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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Arbaclofen


Arbaclofen placarbil.svg

Arbaclofen placarbil

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

NDA filed

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 Rbaclofen. 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.

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
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

Arbaclofen placarbil
Arbaclofen placarbil.svg
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 Yes
ChEMBL CHEMBL2107312 Yes
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
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CADROFLOXACIN


Cadrofloxacin StructureCadrofloxacin.png

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

NDA Filed in china

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


Nolatrexed.png

Nolatrexed

NDA Filed in china

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; Rt = 11.8 min); Rf = 0.31 [ethyl acetate/(0.63 M NH3 in ethanol) = 6/4]; Mp 300−302 °C (lit.:(J. Med. Chem. 1993, 36, 733746) a tan solid; Mp 301−302 °C); MS (ESI+) m/z: 285.1 [M + 1]+; the major impurity: 3.0% (Rt = 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): 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 : 23457 · HCl1 or in part, 6 pass through a B step ( 2365 ) 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

  1. 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.
  2. “Nolatrexed”. PubChem.gov. Pub Chem. Retrieved 12 August 2014.
Nolatrexed
Nolatrexed.png
Names
IUPAC name

2-Amino-6-methyl-5-(4-pyridylthio)-1H-quinazolin-4-one
Identifiers
147149-76-6 Yes
ChemSpider 97268 
Jmol 3D model Interactive image
PubChem 108189
UNII K75ZUN743Q Yes
Properties
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


Enclomiphene citrate

NDA FILED Hypogonadism, Repros Therapeutics

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

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
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.
PATENT
PAPER
Chem Commun (London) 2015, 51(44): 9133
Chem. Commun., 2015, 51, 9133-9136
DOI: 10.1039/C5CC01968K

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, Hypogonadism, Repros Therapeutics

Plecanatide 普卡那肽 ليكاناتيد плеканатид


STR1

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

Molecular Formula: C65H104N18O26S4
Molecular Weight: 1681.88626 g/mol

Novel Chronic Idiopathic Constipation Drug Under FDA Review

Plecanatide is a once-daily, oral, uroguanylin analog
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.

RELATED: NDA Submitted for Chronic Idiopathic Constipation Drug Plecanatide

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:

Figure CN104628827AD00031

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.

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

[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.

 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 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.

 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 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.

 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.

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

OR

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

Pacritinib


 

Pacritinib skeletal.svg

Pacritinib

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

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.

 

 

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.

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.

Pacritinib.png

STR1

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.

Figure US20110263616A1-20111027-C00002

  • 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

Abstract Image

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2V617F), 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 JAK2WT and JAK2V617F, 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.

str1

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
Copyright © 2011 American Chemical Society
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

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
Pacritinib skeletal.svg
Systematic (IUPAC) name
(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.12,6.18,12]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

Map of S*Bio Pte Ltd
S*Bio Pte Ltd 
Address: 1 Science Park Rd, Singapore 117528
Phone:+65 6827 5000
Image
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.
Highlights
• Principle lead and inventor of 3 clinical stage candidates,
1) SB1518 (Pacritinib)-A selective JAK2 inhibitor for myleofibrosis into phase 2,
2) SB1317 (TG02)-A mutikinase inhibitor CDK, JAK2, FLT3, and ERK5 into phase 1 and
3) SB1578-A more selective JAK2 inhibitor than pracritinib for autoimmune diseases such as Rheumatoid Arthritis (RA) and Psoriasis into phase 1

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

///////

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

TECOVIRIMAT


Tecovirimat.svg

 

Figure US08802714-20140812-C00014

 

Tecovirimat

4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop(f)isoindol-2(1H)-yl)-benzamide

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

4 -trifluoromethyl -N- (3, 3a, 4, 4a, 5, 5a, 6, 6a- octahydro-1, 3 -dioxo-4, 6 -ethenocycloprop [f] isoindol -2 ( 1H) -yl ) – benzamide

Details

NDA FILED IN  US

2006 ORPHAN DRUG DESIGNATION IN US FOR SMALL POX

2010 ORPHAN DRUG DESIGNATION IN US FOR ORTHOPOX VIRUS

 

A core protein cysteine protease inhibitor potentially for treatment of smallpox infection.

SIGA TECHNOLOGIES INNOVATOR
SIGA-246; ST-246

CAS No. 869572-92-9

C19H15F3N2O3,

376.32921 g/mol

The Orthopox genus (Orthopoxyiridae) is a member of the Poxyiridae family and the Choropoxivirinae subfamily. The genus consists of numerous viruses that cause significant disease in human and animal populations. Viruses in the orthopox genus include cowpox, monkeypox, vaccina, and variola (smallpox), all of which can infect humans.

The smallpox (variola) virus is of particular importance. Recent concerns over the use of smallpox virus as a biological weapon has underscored the necessity of developing small molecule therapeutics that target orthopoxviruses. Variola virus is highly transmissible and causes severe disease in humans resulting in high mortality rates (Henderson et al. (1999) JAMA. 281:2127-2137). Moreover, there is precedent for use of variola virus as a biological weapon. During the French and Indian wars (1754-1765), British soldiers distributed blankets used by smallpox patients to American Indians in order to establish epidemics (Stern, E. W. and Stern A. E. 1945. The effect of smallpox on the destiny of the Amerindian. Boston). The resulting outbreaks caused 50% mortality in some Indian tribes (Stern, E. W. and Stern A. E.). More recently, the soviet government launched a program to produce highly virulent weaponized forms of variola in aerosolized suspensions (Henderson, supra). Of more concern is the observation that recombinant forms of poxvirus have been developed that have the potential of causing disease in vaccinated animals (Jackson et al. (2001) J. Virol., 75:1205-1210).

The smallpox vaccine program was terminated in 1972; thus, many individuals are no longer immune to smallpox infection. Even vaccinated individuals may no longer be fully protected, especially against highly virulent or recombinant strains of virus (Downie and McCarthy. (1958) J. Hyg. 56:479-487; Jackson, supra). Therefore, mortality rates would be high if variola virus were reintroduced into the human population either deliberately or accidentally.

