INTRODUCTION:

The last decade has witnessed the discovery of the multiplicity of serotonin 5-HT receptors^1,2,3 and several 5-HT ligands have been studied with regard to their affinity, specificity and potential therapeutic application. The antipsychotic action has been suggested due to a blockade of the mesocorticolimbic dopaminergic system^4,5. Antipsychotic drugs antagoniszing central dopaminergic receptors have been used for several decades in the treatment of psychiatric disorders Schizophrenia⁶. Although these drugs can reduce the positive symptoms of Schizophrenia, they unfortunately often induce extapyramidal side effects and are furthermore often not able to control the negative symptoms. The current status of antipsychotic agents and our previous works on the design and synthesis of new series of novel 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)-N-(benzo[d]thiazol-2-yl) acetamide derivatives (In press), Synthesis and Pharmacological screening of new coumarinoacetamides⁷, Synthesis and Neuroleptic activity of new Coumarinoacetamides with special reference to Atypical Antipsychotic Activity⁸ have shown antipsychotic activity assuming their interaction with serotoninergic 5HT and Dopaminergic D₂ receptor activity.

In an effort to increase such properties and gain access to new neuroleptic agents with or without reduced extrapyramidal side-effects and our previous work leads us to synthesized new 7-(3-(benzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one derivatives (4a-4k) in which benzothiazole derivatives attached with Chromen-2-one moiety by ethoxy polar side chain linkage. Benzothiazole derivatives were reported to have 5HT antagonistic property⁹ where as Chromen-2-one moiety was reported for their dopaminergic D₂ antagonistic activity¹⁰. The combination of these two antagonistic moieties could possibly lead to a new series of antipsychotic drugs with reduced CNS side-effects.

MATERIAL AND METHOD:

Melting points were determined by open capillary method on Campbel electronic apparatus and are uncorrected. The purity of the synthesized compounds was checked by TLC using precoated silica G₂₅₄ plates and visualized in iodine and also by UV light. The IR spectra of synthesized compounds were recorded on a Jasco-V-5300 FTIR in potassium bromide discs. The ¹H NMR was recorded on a 300 MHz Jeol spectrophotometer in DMSO and using tetramethylsilane as internal standard.

Experimental Method:

The general methods of synthesis exemplified were illustrated as below

General method of synthesis of 7-hydroxy-4 methyl-2H-chromen-2-one (1)

(Scheme 1)

The method of Pechmann and Duisberg¹¹ was followed for the preparation of 7-hydroxy-4 methyl-2H-chromen-2-one (1). 100ml of conc. H₂SO₄ was kept in an ice-bath. When temperature fell below 10⁰C, a solution of resorcinol (10gm, 0.091 moles) and ethylacetoacetate (13ml, 0.103 moles) was added with continuous stirring for 2hr. The temperature was maintained below 10⁰C throughout the addition. The reaction mixture was kept at room temperature for 18 hr after which it was poured with vigorous stirring into the mixture of 200gm of crushed ice and 300ml of distilled water. Precipitate was collected by vacuum filtration and washed with cold water (325ml). The solid was dissolved in 150ml of 5% NaOH, filtered, and 2M H₂SO₄ (55ml) was added to it with vigorous stirring until the solution was acidic. The crude 7-hydroxy-4 methyl-2H-chromen-2-one (1) was collected by filtration at the pump, washed with cold water and dried. The product was recrystallized from ethanol.

Scheme of Synthesis of Final Compounds (4a-4k)

Scheme I : Synthesis of 7-hydroxy-4 methyl-2H-chromen-2-one (1)

a.conc.H₂SO₄, b.5% NaOH, c.2M H₂SO₄,

General method of synthesis of 7-(3-Chloropropoxy)-4-methyl-2H-chromen-2-one (2), (Scheme 2):

7-hydroxy-4-methyl-2H-chromen-2-one (1) (0.01 mol) was dissolved in 10ml acetonitrile with anhydrous K₂CO₃ (0.01 mol) was added to the solution. 1-Bromo 3-Chloropropane (0.01 mol) was added drop wise to the mixture in the round bottom flask over a period of 15 min. The reaction was refluxed for 18 hr. The filtrate was removed under vacuum using molecular distiller to afford dry solid. The solid obtained was dissolved in dichloromethane; the organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was separated and evaporated to dryness to afford crude products (2) which was then recrystallized using ethanol.

