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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Thiotepa, チオテパ ,тиотепа , ثيوتيبا , 塞替派 ,


ChemSpider 2D Image | thiotepa | C6H12N3PS

Thiotepa, チオテパ

  • Use:antineoplastic, alkylating agent
  • Chemical name:1,1′,1”-phosphinothioylidynetrisaziridine
  • Formula:C6H12N3PS
  • MW:189.22 g/mol
  • CAS:52-24-4
  • EINECS:200-135-7
  • LD50:14500 μg/kg (M, i.v.); 38 mg/kg (M, p.o.);
    9400 μg/kg (R, i.v.)
  • Aziridine, 1,1′,1”-phosphinothioylidynetris-
    Aziridine, 1-[bis(1-aziridinyl)phosphinothioyl]-
    N,N’,N”-Triethylenethiophosphoramide
    Phosphorothioic tri(ethyleneamide)
    SZ2975000
    T3NTJ APS&- AT3NTJ&- AT3NTJ [WLN]
    Thiofozil
    Thiotef
    1,1′,1”-Phosphorothioyltriaziridine

JAPAN APPROVED, Rethio, PMDA, 2019/3/26

тиотепа [Russian] [INN]
ثيوتيبا [Arabic] [INN]
塞替派 [Chinese] [INN]

Thiotepa (INN,[1] chemical name: N,N′,N′′-triethylenethiophosphoramide) is an alkylating agent used to treat cancer.

Thiotepa is an organophosphorus compound with the formula SP(NC2H4)3.[2] It is an analog of N,N′,N′′-triethylenephosphoramide (TEPA), which contains tetrahedral phosphorus and is structurally akin to phosphate. It is manufactured by heating aziridine with thiophosphoryl chloride.

History

Thiotepa was developed by the American Cyanamid company in the early 1950s and reported to media outlets in 1953.[3] In 1959, thiotepa was registered with the Food and Drug Administration (FDA) as a drug therapy for several solid cancers.[4]

On January 29, 2007, the European Medicines Agency designated thiotepa as an orphan drug. On April 2, 2007, the United States FDA designated thiotepa as a conditioning treatment for use prior to hematopoietic stem cell transplantation.[5] Adienne Pharma & Biotech (Italy), the owner of thiotepa (Tepadina) applied for these designations.

Use

Thiotepa is indicated for use in combination with other chemotherapeutic agents. This can be with or without total body irradiation (TBI), as a conditioning treatment prior to allogeneic or autologous hematopoietic progenitor cell transplantation (HPCT) in hematological diseases in adult and pediatric patients. These diseases include Hodgkin’s disease and leukaemia. Thiotepa is also used with high-dose chemotherapy with HPCT support to treat certain solid tumors in adult and pediatric patients.[6]

Thiotepa is used in the palliation of many neoplastic diseases. The best results are found in the treatment of adenocarcinoma of the breast, adenocarcinoma of the ovarypapillary thyroid cancer and bladder cancer. Thiotepa is used to control intracavitary effusions caused by serosal neoplastic deposits.[6]

Intravesical use

Thiotepa is used as intravesical chemotherapy in bladder cancer.[7]

It may be used prophylactically to prevent seeding of tumor cells at cystoscopic biopsy; as an adjunctive agent at the time of biopsy; or as a therapeutic agent to prevent recurrence after cystoscopic resection of bladder tumor (transurethral resection of bladder tumor, TURBT). For intravesical use, thiotepa is given in 30 mg doses weekly, for four to six weeks. Efficacy in tumor control may reach 55 percent. The main toxicity of this therapy is bone marrow suppression due to systemic absorption of the drug.

Side effects

The main side effect of thiotepa is bone marrow suppression resulting in leukopeniathrombocytopenia and anemia.[8] Liver and lung toxicity may also occur.

SYN

Image result for thiotepa

NMR

<sup>1</sup>H NMR spectrum of C<sub>6</sub>H<sub>13</sub>N<sub>3</sub>P<sub></sub>S<sub></sub> in CDCL3 at 400 MHz.<br>Click to toggle size.

Fig 5. 1H NMR spectrum of C6H13N3PS in CDCL3 at 400 MHz.

R.J. Abraham, M. Mobli Modelling 1H NMR Spectra of Organic Compounds:
  Theory, Applications and NMR Prediction Software, Wiley, Chichester, 2008.

References

  1. ^ “International Non-Proprietary Names for Pharmaceutical Preparations. Recommended International Non-Proprietary Names (Rec. I.N.N.): List 4” (PDF). World Health Organization. March 1962. p. 111. Retrieved 27 November 2016.
  2. ^ Maanen, M. J.; Smeets, C. J.; Beijnen, J. H. (2000). “Chemistry, pharmacology and pharmacokinetics of N,N’,N” -triethylenethiophosphoramide (ThioTEPA)”. Cancer Treatment Reviews26 (4): 257–268. doi:10.1053/ctrv.2000.0170PMID 10913381.
  3. ^ Sykes, M. P.; Karnofsky, D. A.; Philips, F. S.; Burchenal, J. H. (1953). “Clinical studies on triethylenephosphoramide and diethylenephosphoramide, compounds with nitrogen-mustard-like activity”. Cancer6 (1): 142–148. doi:10.1002/1097-0142(195301)6:1<142::AID-CNCR2820060114>3.0.CO;2-W.
  4. ^ Kim, Kyu-Won; Roh, Jae Kyung; Wee, Hee-Jun; Kim, Chan (2016). Cancer Drug Discovery: Science and History. Springer. p. 82. ISBN 978-94-024-0844-7.
  5. ^ “EMA Grants Adienne Marketing Rights for Tepadina”dddmag.com. Drug Discovery & Development. 19 March 2010. Retrieved 25 November 2011.
  6. Jump up to:a b “Urgent, thioTEPA update” (PDF)Food and Drug Administration. Adienne Pharma & Biotech. 5 April 2011. Retrieved 25 November 2011.
  7. ^ Droller M. Urothelial Tumors PMPH-USA, 2004. p. 207 ISBN 1550091735
  8. ^ Agnelli, G.; de Cunto, M.; Gresele, P.; del Favero, A. (1982). “Early onset life-threatening myelosuppression after low dose of intravesical thiotepa”Postgraduate Medical Journal58 (680): 380–381. doi:10.1136/pgmj.58.680.380PMC 2426344PMID 6812036.

External links

REF

US 2 670 347 (American Cyanamid; 1954; prior. 1952)

Thiotepa
ThioTEPA.svg
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a682821
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration
IV, intracavitary, intravesical
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Hepatic (CYP2BCYP3A)
Elimination half-life 1.5–4.1 hours
Excretion Renal
6 hours for thiotepa
8 hours for TEPA
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.000.124 Edit this at Wikidata
Chemical and physical data
Formula C6H12N3PS
Molar mass 189.23 g/mol g·mol−1
3D model (JSmol)

//////////////Thiotepa, チオテパ   ,тиотепа ثيوتيبا 塞替派 , JAPAN 2019

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Omidenepag isopropyl, オミデネパグイソプロピル


1187451-19-9.pngImage result for Omidenepag isopropyl

Omidenepag isopropyl

DE-117

Glycine, N-(6-((((4-(1H-pyrazol-1-yl)phenyl)methyl)(3-pyridinylsulfonyl)amino)methyl)-2-pyridinyl)-, 1-methylethyl ester

[[6-[[[4-(Pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)amino]methyl]pyridin-2-yl]amino]acetic acid isopropyl ester

C26H28N6O4S, 520.6033, CAS: 1187451-19-9

APPROVED 2018/9/21 PMDA, JAPAN 2018, Eybelis

Antiglaucoma, Prostaglandin E2 receptor agonist, Treatment of Open-Angle Glaucoma and Ocular Hypertension

  • Originator Ube Industries
  • Developer Santen Pharmaceutical
  • Class Eye disorder therapies; Pyrazoles; Pyridines; Small molecules; Sulfonamides
  • Mechanism of Action Prostaglandin E EP2 receptor agonists
  • Registered Glaucoma; Ocular hypertension
  • 27 Sep 2018 Santen initiates enrolment in the phase III Spectrum 5 trial for Glaucoma and Ocular hypertension in USA (Ophthalmic) (NCT03697811)
  • 21 Sep 2018 Santen Pharmaceutical and Ube Industries plan phase III trials for omidenepag isopropyl in USA in the second half of 2018
  • 21 Sep 2018 Registered for Ocular hypertension and Glaucoma in Japan (Ophthalmic) – First global approval

SYNTHESIS

PATENT

WO 2009113600

WO 2010113957

JP 2011057633

PATENT

WO 2015190507

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015190507&tab=FULLTEXT&maxRec=1000

[Example 1]
[Formula
10] 2 – {[6 – ({N-[4-(1H-pyrazol-1-yl) benzyl] pyridin-3-sulfonamido} methyl) pyridin-2-yl] amino} Synthesis of isopropyl acetate
 To a glass vessel having an inner volume of about 50 ml equipped with a stirring device, a thermometer and an upper cooling device, 3.21 g (10.00 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] , 2.43 g (10.0 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 6.65 g (20.4 mmol) of cesium carbonate and 17.6 g of acetonitrile was added, and the mixture was heated and stirred at 80 ° C. In the high performance liquid chromatography analysis, the reaction was carried out for 2 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate became 0.03% or less, I went for hours. The reaction conversion ratios of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate after heating and stirring 1 hour and 2 hours were 99.88% and 99.97% . After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography revealed that 5.08 g of the objective substance was contained (reaction yield: 97.5%). Next, the reaction solution was concentrated under reduced pressure until the weight of the liquid reached 7.85 g, 42.8 g of toluene was added, and the mixture was washed three times with water. 31.5 ml (31.5 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. Note that 0.17 g (corresponding to 3.2% yield) of target product was contained in the organic layer after liquid separation. 42.8 g of toluene and 34.6 ml (34.6 mmol) of 1 mol / L sodium hydroxide aqueous solution were added to the obtained aqueous layer, and the mixture was heated to 40 ° C. and stirred for 20 minutes. After filtration at 40 ° C. in the hot state, liquid separation was carried out. The obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure until the weight of the liquid reached 8.97 g, and 7.40 g of 2-propanol was added. After warming to 60 ° C., it was slowly cooled and stirred at 33 ° C. for 30 minutes, then slowly cooled to 5 ° C. or less, and further stirred at the same temperature for 1 hour. Precipitated The solid was filtered, washed with chilled 2-propanol and then vacuum dried at 50 ° C. to give 2 – {[6 – ({N- [4- (1 H-pyrazol- 1 – yl) benzyl] pyridine- 3 – sulfonamido} methyl) pyridin-2-yl] amino} acetic acid was obtained as a slightly brown solid (2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate Isolated yield of standard 75.1%). The quantitative purity by HPLC high performance chromatography method was 99.5%, and 0.04% of N- [4- (1H-pyrazol-1-yl) benzyl] pyridine-3-sulfonamide as a raw material was contained It was. Also, in the measurement (wavelength 260 nm) by the HPLC high performance liquid chromatography method, there was no impurity showing an area% of 0.1% or more.
 Physical property values of the obtained 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl) pyridin-2- yl] amino} , It was as follows.
EI-MS (m /
z):. 520 [M] CI-MS (m /
[Mz):. + 1] 1 H-NMR (CDCl 3, [delta] (ppm)): 1.24 (6H, d, J = 6.3 Hz), 5.07 (1 H, se, J = 5.5 Hz), 3.82 (2 H, d, J = 5.5 Hz), 4.31 (2 H, s), 4.64 (2 H, s), 4.94 J = 6.3 Hz), 6.26 (1 H, d, J = 8.3 Hz), 6.41 (1 H, dd, J = 7.2, 0.5 Hz), 6.46 (1 H, dd, J = 2.5, 1.8 Hz), 7.25 (2H, m), 7.71 (1H, dd, J = 8.3, 7.2 Hz), 7.32 (1H, ddd, J = 8.0, 4.9, 0.8 Hz), 7.37-7.42 J = 1.8, 0.6 Hz), 7.93 (1 H, dd, J = 2.6, 0.6 Hz), 7.94 (1 H, ddd, J = 8.0, 2.4, 1.7 Hz), 8.69 (1 H, dd, J = 4.8, 1.6 Hz ), 8.98 (IH, dd, J = 2.4, 0.8
Hz). 13 C-NMR (CDCl 3, δ (ppm)): 21.8, 43.7, 51.0, 51.1, 68.9, 107.4, 107.7, 112.6, 119.2, 123.3, 126.7, 129.9, 133.8, 134.6, 137.3, 137.6, 139.8, 141.1, 148.0, 152.6, 153.2, 157.3 , 1737 (C = O), (2981, 2933) (CH), 3437 (NH) , 170.5.
IR (KBr cm -1 ): 764 (CH), 1161 (S = O), 1525 .
elemental analysis; Calcd: C, 59.80%; H, 5.31%; N, 16.07%
Found: C, 59.98%; H, 5.42%; N, 16.14%.
[Example 2]
[Formula
11] 2 – ({6 – [(N-benzyl-3-sulfonamido) methyl] pyridin-2-yl} amino) -acetic acid isopropyl
 0.253 g (1.02 mmol) of N-benzylpyridine-3-sulfonamide, 0.253 g (1.02 mmol) of 2- { 0.243 g (1.00 mmol) of isopropyl acetate, 0.665 g (2.04 mmol) of cesium carbonate and 1.76 g of acetonitrile were added, and the mixture was heated and stirred at 80 ° C. did. In the high performance liquid chromatography analysis, the reaction was carried out for 2 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate became 0.03% or less, I went for hours. The reaction conversion rates of 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetic acid isopropyl acetate after 1 hour and 2 hours from the start of heating and stirring were 99.81% and 99.99% It was. After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high-performance liquid chromatography revealed that 0.430 g of the target product was contained (reaction yield: 94.5%). Next, the reaction solution was concentrated under reduced pressure until the weight of the liquid reached 0.785 g, 4.3 g of toluene was added, and the mixture was washed three times with water. At this time, an emulsion containing the desired product was produced, but it was discarded together with the aqueous layer. 3.15 ml (3.15 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. To the obtained aqueous layer, 4.27 g of toluene and 3.46 ml (3.46 mmol) of 1 mol / L sodium hydroxide aqueous solution were added, the mixture was heated to 40 ° C. and stirred for 20 minutes. After separation, the obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure to a liquid weight of 0.239 g to obtain isopropyl 2 – ({6 – [(N-benzylpyridine-3-sulfonamido) methyl] pyridin-2-yl} amino) acetate as a light brown solid (Obtained as a raw material based on isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate Rate 53.8%). The quantitative purity by HPLC high performance liquid chromatography method was 98.0%. Also, in the measurement (wavelength 260 nm) by the HPLC high performance liquid chromatography method, there was no impurity showing an area% of 0.1% or more.
 Physical property values of the obtained 2 – ({6 – [(N-benzylpyridine-3-sulfonamido) methyl] pyridin-2-yl} amino) acetate isopropylate were as follows.
EI-MS (m /
z):. 454 [M] CI-MS (m /
[Mz):. + 1] 1 H-NMR (CDCl 3 , [delta] (ppm)): 1.27 (6H, d, J = 5.3 Hz), 5.09 (1 H, sep, J = 6.3 Hz), 3.82 (2H, d, J = 5.4 Hz), 4.31 (2H, s), 4.62 7.26 – 7.33 (7 H, m), 7.90 – 7.93 (1 H, m), 8.69 (1 H, m), 6.26 (1 H, d, J = 8.3 Hz)
13 C-NMR (CDCl 3 , δ (ppm)): 21.8, 43.8, 51.1, 51.6, 69.0, 1 H, dd, J = 4.8, 1.6 Hz), 8.95 (1 H, dd, J = 107.2, 112.6, 123.2, 127.9, 128.6, 128.8, 134.7, 135.6, 137.6, 137.7, 148.2, 152.5, 153.6, 157.3, 170.5
IR (KBr cm -1
Calcd: C, 60.77%; H, 5.77%; N, 12.33%
Found (C = : C, 61.03%; H, 5.85%; N, 12.15%.
Example 3 Synthesis
of
2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl) pyridin- Synthesis of isopropyl acetate
 641 mg (2.04 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] pyridine-3-sulfonamide was added to a glass container having an inner volume of about 30 ml equipped with a stirrer, a thermometer and an upper cooling device, , 485 mg (2.00 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 1.33 g (4.08 mmol) of cesium carbonate and 3.53 g And the mixture was stirred at 30 ° C. The reaction was carried out for 26 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate was 0.3% or less in the high performance liquid chromatography analysis, I went for hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography showed that 991 mg of the desired product was contained (reaction yield 95.2%).
Example 4
Synthesis of Isopropyl Acetate of 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido) methyl)
 To a glass container having an inner volume of about 50 ml equipped with a stirring device, a thermometer and an upper cooling device, 3.21 g (10.00 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] 2.43 g (10.0 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 2.82 g (20.4 mmol) potassium carbonate obtained in Example 6 and 17.6 g of acetonitrile was added, and the mixture was heated and stirred at 80 ° C. The reaction was carried out for 10 hours in the high performance liquid chromatography analysis until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-ylamino] acetate as raw material was 0.03% or less. The reaction conversion rate of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate was 43.9% after 1 hour from the start of heating and stirring. After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography revealed that 5.00 g of the target product was contained (reaction yield 96.0%). Next, the reaction solution was concentrated under reduced pressure until the weight of the liquid reached 7.85 g, 42.77 g of toluene was added, and then washed three times with water. 31.5 ml (31.5 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. Incidentally, 0.62 g (corresponding to a yield of 11.8%) of the target product was contained in the organic layer after liquid separation. 42.77 g of toluene and 34.6 ml (34.6 mmol) of a 1 mol / L sodium hydroxide aqueous solution were added to the obtained aqueous layer, and the mixture was heated to 40 ° C. and stirred for 20 minutes. After filtration at 40 ° C. in the hot state, liquid separation was carried out. The obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure until the weight of the liquid reached 8.97 g, and 7.40 g of 2-propanol was added. After heating to 60 ° C., it was slowly cooled and stirred at a temperature at which crystal began to precipitate for 30 minutes, then slowly cooled to 5 ° C. or less, and stirred at the same temperature for 1 hour. The obtained slurry was filtered, and the obtained filtrate was washed with water After washing with cooled 2-propanol and vacuum drying at 50 ° C., 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine- Methyl) pyridin-2-yl] amino} acetic acid 3.90 g as a slightly brown solid (isolation based on isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate Rate 74.9%). The quantitative purity by HPLC high performance chromatography method was 99.0%, and 0.11% of N- [4- (1H-pyrazol-1-yl) benzyl] pyridine-3-sulfonamide as a raw material was contained It was.
 Physical property values of the obtained 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl) pyridin-2- yl] amino} , It was as follows.
EI-MS (m /
z):. 520 [M] CI-MS (m /
[Mz):. + 1] 1 H-NMR (CDCl 3, [delta] (ppm)): 1.24 (6H, d, J = 6.3 Hz), 5.07 (1 H, se, J = 5.5 Hz), 3.82 (2 H, d, J = 5.5 Hz), 4.31 (2 H, s), 4.64 (2 H, s), 4.94 J = 6.3 Hz), 6.26 (1 H, d, J = 8.3 Hz), 6.41 (1 H, dd, J = 7.2, 0.5 Hz), 6.46 (1 H, dd, J = 2.5, 1.8 Hz), 7.25 (2H, m), 7.71 (1H, dd, J = 8.3, 7.2 Hz), 7.32 (1H, ddd, J = 8.0, 4.9, 0.8 Hz), 7.37-7.42 J = 1.8, 0.6 Hz), 7.93 (1 H, dd, J = 2.6, 0.6 Hz), 7.94 (1 H, ddd, J = 8.0, 2.4, 1.7 Hz), 8.69 (1 H, dd, J = 4.8, 1.6 Hz ), 8.98 (IH, dd, J = 2.4, 0.8
Hz). 13 C-NMR (CDCl 3, δ (ppm)): 21.8, 43.7, 51.0, 51.1, 68.9, 107.4, 107.7, 112.6, 119.2, 123.3, 126.7, 129.9, 133.8, 134.6, 137.3, 137.6, 139.8, 141.1, 148.0, 152.6, 153.2, 157.3 , 1737 (C = O), (2981, 2933) (CH), 3437 (NH) , 170.5.
IR (KBr cm -1 ): 764 (CH), 1161 (S = O), 1525 .
elemental analysis; Calcd: C, 59.80%; H, 5.31%; N, 16.07%
Found: C, 59.98%; H, 5.42%; N, 16.14%.
Comparative Example 1
Synthesis of Isopropyl Acetate of 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl)
 To a glass vessel having an inner volume of about 50 ml equipped with a stirring device, a thermometer and an upper cooling device, 3.21 g (10.00 mmol) of N- [4- (1H-pyrazol-1-yl) benzyl] , 2.43 g (10.0 mmol) of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate obtained in Example 6, 2.16 g (20.4 mmol) of sodium carbonate and 17.6 g of acetonitrile was added, and the mixture was heated and stirred at 80 ° C. In the high performance liquid chromatography analysis, the reaction was carried out for 110 hours until the area percentage of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate became 0.05% or less. The reaction conversion rate of isopropyl 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate 1 hour after the start of heating and stirring was 0.92%. After completion of the reaction, the reaction solution was cooled to room temperature, filtered using Celite (trade name), and the filtrate was washed with acetonitrile. Quantitative analysis of the obtained filtrate by high performance liquid chromatography revealed that 0.72 g of the target product was contained (reaction yield: 13.8%). Next, the solution was concentrated under reduced pressure until the weight of the solution reached 7.85 g, 42.6 g of toluene was added, and the mixture was washed three times with water. Since the tar component was separated at the time of washing with water, it was discarded together with the aqueous layer. 31.5 ml (31.5 mmol) of 1 mol / L hydrochloric acid was added to the obtained organic layer, and the mixture was stirred at room temperature for 20 minutes and then separated. 42.6 g of toluene and 34.6 ml (34.6 mmol) of 1 mol / L sodium hydroxide aqueous solution were added to the obtained aqueous layer, and the mixture was heated to 40 ° C. and stirred for 20 minutes. After filtration at 40 ° C. in the hot state, liquid separation was carried out, and the obtained organic layer was washed twice with water. The organic layer was concentrated under reduced pressure to give isopropyl acetate (2 – {[6 – ({N- [4- (1 H-pyrazol- 1 – yl) benzyl] pyridine- To obtain a dark brown viscous liquid containing 0.764. The quantitative purity by HPLC high performance chromatography method was 60.2%, the pure content was 0.
 Physical property values of the obtained 2 – {[6 – ({N- [4- (1 H-pyrazol-1 -yl) benzyl] pyridine-3-sulfonamido} methyl) pyridin-2- yl] amino} , It was as follows.
EI-MS (m /
z):. 520 [M] CI-MS (m /
[Mz):. + 1] 1 H-NMR (CDCl 3, [delta] (ppm)): 1.24 (6H, d, J = 6.3 Hz), 5.07 (1 H, se, J = 5.5 Hz), 3.82 (2 H, d, J = 5.5 Hz), 4.31 (2 H, s), 4.64 (2 H, s), 4.94 J = 6.3 Hz), 6.26 (1 H, d, J = 8.3 Hz), 6.41 (1 H, dd, J = 7.2, 0.5 Hz), 6.46 (1 H, dd, J = 2.5, 1.8 Hz), 7.25 (2H, m), 7.71 (1H, dd, J = 8.3, 7.2 Hz), 7.32 (1H, ddd, J = 8.0, 4.9, 0.8 Hz), 7.37-7.42 J = 1.8, 0.6 Hz), 7.93 (1 H, dd, J = 2.6, 0.6 Hz), 7.94 (1 H, ddd, J = 8.0, 2.4, 1.7 Hz), 8.69 (1 H, dd, J = 4.8, 1.6 Hz ), 8.98 (IH, dd, J = 2.4, 0.8
Hz). 13 C-NMR (CDCl 3, δ (ppm)): 21.8, 43.7, 51.0, 51.1, 68.9, 107.4, 107.7, 112.6, 119.2, 123.3, 126.7, 129.9, 133.8, 134.6, 137.3, 137.6, 139.8, 141.1, 148.0, 152.6, 153.2, 157.3 , 1737 (C = O), (2981, 2933) (CH), 3437 (NH) , 170.5.
IR (KBr cm -1 ): 764 (CH), 1161 (S = O), 1525 .
Example 5
Synthesis of 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} acetate isopropylate
 948 g of 2-propanol and 76.7 g of concentrated sulfuric acid were added to a glass container having an inner volume of about 2 L and equipped with a stirring device, a thermometer and an upper cooling device, and the mixture was heated to 75 ° C. To this was added 2 – {[(t-butoxycarbonyl) (6-hydroxymethylpyridin-2-yl)] amino} acetic acid tert- butyl ester synthesized by the method described in Reference Example 3- (b) A mixed solution of 135 g of butyl, 45 g of toluene and 311 g of 2-propanol was added dropwise over 40 minutes, followed by heating and stirring at 78 ° C. for 6 hours. After cooling, 677 g of toluene and 406 g of water were added under an internal pressure of 20 hPa and an external temperature of 40 ° C. until the amount of liquid reached 309 g, and the mixture was stirred at room temperature and then separated. The obtained aqueous layer was added dropwise to a mixed solution of 129 g of separately prepared sodium hydrogencarbonate, 812 g of water, and 677 g of toluene over 20 minutes, stirred at room temperature for 1 hour, separated, and the aqueous layer was washed with 338 g . The obtained organic layer was mixed and washed with 426 g of a 5 wt% sodium chloride aqueous solution to obtain 1370 g of an organic layer. Approximately 1356 g of this was taken out, concentrated to a liquid volume of 113 g, and then toluene was added until the liquid amount reached 300 g. 190 g of n-heptane was added to the solution, and the solution was warmed to 45 ° C. to dissolve the crystals, followed by cooling to 35 ° C. A small amount of separately synthesized seed crystals was added in the same way and stirred at 35 ° C. for 1 hour, the crystals gradually increased. 365 g of n-heptane was added dropwise over 30 minutes, cooled for 40 minutes until the internal temperature reached 5 ° C., and stirred at the same temperature for 30 minutes. The precipitated crystals were separated by filtration, washed with n-heptane and then dried under reduced pressure at 50 ° C. to obtain 70.4 g of isopropyl 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} . The quantitative purity by HPLC high performance chromatography was 94.3%, and the pure content was 66.4 g (raw material 2 – {[(t-butoxycarbonyl) (6-hydroxymethylpyridin-2-yl )] Amino} acetate as t-butyl acetate in an isolated yield of 74.7%).
 Physical properties of the obtained 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} acetate isopropyl were as follows.
EI-MS (m /
z):. 224 [M] CI-MS (m /
[Mz):. + 1] 1 H-NMR (CDCl 3, [delta] (ppm)): 1.27 (6H, d, J = 6.3 Hz), 3.76 (IH, s), 4.10 (2H, d, J = 5.5 Hz), 4.59 (2H, s), 5.00 (IH, s), 5.10 (IH, m), 6.36
13 C-NMR (CDCl 3, δ (ppm) ), 6.51 (1 H, dd, J = 7.3, 0.7 Hz), 7.41 (1 H, ddd, J = 5.74, 3.88 Hz ) ): 21.8, 44.1, 63.5, 69.0, 106.6, 109.5, 138.0, 156.8, 156.9, 170.7
IR (KBr cm -1): 416, 469, 531, 559, 731, 785, 826, 862, 903, 916, 941, 980, 1014, 1052, 1082, 1106, 1131, 1147, 1182, 1217, 1256, 1276, 1347, 1378,
Calcd: C, 58.91% Calcd: C, 58.91% (C = O) ; H, 7.19%; N, 12.49%
Found: C, 58.99%; H, 7.17%; N, 12.48%.
Example 6
Synthesis of 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate isopropylate
 To a solution of 35.7 g of isopropyl 2 – {[6- (hydroxymethyl) pyridin-2-yl] amino} acetate obtained in Example 5 in 396 g of methylene chloride was added 19.6 g of thionyl chloride at room temperature Was added dropwise over 20 minutes, and the mixture was stirred at room temperature for 1 hour. The obtained reaction solution was added dropwise to a mixed liquid slurry of 37.8 g of sodium hydrogencarbonate and 149 g of water, and the mixture was stirred at room temperature for 20 minutes. After liquid separation, 6.73 g of magnesium sulfate was added to the organic layer, dehydrated and the filtrate was concentrated to dryness at 50 ° C. to obtain 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate 37 .8 g as a light brown solid.
 Physical properties of the obtained 2 – {[6- (chloromethyl) pyridin-2-yl] amino} acetate isopropyl were as follows.
EI-MS (m /
z):. 242 [M] CI-MS (m /
[Mz):. + 1] 1 H-NMR (CDCl 3, [delta] (ppm)): 1.24 (6H, m) J = 8.3 Hz), 4.7 (2H, d, J = 5.4 Hz), 4.48 (2H, s), 5.03 (IH, s), 5.10 (IH, m), 6.39
13 C-NMR (CDCl 3, δ (ppm)): 21.8, 44.0, 44.7, 68.9, 107.7, 112.2, 138.1, 1 H NMR (CDCl 3, δ (ppm)): 7.43 (1H, dd, J = 7.8, 7.8 Hz)154.6, 157.3, 170.7
IR (KBr cm -1): 415, 446, 530, 560, 627, 735, 804, 827, 874, 903, 939, 952, 982, 1042, 1088, 1108, 1128, 1144, 1167, 1180, 1219, 1269, 1281, 1350,
Elemental analysis: 1378, 1400, 1420, 1434, 1470, 1525 (C = N), 1580, 1613, 1690, 1728 (C = O), 2878, 2934 (CH), 2981 (CH), 3379Calcd: C, 54.44%; H, 6.23%; N, 11.54%
Found: C, 54.46%; H, 6.23%; N, 11.56%.

