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ORGANIC SPECTROSCOPY

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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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Fosdenopterin hydrobromide


Fosdenopterin hydrobromide.png
FOSDENOPTERIN HYDROBROMIDE

Fosdenopterin hydrobromide

FDA APPR 2021/2/26, NULIBRY

BBP-870/ORGN001

a cyclic pyranopterin monophosphate (cPMP) substrate replacement therapy, for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.

ホスデノプテリン臭化水素酸塩水和物;
FormulaC10H14N5O8P. 2H2O. HBr
CAS2301083-34-9DIHYDRATE
Mol weight480.1631

2301083-34-9

(1R,10R,12S,17R)-5-amino-11,11,14-trihydroxy-14-oxo-13,15,18-trioxa-2,4,6,9-tetraza-14λ5-phosphatetracyclo[8.8.0.03,8.012,17]octadeca-3(8),4-dien-7-one;dihydrate;hydrobromide

1,3,2-DIOXAPHOSPHORINO(4′,5′:5,6)PYRANO(3,2-G)PTERIDIN-10(4H)-ONE, 8-AMINO-4A,5A,6,9,11,11A,12,12A-OCTAHYDRO-2,12,12-TRIHYDROXY-, 2-OXIDE, HYDROBROMIDE, HYDRATE (1:1:2), (4AR,5AR,11AR,12AS)-

CYCLIC PYRANOPTERIN MONOPHOSPHATE MONOHYDROBROMIDE DIHYDRATE

(4aR,5aR,11aR,12aS)-8-Amino-2,12,12-trihydroxy-4a,5a,6,7,11,11a,12,12aoctahydro-2H-2lambda5-(1,3,2)dioxaphosphinino(4′,5′:5,6)pyrano(3,2-g)pteridine-2,10(4H)-dione, hydrobromide (1:1:2)

1,3,2-Dioxaphosphorino(4′,5′:5,6)pyrano(3,2-g)pteridin-10(4H)-one, 8-amino-4a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-, 2-oxide, hydrobromide, hydrate (1:1:2), (4aR,5aR,11aR,12aS)-

1,3,2-Dioxaphosphorino(4′,5′:5,6)pyrano(3,2-g)pteridin-10(4H)-one, 8-amino-4a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-, 2-oxide,hydrobromide, hydrate (1:1:2), (4aR,5aR,11aR,12aS)-

ALXN1101 HBrUNII-X41B5W735TX41B5W735TD11780

Nulibry Approved for Molybdenum Cofactor Deficiency Type A - MPR
Thumb
ChemSpider 2D Image | Cyclic pyranopterin monophosphate | C10H14N5O8P
Cyclic pyranopterin monophosphate.svg

C10H14N5O8P, Average: 363.223

150829-29-1

  • ALXN-1101
  • WHO 11150
  • Synthesis ReferenceClinch K, Watt DK, Dixon RA, Baars SM, Gainsford GJ, Tiwari A, Schwarz G, Saotome Y, Storek M, Belaidi AA, Santamaria-Araujo JA: Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway. J Med Chem. 2013 Feb 28;56(4):1730-8. doi: 10.1021/jm301855r. Epub 2013 Feb 19.

Fosdenopterin (or cyclic pyranopterin monophosphatecPMP), sold under the brand name Nulibry, is a medication used to reduce the risk of death due to a rare genetic disease known as molybdenum cofactor deficiency type A (MoCD-A).[1]

Adverse effects

The most common side effects include complications related to the intravenous line, fever, respiratory infections, vomiting, gastroenteritis, and diarrhea.[1]

Mechanism of action

People with MoCD-A cannot produce cyclic pyranopterin monophosphate (cPMP) in their body.[1] Fosdenopterin is an intravenous medication that replaces the missing cPMP.[1][2] cPMP is a precursor to molybdopterin, which is required for the enzyme activity of sulfite oxidasexanthine dehydrogenase/oxidase and aldehyde oxidase.[3]

History

Fosdenopterin was developed by José Santamaría-Araujo and Guenter Schwarz at the German universities TU Braunschweig and the University of Cologne.[4][5]

The effectiveness of fosdenopterin for the treatment of MoCD-A was demonstrated in thirteen treated participants compared to eighteen matched, untreated participants.[1][6] The participants treated with fosdenopterin had a survival rate of 84% at three years, compared to 55% for the untreated participants.[1]

The U.S. Food and Drug Administration (FDA) granted the application for fosdenopterin priority reviewbreakthrough therapy, and orphan drug designations along with a rare pediatric disease priority review voucher.[1] The FDA granted the approval of Nulibry to Origin Biosciences, Inc., in February 2021.[1] It is the first medication approved for the treatment of MoCD-A.[1]

References

  1. Jump up to:a b c d e f g h i j “FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A”U.S. Food and Drug Administration (FDA) (Press release). 26 February 2021. Retrieved 26 February 2021.  This article incorporates text from this source, which is in the public domain.
  2. ^ DrugBank DB16628 . Accessed 2021-03-05.
  3. ^ Santamaria-Araujo JA, Fischer B, Otte T, Nimtz M, Mendel RR, Wray V, Schwarz G (April 2004). “The tetrahydropyranopterin structure of the sulfur-free and metal-free molybdenum cofactor precursor”The Journal of Biological Chemistry279 (16): 15994–9. doi:10.1074/jbc.M311815200PMID 14761975.
  4. ^ Schwarz G, Santamaria-Araujo JA, Wolf S, Lee HJ, Adham IM, Gröne HJ, et al. (June 2004). “Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli”Human Molecular Genetics13 (12): 1249–55. doi:10.1093/hmg/ddh136PMID 15115759.
  5. ^ Tedmanson S (5 November 2009). “Doctors risk untried drug to stop baby’s brain dissolving”TimesOnline.
  6. ^ Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, et al. (November 2015). “Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study”. Lancet386 (10007): 1955–63. doi:10.1016/S0140-6736(15)00124-5PMID 26343839S2CID 21954888.

External links

Molybdenum cofactor deficiency (MoCD) is an exceptionally rare autosomal recessive disorder resulting in a deficiency of three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde oxidase.1 Signs and symptoms begin shortly after birth and are caused by a build-up of toxic sulfites resulting from a lack of SOX activity.1,5 Patients with MoCD may present with metabolic acidosis, intracranial hemorrhage, feeding difficulties, and significant neurological symptoms such as muscle hyper- and hypotonia, intractable seizures, spastic paraplegia, myoclonus, and opisthotonus. In addition, patients with MoCD are often born with morphologic evidence of the disorder such as microcephaly, cerebral atrophy/hypodensity, dilated ventricles, and ocular abnormalities.1 MoCD is incurable and median survival in untreated patients is approximately 36 months1 – treatment, then, is focused on improving survival and maintaining neurological function.

The most common subtype of MoCD, type A, involves mutations in MOCS1 wherein the first step of molybdenum cofactor synthesis – the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP) – is interrupted.1,3 In the past, management strategies for this disorder involved symptomatic and supportive treatment,5 though efforts were made to develop a suitable exogenous replacement for the missing cPMP. In 2009 a recombinant, E. coli-produced cPMP was granted orphan drug designation by the FDA, becoming the first therapeutic option for patients with MoCD type A.1

Fosdenopterin was approved by the FDA on Februrary 26, 2021, for the reduction of mortality in patients with MoCD type A,5 becoming the first and only therapy approved for the treatment of MoCD. By improving the three-year survival rate from 55% to 84%,7 and considering the lack of alternative therapies available, fosdenopterin appears poised to become a standard of therapy in the management of this debilitating disorder.

Fosdenopterin replaces an intermediate substrate in the synthesis of molybdenum cofactor, a compound necessary for the activation of several molybdenum-dependent enzymes including sulfite oxidase (SOX).1 Given that SOX is responsible for detoxifying sulfur-containing acids and sulfites such as S-sulfocysteine (SSC), urinary levels of SSC can be used as a surrogate marker of efficacy for fosdenopterin.7 Long-term therapy with fosdenopterin has been shown to result in a sustained reduction in urinary SSC normalized to creatinine.7

Animal studies have identified a potential risk of phototoxicity in patients receiving fosdenopterin – these patients should avoid or minimize exposure to sunlight and/or artificial UV light.7 If sun exposure is necessary, use protective clothing, hats, and sunglasses,7 in addition to seeking shade whenever practical. Consider the use of a broad-spectrum sunscreen in patients 6 months of age or older.8

Molybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder in which patients are deficient in three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde dehydrogenase.1 The loss of SOX activity appears to be the main driver of MoCD morbidity and mortality, as the build-up of neurotoxic sulfites typically processed by SOX results in rapid and progressive neurological damage. In MoCD type A, the disorder results from a mutation in the MOCS1 gene leading to deficient production of MOCS1A/B,7 a protein that is responsible for the first step in the synthesis of molybdenum cofactor: the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP).1,4

Fosdenopterin is an exogenous form of cPMP, replacing endogenous production and allowing for the synthesis of molybdenum cofactor to proceed.7

  1. Mechler K, Mountford WK, Hoffmann GF, Ries M: Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet Med. 2015 Dec;17(12):965-70. doi: 10.1038/gim.2015.12. Epub 2015 Mar 12. [PubMed:25764214]
  2. Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, Hennermann JB, Jameson E, Konig K, McGregor TL, Font-Montgomery E, Santamaria-Araujo JA, Santra S, Vaidya M, Vierzig A, Wassmer E, Weis I, Wong FY, Veldman A, Schwarz G: Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet. 2015 Nov 14;386(10007):1955-63. doi: 10.1016/S0140-6736(15)00124-5. Epub 2015 Sep 3. [PubMed:26343839]
  3. Iobbi-Nivol C, Leimkuhler S: Molybdenum enzymes, their maturation and molybdenum cofactor biosynthesis in Escherichia coli. Biochim Biophys Acta. 2013 Aug-Sep;1827(8-9):1086-101. doi: 10.1016/j.bbabio.2012.11.007. Epub 2012 Nov 29. [PubMed:23201473]
  4. Mendel RR: The molybdenum cofactor. J Biol Chem. 2013 May 10;288(19):13165-72. doi: 10.1074/jbc.R113.455311. Epub 2013 Mar 28. [PubMed:23539623]
  5. FDA News Release: FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A [Link]
  6. OMIM: MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A (# 252150) [Link]
  7. FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
  8. Health Canada: Sun safety tips for parents [Link]

SYN

Journal of Biological Chemistry (1995), 270(3), 1082-7.

https://linkinghub.elsevier.com/retrieve/pii/S0021925818829696

PATENT

WO 2005073387

PATENT

WO 2012112922

PAPER

 Journal of Medicinal Chemistry (2013), 56(4), 1730-1738

https://pubs.acs.org/doi/10.1021/jm301855r

Abstract Image

Cyclic pyranopterin monophosphate (1), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and d-galactose phenylhydrazone to give the pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-tert-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to give 1·HBr. Synthesized 1·HBr had in vitro efficacy comparable to that of 1 of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase–molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up.

str1
str2
str3
str4

PAPER

 European Journal of Organic Chemistry (2014), 2014(11), 2231-2241.

https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.201301784

Abstract

The first synthesis of an oxygen‐stable analogue of the natural product cyclic pyranopterin monophosphate (cPMP) is reported. In this approach, the hydropyranone ring is annelated to pyrazine by a sequence comprising ortho‐lithiation/acylation of a 2‐halopyrazine, followed by nucleophilic aromatic substitution. The tetrose substructure is introduced from the chiral pool, from D‐galactose or D‐arabitol.

image

Abstract

Molybdenum cofactor (Moco) deficiency is a lethal hereditary metabolic disease. A recently developed therapy requires continuous intravenous supplementation of the biosynthetic Moco precursor cyclic pyranopterin monophosphate (cPMP). The limited stability of the latter natural product, mostly due to oxidative degradation, is problematic for oral administration. Therefore, the synthesis of more stable cPMP analogues is of great interest. In this context and for the first time, the synthesis of a cPMP analogue, in which the oxidation‐labile reduced pterin unit is replaced by a pyrazine moiety, was achieved starting from the chiral pool materials D‐galactose or D‐arabitol. Our synthesis, 13 steps in total, includes the following key transformations: i) pyrazine lithiation, followed by acylation; ii) closure of the pyrane ring by nucleophilic aromatic substitution; and iii) introduction of phosphate.

Patent

https://patents.google.com/patent/US9260462B2/en

Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder. Moco consists of molybdenum covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by a biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclic pyranopterin monophosphate; cPMP), MPT, and adenylated MPT. Mutations in the Moco biosynthetase genes result in the loss of production of the molybdenum dependent enzymes sulfite-oxidase, xanthine oxidoreductase, and aldehyde oxidase. Whereas the activities of all three of these cofactor-containing enzymes are impaired by cofactor deficiency, the devastating consequences of the disease can be traced to the loss of sulfite oxidase activity. Human Moco deficiency is a rare but severe disorder accompanied by serious neurological symptoms including attenuated growth of the brain, untreatable seizures, dislocated ocular lenses, and mental retardation. Until recently, no effective therapy was available and afflicted patients suffering from Moco deficiency died in early infancy.

It has been found that administration of the molybdopterin derivative precursor Z, a relatively stable intermediate in the Moco biosynthetic pathway, is an effective means of therapy for human Moco deficiency and associated diseases related to altered Moco synthesis (see U.S. Pat. No. 7,504,095). As with most replacement therapies for illnesses, however, the treatment is limited by the availability of the therapeutic active agent.

Scheme 3.

Figure US09260462-20160216-C00133

Scheme 4.

Figure US09260462-20160216-C00140

(I).

Figure US09260462-20160216-C00141

 Scheme 6.

Figure US09260462-20160216-C00142

 (I).

Figure US09260462-20160216-C00143

Scheme 8.

Figure US09260462-20160216-C00144

(I).

Figure US09260462-20160216-C00145

 Scheme 10.

Figure US09260462-20160216-C00146

EXAMPLESExample 1Preparation of Precursor Z (cPMP)

Figure US09260462-20160216-C00214
Figure US09260462-20160216-C00215

Experimental

Air sensitive reactions were performed under argon. Organic solutions were dried over anhydrous MgSOand the solvents were evaporated under reduced pressure. Anhydrous and chromatography solvents were obtained commercially (anhydrous grade solvent from Sigma-Aldrich Fine Chemicals) and used without any further purification. Thin layer chromatography (t.l.c.) was performed on glass or aluminum sheets coated with 60 F254 silica gel. Organic compounds were visualized under UV light or with use of a dip of ammonium molybdate (5 wt %) and cerium(IV) sulfate 4H2O (0.2 wt %) in aq. H2SO(2M), one of I(0.2%) and KI (7%) in H2SO(1M), or 0.1% ninhydrin in EtOH. Chromatography (flash column) was performed on silica gel (40-63 μm) or on an automated system with continuous gradient facility. Optical rotations were recorded at a path length of 1 dm and are in units of 10−1 deg cmg−1; concentrations are in g/100 mL. 1H NMR spectra were measured in CDCl3, CD3OD (internal Me4Si, δ 0 ppm) or D2O(HOD, δ 4.79 ppm), and 13C NMR spectra in CDCl(center line, δ 77.0 ppm), CD3OD (center line, δ 49.0 ppm) or DMSO d(center line δ 39.7 ppm), D2O (no internal reference or internal CH3CN, δ 1.47 ppm where stated). Assignments of 1H and 13C resonances were based on 2D (1H—1H DQF-COSY, 1H—13C HSQC, HMBC) and DEPT experiments. 31P NMR were run at 202.3 MHz and are reported without reference. High resolution electrospray mass spectra (ESI-HRMS) were recorded on a Q-TOF Tandem Mass

Spectrometer. Microanalyses were performed by the Campbell Microanalytical Department, University of Otago, Dunedin, New Zealand.

