Indian Journal of Chemi stry Vol. 4 1 B. Deccmbcr 2002. pp. 2647-2654

Synthesis of some newer indolyl-thiadiazolyl-pyrazolines and indolyl-oxadiazolyl-pyrazolines as potential anti-inflammatory agents

Shalabh Sharmat,V irendra Kishor Sri vastava & Ashok Kumar*

Med icinal Chcm istry Di vis ion. Dcpartment o f Pharmaco logy, Lala Lajpat Rai Me morial Mcdi cal College. Mccrut (U. P.)-250 004 , Indi a.

Receil'ed 20 lillie 2001 : accepted (revised ) I Marcil 2002

Somc ncw l-acctyl-5-substitlltcdaryl-3- r5 ' -(3" -indol ylmcthyl)-2' -am i no- I ' .3' ,4' .-thiadiazo l-2' N-y l]-2-pyrazol incs 6a-6c

and l -accty l-5-slibstilUtedary l-3-1 5' -(3" -i ndolylmcthyl)-2 ' -amino- I ' .3' ,4' -oxadiazol -2' N-yll- 2-py razol ines 6'a-6'c have becn

sy nthes ized by 5-(3' - indo lymcthy l)- I ,3,4-thiadiazoly l-2-ami nosubstitutcdchalkoncs Sa-Sc and 5-(3' -indo ly lmcthy l)- I ,3 ,4-

oxad iazolyl-2-aminosubstilUtcdchalkoncs S'a-S'c, rcspec ti vc ly. All these co mpounds o f the present series have been

scrcened for the ir ant i-inflammatory acti vity. Compounds 6c and 6'c are found to be most ac tive co mpound o f thi s scries. wh ich show 47 .6% and 49 .0% inflammation inhibitory act ivity at a dose of SO mg/kg p.o., while standa rd drug phcnylbutazone exhibit 45 .6% ami -infl ammatory act ivity at same dosc. Thc structure of thesc compounds has bccn illu trated by IR and I H NMR spcctra .

Indole derivatives have been reported to posses different biological and pharmacological ac ti vities like, anti-inflaml1lator/ ·2, CNS depressant3

, anticonvul­sant4 and psychotropic5 acti vities . Indol1lethac in6

,

which is an indole derivative, has been successfully utili zed by the clinicians for the treatment of different inflam matory di sorders like different kind of arthriti s. The major problem with this drug taken ei ther ora ll y or subcutaneously is gasteric ulcerati on and hemor­rhage, probably due to systemic as topical action. As they are more ulcerogenic when admin istered orall y, the primary insult is due to inhibition of prostaglandin biosynthesis at mucosal level and topical insult mi ght be due to local irritation caused by high drug concen­tration and erosive property of carboxy lic group. Furthermore, various deri vati ves of 1,3,4- oxa-d· I 7·8 1 34 h' d' I 9·1 0 d I' 11 ·10 taZO es , , , -t la lazo es an pyrazo Ines -of different heterocyc lic nucl ei, are well known to exhibit potent anti-infl ammatory actlVlty. These findings prompted us to synthesize a new series of 1-acety 1-5 -substitutedary 1-3-[5' -(3" -indolyll1lethy 1)-2'­amino- I',3',4'-thiadiazol-2' N-y l]-2-pyrazolines and 1-acetyl-5-substituted aryl-3-[5'-(3" -indolylmethyl)-2'­amino-I' ,3',4' oxadiazol-2'N-yl]-2-pyrazolines by incorporating 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl and pyrazolinyl moieties at 3-position of indole nucleus with a hope to develop better anti-inflammatory agents with lesser side effects.

t Th is paper is a part of Ph .D thcs is

The reaction sequence lead ing to the formation of different titl e compounds is outlined in Scheme I. The reacti on of indole with ethylchloroacetate in the pres­ence of dry acetone and anhydrous K2C03 yielded the des ired ethyl-3- indole-acetate 1 in quantitative yield which was converted into 1-(3'-acetylindolyl)-thio­semicarbazide 2 and 1-(3 '-acety lindolyl)-semicarba­zide 2' on treatment with thiosemicarbazide and semi­carbazide hydrochloride, respectively. Compou nds 2 and 2' further cycl ised into their corresponding 1,3,4-thiadiazole and 1,3,4-oxadiazole ring by elimination of one H20 molecule on treatment with conc. H2S04

