Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Ferric pyrophosphate citrate

1802359-96-1

tetrairon(3+) bis((phosphonooxy)phosphonic acid) tris(2-hydroxypropane-1,2,3-tricarboxylate) (hydrogen phosphonooxy)phosphonate

Iron(3+) diphosphate (4:3)

Proper name: ferric pyrophosphate citrate Chemical names: Iron (3+) cation; 2-oxidopropane-1,2,3-tricarboxylate; diphosphate 1,2,3-propanetricarboxylic acid, 2-hydroxy-, iron (3+), diphosphate Molecular formula: [Fe4 3+(C6H5O7)3(P2O7)3] Molecular mass: 1313

Physicochemical properties: TRIFERIC AVNU (ferric pyrophosphate citrate) contains no asymmetric centers. Ferric pyrophosphate citrate is a yellow to green amorphous powder. The drug substance does not melt, or change state, below 300 °C. Thermal decomposition was observed at 263 ± 3ºC. Ferric pyrophosphate citrate is freely soluble in water (>100 g/L). Ferric pyrophosphate citrate is completely insoluble in most organic solvents (MeOH, Acetone, THF, DMF, DMSO). A 5% solution in water exhibits a solution pH of about 6.  … https://pdf.hres.ca/dpd_pm/00060816.PDF

• Ferric pyrophosphate citrate
• FPC
• SFP
• Tetraferric nonahydrogen citrate pyrophosphate
• Triferic

Active Moieties

CANADA

Image may be NSFW.
Clik here to view.

Summary Basis of Decision – Triferic AVNU – Health Canada

Date SBD issued:2021-07-29

The following information relates to the new drug submission for Triferic AVNU.

Iron (supplied as ferric pyrophosphate citrate)

Drug Identification Number (DIN):

DIN 02515334 – 1.5 mg/mL iron (supplied as ferric pyrophosphate citrate), solution, intravenous administration

Rockwell Medical Inc.

New Drug Submission Control Number: 239850

On April 22, 2021, Health Canada issued a Notice of Compliance to Rockwell Medical Inc. for the drug product Triferic AVNU.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.

Triferic AVNU, an iron preparation, was authorized for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.

Triferic AVNU is not authorized for use in pediatric patients (<18 years of age), as its safety and effectiveness have not been established in this population. No overall differences in efficacy or safety were observed in geriatric patients (≥65 years of age) compared to younger patients in clinical trials.

Triferic AVNU is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, or component of the container.

Triferic AVNU was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Triferic AVNU (1.5 mg/mL iron [supplied as ferric pyrophosphate citrate]) is presented as a solution. In addition to the medicinal ingredient, the solution contains water for injection.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Triferic AVNU Product Monograph, approved by Health Canada and available through the Drug Product Database.

Health Canada considers that the benefit-harm-uncertainty profile of Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.

Chronic kidney disease (CKD) is a worldwide public health concern. One of the most common comorbidities of CKD-HD patients is anemia, which may be due to low body iron stores (as a result of blood loss during dialysis) and impaired utilization of iron. Consequently, there is an ongoing need to replenish body iron in CKD-HD patients.

Iron deficiency anemia in CKD-HD patients is generally treated using parenteral (intravenous) iron administration used in conjunction with erythropoiesis stimulating agents (ESAs). Intravenous administration is preferred, as oral iron is not well absorbed and gastrointestinal intolerance is common. At the time of authorization of Triferic AVNU, there were four other intravenous iron products marketed in Canada: Dexiron, an iron dextran (≥1,000 mg/dose); Ferrlecit (sodium ferric gluconate; 125 mg/dose); Venofer (iron sucrose; 200 mg/dose); and the more recently approved Monoferric (Iron Isomaltoside 1,000; up to 500 mg/bolus injection and up to 1,500 mg/infusion). Each of these intravenous iron products are indicated for the treatment of iron deficiency anemia and are associated with safety concerns for hypersensitivity reactions. Serious hypersensitivity reactions have been reported, including life threatening and fatal anaphylactic/anaphylactoid reactions.

Triferic AVNU is an iron replacement product delivered via intravenous infusion into the blood lines pre- and post-dialyzer in CKD-HD patients at each hemodialysis treatment. It is a preservative-free sterile solution containing 1.5 mg elemental iron/mL in water for injection.

Triferic AVNU has been shown to be efficacious in maintaining hemoglobin (Hb) during the treatment period in CKD-HD patients. The market authorization was primarily based on the results of two pivotal, randomized, placebo-controlled, single blind, Phase III clinical studies (Studies SFP-4 and SFP-5). Both studies were identical in design and enrolled a combined total of 599 adult patients with CKD-HD who were iron-replete. Patients were randomized to receive either Triferic AVNU added to bicarbonate concentrate with a final concentration of 110 μg of iron/L in dialysate or placebo (standard dialysate) administered 3 to 4 times per week during hemodialysis. All patients were to remain randomized in their treatment group until pre-specified Hb or ferritin criteria were met, indicating the need for a change in anemia management, or until they had completed 48 weeks of treatment. After randomization, patients’ ESA product, doses, or route of administration were not to be changed and oral or intravenous iron administration were not allowed.

The primary efficacy endpoint (mean change in Hb level from baseline to the end-of-treatment period) was met in both pivotal studies. In Study SFP-4, the mean Hb decreased 0.04 g/dL in the Triferic AVNU group compared to 0.39 g/dL in the placebo group. In Study SFP-5, the mean Hb decreased 0.09 g/dL in the Triferic AVNU group compared to 0.45 g/dL in the placebo group. In both studies, the treatment difference in mean hemoglobin change was 0.36 g/dL (p = 0.011) between the Triferic AVNU and the placebo groups. This value was statistically significant for both studies. The treatment difference of 0.35 g/dL was also statistically significant (p = 0.010) for both studies in the analysis using the intent-to-treat population. A high proportion of patients did not complete the planned 48 weeks of study treatment mainly due to protocol-mandated changes in anemia management (ESA dose changes). However, the proportion was similar for both arms and the analysis of Hb change in this subgroup was consistent with that of the primary efficacy analysis. Secondary endpoints which included changes in reticulocyte Hb content, serum ferritin, and pre-dialysis serum iron panel to the end of treatment, were consistent with the primary efficacy results.

The safety of Triferic AVNU was evaluated in seven controlled and uncontrolled Phase II/III studies, which included the two pivotal studies. In total, 1,411 CKD-HD patients were exposed to Triferic AVNU in the clinical program. In the pivotal studies, 78% of patients in the Triferic AVNU group and 75% of patients in the placebo group had at least one treatment-emergent adverse event (TEAE). The most common TEAEs in the Triferic AVNU group (which were higher than the placebo group) were procedural hypotension (21.6%), muscle spasms (9.6%), headache (9.2%), pain in extremity (6.8%), edema peripheral (6.8%) and dyspnoea (5.8%). Serious TEAEs were reported at similar rates for the two groups at 27.7% for the Triferic AVNU group and 27.4% for the placebo group. The most common serious TEAEs occurring in the Triferic AVNU group (which were higher than the placebo group) were cardiac arrest (1.7%), arteriovenous fistula thrombosis (1.7%), and pulmonary edema (1.4%). Few patients discontinued study treatment due to TEAEs (4.5% in the Triferic AVNU group and 2.4% in the placebo group).

In the overall clinical program, there were two cases (0.1%) of hypersensitivity reactions related to treatment out of the 1,411 patients treated with Triferic AVNU. There were no cases of serious hypersensitivity reaction and no cases of anaphylaxis related to Triferic AVNU treatment. A Serious Warnings and Precautions box describing a warning for hypersensitivity reaction has been included in the Product Monograph for Triferic AVNU.

A Risk Management Plan (RMP) for Triferic AVNU was submitted by Rockwell Medical Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. In the RMP, the sponsor included ‘hypersensitivity reactions’ as an important identified risk; ‘systemic/serious infections’ as an important potential risk; and ‘use in pregnant and breastfeeding women’, ‘use in children’ and ‘concomitant use with other intravenous iron product’ as missing information. Labelling for these safety concerns has been included in the Product Monograph and the sponsor has committed to systemically review clinical and post-marketing safety data as part of routine pharmacovigilance activities. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Triferic AVNU Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Triferic AVNU was accepted.

Overall, the therapeutic benefits of Triferic AVNU therapy seen in the pivotal studies are positive and are considered to outweigh the potential risks. Triferic AVNU has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Triferic AVNU Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

• See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
• See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
• See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
• See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
• See the Patent Register for patents associated with medicinal ingredients, if applicable.
• See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.

The Chemistry and Manufacturing information submitted for Triferic AVNU has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored protected from light in the aluminum pouch at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

None of the excipients used in the formulation of Triferic AVNU are of human or animal origin. All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

DIN:

02515334

Product Monograph/Veterinary Labelling:

Date: 2021-04-21  Product monograph/Veterinary Labelling (PDF version ~ 175K)

Company:

ROCKWELL MEDICAL INC
30142 S Wixom Rd
Wixom
Michigan
United States  48393

Class: 

Human

Dosage form(s):

Solution

Route(s) of administration:

Intravenous

Number of active ingredient(s):

1

Schedule(s):

Prescription

Biosimilar Biologic Drug:

No

American Hospital Formulary Service (AHFS):^{See footnote3}

20:04.04   IRON PREPARATIONS

Anatomical Therapeutic Chemical (ATC):^{See footnote4}

B03AC  IRON, PARENTERAL PREPARATIONS

Active ingredient group (AIG) number:^{See footnote5}

0108536041

RXLIST

TRIFERIC®
(ferric pyrophosphate citrate) Solution, for Hemodialysis Use

TRIFERIC®
(ferric pyrophosphate citrate) powder packet for hemodialysis use

DESCRIPTION

Triferic (ferric pyrophosphate citrate) solution, an iron replacement product, is a mixed-ligand iron complex in which iron (III) is bound to pyrophosphate and citrate. It has a molecular formula of Fe₄(C₆H₄O₇)₃(H₂P₂O₇)₂(P₂O₇) and a relative molecular weight of approximately 1313 daltons. Ferric pyrophosphate citrate has the following structure:

Image may be NSFW. Clik here to view.

Triferic Solution

Triferic (ferric pyrophosphate citrate) solution–is a clear, slightly yellow-green color sterile solution containing 27.2 mg of elemental iron (III) per 5 mL (5.44 mg iron (III) per mL) filled in a 5 mL or 272 mg of elemental iron (III) per 50 mL (5.44 mg iron (III) per mL) filled in a 50 Ml low density polyethylene (LDPE) ampule. Each Triferic ampule contains iron (7.5-9.0% w/w), citrate (15-22% w/w), pyrophosphate (15-22% w/w), phosphate (< 2% w/w), sodium (18-25% w/w) and sulfate (20-35%). One Triferic 5 mL ampule is added to 2.5 gallons (9.46 L) of bicarbonate concentrate. One Triferic 50 mL ampule is added to 25 gallons (94.6 L) of master bicarbonate mix.

Triferic Powder Packets

Triferic (ferric pyrophosphate citrate) powder is a slightly yellow-green powder, packaged in single use paper, polyethylene and aluminum foil packets, each containing 272.0 mg of elemental iron (III). Each Triferic packet contains iron (7.5-9.0% w/w), citrate (15-22% w/w), pyrophosphate (15-22% w/w), phosphate (< 2% w/w), sodium (18-25% w/w) and sulfate (20- 35%). One Triferic powder packet is added to 25 (94.6 L) gallons of master bicarbonate mix.

Ferric pyrophosphate citrate (FPC), a novel iron-replacement agent, was approved by the US Food and Drug Administration in January 2015 for use in adult patients receiving chronic hemodialysis (HD). This iron product is administered to patients on HD via the dialysate.

Ferric pyrophosphate citrate is a soluble iron replacement product. Free iron presents several side effects as it can catalyze free radical formation and lipid peroxidation as well as the presence of interactions of iron in plasma. The ferric ion is strongly complexed by pyrophosphate and citrate.¹ FPC is categorized in Japan as a second class OTC drug.⁶ This category is given to drugs with ingredients that in rare cases may cause health problems requiring hospitalization or worst.⁷ It is also FDA approved since 2015.^Label

Iron(III) pyrophosphate is an inorganic chemical compound with the formula Fe₄(P₂O₇)₃.

Synthesis

Anhydrous iron(III) pyrophosphate can be prepared by heating the mixture of iron(III) metaphosphate and iron(III) phosphate under oxygen with the stoichiometric ratio 1:3. The reactants can be prepared by reacting iron(III) nitrate nonahydrate with phosphoric acid.^[2]

It can be also prepared via the following reaction:^[3]3 Na₄P₂O₇(aq) + 4 FeCl₃(aq) → Fe₄(P₂O₇)₃(s) + 12 NaCl(aq)

References

1. ^ W.M.Haynes. CRC Handbook of Chemistry and Physics (97th edition). New York: CRC Press, 2016. pp 4-68
2. ^ Elbouaanani, L.K; Malaman, B; Gérardin, R; Ijjaali, M (2002). “Crystal Structure Refinement and Magnetic Properties of Fe4(P2O7)3 Studied by Neutron Diffraction and Mössbauer Techniques”. Journal of Solid State Chemistry. Elsevier BV. 163 (2): 412–420. doi:10.1006/jssc.2001.9415. ISSN 0022-4596.
3. ^ Rossi L, Velikov KP, Philipse AP (May 2014). “Colloidal iron(III) pyrophosphate particles”. Food Chem. 151: 243–7. doi:10.1016/j.foodchem.2013.11.050. PMID 24423528.

• Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [Article]
• Naigamwalla DZ, Webb JA, Giger U: Iron deficiency anemia. Can Vet J. 2012 Mar;53(3):250-6. [Article]
• Fidler MC, Walczyk T, Davidsson L, Zeder C, Sakaguchi N, Juneja LR, Hurrell RF: A micronised, dispersible ferric pyrophosphate with high relative bioavailability in man. Br J Nutr. 2004 Jan;91(1):107-12. [Article]
• Pratt RD, Swinkels DW, Ikizler TA, Gupta A: Pharmacokinetics of Ferric Pyrophosphate Citrate, a Novel Iron Salt, Administered Intravenously to Healthy Volunteers. J Clin Pharmacol. 2017 Mar;57(3):312-320. doi: 10.1002/jcph.819. Epub 2016 Oct 3. [Article]
• Underwood E. (1977). Trace elements in human and animal nutrition (4th ed.). Academic press.
• KEGG [Link]
• Nippon [Link]
• FDA Reports [Link]

CLIP

https://link.springer.com/article/10.1007/s10534-018-0151-1

Iron deficiency is a significant health problem across the world. While many patients benefit from oral iron supplements, some, including those on hemodialysis require intravenous iron therapy to maintain adequate iron levels. Until recently, all iron compounds suitable for parenteral administration were colloidal iron–carbohydrate conjugates that require uptake and processing by macrophages. These compounds are associated with variable risk of anaphylaxis, oxidative stress, and inflammation, depending on their physicochemical characteristics. Ferric pyrophosphate citrate (FPC) is a novel iron compound that was approved for parenteral administration by US Food and Drug Administration in 2015. Here we report the physicochemical characteristics of FPC. FPC is a noncolloidal, highly water soluble, complex iron salt that does not contain a carbohydrate moiety. X-ray absorption spectroscopy data indicate that FPC consists of iron (III) complexed with one pyrophosphate and two citrate molecules in the solid state. This structure is preserved in solution and stable for several months, rendering it suitable for pharmaceutical applications in solid or solution state.

Iron deficiency with or without associated anemia represents a significant health problem worldwide. While many patients can restore iron levels with the use of oral iron supplements, oral supplementation is not suitable in some patients, including those undergoing chronic hemodialysis for chronic kidney disease (CKD) (Fudin et al. 1998; Macdougall et al. 1996; Markowitz et al. 1997). The limitations of oral iron replacement in patients undergoing hemodialysis likely arise from excessive ongoing losses and insufficient absorption, thus intravenous (IV) iron has become the primary route of administration in such patients (Shah et al. 2016). Multiple IV iron formulations are available, including iron dextran, iron sucrose, sodium ferric gluconate, iron carboxymaltose, ferrumoxytol, and iron isomaltoside (Macdougall et al. 1996). All such formulations are iron–carbohydrate macromolecular complexes, and the majority consist of an iron oxide core surrounded by a carbohydrate moiety (Macdougall et al. 1996; Markowitz et al. 1997).

Intravenous iron products have been used extensively for over 30 years for the treatment of iron-deficiency anemia and to maintain iron balance in hemodialysis patients since these patients have obligatory excessive losses. While these agents are generally well tolerated, they have been associated with risk of anaphylaxis (Wang et al. 2015). Compared to oral iron agents, there may be an increased risk of cardiovascular complications and infections in nondialysis patients with CKD (Macdougall et al. 1996). Additionally, higher mortality rates have been reported with use of high-dose IV iron in hemodialysis patients (Bailie et al. 2015).

Iron possesses oxidizing properties that may cause injury to cells and tissues (Koskenkorva-Frank et al. 2013; Vaziri 2013). Iron loading in general is associated with endocrinological, gastrointestinal, infectious, neoplastic, neurodegenerative, obstetric, ophthalmic, orthopedic, pulmonary, and vascular complications. In addition, excessive or misplaced tissue iron also can contribute to aging and mortality (Weinberg 2010). Normally, the body is able to protect tissues from the damaging effects of iron by regulating iron absorption in the intestine and sequestering iron with iron-binding proteins. However, the concentrations of iron introduced into the bloodstream with IV iron therapy can be as much as 100 times more than that absorbed normally through the intestine. Combined with the fact that IV iron is administered over a period of minutes compared to the slow, regulated absorption in the gut, it is possible that the increased iron load may damage cells and tissues.

A novel parenteral iron formulation, ferric pyrophosphate citrate (FPC), potentially offers a more physiologic delivery of iron. Unlike previous forms of IV iron, FPC contains no carbohydrate shell. Soluble ferric pyrophosphate-citrate complexes, generally referred to as soluble ferric pyrophosphate (SFP) were first described in the mid-1800s by Robiquet and Chapman (Chapman 1862; Robiquet 1857). This class of food-grade iron salts has been available for over 100 years as oral iron supplements and for fortification of food. In the late-1990s, Gupta et al. demonstrated that food-grade SFP could be administered to hemodialysis patients via the dialysate (Gupta et al. 1999). However, the commercially available compounds are poorly characterized and not suitable for further development as a parenteral iron supplement. Therefore, a pharmaceutical-grade SFP was developed. This product had a higher solubility than food-grade SFP and was granted a new USAN name—FPC. In 2015 FPC was approved by the US Food and Drug Administration (FDA) for parenteral delivery by hemodialysis to replace iron losses and thereby maintain hemoglobin levels in hemodialysis-dependent patients with CKD (Rockwell Medical Inc 2018). FPC is currently marketed under the trade name Triferic^® (Rockwell Medical Inc., Wixom, Michigan, USA). FPC is the first carbohydrate-free, noncolloidal, water-soluble iron salt suitable for parenteral administration.

Infrared spectroscopy

Infrared (IR) spectroscopy was used to determine the main functional groups present in FPC. Figure 1 shows a representative IR spectrum of FPC. Peak assignments and positions for FPC as well as for sodium citrate, sodium pyrophosphate, and ferric sulfate, which were used to confirm the peak assignments, are shown in Table 1.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

X-ray spectra of solid and aqueous iron standards and FPC. a XANES spectra of iron (II) and iron (III) standards as well as FPC in the solid and solution phases show that FPC consists exclusively of iron (III) and that the solid-phase structure is maintained in solution. b EXFAS modeling of FPC in the solid phase (top) and in solution (bottom) at Day 1 and Month 4

Chemical composition of ferric pyrophosphate citrate

From: Physicochemical characterization of ferric pyrophosphate citrate

PATENT

https://patents.google.com/patent/WO2017040937A1/enProperties of Conventional SFP

Image may be NSFW.
Clik here to view.

