Indian Journal of Chemistry Vol. 42B, March 2003, pp. 593-60 1

Rapid Communication

Synthesis and cyclooxygenase (COX-V COX-2) inhibiting property of 3,4-

diarylfuranones t

Manojit PalO, Venugopal Rao Veeramanenia,

Srinivas Padakantia, Murali Nagabellia, Akhila

Vangurib, Premkumar Mamnoorb, Seshagiri Rao Casturib, Pari mal Misrab, R amesh

Mullangib & Koteswar Rao Yeleswarapua*

"Chemistry, bB iology, Di scovery Research, Dr. Reddy 's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050,

India e-mail : koteswarraoy @drreddys .com Tel : 91-40-3045439; Fax

91-40-3045438 I 3045007

Received 24 April 2002; accepted (revised) 17 January 2003

A series of diarylfuranone including some 5-hydroxy derivatives and naphthofuranones have been synthesized as a unique c lass of COX-I/COX-2 inhibitors. In contrast to the earlier report of structurally similar rofecoxib, these compounds have been characterized as nonselective but highly potent COX inhibitors. Structure Activity Relationship study confirmed that methoxy and methylsulfanyl moieties are essential for COX activity and replacement or removal of any of this group affect COX-2 potency drastically rather than COX-I efficacy. Studies on in vitro, in vivo screens and pharmacokinetics are discussed.

Sulfonyl-substituted diaryl heterocycle is the most widely used pharmacophore motif for the development of selective COX-2 inhibitors and its simplest form is represented by DUP-69i . The pharmacophore for this series include either a methanesulfonamide (S02NH2) or a methanesulfone (S02Me), which is attached to the p-position of the phenyl ring. This phenyl moiety and a lipophilic moiety are attached to the adjacent positions of the template. The template may consist of a carbocycle,

Br

DuP697 NS398

heterocycle or even acyclic structure, which may adopt favourable geometry. After the discovery of inducible isozyme (COX-2) in 1991, the first breakthrough came with the reports that the diarylheterocycle DUP-697 and NS398 were anti­inflammatory but not u\cerogenic I.2. This observation generated interest and subsequently, enormous efforts were paid by the pharmaceutical research laboratories to convert them into structurally related but clinically better candidates. This rational and scientific approach in this series resulted in celecoxib3 and rofecoxib4 as first generation selective COX-2 inhibitors (Figure 1) to enter the market.

Rofecoxib, a selective COX-2 inhibitor, belongs to a tricyclic class of compounds having furanone ring as a template (Figure 1). Design of rofecoxib involved two way modification4a of DUP-697: (i) replacement of thiophene ring by a five membered lactone along with the C-2 substituent by lone pairs of electron of the lactone oxygen to enhance bioavailability and COX-2 selectivity, (ii) retention of methanesulfone rather than sulfonamide moiety to maximize COX-2 selectivity. Although the Structure Activity Relationship (SAR) study revealed that interchange of 4-methylsulfonyl phenyl with the other phenyl ring led to essentially inactive isomeric compound, however, various possible modifications of bas ic skeleton of rofecoxib 31 have been reported (Figure 2) as is exemplified by 32_345

.6

. Indeed some of these derivatives are more potent and selective than 31. All these reports confirmed that the presence of 4-(methylsulfonyl)phenyl moiety and its position of attachement to the central ring are critical for optimal COX selectivity and potency. However, we have observed that replacement of methylsulfonyl moiety

Celecoxib (35 ) Rofecoxib (31 )

Figure 1- Some selective COX-2 inhibitors. t DRF Publication No. I S3

594 INDIAN J. CHEM., SEC B, MARCH 2003

of rofecoxib analogues by methylsu lfany l group7 led to little change in COX efficacy but produces dramatic change in selectivity. This observation intrigued and prompted us to carryon a detai led study on such type of rofecoxib analogues that would explore a deeper insight on their synthesis and pharmacological profi le as COX inhibitors. In this

o

32; R=C6Hs 33; R=OC6Hs 34; R=OPr-i

Figure 2 - Some furanone derivati ves as selective COX-2 inhibitors.

