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Arbaclofen

May 10, 2016 10:35 am / 2 Comments on Arbaclofen

Arbaclofen placarbil

(3R)-3-(4-chlorophenyl)-4-[[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino]butanoic acid

A GABA (B) receptor agonist potentially for the treatment of muscle spasticity.

AGI-006; STX-209; OS-440

CAS No. 69308-37-8 free

847353-30-4 placarbil

Arbaclofen placarbil (ar-bac-loe-fen pla-kar-bil, also known as XP19986) is a prodrug of R–baclofen. Arbaclofen placarbil possesses more favorable pharmacokinetic profile than baclofen, with less fluctuations in plasma drug levels. It was being developed as a potential treatment for patients with GERD and spasticity due to multiple sclerosis; however, in May 2013 XenoPort announced the termination of development because of unsuccessful results in phase III clinical trials.^[1]

Arbaclofen Placerbil is a prodrug of Arbaclofen, which is a selective gamma-amino-butyric acid type B receptor agonist and the R-enantiomer of baclofen. It was discovered, and has been patented by XenoPort as a new chemical entity with an improved pharmacokinetic profile compared to baclofen, which allows for sustained release properties. ArbaclofenPlacerbil was believed to have therapeutic potential in treating gastroesophogeal reflux disease (GERD) and plasticity; however due to discouraging clinical trial results, the drug was abandoned by XenoPort in 2011 for the treatment of GERD. On May 20th, 2013, XenoPort announced plans to terminate the development of Arbaclofen Placerbil for the treatment of multiple sclerosis.

Autism spectrum disorder (ASD) is a behaviorally defined disorder which has increased in prevalence over the last two decades. Despite decades of research, no effective treatment is currently available. Animal models, as well as other lines of evidence, point to abnormalities in the balance of cortical excitation to inhibition in individuals with ASD, with this imbalance resulting in an overall increase in cortical excitation. To reduce cortical excitatory glutamate pathways, arbaclofen, a selective agonist of the gamma aminobutyric acid receptor type B, has been developed. This article reviews the evidence for this treatment for ASD using a systematic review methodology. Overall, a systematic search of the literature revealed 148 relevant references with the majority of these being review papers or news items that mentioned the potential promise of arbaclofen. Five original studies were identified, four of which used STX209, a form of arbaclofen developed by Seaside Therapeutics, Inc., and one which used R-baclofen. In an animal model, treatment of Fragile X, a genetic disease with ASD features, demonstrated a reversal of behavioral, neurological, and neuropathological features associated with the disease. One double-blind, placebo-controlled study treated children and adults with Fragile X. Results from this study were promising, with signs of improvement in social function, especially in the most severely socially impaired. Two studies, one open-label and one double-blind, placebo-controlled, were conducted in children, adolescents, and young adults with ASD. These studies suggested some improvements in socialization, although the effects were limited and may have been driven by individuals with ASD that were higher-functioning. These studies and others that have used arbaclofen for the treatment of gastroesophageal reflux suggest that arbaclofen is safe and well-tolerated. Clearly, further clinical studies are needed in order to refine the symptoms and characteristics of children with ASD that are best treated with arbaclofen.

Arbaclofen placarbil.png

Fig. 1.

The Structures of R-baclofen (1), arbaclofen placarbil (2), R-baclofen lactam (3), and the potential γ-hydroxy metabolite of R-baclofen (4).

Route 2

Reference：1. Chem. Pharm. Bull. 1995, 43, 1302-1306.

Route 3

Reference：1. Tetrahedron Lett. 1997, 38, 1195-1196.

Route 4

Reference：1. J. Am. Chem. Soc. 2005, 127, 119-125.

2. WO2007066828A1 / US2009137819A1.

Route 5

Reference：1. US2012029230A1

Route 1

Reference：1. Tetrahedron-Asymmetr. 1992, 3, 1213-1221.

2. Tetrahedron Lett. 1991, 32, 6949-6952.

References

http://investor.xenoport.com/releasedetail.cfm?ReleaseID=765868

Arbaclofen placarbil
Systematic (IUPAC) name

(3R)-3-(4-chlorophenyl)-4-[[[(1S)-2-methyl-1-[(2-methylpropanoyl)oxy]propoxy]carbonyl]amino]butanoic acid
Clinical data
Pregnancy category	N/A
Legal status
Legal status	Development terminated
Identifiers
CAS Number	847353-30-4
ATC code	none
PubChem	CID 11281011
ChemSpider	9456008
KEGG	D08861
ChEMBL	CHEMBL2107312
Chemical data
Formula	C₁₉H₂₆ClNO₆
Molar mass	399.86 g/mol

///////AGI-006, STX-209, OS-440, Arbaclofen, autism spectrum disorder, Fragile X, gamma-aminobutyric acid, arbaclofen, R-baclofen, STX209

CC(C)[C@@H](OC(=O)C(C)C)OC(=O)NC[C@H](CC(=O)O)C1=CC=C(C=C1)Cl

DISCLAIMER

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

CADROFLOXACIN

May 9, 2016 1:18 pm / Leave a comment

Cadrofloxacin Structure

Cadrofloxacin , CS 940

3-Quinolinecarboxylic acid, 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-1,4-dihydro-7-[(3S)-3-methyl-1-piperazinyl]-4-oxo-, hydrochloride (1:1)

UNII-1YOQ7J9ACY; 153808-85-6; CADROFLOXACIN HYDROCHLORIDE; 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-7-[(3s)-3-methylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-7-[(3S)-3-methylpiperazin-1-yl]-4-oxoquinoline-3-carboxylic acid

Molecular Formula:	C₁₉H₂₀F₃N₃O₄
Molecular Weight:	411.37501 g/mol

Company：HengRui (Originator), Daiichi Sankyo (Originator), UBE (Originator)

A quinolone antibiotic potentially for the treatment of bacterial infections.

Research Code CS-940

CAS No. 153808-85-6(FREE)

Cas 128427-55-4(Cadrofloxacin HCl)

HYDROCHLORIDE

Molecular Weight	447.84
Formula	C19H20F3N3O4 • HCl

OriginatorSankyo; Ube Industries
DeveloperSankyo
ClassAntibacterials; Quinolones; Small molecules
Mechanism of ActionType II DNA topoisomerase inhibitors
- 20 Jun 1996An animal study has been added to the Bacterial infections pharmacodynamics section
- 24 Mar 1995Phase-II clinical trials for Bacterial infections in Japan (PO)

Cadrofloxacin hydrochloride was studied for the treatment of bacterial infections.The compound was originally developed by UBE and Daiichi Sankyo. However, this study was discontinued. The compound currently was developed by Hengrui.

SYNTHESIS

Decarboxylation of 3,5,6-trifluoro-4- hydroxyphthalic acid (I) upon heating at 140 C in an autoclave furnished 2,4,5-trifluoro-3-hydroxybenzoic acid (II). This was converted to ethyl ester (III) by refluxing in EtOH in the presence of H2SO4. Condensation of (III) with chlorodifluoromethane and NaH in hot DMF produced the corresponding difluoromethyl ether, and subsequent basic hydrolysis of the ethyl ester yielded 3- (difluoromethoxy) -2, 4,5-trifluorobenzoic acid (IV). Alternatively, acid (II) was converted to acid chloride with SOCl2 and subsequently condensed with ammonia to give amide (V). After formation of the difluoromethyl ether (VI) under similar conditions as above, acid (IV) was obtained by diazotization of the amide function of (VI) in hot sulfuric acid. The difluoromethoxy acid (IV) was also prepared by direct alkylation of hydroxy acid (II) with chlorodifluoromethane in the presence of NaOH in hot DMF. acid (IV) was activated as the corresponding acid chloride (VII) with SOCl2. Condensation of acid chloride (VII) with the magnesium salt of diethyl malonate gave rise to the benzoylmalonate (VIII). Further decarbethoxylation of (VIII) by heating in the presence of p-toluenesulfonic acid yielded keto ester (IX). This was condensed with triethyl orthoformate in the presence of Ac2O to give the ethoxyacrylate (X), which was converted to enamine (XII) by treatment with cyclopropylamine (XI). The target quinolone system (XIII) was then obtained by intramolecular cyclization of (XII) in the presence of NaH. Then, ethyl ester (XII) cleavage using boron trifluoride etherate provided the key quinolonecarboxylic acid boron chelate (XIV)

Route

US5073556A / US5348961A.

1 to 8 of 8

Patent ID	Date	Patent Title
US2011159049	2011-06-30	PHARMACEUTICAL COMPOSITION
US2010330165	2010-12-30	USE OF CHEMOTHERAPEUTIC AGENTS
US2007196504	2007-08-23	PHARMACEUTICAL COMPOSITION
US2007197501	2007-08-23	Use Of Chemotherapeutic Agents
US2007148235	2007-06-28	PHARMACEUTICAL COMPOSITION
US2005152975	2005-07-14	Pharmaceutical composition
US2004022848	2004-02-05	Medicinal composition
US2003045544	2003-03-06	Use of chemotherapeutic agents

//////CS 940, Quinolone antibiotic , CADROFLOXACIN, NDA

CC1CN(CCN1)C2=C(C=C3C(=C2OC(F)F)N(C=C(C3=O)C(=O)O)C4CC4)F

Nolatrexed Dihydrochloride

May 9, 2016 1:16 pm / Leave a comment

Nolatrexed

A thymidylate synthase inhibitor potentially for the treatment of hepatocellular carcinoma and nasopharyngeal cancer.

AG-337

CAS No. 147149-76-6 (free)

free form data

(eluents: CH₃CN−H₂O = 10−90, pH 4.94; R_t = 11.8 min); R_f = 0.31 [ethyl acetate/(0.63 M NH₃ in ethanol) = 6/4]; Mp 300−302 °C (lit.:(J. Med. Chem. 1993, 36, 733– 746) a tan solid; Mp 301−302 °C); MS (ESI⁺) m/z: 285.1 [M + 1]⁺; the major impurity: 3.0% (R_t = 13.0 min); Mp 73−77 °C; ¹H NMR (DMSO-d₆): δ 7.95 (d, J = 6.4 Hz, 4 H), 8.81 (d, J = 6.4 Hz, 4 H);

MS (ESI⁺) m/z: 219.2 [M − 1]⁺;

Nolatrexed dihydrochloride.png

152946-68-4(Nolatrexed Dihydrochloride)

2-amino-6-methyl-5-pyridin-4-ylsulfanyl-1H-quinazolin-4-one;dihydrochloride

Nolatrexed dihydrochloride; Thymitaq; 152946-68-4; Nolatrexeddihydrochloride; AG 337; AG-337;

Molecular Formula:	C₁₄H₁₄Cl₂N₄OS
Molecular Weight:	357.25816 g/mol

diHCl data

IR (KBr cm⁻¹):ṽ 3401, 3058, 2929, 1701, 1621, 1471, 799;

¹H NMR (DMSO-d₆): δ 2.43 (s, 3H, −CH₃), 7.53 (d,J = 6.9 Hz, 2H, Pyr-H), 7.67 (d, J = 8.5 Hz, 1H, Ar−H), 7.92 (d, J = 8.5 Hz, 1 Hz, Ar−H), 8.30 (br s, 3H, NH₃), 8.52 (d, J = 6.9 Hz, 2H, Pyr-H); MS (ESI⁺) m/z: 285 [M − 1−2Cl]⁺; (ESI⁺) m/z: 283 [M − 1− 2HCl]⁺.

Pfizer (Originator) , Gilead,LG Life Sciences,北京康辰药业

Nolatrexed is a thymidylate synthase inhibitor.^[1]^[2]

Phase I studies of p.o. administered nolatrexed dihydrochloride (AG337, THYMITAQ), a nonclassical thymidylate synthase inhibitor, were performed to establish the maximum tolerated dose and a recommended dose for Phase II studies. The bioavailability and pharmacokinetic and pharmacodynamic properties of oral nolatrexed were also studied. Forty-five patients were treated with oral nolatrexed every 6 h for 5 days at doses of 288-1000 mg/m2/day. The bioavailability of the oral preparation was determined, and the effect of a standard meal on nolatrexed absorption was investigated at a dose of 800 mg/m2/day. Nolatrexed plasma concentrations were analyzed by high-performance liquid chromatography. Nolatrexed was rapidly absorbed with a median bioavailability of 89% (range 33-116%), with 88% of patients above 70%. The dose-limiting toxicities were gastrointestinal, and the recommended Phase II oral dose was 800 mg/m2/day. After a standard meal, the peak plasma nolatrexed concentration achieved was lower (median, 8.3 microg/ml versus 15.0 microg/ml; P = 0.001), and the time taken to reach the peak was longer (median, 180 min versus 45 min; P = 0.00003), but the trough concentration was higher (median, 3.6 microg/ml versus 2.1 microg/ml; P = 0.004) when compared with the fasted state. The area under the nolatrexed plasma concentration versus time curve was not affected by food. Average trough nolatrexed concentration, but not dose, was significantly related to the % decrease in both thrombocytes (r2 = 0.58; C50 = 6.0 microg/ml, where C50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils (r2 = 0.63; C50 = 0.6 microg/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m2/day for 5 days. Bioavailability was close to 100% and, because inhibition of thymidylate synthase by nolatrexed is rapidly reversible, the slower absorption after a standard meal may result in a shorter duration of noninhibitory concentrations between doses.

Catalytic hydrogenation of 2-bromo-4 -nitrotoluene (I) over Raney-Ni provided aniline (II). Reaction of (II) with chloral hydrate and hydroxylamine gave rise to the isonitrosoacetanilide (III), which was subsequently cyclized to the isatin (IV) by heating in concentrated H2SO4. Oxidative cleavage of isatin (IV) produced the anthranilic acid (V). This was converted to the benzoxazinone (VI) upon refluxing with acetic anhydride. Ring opening of benzoxazinone (VI) with MeOH, followed by acidic hydrolysis of the acetamide function, yielded the anthranilate ester (VII). The quinazoline derivative (VIII) was then obtained by treatment of anthranilate (VII) with chloroformamidine hydrochloride in refluxing diglyme. Finally, displacement of the bromide group of (VIII) with the sodium thiolate of 4-mercaptopyridine (IX) under Ullmann conditions afforded the title pyridyl sulfide.

Dissertation title	[BT] A New Method for Synthesis of Nolatrexed Dihydrochloride

Hangul title	Nolatrexed dihydrochloride Synthesis Process Development

Author	Xueqing Zhao, Fei Li, Weiping Zhuang, Xiaowen Xue, Yuanyang Lian, Jianhui Fan and Dongsheng Fang

Japjimyeong	ORG PROCESS RES DEV	Issue year	2010

Gwonho details	14 (2)	The surface	346-350

ABSTRACT	A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate / sodium methoxide. In the final Ullmann reaction potassium carbonate was employed in place of sodium hydride, and the amount of copper catalysts was significantly reduced. Moreover, sodium sulfide solution was utilized to efficiently remove copper under approximately neutral conditions instead of hydrogen sulfide / methanol under strongly acidic conditions. By means of these modifications, nolatrexed dihydrochloride was ensured to be prepared in good yield and high purity.

Contents	Nolatrexed dihydrochloride (2-Amino-6-methyl-5-(4-pyridylthio) -3 H-quinazolin-4-one dihydrochloride, thymitag, 1) is the HCC cancer therapeutic agent to the TS (thymidylate synthase) folate binding site on the TS inhibitor as DNA replication inhibition, DNA damage, S-phase cell cycle arrest, and caspase-dependent apoptosis induction and clinical 2 on theresults look HCC patients, the survival benefit of showing the current phase III study is in progress in it. under scheme 1 is conducted in a number of synthesis team Nolatrexedillustrates the development process Scheme 1. Synthetic routes A-F from 4-bromo-5-methylisatin (2) to nolatrexed dihydrochloride (1) The scheme 1 When the complex first synthesis process but is A : 2 – 3 – 4 – 5 – 7 · HCl – 1 or in part, 6 pass through a B step ( 2 – 3 – 6 – 5 ) to obtain the desired compound with, but However, these processes are of the desired product quality control had a disadvantage unfulfilled this . after C, D, E process was developed during the E step is a step wherein compound 8 from the first to the one-pot is the most superior process consists in the process also drug of the compound for use as a quality control has difficulty in . more recentlyWennerberg is a new process F compounds were reported for 3 compound directly from the 7fully in the process I scored quality control could be the place . in the process, each reactionstep partially changed by the use of a reagent zoom impurity to minimize the formation of .However, this process also work-up, and purification there have difficulties to process the authors reported a new efficient way . Scheme 2. Synthetic route G from 4-bromo-5-methylisatin (2) to nolatrexed dihydrochloride (1) Scheme 2 The process reported to also have specifically not a new process only takes the best features from several processes previously reported , significant differences that the author is proud director teen two direct compound from 5 will get the , also reported in other processes already advanced mercaptopyridine introducing Ullmann reaction in the processimpurity , to reduce the formation of NaH , instead of K2CO3 were used the copper catalyst in order to minimize the amount of copper scavenge used to H2S instead of Na2S was used . the compound obtained in the process 1 of the purity is 96.6% and 3% with impurities of the 4,4′-dithiodipyridine this was confirmed copper impurity is 20 ppm was below . last Nolatrexed dihydrochloride in the process to obtain a 99.7% purity I scored the desired product , 0.3% ofunidentified impurity, and 10 ppm less than copper because it contains should think very advanced process compared to the previous number of ways . Fortunately Ullmann key contained in the reaction impurity in 4,4′-dithiodipyridine was automatically removed from the crystallization process of the last reaction. Korea Research Institute of Chemical Technology provides incurable disease treatment and research center, Dr. jaedu

View original	http://pubs.acs.org/doi/full/10.1021/op9002517

Route 1

Reference：1. J. Med. Chem. 1993, 36, 733-746.

2. WO9320055A1.

Route 2

Reference：1. Org. Process Res. Dev. 2008, 12, 1195-1200.

Route 3

Reference：1. Org. Process Res. Dev. 2010, 14, 346-350.

2. CN1335307A.

Route 4

Ref Chemical Reagents 2011, 33, 1131-1134..

References

Hughes AN, Rafi I, Griffin MJ, et al. (January 1999). “Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days”. Clin. Cancer Res. 5 (1): 111–8. PMID 9918208.
“Nolatrexed”. PubChem.gov. Pub Chem. Retrieved 12 August 2014.

Nolatrexed
Names

IUPAC name 2-Amino-6-methyl-5-(4-pyridylthio)-1H-quinazolin-4-one
Identifiers
CAS Number	147149-76-6
ChemSpider	97268
Jmol 3D model	Interactive image
PubChem	108189
UNII	K75ZUN743Q
InChI [show]
SMILES [show]
Properties
Chemical formula	C₁₄H₁₂N₄OS
Molar mass	284.34 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////Nolatrexed, thymidylate synthase inhibitor, AG337, THYMITAQ,

CC1=C(C2=C(C=C1)NC(=NC2=O)N)SC3=CC=NC=C3.Cl.Cl

энкломифен Enclomiphene citrate إينكلوميفان

April 29, 2016 1:23 pm / Leave a comment

Enclomiphene citrate

An estrogen receptor (ER) antagonist potentially for treatment of hypogonadotropic hypogonadism.

ICI-46476; RMI-16289

CAS No.15690-57-0(free)

7599-79-3(Enclomiphene citrate)

Molecular Weight	598.08
Formula	C26H28ClNO▪C6H8O7

Ethanamine, 2-[4-[(1E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)

Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl-, (E)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)
Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate (1:1), (E)-
(E)-Clomiphene citrate
Androxal
Clomiphene B citrate

Enclomid
Enclomiphene citrate
trans-Clomiphene citrate

Clomifene is a mixture of two geometric isomers, enclomifene (E-clomifene) and zuclomifene (Z-clomifene). These two isomers have been found to contribute to the mixed estrogenic and anti-estrogenic properties of clomifene.

Enclomifene

Zuclomifene

PATENT

WO 2015138340

EXAMPLE 1

Preparation of trans-clomiphene citrate from

1- {4- [2-(Oiethylamino)ethoxy| phenylj-1 ,2-diphenylethanol

Dehydration

[0023] l-{4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) dissolved in ethanol containing an excess of hydrogen chloride was refluxed 3 hours at 50 °C. The solvent and excess hydrogen chloride were removed under vacuum and the residue was dissolved in dichloromethane. 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanaminium hydrogen chloride (7) was obtained.

