INTRODUCTION:

Prodrug refers to a pharmacologically inactive compound that is converted to an active drug by a metabolic transformation¹. The term “Prodrug” was first introduced by Albert’s. This bioconversion or transformation may occur during and after absorption with in the body^2-4. Most of the drugs have side effects³ i.e. poor bioavailability, short duration of action, no specificity, incomplete absorption, poor aqueous solubility, high first-pass metabolism or other adverse effects effect on GI system, dyspepsia and low bioavailability^3-7. These side effects can be reduced by chemical approach called “Prodrug Approach” or “Prodrug Design”^{2, 12}. Prodrug approach is supposed to be a great method in increasing the desirable properties of drug and reduce side effects⁹. This strategy is an established part of drug development. Today many successful prodrugs have been developed with enhanced therapeutic efficiencies^4-7. Prodrug design may reduce the problem associated with solubility, absorption, distribution, site specificity, instability, toxicity, formulation and bioavailability problem^3-7. Prodrugs are frequently applied to mask polar and ionizable group of a drug molecule to improve membrane permeability and oral absorption²⁰. Prodrug are of many types i.e. ester, amide, carbonyl, azo etc. Ester prodrugs synthesized by reacting carboxylic acid group and alcohol group while amide prodrugs synthesized by coupling of amine and carboxylic acid group⁸. Ester prodrugs are of most common because ester bond is easily hydrolyzed by the many esterases found in body¹¹. The amide prodrugs have limited utility because of their high enzymatic stability in vivo⁸.

Ester based esterase sensitive prodrug system has been used for prodrugs of acids and alcohol⁴. The result from the studies indicated that ester based prodrugs had good chemical stability^{16, 17}.

Ibuprofen is one of the most important NSAID which is an orally administered which effect on a variety of inflammatory mediators¹⁰. It is an effective analgesic and anti-inflammatory agent with a good tolerability profile²². It is absorbed form the gastrointestinal tract. Through its analgesic and anti-inflammatory properties, like other NSAIDs it has some side effects like it affect GI system¹⁹, dyspepsia and low bioavailability²². Major side effect is that prostaglandin (which is necessary for mucosal defense) synthesis could be blocked by NSAIDs^19.Chlorzoxazone ester prodrugs of some acidic NSAIDs induced very little irritancy in the gastric mucosa²¹

Keeping in view the wide ranging biological activities of prodrugs of ibuprofen, it was considered worth while to synthesize some new prodrugs of Ibuprofen of biological and pharmacological interest.

Ibuprofen was made to react with different alcohols, via, 2-phenylethanol and its derivatives, in presence of oxalyl chloride, in dichloromethane (DCM) at ambient temperature, by stirring on magnetic stirrer for 6-8 hrs to yield coupled products. All the products were purified using column chromatography in appropriate solvent system. Chemical structures of compounds were determined by ¹H NMR, and FT-IR.¹H NMR spectra were recorded and peaks were interpreted.

In the present study, we report the synthesis and evaluation of ester prodrugs of Ibuprofen. The alcohol derivatives choose to mask the free carboxylic group of ibuprofen and prodrugs form could show varying degree of lipofilicity and less side effects.

Where:

In Scheme-I

R₁=HR₂=H R₃=H R₄=H R₅=H

Scheme-II

R₁=HR₂=H R₃=Br R₄=H R₅=H

Scheme-III

R₁=HR₂=Cl R₃=Cl R₄=H R₅=H

Scheme-IV

R₁=NO₂R₂=H R₃=H R₄=H R₅=H

Scheme-V

R₁=HR₂=OCH₃ R₃= OCH₃ R₄=H R₅=H

Scheme-VI

R₁=HR₂=H R₃= OCH₃ R₄=H R₅=H

Scheme-VII

R₁= CH₃R₂=H R₃=H R₄=H R₅=H

Objectives:

1. Design, synthesize and characterization novel prodrugs including ibuprofen and alcohol, which could improve the physiochemical and pharmaceutical properties of drug.

2. To increases the utility of ibuprofen by Prodrug Design

Experimental System:

1. Materials:

Chemicals obtained from S.D. fine and Merck was of reagent grade used as such without further purification unless otherwise specified. Solvent used were double distilled on Rota vapor. ¹H NMR spectra were recorded at room temperature on a 400 MHz spectrometer from Bruker in CDCl₃ solution. IR were recorded with resolution 4.00 cm^-1

2. Methods:

To a ice-water cooled solution of Ibuprofen (412mg, 2.0 mmol) in anhydrous dichloromethane (6.0ml, 3.0 ml/mmol), a solution of oxalyl chloride (0.26ml, 3.4mmol) in anhydrous dichloromethane (0.8ml, 3.0 ml/mmol) was added drop wise at 0ºc temperature under nitrogen atmosphere and stirred the reaction mixture for 10 minutes at 0ºc. Then removed the ice-water bath and stirred reaction mixture for 8 hrs at room temperature. Evaporated the volatiles from reaction mixture on high vacuum and diluted with anhydrous dichloromethane and cooled it to 0ºc. A solution of alcohol (2.0 mmol) in anhydrous dichloromethane (6.0ml, 3.0 ml/mmol), was then added at 0ºc, and reaction mixture was stirred at 0ºc for additional 10 minutes. Removed the ice water bath and stirred the reaction mixture for 3-4 hrs. at room temperature.