Variola virus is naturally transmitted via aerosolized droplets to the respiratory mucosa where replication in lymph tissue produces asymptomatic infection that lasts 1-3 days. Virus is disseminated through the lymph to the skin where replication in the small dermal blood vessels and subsequent infection and lysis of adjacent epidermal cells produces skin lesions (Moss, B. (1990) Poxyiridae and Their Replication, 2079-2111. In B. N. Fields and D. M. Knipe (eds.), Fields Virology. Raven Press, Ltd., New York). Two forms of disease are associated with variola virus infection; variola major, the most common form of disease, which produces a 30% mortality rate and variola minor, which is less prevalent and rarely leads to death (<1%). Mortality is the result of disseminated intravascular coagulation, hypotension, and cardiovascular collapse, that can be exacerbated by clotting defects in the rare hemorrhagic type of smallpox (Moss, supra).

A recent outbreak of monkeypox virus underscores the need for developing small molecule therapeutics that target viruses in the orthpox genus. Appearance of monkeypox in the US represents an emerging infection. Monkeypox and smallpox cause similar diseases in humans, however mortality for monkeypox is lower (1%).

Vaccination is the current means for preventing orthopox virus disease, particularly smallpox disease. The smallpox vaccine was developed using attenuated strains of vaccinia virus that replicate locally and provide protective immunity against variola virus in greater than 95% of vaccinated individuals (Modlin (2001) MMWR (Morb Mort Wkly Rep) 50:1-25). Adverse advents associated with vaccination occur frequently (1:5000) and include generalized vaccinia and inadvertent transfer of vaccinia from the vaccination site. More serious complications such as encephalitis occur at a rate of 1:300,000, which is often fatal (Modlin, supra). The risk of adverse events is even more pronounced in immunocompromised individuals (Engler et al. (2002) J Allergy Clin Immunol. 110:357-365). Thus, vaccination is contraindicated for people with AIDS or allergic skin diseases (Engler et al.). While protective immunity lasts for many years, the antibody response to smallpox vaccination is significantly reduced 10 to 15 years post inoculation (Downie, supra). In addition, vaccination may not be protective against recombinant forms of ortho poxvirus. A recent study showed that recombinant forms of mousepox virus that express IL-4 cause death in vaccinated mice (Jackson, supra). Given the side effects associated with vaccination, contraindication of immunocompromised individuals, and inability to protect against recombinant strains of virus, better preventatives and/or new therapeutics for treatment of smallpox virus infection are needed.

Vaccinia virus immunoglobulin (VIG) has been used for the treatment of post-vaccination complications. VIG is an isotonic sterile solution of immunoglobulin fraction of plasma derived from individuals who received the vaccinia virus vaccine. It is used to treat eczema vaccinatum and some forms of progressive vaccinia. Since this product is available in limited quantities and difficult to obtain, it has not been indicated for use in the event of a generalized smallpox outbreak (Modlin, supra).

Cidofovir ([(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine][HPMPC]) is a nucleoside analog approved for treatment of CMV retinitis in AIDS patients. Cidofovir has been shown to have activity in vitro against a number of DNA containing viruses including adenovirus, herpesviruses, hepadnaviruses, polyomaviruses, papillomaviruses, and ortho poxviruses (Bronson et al. (1990) Adv. Exp. Med. Biol. 278:277-83; De Clercq et al. (1987) Antiviral Res. 8:261-272; de Oliveira et al. (1996) Antiviral Res. 31:165-172; Snoeck et al. (2001) Clin Infect. Dis. 33:597-602). Cidofovir has also been found to inhibit authentic variola virus replication (Smee et al. (2002) Antimicrob. Agents Chemother. 46:1329-1335).

However, cidofovir administration is associated with a number of issues. Cidofovir is poorly bioavailable and must be administered intravenously (Lalezari et al. (1997) Ann. Intern. Med. 126:257-263). Moreover, cidofovir produces dose-limiting nephrotoxicity upon intravenous administration (Lalezari et al.). In addition, cidofovir-resistance has been noted for multiple viruses. Cidofovir-resistant cowpox, monkeypox, vaccinia, and camelpox virus variants have been isolated in the laboratory by repeated passage in the presence of drug (Smee, supra). Cidofovir-resistance represents a significant limitation for use of this compound to treat orthopoxvirus replication. Thus, the poor bioavailability, need for intravenous administration, and prevalence of resistant virus underscores the need for development of additional and alternative therapies to treat orthopoxvirus infection

In addition to viral polymerase inhibitors such as cidofovir, a number of other compounds have been reported to inhibit orthopoxvirus replication (De Clercq. (2001) Clin Microbiol. Rev. 14:382-397). Historically, methisazone, the prototypical thiosemicarbazone, has been used in the prophylactic treatment of smallpox infections (Bauer et al. (1969) Am. J. Epidemiol. 90:130-145). However, this compound class has not garnered much attention since the eradication of smallpox due to generally unacceptable side effects such as severe nausea and vomiting. Mechanism of action studies suggest that methisazone interferes with translation of L genes (De Clercq (2001), supra). Like cidofovir, methisazone is a relatively non-specific antiviral compound and can inhibit a number of other viruses including adenoviruses, picornaviruses, reoviruses, arboviruses, and myxoviruses (Id.).

