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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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TOLVAPTAN


TOLVAPTAN

的合成

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

Formula C26H25ClN2O3 
Mol. mass 448.941 g/mol

150683-30-0 CAS NO

+ form  331947-66-1 Rform

OPC-41061

Otsuka…..innovator

UPDATE 2022

Tolvaptan sodium phosphate, Samtasu,

トルバプタンリン酸エステルナトリウム
2022/3/28 JAPAN PPROVED
Formula
C26H24ClN2O6P. 2Na
CAS
 
Mol weight
572.8849

Tolvaptan sodium phosphate (JAN).png

Tolvaptan sodium phosphate

disodium;[(5R)-7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1-benzazepin-5-yl] phosphate

European Medicines Agency (EMA) Accepts Otsuka’s Marketing Authorisation Application (MAA) for Tolvaptan, an Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD)

•Tolvaptan was discovered by Otsuka in Japan and, if approved by the EMA, would become the first pharmaceutical therapy in Europe for patients with ADPKD
•ADPKD is an inherited genetic disease that causes cyst growth in the kidneys, which gradually impairs their functioning. There is no current pharmaceutical treatment option
•Otsuka’s development of tolvaptan as a treatment for ADPKD illustrates the company’s commitment to address significant patient needs for diseases that traditionally have not been a priority for the pharmaceutical industry

TOKYO–(BUSINESS WIRE)–Otsuka Pharmaceutical Co., Ltd. announced today that the European Medicines Agency (EMA) has accepted the submission of a marketing authorisation application (MAA) for the potential approval of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine.

http://www.pharmalive.com/ema-accepts-otsukas-maa-for-tolvaptan

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP).

Tolvaptan is (±)-4′-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-otolu-m-toluidide. The empirical formula is C26H25ClN2O3. Molecular weight is 448.94. The chemical structure is:

SAMSCA® (tolvaptan) Structural Formula Illustration

SAMSCA tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.

SEE NEW UPDATE AT END OF PAGE

Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failurecirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

ChemSpider 2D Image | Tolvaptan | C26H25ClN2O3

Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

Tolvaptan was first approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, then approved by the European Medicines Agency (EMA) on August 3, 2009 and approved by Pharmaceuticals and Medical Devices Agency of Japan on Feb 4, 2013. It was developed and marketed as Samsca® by Otsuka in the US, DE and JP.

UPDATED

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP) and that is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. It is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia [serum sodium < 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction], including patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH).

Samsca® is available as tablet for oral use, containing 7.5 mg/15 mg/30 mg of free Tolvaptan. The recommended starting dose is 15 mg once daily and it may be increased at intervals ≥ 24 hr to 30 mg once daily, and to a maximum of 60 mg once daily as needed to raise serum sodium.

 
 

Synthesis Reference

Bandi Parthasaradhi Reddy, “PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES.” U.S. Patent US20130190490, issued July 25, 2013.

US20130190490

Route 1

Reference:1. US5258510A.

Route 4

Reference:1. CN102060769B.

Route 5
 
 

SYN

SYN

Chemical synthesis:[5] Tolvaptan.png

 

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Figure US20130190490A1-20130725-C00001

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

Tolvaptan and its process for preparation were disclosed in U.S. Pat. No. 5,258,510.

Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro-1H-1-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine, and then reacted with polyphospholic acid. According to the journal, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation oftolvaptan can be prepared by the reduction of 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

Biooganic and Medicinal Chemistry I (2007) 6455-6458, Biooganic andMedicinal Chemistry 14 (2000) 2493-2495 reported in the literature of the intermediate 2 – carboxylic acid -5 – (2 – methyl-benzoylamino) toluene synthesis method,

5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.

……………………………………….

PATENT

CN102382053AFigure CN102382053AD00031

……………………………………………..

PATENT

CN102060769

Figure CN102060769BC00021

Synthesis of Intermediate III: 1.

Example

  2-methyl-4-nitrobenzoic acid (available from Alfa Aesar Tianjin Chemical Co., purity> 99%, 25g,

0.14mol) was added to a 250ml reaction flask, is reacted with thionyl chloride under reflux conditions for 3h, thionyl chloride was distilled off under reduced pressure to give 2-methyl-4-nitrobenzoyl chloride (26.Sg, light yellow oily liquid), without purification, was used directly in the next step.