Me SMe

Path A

a o R

R1

6-20 &23-25 36

R= RI=

6 4-Methoxyphenyl H 7 4-Ethoxyphenyl H 8 3-Fluoro-4-methoxy H

phenyl 9 4-Benzyloxyphenyl H 10 5-lndanyl H 11 4-lsobutylphenyl H 12 3-Methoxyphenyl H 13 3 ,4-Di methox ypheny I H 14 2,4-DiOuorophenyl H 15 4-Chlorophenyl H 16 3-Chlorophenyl H 17 4-TriOuoromethyl phenyl H 18 4-Bromophenyl H 19 4-Hydroxypheny l H 20 4-Thiomethylphenyl H 23 Phenyl Et 24 4-Fluorophenyl Et 25 4-Methoxyphenyl Et

communication , we describe the synthesis and the SAR study of a unique series of furanone derivatives , which are non-selective in COX-) and COX-2 inhibition contrary to the earlier reported structurally similar rofecox ib.

In recent years, a number of methods have been developed for the synthesis of 3,4-disubstituted furanones8 due to their enormous medici nal interest as well as synthetic uti li ty. We however adopted the aldo l- type cycli zation of pheny lacylester8a

-d

.9 for our

purpose due to the simple yet versatile nature of this protocol. Accordingly, the maJonty of the d iary lfuranones listed in Table I were synthesized according to the Schemes I and II.

Synthesis of diarylfuranones 1-5 was carried out following the procedure described in the Iiterature8d

.

Simi larly, the diary lfuranones 6-20 and 23-25 were efficiently prepared from phenacylester 36 generated from ary lacetic acid [obtained from 1-(4-methyl­sulfany lphenyl)-l-ethanone via Willgerodt reaction) and appropriate bromoketone (Scheme I, path-b).

Me

PathB

o R

HO

26-27

R= RI = 26 Phenyl Ethyl 27 4-Fluorophenyl Ethyl

Reagents and condi tions: (a) DBU, CHJCN, 10 °C, 30 min. (b) °2, DBU, CHJCN, 25°C, 6 hrs.

Scheme I

RAPID COMMUNICATIONS 595

Table I-In vitro data for diarylfuranones

Compd ",C,~ % of inhibition (100 ~M)" IC50 (~M)b

'" /, COX-I COX-2 COX-I COX-2 I 0

R 0

1 4-Methoxyphenyl 100 96 0.015 0.172

2 Phenyl 87 0

3 3,4-Difluorophenyl 99 47

4 4-Bromophenyl 96 84

5 4-Trifluoromethyl phenyl 73 70

d10

: \ 0

H3CS

6 4-Methoxyphenyl 89 95 0.007 0.081

7 4-Ethoxyphenyl 100 100 0.024 0.369

8 3-Fluoro-4-methoxy phenyl 100 100 0.009 0.266

9 4-Benzylox ypheny I 60 0 nd nd

10 5-lndanyl 100 4 nd nd

11 4-lsobuty Ipheny I 42 0 nd nd

12 3-Methoxyphenyl 100 4 nd nd

13 3,4-Dimethoxyphenyl 100 2 nd nd

14 2,4-Difluorophenyl 97 0 nd nd

15 4-Chlorophenyl 100 0 nd nd

16 3-Chlorophenyl 70 0 nd nd

17 4-Tritluoromethyl phenyl 65 22 nd nd

18 4-Bromophenyl 100 36 nd nd

19 4-Hydroxyphenyl 100, 87( 1) 100,42(1) nd nd

20 4-Thiomethylphenyl 99, 100(1 ) 100, 66( I ) nd nd

cPo : \ 0

21 4-Methoxypheny l 100, 100( I 0) 91 ,52( 10) nd nd

22 Phenyl 100, 0( 10) 0, (10) nd nd Et

~ I 0

: \ 0

H3CS

23 Phenyl 100 100 0.040 0.185

24 4-Fluorophenyl 100 100 0.018 0.171 25 4-Methoxyphenyl 100 100 0.004 0.108

Et diO

"

I 0

>" \ 0

H3CS

26 Phenyl 100 100 0.099 0.841 27 4-Fluorophenyl 100,100(1 ) 100,55( I ) nd nd

-Contd

596 INDIAN 1. CHEM., SEC B, MARCH 2003

Table I-In vitro data for diarylfuranones (-Contc£)

Compd

28

29

30

31

35

~1 Et

~ OH I 0

~ 1 0

I 0 ~:

:. I 0 MeS

~ I ~

I 0

:. I 0 MeS

Rofecoxib

Celecoxib

% of inhibition (100 ~M)"

COX- I COX-2

96, 63( I ) 100, 56(1)

100 100

100, 100(1) 86,68 (I)

COX-I COX-2

nd nd

0.053

nd

>500

10.70

0.827

nd

0.329

0.036

*Figures in the brackets indicate concentration in JLM. a A verage of at least three determinations. b The result is the mean value of two determinations, and the deviation from the mean is < 10% of the mean value. end = not determined.