and finally neutrali zed with liquid NH3 to give com­pou nds 3 and 3', respecti vely. Furthermore, com­pounds 3 and 3' were acety lated with acety l chloride in dry chloroform, stirred for 2 hr ancl refluxed fo r 6 hI' to furni sh compounds 2-acety lam ino-5-(3'­indolylmethyl)-l ,3,4-thiacliazo le 4 ancl 2-acetylamino-5-(3'-indolylmethyl)-1,3,4-oxadiazole 4' . Moreover. compounds 4 and 4' , when treated with vari ous aro­matic aldehydes separately in sui table solvent in the presence of few drops of 2% NaOH solution and re­fluxed for 10-12 hr resulted in the formati on of 5-(3'­indol ylmethyl)- 1,3,4-thiacliazolyl-2-amino subst ituted chalkones 5a-5e and 5-(3'-indolylmethyl)-1,3,4-oxadiazo lyl-2-ami no substitu ted chalkones S'a-S' e. Compounds Sa-Se and S'a-S'e under went cycli zation in the presence of hydrazine hydrate (99%) and few drops of glacial acetic ac id and refl uxed for 12 hr to

2648 INDI AN J. CHEM., SEC B, DECEMBER 2002

Scheme I

affo rd l-acety l-5-subsitutedary l-3-[5'-(3"- indo ly l me­thy l)-2'-amino-l' ,3' ,4'-thiadiazo l-2' N-y IJ-2-pyrazolines 6a-6e and J -acety l-5-subst itutedaryl-3-[5' -(3"-indoly l­methy l)-2'-amino- l ',3',4'-oxadiazo l-2' N-y IJ-2-py razo­lines 6'a-6'e. The structures of all these compounds

were estab l ished by e lementa l and spec tral (lR and I H NMR) analysis.

Anti-inflammatory activity The study of anti-infl ammatory activity was done

SHARM A el 01. : SYNTH ESIS OF lNDOLYL-THI ADI AZOLYL-PYRAZOLI NES 2649

on albino rats of either sex , pregnancy was excluded in females, we ighing between 80-140g. The rats were di vided into three groups o f six animals each. T wenty newly synthesized compounds were evalu ated fo r their anti-infl ammatory property by using the method of Winter el al.13 The percent anti -infl ammatory acti v­ity was calculated according to the formul a given be­low:

% anti -infl ammatory acti vity = ( I -VII Vc) x 100

where, Vt and Vc are the volume of oedema in drug treated and control group, respecti vely. Phenylbuta­zone was used as the reference drug fo r comparison.

Ulcerogenic Activity (UDso) The ulcerogeni c acti vity was done on albino rats

according to procedure of Verma et al.14 The rats were di vided into groups of six animals each and fasted for 24 hr prior to the admini strati on of the test com­pounds. The water was g iven ad IibitulIl to the ani­mals. The most potent compounds 6c, 6'c and refer­ence drug, phenylbutazone, were g iven intraperito­neall y and the animals were sacrificed 8 hr after drug treatment. The stomach, duodenum and jejunum were removed and examined with hand lens for any evi­dence of (a) shedding of epithelium (b) petechi al and frank hemorrhage and (c) eros ion or di screte ulcera­ti on with or without perfo ration. The presence of any one of these criteria was considered to be an ev idence of ulcerogenic acti vity.

Acute toxicity study (ALDso) The test compounds were in vestigated for their

acute tox icity study (ALD50), in albino mice, accord­ing to the method of Smith l5.

Experimental Section The melting points were taken in open capill ari es

and are uncorrected. All the compounds were rou­tinely checked for the ir homogeneity by TLC on silica ge l-G pl ates. The eluent was a mi xture of benzene and methanol in diffe rent proportion and spots were lo­cated by iodine. The IR spectra were recorded on Paragon-500 FrIR (v max in cm,I) . The IH NMR spectra were recorded in CDCI3 or DMSO-d6 on Brucker DRX-300 FrNMR instrument, chemical shift (8) in ppm. and tetramethylsil ane (TMS ) was used as internal reference. Elemental analys is (C , H, N) of these newly synthesized compounds were done on Carl o Erba-l108 elemental analyzer.

