AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Genistein

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Jun 102016
 

Genistein.svg

Genistein

5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; Baichanin A; Bonistein; 4’,5,7-Trihydroxyisoflavone; GeniVida; Genisteol; NSC 36586; Prunetol; Sophoricol;

CAS Number: 446-72-0
 BIO-300; G-2535; PTI-G-4660; SIPI-9764-I; PTIG-4660; SIPI-9764I
Molecular form.: C₁₅H₁₀O₅
Appearance: Light Tan to Light Yellow Solid
Melting Point: >277°C (dec.)
Mol. Weight: 270.24

Genistein , an isoflavone found in many Fabaceae plants and important non-nutritional constituent of soybeans (Glycine max Merill), is a well-known plant metabolite from phenylpropanoid pathway, chiefly because of its presence in numerous phytoestrogenic dietary supplements. In fact, the compound also strives for higher medicinal status, undergoing dozens of clinical trials for various ailments, from osteoporosis to cancer

IR (KBr, cm–1; inter alia): 3411, 3104, 1651, 1615, 1570, 1519, 1504, 1424, 1361, 1309, 1202, 1179, 1145, 1043, 911, 840, 790.
1H NMR (200 MHz, THF-d8), δ (ppm): 6.17 (d, J = 2,2 Hz, 1H); 6.26 (d, J = 2,2 Hz, 1H); 6.78 (m, 2H); 7.41 (m, 2H); 8.02 (s, 1H); 8.50 (bs, 1H); 9.34 (bs, 1H); 13.02 (s, 1H).
13C NMR (THF-d8), δ (ppm): 94.13; 99.73; 106.20; 115.82; 122.95; 124.17; 130.84; 153.78; 158.73; 159.08; 164.24; 165.16; 181.46.
 

An EGFR/DNA topoisomerase II inhibitor potentially for the treatment of bladder cancer and prostate cancer.

NMR

Genistein; CAS: 446-72-0

REF http://www.wangfei.ac.cn/nmrspectra/7/1/30

SEE https://www.google.com/patents/EP2373326A1?cl=en

Genistein is an angiogenesis inhibitor and a phytoestrogen and belongs to the category of isoflavones. Genistein was first isolated in 1899 from the dyer’s broom, Genista tinctoria; hence, the chemical name. The compound structure was established in 1926, when it was found to be identical with prunetol. It was chemically synthesized in 1928.[1]

Natural occurrences

Isoflavones such as genistein and daidzein are found in a number of plants including lupin, fava beans, soybeans, kudzu, andpsoralea being the primary food source,[2][3] also in the medicinal plants, Flemingia vestita[4] and F. macrophylla,[5][6] and coffee.[7] It can also be found in Maackia amurensis cell cultures.[8]

Extraction and purification

Most of the isoflavones in plants are present in a glycosylated form. The unglycosylated aglycones can be obtained through various means such as treatment with the enzyme β-glucosidase, acid treatment of soybeans followed by solvent extraction, or by chemical synthesis.[9] Acid treatment is a harsh method as concentrated inorganic acids are used. Both enzyme treatment and chemical synthesis are costly. A more economical process consisting of fermentation for in situ production of β-glucosidase to isolate genistein has been recently investigated.[10]

 

Biological effects

Besides functioning as antioxidant and anthelmintic, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen. Isoflavones also produce non-hormonal effects.

Molecular function

Genistein influences multiple biochemical functions in living cells:

Activation of PPARs

Isoflavones genistein and daidzein bind to and transactivate all three PPAR isoforms, α, δ, and γ.[18] For example, membrane-bound PPARγ-binding assay showed that genistein can directly interact with the PPARγ ligand binding domain and has a measurable Ki of 5.7 mM.[19] Gene reporter assays showed that genistein at concentrations between 1 and 100 uM activated PPARs in a dose dependent way in KS483 mesenchymal progenitor cells, breast cancer MCF-7 cells, T47D cells and MDA-MD-231 cells, murine macrophage-like RAW 264.7 cells, endothelial cells and in Hela cells. Several studies have shown that both ERs and PPARs influenced each other and therefore induce differential effects in a dose-dependent way. The final biological effects of genistein are determined by the balance among these pleiotrophic actions.[18][20][21]

Tyrosine kinase inhibitor

The main known activity of genistein is tyrosine kinase inhibitor, mostly of epidermal growth factor receptor (EGFR). Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades.

Redox-active — not only antioxidant

Genistein may act as direct antioxidant, similar to many other isoflavones, and thus may alleviate damaging effects of free radicals in tissues.[22][23]

The same molecule of genistein, similar to many other isoflavones, by generation of free radicals poison topoisomerase II, an enzyme important for maintaining DNA stability.[24][25][26]

Human cells turn on beneficial, detoxyfying Nrf2 factor in response to genistein insult. This pathway may be responsible for observed health maintaining properities of small doses of genistein.[27]

Anthelmintic

The root-tuber peel extract of the leguminous plant Felmingia vestita is the traditional anthelmitic of the Khasi tribes of India. While investigating its anthelmintic activity, genistein was found to be the major isoflavone responsible for the deworming property.[4][28] Genistein was subsequently demonstrated to be highly effective against intestinal parasitessuch as the poultry cestode Raillietina echinobothrida,[28] the pork trematode Fasciolopsis buski,[29] and the sheep liver fluke Fasciola hepatica.[30] It exerts its anthelmintic activity by inhibiting the enzymes of glycolysis and glycogenolysis,[31][32] and disturbing the Ca2+ homeostasis and NO activity in the parasites.[33][34] It has also been investigated inhuman tapeworms such as Echinococcus multilocularis and E. granulosus metacestodes that genistein and its derivatives, Rm6423 and Rm6426, are potent cestocides.[35]

Atherosclerosis

Genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte–endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis.[36]

Cancer links

Genistein and other isoflavones have been identified as angiogenesis inhibitors, and found to inhibit the uncontrolled cell growth of cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival (growth factors). Various studies have found that moderate doses of genistein have inhibitory effects on cancersof the prostate,[37][38] cervix,[39] brain,[40] breast[37][41][42] and colon.[16] It has also been shown that genistein makes some cells more sensitive to radio-therapy.;[43] although, timing of phytoestrogen use is also important. [43]

Genistein’s chief method of activity is as a tyrosine kinase inhibitor. Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades. Inhibition of DNA topoisomerase II also plays an important role in the cytotoxic activity of genistein.[25][44] Genistein has been used to selectively target pre B-cells via conjugation with an anti-CD19 antibody.[45]

Studies on rodents have found genistein to be useful in the treatment of leukemia, and that it can be used in combination with certain other antileukemic drugs to improve their efficacy.[46]

Estrogen receptor — more cancer links

Due to its structure similarity to 17β-estradiol (estrogen), genistein can compete with it and bind to estrogen receptors. However, genistein shows much higher affinity towardestrogen receptor β than toward estrogen receptor α.[47]

Data from in vitro and in vivo research confirms that genistein can increase rate of growth of some ER expressing breast cancers. Genistein was found to increase the rate of proliferation of estrogen-dependent breast cancer when not cotreated with an estrogen antagonist.[48][49][50] It was also found to decrease efficiency of tamoxifen and letrozole – drugs commonly used in breast cancer therapy.[51][52] Genistein was found to inhibit immune response towards cancer cells allowing their survival.[53]

Effects in males

Isoflavones can act like estrogen, stimulating development and maintenance of female characteristics, or they can block cells from using cousins of estrogen. In vitro studies have shown genistein to induce apoptosis of testicular cells at certain levels, thus raising concerns about effects it could have on male fertility;[54] however, a recent study found that isoflavones had “no observable effect on endocrine measurements, testicular volume or semen parameters over the study period.” in healthy males given isoflavone supplements daily over a 2-month period.[55]

Carcinogenic and toxic potential

Genistein was, among other flavonoids, found to be a strong topoisomerase inhibitor, similarly to some chemotherapeutic anticancer drugs ex. etoposide and doxorubicin.[24][56]In high doses it was found to be strongly toxic to normal cells.[57] This effect may be responsible for both anticarcinogenic and carcinogenic potential of the substance.[26][58] It was found to deteriorate DNA of cultured blood stem cells, what may lead to leukemia.[59] Genistein among other flavonoids is suspected to increase risk of infant leukemia when consumed during pregnancy.[60][61]

Sanfilippo syndrome treatment

Genistein decreases pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by adequate dose of genistein.[62] Genistein was found to also possess toxic properties toward brain cells.[57] Among many pathways stimulated by genistein, autophagy may explain the observed efficiency of the substance as autophagy is significantly impaired in the disease.[63][64]

Related compounds

Glycosides

Genistin is the 7-O-beta-D-glucoside of genistein.

Acetylated compounds

Wighteone is the 6-isopentenyl genistein (6-prenyl-5,7,4′-trihydroxyisoflavone)[citation needed]

Pharmaceutical derivatives

  • KBU2046 under investigation for prostate cancer.[65][66]
  • B43-genistein, an anti-CD19 antibody linked to genistein e.g. for leukemia.[67]
  • Genistein has two known synthesis routes: deoxybenzoin route and chalcone route. Deoxybenzoin route uses friedel-craft reaction, and chalcone route uses aldol condensation as shown in figure 2. Developing synthesis of genistein allows the access to the affordable therapy as well as mass production of commercial genistein supplements. However, it would be recommended to consult with the health care provider and discuss the pros and cons before the use since the effects of genistein on human body are not fully understood yet as discussed above.


