AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

ECA Guide on Visual Inspection: updated version for all participants of the Particles event

 regulatory  Comments Off on ECA Guide on Visual Inspection: updated version for all participants of the Particles event
Jul 072016
 

 

The advisory board of the ECA Visual Inspection Group has worked on an update of its visual inspection guide. All participants of the ECA Conference Particles in Parenterals 2016 will receive a copy for free. Read more.

see

http://www.gmp-compliance.org/eca_mitt_05360_15266,15265,Z-PEM_n.html

The advisory board of the ECA Visual Inspection Group has worked on an update of its visual inspection guide. All participants of the ECA Conference Particles in Parenterals 2016, 28-29 September 2016 in Barcelona will receive a copy for free.

The paper, which is much rather supposed to be a reference than a strict requirement, covers Manual and Automated Inspection issues including qualification, validation and revalidation in the following chapters:

  • Manual inspection
  • Automated inspection
  • Inspection of lyophilized product
  • Defect Classes
  • Evaluation of defect classes and trending
  • Batch release
  • Concerns regarding distributed product

The chapter on manual inspection has been extended to also address semi-automated inspection. The chapter on batch release now contains more information and explanation on AQL testing.

More information can also be found on the group’s webpage.

 

//////////ECA Guide, Visual Inspection,  updated version, Particles event

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FDA issues new Draft Guidance on Elemental Impurities

 regulatory  Comments Off on FDA issues new Draft Guidance on Elemental Impurities
Jul 072016
 

The recently issued FDA Guideline on Elemental Impurities as a draft describes the procedure for controlling elemental impurities for medicinal products with and without official USP monograph. Read in what cases the FDA expects the fulfilment of the requirements of the Guideline ICH Q3D respectively of the general USP Chapter <232> und <233>.

see

http://www.gmp-compliance.org/enews_05465_FDA-issues-new-Draft-Guidance-on-Elemental-Impurities_15332,S-AYL_n.html

The ICH Q3D “Guideline for Elemental Impurities” was issued in December 2014 and recommended for adoption in the regulations portfolio of the ICH regions Europe, USA and Japan according to the ICH step-by-step procedure (Step 5). With the publication of the “ICH guideline Q3D on elemental impurities” (EMA/CHMP/ICH/353369/2013) in August 2015 the European Medicines Agency (EMA) implemented this step and determined June 2016 (for medicinal products to be newly approved) and December 2017 (for already approved medicinal products) as the dates for the Guideline to come into effect. The FDA took over the ICH Q3D Guideline in September 2015.

On 30 June 2016 the FDA Guidance for Industry “Elemental Impurities in Drug Products” was issued as a draft and is now open for comments for a period of 60 days.

The requirements of the Guidance apply to

  • New compendial and noncompendial NDA or ANDA drug products
  • Drug products not approved under an NDA or ANDA – as, e.g., compendial and noncompendial nonprescription OTC products.

Compendial medicinal products are generally supposed to fulfil the requirements defined in the general USP Chapters <232> und <233>. However, in the following cases the provisions of ICH Q3D have to be met:

  • For noncompendial drug products,
  • For metallic impurities listed only in ICH Q3D but not in the general USP Chapters <232> and <233>.

Correspondingly these provisions do also apply for changes to approved medicinal products, made with the goal to fulfil the requirements of the chapters <232> and <233> respectively of ICH Q3D. For compendial medicinal products the result of the change must be the compliance with <232> and <233>, noncompendial products have to comply with the provisions of ICH Q3D.

The FDA generally considers these kind of changes as low risk with regard to negative effects on identity, strength, quality, purity or potency. For that reason they are not subject to the CBE change procedure and can be reported to the FDA as part of the annual report.

The general USP Chapter <232> only comprises the PDE values of 15 elements, while ICH Q3D covers 24 elements. Otherwise both chapters were adapted to ICH Q3D and issued in the second supplementary volume of USP 38-NF 33 on 1 December 2015. However, both chapters can only be applied to compendial products starting on 1 January 2018 – the date mentioned in the General Notices 5.60.30 “Elemental Impurities in USP Drug Products and Dietary Supplements”. This is nearly the date (December 2017) determined for the application of ICH Q3D respectively the European Guideline (EMA/CHMP/ICH 353369/2013).

///////////FDA, Draft Guidance, Elemental Impurities

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Discovery and development of natural product oridonin-inspired anticancer agents

 Uncategorized  Comments Off on Discovery and development of natural product oridonin-inspired anticancer agents
Jul 072016
 

Microsoft Word - 2016-6-8_Manuscrpit_Review on Oridonin analogs

Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic.

Highlights

Oridonin displays significant anticancer activities via multi-signaling pathways.

Recent advances in medicinal chemistry of oridonin-like compounds are presented.

The article summarizes the SAR and mechanism studies of relevant drug candidates.

The milestones and future direction of oridonin-based drug discovery are discussed.

Volume 122, 21 October 2016, Pages 102–117

Review article

Discovery and development of natural product oridonin-inspired anticancer agents

  • a Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States
  • b Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States

 

Major milestones achieved in oridonin-inspired drug discovery and development.

 

 

////////Natural product, Oridonin, Diterpenoids, Anticancer agents, Drug discovery, Chemical biology,

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Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review

 Uncategorized  Comments Off on Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review
Jul 062016
 

imageHighlights

Modification of BHT has a significant multivariate effect on antioxidant efficiency.

BDE is the key to rational design and development of antioxidants.
Antioxidant performance of BHT is mainly depending on 13 very crucial parameters.
MPAO is a promising way to increase antioxidant and pharmacological activities.

Abstract

Hindered phenols find a wide variety of applications across many different industry sectors. Butylated hydroxytoluene (BHT) is a most commonly used antioxidant recognized as safe for use in foods containing fats, pharmaceuticals, petroleum products, rubber and oil industries. In the past two decades, there has been growing interest in finding novel antioxidants to meet the requirements of these industries. To accelerate the antioxidant discovery process, researchers have designed and synthesized a series of BHT derivatives targeting to improve its antioxidant properties to be having a wide range of antioxidant activities markedly enhanced radical scavenging ability and other physical properties. Accordingly, some structure–activity relationships and rational design strategies for antioxidants based on BHT structure have been suggested and applied in practice. We have identified 14 very sensitive parameters, which may play a major role on the antioxidant performance of BHT. In this review, we attempt to summarize the current knowledge on this topic, which is of significance in selecting and designing novel antioxidants using a well-known antioxidant BHT as a building-block molecule. Our strategy involved investigation on understanding the chemistry behind the antioxidant activities of BHT, whether through hydrogen or electron transfer mechanism to enable promising anti-oxidant candidates to be synthesized.

 

Volume 101, 28 August 2015, Pages 295–312

Review article

Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review

  • aNanotechnology & Catalysis Research Centre, (NANOCAT), University of Malaya, Block 3A, Institute of Postgraduate Studies Building, 50603 Kuala Lumpur, Malaysia
  • bDepartment of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • cDivision of Human Biology, Faculty of Medicine, International Medical University, 57000 Kuala Lumpur, Malaysia
  • dDrug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • http://www.sciencedirect.com/science/article/pii/S022352341530101X

doi:10.1016/j.ejmech.2015.06.026

SEE

https://www.researchgate.net/publication/278050005_ChemInform_Abstract_Understanding_the_Chemistry_Behind_the_Antioxidant_Activities_of_Butylated_Hydroxytoluene_BHT_A_Review/figures

 

 

 

 

///////////Antioxidant, Butylated hydroxytoluene, Free radical, Reactive oxygen species, Phenol

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Kinetics of Rh(II)-Catalyzed α-Diazo-β-ketoester Decomposition and Application to the [3+6+3+6] Synthesis of Macrocycles on a Large Scale and at Low Catalyst Loadings

 Uncategorized  Comments Off on Kinetics of Rh(II)-Catalyzed α-Diazo-β-ketoester Decomposition and Application to the [3+6+3+6] Synthesis of Macrocycles on a Large Scale and at Low Catalyst Loadings
Jul 062016
 

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Kinetics of Rh(II)-Catalyzed α-Diazo-β-ketoester Decomposition and Application to the [3+6+3+6] Synthesis of Macrocycles on a Large Scale and at Low Catalyst Loadings

Department of Organic Chemistry and Department of Inorganic and Analytical Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
ACS Catal., 2016, 6, pp 4877–4881
DOI: 10.1021/acscatal.6b01283

 

Abstract Image

In the context of [3+6+3+6] macrocyclization reactions, precise kinetics of α-diazo-β-ketoester decomposition were measured by in situ infrared (IR) monitoring. Dirhodium complexes of Ikegami–Hashimoto type—and perchlorinated phthalimido derivatives in particular—performed better than classical achiral complexes. Clear correlations were found between speciation among dirhodium species and catalytic activity. With these results, novel cyclohexyl-derived catalysts were developed, affording good yields of macrocycles (up to 78%), at low catalyst loadings (from 0.01 mol % to 0.001 mol %) and on a large scale (from 1 g to 20 g).

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///////acceptor-acceptor diazo reagents,  dirhodium complexes,  in situ IR monitoring,  kineticslow catalyst loading,  multigram synthesis,  speciation,  ylides

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C–H Arylation of Heterocyclic N-Oxides Through in Situ Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process

 Uncategorized  Comments Off on C–H Arylation of Heterocyclic N-Oxides Through in Situ Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process
Jul 062016
 

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A green and selective method for the generation of biaryl compounds through C–H arylation of heterocyclic N-oxides, in which the addition of ascorbic acid as a promoter is not required for either the generation of an aryldiazonium species or the subsequent arylation, is presented. Reaction conditions were optimized through multivariate data analysis, including orthogonal projections to latent structures (OPLS) and design of experiments (DoE) methodologies, resulting in further sustainability improvements, and were then applied to a range of substrates to establish the scope and limitations of the process. The reaction was studied using in situ infrared spectroscopy and a mechanism is presented that accounts for the available data from this and previous studies. The reaction was also performed on a multigram scale, with calorimetry studies to support further scale-up of this promoter-free transformation.

C–H Arylation of Heterocyclic N-Oxides Through in Situ Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process

API Chemistry, GlaxoSmithKline Research and Development Ltd., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00117

2-(4-(Ethoxycarbonyl)phenyl)pyridine N-Oxide

Orange solid (81 mg, 22% yield), mp 119–120 °C.
1H NMR (DMSO-d6, 400 MHz): δ 8.39–8.38 (m, 1H), 8.07 (d, 2H, J = 8.6 Hz), 8.00 (d, 2H, J = 8.6 Hz), 7.72–7.67 (m, 1H), 7.45–7.48 (m, 2H), 4.37 (q, 2H, J = 7.1 Hz), 1.36 (t, 3H, J = 7.1 Hz) ppm.
13C NMR (DMSO-d6, 100 MHz): δ 165.3 (CIV), 146.6 (CIV), 140.2, 137.2 (CIV), 130.2 (CIV), 129.6, 128.7, 127.7, 126.1, 125.5, 60.9, 14.1 ppm.
HRMS (ESI+): calculated for C14H14NO3 [M+H]+ 244.0960, found 244.0968.
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//////C–H Arylation of Heterocyclic N-Oxides, Situ Diazotisation Of Anilines, Promoters, Green And Selective Coupling Process

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Rifaximin

 Uncategorized  Comments Off on Rifaximin
Jul 062016
 

Rifaximin.png

Rifaximin;

Rifaxidin; Rifacol; Xifaxan; Normix; Rifamycin L 105;L 105 (ansamacrolide antibiotic), L 105SV

(2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-á]-benzimidazole-1,15(2H)-dione,25-acetate

 CAS 80621-81-4,  4-Deoxy-4-methylpyrido[1,2-1,2]imidazo[5,4-c]rifamycin SV,

4-Deoxy-4′-methylpyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV, Rifacol

C43H51N3O11
Molecular Weight: 785.87854 g/mol

 

XIFAXAN tablets for oral administration are film-coated and contain 200 mg or 550 mg of rifaximin.

Rifaximin is an orally administered, semi-synthetic, nonsystemic antibiotic derived from rifamycin SV with antibacterial activity. Rifaximin binds to the beta-subunit of bacterial DNA-dependent RNA polymerase, inhibiting bacterial RNA synthesis and bacterial cell growth. As rifaximin is not well absorbed, its antibacterial activity is largely localized to the gastrointestinal tract.

Rifaximin (trade names:RCIFAX, Rifagut, Xifaxan, Zaxine) is a semisynthetic antibiotic based on rifamycin. It has poor oral bioavailability, meaning that very little of the drug will be absorbed into the blood stream when it is taken orally. Rifaximin is used in the treatment of traveler’s diarrhea, irritable bowel syndrome, and hepatic encephalopathy, for which it receivedorphan drug status from the U.S. Food and Drug Administration in 1998.

 Rifaximin is a rifamycin that was launched in 1988 by Alfa Wasserman for the treatment of bacterial infection, and was commercialized in 2004 by Salix for the treatment of Clostridium difficile-associated diarrhea. In 2008, the product was launched in Germany for the treatment of travelers’ diarrhea caused by non-invasive enteropathogenic bacteria in adults. In 2015, Xifaxan was approved in the U.S. for the treatment of abdominal pain and diarrhea in adult men and women with irritable bowel syndrome with diarrhea. At the same year, Aska filed an application for approval of the product in Japan for the treatment of hepatic encephalopathy.

Rifaximin is licensed by the U.S. Food and Drug Administration to treat traveler’s diarrhea caused by E. coli.[1] Clinical trials have shown that rifaximin is highly effective at preventing and treating traveler’s diarrhea among travelers to Mexico, with fewside effects and low risk of developing antibiotic resistance.[2][3][4] It is not effective against Campylobacter jejuni, and there is no evidence of efficacy against Shigella or Salmonella species.

Launched – 1988 Alfa Wassermann Infection, bacterial
Launched – 2004 Salix Traveler’s diarrhea
Launched – 2010 Salix Encephalopathy, hepatic
Launched – 2015 Salix Irritable bowel syndrome (Diarrhea predominant)
Launched Alfa Wassermann
Merck & Co.
Hyperammonemia

The drug is also at Salix in phase II trials for the treatment of Crohn’s disease. Alfa Wasserman is also conducting phase II trials for Crohn’s disease. The product was approved and launched in the U.S. for the maintenance of remission of hepatic encephalopathy in 2010. Mayo Clinic is conducting phase II clinical trials in the U.S. for the treatment of primary sclerosing cholangitis and the University of Hong Kong is also conducting Phase II trials for the treatment of functional dyspepsia.

It may be efficacious in relieving chronic functional symptoms of bloating and flatulence that are common in irritable bowel syndrome (IBS),[5][6] especially IBS-D.

In February 1998, Salix was granted orphan drug designation by the FDA for the use of rifaximin to treat hepatic encephalopathy. In 2009, a codevelopment agreement was established between Lupin and Salix in the U.S. for the development of a new formulation using Lupin’s bioadhesive drug delivery technology.

There was recentlya pilot-study done on the efficacy of rifaximin as a means of treatment for rosacea, according to the study, induced by the co-presence of small intestinal bacterial overgrowth.[7]

In the United States, rifaximin has orphan drug status for the treatment of hepatic encephalopathy.[8] Although high-quality evidence is still lacking, rifaximin appears to be as effective as or more effective than other available treatments for hepatic encephalopathy (such as lactulose), is better tolerated, and may work faster.[9] Hepatic encephalopathy is a debilitating condition for those with liver disease. Rifaximin is an oral medication taken twice daily that helps patients to avoid reoccurring hepatic encephalopathy. It has minimal side effects, prevents reoccurring encephalopathy and high patient satisfaction. Patients are more compliant and satisfied to take this medication than any other due to minimal side effects, prolong remission, and overall cost.[10] Rifaximin helps patients avoid multiple readmissions from hospitals along with less time missed from work as well. Rifaximin should be considered a standard prescribed medication for those whom have episodes of hepatic encephalopathy.

The drawbacks to rifaximin are increased cost and lack of robust clinical trials for HE without combination lactulose therapy.

Also treats hyperammonemia by eradicating ammoniagenic bacteria.

Mechanism of action

Rifaximin interferes with transcription by binding to the β-subunit of bacterial RNA polymerase.[11] This results in the blockage of the translocation step that normally follows the formation of the first phosphodiester bond, which occurs in the transcription process.[12]

Efficacy

A 2011 study in patients with IBS (sans constipation) indicated 11% showed benefits over a placebo.[13] The study was supported by Salix Pharmaceuticals, the patent holder.[13] A 2010 study in patients treated for Hepatic Cirrhosis with hospitalization involving Hepatic encephalopathy resulted in 22% of the rifaxmin treated group experiencing a breakthrough episode of Hepatic encephalopathy as compared to 46% of the placebo group. The majority patients were also receivingLactulose therapy for prevention of hepatic encephalopathy in addition to Rifaximin.[14] Rifaximin shows promising results, causing remission in up to 59% of people with Crohn’s disease and up to 76% of people with Ulcerative Colitis.[15]

Availability

In the United States, Salix Pharmaceuticals holds a US Patent for rifaximin and markets the drug under the name Xifaxan, available in tablets of 200 mg and 550 mg.[16][17] In addition to receiving FDA approval for traveler’s diarrhea and (marketing approved for)[17] hepatic encephalopathy, Xifaxan received FDA approval for IBS in May 2015.[18] No generic formulation is available in the US and none has appeared due to the fact that the FDA approval process was ongoing. If Xifaxan receives full FDA approval for hepatic encephalopathy it is likely that Salix will maintain marketing exclusivity and be protected from generic formulations until March 24, 2017.[17] Price quotes received on February 21, 2013 for Xifaxan 550 mg in the Denver Metro area were between $23.57 and $26.72 per tablet. A price quote received on June 24, 2016 for Xifaxan 550 mg was $31.37 per tablet.

Rifaximin is approved in 33 countries for GI disorders.[19][20] On August 13, 2013, Health Canada issued a Notice of Compliance to Salix Pharmaceuticals Inc. for the drug product Zaxine.[21] In India it is available under the brand names Ciboz and Xifapill.[

SPECTRA

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APT 13C NMR RIFAXIMIN

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1H NMR PARTIAL

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IR

 

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Direct infusion mass analysis ESI (+)

 

 

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IH NMR

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  • [-]ESI    FRAG PATHWAY

Synthesis

Rifaximin is a broad-spectrum antibiotic belonging to the family of Rifamycins and shows its antibacterial activity, in the gastrointestinal tract against localized bacteria that cause infectious diarrhoea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn’s disease, and/or pancreatic insufficiency.

Rifaximin is sold under the brand name Xifaxan® in US for the treatment of Travellers’ diarrhoea and Hepatic Encephalopathy. The chemical name of Rifaximin is (2S , 16Z, 18E,20S ,21 S ,22R,23R,24R,25S ,26S ,27S ,28E)-5,6,21 ,23 ,25-pentahydroxy-27-methoxy-2,4,1 l,16,20,22,24,26-octamethyl-2,7(epoxypentadeca-[l,l l,13]trienimino) benzofuro[4,5-e]pyrido[l,2-a]-benzimidazole-l,15(2H)-dione,25-acetate and the molecular formula is G^HsiNsOn with a molecular weight of 785.9. The structural formula of Rifaximin is:

Formula I

Rifaximin was first described and claimed in Italian patent IT 1154655 and U.S. Pat. No.4,341,785. These patents disclose a process for the preparation of Rifaximin and a method for the crystallisation thereof. The process for the preparation of Rifaximin is as depicted in scheme I given below:

Scheme -I

U.S. Pat. No. 4,179,438 discloses a process for the preparation of 3-bromorifamycin S which comprises reaction of rifamycin S with at least two equivalents of bromine, per one mole of rifamycin S in the presence of at least one mole of pyridine per each equivalent of bromine and in the presence of ethanol, methanol or mixtures thereof with water at a

temperature not above the room temperature. The process is shown in the scheme given below:

Rifamycin S 3-Bromo-Rifamycin-S

U.S. Patent No.4,557, 866 discloses a process for one step synthesis of Rifaximin from Rifamycin O, which is shown in scheme II given below:

Rifamycin O                                                                                                               Rifaximin

Scheme -II

US ‘866 patent also discloses purification of Rifaximin by performing crystallization of crude Rifaximin from a 7:3 mixture of ethyl alcohol/water followed by drying both under atmospheric pressure and under vacuum. The crystalline form which is obtained has not been characterized.

U.S. Patent No. 7,045,620 describes three polymorphic forms α, β and γ of Rifaximin. Form a and β show pure crystalline characteristics while the γ form is poorly crystalline. These polymorphic forms are differentiated on the basis of water content and PXRD. This patent also discloses processes for preparation of these polymorphs which involve use of specific reaction conditions during crystallization like dissolving Rifaximin in ethyl alcohol at 45-65°C, precipitation by adding water to form a suspension, filtering suspension and washing the resulted solid with demineralized water, followed by drying at room temperature under vacuum for a period of time between 2 and 72 hours. Crystalline forms a and β are obtained by immediate filtration of suspension when temperature of reaction mixture is brought to 0°C and poorly crystalline form γ is obtained when the reaction mixture is stirred for 5-6 hours at 0°C and then filtered the suspension. In addition to above these forms are also characterized by specific water content. For a form water content should be lower than 4.5%, for β form it should be higher than 4.5% and to obtain γ form, water content should be below 2%.

U.S. Patent No. 7,709,634 describes an amorphous form of Rifaximin which is prepared by dissolving Rifaximin in solvents such as alkyl esters, alkanols and ketones and precipitating by addition of anti-solvents selected from hydrocarbons, ethers or mixtures thereof.

