MHz spectrometer using TMS as internal reference (chemical shifts in 8, ppm), and mass spectra on a Shimadzu GCMS-QP 1000 Ex mass spectrometer. Microanalytical data were obtained from the Microanalytical Data Unit at Cairo Uni versity, Egypt.

Ethyl (2Z)-3-(6-amino-s-cyano-4-ethoxycarbo­nylpyridin-2-yl)-3-cyano-2-methylacrylate 5. Method A. To a mixture of ethyl pyruvate (0.0 1 mole) , malononitrile (0.01 mol e) and ethanol (20 mL), a few drops of piperidine were added . The reacti on mixture was heated under reflux for 3hr. The reaction product was left overnight and the sol id product formed was collected by filtration and crystalli zed from aceti c acid .

Method B. A mixture of ethyl pyruvate (0.01 mole), malononitrile (0.01 mole) , acetic acid (1 5 mL) and acetic anhydride (5 mL) was heated under reflux for 2hr. Aceti c acid was evaporated under vac uu m and the solid product obtained was filtered and crystalli zed fro m acetic acid to give 5, yie ld 76%, m.p. 152°C IR: 3459, 3312 (NH2), 22 17, 2220 (CN), 1738, 1722 (CO) cm

o

,; 'H NMR: 0 8.2 1 (s, 1 H, pyridine-H), 6.38 (br. , 2H, NH2), 4.27 (q, 4H,

Table I -III vitro bactericidal and fungicidal activity of some newly synthes ized compounds

Compd s. al/reliS /3. subtilis E. coli /3. cereus A.niger

5 ++ ++ + + + 9a ++ + ++ + + 9c +++ ++ +++ ++ ++ 13 ++ +++ ++ +++ + 14 + + + + + 18 +++ + + + + 20a + ++ ++ ++ 22 ++ + + + 23a + +++ ++ +

Slight effect = +; Moderate effect = ++; Severe effect = +++

2 x -CH2) , 1.53 (s, 3H, Me) , 1.25 (t, 6H, 2Me), I3C NMR: 8 169.25, 163.52 (2CO-ester), 116.20, 11 2.06 (2CN), 150.38, 148.45, 142.23, 138.25 , 132.80 (pyridine carbons), 123.00, 11l.l2 (ethylenic carbons), 72.82, 64.12 (2 x -CHrester), 19.69, 14.58, 14.48 (3Me). MS: mlz 328 (M+). Anal. Calcd for C'6H'6N40 4: C, 58.52; H, 4.92; N, 17.06. Found: C, 58.66; H, 4.86; N, 16.84%.

General Method for preparation of pyridine derivatives 9a, b. To a solution of ethyl pyruvate (0.0 1 mole) in acetone (15 mL), phenyl isothiocyanate (0.01 mole) or benzoyl isothiocyanate (0.01 mole), prepared from benzoy l chloride (0 .01 mole) and ammonim isothiocyanate (0.01 mole) in acetone (15 mL), was added. The reaction mixture was refluxed for I hr and to thi s malononitril e (0.01 mole) and a few drops of piperidine in situ were added and refl uxed further for 2hr. The reaction mixture was poured into ice-cold water and the solid product obtained was filtered and crys tallized from ethanol­chloroform.

Ethyl 6-amino-s-cyano-l-phenyl-2-thioxo- l,2-dihydropyridine-4-carboxylate 9a: yield 69 %, m.p. 157 -58°C; IR: 3440, 3310 (NH2), 22 16 (CN), 1739 (CO) cm

o

' ; 'H NMR: 8 8.3 1 (s, IH, pyridine-H), 7 .73-7.1 2 (m,5H,C6HS), 6.43 (br, 2H, NH2), 4 .27 (q, 2H, CH2), 1.25 (t, 3H,Me); MS: mlz 299 (M+) . Anal. Calcd for C ,sH 13N30 2S: C, 60.17; H, 4 .38; N, 14.03 . Found : C, 59.98; H, 4.44; N, 14.21 %.

Ethyl 6-amino- l -benzoyl-s-cyano-2-thioxo-l,2-dihydropyridine-4-carboxylate 9b: yield 65 %, m.p. I 45-46°C; IR: 3420, 3300 (NH2) , 22 18 (CN), 1739, 1680 (CO) cm

oj; 'H NMR: 88.21 ( s, IH, pyridine-H),

7.87-7.41 (m, 5H, C6HS), 6.41 (br, 2H, NH2), 4.26 (q, 2H, CH2), 1.22 (t, 3H, Me) . Anal. Calcd for C' 6H 13N303S: C, 58.69; H, 4.01; N, 12.83. Found: C, 58 .66; H, 4 .04; N, 12.52%.

