Drug Regulatory Authorities To Treat Racemic Drugs Biology Essay

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In recent years there is an enhanced tendency for drug regulatory authorities to treat racemic drugs as containing 50% impurities1,2 and accordingly to encourage the development of chiral drugs containing only one enantiomer.3 However, in some cases a drug containing a mixture of enantiomers is preferable to a pure chiral drug,4 and hence the current policy is not to draw definitive guidelines forbidding racemic drugs but to demand that the pharmaceutical companies justify their reasons for preferring a mixture of enantiomers over one stereoisomer. Any decision whether to develop an optically active chiral drug or a racemic drug should take into account the relative potency of the two drug enantiomers, both in the principal therapeutic activity and inside effects.5

Moclobemide, p-chloro-N-2-(morpholinomethyl) benzamide (1) is a short acting, selective and reversible inhibitor of MAO-A,6,7 well tolerated, widely available for clinical use, and an effective antidepressant. Monomine oxidase (MAO) is a flavoprotein of the mitochondrial outer membranes of neuronal cells, involved in the biodegradation of aromatic monoamines, including classical neurotransmitters such as serotonin, adrenaline, and dopamine, playing a central role in several psychiatric and neurological disorders.

A variety of moclobemide derivatives has been prepared, and studies on structure-activity relationships reveal that both the morpholine and phenyl rings are necessary for antidepressant activity.8,9 However effects of changes in the aliphatic chain length on biological activity have not been reported.

A well-known class of 5-HT1A receptor ligands are the "long chain" arylpiperazine derivatives. Among these Buspirone (2) a partial agonist at 5-HT1A receptors is an effective antianxiety and was the first arylpiperizine approved for clinical use. On the other hand Moclobemide, a reversible MAO-A inhibitor exerts its anti-depressant therapeutic effect by preventing the degradation of neurotransmitters and xenobiotic amines (oxidative deamination), modulation the level of these biogenic amines.

Literature Review:

K. Kulig et al., reported10 stereocontrolled synthesis of the enantiomers of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one (9).

Preliminary biological studies showed that compound 9 prevented or ameliorated the adrenaline-, barium chloride induced arrhythmia and statistically diminished arrhythmias associated with coronary artery occlusion and reperfusion in the isolated rat heart. Compound 9 demonstrates potent local anesthetic properties and depressed the depolarization phase of the action potential of cardiac cells. According to Williams classification compound 9 is in class of antiarrhythmic drugs.11 Compound 9 also showed hypertensive effects and displayed α1 and α2 adrenergic blocking activities.

According to K. Kulig procedure, the required non-racemic epoxides were obtained via the Sharpless AD and epoxidation. As the starting material for their synthesis, 1-allylpyrrolidin-2-one (4) was used. Compound 4 was obtained by reaction between tetrahydrofuran-2-one and allylamine. Oxidation of 4 by standard procedures with commercially available AD-mix α or β provided the diols (S)-(+)-5 or (R)-(-)-6 in 70-80% yield. AD-mix α or β is a mixture of potassium osmate, K3[Fe(CN)6], K2CO3 and (DHQ)2-PHAL (AD-mix α) and (DHQD)2-PHAL (AD-mix β), respectively. The diols (S)-(+)-5 and (R)-(-)-6 were easily converted to the epoxides (S)-(+)-7 and (R)-(-)-8 using the process based on the acetoxonium ion-mediated formation of acetate esters of halohydrins.

Subsequently, base-mediated ester saponification and cyclization give the enantiomeric epoxides (S)-(+)-7 and (R)-(-)-8. Finally the aminolysis of compounds (S)-(+) and (R)-(-) with 1-phenylpiperizine gave the enantiomers of compound (S)-(+)-9 and (R)-(-)-9.

Later Barbara Filipek et al., reported12 the synthesis of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidine (10) by the reduction of 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one (9) with lithium aluminum hydride (LAH), which was isolated as free base and water-soluble dihydrochloride salt (11).

Objective and results of the Present study

Although, a variety of methods for the synthesis of Moclobemide and phenylpiperizine derivatives have been developed, there is no report dealing with the obtension of 4-arylpiperizine, connected with racemic or isomers of methyl-2-(4-chlorophenyl)-3-butanoic acid framework of Moclobemide in a single chemical entity.