37 38 39 29-30

R'=H,Me R= R'= 29 C6HsSMe-p H 30 C6HsSMe-p Methyl

Reagents and conditions: (a) Br2, HBr. CH)C02H (b) DMF, KOH, RCH2C02H, 10 °C -R.T. , 1.0 h (c) DBlI, CH)CN, 10°C, 30 min. then dil HCI , 10°C, 30 min.

Scheme II

Scheme II describes the synthesis of furanone derivatives from u-tetralone 37. Brornination of 37 fol1owed by reaction9a with arylacetic acid led to the ester 38, which was then cyc1ized to the furanone derivatives 29, 30. Furanones 22 and 23 were prepared according to the procedure depicted in Scheme I (path-a) where appropriate acetophenone was used.

All the cyc1ization reactions were performed strictly under inert atmosphere at 10 dc. Interestingly temperature, concentration of DBU, along with the presence of oxygen in the cyc1ization step of Schemes I and II was found to be critical. A side

product was isolated, sometimes even as a major product, when the reaction was performed in the presence of three equivalents of DB U under oxygen atmosphere at 25-30 dc. Depending on the nature of the esters used (36; R'= H or alkyl ), these products were identified as either 3,4-diaryl-substituted maleic anhydride or 5-hydroxyfuranones 26-28, respectively (Scheme I, path-b) 9b-c .

Mechanistically, the cyc1ization of ester proceeds through the usual aldol-type condensation reaction in the presence of DBU leading to the formation of furanones. However, isolation of 5-hydroxyfuranones cou ld be accounted for by its further reaction with

RAPID COMMUN ICATIONS 597

oxygen in the presence of DBU. This involves facile generation of carbanion that may subsequently react with molecular oxygen followed by the cleavage of 0-0 bonds. To confirm thi s mechanistic sequence, furanone 23 was treated with DBU in acetonitrile under the oxygen atmosphere where 26 was isolated in good yield. Thus, the ox idati ve cyclization reaction proceeds through the stepwise formation of furanone followed by its oxidation to the corresponding 5-hydroxy derivative.

Compounds synthesized were tested in initi al screens for selectivity and potency in in vitro against recombinant human COX-2 (expressed in sf9 insect cells using baculovirus) and COX-l (Ram Seminal ves icles) enzyme. Selected compounds were subsequently tested in human whole blood assay for both COX- l and COX-2 acti vi tylO. In vivo activity was evaluated using carrageenan-induced rat paw edema model l l

.

The first compound sy nthesized in this se ries i.e., 3-( 4-methoxyphenyl )-4-( 4-methylsulfanyl phenyl)-2,5 -dihydro-2-furanone 1 was characterized as a nonselecti ve but highly potent COX inhibitor (compd 1, Table I ). Interchange of position of ary l moieties with each other did not affec t the activi ty pattern (compd 6, Table I).

Replacement of methoxy by ethoxy group (compd 7, Table I) or attachment of a fluori ne atom at ortho­position of methoxy group (compd 8, Table I) had no significant effect on COX inhibiting actIvIty. However, a larger group such as benzyloxy (compd 9, Table I) in place of methoxy led to complete decrease in COX activity suggest ing that the latter binds in an enzyme pocket that is more restricted for a bulky group. In order to understand the ro le of methy lsulfanyl and methoxy group in COX acti vity , this series was investigated further. It was observed that removal of methylsulfanyl moiety (compd 21 ,