A. Preparation of (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one mono hydrate (1)

2,5,6-Triamino-3,4-dihydropyrimidin-4-one dihydrochloride (Pfleiderer, W.; Chem. Ber. 1957, 90, 2272; Org. Synth. 1952, 32, 45; Org. Synth. 1963, Coll. Vol. 4, 245, 10.0 g, 46.7 mmol), D-galactose phenylhydrazone (Goswami, S.; Adak, A. K. Tetrahedron Lett. 2005, 46, 221-224, 15.78 g, 58.4 mmol) and 2-mercaptoethanol (1 mL) were stirred and heated to reflux (bath temp 110° C.) in a 1:1 mixture of MeOH—H2O (400 mL) for 2 h. After cooling to ambient temperature, diethyl ether (500 mL) was added, the flask was shaken and the diethyl ether layer decanted off and discarded. The process was repeated with two further portions of diethyl ether (500 mL) and then the remaining volatiles were evaporated. Methanol (40 mL), H2O (40 mL) and triethylamine (39.4 mL, 280 mmol) were successively added and the mixture seeded with a few milligrams of 1. After 5 min a yellow solid was filtered off, washed with a little MeOH and dried to give 1 as a monohydrate (5.05 g, 36%) of suitable purity for further use. An analytical portion was recrystallized from DMSO-EtOH or boiling H2O. MPt 226 dec. [α]D 20 +135.6 (c1.13, DMSO). 1H NMR (DMSO d6): δ 10.19 (bs, exchanged D2O, 1H), 7.29 (d, J=5.0 Hz, slowly exchanged D2O, 1H), 5.90 (s, exchanged D2O, 2H), 5.33 (d, J=5.4 Hz, exchanged D2O, 1H), 4.66 (ddd, J˜5.0, ˜1.3, ˜1.3 Hz, 1H), 4.59 (t, J=5.6 Hz, exchanged D2O, 1H), 4.39 (d, J=10.3 Hz, exchanged D2O, 1H), 3.80 (bt, J˜1.8 Hz, exchanged D2O, 1H), 3.70 (m, 1H), 3.58 (dd, J=10.3, 3.0 Hz, 1H), 3.53 (dt, J=10.7, 6.4 Hz, 1H), 3.43 (ddd, J=11.2, 5.9, 5.9 Hz, 1H), 3.35 (t, J=6.4 Hz, 1H), 3.04 (br m, 1H). 13C NMR (DMSO dcenter line 6 39.7): δ 156.3 (C), 150.4 (C), 148.4 (C), 99.0 (C), 79.4 (CH), 76.5 (CH), 68.9 (CH), 68.6 (CH), 60.6 (CH2), 53.9 (CH). Anal. calcd. for C10H15N5O5H2O 39.60; C, 5.65; H, 23.09; N. found 39.64; C, 5.71; H, 22.83; N.

B. Preparation of Compounds 2 (a or b) and 3 (a, b or c)

Di-tert-butyl dicarbonate (10.33 g, 47.3 mmol) and DMAP (0.321 g, 2.63 mmol) were added to a stirred suspension of 1 (1.5 g, 5.26 mmol) in anhydrous THF (90 mL) at 50° C. under Ar. After 20 h a clear solution resulted. The solvent was evaporated and the residue chromatographed on silica gel (gradient of 0 to 40% EtOAc in hexanes) to give two product fractions. The first product to elute was a yellow foam (1.46 g). The product was observed to be a mixture of two compounds by 1H NMR containing mainly a product with seven Boc groups (2a or 2b). A sample was crystallized from EtOAc-hexanes to give 2a or 2b as a fine crystalline solid. MPt 189-191° C. [α]D 20 −43.6 (c 0.99, MeOH). 1H NMR (500 MHz, CDCl3): δ 5.71 (t, J=1.7 Hz, 1H), 5.15 (dt, J=3.5, ˜1.0, 1H), 4.97 (t, J=3.8, 1H), 4.35 (br t, J=˜1.7, 1H), 4.09-3.97 (m, 3H), 3.91 (m, 1H), 1.55, 1.52, 1.51, 1.50, 1.45 (5s, 45H), 1.40 (s, 18H). 13C NMR (125.7 MHz, CDCl3): δ 152.84 (C), 152.78 (C), 151.5 (C), 150.9 (C), 150.7 (2×C), 150.3 (C), 149.1 (C), 144.8 (C), 144.7 (C), 118.0 (C), 84.6 (C), 83.6 (C), 83.5 (C), 82.7 (3×C), 82.6 (C), 76.3 (CH), 73.0 (CH), 71.4 (CH), 67.2 (CH), 64.0 (CH2), 51.4 (CH), 28.1 (CH3), 27.8 (2×CH3), 27.7 (CH3), 27.6 (3×CH3). MS-ESI+ for C45H72N5O19 +, (M+H)+, Calcd. 986.4817. found 986.4818. Anal. calcd. for C45H71N5O19H2O 54.39; C, 7.39; H, 6.34; N. found 54.66; C, 7.17; H, 7.05; N. A second fraction was obtained as a yellow foam (2.68 g) which by 1H NMR was a product with six Boc groups present (3a, 3b or 3c). A small amount was crystallized from EtOAc-hexanes to give colorless crystals. [α]D 2O −47.6 (c, 1.17, CHCl3). 1H NMR (500 MHz, CDCl3): δ 11.10 (br s, exchanged D2O, 1H), 5.58 (t, J=1.8 Hz, 1H), 5.17 (d, J=3.4 Hz, 1H), 4.97 (t, J=3.9 Hz, 1H), 4.62 (s, exchanged D2O, 1H), 4.16 (dd, J=11.3, 5.9 Hz, 1H), 4.12 (dd, J=11.3, 6.4 Hz, 1H), 3.95 (dt, J=6.1, 1.1 Hz, 1H), 3.76 (m, 1H), 1.51, 1.50, 1.49, 1.48, 1.46 (5s, 54H). 13C NMR (125.7 MHz, CDCl3): δ 156.6 (C), 153.0 (C), 152.9 (C), 151.9 (C), 150.6 (C), 149.4 (2×C), 136.2 (C), 131.8 (C), 116.9 (C), 85.0 (2×C), 83.3 (C), 82.8 (C), 82.49 (C), 82.46 (C), 73.3 (CH), 71.5 (CH), 67.2 (CH), 64.5 (CH2), 51.3 (CH), 28.0, 27.72, 27.68, 27.6 (4×CH3). MS-ESI+ for C40H64N5O17 +, (M+H)+calcd. 886.4287. found 886.4289.

C. Preparation of Compound 4a, 4b or 4c

Step 1—The first fraction from B above containing mainly compounds 2a or 2b (1.46 g, 1.481 mmol) was dissolved in MeOH (29 mL) and sodium methoxide in MeOH (1M, 8.14 mL, 8.14 mmol) added. After leaving at ambient temperature for 20 h the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated.

Step 2—The second fraction from B above containing mainly 3a, 3b or 3c (2.68 g, 3.02 mmol) was dissolved in MeOH (54 mL) and sodium methoxide in MeOH (1M, 12.10 mL, 12.10 mmol) added. After leaving at ambient temperature for 20 h the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated.

The products from step 1 and step 2 above were combined and chromatographed on silica gel (gradient of 0 to 15% MeOH in CHCl3) to give 4a, 4b or 4c as a cream colored solid (1.97 g). 1H NMR (500 MHz, DMSO d6): δ 12.67 (br s, exchanged D2O, 1H), 5.48 (d, J=5.2 Hz, exchanged D2O, 1H), 5.43 (t, J=˜1.9 Hz, after D2O exchange became a d, J=1.9 Hz, 1H), 5.00 (br s, exchanged D2O, 1H), 4.62 (d, J=5.7 Hz, exchanged D2O, 1H), 4.27 (d, J=6.0 Hz, exchanged D2O, 1H), 3.89 (dt, J=5.2, 3.8 Hz, after D2O became a t, J=3.9 Hz, 1H), 3.62 (dd, J=6.0, 3.7 Hz, after D2O exchange became a d, J=3.7 Hz, 1H), 3.52-3.39 (m, 4H), 1.42 (s, 9H), 1.41 (s, 18H). 13C NMR (125.7 MHz, DMSO d6): δ 157.9 (C), 151.1, (C), 149.8 (2×C), 134.6 (C), 131.4 (C), 118.8 (C), 83.5 (2×C), 81.3 (C), 78.2 (CH), 76.5 (CH), 68.1 (CH), 66.8 (CH), 60.6 (CH2), 54.4 (CH), 27.9 (CH3), 27.6 (2×CH3). MS-ESI+ for C25H40N5O11 +, (M+H)+ calcd. 586.2719. found 586.2717.

D. Preparation of Compound 5a, 5b or 5c

Compound 4a, 4b or 4c (992 mg, 1.69 mmol) was dissolved in anhydrous pyridine and concentrated. The residue was dissolved in anhydrous CH2Cl(10 mL) and pyridine (5 mL) under a nitrogen atmosphere and the solution was cooled to −42° C. in an acetonitrile/dry ice bath. Methyl dichlorophosphate (187 μL, 1.86 mmol) was added dropwise and the mixture was stirred for 2 h 20 min. Water (10 mL) was added to the cold solution which was then removed from the cold bath and diluted with ethyl acetate (50 mL) and saturated NaCl solution (30 mL). The organic portion was separated and washed with saturated NaCl solution. The combined aqueous portions were extracted twice further with ethyl acetate and the combined organic portions were dried over MgSOand concentrated. Purification by silica gel flash column chromatography (eluting with 2-20% methanol in ethyl acetate) gave the cyclic methyl phosphate 5a, 5b or 5c (731 mg, 65%). 1H NMR (500 MHz, CDCl3,): δ 11.72 (bs, exchanged D2O, 1H), 5.63 (t, J=1.8 Hz, 1H), 5.41 (s, exchanged D2O, 1H), 4.95 (d, J=3.2 Hz, 1H), 4.70 (dt, J=12.4, 1.8 Hz, 1H), 4.42 (dd, J=22.1, 12.1 Hz, 1H). 4.15 (q, J=3.7 Hz, 1H), 3.82 (s, 1H), 3.75 (s, 1H), 3.58 (d, J=11.7 Hz, 3H), 2.10 (bs, exchanged D20, 1H+H2O), 1.50 (s, 9H), 1.46 (s, 18H). 13C NMR (125.7 MHz, CDCl3, centre line δ 77.0): δ 157.5 (C), 151.2 (C), 149.6 (2×C), 134.5 (C), 132.3 (C), 117.6 (C), 84.7 (2×C), 82.8 (C), 77.3 (CH), 74.8 (d, J=4.1 Hz, CH), 69.7 (CH2), 68.8 (d, J=4.1 Hz, CH), 68.6 (d, J=5.9 Hz, CH), 56.0 (d, J=7.4 Hz, CH3), 51.8 (CH), 28.1 (CH3), 27.8 (CH3). MS-ESI+ for C26H40N5NaO13P+ (M+Na)+, calcd. 684.2252. found 684.2251.

E. Preparation of Compound 6a, 6b or 6c

Compound 5a, 5b or 5c (223 mg, 0.34 mmol) was dissolved in anhydrous CH2Cl(7 mL) under a nitrogen atmosphere. Anhydrous DMSO (104 μL, 1.46 mmol) was added and the solution was cooled to −78° C. Trifluoroacetic anhydride (104 μL, 0.74 mmol) was added dropwise and the mixture was stirred for 40 min. N,N-diisopropylethylamine (513 μL, 2.94 mmol) was added and the stirring was continued for 50 min at −78° C. Saturated NaCl solution (20 mL) was added and the mixture removed from the cold bath and diluted with CH2Cl(30 mL). Glacial acetic acid (170 μL, 8.75 mmol) was added and the mixture was stirred for 10 min. The layers were separated and the aqueous phase was washed with CH2Cl(10 mL). The combined organic phases were washed with 5% aqueous HCl, 3:1 saturated NaCl solution:10% NaHCOsolution and saturated NaCl solution successively, dried over MgSO4, and concentrated to give compound 6a, 6b or 6c (228 mg, quant.) of suitable purity for further use. 1H NMR (500 MHz, CDCl3): δ 5.86 (m, 1 H), 5.07 (m, 1 H), 4.70-4.64 (m, 2 H), 4.49-4.40 (m, 1 H), 4.27 (m, 1 H), 3.56, m, 4 H), 1.49 (s, 9 H), 1.46 (s, 18 H) ppm. 13C NMR (500 MHz, CDCl3): δ 157.5 (C), 151.1 (C), 150.6 (2 C), 134.6 (C), 132.7 (C), 116.6 (C), 92.0 (C), 84.6 (2 C), 83.6 (C), 78.0 (CH), 76.0 (CH), 70.4 (CH2), 67.9 (CH), 56.2 (CH3) δ6.0 (CH), 28.2 (3CH3), 26.8 (6 CH3) ppm. 31P NMR (500 MHz, CDCl3): δ−6.3 ppm.

F. Preparation of compound 7: (4aR,5aR,11aR,12aS)-1,3,2-Dioxaphosphorino[4′,5′:5,6]pyrano[3,2-g]pteridin-10(4H)-one,8-amino-4-a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-2-oxide

Compound 6a, 6b or 6c (10 mg, 14.8 μmol was dissolved in dry acetonitrile (0.2 mL) and cooled to 0° C. Bromotrimethylsilane (19.2 μL, 148 μmol) was added dropwise and the mixture was allowed to warm to ambient temperature and stirred for 5 h during which time a precipitate formed. HCl(aq) (10 μl, 37%) was added and the mixture was stirred for a further 15 min. The mixture was centrifuged for 15 min (3000 g) and the resulting precipitate collected. Acetonitrile (0.5 mL) was added and the mixture was centrifuged for a further 15 min. The acetonitrile wash and centrifugation was repeated a further two times and the resulting solid was dried under high vacuum to give compound 7 (4 mg, 75%). 1H NMR (500 MHz, D2O): δ 5.22 (d, J=1.6 Hz, 1H), 4.34 (dt, J=13, 1.6 Hz, 1H), 4.29-4.27 (m, 1H), 4.24-4.18 (m, 1H), 3.94 (br m, 1H), 3.44 (t, J=1.4 Hz, 1H). 31P NMR (500 MHz, D2O): δ −4.8 MS-ESI+ for C10H15N5O8P+, (M+H)+calcd. 364.0653. found 364.0652.

Example 2Comparison of Precursor Z (cPMP) Prepared Synthetically to that Prepared from E. Coli in the In vitro Synthesis of Moco

In vitro synthesis of Moco was compared using samples of synthetic precursor Z (cPMP) and cPMP purified from E. coli. Moco synthesis also involved the use of the purified components E. coli MPT synthase, gephyrin, molybdate, ATP, and apo-sulfite oxidase. See U.S. Pat. No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum cofactor (Moco)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Gunter, Informa Plc, 2002, Vol. 39, pages 317-68. The assay is based on the conversion of cPMP into MPT, the subsequent molybdate insertion using recombinant gephyrin and ATP, and finally the reconstitution of human apo-sulfite oxidase.

As shown in FIG. 1, Moco synthesis from synthetic cPMP was confirmed, and no differences in Moco conversion were found in comparison to E. coli purified cPMP.

Example 3Comparison of Precursor Z (cPMP) Prepared Synthetically to that Prepared from E. coli in the In vitro Synthesis of MPT

In vitro synthesis of MPT was compared using samples of synthetic precursor Z (cPMP) and cPMP purified from E. coli. MPT synthesis also involved the use of in vitro assembled MPT synthase from E. coli. See U.S. Pat. No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum cofactor (Moco)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Gunter, Informa Plc, 2002, Vol. 39, pages 317-68. Three repetitions of each experiment were performed and are shown in FIGS. 2 and 3.

As shown in FIGS. 2 and 3, MPT synthesis from synthetic cPMP confirmed, and no apparent differences in MPT conversion were found when compared to E. coli purified cPMP. A linear conversion of cPMP into MPT is seen in all samples confirming the identity of synthetic cPMP (see FIG. 2). Slight differences between the repetitions are believed to be due to an inaccurate concentration determination of synthetic cPMP given the presence of interfering chromophores.

Example 4Preparation of Precursor Z (cPMP)

A. Preparation of Starting Materials

Figure US09260462-20160216-C00216

B. Introduction of the protected Phosphate

Figure US09260462-20160216-C00217


The formation of the cyclic phosphate using intermediate [10] (630 mg) gave the desired product [11] as a 1:1 mixture of diastereoisomers (494 mg, 69%).

Figure US09260462-20160216-C00218

C. Oxidation and Overall Deprotection of the Molecule

Oxidation of the secondary alcohol to the gem-diol did prove successful on intermediate [12], but the oxidized product [13] did show significant instability and could not be purified. For this reason, deprotection of the phosphate was attempted before the oxidation. However, the reaction of intermediate [11] with TMSBr led to complete deprotection of the molecule giving intermediate [14]. An attempt to oxidize the alcohol to the gem-diol using Dess-Martin periodinane gave the aromatized pteridine [15].

Oxidation of intermediate [11] with Dess-Martin periodinane gave a mixture of starting material, oxidized product and several by-products. Finally, intermediate [11] was oxidized using the method described Example 1. Upon treatment, only partial oxidation was observed, leaving a 2:1 mixture of [11]/[16]. The crude mixture was submitted to the final deprotection. An off white solid was obtained and analyzed by 1H-NMR and HPLC-MS. These analyses suggest that cPMP has been produced along with the deprotected precursor [11].