In this Chapter, we describe the synthesis of 3-benzoimidazol-1-yl-1-(4-phenyl-piperizin-1-yl)-propan-1-one (6a), 3-benzoimidazol-1-yl-1-(4-nitrophenyl-piperizin-1-yl)-propan-1-one (6b) and a series of its derivatives 8a-e as potential anti-inflammatory action, based on structural moieties related to reversible MAO-A inhibitor Moclobemide and typical 5-HT1A ligands.

Novel molecules synthesized purified by column chromatography

Scheme 1

Scheme 2

Experimental

Preparation of 3-benzoimidazole-1-yl-propionic acid methyl ester (2):

To a THF solution of benzimidazole (1, 10 g, 80 mmol) methyl acrylate (4.54g, 52.8 mmol) is added. To this CAN (2.89 g, 8 mmol) is added and the mixture is refluxed at 60 oC for 24 h under air atmosphere. Then the solvent is concentrated under reduced pressure and purified by silica gel (60-120 mesh) column chromatography using ethyl acetate, hexane as eluent. The compound is obtained as a syrupy liquid. Yield: 62.03%. IR (KBr) : max 1734 (C=O), 1497 (C=N), 1207 (c-o) cm-1. 1H NMR(300 MHz, CDCl3):  2.85 (t, 2H, J=6.592Hz, CH2-CO), 3.66 (s, 3H, -OCH3), 4.49 (t, 2H, J=6.592Hz, N-CH2), 7.22-7.28 (m, 2H, Ar-H), 7.33 (m, 1H, Ar-H), 7.76 (m, 1H, Ar-H), 7.91 (s, 1H, N=CH). Mass: ESI-MS m/z 205 [M+H]+

Preparation of 3-benzoimidazol-1-yl-propionic acid (3):

The compound 3-benzoimidazol-1-yl-propionicacidmethylester (2) is taken in 20 mL of THF: Water system (2:1). To this lithium hydroxide (1.23 g, 29.41mmol) is added at OOC. Then the mixture was stirred at RT for 1 hr Progress of reaction is monitored by TLC. After completion of reaction solvents ware distilled under reduced pressure. Organic compound is dissolved in methanol, filtered, concentrated, and purified by silica gel column chromatography. Using ethyl acetate: hexane (80; 20). A colorless crystalline solid is obtained. Yield: 82.16%; m.p: 285-287 oC. IR (KBr): max 3415(-OH), 1588 (C=O) cm-1. 1H NMR(300 MHz, DMSO-d6):  2.81 (t, 2H, J=6.267Hz, CH2-CO-), 4.49 (t, 2H,J=6.267Hz, N-CH2), 7.17-7.27 (m, 2H, Ar-H), 7.44 (d, 1H, Ar-H), 7.66-7.70 (m, 1H, Ar-H), 8.02 (s, 1H, N=CH). Mass: EI-MS m/z 191 [M+H]+

Preparation of 3-benzoimidazol-1-yl-propionyl chloride (4):

3-benzoimidazol-1-yl-propionic acid (3) (1g, 5.26 mmol) is taken in thionyl chloride (40ml) and is refluxed smoothly in an oil bath at 400C for 3hr.the solvent is distilled off, and the resultant mass is immediately kept for further step, as the acid chloride is unstable.

Preparation of 3-benzoimidazol-1-yl-1-(4-phenyl-piperizin-1-yl) - propan-1- one (6):

3-benzoimidazol-1-yl-propionyl chloride (4) (0.45g, 2 mmol) in dry MeOH is slowly added to a stirred solution at 00C.of 4-phenyl -1-piparazine(0.324g, 2 mmol), pyridine (0.158g, 2 mmol) and dry MeOH (50ml) in N2 atmosphere. The mixture is maintained with stirring for 6hrs at room temperature and then it is poured into water (100ml). The solution is extracted with dichloromethane (3x50ml), and organic layer s are dried over MgSO4 and concentrated and purified by silica gel column chromatography Using ethyl acetate: hexane (80; 20). The compound obtained as a brown viscous mass. Yield: 25%. IR (KBr): max 2924 (C-H), 1645 (C=O) cm-1. 1H NMR (300 MHz, DMSO-d6):  2.90 (t, 2H, J=6.421Hz, CH2-CO-), 2.95 (t, 2H, -NCH2), 3.10 (t, 2H, -NCH2) 3.40 (t, 4H, J=5.099Hz, N-CH2), 3.75 (t, 4H, J =5.099Hz, N-CH2), 4.60 (t, 2H, J=6.241Hz, N-CH2 Ar), 6.81 (d, 2H, Ar-H), 7.14-7.32 (m, 4H, Ar-H), 7.51-5.54 (m, 2H, Ar-H), 7.69 (s, 1H, Ar-H), 8.10 (s, 1H, Ar-H), 8.28 (brs, 1H, N-CH). Mass:ESI- MS m/z 335 [M+H]+ Anal. Cald for C20H22N4O: C, 71.83, H, 6.63. Found: C, 71.76, H, 6.45.