Another class of compounds potentially useful for the treatment of poxviruses is represented by inhibitors of S-adenosylhomocysteine hydrolase (SAH). This enzyme is responsible for the conversion of S-adenosylhomocysteine to adenosine and homocysteine, a necessary step in the methylation and maturation of viral mRNA. Inhibitors of this enzyme have shown efficacy at inhibiting vaccinia virus in vitro and in vivo (De Clercq et al. (1998) Nucleosides Nucleotides. 17:625-634.). Structurally, all active inhibitors reported to date are analogues of the nucleoside adenosine. Many are carbocyclic derivatives, exemplified by Neplanacin A and 3-Deazaneplanacin A. While these compounds have shown some efficacy in animal models, like many nucleoside analogues, they suffer from general toxicity and/or poor pharmacokinetic properties (Coulombe et al. (1995) Eur. J. Drug Metab Pharmacokinet. 20:197-202; Obara et al. (1996) J. Med. Chem. 39:3847-3852). It is unlikely that these compounds can be administered orally, and it is currently unclear whether they can act prophylactically against smallpox infections. Identification of non-nucleoside inhibitors of SAH hydrolase, and other chemically tractable variola virus genome targets that are orally bioavailable and possess desirable pharmicokinetic (PK) and absorption, distribution, metabolism, elimination (ADME) properties would be a significant improvement over the reported nucleoside analogues. In summary, currently available compounds that inhibit smallpox virus replication are generally non-specific and suffer from use limiting toxicities and/or questionable efficacies.

In U.S. Pat. No. 6,433,016 (Aug. 13, 2002) and U.S. Application Publication 2002/0193443 A1 (published Dec. 19, 2002) a series of imidodisulfamide derivatives are described as being useful for orthopox virus infections.

Synthesis 

str2

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

RAW MATERIAL

Key RM is

4,​6-​Etheno-​1H-​cycloprop[f]​isobenzofuran-​1,​3(3aH)​-​dione, 3a,​4,​4a,​5,​5a,​6-​hexahydro-​, (3aR,​4R,​4aR,​5aS,​6S,​6aS)​-​rel

cas  944-41-2, [US7655688]

SCHEMBL3192622.png

Molecular Formula: C11H10O3
Molecular Weight: 190.1953 g/mol
  • 4,6-Etheno-1H-cycloprop[f]isobenzofuran-1,3(3aH)-dione, 4,4a,5,5a,6,6a-hexahydro-, (3aα,4β,4aα,5aα,6β,6aα)-
  • Tricyclo[3.2.2.02,4]non-8-ene-6,7-dicarboxylic anhydride, stereoisomer (8CI)
  • 3,6-Cyclopropylene-Δ4-tetrahydrophthalic anhydride

MP 94-96 °C

Ref, Dong, Ming-xin; European Journal of Medicinal Chemistry 2010, V45(9), Pg 4096-4103

SMILES……….

O=C1OC(=O)[C@H]4[C@@H]1[C@H]3C=C[C@@H]4[C@@H]2C[C@@H]23

SYNTHESIS CONTINUED…….

 

ST-246

 

Patent

WO2014028545
 
 
 

The present invention provides a process for making ST-246 outlined in Scheme 1

P = Boc

Scheme 1

The present invention also provides a process for making ST-246 outlined in

Scheme 2

Scheme 2

The present invention further provides a process for making ST-246 outlined in Scheme 3

ST-246

P = Boc

Scheme 3

P = Boc

Scheme 4

The present invention further provides a process for making ST-246 outlined in

Scheme 5

Scheme 5

 

Example 1 : Synthetic Route I:

P = Boc

Scheme 1

Step A. Synthesis of Compound 6 (P = Boc)

To a mixture of compound 3 (5.0 g, 26.3 mmol, synthesized according to WO041 12718) in EtOH (80 mL, EMD, AX0441 -3) was added terf-butyl carbazate 5 (3.65 g, 27.6 mmol, Aldrich, 98%). The reaction mixture was heated to reflux for 4 h under nitrogen atmosphere. LC-MS analysis of the reaction mixture showed less than 5% of compound 3 remained. The reaction mixture was evaporated under reduced pressure. The residue was recrystallized from EtOAc – hexanes, the solid was filtered, washed with hexanes (50 mL) and dried under vacuum to afford compound 6 (3.1 g, 39% yield) as a white solid. The filtrate was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to give an additional 3.64 g (46% yield) of compound 6 as a white solid. Total yield: 6.74 g (84% yield). 1H NMR in CDCI3: δ 6.30 (br s, 1 H), 5.79 (t, 2H), 3.43 (s, 2H), 3.04 (s, 2H), 1 .46 (s, 9H), 1 .06-1 .16 (m, 2H), 0.18-0.36 (m, 2H); Mass Spec: 327.2 (M+Na)+

Step B. Synthesis of Compound 7 (HCI salt)

Compound 6 (3.6 g, 1 1 .83 mmol) was dissolved in /-PrOAc (65 mL, Aldrich, 99.6%). 4M HCI in dioxane (10.4 mL, 41 .4 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature overnight (18 h) under nitrogen atmosphere. The resulting solid was filtered, washed with /-PrOAc (15 mL) and dried under vacuum to yield HCI salt of compound 7 (1 .9 g, 67% yield) as a white solid. The filtrate was concentrated to 1/3 its volume and stirred at 10 – 15 °C for 30 min. The solid was filtered, washed with minimal volume of /-PrOAc and dried to afford additional 0.6 g (21 % yield) of compound 7. Total yield: 2.5 g (88% yield). 1 H NMR in DMSO-d6: δ 6.72 (br s, 3H), 5.68 (m, 2H), 3.20 (s, 2H), 3.01 (s, 2H), 1 .07-1 .17 (m, 2H), 0.18-0.29 (m, 1 H), -0.01 -0.07 (m, 1 H); Mass Spec: 205.1 (M+H)+

Step C. Synthesis of ST-246

To a mixture of compound 7 (0.96 g, 4 mmol) in dry dichloromethane (19 mL) was added triethylamine (1 .17 mL, 8.4 mmol, Aldrich) keeping the temperature below 20 °C. The resulting solution was stirred for 5 minutes at 15 – 20 °C, to it was added drop-wise 4-(trifluoromethyl)benzoyl chloride 8 (0.63 mL, 4.2 mmol, Aldrich, 97%) and the reaction mixture was stirred at room temperature overnight (18 h). LC-MS and TLC analysis showed the correct molecular weight and Rf value of ST-246 but the reaction was not complete. Additional 0.3 mL (2 mmol, 0.5 eq) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15 – 20 °C. The reaction was then stirred at room temperature overnight (19 h). LC-MS analysis indicated ca. 5% of starting material 7 still remained. The reaction was stopped and dichloromethane (30 mL) was added. The organic phase was washed with water (30 mL), saturated aqueous NH CI (30 mL), water (15 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 -50% EtOAc in hexanes to afford ST-246 (0.34 g, 23% yield) as an off-white solid. Analytical data (1H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent.