U.S. Patent No. 8,193,196 describes two polymorphic forms of Rifaximin, designated δ and ε respectively. Form δ has water content within the range from 2.5 to 6% by weight (preferably from 3 to 4.5%).

U.S. Patent No 8,067,429 describes a-dry, β-1, β-2, ε-dry and amorphous forms of Rifaximin.

U.S. Patent No. 8,227,482 describes polymorphs Form μ, Form π, Form Omicron, Form Zeta, Form Eta, Form Iota and Form Xi of Rifaximin.

International application publications WO 2008/035109, WO 2008/155728, WO 2012/035544, WO 2012/060675, and WO 2012/156533 describes various amorphous or poorly crystalline forms of Rifaximin.

These polymorphic forms are obtained under different experimental conditions and are characterized by XRPD pattern.

The polymorphic forms of Rifaximin obtained from the prior art methods have specific water content. Transition between different polymorphic forms of Rifaximin occurs by drying or wetting of the synthesized Rifaximin. Hence, it is evident from above that Rifaximin can exist in number of polymorphic forms, formation of these polymorphic forms depends upon specific reaction conditions applied during crystallization and drying.

Rifaximin is a semi-synthetic, rifamycin-based non-systematic antibiotic. It is chemically termed as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26 S,27S, 28E)-5,6,21,23,255-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]-benzimida-zole-1,15(2H)-dione,25-acetate (I).

Figure imgb0001

Rifaximin is used for treatment of travelers’ diarrhea caused by noninvasive strains of Escherichia coli.

Rifaximin was first disclosed in US4341785 which also discloses a process for its preparation and a method for crystallization of rifaximin using suitable solvents or mixture of solvents. However, this patent does not mention the polymorphism of rifaximin.

Canadian patent CA1215976 discloses a process for the synthesis of imidazo rifamycins which comprises reacting rifamycin S with 2-amino-4-methyl pyridine.

US4557866 discloses a process for preparation of rifaximin, but does not mention the polymorphs of rifaximin.

US7045620 discloses crystalline polymorphic forms of rifaximin which are termed as rifaximin α, rifaximin β and rifaximin γ. These polymorphic forms are characterized using X-ray powder diffraction. Further this patent mentions that γ form is poorly crystalline with a high content of amorphous component. This patent also discloses processes for preparation of these polymorphs which involve use of processes of crystallization and drying as disclosed in US4557866along with control of temperature at which the product is crystallized, drying process, water content thereof. Further, according to this patent, crystal formation depends upon the presence of water within the crystallization solvent.

The above patent discloses rifaximin α which is characterized by water content lower than 4.5% & powder X-ray diffractogram having significant peaks are at values of diffraction angles 2θ of 6.6°; 7.4°; 7.9°, 8.8°, 10.5°, 11.1 °, 11.8°, 12.9°, 17.6°, 18.5°, 19.7°, 21.0°, 21.4°, 22.1°; rifaximin β which is characterized by water content higher than 4.5% & powder X-ray diffractogram having significant peaks are at values of diffraction angles 2θ of 5.4°; 6.4°; 7.0°, 7.8°, 9.0°, 10.4°, 13.1°, 14.4°, 17.1°, 17.9°, 18.3°, 20.9° and rifaximin γ which is characterized by poorer powder X-ray diffractogram because of poor crystallinity. The significant peaks are at values of diffraction angles 2θ of 5.0°; 7.1°; 8.4°.

US2005/0272754 also discloses polymorphs of rifaximin namely rifaximin α form, rifaximin β form & rifaximin γ form characterized by powder X-ray diffractogram, intrinsic dissolution rates and processes of preparation of polymorphic forms of rifaximin. However, none of the above patents disclose a wholly amorphous form of rifaximin.

It is a well known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties. The amorphous form of a drug may exhibit different dissolution characteristics and in some case different bioavailability patterns compared to crystalline forms.

Further, amorphous and crystalline forms of a drug may have different handling properties, dissolution rates, solubility, and stability.

Furthermore, different physical forms may have different particle size, hardness and glass transition temperatures. Amorphous materials do not exhibit the three-dimensional long-range orders found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random.

Amorphous solids do not give a definitive x-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a specific melting point and tend to liquefy at some point beyond the glass transition temperature. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide enhanced bioavailability characteristics such as a higher rate and extent of absorption of the compound from the gastrointestinal tract. Also, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in the manufacturing process of solid dosage form such as compressibility.

Drugs Fut 1982,7(4),260
The reaction of rifamycin S (I) with pyridine perbromide (II) in 2-propanol/chloroform (70/30) mixture at 0 C gives 3-bromorifamicin S (III), which is then condensed with 2-amino-4-methyl-pyridine (IV) at 10 C. The o-quinoniminic compound (V) is then obtained. This compound is finally reduced with ascorbic acid.
US 262123
The reaction of rifamycin S (I) with pyridine perbromide (II) in 2-propanol/chloroform (70/30) mixture at 0 C gives 3-bromorifamicin S (III), which is then condensed with 2-amino-4-methyl-pyridine (IV) at 10 C. The o-quinoniminic compound (V) is then obtained. This compound is finally reduced with ascorbic acid.

PATENT

https://www.google.com/patents/EP2069363B1?cl=e

The schematic representation for preparation of amorphous rifaximin is as follows :

Figure imgb0002

Amorphous rifaximin according to the present invention can be characterized by various parameters like solubility, intrinsic dissolution, bulk density, tapped density.

Rifaximin is known to exist in 3 polymorphic Forms namely α Form, β Form & γ Form of which the α Form is thermodynamically the most stable. Hence, the amorphous form of rifaximin was studied in comparison with α Form.

Further, when intrinsic dissolution of amorphous rifaximin is carried out against the α Form, it is observed that the amorphous rifaximin has better dissolution profile than α Form which is shown in table below (this data is also shown graphically in Figure 3):

Dissolution medium : 1000 ml of 0.1M Sodium dihydrogen phosphate monohydrate + 4.5g of sodium lauryl sulphate

Temperature : 37±0.5°C

Rotation speed : 100 rpm

Particle size : Amorphous rifaximin – 11 microns

α Form of rifaximin – 13 microns

 

  • Time in minutes % Release of Amorphous Rifaximin % Release of α Form of Rifaximin
    15 1.1 0.8
    30 1.9 1.8
    45 2.9 3.0
    60 3.7 4.4
    120 8.1 11.0
    180 12.6 18.0
    240 16.6 24.6
    360 24.7 38.7
    480 32.0 47.5
    600 39.5 52.7
    720 46.4 56.4
    960 60.4 62.9
    1200 72.9 67.8
    1400 83.0 72.7
    Amorphous rifaximin exhibits bulk density in the range of 0.3 – 0.4 g/ml and tapped density is in the range of 0.4 – 0.5 g/ml while the α Form rifaximin exhibits bulk density in the range of 0.2 – 0.3 g/ml & tapped density is in the range of 0.3 – 0.4 g/ml. These higher densities of amorphous rifaximin are advantageous in formulation specifically in tablet formulation, for example, it gives better compressibility.

 

CLIP

Rifaximin (CAS NO.: 80621-81-4), with other name of 4-Deoxy-4-methylpyrido[1,2-1,2]imidazo[5,4-c]rifamycin SV, could be produced through many synthetic methods.

Following is one of the reaction routes:

The reaction of rifamycin S (I) with pyridine perbromide (II) in 2-propanol/chloroform (70/30) mixture at 0 C gives 3-bromorifamicin S (III), which is then condensed with 2-amino-4-methyl-pyridine (IV) at 10 C. The o-quinoniminic compound (V) is then obtained. This compound is finally reduced with ascorbic acid.

POLYMORPHISM

Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class, exactly it is a pyrido-imidazo rifamycin described and claimed in Italian Patent IT 1154655, while European Patent EP 0161534 describes and claims a process for its production starting from rifamycin O (The Merck Index, XIII Ed., 8301).

Both these patents describe the purification of rifaximin in a generic way stating that crystallization can be carried out in suitable solvents or solvent systems and summarily showing in some examples that the reaction product can be crystallized from the 7:3 mixture of ethyl alcohol/water and can be dried both under atmospheric pressure and under vacuum without specifying in any way either the experimental conditions of crystallization and drying, or any distinctive crystallographic characteristic of the obtained product.

The presence of different polymorphs had just not been noticed and therefore the experimental conditions described in both patents had been developed with the goal to get a homogeneous product having a suitable purity from the chemical point of view, independent from the crystallographic aspects of the product itself.

It has now been found, unexpectedly, that there are several polymorphous forms whose formation, besides the solvent, depends on time and temperature conditions under which both crystallization and drying are carried out.

In the present application, these orderly polymorphous forms will be, later on, conventionally identified as rifaximin α (FIG. 1) and rifaximin β (FIG. 2) on the basis of their respective specific diffractograms, while the poorly crystalline form with a high content of amorphous component will be identified as rifaximin γ (FIG. 3).

Rifaximin polymorphous forms have been characterized through the technique of the powder X-ray diffraction.

The identification and characterization of these polymorphous forms and, simultaneously, the definition of the experimental conditions for obtaining them is very important for a compound endowed with pharmacological activity which, like rifaximin, is marketed as medicinal preparation, both for human and veterinary use. In fact it is known that the polymorphism of a compound that can be used as active ingredient contained in a medicinal preparation can influence the pharmaco-toxicologic properties of the drug. Different polymorphous forms of an active ingredient administered as drug under oral or topical form can modify many properties thereof like bioavailability, solubility, stability, colour, compressibility, flowability and workability with consequent modification of the profiles of toxicological safety, clinical effectiveness and productive efficiency.

What mentioned above is confirmed by the fact that the authorities that regulate the grant of marketing authorization of the drugs market require that the manufacturing methods of the active ingredients are standardized and controlled in such a way that they give homogeneous and sound results in terms of polymorphism of production batches (CPMP/QWP/96, 2003—Note for Guidance on Chemistry of new Active Substance; CPMP/ICH/367/96—Note for guidance specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances; Date for coming into operation: May 2000).

The need for the above-mentioned standardization has further been strengthened in the field of the rifamycin antibiotics by Henwood S. Q., de Villiers M. M., Liebenberg W. and Lotter A. P., Drug Development and Industrial Pharmacy, 26 (4), 403-408, (2000), who have ascertained that different production batches of the rifampicin (INN) made from different manufacturers differ from each other in that they show different polymorphous characteristics, and as a consequence they show different dissolution profiles, along with a consequent alteration of the respective pharmacological properties.

By applying the crystallization and drying processes generically disclosed in the previous patents IT 1154655 and EP 0161534 it has been found that under some experimental conditions a poorly crystalline form of rifaximin is obtained, while under other experimental conditions other polymorphic crystalline forms of Rifaximin are obtained. Moreover it has been found that some parameters, absolutely not disclosed in the above-mentioned patents, like for instance preservation conditions and the relative ambient humidity, have the surprising effect to determine the polymorph form.

The polymorphous forms of rifaximin object of the present patent application were never seen or hypothesized, while thinking that, whichever method was used within the range of the described condition, a sole homogeneous product would always have been obtained, irrespective of crystallizing, drying and preserving conditions. It has now been found that the formation of α, β and γ forms depends both on the presence of water within the crystallization solvent, on the temperature at which the product is crystallized and on the amount of water present in the product at the end of the drying phase. Form α, form β and form γ of rifaximin have then been synthesized and they are the object of the invention.

Moreover it has been found that the presence of water in rifaximin in the solid state is reversible, so that water absorption and/or release can take place in time in presence of suitable ambient conditions; consequently rifaximin is susceptible of transition from one form to another, also remaining in the solid state, without need to be again dissolved and crystallized. For instance polymorph α, getting water by hydration up to a content higher than 4.5%, turns into polymorph β, which in its turn, losing water by drying up to a content lower than 4.5%, turns into polymorph α.

These results have a remarkable importance as they determine the conditions of industrial manufacturing of some steps of working which could not be considered critical for the determination of the polymorphism of a product, like for instance the washing of a crystallized product, or the preservation conditions of the end product, or the characteristics of the container in which the product is preserved.

The above-mentioned α, β and γ forms can be advantageously used as pure and homogeneous products in the manufacture of medicinal preparations containing rifaximin.

As already said, the process for manufacturing rifaximin from rifamycin O disclosed and claimed in EP 0161534 is deficient from the point of view of the purification and identification of the product obtained; it shows some limits also from the synthetic point of view as regards, for instance, the very long reaction times, from 16 to 72 hours, not very suitable to an industrial use and moreover because it does not provide for the in situ reduction of rifaximin oxidized that may be formed within the reaction mixture.

Therefore, a further object of the present invention is an improved process for the industrial manufacturing of the α, β and γ forms of rifaximin, herein claimed as products and usable as defined and homogeneous active ingredients in the manufacture of the medicinal preparations containing such active ingredient.

PATENT

https://www.google.com/patents/US20090234114

FIG. 1 is a powder X-ray diffractogram of rifaximin polymorphic form α.

FIG. 2 is a powder X-ray diffractogram of rifaximin polymorphic form β.

FIG. 3 is a powder X-ray diffractogram of rifaximin polymorphic form γ.

 PATENT

Patent US20130004576

Rifaximin (INN; see The Merck Index, XIII Ed., 8304, CAS no. 80621-81-4), IUPAC nomenclature (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25 pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-(1,11,13)trienimino)benzofuro(4,5-e)pyrido(1,2,-a)benzimidazole-1,15(2H)-dione,25-acetate) is a semi-synthetic antibiotic belonging to the rifamycin class of antibiotics. More precisely rifaximin is a pyrido-imidazo rifamycin described in the Italian patent IT 1154655, whereas the European patent EP 0161534 discloses a process for rifaximin production using rifamycin O as starting material (The Merck Index, XIII Ed., 8301).

U.S. Pat. No. 7,045,620, US 2008/0262220, US 7,612,199, US 2009/0130201 and Cryst. Eng. Comm., 2008, 10 1074-1081 (2008) disclose new forms of rifaximin.

WO 2008/035109 A1 discloses a process to prepare amorphous rifaximin, which comprises reaction of rifamycin S with 2-amino-4 picoline in presence of organic solvent like dichloromethane, ethylacetate, dichloroethylene, chloroform, in an inert atmosphere. When water is added to the reaction mixture, a solid precipitate corresponding to amorphous rifaximin is obtained.

The process described in this document can be assimilated to a crash precipitation, wherein the use of an anti-solvent causes the precipitation of rifaximin without giving any information about the chemical physical and biological characteristics of the rifaximin obtained.

WO 2009/108730 A2 describes different polymorphous forms of rifaximin and also amorphous forms of rifaximin. Amorphous forms are prepared by milling and crash precipitation and with these two different methods the amorphous rifaximin obtained from these two different processes has the same properties.

FIG. 4: 13C-NMR spectrum of rifaximin obtained by spray drying process.

FIG. 5: FT-IR spectrum of rifaximin obtained by spray drying process.

Patent

WO 2015014984

Rifaximin, lUPAC name:

(2S,16Z,18E,20S,21 S,22H,23H,24H,25S,26S,27S,28£)-5,6,21 ,23,25-pentahydroxy- 27-methoxy-2,4,1 1 ,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1 ,1 1 ,13]-trienimmino)-benzofuro-[4,5-e]-pirido-[1 ,2-oc]-benzimidazol-1 , 15(2 -/)-dione,25-acetate, is the compound of formula (I):

Rifaximin is a broad-spectrum antibiotic belonging to the family of rifamycins, devoid of systemic activity. In view of its physicochemical properties, it is not adsorbed in the gastrointestinal tract and therefore exerts its antimicrobial action inside the gastrointestinal tract. Rifaximin therefore has applications in the treatment of diarrhoea and of microbial infections of the gastrointestinal tract typically caused by E. coli, a microorganism which, being incapable of passing through the mucosa of the gastrointestinal tract, remains in contact with the gastrointestinal fluids. Rifaximin also has applications for the treatment of irritable bowel syndrome, Crohn’s disease, diverticulitis and for antibiotic prophylaxis preceding surgical operations on the intestines.

Rifaximin was obtained and described for the first time in the EP161534 starting from rifamycin O and 2-amino-4-picoline in the presence of ethanol/water and

ascorbic acid/HCI to obtain raw rifaximin which is then treated with Ethanol/water to obtain crystallized rifaximin.

Polymorphic forms of rifaximin, and processes for their synthesis and purification, are described in various documents of the known art.

Rifaximin K was firstly described in WO2012/156951 . Such a crystalline form resulted to be more stable in the presence of humidity than the other known crystalline forms of rifaximin, thus enabling the storage, even for prolonged periods. Such a polymorph was obtained by a process starting from rifaximin comprising the following steps: -suspending or dissolving rifaximin in a 1 ,2-dimethoxyethane based solvent, recovering the product and drying to remove said 1 ,2-dimethoxyethane based solvent. In one of the embodiments of the invention 1 ,2-dimethoxyethane is used as the unique solvent of rifaximin, in other 1 ,2-dimethoxyethane is described as used in combination of n-heptane, methanol, acetonitrile, R-COO-R1 esters wherein R and R1 are independently C3-C6 alkyl radicals, and C3-C7 alkyl ketones, ethanol, isopropanol and water.

Paper

The synthesis of 4-deoxypyrido(1′,2′-1,2)imidazo(5,4-c)rifamycin SV derivatives
J Antibiot 1984, 37(12): 1611

 

STR1.jpg

 

 

LAST STEP DEPICTED AGAIN

STR1.jpg

Treatment of rifamycin S (I) with Pyr·Br2 in 2-PrOH/CHCl3 gives 3-bromorifamycin S (II) (1), which upon cyclocondensation with 2-amino-4-methyl-pyridine (III) (1,2,3) in CHCl3 (2) or EtOH (3) yields imine derivative (IV). Finally, reduction of (IV) with L-(+)- ascorbic acid (1,2,3) in MeOH (2) or EtOH (3) provides the target rifaximin (1,2,3).

STR1.jpg

 

PATENT

WO 2005044823, WO 2012035544, WO 2015014984

STR1.jpg

Rifaximin is prepared by the cyclocondensation of rifamycin-O  with 2-amino-4-picoline  in a solvent mixture such as acetone, acetonitrile, EtOH, MIBK, propylene glycol, i-PrOH or t-BuOH and H2O at 50 °C or EtOH/aceone/H2O or optionally in the presence of I2 in CH2Cl2

PATENT

WO 2015159275

The process is shown in the scheme given below:

Rifamycin-S

3-halo-Rifamycin-S

Examples

Example 1;

5g of Rifamycin S, 3.1 gms of 2-amino-4-methyl pyridine, 0.45 g of iodine, 1.65 ml of acetic acid and 20ml of acetonitrile were charged in a clean and dry round bottom flask followed by stirring the resultant reaction mixture at about 30°C for about 30 hours. The reaction progress was monitored by TLC, after completion of reaction, the reaction mass was quenched by adding a mixture of 4.0g of ascorbic acid dissolved in 20 ml of water. The resultant reaction suspension was stirred at about 25°C for about 15mins. 25 ml of dichloromethane was charged and stirred for about 15mins. followed by separation of organic and aqueous phases. The aqueous phase was extracted with 25 ml of dichloromethane followed by separation of organic and aqueous phases. The organic phases were combined and distilled at below about 50°C to yield Rifaximin as residue. 11.25ml of purified water and 11.25ml of ethanol were charged to the residue and stirred at about 30°C for about 15 mins. The resultant reaction

suspension was heated to about 75°C and stirred for about 30mins. The resultant reaction solution further cooled to about 25 °C and stirred for about 2 hours followed by further cooling to about 5°C for about 3 hours. The solid precipitated was filtered and the solid was washed with a mixture of 2.5ml of ethanol and 2.5 ml of purified water. The solid obtained was dried at about 50°C for about 10 hours to afford 3 g. of Rifaximin as crystalline form. Purity by HPLC: 99.85 area %.

PAPER

European journal of medicinal chemistry (2015), 103, 551-62

 

Patent

https://www.google.com/patents/WO2013027227A1?cl=en

Examples

Example 1 : Purification of Rifamycin S

Rifamycin S (500g) and Ethanol (1.5L) were stirred and refluxed for 1 hour. The reaction mixture was then cooled slowly to ambience, stirred at this temperature for 2 hour and filtered. The product dried in vacuum oven at 40 °C to obtain 475g of pure Rifamycin S showing the des acetyl impurity below to 0.6%.

Example 2: Preparation of rifaximin

Rifamycin S (300 g) was stirred in dichloromethane (900 ml) at room temperature for 15 minutes to get a clear solution and then 2-Amino-4-methyl pyridine (139.2g) was added at room temperature under nitrogen atmosphere. Iodine (57. Og) dissolved in dichloromethane (2100ml), was added drop wise in 30-45 minutes at room temperature. The reaction mass was stirred for 22-24 hours at 25-30 °C. After completion of the reaction, a 20% solution of L(-) ascorbic acid in water (300 ml) was added. The reaction mixture was stirred for 45-60 minutes at room temperature and then cooled to 10-15 °C. The pH of the resulting solution was adjusted to 1.5-2.0 with slow addition of dilute hydrochloric acid under stirring. The reaction mass was stirred for 15-20 minutes and layers were separated. The organic layer was washed with demineralized water (1500 ml), 10% sodium thiosulfate solution (1500 ml) and with demineralized water till pH was neutral. The solvent was distilled off under vacuum at 40-45 °C to get a residue which was taken in cyclohexane (1500 ml) and stirred for 1 hour. The resulting solid was filtered, washed with cyclohexane (300 ml) crystallized from a mixture of ethyl alcohol and water (600ml; 420ml ethyl alcohol and 180 ml water) to get 240g of crude rifaximin having purity 99.3% by HPLC.

