Ponalrestat

Ponalrestat

Phase III

An aldose reductase inhibitor potentially for the treatment of diabetes.

Imperial Chemical Industries Limited  innovator

ICI-128436; MK-538; ICI-plc

CAS No.72702-95-5

Statil; Statyl;

3-[(4-Bromo-2-fluorophenyl)methyl]-3,4-dihydro-4-oxo-1-phthalazineacetic acid

Statil™ (3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-ylacetic acid)

Molecular Formula	C17H12BrFN2O3
Molecular Weight	391.19

IC50:Aldose reductase: IC50 = 7 nM (bovine); Aldose reductase: IC50 = 16 nM (rat); Aldose reductase: IC50 = 21 nM (pig); Aldose Reductase: IC50 = 21 nM (human); Rattus norvegicus:

Medicinal Chemistry, 2009, Vol. 5, No. 5,

Synthesis of ethyl 2-(3-oxo-1,3-dihydro-1-isobenzofurany liden)acetate (2) A solution of phthalic anhydride (1.0 equiv.) and ethyl 2- (1,1,1-triphenyl-5 -phosphanylidene)acetate (1.1 equiv.) in 300 ml of dichloromethane (DCM) was refluxed for 3 hr. DCM was removed by vacuum at 40-50 o C. 2×150 ml of hexane was added to the resulting sticky solid, stirred for 10 min and the un-reacted 2-(1,1,1-triphenyl-5 -phosphanylidene)acetate was removed by filtration. The organic solvent was removed under vacuum and the resulting crude semisolid was taken to next step without further purification. Yield: 84%. 1 H-NMR CDCl3; (ppm): 1.1 (t, 3H), 4.2 (q, 2H), 6.0 (s, 1H), 7.6 (t, 1H), 7.7 (t, 1H), 7.8 (d, 1H), 8.9 (d, 1H). S

Synthesis of ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl) acetate (3) A mixture of 2 (1.0 equiv.), hydrazine hydrate (0.8 equiv) and PTSA (1.0 equiv.) was ground by pestle and mortar at room temperature for 8 min. On completion, as indicated by TLC, the reaction mixture was treated with water. The resultant product was filtered, washed with water and recrystallized from DMF to give 3 in high yields (86%).1 H-NMR CDCl3; (ppm): 1.1 (t, 3H), 3.9 ( s, 2H), 4.1 (q, 2H), 7.6

Synthesis of 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4- dihydro-1-phthalazinyl]acetic acid (4)

A mixture of 3 (1.0 equiv.), NaOH (5.0 equiv.), and THF was stirred for 30 min at 40-50 o C. 4-bromo-1-bromomethyl-2-fluoro benzene (1.1 equiv.) was added to the reaction mixture and stirred for 2 hr at 50-60 o C. Water was added to the reaction mixture and stirred at room temperature for 1 hr. pH was adjusted to 2-3 using cold acetic acid. THF was removed and the aqueous phase was extracted with ethyl acetate (2×50 ml), washed with brine, dried over sodium sulphate and evaporated. The solid was crystallized with methanol to give 4 with 54 % yield.

1H-NMR (DMSOd6); (ppm): 3.98 (s, 2H), 5.3 (s, 2H), 7.17 (t, 1H), 7.35 ( dd, 1H, J1= 8.0, J2= 1.6), 7.55 (dd, 1H, J1= 8.0, J2= 1.6), 7.87 (t, 1H), 7.9 (t, 1H), 7.95 (t, 1H0, 8.29 (d, 1H).

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C1=CC=C2C(=C1)C(=NN(C2=O)CC3=C(C=C(C=C3)Br)F)CC(=O)O



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Cairo University

Department of Pharmaceutics

Cairo, Giza, Egypt

Cairo, Giza, Egypt

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Abstract: The title compound, ethyl 3-{2-[(3-methyl-1H-indol-2-yl)carbonyl]hydrazinylidene} butanoate (3), was prepared via reaction of 3-methyl-1H-indole-2-carbohydrazide (1) and ethyl 3-oxo­butanoate (2) under reflux. The structure of the synthesized compound was assigned on the basis of elemental analysis, IR, 1H-NMR, mass spectral and X-ray data.




http://www.mdpi.com/1422-8599/2012/1/M749

Molbank 2012, 2012(1), M749; doi:10.3390/M749

Short Note

Ethyl 3-{2-[(3-Methyl-1H-indol-2-yl)carbonyl]­hydrazinylidene}­butanoate

Thoraya A. Farghaly and Sobhi M. Gomha * 

 E-Mail: s.m.gomha@hotmail.com.

Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt

* Author to whom correspondence should be addressed.

DR SOBHI M GOMHA - UNIVERSITY OF CAIRO

http://cu.edu.eg/ar/Home

جامعة القاهرة

التميز في التعليم الجامعي

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CAIRO UNIV

Synthesis of Ethyl 3-{2-[(3-Methyl-1H-indol-2-yl)carbonyl]hydrazinylidene}butanoate (3)

A mixture of the hydrazide 1 (1.89 g, 10 mmol) and ethyl 3-oxobutanoate 2 (10 mmol) in absolute

ethanol (20 mL) was heated at reflux temperature for 2 h. The reaction mixture was then cooled and

the formed precipitate was filtered off, washed with ethanol to afford the title compound 3. Yield:

84%; yellow microcrystals (from ethanol); mp: 238–240 °C.

 IR (KBr): v 1706, 1668 (2 C=O), 3409,3234 (2 NH) cm−1

1H NMR (DMSO-d6): δ 1.24 (t, J = 7.0 Hz, 3H, CH3), 2.03 (s, 3H, CH3), 2.53 (s,

3H, CH3), 3.43 (s, 2H, CH2), 4.23 (q, J = 7.0 Hz, 2H, CH2), 6.87–7.98 (m, 4H, ArH ), 10.38 (s, 1H,

D2O exchangeable, NH), 11.21 (s, 1H, D2O exchangeable, NH). 

MS m/z (%): 301 (M+, 42), 189 (100),155 (318), 117 (46), 77 (21).

Anal. Calcd for C16H19N3O3 (301.34): C, 63.77; H, 6.36; N, 13.94. Found C, 63.39; H, 6.46; N, 13.65.

References and Notes

1. Ismail, M.F.; Shmeiss, N.A.M.M.; El-Diwani, H.I.; Arbid, M.S. Synthesis and pharmacological

activity of some 2,3-diphenylindole derivative. Indian J. Chem. Sect. B 1997, 36B, 288–292.

2. von Angerer, E.; Knebel, N.; Kager, M.; Ganss, B.J. 1-(Aminoalkyl)-2-phenylindoles as novel

pure Estrogen Antagonists. J. Med. Chem. 1900, 33, 2635–2640. 

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