PAPER

Journal of Medicinal Chemistry (2018), 61(15), 6869-6891.

Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl

 Pharmaceuticals Research LaboratoryUBE Industries, Ltd.1978-5 Kogushi, Ube, Yamaguchi 755-8633, Japan
 R&D DivisionSanten Pharmaceutical Co., Ltd.Grand Front Osaka Tower A 4-20, Ofukacho, Kita-ku, Osaka 530-8552, Japan
§ R&D DivisionSanten Inc.6401 Hollis Street, Suite 125, Emeryville, California 94608, United States
J. Med. Chem.201861 (15), pp 6869–6891
DOI: 10.1021/acs.jmedchem.8b00808
*Phone: (+81)836-31-6432. Fax: (+81)836-31-4383. E-mail: 30487u@ube-ind.co.jp.
Abstract Image

EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma.

Isopropyl (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2- ylamino)acetate (OMDI)

white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.87 (dd, J = 2.4, 0.7 Hz, 1H), 8.75 (dd, J = 4.8, 1.6 Hz, 1H), 8.48 (dd, J = 2.4, 0.5 Hz, 1H), 8.08 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.80–7.77 (m, 2H), 7.74 (dd, J = 1.8, 0.5 Hz, 1H), 7.51 (ddd, J = 8.1, 4.8, 0.7 Hz, 1H), 7.36–7.33 (m, 2H), 7.26 (dd, J = 8.3, 7.1 Hz, 1H), 6.89 (t, J = 6.1, 1H), 6.54 (dd, J = 2.4, 1.8 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 7.1 Hz, 1H), 4.87 (sept, J = 6.3 Hz, 1H), 4.62 (s, 2H), 4.21(s, 2H), 3.76 (d, J = 6.1 Hz, 2H), 1.10 (d, J = 6.3 Hz, 6H). 13C NMR (proton-decoupled spectrum, 500 MHz, DMSO-d6) δ 171.2 (s), 158.1 (s), 153.4 (s), 153.2 (s), 147.6 (s), 141.4 (s), 139.6 (s), 137.5 (s), 137.0 (s), 135.1 (s), 134.4 (s), 129.9 (s), 128.2 (s), 124.4 (s), 118.8 (s), 111.4 (s), 108.3 (assigned for two nonequivalent carbons with identical chemical shift), 68.0 (s), 51.9 (s), 51.2 (s), 43.1 (s), 22.0 (s). MS (CI+) m/z521 (M + H)+. IR wavelength [cm–1] 3437 (N–H), 1736 (C═O), 1608, 1525, and 1511 (C═C and C═N), 1321 (SO2), 1161 (SO2). Elemental analysis [%] (average of three experiments) calculated for C26H28N6O4S: C 59.98, H 5.42, N 16.14. Found: C 59.76, H 5.28, N 16.01. TLC Rf value 0.39 (ethyl acetate).

//////////////Omidenepag isopropyl, JAPAN 2018, オミデネパグイソプロピル , DE-117, UBE, SANTEN

CC(C)OC(=O)CNc1cccc(CN(Cc2ccc(cc2)n3cccn3)S(=O)(=O)c4cccnc4)n1

Evocalcet, エボカルセト , Эвокальцет , إيفوكالسيت , 依伏卡塞 ,


Evocalcet.pngImage result for EvocalcetEvocalcet.svg

Evocalcet

C24H26N2O2,  374.484 

Evocalcet; UNII-E58MLH082P; E58MLH082P; 870964-67-3; Evocalcet [INN]; Orkedia (TN)
エボカルセト

Эвокальцет [Russian] [INN]

إيفوكالسيت [Arabic] [INN]
依伏卡塞 [Chinese] [INN]
2-[4-[(3S)-3-[[(1R)-1-naphthalen-1-ylethyl]amino]pyrrolidin-1-yl]phenyl]acetic acid
KHK-7580
MT-4580
UNII:E58MLH082P
{4-[(3S)-3-{[(1R)-1-(1-Naphthyl)ethyl]amino}-1-pyrrolidinyl]phenyl}acetic acid
10098
870964-67-3 [RN]
Benzeneacetic acid, 4-[(3S)-3-[[(1R)-1-(1-naphthalenyl)ethyl]amino]-1-pyrrolidinyl]-
E58MLH082P
KHK-7580 / KHK7580 / MT-4580

Image result for Evocalcet

エボカルセト
Evocalcet

C24H26N2O2 : 374.48
[870964-67-3]

WP_000286

KHK 7580 …..example

3.008
Figure US20140080770A1-20140320-C00373
Figure US20140080770A1-20140320-C00374
Figure US20140080770A1-20140320-C00375
2HCl MS · APCI: 375[M + H]+

Figure imgb0350

in EP1757582

4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid

4-​[(3S)​-​3-​[[(1R)​-​1-​(1-​naphthalenyl)​ethyl]​amino]​-​1-​pyrrolidinyl]​-Benzeneacetic acid,

BASE ….870964-67-3

DI HCL SALT …….870856-31-8

MF C24 H26 N2 O2 BASE

MW 374.48 BASE

KHK-7580

KHK-7580; MT-4580

Mitsubishi Tanabe Pharma Corp… innovator

Kyowa Hakko Kirin Co Ltd.. licencee

4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid,

Evocalcet (trade name Orkedia) is a drug for the treatment of hyperparathyroidism.[1] It acts as a calcium-sensing receptor agonist.[2]

In 2018, it was approved in Japan for treatment of secondary hyperparathyroidism in patients on dialysis.[3]

useful as calcium-sensitive receptor (CaSR) agonists for treating hyperparathyroidism.  a CaSR agonist, being developed by Kyowa Hakko Kirin, under license from Mitsubishi Tanabe, for treating secondary hyperparathyroidism (phase 2 clinical, as of March 2015).

WO2005115975,/EP1757582

http://www.google.co.in/patents/EP1757582A1?cl=en

Example no

3.008
Figure US20140080770A1-20140320-C00373
Figure US20140080770A1-20140320-C00374
Figure US20140080770A1-20140320-C00375
2HCl MS · APCI: 375[M + H]+

Figure imgb0350

WO 2015034031A1

http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=20150312&CC=WO&NR=2015034031A1&KC=A1

Mitsubishi Tanabe Pharma Corporation

The present invention provides a novel crystal form of an arylalkylamine
compound. Specifically, a novel crystal form of
4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid has
excellent stability, and is therefore useful as an active ingredient for
a medicine. The present invention also provides an industrially
advantageous method for producing an arylalkylamine compound.

WP_000287

WO 2015034031A1

http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=20150312&CC=WO&NR=2015034031A1&KC=A1
Mitsubishi Tanabe Pharma Corporation

The present invention provides a novel crystal form of an arylalkylamine compound. Specifically, a novel crystal form of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid has excellent stability, and is therefore useful as an active ingredient for a medicine. The present invention also provides an industrially advantageous method for producing an arylalkylamine compound.

 

PATENT

http://www.google.co.in/patents/US20140080770?cl=und

Reference Example 3.001

Figure US20140080770A1-20140320-C00042

(1) To a mixed solution containing 33.5 g of 3-hydroxypiperidine and 62.7 ml of triethylamine dissolved in 250 ml of methylene chloride was added dropwise a solution of 55.7 ml of benzyloxycarbonyl chloride in 150 ml of methylene chloride, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous citric acid and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate.

MS•APCI (m/z): 236 [M+H]+

(2) 800 ml of a solution of 52.4 ml of oxalyl chloride in methylene chloride was cooled to −78° C., 53.2 ml of DMSO was added dropwise to the solution, and the mixture was stirred at −78° C. for 0.5 hour. A solution of 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate dissolved in 200 ml of methylene chloride was added dropwise to the mixture, and further 293 ml of triethylamine was added dropwise to the same, and the mixture was stirred for 16 hours while a temperature thereof was gradually raised to room temperature. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated to obtain 83.7 g of 1-benzyloxycarbonyl-3-piperidone. MS•APCI (m/z): 234 [M+H]+
(3) To a solution of 83.7 g of 1-benzyloxycarbonyl-3-piperidone dissolved in 1.2 liters of methylene chloride was added 55.0 g of (R)-(+)-1-(1-naphthyl)ethylamine, and after the mixture was stirred at room temperature for 2 hours, 69 ml of acetic acid and 160 g of sodium triacetoxy borohydride were added to the mixture, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous sodium hydroxide to make the mixture basic, and then, chloroform was added to the mixture, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 98.7 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
(4) To a solution of 40.95 g of triphosgene dissolved in 800 ml of methylene chloride was added dropwise a mixed solution containing 80.6 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate and 86.6 ml of triethylamine dissolved in 200 ml of methylene chloride at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was washed with 200 ml of diethyl ether, and the crystal collected by filtration was recrystallized from chloroform and diethyl ether to obtain 48.9 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.

Further, the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=8:1→0:1) to obtain 5.82 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate and 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.

(5) To a solution containing 54.6 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 700 ml of tetrahydrofuran was added 350 ml of water, and the mixture was stirred under reflux for 15 hours. After tetrahydrofuran was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added thereto, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 24.3 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
(6) To a solution containing 24.2 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10% wet), and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 40 hours. Palladium carbon was removed, and the solvent was evaporated, the residue was washed with ethyl acetate-chloroform (10:1), and collected by filtration to obtain 15.3 g of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine (the following Reference example Table, Reference example 3.001(a)). MS•APCI (m/z): 255 [M+H]+
(7) By using 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (5) to obtain 4.74 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+

Moreover, by using 4.7 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (6) to obtain 2.89 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine. MS•APCI (m/z): 255 [M+H]+

(8) To a solution of 3.46 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine dissolved in 15 ml of methanol was added dropwise 20 ml of a solution of 4M hydrochloric acid in ethyl acetate, and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, washed and dried to obtain 3.33 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine dihydrochloride

3.008
Figure US20140080770A1-20140320-C00373
Figure US20140080770A1-20140320-C00374
Figure US20140080770A1-20140320-C00375
2HCl MS · APCI: 375[M + H]+
TABLE A3
Figure US20140080770A1-20140320-C00350
Example No. R1—X—
Figure US20140080770A1-20140320-C00351
—Ar Salt Physical properties, etc.

CLIP

see all at   http://drugpatentsint.blogspot.in/2015/03/wo-2015034031.html

see all at   http://drugpatentsint.blogspot.in/2015/03/wo-2015034031.html

see all at   http://drugpatentsint.blogspot.in/2015/03/wo-2015034031.html

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see all at   http://drugpatentsint.blogspot.in/2015/03/wo-2015034031.html

do not miss out on above click

 http://www.kyowa-kirin.com/research_and_development/pipeline/

KHK7580 -Secondary Hyperparathyroidism

JP

Company Mitsubishi Tanabe Pharma Corp.
Description Calcium receptor agonist
Molecular Target
Mechanism of Action Calcium-sensing receptor (CaSR) agonist
Therapeutic Modality Small molecule
Latest Stage of Development Phase II
Standard Indication Thyroid disease
Indication Details Treat hyperparathyroidism in patients receiving hemodialysis; Treat secondary hyperparathyroidism (SHPT)
Regulatory Designation
Partner

Kyowa Hakko Kirin Co. Ltd.

August 29, 2014

Kyowa Hakko Kirin Announces Commencement of Phase 2b Clinical Study of KHK7580 in Patients with Secondary Hyperparathyroidism in Japan

Tokyo, Japan, August 29, 2014 — Kyowa Hakko Kirin Co., Ltd. (Tokyo: 4151, President and CEO: Nobuo Hanai, “Kyowa Hakko Kirin”) today announced the initiation of a phase 2b clinical study evaluating KHK7580 for secondary hyperparathyroidism patients receiving hemodialysis in Japan.