Preparation of 3-benzoimidazol-1-yl-1-(4-phenyl-piperizin-1-yl)- propan-1- one (6a):

To a solution of compound 3 (100 mg, 0.28 mmol), EDC (53 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), DIPEA (72 mg, 0.56 mmol) and 4-phenyl -1-piparazine 5a, (45 mg, 0.28 mmol) in CH2Cl2 (5 mL) was stirred for overnight and solvents was evaporated under vacuum. The residue obtained was dissolved in water and extracted with ethyl acetate (3 Ã- 25 mL). The organic phases were washed with sat. sodium bicarbonate solution, dried over sodium sulphate and evaporated under vacuum. The residue obtained was purified by column chromatography over silica gel using ethyl acetate: hexane (80; 20), to afford 3-benzoimidazol-1-yl-1-(4-phenyl-piperizin-1-yl)- propan-1- one (6a) as a brown viscous mass. Yield: 85%. IR (KBr): max 2924 (C-H), 1645 (C=O) cm-1. 1H NMR (300 MHz, DMSO-d6):  2.90 (t, 2H, J=6.421Hz, CH2-CO-), 2.95 (t, 2H, -NCH2), 3.10 (t, 2H, -NCH2) 3.40 (t, 4H, J=5.099Hz, N-CH2), 3.75 (t, 4H, J =5.099Hz, N-CH2), 4.60 (t, 2H, J=6.241Hz, N-CH2 Ar), 6.81 (d, 2H, Ar-H), 7.14-7.32 (m, 4H, Ar-H), 7.51-5.54 (m, 2H, Ar-H), 7.69 (s, 1H, Ar-H), 8.10 (s, 1H, Ar-H), 8.28 (brs, 1H, N-CH). Mass:ESI- MS m/z 335 [M+H]+ Anal. Cald for C20H22N4O: C, 71.83, H, 6.63. Found: C, 71.76, H, 6.45.

Preparation of 3-(1H-benzo[d]imidazol-1-yl)-1-(4-nitrophenyl-piperizin-1-yl)-propan-1-one (6b):

To a solution of compound 3 (100 mg, 0.28 mmol), EDC (53 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), DIPEA (72 mg, 0.56 mmol) and 1-(4-nitro phenyl) piparazine 5b, (45 mg, 0.28 mmol) in CH2Cl2 (5 mL) was stirred for overnight and solvents was evaporated under vacuum. The residue obtained was dissolved in water and extracted with ethyl acetate (3 Ã- 25 mL). The organic phases were washed with sat. sodium bicarbonate solution, dried over sodium sulphate and evaporated under vacuum. The residue obtained was purified by column chromatography over silica gel using ethyl acetate: hexane (80; 20), to afford 3-benzoimidazol-1-yl-1-(4-nitrophenyl-piperizin-1-yl)- propan-1- one (6b) as a brown viscous mass. Yield: 85%. IR (KBr): max 2925 (C-H), 1642 (C=O) cm-1. 1H NMR (300 MHz, DMSO-d6):  2.90 (t, 2H, J=6.421Hz, CH2-CO-), 3.20 (t, 2H, -NCH2), 3.35 (t, 2H, J=5.099Hz, N-CH2), 3.45 (t, 2H, J =5.099Hz, N-CH2), 3.75 (t, 2H, N-CH2), 4.65 (t, 2H, J=6.241Hz, N-CH2 Ar), 6.75 (d, 2H, Ar-H), 7.26-7.90 (m, 5H, Ar-H),8.15(brs, 1H, N-CH). Mass: ESI- MS m/z 379 [M+H]+ Anal. Cald for C20H21N5O3: C, 63.31; H, 5.58. Found C, 63.41, H, 5.55.