  Intermediate II (20g, 0.1moI) and 2_ methyl _4_ nitrobenzoylchloride (22.4g, 0.llmol) was added to a 250ml reaction flask. Dichloromethane (50ml), cooled to ice bath with stirring to dissolve O~5 ° C, was slowly added dropwise N- methylmorpholine (11.2g, 0.llmol), Bi dropwise with stirring while, at room temperature the reaction 4h. TLC [developing solvent: ethyl acetate – petroleum ether (I: I), hereinafter] is displayed after completion of the reaction, saturated aqueous sodium bicarbonate (20ml), stirred for lOmin, filtered, the filter cake with dichloromethane (15ml X 2 ) washing. The filtrate and washings were combined, washed with saturated sodium chloride solution (30ml X 3), dried over anhydrous sodium sulfate and filtered. The filtrate under reduced pressure to recover the solvent, the residue was recrystallized from anhydrous methanol to give a white powder 111 (27.5g, 75.2%), mp 154.8 ~155.6 ° C. Purity 97.9% (HPLC normalization method).

Synthesis of Intermediate IV:

Intermediate III (10g, 28mmol) was added to a 250ml reaction flask, concentrated hydrochloric acid (40ml) and ethanol (50ml), with stirring, was slowly added dropwise stannous chloride (20g, 88mmol) in ethanol (40ml) . Bi room temperature drops 5h. After TLC showed completion of the reaction, ethanol was distilled off under reduced pressure to about 70ml, the residue was -10 ° C -0 ° C allowed to stand overnight to cool. Filtered, and the filter cake was washed with water poured into water (40ml) in. Plus 20% sodium hydroxide solution (approximately 60ml) was adjusted to pH 9. Filtered, washed with ethanol and recrystallized to give a pale yellow powdered solid IV (6.3g, 68.7%), mp 190.4~191.1 ° C. Purity 97.2% (HPLC normalization method).

Synthesis of intermediate V:

  Intermediate IV (5g, 15mmol) and triethylamine (2.3g, 23mmol) was added followed by IOOml reaction flask was added dichloromethane (30ml), stir until dissolved. Solution of o-methylbenzoyl chloride (2.8g, 18mmol), dropwise at room temperature completion of the reaction Ih0 TLC showed the reaction was complete was poured into ice-water (about 40ml) in, (20ml X 3) and extracted with dichloromethane, the combined organic phases, and saturated sodium chloride solution successively (25ml X 3), dried over anhydrous sodium sulfate and filtered with 5% hydrochloric acid (25ml X 3). The filtrate under reduced pressure to recover the solvent (about 50ml), dried over anhydrous methanol residue – petroleum ether (2: 1) and recrystallized to give white crystals of Intermediate V (6.2g, 90.9%), mp 121.1 ~123.6 ° C. Purity 98.6% (HPLC normalization method).

Synthesis of tolvaptan: Example 4

Intermediate V (5g, Ilmmol) IOOml added to the reaction flask, was added anhydrous methanol (25ml), stirred and then added portionwise sodium borohydride (0.65g, 17mmol) to the reaction mixture, addition was complete the reaction at room temperature lh. After TLC showed the reaction was complete, the methanol recovered under reduced pressure (approximately 20ml), the residue was added methylene chloride (25ml), (25mlX3) and washed with saturated sodium chloride solution. Anhydrous sodium sulfate and filtered, and the filtrate under reduced pressure to recover the solvent, the residue with absolute methanol – petroleum ether (2: 1) and recrystallized tolvaptan white crystals (4.85g, 96.6%), mp 220.1~221.5 ° C. Purity 99.2% (HPLC normalization method). ES1-HRMS (C26H25C1N203, m / z) found (calc): 447.1476 (447.1481) [MH] – “

…………..

PATENT

http://www.google.com/patents/WO2012046244A1?cl=en

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxylH-l- benzazepin- 1 -yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

Tolvaptan and its process for preparation were disclosed in U.S. patent no. 5,258,510. Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5- one, 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine and 7-chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-lH-l- benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p- toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-l-p- toluenesulfonyl-lH-l-benzazepine, and then reacted with polyphospholic acid.