This randomized, placebo-controlled, double-blind, parallel-group, multi-center study is designed to evaluate efficacy and safety in cohorts comprising KHK7580, its placebo and cinacalcet and initial dose of KHK7580 for secondary hyperparathyroidism patients receiving hemodialysis.

KHK7580 is a small molecular compound produced by Mitsubishi Tanabe Pharma Corporation (President & Representative Director, CEO: Masayuki Mitsuka, “Mitsubishi Tanabe Pharma”). Kyowa Hakko Kirin signed a license agreement of KHK7580 with Mitsubishi Tanabe Pharma for the rights to cooperative research, develop, market and manufacture the product in Japan and some part of Asia on March 2008.

The Kyowa Hakko Kirin Group is contributing to the health and prosperity of the world’s people by pursuing advances in life sciences and technology and creating new value.

Outline of this study

CLINICALTRIALS.GOV IDENTIFIER New window opensNCT02216656
TARGET POPULATION Secondary hyperparathyroidism patients receiving hemodialysis
TRIAL DESIGN Randomized, placebo-controlled, double-blind (included open arm of cinacalcet), parallel-group, multi-center study
ADMINISTRATION GROUP KHK7580, Placebo, cinacalcet
TARGET NUMBER OF SUBJECTS 150
PRIMARY OBJECTIVE Efficacy
TRIAL LOCATION Japan
TRIAL DURATION Jul. 2014 to Jun. 2015

Contact:

Kyowa Hakko Kirin
Media Contact:
+81-3-3282-1903
or
Investors:
+81-3-3282-0009

Update on march 2016

New comment waiting approval on New Drug Approvals

M.F. Balandrin commented on KHK 7580 structure cracked

KHK 7580 …..example 3.008 2HCl MS · APCI: 375[M + H]+ in …

The calcimimetic agent, KHK-7580, currently entering Phase III clinical trials, has now been given the INN (WHO) generic name, evocalcet. Its chemical structure has also now been published and it is, in fact, correct as proposed by Dr. Crasto (Well Done!!):

http://www.drugspider.com/drug/evocalcet

https://tripod.nih.gov/ginas/app/substance/f580b9fd

http://www.medkoo.com/products/6729

(Etymologically, in classical Latin, “evolutio” refers to “the unrolling of a scroll” and “evocare” refers to a “call out”…).

http://www.medkoo.com/products/6729

img

Name: Evocalcet
CAS#: 870964-67-3
Chemical Formula: C24H26N2O2
Exact Mass: 374.19943

Evocalcet is a calcium-sensing receptor agonist. The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. The calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). CaSR is expressed in all of the organs of the digestive system. CaSR plays a key role in gastrointestinal physiological function and in the occurrence of digestive disease. High dietary Ca2+ may stimulate CaSR activation and could both inhibit tumor development and increase the chemotherapeutic sensitivity of cancer cells in colon cancer tissues. (Last update: 12/15/2015).

Synonym: MT-4580; MT 4580; MT4580; KHK-7580; KHK7580; KHK 7580; Evocalcet

IUPAC/Chemical Name: 2-(4-((S)-3-(((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)phenyl)acetic acid

2

https://tripod.nih.gov/ginas/app/substance/f580b9fd

Structure of EVOCALCET

http://www.drugspider.com/drug/evocalcet

INN NAME
Evocalcet
LAB CODE(S)
MT-4580
KHK-7580
CHEMICAL NAME
{4-[(3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}pyrrolidin-1-yl]phenyl}acetic acid
CHEMICAL STRUCTURE
MOLECULAR FORMULA
C24H26N2O2
SMILES
O=C(O)CC1=CC=C(N2C[C@@H](N[C@@H](C3=C4C=CC=CC4=CC=C3)C)CC2)C=C1
CAS REGISTRY NUMBER
870964-67-3
ORPHAN DRUG STATUS
No
ON FAST TRACK
No
NEW MOLECULAR ENTITY
Yes
ORIGINATOR
DEVELOPER(S)
CLASS
MECHANISM OF ACTION
WHO ATC CODE(S)
EPHMRA CODE(S)
CLINICAL TRIAL(S)
CONDITIONS INTERVENTIONS PHASES RECRUITMENT SPONSOR/COLLABORATORS
Secondary Hyperparathyroidism Drug: KHK7580 Phase 3 Recruiting Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: KHK7580 Phase 3 Recruiting Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: KHK7580|Drug: KRN1493 Phase 2|Phase 3 Recruiting Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: Placebo|Drug: KHK7580 low dose|Drug: KHK7580 middle dose|Drug: KHK7580 high dose|Drug: KRN1493 Phase 2 Completed Kyowa Hakko Kirin Company, Limited
Hyperparathyroidism Drug: KHK7580 Phase 1|Phase 2 Completed Kyowa Hakko Kirin Company, Limited
Secondary Hyperparathyroidism Drug: KHK7580 Phase 1 Completed Kyowa Hakko Kirin Company, Limited
UPDATED ON
11 Oct 2015

CLIP

https://www.sciencedirect.com/science/article/pii/S0960894X18303676

Image result for Evocalcet

Scheme 1. Synthesis of key intermediates S4S5S9, and S10. Reagents and conditions: (a) Tf2O, i-Pr2NEt, CH2Cl2, −20 °C. Then, (R)-(+)-1-(1-naphthyl)ethylamine, −20 °C to rt (S1 57%); (b) triphosgene, Et3N, CH2Cl2, −20 °C to 5 °C. Then, i-Pr2NEt, tert-butanol, 70 °C; (c) separation via silica gel chromatography (S2 31%, S3 33% in 2 steps); (d) HClchloroform1,4-dioxane, rt (S4 > 94%, S5 > 94%); (e) (R)-(+)-1-(1-naphthyl)ethylamine, NaBH(OAc)3acetic acid, CH2Cl2, rt (S6 79%); (f) triphosgene, Et3N, CH2Cl2, 0 °C to rt; (g) separation via filtration and silica gel chromatography (S7 58%, S8 16% in 2 steps); (h) water, tetrahydrofuranreflux; (i) H2, Pd/C, methanol, rt (S9 50% in 2 steps); (j) HCl, ethyl acetate, methanol, rt (S10 31% in 3steps).

Scheme 2. Synthesis of 215 and evocalcet (16). Reagents and conditions: (a) aryl iodide or aryl bromide, palladium acetate, (rac)-BINAP, sodium tert-butoxide, toluene, 80 °C or reflux; (b) HCl, ethyl acetate or 1,4-dioxane, rt; (c) tert-butyl 4-fluorobenzoate, potassium carbonate, DMSO, 130 °C; (d) HCl, 1,4-dioxane, 45 °C; (e) 2-aminoethanol, EDC hydrochlorideHOBt, Et3N, DMF, rt; (f) 5-(4-bromophenyl)-2-(triphenylmethyl)–2H-tetrazole, Pd2(dba)3, (2-biphenyl)di-tert-butylphosphine, sodium tert-butoxide, toluene, rt; (g) HCl, water, 1,4-dioxane, rt; (h) tert-butyl 4-bromobenzoate, palladium acetate, (rac)-BINAP, sodium tert-butoxide, toluene, reflux; (i) trifluoroacetic acid, rt. Then, HCl, ethyl acetate or 1,4-dioxane, rt (2 23%, 3 21%, 4 44%, 5 34%, 620%, 7 55%, 8 29%, 9 21%, 10 19%, 11 40%, 13 26%, 14 69%, 15 69% in 2 steps); (j) 3-(trifluoromethoxy)phenylboronic acid, copper acetate, Et3N, CH2Cl2molecular sieve 4A, rt (S117%); (k) (COCl)2, DMSO, Et3N, CH2Cl2, −60 °C to rt (S12 was used in the next step without purification); (l) (R)-(+)-1-(1-naphthyl)ethylamine, NaBH(OAc)3acetic acid, CH2Cl2, rt. Then, separation of isomers; (m) HCl, ethyl acetate, rt (12 10% in 2 steps); (n) ethyl 4-bromophenylacetate, Pd2(dba)3, (2-biphenyl)di-tert-butylphosphine, sodium tert-butoxide, toluene, rt (S13 63%); (o) aqueous sodium hydroxide solution, ethanol, rt (evocalcet (16) 73%).

evocalcet as a white crystal. MS-APCI (m/z): 375 [M+H]+ .

1H NMR (400 MHz, DMSO-d6) δ 8.25-–8.37 (m, 1H), 7.88–7.97 (m, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.39–7.57 (m, 3H), 7.01 (d, J = 8.6 Hz, 2H), 6.38 (d, J = 8.6 Hz, 2H), 4.74 (q, J = 6.4 Hz, 1H), 3.37 (s, 2H), 3.18–3.34 (m, 3H), 3.03–3.15 (m, 1H), 2.89–3.02 (m, 1H), 1.95–2.11 (m, 1H), 1.80–1.94 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H).

Anal. Calcd for C24H26N2O2: C 76.98; H 7.00; N 7.48. Found: C 76.83; H 7.06; N 7.46.

HPLC 99.6% (25.4 min, Inertsil ODS-3V [5 μm, 4.6 × 250 mm], 0.05% TFA in H2O/0.05% TFA in CH3CN [95:5 to 0:100/60 min]).

References

  1. Jump up^ Kawata, Takehisa; Tokunaga, Shin; Murai, Miki; Masuda, Nami; Haruyama, Waka; Shoukei, Youji; Hisada, Yutaka; Yanagida, Tetsuya; Miyazaki, Hiroshi; Wada, Michihito; Akizawa, Tadao; Fukagawa, Masafumi (2018). “A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro”. PLOS ONE13 (4): e0195316. doi:10.1371/journal.pone.0195316PMID 29614098.
  2. Jump up^ Miyazaki, Hiroshi; Ikeda, Yousuke; Sakurai, Osamu; Miyake, Tsutomu; Tsubota, Rie; Okabe, Jyunko; Kuroda, Masataka; Hisada, Yutaka; Yanagida, Tetsuya; Yoneda, Hikaru; Tsukumo, Yukihito; Tokunaga, Shin; Kawata, Takehisa; Ohashi, Rikiya; Fukuda, Hajime; Kojima, Koki; Kannami, Ayako; Kifuji, Takayuki; Sato, Naoya; Idei, Akiko; Iguchi, Taku; Sakairi, Tetsuya; Moritani, Yasunori (2018). “Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism”. Bioorganic & Medicinal Chemistry Letters28 (11): 2055–2060. doi:10.1016/j.bmcl.2018.04.055.
  3. Jump up^ “Kyowa Hakko Kirin Launches ORKEDIA® TABLETS (Evocalcet) for the Treatment of Secondary Hyperparathyroidism in Patients on Maintenance Dialysis in Japan” (Press release). Kyowa Hakko Kirin. May 22, 2018.
Evocalcet
Evocalcet.svg
Clinical data
Trade names Orkedia
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C24H26N2O2
Molar mass 374.48 g·mol−1

///////////////Evocalcet,  エボカルセト , Эвокальцет ,  إيفوكالسيت , 依伏卡塞 , JAPAN 2018, KHK-7580, MT-4580, UNII:E58MLH082P, ORKEDIA

SMILES Code: O=C(O)CC1=CC=C(N2C[C@@H](N[C@@H](C3=C4C=CC=CC4=CC=C3)C)CC2)C=C1

 C[C@H](c1cccc2c1cccc2)N[C@H]3CCN(C3)c4ccc(cc4)CC(=O)O

Spiramycin, スピラマイシン


8025-81-8.pngSpiramycin I.svg

ChemSpider 2D Image | [(11E,13E)-6-({5-[(4,5-Dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl}oxy)-10-{[5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy }-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxooxacyclohexadeca-11,13-dien-7-yl]acetaldehyde | C43H74N2O14Spiramycin.png2D chemical structure of 8025-81-8

ThumbChemSpider 2D Image | 033ECH6IFG | C43H74N2O14

Spiramycin

スピラマイシン

CAS: 8025-81-8

Sanofi INNOVATOR

Molecular Formula: C43H74N2O14
Molecular Weight: 843.065 g/mol

[(11E,13E)-6-({5-[(4,5-Dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl}oxy)-10-{[5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy }-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxooxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

2-[(11E,13E)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

Leucomycin V, 9-O-[(2R,5S,6R)-5-(dimethylamino)tetrahydro-6-methyl-2H-pyran-2-yl]-

033ECH6IFG
24916-50-5 [RN]
Spiramycin I
[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-10-{[(2R,5S,6S)-5-(dimethylamino)-6
  • Provamycin
  • Rovamycin
  • RP 5337
  • Sequamycin
  • IL 5902
  • NSC-64393
  • ATC:J01FA02
  • Use:macrolide antibiotic
  • EINECS:232-429-6
  • LD50:130 mg/kg (M, i.v.); 2900 mg/kg (M, p.o.);
    170 mg/kg (R, i.v.); 3550 mg/kg (R, p.o.);
    5200 mg/kg (dog, p.o.)

2018/7/2 japan approved, UNII: 71ODY0V87H

Solubility

Slightly soluble in water

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621

Soluble in most organic solvents

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621

Spectral Properties

UV max (ethanol): 231nm

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621

Specific optical rotation: -80 deg at 20 deg C/D

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1621
スピラマイシン
Spiramycin


スピラマイシン酢酸エステル JP17
Spiramycin Acetate

A macrolide antibiotic produced by Streptomyces ambofaciens. The drug is effective against gram-positive aerobic pathogens, N. gonorrhoeae, and staphylococci. It is used to treat infections caused by bacteria and Toxoplasma gondii.

Spiramycin is a macrolide antimicrobial agent with activity against gram-positive organisms, including Streptococcus pyogenes (group A beta-hemolytic streptococci), S. viridans, Corynebacterium diphtheriae, and methicillin-sensitive Staphylococcus aureus. Spiramycin is a 16-membered ring macrolide. It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium species. Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action.

Spiramycin is a macrolide antibiotic and antiparasitic It is used to treat toxoplasmosis and various other infections of soft tissues. Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2]

Spiramycin has been used in Europe since the year 2000 under the trade name “Rovamycine”, produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacıbaşı İlaç, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.

Spiramycin is a 16-membered ring macrolide. It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibiotic action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium species. Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration

Synthesis Path

  • From culture of Streptomyces ambofaciens.

Trade Names

Country Trade Name Vendor Annotation
D Rovamycine Teofarma
Selectomycin Grünenthal
F Bi Missilor Pierre Fabre
Birodogyl Sanofi-Aventis
Missilor Pierre Fabre comb.
Rodogyl Pierre Fabre
Rovamycine Grünenthal
I Rovamicina Sanofi-Aventis
Rovamycina Teofarma
Spiromix Pulitzer

Spiramycin

Title: Spiramycin
CAS Registry Number: 8025-81-8
Manufacturers’ Codes: RP-5337
Trademarks: Selectomycin (Grñenthal); Rovamicina (RPR); Rovamycin (RPR)
Literature References: Antibiotic substance classified in the erythromycin-carbomycin group and produced by Streptomyces ambofaciens from soil of northern France: Cosar et al., C.R. Seances Soc. Biol. Ses Fil. 234, 1498 (1952); Pinnert-Sindico et al.,Antibiot. Annu. 1954-1955, 724; Ninet, Verrier, US 2943023 (1960 to Rhône-Poulenc), see also US 3000785 (1961 to Rhône-Poulenc). Antibacterial activity and toxicity: H. Sous et al., Arzneim.-Forsch. 8, 386 (1958). Separation into 3 components named spiramycin I, II and III: Preud’homme, Charpentier, US 2978380 and US 3011947 (1961 to Rhône-Poulenc). Structure: Kuehne, Benson, J. Am. Chem. Soc. 87, 4660 (1965). Revised structure: Omura et al., ibid. 91, 3401 (1969); Mitscher et al., J. Antibiot. 26,55 (1973). Revised configuration at C-9: Freiberg et al., J. Org. Chem. 39, 2474 (1974). Symposium on pharmacology, antibacterial spectrum, and clinical efficacy: J. Antimicrob. Chemother. 22, Suppl. B, 1-213 (1988).
Properties: Amorphous base, slightly sol in water. [a]D20 -80° (methanol). uv max (ethanol): 231 nm. Sol in most organic solvents. Active on gram-positive bacteria and rickettsiae. Cross resistance between microorganisms resistant to erythromycin and carbomycin. LD50 in rats (mg/kg): 9400 orally; 1000 s.c.; 170 i.v. (Sous).
Optical Rotation: [a]D20 -80° (methanol)
Absorption maximum: uv max (ethanol): 231 nm
Toxicity data: LD50 in rats (mg/kg): 9400 orally; 1000 s.c.; 170 i.v. (Sous)
Derivative Type: Embonate
Trademarks: Spira 200 (RMB)
Derivative Type: Hexanedioate
Additional Names: Spiramycin adipate
Trademarks: Stomamycin (Chassot); Suanovil (Biokema)
Derivative Type: Spiramycin I
CAS Registry Number: 24916-50-5
Additional Names: Foromacidin A
Molecular Formula: C43H74N2O14
Molecular Weight: 843.05
Percent Composition: C 61.26%, H 8.85%, N 3.32%, O 26.57%
Properties: Crystals, mp 134-137°. [a]D20 -96°.
Melting point: mp 134-137°
Optical Rotation: [a]D20 -96°
Derivative Type: Spiramycin I triacetate
Properties: Crystals, mp 140-142°. [a]D20 -92.5°.
Melting point: mp 140-142°
Optical Rotation: [a]D20 -92.5°
Derivative Type: Spiramycin II
CAS Registry Number: 24916-51-6
Additional Names: Foromacidin B
Molecular Formula: C45H76N2O15
Molecular Weight: 885.09
Percent Composition: C 61.07%, H 8.65%, N 3.17%, O 27.11%
Properties: Crystals, mp 130-133°. [a]D20 -86°.
Melting point: mp 130-133°
Optical Rotation: [a]D20 -86°
Derivative Type: Spiramycin II diacetate
Properties: Crystals from cyclohexane, mp 156-160°. [a]D20 -98.4°.
Melting point: mp 156-160°
Optical Rotation: [a]D20 -98.4°
Derivative Type: Spiramycin III
CAS Registry Number: 24916-52-7
Additional Names: Foromacidin C
Molecular Formula: C46H78N2O15
Molecular Weight: 899.12
Percent Composition: C 61.45%, H 8.74%, N 3.12%, O 26.69%
Properties: Crystals, mp 128-131°. [a]D20 -83°.
Melting point: mp 128-131°
Optical Rotation: [a]D20 -83°
Derivative Type: Spiramycin III diacetate
Properties: Crystals from cyclohexane, mp 140-142°. [a]D20 -90.4°.
Melting point: mp 140-142°
Optical Rotation: [a]D20 -90.4°
Therap-Cat: Antibacterial.
Therap-Cat-Vet: Antibacterial; growth promotant.
Keywords: Antibacterial (Antibiotics); Macrolides.
Spiramycin
Spiramycin I.svg
Clinical data
Synonyms 2-[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-10-{[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
Routes of
administration
oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
E number E710 (antibiotics) Edit this at Wikidata
ECHA InfoCard 100.029.476 Edit this at Wikidata
Chemical and physical data
Formula C43H74N2O14
Molar mass 843.053 g/mol
3D model (JSmol)
Solubility in water Insoluble in water; Very soluble in acetonitrile and methanol; Almost completely(>99.5) in ethanol. mg/mL (20 °C)

References

  1. Jump up^ Spiramycin advanced consumer information | Drugs.com
  2. Jump up^ Toxoplasmosis at MayoClinic.com

References

    • Pinnert-Sindico, S. et al.: Antibiot. Annu. (ABANAE) 1954-1955, 724.
    • US 2 943 023 (Rhône-Poulenc; 28.6.1960; F-prior. 30.5.1956).
    • US 2 978 380 (Rhône-Poulenc; 4.4.1961; F-prior. 30.11.1955).
    • US 3 000 785 (Rhône-Poulenc; 19.9.1961; F-prior. 31.7.1953).
    • US 3 011 947 (Rhône-Poulenc; 5.12.1961; F-prior. 30.11.1955).
    • CN 107266512

      CN 107840864

DB06145.png

Spiramycin I)

///////////Spiramycin, スピラマイシン , japan 2018, Provamycin, Rovamycin, RP 5337, Sequamycin, IL 5902, NSC-64393, ATC:J01FA02, Use:macrolide antibiotic, EINECS:232-429-6

 

O=CCC4C(OC2OC(C(OC1OC(C)C(O)C(O)(C)C1)C(N(C)C)C2O)C)C(OC)C(O)CC(=O)OC(C)C\C=C\C=C\C(OC3OC(C)C(N(C)C)CC3)C(C)C4

Bedaquiline fumarate, ベダキリンフマル酸塩


Bedaquiline fumarate.png

Bedaquiline fumarate; Bedaquiline (fumarate); Cas 845533-86-0; UNII-P04QX2C1A5; P04QX2C1A5;

Bedaquiline fumarate

(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol;(E)-but-2-enedioic acid

  • R 207910
  • TMC 207
Molecular Formula: C36H35BrN2O6
Molecular Weight: 671.588 g/mol
Product
Formula
C32H31BrN2O2. C4H4O4
CAS

845533-86-0 FUMARATE
FREE FORM 843663-66-1
Mol weight
671.5769
2018/1/19  PMDA

JAPAN

APPROVED

Bedaquiline fumarate Sirturo Janssen Pharmaceutical

ベダキリンフマル酸塩
Bedaquiline Fumarate

C32H31BrN2O2▪C4H4O4 : 671.58
[845533-86-0]

FREE FORM

  1.  Saga, Yutaka; Journal of the American Chemical Society 2010, Vol132(23), Pg 7905-7907 , -168.0 ° Conc: 0.8 g/100mL; Solv:DMF; Wavlenght: 589.3 nm; Temp: 25 °C
  2.  Chandrasekhar, Srivari; European Journal of Organic Chemistry 2011, (11), PG 2057-2061, S2057/1-S2057/18  -165.2 °       Conc: 0.8 g/100mL; Solv: DMF ; Wavlenght: 589.3 nm; Temp: 25 °, MP 104 °C

EMA

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002614/WC500163215.pdf

The applicant Janssen-Cilag International N.V. submitted on 28 August 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for SIRTURO, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 21 July 2011. SIRTURO was designated as an orphan medicinal product EU/3/05/314 on 26 August 2005. SIRTURO was designated as an orphan medicinal product in the following indication: treatment of tuberculosis. The applicant applied for the following indication: SIRTURO is indicated in adults (≥ 18 years) as part of combination therapy of pulmonary tuberculosis due to multi-drug resistant Mycobacterium tuberculosis.

