Name: Ivacaftor CAS#: 873054-44-5 VX-770, until 2016.12 we have 800g in stock

Name: Ivacaftor CAS#: 873054-44-5 VX-770, until 2016.12 we have 800g in stock.

We produced more than 60kg to India in 2015-2016.

Attaching NMR for you. HPLC 99 

GMP plant produce.

http://www.eosmedchem.com/873054-44-5.html

Web: www.eosmedchem.com

Email: info@eosmedchem.com; eosmedchem@gmail.com

Description: Ivacaftor, also known as VX-770, is a drug used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, who account for 4–5% cases of cystic fibrosis, and is included in a combination drug, lumacaftor/ivacaftor, which is used to treat people with cystic fibrosis who have the F508del mutation in CFTR. Ivacaftor is a "potentiator" of CFTR, meaning it increases the probability that the defective channel will be open and allow chloride ions pass through the channel pore.

Name: Ivacaftor 
CAS#: 873054-44-5 
Chemical Formula: C24H28N2O3 
Exact Mass: 392.20999 
Molecular Weight: 392.49072 
Elemental Analysis: C, 73.44; H, 7.19; N, 7.14; O, 12.23

Synonym: VX770; VX 770; VX-770; Ivacaftor; brand name: KALYDECO.

IUPAC/Chemical Name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

SMILES Code: O=C(C1=CNC2=C(C=CC=C2)C1=O)NC3=CC(O)=C(C(C)(C)C)C=C3C(C)(C)C

REFERENCES

1: Davis PB. Therapy for cystic fibrosis--the end of the beginning? N Engl J Med. 2011 Nov 3;365(18):1734-5. PubMed PMID: 22047565.

2: Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. PubMed PMID: 22047557; PubMed Central PMCID: PMC3230303.

3: Kim Chiaw P, Eckford PD, Bear CE. Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy. Essays Biochem. 2011 Sep 7;50(1):233-48. PubMed PMID: 21967060.

4: Pyle LC, Ehrhardt A, Mitchell LH, Fan L, Ren A, Naren AP, Li Y, Clancy JP, Bolger GB, Sorscher EJ, Rowe SM. Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators. Am J Physiol Lung Cell Mol Physiol. 2011 Oct;301(4):L587-97. Epub 2011 Jul 1. PubMed PMID: 21724857; PubMed Central PMCID: PMC3191754.

5: Opar A. Excitement mounts for first disease-modifying cystic fibrosis drugs. Nat Rev Drug Discov. 2011 Jul 1;10(7):479-80. doi: 10.1038/nrd3488. PubMed PMID: 21720393.

6: Sheridan C. First cystic fibrosis drug advances towards approval. Nat Biotechnol. 2011 Jun 7;29(6):465-6. doi: 10.1038/nbt0611-465. PubMed PMID: 21654649.

7: Yu W, Chiaw PK, Bear CE. Probing conformational rescue induced by a chemical corrector of F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutant. J Biol Chem. 2011 Jul 15;286(28):24714-25. Epub 2011 May 21. PubMed PMID: 21602569; PubMed Central PMCID: PMC3137047.

8: Dolgin E. Orphan cystic fibrosis drugs find sister diseases. Nat Med. 2011 Apr;17(4):397. PubMed PMID: 21475214.

9: Dolgin E. Mutation-specific cystic fibrosis treatments on verge of approval. Nat Med. 2011 Apr;17(4):396-7. PubMed PMID: 21475213.

10: Erlinger S. Molecular repair of a defective CFTR protein in cystic fibrosis. Clin Res Hepatol Gastroenterol. 2011 Apr;35(4):254-6. Epub 2011 Feb 23. PubMed PMID: 21349786.

11: Antoniu SA. Cystic fibrosis transmembrane regulator potentiators as promising cystic fibrosis therapies. Expert Opin Investig Drugs. 2011 Mar;20(3):423-5. Epub 2011 Feb 9. PubMed PMID: 21303308.

12: Welsh MJ. Targeting the basic defect in cystic fibrosis. N Engl J Med. 2010 Nov 18;363(21):2056-7. PubMed PMID: 21083391.

13: Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003. PubMed PMID: 21083385; PubMed Central PMCID: PMC3148255.