1318 INDIAN J. CHEM., SEC B, JUNE 2004

E thyIS-cyano-6-(N,N-dimcthylamino) -I-phenyl-2-thioxo-l ,2-dihydropyridinc-4-carboxylatc 9c. To a suspension of 9a (0.0 1 mole), and potass iu m carbonate (- 1.5g) in e thanol-DMF mix ture (2: 1) methyl iodide (0.02 mole) was added . The reaction mix ture was refluxed fo r 3hr and neutra li zed the (;xcess of potassi urn carbonate after cool i ng the reacti o n mi xture with d il. HC I. T he so li d prod uct so l'ormed was filtered and crysta lli zed fro m DM F/EtO H mix ture, yie ld 73 %, m. p. 177-78°C; IR: 2220 (CN),

1739 (CO) cm-I; I H NMR: 8 8.32 (s, 1 H, pyr idi ne-H), 7.74-7. 13 (m, 5 H, C6Hs), 4.27 (q, 2H, C H2)' 2.85 (s,6 H,2Me), 1.27 (t, 3 H,Me). Anal. Calcd fo r C17H17N30 2S: C, 62.35; H, 5.24; N, 12.83 . Fou nd: C , 62.33; H, 5 .04 ; N, 12.9 1 %.

Ethyl 4- (m-nitro phcnyl)-2-oxo-3-butenoate 10. A mi xture of ethyl pyru vate (0.0 1 mo le), /1/ ­

nitrobenzaldehyde (0.0 1 mole) and pi peri d ine (5 drops) in ethano l (20 mL) was heated under refl ux fo r 2hr. T he solid product obtained after cooling was co ll ec ted by filtration and crys ta lli zed from ethano l. Data of compound 10 was s i mi la r to o ne desc ribed ea rl ier. 19

2- Ami no-3-cya no-6-ethoxyca I" bony 1-4H -4-(m­nitrophenyl)pyran 13. To a sol uti on of 10 (0.0 1 mo le) in ethano l (20 mL), malono nitril e (0.0 1 mole) and pi peri d ine (5 drops) were added. The reaction mix ture was heated under re flu x for 3hr. T he solid prod uct so formed after cooli ng was co ll ected by fi ltrati on and crysta ll ized fro m DM F, y ie ld 74 %, m.p. 180°C; IR: 3350, 3302 (NH2), 22 19 (CN), 1735(CO) cnf'; 'H NMR: 87.70-7.31 (m, 4H, C6 H4), 6.37 (br, 2H, NH2), 5.5 1 (d, 1 H, pyran-5 H) 5.4 1 (d , I H, pyran-4H) , 4.23 (q , 2H , C H2), l.27 (t, 3 H,Me). Ana l. Calcd for CI sH13N30 S: C, 57. 13; H, 4 .16; N, 13.32. Found : C, 57. 11 ;H, 4.24; , 13 .36 %.

2-Hydroxy-6-ethoxycarbonyl-4-(IIl-nitrophenyl)­pyridine-3-carbonitrile 14. A mixture of 13 (0.01 mole), aceti c acid ( 15 mL) and ammoni um acetate (5 g) was heated under reflux for 3hr. The reaction mixture was poured into ice-cold water and the solid product obtai ned was fi Ite red and crystal I ized from DMF/EtOH mi xture, yield ing 6 1 % of 14, m.p. 193°C; IR: 3456 (OH), 2221 (CN) , 1735 (CO) cm-I; 'H

NMR: 0 10.5 (br, IH, OH), 8.13 (s, IH, pyr idi ne-H) , 7.73-7 .21 (m,4H,C6H4)' 4.29 (q, 2H, CH2), l.23 (t, 3H,Me). MS: mlz 313 (M+). Anal. Calcd fo r CISHli NJOs: C, 57.50; H, 3.54; N, 13.41. Found: C, 57.87; H, 3.45; N , 13.20 %.

General method for preparation of pyridine derivatives 18-23. To a soluti on of 5 (0.0 I mole) or

9a (0 .01 mole) in ethano l (20 mL), hydrazine hydrate (0.01 mole) or anil ine (0 .0 1 mole) o r 2-aminopyrid ine (0.0 1 mole) was added . The reaction mi xtu re was heated under reflux fo r 3hr and was treated with ice ­co ld wate r. The so lid product thu s obta ined was fi ltered and crys ta llized from proper so lvent.