Table I) led to decrease in COX-2 inhibition without affecting COX-I, whereas removal of both the groups (compd 22, Table I) resulted in complete decrease in COX-2 but moderate decrease in COX-l inhibition. Change in position of methoxy group (compd 12, Table I) also resulted in complete decrease in COX-2 potency . These observations indicate that both methoxy and methylsulfanyl moiety are essential fo r COX activity and replacement or removal of any of thi s group affects COX-2 potency drastically rather than COX-l efficacy. This was further supported by the data presented in Table I (compds 2-5 and 13-20). Interestingly, removal of methoxy group was compensated by the attachment of an ethyl substituent at the C-5 position of the lactone ring (compds 23 and 24, Table I). Extension of the C-5 attachment to the adj acent phenyl ring (compd 29, Table I) led to moderate decrease in COX-2 potency. However, presence of another substituent e.g., hydroxy group at C-5 position led to significant decrease in COX-2 potency (compds 26 and 27, Table I). Thus, the ethyl chain at the C-5 position imparted the requ ired conformation that was perhaps needed for the COX-2 inhibition. COX-l potency was not affected drastically except where nei ther methoxy nor methylsulfanyl moiety was present as pharmacophore (compd 28, Table I) .

Some of these furanone derivatives selected based on their impressive ICso values, were tested in vivo at a dose of 30 mg/ kg p.o. and the percentage of inhibition of paw edema was calculated. Compound 1 (compd 1, Table I), which exhibited max imum inhibition at 30 mg/ kg p.o., was selected for further study . The COX-l and COX-2 potency of 1 was measured by human whole blood assay and compared with celecoxib, rofecoxib and indomethacin (see Table II). ICso values for COX-l was determined by measuring TXB-2 production in human whole blood

Table II-In vitro (human whole blood assay) and in vivo (rat paw edema assay) data

Entry Compd ICso", JlM Log pb ED30

COX- I COX-2 (mg/kgC)

I 0.005 0.186 3.74±0.4 1 1.17±0.33

2 Rofecox ib 5.4 0.580 1.54±0.43 1.02±0.12

3 Celecoxib 10.0 0. 187 3.01±0.86

4 Indomethacin 0.213 0.247

a The result is the mean va lue of two determinations, and the deviat ion from the mean is < 10% of the mean value. bCa1culated using the ACDLabs program developed by Advanced Chemistry Development Inc ., Canada. cED)o va lues were d::termined using a minimum of four dose points, 6 animals/group.

598 INDIAN J. CHEM., SEC B, MARCH 2003

and for COX-2 inhibition was determined by measuring lipopolysaccharide induced PGE2 production in human whole blood.

As can be seen from Table II, compound 1 is comparable to celecoxib, rofecoxib and indomethacin with respect to COX-2 inhibition. However, its abnormally low ICso value for COX-l inhibition prompted further investigation. The inhibition of COX-2 by rofecoxib is reported to be occurring via a two-step time-dependent mechanism9b (leading to a tightly bound inhibited complex), whereas weak inhibition of COX-I is non-time dependent. Inhibition of both the isoforms by non-selective COX inhibitors such as indomethacin and flurbiprofen is time dependent l2. Since a large number of furanone derivatives, as described above, exhibited non­selective inhibition of COX enzymes, their mechanism of action therefore, could be different from that of rofecoxib.

According to the pharmacokinetic study compound 1 (Cmux 0. l2±0.0 lltM) and rofecoxib ( C,nax

5.61±1.1OItM) displayed substantially different pharmacokinetics in male rats when dosed orally at 100 mg/ kg. Thus, the furanone derivative 1 exhibited discouraging oral phannacokinetics l3 when compared to rofecoxib. Although the purpose of incorporation of lactone moiety into DUP-697 in the design of refecoxib was to address the oral absorption issue, this was however, not achieved in 14. Theoretically, the 10gP value, as calculated for 1 was found to be higher than rofecoxib (Table II), which supports the pharmacokinetic data and could be the reason for poor absorption associated with 1. Surprisingly, in spite of poor pharmacokinetics, compound 1 exhibited substantial inhibition of rat paw edema and the ED30 value for 1 was noted as 1.17±0.33 mg/kg, fairly comparable to rofecoxib (Table II). Experimental evidences suggese3 that COX-! has significant contribution to PG synthesis in inflammation and thus inhibition of COX-! might be a required process for anti-inflammatory activity. This was further supported by the clinical efficacy of piroxicam, a relatively COX-! selective inhibitor. So the high potency of 1 perhaps could be justified by its low ICso values for both COX-I/COX-2 inhibitions. We anticipated that metabolism of furanone 1 may lead to the generation of corresponding sulfoxide and/or su lfone along with the other related metabolites as reported in the case of rofecox ib l4a . Accordingly, we have synthesized l4b and found that they are less or moderately active in in vitro (COX-I & COX-2 is 63 & 15 for sulfoxide at

l~) and more importantly in in vivo (5% for sulfoxide and 27% for sulfone at 30 mg/kg) . These observations rule out the possibility that 1 may act as a prodrug of either sulfoxide or sulfone in vivo. Further study on pharmacodynamics of 1 is however, needed to confirm this conclusion.