14: Sloane PA, Rowe SM. Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis. Curr Opin Pulm Med. 2010 Nov;16(6):591-7. Review. PubMed PMID: 20829696.

15: Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30. Epub 2009 Oct 21. PubMed PMID: 19846789; PubMed Central PMCID: PMC2773991.

16: Jones AM, Helm JM. Emerging treatments in cystic fibrosis. Drugs. 2009 Oct 1;69(14):1903-10. doi: 10.2165/11318500-000000000-00000. PubMed PMID: 19747007.

EOS Med Chem produce Ozanimod 1306760-87-1 in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok

Name: Ozanimod
CAS#: 1306760-87-1
Chemical Formula: C23H24N4O3
Exact Mass: 404.18484
Molecular Weight: 404.46
Elemental Analysis: C, 68.30; H, 5.98; N, 13.85; O, 11.87

EOS Med Chem produce Ozanimod  1306760-87-1  in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.
Ozanimod  1306760-87-1  Intermediates, EOS Med Chem have 8; Ozanimod  1306760-87-1  Impurity we have 10, all from GMP, FDA plant.
Now Ozanimod  1306760-87-1  DMF document is preparing.
Until 2016, Aug, Ozanimod  1306760-87-1  more than produced 25kg API, 120kg Intermediates

Ozanimod RPC-1063 1306760-87-1, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile 60899-34-5, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (Z)-N-(4-cyano-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide
Ozanimod Intermediates N-((S)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide 1306763-73-4, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (S)-1-amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride 1306763-57-4, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.Ozanimod Intermediates (S)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-30-3
Ozanimod Intermediates (S)-tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-61-0, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (S)-tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-62-1, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (S)-tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-63-2, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate 1306763-64-3, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 1306763-71-2, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1306763-73-5, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Ozanimod Intermediates (R)-N-((R)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide 1306763-28-9, assay 99% in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Description: Ozanimod, also known as RPC1063, is a selective sphingosine 1 phosphate receptor modulators and methods which may be useful in the treatment of S1P1-​associated diseases.
Synonym: RPC1063; RPC-1063; RPC 1063; Ozanimod.
IUPAC/Chemical Name: (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile
SMILES Code: N#CC1=CC(C2=NC(C3=CC=CC4=C3CC[C@@H]4NCCO)=NO2)=CC=C1OC(C)C

Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

1. Martinborough, Esther; Boehm, Marcus F.; Yeager, Adam Richard; Tamiya, Junko; Huang, Liming; Brahmachary, Enugurthi; Moorjani, Manisha; Timony, Gregg Alan; Brooks, Jennifer L.; Peach, Robert; et al. Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis of aryl(indanyl)​oxadiazoles and their use in the treatment of S1P1-​associated diseases. PCT Int. Appl. (2011), WO 2011060392 A1 20110519.

Selonsertib free base , CAS#: 1448428-04-3

Name:

Selonsertib free base

CAS#: 1448428-04-3 (free base)

Chemical Formula: C24H24FN7O

Exact Mass: 445.20264

Molecular Weight: 445.5

Elemental Analysis: C, 64.71; H, 5.43; F, 4.26; N, 22.01; O, 3.59

Selonsertib free base , CAS#: 1448428-04-3 (free base), until 2016 end, we have produced more than 1000g, to be world biggest supplier.

HPLC 99,%, NMR, MS is ok.

Related CAS #: 1448428-04-3 (free base); 1448428-05-4 (HCl)  

Synonym: GS-4997; GS4997; GS 4997; Selonsertib free base.

IUPAC/Chemical Name: 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

InChi Key: YIDDLAAKOYYGJG-UHFFFAOYSA-N

InChi Code: InChI=1S/C24H24FN7O/c1-14(2)32-13-27-30-23(32)19-5-4-6-22(28-19)29-24(33)17-10-21(15(3)9-18(17)25)31-11-20(26-12-31)16-7-8-16/h4-6,9-14,16H,7-8H2,1-3H3,(H,28,29,33)

SMILES Code: O=C(NC1=NC(C2=NN=CN2C(C)C)=CC=C1)C3=CC(N4C=C(C5CC5)N=C4)=C(C)C=C3F

Description: Selonsertib, also known as GS-4997, is an orally bioavailable inhibitor of apoptosis signal-regulating kinase 1 (ASK1), with potential anti-inflammatory, antineoplastic and anti-fibrotic activities. GS-4997 targets and binds to the catalytic kinase domain of ASK1 in an ATP-competitive manner, thereby preventing its phosphorylation and activation. GS-4997 prevents the production of inflammatory cytokines, down-regulates the expression of genes involved in fibrosis, suppresses excessive apoptosis and inhibits cellular proliferation.

