Manjunath Ghate* & Manohar V Kulkarni.

Transcription

1 Indian Journal of Chemistry Vol. 44B, August 2005, pp Synthesis and anti-inflammatory activity of 4-(5'-acetyl-6'-hydroxy -3'-methylbenzofuran-2'-yl) coumarin and 6-acetyl-3, 7-dimethyl-2-(coumarin-4'-yl) furo [3,2-g] chromen-5-one Manjunath Ghate* & Manohar V Kulkarni Department of Chemistry, Karnatak University, Dharwad , India Department of Pharmaceutical Chemistry, Krupanidhi College of Pharmacy, Koramangala, Bangalore , India eceived 19 November 2003; accepted (revised) 1 March ghate72@yahoo.com Various 4-bromomethylcoumarins 1 have been reacted with diacetyl resorcinol 2 to afford corresponding ethers 3, which undergo intermolecular aldol condensation followed by dehydration to form 4-(5'-acetyl-6'-hydroxy-3'- methylbenzofuran-2'-yl) coumarin 4. Further compound 4 on reaction with sodium acetate and acetic anhydride afford 6- acetyl-3, 7-dimethyl-2-(coumarin 4'-yl) furo [3,2-g] chromen-5-one 5. Their structures have been confirmed by I, NM and mass spectral data. f these compounds, 4e, 4f and 5e show good anti-inflammatory and analgesic activity. Keywords: Bromomethylcoumarins, diacetyl resorcinol, aldol condensation, chromone, anti-inflammatory activity IPC: Int.Cl. 7 C 07 D 311/00 // A 61 P 29/00 Coumarins are well-known natural products displaying a broad range of biological activities 1. Most of the synthetic coumarin derivatives have been found to possess diverse biological activities namely anticoagulant 2, spasmolytic 3, anthelmintic 4, diuretic 5 and anti-inflammatory 6 activities. 4-Pyridyl and 4-piperidylcoumarins have been found to exhibit CNS depresssant and analgesic activities in animal models 7-9. The halogenated furanylcoumarins show antimicrobial action 10, whereas isoxazolinyl and oxadiazolyl coumarins 11 inhibit enzymes like glucouronidase and 1,2-lipoxygenase. Further, 2-biheterocyclic benzofurans with furan 12, chromone 13 ring systems exhibit antibacterial, psychotropic and anti-inflammatory properties. ecently, we have found that ether linkage with biocompatible fragments like vanillin which were cyclised to form benzofuranyl coumarins leads to compounds with pronounced anti-inflammatory activity 14. In view of these observations and in continuation of our work on biheterocyclic coumarins the present paper reports the synthesis of 4-(furochromonyl)coumarin and 4-(benzofuranyl)coumarin and their pharmacological activities. The nucleophilic reactivity of diacetyl resorcinol has been exploited for the synthesis of these compounds. The basic synthetic route is outlined in Scheme I. The required 4-bromomethylcoumarins 1 have been synthesized by the Pechmann cyclization of various phenols with 4-bromoethylacetoacetate. eaction of 4-bromomethyl coumarins 1 with 2,4-diacetylresorcinol 2 in the presence of anhydrous potassium carbonate in dry actone gives ethers 3. The ether 3 on refluxing in dry dioxane in the presence of K 2 C 3 undergoes an intramolecular aldol condensation followed by dehydration to afford 4-(5'-acetyl-6'-hydroxy-3'-methyl-benzofuran- 2'-yl)coumarin 4. After the reaction was completed the product was concentrated and precipitated by pouring into ice. The formation of benzo[b]furanylcoumarin 4 involves the generation of carbanion at the active methylene group (4-CH 2 ) which undergoes an intramolecular aldol condensation via 2, 3-dihydrobenzofuran-3-ol followed by dehydration resulting in the formation of a conjugated biheterocyclic system. Towards the end of the subjection the compound 4 having ortho-hydroxyacetophenone moiety underwent Kostanecki method of cyclisation in the presence of sodium acetate and acetic anhydride to afford 6-acetyl-3,7-dimethyl-2-(coumarin-4'-yl) furo [3,2-g]- chromen 5-one 5 (Table I). It is interesting to note that the acylated product was obtained instead of 3-methylchromone. It is worthy to note that the reaction