Disease to be treated About a third of the global population, more than 2 billion people, is infected with M. tuberculosis, of which the majority is latent. The life time risk to fall ill in overt TB is around 10% in general, but many times higher (around 10% annual risk) in untreated HIV-positive individuals. Tuberculosis is the leading cause of death in the latter population. It was estimated that a total of 8.8 million new TB cases occurred in 2010, including 1.1 million people co infected with HIV, and that about 1.45 million people died due to TB. During more recent years the burden of TB resistant to first line therapy has increased rapidly. Such multidrug resistant tuberculosis (defined later in this assessment report) has been reported in all regions of the world. Presently around 500.000 of new MDR cases are estimated to emerge every year, which is close to 5% of all new TB cases. China and India carried nearly 50% of the total burden of incident MDR-TB cases in 2008, followed by the Russian Federation (9%). The incidence of MDR-TB in US and EU was reported to be 1.1% and 2.4%, respectively. Within the EU, the incidence is much higher in certain Eastern European countries, with the largest burden in Romania, Latvia and Lithuania. MDR TB is an orphan disease in the EU, US and in Japan.

Current TB therapy and definitions Treatment of pulmonary drug susceptible TB typically takes 6 months resulting in cure rates in well over 90% of cases with good treatment adherence. The two most important drugs in this treatment are isoniazid (INH) and rifampicin (RIF). TB with resistance to at least both INH and RIF is called multidrug resistant (MDR) TB. The two most important “classes” of second-line TB drugs to be used in such cases are injectable drugs (the aminoglycosides amikacin and kanamycin, and the related agent capreomycin) and fluoroquinolones. Apart from these agents a number of miscellaneous drugs are used in addition, as part of combination therapy. The effectiveness of these latter miscellaneous drugs is generally lower, the tolerability is problematic and established breakpoints for resistance determination are lacking.

The term pre-XDR (pre-extensively drug resistant) TB is used when resistance is present also to one of the two main second-line class agents (injectables or any of the fluoroquinolones), and XDR-TB when resistance is present to INH+RIF + injectables + fluoroquinolones. The WHO standard treatment for MDR-TB is commonly divided into 2 phases: • a 4 to 6-month intensive treatment phase in which an injectable drug plus 3-4 other drugs, including a fluoroquinolone, • a continuation phase without the injectable drug and often without pyrazinamide (PZA) for a total duration of 18-24 months. Using this approach, cure rates in MDR-TB are much lower than those seen in DS-TB (ranging from less than 50% to around 75%), despite the higher number of agents and longer treatment duration. Hence, MDR TB is associated with a high mortality and is considered an important major threat to public health. More recent approaches to evaluate various MDR TB regimens have yielded somewhat more optimistic outcomes, despite shorter treatment durations. In these non-randomised studies (with low number of patients) cure rates in the range of 90% were achieved by including a fourth generation fluoroquinolone and by increasing the number of agents even further, to include up to 7 agents in the intensive phase, and still 4-5 agents in a second phase.

About the product SIRTURO (bedaquiline, formerly known as TMC 207) is a new agent of a unique class, specific for mycobacteria, and seemingly without cross-resistance to available TB agents. A large number of pre-clinical studies showed promising results for bedaquiline. For example, in animal models bedaquiline + pyrazinamide cured TB at a higher rate than the traditional first line combination, even when therapy was shortened for the former combination. The clinical program for bedaquiline has been aimed at treating MDR-TB, and data is now available from phase 2b studies of moderate size, both placebo-controlled and non-controlled studies. The treatments given in these studies were similar to those recommended by the WHO, although the number of agents used was slightly higher (five agents in the preferred background regimens). Bedaquiline (versus placebo in the controlled study) was added during the first (intensive) treatment phase, while the background regimens were generally unchanged throughout the complete course of therapy (18-24 months). On the basis of these studies, the applicant submitted an application for a conditional approval for bedaquiline, with the proposed indication: treatment of adult patients infected with pulmonary tuberculosis due to MDR M. tuberculosis, as part of combination therapy. In line with the approach in the phase 2 studies, Sirturo is only to be used during the first 6 months of therapy. However the planned pivotal study (as a specific obligation) will test for 40 weeks of bedaquiline treatment.

In 2009, the drug candidate was licensed to Global Alliance TB Drug Development by Tibotec worldwide for the treatment of tuberculosis.

Bedaquiline (INN) is chemically designated as (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol with fumaric acid (1:1), and has the following structure:

str4

Bedaquiline fumarate is a white to almost white powder. It contains two asymmetric carbon atoms, C-1 (R), C-2 (S) and exhibits ability to rotate the orientation of linearly polarized light (optical rotation). The substance is non-hygroscopic. It is practically insoluble in aqueous media over a wide pH range and very slightly soluble in 0.01 N HCl. The substance is soluble in a variety of organic solvents. Due to the low solubility Log KD (log P) could not be determined experimentally. In Biopharmaceutics Classification System (BCS) bedaquiline is classified as a Class 2 compound (expressing low solubility and high permeability). Bedaquiline exists in only one non-solvated crystalline form: Form A. In addition 2 pseudopoly-morphs were found: Form B and Form C. The substance can also be made amorphous. Sufficient evidence was provided to demonstrate that Form A is obtained by the employed manufacturing process of the active substance. Particle size was considered a critical quality attribute of the active substance as bedaquiline is not dissolved in the dosage form. Therefore an appropriate test on particle size determination was included in the active substance specification. The acceptance criteria are based upon the capabilities of the milling process, batch and stability data, and the known impact of the particle size on manufacturability, in-vitro release, and in-vivo performance

Bedaquiline is a bactericidal antimycobacterial drug. Chemically it is a diarylquinoline. FDA approved on December 28, 2012.

Image result for Bedaquiline fumarate

Bedaquiline is indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).

Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis.[1] It is specifically used to treat multi-drug-resistant tuberculosis(MDR-TB) when other treatment cannot be used.[1][5] It should be used along with at least three other medications for tuberculosis.[1][5] It is used by mouth.[5]

Common side effects include nausea, joint pains, headaches, and chest pain.[1] Serious side effects include QT prolongation, liver dysfunction, and an increased risk of death.[1] While harm during pregnancy has not been found, it has not been well studied in this population.[6] It is in the diarylquinoline antimycobacterialclass of medications.[1] It works by blocking the ability of M. tuberculosis to make adenosine 5′-triphosphate (ATP).[1]

Bedaquiline was approved for medical use in the United States in 2012.[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] The cost for six months is approximately $900 USD in low income countries, $3,000 USD in middle income countries, and $30,000 USD in high income countries.[5]

SIRTURO (bedaquiline) for oral administration is available as 100 mg strength tablets. Each tablet contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. Bedaquiline is a diarylquinoline antimycobacterial drug.

Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media. The chemical name of bedaquiline fumarate is (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1). It has a molecular formula of C32H31BrN2O2 · C4H4O4 and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is the following:

SIRTURO (bedaquiline) Structural Formula Illustration

SIRTURO (bedaquiline) contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose 2910 15 mPa.s, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing).

Medical uses

Its use was formally approved (Dec 2012) by the U.S. Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a Fast-Trackaccelerated approval, for use only in cases of multidrug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.[8]

As of 2013 Both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for patients with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.[9][10]

Clinical trials

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.[11] It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death (further detailed in the Adverse effects section).[12]

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.[11]

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).[13][14]

Side effects

The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel.[15] All patients on bedaquiline should have monitoring with a baseline and repeated ECGs.[16] If a patient has a QTcF of > 500ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.

There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo.[17] 10 deaths occurred in the bedaquiline group out of 79, while 2 occurred in the placebo group, out of 81.[12] Of the 10 deaths on bedaquiline, 1 was due to a motor vehicle accident, 5 were judged as due to progression of the underlying tuberculosis and 3 were well after the patient had stopped receiving bedaquiline.[17] However, there is still significant concern for the higher mortality in patients treated with bedaquiline, leading to the recommendation to limit its use to situations where a 4 drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval and the placement of a prominent black box warning.[17][11]

Drug interactions

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the hepatic enzyme responsible for oxidative metabolism of the drug.[16] Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experienced[16]

Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided.[9] Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.

Mode of action

Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. ATP production is required for cellular energy production and its loss leads to cell death, even in dormant or nonreplicating mycobacteria.[18] It is the first member of a new class of drugs called the diarylquinolines.[18] Bedaquiline is bactericidal.[18]

Resistance

The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance.[19]

History

Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years.[20] It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[21]

Bedaquiline was approved for medical use in the United States in 2012.[1]

It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug, a type of temporary approval for diseases lacking other viable treatment options.[22] By gaining approval for a drug that treats a neglected disease, J&J is now able to request expedited FDA review of a future drug.[23]

When it was approved by the FDA on the 28th December 2012, it was the first new medicine for TB in more than forty years.[24][25]

Bedaquiline, formally called (1R, 2S)-1-(6-Bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol in chemistry and known as Sirturo in commercial, is a new anti-mycobacterial medicine of diarylquinolines. It impinges on the
ATP synthesis of Mycobacterium tuberculosis by inhibiting the activity of proton pump on the cell’s ATP synthetase, and thereby eliminates M. tuberculosis (TB). It’s used for adult multi-drug resistant tuberculosis (MDR-PTB).

Image result for Bedaquiline fumarate

PATENT

US 20050148581

WO 2005117875

WO 2006125769

CA 2529265

WO 2006131519

JP 2011168519

CN 105017147

CN 105085395

CN 105198808

CN 105085396

WO 2016116076

WO 2016058564

WO 2016116075

WO 2016116073

WO 2016198031

CN 106866525

CN 106279017

CN 107602464

PATENT

WO 2017015793

The chemical name of beidaquinoline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-2-butanol, the first drug developed by Johnson & Johnson in the United States to inhibit mycobacterium adenosine triphosphate (ATP) synthetase, was first introduced in the United States in December 2012 for the treatment of adult multidrug-resistant tuberculosis. The trade name is Sirturo. Beidaquinoline shows strong selectivity for Mycobacterium tuberculosis ATP synthase. Its novel mechanism of action makes it not cross-resistance with other anti-tuberculosis drugs, which will greatly reduce the drug resistance of Mycobacterium tuberculosis. It shows good activity against MDR-TB in macrophages, suggesting that it has the effect of shortening treatment time.

The synthesis of beidaquinoline has been reported in the literature. The specific synthesis route is as follows:

The patent WO2004011436 mentions the use of column chromatography to separate and purify the crude product, but this method is not conducive to industrialization; in addition, a method for isolating and purifying beraquinoline diastereomer A is disclosed in Step C of the Example of WO2006125769. . However, although the purity of the diastereomer A obtained by the separation and purification method disclosed in this patent is 82%, it is actually only possible to achieve the reaction conversion rate of more than 80%. The actual study found that due to the difficult control of the reaction conditions for the preparation of bedaquino, the control conditions for water, temperature, and drip rate are harsh and the reaction is unstable, and it cannot be ensured that the conversion rate reaches more than 80% per batch, and the conversion is usually When the rate is between 60-80%, the ratio of diastereomer B to diastereomer A obtained by this method is between 1:1 and 1:3, and the next step is chiral separation. It has an impact; even the conversion rate is sometimes as low as about 50%. When the conversion rate is as low as 50%, since the amount of the product in the reaction liquid is small, as in the method using patent WO 2006125769, the isolated product can hardly be purified even if the product is separated and purified by the purification method disclosed in this patent. The resulting diastereomer A is also of low purity.

Example 1
Reaction material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA (20g) reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 56%. After quenching the reaction, n-heptane (40 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 0° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 50% acetic acid aqueous solution to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 15% hydrochloric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by layering the filtrate, adjusted to alkaline with aqueous ammonia, extracted with toluene and free, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure to obtain a product that is not correct. Enantiomer A (4.9 g), purity 89%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (40 ml), DMSO (4.9 ml), and R-binaphthol phosphate (2.62 g) were added to diastereomer A (4.9 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitates are separated out; at room temperature, the filter cake is washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.07 g);
Split salt (2.07g), toluene (37ml), potassium carbonate (1.51g) and water (13ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, at this time organic layer TLC monitoring; washed with purified water to neutral pH (20ml × 3 times); organic layer was concentrated under reduced pressure to give a colorless oil (1.5g); add toluene (1ml) to heat the whole Dissolve, add ethanol (12ml) and stir at room temperature for 0.5h. Precipitate the solid, and stir in ice water bath for 1h. Filter and wash the filter cake with ethanol. Dry it in vacuo at 50-60°C to give bedaquinoline (1.07g). The HPLC purity is >99%. .
Example 2
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 65%. After quenching the reaction, diisopropyl ether (160 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 5° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 10% aqueous formic acid to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 5% aqueous sulfuric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. Filtration, filtration of the filtrate, the product was transferred to the aqueous layer, the raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer, and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. The product was diastereoisomer A (5.7 g), purity 92%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.7 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. Cooling, precipitated salt precipitation; filtered at room temperature, washed with acetone cake, 50-60 ° C vacuum drying salt (2.6g);
The resolved salt (2.41 g), toluene (39 ml), potassium carbonate (1.58 g) and water (14 ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% aqueous potassium carbonate solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.6g); toluene was added (1ml) to heat the solution and ethanol was added (12ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.19 g) with an HPLC purity of >99%.
Example 3
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 75%. After quenching the reaction, diisopropyl ether (400 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 2° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 60% aqueous solution of propionic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as a raw material, and 40% methanesulfonic acid aqueous solution was added to the organic layer for stirring to make the product salified. Precipitated in the water layer. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.0 g), purity 94%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.0 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomeric A (6.0 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolved salt (2.59 g).
The resolved salt (2.59g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.7 g); toluene (1 ml) was added and heated to complete dissolution, and ethanol (12 ml) was added. The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedaquinoline (1.20 g) with an HPLC purity of >99%.
Example 4
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 70%. After quenching the reaction, petroleum ether (16 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 3° C. and filtered to remove diastereoisomer B. The obtained filtrate was washed with 30% acetic acid aqueous solution to remove 3-methylamino-1-(naphthalen-5-yl)acetone as a raw material, and 25% phosphoric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be slightly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (5.72 g), purity 88%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.72 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.43 g);
Split salt (2.43g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml x 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); toluene (1 ml) was added for heating and ethanol was added (12 ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, and the filter cake was washed with ethanol. Drying in vacuo at 50-60° C. gave bedaquinoline (1.16 g) with an HPLC purity of >99%.
Example 5
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction was 80% by HPLC analysis. After quenching the reaction, n-hexane (80 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 1° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 40% aqueous acetic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as starting material, and 20% aqueous hydrochloric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.1 g), purity 96%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.1 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomer A (6.1 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolution salt (2.69 g).
The resolved salt (2.69g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml×3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.8g); toluene (1ml) was added to heat to dissolve and ethanol (12ml) was added. The precipitated solid was stirred for 0.5 h at room temperature, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.28 g) with an HPLC purity of >99%.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(10), 1019-1024

6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
 Medicinal Chemistry Department (Infectious Diseases), Janssen Pharmaceuticals, Campus de Maigremont, BP315, 27106 Val de Reuil Cedex, France
§ Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States
 Infectious Diseases BVBA, Janssen Pharmaceuticals, Beerse, Belgium
 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
ACS Med. Chem. Lett.20178 (10), pp 1019–1024
DOI: 10.1021/acsmedchemlett.7b00196
Publication Date (Web): September 22, 2017
Copyright © 2017 American Chemical Society

Abstract

Abstract Image

Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

PAPER

Chinese Chemical Letters (2015), 26(6), 790-792

PAPER

Organic & Biomolecular Chemistry (2016), 14(40), 9622-9628.

http://pubs.rsc.org/en/content/articlelanding/2016/ob/c6ob01893a/unauth#!divAbstract

New synthetic approaches towards analogues of bedaquiline

Abstract

Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

Graphical abstract: New synthetic approaches towards analogues of bedaquiline
http://www.rsc.org/suppdata/c6/ob/c6ob01893a/c6ob01893a1.pdf

PAPER

 Topics in Organometallic Chemistry (2011), 37(Bifunctional Molecular Catalysis), 1-30

PAPER

Saga, Yutaka; Journal of the American Chemical Society 2010, Vol132(23), Pg 7905-7907

Catalytic Asymmetric Synthesis of R207910

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
J. Am. Chem. Soc.2010132 (23), pp 7905–7907
DOI: 10.1021/ja103183r
Publication Date (Web): May 20, 2010
Copyright © 2010 American Chemical Society

Abstract

Abstract Image

The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate α-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)3 and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu4NCl, α-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the γ-position of 4, followed by regio- and enantioselective protonation at the α-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu4NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF•3PPh3•2EtOH (10 mol %) in the presence of KOtBu (15 mol %), ZnCl2 (1 equiv), and Bu4PBF4 (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the α-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic α-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.

https://pubs.acs.org/doi/suppl/10.1021/ja103183r/suppl_file/ja103183r_si_001.pdf

1 in 62 % yield (6.5 mg, 0.012 mmol ). 1H NMR (500 MHz, CDCl3) : 1.91-1.95 (m, 1H), 1.98 (s, 6H), 1.99-2.10 (m, 2H), 2.52 (d, J = 14.1 Hz, 1H), 4.21 (s, 3H), 5.89 (s, 1H), 6.87-6.89 (m, 3H), 7.10-7.15 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 8.5 Hz, 1H), 7.61 (t, J = 8.5 Hz, 1H), 7.63-7.67 (m, 2H), 7.72 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 8.5 Hz, 1H), 8.89 (s, 1H); 13C NMR (126 MHz, CDCl3) : 29.7, 33.5, 44.7, 49.5, 54.2, 56.4, 82.6, 117.0, 124.5, 125.0, 125.1, 125.3, 125.8, 126.9, 127.1, 127.4, 127.9, 128.0, 128.1, 128.5, 129.8, 129.9, 131.9, 132.7, 133.3, 134.7, 138.8, 140.6, 141.8, 143.8, 161.4; IR (KBr, cm-1 ):  3443; MS (ESI) m/z 555 (M+H) + ; HRMS (FAB) calcd for C32H32N2O2Br (M+H) + 555.1647. Found 555.1644; [] 26 D – (c = 0.3, DMF).

PAPER

Gaurrand, Sandrine; Chemical Biology & Drug Design 2006, VOL 68(2), PG 77-84 

http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=1&sid=fac0fcc3-2a10-4f5f-8e20-d057adf71ce9%40sessionmgr4006

str1 str2

PAPER

Chandrasekhar, Srivari; European Journal of Organic Chemistry 2011, (11), PG 2057-2061, S2057/1-S2057/18

Srivari Chandrasekhar

Dr.Chandrasekhar S
Director 
CSIR-Indian Institute of Chemical Technology                              
(Council of Scientific and Industrial Research)
Ministry of Science & Technology, Government of India
Tarnaka, Hyderabad-500007, Telangana, INDIA

Landline 27193030
Mobile 9440802787
Fax
Email ID director@iict.res.in
Alternate Email ID srivaric@iict.res.in
Alternate URL http://www.iictindia.org/staffprofiles/staffProfile.aspx?emp_id=iict1372

READ

http://www.iictindia.org/staffprofiles/staffprofile.aspx?qry=1372

(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)- 2-(naphthalen-1-yl)-1-phenylbut-an-2-ol (3a): A solution of 16a and 16b (6.0 g, 10.2 mmol) in Me2NH (200 mL, 8.0 m in THF) was stirred at 45 °C for 24 h. The solution was filtered and the filtrate concentrated under reduced pressure to afford the crude product which on purification by silica gel column chromatography (eluent: ethyl acetate/hexane = 1:6) furnished 3a and 3b as white solids (4.8 g, 90%) (1:1 w/w).