Chlorination

The hydrochloride salt (7) solution obtained above was treated with 1.05 equivalents of N-chlorosuccinimide and stirred at room temperature for about 20 hours. Completion of the reaction was confirmed by HPLC. The hydrochloride salt was converted to the free base by addition of saturated aqueous bicarbonate solution. The mixture was stirred at room temperature for 30 minutes after which the phases were separated and the organic phase was evaporated in vacuo. 2-{4-[2-chloro-l,2- diphenylvinyl]phenoxy}-N,N-diethylethanamine (clomiphene -1.8:1 E:Z mixture) (8) was obtained.

Separation of clomiphene isomers

Clomiphene (8) obtained above is dissolved in methanol and racemic binaphthyl- phosphoric acid (BPA) is added under stirring. When the precipitate begins separating from the solution, stirring is stopped and the mixture is allowed to settle at room temperature for 2 hours. The precipitate is filtered, washed with methanol and ether and dried. Trans-clomiphene-BPA salt (3) is obtained.

The enclomiphene-BPA salt (3) obtained above is extracted with ethyl acetate and NH₃ solution. To the organic solution washed with water and dried, citric acid dissolved in ethanol is added. The solution is allowed to settle for about one hour at room temperature; the precipitate is then filtered and dried under vacuum. The obtained precipitate, trans-clomiphene citrate (1) is dissolved in 2-butanone for storage.

EXAMPLE 2

Synthesis of Clomiphene Using a Single Solvent

Step 1 – Dehydration of l-i4-r2-(Diethylamino)ethoxy1phenyl|-l,2- diphenylefhanol to form 2-{4-[(Z)-l,2-diphenylvinyllphenoxy}-N,N-diethylethanaminium hydrogen sulfate (7) [0030] The synthesis route described in Example 1 utilized HC1 for the dehydration step and utilized ethanol at 50 °C as the solvent. Sulfuric acid was investigated as an alternative to HC1 for the dehydration step (as described in Example 1) in part due to the more favorable corrosion profile of sulfuric acid. Dichloromethane (methylene chloride) was investigated as an alternative solvent for the dehydration step as this would render removal of the ethanol solvent prior to the chlorination step unnecessary.

A 100 mL 3-neck round bottom flask, fitted with a temperature probe and a stir bar, was charged with l- {4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) (6.60 g, 16.9 mmol) and 66 mL (lxlO³ mmol) of methylene chloride to give a yellow solution which was cooled in an ice bath to 0 °C. Concentrated sulfuric acid (H₂S0₄, 0.96 mL, 18.1 mmol) was added at a rate such that the internal temperature did not exceed 5 °C. Upon completion of the addition, the mixture was allowed to stir one hour at ambient temperature. Completion of the reaction was confirmed by high performance liquid chromatography (HPLC). The reaction resulted in 7.96 grams of 2- (4-[(Z)- 1 ,2- diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7), a yield of 100%. Thus, sulfuric acid was demonstrated to be a suitable acid for the dehydration step.

[0042] Using these HPLC conditions, starting material has a retention time of 3.30 min and product has a retention time of 4.05 min.

It was determined that removal of water produced by the dehydration reaction was important before performing the chlorination step. When ethanol is used as the solvent for this reaction, as in Example 1, the water is removed azeotropically upon removal of the ethanol. Several methods of drying the dichloromethane solution were attempted. Drying with MgS0₄ had a deleterious effect on the subsequent chlorination step, rendering the chlorination process very messy with a number of new impurities observed following HPLC analysis which were determined to be the corresponding chlorohydrins. On the other hand, a wash with brine was sufficient to remove enough water and had no deleterious effect on the chlorination step. Accordingly, the solution was stirred vigorously with brine (66 ml) for 30 minutes and then the phases were separated prior to chlorination step.

Step 2- Synthesis of 2-|4-r2-chloro-L2-diphenylvinyl1phenoxyl-N,N- diethylethanamine 8

The solution of 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7.94 grams) in methylene chloride obtained in step 1 is stirred at room temperature and treated with N-chlorosuccinimide (2.37 g, 17.7 mmol, 1.05 equivalents) in a single portion and left to stir at room temperature for 12 hours. The yellow solution became orange and then went back to yellow. After 12 hours, a sample was removed, concentrated and assayed by HPLC to confirm the extent of reaction. HPLC analysis revealed that the reaction had proceeded but not to completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred at room temperature for an additional 4 hours. The reaction was again assayed by HPLC which revealed that the reaction was near completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred for an additional 12 hours at room temperature. The reaction was again assayed by HPLC and an additional 0.058 equivalents of N-chlorosuccinimide (131 mg, 0.98 mmol) was added and the solution stirred for an additional 4 hours. HPLC indicated that the reaction was complete at that point. The reaction was carefully quenched by slow addition of 66 mL (600 mmol) of saturated aqueous sodium bicarbonate solution and the quenched mixture was stirred for 30 minutes at room temperature – the reaction mixture pH should be about 8-9 after addition of saturated aqueous sodium bicarbonate solution. The reaction yielded 6.86 grams of 2-{4-[2-chloro-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanamine (8). The phases were separated and the organic phase was evaporated in vacuo. The resulting light brown oil was transferred to a tared amber bottle using a small volume of dichloromethane.

[0055] Using these HPLC conditions, the retention time of product is 15 minutes.

Chromatographic Separation of Clomiphene Isomers

Clomiphene (mixture of isomers) in free base form obtained by steps 1 and 2 is loaded onto a chromatographic column (e.g. batch high pressure chromatography or moving bed chromatography) using the same solvent as used in steps 1 and 2 (here DCM) in order to separate the cis- and trans-clomiphene isomers. Trans-clomiphene is preferably eluted using a solvent suitable for recrystallization.

PATENT

Indian (1978), IN 143841

http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19780211&CC=IN&NR=143841B&KC=B

PAPER

Separation of E- and Z-isomers of clomiphene citrate by high-performance liquid chromatography using methenamine as mobile phase modifier
Journal of Chromatography (1984), 298, (1), 172-4.

http://www.sciencedirect.com/science/article/pii/S0021967301927074

PATENT

http://www.google.com/patents/CN103351304A?cl=en

SYTHESIS

Patent
US2914562https://www.google.co.in/patents/US2914562PATENTUS2914529

http://www.google.co.in/patents/US2914529

PAPER

J. Med. Chem.1967, 10, 84–86.

http://pubs.acs.org/doi/pdf/10.1021/jm00313a017

J. Org. Chem.1983, 48, 2782-2784.

http://pubs.acs.org/doi/pdf/10.1021/jo00164a036

PAPER

Chem Commun (London) 2015, 51(44): 9133

Chem. Commun., 2015, 51, 9133-9136
DOI: 10.1039/C5CC01968K

A transition-metal-free, ambient-pressure, and general methodology for carbonylative Suzuki coupling has been developed.

Graphical abstract: Transition-metal-free, ambient-pressure carbonylative cross-coupling reactions of aryl halides with potassium aryltrifluoroborates

CN103351304A *	Jul 1, 2013	Oct 16, 2013	暨明医药科技（苏州）有限公司	Synthesis method of clomiphene
US2914563 *	Aug 6, 1957	Nov 24, 1959	Wm S Merrell Co	Therapeutic composition
US3848030 *	Mar 10, 1972	Nov 12, 1974	Richardson Merrell Spa	Optical isomers of binaphthyl-phosphoric acids
US5681863 *	Dec 5, 1994	Oct 28, 1997	Merrell Pharmaceuticals Inc.	Non-metabolizable clomiphene analogs for treatment of tamoxifen-resistant tumors

Reference
1	*	RAO ET AL.: “Synthesis of carbon-14 labeled clomiphene.“, JOUMAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 22, no. 3, 1985, pages 245 – 255, XP055180053, Retrieved from the Internet <URL:http://onlinelibrary. wiley .com/doi/10.1002/jlcr.2580220306/abstract> [retrieved on 20150504]

//////////энкломифен, Enclomiphene citrate, إينكلوميفان , ICI-46476, RMI-16289, nda filed,

Plecanatide 普卡那肽 ليكاناتيد плеканатид

April 21, 2016 1:59 pm / 4 Comments on Plecanatide 普卡那肽 ليكاناتيد плеканатид

PLECANATIDE; UNII-7IK8Z952OK; (3-Glutamic acid(D>E))human uroguanylin (UGN); 467426-54-6;

Molecular Formula:	C₆₅H₁₀₄N₁₈O₂₆S₄
Molecular Weight:	1681.88626 g/mol

IUPAC Condensed

H-Asn-Asp-Glu-Cys(1)-Glu-Leu-Cys(2)-Val-Asn-Val-Ala-Cys(1)-Thr-Gly-Cys(2)-Leu-OH

(2S)-2-[[(1R,4S,7S,10S,13S,16R,21R,27S,34R,37S,40S)-10-(2-amino-2-oxoethyl)-34-[[(2S)-4-carboxy-2-[[(2S)-3-carboxy-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]propanoyl]amino]butanoyl]amino]-37-(2-carboxyethyl)-27-[(1R)-1-hydroxyethyl]-4-methyl-40-(2-methylpropyl)-3,6,9,12,15,23,26,29,35,38,41-undecaoxo-7,13-di(propan-2-yl)-18,19,31,32-tetrathia-2,5,8,11,14,22,25,28,36,39,42-undecazabicyclo[14.13.13]dotetracontane-21-carbonyl]amino]-4-methylpentanoic acid

L-Leucine, L-asparaginyl-L-alpha-aspartyl-L-alpha-glutamyl-L-cysteinyl-L-alpha-glutamyl-L-leucyl-L- cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-, cyclic (4->12),(7->15)-bis(disulfide)

L-Asparaginyl-L-α-aspartyl-N-{(1R,4S,7S,10S,13S,16R,19S,22S,25R,32S,38R)-10-(2-amino-2-oxoethyl)-22-(2-carboxyethyl)-38-{[(1S)-1-carboxy-3-methylbutyl]carbamoyl}-32-[(1R)-1-hydroxyethyl]-19-isobut yl-7,13-diisopropyl-4-methyl-3,6,9,12,15,18,21,24,30,33,36-undecaoxo-27,28,40,41-tetrathia-2,5,8,11,14,17,20,23,31,34,37-undecaazabicyclo[14.13.13]dotetracont-25-yl}-L-α-glutamine

Plecanatide
RN: 467426-54-6

Molecular FormulaC₆₅H₁₀₄N₁₈O₂₆S₄
Average mass1681.886 Da
- 105: PN: WO2012037380 SEQID: 105 claimed protein
- 1: PN: US20100152118 SEQID: 1 claimed protein
- 1: PN: WO2008151257 SEQID: 1 claimed protein
- 1: PN: WO2010065751 SEQID: 1 claimed protein
- 1: PN: WO2011069038 SEQID: 1 claimed sequence
- 1: PN: WO2012037380 SEQID: 1 claimed protein
- 1: PN: WO2014131024 SEQID: 1 claimed protein
- 1: PN: WO2015054649 SEQID: 1 claimed protein
- 20: PN: WO02078683 SEQID: 20 claimed protein
- 78: PN: WO2010065751 SEQID: 105 claimed protein
- Plecanatide
- SP 304

ChemSpider 2D Image | Plecanatide | C65H104N18O26S4

Plecanatide

Molecular FormulaC₆₅H₁₀₄N₁₈O₂₆S₄
Average mass1681.886 Da

плеканатид [Russian] [INN]

بليكاناتيد [Arabic] [INN]

普卡那肽 [Chinese] [INN]

7IK8Z952OK

Guanilib

L-α-Glutamine, L-asparaginyl-L-α-aspartyl-N-[(1R,4S,7S,10S,13S,16R,19S,22S,25R,32S,38R)-10-(2-amino-2-oxoethyl)-22-(2-carboxyethyl)-38-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-32-[(1R)- 1-hydroxyethyl]-4-methyl-7,13-bis(1-methylethyl)-19-(2-methylpropyl)-3,6,9,12,15,18,21,24,30,33,36-undecaoxo-27,28,40,41-tetrathia-2,5,8,11,14,17,20,23,31,34,37-undecaazabicyclo[14.13.13]dotetracont-2 5-yl]-

ChemSpider 2D Image | Plecanatide | C65H104N18O26S4

CLIPS

Lea Eslava-Kim, PharmD

April 19, 2016

Novel Chronic Idiopathic Constipation Drug Under FDA Review

http://www.empr.com/drugs-in-the-pipeline/novel-chronic-idiopathic-constipation-drug-under-fda-review/article/490799/

Plecanatide is a once-daily, oral, uroguanylin analog

Synergy Pharmaceuticals announced the Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for plecanatide for the treatment of chronic idiopathic constipation (CIC).

The NDA submission was based on data from two double-blind, placebo-controlled Phase 3 trials and one open-label long term safety study in over 3,500 patients with CIC.

The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of January 29, 2017 to make a decision on the NDA.

Plecanatide is a once-daily, oral, uroguanylin analog currently under development for the treatment of CIC and irritable bowel syndrome with constipation (IBS-C). It is designed to replicate the function of uroguanylin, a naturally occurring GI peptide, by working locally in the upper GI tract to stimulate digestive fluid movement and support regular bowel function.

PATENT

CN 104628827

http://www.google.com/patents/CN104628827A?cl=en

Prica exenatide Synergy Pharmaceuticals developed by the United States for the GC-C receptor in development of drugs, administered orally Limited.Currently underway include chronic idiopathic constipation (CIC) and constipation irritable bowel syndrome (IBS-C), including the phase III clinical trials. It is expected to receive US FDA clearance to market in recent years. Prica that peptides CAS: 467426-54-6 English name plecanatide, structural formula is as follows:

Preparation Prica that peptides from Shenzhen Han Yu medicine was first reported (CN103694320A), using a solid-phase synthesis of linear peptides in solution and then the two-step method to get into the ring, respectively. Since the method to form a ring carved in solution twice, the solution of complex composition, separation and purification difficult, the method should be improved.

Example 1

Weigh the degree of substitution of 0. 51mmol / g of Fmoc-Leu- Wang resin 10g (5. Lmmol), added to the solid phase reactor, DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH 6. 34g, H0Bt 2. 07g, DIC 2. 37mL was dissolved in DMF, added to the reactor uniformly mixed, the reaction at room temperature 2h. Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

Repeat the above steps, in accordance with the order of the sequence, followed by deprotection, coupling Fmoc-Gly-OH, Fmoc-Thr (tBu) -OH, Fmoc-Cys- (Mmt) -OH, Fmoc-Ala-OH, Fmoc- Val-OH, Fmoc-Asn (Trt) -〇H, Fmoc-Val-OH, Fmoc-Cys (Acm) -OH, Fmoc-Leu-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Cys (StBu) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Asp (OtBu) -OH, Boc-Asn (Trt) -〇H〇

To a prepared peptide resin reactor volume percentage of 15% DMF solution of mercapto ethanol, reaction 2h; then DCM was added a solution of 20-fold amount DTNP reaction lh; was added after washing 1% TFA containing TIS 5% of DCM solution reaction 20min.

Preparation of peptide resin obtained after sufficiently washed with DMF, DMF was added 10 times the amount in the reaction solution 12 lh. Full wash sash.

After the preparation of the peptide resin was added in a volume ratio of 95/2/2/1 TFA / TIS / EDT / H lysis reagent 20 is added in an amount 20mL / g, the reaction ice bath lh, stirring was continued at room temperature 5h, then filtration.After lysis reagent suction filtrate using a rotary evaporator until no overflow TFA, precipitated reagent was added standing; Pulika centrifugation the precipitated crude peptide was peptide to give 8. 67g〇

The preparation of the crude peptide was obtained Pulika peptide using preparative HPLC system, wavelength 214nm, C18 reversed-phase column packing for the separation, the mobile phase of water and acetonitrile were used, with a gradient elution method to collect the target polypeptide The absorption peak. Using rotary evaporation at 30 ° C to remove most of the acetonitrile, were freeze-dried to obtain a purified Prica exenatide refined products.

Example 2

Weigh the degree of substitution of 0. 2mmol / g of Fmoc-Leu- Wang resin 10g (2mmol), added to the solid phase reactor. DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH1. 24g, HOBtO. 406g, DIC 0 • 465mL dissolved in DMF solution, after mixing into the reactor at room temperature the reaction 2h.Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

[0053] To illustrate the preparation of the present embodiment obtained peptide resin reactor volume percent of a DMF solution of 30% mercaptoethanol, reaction 4h; then 5-fold amount DTNP in DCM reaction lh; was added after washing 1% TFA containing TIS 5% in DCM reaction 20min.

Preparation of peptide resin obtained after sufficiently washed with DMF, 20 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

Peptide Resin [0055] Preparation was added volume ratio of 82. 5/5/5/5/2. 5 TFA / thioanisole / H20 / phenol / EDT cleavage reagents, added in an amount 10mL / g, the reaction ice bath 0 After. 5h, stirring was continued at room temperature for lh, then suction filtered. After lysis reagent suction filtrate to the non-use of force blowing TFA overflow, adding precipitation reagent standing; centrifugation precipitated Prica exenatide crude peptide to give 1. 52g.

Example 3

Weigh the degree of substitution of 0. 6mmol / g of Fmoc-Leu- Wang resin 10g (6mmol), added to the solid phase reactor, DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH 7. 46g, H0Bt2. 44g, DIC 2. 79mL was dissolved in DMF, added to the reactor uniformly mixed, the reaction at room temperature 2h.Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

To the prepared peptide resin reactor volume percentage of 25% DMF solution of mercapto ethanol, reaction 3h; then 10-fold amount DTNP in DCM reaction lh; was added 1% TFA washed containing TIS5% DCM solution Reaction 20min〇

Preparation of peptide resin obtained after sufficiently washed with DMF, 15 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

Preparation of the peptide resin was added in a volume ratio of 90/5/3/2 TFA / thioanisole / anisole / EDT cleavage reagents, added in an amount 20mL / g, the ice bath was reacted 0.lh, stirring was continued at room temperature The reaction 10h, then filtration. After lysis reagent suction filtrate using a rotary evaporator until no overflow TFA, precipitated reagent was added standing; Pulika centrifugation the precipitated crude peptide was peptide to give 8. 46g.

Although the above has been described with general, specific embodiments and test, the present invention has been described in detail, but on the basis of the present invention, it may make some changes or improvements, which the skilled artisan It is obvious. Thus, the present invention without departing from the spirit on the basis of these modifications or improvements made, belong to the scope of the invention as claimed.

PATENT

CN 104211777

http://www.google.com/patents/CN104211777A?cl=en

The pickup exenatide (Plecanatide) is a synthetic analogue of guanylin urine (urine guanylin is a natriuretic hormone, can regulate gastrointestinal transport of ions and liquid), pickup exenatide enter After in vivo and guanylate gastrointestinal tract endothelial cells cyclase C binding and activation, activation of the cystic fibrosis transmembrane conductance regulator (CFTR), to promote chloride and water into the intestine, thereby promoting bowel motility, improve constipation symptoms.

Synergy company announced its pick in the research of new drugs that peptide (code: SP304) on October 6, 2010 the treatment of gastrointestinal disorders II a clinical experimental results. The study, conducted in patients with chronic constipation showed that the drugs can improve bowel function in patients, promote intestinal motility and reduce abdominal discomfort shape. In the experiment, there was no diarrhea and other adverse reactions, at the doses tested did not detect the pickup system that peptides are absorbed. The drug is expected for the treatment of chronic constipation (CC), constipation-predominant irritable bowel syndrome (IBS-C) and other gastrointestinal disorders. CC and IBS-C is a common gastrointestinal disease that can cause serious impact on the work and the quality of life of patients. Synergy will continue to conduct clinical trials of other pickups that peptide.