1: Nelson CH, Wang L, Fang L, Weng W, Cheng F, Hepner M, Lin J, Garnett C, Ramanathan S. A Quantitative Framework to Evaluate Proarrhythmic Risk in a First-in-Human Study to Support Waiver of a Thorough QT Study. Clin Pharmacol Ther. 2015 Dec;98(6):630-8. doi: 10.1002/cpt.204. Epub 2015 Sep 29. PubMed PMID: 26259519.

2: Lin JH, Zhang JJ, Lin SL, Chertow GM. Design of a phase 2 clinical trial of an ASK1 inhibitor, GS-4997, in patients with diabetic kidney disease. Nephron. 2015;129(1):29-33. doi: 10.1159/000369152. Epub 2014 Dec 17. PubMed PMID: 25531162.

EOS Med Chem produce NLG919 (GDC-0919) 1402836-58-1 in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok

Name: NLG919 (GDC-0919)

CAS#: 1402836-58-1

Chemical Formula: C18H22N2O

Exact Mass: 282.17321

Molecular Weight: 282.38

Elemental Analysis: C, 76.56; H, 7.85; N, 9.92; O, 5.67

EOS Med Chem produce NLG919 (GDC-0919) 1402836-58-1 in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

NLG919 (GDC-0919) 1402836-58-1 Intermediates, EOS Med Chem have 8; NLG919 (GDC-0919) 1402836-58-1 Impurity we have 10, all from GMP, FDA plant.

Now NLG919 (GDC-0919) 1402836-58-1 DMF document is preparing.

Until 2016, Aug, NLG919 (GDC-0919) 1402836-58-1 more than produced 25kg API, 120kg Intermediates

NLG-919 API and  intermediates 96797-15-8 ≥98.0% 4-Iodo-1-tritylimidazole

NLG-920 API and  intermediates 40138-16-7 ≥98.0% 2-Formylbenzeneboronic acid

NLG-921 API and  intermediates 1402838-08-7 ≥98.0% 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde

Synonym: GDC0919; GDC-0919; GDC 0919; NLG919; NLG 919; NLG-919; RG6078; RG-6078; RG 6078.

IUPAC/Chemical Name: 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

SMILES Code: OC(C1CCCCC1)CC(C2=C3C=CC=C2)N4C3=CN=C4

Description: GDC-0919, also known as NLG919 and RG6078, is an orally available inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), with potential immunomodulating and antineoplastic activities. Upon administration, NLG919 targets and binds to IDO1, a cytosolic enzyme responsible for the oxidation of the essential amino acid tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, this agent increases tryptophan levels, restores the proliferation and activation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, T-lymphocytes, and causes a reduction in tumor-associated regulatory T-cells (Tregs). Activation of the immune system, which is suppressed in many cancers, may induce a cytotoxic T-lymphocyte (CTL) response against the IDO1-expressing tumor cells.

1: Li M, Bolduc AR, Hoda MN, Gamble DN, Dolisca SB, Bolduc AK, Hoang K, Ashley C, McCall D, Rojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn  DH, Johnson TS. The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer. 2014 Jul 7;2:21. doi: 10.1186/2051-1426-2-21.  eCollection 2014. PubMed PMID: 25054064; PubMed Central PMCID: PMC4105871.

EOS Med Chem produce Carfilzomib in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok

EOS Med Chem produce Carfilzomib in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Carfilzomib Intermediates, EOS Med Chem have 8; Carfilzomib Impurity we have 10, all from GMP, FDA plant.

Now Carfilzomib DMF document is preparing.