Example 3: Preparation of rifaximin

Step-1: Preparation of crude rifaximin

Rifamycin S (300 g) was stirred in dichloromethane (900 ml) at room temperature for 15 minutes to get a clear solution and then 2-amino-4-methyl pyridine (139.2g) was added at room temperature under nitrogen atmosphere. Iodine (57. Og) dissolved in dichloromethane (2100ml), was added drop wise in 30-45 minutes at room temperature and was stirred for 22-24 hours. After completion of the reaction, a 20% solution of L (-) ascorbic acid in water (300 ml) was added and stirred for 45-60 minutes. The reaction mass was cooled to 10-15 °C and pH of the resulting solution was adjusted to 1.5-2.0 with slow addition of dilute hydrochloric acid under stirring. The reaction mass was stirred for 15-20 minutes and layers were separated and the organic layer was washed with demineralized water (1500 ml), with 10% sodium thiosulfate solution (1500 ml) and demineralized water till pH was neutral. The solvent was distilled off under vacuum at 40-45 °C to obtain a residue which was crystallized from a mixture of ethyl alcohol and water (378ml ethyl alcohol and 162 ml water) and dried at 35-40 °C to obtain 240g crude rifaximin having purity 98.8% by HPLC. Step-2: Purification of crude rifaximin

Crude rifaximin (240g) was stirred in dichloromethane (2400ml) at room temperature, a neutral alumina (240g) was added, stirred for 1 hour and filtered. The solvent was then distilled off and residue was treated with ethyl acetate (2400ml) and stirred to dissolution. The resulting residue was crystallized from a mixture of ethyl alcohol and water (302ml ethyl alcohol and 130ml water) and dried at 35-40 “C to obtain 192g of rifaximin having purity 99.8% by HPLC.

PATENT

https://www.google.com/patents/US9018225

PAPER

https://www.researchgate.net/profile/Miriam_Barbanti/publication/245268795_Viscomi_G_C_et_al_Crystal_forms_of_rifaximin_and_their_effect_on_pharmaceutical_properties_Cryst_Eng_Comm_10_1074-1081/links/556ec70d08aefcb861dba679.pdf

 

STR1

 

STR1

PATENTS

US4341785 May 11, 1981 Jul 27, 1982 Alfa Farmaceutici S.P.A. Imidazo-rifamycin derivatives with antibacterial utility
US4557866 Apr 26, 1985 Dec 10, 1985 Alfa Farmaceutici S.P.A. Process for the synthesis of pyrido-imidazo rifamycins
US7045620 Dec 5, 2003 May 16, 2006 Alfa Wassermann, S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations
US7612199 Jun 4, 2009 Nov 3, 2009 Alfa Wassermann, S.P.A. Polymorphic forms α, β, and γ of rifaximin
US7902206 Mar 8, 2011 Alfa Wassermann, S.P.A. Polymorphic forms α, β and γ of rifaximin
US7906542 May 13, 2008 Mar 15, 2011 Alfa Wassermann, S.P.A. Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin
US7915275 Mar 29, 2011 Alfa Wassermann, S.P.A. Use of polymorphic forms of rifaximin for medical preparations
US7923553 Apr 12, 2011 Alfa Wassermann, S.P.A. Processes for the production of polymorphic forms of rifaximin
US7928115 Apr 19, 2011 Salix Pharmaceuticals, Ltd. Methods of treating travelers diarrhea and hepatic encephalopathy
US8158644 Apr 17, 2012 Alfa Wassermann, S.P.A. Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin
US8158781 Mar 4, 2011 Apr 17, 2012 Alfa Wassermann, S.P.A. Polymorphic forms α, β and γ of rifaximin
US8193196 Feb 27, 2006 Jun 5, 2012 Alfa Wassermann, S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US20050272754 * May 24, 2005 Dec 8, 2005 Alfa Wassermann S.P.A. Polymorphic forms of rifaximin, processes for their production and uses thereof
Reference
1 Viscomi, G. C., et al., “Crystal forms of rifaximin and their effect on pharmaceutical properties“, Cryst Eng Comm, 2008, 10, 1074-1081, (May 28, 2008), 1074-1081.
Citing Patent Filing date Publication date Applicant Title
US9186355 Mar 30, 2015 Nov 17, 2015 Novel Laboratories Rifaximin crystalline forms and methods of preparation thereof
WO2008035109A1 * Sep 24, 2007 Mar 27, 2008 Cipla Limited Rifaximin
WO2009108730A2 * Feb 25, 2009 Sep 3, 2009 Salix Pharmaceuticals, Ltd. Forms of rifaximin and uses thereof
WO2011080691A1 * Dec 27, 2010 Jul 7, 2011 Silvio Massimo Lavagna Method for the production of amorphous rifaximin
EP1698630A1 * Mar 3, 2005 Sep 6, 2006 ALFA WASSERMANN S.p.A. New polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US20080262220 * May 13, 2008 Oct 23, 2008 Giuseppe Claudio Viscomi Polymorphic forms alpha, beta and gamma of rifaximin
US20090082558 * Sep 20, 2007 Mar 26, 2009 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation

 

REFERENCED BY
Citing Patent Filing date Publication date Applicant Title
WO2015014984A1 * Aug 1, 2014 Feb 5, 2015 Clarochem Ireland Ltd. A process for preparing rifaximin k
CN103360357A * Aug 7, 2013 Oct 23, 2013 中国药科大学 A simvastatin-gliclazide co-amorphous compound
US9359374 Jun 13, 2013 Jun 7, 2016 Apotex Pharmachem Inc. Polymorphic forms of rifaximin
US4341785 * May 11, 1981 Jul 27, 1982 Alfa Farmaceutici S.P.A. Imidazo-rifamycin derivatives with antibacterial utility
US4557866 * Apr 26, 1985 Dec 10, 1985 Alfa Farmaceutici S.P.A. Process for the synthesis of pyrido-imidazo rifamycins
US7045620 * Dec 5, 2003 May 16, 2006 Alfa Wassermann, S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations
Citing Patent Filing date Publication date Applicant Title
US8518949 Jun 4, 2012 Aug 27, 2013 Alfa Wassermann S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US20140079783 * Jul 3, 2013 Mar 20, 2014 Alfa Wassermann Spa Pharmaceutical Compositions Comprising Rifaximin and Amino acids, Preparation Methods and Use Thereof
CN101836959A * May 20, 2010 Sep 22, 2010 山东达因海洋生物制药股份有限公司 Method for preparing almost bitterless rifaximin dry suspension
CN103269587A * Jun 3, 2011 Aug 28, 2013 萨利克斯药品有限公司 New forms of rifaximin and uses thereof
WO2011153444A1 * Jun 3, 2011 Dec 8, 2011 Salix Pharmaceuticals, Ltd New forms of rifaximin and uses thereof

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External links

Patents
Patent Number Pediatric Extension Approved Expires (estimated)
US6861053 No 1999-08-11 2019-08-11 Us
US7045620 No 2004-06-19 2024-06-19 Us
US7452857 No 1999-08-11 2019-08-11 Us
US7605240 No 1999-08-11 2019-08-11 Us
US7612199 No 2004-06-19 2024-06-19 Us
US7718608 No 1999-08-11 2019-08-11 Us
US7902206 No 2004-06-19 2024-06-19 Us
US7906542 No 2005-06-01 2025-06-01 Us
US7915275 No 2005-02-23 2025-02-23 Us
US7928115 No 2009-07-24 2029-07-24 Us
US7935799 No 1999-08-11 2019-08-11 Us
US8158644 No 2004-06-19 2024-06-19 Us
US8158781 No 2004-06-19 2024-06-19 Us
US8193196 No 2007-09-02 2027-09-02 Us
US8309569 No 2009-07-18 2029-07-18 Us
US8518949 No 2006-02-27 2026-02-27 Us
US8642573 No 2009-10-02 2029-10-02 Us
US8741904 No 2006-02-27 2026-02-27 Us
US8829017 No 2009-07-24 2029-07-24 Us
US8835452 No 2004-06-19 2024-06-19 Us
US8853231 No 2004-06-19 2024-06-19 Us
US8946252 No 2009-07-24 2029-07-24 Us
US8969398 No 2009-10-02 2029-10-02 Us
Properties
Rifaximin
Rifaximin.svg
Rifaximin ball-and-stick.png
Systematic (IUPAC) name
(2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro
[4,5-e]pyrido[1,2-a]-benzimida-zole-1,15(2H)-dione,25-acetate
Clinical data
Trade names Xifaxan, Xifaxanta, Normix, Rifagut
AHFS/Drugs.com Monograph
MedlinePlus a604027
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability < 0.4%
Metabolism Hepatic
Biological half-life 6 hours
Excretion Fecal (97%)
Identifiers
CAS Number 80621-81-4 Yes
ATC code A07AA11 (WHO) D06AX11(WHO) QG51AA06 (WHO)QJ51XX01 (WHO)
PubChem CID 6436173
DrugBank DB01220 Yes
ChemSpider 10482302 Yes
UNII L36O5T016N Yes
KEGG D02554 Yes
ChEBI CHEBI:75246 
ChEMBL CHEMBL1617 Yes
Chemical data
Formula C43H51N3O11
Molar mass 785.879 g/mol

Giuseppe Viscomi, Manuela Campana, Dario Braga, Donatella Confortini, Vincenzo Cannata, Paolo Righi, Goffredo Rosini, “Polymorphic forms of rifaximin, processes for their production and uses thereof.” U.S. Patent US20050272754, issued December 08, 2005.

US20050272754

 

Title: Rifaximin
CAS Registry Number: 80621-81-4
CAS Name: (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-25-(Acetyloxy)-5,6,21,23-tetrahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]benzimidazole-1,15(2H)-dione
Additional Names: 4-deoxy-4¢-methylpyrido[1¢,2¢-1,2]imidazo[5,4-c]rifamycin SV; rifamycin L 105; rifaxidin
Manufacturers’ Codes: L-105
Trademarks: Fatroximin (Fatro); Flonorm (Schering-Plough); Normix (Alfa); Rifacol (Formenti); Xifaxan (Salix)
Molecular Formula: C43H51N3O11
Molecular Weight: 785.88
Percent Composition: C 65.72%, H 6.54%, N 5.35%, O 22.39%
Literature References: Nonabsorbable semisynthetic rifamycin antibiotic. Prepn: BE 888895; E. Marchi, L. Montecchi, US4341785 (1981, 1982 both to Alfa); E. Marchi et al., J. Med. Chem. 28, 960 (1985); and NMR study: M. Brufani et al., J. Antibiot.37, 1611 (1984). X-ray crystal structure: idem et al., ibid. 1623. In vitro and in vivo antibacterial activity: A. P. Venturini, E. Marchi,Chemioterapia 5, 257 (1986). Toxicological study: G. Borelli, D. Bertoli, ibid. 263. Clinical trial in travelers’ diarrhea: R. Steffen et al., Am. J. Gastroenterol. 98, 1073 (2003). Review of activity, pharmacokinetics and clinical experience in gastrointestinal infections: J. C. Gillis, R. N. Brogden, Drugs 49, 467-484 (1995); D. B. Huang, H. L. DuPont, J. Infection 50, 97-106 (2005).
Properties: Red orange powder, mp 200-205° (dec). uv max: 232, 260, 292, 320, 370, 450 nm (E1%1cm 489, 339, 295, 216, 119, 159). Sol in alcohols, ethyl acetate, chloroform, toluene. Insol in water. LD50 orally in rats: >2000 mg/kg (Borelli, Bertoli).
Melting point: mp 200-205° (dec)
Absorption maximum: uv max: 232, 260, 292, 320, 370, 450 nm (E1%1cm 489, 339, 295, 216, 119, 159)
Toxicity data: LD50 orally in rats: >2000 mg/kg (Borelli, Bertoli)
Therap-Cat: Antibacterial.
Therap-Cat-Vet: Antibacterial.
Keywords: Antibacterial (Antibiotics); Ansamycins.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MORE…….

Rifaximin, alpha-0817185, L-105, Xifaxan, Lumenax, Flonorm, RedActiv, Rifacol, Normix

Drug Name XIFAXAN
Application Number 021 361 Number 001
Active ingredients RIFAXIMIN Market Status prescription
Dosage form or route of administration TABLET; ORAL specification 200MG
Treatment equivalent code Drug Reference Yes
Date of approval 2004/05/25 The applicant SALIX PHARMACEUTICALS INC
Chemistry New molecular entity (NME) Review Categories Standard review drug
Patents related to this product information (from the Orange Book Orange Book)
Patent No Patent expiration date Whether the compound patent Whether or not product patents Patents purpose code Patent Download
7928115 2029/07/24 U-1121 PDF format
8741904 2026/02/27 Y U-1526 PDF format
7612199 2024/06/19 Y Y PDF format
8853231 2024/06/19 Y PDF format
9271968 2026/02/27 Y PDF format
8158644 2024/06/19 Y PDF format
8193196 2027/09/02 Y Y PDF format
7906542 2025/06/01 Y Y PDF format
8158781 2024/06/19 Y PDF format
7045620 2024/06/19 Y Y PDF format
8518949 2026/02/27 Y PDF format
8835452 2024/06/19 Y Y PDF format
7902206 2024/06/19 Y Y PDF format
History Patent Information
7045620 2024/05/22 Y PDF format
8642573 2029/10/02 U-1481 PDF format
Related to this product market exclusivity protection information
Exclusivity Code Expiration date
no
Historical market exclusivity protection information
NCE 2009/05/25
And information related to drug registration
Application Number Amendment No. Approval Conclusion Disclosure Document Type Document creation time Obtaining Documentation
021 361 013 AP Label 2014/03/13 download
021 361 013 AP Letter 2014/03/14 download
021 361 012 AP Letter 2015/05/28 download
021 361 012 AP Label 2015/05/29 download
021 361 011 AP Label 2010/03/05 download
021 361 011 AP Letter 2010/03/08 download
021 361 009 AP Label 2010/11/17 download
021 361 009 AP Letter 2010/11/18 download
021 361 006 AP Label 2007/02/02 download
021 361 006 AP Letter 2007/02/12 download
021 361 000 AP Letter 2004/06/01 download
021 361 000 AP Label 2004/06/01 download
021 361 000 AP Review 2004/08/27 download
Regulatory approval history information
Application Number Amendment No. Approval Conclusion Approval Date Approval of the content
021 361 016 AP 2015/10/15 Manufacturing Change or Addition
021 361 015 AP 2016/06/16 Manufacturing Change or Addition
021 361 014 AP 2015/04/23 Manufacturing Change or Addition
021 361 013 AP 2014/03/12 Labeling Revision
021 361 012 AP 2015/05/27 Efficacy Supplement with Clinical Data to Support
021 361 011 AP 2010/03/03 Labeling Revision
021 361 009 AP 11/15/2010 Labeling Revision
021 361 006 AP 2007/01/30 Labeling Revision
021 361 000 AP 2004/05/25 Approval

///////Rifaximin,  Rifaxidin,  Rifacol,  Xifaxan,  Normix,  Rifamycin L 105, 80621-81-4, Rifaximin, alpha-0817185, L-105, Xifaxan, Lumenax, Flonorm, RedActiv, Rifacol, Normix

CC1C=CC=C(C(=O)NC2=C(C3=C(C4=C(C(=C3O)C)OC(C4=O)(OC=CC(C(C(C(C(C(C1O)C)O)C)OC(=O)C)C)OC)C)C5=C2N6C=CC(=CC6=N5)C)O)C

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NINTEDANIB

 Uncategorized  Comments Off on NINTEDANIB
Jul 062016
 

Nintedanib

NINTEDANIB, BBIF 1120, Intedanib

Boehringer Ingelheim Corp

As a potential treatment for a range of different solid tumour types
CAS 656247-17-5
CAS 1377321-64-6 (nintedanib bisethanesulfonate)
CAS [656247-18-6]  mono ethane sulfonate
3(Z)-[1-[4-[N-Methyl-N-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenylamino]-1-phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
MW 539.62, MF C31 H33 N5 O4

Launched 2014 USA….Idiopathic pulmonary fibrosis

 chinese, japanese  尼达尼布    ニンテダニブ

ChemSpider 2D Image | Nintedanib esylate | C33H39N5O7S

Ethanesulfonic acid – methyl (3Z)-3-{[(4-{methyl[(4-methyl-1-piperazinyl)acetyl]amino}phenyl)amino](phenyl)methylene}-2-oxo-6-indolinecarboxylate (1:1)

Nintedanib esylate

Cas 656247-18-6 [RN]

Methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate ethanesulfonate

Nintedanib esylate [USAN]

(3Z)-2,3-Dihydro-3-[[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-1H-indole-6-carboxylic acid methyl ester ethanesulfonate

1H-Indole-6-carboxylic acid, 2,3dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-,methyl ester, (3Z)-, ethanesulfonate (1:1)

Nintedanib esylate, 656247-18-6, UNII-42F62RTZ4G, , NSC753000, NSC-753000, KB-62821
Molecular Formula: C33H39N5O7S   Molecular Weight: 649.75706

ニンテダニブエタンスルホン酸塩

Highly crystalline (mp = 305 °C) and exhibits a log P of 3.0 and good aqueous solubility (>20 mg/mL in water)…..J. Med. Chem., 2015, 58 (3), pp 1053–1063

str1
Nintedanib esilate is a bright yellow powder soluble in water. The solubility increases at lower pH and decrease at higher pH due to the non-protonated free base which has a low solubility in water.At room temperature, the active substance exists only in one single crystalline form . The active substance contains no chiral centres. The double bond at C
-3 of the indole moiety allows forE/Zisomerism, but the activesubstance is the Z

Trade Name:Ofev® / Vargatef®

MOA:Tyrosine kinase inhibitor

Indication:Idiopathic pulmonary fibrosis (IPF); Non small cell lung cancer (NSCLC)

In 2011, orphan drug designation was assigned in the U.S. and Japan for the treatment of idiopathic pulmonary fibrosis. In 2013, orphan drug designation was also assigned for the same indication in the E.U. In 2014, a Breakthrough Therapy Designation was assigned to the compound for the treatment of idiopathic pulmonary fibrosis.

Nintedanib (formerly BIBF 1120) is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) being developed by Boehringer Ingelheim as an anti-angiogenesis anti-cancer agent under the trade name Vargatef, and recently approved for treatment of idiopathic pulmonary fibrosis as Ofev.

The use of nintedanib or its salts, particularly its esylate salt is claimed for treating non-small cell lung cancer (NSCLC) in a patient who has received prior treatment with an anti-tumor therapy other than with nintedanib, wherein the patient to be treated is selected for treatment on the basis showing progression of the cancer within a period of 9 months or less after the initiation of said prior treatment. It is also claimed that the compound may be administered in combination with an anti-cancer drug, eg docetaxel. Nintedanib is known to be an antagonist of FGF-1, FGF-2, FGF-3, VEGF-1, VEGF-2, VEGF-3, PDGF-α and PDGF-β receptors.
Use of nintedanib for the treatment of non-small cell lung cancer in a patient who has received prior anti-tumour therapy other than with nintedanib. Boehringer Ingelheim has developed and launched Ofev, an oral capsule formulation of nintedanib, for the treatment of idiopathic pulmonary fibrosis (IPF), hepatic insufficiency and cancer, including metastatic NSCLC, ovarian, prostate and colorectal cancer. In October 2014, the US FDA approved the drug and an NDA was filed in Japan for IPF. Picks up from WO2014049099, claiming pharmaceutical combinations comprising nintedanib and sunitinib.
Nintedanib is an indolinone derivative angiogenesis inhibitor, originated at Boehringer Ingelheim. In 2014, the product candidate was approved and launched in the U.S. for the treatment of idiopathic pulmonary fibrosis, and a positive opinion was received by the EMA for the same indication. Also in 2014, Nintedanib was approved in the E.U. for the oral treatment of locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy, in combination with docetaxel.The drug candidate is a small-molecule triple kinase inhibitor targeting the angiogenesis kinases (angiokinases) vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR). By allowing the vascularization necessary for the nourishment of tumors, these angiokinases have been implicated in tumor growth, proliferation and metastasis. In previous studies, intedanib potently and selectively inhibited human endothelial cell proliferation and induced apoptosis in human umbilical vein endothelial cells (HUVEC). It showed good oral bioavailability and tolerance, and significant antitumor activity was observed in a number of human tumor xenograft models.

Mechanism of action

Nintedanib is an indolinone-derived drug that inhibits the process of blood vessel formation (angiogenesis). Angiogenesis inhibitors stop the formation and reshaping of blood vessels in and around tumours, which reduces the tumour’s blood supply, starving tumour cells of oxygen and nutrients leading to cell death and tumour shrinkage. Unlike conventional anti-cancer chemotherapy which has a direct cell killing effect on cancer cells, angiogenesis inhibitors starve the tumour cells of oxygen and nutrients which results in tumour cell death. One of the advantages of this method of anti-cancer therapy is that it is more specific than conventional chemotherapy agents, therefore results in fewer and less severe side effects than conventional chemotherapy.

The process of new blood vessel formation (angiogenesis) is essential for the growth and spread of cancers. It is mediated by signaling molecules (growth factors) released from cancer cells in response to low oxygen levels. The growth factors cause the cells of the tumour’s blood vessel to divide and reorganize resulting in the sprouting of new vessels in and around the tumour, improving its blood supply.

