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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 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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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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

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Pemafibrate, Пемафибрат , بيرمافيبرات , 佩玛贝特 , ペマフィブラート ,


 

 

img

Pemafibrate

NDA Filing Japan, Phase 2 in EU, US

A PPAR-α agonist potentially for the treatment of dyslipidemia.

K-877, K-13675, (R)-

CAS No. 848259-27-8,

Molecular Formula,C28-H30-N2-O6,Molecular Weight,490.553

(2R)-2-[3-({(1,3-benzoxazol-2-yl)[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid
(R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid
  • Originator Kowa Pharmaceutical
  • Class Antihyperlipidaemics
  • Mechanism of Action Peroxisome proliferator-activated receptor alpha agonists
  • Preregistration Dyslipidaemias

Most Recent Events

  • 01 Feb 2016 Kowa Research Institute completes a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)
  • 12 Jan 2016 Kowa Research Institute plans the phase III PROMINENT trial for Dyslipidaemia (In patients with diabetes mellitus) in countries worldwide
  • 01 Jan 2016 Kowa Research Institute initiates a phase I drug-interaction trial in Healthy volunteers in USA (PO) (NCT02719431)

UPDATE ADDED  ON MARCH 2017

Pemafibrate.svg

ChemSpider 2D Image | pemafibrate | C28H30N2O6

Pemafibrate

  • Molecular FormulaC28H30N2O6
  • Average mass490.548 Da
Пемафибрат [Russian] [INN]
بيرمافيبرات [Arabic] [INN]
佩玛贝特 [Chinese] [INN]
ペマフィブラート
(2R)-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butyric acid
(R)-2-(3-((benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butanoic acid
848259-27-8 [RN]
CHEMBL247951
K-13675, (R)-
UNII:17VGG92R23
(2R)-2-[3-({1,3-Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid
Butanoic acid, 2-[3-[[2-benzoxazolyl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]-, (2R)-
Parmodia (TN)
Antihyperlipidemic, Triglyceride synthesis inhibitor, Peroxisome proliferator-activated receptor (PPAR) alpha agonist

Pemafibrate, marketed as Parmodia, is a peroxisome proliferator-activated receptor alpha (PPARα) agonist. It is developed and marketed by Kowa Pharmaceuticals.

In 3 July 2017, Pharmaceuticals and Medical Devices Agency approved it in Japan. It is available in 0.1 mg tablets.[1]

References

  1.  Pemafibrate, pharmacodia.com
ペマフィブラート
Pemafibrate

C28H30N2O6 : 490.55
[848259-27-8]
Pemafibrate
Pemafibrate.svg
Clinical data
Trade names Parmodia
Synonyms K-13675
Routes of
administration
Oral
Identifiers
CAS Number
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C28H30N2O6
Molar mass 490.56 g·mol−1
3D model (JSmol)

////////////Pemafibrate, Пемафибрат بيرمافيبرات 佩玛贝特 ,  ペマフィブラート , 

 

Pemafibrate, also known as K-877 and (R)-K 13675, is a PPAR alpha agonist. (R)-K-13675 decreases the secretion of inflammatory markers without affecting cell proliferation or tube formation. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and has been implicated in inflammation. (R)-K-13675 was associated with the inhibition of inflammatory responses without affecting cell proliferation or angiogenesis, and subsequently may induce an anti-atherosclerotic effect.

Pemafibrate had been filed NDA by Kowa for the treatment of dyslipidemia in the Japan in 2015.

Pemafibrate is in phase II clinical trials for the treatment of dyslipidemia in the US and EU.

 

 

Route 1
str6

Reference:1. US2009023944A1.

Route 2
str6

Reference:1. US2009076280A1.

http://www.google.com/patents/US20090076280

Example 5 Synthesis of (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butyric acid (Compound (6))

  • Ethyl (R)-2-{3-[N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenyloxy}butylate (26.0 g) was dissolved in ethanol (200 mL), and 1.5N NaOH (50 mL) was added to the solution, followed by stirring for 1 hour at room temperature. The reaction mixture was washed with diethyl ether, and the formed aqueous layer was acidified with 4N HCl under ice cooling. The thus-treated aqueous layer was extracted with ethyl acetate, and the extract was washed sequentially with water and saturated brine. The washed extract was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol=10/1), to thereby yield the target product (21.3 g, 87%, 98% ee).