Example 2: Synthetic Route II

Scheme 2

Step A. Synthesis of Compound 9

A mixture of compound 4 (2.0 g, 9.8 mmol) and maleic anhydride 2 (0.96 g, 9.8 mmol, Aldrich powder, 95%) in o-xylene (100 mL, Aldrich anhydrous, 97%) was heated to reflux using a Dean-Stark trap apparatus overnight. After 18 h, LC-MS analysis at 215 nm showed the desired product 9 (86%), an uncyclized product (2.6%) and a dimer by-product (1 1 .6%).

Uncyclized product (MS = 303) Dimer by-product (MS = 489)

The reaction mixture was cooled to 45 °C and evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the insoluble solid (mostly uncyclized product) was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 50% EtOAc in hexanes to yield compound 9 (1 .5 g, 54% yield) as an off-white solid. 1 H NMR in CDCI3: δ 8.44 (s, 1 H), 7.91 (d, 2H), 7.68 (d, 2H), 6.88 (s, 2H); Mass Spec: 285.1 (M+H)+

Step B. Synthesis of ST-246 (Route II)

A mixture of compound 9 (0.97 g, 3.4 mmol) and cycloheptatriene 1 (0.51 mL, 4.42 mmol, distilled before use, Aldrich tech 90%) in toluene (50 mL, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 1 .5 h at 95 °C, LC-MS analysis at 254 nm showed 29% conversion to the desired product (endo:exo = 94:6). The resulting solution was continued to be heated at same temperature overnight. After 18 h at 95 °C, LC-MS analysis indicated 75% conversion with an endo:exo ratio of 94:6. The reaction temperature was increased to 1 10 °C and the reaction was monitored. After heating at 1 10 °C for 7 h, LC-MS analysis at 254 nm showed 96.4% conversion to the desired product (endo:exo = 94:6). The volatiles were removed by evaporation under reduced pressure and the reside was purified by column chromatography eluting with 30% EtOAc in hexanes to afford ST-246 (0.29 g, 22.6% yield, HPLC area 99.7% pure and 100% endo isomer) as a white solid. Analytical data (1H NMR, LC-MS and HPLC by co-injection) were matched with those of ST-246 synthesized according to WO041 12718 and were consistent. An additional 0.5 g of ST-246 (38.9% yield, endo:exo = 97: 3) was recovered from column chromatography. Total Yield: 0.84 g (65.4% yield). 1H NMR of ST-246 exo isomer in CDCI3: δ 8.62 (s, 1 H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1 .17 (s, 2H), 0.24 (q, 1 H), 0.13 (m, 1 H); Mass Spec: 377.1 (M+H)+

Example 3: Synthetic Route III

ST-246 9

P = Boc

Scheme 3

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (15.2 g, 155 mmol, Aldrich powder 95%) and terf-butyl carbazate 5 (20.5 g, 155 mmol, Aldrich, 98%) in anhydrous toluene (150 mL, Aldrich anhydrous) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (20% by HPLC area), imine byproduct (18%) and disubstituted by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 25% EtOAc in hexanes to afford compound 10 (5.98 g, 18% yield, HPLC area >99.5% pure) as a white solid. 1 H NMR in DMSO-d6: δ 9.61 (s, 1 H), 7.16 (s, 2H), 1 .42 (s, 9H); Mass Spec: 235.1 (M+Na)+.

duct

C9H12N204 C14H22N405

Mol. Wt.: 212.2 Mol. Wt.: 326.35

Step B. Synthesis of Compound 11 (HCI salt)

Compound 10 (3.82 g, 18 mmol) was dissolved in /-PrOAc (57 mL, Aldrich, 99.6%). 4M HCI in dioxane (15.8 mL, 63 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The solution was stirred overnight (24 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with /-PrOAc (10 mL) and dried at 45 °C under vacuum for 1 h to afford HCI salt of compound 11 (2.39 g, 89% yield) as a white solid. 1 H NMR in CD3OD: δ 6.98 (s, 2H); Mass Spec: 1 13.0 (M+H)+

Step C. Synthesis of Compound 9 (Route III)

To a mixture of compound 11 (1 .19 g, 8 mmol) in dry dichloromethane (24 mL) was added diisopropylethylannine (2.93 mL, 16.8 mmol, Aldrich redistilled grade) keeping the temperature below 20 °C. The resulting solution was stirred for 5 minute at 15 – 20 °C and to it was added 4-(trifluoromethyl)benzoyl chloride 8 (1 .31 mL, 8.8 mmol, Aldrich, 97%) drop-wise. The reaction was stirred at room temperature for 5 h. LC-MS analysis showed the correct MW but the reaction was not complete. Additional 0.48 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction mixture at 15 – 20 °C and the reaction mixture was stirred at room temperature overnight (21 h). The reaction was stopped and dichloromethane (50 mL) was added. The organic phase was washed with water (50 mL), saturated aqueous NH4CI (50 mL), water (30 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 35% EtOAc in hexanes to afford compound 9 (0.8 g, 35% yield) as a light pink solid. Analytical data (1H NMR and LC-MS) were consistent with those of compound 9 obtained in Synthetic Route II.