Scheme II: Synthesis of 7-(3-Chloropropoxy)-4-methyl-2H-chormen-2-one

a.Acetonitrile, b. anhydrousK₂CO₃, c. Dichloromethane

General method of synthesis of 2-amino benzothiazoles substituted derivatives (3a-3k) (Scheme 3):

2-amino benzothiazole substituted derivatives was synthesis by following method¹². To glacial acetic acid (20ml) precooled to 5⁰C were added 8gm (0.08mol) of potassium thiocynate and 1.45gm (0.01mol) of substituted aniline. The mixture was placed in freezing mixture of ice and salt and mechanically stirred while 1.6ml of bromine in 6ml of glacial acetic acid was added from dropping funnel at such a rate that the temperature doesn’t rise beyond 0⁰C. After addition of bromine for 105 minutes, the solution was stirred for an additional 2 hours at 0⁰C and at room temperature for 10 hour. It was then allowed to stand overnight during which period an orange precipitate was settled at the bottom where 6ml water was added quickly and slurry was heated at 85⁰C on steam bath and filtered in hot condition. The orange residue was placed in a reaction flask and treated with 10ml of glacial acetic acid, heated again to 85⁰ and filtered in hot state. The combined filtrate was cooled and neutralized with concentrated ammonia to pH 6 when dark yellow precipitate was collected and recrystallised from benzene.

Scheme III: Synthesis 2-amino Benzothiazole substituted derivatives (3a-3k)

a. Gl. Acetic Acid, b. Bromine, c. Benzene

General method of synthesis 7-(3-(benzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one derivatives (4a-4k) (Scheme 4):

A mixture of 7-(3-Chloropropoxy)-4-methyl-2H-chromen-2-one (2) with compounds 3a-3k (0.01 mol) was added to the reaction flask and refluxed in dry pyridine for 24 hours. The solvent was distilled off. The mixture was collected and poured on to cursed ice. The solid product was filtered and recrystallised from ethanol.

Figure 1: %Inhibition of apomorphine induced climbing behavior, at the dose of 5 mg/kg.

*n = 6, p < 0.05, $ Dose of Olanzapine was 1mg/kg, Apomorphine 1mg/kg

Pharmacological Evaluation of Atypical Antipsychotics Activity:

Pharmacological evaluation of atypical antipsychotic activity was performed by testing their ability to inhibit apomorphine induced climbing behavior (Fig. 1) and 5HTP induced head twitches in mice (Fig. 2).

Figure 2: % Inhibition of 5-HTP induced head twitches at the dose of 5 mg/kg.

*n = 6, p < 0.05, $ Dose of Olanzapine was 1mg/kg

Animals: Albino Swiss male mice, 20-25 g were maintained on standard pallet diet and given tap water ad libitum. The experiments were performed in a quiet room with an ambient temperature of 22^0+_2⁰C and between 12.00- 18.00 hrs each day to avoid behavioral changes resulting from circadian rhythm. The test compounds were suspended in 3% gum acacia in water for injection. All the injections were given intraperitoneally (i.p). The effects of the test compounds and vehicle control (3% gum acacia 5ml/Kg) on drug induced models were observed by injecting test compounds 30 minutes prior to the apomorphine and 5HTP.

Apomorphine induced Climbing Behavior¹³:

The animals were grouped randomly containing six animals in each group. The test groups received dose of test compounds 5 mg/kg body weight. The control and standard group received 3% gum acacia 5ml/kg and olanzepine 1mg/kg body weight respectively. Climbing behaviour was assessed in the animals by placing them individually in cylindrical wire mesh cage (height 18cm, diameter 14 cm) 5 minute after administration of apomorphine (1.0 mg/kg) The animals were kept in the cage, and observed at the interval of 10, 20, 30 minute after the administration of apomorphine. The following score was assigned to an individual animal: 0, when all four paws on the floor; 1, when two paws on the mesh; and 2, when all the four paws on the mesh. The score was summed up for each animal. Data were expressed as percentage of blockage of climbing relative to apomorphine-treated control mice.