Because the analytical HPLC conditions gave a good separation of cPMP from the major impurities, this method will be repeated on a prep-HPLC in order to isolate the final material.

CLIP

BridgeBio Pharma And Affiliate Origin Biosciences Announces FDA Acceptance Of Its New Drug Application For Fosdenopterin For The Treatment Of MoCD Type A

Application accepted under Priority Review designation with Breakthrough Therapy Designation and Rare Pediatric Disease Designation previously grantedThere are currently no approved therapies for the treatment of MoCD Type A, which results in severe and irreversible neurological injury for infants and children.This is BridgeBio’s first NDA acceptanceSAN FRANCISCO, September 29, 2020 – BridgeBio Pharma, Inc. (Nasdaq: BBIO) and affiliate Origin Biosciences today announced the US Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for fosdenopterin (previously BBP-870/ORGN001), a cyclic pyranopterin monophosphate (cPMP) substrate replacement therapy, for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.The NDA has been granted Priority Review designation. Fosdenopterin has previously been granted Breakthrough Therapy Designation and Rare Pediatric Disease Designation in the US and may be eligible for a priority review voucher if approved. It received Orphan Drug Designation in the US and Europe. This is BridgeBio’s first NDA acceptance.“We want to thank the patients, families, scientists, physicians and all others involved who helped us reach this critical milestone,” said BridgeBio CEO and founder Neil Kumar, Ph.D. “MoCD Type A is a devastating disease with a median survival of less than four years and we are eager for our investigational therapy to be available to patients, who currently have no approved treatment options. BridgeBio exists to help as many patients as possible afflicted with genetic diseases, no matter how rare. We are grateful that the FDA has accepted our first NDA for priority review and we look forward to submitting our second NDA later this year for infigratinib for second line treatment of cholangiocarcinoma.”About Fosdenopterin
Fosdenopterin is being developed for the treatment of patients with MoCD Type A. Currently, there are no approved therapies for the treatment of MoCD Type A, which results in severe and irreversible neurological injury with a median survival between 3 to 4 years. Fosdenopterin is a first-in-class cPMP hydrobromide dihydrate and is designed to treat MoCD Type A by replacing cPMP and permitting the two remaining MoCo synthesis steps to proceed, with activation of MoCo-dependent enzymes and elimination of sulfites.About Molybdenum Cofactor Deficiency (MoCD) Type A
MoCD Type A is an ultra-rare, autosomal recessive, inborn error of metabolism caused by disruption in molybdenum cofactor (MoCo) synthesis which is vital to prevent buildup of s-sulfocysteine, a neurotoxic metabolite of sulfite. Patients are often infants with severe encephalopathy and intractable seizures. Disease progression is rapid with a high infant mortality rate.Those who survive beyond the first few month’s experience profuse developmental delays and suffer the effects of irreversible neurological damage, including brain atrophy with white matter necrosis, dysmorphic facial features, and spastic paraplegia. Clinical presentation that can be similar to hypoxic-ischemic encephalopathy (HIE) or other neonatal seizure disorders may lead to misdiagnosis and underdiagnosis. Immediate testing for elevated sulfite levels and S-sulfocysteine in the urine and very low serum uric acid may help with suspicion of MoCD.About Origin Biosciences
Origin Biosciences, an affiliate of BridgeBio Pharma, is a biotechnology company focused on developing and commercializing a treatment for Molybdenum Cofactor Deficiency (MoCD) Type A. Origin is led by a team of veteran biotechnology executives. Together with patients and physicians, the company aims to bring a safe, effective treatment for MoCD Type A to market as quickly as possible. For more information on Origin Biosciences, please visit the company’s website at www.origintx.com.

About BridgeBio Pharma
BridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBio’s pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development. For more information visit bridgebio.com.

Clinical data
Trade namesNulibry
Other namesPrecursor Z, ALXN1101
License dataUS DailyMedFosdenopterin
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number150829-29-1
PubChem CID135894389
DrugBankDB16628
ChemSpider17221217
UNII4X7K2681Y7
KEGGD11779
ChEMBLChEMBL2338675
CompTox Dashboard (EPA)DTXSID90934067 
Chemical and physical data
FormulaC10H14N5O8P
Molar mass363.223 g·mol−1
3D model (JSmol)Interactive image
hideSMILESNC1=NC(=O)C2=C(N[C@@H]3O[C@@H]4COP(=O)(O)O[C@@H]4C(O)(O)[C@@H]3N2)N1
hideInChIInChI=1S/C10H14N5O8P/c11-9-14-6-3(7(16)15-9)12-4-8(13-6)22-2-1-21-24(19,20)23-5(2)10(4,17)18/h2,4-5,8,12,17-18H,1H2,(H,19,20)(H4,11,13,14,15,16)/t2-,4-,5+,8-/m1/s1Key:CZAKJJUNKNPTTO-AJFJRRQVSA-N

//////////Fosdenopterin hydrobromide, ホスデノプテリン臭化水素酸塩水和物 , ALXN1101 HBrUNII-X41B5W735TX41B5W735TD11780, BBP-870/ORGN001, Priority Review designation, Breakthrough Therapy Designation, Rare Pediatric Disease Designation, Orphan Drug Designation, molybdenum cofactor deficiency, ALXN-1101, WHO 11150, FDA 2021, APPROVALS 2021

#Fosdenopterin hydrobromide, #ホスデノプテリン臭化水素酸塩水和物 , #ALXN1101 HBr, #UNII-X41B5W735TX41B5W735T, #D11780, #BBP-870/ORGN001, #Priority Review designation, #Breakthrough Therapy Designation, #Rare Pediatric Disease Designation, #Orphan Drug Designation, #molybdenum cofactor deficiency, #ALXN-1101, #WHO 11150, #FDA 2021, #APPROVALS 2021

C1C2C(C(C3C(O2)NC4=C(N3)C(=O)NC(=N4)N)(O)O)OP(=O)(O1)O.O.O.Br

Ansuvimab-zykl


Ebola Virus Treatment Ebanga Gets FDA Approval - MPR

Ansuvimab-zykl

FDA APPROVED, 12/21/2020, EBANGA

To treat ebola

https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-treatment-ebola-virus

The U.S. Food and Drug Administration approved Ebanga (Ansuvimab-zykl), a human monoclonal antibody, for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga blocks binding of the virus to the cell receptor, preventing its entry into the cell.

Zaire ebolavirus is one of four Ebolavirus species that can cause a potentially fatal human disease. It is transmitted through blood, body fluids, and tissues of infected people or wild animals, and through surfaces and materials, such as bedding and clothing, contaminated with these fluids. Individuals who care for people with the disease, including health care workers who do not use correct infection control precautions, are at the highest risk for infection.

During an Ebola outbreak in the Democratic Republic of the Congo (DRC) in 2018-2019, Ebanga was evaluated in a clinical trial (the PALM trial). The PALM trial was led by the U.S. National Institutes of Health and the DRC’s Institut National de Recherche Biomédicale with contributions from several other international organizations and agencies.

In the PALM trial, the safety and efficacy of Ebanga was evaluated in a multi-center, open-label, randomized controlled trial. 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. The primary analysis population was all patients who were randomized and concurrently eligible to receive either Ebanga or the investigational control during the same time period of the trial. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

The most common symptoms experienced while receiving Ebanga include: fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection. Hypersensitivity, including infusion-related events, can occur in patients taking Ebanga, and treatment should be discontinued in the event of a hypersensitivity reaction.

Patients who receive Ebanga should avoid the concurrent administration of a live virus vaccine against Ebolavirus. There is the potential for Ebanga to inhibit replication of a live vaccine virus and possibly reduce the efficacy of this vaccine.

Ebanga was granted an Orphan Drug designation, which provides incentives to assist and encourage drug development for rare diseases. Additionally, the agency granted Ebanga a Breakthrough Therapy designation.

FDA granted the approval to Ridgeback Biotherapeutics, LP.

Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.[1][2]

The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection.[1]

Ansuvimab was approved for medical use in the United States in December 2020.[1][2]

Chemistry

The drug is composed of a single monoclonal antibody (mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo.[3] In work supported by the United States National Institutes of Health and the Defense Advanced Projects Agency, the heavy and light chain sequences of ansuvimab mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of Medimmune.[4][5]

Mechanism of action

Neutralization

Ansuvimab is a monoclonal antibody therapy that is infused intravenously into patients with Ebola virus disease. Ansuvimab is a neutralizing antibody,[3] meaning it binds to a protein on the surface of Ebola virus that is required to infect cells. Specifically, ansuvimab neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of ansuvimab, would interact with virus’s cell receptor protein, Niemann-Pick C1 (NPC1).[6][7][8] This “competition” by ansuvimab prevents Ebola virus from binding to NPC1 and “neutralizes” the virus’s ability to infect the targeted cell.[6]

Effector function

Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to “kill” virus particles directly and/or kill infected cells using antibody-mediated “effector functions” such as opsonization, complement-dependent cytotoxicityantibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity.[3] Other functional killing tests have not been performed.

History

Ansuvimab is a monoclonal antibody that is being evaluated as a treatment for Ebola virus disease.[9] Its discovery was led by the laboratory of Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and J. J. Muyembe-Tamfum from the Institut National pour la Recherche Biomedicale (INRB) in the Democratic Republic of Congo, working in collaboration with the Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.[3][10] Ansuvimab was isolated from the blood of a survivor of the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo roughly ten years later.[3]

In 2018, a Phase 1 clinical trial of ansuvimab was conducted by Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Julie E. Ledgerwood.[5][4][11] Ansuvimab is also being evaluated during the 2018 North Kivu Ebola outbreak.[12]

Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside REGN-EB3, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak.[13][14]

Discovery

A 2016 paper describes the efforts of how ansuvimab was originally developed as part of research efforts lead by Dr. Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the Democratic Republic of Congo.[3][10] This collaborative effort also involved researchers from Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.[3][10] A survivor from the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo donated blood to the project that began roughly ten years after they had recovered.[3] Memory B cells isolated from the survivor’s blood were immortalized, cultured and screened for their ability to produce monoclonal antibodies that reacted with the glycoprotein of Ebola virus. Ansuvimab was identified from one of these cultures and the antibody heavy and light chain gene sequences were sequenced from the cells.[3] These sequences were then cloned into recombinant DNA plasmids and purified antibody protein for initial studies was produced in cells derived from HEK 293 cells.[3]

Ansuvimab and mAb100 combination

In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived.[3]

Ansuvimab monotherapy

In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived.[3] Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies.[5][4]

Development

Ansuvimab was developed by the Vaccine Research Center with support of the United States National Institutes of Health and the Defense Advanced Projects Agency. The heavy and light chain sequences of ansuvimab mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans.[4][5]

Human safety testing

In early 2018,[9] a Phase 1 clinical trial of ansuvimab’s safety, tolerability and pharmacokinetics was conducted by Dr. Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Dr. Julie E. Ledgerwood.[5][4][11] The study was performed in the United States at the NIH Clinical Center and tested single dose infusions of ansuvimab infused over 30 minutes. The study showed that ansuvimab was safe, had minimal side effects and had a half-life of 24 days.[5][4]

Ridgeback Biotherapeutics

A license for ansuvimab was obtained by Ridgeback Biotherapeutics in 2018, from the National Institutes of HealthNational Institute of Allergy and Infectious Diseases.[15] Ansuvimab was given orphan drug status in May 2019 and March 2020.[16][17][18]

Experimental use in the Democratic Republic of Congo

During the 2018 Équateur province Ebola outbreak, ansuvimab was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. Ansuvimab was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. Ansuvimab was sent along with other therapeutic agents to the outbreak sites.[19][20][11] However, the outbreak came to a conclusion before any therapeutic agents were given to patients.[11]

Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols.[11] In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3.[21][22][13][12]

In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab (Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by Zaire ebolavirus.[23]

FDA approves ansuvimab-zykl for Ebola virus infection

DECEMBER 21, 2020 BY JANICE REICHERThttps://www.antibodysociety.org/antibody-therapeutic/fda-approves-ansuvimab-zykl-for-ebola-virus-infection/embed/#?secret=zWW0Sr0BdW

On December 21, 2020, the US Food and Drug Administration approved Ebanga (ansuvimab-zykl) for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga had been granted US Orphan Drug designation and Breakthrough Therapy designations. Ansuvimab is a human IgG1 monoclonal antibody that binds and neutralizes the virus.

The safety and efficacy of Ebanga were evaluated in the multi-center, open-label, randomized controlled PALM trial. In this study, 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

Ebanga is the 12th antibody therapeutic to be granted a first approval in the US or EU during 2020.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.

References

  1. Jump up to:a b c d “FDA Approves Treatment for Ebola Virus”U.S. Food and Drug Administration. 21 December 2020. Retrieved 23 December 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b “Ridgeback Biotherapeutics LP Announces the Approval of Ebanga for Ebola” (Press release). Ridgeback Biotherapeutics LP. 22 December 2020. Retrieved 23 December 2020– via Business Wire.
  3. Jump up to:a b c d e f g h i j k l Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, et al. (March 2016). “Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody”Science351 (6279): 1339–42. Bibcode:2016Sci…351.1339Cdoi:10.1126/science.aad5224PMID 26917593.
  4. Jump up to:a b c d e f Clinical trial number NCT03478891 for “Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults” at ClinicalTrials.gov
  5. Jump up to:a b c d e f Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, et al. (March 2019). “Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody ansuvimab targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study”Lancet393 (10174): 889–898. doi:10.1016/S0140-6736(19)30036-4PMC 6436835PMID 30686586.
  6. Jump up to:a b Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, et al. (March 2016). “Structural and molecular basis for Ebola virus neutralization by protective human antibodies”Science351 (6279): 1343–6. Bibcode:2016Sci…351.1343Mdoi:10.1126/science.aad6117PMC 5241105PMID 26917592.
  7. ^ Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. (August 2011). “Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection”Nature477 (7364): 344–8. Bibcode:2011Natur.477..344Cdoi:10.1038/nature10380PMC 3230319PMID 21866101.
  8. ^ Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. (August 2011). “Ebola virus entry requires the cholesterol transporter Niemann-Pick C1”Nature477 (7364): 340–3. Bibcode:2011Natur.477..340Cdoi:10.1038/nature10348PMC 3175325PMID 21866103.
  9. Jump up to:a b “NIH begins testing Ebola treatment in early-stage trial”National Institutes of Health (NIH). 2018-05-23. Retrieved 2018-10-15.
  10. Jump up to:a b c Hayden EC (2016-02-26). “Ebola survivor’s blood holds promise of new treatment”Naturedoi:10.1038/nature.2016.19440ISSN 1476-4687.
  11. Jump up to:a b c d e “NIH VideoCast – CC Grand Rounds: Response to an Outbreak: Ebola Virus Monoclonal Antibody (mAb114) Rapid Clinical Development”videocast.nih.gov. Retrieved 2019-08-09.
  12. Jump up to:a b Kingsley-Hall A. “Congo’s experimental mAb114 Ebola treatment appears successful: authorities | Central Africa”http://www.theafricareport.com. Retrieved 2018-10-15.
  13. Jump up to:a b McNeil DG (12 August 2019). “A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo”The New York Times. Retrieved 13 August 2019.
  14. ^ Molteni M (12 August 2019). “Ebola is Now Curable. Here’s How The New Treatments Work”Wired. Retrieved 13 August 2019.
  15. ^ “Ridgeback Biotherapeutics LP announces licensing of mAb114, an experimental Ebola treatment, from the National Institute of Allergy and Infectious Diseases” (Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
  16. ^ “Ansuvimab Orphan Drug Designations and Approvals”accessdata.fda.gov. 8 May 2019. Retrieved 24 December 2020.
  17. ^ “Ansuvimab Orphan Drug Designations and Approvals”accessdata.fda.gov. 30 March 2020. Retrieved 24 December 2020.
  18. ^ “Ridgeback Biotherapeutics LP Announces Orphan Drug Designation for mAb114”(Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
  19. ^ Check Hayden, Erika (May 2018). “Experimental drugs poised for use in Ebola outbreak”Nature557 (7706): 475–476. Bibcode:2018Natur.557..475Cdoi:10.1038/d41586-018-05205-xISSN 0028-0836PMID 29789732.
  20. ^ WHO: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus Disease. https://www.who.int/emergencies/ebola/MEURI-Ebola.pdf
  21. ^ Mole B (2019-08-13). “Two Ebola drugs boost survival rates, according to early trial data”Ars Technica. Retrieved 2019-08-17.
  22. ^ “Independent monitoring board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates”National Institutes of Health (NIH). 2019-08-12. Retrieved 2019-08-17.
  23. ^ “FDA Approves First Treatment for Ebola Virus”U.S. Food and Drug Administration(FDA) (Press release). 14 October 2020. Retrieved 14 October 2020.  This article incorporates text from this source, which is in the public domain.