2 GHATE et al.: SYNTHESIS F 4-(FUCHMNYL)- AND 4-(BENZFUANYL)-CUMAIN 1675 Br H H K 2 C 3 acetone, stirr 2a-f 1 3a-f H K 2 C 3 Dioxane, reflux did not proceed by the addition of equimolar quantity of the acetic anhydride instead the reaction underwent smoothly by the addition of excess amount of acetic anhydride. I, NM and mass spectral data confirmed the formation of acylated product. esults and Discussion The intermediates 3 (= 6- ) exhibited two bands in the I spectrum around 1670 and 1716 cm 1 that were assignable to aromatic carbonyl and lactone carbonyl stretching, respectively. The H stretching vibration was observed around 3084cm -1, is due to the intramolecular hydrogen bonding. The 1 H NM spectrum indicated the presence of and two C protons as a singlet at δ 2.44 and 2.54, respectively. The methylene protons were observed as singlet at δ 5.32, whereas the C 3 -H of coumarin was found at δ 6.52 and the aromatic multiplet was observed in the region at δ The H proton was observed in the downfield region at δ as singlet, which is exchangeable with D 2 (Table I). Compound 4 (=6- ) in its I spectum exhibited lactone carbonyl stretching band at 1728 cm -1 whereas the carbonyl of acetophenone moiety was observed at 1672cm -1 which is due to the hydrogen bonding with orthohydroxy group. A band observed at 3085 cm -1 was due to H stretching vibration. The 1 H NM spectrum indicated the presence of of coumarin, of benzofuran and C- of benzofuran as a singlet at δ 2.49, 2.57 and 2.66, respectively. The absence of methylene proton in the 4a-f H Scheme I ( C) 2 CNa o C 5a-d region of δ 5-6 indicate that CH 2 was involved in the cyclization. The C 3 -H of coumarin was observed as singlet at δ 6.63 and the aromatic multiplet observed at δ The H proton was observed in downfield region at δ which disappeared on D 2 exchange. Compound 5 (=6- ) exhibited broad band in the I spectrum around 1710 and 1718 cm -1 which was assigned to lactone carbonyl of coumarin and chromone. The absence of H band at the region of cm -1 was indicated by the formation of cyclised product. The 1 H NM spectrum of 5 (=6- ) indicated four singlets at δ 2.42, 2.45, 2.49 and 2.67 due to of coumarin, of benzofuran, of chromone and C- of chromone respectively. The C 3 -H of coumarins observed at δ 6.50, whereas the aromatic multiplet was observed around δ However, the absence of H peak in the region δ indicated the formation possible cyclised product chromone 5. Pharmacological Screening Seven of the new compounds prepared were screened for their pharmacological activity. Anti-inflammatory activity The compounds 4a, 4b, 4e, 4f, 5a, 5b, 5d were screened for anti-inflammatory activity by the carageenan induced edema model in rats 18 using phenylbutazone as standard. The rats were divided into two groups of six animals. ne group was kept as

3 1676 INDIAN J. CHEM., SEC B, AUGUST 2005 Table I Characterization data of compounds 3a-f, 4a-f and 5a-d Compd Mol. m.p. Yield Calcd (Found) % formula o C (%) C H 3a 6- C 21 H ( b 7- C 21 H ( c 5,6-Benzo C 24 H ( d 7,8-Benzo C 24 H ( e 6- C 21 H ( f 6-Cl C 20 H 15 6 Cl ( a 6- C 21 H ( b 7- C 21 H ( c 5,6-Benzo C 24 H ( d 7,8-Benzo C 24 H ( e 6- C 21 H ( f 6-Cl C 20 H 15 5 Cl ( a 6- C 25 H ( b 7- C 25 H ( c 5,6-Benzo C 28 H ( d 7,8-Benzo C 28 H (74.66 H signal was disappeared on D 2 exchange ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) 1 H NM (δ, ppm) 2.44 (s, 3H, ), 2.60 (s, 6H, C- ), 4.50 (s, 2H, CH 2 ), 6.52 (s, 1H, C 3 -H of coumarin), (m, 5H, Ar-H), (s, 1H, H) (s, 3H, ), 2.67 (s, 6H, C- ), 4.49 (s, 2H, CH 2 ), 6.47 (s, 1H, C 3 -H of coumarin), (m, 5H, Ar-H), (s, 1H, H) and 2.58 (s, 6H, C- ), 5.32 (s, 2H, CH 2 ), 6.64 (s, 1H, C 3 -H of coumarin), (m, 8H, Ar-H), (s, 1H, H) and 2.65 (s, 6H, C- ), 5.64 (s, 2H, CH 2 ), 6.34 (s, 1H, C 3 -H of coumarin), (m, 8H, Ar-H), (s, 1H, H) (s, 3H, ), 2.60 (s, 6H, C- ), 5.25 (s, 2H, CH 2 ) 6.53 (s, 1H, C 3 -H of coumarin), (m, 5H, Ar-H), (s, 1H, H) (s, 6H, C- ), 5.26 (s, 2H, CH 2 ) 6.38 (s, 1H, C 3 - H of coumarin), (m, 5H, Ar-H), (s, 1H, H) (s, 3H, ), 2.57 (s, 3H, of benzofuran), 2.66 (s, 3H, C- ), 6.52 (s, 1H, C 3 -H of coumarin), (m, 5H, Ar-H), (s, 1H, H) (s, 3H, ), 2.59 (s, 3H, of benzofuran, 2.65 (s, 3H, C- ), 6.42 (s, 1H, C 3 -H of coumarin), (m, 5H, Ar-H), (s, 1H, H) (s, 3H, of benzofuran, 2.69 (s, 3H, C- ), 6.55 (s, 1H, C 3 -H of coumarin), (m, 8H, Ar-H), (s, 1H, H) (s, 3H, of