3-Benzoimidazol-1-yl-1-amine propanones 8a-e:

General Procedure: To a solution of compound 3 (100 mg, 0.28 mmol), EDC (53 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), DIPEA (72 mg, 0.56 mmol) and amine 7a-e (45 mg, 0.28 mmol) in CH2Cl2 (5 mL) was stirred for overnight and solvents was evaporated under vacuum. The residue obtained was dissolved in water and extracted with ethyl acetate (3 Ã- 25 mL). The organic phases were washed with sat. sodium bicarbonate solution, dried over sodium sulphate and evaporated under vacuum. The residue obtained was purified by column chromatography over silica gel using ethyl acetate: hexane (80; 20), to afford following compounds:

3-(1H-benzo[d]imidazol-1-yl)-N-methyl-N-phenethylpropanamide (8a)

The general synthetic method described above afforded 8a as off white solid. Yield 86%. IR (KBr): νmax 2924. 1H NMR (CDCl3): δ 2.60 (t, 2H, -CH2-Ar), 2.70 (t, 2H, -CH2-CO), 3.38 (t, 2H, -N-CH2), 3.50 (s, 3H, -N-CH3), 3.60 (t, 2H, -N-CH2), 7.00-7.85 (m, 10H, Ar-H). ES-MS: m/z 330 [M+Na]. Anal. Cald for CH21N3O: C, 74.24; H, 6.89. Found: C, 74.14; H, 6.52.

3-(1H-benzo[d]imidazol-1-yl)-N-(2-pheneylpropyl) propanamide (8b)

The general synthetic method described above afforded 8a as off white solid. Yield 82%. IR (KBr): νmax 2922, 1H NMR (CDCl3): δ 1.00 (d, 3H, -CH3), 2.55 (t, 2H, -CH2-CO), 2.75 (t, 1H, -Ar-CH), 3.38 (t, 2H, -N-CH2), 3.50 (s, 3H, -N-CH3), 3.60 (t, 2H, -N-CH2), 7.00-7.85 (m, 10H, Ar-H). Mass: ESI- MS m/z 308[M+Na]. Anal. Cald for C19H21N3O: C, 74.24; H, 6.89. Found: C, 74.14; H, 6.54.

3-(1H-benzo[d]imidazol-1-yl)-1-(pyrolidin-1yl)propan-1-one (8c)

The general synthetic method described above afforded 8c as off white solid. Yield 80%. IR (KBr): νmax. 2970. 1H NMR (CDCl3): δ 1.80-1.98 (m, 4H, 2CH2), 2.80 (t, 2H, -CH2-CO), 3.18 (t, 2H, -NCH2), 3.45 (t, 2H, -NCH2), 4.60 (t, 2H-, -NCH2-Ar), 6.40 (s, 1H, Ar-H), 7.25-8.18 (m, 4H, Ar-H). Mass: ESI- MS m/z 224[M+H]. Anal. Cald for C14H17N3O: C, 69.11; H, 7.04. Found: C, 69.10; H, 7.06.

3-(1H-benzo[d]imidazol-1-yl)-1-(pyrolidin-1yl)propan-1-one (8d)

The general synthetic method described above afforded 8d as off white solid. Yield 78%. IR (KBr): νmax.2925. 1H NMR (CDCl3): δ 1.70-1.95 (m, 6H, 3CH2), 2.70 (t, 2H, -CH2-CO), 3.20 (t, 2H, -NCH2), 3.30 (t, 2H, -NCH2), 4.6 0(t, 2H-, -NCH2-Ar), 6.39 (s, 1H, Ar-H), 7.45-8.12 (m, 4H, Ar-H). Mass:ESI- MS m/z 258[M+H]. Anal. Cald for C15H19N3O: C, 70.01; H, 7.44. Found: C, 70.11; H, 7.34.

3-(1H-benzo[d]imidazol-1-yl)-1-(pyrolidin-1yl)propan-1-one (8e)

The general synthetic method described above afforded 8e as off white solid. Yield 80%. IR (KBr): νmax.2964. 1H NMR (CDCl3): δ 2.80 (t, 2H, -CH2-CO), 3.25 (t, 4H, -2CH2O), 3.45 (t, 4H, 2-NCH2), 4.60 (t, 2H,-NCH2-Ar), 6.39 (s, 1H, Ar-H), 7.30-8.10 (m, 4H, Ar-H). Mass: ESI-MS m/z 260[M+H]. Anal. Cald for C14H17N3O2: C, 64.85; H, 6.61. Found: C, 64.35; H, 6.52.