External links

  • “Ansuvimab”Drug Information Portal. U.S. National Library of Medicine.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetZaire ebolavirus
Clinical data
Trade namesEbanga
Other namesAnsuvimab-zykl, mAb114
License dataUS DailyMedAnsuvimab
Routes of
administration
Intravenous
Drug classMonoclonal antibody
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number2375952-29-5
DrugBankDB16385
UNIITG8IQ19NG2
KEGGD11875
Chemical and physical data
FormulaC6368H9924N1724O1994S44
Molar mass143950.15 g·mol−1

//////////Ansuvimab-zykl , EBANGA, FDA 2020, 2020 APPROVALS, MONOCLONAL ANTIBODY, Orphan Drug designation, , Breakthrough Therapy designation , Ridgeback Biotherapeutics, 

Lumasiran


OXLUMO (lumasiran) Structural Formula - Illustration

The molecular formula of lumasiran sodium is C530H669F10N173O320P43S6Na43 and the molecular weight is 17,286 Da.

lumasiran

CAS 1834610-13-7

FDA APPROVED, 11/23/2020, Oxlumo

To treat hyperoxaluria type 1
Press Release
Drug Trials Snapshot

RNA, (Gm-​sp-​Am-​sp-​Cm-​Um-​Um-​Um-​(2′-​deoxy-​2′-​fluoro)​C-​Am-​(2′-​deoxy-​2′-​fluoro)​U-​(2′-​deoxy-​2′-​fluoro)​C-​(2′-​deoxy-​2′-​fluoro)​C-​Um-​Gm-​Gm-​Am-​Am-​Am-​Um-​Am-​Um-​Am)​, 3′-​[[(2S,​4R)​-​1-​[29-​[[2-​(acetylamino)​-​2-​deoxy-​β-​D-​galactopyranosyl]​oxy]​-​14,​14-​bis[[3-​[[3-​[[5-​[[2-​(acetylamino)​-​2-​deoxy-​β-​D-​galactopyranosyl]​oxy]​-​1-​oxopentyl]​amino]​propyl]​amino]​-​3-​oxopropoxy]​methyl]​-​1,​12,​19,​25-​tetraoxo-​16-​oxa-​13,​20,​24-​triazanonacos-​1-​yl]​-​4-​hydroxy-​2-​pyrrolidinyl]​methyl hydrogen phosphate]​, complex with RNA (Um-​sp-​(2′-​deoxy-​2′-​fluoro)​A-​sp-​Um-​Am-​Um-​(2′-​deoxy-​2′-​fluoro)​U-​Um-​(2′-​deoxy-​2′-​fluoro)​C-​(2′-​deoxy-​2′-​fluoro)​C-​Am-​Gm-​Gm-​Am-​(2′-​deoxy-​2′-​fluoro)​U-​Gm-​(2′-​deoxy-​2′-​fluoro)​A-​Am-​Am-​Gm-​Um-​Cm-​sp-​Cm-​sp-​Am) (1:1)

Nucleic Acid Sequence

Sequence Length: 44, 23, 2115 a 8 c 7 g 14 umultistranded (2); modified

OXLUMO is supplied as a sterile, preservative-free, clear, colorless-to-yellow solution for subcutaneous administration containing the equivalent of 94.5 mg of lumasiran (provided as lumasiran sodium) in 0.5 Ml of water for injection and sodium hydroxide and/or phosphoric acid to adjust the pH to ~7.0.

Lumasiran An investigational RNAi Therapeutic for Primary Hyperoxaluria Type 1 (PH1)

Overview • Lumasiran (ALN-GO1) is an investigational, subcutaneously administered (under the skin) RNA interference (RNAi) therapeutic targeting glycolate oxidase (GO) in development for the treatment of primary hyperoxaluria type 1 (PH1).

• PH1 is a rare, life-threatening disease that can cause serious damage to kidneys and progressively to other organs.1

• PH1 is characterized by the pathologic overproduction of oxalate by the liver. Oxalate is an end product of metabolism that, when in excess, is toxic and accumulates in the kidneys forming calcium oxalate crystals.1,2

• Symptoms of PH1 are often associated with recurrent kidney stones and include flank pain, urinary tract infections, painful urination, and blood in the urine.2,3

• Currently, the only curative treatment is a liver transplant, to correct the metabolic defect, combined with a kidney transplant, to replace the terminally damaged kidneys.1,3 Clinical Development

• The safety and efficacy of lumasiran are being evaluated in a randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study of approximately 30 PH1 patients, called ILLUMINATE-A (NCT03681184).

• The primary endpoint is percent change in 24-hour urinary oxalate excretion from baseline to Month 6.

• Key secondary and exploratory endpoints in ILLUMINATE-A will evaluate additional measures of urinary oxalate, estimated glomerular filtration rate (eGFR), safety, and tolerability. 

Regulatory Designations • Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) • Priority Medicines (PRIME) Designation from the European Medicines Agency (EMA) • Orphan Drug Designations in both the U.S. and the European Union

Alnylam Announces U.S. Food and Drug Administration Has Granted Priority  Review of the Lumasiran New Drug Application for the Treatment of Primary  Hyperoxaluria Type 1 | Business Wire

/////////lumasiran, fda 2020, 2020 approvals, Oxlumo, Breakthrough Therapy Designation, Orphan Drug, Priority Medicines (PRIME) Designation

Teprotumumab-trbw


Image result for teprotumumab-trbw

Tepezza (teprotumumab-trbw)

Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease

UNIIY64GQ0KC0A

CAS number1036734-93-6

R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001

Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).

FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020

Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.

“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”

Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.

Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.

The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.

The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.

The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.

Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).[1]

The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache.[1] Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.[1]

It is a human monoclonal antibody developed by Genmab and Roche. It binds to IGF-1R.

Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphomanon-small cell lung cancer and sarcoma.[2][3] Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.

Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials.[4] It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema.[5] It was granted Breakthrough TherapyOrphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.[6]

In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis.[7] In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED.[8] On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.[9]

History[edit]

Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.[1]

Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo.[1] Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.[1]

The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation.[1] The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.[1]

References

  1. Jump up to:a b c d e f g h “FDA approves first treatment for thyroid eye disease”U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ https://clinicaltrials.gov/ct2/show/NCT01868997
  3. ^ http://adisinsight.springer.com/drugs/800015801
  4. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  5. ^ http://adisinsight.springer.com/drugs/800015801
  6. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  7. ^ Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”The New England Journal of Medicine376 (18): 1748–1761. doi:10.1056/NEJMoa1614949PMC 5718164PMID 28467880.
  8. ^ “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”Horizon Pharma plc. Retrieved 22 March 2019.
  9. ^ “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”Horizon Therapeutics plc. Retrieved 27 August 2019.

External links

Teprotumumab
Monoclonal antibody
Type Whole antibody
Source Human
Target IGF-1R
Clinical data
Other names teprotumumab-trbw, RG-1507
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
ECHA InfoCard 100.081.384 Edit this at Wikidata
Chemical and physical data
Formula C6476H10012N1748O2000S40
Molar mass 145.6 kg/mol g·mol−1

/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza,  Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS,  active thyroid eye disease, Teprotumumab

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease

FDA approves first treatment Givlaari (givosiran) for inherited rare disease


Today, the U.S. Food and Drug Administration granted approval to Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood).
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”
The approval of Givlaari was based on the results of a clinical trial of 94 patients with acute hepatic porphyria. Patients received a placebo or Givlaari. Givlaari’s performance was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home. Patients who received Givlaari experienced 70% fewer porphyria attacks compared to patients receiving a placebo.
Common side effects for patients taking Givlaari were nausea and injection site reactions. Health care professionals are advised to monitor patients for anaphylactic (allergic) reaction and renal (kidney) function. Patients should have their liver function tested before and periodically during treatment.
The FDA granted this application Breakthrough Therapy designation and Priority Review designation. Givlaari also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Givlaari to Alnylam Pharmaceuticals.

http://s2027422842.t.en25.com/e/es?s=2027422842&e=277662&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=d02d631b3809408d94ccf3f5bec31dbd&elqaid=10358&elqat=1

///////////Givlaari, givosiran, fda 2019, Breakthrough Therapy designation,  Priority ReviewOrphan Drug

Ritlectinib, PF 06651600


Image result for PF-06651600

Image result for PF-06651600

Ritlectinib

PF-06651600

CAS 1792180-81-4

C₁₅H₁₉N₅O, 285.34, UNII-2OYE00PC25

1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one

Image result for PF-06651600

 1-[(2S,5R)-2-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-piperidinyl]-2-propen-1-one malonate

PF-06651600 malonate
CAS: 2140301-97-7 (malonate)
Chemical Formula: C18H23N5O5

Molecular Weight: 389.412

PHASE 2  alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis.

PF-06651600 is a potent and selective JAK3 inhibitor. PF-06651600 is a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor PF-06651600 led to its evaluation in several human clinical studies. JAK3 was among the first of the JAKs targeted for therapeutic intervention due to the strong validation provided by human SCID patients displaying JAK3 deficiencies

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitors in development as potential medicines. PF-06651600 is a highly selective and orally bioavailable Janus Kinase 3 (JAK3) inhibitor that represents a potential immunomodulatory therapy. With the favorable efficacy, safety profile, and ADME properties, this JAK3-specific covalent inhibitor has been under clinical investigation for the treatment of alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Supported by positive results from a Phase 2 study, 1 was granted Breakthrough Therapy designation by the FDA on Sept. 5, 2018 for treatment of alopecia areata.

SYN

PAPER

J. Med. Chem. 201760 (5), 19711993DOI: 10.1021/acs.jmedchem.6b01694

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01694

Paper

Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600, 

Yong Tao*

Cite This:Org. Process Res. Dev.2019XXXXXXXXXX-XXX

Publication Date:July 19, 2019

https://doi.org/10.1021/acs.oprd.9b00198

A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO2 with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten–Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1·TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00198

1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one p-Toluenesulfonate (1·TsOH)

1·TsOH (4.41 kg, 9.64 mol) as a white powder in 89.6% yield (accounting for the amount of seed charged). Achiral HPLC purity: 99.6% with 0.22% of dimer 15. Chiral SFC purity: >99.7%. Mp 199 °C. Rotomers observed for NMR spectroscopies. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.68 (brs, 1H), 9.22 (brs, 1H), 8.40 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (m, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 1.2 Hz, 1H), 6.84 (m, 1H), 6.13 (m, 1H), 5.70 (m, 1H), 4.81 (m, 0.5H), 4.54 (m, 0.5H), 4.41 (m, 0.5H), 4.12 (m, 0.5H), 3.99 (m, 1H), 3.15 (m, 0.5H), 2.82 (m, 0.5H), 2.29 (s, 3H), 1.91–1.72 (m, 4H), 1.24–1.17 (m, 3H). 13C NMR (100 MHz, DMSO-d6): δ ppm 165.52, 165.13, 150.50, 145.64, 143.06, 138.48, 129.51, 129.24, 128.67, 127.99, 127.73, 125.97, 125.02, 102.30, 49.53, 48.92, 47.27, 43.83, 42.96, 29.37, 28.41, 25.22, 21.28, 16.97, 15.51. HRMS (ESI) m/z: calculated for C15H20N5O [M + H]+286.1668; observed 286.1692.

PAPER

Telliez JB, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451.

PATENT

WO 2015083028

https://patents.google.com/patent/WO2015083028A1

PATENT

WO 2020084435

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020084435&tab=PCTDESCRIPTION&_cid=P12-KIL68Y-23557-1

1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one has the structural formula:

The synthesis of 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one is described in WO2015/083028, commonly assigned to the assignee of the present invention and which is incorporated herein by reference in its entirety. 1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one is useful as an inhibitor of protein kinases, such as the enzyme Janus Kinase (JAK) and as such is useful therapy as an immunosuppressive agent for organ transplants, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, alopecia, vitiligo, Alzheimer’s disease, leukemia and other indications where immunosuppression would be desirable. See ACS Chem. Biol. , 2016, 11 (12), pp 3442-3451 . The present invention relates to a novel p-toluenesulfonic acid salt and crystalline solid form of the said salt of 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one that demonstrate improved properties for use in a pharmaceutical dosage form, particularly for oral dosage forms.

Preparations

Scheme 1. Synthesis of 1

Scheme 2. Alternate Synthesis of Intermediates 7 and 10

1. K2C03, MIBK/water 1. H2, H2O

2. EtOAc, aq. NaCI Pd(OH)2/C (wet)

3. MeOH, H20 2. NaOH, MeOH

7 + 8 –  9 – – 10 . H2O

89% 89%

Scheme 3. First Alternate Preparation of 1

Scheme 4. Second Alternate Preparation of 1

Preparation 1

ferf-Butyl (6-methylpyridin-3-yl)carbamate (3). To a 3000L reactor was charged 2 (72.00 kg, 665.8 mol) and THF (660 kg). A solution of NH4CI (1 .07 kg , 20 mol) in water (72 kg, 4000 mol) was added. The mixture was heated to 57 °C and Di-f-butyl dicarbonate (220.0 kg, 1003 mol) was added slowly with rinse of THF (45 kg) while maintaining the temperature between 55 – 60 °C. The mixture was stirred at 55 – 60 °C for 10 h. Upon reaction completion, the slurry was cooled to 20 °C and ethyl acetate (654 kg) and water (367 kg) were added. The organic phase was separated, washed by water (2 x 360 kg) and stirred with active carbon (22 kg) for 5 h. The mixture was filtered through a layer of diatomaceous earth (22 kg) with THF rinse and the filtrates were concentrated under vacuum at <40 °C to a residual volume of ~370 L. n-Heptane (500 kg) was added slowly over 1 h and the resulting slurry was cooled to 20 °C and stirred for 2 h. The solid was collected by centrifuge with an n-heptane wash (420 kg), then dried at 45 °C under vacuum for 20 h to give 3 (131 .15 kg, 629.7 mol) as a white powder in 94.5% yield. HPLC purity: 99.9%. 1H NMR (400 MHz, DMSO-c/6): d ppm 9.42 (brs, 1 H), 8.48 (d, J = 1 .9 Hz, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 2.38 (s, 3H), 1 .49 (s, 9H). 13C NMR (100 MHz, DMSO-d6y d ppm 153.34, 151 .56, 139.75, 134.13, 126.10, 123.09, 79.87, 28.56, 23.70. HRMS (ESI) m/z: calculated for C11H17N2O2 [M + H]+ 209.1290; observed 209.1285.

Preparation 2

ferf-Butyl (6-methylpiperidin-3-yl)carbamate (rac-4). To a 3000L reactor was charged 3 (137.0 kg, 667.8 mol), ethanol (988 kg) and acetic acid (139 kg). The reactor was purged with nitrogen three times and 5 wt% Rhodium on carbon (wet, 27.4 kg, 20 wt% loading relative to 3) was added. The reactor was purged with nitrogen three times and then with hydrogen three times. The hydrogen pressure was adjusted to 0.34 – 0.38 MPa and the reactor temperature was adjusted to 47 °C. The mixture was stirred at 45 – 60 °C under hydrogen pressure at 0.34 – 0.38 MPa for 10 h. Upon reaction completion, the reactor was cooled to 20 °C and flushed with nitrogen. The mixture was filtered through a layer of diatomaceous earth (20 kg) with an ethanol rinse (1320 kg) and the filtrates were concentrated under vacuum at <50 °C to a residual volume of ~350 L. n-Heptane (571 kg) was added and the mixture was concentrated under vacuum at <50 °C to a residual volume of~350 L. This operation was repeated twice until the residual acetic acid <8.0%. Ethanol (672 kg) was added and the mixture was concentrated under vacuum at <50 °C to a residual volume of ~350 L. This operation was repeated twice until the residual n-heptane was <0.2% and water was <0.2%. Ethanol (889 kg) was added and the solution (1254 kg) was transferred to drums for use in the subsequent classical resolution step. Achiral HPLC assay indicated that the solution contained 10.8 wt% of the total reduced product (rac-4) in 96% mass recovery and chiral SFC showed that the solution contained 36.3% of the desired stereoisomer cis-4.