Ethyl-3-indole-acetate 1. Ethylchloro acetate

(0 .1 mole) and anhydrous KcC0 3 (5 .0 g) were added to the soluti on of indole (0 . 1 mole) in methanol (60 mL). The reaction mi xture was refl uxed fo r 10 hr, cooled and the excess of solvent was removed. T he solid thus obtained was washed with water and recrystalli sed from ethanol to furni sh compound 1, m.p. 44°C , y ield 70% (Found: C , 70.62 ; H, 6.70; N, 6.78. Calcd fo r C I2H I30 2N : C, 70.94 ; H, 6.40 ; 6 .90 %). IR (KBr): 3 145 (N-H), 3005 (C-H aromati c), 2925 (C-H aliphatic), 1735 (C=O), 1580 cm- I (C =-=C of aromati c ring) ; IH NMR (CDCI3): 87 .65-7.40 (m, 5H, Ar-H) , 8.20 (s, IH , NH of indole, exchangeable with D20 ), 6.80 (s , 2H, CH2 attached to indole nu­cleus), 4 .20 (q, 2H, J = 7 Hz, -COOCHr CH3 ), 1.40 (t, 3H, J = 7Hz, -COOCHr CH3)'

1-(3' -AcetylindoJyJ)-thiosemicarbazide 2. A mi x­ture of compound 1 (0.075 mole) and thiosemicarba­zide (0.075 mole) in methanol (60 mL) was reflu xed on water-bath fo r about 10 hr, concentrated , cooled. poured onto crushed ice, filtered and recrystalli sed

from ethanol-water, m.p. 235°C, yield 65% (Found: C, 53.39; H, 4.56; N, 22.75. Calcd fo r C II H I20 N4S: C, 53 .22; H, 4.83 ; N, 22.58 %). IR (KBr): 3 160 ( -H), 3025 (C-H aromatic), 2920 (C-H aliphati c) , 1695 (C=O), 1600 (C=-=C of aromatic ring), 11 80 cm,l

(C=S); IH NMR (CDCI3): 87.60-7.40 (m, 5H, Ar-H), 8.30 (s, I H, NH of indole, exchangeable with 0 20 ), 6.85 (s, 2H, CH2 attached to indole nucleus), 7 .95 (m, 4H , NHNHCSNH2, exchangeable with D20 ).

1-(3'-AcetylindoJyl)-semicarbazide 2'. To a solu­tion of compound 1 (0 .075 mole) in e thanol (60 mL), semi carbazide hydrochlo ride (0.075 mole) was added, and reflu xed for about 10 hr in the presence of anhy­drous NaOH. The excess of solvent was di stilled off under reduced pressure and resulting solid mass poured into ice-water, filtered. The separated solid was washed several times with water, then recrystal­li sed from absolute ethanol to g ive compound 2' , m.p. 280°C, yield 60 % (Found : C , 57 .07; H, 5.34; N, 24.02. Calcd for C IIHI 20 2N4: C, 56.89; H, 5. 17 ; N, 24. 14 %). IR (KBr): 3 150 (N-H), 3032 (C- H aro­mati c) , 2922 (C-H aliphati c), 1700 (C=O), 1600 (C=-=C of aromatic ring), 1220 (C-N) , 1040 cm·1 (N­N) ; IH NMR (COCl) : 8 7 .65-7.40 (m, 5H, Ar-H), 8. 15 (s, I H, NH of indole, exchangeable with 0 20 ), 6.90(s, 2H, CH2, attached to indo le nucleus). 8.50 (m, 4H, NHNHCONH2, exchangeable with DcO).

2-Amino-S-(3' -indoJylmethyJ)-I , 3, 4-thidiazole 3 . A mi xture of compound 2 (0 .05 mole) and conc. H2S04 (20 mL) was kept ove rni ght at room tempera­ture. Thi s reaction mi xture was poured into ice-co ld

2650 INDI AN J. CHEM .. SEC B. DECEMBER 2002

water and neutra lized with liquid ammonia and fil­tered. The produc t obtained was washed w ith wate r and recry sta ll ised from e than o l to ge t compound 3,

m .p. 245°C, y ie ld 70 % (Found: C,57.52, H, 4.68 ; ,24.47. Calcd for CIIHION4 S: C, 57.39 ; H, 4.34; N,