Until 2016, Aug, Carfilzomib more than produced 25kg API, 120kg Intermediates

Carfilzomib API and  intermediates 247068-85-5 ≥99.0% (2S)-2-Amino-4-methyl-1-[(2R)-2-methyloxiranyl]-1-pentanone trifluoroacetate

Carfilzomib API and  intermediates 868540-16-3 ≥99.0% (alphaS)-alpha-[(4-Morpholinylacetyl)amino]benzenebutanoyl-L-leucyl-L-phenylalanine

Name: Carfilzomib (PR171)

CAS#: 868540-17-4

Chemical Formula: C40H57N5O7

Exact Mass: 719.4258

Molecular Weight: 719.91

Elemental Analysis: C, 66.73; H, 7.98; N, 9.73; O, 15.56

Synonym: PR171; PR-171; PR 171; Carflizomib. brand name: Kyprolis

IUPAC/Chemical Name: (S)-4-methyl-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide

SMILES Code: CC(C)C[C@H](NC([C@@H](NC(CN1CCOCC1)=O)CCC2=CC=CC=C2)=O)C(N[C@@H](CC3=CC=CC=C3)C(N[C@@H](CC(C)C)C([C@]4(C)OC4)=O)=O)=O.

Description: Carfilzomib, also known as PR-171, is a tetrapeptide epoxyketone and an epoxomicin derivate with potential antineoplastic activity. Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme responsible for degrading a large variety of cellular proteins. Inhibition of proteasome-mediated proteolysis results in an accumulation of polyubiquinated proteins, which may lead to cell cycle arrest, induction of apoptosis, and inhibition of tumor growth. Carfilzomib was approved by the FDA for use in patients with relapsed and refractory multiple myeloma on 20 July 2012.

According to Wikipedia, Carfilzomib is derived from epoxomicin, a natural product that was shown by the laboratory of Craig Crews at Yale University to inhibit the proteasome.  The Crews laboratory subsequently invented a more specific derivative of epoxomicin named YU101, which was licensed to Proteolix, Inc.. Scientists at Proteolix modified YU101 to create carfilzomib, which they advanced to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval. Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009. In January 2011, the U.S. FDA granted carfilzomib fast-track status, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib. In December 2011, the FDA granted Onyx standard review designation,  for its new drug application submission based on the 003-A1 study, an open-label, single-arm Phase 2b trial. The trial evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide. Carfilzomib was approved by the FDA for use in patients with relapsed and refractory multiple myeloma on 20 July 2012.  Onyx expects to launch the drug in the U.S. on 1 August 2012. When it launches, it will cost $10,000 per 28-day cycle, making it the most expensive FDA-approved drug for multiple myeloma.  (source: http://en.wikipedia.org/wiki/Carfilzomib).

  

Carfilzomib is a next generation proteasome inhibitor that selectively targets the proteasome with minimal affinity for off-target proteases. To date, carfilzomib has generated a positive signal in multiple early-stage studies with an encouraging safety profile, including low rates of neuropathy, a known side effect of some approved multiple myeloma therapies. Carfilzomib primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S).

  

About epoxomicin : Epoxomicin is a naturally occurring selective proteasome inhibitor with anti-inflammatory activity. It was originally discovered in 1992. (source: http://en.wikipedia.org/wiki/Epoxomicin).  Epoxomicin  has the following chemical name: (2S,3S)-N-((2S,3R)-3-hydroxy-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxobutan-2-yl)-3-methyl-2-((2S,3S)-3-methyl-2-(N-methylacetamido)pentanamido)pentanamide.

  

epoxomicin :

  

  

Chemical Formula: C28H50N4O7

Exact Mass: 554.36795

Molecular Weight: 554.72

Elemental Analysis: C, 60.63; H, 9.09; N, 10.10; O, 20.19

  

Carfilzomib is an epoxomicin derivative. Structurally, carfilzomib possesses the molecular backbone of epoxomicin with 5 different substituted group (see the following graphic A, B, C, D, and E).

  

  

  

REFERENCES

1: Kim KB, Crews CM. From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes. Nat Prod Rep. 2013 May;30(5):600-4. doi: 10.1039/c3np20126k. Review. PubMed PMID: 23575525; PubMed Central PMCID: PMC3815659.

2: Kortuem KM, Stewart AK. Carfilzomib. Blood. 2013 Feb 7;121(6):893-7. doi: 10.1182/blood-2012-10-459883. Review. PubMed PMID: 23393020.