Another example of SFP is the composition is the chelate composition described in US Patent Nos. 7,816,404 and 8,178,709. The SFP may be a ferric pyrophosphate citrate (FPC) comprising a mixed-ligand iron compound comprising iron chelated with citrate andpyrophosphate, optionally FPC has the following formula: Fe4(C₆H₄0₇)₃(H₂P₂0₇)2(P₂0₇) (relative MW 1313 daltons), e.g., structure (I):

Image may be NSFW.
Clik here to view.

[0036] An exemplary SFP according to the present disclosure is known to have the properties described in Table 3.Table 3 – Properties of SFP according to the present disclosure

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

one time

$10.00

Click here to purchase.

////////////ferric pyrophosphate citrate, Triferic AVNU, , Ferric pyrophosphate citrate, FPC, SFP, Tetraferric nonahydrogen citrate pyrophosphate, Triferic, FDA 2015, APPROVALS 2021, CANADA 2021, hemodialysis-dependent chronic kidney disease 

[Fe+3].[Fe+3].[Fe+3].[Fe+3].OP(O)(=O)OP(O)(O)=O.OP(O)(=O)OP(O)(O)=O.OP([O-])(=O)OP([O-])([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O

[ Fig. 0001] Image may be NSFW.
Clik here to view.[ Fig. 0002] Image may be NSFW.
Clik here to view.[ Fig. 0003] Image may be NSFW.
Clik here to view.[ Fig. 0004] Image may be NSFW.
Clik here to view.

SY 5609

CAS 2519828-12-5

Cancer, solid tumor

PHASE 1

A highly selective and potent oral inhibitor of cyclin-dependent kinase 7 (CDK7) for potential treatment of advanced solid tumors that harbor the Rb pa thway alterations (Syros Pharmaceuticals, Inc., Cambridge, Massachusetts, USA)

SY-5609 is an oral non-covalent CDK7 inhibitor in early clinical development at Syros Pharmaceuticals for the treatment of patients with advanced breast, colorectal, lung or ovarian cancer, or with solid tumors of any histology that harbor Rb pathway alterations.

• OriginatorSyros Pharmaceuticals
• ClassAntineoplastics; Small molecules
• Mechanism of ActionCyclin-dependent kinase-activating kinase inhibitors
• Phase IBreast cancer; Solid tumours

• 05 Aug 2021Roche plans the phase I/Ib INTRINSIC trial in Colorectal cancer (Combination therapy, Metastatic disease) in USA, Canada, Italy, South Korea, Spain and United Kingdom (NCT04929223)
• 05 Aug 2021Roche and Syros Pharmaceuticals enters into a clinical trial collaboration to evaluate atezolizumab in combination with SY 5609 in a clinical trial
• 05 Aug 2021Syros Pharmaceuticals plans a phase I trial in Cancer in second half of 2021
• NCT04247126
• https://clinicaltrials.gov/ct2/show/NCT04247126

Image may be NSFW.
Clik here to view.

At #ESMO21, we will be presenting new preclinical and clinical data on SY-5609, our highly selective and potent oral CDK7 inhibitor. #oncology #biotech Learn more: https://lnkd.in/gqYmWYhb

A Promising Approach for Difficult-to-Treat Cancers

SY-5609 is a highly selective and potent oral inhibitor of the cyclin-dependent kinase 7 (CDK7) in a Phase 1 dose-escalation trial in patients with advanced breast, colorectal, lung, ovarian or pancreatic cancer, or with solid tumors of any histology that harbor Rb pathway alterations.

SY-5609 represents a new approach to treating cancer that we believe has potential in a range of difficult-to-treat cancers. It has shown robust anti-tumor activity, including complete regressions, in preclinical models of breast, colorectal, lung and ovarian cancers at doses below the maximum tolerated dose. In preclinical studies of breast, lung and ovarian cancers, deeper and more sustained responses were associated with the presence of Rb pathway alterations. SY-5609 has also shown substantial anti-tumor activity in combination with fulvestrant in treatment-resistant models of estrogen receptor-positive breast cancer, including those resistant to both fulvestrant and a CDK4/6 inhibitor. Early dose-escalation data demonstrated proof-of-mechanism at tolerable doses.

Syros to Present New Data from Phase 1 Clinical Trial of SY-5609 in Oral Presentation at ESMO Congress 2021SEPTEMBER 13, 2021

Management to Host Conference Call on Monday, September 20, 2021 at 4:00 p.m. ET

CAMBRIDGE, Mass.–(BUSINESS WIRE)– Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, today announced that it will present new data from the dose-escalation portion of the Phase 1 clinical trial of SY-5609, its highly selective and potent oral cyclin-dependent kinase 7 (CDK7) inhibitor, at the ESMO Congress 2021, taking place virtually September 16-21, 2021. The oral presentation will include safety, tolerability, and initial clinical activity data for SY-5609 in patients with breast, colorectal, lung, ovarian and pancreatic cancers, as well as in patients with solid tumors of any histology harboring Rb pathway alterations.

In separate poster presentations, Syros will present new preclinical data evaluating the antitumor and pharmacodynamic activity of intermittent dosing regimens for SY-5609 in ovarian cancer models, as well as new preclinical data evaluating antitumor activity of SY-5609 as a single agent and in combination with chemotherapy in KRAS-mutant models.

The abstracts for the two poster presentations are now available online on the ESMO conference website at: https://www.esmo.org/meetings/esmo-congress-2021/abstracts, and the presentations will become available for on-demand viewing starting September 16 at 08:30 CEST (September 16 at 2:30 a.m. ET). The abstract for the oral presentation on the Phase 1 dose-escalation data will remain embargoed until September 17 at 00:05 CEST (September 16 at 6:05 p.m. ET).

Details of the oral presentation are as follows:

Presentation Title: Tolerability and Preliminary Clinical Activity of SY-5609, a Highly Potent and Selective Oral CDK7 Inhibitor, in Patients with Advanced Solid Tumors
Session Date & Time: Monday, September 20, 17:30-18:30 CEST (11:30-12:30 p.m. ET)
Presentation Time: 17:55-18:00 CEST (11:55-12:00 p.m. ET)
Session Title: Mini Oral Session: Developmental Therapeutics
Presenter: Manish Sharma, M.D., START Midwest
Abstract Number: 518MO

Details of the poster presentations are as follows:

Presentation Title: Preclinical Evaluation of Intermittent Dosing Regimens on Antitumor and PD Activity of SY-5609, a Potent and Selective Oral CDK7 Inhibitor, in Ovarian Cancer Xenografts
Abstract Number: 14P
Presentation Title: SY-5609, a Highly Potent and Selective Oral CDK7 inhibitor, Exhibits Robust Antitumor Activity in Preclinical Models of KRAS Mutant Cancers as a Single Agent and in Combination with Chemotherapy
Abstract Number: 13P

Conference Call Information

Syros will host a conference call on Monday, September 20, 2021 at 4:00 p.m. ET to discuss the new clinical and preclinical data for SY-5609, which will be presented at the ESMO Congress 2021.

To access the live conference call, please dial 866-595-4538 (domestic) or 636-812-6496 (international) and refer to conference ID 4648345. A webcast of the call will also be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 30 days following the conference call.

About Syros Pharmaceuticals

Syros is redefining the power of small molecules to control the expression of genes. Based on its unique ability to elucidate regulatory regions of the genome, Syros aims to develop medicines that provide a profound benefit for patients with diseases that have eluded other genomics-based approaches. Syros is advancing a robust clinical-stage pipeline, including: tamibarotene, a first-in-class oral selective RARα agonist in RARA-positive patients with higher-risk myelodysplastic syndrome and acute myeloid leukemia; SY-2101, a novel oral form of arsenic trioxide in patients with acute promyelocytic leukemia; and SY-5609, a highly selective and potent oral CDK7 inhibitor in patients with select solid tumors. Syros also has multiple preclinical and discovery programs in oncology and monogenic diseases.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210913005090/en/

PATENT

CN(C)C\C=C\C(=O)Nc1ccc(cc1)C(=O)Nc1cccc(c1)Nc1ncc(Cl)c(n1)c1c[NH]c2ccccc21

THZ1; 1604810-83-4; THZ-1; HY-80013

Image may be NSFW.
Clik here to view.

CLIP

SY 1365 MEVOCICLIB, CAS 1816989-16-8

CN(C)C\C=C\C(=O)Nc1ccc(nc1)C(=O)N[C@]1(C)C[C@@H](CCC1)Nc1ncc(Cl)c(n1)c1c[NH]c2ccccc21

Image may be NSFW.
Clik here to view.

PATENT

Image may be NSFW.
Clik here to view.

PATENT

3-fluoro-4-(methylamino)-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide (Compound 130)

Image may be NSFW. Clik here to view.

3-chloro-4-[[4-(dimethylamino)-3-hydroxy-butanoyl]amino]-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 129)

Image may be NSFW. Clik here to view.

4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1-methylcyclohexyl)benzamide (Compound 128)

Image may be NSFW. Clik here to view.

4-amino-3-fluoro-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 127)

Image may be NSFW. Clik here to view.

4-amino-N-((1S,3R)-3-((5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 126)

Image may be NSFW. Clik here to view.

4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 124)

Image may be NSFW. Clik here to view.

Example 25 Synthesis of N1-(4-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)oxalamide (Compound 113)

Image may be NSFW. Clik here to view.

Example 24 Synthesis of N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)-4-(4-(dimethylamino)butanamido)benzamide (Compound 105)

Image may be NSFW. Clik here to view.

PATENT

4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.1^3,7]decanyl)benzamide (Compound 100).

Image may be NSFW.
Clik here to view.

+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5 hydroxycyclohexyl)benzamide (Compound 101)

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide (Compound 102)

Image may be NSFW.
Clik here to view.

(1S,3R)-N-(4-aminophenyl)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamide (Compound 106)

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-cyclopropyl-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl (Compound 103)

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide (Compound 108)

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-cyano-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide (Compound 107)

Image may be NSFW.
Clik here to view.

(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide (Compound 110)

Image may be NSFW.
Clik here to view.

4-amino-N-(5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-yl)benzamide (Compound 104)

Image may be NSFW.
Clik here to view.

4-amino-N4(1R,5S)-5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide (Compound 115)

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzenesulfonamide (Compound 109).

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluorobenzamide (Compound 112)

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide (Compound 111).

Image may be NSFW.
Clik here to view.

(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexyl)benzamide (Compound 116).

Image may be NSFW.
Clik here to view.

N-((1S,3R)-3-(4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-4-aminobenzamide (Compound 114).

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholinobenzamide(Compound 117).

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyridin-2-ylamino)cyclohexyl)benzamide (Compound 118).

Image may be NSFW.
Clik here to view.

3-amino-N-(trans-4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl (Compound 119).

Image may be NSFW.
Clik here to view.

(1S,3R)-N1-(R)-1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine (Compound 120).

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

(1S,3R)-N1-(4-aminobenzyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-N1-methylcyclohexane-1,3-diamine.HCl (Compound 122).

Image may be NSFW.
Clik here to view.

4-amino-N-((1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl (Compound 123).

Image may be NSFW.
Clik here to view.

Synthesis of 5-amino-N-((1S,3R)-3-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)picolinamide (Compound 125)

Image may be NSFW.
Clik here to view.

Synthesis of N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)-4-(4-(dimethylamino)butanamido)benzamide (Compound 105)

Image may be NSFW.
Clik here to view.

Synthesis of N1-(4-(((1S,3R)-3-)(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)oxalamide (Compound 113)

Image may be NSFW.
Clik here to view.

Synthesis of 4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 124)

Image may be NSFW.
Clik here to view.

Synthesis of 4-amino-N-((1S,3R)-3-((5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide (Compound 126)

Image may be NSFW.
Clik here to view.

Synthesis of 4-amino-3-fluoro-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 127).

Image may be NSFW.
Clik here to view.

Synthesis of 4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl) pyrimidin-2-yl)amino)-1-methylcyclohexyl)benzamide (Compound 128)

Image may be NSFW.
Clik here to view.

Synthesis of 3-chloro-4-[[4-(dimethylamino)-3 hydroxy-butanoyl]amino]-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide (Compound 129).

Image may be NSFW.
Clik here to view.

Synthesis of 3-fluoro-4-(methylamino)-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide (Compound 130)

Image may be NSFW.
Clik here to view.

//////////////SY 5609, 2519828-12-5, Cancer, solid tumor, PHASE 1, SYROS

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

MEVOCICLIB,

CAS 1816989-16-8

SY 1365

N-[(1S,3R)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-1-methylcyclohexyl]-5-[[(E)-4-(dimethylamino)but-2-enoyl]amino]pyridine-2-carboxamide

N-((lS,3R)-3-(5-chloro-4-(lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcvclohexyl)-5-((E)-4-(dimethylamino)but-2-enamido)picolinamide

HS Tariff Code: 2934.99.9001

Syros

• OriginatorSyros Pharmaceuticals
• ClassAmides; Amines; Antineoplastics; Chlorinated hydrocarbons; Cyclohexanes; Indoles; Pyridines; Pyrimidines; Small molecules
• Mechanism of ActionCyclin-dependent kinase-activating kinase inhibitors
• DiscontinuedAcute myeloid leukaemia; Breast cancer; Haematological malignancies; Ovarian cancer; Solid tumours

• 23 Oct 2019Discontinued – Preclinical for Haematological malignancies and Acute myeloid leukaemia in the USA (Parenteral); Phase-I for Solid tumours, Ovarian cancer and Breast cancer in the USA (IV) because data obtained did not support an optimal profile for patients and indicated higher or frequent dosing
• 07 Dec 2018Pharmacodynamics data from preclinical trials in Breast cancer presented at the 41st Annual San Antonio Breast Cancer Symposium (SABCS-2018)
• 15 Nov 2018Adverse events, efficacy and pharmacokinetics data from a phase I trial in Solid tumours presented at the 30^th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium (EORTC-NCI-AACR-2018)

Mevociclib (SY-1365) is a potent and first-in-class selective CDK7 inhibitor, with a K_i of 17.4 nM. Mevociclib exhibits anti-proliferative and apoptotic effects in solid tumor cell lines. Mevociclib possesses anti-tumor activity in hematological and multiple aggressive solid tumors.

Mevociclib, also known as SY-1365, is a CDK7 inhibitor. In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL-XL expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial anti-tumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax.

Syn

WO2015154038

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015154038

Example 16. Synthesis of N-((lS,3R)-3-(5-chloro-4-(lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcvclohexyl)-5-((E)-4-(dimethylamino)but-2-enamido)picolinamide (Compound 267).

[251] (+/-) Benzyl tert-butyl ((lS,3R)-l-methylcvclohexane-l,3-diyl)dicarbamate

Image may be NSFW.
Clik here to view.

(+/-)

[252] A solution of (+/-)-(lS,3R) -3-((ieit-¾itoxycarbonyl)amino)–l -raethylcyclohexanecarboxylic acid prepared as in WO2010/148197 (4.00 g, 15.5 mmol) in toluene (Ϊ 55 mL) was treated with Et₃N (2.4 mL, 17.1 mmol) and DPPA (3.68 mL, Ϊ7.1 mmol) and heated at reflux for lh. Benzyl alcohol (8.0 mL, 77.7 mmol) and Et₃N (4.4 mL , 31 .4 mmol) were added to the reaction mixture and the solution was heated at 100 °C for 72h. The mixture was cooled to room temperature and then diluted with EtOAc (300 mL) and H₂0 (300 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organics layers were washed with brine (100 mL), filtered and evaporated to dryness. The residue was purified by Si0₂ chromatography (EtOAc in hexanes, 0 to 50% gradient) and afforded the title compound (3.40 g, 9.38 mmol, 60%) as a white solid.

[253] Benzyl tert-butyl ((lS,3R)-l-methylcvclohexane-l,3-diyl)dicarbamate and benzyl tert- -l-methylcvclohexane-l,3-diyl)dicarbamate

Image may be NSFW.
Clik here to view.

(+/-)

[254] Both enantiomers of (+/-)-Benzyl tert-butyl ((lS,3R)-l-methylcyclohexane-l,3-diyl)dicarbamate (3.40 g, 9.38 mmol) were separated using preparative chiral HPLC (Chiralpak IA, 5 urn, 20×250 mm; hex/MeOH/DCM = 90/5/5) to yield both compounds benzyl tert-butyl ((lS,3R)-l-methylcyclohexane-l,3-diyl)dicarbamate (1.20 g, 3.31 mmol) and benzyl iert-butyl ((lR,3S)-l-methylcyclohexane-l,3-diyl)dicarbamate (1.15 g, 3.17 mmol) as white solids.

255 Benzyl ((lS,3R)-3-amino-l-methylcvclohexyl)carbamate hydrochloride

Image may be NSFW.
Clik here to view.

[256] A solution of benzyl tert-butyl ((lS,3R)-l-methylcyclohexane-l,3-diyl)dicarbamate (700 mg, 1.93 mmol) in DCM (19 mL) was treated with a 4M solution of HCI in dioxane (9.66 mL, 38.6 mmol) and stirred 16h at rt. The mixture was evaporated to dryness and afforded the title compound (577 mg, 1.93 mmol, 100%) as a white solid which was used in the next step without further purification.

[257] (lS,3R)-Benzyl-3-(5-chloro-4-(l-(phenylsulfonyl)-lH ndol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamate

Image may be NSFW.
Clik here to view.

[258] A solution of 3-(2,5-dichloropyrimidin-4-yl)-l-(phenylsulfonyl)-lH-indole (1.02 g, 2.53 mmol), benzyl (( iS,3 )-3- amino- 1 -methylcyclohexyljcarbaniaie hydrochloride (577 mg, 1.93 mmol) and DIPEA (1.15 mL, 6.60 mmol) in NMP (11 mL) was heated at 135 °C (microwave) for 60 min. The cooled mixture was diluted with EtOAc (250 mL), washed with H₂0 (100 mL), brine (100 mL), dried over MgS0₄, filtered and evaporated to dryness. The residue was purified by Si0₂ chromatography (EtOAc in DCM, 0 to 50% gradient) and afforded the title compound (747 mg, 1.19 mmol, 54%) as a yellow foam.

[259] (lS,3R)-N-(5-chloro-4-(l-(phenylsulfonyl)-lH ndol-3-yl)pyrimidin-2-yl)-3-methylcvclohexane-l,3-diamine

Image may be NSFW.
Clik here to view.

[260] A cooled (-78°C) solution of (lS,3R)-benzyl-3-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexylcarbamate (747 mg, 1.19 mmol) in DCM (39 mL) was treated with a 1M solution of BBr₃ in DCM (2.83 mL, 2.83 mmol) and was slowly warmed up to rt. MeOH (10 mL) was added to the mixture was the resulting solution was stirred lh at rt. The resulting mixture was evaporated to dryness. The residue was purified by reverse phase chromatography (C₁₈, H₂0/ACN +0.1% HC0₂H, 0 to 60% gradient) and afforded the title compound (485 mg, 0.978 mmol, 83%) as a yellow solid.

[261] 5-amino-N-( ( lS,3R)-3-( 5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcvclohexyl)picolinamide

Image may be NSFW.
Clik here to view.

[262] A solution of (lR,3S)-N-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-yl)-3-methylcyclohexane-l,3-diamine (75.0 mg, 0.150 mmol) and 5-aminopicolinic acid (25.0 mg, 0.180 mmol) in DMF (5.0 mL) was treated with HBTU (86.0 mg, 0.230 mmol) and DIPEA (79 μί, 0.45 mmol). The resulting mixture was stirred 5h at rt and diluted with MeTHF (50 mL) and saturated NaHC0₃ (50 mL). The layers were separated and the aqueous layer was extracted with MeTHF (2 x 50 mL). The combined organic layers were dried over MgS0₄, filtered and evaporated to dryness. The residue was purified by Si0₂ chromatography (EtOAc in DCM, 0 to 50% gradient) and afforded the title compound (74.0 mg, 0.120 mmol, 79%) as a light yellow oil.

[263] 5-amino-N-((lS,3R)-3-(5-chloro-4-(lH ndol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexyDpicolinamide

Image may be NSFW.
Clik here to view.