24.35 %). IR ( KBr): 3350 (N I-h), 3 140 (N-H), 3018 (C- H aro matic) , 29 15 (C-H a liphati c) , 1565 (C==C of a romat ic rin g) , 1205 (C- N), 1030 (N-N) , 730 (C-S­

C), 1596 cm·1 (C=N); IH NMR (C OCl ) : 8 7 .58-7.35 (m , 5H, Ar-H), 8.25 (s, 1 H, NH of indol e, exchange­ab le with O}O) , 6.82 (s, 2H , CH2, attached to ind o le nucleus) , 5.75 (bs, 2H , NN2, exchan geabl e with 0 20 ).

2-Amino-5-(3'-indolylmcthyI)-1,3,4-oxadiazole 3'.

A mi xture of 1-(3'-acetylin olyl)·semicarbaz ide 2' (0.05 mo le) and concentrated H2S0~ (20 mL) was kep t overni ght a t roo m temperature and then 300 mL ice cold water was added into the reac ti on mi xture and shake the contents. Then reacti on mi xture was neutrali zed w ith liquid ammonia. The solid thus ob­tained was washed with wate r and recry ·talli sed w ith

methano l, m.p . 220°C , yie ld 65 % (Found : C , 61.93 , H, 4.27; N, 26.34. Caled fo r CIIHl o ON~: C, 61.68; H, 4 .67; N, 26. 17%). JR (KBr): 3355 (N H2), 3165 (N-H), 3025 (C- H a romatic), 2915 (C-H a li phatic), 1550 (C==C of aromatic rin g), 12 lO (C-O-C), 1047 (N-N),

1610 cm·1 (C=N); IH NMR (C OCl]): 87.60-7.45 (m. 5H . Ar-H), 8.20 (s , IH , NH of indole, exchangeahk w ith 0 20 ), 6.92 (s, 2 H, CH2 attached to indo le IlU ­

c leus), 5 .76(hs,2 H,NH2' exchangeab le with 0 20 ).

2-Acety lamino-5-(3' -indolylmcthy l)-1,3,4-thiad ia­zoIc 4. A so lutil on of acety l ch lo ride (0.02mole) in dry chloroform (20 mL) was added drop wise at 0-

5°C temperature to the vigorou sly stirred soluti on of

2-amino-5-0' -indo ly lmethy l)- I ,3,4- thidi azo le 3 (0.02 mole) in dry c hl oroform (50 mL) . The reac tio n mi x­ture further st irred w ith the he lp of mechanical s tirrer for 2 hI' at 1'00111 temperature a nd the n refluxed for 6 hI' on water bath. The excess of solvent was distilled off, cooled and poured o nto crushed ice. The resulting mixture was filtered to afford so lid product, washed w ith pel.ether and rec rys tall ised fro m e thano l-water,

m.p.258 °C, y ie ld 80 % (Found : C , 57. J 2; H, 4 .63; N, 20.28. Caled for C I]H I20N4S: C , 57.35; H, 4.41 ; N, 20.59%) . IR (KBr): 3150 (N- H), 30 10 (C-H aro­matic) , 2930 (C-H aliphatic), 1705 (C=O), I 540(C==C of aromatic ring), 735 (C-S-C), 1047 (N­

N), 1590 c m' l (C=N); IH NMR (C OC '-,): 87.55-7 .35 (m, SH, A r-H ), 8. 15 (s, 1 H, N H of indo le , exchange­able with 0 20 ), 6.80 (5, 2H , CH2, attached to indo le

,

nucleus), 8.45 (bs, 2H, NHCO, exchangeable with 0 20),2.45 (s, 3H, COCH]).