The structure of the peptide pickup that is:

H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15)

Example 30:

H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15) Preparation of

embodiments will be prepared by the method of Example 18 H-Asn (Trt) -Asp (OtBu) -Asp (OtBu) -Cys (mmt) -Glu (Ot Bu) -Leu-Cys (StBu) -Val-Asn ( Trt) -Val-Ala-Cys (mmt) -Thr (tBu) -Gly-Cys (StBu) -Leu-CT C resin (IOOmmol, 472. 88g) disposed cracking reactor to 10ml / g resin ratio Add lysis reagent (TFA: EDT: water = 95: 2 5:.. 2 5 (V / V)), stirred at room temperature 2h. The reaction was filtered with sand core funnel, and then added a small amount of TFA The resin was washed in the funnel, collecting the filtrate, the combined filtrate was concentrated. Frozen in dry diethyl ether was added (100ml / g peptide purpose tree months) and the solution was precipitated, centrifuged to remove the precipitate was washed with diethyl ether after dry ether three times, and dried in vacuo to give a white solid powder was approximately 180g, i.e., H-Asn-Asp-Asp -Cys-Glu-Leu-Cys (StBu) -Val-Asn-Val-Ala-Cys-Thr-Gly-Cy s (StBu) -Leu-OH. The solid was dissolved with water to lmg / ml solution. Was added an aqueous solution of 1% by volume of H2O2, the reaction was stirred at room temperature 30min, to prepare H-Asn-Asp-Asp-Cys-Glu-Leu-Cys (StBu) -Val-Asn-Val-Ala-Cys-Thr-Gl y-Cys (StBu) -Leu-OH (disulfide 4-12) was treated with a rotary evaporator after drying the compound containing 500ml 20% β- mercaptoethanol and 0. IM N- methylmorpholine were dissolved in water, followed by stirring After 12h the reaction, the reaction solution was diluted with water to 3mg / ml was about 60L, dissolved in ethanol was added with IL 300mmol I2 solution, the reaction was stirred at room temperature 2h. Adding an appropriate amount Vc remove excess I2, until the color of the reaction solution was transparent, i.e., to give H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-As n-Val-Ala-Cys-Thr-Gly-Cys-L eu_0H (disulfide bonds 4-12, 7-15).

PATENT

WO 2014197720

CN 103694320

WO 2012118972

WO 2012037380

WO 2011069038

US 20100152118

WO 2010065751

///Plecanatide, 普卡那肽 , ليكاناتيد , плеканатид, 467426-54-6, Chronic Idiopathic Constipation, NDA, SP 304, SYNERGY, PEPTIDE,

C[C@H]1C(=O)N[C@H]2CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@H](NC(=O)CNC(=O)[C@@H](NC2=O)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)C(C)C)CC(=O)N)C(C)C)CC(C)C)CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N

O=C(N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC1=O)CC(C)C)CSSC[C@H](NC(=O)CNC(=O)[C@@H](NC2=O)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)C)C(C)C)[C@@H](N)CC(N)=O

updated

Plecanatide (brand name Trulance), is a drug approved by the FDA for the treatment of chronic idiopathic constipation (CIC)^[1] and irritable bowel syndrome with constipation. Plecanatide is an agonist of guanylate cyclase-C. Plecanatide increases intestinal transit and fluid through a buildup of cGMP.^[2]^[3]

Medical uses

As of January 2017, plecanatide is approved in the United States for the treatment of chronic idiopathic constipation in adults.^[1] The presence of this condition is determined using the Rome III diagnostic criteria for chronic constipation which requires that the patient meet stool frequency, stool consistency, incomplete evacuation, and straining requirements in addition to not being a likely candidate for irritable bowel syndrome.^[4] The symptoms should also have been present for at least three of the last six months to establish the chronic nature of the condition before treatment with plecanatide is indicated.^[4]

Plecanatide has been shown to be safe and effective. It has shown to be at least equally as effective as its main competitor, linaclotide (brand name Linzess), but has been shown to have a lower rate of diarrhea as an adverse drug reaction.^[5]

Contraindications

Plecanatide has not been shown to be safe or effective in persons 6 years to 18 years of age.^[6] Use of plecanatide by persons under the age of 6 poses a serious dehydration risk and studies have demonstrated plecanatide can cause death in juvenile mice due to this dehydrating effect.^[6]

Use of plecanatide is also contraindicated in persons who are suspected of having a mechanical gastrointestinal obstruction.^[6]

Pharmacology

Structure and function

Plecanatide is a 16 amino acid peptide with the amino acid sequence:

H-Asn¹-Asp²-Glu³-Cys⁴-Glu⁵-Leu⁶-Cys⁷-Val⁸-Asn⁹-Val¹⁰-Ala¹¹-Cys¹²-Thr¹³-Gly¹⁴-Cys¹⁵-Leu¹⁶-OH

Is nearly structurally identical to human uroguanylin, apart from the substitution of Asp³ with Glu³.^[7] Disulfide bonds exist between Cys⁴ and Cys¹², as well as Cys⁷ and Cys¹⁵.^[8]

Plecanatide has two important motifs. The first being the acidic residues Asp² and Glu³ which modulate the affinity for its receptor in response to environmental pH.^[6]^[7]^[9] Simulations predict the optimal activity of Plecanatide to occur at pH 5, making it suitable for targeting cells within the proximal intestine, which has a pH of between 5 and 6.^[6] The second is the ACTGC motif (residues Ala¹¹ to Cys¹⁵) which is the region responsible for its binding to the receptor, guanylate cyclase-C.^[10]

Mechanism of action

Plecanatide works as a laxative by drawing water in to the gastrointestinal tract thereby softening stool and encouraging its natural passage.

Similar to its endogenous counterpart, plecanatide activates guanylate cyclase-C on endothelial cells within the gastrointestinal tract.^[7] The activation of guanylate cyclase-C catalyses the production of the second messenger guanosine 3’,5’-cyclic monophosphate (cGMP) which leads to the protein kinase A (PKA) and protein kinase G II (PKGII)-mediated phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.^[11]^[12] CFTR is an anion channel and upon activation it will secrete negatively charged ions, particularly chloride (Cl⁻) and bicarbonate (HCO₃⁻) in to the GI tract lumen.^[13]^[14] This disruption to the electrochemical gradient is in part rectified by the passive secretion of positively charged sodium ions in to the lumen and water follows by osmosis.^[13]

Plecanatide is also known to have an anti-nociceptive effect in animal models, however the exact mechanism of action is not yet fully elucidated.^[6] It has been suggested that this may be in part to the anti-inflammatory action of guanylate cyclase-C by its inhibition of pro-inflammatory cytokines, or through the inhibition of associated sensory neurons.^[15]

Pharmacokinetics and metabolism

As plecanatide acts on receptors present on the apical side of endothelial cells lining the gastrointestinal tract it is able to impart its effect without ever entering circulation.^[7] As with most orally ingested peptides, plecanatide is degraded by intestinal enzymes, and so very little of the active drug enters systemic circulation.^[6] Minimal amounts of the drug are expected to be transported in to the body, and concentrations of plecanatide and its metabolites are undetectable in plasma following the recommended dosage of 3 mg.^[6]^[7] It has also been shown that dosages up to 48.6 mg produced no detectable concentration of plecanatide in human plasma at any time point after ingestion.^[7]

Commercialization

Plecanatide, branded as Trulance, is manufactured by Synergy Pharmaceuticals.^[16]

PATENT

WO-2020250102

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020250102&tab=PCTDESCRIPTION&_cid=P12-KJ0SK6-65801-1Plecanatide is an agonist of the guanylate cyclase type-C receptor (“GCC agonists”). Plecanatide is a 16 amino acid peptide with the following chemical name: L- Leucine, L-asparaginyl-L-a-aspartyl-L-a-glutamyl-L-cysteinyl-L-a-glutamyl-L-leucyl-L-cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-Lcysteinyl-, cyclic (4 12),(7 15)-bis(disulfide). The amino acid sequence for Plecanatide is shown below:

Formula I

Plecanatide is approved in the United States under the trade name TRULANCE™ for treatment of Chronic Idiopathic Constipation (CIC) in adult patients.

Plecanatide is described in US patent No. 7,041,786. The US‘786 patent discloses that the peptide including plecanatide are synthesized and purified (>95% purity) using a published procedure of Klodt, et al., J. Peptide Res. 50:222-230 (1997). The article discloses general solid-phase synthesis, deprotection of Fmoc groups with 20% piperidine in NMP, deprotection of dry peptidyl resins by using a mixture of TFA/EDT/H2O, formation of disulfide bond by air oxidation and with iodine, acidification with TFA, purification using preparative C^1S-HPLC column (buffer A: 0.1% TFA, buffer B: 0.1% TFA in MeCN/water, 80:20).

US Patent No. US 9,580,471 describes a process for preparation of plecanatide using combination of solid and solution phase synthesis. Further, US ‘471 describes purification process of peptide on RP-HPLC column followed by desalination by eluting column with aq. alcohol, concentration of obtained fractions and then precipitation with diethyl ether or MTBE to obtain Plecanatide.

The inventors of the present invention developed an improved process for the preparation of pure Plecanatide, which is simple, cost-effective, and avoids or reduces content of impurities and makes the process robust.

EXAMPLES

EXAMPLE 1: Synthesis of H-Gly-Cys(Acm)-Leu-Otbu (Fragment B)

Step -I: Synthesis of H-Cys(Acm)-Lue-Otbu.

H-Leu-(Otbu).HCl (356.27gm,l.leq), HOBT(222.97gm,1.0eq) were added to a solution of Fmoc-Cys(Acm)-OH (600.0 g, l.Oeq) in DMF (3.0L) and then cooled to 5-10°C. HBTU (603.9gm, 1.1 eq) and DIPEA(883.4 ml, 3.5eq) were added to the reaction mass. After completion of the reaction, the product was extracted with ethyl acetate (6.0L) and then washed with HC1, 5% aq sodium bicarbonate soln, 10%NaCl solution and water. The organic layer was collected, filtered and the filtrate was concentrated to obtain Fmoc-protected dipeptide. The obtained product was proceeded for next step without any further purification. Yield: 945 g Fmoc-Cys (Acm)-Leu-Otbu (945 g, leq) was taken in flask containing DMF (1.89 L) and cooled the solution to 5-10°C. Tertiary butyl amine (255 ml 1.5eq) was added slowly to the solution and stirred for 15min. After completion of reaction, the reaction mass was cooled to 5-10°C. Water and IN HC1 were added to the

solution and the obtained aqueous solution was washed with hexane. The pH of product was adjusted to 8 to 8.5 with saturated sodium bicarbonate solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with 10% NaCl solution and water and then filtered. The obtained filtrate was evaporated completely to obtained light yellow thick residue H-Cys(Acm)-Leu-Otbu. Yield: 450 g.

Step -II: Synthesis of H-Gly-Cys (Acm)-Lue-Otbu.

H-Cys (Acm)-Leu-Otbu (450.0 g, l.leq) was taken in flask containing DMF (1.68 L). Fmoc-Gly-OH (336.45g, l.Oeq), HOBT (174.2g, l.Oeq) were added to the solution and then cooled to 5-10°C. HBTU (472g, l.leq) and DIPEA (414.15ml, 2.1eq) were added and stirred. After completion of the reaction, ethyl acetate was added to the above reaction mass and washed with pre-cooled 0.5N HC1, 5% aqueous NaHCC solution (pre-cooled), 10%NaCl solution and water. The resultant organic layer was evaporated completely to give Fmoc-Gly-Cys (Acm)-Leu-Otbu. Yield: 825 g.

Fmoc-Gly-Cys(Acm)-Leu-Otbu (825g, leq) was taken in flask containing THF (1650ml) and cooled to 5-10° C. Tertiary butyl amine (338 ml 2.5eq) was added slowly to the solution. After completion of reaction, the solution was cooled to 5-10°C and then water (2.48L) was added to the reaction mass. The aqueous reaction mass was washed with hexane, 50% ethyl acetate in hexane, then the product was extracted with dichlorome thane. The dichloromethane layer was washed with 10%NaCl solution and water. The (collected) organic layer was dried with anhydrous sodium sulphate and then filtered. The obtained filtrate was evaporated completely to obtain H-Gly-Cys (Acm)-Leu-Otbu as light yellow semi solid. Yield: 392 g; HPLC purity: -92%.

EXAMPLE 2: Fmoc-Cvs(Acm)-Val-Asn(Trt)-Val-Ala-Cvs(Trt)-Thr(Otbu)-2CTC. (Fragment-A)

Step A: CTC resin (750gm) was taken in a SPPS reactor, 7.5L of dry dichloromethane (DCM) was added and allowed it to swell for 20min and drained.

Step B: A solution of Fmoc-Thr(otbu)-OH (954gm, 2eq) and DIEA (627.6ml, 3eq) in dry dichloromethane (3.75L) were added to the resin at step A and stirred for at room temperature and drained.

The resin was then capped with DIEA (1%) solution in DCM: methanol (1: 1)) and then drained. Thereafter, washed the resin with one bed volume of DMF (2 times), DCM (2 times) and MTBE (2 times), isolated and dried. Yield: 1150gm

The above resin was deblocked with 20% piperidine in DMF and washed with DMF (2times), IPA (2 times) and DMF (2 times).

Step C: To a solution of Fmoc-Cys (Trt)-OH (808g, 1.5eq.) and HOBT (212.5g, 1.5eq) in DMF, DIC (323ml, 2.25eq) was added. The obtained reaction mixture was added to the resin in Step B and stirred. After completion of the reaction the resin was drained and washed with DMF (2 times) and then resin was deblocked with 20% piperidine in DMF and then washed with DMF, IPA and DMF.

Step-D: Followed by sequential coupling of Fmoc-Ala-OH, Fmoc-Val-OH, Fmoc-Asn (Trt)-OH, Fmoc-Val-OH similar to the procedure described in step-C.

Step E: To a solution of Fmoc-Cys (acm)-OH (572g, 1.5eq.) and HOBT (212.5g, 1.5eq) in DMF, DIC (323ml, 2.25eq) was added. The obtained reaction mixture was added to the resin in Step D and stirred. After completion of the reaction, the resin was drained and washed with DMF (2 times) DCM (2 times) and MTBE (2 times). It was isolated and dried to give FMOC-Cys (Acm)-Val-Asn (Trt)-Val-Ala-Cys (Trt)-Thr(otbu)-2CTC Resin. Yield: 2.17 kg.

Step F: Selective cleavage of 2-chloro trityl resin from the Fmoc-Cys(acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(otbu)-2CTC Resin was performed with a mixture 1%TFA in dichloromethane and then above peptidyl resin was taken in SPPS reactor and treated with a solution of 1% TFA in DCM and drained. The filtrate was immediately neutralized with precooled saturated NaHC0₃ Solution to precipitate the product. The same process was repeated 3 more times and dried to obtain off-white solid. The obtained solid was further purified by treating with MTBE (2ml/g of product) to give Fmoc-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(tbu)-OH. Yield: 1133gm; Purity: 94.29%.

EXAMPLE-3: Synthesis of Boc-Asn(Xan)-Asp(Otbu)-Glu(Otbu)-Cys(Trt)-Glu(Otbu)-Leu-2CTC (Fragment D)

Step A: CTC resin (445gm) was taken in a SPPS reactor, 4.45L of dry dichloromethane was added and allowed it to swell for 20min and drained.

Step B: A solution of Fmoc-Leu-OH (525gm, 2eq) and DIEA (388.6ml, 3eq) in dry dichloromethane (2.22L) was added to the resin at step A and stirred at room temperature and drained.

The resin was then capped with DIEA (1%) solution in DCM: methanol (1:1)). Thereafter, washed the resin with one bed volume of DMF (2 times), DCM (2 times) and MTBE (2 times), isolated and dried. Yield: 700gm.

The above resin was deblocked with 20% piperidine in DMF for 10 and 15 minutes and washed with of DMF (2times), IPA (2 times) and DMF (2 times).

Step C: To a solution of Fmoc-Glu(Otbu)-OH (553gm, 2.0eq.) and HOBT (200.5gm, 2.0eq) in DMF, DIC (305ml, 3.0 eq) was added. It was added to the resin in Step B. After completion of the reaction, the resin was drained and washed with DMF.

The above resin was deblocked with 20% piperidine in DMF for 10 and 15 minutes and washed with of DMF (2times), IPA (2 times) and DMF (2 times).

Step D: Sequential coupling of Fmoc-Cys(Trt)-OH, Fmoc-Glu(Otbu)-OH, Fmoc-Asp(Otbu)-OH, Fmoc-Asp(Otbu)-OH similar to the procedure of step-C.

Step-E: To a solution of Boc-Asn(xan)-OH (537gm, 2.0eq.) and HOBT (200.5gm, 2.0eq) in DMF, DIC (305ml, 3.0eq) were added and stirred. It was added to the resin in Step F and stirred. After completion of the reaction, the resin was drained and washed with DMF (2 times), DCM (2 times) and MTBE (2 times). It was isolated and dried to give Boc-Asn(Xan)-Asp(Otbu)-Glu(Otbu)-Cys(Trt)-Glu(Otbu)-Leu-2CTC resin. Yield: 1.37kg.

Step H: Selective cleavage of 2-chloro trityl resin from the Boc-Asn(Xan)-Asp(Otbu)-Glu(Otbu)-Cys(Trt)-Glu(Otbu)-Leu-2CTC resin was performed with a mixture 1%TFA in dichloromethane.

The above peptidyl resin was taken in SPPS reactor and treated with a solution of 1% TFA in DCM. The filtrate was neutralized with precooled saturated NaHC0₃

solution. The same process was repeated 3 more times, the collected organic solution was washed with water, dried with sodium sulphate and evaporated to obtain off-white solid. The obtained solid was further purified by treating with MTBE (2ml/g of product) to give Boc-Asn(Xan)-Asp(Otbu)-Glu(Otbu)-Cys(Trt)-Glu(Otbu)-Leu-OH. Yield: 720g; Purity: 90.74%.

EXAMPLE 4: Synthesis of H-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(tbu) -Gly- Cys( Acm) -Leu-Otbu .

Fmoc-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(tbu)-OH (Fragment- A) (500.0 g, l.Oeq) was taken in a round bottom flask containing DMF (2.5F). H-Gly-Cys (Acm)-Feu-Otbu (Fragment B) (209g, 1.5eq) was added to the reaction mass and cooled to -10 to -15°C. HOAT (50g, l.leq) and HATU (151.75g , 1.2 eq) were added to reaction mass and then DIPEA (116ml, 2eq) was added drop wise while stirring at -10 to-15°C. After completion of the reaction, methanol (15. OF) was added to the above reaction mass (solid formation was observed), then pH of the reaction mixture was adjusted with IN HC1 up to pH 3, stirred for one hour, filtered and dried to give dec apep tide. Yield: 700g.

The above obtained decapeptide (700g, FOeq) was taken in a round bottom flask containing DMF (4.2 F) and cooled the solution to 5-10°C. Tertiary butyl amine (77.30ml 2.0eq) was added and stirred the reaction mass for 15min at 5-10°C and then stirred at R.T. After completion of the reaction, methanol (25.20F) was added to precipitate the product. The obtained solid was filtered and dried to give NH2-Cys (Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(otbu)- Gly-Cys (Acm)-Fue-Otbu. Yield: 437g; HPFC purity: -97%

EXAMPLE 5: Synthesis of Boc-Asn(Xan)-Asp(Otbu)-Glu(Otbu)-Cys(Trt)- Glu(Otbu)-Leu-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(otbu)-Gly- Cys(Acm)-Leu-Otbu.

NH2-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(otbu)-Gly-Cys-(Acm)-Lue-Otbu, (435.0g,F0eq) and Boc-Asn(Xan)-Asp(Otbu)-Glu(Otbu)-Cys(Trt)-Glu(Otbu)-Leu-OH (Fragment D), (365.0 g, 0.9eq) were taken in a round bottom

flask containing DMF (2.61 L). The solution obtained was cooled to -10 to -15°C and then HO AT (42.0g, 1.2eq) and HATU (118g, 1.2eq) were added. DIPEA (90 ml, 2.0eq) was added to the reaction mass and stirred at -10 to-15°C. Methanol (13.0L) was added to the above reaction mass to precipitate the product. The obtained solid was filtered and dried to give Boc-Asn(Xan)-Asp(Otbu)-Glu(Otbu)-Cys(Trt)-Glu(Otbu)-Leu-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(otbu)-Gly-Cys(Acm)-Leu-Otbu as off-white solid. Yield: 750g.

EXAMPLE 6: Synthesis of H-Asn-Asp-Glu-Cys-Glu-Leu-Cys(Acm)-Val-Asn-Val-Ala-Cys-Thr-Gly-Cys(Acm)-Leu-OH.