3: Thompson JL. Carfilzomib: a second-generation proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. Ann Pharmacother. 2013 Jan;47(1):56-62. doi: 10.1345/aph.1R561. Epub 2013 Jan 8. Review. PubMed PMID: 23300152.

4: Carfilzomib (Kryprolis) for multiple myeloma. Med Lett Drugs Ther. 2012 Dec 24;54(1406):103-4. Review. PubMed PMID: 23282792.

5: McCormack PL. Carfilzomib: in relapsed, or relapsed and refractory, multiple myeloma. Drugs. 2012 Oct 22;72(15):2023-32. doi: 10.2165/11209010-000000000-00000. Review. PubMed PMID: 22994535.

6: Kuhn DJ, Orlowski RZ, Bjorklund CC. Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs). Curr Cancer Drug Targets. 2011 Mar;11(3):285-95. Review. PubMed PMID: 21247387.

EOS Med Chem produce Afatinib in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok

EOS Med Chem produce Afatinib in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Afatinib Intermediates, EOS Med Chem have 8; Afatinib Impurity we have 10, all from GMP, FDA plant.

Now Afatinib DMF document is preparing.

Until 2016, Aug, Afatinib more than produced 25kg API, 120kg Intermediates

Afatinib API and   intermediates 848133-35-7 ≥98.0% trans-4-Dimethylaminocrotonic acid hydrochloride

Afatinib API and   intermediates 13991-36-1 ≥98.0% 4-Bromocrotonic Acid

Afatinib API and   intermediates 162012-69-3 ≥98.0% 7-Fluoro-6-nitro-4-hydroxyquinazoline

Afatinib API and   intermediates 162012-67-1 ≥98.0% 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-

Afatinib API and   intermediates 179552-73-9 ≥98.0% 7-Chloro-N-(3-chloro-4-fluorophenyl)-6-nitro-4-quinazolinamine

Name: Afatinib free base

CAS#: 439081-18-2 (free base)

Chemical Formula: C24H25ClFN5O3

Exact Mass: 485.163

Molecular Weight: 485.94

Elemental Analysis: C, 59.32; H, 5.19; Cl, 7.30; F, 3.91; N, 14.41; O, 9.88

Description: Afatinib, also know as BIBW 2992, is an orally bioavailable dual receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. EGFR/HER2 tyrosine kinase inhibitor BIBW 2992 irreversibly binds to and inhibits human epidermal growth factor receptors 1 and 2 (EGFR-1; HER2), which may result in the inhibition of tumor growth and angiogenesis. EGFR/HER2 are RTKs that belong to the EGFR superfamily; both play major roles in tumor cell proliferation and tumor vascularization and are overexpressed in many cancer cell types. Afatinib is approved in much of the world (including the United States, Canada, the United Kingdom and Australia) for the treatment of metastatic non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim. It acts as an angiokinase inhibitor.

Synonym: BIBW-2992; BIBW 2992; BIBW2992. Afatinib free base; trade name: Gilotrif, Tomtovok and Tovok.

IUPAC/Chemical Name: (S,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide.

SMILES Code: O=C(NC1=CC2=C(NC3=CC=C(F)C(Cl)=C3)N=CN=C2C=C1O[C@@H]4COCC4)/C=C/CN(C)C

Related:

439081-18-2(Afatinib free base);

850140-73-7 (Afatinib dimaleate)

As of July 2012, it is undergoing Phase III clinical trials for this indication and breast cancer, as well as Phase II trials for prostate  and head and neck cancer,  and a Phase I glioma trial.  Afatinib is not a first-line treatment; it is only used after other therapies have failed. In October 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug. Fall 2010 interim results suggested the drug extended progression-free survival threefold compared to placebo, but did not extend overall survival.  In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion. Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib. Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.

  

  

REFERENCES

 1: Belani CP. The role of irreversible EGFR inhibitors in the treatment of non-small cell lung cancer: overcoming resistance to reversible EGFR inhibitors. Cancer Invest. 2010 May;28(4):413-23. Review. PubMed PMID: 20307200.

2: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Dec;31(10):661-700. PubMed PMID: 20140276.

3: Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010 Mar;29(1):37-48. Review. PubMed PMID: 20127143.