In summary, we have described the synthesis of 4,5-diarylfuranones via aldol type condensation or oxidative cyclization of phenacyl ester including the first synthesis of naphthofuranones along with the novel synthesis of 5-hydroxydiarylfuranones as well. These fural1iones are structurally simjlar to highly selective rofecoxib and other furanones ls , but exhibit non-selective nature of NSAIDs. Methylsulfanyl and methoxy groups have been proved to be the key features in regulating the COX inhibitory activity of this series. Compound 1 exhibited excellent anti­inflammatory activity in the carrageenan-induced rat paw edema assay following oral administration. Because of their impressive ICso values for COX inhibition, these compounds could be useful for the treatment of pain and inflammation like piroxicam or in other therapeutic areas l6. To summarize, diarylfuranone 1 has been identified as a potent inhibitor of COX isoenzymes with interesting pharmacological properties.

Experimental Section General methods. All the solv~nts used were

commercially available and distilled before use. Reac­tions were monitored by TLC on silica gel plates (60 F254; Merck), visualizing with ultrav iolet light or iodine spray. Flash chromatography was performed on a silica gel (SRL 230-400 mesh) using distilled petroleum ether, ethyl acetate, dichloromethane, chlo­roform and methanol. IH and I3C NMR spectra were recorded in CDCl3 solution on Varian Gemini 200 and 50 MHz spectrometers respectively using TMS as internal standard (chemical shift in 6, ppm), infrared spectra on a Perkin-Elmer 1650 IT- IR spectrometer; UV spectra on a Shimadzu UV 2100S UV -VIS re­cording spectrophotometer; and MS spectra were ob­tained on a HP-5989A mass spectrometer. Melting points were determined using Buchi melting point B-540 apparatus and are uncorrected . Microanalyses were performed using Perkin-Elmer 2400 C H N S/ 0 analyzer.

Typical experimental procedures fOl' the prepa­ration of furanone

Preparatfion of 7 -methyl-a-tetralone 37 (R 1=

CH3), To a mixture of toluene (25 mL) and butyrolac-

RAPID COMMUNICATIONS 599

tone (5 mL, 61.39 mmoles) was added aluminium chloride (20 g, 150.37 mmoles) slowly and portion­wise at 25°C with vigorous stirring. The mixture was then heated to 100 °C and stirring continued for 8 hr. After cooling to room temperature the mixture was poured into crushed ice (100 g), extracted with EtOAc (3 x 50 mL) washed with water (2 x 100 mL), dried over anhydrous Na2S04 and concentrated. The result­ing liquid isolated was purified by column chromatog­raphy over silica gel using 5% EtOAc-petroleum ether (60-80°C) to give 8g (81 %) of the title compound as pale yellow oil. 'H NMR (200 MHz, CDCb): J 7.93 (d, 1= 7.88 Hz, 1H), 7.30-7 .05 (m, 2H), 2.91 (t, 1=5.72 Hz, 2H), 2.63 (t, 1=6.23 Hz, 2H), 2.37(s, 3H), 2.11 (t, 1=6.23 Hz, 2H); IR (KBr, cm-'): 1682, 1608; MS (CI, i-Butane): mlz 160 (M+, 30).

Preparation of 2-bromo-a-tetralone 38 (R2=H, CH3). To a solution of 37 (R'= H, CH3) (6.25 mrnoles) in acetic acid (10 mL) was added 40% aque­ous solution of HBr (1mL) followed by the addition of bromine (6.18 mmoles) solution in acetic acid (2 mL) at 25°C. The solution was stirred for 3 hr at 25 °C and then poured into water (10 mL) followed by extraction with EtOAc (2 x 30 mL). Combined or­ganic layer was washed with water (3 x 50 mL), dried over anhydrous Na2S04 and concentrated to give the desired bromo ketone.