[264] A solution of 5-amino-N-((lS,3R)-3-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexyl)picolinamide (74.0 mg, 0.120 mmol) in 1,4-dioxane (4.0 mL) was treated with a 2M solution of NaOH in H₂0 (960 μί, 4.78 mmol) and heated at 60°C for lh. The cooled mixture was diluted with MeTHF (30 mL) and H₂0 (30 mL). The layers were separated and the aqueous layer was extracted with MeTHF (3 x 30 mL). The combined organic layers were dried over MgS0₄, filtered and evaporated to dryness affording the title compound (57.0 mg, 0.120 mmol, 100%) as a light yellow oil which was used in the next step without further purification.

[265] N-((lS,3R)-3-(5-chloro-4-(lH ndol-3-yl)pyrimidin-2-ylamino)-l-methylcvd^

( ( E)-4-(dimethylamino)but-2-enamido )picolinamide ( Compound 267)

Image may be NSFW.
Clik here to view.

[266] A cooled (-78°C) solution of 5-amino-N-((lS,3R)-3-(5-chloro-4-(lH-indol-3-yl)pyrimidin-2-ylamino)-l-methylcyclohexyl)picolinamide (57.0 mg, 0.120 mmol) and DIPEA (104 0.598 mmol) in THF/NMP (4.0 mL/1.0 mL) was treated with a 54.2 mg/mL solution of (E)-4-bromobut-2-enoyl chloride in DCM (104 μί, 0.598 mmol). The resulting mixture was stirred 4h at -78°C before addition of a 2M solution of dimethylamine in THF (359 μί, 0.717 mmol). The resulting mixture was warmed up to rt and stirred 45min at this temperature before being evaporated to dryness. The residue was purified by reverse phase chromatography (C₁₈, H₂0/ACN +0.1% HC0₂H, 0 to 50% gradient) and afforded the title compound (15.0 mg, 0.026 mmol, 22%) as a white solid after lyophilization. LCMS: Calculated: 587.12; Found (M+H⁺): 587.39. 1H NMR (500 MHz, DMSO) δ 11.84 (s, 1H), 10.54 (s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.64 (s, 1H), 8.47 (s, 1H), 8.25 (dd, J = 8.6, 2.4 Hz, 2H), 7.98 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.25 – 7.07 (m, 3H), 6.81 (dt, J = 15.5, 5.8 Hz, 1H), 6.29 (d, J = 15.4 Hz, 1H), 4.23 – 4.08 (m, 1H), 3.08 (dd, J = 5.7, 1.1 Hz, 2H), 2.46 – 2.37 (m, 1H), 2.18 (s, 6H), 2.04 – 1.95 (m, 2H), 1.87 – 1.70 (m, 3H), 1.63 – 1.46 (m, 4H), 1.39 – 1.26 (m, 1H).

Ref

• [1]. Hu S, et al. Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7. Cancer Res. 2019 May 7.[2]. Shanhu Hu, et al. SY-1365, a potent and selective CDK7 inhibitor, exhibits promising anti-tumor activity in multiple preclinical models of aggressive solid tumors.

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

CN(C)C\C=C\C(=O)Nc1ccc(nc1)C(=O)N[C@]1(C)C[C@@H](CCC1)Nc1ncc(Cl)c(n1)c1c[NH]c2ccccc21

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

ONE TIME TO MAINTAIN THIS BLOG

$10.00

Click here to purchase.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

H-Pro-Gly-Gln-Glu-His-Pro-Asn-Ala-Arg-Lys-Tyr-Lys-Gly-Ala-Asn-Lys-Lys-Gly-Leu-Ser-Lys-Gly-Cys(1)-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys(1)-OH

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
H-PGQEHPNARKYKGANKKGLSKGC(1)FGLKLDRIGSMSGLGC(1)-OH

PEPTIDE1{P.G.Q.E.H.P.N.A.R.K.Y.K.G.A.N.K.K.G.L.S.K.G.C.F.G.L.K.L.D.R.I.G.S.M.S.G.L.G.C}$PEPTIDE1,PEPTIDE1,23:R3-39:R3$$$

L-prolyl-glycyl-L-glutaminyl-L-alpha-glutamyl-L-histidyl-L-prolyl-L-asparagyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysyl-glycyl-L-alanyl-L-asparagyl-L-lysyl-L-lysyl-glycyl-L-leucyl-L-seryl-L-lysyl-glycyl-L-cysteinyl-L-phenylalanyl-glycyl-L-leucyl-L-lysyl-L-leucyl-L-alpha-aspartyl-L-arginyl-L-isoleucyl-glycyl-L-seryl-L-methionyl-L-seryl-glycyl-L-leucyl-glycyl-L-cysteine (23->39)-disulfide

(4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,43S,49S,52R)-52-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-5-oxo-2-[[2-[[(2S)-pyrrolidine-2-carbonyl]amino]acetyl]amino]pentanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]hexanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]acetyl]amino]-40-(4-aminobutyl)-49-benzyl-28-[(2S)-butan-2-yl]-31-(3-carbamimidamidopropyl)-34-(carboxymethyl)-16,22-bis(hydroxymethyl)-10,37,43-tris(2-methylpropyl)-19-(2-methylsulfanylethyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecazacyclotripentacontane-4-carboxylic acid

Vosoritide

1480724-61-5[RN]BMN 111L-Cysteine, L-prolylglycyl-L-glutaminyl-L-α-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-, cyclic (23→39)-disulfideL-prolylglycyl-(human C-type natriuretic peptide-(17-53)-peptide (CNP-37)), cyclic-(23-39)-disulfideUNII:7SE5582Q2Pвосоритид [Russian] [INN]فوسوريتيد [Arabic] [INN]伏索利肽 [Chinese] [INN]

Voxzogo, 2021/8/26 EU APPROVED

Product details
Name	Voxzogo
Agency product number	EMEA/H/C/005475
Active substance	Vosoritide
International non-proprietary name (INN) or common name	vosoritide
Therapeutic area (MeSH)	Achondroplasia
Anatomical therapeutic chemical (ATC) code	M05BX
OrphanImage may be NSFW. Clik here to view.	This medicine was designated an orphan medicine. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. For more information, see Orphan designation.

On 24 January 2013, orphan designation (EU/3/12/1094) was granted by the European Commission to BioMarin Europe Ltd, United Kingdom, for modified recombinant human C-type natriuretic peptide for the treatment of achondroplasia.

The sponsorship was transferred to BioMarin International Limited, Ireland, in February 2019.

This medicine is now known as Vosoritide.

The medicinal product has been authorised in the EU as Voxzogo since 26 August 2021.

PEPTIDE

Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia.^[1]

The most common side effects include injection site reactions (such as swelling, redness, itching or pain), vomiting and decreased blood pressure.^[1]

Vosoritide was approved for medical use in the European Union in August 2021.^[1][2]

Voxzogo is a medicine for treating achondroplasia in patients aged 2 years and older whose bones are still growing.

Achondroplasia is an inherited disease caused by a mutation (change) in a gene called fibroblast growth-factor receptor 3 (FGFR3). The mutation affects growth of almost all bones in the body including the skull, spine, arms and legs resulting in very short stature with a characteristic appearance.

Achondroplasia is rare, and Voxzogo was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 24 January 2013. Further information on the orphan designation can be found here: ema.europa.eu/medicines/human/orphan-designations/EU3121094.

Voxzogo contains the active substance vosoritide.

Image may be NSFW.
Clik here to view.

Medical uses

Vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed.^[1]

Mechanism of action

Image may be NSFW.
Clik here to view.

A: Chondrocyte with constitutionally active FGFR3 that down-regulates its development via the MAPK/ERK pathway
B: Vosoritide (BMN 111) blocks this mechanism by binding to the atrial natriuretic peptide receptor B (NPR-B), which subsequently inhibits the MAPK/ERK pathway at the RAF-1 protein.^[3]

Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3).^[1] FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor. It does so by inhibiting the development (cell proliferation and differentiation) of chondrocytes, the cells that produce and maintain the cartilaginous matrix which is also necessary for bone growth. Children with achondroplasia have one of several possible FGFR3 mutations resulting in constitutive (permanent) activity of this receptor, resulting in overall reduced chondrocyte activity and thus bone growth.^[3]

The protein C-type natriuretic peptide (CNP), naturally found in humans, reduces the effects of over-active FGFR3. Vosoritide is a CNP analogue with the same effect but prolonged half-life,^[3] allowing for once-daily administration.^[4]

Chemistry

Vosoritide is an analogue of CNP. It is a peptide consisting of the amino acids proline and glycine plus the 37 C-terminal amino acids from natural human CNP. The complete peptide sequence isPGQEHPNARKYKGANKKGLS KGCFGLKLDR IGSMSGLGC

with a disulfide bridge between positions 23 and 39 (underlined).^[5] The drug must be administered by injection as it would be rendered ineffective by the digestive system if taken by mouth.

History

Vosoritide is being developed by BioMarin Pharmaceutical and, being the only available causal treatment for this condition, has orphan drug status in the US as well as the European Union.^[1][2][6] As of September 2015, it is in Phase II clinical trials.^[7][4]

Society and culture

Controversy

Some people with achondroplasia, as well as parents of children with this condition, have reacted to vosoritide’s study results by saying that dwarfism is not a disease and consequently does not need treatment.^[8]

Research

Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew 6.1 centimetres (2.4 in) in six months, compared to 4.0 centimetres (1.6 in) in the six months before the treatment (p=0.01).^[9] The body proportions, more specifically the ratio of leg length to upper body length – which is lower in achondroplasia patients than in the average population – was not improved by vosoritide, but not worsened either.^[7][10]

As of September 2015, it is not known whether the effect of the drug will last long enough to result in normal body heights,^[10] or whether it will reduce the occurrence of achondroplasia associated problems such as ear infections, sleep apnea or hydrocephalus. This, together with the safety of higher doses, is to be determined in further studies.^[4]

References

1. ^ Jump up to:^{a b c d e f g} “Voxzogo EPAR”. European Medicines Agency. 23 June 2021. Retrieved 9 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
2. ^ Jump up to:^a b “European Commission Approves BioMarin’s Voxzogo (vosoritide) for the Treatment of Children with Achondroplasia from Age 2 Until Growth Plates Close”. BioMarin Pharmaceutical Inc. (Press release). 27 August 2021. Retrieved 9 September 2021.
3. ^ Jump up to:^a b c Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al. (December 2012). “Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia”. American Journal of Human Genetics. 91 (6): 1108–14. doi:10.1016/j.ajhg.2012.10.014. PMC 3516592. PMID 23200862.
4. ^ Jump up to:^a b c Clinical trial number NCT02055157 for “A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)” at ClinicalTrials.gov
5. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN): List 112” (PDF). WHO Drug Information. 28 (4): 539. 2014.
6. ^ “Food and Drug Administration Accepts BioMarin’s New Drug Application for Vosoritide to Treat Children with Achondroplasia” (Press release). BioMarin Pharmaceutical. 2 November 2020. Retrieved 9 September 2021 – via PR Newswire.
7. ^ Jump up to:^a b Spreitzer H (6 July 2015). “Neue Wirkstoffe – Vosoritid”. Österreichische Apothekerzeitung (in German) (14/2015): 28.
8. ^ Pollack A (17 June 2015). “Drug Accelerated Growth in Children With Dwarfism, Pharmaceutical Firm Says”. The New York Times.
9. ^ “BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study”. BioMarin. 17 June 2015.
10. ^ Jump up to:^a b “Vosoritid” (in German). Arznei-News.de. 20 June 2015.

External links

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

/////////Vosoritide, Voxzogo, PEPTIDE, ボソリチド (遺伝子組換え) , восоритид , فوسوريتيد , 伏索利肽 , APPROVALS 2021, EU 2021, BMN 111, ORPHAN DRUG

CCC(C)C1C(=O)NCC(=O)NC(C(=O)NC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)NCC(=O)NC(CSSCC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCNC(=N)N)CC(=O)O)CC(C)C)CCCCN)CC(C)C)CC2=CC=CC=C2)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)C(CC(=O)N)NC(=O)C(C)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CC3=CC=C(C=C3)O)NC(=O)C(CCCCN)NC(=O)C(CCCNC(=N)N)NC(=O)C(C)NC(=O)C(CC(=O)N)NC(=O)C4CCCN4C(=O)C(CC5=CN=CN5)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)N)NC(=O)CNC(=O)C6CCCN6)C(=O)O)CC(C)C)CO)CCSC)CO

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

ONE TIME TO MAINTAIN THIS BLOG

$10.00

Click here to purchase.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Verdiperstat

AZD 3241; BHV-3241

CAS No. : 890655-80-8

1-(2-propan-2-yloxyethyl)-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one

4H-​Pyrrolo[3,​2-​d]​pyrimidin-​4-​one, 1,​2,​3,​5-​tetrahydro-​1-​[2-​(1-​methylethoxy)​ethyl]​-​2-​thioxo-

1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d] pyrimidin-4-one

l-(2-Isopropoxyethyl)-2-thioxo-l,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one

• Molecular FormulaC₁₁H₁₅N₃O₂S
• Average mass253.321 Da

AZD-3241, BHV-3421, UNII-TT3345YXVR, TT3345YXVR, BHV-3241, WHO 10251вердиперстат [Russian] [INN]فيرديبيرستات [Arabic] [INN]维地泊司他 [Chinese] [INN]

• OriginatorAstraZeneca
• DeveloperAstraZeneca; Biohaven Pharmaceuticals
• ClassAntiparkinsonians; Ethers; Organic sulfur compounds; Pyrimidinones; Small molecules
• Mechanism of ActionPeroxidase inhibitors

• Orphan Drug StatusYes – Multiple system atrophy
• Phase IIIMultiple system atrophy

• Phase II/IIIAmyotrophic lateral sclerosis
• DiscontinuedParkinson’s disease

• 23 Jun 20213574186: Added patent info and HE
• 23 Jun 2021Biohaven Pharmaceuticals has patents pending for the composition of matter of verdiperstat, pharmaceutical compositions and various neurological diseases in Europe, Japan and other countries
• 01 Nov 2020Brigham and Women’s Hospital plans a phase I trial for Multiple System Atrophy in USA , (NCT04616456)

EU/3/14/1404: Orphan designation for the treatment of multiple system atrophy

This medicine is now known as verdiperstat.

On 16 December 2014, orphan designation (EU/3/14/1404) was granted by the European Commission to Astra Zeneca AB, Sweden, for 1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d] pyrimidin-4-one for the treatment of multiple system atrophy.

The sponsorship was transferred to Richardson Associates Regulatory Affairs Limited, Ireland, in March 2019.

The sponsorship was transferred to Biohaven Pharmaceutical Ireland DAC, Ireland, in September 2021.

Key facts

VERDIPERSTAT

For Initial Indications in Multiple System Atrophy (MSA) and Amyotrophic Lateral Sclerosis (ALS)

Verdiperstat is a first-in-class, potent, selective, brain-penetrant, irreversible myeloperoxidase (MPO) enzyme inhibitor. Verdiperstat was progressed through Phase 2 clinical trials by AstraZeneca. Seven clinical studies were completed by AstraZeneca, including four Phase 1 studies in healthy subjects, two Phase 2a studies in subjects with Parkinson’s Disease, and one Phase 2b study in subjects with MSA. These Phase 2 clinical studies provide evidence that verdiperstat achieves peripheral target engagement (i.e., reduces MPO specific activity in plasma) and central target engagement in the brain and offer proof of its mechanism of action (i.e., reduce microglial activation and neuroinflamation).

A Phase 3 clinical trial to evaluate the efficacy of verdiperstat in MSA is currently ongoing. A Phase 2/3 trial to evaluate the efficacy of verdiperstat in ALS is currently ongoing as part of the HEALEY ALS Platform Trial.

Verdiperstat has received Fast Track and Orphan Drug designations by the U.S. Food and Drug Administration (FDA) and the European Medicine Agency due to the unmet medical needs in MSA.

Verdiperstat Overview

DESCRIPTIONClick to expendFirst-in-class, brain-penetrant, irreversible inhibitor of MPO

CLINICAL STATUSClick to expendOver 250 healthy volunteers and patients have been treated with verdiperstat in Phase 1 and Phase 2 studies. A Phase 3 study in MSA is currently underway and a Phase 2/3 study in ALS is currently enrolling.
Verdiperstat (AZD3241) is a selective, irreversible and orally active myeloperoxidase (MPO) inhibitor, with an IC₅₀ of 630 nM, and can be used in the research of neurodegenerative brain disorders.

Image may be NSFW.
Clik here to view.

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

Image may be NSFW.
Clik here to view.

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• FACEBOOK

join me on twitter a

Anthony Melvin Crasto Dr. | twitter

• Twitter

+919321316780 call whatsaapp

Image may be NSFW.
Clik here to view.

PATENTWO 2006062465https://patents.google.com/patent/WO2006062465A1/enExample 9 l-(2-Isopropoxyethyl)-2-thioxo-l,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one (a) 3-[(2-Isopropoxyethyl)ωnino]-lH-pyrwle-2-carboxylic acid ethyl ester Trichlorocyanuric acid (1.84 g, 7.93 mmol) was added to a solution of 2- isopropoxyethanol (0.75 g, 7.21 mmol) in CH₂Cl₂ (3 mL). The reaction mixture was cooled to 0 °C and TEMPO (0.022 g, 0.14 mmol) was carefully added in small portions. The mixture was stirred at r.t. for 20 minutes then filtered through Celite and washed with CH₂Cl₂. The filtrate was kept cold, 0 °C, during filtration. The aldehyde solution was added to a stirred mixture of 3-amino-lH-pyrrole-2-carboxylic acid ester (0.83 g, 5.41 mmol) and HOAc (0.62 mL, 10.8 mmol) at 0 °C in methanol (5 mL). The mixture was stirred for 20 minutes, then NaCNBH₃ (0.34 g, 5.41 mmol) was added. After stirring at r.t for 2 h, the solution was evaporated onto silica and purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate) to yield the title compound (0.75 g, 58%) as an oil. ¹H NMR (DMSO-d₆) δ ppm 10.72 (IH, br s), 6.76-6.74 (IH, m), 5.66-5.65 (IH, m), 5.34(1H, br s), 4.17 (2H, q, J=7.0 Hz), 3.59-3.49 (3H, m), 3.15 (2H, q, J=5.6 Hz), 1.26 (3H, t, J=7.0 Hz), 1.10 (3H, s), 1.08 (3H, s); MS (ESI) m/z 241 (M +1).(b) l-(2-Isopropoxyethyl)-2-thioxo-l,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one The title compound (0.17 g, 23%) was prepared in accordance with the general method B using 3-[(2-isopropoxyethyl)amino]-lH-pyrrole-2-carboxylic acid ethyl ester (0.7 g, 2.91 mmol) and ethoxycarbonyl isothiocyanate (0.40 mL, 3.50 mmol).¹H NMR (DMSO-d₆) δ ppm 12.74 (2H, br s), 7.35 (IH, d, J=2.8 Hz), 6.29 (IH, d, J=3.0Hz), 4.49 (2H, t, J=6.3 Hz), 3.72 (2H, t, J=6.3 Hz), 3.60-3.58 (IH, m), 1.02 (3H, s), 1.01 (3H, s);MS (ESI) m/z 254 (M +1).

/////////verdiperstat, вердиперстат , فيرديبيرستات , 维地泊司他 , WHO 10251, AZD-3241, BHV-3421, UNII-TT3345YXVR, TT3345YXVR, BHV-3241, AZD 3241, BHV 3241, BHV 3421

CC(C)OCCN1C2=C(C(=O)NC1=S)NC=C2

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

ONE TIME TO MAINTAIN THIS BLOG

$10.00

Click here to purchase.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Mobocertinib

1847461-43-1

MF C32H39N7O4
MW 585.70

propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate

TAK-788, AP32788, TAK788, UNII-39HBQ4A67L, AP-32788, 39HBQ4A67L

US10227342, Example 10, MFCD32669806, NSC825519, s6813, TAK-788;AP32788, WHO 11183

NSC-825519, example 94 [WO2015195228A1], GTPL10468, BDBM368374, BCP31045, EX-A3392

US FDA APPROVED 9/15/2021, Exkivity, To treat locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutation

Image may be NSFW.
Clik here to view.