Protected peptide (500.0 g) obtained in example 5 was treated with a pre-cooled solution of 84% TFA (4200 ml), 5% TIPS (250 ml), 5% H₂0 (250 ml), 5% DTT (250 gm), 1%DMS (50ml) for 2 hrs at R.T. The product was precipitated by the addition of reaction mass to the pre-cooled MTBE, filtered the product under nitrogen and washed with MTBE and dried. Yield: 310.0g; Purity: 73 %.

EXAMPLE 7: PREPARATION OF CRUDE PLECANATIDE

Linear 1-16 peptide obtained from example 6 was dissolved in degassed 0.015 M ammonium hydroxide solution at a concentration of lg /0.75 L, pH was adjusted between 8 .5to 9.0 by using ammonia solution. After dissolution of compound, H2O2 (200 pi / g) was added. After completion of oxidation, the pH was adjusted between 3 to 4 by IN HC1 to obtain mono cyclized 1-16 peptide solution and then solution was treated with 5% iodine in acetonitrile, till the yellow color persist. The reaction mixture with excess of iodine was quenched with 0.1M aqueous ascorbic acid solution and the pH was adjusted between 6.5 and 7 by using ammonia solution. The solution was filtered through 2.4 micron. The obtained filtrate was used as such for next stage purification.

EXAMPLE 8: PURIFICATION OF PLECANATIDE

Stage 1: Crude Plecanatide solution obtained from example 7 was purified on preparative HPLC, column was packed with reverse phase C18 hybrid silica using Tris HC1 pH 7(as buffer A) and 100% acetonitrile (as buffer B).The fractions were collected and purity of fractions were monitored by analytical HPLC. Fractions containing > 94% pure Plecanatide were pooled as main pool; and fractions not meeting the pooling criteria were re-processed in a similar manner.

Stage 2: The main pool obtained from stage 1 purification were diluted with equal amount of purified water and re-purified on preparative HPLC, column was packed with reverse phase C18 hybrid silica using Tris HC1 pH 7(as buffer A) and 100% acetonitrile (as buffer B).The fractions were collected and purity of fractions were monitored by analytical HPLC. Fractions containing > 98.5% pure Plecanatide were pooled as main pool for desalting. (OR)

The main pool obtained from stage- 1 purification were diluted with equal amount of purified water and re-purified on preparative HPLC, column was packed with reverse phase C18 hybrid silica using TEAP (as buffer A) and acetonitrile (as buffer B).The fractions were collected and purity of fractions were monitored by analytical HPLC. Fractions containing > 98.5% pure Plecanatide were pooled as main pool for desalting.

EXAMPLE 9: DE SALTING AND LYOPHILIZATION

The main pool obtained from the purification were diluted with equal amount of purified water and loaded on preparative HPLC, column was packed with reverse phase C18 hybrid silica.

The fractions containing pure Plecanatide (>98.5%) were pooled; the organic modifier was removed under reduced pressure and filtered through 0.2 micron filter. The resulting peptide solution was freeze-dried to isolate Plecanatide.

After completion of lyophilization cycle, the compound was unloaded and dissolved in purified water at a concentration Of 70 g /L, filtered through 0.2 micron filter. The resulting peptide solution was freeze-dried to obtain white solid lyophilized powder as Plecanatide. Purity: 99.1 %

EXAMPLE 10: PREPARATION OF MONO CYCLIZED PLECANATIDE

Linear 1-16 peptide obtained from example 6 was dissolved in degassed 0.015 M ammonium hydroxide solution at a concentration of lg /0.75 L, the pH was adjusted between 8 .5to 9.0 by using ammonia solution. After dissolution of compound, H2O2 (200pl / g) was added and stirred for 30 minutes. The progress of oxidation was monitored by analytical reverse phase HPLC & Ellman’s test. After completion of oxidation, the pH was adjusted between 6.5 and 7 by using IN HC1 to obtain mono cyclized 1-16 peptide solution.

EXAMPLE 11: PURIFICATION OF MONO CYCLIZED PLECANATIDE

Mono cyclized solution obtained from example 10 was purified on preparative HPLC, column packed with reverse phase C18 hybrid silica using Tris HC1 pH 7(as buffer A) and 100% acetonitrile (as buffer Bj.Thc fractions were collected and purity were monitored by analytical HPLC. Lractions containing > 95% pure Plecanatide were pooled as main pool; and fractions not meeting the pooling criteria were re-processed in a similar manner.

EXAMPLE 12: PREPARATION OF CRUDE PLECANATIDE

The resultant purified solution was diluted with equal amount of water, adjusted pH 3.5 with IN HC1 and treated with 5% iodine in acetonitrile, till the yellow color persist and the reaction mass was stirred for two hours.

The completion of oxidation was monitored by analytical reverse phase HPLC; quenched the excess iodine with 0.1 M aqueous ascorbic acid solution and then pH was adjusted between 6.5 and 7 by using ammonia solution. The solution was filtered through 2.4 micron filter and used as such for next stage purification.

EXAMPLE 13: PURIFICATION OF PLECANATIDE

The main pool obtained from stage 1 purification were purified on preparative HPLC, column was packed with reverse phase C18 hybrid silica using Tris HC1 pH 7 (buffer A) and 100% acetonitrile (buffer B). The fractions were collected and purity of fractions were monitored by analytical HPLC. Fractions containing > 98.5% pure Plecanatide were pooled as main pool for desalting. (OR)

The main pool obtained from stage 1 purification further purified on preparative HPLC, the column was packed with reverse phase C18 hybrid silica using TEAP (as buffer A) and acetonitrile (as buffer B). Fractions containing > 98.5% pure Plecanatide were pooled as main pool for desalting.

EXAMPLE 14: DE SALTING AND LYOPHILIZATION

The main pool obtained from the purification were diluted with equal amount of purified water and loaded on preparative HPLC, column packed with reverse phase C18 hybrid silica.

De-salting was done by passing 5 void volume of 0.1% acetic acid in purified water fallowed by elution of product from the column by using 30% acetonitrile (HPLC grade) in purified water containing 0.1% acetic acid. The fractions were collected and purity of fractions were monitored by analytical HPLC. The fractions containing pure Plecanatide (>98.5%) were pooled; the organic modifier was removed under reduced pressure and filtered through 0.2 micron filter. The resulting peptide solution was freeze-dried to isolate Plecanatide.

After completion of lyophilization cycle, unload the compound and dissolve in purified water at a concentration Of 70 g /L, filtered through 0.2 micron filter. The resulting peptide solution was freeze-dried to obtain white solid lyophilized powder as Plecanatide.

Purity: 99% by HPLC

CLIPS

Lea Eslava-Kim, PharmD

April 19, 2016

Novel Chronic Idiopathic Constipation Drug Under FDA Review

http://www.empr.com/drugs-in-the-pipeline/novel-chronic-idiopathic-constipation-drug-under-fda-review/article/490799/

Plecanatide is a once-daily, oral, uroguanylin analog

The NDA submission was based on data from two double-blind, placebo-controlled Phase 3 trials and one open-label long term safety study in over 3,500 patients with CIC.

The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of January 29, 2017 to make a decision on the NDA.

PATENT

CN 104628827

http://www.google.com/patents/CN104628827A?cl=en

Example 1

Preparation of peptide resin obtained after sufficiently washed with DMF, DMF was added 10 times the amount in the reaction solution 12 lh. Full wash sash.

Example 2

Preparation of peptide resin obtained after sufficiently washed with DMF, 20 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

Example 3

Preparation of peptide resin obtained after sufficiently washed with DMF, 15 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

PATENT

CN 104211777

http://www.google.com/patents/CN104211777A?cl=en

The structure of the peptide pickup that is:

H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15)

Example 30:

H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15) Preparation of

PATENT

WO 2014197720

CN 103694320

WO 2012118972

WO 2012037380

WO 2011069038

US 20100152118

WO 2010065751

///Plecanatide, 普卡那肽 , ليكاناتيد , плеканатид, 467426-54-6, Chronic Idiopathic Constipation, NDA, SP 304, SYNERGY, PEPTIDE,

References

^ Jump up to:^a ^b “FDA approves Trulance for Chronic Idiopathic Constipation”. FDA.gov. U.S. Food and Drug Administration. Retrieved 20 January 2017.
^ “TRULANCE package insert” (PDF). Trulance website. Synergy Pharmaceuticals Inc. 420 Lexington Avenue, Suite 2012 New York, New York 10170. Retrieved 20 January 2017.
^ Thomas RH, Luthin DR (June 2015). “Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents”. Pharmacotherapy. 35 (6): 613–30. doi:10.1002/phar.1594. PMID 26016701.
^ Jump up to:^a ^b Rome III : the functional gastrointestinal disorders. Drossman, Douglas A. (3rd ed.). McLean, Va.: Degnon Associates. 2006. ISBN 9780965683753. OCLC 79476570.
^ “Trulance – FDA prescribing information, side effects and uses”. Drugs.com. Retrieved 2017-10-27.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h Al-Salama ZT, Syed YY (April 2017). “Plecanatide: First Global Approval”. Drugs. 77 (5): 593–598. doi:10.1007/s40265-017-0718-0. PMID 28255961.
^ Jump up to:^a ^b ^c ^d ^e ^f Shailubhai K, Comiskey S, Foss JA, Feng R, Barrow L, Comer GM, Jacob GS (September 2013). “Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses”. Digestive Diseases and Sciences. 58 (9): 2580–6. doi:10.1007/s10620-013-2684-z. PMID 23625291.
^ Chang WL, Masih S, Thadi A, Patwa V, Joshi A, Cooper HS, et al. (February 2017). “+/Min-FCCC mice”. World Journal of Gastrointestinal Pharmacology and Therapeutics. 8(1): 47–59. doi:10.4292/wjgpt.v8.i1.47. PMC 5292606. PMID 28217374.
^ Hamra FK, Eber SL, Chin DT, Currie MG, Forte LR (March 1997). “Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity”. Proceedings of the National Academy of Sciences of the United States of America. 94 (6): 2705–10. Bibcode:1997PNAS…94.2705H. doi:10.1073/pnas.94.6.2705. PMC 20153. PMID 9122260.
^ Forte LR (November 2004). “Uroguanylin and guanylin peptides: pharmacology and experimental therapeutics”. Pharmacology & Therapeutics. 104 (2): 137–62. doi:10.1016/j.pharmthera.2004.08.007. PMID 15518884.
^ Hamra FK, Forte LR, Eber SL, Pidhorodeckyj NV, Krause WJ, Freeman RH, et al. (November 1993). “Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase”. Proceedings of the National Academy of Sciences of the United States of America. 90 (22): 10464–8. Bibcode:1993PNAS…9010464H. doi:10.1073/pnas.90.22.10464. PMC 47797. PMID 7902563.
^ Bijvelds MJ, Loos M, Bronsveld I, Hellemans A, Bongartz JP, Ver Donck L, et al. (December 2015). “Inhibition of Heat-Stable Toxin-Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors”. The Journal of Infectious Diseases. 212 (11): 1806–15. doi:10.1093/infdis/jiv300. PMID 25999056.
^ Jump up to:^a ^b Gadsby DC, Vergani P, Csanády L (March 2006). “The ABC protein turned chloride channel whose failure causes cystic fibrosis”. Nature. 440 (7083): 477–83. Bibcode:2006Natur.440..477G. doi:10.1038/nature04712. PMC 2720541. PMID 16554808.
^ Park HW, Nam JH, Kim JY, Namkung W, Yoon JS, Lee JS, et al. (August 2010). “Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion”. Gastroenterology. 139 (2): 620–31. doi:10.1053/j.gastro.2010.04.004. PMID 20398666.
^ Eutamene H, Bradesi S, Larauche M, Theodorou V, Beaufrand C, Ohning G, et al. (March 2010). “Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain”. Neurogastroenterology and Motility. 22 (3): 312–e84. doi:10.1111/j.1365-2982.2009.01385.x. PMID 19706070.
^ “Plecanatide – brand name list from Drugs.com”. Drugs.com.

Plecanatide
Clinical data

Trade names	Trulance
Other names	SP-304
License data	US FDA: Plecanatide
Routes of administration	By mouth
ATC code	A06AX07 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	467426-54-6
PubChem CID	70693500
IUPHAR/BPS	9069
DrugBank	DB13170
ChemSpider	28530494
UNII	7IK8Z952OK
KEGG	D09948
ChEMBL	ChEMBL2103867
CompTox Dashboard (EPA)	DTXSID60196933
Chemical and physical data
Formula	C₆₅H₁₀₄N₁₈O₂₆S₄
Molar mass	1681.89 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CC1C(=O)NC2CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(NC(=O)CNC(=O)C(NC2=O)C(C)O)C(=O)NC(CC(C)C)C(=O)O)C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)C(C)C)CC(=O)N)C(C)C)CC(C)C)CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CC(=O)O)NC(=O)C(CC(=O)N)N
InChI [hide] InChI=1S/C65H104N18O26S4/c1-25(2)15-34-55(98)80-41-24-113-110-21-38(58(101)77-37(65(108)109)16-26(3)4)71-44(87)20-69-62(105)50(30(10)84)83-61(104)40(78-51(94)29(9)70-63(106)48(27(5)6)81-57(100)35(18-43(68)86)76-64(107)49(28(7)8)82-60(41)103)23-112-111-22-39(59(102)73-32(53(96)75-34)11-13-45(88)89)79-54(97)33(12-14-46(90)91)72-56(99)36(19-47(92)93)74-52(95)31(66)17-42(67)85/h25-41,48-50,84H,11-24,66H2,1-10H3,(H2,67,85)(H2,68,86)(H,69,105)(H,70,106)(H,71,87)(H,72,99)(H,73,102)(H,74,95)(H,75,96)(H,76,107)(H,77,101)(H,78,94)(H,79,97)(H,80,98)(H,81,100)(H,82,103)(H,83,104)(H,88,89)(H,90,91)(H,92,93)(H,108,109)/t29-,30+,31-,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,48-,49-,50-/m0/s1 Key:NSPHQWLKCGGCQR-DLJDZFDSSA-N

////////////PLECATANIDE, плеканатид , بليكاناتيد , 普卡那肽 , 7IK8Z952OK, Guanilib

Pacritinib

January 17, 2016 11:54 am / Leave a comment

ChemSpider 2D Image | Pacritinib | C28H32N4O3

Pacritinib

パクリチニブ;

Formula	C28H32N4O3
CAS	937272-79-2
Mol weight	472.5787

UPDATE FDA APPROVED 2/28/2022, Vonjo

To treat intermediate or high-risk primary or secondary myelofibrosis in adults with low platelets

A Jak2 inhibitor potentially for the treatment of acute myeloid Leukemia and myelofibrosis.

UNII-G22N65IL3O

пакритиниб

باكريتينيب

帕瑞替尼

ONX-0803; SB-1518
CAS No. 937272-79-2

472.57868 g/mol, C₂₈H₃₂N₄O₃

S*Bio Pte Ltd. and concert innovator

11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene

(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-Dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene

11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene

SB-1518|||(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene

Pacritinib (SB1518) is a potent and selective inhibitor of Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3) with IC50s of 23 and 22 nM, respectively.

UPDATED

Pacritinib, sold under the brand name Vonjo, is an anti-cancer medication used to treat myelofibrosis.^[1]^[2] It is a macrocyclic Janus kinase inhibitor. It mainly inhibits Janus kinase 2 (JAK2) and Fms-like tyrosine kinase 3 (FLT3).

Common side effects include diarrhea, low platelet counts, nausea, anemia, and swelling in legs.^[2]

Medical uses

Pacritinib in indicated to treat adults who have a rare form of a bone marrow disorder known as intermediate or high-risk primary or secondary myelofibrosis and who have platelet (blood clotting cells) levels below 50,000/µL.^[1]^[2]

History

The effectiveness and safety of pacritinib were demonstrated in a study that included 63 participants with intermediate or high-risk primary or secondary myelofibrosis and low platelets who received pacritinib 200 mg twice daily or standard treatment.^[2] Effectiveness was determined based upon the proportion of participants who had a 35% or greater spleen volume reduction from baseline to week 24.^[2] Nine participants (29%) in the pacritinib treatment group had a 35% or greater spleen volume reduction, compared to one participant (3%) in the standard treatment group.^[2]

The U.S. Food and Drug Administration (FDA) granted the application for pacritinib priority review, fast track, and orphan drug designations.^[2]

Society and culture

Names

Pacritinib is the International nonproprietary name (INN).^[3]^[4]

References

^ Jump up to:^a ^b ^c “Enforcement Reports”. Accessdata.fda.gov. Retrieved 5 March 2022.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “FDA approves drug for adults with rare form of bone marrow disorder”. U.S. Food and Drug Administration. 1 March 2022. Retrieved 3 March 2022. This article incorporates text from this source, which is in the public domain.
^ World Health Organization (2010). “International nonproprietary names for pharmaceutical substances (INN). proposed INN: list 104” (PDF). WHO Drug Information. 24 (4): 386. hdl:10665/74579.
^ World Health Organization (2011). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 66”. WHO Drug Information. 25 (3). hdl:10665/74683.

External links

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

OLD—

Pacritinib (INN^[1]) is a macrocyclic Janus kinase inhibitor that is being developed for the treatment of myelofibrosis. It mainly inhibits Janus kinase 2 (JAK2). The drug is in Phase III clinical trials as of 2013.^[2] The drug was discovered in Singapore at the labs of S*BIO Pte Ltd. It is a potent JAK2 inhibitor with activity of IC₅₀ = 23 nM for the JAK2WT variant and 19 nM for JAK2V617F with very good selectivity against JAK1 and JAK3 (IC₅₀ = 1280 and 520 nM, respectively).^[3]^[4] The drug is acquired by Cell Therapeutics, Inc. (CTI) and Baxter international and could effectively address an unmet medical need for patients living with myelofibrosis who face treatment-emergent thrombocytopenia on marketed JAK inhibitors.^[5]

Pacritinib is an orally bioavailable inhibitor of Janus kinase 2 (JAK2) and the JAK2 mutant JAK2V617F with potential antineoplastic activity. Oral JAK2 inhibitor SB1518 competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders; the JAK2V617F gain-of-function mutation involves a valine-to-phenylalanine modification at position 617. The JAK-STAT signaling pathway is a major mediator of cytokine activity.

Synthesis Reference

A245943 — William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, Goh KC, Ong WC, Goh SK, Hart S, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW: Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6). 1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011 Jul 14;54(13):4638-58. doi: 10.1021/jm200326p. Epub 2011 Jun 15.

The compound 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) was first described in PCT/SG2006/000352 and shows significant promise as a pharmaceutically active agent for the treatment of a number of medical conditions and clinical development of this compound is underway based on the activity profiles demonstrated by the compound.

In the development of a drug suitable for mass production and ultimately commercial use acceptable levels of drug activity against the target of interest is only one of the important variables that must be considered. For example, in the formulation of pharmaceutical compositions it is imperative that the pharmaceutically active substance be in a form that can be reliably reproduced in a commercial manufacturing process and which is robust enough to withstand the conditions to which the pharmaceutically active substance is exposed.
In a manufacturing sense it is important that during commercial manufacture the manufacturing process of the pharmaceutically active substance be such that the same material is reproduced when the same manufacturing conditions are used. In addition it is desirable that the pharmaceutically active substance exists in a solid form where minor changes to the manufacturing conditions do not lead to major changes in the solid form of the pharmaceutically active substance produced. For example it is important that the manufacturing process produce material having the same crystalline properties on a reliable basis and also produce material having the same level of hydration.
In addition it is important that the pharmaceutically active substance be stable both to degradation, hygroscopicity and subsequent changes to its solid form. This is important to facilitate the incorporation of the pharmaceutically active substance into pharmaceutical formulations. If the pharmaceutically active substance is hygroscopic (“sticky”) in the sense that it absorbs water (either slowly or over time) it is almost impossible to reliably formulate the pharmaceutically active substance into a drug as the amount of substance to be added to provide the same dosage will vary greatly depending upon the degree of hydration. Furthermore variations in hydration or solid form (“polymorphism”) can lead to changes in physico-chemical properties, such as solubility or dissolution rate, which can in turn lead to inconsistent oral absorption in a patient.
Accordingly, chemical stability, solid state stability, and “shelf life” of the pharmaceutically active substance are very important factors. In an ideal situation the pharmaceutically active substance and any compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active substance such as its activity, moisture content, solubility characteristics, solid form and the like.
In relation to 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene initial studies were carried out on the hydrochloride salt and indicated that polymorphism was prevalent with the compound being found to adopt more than one crystalline form depending upon the manufacturing conditions. In addition it was observed that the moisture content and ratio of the polymorphs varied from batch to batch even when the manufacturing conditions remained constant. These batch-to-batch inconsistencies and the exhibited hygroscopicity made the hydrochloride salt less desirable from a commercial viewpoint.
Accordingly it would be desirable to develop one or more salts of 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene which overcome or ameliorate one or more of the above identified problems.