Reaction completion was checked by TLC using Ethyl acetate-Hexane (1:4) as an eluting solvent. Reaction was quenched by addition of water (10 ml). The organic

compound was extracted with ethyl acetate (3x20ml). Organic layer was washed with brine (3x20ml), dried over anhydrous Na₂SO₄and concentrated in vacuum.

Purification was done by column chromatography using silica (100-200) in ethyl acetate-hexane give required compounds as viscous liquids.

RESULTS AND DISCUSSION:

Scheme-I: Preparation of 2-phenylethyl 2-[4-(2-methylpropyl) phenyl] propanoate

¹H NMR (400 MHz, CDCl₃), δ 7.31 (d, J=7.3, 1H, Ar H), 7.23 (d, J=7.5, 2H, ArH), 7.19 (dd, J=3.2, 7.9, 2H, ArH), 7.11 (d, J=8.1, 2H, ArH), 7.08 (dd, J=8.0, 9.4, 2H, ArH), 4.32-4.22 (m, 2H, OCH₂), 3.67 (q, J=6.8, 1H, CH*), 2.85 (dt, J=7.0, 15.9, 2H, CH₂-Ph), 2.44 (d, J=6.8, 2H, CH₂-Ph), 1.84 (sex, J=6.8, 1H, CH*), 1.48 (d, J=7.2, 3H, CH₃), 0.90 (d, J=6.6, 6H, 2xCH₃)

IR: 1733 cm^-1 (ester)

Scheme-II: Preparation of 2-(4-bromophenyl)ethyl 2-[4-(2-methylpropyl)phenyl]propanoate

¹H NMR (400 MHz, CDCl₃), δ 7.36-7.31 (m, 2H, ArH), 7.13 (d, J=6.2, 2H, ArH), 7.08 (dd, J=8.2, 13.6, 2H, ArH ), 6.93 (d, J=8.3, 2H, ArH), 4.32-4.18 (m, 2H, OCH₂), 3.65 (q, J=7.2, 1H, CH*), 2.80 (dt, J=5.3, 6.7, 2H, CH₂-Ph), 2.44 (d, J=7.1, 2H, CH₂-Ph), 1.86 (sex, J=6.8, 1H, CH*), 1.44 (d, J=6.8, 3H, CH₃), 0.90 (d, J=6.6, 6H, 2xCH₃)

IR: 1735 cm^-1 (ester)

Scheme-III: Preparation of 2-(3,4-dichlorophenyl)ethyl 2-[4-(2-methylpropyl)phenyl]propanoate

¹H NMR (400 MHz,CDCl₃), δ 7.25 (d, J=8.2, 1H, ArH), 7.20 (d, J=2.0, 1H, ArH), 7.12 (dd, J=1.8, 6.2, 2H, ArH), 7.07 (d, J=8.2, 2H, ArH), 6.86 (dd, J=2.0, 8.2, 1H, ArH), 4.31-4.17 (m, 2H, OCH₂), 3.64 (q, J=7.1, 1H, CH*), 2.81 (dt, J=2.1, 6.5, 2H, CH₂-Ph), 2.45(d, J=7.1, 2H, CH₂-Ph), 1.85 (sex, J=6.8, 1H, CH*), 1.45 (d, J=7.2, 3H, CH₃), 0.90 (d, J=6.6, 6H, 2xCH₃)

IR: 1736 cm^-1 (ester)

Scheme-IV: Preparation of 2-(2-nitrophenyl)ethyl 2-[4-(2-methylpropyl)phenyl]propanoate

¹H NMR (400 MHz, CDCl₃), δ 7.92 (dd, J=1.8, 7.8, 1H, ArH), 7.35 (dt, J=1.9, 7.2, 2H, ArH), 7.14 (d, J=8.1, 2H, ArH), 7.09-7.06 (m, 3H, ArH), 4.43-4.32 (m, 2H, OCH₂), 3.64 (q, J=7.2, 1H, CH*), 3.17 (dt, J=6.7, 12.7, 2H, CH₂-Ph), 2.45 (d, J=7.1, 2H, CH₂-Ph), 1.85 (sex, J=6.8, 1H, CH*), 1.44 (d, J=7.1, 3H, CH₃), 0.90 (d, J=6.6, 6H, 2xCH₃)

IR: 1736 cm^-1 (ester)

Table –I: General data for various prodrugs:

Compound	Molecular formula	Molecular weight	% yield
Ibuprofen	C₁₃H₁₈O₂	206
2-phenyethanol derivative	C₂₁H₂₆O₂	310	87
2-(4-bromophenyl)ethanol derivative	C₂₁H₂₅O₂Br	389	79
2-(3, 4-dichlorophenyl) ethanol derivative	C₂₁H₂₄O₂Cl₂	379	80
2-(2-nitrophenyl)ethanol acid derivative	C₂₁H₂₅O₄N	355	86
2-(3,4-dimethoxyphenyl)ethanol derivative	C₂₃H₃₀O₄	370	83
2-(4-methoxyphenyl)ethanol derivative	C₂₂H₂₈O₃	340	85
2-(2-methylphenyl)ethanol derivative	C₂₂H₂₈O₂	324	88