MEDIUM_10555_2010_9238_Fig2_HTML.jpg
Figure 2. Synthesis of genistein via deoxybenzoin route or chalcone route. 10

https://chemprojects263sp11.wikispaces.com/genistein

Paper

Identification of Benzopyran-4-one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors
ChemMedChem (2011), 6, (8), 1340-1346

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201100120/abstract

 

PATENT

By Achmatowicz, Osman et al

From Pol., 204473

STR1

 

References

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  52. Jump up^ Tonetti, Debra A.; Zhang, Yiyun; Zhao, Huiping; Lim, Sok-Bee; Constantinou, Andreas I. (2007). “The Effect of the Phytoestrogens Genistein, Daidzein, and Equol on the Growth of Tamoxifen-Resistant T47D/PKCα”. Nutrition and Cancer 58 (2): 222–9.doi:10.1080/01635580701328545. PMID 17640169.
  53. Jump up^ Jiang, Xinguo; Patterson, Nicole M.; Ling, Yan; Xie, Jianwei; Helferich, William G.; Shapiro, David J. (2008). “Low Concentrations of the Soy Phytoestrogen Genistein Induce Proteinase Inhibitor 9 and Block Killing of Breast Cancer Cells by Immune Cells”.Endocrinology 149 (11): 5366–73. doi:10.1210/en.2008-0857. PMC 2584580.PMID 18669594.
  54. Jump up^ Kumi-Diaka, James; Rodriguez, Rosanna; Goudaze, Gould (1998). “Influence of genistein (4′,5,7-trihydroxyisoflavone) on the growth and proliferation of testicular cell lines”. Biology of the Cell 90 (4): 349–54. doi:10.1016/S0248-4900(98)80015-4.PMID 9800352.
  55. Jump up^ Mitchell, Julie H.; Cawood, Elizabeth; Kinniburgh, David; Provan, Anne; Collins, Andrew R.; Irvine, D. Stewart (2001). “Effect of a phytoestrogen food supplement on reproductive health in normal males”. Clinical Science 100 (6): 613–8. doi:10.1042/CS20000212.PMID 11352776.
  56. Jump up^ Lutz, Werner K.; Tiedge, Oliver; Lutz, Roman W.; Stopper, Helga (2005). “Different Types of Combination Effects for the Induction of Micronuclei in Mouse Lymphoma Cells by Binary Mixtures of the Genotoxic Agents MMS, MNU, and Genistein”. Toxicological Sciences 86 (2): 318–23. doi:10.1093/toxsci/kfi200. PMID 15901918.
  57. ^ Jump up to:a b Jin, Ying; Wu, Heng; Cohen, Eric M.; Wei, Jianning; Jin, Hong; Prentice, Howard; Wu, Jang-Yen (2007). “Genistein and daidzein induce neurotoxicity at high concentrations in primary rat neuronal cultures”. Journal of Biomedical Science 14 (2): 275–84.doi:10.1007/s11373-006-9142-2. PMID 17245525.
  58. Jump up^ Schmidt, Friederike; Knobbe, Christiane; Frank, Brigitte; Wolburg, Hartwig; Weller, Michael (2008). “The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines”. Oncology Reports 19 (4): 1061–6.doi:10.3892/or.19.4.1061. PMID 18357397.
  59. Jump up^ van Waalwijk van Doorn-Khosrovani, Sahar Barjesteh; Janssen, Jannie; Maas, Lou M.; Godschalk, Roger W. L.; Nijhuis, Jan G.; van Schooten, Frederik J. (2007). “Dietary flavonoids induce MLL translocations in primary human CD34+ cells”. Carcinogenesis 28(8): 1703–9. doi:10.1093/carcin/bgm102. PMID 17468513.
  60. Jump up^ Spector, Logan G.; Xie, Yang; Robison, Leslie L.; Heerema, Nyla A.; Hilden, Joanne M.; Lange, Beverly; Felix, Carolyn A.; Davies, Stella M.; Slavin, Joanne; Potter, John D.; Blair, Cindy K.; Reaman, Gregory H.; Ross, Julie A. (2005). “Maternal Diet and Infant Leukemia: The DNA Topoisomerase II Inhibitor Hypothesis: A Report from the Children’s Oncology Group”. Cancer Epidemiology Biomarkers & Prevention 14 (3): 651–5. doi:10.1158/1055-9965.EPI-04-0602. PMID 15767345.
  61. Jump up^ Azarova, Anna M.; Lin, Ren-Kuo; Tsai, Yuan-Chin; Liu, Leroy F.; Lin, Chao-Po; Lyu, Yi Lisa (2010). “Genistein induces topoisomerase IIbeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia”. Biochemical and Biophysical Research Communications 399 (1): 66–71. doi:10.1016/j.bbrc.2010.07.043.PMC 3376163. PMID 20638367.
  62. Jump up^ Piotrowska, Ewa; Jakóbkiewicz-Banecka, Joanna; Barańska, Sylwia; Tylki-Szymańska, Anna; Czartoryska, Barbara; Węgrzyn, Alicja; Węgrzyn, Grzegorz (2006). “Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses”. European Journal of Human Genetics 14(7): 846–52. doi:10.1038/sj.ejhg.5201623. PMID 16670689.
  63. Jump up^ Ballabio, A. (2009). “Disease pathogenesis explained by basic science: Lysosomal storage diseases as autophagocytic disorders”. International Journal of Clinical Pharmacology and Therapeutics 47 (Suppl 1): S34–8. doi:10.5414/cpp47034.PMID 20040309.
  64. Jump up^ Settembre, Carmine; Fraldi, Alessandro; Jahreiss, Luca; Spampanato, Carmine; Venturi, Consuelo; Medina, Diego; de Pablo, Raquel; Tacchetti, Carlo; Rubinsztein, David C.; Ballabio, Andrea (2007). “A block of autophagy in lysosomal storage disorders”. Human Molecular Genetics 17 (1): 119–29. doi:10.1093/hmg/ddm289. PMID 17913701.
  65. Jump up^ Xu, Li; Farmer, Rebecca; Huang, Xiaoke; Pavese, Janet; Voll, Eric; Irene, Ogden; Biddle, Margaret; Nibbs, Antoinette; Valsecchi, Matias; Scheidt, Karl; Bergan, Raymond (2010). “Abstract B58: Discovery of a novel drug KBU2046 that inhibits conversion of human prostate cancer to a metastatic phenotype”. Cancer Prevention Research 3 (12 Supplement): B58. doi:10.1158/1940-6207.PREV-10-B58.
  66. Jump up^ “New Drug Stops Spread of Prostate Cancer” (Press release). Northwestern University. April 3, 2012. Retrieved September 27, 2014.
  67. Jump up^ Chen, Chun-Lin; Levine, Alexandra; Rao, Asha; O’Neill, Karen; Messinger, Yoav; Myers, Dorothea E.; Goldman, Frederick; Hurvitz, Carole; Casper, James T.; Uckun, Fatih M. (1999). “Clinical Pharmacokinetics of the CD19 Receptor-Directed Tyrosine Kinase Inhibitor B43-Genistein in Patients with B-Lineage Lymphoid Malignancies”. The Journal of Clinical Pharmacology 39 (12): 1248–55. doi:10.1177/00912709922012051. PMID 10586390.

External links

 

 

Abstract Image

Development and scale-up of the synthetic process for genistein preparation are described. The process was designed with consideration for environmental and economical aspects and optimized in a laboratory scale. In a scale up, on every step quantity of the environmentally unfriendly substrates or solvents was reduced without compromising the quality of the final product, and the waste load was significantly diminished. The optimal duration times of the individual stages were determined, and the number of operations was reduced, leading to lowering of energy consumption. Elaborated process secures good yield and quality expected for pharmaceutical substances.

Technical Process for Preparation of Genistein

Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00425
Publication Date (Web): June 03, 2016
Copyright © 2016 American Chemical Society

 

Genistein
Genistein.svg
Genistein molecule
Names
IUPAC name

5,7-Dihydroxy-3-(4-hydroxyphenyl)chromen-4-one
Other names

4′,5,7-Trihydroxyisoflavone
Identifiers
446-72-0 Yes
ChEBI CHEBI:28088 Yes
ChEMBL ChEMBL44 Yes
ChemSpider 4444448 Yes
DrugBank DB01645 Yes
2826
Jmol 3D model Interactive image
KEGG C06563 Yes
PubChem 5280961
UNII DH2M523P0H Yes
Properties
C15H10O5
Molar mass 270.24 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Akiyama, T., et al.: J. Biol. Chem., 262, 5592 (1987), O’Dell, T.J., et al.: Nature, 353, 588 (1991), Aharonovits, O., et al.: Biochim Biophys. Acta, 1112, 181 (1992), Platanias, L.C., et al.: J. Biol. Chem., 267, 24053 (1992), Yoshida, H., et al.: Biochim. Biophys. Acta, 1137, 321 (1992), Uckun, F.M., et al.: Science, 267, 886 (1995), Merck Index 12th ed. 4395, Huang, R.Q.; Fang, M.J.; Dillon, G.H., Mol. Brain Res. 67: 177-183 (1999)

 

//////BIO-300,  G-2535,  PTI-G-4660,  SIPI-9764-I,  PTIG-4660,  SIPI-9764I, Genistein, phase 2, national cancer institute

Oc1ccc(cc1)C\3=C\Oc2cc(O)cc(O)c2C/3=O

Supporting Info

 

Start of the Euro 2016

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ND 630, NDI 010976

 Uncategorized  Comments Off on ND 630, NDI 010976
Jun 102016
 

str1

 

ndi molecul
str1
ND 630, NDI 010976,  ND-630, NDI-010976
1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid
2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid
2-[1-[(2R)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid
CAS 1434635-54-7
Thieno[2,​3-​d]​pyrimidine-​3(2H)​-​acetic acid, 1,​4-​dihydro-​1-​[(2R)​-​2-​(2-​methoxyphenyl)​-​2-​[(tetrahydro-​2H-​pyran-​4-​yl)​oxy]​ethyl]​-​α,​α,​5-​trimethyl-​6-​(2-​oxazolyl)​-​2,​4-​dioxo-
Molecular Formula: C28H31N3O8S
Molecular Weight: 569.62604 g/mol
Company Nimbus Therapeutics LLC
Description Small molecule allosteric inhibitor of acetyl-coenzyme A carboxylase alpha (ACACA; ACC1) and acetyl-coenzyme A carboxylase beta (ACACB; ACC2)
Molecular Target Acetyl-Coenzyme A carboxylase alpha (ACACA) (ACC1) ; Acetyl-Coenzyme A carboxylase beta (ACACB) (ACC2)
Mechanism of Action Acetyl-coenzyme A carboxylase alpha (ACACA) (ACC1) inhibitor; Acetyl-coenzyme A carboxylase beta (ACACB) (ACC2) inhibitor
Therapeutic Modality Small molecule
Preclinical Diabetes mellitus; Hepatocellular carcinoma; Metabolic syndrome; Non-alcoholic steatohepatitis; Non-small cell lung cancer
CHEMBL3407547.png

Acetyl CoA carboxylase 1/2 allosteric inhibitors – Nimbus Therapeutics

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting, San Francisco, CA, USA

Nimbus compounds targeting liver disease in rat models

Data were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND-630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively, EC50 values in HepG2 serum free and 10% serum of 9 and 66 nM, respectively, and 2-fold C2C12 fatty acid oxidation (FAOxn) stimulation at 200 nM. Rat FASyn (synthase), malonyl-CoA (liver) and malonyl-COA (muscle) respective ED50 values were 0.14 mg/kg po, 0.8 and 3 mg/kg. The rat respiratory quotient (RQ) MED was 3 mg/kg po. ADME data showed low multispecies intrinsic clearance (human, mouse, rat, dog, monkey). NDI-010976 was eliminated predominantly as the parent drug. Additionally, P450 inhibition was > 50 microM. In liver and muscle, NDI-010976 modulated key metabolic parameters including a dose-dependent reduction in the formation of the enzymatic product of acetyl coA carboxyloase malonyl coA; the ED50 value was lower in muscle. The drug also decreased FASyn dose dependently and increased fatty acid oxidation in the liver (EC50 = 0.14 mg/kg). In 28-day HS DIO rats, NDI-010976 favorably modulated key plasma and liver lipids, including decreasing liver free fatty acid, plasma triglycerides and plasma cholesterol; this effect was also seen in 37-day ZDF rats

 PATENT

http://www.google.com/patents/WO2013071169A1?cl=en

 

Example 76: Synthesis of 2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid (1-181).

