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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Cavosonstat (N-91115)


Cavosonstat.png

Cavosonstat (N-91115)

CAS 1371587-51-7

C16H10ClNO3, 299.71 g/mol

UNII-O2Z8Q22ZE4, O2Z8Q22ZE4, NCT02589236; N91115-2CF-05; SNO-6

3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid

Treatment of Chronic Obstructive Pulmonary Diseases (COPD), AND Cystic fibrosis,  Nivalis Therapeutics, phase 2

The product was originated at Nivalis Therapeutics, which was acquired by Alpine Immune Sciences in 2017. In 2018, Alpine announced the sale and transfer of global rights to Laurel Venture Capital for further product development.

In 2016, orphan drug and fast track designations were granted to the compound in the U.S. for the treatment of cystic fibrosis.

  • Originator N30 Pharma
  • Developer Nivalis Therapeutics
  • Class Small molecules
  • Mechanism of Action Cystic fibrosis transmembrane conductance regulator modulators; Glutathione-independent formaldehyde dehydrogenase inhibitors; Nitric oxide stimulants
  • Orphan Drug Status Yes – Cystic fibrosis
  • 20 Jul 2018 Laurel Venture Capital acquires global rights for cavosonstat from Alpine Immune Sciences
  • 20 Jul 2018 Laurel Venture Capital plans a phase II trial for Asthma
  • 24 Jun 2018 Biomarkers information updated

 Cavosonstat, alos known as N91115) an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.

cavosonstat-n91115Cavosonstat (N91115) was an experimental therapy being developed by Nivalis Therapeutics. Its primary mechanism of action was to inhibit the S-nitrosoglutathione reductase (GSNOR) enzyme and to stabilize cystic fibrosis transmembrane regulator (CFTR) protein activity. A press release published in February announced the end of research for this therapy in cystic fibrosis (CF) patients with F508del mutations. The drug, which did not meet primary endpoints in a Phase 2 trial, had been referred to as the first of a new class of compounds that stabilizes the CFTR activity.

History of cavosonstat

During preclinical studies, N91115 (later named cavosonstat) demonstrated an improvement in cystic fibrosis transmembrane regulator (CFTR) stability.

Phase 1 study was initiated in 2014 to evaluate the safety, tolerability, and pharmacokinetics (how a drug is processed in the body) of the drug in healthy volunteers. Later that year, the pharmacokinetics of the drug were assessed in another Phase 1 trial involving CF patients with F508del mutation suffering from pancreatic insufficiency. Results were presented a year later by Nivalis, revealing good tolerance and safety in study participants.

A second, much smaller Phase 2 study (NCT02724527) assessed cavosonstat as an add-on therapy to ivacaftor (Kalydeco). This double-blind, randomized, placebo-controlled study included 19 participants who received treatment with cavosonstat (400 mg) added to Kalydeco or with placebo added to Kalydeco. The primary objective was change in lung function from the study’s start to week 8. However, the treatment did not demonstrate a benefit in lung function measures or in sweat chloride reduction at eight weeks (primary objective). As a result, Nivalis decided not to continue development of cavosonstat for CF treatment.

The U.S. Food and Drug Administration (FDA) had granted cavosonstat both fast track and orphan drug designations in 2016.

How cavosonstat works

The S-nitrosoglutathione (GSNO) is a signaling molecule that is present in high concentrations in the fluids of the lungs or muscle tissues, playing an important role in the dilatation of the airways. GSNO levels are regulated by the GSNO reductase (GSNOR) enzyme, altering CFTR activity in the membrane. In CF patients, GSNO levels are low, causing a loss of the airway function.

Cavosonstat’s mechanism of action is achieved through GSNOR inhibition, which was presumed to control the deficient CFTR protein. Preclinical studies showed that cavosonstat restored GSNO levels.

PATENT
WO 2012083165

The chemical compound nitric oxide is a gas with chemical formula NO. NO is one of the few gaseous signaling molecules known in biological systems, and plays an important role in controlling various biological events. For example, the endothelium uses NO to signal surrounding smooth muscle in the walls of arterioles to relax, resulting in vasodilation and increased blood flow to hypoxic tissues. NO is also involved in regulating smooth muscle proliferation, platelet function, and neurotransmission, and plays a role in host defense. Although NO is highly reactive and has a lifetime of a few seconds, it can both diffuse freely across membranes and bind to many molecular targets. These attributes make NO an ideal signaling molecule capable of controlling biological events between adjacent cells and within cells.

[0003] NO is a free radical gas, which makes it reactive and unstable, thus NO is short lived in vivo, having a half life of 3-5 seconds under physiologic conditions. In the presence of oxygen, NO can combine with thiols to generate a biologically important class of stable NO adducts called S-nitrosothiols (SNO’s). This stable pool of NO has been postulated to act as a source of bioactive NO and as such appears to be critically important in health and disease, given the centrality of NO in cellular homeostasis (Stamler et al., Proc. Natl. Acad. Sci. USA, 89:7674-7677 (1992)). Protein SNO’s play broad roles in the function of cardiovascular, respiratory, metabolic, gastrointestinal, immune, and central nervous system (Foster et al., Trends in Molecular Medicine, 9 (4): 160-168, (2003)). One of the most studied SNO’s in biological systems is S-nitrosoglutathione (GSNO) (Gaston et al., Proc. Natl. Acad. Sci. USA 90: 10957-10961 (1993)), an emerging key regulator in NO signaling since it is an efficient trans-nitrosating agent and appears to maintain an equilibrium with other S-nitrosated proteins (Liu et al., Nature, 410:490-494 (2001)) within cells. Given this pivotal position in the NO-SNO continuum, GSNO provides a therapeutically promising target to consider when NO modulation is pharmacologically warranted.

[0004] In light of this understanding of GSNO as a key regulator of NO homeostasis and cellular SNO levels, studies have focused on examining endogenous production of GSNO and SNO proteins, which occurs downstream from the production of the NO radical by the nitric oxide synthetase (NOS) enzymes. More recently there has been an increasing understanding of enzymatic catabolism of GSNO which has an important role in governing available concentrations of GSNO and consequently available NO and SNO’s.

[0005] Central to this understanding of GSNO catabolism, researchers have recently identified a highly conserved S-nitrosoglutathione reductase (GSNOR) (Jensen et al., Biochem J., 331 :659-668 (1998); Liu et al., (2001)). GSNOR is also known as glutathione-dependent formaldehyde dehydrogenase (GSH-FDH), alcohol dehydrogenase 3 (ADH-3) (Uotila and Koivusalo, Coenzymes and Coƒactors., D. Dolphin, ed. pp. 517-551 (New York, John Wiley & Sons, (1989)), and alcohol dehydrogenase 5 (ADH-5). Importantly GSNOR shows greater activity toward GSNO than other substrates (Jensen et al., (1998); Liu et al., (2001)) and appears to mediate important protein and peptide denitrosating activity in bacteria, plants, and animals. GSNOR appears to be the major GSNO-metabolizing enzyme in eukaryotes (Liu et al., (2001)). Thus, GSNO can accumulate in biological compartments where GSNOR activity is low or absent (e.g. , airway lining fluid) (Gaston et al., (1993)).

[0006] Yeast deficient in GSNOR accumulate S-nitrosylated proteins which are not substrates of the enzyme, which is strongly suggestive that GSNO exists in equilibrium with SNO-proteins (Liu et al., (2001)). Precise enzymatic control over ambient levels of GSNO and thus SNO-proteins raises the possibility that GSNO/GSNOR may play roles across a host of physiological and pathological functions including protection against nitrosative stress wherein NO is produced in excess of physiologic needs. Indeed, GSNO specifically has been implicated in physiologic processes ranging from the drive to breathe (Lipton et al., Nature, 413: 171-174 (2001)) to regulation of the cystic fibrosis transmembrane regulator (Zaman et al., Biochem Biophys Res Commun, 284:65-70 (2001)), to regulation of vascular tone, thrombosis, and platelet function (de Belder et al., Cardiovasc Res.; 28(5):691-4 (1994)), Z. Kaposzta, et al., Circulation; 106(24): 3057 – 3062, (2002)) as well as host defense (de Jesus-Berrios et al., Curr. Biol., 13: 1963-1968 (2003)). Other studies have found that GSNOR protects yeast cells against nitrosative stress both in vitro (Liu et al., (2001)) and in vivo (de Jesus-Berrios et al., (2003)).

[0007] Collectively, data suggest GSNO as a primary physiological ligand for the enzyme S-nitrosoglutathione reductase (GSNOR), which catabolizes GSNO and

consequently reduces available SNO’s and NO in biological systems (Liu et al., (2001)), (Liu et al., Cell, 116(4), 617-628 (2004)), and (Que et al., Science, 308, (5728): 1618-1621 (2005)). As such, this enzyme plays a central role in regulating local and systemic bioactive NO. Since perturbations in NO bioavailability has been linked to the pathogenesis of numerous disease states, including hypertension, atherosclerosis, thrombosis, asthma, gastrointestinal disorders, inflammation, and cancer, agents that regulate GSNOR activity are candidate therapeutic agents for treating diseases associated with NO imbalance.

[0008] Nitric oxide (NO), S-nitrosoglutathione (GSNO), and S-nitrosoglutathione reductase (GSNOR) regulate normal lung physiology and contribute to lung pathophysiology. Under normal conditions, NO and GSNO maintain normal lung physiology and function via their anti-inflammatory and bronchodilatory actions. Lowered levels of these mediators in pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) may occur via up-regulation of GSNOR enzyme activity. These lowered levels of NO and GSNO, and thus lowered anti-inflammatory capabilities, are key events that contribute to pulmonary diseases and which can potentially be reversed via GSNOR inhibition.

[0009] S-nitrosoglutathione (GSNO) has been shown to promote repair and/or regeneration of mammalian organs, such as the heart (Lima et al., 2010), blood vessels (Lima et al., 2010) skin (Georgii et al., 2010), eye or ocular structures (Haq et al., 2007) and liver (Prince et al., 2010). S-nitrosoglutathione reductase (GSNOR) is the major catabolic enzyme of GSNO. Inhibition of GSNOR is thought to increase endogenous GSNO.

[0010] Inflammatory bowel diseases (IBD’s), including Crohn’s and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal (GI) tract, in which NO, GSNO, and GSNOR can exert influences. Under normal conditions, NO and GSNO function to maintain normal intestinal physiology via anti-inflammatory actions and maintenance of the intestinal epithelial cell barrier. In IBD, reduced levels of GSNO and NO are evident and likely occur via up-regulation of GSNOR activity. The lowered levels of these mediators contribute to the pathophysiology of IBD via disruption of the epithelial barrier via dysregulation of proteins involved in maintaining epithelial tight junctions. This epithelial barrier dysfunction, with the ensuing entry of micro-organisms from the lumen, and the overall lowered anti-inflammatory capabilities in the presence of lowered NO and GSNO, are key events in IBD progression that can be potentially influenced by targeting GSNOR.

[0011] Cell death is the crucial event leading to clinical manifestation of

hepatotoxicity from drugs, viruses and alcohol. Glutathione (GSH) is the most abundant redox molecule in cells and thus the most important determinant of cellular redox status. Thiols in proteins undergo a wide range of reversible redox modifications during times of exposure to reactive oxygen and reactive nitrogen species, which can affect protein activity. The maintenance of hepatic GSH is a dynamic process achieved by a balance between rates of GSH synthesis, GSH and GSSG efflux, GSH reactions with reactive oxygen species and reactive nitrogen species and utilization by GSH peroxidase. Both GSNO and GSNOR play roles in the regulation of protein redox status by GSH.

[0012] Acetaminophen overdoses are the leading cause of acute liver failure (ALF) in the United States, Great Britain and most of Europe. More than 100,000 calls to the U.S. Poison Control Centers, 56,000 emergency room visits, 2600 hospitalizations, nearly 500 deaths are attributed to acetaminophen in this country annually. Approximately, 60% recover without needing a liver transplant, 9% are transplanted and 30% of patients succumb to the illness. The acetaminophen-related death rate exceeds by at least three-fold the number of deaths due to all other idiosyncratic drug reactions combined (Lee, Hepatol Res 2008; 38 (Suppl. 1):S3-S8).