According to the journal, 7-chloro- 1 -(2 -methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro- l-[2-methyl-4-[(2- methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine can be prepared by reacting l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- lH-l-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation of tolvaptan can be prepared by the reduction of 7-chloro- l-[2-methyl-4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

 SYNTHESIS CONSTRUCTION

to1

TO0

to2

to3

to4

to5

Reference example 1 :

Preparation of methyl 5-chloro-2-nitrobenzoate

Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5- chloro-2-nitrobenzoate (534 gm). Reference example 2:

Preparation of methyl 2-amino-5-chlorobenzoate

A mixture of methyl 5-chloro-2-nitrobenzoate (534 gm) as obtained in reference example 1 and concentrated hydrochloric acid (2250 ml) was added to ethyl acetate (1120 ml). To the reaction mixture was added a solution of tin chloride (1680 gm) in ethyl acetate (2250 ml). The reaction mass was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with aqueous sodium hydroxide solution (2650 ml). The separated aqueous layer was extracted with ethyl acetate and then concentrated to obtain a residual solid of methyl 2- amino-5-chlorobenzoate (345 gm). Reference example 3:

Preparation of methyl 5-chIoro-2-(N-p-toluenesulfonyl)aminobenzoate

To a solution of methyl-2-amino-5-chloro benzoate (345 gm) as obtained in reference example 2 in pyridine (1725 ml) was added p-toluenesulfonyl chloride (425 gm). The reaction mixture was stirred for 2 hours at room temperature and poured to the ice water. The separated solid was filtered and dried to obtain 585 gm of methyl 5- chloro-2-(N-p-toluenesulfonyl)aminobenzoate.

Reference example 4:

Preparation of methyl 5-chloro-2-[N-(3-ethoxycarbonyI)propyI-N-p- toluenesulfonyl] aminobenzoate

Methyl 5-chloro-2-(N-p-toluenesulfonyl)aminobenzoate (585 gm) as obtained in reference example 3, ethyl-4-bromo butyrate (369.6 gm) and potassium carbonate (664 gm) in dimethylformamide (4400 ml) were added at room temperature. The contents were heated to 120°C and maintained for 2 hours. The reaction mass was poured into water and filtered. The solid obtained was dried to give 726 gm of methyl 5-chloro-2-[N- (3 -ethoxycarbonyl)propyl-N-p-toluenesulfonyl] aminobenzoate.

Reference example 5:

Preparation of 7-chloro-4-ethoxycarbonyI-5-oxo-N-p-toluenesufonyl-2,3,4,5- tetrahydro-lH-l-benzazepine

To a heated mixture of potassium tetrabutoxide (363 gm) in toluene (1000 ml) at 70°C was added portion wise methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p- toluenesulfonyl]aminobenzoate (726 gm) as obtained in reference example 4. The contents were heated to reflux and maintained for 30 minutes. The reaction mass was then cooled to room temperature and then poured to the ice water. The layers were separated and the aqueous layer was extracted with toluene. The solvent was distilled off under reduced pressure to obtain a residual solid of 7-chloro-4-ethoxycarbonyl-5-oxo-N- p-toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine (455 gm).

Example 1:

Preparation of 7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine

7-Chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (455 gm) as obtained in reference example 5 was added to aqueous sulfuric acid (80%, 2275 ml). The contents heated to 75°C and maintained for 2 hours. The reaction mass was then cooled to room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 7.5 to 8.0 with sodium hydroxide solution (2575 ml). The solid obtained was collected by filtration and dried to give 160 gm of 7- chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 -benzazepine.

Example 2:

Preparation of 7-chIoro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l- benzazepine

7-Chloro-5-oxo-2,3,4,5-tetrahydro-lH-l -benzazepine (160 gm) as obtained in example 1 was dissolved in methylene dichloride (480 ml) and then added aqueous sodium bicarbonate solution (20%, 68.75 gm). The reaction mixture was then cooled to 0 to 5°C and then added 2-methyl-4-nitrobenzoylchloride (180 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (170 ml). The layers were separated and the aqueous layer was extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual mass. To the residual mass was dissolved in isopropyl alcohol (7300 ml) and maintained for 2 hours at reflux temperature. The separated solid was filtered and dried to obtain 250 gm of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine. Example 3:

Preparation of l-(4-amino-2-methylbenzoyl)-7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH- 1-benzazepine

7-Chloro- 1 -(2-methyl-4-nitrobenzoyl)-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (250 gm) as obtained in example 2 was dissolved in methanol (575 ml) and then added a solution of tin chloride (630 gm) in methanol (1130 ml). The reaction mixture was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with sodium hydroxide solution (1250 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under vacuum to obtain a residual solid of l-(4- amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (185 gm).