PATENT

str1

US 2011263616

http://www.google.com/patents/US20110263616

11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26triaza-tetra-cyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) which have been found to have improved properties. In particular the present invention relates to the maleate salt of this compound. The invention also relates to pharmaceutical compositions containing this salt and methods of use of the salt in the treatment of certain medical conditions.

PATENT

http://www.google.com/patents/US8415338

Representative Procedure for the Synthesis of Compounds Type (XVIIId) [3-(2-Chloro-pyrimidin-4-yl)-phenyl]-methanol (XIIIa2)

Compound (XIIIa2) was obtained using the same procedure described for compound (XIIIa1); LC-MS (ESI positive mode) m/z 221 ([M+H]⁺).

4-(3-Allyloxymethyl-phenyl)-2-chloro-pyrimidine (XVa2)

Compound (XVa2) was obtained using the same procedure described for compound (XVa1); LC-MS (ESI positive mode) m/z 271 ([M+H]⁺).

[4-(3-Allyloxymethyl-phenyl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (XVIId1)

Compound (XVIId1) was obtained using the same procedure described for compound (XVIIb1); LC-MS (ESI positive mode) m/z 501.

Macrocycle Example 3 Compound 13

Compound (13) was obtained using the same procedure described for compound (1) HPLC purity at 254 nm: 99%; LC-MS (ESI positive mode) m/z 473 ([M+H]⁺); ¹H NMR (MeOD-d₄) δ 8.79 (d, 1H), 8.46 (d, 1H), 8.34-8.31 (m, 1H), 7.98-7.96 (m, 1H), 7.62-7.49 (m, 2H), 7.35 (d, 1H), 7.15-7.10 (m, 1H), 7.07-7.02 (m, 1H), 5.98-5.75 (m, 2H, 2×=CH), 4.67 (s, 2H), 4.67 (s, 2H), 4.39-4.36 (m, 2H), 4.17 (d, 2H), 4.08 (d, 2H), 3.88-3.82 (m, 2H), 3.70 (t, 2H), 2.23-2.21 (m, 2H), 2.10-2.07 (m, 2H).

PAPER

J MC 2011, 54 4638

http://pubs.acs.org/doi/abs/10.1021/jm200326p

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2^V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC₅₀ = 23 and 19 nM for JAK2^WT and JAK2^V617F, respectively) and FLT3 (IC₅₀ = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC₅₀ = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c(SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.

Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma

S*BIO Pte. Ltd., 1 Science Park Road, #05-09, The Capricorn, Singapore Science Park II, Singapore 117528

J. Med. Chem., 2011, 54 (13), pp 4638–4658

DOI: 10.1021/jm200326p

Publication Date (Web): May 23, 2011

Tel: (0065) 6827-5021. Fax: (0065) 6827-5005. E-mail: anthony_william@sbio.com.

(21c)

The title compound was synthesized from 21a and pyrrolidine (yield, 83%; mixture of trans/cis85:15 by NMR). LC-MS (ESI positive mode) m/z 473 ([M + H]⁺). HRMS: theoretical C₂₈H₃₂N₄O₃MW, 472.2474; found, 473.2547. ¹H NMR (MeOD-d₄): δ 8.79 (d, 1H), 8.46 (d, 1H), 8.34–8.31 (m, 1H, CH), 7.98–7.96 (m, 1H), 7.62–7.49 (m, 2H), 7.35 (d, 1H), 7.15–7.10 (m, 1H), 7.07–7.02 (m, 1H), 5.98–5.75 (m, 2H), 4.67 (s, 2H), 4.67 (s, 2H), 4.39–4.36 (m, 2H), 4.17 (d, 2H), 4.08 (d, 2H), 3.88–3.82 (m, 2H), 3.70 (t, 2H), 2.23–2.21 (m, 2H), 2.10–2.07 (m, 2H); chloride content (titration) 7.7% (1.18 equivs); water content (Karl Fischer) 6.1% (1.85 equivs); Anal. Calcd. for C₂₈H₃₂N₄O₃·1.18HCl·1.85H₂O: C, 61.46; H, 6.46; N, 10.24; Cl, 7.65. Found: C, 61.99; H, 6.91; N, 10.25; Cl, 7.45.

References

1 “International Nonproprietary Names for Pharmaceutical Substances (INN) List 104” (PDF). WHO Drug Information 24 (4): 386. 2010.

2“JAK-Inhibitoren: Neue Wirkstoffe für viele Indikationen”. Pharmazeutische Zeitung (in German) (21). 2013.

3William, A. D.; Lee, A. C. -H.; Blanchard, S. P.; Poulsen, A.; Teo, E. L.; Nagaraj, H.; Tan, E.; Chen, D.; Williams, M.; Sun, E. T.; Goh, K. C.; Ong, W. C.; Goh, S. K.; Hart, S.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. (2011). “Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma”. Journal of Medicinal Chemistry 54 (13): 4638–58. doi:10.1021/jm200326p. PMID 21604762.

4Poulsen, A.; William, A.; Blanchard, S. P.; Lee, A.; Nagaraj, H.; Wang, H.; Teo, E.; Tan, E.; Goh, K. C.; Dymock, B. (2012). “Structure-based design of oxygen-linked macrocyclic kinase inhibitors: Discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3)”. Journal of Computer-Aided Molecular Design 26 (4): 437–50. doi:10.1007/s10822-012-9572-z. PMID 22527961.

5http://www.pmlive.com/pharma_news/baxter_licenses_cancer_drug_from_cti_in_$172m_deal_519143

US8153632 *	Nov 15, 2006	Apr 10, 2012	S*Bio Pte Ltd.	Oxygen linked pyrimidine derivatives
US8415338 *	Apr 4, 2012	Apr 9, 2013	Cell Therapeutics, Inc.	Oxygen linked pyrimidine derivatives
US20110294831 *	Dec 9, 2009	Dec 1, 2011	S*Bio Pte Ltd.	11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt

Patent	Submitted	Granted
OXYGEN LINKED PYRIMIDINE DERIVATIVES [US8153632]	2009-03-19	2012-04-10
ANTIVIRAL JAK INHIBITORS USEFUL IN TREATING OR PREVENTING RETROVIRAL AND OTHER VIRAL INFECTIONS [US2014328793]	2012-11-30	2014-11-06
OXYGEN LINKED PYRIMIDINE DERIVATIVES [US2013172338]	2013-02-20	2013-07-04
METHOD OF SELECTING THERAPEUTIC INDICATIONS [US2014170157]	2012-06-15	2014-06-19
CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY [US2014357557]	2014-05-30	2014-12-04
11-(2-PYRROLIDIN-1-YL-ETHOXY)-14,19-DIOXA-5,7,26-TRIAZA-TETRACYCLO[19.3.1.1(2,6).1(8,12)]HEPTACOSA-1(25),2(26),3,5,8,10,12(27),16,21,23-DECAENE MALEATE SALT [US2011263616]	2011-10-27
11-(2-PYRROLIDIN-1-YL-ETHOXY)-14,19-DIOXA-5,7,26-TRIAZA-TETRACYCLO[19.3.1.1(2,6).1(8,12)]HEPTACOSA-1(25),2(26),3,5,8,10,12(27),16,21,23-DECAENE CITRATE SALT [US2011294831]	2011-12-01
BIOMARKERS AND COMBINATION THERAPIES USING ONCOLYTIC VIRUS AND IMMUNOMODULATION [US2014377221]	2013-01-25	2014-12-25
Oxygen linked pyrimidine derivatives [US8415338]	2012-04-04	2013-04-09

Pacritinib
Systematic (IUPAC) name

(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1^2,6.1^8,12]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
Clinical data
Legal status	Investigational
Routes of administration	Oral
Identifiers
ATC code	None
PubChem	CID: 46216796
ChemSpider	28518965
ChEMBL	CHEMBL2035187
Synonyms	SB1518
Chemical data
Formula	C₂₈H₃₂N₄O₃
Molecular mass	472.58 g/mol

str1

S*Bio Pte Ltd

Address: 1 Science Park Rd, Singapore 117528

Phone:+65 6827 5000

S*BIO Pte Ltd. provides research and clinical development services for small molecule drugs for the treatment of cancer in Singapore. The company’s products include JAK2 inhibitors, such as SB1518 for leukemia/myelofibrosis, lymphoma, and polycythemia; and SB1578 for RA/psoriasis. The company also offers SB939, a histone deacetylases for MDS/AML+combo, prostate cancer, sarcoma, pediatric tumor, and myelofibrosis; SB2602, a mTOR inhibitor; SB2343, a mTOR/PI3K inhibitor; and SB1317, a CDK/Flt3 inhibitor. The company was founded in 2000 and is based in Singapore. S*BIO Pte Ltd. operates as a subsidiary of Chiron Corporation Limited.

SEE……..http://apisynthesisint.blogspot.in/2016/01/pacritinib.html

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Pacritinib
Clinical data

Trade names	Vonjo
Other names	SB1518
License data	US DailyMed: Pacritinib
Routes of administration	By mouth
ATC code	L01EJ03 (WHO)
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
show IUPAC name
CAS Number	937272-79-2
PubChem CID	46216796
DrugBank	DB11697
ChemSpider	28518965
UNII	G22N65IL3O
KEGG	D11768
ChEMBL	ChEMBL2035187
PDB ligand	6T3 (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₂₈H₃₂N₄O₃
Molar mass	472.589 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

///////Vonjo, FDA APPTOVESD 2022, APPROVALS 2022, PACRITINIB, パクリチニブ, priority review, fast track, orphan drug, UNII-G22N65IL3O, пакритиниб , باكريتينيب , 帕瑞替尼 , SB 1518

c1cc2cc(c1)-c3ccnc(n3)Nc4ccc(c(c4)COC/C=C/COC2)OCCN5CCCC5

C1CCN(C1)CCOC2=C3COCC=CCOCC4=CC=CC(=C4)C5=NC(=NC=C5)NC(=C3)C=C2

Lixivaptan

December 13, 2015 2:15 am / Leave a comment

Lixivaptan

CRTX-080; VPA-985; WAY-VPA-985

N-[3-chloro-4-(6,11-dihydropyrrolo[2,1-c][1,4]benzodiazepine-5-carbonyl)phenyl]-5-fluoro-2-methylbenzamide

5-fluoro-2-methyl-N-(4-(5H-pyrrolo(2,1-c)-(1,4)benzodiazepin-10-(11H)-ylcarbonyl)-3-chlorophenyl)benzamide
N-4-(3-chloro-4-(5H-pyrrolo(2,1-C)(1,4)benzodiazepin-10(11H)-ylcarbonyl)phenyl)-5-fluoro-2-methylbenzamide
N-[3-chloro-4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylBenzamide
N-(3-CHLORO-4-{3,9-DIAZATRICYCLO[8.4.0.0(3),?]TETRADECA-1(10),4,6,11,13-PENTAENE

CAS 168079-32-1

MW 473.9,

	MF C₂₇H₂₁ClFN₃O₂

A vasopressin (AVP) V2 antagonist potentially for treatment of heart failure and hyponatremia.

Lixivaptan (VPA-985) is a phase III pharmaceutical being developed by Cardiokine, Inc., a specialty pharmaceutical company based in Philadelphia, PA, focused on the development of pharmaceuticals for the treatment and prevention of cardiovascular diseases. Lixivaptan is, as of May 2010, in Phase III clinical trials involving patients with hyponatremia, including those with concomitant heart failure.^[1] Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. Lixivaptan may help some patients eliminate excess fluids while retaining electrolytes.

ChemistryLixivaptan is synthesized as follows:^[2]

Mechanism of action

Lixivaptan is a potent, non-peptide, selective vasopressin 2 receptor antagonist. The oral capsule works by reducing the action of the hormone vasopressin that blocks fluid excretion. Lixivaptan acts by blocking vasopressin, an anti-diuretic hormone that causes the kidneys to retain water. When the body needs to remain hydrated under certain conditions, vasopressin can have protective effects. But an excess of vasopressin is counterproductive in a body retaining too much fluid. The drug shows promise in treating heart failure in patients with hyponatremia.

THE BALANCE study

In February 2008, Cardiokine and its worldwide partner, Biogen Idec, initiated THE BALANCE (Treatment of HyponatrEmia BAsed on LixivAptan in N Yha class III/IV Cardiac patient Evaluation) study. THE BALANCE study is a 650-patient Phase III, global, multi-center, randomized, placebo-controlled, double-blind, study of lixivaptan for hyponatremia in patients with heart failure. The primary objective is to evaluate the safety and effectiveness of lixivaptan, when compared to the placebo, in increasing serum sodium from baseline in heart failure patients with hyponatremia.^[3]^[4]

Previous studies

In previous studies, lixivaptan improved blood sodium levels, lowered body weight and increased urine volume. Those studies suggest that lixivaptan may play an important role in treating hyponatremia and the signs and symptoms of water retention associated with heart failure, Syndrome of Inappropriate Anti-Diuretic Hormone(SIADH), and Liver Cirrhosis with Ascites (LCWA). In clinical trials involving patients with water volume overload, lixivaptan resulted in correction of hyponatremia together with marked aquaresis.

Vaptans

The vasopressin receptor antagonists, dubbed vaptans, target the vasopressin hormonal feedback system. Vasopressin, also called the anti-diuretic hormone or ADH, is an important part of regulation in the circulatory system and is integral to the balance of water in the body. As a fundamental part of hormonal control in the body, it is implicated in many different conditions. Vaptans can be administered orally or intravenously. They work by competing for the active sites on cells meant for vasopressin binding—in this way, the vasopressin is blocked from acting, which earns the title of vasopressing antagonists.

SYNTHESIS COMING………………..

JMC 1998, 41, 2442

US 5516774

http://www.google.co.in/patents/US5516774

CN103694240

Lixiputan (Lixivaptan, I) is pressurized by a Wyeth (wyeth) research and development of non-peptide hormone arginine oral selective V2 receptor antagonist, chemical name N- [3- chloro-4- (10, 11- dihydro -5H- pyrrolo [2,1-c] [1,4] benzodiazepine-10-yl carbonyl) phenyl] -5-fluoro-2- methylbenzamide. Clinical studies have shown that, compared with traditional diuretic, Lixiputan for the treatment of congestive heart failure (CHF), cirrhosis of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion disorders (SIADH) patients, its in increase free water clearance without affecting renal sodium discharge, it will not activate the neuroendocrine system, and has a high safety and tolerability. Lixiputan V2 receptor selectivity higher than in May 2009 the FDA approved tolvaptan, Phase III clinical studies for the treatment of hyponatremia have been completed in the United States, in the pre-registration stage.

Document (Journalof medicinal chemistry, 1998,41 (14):. 2442-2444) reported Lixiputan there are two synthetic routes, one route to 10,11-dihydro -5H- pyrrolo [2, ι-c] [1,4] benzodiazepine (2) as raw materials, in turn with 2-chloro-4-nitrobenzoyl and 5-fluoro-2-methylbenzoyl docking, to obtain I; the second is the first line of 2-chloro-4-amino benzoic acid methyl ester (5) and 5-fluoro-2-methylbenzoyl chloride (7) butt, by hydrolysis, acylation reaction of 2-chloro-like -4 – [(5-fluoro-2-methylbenzoyl) amino] benzoyl chloride (10), and then with 2 reaction of I. 2 As the raw material is expensive, Route One to two as the starting material, the multi-step reaction, its low efficiency, high cost of production. Therefore, this study reference line two, 2-chloro-4-nitro-benzoic acid (3) as the starting material, by esterification, hydrogenation, acylation, hydrolysis, chloride, and so the reaction of 10; 10 and then with 2 After acylation reaction of N- I. I synthetic route follows.

The chemical structure:

formula = C27H21ClFN3O2

Molecular Weight: 473.93

The method for producing foreign products have been reported, such as the literature Journal of medicinalchemistry, 1998,41 (14):. 2442-2444 and US, 5516774 [P], 1996-5-14. Currently, Lixiputan (Iixivaptan) abroad in Phase III clinical studies, there are good prospects for development, given the value of the pharmaceutical compounds, high purity, with a very determined and reproducible crystalline compounds are important .

The present inventors have repeated the document US, 5,516,774 Lixiputan method of purity, obtained was 97.5%, mpl91-195 ° C, by the study of a plurality of batches, the melting point of the same, by a powder X- ray diffraction pattern See

preparation of Lixiputan solvate Lixiputan, by two synthetic methods. As literature Journalof medicinal chemistry, 1998, 41 (14):. 2442-2444 and US, 5516774 [P],

The method reported in [0026] 1996-5-14. Preclude the use of the route of the present invention is represented by the following reaction:

synthetic Lixiputan by proton nuclear magnetic resonance spectroscopy (1H-NMRX mass spectrometry (MS), infrared spectroscopy (IR) and other confirmed its chemical structure (see Figure 3 MS). Test equipment for nuclear magnetic resonance Bruker AV400 meter, gas generation agent for CambridgeIsotope Laboratories Company DMS0_d6.

ES1-HRMS (m / z): 474.17 [M + H] + NMR (400MHz, DMS0_d6) δ: 10.49 (s, 1H), 7.84 (s, 1H), 7.40 (d, J = 6.8Hz, 2H), 7.33 (d, J = 8.4Hz, 3H), 7.23 (t, J = 8.4Hz, 1H), 7.13 (t, J = 5.6Hz, 2H), 7.05 (d, J = 6.8Hz, 1H) , 6.82 (s, 1H), 5.94 (d, J = 32Hz, 2H), 5.23 (br, 4H), 2.30 (s, 3H).

The product obtained, with a purity of 97.5%, mp 191-195 ° C.

Lixiputan solvates H NMR spectrum, δ: 1.147-1.182 “3” methyl hydrogens; δ: 1.971-1.977 for the “I” position methyl hydrogen; δ: 3.994-4.047 “2” position methylene hydrogen.

CN104059070

CN104140429

IN 2012 MUM 03309

References

1 Lixivaptan: a novel vasopressin receptor antagonist
2 Albright, J. D.; Reich, M. F.; Delos Santos, E. G.; Dusza, J. P.; Sum, F. W.; Venkatesan, A. M.; Coupet, J.; Chan, P. S.; Ru, X.; Mazandarani, H.; Bailey, T. (1998). “5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]- [1,4]benzodiazepin-10(11H)-ylcarbonyl)-3- chlorophenyl]benzamide (VPA-985): An Orally Active Arginine Vasopressin Antagonist with Selectivity for V2Receptors”. Journal of Medicinal Chemistry 41 (14): 2442–2444. doi:10.1021/jm980179c. PMID 9651149.
3 http://www.clinicaltrials.gov/ct2/show/NCT00578695?term=Lixivaptan+Heart+Failure&rank=3
4 http://onlinelibrary.wiley.com/doi/10.1111/j.1752-8062.2010.00217.x/pdf

Patent	Submitted	Granted
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5854237]	1998-12-29
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5889001]	1999-03-30
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5843944]	1998-12-01
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5624923]	1997-04-29
Compositions for delivery of insoluble agents [US8877746]	2010-08-24	2014-11-04

Patent	Submitted	Granted
AURIS FORMULATIONS FOR TREATING OTIC DISEASES AND CONDITIONS [US2009306225]	2009-12-10
Vasopressin antagonist and diuretic combination [US6656931]	2003-04-10	2003-12-02
Pharmaceutical carrier formulation [US6437006]		2002-08-20
Vasopressin antagonist formulation and process [US6352718]		2002-03-05
Nonpeptide agonists and antagonists of vasopressin receptors [US2002128208]	2002-09-12
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5968930]	1999-10-19
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5968937]	1999-10-19
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5516774]	1996-05-14
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5733905]	1998-03-31
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5736540]	1998-04-07

Lixivaptan
Systematic (IUPAC) name

N-[3-chloro-4-(6,11-dihydropyrrolo[2,1-c][1,4]benzodiazepine-5-carbonyl)phenyl]-5-fluoro-2-methylbenzamide
Identifiers
CAS Number	168079-32-1
ATC code	None
PubChem	CID: 172997
IUPHAR/BPS	2238
ChemSpider	151067
UNII	8F5X4B082E
ChEMBL	CHEMBL49429
Chemical data
Formula	C₂₇H₂₁Cl F N₃O₂
Molecular mass	473.926 g/mol

CN102020609A *	Sep 17, 2009	Apr 20, 2011	北京本草天源药物研究院	Tolvapta crystal or amorphous substance and preparation method thereof
CN102918038A *	Mar 31, 2011	Feb 6, 2013	万梯雅有限公司	New polymorph
US5516774 *	Jun 13, 1994	May 14, 1996	American Cyanamid Company	Tricyclic diazepine vasopressin antagonists and oxytocin antagonists


1	*	吕扬等: “《晶型药物》”, 31 October 2009, article “”第七章晶型药物的研究方法”“, pages: 136-139

//////////Lixivaptan, CRTX-080, VPA-985, WAY-VPA-985

CC1=C(C=C(C=C1)F)C(=O)NC2=CC(=C(C=C2)C(=O)N3CC4=CC=CN4CC5=CC=CC=C53)Cl

Iptakalim Hydrochloride 盐酸埃他卡林

December 4, 2015 12:28 pm / Leave a comment

Iptakalim Hydrochloride 盐酸埃他卡林

A K(ir) 6.1/SUR2B activator potentially for the treatment of pulmonary arterial hypertension.

