Sanofi and Regeneron have announced that the US Food and Drug Administration (FDA) has approved Praluent® (alirocumab) Injection.
Image may be NSFW. Clik here to view.
Praluent is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low-density lipoprotein (LDL) cholesterol. The effect of Praluent on cardiovascular morbidity and mortality has not been determined.
A Warning Letter issued by the US Food & Drug Administration (FDA) to an Indian API manufacturer on 13 July 2015 shows again a clear focus on the missing integrity of data. Specifically, the following issues are addressed:
1. Activities were not recorded at the time they were carried out and original data were deleted:
Entries in the manufacturing protocols were made only days after the relevant activities had been conducted. Further, batches were released before all results were available.
In particular the use of “rough notes” was criticised as these original data were completely destroyed after transfer in the batch records.
2. Due to unauthorised access to data systems, data could be modified or deleted:
Specifically HPLC, GC, and Karl Fischer Titrators were concerned. For instance, for the GC instrument multiple copies of raw data were found in the waste. And there was no password regulation for the data systems…
Drug major Sandoz will discontinue operations at its Turbhe site (Maharashtra) by end December 2016, as part of global plans to optimise its manufacturing network.
Image may be NSFW. Clik here to view.
The Turbhe sites employs 170 people and manufactures antibiotics and active pharmaceutical ingredients (API), a note from the company said. Sandoz is the generic drugs arm of pharmaceutical company Novartis.
“Sandoz will refocus its manufacturing set up in India as part of its strategy to optimise its global manufacturing network, while continuing to serve patients in India,” the company said. As part of the plan, Sandoz will focus its manufacturing at other sites which employ over 1,300 employees and produce over three billion tablets and 180 tonnes of API annually, it added. The company has two manufacturing facilities at Kalwe and Mahad.
“We made the announcement today to ensure our associates are informed as soon as possible about our decisions and to ensure a transparent process,” Vivek Devaraj, Sandoz Country Head in India, said in the statement. “We are committed to managing the process with care, sensitivity and respect for all impacted associates at Turbhe, to supporting our customers through the transition and to meeting patient needs for access to important medicines,” he added.
In 2012, the company had shut down its formulations and API development centres, respectively. Drug companies have in the past shut down plants in India as a fallout of global strategies, mergers and acquisitions. At present, Pfizer’s plant in Thane faces an uncertain future.
Image may be NSFW. Clik here to view.
……………………
ABOUT PFIZER
Image may be NSFW. Clik here to view.There has been practically no production at Pfizer’s Thane plant (pic above) since 2013.
Image may be NSFW. Clik here to view.
Sandoz India’s Turbhe plant to down shutters by December 2016
Less than a week after Sandoz, the generic division of Novartis, announced that it would discontinue operations at its Turbhe site by end December 2016, another MNC, Pfizer India announced the closure of its manufacturing facility at Thane, two months from today, from September 16, 2015.
According to Pfizer India spokesperson, the Thane plant was commissioned in the 1960s, manufacturing medicines for both domestic and international markets but there has been ‘practically been no production activity at this plant since 2013′. Hence closure of the site would not impact supply of Pfizer India’s medicines.
Both plant closures are a consolidation of manufacturing facilities, with the shutting down of older facilities and re-direction to more modern facilities, with Pfizer India’s statement attributing the decision to ‘an assessment of its long term viability and its ability to achieve the needed production.’
132 of the 212 Pfizer India workmen at the Thane plant had already taken up the voluntary retirement scheme (VRS) offered by the company and the statement indicated that the remaining 80 workmen who continued to receive full wages despite plant inactivity, would also receive requisite compensation as mandated by law.
While the close down process is in the final stages at Pfizer India’s Thane facility, Sandoz’ July 10 announcement is the beginning of the process at its Turbhe plant, which employs 170 associates and manufactures antibiotics and APIs.
“We made the announcement (on July 10) to ensure our associates are informed as soon as possible about our decisions and to ensure a transparent process,” said Vivek Devaraj, Sandoz Country Head in India. He said the company was “committed to managing the process with the utmost care, sensitivity and respect for all impacted associates at Turbhe, to supporting our customers through the transition and to meeting patient needs for access to important medicines.” Manufacturing would now focus at its other sites which employ over 1,300 associates and produce over three billion tablets and 180 tonnes of API annually.”
/////////Sandoz, shutter, Indian API facility, Pfizer
Vincaleukoblastin-23-oic acid, O4-deacetyl-, 2-[(2-mercaptoethoxy)carbonyl]hydrazide, disulfide with N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-γ-glutamyl-L-α-aspartyl-L-arginyl-L-α-aspartyl-L-α-aspartyl-L-cysteine
Endocyte innovator
Vintafolide is an investigational targeted cancer therapeutic currently under development by Endocyte and Merck & Co.[1] It is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor, which is overexpressed on certain cancers, such as ovarian cancer, and a potent chemotherapy drug, vinblastine.[2] It is being developed with a companion imaging agent, etarfolatide, that identifies patients that express the folate receptor and thus would likely respond to the treatment with vintafolide.[3] A Phase 3 study evaluating vintafolide for the treatment of platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study(TARGET trial) in non-small-cell lung carcinoma (NSCLC) are ongoing.[4] Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.[5]
A Marketing Authorization Application (MAA) filing for vintafolide and etarfolatide for the treatment of patients withfolate receptor-positive platinum-resistant ovarian cancer in combination with doxorubicin, pegylated liposomal doxorubicin (PLD), has been accepted by the European Medicines Agency.[6] The drug received an orphan drug status in Europe in March 2012.[1]Merck & Co. acquired the development and marketing rights to this experimental cancer drug from Endocyte in April 2012.[1] The drug received orphan drug status in Europe in March 2012.[3]Endocyte remains responsible for the development and commercialization of etarfolatide, a non-invasive companion imaging agent used to identify patients expressing the folate receptor that will likely respond to treatment with vintafolide.[4] Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.[5]
In 2014 Merck and Endocyte stopped a late-stage study of vintafolide in treating ovarian cancer on the recommendation of a data safety monitoring board, saying that the drug failed to improve progression-free survival.[7]
Vintafolide is folate-conjugated with DAVBLH, which is a derivative of the vinca alkaloid vinblastine.Vinblastine is a microtubule-destabilizing agent that binds tubulin and causes M phase-specific cell cycle arrest and apoptosis of mitotically active cells. Vinblastine is an extremely potent chemotherapeutic agent but has significant toxicities including bone marrow suppression, neurotoxicity, gastrointestinal toxicity and vesicant injury.
Endocyte’s desacetylvinblastinehydrazide/folate conjugate (EC-145) is a folate-targeted cytotoxic anticancer drug in early development for the treatment of non-small cell lung cancer (NSCLC) and breast cancer. The compound had been pre-registered in the E.U. by Merck for the treatment of ovarian cancer, but the application was withdrawn due to lack of efficacy.
In 2012, the product was licensed to Merck & Co. by Endocyte for worldwide exclusive development and commercialization. In 2014, however, this license agreement was terminated and Endocyte regained all rights.
Folates can serve as one-carbon donors in reactions that are critical in the de novo biosynthesis of purines and thymidylate, amino acid metabolism and methylation reactions. Folate can enter a cell by two routes: RFC or by membrane-bound FRs. RFC is a bidirectional anion transporter that is the normal entry method for reduced folates in most cells. By contrast, FRs are expressed in a limited distribution in normal tissues but are overexpressed in multiple cancers including ovarian, lung, breast and colorectal cancer. FRs bind folate derivatives with high affinity and mediate their internalization by endocytosis. Given that FRs are not typically expressed on the luminal surface of epithelial cells, making them inaccessible to normal circulation, they are attractive therapeutic targets with limited toxicity. In addition to the therapeutic agent vintafolide, a radiodiagnostic agent (99mTc-etarfolatide [EC20]) has been developed to allow single-photon emission computed tomography (SPECT) imaging to identify FR-expressing tissues (tumors).
In 2012, orphan drug designations were assigned in the E.U. for the treatment of ovarian cancer and to be used with folic acid for the diagnosis of positive folate-receptor status in ovarian cancer. In 2013, orphan drug designation was assigned in the U.S. for the treatment of ovarian cancer.
Vintafolide is a water-soluble derivative of folic acid and the vinca alkaloid DAVLBH. The molecules are connected through a hydrophilic L-peptide spacer and a disulfide linker (Figure 1). The disulfide linker serves as a cleavable bond that is necessary for drug release following receptor mediated endocytosis. The disulfide bond is reduced in the acidic environment of the endosome, leading to efficient release of vinblastine.
Structure of vintafolide and mechanism of release of the payload in the endosome.
Image may be NSFW. Clik here to view.
Mechanism of action
Folate is required for cell division, and rapidly dividing cancer cells often express folate receptors in order to capture enough folate to support rapid cell growth. Elevated expression of the folate receptor occurs in many diseases, including other aggressively growing cancers and inflammatory disorders.[8] Vintafolide binds to the folate receptor and is subsequently taken up by the cell through a natural internalization process called endocytosis. Once inside the cell, vintafolide’s linker releases the chemotherapy drug which kills the cell.[3]
An efficient synthesis of the folate receptor (FR) targeting conjugate EC145 is described. EC145 is a water soluble derivative of the vitamin folic acid and the potent cytotoxic agent, desacetylvinblastine monohydrazide. Both molecules are connected in regioselective manner via a hydrophilic peptide spacer and a reductively labile disulfide linker.
Image may be NSFW. Clik here to view.
………approach for the design and regioselective synthesis of a FA-vinca alkaloid conjugate 1 (EC145,BELOW). As indicated in the retrosynthetic scheme, 1 can be assembled by tethering a FA-Spacer unit 2 to the highly potent cytotoxic molecule, desacetylvinblastine monohydrazide 3, via a linker containing a reducible disulfide bond. The latter is important for drug delivery applications since real-time imaging using a fluorescence resonance energy transfer technique has recently demonstrated that reduction-mediated release of the drug cargo from a disulfide linked FA-conjugate efficiently occurs within the endosomes of cancer cells.
The compounds of Examples 16a and 16b were prepared from the peptidyl fragment Pte-Glu-Asp-Arg-Asp-Asp-Cys-OH , prepared according to the general procedure described in Scheme 12. The Michael addition of this peptidyl fragment to the maleimido derivative of seco-CBI-bis-indole resulted in the folate conjugates Example 16a. The peptidyl fragment also reacted with either the thiosulfonate or pyridyldithio-activated vinblastine to form Example 16b. The maleimido derivative of seco-CBI-bis-indole, and the thiosulfonate and pyridyldithio- activated vinblastine intermediates were prepared using the procedures described herein for other examples.
Folate-targeted drugs have been developed and are being tested in clinical trials as cancer therapeutics. EC145, also known as vintafolide, comprises a highly potent vinca alkaloid cytotoxic compound, desacetylvinblastine hydrazide (DAVLBH), conjugated to folate. The EC 145 molecule targets the folate receptor found at high levels on the surface of epithelial tumors, including non-small cell lung carcinomas (NSCLC), ovarian, endometrial and renal cancers, and others, including fallopian tube and primary peritoneal carcinomas. It is believed that EC 145 binds to tumors that express the folate receptor delivering the vinca moiety directly to cancer cells while avoiding normal tissue. Thus, upon binding, EC 145 enters the cancer cell via endocytosis, releases DAVLBH and causes cell death or inhibits cell function. EC 145 has the following formula
and has been accorded the Chemical Abstracts Registry Number 742092-03-1. As used herein, according to the context, the term EC 145 means the compound, or a pharmaceutically acceptable salt thereof; and the compound may be present in a solid, solution or suspension in an ionized form, including a protonated form. EC145 is disclosed in U.S. Patent No. 7,601,332; and particular uses and an aqueous liquid pH 7.4, phosphate-buffered formulation for intravenous administration are disclosed in WO 2011/014821. As described in WO 2011/014821, it is necessary to store the aqueous liquid formulation in the frozen state to ensure its stability. To avoid this necessity, a formulation is needed which has adequate stability at ambient temperature.
As one aspect of the invention described herein, there is provided a pharmaceutical composition of EC145 which is a lyophilized solid which has adequate stability for storage at ambient temperature and which is capable of redissolving in an aqueous diluent prior to administration.
In another aspect of the invention, there is provided a pharmaceutical composition of EC 145 which is an X-ray amorphous solid which has adequate stability for storage at ambient temperature and which is capable of redissolving in an aqueous diluent prior to administration.
N-(4-{[(2-Amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-γ-glutamyl-L-α-aspartyl-L-arginyl-L-α-aspartyl-L-α-aspartyl-L-cysteine disulfide with methyl (5S,7R,9S)-5-ethyl-9-[(3aR,4R,5S,5aR,10bR,13aR)-3a-ethyl-4,5-dihydroxy-8-methoxy-6-methyl-5-({2-[(2-sulfanylethoxy)carbonyl]hydrazinyl}carbonyl)-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-5-hydroxy-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indol-9-carboxylate
Dosio, F.; Milla, P.; Cattel, L. (2010). “EC-145, a folate-targeted Vinca alkaloid conjugate for the potential treatment of folate receptor-expressing cancers”. Current opinion in investigational drugs (London, England : 2000)11 (12): 1424–1433. PMID21154124.edit
“Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay” 338 (2). March 2005. pp. 284–93. doi:10.1016/j.ab.2004.12.026.PMID15745749.
The U.S. Food and Drug Administration today approved Repatha (evolocumab) injection for some patients who are unable to get their low-density lipoprotein (LDL) cholesterol under control with current treatment options.
August 27, 2015
Release
The U.S. Food and Drug Administration today approved Repatha (evolocumab) injection for some patients who are unable to get their low-density lipoprotein (LDL) cholesterol under control with current treatment options.
Repatha, the second drug approved in a new class of drugs known as PCSK9 inhibitors, is approved for use in addition to diet and maximally-tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, such as heart attacks or strokes, who require additional lowering of LDL cholesterol.
Familial hypercholesterolemia (encompassing both HeFH and HoFH) is an inherited condition that causes high levels of LDL cholesterol. A high level of LDL cholesterol in the blood is linked to cardiovascular or heart disease. Heart disease is the number one cause of death for Americans, both men and women. According to the Centers for Disease Control and Prevention, about 610,000 people die of heart disease in the United States every year– that equals one in every four deaths.
“Repatha provides another treatment option in this new class of drugs for patients with familial hypercholesterolemia or with known cardiovascular disease who have not been able to lower their LDL cholesterol enough with statins,” said John Jenkins, M.D., director of the Office of New Drugs, Center for Drug Evaluation and Research. “Cardiovascular disease is a serious threat to the health of Americans, and the FDA is committed to facilitating the development and approval of effective and safe drugs to address this important public health problem.”
Repatha is an antibody that targets a specific protein, called PCSK9. PCSK9 reduces the number of receptors on the liver that remove LDL cholesterol from the blood. By blocking PCSK9’s ability to work, more receptors are available to get rid of LDL cholesterol from the blood and, as a result, lower LDL cholesterol levels.
The efficacy and safety of Repatha were evaluated in one 52-week placebo-controlled trial and eight 12-week placebo-controlled trials in participants with primary hyperlipidemia, including two that specifically enrolled participants with HeFH and one that enrolled participants with HoFH. In one of the 12-week studies, 329 participants with HeFH, who required additional lowering of LDL cholesterol despite statins with or without other lipid-lowering therapies, were randomized to receive Repatha or placebo for 12 weeks. Participants taking Repatha had an average reduction in LDL cholesterol of approximately 60 percent, compared to placebo.
The most common side effects of Repatha include nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising where the injection is given. Allergic reactions, such as rash and hives, have been reported with the use of Repatha. Patients should stop using Repatha and get medical help if they experience symptoms of a serious allergic reaction.
Multiple clinical trials have demonstrated that statins lower the risk of having a heart attack or stroke. A trial evaluating the effect of adding Repatha to statins for reducing cardiovascular risk is ongoing.
Repatha is marketed by Amgen Inc., of Thousand Oaks, Calif.
Developer Amgen; KAI Pharmaceuticals; Ono Pharmaceutical
ClassDisulfides; Peptides
Mechanism of ActionCalcium-sensing receptor agonists
New Parathyroid Disease Drug Seeks FDA Approval
Amgen is seeking FDA approval for etelcalcetide (AMG 461), the first calcimimetic agent administered intravenously after dialysis to treat secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD).
The term “AMG 416” refers to the compound having the chemical name: JV-acetyl-D- cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with L- cysteine, which may be represented as:
H-L-Cys-OH
S— S
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2
The terms “AMG 416 hydrochloride” or “AMG 416 HQ” are interchangeable and refer to the compound having the chemical name: N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl- D-arginyl-D-alanyl-D-arginamide disulfide with L-cysteine hydrochloride, which may be represented as:
D-Argininamide, N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-, disulfide with L-cysteine, hydrochloride (1:?)
N-Acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide disulfide with L-cysteine hydrochloride
Amgen today announced the submission of a New Drug Application (NDA) with the United States Food and Drug Administration (FDA) for etelcalcetide (formerly AMG 416) for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) on hemodialysis. If approved, etelcalcetide will be the first calcimimetic agent that can be administered intravenously at the end of the dialysis session.
“Secondary hyperparathyroidism is a serious, progressive disease that can lead to significant clinical consequences and is also associated with a high pill burden for patients,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “We look forward to working with regulatory authorities during the review process to bring this important treatment to market, helping to fill an unmet need for the many patients impacted by this disease.”