5-HTP induced Head Twiches¹⁴:

The mice were grouped and administered test compounds and control similarly but the standard group received olanzepine (1 mg/kg, b.w). The head twitches in mice were counted after 20 minutes of 5-HTP (100mg/kg) administration at an interval of 5 minutes and for a period of 1hour.

RESULTS AND DISCUSSION:

The physicochemical characterizations of the all compounds were carried out. The physicochemical characterization of the target compounds were summarized in table 1.

Table-1: Physicochemical data of synthesized compounds (4a-4k)

Cmpd	Mol. Formula	R₁	R₂	R₃	Yield (%)	m.p(⁰)♦	Rf*
4a	C₂₀H₁₈N₂O₃S	-	-	-	7280	168-16184	0.56
4b	C₂₀H₁₇ClN₂O₃S	-	-	Cl	59	129-131	0.58
4c	C₂₁H₂₀N₂O₄S	-	-	OCH₃	51	153	0.61
4d	C₂₀H₁₇N₃O₅S	-	-	NO₂	68	148	0.52
4e	C₂₀H₁₇ClN₂O₃S	Cl	-	-	63	155	0.51
4f	C₂₀H₁₇FN₂O₃S	-	-	F	57	139-141	0.49
4g	C₂₀H₁₆ClFN₂O₃S	-	Cl	F	54	107	0.39
4h	C₂₁H₂₀N₂O₃S	CH₃	-	-	61	133-134	0.64
4i	C₂₁H₂₀N₂O₃S	-	-	CH₃	56	129-130	0.59
4j	C₂₀H₁₇ClN₂O₃S	-	Cl	-	23	112	0.61
4k	C₂₀H₁₇BrN₂O₃S	Br	-	-	34	108	0.59

♦ Melting points were uncorrected

*Mobile phase for (4a-4k) [Benzene; Ethyl acetate : 4;1]

7-Hydroxy-4-methyl chromen-2-one (1)

The method of Pechman and Duisberg was followed for the synthesis of 7-Hydroxy-4-methyl chromen-2-one. Yield: 51%; m.p. 181-182; Rf: 0.45 [benzene; ethyl acetate: 4:1] IR (KBr) cm^-1: 3500(-OH), 2957(aromatic C-H), 1680(C=O), 1601-1452(C=C), 1336-1159(-C-CO-O), 1215(-C-O phenol) and 746(C-H out of plane). ¹H NMR (DMSO): 10.5(b,1H,-OH), 7.51-7.53(d,1H,C₅-H), 6.6-6.9(m,2H,C₆-H), 6.06(s,1H,C₃-H), 2.29(s,3H,C₄-CH₃).

7-(3-Chloropropoxy)-4-methyl-2H-chromen-2-one (2):

Yield: 61%; m.p. 81-82; Rf: 0.68 [benzene; ethyl acetate: 4:1] IR (KBr) cm^-1: 2937.6(aromatic C-H) 1706(C=O streching), 1617(aromatic C=C streching), 1388-1237(-C-CO-O stretching), 642(C-Cl stretching) and 860(C-H out of plane), ¹H NMR (DMSO): 7.20(d,1H,C₅-H), 6.5-6.9(d,2H,C₆-H and C₈-H), 6(s,1H,C₃-H), 4.14(t,2H,CH₂-O linkage). 3.82(t, 2H, Cl-CH₂ linkage), 2.01(m, 2H, 2-CH₂ linkage), 1.7(s, 3H, CH₃ at C₄)

General method of synthesis 7-(3-(benzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one derivatives (4a-4k)

7-(3-(benzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4a)