Preparation 3

ferf-Butyl ((3R,6S)-6-methylpiperidin-3-yl)carbamate (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid salt (15). To a 2000L reactor (R1 ) was charged rac-4 as a 10.8 wt% solution in ethanol (620.5 kg, ~312.7 mol. of all 4 isomers). The solution was concentrated under vacuum at <45 °C to a residual volume of ~210 L and then cooled to 20 °C. To a 3000 L reactor (R2) was charged (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid 14 (47.0 kg, 136.1 mol) and ethanol (1 125 kg). With high speed agitation, reactor R2 was heated to 70 °C, stirred at 68 – 70 °C for ~2 h to dissolve all solid 14, and then seeded with crystalline 15 (1 1 g). The solution containing 4 in reactor R1 was slowly transferred to reactor R2 over 30 min with ethanol rinse (160 kg). Reactor R2 was stirred at ~74 °C for 3 h and then cooled to 22 °C with a linear cooling rate over a period of 5 h and stirred for 16 h. The solid was collected by centrifuge with ethanol wash (2 x 200 kg). The wet cake (with 97.1 % e.e.) was charged back to reactor R2. The slurry was heated to 74 °C and the mixture was stirred for 17 h. The mixture was then cooled to 22 °C with a linear cooling rate over a period of 5 h and stirred for 4 h. The solid was collected by centrifuge with ethanol wash (2 x 200 kg) and dried at 35 °C under vacuum for 25 h to give 15 (56.05 kg, 100.2 mol) as a white powder in 30.7% yield over 2 steps. Chiral HPLC purity: 99.1 %. 1H NMR (400 MHz, DMSO-d6): d ppm 9.46 (d, J = 7.0 Hz, 1 H), 9.07 (d, J = 2.2 Hz, 2H), 8.96 (t, J = 2.2 Hz, 1 H), 7.49 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 7.3, 1 H), 7.1 1 (m, 1 H), 5.31 (d, J = 7.0 Hz, 1 H), 3.66 (m, 1 H), 2.98 (m, 3H), 1 .63 (m, 2H), 1 .45 (m, 2H), 1 .40 (s, 9H), 1 .1 1 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 172.71 , 161 .71 , 155.42, 148.51 , 141 .27, 137.70, 128.29, 128.25, 128.02, 127.05, 121 .12, 78.49, 59.74, 50.66, 46.29, 43.34, 28.66, 26.88, 26.1 1 , 18.60.

Preparation 4

Benzyl (2S,5R)-5-amino-2-methylpiperidine-1 -carboxylate hydrochloride (7»HCI) -telescoped process. To a 2000L reactor was charged 15 (70.0 kg, 125 mol) and MTBE (500 kg). The mixture was cooled to 12 °C and 6.9 wt% aqueous NaOH solution (378 kg, 652 mol) was added slowly while maintaining the temperature between 10 – 25 °C. The mixture was stirred at 18 °C for 1 h . The organic phase was separated and washed with 3.8 wt% aqueous NaOH solution (2 x 221 kg) and then 25 wt% aqueous NaCI solution (2 x 220 kg). The organic layer (containing the free base cis-4) was concentrated under vacuum at <40 °C to a residual volume of ~300 L and then cooled to 20 °C. NaHCOs (53 kg, 632 mol) and water (200 kg) were added and the mixture was cooled to 7 °C. Benzyl chloroformate (32.30 kg, 189.3 mol) was added slowly while maintaining the temperature between 5 – 20 °C. The mixture was stirred at 17 °C for 20 h. Upon reaction completion, the mixture was cooled to 12 °C, 25 wt% aqueous ammonium hydroxide solution (79 kg, 1 160 mol) was added slowly while maintaining the temperature between 10 – 20 °C, and the mixture was stirred at 15 °C for 1 h. The organic phase was separated and washed with 25 wt% aqueous NaCI solution (3 x 90 kg). The organic layer (containing 5) was concentrated under vacuum at <45 °C to a residual volume of ~150 L. Isopropyl acetate (310 kg) was added and the mixture was concentrated under vacuum at <45 °C to a residual volume of ~150 L. This operation was repeated twice to meetthe criteria of water <0.1 % (by KF). Isopropyl acetate (130 kg) was then added and the mixture was cooled to -3 °C. 4-5N HCI in methanol (181 kg, ~730 mol) was added slowly while maintaining the temperature between -5 to 5 °C, and the mixture was stirred at 3 °C for 12 h. Upon reaction completion, the mixture was cooled to -3 °C and MTBE (940 kg) was added slowly while maintaining the temperature between -5 to 5 °C. The resulting slurry was stirred at 3 °C for 3 h. The solid was collected by centrifuge with MTBE washes (4 x 70 kg), and then dried at 45 °C under vacuum for 20 h to give 7»HCI (28.60 kg, 100.4 mol) as a white powder in 80.3% yield. Achiral HPLC purity: 100%. Chiral SFC purity: 99.8% e.e. 1H NMR (400 MHz, DMSO-d6): d ppm 8.36 (brs, 3H), 7.37 (m, 5H), 5.09 (s, 2H), 4.31 (m, 1 H), 4.16 (d, J = 8.2 Hz, 1 H), 3.00 (m, 2H), 1 .82 (m, 2H), 1 .59 (m, 2H), 1 .1 1 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 154.71 , 137.24, 128.92, 128.34, 128.00, 66.89, 47.20, 45.66, 40.68, 28.16, 23.02, 15.67. HRMS (ESI) m/z. calculated for C H N O [M + H]+ 249.1603; observed 249.1598.

Preparation 5

Benzyl (2S, 5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2 -methyl-piperidine-1 -carboxylate (9). To a 2000L reactor was charged 7»HCI (88.6 kg, 31 1 .12 mol), 8 (56.0 kg, 298 mol), K2C03 (133.0 kg, 962.3 mol), water (570 kg) and MIBK (101 kg). The mixture was heated to 90 °C and stirred at this temperature for 22 h. Upon reaction completion, the mixture was cooled to 56 °C and ethyl acetate (531 kg) was added. After cooling the mixture to 22 °C, the organic phase was separated, washed with water (570 kg) and concentrated under vacuum at <40 °C to a residual volume of ~220 L. Methanol (360 kg) was added slowly over a period of 1 h and the mixture concentrated under vacuum at <50 °C to a residual volume of ~220 L. This operation was repeated three times until residual MIBK reached <5 wt%. Methanol (270 kg) was added, followed by seeding with 9 (120 g). The mixture was stirred at 22 °C for >4 h and water (286 kg) was added slowly over 4 h. The slurry was stirred for 10 h and the solid was then collected by centrifuge. The wet cake (165.6 kg) was charged back to a clean reactor and water (896 kg) was added. The slurry was heated to 55 °C and stirred at this temperature for 7 h; and then cooled to 22 °C and stirred at this temperature for 2 h. The solid was collected by centrifuge with water wash (3 x 170 kg) and dried at 55 °C under vacuum for 20 h to give 9 (106.62 kg, 266.6 mol) as a white powder in 89.5% yield. Achiral HPLC purity: 99.7%. 1H NMR (400 MHz, DMSO-d6): d ppm 1 1 .71 (brs, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.38 (m, 5H), 7.10 (s, 1 H), 6.57 (d, J = 2.7 Hz, 1 H), 5.1 1 (m, 2H), 4.39 (m, 1 H), 4.17 (m, 1 H), 4.01 (m, 1 H), 3.36 (s, 2H), 2.77 (m, 1 H), 1 .73-1 .81 (m, 4H), 1 .16 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 156.65, 154.74, 153.04, 151 .31 , 137.43, 128.89, 128.27, 127.96, 122.13, 101 .65, 99.51 , 66.75, 49.10, 47.32, 45.64, 42.98, 29.05, 25.08. HRMS (ESI) m/z. calculated for C20H22CIN5O2 [M + H]+ 400.1540; observed 400.1535.

Preparation 6

N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-dlpyrimidin-4-amine monohydrate (10·H2O) To a 1600L reactor was charged water (570 kg). The reactor was purged with nitrogen three times. 10% Pd(OH)2/C (wet, 3.2 kg) and 9 (53.34 kg, 133.2 mol) were added with water rinses (2 x 55 kg). The reactor was purged with nitrogen three times and then with hydrogen three times. The hydrogen pressure was adjusted to 0.34 – 0.38 MPa and the reactor temperature was adjusted to 77 °C. The mixture was stirred at 75 – 80 °C under a hydrogen pressure of 0.34 -0.38 MPa for 10 h. Upon reaction completion, the reactor was cooled to 20 °C and purged with nitrogen. The mixture was filtered through a layer of diatomaceous earth (8 kg) with a water rinse (460 kg), and the filtrates were transferred to a 3000L reactor. Methanol (260 kg) was added, followed by slow addition of 50 wt% aqueous sodium hydroxide (12.0 kg , 150 mol) while maintaining the temperature between 15 – 25 °C. The slurry was heated to 55 °C and stirred for 2 h; then cooled to 22 °C and stirred for 10 h. The solid was collected by centrifuge with a 10:1 water/methanol wash (3 x 1 10 kg) and then dried at 55 °C under vacuum for 20 h to give 10·H2O (30.90 kg, 266.6 mol) as a white powder in 89.1 % yield. Achiral HPLC purity: 99.7%. Chiral SFC

purity: 99.8% e.e. 1H NMR (400 MHz, DMSO-d6): d ppm 1 1 .48 (brs, 1 H), 8.08 (s, 1 H), 7.07 (s, 1 H), 6.85 (d, J = 7.3 Hz, 1 H), 6.64 (s, 1 H), 4.16 (m, 1 H), 3.35 (brs, 2H), 2.96 (d, J = 12.7 Hz, 1 H), 2.82 (d, J = 12.7 Hz, 1 H), 2.67 (m, 1 H), 2.04 (brs, 1 H), 1 .92 (m, 1 H), 1 .63 (m, 1 H), 1 .44 (m, 1 H), 1 .33 (m, 1 H), 1 .03 (d, J = 6.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 155.95, 151 .87, 150.74, 121 .20, 102.97, 99.20, 51 .27, 49.94, 44.78, 29.97, 28.69, 22.35. HRMS (ESI) m/z\ calculated for C12H17N5 [M + H]+ 232.1562; observed 232.1558.

Preparation 7

1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one (1 ). To a 100L reactor was charged water (18.0 L), 10·H2q (3.60 kg, 14.4 mol) and THF (36.0 L). The mixture was heated to 53 °C and stirred for 15 min to dissolve all the solids. The solution was then cooled to 18 °C and K3PO4 (6.38 kg, 30.1 mol) was added. The mixture was stirred at 18 °C for 10 min to dissolve all the solids, and then cooled to 10 °C. 3-Chloropropionyl chloride (2.20 kg, 17.3 mol) was added while maintaining the temperature <20 °C. The mixture was then stirred at 20 °C for 2 h. Upon reaction completion, 2 N aqueous NaOH solution (23.50 kg, 43.76 mol) was added while maintaining the temperature <25 °C. The mixture was stirred at 22 °C for >12 h until the elimination reaction was complete (11 <0.2%). KH2PO4 (10.32 kg, 75.8 mol) was added and the mixture was stirred at 20 °C for 10 min. The organic phase was separated and then washed with 23.5 wt% aqueous NaCI solution (2 x 8.5 kg). The isolated organic phase was concentrated under vacuum at <30 °C to a residual volume of ~10 L, whereupon MEK (39.6 L) was added. This operation was repeated once or twice until residual THF was <1 % and water was <2%. MgS04 (0.96 kg), Silica gel (4.90 kg) and Darco™ G-60 (0.48 kg) were added to the MEK solution, and the mixture was stirred at 20 °C for 1 h, then filtered through a layer of Diatomaceous Earth with a MEK rinse (76 L). The combined filtrates were concentrated under vacuum at <30 °C to a residual volume of ~8 L. The concentration of the residual solution was measured by qNMR, and the solution was transferred to a container with a rinse using the calculated amount of MEK to adjust the final concentration to 30 wt%. Thus, a 30 wt% solution of 1 in MEK (1 1 .09 kg, 1 1 .66 mol of 1) with 98.7% purity was obtained in 81 % yield, which was stored in a cold room (2 – 8 °C) for the next step.

Preparation 8

1 -((2S,5R)-5-((7H-pyrrolo[2,3-cdpyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one p-toluenesulfonate (1»TsOH). To a 20L reactor was charged a 30 wt% solution of 1 in MEK (9.80 kg, 10.30 mol of 1) and silica gel (0.74 kg). The mixture was stirred at 22 °C for 15 min and filtered through a 0.45 micron Teflon cartridge filter with a MEK rinse (7.89 kg, 9.8 L), collecting in a 100L reactor. Water (1 .27 L) was added, followed by a solution of p-toluenesulfonic acid monohydrate (2.18 kg, 1 1 .3 mol) in MEK (4.75 kg, 5.9 L) with a MEK rinse (3.14 kg, 3.9 L), followed by the addition of 1 »TsOH seed (188 g, 0.41 mol). The mixture was stirred at 22 °C for

4 h to form a slurry and MEK (31 .56 kg, 39.2 L) was added slowly over a period of 3 h. The slurry was stirred at 22 °C for an additional 2 h and then filtered. The cake was washed with MEK (4.02 kg, 5 L) and then dried at 50 °C under vacuum for 10 h to give 1 »TsOH (4.41 kg, 9.64 mol) as a white powder in 89.6% yield (accounting for the amount of seed charged). Achiral HPLC purity: 99.6% with 0.22% of dimer 15. Chiral SFC purity: >99.7%. m.p. 199 °C. Rotomers observed for NMR spectroscopies. Ή NMR (400 MHz, DMSO-d6): d ppm 12.68 (brs, 1 H), 9.22 (brs, 1 H), 8.40 (s, 1 H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (m, 1 H), 7.12 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 1 .2 Hz, 1 H), 6.84 (m, 1 H), 6.13 (m, 1 H), 5.70 (m, 1 H), 4.81 (m, 0.5H), 4.54 (m, 0.5H), 4.41 (m, 0.5H), 4.12 (m, 0.5H), 3.99 (m, 1 H), 3.15 (m, 0.5H), 2.82 (m, 0.5H), 2.29 (s, 3H), 1 .91 -1 .72 (m, 4H), 1 .24-1 .17 (m, 3H). 13C NMR (100 MHz, DMSO-c/6): d ppm 165.52, 165.13, 150.50, 145.64, 143.06, 138.48, 129.51 , 129.24, 128.67, 127.99, 127.73, 125.97, 125.02, 102.30, 49.53, 48.92, 47.27, 43.83, 42.96, 29.37, 28.41 , 25.22, 21 .28, 16.97, 15.51 . HRMS (ESI) m/z: calculated for Ci5H2oN50 [M + H]+ 286.1668; observed 286.1692.

Comparative Example

Preparation of 1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methyl-piperidin-1 -yl)prop-2-en-1 -one Malonic Acid Salt (Form 1 )

A 250 ml_ round bottom flask was charged with 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one (4.10 g, 14.4 mmol), MEK (Methyl Ethyl Ketone (15.0 ml_/g, 687 mmol, 49.5 g, 61 .5 ml_)). To the solution, malonic acid (0.950 equiv. 13.7 mmol, 1 .42 g) was added in one portion. The mixture was heated to 50 °C and stirred at 50 °C for 15min. The heating was turned off and the slurry was stirred for 16 hours. The resulting white slurry was filtered. The filter cake was washed with MEK (2 X 5 ml_) and dried in a vacuum oven (40 °C) for 2 hours give 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one malonic acid salt (Form 1) (4.48 g, 1 1 .5 mmol, 4.48 g, 80.1 % Yield) as white powder.

REFERENCES

1: D’Amico F, Fiorino G, Furfaro F, Allocca M, Danese S. Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin Investig Drugs. 2018 Jul;27(7):595-599. doi: 10.1080/13543784.2018.1492547. Epub 2018 Jul 6. Review. PubMed PMID: 29938545.

2: Robinette ML, Cella M, Telliez JB, Ulland TK, Barrow AD, Capuder K, Gilfillan S, Lin LL, Notarangelo LD, Colonna M. Jak3 deficiency blocks innate lymphoid cell development. Mucosal Immunol. 2018 Jan;11(1):50-60. doi: 10.1038/mi.2017.38. Epub 2017 May 17. PubMed PMID: 28513593; PubMed Central PMCID: PMC5693788.

3: Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM, Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J, Langille J, Vajdos F, Chrencik J, Telliez JB. Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop -2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J Med Chem. 2017 Mar 9;60(5):1971-1993. doi: 10.1021/acs.jmedchem.6b01694. Epub 2017 Feb 16. PubMed PMID: 28139931.

4: Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. Epub 2016 Nov 10. PubMed PMID: 27791347.

5: Walker G, Croasdell G. The European League Against Rheumatism (EULAR) – 17th Annual European Congress of Rheumatology (June 8-11, 2016 – London, UK). Drugs Today (Barc). 2016 Jun;52(6):355-60. doi: 10.1358/dot.2016.52.6.2516435. PubMed PMID: 27458612.