2-Acetylamino-5-(3'-indolylmethy 1)-1,3,4-oxadia­

zoIc 4'. To a solution o f 2-amino-5-(3'-indolyl­

methyl )- I ,3,4-oxadiazole 3' (0.02 mo le) in dry c hloro­form (50 mL), acetyl ch loride (0 .02 mole) was added

drop by drop at 0-5°C temperatu re w ith constant stir­ring. Furthe r the reaction mixture was stirred for 2 hI' at room tempe rature and then re flu xed for 6 hr. The excess of solvent was re moved, washed, filtered and rec rystalli sed fro m methanol. The puri ty of compound

,vas checked by TLC, m .p. 245 °C, yield 75 % (Found: C , 60.59, H , 4.27; N , 21.57. Calcd for C I3 H I 202N~: C, 60.94; H, 4 .69; N, 21.88 %). IR (KBr): 3170 (N-H), 3020 (C- H aromatic), 2930 (C-H liphat ic), 1555 (C==C of aromat ic ring), 12 15 (C-O-C), 1032 ( -N),

1700 cm·1 (C=O); IH NMR (C OC h) : 87 .70-7 .55 (m, 5H, Ar-H), 8.20 (s, IH , NH of indo le, exchangeable with D20 ), 6.90 (s, 2H , CH2 attac hed to indo le nu­cl eus), 8.50 (bs, 2H , NHCO, exchangeable w ith 0 20), 2.40 (s, 3 H, COCH, ).

5-(3'-Indolyhnethyl)-l ,3,4-thiadiazolyl-2-amino­(p-dimcthylaminophcnyl)chalkone 5d. To a soluti on of compound 4 (0.0 I mole) in methanol (50 mL), p­di meth y lamino benza ldehyde (0.0 I mole) was added in the presence of 2% NaOH solutio n. The react ion mi x­ture was heated under re tlux for 12 hr. The excess of so l ven t di sti li ed off, cooled , fi Ite red and the res idue was thoroughly washed w ith co ld wa ter a nd recrysta l­

li sed with e thano l- wate r, m.p.222°C, y ie ld 60 % (Found: C , 65.77; H, 5.45 ; N, 17. 13. Cac ld fo r C2::> H2IONsS: C , 65 .51 ; H, 5 .2 1; , 17.37%). IR ( KBr): 3 160 (N-H), 3050 (C- H a ro matic), 2920 (C-H a liphati c) , 1700 (C=O); 1530 (C==C of aromatic ring) , 1600 (C=N ), 1062 ( - ), 1140 em· 1 (C-S-C) ;

I H NMR (CDC I,): 87.70-7.20 (Ill, 9H, Ar-H), 8. 18 (s, I H, NH of indole , exchangeab le w ith D20 ), 6.90 (s, 2 H, CH 2 attached to indo le nuc le us), 8.S0 (bs, 2 H, NHCO, exchangeable with O~O), 6.40 (d, I H, COCH=) ; 9.15 (d IH , =CH-Ar), 2. 15 [s, 6 H,

N(CH3) ~]. Various o ther 5-(3'-indo ly lme th y l)- 1,3,4-thiadi azo lyl-2-aminosubstitutedcha lko nes Sa, 5b, 5c and Se were prepared with di ffe re nt aromatic a lde­hydes by following the above mentio ned method. Th e ir physical and analy ti ca l da ta are g iven in Table l.

5-(3'-Indolylmcthyl)-l ,3,4-oxaadiazolyl-2-amino­

{p-hydroxy-m-mcthoxyphenyl)chaHwne Sc'. Com­

pound 4' (0 .0 I mole) in methano l (50 mL) and p­hydroxY-III-methoxybenzalde hyde (0 .0 I mo le) , in the

SHARMA el al. : SYNTHESIS OF INDOL YL-THIADIAZOL YL-PYRAZOLIN ES 2651

Table I--Charac leri zal ion dala and anli-infl am malory aCli vilY of compounds Sa~Se and S'a-S'c

COlllpd R

Sa -@ Sb -@OCH3

Sc

Sd -@-N(CH3)2

Sc -@-OH S'a -@ S'b -@OCHl

S'c ~CH3

~OH

S'd -@-N(CH)l S'c -@-OH

'c. 1-1 , N were found wilhin + 0.4%

m.p. Yicld Recryslali salion °C (%) solvelll

280 62

230 58

250 65

222 60

245 48

230 so

242 60

265 48

290 56

270 45

DM F

Acelic ac id

Melhanol-walcr

Elhanol-waler

AcelOne-pel. elher

Elhanol-waler

DM F

Melhanol-wale r

Melhanol-waler

Aceli c ac id

pre ence of 2% NaOH so luti o n, were reflu xed fo r 12 hr. Co mpleti on o f the reac ti on was monitored on TLC. The reacti on mi xture was co ncentrated , coo led and poured into ice water. The separated solid was filt ered o lT and rec rys talli zed with meth ano l-wate r to