Table –II: Solubility data for various prodrugs

Solvent	water	ethanol	chloroform	Acetone	Diethyl ether
2-phenylethanol derivative	insoluble	soluble	soluble	soluble	soluble
2-(4-bromophenyl) ethanol derivative	insoluble	soluble	soluble	soluble	soluble
2-(3, 4-dichlorophenyl) ethanol derivative	insoluble	soluble	soluble	soluble	soluble
2-(2-nitrophenyl)ethanol acid derivative	insoluble	soluble	soluble	soluble	soluble
2-(3,4dimethoxyphenyl) ethanol derivative	insoluble	soluble	soluble	soluble	soluble
2-(4-methoxyphenyl) ethanol derivative	insoluble	soluble	soluble	soluble	soluble
2-(2-methylphenyl) ethanol derivative	insoluble	soluble	soluble	soluble	soluble

Scheme-V: Preparation of 2-(3,4-dimethoxyphenyl)ethyl 2-[4-(2-methylpropyl)phenyl]propanoate

¹H NMR (400 MHz, CDCl₃), δ 7.16 (dd, J=6.0, 7.8, 2H, ArH), 7.07 (d, J=8.1, 2H, ArH), 6.75 (d, 8.1, 1H, ArH), 6.66 (dt, J=1.9, 6.6, 2H, ArH), 4.25 (dt, J=2.9, 7.1, 2H, OCH₂), 3.85 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 3.67 (q, J=7.2, 1H, CH*), 2.82 (dt, J=6.2,7.5, 2H, CH₂-Ph), 2.44 (d, J=7.2, 2H, CH₂-Ph), 1.83 (sex, J=6.7, 1H, CH*), 1.46(d, J=7.2, 3H, CH₃), 0.90 (d, J=6.6, 6H, 2xCH₃),

IR: 1733 cm^-1 (ester)

Scheme-VI: Preparation of 2-(4-methoxyphenyl)ethyl 2-[4-(2-methylpropyl)phenyl]propanoate

¹H NMR (400 MHz, CDCl₃), δ 7.17-7.15 (m, 2H, ArH), 7.07(d, J=8.1, 2H, ArH), 7.00 (dd, J=2.1, 6.7, 2H, ArH), 6.78(dd, J=2.1,6.5, 2H, ArH), 4.23 (dt, J=3.2,7.0, 2H, OCH₂), 3.78 (s, 3H, OCH₃), 3.66 (q, J=7.1, 1H, CH*), 2.81 (dd J=5.5, 7.0, 2H, CH₂-Ph), 2.45 (d, J=7.2, 2H, CH₂-Ph), 1.84 (sex, J=6.8, 1H, CH*), 1.45 (d, J=7.2, 3H, CH₃), 0.90 (d, J=6.6, 6H, 2xCH₃)

IR: 1733 cm^-1 (ester)

Scheme-VII: Preparation of 2-(2-methylphenyl)ethyl 2-[4-(2-methylpropyl)phenyl]propanoate

¹H NMR (400 MHz, CDCl₃), δ 7.16 (d, J=8.1, 2H, ArH), 7.12 (dd, J=1.4, 5.3, 2H, ArH), 7.08 (d, J=4.9, 2H, ArH), 7.05 (dd, J=6.2, 8.8, 2H, ArH), 4.24 (t, J=7.2, 2H, OCH₂), 3.67 (q, J=7.1, 1H, CH*), 2.88 (dd, J=6.3,7.4, 2H, CH₂-Ph), 2.44 (d, J=7.2, 2H, CH₂-Ph), 2.29 (s, 3H, OCH₃), 1.84 (sex, J=6.8, 1H, CH*), 1.46 (d, J=7.2, 3H, CH₃), 0.90 (d, J=6.6, 6H, 2xCH₃)

IR: 1734 cm^-1 (ester)

CONCLUSION:

In the present study, the free acidic group of ibuprofen was temporarily masked by a premoiety so as not to expose stomach’s mucosa to this free carboxylic acid group. Several ester prodrugs of ibuprofen were synthesized by selecting corresponding alcohols viz. 2-phenylethanol and its derivatives. The selection was done in such a manner that prodrugs with varying degree of lipofilicity could be obtained. Direct coupling was done by oxalyl chloride for preparation of these ester prodrugs. The Physicochemical data including solubility was reported in tables.

ACKNOWLEDGEMENT:

The author is grateful to Dr. S. Arora, Reader, Deptt. Of Chemistry, K.U. Kurukshetra for providing basic research facilities and help in the making of this project

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Received on 06.10.2009 Modified on 08.11.2009

Asian J. Research Chem. 3(1): Jan.-Mar. 2010; Page 145-147