////////////PF-06651600, PF 06651600, PF06651600, Breakthrough Therapy designation, PHASE 2,   alopecia areata, rheumatoid arthritis, Crohn’s disease,  ulcerative colitis, Ritlectinib

C=CC(N1[C@@H](C)CC[C@@H](NC2=C3C(NC=C3)=NC=N2)C1)=O

ブレキサノロン , Brexanolone, Allopregnanolone


Allopregnanolone.png

ChemSpider 2D Image | Allopregnanolone | C21H34O2

Image result for Brexanolone

Brexanolone

318.501 g/mol, C21H34O2

CAS: 516-54-1

ブレキサノロン

MFCD00003677
Pregnan-20-one, 3-hydroxy-, (3α,5α)-
Pregnan-20-one, 3-hydroxy-, (3α,5α)- [ACD/Index Name]
S39XZ5QV8Y
TU4383000
UNII:S39XZ5QV8Y
(1S,2S,7S,11S,14S,15S,5R,10R)-14-acetyl-5-hydroxy-2,15-dimethyltetracyclo[8.7.0.0<2,7>.0<11,15>]heptadecane
(+)-3a-Hydroxy-5a-pregnan-20-one
(+)-3α-Hydroxy-5α-pregnan-20-one
(3α,5α)-3-Hydroxypregnan-20-one [ACD/IUPAC Name]
10446
3211363 [Beilstein]
3a-Hydroxy-5a-pregnan-20-one

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD. 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633919.htm?utm_campaign=031919_PR_FDA%20approves%20new%20drug%20for%20post-partum%20depression&utm_medium=email&utm_source=Eloqua

March 19, 2019

Release

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD.

“Postpartum depression is a serious condition that, when severe, can be life-threatening. Women may experience thoughts about harming themselves or harming their child. Postpartum depression can also interfere with the maternal-infant bond. This approval marks the first time a drug has been specifically approved to treat postpartum depression, providing an important new treatment option,” said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Because of concerns about serious risks, including excessive sedation or sudden loss of consciousness during administration, Zulresso has been approved with a Risk Evaluation and Mitigation Strategy (REMS) and is only available to patients through a restricted distribution program at certified health care facilities where the health care provider can carefully monitor the patient.”

PPD is a major depressive episode that occurs following childbirth, although symptoms can start during pregnancy. As with other forms of depression, it is characterized by sadness and/or loss of interest in activities that one used to enjoy and a decreased ability to feel pleasure (anhedonia) and may present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, or suicidal ideation.

Zulresso will be available only through a restricted program called the Zulresso REMS Program that requires the drug be administered by a health care provider in a certified health care facility. The REMS requires that patients be enrolled in the program prior to administration of the drug. Zulresso is administered as a continuous IV infusion over a total of 60 hours (2.5 days). Because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring (monitors oxygen levels in the blood). While receiving the infusion, patients must be accompanied during interactions with their child(ren). The need for these steps is addressed in a Boxed Warning in the drug’s prescribing information. Patients will be counseled on the risks of Zulresso treatment and instructed that they must be monitored for these effects at a health care facility for the entire 60 hours of infusion. Patients should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away.

The efficacy of Zulresso was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of Zulresso or placebo and were then followed for four weeks. One study included patients with severe PPD and the other included patients with moderate PPD. The primary measure in the study was the mean change from baseline in depressive symptoms as measured by a depression rating scale. In both placebo controlled studies, Zulresso demonstrated superiority to placebo in improvement of depressive symptoms at the end of the first infusion. The improvement in depression was also observed at the end of the 30-day follow-up period.

The most common adverse reactions reported by patients treated with Zulresso in clinical trials include sleepiness, dry mouth, loss of consciousness and flushing. Health care providers should consider changing the therapeutic regimen, including discontinuing Zulresso in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors.

The FDA granted this application Priority Review and Breakthrough Therapydesignation.

Approval of Zulresso was granted to Sage Therapeutics, Inc.

Allopregnanolone, also known as 5α-pregnan-3α-ol-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP), as well as brexanolone (USAN),[1] is an endogenous inhibitory pregnane neurosteroid[2] which has been approved by the FDA as a treatment for post-partum depression. It is synthesized from progesterone, and is a potent positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.[2] Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolyticsedative, and anticonvulsant activity.[2][3][4] Endogenously produced allopregnanolone exerts a pivotal neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.[5] The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD).[2]

Biochemistry

Biosynthesis

The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.[2] Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[6]

Biological activity

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[2] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunitsexhibit the greatest potentiation.[7] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear.[8][9] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[10] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[11] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDAAMPAkainate, and glycine receptors.[12]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).[12] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.[13] In addition, allopregnanolone has recently been found to be an agonist of the newly discovered membrane progesterone receptors (mPR), including mPRδmPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[14][15] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[14][16] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[12][17]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[18] including α1 subtypes Cav1.2 and Cav1.3.[19] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.[19] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[19] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[20] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.[20]

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressantanxiolyticstress-reducingrewarding,[21] prosocial,[22] antiaggressive,[23]prosexual,[22] sedativepro-sleep,[24] cognitivememory-impairmentanalgesic,[25] anestheticanticonvulsantneuroprotective, and neurogenic effects.[2] Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of moodanxietypremenstrual syndromecatamenial epilepsy, and various other neuropsychiatric conditions.[26][27][28]

Increased levels of allopregnanolone can produce paradoxical effects, including negative moodanxietyirritability, and aggression.[29][30][31] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.[29][30] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[26][31] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[32]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[33][34]

Chemistry

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is very closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone(5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one).

Derivatives

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione).

Research

Allopregnanolone and the other endogenous inhibitory neurosteroids have short terminal half-lives and poor oral bioavailability, and for these reason, have not been pursued for clinical use as oral therapies, although development as a parenteral therapy for multiple indications has been carried out. However, synthetic analogs with improved pharmacokineticprofiles have been synthesized and are being investigated as potential oral therapeutic agents.

In other studies of compounds related to allopregnanolone, exogenous progesterone, such as oral micronized progesterone (OMP), elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[35] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.[35] As a result, there has been some interest in using OMP to treat catamenial epilepsy,[36] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to OMP, oral pregnenolonehas also been found to act as a prodrug of allopregnanolone,[37][38][39] though also of pregnenolone sulfate.[40]

Allopregnanolone has been under development by Sage Therapeutics as an intravenously administered drug for the treatment of super-refractory status epilepticuspostpartum depression, and essential tremor.[41] As of 19 March 2019 the FDA has approved allopregnanolone for postpartum depression.

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  22. Jump up to:a b Frye CA (December 2009). “Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions”Psychoneuroendocrinology. 34 Suppl 1: S143–61. doi:10.1016/j.psyneuen.2009.07.005PMC 2898141PMID 19656632.
  23. ^ Pinna G, Costa E, Guidotti A (February 2005). “Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior”Proc. Natl. Acad. Sci. U.S.A102 (6): 2135–40. doi:10.1073/pnas.0409643102PMC 548579PMID 15677716.
  24. ^ Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). “Steroid hormones and sleep regulation”Mini Rev Med Chem12 (11): 1040–8. doi:10.2174/138955712802762167PMID 23092405.
  25. ^ Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). “Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain”. Prog. Neurobiol113: 70–8. doi:10.1016/j.pneurobio.2013.07.004PMID 23948490.
  26. Jump up to:a b Bäckström T, Andersson A, Andreé L, et al. (December 2003). “Pathogenesis in menstrual cycle-linked CNS disorders”. Ann. N. Y. Acad. Sci1007: 42–53. doi:10.1196/annals.1286.005PMID 14993039.
  27. ^ Guille C, Spencer S, Cavus I, Epperson CN (July 2008). “The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment”Epilepsy Behav13 (1): 12–24. doi:10.1016/j.yebeh.2008.02.004PMC 4112568PMID 18346939.
  28. ^ Finocchi C, Ferrari M (May 2011). “Female reproductive steroids and neuronal excitability”. Neurol. Sci. 32 Suppl 1: S31–5. doi:10.1007/s10072-011-0532-5PMID 21533709.
  29. Jump up to:a b Bäckström T, Haage D, Löfgren M, et al. (September 2011). “Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons”. Neuroscience191: 46–54. doi:10.1016/j.neuroscience.2011.03.061PMID 21600269.
  30. Jump up to:a b Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (September 2009). “Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators”. Psychoneuroendocrinology34 (8): 1121–32. doi:10.1016/j.psyneuen.2009.02.003PMID 19272715.
  31. Jump up to:a b Bäckström T, Bixo M, Johansson M, et al. (February 2014). “Allopregnanolone and mood disorders”. Prog. Neurobiol113: 88–94. doi:10.1016/j.pneurobio.2013.07.005PMID 23978486.
  32. ^ Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (August 2006). “Allopregnanolone concentration and mood–a bimodal association in postmenopausal women treated with oral progesterone”. Psychopharmacology187 (2): 209–21. doi:10.1007/s00213-006-0417-0PMID 16724185.
  33. ^ Mellor DJ, Diesch TJ, Gunn AJ, Bennet L (2005). “The importance of ‘awareness’ for understanding fetal pain”. Brain Res. Brain Res. Rev49 (3): 455–71. doi:10.1016/j.brainresrev.2005.01.006PMID 16269314.
  34. ^ Lagercrantz H, Changeux JP (2009). “The emergence of human consciousness: from fetal to neonatal life”Pediatr. Res65 (3): 255–60. doi:10.1203/PDR.0b013e3181973b0dPMID 19092726[…] the fetus is sedated by the low oxygen tension of the fetal blood and the neurosteroid anesthetics pregnanolone and the sleep-inducing prostaglandin D2 provided by the placenta (36).
  35. Jump up to:a b Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T (June 2006). “Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone”. Maturitas54 (3): 238–44. doi:10.1016/j.maturitas.2005.11.005PMID 16406399.
  36. ^ Orrin Devinsky; Steven Schachter; Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6.
  37. ^ Saudan C, Desmarchelier A, Sottas PE, Mangin P, Saugy M (2005). “Urinary marker of oral pregnenolone administration”. Steroids70 (3): 179–83. doi:10.1016/j.steroids.2004.12.007PMID 15763596.
  38. ^ Piper T, Schlug C, Mareck U, Schänzer W (2011). “Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration”. Drug Test Anal3(5): 283–90. doi:10.1002/dta.281PMID 21538944.
  39. ^ Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I (2013). “Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits”Biol. Psychiatry73 (11): 1045–53. doi:10.1016/j.biopsych.2012.12.008PMC 3648625PMID 23348009.
  40. ^ Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, Mattern C, Farr SA (2010). “Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration”Eur. J. Pharmacol641 (2–3): 128–34. doi:10.1016/j.ejphar.2010.05.033PMC 3008321PMID 20570588.
  41. ^ “Brexanolone – Sage Therapeutics”. AdisInsight.

Further reading

Allopregnanolone
Skeletal formula of allopregnanolone
Ball-and-stick model of the allopregnanolone molecule
Names
IUPAC name

1-(3-Hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone
Other names

ALLO; Allo; ALLOP; AlloP; Brexanolone; 5α-Pregnan-3α-ol-20-one; 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP; Zulresso
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
Properties
C21H34O2
Molar mass 318.501 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////Brexanolone, Priority Review, Breakthrough Therapy designation, Zulresso, Sage Therapeutics Inc, FDA 2019, ブレキサノロン , Brexanolone, Allopregnanolone

CC(=O)C1CCC2C1(CCC3C2CCC4C3(CCC(C4)O)C)C

FDA approves treatment Poteligeo (mogamulizumab-kpkc) for two rare types of non-Hodgkin lymphoma


 

FDA approves treatment for two rare types of non-Hodgkin lymphoma

The U.S. Food and Drug Administration today approved Poteligeo (mogamulizumab-kpkc) injection for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.

August 8, 2018

Release

The U.S. Food and Drug Administration today approved Poteligeo (mogamulizumab-kpkc) injection for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.

“Mycosis fungoides and Sézary syndrome are rare, hard-to-treat types of non-Hodgkin lymphoma and this approval fills an unmet medical need for these patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to expedite the development and review of this type of targeted therapy that offers meaningful treatments for patients.”

Non-Hodgkin lymphoma is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system. MF and SS are types of non-Hodgkin lymphoma in which lymphocytes become cancerous and affect the skin. MF accounts for about half of all lymphomas arising from the skin. It causes itchy red rashes and skin lesions and can spread to other parts of the body. SS is a rare form of skin lymphoma that affects the blood and lymph nodes.

Poteligeo is a monoclonal antibody that binds to a protein (called CC chemokine receptor type 4 or CCR4) found on some cancer cells.

The approval was based on a clinical trial of 372 patients with relapsed MF or SS who received either Poteligeo or a type of chemotherapy called vorinostat. Progression-free survival (the amount of time a patient stays alive without the cancer growing) was longer for patients taking Poteligeo (median 7.6 months) compared to patients taking vorinostat (median 3.1 months).

The most common side effects of treatment with Poteligeo included rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain and upper respiratory tract infection.

Serious warnings of treatment with Poteligeo include the risk of dermatologic toxicity, infusion reactions, infections, autoimmune problems (a condition where the immune cells in the body attack other cells or organs in the body), and complications of stem cell transplantation that uses donor stem cells (allogeneic) after treatment with the drug.

The FDA granted this application Priority Review and Breakthrough Therapydesignation. Poteligeo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted this approval to Kyowa Kirin, Inc.

///////////////// Poteligeo, mogamulizumab-kpkc, fda 2018, Kyowa Kirin, Priority Review, Breakthrough Therapy designation,  Orphan Drug designation

Larotrectinib, ларотректиниб , 拉罗替尼 ,


Image result for LarotrectinibImage result for Larotrectinib

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib

ARRY-470, LOXO-101, PF9462I9HX

Molecular Formula: C21H22F2N6O2
Molecular Weight: 428.444 g/mol
(3S)-N-{5-[(2R)-2-(2,5-Difluorphenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidincarboxamid
(S)-N-{5-[(R)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carboxamide
10360
1223403-58-4 [RN]
UNII:PF9462I9HX
ларотректиниб [Russian] [INN]
拉罗替尼 [Chinese] [INN]
(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide
NTRK-fusion solid tumours
TRK inhibitor
orphan drug designation in the U.S
In 2013, Array Biopharma licensed the product to Loxo Oncology for development and commercialization in the U.S. In 2016, breakthrough therapy designation was received in the U.S. for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments. In 2017, Bayer acquired global co-development and commercialization rights from Loxo Oncology.
  • Originator Array BioPharma
  • Developer Array BioPharma; Loxo Oncology; National Cancer Institute (USA)
  • Class Antineoplastics; Pyrazoles; Pyrimidines; Pyrrolidines; Small molecules
  • Mechanism of Action Tropomyosin-related kinase antagonists
  • Orphan Drug Status Yes – Solid tumours; Soft tissue sarcoma

Highest Development Phases

  • Preregistration Solid tumours
  • Phase II Histiocytosis; Non-Hodgkin’s lymphoma
  • Phase I/II CNS cancer
  • Preclinical Precursor cell lymphoblastic leukaemia-lymphoma

Most Recent Events

  • 29 May 2018 FDA assigns PDUFA action date of 26/11/2018 for larotrectinib for Solid tumors
  • 29 May 2018 Larotrectinib receives priority review status for Solid tumors in the US
  • 29 May 2018 The US FDA accepts NDA for larotrectinib for Solid tumours for review

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib sulfate

(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;sulfuric acid

Larotrectinib (LOXO-101) sulfate is an oral potent and selective ATP-competitive inhibitor of tropomyosin receptor kinases (TRK).