Step D. Synthesis of ST-246 (Route III)

A mixture of compound 9 (0.5 g, 1 .76 mmol) and cycloheptatriene 1 (0.33 mL, 3.17 mmol, distilled before to use, Aldrich tech 90%) in toluene (10 mL, Aldrich anhydrous) was heated at 1 10 – 1 15 °C under nitrogen atmosphere. After 6 h, LC-MS analysis at 254 nm showed 95% conversion to the desired product (endo:exo = 94:6). The resulting solution was heated at same temperature overnight (22 h). LC-MS analysis at 254 nm showed no starting material 9 remained and the desired product (endo:exo = 93:7). The reaction mixture was concentrated and purified by column chromatography eluting with 25 – 35% EtOAc in hexanes to afford ST-246 (0.39 g, HPLC area >99.5% pure with a ratio of endo:exo = 99:1 ) as a white solid. Analytical data (1 H NMR, LC-MS and HPLC by co-injection) were compared with those of ST-246 synthesized according to WO041 12718 and were found to be consistent. An additional 0.18 g of ST-246 (HPLC area >99.5% pure, endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 0.57 g (86% yield).

Example 4 ; Synthetic Route IV:

P = Boc

Scheme 4

Step A. Synthesis of Compound 10

A mixture of maleic anhydride 2 (3.4 g, 34.67 mmol, Aldrich powder, 95%) and terf-butyl carbazate 5 (4.6 g, 34.67 mmol, Aldrich, 98%) in anhydrous toluene (51 ml_, Aldrich) was heated to reflux using a Dean-Stark trap apparatus under nitrogen atmosphere. After refluxing for 2.5 h, no starting material 2 remained and LC-MS analysis at 254 nm showed the desired product 10 (19% HPLC area), imine by-product (18%) and another by-product (56%). The reaction mixture was concentrated and purified by column chromatography eluting with 30% EtOAc in hexanes to afford compound 10 (1 .0 g, 13.6% yield, HPLC area >99% pure) as a white solid. Analytical data (1H NMR and LC-MS) were consistent with those of compound 10 obtained in Synthetic Route III.

Im ine by-product

Mol. Wt.: 212.2

Step B. Synthesis of Compound 6

A mixture of compound 10 (4.4 g, 20.74 mmol) and cycloheptatriene 1 (3.22 mL, 31 .1 mmol, distilled before to use, Aldrich tech 90%) in toluene (88 mL, 20 volume, Aldrich anhydrous) was heated at 95 °C under nitrogen atmosphere. After 15 h at 95 °C, LC-MS analysis showed 83% conversion to the desired product. The reaction mixture was heated at 105 °C overnight. After total 40 h at 95 – 105 °C, LC-MS analysis at 254 nm showed -99% conversion to the desired product (endo:exo = 93:7). The reaction mixture was concentrated and the crude was purified by column chromatography eluting with 25 – 50 % EtOAc in hexanes to afford compound 6 (2.06 g, 32.6% yield, HPLC area 99.9% pure and 100% endo isomer) as a white solid. 1 H NMR and LC-MS were consistent with those of compound 6 obtained in Synthetic Route I. An additional 4.0 g of 6 (63.4% yield, HPLC area 93% pure with a ratio of endo:exo = 91 : 9) was recovered from column chromatography. Total Yield: 6.06 g (96% yield).

Step C. Synthesis of Compound 7 (HCI salt)

Compound 6 (2.05 g, 6.74 mmol) was dissolved in /-PrOAc (26 mL, Aldrich, 99.6%). 4M HCI in dioxane (5.9 mL, 23.58 mmol, Aldrich) was added drop-wise to the above solution keeping the temperature below 20 °C. The solution was stirred overnight (18 h) at room temperature under nitrogen atmosphere. The resulting solid was filtered, washed with /-PrOAc (5 mL) and dried under vacuum to yield HCI salt of compound 7 (1 .57 g, 97% yield) as a white solid. Analytical data (1 H NMR and LC-MS) were consistent with those of compound 7 in Synthetic Route I.

Step D. Synthesis of ST-246 (Route IV)

To a mixture of compound 7 (0.84 g, 3.5 mmol) in dichloromethane (13 mL) was added diisopropylethylamine (1 .34 mL, 7.7 mmol) keeping the temperature below 20 °C and the resulting solution was stirred for 5 – 10 minutes. 4-(Trifluoromethyl)benzoyl chloride 8 (0.57 mL, 3.85 mmol, Aldrich, 97%) was added to above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature for 2 h. Additional 0.2 mL (0.4 equiv) of 4-(trifluoromethyl)benzoyl chloride 8 was added to the reaction keeping the temperature below 20 °C. The reaction was stirred at room temperature overnight (24 h). The reaction mixture was diluted with dichloromethane (20 mL). The organic phase was washed with water (20 mL), saturated aqueous NH4CI (20 mL), water (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 30 – 35% EtOAc in hexanes to afford ST-246 (0.25 g, 19% yield, HPLC area >99.5% pure) as a white solid. Analytical data (1H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

Example 5: Synthetic Route V:

Scheme 5

Step A. Synthesis of Compound 13

To a mixture of compound 7 (1 .6 g, 6.65 mmol, synthesized according to Synthetic Route I) in dichloromethane (80 ml_,) was added triethylamine (2.04 ml_, 14.63 mmol) keeping the temperature below 20 °C and the resulting solution was stirred for 5 – 10 minute. 4-lodobenzoyl chloride 12 (1 .95 g, 7.31 mmol, 1 .1 equiv, Aldrich) was added portion-wise under nitrogen atmosphere to the above solution keeping the temperature below 20 °C. The reaction mixture was stirred at room temperature overnight. After 17 h and 19 h, additional 0.35 g (0.2 equiv) of acid chloride 12 was added to the reaction keeping the temperature below 20 °C. After 24 h, additional 0.18 g (0.1 equiv, used total 1 .6 equiv) of acid chloride 12 was added and the reaction was continued to stir at room temperature overnight (total 43 h). LC-MS analysis at 215 nm showed 43% of the desired product (13) and -5% of compound 7. The reaction was diluted with dichloromethane (100 ml_). The organic phase was washed with saturated aqueous NH4CI (100 ml_), water (100 ml_) and saturated aqueous NaHCO3 (100 ml_). The organic phase was separated, dried over Na2SO4, filtered and concentrated to give crude product. The crude product was purified by column chromatography eluting with 25 – 50% EtOAc in hexanes to afford compound 13 (1 .63 g, 57% yield, HPLC area 93% pure) as a white solid. 1 H NMR in DMSO-d6: δ 1 1 .19 and 10.93 (two singlets with integration ratio of 1 .73:1 , total of 1 H, same proton of two rotamers), 7.93 (d, 2H), 7.66 (d, 2H), 5.80 (s, 2H), 3.36 (s, 2H), 3.27 (s, 2H), 1 .18 (s, 2H), 0.27 (q, 1 H), 0.06 (s,1 H); Mass Spec: 435.0 (M+H)+