179.7, C9H21N.HCl

CAS No. 642407-44-1(Iptakalim)

642407-63-4(Iptakalim Hydrochloride)

N-(1-methylethyl)-2,3-dimethyl-2-butylamine

	Catholic Healthcare West (D/B/A/ St. Joseph’s Hospital And Medical Center)

Catholic Healthcare West (D/B/A/ St. Joseph’s Hospital And Medical Center)

Hypertension is a multifactorial disorder, and effective blood pressure control is not achieved in most individuals. According to the most recent report of the American Heart Association, for 2010, the estimated direct and indirect financial burden for managing hypertension is estimated to be $76.6 billion. Overall, almost 75% of adults with cardiovascular diseases/comorbidities have hypertension, which is associated with a shorter overall life expectancy. Alarmingly, rates of prehypertension and hypertension are increasing among children and adolescents due, in part, to the obesity epidemic we currently face. There is also the problem of an aging population and the growing rates of diabetes and obesity in adults, all factors that are associated with high blood pressure.Thus, the need is great for novel drugs that target the various contributing causes of hypertension and the processes leading to end organ damage.

Iptakalim (IPT), chemically 2, 3–dimethyl-N-(1-methylethyl)-2-butanamine hydrochloride, is novel adenosine triphosphate–sensitive potassium (K_ATP) channel opener. K_ATP channels are composed of discrete pore-forming inward rectifier subunits (Kir6.1s) and regulatory sulphonylurea subunits (SUR).IPT shows high selectivity for cardiac K_ATP (SUR2A/Kir6.2) and vascular K_ATP (SUR2B/Kir6.1 or SUR6B/Kir6.2). Because of this high selectivity, IPT does not exhibit the adverse side effects associated with the older nonspecific K⁺ channel openers, which limit their use to the treatment of severe or refractory hypertension. IPT produces arteriolar and small artery vasodilatation, with no significant effect on capacitance vessels or large arteries. Vasodilatation is induced by causing cellular hyperpolarization via the opening of K⁺ channels, which in turn decreases the opening probability of L-type Ca²⁺ channels. Of particular note, IPT is very effective in lowering the blood pressure of hypertensive humans but not of those with normal blood pressure.

The present compd relates generally to a novel method for decreasing a human’s cravings for cigarettes and reducing instances of relapse during detoxification once smoking abstinence has been achieved, and more specifically, to a method for decreasing nicotine use by treating a human with a novel type of nicotinic acetylcholine receptor antagonist, iptakalim hydrochloride (IPT).

Cigarette smoking is a prevalent, modifiable risk factor for increased morbidity and mortality in the United States, and perhaps in the world. Smokers incur medical risks attributable to direct inhalation. Bystanders, termed passive smokers, also incur medical risks from second-hand smoke. Society, as a whole, also bears the economic costs associated with death and disease attributable to smoking. Although the majority of smokers have tried repeatedly to quit smoking, eighty percent of smokers return to tobacco in less than two years after quitting. Therefore, tobacco dependence is a health hazard for millions of Americans.
Nicotine is the biologically active substance that is thought to promote the use of tobacco products by approximately one-quarter of the world populations. Tobacco-related disease is personally and economically costly to the any nation. Unfortunately, once use of tobacco has begun, it is hard for a smoker to quit because of nicotinic dependence and addiction.
The initiation and maintenance of tobacco dependence in a human is due to certain bio-behavioral and neuromolecular mechanisms. Nicotinic acetylcholine receptors (nAChRs) in humans are the initial binding sites for nicotine. The binding of nicotine to nAChRs is thought to modulate the brain’s “reward” function by triggering dopamine release in the human brain. The nAChRs exist as a diverse family of molecules composed of different combinations of subunits derived from at least sixteen genes. nAChRs are prototypical members of the ligand-gated ion channel superfamily of neurotransmitter receptors. nAChRs represent both classical and contemporary models for the establishment of concepts pertaining to mechanisms of drug action, synaptic transmission, and structure and function of transmembrane signaling molecules.
Basic cellular mechanisms of nicotinic dependence also involve the functional state changes during repeated nicotinic agonists exposure and receptor changes in the number of receptors during chronic nicotinic exposure. nAChRs can exist in many different functional states, such as resting, activated, desensitized or inactivated The activation and/or desensitization of nAChRs plays an important role in initiating nicotinic tolerance and dependence. Recovery from receptor activation and/or desensitization contributes to nicotinic withdrawal symptoms.
The most abundant form of nAChRs in the brain contains α4 and β2 subunits. α4β2-nAChRs bind nicotine with high affinity and respond to levels of nicotine found in the plasma of smokers. α4β2-nAChR also have been implicated in nicotine self-administration, reward, and dependence. Therefore, selective drug action at nAChRs, especially at those containing α4 subunits, is thought to be an ideal way for nicotine cessation and reducing nicotine withdrawal syndrome. Unfortunately, thus far, no optimal compound can meet this purpose. The brain-blood-barrier permeable nAChR antagonist, mecamylamine is popularly used systemically but exhibits much less nAChR subtype selectivity.
Although a variety of psychopharmacological effects contribute to drug reinforcement, actions on the mesolimbic dopaminergic pathway is the predominant hypothesis for mechanisms of nicotinic reward. The mesolimbic dopaminergic pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to forebrain structures including the prefrontal cortex and to limbic areas such as the olfactory tubercle, the amygdala, the septal region, and the nucleus accumbens. Many studies have indicated that dopamine release in the nucleus accumbens of the human brain is “rewarding” or signals an encounter with a “reward” from the environment. Other substances, such as alcohol, cocaine, and opiates, operate in the same manner, resulting in a cycle of substance or alcohol abuse.
Therefore, a considerable need exists for a novel compound that can selectively block α4 subtypes of nAChRs to prevent smoking-induced “reward”, to limit increasing nicotine-induced dopamine release, and/or to diminish nicotinic withdrawal symptoms.

Patent

https://www.google.com/patents/US20040266822

Example 1

Production of N-(1-methylethyl)-2,3-dimethyl-2-butylamine (Compound 1): Method 1. The solution of 7.6 g (0.0745 mole) 2,3-dimethyl-2-butanol in 3.24 mL glacial acetic acid was cooled and maintained at −5 to −8 degree of centigrade (° C.), then was added 7.3 g (0.49 mole) of powdered potassium cyanide in several times under stirring. 32.4 mL concentrated sulfuric acid was added dropwise while keeping the temperatue below 20° C., after which, the reaction mixture was stirred for 3.5 hours below 20° C. and another 6 hours at room temperature, then stood overnight. After poured into ice colded water, the mixture was adjusted to pH10 with 20% aqueous sodium hydroxide solution, and extracted with ether (×4). The extract was dried over anhydrous sodium sulfate. After filtration on the next day, the dessicator was removed, and the filtrate was evaporated off the ether, then distilled in vacuum to give 8.8 g (yield 91.6%) N-[2-(2,3-dimethylbutyl)]-fomide; bp 105-108° C./5 mmHg.
To the mixture of 7.7 g (0.0597 mole) N-[2-(2,3-dimethylbutyl)]-formide, 6.2 mL ethanol and 51.6 mL wate, 17.4 mL concentrated hydrochloric acid was added. The reaction mixture was refluxed for 4 hours in the oil bath, then distilled off ethanol in vacuum. The residue was adjusted to above pH12 with 40% aqueous sodium hydroxide solution, and extracted with ether. The extract was dried over anhydrous potassiun carbonate. After recovering the ether, The residue was distilled at atmosphere to give 3.75 g (yield 62.2%) 2,3-dimethyl-2-butylamine, bp 97-104° C.
The mixture of 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45 g (0.0524 mole) 2-bromopropane, 3.0 mL glycol and 22.0 mL toluene was added into an autoclave, and heated with stirring for 17 hours at temperature of 170° C., after which, the organic layer was separated and extracted with 6N hydrochloric acid (15 mL×4). The extract was combined and washed once with toluene, then adjusted to pH 12-13 with 4% aqueous sodium hydroxide in the ice bath. The mixture was extracted with ether and then dried over anhydrous potassium carbonate. After recovering the ether, The filtrate was distilled to yield the fraction of bp 135-145° C. (yield 68.8%). The hydrochloride’s Mp is 228-230° C. (1-PrOH-Et₂O). Elemental analysis for C₉H₂₂ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C, 60.14; H, 12.48; N, 7.31, Cl 19.67.
¹H-NMR(D₂O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M+), 100(B).
Method 2. To the mixture of 288 mL glacial acetic acid, 412 g (6.86 mole) urea and 288 g (3.43 mole) 2,3-dimethyl-2-butene, the solution of 412 mL concentrated sulfuric acid and 412 mL of glacial acetic acid was added dropwise under stirring, while maintaining the reaction temperature at the range of 45° C. to 50° C., then stirred for 5 hours at the temperature of 50-55° C. The mixture stood overnight. Next day, the mixture was reacted for another 7 hours at the temperature of 50-55° C., then poured into the solution of 1200 g (30 mole) sodium hydroxide in 8L glacial water. The resulting solid was filtered, washed with water (200 mL×5) and dried to give 404 g (yield 81.8%) N-(2,3-dimethyl-2-butyl)urea as white solid, mp 175-176° C. Elemental analysis for C₇H₁₆N₂O(%): Calculated C 58.30, H 11.18, N 19.42; Found C, 58.70; H, 11.54; N, 19.25, ¹H-NMR(CDCl₃, ppm) 0.88-0.91(d, 6H, 2×CH₃), 1.26(s, 6H, 2×CH₃), 2.20-2.26(m, 1H, CH), 4,45(br, 2H), 4.65(br, 1H). MS(m/z) 145.0, 144.0(M⁺), 143.0, 129.1, 101.0, 86.1, 69.1, 58.0(B).
To the mixture of 196 g (1.36 mole) N-(2,3-dimethyl-2-butyl)urea and 392 mL glycol or tri-(ethanol)amine, a solution of 118 g (2.95 mole) sodium hydroxide in 118 mL water was added. The reaction mixture was heated for 8 hours in an oil bath at temperature of 120° C., then distilled at atmosphere to collect the fraction of bp 95-102° C. To the fraction, 75 g anhydrous potassium carbonate and. 40 g sodium hydroxide were added. The resulting mixture was distilled to give 88.5 g (yield 64.3%) 2,3-dimethyl-2-butylamine as colorless liquid, bp 99-101° C.
¹H-NMR(CDCl₃, ppm) 0.88-0.91(d, 6H, 2×CH₃), 1.04 (s, 6H, 2×CH₃), 1.53(m, 1H, CH).
To a 50.0 ml autoclave, 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45 g (0.0524 mol) 2-bromopropane, 3.0 ml glycol and 22.0 ml toluene were added, and heated with stirring for 17 hours at 170° C., after which the organic layer was seperated and extracted with 6N hydrochloric acid (15 ml×4). The extract was combined and washed once with toluene, then adjusted to pH 12-13 with 4% aqueous sodium hydroxide in the ice bath. The mixture was extracted with ether and then dried over anhydrous potassium carbonate the ether was recovered, and distilled to give the fraction of bp 135-145° C. (yield 68.8%). mp of the hydrochloride is 228-230° C., (i-PrOH: Et₂O). Elemental analysis for C₉H₂₂ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C 60.14, H 12.48, N 7.31, Cl 19.67. ¹H-NMR(D₂O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M⁺), 100(B).
Method 3. a solution of 0.10 mole enamine (prepared from the condensation of methyl iso-propyl ketone and iso-propylamine) in 20 mL hexane was filled with N₂and added dropwise to a solution containing 0.10 mole lithium methide with stirring in ice bath. After the reaction is complete, the mixture was poured into 500 g glacial water, and stirred. The aqueous layer was extracted with ether (×2). The resulting organic layer was concentrated. 3N hydrochloric acid was added to acified the organic layer to pH<1. The mixture was kept minutes and adjusted to pH>11 with 10% aqueous sodium hydroxide, then extracted with ether (×3). The extract was dried over anhydrous potassium carbonate and filtered. The filtrate was distilled at atmosphere to give a fraction of bp 140-145° C. with a yield of 80%.

REF

http://www.google.com/patents/US20060293393

//////Iptakalim Hydrochloride, 盐酸埃他卡林 , K(ir) 6.1/SUR2B activator, pulmonary arterial hypertension, nda

see……….http://apisynthesisint.blogspot.in/2015/12/iptakalim-hydrochloride.html

Defibrotide

October 1, 2015 5:17 am / Leave a comment

Image result for DEFIBROTIDE SODIUM

Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate. The primary structure of defibrotide sodium is shown below.

DEFITELIO (defibrotide sodium) injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8.

Defibrotide is the sodium salt of a mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has been shown to have antithrombotic, anti-inflammatory and anti-ischemic properties (but without associated significant systemic anticoagulant effects). It is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries, but is currently not approved in the USA. The manufacturer is Gentium.

Defibrotide is used to treat or prevent a failure of normal blood flow (occlusive venous disease, OVD) in the liver of patients who have had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others.

In 2012, an IND was filed in Japan seeking approval of the compound for the treatment of veno-occlusive disease.

Approved 3/30/3016 US FDA, defibrotide sodium, (NDA) 208114

Image result for DEFIBROTIDE SODIUM

To treat adults and children who develop hepatic veno-occlusive disease with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation

Polydeoxyribonucleotides from bovine lung or other mamalian organs with molecular weight between 15,000 and 30,000 Da

CAS 83712-60-1

Defibrotide is a polydisperse mixture of oligonucleotides produced by random, chemical cleavage (depolymerisation) of porcine DNA. It is predominantly single stranded, of varying base sequence, lengths and conformations; unfolded, folded or combined. The mean oligonucleotide length is 50 bases with a mean molecular weight of 17 ± 4 kDa. No individually defined component is at more than femtomolar concentration. The only meaningful scientific information that can be obtained about the biochemical nature of defibrotide (aside from determination of percentage of each nucleobase) is a measurement of its average length and its average percentage double stranded character. Therefore, it can be established that this active substance is of highly heterogenic nature.

Image result for DEFIBROTIDE SODIUM

Defibrotide (Defitelio, Gentium)^[1] is a deoxyribonucleic acid derivative (single-stranded) derived from cow lung or porcine mucosa. It is an anticoagulant with a multiple mode of action (see below).

It has been used with antithrombin III.^[2]

Jazz Pharmaceuticals plc announced that the FDA has accepted for filing with Priority Review its recently submitted New Drug Application (NDA) for defibrotide. AS ON OCT 2015

Defibrotide is an investigational agent proposed for the treatment of patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with evidence of multi-organ dysfunction (MOD) following hematopoietic stem-cell transplantation (HSCT).

Priority Review status is designated for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists. Based on timelines established by the Prescription Drug User Fee Act (PDUFA), FDA review of the NDA is expected to be completed by March 31, 2016.

“The FDA’s acceptance for filing and Priority Review status of the NDA for defibrotide is an important milestone for Jazz and reflects our commitment to bringing meaningful medicines to patients who have significant unmet needs,” said Karen Smith, M.D., Ph.D., Global Head of Research and Development and Chief Medical Officer of Jazz Pharmaceuticals. “We look forward to continuing to work closely with the FDA to obtain approval for defibrotide for patients with hepatic VOD with evidence of MOD in the U.S. as quickly as possible, as there are no other approved therapies for treating this rare, often fatal complication of HSCT.”

The NDA includes safety and efficacy data from three clinical studies of defibrotide for the treatment of hepatic VOD with MOD following HSCT, as well as a retrospective review of registry data from the Center for International Blood and Marrow Transplant Research. The safety database includes over 900 patients exposed to defibrotide in the clinical development program for the treatment of hepatic VOD.

The compound was originally developed under a collaboration between Sanofi and Gentium. In December 2001, Gentium entered into a license and supply agreement with Sigma-Tau Pharmaceuticals, pursuant to which the latter gained exclusive rights to distribute, market and sell the product for the treatment of VOD in the U.S. This agreement was expanded in 2005 to include all of North America, Central America and South America.

Defibrotide was granted orphan drug designations from the FDA in July 1985, May 2003 and January 2007 for the treatment of thrombotic thrombocytopenic purpura (TTP), for the treatment of VOD and for the prevention of VOD, respectively. Orphan drug was also received in the E.U. for the prevention and treatment of hepatic veno-occlusive disease (VOD) in 2004 and for the prevention of graft versus host disease (GvHD) in 2013.

Pharmacokinetics

Defibrotide is available as an oral, intravenous, and intramuscular formulation. Its oral bioavailability is in the range of 58-70% of theparenteral forms. T1/2 alpha is in the range of minutes while T1/2 beta is in the range of hours in studies with oral radiolabelleddefibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug’s short half-life, it is necessary to give the daily dose divided in 2 to 4 doses (see below).

In 2014, Jazz Pharmaceuticals (parent of Gentium) acquired the rights of the product in U.S. and in the Americas

Mode of action

The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator (tPA-)function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent studies have shown. It is yet unclear, if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke).

Unlike heparin and warfarin, defibrotide appears to have a relatively mild anticoagulant activity, which may be beneficial in the treatment of patients at high risk of bleeding complications. Nevertheless, patients with known bleeding disorders (e.g., hemophilia A) or recent abnormal bleedings should be treated cautiously and under close medical supervision.

The drug was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. It is currently not approved in the USA. The manufacturer is Gentium.

Defibrotide also received fast track designation from the FDA for the treatment of severe VOD in recipients of stem cell transplants. In 2011, the compound was licensed to Medison Pharma by Gentium in Israel and Palestine. The license covers the management of named-patient sales program and local registration, authorization, marketing, reimbursement and medical affairs for the treatment of peripheral vascular disease.

Usual indications

Defibrotide is used to treat or prevent a failure of normal blood flow (Veno-occlusive disease, VOD) in the liver of patients having had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others. Without intensive treatment, VOD is often a fatal condition, leading to multiorgan failure. It has repeatedly been reported that defibrotide was able to resolve the condition completely and was well tolerated.

Other indications are: peripheral obliterative arterial disease, thrombophlebitis, and Raynaud’s phenomenon. In very high doses, defibrotide is useful as treatment of acute myocardial infarction. The drug may also be used for the pre- and postoperative prophylaxis of deep venous thrombosis and can replace the heparin use during hemodialytic treatments.

It has been investigated for use in treatment of chronic venous insufficiency.^[3]

Potential indications in the future

Other recent preclinical studies have demonstrated that defibrotide used in conjunction with Granulocyte Colony-Stimulating Factor (rhG-CSF) significantly increases the number of Peripheral Blood Progenitor Cells (Stem cells). The benefit of this increase in stem cells may be crucial for a variety of clinical indications, including graft engineering procedures and gene therapy programs. This would expand the clinical usefulness of defibrotide to a complete distinct area.

Very recently (since early 2006) combination therapy trials (phase I/II) with defibrotide plus melphalan, prednisone, and thalidomide in patients with multiple myeloma have been conducted. The addition of defibrotide is expected to decrease the myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage.