[0013] Liver transplantation has become the primary treatment for patients with fulminant hepatic failure and end-stage chronic liver disease, as well as certain metabolic liver diseases. Thus, the demand for transplantation now greatly exceeds the availability of donor organs, it has been estimated that more than 18 000 patients are currently registered with the United Network for Organ Sharing (UNOS) and that an additional 9000 patients are added to the liver transplant waiting list each year, yet less than 5000 cadaveric donors are available for transplantation.

[0014] Currently, there is a great need in the art for diagnostics, prophylaxis, ameliorations, and treatments for medical conditions relating to increased NO synthesis and/or increased NO bioactivity. In addition, there is a significant need for novel compounds, compositions, and methods for preventing, ameliorating, or reversing other NO-associated disorders. The present invention satisfies these needs.

Schemes 1-6 below illustrate general methods for preparing analogs.

[00174] For a detailed example of General Scheme 1 see Compound IV-1 in Example 1.

[00175] For a detailed example of Scheme 2, A conditions, see Compound IV-2 in Example 2.

[00176] For a detailed example of Scheme 2, B conditions, see Compound IV-8 in Example 8.

[00177] For a detailed example of Scheme 3, see Compound IV-9 in Example 9.

[00178] For a detailed example of Scheme 4, Route A, see Compound IV-11 in Example 11.

[00179] For a detailed example of Scheme 4, Route B, see Compound IV-12 in Example 12.

[00180] For a detailed example of Scheme 5, Compound A, see Compound IV-33 in Example 33.

[00181] For a detailed example of Scheme 5, Compound B, see Compound IV-24 in Example 24.

[00182] For a detailed example of Scheme 5, Compound C, see Compound IV-23 in Example 23.

Example 8: Compound IV-8: 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid

[00209] Followed Scheme 2, B conditions:

[00210] Step 1: Synthesis of 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid:

[00211] A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1) (200 mg, 1.04 mmol), 4-carboxy-2-chlorophenylboronic acid (247 mg, 1.24 mmol) and K2CO3(369 mg, 2.70 mmol) in DEGME / H2O (7.0 mL / 2.0 mL) was degassed three times under N2 atmosphere. Then PdCl2(dppf) (75 mg, 0.104 mmol) was added and the mixture was heated to 110 °C for 3 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, yield 46%) as a yellow solid, which was used for the next step without further purification.

[00212] Step 2: Synthesis of Compound IV-8: To a suspension of 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, 0.479 mmol) in anhydrous CH2Cl2 (5 mL) was added AlCl3 (320 mg, 2.40 mmol). The reaction mixture was refluxed overnight. The mixture was quenched with saturated NH4Cl (10 mL) and the aqueous layer was extracted with CH2Cl2 / MeOH (v/v=10: l, 30 mL x3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive) to give 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (25 mg, yield 18%). 1H NMR (DMSO, 400 MHz): δ 10.20 (brs, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.10-8.00 (m, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 6.4, 2.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), MS (ESI): m/z 299.9 [M+H]+.

PATENT
WO 2012048181
PATENT
WO 2012170371

REFERENCES

1: Donaldson SH, Solomon GM, Zeitlin PL, Flume PA, Casey A, McCoy K, Zemanick ET,
Mandagere A, Troha JM, Shoemaker SA, Chmiel JF, Taylor-Cousar JL.
Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic
fibrosis adults homozygous for F508DEL-CFTR. J Cyst Fibros. 2017 Feb 13. pii:
S1569-1993(17)30016-4. doi: 10.1016/j.jcf.2017.01.009. [Epub ahead of print]
PubMed PMID: 28209466.

//////////Cavosonstat, N-91115, Orphan Drug Status, NCT02589236, N91115-2CF-05,  SNO-6, PHASE 2, N30 Pharma, Nivalis Therapeutics, CYSTIC FIBROSIS, FAST TRACK

O=C(O)C1=CC=C(C2=NC3=CC=C(O)C=C3C=C2)C(Cl)=C1

Deutivacaftor


2D chemical structure of 1413431-07-8

Ivacaftor D9.png

Structure of DEUTIVACAFTOR

Deutivacaftor

RN: 1413431-07-8
UNII: SHA6U5FJZL

N-[2-tert-butyl-4-[1,1,1,3,3,3-hexadeuterio-2-(trideuteriomethyl)propan-2-yl]-5-hydroxyphenyl]-4-oxo-1H-quinoline-3-carboxamide

Molecular Formula, C24-H28-N2-O3, Molecular Weight, 401.552

Synonyms

  • CTP-656
  • D9-ivacaftor
  • Deutivacaftor
  • Ivacaftor D9
  • UNII-SHA6U5FJZL
  • VX-561
  • WHO 10704

Treatment of Cystic Fibrosis

  • Originator Concert Pharmaceuticals
  • Class Amides; Aminophenols; Antifibrotics; Organic deuterium compounds; Quinolones; Small molecules
  • Mechanism of Action Cystic fibrosis transmembrane conductance regulator stimulants
  • Orphan Drug Status Yes – Cystic fibrosis
  • Phase II Cystic fibrosis
  • 15 Apr 2019 Vertex Pharmaceuticals plans a phase II trial for Cystic fibrosis in April 2019 , (EudraCT2018-003970-28), (NCT03911713)
  • 11 Apr 2019 Vertex Pharmaceuticals plans a phase II trial for Cystic Fibrosis (Combination therapy) in May 2019 (NCT03912233)
  • 24 Oct 2018 Vertex Pharmaceuticals plans a phase II trial for Cystic fibrosis (with gating mutation) in the US in the first half of 2019

Patent

WO 2012158885

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=A7EFB561D919F34531D65DF294F8D74C.wapp1nB?docId=WO2012158885&tab=PCTDESCRIPTION&queryString=%28+&recNum=99&maxRec=1000

Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, nonradioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res, 1985, 14: 1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol, 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem., 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

[9] This invention relates to novel derivatives of ivacaftor, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a CFTR (cystic fibrosis transmembrane conductance regulator) potentiator.

[10] Ivacaftor, also known as VX-770 and by the chemical name, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, acts as a CFTR potentiator. Results from phase III trials of VX-770 in patients with cystic fibrosis carrying at least one copy of the G551D-CFTR mutation demonstrated marked levels of improvement in lung function and other key indicators of the disease including sweat chloride levels, likelihood of pulmonary exacerbations and body weight. VX-770 is also currently in phase II clinical trials in combination with VX-809 (a CFTR corrector) for the oral treatment of cystic fibrosis patients who carry the more common AF508-CFTR mutation. VX-770 was granted fast track designation and orphan drug designation by the FDA in 2006 and 2007, respectively.

[11] Despite the beneficial activities of VX-770, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

Patent

US 20140073667

Patent

JP 2014097964

PATENT

WO 2018183367

https://patentscope.wipo.int/search/zh/detail.jsf?docId=WO2018183367&tab=PCTDESCRIPTION&office=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A61K%22&sortOption=%E5%85%AC%E5%B8%83%E6%97%A5%E9%99%8D%E5%BA%8F&queryString=&recNum=555&maxRec=186391

The use according to embodiment 1, comprising administering to the patient an effect amount of (N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-l, 1, 1,3, 3,3-d6)phenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (Compound Il-d):

Il-d

PATENT

WO 2019018395,

CONTD…………………………..

//////////////////deutivacaftor, Orphan Drug Status, Cystic fibrosis, CTP-656, D9-ivacaftor, Deutivacaftor, Ivacaftor D9, UNII-SHA6U5FJZL, VX-561, WHO 10704, PHASE 2

[2H]C([2H])([2H])C(c1cc(c(NC(=O)C2=CNc3ccccc3C2=O)cc1O)C(C)(C)C)(C([2H])([2H])[2H])C([2H])([2H])[2H]

OLACAFTOR, VX 440


Image result for VX 440

NHOUNZMCSIHKHJ-FQEVSTJZSA-N.png

OLACAFTOR, VX 440

CAS 1897384-89-2

Molecular Formula: C29H34FN3O4S
Molecular Weight: 539.666 g/mol

CFTR corrector; UNII-RZ7027HK8F; RZ7027HK8F;

Target-based Actions, CFTR modulator

Indications, Cystic fibrosis

CS-0044588

UNII-RZ7027HK8F

RZ7027HK8F

Olacaftor (VX-440, VX440) is a next-generation CFTR corrector, shows the potential to enhance the amount of CFTR protein at the cell’s surface and for treatment of cystic fibrosis..

  • Originator Vertex Pharmaceuticals
  • Class Pyridines; Pyrrolidines
  • Mechanism of Action Cystic fibrosis transmembrane conductance regulator stimulants
  • Phase II Cystic fibrosis
  • 01 Jun 2018 Chemical structure information added
  • 01 Aug 2017 Vertex Pharmaceuticals completes a phase II trial in Cystic fibrosis (In adolescents, In adults, In the elderly, Combination therapy) in USA, Australia, Austria, Belgium, Canada, Denmark, Germany, Italy, Spain, Netherlands and United Kingdom (PO) (NCT02951182) (EudraCT2016-000454-36)
  • 18 Jul 2017 Efficacy and events data from a phase II trial in Cystic fibrosis released by Vertex Pharmaceuticals

PATENT

WO2016057572

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B67642F2D5C265D1AF3AC60194173694.wapp1nB?docId=WO2016057572&recNum=6&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A01N%22&sortOption=Pub+Date+Desc&maxRec=22922

PATENT

US9782408

PATENT

WO-2019028228

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019028228&tab=PCTDESCRIPTION&maxRec=1000

Processes for preparing (S)-2,2,4-trimethylpyrrolidine and its salts, particularly hydrochloride comprising the reaction of 2,2,6,6-tetramethyl-piperidin-4-one with chloroform and a base (sodium hydroxide), followed by reaction with an acid (hydrochloric acid), hydrogenation, reduction and salt synthesis is claimed. Also claimed is a process for the preparation of an intermediate of (S)-2,2,4-trimethylpyrrolidine hydrochloride. The compound is useful as an intermediate for the synthesis of CFTR modulators, useful for treating cystic fibrosis.
(5)-2,2,4-trimethylpyrrolidine free base and salt forms thereof, (R)-2,2,4-trimethylpyrrolidine free base and salt forms thereof, (,S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, and 5,5-dimethyl-3-methylenepyrrolidin-2-one are useful molecules that can be used in the synthesis of pharmaceutically active molecules, such as modulators of CFTR activity, for example those disclosed in PCT Publication Nos. WO 2016/057572, WO 2018/064632, and WO 2018/107100, including the following molecules, which are being investigated in clinical trials for the treatment of cystic fibrosis:

[0003] There remains, however, a need for more efficient, convenient, and/or economical processes for the preparation of these molecules.

