N,N 1, - NISCAIRnopr.niscair.res.in/bitstream/123456789/22073/1/IJCB 41B(10) 2172 … · Glycolamide ester prodrugs of some frequently used NSAIDs have been prepared by condensing

Indian Journal of Chemistry Vol. 4 1 8, October 2002, pp. 2 1 72-2 1 75

Synthesis and biological evaluation of glycolamide esters as potential prodrugs of

some non-steroidal anti-inflammatory drugs

M S Y Khan* & R M Khan

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 1 10062, India

Received 4 January 2002; accepted 12 April 2002

Glycolamide ester prodrugs of some frequently used NSAIDs have been prepared by condensing them with N,N­disubstituted-2-chloroacetamides. These compounds were evaluated for their or toxicity in rats, which was markedly reduced in comparison to their parent moieties, their anti-inflammatory and analgesic activities were comparable to the parent drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications in the world. In 1988, it was estimated that 100 million prescriptions were written for NSAIDs annually in the United States alonel •2 . The major limiting side effects of chronic NSAIDs are gastrointestinal (GI) symptoms and complications. Prevalence studies have demonstrated that gastric or duodenal ulcers are present in 1 5-20% of patients taking NSAIDs chronically3.

4. The incidences of significant

gastrointestinal complications (bleeding, perforation, or gastric outlet obstruction) have been estimated to be 1 -4% per year from population studies5-7 . Even though the incidences of significant complications seem small, the large number of patients at risk make NSAID-induced GI complications a significant health hazard.

In addition to the increased morbidity and mortality, these GI complications contribute considerably to the cost of care. Database studies have suggested that the direct cost of treating GI symptoms and complications comprise 3 1 -40% of the total cost of care for arthritis patients8•9 and that adverse event occurs in 25% of patients. Numerous perspective studies have identified a prevalence of 1 5-20% for gastric ulcers and 5-8% for duodenal ulcers after 1 2 weeks o f therapl.

Viewing the above important factors the present studies were undertaken to modify the existing NSAIDs associated with 01 toxicities by the prodrug approach so as to alleviate these undesirable effects. In the present studies, the free acidic group in these drugs was temporarily masked by a promoiety so as not to expose stomach's mucosa to this free

carboxylic acidic group. The glycolamide ester prodrugs of ibuprofen 1 , diclofenac 2, naproxen 3, mefenamic acid 4 and indomethacin 5 were synthesised. The glycolamide esters have been reported to be bioreversible and chemically stable prodrugs of carboxylic acid drugs 10. 1 1 . These prodrugs were synthesised by condensing these NSAIDs with N,N-disubstituted-2-chloroacetamides by following the Scheme I. Their ulcerogenic potential was determined in rats and compared with parent drugs. These prodrugs were also evaluated for their anti­inflammatory and analgesic activities to find out their efficacy in comparison to the parent compounds.

Biological Evaluations Anti-inflammatory activity

Anti-inflammatory activity was determined by the method of Winter et al.. 1 2 against carrageenan induced rat paw edema. Percentage reduction in edema at 3 hr in comparison to control is presented in Table I. All the glycolamide ester prodrugs showed activity comparable to their parent drugs, however, prodrugs 2a and 2b of diclofenac 2 showed improved activity over their parent moiety.

Analgesic activity Analgesic activity was determined in mice by

acetic acid induced writhing method 1 3 . The decrease in number of writhings expressed as percentage protection with reference to control is given in Table I. These prodrugs were found to be more active than their parent drugs. Prodrugs 3a and 3b of naproxen 3 and 4a and 4b of mefenamic acid 4 in particular showed a marked increase in activity. All