2-Bromo-a-tetralone ·38 (R2 = H): yield 67 %; 'H NMR (200 MHz, CDCb): J 8.2-8.0 (m, 1H), 7.6-7.2 (m, 3H), 4.7 (m, IH) , 3.4-3.2 (m, 1H), 3.0-2 .89 (m, IH), 2.7-2.4 (m, 2H); IR (KBr, cm-' ): 1684, 1599; MS (Cl , CH4): mlz 226 (M+, 25 ), 144 (60), 118 (100).

2-Bromo-7-methyl-a-tetralone 38 (R2 = CH3):

yield 30 %; 'H NMR (200 MHz, CDCb): () 8.04-8.00 (m, IH), 7.4-7.0 (m, 2H), 4.7 (m, IH), 3.4-3.2 (m, 2H), 3.0-2.8 (m, 2H), 2.6-2.3 (m, 5H); IR (KEr, cm-') : 1682, 1610; MS (CI, i-Butane) : mlz 240 (M+, 9), 132 (100). .

Preparation of an ester 39. To a solution of ary­lacetic ac id (21.9 mmoles) in DMF (50 mL) was added slowly a solution of potass ium hydroxide (26.3 mrnoles) in water (10 mL) and the mixture was stirred for 0.5 hr at 1O-15°C. A solution of 38 (26.3 mmoles) in DMF (50 mL) was added to this mixture and sti r­ring was continued for 3 hr at 25°C. The mixture was then poured into water (250 mL) and extracted with EtOAc (2 x ISO mL). Combined organic layer was washed with water, dried over anhydrous Na2S 0 4 and concentrated in vacuo. The resulting residue was puri­fied over silica gel using 10% EtOAc-petroleum ether (60-80 DC) (500 mL) to give the required ester 39.

1-0xo-l ,2,3,4-tetrahydro-2-naphthalenyl-2-( 4-methylsulfanylphenyl)acetate 39 ( R = H, R' = C6HsSMe-p): low melting solid; yield 41 %; 'H NMR (200 MHz, CDCb): J 8.00 (d, 1 = 7.88 Hz, IH), 7.5 1-7.20 (m, 7H), 5.55 (m, IH), 3.76 (s, 2H), 3.19-3.11 (m, 2H), 2.46 (s, 3H), 2.36-2.28 (m, 2H); IR (KEr, cm-') : 1743, 1701,1603; MS (CI, i-Butane): mlz 326 (M+, 10), 164 (100). Anal. Found: C, 69.92; H, 5.56. C'9H' S0 3S requires C, 70.06; H, 5.52%.

7 -Methyl-l-oxo-l,2,3,4-tetrahydro-2-naphthale­nyl-2-(4-methylsulfanylphenyl)acetate 39 ( R = Me, R' = C6HsSMe-p): low melting solid; yield 55 %; 'H NMR (200 MHz, CDCh): J 7.91 (d, 1 = 8.21 Hz, IH) , 7.31-7 .04 (m, 6H), 5.52 (m, IH), 3.75 (s, 2H), 3.11-3.01 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 2.31-2.25 (m, 2H); IR (KBr, cm-') : 1741, 1697, 1608; MS (CI, i-Butane) mlz 341 (M+, 28), 177 (70), 164 (100) ; Anal. Found: C, 70.46; H, 5.93. C2oH200 3S requires C, 70.56; H, 5.92%.

Preparation of furanones 29, 30, 26 and 28 General procedure. To a solution of 39 (7.6

mrnoles) in acetonitrile (50 mL) was added slowly di azobicyc!o[5.4.0]undec-7ene (11.5 mmoles) under nitrogene atmosphere at 1O-15°C. The mixture was stirred for 0.5 hr at 1O-15°C followed by the addition of water (50 mL) and 2N HCI (50 mL). The mixture was extracted with EtOAc (3 x 50 mL) . Combined organic layer was washed with water (2 x 100 mL) and dried over anhydrous Na2S04. After removal of solvent under vacuum the crude product was puri fied by column chromatography over silica gel using 10% EtOAc-petroleum ether (60-80 0c) (400 mL) to give the desired product.