Etelcalcetide is a novel calcimimetic agent that suppresses the secretion of parathyroid hormone and is in clinical development for the treatment of SHPT in patients with CKD on hemodialysis. Etelcalcetide is administered intravenously three times per week at the end of each dialysis session. It acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in parathyroid hormone (PTH). Sustained elevations in PTH are known to be associated with significant clinical consequences for patients with CKD.
The submission includes data from three Phase 3 studies, all of which met the primary endpoints, including two pooled placebo-controlled trials in more than 1,000 patients and a head-to-head study evaluating etelcalcetide compared with cinacalcet.
About Secondary Hyperparathyroidism SHPT is a common and serious condition that is often progressive among patients with CKD, and it affects many of the approximately two million people throughout the world who are receiving dialysis, including 450,000 people in the U.S. The disorder develops early in the course of CKD and usually manifests as increased levels of PTH as a result of increased production from the parathyroid glands (four small glands in the neck). Patients with end stage renal disease who require maintenance dialysis often have substantial elevations of PTH that are commonly associated with abnormal calcium and phosphorus levels and an increased risk of significant clinical consequences.
About Etelcalcetide (AMG 416) Etelcalcetide is a novel calcimimetic agent in clinical development for the treatment of SHPT in CKD patients on hemodialysis that is administered intravenously at the end of the dialysis session. Etelcalcetide binds to and activates the calcium-sensing receptor on the parathyroid gland, thereby decreasing PTH levels.
About Sensipar® (cinacalcet) Sensipar® (cinacalcet) is the first oral calcimimetic agent approved by the FDA for the treatment of SHPT in adult patients with CKD on dialysis. Sensipar is not indicated for use in adult patients with CKD who are not on dialysis because of an increased risk of hypocalcemia. The therapy is also approved in the U.S. for treatment of hypercalcemia in adult patients with parathyroid carcinoma and hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. Sensipar binds to the calcium-sensing receptor, resulting in a drop in PTH levels by inhibiting PTH synthesis and secretion. In addition, the reductions in PTH lower serum calcium and phosphorus levels.
A variety of compounds having activity for lowering parathyroid hormone levels have been described. See International Publication No. WO 2011/014707. In one embodiment, the compound may be represented as follows:
H-L-Cys-OH
S— S
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH2
The main chain has 7 amino acids, all in the D-configuration and the side-chain cysteine residue is in the L-configuration. The amino terminal is acetylated and the carboxyl-terminal is amidated. This compound (“AMG-416”) has utility for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients. A liquid formulation comprising AMG-416 may be administered to a subject intravenously. The hydrochloride salt of AMG-416 may be represented as follows:
Therapeutic peptides pose a number of challenges with respect to their formulation. Peptides in general, and particularly those that contain a disulfide bond, typically have only moderate or poor stability in aqueous solution. Peptides are prone to amide bond hydrolysis at both high and low pH. Disulfide bonds can be unstable even under quite mild conditions (close to neutral pH). In addition, disulfide containing peptides that are not cyclic are particularly prone to dimer formation. Accordingly, therapeutic peptides are often provided in lyophilized form, as a dry powder or cake, for later reconstitution. A lyophilized formulation of a therapeutic peptide has the advantage of providing stability for long periods of time, but is less convenient to use as it requires the addition of one or more diluents and there is the potential risk for errors due to the use of an improper type or amount of diluent, as well as risk of contamination. In addition, the lyophilization process is time consuming and costly.
Accordingly, there is a need for an aqueous liquid formulation comprising a peptide agonist of the calcium sensing receptor, such as AMG 416. It would be desirable for the liquid formulation to remain stable over a relevant period of time under suitable storage conditions and to be suitable for administration by intravenous or other parenteral routes.
…………………………………
Milestones
25 Aug 2015Preregistration for Secondary hyperparathyroidism in USA (IV)
29 May 2015Pooled analysis efficacy and adverse events data from two phase III trials in secondary hyperparathyroidism released by Amgen
21 Apr 2015Amgen plans to submit Biological License Application to USFDA and Marketing Authorisation Application to EMA for Secondary hyperparathyroidism
KAI-4169, a novel calcium sensing receptor agonist, decreases serum iPTH, FGF-23 and improves serum bone markers in a phase 2 study in hemodialysis subjects with chronic kidney disease-mineral and bone disorder
49th Congr Eur Renal Assoc – Eur Dialysis Transpl Assoc (May 24-27, Paris) 2012, Abst SAO054
KAI-4169, a novel peptide agonist of the calcium sensing receptor, attenuates PTH and soft tissue calcification and restores parathyroid gland VDR levels in uremic rats
49th Congr Eur Renal Assoc – Eur Dialysis Transpl Assoc (May 24-27, Paris) 2012, Abst SAO014
Long term safety and efficacy of velcalcetide (AMG 416), a calcium-sensing receptor (CaSR) agonist, for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients
Kidney Week (November 5-10, Atlanta, GA) 2013, Abst SA-PO575
Preclinical PK and PD relationship for KAI-4169, a novel calcimimetic
93rd Annu Meet Endo Soc (June 4-7, Boston) 2011, Abst P1-198
KAI-4169, a novel calcimimetic for the treatment of secondary hyperparathyroidism
93rd Annu Meet Endo Soc (June 4-7, Boston) 2011, Abst P2-98
Characterization of KAI-4169, a novel peptide for the treatment of chronic kidney disease – Mineral and bone disorder, in a phase I study in healthy males
44th Annu Meet Am Soc Nephrol (ASN) (November 8-13, Philadelphia) 2011, Abst FR-PO1238
Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, to treat patients with cancer.
The filing of patents claiming new crystalline forms, usually 4−6 years after the original product patent, is a typical strategy applied by such companies to extend patent protection. This patent protection approach by big pharma forces generic bulk producers to discover and file patents on new polymorphs if they want to market the drug after expiry of the product patents.
Polymorphism is of paramount importance due to its effect on some physical characteristics of powders such as melting point, flowability, vapour pressure, bulk density, chemical reactivity, apparent solubility and dissolution rate, and optical and electrical properties. In other words, polymorphism can affect drug stability, manipulation, and bioavailability
the principal aim of generic bulk producers was to generate a competitive market advantage by protecting their new crystal form.
An invention must:
A. be novel.
B. not be obvious for a person skilled in the art
C. be useful.
D. contain sufficient details to allow others to reproduce the invention.
Crystalline form patents represent a small but very important segment of product patents because of the possibility to extend the medicine market protection, thus delaying competition from generic firms. We think that for these specific types of patent applications, the following basic rules should be applied:
1. The crystalline form cannot be characterised by a single technique.
2. When a pharmaceutical application or advantage is claimed to justify the usefulness of the patent application, volatile impurities must comply with ICH guidelines,23 and the new crystalline form must be sufficiently stable to be used as a medicine.
3. A new polymorph must have an advantage over the one previously described. The claiming of a crystalline form or solvate without a clear understanding of the usefulness is common to several patent case studies. From our direct experience, an interesting example is Cabergoline (Parkinson’s disease): the originator and generic companies claimed up to 14 crystalline forms and solvates.24 What is the meaning of all these patent applications? Where is the advantage with respect to the previously reported crystalline forms or solvates?
Polymorphic forms of a compound of Formula (I):.US8809349
herein referred to as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of a compound of Formula (I), or a salt, solvate, or hydrate thereof; or a mixture of two or more thereof. In one embodiment, the polymorphic form of a compound of Formula (I) can be a crystalline form, a partially crystalline form, an amorphous form, or a mixture of crystalline form(s) and/or amorphous form(s).
(XRPD) peaks
Polymorph Form A has the following characteristic X-ray Powder Diffraction (XRPD) peaks: 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°);
polymorph Form B has the following characteristic XRPD peaks: 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°);
polymorph Form C has the following characteristic XRPD peaks: 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°);
polymorph Form D has the following characteristic XRPD peaks: 2θ=11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°);
polymorph Form E has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°);
polymorph Form F has the following characteristic XRPD peaks: 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°);
polymorph Form G has the following characteristic XRPD peaks: 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°);
polymorph Form H has the following characteristic XRPD peaks: 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°);
polymorph Form I has the following characteristic XRPD peaks: 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°); and
polymorph Form J has the following characteristic XRPD peaks: 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°).
“Enantiomerically pure”
As used herein, and unless otherwise specified, the term “enantiomerically pure” means a stereomerically pure composition of a compound having one or more chiral center(s).
As used herein, and unless otherwise specified, the terms “enantiomeric excess” and “diastereomeric excess” are used interchangeably herein. In some embodiments, compounds with a single stereocenter can be referred to as being present in “enantiomeric excess,” and those with at least two stereocenters can be referred to as being present in “diastereomeric excess.” For example, the term “enantiomeric excess” is well known in the art and is defined as:
Thus, the term “enantiomeric excess” is related to the term “optical purity” in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being enantiomerically pure. A compound which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee. A 90% ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question.
Some compositions described herein contain an enantiomeric excess of at least about 50%, 75%, 90%, 95%, or 99% of the S enantiomer. In other words, the compositions contain an enantiomeric excess of the S enantiomer over the R enantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of at least about 50%, 75%, 90%, 95%, or 99% of the R enantiomer. In other words, the compositions contain an enantiomeric excess of the R enantiomer over the S enantiomer.
GRAPHS
FIG. 1 shows an X-ray powder diffraction (XRPD) for Polymorph Form A.
FIG. 2 shows an XRPD for Polymorph Form B.
FIG. 3 shows an XRPD for Polymorph Form C.
FIG. 4 shows an XRPD for Polymorph Form D.
FIG. 5 shows an XRPD for Polymorph Form E.
FIG. 6 shows an XRPD for Polymorph Form F.
FIG. 7 shows an XRPD for Polymorph Form G.
FIG. 8 shows an XRPD for Polymorph Form H.
FIG. 9 shows an XRPD for Polymorph Form I.
FIG. 10 shows an XRPD for Polymorph Form J.
FIG. 11 shows an XRPD for amorphous compound of Formula (I).
FIG. 12 shows a differential scanning calorimetry (DSC) thermogram for Polymorph Form A.
FIG. 13 shows a DSC for Polymorph Form B.
FIG. 14 shows a DSC for Polymorph Form C.
FIG. 15 shows a DSC for Polymorph Form D.
FIG. 16 shows a DSC for Polymorph Form E.
FIG. 17 shows a DSC for Polymorph Form F.
FIG. 18 shows a DSC for Polymorph Form G.
FIG. 19 shows a DSC for Polymorph Form H.
FIG. 20 shows a DSC for Polymorph Form I.
FIG. 21 shows a DSC for Polymorph Form J.
FIG. 22 shows a DSC thermogram and a thermogravimetric analysis (TGA) for Polymorph Form A.
FIG. 23 shows two DSC thermograms for Polymorph Form C.
FIG. 24 shows a DSC and a TGA for Polymorph Form F.
FIG. 25 shows a panel of salts tested for formation of crystalline solids in various solvents.
FIG. 26 shows a single crystal X-ray structure of Polymorph Form G MTBE (t-butyl methyl ether) solvate of a compound of Formula (I).
FIG. 27 shows an FT-IR spectra of Polymorph Form C.
FIG. 28 shows a 1H-NMR spectra of Polymorph Form C.
FIG. 29 shows a 13C-NMR spectra of Polymorph Form C.
FIG. 30 shows a dynamic vapor sorption (DVS) analysis of Polymorph Form C.
FIG. 31 shows representative dissolution profiles of capsules containing Polymorph Form C.
FIG. 1 shows an X-ray powder diffraction (XRPD) for Polymorph Form A.
Image may be NSFW. Clik here to view.
FIG. 1 shows a representative X-ray powder diffraction (XRPD) for polymorph Form A.
In one embodiment, polymorph Form A can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 1. In one embodiment, polymorph Form A can be characterized as having at least one XRPD peak selected from 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°). In one embodiment, polymorph Form A can be characterized as having at least one XRPD peak selected from 2θ=9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°) in combination with at least one XRPD peak selected from 2θ=15.6° (±0.2°) and 19.2° (±0.2°). In another embodiment, polymorph Form A can be characterized as having at least one XRPD peak selected from 2θ=9.6° (±0.2°), 12.2° (±0.2°), 15.6° (±0.2°), 18.3° (±0.2°), and 19.2° (±0.2°) in combination with at least one XRPD peak selected from 2θ=9.1° (±0.2°), 9.4° (±0.2°), 12.4° (±0.2°), 14.8° (±0.2°), 16.3° (±0.2°), 17.7° (±0.2°), 21.1° (±0.2°), 21.9° (±0.2°), 24.0° (±0.2°), and 26.9° (±0.2°). In one embodiment, polymorph Form A can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 1.
FIG. 2 shows an XRPD for Polymorph Form B.
Image may be NSFW. Clik here to view.
FIG. 2 shows a representative XRPD for polymorph Form B.
In one embodiment, polymorph Form B can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 2. In one embodiment, polymorph Form B can be characterized as having at least one XRPD peak selected from 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°). In one embodiment, polymorph Form B can be characterized as having at least one XRPD peak selected from 2θ=7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°) in combination with at least one XRPD peak selected from 2θ=14.0° (±0.2°) and 15.0° (±0.2°). In another embodiment, polymorph Form B can be characterized as having at least one XRPD peak selected from 2θ=7.9° (±0.2°), 13.4° (±0.2°), 14.0° (±0.2°), 15.0° (±0.2°), and 23.4° (±0.2°) in combination with at least one XRPD peak selected from 2θ=9.5° (±0.2°), 12.7° (±0.2°), 13.6° (±0.2°), 14.2° (±0.2°), 15.7° (±0.2°), 19.0° (±0.2°), 22.3° (±0.2°), 24.2° (±0.2°), 24.8° (±0.2°), and 26.9° (±0.2°). In one embodiment, polymorph Form B can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 2.
FIG. 3 shows an XRPD for Polymorph Form C.
In one embodiment, polymorph Form C can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 3. In one embodiment, Form C can be characterized by having at least one XRPD peak selected from 2θ=10.5° (±0.2°), 13.7° (±0.2°), and 24.5° (±0.2°). In another embodiment, Form C can be characterized by having at least one XRPD peak selected from 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°). In one embodiment, polymorph Form C can be characterized as having at least one XRPD peak selected from 2θ=10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°) in combination with at least one XRPD peak selected from 2θ=6.6° (±0.2°) and 12.5° (±0.2°). In another embodiment, polymorph Form C can be characterized as having at least one XRPD peak selected from 2θ=6.6° (±0.2°), 10.4° (±0.2°), 12.5° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°) in combination with at least one XRPD peak selected from 2θ=8.8° (±0.2°), 9.9° (±0.2°), 13.4° (±0.2°), 15.5° (±0.2°), 16.9° (±0.2°), 19.8° (±0.2°), 21.3° (±0.2°), 23.6° (±0.2°), 25.3° (±0.2°), and 27.9° (±0.2°). In one embodiment, polymorph Form C can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 3.
Image may be NSFW. Clik here to view.
FIG. 4 shows an XRPD for Polymorph Form D.
Image may be NSFW. Clik here to view.
In one embodiment, polymorph Form D can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 4. In one embodiment, polymorph Form D can be characterized as having at least one XRPD peak selected from 2θ=11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°). In one embodiment, polymorph Form D can be characterized as having at least one XRPD peak selected from 2θ=11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°) in combination with at least one XRPD peak selected from 2θ=9.2° (±0.2°) and 18.3° (±0.2°). In another embodiment, polymorph Form D can be characterized as having at least one XRPD peak selected from 2θ=9.2° (±0.2°), 11.4° (±0.2°), 17.4° (±0.2°), 18.3° (±0.2°), and 22.9° (±0.2°) in combination with at least one XRPD peak selected from 2θ=9.8° (±0.2°), 12.2° (±0.2°), 15.8° (±0.2°), 16.2° (±0.2°), 16.8° (±0.2°), 18.9° (±0.2°), 19.9° (±0.2°), 20.0° (±0.2°), 24.9° (±0.2°), and 29.3° (±0.2°). In one embodiment, polymorph Form D can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 4.
FIG. 5 shows an XRPD for Polymorph Form E. US8809349
In one embodiment, polymorph Form E can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 5. In one embodiment, polymorph Form E can be characterized as having at least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°). In one embodiment, polymorph Form E can be characterized as having at least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°) in combination with at least one XRPD peak selected from 2θ=12.7° (±0.2°) and 13.9° (±0.2°). In another embodiment, polymorph Form E can be characterized as having at least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.3° (±0.2°), 12.7° (±0.2°), 13.9° (±0.2°), and 24.4° (±0.2°) in combination with at least one XRPD peak selected from 2θ=12.4° (±0.2°), 13.3° (±0.2°), 14.3° (±0.2°), 15.5° (±0.2°), 17.4° (±0.2°), 18.5° (±0.2°), 22.0° (±0.2°), 23.9° (±0.2°), 24.1° (±0.2°), and 26.4° (±0.2°). In one embodiment, polymorph Form E can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 5.