benzofuran, 2.62 (s, 3H, C- ), 6.40 (s, 1H, C 3 -H of coumarin), (m, 8H, Ar-H), (s, 1H, H) (s, 3H, ), 2.58 (s, 3H, of benzofuran), 2.60 (s, 3H, C- ), 6.53 (s, 1H, C 3 -H of coumarin), (m, 5H, Ar-H), (s, 1H, H)) (s, 3H, of benzofuran), 2.60 (s, 3H, C- ), 6.43 (s, 1H, C 3 -H of coumarin), (m, 5H, Ar-H), (s, 1H, H) (s, 3H, ), 2.45 (s, 3H, of benzofuran), 2.49 (s, 3H, of chromone) 2.67 (s, 3H, C- ), 6.50 (s, 1H, C 3 -H of coumarin), (m, 6H, Ar-H) (s, 3H, ), 2.47 (s, 3H, of benzofuran), 2.49 (s, 3H, of chromone) 2.68 (s, 3H, C- ), 6.52 (s, 1H, C 3 -H of coumarin), (m, 6H, Ar-H) (s, 3H, of benzofuran),2.52 (s, 3H, of chromone) 2.69 (s, 3H, C- ), 6.51 (s, 1H, C 3 -H of coumarin), (m, 9H, Ar-H) (s, 3H, of benzofuran),2.53 (s, 3H, of chromone), 2.70 (s, 3H, C- ), 6.53 (s, 1H, C 3 -H of coumarin), (m, 9H, Ar-H).

4 GHATE et al.: SYNTHESIS F 4-(FUCHMNYL)- AND 4-(BENZFUANYL)-CUMAIN 1677 control and other as standard had received 0.5% sodium carboxymethyl cellulose and phenylbutazone at a dose of 100mg/kg body weight orally. ut of the five compounds tested, three compounds showed significant (p < 0.05) activity. Among these compounds the compound 5a (=6- ) was found to be highly active with 62.5% edema inhibition and compounds 4e and 4f with methoxy and chloro groups were also found to be quite active. However, the other compounds were found to be less active. The edema volume and percentage inhibitions after 3hr are given in Table II. Analgesic activity The method was based on acetic acid induced writhing in mice 19. Group of three mice (in each group) were administered with test compounds, control and standard. The standard drug used was aspirin at a dose of 100mg/kg body weight orally. Among these compounds only three compounds 4e, 4f and 5a showed significant activity compared to standard phenylbutazone. However, other compounds were found to be less active compared to the standard. Compound 4e having the methoxy substitution in the 6 th position of coumarin ring was found to be more active (62.5%) among all these compounds. The percentage writhing inhibitions in 15 min are given in Table II Anti-inflammatory activity of the compounds 4a, 4b, 4e, 4f, 5a, 5b and 5d Group Compd Edema volume Edema (ml) ±SD after inhibition in (%) 3hr 1 4a 0.40± b 0.32± e 0.18± * 4 4f 0.18± * 5 5a 0.15± * 6 5b 0.29± d 0.26± Control 0.42±0.03 Phenylbutazone 0.13± * ±SD: Edema volume measured 3 hr after carageenan injection and expressed as mean ±standard deviation. * Statistically significant (p<0.05 Mann Whitney). Table III. Experimental Section The melting points were determined in open capillaries and are uncorrected. The I spectra were recorded on a Thermo Nicolet spectrometer; and 1 H NM on a Bruker Varian 300 MHz in CDCl 3 +DMS-d 6. Preparation of 4-[(2',4'-diaacetyl-5'-hydroxy)- phenoxymethyl]coumarins 3. A mixture of equimolar quantity of diacetyl resorcinol (0.004 mole, 0.53 g) and substituted 4-bromomethylcoumarins (0.004 mole, 1 g) was stirred for 10 hr in the presence of potassium carbonate (0.5 g) in dry acetone. The reaction was carried out in dry condition fitted with a guard tube. The reaction mixture was concentrated and poured onto crushed ice. The solid separated was filtered and washed with 10% HCl and twice with 100 ml of water. A white coloured solid thus obtained, was dried and recrystallised from dioxane-alcohol mixture to get 3 (Table I). Preparation of 4-(5'-acetyl-6'-hydroxy-3'- methyl-benzofuran-2'-yl)coumarin 4. Equimolar quantity of compound 3 and anhydrous potassium carbonate was refluxed in dry dioxane for 24 hr. The excess dioxane was removed under reduced pressure and the reaction mixture was poured into crushed ice. The solid separated was filtered and washed with dil. Table III Analgesic activity of compounds 4a, 4b, 4e, 4f, 5a, 5b and 5d Group Compd No. of writhing in15 minutes Writhing inhibition in (%) 1 4a 62± b 61± e 41±8 36.9* 4 4f 46±5 32.3* 5 5a 45±9 30.7* 6 5b 50± d 48± Control 68±8 Phenylbutazone 28± * ±SD: No. of writhes in 15 minutes beginning 5minutes after acetic acid injection, and expressed as ±std deviation * Statistically significant (p<0.05 student "t" test).