Figure imgf000193_0001

Synthesis of compound 76.1. Into a 250-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed oxan-4-ol (86 g, 842.05 mmol, 2.01 equiv) and FeCl3 (10 g). This was followed by the addition of 57.2 (63 g, 419.51 mmol, 1.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 500 mL of H20. The resulting solution was extracted with 3×1000 mL of ethyl acetate and the organic layers combined. The resulting solution was extracted with 3×300 mL of sodium chloride (sat.) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 22 g (21%) of 76.1 as a white solid.

Synthesis of compound 76.2. The enantiomers of 76.1 (22g) were resolved by chiral preparative HPLC under the following conditions (Gilson Gx 281): Column: Venusil Chiral OD-

H, 21.1 *25 cm, 5 μιη; mobile phase: hexanes (0.2% TEA) and ethanol (0.2% TEA) (hold at 10% ethanol (0.2%TEA) for 13 min); detector: UV 220/254 nm. 11.4 g (52%) of 76.2 were obtained as a white solid.

Synthesis of compound 76.3. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 70.1 (12 g, 20.49 mmol, 1.00 equiv), tetrahydrofuran (200 mL), 76.2 (6.2 g, 24.57 mmol, 1.20 equiv) and DIAD (6.5 g, 32.18 mmol, 1.57 equiv). This was followed by the addition of a solution of triphenylphosphane (8.4 g, 32.03 mmol, 1.56 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at 0 °C in 60 min. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 17 g (crude) of 76.3 as a white solid.

Synthesis of compound 76.4. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 76.3 (17 g, crude), toluene (300 mL), Pd(PPh3)4 (1.7 g, 1.47 mmol, 0.07 equiv) and 2-(tributylstannyl)-l,3-oxazole (8.6 g, 24.02 mmol, 1.16 equiv). The resulting solution was stirred overnight at 110 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). Purification afforded 6 g of 76.4 as a white solid.

Synthesis of compound 1-181. Into a 250-mL 3-necked round-bottom flask, was placed 76.4 (6 g, 7.43 mmol, 1.00 equiv), tetrahydrofuran (100 mL), TBAF (2.3 g, 8.80 mmol,

I .18 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50: 1). This resulted in 3.4 g (80%) of Compound 1-181 as a white solid.

Purification: MS (ES): m/z 570 (M+H)+, 592 (M+Na)+.

1H NMR (300 MHz, DMSO- d6): δ 1.22-1.36 (m, 2H), 1.62 (m, 8H), 2.75 (s, 3H), 3.20-3.39 (m, 3H), 3.48-3.58 (m, 2H), 3.80 (s, 3H), 3.85-4.20 (m, 2H), 5.30 (m, 1H), 7.03 (m, 2H), 7.33-7.50 (m, 3H), 8.2 (s, 1H).

Figure imgf000193_0001

ndi molecul

Preparation of ND-630.1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid, ND-630, was prepared as described (49)…….http://www.pnas.org/content/113/13/E1796.full.pdf
Harriman GC, Masse CE, Harwood HJ, Jr, Baht S, Greenwood JR (2013) Acetyl-CoA
carboxylase inhibitors and uses thereof. US patent publication US 2013/0123231.
CLIPS

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting,  San Francisco, CA, USA

Conference: 66th Annual Meeting of the American Association for the Study of Liver Diseases Conference Start Date: 13-Nov-2015

…candidates for minimizing IR injury in liver transplantation.Nimbus compounds targeting liver disease in rat modelsData were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND–630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively…

REFERENCES

November 13-17 2015
The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting  San Francisco, CA, USA ,
WO-2014182943

WO-2014182951 

WO-2014182945

WO-2014182950 

Patent ID Date Patent Title
US2015203510 2015-07-23 ACC INHIBITORS AND USES THEREOF
US2013123231 2013-05-16 ACC INHIBITORS AND USES THEREOF

/////// ND 630, NDI 010976,  ND-630, NDI-010976, NIMBUS, GILEAD, 1434635-54-7

O=C(O)C(C)(C)N4C(=O)c1c(C)c(sc1N(C[C@H](OC2CCOCC2)c3ccccc3OC)C4=O)c5ncco5

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Pexidartinib

 orphan status, Phase 3 drug, Uncategorized  Comments Off on Pexidartinib
Jun 102016
 

Pexidartinib

PLX-3397

5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine

N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine

Phase III

A Multi-targeted tyrosine kinase inhibitor potentially for the treatment of tenosynovial giant cell tumor (TGCT).

CAS No.: 1029044-16-3
Mol. Formula: C20H15ClF3N5
Mol. Weight: 417.81
  • Pexidartinib; 1029044-16-3; PLX-3397; 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine; 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine; 5-[(5-Chloro-1h-Pyrrolo[2,3-B]pyridin-3-Yl)methyl]-N-{[6-(Trifluoromethyl)pyridin-3-Yl]methyl}pyridin-2-Amine;
  • Originator Plexxikon
  • Developer Barbara Ann Karmanos Cancer Institute; Columbia University; Merck & Co; National Cancer Institute (USA); Plexxikon; University of California at San Francisco
  • Class 2 ring heterocyclic compounds; Antineoplastics; Fluorine compounds; Pyridines; Pyrroles; Small molecules
  • Mechanism of Action Fms-like tyrosine kinase 3 inhibitors; Immunomodulators; Macrophage colony stimulating factor receptor antagonists; Proto oncogene protein c-akt inhibitors; Proto oncogene protein c-kit inhibitors
  • Orphan Drug Status Yes – Giant cell tumour of tendon sheath; Pigmented villonodular synovitis
  • Phase III Pigmented villonodular synovitis
  • Phase II Glioblastoma; Malignant melanoma; Prostate cancer
  • Phase I/II Breast cancer; Leukaemia; Peripheral nervous system diseases; Sarcoma; Solid tumours
  • Phase I Gastrointestinal stromal tumours
  • No development reported Neurological disorders; Rheumatoid arthritis
  • Discontinued Acute myeloid leukaemia; Hodgkin’s disease

Most Recent Events

  • 25 May 2016 Plexxikon and AstraZeneca plan the MEDIPLEX phase I trial for Solid tumours (Combination therapy, Metastatic disease) in France (NCT02777710)
  • 05 Apr 2016 Daiichi Sankyo plans a phase I trial for Solid tumours (Late-stage disease, Second-line therapy or greater) in Taiwan (PO) (NCT02734433)
  • 11 Mar 2016 Plexxikon re-initiates enrolment in a phase Ib trial in Solid tumours and Gastrointestinal stromal tumours in USA (NCT02401815)

 

Multi-targeted receptor tyrosine kinase inhibitor of CSF1R, c-Kit, and FLT3 (IC50 values 13 nM, 27 nM, and 11 nM, respectively) Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

Plexxikon is conducting phase III clinical studies with PLX-3397 for the treatment of pigmented villonodular synovitis. Phase II clinical studies are ongoing for the oral treatment of melanoma and glioblastoma multiforme. Additional early clinical trials are underway for the treatment of metastatic breast cancer, for the treatment of prostate cancer (adenocarcinoma), and for the treatment of malignant peripheral nerve sheath tumor. No recent development has been reported from preclinical studies for the treatment of systemic lupus erythematosus and for the treatment of multiple sclerosis. Prior to patient enrollment, a phase I clinical trial by Plexxikon for the treatment of rheumatoid arthritis was withdrawn. Daiichi Sankyo (parent of Plexxikon) decided to discontinue phase II trials of the product for the treatment of castration-resistant prostate cancer and for the treatment of Hodgkin’s lymphoma after reviewing its clinical study results and also have discontinued phase II studies for the treatment of acute myeloid leukemia due to strategic reasons.

Pexidartinib.png

In 2014, orphan drug designation was assigned to the compound in the US for the treatment of pigmented villonodular synovitis andf giant cell tumor of the tendon sheath. In 2015, the compound was granted orphan designation in the E.U. for the treatment of tenosynovial giant cell tumor, localised and diffuse type. In the same year, the product was granted breakthrough therapy designation for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity.

C-fms and c-kit arc both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.

c-Fms
C-fms is a member of the family of genes originally isolated from the Susan McDonough strain ot teline sarcoma viruses, The cellular proto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes for the receptor for the macrophage colony-stimuktmg tactor (M- CSF) C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage, and upon binding of Vf-CSF to the extracellular domain of c-fms, the receptor dimeπzes and trans- autophosphorylates cytoplasmic tyrosine residues

M-CSF, first described by Robinson and co-workers (Blood 1969, 33 396-9), is a cytokine that controls the production, differentiation, and function of macrophages M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemota\is, and secondary cytokine production of additional factors in monocytes and macrophages Examples of such additional factors include granulocyte colony stimulating lactor (G-CSF) interleukin-6 (IL-6), and mterleukm-8 (IL-8) M-CSF stimulates hematopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism Furthermore, M-CSF is important in pregnancy Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, lnt J Hematol 1998, 67 109-22) l hc elevated semm levels of M-CSF m early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opm Hematol 1998, 5 181-5)

Related to c-fms and c-kit are two p_latelet -derived growth factor receptors, alpha (i e , pdgfra) and beta (pdgfrb) (PDGF) 1 he gene coding for pdgfra is located on chromosome 4ql 1 -q!2 in the same region of chromosome 4 as the oncogene coding for c-kit The genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5 They are oriented head to tail with the 5-pnme exon of the c-fms gene located only 500 bp from the last 3-pπme exon of the gene coding for pdgfra Most gastrointestinal stromal tumors (GIST) have activating mutations in c-kit and most patients with GISTs respond well to Gleevec, which inhibits c-kit Hemπch et al (Science 2003, 299 “OS-IO) have shown that approximately 35% of GISTs lacking c-krt mutations, have intragenic activation mutations m tht gene encoding pdgfra, and that tumors expressing c-kit or pdgfrd are indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression Thus, c kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms m GISTs [0007} Similarly, the observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation points out a role for c-frns in diseases, such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of c-fms can ameliorate disease associated with increased levels of M-CSF.

c-Kit
The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of melanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded by the Sl locus, and has also been called “kit ligand” (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol 1997, 153:337-344; Vliagoftis, et al,, Clin Immunol 1997, 100:435-440; Broudy, Blood 1997, 90: 1345-1364; Pignon, Hermatol Cell Ther 1997, 39: 1 14-1 16; and Lyman, et al., Blood 1998, 91 : 1 101 -1 134.). Herein the abbreviation SCF refers to the physiological ligand for c-kit.

SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form, a soluble, glycosylated protein which noncovalently dimerizcs. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-kit on germ cells.