Example 4:

Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-dxo- 2,3,4,5-tetrahydro-lH-l-benzazepine

1 -(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5°C and then added 2-methyl benzoyl chloride (95.7 gm) slowly. -The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-l-[2- methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm). Example 5:

Preparation of tolvaptan

7-Chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-1 -benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1%, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.

……………….

t1.

Process used to prepare Tolvaptan involves condensing 7-chloro-1, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one with 2-methyl, 4-nitro benzoyl chloride, followed by reduction using SnCl2/HCl catalyst resulting in amine which is then condensed with o-toluoyl chloride followed by reduction with sodium borohydride to give Tolvaptan

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SYN 1

Synthetic Reference

Cordero-Vargas, Alejandro; Quiclet-Sire, Beatrice; Zard, Samir Z. A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan. Bioorganic & Medicinal Chemistry. Volume 14. Issue 18. Pages 6165-6173. 2006.

SYN 2

Synthetic Reference

Torisawa, Yasuhiro; Abe, Kaoru; Muguruma, Yasuaki; Fujita, Shigekazu; Ogawa, Hidenori; Utsumi, Naoto; Miyake, Masahiro. Process for preparation of benzoylaminobenzoylbenzazepinones by reaction of benzazepinones with benzoylaminophenyl halides in the presence of carbonylating agents. Assignee Otsuka Pharmaceutical Co.,

SYN 3

Synthetic Reference

Zard, Samir; Cordero Vargas, Alejandro; Sire, Beatrice. Improved process for the preparation of benzazepines and their derivatives. Assignee Centre National de la Recherche Scientifique CNRS, Fr.; Ecole Polytechnique. FR 2867187. (2005).

SYN 4

Synthetic Reference

Gao, Junlong; Li, Peng; Liu, Kai; Guo, Dapeng. Method for preparing high-purity Tolvaptan intermediate. Assignee Jiangsu Hengrui Medicine Co., Ltd., Peop. Rep. China. CN 108503586. (2018).

SYN 5

Synthetic Reference

Han, Shin; Jeon, Seong Hyeon; Lee, Shin Yoon. Improved method for preparing synthetic intermediates for tolvaptan. Assignee Hexa Pharmatec Co., Ltd., S. Korea. JP 2018012690. (2018).

SYN 6

Synthetic Reference

Guo, Xinfu; Wang, Qiang; Liu, Zhaoguo; Wang, Zhipeng. Preparation method of tolvaptan. Assignee Tianjin Taipu Pharmaceutical Co., Ltd., Peop. Rep. China. CN 106883175. (2017).

SYN 7

Synthetic Reference

Lixin, Juanzi; Li, Jianzhi; Ma, Xilai; Chi, Wangzhou; Liu, Hai; Hu, Xuhua; Zheng, Xiaoli; Zhai, Zhijun; Li, Jianxun. Process for the preparation of tolvaptan. Assignee Shanghai Tianci International Pharmaceutical Co., Ltd., Peop. Rep. China. CN 105753735. (2016).

STR8

Synthetic Reference

Patel, Dhaval J.; Shah, Tejas C.; Singh, Manoj Kumar. A process for the preparation of tolvaptan. Assignee Cadila Healthcare Limited, India. IN 2012MU01559. (2014).

STR9

Synthetic Reference

Sethi, Madhuresh Kumar; Rawat, Vijendrasingh; Thirunavukarasu, Jayaprakash; Yerramala, Raja Krishna; Kumar, Anish. Improved process for the preparation of tolvaptan. Assignee Matrix Laboratories Ltd., India. IN 2011CH01303. (2013).