IR (KBr): 3181.5(N-H stretching), 1673.5(C=O stretching), 1587-1440(Ar C=C stretching), 1271(C-N stretching), 1155.7(CO-O-C stretching), 1291(C-O-O stretching), 808(Ar C-H out of plane), 748(C-S stretching) cm^-1. ¹H NMR (δ, ppm, DMSO): 8.11(t, 1H, N-H), 7.10(d,1H,C₅-H), 6.5-6.9(d,2H,C₆-H and C₈-H in chromen-2-one), 5.87(s,1H,C₃-H in chromen-2-one), 4.24(t,2H,CH₂-O linkage), 3.30(t, 2H, N-CH₂ linkage), 2.15(m, 2H, C-CH₂-C linkage), 1.81(s, 3H, CH₃ at C₄ in chromen-2-one), 7.4-7.6(m,2H, C_5’-H and C_6’-H in Benzothiazole), 8.10-8.20(d,2H,C_4’-H andC_7’H in benzothiazole)

7-(3-(6-Chlorobenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4b)

IR (KBr): 3182(N-H stretching), 3066(Ar C-H stretching), 1685(C=O stret), 1555-1365 (C=C), 1266(C-N), 1156(CO-O-C stert), 1295(C-O-O stretching), 681(C-Cl stretching), 764(C-S stretching) cm^-1. ¹H NMR (δ, ppm, DMSO): 8.05(t, 1H, N-H), 7.14(d,1H,C₅-H), 6.5-6.9(d,2H,C₆-H and C₈-H in chromen-2-one), 5.95(s,1H,C₃-H in chromen-2-one), 4.35(t,2H,CH₂-O linkage). 3.48(t, 2H, N-CH₂ linkage), 2.22(m, 2H, C-CH₂-C linkage), 1.76(s, 3H, CH₃ at C₄ in chromen-2-one), 7.58(d, 1H, C_5’-H in Benzothiazole), 8.10-8.20(d, 2H, C_4’-HandC_7’-H in benzothiazole)

7-(3-(6-methoxybenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4c)

IR (KBr): 3100(N-H), 2941(C-H), 1735(C=O), 1688(C=O), 1264(C-N), 1148(CO-O-C), 847.7(Ar C-H out of plane), 724(C-S) cm^-1. ¹H NMR (δ, ppm, CDCl₃): 8.02(t, 1H, N-H), 7.08(d,1H,C₅-H), 6.4-6.8(d,2H,C₆-H and C₈-H in chromen-2-one), 5.79(s,1H,C₃-H in chromen-2-one), 4.10(t,2H,CH₂-O linkage). 3.09(t, 2H, N-CH₂ linkage), 2.10(m, 2H, C-CH₂-C linkage), 1.77(s, 3H, CH₃ at C₄ in chromen-2-one), 7.5(s,1H,C_7’-H in Benzothiazole), 7.97(d,1H,C_4’-H in benzothiazole), 7.02(d,1H,C_5’-H in benzothiazole), 3.84(S,3H,OCH₃ in benzothiazole)

7-(3-(6-nitrobenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4d)

IR (KBr): 3010(N-H), 2939(C-H stretching), 1714-1615(C=O), 1510(C=C), 1274(C-O-O stretching), 1226(C-N), 751(C-S) cm^-1. ¹H NMR (δ, ppm, CDCl₃): 8.35(t, 1H, N-H), 7.26(d,1H,C₅-H), 6.4-6.9(d,2H,C₆-H and C₈-H in chromen-2-one), 5.88(s,1H,C₃-H in chromen-2-one), 4.11(t,2H,CH₂-O linkage). 3.08(t, 2H, N-CH₂ linkage), 1.95(m, 2H, C-CH₂-C linkage), 1.78(s, 3H, CH₃ at C₄ in chromen-2-one), 8.17-8.30(m, 2H, C_4’-H and C_5’-H in Benzothiazole), 8.81(s, 1H, C_7’-H in benzothiazole).