 

 

STR1

PATENT

WO 2008063888

 

PATENT

WO 2008064265

 

PATENT

WO 2008064255

PATENT

WO 2012158957

Fragments in the clinic: PLX3397

Practical Fragments covers a wide variety of journals. J. Med. Chem., Bioorg. Med. Chem. Lett., Drug Disc. Today, and ACS Med. Chem. Lett. are all well-represented, but we also range further afield, from biggies such asNature and Science to more niche titles such as ChemMedChem, Acta. Cryst. D., and Anal. Chim. Acta. The increasingly clinical relevance of fragment-based approaches is highlighted by a recent paper by William Tap and a large group of collaborators appearing in the New England Journal of Medicine. This reports on the results of the Daiichi Sankyo (née Plexxikon) drug PLX3397 in a phase I trial for tenosynovial giant-cell tumor, a rare but aggressive cancer of the tendon sheath.

The story actually starts with a 2013 paper by Chao Zhang and his Plexxikon colleagues in Proc. Nat. Acad. Sci. USA. The researchers were interested in inhibiting the enzymes CSF1R (or FMS) and KIT; both kinases are implicated in cancer as well as inflammatory diseases. The team started with 7-azaindole, the same fragment they used to discover vemurafenib. Structural studies of an early derivative, PLX070, revealed a hydrogen bond between the ligand oxygen and a conserved backbone amide. Further building led to PLX647, with good activity against both CSF1R and KIT. Selectivity profiling against a panel of 400 kinases revealed only two others with IC50values < 0.3 µM. The molecule was active in cell-based assays, had good pharmacokinetics in mice and rats, and was active in rodent models of inflammatory disease.

The new paper focuses on the results of a clinical trial with PLX3397, a derivative of PLX647. Despite its close structural similarity to PLX647, it binds to CSF1R in a slightly different manner. Both inhibitors bind to the inactive form of the kinase, but PLX3397 also recruits the so-called juxtamembrane domain of the kinase to stabilize this autoinhibited conformation. Pharmacokinetic and pharmacodynamics studies in animals were also positive.

http://practicalfragments.blogspot.in/2015/10/fragments-in-clinic-plx3397.html

Tenosynovial giant-cell tumor seems to be dependent on CSF1R, so the researchers performed a phase 1 dose-escalation study with an extension in which patients treated with the chosen phase 2 dose were treated longer. Of the 23 patients in this extension, 12 had a partial response and 7 had stable disease. A quick search ofclinicaltrials.gov reveals that PLX3397 is currently in multiple trials for several indications, including a phase 3 trial for giant cell tumor of the tendon sheath.

Several lessons can be drawn from these studies. First, as the authors note, one fragment can give rise to multiple different clinical candidates. Indeed, in addition to vemurafenib, 7-azaindole was also the starting point forAZD5363. This is a good counterargument to those who believe that novelty is essential in fragments.

A second, related point is that selectivity is also not necessary for a fragment. The fact that 7-azaindole comes up so frequently as a kinase-binding fragment has not prevented researchers from growing it into remarkably selective inhibitors. An obvious corollary is that even subtle changes to a molecule can have dramatic effects: the added pyridyl nitrogen in PLX3397 is essential for stabilizing a unique conformation of the enzyme.

 

Patent ID Date Patent Title
US2015265586 2015-09-24 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US2014243365 2014-08-28 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US8722702 2014-05-13 Compounds modulating c-fms and/or c-kit activity and uses therefor
US2014045840 2014-02-13 COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
US2013274259 2013-10-17 KINASE MODULATION AND INDICATIONS THEREFOR
US8404700 2013-03-26 Compounds modulating c-fms and/or c-kit activity and uses therefor
US2011230482 2011-09-22 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY
US7893075 2011-02-22 Compounds modulating c-fms and/or c-kit activity and uses therefor

//////1029044-16-3, Pexidartinib , PLX-3397, PHASE3

FC(F)(F)c1ccc(cn1)CNc2ccc(cn2)Cc4cnc3ncc(Cl)cc34

Start of the Euro 2016

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Gilteritinib for Treatment of Acute Myeloid Leukemia

 Phase 3 drug, Uncategorized  Comments Off on Gilteritinib for Treatment of Acute Myeloid Leukemia
Jun 102016
 

Gilteritinib

ASP-2215

Treatment of Acute Myeloid Leukemia

6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine-2-carboxamide

C29H44N8O3, 552.71

Phase III

A FLT3/AXL inhibitor potentially for the treatment of acute myeloid leukemia.

CAS No. 1254053-43-4

Astellas Pharma  INNOVATOR
Mechanism Of Action Axl receptor tyrosine kinase inhibitors, Fms-like tyrosine kinase 3 inhibitors, Proto oncogene protein c-kit inhibitors
Who Atc Codes L01X-E (Protein kinase inhibitors)
Ephmra Codes L1H (Protein Kinase Inhibitor Antineoplastics)
Indication Cancer, Hepatic impairment

Gilteritinib(ASP-2215) is a potent FLT3/AXL inhibitor with IC50 of 0.29 nM/<1 nM respectively; shows potent antileukemic activity against AML with either or both FLT3-ITD and FLT3-D835 mutations.
IC50 value: 0.29 nM(FLT3); <1 nM(Axl kinase)
Target: FLT3/AXL inhibitor
ASP2215 inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. ASP2215 decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells. ASP2215 may have potential use in treating AML.

SYNTHESIS

STR1

PATENT

WO 2010128659

 

Patent

WO 2015119122

Compound A is 6-ethyl-3 – ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- a (tetrahydro -2H- pyran-4-ylamino) pyrazine-2-carboxamide, its chemical structure is shown below.
[Formula 1]

Gilteritinib fumarate

1254053-84-3.png

2D chemical structure of 1254053-84-3

Gilteritinib fumarate [USAN]

RN: 1254053-84-3

UNII: 5RZZ0Z1GJT

2-Pyrazinecarboxamide, 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-, (2E)-2-butenedioate (2:1)

  • ASP-2215 hemifumarate
  • Molecular Formula, 2C29-H44-N8-O3.C4-H4-O4, Molecular Weight, 1221.5108

Astellas Inititaties Phase 3 Registration Trial of gilteritinib (ASP2215) in Relapsed or Refractory Acute Myeloid Leukemia Patients

gilteritinib-ASP2215

TOKYO, Japan I October 28, 2015 I Astellas Pharma Inc. (TSE:4503) today announced dosing of the first patient in a randomized Phase 3 registration trial of gilteritinib (ASP2215)versus salvage chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The primary endpoint of the trial is overall survival (OS).

Gilteritinibis a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinibhas demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML.

The gilteritinib Phase 3 trial follows a Phase 1/2 trial, which evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in the dose escalation phase. Preliminary data from the Phase 1/2 trial presented at the 2015 American Society of Clinical Oncology annual meeting demonstrated a 57.5 percent overall response rate and a 47.2 percent composite Complete Response (CR) rate (CR + CR with incomplete platelet recovery + CR with incomplete hematologic recovery) in 106 patients with FLT3 mutations who received 80 mg and higher doses. Median duration of response was 18 weeks across all doses and median OS was approximately 27 weeks at 80 mg and above in FLT3 mutation positive patients. Common drug-related adverse events (> 10%) observed in the study were diarrhea (13.4%), fatigue (12.4%) and AST increase (11.3%). At the 450 mg dose, two patients reached dose-limiting toxicity (grade 3 diarrhea and ALT/AST elevation) and the maximum tolerated dose was determined to be 300 mg.

On October 27, 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for SAKIGAKE.

About the Phase 3 Study

The Phase 3 trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in patients with Acute Myeloid Leukemia (AML). The study will enroll 369 patients with FLT3 activating mutation in bone marrow or whole blood, as determined by central lab, AML who are refractory to or have relapsed after first-line AML therapy. Subjects will be randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy consisting of LoDAC (low-dose cytarabine), azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin). The primary endpoint of the trial is OS. For more information about this trial go to www.clinicaltrials.gov, trial identifier NCT02421939.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib.

About Acute Myeloid Leukemia

Acute myeloid leukemia is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the//www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf” target=”_blank” rel=”nofollow”>American Cancer Society, in 2015, there will be an estimated 20,830 new cases of AML diagnosed in the United States, and about 10,460 cases will result in death.

About SAKIGAKE

The SAKIGAKE designation system can shorten the review period in the following three approaches: 1.) Prioritized Consultation 2.) Substantial Pre-application Consultation and 3.) Prioritized Review. Also, the system will promote development with the following two approaches: 4.) Review Partner System (to be conducted by the Pharmaceuticals and Medical Devices Agency) and 5.) Substantial Post-Marketing Safety Measures.

About Astellas

Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. We focus on Urology, Oncology, Immunology, Nephrology and Neuroscience as prioritized therapeutic areas while advancing new therapeutic areas and discovery research leveraging new technologies/modalities. We are also creating new value by combining internal capabilities and external expertise in the medical/healthcare business. Astellas is on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at www.astellas.com/en.

SOURCE: Astellas Pharma

////////1254053-43-4, Gilteritinib, ASP-2215, PHASE 3, ASP 2215, Astellas Pharma, Acute Myeloid Leukemia

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.C(=C/C(=O)O)\C(=O)O

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Ponesimod

 Phase 3 drug, Uncategorized  Comments Off on Ponesimod
Jun 092016
 

Ponesimod.svg

Ponesimod

Phase III

MW 460.97, C23 H25 Cl N2 O4 S

A sphingosine-1-phosphate receptor 1 (S1P1) agonist potentially for the treatment of multiple sclerosis.

  • (2Z,5Z)-5-[[3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylene]-3-(2-methylphenyl)-2-(propylimino)-4-thiazolidinone
  • 5-[3-Chloro-4-[((2R)-2,3-dihydroxypropyl)oxy]benz-(Z)-ylidene]-2-((Z)-propylimino)-3-(o-tolyl)thiazolidin-4-one
  • ACT 128800

ACT-128800; RG-3477; R-3477

CAS No. 854107-55-4

SYNTHESIS

STR1

Ponesimod

str1

str1

 

NMR CDCL3 FROM NET

 

 

STR1

 

 

STR1

 

 

STR1

 

STR1

 

STR1

SEE……http://www.slideserve.com/truda/discovery-of-the-novel-orally-active-s1p-1-receptor-agonist-act-128800-ponesimod

Ponesimod (INN, codenamed ACT-128800) is an experimental drug for the treatment of multiple sclerosis (MS) and psoriasis. It is being developed by Actelion.

The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod’s side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Biology and pharmacology of sphingosine-1-phosphate receptor 1

The past decades have witnessed major advances in the treatment of autoimmune and chronic inflammatory diseases. A plethora of novel therapies targeting specific molecules involved in the inflammatory or immune system activation cascades have become available. These have significantly increased our understanding of disease pathogenesis and improved the management of immune-mediated disorders. However, most of the targeted therapies are biological drugs which need to be injected, are eliminated slowly (e.g. over several weeks) and can lose efficacy or tolerability due to their potential immunogenicity. In an attempt to overcome these hurdles, pharmaceutical research has made considerable efforts to develop novel oral targeted therapies for autoimmune and chronic inflammatory diseases.