/////////////////////

t2 t3 t4

Title: Tolvaptan
CAS Registry Number: 150683-30-0
CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide
Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine
Manufacturers’ Codes: OPC-41061
Molecular Formula: C26H25ClN2O3
Molecular Weight: 448.94
Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%
Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549; eidem, US 5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).
Properties: Colorless prisms, mp 225.9°.
Melting point: mp 225.9°
Therap-Cat: In treatment of congestive heart failure.
Keywords: Vasopressin Receptor Antagonist.

  1. Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304PMID 16211205.
  2.  Otsuka Maryland Research Institute, Inc.
  3. Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963PMID 15113814.
  4. (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
  5. Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
  6. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery
  • Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.

G. R. Belum, V. R. Belum, S. K. Chaitanya Arudra, and B. S. N. Reddy, “The Jarisch-Herxheimer reaction: revisited,” Travel Medicine and Infectious Disease, vol. 11, no. 4, pp. 231–237, 2013.
H. D. Zmily, S. Daifallah, and J. K. Ghali, “Tolvaptan, hyponatremia, and heart failure,” International Journal of Nephrology and Renovascular Disease, vol. 4, pp. 57–71, 2011.
M. N. Ferguson, “Novel agents for the treatment of hyponatremia: a review of conivaptan and tolvaptan,” Cardiology in Review, vol. 18, no. 6, pp. 313–321, 2010.
H. Ogawa, H. Miyamoto, K. Kondo, et al., US5258510, 1993.
K. Kondo, H. Ogawa, H. Yamashita et al., “7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist,” Bioorganic and Medicinal Chemistry, vol. 7, no. 8, pp. 1743–1754, 1999.

WO2012046244A1 * Aug 23, 2011 Apr 12, 2012 Hetero Research Foundation Process for preparing tolvaptan intermediates
CN102060769A * Dec 20, 2010 May 18, 2011 天津药物研究院 Preparation method of tolvaptan
CN102060769B Dec 20, 2010 Sep 18, 2013 天津药物研究院 Preparation method of tolvaptan
US9024015 Aug 23, 2011 May 5, 2015 Hetero Research Foundation Process for preparing tolvaptan intermediates
Cited Patent Filing date Publication date Applicant Title
CN101817783A May 12, 2010 Sep 1, 2010 天津泰普药品科技发展有限公司 Method for preparing tolvaptan intermediate
WO2007026971A2 Sep 1, 2006 Mar 8, 2007 Otsuka Pharma Co Ltd Process for preparing benzazepine compounds or salts thereof
Reference
1   Cordero-Vargas, Alejandro
2   Kondo, Kazumi et al.7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist.《Bioorganic & Medicinal Chemistry》.1999,1743-1757.
3   Quiclet-Sire, Beatrice
4   Torisawa, Yasuhiro et al.Aminocarbonylation route to tolvaptan.《Bioorganic & Medicinal Chemistry Letters》.2007,6455-6458.
5   Zard, Samir Z.A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan.《Bioorganic & Medicinal Chemistry》.2006,6165-6173.

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CC1=CC=CC=C1C(=O)NC2=CC(=C(C=C2)C(=O)N3CCCC(C4=C3C=CC(=C4)Cl)OP(=O)([O-])[O-])C.[Na+].[Na+]

////////////UPDATE 2022

Tolvaptan
(RS)-Tolvaptan Structural Formula V1.svg
Tolvaptan ball-and-stick model.png
Clinical data
Trade names Samsca, Jinarc, Jynarque, others
Other names OPC-41061
AHFS/Drugs.com Monograph
MedlinePlus a609033
License data
Pregnancy
category
  • UK: Contraindicated
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Unknown (40% absorbed)
Protein binding 99%
Metabolism Liver (CYP3A4-mediated)[7]
Elimination half-life 12 hours (terminal)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.219.212 Edit this at Wikidata
Chemical and physical data
Formula C26H25ClN2O3
Molar mass 448.95 g·mol−1
3D model (JSmol)
 ☒check (what is this?)  (verify)

Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failurecirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.[8] Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.[9]

The U.S. Food and Drug Administration (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of polycystic kidney disease.[10] The FDA granted Jynarque an orphan drug designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.[11]

Tolvaptan is available as a generic medication.[12]

Medical uses

Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.[13]