Step B. Synthesis of ST-246 (Route V)

Anhydrous DMF (6 ml_) was added to a mixture of compound 13 (0.2 g, 0.46 mmol), methyl 2, 2-difluoro-2-(fluorosulfonyl)acetate (0.44 ml_, 3.45 mmol, Aldrich) and copper (I) iodide (90 mg, 0.47 mmol). The reaction mixture was stirred at -90 °C for 4 h. LC-MS analysis at 254 nm indicated no starting material 13 remained and showed 48% HPLC area of ST-246. The reaction mixture was cooled to 45 °C and DMF was removed under reduced pressure. The residue was slurried in EtOAc (30 mL) and insoluble solid was removed by filtration. The filtrate was concentrated and purified by column chromatography eluting with 25 – 35% EtOAc in hexanes to afford ST-246 (55

mg, 32% yield, 95% pure by HPLC at 254 nm) as off-white solid. Analytical data (1H NMR and LC-MS) were consistent with those of ST-246 synthesized according to WO041 12718.

PAPER

N-(3,3a,4,4a,5,5a,6,6a-Octahydro-1,3-dioxo-4,6- ethenocycloprop[f]isoindol-2-(1H)-yl)carboxamides:  Identification of Novel Orthopoxvirus Egress Inhibitors

ViroPharma Incorporated, 397 Eagleview Boulevard, Exton, Pennsylvania 19341, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, Maryland 21702, University of Alabama, Birmingham, Alabama 35294, and SIGA Technologies, Inc., 4575 SW Research Way, Corvallis, Oregon 97333

J. Med. Chem.200750 (7), pp 1442–1444

DOI: 10.1021/jm061484y

Abstract Image

A series of novel, potent orthopoxvirus egress inhibitors was identified during high-throughput screening of the ViroPharma small molecule collection. Using structure−activity relationship information inferred from early hits, several compounds were synthesized, and compound 14was identified as a potent, orally bioavailable first-in-class inhibitor of orthopoxvirus egress from infected cells. Compound 14 has shown comparable efficaciousness in three murine orthopoxvirus models and has entered Phase I clinical trials.

http://pubs.acs.org/doi/suppl/10.1021/jm061484y/suppl_file/jm061484ysi20070204_060607.pdf

General Procedure for synthesis of compounds 2-14, 16-18.

N-(3,3a,4,4a,5,5a,6,6aoctahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-4- (trifluoromethyl)benzamide (14).

A mixture of 2.00 g (9.8 mmol) of 4-(trifluoromethyl) benzoic acid hydrazide, 1.86 g (9.8 mmol) of 4,4a,5,5a,6,6a-hexahydro-4,6-etheno-1Hcycloprop[f]isobenzofuran-1,3(3aH)-dione, and one drop of diisopropylethylamine in 40 mL of absolute ethanol was refluxed for 4.5 h. Upon cooling to rt, 4 mL of water was added, and the product began to crystallize. The suspension was cooled in an ice bath, and the precipitate collected by filtration. The crystalline solid was air-dried affording 3.20 g (87%) of the product as a white solid;

Mp 194-195 ºC. 1 H NMR, (300 MHz, d6 -DMSO) δ 11.20, 11.09 (2 brs from rotamers, 1H), 8.06 (d, J= 7.8 Hz, 2H), 7.90 (d, J= 7.8 Hz, 2H), 5.78 (m, 2H), 3.26 (m, 4H), 1.15 (m, 2H), 0.24 (dd, J= 7.2, 12.9 Hz, 1H), 0.04 (m, 1H).

Anal. calcd. for C19H15F3N2O3● 0.25H2O: %C, 59.92; %H, 4.10; %F, 14.97; %N, 7.36; %O, 13.65. Found: %C, 59.97; %H, 4.02; %F, 14.94; %N, 7.36; %O, 13.71.

 

 

 

 

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Example 1

Preparation of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide

 

a. Preparation of Compounds 1(a) and 1(b).

 

note……………

1a is  desired

1b not desired

A mixture of cycloheptatriene (5 g, 54.26 mmol) and maleic anhydride (6.13 g, 62.40 mmol) in xylenes (35 mL) was heated at reflux under argon overnight. The reaction was cooled to room temperature and a tan precipitate was collected by filtration and dried to give 2.94 grams (28%) of the desired product, which is a mixture of compounds 1(a) and 1(b). Compound 1(a) is normally predominant in this mixture and is at least 80% by weight. The purity of Compound 1(a) may be further enhanced by recrystallization if necessary. Compound 1(b), an isomer of compound 1(a) is normally less than 20% by weight and varies depending on the conditions of the reaction. Pure Compound 1(b) was obtained by concentrating the mother liquid to dryness and then subjecting the residue to column chromatography. Further purification can be carried out by recrystallization if necessary. 1H NMR (500 MHz) in CDCl3: δ 5.95 (m, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 1.12 (m, 2H), 0.22 (m, 1H), 0.14 (m, 1H).

b. Preparation of N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. desired

A mixture of compound 1(a) (150 mg, 0.788 mmol) and 4-trifluoromethylbenzhydrazide (169 mg, 0.827 mmol) in ethanol (10 mL) was heated under argon overnight. The solvent was removed by rotary evaporation. Purification by column chromatography on silica gel using 1/1 hexane/ethyl acetate provided 152 mg (51%) of the product as a white solid.

c. Preparation of N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide. UNWANTED

N-[(3aR,4S,4aS,5aR,6R,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]4-(trifluoromethyl)-benzamide was prepared and purified in the same fashion as for N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide by replacing 1(a) with 1(b) and was obtained as a white solid. 1H NMR (300 MHz) in CDCl3: δ 8.62 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 5.96 (m, 2H), 3.43 (s, 2H), 2.88 (s, 2H), 1.17 (s, 2H), 0.24 (q, 1H), 0.13 (m, 1H); Mass Spec: 377.1 (M+H)+.