Results and discussion

The synthesis of the title benzoimidazol 4-phenyl-piperizin-1-yl)-propanone (6a) started by reaction of 1H-benzoimidazole (1) by treating with methyl acrylate using CAN as a catalyst in THF. The compound is obtained as syrup in 62.03% yield. The 1H NMR spectrum of 3-Benzoimidazol-1-yl-propionicacidmethylester reveals the presence of a triplet at  2.85 ppm with coupling constant J=6.592Hz integrating for two protons is assignable to methylene protons adjacent to carbonyl group. A singlet at  3.66 ppm integrating for three protons is assignable to methoxy protons. Another triplet at  4.49 ppm with coupling constant J=6.592Hz, integrating for two protons is assignable to methylene proton adjacent to nitrogen. Multiplets at  7.76 ppm, 7.33 ppm, 7.22-7.28 ppm integrating for four protons are assignable to aromatic protons. A singlet at  7.91 ppm integrating for one proton is assignable to N=CH proton. The strong absorption band in its IR spectrum at 1734 cm-1 shows the presence of ester C=O group. An absorption band at 1497 cm-1 shows the presence of C=N bond. The molecular ion peak at M/z 205 in its ESI Mass spectrum corresponding to [M+H]+ further confirms the structure.

The reaction of 3-benzoimidazol-1-yl-propionic acid methyl ester (2) with LiOH in THF & water results in the formation of 3-benzoimidazol-1-yl-propionic acid (3), as a white solid, in 82.61 % yield. The 1H NMR spectra of 3-benzoimidazol-1-yl-propionic acid reveals the presence of a triplet at  2.81 ppm with coupling constant J=6.627Hz integrating for two protons is assignable to methylene protons adjacent to carbonyl group. A triplet at  4.49 ppm with coupling constant J= 6.267Hz integrating for two protons is assignable to methylene protons adjacent to nitrogen. NMR signals from  7.17-7.70 ppm integrating for four protons is assignable to aromatic protons. A singlet at  8.02 pm integrating for one proton is assignable to N=CH proton. The absence of methoxy signals at  3.66 ppm in compound (3) confirms the hydrolysis of ester. The strong adsorption band in its IR spectrum at 3415 cm-1 shows the presence of -OH bond. And absorption band at 1588 cm-1 shows the presence of C=O group. The molecular ion peak at m/z 191 in its EI mass spectrum corresponding to [M+H]+ further confirms the structure.

Acidic functionality in compound 3 was exploited to prepare 3-benzoimidazol-1-yl-(4-phenyl-piperizin-1-yl)-propan-1-one (6a) and 4-nitro-phenyl piperizin-1yl-propan-1-one (6b) by the reaction with 4-phenyl piperazine and 4-nitro phenyl piperizine by utilizing peptide coupling reagents EDC∙HCl and HOBt (Scheme 1). The 1H NMR spectrum 3-benzoimidazol-1-yl-(4-phenyl-piperizin-1-yl)-propan-1-one (6a) reveals the presence of a triplet at  2.90 ppm with coupling constant J=6.421 Hz integrating for two protons is assignable to methylene protons adjacent to carbonyl group. A triplet at  3.48 ppm with coupling constant J= 5.099Hz integrating for four protons and another triplet at  3.68 ppm with coupling constant J= 5.099 Hz integrating for four protons of piperizine. A triplet at  4.59 ppm with coupling constant J= 6.421Hz integrating for two protons is assignable to methylene protons adjacent to nitrogen. Proton signals from  6.81 to  7.69 ppm integrating for nine protons are assignable to aromatic protons. A broad singlet at  8.28 ppm integrating for one proton is assignable to N=CH proton. The strong absorption band in its IR spectrum at 2923 cm-1 shows the presence of -CH bond, and at 1638 cm-1 shows the presence of C=O bond. The molecular ion peak at m/z 335 in ESI mass spectrum corresponding to [M+H]+ further confirms the structure.

Acidic functionality in compound 3 was exploited to prepare variety of amides 8a-e by reaction with various secondary amines 7a-e by utilizing peptide coupling reagents EDC∙HCl and HOBt (Scheme 2) and which were confirmed by IR, 1H NMR, Mass and Elemental analysis.

Table-1: Data of the synthesized compounds

compoundcode

Molecular formula

Molecular weight

MP OC

% Yield

6a

C21H25N4O

349

85%

6b

C21H24N5O3

394

85%

8a

C20 H24N3O

322

86%

8b

C20 H24N3O

322

82%

8c

C15H20N3O

258

80%

8d

C20 H24N3O

272

78%

8e

C15 H20N3O2

274

80%

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