Sphingosine-1-phosphate receptor 1 (S1P1R) is one of five known G protein-coupled receptors with nanomolar affinity for the lysophospholipid sphingosine-1-phosphate (S1P), which is generated through physiologic metabolism of the cell membrane constituent sphingomyelin by all cells [Brinkmann, 2007]. S1P receptors, including S1P1R, are widely expressed in many tissues [Chun et al. 2010]. S1P1R expression on lymphocytes controls their egress from thymus and secondary lymphoid organs [Cyster and Schwab, 2012]. Lymphocyte egress requires a gradient of S1P concentration, which is established by a high S1P concentration in blood and lymph compared with a low concentration in the interstitial fluid of lymphoid organs [Grigorova et al. 2009].

Synthetic S1P1 receptor modulators disrupt the interaction of the physiologic S1P ligand with S1P1R by promoting initial activation followed by sustained internalization and desensitization of S1P1R [Hla and Brinkmann, 2011; Pinschewer et al. 2011]. Experiments conducted in animal models of transplant rejection, multiple sclerosis, lupus erythematosus, arthritis and inflammatory bowel disease with the first-generation, nonselective S1P receptor modulator, fingolimod, have demonstrated the potential efficacy of this mode of action across several immune-mediated chronic inflammatory conditions [Brinkmann, 2007]. Fingolimod is a structural analog of sphingosine that is phosphorylated in the body by a sphingosine kinase to generate the bioactive form of the drug, fingolimod phosphate, which binds to multiple S1P receptors [Brinkmann, 2007]. Clinical trials in multiple sclerosis (MS) have confirmed the efficacy of fingolimod in relapsing MS, but not in primary progressive disease, and led to the approval of the first oral medication for the treatment of relapsing forms of MS in 2010 [Kappos et al. 2010].

The mechanism of action of fingolimod has increased our understanding of MS pathogenesis. T and B cells, but not natural killer (NK) cells, express functional S1P1R and are affected by fingolimod [Cyster and Schwab, 2012]. Furthermore, S1P1R is differentially expressed and regulated in functionally distinct subsets of lymphocytes and fingolimod has been shown to predominantly affect naïve T cells and central memory T cells (TCM) while sparing effector memory T cells (TEM), and terminally differentiated effector T cells (TE) in patients with relapsing MS [Mehling et al. 2008, 2011]. This has raised the possibility that, at least in MS, retention of TCM cells, which include pro-inflammatory T helper 17 (Th17) cells, by fingolimod may prevent their accumulation in the cerebrospinal fluid (CSF) and subsequent differentiation to TE cells in the central nervous system (CNS) [Hla and Brinkmann, 2011]. The effects of S1P1R modulation on B cells are less well defined. Recent data from patients with relapsing MS have shown predominant reduction of memory B cells and recently activated memory B cells (CD38int-high) in peripheral blood after treatment with fingolimod [Claes et al. 2014; Nakamura et al. 2014]. As memory B cells are implicated in the pathogenesis of MS and other autoimmune diseases, these observations suggest another potential mechanism underlying the therapeutic effects of S1P1R modulators.

Astrocytes, microglia, oligodendrocytes and neurons express various S1P receptors including S1P1R, S1P3R and S1P5R. Fingolimod has been shown to penetrate the CNS tissues and in vitro studies have shown activation of astrocytes and oligodendrocytes by fingolimod [Foster et al. 2007]. Conditional deletion of S1P1R on neural cells in mice reduced the severity of experimental autoimmune encephalomyelitis (EAE) and reductions in the clinical scores were paralleled by decreased demyelination, axonal loss and astrogliosis [Choi et al. 2011]. Unfortunately, there was no beneficial effect in a recently completed, large study of fingolimod in patients with primary progressive MS [Lublin et al. 2015], suggesting that the direct effect on CNS cells alone may not be sufficient. Taken together, these data suggest the possibility of a direct beneficial effect of S1P1R modulation in the brain of patients with relapsing MS [Dev et al. 2008]; however, its contribution to efficacy relative to the immunological effects remains unclear.

Initial studies in rodents suggested that modulation of S1P3R on cardiac myocytes by fingolimod was associated with a reduction of heart rate (HR) by activation of G-protein-coupled inwardly rectifying potassium channels (GIRK) that regulate pacemaker frequency, and the shape and duration of action potentials [Koyrakh et al. 2005; Camm et al. 2014]. Modulation of S1P2R and S1P3R on myofibroblasts by fingolimod was also shown to stimulate extracellular matrix synthesis [Sobel et al. 2013]. Modulation of these receptors on vascular smooth muscle cells appeared to be associated with vasoconstriction, leading to the slight increase in blood pressure observed with fingolimod treatment [Salomone et al. 2003; Watterson et al. 2005; Hu et al. 2006; Lorenz et al. 2007; Kappos et al. 2010]. These observations raised the possibility that some side effects associated with fingolimod treatment could be avoided by more selective S1P1R modulators, thus triggering the search for novel compounds.

Currently, there are several selective S1P1R modulators in clinical development [Gonzalez-Cabrera et al.2014; Subei and Cohen, 2015]. Here we review data and the development status of ponesimod, a selective S1P1R modulator developed by Actelion Pharmaceuticals Ltd.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Ponesimod, a selective, rapidly reversible, orally active, sphingosine-1-phosphate receptor modulator

Ponesimod (ACT-128800 (Z,Z)-5-[3-chloro-4-(2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolylthiazolidin-4-one) is a selective, rapidly reversible, orally active, S1P1R modulator. Ponesimod emerged from the discovery of a novel class of S1P1R agonists based on the 2-imino-thiazolidin-4-one scaffold (Figure 1) [Bolli et al. 2010]. Ponesimod activates S1P1R with high potency [half maximal effective concentration (EC50) of 5.7 nM] and selectivity. Relative to the potency of S1P, the potency of ponesimod is 4.4 higher for S1P1R and 150-fold lower for S1P3R, resulting in an approximately 650-fold higher S1P1R selectivity compared with the natural ligand.

Figure 1.

Chemical structure of ponesimod, C23H25N2O4CIS (molecular weight 460.98).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Clinical trials

In a 2009–2011 Phase II clinical trial including 464 MS patients, ponesimod treatment resulted in fewer new active brain lesions thanplacebo, measured during the course of 24 weeks.[3][4]

In a 2010–2012 Phase II clinical trial including 326 patients with psoriasis, 46 or 48% of patients (depending on dosage) had a reduction of at least 75% Psoriasis Area and Severity Index (PASI) score compared to placebo in 16 weeks.[3][5]

SEE https://clinicaltrials.gov/ct2/show/NCT02425644

Adverse effects

Common adverse effects in studies were temporary bradycardia (slow heartbeat), usually at the beginning of the treatment,dyspnoea (breathing difficulties), and increased liver enzymes (without symptoms). No significant increase of infections was observed under ponesimod therapy.[3] QT prolongation is detectable but was considered to be too low to be of clinical importance in a study.[6]

Mechanism of action

Like fingolimod, which is already approved for the treatment of MS, ponesimod blocks the sphingosine-1-phosphate receptor. This mechanism prevents lymphocytes (a type of white blood cells) from leaving lymph nodes.[3] Ponesimod is selective for subtype 1 of this receptor, S1P1.[7]

 

PAPER

Bolli, Martin H.; Journal of Medicinal Chemistry 2010, V53(10), P4198-4211 CAPLUS

2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1Receptor Agonists

Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
J. Med. Chem., 2010, 53 (10), pp 4198–4211
DOI: 10.1021/jm100181s
Publication Date (Web): May 06, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: + 41 61 565 65 70. Fax: + 41 61 565 65 00. E-mail:martin.bolli@actelion.com.
Abstract Image

Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P1 through S1P5. Agonists of the S1P1 receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure−activity relationships of a novel class of S1P1 receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P1 receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.

(Z,Z)-5-[3-Chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one (8bo)

…………..DELETED…………… column chromatography on silica gel eluting with heptane:ethyl acetate 1:4 to give the title compound (1.34 g, 37%) as a pale-yellow foam.
1H NMR (CDCl3): δ 0.94 (t, J = 7.3 Hz, 3 H), 1.58−1.70 (m, 2 H), 2.21 (s, 3 H), 3.32−3.48 (m, 2 H), 3.82−3.95 (m, 3 H), 4.12−4.27 (m, 4 H), 7.07 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 7.0 Hz, 1 H), 7.31−7.39 (m, 3 H), 7.49 (dd, J = 8.5, 2.0 Hz, 1 H), 7.64 (d, J= 2.0 Hz, 1 H), 7.69 (s, 1 H).
13C NMR (CDCl3): δ 11.83, 17.68, 23.74, 55.42, 63.46, 69.85, 70.78, 133.48, 120.75, 123.71, 127.05, 128.25, 128.60, 129.43, 130.06, 131.13, 131.50, 134.42, 136.19, 146.98, 154.75, 166.12. LC-MS (ES+): tR 0.96 min. m/z: 461 (M + H).
HPLC (ChiralPak AD-H, 4.6 mm × 250 mm, 0.8 mL/min, 70% hexane in ethanol): tR 11.8 min. Anal. (C23H25N2O4SCl): C, H, N, O, S, Cl.

PATENT

WO 2014027330

https://www.google.com/patents/WO2014027330A1?cl=3Den

The present invention relates inter alia to a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (hereinafter also referred to as the “COMPOUND” or “compound (2)”), especially in crystalline form C which form is described in WO 2010/046835. The preparation of COMPOUND and its activity as immunosuppressive agent is described in WO 2005/054215. Furthermore, WO 2008/062376 describes a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one which can be used as an intermediate in the preparation of COMPOUND.

Example 1 a) below describes such a process of preparing (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one according to WO 2008/062376. According to WO 2008/062376 the obtained (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one can then be transformed into COMPOUND by using standard methods for the alkylation of phenols. Such an alkylation is described in Example 1 b) below. Unfortunately, this process leads to the impurity (2Z,5Z)-5-(3-chloro-4-((1 ,3-dihydroxypropan-2-yl)oxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one which is present in about 2% w/w in the crude product (see Table 1 ) and up to 6 recrystallisations are necessary in order to get this impurity below 0.4% w/w (see Tables 1 and 2) which is the specified limit based on its toxicological qualification.

the obtained (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one to form (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (2):


.

The reaction of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one can be performed under conditions which are typical for a Knoevenagel condensation. Such conditions are described in the literature for example in Jones, G., Knoevenagel Condensation in Organic Reaction, Wiley: New York, 1967, Vol. 15, p 204; or Prout, F. S., Abdel-Latif, A. A., Kamal, M. R., J. Chem. Eng. Data, 2012, 57, 1881-1886.