1-( 4-Methylsulfanylphenyl)-2,3a,4,S-tetrahydro­naphtho[2,1-b]furan-2-one 29: yield 13%; mp 112-14 °C; 'H NMR (200 MHz,CDCb): J 7.6-7 .0 (m, 8H), 5.11 (dd, 1 = 4.95 Hz, 1H), 3.19 (m, 2H), 2.6 (m, lH), 2.5 (m, 3H), 2.0 (s, IH); IR (KEr, cm-'): 1742, 1657, 1597; MS (CI, i-Butane): mlz 309 (M+, 30), 308 (100). Anal. Found: C, 74.2 1; H, 5.13. C'9H'60 2S re­quires C, 74.00; H, 5.23%.

8-Methyl-l-( 4-methylsulfanylphenyl)-2,3a,4,S-tet­rahydronaphtho[2,1-b]furan-2-one 30: yield 32%, mp 144-45 DC; 'H NMR (200 MHz, CDCI3): J 7.9 (d, 1=8 .3 Hz, 2H), 7.68 (d, 1= 8.07 Hz, 2H), 7.3-7.1 (m, 2H), 7.0 (d, 1= 8.3 Hz, IH), 5.11 (dd, 1= 4.99 Hz, IH), 3.18 (m, 2H), 3.09 (s, 3H), 2.76-2 .7 (m, IH), 2.34 (s, 3H), 2.06 (m, IH); I3C NMR (50 MHz, CDCI3): 6 172.48 (C=O), 159.42, 142.38, 138 .55, 136.71 , 132.64, 131.56, 130.31, 130.03, 129.52, 129.38, 127.66, 127.6 1, 126.50, 123.89,78.74,29.73,

600 INDIAN J. CHEM., SEC B, MARCH 2003

27 .38,21.48, 15.90; IR (KBr, cm· I): 1739; MS (CI, i­Butane): mlz 322 (M+, 100), 246 (40), 218 (42), 203 (51). Anal. Found: C, 74.58; H, 5.61. C2oHI 80 2S re­quires C, 74.51; H, 5.63 %.

5-Ethy 1-5-hydroxy -3-( 4-meth y Isulfan yl ph en y 1 )-4-phenyl-2,5-dihydro-2-furanone 26: yield 35%; IH NMR (200 MHz, CDCI3) : £5 7.52-7 .13 (m, 9H), 3.86 (bs, 1 H, D20 exchangeable), 2.47 (s, 3H), 2.11 (m,lH), 1.92 (m,IH), 0.89 (t, J= 7.47 Hz, 3H); IR (KBr, cm'I): 3363, 1740; MS (CI, i-Butane): mlz 326 (M+, 10),308 (100), 205 (57). Anal. Found: C, 69.81; H, 5.67. CI9HI 80 3S requires C, 69.92; H, 5.56%.

5-Ethyl-5-hydroxy-3,4-diphenyl-2,5-dihydro-2-furanone 28: yield 89%; mp 93-94 DC; IH NMR (200 MHz, CDCb): £5 7.5-7.2 (m,lOH), 3.55 (bs, IH , D20 exchangeable), 2.09-2.02 (m, 2H), 0.91-0.83 (t, J=7.4Hz, 3H); 13C NMR (50 MHz, CDCb): £5 172.46 (C=O), 159.64, 139.36, 131.25, 129.87, 129.71 , 129.45, 128.92, 128.68, 128.54, 127.86, 126.16, 126.03, 125.78, 125.53 , 115.73, 25.48 (CH2), 8.05 (CH3); IR (KBr, cm'I): 3319, 1739; MS (CI, i­Butane): I11/Z 280 (M+, 11),262 (93),178 (100). Anal. Found: C, 77 .21; H, 5.66. CI8HI 60 3 requires C, 77.13 ; H, 5.75 %.

Acknowledgement The authors thank Dr A Venkateswarlu, Dr R Ra­

jagopalan and Prof. J Iqbal for their constant encour­agement and the Analytical Department for spectral support. Authors also thank Mr P Vijayaraghavan and Mr P Karuppasamy for their help in manuscript preparation.

References and Notes I Gans K R, Galbraith W K, Roman R J, Haber S B, Kerr J S,

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2 Futaki N, Takahashi S, Yokoyama M, Arai I, Higuchi S & Otomo S, Prostaglandins, 47,1994,55.