Tolvaptan (Jynarque) is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).[14]

Side effects

The FDA has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure.[15] When using to treat hyponatremia, it may cause too rapid correction of hyponatremia resulting in fatal osmotic demyelination syndrome.[16]

Pharmacology

Tolvaptan is a selective vasopressin V2 receptor antagonist.[13][14]

Chemistry

Tolvaptan is a racemate, a 1:1 mixture of the following two enantiomers:[17]

Enantiomers of tolvaptan
(R)-Tolvaptan Structural Formula V1.svg
(R)-Tolvaptan
CAS number: 331947-66-1
(S)-Tolvaptan Structural Formula V1.svg
(S)-Tolvaptan
CAS number: 331947-44-5

References

  1. ^ “Samsca 15 mg tablets – Summary of Product Characteristics (SmPC)”(emc). Retrieved 14 December 2020.
  2. ^ “Jinarc 15 mg tablets – Summary of Product Characteristics (SmPC)”(emc). 21 April 2020. Retrieved 14 December 2020.
  3. ^ “Jynarque- tolvaptan kit Jynarque- tolvaptan tablet”DailyMed. 31 March 2020. Retrieved 14 December 2020.
  4. ^ “Samsca- tolvaptan tablet”DailyMed. 26 October 2020. Retrieved 14 December 2020.
  5. ^ “Samsca EPAR”European Medicines Agency (EMA). Retrieved 14 December 2020.
  6. ^ “Jinarc EPAR”European Medicines Agency (EMA). Retrieved 14 December 2020.
  7. ^ Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther10 (3): 165–71. doi:10.1177/107424840501000304PMID 16211205S2CID 39158242.
  8. ^ “Drug Approval Package: Samsca (Tolvaptan) Tablets NDA #022275”U.S. Food and Drug Administration (FDA). 21 July 2009. Retrieved 15 August 2020Lay summary (PDF). {{cite web}}Cite uses deprecated parameter |lay-url= (help)
  9. ^ “Drug Approval Package: Jynarque (tolvaptan)”U.S. Food and Drug Administration (FDA). 8 June 2018. Retrieved 15 August 2020.
  10. ^ “Otsuka Maryland Research Institute, Inc. Granted Fast Track Designation For Tolvaptan In PKD”Medical News Today. Healthline Media UK Ltd. Retrieved 6 December 2018.
  11. ^ “Tolvaptan Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 6 April 2012. Retrieved 15 August 2020.
  12. ^ “Drugs@FDA: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 15 August 2020.
  13. Jump up to:a b “Samsca- tolvaptan tablet”DailyMed. 28 May 2019. Retrieved 15 August 2020.
  14. Jump up to:a b “Jynarque- tolvaptan kit Jynarque- tolvaptan tablet”DailyMed. 31 March 2020. Retrieved 15 August 2020.
  15. ^ “U.S. Food and Drug Administration.” Samsca (Tolvaptan): Drug Safety Communication. N.p., 30 Apr. 2013. Web. 1 June 2014. <http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm>[dead link]
  16. ^ Goodman & Gilman’s the pharmacological basis of therapeutics. Brunton, Laurence L, Knollmann, Björn C, Hilal-Dandan, Randa (Thirteenth ed.). New York. 5 December 2017. ISBN 9781259584732OCLC 994570810.
  17. ^ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 222.

Further reading

External links

  • “Tolvaptan”Drug Information Portal. U.S. National Library of Medicine.

Synthesis

Synthesis of Tolvaptan
Fugure 1: Synthesis of Tolvaptan

wdt-3

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Title: Tolvaptan

CAS Registry Number: 150683-30-0

CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide

Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine

Manufacturers’ Codes: OPC-41061

Molecular Formula: C26H25ClN2O3

Molecular Weight: 448.94

Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%

Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549eidemUS 5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).

Properties: Colorless prisms, mp 225.9°.

Melting point: mp 225.9°

Therap-Cat: In treatment of congestive heart failure.

Keywords: Vasopressin Receptor Antagonist.