give compound 5c', m.p.265°C, y ie ld 48 % (Fo und : C, 64.38: H, 4.88 ; N, 14.72. Calcd fo r C" , H ' RO~N4: C, 64.62; H, 4.62; N, 14.36%). ]R (KBr): 3560 (O-H), 3 135 (N-H ), 3080 (C- H aromatic), 2960 (C-H a li ­phati c), 1720 (C=O), 1588 (C=N); lO47 (N-N ), 11 25

em" (C-O-C); ' H NMR (COCl}): 87.65-7.45 (m, 8H, Ar-H) , 8.20 (s, I H, H of indo le, exchangeabl e with 0 20), 6.95 (s, 2 H, CH2 attached to indo le nucleus) , 8.65 (bs, 2H, NHCO, exchangeable w ith D20 ), 6.45

Mol. fo rmul a

Found (Calcd) % t

C H

66.92 4.76 (66.66 4.44

64.35 4.33 (666 1 4.62

62. 19 4. 19 (62.07 4.43

65.77 5.45 (65 .5 I 5.2 1

63.58 4.39 (63.83 4.26

69.9 1 4.92 (69.77 4.65

67.09 4.53 (67.38 4.8 1

64.38 4.88 (64 .62 4.62

68.45 5.22 (68.22 5.43

66.84 4. 15 (66.67 4.44

15.72 15.55)

14. 17 14.36)

13.52 13.79)

17. 13 17.37)

14.63 14.89)

16.47 16.28)

14.63 14.97 )

14.72 14.36)

18.32 18.09)

15.78 15.55)

Dose mg/kg

p.o.

so

so

so

so

so

so

so

so

so

so

% An li­in fi am ma­lory ac ivily

24.3

35.3

39.9

27 .8

32.3

28 .1 2

40.6

42 .0

30. 13

34.2

(d, I H,-COCH=); 9.20 (d I H, =CH- Ar); 3.48 (s, 3H. OCH3), 11.20 (ss, I H, OH, exchangeable w ith D20).

The diffe rent other 5-(3'-indo ly lmethyl)- I,3,4-

oxadi azo ly l-2-aminosubstitutedchalkones 5' a, 5'b, 5' d and S'e were synthes ized by using di ffe rent aromat ic aldehydes simil arl y. The ir phys ica l and analyti ca l data are depic ted in Table l.

l-Acetyl-5-(p-dimcthylaminophcnyl)-3-[5'-(3"­indolylmcthyl)-2'-amino-l' ,3',4'-thiadiazol-2' N-yIJ-2-pyrazoline 6d. Hydraz ine hydrate 99% (0 .04 mo le) was added to a so luti on of co mpound 5d (0.02 mo le) in ethano l (40 mL) in the presence of few drops of glac ial aceti c ac id and the reacti on mi xture was re­flu xed for 12 hr. di still ed o ff, and coo led. The sepa-

2652 INDI AN J. CHEM. , SEC B, DECEMB ER 2002

rated solid was filtered washed with water and recrys­talli sed with acetone/pet. ether. m.p. 233°C, yield 50% (Found : C, 61.38; H, 5.21; N, 21.62 . Cacld for C24 H250N7S: C, 61.00; H, 5.44; N, 2 1.35%). IR (K Br): 3130 (N-H ), 3040 (C-H aromatic) , 2922 (C-H aliphatic), 1710 (C=O) , 1603 (C=N), 1050 (N-N), 746 cm'l (C-S-C) ; 'H NMR (COCI 3): 87.70-7.25 (m, 9H , Ar-H), 8.20 (s, I H, NH of indole, exchangeable with 0 20 ), 6.92 (s, 2H, CH2, attached to indole nucleus), 5.70 (bs, 2H, NH, exchangeabl e with 0 20 ), 5.25 (d, 2H, CH2 of pyrazoline ring); 6.60 (t, I H, CH-Ar of

pyrazoline ring), 2.50 (s, 3H , COCH}), 2.20 [s, 6H, N(CH3)2l Other l-acetyl-5-subst it tedaryl-3-[5'-(3"­indolylmethyl )-2' -amino-I' ,3',4' -thiadiazol-2' N-y 1] -2-pyrazolines 6a, 6b, 6c and 6e were prepared in the similar manner. Their physical and analytical data are mentioned in Table II.