Optical Purity:

  • Measurement conditions: HPLC
  • Column: CHIRALPAK AD
  • Solvent: n-hexane/IPA/TFA=100/30/0.1
  • Flow rate: 2 mL/min
  • Retention time: 4.19 min (S-form; 3.68 min)
  • 1H-NMR (400 MHz, CD3OD) δ ppm: 0.94 (t, J=7 Hz, 3H), 1.81 (m, 2H), 1.99 (quintet, J=6 Hz, 2H), 3.60 (t, J=7 Hz, 2H), 3.61 (s, 3H), 3.85 (t, J=6 Hz, 2H), 4.40 (t, J=6 Hz, 1H), 4.65 (s, 2H), 6.69-6.80 (m, 7H), 6.91 (dt, J=7, 1 Hz, 1H), 7.05 (dt, J=7, 1 Hz, 1H), 7.12-7.18 (m, 4H).

 

Route 3
str6

Reference:1. Bioorg. Med. Chem. Lett. 200717, 4689-4693.

 

Landmark Trial Entitled “PROMINENT” To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C

Trial will evaluate if lowering triglycerides and increasing functional HDL with Kowa’s potent selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator, K-877 (pemafibrate) can reduce the elevated risk of cardiovascular disease in high-risk diabetic patients who are already taking statins

Jan 12, 2016, 09:00 ET from Kowa Research Institute, Inc.

RESEARCH TRIANGLE PARK, N.C., Jan. 12, 2016 /PRNewswire/ — Kowa Research Institute, Inc., announced plans to conduct an international, multi-center cardiovascular outcomes trial evaluating triglyceride reduction and increasing functional HDL with K-877 (pemafibrate), in high-risk diabetic patients with high triglyceride and low HDL-C levels who are already taking statins.  K-877 is a highly potent and selective peroxisome proliferator activator receptor-alpha (PPAR-alpha) modulator (SPPARMalpha), a promising category of metabolic therapy.

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention (CCVDP) at Brigham and Women’s Hospital (BWH), a teaching affiliate of Harvard Medical School, and Aruna Pradhan, MD, a cardiologist at BWH, will be co-Principal Investigators of the planned trial.

“This trial is unprecedented,” said Gary Gordon, MD, President, Kowa Research Institute, Inc. “Statins are effective in lowering cardiovascular risk among patients with high cholesterol, but residual risk remains, particularly in patients with high triglyceride levels and low HDL-C levels.  Kowa will be the first company to run a major, randomized clinical trial investigating whether modulating PPAR-alpha to lower triglycerides and increase functional HDL in diabetic patients can reduce cardiovascular risk when added to statin therapy.”

Evidence supports a role for triglyceride-rich lipoproteins and low HDL-C as important contributors to atherosclerosis.  Kowa specifically set out to create the most potent and selective PPAR-alpha modulator ever developed, and succeeded with K-877, which is at least 1,000 times as potent and selective as other drugs.  Kowa has completed clinical development of K-877 for hyperlipidemia in Japan, and has submitted it to the PMDA for approval as a new drug.  Kowa’s clinical studies have shown K-877 significantly reduces triglycerides, ApoC3, and remnant cholesterol and increases functional HDL and FGF21.

The Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs (PROMINENT) Phase 3 K-877 cardiovascular outcomes trial will recruit an estimated 10,000 high-risk diabetic patients worldwide.  All participants will receive aggressive, standard of care management of cardiovascular risk factors including treatment with high-intensity statins.  In addition, patients will receive either K-877 or placebo.  The trial will include diabetic patients with and without established cardiovascular disease and will test whether K-877 reduces the occurrence of heart attacks, hospitalizations for unstable angina requiring unplanned revascularization, stroke, or death from cardiovascular causes.

“Cardiovascular disease remains the number one cause of death worldwide,” said Dr. Gordon.  “Reducing residual cardiovascular risk with K-877 would be valuable to physicians managing patients’ cardiovascular disease.”