[0004] Disclosed herein are processes for preparing 5,5-dimethyl-3-methylenepyrrolidin-2-one, (,S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, (,S)-2,2,4-trimethylpyrrolidine, and (R)-2,2,4-trimethylpyrrolidine, and their salt forms:


trimethylpyrrolidine-2-one)); ((R)-3,5,5-trimethylpyrrolidine-2-one));

((,S)-2,2,4-trimethylpyrrolidine) ;and 

Scheme 1. Synthesis of (S)-2,2,4-trimethylpyrrolidine

(2) (3) (4S) (1 S)

Scheme 2. Synthesis of (R)-2,2,4-trimethylpyrrolidine

(2) (3) (4R) (1 R)

Scheme 3. Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

3 C

EXAMPLES

Example 1. Reaction (a) and (b): Synthesis of 5,5-dimethyl-3-methylenepyrrolidin- 2-one

(2) (3) C (3)

Example 1A:

[0055] 2,2,6,6-tetramethylpiperidin-4-one (50.00 g, 305.983 mmol, 1.000 equiv), tributylmethylammonium chloride (2.89 g, 3.0 mL, 9.179 mmol, 0.030 equiv), chloroform (63.92 g, 43.2 mL, 535.470 mmol, 1.750 equiv), and DCM (dichloromethane) (100.0 mL, 2.00 vol) were charged to a 1000 mL three-neck round bottom flask equipped with an overhead stirrer. The reaction mixture was stirred at 300 rpm, and 50 wt% NaOH (195.81 g, 133.2 mL, 2,447.863 mmol, 8.000 equiv) was added dropwise (via addition funnel) over 1.5 h while maintaining the temperature below 25 °C with intermittent ice/acetone bath. The reaction mixture was stirred at 500 rpm for 18 h, and monitored by GC (3% unreacted piperidinone after 18 h). The suspension was diluted with DCM (100.0 mL, 2.00 vol) and H2O (300.0 mL, 6.00 vol), and the phases were separated. The aqueous phase was extracted with DCM (100.0 mL, 2.00 vol). The organic phases were combined and 3 M hydrochloric acid (16.73 g, 153.0 mL, 458.974 mmol, 1.500 equiv) was added. The mixture was stirred at 500 rpm for 2 h. The conversion was complete after approximately 1 h. The aqueous phase was saturated with NaCl, H2O (100.0 mL, 2.00 vol) was added to help reduce the emulsion, and the phases were separated. The aqueous phase was extracted with DCM (100.0 mL, 2.00 vol) twice. H2O (100.0 mL, 2.00 vol) was added to help with emulsion separation. The organic phases were combined, dried (MgS04), and

concentrated to afford 32.6 g (85%) of crude Compound (3) as a pale orange clumpy solid. The crude was recrystallized from hot (90°C) iPrOAc (isopropyl acetate) (71.7 mL, 2.2 vol. of crude), cooled to 80 °C, and -50 mg of crystalline Compound (3) was added for seeding. Crystallization started at 77 °C, the mixture was slowly cooled to ambient temperature, and aged for 2 h. The solid was collected by filtration, washed with 50/50 iPrOAc/heptane (20.0 mL, 0.40 vol) twice, and dried overnight in the vacuum oven at 40 °C to afford the desired product (23.70 g, 189.345 mmol, 62% yield) as a white sand colored crystalline solid. ¾ MR (400 MHz, CDCh, 7.26 ppm) δ 7.33 (bs, 1H), 5.96-5.95 (m, 1H), 5.31-5.30 (m, 1H), 2.6 (t, J= 2.5 Hz, 2H), 1.29 (s, 6H).

Synthesis IB:

[0056] i. Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidin-4-one (257.4 kg, 1658.0 mol, 1.00 eq.), tri-butyl methyl ammonium chloride (14.86 kg, 63.0 mol, 0.038 eq.), chloroform (346.5 kg, 2901.5 mol, 1.75 eq.) and DCM (683.3 kg) were added to a 500 L enamel reactor. The reaction was stirred at 85 rpm and cooled to 15~17°C. The solution of 50wt% sodium hydroxide (1061.4 kg, 13264.0 mol, 8.00 eq.) was added dropwise over 40 h while maintaining the temperature between 15~25°C. The reaction mixture was stirred and monitored by GC.

ii. The suspension was diluted with DCM (683.3 kg) and water (1544.4 kg). The organic phase was separated. The aqueous phase was extracted with DCM (683.3 kg). The organic phases were combined, cooled to 10°C and then 3 M hydrochloric acid (867.8 kg, 2559.0 mol, 1.5 eq.) was added. The mixture was stirred at 10-15 °C for 2 h. The organic phase was separated. The aqueous phase was extracted with DCM (683.3 kg x 2). The organic phases were combined, dried over Na2S04 (145.0 kg) for 6 h. The solid was filtered off and washed with DCM (120.0 kg). The filtrate was stirred with active charcoal (55 kg) for 6 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure (30~40°C, -O. lMPa). Then isopropyl acetate (338 kg) was added and the mixture was heated to 87-91°C, stirred for 1 h. Then the solution was cooled to 15 °C in 18 h and stirred for 1 h at 15 °C. The solid was collected by filtration, washed with 50% isopropyl acetate/hexane (80.0 kg x 2) and dried overnight in the vacuum oven at 50 °C to afford 5,5-dimethyl-3-methylenepyrrolidin-2-one as an off white solid, 55% yield.

Example 2. Reaction (c): Synthesis of (S)-3,5,5-trimethyl-pyrrolidin-2-one from 5,5-dimethyl-3-methylenepyrrolidin-2-one

(3) (4S)

Example 2A: Use of Rh Catalyst

[0057] Step 1 : Preparation of Rh Catalyst Formation: In a 3 L Schlenk flask, 1.0 L of tetrahydrofuran (THF) was degassed with an argon stream. Mandyphos Ligand SL-M004-1 (1.89 g) and [Rh(nbd)Cl]2 (98%, 0.35 g) (chloronorbornadiene rhodium(I) dimer) were added. The resulting orange catalyst solution was stirred for 30 min at room temperature to form a catalyst solution.

[0058] Step 2: A 50 L stainless steel autoclave was charged with 5,5-dimethyl-3-methylenepyrrolidin-2-one (6.0 kg, Compound (3)) and THF (29 L). The autoclave was

sealed and the resulting suspension was flushed with nitrogen (3 cycles at 10 bar), and then released of pressure. Next the catalyst solution from Step 1 was added. The autoclave was flushed with nitrogen without stirring (3 cycles at 5 bar) and hydrogen (3 cycles at 5 bar). The pressure was set to 5 bar and a 50 L reservoir was connected. After 1.5 h with stirring at 1000 rpm and no hydrogen uptake the reactor was flushed again with nitrogen (3 cycles at 10 bar) with stirring and additional catalyst solution was added. The autoclave was again flushed to hydrogen with the above described procedure (3 x 5 bar N2, 3 x 5 bar H2) and adjusted to 5 bar. After 2 h, the pressure was released, the autoclave was flushed with nitrogen (3 cycles at 5 bar) and the product solution was discharged into a 60 L inline barrel. The autoclave was charged again with THF (5 L) and stirred with 1200 rpm for 5 min. The wash solution was added to the reaction mixture.

[0059] Step 3 : The combined solutions were transferred into a 60 L reactor. The inline barrel was washed with 1 L THF which was also added into the reactor. 20 L THF were removed by evaporation at 170 mbar and 40°C. 15 L heptane were added. The distillation was continued and the removed solvent was continuously replaced by heptane until the THF content in the residue was 1% w/w (determined by NMR). The reaction mixture was heated to 89°C (turbid solution) and slowly cooled down again (ramp: 14°C/h). Several heating and cooling cycles around 55 to 65°C were made. The off-white suspension was transferred to a stirred pressure filter and filtered (ECTFE-pad, d = 414 mm, 60 my, Filtration time = 5 min). 10 L of the mother liquor was transferred back into the reactor to wash the crystals from the reactor walls and the obtained slurry was also added to the filter. The collected solid was washed with 2 x 2.5 1 heptane, discharged and let dry on the rotovap at 40°C and 4 mbar to obtain the product, (S)-3,5,5-trimethyl-pyrrolidin-2-one; 5.48 Kg (91%), 98.0% ee.

Synthesis 2B: Use of Ru Catalyst

[0060] The reaction was performed in a similar manner as described above in Example 2A except the use of a Ru catalyst instead of a Rh catalyst.

[0061] Compound (3) (300 g) was dissolved in THF (2640 g, 10 Vol) in a vessel. In a separate vessel, a solution of [RuCl(p-cymene){(R)-segphos}]Cl (0.439g, 0.0002 eq) in THF (660 g, 2.5 Vol) was prepared. The solutions were premixed in situ and passed

through a Plug-flow reactor (PFR). The flow rate for the Compound (3) solution was at 1.555 mL/min and the Ru catalyst solution was at 0.287 mL/min. Residence time in the PFR was 4 hours at 30 °C, with hydrogen pressure of 4.5 MPa. After completion of reaction, the TFIF solvent was distilled off to give a crude residue. Heptane (1026 g, 5 vol) was added and the resulting mixture was heated to 90 °C. The mixture was seeded with 0.001 eq. of Compound 4S seeds. The mixture was cooled to -15 °C at 20 °C/h. After cooling, heptane (410 g, 2 vol) was added and the solid product was recovered by filtration. The resulting product was dried in a vacuum oven at 35 °C to give (S)-3,5,5-trimethyl-pyrrolidin-2-one (281.77 g, 98.2 % ee, 92 % yield).

Example 2C: Analytical Measurements

[0062] Analytical chiral HPLC method for the determination of the conversion, chemoselectivity and enantiomeric excess of the products form Example 2A and 2B was made under the following conditions: Instrument: Agilent Chemstation 1100; Column: Phenomenex Lux 5u Cellulose— 2, 4.6 mm x 250 mm x 5 um, LHS6247; Solvent:

Heptane/iPrOH (90: 10); Flow: 1.0 ml/min; Detection: UV (210 nm); Temperature: 25°C; Sample concentration: 30 μΐ of reaction solution evaporated, dissolved in 1 mL;

heptane/iPrOH (80/20); Injection volume: 10.0 
Run time 20 min; Retention times: 5,5–dimethyl-3-methylenepyrrolidin-2-one: 13.8 min, (,S)-3,5,5-trimethyl-pynOlidin-2-one: 10.6 min, and (R)-3,5,5-trimethyl-pyrrolidin-2-one: 12.4 min.

Example 3: Alternate Synthesis of (S)-3,5,5-trimethyl-pyrrolidin-2-one from 5,5-dimethyl-3-methylenepyrrolidin-2-one

Ru(Me-allyl)2(C0D)2BF4

1 eq HBF4 Et20

5 bar H2 at 45°C

[0063] Mandyphos (0.00479 mmol, 0.12 eq) was weighed into a GC vial. In a separate vial, Ru(Me-allyl)2(COD) (16.87 mg, 0.0528 mmol) was weighed and dissolved in DCM (1328 \iL). In another vial HBF4 Et20 (6.6 μΐ,) and BF3 Et20 (2.0 μΐ,) were dissolved in DCM (240 μΐ.). To the GC vial containing the ligand was added, under a flow of argon, the Ru(Me-allyl)2(COD) solution (100 μΐ,; 0.00399 mmol, O. leq) and the HBF4 Et20 / BF3 -Et20 solution (20 μΐ^ 1 eq HBF4 Et20 and catalytic BF3 Et20). The resulting mixtures were stirred under a flow of argon for 30 minutes. 5,5-dimethyl-3-methylenepyrrolidin-2-one (5 mg, 0.0399 mmol) in EtOH (1 mL) was added. The vials were placed in the hydrogenation apparatus. The apparatus was flushed with H2 (3 χ) and charged with 5 bar H2. After standing for 45 minutes, the apparatus was placed in an oil bath at temperature of 45°C. The reaction mixtures were stirred overnight under H2. 200 μΙ_, of the reaction mixture was diluted with MeOH (800 μΐ.) and analyzed for conversion and ee. 1H MR (400 MHz, Chloroform-d) δ 6.39 (s, 1H), 2.62 (ddq, J = 9.9, 8.6, 7.1 Hz, 1H), 2.17 (ddd, J = 12.4, 8.6, 0.8 Hz, 1H), 1.56 (dd, J = 12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H).

IPC analytical method for Asymmetric Hydrogenation

(3) (4S) (4R)

Example 4. Synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride from (S)-3,5,5-trimethyl-pyrrolidin-2-one

(4S) (1S)HCI

Example 4A:

[0064] Anhydrous THF (100 ml) was charged to a dry 750 ml reactor and the jacket temperature was set to 50° C. Once the vessel contents were at 50° C, LiAlH4pellets (10 g, 263 mmol, 1.34 eq.) were added. The mixture was stirred for 10 minutes, then a solution of (4S) (25 g, 197 mmol) in anhydrous THF (100 ml) was added dropwise over 45 minutes, maintaining the temperature between 50-60° C. Once the addition was complete the jacket temperature was increased to 68° C and the reaction was stirred for 18.5 hrs. The reaction mixture was cooled to 30° C then saturated sodium sulfate solution (20.9 ml) was added dropwise over 30 minutes, keeping the temperature below 40° C. Vigorous evolution of hydrogen was observed and the reaction mixture thickened but remained mixable. The mixture thinned towards the end of the addition. The mixture was cooled to 20° C, diluted with iPrOAc (100 ml) and stirred for an additional 10 minutes. The suspension was then drained and collected through the lower outlet valve, washing through with additional iPrOAc (50 ml). The collected suspension was filtered through a Celite pad on a sintered glass funnel under suction and washed with iPrOAc (2×50 ml).