2-[(Z)-Propylimino]-3-o-tolyl-thiazolidin-4-one can be prepared as described in WO 2008/062376, preferably without the isolation and/or purification of intermediates such as the thiourea intermediate that occurs after reacting o-tolyl-iso-thiocyanate with n-propylamine. Preferably 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one obtained according to WO 2008/062376 is also not isolated and/or purified before performing the Knoevenagel condensation, i.e. before reacting 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one with (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ), i.e. in a preferred embodiment compound (2) is prepared in a one-pot procedure analogous to that described in WO 2008/062376.

 

Example 1 : (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one

a) Preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one:

Acetic acid solution: To acetic acid (149.2 mL) are added sodium acetate (1 1 .1 1 g, 2.00 eq.) and 3-chloro-4-hydroxybenzaldehyde (10.60 g, 1.00 eq.) at 20 °C. The mixture is stirred at 20 °C until complete dissolution (2 to 3 h).

n-Propylamine (4.04 g, 1.00 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 40 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (13.53 g, 1.00 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). 70 mL of dichloromethane are distilled off under atmospheric pressure and jacket temperature of 60 °C. The temperature is adjusted to 42 °C and the acetic acid solution is added to the reaction mixture. The resulting solution is heated to 58 °C and stirred at this temperature for 15 h before IPC (conversion specification≥ 95 %). 25 mL of solvents are distilled off under vacuum 900 – 500 mbars and jacket temperature of 80 °C. The temperature is adjusted to 60 °C and water (80.1 mL) is added to the reaction mixture over 1 h. The resulting yellow suspension is stirred at 60 °C for 30 min. The suspension is cooled to 20 °C over 1 h and stirred at this temperature for 30 min.

The product is filtered and washed with a mixture of acetic acid (30 mL) and water (16 mL) and with water (50 mL) at 20 °C. The product is dried under vacuum at 50 °C for 40 h to afford a pale yellow solid; yield 25.93 g (78 %).

b) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

To a suspension of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one (10.00 g, 1.00 eq.) in ethanol (47.2 mL) is added (R)-3-chloro-1 ,2-

propanediol (3.37 g, 1.18 eq.) at 20 °C. Potassium tert-butoxide (3.39 g, 1.13 eq.) is added in portions at 20 °C. The resulting fine suspension is stirred at 20 °C for 25 min before being heated to reflux (88 °C). The reaction mixture is stirred at this temperature for 24 h before IPC (conversion specification≥ 96.0 %). After cooling down to 60 °C, acetonitrile (28.6 mL) and water (74.9 mL) are added. The resulting clear solution is cooled from 60 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.010 g, 0.001 eq.; crystalline form C can be prepared as described in WO 2010/046835) are added at 50 °C. The suspension is heated from 0 °C to 50 °C, cooled to 0 °C over 6 h and stirred at this temperature for 12 h.

The product is filtered and washed with a mixture of acetonitrile (23.4 mL) and water (23.4 mL) at 0 °C. The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield 1 1.91 g (84 %).

c) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

Recrystallisation I: The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in acetonitrile (30 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 12.8 mL).

Recrystallisation II: The wet product is dissolved in acetonitrile (27.0 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 1 1.3 mL).

Recrystallisation III: The wet product is dissolved in acetonitrile (24.3 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4- one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 10.1 mL).

Recrystallisation IV: The wet product is dissolved in acetonitrile (21.9 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 9.1 mL).

Recrystallisation V: The wet product is dissolved in acetonitrile (19.7 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 8.2 mL).

Recrystallisation VI: The wet product is dissolved in acetonitrile (23.9 mL) at 70 °C. Water (20 mL) is added at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h.

During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2- (propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed twice with a mixture of acetonitrile (4.5 mL) and water (4.5 mL) at -10 °C.

The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield: 7.0 g (70 %).

Example 2: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde

Potassium tert-butoxide (1 18 g, 1.20 eq.) is added to n-propanol (963 mL) followed by 3-chloro-4-hydroxybenzaldehyde (137 g, 1.00 eq.). To the mixture is added (R)-3-chloro-1 ,2-propanediol (126 g, 1.30 eq.). The suspension is heated to 90 °C and stirred at this temperature for 17 h. Solvent (500 mL) is distilled off at 120 °C external temperature and reduced pressure. Water is added (1.1 L) and solvent (500 mL) is removed by distillation. The turbid solution is cooled to 20 °C. After stirring for one hour a white suspension is obtained. Water (500 mL) is added and the suspension is cooled to 10 °C. The suspension is filtered and the resulting filter cake is washed with water (500 mL). The product is dried at 50 °C and reduced pressure to yield 149 g of a white solid (73%), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.

Example 3: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde

Potassium tert-butoxide (8.60 g, 1.20 eq.) is added to n-propanol (70 mL) below 15 °C, the temperature is allowed to rise. After the addition the temperature is corrected again to below 15 °C before addition of 3-chloro-4-hydroxybenzaldehyde (10 g, 1 .00 eq.). The suspension is heated to 40 °C and stirred for 30 min. (R)-3-Chloro-1 ,2-propanediol (9.18 g, 1.30 eq.) is added at 40 °C. The resulting suspension is heated to 60 °C and stirred at this temperature for 15 h then heated to 94 °C till meeting the IPC-specification (specification conversion≥ 90.0 %). The mixture is cooled to 30 °C and n-propanol is partially distilled off (-50 mL are distilled off) under reduced pressure and a maximum temperature of 50 °C, the jacket temperature is not allowed to raise above 60 °C.

Water (81 mL) is added and a second distillation is performed under the same conditions (24 mL are distilled off). The mixture is heated till homogeneous (maximum 54 °C) and then cooled to 24 °C. At 24 °C the mixture is seeded with crystalline (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of form A (0.013 g, 0.00085 eq.). How to obtain the crystalline seeds is described in Examples 2 and 5. The reaction mixture is cooled to 0 °C over 7.5 h.

The product is filtered and washed with water (2 x 35 mL) and once with methyl tert-butyl ether (20 mL) at 5 °C. The product is dried under vacuum at 40 °C for 20 h to afford an off-white solid; yield: 10.6 g (72 %), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.

Example 4: (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)- 3-(o-tolyl)thiazolidin-4-one

a) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

n-Propylamine (5.23 g, 1.32 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 15 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (14.88 g, 1.10 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). Dichloromethane is partially distilled off (66 mL are distilled off) under atmospheric pressure and jacket temperature of 60 °C. Ethanol (1 1 1.4 mL), sodium acetate (12.75 g, 2.30 eq.) and (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde from Example 3 (14.38 g, 0.93 eq.) are added. The remaining dichloromethane and a part of ethanol are distilled off (49.50 mL are distilled off) under atmospheric pressure and jacket temperature up to 85 °C. The reaction mixture (orange suspension) is stirred for 3 – 5 h under reflux (78 °C) before IPC (conversion specification≥ 97.0 %).

Water (88.83 mL) is added and the temperature adjusted to 40 °C before seeding with micronized (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.075 g, 0.0024 eq.). The reaction mixture is cooled to 0 °C over 5 h, heated up to 40 °C, cooled to 0 °C over 6 h and stirred at this temperature for 2 h.

The product is filtered and washed with a 1 :1 ethanohwater mixture (2 x 48 mL) at 0 °C. The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 24.71 g (86 %).

b) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in ethanol (40 mL) at 70 °C. The temperature is adjusted at 50 °C for seeding with micronised (2Z,5Z)-5-(3-chloro-4-((R)-2,3- dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.016 g, 0.0016 eq.). The reaction mixture is cooled from 50 °C to 0 °C over 4 h, heated up to 50 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h.

The product is filtered and washed with ethanol at 0 °C (2 x 12.8 mL). The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 9.2 g (92 %).

Example 5: Preparation of crystalline seeds of (R)-3-chloro-4-(2,3-dihydroxypropoxy)- benzaldehyde

10 mg of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of at least 99.5% purity by 1 H-NMR assay is dissolved in a 4 mL vial by adding 1 mL of pure ethanol (puriss p. a.). The solvent is allowed to evaporate through a small hole in the cap (approx. 2 mm of diameter) of the vial until complete dryness. The white solid residue is crystalline (R)-3-chloro-4-(2,3- dihydroxypropoxy)-benzaldehyde in crystalline form A. Alternatively, methanol or methylisobutylketone (both in puriss p. a. quality) is used. This procedure is repeated until sufficient seeds are made available.

PATENT

WO 2005054215

SEE https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005054215

 

 

 

 

WO2005054215A1 Nov 16, 2004 Jun 16, 2005 Actelion Pharmaceuticals Ltd 5-(benz- (z) -ylidene) -thiazolidin-4-one derivatives as immunosuppressant agents
WO2008062376A2 Nov 22, 2007 May 29, 2008 Actelion Pharmaceuticals Ltd New process for the preparation of 2-imino-thiazolidin-4-one derivatives
WO2010046835A1 Oct 19, 2009 Apr 29, 2010 Actelion Pharmaceuticals Ltd Crystalline forms of (r) -5- [3-chloro-4- ( 2, 3-dihydroxy-propoxy) -benz [z] ylidene] -2- ( [z] -propylimino) -3-0-tolyl-thiazolidin-4-one
Reference
1 * BOLLI, M.H. ET AL.: “2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1 Receptor Agonists“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 10, 2010, pages 4198-4211, XP55090073, ISSN: 0022-2623, DOI: 10.1021/jm100181s

References

  1. “Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: Favorable impact of dose up-titration”. The Journal of Clinical Pharmacology 54: 179–88. Feb 2014. doi:10.1002/jcph.244. PMID 24408162.
  2.  “Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans”. Xenobiotica 45: 139–49. Feb 2015. doi:10.3109/00498254.2014.955832. PMID 25188442.
  3. H. Spreitzer (29 September 2014). “Neue Wirkstoffe – Ponesimod”. Österreichische Apothekerzeitung (in German) (20/2014): 42.
  4.  “Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial”. Journal of Neurology, Neurosurgery 85: 1198–208. Nov 2014. doi:10.1136/jnnp-2013-307282. PMC 4215282. PMID 24659797.
  5.  “Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial”. The Lancet 384: 2036–45. Dec 2014. doi:10.1016/S0140-6736(14)60803-5. PMID 25127208.
  6. “Effect of Ponesimod, a selective S1P1 Receptor Modulator, on the QT Interval in Healthy Subjects”. Basic 116: 429–37. May 2015.doi:10.1111/bcpt.12336. PMID 25287214.
  7.  “Ponesimod”. Actelion. Retrieved 31 October 2014.

ABOUT PONESIMOD

Ponesimod is a potent orally active, selective sphingosine-1-phosphate receptor 1 (S1P1) immunomodulator.

Ponesimod prevents lymphocytes from leaving lymph nodes, thereby reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. The lymphocyte count reduction is rapid, dose-dependent, sustained upon continued dosing, and quickly reversible upon discontinuation. Initial data suggest that ponesimod does not cause lymphotoxicity by destroying/depleting lymphocytes or interfering with their cellular function. Other blood cells e.g. cells of the innate immune system are largely unaffected. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.

