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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai), INDIA, worlddrugtracker, 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.8 Million hits on google, world acclamation from industry, academia, drug authorities for websites, blogs and educational contributionn, सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।...........P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Sunday, 13 December 2015

PRANIDIPINE


str1
File:Pranidipine structure.svg
Pranidipine , OPC-13340, FRC 8411
Acalas®
NDA Filing in Japan
A calcium channel blocker potentially for the treatment of angina pectoris and hypertension.
CAS No. 99522-79-9
  • Molecular FormulaC25H24N2O6
  • Average mass448.468
methyl (2E)-3-phenylprop-2-en-1-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Methyl-(2E)-3-phenyl-2-propen-1-yl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridindicarboxylat  (E)-Cinnamyl methyl (±)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate
Methyl cinnamyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate
trans-Cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, methyl (2E)-3-phenyl-2-propen-1-yl ester
Pranidipine is a calcium channel blocker. It is a long acting calcium channel antagonist of the dihydropyridine group.[1]







PATENT

 EP 0173126 http://www.google.com/patents/EP0173126A1?cl=en



 PAPER


 Der Pharmacia Sinica, 2014, 5(1):11-17


  pelagiaresearchlibrary.com/der-pharmacia-sinica/vol5-iss1/DPS-2014-5-1-11-17.pdf   str1  
CLICK ON IMAGE FOR CLEAR VIEW
Preparation of Pranidipine Hydrochloride(2):
To a suspension of (Z)-2-(3-nitrobenzylidene)-3-oxobutanoic acid(3) (1.2 kg, 5.10 mol) in dichloromethane (6 L)
was added triethylamine(0.77 kg, 7.65 mol) and cinnamyl chloride (0.85 kg, 5.61 mol). The reaction mixture was
heated to 45°C and maintained for 2 hrs. The suspension was cooled to 25 to 30°C and washed with 2.4 Lof DM
water. DCM layer was separated and concentrated under vacuum below 40°C. The concentrated mass was dissolved
in 7.2 L isopropyl alcohol and methyl-3-amino crotonate (0.52 kg, 4.5mol) was added to it. Temperatureof reaction
mixture was slowly raised to 70°C and maintained for 8 hours. Reaction mass was concentrated under vacuum
below 40°C.To the crude residue, ethyl acetate-HCl(0.28 kg, 7.6 mol) was added and the reaction mixture was
stirred for 24 hours at 25°C-30°C. Reaction mixturewas filtered and the solid residue was dried under
vacuum toafford 1.6 kg of Pranidipine hydrochloride (2)in 85% yield with 98 % purity.
1H-NMR(DMSO):
δ2.29 (s, 3H),2.32 (s, 3H), 3.55 (s, 3H), 4.60-4.74 (m, 2H), 5.04(s, 1H), 6.26-6.33 (m, 1H), 6.50 (d, 1H), 7.24-7.3
8 (m, 5H), 7.53(t, 1H), 7.63 (d,1H), 7.98-8.01 (m, 1H), 9.08 (brs, 1H)
Preparation of (Z)-2-(3-nitrobenzylidene)-3-oxobutanoic acid(3):
To a suspension of (Z)-t-butyl 2-(3-nitrobenzylidene)-3-oxobutanoate(10) (1.5 kg, 5.14 mol) in dichloromethane
(7.5 L) was added trifluoroacetic acid (1.76 kg, 15.44 mol) and reaction mass was stirred at 25°C to 30°C for 24 hrs.
The reaction mass was concentrated under vacuum below 40°C and stripped with toluene. The concentratedmass
was dissolved in 4.5 L toluene and the solution wasstirred for 8 hours at 25°C to 30°C. Reaction mixture was
filtered and solid washed with toluene and dried at35°C to 40°C to give 1.152 kg of (Z)-2-(3-nitrobenzylidene)-3-
oxobutanoic acid(3) in 96 % yield. M.P: 120°C; Mol.Wt: 235.20; Mol.Formula: C11H9NO5;1H-NMR(DMSO):
δ2.46 (s, 3H), 7.76-7.83 (m, 2H), 8.02 (d, 1H), 8.28-8.31 (dd, 1H), 8.51 (s, 1H), 13.63 (brs, 1H).Anal.Calcd for
C11H10NO5 : C, 55.93; H, 4.27; N, 5.93. Found: C, 56.19;H, 4.09; N, 6.27
Preparation of (Z)-tertiary- butyl 2-(3-nitrobenzylidene)-3-oxobutanoate(10):
To a suspension of 3-nitrobenzaldehyde(5) (1 kg, 6.61 mol) in isopropyl alcohol (6 L) was addedt-butylacetoacetate (1.14 kg, 7.27 mol),piperidine (0.12 kg, 1.32 mol) and acetic acid (0.79 kg, 1.32 mol). The reactionmass was stirred at 25°C to 30°C for 6 hrs. The suspension was cooled to -5 to 0°C, filtered, residuewashed withisopropyl alcohol and dried at 35°C to 40°C to give
1.750 kg of (Z)-t-butyl 2-(3-nitrobenzylidene)-3-oxobutanoate(10)in 91% yield; M.P: 80°C; Mol. Wt: 291.31; Mol.Formula: C15H17NO5
1H-NMR(CDCl3):
δ1.55(s, 9H), 2.44 (s, 3H), 7.50 (s, 1H),7.59 (t, 1H),7.80 (d, 1H), 8.24- 8.27 (dd,J=1H),δ8.41 (t, 1H).
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CLICK ON IMAGE FOR CLEAR VIEW