4: Sos ML, Rode HB, Heynck S, Peifer M, Fischer F, Klüter S, Pawar VG, Reuter C, Heuckmann JM, Weiss J, Ruddigkeit L, Rabiller M, Koker M, Simard JR, Getlik M, Yuza Y, Chen TH, Greulich H, Thomas RK, Rauh D. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res. 2010 Feb 1;70(3):868-74. Epub 2010 Jan 26. PubMed PMID: 20103621.

5: Doebele RC, Oton AB, Peled N, Camidge DR, Bunn PA Jr. New strategies to overcome limitations of reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer. Lung Cancer. 2010 Jan 19. [Epub ahead of print] PubMed PMID: 20092908.

6: Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, Koutcher JA, Spassova M, Ouerfelli O, Mellinghoff IK, Zakowski MF, Politi KA, Pao W. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest. 2009 Oct;119(10):3000-10. doi: 10.1172/JCI38746. Epub 2009 Sep 14. PubMed PMID: 19759520; PubMed Central PMCID: PMC2752070.

7: Ocaña A, Amir E. Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions. Cancer Treat Rev. 2009 Dec;35(8):685-91. Epub 2009 Sep 4. Review. PubMed PMID: 19733440.

8: Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer. 2009 Jul;10(4):281-9. Review. PubMed PMID: 19632948; PubMed Central PMCID: PMC2758558.

9: Perera SA, Li D, Shimamura T, Raso MG, Ji H, Chen L, Borgman CL, Zaghlul S, Brandstetter KA, Kubo S, Takahashi M, Chirieac LR, Padera RF, Bronson RT, Shapiro GI, Greulich H, Meyerson M, Guertler U, Chesa PG, Solca F, Wistuba II, Wong KK. HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):474-9. Epub 2009 Jan 2. PubMed PMID: 19122144; PubMed Central PMCID: PMC2626727.

10: Minkovsky N, Berezov A. BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Curr Opin Investig Drugs. 2008 Dec;9(12):1336-46. Review. PubMed PMID: 19037840.

EOS Med Chem produce Crizotinib 877399-52-5 in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok

EOS Med Chem produce Crizotinib 877399-52-5 in GMP plant, C-GMP standard, now COA, NMR, HPLC, MS is ok.

Crizotinib 877399-52-5 Intermediates, EOS Med Chem have 8; Crizotinib 877399-52-5 Impurity we have 10, all from GMP, FDA plant.

Now Crizotinib 877399-52-5 DMF document is preparing.

Until 2016, Aug, Crizotinib 877399-52-5 more than produced 25kg API, 120kg Intermediates

Crizotinib API and  intermediates 877397-65-4 ≥98.0% (S)-1-(2,6-Dichloro-3-fluorophenyl)ethanol

Crizotinib API and  intermediates 330156-50-8 ≥98.0% (R)-1-(2,6-Dichloro-3-fluorophenyl)ethanol

Crizotinib API and  intermediates 756520-66-8 ≥98.0% Benzenemethanol,2,6-dichloro-3-fluoro-a-methyl-

Crizotinib API and  intermediates 877399-00-3 ≥98.0% [5-Bromo-3-[(1R)-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-yl]amine

Name: Crizotinib

CAS#: 877399-52-5

Chemical Formula: C21H22Cl2FN5O

Exact Mass: 449.11854

Molecular Weight: 450.34

Elemental Analysis: C, 56.01; H, 4.92; Cl, 15.74; F, 4.22; N, 15.55; O, 3.55

Description: Crizotinib, also known as PF-02341066, is an orally bioavailable agent belonging to the class of c-met/hepatocyte growth factor receptor (HGFR) tyrosine kinase inhibitors with potential antineoplastic activity. Crizotinib was approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and childre. Crizotinib inhibits the membrane receptor MET and activation of the MET signaling pathway, which may block tumor cell growth, migration and invasion, and tumor angiogenesis in susceptible tumor cell populations. Crizotinib was approved in 2011.

Synonym: PF02341066; PF-02341066; PF 02341066; PF2341066; PF-2341066; PF 2341066; Crizotinib; US brand name: Xalkori;

IUPAC/Chemical Name: (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

SMILES Code: NC1=NC=C(C2=CN(C3CCNCC3)N=C2)C=C1O[C@@H](C4=C(Cl)C=CC(F)=C4Cl)C

1.  Crizotinib's phyisical and chemical properties:

Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation).