FIG. 6 shows an XRPD for Polymorph Form F. US8809349
In one embodiment, polymorph Form F can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 6. In one embodiment, polymorph Form F can be characterized as having at least one XRPD peak selected from 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°). In one embodiment, polymorph Form F can be characterized as having at least one XRPD peak selected from 2θ=9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°) in combination with at least one XRPD peak selected from 2θ=14.0° (±0.2°) and 19.2° (±0.2°). In another embodiment, polymorph Form F can be characterized as having at least one XRPD peak selected from 2θ=9.6° (±0.2°), 14.0° (±0.2°), 17.3° (±0.2°), 19.2° (±0.2°), and 24.6° (±0.2°) in combination with at least one XRPD peak selected from 2θ=12.4° (±0.2°), 16.1° (±0.2°), 16.6° (±0.2°), 17.1° (±0.2°), 20.8° (±0.2°), 21.5° (±0.2°), 22.0° (±0.2°), 24.3° (±0.2°), 25.2° (±0.2°), and 25.4° (±0.2°). In one embodiment, polymorph Form F can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 6.
FIG. 7 shows an XRPD for Polymorph Form G. US8809349
In one embodiment, polymorph Form G can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 7. In one embodiment, polymorph Form G can be characterized as having at least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°). In one embodiment, polymorph Form G can be characterized as having at least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°) in combination with at least one XRPD peak selected from 2θ=10.6° (±0.2°) and 19.6° (±0.2°). In another embodiment, polymorph Form G can be characterized as having at least one XRPD peak selected from 2θ=6.7° (±0.2°), 9.5° (±0.2°), 10.6° (±0.2°), 19.0° (±0.2°), and 19.6° (±0.2°) in combination with at least one XRPD peak selected from 2θ=13.4° (±0.2°), 15.0° (±0.2°), 15.8° (±0.2°), 17.8° (±0.2°), 20.7° (±0.2°), 21.2° (±0.2°), 22.8° (±0.2°), 23.8° (±0.2°), 24.3° (±0.2°), and 25.6° (±0.2°). In one embodiment, polymorph Form G can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 7.
FIG. 8 shows an XRPD for Polymorph Form H. US8809349
In one embodiment, polymorph Form H can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 8. In one embodiment, polymorph Form H can be characterized as having at least one XRPD peak selected from 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°). In one embodiment, polymorph Form H can be characterized as having at least one XRPD peak selected from 2θ=8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°) in combination with at least one XRPD peak selected from 2θ=17.3° (±0.2°) and 18.5° (±0.2°). In another embodiment, polymorph Form H can be characterized as having at least one XRPD peak selected from 2θ=8.9° (±0.2°), 9.2° (±0.2°), 14.1° (±0.2°), 17.3° (±0.2°), and 18.5° (±0.2°) in combination with at least one XRPD peak selected from 2θ=7.1° (±0.2°), 10.6° (±0.2°), 11.3° (±0.2°), 11.6° (±0.2°), 16.2° (±0.2°), 18.3° (±0.2°), 18.8° (±0.2°), 20.3° (±0.2°), 21.7° (±0.2°), and 24.7° (±0.2°). In one embodiment, polymorph Form H can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 8.
FIG. 9 shows an XRPD for Polymorph Form I.
In one embodiment, polymorph Form I can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 9. In one embodiment, polymorph Form I can be characterized as having at least one XRPD peak selected from 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°). In one embodiment, polymorph Form I can be characterized as having at least one XRPD peak selected from 2θ=9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°) in combination with at least one XRPD peak selected from 2θ=11.4° (±0.2°) and 14.2° (±0.2°). In another embodiment, polymorph Form I can be characterized as having at least one XRPD peak selected from 2θ=9.7° (±0.2°), 11.4° (±0.2°), 14.2° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°) in combination with at least one XRPD peak selected from 2θ=9.2° (±0.2°), 14.7° (±0.2°), 15.5° (±0.2°), 16.7° (±0.2°), 17.3° (±0.2°), 18.4° (±0.2°), 21.4° (±0.2°), 22.9° (±0.2°), 29.1° (±0.2°), and 34.1° (±0.2°). In one embodiment, polymorph Form I can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 9.
FIG. 10 shows an XRPD for Polymorph Form J.
In one embodiment, polymorph Form J can be characterized by any one, two, three, four, five, six, seven, eight, nine, ten, or more of significant peak(s) of FIG. 10. In one embodiment, polymorph Form J can be characterized as having at least one XRPD peak selected from 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). In one embodiment, polymorph Form J can be characterized as having at least one XRPD peak selected from 2θ=9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°) in combination with at least one XRPD peak selected from 2θ=16.4° (±0.2°) and 17.9° (±0.2°). In another embodiment, polymorph Form J can be characterized as having at least one XRPD peak selected from 2θ=9.1° (±0.2°), 16.4° (±0.2°), 17.3° (±0.2°), 17.9° (±0.2°), and 18.3° (±0.2°) in combination with at least one XRPD peak selected from 2θ=9.4° (±0.2°), 10.1° (±0.2°), 10.7° (±0.2°), 14.0° (±0.2°), 14.3° (±0.2°), 15.5° (±0.2°), 16.9° (±0.2°), 19.9° (±0.2°), 24.0° (±0.2°), and 24.7° (±0.2°). In one embodiment, polymorph Form J can be characterized in that it has substantially all of the peaks in its XRPD pattern as shown in FIG. 10.
FIG. 11 shows an XRPD for amorphous compound of Formula (I).
FIG. 12 shows a differential scanning calorimetry (DSC) thermogram for Polymorph Form A.
FIG. 13 shows a DSC for Polymorph Form B.
FIG. 14 shows a DSC for Polymorph Form C.
FIG. 15 shows a DSC for Polymorph Form D.
FIG. 16 shows a DSC for Polymorph Form E.
FIG. 17 shows a DSC for Polymorph Form F.
FIG. 18 shows a DSC for Polymorph Form G.
FIG. 19 shows a DSC for Polymorph Form H.
FIG. 20 shows a DSC for Polymorph Form I.
FIG. 21 shows a DSC for Polymorph Form J.
FIG. 22 shows a DSC thermogram and a thermogravimetric analysis (TGA) for Polymorph Form A.
FIG. 23 shows two DSC thermograms for Polymorph Form C.
FIG. 24 shows a DSC and a TGA for Polymorph Form F.
FIG. 25 shows a panel of salts tested for formation of crystalline solids in various solvents.
FIG. 26 shows a single crystal X-ray structure of Polymorph Form G MTBE (t-butyl methyl ether) solvate of a compound of Formula (I).
FIG. 27 shows an FT-IR spectra of Polymorph Form C.
Image may be NSFW. Clik here to view.
FIG. 28 shows a 1H-NMR spectra of Polymorph Form C.
Image may be NSFW. Clik here to view.
FIG. 29 shows a 13C-NMR spectra of Polymorph Form C.
Image may be NSFW. Clik here to view.
FIG. 30 shows a dynamic vapor sorption (DVS) analysis of Polymorph Form C.
FIG. 31 shows representative dissolution profiles of capsules containing Polymorph Form C.
Enantiomers
Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), the formation and crystallization of chiral salts, or prepared by asymmetric syntheses. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
“Tautomer”
The term “tautomer” is a type of isomer that includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). “Tautomerization” includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerizations (i.e., the reaction providing a tautomeric pair) can be catalyzed by acid or base, or can occur without the action or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enamine tautomerizations. An example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. Another example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
As defined herein, the term “Formula (I)” includes (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one in its imide tautomer shown below as (1-1) and in its lactim tautomer shown below as (1-2):
“polymorph” can be used herein to describe a crystalline material, e.g., a crystalline form. In certain embodiments, “polymorph” as used herein are also meant to include all crystalline and amorphous forms of a compound or a salt thereof, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms of the compounds or a salt thereof, as well as mixtures thereof.
As used herein, and unless otherwise specified, a particular form of a compound of Formula (I) described herein (e.g., Form A, B, C, D, E, F, G, H, I, J, or amorphous form of a compound of Formula (I), or mixtures thereof) is meant to encompass a solid form of a compound of Formula (I), or a salt, solvate, or hydrate thereof, among others.
The polymorphs made according to the methods provided herein can be characterized by any methodology known in the art. For example, the polymorphs made according to the methods provided herein can be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), hot-stage microscopy, optical microscopy, Karl Fischer analysis, melting point, spectroscopy (e.g., Raman, solid state nuclear magnetic resonance (ssNMR), liquid state nuclear magnetic resonance (1H- and 13C-NMR), and FT-IR), thermal stability, grinding stability, and solubility, among others.
“Solid form”
The terms “solid form” and related terms herein refer to a physical form comprising a compound provided herein or a salt or solvate or hydrate thereof, which is not in a liquid or a gaseous state. Solid forms can be crystalline, amorphous, disordered crystalline, partially crystalline, and/or partially amorphous.
“Crystalline,”
The term “crystalline,” when used to describe a substance, component, or product, means that the substance, component, or product is substantially crystalline as determined, for example, by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005).
As used herein, and unless otherwise specified, the term “crystalline form,” “crystal form,” and related terms herein refer to the various crystalline material comprising a given substance, including single-component crystal forms and multiple-component crystal forms, and including, but not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. In certain embodiments, a crystal form of a substance can be substantially free of amorphous forms and/or other crystal forms. In other embodiments, a crystal form of a substance can contain about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% of one or more amorphous form(s) and/or other crystal form(s) on a weight and/or molar basis.
Certain crystal forms of a substance can be obtained by a number of methods, such as, without limitation, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces, such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, solvent-drop grinding, microwave-induced precipitation, sonication-induced precipitation, laser-induced precipitation, and/or precipitation from a supercritical fluid. As used herein, and unless otherwise specified, the term “isolating” also encompasses purifying.
Characterizing crystal forms and amorphous forms
Techniques for characterizing crystal forms and amorphous forms can include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.
PEAK
As used herein, and unless otherwise specified, the term “peak,” when used in connection with the spectra or data presented in graphical form (e.g., XRPD, IR, Raman, and NMR spectra), refers to a peak or other special feature that one skilled in the art would recognize as not attributable to background noise. The term “significant peak” refers to peaks at least the median size (e.g., height) of other peaks in the spectrum or data, or at least 1.5, 2, or 2.5 times the background level in the spectrum or data.
“Pharmaceutically acceptable carrier”
“pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the present disclosure is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
“Substantially pure”
the term “substantially pure” when used to describe a polymorph, a crystal form, or a solid form of a compound or complex described herein means a solid form of the compound or complex that comprises a particular polymorph and is substantially free of other polymorphic and/or amorphous forms of the compound. A representative substantially pure polymorph comprises greater than about 80% by weight of one polymorphic form of the compound and less than about 20% by weight of other polymorphic and/or amorphous forms of the compound; greater than about 90% by weight of one polymorphic form of the compound and less than about 10% by weight of other polymorphic and/or amorphous forms of the compound; greater than about 95% by weight of one polymorphic form of the compound and less than about 5% by weight of other polymorphic and/or amorphous forms of the compound; greater than about 97% by weight of one polymorphic form of the compound and less than about 3% by weight of other polymorphic and/or amorphous forms of the compound; or greater than about 99% by weight of one polymorphic form of the compound and less than about 1% by weight of other polymorphic and/or amorphous forms of the compound.
“Stable”
The term “stable” refers to a compound or composition that does not readily decompose or change in chemical makeup or physical state. A stable composition or formulation provided herein does not significantly decompose under normal manufacturing or storage conditions. In some embodiments, the term “stable,” when used in connection with a formulation or a dosage form, means that the active ingredient of the formulation or dosage form remains unchanged in chemical makeup or physical state for a specified amount of time and does not significantly degrade or aggregate or become otherwise modified (e.g., as determined, for example, by HPLC, FTIR, or XRPD). In some embodiments, about 70 percent or greater, about 80 percent or greater, about 90 percent or greater, about 95 percent or greater, about 98 percent or greater, or about 99 percent or greater of the compound remains unchanged after the specified period. In one embodiment, a polymorph provided herein is stable upon long-term storage (e.g., no significant change in polymorph form after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, 48, 54, 60, or greater than about 60 months).
Amorphous form
In one embodiment, an amorphous form of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, can be made by dissolution of a crystalline form followed by removal of solvent under conditions in which stable crystals are not formed. For example, solidification can occur by rapid removal of solvent, by rapid addition of an anti-solvent (causing the amorphous form to precipitate out of solution), or by physical interruption of the crystallization process. Grinding processes can also be used. In other embodiments, an amorphous form of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, can be made using a process or procedure described herein elsewhere.
In certain embodiments, an amorphous form can be obtained by fast cooling from a single solvent system, such as, e.g., ethanol, isopropyl alcohol, t-amyl alcohol, n-butanol, methanol, acetone, ethyl acetate, or acetic acid. In certain embodiments, an amorphous form can be obtained by slow cooling from a single solvent system, such as, e.g., ethanol, isopropyl alcohol, t-amyl alcohol, or ethyl acetate.
In certain embodiments, an amorphous form can be obtained by fast cooling from a binary solvent system, for example, with acetone or DME as the primary solvent. In certain embodiments, an amorphous form can be obtained by slow cooling from a binary solvent system, for example, with ethanol, isopropyl alcohol, THF, acetone, or methanol as the primary solvent. In some embodiments, an amorphous form can be obtained by dissolution of a compound of Formula (I) in t-butanol and water at elevated temperature, followed by cooling procedures to afford an amorphous solid form.
Salt Forms
In certain embodiments, a compound of Formula (I) provided herein is a pharmaceutically acceptable salt, or a solvate or hydrate thereof. In one embodiment, pharmaceutically acceptable acid addition salts of a compound provided herein can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In other embodiments, if applicable, pharmaceutically acceptable base addition salts of a compound provided herein can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Exemplary bases include, but are not limited to, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, a pharmaceutically acceptable base addition salt is ammonium, potassium, sodium, calcium, or magnesium salt. In one embodiment, bis salts (i.e., two counterions) and higher salts (e.g., three or more counterions) are encompassed within the meaning of pharmaceutically acceptable salts.
In certain embodiments, salts of a compound of Formula (I) can be formed with, e.g., L-tartaric acid, p-toluenesulfonic acid, D-glucaronic acid, ethane-1,2-disulfonic acid (EDSA), 2-naphthalenesulfonic acid (NSA), hydrochloric acid (HCl) (mono and bis), hydrobromic acid (HBr), citric acid, naphthalene-1,5-disulfonic acid (NDSA), DL-mandelic acid, fumaric acid, sulfuric acid, maleic acid, methanesulfonic acid (MSA), benzenesulfonic acid (BSA), ethanesulfonic acid (ESA), L-malic acid, phosphoric acid, and aminoethanesulfonic acid (taurine).
(R)- and (S)-isomers
In some embodiments, the (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
XRPD
Compounds and polymorphs provided herein can be characterized by X-ray powder diffraction patterns (XRPD). The relative intensities of XRPD peaks can vary depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed, among other parameters. Moreover, instrument variation and other factors can affect the 2θ peak values. Therefore, in certain embodiments, the XRPD peak assignments can vary by plus or minus about 0.2 degrees theta or more, herein referred to as “(±0.2°)”.
XRPD patterns for each of Forms A-J and amorphous form of the compound of Formula (I) were collected with a PANalytical CubiX XPert PRO MPD diffractometer using an incident beam of CU radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kα X-rays through the specimen and onto the detector. Samples were placed on Si zero-return ultra-micro sample holders. Analysis was performed using a 10 mm irradiated width and the following parameters were set within the hardware/software:
X-ray tube:
Cu Kα, 45 kV, 40 mA
Detector:
X′Celerator
Slits:
ASS Primary Slit: Fixed 1°
Divergence Slit (Prog):
Automatic – 5 mm irradiated length
Soller Slits:
0.02 radian
Scatter Slit (PASS):
Automatic – 5 mm observed length
Scanning
Scan Range:
3.0-45.0°
Scan Mode:
Continuous
Step Size:
0.03°
Time per Step:
10 s
Active Length:
2.54°
DSC
Compounds and polymorphs provided herein can be characterized by a characteristic differential scanning calorimeter (DSC) thermogram. For DSC, it is known in the art that the peak temperatures observed will depend upon the rate of temperature change, the sample preparation technique, and the particular instrument employed, among other parameters. Thus, the peak values in the DSC thermograms reported herein can vary by plus or minus about 2° C., plus or minus about 3° C., plus or minus about 4° C., plus or minus about 5° C., plus or minus about 6° C., to plus or minus about 7° C., or more. For some polymorph Forms, DSC analysis was performed on more than one sample which illustrates the known variability in peak position, for example, due to the factors mentioned above. The observed peak positional differences are in keeping with expectation by those skilled in the art as indicative of different samples of a single polymorph Form of a compound of Formula (I).
Impurities in a sample can also affect the peaks observed in any given DSC thermogram. In some embodiments, one or more chemical entities that are not the polymorph of a compound of Formula (I) in a sample being analyzed by DSC can result in one or more peaks at lower temperature than peak(s) associated with the transition temperature of a given polymorph as disclosed herein.
DSC analyses were performed using a Mettler 822e differential scanning calorimeter. Samples were weighed in an aluminum pan, covered with a pierced lid, and then crimped. General analysis conditions were about 30° C. to about 300° C.-about 350° C. ramped at about 10° C./min. Several additional ramp rates were utilized as part of the investigation into the high melt Form B, including about 2° C./min, about 5° C./min, and about 20° C./min. Samples were analyzed at multiple ramp rates to measure thermal and kinetic transitions observed.