3a: M.p. 104 °C. [α]D 25 = –165.2 (c = 0.8, DMF). (2S)- R207910 (3a)

1 H NMR (300 MHz, CDCl3): δ = 8.89 (s, 1 H, H4), 8.61 (d, J = 8.6 Hz, 1 H, H20), 7.96 (d, J = 2.0 Hz, 1 H, H5), 7.92 (d, J = 7.4 Hz, 1 H, H14), 7.87 (d, J = 8.1 Hz, 1 H, H17), 7.72 (d, J = 8.8 Hz, 1 H, H8), 7.68–7.56 (m, 3 H, H7, H16, H19), 7.48 (t, J = 7.6 Hz, 1 H, H18), 7.30 (t, J = 7.7 Hz, 1 H, H15), 7.17–7.10 (m, 2 H, H24), 6.93–6.83 (m, 3 H, H25, H26), 5.89 (s, 1 H, H11), 4.21 (s, 3 H, H30), 2.60–2.51 (m, 1 H, H27), 2.18–2.02 (m, 2 H, H27, H28), 1.99 (s, 6 H, H29), 1.95–1.85 (m, 1 H, H28) ppm.

13C NMR (75 MHz, CDCl3): δ = 161.3, 143.7, 141.6, 140.5, 138.7, 134.6, 131.9, 129.9, 129.8, 129.7, 128.4, 128.1, 127.8, 127.3, 127.1, 126.8, 125.7, 125.2, 125.1, 125.0, 124.4, 116.9, 82.4, 56.2, 54.1, 49.5, 44.6, 33.4, 29.6 ppm.

IR (KBr): ν˜ = 3441 cm–1.

HRMS (ESI) calcd. for C32H32BrN2O2 [M + H]+ 555.1642; found 555.1671.

(2R)-R207910

References[

  1. Jump up to:a b c d e f g h i j “Bedaquiline Fumarate”. The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  2. Jump up^ Diacon AH, Pym A, Grobusch M, et al. (2009). “The diarylquinoline TMC207 for multidrug-resistant tuberculosis”. N Engl J Med360 (23): 2397–405. doi:10.1056/NEJMoa0808427PMID 19494215.
  3. Jump up to:a b c “Bedaquiline”. Archived from the original on 20 May 2013. Retrieved 28 April 2014.
  4. Jump up^ “Sirturo: Clinical Pharmacology”Archived from the original on 28 February 2015. Retrieved 28 April 2014.
  5. Jump up to:a b c d The selection and use of essential medicines: Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children) (PDF). World Health Organization. 2015. p. vii, 29. ISBN 9789241209946Archived(PDF) from the original on 20 December 2016. Retrieved 10 December 2016.
  6. Jump up^ “Bedaquiline (Sirturo) Use During Pregnancy”http://www.drugs.comArchived from the original on 20 December 2016. Retrieved 10 December 2016.
  7. Jump up^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  8. Jump up^ “Press Announcements – FDA approves first drug to treat multi-drug resistant tuberculosis”http://www.fda.gov. Dec 2012. Archivedfrom the original on 2016-12-19.
  9. Jump up to:a b Centers for Disease Control and Prevention (2013-10-25). “Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis”. MMWR62 (RR-09): 1–12. ISSN 1545-8601PMID 24157696.
  10. Jump up^ WHO (2013). The use of bedaquiline in the treatment of multidrug-resistant tuberculosis : interim policy guidanceArchived from the original on 2017-09-10.
  11. Jump up to:a b c Field, Stephen K. (2015-07-01). “Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?”Therapeutic Advances in Chronic Disease6(4): 170–184. doi:10.1177/2040622315582325ISSN 2040-6223PMC 4480545Freely accessiblePMID 26137207Archived from the original on 2015-10-28.
  12. Jump up to:a b Diacon, Andreas H.; Pym, Alexander; Grobusch, Martin P.; de los Rios, Jorge M.; Gotuzzo, Eduardo; Vasilyeva, Irina; Leimane, Vaira; Andries, Koen; Bakare, Nyasha (2014-08-21). “Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline”New England Journal of Medicine371 (8): 723–732. doi:10.1056/NEJMoa1313865ISSN 0028-4793PMID 25140958.
  13. Jump up^ BPaMZ @ TB Alliance Archived 2017-02-19 at the Wayback Machine.
  14. Jump up^ Two new drug therapies might cure every form of tuberculosis. Feb 2017 Archived 2017-02-20 at the Wayback Machine.
  15. Jump up^ Drugs.com: Sirturo Side Effects Archived 2013-09-23 at the Wayback Machine.
  16. Jump up to:a b c “Prescribing Information for Bedaquiline” (PDF). Archived (PDF) from the original on 24 August 2013. Retrieved 28 April 2014.
  17. Jump up to:a b c Cox, Edward; Laessig, Katherine (2014-08-21). “FDA Approval of Bedaquiline — The Benefit–Risk Balance for Drug-Resistant Tuberculosis”New England Journal of Medicine371(8): 689–691. doi:10.1056/NEJMp1314385ISSN 0028-4793PMID 25140952.
  18. Jump up to:a b c Worley, Marylee V.; Estrada, Sandy J. (2014-11-01). “Bedaquiline: A Novel Antitubercular Agent for the Treatment of Multidrug-Resistant Tuberculosis”Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy34 (11): 1187–1197. doi:10.1002/phar.1482ISSN 1875-9114Archivedfrom the original on 2016-12-20.
  19. Jump up^ Andries, Koen; Villellas, Cristina; Coeck, Nele; Thys, Kim; Gevers, Tom; Vranckx, Luc; Lounis, Nacer; Jong, Bouke C. de; Koul, Anil (2014-07-10). “Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline”PLOS ONE9 (7): e102135. doi:10.1371/journal.pone.0102135ISSN 1932-6203PMC 4092087Freely accessiblePMID 25010492Archived from the original on 2017-09-10.
  20. Jump up^ Protopopova M, Bogatcheva E, Nikonenko B, Hundert S, Einck L, Nacy CA (May 2007). “In search of new cures for tuberculosis”(PDF). Med Chem3 (3): 301–16. doi:10.2174/157340607780620626PMID 17504204.[permanent dead link]
  21. Jump up^ de Jonge MR, Koymans LH, Guillemont JE, Koul A, Andries K (June 2007). “A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910”. Proteins67 (4): 971–80. doi:10.1002/prot.21376PMID 17387738.
  22. Jump up^ Walker, Joseph; Tadena, Nathalie (December 31, 2012). “J&J Tuberculosis Drug Gets Fast-Track Clearance”. Wall Street Journal. Archived from the original on September 23, 2015. Retrieved 2013-01-01.
  23. Jump up^ Edney, Anna (December 31, 2012). “J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB”. Bloomberg. Archivedfrom the original on January 4, 2013. Retrieved 2013-01-01.
  24. Jump up^ “FDA Approves 1st New Tuberculosis Drug in 40 Years”. ABC News. Archived from the original on 4 January 2013. Retrieved 31 December 2012.
  25. Jump up^ “F.D.A. Approves New Tuberculosis Drug”. New York Times. Archived from the original on 8 January 2013. Retrieved 31 December 2012.
Bedaquiline
Bedaquiline.svg
Clinical data
Trade names Sirturo
Synonyms Bedaquiline fumarate,[1]TMC207,[2] R207910, AIDS222089
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
by mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding >99.9% [4]
Metabolism Liver, by CYP3A4[3]
Biological half-life 5.5 months [3]
Excretion fecal[3]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C32H31BrN2O2
Molar mass 555.5 g/mol
3D model (JSmol)

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 2 (FDA Orange Book Patent ID)
Patent 8546428
Expiration Mar 19, 2029
Applicant JANSSEN THERAP
Drug Application N204384 (Prescription Drug: SIRTURO. Ingredients: BEDAQUILINE FUMARATE)
FDA Orange Book Patents: 2 of 2 (FDA Orange Book Patent ID)
Patent 7498343
Expiration Oct 2, 2024
Applicant JANSSEN THERAP
Drug Application N204384 (Prescription Drug: SIRTURO. Ingredients: BEDAQUILINE FUMARATE)
Patent ID

Patent Title

Submitted Date

Granted Date

US7498343 Mycobacterial inhibitors
2005-07-07
2009-03-03
US8546428 FUMARATE SALT OF (ALPHA S, BETA R)-6-BROMO-ALPHA-[2-(DIMETHYLAMINO)ETHYL]-2-METHOXY-ALPHA-1-NAPHTHALENYL-BETA-PHENYL-3-QUINOLINEETHANOL
2010-02-04

//////////////Bedaquiline, JAPAN 2018, R 207910, Sirturo, TMC 207, FDA 2012, EMA 2014, ベダキリンフマル酸塩

CN(C)CCC(C1=CC=CC2=CC=CC=C21)(C(C3=CC=CC=C3)C4=C(N=C5C=CC(=CC5=C4)Br)OC)O.C(=CC(=O)O)C(=O)O

Fosravuconazole L-lysine ethanolate, ホスラブコナゾール L-リシンエタノール付加物


Image result for Fosravuconazole L-lysine ethanolate

Image result for Fosravuconazole L-lysine ethanolate

C23H20F2N5O5PS▪C6H14N2O2▪C2H6O : 739.73
[914361-45-8]

[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-yl]oxymethyl dihydrogen phosphate;(2S)-2,6-diaminohexanoic acid;ethanol

L-Lysine [[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy]methyl dihydrogen phosphate ethanol

BFE-1224
BMS-379224
E-1224

ravuconazole prodrugs, ravuconazole methyl phosphate

fosravuconazole bis(L-lysine)

ホスラブコナゾール L-リシンエタノール付加物

Formula
C23H20F2N5O5PS. C6H14N2O2. C2H6O
CAS
914361-45-8
Mol weight
739.727

Antifungal, Ergosterol biosynthesis inhibitor

Fungal infection; Onychomycosis; Trypanosoma cruzi infection

PMDA JAPAN APPROVED

2018/1/19 PMDA APPROVED Fosravuconazole L-lysine ethanolate Nailin Sato Pharmaceutical

FOR

Tinea, nail (onychomycosis)

NOTE THIS STR

Image result for fosravuconazole

  • 4-[2-[(1R,2R)-2-(2,4-Difluorophenyl)-1-methyl-2-[(phosphonooxy)methoxy]-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thiazolyl]benzonitrile
  • E 1224
  • Fosravuconazole
  • CAS  351227-64-0

Drugs for Neglected Diseases initiative (DNDi), under license from Eisai, is developing fosravuconazole for CD  and eumycetoma 

In February 2013, the drug was in phase II/III development by Seren Pharmaceuticals for onychomycosis in North America, Europe and Asia, including Japan,

In 2010, the product was licensed exclusively to Brain Factory (now Seren Pharma) for development, commercialization and sublicense in Japan for the treatment of fungal infections. In 2014, Seren Pharma signed an agreement with Sato Pharma, granting them the development and commercialization rights of the product in Japan

Sato Pharmaceutical Co., Ltd. has obtained marketing and manufacturing approval for the oral antifungal agent, Nailin capsules 100mg containing the active ingredient fosravuconazole L-lysine ethanolate (fosravuconazole) for the treatment of onychomycosis in Japan.

Sato Pharma conducted a phase III clinical study of the agent in patients with onychomycosis in Japan, and after confirming efficacy and safety of the agent in the study, the company applied for marketing and manufacturing authorization in January 2017.

Fosravuconazole, the active ingredient of Nailin capsules 100mg, is a new triazole class oral antifungal component discovered by Eisai.

Fosravuconazole, the active ingredient of Nailin capsules 100mg, is a new triazole class oral antifungal component discovered by Eisai. By providing Nailin capsules 100mg as a new option for the treatment of onychomycosis, Sato Pharma and Eisai will strive to fulfil the needs of onychomycosis patients and healthcare professionals.

Onychomycosis is a fungal infection of the toenails or fingernails that may involve any component of the nail unit, including the matrix, bed, or plate. With Sato Pharma now having obtained marketing and manufacturing approval for Nailin capsules 100mg, as an oral treatment for onychomycosis, this is the first new treatment for the disease in approximately 20 years.

Fosravuconazole is a prodrug of ravuconazole originated by Eisai. In 2018, the product was approved in Japan for the treatment of onychomycosis. Fosravuconazole is being tested in phase II clinical studies at Eisai and Drugs for Neglected Diseases Initiative (DNDi) for the treatment of american trypanosomiasis (Chagas disease)

Image result for Fosravuconazole L-lysine ethanolate WIKI

Onychomycosis due to Trichophyton rubrum, right and left great toe. Tinea unguium.
Image/CDC

Sato Pharmaceutical Co., Ltd. obtained marketing and manufacturing approval for the oral antifungal agent NAILIN Capsules 100mg containing the active ingredient fosravuconazole L-lysine ethanolate (fosravuconazole) for the treatment of onychomycosis in Japan on January 19, 2018.
Fosravuconazole, the active ingredient of NAILIN Capsules 100mg, is a new triazole class oral antifungal component discovered by Eisai. Sato Pharma conducted a Phase III clinical study of the agent in patients with onychomycosis in Japan, and after confirming efficacy and safety of the agent in the study, Sato Pharma applied for marketing and manufacturing authorization in January 2017.Sato Pharma and Eisai Co., Ltd. are jointly providing information on its proper use.

Onychomycosis is a fungal infection of the toenails or fingernails that may involve any component of the nail unit, including the matrix, bed, or plate.

Onychomycosis affects 1 in every 10 Japanese people, and there are an estimated approximately 11 million sufferers in Japan. With Sato Pharma now having obtained marketing and manufacturing approval for NAILIN Capsules 100mg, as an oral treatment for onychomycosis, this is the first new treatment for the disease in approximately 20 years.

Image result for Onychomycosis

Sato Pharmaceutical Co. Ltd., Eisai Co. Ltd., and Seren Pharmaceuticals Inc. announced that Sato Pharma and Eisai will co-promote a new triazole class oral antifungal agent (development code: BFE1224) containing the active ingredient fosravuconazole L-lysine ethanolate (fosravuconazole) in Japan, based on an agreement between the three companies. The agent is currently under regulatory review for the treatment of onychomycosis.

After receiving regulatory approval, Sato Pharma will begin distributing the agent, and Sato Pharma and Eisai will jointly provide information on its proper use.

Fosravuconazole is a new oral antifungal component developed by Eisai. In 2010, Eisai concluded a license agreement with Seren Pharma (formerly known as Brain Factory Co., Ltd.), granting them exclusive rights to develop, commercialize, and sublicense the agent in Japan.

In 2014, Seren Pharma concluded an agreement with Sato Pharma, granting them the development and commercialization rights, and both companies continued to develop the agent for treating onychomycosis. In January 2017, Sato Pharma applied for marketing authorization for the agent.

Sato Pharma, Eisai, and Serena Pharma will cooperate to maximize the value of fosravuconazole in order to fulfil the unmet medical needs of patients with fungal diseases.

Courtesy- techno.bigmir

PATENT

WO 2006118351

Journal of the American Chemical Society, 139(31), 10733-10741; 2017

PAPER

BMS-379224, a water-soluble prodrug of ravuconazole
42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-817

PATENT

WO 2006118351

WO 2007072851

WO 2001052852

WO 2006026274

WO 2013082102

WO 2013157584

////////////ホスラブコナゾール L-リシンエタノール付加物, Fosravuconazole L-lysine ethanolate, Nailin, SATO, BFE-1224, BMS-379224, E-1224, JAPAN 2018, ravuconazole prodrugs, ravuconazole methyl phosphate, fosravuconazole bis(L-lysine), Drugs for Neglected Diseases initiative, DNDi

CCO.CC(C1=NC(=CS1)C2=CC=C(C=C2)C#N)C(CN3C=NC=N3)(C4=C(C=C(C=C4)F)F)OCOP(=O)(O)O.C(CCN)CC(C(=O)O)N

Baloxavir marboxil, バロキサビルマルボキシル , балоксавир марбоксил , بالوكسافير ماربوكسيل , 玛巴洛沙韦 ,


Image result for japan animated flag

str1

1985606-14-1.pngBaloxavir marboxil.png

Image result for XofluzaChemSpider 2D Image | baloxavir marboxil | C27H23F2N3O7S

Baloxavir marboxil

バロキサビルマルボキシル

балоксавир марбоксил [Russian] [INN]

بالوكسافير ماربوكسيل [Arabic] [INN]
玛巴洛沙韦 [Chinese] [INN]

Carbonic acid, [[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy]methyl methyl ester

({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate

  1. (((12aR)-12-((11S)-7,8-Difluoro-6,11-dihydrodibenzo(b,E)thiepin-11-yl)-6,8-dioxo-3,4,6,8,12,12ahexahydro-1H-(1,4)oxazino(3,4-C)pyrido(2,1-F)(1,2,4)triazin-7-yl)oxy)methyl methyl carbonate
  2. Carbonic acid, (((12aR)-12-((11S)-7,8-difluoro-6,11-dihydrodibenzo(b,E)thiepin-11-yl)-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-(1,4)oxazino(3,4-C)pyrido(2,1-F)(1,2,4)triazin-7-yl)oxy)methyl methyl ester

Antiviral

In Japan the product is indicated for treatment influenza types A and B in adults and children

RG-6152

UNII-505CXM6OHG

  • Originator Shionogi
  • Developer Roche; Shionogi
  • Class Antivirals; Dibenzothiepins; Esters; Pyridines; Small molecules; Triazines
  • Mechanism of Action Endonuclease inhibitors

Highest Development Phases

  • Marketed Influenza A virus infections; Influenza B virus infections
  • Phase III Influenza virus infections
  • Preclinical Influenza A virus H5N1 subtype
Xofluza (TN)
Antiviral
Formula
C27H23F2N3O7S
Cas
1985606-14-1
Mol weight
571.5492
2018/2/23 PMDA JAPAN APPROVED Baloxavir marboxil Xofluza Shionogi

Image result for japan animated flag

バロキサビル マルボキシル
Baloxavir Marboxil

C27H23F2N3O7S : 571.55
[1985606-14-1]

Image result for ShionogiImage result for Xofluza

2D chemical structure of 1985606-14-1

https://chem.nlm.nih.gov/chemidplus/sid/1985606141

Baloxavir marboxil (trade name Xofluza, compound code S-033188/S-033447) is a medication being developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B. The drug was in late-stage trials in Japan and the United States as of early 2018, with collaboration from Roche AG.[1].

It was approved for sale in Japan on February 23, 2018.[2]

Baloxavir marboxil is a medication developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B. The drug was approved for use in Japan in February 2018 and is in late phase trials in the United States as of early 2018. Roche, which makes Tamiflu, has acquired the license to sell Xofluza internationally, but it may not be until 2019 that it could be available in the United States [7]. Interestingly, a study has determined that administering Baloxavir marboxil with neuraminidase inhibitors leads to a synergistic effect in influenza treatment

Image result for Xofluza

It is an influenza therapeutic agent (cap-dependent endonuclease inhibitor), characterized by only taking one dose. Unlike neuraminidase inhibitors such as oseltamivir (Tamiflu) and zanamivir (Relenza) that inhibit the action of neuraminidase, which liberates viruses from the infected cells surface, baloxavir marboxil may prevent replication by inhibiting the cap-dependent endonuclease activity of the viral polymerase.[3]

In October 2015, the Japanese Ministry of Health, Labour and Welfare granted Sakigake status to Shionogi’s baloxavir marboxil for A type or B -type influenza virus infection . In October 2015, the drug was designated for Priority Review by the Ministry of Health, Labour and Welfare, presumably for the treatment of A type or B -type influenza virus infection .

This drug is a CAP endonuclease inhibitor [1]. The influenza endonuclease is an essential subdomain of the viral RNA polymerase enzyme. CAP endonuclease processes host pre-mRNAs to serve as primers for viral mRNA and therefore has been a common target for studies of anti-influenza drugs.

Viral gene transcription is primed by short-capped oligonucleotides that are cleaved from host cell pre mRNA by endonuclease activity. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5′ end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription.The N-terminal domain of PA subunit (PAN) has been confirmed to accommodate the endonuclease activity residues, which is highly preserved among subtypes of influenza A virus and is able to fold functionally [4]. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5′ end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription. The endonuclease domain binds the N-terminal half of PA (PAN) and contains a two-metal (Mn2+) active site that selectively cleaves the pre-mRNA substrate at the 3′ end of a guanine [3].