CURRENT STATUS

OPTIMUM (Oral Ponesimod versus Teriflunomide In relapsing MUltiple sclerosis) is a Phase III multi-center, randomized, double-blind, parallel-group, active-controlled superiority study to compare the efficacy and safety of ponesimod to teriflunomide in patients with relapsing multiple sclerosis (RMS). The study aims to determine whether ponesimod is more efficacious than teriflunomide in reducing relapses. The study is expected to enroll approximately 1’100 patients, randomized in 2 groups in a 1:1 ratio to receive ponesimod 20 mg/day or teriflunomide 14 mg/day, and is expected to last a little over 3 years. An additional study to further characterize the utility and differentiation of ponesimod in multiple sclerosis is being discussed with Health Authorities.

Ponesimod is also evaluated in a Phase II open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in patients suffering from moderate or severe chronic graft versus host disease (GvHD)inadequately responding to first- or second-line therapy. The study will also investigate the clinical response to ponesimod treatment in these patients. Approximately 30 patients will be enrolled to receive ponesimod in escalating doses of 5, 10, and 20 mg/day over the course of 24 weeks. The study is being conducted at approximately 10 sites in the US and is expected to last approximately 18 months.

AVAILABLE CLINICAL DATA

The decision to move into Phase III development was based on the Phase IIb dose-finding study with ponesimod in patients with relapsing-remitting multiple sclerosis. A total of 464 patients were randomized into this study and the efficacy, safety and tolerability of three ponesimod doses (10, 20, and 40 mg/day) versus placebo, administered once daily for 24 weeks.

The primary endpoint of this study was defined as the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans at weeks 12, 16, 20, and 24 after study drug initiation. A key secondary endpoint of this study was the annualized relapse rate over 24 weeks of treatment. Patients who completed 24 weeks of treatment were offered the opportunity to enter into an extension study. This ongoing trial is investigating the long-term safety, tolerability, and efficacy of 10 and 20 mg/day of ponesimod in patients with relapsing-remitting multiple sclerosis, in a double-blind fashion. The study continues to provide extensive safety and efficacy information for ponesimod in this indication, with some patients treated for more than 6 years.

The safety database from all studies with ponesimod now comprises more than 1,300 patients and healthy volunteers.

MILESTONES

2015 – Phase III program in multiple sclerosis initiated
2011 – Phase IIb dose-finding study in multiple sclerosis successfully completed
2006 – Entry-into-man
2004 – Preclinical development initiated

KEY SCIENTIFIC LITERATURE

Olsson T et al. J Neurol Neurosurg Psychiatr. 2014 Nov;85(11):1198-208. doi: 10.1136/jnnp-2013-307282. Epub 2014 Mar 21

Freedman M.S, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 420 (P923).

Fernández Ó, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 417 (P919).

Piali L, Froidevaux S, Hess P, et al. J Pharmacol Exp Ther 337(2):547-56, 2011

Bolli MH, Abele S, Binkert C, et al. J Med Chem. 53(10):4198-211, 2010

Kappos L et al. N Engl J Med. 362(5):387-401, 2010

Ponesimod
Ponesimod.svg
Ponesimod ball-and-stick model.png
Systematic (IUPAC) name
(2Z,5Z)-5-{3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one
Clinical data
Routes of
administration		 Oral
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Metabolism 2 main metabolites
Biological half-life 31–34 hrs[1]
Excretion Feces (57–80%, 26% unchanged), urine (10–18%)[2]
Identifiers
CAS Number 854107-55-4
ATC code none
PubChem CID 11363176
ChemSpider 9538103
ChEMBL CHEMBL1096146
Synonyms ACT-128800
Chemical data
Formula C23H25ClN2O4S
Molar mass 460.974 g/mol

////Ponesimod, Phase III , A sphingosine-1-phosphate receptor 1, S1P1 agonist, multiple sclerosis.  ACT-128800; RG-3477; R-3477, autoimmune disease, lymphocyte migration, multiple sclerosis, psoriasis, transplantation

CCC/N=C\1/N(C(=O)/C(=C/C2=CC(=C(C=C2)OC[C@@H](CO)O)Cl)/S1)C3=CC=CC=C3C

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WHO defines Requirements on Zones E and F

 regulatory  Comments Off on WHO defines Requirements on Zones E and F
Jun 092016
 

In May, the WHO published a draft guideline which describes the recommendations for ventilation systems used in the manufacture of non-sterile dosage forms. It also contains for the first time a definition for microbial requirements with regard to the zones E and F. Read more about the ventilation sytems recommendations.

http://www.gmp-compliance.org/enews_05367_WHO-defines-Requirements-on-Zones-E-and-F_15221,15231,15612,15266,Z-PEM_n.html

In May 2016, the WHO published a draft guideline which describes the recommendations for ventilation systems used in the manufacture of non-sterile dosage forms. From a technical point of view, the guideline is very interesting and includes a detail which may be overlooked: it contains – as first international GMP guideline – a proposal for the definition of microbiological requirements concerning the zones E and F. So far, the approach to extend the zoning via the zones A-D defined in Annex 1 to the zones E and F and thus define microbial limits had only been available in an Aide Memoire of the ZLG (in German language). Now for the first time, this information is available in an international guide. As there are far less regulations in the area of non-sterile medicinal products than in sterile manufacturing, the proposal should be of great interest.

Access the draft Supplementary Guideline on GMPs for Heating, Ventilation and Air-Conditioning Systems for non-sterile Dosage Forms on the WHO webpage to find more detailed information. The deadline for comments ends on 12 July 2016.

 

////////WHO, microbial requirements,  zones E,  F

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Dr Anthony’s New Drug Approvals hits 13 lakh views in 212 countries

 drugs  Comments Off on Dr Anthony’s New Drug Approvals hits 13 lakh views in 212 countries
Jun 082016
 

str1

Dr Anthony’s New Drug Approvals hits 13 lakh views in 212 countries

An Indian helping millions

9e3e7-new-india-map

MAKING INDIANS FEEL PROUD

LINK

https://newdrugapprovals.org/

////////blog, Dr Anthony , New Drug Approvals,  13 lakh views, 212 countries, India

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ABT-530, Pibrentasvir

 Phase 3 drug, Uncategorized  Comments Off on ABT-530, Pibrentasvir
Jun 082016
 

STR1

Pibrentasvir

ABT-530, Pibrentasvir, A 1325912.0

Dimethyl N,N’-([(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}pyrrolidine-2,5-diyl]bis{(6-fluoro-1H-benzimidazole-5,2-diyl)[(2S)-pyrrolidine-2,1-diyl][(2S,3R)-3-methoxy-1-oxobutane-1,2-diyl]})biscarbamate

Methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

Dimethyl N,N’-(((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis((6-fluoro-1H-benzimidazole-5,2-diyl)((2S)-pyrrolidine-2,1-diyl)((2S,3R)-3-methoxy-1-oxobutane-1,2-diyl)))biscarbamate

Methyl ((2S,3R)-1-((2S)-2-(5-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)-5-(6-fluoro-2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)pyrrolidin-2-yl)-1H-benzimidazol-5-yl)pyrrolidin-2-yl)-6-fluoro-1H-benzimidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-yl)carbamate

Phase III

Abbott Laboratories  INNOVATOR

A protease inhibitor potentially for the treatment of HCV infection.

Hepatitis C virus NS 5 protein inhibitors

CAS No. 1353900-92-1

MF C57H65F5N10O8

MW 1113.1925 MW

Pibrentasvir

1353900-92-1.pngPibrentasvir

SYNTHESIS

STR1

PATENT

WO 2012051361

http://www.google.com/patents/WO2012051361A1?cl=en

Figure imgf000325_0001

Example 3.52 methyl {(2S,3R)-l-[(2S)-2-{5-[(2R,5R)-l-{3,5-difluoro-4-[4-(4- fluorophenyl)piperidin-l-yl]phenyl}-5-(6-fluoro-2-{(2.S)-l-[A^-(methoxycarbonyl)-0-methyl-L- threonyl]pyiTolidin-2-yl}-l f-benzimidazol-5-yl)pyiTolidin-2-yl]-6-fluoro-l f-benzimidaz yl}pyrrolidin-l-yl]-3-methoxy-l-oxobutan-2-yl}carbamatelH NMR (400 MHz, DMSO) δ 12.36 – 12.06 (m, 2H), 7.41 (dd, J = 11.2, 6.3, 1H), 7.34 (dd, J = 10.4, 4.8, 1H), 7.30 – 7.20 (m, 3H), 7.17 – 6.98 (m, 5H), 5.98 – 5.82 (m, 2H), 5.65 – 5.47 (m, 2H), 5.17 – 5.06 (m, 2H), 4.25 (dd, J = 15.6, 8.1, 2H), 3.88 – 3.74 (m, 3H), 3.53 (d, J = 1.3, 6H), 3.49 – 3.38 (m, 2H), 3.31 (d, 1H), 3.25 (d, J = 3.7, 1H), 3.13 (d, J = 1.3, 3H), 3.03 (d, J = 2.3, 3H), 3.00 – 2.84 (m, 3H), 2.60 – 2.53 (m, J = 2.5, 2H), 2.26 – 1.55 (m, 14H), 1.28 – 1.13 (m, 1H), 1.10 – 0.88 (m, 6H). MS (ESI; M+H) m/z = 1113.4.

Figure imgf000199_0002

Intermediate 5

( 15,45)- 1 ,4-bis(4-chloro-3 -nitrophenyl)butane- 1 ,4-diyl dimethanesulfonate Intermediate 5A

2-bromo- 1 -(4-chloro-3 -nitrophenyl)ethanone

Method A:

To a flask equipped with a magnetic stir bar and under an atmosphere of N2 was added 4′- chloro-3 ‘-nitroacetophenone (10.0 g, 50.1 mmol) and THF (100 mL). To this stirring mixture was added portion-wise phenyltrimethylammonium tribromide (19.78 g, 52.6 mmol) over a 15 minutes time period. The resultant mixture was then stirred with monitoring every hour via LCMS. After 3 hours, the mixture was then filtered and resulting solids washed with EtOAc. The organic solution was then concentrated, and 10% aq. NaHCC^ were added, and the mixture was washed with EtOAc (2×300 mL). The combined organic layers were then washed with brine, dried (MgSO^), filtered and concentrated. The residue material was then subjected to purification via crystallization. The residue was dissolved in EtOAc (100 mL) and hexanes were slowly added until the mixture was cloudy. After standing for a few hours, 2-bromo- l-(4-chloro-3-nitrophenyl)ethanone (9.81 g, 70%) was collected as an off white colored solid product. !H NMR (500 MHz, DMSO-cfe) δ ppm 5.00 (s, 2 H) 7.98 (d, J=8.54 Hz, 1 H) 8.24 (dd, J=8.54, 2.14 Hz, 1 H) 8.61 (d, J=1.98 Hz, 1 H).