    

2 . The solubility of crizotinib:

The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.

  

3. Mechanism of action:

Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d'Origine Nantais (RON). Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases . Crizotinib demonstrated concentration-dependent inhibition of ALK and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.

  

Crizotinib also inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms. Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that crizotinib may also act via inhibition of angiogenesis in malignant tumors.(source: http://en.wikipedia.org/wiki/Crizotinib).

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.

      

REFERENCES

1: Ou SH, Tong WP, Azada M, Siwak-Tapp C, Dy J, Stiber JA. Heart rate decrease during crizotinib treatment and potential correlation to clinical response. Cancer. 2013 Mar 15. doi: 10.1002/cncr.28040. [Epub ahead of print] PubMed PMID: 23505007.

2: Kaneda H, Okamoto I, Nakagawa K. Rapid Response of Brain Metastasis to Crizotinib in a Patient with ALK Rearrangement-Positive Non-Small-Cell Lung Cancer. J Thorac Oncol. 2013 Apr;8(4):e32-3. doi: 10.1097/JTO.0b013e3182843771. PubMed PMID: 23486271.

3: Maillet D, Martel-Lafay I, Arpin D, Pérol M. Ineffectiveness of Crizotinib on Brain Metastases in Two Cases of Lung Adenocarcinoma with EML4-ALK Rearrangement. J Thorac Oncol. 2013 Apr;8(4):e30-1. doi: 10.1097/JTO.0b013e318288dc2d. PubMed PMID: 23486270.

4: Pilotto S, Peretti U, Novello S, Rossi G, Milella M, Giaj Levra M, Ciuffreda L, Massari F, Brunelli M, Tortora G, Bria E. PROFILing non-small-cell lung cancer patients for treatment with crizotinib according to anaplastic lymphoma kinase abnormalities: translating science into medicine. Expert Opin Pharmacother. 2013 Apr;14(5):597-608. doi: 10.1517/14656566.2013.778828. Epub 2013 Mar 9. PubMed PMID: 23472711.

5: Sun Y, Nowak KA, Zaorsky NG, Winchester CL, Dalal K, Giacalone NJ, Liu N, Werner-Wasik M, Wasik MA, Dicker AP, Lu B. ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. Mol Cancer Ther. 2013 Feb 26. [Epub ahead of print] PubMed PMID: 23443800.

6: Huang D, Kim DW, Kotsakis A, Deng S, Lira P, Ho SN, Lee NV, Vizcarra P, Cao JQ, Christensen JG, Kim TM, Sun JM, Ahn JS, Ahn MJ, Park K, Mao M. Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics. 2013 Feb 20. doi:pii: S0888-7543(13)00034-7. 10.1016/j.ygeno.2013.02.006. [Epub ahead of print] PubMed PMID: 23434628.

7: Zheng X, He K, Zhang L, Yu J. Crizotinib induces PUMA-dependent apoptosis in colon cancer cells. Mol Cancer Ther. 2013 Feb 20. [Epub ahead of print] PubMed PMID: 23427294.

8: Srivastava N, VanderLaan PA, Kelly CP, Costa DB. Esophagitis: a novel adverse event of crizotinib in a patient with ALK-positive non-small-cell lung cancer. J Thorac Oncol. 2013 Mar;8(3):e23-4. doi: 10.1097/JTO.0b013e31827e2451. PubMed PMID: 23407563.

9: Browning ET, Weickhardt AJ, Camidge DR. Response to crizotinib rechallenge after initial progression and intervening chemotherapy in ALK lung cancer. J Thorac Oncol. 2013 Mar;8(3):e21. doi: 10.1097/JTO.0b013e31827a892c. PubMed PMID: 23407562.

10: Nonaka S, Yamaguchi S, Nagasawa T, Tahara M. [Pharmacology profile of crizotinib (Xalkori(®)Capsules) and clinical findings on this drug]. Nihon Yakurigaku Zasshi. 2013 Feb;141(2):106-13. Japanese. PubMed PMID: 23391552.