Angiogenesis is a process that is essential for the growth and spread of all solid tumours, blocking it prevents the tumour from growing and may result in tumour shrinkage as well as a reduction in the spread of the cancer to other parts of the body. Nintedanib exerts its anti-cancer effect by binding to and blocking the activation of cell receptors involved in blood vessel formation and reshaping (i.e. VEGFR 1-3, FGFR 1-3 AND PDGFRα and β). Inhibition of these receptors in the cells that make up blood vessels (endothelial cells, smooth muscle cells and pericytes) by Nintedanib leads to programmed cell death, destruction of tumor blood vessels and a reduction in blood flow to the tumour. Reduced tumour blood flow inhibits tumor cell proliferation and migration hence slowing the growth and spread of the cancer.[1]

Adverse effects

Preclinical studies have shown that nintedanib binds in a highly selective manner to the ATP binding pocked of its three target receptor families, without binding to similarly shaped ATP domains in other proteins, which reduces the potential for undesirable side effects.[2]

The most common side effects observed with nintedanib were reversible elevation in liver enzymes (10-28% of patients) and gastrointestinal disturbance (up to 50%). Side effects observed with nintedanib were worse with the higher 250 mg dose, for this reason subsequent trials have used the equally clinically effective 200 mg dose.[1][2][3][4][5][6][7][8][9]

Nintedanib inhibits the growth and reshaping of blood vessels which is also an essential process in normal wound healing and tissue repair. Therefore a theoretical side effect of nintedanib is reduced wound healing however, unlike other anti-angiogenic agents, this side effect has not been observed in patients receiving nintedanib.

Studies

Preclinical studies have demonstrated that nintedanib selectively binds to and blocks the VEGF, FGF and PDGF receptors, inhibiting the growth of cells that constitute the walls of blood vessels (endothelial and smooth muscle cells and pericytes) in vitro. Nintedanib reduces the number and density of blood vessels in tumours in vivo, resulting in tumour shrinkage.[1][2] Nintedanib also inhibits the growth of cells that are resistant to existing chemotherapy agents in vitro, which suggests a potential role for the agent in patients with solid tumours that are unresponsive to or relapse following current first line therapy.[10]

Early clinical trials of nintedanib have been carried out in patients with non-small cell lung, colorectal, uterine, endometrial, ovarian and cervical cancer and multiple myeloma.[4][5][7][8][9] These studies reported that the drug is active in patients, safe to administer and is stable in the bloodstream. They identified that the maximum tolerated dose of nintedanib is 20 0 mg when taken once a day.

Clinical studies

In the first human trials, nintedanib halted the growth of tumours in up to 50% of patients with non-small cell lung cancer and 76% of patients with advanced colorectal cancer and other solid tumours.[4][8] A complete response was observed in 1/26 patients with non-small cell lung and 1/7 patients with ovarian cancer treated with nintedanib. A further 2 patients with ovarian cancer had partial responses to nintedanib.[8][9]

Two phase II trials have been carried out assessing the efficacy, dosing and side effects of nintedanib in non-small cell lung and ovarian cancer. These trials found that nintedanib delayed relapse in patients with ovarian cancer by two months[6] and that overall survival of patients with non-small cell lung who received nintedanib was similar to that observed with the FDA approved VEGFR inhibitor sorafenib. These trials also concluded that increasing the dose of the nintedanib has no effect on survival.[3]

SYNTHESIS

WO2009071523A1

NINTEDANIB JYOJO

MORE SYNTHESIS

Route 1

Reference:1. WO0127081A1.

2. US6762180B1.

3. J. Med. Chem. 2009, 52, 4466-4480.

Route 2

Reference:1. WO2009071523A1 / US8304541B2.

Route 3

Reference:1. CN104262232A.

Route 4

Reference:1. CN104844499A.

Current clinical trials

Nintedanib is being tested in several phase I to III clinical trials for cancer. Angiogenesis inhibitors such as nintedanib may be effective in a range of solid tumour types including; lung, ovarian, metastatic bowel, liver and brain cancer. Patients are also being recruited for three phase III clinical trials that will evaluate the potential benefit of nintedanib when added to existing 1st line treatments in patients with ovarian.[11] and 2nd line treatment in non-small cell lung cancer [12][13] The phase III trials of nintedanib in lung cancer have been named LUME-Lung 1 and LUME-Lung 2.

Current phase II trials are investigating the effect of nintedanib in patients with metastatic bowel cancer, liver cancer and the brain tumour: glioblastoma multiforme.[14]

Phase III trials are investigating the use of nintedanib in combination with the existing chemotherapy agents permexetred and docetaxel in patients with non-small cell lung cancer,[15] and in combination with carboplatin and paclitaxel as a first line treatment for patients with ovarian cancer.[16]

A phase III clinical trial was underway examining the safety and efficacy of nintedanib on patients with the non-cancerous lung condition idiopathic pulmonary fibrosis.[17] Nintedanib, under the brand name Ofev, was approved by the FDA for treatment of idiopathic pulmonary fibrosis on 15 Oct 2014. [18]

In terms of clinical development, additional phase III clinical trials are ongoing for the treatment of epithelial ovarian cancer, fallopian tube or primary peritoneal cancer, in combination with chemotherapy, and for the treatment of refractory metastatic colorectal cancer. Phase II clinical trials are also ongoing at the company for the treatment of glioblastoma multiforme, previously untreated patients with renal cell cancer, and for the treatment of patients with unresectable malignant pleural mesothelioma. The National Cancer Center of Korea (NCC) is evaluating the compound in phase II studies as second line treatment for small cell lung cancer (SCLC). The Centre Oscar Lambret is also conducting phase II clinical trials for the treatment of breast cancer in combination with docetaxel. Phase II trials are under way at EORTC as second line therapy for patients with either differentiated or medullary thyroid cancer progressing after first line therapy. The compound is also in early clinical development for the treatment of cancer of the peritoneal cavity, hepatocellular carcinoma, acute myeloid leukemia and ovarian cancer. Clinical trials have been completed for the treatment of prostate cancer and for the treatment of colorectal cancer. Boehringer Ingelheim is also conducting phase I/II clinical trials for the treatment of NSCLC and acute myeloid leukemia in addition to low-dose cytarabine. Phase I clinical studies are ongoing at the company for the treatment of epithelial ovary cancer and for the treatment of patients with mild and moderate hepatic impairment. The company had been evaluating the compound in early clinical trials for the treatment of prostate cancer in combination with docetaxel, but recent progress reports for this indication are not available at present.

In 2011, orphan drug designation was assigned in the U.S. and Japan for the treatment of idiopathic pulmonary fibrosis. In 2013, orphan drug designation was also assigned for the same indication in the E.U. In 2014, a Breakthrough Therapy Designation was assigned to the compound for the treatment of idiopathic pulmonary fibrosis.

PAPER

http://pubs.acs.org/doi/full/10.1021/jm501562a

Nintedanib: From Discovery to the Clinic

Department of Medicinal Chemistry; §Department of Drug Metabolism and Pharmacokinetics; Department of Non-Clinical Drug Safety; Department of Translational Medicine and Clinical Pharmacology; Department of Respiratory Diseases Research; and #Corporate Division Medicine, TA Oncology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany
Clinical Development and Medical Affairs, Respiratory, Boehringer Ingelheim Inc., Ridgefield, Connecticut 06877, United States
Boehringer Ingelheim RCV GmbH & Co. KG, A-1121 Vienna, Austria
J. Med. Chem., 2015, 58 (3), pp 1053–1063
DOI: 10.1021/jm501562a
Abstract Image

Nintedanib (BIBF1120) is a potent, oral, small-molecule tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor receptor (FGFR) family, the platelet-derived growth factor receptor (PDGFR) family, as well as Src and Flt-3 kinases. The compound was identified during a lead optimization program for small-molecule inhibitors of angiogenesis and has since undergone extensive clinical investigation for the treatment of various solid tumors, and in patients with the debilitating lung disease idiopathic pulmonary fibrosis (IPF). Recent clinical evidence from phase III studies has shown that nintedanib has significant efficacy in the treatment of NSCLC, ovarian cancer, and IPF. This review article provides a comprehensive summary of the preclinical and clinical research and development of nintedanib from the initial drug discovery process to the latest available clinical trial data.

  1. Roth, G. J.; Heckel, A.; Colbatzky, F.; Handschuh, S.; Kley, J.; Lehmann-Lintz, T.; Lotz, R.; Tontsch-Grunt,U.; Walter, R.; Hilberg, F.Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120) J. Med. Chem.2009, 52, 44664480
  2. 2.Roth, G. J.; Sieger, P.; Linz, G.; Rall, W.; Hilberg, F.; Bock, T. 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone monoethanesulphonate and the use thereof as a pharmaceutical composition. WO2004/013099. 2004.

  3. 3.Merten, J.; Linz, G.; Schnaubelt, J.; Schmid, R.; Rall, W.; Renner, S.; Reichel, C.; Schiffers, R. Process for the manufacture of an indolinone derivative. WO2009/071523. 2009

PAPER

http://pubs.acs.org/doi/abs/10.1021/jm900431g

J. Med. Chem., 2009, 52 (14), pp 4466–4480
DOI: 10.1021/jm900431g
Abstract Image

Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.

PATENT

WO-2014180955

The present invention relates to a beneficial treatment of tumours in patients suffering from NSCLC, and to a clinical marker useful as predictive variable of the responsiveness of tumours in patients suffering from NSCLC. The present invention further relates to a method for selecting patients likely to respond to a given therapy, wherein said method optionally comprises the use of a specific clinical marker. The present invention further relates to a method for delaying disease progression and/or prolonging patient survival of NSCLC patients, wherein said method comprises the use of a specific clinical marker.

The monoethanesulphonate salt form of this compound presents properties which makes this salt form especially suitable for development as medicament. The chemical structure of 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)-methylcarbonyl)-N-methyl-amino)-anilino)- 1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone-monoethanesulphonate (ΓΝΝ name nintedanib esylate) is depicted below as Formula Al .

Formula Al

This compound is thus for example suitable for the treatment of diseases in which angiogenesis or the proliferation of cells is involved. The use of this compound for the treatment of immunologic diseases or pathological conditions involving an

immunologic component is being described in WO 2004/017948, the use for the treatment of, amongst others, oncological diseases, alone or in combination, is being described in WO 2004/096224 and WO 2009/147218, and the use for the treatment of fibrotic diseases is being described in WO 2006/067165.

A method using biomarkers for monitoring the treatment of an individual with the compound 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-l -phenyl-methylene] -6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof, wherein it is determined if a sample from said individual comprises a biomarker in an amount that is indicative for said treatment, is disclosed in WO 2010/103058.

PATENT

http://www.google.com/patents/US20110201812

The present invention relates to a process for the manufacture of a specific indolinone derivative and a pharmaceutically acceptable salt thereof, namely 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and its monoethanesulfonate, to new manufacturing steps and to new intermediates of this process.

The indolinone derivative 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and its monoethanesulfonate are known from the following patent applications: WO 01/027081, WO 04/013099, WO 04/017948, WO 04/096224 and WO 06/067165. These patent applications disclose the compound, a process for its manufacture, a specific salt form of this compound and the use of the compound or its salt in a pharmaceutical composition to treat oncological or non-oncological diseases via inhibition of the proliferation of target cells, alone or in combination with further therapeutic agents. The mechanism of action by which the proliferation of the target cells occurs is essentially a mechanism of inhibition of several tyrosine kinase receptors, and especially an inhibition of the vascular endothelial growth factor receptor (VEGFR).

Figure US20110201812A1-20110818-C00001

Figure US20110201812A1-20110818-C00003

Figure US20110201812A1-20110818-C00004

EXAMPLE 1Synthesis of the 6-methoxycarbonyl-2-oxindole in accordance with the process shown in synthesis scheme CSynthesis of benzoic acid, 4-chloro-3-nitro-, methylester

    • 20 kg of 4-chloro-3-nitro-benzoic acid (99.22 mol) is suspended in 76 L methanol. 5.9 kg thionylchloride (49.62 mol) is added within 15 minutes and refluxed for about 3 hours. After cooling to about 5° C., the product is isolated by centrifugation and drying at 45° C.
    • Yield: 19.0 kg (88.8% of theoretical amount)
    • Purity (HPLC): 99.8%

Synthesis of propanedioic acid, [4-(methoxycarbonyl)-2-nitrophenyl]-, dimethylester

    • 12.87 kg of malonic acid, dimethylester (97.41 mol) is added to a hot solution (75° C.) of 10.73 kg sodium-tert.amylate (97.41 mol) in 35 L 1-methyl-2-pyrrolidinone (NMP). A solution of 10 kg benzoic acid, 4-chloro-3-nitro-, methylester (46.38 mol) in 25 L 1-methyl-2-pyrrolidinone is added at 75° C. After stirring for 1.5 hours at about 75° C. and cooling to 20° C., the mixture is acidified with 100 L diluted hydrochloric acid to pH 1. After stirring for 1.5 hours at about 5° C., the product is isolated by centrifugation and drying at 40° C.
    • Yield: 13.78 kg (95.4% of theoretical amount)
    • Purity (HPLC): 99.9%
    • Alternatively, propanedioic acid, [4-(methoxycarbonyl)-2-nitrophenyl]-, dimethylester can be synthesized as follows:
    • 33.1 kg of malonic acid, dimethylester (250.6 mol) and 27.0 kg benzoic acid, 4-chloro-3-nitro-, methylester (125.3 mol) are subsequently added to a solution of 45.1 kg sodium-methylate (250.6 mol) in 172 kg 1-methyl-2-pyrrolidinone (NMP) at 20° C. After stirring for 1.5 hours at about 45° C. and cooling to 30° C., the mixture is acidified with 249 L diluted hydrochloric acid. At the same temperature, the mixture is seeded, then cooled to 0° C. and stirred for an additional hour. The resulting crystals are isolated by centrifugation, washed and dryed at 40° C.
    • Yield: 37.5 kg (86% of theoretical amount)
    • Purity (HPLC): 99.7%

Synthesis of 6-methoxycarbonyl-2-oxindole

A solution of 13 kg propanedioic acid, [4-(methoxycarbonyl)-2-nitrophenyl]-, dimethylester (41.77 mol) in 88 L acetic acid is hydrogenated at 45° C. and under 40-50 psi in the presence of 1.3 kg Pd/C 10%. After standstill of the hydrogenation, the reaction is heated up to 115° C. for 2 hours. The catalyst is filtered off and 180 L water is added at about 50° C. The product is isolated after cooling to 5° C., centrifugation and drying at 50° C.

    • Yield: 6.96 kg (87.2% of theoretical amount)
    • Purity (HPLC): 99.8%

EXAMPLE 2Synthesis of the “chlorimide” (methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate)

Figure US20110201812A1-20110818-C00031

Method 1

6-methoxycarbonyl-2-oxindole (400 g; 2.071 mol) is suspended in toluene (1200 ml) at room temperature. Chloroacetic anhydride (540 g; 3.095 mol) is added to this suspension. The mixture is heated to reflux for 3 h, then cooled to 80° C. and methyl cyclohexane (600 ml) is added within 30 min. The resulting suspension is further cooled down to room temperature within 60 min. The mother liquor is separated and the solid is washed with ice cold methanol (400 ml). The crystals are dried to afford 515.5 g (93.5%) of the “chlorimide” compound as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ: 8.66 (s, 1H, 6-H); 7.86 (d, J=8.3 Hz, 1H, 8-H); 7.52 (d, J=8.3 Hz, 1H, 9-H); 4.98 (s, 2H, 15-H2); 3.95 (s, 3H, 18-H3); 3.88 (s, 2H, 3-H2). 13C-NMR (126 MHz, DMSO-d6) δ: 174.7 (C-2); 36.0 (C-3); 131.0 (C-4); 140.8 (C-5); 115.7 (C-6); 128.9 (C-7); 126.1 (C-8); 124.6 (C-9); 166.6 (C-10); 165.8 (C-13); 46.1 (C-15); 52.3 (C-18). MS: m/z 268 (M+H)+. Anal. calcd. for C12H10ClNO4: C, 53.85; H, 3.77; Cl, 13.25; N, 5.23. Found: C, 52.18; H, 3.64; Cl, 12.89; N, 5.00.

Method 2

6-Methoxycarbonyl-2-oxindole (10 g; 0.052 mol) is suspended in n-butyl acetate (25 ml) at room temperature. To this suspension a solution of chloroacetic anhydride (12.8 g; 0.037 mol) in n-butyl acetate (25 ml) is added within 3 min. The mixture is heated to reflux for 2 h, then cooled to 85° C. and methyl cyclohexane (20 ml) is added. The resulting suspension is further cooled down to room temperature and stirred for 2 h. The mother liquor is separated and the solid is washed with methanol (400 ml) at ambient temperature. The crystals are dried to afford 12.7 g (91.5%) of the “chlorimide” compound as a slightly yellow solid.

EXAMPLE 3Synthesis of the “chlorenol” (methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

Figure US20110201812A1-20110818-C00032

Method 1

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol) is suspended in toluene (60 ml) at ambient temperature. Acetic anhydride (16.2 g; 0.157 mol) is added to this suspension. The mixture is heated to not less than 104° C. and trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within 60 min. During the addition period and subsequent stirring at the same temperature for 3 h, volatile parts of the reaction mixture are distilled off. The concentration of the reaction mixture is kept constant by replacement of the distilled part by toluene (40 ml). The mixture is cooled down to 5° C., stirred for 1 h and filtrated. The solid is subsequently washed with toluene (14 ml) and with a mixture of toluene (8 ml) and ethyl acetate (8 ml). After drying, 16.3 g (91.7%) of the “chlorenol” compound are isolated as slightly yellow crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 8.73 (d, J=1.5 Hz, 1H, 6-H); 8.09 (d, J=8.0 Hz, 1H, 9-H); 7.90 (dd, J=8.1; 1.5 Hz, 1H, 8-H); 7.61-7.48 (m, 5H, 21-H, 22-H, 23-H, 24-H, 25-H); 4.85 (s, 2H, 18-H2); 3.89 (s, 3H, 27-H3); 3.78 (s, 3H, 15-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 165.9 (C-2+C16); 103.9 (C-3); 127.4; 128.6; 130.0; 135.4 (C-4+C-5+C-7+C-20); 115.1 (C-6); 126.1 (C-8); 122.5 (C-9); 166.7 (C-10); 173.4 (C-13); 58.4 (C-15); 46.4 (C-18); 128.6 (C-21+C-22+C-24+C-25); 130.5 (C-23); 52.2 (C-27). MS: m/z 386 (M+H)+. Anal. calcd. for C20H16ClNO5: C, 62.27; H, 4.18; Cl, 9.19; N, 3.63. Found: C, 62.21; H, 4.03; Cl, 8.99; N, 3.52.

Method 2

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol) is suspended in xylene (60 ml) at ambient temperature. Acetic anhydride (16.2 g; 0.157 mol) is added to this suspension. The mixture is heated to reflux, trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within 40 min and heating is maintained for 4 h. The mixture is cooled down to 0° C. and the mother liquor is separated. The solid is subsequently washed with xylene (14 ml) and a mixture of xylene (8 ml) and ethyl acetate (8 ml). After drying 14.3 g (81.0%) of the “chlorenol” compound are isolated as yellow crystals.

Method 3

Methyl-1-(chloroacetyl)-2-oxoindoline-6-carboxylate (12.0 g; 0.045 mol) is suspended in toluene (60 ml) at ambient temperature. Acetic anhydride (16.2 g; 0.157 mol) is added to this suspension. The mixture is heated to reflux, trimethyl orthobenzoate (20.0 g; 0.108 mol) is added within 40 min and heating is maintained for 3 h. The mixture is cooled down to 0° C. and the mother liquor is separated. The solid is subsequently washed with toluene (14 ml) and a mixture of toluene (8 ml) and ethyl acetate (8 ml). After drying 15.3 g (87.3%) of the “chlorenol” compound are isolated as fawn crystals.

EXAMPLE 4Synthesis of the “enolindole” (methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate)

Figure US20110201812A1-20110818-C00033

Method 1

A solution of potassium hydroxide (0.41 g, 0.006 mol) in methanol (4 ml) is added at 63° C. to a suspension of methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (8.0 g; 0.020 mol) in methanol (32 ml). The mixture is then stirred for 30 min, cooled to 0° C. and stirring is maintained for 2 h. After filtration, the solid is washed with methanol (24 ml) and dried to afford 6.0 g (94.6%) of the “enolindole” compound as yellow crystals. 1H-NMR (500 MHz, CDCl3) δ: 8.08 (s, 1H, 1-H); 7.88 (d, J=7.8 Hz, 1H, 9-H); 7.75 (m, 1H, 8-H); 7.52-7.56 (m, 3H, 18-H, 19-H, 20-H); 7.40-7.45 (m, 3H, 6-H, 17-H, 21-H); 3.92 (s, 3H, 23-H3); 3.74 (s, 3H, 13-H3). 13C-NMR (126 MHz, CDCl3) δ: 168.8 (C-2); 107.4 (C-3); 130.8 (C-4); 138.2 (C-5); 109.4 (C-6); 128.2 and 128.3 (C-7, C-16); 123.5 (C-8); 123.1 (C-9); 170.1 (C-11); 57.6 (C-13); 167.2 (C-14); 128.7 and 128.9 (C-17, C-18, C-20, C-21); 130.5 (C-19); 52.1 (C-23). MS (m/z): 310 (M+H)+. Anal. calcd. for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.34; H, 4.92; N, 4.56.