 

FINAL COMPD SYNTHESIS

TABLE 1
Example **Mass
Number R6 *NMR Spec Name
 1 1H NMR in DMSO-d6: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H) 375 (M − H)− N-[(3aR,4R,4aR,5aS,6S, 6aS)-3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6-ethenocycloprop[f] isoindol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

 

TABLE 1 EXAMPLE 1

N- [(3aR,4R,4aR,5aS,6S, 6aS)- 3,3a,4,4a,5,5a,6,6a- octahydro-1,3-dioxo- 4,6- ethenocycloprop[f]iso- indol-2(1H)-yl]-4- (trifluoromethyl)- benzamide

1H NMR in DMSO-d6: δ 11.35 (d, 1H); 11.09 (d, 1H); 8.08 (d, 2H); 7.92 (d, 2H); 5.799 (s, 2H); 3.29 (brs, 4H); 1.17 (m, 2H); 0.26 (m, 1H); 0.078 (s, 1H), 375 (M − H)

EXAMPLE 42 Characterization of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide (“ ”)

In the present application, ST-246 refers to: N-[(3aR,4R,4aR,5aS,65,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide.

Physico-Chemical Properties

Appearance: ST-246 is a white to off-white powder.

Melting Point: Approximately 196° C. by DSC.

Permeability: The calculated log P is 2.94. Based on the partition coefficient, ST-246 is expected to have good permeability.

Particle Size: The drug substance is micronized to improve its dissolution in the gastrointestinal fluids. The typical particle size of the micronized material is 50% less than 5 microns.

Solubility: The solubility of ST-246 is low in water (0.026 mg/mL) and buffers of the gastric pH range. Surfactant increases its solubility slightly. ST-246 is very soluble in organic solvents. The solubility data are given in Table 5.

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Tecovirimat (ST-246) is an antiviral with activity against orthopoxviruses such as smallpox and is currently undergoing clinical trials. It was previously owned by Viropharma and discovered in collaboration with scientists at USAMRIID. It is currently owned and is synthesized by Siga Technologies, a drug development company in the biodefense arena. It works by blocking cellular transmission of the virus, thus preventing the disease. Tecovirimat has been effective in laboratory testing, with no serious side effects reported to date. Despite not yet having FDA approval for medical use, tecovirimat is stockpiled in the US Strategic National Stockpile as a defense against a smallpox outbreak.[1]

Clinical study

The results of clinical trials involving tecovirimat supports its use against smallpox and other related orthopoxviruses. It has shown potential for a variety of uses including prophylaxis, as a post-exposure therapeutic, as a therapeutic and an adjunct to vaccination.[2]

Tecovirimat can be taken orally and has recently been granted permission to conduct Phase II trials by the U.S. Food and Drug Administration (FDA). In phase I trials tecovirimat was generally well tolerated with no serious adverse events.[3] Due to its importance for biodefense, the FDA has designated tecovirimat for ‘fast-track’ status, creating a path for expedited FDA review and eventual regulatory approval.

Tecovirimat is an orthopoxvirus egress inhibitor. Tecovirimat appears to target the V061 gene in cowpox, which is homologous to the vaccinia virus F13L. By targeting this gene, tecovirimat inhibits the function of a major envelope protein required for the production of extracellar virus. Thus the virus is prevented from leaving the cell, and the spread of the virus within the body is prevented.[4]

 

References

  1. Damon, Inger K.; Damaso, Clarissa R.; McFadden, Grant (2014). “Are We There Yet? The Smallpox Research Agenda Using Variola Virus”. PLoS Pathogens 10 (5): e1004108.doi:10.1371/journal.ppat.1004108PMID 24789223.
  2. Siga Technologies
  3. Jordan, R; Tien, D; Bolken, T. C.; Jones, K. F.; Tyavanagimatt, S. R.; Strasser, J; Frimm, A; Corrado, M. L.; Strome, P. G.; Hruby, D. E. (2008). “Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor”Antimicrobial Agents and Chemotherapy 52 (5): 1721–1727. doi:10.1128/AAC.01303-07PMC 2346641PMID 18316519.
  4. Yang, G; Pevear, D. C.; Davies, M. H.; Collett, M. S.; Bailey, T; Rippen, S; Barone, L; Burns, C; Rhodes, G; Tohan, S; Huggins, J. W.; Baker, R. O.; Buller, R. L.; Touchette, E; Waller, K; Schriewer, J; Neyts, J; Declercq, E; Jones, K; Hruby, D; Jordan, R (2005). “An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge”Journal of Virology 79 (20): 13139–13149. doi:10.1128/JVI.79.20.13139-13149.2005PMC 1235851PMID 16189015.