KHAN et al. . : SYNTHESIS AND BIOLOGICAL EV ALUA TION OF GL YCOLAMIDE ESTERS

�OH

1 o ceOH h& 4

GI H£O OH �N

I � llAGI �

2

MeO�OH

��I� O N �o GIN

5

H2 �1 H2 �1 RGOOH + GI ...... GyN,R1 o _GyN, RGOO II R1 o

R 1 = ethyl or isopropyl R = 1 to 5 minus carboxyl group Scheme I

Table I--Comparative study of Glycolamide prodrugs with respect to their gastrointestinal toxicity, analgesic and anti-inflammatory activities

Compd Gastric Ulcers (mean/score) Analgesic activity Anti-inflammatory activity No. of Writhings/% Protection Mean paw volume/% Inhibition

la 1 .5±O.27/ 1 .0 I 0.49± 1 . 84/64.2 0.27 1 ±O.0 1 2/57. 1 Ib 1 .66±O.29/1 .0 9.83±O.81/66.4 0.233±0.08/63.0 Ibuprofen 1 9. 16± 1 .27/3.0 1 0.99±2.33/62.5 0.237±0.033/62.4 2a 2.0±0. 16/2.0 8. 16±O. 19172. I 0.250±0.039/60.4 2b 1 .83±0.22/1 .0 8.99±0.45/69.3 0.256±0.087 /59.4 Diclofenac Na 2 7 . 16±0.79/3.0 9.99±1 .23/65.9 0.333±0.039/47.2 3a 2.83±O.6212.0 1 1 .66±O.89/60.2 0.268±0.0 12/57.5 3b 1 . 1 6±O.33/ 1 .0 1 2.33±O.67/57.9 0.276±O.033/56.2 Naproxen 3 9.66±1 .33/3.0 14.33± 1 .46/50.0 0.0.250±0.0 19/60.3 4a 2.5±O.5912.0 1 1 .83±O.62/59.6 0.283±0.085/55.2 4b 3.0±O.82/2.0 9.66±O.94/67.0 0.263±0.04/58.3 Mefenamic acid 4 12.33±1 .45/4.0 14.33± 1 .03/5 1 . 1 0.288±O.04/54.3 Sa 1 .66±O.39/1 .0 1O. 16± 1 . l 4/65.3 0.273±0.092/56.8 5b 2.83±O.6912.0 1O.83±O.94/63.0 0.257±0.0 12/59.3 Indomethacin 5 I I .33±2.79/4.0 1 1 .83±O.67/59.6 0.272±O.092/56.9

Control -/- 29.33±1 .07/- 0.632±O.56/-

± Indicates standard error (n = 6).

2 173

other glycol amide esters showed activity comparable to their parent drugs.

.

Gastrointestinal toxicity Subacute gastrointestinal toxIcity studies were

done by the method of Wilhemi et at. 14. The animals

were divided in groups with six animals in each group. Control group was given only 0.5% CMC suspension. Compounds were administered orally once in a day for 1 0 days. The animals were fasted for 8 hr prior to dosing and for 4 hr post dosing. Food was available at all other times, free access to water

2 1 74 I N DIAN J . CHEM., S EC B, OCTOBER 2002

was provided throughout the experiment. Four hr after the last dose, the an imals were sacrificed using chloroform. The abdomen was opened at the midline and the stomach and the first 3cm of the duodenum were removed. The stomach was opened along the larger curvature and washed wi th di stilled water. The mucus was wiped off and the numbers of ulcers were examined by means of a magnifying glass. All u lcers were counted and recorded as average number of u lcers per animal and assessed as score rNo ulcers (0.0), less than 2 ulcers ( 1 .0 ) , 2-5 u lcers (2 . c) , 5- 1 0 ulcers (3 .0), more than 1 0 ulcers (4.c) J . The results are given in Table I . Al l the synthesised glycolamide esters considerably reduced GI toxicity as compared to the ir parent drugs. Prodrugs 3a and 3b showed 70-88% less ulceration than naproxen 3 whi le prodrugs la, I b and Sa, Sb were found to be less u lcerogenic by 75-84% in comparison to their parent drugs 1 and 5. Prodrugs of 2 and 4 were less ulcerogen ic by 66-80%.