Mobocertinib succinate Chemical Structure

CAS No. : 2389149-74-8

Image may be NSFW.
Clik here to view.

Mobocertinib mesylateCAS# 2389149-85-1 (mesylate)C33H43N7O7S
Molecular Weight: 681.809

CAS #: 2389149-85-1 (mesylate)   1847461-43-1 (free base)   2389149-74-8 (succinate)   2389149-76-0 (HBr)   2389149-79-3 (HCl)   2389149-81-7 (sulfate)   2389149-83-9 (tosylate)   2389149-87-3 (oxalate)   2389149-89-5 (fumarate)

JAPANESE ACCEPTED NAME

Mobocertinib Succinate

Image may be NSFW.
Clik here to view.

Propan-2-yl 2-[4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-(prop-2-enamido)anilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate monosuccinate

C₃₂H₃₉N₇O₄Image may be NSFW.
Clik here to view.C₄H₆O₄ : 703.78
[2389149-74-8]

FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations……. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mobocertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20

On September 15, 2021, the Food and Drug Administration granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals, Inc.) for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Today, the FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to select patients with the above mutations for mobocertinib treatment.

Approval was based on Study 101, an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 114 patients whose disease had progressed on or after platinum-based chemotherapy. Patients received mobocertinib 160 mg orally daily until disease progression or intolerable toxicity.

The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review (BICR) and response duration. The ORR was 28% (95% CI: 20%, 37%) with a median response duration of 17.5 months (95% CI: 7.4, 20.3).

The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

The recommended mobocertinib dose is 160 mg orally once daily until disease progression or unacceptable toxicity.

View full prescribing information for mobocertinib.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), and United Kingdom’s Medicines & Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 6 weeks ahead of the FDA goal date.

This application was granted priority review, breakthrough therapy designation and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.Takeda’s EXKIVITYImage may be NSFW.
Clik here to view. (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC…….. https://www.takeda.com/newsroom/newsreleases/2021/takeda-exkivity-mobocertinib-approved-by-us-fda/September 15, 2021

• Approval based on Phase 1/2 trial results, which demonstrated clinically meaningful responses with a median duration of response (DoR) of approximately 1.5 years
• Next-generation sequencing (NGS) companion diagnostic test approved simultaneously to support identification of patients with EGFR Exon20 insertion mutations

OSAKA, Japan, and CAMBRIDGE, Mass. September 15, 2021 – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that the U.S. Food and Drug Administration (FDA) has approved EXKIVITY (mobocertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. EXKIVITY, which was granted priority review and received Breakthrough Therapy Designation, Fast Track Designation and Orphan Drug Designation from the FDA, is the first and only approved oral therapy specifically designed to target EGFR Exon20 insertion mutations. This indication is approved under Accelerated Approval based on overall response rate (ORR) and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“The approval of EXKIVITY introduces a new and effective treatment option for patients with EGFR Exon20 insertion+ NSCLC, fulfilling an urgent need for this difficult-to-treat cancer,” said Teresa Bitetti, president, Global Oncology Business Unit, Takeda. “EXKIVITY is the first and only oral therapy specifically designed to target EGFR Exon20 insertions, and we are particularly encouraged by the duration of the responses observed with a median of approximately 1.5 years. This approval milestone reinforces our commitment to meeting the needs of underserved patient populations within the oncology community.”

The FDA simultaneously approved Thermo Fisher Scientific’s Oncomine Dx Target Test as an NGS companion diagnostic for EXKIVITY to identify NSCLC patients with EGFR Exon20 insertions. NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon20 insertions.

“EGFR Exon20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute. “The approval of EXKIVITY (mobocertinib) marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed, but also lacking targeted treatment options that can improve response rates,” said Marcia Horn, executive director, Exon 20 Group at ICAN, International Cancer Advocacy Network. “As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals and scientists across the globe who contributed to the approval of this promising targeted therapy.”

The FDA approval is based on results from the platinum-pretreated population in the Phase 1/2 trial of EXKIVITY, which consisted of 114 patients with EGFR Exon20 insertion+ NSCLC who received prior platinum-based therapy and were treated at the 160 mg dose. Results were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting from the Phase 1/2 trial and demonstrated a confirmed ORR of 28% per independent review committee (IRC) (35% per investigator) as well as a median DoR of 17.5 months per IRC, a median overall survival (OS) of 24 months and a median progression-free survival (PFS) of 7.3 months per IRC.

The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The EXKIVITY Prescribing Information includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

The FDA review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE), which provides a framework for concurrent submission and review of oncology products among international partners. We look forward to continuing our work with regulatory agencies across the globe to bring mobocertinib to patients.

About EXKIVITY (mobocertinib)

EXKIVITY is a first-in-class, oral tyrosine kinase inhibitor (TKI) specifically designed to selectively target epidermal growth factor receptor (EGFR) Exon20 insertion mutations.

EXKIVITY is approved in the U.S. for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Results from the Phase 1/2 trial of mobocertinib have also been accepted for review by the Center for Drug Evaluation (CDE) in China for locally advanced or metastatic NSCLC patients with EGFR Exon20 insertion mutations who have been previously treated with at least one prior systemic chemotherapy.

For more information about EXKIVITY, visit http://www.EXKIVITY.com. For the Prescribing Information, including the Boxed Warning, please visit https://takeda.info/Exkivity-Prescribing-Information.

About EGFR Exon20 Insertion+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 2.2 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.^1,2 Patients with epidermal growth factor receptor (EGFR) Exon20 insertion+ NSCLC make up approximately 1-2% of patients with NSCLC, and the disease is more common in Asian populations compared to Western populations.^3-7 This disease carries a worse prognosis than other EGFR mutations, as EGFR TKIs – which do not specifically target EGFR Exon20 insertions – and chemotherapy provide limited benefit for these patients.

Takeda is committed to continuing research and development to meet the needs of the lung cancer community through the discovery and delivery of transformative medicines.

EXKIVITY IMPORTANT SAFETY INFORMATION

QTc Interval Prolongation and Torsades de Pointes: EXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation.  Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc.  Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation.

Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold EXKIVITY in patients with suspected ILD/pneumonitis and permanently discontinue EXKIVITY if ILD/pneumonitis is confirmed.

Cardiac Toxicity: Monitor cardiac function, including left ventricular ejection fraction, at baseline and during treatment. Withhold, resume at reduced dose or permanently discontinue based on severity.

Diarrhea: Diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Monitor electrolytes and advise patients to start an antidiarrheal agent at first episode of diarrhea and to increase fluid and electrolyte intake. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception.

Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.^[2][3]

The most common side effects include diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.^[2]

Mobocertinib is a small molecule tyrosine kinase inhibitor. Its molecular target is epidermal growth factor receptor (EGFR) bearing mutations in the exon 20 region.^[4][5]

Mobocertinib was approved for medical use in the United States in September 2021.^[2][3] It is a first-in-class oral treatment to target EGFR Exon20 insertion mutations.^[3]

Medical uses

Mobocertinib is indicated for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.^[2]

PATENT

WO 2019222093

https://patents.google.com/patent/WO2019222093A1

Image may be NSFW.
Clik here to view.

Scheme I

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Example 1 Procedure for the preparation of isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate (Compound (A)).

Image may be NSFW.
Clik here to view.

[00351] Step 1 : Preparation of isopropyl 2-chloro-4-(l -methyl- lH-indo 1-3 -yl)pyrimidine-5- carboxylate.

Image may be NSFW.
Clik here to view.

[00352] To a 2 L Radley reactor equipped with a mechanical stirrer, a thermometer, and a refluxing condenser was charged isopropyl 2,4-dichloropyrimidine-5-carboxylate (100 g, 42.5 mmol, 1.00 eq.) andl,2-dimethoxyethane (DME, 1.2 L, 12 vol) at RT. The mixture was cooled to 3 °C, and granular AlCb (65.5 g, 49.1 mmol, 1.15 eq.) was added in 2 portions (IT 3-12 ^°C, jacket set 0 °C). The white slurry was stirred 15-25 °C for 60 minutes. 1 -Methylindole (59 g, 44.9 mmol, 1.06 eq.) was added in one portion (IT 20-21°C). DME (100 mL) was used to aid 1- Methylindole transfer. The reaction mixture was aged for at 35 °C for 24 h. Samples (1 mL) were removed at 5 h and 24 h for HPLC analysis (TM1195).[00353] At 5 h the reaction had 70 % conversion, while after 24 h the desired conversion was attained (< 98%).[00354] The reaction mixture was cooled to 0 °C to 5 °C and stirred for 1 h. The solids were collected via filtration and washed with DME (100 mL). The solids (AlCb complex) were charged back to reactor followed by 2-MeTHF (1 L, 10 vol), and water (400 mL, 4 vol). The mixture was stirred for 10 minutes. The stirring was stopped to allow the layers to separate.The organic phase was washed with water (200 mL, 2 vol). The combined aqueous phase was re-extracted with 2-MeTHF (100 mL, 1 vol).[00355] During workup a small amount of product title compound started to crystallize.Temperature during workup should be at about 25-40 °C.[00356] The combined organic phase was concentrated under mild vacuum to 300-350 mL (IT 40-61 °C). Heptane (550 mL) was charged while maintaining the internal temperature between 50 °C and 60 °C. The resulting slurry was cooled at 25 °C over 15 minutes, aged for 1 h (19-25 °C) and the resulting solids isolated by filtration.[00357] The product was dried at 50 °C under vacuum for 3 days to yield 108.1 g (77 % yield) of the title compound, in 100% purity (AUC) as a yellow solid.‘H NMR (400 MHz, DMSO-i/e) d ppm 1.24 (d, J= 6.53 Hz, 6 H) 3.92 (s, 3 H) 5.19 (spt, J=6.27 Hz, 1 H) 7.25 – 7.35 (m, 2 H) 7.59 (d, J=8.03 Hz, 1 H) 8.07 (s, 1 H) 8.16 (d, J= 7.53 Hz, 1 H) 8.82 (s, 1 H).[00358] Step 2: Preparation of isopropyl 2-((4-fhioro-2-methoxy-5-nitrophenyl)amino)-4-(l- methyl-lH-indol-3-yl)pyrimidine-5-carboxylate.

Image may be NSFW.
Clik here to view.

[00359] A mixture of the product of step 1 (85.0 g, 258 mmol, 1.0 eq.), 4-fluoro-2-methoxy- 5nitroaniline (57.0 g, 306 mmol, 1.2 eq.) and PTSA monohydrate (13.3 g, 70.0 mmol, 0.27 eq.) in acetonitrile (1.4 L, 16.5 v) was heated to 76-81 °C under nitrogen in a 2 L Radley reactor. IPC at 19 h indicated that the reaction was complete.[00360] The reaction mixture was cooled to 25 °C and water (80 mL) was charged in one portion (IT during charge dropped from 25 °C to 19 °C). The reaction mixture was aged for 1 h at 21 °C and then the resulting solids were isolated by filtration. The product was washed with EtOAc (2 x 150 mL) and dried in high vacuum at 50 °C to 60 °C for 44 h to give 121.5 g of the title compound (98% yield), HPLC purity 100 % a/a; NMR indicated that PTSA was purged.¾ NMR (400 MHz, DMSO-7,) d ppm 1.21 (d, 7=6.02 Hz, 6 H) 3.91 (s, 3 H) 4.02 (s, 3 H) 5.09 (spt, 7=6.27 Hz, 1 H) 7.10 (t, 7=7.53 Hz, 1 H) 7.26 (t, 7=7.58 Hz, 1 H) 7.42 (d, 7=13.05 Hz, 1 H) 7.55 (d, 7=8.53 Hz, 1 H) 7.90 (br d, 7=7.53 Hz, 1 H) 7.98 (s, 1 H) 8.75 (s, 1 H) 8.88 (d, 7=8.03 Hz, 1 H) 9.03 (s, 1 H).[00361] Step 3: Preparation of isopropyl 2-((4-((2-(dimethylamino)ethyl(methyl)amino)-2- methoxy-5-nitrophenyl)amino)-4-(l-methyl-lH-indol-3-yl)pyrimidine-5-carboxylate.

Image may be NSFW.
Clik here to view.

[00362] A 50 L flask was charged 1.500 kg of the product of step 2 (3.1 moles, l.O equiv.), 639.0 g A,A,A-trimethylethylenediamine (6.3 mol, 2 equiv.), and 21 L MeCN. The resulting slurry was mixed for 7 hours at reflux. The reaction was cooled overnight. Water (16.5 L) was added before the solids were isolated. After isolation of the solids, a wash of 2.25 L MeCN in 2.25 L water was conducted to provide the title compound. The solids were dried, under vacuum, at 75 °C. HPLC purity a/a % of the dry solid was 99.3%.¾ NMR (400 MHz, DMSO-7,) d ppm 1.22 (d, 7=6.02 Hz, 6 H) 2.09 – 2.13 (m, 1 H) 2.19 (s, 6 H) 2.49 – 2.52 (m, 1 H) 2.89 (s, 3 H) 3.29 – 3.35 (m, 2 H) 3.89 (s, 3 H) 3.94 (s, 3 H) 5.10 (spt, 7=6.19 Hz, 1 H) 6.86 (s, 1 H) 7.07 (br t, 7=7.53 Hz, 1 H) 7.24 (t, 7=7.28 Hz, 1 H) 7.53 (d, 7=8.53Hz, 1 H) 7.86 – 8.02 (m, 2 H) 8.36 (s, 1 H) 8.69 (s, 1 H) 8.85 (s, 1 H).[00363] Step 4: Preparation of isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)- amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indo 1-3 -yl)pyrimidine-5-carboxy late.

Image may be NSFW.
Clik here to view.

[00364] To a mixture of the product of step 3 (1.501 kg, 2.67 mol, 1.00 eq.) and 10% Pd/C (64 % wet, 125.0 g, 0.01 1 eq.) was added 2-MeTHF (17.7 L) in a 20 L pressure reactor. The mixture was hydrogenated at 6- 10 psi ¾ and at 40 °C until IPC indicated complete conversion (1 1 h, the reaction product 99.0%). The reaction mixture was filtered (Celite), and the pad rinsed with MeTHF (2.5 L total). The filtrate was stored under N2 in a refrigerator until crystallization.[00365] Approximately 74% of 2-MeTHF was evaporated under reduced pressure while maintaining IT 23-34 °C (residual volume in the reactor was approximately 4.8 L). To the mixture was added n-heptane (6 L) over 15 min via dropping funnel. The resulting slurry was aged at room temperature overnight. The next day the solids on the walls were scraped to incorporate them into the slurry and the solids were isolated by filtration. The isolated solids were washed with n-heptane containing 5% MeTFlF (2 x 750 mL), and dried (75 °C, 30 inch Flg) to yield 1287 g (91 % yield) of the title compound as a yellow solid. F1PLC purity: 99.7% pure.[00366] ¾ NMR (400 MHz, DMSO- ) d ppm 1.20 (d, .7=6.02 Hz, 6 H) 2.21 (s, 6 H) 2.37 -2.44 (m, 2 H) 2.68 (s, 3 H) 2.93 (t, .7=6.78 Hz, 2 H) 3.74 (s, 3 H) 3.90 (s, 3 H) 4.60 (s, 2 H) 5.08 (spt, 7=6.19 Hz, 1 H) 6.80 (s, 1 H) 7.08 – 7.15 (m, 1 H) 7.19 – 7.26 (m, 2 H) 7.52 (d, .7=8.03 Hz, 1 H) 7.94 – 8.01 (m, 2 H) 8.56 (s, 1 H) 8.66 (s, 1 H).[00367] Step 5: Preparation of isopropyl 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxy-5 -(3 -(phenylsulfonyl)propanamido)phenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate.

Image may be NSFW.
Clik here to view.

lnt-5[00368] A mixture of the product of step 4 (1.284 kg, 2.415 mol, 1.0 eq.) and 3- (phenylsulfonyl)propionic acid (0.5528 kg, 2.580 mol, 1.07 eq.) in anhydrous DCM (8.5 L) was cooled to 2 °C, and treated with DIEA (0.310 kg, 2.399 mol, 1.0 eq.). To the reaction mixture was charged over 40 min, 50 % w/w T3P in MeTHF (1.756 kg, 2.759 mol, 1.14 eq.) while maintaining the internal temperature between 0 °C and 8 °C. The mixture was stirred at 0 °C to 5 °C for 15 minutes and then warmed over 30 min to 15 °C then held at 15 °C to 30 °C for 60 min.[00369] The reaction was quenched with water (179 mL). The reaction mixture was stirred at ambient temperature for 30 min then DIEA (439 g) was charged in one portion. The resulting mixture was aged for 15 min, and then treated with 5% aqueous K₂CO₃ (7.3 L) at 22-25 °C. The organic layer was separated and the aqueous layer back extracted with DCM (6.142 L). The combined organic extract was washed with brine (2 x 5.5 L).[00370] The organic extract was concentrated to 6.5 L, diluted with EtOFl, 200 Proof (14.3 kg), and the mixture concentrated under vacuum (23-25 inch Flg/IT40-60 °C) to a residual volume of 12.8 L.[00371] The residual slurry was treated with EtOFl, 200 Proof (28.8 Kg), and heated to 69 °C to obtain a thin slurry. The reaction mixture was cooled to 15 °C over 2 h, and stored overnight at 15 °C under nitrogen.[00372] The next day, the mixture was cooled to 5 ^°C, and aged for 30 minutes. The resulting solid was isolated by filtration, washed with EtOFl (2 x 2.16 kg) and dried to give 1.769 kg (100% yield) of the title compound. F1PLC purity 99.85%.‘H NMR (400 MHz, DMSO-i¾ d ppm 1.08 – 1.19 (m, 8 H) 2.15 (s, 6 H) 2.32 (t, J= 5.77 Hz, 2 H) 2.66 – 2.76 (m, 5 H) 2.88 (br t, J= 5.52 Hz, 2 H) 3.48 (qd, J= 7.03, 5.02 Hz, 1 H) 3.60 – 3.69 (m, 2 H) 3.83 (s, 3 H) 3.89 (s, 3 H) 4.40 (t, J=5.02 Hz, 1 H) 5.04 (quin, J=6.27 Hz, 1 H) 7.01 – 7.09 (m, 2 H) 7.22 (t, J= 7.53 Hz, 1 H) 7.52 (d, J= 8.53 Hz, 1 H) 7.67 – 7.82 (m, 4 H) 7.97 (s, 1 H) 7.98 – 8.00 (m, 1 H) 8.14 (s, 1 H) 8.61 – 8.70 (m, 3 H) 10.09 (s, 1 H).[00373] Step 6: Preparation of isopropyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3-yl)pyrimidine-5-carboxylate (Compound (A)).