The administration of a CAP endonuclease inhibitor, such as Baloxavir marboxil, prevents the above process from occurring, exhibiting its action at the beginning of the pathway before CAP endonuclease may exert its action

Image result for Xofluza

It achieves this by inhibiting the process known as cap snatching[4], which is a mechanism exploited by viruses to hijack the host mRNA transcription system to allow synthesis of viral RNAs.

Image result for Xofluza

Shionogi, in collaboration with licensee Roche (worldwide except Japan and Taiwan), have developed and launched baloxavir marboxil

In March 2018, Shionogi launched baloxavir marboxil for the treatment of influenza types A and B in Japan . In September 2017, Shionogi was planning to file an NDA in the US; in February 2018, the submission remained in preparation

By September 2016, baloxavir marboxil had been awarded Qualified Infectious Disease Product (QIDP) designation in the US

In March 2017, a multicenter, randomized, double-blind, parallel-group, phase III study (NCT02954354; 1601T0831; CAPSTONE-1) was initiated in the US, Canada and Japan to compare a single dose of baloxavir marboxil versus placebo or oseltamivir bid for 5 days in influenza patients aged from 12 to 64 years of age (n = 1494). The primary endpoint was the time to alleviation of symptoms (TTAS).

PATENTS

JP 5971830

Kawai, Makoto; Tomita, Kenji; Akiyama, Toshiyuki; Okano, Azusa; Miyagawa, Masayoshi

PATENTS

WO 2017104691

Shishido, Takao; Noshi, Takeshi; Yamamoto, Atsuko; Kitano, Mitsutaka

In Japanese Patent Application No. 2015-090909 (Patent No. 5971830, issued on Aug. 17, 2016, Registered Publication), a compound having a CEN inhibitory action and represented by the formula:
[Chemical Formula 2]

is described. Anti-influenza agents of six mechanisms are enumerated as drugs that can be used together with the above compounds. However, no specific combinations are described, nor is it disclosed nor suggested about the combined effect.

Synthesis Example 2
[formula 39]

Compound III-1 (1.00g, 2.07mmol) to a suspension of DMA (5 ml) of chloromethyl methyl carbonate (0.483 g, 3.10 mmol) and potassium carbonate (0 .572 g, 4.14 mmol) and potassium iodide (0.343 g, 2.07 mmol) were added, the temperature was raised to 50 ° C. and the mixture was stirred for 6 hours. Further, DMA (1 ml) was added to the reaction solution, and the mixture was stirred for 6 hours. The reaction solution was cooled to room temperature, DMA (6 ml) was added, and the mixture was stirred at 50 ° C. for 5 minutes and then filtered. 1 mol / L hydrochloric acid water (10 ml) and water (4 ml) were added dropwise to the obtained filtrate under ice cooling, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure at 60 ° C. for 3 hours to obtain compound II-4 (1.10 g, 1.93 mmol, yield 93%).
1 H-NMR (DMSO-D 6) δ: 2.91-2.98 (1 H, m), 3.24-3.31 (1 H, m), 3.44 (1 H, t, J = 10.4 Hz) J = 10.8, 2.9 Hz), 4.06 (1 H, d, J = 14.3 Hz), 4.40 (1 H, dd, J = 11.5, 2.8 Hz), 3.73 (3 H, s), 4.00 , 5.67 (1 H, d, J = 6.5 Hz), 5.72 (1 H, d, J = 11.8 Hz), 4.45 (1H, dd, J = 9.9, 2.9 Hz), 5.42 J = 8.0, 1.1 Hz), 7.14 – 7.18 (1 H, m ), 7.23 (1 H, d, J = 7.8 Hz), 7.37 – 7.44 (2 H, m)

PATENTS

JP 6212678

PATENTS

JP 6249434

JP 5971830

SYNTHESIS OF KEY INTERMEDIATE

SYNTHESIS OF KEY INTERMEDIATE

SYNTHESIS OF FINAL PRODUCT

Japan’s New Drug: One Pill May Stop The Flu in Just One Day

 Opinions expressed by Forbes Contributors are their own.

Isao Teshirogi, president and chief executive officer of Shionogi & Co., speaks during an interview in Tokyo, Japan. Photographer: Kiyoshi Ota/Bloomberg

One day, you may be able to stop flu viruses in your body in just one day with just one pill. Based on an announcement yesterday, that day may be someday very soon in May in Japan.

On Friday, Japanese pharmaceutical company Shionogi announced that the flu medication that they have developed, Xofluza, otherwise known as baloxavir marboxil (which sounds a bit like a Klingon General), has been approved to be manufactured and sold in Japan. Beginning in October 2015, the medication underwent priority review by Japan’s Ministry of Health, Labor, and Welfare. Shionogi filed for approval in the autumn of 2017. Compared to Tamiflu, which requires two doses each day for five days, apparently only a single dose of Xofluza will be needed to treat the flu. Even though Xofluza has received approval, people will have to wait until the Japanese national insurance sets a price for the medication, which according to Preetika Rana writing for the Wall Street Journal, may not occur until May.

Xofluza works via a different mechanism from neuroaminidase inhibitors like Tamiflu (oseltamivir) and Relenza (zanamivir). Flu viruses are like squatters in your home that then use the furniture and equipment in your home to reproduce. Yes, I know, that makes for a lovely picture. A flu infection begins when flu viruses reach your lungs. Each flu virus will enter a cell in your lungs and then use your cell’s genetic material and protein production machinery to make many, many copies of itself. In order to do this, the flu virus uses “cap-snatching”, which has nothing to do with bottle caps or Snapchat. The virus employs an endonuclease enzyme to clip off and steal the caps or ends of your messenger RNA and then re-purposes these caps to reproduce its own genetic material. After the virus has made multiple copies of itself, the resulting viruses implement another enzyme called a neuroaminidase to separate themselves from parts of the host cell and subsequently spread throughout the rest of your body to cause havoc. While Tamiflu, Relenza, and other neuroaminidase inhibitors try to prevent the neuroaminidase enzyme from working, Xofluza acts at an earlier step, stopping the “cap-snatching” by blocking the endonuclease enzyme.

In a clinical trial, Xofluza stopped an infected person from shedding flu virus sooner than Tamiflu. (Photo Illustration by Ute Grabowsky/Photothek via Getty Images)

By acting at an earlier step before the virus has managed to replicate, Xofluza could stop a flu virus infection sooner than neuroaminidase inhibitors. The results from Shionogi’s Phase III CAPSTONE-1 clinical trial compared Xofluza (then called Cap-dependent Endonuclease Inhibitor S-033188, which doesn’t quite roll off the tongue) with oseltamivir and placebo, with results being published in Open Forum Infectious Diseases. The study found that baloxavir marboxil (or Xofluza) stopped an infected person from shedding flu virus earlier (median 24 hours) than oseltamivir (median 72 hours). Those taking baloxavir marboxil also had lower measured amounts of viruses than those taking oseltamivir throughout the first 3 days of the infection. Baloxavir marboxil also seemed to shorten the duration of flu symptoms (median 53.7 hours compared to a median of 80.2 hours for those taking placebo). Since symptoms are largely your body’s reaction to the flu virus, you can begin shedding virus before you develop symptoms, and symptoms can persist even when you are no longer shedding the virus.

The key with any of these flu medications is early treatment, especially within the first 24 to 48 hours of infection, which may be before you notice any symptoms. Once the virus has replicated and is all over your body, your options are limited. The vaccine still remains the best way to prevent an infection.

In the words of Alphaville, this new drug could be big in Japan. While Xofluza won’t be available in time to help with the current flu season, this year’s particularly harsh flu season has highlighted the need for better ways to treat the flu. But will the United States see Xofluza anytime soon? Similar to Pokemon, Xofluza may need a year or two to reach the U.S. market. But one day, one pill and one day may be a reality in the U.S.

http://www.shionogi.co.jp/en/company/news/2018/pmrltj0000003nx1-att/e180223.pdf

XOFLUZA TM (Baloxavir Marboxil) Tablets 10mg/20mg Approved for the Treatment of Influenza Types A and B in Japan Osaka, Japan, February 23, 2018 – Shionogi & Co., Ltd. (Head Office: Osaka; President & CEO: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) announced that XOFLUZATM (generic name: baloxavir marboxil) tablets 10mg/20mg was approved today by the Ministry of Health, Labour and Welfare for the treatment of Influenza Types A and B. As the cap-dependent endonuclease inhibitor XOFLUZATM suppresses the replication of influenza viruses by a mechanism different from existing anti-flu drugs, XOFLUZATM was designated for Sakigake procedure with priority review by the Ministry of Health, Labour, and Welfare of Japan in October 2015. Shionogi filed for approval to manufacture and sell XOFLUZATM in October 25, 2017. As the treatment with XOFLUZATM requires only a single oral dose regardless of age, it is very convenient, and is expected to improve adherence. XOFLUZATM is expected to be a new treatment option that can improve the quality of life in influenza patients. Shionogi will launch the product immediately after the National Health Insurance (NHI) price listing. Shionogi’s research and development targets infectious disease as one of its priority areas, and Shionogi have positioned “protecting people from the threat of infectious diseases” as one of its social mission targets. Shionogi strives constantly to bring forth innovative drugs for the treatment of infectious diseases, to protect the health of patients we serve.

References

  1. Jump up^ Rana, Preetika (10 February 2018). “Experimental Drug Promises to Kill the Flu Virus in a Day”. Wall Street Journal.
  2. Jump up^ “XOFLUZA (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan”. 23 February 2018 – via http://www.publicnow.com.
  3. Jump up^ Dias, Alexandre; Bouvier, Denis; Crépin, Thibaut; McCarthy, Andrew A.; Hart, Darren J.; Baudin, Florence; Cusack, Stephen; Ruigrok, Rob W. H. (2009). “The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit”. Nature458(7240): 914–918. doi:10.1038/nature07745ISSN 0028-0836.
  4. Jump up^ “Cap snatching”.
Baloxavir marboxil
Baloxavir marboxil.svg
Identifiers
CAS Number
PubChem CID
UNII
KEGG
Chemical and physical data
Formula C27H23F2N3O7S
Molar mass 571.55 g·mol−1
3D model (JSmol)

Shionogi & Company, Limited(塩野義製薬株式会社 Shionogi Seiyaku Kabushiki Kaisha) is a Japanesepharmaceutical company best known for developing Crestor. Medical supply and brand name also uses Shionogi (“シオノギ”).

Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines produced are for hyperlipidaemiaantibiotics, and cancer medicines.

In Japan it is particularly known as a producer of antimicrobial and antibiotics. Because of antibiotic resistance and slow growth of the antibiotic market, it has teamed up with US based Schering-Plough to become a sole marketing agent for its products in Japan.

Shionogi had supported the initial formation of Ranbaxy Pharmaceuticals, a generic manufacturer based in India. In 2012 the company became a partial owner of ViiV Healthcare, a pharmaceutical company specialising in the development of therapies for HIV.[3]

The company is listed on the Tokyo Stock Exchange and Osaka Securities Exchange and is constituent of the Nikkei 225 stock index.[4]

Medicines
Media
  • Shionogi has a close relationship with Fuji Television Network, Inc., because Shionogi is the sponsor of “Music Fair” (as of 2018, aired on 17 TV stations including TV Oita System Co.) started in 1964.
  • Shionogi was a main sponsor of Team Lotus during the age 1991/1994.[5]
References
  1. “Shionogi Company Profile”. Retrieved March 18, 2014.
  2. “Shionogi Annual Report 2013” (PDF). Retrieved March 18, 2014.
  3. “Shionogi and ViiV Healthcare announce new agreement to commercialise and develop integrase inhibitor portfolio”. viivhealthcare.com. Retrieved 18 March 2014.
  4. “Components:Nikkei Stock Average”Nikkei Inc. Retrieved March 11,2014.
  5. Perry, Alan. “Sponsor Company Profiles”. Retrieved 25 April 2012.
External links

/////////Baloxavir marboxil, バロキサビルマルボキシル, JAPAN 2018,  Xofluza,  S-033188, S-033447, RG-6152, Qualified Infectious Disease Product, Priority Review, SAKIGAKE, балоксавир марбоксил بالوكسافير ماربوكسيل 玛巴洛沙韦 Shionogi, roche

COC(=O)OCOC1=C2C(=O)N3CCOCC3N(N2C=CC1=O)C4C5=C(CSC6=CC=CC=C46)C(=C(C=C5)F)F

Elobixibat hydrate, エロビキシバット水和物


Elobixibat skeletal.svgChemSpider 2D Image | Elobixibat | C36H45N3O7S2Elobixibat.png

Elobixibat

  • Molecular FormulaC36H45N3O7S2
  • Average mass695.888 Da
 CAS 439087-18-0 [RN]
A3309
AZD7806
Glycine, N-[(2R)-2-[[2-[[3,3-dibutyl-2,3,4,5-tetrahydro-7-(methylthio)-1,1-dioxido-5-phenyl-1,5-benzothiazepin-8-yl]oxy]acetyl]amino]-2-phenylacetyl]-
N-{(2R)-2-[({[3,3-Dibutyl-7-(methylsulfanyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenylacetyl}glycine
A-3309
AJG-533
AZD-7806
A-3309; AJG-533; Goofice
Image result for Elobixibat

Elobixibat hydrate

Approved 2018/1/19 Japan pmda

TRADE NAME Goofice  to EA Pharma

エロビキシバット水和物

C36H45N3O7S2▪H2O : 713.9
[1633824-78-8] CAS OF HYDRATE

Image result for Goofice

Gooffice ® tablet 5 mg (hereinafter referred to as Gooffice ® ) is an oral chronic constipation remedy drug containing as active ingredient Erobi vat having bile acid transporter inhibitory action. It is the world’s first bile acid transporter inhibitor.

Elobixibat is an inhibitor of the ileal bile acid transporter (IBAT),[1] undergoing development in clinical trials for the treatment of chronic constipation and irritable bowel syndrome with constipation (IBS-C).

Mechanism of action

IBAT is the bile acid:sodium symporter responsible for the reuptake of bile acids in the ileum which is the initial step in the enterohepatic circulation. By inhibiting the uptake of bile acids, elobixibat increases the bile acid concentration in the gut, and this accelerates intestinal passage and softens the stool. Following several phase II studies, it is now undergoing phase III trials.[2]

Drug development

The drug was developed by Albireo AB, who licensed it to Ferring Pharmaceuticals for further development and marketing.[3] Albireo has partnered with Ajinomoto Pharmaceuticals, giving the Japan-based company the rights to further develop the drug and market it throughout Asia.[4]

  • OriginatorAstraZeneca
  • DeveloperAlbireo Pharma; EA Pharma
  • Class2 ring heterocyclic compounds; Amides; Carboxylic acids; Laxatives; Small molecules; Sulfides; Sulfones; Thiazepines
  • Mechanism of ActionSodium-bile acid cotransporter-inhibitors
  • Orphan Drug StatusNo
  • New Molecular EntityYes

Highest Development Phases

  • RegisteredConstipation
  • DiscontinuedDyslipidaemias; Irritable bowel syndrome

Most Recent Events

Approved 2018/1/19 japan pmda

  • 24 Jan 2018Elobixibat is still in phase II trials for Constipation in Indonesia, South Korea, Taiwan, Thailand and Vietnam (Albireo pipeline, January 2018)
  • 24 Jan 2018Discontinued – Phase-II for Irritable bowel syndrome in USA and Europe (PO) (Alberio pipeline, January 2018)
  • 19 Jan 2018Registered for Constipation in Japan (PO) – First global approval
  • In 2012, the compound was licensed to Ajinomoto (now EA Pharma) by Albireo for exclusive development and commercialization rights in several Asian countries. At the same year, the product was licensed to Ferring by Albireo worldwide, except Japan and a small number of Asian markets, for development and marketing. However, in 2015, this license between Ferring and Albireo was terminated and Albireo is seeking partner for in the U.S. and Europe. In 2016, Ajinomoto and Mochida signed an agreement on codevelopment and comarketing of the product in Japan.

Elobixibat

albireo_logo_nav.svg

Elobixibat is an IBAT inhibitor approved in Japan for the treatment of chronic constipation, the first IBAT inhibitor to be approved anywhere in the world.  EA Pharma Co., Ltd., a company formed via a 2016 combination of Eisai’s GI business with Ajinomoto Pharmaceuticals and focused on the gastrointestinal disease space, is the exclusive licensee of elobixibat for the treatment of gastrointestinal disorders in Japan and other select countries in Asia (not including China) and is expected to co-market elobixibat in Japan with Mochida Pharmaceutical Co., Ltd., and to co-promote elobixibat in Japan with Eisai, under the trade name GOOFICE®.

We also believe that elobixibat has potential benefit in the treatment of NASH based on findings on relevant parameters in clinical trials of elobixibat that we previously conducted in patients with chronic constipation and in patients with elevated cholesterol and findings on other parameters relevant to NASH from nonclinical studies that we previously conducted with elobixibat or a different IBAT inhibitor. In particular, in a clinical trial in dyslipidemia patients, elobixibat given for four weeks reduced low-density lipoprotein (LDL) cholesterol, with the occurrence of diarrhea being substantially the same as the placebo group. Also, in other clinical trials in constipated patients, elobixibat given at various doses and for various durations reduced LDL-cholesterol and, in one trial, increased levels of glucagon-like peptide 1 (GLP-1). Moreover, A4250 (an IBAT inhibitor) showed significant improvement (p < 0.05) on the nonalcoholic fatty liver disease activity score in an established model of NASH in mice known as the STAM™ model and improvement in liver inflammation and fibrosis in another preclinical mouse model. We are considering conducting a Phase 2 clinical trial of elobixibat in NASH

These benzothiazepines possess ileal bile acid transport (IBAT) inhibitory activity and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions and they are useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said benzothiazepine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit IBAT in a warm-blooded animal, such as man.
It is well-known that hyperlipidaemic conditions associated with elevated
concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for cardiovascular atherosclerotic disease (for instance “Coronary Heart Disease: Reducing the Risk; a Worldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association” Grundy S, Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134-46). Interfering with the circulation of bile acids within the lumen of the intestinal tracts is found to reduce the level of cholesterol. Previous established therapies to reduce the concentration of cholesterol involve, for instance, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. Frequently used bile acid binders are for instance cholestyramine and cholestipol. One recently proposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) involved the treatment with substances with an IBAT inhibitory effect.
Re-absorption of bile acid from the gastro-intestinal tract is a normal physiological process which mainly takes place in the ileum by the IBAT mechanism. Inhibitors of EBAT can be used in the treatment of hypercholesterolaemia (see for instance “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties”, Biochemica et Biophysica Acta, 1210 (1994) 255- 287). Thus, suitable compounds having such inhibitory IBAT activity are also useful in the treatment of hyperlipidaemic conditions.

Compounds possessing such IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/50051 and EP 0 864 582.
A further aspect of this invention relates to the use of the compounds of the invention in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocytes, monocytes and/or macrophage infiltration, intimal thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks.

PATENTS

WO 2002050051

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=4E054324A28B9E2E7C3C73102D1560EC.wapp1?docId=WO2002050051&recNum=237&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A61K%22%26fq%3DPAF_M%3A%22ASTRAZENECA+AB%22&sortOption=Relevance&maxRec=655

STARKE, Ingemar; (SE).
DAHLSTROM, Mikael; (SE).
BLOMBERG, David; (SE)

ASTRAZENECA 

SYNTHESIS

WO 2002050051, WO 1996016051

STR1

PATENT

WO 2003051821

WO 2003020710

TW I291951

WO 2013063512

WO 2013063526

US 20140323412

EP 3012252

PATENT

WO 2003020710

https://patents.google.com/patent/WO2003020710A1/und

STR1

PATENT

WO 2014174066 

WO 02/50051 discloses the compound 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘- [/V-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (elobixibat; lUPAC name: /V-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenyl-ethanolyl}glycine). This compound is an ileal bile acid transporter (I BAT) inhibitor, which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases. According to the experimental section of WO 02/50051 , the last synthetic step in the preparation of elobixibat consists of the hydrolysis of a ie f-butoxyl ester under acidic conditions. The crude compound was obtained by evaporation of the reaction mixture under reduced pressure and purification of the residue by preparative HPLC using acetonitrile/ammonium acetate buffer (50:50) as eluent (Example 43). After freeze drying the product, no crystalline material was identified.

Example 1

Preparation of crystal modification I

Toluene (1 1 .78 L) was charged to a 20 L round-bottom flask with stirring and 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘-[/\/’-(i-butoxycarbonylmethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (2.94 kg) was added. Formic acid (4.42 L) was added to the reaction mass at 25-30 °C. The temperature was raised to 1 15-120 °C and stirred for 6 hours. The reaction was monitored by HPLC to assure that not more than 1 % of the starting material remained in the reaction mass. The reaction mass was cooled to 40-43 °C. Purified water (1 1 .78 L) was added while stirring. The reaction mass was further cooled to 25-30 °C and stirred for 15 min.