1-Aeety 1-5-(p-hydroxy -meta-methoxyphenyl)-3-[5' -(3" -indolylmethyJ) -2' -amino-l',3'.,4' -oxa diazol-2'N-yIJ-2-pyrazoIine 6e'. To a solution of compound 5'e (0.02 mole) in ethanol (40 mL), hydrazine hydrate 99% (0.04 mole) and few drops of glac ial acetic ac id

Table II--Charac teri zati on data and anti-inflammatory acti vity of compounds 6a-6e and 6'a-6'e

Compd

6a

6b

6e

6d

6e

6'a

6'b

6'e

6'd

6'c

Phenyl Butazone

R

-@ -@-OCH3

~CH3

~OH

~N(CH3)2

-@-OH

-@ -@-

OCH3

~CH3

~OH

~N(CH') 2

-@-OH

tc ,H. N were found within ± 0.4%

Ill.p. Yield Reerys tali sa tion °c (%) solvent

225 45

205 60

2 1S 4S

233 50

24 1 50

2 10 48

190 55

286 50

240 54

277 65

Acetic ac id

Ethanol-water

Aeetonc-pcl. ct her

Ace tic acid

Ethanol-water

Methanol -watcr

Mcthanol-watcr

Methanol -watcr

Acetic ac id

Mol. fo rmul a

Found (Ca lcd) %t

C H N

63.7 1 4.66 20.44 (63.46 4.8 1 20.1 9)

6 1.44 4.73 18.65 (6 1.88 4.93 I S.83)

59.48 4.97 (59.74 4 .76

I S.37 18. 18)

61.38 5.21 21.62 (6 1.00 5.44 21.35)

6 1.29 4.32 19.71 (6 1.11 4.62 19.44)

nn.33 5.2 1 2 1.28 (6n.OO 5.00 21.00)

64.02 5.00 19.2n (64. 18 5 .11 19.53)

6 1.49 4.58 18.69 (6 1.88 4 .93 18.83)

65.32 5.34 22.27 (65'(ll 5.64 22.12 )

63.72 4.66 20.02 (63.46 4.80 20.1 9)

Dose % Anti -Il1g/kg inll all1

p.o. mator),

SO

50

25 50 100

50

50

50

50

25 50 100

50

50

25 SO 100

acivity

28.7

40.7

28.4 47.6 66.0

30.0

36.2

33.3

43 .6

30.~

49 .0 69.47

32.1 3

37.25

26.5 45.6 65.1

SHARMA el al. : SYNTH ESIS OF INDOLYL-THIADIAZOLYL-PYRAZOLINES 2653

were added into it. The reaction mi xture was refluxed for 12 hr. The excess of solvent was removed through distillation and separated product was recrystalli sed

from methanol-water, m.p.2 86°C, yie ld 50 % (Found : C, 61.49 ; H, 4 .58; N, 18.69. Cacld for C 23 Hn 0 4N6: C, 61.88 ; H, 4 .93; N, 18.83%). IR (KBr): 3520 (O-H), 3 150 (N -H), 3070 (C- I-I aromatic), 2945 (C-I-I ali­phatic) , 1710 (C=O), 1590 (C=N), 1035 (N-N), 11 20

cn'-' (C-O-C); ' H NMR (COCl}): 87.60.7.15 (m, 81-1 , Ar-H), 8. 15(s, IH , NH of indo le, exchangeab le with 0 20), 6.85 (s, 21-1 , CH2 attached to indole nucleus), 5.75 (bs, 11-1, NH, exchangeable with 0 20 ), 6.55 (t, II-1 ,CH-Ar of pyrazoline ring) , 5.30 (d, 2 1-1 , CH2 of pyrazoline ring), 2.52 (s, 31-1 , COCH}), 3.45 (s, 3H, OCH3), 11.15 (ss, I H, OH, exchangeable with 0 20). A number of l-acety l-5-substitutedary l-3-[5'- (3"­indolylmethyl)-2'-amino-I',3',4'-oxadiazol-2' N-y l]-2-pyrazo lines 6'a, 6'b, 6'd and 6'e have been sy nthe­sized in the similar way. Their phys ical and analytical data are shown in Table II