Image may be NSFW.
Clik here to view.

compound (A)[00374] The product of step 5 (1.600 kg, 2.198 mol, 1.0 equiv.) was dissolved in anhydrous THF (19.5 kg) and was treated at -1 °C to 1 °C with 2M KOSi(CH3)3 in THF (2.72 L, 5.44 mol, 2.47 equiv.). KOSi(CFb)3 was added over 5 minutes, reactor jacket set at -5 °C to 10 °C. 2 M KOSi(CFh)3 solution was prepared by dissolving 871 g of KOSi(CFh)3 technical grade (90%) in 3.056 L of anhydrous TF1F.[00375] The reaction mixture was aged for 60 minutes. Potable water (22 L) was charged to the reaction mixture over 1 10 minutes, while maintaining temperature at 2-7 °C. The resulting suspension was aged at 3-7 °C for 60 minutes; the product was isolated by filtration (the filtration rate during crude product isolation was (1.25 L/min), washed with potable water (2 x 1.6 L) and air dried overnight and then in high vacuum for 12 h at 45 °C to give 1.186 kg of crude title compound (92% yield).‘H NMR (500 MHz, DMSO-i¾ d ppm 1.05 (t, J= 7.09 Hz, 2 H) 1.1 1 (d, J= 6.36 Hz, 6 H) 2.1 1 (s, 6 H) 2.28 (br t, .7=5.38 Hz, 3 H) 2.55 – 2.67 (m, 3 H) 2.69 (s, 3 H) 2.83 (br t, .7=5.38 Hz, 3 H) 3.31 (s, 3 H) 3.36 – 3.51 (m, 2 H) 3.54 – 3.70 (m, 3 H) 3.75 – 3.82 (m, 3 H) 4.33 (t, .7=5.14 Hz, 1 H) 4.99 (dt, 7=12.35, 6.30 Hz, 2 H) 5.75 (s, 1 H) 6.95 – 7.07 (m, 2 H) 7.17 (br t, .7=7.58 Hz, 2 H) 7.48 (d, 7=8.31 Hz, 2 H) 7.62 – 7.71 (m, 3 H) 7.71 – 7.83 (m, 2 H) 7.93 (d, .7=7.83 Hz, 3 H) 8.09 (s, 2 H) 8.53 – 8.67 (m, 3 H) 10.03 (s, 2 H).[00376] Step 7: Preparation of polymorphic Form-I of isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate (Free base Compound (A)).[00377] Method 1 : The crude product of step 6 (1.130 kg) was recrystallized by dissolving it in EtOAc (30.1 kg) at 75 °C, polish filtered (1.2 pm in-line filter), followed by concentration of the filtrate to 14 L of residue (IT during concentration is 58-70 °C). The residual slurry was cooled to 0 ^°C over 70 minutes and then aged at 0-2 °C for 30 minutes. Upon isolation the product was dried to a constant weight to give 1.007 kg (89% recovery) of the title compound as polymorphic Form-I. Purity (HPLC, a/a %, 99.80%).

PATENT

WO 2015195228

https://patents.google.com/patent/WO2015195228A1/en

PATENT

US10227342, Example 10

https://patents.google.com/patent/US10227342

References

1. ^ Jump up to:^a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf
2. ^ Jump up to:^{a b c d e} “FDA grants accelerated approval to mobocertinib for metastatic non-sma”. U.S. Food and Drug Administration (FDA). 16 September 2021. Retrieved 16 September 2021. Image may be NSFW.
   Clik here to view. This article incorporates text from this source, which is in the public domain.
3. ^ Jump up to:^a b c “Takeda’s Exkivity (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC” (Press release). Takeda Pharmaceutical Company. 15 September 2021. Retrieved 16 September 2021 – via Business Wire.
4. ^ “TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy for Non-Small Cell Lung Cancer (NSCLC) With EGFR Exon 20 Insertion Mutations”. Clinicaltrials.gov. Retrieved 17 February 2021.
5. ^ Zhang SS, Zhu VW (2021). “Spotlight on Mobocertinib (TAK-788) in NSCLC with EGFR Exon 20 Insertion Mutations”. Lung Cancer. Auckland, N.Z. 12: 61–65. doi:10.2147/LCTT.S307321. PMC 8286072. PMID 34285620.

External links

• “Mobocertinib”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT02716116 for “A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer” at ClinicalTrials.gov

////////////mobocertinib, Exkivity, TAK 788, AP32788, fda 2021, approvals 2021, cancer

CC(C)OC(=O)C1=CN=C(N=C1C2=CN(C3=CC=CC=C32)C)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

one time to maintain this blog

$10.00

Click here to purchase.

Image may be NSFW.
Clik here to view.

VX 759
CAS#: 478025-29-5
Chemical Formula: C22H27NO3S
Molecular Weight: 385.522

478025-29-5

Drug Name：VCH-759Research Code：VX-759; BCH-27759; VCH-759

VX-759; BCH-27759; VCH-759; VX759; BCH27759; VCH759; VX 759; BCH 27759; VCH 759; NNI-1

3-(N-isopropyl-4-methylcyclohexane-1-carboxamido)-5-phenylthiophene-2-carboxylic acid

• 3-[[(trans-4-Methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-phenyl-2-thiophenecarboxylic acid
• 3-[Isopropyl(trans-4-methylcyclohexylcarbonyl)amino]-5-phenylthiophene-2-carboxylic acid
• NNI 1

MOA：NS5B inhibitorIndication：HCV infectionStatus：Phase Ⅱ (Discontinued)Company：Vertex (Originator)

Image may be NSFW.
Clik here to view.

VCH-759 had been in phase II clinical trials by ViroChem Pharma (acquired by Vertex in 2009) for the treatment of HCV infection. However, this research has been discontinued.

Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology 26 (suppl 1 ): 71 S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of responders, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon (Peg-IFN), both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359-362), HCV is now widely accepted as the most common causative agent of post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-362; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci. USA 87:2057-2061 ), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5′ nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al ‘An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5′ noncoding region’ RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2^nd Edition, p931-960; Raven Press, N.Y.). Following the termination codon at the end of the long ORF, there is a 3′ NTR which roughly consists of three regions: an – 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the “3′ X-tail” (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261 ). The 3′ NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.

The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S. E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1 b isolates) and inter-typically (-85% aa identity between genotype 1 a and 1 b isolates). The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al.. (2000) Journal of Virology, 74(4): 2046-2051 ). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to be useful to treat HCV infection.

Although the predominant HCV genotype worldwide is genotype 1, this itself has two main subtypes, denoted 1a and 1 b. As seen from entries into the Los Alamos HCV database

(www.hcv.lanl.gov) (Table 1 ) there are regional differences in the distribution of these subtypes: while genotype 1 a is most abundant in the United States, the majority of sequences in Europe and Japan are from genotype 1 b.

Table 1

Image may be NSFW.
Clik here to view.

Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit replication of both genotype 1 a and genotype 1 b of HCV.

PATENT

WO 2002100851

WO 2007071434 

PATENT

WO 2009000818 

Compound A
5-Phenyl-3-[[(frans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2-thiophenecarboxylic acid

Image may be NSFW.
Clik here to view.

To a mixture of methyl S-^trans^-methylcyclohexyOcarbonylKI-methylethy^aminol-S-phenyl-2-thiophenecarboxylate (Intermediate 31 ) (390 mg) in THF/MeOH/water (3:2:1, vol/vol, 40 ml. total) was added lithium hydroxide monohydrate (246 mg). The mixture was stirred at room temperature for 20 hours, the solvents removed in vacuo, and the residue partitioned between water (40 ml.) and ethyl acetate (40 ml_). The organic layer was dried

(Na₂SC>₄), evaporated and triturated with ether to give the title compound.
MS calcd for (C₂₂H₂₇NO₃S+ H)⁺: 356
MS found (electrospray): (M+H)⁺ =356

Compounds A, B, C and D may be made according to the processes described in WO2002/100851 or as described hereinabove.

Structures of Compounds A, B, C and D are shown below for the avoidance of doubt.

Image may be NSFW.
Clik here to view.

The compounds of Formula (I) which have been tested demonstrate a surprisingly superior potency as HCV polymerase inhibitors, as shown by the IC₅O values in the cell-based assays across both of the 1 a and 1 b genotypes of HCV, compared to Compounds A, B, C and D. Accordingly, the compounds of Formula (I) are of great potential therapeutic benefit in the treatment and prophylaxis of HCV.

PAPER

Bioorganic & Medicinal Chemistry Letters (2016), 26(18), 4536-4541.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X16300427

Image may be NSFW.
Clik here to view.

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

Image may be NSFW.
Clik here to view.

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• FACEBOOK

join me on twitter a

Anthony Melvin Crasto Dr. | twitter

• Twitter

+919321316780 call whatsaapp

////////////////VX-759, BCH-27759, VCH-759, VX759,  BCH27759, VCH759, VX 759, BCH 27759, VCH 759, NNI-1

O=C(C1=C(N(C(C2CCC(C)CC2)=O)C(C)C)C=C(C3=CC=CC=C3)S1)O

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

ONE TIME

$10.00

Click here to purchase.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Biapenem

• Molecular FormulaC₁₅H₁₈N₄O₄S
• Average mass350.393 Da

BiapenernCL 186-815LJ C10,627LJ C10627LJC 10627MFCD00864863 [MDL number]omegacinYR5U3L9ZH1

(4R,5S,6S)-3-((6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[4R-[4a,5b,6b(R*)]]-6-[[2-Carboxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5 H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

120410-24-4[RN]

5H-Pyrazolo[1,2-a][1,2,4]triazol-4-ium, 6-[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-, inner salt [ACD/Index Name]

6-[[(4R,5S,6S)-2-Carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

7074

(4R,5S,6S)-3-(6,7-Dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-ylsulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

TL8000539UNII:YR5U3L9ZH1UNII-YR5U3L9ZH1биапенем

بيابينام比

阿培南

INDIA CDSCO APPROVED 25 SEPT 2021, BDR PHARMA,  Image may be NSFW.
Clik here to view.
https://www.cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCTApprovals/BDR.pdfhttps://medicaldialogues.in/news/industry/pharma/bdr-pharma-gets-dcgi-nod-for-generic-antibiotic-drug-biapenem-82384

Biapenem

CAS Registry Number: 120410-24-4 
CAS Name: 6-[[(4R,5S,6S)-2-Carboxy-6-((1R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

Additional Names: (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]-triazolium-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

Manufacturers’ Codes: LJC-10627; L-627; CL-186815 
Molecular Formula: C15H18N4O4SMolecular Weight: 350.39

Percent Composition: C 51.42%, H 5.18%, N 15.99%, O 18.26%, S 9.15% 
Literature References: 1-b-methyl-carbapenem antibiotic. Prepn: T. Kumagai et al.,EP289801; eidem,US4990613 (1988, 1991 both to Lederle). Total synthesis: Y. Nagao et al.,J. Org. Chem.57, 4243 (1992). Renal dehydropeptidase stability: M. Hikida et al.,Antimicrob. Agents Chemother.36, 481 (1992). In-vitro antimicrobial spectrum: H. M. Wexler et al.,J. Antimicrob. Chemother.33, 629 (1994); H. Y. Chen, D. M. Livermore, ibid. 949. Clinical pharmacokinetics: M. Nakashima et al.,Int. J. Clin. Pharmacol. Ther. Toxicol.31, 70 (1993). Clinical evaluation: H. Meguro et al.,Jpn. J. Antibiot.47, 903 (1994). 
Properties: Amorphous, pale yellow powder from acetone/water, occurs as hemihydrate. [a]D20 -32.9° (c = 0.5)

.Optical Rotation: [a]D20 -32.9° (c = 0.5)

Therap-Cat: Antibacterial.Keywords: Antibacterial (Antibiotics); ?Lactams; Carbapenems.

Image may be NSFW.
Clik here to view.

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

Image may be NSFW.
Clik here to view.

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• FACEBOOK

join me on twitter a

Anthony Melvin Crasto Dr. | twitter

• Twitter

+919321316780 call whatsaapp

Biapenem (INN) is a carbapenem antibiotic. It has in vitro activity against anaerobes.^[1] 1-β-methyl-carbapenem antibiotic. Approved in Japan in 2001.

syn

CN 110343122

https://patents.google.com/patent/CN110343122B/en

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

PATENT

EP 168707

EP 289801

JP 02088578

ZA 9100014

EP 533149

CN 1995040

IN 2006DE01555

CN 101121716

IN 2008CH00177

CN 101805359

CN 101851206

CN 101935321

CN 111875622

WO 2018074916

WO 2016059622

US 20150328323

WO 2015151081

WO 2015155753

WO 2015151078

US 20150284416

WO 2015151080

US 20150038726

WO 2014104488

IN 2013MU00181

WO 2014111957

CN 103570750

WO 2014097221

IN 2012CH01371

WO 2013150550

PAPERS

 Journal of Organic Chemistry (1992), 57(15), 4243-9.

Heterocycles (1993), 36(8), 1729-34.

Journal of Antibiotics (1993), 46(12), 1866-82.

e-EROS Encyclopedia of Reagents for Organic Synthesis (2008), 1-3.

Bioorganic & medicinal chemistry letters (2009), 19(17), 5162-5.

 IP.com Journal (2014), 14(12A), 1-3

IP.com Journal (2014), 14(10A), 1-2.

Bioorganic & medicinal chemistry (2013), 21(18), 5841-50.

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

one time

$10.00

Click here to purchase.

PATENT

https://patents.google.com/patent/WO2014097221A1/esBiapenem is chemically known as 6-[[2(4R,5S,6S)-carboxy-6-[(lR)- hydroxy ethyl] -4-methyl-7-oxo- 1 -azabicyclo [3.2.0]hept-2-en-3 -yljthio] 6,7-dihydro-5H- pyrazolo[l,2-a][l,2,4]triazol-4-ium inner salt, and is represented by Formula 1. It is indicated for the treatment of bacterial infection and sepsis.

Image may be NSFW.
Clik here to view.

Formula 1U.S. Patent No. 4,866,171, in Example 6, discloses the purification of biapenem using chromatography and/or lyophilization techniques. This patent also describes a process for the conversion of amorphous biapenem into a crystalline form by dissolving the amorphous biapenem in water while heating, followed by cooling, then washing the obtained crystals with a 50% aqueous ethanol solution.U.S. Patent No. 5,241,073 describes a process for the purification of biapenem involving column chromatography and crystallization with ethanol.U.S. Patent No. 5,286,856 describes a process for the crystallization of biapenem from an aqueous solution, comprising maintaining the temperature of the aqueous solution from eutectic temperature (-10°C to -2°C) to a temperature lower than 0°C, followed by lyophilization.The Journal of Organic Chemistry, 63(23):8145-8149 (1998) describes the purification of biapenem involving resin chromatography.The present invention provides an alternate process for the purification of biapenem that avoids making use of tedious techniques like chromatography and lyophilization. At the same time, it results in a high yield and high purity of the final product. Advantageously, the crystalline biapenem of this invention can be directly isolated from the reaction mixture. Further, the process of the present invention involves fewer steps, is easily scalable, and industrially advantageous.EXAMPLESExample 1 : Purification of BiapenemBiapenem (12 g) was added into water (300 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.6 g) was added to the reaction mixture and stirred for 10 minutes to 15 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (36 mL). The filtrate obtained was passed through a 0.45 micron filter, and its pH was adjusted to 5.5 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (336 mL) was added to the reaction mixture at 5°C to 10°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (60 mL). The solid was dried under reduced pressure (720 mmHg) at 30°C to 35°C to obtain the title product as white crystals.Yield: 84%HPLC Purity: 99.87% Example 2: Purification of BiapenemBiapenem (18 g) was added into water (450 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.9 g) was added to the reaction mixture and stirred for 30 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (54 mL). The filtrate obtained was passed through a 0.45 micron filter and its pH was adjusted to 4.9 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (504 mL) was added to the reaction mixture at 10°C to 15°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (90 mL). The solid was dried under reduced pressure (720 mmHg) at 35°C to 40°C to obtain the title product as white crystals.Yield: 81.77%HPLC Purity: 99.80% 
PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013150550

The present invention relates to an improved process for the preparation of carbapenem antibiotic; more particularly relates to the preparation of Ertapenem monosodium salt of formula (I) having purity greater than 98.5% and having pharmaceutically acceptable level of residual solvent and palladium content.

Image may be NSFW.
Clik here to view.

The US patents namely US 5,478,820 and US 5,856,321 disclose various processes for preparing Ertapenem and its sodium salt. Example 12 of US 5,478,820 discloses a process in which the Ertapenem was isolated using column purification followed by freeze-drying technique. According to Example-4 of this patent disodium salt of Ertapenem was prepared by dissolving crude product in water using NaHCO₃, followed by purification using column chromatography and subsequent lyophilization.

US 6,504,027 provides a process for preparing Ertapenem in crystalline form which comprises deprotecting and extracting a polar organic solution containing a crude mono-protected Ertapenem of formula

Image may be NSFW.
Clik here to view.

wherein P represents protecting group and X represents charge balancing group like sodium

with C4.10 alcohol in the presence of ion-pairing reagent followed by adjusting the pH of the aqueous layer to 5.5 and crystallizing using methanol and 1-propanol to produce a crystalline compound; this patent process involves operations like

multiple extractions which is cumbersome in plant and said operation affects the overall yield.

US 7,145,002 provides a process for producing Ertapenem or its sodium salt and/or its solvate in crystalline form. This patent states (refer para 3, lines 31-41) that contact of Ertapenem sodium with water and alcoholic solvents results in the formation of crystalline solvates. The processes reported in examples- 1 & 2 provide crystalline Ertapenem monosodium which is isolated from a mixture of methanol, 1-propanol and water followed by washing with aqueous isopropyl alcohol which results in the formation of crystalline solvate of Ertapenem sodium. Applicant found the Ertapenem monosodium obtained according to this process contain higher amount of residual solvent and palladium content.

US 7,022,841 provide a process for reducing the levels of organic solvents in Ertapenem to pharmaceutically acceptable levels. This patent discloses (Refer para 1, lines 52-60) that Ertapenem sodium obtained from water/alcohol mixture according to US 7, 145,002 becomes amorphous when water content of the solid is reduced and further the organic solvent present in the solid is not readily removed. In view of this drawback, this patent provides a process wherein the water content of Ertapenem sodium is maintained between 13-25% during the washing and drying process. This patent further discloses that (Refer para 9, lines 6-14) the washing of Ertapenem sodium can be carried out using anhydrous solvents which results in the formation of amorphous solid, which is then dried using hydrated nitrogen by increasing the water content of the solid. Due to the hygroscopic and unstable nature of Ertapenem sodium when in contact with water, the above processes result in more degradation of Ertapenem. The patent further discloses in example 5 that the degradation of Ertapenem sodium is more when it takes more time for drying.

Further this patent requires repetitive washing and control of moisture content to get the desired results.

For isolation of Ertapenem sodium from the reaction mass, all the above discussed prior art patents utilize methanol and 1-propanol as crystallization solvent. The filtration of Ertapenem sodium formed by using these solvents or their mixture takes longer time duration and subsequent drying for the removal of residual solvent also takes several hours due to occlusion of solvent into Ertapenem sodium. During these operations the Ertapenem sodium degrades an results in the formation of many impurities such as several dimers, methanolysis impurity etc., and hence the reported processes is not suitable to manufacture Ertapenem sodium on commercial scale with purity greater than 98.5% and with pharmaceutically acceptable level of residual solvent content.

Image may be NSFW.
Clik here to view.

Methanolysis impurity Dimer-I

Image may be NSFW.
Clik here to view.

Dimer-II

Further the applicant found that Ertapenem monosodium isolated by following the process reported in prior art was having palladium content above the pharmaceutically acceptable level. Hence the process reported in prior art is not suitable on manufacturing scale where maintaining stringent technological condition is cumbersome and involves higher operating cost.

Thus all the reported processes suffer in terms of one or more of the following facts:

^■ Filtration time of Ertapenem sodium takes several hours.

^■ Drying time takes several hours due to occlusion of solvent and nature of the solid.

^■ Stringent technological condition is required for maintenance of moisture content during washing & drying operation.

■ Palladium content is found to be higher (greater than 25 ppm) which is not acceptable for pharmaceutical products.

■ The isolated Ertapenem sodium is having higher amount of residual solvents.

■ The purity is reduced over to several hours of filtration & drying.

With our continued research for developing a process for the preparation of Ertapenem monosodium of formula (I) to overcome the above mentioned drawbacks, we surprisingly found that when esters of organic acid were used as solvents in place of 1-propanol, the solid obtained was easily filterable with less cycle time. Further the washing with hydrocarbon solvents containing 0-75% alcoholic solvent followed by drying results in Ertapenem having residual solvent content well below the pharmaceutically acceptable levels. The use of thiourea, thiosemicarbazide or their N-substituted derivatives in the presence of organic solvents during isolation brings down the palladium content to pharmaceutically acceptable level.

The Ertapenem or its sodium salt can be prepared according the processes provi

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

(I)

P’ and P” represent carboxylic protecting groups and X is H or Na

Scheme-1

The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention.