Method 2

A suspension of methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (7.0 g; 0.018 mol) in methanol (28 ml) is heated to reflux. Within 3 min, a solution of sodium methoxide in methanol (0.24 g, 30 (w/w), 0.001 mol) is added to this suspension. The mixture is then stirred for 30 min, cooled to 5° C. and stirring is maintained for 2 h. After filtration, the solid is washed with methanol (9 ml) and dried to afford 5.4 g (89.7%) of the “enolindole” compound as yellow crystals.

Method 3

A suspension of methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (8.0 g; 0.021 mol) in methanol (32 ml) is heated to reflux. A solution of sodium methoxide in methanol (0.74 g, 30% (w/w), 0.004 mol), further diluted with methanol (4 ml), is added dropwise to this suspension. The mixture is then stirred for 90 min, cooled to 0° C. and stirring is maintained for 2 h. After filtration, the solid is washed with methanol (24 ml) and dried to afford 5.9 g (91.2%) of the “enolindole” compound as yellow crystals.

EXAMPLE 5Synthesis of the “chloroacetyl” (N-(4-nitroanilino)-N-methyl-2-chloro-acetamide)

Figure US20110201812A1-20110818-C00034

Method 1

A suspension of N-methyl-4-nitroaniline (140 g; 0.920 mol) in ethyl acetate (400 ml) is heated to 70° C. Within 90 min, chloro acetylchloride (114 g; 1.009 mol) is added to this suspension. The resulting solution is then refluxed for 1 h, cooled to 60° C. and methyl cyclohexane (245 ml) is added. The suspension is further cooled down to 0° C. and stirred for 1 h. The reaction mixture is filtrated, washed with methyl cyclohexane (285 ml) and the precipitate is dried to afford 210.4 g (92.7%) of the “chloroacetyl” compound as white crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 8.29 (d, J=8.5 Hz, 2H, 1-H+3-H); 7.69 (d, J=8.5 Hz, 2H, 4-H+6-H); 4.35 (s, 2H, 9-H2); 3.33 (s, 3H, 12-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 124.6 (C-1+C-3); 145.6 (C-2); 127.4 (C-4+C-6); 148.6 (C-5); 165.6 (C-8); 42.7 (C-9); 37.2 (C-12). MS (m/z): 229 (M+H)+. Anal. calcd. for C9H9ClN2O3: C, 47.28; H, 3.97; N, 12.25. Found: C, 47.26; H, 3.99; Cl, 15.73; N, 12.29.

Method 2

A suspension of N-methyl-4-nitroaniline (20.0 g; 0.131 mol) in ethyl acetate (20 ml) is heated to 60° C. Within 15 min, a solution of chloro acetic anhydride (26.0 g; 0.151 mol) in ethyl acetate (60 ml) is added to this suspension. The resulting solution is then refluxed for 1 h, cooled to 75° C. ° C. and methyl cyclohexane (80 ml) is added. After seeding at 60° C., the suspension is further cooled down to 0° C. and stirred for 1 h. The reaction mixture is filtrated, washed with methyl cyclohexane (40 ml) and the precipitate is dried to afford 25.9 g (83.3%) of the “chloroacetyl” compound as grey crystals.

EXAMPLE 6Synthesis of the “nitroaniline” (N-(4-nitrophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide) and of the “aniline” (N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide)

Figure US20110201812A1-20110818-C00035

Method 1

A suspension of N-(4-nitroanilino)-N-methyl-2-chloro-acetamide (20.0 g; 0.087 mol) in toluene (110 ml) is heated to 40° C. Within 30 min, 1-methylpiperazine (21.9 g; 0.216 mol) is added dropwise. After purging of the dropping funnel with toluene (5 ml) the reaction mixture is stirred for 2 h at 55° C., cooled to ambient temperature and washed with water (15 ml). The organic layer is diluted with isopropanol (100 ml) and Pd/C (10%; 1.0 g) is added. After subsequent hydrogenation (H2, 4 bar) at 20° C. the catalyst is removed. Approximately ⅘ of the volume of the resulting solution is evaporated at 50° C. The remaining residue is dissolved in ethyl acetate (20 ml) and toluene (147 ml) heated to 80° C., then cooled to 55° C. and seeded. The reaction mixture is further cooled to 0° C. and stirred for 3 h at the same temperature. After filtration, the solid is washed with ice cold toluene (40 ml) and dried to afford 20.2 g (88.0%) of the “aniline” compound as white crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 6.90 (d, J=8.5 Hz, 2H, 4-H+6-H); 6.65 (d, J=8.5 Hz, 2H, 1-H+3-H); 5.22 (2H, 19-H2); 3.04 (s, 3H, 9-H3); 2.79 (s, 2H, 11-H2); 2.32 (m, 4H, 13-H2+17-H2); 2.23 (m, 4H, 14-H2+16-H2); 2.10 (s, 3H, 18-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 114.0 (C-1+C-3); 148.0 (C-2); 127.6 (C-4+C-6); 131.5 (C-5); 168.9 (C-8); 36.9 (C-9); 58.5 (C-11); 52.4 (C-13+C-17); 54.6 (C-14+C-16); 45.7 (C-18). MS (m/z): 263 (M+H)+. Anal. calcd. for C14H22N4O: C, 64.09; H, 8.45; N, 21.36. Found: C, 64.05; H, 8.43; N, 21.39.

Method 2

A suspension of N-(4-nitroanilino)-N-methyl-2-chloro-acetamide (14.5 g; 0.063 mol) in ethyl acetate (65 ml) is heated to 40° C. Within 30 min, 1-methylpiperazine (15.8 g; 0.156 mol) is added dropwise. After purging of the dropping funnel with ethyl acetate (7 ml) the reaction mixture is stirred at 50° C. for 90 min, cooled to ambient temperature and washed with water (7 ml). The organic layer is diluted with isopropanol (75 ml) and dried over sodium sulphate. After separation of the solid, Pd/C (10%; 2.0 g) is added and the solution is hydrogenated (H2, 5 bar) at ambient temperature without cooling. Subsequently the catalyst is removed by filtration and the solvent is evaporated at 60° C. The remaining residue is dissolved in ethyl acetate (250 ml) and recrystallized. After filtration and drying 10.4 g (60.4%) of the “aniline” compound are isolated as white crystals.

EXAMPLE 7Synthesis of the “anilino” (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone)

Figure US20110201812A1-20110818-C00036

Method 1

A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10.0 g; 0.032 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (8.6 g; 0.032 mol) in a mixture of methanol (72 ml) and N,N-dimethylformamide (18 ml) is heated to reflux. After 7 h of refluxing the suspension is cooled down to 0° C. and stirring is maintained for additional 2 h. The solid is filtered, washed with methanol (40 ml) and dried to afford 15.4 g (88.1%) of the “anilino” compound as yellow crystals. 1H-NMR (500 MHz, DMSO-d6) δ: 11.00 (s, 1H, 23-H); 12.23 (s, 19-H); 7.61 (t; J=7.1 Hz, 1H, 33-H); 7.57 (t, J=7.5 Hz, 2H, 32-H+34-H); 7.50 (d, J=7.7 Hz, 2H, 31-H+35-H); 7.43 (d, J=1.6 Hz, 1H, 29-H); 7.20 (dd, J=8.3; 1.6 Hz, 1H, 27-H); 7.13 (d, J=8.3 Hz, 2H, 14-H+18-H); 6.89 (d, 8.3 Hz, 2H, 15-H+17-H); 5.84 (d, J=8.3 Hz, 1H, 26-H); 3.77 (s, 3H, 40-H3); 3.06 (m, 3H, 12-H3); 2.70 (m, 2 H, 8-H2); 2.19 (m, 8H, 2-H2, 3-H2, 5-H2, 6-H2); 2.11 (s, 3H, 7-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 54.5 (C-2+C-6); 52.2 (C-3+C-5); 45.6 (C-7); 59.1 (C-8); 168.5 (C-9); 36.6 (C-12); 140.1 (C-13); 127.6 (C-14+C-18); 123.8 (C-17+C-15); 137.0 (C-16); 158.3 (C-20); 97.5 (C-21); 170.1 (C-22); 136.2 (C-24); 128.9 (C-25); 117.2 (C-26); 121.4 (C-27); 124.0 (C-28); 109.4 (C-29); 131.9 (C-30); 128.4 (C-31+C-35); 129.4 (C-32+C-34); 130.4 (C-33); 166.3 (C-37); 51.7 (C-40). MS (m/z): 540 (M+H)+. Anal. calcd. for C31H33N5O4: C, 69.00; H, 6.16; N, 12.98. Found: C, 68.05; H, 6.21; N, 12.81.

Method 2

A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (20.0 g; 0.064 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (17.1 g; 0.065 mol) in methanol (180 ml) is heated to reflux for 7.5 h. The resulting suspension is cooled down to 10° C. within 1 h and stirring is maintained for 1 h. After filtration, the solid is washed with ice cold methanol (80 ml) and dried to afford 31.0 g (89.0%) of the “anilino” compound as yellow crystals.

EXAMPLE 8Synthesis of the 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, monoethanesulfonate

Figure US20110201812A1-20110818-C00037

A suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone (30.0 g; 0.055 mol) in methanol (200 ml) and water (2.4 ml) is heated to 60° C. Aqueous ethanesulfonic acid (70% (w/w); 8.75 g; 0.056 mol) is added to the reaction mixture. The resulting solution is cooled to 50° C., seeded and then diluted with isopropanol (200 ml). The mixture is further cooled to 0° C. and stirred for 2 h at this temperature. The precipitate is isolated, washed with isopropanol (120 ml) and dried to furnish 35.1 g (97.3%) of the monoethanesulfonate salt of the compound as yellow crystals. 1H-NMR (400 MHz, DMSO-d6) δ: 12.26 (s, 11-H); 10.79 (s, 1H, 1-H); 9.44 (s, 1H, 24-H); 7.64 (m, 1H, 32-H); 7.59 (m, 2H, 31-H+33-H); 7.52 (m, 2H, 30-H+34-H); 7.45 (d, J=1.6 Hz, 1H, 7-H); 7.20 (dd, J=8.2; 1.6 Hz, 1H, 5-H); 7.16 (m, 2H, 14-H+16-H); 6.90 (m, 2H, 13-H+17-H); 5.85 (d, J=8.2 Hz, 1H, 4-H); 3.78 (s, 3H, 37-H3); 3.45-2.80 (broad m, 4H, 23-H2+25-H2); 3.08 (s, 3H, 28-H3); 2.88 (s, 2H, 20-H2); 2.85-2.30 (broad m, 4H, 22-H2+26-H2); 2.75 (s, 3H, 27-H3); 2.44 (q, J=7.4 Hz, 2H, 39-H2); 1.09 (t, J=7.4 Hz, 3H, 38-H3). 13C-NMR (126 MHz, DMSO-d6) δ: 9.8 (C-38); 36.6 (C-28); 42.3 (C-27); 45.1 (C-39); 51.7 (C-37); 48.9 (C-22+C-26); 52.6 (C-23+C-25); 57.5 (C-20); 97.7 (C-3); 109.5 (C-7); 117.3 (C-4); 121.4 (C-5); 123.8 (C-13+C-17); 124.1 (C-6); 127.7 (C-14+C-16); 128.4 (C-30+C-34); 128.8 (C-9); 129.5 (C-31+C-33); 130.5 (C-32); 132.0 (C-29); 168.5 (C-9); 136.3 (C-8); 137.3 (C-12); 139.5 (C-15); 158.1 (C-10); 166.3 (C-35); 168.0 (C-19); 170.1 (C-2). MS (m/z): 540 (M(base)+H)+. Anal. calcd. for C33H39N5O7S: C, 60.17; H, 6.12; N, 10.63; S, 4.87. Found: C, 60.40; H, 6.15; N, 10.70; S, 4.84.

CLIPS

Figure

After a classical malonic ester addition to arene 3, the resulting nitro benzene (4) is hydrogenated under acidic conditions, furnishing the 6-methoxycarbonyl-substituted oxindole 5 via decarboxylative cyclization. Condensation of 5 with trimethyl orthobenzoate in acetic anhydride leads to compound 6, one of the two key building blocks of the synthesis. The concomitant N-acetylation of the oxindole activates the scaffold for the condensation reaction.
The aniline side chain (9) can be prepared by a one-pot bromo-acetylation/amination of the para-nitro-phenylamine (7) using bromoacetyl bromide and N-methylpiperazine and a subsequent hydrogenation furnishing 9 as the second key building block. Condensation of both building blocks in an addition–elimination sequence and subsequent acetyl removal with piperidine furnishes 2 as free base (pKa = 7.9), which subsequently is converted into its monoethanesulfonate salt (1). Compound 1 is highly crystalline (mp = 305 °C) and exhibits a log P of 3.0 and good aqueous solubility (>20 mg/mL in water).

CLIPS

see

http://www.yaopha.com/2014/07/09/synthesis-of-vargatef-nintedanib-boehringer-ingelheim-idiopathic-pulmonary-fibrosis-drug/

NINTEDANIB SINA

CLICK ON PIC

Updates………..

“J.Med.Chem” 2009 Vol. 52, page 4466-4480 and the “Chinese Journal of Pharmaceuticals” 2012, Vol. 43, No. 9, page 726-729 reported a further intermediate A and B synthesis, and optimized from the reaction conditions, the reaction sequence, the feed ratio and catalyst selection, etc., so that the above-described synthetic routes can be simplified and reasonable.

PATENT

CN105461609A

NINTE PIC

MACHINE TRANSLATED FROM CHINESE

Synthesis of Trinidad Neeb (I),

A 500ml reaction flask was charged 30g of compound V, 22.5g compound of the VI, ethanol 300ml, sodium bicarbonate and 15g, the reaction was heated to reflux for 2 hours, the reaction mixture was added to 600ml of water, there are large amount of solid precipitated, was filtered, the cake washed with 100ml washed once with methanol, a yellow solid 41.9g refined Trinidad Neeb (I). Yield 92.7%.

4 bandit R (400MHz, dmso) δ11 · 97 (s, 1H), 8.38 (s, 1H), 7.97 (dd, J = 11.9, 5.0Hz, 2H), 7.67 (d, J = 8.1Hz, 1H), 7.16 (ddd, J = 26.9, 22.1, 7.0Hz, 5H), 6.85 (d, J = 8.6Hz, 2H), 6.63 (d, J = 8.7Hz, 2H), 3.90 (s, 3H), 2.99 (s, 3H), 2.69 (s, 2H), 2.51-2.24 (m, 8H), 2.20 (s, 3H) MS:. m / z540 (m + 1) + 2 Example: Preparation of compound IV 250ml reaction flask was added 28.7g of 2- oxindole-6-carboxylate, 130ml ethanol, stirred open, then added 30.3ml (31.8g) benzaldehyde, 2.97 mL piperidine was heated to 70 ° C-80 after ° C for 2 hours, allowed to cool to 20 ° C- 30 ° C, the precipitate was filtered, the filter cake was washed with absolute ethanol, 50 ° C 5 hours and dried in vacuo give a yellow solid 38.7g (IV of), yield: 92.4% Preparation of compound V square in 500ml reaction flask was added 30g compound IV, dichloromethane 360ml, cooled with ice water to 0-5 ° C, 71/92 bromine 3.lml (9.7g), drop finished warmed to 20- 30 ° C, 3 hours after the reaction, the reaction solution was washed once with 150ml dichloromethane layer was concentrated oil was done by adding 200ml ethanol crystallization, filtration, 60 ° C and dried under vacuum 36.lg white solid (V ), yield: 93 · 8%.

 After Trinidad Technip (I) are synthesized in the reaction flask was added 500ml of 30g compound V, 33.0g compound of the VI, ethanol 300ml, sodium bicarbonate, 15g, was heated to reflux for 2 hours, the reaction mixture was added to 600ml water, there are large amount of solid precipitated, was filtered, the filter cake washed once with 100ml methanol obtained 42.3g of yellow solid was purified by Technip Trinidad (I). Yield 93.6%.

 ΧΗNMR (400MHz, dmso) δ11.94 (s, 1Η), 8.36 (s, 1H), 7.96 (dd, J = 11.9, 5.0Hz, 2H), 7.67 (d, J = 8.1Hz, 1H) , 7.16 (ddd, J = 26.9, 22.1, 7.0Hz, 5H), 6.85 (d, J = 8.6Hz, 2H), 6.61 (d, J = 8.7Hz, 2H), 3.90 (s, 3H), 2.99 ( s, 3H), 2.65 (s, 2H), 2.50-2.30 (m, 8H), 2.20 (s, 3H) MS:. m / z540 (m + 1) + square

PATENT

WO2016037514

(I) 2.30g, yield 85.3%. Melting point 241 ~ 243 ℃, Mass spectrum (the EI): m / Z 540 (the M + the H), 1 the H NMR (of DMSO D . 6 ): 2.27 (S, 3H), 2.43 (m, 8H), 2.78 (S, 2H) , 3.15 (s, 3H), 3.82 (s, 3H), 5.97 (d, J = 8.3Hz, 1H), 6.77 (d, J = 8.7Hz, 1H), 6.96 (d, J = 8.6Hz, 2H) , 7.32-7.62 (m, 8H), 8.15 (s, 1H), 12.15 (s, 1H).

CLIPS

http://pubs.rsc.org/en/content/articlelanding/2015/ay/c5ay01207d#!divAbstract

Nintedanib
Nintedanib

Nintedanib
Systematic (IUPAC) name
Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
Clinical data
Trade names Vargatef, Ofev
AHFS/Drugs.com Consumer Drug Information
Pregnancy cat.
Legal status
Routes Oral and intravenous
Identifiers
CAS number 656247-17-5 
ATC code None
Chemical data
Formula C31H33N5O4 
Mol. mass 539.6248 g/mol

References

  1. Hilberg, F.; G. J. Roth, M. Krssak, S. Kautschitsch, W. Sommergruber, U. Tontsch-Grunt, P. Garin-Chesa, G. Bader, A. Zoephel, J. Quant, A. Heckel, W. J. Rettig (2008). “BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy”. Cancer Res 68 (12): 4774–82. doi:10.1158/0008-5472.CAN-07-6307. ISSN 1538-7445. PMID 18559524.
  2. Hilberg, F.; U. Tontsch-Grunt, F. Colbatzky, A. Heckel, R. Lotz, J.C.A. van Meel, G.J. Roth (2004). “BIBF1120 a novel, small molecule triple angiokinase inhibitor: profiling as a clinical candidate for cancer therapy”. European Journal of Cancer Supplements 2 (50).
  3. Reck, M.; R. Kaiser; C. Eschbach; M. Stefanic; J. Love; U. Gatzemeier; P. Stopfer; J. von Pawel (2011). “A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer”. Ann Oncol. ISSN 1569-8041.
  4. Okamoto, I.; H. Kaneda, T. Satoh, W. Okamoto, M. Miyazaki, R. Morinaga, S. Ueda, M. Terashima, A. Tsuya, A. Sarashina, K. Konishi, T. Arao, K. Nishio, R. Kaiser, K. Nakagawa (2010). “Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors”. Mol Cancer Ther 9 (10): 2825–33. doi:10.1158/1535-7163.MCT-10-0379. ISSN 1538-8514. PMID 20688946.
  5. Mross, K.; M. Stefanic, D. Gmehling, A. Frost, F. Baas, C. Unger, R. Strecker, J. Henning, B. Gaschler-Markefski, P. Stopfer, L. de Rossi, R. Kaiser (2010). “Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors”. Clin Cancer Res 16 (1): 311–9. doi:10.1158/1078-0432.CCR-09-0694. ISSN 1078-0432. PMID 20028771.
  6. Ledermann, J.A. (2009). “A randomised phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC)”. J Clin Oncol 27 (15s): (suppl; abstr 5501).
  7. Kropff, M.; J. Kienast; G. Bisping; W. E. Berdel; B. Gaschler-Markefski; P. Stopfer; M. Stefanic; G. Munzert (2009). “An open-label dose-escalation study of BIBF 1120 in patients with relapsed or refractory multiple myeloma”. Anticancer Res 29 (10): 4233–8. ISSN 1791-7530. PMID 19846979.
  8. Ellis, P. M.; R. Kaiser; Y. Zhao; P. Stopfer; S. Gyorffy; N. Hanna (2010). “Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients”. Clin Cancer Res 16 (10): 2881–9. doi:10.1158/1078-0432.CCR-09-2944. ISSN 1078-0432. PMID 20460487.
  9. du Bois, A.; J. Huober; P. Stopfer; J. Pfisterer; P. Wimberger; S. Loibl; V. L. Reichardt; P. Harter (2010). “A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies”. Ann Oncol 21 (2): 370–5. doi:10.1093/annonc/mdp506. ISSN 1569-8041. PMID 19889612.
  10. Xiang, Q. F.; F. Wang; X. D. Su; Y. J. Liang; L. S. Zheng; Y. J. Mi; W. Q. Chen; L. W. Fu (2011). “Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance”. Cell Oncol (Dordr) 34 (1): 33–44. doi:10.1007/s13402-010-0003-7. ISSN 2211-3436.
  11. “Boehringer Ingelheim – AGO-OVAR 12 / LUME-Ovar 1 Trial Information”. 2011.
  12. “Boehringer Ingelheim – LUME-Lung 2 Trial Information”. 2011.
  13. “Boehringer Ingelheim – LUME-Lung 1 Trial Information”. 2011.
  14. http://clinicaltrials.gov/ct2/results?term=++%09+BIBF+1120&phase=1
  15. http://clinicaltrials.gov/ct2/show/NCT00805194 Phase III LUME-Lung 1: BIBF 1120 Plus Docetaxel as Compared to Placebo Plus Docetaxel in 2nd Line Non Small Cell Lung Cancer
  16. http://clinicaltrials.gov/ct2/show/NCT01015118 Phase III BIBF 1120 or Placebo in Combination With Paclitaxel and Carboplatin in First Line Treatment of Ovarian Cancer
  17. http://clinicaltrials.gov/ct2/show/NCT01335477 Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II
  18. “FDA approves Ofev to treat idiopathic pulmonary fibrosis”. 2014.
  19. F. Hilberg et al. Cancer Res. 2008, 68, 4774

    2. M. Reck et al. Ann. Oncol. 2011, 22, 1374

    3. M. Reck et al. J. Clin. Oncol. 2013 (suppl.), Abst LBA8011

    4. N. H. Hanna et al. J. Clin. Oncol. 2013, 2013 (suppl.), Abst 8034

    5. J.A. Ledermann et al. J. Clin Oncol. 2011, 29, 3798

    6. Glioblastoma: A. Muhac et al. J. Neurooncol. 2013, 111, 205

    7. O. Bouche et al. Anticancer Res. 2011, 31, 2271

    8. T. Eisen et al. J. Clin. Oncol. 2013 (suppl.), Abst. 4506

    MORE…………….