    • Crystalline Form (I-HS) OF

SULFATE SALT REPORTED IN https://patents.google.com/patent/US20170165267

nmr  http://file.selleckchem.com/downloads/nmr/s796001-loxo-101-methanol-hnmr-selleck.pdf

Figure US20170165267A1-20170615-C00006Figure US20170165267A1-20170615-C00007

Molecular Weight 526.51
Formula C21H22F2N6O2.H2O4S
CAS No. 1223405-08-0
  1. LOXO-101 sulfate
  2. Larotrectinib sulfate
  3. LOXO-101 (sulfate)
  4. 1223405-08-0
  5. UNII-RDF76R62ID
  6. RDF76R62ID
  7. ARRY-470 sulfate
  8. LOXO-101(sulfate)
  9. Larotrectinib sulfate [USAN]
  10. PXHANKVTFWSDSG-QLOBERJESA-N
  11. HY-12866A
  12. s7960
  13. AKOS030526332
  14. CS-5314

LOXO-101 is a small molecule that was designed to block the ATP binding site of the TRK family of receptors, with 2 to 20 nM cellular potency against the TRKA, TRKB, and TRKC kinases. IC50 value: 2 – 20 nM Target: TRKA/B/C in vitro: LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. LOXO-101 is evaluated for off-target kinase enzyme inhibition against a panel of 226 non-TRK kinases at a compound concentration of 1,000 nM and ATP concentrations near the Km for each enzyme. In the panel, LOXO-101 demonstrates greater than 50% inhibition for only one non-TRK kinase (TNK2 IC50, 576 nM). Measurement of proliferation following treatment with LOXO-101 demonstrates a dose-dependent inhibition of cell proliferation in all three cell lines. The IC50 is less than 100 nM for CUTO-3.29 and less than 10 nM for KM12 and MO-91, consistent with the known potency of this drug for the TRK kinase family. [1] LOXO-101 demonstrates potent and highly-selective inhibition of TRKA, TRKB, and TRKC over other kinase- and non-kinase targets. LOXO-101 is a potent, ATP-competitive TRK inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members in binding and cellular assays, with 100x selectivity over other kinases. [2] in vivo: Athymic nude mice injected with KM12 cells are treated with LOXO-101 orally daily for 2 weeks. Dose-dependent tumor inhibition is observed, demonstrating the ability of this selective compound to inhibit tumor growth in vivo. [1]

Image result for Larotrectinib

DOI

https://doi.org/10.1038/nrd.2018.4

SYNTHESIS

WO 2010048314

Synthesis of larotrectinib

N-Boc-pyrrolidine as starting material The method involves enantioselective deprotonation, transmetalation with ZnCl2, Negishi coupling with 2-bromo-1,4-difluorobenzene,

N-arylation with 5-chloropyrazolo[1,5-a]pyrimidine, nitration, nitro reduction and condensation with CDI and 3(S)-pyrrolidinol.

PRODUCT Patent

WO 2010048314

https://patents.google.com/patent/WO2010048314A1

InventorJulia HaasSteven W. AndrewsYutong JiangGan Zhang

Original AssigneeArray Biopharma Inc.

Priority date 2008-10-22

Example 14


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide

[00423] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difiuorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (17 mg, 0.19 mmol) [purchased from Suven Life Sciences] was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (30 mg, 74% yield). MS (apci) m/z = 429.2 (M+H).

Example 14A


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolori,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide sulfate

[00424] To a solution of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-3 -hydroxypyrrolidine- 1 -carboxamide (4.5 mg, 0.011 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in MeOH (105 μL, 0.011 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3 -hydroxypyrrolidine- 1 -carboxamide sulfate (5.2 mg, 0.0099 mmol, 94 % yield) as a yellow solid.

PATENT

WO 2017201241 

Examples

Preparation of 10:

1)

(R,E)-N-(2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (17): Compound 16 and (R)-2-methylpropane-2-sulfinamide (1.05 eq.) were charged to a reactor outfitted with a mechanical stirrer, reflux condensor, J-Kem temperature probe under N2. DCM (3 mL/g of 14) was added (endothermic from 22 °C to about 5 °C) followed by addition of cesium carbonate (0.70 eq.) (exothermic to -50 °C). Once the addition was complete, the reaction mixture was stirred at room temperature for 3 h (slowly cools from about 40 °C). When the reaction was called complete (HPLC) the mixture was filtered through Celite. The Celite pad (0.3 wt eq) was equilibrated with DCM (1 mL/g of 16), and the reaction mixture was poured through the pad. The Celite cake was washed with DCM (2 x 1 mL/g), and the filtrate concentrated partially to leave about 0.5 to 1 mL/g DCM remaining. The orange solution was stored at room temperature (generally overnight) and used directly in the next reaction. (100% yield was assumed).

2)

(R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19): To a reactor equipped with overhead stirring, reflux condensor, under

nitrogen, was added magnesium turnings (2.0 eq), and THF (8 mL/g of 17). The mixture was heated to 40 °C. Dibal-H (25% wt in toluene, 0.004 eq) was added to the solution, and the suspension heated at 40 °C for 25 minutes. A solution of 2-(2-bromoethyl)-l,3-dioxane (18) (2 eq) in THF (4.6 mL/g of 17) was added dropwise to the Mg solution via addition funnel. The solution temperature was maintained < 55 °C. The reaction progress was monitored by GC. When the Grignard formation was judged complete, the solution was cooled to -30 °C, and 17 (1.0 eq, in DCM) was added dropwise via addition funnel. The temperature was kept between -30 °C and -20 °C and the reaction was monitored for completion (FIPLC). Once the reaction was called complete, the suspension (IT = -27.7 °C) was vacuum transferred to a prepared and cooled (10 °C) 10% aqueous citric acid solution (11 mL/g of 17). The mixture temperature rose to 20 °C during transfer. The milky solution was allowed to stir at ambient temperature overnight. MTBE (5.8 mL/g) was added to the mixture, and it was transferred to a separatory funnel. The layers were allowed to separate, and the lower aqueous layer was removed. The organic layer was washed with sat. NaHC03 (11 mL/g) and then sat. NaCl (5.4 mL/g). The organic layer was removed and concentrated to minimum volume via vacuum distillation. MTBE (2 mL/g) was added, and the mixture again concentrated to minimum volume. Finally MTBE was added to give 2 mL/g total MTBE (GC ratio of MTBE:THF was about 9: 1), and the MTBE mixture was heated to 50 °C until full dissolution occurred. The MTBE solution was allowed to cool to about 35 °C, and heptane was added portion -wise. The first portion (2 mL/g) is added, and the mixture allowed to stir and form a solid for 1-2 h, and then the remainder of the heptane is added (8 mL/g). The suspension was allowed to stir for >lh. The solids were collected via filtration through polypropylene filter cloth (PPFC) and washed with 10% MTBE in heptane (4 mL/g. The wet solid was placed in trays and dried in a vacuum oven at 55 °C until constant weight (3101 g, 80.5%, dense white solid, 100a% and 100wt%).

3)

(R)-2-(2,5-difluorophenyl)pyrrolidine (R)-2-hydroxysuccinate (10): To a flask containing 4: 1 TFA:water (2.5 mL/g, pre-mixed and cooled to <35 °C before adding 19) was added (R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19) (1 eq). The mixture temperature rose from 34 °C to 48 °C and was stirred at ambient temperature for 1 h. Additional TFA (7.5 mL/g) was added, followed by triethylsilane (3 eq) over 5 minutes. The biphasic mixture was stirred vigorously under nitrogen for 21 h until judged complete (by GC, <5% of imine). The mixture was then concentrated under vacuum until -10 kg target mass (observed 10.8 kg after concentration). The resulting concentrate was transferred to a separatory funnel and diluted with MTBE (7.5 mL/g), followed by water (7.5 mL/g). The layers were separated. The MTBE layer was back-extracted with 1M HC1 (3 mL/g). The layers were separated, and the aqueous layers were combined in a round-bottomed flask with DCM (8 mL/g). The mixture was cooled in an ice bath and 40% NaOH was charged to adjust the pH to >12 (about 0.5 mL/g; the temperature went from 24 °C to 27 °C, actual pH was 13), and the layers separated in the separatory funnel. The aqueous layer was back-extracted twice with DCM (2 x 4 mL/g). The organic layers were concentrated to an oil (<0.5 mL/g) under vacuum (rotovap) and EtOH (1 mL/g based on product) was added. The yellow solution was again concentrated to an oil (81% corrected yield, with 3% EtOH, 0.2% imine and Chiral HPLC showed 99.7%ee).

Salt formation: To a solution of (R)-2-(2,5-difluorophenyl)pyrrolidine 10 (1 eq) in EtOH (15 mL/g) was added Z)-(+)-Malic Acid (1 eq). The suspension was heated to 70 °C for 30 minutes (full dissolution had occurred before 70 °C was reached), and then allowed to cool to room temperature slowly (mixture was seeded when the temperature was < 40 °C). The slurry was stirred at room temperature overnight, then cooled to <5 °C the next morning. The suspension was stirred at <5 °C for 2h, filtered (PPFC), washed with cold EtOH (2 x 2 mL/g), and dried (50-55 °C) under vacuum to give the product as a white solid (96% based on 91% potency, product is an EtOH solvate or hemi- solvate).

Preparation of the compound of Formula I:

1)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3-nitropyrazolo[l,5-a]pyrimidine (11):

Compound 5 and 10 (1.05 eq) were charged to a reactor outfitted with a mechanical stirrer, J-Kem temperature probe, under N2. EtOH and THF (4: 1, 10 mL/g of 5) were added and the mixture was cooled to 15-25 °C. Triethylamine (3.5 eq) was added and the internal temp generally rose from 17.3 – 37.8 °C. The reaction was heated to 50 – 60 °C and held at that temperature for 7 h. Once the reaction is judged complete (HPLC), water (12 mL/g of 5) is added maintaining the temperature at 50 – 60 °C. The heat is removed and the suspension was slowly cooled to 21 °C over two h. After stirring at -21 °C for 2 h, the suspension was centrifuged and the cake was washed with water (3 x 3 mL/g of 5). The solid was transferred to drying trays and placed in a vacuum oven at 50 – 55 °C to give 11.

2)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine fumarate Pt/C hydrogenation (12 fumarate): To a Parr reactor was charged 11 (1.0 eq), 5% Pt/C ~ 50 wt% water (2 mol% Pt / Johnson Matthey B 103018-5 or Sigma Aldrich 33015-9), and MeOH (8 mL/g). The suspension was stirred under hydrogen at 25-30 psi and the temperature was maintained below 65 °C for ~8 h. When the reaction was called complete (HPLC), the reaction was cooled to 15 – 25 °C and the hydrogen atmosphere was replaced with a nitrogen atmosphere. The reaction mixture was filtered through a 2 micron bag filter and a 0.2 micron line filter in series. The filtrate from the Pt/C hydrogenation was transferred to a reactor under nitrogen with mechanical stirring and then MTBE (8 mL/g) and fumaric acid (1.01 eq) were charged. The mixture was stirred under nitrogen for 1 h and solids formed after -15 min. The mixture was cooled to -10 to -20 °C and stirred for 3 h. The suspension was filtered (PPFC), washed with MTBE (-2.5 mL/g), and the solids was dried under vacuum at 20-25 °C with a nitrogen bleed to yield an off-white solid (83% yield).

3)

Phenyl (5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3,3a-dihydropyrazolo[l,5-a]pyrimidin-3-yl)carbamate (13): To a 5 to 15°C solution of 12-fumarate (1.0 eq) in 2-MeTHF (15 mL/g) was added a solution of potassium carbonate (2.0 eq.) in water (5 mL/g) followed by phenyl chloroformate (1.22 eq.) (over 22 min, an exotherm from 7 °C to 11 °C occurred). The mixture was stirred for 2 h and then the reaction was called complete (HPLC). The stirring ceased and the aqueous layer was removed. The organic layer was washed with brine (5 mL/g) and concentrated to ca. 5 mL/g of 2-MeTHF under vacuum and with heating to 40 °C. To the 2-MeTHF solution was added heptanes (2.5 mL/g) followed by seeds (20 mg, 0.1 wt%). This mixture was allowed to stir at room temperature for 2 h (until a solid formed), and then the remainder of the heptanes (12.5 mL/g) was added. The mixture was stirred at ambient temperature for 2 h and then the solids were collected via filtration (PPFC), washed with 4: 1 heptanes :MeTHF (2 x 2 mL/g), and dried to give 13 (96%).

4)

(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate: To a flask containing 13 (1.0 eq) was added a solution of (S)-pyrrolidin-3-ol (1.1 eq.) in EtOH (10 mL/g). The mixture was heated at 50 – 60 °C for 5 h, called complete (HPLC), and then cooled to 20-35 °C. Once <35°C, the reaction was polish-filtered (0.2 micron) into a clean reaction vessel and the mixture was cooled to -5 to 5 °C. Sulfuric acid (1.0 eq.) was added over 40 minutes, the temperature rose to 2 °C and the mixture was seeded. A solid formed, and the mixture was allowed to stir at -5 to 5 °C for 6.5 h. Heptanes (10 mL/g) was added, and the mixture stirred for 6.5 h. The

suspension was filtered (PPFC), washed with 1 : 1 EtOH:heptanes (2 x 2 mL/g), and dried (under vacuum at ambient temperature) to give Formula I (92.3%).

Preparation of the hydrogen sulfate salt of the compound of Formula I:

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)-N-(5- ((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (,S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1 : 1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5 :95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5 :95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate.

PATENT

US2017165267

https://patents.google.com/patent/US20170165267

Provided herein is a novel crystalline form of the compound of Formula I:

[0000]

Figure US20170165267A1-20170615-C00001

also known as (S)—N-(5-((R)-2-(2, 5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. In particular, the novel crystalline form comprises the hydrogen sulfate salt of the compound of Formula I in a stable polymorph form, hereinafter referred to as crystalline form (I-HS) and LOXO-101, which can be characterized, for example, by its X-ray diffraction pattern—the crystalline form (I-HS) having the formula:

[0000]

Figure US20170165267A1-20170615-C00002

In some embodiments of the above step (c), the base is an alkali metal base, such as an alkali metal carbonate, such as potassium carbonate.

Figure US20170165267A1-20170615-C00004

Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine Step A—Preparation of sodium pyrazolo[1,5-a]pyrimidin-5-olate

A solution of 1H-pyrazol-5-amine and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOH under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wt % solution in EtOH), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOH. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1.5 area % of 1H-pyrazol-5-amine was observed by TRK1PM1 HPLC to follow the progression of the reaction using 20 μL of slurry diluted in 4 mL deionized water and 5 μL injection at 220 nm.

After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mL/g) of heptane and then refluxed at 70° Celsius for 1 hour. The slurry was then cooled to room temperature overnight. The solid was collected by filtration on a tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4 mL/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[1,5-a]-pyrimidin-5-olate was obtained in 93-96% yield (corrected) and larger than 99.5 area % observed by HPLC (1 mg/mL dilution in deionized water, TRK1PM1 at 220 nm).

Step B—Preparation of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one

A tared round bottom flask was charged with sodium pyrazolo[1,5-a]pyrimidin-5-olate that was dissolved at 40-45° Celsius in 3.0 vol. (3.0 mL/g) of deionized water, and then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g deionized water content). Gas chromatography (GC) for residual EtOH (30 μL of solution dissolved in ˜1 mL MeOH) was performed showing less than 100 ppm with traces of ethyl nitrate fumes being observed below upon later addition of HNO3. In some cases, the original solution was charged with an additional 1.5 vol. (1.5 mL/g) of DI water, then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g DI water content). Gas chromatograph for residual EtOH (30 μL of solution dissolved in about 1 mL MeOH) was performed showing <<100 ppm of residual EtOH without observing any ethyl nitrate fumes below upon later addition of HNO3.

A round bottom vessel outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control was charged with 3 vol. (3 mL/g, 10 equiv) of >90 wt % HNOand cooled to about 10° Celsius under a nitrogen atmosphere using external ice-water cooling bath under a nitrogen atmosphere. Using a pressure equalizing addition funnel, the HNO3solution was charged with the 1.75-1.95 volumes of a deionized water solution of sodium pyrazolo[1,5-a]pyrimidin-5-olate (1.16-1.4 mL DI water/g of sodium pyrazolo[1,5-a]pyrimidin-5-olate) at a rate to maintain 35-40° Celsius internal temperature under cooling. Two azeotropes were observed without any ethyl nitrate fumes. The azeotrope flask, the transfer line (if applicable) and the addition funnel were rinsed with 2×0.1 vol. (2×0.1 mL/g) deionized water added to the reaction mixture. Once the addition was complete, the temperature was gradually increased to about 45-50° Celsius for about 3 hours with HPLC showing >99.5 area % conversion of sodium pyrazolo[1,5-a]pyrimidin-5-olate to 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one.

Step C—Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine

3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one was charged to a round bottom flask outfitted with a mechanical stirrer, a heating mantle, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive N2pressure control. Under mechanical stirring the solids were suspended with 8 volumes (8 mL/g) of CH3CN, and then charged with 2,6-lutitine (1.05 equiv) followed by warming the slurry to about 50° Celsius. Using a pressure equalizing addition funnel, the mixture was dropwise charged with 0.33 equivalents of POCl3. This charge yielded a thick, beige slurry of a trimer that was homogenized while stirring until a semi-mobile mass was observed. An additional 1.67 equivalents of POClwas charged to the mixture while allowing the temperature to stabilize, followed by warming the reaction mixture to a gentle reflux (78° Celsius). Some puffing was observed upon warming the mixture that later subsided as the thick slurry got thinner.