About Kowa Company, Ltd. and Kowa Research Institute, Inc.
Kowa Company, Ltd. (Kowa) is a privately held multinational company headquartered in Nagoya, Japan. Established in 1894, Kowa is actively engaged in various manufacturing and trading activities in the fields of pharmaceuticals, life science, information technology, textiles, machinery and various consumer products. Kowa’s pharmaceutical division is focused on research and development for cardiovascular therapeutics (dyslipidemia, type 2 diabetes and atherosclerosis), ophthalmology and anti-inflammatory agents. The company’s flagship product, LIVALO® (pitavastatin), is approved in 45 countries around the world.

Kowa Research Institute, Inc., headquartered in Research Triangle Park, NC, is the division of Kowa responsible for the clinical development of Kowa’s new drugs in the United States. Kowa Research Institute was established in 1997 in California and began operations at the current location in 2003.  For more information about Kowa Research Institute, visit www.kowaus.com.

1 NCT00610441 Dose Finding Study in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)(174007/P05805/MK-8777-003) Completed Drug: MK-8777|Drug: Placebo Phase 2 Merck Sharp & Dohme Corp.
2 NCT00610649 Trial to Determine the Maximum Tolerated Dose (MTD) Based on Safety and Tolerability, of Org 26576 in Participants With Major Depressive Disorder (174001/P05704/MK-8777-001) Completed Drug: MK-8777|Drug: Placebo Phase 2 Merck Sharp & Dohme Corp.
3 NCT02073084 A Thorough Corrected QT Interval Trial Completed Drug: K-877 Low Dose|Drug: Moxifloxacin|Other: Placebo|Drug: K-877 High Dose Phase 1 Kowa Research Institute, Inc.
4 NCT02273986 Drug-Drug Interaction Study in Health Adult Volunteers Completed Drug: Digoxin|Drug: K-877 Phase 1 Kowa Research Institute, Inc.
5 NCT02275962 Drug-Drug Interaction Study in Healthy Adult Volunteers Active, not recruiting Drug: K-877|Drug: Rifampin Phase 1 Kowa Research Institute, Inc.
6 NCT02275975 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Fluconazole Phase 1 Kowa Research Institute, Inc.
7 NCT02275988 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Clarithromycin Phase 1 Kowa Research Institute, Inc.
8 NCT02276001 Drug-Drug Interaction Study in Healthy Adult Volunteers Completed Drug: K-877|Drug: Cyclosporine Phase 1 Kowa Research Institute, Inc.

2D chemical structure of 848259-27-8

US6653334 * Dec 27, 2002 Nov 25, 2003 Kowa Co., Ltd. Benzoxazole compound and pharmaceutical composition containing the same
US7109226 * Sep 3, 2004 Sep 19, 2006 Kowa Co., Ltd. PPAR-activating compound and pharmaceutical composition comprising the compound
US7183295 * Apr 20, 2006 Feb 27, 2007 Kowa Co., Ltd. PPAR-activating compound and pharmaceutical composition comprising the compound

///////Pemafibrate, NDA,  Kowa, dyslipidemia,  Japan, 2015, phase II clinical trials,  US and EU, K-877, K-13675, (R)-

CC[C@H](C(=O)O)Oc1cccc(c1)CN(CCCOc2ccc(cc2)OC)c3nc4ccccc4o3

CC[C@@H](OC1=CC=CC(CN(C2=NC3=CC=CC=C3O2)CCCOC4=CC=C(OC)C=C4)=C1)C(O)=O

 

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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PATENT

US20140316145

CLICK ON IMAGE

http://www.google.com/patents/US8802714

 

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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PATENT

http://www.google.com/patents/CN101445478A?cl=en

 

 

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

NDA, ANDA AND IND by DR ANTHONY CRASTO


Aripiprazole lauroxil ……….Alkermes submits new drug application


Aripiprazole3DanBall.gif

Aripiprazole2D1.svg

 

Aripiprazole

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

END AUG 2014

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

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

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

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

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

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

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

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

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

Aripiprazole lauroxil [USAN]  CAS  1259305-29-7

 

 

 