7-(3-(4-Chlorobenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4e)

IR (KBr): 3005(N-H), 2983(C-H), 1710-1612(C=O), 1547(C=C), 1146(CO-O-C), 592(C-Cl), 760(C-S) cm^-1. ¹H NMR (δ, ppm, DMSO): 8.38(t, 1H, N-H), 7.27(d,1H,C₅-H), 6.4-6.9(d,2H,C₆-H and C₈-H in chromen-2-one), 5.91(s,1H,C₃-H in chromen-2-one), 4.12(t,2H,CH₂-O linkage). 3.25(t, 2H, N-CH₂ linkage), 1.95(m, 2H, C-CH₂-C linkage), 1.78(s, 3H, CH₃ at C₄ in chromen-2-one), 7.4-7.5(m, 2H, C_5’-H and C_6’-H in Benzothiazole), 8.0 (d, 1H, C_7’-H in benzothiazole).

7-(3-(6-fluorobenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4f)

IR (KBr): 3140(N-H), 2939(Ar C-H), 1714-1615(C=O), 1510-1343(C=C), 1146(CO-O-C), 1247(C-O-O), 830(C-F), 751(C-S) cm-1. ¹H NMR (δ, ppm, DMSO): 8.26(t, 1H, N-H), 7.18(d,1H,C₅-H), 6.4-6.9(d,2H,C₆-H and C₈-H in chromen-2-one), 5.97(s,1H,C₃-H in chromen-2-one), 4.31(t,2H,CH₂-O linkage). 3.25(t, 2H, N-CH₂ linkage), 2.11(m, 2H, C-CH₂-C linkage), 1.70(s, 3H, CH₃ at C₄ in chromen-2-one), 7.2(d, 1H, C_5’-H in Benzothiazole), 7.8(s, 1H, C_7’-H in Benzothiazole) 8.15(d, 2H, C_4’-H in benzothiazole).

7-(3-(5-chloro-6-fluorobenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4g)

IR (KBr): 3182(N-H), 3066(C-H), 1702-1685(C=O), 1589-1365(C=C), 681(C-Cl), 806(C-F), 1156(CO-O-C stretching), 764(C-S stretching), 1295(C-O-O) cm^-1. ¹H NMR (δ, ppm, DMSO): 8.16(t, 1H, N-H), 7.29(d,1H,C₅-H), 6.4-6.9(d,2H,C₆-H and C₈-H in chromen-2-one), 6.03(s,1H,C₃-H in chromen-2-one), 4.15(t,2H,CH₂-O linkage). 3.43(t, 2H, N-CH₂ linkage), 2.24(m, 2H, C-CH₂-C linkage), 1.19(s, 3H, CH₃ at C₄ in chromen-2-one), 7.99(s, 1H, C_7’-H in Benzothiazole), 8.19(s, 1H, C_4’-H in benzothiazole)

7-(3-(4-methylbenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4h)

IR (KBr): 3127(N-H), 2908(C-H), 1715-1693(C=O), 1555(C=C), 1211(C-N), 856(C-H out of plane), 1177(CO-O-C), 733(C-S Stretching) cm^-1. ¹H NMR (δ, ppm, DMSO): 8.10(t, 1H, N-H), 7.18(d,1H,C₅-H), 6.4-6.9(d,2H,C₆-H and C₈-H in chromen-2-one), 5.81(s,1H,C₃-H in chromen-2-one), 4.07(t,2H,CH₂-O linkage). 3.11(t, 2H, N-CH₂ linkage), 2.01(m, 2H, C-CH₂-C linkage), 1.84(s, 3H, CH₃ at C₄ in chromen-2-one), 7.3-7.4(m, 2H, C_5’-H and C_6’-H in Benzothiazole), 7.62(d, 1H, C_7’-H in benzothiazole), 2.22(s, 3H,-CH₃ of Benzothiazole)

7-(3-(6-methylbenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4i)

IR (KBr): 3009(N-H), 2916(C-H), 1733-1611(C=O), 1485(C=C), 1211(C-N), 1153(CO-O-C), 847(C-H), 754(C-S stretching) cm^-1. ¹H NMR (δ, ppm, CDCl₃): 8.02(t, 1H, N-H), 7.08(d,1H,C₅-H in chromen-2-one), 6.4-6.6(d,2H,C₆-H and C₈-H in chromen-2-one), 5.82(s,1H,C₃-H in chromen-2-one), 3.84(t,2H,CH₂-O linkage). 3.01(t, 2H, N-CH₂ linkage), 1.98(m, 2H, C-CH₂-C linkage), 1.67(s, 3H, CH₃ at C₄ in chromen-2-one), 7.9-(s, 1H, C_7’-H in Benzothiazole), 8.1(d, 1H, C_4’-H in Benzothiazole), 7.31(d, 1H, C_5’-H in benzothiazole), 2.45(s, 3H, -CH₃ in Benzothiazole).