5 1678 INDIAN J. CHEM., SEC B, AUGUST 2005 HCl (10%) and finally with water and dried. ecrystallisation was done in dioxane to get 4 (Table I). Preparation of 6-acetyl-3, 7-dimethyl-2-(coumarin-4'-yl) furo [3, 2-g] chromen-5-one 5. A mixture of benzo furanyl coumarins 2 (0.5 g), sodium acetate (1 g) and acetic anhydride (1 ml) was refluxed at o C for 3 hr. The reaction mixture was poured onto crushed ice, stirred and left overnight. The separated product was filtered and washed with water and dried in vacuo. It was recrystallised from dioxane to get 5 (Table I). Conclusion The new series of coumarinyl furochromones 5 were prepared from benzofuranylcoumarins 4. Some of these compounds were tested for their analgesic and anti-inflammatory activities in animal models. It is evident from the animal experiments that compounds 4e, 4f and 5a showed very significant anti-inflammatory and analgesic activities. However, other compounds were moderately less active. Acknowledgement Authors are thankful to the Chairman, Department of Chemistry, Karnatak University, Dharwad and to Prof. Amit Kumar Das, Principal, Krupanidhi College of Pharmacy, Bangalore. 3 Andreani L L & Lapi E, Bull Chem Farm, 99, 1960, Zhang Y L, Chen B, Zheng K, Xu M, Zhang L & Lei X, Yaoxue XueBao, 17, 1982, 17; Chem Abstr, 96, 1982, Bonsignore L, Loy G, Secci D & Calignano L, European J Med Chem, 28, 1993, Kulkarni M V, Pujar B G & Patil V D, Arch Pharm, 316 (1), 1981, Pachecho H & Goho, Bull Soc Chim, France 1960, Moffet B, J Med Chem, 7, 1946, Thomson W & azdan K, South African Pat, ; Chem Abstr, 7, 1969, 68161d. 10 Sreenivasulu B, Sundaramurthy V & Subbarao N V, J Indian Chem Soc, 51, 1974, Nicolaides D & Fylakatakior N, J Heterocycl Chem, 33, 1996, Gullanmel J, oger, Lewrre M, Hercourt A & Cavin, Far Med Chem, 1, 1983, Banerji K D & Poddar D, J Indian Chem Soc, 51, 1972, Ghate Manjunath D, Kulkarni M V, Shobha & Kattimani S Y, European J Med Chem, 2003, 38, Hanmautgad S S, Kulkarni M V & Patil V D, Indian J Chem, 25B, 1985, Khan I A & Kulkarni M V, Indian J Chem, 38B, 1999, Shastry L A, Ghate M D & Kulkarni M V, Indian J Chem, 43B, 2004, Ghosh M N, Toxicology Studies in Fundamental Pharmacology, edited by Scientific Book Agency, Calcutta, 1984, Collier H J, Dinnen L C & Johnson C A, Br J Pharmacol Chemother, 32, 1968, 295. eferences 1 Murray D, Mendez J & Brown S A, edited by Murray, J Mendez and S Brown, The Natural Coumarins: ccurrence, Chemistry and Biochemistry, (John Wiley & Sons, New York, NY) 1982, Lednier D & Mitscher L A, The rganic Chemistry of Drug Synthesis, edited by (John Wiley and Sons, New York), 1977, 330 and reference cited therein.