Experimental Section Melting points were taken in open capi l laries and

are uncorrected. I H N M R spectra were recorded in CDC!., on a Bruker 300 MHz instrument us ing TMS as internal standard. Chemical shift values are reported in ppm (8). Purity of the compounds was checked by TLC on s i lica gel G plates and the spots were located by exposure to iodine vapours. Microanalyses of all these compounds were within ± 0.4%.

General method of synthesis of N,N-disubsti­tuted-2-chloro acetamides. N,N-diethyl-2-chloroa­cetamide and N,N-diisopropyl -2-chloro-acet-amide were prepared by reported method 1 5 .

General method for synthesis of glycol amide

esters. To a solution of the appropriate N S A I D (0.0 1 mole) in ethyl acetate (40 mL) were added triethy lamine (0.0 I I mole; 1 .53mL), sodium iodide (0.00 I mol ; 0. 1 5g) and N,N-di-substituted -2-chloro­acetamide (O.O l mole). The mixture was refluxed for 3 hr on a water-bath, cooled and fi ltered. The filtrate was washed with 2% sodium thiosulphate sol ution, 2% sodium bicarbonate and water, dried and ethyl acetate removed under reduced pressure. A semi-solid mass so obtained was puri fied on a column of sil ica gel and crystal l ised from ethanol to give TLC pure crystal line compounds.

N,N-DiethylcarbamoylmethyI 2-(4-isobutylphenyl) propionate la: Yield 2 .6g (8 1 %), semi-solid (Found: C, 7 1 .23; H, 9.28; N , 4. 1 8 . C I 9H29N03 requires C,

7 1 .44; H , 9 . 1 5 ; N , 4.38 %); I H N M R (CDCb): 80.9 (d, 6H, -CH(CH3)2) ; 1 . 1 2 and 1 . 1 3 (t, 3H each, 2xN(CH2CH) ; 1 .5 (d, 3H, >CH-CH3) ; 1 . 83 (m, I H , -CH(CH3h); 2.4 (d, 2H, CHz); 3 . 1 9 and 3 .35 (q, 2H each, , 2xN(CH2CH3) ; 3 .83 (q, I H , >CH-CH3) ; 4.6 and 4.7 (d, IH each, OCH2CO); 7.07 and 7 .2 (d, 2H each, aromatic) .

N,N-Diisopropylcarbamoylmethyl 2-(4-isobutyl­phenyl)-propionate Ib: Yield 2 .8g (80%), sem i-solid (Found: C, 72.2 1 ; H, 9.64: N, 3 .89. C21 H13NO)

requires C, 72.58 ; H, 9.57 ; N, 4.03%) ; C(CDCl,) : 0 0.8 (d , 6H, -CH(CH1h); 1 . 1 and 1 .3 (m, 6H each, 2xN­CH(CH1h); 1 .45 (d, 3H, >CH-CH) ; 1 .7 (m, I H, -CH­(CH3h); 2.35 (d, 2H, C H2); 3 .39 and 3.5 (m, I H each, 2xM-CH(CH.,h); 3 .79 (q, I J l. >CH:C H 3 ) ; 4.4 and 4.6 (d, I H each, OCH2CO); '1 .0 and 7 . 1 (d, 2H each, aromatic) .

N,N-Diethylcarbamoylmethyl 2-[(2',6'-dichloro­

phenyl) amino]phenyl acetate 2a: Yield 3 .5g (85 .7%) , yel low crystals , m.p . 90-92° (Found: C, 58 .42; 1- 1 , 5 .5 1 ; N , 6.58. C2ol-lnN20,Cl2 requires C,

58 .69 ; H, 5 .42; N , 6.84%); I H NMR (CDC,, ) : 8 1 . 1 2 and 1 . 1 7 (t , 3H each, 2xN(CH2CH, ) ; 3 . 2 and 3 . 7 (q, 2H each, 2xN(CH2CI-I) ; 3.9 (s , 2H CHz); 4.77 (s, 21-1 , OCH2CO); 6.5 (dd, I H, 1-13 ) ; 6.86 (s, 1 1-1, N I-I ) ; 6.96 (m, 2H, H4, 1-1 5 ) ; 7. 1 (dt, I H , H4'); 7 .25 (dd, I H, H6) ; 7 .3 1 (d , 2 1-1 , H3 ', H5' ) .