EOS Med Chem produce 60410-16-4 to be China biggest

CBNumber: CB3434428
Chemical Name: (1R,3S)-4-CYCLOPENTENE-1,3-DIOL 1-ACETATE
Molecular Formula: C7H10O3
Formula Weight: 142.15
CAS No.: 60410-16-4

EOS Med Chem produce 60410-16-4 to be China biggest.
60410-16-4 HPLC 99%, NMR, MS, COA is OK.
60410-16-4 Size batch could be 100kg.

EOS Med Chem produce 64248-60-8 2,6-Difluorobenzotrifluoride to be China biggest

EOS Med Chem produce 64248-60-8 2,6-Difluorobenzotrifluoride to be China biggest.

64248-60-8 2,6-Difluorobenzotrifluoride HPLC 99%, NMR, MS, COA is OK.

64248-60-8 2,6-Difluorobenzotrifluoride Size batch could be 1000kg.

331-25-9 3-Fluorophenylacetic acid Assay more than 99%, NMR, HPLC, MS is ok

Since 2008, we start to produce 331-25-9 3-Fluorophenylacetic acid, until 2016, we could be 331-25-9 3-Fluorophenylacetic acid one of world biggest supplier.

Each year, we exported more than 10T to all the world.

My standard could be Japan stand.

331-25-9 3-Fluorophenylacetic acid Assay more than 99%, NMR, HPLC, MS is ok.

Glad to serve you.

HBTU biggest supplier

HBTU 94790-37-1 is a commonly used coupling reagent, and can be used in solid phase peptide synthesis. It is reported to convert carboxylic acids into azides efficiently and practically. This process may be used with a wide range of carboxylic acids including N-protected amino acids. It has also been reported to be useful in one-pot synthesis of dipeptidyl urea esters, ureas, and carbamates from acids.

1. Sureshbabu, V.V., et al. 2010. Org. Biomol. Chem. 8: 835-840. PMID: 20135041

EOS Med Chem produce HBTU 94790-37-1 to be China biggest.

HBTU 94790-37-1 HPLC 99%, NMR, MS, COA is OK.

HBTU 94790-37-1 Size batch could be 100kg.

HATU biggest

Name: HATU

CAS#: 148893-10-1

Chemical Formula: C10H15F6N6OP

Exact Mass:

Molecular Weight: 380.24

Elemental Analysis: C, 31.59; H, 3.98; F, 29.98; N, 22.10; O, 4.21; P, 8.15

Synonym: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide

IUPAC/Chemical Name: [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium;hexafluorophosphate

SMILES Code: C/[N+](C)=C(N(C)C)\ON1N=NC2=CC=CN=C21.F[P-](F)(F)(F)(F)F

Description: HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) is a reagent used in peptide coupling chemistry to generate an active ester from a carboxylic acid. HATU is used along with Hünig's base (N,N-diisopropylethylamine, DIPEA) to form amide bonds. Generally DMF is used as solvent, although other polar organic solvents can also be used. (Source: https://en.wikipedia.org/wiki/HATU).

1: Aaronson JG, Klein LJ, Momose AA, O'Brien AM, Shaw AW, Tucker TJ, Yuan Y, Tellers DM. Rapid HATU-mediated solution phase siRNA conjugation. Bioconjug Chem. 2011 Aug 17;22(8):1723-8. doi: 10.1021/bc2001227. Epub 2011 Jul 11. PubMed PMID: 21744777.

2: Hołyńska M, Kubiak M. Supramolecular motifs in the first structures of organic carboxylate salts of 1-(diaminomethylene)thiourea (HATU). Acta Crystallogr C. 2009 Aug;65(Pt 8):o410-3. doi: 10.1107/S0108270109026390. Epub 2009 Jul 15. PubMed PMID: 19652326.

3: Xiao Z, Yang MG, Li P, Carter PH. Synthesis of 3-substituted-4(3H)-quinazolinones via HATU-mediated coupling of 4-hydroxyquinazolines with amines. Org Lett. 2009 Mar 19;11(6):1421-4. doi: 10.1021/ol802946p. PubMed PMID: 19243133.

4: Yung A, Papworth-Smith J, Wilkinson SM. Occupational contact urticaria from the solid-phase peptide synthesis coupling agents HATU and HBTU. Contact Dermatitis. 2003 Aug;49(2):108-9. PubMed PMID: 14641366.