 

Referenced by
Citing Patent Filing date Publication date Applicant Title
CN101912389A * Aug 9, 2010 Dec 15, 2010 中国人民解放军军事医学科学院微生物流行病研究所 Pharmaceutical composition containing ST-246 and preparation method and application thereof
CN102406617A * Nov 30, 2011 Apr 11, 2012 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN102406617B Nov 30, 2011 Aug 28, 2013 中国人民解放军军事医学科学院生物工程研究所 Tecovirimat dry suspension and preparation method thereof
CN103068232B * Mar 23, 2011 Aug 26, 2015 西佳科技股份有限公司 多晶型物形式st-246和制备方法
US8530509 Jul 29, 2011 Sep 10, 2013 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US8802714 Aug 14, 2013 Aug 12, 2014 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US9045418 Jul 3, 2014 Jun 2, 2015 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of Orthopoxvirus infections and associated diseases

Patent Citations
Cited Patent Filing date Publication date Applicant Title
US20070287735 * Apr 23, 2007 Dec 13, 2007 Siga Technologies, Inc. Chemicals, compositions, and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US20090011037 * Apr 23, 2008 Jan 8, 2009 Cydex Pharmaceuticals, Inc. Sulfoalkyl Ether Cyclodextrin Compositions and Methods of Preparation Thereof
US8530509 Jul 29, 2011 Sep 10, 2013 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US8802714 Aug 14, 2013 Aug 12, 2014 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US9045418 Jul 3, 2014 Jun 2, 2015 Siga Technologies, Inc. Compounds, compositions and methods for treatment and prevention of Orthopoxvirus infections and associated diseases

 

Classifications
Tecovirimat
Tecovirimat.svg
Systematic (IUPAC) name

N-{3,5-Dioxo-4- azatetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-en-4- yl}-4-(trifluoromethyl)benzamide

Identifiers
UNII F925RR824R Yes
ChEMBL CHEMBL1242629 Yes
Synonyms ST-246
Chemical data
Formula C19H15F3N2O3
Molecular mass base: 376.3 g/mol

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

FC(F)(F)c1ccc(cc1)C(=O)NN1C(=O)C2C(C3C=CC2C2CC32)C1=O

Lixivaptan


Lixivaptan structure.svg

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

 CAS 168079-32-1

MW 473.9,

 MF C27H21ClFN3O2

NDA Filing

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]

Lixivaptan rx.png

 

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
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.

 

Figure CN103694240AD00041

The chemical structure:

 

Figure CN103694240AD00042

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:

 

Figure CN103694240AD00071

  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.

Figure CN103694240AD00072

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
Lixivaptan.png

References

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
Lixivaptan structure.svg
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 Yes
ChEMBL CHEMBL49429 
Chemical data
Formula C27H21ClFN3O2
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
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


Iptakalim Hydrochloride  盐酸埃他卡林

NDA Filed china

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)

str1

 str1

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 (KATP) channel opener. KATP channels are composed of discrete pore-forming inward rectifier subunits (Kir6.1s) and regulatory sulphonylurea subunits (SUR).IPT shows high selectivity for cardiac KATP (SUR2A/Kir6.2) and vascular KATP (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 N2 and 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


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.

str1

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

  1.  “Jazz Pharma Acquiring Gentium for $1B”. Gen. Eng. Biotechnol. News (paper) 34 (2). January 15, 2014. p. 10.
  2.  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.
  3.  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

WO2003101468A1 * Jun 2, 2003 Dec 11, 2003 Guenther Eissner Method for the protection of endothelial and epithelial cells during chemotherapy
US4985552 Jul 5, 1989 Jan 15, 1991 Crinos Industria Farmacobiologica S.P.A. Process for obtaining chemically defined and reproducible polydeoxyribonucleotides
US5223609 May 26, 1992 Jun 29, 1993 Crinos Industria Farmacobiologica S.P.A. Process for obtaining chemically defined and reproducible polydeoxyribonucleotides
Cited Patent Filing date Publication date Applicant Title
WO1999026639A1 * 24 Nov 1998 3 Jun 1999 Allegheny University Of The He Methods for mobilizing hematopoietic facilitating cells and hematopoietic stem cells into the peripheral blood
EP0317766A1 * 20 Oct 1988 31 May 1989 Crinos Industria Farmacobiologica S.p.A. A method for preventing blood coaguli from being formed in the extra-body circuit of dialysis apparatus and composition useful thereof
EP0416678A1 * 10 Aug 1990 13 Mar 1991 Crinos Industria Farmacobiologica S.p.A. Topical compositions containing Defibrotide
US5199942 * 26 Sep 1991 6 Apr 1993 Immunex Corporation Method for improving autologous transplantation
US5977083 * 5 Jun 1995 2 Nov 1999 Burcoglu; Arsinur Method for using polynucleotides, oligonucleotides and derivatives thereof to treat various disease states
Reference
1 * CARLO-STELLA, C. (1) ET AL: “Defibrotide significantly enhances peripheral blood progenitor cell mobilization induced by recombinant human granulocyte colony – stimulating factor ( rhG – CSF.” BLOOD, ( NOVEMBER 16, 2000 ) VOL. 96, NO. 11 PART 1, PP. 553A. PRINT. MEETING INFO.: 42ND ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY SAN FRANCISCO, CALIFORNIA, USA DECEMBER 01-05, 2000 AMERICAN SOCIETY OF HEMATOLOGY. , XP002176349
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
Citing Patent Filing date Publication date Applicant Title
WO2005017160A2 * 12 Aug 2004 24 Feb 2005 Childrens Hosp Medical Center Mobilization of hematopoietic cells
WO2009115465A1 * 13 Mar 2009 24 Sep 2009 Gentium Spa Synthetic phosphodiester oligonucleotides and therapeutical uses thereof
EP2103689A1 * 19 Mar 2008 23 Sep 2009 Gentium S.p.A. Synthetic phosphodiester oligonucleotides and therapeutical uses thereof
US7417026 12 Aug 2004 26 Aug 2008 Children’s Hospital Medical Center Mobilization of hematopoietic cells
US7915384 5 Jan 2009 29 Mar 2011 Children’s Hospital Medical Center Chimeric peptides for the regulation of GTPases
US8242246 28 Feb 2011 14 Aug 2012 Children’s Hospital Medical Center Chimeric peptides for the regulation of GTPases
US8674075 13 Aug 2012 18 Mar 2014 Children’s Medical Center Corporation Chimeric peptides for the regulation of GTPases
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 Yes
ATC code B01AX01
DrugBank DB04932 Yes
UNII 438HCF2X0M Yes
KEGG D07423 Yes

///////////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

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