Example- I

Preparation of Ertapenem monosodium of formula (I)

Step-I:

To a stirred solution of p-nitrobenzyl (4R,5S,6S)-3-(diphenyloxy)phosphoryloxy-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (compound II) (100 g) and (2S,4S)-2-[[(3-carboxyphenyl) amino]carbonyl]-4-mercapto-l-(4-nitrobenzyl)pyrrolidinecarboxylate (compound III) (75 g) in N,N-dimethylformamide was added Ν,Ν-diisopropylethylamine at -30 to -40° C and stirred. The reaction mass, after completion of the reaction, was quenched with a mixture of phosphate buffer solution-ethyl acetate and the pH was adjusted to 5 – 6 with phosphoric acid. The organic layer was separated, washed with water and subjected to carbon treatment. To the organic layer containing the compound of formula (IV) (wherein P’ and P” refers to p-nitrobenzyl), a solution of sodium 2-ethylhexanoate (42 g in 500 mL methanol) was added and taken to next step as such. (If required the compound of formula (IV) is isolated either as sodium salt or as free acid by following the process reported in prior art and taken further)

Step-II:

To the Step-I organic layer containing the compound of formula (IV) (wherein P’ and P” refers to p-nitrobenzyl & X is Na), 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8- 10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered to remove palladium on carbon. To the filtrate, thiourea (5 g) and tetrahydrofuran were added and stirred. The aqueous layer was separated and treated with carbon and neutral alumina at 10-15° C while degassing and filtered. The filtrate was added to methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol (200 ml) and dried under vacuum. Yield: 46 g; Purity by HPLC: 98.93%; Palladium content: 1.8 ppm by ICP MS

The HPLC purity of Ertapenem monosodium was checked using the following parameters

Column : Zorbax Eclipse plus C8, (50 mm x 4.6 mm), 1.8μ).

Mobile phase : Ammoniam acetate buffer: Acetonitile: water

Detector : UV at 250 nm

Flow rate : 0.5 mL/min

Run time : 45 min.

Example- II

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8-10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and 2-methyltetrahydrofuran and the layers separated. The aqueous layer was treated with carbon & neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with cyclohexane (200 ml) and

dried under vacuum. Yield: 44 g; Purity by HPLC: 98.84%; Palladium content: 0.93 ppm by ICP MS

The term ICP MS method refers to the inductively coupled plasma mass spectrometry. The following parameter was used to determine the content of palladium.

The carbapenem was digested in a closed vessel system in presence of reagents Nitric acid, Hydrogen peroxide and Hydrochloric acid by using Microwave reaction system with microwave radiation power 1200 Watts. The digested sample was introduced into inductively coupled plasma mass spectrometer by help of Peltier cooled spray chamber. The sample aerosol is getting atomized then ionized in the argon plasma. The ionized Palladium was estimated by using Quadrupole mass detector. The sample was quantified against NIST traceable reference standards at mass number ! 05.

Example- III

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and tetrahydrofuran and the layers separated. The aqueous layer was separated and treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of toluene: ethanol (200 ml) and dried under vacuum. Yield: 42 g; Purity by HPLC: 99.03%

Example- IV

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction was filtered and the filtrate was treated with thiosemicarbazide and tetrahydrofuran and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C followed by the addition of ethyl acetate and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol (200 ml) and dried under vacuum. Yield: 41 g; Purity by HPLC: 99.13%; Palladium content: 1.71 ppm by ICP MS

Example- V

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8-10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and 2-methyltetrahydrofuran and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, a mixture of ethyl acetate containing 10% methyl acetate was added and stirred. The solid obtained was

filtered, washed with cyclohexane:ethanol and dried under vacuum. Yield: 40.5 g; Purity by HPLC: 98.77%; Palladium content: 1.43 ppm by ICP MS

Example-VI

Image may be NSFW.
Clik here to view.

(V ) (V I )

The diprotected Meropenem of formula (V) (where P and P’ were p-nitrobenzyl) was dissolved in tetrahydrofuran and 3-(N-morpholino)propanesulfonic acid buffer and hydrogenated using palladium on carbon at 9-10 kg hydrogen pressure. The mass was filtered and the filtrate was washed with ethyl acetate. The aqueous layer was treated with thiourea and 2-methyltetrahydrofuran. The aqueous layer was separated, treated with carbon and degassed. The carbon was filtered off and acetone was added to the filtrate to crystallize Meropenem trihydrate of formula (VI). The product was filtered and washed with aq. acetone and dried under vacuum to get Meropenem trihydrate. Purity: 99.8%; Pd content: 0.08 ppm

Reference example-I:

Preparation of Ertapenem monosodium of formula (I)

To Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered. The filtrate was treated with thiourea and tetrahydrofuran and the layers separated. The aqueous layer was treated with carbon and neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass ethyl acetate was added and stirred. The solid obtained was filtered, washed with ethanol (5 * 100 ml) and dried under vacuum. Yield: 31 g; Purity by HPLC: 96.76%

Reference example-II:

Preparation of Ertapenem monosodium of formula (I)

To the Step-I reaction mass , as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction was filtered and the layers separated. The aqueous layer was treated with carbon and neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol and dried under vacuum. Yield: 43 g; Purity by HPLC: 98.6%; Palladium content: 35.8 ppm by ICP MS.

Reference example-HI:

Preparation of Ertapenem monosodium of formula (I)

To the Step-I reaction mass as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with 1-propanol at -5° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass methanol and 1-propanol were added and stirred. The solid obtained was filtered, washed with ethanol and dried under nitrogen atmosphere in vacuum. Yield: 25 g; Purity by HPLC: 97 %.: palladium content: 38.2 ppm

The following tables illustrate the advantages of the present invention over prior art process:

Table-I: Comparison of present process with prior art process

Image may be NSFW.
Clik here to view.

The crystallization and washing method disclosed in US 7,022,841 was followed.

The above table indicates that the use of ethyl acetate as crystallization solvent results with improved yield and high purity with less filtration and drying time thereby increasing the productivity significantly on manufacturing scale. Further the use of thiourea or thiosemicarbazide as reagents in the present process results in the pharmaceutically acceptable level of palladium content.

Table-II: Comparison of solvents for washing Ertapenem monosodium

Image may be NSFW.
Clik here to view.

The above table indicates that the use of hydrocarbon solvents containing 0-75% of alcoholic solvent helps in washing to remove the residual solvent content in shorter duration and with single run wash. On the other hands the use of ethanol alone results in Ertapenem monosodium having less yield and purity requiring repetitive washing.

Table-IH: Effect of different reagent in reduction of palladium content

Image may be NSFW.
Clik here to view.

Reagent : thiourea, thiosemicarbazide or its N-substituted derivatives

Advantages of the process of the present invention:

> The use of ester of an organic acid for the crystallization of Ertapenem sodium results in fast filtration and reduced cycle time, thereby increasing the productivity.

> Washing of Ertapenem sodium with hydrocarbon solvent optionally containing alcohol results in improved physical nature of Ertapenem sodium resulting in reduced washing and drying time thereby avoid the degradation of Ertapenem and providing Ertapenem sodium with purity greater than 98.5% by HPLC.

Use of thiourea, thiosemicarbazide or their N-substituted derivatives in the process results in Ertapenem sodium having pharmaceutically acceptable level of palladium content.

PATENT

https://patents.google.com/patent/WO2002057266A1/enEXAMPLE

Image may be NSFW.
Clik here to view.

PNB = p-nitrobenzyl

Image may be NSFW.
Clik here to view.

Ia’A hydrogenator is charged with 63 g of 10% Pd on carbon catalyst (dry weight) in 1.8 L of water. The vessel is placed under hydrogen then vented and placed under nitrogen. Sodium hydroxide (68 g, 50%) is charged adjusting the pH to about 7.5 with carbon dioxide.The enol phosphate (170 g) and the thiol (86 g) are dissolved in 1.3^‘L of N- ethylpyrrolidinone (NEP). The mixture is cooled to below -40°C and 1,1,3,3- tetramethylguanidine (109 g) is added. After 3 hours, the reaction mixture is quenched into the hydrogenator at below 15°C adjusting the pH to about 8 with carbon dioxide. The vessel is placed under hydrogen. When the reaction is complete, the hydrogen is vented and the reaction mixture is treated with activated carbon and filtered. The filtrate is extracted with iso-amyl alcohol containing diphenylphosphoric acid (240 g) and 50% NaOH (44 g). The resulting aqueous solution is further extracted with iso-amyl alcohol to give an aqueous solution containing at least 90 mg/mL of the product. Both extractions are performed using two CINC centrifugal separators set in series for countercurrent extraction. The pH is adjusted to 5.5 with acetic acid. The product is crystallized by adding equal volumes of methanol and 1- propanol at below -5°C and isolated by filtration. The solid is washed with a mixture of 2-propanol and water (85: 15 v/v) then dried to yield a compound of formula la’.While certain preferred embodiments of the invention have been described herein in detail, numerous alternative embodiments are contemplated as falling within the scope of the appended claims. Consequently the invention is not to be limited thereby.

Patent Citations

Publication numberPriority datePublication dateAssigneeTitleUS4866171A1987-04-111989-09-12Lederle (Japan), Ltd.(1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio-6-[R-1-hydroxyethyl]-1-methyl-carbapenum-3-carboxylateUS5241073A1990-10-121993-08-31Lederle (Japan)Process for preparing (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo [1,2-a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate and starting materials thereofUS5286856A1991-09-201994-02-15Takeda Chemical Industries, Ltd.Production of crystalline penemWO2002057266A1 *2001-01-162002-07-25Merck & Co., Inc.Improved process for carbapenem synthesisWO2009047604A1 *2007-10-082009-04-16Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of carbapenem antibioticCN102268025A *2011-07-152011-12-07海南美兰史克制药有限公司一种比阿培南化合物及其制法

References

1. ^ Aldridge KE, Morice N, Schiro DD (April 1994). “In vitro activity of biapenem (L-627), a new carbapenem, against anaerobes”. Antimicrob. Agents Chemother. 38 (4): 889–93. doi:10.1128/aac.38.4.889. PMC 284564. PMID 8031067.

External links

• (in Japanese) Omegacin

ClinicalTrials.gov

NIPH Clinical Trials Search of Japan

/////////BIAPENEM, TL8000539, UNII:YR5U3L9ZH1, UNII-YR5U3L9ZH1, биапенем, بيابينام ,比阿培南 , Biapenern, CL 186-815, CL 186815, L 627, LJC 10627, Omegacin, Antibacterial, Antibiotics, Lactams, Carbapenems, ind 2021, india 2021, approvals 2021

CC1C2C(C(=O)N2C(=C1SC3CN4C=NC=[N+]4C3)C(=O)[O-])C(C)O

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Avacopan

アバコパン

авакопан [Russian] [INN]

أفاكوبان [Arabic] [INN]

阿伐可泮 [Chinese] [INN]

(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

(2R,3S)-2-(4-Cyclopentylaminophenyl)-l-(2-fluoro-6-methylbenzoyl)piperidine-3- carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

3-​Piperidinecarboxamid​e, 2-​[4-​(cyclopentylamino)​phenyl]​-​1-​(2-​fluoro-​6-​methylbenzoyl)​-​N-​[4-​methyl-​3-​(trifluoromethyl)​phenyl]​-​, (2R,​3S)​-

• (2R,3S)-2-[4-(Cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]-3-piperidinecarboxamide
• (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

APPROVED PMDA JAPAN 2021/9/27, Tavneos

Image may be NSFW.
Clik here to view.

Anti-inflammatory, Complement C5a receptor antagonist

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis

Avacopan

Image may be NSFW.
Clik here to view.

(2R,3S)-2-[4-(Cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

C₃₃H₃₅F₄N₃O₂ : 581.64
[1346623-17-3]

CCX 168

Avacopan wasunder investigation in clinical trial NCT02994927 (A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis).

VFMCRP announces approval for TAVNEOS^® (avacopan) for the treatment of ANCA-associated vasculitis in Japan

• First orally administered therapy for the treatment of two types of ANCA-associated vasculitis approved in Japan
• Partner Kissei to market TAVNEOS^® in Japan, with launch expected as soon as possible following National Health Insurance (NHI) price listing

September 27, 2021 02:02 AM Eastern Daylight Time

ST. GALLEN, Switzerland–(BUSINESS WIRE)–Vifor Fresenius Medical Care Renal Pharma (VFMCRP) today announced that Japan’s Ministry of Health and Labor Welfare (MHLW) has granted its partner, Kissei Pharmaceutical Co., Ltd., marketing authorization approval for TAVNEOS^® for the treatment of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two main types of ANCA-associated vasculitis, a rare and severe autoimmune renal disease with high unmet medical need.

“We are delighted that TAVNEOS^® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone”

Tweet this

“We are delighted that TAVNEOS^® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone,” said Abbas Hussain, CEO of Vifor Pharma Group. “ANCA-associated vasculitis is officially designated an intractable disease in Japan, indicating a rare disease without any effective treatment but for which long-term treatment is required. There is significant unmet medical need of over 10,000 patients in Japan, and we believe in the potential of TAVNEOS^® for treating it. We are confident that Kissei will fully focus on bringing this breakthrough treatment to this patient population, helping them lead better, healthier lives.”

The approval is based on the marketing authorization application filing by Kissei which was supported by positive clinical data from the pivotal phase-III trial ADVOCATE in a total of 331 patients with MPA and GPA in 18 countries and regions, including Japan. TAVNEOS^® demonstrated superiority over standard of care at week 52 based on Birmingham Vasculitis Activity Score (BVAS).

VFMCRP holds the rights to commercialize TAVNEOS^® outside the U.S.. In June 2017, VFMCRP granted Kissei the exclusive right to develop and commercialize TAVNEOS^® in Japan. Kissei expects to begin to market TAVNEOS^® as soon as possible following NHI price listing. Outside Japan, TAVNEOS is currently in regulatory review with various agencies, including the U.S. Food and Drug Administration and the European Medicines Agency.

About Vifor Pharma Group

Vifor Pharma Group is a global pharmaceuticals company. It aims to become the global leader in iron deficiency, nephrology and cardio-renal therapies. The company is a partner of choice for pharmaceuticals and innovative patient-focused solutions. Vifor Pharma Group strives to help patients around the world with severe and chronic diseases lead better, healthier lives. The company develops, manufactures and markets pharmaceutical products for precision patient care. Vifor Pharma Group holds a leading position in all its core business activities and consists of the following companies: Vifor Pharma and Vifor Fresenius Medical Care Renal Pharma (a joint company with Fresenius Medical Care). Vifor Pharma Group is headquartered in Switzerland, and listed on the Swiss Stock Exchange (SIX Swiss Exchange, VIFN, ISIN: CH0364749348).

For more information, please visit viforpharma.com.

About Kissei Pharmaceutical Co., Ltd.

Kissei Pharmaceutical Co., Ltd. is a Japanese pharmaceutical company with approximately 70 years of history. Based on its management philosophy, “contributing to society through high-quality, innovative pharmaceutical products” and “serving society through our employees”, Kissei is concentrating on providing innovative pharmaceuticals to patients worldwide as a strongly R&D-oriented corporation. Kissei is engaged in R&D and licensing activities in the field of nephrology/dialysis, urology, and unmet medical needs in other disease areas. Kissei has an established collaboration with VFMCRP for sucroferric oxyhydroxide which Kissei fully developed in Japan as P-TOL^® (known as Velphoro^® in Europe/US) for the treatment of hyperphosphatemia. Since the launch in 2015, the market share of P-TOL^® has been steadily expanding in Japan. For more information about Kissei Pharmaceutical, please visit www.kissei.co.jp.

About ChemoCentryx Inc.

ChemoCentryx is a biopharmaceutical company developing new medications for inflammatory and autoimmune diseases and cancer. ChemoCentryx targets the chemokine and chemoattractant systems to discover, develop and commercialize orally-administered therapies. Besides ChemoCentryx’s lead drug candidate, avacopan, ChemoCentryx also has early stage drug candidates that target chemoattractant receptors in other inflammatory and autoimmunediseases and in cancer.

About ANCA-associated vasculitis

ANCA-associated vasculitis is a systemic disease in which over-activation of the complement pathway further activates neutrophils, leading to inflammation and destruction of small blood vessels. This results in organ damage and failure, with the kidney as the major target, and is fatal if not treated. Currently, treatment for ANCA-associated vasculitis consists of courses of non-specific immuno-suppressants (cyclophosphamide or rituximab), combined with the administration of daily glucocorticoids (steroids) for prolonged periods of time, which can be associated with significant clinical risk including death from infection.

About TAVNEOS^® (avacopan)

Avacopan is an orally-administered small molecule that is a selective inhibitor of the complement C5a receptor C5aR1. By precisely blocking the receptor (the C5aR) for the pro-inflammatory complement system fragment, C5a on destructive inflammatory cells such as blood neutrophils, avacopan arrests the ability of those cells to do damage in response to C5a activation, which is known to be the driver of inflammation. Moreover, avacopan’s selective inhibition of only the C5aR1 leaves the beneficial C5a l pathway through the C5L2 receptor functioning normally.

ChemoCentryx is also developing avacopan for the treatment of patients with C3 Glomerulopathy (C3G) and hidradenitis suppurativa (HS). The U.S. Food and Drug Administration has granted avacopan orphan-drug designation for ANCA-associated vasculitis, C3G and atypical hemolytic uremic syndrome. The European Commission has granted orphan medicinal product designation for avacopan for the treatment of two forms of ANCA vasculitis: microscopic polyangiitis and granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), as well as for C3G. In October 2020, European Medicines Agency (EMA) accepted to review the Marketing Authorization Application (MAA) for avacopan for the treatment of patients with ANCA-associated vasculitis (granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)).

On May 6, 2021 the U.S. Food & Drug Administration’s (FDA’s) Arthritis Advisory Committee narrowly voted in support of avacopan, a C5a receptor inhibitor, for the treatment of adult patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. Although the panelists were excited about the possibility of a steroid-sparing therapy, some raised questions about whether results from the single phase 3 trial could adequately inform the risk/benefit assessment.¹ The FDA will weigh the panel’s recommendation as it considers possible approval.

Treatment Needs for ANCA-Associated Vasculitis

ANCA-associated vasculitis is a rare, severe and sometimes fatal form of vasculitis characterized by inflammation of small vessels, often including those in the kidney. One factor that distinguishes it from other forms of vasculitis is the dom­inant role of neutrophils in its pathogenesis. From work in both animal and mouse models, we know activation of the alternative complement pathway plays a role in the disease pathogenesis, triggering attraction and activation of neutrophils in a complex feedback loop.^1-3

Morbidity and mortality from ANCA-associated vasculitis has improved in recent decades, partly due to the introduction of new treatment regimens. The FDA approved rituximab for ANCA-associated vasculitis in 2011, and, in 2018, its label was extended to include maintenance therapy. Most patients with newly diagnosed ANCA-associated vasculitis are now started on a tapering dose of glucocorticoids, paired either with cyclo­phosphamide or rituximab, with a later follow-up maintenance dose of rituximab at around six months.

High doses of glucocorticoids are often used for remission induction, and they may also be employed as part of maintenance therapy, flare management and relapsing disease. This is a concern for practitioners, who hope to reduce the toxicity that results from glucocorticoid use, especially when given at high doses for prolonged periods.

Avacopan is the first drug to be specifically developed for a vasculitis indication. Other vasculitis therapies—such as tocilizumab for giant cell arteritis or rituximab for ANCA-associated vasculitis—were first approved for other diseases. Avacopan is an oral C5a receptor antagonist that selectively blocks the effects of C5a, thus dampening neutrophil attraction and activation. It does not have FDA approval for other indications, but has orphan drug status for ANCA-associated vasculitis (specifically for microscopic polyangiitis and granulomatosis with polyangiitis) and for C3 glomerulopathy, a rare kidney disease.

Arthritis Advisory Panel Meeting

The FDA generally requires evidence from at least two adequate and well-controlled phase 3 trials to establish effectiveness of a drug. However, it exercises regulatory flexibility in certain circumstances, such as for some rare diseases. In this case, it may consider the results of a well-designed single study if the evidence is statistically persuasive and clinically meaningful.⁴

Study design is a challenge for any manufacturer attempting to develop a product to potentially decrease steroid use because the FDA does not accept steroid sparing as an assessable outcome for clinical trials. For example, in the GiACTA trial, the phase 3 trial used as evidence for approval of tocilizumab for patients with giant cell arteritis, the biotechnology company Genentech wanted to give tocilizumab and demonstrate patients could then be safely taken off glucocorticoids. But the FDA required a more complicated multi-arm design.⁵

Other issues come up because of the way gluco­corticoids have been used historically. Although they have been used for vasculitis since before drug licensing was introduced, glucocorticoids are not themselves licensed for ANCA-associated vasculitis, which brings up certain regulatory barriers in study design. Additionally, the efficacy of glucocorticoids in vasculitis to control disease activity or prevent relapse has never been officially quantified in a placebo-controlled trial.