    Reference:

    [6]. Japan PMDA.

    [7]. Drug@FDA, NDA205832 Pharmacology Review(s).

    [8]. Med. Chem. 2015, 58, 1053-1063.

    [9]. Drug@EMA, EMEA/H/C/002569 Vargatef: EPAR-Assessment Report.

    [10]. Drug Des. Devel. Ther. 2015, 9, 6407-6419.

    [11]. Cancer Res. 2008, 68, 4774-4782.

    [12]. J. Med. Chem. 2009, 52, 4466-4480.

    [13]. J. Pharmacol. Exp. Ther. 2014, 349, 209-220.

    [14]. Clin. Cancer. Res. 2015, 21, 4856-4867.

    Merten, J.; et. al. Process for the manufacture of an indolinone derivative. US20110201812A1
    2. Roth, G. J.; et. al. 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition. WO2004013099A1
    3. Roth, G. J.; et. al. Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120). J Med Chem, 2009, 52(14), 4466-4480.

  20. ニンテダニブエタンスルホン酸塩
    Nintedanib Ethanesulfonate

    C31H33N5O4.C2H6O3S : 649.76
    [656247-18-6]
    US7119093 * Jul 21, 2003 Oct 10, 2006 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition

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

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TAK 243

 phase 1, Uncategorized  Comments Off on TAK 243
Jul 052016
 

img

STR1

TAK-243, AOB 87172, MLN-7243

CAS 1450833-55-2
Chemical Formula: C19H20F3N5O5S2
Molecular Weight: 519.5142

Sulfamic acid, [(1R,​2R,​3S,​4R)​-​2,​3-​dihydroxy-​4-​[[2-​[3-​[(trifluoromethyl)​thio]​phenyl]​pyrazolo[1,​5-​a]​pyrimidin-​7-​yl]​amino]​cyclopentyl]​methyl ester

((lR,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[l ,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate

methyl ((1S,2R,3S,4R)-2,3-dihydroxy-4-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)sulfamate

Phase I

Millennium Pharmaceuticals, Inc. INNOVATOR

Roushan AFROZE, Indu T. Bharathan,Jeffrey P. CIAVARRI, Paul E. Fleming,Jeffrey L. Gaulin, Mario Girard, Steven P. Langston, Francois R. SOUCY, Tzu-Tshin WONG, Yingchun Ye,

A UAE inhibitor potentially for the treatment of solid tumors.

TAK-243, also known as MLN7243 and AOB87172, is a small molecule inhibitor of ubiquitin-activating enzyme (UAE), with potential antineoplastic activity. UAE inhibitor MLN7243 binds to and inhibits UAE, which prevents both protein ubiquitination and subsequent protein degradation by the proteasome. This results in an excess of proteins in the cells and may lead to endoplasmic reticulum (ER) stress-mediated apoptosis. This inhibits tumor cell proliferation and survival. UAE, also called ubiquitin E1 enzyme (UBA1; E1), is more active in cancer cells than in normal, healthy cells.

Research Code TAK-243; MLN-7243, TAK-243; TAK 243; TAK243; MLN7243; MLN-7243; MLN 7243; AOB87172; AOB-87172; AOB 87172.

CAS No. 1450833-55-2(MLN 7243)

  • Originator Millennium
  • Developer Takeda Oncology
  • Class Antineoplastics
  • Mechanism of Action Ubiquitin-protein ligase inhibitors
  • Phase I Solid tumours

Most Recent Events

  • 01 Feb 2014 Phase-I clinical trials in Solid tumours (late-stage disease, second-line therapy or greater) in USA (IV)
  • 18 Dec 2013 Preclinical trials in Solid tumours in USA (IV)
  • 18 Dec 2013 Millennium plans a phase I trial for Solid tumours (late-stage disease, second-line therapy or greater) in USA (NCT02045095)

 

 

Cancer is the second most common cause of death in the U.S. and accounts for one of every eight deaths globally (American Cancer Society, Cancer Facts and Figures, 2014). The American Cancer Society expects that in 2014 at least 1,665,540 new cancer cases will be diagnosed in the US and 585,720 Americans are expected to die of cancer, almost 1 ,600 people per day. Currently available paradigms for treating solid tumors may include systemic treatment such as chemotherapy, hormonal therapy, use of targeted agents and biological agents, either as single agents or in combination. These treatments can be delivered in combination with localized treatments such as surgery or radiotherapy. These anti-cancer paradigms can be use in the curative setting as adjuvant or neo-adjuvant treatments or in the metastatic setting as palliative case for prolonged survival and to help manage symptoms and side-effects. In hematological cancers, stem cell transplants may also be an option in certain cancers as well as chemotherapy and/or radiation. Although medical advances have improved cancer survival rates, there remains a continuing need for new and more effective treatments.

Ubiquitin is a small 76-amino acid protein that is the founding member of a family of posttranslational modifiers known as the ubiquitin-like proteins (Ubls). Ubls play key roles in controlling many biological processes including cell division, cell signaling and the immune response. There are 8 known human Ubl activating enzymes (known as Els) (Schulman, B.A., and J.W. Harper, 2009, Ubiquitin-like protein activation by El enzymes: the apex for downstream signalling pathways, Nat Rev Mol Cell Biol 10:319-331). Ubiquitin and other Ubls are activated by a specific El enzyme which catalyzes the formation of an acyl-adenylate intermediate with the C-terminal glycine of the Ubl. The activated Ubl molecule is then transferred to the catalytic cysteine residue within the El enzyme through formation of a thioester bond intermediate. The El -Ubl intermediate and an E2 enzyme interact, resulting in a thioester exchange wherein the Ubl is transferred from the El to active site cysteine on the E2. The Ubl is then conjugated, i.e. transferred, to the target protein, either directly or in conjunction with an E3 ligase enzyme, through isopeptide bond formation with the amino group of a lysine side chain in the target protein. Eukaryotic cells possess ~35 ubiquitin E2 enzymes and >500 ubiquitin E3 enzymes. The E3 enzymes are the specificity factors of the ubiquitin pathway which mediate the selective targeting of specific cellular substrate proteins (Deshaies, R.J., and C.A. Joazeiro, 2009, RING domain E3 ubiquitin ligases, Annu Rev Biochem 78:399-434; Lipkowitz, S., and A.M. Weissman, 2011, RTNGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis, Nat Rev Cancer 11 :629-643; Rotin, D., and S. Kumar, 2009, Physiological functions of the HECT family of ubiquitin ligases, Nat Rev Mol Cell Biol 10:398-409).

Two El enzymes have been identified for ubiquitin, UAE (ubiquitin-activating enzyme) and UBA6 (Jin, J., et al., 2007, Dual El activation systems for ubiquitin differentially regulate E2 enzyme charging, Nature 447: 1135-1138). UAE is the El responsible for the majority (>99%) of ubiquitin flux within the cell. UAE is capable of charging each of the approximately -35 E2 enzymes with the exception of Usel, which is the only E2 known to exclusively work with UBA6 (Jin et al., 2007). Inhibition of UAE is sufficient to dramatically impair the great majority of ubiquitin-dependent cellular processes (Ciechanover, A., et al., 1984, Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85, Cell 37:57-66; Finley, D., A. et al., 1984, Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85, Cell 37:43-55).

The cellular signals generated by ubiquitin are diverse. Ubiquitin can be attached to substrates as a single entity or as polyubiquitin polymers generated through isopeptide linkages between the C-terminus of one ubiquitin and one of the many lysines on a second ubiquitin. These varied modifications are translated into a variety of cellular signals. For example, conjugation of a lysine 48 -linked polyubiquitin chain to a substrate protein is predominantly associated with targeting the protein for removal by the 26S proteasome. A single ubiquitin modification, or monoubiquination, typically affects protein localization and/or function. For example, monoubiquitination modulates the following: 1) the function of Histones 2a and 2b (Chandrasekharan, M.B., et al., 2010, Histone H2B ubiquitination and beyond: Regulation of nucleosome stability, chromatin dynamics and the trans-histone H3 methylation, Epigenetics 5:460-468), 2) controls the nucleo-cytoplasmic shuttling of PTEN (Trotman, L,C, et al., 2007, 3) ubiquitination regulates PTEN nuclear import and tumor suppression, Cell 128: 141-156), 4) drives localization of the FANCD2 protein to sites of DNA damage (Gregory, R.C., et al., 2003, Regulation of the Fanconi anemia pathway by monoubiquitination, Semin Cancer Biol 13:77-82) and 5) promotes the internalization and endosomal/lysosomal turnover of some cell surface receptors, like EGFR (Mosesson, Y., and Y. Yarden, 2006, Monoubiquitylation: a recurrent theme in membrane proteintransport. Isr Med Assoc J 8:233-237). Other forms of polyubiquitination chains occur on lysine positions 11, 29 and 63, impacting various cellular roles including cell cycle, DNA repair and autophagy (Behrends, C, and J.W. Harper, 2011, Constructing and decoding unconventional ubiquitin chains, Nat Struct Mol Biol 18:520-528; Bennett, E.J., and J.W. Harper, 2008, DNA damage: ubiquitin marks the spot, Nat Struct Mol Biol 15:20-22; Komander, D., 2009, The emerging complexity of protein ubiquitination, Biochem Soc Trans 37:937-953).

UAE-initiated ubiquitin conjugation plays an important role in protein homeostasis, cell surface receptor trafficking, transcription factor turnover and cell cycle progression. Many of these processes are important for cancer cell survival and it is believed that tumor cells may have increased sensitivity to UAE inhibition as a result of their rapid growth rate, increased metabolic demands and oncogene fueled protein stress. Preclinical studies with PYZD-4409, a UAE inhibitor, demonstrated this compound induced cell death in both leukemia and myeloma cell lines and induced anti-tumor activity in a mouse acute myeloid leukemia (AML model). (Xu, W.G., et al., 2010, The ubiquitin-activating enzyme El as a therapeutic target for the treatment of leukemia and multipie myeloma, Blood, 115:2251-59). Thus, UAE represents a protein homeostasis target opportunity for the treatment of cancer.

 

 

Abstract A164: The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when combined with radiation, carboplatin and docetaxel

Michael A. Milhollen, Judi Shi, Tary Traore, Jessica Huck, Darshan Sappal, Jennifer Duffy, Eric Lightcap, Yuko Ishii, Jeff Ciavarri, Paul Fleming, Neil Bence, Marc L. Hyer
Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA

Abstract

Clinical results of VELCADE® (bortezomib) For Injection have prompted evaluation of other enzymes within the ubiquitin proteasome system (UPS) as druggable targets for human cancer. We have identified a first in class investigational drug, TAK-243 (MLN7243), which targets the ubiquitin activating enzyme, UAE (UBA1), an essential cellular enzyme responsible for activating > 99% of all cellular ubiquitin. Ubiquitin is involved in multiple cellular processes including ubiquitin-dependent protein turnover, cell cycle progression, regulation of apoptosis, protein localization and response to DNA damage. Experiments combining targeted siRNA knockdown with TAK-243 identified DNA damage repair genes necessary for UAE inhibitor-induced cell death. A more focused approach revealed TAK-243 treatment blocked essential monoubiquitination events within the Translesion synthesis (TLS), Fanconi Anemia (FA) and Homologous recombination (HR) pathways. Inhibition of UAE prevented mono-ubiquitin signaling of key mediators within these pathways, including PCNA and FANCD2, by blocking formation of their specific E2-ubiquitin thioesters. In vitro cell-based assays combining TAK-243 with ultraviolet (UV) and radiation, both known to induce DNA damage, yielded inhibition of cell growth and enhanced DNA damage as observed through colony formation assays and Comet assay detection, respectively. Xenograft tumor bearing mice were treated with carboplatin or docetaxel, combined with TAK-243, to evaluate combination benefits in vivo. Synergistic and additive anti-tumor combination benefits were observed in animals treated with TAK-243 + carboplatin and TAK-243 + docetaxel. These important mechanistic in vitro and in vivo studies indicate the dependency of ubiquitination signaling in DNA damage repair and provide a mechanistic rationale for combining radiation, carboplatin or docetaxel with TAK-243 in the clinical setting. Currently, TAK-243 is being evaluated in a solid tumor phase I clinical trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity (ClinicalTrials.gov identifier: NCT02045095).

Citation Format: Michael A. Milhollen, Judi Shi, Tary Traore, Jessica Huck, Darshan Sappal, Jennifer Duffy, Eric Lightcap, Yuko Ishii, Jeff Ciavarri, Paul Fleming, Neil Bence, Marc L. Hyer. The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when combined with radiation, carboplatin and docetaxel. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A164.

 

PATENT

WO 2013123169

https://www.google.com/patents/WO2013123169A1?cl=en

 

Scheme 1 : General route for 2-substituted ((1R,2R,3S,4R)-2,3-dihydroxy-4- (pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamates

Figure imgf000055_0001

A genera! route for the synthesis of compounds represented by structure iv wherein Z is an optionally substituted fused or non-fused aryl or heteroaryl ring is outlined above in Scheme 1. Compound i (obtained by coupling an appropriately protected cyclopentylamine or salt thereof with 2-bromo-7-chloropyrazolo[1 ,5-a]pyrimidine in the presence of a suitable base as described below in the procedure of Examples 1a and 1b) is transformed to a compound of formula iii by coupling with a metal substituted compound Z-M via a palladium catalyzed reaction. A compound of formula iii can also be obtained by first transforming i to a metal substituted compound of formula ii using suitable boron or tin containing reagents, and then coupling with a halogen substituted compound Z-X via a palladium catalyzed reaction. Compounds of formula iv are then obtained by reaction with an appropriate sulfamating reagent (for example chlorosulfonamide or see Armitage, I. et. al. U.S. Patent Application US2009/0036678, and Armitage, I. et. al. Org. Lett., 2012, 14 (10), 2626-2629) followed by appropriate deprotection conditions.

Scheme 2: General route for 5-halogen substituted, 2 -substituted ((1R,2R,3S,4R)- 2,3-dihydroxy-4-(pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamates

Figure imgf000056_0001
Figure imgf000056_0002

A general route for the synthesis of compounds represented by structure ix wherein Z is an optionally substituted fused or non-fused aryl or heteroaryl ring and X is a halogen is outlined above in Scheme 2. Cyclization of amino-pyrazole v with a suitable diester and an appropriate base at an elevated temperature is followed by reaction with an appropriate halogenating reagent such as POCI3 at an elevated temperature to give compounds of formula vii. Compounds of formula viii are then obtained by reaction with an appropriately protected cyc!opentylamine or a salt thereof in the presence of a suitable base. Sulfamation and deprotection following Method 1 as described previously provides compounds of formula ix.

Scheme 3: General route for 5-alkyl substituted, 2-substituted ((1R,2R,3S,4R)-2,3- dihydroxy-4-(pyrazolo[1 ,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamates

Figure imgf000057_0001

SIMILAR COMPD

Example 17. Synthesis of (s.e.)-{(1 ,2R,3S,4R)-4-[(3,6-dichloro-2-{3- [(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3- dihydroxycyclopentyl}methyl sulfamate (1-124) and (s.e.)-{(1 ,2R,3S,4R)-4-[(6-chloro-2-{3- [(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,5^]pyrimidin-7-y[)arnino]-2,3- dihydroxycyclopentyl}methyl sulfamate 0-125).

Figure imgf000124_0001
                                                                             SIMILAR NOT SAME

Step 1. To a vial containing s.e {(1 ,2 ,3S,4 )-2,3-dihydroxy-4-t(2-{3- [(t rif I u orometh y l)sulf a nyl] phen l}p^

sulfamate (0.82 g, 0.0015 mol) and cooled to 0 °C is added N-chlorosuccinimide (126 mg, 0.000943 mol) as a solution in 12 mL of N,N-dimethy)formamide. The reaction mixture is stirred overnight with warming to rt. Saturated sodium bicarbonate solution is added and the reaction mixture is extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material is first purified by column chromatography (eluent: methanol/methylene chloride) and then purified by HPLC to afford both the dichloro (LCMS: (FA) +1 588) and mono chloro (LCMS: (FA) M+1 554) titlecompounds.

 

PATENT

WO 2016069393

UAE inhibitors are disclosed in patent application publications WO2013/123169 and US 2014/0088096. In one embodiment, the UAE inhibitor is a compound having the following structure (Compound 1):


(Compound 1);

or a pharmaceutically acceptable salt thereof. The Compound 1 is named ((lR,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[l ,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate.

process for making Compound 1 :


Compound 1;

or pharmaceutically acceptable salt thereof, comprising the steps of:

a) contacting Compound 9 or a salt, solvate or hydrate thereof with 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum’s acid):


Compound 9

under coupling conditions to provide compound 8 or a salt, solvate or hydrate thereof:


Compound 8

b) subjecting compound 8 or a salt, solvate or hydrate thereof to cyclization conditions to provide compound 7 or a salt, solvate or hydrate thereof


Compound 7

c) contacting Compound 7 or a salt, solvate or hydrate thereof with benzotriazole under chlorination displacement conditions to provide Compound 5 or a salt, complex, solvate or hydratei thereof


; Compound 5

d) contacting Compound 5 or a salt, complex, solvate or hydrate thereof with Compound 6 or a solvate or hydrate thereof:


; Compound 6

under displacement reaction conditions to provide Compound 3 or a salt, solvate or hydrate thereof

solvate or hydrate thereof with Compound


Cl ; Compound 4

under sulfamoylating reaction conditions to provide Compound 2 or a salt, solvate or hydrate thereof


; Compound 2

f) contacting Compound 2 or a salt, solvate or hydrate thereof with an acid under sulfamoylation conditions to provide Compound 1 or a pharmaceutically acceptable salt thereof

COMPD1

 

Example 1: Synthesis of S-iB-Ktrifluoromethyltsulfanyllphenyll-lH-pyrazol-S-amine

Step A: 3-((trifluoromethyl)thio)benzoate

To dimethylcarbonate (68 mL) was added 3-((trifluoromethyl)thio)benzoic acid (100 g, Beta Pharma Scientific) and a catalytic amount of sulfuric acid (2.4 mL). The mixture was then heated to 90°C for 5h. The reaction was then cooled to room temperature and quenched with sodium bicarbonate (1.0 L). To the aqueous layer was with ethyl acetate (1.0 L). The phases were separated and this process was repeated with ethyl acetate (1.0 L). The organic layers were combined and concentrated with a rotovap to give a light orange oil. The methyl 3-((trifluoromethyl)thio)benzoate (105g, 99%) was taken on crude to the next reaction. Ή NMR (300 MHz, CHLOROFORM-^ δ ppm 3.99 (s, 3 H) 7.49 – 7.58 (m, 1 H) 7.85 (d, J=l.62 Hz, 1 H) 8.17 (dt, J=7.69, 1.43 Hz, 1 H) 8.32 – 8.44 (m, 1 H).

Step B: 3-oxo-3-(3-((trifluoromcthvnthio)phcnyl>proDaneiiitrilc

Methyl 3-((trifluoromethyl)thio)benzoate (100.0 g) in tetrahydrofuran (1.0 L) was added acetonitrile (44.2 mL, 847 rnmol) and 1M (in THF) potassium tert-butoxide (95.01 g). The reaction was complete in 10 min by HPLC analysis. The reaction was quenched with 1M HC1 (1.0 L) and then extracted with three times with (1.0 L) of ethyl acetate. The organic layers with 3-oxo-3-(3-((trifluoromethyl)thio)phenyl)propanenitrile were then concentrated to dryness. This material (lOO.Og, 96.3%) was taken on crude with further purification. Ή NMR (300 MHz, CHLOROFORM-rf) δ ppm 4.12 (s, 2 H) 7.51 – 7.75 (m, 1 H) 7.89 – 8.01 (m, 1 H) 8.01 – 8.10 (m, 1 H) 8.20 (s, 1 H)

Step C: 3-}3-htrifliioromethv sulfan llphenyl}-lH-pyrazol-5-amine

[0152] To 3-oxo-3-{3-[(trifluoromethyl)sulfanyl]phenyl}propanenitrile (100.0 g,) in ethanol (1000.0 mL) was added hydrazine hydrate (59.52 mL). The reaction was heated to 100°C for lh at which point HPLC analysis showed the reaction was complete. The reaction was concentrated to dryness on a rotovap to give a brown oil. The oil was taken up in ethyl acetate (1.0 L) and extracted with water (1.0 L). The phases were separated and the organic phase was concentrated. Upon concentration 3-{3-[(trifluoromethyl)sulfanyl]phenyl}-lH-pyrazol-5-amine was obtained (80.8 g; Yield = 76.4%) . !H NMR (300 MHz, CHLOROFORM-^ δ ppm 5.95 (s, 1 H) 6.73 (br s, 1 H) 7.13 – 7.34 (m, 2 H) 7.42 – 7.74 (m, 3 H) 7.85 (s, 1 H).