Anti-inflammatory activity against carrageenan induced rat's paw oedema

Twenty substituted derivatives have been prepared and screened for their anti-inflammatory acti vity at a dose at 50 mg/kg p.o. The results of the study are shown in Tables I and II . Most of these congeners showed potent an ti-infl am matory act ivity rang ing from 24 .3% to 49 .0% and were found stati sti ca ll y significant. All these compounds were compared with standard drug, phenylbutazone, which provided with 45.6% inhibiti on of oedema at the identi cal dose. The two most acti ve compounds of the present series (compounds 6c and 6'c) ex hibited most poten t anti­in flammato ry act ivity (47.6% and 49.0%, respec­

ti vely). These two compounds (6c and 6'c) exhibited higher inflammati on inhibitin g property in compari­son to phenylbutazone at 50 mg/kg p.o. By consider­ing their potentiality, compounds 6c, 6'c and standard drug, phenylbutazone were further tested for their anti -infl ammatory activi ty at three different graded doses i.e. 25 , 50, 100 mg/kg p.o. and result are de­picted in Table II.

Ulceroginc Activity (UDso)

Only compounds 6c, 6'c and phenylbutazone were tested for ul cerogenic li ab ility . Compound 6c was found to be less ulcerogen ic because at dose of 175.7 mg/kg i.p. (U Oso), it produced ulcers in 50% animals, whil e compou nd 6'c and phenylbutazone

produced ulcers in 50% animals at 168.2 and 66.6 mg/kg i.p., respec ti ve ly.

Acute toxicity study (ALDso) All the compounds have show n ALOso >

1000 mg/kg p.o. , except compound 6c, which showed ALOso > 1600 mg/kg p.o. Therefore, these compounds ex hibited good safety marg in .

Structure activity relationship SAR study of indo le nuc leus has revealed that sub­

stitution at 3-pos iti on of indo le nucleus markedly en­hanced the anti-inflammatory acti vity. Furthermore, indo le was substituted with thi ad iazo ly l and oxadia­zoly moieti es at its 3-pos iti on. These compounds fur­ther converted into different substituted chalkones and finally cyclized into their corresponding pyrazolines. It was noti ced that the chalkones showed mild to moderate anti-infl ammatory activity. The infl amma­tion inhibiting property increased o n cycl izati on of

chalko nes 5a-Se and 5'a-5'e into their corresponding pyrazolines 6a-6e and 6'a-6'e . Moreover, it has been

observed that when compounds 6c and 6'c were sub­stituted at 5-position of pyrazo line ring with phenyl group hav ing methoxy group at mela- and hydroxyl group at para- position they showed maximum per­centage inhibition of rat ' s paw oedema (47 .6 % and 49 .00 %, respecti ve ly). On the other hand compound

6b and 6'b substi tuted at 5-position of pyrazoline ring, with phenyl ring hav ing methoxy group at para­position, have shown substanti ve anti -i nflammatory activi ty (40.4% and 43.6%, respectively) . Further it is ev ident from the result depicted in Tables I and II that the compounds 6'a-6'e having oxad iazo lylmoiety ex hibited better anti- inflammatory activity th an the compounds 6a-6e hav ing thidiazolyl moiety. Similar result have also been reported by Mazzone el al. ' 6

Hence, it may be conc luded that substitution in

chalko nes (5a-5e and 5'a-S'e) and pyrazolines (6a-6e and 6'a-6'e) with phenyl group at lI1ela-postion and hydroxy l group at para-position show max imum anti ­inflammatory act ivity.

Subst itution in chalkones (5a-5e and 5'a-S'e) and pyrazolines (6a-6e and 6'a-6'e), with o nl y phenyl group possess minimum anti -infl ammatory ac ti vity.

The compounds whi ch contain oxad iazo ly l moiety exh ibit better inflammation inhibiting property than the compounds having thiadiazolyl moiety.

Cycl izat ion of cha lko nes into their corresponding five membered heterocyc lic ring structure pyrazoline, enhance the anti - infl ammatory act ivity.

2654 I DIAN J. CHEM., SEC 13, DECEMBER 2002

Acknowledgement We are thankful to Director, CDRI , Lucknow

(U .P.), India for elemental and spectral analysis of newly sy nthesized compounds.

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