N,N-DiisopropyJcarbamoylmethyJ 2-[(2', 6'­dichlorophenyl) amino] phenyl acetate 2b: Yield 3 .8g (87%), yel low crystals, m.p. I 1 8-20° (Found: C, 60. 1 8 ; H, 5 .73 ; N, 6. 1 9. C21 H2c,N20,Cl2 requires C,

60.42; H, 5 .99: N, 6.40%); I H NMR (CDCb) : 8 1 .2 and 1 .3 (m, 61-1 each, 2xN-CH (CHlh); 3 .48 and 3 .6 (m, I H each, 2xN-CH(CH3h); 3 .9 (s, 2H, CH2); 4.73 (s , 2H, OCH2CO) ; 6.52 (dd, I H, H3); 6.87 (s, I H, N H ) ; 6.96 (m, 2H, H4, H5); 7. 1 1 (dt, 1 H , 1-14'); 7.2 (dd, 1 1-1 , 1-16) ; 7.32 (d, 2H, H3' , H5') .

N,N-Diethylcarbamoylmethyl-6-methoxy-a-me­thyl-2-naphthyl acetate 3a: Yield 2.8g (82%), m.p. 52-54° (Found: C, 69.73; H , 7 . 1 8 ; N, 4.28. C2oH25NO.j requires C, 69.95; H, 7.34 ; N, 4.08%); 1 1-1 NM R (CDCb): 8 1 .05 and 1 . 1 2 (t , 3H each, 2xN(CH2CH,,) ; 1 .52 (d, 3H, >CH-CH3) ; 3 . 1 and 3 .27 (q, 21-1 each, 2xN(CH2CH) ; 3 .79 (s, 3H, -OCH3) ; 3 .9 1 (q, I H, >CH-CH3); 4 .44 and 4.69 (d, I H each, OCH2CO) ; 7 .0 (m, 2H, H5 , H7) ; 7 .33 (m, 1 H, H3) ; 7 .60 (m, 3H, H I , H4, H8) .

N,N-Diisopropylcarbamoylmethyl 6-methoxy-a­methyl-2-naphthyl acetate 3b: Yield; 2.5g (67%), semi-solid (Found: C, 7 1 .25 ; H , 7 .64; N , 3.49 .

KHAN et al .. : SYNTHESIS AND BIOLOGICAL EV ALUATION OF GL YCOLAMIDE ESTERS 2 175

C22H29N04 requires C, 7 1 . 1 3 ; H , 7 .87 ; N, 3 .77%); lH NMR (COCl)) : 8 1 . 1 and 1 .3 (m, 6H each, 2xN­CH(CH3h); I .S (d, 3H, >CH-CH3) ; 3 .39 and 3 .56 (m, I H each, 2xN-CH(CH3h); 3 .7 (s, 3H, -OCH3); 3.9 (q, IH, >CH-CH}) ; 4.6 (s, 2H, OCH2CO); 7 . 1 2 (m, 2H, HS, H7) ; 7 .43 (m, I H, H3) ; 7 .7 (m, 3H, H I , H4, H8) .