Example 2: f R.2R.3St4RV2.3-dihvdroxy-4-ff2-r3- ((trifluoromethylHhio)phenvnpyrazolo[l,5-alpyrimidin-7-yl¼mino)cvclopentyl)metliyl sulfamate

Step 1: f2.2-dimethyl-5-ffl3-(3-((triiluoromethvnthio phenvn-lH-pyrazol-5- amino methyleBC>-1.3-dioxane-4,6-dione)

[0155] To trimethoxy orthoformate (2.0 L), at 20°C and under a blanket of nitrogen, was added 2,2-dimethyl-l,3-dioxane-4,6-dione (361.35 g). The resulting white suspension went clear within minutes and was heated to 85°C over 15 minutes. The reaction was held at 85°C for 120 minutes. While the reaction was heated and stirred another solution of 3-(3-((trifluoromethyl)thio)pheny])-lH-pyrazol-5-amine (500.0 g) was made. To a 4L RBF was added 3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5-amine (500.0 g) and then trimethoxy orthoformate (1.4 L) added into this solid. This solution was mixed to dissolve the solids and resulted a dark brown solution. The solution of 3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5-amine (-1.8L in trimethoxy orthoformate) was added to the reactor over 30 minutes while maintaining the reaction temperature at 85°C. The reaction was then stirred for 20 minutes with white solids forming in the solution. After 20 minutes the reaction was sampled and the UPLC showed the complete conversion of 3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5 -amine to 2,2-dimethyl-5-(((3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5-yl)amino)methylene)-l ,3-dioxane-4,6-dione. The reaction was cooled to 20 °C over 20 minutes and maintained at that temperature for 20 additional minutes. At this point, a thick white slurry had formed and the reaction was filtered using a Nutche Filter over 15 minutes. The reactor was washed with 1L of ethyl acetate and this solution was then mixed with the filter cake and removed by filtration. The cake was dried for -40 minutes on the filter and then transferred to a vacuum oven and heated at 40°C under full vacuum overnight (16 hours). The reaction was then analyzed by FfPLC and NMR to give 2,2-dimethyl-5-(((3-(3 -((trifluoromethyl)thio)phenyi lH-pyrazol-5-yl)amino)methylene)- 1 ,3-dioxane-4,6-dione (635.3 g, 79%) XH NMR (300 MHz, DMSO-cfe) δ ppm 1.68 (s, 6 H) 7.05 (d, J=2.05 Hz, 1 H) 7.64 -7.77 (m, 2 H) 7.77 – 8.03 (m, 1 H) 8.12 (s, 1 H) 8.72 (d, J=14.36 Hz, 1 H) 1 1.35 (d, J=14.66 Hz, 1 H) 13.47 (s, 1 H).

[0156] Step 2: 2-( 3-f(trifluoromethyl)thio phenyl)pyrazoIo [1,5-al pyrimidin-7-ol

[0157] A solution of 2,2-dimethyl-5-(((3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5-yl)amino)methylene)-l,3-dioxane-4,6-dione (615.00 g) in 1,2-dichIorobenzene (6.3 L) was stirred at ambient temperature for 10 minutes. The solution was then heated to 150°C over 75 minutes. The reaction was maintained at this temperature for 16 hours. An sample was taken after 16 hours and the UPLC analysis showed the complete conversion of 2,2-dimethyl-5-(((3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5-yI)amino)methylene)-l,3-dioxane-4,6-dione to 2-(3- ((trifluoromethyl)tmo)phenyl)pyrazolo[l,5-a]pyrimidin-7-ol. The reaction was cooled to 20°C over 130 minutes. At this point, a thick white slurry had formed and the reaction was filtered using a Nutche Filter over 15 minutes. The reactor was washed with 1.8 L of acetonitrile and this solution was then mixed with the filter cake and then the solvent was removed by filtration. The cake was dried for ~40 minutes on the filter and then transferred to a vacuum oven and heated at 40°C under full vacuum overnight (16 hours). The reaction was then analyzed by HPLC and NMR to give 2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-ol (331.2 g, 72%) Ή NMR (300 MHz, METHANOL-^) δ ppm 6.55 (d, J=7.33 Hz, 1 H) 7.59 (s, 1 H) 8.40 – 8.52 (m, 1 H) 8.53 – 8.64 (m, 1 H) 8.69 (d, J=7.62 Hz, 1 H) 9.01 (dt, J=7.77, 1.39 Hz, 1 H) 9.12 (s, 1 H) 13.34 (s, 1 H).

[0158] Step 3: l-(2-(3-(f trffluoromethvmhiotohenvnpyrazolo n.5-al pyrimidin-7-vn-lH-benzofdiri.2.31triazole: triethylamine: hydrochloride complex (1:1.25:1.25 molesimolestmolest

[0159] To a solution of 2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-ol (30.00 g), benzotriazole (287.02 g) in acetonitrile (3000 mL) and triethylamine (403.00 mL) at 0°C, was added phosphoryl chloride (108 mL) slowly under a blanket of nitrogen, maintaining < 10°C. The reaction was then warmed to 80°C over 45 minutes and stirred for 240 minutes. HPLC indicated complete

consumption of starting material. To the reaction mixture was added acetonitrile (3000 mL) while maintaining the temperature at 80°C. The reaction was then cooled to 20°C over 80 minutes. The reaction was then stirred at ambient temperature for 14 hours. At this point, a thick slurry had formed and the reaction was filtered using a Nutche filter over 15 minutes. The reactor was washed twice with 900 mL of acetonitrile and this solution was then mixed with the filter cake and then the solvent was removed by filtration. The cake was dried for -40 minutes on the filter and then transferred to a vacuum oven and heated at 40°C under full vacuum overnight (16h). The reaction was then analyzed by HPLC and NMR to give l-(2-(3-((trifluorometJiyl)thio)phe

triethylamine: hydrochloride complex (1:1.25:1.25 moles:moles:moles) (438.1 g, 83%). ¾ NMR (300 MHz, DMSO-</6) δ ppm 1.19 (t, J=7.33 Hz, 12 H) 3.07 (qd, J=7.28, 4.84 Hz, 8 H) 7.60 – 7.78 (m, 6 H) 7.80 – 7.87 (m, 1 H) 8.15 (dt, J=7.99, 1.28 Hz, 1 H) 8.24 (s, 1 H) 8.33 (dt, J=8.14, 0.92 Hz, 1 H) 8.85 (d, J=4.69 Hz, 1 H).

[0160] Step 4: ff3aR4R.6R.6aS 2.2-dimethyl-6-ff2-f3~mrifluoromethyl)thio)phenvnpyrazoloil.5-alD\timidin-7-yl¼mino)tctralivdro-3aH-cvcLoDentaldlll,31dioxol-4-vnincthanol

[0161] To the reactor was added l-(2 3-((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-lH-benzo[d][l,2,3]triazole: triethylamine: hydrochloride complex (1 :1.25: 1.25 moles :moles:moles) (430.0 g) and ((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methanol hydrochloride (209.0 g) and then triethylamine (2103 mL) was added. The reaction was then heated to 80°C, under a blanket of nitrogen. After 360 minutes, HPLC analysis indicated that the reaction mixture contained <1% starting material and the reaction was cooled to 20°C over 60 minutes. To the reaction was added ethyl acetate (3.5 L) and water (3.5 L). After stirring for 10 minutes the phases were separated and the aqueous layer was back extracted with ethyl acetate (3.5 L). The organic layers were combined and concentrated to form a dark, brown oil. Acetonitrile (4.5 L) was added and the solution was concentrated to dryness to give an orange solid. The solids was transferred back to the reaction with water (4.3 L), heated to 50°C, and stirred for 20 minutes. White solids formed in this hot solution and were isolated by filtration using a Nutche Filter over 15 minutes. The solids were dried under vacuum for 15 minutes on the filter and then dissolved in acetonitrile (4.0 L) at 0°C. The solution was stirred for 1 minutes. The solution was then filtered through a fritted funnel to remove the hydrolysis solid by product and the solution was concentrated to dryness. The solids were dried in a vacuum oven at full vacuum overnight (40°C, 16 hours). The reaction was then analyzed by HPLC and NMR to give ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3 -((trifluoromethyl)thio)phenyl)pyrazolo[ 1 ,5 -a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methanoI (349.2 g, 88%). Ή NMR (300 MHz, DMSO-<¾) δ ppm 1.25 (s, 3 H) 1.47 (s, 3 H) 1.76 – 1.90 (m, 1 H) 2.25 (br d, J-3.22 Hz, 1 H) 2.33 – 2.47 (m, 1 H) 3.46 – 3.67 (m, 2 H) 4.08 (br d, J=5.57 Hz, 1 H) 4.48 – 4.64 (m, 2 H) 5.19 (t, J=4.40 Hz, 1 H) 6.28 (d, J=5.28 Hz, 1 H) 7.06 (s, 1 H) 7.58 – 7.71 (m, 1 H) 7.72 – 7.80 (m, 1 H) 8.12 – 8.24 (m, 2 H) 8.31 (d, J=7.62 Hz, 1 H) 8.42 (s, 1 H).

[0162] Step 5: ((3aR.4R.6R.6aS 2.2-dimethyl-6-ff2-f3-fftrifluoroinethYmhio)phenvnpyrazolo[1.5-al Dyrimidin-7-vnan] iiio>tetrahvdro-3aH-cvclonen ta [dl [1,31 dioTOl-4-yl )meth yl tert-bntoxycarbonylsulfamate

[0163] ((3aR,4R,6R,6aS)-2,2-dime l-6-((2-(3-((trifluorome

7-yl)amino)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methanol (6.0 g) was dissolved in 2-methyltetrahedrafuran (60.0 mL) and to this solution was added pyridinium p-toluenesulfonate (5.9 g). This formed a precipitated and to this white slurry was added (4-aza-l-azoniabicyclo[2.2.2]oct-l-ylsulfonyl)(tert-butoxycarbonyl)azanide-l,4-diazabicyclo[2.2.2]octane (1 :1) hydrochloride1 (17.0 g). The mixture was stirred at ambient temperature until the HPLC showed <1% ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methanol remaining starting material (-300 minutes). The reaction was quenched with water (60 mL) and the phases were separated. To the organic layer was added acetonitrile (60 mL) and the mixture was concentrated using a rotovap at 50°C to ~60 mL. The mixture was allowed to cool to room temperature and stirred overnight. During this time a white slurry formed. White solids were filtered using a medium fritted filter. The solid was dried in a vacuum oven at full vacuum overnight (40 °C). The reaction was then analyzed by HPLC and NMR to give ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3-((trifluoromethyI)tM^

cyclopenta[d][l,3]dioxol-4-yl)methyl tert-butoxycarbonylsulfamate (5.03 g, 68%). [H NMR (300 MHz, DMSO- 6) δ ppm 1.26 (s, 3 H) 1.42 (s, 9 H) 1.51 (s, 3 H) 2.33 – 2.48 (m, 2 H) 3.30 (br s, 1 H) 4.06 – 4.21 (m, 1 H) 4.29 (d, J=5.28 Hz, 2 H) 4.52 (dd, J=7.18, 5.13 Hz, 1 H) 4.76 (dd, J=7.18, 4.54 Hz, 1 H) 6.35 (d, J=5.57 Hz, 1 H) 7.08 (s, 1 H) 7.63 – 7.72 (m, 1 H) 7.74 – 7.82 (m, 1 H) 8.01 (d, ^=7. 2 Hz, 1 H) 8.21 (d, J=5.28 Hz, 1 H) 8.31 (dt, J=7.84, 1.36 Hz, 1 H) 8.48 (s, 1 H) 1 1.92 (br s, 1 H)

[0164] Step 6: f R,2R3S.4R)-2J-dihvdroxy-4-((2-(3-fftrifluoromethvDthio^phenvnpyrazolori.5-a]pyrimidin-7-yl)aminokvcl nent\l)methyl sulfamate

[0165] To a solution of ((3aR,4R,6R!6aS)-2,2-dimethyl-6-((2-(3- ((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methyl tert-butoxycarbonylsulfamate (2.0 g) in acetonitrile (11 mL) at 0°C was added phosphoric acid (1 1 mL) while maintaining the temperature below 10°C. This mixture was warmed to ambient temperature and stirred for 4 hours. At this time HPLC analysis showed that <1% ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3 -((trifluoromethyl)thio)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methyl tert-butoxycarbonylsulfamate starting material or reaction intermediates remained. To the reaction was added ethyl acetate (1 1 mL) and water (11 mL) and saturated Na2C03 (10 mL) dropwise. After this addition was complete saturated Na2C03 was added until the pH was between 6-7. The phases were separated and to the organic layer was added acetonitrile (30 mL) and the mixture was concentrated on a rotovap to ~16 mL. The mixture was stirred overnight. During this time a white slurry formed. The white solids were filtered using a medium filtted filter. The solid was dried in a vacuum oven at full vacuum overnight (40°C). The reaction was then analyzed by HPLC and NMR to give ((lR,2R,3S,4R)-2,3-dihydroxy-4-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl sulfamate (1.5g ,84%). lH NMR (300 MHz, DMSO-c¾) δ ppm 1.44 – 1.61 (m, 1 H) 2.20 – 2.42 (m, 2 H) 3.78 (q, J-4.50 Hz, 1 H) 3.90 – 4.09 (m, 3 H) 4.09 – 4.22 (m, 1 H) 4.80 (d, ^5.28 Hz, 1 H) 5.03 (d, J=5.28 Hz, 1 H) 6.31 (d, J=5.57 Hz, 1 H) 7.05 (s, 1 H) 7.48 (s, 2 H) 7.62 – 7.72 (m, 1 H) 7.77 (d, J=7.92 Hz, 2 H) 8.17 (d, J=5.28 Hz, 1 H) 8.31 (dt, ^7.70, 1.43 Hz, 1 H) 8.47 (s, 1 H).

[0166] Example 3: fflR.2R.3S.4RV2.3-dihvdrosy-4-ff2-f3- ( ( trifluoroniethyl )thio)ph en vDpyrazolo 11,5-a I pyi Lmidin-7-Yl)amino)cvclopcntyl>m ethyl sulfama te

[0167] Step 1: .2-dimethyl-5-ff -(3-frtrifluoromethvnthio)phenvn-lH-pyrazol-5-yl)ainino)methylene -l,3-dioxane-4,6-dione)

[0168] Under a blanket of nitrogen at 20°C, Meldrum’s acid (18.6 Kg) and isopropanol (33 L) were placed in a 100 L glass-lined reactor. Trimethyl orthoformate (15.5 Kg (16.0L)) and isopropanol (11 L) were added and the mixture was heated to 80 °C for 40 min, whereby a small amount of methanol distilled off (<0.5 L). The mixture was stirred for 2 h at 80 °C. in a separate 160 L glass-lined reactor under nitrogen at 20 °C, 3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5-amine (prepared in the manner described above) was mixed with isopropanol ( 10.9 kg, 42.0 mmol) and heated up to 80 °C within 60 min. The content of the 100 L reactor was transferred into the reaction mixture in the 160 L reactor at 80 °C, which was completed after 3 min. The reaction mixture was stirred for 30 min at 78 °C, the reaction was then cooled to 60 °C. HPLC analysis showed the reaction was 99.56% complete (product%/(product%+starting material0/.). The reaction mixture was cooled to 20 °C within 100 min, then the mixture was stirred for further 100 min at 20 °C. The suspension was then transferred onto a pressure filter. At 1.2 bar nitrogen, the solids were collected on the filter. The filter cake was washed 4 x with ethyl acetate (18 L each time). The wet cake was dried on the filter for 17 h at 20°C using a slight stream of nitrogen/vacuum (200-100 mbar). The wet product (14.7 kg) was further dried at the rotavap for approx. 24 h at 40-50 °C. 11,75 kg of the crude title compound was obtained (68% yield). NMRspectrum was consistent with that described above in Example 2.

[0169] Step 2: 2-(3-fftrifluoromethvnthio)phenYnpyrazolori.S-a1pyrimidin-7-ol

[0170] Under nitrogen at 20 °C, (2,2-dimethyl-5-(((3-(3-((trifluoromethyl)thio)phenyl)-lH-pyrazol-5-yl)amino)methylene)-l ,3-dioxane-4,6-dione) was placed in the reactor. 1 ,2-Dichlorobenzene (117 L) was added. The suspension was heated to 147°C for 90 min to give a solution, then it was stirred at 147°C for 18 h. Before sampling, the reaction was cooled to 60°C. HPLC analysis showed the reaction was 92.28% completion (product%/(product%+starting material%). The mixture was heated up again to 147°C and stirred for further 5 h at this temperature. HPLC analysis showed the reaction was 96.51% complete (product%/(product%+starting material%). The mixture was then stirred for 48 hours at 20°C, then it was heated again to 147°C und stirred at this temperature for 5 h. Before sampling, the reaction was cooled to 60°C. HPLC analysis showed the reaction was 98.47% completion (product%/(product%+starting material%). The mixture was heated up again to 146°C and stirred for further 5 h at this temperature.

Before sampling, the reaction was cooled to 60°C. HPLC analysis showed the reaction was 99.35% complete (product%/(product%+starting material%). The reaction was cooled to 20°C and the suspension was transferred in a pressure filter. The solids were collected on the filter at 1.8-3 bar N2 over a greater than 10 hour period. The filter cake was washed 4 x with acetonitrile (17 L), then it was dried on the filter for 18 h at 20°C/200-100 mbar, using a slight stream of N2. The material was transferred to a 50 L flask and dried on a rotavap at 50-60°C / 24-14 mbar for 2 d. 6.118 kg of the crude title compound was obtained (70% yield). NMR spectrum was consistent with that described above in Example 2.

[0171] Step 3: l-f2-f3- trifluoromethYnthio^phenvnpyrazoIo[1.5-alpyriinidiii-7-vn-lH-benzofdl [1.2.31 triazolc: triethylamine: hydrochloride complex ( 1 :0.21:0.21 moles:moles:moles)

[0172] Under N2 at 20°C, acetonitrile (30 L) was placed in the reactor, 2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-ol (6.00 kg) and lH-benzotriazol (5.83 kg) was added. A further portion of acetonitrile (30 L) was added, then the mixture was stirred at 20°C. Stirring proceeded over night. Triethylamine (8.16 L) was added at 20°C over 6 min. The yellow suspension was heated up to 45°C for 40 min. While stirring at 150 rpm, phosphoryl chloride (4.562 kg) was slowly added for 45 min. By controlling the addition, the reagent was dropped directly into the mixture to avoid the formation of lumps. The addition was exothermic, a maximum temperature of 53°C was observed. The brown suspension was heated up to 80°C over 1 h, then the reaction mixture was stirred for 5 h at this temperature. Acetonitrile (30 L) was added over 20 min keeping the internal temperature between 75-80°C. HPLC analysis showed the reaction was 98.31% completion (product%/(product%+starting material%).The mixture (brown suspension) was further stirred at 80°C for 70 min. HPLC analysis showed the reaction was 99.48% completion (product%/(product%+starting material%). Acetonitrile (61 L) was added over 30 min maintaining the temperature between 75-80°C. The pale brown suspension was stirred at 80°C for 90 min, then it was cooled to 20°C over 2.5 h. The mixture was stirred for 12 h at 20°C. The mixture was transferred in a pressure filter. The filter cake was washed twice with acetonitrile ( 18 L). Both wash steps were done at 3.5-4 bar N2. Each of these filtrations took overnight to go to completion. The filter cake was dried on the filter for 7.5 h. The material was transferred in a 50 L flask and dried at the rotavap at Ta 40-50°C / 50-11 mbar for 3 d to get a dry mass of 99.88% . The yield of l -(2-(3-((trifluoromethyl)t]iio)phenyl)pyrazolo[l ,5-a]pyrimidin-7-yl)-lH-benzo[d][l,2,3]triazole: triethylamine: hydrochloride complex (1 :0.21 :0.21 moles:moles:moles) was 7.948 kg (75%). NMR spectrum was consistent with that described above in Example 2.