Cautions and contraindications

The efficacy of the drug has been reported to be poorer in patients with diabetes mellitus.
Pregnancy: The drug should not be used during pregnancy, because adequate and well controlled human studies do not exist.
Lactation: No human data is available. In order to avoid damage to the newborn, the nursing mother should discontinue either the drug or breastfeeding, taking into account the importance of treatment to the mother.
Known Bleeding Disorders or Bleeding Tendencies having occurred recently: Defibrotide should be used cautiously. Before initiation of treatment, the usual coagulation values should be obtained as baseline and regularly controlled under treatment. The patient should be observed regularly regarding local or systemic bleeding events.

Side-effects

Increased bleeding and bruising tendency, irritation at the injection site, nausea, vomiting, heartburn, low blood pressure. Serious allergic reactions have not been observed so far.

Drug interactions

Use of heparin with defibrotide may increase the aPTT, reflecting reduced ability of the body to form a clot. Nothing is known about the concomitant application of other anticoagulants than heparin and dextran containing plasma-expanders, but it can be anticipated that the risk of serious bleeding will be increased considerably.

PATENT

WO 2001078761

G-CSF (CAS registry number 143011-2-7/Merck Index, 1996, page 4558) is a haematopoietic growth factor which is indispensable in the proliferation and differentiation of the progenitor cells of granulocytes; it is a 18-22 kDa glycoprotein normally produced in response to specific stimulation by a variety of cells, including monocytes, fibroblasts and endothelial cells. The term defibrotide (CAS registry number 83712-60-1) normally identifies a polydeoxyribonucleotide obtained by extraction (US 3,770,720 and US 3,899,481) from animal and/or vegetable tissue; this polydeoxyribonucleotide is normally used in the form of a salt of an alkali metal, generally sodium. Defibrotide is used principally for its anti- thrombotic activity (US 3,829,567) although it may be used in different applications, such as, for example, the treatment of acute renal insufficiency (US 4,694,134) and the treatment of acute myocardial ischaemia (US 4,693,995). United States patents US 4,985,552 and US 5,223,609, finally, describe a process for the production of defibrotide which enables a product to be obtained which has constant and well defined physico-chemical characteristics and is also free from any undesired side-effects

References

“Jazz Pharma Acquiring Gentium for $1B”. Gen. Eng. Biotechnol. News (paper) 34 (2). January 15, 2014. p. 10.
Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor T (June 2006). “Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy”. Haematologica 91 (6): 795–800. PMID 16769582.
Coccheri S, Andreozzi GM, D’Addato M, Gensini GF (June 2004). “Effects of defibrotide in patients with chronic deep insufficiency. The PROVEDIS study”. Int Angiol 23 (2): 100–7.PMID 15507885.

External links

Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993;45:259-94.
http://www.globalrx.com/medinfo/Defibrotide.htm
Fisher J, Holland TK, Pescador R, Porta R, Ferro L (January 1996). “Study on pharmacokinetics of radioactive labelled defibrotide after oral or intravenous administration in rats”. Thromb. Res. 81 (1): 55–63. doi:10.1016/0049-3848(95)00213-8. PMID 8747520.
http://www.gentium.it/Defibrotide.aspx (information provided by manufacturer)
“Melphalan: profile and news”. Archived from the original on 2007-09-28. (on cytostatic combination therapy)
Beşişik SK, Oztürk GB, Calişkan Y, Sargin D (March 2005). “Complete resolution of transplantation-associated thrombotic microangiopathy and hepatic veno-occlusive disease by defibrotide and plasma exchange”. Turk J Gastroenterol 16 (1): 34–7. PMID 16252186.

WO2003101468A1 *	Jun 2, 2003	Dec 11, 2003	Guenther Eissner	Method for the protection of endothelial and epithelial cells during chemotherapy
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US5223609	May 26, 1992	Jun 29, 1993	Crinos Industria Farmacobiologica S.P.A.	Process for obtaining chemically defined and reproducible polydeoxyribonucleotides

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Reference
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2	*	GURSOY A: “PREPARATION, CHARACTERIZATION AND ANTI-INFLAMMATORY EFFECT OF DEFIBROTIDE LIPOSOMES” PHARMAZIE,DD,VEB VERLAG VOLK UND GESUNDHEIT. BERLIN, vol. 48, no. 7, 1 July 1993 (1993-07-01), pages 549-550, XP000372658 ISSN: 0031-7144

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US8980862	12 Nov 2010	17 Mar 2015	Gentium S.P.A.	Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD)

Defibrotide
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	X
Legal status	Rx only (where available)
Routes of administration	oral, i.m., i.v.
Pharmacokinetic data
Bioavailability	58 – 70% orally (i.v. and i.m. = 100%)
Biological half-life	t1/2-alpha = minutes; t1/2-beta = a few hours
Identifiers
CAS Registry Number	83712-60-1
ATC code	B01AX01
DrugBank	DB04932
UNII	438HCF2X0M
KEGG	D07423

///////////Approved, 3/30/3016, US FDA, defibrotide sodium, NDA 208114, FDA 2016

Updates……….

FDA approves first treatment for rare disease in patients who receive stem cell transplant from blood or bone marrow

For Immediate Release

March 30, 2016

Release

The U.S. Food and Drug Administration today approved Defitelio (defibrotide sodium) to treat adults and children who develop hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation (HSCT). This is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.

HSCT is a procedure performed in some patients to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in patients who receive chemotherapy and HSCT. Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs. Fewer than 2 percent of patients develop severe hepatic VOD after HSCT, but as many as 80 percent of patients who develop severe hepatic VOD do not survive.

“The approval of Defitelio fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

The efficacy of Defitelio was investigated in 528 patients treated in three studies: two prospective clinical trials and an expanded access study. The patients enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after HSCT. The studies measured the percentage of patients who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of patients treated with Defitelio were alive 100 days after HSCT. Based on published reports and analyses of patient-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for patients with severe hepatic VOD who received only supportive care or interventions other than Defitelio.

The most common side effects of Defitelio include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects of Defitelio that were identified include bleeding (hemorrhage) and allergic reactions. Defitelio should not be used in patients who are having bleeding complications or who are taking blood thinners or other medicines that reduce the body’s ability to form clots.

The FDA granted the Defitelio application priority review status, which facilitates and expedites the development and review of certain drugs in light of their potential to benefit patients with serious or life-threatening conditions. Defitelio also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Defitelio is marketed by Jazz Pharmaceuticals based in Palo Alto, California

Aripiprazole lauroxil ……….Alkermes submits new drug application

August 28, 2014 9:33 am / 1 Comment on Aripiprazole lauroxil ……….Alkermes submits new drug application

Aripiprazole

7-[4-[4-(2,3-dichlorophenyl)-1- piperazinyl]butoxy]- 3,4-dihydro-2(1H)-quinolinone.

END AUG 2014

The US Food and Drug Administration (FDA) has received a new drug application (NDA) from Ireland-based Alkermes for its aripiprazole lauroxil to treat schizophrenia.

Aripiprazole lauroxil is an injectable atypical antipsychotic with one-month and two-month formulations, developed for the treatment of schizophrenia, which is a chronic, severe and disabling brain disorder.

The company has submitted the application based on positive results from the pivotal phase three study that assessed the efficacy and safety of aripiprazole lauroxil, where the drug demonstrated significant improvements in schizophrenia symptoms when compared to a placebo.

“We have designed aripiprazole lauroxil to be a differentiated treatment option for schizophrenia, with a ready-to-use format with multiple dosing options.”

Alkermes CEO Richard Pops said: “We have designed aripiprazole lauroxil to be a differentiated treatment option for schizophrenia, with a ready-to-use format with multiple dosing options, to help meet the individual needs of patients and their healthcare providers.

“These attributes, together with the robust clinical data observed in the pivotal study, position aripiprazole lauroxil to be a meaningful new entrant in the growing long-acting injectable antipsychotic market, and we look forward to working with the FDA to bring this important new medication to patients and physicians as quickly as possible.”

The study, in which both doses of aripiprazole lauroxil tested, including 441mg and 882mg, reached the primary endpoint with statistically significant and clinically meaningful reductions in positive and negative syndrome scale (PANSS) scores, according to the company.

In addition, it met all secondary endpoints and demonstrated significant improvements in schizophrenia symptoms against the placebo.

ALKS 9070
ALKS 9072
Aripiprazole lauroxil
RDC 3317
RDC-3317
UNII-B786J7A343

Aripiprazole lauroxil [USAN] CAS 1259305-29-7

Systematic (IUPAC) name
7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Clinical data
Trade names	Abilify
AHFS/Drugs.com	monograph
MedlinePlus	a603012
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B3 (AU) C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a depot)
Pharmacokinetic data
Bioavailability	87%^[1]^[2]^[3]^[4]
Protein binding	>99%^[1]^[2]^[3]^[4]
Metabolism	Hepatic (liver; mostly via CYP3A4 and CYP2D6^[1]^[2]^[3]^[4])
Half-life	75 hours (active metabolite is 94 hours)^[1]^[2]^[3]^[4]
Excretion	Renal (27%; <1% unchanged), Faecal (60%; 18% unchanged)^[1]^[2]^[3]^[4]
Identifiers
CAS number	129722-12-9
ATC code	N05 AX12
PubChem	CID 60795
IUPHAR ligand	34
DrugBank	DB01238
ChemSpider	54790
UNII	82VFR53I78
KEGG	D01164
ChEBI	CHEBI:31236
ChEMBL	CHEMBL1112
Chemical data
Formula	C₂₃H₂₇Cl₂N₃O₂
Mol. mass	448.385

Aripiprazole (/ˌ ɛər ɨ ˈ p ɪ p r ə z oʊ l / AIR-i-PIP-rə-zohl; brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation (or atypical) class of antipsychotics that is primarily used in the treatment of schizophrenia, bipolar disorder, major depressive disorder (as an add on to other treatment), tic disorders, and irritability associated with autism.^[5]

It was approved by the U.S. Food and Drug Administration (FDA) for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007;^[6] and to treat irritability in children with autism on 20 November 2009.^[7] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.^[1]

Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Regulator status

In the United States, the FDA has approved aripiprazole for the treatment of schizophrenia in adults and adolescents (aged 13–17), of manic and mixed episodes associated with Bipolar I (One) Disorder with or without psychotic features in adults, children and adolescents (aged 10–17),^[59] of irritability associated with autism in pediatric patients (aged 6–17),^[60] and of depression when used along with antidepressants in adults.^[61]

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.^[62]

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.^[63] It has not been FDA-approved for use as monotherapy in unipolar depression.

Patent status

Otsuka’s US patent on aripiprazole expires on October 20, 2014;^[64] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[62] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.^[65] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[1][2]

Dosage forms

Abilify 2mg tablets (US)

Intramuscular injection, solution: 9.75 mg/mL (1.3 mL)
Solution, oral: 1 mg/mL (150 mL) [contains propylene glycol, sucrose 400 mg/mL, and fructose 200 mg/mL; orange cream flavor]
Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
Tablet, orally disintegrating: 10 mg [contains phenylalanine 1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]

Synthesis

Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amine:^[66]

U.S. Patent No.4, 734, 416 and U.S. Patent No.5,006,528 discloses the Aripiprazole, 7-{4- [4- (2, 3-dichlorophenyl) -1-piperazinyl] butoxy}- 3,4-dihydro-2 (IH) -quinolinone or 7-{4-[4- (2, 3-dichlorophenyl) -1- piperazinyl] butoxy}-3, 4-dihydro carbostyril, is a typical antipsychotic agent useful for the treatment of Schizophrenia, having the formula as given below.

Aripiprazole

U.S. patent No.5,006,528 discloses preparation of Aripiprazole and its pharmaceutically acceptable acid-addition salts. The process for the preparation of acid salts involves reaction of Aripiprazole with a pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like; organic acids such as oxalic acid, maleic acid, fumaric acid, maleic acid, tartaric acid, citric acid, . benzoic acid and the like as per Scheme-1. Scheme- 1

a. K₂CO₃, Water K CH₂CI₂ c. Column chromatographic purification d. n-Hexane – Ethaπol

ARIPIPRAZOLE ACID SALT

The product Aripiprazole _.obtained by the above process has melting point of 139.0° – 139.5°C.

The process involves purification of the intermediate, 7-(4- bromobutoxy) -3, 4-dihydrocarbostyril (III) by silica gel column chromatography to remove impurities formed during the reaction. The process further involves two recrystallizations of Aripiprazole from ethanol to obtain the pure Aripiprazole though compromising on yields by increasing the operational cost of the product. PCT publication WO 03/026659 discloses low hygroscopic forms of

Aripiprazole and the process for their preparation from the Aripiprazole hydrate Form ^SA’ . It further states that the anhydrous

Aripiprazole made by the Japanese patent publication No. 191256/1990, yields the Aripiprazole, which is significantly hygroscopic. As per PCT publication WO 03/026659 anhydrous crystals of Aripiprazole exist as type-I crystals and type-II crystals. Further discloses that the type-I crystals are prepared -by recrsytallization from ethanol solution of

Aripiprazole or by heating Aripiprazole hydrate at 80⁰C and type-II crystals by heating type-I crystals at 130 to 140⁰C for 15 hrs.

PCT application Publication WO 03/026659 discloses process for the Aripiprazole polymorphic form-B by heating the Aripiprazole hydrate

‘A’ at 90 – 125°C for about 3 – 50 hrs. The process for Polymorphic

Form-C is by heating the Aripiprazole anhydrous to a temperature of 140

– 150⁰C. The process for Form-D is recrystallization from toluene; process for Form-E is heating with acetonitrile or by recrystallization from acetonitrile and the process for Form-F is by heating the suspension of anhydrous Aripiprazole in acetone. The polymorphic Form-G is by heating to 170⁰C for at least 2 weeks in a sealed tube, which is a glassy mass.

PCT publication WO 03/026659 further discloses the characterization data X-ray diffraction pattern; IR absorption and DSC of Form B, Form C, Form-D, Form-E, Form-F and Form-G.It further reported the melting point of Aripiprazole anhydrous Form B as 139.7°C-

Research

Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behavior in animal models without significantly affecting other rewarding behaviors (such as food self-administration).^[67] Aripiprazole may be counter-therapeutic as treatment for methamphetamine dependency because it increased methamphetamine’s stimulant and euphoric effects, and increased the baseline level of desire for methamphetamine.^[68]

http://www.google.com/patents/WO2006030446A1?cl=en

Scheme-3

Aripiprazole Acid addition salt

Form-A, B, C , D , E , F Type-I & Type-II Aripiprazole acid salts used for the preparation of polymorphs

…………………………….

patent expiry

………………….patent…..approved….exp

United States	5006528	1994-10-20	2014-10-20
United States	7115587	2005-01-21	2025-01-21

Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amineU.S. Patent 5,006,528

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2 (1H)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia (U.S. Pat. No. 4,74,416 and U.S. Pat. No. 5,006,528). Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. Onset of schizophrenia typically occurs between the age of 16 and 25 and affects 1 in 100 individuals worldwide. It is more prevalent, than Alzheimer’s disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome. Moreover, early therapeutic intervention can avert costly hospitalization.

Aripiprazole (Aripiprazole) is an atypical antipsychotic, on 15 November 2002 by the U.S. FDA clearance to market, its efficacy is through the dopamine D2 receptor and serotonin 5HT1A receptor partial agonist activity and serotonin 5HT2A receptor antagonism activity mediated common. With its unique mechanism of action and safety assessment, aripiprazole known as third-generation antipsychotic drugs.

[0003] Aripiprazole is a quinolinone derivative, developed by the Japanese company Otsuka Pharmaceutical, the chemical name

Is: 7 – {4 – [4 – (2,3 – dichlorophenyl)-1_ piperazinyl] butoxy} -3,4 – dihydro-quinolone, the following structural formula:

[0004]

[0005] For the preparation of aripiprazole, Japanese OtsukaPharmaceutical’s patent EP 0367141A2, and related patents US4234585, CN89108934 preparation methods described in 5. In addition, the patent CN1450056A, CN1562973A, CN1784385A, CN1680328A, CN1576273A, etc. describe some of these five Preparation

Method is very similar way. These preparation methods are direct or indirect use of 7 – hydroxy -3,4 – dihydro – quinolin-2 – one (HCS) that the key to higher prices of raw materials, and some methods involve harsh reaction conditions, poor selectivity, low yield, but also increases the cost of industrial production of the product.

[0006] Chinese patent CN1304373C preparation method is not described in the 7 – hydroxy-3 ,4 _ dihydro-2_ (1H) – quinoline

Quinolone intermediates for their preparation of the core reaction is as follows:

[0007]

[0008] This reaction is Friedel-Crafts alkylation reaction, there is a harsh reaction conditions, the yield is low, the reaction selectivity is poor, the shortcomings of high emissions, is not conducive to industrial mass production. SUMMARY OF THE INVENTION

[0009] In order to solve the above problems, the present invention provides a simple, high selectivity, high yield, low cost, environmentally friendly, easy to prepare industrialization aripiprazole and intermediates thereof.

[0010] The technical solution of the present invention, the present invention provides in one aspect a process for preparingaripiprazole novel intermediates.

[0011] The present invention, on the other hand provides a method for the preparation of intermediates.

[0012] The present invention provides the use of the other intermediates for preparing aripiprazole two new preparation methods.

[0013] Specifically, the present invention relates to novel intermediates, compounds of formula ⑴:

[0014]

[0015] wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl and other common alkyl groups in any one, and preferably is ethyl.

[0016] Compound of formula ⑴: 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate, is the following prepared by the procedure:

[0017] Step one, the acylation reaction: with 4 – methyl – 3 – nitro-phenol (VIII) and acetic anhydride as the raw material, DMAP as catalyst, to give 4 – methyl – 3 – nitrophenyl acetate ( VII).

[0018] wherein 4 – methyl – 3 – nitro-phenol (VIII), acetic anhydride, DMAP molar ratio is preferably 1: 1.0 to 1.4: 0.05, at room temperature, the reaction time is preferably 0.5 to 3 hours.

[0019] Step two, the bromination reaction: The resulting product, 4 to Step one – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide and benzoyl peroxide as a raw material , carbon tetrachloride solvent reflux, to give 4 – bromomethyl-3 – nitrophenyl acetate (VI).

[0020] wherein 4 – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide, benzoyl peroxide molar ratio is preferably 1: 1 to 1.2: 0.05, reaction time is preferably 4-18 hours.

[0021] Step three, instead of the reaction: in an appropriate solvent, adding an alkaline agent and diethyl malonate was stirred in an ice bath, was added dropwise step two the resulting product, 4 – bromomethyl-3 – nitrophenyl yl acetate (VI) solution after completion of the addition reaction of 1 to 3 hours to obtain a brown liquid product, 2 – (4_ acetoxy-2 – nitrobenzyl) malonate (V).

[0022], wherein the alkali agent is a common organic or inorganic base selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide; the solvent is selected from tetrahydrofuran, methanol, ethanol, butanol, tert-butanol, toluene or N, N-dimethylformamide; 4 – bromomethyl-3 – nitrophenyl acetate (VI), alkaline agent and lipid diethyl molar ratio is preferably 1: 1.0 to 1.8: 1.0 to 1.4.

[0023] Step 4 Hydrolysis decarboxylation: the product obtained in Step Three 2 – (4_ acetoxy-2 – nitro-benzyl)-malonic acid diethyl ester (V) was added concentrated hydrochloric acid and a suitable solvent, heating and stirring reflux, to give a yellow solid product 3 – (4_ hydroxy-2 – nitrophenyl) propionic acid (IV).

[0024] wherein the solvent is selected from water, methanol, ethanol or acetic acid, water soluble solvent, was heated with stirring under reflux time is preferably 3 to 18 hours. [0025] Step five, the esterification reaction: the product obtained in step 4, 3 – (4 – hydroxy-2 – nitrophenyl) propionic acid (IV) was added to an appropriate solvent, the mixture was stirred in an ice bath, was added dropwise thionyl sulfone, after completion of the addition reaction of 1 to 3 hours, to give a pale brown liquid product 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III).

[0026] wherein the solvent is selected from anhydrous methanol, ethanol, propanol, isopropanol, butanol, t-butanol, benzyl alcohol, alcohol and other common solvents.