[0065] The filtrate was transferred back to the cleaned reactor and cooled to 0° C under nitrogen. 4M HCI in dioxane (49.1 ml, 197 mmol, leq.) was then added dropwise over 15 minutes, maintaining the temperature below 20°C. A white precipitate formed. The reactor was then reconfigured for distillation, the jacket temperature was increased to 100 °C, and distillation of solvent was carried out. Additional z-PrOAc (100 mL) was added during concentration, after >100 mL distillate had been collected. Distillation was continued until -250 mL total distillate was collected, then a Dean-Stark trap was attached and reflux continued for 1 hour. No water was observed to collect. The reaction mixture was cooled to 20 °C and filtered under suction under nitrogen. The filtered solid was washed with i-PrOAc (100 mL), dried under suction in nitrogen, then transferred to a glass dish and dried in a vacuum oven at 40 °C with a nitrogen bleed. Compound (1S)»HC1 was obtained as a white solid (24.2g, 82%).

Synthesis 4B:

[0066] To a glass lined 120 L reactor was charged LiAlH4 pellets (2.5 kg 66 mol, 1.2 equiv.) and dry THF (60 L) and warmed to 30 °C. To the resulting suspension was charged (¾)-3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over 2 hours while maintaining the reaction temperature at 30 to 40 °C. After complete addition, the reaction temperature was increased to 60 – 63 °C and maintained overnight. The reaction mixture was cooled to 22 °C and sampled to check for completion, then cautiously quenched with the addition of EtOAc (1.0 L, 10 moles, 0.16 eq) followed by a mixture of THF (3.4 L) and water (2.5 kg, 2.0 eq) then followed by a mixture of water (1.75 kg) with 50 % aqueous sodium hydroxide (750 g, 2 eq water with 1.4 eq sodium hydroxide relative to aluminum), followed by 7.5 L water (6 eq “Fieser” quench). After the addition was completed, the reaction mixture was cooled to room temperature, and the solid was removed by filtration and washed with THF (3 x 25 L). The filtrate and washings were combined and treated with 5.0 L (58 moles) of aqueous 37% HC1 (1.05 equiv.) while maintaining the temperature below 30°C. The resultant solution was concentrated by vacuum distillation to a slurry in two equal part lots on the 20 L Buchi evaporator.

Isopropanol (8 L) was charged and the solution reconcentrated to near dryness by vacuum distillation. Isopropanol (4 L) was added and the product slurried by warming to about 50 °C. Distillation from Isopropanol continued until water content by KF is < 0.1 %. Methyl tertbutyl ether (6 L) was added and the slurry cooled to 2-5 °C. The product was collected by filtration and rinsed with 12 L methyl tert-butyl ether and pulled dry with a strong nitrogen flow and further dried in a vacuum oven (55 °C/300 torr/N2 bleed) to afford (S)-2,2,4-trimethylpyrrolidine»HCl ((1S HC1) as a white, crystalline solid (6.21 kg, 75% yield). ¾ NMR (400 MHz, DMSO-^6) δ 9.34 (s, 2H), 3.33 (dd, J= 11.4, 8.4 Hz, 1H), 2.75 (dd, J= 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, 7= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, 7= 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, 7= 6.6 Hz, , 3H).

Synthesis 4C:

[0067] With efficient mechanical stirring, a suspension of LiAlH4 pellets (100 g 2.65 mol; 1.35 eq.) in THF (1 L; 4 vol. eq.) warmed at a temperature from 20 °C – 36 °C (heat of mixing). A solution of (¾)-3,5,5-trimethylpyrrolidin-2-one (250 g; 1.97 mol) in THF (1 L; 4 vol. eq.) was added to the suspension over 30 min. while allowing the reaction temperature to rise to -60 °C. The reaction temperature was increased to near reflux (-68 °C) and maintained for about 16 h. The reaction mixture was cooled to below 40 °C and cautiously quenched with drop-wise addition of a saturated aqueous solution of Na2S04 (209 mL) over 2 h. After the addition was completed, the reaction mixture was cooled to ambient temperature, diluted with /-PrOAc (1 L), and mixed thoroughly. The solid was removed by filtration (Celite pad) and washed with /-PrOAc (2 x 500 mL). With external cooling and N2 blanket, the filtrate and washings were combined and treated with drop-wise addition of anhydrous 4 M HC1 in dioxane (492 mL; 2.95 mol; 1 equiv.) while maintaining the temperature below 20 °C. After the addition was completed (20 min), the resultant suspension was concentrated by heating at reflux (74 – 85 °C) and removing the distillate. The suspension was backfilled with /-PrOAc (1 L) during concentration. After about 2.5 L of distillate was collected, a Dean-Stark trap was attached and any residual water was azeotropically removed. The suspension was cooled to below 30 °C when the solid was collected by filtration under a N2 blanket. The solid is dried under N2 suction and further dried in a vacuum oven (55 °C/300 torr/N2 bleed) to afford 261 g (89% yield) of (S 2,2,4-trimethylpyrrolidine»HCl ((1S HC1) as a white, crystalline solid. ¾ NMR (400 MHz, DMSO-^6) δ 9.34 (s, 2H), 3.33 (dd, J = 11 A, 8.4 Hz, 1H), 2.75 (dd, J= 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, J= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, J = 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J= 6.6 Hz, 3H). ¾ MR (400 MHz, CDCh) δ 9.55 (d, J= 44.9 Hz, 2H), 3.52 (ddt, J= 12.1, 8.7, 4.3 Hz, 1H), 2.94 (dq, J= 11.9, 5.9 Hz, 1H), 2.70 – 2.51 (m, 1H), 2.02 (dd, J= 13.0, 7.5 Hz, 1H), 1.62 (s, 3H), 1.58 – 1.47 (m, 4H), 1.15 (d, J= 6.7 Hz, 3H).

Synthesis 4D:

[0068] A 1L four-neck round bottom flask was degassed three times. A 2M solution of LiAlHun THF (100 mL) was charged via cannula transfer. (¾)-3,5,5-trimethylpyrrolidin-2-one (19.0 g) in THF (150 mL) was added dropwise via an addition funnel over 1.5 hours at 50-60 °C, washing in with THF (19 mL). Upon completion of the addition, the reaction was stirred at 60 °C for 8 hours and allowed to cool to room temperature overnight. GC analysis showed <1% starting material remained. Deionized water (7.6 mL) was added slowly to the reaction flask at 10-15 °C, followed by 15% potassium hydroxide (7.6 mL). Isopropyl acetate (76 mL) was added, the mixture was stirred for 15 minutes and filtered, washing through with isopropyl acetate (76 mL). The filtrate was charged to a clean and dry 500 mL four neck round bottom flask and cooled to 0-5 °C. 36% Hydrochloric acid (15.1 g, 1.0 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (190 mL), was carried out to leave a residual volume of -85 mL. Karl Fischer analysis = 0.11% w/w H2O. MTBE (methyl tertiary butyl ether) (19 mL) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (25 mL) and drying under vacuum at 40-45 °C to give crude (,S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (17.4 g, 78% yield). GC purity = 99.5%. Water content = 0.20% w/w. Chiral GC gave an ee of 99.0% (S). Ruthenium content = 0.004 ppm. Lithium content = 0.07 ppm. A portion of the dried crude ,S)-2,2,4-trimethylpyrrolidine hydrochloride (14.3g) was charged to a clean and dry 250 mL four-neck round bottom flask with isopropanol (14.3 mL) and the mixture held at 80-85 °C (reflux) for 1 hour to give a clear solution. The solution was allowed to cool to 50 °C (solids precipitated on cooling) then MTBE (43 mL) was added and the suspension held at 50-55 °C (reflux) for 3 hours. The solids were filtered off at 10 °C, washing with MTBE (14 mL) and dried under vacuum at 40 °C to give recrystallised (S)- 2.2.4- trimethylpyrrolidine hydrochloride ((1S)»HC1) as a white crystallised solid (13.5 g, 94% yield on recrystallisation, 73% yield). GC purity = 99.9%. Water content = 0.11% w/w. 99.6% ee (Chiral GC) (S). Ruthenium content = 0.001 ppm. Lithium content = 0.02 ppm.

Synthesis 4E:

[0069] A reactor was charged with lithium aluminum hydride (LAH) (1.20 equiv.) and 2-MeTHF (2-methyltetrahydrofuran) (4.0 vol), and heated to internal temperature of 60 °C while stirring to disperse the LAH. A solution of (¾)-3,5,5-trimethylpyrrolidin-2-one (1.0 equiv) in 2-MeTHF (6.0 vol) was prepared and stirred at 25 °C to fully dissolve the (S)- 3.5.5- trimethylpyrrolidin-2-one. The (¾)-3,5,5-trimethylpyrrolidin-2-one solution was added slowly to the reactor while keeping the off-gassing manageable, followed by rinsing the addition funnel with 2-MeTHF (1.0 vol) and adding it to the reactor. The reaction was stirred at an internal temperature of 60 ± 5 °C for no longer than 6 h. The internal temperature was set to 5 ± 5 °C and the agitation rate was increased. A solution of water (1.35 equiv.) in 2-MeTHF (4.0v) was prepared and added slowly to the reactor while the internal temperature was maintained at or below 25 °C. Additional water (1.35 equiv.) was charged slowly to the reactor while the internal temperature was maintained at or below 25 °C. Potassium hydroxide (0.16 equiv.) in water (0.40 vol) was added to the reactor over no less than 20 min while the temperature was maintained at or below 25 °C. The resulting solids were removed by filtration, and the reactor and cake were washed with 2-MeTHF (2 x 2.5 vol). The filtrate was transferred back to a jacketed vessel, agitated, and the temperature was adjusted to 15 ± 5 °C. Concentrated aqueous HC1 (35-37%, 1.05 equiv.) was added slowly to the filtrate while maintaining the temperature at or below 25 °C and was stirred no less than 30 min. Vacuum was applied and the solution was distilled down to a total of 4.0 volumes while maintaining the internal temperature at or below 55 °C, then 2-MeTHF (6.00 vol) was added to the vessel. The distillation was repeated until Karl Fischer analysis (KF) < 0.20% w/w H2O. Isopropanol was added (3.00 vol), and the temperature was adjusted to 70 °C (65 – 75 °C) to achieve a homogenous solution, and stirred for no less than 30 minutes at 70 °C. The solution was cooled to 50 °C (47 – 53 °C) over 1 hour and stirred for no less than 1 h, while the temperature was maintained at 50°C (47 – 53 °C). The resulting slurry was cooled to -10 °C (-15 to -5°C) linearly over no less than 12 h. The slurry was stirred at -10 °C for no less than 2 h. The solids were isolated via filtration or centrifugation and were washed with a solution of 2-MeTHF (2.25 vol) and IPA (isopropanol) (0.75 vol). The solids were dried under vacuum at 45 ± 5 °C for not less than 6 h to yield (,S)-2,2,4-trimethylpyrrolidine hydrochloride ((1S)»HC1).

Example 5: Phase Transfer Catalyst (PTC) Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0070] Various PTCs were tested as described below:

[0071] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq.), PTC (0.05 eq.), and chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added dropwise over 2 min. The reaction mixture was stirred until completion as assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic

phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion and assessed by

HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. The reaction results are summarized in the following table:

Example 6: Solvent Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0072] Various solvents and amounts were tested as described below:

[0073] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”)), tetrabutylammonium hydroxide (0.12 g, 0.153 mmol, 0.050 eq), chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.), and solvent (2v or 4v, as shown below) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion and assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. Reaction results are summarized in the following table:

Example 7: Base Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0074] In this experiment, various concentrations of NaOH were tested as described below:

[0075] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”), tetrabutylammonium hydroxide (0.12 g, 0.153 mmol, 0.050 eq), and chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath, and a solution of an amount wt% sodium hydroxide as shown in the Table below in water (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion and assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase is extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL,

2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC.