N,N-Diethylcarbamoylmethyl 2-(2', 3'-dimethyl­

phenyl) amino benzoate 4a: Yield 2 .3g (65%), semi­solid (Found: C, 70.89; H , 7 . 14 ; N , 7 .72. C21H26N203 requires C, 7 1 . 1 6; H, 7 .39; N, 7 .90%); l H NMR (COCb) : 8 1 .06 and 1 . 1 4 (t, 3H each, 2xN(CH2CH}) ; 2.08 (s , 3H, CH3) ; 2 .24 (s, 3H, CH3); 3 . 1 8 and 3 .33 (q, 2H each, 2xN(CH2CH3); 4.89 (s, 2H, OCH2CO); 6 .S (m, 2H, H4' , H6') ; 6.9 (dt, I H, H5 ' ) ; 7 .04 (m, 2H, H3, H5); 7 .20 (m, l H, H4); 7 .98 (m, I H, H6) ; 9.0 (bs, I H, NH).

N,N-Diisopropylcarbamoylmethyl 2-(2', 3'· dimethyl phenyl) amino benzoate 4b: Yield 2 .9g (76%), semi-solid (Found: C, 72.48 ; H, 7 .68; N, 7 .46. C23H30N203 requires C, 72.22; H, 7 .9 1 N, 7 .32%); lH NMR (COCl)): 8 1 . 14 and 1 .3 (m, 6H each, 2xN­CH(CH3U; 2. 1 (s, 3H, CH3); 2.2 (s, 3H, CH3); 3 .39 and 3.5 (m, I H each, 2xN-CH(CH)h); 4.6 (s, 2H, OCH2CO); 6.5 (m, 2H, H4' H6') ; 6.9 (m, 1 H, H5') ; 7 .0S (m, I H, H3, HS); 7 . 1 (m, I H, H4); 7 .98 (m, I H, H6); 8 .9 (bs, 1 H, NH).

N,N-DiethylcarbamoyJmethyl l-(p-chlorobenzoyl)-5- methoxy -2 - methyl-3-indolyl acetate 5a: Yield 3 .8g (8 1 %), m.p. 1 1 2- 1 14° (Found: C, 63 .57 ; H , S .43 ; N, S .74. C2sH27ClN20S requires C, 63.76; H, 5 .78 ; N , 5.95%); l H NMR (COCb) : 8 1 . 1 and 1 . 14 (t, 3H each, 2xN(CH2CH3); 2.4 (s, 3H, CH3) ; 3 .2 and 3 .4 (q, 2H each, 2xN(CH2CH3) ; 3 . 8 1 (s , 2H, CH2) ; 3 . 83 (s , 3H, -OCH3); 4.7 (s, 2H, OCH2CO) ; 6.64 (dd, I H, H6); 6 .85 (d, I H, H7) ; 7 .02 (d, I H, H4) ; 7 .43 and 7 .63 (d, 2H each, p-chlorobenzoyl) .

N,N -Diisopropylcarbamoylmethyl-l-(p-chloroben­

zoyl)-5-methoxy-3-indolyl acetate 5b: Yield 4.2g

(84%), m.p. 1 42- 1 44° (Found: C, 64.8 1 ; H , 6.4 1 ; N, 5 .39. C27H3 1CIN20S requires C, 64.99; H , 6.26; N, 5 .6 1 %) ; l H NMR (COCh): 8 1 .2 and 1 .4 (m, 6H each, 2xN-CH(CHJ}2), 2.39 (s, 3H, CH3); 3.48 and 3.67 (m, I H each, 2xN-CH(CH3h) 3 . 85 (s, 2H, CH2); 3 .87 (s, 3H, -OCH3); 4.7 1 (s, 2H, OCH2CO); 6.6 (dd, I H, H6); 6 .8 (d, I H, H7) ; 7 .07 (d, I H , H4) ; 7 .47 and 7 .66 (d, 2H each, p-chlorobenzoyl) .

Acknowledgement

The authors are thankful to late Hk. Abdul Hameed Sahib (Founder of lamia Hamdard) and Mr. Abdul Mueed (President, Hamdard National Foundation) for their interest i n these studies. One of the authors (RMK) is thankful to CSIR, New Oelhi for the award of a Senior Research Fellowship (SRF).

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