Method B:

In a 500 mL round-bottomed flask was added l -(4-chloro-3-nitrophenyl)ethanone (1 1.98 g, 60 mmol) in benzene (75 mL) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was added dropwise over 5 minutes to give a deep red solution. The mixture was stirred for 1 hour to give a yellow solution that was concentrated in vacuo to a yellow solid. Recrystallized from 9: 1 hexane/ethyl acetate gave 2-bromo-l -(4-chloro-3-nitrophenyl)ethanone as yellow needles.

Figure imgf000216_0002

Intermediate 21

(1 S,4S)-1 -(4-chloro-2-fluoro-5 -nitrophenyl)-4-(4-chloro-3 -nitrophenyl)butane- 1 ,4-diyl

dimethanesulfonate

Intermediate 21 can be made from Intermediate 20B and l-(4-chloro-3-nitrophenyl)ethanone (commercially available from Aldrich) following the general methods to prepare Intermediate 20E.

Figure imgf000228_0001

l-(2,6-difluoro-4-nitrophenyl)piperidin-4-one

The crude 8-(2,6-difluoro-4-nitrophenyl)-l,4-dioxa-8-azaspiro[4.5]decane from the preceding procedure was dissolved in 4:1 acetone:water (100 mL). Concentrated HC1 (5 mL) was added, and the resulting mixture was stirred at 50 °C for 8 hours and then cooled to room temperature. The mixture was concentrated in vacuo to approximately 20 mL, which was carefully added to concentrated aq. NaHCC^ (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The crude product was triturated with Et20 and hexanes to give a bright-yellow solid that was collected and dried to provide the title compound (7.13 g, 81%).

PATENT

WO 2015171993

The present invention features crystalline polymorphs of methyl {(2S,3R)-1- [(2S)-2-{5-[(2R,5R)-l-{3,5-difluoro-4 4-(4-fluorophenyl)piperidin-l-yl]phenyl}-5-(6-fluoro-2-{(2S)- 1 -[N-(methoxycarbonyl)-0-methyl-L-threonyl]pyrrolidin-2-yl} – 1 H-benzimidazol-5-yl)pyrrolidin- -yl] -6-fluoro- 1 H-benzimidazol-2-yl} pyrrolidin- 1 -yl] -3 -methoxy- 1 -oxobutan-2-

yl} carbamate
, herein “Compound I”). Compound I is a potent HCV NS5A inhibitor and is described in U.S. Patent Application Publication No. 2012/0004196, which is incorporated herein by reference in its entirety.

 

 

 

 

//////////1353900-92-1, PHASE 3, ABT-530, Pibrentasvir, ABT 530, A 1325912.0

C[C@H]([C@@H](C(=O)N1CCC[C@H]1c2[nH]c3cc(c(cc3n2)[C@H]4CC[C@@H](N4c5cc(c(c(c5)F)N6CCC(CC6)c7ccc(cc7)F)F)c8cc9c(cc8F)[nH]c(n9)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)OC)NC(=O)OC)F)NC(=O)OC)OC

C[C@H]([C@@H](C(=O)N1CCC[C@H]1c2[nH]c3cc(c(cc3n2)[C@H]4CC[C@@H](N4c5cc(c(c(c5)F)N6CCC(CC6)c7ccc(cc7)F)F)c8cc9c(cc8F)[nH]c(n9)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)OC)NC(=O)OC)F)NC(=O)OC)OC

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Synthesis, Biological Evaluation and Validation Studies of Novel 5-(Substituted Aldehyde)-2-imino-7-methyl-3-oxo-N-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carboxamide Scaffolds

 Uncategorized  Comments Off on Synthesis, Biological Evaluation and Validation Studies of Novel 5-(Substituted Aldehyde)-2-imino-7-methyl-3-oxo-N-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carboxamide Scaffolds
Jun 072016
 

synthesis

Procedure for the synthesized derivatives (1-3)

Step 1: The synthesis of Intermediate-1 (2-imino-6-methyl-4- (substituted aldehyde)-N-phenyl-1,2,3,4-tetrahydropyrimidine-5- carboxamide): A mixture of substituted aldehyde (0.01 mol), guanidine nitrate (0.015 mol) and acetoacetanilide (0.01 mol) were placed in round bottom flask in methanol (50 ml) and added aluminum chloride (0.003 mol) with 2-3 drops of conc. hydrochloric acid as catalyst amount then the reaction mixture was refluxed for 11-12 hrs after that the reaction mixture was cooled to room temperature and poured into crushed ice water with vigorous stirring, filtered and recrystallized with methanol [10].

Step 2: The synthesis of 5-(substituted aldehyde)-7-methyl-3-oxo-N-phenyl-2-((3,4,5,6-tetrahydroxy-tetrahydro-2H-pyran- 2-yl)methylene)-1,2,3,5-tetrahydroimidazo[1,2-a] pyrimidine-6- carboxamide derivatives: A mixture of intermediate-1 (0.01 mol), sodium benzoate (2 g), dextrose (0.01 mol), glacial acetic acid (20 ml), ethyl acetoacetate (15 ml) and monochloroacetic acid (0.015 mol) were taken in RBF and refluxed with controlled temperature at 140-142°C for 6-7 hrs. The reaction mixture was cooled at room temperature and poured into ice cold water to yielded solid precipitate or titled compounds (1-3), filtered and recrystallized with methanol.

Compound 1 (7-Methyl-3-oxo-N-phenyl-2-((3,4,5,6- tetrahydroxy-tetrahydro-2H-pyran-2-yl)methylene)-5-(3,4,5- trimethoxyphenyl)-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6- carboxamide): IR (KBr pellets, cm-1): 3062 (C-H str., phenyl nucleus), 1596 (C=C str., phenyl nucleus), 694 (C-C str., phenyl nucleus), 1630 (C=O str.,), 3321 (N-H str., 2˚amide), 1630 (N=CH str., pyrimidine), 1244 (C-N str., pyrimidine), 2779 (C-H str., cyclic ether), 1126 (C-O-C str., aryl ether), 3321 (O-H str., polyhydroxy on dextrose), 1244 (C-O-C str., OCH3); 1H NMR (DMSO-d6, δppm): 7.45-7.49 (m, 7H, Ar-H), 2.10 (s, 1H, NH, amide), 8.25 (s, 1H, NH, amide), 3.86-4.22 (m, 5H, CH, tetrahydropyran), 2.10 (m, 4H, OH alcohol), 3.86 (m, 9H, OCH3).

Synthesis, Biological Evaluation and Validation Studies of Novel 5-(Substituted Aldehyde)-2-imino-7-methyl-3-oxo-N-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carboxamide Scaffolds

Jyoti Rani, Monika Saini, Sanjiv Kumar and Prabhakar Kumar Verma*
Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124 001, Haryana, India
*Corresponding Author : Prabhakar Kumar Verma
Department of Pharmaceutical Sciences
Maharshi Dayanand University
Rohtak-124 001, Harayana, India
Tel: 9992581437
E-mail: vermapk422@rediffmail.com
Received March 07, 2016; Accepted March 29, 2016; Published March 31, 2016
Citation: Rani J, Saini M, Kumar S, Verma PK (2016) Synthesis, Biological Evaluation and Validation Studies of Novel 5-(Substituted Aldehyde)-2-imino-7-methyl-3-oxo-N-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carboxamide Scaffolds. Med chem (Los Angeles) 6:218-223. doi:10.4172/2161-0444.1000349
Copyright: © 2016 Rani J, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

link

http://www.omicsonline.org/open-access/synthesis-biological-evaluation-and-validation-studies-of-novel-5substituted-aldehyde2imino7methyl3oxonphenyl1235tetrahydroimidazo-2161-0444-1000349.php?aid=71794

///////////// 5-(Substituted Aldehyde)-2-imino-7-methyl-3-oxo-N-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carboxamide,  Scaffolds

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A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters

 MANUFACTURING  Comments Off on A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters
Jun 072016
 

In the pharmaceutical tablet film coating process, we clarified that a difference in exhaust air relative humidity can be used to detect differences in process parameters values, the relative humidity of exhaust air was different under different atmospheric air humidity conditions even though all setting values of the manufacturing process parameters were the same, and the water content of tablets was correlated with the exhaust air relative humidity. Based on this experimental data, the exhaust air relative humidity index (EHI), which is an empirical equation that includes as functional parameters the pan coater type, heated air flow rate, spray rate of coating suspension, saturated water vapor pressure at heated air temperature, and partial water vapor pressure at atmospheric air pressure, was developed. The predictive values of exhaust relative humidity using EHI were in good correlation with the experimental data (correlation coefficient of 0.966) in all datasets. EHI was verified using the date of seven different drug products of different manufacturing scales. The EHI model will support formulation researchers by enabling them to set film coating process parameters when the batch size or pan coater type changes, and without the time and expense of further extensive testing.

EHI is defined as the following equation:

In general, pharmaceutical film coatings are applied in order to protect core tablets from light or for masking the taste of the active pharmaceutical ingredients. Therefore, the surface state of the coating layer is important to maintain the expected performance. During the coating process, however, the coating layer surface state is affected by the water content of the tablets. In a conventional approach, the water content of drug products is maintained at the validated level by monitoring the product’s temperature and/or the exhaust air temperature during the coating process. In a scale up study, the batch scale and manufacturing equipment are changed according to the progress of the process development stage. At each stage, the water content of drug products is constantly monitored and well-controlled to secure the consistency of the drug product’s quality. In this approach, numerous experiments are necessary to optimize the process parameters in each batch scale. As a result, the costs of materials, human resources, and time for development will become considerable.

A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters

Yasuhiro Suzuki1), Tatsuya Suzuki1), Hidemi Minami1), Katsuhide Terada2)

1) Formulation Technology Research Laboratories, Daiichi Sankyo Co., Ltd. 2) Faculty of Pharmaceutical Science, Toho University

Released on J-STAGE 20160301

https://www.jstage.jst.go.jp/article/cpb/64/3/64_c15-00644/_article

Chemical and Pharmaceutical Bulletin
Vol. 64 (2016) No. 3 p. 215-221

http://doi.org/10.1248/cpb.c15-00644

Conclusion

In this study, the relationship between film coating process parameters and EARH was clarified. In addition, it was confirmed that the EARH affected the water content of tablets. These results indicated that the water content of tablets can be regulated by controlling the EARH. From these results, we proposed the EHI for quantification of the pharmaceutical film coating process. The fitting parameters in the EHI equation were set using the experimental data of 10 drug products and 7 kinds of pan coaters. These fitting parameters of EHI were validated by evaluating the correlation coefficient determined by comparing the calculated values of EARH and the measured experimental values of EARH from various drug products, pan coater scales and coating parameters. The main advantage of the EHI method is that commercial scale coating conditions can be predicted using only one film coating experimental result from a lab-scale pan coater.

/////////pan coater, exhaust air relative humidity index (EHI), scale up, drying ability, atmospheric air, tablet water content

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