E thyl 2-amino-6-(3-amino-S-methyl-6-oxo-l ,6-dihydl'opyridazin-4-yl)-3-cyanoisonicotinate 18: yie ld 65 % fro m DMF, m.p. > 250°C ; IR: 3440, 3420, 3342, 3320 (NH2 and NH), 2 194 (eN), 1736, 1675 (CO) cm-I; I H NMR : 8 8.32 (s, 1 H, pyridine-H), 6.53, 6.41,6.3 1 (b r, 5 H, 2N Hz and N H), 4.23 (q , 2H, CH2), 1.71 (s, 3H, Me), 1.32 (t, 3H, Me). 13C NM R: 8 163 .50, 162.32 (2CO), 150.23,148.45, 147.41 , 145 .50 , 143.4 1, 142.22, 138.30, 133.93 (pyrid ine and pyridazine carbons), 11 6.32 (C ), 48.41 (CH2), 16 .35, 14.46 (2 Me). Anal. Calcd fo r C14 H14N60 3: C, 53.48; H, 4.49; ,26.74. Fou nd : C, 53.50; H, 4 .52; N, 26.57 %.

E thyl 2-amino-3-cyano-6-(2-imino-4-rnethyl-S­oxo-l-phenyl-2,S-dihydro-lll-pyrrol-3-yl) isonico­tinate 20a: yie ld 72 % from DM F, m. p. 2 13uC; lR: 3445, 3340, 3320 (NH2 and NH ), 221 1 (CN), 1737,

1665 (CO) cm-'; ' H NMR : 0 8.23 (s, I H, pyri di ne-H), 7.73-7 .33 (m, 5 H, C6HS), 6.63, 6.5 1{br, 3H, NH2 and N H), 4.25 (q , 2H, C H2), 1.73 (s, 3H, Me), 1.2] (t, 3H,Me). 13C NMR: 165.3 1, 163.67, (2CO), 159.93 (C=NH ), 149.98, 148.50 , 147.3 1, 146.01 , 145.33 , 143.36, 14 1.7 1, 14 1.03, 140.96, 139.38, 138.60, 137.4 1, 135.96 (phenyl, pyrro le and pyridine), 116.31 (CN), 48.3 1 (CH2), 15.69, 14_36 (2Me). MS : mlz 375 (M+). Anal. Calcd fo r C20H I7Ns0 3: C , 63.98; H, 4 .57 ; N, 18.65. Fou nd : C, 63.7 1; H, 4.52; r , 18.56 %.

E thyl 2-amino-3-cyano-6-(2-irnino-4-methyl-S­oxo-l-pyridin-2-yl-2,S-dihydro-lH-pyrrol-3-yl) iso­nicotinate 20b: yie ld 73 % fro m DM F, m.p. > 250"C; lR: 3446, 3342, 33 15 (N H2 and NH), 2213 (C ), 1738, 167 1 (CO) c m-I; ' H NMR: 8 8.23 (s, 1 H, pyrid ine- H), 8. 12-7 .53 (m, 4H, pyridyl), 6.62, 6.43 (br, 3H, N H2 and NH), 4.25 (q , 2H, C H2), 1.67 (s, 3H, Me), 1.3 1 (t, 3H,Me). Anal. Calcd fo r C 19H 16N60 3: C, 60.62; H, 4 .29; N, 22.33. Found : C, 60.62; H , 4.20; N, 22.06 %.

1,8-Diamino-3H -6-thioxo-7 -phenylpyrido[3,4-d]­pyr idazine-4-one 22: yield 71 % from DM F, m.p. 183°C; IR: 3441-3320 (NH2 and NH), 1665 (CO) cm· l

; 'H NMR: 8 8.32 (s, IH, pyridine-H), 7.73-7 . 13 (m, 5H, C6Hs), 6.61, 6.54, 6.32 (br, 5H, 2NH2 and NH). Anal. Calcd for C I3H llNsOS: C, 54.71; H, 3.89; N, 24 .54. Found: C, 54.71;H, 3.82; N , 24.56 %.

ELASSAR el a l. : S YNTH ESIS OF PO LY FUNCTION ALLY SU BSTITUT ED PY RTDINES 131 9

l-Amino-7 -imino-5-oxo-2,6-diphenylpyrrolo[3,4-c]pyridine-3-thione 23a: yield 71 % from DMF, m.p. 174°C; LR: 34 19-3309 (NH2 and NH), 1670 (CO). IH NMR: 8 8.23 (s, IH, pyridine-H), 7.83-7 . 11 (m, 10H, 2C6HS), 6.63, 6.54 (br, 3H, NHz and NH). M S: ml z 346 (M+). Anal. Calcd fo r C19H1 4N40S: C, 65 .86; H, 4.08; N, 16.17 . Found : C, 65 .68; H, 4. 12; N, 16.06%.

l-Amino-7 -imino-5-oxo-2-phenyl-6-pyridin-2-yl­pyrrolo[3,4-c]pyridine-3-thione 23b: yield 72% from DMF, m.p. 2 12°C; IR: 3442, 34 10, 33 19 (NH2 and NH),1 67 1 (CO); IH NMR: 88.23 (s, 1H,pyri dine­H), 8.13-7. 11 (m, 9H, pyridyl and C6Hs), 6.62 , 6.42 (br. 3H, NH2 and NH). Anal. Calcd fo r C 1gH 13NsOS: C, 62.22; H, 3.77; N, 20. 16. Found: C, 62.22; H, 3.62 ;

, 20.16 %.