[0173] Step 4: 3aR4R.6R,6aS)-2,2-dimethYl-6-f(2-f3-ffMfluoromethvnthio phenvnpyrazolori.5-alDyrimidin-7-yl)amino)tetrahvdro-3aH- vclopenta Idl [1.31 dioxol-4-vDmethanol

[0174] Under N2 in a 160 L glasslined reactor, triethylamine (21%) compound with l -(2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[ 1 ,5 -a] pyrimidin-7-yI) – 1 H-benzo [d] [ 1 ,2,3 Jtriazole (21 %) hydrochloride (7.86 kg) was dissolved in triethylamine (23.3 L) at 20°C. ((3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methanol hydrochloride (4.49 kg) was added, followed by triethylamine (23 L). The reaction mixture was heated up to 80°C over 1 h, and then the mixture was stirred for 8 h at 80°C. The mixture was then cooled to 20°C. HPLC analysis showed the reaction was 99.97% complete (product%/(product%+starting material%). Water (66 L) was then added over 30 min at 20-25°C (exotherm), whereby a brown suspension was obtained. The mixture was concentrated at 60°C, 150-95 mbar, until 42 L solvent was distilled off. The suspension was heated to 50°C, and the solids were collected on a 90 L pressure filter (1.2 bar N2), which took 40 min. During this process, the material on the filter was not actively heated. The remaining solids in the reactor were rinsed with 15 L of the mother liquor. The wet filter cake was transferred back in the reactor. Water (64 L) was added. The mixture was heated up to 50°C over 30 min. The washed solids were collected on the 90 L pressure filter. Remaining mother liquor in the filter cake was pressed off at 1.2 bar N2 for 50 min (50 L mother liquor was used to rinse the reactor). The filter cake was dried on the pressure filter for 13.5 h, applying a slight stream of N2 / vac at 20°C to afford 10.247 kg of crude ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3-((trifluoromethyl)tWo)phenyl)pyrazolo[l ,5-a]pyrimidin-7-yl)ammo)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methanol. The wet filter cake was isolated. The wet filter cake was loaded into the reactor. Acetonitrile (65 L) was added, followed by activated charcoal (6.59 kg). The mixture was heated to 50°C for 30 min and stirred for 2 h at 50°C. Meanwhile a bed of celite (4.25 kg) had been prepared in the 90 L pressure filter, using acetonitrile (20 L) for conditioning. The bed was heated at 50°C. The black suspension was transferred on the filter and pushed through the Celite plug at 2 bar. The filtrate was transferred to a 200 L stirring tank via a heat resistant tube and a 0.45 μιη inline filter. The operation needed 18 min for completion. For washing, acetonitrile (50 L) which had been warmed up in the reactor to 50°C and transferred over the warmed filter cake and pushed through at 2 bar. Again, the filtrate was transferred in the 200 L stirring tank via a heat resistant tube and a 0.45 μιη inline filter. The operation needed 10 min for completion. The reactor was cleaned to remove attached charcoal (abrasive cleaning, using NaCl /acetone). The filtrate in the stirring tank was transferred in the reactor and concentrated at 50°C / 120 mbar until 63 L were distilled off. While well stirring (300 rpm) and 50°C, Water (1 10 L) was slowly added over 2 h. A pale yellow suspension was formed. The concentrate was cooled to 20°C for 3 h, then stirred at this temperature for 13 h. The solids were collected on a 50 L filter, using 1.2 bar N2 to push the filtrate through. The filter cake was washed twice with water (18 L), then dried on the filter for 24 h at 200-100 mbar, using a slight stream of N2. 4.563 kg of the title compound was obtained 55% yield. NMR spectrum was consistent with that described above in Example 2.

[0175] Step 5: (f3aR,4R,6R,6aS)-2^-dimethyl-6-(f2-f3-fftrifluorQmethvnthio phenvnpyrazolo[1.5- |pyrimidm-7-vnamino)teti ahYclro-3aH-cvclopenta|d||1.3ldioxol-4-yl mcthyl tert-butoxycarbonylsutfamatc

[0176] Under N2 at 20°C, ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3- ((trifluoromethyl)thio)phenyl)pyrazolo[ 1 , 5 -a]pyrimidin-7-yl)amino)tetrahydro-3 aH-cyclopenta[d][l,3]dioxol-4-yl)methanol (4.019 kg) was placed in a 160 L glasslined reactor, then 2-methyl-tetrahydrofuran (40 L) was added. The mixture was stirred at 150 rpm for 30 min at 20°C, whereby a clear solution was formed. A KF measurement was taken and showed the water content to be 0.036% H20. The solution was stirred over night at 20 °C. The next morning, PPTS (2.2 kg) was loaded into the reactor. At 20°C, (4-aza-l-azoniabicyclo[2.2.2]oct-l-yIsulfonyl)(tert-butoxyc£u-bonyl)azanide-l,4-diazabicyclo[2.2.2]octane (1:1) hydrochloride (10.2 kg) was added. Stirring of the heterogeneous mixture was started at 130 rpm. The reaction was stirred with 200 rpm for 1 h at 20°C, then with increased speed of 250 rpm for an additional hour. HPLC analysis showed the conversion to be 87.3%. The reaction mass was stirred with 300 rpm for 2 h at 20°C. HPLC analysis showed the conversion to be 95.6%. The reaction mass was stirred with 300 rpm for 2 h at 20°C. HPLC analysis showed the conversion to be 97.7%. NaHC03 3.7% (40 L) was added to the mixture at 20°C and the reaction was stirred at 300 rpm for 10 min. Most of the solids from the reaction mixture went into solution. To dissolve remaining material which was attached at the top of the reactor, the bilayered mixture was stir up shortly by a N2 stream from the bottom. The layers were separated, which was completed after 13 min. The aqueous layer was discharged, the organic layer remained in the reactor. The org. layer was a brown solution, the aqueous layer was colorless and turbid. The pH of aqueous layer was approx. 8 (pH stick). NaHC03 3.7% (40 L) was added to the mixture at 20°C and it was stirred at 300 rpm for 10 min. The layers were separated, which was completed after 27 min. The aqueous layer was discharged, the organic layer remained in the reactor. The organic layer was a brown solution, the aqueous layer was colorless and turbid. The pH of aqueous layer was approx. 8-9 (pH stick) and the pH of organic layer was approx. 8 (pH stick, wet). The product in organic layer was transferred in the feeding tank and stored temporarily (approx. 30 min) at 20°C. The reactor was optically cleaned using a mixture of 2-methyltetrahydrofuran (30 L) and H20 (20 L). The org. layer was placed in the reactor and stored at -20°C for 14.5 h . While stirring at 150 rpm, the org. layer (suspension) was diluted with acetonitrile (16 L) and water (15 L) and warmed up to 5°C. At 5°C, acetic acid (0.172 kg) was added over 5 min. to a pH of 6; resulting in a mixture that was a pale brown solution. ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methyl tert-butoxycarbonylsulfamate (2.0 g; prepared in a similar manner to that described above Example 2, Step 5) was added as seed. At 5°C, acetic acid (0.515 kg) was added over 15 min. to pH 4-5; a suspension formed. The feeding tank was rinsed with water (1.6 L). The mixture was stirred at 5°C with 90 rpm for 1.5 h, then it was transferred in a 50 L filter and filtered at 1.2 bar N2, in only 4 min. The filter cake was washed 4 x with cold acetonitrile (8 L, 0-5°C), then it was dried on the filter at 20°C for 8 h at 200 mbar, using a slight stream of N2. The yield of the title compound was 3.594 kg (62%). MR spectrum was consistent with that described above in Example 2.

[0177] Step 6: friR.2R.3S.4R 2.3-dihvdroxY-4-ff2-f3-fftrifluoromethvntliio phenvnDyrazolori.5-alpyrimidin-7-yl)aminokvciopent>T)mcthyl sulfamate Compound 1

[0178] 3.538 kg of ((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)methyl tert-butoxycarbonylsulfamate was suspended in 13.5 kg of acetonitrile and cooled to 5°C. To this mixture was added 27.3 kg of H3PO4 over 1 hour and 50 minutes. The reaction was warmed to 20°C over 50 minutes and then stirred for 8h at 22°C. HPLC analysis showed the reaction was 99.69% complete. To the first portion (50% of the reaction mixture) was added 8.9 kg of water and 7.95 kg of ethyl acetate. The pH was then adjusted to 6.5 with 48 L of saturated sodium carbonate. 7.7 kg of ethyl acetate was added and the phases were separated. To the second portion (50% of the reaction mixture) was added 8.9 kg of water and 7.95 kg of ethyl acetate. The pH was then adjusted to 6.15 with 48 L of saturated sodium carbonate. 7.7 kg of ethyl acetate was added and the phases were separated. The organic phases were combined in a vessel (rinsed with 1.8 kg of ethyl acetate) and washed with 17.8 kg of water. The phases were separated and 17.8 kg of water and 0.237 kg of NaCl were added and the phases were separated. A repeat of wash with 17.8 kg of water and 0.237 kg of NaCl was added and the phases were separated. The organic layers were then combined and the temperature of the mixture was raised to 40°C and the pressure was reduced to 300-142 mbar. 27 L of liquid was distilled off over 4h. 31.7 kg of acetonitrile were then added to the solution and the temperature of the mixture was raised to 38°C and the pressure was reduced to 320-153 mbar. 26 L of liquid was distilled over 3h. 31.7 kg of acetonitrile were then added to the solution and the temperature of the mixture was raised to 37°C and the pressure was reduced to 320-153 mbar. 34 L of liquid was distilled over 2h. The suspension was stirred for lh at 50°C and then cooled to 20-25°C over 3h. The reaction was stirred overnight and the product was filtered and washed with 8.9 kg of acetonitrile twice. The cake was dried for 2h at 20°C (33 mbar) then at 40-45°C (1 mbar) to afford 2.08 kg (75.8%) of the title compound. 2.066 kg of ((lR,2R,3S,4R)-2,3-dihydroxy-4-((2-(3 -((trifluoromethyl)thio)phenyl)pyrazolo[ 1 , 5 -a]pyrimidin-7-yl)amino)cyclopenty l)methy 1 sulfamate was loaded into a reactor with 9.76 kg of acetronitrile and 4.12 kg of water and heated at a temperature of 56 °C for 1 hour and 10 minutes until dissolved. The solution was polished filtered and the filter was

rinsed with 3.16 kg acetonitrile and 1.37 kg of water. To the resulting solution was added with 11.0 kg of water over 45 minutes while maintaining the reaction temperature between 52-55°C. 0.009 kg of (( 1 R,2R,3S,4R)-2,3 -dihydroxy-4-((2-(3 -((trifluoromethyl)thio)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl sulfamate was added as seed (prepared in a similar manner to that described above Example 2, Step 5). A suspension was visible after 10 minutes of stirring. To the solution was added 9.62 kg of water over 3h while maintaining the reaction temperature between 50-55°C. The suspension was then cooled over 3h to 20°C and stirred for 12h at 22-23°C. The suspension was then filtered and washed twice with 13.7 kg of water. The product was dried at 40°C. 1.605 kg of the title compound was obtained in 78% yield. NMR spectrum was consistent with that described above in Example 2.

 

PATENT

WO2016069392

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016069392&recNum=162&docAn=US2015057062&queryString=FP:(%22cancer%22)%20AND%20EN_ALL:nmr&maxRec=28697

SYNTHESIS

STR1

STR1

STR1

 

Juno reaches Jupiter!

///////////////1450833-55-2, MLN 7243, TAK-243,  TAK 243,  TAK243,  MLN7243; MLN-7243,  MLN 7243,  AOB87172,  AOB-87172,  AOB 87172, Millennium Pharmaceuticals, Inc., PHASE 1, TAKEDA ONCOLOGY
COS(=O)(=O)N[C@H]1C[C@H]([C@@H]([C@@H]1O)O)NC2=CC=NC3=CC(=NN23)C4=CC(=CC=C4)SC(F)(F)F
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PF-06282999

 phase 1, Uncategorized  Comments Off on PF-06282999
Jul 052016
 

  Figure imgf000061_0002

PF 6282999

Alternative Names: PF-06282999; PF-6282999, PF-06282999

Cas 1435467-37-0

[2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide]

2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide

MF C13H12ClN3O3S
Molecular Weight: 325.767
Elemental Analysis: C, 47.93; H, 3.71; Cl, 10.88; N, 12.90; O, 14.73; S, 9.84

Irreversible inactivator of myeloperoxidase

Currently in clinical trials for the potential treatment of cardiovascular diseases.

Phase I

  • Phase I Acute coronary syndromes

Most Recent Events

  • 01 Mar 2015 Pfizer terminates phase I trial in Healthy volunteers in USA (NCT01965600)
  • 10 Sep 2014 Pfizer completes enrolment in its phase I trial in Healthy volunteers in USA (NCT01965600)
  • 01 Feb 2014 Phase-I clinical trials in volunteers in USA (PO)

A drug potentially for the treatment of acute coronary syndrome (ACS).

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PF-06282999 is a potent and selective myeloperoxidase Inhibitor which is potential useful for the Treatment of Cardiovascular Diseases. PF-06282999 displayed excellent oral pharmacokinetics in preclinical species and robust irreversible inhibition of plasma MPO activity both in human blood stimulated exogenously and in plasma collected after oral (po) administration to lipopolysaccharide (LPS)-treated cynomolgus monkeys.

PF-06282999 has been advanced into first-in-human pharmacokinetics and safety studies. Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson’s diseases, implying that MPO inhibitors may represent a therapeutic treatment option

The thiouracil derivative PF-06282999 [2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide] is an irreversible inactivator of myeloperoxidase and is currently in clinical trials for the potential treatment of cardiovascular diseases. Concerns over idiosyncratic toxicity arising from bioactivation of the thiouracil motif to reactive species in the liver have been largely mitigated through the physicochemical (molecular weight, lipophilicity, and topological polar surface area) characteristics of PF-06282999, which generally favor elimination via nonmetabolic routes.

To test this hypothesis, pharmacokinetics and disposition studies were initiated with PF-06282999 using animals and in vitro assays, with the ultimate goal of predicting human pharmacokinetics and elimination mechanisms. Consistent with its physicochemical properties, PF-06282999 was resistant to metabolic turnover from liver microsomes and hepatocytes from animals and humans and was devoid of cytochrome P450 inhibition. In vitro transport studies suggested moderate intestinal permeability and minimal transporter-mediated hepatobiliary disposition. PF-06282999 demonstrated moderate plasma protein binding across all of the species.

Pharmacokinetics in preclinical species characterized by low to moderate plasma clearances, good oral bioavailability at 3- to 5-mg/kg doses, and renal clearance as the projected major clearance mechanism in humans. Human pharmacokinetic predictions using single-species scaling of dog and/or monkey pharmacokinetics were consistent with the parameters observed in the first-in-human study, conducted in healthy volunteers at a dose range of 20-200 mg PF-06282999.

In summary, disposition characteristics of PF-06282999 were relatively similar across preclinical species and humans, with renal excretion of the unchanged parent emerging as the principal clearance mechanism in humans, which was anticipated based on its physicochemical properties and supported by preclinical studies.

STR1

PAPER

Journal of Medicinal Chemistry (2015), 58(21), 8513-8528.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00963

Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases

Abstract Image

Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson’s diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.

tan solid (mp = 165.3 °C).

1H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1 H), 7.57 (dd, J = 9.03, 2.68 Hz, 1 H), 7.33 (s, 1 H), 7.17–7.23 (m, 2 H), 7.10 (s, 1 H), 5.89 (d, J = 1.71 Hz, 1 H), 5.41 (br s, 1 H), 3.89 (br s, 1 H), 3.84 (s, 3 H).

MS (ES+) m/z: 326.0 [M + H]+. HRMS: m/z calcd for C13H13ClN3O3S [M + H]+ 326.0366, found 326.0361.

Anal. Calcd for C13H12ClN3O3S: C, 47.93; H, 3.71; N, 12.90; S, 9.84. Found: C, 47.81; H, 3.70; N, 12.83; S, 9.83. HPLC purity: >95%.

PATENT

WO 2013068875

http://www.google.co.in/patents/WO2013068875A1?cl=en

Beta Keto Ester Route Section

A. Carboxylic Acid Route Section

Preparation 1

Figure imgf000060_0001

Ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate

A 3000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with magnesium ethoxide (67.46 g, 589.51 mmoles) and THF (1 100 mL), and the resulting mixture was stirred as ethyl hydrogen malonate (162.26 g, 1 .18 moles; 145.00 mL diluted in 100 ml of THF) was added and the mixture was heated at 45 °C for 4 hours. Meanwhile, a 2000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with 5-chloro-2-methoxybenzoic acid (100 g, 536 mmoles) and THF (600 mL). To this mixture stirring at room temperature was added 1 , 1 ‘-carbonyldiimidazole (95.59 g, 589.5 mmoles) in portions to avoid excess foaming. After stirring for 3 hours at room temperature the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45 °C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (1 L) followed by 2 N HCI (500 mL). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCI (500 mL), saturated sodium bicarbonate (500 mL), and water (500 mL). The organic phase was concentrated under reduced pressure, the residue taken up in ethyl acetate (1000 mL) and concentrated again to afford the title compound (104.94 g).

MS (ES+) 257.2 [M+1 ]+. 1 H NMR showed product as a 7.5:1 keto:enol mixture. For the keto tautomer: 1 H NMR (500 MHz, CDCI3) δ ppm 7.85 (d, J=2.93 Hz, 1 H) 7.45 (dd, J=8.90, 2.81 Hz, 1 H) 6.92 (d, J=8.78 Hz, 1 H) 4.18 (q, J=7.16 Hz, 2 H) 3.95 (s, 2 H) 3.90 (s, 3 H) 1 .24 (t, J=7.07 Hz, 3 H). Preparation 2

Figure imgf000061_0001

(Z)-Ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65 °C for 1 hour before cooling to 50 °C and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 ml.) and ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating to reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10 °C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65 °C) for 14 hours to afford the title compound (339.4 g).

MS (ES+) 313.2 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.80 (t, J=5.00 Hz, 1 H) 7.47 (dd, J=8.90, 2.81 Hz, 1 H) 7.27 (br. s., 1 H) 7.22 (d, J=2.68 Hz, 1 H) 7.14 (d, J=8.78 Hz, 1 H) 7.09 (br. s., 1 H) 4.30 (s, 1 H) 4.03 (q, J=7.07 Hz, 2 H) 3.80 (s, 3 H) 3.56 (br. s., 1 H) 3.45 (br. s., 1 H) 1.18 (t, J=7.07 Hz, 3 H).

Example 1

Figure imgf000061_0002

2-( 6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3, 4-dihydropyrimidin

acetamide

A reaction vessel equipped with an efficient stirrer was charged with (Z)-ethyl 3-((2- amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (15 g, 50.2 mmol), butyl acetate (150 ml.) and trimethylsilyl isothiocyanate (160.7 mmole, 21 .1 g, 22.7 ml.) and the mixture was heated to reflux. After 15 hours, the mixture was cooled to 30 °C and treated with 1 N aqueous sodium hydroxide (1 12.5 ml_, 1 12.5 mmoles). After 30 min, the organic layer was separated and extracted with another portion of 1 N sodium hydroxide (37.5 ml_, 37.5 mmoles). The combined aqueous phases were extracted twice with dichloromethane (2 x 45 mL), filtered, and treated with 6N HCI until a pH of 2.5 was achieved. After stirring for 1 hour, the resulting solid was isolated by vacuum filtration, resuspended in 100 mL of a 1 :1 methanol-water solution, heated with stirring at 50 °C for 2 hours, and cooled to room temperature before collecting the solid by vacuum filtration, pulling dry and drying in a vacuum oven (20 mm Hg, 50 °C) for 12 hours to afford 8.7 g of the desired product as a tan solid.

MS (ES+) 326.0 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.85 (s, 1 H) 7.57 (dd, J=9.03, 2.68 Hz, 1 H) 7.33 (s, 1 H) 7.17 – 7.23 (m, 2 H) 7.10 (s, 1 H) 5.89 (d, J=1.71 Hz, 1 H) 5.41 (br. s, 1 H) 3.89 (br. s, 1 H) 3.84 (s, 3 H).

Alternative Preparation of Example 1

Figure imgf000062_0001

2-( 6-( 5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3, 4-dihydropyrimidin- 1 ( 2H)-yl) acetamide A slurry of (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2- methoxyphenyl)acrylate (20 g, 63 mmol) in a mixture of butyl acetate (140 mL) and DMF (38 mL) was treated with trimethylsilyl isothiocyanate (16.8 g, 125 mmol) and the mixture was heated at 1 15-120 °C for 5-6 hours. The mixture was cooled to 0-5 °C, butyl acetate (100 mL) was added and the mixture was slurried for 8 hours. The formed solids were filtered, and the filter cake was washed with butyl acetate (2 x 100 mL). The solid was dried in a vacuum oven at 50 °C for 12 hours to a tan solid. The solid was dissolved in a 5:1 mixture of DMF and water at room temperature and additional water was added slowly to crystallize the material. The slurry was cooled to 10 °C and stirred for 8 hours, followed by filtration and washing with water. The filter cake was dried in a vacuum oven at 50 °C for 8 hours. The solid was dissolved in a 1 :1 mixture of methanol and water and the slurry was heated to 50 °C and held at this temperature for 2 hours. After cooling to 10 °C over 30 minutes, the slurry was held at this temperature for 1 hour, filtered and washed with water and dried in a vacuum oven at 50 °C for 8 hours to give the title compound as a white solid. MS (ES+) 326.0 [M+1]+.1H NMR (500 MHz, DMSO-d6) δ ppm 12.85 (s, 1 H) 7.57 (dd, J=9.03, 2.68 Hz, 1 H) 7.33 (s, 1 H) 7.17 – 7.23 (m, 2 H) 7.10 (s, 1 H) 5.89 (d, J=1.71 Hz, 1 H) 5.41 (br. s, 1 H) 3.89 (br. s, 1 H) 3.84 (s, 3 H).

 

 

REFERENCES

1: Ruggeri RB, Buckbinder L, Bagley SW, Carpino PA, Conn EL, Dowling MS, Fernando DP, Jiao W, Kung DW, Orr ST, Qi Y, Rocke BN, Smith A, Warmus JS, Zhang Y, Bowles D, Widlicka DW, Eng H, Ryder T, Sharma R, Wolford A, Okerberg C, Walters K, Maurer TS, Zhang Y, Bonin PD, Spath SN, Xing G, Hepworth D, Ahn K, Kalgutkar AS. Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases. J Med Chem. 2015 Oct 28. [Epubahead of print] PubMed PMID: 26509551.

////////////PF 06282999, 1435467-37-0, PFIZER, PHASE 1, PF-06282999; PF-6282999, PF06282999, ACUTE CORONARY SYNDROME

O=C(N)CN(C(N1)=S)C(C2=CC(Cl)=CC=C2OC)=CC1=O

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