Isothermal holding experiments were also performed utilizing the DSC. Samples were ramped at about 10° C./min to temperature (about 100° C. to about 250° C.) and held for about five minutes at temperature before rapid cooling to room temperature. In these cases, samples were then analyzed by XRPD or reanalyzed by DSC analysis.
TGA
A polymorphic form provided herein can give rise to thermal behavior different from that of an amorphous material or another polymorphic form. Thermal behavior can be measured in the laboratory by thermogravimetric analysis (TGA) which can be used to distinguish some polymorphic forms from others. In one embodiment, a polymorph as disclosed herein can be characterized by thermogravimetric analysis.
TGA analyses were performed using a Mettler 851e SDTA/TGA thermal gravimetric analyzer. Samples were weighed in an alumina crucible and analyzed from about 30° C. to about 230° C. and at a ramp rate of about 10° C./min.
DVS
Compounds and polymorphs provided herein can be characterized by moisture sorption analysis. This analysis was performed using a Hiden IGAsorp Moisture Sorption instrument. Moisture sorption experiments were carried out at about 25° C. by performing an adsorption scan from about 40% to about 90% RH in steps of about 10% RH and a desorption scan from about 85% to about 0% RH in steps of about −10% RH. A second adsorption scan from about 10% to about 40% RH was performed to determine the moisture uptake from a drying state to the starting humidity. Samples were allowed to equilibrate for about four hours at each point or until an asymptotic weight was reached. After the isothermal sorption scan, samples were dried for about one hour at elevated temperature (about 60° C.) to obtain the dry weight. XRPD analysis on the material following moisture sorption was performed to determine the solid form.
Optical Microscopy
Compounds and polymorphs provided herein can be characterized by microscopy, such as optical microscopy. Optical microscopy analysis was performed using a Leica DMRB Polarized Microscope. Samples were examined with a polarized light microscope combined with a digital camera (1600×1200 resolution). Small amounts of samples were dispersed in mineral oil on a glass slide with cover slips and viewed with 100× magnification.
Karl Fischer Analysis
Compounds and polymorphs provided herein can be characterized by Karl Fischer analysis to determine water content. Karl Fischer analysis was performed using a Metrohm 756 KF Coulometer. Karl Fisher titration was performed by adding sufficient material to obtain 50 μg of water, about 10 to about 50 mg of sample, to AD coulomat.
Raman Spectroscopy
Compounds and polymorphs provided herein can be characterized by Raman spectroscopy. Raman spectroscopy analysis was performed using a Kaiser RamanRXN1 instrument with the samples in a glass well. Raman spectra were collected using a PhAT macroscope at about 785 nm irradiation frequency and about 1.2 mm spot size. Samples were analyzed using 12 to 16 accumulations with about 0.5 to about 12 second exposure time and utilized cosmic ray filtering. The data was processed by background subtraction of an empty well collected with the same conditions. A baseline correction and smoothing was performed to obtain interpretable data when necessary.
FT-IR
Compounds and polymorphs provided herein can be characterized by FT-IR spectroscopy. FT-IR spectroscopy was performed using either a Nicolet Nexus 470 or Avatar 370 Infrared Spectrometer and the OMNIC software. Samples were analyzed using a diamond Attenuated Total Reflection (ATR) accessory. A compound sample was applied to the diamond crystal surface and the ATR knob was turned to apply the appropriate pressure. The spectrum was then acquired and analyzed using the OMNIC software. Alternative sample preparations include solution cells, mulls, thin films, and pressed discs, such as those made of KBr, as known in the art.
NMR
Compounds and polymorphs provided herein can be characterized by nuclear magnetic resonance (NMR). NMR spectra were obtained using a 500 MHz Bruker AVANCE with 5-mm BBO probe instrument. Samples (approximately 2 to approximately 10 mg) were dissolved in DMSO-d6 with 0.05% tetramethylsilane (TMS) for internal reference. 1H-NMR spectra were acquired at 500 MHz using 5 mm broadband observe (1H-X) Z gradient probe. A 30 degree pulse with 20 ppm spectral width, 1.0 s repetition rate, and 32-64 transients were utilized in acquiring the spectra.
High-Performance Liquid Chromatography
Compounds and polymorphs provided herein can be analyzed by high-performance liquid chromatography using an Agilent 1100 instrument. The instrument parameters for achiral HPLC are as follows:
Column:
Sunfire C18 4.6 × 150 mm
Column Temperature:
Ambient
Auto-sampler Temperature:
Ambient
Detection:
UV at 250 nm
Mobile Phase A:
0.05% trifluoroacetic acid in water
Mobile Phase B:
0.05% trifluoroacetic acid in MeCN
Flow Rate:
1.0 mL/minute
Injection Volume:
10 μL
Data Collection time:
20 minutes
Re-equilibration Time:
5 minutes
Diluent & Needle Wash:
MeOH
Gradient Conditions:
Time (minutes)
% A
% B
0.0
90
10
3.5
90
10
10.0
10
90
15.0
10
90
18.0
90
10
20.0
90
10
Compounds and polymorphs provided herein can be analyzed by high-performance liquid chromatography using a chiral HPLC column to determine % ee values:
Column:
Chiralpak IC, 4.6 mm × 250 mm, 5 μm.
Column Temperature:
Room Temperature
Sample Temperature:
Room Temperature
Detection:
UV at 254 nm
Mobile Phase A:
60% Hexane 40% (IPA: EtOH = 2:3) with 0.2%
Acetic Acid and 0.1% DEA
Isocratic:
100% A
Flow Rate:
1 mL/min
Diluent:
Methanol
Injection Volume:
10 μL
Analysis Time:
25 min
Example 8
Analytical Data of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
Provided herein are analytical data of various purified samples of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one, the compound of Formula (I). Confirmation of the structure of the compound of Formula (I) was obtained via single crystal X-ray diffraction, FT-IR, 1H-NMR and 13C-NMR spectra.
A single crystal structure of a tert-butyl methyl ether solvate of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (e.g., polymorph Form G) was generated and single crystal X-ray data was collected. The structure is shown in FIG. 26, which further confirmed the absolute stereochemistry as the S-enantiomer.
FT-IR spectra of Form C of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one was obtained, and shown in FIG. 27.
1H-NMR and 13C-NMR spectra of a sample of Form C of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one were obtained, and are provided in FIG. 28 and FIG. 29, respectively.
Example 9
General Methods for the Preparation of Polymorphs Form A, B, C, D, E, F, G, H, I, J of the Compound of Formula (I)
General Method A: Single Solvent Crystallization with Fast Cooling or Slow Cooling
A sample of a compound of Formula (I) (e.g., Form A or Form C) is placed into a vial equipped with stir bar and dissolved with a minimal amount of solvent (such as about 0.2 mL to about 0.3 mL) at an elevated temperature. The resulting solution is polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, the vial is placed in a refrigerator (e.g., about 4° C.) overnight in a fast cooling procedure, or cooled to ambient temperature at a rate of about 20° C./h and allowed to equilibrate without stiffing at ambient temperature overnight in a slow cooling procedure. Optionally, a sample without solids can be scratched with an implement known in the art (e.g., a spatula) to initiate crystallization. The solution can be allowed to equilibrate for a period of time, such as approximately 8 hours. For a slow cooling sample, if scratching does not provide solids after about 8 hours, then a stir bar can be added and the sample then stirred overnight. A sample without precipitation can be evaporated to dryness under a gentle gas stream, such as argon, nitrogen, ambient air, etc. The precipitated solids can be recovered by vacuum filtration, centrifuge filtration, or decanted as appropriate to afford the Form as indicated below.
General Method B: Multi-Solvent Crystallization with Fast Cooling or Slow Cooling
Multi-solvent (e.g., binary) solvent crystallizations can be performed. Primary solvents include, but are not limited to, ethanol, isopropyl alcohol, methanol, tetrahydrofuran, acetone, methyl ethyl ketone, dioxane, NMP, DME, and DMF. Anti-solvents include, but are not limited to, MTBE, DCM, toluene, heptane, and water.
A sample of a compound of Formula (I) (e.g., Form A or Form C) is placed into a vial equipped with stir bar and dissolved with a minimal amount of solvent (such as about 0.2 mL to about 0.3 mL) at an elevated temperature. The resulting solution is polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, the anti-solvent is added until turbidity is observed. After hot filtration, the vial is placed in a refrigerator (e.g., about 4° C.) overnight in a fast cooling procedure, or cooled to ambient temperature at a rate of about 20° C./h and allowed to equilibrate without stirring at ambient temperature overnight in a slow cooling procedure. Optionally, a sample without solids can be scratched with an implement known in the art (e.g., a spatula) to initiate crystallization. The solution can be allowed to equilibrate for a period of time, such as approximately 8 hours. For a slow cooling sample, if scratching does not provide solids after about 8 hours, then a stir bar can be added and the sample then stirred overnight. A sample without precipitation can be evaporated to dryness under a gentle gas stream, such as argon, nitrogen, ambient air, etc. The precipitated solids can be recovered by vacuum filtration, centrifuge filtration, or decanted as appropriate to afford the Form as indicated below.
General Method C: Slurry Procedures to Afford Formula (I) Polymorph Forms
A mixture of one or more Forms (e.g., Form A or Form C) of the compound of Formula (I) are placed in a vial equipped with a stir bar. A minimal amount of solvent (e.g., a single solvent or a mixture/solution of two or more solvents) is added to the vial to form a heterogeneous slurry. Optionally, the vial can be sealed to prevent evaporation. The slurry is stirred for a period of time ranging from less than about an hour, to about 6 hours, to about 12 hours, to about 24 hours, to about 2 days, to about 4 days, to about 1 week, to about 1.5 weeks, to about 2 weeks or longer. Aliquots can be taken during the stirring period to assess the Form of the solids using, for example, XRPD analysis. Optionally, additional solvent(s) can be added during the stirring period. Optionally, seeds of a given polymorph Form of the compound of Formula (I) can be added. In some cases, the slurry is then stirred for a further period of time, ranging as recited above. The recovered solids can be recovered by vacuum filtration, centrifuge filtration, or decanted as appropriate to afford the Form as indicated below.
Example 10
Preparation of Polymorphs Form A, B, C, D, E, F, G, H, I, J of the Compound of Formula (I)
Form A
Single Solvent Crystallizations to Afford Formula (I) Form A
1. Fast Cooling Procedure From MeCN: Approximately 23 mg of Formula (I) Form A was placed into a 20-mL glass vial equipped with a stir bar. To the vial was added a minimal amount of acetonitrile (7.4 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, the vial was placed in a refrigerator (4° C.) overnight. Once at 4° C., the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. The crystals were collected by decanting off the liquid and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
2. Slow Cooling Procedure From MeCN: Approximately 24 mg of Formula (I) Form A was placed into a 20-mL glass vial equipped with a stir bar. To the vial was added a minimal amount of acetonitrile (8 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, the vial was cooled to ambient temperature at a rate of 20° C./h and allowed to equilibrate without stirring at ambient temperature overnight. After the equilibration hold at ambient temperature, the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. The crystals were collected by decanting off the liquids and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
3. Slow Cooling Procedure From n-Butanol: Approximately 23 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of n-butanol (0.6 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, the vials were cooled to ambient temperature at a rate of 20° C./h and allowed to equilibrate without stirring at ambient temperature overnight. After the equilibration hold at ambient temperature, the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. To further induce crystallization, a stir bar was added to the vial and the contents stirred overnight. The resulting crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
Binary Solvent Crystallizations to Afford Formula (I) Form A
1. Fast Cooling Procedure From Acetone/DCM: Approximately 23.5 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of acetone (2.6 ml) to just dissolve the solids at 50° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (5.0 ml) was added portion-wise. After the anti-solvent addition, the vials were placed in a refrigerator (4° C.) overnight. Once at 4° C., the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. The crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
2. Fast Cooling Procedure From MEK/DCM: Approximately 23 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of MEK (2.2 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (5.0 ml) was added portion-wise. After the anti-solvent addition, the vial was placed in a refrigerator (4° C.) overnight. Once at 4° C., the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. The crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
3. Fast Cooling Procedure From DMF/DCM: Approximately 24 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of DCM (0.2 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (7.0 ml) was added portion-wise. After the anti-solvent addition, the vial was placed in a refrigerator (4° C.) overnight. Once at 4° C., the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. The crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
4. Fast Cooling Procedure From Dioxane/DCM: Approximately 24.4 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of dioxane (0.8 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (7.0 ml) was added portion-wise. After the anti-solvent addition, the vial was placed in a refrigerator (4° C.) overnight. Once at 4° C., the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. The crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
5. Slow Cooling Procedure From Acetone/DCM: Approximately 22 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of acetone (2.5 ml) to just dissolve the solids at 50° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (5.0 ml) was added portion-wise. After the anti-solvent addition, the vial was cooled to ambient temperature at a rate of 20° C./h and allowed to equilibrate without stirring at ambient temperature overnight. After the equilibration hold at ambient temperature, the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. To further induce crystallization, a stir bar was added to the vial and the contents stirred overnight. The resulting crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
6. Slow Cooling Procedure From MEK/DCM: Approximately 23.4 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of MEK (2.2 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (5.0 ml) was added portion-wise. After the anti-solvent addition, the vial was cooled to ambient temperature at a rate of 20° C./h and allowed to equilibrate without stirring at ambient temperature overnight. After the equilibration hold at ambient temperature, the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. The resulting crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
7. Slow Cooling Procedure From Dioxane/DCM: Approximately 24 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of dioxane (0.8 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (7.0 ml) was added portion-wise. After the anti-solvent addition, the vial was cooled to ambient temperature at a rate of 20° C./h and allowed to equilibrate without stirring at ambient temperature overnight. After the equilibration hold at ambient temperature, the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. To further induce crystallization, a stir bar was added to the vial and the contents stirred overnight. The resulting crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
8. Slow Cooling Procedure From DMF/DCM: Approximately 23.5 mg of Formula (I) Form A was placed into a 2-dram glass vial equipped with a stir bar. To the vial was added a minimal amount of DMF (0.2 ml) to just dissolve the solids at 70° C. The resulting solution was polish filtered through a 0.45 μm syringe filter into a clean preheated vial. After hot filtration, DCM (7.0 ml) was added portion-wise. After the anti-solvent addition, the vial was cooled to ambient temperature at a rate of 20° C./h and allowed to equilibrate without stirring at ambient temperature overnight. After the equilibration hold at ambient temperature, the contents of the vial were periodically scratched with a spatula to induce crystallization, and then allowed to equilibrate for approximately 8 hours. To further induce crystallization, a stir bar was added to the vial and the contents stirred overnight. To further induce crystallization, the contents of the vial were concentrated under a gentle stream of nitrogen to near dryness. The resulting crystals were collected by filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
Slurry Procedure to Afford Formula (I) Form A
1. Procedure from CH2Cl2 and from IPA: Form C (1 g) was slurried in five volumes of dichloromethane. After holding for 15 hours, filtration, and drying, Form A was isolated in 82% yield. Scale-up was performed on a 20 g scale with a water-wet cake of Form C to yield Form A in 92% yield. Drying at 70° C. for six days indicated no degradation in chemical or chiral purity. Slurrying dry Form C in isopropyl alcohol using a similar method also yielded Form A.
2. Procedure for Competitive Slurry Experiment (using forms A, B and C): Competitive slurries were performed by charging approximately a 50/50 mixture of Forms A and C (11.2 mg of Form A and 11.7 mg Form C) to a 1-dram glass vial equipped with a glass stir bar. To the vial was added 600 μL of MeCN. The vial cap was wrapped with parafilm to prevent evaporation. The slurry was stirred for 1 day and an aliquot was taken. The contents of the vial were allowed to stir for an additional week and another aliquot was taken. Both aliquots were centrifuge filtered for five minutes at 8000 RPM. XRPD analysis was performed on the solids from each aliquot to show that the Formula (I) had converted to Form A at both time points. After the one week aliquot was taken, an additional 300 μL of acetonitrile was added to the remaining slurry and allowed to equilibrate for one day. The slurry was then seeded with approximately 3.2 mg of Form B and allowed to equilibrate for an additional three days. The solids were isolated by centrifuge filtration (5 minutes at 8000 RPM) and dried over night under vacuum. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
3. Procedure for Competitive Slurry Experiment (using forms A, C, D, and E): Competitive slurries were performed by charging an approximately equal mixture of each form (7.8 mg of Form A, 7.7 mg Form C, 7.7 mg of Form D, and 8.2 mg of Form E) to a 1-dram glass vial equipped with a glass stir bar. To the vial was added 1 ml of 2-propanol. The vial cap was wrapped with parafilm to prevent evaporation. The slurry was mixed for 1 day and an aliquot was taken. The contents of the vial were allowed to stir for an additional week and another aliquot was taken. Both aliquots were centrifuge filtered for five minutes at 8000 RPM. XRPD analysis was performed on the solids from each aliquot to show that the Formula (I) had converted to Form A at both time points. After the one week aliquot was taken, the remaining solids were isolated by centrifuge filtration (5 minutes at 8000 RPM) and dried over night under vacuum. The dried solids were evaluated for crystallinity and form by XRPD which indicated the crystalline material was polymorph Form A.
Using the General Method B of Example 9, the following experiments detailed in Tables 4 and 5 were performed to afford Formula (I) Form C. Table 4 experiments were conducted using the fast cooling procedure, while Table 5 experiments were conducted using the slow cooling procedure.