Procedure of antimicrobial tests A solution of the tes ted compounds (0.01 mole), 5 ,

9a,c, 13, 14, 18, 20a, 22 and 23a [prepared by disso lving 400 ~g/mL (w/v) in steril e DMSO] was poured aseptica lly in a we ll of six mm di ameter made by a borer in the seeded agar medium. After trans­ferri ng via pipette the same vo lume in we ll s of all tested microorgani sms, bacteri a test plates were incubated at 37°C for 24 hr and fungal test plates were incubated at 25°C fo r 48 hr. The act ivit ies were ex pressed as inhibit ion zones (mm, di ameter, as clear areas). The least concentration , wh ich showed inhi bitory effect on any spec ific microorganism, was considered as the minimum inhibitory concentration (MIC) which was determined usi ng streptomycin and mycostatin (50 ~g/mL) as the references (el Table I).

Acknowledgement The au thor is gratefu l to Dr I H Abbas for the

antimicrobial activity tests.

References . I Yoon S J, Lee S W, Kim N D, Park Y K. Lee G H, Kim J W,

Park S J, Park H J & Shi!1 D H, PCT 111 1 Appl WO 200 1038306A I2001 ; CheIllAbslr, 135 , 2001, 19554.

2 Uc hiyama T Fa mlllashia. 36, 2000, 990.

3 Ki so Y & Fuji no M, lpll Kokai Tokkyo Koh o lP 2000 , 309598 A2 2000, Chelll Abslr, 133 , 2000, 350514.

4 Lebon F, Ledeeq M , Dieu M, Demazy C, Remacle J, Lapouyade R, Kahn 0 & Durant F, 1 /llorg Biochelll . 86. 2001, 547.

5 Knyazhanski i M I, Makarova N T, O lekhnovich E P & Kh arlanov A, Zh Org Khilll, 32, 1996, 1097.

6 Kurfurst A, Lhotak P, Petrn M & Kuthan J, Collecl C:ech Chelll COIII/III III . 54 , 1989,462.

7 Zheng J, Li L -M, King L Doyl e T W & Chen S -H , Frall l Biolec/lIlol Pha rill , I 2000, 314.

S Arora V K & Knau s E E, .! Heleracycl Chelll . 36, J 999, 20 I.

9 Findlay J W A & Coker G G, US 4 ,639 , 459 (CI 514-343 ; A61K 3 1/44) 1987 ; ChelllAbslr, 106 , 1987, 196267s.

10 Si rcar I, El!r Pal Appl EP 206,747 (C I C07D211190) 1986, Chelll Abslr, 106, 1987, 176173e.

i I Ga ll ardo C A, Spall ES 544/510 (CI C07D21 1/90) 1986, Chelll Ahslr, 106, 1987 , 4898d .

12 Katritzky A R, Abdel-Fattah A A A, Tymoshenko D 0 & Essawy S A, SYll lhesis, 12, 1999,2114.

13 Karp G M, Samant D, Mukhopadhyay S, Condon M E & Kleemann A, SYll lhesis. 8,2000, 1078.

14 Yak unin Ya Yu, Dyachen ko V D & Li lvi nov V P, Chelll islr\' of Helerocycl COII/pollllds 408. 2001, 831.

15 Yakunin Ya Yu, Dyachenko V D & Litvi nov V P, Chell/islr\'

of Helerocycl COl1lpollnds, 407, 2001 ,633 .

16 EI-Torgoman A M, Eisakka T, Elas:ar A Z A & Kandee! Z E. /lI lemaliollall Chell/, 1, 1990, 181.

17 Erian A W. Sheri f S M, E lassar A Z A & Elkholy Y M. Telrahedroll, 53 , 1994, 1877.

18 Elassar A Z A, Phannazie, 53, 1998,223.

19 Le Bris M - T, 1 Helerocycl C/lCIlI , 22 , 1985 , 1275.

20 Dell C P, Howe T J & Prowse W J, .! Helerocycl Chelll , 31 , 1994, 749.

21 Olto l-I H, Rinus 0 & Schmel z H, Monalsh Chern, 110.1979, 249 .

22 Otto H H & Ri nus 0, Arch PI:arm (Weinheim) , 1979, 312.