ADVOCATE Design

For avacopan, ChemoCentryx based its application on a single phase 3 trial and two phase 2 trials.^1-3 In pre-meeting documents and during the meeting itself, the company drew comparisons to the RAVE trial, used to establish the non-inferiority of rituximab to standard cyclophosphamide therapy in patients with ANCA-associated vasculitis.⁶ In this case, a single phase 3 trial (with supporting phase 2 data) was used as evidence for approval of rituximab.

The phase 3 trial of avacopan, ADVOCATE, used a similar, double-blind, double-dummy design.¹ ADVOCATE included 331 patients with either new or relapsing ANCA-associated vasculitis. Half the participants received 30 mg of avacopan twice a day orally, as well as a prednisone placebo, out to the study’s end at 12 months. The other half received oral prednisone (tapered to 0 mg at five months) plus an avacopan placebo.

Additionally, patients received immunosuppressive treatment, either cyclo­phosphamide (35%) or rituximab (65%), at the discretion of the prescribing physician. Patients who had received cyclophosphamide also received follow-up azathio­prine at week 15. But after initial treatment, no patients received maintenance rituximab, as would now be common practice.

Prior to enrollment, many participants were already receiving glucocorticoids as part of their treatment, to help get their disease under control. Thus, open-label prednisone treatment continued to be tapered for the early part of the trial in both groups up to the end of week 4. This had to be tapered to 20 mg or less of prednisone daily before beginning the trial, in both treatment groups.

As reported by the investigators, at week 26, the avacopan group was non-inferior to the prednisone group in terms of sustained remission. At the study’s conclusion at week 52, 66% of patients in the avacopan group were in sustained remission, as were 55% of those in the prednisone group. Thus, in terms of remission, avacopan was superior to gluco­corticoids at week 52 (P=0.007).

The researchers also provided encouraging secondary endpoints related to a number of other parameters, including reduced glucocorticoid-related toxicities, fewer relapses, better quality of life measures and improvements in kidney functioning (e.g., glomerular filtration rate changes).

David R.W. Jayne, MD, a professor of clinical auto­immunity at the University of Cambridge and director of the Vasculitis and Lupus Service at Addenbrooke’s Hospital, Cambridge, England, was one of the ADVOCATE investigators and says that in the context of previous vasculitis trials, which have only rarely displayed positive effects from interventions, the ADVOCATE results are impressive.

“We’ve never seen quality-of-life benefits or [glomerular filtration rate] recovery benefits in other vasculitis trials, but we saw them consistently in this one,” says Dr. Jayne.

………………………………………………………………………………………………………………………….

Image may be NSFW.
Clik here to view.

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

Image may be NSFW.
Clik here to view.

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• FACEBOOK

join me on twitter 

Anthony Melvin Crasto Dr. | twitter

• Twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

Image may be NSFW.
Clik here to view.

……………………………………………………………………………………………………………………………

PATENT

Example 1: Preparation of Free Base Crystalline Form of Compound 1

Example 2: Preparing an Amorphous Form of Compound 1

PATENT

WO 2021163329 

https://patents.google.com/patent/WO2021163329A1/en

PATENT

https://patents.google.com/patent/US20170283446A1/en

PATENT

Example 1: A Besylate Salt of Compound 1 (Form I)

Image may be NSFW. Clik here to view. (MOL) (CDX)

PATENT

 WO 2011163640

https://patents.google.com/patent/WO2011163640A1

Image may be NSFW.
Clik here to view.

Example 11[0147] The following are representative compounds prepared and evaluated using methods similar to the examples herein. Characterization data is provided for the compounds below. Biological evaluation is shown in Figure 1 for these compounds and others prepared as described herein.(2R,3S)-2-(4-Cyclopentylaminophenyl)-l-(2-fluoro-6-methylbenzoyl)piperidine-3- carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

Image may be NSFW.
Clik here to view.

[0148] 1H NMR (400 MHz, TFA-d) δ 7.91 (d, J= 8.6 Hz, 1 H), 7.84 (d, J= 8.6 Hz, 1 H), 7.58-6.82 (m, 8 H), 6.75 (t, J= 8.6 Hz, 1 H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-.169 (m, 7H)

PATENTUS 20110275639https://patents.google.com/patent/US20110275639PATENT
https://patents.google.com/patent/US20160090357A1/en

• [0097]This example illustrates the preparation of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide by the method provided more generally in FIG. 1 (Scheme 1) using the reagents provided below:
• [0098]Step 1:
• [0099]An oven-dried 12 L, 3-necked flask equipped with a mechanical stirrer, condenser, and thermometer was charged with acrolein diethyl acetal (1127 g, 8.666 mole, 1.05 equiv.) and warmed up to 40° C. A mixture of solid ethyl 3-(4-nitrophenyl)-3-oxo-propanoate (1956 g, 8.253 mole) and (R)-(−)-2-phenylglycinol (>99.5% e.e., 1187 g, 8.666 mole, 1.05 equiv.) was added in portions over 40 min. to maintain a stirrable mixture at an internal temperature of approximately 40° C. After all solids were added, the mixture was stirred at 40° C. for 10 minutes. 4M HCl in dioxane (206.2 mL, 0.825 mole, 10 mol. %) was subsequently added through the condenser within 2 minutes and the internal temperature was increased to 70 OC. The reaction was stirred for 22 h whereupon LC-MS showed consumption of starting materials and enamine intermediate. The heating was turned off and ethanol (6.6 L) was added. The solution was then seeded with 4 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate and stirred at room temperature for 18 h. The solid was subsequently filtered off and 0.1 L of ethanol was used to rinse the flask and equipment onto the filter. The isolated solid was then washed three times on the filter with ethanol (250 mL each) and dried under vacuum to generate 1253 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate as a bright yellow solid (38% yield, 98.5% HPLC wt/wt purity, 0.15 wt % of EtOH).
• [0100]Step 2:
• [0101]260 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate (0.659 mol), 0.66 L of ethanol, and 56 g of palladium catalyst (10% Pd/C, Degussa type E101 NE/W, 50% wet, 21.5 wt. % of powder, 4.0 mol % Pd) were placed in a 2.2 L Parr bottle and purged with nitrogen. The bottle was mounted on a Parr shaker apparatus and hydrogen was added at a rate to keep the external temperature of the bottle below 30° C. After 4 hours, the consumption of hydrogen slowed down. The bottle was then shaken under 50 psi of hydrogen for 2 hours. 94 mL of glacial acetic acid (1.65 mol, 2.5 equiv.) was subsequently added to the bottle and the bottle was purged three times with hydrogen at 50 psi. The bottle was then shaken under 35-55 psi of hydrogen for 48 hours, keeping the temperature below 30° C. The bottle was removed from the apparatus and 55 mL of 12M HCl aq. was added (0.659 mol, 1 equiv.) followed by 87 mL of cyclopentanone (0.989 mol, 1.5 equiv.). The bottle was purged three times with hydrogen at 50 psi and then shaken under 50 psi of hydrogen for 16-20 hours. The mixture was removed from the apparatus and filtered through a fritted funnel containing celite (80 g) and then washed three times with 0.125 L of ethanol. 54.1 g of anhydrous sodium acetate (0.659 mol, 1 equiv.) was added and the mixture was concentrated in vacuo at 40-55° C. to remove 0.9 L of the volatile components. 2.0 L of acetonitrile was added and 2.0 L of volatile components were removed in vacuo. The crude material was diluted with 1.0 L of acetonitrile and mechanically stirred at r.t. for 30 minutes. The mixture was filtered through Celite (40 g) and the cake was washed with 0.28 L of acetonitrile. The combined filtrates gave a solution of the crude amine acetate (Solution A, e.e. =78%). Solutions A of two independent runs were combined for further processing.
• [0102]In a 12-L 3-neck flask equipped with a mechanical stirrer, internal thermometer, and reflux condenser (−)-O,O′-di-p-toluoyl-L-tartaric acid (1.019 kg, 2.64 mol, 2 equiv.) was dissolved in 5.8 L of acetonitrile. The mixture was heated to 60° C. with stirring, followed by a quick addition of 1 L of Solution A. The resultant solution was seeded with 4 g of the crystalline ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) and stirred at 60° C. for 15 minutes. After 15 minutes at 60 OC the seed bed has formed. The remaining amount of Solution A was added over a period of 2.5 hours, maintaining an internal temperature at 60° C. When the addition was complete, the heat source was turned off and the mixture was stirred for 17 hours, reaching a final temperature of 22.5° C. The suspension was filtered and the solids were washed with 0.50 L of acetonitrile to rinse the equipment and transfer all solids onto the filter. The resultant wet solids were washed on the funnel with 3.0 L of acetonitrile and dried in a vacuum oven at 45° C. for 48 hours to provide 1.005 kg of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) as an off-white solid (70% yield, contains 1 wt. % of acetonitrile). The enantiomeric ratio of the product was 99.4:0.6.
• [0103]Step 3:
• [0104]In a 5 L 3-necked flask equipped with a mechanical stirrer and an addition funnel, solid anhydrous potassium carbonate (K₂CO₃, 226 g, 1.64 mol, 4.1 equiv.) was dissolved in H₂O (0.82 L) and cooled to ambient temperature. MTBE (0.82 L) was added, followed by solid ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) (436 g, 0.400 mol). The mixture was vigorously stirred at r.t. for 1 hour, then 2-fluoro-6-methylbenzoyl chloride (72.5 g, 0.420 mmol, 1.05 equiv.) in MTBE (0.14 L) was added dropwise over 1 hour. The product started precipitating from the reaction before addition of the acid chloride was completed. The reaction was vigorously stirred at r.t. for 30 minutes and monitored by LC-MS for the disappearance of starting material. The mixture was subsequently transferred to a 5 L evaporation flask using 0.3 L of MTBE to rinse the equipment and remove all solids. The mixture was concentrated in vacuo to remove the MTBE, then 0.3 L of heptane was added and the mixture was evaporated again to leave only the product suspended in aqueous solution. The flask was removed from the rotavap and water (0.82 L) and heptane (0.82 L) were added. The suspension was vigorously stirred for 16 hours using a mechanical stirrer. The contents were then filtered and the solid was washed with water (2×0.42 L) and heptane (0.42 L). The solid was dried in a vacuum oven at 45° C. to provide 172 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate as an off-white powder (95% yield).
• [0105]Step 4:
• [0106]A 0.5 L 3-necked round-bottom flask was dried overnight in an oven at 200° C. and then cooled under a stream of nitrogen. The flask was equipped with a magnetic stir bar, nitrogen inlet, and a thermometer. The flask was charged with 30.2 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate (66.7 mmol), 11.5 mL of 4-methyl-5-trifluoromethylaniline (80 mmol, 1.2 equiv.) and 141 mL of dry toluene under an atmosphere of nitrogen. Nitrogen was bubbled through the resultant solution for 10 minutes and then the solution was warmed to 30° C. The oil bath was removed and 100 mL of a 2 M solution of AlMe₃ in toluene (Aldrich, 200 mmol, 3 equiv.) was cannulated into the reaction mixture at a rate maintaining the reaction temperature between 35-40° C., a process that took approximately 45 minutes. The temperature of the reaction mixture was then increased to 55° C. over a period of 1 hour and the reaction mixture was stirred at 55° C. for 8 hours, whereupon all of the starting ester was consumed (monitored by LC-MS). The reaction was subsequently cooled overnight to ambient temperature and the solution was then cannulated into a mechanically stirred 1 L flask containing a solution of 67.8 g of sodium potassium tartrate tetrahydrate (240 mmol, 3.6 equiv.) in 237 mL of water, pre-cooled to 10 OC in an ice bath. The addition process took approximately 30 minutes, during which the reaction mixture self-heated to 57° C. The empty reaction flask was subsequently rinsed with 20 mL of dry toluene and the solution was combined with the quench mixture. The mixture was then cooled to r.t. with stirring, 91 mL of ethyl acetate was added, and the mixture was stirred an additional 15 minutes. The mixture was subsequently filtered through a pad of Celite and the filtrate was allowed to separate into two layers. The organic layer was then separated and washed with a solution of 5.7 g of sodium potassium tartrate tetrahydrate (20 mmol) in 120 mL of water and then with two 120 mL portions of water. The wet organic solution was concentrated in vacuo to a weight of ˜150 g and a solvent exchange with ethanol was performed maintaining a total volume of 0.2-0.3 L, until <1 mol. % toluene with respect to ethanol was observed by ¹H NMR. The solution was then evaporated at elevated temperature to a weight of 223 g and heated to reflux. Mechanical stirring was initiated and 41 mL of water was added. The resulting solution was seeded with (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide crystals at 60 OC and then slowly cooled to r.t. over 2 hours. The slurry was subsequently stirred for 18 hours and the solids were filtered off. The solids were then washed with two 30 mL portions of 7:3 ethanol/water and dried in a vacuum oven for 24 hours at 50 OC to afford 31.0 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as off-white crystals (80% yield). Analytical data: HPLC purity: 99.59%; >99.8% d.e. and e.e. by HPLC; ICP-OES Pd: <1 ppm; Al: δ ppm; residual toluene by headspace GC-MS: 15 ppm; microash<0.1%; K—F 0.1%. ¹H NMR (400 MHz, TFA-d) δ 7.91 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.58-6.82 (m, 8H), 6.75 (t, J=8.6 Hz, 1H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-1.69 (m, 7H), MS: (ES) m/z 582 (M+H⁺).

PATENT

WO2019236820

The present disclosure is directed to, inter alia, methods of treating ANCA-associated vasculitis (AAV) in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of avacopan, having the structure shown below:

Image may be NSFW.
Clik here to view.

References

1. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021 Feb 18;384(7):599–609.
2. Merkel PA, Niles J, Jimenez R, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis. ACR Open Rheumatol. 2020;2(11):662–671.
3. Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol. 2017 Sep;28(9):2756–2767.
4. U.S. Department of Health and Human Services. Food and Drug Administration. Demonstrative substantial evidence of effectiveness for human drug and biological products: Guidance for industry. 2019.
5. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017 Jul 27;377(4):317–328.
6. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221–232.
7. Warrington KJ. Avacopan—time to replace glucocorticoids? N Engl J Med. 2021 Feb 18;384(7):664–665.

////////////Avacopan, アバコパン , JAPAN 2021, APPROVALS 2021, CCX 168, авакопан , أفاكوبان , 阿伐可泮 , 

CC1=C(C(=CC=C1)F)C(=O)N2CCCC(C2C3=CC=C(C=C3)NC4CCCC4)C(=O)NC5=CC(=C(C=C5)C)C(F)(F)F

Image may be NSFW.
Clik here to view.

NEW DRUG APPROVALS

ONE TIME

$10.00

Click here to purchase.

Image may be NSFW.
Clik here to view.

LIDOCAINE

CAS Registry Number: 137-58-6 
CAS Name: 2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide 
Additional Names: 2-diethylamino-2¢,6¢-acetoxylidide; w-diethylamino-2,6-dimethylacetanilide; lignocaine 
Trademarks: Cuivasil (IDC); Lidoderm (Hind); LidoPosterine (Kade); Vagisil (Combe) 
Molecular Formula: C14H22N2O 
Molecular Weight: 234.34 
Percent Composition: C 71.75%, H 9.46%, N 11.95%, O 6.83% 
Literature References: Long-acting, membrane stabilizing agent against ventricular arrhythmia. Originally developed as a local anesthetic. Prepn: N. M. Löfgren, B. J. Lundqvist, US2441498 (1948 to Astra); A. D. H. Self, A. P. T. Easson, GB706409 (1954 to May & Baker); I. P. S. Hardie, E. S. Stern, GB758224 (1956 to J. F. Macfarlane & Co.); Zhuravlev, Nikolaev, Zh. Obshch. Khim.30, 1155 (1960). Toxicity studies: E. R. Smith, B. R. Duce, J. Pharmacol. Exp. Ther.179, 580 (1971); G. H. Kronberg et al.,J. Med. Chem.16, 739 (1973). Review of pharmacokinetics: N. L. Benowitz, W. Meister, Clin. Pharmacokinet.3, 177 (1978). Review of action as local anesthetic: Löfgren, Studies on Local Anesthetics: Xylocaine, A New Synthetic Drug (Hoeggstroms, Stockholm, 1948); Cooper, Pharm. J.171, 68 (1953). Reviews of anti-arrhythmic agents: J. L. Anderson et al.,Drugs15, 271 (1978); L. H. Opie, Lancet1, 861 (1980); E. Carmeliet, Ann. N.Y. Acad. Sci.427, 1 (1984). Comprehensive description: K. Groningsson et al.,Anal. Profiles Drug Subs.14, 207-243 (1985); M. F. Powell, ibid.15, 761-779 (1986). Review of use in treatment of postherpetic neuralgia: P. S. Davies, B. S. Galer, Drugs64, 937-947 (2004).Properties: Needles from benzene or alcohol, mp 68-69°. bp4 180-182°; bp2 159-160°. Insol in water. Sol in alcohol, ether, benzene, chloroform, oils. Partition coefficient (octanol/water, pH 7.4): 43. 
Melting point: mp 68-69° 
Boiling point: bp4 180-182°; bp2 159-160° 
Log P: Partition coefficient (octanol/water, pH 7.4): 43 
Derivative Type: Hydrochloride 
CAS Registry Number: 73-78-9; 6108-05-0 (monohydrate) 
Trademarks: Basicaina (Galenica); Batixim (So.Se.); Dynexan (Kreussler); Heweneural (Hevert); Licain (DeltaSelect); Lidesthesin (Ritsert); Lidofast (Angelini); Lidoject (Hexal); Lidrian (Baxter); Odontalg (Giovanardi); Sedagul (Wild); Xylocaine (AstraZeneca); Xylocard (AstraZeneca); Xylocitin (Jenapharm); Xyloneural (Strathmann) 
Molecular Formula: C14H22N2O.HCl 
Molecular Weight: 270.80 
Percent Composition: C 62.09%, H 8.56%, N 10.34%, O 5.91%, Cl 13.09% 
Properties: Crystals, mp 127-129°; monohydrate, mp 77-78°. Very sol in water, alcohol; sol in chloroform. Insol in ether. pH of 0.5% aq soln: 4.0-5.5. LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg). 
Melting point: mp 127-129°; mp 77-78° 
Toxicity data: LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg) 
Therap-Cat: Anesthetic (local); antiarrhythmic (class IB). 
Therap-Cat-Vet: Anesthetic (local). 
Keywords: Anesthetic (Local); Antiarrhythmic.

Image may be NSFW.
Clik here to view.

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

Image may be NSFW.
Clik here to view.