Patent		 Submitted Granted
Process for the preparation of 1,4 - dihydropyridines and novel 1,4-dihydropyridines useful as therapeutic agents [US2003230478] 2003-12-18
Advanced Formulations and Therapies for Treating Hard-to-Heal Wounds [US2014357645] 2014-08-19 2014-12-04
METHODS OF TREATING CARDIOVASCULAR AND METABOLIC DISEASES [US2014322199] 2012-08-06 2014-10-30
Protein Carrier-Linked Prodrugs [US2014323402] 2012-08-10 2014-10-30
sGC STIMULATORS [US2014323448] 2014-04-29 2014-10-30
TREATMENT OF ARTERIAL WALL BY COMBINATION OF RAAS INHIBITOR AND HMG-CoA REDUCTASE INHIBITOR [US2014323536] 2012-12-07 2014-10-30
Agonists of Guanylate Cyclase Useful For the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders [US2014329738] 2014-03-28 2014-11-06
METHODS, COMPOSITIONS, AND KITS FOR THE TREATMENT OF CANCER [US2014335050] 2012-05-25 2014-11-13
ROR GAMMA MODULATORS [US2014343023] 2012-09-18 2014-11-20
High-Loading Water-Soluable Carrier-Linked Prodrugs [US2014296257] 2012-08-10 2014-10-02  
Pranidipine.png
Publication Number Publication Date IPCR Assignee/Applicant Structure hits Tools
1.
US-20150342954-A1		 2015-12-03
A61K 31/52 IRONWOOD PHARMACEUTICALS INC
2-BENZYL, 3-(PYRIMIDIN-2-YL) SUBSTITUTED PYRAZOLES USEFUL AS SGC STIMULATORS
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
2.
EP-2558474-B1		 2015-11-25
C07D 498/04 RIGEL PHARMACEUTICALS INC
2, 4-PYRIMIDINEDIAMINE COMPOUNDS AND PRODRUGS THEREOF AND THEIR USES
EN
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
3.
US-20150307580-A1		 2015-10-29
C07K 14/605 MERCK SHARP & DOHME
OXYNTOMODULIN ANALOGS
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
4.
US-20150305974-A1		 2015-10-29
A61H 23/02 SYMPARA MEDICAL INC
METHODS AND DEVICES FOR TREATING HYPERTENSION
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
5.
WO-2015164658-A1		 2015-10-29
A61H 23/00 SYMPARA MEDICAL INC
METHODS AND DEVICES FOR TREATING HYPERTENSION
EN
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
6.
EP-2527360-B1		 2015-10-28
C07K 7/08 SYNERGY PHARMACEUTICALS INC
Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EN
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
7.
WO-2015157471-A1		 2015-10-15
A61K 31/198 METHODIST HOSPITAL
INOS-INHIBITORY COMPOSITIONS AND THEIR USE AS BREAST CANCER THERAPEUTICS
EN
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
8.
US-20150284411-A1		 2015-10-08
C07D 519/00 APGAR JAMES M
NOVEL AZABENZIMIDAZOLE HEXAHYDROFURO[E,2-B]FURAN DERIVATIVES
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
9.
US-20150283202-A1		 2015-10-08
A61K 38/10 SYNERGY PHARMACEUTICALS INC
AGONISTS OF GUANYLATE CYCLASE USEFUL FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA, ATHEROSCLEROSIS, CORONARY HEART DISEASE, GALLSTONE, OBESITY AND OTHER CARDIOVASCULAR DISEASES
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1
10.
US-9150512-B2		 2015-10-06
C07D 209/64 JANSSEN PHARMACEUTICA NV
Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1

References

Jin Yang, Keisuke Fukuo, Shigeto Morimoto, Tadaaki Niinobu, Toshimitsu Suhara, Toshio Ogihara (2000). "Pranidipine Enhances the Action of Nitric Oxide Released From Endothelial Cells". Hypertension 35: 82–85. doi:10.1161/01.hyp.35.1.82.   http://pelagiaresearchlibrary.com/der-pharmacia-sinica/vol5-iss1/DPS-2014-5-1-11-17.pdf.........NICARDIPINE
Pranidipine
Pranidipine structure.svg
Names
IUPAC name
methyl (2E)-phenylprop-2-en-1-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Other names
2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-methyl O3-[(E)-3-phenylprop-2-enyl] ester
Identifiers
99522-79-9 Yes
ChEMBL ChEMBL1096842 
ChemSpider 4940726 
Jmol interactive 3D Image
MeSH C048161
PubChem 6436048
UNII 9DES9QVH58 Yes
Properties
C25H24N2O6
Molar mass 448.46786

SEE.........http://newdrugapprovals.org/2015/12/11/pranidipine/



  ////////// CC1=C(C(C(=C(N1)C)C(=O)OCC=CC2=CC=CC=C2)C3=CC(=CC=C3)[N+](=O)[O-])C(=O)OC



 see dipine series...........http://organicsynthesisinternational.blogspot.in/p/dipine-series.html Nilvadipine - Wikipedia, the free encyclopedia
en.wikipedia.org
manidipine
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