Reaction results are summarized in the following table:

Example 8: Phase Transfer Catalyst (PTC) Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0076] Various amounts of PTCs were tested as described below:

Tetrabutylammonium hydroxide (0.01 eq.), TBAB (0.01 eq.), Tributylmethylammonium chloride (0.01 eq.), Tetrabutylammonium hydroxide (0.02 eq.), TBAB (0.02 eq.), Tributylmethylammonium chloride (0.02 eq.), Tetrabutylammonium hydroxide (0.03 eq.), TBAB (0.03 eq.), Tributylmethylammonium chloride (0.03 eq.).

[0077] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”)), PTC (0.12 g, 0.153 mmol, 0.050 eq), and chloroform (1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath, and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion, assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H20 (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. The reaction results are summarized in the following table:

Reactions Conditions Result

8D Tetrabutylammonium hydroxide Almost complete

(0.02 eq.) overnight (2% starting

material), 82% solution yield

8E TBAB (0.02 eq.) Almost complete

overnight (2% starting material), 71% solution yield

8F Tributylmethylammonium chloride Incomplete overnight (4%

(0.02 eq.) starting material), 72%

solution yield

8G Tetrabutylammonium hydroxide Almost complete

(0.03 eq.) overnight (3% starting

material), 76% solution yield

8H TBAB (0.03 eq.) Almost complete

overnight (3% starting material), 76% solution yield

81 Tributylmethylammonium chloride Almost complete

(0.03 eq.) overnight (2% starting

material), 78% solution yield

Example 9. Preparation of 2,2,6,6-tetramethylpiperidin-4-one hydrochloride

2,2,6,6-tetramethylpiperidin-4-one 2,2,6,6-tetramethylpiperidin-4-one hydrochloride

[0078] 2,2,6,6-tetramethyl-4-piperidinone (30 g, 193.2 mmol, 1.0 eq) was charged to a 500 mL nitrogen purged three necked round bottomed flask equipped with condenser. IPA (300 mL, 10 vol) was added to the flask and the mixture heated to 60 °C until dissolved.

[0079] To the solution at 60 °C was added 5-6 M HC1 in IPA (40 mL, 214.7 mmol, 1.1 eq) over 10 min and the resulting suspension stirred at 60 °C for 30 min then allowed to cool to ambient temperature. The suspension was stirred at ambient temperature overnight, then filtered under vacuum and washed with IPA (3 x 60 mL, 3 x 2 vol). The cream colored solid was dried on the filter under vacuum for 10 min.

[0080] The wet cake was charged to a 1 L nitrogen purged three necked round bottomed flask equipped with condenser. IPA (450 mL, 15 vol) was added to the flask and the suspension heated to 80 °C until dissolved. The mixture was allowed to cool slowly to ambient temperature over 3 h and the resulting suspension stirred overnight at ambient temperature.

[0081] The suspension was filtered under vacuum, washed with IPA (60 mL, 2 vol) and dried on the filter under vacuum for 30 min. The resulting product was dried in a vacuum oven at 40 °C over the weekend to give a white crystalline solid, 21.4 g, 64% yield.

Example 10. Synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride from (S)-3,5,5-trimethyl-pyrrolidin-2-one

[0082] Each reactor was charged with (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF, H2, and the catalyst shown in the below table. The reactor was heated to 200 C and pressurized to 60 bar, and allowed to react for 12 hours. GC analysis showed that (S)-2,2,4-trimethylpyrrolidine was produced in the columns denoted by “+.”

[0083] A 2.5% solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 2% Pt-0.5%>Sn/SiO2catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 130 °C under 80 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%>

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (74.8%> yield, 96.1% ee).

Alternate synthesis

[0084] A 2.5%) solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 4% Pt-2%>Sn/Ti02catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 200 °C under 50 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (88.5% yield, 29.6%> ee).

Alternate synthesis

[0085] A 2.5% solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 2% Pt-0.5%>Sn/TiO2 catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 150 °C under 50 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%>

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H20. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (90.9% yield, 98.0%> ee).

Alternate synthesis

[0086] A 2.5%) solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.03 mL/min into a packed bed reactor prepacked with 2% Pt-8%>Sn/Ti02catalyst immobilized on silica gel. H2 gas was also flowed into the packed bed reactor at 40 mL/min. The reaction was carried out at 180 °C under 55 bar pressure with a residence time of 6 min. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36% Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (,S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (90.4%> yield, 96.8%> ee).

Patent

WO 2019010092

PATENT

US 20160095858

https://patents.google.com/patent/US20160095858A1/en

Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.

In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000 disease causing mutations in the CF gene have been identified (http://cftr2.org). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as F508del. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.

The deletion of residue 508 in F508del prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of F508del in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.

Accordingly, there is a need for novel treatments of CFTR mediated diseases.

////////////////OLACAFTOR, VX 440, Phase II,  Cystic fibrosis, CS-0044588UNII-RZ7027HK8FRZ7027HK8F

CC1CC(N(C1)C2=C(C=CC(=N2)C3=CC(=CC(=C3)F)OCC(C)C)C(=O)NS(=O)(=O)C4=CC=CC=C4)(C)C

RPL 554


STR1

RPL554.png

ChemSpider 2D Image | RPL-554 | C26H31N5O4

UNII-3E3D8T1GIX.png

RPL-554

  • Molecular FormulaC26H31N5O4
  • Average mass477.555
RPL 554
Urea, N-[2-[(2E)-6,7-dihydro-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl]ethyl]-
(2-[(2E)-9,10-DIMETHOXY-4-OXO-2-[(2,4,6-TRIMETHYLPHENYL)IMINO]-2H,3H,4H,6H,7H-PYRIMIDO[4,3-A]ISOQUINOLIN-3-YL]ETHYL)UREA
2-[9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-3-yl]ethylurea
{2-[(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-2H,3H,4H,6H,7H-pyrimido[4,3-a]isoquinolin-3-yl]ethyl}urea
2-[4-keto-9,10-dimethoxy-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[4,3-a]isoquinolin-3-yl]ethylurea
2-[9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[4,3-a]isoquinolin-3-yl]ethylurea
298680-25-8  CAS
UNII:3E3D8T1GIX

CFTR stimulator; PDE 3 inhibitor; PDE 4 inhibitor

RPL-554 is a mixed phosphodiesterase (PDE) III/IV inhibitor in phase II clinical development at Verona Pharma for the treatment of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD) and inflammation.

RPL-554 is expected to have long duration of action and will be administered nasally thereby preventing gastrointestinal problems often resulting from orally administered PDE4 antiinflammatory drugs.

The company is now seeking licensing agreements or partnerships for the further development and commercialization of the drug.

RPL-554 (LS-193,855) is a drug candidate for respiratory diseases. It is an analog of trequinsin, and like trequinsin, is a dual inhibitor of the phosphodiesterase enzymes PDE-3 and PDE-4.[1] As of October 2015, inhaled RPL-554 delivered via a nebulizer was in development for COPD and had been studied in asthma.[2]

PDE3 inhibitors act as bronchodilators, while PDE4 inhibitors have an anti-inflammatory effect.[1][3]

RPL554 was part of a family of compounds invented by Sir David Jack, former head of R&D for GlaxoSmithKline, and Alexander Oxford, a medicinal chemist; the patents on their work were assigned to Vernalis plc.[4][5]:19-20

In 2005, Rhinopharma Ltd, acquired the rights to the intellectual property from Vernalis.[5]:19-20 Rhinopharma was a startup founded in Vancouver, Canada in 2004 by Michael Walker, Clive Page, and David Saint, to discover and develop drugs for chronic respiratory diseases,[5]:16 and intended to develop RPL-554, delivered with an inhaler, first for allergic rhinitis, then asthma, then forCOPD.[5]:16-17 RPL554 was synthesized at Tocris, a contract research organization, under the supervision of Oxford, and was studied in collaboration with Page’s lab at King’s College, London.[1] In 2006 Rhinopharma recapitalized and was renamed Verona Pharma plc.[5]

This was first seen in April 2015 when it was published as a France national. Verona Pharma (formerly Rhinopharma), under license from Kings College via Vernalis, is developing the long-acting bronchodilator, RPL-554 the lead in a series dual inhibitor of multidrug resistant protein-4 and PDE 3 and 4 inhibiting trequinsin analogs which included RPL-565, for treating inflammatory respiratory diseases, such as allergic rhinitis, asthma, and COPD.

RPL554

Verona Pharma’s lead drug, RPL554, is a “first-in-class” inhaled drug under development for chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis. The drug is an inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes, two enzymes known to be of importance in the development and progression of immunological respiratory diseases. The drug has the potential to act as both a bronchodilator and an anti-inflammatory which would significantly differentiate it from existing drugs.

RPL554 was selected from a class of compounds co-invented by Sir David Jack, the former Director of Research at Glaxo who led the team that discovered many of the commercially successful drugs in the respiratory market.

Verona Pharma has successfully completed two double-blind placebo controlled randomised Phase 2b studies of RPL554: one in mild to moderate asthma and another in mild to moderate COPD. The drug was found to be well tolerated, free from drug-related adverse effects (especially cardiovascular and gastro-intestinal effects) and generated significant bronchodilation.  Additionally, double-blind placebo controlled exploratory studies in healthy volunteers challenged with an inhaled irritant also generated consistent, clinically meaningful anti-inflammatory effects.

Verona Pharma is also carrying out exploratory studies to investigate the potential of RPL554 as a novel treatement for cystic fibrosis. In November 2014, the Company received a Venture and Innovation Award from the UK Cystic Fibrosis Trust to further such studies.

For further information on the potential of RPL554 for the treatment of respiratory diseases, refer to the peer-reviewed paper available on-line in the highly-respected medication journal, The Lancet Respiratory Medicine, entitledEfficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials”.

The competitive advantages of RPL554 include the following:
  • combining bronchodilator (PDE 3) and anti-inflammatory actions (PDE 4) in a single drug, something that is currently only achieved with a combination LABA and glucocorticosteroid inhaler,
  • unique in not using steroids or beta agonists, which have known side effects,
  • planned to be administered by nasal inhalation, thereby reducing the unwanted gastrointestinal side effects of many orally administered drugs.
History of Clinical Trials
  • Following completion in May 2008 of toxicological studies of RPL554, the Company commenced in February 2009 a Phase I/IIa clinical trial of the drug at the Centre for Human Drug Research (CHDR) at Leiden in the Netherlands. In September 2009, the Company announced that it had successfully completed the trial, demonstrating that RPL554 has a good safety profile and has beneficial effects in terms of bronchodilation and bronchoprotection in asthmatics and a reduction in the numbers of inflammatory cells in the nasal passages of allergic rhinitis patients.
  • In November 2010, the Company successfully completed a further trial that examined the safety and bronchodilator effectiveness of the drug administered at higher doses.
  • In August 2011, the Company demonstrated that bronchodilation is maintained over a period of 6 days with daily dosing of RPL554 in asthmatics.
  • In November 2011, the Company successfully demonstrated safety and bronchodilation of RPL554 in patients with mild to moderate forms of COPD.
  • In March 2013, the Company demonstrated positive airway anti-inflammatory activity with respect to COPD at a clinical trial carried out at the Medicines Evaluation Unit (MEU) in Manchester, UK.

Synthesis

WO 2000058308

STR1

Cyclization of 1-(3,4-dimethoxyphenethyl)barbituric acid  in refluxing POCl3 produces the pyrimidoisoquinolinone , which is further condensed with 2,4,6-trimethylaniline  in boiling isopropanol to afford the trimethylphenylimino derivative . Subsequent alkylation of with N-(2-bromoethyl)phthalimide in the presence of K2CO3 and KI, followed by hydrazinolysis of the resulting phthalimidoethyl compound  yields the primary amine . This is finally converted into the title urea RPL 554 by reaction with sodium cyanate in aqueous HCl.

Example 1 : 9 Λ 0-Dimethoxy-2-(2.4-6-trimethy-phen yliminoY-3-(N-carbamoyl-2- aminoethylV3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one

Figure imgf000029_0001

Sodium cyanate (6.0g, 0.092 mol) in water (100 ml) was added dropwise to a stirred solution of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7- tetrahydro-2H-pyrimido[6,l-a]isoquinolin-4-one, prepared according to Preparation 4 above (20.0g, 0.046 mol) in water (600 ml) and IN ΗC1 (92 ml) at 80°C. After stirring for 2h at 80°C the mixture was cooled in an ice-bath and basified with 2N NaOH. The mixture was extracted with dichloromethane (3 x 200 ml) and the combined extract was dried (MgSO- ) and evaporated in vacuo. The resulting yellow foam was purified by column chromatography on silica gel eluting with CH2CI2 / MeOH (97:3) and triturated with ether to obtain the title compound as a yellow solid, 11.9g, 54%.