[0027] Step VI substitution reaction: 1,4 – dibromobutane was added to an appropriate solvent and an alkaline reagent, heated to 50 ~ 100 ° C, the product obtained was added dropwise Step Five 3 – (4_ hydroxy – nitrophenyl) propionate (III) solution, after the addition was complete the reaction was kept 2 to 4 hours to obtain a brown liquid product 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II).

[0028] wherein the solvent is selected from methanol, 95% ethanol, ethanol, acetonitrile and N, N-dimethylformamide, and the like; said alkaline agent is a common organic or inorganic weak base, such as triethylamine, pyridine, potassium carbonate, sodium carbonate, etc..

[0029] Step 7 condensation reaction: the product obtained in Step Six 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II) adding a suitable solvent, (2,3 – dichlorophenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, to obtain

The intermediate product 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl)-piperazin-1 – yl) butoxy)-2 – nitrophenyl) propionate ⑴.

[0030] Among them, 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate (I), (2, 3 – dichloro-phenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, the four molar ratio is preferably 1: 0.9 to 1.0: 2.0 to 2.2: 0.05 to 0.5. The solvent is selected from methanol, ethanol and N, N-dimethylformamide, acetonitrile and the like. Step six of the alkaline reagent and alkaline reagent used in the same, said catalyst is a common low-iodine salts, such as sodium iodide, potassium iodide.

[0031] The present invention provides two other hand, the use of a compound of formula ⑴ preparing aripiprazole new method.

[0032] Method one: ⑴ intermediate compound of formula in an appropriate solvent in the acid or salt or a base in the presence of a reducing agent under the action of restoring ring closure reaction to obtain aripiprazole.

[0033] Method one reductive cyclization of the reducing agent used is iron, zinc, sodium sulfide, stannous chloride, and preferably iron; reaction solvent is selected from water, methanol, ethanol, ethyl acetate or in one or more of the mixed solvent; said acid is a common organic or inorganic acid, preferably acetic acid or hydrochloric acid; said salt is a common inorganic or organic salts selected from chloride, ferrous chloride, , ammonium sulfate, calcium chloride, zinc chloride, sodium chloride, sodium bromide or sodium acetate and the like; common said base is an inorganic base selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate; the reduction ring-closing reaction temperature range of 30 ~ 140 ° C, preferably about 80 ° C; reaction time ranges from about 0.5 to 8 hours, preferably 2 hours.

[0034] Method two: ⑴ intermediate compound of formula in an appropriate solvent in the first catalyst, the reduction reaction, and then carried out in a suitable solvent can be prepared by cyclization of aripiprazole.

[0035] The reduction reaction of the second approach, the reducing agent is hydrogen or a carboxylic acid; the catalyst is selected from molybdenum, molybdenum dioxide or Raney nickel, preferably Raney nickel; the solvent is selected from methanol, ethanol, ethyl acetate or acetic acid, preferably ethanol; said ring-closing reaction of the solvent is selected from N, N-dimethylformamide, trichlorobenzene or xylene; reaction temperature range of 50 ~ 180 ° C, preferably about 70 ~ 150 ° C; reaction time the range of about 1 to 8 hours.

[0036] In summary, the present invention is described for preparing aripiprazole method in 4– methyl – 3 – nitro-phenol (VIII) as a starting material, by acetylation protected hydroxy, radical instead of 4 – bromomethyl-3 – nitrophenyl acetate (VI), the diethyl malonate and a nucleophilic substitution reaction to obtain 2 – (4_ acetoxy-2 – nitrobenzyl ) malonic acid diethyl ester (V), which is decarboxylated by hydrolysis, esterification, to give 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III), the reaction product with dibromobutane an ether compounds, and with (2,3 – dichlorophenyl)-piperazine hydrochloride 1_ condensation, to give 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl) piperazine -1 – yl) butoxy) -2 – nitrophenyl) propionate (I), and then by reductive cyclization step, or first reduced and then ring-closing reaction of aripiprazole. The synthetic route of the present invention is as follows: [0037]

According to Example 1 of Japanese Unexamined Patent Publication No. 191256/1990, anhydrous aripiprazole crystals are manufactured for example by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with 1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting raw anhydrousaripiprazole with ethanol. Also, according to the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996), anhydrousaripiprazole crystals are manufactured by heating aripiprazole hydrate at 80° C. However, the anhydrous aripiprazole crystals obtained by the aforementioned methods have the disadvantage of being significantly hygroscopic.

The hygroscopicity of these crystals makes them difficult to handle since costly and burdensome measures must be taken in order ensure they are not exposed to moisture during process and formulation. Exposed to moisture, the anhydrous form can take on water and convert to a hydrous form. This presents several disadvantages. First, the hydrous forms of aripiprazole have the disadvantage of being less bioavailable and less dissoluble than the anhydrous forms ofaripiprazole. Second, the variation in the amount of hydrous versus anhydrousaripiprazole drug substance from batch to batch could fail to meet specifications set by drug regulatory agencies. Third, the milling may cause the drug substance, Conventional Anhydrous Aripiprazole, to adhere so manufacturing equipment which may further result in processing delay, increased operator involvement, increased cost, increased maintenance, and lower production yield. Fourth, in addition to problems caused by introduction of moisture during the processing of these hygroscopic crystals, the potential for absorbance of moisture during storage and handling would adversely affect the dissolubility of aripiprazole drug substance. Thus shelf-life of the product could be significantly decreased and/or packaging costs could be significantly increased. It would be highly desirable to discover a form of aripiprazole that possessed low hygroscopicity thereby facilitating pharmaceutical processing and formulation operations required for producing dosage units of an aripiprazole medicinal product having improved shelf-life, suitable dissolubility and suitable bioavailability.

Also, Proceedings of the 4 the Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) state that, anhydrous aripiprazole crystals exist as type-I crystals and type-II crystals; the type-I crystals of anhydrous aripiprazolecan be prepared by recrystallizing from an ethanol solution of aripiprazole, or by heating aripiprazole hydrate at 80° C.; and the type-II crystals of anhydrousaripiprazole can be prepared by heating the type-I crystals of anhydrousaripiprazole at 130 to 140° C. for 15 hours.

By the aforementioned methods, anhydrous aripiprazole type-II crystals having high purity can not be easily prepared in an industrial scale with good repeatability.

Chemical Synthesis of Aripiprazole (active ingredient for Abilify)

Experimental Procedures for the preparation of Aripiprazole (Abilify, aripiprazole)

US 5,006,528 discloses process for the preparation of Aripiprazole in two steps The first step comprises synthesis of 7 -. (4-bromobutoxy) -3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3, 4 -dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield The resulting 7-BBQ is further reacted with 1 -. (2,3 – dichlorophenyl)-piperazine to obtain Aripiprazole.

Preparation of 7 – (4-Bromobutoxy) 3 ,4-dihydro-2 (1H) quinolinon ( 7 – (4-Bromobutoxy) 3 ,4-dihydrocarbostyril; 7-BBQ)

7-Hydroxy-3 ,4-dihydro-2 (1H)-quinolinone (aka 7-Hydroxy-3 ,4-dihydrocarbostyril, 60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40 – 45 ° C for 24 hours Reaction mass was cooled upto room temperature and was filtered off The resulting filtrate was distilled off.. under vacuum. The resultant mass was cooled to 25-30 ° C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The . solid was filtered and dried under vacuum at 55-60 ° C for 20 hours to obtain title compound mp 110.5-111 ° C; 1H NMR (DMSO-d6) ä 1.81 (2H, m,-CH2-), 1.95 (2H , m,-CH2-), 2.41 (2H, t, J) 7 Hz,-CH2CO-), 2.78 (2H, t, J) 7 Hz,-CH2-C-CO-), 3.60 (2H, t, J) 6 Hz,-CH2Br), 3.93 (2H, t, J) 6 Hz, O-CH2-), 6.43 (1H, d, J) 2.5 Hz), 6.49 (1H, dd, J) 2.5, 8 Hz ), 7.04 (1H, d, J) 8 Hz), 9.98 (1H, s, NHCO). Anal. (C13H16NO2Br) C, H, N.

Yield: 73-75%; Purity: 93-95%

Preparation of Aripiprazole (7 – {4 – [4 – (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One)

7 – (4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30 ° C. To this potassium carbonate (67.2 gm) and l – (2,3 – dichlorophenyl). piperazine hydrochloride (44.9gm) were added under stirring The reaction mixture was refluxed at 80-85 ° C for 8 hours The reaction mass was cooled to room temperature, filtered and the resulting solid was washed. with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80 ° C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to . obtain title compound Yield: 75-80%; Dimer Impurity: <0.1% 1H NMR:. DMSO-d6 d 9.96 [1H, s, NH]; 7.29 [2H, m, Ar]; 7.13 [1H, q, Ar ]; 7.04 [1H, d, Ar]; 6.49 [1H, dd, Ar]; 6.45 [1H, d, Ar]; 3.92 [2H, t,-CH2-O-]; 2.97 [4H, bb, 2 ( -CH2-)]; 2.78 [2H, t,-CH2-N2-)]; 2.39 [4H, m, 2 (-CH2-)]; 1.73 [2H, m, – CH2-]; 1.58 [2H, m .,-CH2-] IR: cm-1 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588 .

Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water

Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85 ° C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30 ° C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 6 hours to obtain title compound.

Yield: 87-89% HPLC Purity: 99.89

Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.

Hydrate A: Below detectable limit (BDL) at limit of detection 1%.

Particle Size Distribution: d ₁₀ = 15.83 m, d ₅₀ = 60.12 m, d ₉₀ = 144.99 m

Preparation of aripiprazole anhydrous Type I using ethanol and water

Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85 ° C for 1-2 hours. The resulting mixture was cooled to 25-30 ° C within 4 hours and . stirred for 3 hours The resulting solid was filtered and dried under suction for 1 hour The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 3 hours to obtain title compound Yield:.. 90% HPLC Purity: 99.9 %

Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.

Hydrate A: Below detectable limit (BDL) at limit of detection 1%.

Particle Size Distribution: d ₁₀ = 22.01 m, d ₅₀ = 105.10 m, d ₉₀ = 232.97 m

For the Process of references Aripiprazole (Abilify, Japanese: Oh, Bldg re phi, Ann reピplastic AKZO have suitable; Chinese: Ann-law who, aripiprazole)

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi, Tatsuyoshi Tanaka, Tetsuro Kikuchi, Katsura Tottori, Yasufumi Uwahodo, and Takao Nishi; Novel Antipsychotic Agents with Dopamine autoreceptor Agonist Properties: Synthesis and Pharmacology of 7 – [4 – (4-Phenyl-1- piperazinyl) butoxy] – 3,4-dihydro-2 (1H)-quinolinone Derivatives ; J. Med Chem. 1998, 41, 658-667.

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi; Carbostyril Derivatives , Otsuka Pharmaceutical Co., Ltd.;. U.S. Patent 5006528 ; Issue Date: Apr 9, 1991

BANDO, Takuji, YANO, Katsuhiko, FUKANA, Makoto, AOKI, Satoshi; Method for producing fine particles of aripiprazole anhydride crystals b; OTSUKA PHARMACEUTICAL CO, LTD, WO 2013002420 A1..

Yuanqiu Hui, Chen Hongwen, Qian Wen, firewood rain column, Xu Dan, Yang Zhimin, Tian Zhoushan; method for preparing high purity of aripiprazole; NJCTT Pharmaceutical Co., Ltd.; application number: 201210292382.0; Publication Number: CN102863377A; Publication date: 2013.01.09 After (The invention relates to the field of medicine and chemical industry, in particular to a method for preparing high purity of aripiprazole would join aripiprazole A solvent is heated, filtered, and the filtrate was added to a solvent B, low temperature mixing, filtration, the filter cake is suspended in water, adjusted to alkaline pH of the aqueous solution, filtration, high temperature vacuum dried to obtain a high-purity refined product Aripiprazole This method is simple, high purity, suitable for the industrial the large-scale application)

ZHENG Siji, LIU Xiaoyi, FU Linyong, TAN Bo, ZHOU Min:.. ARIPIPRAZOLE MEDICAMENT FORMULATION AND PREPARATION METHOD THEREFOR / FORMULATION DE MÉDICAMENT ARIPIPRAZOLE ET SON PROCÉDÉ DE PRÉPARATION / a aripiprazole pharmaceutical formulation and preparation method SHANGHAI ZHONGXI. PHARMACEUTICAL January 2013: WO 2013/000391

Zheng Si Ji, Liu Xiaoyi, Fulin Yong, Tan Bo, Zhou Min: A aripiprazole pharmaceutical formulation and preparation method; Shanghai Pharmaceutical Co., Ltd. and Western; Publication date: 2013.01.02: Application Number: CN 201210235157.3; Publication Number: CN102846543A (the invention provides a method for preparing aripiprazole pharmaceutical formulation, comprising the steps of: an acidic solution containing aripiprazole is dissolved in the acidulant, to obtain an acidic solution containing the drug; Thereafter, the resulting drug-containing acidic solution alkalizing agents and materials prepared by wet granulation or suspension to give aripiprazole pharmaceutical formulation; said excipients include antioxidants)

Zheng Si Ji; Tan wave; Fulin Yong; Liu Xiaoyi; Yuanshao Qing; Cao Zhihui; aripiprazole Ⅰ type microcrystalline, aripiprazole solid preparation and preparation methods; application number: 201110180032.0; Publication Number: CN102850268A; Publication Date: 2013.01.02

Cai Fu Bo, Qin Xinrong, Du Xiaochun, Li Ling; kind of aripiprazole improved method of synthesis; Chengdu Nakasone Pharmaceutical Group Co., Ltd.; Application Number: 200910058148.X; Publication Number: CN101781246A; Publication date: 2010.07.21 (the invention provides a method of synthesis of aripiprazole improved method according to the modified method of the present invention, aripiprazole into the etherification reaction and condensation reaction of two-step synthesis, by an etherification reaction in the quinolone compound and at least 6-fold molar equivalents of 1,4 – dihalo-butane reacted with a non-polar solvent ether aripiprazole precipitate, and recovering 1,4 – dihalo-butane recycling; azeotropic condensation reaction of a ketone to be / water mixture as solvent, aripiprazole etherified with a piperazine compound or a salt thereof in the presence of a base under reflux and alkaline metal iodide compound conditions, the amount of water added to the end of the reaction, cooling crystallization, filtration, and dried to give aripiprazole. improved high yield synthesis of high purity, step simple, low cost, suitable for industrial production.)

GUPTA, Vijay Shankar, KUMAR, Pramod, VIR, Dharam; Process for producing aripiprazole in anhydrous type i crystals; JUBILANT LIFE SCIENCES LIMITED; WO 2012131451 A1

SRIVASTAVA JAYANT GUPTA Vijay Shankar;. Improved process for the preparation of 7 (4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole; wo2011030213 A1

No Generic Abilify in the US until April 2015

On May 7, 2012, The US Court of Appeals for the Federal Circuit ruled in favor of Otsuka Pharmaceutical Co., Ltd. In its patent litigation against several companies including Israel-based Teva and Weston, Ontario-based Apotex seeking FDA approval to market generic copies of Abilify ®.. The Federal Circuit Affirmed a Decision of the U.S. District Court for the District of New Jersey Holding that the asserted claims ofU.S. Patent No. 5,006,528 Covering aripiprazole, the active Ingredient in Abilify ®, are Valid, THUS Maintaining Patent and Regulatory Protection for Abilify ® in the U.S. until at least April 20, 2015 . The Case is Otsuka Pharma Co.. V. sand Inc.., 2011-1126 and 2011-1127, US Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, US District Court for the District of New Jersey (Trenton).

Chemical Name for Aripiprazole (Abilify for active Ingredient): 7 – {4 – [4 – (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One
CAS Number 129722 -12-9
aripiprazole chemical name 7 – [4 – [4 – (2,3 – dichlorophenyl) -1 – piperazinyl] butoxy] -3,4 – dihydro-2 ( 1H) – quinolinone

Aripiprazole (, Aripiprazole, Abilify) is an atypical antipsychotic medication for the quinoline derivatives, aripiprazole is a dopamine system stabilizer first, positive and schizophrenia negative symptoms have a significant effect. For the treatment of schizophrenia, the development of Otsuka Pharmaceutical Co., Ltd., in November 15, 2002 by the U.S. Food and Drug Administration (FDA) approval in the U.S., domestic aripiprazole has (Booz clear (brisking, manufacturers : Chengdu Nakasone Pharmaceutical), Austrian (Manufacturer: Shanghai Pharmaceutical Co., Ltd. and Western)) have been approved by the listing in China. On sale in the United States where the law by Bristol-Myers Squibb is responsible. An law where the main patent protection in the United States, and more than three-quarters of its sales from the U.S., patent will expire in April 2015.

Aripiprazole synthetic route

7 – hydroxy-3 ,4. Dihydro -2 (1H) – quinolinone as a starting material, 1,4. Dibromobutane ether to give 7 – (4 – Bromo-butoxy) -3,4 – dihydro – 2 (1H) quinolinone, and then with 1 – (2,3 – dichlorophenyl) piperazine acid condensation aripiprazole (7 – [4 – [4 – (2,3 – dichlorophenyl) -1 – piperazinyl] butoxy] -3,4 – dihydro -2 (1H) – quinolinone)

Aripiprazole preparation method

7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone
A reaction flask was added 7 – hydroxy – 3,4 – dihydro -2 (1H) – quinolone 32.6 g (0.2mol), 1,4 – dibromo butane 129.5g (0.6mol), 11.2% KOH solution 250ml (0.5mol) and DMF975ml, was heated to 60 º C for 2h diluted with 1L water, the aqueous layer with ethyl acetate. acetate (300ml × 2) and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover the solvent, the residue was recrystallized from isopropanol, to give 7 – (4 – Bromo-butoxy) – 3,4 – dihydro -2 (1H) – quinolone 38.7g, yield 68%, mp108 ~ 110 º C.

Synthesis of aripiprazole
in the reaction flask was added 7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone, 29.8g (0.1mol), KI25g (0.15mol) 95% Ethanol 596ml, stirred and heated to 60 º C, was added N-2 30min after 3 – dichlorophenyl piperazine 23.1g (0.1mol) and triethylamine 20ml (0.15mol), stirred for 8h at 60 º C the mixture is filtered. crystallization filtrate was cooled, filtered and the filter cake was recrystallized twice from ethanol and dried to obtain aripiprazole 25.6g, yield 57%, mp138.9 ~ 139.6 º C.

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External links

WO2006079548A1 *	Jan 27, 2006	Aug 3, 2006	Sandoz Ag	Organic compounds
WO2006079549A1	Jan 27, 2006	Aug 3, 2006	Sandoz Ag	Salts of aripiprazole
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EP1844036A1 *	Jan 27, 2006	Oct 17, 2007	Sandoz AG	Salts of aripiprazole
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EP2359816A1	Feb 8, 2011	Aug 24, 2011	Sanovel Ilac Sanayi ve Ticaret A.S.	Aripiprazole formulations
US7504504	Dec 16, 2004	Mar 17, 2009	Teva Pharmaceutical Industries Ltd.	Methods of preparing aripiprazole crystalline forms
US7714129	Sep 29, 2006	May 11, 2010	Teva Pharmaceutical Industries Ltd.	Methods of preparing anhydrous aripiprazole form II
US8008490	Jan 27, 2006	Aug 30, 2011	Sandoz Ag	Polymorphic forms of aripiprazole and method
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IUPAC Condensed

L-Leucine, L-asparaginyl-L-alpha-aspartyl-L-alpha-glutamyl-L-cysteinyl-L-alpha-glutamyl-L-leucyl-L- cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-, cyclic (4-&gt;12),(7-&gt;15)-bis(disulfide)

Plecanatide RN: 467426-54-6

Novel Chronic Idiopathic Constipation Drug Under FDA Review

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Approved 3/30/3016 US FDA, defibrotide sodium, (NDA) 208114

Polydeoxyribonucleotides from bovine lung or other mamalian organs with molecular weight between 15,000 and 30,000 Da

Jazz Pharmaceuticals plc announced that the FDA has accepted for filing with Priority Review its recently submitted New Drug Application (NDA) for defibrotide. AS ON OCT 2015

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L-Leucine, L-asparaginyl-L-alpha-aspartyl-L-alpha-glutamyl-L-cysteinyl-L-alpha-glutamyl-L-leucyl-L- cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-, cyclic (4->12),(7->15)-bis(disulfide)

Plecanatide
RN: 467426-54-6