Using General Method C of Example 9, the following experiments detailed in Table 6 were performed to afford the polymorph Form of the compound of Formula (I) as indicated.
[00653] Using the XRPD instrument and parameters described above, the following XRPD peaks were observed for Formula (I) Polymorph Forms A, B, C, D. E, F, G, H, I, and J. The XRPD traces for these ten polymorph forms are given in Figures 1-10, respectively. In Table 7, peak position units are °2Θ. In one embodiment, a given polymorph Form can be characterized as having at least one of the five XRPD peaks given in Set 1 in Table 7. In another embodiment, the given Form can be characterized as having at least one of the five XRPD peaks given in Set 1 in combination with at least one of the XRPD peaks given in Set 2 in Table 7. In some embodiments, one or more peak position values can be defined as being modified by the term “about” as described herein. In other embodiments, any given peak position is with ±0.2 2Θ (e.g., 9.6+0.2 2Θ).
[00654] Using the DSC instrument and parameters described above, the following DSC peaks were observed for the compound of Formula (I) polymorph Forms A, B, C, D. E, F, G, H, I, and J. The DSC thermograms for these nine polymorph forms are given in FIGS. 12-24, respectively, and peak positions are given in Table 8. Further DSC data for Polymorph Forms A, B, C, D. E, F, G, H, I, and J is given in Table 9 below. Unless marked with a Λ that indicates an exothermic peak, all peaks are endothermic.
Table 9 summarizes non-limiting exemplary preparation techniques for Formula (I) Polymorph Forms A-J and representative analytical data as described below and elsewhere.
Dabigatran (Pradaxa in Australia, Canada, Europe and USA, Prazaxa in Japan) is an oralanticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in some cases it offers an alternative towarfarin as the preferred orally administered anticoagulant (“blood thinner”) since it cannot be monitored by blood tests forinternational normalized ratio (INR) monitoring while offering similar results in terms of efficacy. There is no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,[2][3] unlike warfarin,[4] although a potential dabigatran antidote (pINN: idarucizumab) is undergoing clinical studies.[5] It was developed by the pharmaceutical company Boehringer Ingelheim.
It appears to be as effective as warfarin in preventing nonhemorrhagic strokes and embolic events in those with afib not due to valve problems.[7]
Image may be NSFW. Clik here to view.
Contraindications
Dabigatran is contraindicated in patients who have active pathological bleeding since dabigatran can increase bleeding risk and can also cause serious and potentially life-threatening bleeds.[8] Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g. anaphylaxis or anaphylactic shock).[8] The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valve due to the increased risk of thromboembolic events (e.g. valve thrombosis, stroke, and myocardial infarction) and major bleeding associated with dabigatran in this population.[8][9][10]
Adverse effects
The most commonly reported side effect of dabigatran is GI upset. When compared to people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of GI bleeding was significantly higher. Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. The lower pH has previously been associated with dyspepsia; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding.[11]
A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[12]
Reduced doses should be used in those with poor kidney function.[13]
Pharmacokinetics
Dabigatran has a half-life of approximately 12-14 h and exert a maximum anticoagulation effect within 2-3 h after ingestion.[14] Fatty foods delay the absorption of dabigatran, although the bio-availability of the drug is unaffected.[1] One study showed that absorption may be moderately decreased if taken with a proton pump inhibitor.[15] Drug excretion through P-glycoprotein pumps is slowed in patients taking strong p-glycoprotein pump inhibitors such as quinidine, verapamil, and amiodarone, thus raising plasma levels of dabigatran.[16]
History
Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin, but also trypsin. Addition of ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbedprodrug, BIBR 1048 (dabigatran etexilate).[17]
On March 18, 2008, the European Medicines Agency granted marketing authorisation for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery and for non-valvular atrial fibrillation.[18]
The National Health Service in Britain authorised the use of dabigatran for use in preventing blood clots in hip and knee surgery patients. According to a BBC article in 2008, Dabigatran was expected to cost the NHS £4.20 per day, which was similar to several other anticoagulants.[19]
Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,[20] for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery. Approval for atrial fibrillation patients at risk of stroke came in October 2010.[21][22]
The U.S. Food and Drug Administration (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.[23][24][25][26] The approval came after an advisory committee recommended the drug for approval on September 20, 2010[27] although caution is still urged by some outside experts.[28]
On February 14, 2011, the American College of Cardiology Foundation and American Heart Association added dabigatran to their guidelines for management of non-valvular atrial fibrillation with a class I recommendation.[29]
In May 2014 the FDA reported the results of a large study comparing dabigatran to warfarin in 134,000 Medicare patients. The Agency concluded that dabigatran is associated with a lower risk of overall mortality, ischemic stroke, and bleeding in the brain than warfarin. Gastrointestinal bleeding was more common in those treated with dabigatran than in those treated with warfarin. The risk of heart attack was similar between the two drugs. The Agency reiterated its opinion that dabigatran’s overall risk/benefit ratio is favorable.[30]
On July 26, 2014, the British Medical Journal (BMJ) published a series of investigations that accused Boehringer of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. Review of internal communications between Boehringer researchers and employees, the FDA and the EMA revealed that Boehringer researchers found evidence that serum levels of dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require monitoring.[31][32]
Research
In August 2015, an article found that idarucizumab was able to reverse the anticoagulation effects of dabigatran within minutes.[33]
Eikelboom, JW; Connolly, SJ; Brueckmann, M et al. (September 2013). “Dabigatran versus Warfarin in Patients with Mechanical Heart Valves”. N Engl J Med369: 1206–1214.doi:10.1056/NEJMoa1300615. PMID23991661.
ML Blommel et al. (2011). “Dabigatran etexilate: A novel oral direct thrombin inhibitor”.Am J Health Syst Pharm68 (16): 1506–19. doi:10.2146/ajhp100348. PMID21817082.
Stangier J, Eriksson BI, Dahl OE et al. (May 2005). “Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement”. J Clin Pharmacol45 (5): 555–63.doi:10.1177/0091270005274550. PMID15831779.
Merli G, Spyropoulos AC, Caprini JA; Spyropoulos; Caprini (August 2009). “Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations”. Ann Surg250 (2): 219–28.doi:10.1097/SLA.0b013e3181ae6dbe. PMID19638915.
Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK; Curtis; Ellenbogen; Estes Na; Ezekowitz; Jackman; January; Lowe; Page; Slotwiner; Stevenson; Tracy; Fuster; Rydén; Cannom; Crijns; Curtis; Ellenbogen; Halperin; Kay; Le Heuzey; Lowe; Olsson; Prystowsky; Tamargo; Wann; Jacobs; Anderson; Albert et al. (March 2011). “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines”. Circulation123 (10): 1144–50. doi:10.1161/CIR.0b013e31820f14c0. PMID21321155.
Moore TJ, Cohen MR, Mattison DR; Cohen; Mattison (July 2014). “Dabigatran, bleeding, and the regulators”. BMJ349: g4517. doi:10.1136/bmj.g4517. PMID25056265.
Pollack, Charles V.; Reilly, Paul A.; Eikelboom, John; Glund, Stephan; Verhamme, Peter; Bernstein, Richard A.; Dubiel, Robert; Huisman, Menno V.; Hylek, Elaine M. (2015-01-01).“Idarucizumab for Dabigatran Reversal”. New England Journal of Medicine373 (6).doi:10.1056/nejmoa1502000.
The chemical name for dabigatran etexilate mesylate, a direct thrombininhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The empirical formula is C34H41N7O5 • CH4O3S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:
Image may be NSFW. Clik here to view.
Dabigatran etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.
The 150 mg capsule for oral administration contains 172.95 mg dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate, and the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. The capsule shell is composed of carrageenan, FD&C Blue No. 2 (150 mg only), FD&C Yellow No. 6, hypromellose, potassium chloride, titanium dioxide, and black edible ink. The 75 mg capsule contains 86.48 mg dabigatran etexilate mesylate, equivalent to 75 mg dabigatran etexilate, and is otherwise similar to the 150 mg capsule.
DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE”
Abstract
A novel process is described for the production of Dabigatran etexilate mesylate, a 5 compound having the following structural formula: and two novel intermediates of said process.
(WO2015124764) SYNTHESIS PROCESS OF DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATEclick herefor patent
Dabigatran etexilate mesylate is an active substance developed by Boehringer
Ingelheim and marketed under the name Pradaxa® in the form of tablets for oral administration; Dabigatran etexilate mesylate acts as direct inhibitor of thrombin (Factor I la) and is used as an anticoagulant, for example, for preventing strokes in patients with atrial fibrillation or blood clots in the veins (deep vein thrombosis) that could form following surgery.
Dabigatran etexilate mesylate is the INN name of the compound 3-({2-[(4-{Amino-[(E)-hexyloxycarbonylimino]-methyl}-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate methanesulphonate, having the following structural formula:
Image may be NSFW. Clik here to view.
The family of compounds to which Dabigatran etexilate belongs was described for the first time in patent US 6,087,380, which also reports possible synthesis pathways.
The preparation of polymorphs of Dabigatran etexilate or Dabigatran etexilate mesylate is described in patent applications US 2006/0276513 A1 , WO 2012/027543 A1 , WO 2008/059029 A2, WO 2013/124385 A2, WO 2013/124749 A1 , WO 2013/1 1 1 163 A2 and WO 2013/144903 A1 , while patent applications WO 2012/044595 A1 , US 2006/0247278 A1 , US 2009/0042948 A2, US 2010/0087488 A1 and WO 2012/077136 A2 describe salts of these compounds.
One of the objects of the invention is to provide an alternative process for the preparation of Dabigatran etexilate mesylate and two novel intermediates of the process.
These objects are achieved with the present invention, which, in a first aspect thereof, relates to a process for the production of Dabigatran etexilate mesylate, comprising the following steps:
a) reacting 4-methylamino-3-nitrobenzoic acid (I) with thionyl chloride to give 4- methylamino-3-nitrobenzoyl chloride hydrochloride (II):
Image may be NSFW. Clik here to view.
(I) (ID
b) reacting compound (II) with 3-(2-pyridylamino) ethyl propanoate (III) to give the compound 3-[(4-methylamino-3-nitro-benzoyl)-pyridyn-2-yl-amino]-ethyl propanoate (IV):
Image may be NSFW. Clik here to view.
(II) (IV)
reducing compound (IV) with hydrogen to 3-[(3-amino-4-methyl benzoyl)-pyridin-2-yl-amino]ethyl propanoate (V):
Image may be NSFW. Clik here to view.
(IV) (V)
d) reacting N-(4-cyanophenyl)glycine (VI) with 1 ,1 -carbonyldiimidazole (CDI) to give 4-(2-imidazol-1 -yl-2-oxo-ethylamino)-benzonitrile (VII):
Image may be NSFW. Clik here to view.
(VI) (VII)
e) reacting compound (VII) with compound (V) obtained in step c) to give one of compounds 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino- benzoyl}-pyridin-2-yl-amino)-ethyl propanoate (VIII) and 3-[(3-amino-4-{[(2- (4-cyano-phenylamino)-acetyl]-methylamino}-benzoyl)-pyridin-2-yl- amino]ethyl propanoate (IX), or a mixture of the two compounds (VIII) and (IX):
Image may be NSFW. Clik here to view.
f) transforming, through treatment with acetic acid, compounds (VIII) or (IX) or the mixture thereof into the compound 3-({2-[(4-cyano-phenylamino)-methyl]- 1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate (X), and then treating compound (X) with hydrochloric or nitric acid to form the corresponding salt (XI):
CHsCOOH
[(VIII) ; (IX)]
Image may be NSFW. Clik here to view.
Image may be NSFW. Clik here to view.
wherein A is a chlorine or nitrate anion;
liberating in solution compound (X) from salt (XI), and reacting compound (X) in solution with ethyl alcohol in the presence of hydrochloric acid and 2,2,2-trifluoroethanol to give the compound 3-({2-[(4-ethoxycarbonimidoyl-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate hydrochloride (XII):
Image may be NSFW. Clik here to view.
reacting compound (XII) with ammonium carbonate to form compound Dabigatran ethyl ester (XIII):
Image may be NSFW. Clik here to view.
reacting compound (XIII) with maleic acid to produce the maleate salt thereof (XI 11 ‘) and isolating the latter:
Image may be NSFW. Clik here to view.
j) reacting maleate salt (XI 11 ‘) with hexyl chloroformate to give compound Dabigatran etexilate (XIV :
hexyl chloroformate
Image may be NSFW. Clik here to view.
k) reacting compound (XIV) with methanesulfonic acid to give the salt Dabigatran etexilate mesylate:
Image may be NSFW. Clik here to view.
a gatran etex ate mesy ate
EXAMPLE 12
Preparation of Dabigatran etexilate mesylate (step k).
All the Dabigatran etexilate obtained in Example 1 1 (4.7 kg; 7.49 moles) is loaded into a reactor along with 28.2 kg of acetone and the mass is heated at 50-60 °C until a complete solution is obtained; it is then filtered to remove suspended impurities. The filtered solution is brought to 28-32 °C. Separately, a second solution is prepared by dissolving 0.705 kg (7.34 moles) of methanesulfonic acid in 4.7 kg of acetone; the second solution is cooled down to 0-10 °C. The second solution is poured into the Dabigatran etexilate solution during 30 minutes, while maintaining the temperature of the resulting solution at 28-32 °C with cooling. The salt of the title is formed. The mass is maintained at 28-32 °C for 2 hours, then cooled to 18-23 °C to complete precipitation and the system is maintained at this temperature for 2 hours; lastly, centrifugation takes place, washing the precipitate with 5 kg of acetone. The precipitate is dried at 60 °C.
4.88 kg of Dabigatran etexilate mesylate, equal to 6.74 moles of compound, are obtained, with a yield in this step of 90%.
EXAMPLE 13
0.5 g of the crystalline compound (XIV) obtained in Example 1 1 are ground thoroughly and loaded into the sample holder of a Rigaku Miniflex diffractometer with copper anode.
The diffractogram shown in Figure 1 is obtained; a comparison with the XRPD data of the known Dabigatran etexilate polymorphs allows to verify that the polymorph of Example 1 1 is novel.
EXAMPLE 14
0.7 g of the crystalline compound (XIV) obtained in Example 1 1 are loaded into
the sample holder of a Perkin-Elmer DSC 6 calorimeter, performing a scan from ambient T to 350 °C at a rate of 10 °C/min in nitrogen atmosphere. The graph of the test is shown in Figure 2, and shows three endothermic phenomena with peaks at 83.0-85.0 °C, 104.0-104.2 °C and 129.9 °C; events linked to the thermal decomposition of the compound are evident at about 200 °C.
Image may be NSFW. Clik here to view.
Figure 1 is an XRPD spectrum of the novel polymorph of Dabigatran etexilate of the invention;
Image may be NSFW. Clik here to view.
Figure 2 is the graph of a DSC test on the novel polymorph of Dabigatran etexilate of the invention.
1 – methyl- lH-benzimidazole-5-carbonyl)pyridm-2-ylamino]propionate base (52.6 kg) (which has preferably been purified beforehand by recrystallization from ethyl acetate) is placed in an agitator apparatus which has been rendered inert and then 293 kg of acetone is added. The contents of the apparatus are heated to 40° C to 46° C with stirring. After a clear solution has formed, the contents of the apparatus is filtered into a second agitator apparatus through a lens filter and then cooled to 30° C to 36° C. 33 kg of acetone precooled to 0° C to 5° C, 7.9 kg of 99.5% methanesulfonic acid, and for rinsing another 9 kg of acetone are placed in the suspended container of the second apparatus. The contents of the suspended container are added in metered amounts to the solution of ethyl 3-[(2-{[4-(hexyloxycarbonylamino- iminomethyl)phenylamino]methyl} – 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-
2- ylamino]propionate base at 26° C to 36° C within 15 to 40 minutes. Then the mixture is stirred for 40 to 60 minutes at 26° C to 33° C. It is then cooled to 17° C to 23° C and stirred for a further 40 to 80 minutes. The crystal suspension is filtered through a filter dryer and washed with a total of 270 L of acetone. The product is dried in vacuum at a maximum of 50° C for at least 4 hours. Yield: 54.5-59.4 kg;
90%-98% of theory based on ethyl 3-[(2-{[4-(hexyloxycarbonyl- ammoiminomethyl)phenylamino]methyl} – 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridm-2-ylamino]propionate base.
Preparation of starting material: Dabigatran Etexilate free base
Dabigatran Etexilate free base can be prepared according to the procedures disclosed in US 6087380 – example 113 or US 7202368 – example 5 Example 1
2.08 g of dabigatran etexilate free base was dissolved in 14.7 ml of acetone at 30 – 36 °C. 0.210 ml of methanesulfonic acid diluted in 2.20 ml of acetone was added within 15 – 40 min. at 26 – 36 °C. The resulting mixture was first steered for 40 – 60 min. at 26 – 36 °C and then for 40 – 80 min at 17 – 23 °C.
The resulting crystalline product was filtered off, washed with 17.87 ml of acetone and dried at 50 °C for 18 hours at 540 mbar.
(Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 210009,China)
4-Methylamino-3-nitrobenzoic acid(3) was prepared from 3-nitro-4-chlorobenzoic acid by methylamination. 3-[(Pyridin-2-yl)amino]propinoic acid ethyl ester(5) was prepared from 2-aminopyridine and ethyl acrylate by Michael addition. Dabigatran etexilate was synthesized from compounds 3 and 5 via condensation, catalytic hydrogenation, acylation with N-(4-cyanophenyl)glycine(9), cyclization, Pinner reaction, followed by reaction with n-hexyl chlorofomate. The overall yield is about 40% and the structure of the product was determined by IR, 1H NMR and MS.
† Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1111 North Zhongshan No. 1 Road, Shanghai 200437, P. R. China
‡ Department of Pharmacy, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021,P. R. China
Synthetic impurities that are present in dabigatran etexilate mesylate were studied, and possible pathways by which these impurities are formed during the manufacturing process were examined. The impurities were monitored by high-performance liquid chromatography, and their structures were determined by mass spectrometry and 1H and 13C NMR. Potential causes for the formation of these impurities are discussed, and strategies to minimize their formation are also described.
NEOVACS, a leader in active immunotherapies for the treatment of autoimmune diseases, today announced that it has been granted first approvals by regulatory agencies and ethics committees in several European countries for a Phase IIb clinical trial of IFNα-Kinoid in Systemic Lupus Erythematosus (SLE) or lupus.
The upcoming trial was notably assessed favorably using the Voluntary Harmonization Procedure (VHP) of Europe’s Heads of Medicine Agencies, which allows for a harmonized assessment of clinical trials by relevant national health authorities.
Acceptance by competent authorities enables Neovacs to initiate IFN-K-002, a Phase IIb clinical study to assess the biological and clinical efficacy of Neovacs’ lead active immunotherapy product candidate IFNα-Kinoid in patients suffering from lupus. Inclusion of first patients is expected to begin in the coming weeks. Approvals from other European, Asian and Latin American countries are expected in the second half of 2015.
Phase IIB trial design for IFN-K-002 in SLE
IFN-K-002 is a double-blind, randomized, placebo-controlled multicentric Phase IIb clinical trial designed to assess the efficacy and safety of IFNα-Kinoid in moderate to severe lupus patients. The study will recruit 166 patients across 19 countries in Europe, Asia and Latin America.
The co-primary endpoints for the trial are biological efficacy and clinical efficacy nine months after first immunization with IFNα-Kinoid. Biological efficacy is defined as IFNα-signature neutralization, while clinical efficacy will be measured by the BILAG-based1 Composite Lupus Assessment (BICLA) response.
Timelines for the study
Regulatory and ethics committee approvals pave the way for a rapid initiation of the study IFN-K-002. These centers will begin screening and immunizing patients in the coming weeks. Results of the clinical trial are expected in the first quarter of 2017.
About Neovacs
Created in 1993, Neovacs is today a leading biotechnology company focused on an active immunotherapy technology platform (Kinoids) with applications in autoimmune and/or inflammatory diseases. On the basis of the company’s proprietary technology for inducing a polyclonal immune response (covered by five patent families that potentially run until 2032) Neovacs is focusing its clinical development efforts on IFNα-Kinoid, an immunotherapy being developed for the indication of lupus and dermatomyositis. Neovacs is also conducting preclinical development works on other therapeutic vaccines in the fields of auto-immune diseases, oncology and allergies. The goal of the Kinoid approach is to enable patients to have access to safe treatments with efficacy that is sustained in these life-long diseases.
CAS 260790-58-7 (Monohydrate)
CAS 260790-59-8 (MonoHBr)
CAS 260790-60-1 (Monomethanesulfonate)
ASTRAZENECA INNOVATOR
Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement forwarfarin[1] that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports ofhepatotoxicity (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).[2]
Ximelagatran is an ester prodrug of melagatran, a potent, direct, and reversible thrombin inhibitor (Ki = 1.2 nM). While melagatran has poor oral bioavailability, ximelagatran displays good bioavailability resulting, in part, from rapid absorption at the gastrointestinal tract, as well as rapid onset of action.Ximelagatran is converted to melagatran by reduction and hydrolysis at the liver and other tissues. It is used as an anticoagulant in a variety of situations, including thromboembolic disorders, stroke prevention in atrial fibrillation, and therapy in vein thrombosis
Method of action
Ximelagatran, a direct thrombin inhibitor,[3] was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues throughdealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).
Uses
Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well documented,[4][5][6] except for non valvular atrial fibrillation.
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by vitamin K and heparin by protamine sulfate.
Side-effects
Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzymelevels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications.[2]
Eriksson, H; Wahlander K; Gustafsson D; Welin LT; Frison L; Schulman S; THRIVE Investigators (January 2003). “A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I”. Journal of Thrombosis and Haemostasis1 (1): 41–47. doi:10.1046/j.1538-7836.2003.00034.x. PMID12871538.
Francis, CW; Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr; EXULT A Study Group (October 2003). “Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement”. New England Journal of Medicine349 (18): 1703–1712.doi:10.1056/NEJMoa035162. PMID14585938.
Schulman, S; Wåhlander K; Lundström T; Clason SB; Eriksson H; THRIVE III investigators (October 2003). “Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran”. New England Journal of Medicine349 (18): 1713–1721. doi:10.1056/NEJMoa030104. PMID14585939.
The U.S. Food and Drug Administration approved Varubi (rolapitant) to prevent delayed phase chemotherapy-induced nausea and vomiting (emesis). Varubi is approved in adults in combination with other drugs (antiemetic agents) that prevent nausea and vomiting associated with initial and repeat courses of vomit-inducing (emetogenic and highly emetogenic) cancer chemotherapy.
Nausea and vomiting are common side effects experienced by cancer patients undergoing chemotherapy. Symptoms can persist for days after the chemotherapy drugs are administered. Nausea and vomiting that occurs from 24 hours to up to 120 hours after the start of chemotherapy is referred to as delayed phase nausea and vomiting, and it can result in serious health complications. Prolonged nausea and vomiting can lead to weight loss, dehydration and malnutrition in cancer patients leading to hospitalization.
“Chemotherapy-induced nausea and vomiting remains a major issue that can disrupt patients’ lives and sometimes their therapy,” said Amy Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Today’s approval provides cancer patients with another treatment option for the prevention of the delayed phase of nausea and vomiting caused by chemotherapy.”
Varubi is a substance P/neurokinin-1 (NK-1) receptor antagonist. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by certain cancer chemotherapies, particularly in the delayed phase. Varubi is provided to patients in tablet form.
The safety and efficacy of Varubi were established in three randomized, double-blind, controlled clinical trials where Varubi in combination with granisetron and dexamethasone was compared with a control therapy (placebo, granisetron and dexamethasone) in 2,800 patients receiving a chemotherapy regimen that included highly emetogenic (such as cisplatin and the combination of anthracycline and cyclophosphamide) and moderately emetogenic chemotherapy drugs. Those patients treated with Varubi had a greater reduction in vomiting and use of rescue medication for nausea and vomiting during the delayed phase compared to those receiving the control therapy.
Varubi inhibits the CYP2D6 enzyme, which is responsible for metabolizing certain drugs. Varubi is contraindicated with the use of thioridazine, a drug metabolized by the CYP2D6 enzyme, because use of the two drugs together may increase the amount of thioridazine in the blood and cause an abnormal heart rhythm that can be serious.
The most common side effects in patients treated with Varubi include a low white blood cell count (neutropenia), hiccups, decreased appetite and dizziness.
Varubi is marketed by Tesaro Inc., based in Waltham, Massachusetts.
Both the ECA Academy and the European Qualified Person Association (EQPA) are often contacted by people who would like to become a Qualified Person (QP according the EU Directives) in a Member State of the European Union or outside the EU to release products for the EU market. Questions are for example:
“Can I become a QP and live and work outside the EU?”
“I work for an American company that would like to export medicinal product to the EU. How can we hire a QP here in the U.S.?”
“I am an Irish Citizen living and working in Australia. I am thinking of studying a course by distance learning…
All participants of the GMP training course “GMP-compliant Product Transfer” will receive a special version of the Guideline Manager CD including documents and templates useable for site change projects. Read more.
According to the European GMP-Rules, written procedures for tranfser activities and their documentation are required. For example, a Transfer SOP, a transfer plan and a report are now mandatory and will be checked during inspections.
As a participant of the GMP education course “GMP-compliant Product Transfer” in Prague, from 20-22 October 2015 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.
Image may be NSFW. Clik here to view.
Regulatory Guidance Documents like the WHO guideline on transfer of technology in pharmaceutical manufacturing and the…
Christopher, John A (2014). “Small-molecule antagonists of the orexin receptors”. Pharmaceutical Patent Analyst3 (6): 625–638.doi:10.4155/ppa.14.46. ISSN2046-8954.
Boss, Christoph (2014). “Orexin receptor antagonists – a patent review (2010 to August 2014)”. Expert Opinion on Therapeutic Patents24 (12): 1367–1381.doi:10.1517/13543776.2014.978859. ISSN1354-3776.
Dabigatran etexilate (a compound of formula (I)) is the international commonly accepted non-proprietary name for ethyl 3-{[(2-{[(4-{[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate, which has an empirical formula of C34H41N7O5 and a molecular weight of 627.73.
Dabigatran etexilate is the pro-drug of the active substance, dabigatran, which has a molecular formula C25H25N7O3 and molecular mass 471.51. The mesylate salt (1:1) of dabigatran etexilate is known to be therapeutically useful and is commercially marketed as oral hard capsules in the United States and in Europe under the trade mark Pradaxa™ for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Additionally, it is also marketed in Europe under the same trade mark for the primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.
Dabigatran etexilate was first described in U.S. Patent No. 6,087,380 , according to which the synthesis of dabigatran etexilate was carried out in three synthetic steps (see Scheme 1). Example 58 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and N-(4-cyanophenyl)glycine (compound III) in the presence of N,N‘-carbonyldiimidazole (CDI) in tetrahydrofuran to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound IV), which is subsequently reacted with ethanolic hydrochloric acid, ethanol and ammonium carbonate to give the hydrochloride salt of ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Finally, example 113 describes the reaction between compound V and n-hexyl chloroformate (compound VI), in the presence of potassium carbonate, in a mixture of tetrahydrofuran and water, to give dabigatran etexilate after work-up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate.
U.S. Patent No. 7,202,368 describes an alternative process for the synthesis of dabigatran etexilate (see Scheme 2). Example 3 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound VII) in the presence of a coupling agent such as N,N‘-carbonyldiimidazole (CDI), propanephosphonic anhydride (PPA), or pivaloyl chloride, to give ethyl 3-{[(2-{[(4-{1,2,4-oxadiazol-5-on-3-yl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound VIII), which is subsequently hydrogenated (Example 4) in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Then, Example 5 describes the acylation of compound V with n-hexyl chloroformate (compound VI) to give dabigatran etexilate. Finally, Example 6 describes the conversion of dabigatran etexilate into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, VII, VIII and V, no information is given neither about the purity of the isolated dabigatran etexilate nor about its mesylate salt.
European Patent Applications EP 1966171A and EP 1968949Adescribe similar processes for the synthesis of dabigatran etexilate to that depicted in Scheme 2, but without isolating some of the intermediate compounds. HPLC purities higher than 99% are described for both dabigatran etexilate (see Examples 6B and 6C ofEP 1966171A ) and its mesylate salt (see Example 9 ofEP 1966171A and Example 7 ofEP 1968949A). However, no information is given about the structure of the impurities present in dabigatran etexilate and / or its mesylate salt.
PCT Patent Application WO 2010/045900 describes the synthesis of dabigatran etexilate mesylate with 99.5% purity by HPLC (Examples 3 and 4) by following a similar synthetic process to that described in Scheme 1. However, no information is given about the structure of the impurities present in the mesylate salt of dabigatran etexilate.
The Committee for Medicinal Products for Human use (CHMP) assessment report for Pradaxa (i.e. dabigatran etexilate mesylate salt 1:1) reference EMEA/174363/2008, as published in the European Medicines Agency website on 23/04/2008, describes (page 8) that the proposed specifications for impurities in the active substance are for some specified impurities above the qualification threshold of the ICH guideline “Impurities in new drug substances”, i.e. above 0.15%. However, no information is given about the structure of the impurities present in the mesylate salt of dabigatran etexilate.
There is still further provided by the present invention a process of preparing dabigatran etexilate mesylate, which process comprises the following synthetic steps:
300 g (1.49 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 769 g of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, a clear solution was obtained. The solution was kept at reflux temperature for 2 hours and total consumption of 4-chloro-3-nitrobenzoic acid was checked by TLC. The solution was cooled to room temperature, and pH was adjusted to about 1 by addition of 2M aqueous sulphuric acid. Precipitation of a yellow solid was observed, which was isolated by filtration. The filtered cake was washed with water and subsequently with methanol to obtain 331 g of wet 4-(methylamino)-3-nitrobenzoic acid as a yellow powder. Purity (HPLC, method 2): 99.1 %.
75.2 g (0.80 mol) of 2-aminopyridine and 88.0 g (0.88 mol) of ethyl acrylate were dissolved in 20 mL of acetic acid. The mixture was heated to 80°C and stirred for 24 hours at the same temperature. Solvent was removed under vacuum, and the title compound was isolated by vacuum distillation (b.p. 160-172°C, 10-15 mmHg) to obtain 77.0 g of ethyl 3-(2-pyridylamino)propionate as a white solid. Yield: 49.6 %.
c) Ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)aminolpropanoate hydrochloride
50 g (0.25 mol) of 4-(methylamino)-3-nitrobenzoic acid as obtained in step (a) were suspended in a mixture of 459.2 g of thionyl chloride and 3 mL of N,N-dimethylformamide. The mixture was stirred at reflux temperature for 45 minutes. Excess thionyl chloride was removed by vacuum distillation. The residue was dissolved in 300 mL of toluene, which was subsequently removed by vacuum distillation to remove completely any residual thionyl chloride. The brownish crystalline residue obtained was dissolved in 280 mL of tetrahydrofuran at 60°C. At this point, 35.1 g of triethylamine were added to the solution. Then, a solution of 45 g (0.23 mol) of ethyl 3-(2-pyridylamino)propanoate as obtained in step (b) in 95 mL of tetrahydrofuran was added dropwise over the reaction mixture, keeping the temperature at about 30°C. The resulting mixture was stirred overnight at room temperature. Solvent was removed by vacuum distillation, and the residue was dissolved in 1 L of dichloromethane. The resulting solution was washed with 500 mL of water, 500 mL of 2M hydrochloric acid, 500 mL of saturated sodium bicarbonate and 500 mL of water. The organic phase was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved with 600 mL of ethyl acetate, and dry hydrogen chloride was bubbled into the solution until precipitation was completed. The solid was isolated by filtration and dried to obtain 63 g of the title compound, which was recrystallized in a mixture of 450 mL of ethanol and 50 mL of acetonitrile at reflux temperature. After cooling to 10°C, solid was isolated by filtration and dried to yield 44.7 g of ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride as a yellow solid. Yield: 47.2 %. Purity (HPLC, method 1): 97.6 %.
82.2 g (0.20 mol) of ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate hydrochloride as obtained in step (c) were suspended in 1.1 L of isopropanol, in the presence of 126.7 g of ammonium formate and 17.5 g of a 5 % Pd/C catalyst (55% water content). The reaction mixture was stirred at reflux temperature for 2.5 hours. After cooling to room temperature, the catalyst was removed by filtration, the filtrate was concentrated under vacuum, and the residue was dissolved in 1.5 L of ethyl acetate. The resulting solution was washed with 800 mL of saturated sodium bicarbonate and with 800 mL of water. The organic phase was dried with anhydrous sodium sulfate and was concentrated under vacuum to yield 44 g of ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate as a dark oil. Yield: 63.9 %. Purity (HPLC, method 2): 90.8 %.
54.0 g (0.46 mol) of 4-aminobenzonitrile and 106.5 g (0.92 mol) of sodium chloroacetate were suspended in 750 mL of water, and the resulting mixture was stirred at reflux temperature for 4 hours. After cooling to room temperature, pH was adjusted to 8-9 with sodium bicarbonate. The resulting solution was washed with 2 x 200 mL of ethyl acetate, and 5M hydrochloric acid was added to the aqueous phase until pH=3. The precipitated solid was isolated by filtration, washed with 100 mL of water and dried to yield 57.1 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 70.9 %. Purity (HPLC, method 3): 88.4 %.
f) Ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate (salt of compound IV)
25.7 g (0.15 mol) of 2-(4-cyanophenylamino)acetic acid as obtained in step (e) and 22.8 g (0.14 mol) of 1,1′-carbonyldiimidazole were suspended in 720 mL of tetrahydrofuran. The mixture was stirred at reflux temperature for 1 hour. Then, a solution of 44.0 g (0.13 mol) of ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate as obtained in step (d) in 180 mL of tetrahydrofuran was added dropwise over the reaction mixture. The resulting mixture was stirred overnight at reflux temperature, and the solvent was removed by distillation under vacuum. The resulting residue was dissolved in 486 mL of acetic acid and heated to reflux temperature for 1 hour. After cooling to room temperature, solvent was removed by distillation under vacuum. The resulting residue was dissolved in 450 mL of ethyl acetate, and the solution was washed with 450 mL of water. The organic phase was dried with anhydrous sodium sulfate and heated to 50-60°C. At this temperature, 15.1 g (0.17 mol) of oxalic acid were added, and the resulting mixture was stirred for 1 hour at 50-60°C. After cooling to room temperature, the precipitated solid was filtered and dried under vacuum, to yield 47.7 g of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate as a brownish solid. Yield: 64.8 %. Purity (HPLC, method 1): 87.9 %
47.7 g (83 mmol) of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate as obtained in step (f) and 21.8 g of p-toluenesulfonic acid were suspended in 142 g of a 10M hydrogen chloride solution in ethanol. The mixture was stirred at room temperature for 24 hours. At this point, 400 mL of ethanol were added and the resulting mixture was cooled to 0°C. Ammonia gas was bubbled at this temperature until formation of precipitate was completed. The mixture was stirred at 10°C for 2 hours, and then was stirred at room temperature overnight. Solvent was removed by distillation under vacuum. The residue was dissolved in a mixture of 400 mL of ethanol, 400 mL of water and 2.3 g of sodium hydroxide at 55°C, and was stirred at this temperature for 45 minutes. After cooling to 10°C, the mixture was stirred at this temperature for 1 hour. The solid was removed by filtration and discarded. The mother liquors were concentrated under vacuum to remove ethanol. The precipitated solid was isolated by filtration, washed with 200 mL of water and with 2 x 100 mL of acetone, to yield 34.7 g of ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate as an off-white solid. Yield: 83.4 %. Purity (HPLC, method 3): 83 %.