M.p.: 234-236°C m/z: C26H31N5O4 requires M=477 found (M+l) = 478

HPLC: Area (%) 99.50 Column ODS (150 x 4.6 mm)

MP pH3 KH2PO4 / CH3CN (60/40)

FR (ml/min) 1.0 RT (min) 9.25 Detection 250 nm

lK NMR (300 MHz, CDCI3): δ 1.92 (1H, br s, NH), 2.06 (6H, s, 2xCH3), 2.29 (3H, s, CH3), 2.92 (2H, t, CH2), 3.53 (2H, m, CH2), 3.77 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.05 (2H, t, CH2), 4.40 (2H, t, CH2), 5.35 (2H, br s, NH2), 5.45 (1H, s, C=CH), 6.68 (1H, s, ArH), 6.70 (1H, s, ArH), 6.89 (2H, s, 2xArH).

Preparation 1 : Synthesis of 2-Chloro-6.7-d-hydro-9.10-Dimethoxy-4H-pyrimido- [6,l-a]isoquinoHn-4-one (shown as (1) in Figure 1

Figure imgf000027_0001

A mixture of l-(3,4-dimethoxyphenyl) barbituric acid (70g, 0.24mol), prepared according to the method described in B. Lai et al. J.Med.Chem. 27 1470-1480 (1984), and phosphorus oxychloride (300ml, 3.22mol) was refluxed for 2.5h. The excess phosphorous oxychloride was removed by distillation (20mmHg) on wa ming. After cooling the residue was slurried in dioxan (100ml) and cautiously added to a vigorously stirred ice/water solution (11). Chloroform (11) was added and the resulting mixture was basified with 30% sodium hydroxide solution. The organic layer was separated and the aqueous phase further extracted with chloroform (2x750ml). The combined organic extracts were washed with water (1.51), dried over magnesium sulphate and concentrated in vacuo to leave a gummy material (90g). This was stirred in methanol for a few minutes, filtered and washed with methanol (200ml), diethyl ether (2x200ml) and dried in vacuo at 40°C to yield the title compound as a yellow/orange solid. 47g, 62%

(300MHz, CDCI3) 2.96(2H, t, C(7) H2); 3.96(6H, s, 2xOCH3; 4.20(2H, t, C(6) H2); 6.61(1H, s, C(1) H); 6.76(1H, s, Ar-H); 7.10(1H, s, Ar-H). Preparation 2: 9.10-Dimethoxy-2-(2.4.6-trimethylphenyliminoV3.4.6.7- tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one (shown as (2) in Figure 1

2-Chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-4-one, prepared according to Preparation 1, (38.5g, 0.13 mol) and 2,4,6-trimethylaniline (52.7g, 0.39 mol) in propan-2-ol (3 1) was stirred and heated at reflux, under nitrogen, for 24h. After cooling to room temperature, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel, eluting with CΗ2CI2 /

MeOH, initially 98:2, changing to 96:4 once the product began to elute from the column. The title compound was obtained with a slight impurity, (just above the product on tic). Yield 34.6g, 67%.

Preparation 3: 9.10-Dimethoxy-2-(2.4.6-trimethylphenyliminoV3-(2-N- phthalimidoethyπ-3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one

(shown as (3 in Figure 1)

A mixture of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H- pyrimido[6,l-a]isoquinolin-4-one (which was prepared according to Preparation 2) (60.0g, 0.153 mol), potassium carbonate (191g, 1.38 mol), sodium iodide (137g, 0.92 mol) and N-(2-bromoethyl)phthalimide (234g, 0.92 mol) in 2-butanone (1500 ml) was stirred and heated at reflux, under nitrogen, for 4 days. After cooling to room temperature the mixture was filtered and the filtrate was evaporated in vacuo. The residue was treated with methanol (1000 ml) and the solid filtered off, washed with methanol and recrystallised from ethyl acetate to obtain the title compound as a pale yellow solid in yield 40. Og, 46%. Evaporation of the mother liquor and column chromatography of the residue on silica gel (CΗ2C-2 / MeOH 95:5) provided further product 11.7g, 13.5%. Preparation 4: 9.10-Dimethoxy-2-(2A6-trimethylphenylimino)-3-(2-arninoethyO- 3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquino-in-4-one (shown as (4) in Figure 1)

A mixture of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-N- phthalimidoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,l-a]isoquinolin-4-one (22. Og, 0.039 mol), prepared according to Preparation 3, and hydrazine hydrate (11.3g, 0.195 mol) in chloroform (300 ml) and ethanol (460 ml) was stined at room temperature, under nitrogen, for 18h. Further hydrazine hydrate (2.9g, 0.05 mol) was added and the mixture was stirred a further 4h. After cooling in ice / water, the solid was removed by filtration and the filtrate evaporated in vacuo. The residue was dissolved in dichloromethane and the insoluble material was removed by filtration. The fitrate was dried (MgSO-i) and evaporated in vacuo to afford the title compound as a yellow foam in yield 16.2g, 96%.

PATENT

WO-2016128742

Novel crystalline acid addition salts forms of RPL-554 are claimed, wherein the salts, such as ethane- 1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid. .

RPL554 (9, 10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(/V-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6, l-a]isoquinolin-4-one) is a dual PDE3/PDE4 inhibitor and is described in WO 00/58308. As a combined PDE3/PDE4 inhibitor, RPL554 has both antiinflammatory and bronchodilatory activity and is useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). The structure of RPL554 is shown below.

Owing to its applicability in the treatment of respiratory disorders, it is often preferable to administer RPL554 by inhalation. Franciosi et al. disclose a solution of RPL554 in a citrate-phosphate buffer at pH 3.2 (The Lancet: Respiratory Medicine 11/2013; l(9):714-27. DOI: 10.1016/S2213-2600(13)70187-5). The preparation of salts of RPL554 has not been described.

PATENT

http://www.google.ch/patents/WO2000058308A1?cl=en&hl=de

PATENT

http://www.google.ch/patents/WO2012020016A1?cl=en

U.S. Pat. No. 6,794,391, 7,378,424, and 7,105,663, which are each incorporated herein by reference, discloses compound RPL-554 (N-{2-[(2iT)-2-(mesityiimino)-9,10- dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,l-a]-isoquinolin-3 4H)-yl]ethyl}urea).

Figure imgf000003_0001

It would be beneficial to provide a composition of a stable polymorph of RPL-554, that has advanrtages over less stable polymorphs or amorphous forms, including

stability, compressibility, density, dissolution rates, increased potency or. lack toxicity.

WO2000058308A1 * Mar 29, 2000 Oct 5, 2000 Vernalis Limited DERIVATIVES OF PYRIMIDO[6,1-a]ISOQUINOLIN-4-ONE
US6794391 Sep 26, 2001 Sep 21, 2004 Vernalis Limited Derivatives of pyrimido[6.1-a]isoquinolin-4-one
US7105663 Feb 24, 2004 Sep 12, 2006 Rhinopharma Limited Derivatives of pyrimido[6,1-a]isoquinolin-4-one
US7378424 Feb 24, 2004 May 27, 2008 Verona Pharma Plc Derivatives of pyrimido[6, 1-A]isoquinolin-4-one
Patent ID Date Patent Title
US7378424 2008-05-27 Derivatives of pyrimido[6, 1-A]isoquinolin-4-one
US7105663 2006-09-12 Derivatives of pyrimido[6, 1-a]isoquinolin-4-one
US6794391 2004-09-21 Derivatives of pyrimido[6.1-a]isoquinolin-4-one
US2004001895 2004-01-01 Combination treatment for depression and anxiety
US2003235631 2003-12-25 Combination treatment for depression and anxiety
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US2015210655 2015-07-30 CERTAIN (2S)-N-[(1S)-1-CYANO-2-PHENYLETHYL]-1, 4-OXAZEPANE-2-CARBOXAMIDES AS DIPEPTIDYL PEPTIDASE 1 INHIBITORS
US2014349969 2014-11-27 COMPOUNDS AND METHODS FOR TREATING PAIN
US2014242174 2014-08-28 TREATING COUGH AND TUSSIVE ATTACKS
US2013252924 2013-09-26 Compounds and Methods for Treating Pain
US2013225616 2013-08-29 CRYSTALLINE FORM OF PYRIMIDIO[6, 1-A] ISOQUINOLIN-4-ONE COMPOUND
US2012302533 2012-11-29 DERIVATIVES OF PYRIMIDO [6, 1-A] ISOQUINOLIN-4-ONE
US8242127 2012-08-14 Derivatives of pyrimido[6, 1-A]isoquinolin-4-one
US2011201665 2011-08-18 Compositions, Methods, and Kits for Treating Influenza Viral Infections
US2011028510 2011-02-03 Compositions, Methods, and Kits for Treating Influenza Viral Infections
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WO2012020016A1 * 9. Aug. 2011 16. Febr. 2012 Verona Pharma Plc Crystalline form of pyrimidio[6,1-a]isoquinolin-4-one compound
WO2014140647A1 17. März 2014 18. Sept. 2014 Verona Pharma Plc Drug combination
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US8883857 8. März 2013 11. Nov. 2014 Baylor College Of Medicine Small molecule xanthine oxidase inhibitors and methods of use
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References

  1. Boswell-Smith V et al. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther. 2006 Aug;318(2):840-8. PMID 16682455
  2.  Nick Paul Taylor for FierceBiotech. October 1, 2015 Verona sets sights on PhIIb after COPD drug comes through early trial
  3.  Turner MJ et al. The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia. Am J Physiol Lung Cell Mol Physiol. 2016 Jan 1;310(1):L59-70. PMID 26545902
  4. Jump up^ see US20040171828, identified in the citations of PMID 16682455
  5. ISIS Resources, PLC. August 23, 2006 Proposed Acquisition of Rhinopharma

REFERENCES

1: Calzetta L, Cazzola M, Page CP, Rogliani P, Facciolo F, Matera MG. Pharmacological characterization of the interaction between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated bronchi and small airways. Pulm Pharmacol Ther. 2015 Jun;32:15-23. doi: 10.1016/j.pupt.2015.03.007. Epub 2015 Apr 18. PubMed PMID: 25899618.

2: Franciosi LG, Diamant Z, Banner KH, Zuiker R, Morelli N, Kamerling IM, de Kam ML, Burggraaf J, Cohen AF, Cazzola M, Calzetta L, Singh D, Spina D, Walker MJ, Page CP. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013 Nov;1(9):714-27. doi: 10.1016/S2213-2600(13)70187-5. Epub 2013 Oct 25. PubMed PMID: 24429275.

3: Wedzicha JA. Dual PDE 3/4 inhibition: a novel approach to airway disease? Lancet Respir Med. 2013 Nov;1(9):669-70. doi: 10.1016/S2213-2600(13)70211-X. Epub 2013 Oct 25. PubMed PMID: 24429260.

4: Calzetta L, Page CP, Spina D, Cazzola M, Rogliani P, Facciolo F, Matera MG. Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther. 2013 Sep;346(3):414-23. doi: 10.1124/jpet.113.204644. Epub 2013 Jun 13. PubMed PMID: 23766543.

5: Gross N. The COPD pipeline XX. COPD. 2013 Feb;10(1):104-6. doi: 10.3109/15412555.2013.766103. PubMed PMID: 23413896.

6: Gross NJ. The COPD Pipeline XIV. COPD. 2012 Feb;9(1):81-3. doi: 10.3109/15412555.2012.646587. PubMed PMID: 22292600.

7: Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6, 7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquino lin-4-one]. J Pharmacol Exp Ther. 2006 Aug;318(2):840-8. Epub 2006 May 8. PubMed PMID: 16682455.