3 (a) Simon L S, Lanza F L, Lipsky P E, Hubbard R C, Talwalker S, Schwart B 0 , Isakson P C & Geis G S, Arthritis Rheumatism, 41,1998, 159 1. (b) Penning T 0, Talley J J, Bertenshaw S R, Carter J S, Collins P W, Doctor S, Graneto M J, Lee L F, Malecha J W, Miyashiro J M, Rogers R S, Rogier ° J, Yu S S, Anderson G 0 , Berton E G, Cogburn J N, Gregory S A, Kobolt C M, Perkins W E, Seibert K, Veenhui zen A W, Zhang Y Y & laskson PC, J Med Chem, 40,1997,1347.

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5 Riendeau 0 , Percival M 0 , Boyce S, Brideau C, Charl son S, Cromlish W, Ethier 0 , Evans J, Falgueyret J -P, Ford­Hutchinson A W, Gordon R, Greig G, Gresser M, Guay J, Kargman S, Leger S, Mancini J A, a Neil G, Ouellet M, Rodger I W, Therien M, Wang Z, Webb J K, Wong E, Xu L, Young R N, Zamboni R, Prasi t P & Chan C -C, B J Pharmacol, 121 , 1997,105.

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7 Habeeb A G, Praveen Rao P N & Knaus E E, J Med Chem, 2001,44,3039 and references cited therein.

8 Synthesis from a-haloketone and arylacetic acid (a) Dikshit ° K, Shing S, Sing M M & Kamboj V P, Indian J Chem, lOB, 19910, 954. (b) Vijayaraghavan S T & Balasubramanian T R, Indian J Chem, 25B, 1986, 760. (c) Wakharkar R 0 , Deshpande V H, Landge A B & Upadhye B K, Synth Commun, 17, 1987, 151 3. (d) Therien M, Gauthier J Y, Leblanc Y, Leger S, Perrier H, Prasit P & Wang Z, Synthesis, 12, 2001, 1778. Synthesis via magnesium mediated carbometallation of propargyl alcohols: (e) Forgione P, Wilson P ° & Fallis A G, Tetrahedron Lett , 41 , 2000, 17 and references cited therein . Synthesis by palladium catalyzed reactions (f) Crisp G T & Meyer A G, J Org Chem, 57,1992,6972. (g) Mahon R, Richecoeur A M E & Sweeney J B, J Org Chem, 64, 1999,328. (h) Rossi R, Bellina F & Raugei E, SYlliell, 12, 2000, 1749 and references cited therein .

9 (a) The reaction of 2-bromo-a-tetralone wi th arylaceti c ac id was affected by the concentration of alkali . The bromo compound participated in eliminati on reaction in the presence of excess alkali leading to the formation of a , ~­unsaturated ketone rather than the required ester. (b) A detailed report on the reaction mechanism and related studies will be publi shed elsewhere. For a preliminary account see Pattabiraman V R, Padakami P S, Veeramaneni V R, Pal M & Yeleswarapu K R, Synlett . 2002, 947. (c) Padakanti S, Veeramaneni V R, Pattabiraman V R, Pal M & Yeleswarapu K R, Tetrahedron Lett,2002, 43,8715.

10 Brideau C, Kargman S, Liu S, Dallob A L, Ehrich E W, Rodger I W & Chan C -C, Injlamm Res, 45. 1996,68.

II Chan C -C, Boyce S, Brideau C, Ford-Hutchinson A W, Gordon R, Guoy 0 , Hill R G, Li C oS, Mancini J, Penneton M, Prasit P, Rasori R, Riendeau 0 , Roy P, Tagari P, Vickers

RAPID COMMUNICATIONS 601

P, Wong E & Rodger I W, J Pharmacol Exp Ther, 274, 1995,1531.

12 Rome L H & Lands W EM, Proc Natl Acad Sci USA, 72, 1975,4863.

13 Meyer-Kirchrath J & Schor K, Curr Med Chem, 7, 2000, 1121.

14 (a) Halpin R A, Geer L A, Zhang K E, Marks T M, Dean D C, Jones A N, Melillo D, Doss G & Vyas K P, Drug Metab Dispos, 28, 2000, 1244.

(b) We have synthesized all the possible major metabolites of I , the details of which along with their pharmacological properties will be communicated soon.

15 Pal M, Rao Y K, Rajagopalan R, Misra P, Kumar P M & Rao C S, World Patent WO 01/90097, 29 Nov 2001 ; Chem Abstr, 2002, 136,5893.

16 It has been shown that COX-I select ive inhibitor such as Resveratrol could be useful as ant icancer agent, for example see, Drug Data Rep, 19(4), 1997, 372.