7-(3-(5-chlorobenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4j)

IR (KBr): 3116(N-H), 2916(C-H), 1718-1635(C=O), 1561(C=C), 1266(C-N stretching), 1152(CO-O-C stretching), 852(C-H) cm^-1.¹H NMR (δ, ppm, DMSO): 8.47(t, 1H, N-H), 7.42(d,1H,C₅-H), 6.5-6.6(d,2H,C₆-H and C₈-H in chromen-2-one), 5.92(s,1H,C₃-H in chromen-2-one), 3.99(t,2H,CH₂-O linkage). 3.08(t, 2H, N-CH₂ linkage), 2.08(m, 2H, C-CH₂-C linkage), 1.75(s, 3H, CH₃ at C₄ in chromen-2-one), 7.76(d, 1H, C_6’-H in Benzothiazole), 8.0-8.1(d, 2H, C_4’-H and C_7’-H in benzothiazole)

7-(3-(4-bromobenzo[d]thiazol-2-ylamino)propoxy)-4-methyl-2H-chromen-2-one (4k)

IR (KBr): 3104(N-H), 2904(C-H), 1732-1666(C=O), 1451(C=C), 1248(C-N), 1181(CO-O-C), 746(C-S), 655(C-Cl) cm^-1. ¹H NMR (δ, ppm, DMSO): 8.24(t, 1H, N-H), 7.40(d, 1H, C₅-H in chromen-2-one), 6.5-6.6(d, 2H, C₆-H and C₈-H in chromen-2-one), 5.97(s, 1H, C₃-H in chromen-2-one), 3.99(t, 2H, CH₂-O linkage). 3.12(t, 2H, N-CH₂ linkage), 2.02(m, 2H, C-CH₂-C linkage), 1.75(s, 3H, CH₃ at C₄ in chromen-2-one), 7.42(m, 1H, C_5’-H in Benzothiazole), 7.70-8.0 (d, 2H, C_4’-H and C_7’-H in benzothiazole)

CONCLUSIONS:

Our study suggests that all the synthesized compounds provide a chemical class of compounds that showed significant antipsychotic activity in pharmacological model predictive of dopamine D₂ antagonist activity and also had significant serotonin 5-HT receptor antagonistic activity, an index of hypothesized atypical antipsychotic profile. The compounds which were substituted with Chloro, Bromo at ortho position and Nitro, Methyl and Chloro at Meta position showed significant dopamine (D₂) receptor antagonistic activity and the compounds which were substituted with Chloro, Bromo at ortho position and Chloro, Fluoro and Methoxy at Meta position showed significant serotonin (5HT) receptor antagonistic activity. From this data we can conclude that compounds 7-(2-(4-chlorobenzo[d]thiazol-2-ylamino)ethoxy)-4-methyl-2H-chromen-2-one (4e) and 7-(2-(6-methoxybenzo[d]thiazol-2-ylamino)ethoxy)-4-methyl-2H-chromen-2-one (4c) have better atypical antipsychotic profile. Detail toxicity study is required for characterization of the compounds for the therapeutic utility.

ACKNOWLEDGEMENTS

The author gratefully acknowledge and thanks TVES College of Pharmacy, Faizpur, for providing Animal activity on albino mice for biological evaluation of the compounds and also thanks are due to University of Pune for providing ¹HNMR and elemental analysis respectively.

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Received on 22.11.2010 Modified on 10.12.2010

Asian J. Research Chem. 4(4): April, 2011; Page 591-596-706