33.7 g (67 mmol) of ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate as obtained in step (g) and 24.7 g of potassium carbonate were suspended in a mixture of 280 mL of water and 1.4 L of tetrahydrofuran. After stirring at room temperature for 15 minutes, 9.2 g (56 mmol) of hexyl chloroformate were added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The organic phase was extracted, washed with 400 mL of brine and dried with anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting solid was purified by column chromatography eluting with ethyl acetate, to yield 24.9 g of dabigatran etexilate as an off-white solid. Yield: 71.0 %. Purity (HPLC, method 1): 96.3 %.
i) Dabigatran etexilate mesylate
18.7 g (30 mmol) of dabigatran etexilate as obtained in step (h) were suspended in 103 g of acetone. The mixture was heated to 45°C. After cooling to 36°C, a solution of 2.83 g of methanesulfonic acid in 11.6 g of acetone at 0°C was added dropwise over the reaction mixture. The reaction was stirred at 23-33°C for 90 minutes and at 17-23°C for 60 minutes. The resulting solid was isolated by filtration, washed with 97 mL of acetone and dried at 50°C under vacuum, to yield 18.7 g of dabigatran etexilate mesylate as a pale yellow solid. Yield: 86.7 %. Purity (HPLC, method 1): 98.8 %.
The procedure described in WO 9837075 produces compound VI in the form of its base or acetate. Both these products require chromatographic purification, which is very difficult to apply in the industrial scale. This purification method burdens the process economy very much and has a negative impact on the yield.
In the next stage acidic hydrolysis of the nitrile function of compound VI and a reaction with ammonium carbonate is performed to produce the substance of formula VII. The reaction is shown in Scheme 2.
Scheme 2 The procedure in accordance with WO 9837075 produces substance VII in the monohydro chloride form.
When reproducing the procedure of WO 9837075 we found out, in line with WO 9837075, that compound VII prepared by this method required subsequent chromatographic purification as it was an oily substance with a relatively high content of impurities. We did not manage to find a solvent that would enable purification of this substance by crystallization.
The last stage is a reaction of intermediate VII with hexyl chloroformate producing dabigatran and its transformation to a pharmaceutically acceptable salt; in the case of the above mentioned patent application it is the methanesulfonate.
To 9.1 g of compound VII-2HC1 (0.016 mol) 270 ml of chloroform and 9 ml (0.064 mol) of triethylamine are added. Then, a solution of 3.1 ml (0.018 mol) of hexyl chloroformate in chloroform is added dropwise at the laboratory temperature. After one hour the reaction mixture is shaken with brine and the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 8.6 g (86%)
This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated precipitate is aspirated and dried at the laboratory temperature. Yield: 75%; content according to HPLC: 99.5%. 27
Example 4:
Preparation of dabigatran mesylate
9 g of compound VII-HCl (0.017 mol) were dissolved in 300 ml of chloroform. 6, ml of triethylamine were added to this solution and then a solution of 3.4 ml (0.02 mol) of hexyl chloroformate in chloroform was added dropwise. After one hour the reaction mixture is shaken with brine, the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 9.6 g (90%)
This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated evaporation residue is aspirated and dried at the laboratory temperature. Yield: 73%; content according to HPLC: 99.5%.
DabigatranEtexilateMesylate chemically know as N-[[2-[[[4-[[[(hexyloxy) carbonyl] amino]-iminomethyl] phenyl] amino] . methyl]-l -methyl-lH- benzimidazol-5-yl] carbonyI]-N-2- pyridinyl-beta-Alanine ethyl ester methanesulfonate having the formula I as provided below,
is a direct thrombin inhibitor having anti – coagulant activity when administered orally.
DabigatranEtexilate is first time reported in the US patent 6087380 (hereinafter referred as US’380) in which the process fo the preparation of DabigatranEtexilate is disclosed in the Example 49, 58a and Example 59, said process for the preparation of DabigatranEtexilate is depicted below:
In accordance to the process in the Patent US’380 the substance requires complex purifying operations, such as chromatography for the production of high- quality API. Further the chromatographic purification is expensive and difficult to implement in large scale. The impurity in the Dabigatran single prodrug and Dabigatran Etexilate affects the purity of the final product DabigatranEtexilateMesylate.. Hence there is a necessity to maintain the purity level of every intermediate involved in the preparation of DabigatranEtexilateMesylate.
The patent application US201 1082299 discloses a process for the preparation Dabigatran from 3- ([2-[(4-cyanophenyl amino)-methyl]- l-methyl- l H-benzimidazole-5-carbonyl]-pyridin-2-yl-amino) ethyl propionate oxalate as one of the intermediate in order to overcome the problem of the process depicted in the product pate
The patent US81 19810 discloses the process for the preparation Dabigatran from 3- ([2-[(4-cyanophenylamino)-methyl]-l-methyl-lH- benzimidazole-5-carbonyl]-pyridin-2-yl-amino) ethyl propionate hydro bromide as one of the intermediate in order to overcome the problem of the process depicted in the product patent.
which is DabigatranEtexilate are exemplified in the examples of the patent US’380. The patent US’380 has no information about the solid state properties of the single prodrug of Dabigatran and DabigatranEtexilate. However, a similar process described in a publication of Hauel et al in Journal of Medicinal Chemistry, 2002, 45, .1757 – 1766, wherein DabigatranEtexilate is characterized by 128 – 129°C.
The PCT publication WO2006131491 discloses the anhydrous form [ of DabigatranEtexilate having the melting point 135°C, anhydrous form II of DabigatranEtexilate having the melting point 150°C, and hydrate form of DabigatranEtexilate having the melting point 90°C.
The PCT publication WO2008059029 discloses anhydrous form III of DabigatranEtexilate having melting point 128°C, anhydrous form IV of DabigatranEtexilate having the melting point 133°C, and mono hydrate form I of DabigatranEtexilate having melting point 128°C and mono hydrate form II of DabigatranEtexilate having melting point 123°C.
The different forms of the single prodrug of Dabigatran and/or the DabigatranEtexilate are disclosed in the patent applications of WO2012027543, WO2012004396 and WO 2012044595.
The patent application US2007185333 discloses the process ; for the preparation of DabigatranEtexilateMesylate from the DabigatranEtexilate by adding acetone solution of , methanesulfonic acid in an acetone solution of DabigatranEtexilate.
The patent application US 200601 83779 discloses the process for the preparation of DabigatranEtexilateMesylate from the DabigatranEtexilate by adding ethylacetate solution of methanesulfonic acid in an ethylacetate solution of DabigatranEtexilate.
Example-9: Process for the preparation of DabigatranEtexilateMesylate from DabigatranEtexilate
[0086] The DabigatranEtexilate (0.04 mol) was dissolved in acetone (250.0 ml) and added Methanesulfonic acid (0.04 mol) in Ethyl acetate (25 ml) at 25-30°C. Stirred the reaction mass for 3 hrs at the same temperature, the isolated solid was filtered and washed with acetone, dried under vacuum to get the DabigatranEtexilateMesylate. Yield: 85 %, Purity: Not less than 99.0%
Example 10: Process for the preparation of DabigatranEtexilateMesylate
[0087] To a solution of DabigatranEtexilate (0.04 mol) in Acetone (8 volumes) and Ethanol (2 volumes), Methanesulfonic acid solution [Methanesulfonic acid (0.04 mol) was dissolved in Ethyl acetate (25 ml) was added at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, the resultant solid was filtered, washed with acetone and dried under vacuum. Yield: 93%
l-methyl-2-|Tvi-[4-(TSi-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazole- 5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide is commonly known as Dabigatran etexilate. Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors developed by Boehringer Ingelheim and is used for the treatment of thrombosis, cardiovascular diseases, and the like. Dabigatran etexilalte mesylate was approved in both US and Europe and commercially available under the brand name Pradaxa.
Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075.
The disclosed process involves the reaction of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2- yl)benzamido)propanoate with 2-(4-cyanophenylamino) acetic acid in the presence of N,N- carbonyldiimidazole in tetrahydrofuran to provide ethyl 3-(2-((4-cyanophenylamino)methyl)-l- methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole-5-carboxamido)propanoate, which is further converted into l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride by reacting with ammonium carbonate in ethanol, followed by treating with ethanolic hydrochloric acid. The obtained compound was reacted with n-hexyl chloroformate in presence of potassium carbonate in tetrahydrofuran/water provides Dabigatran etexilate and further conversion into its mesylate salt was not disclosed. The purity of Dabigatran etexilate prepared as per the disclosed process is not satisfactory, and also the said process involves chromatographic purification which is expensive and difficult to implement in the large scale. Hence the said process is not suitable for commercial scale up.
Moreover, the said process proceeds through the l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride (herein after referred as “Dabigatran hydrochloride”), which degrades to form impurities and resulting in the formation of Dabigatran etexilate with low purity. In view of intrinsic fragility of Dabigatran hydrochloride, there is a need in the art to develop a novel salt form of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2- pyridyl)-N-(2-ethoxycarbonyl ethyl)amide, which enhances the purity of the final compound.
The prior reported processes disclosed in WO2012004396 and WO2008095928 Al involves the usage of inorganic salts like hydrochloride and hydrobromide salts of ethyl 3-(2-((4- cyanophenylamino)methyl)- 1 -methyl -N-(pyridin-2-yl)- 1 H-benzo[d]imidazole-5-carboxamido) propanoate (herein after referred as “cyano intermediate”) and ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)- 1 -methyl -N-(pyridin-2-yl)- 1 H-benzo[d]imidazole-5-carboxamido) propanoate (herein after referred as “amidino intermediate”). The inorganic acid addition salts are less stable when compared to the organic acid addition salts and also the process for the preparation of organic acid addition salts is very much easy when compared to inorganic acid addition salt. Inorganic acid addition salts of amidine intermediate seem to be hygroscopic in nature. Therefore, organic acid addition salts are always preferable to synthesize stable salts which in-turn enhances the purity of the final compound.
The oxalate salt of cyano intermediate was disclosed in WO2009111997. However as on date, there is no other organic acid addition salts of cyano intermediate were reported in the prior art for preparing pure Dabigatran etexilate. Henceforth, there is a need to develop a novel organic acid addition salt of cyano intermediate compound which is very much efficient when compared to its corresponding oxalate salt and that result in the formation of final compound with high purity and yield.
The process disclosed in WO 98/37075 also involves the reduction of, ethyl 3-(4- (methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “nitro compound”) using Pd-C in a mixture of dichloromethane and methanol under hydrogen pressure to provide ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “diamine compound”).
The reduction of nitro compound through catalytic hydrogenation in the presence of tertiary amine under hydrogen pressure was also disclosed in WO2009153214; and in presence of inorganic base under hydrogen pressure was also disclosed in WO2012004397.
However, most of the prior art processes proceed through catalytic hydrogenation which involves the pressure reactions. Handlings of these pressure reactions are not suitable for the large scale process. Therefore, there is a significant need in the art to provide a simple reduction process which avoids the difficulties associated with catalytic hydrogenation.
JMC, 2002, 45(9), 1757-1766 disclosed a process for the preparation of ethyl 3-(3-amino- 4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate starting from 4-(methylamino)-3- nitrobenzoic acid. The disclosed process involves the conversion of 4-(methylamino)-3- nitrobenzoic acid into its acid chloride using thionyl chloride and the obtained compound was reacted with ethyl 3-(pyridin-2-ylamino)propanoate to provide nitro compound, followed by catalytic reduction using Pd-C to provide diamine compound.
However, particularly in large scale synthesis the reduction reaction occasionally stops due to catalyst poisoning which leads to incomplete reaction and requires additional catalyst to complete the reaction. Moreover the sulfur impurities which are present in nitro compound formed due to the reaction with thionyl chloride in the previous stages of the synthesis of diamine compound are strongly influence the reaction time, quality and catalyst consumption in the manufacturing process.
Surprisingly, the problem associated with the catalytic hydrogenation and catalyst poisoning is solved by the present invention by adopting a suitable reducing agent such as Fe- acetic acid and Fe-hydrochloric acid.
The crystalline forms-I, II, V and VI of Dabigatran etexilate oxalate were disclosed in WO2008043759 and WO2011110876.
The crystalline forms-Ill, IV and V of Dabigatran etexilate fumarate were disclosed in WO2008043759 and WO2011110876.
Various different salts for Dabigatran etexilate and their polymorphs were reported in WO98/37075, WO03074056, WO2005028468, WO2006114415, WO2008043759, WO2011110876, WO2012027543 and WO2012044595.
The process for the preparation of crystalline form-I of Dabigatran etexilate mesylate was described in WO2005028468 and WO2012027543.
HPLC analysis of Innovator Tablet
The present inventors has also analyzed the Pradaxa 110 mg tablet having Lot no: 808809 and compared with dabigatran etexilate mesylate obtained from the present invention and found that, the impurity profile of both the products are similar to each other i.e., amide impurity, despyridyl ethyl ester etc. are well present even in Pradaxa tablet. Henceforth, we can presume that these impurities are known from the art.
a) Dabigatran etexilate (Formula-1) and Dabigatran etexilate mesylate (Formula-la):
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength
UV-detector; Column: Zorbax Eclipse XDB CI 8, 100 X 4.6mm, 3.5 μιη θΓ Equivalent; Flow Rate: 1.0 mL/min; Wavelength : 300 nm; Column temperature: 25°C; Injection volume: 5 μΐ,; Run time: 50 minutes; Auto sampler temperature: 5°C; Buffer: Dissolve 0.63gm of Ammonium formate in lOOOmL of Milli-Q- Water and mix well. Adjust its pH to 8.2 with Ammonia and filtered through 0.22 μιη nylon membrane and degas it. Mobile phase-A: Buffer; Mobile phase- B: Acetonitrile: Water (80:20) v/v; Diluent: N,N-Dimethylformamide; Needle wash: Diluent; Elution: Gradient. b) Ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole-5-carboxamido)propanoate methanesulfonate (Formula-10)
Apparatus : A liquid chromatograph is equipped with variable wavelength UV- Detector; Column: Zorbax SB CN 150 x 4.6mm, 5μπι (or) Equivalent (Make: Agilent and PNo: 883975- 905); Flow Rate: 1.0 mL / min; Column temperature: 25°C; Wave length: 290 nm; Injection volume: 5 μΐ-.; Run time: 60 minutes; Elution: Gradient; Diluent: Water: Acetonitrile (70:30) v/v; Needle wash: Diluent; Buffer: Weigh accurately about 2 g of 1 -Octane sulphonic acid sodium salt anhydrous and add 5 mL of Ortho phosphoric acid in 1000 mL of Milli-Q- Water and mix well, filter this solution through 0.22 μηι^ΐοη membrane and sonicate to degas; Mobile Phase- A: Buffer(100%);Mobile Phase- B: Acetonitrile: Methanol (90: 10) v/v. c) Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH- benzo[d] imidazole-5-carboxamido)propanoate methanesulfonate (Formula-11)
Apparatus : A liquid chromatographic system is to be equipped with variable wavelength UV- Detector and Integrator; Column : Zodiac CI 8 250 X 4.6 mm, 5 μηι (or) equivalent (Make: Zodiac and PNo. ZLS.C18.46.250.0510 ); Flow Rate: 1.0 mL/min; Wavelength: 290 nm; Column temperature: 25°C; Injection Volume: 5μί; Run time: 55 min; Elution: Gradient;
Buffer: Take 5 mL of Ortho phosphoric acid(85%) and 2 g of 1 -Octane sulfonic acid sodium salt anhydrous in 1000 mL of Milli-Q-water and adjust its pH to 2.5 with Triethyl amine filter, through 0.22 μπι Nylon membrane filter paper and sonicate to degas it; Mobile Phase-A: Buffer(l 00%) Mobile Phase-B: Acetonitrile: Water (90: 10) v/v; Diluent : Water: Acetonitrile (80:20) v/v.
Morphology: Method of analysis: Samples were mounted on aluminium stubs using double adhesive tape, coated with gold using HUS-5GB vacuum evaporation and observed in Hitachi S-3000 N SEM at an acceleration voltage of 10KV.