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

• Twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

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

CLIP

https://pubs.acs.org/doi/10.1021/ed076p1557

http://www.asianjournalofchemistry.co.in/User/ViewFreeArticle.aspx?ArticleID=19_7_12

PATENT

https://patents.google.com/patent/CN102070483B/en#:~:text=The%20method%20comprises%20the%20following,as%20solvent%20and%20carbonate%20isPreparation method of the present invention, it can be two-step approach, comprises the steps:1) 2,6-xylidine is dissolved in the acetone, adds carbonate then, the back that stirs drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be stirring reaction 3h down; After-filtration is finished in reaction, and after filter cake was washed with water to filtrate and is neutrality, drying made intermediate chloracetyl-2, the 6-xylidine, and yield is about about 94%; 
2) intermediate that step 1) is made is dissolved in the acetone, adds carbonate then, and the back that stirs drips diethylamine, back flow reaction 8h; After-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, in the step 1) 2, the mol ratio of 6-xylidine, chloroacetyl chloride and carbonate is 1: 1.2～1.7: 1.3～2.0, is preferably 1: 1.5: 1.6. 
Step 2) intermediate chloracetyl-2 in, the mol ratio of 6-xylidine, diethylamine and carbonate is 1: 1.5～2.5: 1.2～2.0, is preferably 1: 2: 1.5.In addition, preparation method of the present invention owing to all be that solvent, carbonate are catalyzer with acetone in the two-step reaction, therefore can further optimize reaction process on the basis of two-step approach, namely the intermediate of Sheng Chenging needn’t pass through aftertreatment, prepares lignocaine by one kettle way.Described one kettle way comprises the steps: 2,6-xylidine is dissolved in the acetone, adds carbonate then, after stirring, drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be reaction 3h down; After reaction is finished, without processing, directly drip diethylamine, back flow reaction 8h, after-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, described 2, the mol ratio of 6-xylidine, chloroacetyl chloride, diethylamine and carbonate is 1: 1.2～1.7: 1.5～2.5: 2.5～3.5, is preferably 1: 1.5: 2: 2.5. 
In addition, preparation method of the present invention adopts TLC monitoring reaction progress, and the developping agent of TLC is sherwood oil: ethyl acetate (V/V)=3: 1.The invention has the advantages that, the method synthesis technique for preparing lignocaine of the present invention is simple, do not need in the intermediate aftertreatment first pickling numerous and diverse step of alkali cleaning again, avoided unnecessary loss, therefore the yield of the intermediate that makes of the inventive method and lignocaine is all higher, and the lignocaine purity that makes is good, reaches more than 99%, has favorable industrial application prospect; In addition, the inventive method uses acetone to make solvent, and this solvent is nontoxic substantially non-stimulated, and can recycle, and is environmentally friendly. 
EmbodimentBelow further specify the present invention by specific embodiment, but be not used for limiting the scope of the invention. 
Embodiment 1 two-step approach prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 200g salt of wormwood again, and mechanical stirring evenly back drips 100mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 156g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 94%, fusing point is 145.0～147.0 ℃.2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 112g salt of wormwood, drips the 60g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 90g white powder, is lignocaine, yield is 95%, and fusing point is 67.0～68.0 ℃, and content is 99.05%. 
Embodiment 2 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 163g salt of wormwood again, and mechanical stirring evenly back drips 80mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 136g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 82%, fusing point is 145～146 ℃. 
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 90g salt of wormwood, drips the 45g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 84g white powder, is lignocaine, yield is 89%, and fusing point is 66～67 ℃, and content is 99.15%. 
Embodiment 3 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 250g salt of wormwood again, and mechanical stirring evenly back drips 113mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 150g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 90%, fusing point is 147～148 ℃. 
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 150g salt of wormwood, drips the 75g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 88g white powder, is lignocaine, yield is 93%, and fusing point is 68～69 ℃, and content is 98.75%. 
Embodiment 4 one kettle ways prepare lignocaineIn the 5000mL there-necked flask, add 305g 2, the 6-xylidine, make solvent with 2000mL acetone, add 700g salt of wormwood again, mechanical stirring evenly back slowly drips 230mL chloroacetyl chloride (1.5h drips off), room temperature (35 ℃) is stirring reaction 3h down, and TLC point plate (use sherwood oil: ethyl acetate (V/V)=3: 1 is made developping agent) demonstration reacts completely; Dropwise 5 50g diethylamine then, the back back flow reaction 8h that stirs, TLC monitoring (developping agent is the same) shows and reacts completely; The reaction solution suction filtration, filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, gets light yellow solid, uses sherwood oil recrystallization secondary then, makes 482g white lignocaine crystal, and total recovery is 82%, and fusing point is 68.0～69.0 ℃, and content is 99.75%. 
Comparative example 1 existing method prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineIn the 1000mL there-necked flask, with 102g 2, the 6-xylidine is dissolved in the 400mL glacial acetic acid, stirs slowly to add the 100mL chloroacetyl chloride down, is heated to 45 ℃, adds 200g solid sodium acetate (containing crystal water) then, reaction 2h; After reaction finished, ice bath was cooled to below 10 ℃, suction filtration, filter cake is washed with water to filtrate and is neutral, and drying is 1 hour under 100 ℃ of temperature, makes the 111g white powder, be intermediate chloracetyl-2,6-xylidine, yield are that 67% fusing point is 145.0～148.0 ℃. 
2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL toluene, and the dissolving back drips 60g diethylamine, back flow reaction 3.5h fast; After reaction finished, ice bath was cooled to 5 ℃, suction filtration, filtrate is used the 3mol/L hcl as extraction agent, and the acid solution that extraction is obtained is cooled to 10 ℃ then, stirs slowly to add 6mol/L KOH solution down, be alkalescence (pH8～9) to solution, with pentane extraction, organic layer was after washing, Anhydrous potassium carbonate drying after ice bath was cooled to 20 ℃, vapor bath is steamed and is desolventized, make the 74g white powder, be lignocaine, yield is 78%, fusing point is 66.0～67.0 ℃, and content is 97.15%.Embodiment 1 compares with comparative example 1, its intermediate chloracetyl-2, and the yield of 6-xylidine obviously improves, and reaches 94%, and the total recovery of final product lignocaine also is significantly improved, and the content of lignocaine is brought up to about 99%.Embodiment 4 compares with comparative example 1, and the total recovery of lignocaine is significantly improved, and reach 82%, and content is brought up to more than 99%. 
Though above with a general description of the specific embodiments, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention. 
CLIPhttps://www.cerritos.edu/chemistry/chem_212/Documents/Lab/10_lidocaine.pdf

Image may be NSFW.
Clik here to view.

Procedure: (1st week)A: Synthesis of 2,6-Dimethylaniline via Reduction of 2,6-Dimethylnitrobenzene 1. Dissolve1.0 g of 2,6-dimethylnitrobenzene in 10 mL of glacial acetic acid in a 50 mL Erlenmeyer flask. 2. In a 25 mL flask, dissolve 4.6 grams of SnCl2 · 2H2O in 8 mL of concentrated HCl, inside the fume hood. 3. Add the SnCl2 solution in one portion to the nitroxylene solution, magnetically swirl and mix, and let the mixture stand for 15 minutes. 4. Cool the mixture and collect the crystalline salt (dimethylaniline in the salt form: C6H5NH3 +Cl- ) in a Buchner funnel. 5. Transfer the moist crystals to an Erlenmeyer flask, add 5-10 mL of water, and make the solution strongly basic (to remove the acid and change C6H5NH3 +Clback intoC6H5NH2) by adding 30% KOH solution (12 to 17 mL required). 6. After cooling extract with three 10 mL portions of ether, rinse the ether extracts twice with 10 mL of water, and dry over K2CO3. 7. Evaporate the dried and filtered solution to an oil, transfer and rinse into a 50 mL Erlenmeyer flask, complete evaporation, weigh, and calculate the %yield of 2,6-dimethylaniline. 
B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield. 
B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield. 
D. Synthesis of the bisulfate salt of lidocaine 1. Dissolve the lidocaine in ether (10 mL per gram of lidocaine) and add 2 mL of 2.2 M sulfuric acid in ethanol per gram of lidocaine. 2. Stir and scratch with a glass rod to mix and induce crystallization. 3. Dilute the mixture with an equal volume of acetone to aid filtration and collect the salt in a small Buchner funnel. 4. Rinse the solid on the funnel with a few milliliters of acetone and air dry and weigh the product. 5. Calculate the % yield of this step. *** Overall % Yield The overall % YCLIPhttp://home.sandiego.edu/~khuong/chem302L/Handouts/Lidocaine_handout_Su07.pdfSynthetic Strategy Lidocaine will be prepared via a three-step linear synthesis starting from 2,6-dimethylnitrobenzene. The reduction of 2,6-dimethylnitrobenzene 1 with three equivalents of stannous chloride (SnCl2) yields the ammonium salt 2. It is very important that the reaction mixture is strongly acidic during this reaction because the reduction of nitrobenzene using different reducing reagents and conditions can afford a variety of functional groups: nitroso, hydroxylamine (zinc dust, pH 4), azoxy (sodium arsenite), azo (zinc, weakly basic), or hydrazo (zinc, strongly basic). In industrial settings, often iron or tin with hydrochloric acid is used instead of stannous chloride because iron and tin are cheaper, but the reduction takes much longer. In the workup portion of the reaction, the ammonium salt 2 is reacted with an aqueous potassium hydroxide solution, liberating the free 2,6-dimethylaniline 3 in an acid-base reaction.

Image may be NSFW.
Clik here to view.

The reaction of 3 with the bifunctional α-chloroacetyl chloride leads to α-chloro-2,6-dimethylacetanilide 4. A slight excess of the acid chloride is used to ensure the complete conversion of the amine to the amide. The formation of the amide is a result of the significantly higher reactivity (~106 times) of the acyl chloride over the alkyl chloride. The addition of sodium acetate solution avoids the formation of HCl which would protonate unreacted 3 causing it to co-precipitate with the desired product 4.

Image may be NSFW.
Clik here to view.

In the last step, diethylamine performs a nucleophilic substitution (SN2) on the remaining alkyl chloride. Diethylamine serves both as a nucleophile to form lidocaine 5, and as acid scavenger, leading to formation of NH2Et2 + Cl- in this reaction. Since diethylamine is not a very strong nucleophile, it is used in excess here to improve the yield and speed up the reaction. The unreacted amine is later removed by extraction with water. The aqueous extraction of lidocaine with acid separates the unreacted chloroanilide 4 and the lidocaine. After addition of a strong base like aqueous potassium hydroxide, crude lidocaine is obtained.

Image may be NSFW.
Clik here to view.

Procedure Synthesis of 2,6-dimethylaniline (3) Dissolve 15 g of SnCl2•2H2O in 27 mL of concentrated hydrochloric acid. If necessary, heat the mixture gently. Add this solution in one portion to a solution of 3 mL of 2,6-dimethylnitrobenzene in 34 mL of glacial acetic acid. Swirl the resulting mixture and then allow it to stand for 15 minutes before placing the mixture in an ice bath. Collect the formed precipitate by vacuum filtration. Place the wet precipitate obtained above in a beaker and add 20 mL of water. Neutralize the acidic mixture by carefully adding an 8 M aqueous potassium hydroxide with continuous stirring until basic to litmus. Place the mixture in an ice bath. Upon cooling to room temperature, extract the mixture three times with diethyl ether. Combine the organic layers and wash them twice with water and once with brine. Dry the organic layer over anhydrous potassium carbonate. Decant away from the drying agent and evaporate the diethyl ether from a dry, preweighed flask using a rotary evaporator. The oily residue will be your crude product 3. Obtain and record the following information: 1. crude product description (co2. crude weight/percent yieldSynthesis of α-chloro-2,6-dimethylacetanilide (4) Dissolve 3 in 17 mL of glacial acetic acid. Add 1.1 equivalents (based on the moles of 3) of α-chloroacetyl chloride to this solution. Heat the solution to 40-50 o C for ten minutes to complete the reaction. Upon cooling, add a solution of ~3.3 g sodium acetate trihydrate in 67 mL water and then place the resulting mixture in an ice bath. Collect the precipitate by vacuum filtration. Rinse the filter cake with copious amounts of water in order to remove the acetic acid. It is important that the product be completely free of acetic acid after this step (why?). The pH of the individual water rinses can be checked with litmus paper to determine if the product is acid free. Allow for the product to air-dry on a watch glass until the next meeting. There is a reasonable chance that you will not obtain a precipitate as described above. If this is the case, you can try “seeding” using a small sample of authentic product from a classmate. If this does not work, check the TLC to be sure that you have formed product and devise an extractive workup that will separate the unreacted aniline 3 from the desired product 4. (Make sure you understand how to do this even if you obtain a precipitate in the first place). After the aqueous workup and following removal of solvent, you should obtain a solid. If not, check the TLC, using a sample of authentic product from a classmate as a standard. If the product appears relatively pure, you can continue even though the material is not a solid. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. mp (if a solid) 
4. TLC analysis 5. IR (check for presence of amide functional group) Synthesis of lidocaine; α-(N,N-diethylamino)-2,6-dimethylacetanilide (5). In a round bottom flask, dissolve α-chloro-2,6-dimethylacetanilide 4 in 17 mL of toluene. Before continuing, spot several (4 to 5) TLC plates in advance with this solution of 4. Provide three lanes and spot the 4 on the “SM” and “CO-SPOT” lanes. You will use these plates to monitor the progress of this reaction. Add three equivalents of diethylamine to the round bottom flask, and reflux the mixture vigorously until the reaction is complete. The amount of time required for complete reaction depends on many factors but it will likely take anywhere from more than a few minutes up to several hours. If the reaction is not complete when your lab period ends, you can stopper the reaction and reflux it for additional time at the next period. Usually a white precipitate forms during the reflux. Upon cooling, transfer the reaction mixture to a separatory funnel and extract the mixture three times with water. Next, extract the organic layer with two portions of 3 M hydrochloric acid. Cool the combined acidic aqueous extracts in an ice bath and then add 8 M aqueous potassium hydroxide slowly until the mixture is strongly basic again. The formation of a thin, dark yellow oily layer on top or a white solid is observed at this point. Place the mixture in an ice bath. Once the mixture is chilled, try to initiate the crystallization of the final product if no solid has formed at this point. Collect the obtained precipitate by filtration using a Büchner funnel. Wash it with twice with water and then press it as dry as possible. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. TLC analysis Recrystallize the crude product from hexanes. Regardless of the final physical state of your product (solid or oil), obtain and record the following: 1. pure product description (color, physical state, etc.) 2. pure product weight/percent yield 3. overall (three-step) percent yield (from starting material 1) 4. TLC analysis 5. melting point (if a solid) 6. IR 7. 1 H and 13C NMR spectra of lidocaine will be given to you. Turn in a sample of your final product. 

¹H NMR

Image may be NSFW.
Clik here to view.

13C NMR

Image may be NSFW.
Clik here to view.

MS

Image may be NSFW.
Clik here to view.

IR KBR

Image may be NSFW.
Clik here to view.

Image may be NSFW.
Clik here to view.

Lidocaine is an antiarrhythmic medicine and also serves as a local anaesthetic drug. It is utilized in topical application to relieve pain, burning and itching sensation caused from skin inflammations. This drug is mainly used for minor surgeries. Figure 1 shows the ¹H NMR spectrum of 200 mM lidocaine in CDCl₃.

Image may be NSFW.
Clik here to view.

Figure 1. Proton NMR spectrum of 200 mM lidocaine in CDCl₃.

¹H NMR Relaxation

Figures 2, 3 and 4 show the relaxation time measurements. It can be seen that the relaxation times are shortest for the CH₂ protons and longest for the CH protons. The first data point amplitude increases with the number of protons for the related peak.

Image may be NSFW.
Clik here to view.

Figure 2. Proton T₁ relaxation time measurement of 200 mM lidocaine in CDCl₃.

Image may be NSFW.
Clik here to view.

Figure 3. Proton T₂ relaxation time measurement of 200 mM lidocaine in CDCl₃.

Image may be NSFW.
Clik here to view.

Figure 4. COSY spectrum of 200 mM lidocaine in CDCl₃. The cross-peaks and corresponding exchanging protons are labeled by colour-coded arrows and ellipses.

2D COSY

Figure 4 shows the 2D COSY spectrum where two spin systems (6,7,8) to (10,11) can be clearly seen. For instance, the methyl groups at 10 and 11 positions bond to aromatic protons at 6 and 8 positions, while the methyl groups at 16 and 17 positions bond to the ethylene groups at 14 and 15 positions. No coupling occurs at positions (6,7,8) to (16,17) or (14,15).

2D Homonuclear J-Resolved Spectroscopy

The chemical shift in the 2D homonuclear j-resolved spectrum appears along the direct (f₂) direction and the effects of coupling between protons appear along the indirect (f₁) dimension. This enables the assignment of chemical shifts of multiplets and may help in measuring unresolved couplings. Also, a decoupled 1D proton spectrum is produced by the projection along the f1 dimension. The 2D homonuclear j-resolved spectrum of lidocaine, plus the 1D proton spectrum (blue line) are shown in Figure 5.

Image may be NSFW.
Clik here to view.

Figure 5. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl₃. The multiplet splitting frequencies for different couplings are colour- coded.

The projection which is vertical reveals how the multiplets disintegrate into a single peak, which makes the 1D spectrum more simplified. Peak multiplicities are produced by vertical traces from peaks in the 2D spectrum and help in determining the frequencies of proton-proton coupling. When coupling frequencies are compared between different peaks, information can be obtained regarding which peaks are bonded to each other. Also, Information regarding the coupling strength can be obtained from the size of the coupling frequencies. These couplings substantiate the results of the COSY experiment.

However, in this experiment, the effects of second order coupling appear in the f1 direction as additional peaks which are equidistant from the coupling partners detached from the zero frequency in the f1 dimension. These peaks provide proof of second order coupling partners, but are generally considered as artifacts. Figure 6 shows these coupling partners and additional peaks marked by colour-coded arrows and ellipses.

Image may be NSFW.
Clik here to view.

Figure 6. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl₃ showing the extra peaks due to strong couplings.

1D ¹³C Spectra

Figure 7 shows the ¹³C NMR spectra of 1 M lidocaine in CDCl₃. Since the 1D Carbon experiment is highly susceptible to the ¹³C nuclei in the specimen, it easily and clearly resolves 9 resonances. In this experiment, only carbons coupled to protons are seen.

Image may be NSFW.
Clik here to view.

Figure 7. Carbon spectra of 1 M lidocaine in CDCl₃.

Given the fact that the DEPT spectra do not display the peaks at 170 and 135ppm, they must be part of quaternary carbons. The DEPT-135 and the DEPT-45 experiments provide signals of CH_3, CH₂ and CH groups, while the DEPT-90 experiment provides only the signal of CH groups. However, in DEPT-135 the CH₂ groups occur as negative peaks. It can thus be summed up that the peaks between 45 and 60ppm belong to ethylene groups; the peaks between 10 and 20ppm are part of the methyl groups; and the peaks between 125 and 130ppm belong to methyne groups. A similar study can be carried out on the C and CH peaks.

Heteronuclear Correlation

The Heteronuclear Correlation (HETCOR) experiment identifies the proton signal that appears along the indirect dimension and the carbon signal along the direct dimension. Figure 8 shows the HETCOR spectrum of 1 M lidocaine in CDCl₃. in the 2D spectrum, the peaks reveal which proton is attached to which carbon. This experiment helps in resolving assignment uncertainty from the ID carbon spectra.

Image may be NSFW.
Clik here to view.

Figure 8. HETCOR spectrum of 1 M lidocaine in CDCl₃.

Heteronuclear Multiple Quantum Coherence

Heteronuclear Multiple Quantum Coherence (HMQC) is similar to the HETCOR experiment and is utilized to associate proton resonances to the carbons that are coupled directly to those protons. But in the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 9 shows the HMQC spectrum of 1 M lidocaine in CDCl₃. In the 2D spectrum, the peaks show which proton is attached to which carbon. For conclusive peak assignment, a similar study with the HETCOR spectrum can be carried out.

Image may be NSFW.
Clik here to view.

Figure 9. HMQC spectrum of 1 M lidocaine in CDCl₃.

Heteronuclear Multiple Bond Correlation

The Heteronuclear Multiple Bond Correlation (HMBC) experiment can be employed to achieve long-range correlations of proton and carbon via two or three bond couplings. Similar to the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 10 shows the HMBC spectrum of 1 M lidocaine in CDCl₃.

Image may be NSFW.
Clik here to view.

Figure 10. HMBC spectrum of 1 M lidocaine in CDCl₃, with some of the long-range couplings marked.

The couplings amid the molecular positions appear analogous to the couplings seen in the COSY spectrum; however, the HMBC also displays couplings to quaternary carbons, which are not seen either in HMQC or COSY experiments. In addition, there is a correlation between protons and carbons. This is attributed to three-bond bonding from 14 and 15 and vice versa, as shown in light green in Figure 1.

SYN

Synthesis of lidocaine T. J. Reilly (1999). “The Preparation of Lidocaine”. J. Chem. Ed. 76 (11): 1557.