RPL-554
RPL554.png
Systematic (IUPAC) name
N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea
Identifiers
PubChem CID 9934746
ChemSpider 8110374 Yes
Synonyms 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one
Chemical data
Formula C26H31N5O4
Molar mass 477.554 g/mol

///////////RPL-554, LS-193,855, 298680-25-8, UNII:3E3D8T1GIX, RPL554, RPL 554, phase 2, Chronic Obstructive Pulmonary Diseases , COPD, Allergic Rhinitis, Asthma Therapy, Cystic Fibrosis, Inflammation, Bronchodilators

Cc3cc(C)cc(C)c3N=c2cc1-c(cc4OC)c(cc4OC)CCn1c(=O)n2CCNC(N)=O

Vertex Pharmaceuticals: Another FDA Orphan Drug Designation For Cystic Fibrosis


Orphan Druganaut Blog

On April 24th , Vertex Pharmaceuticals’ investigational drug VX-661 ((R)-1-(2,2-difluorobenzo [d][1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide) receives FDA Orphan Drug Designation (ODD) for the treatment of Cystic Fibrosis (CF) :
FDA Orphan Drug Designation Database Record
Generic Name:(R)-1-(2,2-difluorobenzo [d][1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide
Trade Name:n/a
Date Designated:04-24-2014
Orphan Designation:Treatment of cystic fibrosis
Orphan Designation Status:Designated
FDA Orphan Approval Status:Not FDA Approved for Orphan Indication
Sponsor: Vertex Pharmaceuticals Inc. 50 Northern Avenue Boston, MA 02210-1862 The sponsor address listed is the last reported by the sponsor to OOPD.

.

VX-661 is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) corrector. VX-661 is being studied in combination with Kalydeco (Ivacaftor) for patients who have the F508del mutation. VX-661 is currently recruiting participants for a Phase II clinical trial to evaluate the safety and efficacy of VX-661 in combination with Kalydeco in subjects with CF who are homozygous (have 2 copies) for the F508del CFTR…

View original post 173 more words

LUMACAFTOR an Orphan drug in clinical trial for oral the treatment of cystic fibrosis


Lumacaftor

3-[6-[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropylcarboxamido]-3-methylpyridin-2-yl]benzoic acid

3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid

VRT-826809
VX-809

US patents:  US8124781, US8461342
Indication:Cystic fibrosis
Developmental status:Phase III (US, UK, EU)
Developer:Vertex

Vertex Pharmaceuticals
Company Vertex Pharmaceuticals Inc.
Description Small molecule cystic fibrosis transmembrane conductance regulator (CFTR) corrector
Molecular Target Cystic fibrosis transmembrane conductance regulator (CFTR)
Mechanism of Action CFTR stabilizer
Latest Stage of Development Phase III
Indication Cystic fibrosis (CF)
cas  936727-05-8

http://www.ama-assn.org/resources/doc/usan/lumacaftor.pdf  for all data

see……http://orgspectroscopyint.blogspot.in/2015/03/lumacaftor.html

Lumacaftor (USAN, codenamed VX-809) is an experimental drug for the treatment of cystic fibrosis being developed by Vertex Pharmaceuticals. The drug is designed to be effective in patients that have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease. F508del, meaning that the amino acid phenylalanine in position 508 is missing, is found in about 60% of cystic fibrosis patients in Europe,[1] and in about 90% of persons with some mutation in the CFTR gene.

A corrector molecule, one of two new classes of ion channel modulators. The corrector modulators enhance the number of channels of the CFTR protein at the cell surface. in combination with ivacaftor in homozygous F508del pts

Results from a Phase II clinical trial indicate that patients with the most common form of genetic mutation causing cystic fibrosis—homozygous F508del—had a mean increase of 7.4% in lung function (FEV1) on a combination of lumacaftor and ivacaftor.[2]

VX-809 is an investigational corrector compound in a phase II clinical trial for oral the treatment of cystic fibrosis. The trial will evaluate single and multiple doses of VX-809 in healthy volunteers. This compound has resulted from a collaboration with the Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) . In 2010, orphan drug designation was assigned in the E.U. and the U.S. for the treatment of CF.

VX-809 may act to restore the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the defective cell membrane protein responsible for the progression of CF. VX-809 and other corrector compounds were designed to increase the amount of DF508-CFTR on the surface of cells lining the airway, which may result in an increase in chloride transport across the cell surface in patients with the DF508-CFTR mutation.

On January 11, 2013, the combination regimen of Lumacaftor (VX-809) and Kalydeco (Ivacaftor) was awarded by U.S. FDA with Breakthrough Therapy Designation as part of the agency’s efforts to accelerate the development and approval of drugs for serious and life-threatening disease.Breakthrough Therapy Designation for the combination regimen of VX-809 with ivacaftor was based on the Phase II combination data announced in 2012. Vertex Pharmaceuticals will report results from two Phase III trials (NCT01807949 (TRANSPORT) and NCT01807923 (TRAFFIC)) of the combination of Kalydeco + VX-809 in the middle of 2014. Positive data from TRAFFIC and TRANSPORT could open up a market with peak sales of approximately $6 billion, estimate analysts.

Lumacaftor skeletal.svg

  • 1      Merk; Schubert-Zsilavecz. Pharmazeutische Zeitung (in German) 156 (37): 24–27.
  • 2      Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery medicine 15 (81): 127–133. PMID 23449115

see……http://orgspectroscopyint.blogspot.in/2015/03/lumacaftor.htm

…………………………

PATENT

 http://www.google.com/patents/EP2639222A1?cl=en

  • CFTR correctors useful in the treatment of cystic fibrosis. Such compounds include 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (hereinafter “Compound 1”) which has the structure below:

  • Compound 1 and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of CFTR mediated diseases.
  • Scheme 1. Synthesis of the acid chloride moiety.

Scheme 2. Synthesis of the amine moiety.

Scheme 3. Formation of an acid salt of 3-(6-(1-(2,2-difluorobcnzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.

  • Synthesis of 3-(6-(1-(2,2-difluorobenzord[d][1,3]dioxol-5-yl) cyclopropancearboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl.
  • [0238]
    Acid Chloride Moiety
  • Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (Compound 18).

  • Commercially available 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride® (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 °C. At the end of addition the temperature is increased to 40 °C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 °C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 °C. The organic phase is cooled to 20 °C then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude Compound 18 that is used directly in the next step.
  • Synthesis of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole (Compound 19).

  • Compound 18 (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol %) is added and SOCl2 (1.2 eq) is added via addition funnel. The SOCl2 is added at a rate to maintain the temperature in the reactor at 15-25 °C. The temperature is increased to 30 °C for 1 hour then cooled to 20 °C then water (4 vol) is added via addition funnel maintaining the temperature at less than 30 °C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. After stirring for 15 to 20 minutes, the layers are allowed to separate. The organic phase is then dried (Na2SO4), filtered, and concentrated to afford crude Compound 19 that is used directly in the next step.
  • Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (compound 20).

  • A solution of Compound 19 (1 eq) in DMSO (1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40 °C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na2SO4), filtered, and concentrated to afford crude compound 20 (95%) that is used directly in the next step.
  • Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile (compound 21).

  • A mixture of compound 20 (1.0 eq), 50 wt % aqueous KOH (5.0 eq) 1-bromo-2-chloroethane (1.5 eq), and Oct4NBr (0.02 eq) is heated at 70 °C for 1 h. The reaction mixture is cooled then worked up with MTBE and water. The organic phase is washed with water and brine then the solvent is removed to afford compound 21.
  • Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (compound 22).

  • Compound 21 is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture is cooled to room temperature and ethanol is evaporated under vacuum. The residue is taken into water and MTBE, 1 M HCl was added and the layers are separated. The MTBE layer was then treated with dicyclohexylamine (0.97 equiv). The slurry is cooled to 0 °C, filtered and washed with heptane to give the corresponding DCHA salt. The salt is taken into MTBE and 10% citric acid and stirred until all solids dissolve. The layers are separated and the MTBE layer was washed with water and brine. Solvent swap to heptane followed by filtration gives compound 22 after drying in a vacuum oven at 50 °C overnight.
  • Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride (compound 7).

  • Compound 22 (1.2 cq) is slurried in toluene (2.5 vol) and the mixture heated to 60 °C. SOCl2 (1.4 eq) is added via addition funnel. The toluene and SOCl2 are distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) is added and distilled again.
  • Synthesis of 14C-(2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (compound 23).

  • A solution of Compound 19 (1 eq) in DMSO (1.25 vol) is added to a slurry of Na14 CN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40 °C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na2SO4), filtered, and concentrated to afford crude compound 23 that is purified by chromatography.
  • Synthesis of 14C-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile (compound 24).

  • A mixture of compound 23 (1.0 eq) and 1,2-dibromoethane (1.8 eq) in THF (3 vol) is cooled to -10 °C via external chiller. 1 M LHMDS in THF (2.5 eq) is added via an addition funnel and at a rate to maintain the temperature in the reactor below 10 °C. One hour after addition is complete, 20% w/v aq. citric acid (13 vol) is added via addition funnel maintaining the temperature in the reactor below 20 C. The external chiller is turned off and after stirring for 30 min the layers are separated. The organic layer is filtered and concentrated to afford crude compound 24 that is purified by chromatography.
  • Synthesis of 14C-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (compound 25).

  • Compound 24 is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture is cooled to room temperature and ethanol is evaporated under vacuum. The residue is taken into water and MTBE. 1 M HCl is added to the mixture and the organic layer is filtered and concentrated to afford compound 25.
  • Synthesis of 14C-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride (compound 26).

  • A mixture of Compound 25, 4-dimethylaminopyridine, and thionyl chloride (SOCl2) in CH2Cl2 is stirred to produce compound 26, which may be further reacted with compound 6 without isolation.
  • Amine Moiety
  • Synthesis of tert-butyl-3-(3-methylpyridin-2-yl)benzoate (compound 4).

  • 2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 °C under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 °C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer is concentrated to afford crude compound 4 (82%) that is used directly in the next step.
  • Synthesis of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (compound 5).

  • Compound 4 (1.0 eq) is dissolved in EtOAc (6 vol). Water (0. 3 vol) is added followed by urea-hydrogen peroxide (3 cq). The phthalic anhydride (3 cq) is added portion-wise as a solid to maintain the temperature in the reactor below 45 °C. After completion of phthalic anhydride addition, the mixture is heated to 45 °C. After stirring for an additional 4 hours, the heat is turned off. 10% w/w aqueous Na2SO3 (1.5 eq) is added via addition funnel. After completion of Na2SO3 addition, the mixture is stirred for an additional 30 minutes and the layers separated. The organic layer is stirred and 10% w/w aq. Na2CO3 (2 eq) is added. After stirring for 30 minutes, the layers are allowed to separate. The organic phase is washed 13% w/v aq NaCl. The organic phase is then filtered and concentrated to afford crude compound 5 (95%) that is used directly in the next step.
  • Synthesis of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate (compound 6).

  • A solution of compound 5 (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 °C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 °C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 °C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2:1 MeCN/water (3 vol), and MeCN (2×1.5 vol). The solid is dried to constant weight (<1% difference) in a vacuum oven at 50 °C with a slight N2 bleed to afford compound 6 as a red-yellow solid (53% yield).
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (compound 8).

  • Compound 7 is dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of compound 6 (1 eq), dimethylaminopyridine (DMAP, 0.02 eq), and triethylamine (3.0 cq) in toluene (4 vol based on compound 6). After 2 hours, water (4 vol based on compound 6) is added to the reaction mixture. After stirring for 30 minutes, the layers are separated. The organic phase is then filtered and concentrated to afford a thick oil of compound 8 (quantitative crude yield). MeCN (3 vol based on crude product) is added and distilled until crystallization occurs. Water (2 vol based on crude product) is added and the mixture stirred for 2 h. The solid is collected by filtration, washed with 1:1 (by volume) MeCN/water (2 x 1 vol based on crude product), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate as a brown solid.
  • Syntheisis of Syntheisis of 3-(6-(1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCL salt (compound 9).

  • To a slurry of compound 8 (1.0 eq) in MeCN (3.0 vol) is added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture is heated to 45 ± 5 °C. After stirring for 24 to 48 hours the reaction is complete and the mixture is allowed to cool to ambient. Water (1.33 vol) is added and the mixture stirred. The solid is collected by filtration, washed with water (2 x 0.3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford compound 9 as an off-white solid.
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1).