Following are the impurities observed during the preparation of Dabigatran etexilate mesylate.
Dabigatran etexilate Dabigatran etexilate Mesylate The process described in the present invention was demonstrated in examples illustrated below.
Example-13: Preparation of Dabigatran etexilate (Formula-1)
n-hexanol (30.8 g) was added to a solution of N, N-carbonyldiimidazole (61.15 g) and dichloromethane (360 ml) at 15-25°C and stirred for 3 hours. The organic layer was washed with water followed by sodium chloride solution. Distilled off the solvent from the organic layer completely under reduced pressure to get amide compound. Acetonitrile (157.5 ml) was added to the obtained amide compound. This was added to a mixture of ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-l-methyl-N-( yridin-2-yl)-lH-benzo[d]imidazole-5- carboxamido)propanoate mesylate compound of formula- 11 (90 g), potassium carbonate (62.5 g), acetonitrile (378 ml) and water (252 ml) at 25-35°C. The reaction mixture was heated to 40- 50°C and stirred for 8 hours. After completion of the reaction, both the organic and aqueous layers were separated; the organic layer was cooled to -5 to +5°C and stirred for 2 hours. Filtered the precipitated solid washed with acetonitrile and water. The obtained compound was dissolved in a mixture of acetone (270 ml) and acetonitrile (270 ml) at 45-50°C. Cooled the reaction mixture to 25-30°C and water (360 ml) was added to it. Filtered the obtained solid and dissolved in the mixture of dichloromethane and sodium chloride solution at 35-40°C. Both the organic and aqueous layers were separated; the organic layer was distilled under reduced pressure and then co-distilled with ethyl acetate. The obtained crude compound was dissolved in ethyl acetate (540 ml) by heating it to 70-80°C and stirred for 30 minutes. Filtered the reaction mixture, the filtrate was cooled to 35-45°C and ethanol (8 ml) was added to the reaction mixture. The reaction mixture was again cooled to 25-35°C and stirred for 3 hours. Filtered the precipitated solid and then dried to get pure title compound.
Yield: 44 g; MR: 128-131 °C. Purity by HPLC: 99.63%.
Preparation of dabigatran etexilate mesylate: l-methyl-2-[N-[4-( -n-hexyloxycarbonylamidino)phenyl] amino methyl]benzimidazol-5- yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl) amide (100 gm) was dissolved acetone (1000 ml) under heating at 25-35 °C. A solution of methane sulfonic acid (13.77 gm) in acetone (100 ml) was added to the reaction mixture. The solution is filtered and after the addition of acetone cooled to approximately 20° C. The precipitated product was filtered and washed with acetone then dried at 50° C under reduced pressure.
USAN (AB-55) BOCOCIZUMAB
PRONUNCIATION boe” koe siz’ ue mab
THERAPEUTIC CLAIM Treatment of dyslipidemia
CHEMICAL NAME
1. Immunoglobulin G2, anti-(human neural apoptosis-regulated proteinase
1)(human-Mus musculus monoclonal PF-04950615 heavy chain), disulfide
with human-Mus musculus monoclonal PF-04950615 light chain, dimer
2. Immunoglobulin G2-kappa, anti-[human proprotein convertase subtilisin/hexin type 9 (neural apoptosis-regulated convertase 1, PC9)], humanized mouse monoclonal antibody; gamma 2 heavy chain (1-444) [humanized VH (Homo sapiens IGHV1-46-1*03 (90.8%) -(IGHD)-IGHJ6*01) [8.8.11] (1-118)-Homo sapiens IGHG2*01 CH2A100>S(327),CH2P101>S(328) (119-444)] (132-214′)-
disulfide with kappa light chain (1′-214′) [humanized V-KAPPA (Homo sapiensIGKV1-39*01 (88.2%)-IGKJ2*01 [6.3.9] (1′-107′)-IGKC*01 (108′-214′)]; dimer
(220-220”:221-221”:224-224”:227-227”)-tetrakisdisulfide
MOLECULAR FORMULA C6414H9918N1722O2012S54
MOLECULAR WEIGHT 145.1 kDa
TRADEMARK None as yet
SPONSOR Pfizer, Inc.
CODE DESIGNATIONS RN316, PF-04950615
CAS REGISTRY NUMBER 1407495-02-6
WHO NUMBER 9840
A phase 2b study of statin patients was presented at the 2014 American College of Cardiology. Monthly or bimonthly injections resulted in significantly reduced LDL-C at week 12.
The Phase 3 SPIRE trials plan to enroll 17,000 patients to measure cardiovascular risk. High risk and statin intolerant subjects will be included.
Vandetanib was the first drug to be approved by FDA (April 2011) for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.[3] Vandetanib was first initially marketed without a trade name,[4] and is being marketed under the trade name Caprelsa since August 2011.[5]
2011 年 4 月 6 by the FDA-approved surgical resection can not be used for locally advanced or metastatic medullary thyroid cancer (medullary thyroid cancer, MTC) of the drug. Vandetanib is vascular endothelial growth factor receptors (vascular endothelial growth factor receptor, VEGFR) and epidermal growth factor receptor (epidermal growth factor receptor, EGFR) antagonists, tyrosine kinase inhibitors (tyrosine kinase inhibitor). Produced by AstraZeneca.
Vandetanib is well absorbed from the gut, reaches peak blood plasma concentrations 4 to 10 hours after application, and has a half-life of 120 hours days on average, per Phase I pharmacokinetic studies. It has to be taken for about three months to achieve a steady-state concentration. In the blood, it is almost completely (90–96%) bound to plasma proteins such as albumin. It is metabolised to N-desmethylvandetanib via CYP3A4 and to vandetanib-N-oxide via FMO1 and 3. Both of these are active metabolites. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites.[2][9][10]
Metabolites of vandetanib (top left): N-desmethylvandetanib (bottom left, via CYP3A4), vandetanib-N-oxide (bottom right, via FMO1 andFMO3), both pharmacologically active, and a minor amount of aglucuronide.[10]
AstraZeneca withdrew EU regulatory submissions for vandetanib (under the proposed trade name Zactima) in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy.[14]
Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.”. Drug Metabol Drug Interact.0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID24643910.
Haberfeld, H, ed. (2012). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
Jump up^Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.”. Drug Metabol Drug Interact.0 (0): 1–11.doi:10.1515/dmdi-2014-0014. PMID24807167.
Martin, P.; Oliver, S.; Kennedy, S. J.; Partridge, E.; Hutchison, M.; Clarke, D.; Giles, P. (2012). “Pharmacokinetics of Vandetanib: Three Phase I Studies in Healthy Subjects”.Clinical Therapeutics34 (1): 221–237. doi:10.1016/j.clinthera.2011.11.011.PMID22206795.
Clinical trial number NCT00687297 for “Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer” at ClinicalTrials.gov
Novartis launches first US ‘biosimilar’ drug at 15 percent discount
LONDON/ZURICH: Novartis kicked off a new era in U.S. medicine on Thursday with the launch of the first “biosimilar” copy of a biotechnology drug approved in the United States, at a discount of 15 percent to the original.
The Swiss drugmaker’s generics unit Sandoz said Zarxio, its form of Amgen’s white blood cell-boosting product Neupogen, would increase access to an important treatment by offering a “high-quality, more affordable version”.
On March 6, 2015, FDA approved the first biosimilar under the Biologics Price Competition and Innovation Act (BPCIA), Sandoz’s Zarxio®. Sandoz submitted Zarxio®as a highly similar, not interchangeable biosimilar, for the same indications as the referenced product. The BPCIA was signed into law in March 2010.
FDA designated “filgrastim-sndz” as the placeholder nonproprietary name rather than the innovator’s name, filgrastim. FDA said that this nonproprietary name “should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilar and other biological products. While the FDA has not yet issued draft guidance on how current and future biological [biosimilar?] products marketed in the United States should be named, the agency intends to do so in the near future.”
Accompanying the news release was a document “Biosimilars: More Treatment Options Are on the Way”. The document includes various quotes and paraphrased statements by Leah Christl, Ph.D., Associate Director for Therapeutic Biologics, to help describe to consumers what biosimilar medications are. Below are some quotes and information from that document:
Biologics are medicines that generally come from living organisms, which can include humans, animals and microorganisms such as yeast and bacteria.
. . .
“Biologics are different from conventional medications. Conventional medications—drugs—are generally made from chemicals, or chemically synthesized, and therefore their structure can be relatively easily defined,” explains Christl.
Unlike conventional medications, biologics can’t be made by following a chemical “recipe.” “Biologics come from living organisms which are variable in nature. In addition, they are generally more complex and not as easy to define and characterize,” Christl explains. For that reason, manufacturing biologics is a far more complex process than manufacturing drugs.
Just as it does for drugs, FDA rigorously and thoroughly evaluates a biologic’s safety and effectiveness before granting it licensure (approval). Currently, biologics are among the fastest growing segments of the prescription product market.
. . .
Christl explains that a biosimilar is a type of biologic that is highly similar to another, already FDA-approved biologic (known as the reference product).
“It is important to note that a biosimilar is not just like a generic drug,” she adds. “Because of the differences in complexity of the structure of the biologic and the process used to make a biologic, biosimilars are not as easy to produce as generics, which are copies of brand name drugs.” A biosimilar is not an exact duplicate of another biologic; rather, a biosimilar is highly similar to the reference product.
Before approving a biosimilar, FDA experts must also first verify that there are no clinically meaningful differences between the biosimilar and its reference product. In other words, it will work the same way as the reference product for its approved indications.
Also, the biosimilar must have the same strength and dosage form (injectable, for example) and route of administration as the reference product. The biosimilar must be manufactured followingCurrent Good Manufacturing Practices.
“Patients can rest assured that they’ll be able to rely upon the safety and effectiveness of an FDA-approved biosimilar, just as they can rely on the reference product that the biosimilar was compared to,” Christl says. Like other biologics, biosimilars generally must be prescribed by a physician.
. . .
“Biosimilars are likely to create greater competition in the medical marketplace,” saysChristl. This could not only increase treatment options for patients, but also lead to less expensive alternatives to comparable products. With an increasing number of biosimilars on the market, consumers may expect to get equally safe and effective treatment, but at lower costs, she says.
Despite the significant achievement for FDA to approve the first biosimilar under the BPCIA, significant questions other than nonproprietary naming remain. First, Sandoz chose not to take advantage of the pre-approval patent exchange mechanism of the BPCIA, which could have addressed possible patent challenges that may prevent Sandoz from marketing Zarxio®until certain patents are invalidated, are found unenforceable, or have expired. Second, because this and other non-interchangeable versions of biosimilars are not expected to have automatic substitution based on the BPCIA, it remains unclear how ready physicians or patients will be to try a biosimilar version over its referenced product. Third, company representatives from Sandoz and other biosimilar manufacturers have not indicated at what price their biosimilar products will be sold, at times suggesting “at parity,” which may cause reimbursement issues. Fourth, many states have enacted rules that include special physician notification provisions, even when interchangeable biosimilars are dispensed to patients. And there are still issues surrounding pharmacovigilance and risk management when there are innovator and corresponding biosimilar versions marketed. Nevertheless, FDA proclaims that more biosimilars are on the way, as additional companies have indicated that they have submitted or FDA has filed their biosimilar applications. Sandoz’s Zarxio® then is just the tip of the iceberg of what is coming with more issues to be resolved along the way.
ZARXIO is produced by Escherichia coli(E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. ZARXIO has a molecular weight of 18,800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from humanDNA sequence analysis, except for the addition of an N-terminal methioninenecessary for expression in E coli. Because ZARXIO is produced in E coli, the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.
ZARXIO injection is a sterile, clear, colorless to slightly yellowish , preservative-free liquid containing filgrastimsndz at a specific activity of 1.0 x 108 U/mg (as measured by a cell mitogenesis assay). The product is available in single-use prefilled syringes. The single-use prefilled syringes contain either 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim-sndz. See table below for product composition of each single-use prefilled syringe.
Christopher Conway, Senior Vice President,
Global Sales and Marketing
Christopher Conway has been appointed to lead the company’s discovery business strategy as Senior Vice President of Discovery and Development and Global Commercial Sales.
Image may be NSFW. Clik here to view.
September 3, 2015
SEE AN UPDATEFRO AMRI
QUOTE
Dear industry colleague,
As we continue to support the research and development that leads to the commercialization of pharmaceutical products, it is critical that we align our focus on R&D with the commercial demands of the market. Today, AMRI has announced an organizational change in our Discovery and Development Services (DDS) business. These changes are expected to drive top and bottom line growth for the Discovery and Development Solutions (DDS) business through strong commercial leadership; strengthen the DDS strategy and aggressively pursue the most valuable growth opportunities, externally and internally; and ensure that our service offerings are well aligned with your needs and the needs of the market.
Effective immediately, Christopher Conway has been appointed to lead the company’s discovery business strategy as Senior Vice President of Discovery and Development and Global Commercial Sales. In this role, Chris will head up the global Discovery and Development Solutions (DDS) business leading these businesses in the United States, Europe and Asia. Sales and marketing will also continue to report to him. He succeeds Michael A. Luther, Ph.D., MBA, who will be leaving AMRI to pursue other opportunities. We thank Dr. Luther for his efforts in moving the DDS business along over the last year and wish him the best in his future endeavors.
Related to this announcement, we would like to take the opportunity to announce the hiring of Rory Curtis, Ph.D., who has joined AMRI as Vice President of Discovery Biology and Pharmacology. Rory will also serve as site head with responsibility for scientific operations at AMRI’s Buffalo, N.Y. location. Rory was most recently Senior Director of Human Diseases in Discovery at Cubist Pharmaceuticals, where he developed Cubist’s antibacterial drug discovery into new disease areas such as pain, inflammation and gastro-intestinal disease. Before this, he held positions of increasing responsibility at Elixir Pharmaceuticals, Millennium Pharmaceuticals and Regeneron Pharmaceuticals.
Image may be NSFW. Clik here to view.
Rory Curtis
Vice President of Discovery Biology and Pharmacology, Site Head AMRI Buffalo
In addition to Chris’ current direct reports and Rory, he will have a scientific leadership team reporting into him, which includes Michael P. Trova, Ph.D., Senior Vice President of Chemistry; Raj Shenoy, Senior Director of Global Chemical Development; and Pete Michels, Ph.D., Senior Director of Metabolism and Biotransformations.
Image may be NSFW. Clik here to view.
Michael P. Trova, Ph.D.
Image may be NSFW. Clik here to view.
Pete C. Michels, Ph.D., Senior Director, Chemical Development, Fermentation and Biocatalysis, AMRI
We are very excited about the future of AMRI Drug Discovery and Development and are pleased to welcome Rory to the AMRI discovery team. Market demand for our DDS services continues to grow and these changes will help us increase our market share and strengthen AMRI’s global position in Discovery and Development.
As we approach the second half of 2015, we are looking forward to working with you on a great number of new opportunities in 2016 and beyond. We appreciate your loyalty and support, and continue to remain dedicated to enhancing your pharmaceutical services experience from early discovery through to the commercialization and delivery of drug product. If you have any questions, please feel free to read today’s related press release at www.amriglobal.com, or contact us here.
Sincerely,
Image may be NSFW. Clik here to view.
William S. Marth
President and CEO
Albany Molecular Research Inc. (AMRI) www.amriglobal.com
Image may be NSFW. Clik here to view.
William S. Marth. President and Chief Executive Officer Albany Molecular Research, Inc.
Image may be NSFW. Clik here to view.
Image may be NSFW. Clik here to view.
Albany Molecular Research Inc. (AMRI)
26 Corporate Circle
Albany, NY 12203
Albany Molecular Research Inc. provides global contract research and manufacturing services to the pharmaceutical and biotechnology industries. Our services include Drug Discovery, such as medicinal chemistry, discovery biology and in vitro ADME; Development, such as pre-formulation, formulation and validation; and Manufacturing, such as cGMP API manufacturing.
SINGAPORE RESEARCH CENTRE
Image may be NSFW. Clik here to view.AMRI’s Singapore Research Centre, Pte. Ltd. provides chemistry and biology services to support drug discovery and development programs. AMRI is one of the first drug discovery R&D companies to establish operations in Singapore. Fully integrated with AMRI’s locations in the United States, Asia, and Europe, the Singapore centre offers medicinal chemistry services such as hit-to-lead andlead optimization as well as focused library synthesis / custom synthesis. In the area of biology / in vitro pharmacology, the Singapore Research Centre provides target validation; assay development; HTS; rapid production of SAR quality data; and in vitro ADMET support, including CYP inhibition, metabolic stability (liver microsome assays), and aqueous solubility. As a signatory to the World Patent Treaty, Singapore provides an environment that protects intellectual property, enabling our scientists to conduct proprietary and cutting-edge research on behalf of our customers.
Image may be NSFW. Clik here to view.The Hyderabad Research Centre, Pvt. Ltd. (AMRHRC) is located in Hyderabad, India, an emerging technology metropolis located in South Central India.
All fully integrated with AMRI’s U.S.-based resources, this Centre’s core area of expertise is in the areas of medicinal chemistrysupport, chemical development, custom synthesis of scaffolds and building blocks, process development, GMP analytical services,scale-up and preparation of reference standards.
Image may be NSFW.
Image may be NSFW.
Image may be NSFW.
Image may be NSFW.
Image may be NSFW.
Image may be NSFW.
Image may be NSFW.