Systematic (IUPAC) name
7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Clinical data
Trade names Abilify
AHFS/Drugs.com monograph
MedlinePlus a603012
Licence data EMA:Link, US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a depot)
Pharmacokinetic data
Bioavailability 87%[1][2][3][4]
Protein binding >99%[1][2][3][4]
Metabolism Hepatic (liver; mostly via CYP3A4 and CYP2D6[1][2][3][4])
Half-life 75 hours (active metabolite is 94 hours)[1][2][3][4]
Excretion Renal (27%; <1% unchanged), Faecal (60%; 18% unchanged)[1][2][3][4]
Identifiers
CAS number 129722-12-9 Yes
ATC code N05AX12
PubChem CID 60795
IUPHAR ligand 34
DrugBank DB01238
ChemSpider 54790 Yes
UNII 82VFR53I78 Yes
KEGG D01164 Yes
ChEBI CHEBI:31236 Yes
ChEMBL CHEMBL1112 Yes
Chemical data
Formula C23H27Cl2N3O2 
Mol. mass 448.385

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

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

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

Regulator status

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

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

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

Patent status

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

Dosage forms

Abilify 2mg tablets (US)

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

Synthesis

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

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

Aripiprazole

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

 

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

ARIPIPRAZOLE ACID SALT

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

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

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

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

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

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

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

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

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

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

File:Aripiprazole synthesis.svg

Research

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

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

 

Scheme-3

Aripiprazole Acid addition salt

 

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

…………………………….

patent expiry
………………….patent…..approved….exp
United States 5006528 1994-10-20 2014-10-20
United States 7115587 2005-01-21 2025-01-21
Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amineU.S. Patent 5,006,528
Aripiprazole synth.png

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

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

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

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

[0004]

Figure CN101538252BD00031

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

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

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

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

[0007]

Figure CN101538252BD00032

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

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

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

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

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

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

[0014]

Figure CN101538252BD00041

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Figure CN101538252BD00061

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

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

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

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

Chemical Synthesis of Aripiprazole (active ingredient for Abilify)

Chemical Synthesis of Abilify-Aripirazole-Atypical Antipsychotics-Otsuka-BMS-aripiprazole - Ann re ピ have suitable plastic AKZO

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

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

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

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

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

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

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

Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water
Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85 ° C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30 ° C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 6 hours to obtain title compound.
Yield: 87-89% HPLC Purity: 99.89
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 15.83 m, d 50 = 60.12 m, d 90 = 144.99 m
Preparation of aripiprazole anhydrous Type I using ethanol and water
Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85 ° C for 1-2 hours. The resulting mixture was cooled to 25-30 ° C within 4 hours and . stirred for 3 hours The resulting solid was filtered and dried under suction for 1 hour The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 3 hours to obtain title compound Yield:.. 90% HPLC Purity: 99.9 %
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 22.01 m, d 50 = 105.10 m, d 90 = 232.97 m

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

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

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

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

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

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

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

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

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

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

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

No Generic Abilify in the US until April 2015

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

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

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

Aripiprazole synthetic route

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

Aripiprazole preparation method

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

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

 

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External links

WO2006079548A1 * Jan 27, 2006 Aug 3, 2006 Sandoz Ag Organic compounds
WO2006079549A1 Jan 27, 2006 Aug 3, 2006 Sandoz Ag Salts of aripiprazole
WO2014060324A1 Oct 11, 2013 Apr 24, 2014 Sanovel Ilac Sanayi Ve Ticaret A.S Aripiprazole formulations
EP1844036A1 * Jan 27, 2006 Oct 17, 2007 Sandoz AG Salts of aripiprazole
EP2093217A1 * Jan 27, 2006 Aug 26, 2009 Sandoz AG Polymorph and solvates of aripiprazole
EP2233471A1 * Feb 6, 2009 Sep 29, 2010 Adamed Sp. z o.o. A salt of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4.dihydro-2(1h)-quinolinone with 5-sulfosalicylic acid and its preparation process
EP2359816A1 Feb 8, 2011 Aug 24, 2011 Sanovel Ilac Sanayi ve Ticaret A.S. Aripiprazole formulations
US7504504 Dec 16, 2004 Mar 17, 2009 Teva Pharmaceutical Industries Ltd. Methods of preparing aripiprazole crystalline forms
US7714129 Sep 29, 2006 May 11, 2010 Teva Pharmaceutical Industries Ltd. Methods of preparing anhydrous aripiprazole form II
US8008490 Jan 27, 2006 Aug 30, 2011 Sandoz Ag Polymorphic forms of aripiprazole and method
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