  • A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2 x). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2 x 1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid (98% yield).
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) using water and base.

  • To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60 °C or 90 °C if needed to reduce the level of the t-butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3 x 3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid (97% yield).
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) directly from benzoate.

  • A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 ± 10 °C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 °C and the mixture stirred. The mixture is then heated to 70 ± 10 °C until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid.
  • 1HNMR spectra of Compound 1 are shown in Figures 9-11 (Figures 9 and 10 depict Compound 1 in Form I in a 50 mg/mL, 0.5 methyl cellulose-polysorbate 80 suspension, and Figure 11 depicts Compound 1 as an HCl salt).
  • Table 3 below recites additional analytical data for Compound 1.
  • Table 3.

    Cmpd. No. LC/MS M+1 LC/RTmin NMR
    1 453.3 1.93 H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H)

WO2002096421A1 * May 22, 2002 Dec 5, 2002 Neurogen Corp 5-substituted-2-arylpyridines as crf1 modulators
WO2004072038A1 * Feb 10, 2004 Aug 26, 2004 Vertex Pharma Processes for the preparation of n-heteroaryl-n-aryl-amines by reacting an n-aryl carbamic acid ester with a halo-heteroaryl and analogous processes
WO2007056341A1 Nov 8, 2006 May 18, 2007 Vertex Pharma Heterocyclic modulators of atp-binding cassette transporters
 see……http://orgspectroscopyint.blogspot.in/2015/03/lumacaftor.htm

References

David Andrew Siesel;Processes for producing cycloalkylcarboxamido-pyridine benzoic acids,US patent number US8124781 B2 ;Also published as   CA2707494A1, CN101910134A, EP2231606A2, EP2231606B1, EP2639222A1, EP2639223A1, EP2639224A1, US8592602, US20090176989, US20120190856, WO2009076142A2, WO2009076142A3;Filing date:Dec 4, 2008;Original Assignee:Vertex Pharmaceuticals Incorporated

David Andrew Siesel;Processes for producing cycloalkylcarboxamido-pyridine benzoic acids,US patent number US8461342 B2  ;Also published as  US20100036130, US20120203006, US20130274477, WO2010138484A2, WO2010138484A3;Original Assignee:Vertex Pharmaceuticals Incorporated

Van Goor, Fredrick F. et al;Pharmaceutical compositions in the treatment of CFTR-mediated diseases such as cystic fibrosis;PCT Int. Appl., WO2011133956

Van Goor, Fredrick F. et al;Pharmaceutical compositions in the treatment of CFTR-mediated diseases such as cystic fibrosis.PCT Int. Appl., WO2011133951

Van Goor, Fredrick F. et al;Pharmaceutical compositions for treatment of CFTR-mediated diseases;PCT Int. Appl., WO2011133953

Verwijs, Marinus Jacobus et al;Preparation and pharmaceutical compositions of Lumacaftor for the treatment of cystic fibrosis and other diseases associated with CFTR mutations;PCT Int. Appl., WO2011127241

Keshavarz-Shokri, Ali et al;Preparation of Lumacaftor for therapeutical use;PCT Int. Appl., WO2011127290

Siesel, David;A process for the preparation of solid forms of (((difluorobenzodioxolyl)cyclopropanecarboxamido)methylpyridinyl)benzoic acid;U.S. Pat. Appl. Publ., US20100036130

Siesel, David;A process for the preparation of solid forms of (((difluorobenzodioxolyl)cyclopropanecarboxamido)methylpyridinyl)benzoic acid;PCT Int. Appl., WO2010138484

Young, Christopher;Dosage units of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid;PCT Int. Appl., WO2010037066

Hadida-Ruah, Sara et al;paration of N-pyridinyl carboxamide derivatives as modulators of ATP-binding cassette transporters;U.S. Pat. Appl. Publ., 20080019915

Siesel, David;A process for the preparation of solid forms of (((difluorobenzodioxolyl)cyclopropanecarboxamido)methylpyridinyl)benzoic acid;PCT Int. Appl., WO2009076142

Hadida Ruah, Sara et al;Preparation of N-pyridinyl carboxamide derivatives as modulators of ATP-binding cassette transporters;PCT Int. Appl., WO2007056341

video on cystic fibrosis

second video

Update on 26 mar 2015


LUMACAFTOR
VX 809

3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic Acid
CAS No.: 936727-05-8
Synonyms:
  • VX-809 (Lumacaftor);
  • VX-809;
  • Lumacaftor;
  • 3-(6-{[1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonyl]-amino}-3-methyl-pyridin-2-yl)-benzoic acid;
  • 3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid;
Formula: C24H18F2N2O5
Exact Mass: 452.11800

SMILLES….    Cc1ccc(nc1c2cccc(c2)C(=O)O)NC(=O)C3(CC3)c4ccc5c(c4)OC(O5)(F)F

NMR…………….http://file.selleckchem.com/downloads/nmr/S156503-VX-809-HNMR-Selleck.pdf

 PATENT
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) directly from benzoate.
    Figure imgb0101
  • A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 ± 10 °C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 °C and the mixture stirred. The mixture is then heated to 70 ± 10 °C until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid.
  • 1HNMR spectra of Compound 1 are shown in Figures 9-11 (Figures 9 and 10 depict Compound 1 in Form I in a 50 mg/mL, 0.5 methyl cellulose-polysorbate 80 suspension, and Figure 11 depicts Compound 1 as an HCl salt).
  • Table 3 below recites additional analytical data for Compound 1.
  • Table 3.
    Cmpd. No. LC/MS M+1 LC/RTmin NMR
    1 453.3 1.93 H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H)

logo
1H NMR PREDICT

 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid NMR spectra analysis, Chemical CAS NO. 936727-05-8 NMR spectral analysis, 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid H-NMR spectrum
13C NMR PREDICT3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid NMR spectra analysis, Chemical CAS NO. 936727-05-8 NMR spectral analysis, 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid C-NMR spectrumCAS NO. 936727-05-8, 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid C-NMR spectral analysisCOSY PREDICT

13C NMR PREDICT

WO2002096421A1 * May 22, 2002 Dec 5, 2002 Neurogen Corp 5-substituted-2-arylpyridines as crf1 modulators
WO2004072038A1 * Feb 10, 2004 Aug 26, 2004 Vertex Pharma Processes for the preparation of n-heteroaryl-n-aryl-amines by reacting an n-aryl carbamic acid ester with a halo-heteroaryl and analogous processes
WO2007056341A1 Nov 8, 2006 May 18, 2007 Vertex Pharma Heterocyclic modulators of atp-binding cassette transporters
Patent

http://www.google.co.in/patents/US8124781

Figure US08124781-20120228-C00074

Figure US08124781-20120228-C00075

Figure US08124781-20120228-C00076

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1)

Figure US08124781-20120228-C00093
A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2×). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2×1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight Nbleed to afford Compound 1 as an off-white solid (98% yield).

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1) Using Water and Base

Figure US08124781-20120228-C00094
To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60° C. or 90° C. if needed to reduce the level of the t-butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3×3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight Nbleed to afford Compound 1 as an off-white solid (97% yield).

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1) Directly from Benzoate

Figure US08124781-20120228-C00095
A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70±10° C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50° C. and the mixture stirred. The mixture is then heated to 70±10° C. until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2×3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight Nbleed to afford Compound 1 as an off-white solid.
……………….
WO2011127241

Compound 1

Compound 1 is used as the starting point for the other solid state forms and can be prepared by coupling an acid chloride moiety with an amine moiety according to Schemes 1-4.

Scheme 1. Synthesis of the acid chloride moiety.

1. NaCN

2. H20

socio

Scheme 1 depicts the preparation of l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride, which is used in Scheme 3 to make the amide linkage of Compound 1.

The starting material, 2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid, is commercially available from Saltigo (an affiliate of the Lanxess Corporation). Reduction of the carboxylc acid moiety in 2,2-difluorobenzo[d][l ,3]dioxole-5-carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl2), provides 5-(chloromethyl)-2,2-difluorobenzo[d][l,3]dioxole, which is subsequently converted to 2-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)acetonitrile using sodium cyanide. Treatment of 2-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)acetonitrile with base and l-bromo-2-chloroethane provides 1- (2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarbonitrile. The nitrile moiety in l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarbonitrile is converted to a carboxylic acid using base to give l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.

Scheme 2. Alternative synthesis of the acid chloride moiety.

Touene, H20, 70 °C3 N HC1,

DMSO,

75 °C

Scheme 2 depicts an alternative synthesis of the requisite acid chloride. 5- bromomethyl-2,2-difluoro-l,3-benzodioxole is coupled with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha cyano ethyl ester. Saponification of the ester moiety to the carboxylic acid gives the cyanoethyl compound. Alkylation of the cyanoethyl compound with l-bromo-2-chloro ethane in the presence of base gives the cyanocyclopropyl compound. Treatment of the cyanocyclopropyl compound with base gives the carboxylate salt, which is converted to the carboxylic acid by treatment with acid. Conversion of the carboxylic acid to the acid chloride is then accomplished using a chlorinating agent such as thionyl chloride or the like.

Scheme 3. Synthesis of the amine moiety.

ptBu urea-hydrogen peroxide hthalic anhydride EtOAc, water

Scheme 3 depicts the preparation of the requisite tert-butyl 3-(6-amino-3- methylpyridin-2-yl)benzoate, which is coupled with l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride in Scheme 3 to give Compound 1. Palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid gives tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is subsequently converted to the desired compound. Scheme 4. Formation of an acid salt of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.

Scheme 4 depicts the coupling of l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate using triethyl amine and 4-dimethylaminopyridine to initially provide the tert-butyl ester of Compound 1.

……………………..

WO2010037066

http://www.google.im/patents/WO2010037066A2?cl=en

Syntheisis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCL salt.

HCl

To a slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) is added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture is heated to 45 ± 5 0C. After stirring for 24 to 48 hours the reaction is complete and the mixture is allowed to cool to ambient. Water (1.33 vol) is added and the mixture stirred. The solid is collected by filtration, washed with water (2 x 0.3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford 3-(6-(l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2- yl)benzoic acid • HCl as an off-white solid.

Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1 in Form I).

HCl

Compound 1 in Form I

A slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2 x). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2 x 1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid (98% yield).

Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1 in Form I) using water and base.

Compound 1 in Form I

To a slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60 0C or 90 0C if needed to reduce the level of the t-butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3 x 3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid (97% yield).

Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1 in Form I) directly from benzoate.

Compound 1 in Form I

A solution of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 ± 10 0C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 0C and the mixture stirred. The mixture is then heated to 70 ± 10 0C until the level of 3- (6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin- 2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 in Form I as an off-white solid.

 

NOVARTIS TOBI Podhaler receives FDA approval for cystic fibrosis patients with Pseudomonas aeruginosa


Tobramycin

MAR 22.2013, FDA approves TOBI Podhaler to treat a type of bacterial lung infection in cystic fibrosispatients

The U.S. Food and Drug Administration today approved TOBI Podhaler (tobramycininhalation powder) for the management of cystic fibrosis patients with Pseudomonas aeruginosa, a bacterium that causes lung infections.

Cystic fibrosis is a genetic disease that affects about 30,000 pediatric and adult patients in the United States. Cystic fibrosis causes the body to produce thick, sticky mucus that builds up in the lungs and blocks airways. The buildup of mucus makes it easy for bacteria like P. aeruginosa to grow and cause a chronic lung infection that, over time, can severely damage the lungs. Many patients with cystic fibrosis are treated with antibiotics using a nebulizer machine.

Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius and used to treat various types of bacteria infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.

TOBI Podhaler, a plastic, handheld inhaler device, contains a dry powder formulation of tobramycin, an antibiotic used to treat P. aeruginosa infection. The powder is inhaled twice daily using the Podhaler device for 28 days. Patients should then stop TOBI Podhaler therapy for 28 days before resuming again.

“Today’s approval broadens the available delivery mechanism options for patients withcystic fibrosis who require treatment for P. aeruginosa,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “This product is the first dry powder antibacterial drug delivered with a handheld dry powder inhaler.”

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