The layers were separated and the organic layer was filtered through a celite bed (0.5 kg in 3 L of toluene) and the filtrate was collected. The celite bed was washed with toluene (5.9 L), the filtrates were combined and concentrated at 38-40 °C under vacuum. The reaction mass was then cooled to 25-30 °C to obtain a solid.

Ethanol (3.7 L) was charged to a clean round-bottom flask with stirring, and the solid obtained in the previous step was added. The reaction mass was heated to 40-43 °C and stirred at this temperature for 30 min. The reaction mass was then cooled to 25-30 °C over a period of 30 min., and then further cooled to 3-5 °C over a period of 2 h, followed by stirring at this temperature for 14 h. Ethanol (3.7 L) was charged to the reaction mass with stirring, while maintaining the temperature at 0-5 °C, and the reaction mass was then stirred at this temperature for 1 h. The material was then filtered and washed with ethanol (1 .47 L), and vacuum dried for 30 min. The material was dried in a vacuum tray dryer at 37-40 °C for 24 h under nitrogen atmosphere. The material was put in clean double LDPE bags under nitrogen atmosphere and stored in a clean HDPE drum. Yield 1 .56 kg.

Crystal modification I has an XRPD pattern, obtained with CuKal -radiation, with

characteristic peaks at °2Θ positions: 3,1 ± 0.2, 4,4 ± 0.2, 4,9 ± 0.2, 5,2 ± 0.2, 6,0 ± 0.2, 7,4 ± 0.2, 7,6 ± 0.2, 7,8 ± 0.2, 8,2 ± 0.2, 10,0 ± 0.2, 10,5 ± 0.2, 1 1 ,3 ± 0.2, 12,4 ± 0.2, 13,3 ± 0.2, 13,5 ± 0.2, 14,6 ± 0.2, 14,9 ± 0.2, 16,0 ± 0.2, 16,6 ± 0.2, 16,9 ± 0.2, 17,2 ± 0.2, 17,7 ± 0.2, 18,0 ± 0.2, 18,3 ± 0.2, 18,8 ± 0.2, 19,2 ± 0.2, 19,4 ± 0.2, 20,1 ± 0.2, 20,4 ± 0.2, 20,7 ± 0.2, 20,9 ± 0.2, 21 ,1 ± 0.2, 21 ,4 ± 0.2, 21 ,8 ± 0.2, 22,0 ± 0.2, 22,3 ± 0.2, 22,9 ± 0.2, 23,4 ± 0.2, 24,0 ± 0.2, 24,5 ± 0.2, 24,8 ± 0.2, 26,4 ± 0.2,27,1 ± 0.2 and 27,8 ± 0.2. The X-ray powder diffractogram is shown in FIG. 4.

PATENT

WO 2014174066

エロビキシバット水和物
Elobixibat Hydrate

C36H45N3O7S2▪H2O : 713.9
[1633824-78-8]

References

  1. Jump up^ “INN for A3309 is ELOBIXIBAT”. AlbireoPharma. Archived from the original on 18 January 2012. Retrieved 5 December 2012.
  2. Jump up^ Acosta A, Camilleri M (2014). “Elobixibat and its potential role in chronic idiopathic constipation”Therap Adv Gastroenterol7 (4): 167–75. doi:10.1177/1756283X14528269PMC 4107709Freely accessiblePMID 25057297.
  3. Jump up^ Grogan, Kevin. “Ferring acquires rights to Albireo’s bowel drug”PharmaTimes. Retrieved 23 March 2017.
  4. Jump up^ “Ajinomoto Pharmaceuticals and Albireo Announce Japan and Asia License Agreement for Elobixibat”. Albireo. Retrieved 5 December2012.[permanent dead link]
Elobixibat
Elobixibat skeletal.svg
Clinical data
Routes of
administration
Oral
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C36H45N3O7S2
Molar mass 695.89 g/mol
3D model (JSmol)

//////////Elobixibat hydrate, japan 2018, A-3309, AJG-533, Goofice, A 3309, AJG 533, AZD 7806

CCCCC1(CN(C2=CC(=C(C=C2S(=O)(=O)C1)OCC(=O)NC(C3=CC=CC=C3)C(=O)NCC(=O)O)SC)C4=CC=CC=C4)CCCC

Gilteritinib fumarate ギルテリチニブフマル酸塩


1254053-84-3.png

  1. 1254053-84-3

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

Xospata pmda 2018/9/21  JAPAN 2018

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

CAS No. 1254053-43-4  FREE FORM

  1. 1254053-84-3  FUMARATE
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 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 http://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 http://www.astellas.com/en.

SOURCE: Astellas Pharma

Start of the Euro 2016

////////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

Fidaxomicin, フィダキソマイシン


 

Fidaxomicin.svg

 

Fidaxomicin (C52H74Cl2O18, Mr = 1058.0 g/mol)

Launched – 2011 MERCK, Clostridium difficile-associated diarrhea

CUBIST ….INNOVATOR

OPT-80
PAR-101

Also tiacumicin B or lipiarmycin A3,

A bacterial RNA polymerase inhibitor as macrocyclic antibiotic used to treat clostridium difficile-associated diarrhea (CDAD).

SYNTHESIS

str1

REFERENCES

US 4918174

WO 2006085838

J ANTIBIOTICS 1987, 40, PG 567-574 AND 575-588

 

Idaxomicin(trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrum macrocyclic antibiotic drugs.[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.[3][4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species of bacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.[5] [6]

Fidaxomicin is an antibiotic approved and launched in 2011 in the U.S. for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adults 18 years of age and older. In September 2011, the product received a positive opinion in the E.U. and final approval was assigned in December 2011.

First E.U. launch took place in the U.K. in June 2012. Optimer Pharmaceuticals, now part of Cubist (now, Merck & Co.), is conducting phase III clinical trials for the prevention of Clostridium difficile-associated diarrhea in patients undergoing hematopoietic stem cell transplant

In 2014 Astellas initiated in Europe a phase III clinical study for the treatment of Clostridium difficile infection in pediatric patients. Preclinical studies are ongoing for potential use in the prevention of methicillin-resistant Staphylococcus (MRS) infection.

 

The compound is a novel macrocyclic antibiotic that is produced by fermentation. Its narrow-spectrum activity is highly selective for C. difficile, thus preserving gut microbial ecology, an important consideration for the treatment of CDAD.

It is marketed by Cubist Pharmaceuticals after acquisition of its originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection.

In May 2005, Par Pharmaceutical and Optimer entered into a joint development and collaboration agreement for fidaxomicin. However, rights to the compound were returned to Optimer in 2007. The compound was granted fast track status by the FDA in 2003. In 2010, orphan drug designation was assigned to fidaxomicin in the U.S. by Optimer Pharmaceuticals for the treatment of pediatric Clostridium difficile infection (CDI). In 2011, the compound was licensed by Optimer Pharmaceuticals to Astellas Pharma in Europe and certain countries in the Middle East, Africa, the Commonwealth of Independent States (CIS) and Japan for the treatment of CDAD. In 2011, fidaxomicin was licensed to Cubist by Optimer Pharmaceuticals for comarketing in the U.S. for the treatment of CDAD. In July 2012, the product was licensed by Optimer Pharmaceuticals to Specialised Therapeutics Australia in AU and NZ for the treatment of Clostridium difficile-associated infection. OBI Pharma holds exclusive commercial rights in Taiwan, where the compound was approved for the treatment of CDAD in September 2012, and in December 2012, the product was licensed to AstraZeneca in South America with commercialization rights also for the treatment of CDAD. In October 2013, Optimer Pharmaceuticals was acquired by Cubist.

Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient’s clinical status. It is currently one of the most expensive antibiotics approved for use. A standard course costs upwards of £1350.[7]

Fidaxomicin (also known as OPT-80 and PAR-101 ) is a novel antibiotic agent and the first representative of a new class of antibacterials called macrocycles. Fidaxomicin is a member of the tiacumicin family, which are complexes of 18-membered macrocyclic antibiotics naturally produced by a strain of Dactylosporangium aurantiacum isolated from a soil sample collected in Connecticut, USA.

The major component of the tiacumicin complex is tiacumicin B. Optically pure R-tiacumicin B is the most active component of Fidaxomicin. The chiral center at C(19) of tiacumicinB affects biological activity, and R-tiacumicin B has an R-hydroxyl group attached at this position. The isomer displayed significantly higher activity than other tiacumicin B-related compounds and longer post-antibiotic activity.

Tiacumicins are a family of structurally related compounds that contain the 18-membered macrolide ring shown below.

Figure imgf000002_0001

At present, several distinct Tiacumicins have been identified and six of these

(Tiacumicin A-F) are defined by their particular pattern of substituents R1, R2, and R3 (US Patent No. 4,918,174; J. Antibiotics, 1987, 575-588).

The Lipiarmycins are a family of natural products closely related to the Tiacumicins. Two members of the Lipiarmycin family (A3 and B3) are identical to Tiacumicins B and C respectively (J. Antibiotics, 1988, 308-315; J. Chem. Soc. Perkin Trans 1, 1987, 1353-1359).

The Tiacumicins and the Lipiarmycins have been characterized by numerous physical methods. The reported chemical structures of these compounds are based on spectroscopy (UV-vis, IR and !H and 13C NMR), mass spectrometry and elemental analysis (See for example: J. Antibiotics, 1987, 575-588; J. Antibiotics, 1983, 1312-

1322).

Tiacumicins are produced by bacteria, including Dactylosporangium aurantiacum subspecies hamdenensis, which may be obtained from the ARS Patent Collection of the Northern Regional Research Center, United States Department ofAgriculture, 1815 North University Street, Peoria, IL 61604, accession number NRRL

18085. The characteristics of strain AB 718C-41 are given in J. Antibiotics, 1987,567-574 and US Patent No. 4,918,174.

Lipiarmycins are produced by bacteria including Actinoplanes deccanensis (US Patent No. 3,978,211). Taxonomical studies of type strain A/10655, which has been deposited in the ATCC under the number 21983, are discussed in J. Antibiotics,1975, 247-25.

Tiacumicins, specifically Tiacumicin B, show activity against a variety of bacterial pathogens and in particular against Clostridium difficile, a Gram-positive bacterium (Antimicrob. Agents Chemother. 1991, 1108-1111). Clostridium difficile is an anaerobic spore-forming bacterium that causes an infection of the bowel.

As per WIPO publication number 2006085838, Fidaxomicin is an isomeric mixture of the configurationally distinct stereoisomers of tiacumicin B, composed of 70 to 100% of R-tiacumicin B and small quantities of related compounds, such as S-tiacumicin B and lipiarmycin A4. Fidaxomicin was produced by fermentation of the D aurantiacum subspecies hamdenensis (strain 718C-41 ). It has a narrow spectrum antibacterial profile mainly directed against Clostridium difficile and exerts a moderate activity against some other gram-positive species.

Fidaxomicin is bactericidal and acts via inhibition of RNA synthesis by bacterial RNA polymerase at a distinct site from that of rifamycins. The drug product is poorly absorbed and exerts its activity in the gastrointestinal (Gl) tract, which is an advantage when used in the applied indication, treatment of C. difficile infection (CDI) (also known as C. difficile-associated disease or diarrhoea [CDAD]). Fidaxomicin is available as DIFICID oral tablet in US market.

Its CAS chemical name is Oxacyclooctadeca-3,5,9, 13, 15-pentaen-2-one, 3-[[[6-deoxy-4-0-(3,5dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-0-methyl-P-D-manno pyranosyl]oxy]methyl]-12[[6-deoxy-5-C-methyl-4-0-(2-methyl-1 -oxopropyl)- -D-lyxo-hexo pyranosyl]oxy]-1 1 -ethyl-8-hydroxy-18-[(1 R)-1 -hydroxyethyl] -9,13,15-trimethyl-, (3E.5E, 8S.9E.1 1 S.12R.13E, 15E.18S)-.

Structural formula (I) describes the absolute stereochemistry of fidaxomicin as determined by x-ray.

(I)

WIPO publication number 2004014295 discloses a process for preparation of Tiacumicins that comprises fermentation of Dactylosporangium aurantiacum NRRL18085 in suitable culture medium. It also provides process for isolation of tiacumicin from fermentation broth using techniques selected from the group consisting of: sieving and removing undesired material by eluting with at least one solvent or a solvent mixture; extraction with at least one solvent or a solvent mixture; Crystallization; chromatographic separation; High-Performance Liquid Chromatography (HPLC); MPLC; trituration; and extraction with saturated brine with at least one solvent or a solvent mixture. The product was isolated from /so-propyl alcohol (IPA) having a melting point of 166-169 °C.

U.S. Patent No. 7378508 B2 discloses polymorphic forms A and B of fidaxomicin, solid dosage forms of the two forms and composition thereof. As per the ‘508 patent form A is obtained from methanol water mixture and Form B is obtained from ethyl acetate.

J. Antibiotics, vol. 40(5), 575-588 (1987) discloses purification of Tiacumicins using suitable solvents wherein tiacumicin B exhibited a melting point of 143-145 °C.

PCT application WO2013170142A1 describes three crystalline forms of Fidaxomicn namely, Form-Z, Form-Z1 and Form-C. IN2650/CHE/2013 describes 6 crystalline polymorphic forms of Fidaxomicin namely, Forms I, Form la, Form II, Form Ha, Form III and Form Ilia).

Mechanism

Fidaxomicin binds to and prevents movement of the “switch regions” of bacterial RNAP polymerase. Switch motion is important for opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but especially during opening of double standed DNA during transcription initiation.[8] It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.[3]

Clinical trials

Good results were reported by the company in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment of Clostridium difficile infection (CDI)[9][10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).[11] Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next four weeks.[12]

Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

Approvals and indications

For the treatment of Clostridium difficile-associated diarrhea (CDAD), the drug won an FDA advisory panel’s unanimous approval on April 5, 2011[14] and full FDA approval on May 27, 2011.[15]

 

PAPER

Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B
Angew Chem Int Ed 2015, 54(6): 1929

Enantioselective Synthesis of Putative Lipiarmycin Aglycon Related to Fidaxomicin/Tiacumicin B (pages 1929–1932)

Dr. William Erb, Dr. Jean-Marie Grassot, Dr. David Linder, Dr. Luc Neuville and Prof. Dr. Jieping Zhu

Article first published online: 24 NOV 2014 | DOI: 10.1002/anie.201409475

Thumbnail image of graphical abstract

Chain gang: In the synthesis of the title compound, the ene-diene ring-closing metathesis was used for the formation of the 18-membered macrolactone and the stereogenic centers of the molecule were installed by Brown’s alkoxyallylboration, allylation, and an Evans aldol reaction, while iterative Horner–Wadsworth–Emmons reactions were used for chain elongation.

http://onlinelibrary.wiley.com/doi/10.1002/anie.201409475/full

http://onlinelibrary.wiley.com/store/10.1002/anie.201409475/asset/supinfo/anie_201409475_sm_miscellaneous_information.pdf?v=1&s=75d40b6f8b214578d5a65518e7f384f03f377c35

 

PAPER

Total synthesis of the glycosylated macrolide antibiotic fidaxomicin
Org Lett 2015, 17(14): 3514

http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b01602

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.5b01602/suppl_file/ol5b01602_si_001.pdf

Abstract Image

The first enantioselective total synthesis of fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is reported. This novel glycosylated macrolide antibiotic is used in the clinic for the treatment of Clostridium difficile infections. Key features of the synthesis involve a rapid and high-yielding access to the noviose, rhamnose, and orsellinic acid precursors; the first example of a β-selective noviosylation; an effective Suzuki coupling of highly functionalized substrates; and a ring-closing metathesis reaction of a noviosylated dienoate precursor. Careful selection of protecting groups allowed for a complete deprotection yielding totally synthetic fidaxomicin.

The identity of the synthetic compound to an authentic sample of fidaxomicin (1) was confirmed by coinjection on RP-HPLC and an equimolar mixed NMR-sample with an authentic sample. Rƒ = 0.44 (MeOH/CH2Cl2 1/10).

HRMS ESI calcd. for [C52H74Cl2NaO18] + [M+Na]+ : 1079.4144; found:1079.4151.

1H NMR (600 MHz, Methanol-d4 , containing HCOO- ) δ 7.23 (d, J = 11.5 Hz, 1H), 6.60 (dd, J = 14.9, 11.8 Hz 1H), 5.95 (ddd, J = 14.7, 9.5, 4.8 Hz, 1H), 5.83 (s, 1H), 5.57 (ap t, J = 8.2 Hz, 1H), 5.14 (ap d, J = 10.7, 1H), 5.13 (dd, J = 9.7 Hz, 1H), 5.02 (d, J = 10.2 Hz, 1H), 4.74-4.70 (m, 1H), 4.71 (s, 1H), 4.64 (s, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.44 (d, J = 11.6 Hz, 1H), 4.22 (ap s, 1H), 4.02 (p, J = 6.3 Hz, 1H), 3.92 (dd, J = 3.2, 1.2 Hz, 1H), 3.75 (ddd, J = 13.9, 10.2, 3.3 Hz, 1H) 3.71 (d, J = 9.7 Hz 1H), 3.58-3.52 (m, 2H) 3.54 (s, 3H), 3.15-3.06 (m, 1H), 3.04-2.95 (m, 1H), 2.76-2.66 (m, 3H), 2.60 (hept, J= 7.0 Hz, 1H), 2.49 (ddd, J = 14.9, 9.5, 4.4 Hz, 1H), 2.43 (ddd, J = 13.8, 8.8, 4.5 Hz, 1H), 2.05-1.98 (m, 1H), 1.82 (d, J = 1.3 Hz, 3H), 1.76 (ap s, 3H), 1.66 (ap s, 3H), 1.32-1.27 (m, 4H), 1.22-1.15 (m, 12H), 1.15 (s, 3H), 1.13 (s, 3H), 0.88 (t, J = 7.4 Hz, 3H).

RP-HPLC tR = 14.87 min (A: H2O+0.1% HCOOH; Solvent B: MeCN+0.1% HCOOH; 1 mL/min; T = 20°C; B[%] (tR [min])= 10 (0 to 3); 100 (15).

PATENT

WO 2004014295

http://www.google.co.in/patents/WO2004014295A2?cl=en

The term “Tiacumicin B” refers to molecule having the structure shown below:

Figure imgf000008_0002

Example 1

Dactylosporangium aurantiacum subsp. hamdenensis AB 718C-41 NRRL 18085 (-20 °C stock), was maintained on 1 mL of Medium No. 104 (Table 1). After standard sterilization conditions (30 min., 121 °C, 1.05 kg/cm2) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C-41 NRRL 18085 on a shaker (set @ 250 rpm) at 30 °C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was then transferred aseptically to a fermentation flask containing the same ingredients as in Table 1.

Table 1: Ingredients of Medium No. 104

Figure imgf000013_0001

Fermentation flasks were incubated on a rotary shaker at 30 °C for 3 to 12 days. Samples of the whole culture fermentation broth were filtered. The filter cake was washed with MeOH and solvents were removed under reduced pressure. The residue was re-constituted in methanol to the same volume of the original fermentation broth. Analysis was performed using a Waters BREEZE HPLC system coupling with Waters 2487 2-channel UV/Vis detector. Tiacumincins were assayed on a 50 x 4.6 μm I.D., 5 μm YMC ODS-A column (YMC catalog # CCA AS05- 0546WT) with a mobile phase consisting of 45% acetonitrile in water containing 0.1% phosphoric acid at a flow rate of 1.5 mL/minute. Tiacumicins were detected at 266 nm. An HPLC chromatogram of a crude product (Tiacumicin B retention time @ 12.6 minutes) is shown in Fig. 1. In this example the crude yield of Tiacumicin B was about 250 mg/L after 7 days. After purification by HPLC, the yield of Tiacumicin B was about 100 mg/L.

Example 2

After standard sterilization conditions (30 min, 121 °C, 1.05 kg/cm2) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C- 41 NRRL 18085 and incubated on a shaker (set @ 250 rpm) at 30° C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was transferred aseptically to a seed flask containing the same ingredients as in Table 1 and was incubated on a rotary shaker at 30 °C for 72 hr. Five percent inoculum from the second passage seed flasks was then used to inoculate with AB 718C-41 NRRL 18085 in a 5-liter fermenter containing Medium No. 104 (2.5 L). Excessive foam formation was controlled by the addition of an antifoaming agent (Sigma A-6426). This product is a mixture of non-silicone organic defoamers in a polyol dispersion.

Glucose consumption was monitored as a growth parameter and its level was controlled by the addition of the feeding medium. Feeding medium and conditions in Example 2 were as follows:

Feeding medium:

Figure imgf000014_0001

Fermenter Medium: No. 104

Fermenter Volume: 5 liters

Sterilization: 40 minutes, 121° C, 1.05 kg/cm2

Incubation Temperature: 30 °C.