Otsuka Receives Complete Response Letter From U.S. Food And Drug Administration For Tolvaptan For Use In Patients With Autosomal Dominant Polycystic Kidney Disease


Tokyo, Japan – August 30, 2013 – Otsuka Pharmaceutical Co., Ltd announced today the company has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding the new drug application (NDA) for tolvaptan for the treatment of adult patients with rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The FDA issues CRLs to convey that their initial review of an application is complete; however, they cannot approve the application in its present form and request additional information.
In its letter to Otsuka, the FDA requested Otsuka provide additional data to further evaluate the efficacy and safety of tolvaptan in patients with ADPKD.
READ ALL AT
OLD ARTICLE PASTED

Otsuka Pharmaceutical Submits New Drug Application in Japan for Tolvaptan for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

JUNE 10, 2013 3:46 AM

TOLVAPTAN

may 30 2013

  • Tolvaptan was discovered by Otsuka in Japan, and its primary results from a global clinical trial involving 1,400 ADPKD patients from 15 countries, which demonstrated a statistically significant reduction in the rate of total kidney volume, were published in New England Journal of Medicine in 2012. It is also currently under a fast track review in the US, following our announcement of FDA accepting to review the application in April 2013.
  • ADPKD is a hereditary and often physically and mentally burdensome disease characterized by the development of multiple cysts in the kidneys. ADPKD is often associated with pain, hypertension, decreased kidney function and ultimately, kidney failure that may result in hemodialysis or kidney transplantation.
  • There are estimated to be approximately 31,000 ADPKD patients in Japan, and the diagnosed prevalence is estimated to be between 1:1000 and 1:4000 globally.

(Tokyo, Japan, May 30, 2013) – Otsuka Pharmaceutical Co., Ltd. Today announced it filed an application with the Pharmaceutical and Medical Devices Agency in Japan (PMDA) to market its novel compound tolvaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine in November 2012. The MHLW has designated tolvaptan as an Orphan Drug.http://www.otsuka.co.jp/en/release/2013/0603_02.html

Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failurecirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

Chemical synthesis:[5] Tolvaptan.png

  1. Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304PMID 16211205.
  2.  Otsuka Maryland Research Institute, Inc.
  3. Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963PMID 15113814.
  4. (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
  5. Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
  6. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery
  • Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.

Otsuka Pharmaceutical Submits New Drug Application in Japan for Tolvaptan for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)


TOLVAPTAN

may 30 2013

  • Tolvaptan was discovered by Otsuka in Japan, and its primary results from a global clinical trial involving 1,400 ADPKD patients from 15 countries, which demonstrated a statistically significant reduction in the rate of total kidney volume, were published in New England Journal of Medicine in 2012. It is also currently under a fast track review in the US, following our announcement of FDA accepting to review the application in April 2013.
  • ADPKD is a hereditary and often physically and mentally burdensome disease characterized by the development of multiple cysts in the kidneys. ADPKD is often associated with pain, hypertension, decreased kidney function and ultimately, kidney failure that may result in hemodialysis or kidney transplantation.
  • There are estimated to be approximately 31,000 ADPKD patients in Japan, and the diagnosed prevalence is estimated to be between 1:1000 and 1:4000 globally.

(Tokyo, Japan, May 30, 2013) – Otsuka Pharmaceutical Co., Ltd. Today announced it filed an application with the Pharmaceutical and Medical Devices Agency in Japan (PMDA) to market its novel compound tolvaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine in November 2012. The MHLW has designated tolvaptan as an Orphan Drug.http://www.otsuka.co.jp/en/release/2013/0603_02.html

Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failurecirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

Chemical synthesis:[5] Tolvaptan.png

  1. Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304PMID 16211205.
  2.  Otsuka Maryland Research Institute, Inc.
  3. Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963PMID 15113814.
  4. (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
  5. Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
  6. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery
  • Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.

Otsuka’s New Drug Application for Tolvaptan, the Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD), Accepted for Review by the US Food and Drug Administration (FDA)


Otsuka Pharmaceutical Co., Ltd. announced today that the U.S. Food and Drug Administration (FDA) has accepted for priority review the company’s new drug application (NDA) for the potential use of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results………..read more at financial post

http://www.financialpost.com/markets/news/Otsuka+Drug+Application+Tolvaptan+Investigational+Compound+Autosomal/8231579/story.html

Tolvaptan
and enantiomer
Systematic (IUPAC) name
N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide
Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.
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