The reaction mixture was allowed to reflux until complete dissolution to a dark solution and until HPLC (20 μL diluted in 5 mL of CH3CN, TRK1PM1 HPLC, 5 μL injection, 268 nm) confirmed that no more trimer (RRT 0.92) was present with less than 0.5 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one (RRT 0.79) being observed by manually removing any interfering and early eluting peaks related to lutidine from the area integration. On a 1.9 kg scale, 0 area % of the trimer, 0.25 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one, and 99.5 area % of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine was observed after 19 hours of gentle reflux using TRK1PM1 HPLC at 268 [0000]

Figure US20170165267A1-20170615-C00005

Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate Step A—Preparation of tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate

2-bromo-1,4-difluorobenzene (1.5 eq.) was dissolved in 4 volumes of THF (based on weight of tert-butyl 2-oxopyrrolidine-1-carboxylate) and cooled to about 5° Celsius. A solution of 2.0 M iPrMgCl in THF (1.4 eq.) was added over 2 hours to the mixture while maintaining a reaction temperature below 25° Celsius. The solution was allowed to cool to about 5° Celsius and stirred for 1 hour (GC analysis confirmed Grignard formation). A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.0 eq.) in 1 volume of THF was added over about 30 min while maintaining a reaction temperature below 25° Celsius. The reaction was stirred at about 5° Celsius for 90 min (tert-butyl 2-oxopyrrolidine-1-carboxylate was confirmed to be less than 0.5 area % by HPLC). The reaction was quenched with 5 volumes of 2 M aqueous HCl while maintaining a reaction temperature below 45° Celsius. The reaction was then transferred to a separatory funnel adding 10 volumes of heptane and removing the aqueous layer. The organic layer was washed with 4 volumes of saturated aqueous NaCl followed by addition of 2×1 volume of saturated aqueous NaCl. The organic layer was solvent-switched to heptane (<1% wt THF confirmed by GC) at a distillation temperature of 35-55° Celsius and distillation pressure of 100-200 mm Hg for 2×4 volumes of heptane being added with a minimum distillation volume of about 7 volumes. The mixture was then diluted to 10 volumes with heptane while heating to about 55° Celsius yielded a denser solid with the mixture being allowed to cool to room temperature overnight. The slurry was cooled to less than 5° Celsius and filtered through polypropylene filter cloth. The wet cake was washed with 2×2 volumes of heptane. The solids were dried under vacuum at 55° Celsius until the weight was constant, yielding tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate as a white solid at about 75% to 85% theoretical yield.

Step B—Preparation of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole

tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate was dissolved in 5 vol. of toluene with 2.2 eq. of 12M HCl being added observing a mild exotherm and gas evolution. The reaction was heated to 65° Celsius for 12-24 hours and monitored by HPLC. Upon completion the reaction was cooled to less than 15° Celsius with an ice/water bath. The pH was adjusted to about 14 with 3 equivalents of 2M aqueous NaOH (4.7 vol.). The reaction was stirred at room temperature for 1-2 hours. The mixture was transferred to a separatory funnel with toluene. The aqueous layer was removed and the organic layer was washed with 3 volumes of saturated aqueous NaCl. The organic layer was concentrated to an oil and redissolved in 1.5 volumes of heptane. The resulting suspension was filtered through a GF/F filter paper and concentrated to a light yellow oil of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole with a 90% to 100% theoretical yield.

Step C—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine

Chloro-1,5-cyclooctadiene iridium dimer (0.2 mol %) and (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole (0.4 mol %) were suspended in 5 volumes of MTBE (based on 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole) at room temperature. The mixture was stirred for 1 hour and most of the solids dissolved with the solution turning dark red. The catalyst formation was monitored using an HPLC/PDA detector. The reaction was cooled to less than 5° Celsius and 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (1.0 eq.) was added using a 0.5 volumes of MTBE rinse. Diphenylsilane (1.5 eq.) was added over about 20 minutes while maintaining a reaction temperature below 10° Celsius. The reaction was stirred for 30 minutes below 10° Celsius and then allowed to warm to room temperature. The reaction was stirred overnight at room temperature. The completion of the reaction was confirmed by HPLC and then cooled to less than 5° Celsius. The reaction was quenched with 5 volumes of 2M aqueous HCl maintaining temperature below 20° Celsius. After 10 minutes the ice/water bath was removed and the reaction temperature was allowed to increase to room temperature while stirring for 2 hours. The mixture was transferred to a separatory funnel with 3 volumes of MTBE. The aqueous layer was washed with 3.5 volumes of MTBE followed by addition of 5 volumes of MTBE to the aqueous layer while adjusting the pH to about 14 by adding 0.75 volumes of aqueous 50% NaOH. The organic layer was washed with 5 volumes of aqueous saturated NaCl, then concentrated to an oil, and diluted with 3 volumes of MTBE. The solution was filtered through a polypropylene filter cloth and rinsed with 1 volume of MTBE. The filtrate was concentrated to an oil of (R)-2-(2,5-difluorophenyl)-pyrrolidine with a 95% to 100% theoretical yield and with 75-85% ee.

Step D—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate

(R)-2-(2,5-difluorophenyl)-pyrrolidine (1.0 eq.) was transferred to a round bottom flask charged with 15 volumes (corrected for potency) of EtOH (200 prf). D-malic acid (1.05 eq.) was added and the mixture was heated to 65° Celsius. The solids all dissolved at about 64° Celsius. The solution was allowed to cool to RT. At about 55° Celsius the solution was seeded with (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate (about 50 mg, >97% ee) and stirred at room temperature overnight. The suspension was then filtered through a polypropylene filter cloth and washed with 2×1 volumes of EtOH (200 prf). The solids were dried under vacuum at 55° Celsius, yielding (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate with a 75% to 90% theoretical yield and with >96% ee.

Referring to Scheme 1, suitable bases include tertiary amine bases, such as triethylamine, and K2CO3. Suitable solvents include ethanol, heptane and tetrahydrofuran (THF). The reaction is conveniently performed at temperatures between 5° Celsius and 50° Celsius. The reaction progress was generally monitored by HPLC TRK1PM1.

Figure US20170165267A1-20170615-C00006

Figure US20170165267A1-20170615-C00007

[0247]

Compounds II (5-chloro-3-nitropyrazolo[1,5-a]pyrimidine) and III ((R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate, 1.05 eq.) were charged to a round bottom flask outfitted with a mechanical stirrer, a J-Kem temperature probe and an Nadaptor for positive Npressure control. A solution of 4:1 EtOH:THF (10 mL/g of compound II) was added and followed by addition of triethylamine (NEt3, 3.50 eq.) via addition funnel with the temperature reaching about 40° Celsius during addition. Once the addition was complete, the reaction mixture was heated to 50° Celsius and stirred for 0.5-3 hours to yield compound IV.

To a round bottom flask equipped with a mechanical stirrer, a J-Kem temperature probe, and an Ninlet compound IV was added and followed by addition of tetrahydrofuran (10 mL/g of compound IV). The solution was cooled to less than 5° Celsius in an ice bath, and Zn (9-10 eq.) was added. 6M HCl (9-10 eq.) was then added dropwise at such a rate to keep the temperature below 30° Celsius (for 1 kg scale the addition took about 1.5 hours). Once the exotherm subsided, the reaction was allowed to warm to room temperature and was stirred for 30-60 min until compound IV was not detected by HPLC. At this time, a solution of potassium carbonate (K2CO3, 2.0 eq.) in water (5 mL/g of compound IV) was added all at once and followed by rapid dropwise addition of phenyl chloroformate (PhOCOCl, 1.2 eq.). Gas evolution (CO2) was observed during both of the above additions, and the temperature increased to about 30° Celsius after adding phenyl chloroformate. The carbamate formation was stirred at room temperature for 30-90 min. HPLC analysis immediately followed to run to ensure less than 1 area % for the amine being present and high yield of compound VI in the solution.

To the above solution amine VII ((S)-pyrrolidin-3-ol, 1.1 eq. based on theoretical yield for compound VI) and EtOH (10 mL/g of compound VI) was added. Compound VII was added before or at the same time as EtOH to avoid ethyl carbamate impurities from forming. The above EtOH solution was concentrated to a minimum volume (4-5 mL/g) using the batch concentrator under reduced pressure (THF levels should be <5% by GC), and EtOH (10 mL/g of compound VI) was back-added to give a total of 10 mL/g. The reaction was then heated at 50° Celsius for 9-19 hours or until HPLC shows that compound VI is less than 0.5 area %. The reaction was then cooled to room temperature, and sulfuric acid (H2SO4, 1.0 eq. to compound VI) was added via addition funnel to yield compound I-HS with the temperature usually exotherming at about 30° Celsius.

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

PATENT

CN 107987082

PATENT

https://patents.google.com/patent/US20170281632A1/en

WO 2010/048314 discloses in Example 14A a hydrogen sulfate salt of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. WO 2010/048314 does not disclose the particular form of the hydrogen sulfate salt described herein when prepared according to the method of Example 14A in that document. In particular, WO 2010/048314 does not disclose crystalline form (l-HS) as described below.

(S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I):

Figure US20170281632A1-20171005-C00001

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidi n-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1, 5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

References

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US8865698 Method of treatment using substituted pyrazolo[1, 5-a]pyrimidine compounds
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US8513263 Substituted Pyrazolo[1, 5-a]Pyrimidine Compounds as TRK Kinase Inhibitors
2011-08-11
US2017165267 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
2017-01-05
US2017260589 POINT MUTATIONS IN TRK INHIBITOR-RESISTANT CANCER AND METHODS RELATING TO THE SAME
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US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
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US9447104 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-a]PYRIMIDINE COMPOUNDS
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US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
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US2015073036 NOVEL NTRK1 FUSION MOLECULES AND USES THEREOF
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US2017114067 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
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US2016137654 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
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///////////Larotrectinib, UNII:PF9462I9HX, ларотректиниб , 拉罗替尼 , ARRY-470, LOXO-101, PF9462I9HX, phase 3,  Array BioPharma, Loxo Oncology, National Cancer Institute, BAYER, orphan drug designation, breakthrough therapy designation

C1CC(N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CCC(C4)O)C5=C(C=CC(=C5)F)F.OS(=O)(=O)O

PF 06650833


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PF-06650833

1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide

CAS 1817626-54-2
Chemical Formula: C18H20FN3O4
Molecular Weight: 361.3734

  • Originator Pfizer
  • Class Anti-inflammatories; Antirheumatics
  • Mechanism of Action Interleukin-1 receptor-associated kinase inhibitors
  • Phase II Rheumatoid arthritis
  • Phase I Lupus vulgaris
  • 01 Aug 2018 Pfizer completes a phase II trial in Rheumatoid arthritis (Treatment-experienced) in USA, Ukraine, Taiwan, Serbia, Russia, Romania, Poland, Mexico, South Korea, Georgia, Bosnia-Herzegovina, Australia, Croatia, Spain, Slovakia, Czech Republic, Hungary, Germany, Bulgaria (PO) (NCT02996500)
  • 28 Jul 2018 No recent reports of development identified for phase-I development in Lupus(In volunteers) in USA (PO, Controlled release)
  • 28 Jul 2018 No recent reports of development identified for phase-I development in Lupus(In volunteers) in USA (PO, Immediate release)
  • PF-06650833 is an inhibitor of Interleukin-1 receptor associated kinase 4 (IRAK4). RAK4 is located proximal to TLR/IL-1 receptors, and in preclinical studies, inhibits downstream signaling from these receptors. The development of novel small molecule inhibitors of this kinase has the potential to lead to new therapeutics to treat diseases such as rheumatoid arthritis, lupus, and lymphomas.

Interleukin-1 receptor associated kinase 4 (IRAK-4) is a serine threonine kinases that plays a key role in innate immune signaling. IRAK-4 is activated by the interleukin (IL-1) family receptors (IL-1R, IL-18R, and IL-33R), as well as the Toll-like receptors (TLRs). Inhibition of IRAK-4 blocks the production of inflammatory cytokines such as type I interferons, tumor necrosis factor (TNF), IL-1, IL-6, and IL-12 that are key drivers of autoimmune and inflammatory diseases. IRAK-4 is an attractive therapeutic target for diseases associated with dysregulated inflammation, such as systemic lupus erythematosus and rheumatoid arthritis.

Figure

Figure

First Discovery Synthesis of 1

Conditions: (a) LDA (1.2 equiv), TMSCl (1.3 equiv), THF, −60 °C, 30 min; (b) allyl methyl carbonate (1.1 equiv), Pd(OAc)2 (0.05 equiv), THF, 65 °C, 2 h, 73% (2 steps); (c) LiThCN (1.5 equiv), EtMgCl (1.5 equiv), TMSCl (2.0 equiv), THF, −78 °C, 6 h, 90%; (d) LDA (1.8 equiv), NFSI (1.25 equiv), THF, −78 °C, 1 h, 23% (8), 45% (9); (e) pTsOH (0.05 equiv), MeCN, H2O, 90 °C, 2 h, 97%; (f) 3 (0.9 equiv), KHMDS (2.0 equiv), DMF, THF, −10 °C, 30 min, 84%; (g) H2O2 (10 equiv), K2CO3 (4.0 equiv), DMSO, 20 °C, 2 h, 97%.

CLIP

Image result for PF-06650833

Target: Interleukin-1 receptor associated kinase 4 (IRAK4): This kinase is important in innate immunity, and its inhibition is predicted to be beneficial in treating inflammatory diseases.

Disease: Rheumatoid arthritis, inflammatory bowel disorder

Notes: PF06650833 came from a screening assay that used nuclear magnetic resonance spectroscopy to determine binding between molecular fragments and IRAK4. The initial hit, which bound weakly to IRAK4, was optimized with structure- and property-based medicinal chemistry to generate a series of potent inhibitors, said Katherine Lee, an associate research fellow at Pfizer.

Paper

Improvements to Enable the Large Scale Synthesis of 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833)

§ Medicine DesignPfizer Worldwide Research and Development445 Eastern Point Road, Groton, Connecticut 06340, United States
 Chemical Research and DevelopmentPfizer Worldwide Research and Development445 Eastern Point Road, Groton, Connecticut 06340, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00386
Stephen Wright
Senior Principal Scientist at Pfizer Inc.
New London/Norwich, Connecticut Area
Robert Singer
Robert Singer
Process Chemist -Assoc Research Fellow at Pfizer
New London/Norwich, Connecticut Area

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00386/suppl_file/op8b00386_si_001.pdf

Abstract Image

An improved process for the large scale synthesis of 1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (1), a candidate currently in clinical development, was developed. Key objectives were to eliminate chromatographic purifications, to maximize the reproducibility of each step, and to improve the yield and efficiency of each step relative to the previous discovery syntheses of 1. This work was focused on improvements to the synthesis of the stereochemically complex lactam 2. Steps of particular concern were the preparation of the unsaturated lactam 6, the cuprate conjugate addition reaction to produce 7, and the conversion of 7 to 8 with a high degree of diastereoselection. The solutions to these challenges have permitted the synthesis of 2 in excess of 100 kg, which in turn has permitted 1 to be prepared in sufficient amounts to support further development.

1 (31.3 kg, 91%, 82% overall) as a white, free-flowing powder.

 1H NMR (500 MHz, DMSO): δ 8.86 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 5.9 Hz, 1H), 7.84 (br. s., 1H), 7.74 (s, 1H), 7.70 (br. s., 1H), 7.42 (d, J = 5.9 Hz, 1H), 4.90 (dd, J = 5.9, 53.8 Hz, 1H), 4.54 (dd, J = 3.5, 11.1 Hz, 1H), 4.26 (dd, J = 6.4, 11.0 Hz, 1H), 4.13–4.05 (m, 1H), 3.97 (s, 3H), 2.69–2.54 (m, 1H), 1.68–1.53 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H).

13C NMR{1H} (126 MHz, DMSO): δ 171.0 (d, J = 19.4 Hz), 166.4, 158.4, 155.1, 137.7, 131.8, 130.3, 128.4, 120.3, 115.2, 103.2 (d, J = 4.2 Hz), 90.0 (d, J = 179.2 Hz), 66.3, 56.0, 54.1, 42.2 (d, J = 19.4 Hz), 16.4 (d, J = 8.4 Hz), 12.1.

19F NMR (H decoupled, 376 MHz, DMSO-d6): δ −199.26.

LCMS: 362 (MH+).

capture

//////////////PF-06650833, PF 06650833, PF06650833, PF-6650833, PF 6650833, PF6650833.

O=C(C1=CC2=C(C(OC[C@H]([C@H](CC)[C@@H]3F)NC3=O)=NC=C2)C=C1OC)N

/////////////////PF-06650833, PF 06650833, Phase 3, Atopic dermatitis, PFIZER, Breakthrough Therapy Designation

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