Aeration rate: 0.5-1.5 volumes of air per culture volume and minute

Fermenter Agitation: 300-500 rpm

The fermentation was carried out for 8 days and the XAD-16 resin was separated from the culture broth by sieving. After washing with water the XAD-16 resin was eluted with methanol (5-10 x volume of XAD-16). Methanol was evaporated and the oily residue was extracted three times with ethyl acetate. The extracts were combined and concentrated under reduced pressure to an oily residue. The oily residue was dried and washed with hexane to give the crude product as a pale brown powder and its HPLC chromatogram (Tiacumincin B rete tion time @ 11.8 minutes) is shown in Figure 2. This was purified by silica gel column (mixture of ethyl acetate and hexane as eluent) and the resultant material was further purified by RP-HPLC (reverse phase HPLC) to give Tiacumicin B as a white solid. The purity was determined to be >95% by HPLC chromatography and the chromatogram (Tiacumincin B retention time @ 12.0 minutes) is shown in Figure 3. Analysis of the isolated Tiacumincin B gave identical !H and 13C NMR data to those reported in J. Antibiotics, 1987, 575-588, and these are summarized below. Tiacumicin B: mp 129-140 °C (white powder from RP-HPLC); mp 166-169 °C (white needles from isopropanol); [α]D 20-6.9 (c 2.0, MeOH); MS m/z (ESI) 1079.7(M + Na)+; H NMR (400 MHz, CD3OD) δ 7.21 (d, IH), 6.59 (dd, IH), 5.95 (ddd, IH), 5.83 (br s, IH), 5.57 (t, IH), 5.13 (br d, IH), 5.09 (t, IH), 5.02 (d, IH), 4.71 (m, IH), 4.71 (br s, IH), 4.64 (br s, IH), 4.61 (d, IH), 4.42 (d, IH), 4.23 (m, IH), 4.02 (pentet, IH), 3.92 (dd, IH), 3.73 (m, 2H), 3.70 (d, IH), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H), 2.59 (heptet, IH), 2.49 (ddd, IH), 2.42 (ddd, IH), 2.01 (dq, IH), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, IH), 1.20 (t, 3H), 1.19 (d, 3 H), 1.17 (d, 3H), 1.16 (d, 3H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H); 13C NMR (100 MHz, CD3OD) δ 178.4, 169.7, 169.1, 154.6, 153.9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3, 97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.

PATENT

http://www.google.com/patents/US7378508

macrolide of Formula I:

Figure US07378508-20080527-C00001

Structure of R-Tiacumicin B

The structure of the R-Tiacumicin B (the major most active component) is shown below in Formula I. The X-ray crystal structure of the R-Tiacumicin B was obtained as a colorless, parallelepiped-shaped crystal (0.08×0.14×0.22 mm) grown in aqueous methanol. This x-ray structure confirms the structure shown below. The official chemical name is 3-[[[6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]-methyl]-12(R)-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one.

Figure US07378508-20080527-C00009

7.2.1 Analytical Data of R-Tiacumicin B

The analytical data of R-Tiacumicin B (which is almost entirely (i.e., >90%) R-Tiacumicin).

mp 166-169° C. (white needle from isopropanol);

[α]D 20-6.9 (c 2.0, MeOH);

MS m/z (ESI) 1079.7(M+Na)+;

1H NMR (400 MHz, CD3OD) δ 7.21 (d, 1H), 6.59 (dd, 1H), 5.95 (ddd, 1H), 5.83 (br s, 1H), 5.57 (t, 1H), 5.13 (br d, 1H), 5.09 (t, 1H), 5.02 (d, 1H), 4.71 (m, 1H), 4.71 (br s, 1H), 4.64 (br s, 1H), 4.61 (d, 1H), 4.42 (d, 1H), 4.23 (m, 1H), 4.02 (pentet, 1H), 3.92 (dd, 1H), 3.73 (m, 2H), 3.70 (d, 1H), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H), 2.59 (heptet, 1H), 2.49 (ddd, 1H), 2.42 (ddd, 1H), 2.01 (dq, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, 1H), 1.20 (t, 3H), 1.19 (d, 3H), 1.17 (d, 3H), 1.16 (d, 3 H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H);

13C NMR (100 MHz, CD3OD) δ 178.4, 169.7, 169.1, 154.6, 153.9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3, 97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.

 PATENT
WO2013170142

EXAMPLES

Example 1; General procedure for the preparation of crude Fidaxomycin

Fidaxomycin was prepared by:

i) culturing a microorganism in a nutrient medium to accumulate Fidaxomycin in the nutrient medium;

ii) isolating crude Fidaxomycin from the nutrient medium by methods known from the art;

iii) purifying Fidaxomycin by reversed phase chromatography using a mixture of acetonitrile, water and acetic acid as eluent; and iv) isolating the purified Fidaxomycin from the fractions.

Actionplanes deccanenesis was used during the cultivation. The nutrient medium comprises the following combination based on weight: from about 0% to about 5% Sucrose; from about 0% to about 3% Starch; from about 0.1% to about 1.0 % Soy peptone; from about 2% to about 5% Cotton seed meal; from about 0.01% to about 0.1% Potassium-dihydrogen Phosphate; from about 0.05% to about 0.5% Dipotassium-hydrogen Phosphate; from about 0.05% to about 0.5% Antifoam agent; from about 0% to about 2% Amberlite XAD-16N resin. The preferred temperature of the cultivation is from 28 to 32°C, and the pH is between 6.0 and 8.0. During the cultivation C-source is continuously fed.

The Fidaxomycin fermentation production can also be done by the following procedure:

The Fidaxomycin fermentation production can include a step of inoculation followed by fermentation as follows:

Inoculation: Actinoplanes deccanenesis strain is inoculated into the seed medium. The inoculation parameters are adjusted and maintained until the inoculum transferred to the main fermentation. The inoculum medium comprises: from about 0 to about 5% glucose, from about 0 to about 1% yeast extract, from about 0 to about 1% soy peptone, from about 0 to about 0.5% CaCo3, from about 0 to about 0.2% MgS0 -7H20, from about 0 to about 0.2% K2HP04, from about 0 to about 0.2% KC1, from about 0 to about 0.3% Polypropylene glycol. The pH is adjusted by adding Hydrochloric acid and/or Sodium/potassium hydroxide.

Inoculation parameters :

Inoculation time: 40-48 ± 24 hours.

At the end of the inoculation, the inoculum (or a part of it) is transferred into the sterile fermentation medium at a ratio of 8-15 ± 5 %.

Fermentation: the fermentation medium comprises: from about 0 to aboutl0% Sucrose/Hydrolyzed Starch, from about 0 to about 1% Soy peptone, from about 0 to about 5% Cotton seed meal, from about 0 to about 0.3% K2HP04, from about 0 to about 0.2% KH2P04, from about 0 to aboutl% KC1, from about 0 to about 0.5% Polypropylene glycol (PPG). The pH is adjusted by adding Hydrochloric acid and/or Sodium/potassium hydroxide.

The sterile fermentation medium is seeded with the inoculum.

Feeding:

C-source is fed during the fermentation, For C-source feeding sucrose or hydrolyzed-starch can be applied. Total amount of fed C-source is 0 – 15% related to the initial volume.

Fermentation parameters :

In case of foaming, sterile antifoaming agent should be added.

Fermentation time: 168-192 ± 24 hours.

The inoculation/fermentation medium may also include from about 0% to about 2% Amberlite XAD-16N resin.

Upon completion of fermentation, the Fidaxomycin is extracted from the fermented broth with an organic solvent such as, for example, ethyl acetate, isobutyl acetate or isobutanol. The organic phase is concentrated and the Fidaxomycin is precipitated by addition of an antisolvent such as, for example, n-hexane. Optionally the precipitate can be suspended in a second antisolvent. After filtration and drying, crude Fidaxomycin is obtained.

DIFICID (fidaxomicin) is a macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-Omethyl- β-D- mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxohexopyranosyl] oxy]-11-ethyl-8 -hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-,(3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.

Figure 1: Structural Formula of Fidaxomicin

str1

Image result for Fidaxomicin

Patent

WO 2016024243, New patent, Dr Reddy’s Laboratories Ltd, Fidaxomicin

WO2016024243,  FIDAXOMICIN POLYMORPHS AND PROCESSES FOR THEIR PREPARATION

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Telangana State, India Hyderabad 500034 (IN)

CHENNURU, Ramanaiah; (IN).
PEDDY, Vishweshwar; (IN).
RAMAKRISHNAN, Srividya; (IN)

Aspects of the present application relate to crystalline forms of Fidaxomicin IV, V & VI and processes for their preparation. Further aspects relate to pharmaceutical compositions comprising these polymorphic forms of fidaxomicin

front page image

 

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physico-chemical properties.

Polymorphs are different solid materials having the same molecular structure but different molecular arrangement in the crystal lattice, yet having distinct physico-chemical properties when compared to other polymorphs of the same molecular structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, “Tricky Business,” Science News, August 21 , 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.

There remains a need for additional polymorphic forms of fidaxomicin and for processes to prepare polymorphic forms in an environmentally-friendly, cost-effective, and industrially applicable manner.

G.V. Prasad, chairman, Dr Reddy’s Laboratories

EXAMPLES

Example 1 : Preparation of fidaxomicin Form IV:

Fidaxomicin (0.5 g) and a mixture of 1 ,4-Dioxane (10 mL), THF (10 ml) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature: 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 6 hours.

After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-IV.

Example 2: Preparation of fidaxomicin Form V:

Fidaxomicin (1 g) and a mixture of propylene glycol (10 mL) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 6 hours.

After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.

Example 3: Preparation of fidaxomicin Form VI:

Fidaxomicin (0.5 mg) and MIBK (10 mL) were charged in Easy max reactor (Mettler Toledo) and the mixture was heated to 80°C. n-heptane (20 mL) was added to the solution at the same temperature. The mixture was stirred for 1 hour. The reaction mass was then cooled to 25°C. Solid formed was filtered at 25°C and dried at 40°C in air tray dryer (ATD) to a constant weight to produce crystalline fidaxomicin form VI.

Example 4: Preparation of fidaxomicin Form V:

Fidaxomicin (500 mg) and a mixture of R-propylene glycol (5 mL) and water (15 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 2 hours.

After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.

Example 5: Preparation of fidaxomicin Form V:

Fidaxomicin (1 g) and a mixture of S-propylene glycol (3 ml_) and water (30 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 2 hours.

After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.

Example 6: Preparation of fidaxomicin Form V:

Fidaxomicin (40 g) and a mixture of propylene glycol (400 mL) and water (1600 mL) were charged in Chem glass reactor. The reactor was set to temperature cycle with following parameters:

Starting temperature is 25 °C;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 60 °C over a period of 2 hours;

Cooled to 0 °C over a period of 2 hours;

Temperature raised to 25 °C over a period of 2 hours;

Temperature maintained at 25 °C for 6 hours.

After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.

 

The 10-member board at pharmaceutical major Dr Reddy’s thrives on diversity. Liberally sprinkled with gray hairs, who are never quite impressed with powerpoint presentations, “they want information to be pre-loaded so that the following discussions (at the board level) are fruitful,” says Satish Reddy, Chairman, Dr Reddy’s. That said, the company has now equipped its board members with a customized application (that runs on their tablets) to manage board agenda and related processes.

see at

http://articles.economictimes.indiatimes.com/2014-10-31/news/55631761_1_board-members-board-agenda-dr-reddy-s

Dr. Reddy’s Laboratories Managing Director and Chief Operating Officer Satish Reddy addressing

 

 

References

ARNONE A ET AL: “STRUCTURE ELUCIDATION OF THE MACROCYCLIC ANTIBIOTIC LIPIARMYCIN“, JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1987 (1987-01-01), pages 1353-1359, XP000578201, ISSN: 0300-922X, DOI: 10.1039/P19870001353

Fidaxomicin
Fidaxomicin.svg
Systematic (IUPAC) name
3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
Clinical data
Trade names Dificid, Dificlir
Licence data US FDA:link
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability Minimal systemic absorption[1]
Biological half-life 11.7 ± 4.80 hours[1]
Excretion Urine (<1%), faeces (92%)[1]
Identifiers
CAS Number 873857-62-6 Yes
ATC code A07AA12
PubChem CID 11528171
ChemSpider 8209640 
UNII Z5N076G8YQ 
KEGG D09394 Yes
ChEBI CHEBI:68590 
ChEMBL CHEMBL1255800 
Synonyms Clostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT 80, PAR 01, PAR 101, tiacumicin B
Chemical data
Formula C52H74Cl2O18
Molar mass 1058.04 g/mol
US4918174 26 Sep 1986 17 Apr 1990 Abbott Laboratories Tiacumicin compounds
WO2009025439A1 * 6 May 2008 26 Feb 2009 Genotech Co Ltd Method of extraction and yield-up of tricyclo compounds by adding a solid adsorbent resin as their carrier in fermentation medium
WO2014023616A1 * 30 Jul 2013 13 Feb 2014 Olon Spa Procedure for the production of tiacumicin b
WO2014111254A1 14 Jan 2014 24 Jul 2014 Astellas Pharma Europe Ltd Composition of tiacumicin compounds
WO2015091851A1 18 Dec 2014 25 Jun 2015 Xellia Pharmaceuticals Aps Process for the preparation of tiacumicin
WO2015169451A1 11 May 2015 12 Nov 2015 Astellas Pharma Europe Ltd Treatment regimen tiacumicin compound
CN101128114B 31 Jan 2005 28 Mar 2012 浩鼎生技公司 18-membered macrocycles and analogs thereof
CN102614207B * 31 Jan 2005 13 Jan 2016 默克夏普&多梅有限公司 18元环大环化合物及其类似物
EP1848273A1 * 31 Jan 2005 31 Oct 2007 Optimer Pharmaceuticals, Inc. 18-membered macrocycles and analogs thereof
EP2070530A1 13 May 2005 17 Jun 2009 Optimer Pharmaceuticals, Inc. Treatment of diseases associated with the use of antibiotics
EP2125850A1 22 Jan 2008 2 Dec 2009 Optimer Pharmaceuticals, Inc. Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
EP2305244A1 13 May 2005 6 Apr 2011 Optimer Pharmaceuticals, Inc. Treatment of diseases associated with the use of antibiotics
EP2305245A1 13 May 2005 6 Apr 2011 Optimer Pharmaceuticals, Inc. Treatment of diseases associated with the use of antibiotics
EP2468761A1 22 Jan 2008 27 Jun 2012 Optimer Pharmaceuticals, Inc. Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US7378508 31 Jul 2007 27 May 2008 Optimer Pharmaceuticals, Inc. Polymorphic crystalline forms of tiacumicin B
US7863249 11 Apr 2008 4 Jan 2011 Optimer Pharmaceuticals, Inc. Macrolide polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US7906489 31 Jul 2007 15 Mar 2011 Optimer Pharmaceuticals, Inc. 18-membered macrocycles and analogs thereof
US8044030 28 Nov 2008 25 Oct 2011 Optimer Pharmaceuticals, Inc. Antibiotic macrocycle compounds and methods of manufacture and use thereof
US8586551 31 Aug 2009 19 Nov 2013 Optimer Pharmaceuticals, Inc. 18-membered macrocycles and analogs thereof
US8859510 22 Jan 2008 14 Oct 2014 Optimer Pharmaceuticals, Inc. Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US8883986 4 Mar 2009 11 Nov 2014 Optimer Pharmaceuticals, Inc. Macrolide polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US8916527 15 Mar 2013 23 Dec 2014 Optimer Pharmaceuticals, Inc. Antibiotic macrocycle compounds and methods of manufacture and use thereof
US20110166090 * 7 Jul 2011 Youe-Kong Shue 18-Membered Macrocycles and Analogs Thereof
US20140107054 * 21 Dec 2012 17 Apr 2014 Optimer Pharmaceuticals, Inc. Method of treating clostridium difficile-associated diarrhea
US3978211 * Oct 31, 1974 Aug 31, 1976 Gruppo Lepetit S.P.A. Lipiarmycin and its preparation
US4918174 Sep 26, 1986 Apr 17, 1990 Abbott Laboratories Tiacumicin compounds
US5583115 May 9, 1995 Dec 10, 1996 Abbott Laboratories Dialkyltiacumicin compounds
US5767096 Jul 12, 1996 Jun 16, 1998 Abbott Laboratories Bromotiacumicin compounds
US20060257981 * Jul 15, 2003 Nov 16, 2006 Optimer Pharmaceuticals, Inc. Tiacumicin production
US20070173462 * May 13, 2005 Jul 26, 2007 Optimer Pharmaceuticals, Inc. Treatment of diseases associated with the use of antibiotics
WO2004014295A2 Jul 15, 2003 Feb 19, 2004 Optimer Pharmaceuticals Inc Tiacumicin production
WO2005112990A2 May 13, 2005 Dec 1, 2005 Optimer Pharmaceuticals Inc Treatment of diseases associated with the use of antibiotics

 

WO2006085838A1 * Jan 31, 2005 Aug 17, 2006 Optimer Pharmaceuticals Inc 18-membered macrocycles and analogs thereof
DE2455230A1 * Nov 21, 1974 May 28, 1975 Lepetit Spa Lipiarmycin, verfahren zu seiner herstellung, mikroorganismus zur durchfuehrung des verfahrens und arzneimittel
EP2125850A1 Jan 22, 2008 Dec 2, 2009 Optimer Pharmaceuticals, Inc. Macrocyclic polymorphs, compositions comprising such polymorphs, and methods of use and manufacture thereof
US7378508 Jul 31, 2007 May 27, 2008 Optimer Pharmaceuticals, Inc. Polymorphic crystalline forms of tiacumicin B
Braga et al., “Making crystals from crystals: a green route tocrystal engineering and polymorphism” Chemical Communications (2005) pp. 3635-3645.
2 * Chemical Abstracts registry entry 56645-60-4, Tiacumicin B, Copyright 2007, American Chemical Society, p. 1-2.
3 * Dean, J., Analytical Chemistry Handbook, Published bt McGraw-Hill, Inc., pp. 10.23-10.26.
4 J.E. Hochlowski et al., Tiacumicins, A Novel Complex of 18-Membered Macrolides, J. Antibiotics, vol. XL, No. 5, pp. 575-588 (May 1987).
5 * Jain et al., “Polymorphism in Pharmacy” Indian Drugs (1986) vol. 23, No. 6, pp. 315-329.
6 * Pharmaceutical Dosage Forms: Tablets, vol. 2, Published by Marcel Dekker, Inc., ed. by Lieberman, Lachman, and Schwartz, pp. 462-472.
7 * Polymorphism in Pharmaceutical Solids, published 1999 by Marcel Dekker Inc, ed. by Harry G. Brittain, pp. 1-2.
8 Robert N. Swanson et al., In Vitro and In Vivo Evaluation of Tiacumicins B and C against Clostridium difficile, Antimicrob. Agents Chemother., Jun. 1991, pp. 1108-1111.
9 * The Condensed Chemical Dictionary, Tenth Edition, published 1981 by the Van Nostrand Reinhold Company, revised by Gessner G. Hawley, p. 35 and 835.

 

///////////Fidaxomicin, OPT-80, PAR-101, japan 2018

CC[C@H]1/C=C(/[C@H](C/C=C/C=C(/C(=O)O[C@@H](C/C=C(/C=C(/[C@@H]1O[C@H]2[C@H]([C@H]([C@@H](C(O2)(C)C)OC(=O)C(C)C)O)O)\C)\C)[C@@H](C)O)\CO[C@H]3[C@H]([C@H]([C@@H]([C@H](O3)C)OC(=O)C4=C(C(=C(C(=C4O)Cl)O)Cl)CC)O)OC)O)\C

Fidaxomicin

    • Synonyms:OPT-80; PAR-101; Tiacumicin B
    • ATC:A07AA12
  • Use:macrocyclic, antibotic, RNA polymerase inhibitor
  • Chemical name:3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
  • Formula:C52H74Cl2O8
  • MW:1058.0 g/mol
  • CAS-RN:873857-62-6

Substance Classes

Enzymes

Synthesis Path

Trade Names

Country Trade Name Vendor Annotation
USA Dificid Optimer Pharmceuticals, 2011

Formulations

  • tabl. 200 mg

References

    • WO 2004 014295 (Optimer Pharmaceuticals; 19.2.2004; USA-prior. 29.7.2002).
    • US 7 507 564 (Optimer Pharmaceuticals; 24.3.2009; USA-prior. 29.7.2002).
    • US 7 378 508 (Optimer Pharmaceuticals; 27.5.2008; USA-prior. 22.7.2007).
    • US 3 978 211 (Gruppo Lepetit; 31.10.1974; GB-prior. 22.11.1973).
    • US 4 918 174 (Abbott Laboratories; 17.10.1990; USA-prior. 26.9.1986).
    • EP 923 594 (Abbott Laboratories; 2.10.2002; USA-prior. 12.7.1996).
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