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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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CARMUSTINE


Skeletal formula of carmustinecarmustine.pngChemSpider 2D Image | Carmustine | C5H9Cl2N3O2

CARMUSTINE

Molecular Formula: C5H9Cl2N3O2
Molecular Weight: 214.046 g/mol

CAS 154-93-8

Brain tumor; Hodgkins disease; Multiple myeloma; Non-Hodgkin lymphoma

1,3-bis(2-chloroethyl)-3-nitrosourea

  • Urea, 1,3-bis(2-chloroethyl)-1-nitroso- (8CI)
  • N,N’-Bis(2-chloroethyl)-N-nitrosourea
  • 1,3-Bis(2-chlorethyl)-1-nitrosourea
  • 1,3-Bis(2-chloroethyl)-1-nitrosourea
  • 1,3-Bis(2-chloroethyl)nitrosourea
  • 1,3-Bis(β-chloroethyl)-1-nitrosourea
  • BCNU
  • Becenun
  • BiCNU
  • Carmubris
  • Carmustin
  • Carmustine
  • DTI 015
  • FDA 0345
  • Gliadel
  • Gliadel Wafer
  • NSC 409962
  • Nitrumon
  • SK 27702
  • SRI 1720

A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)
It has the appearance of an orange-yellow solid.Carmustine (bis-chloroethylnitrosoureaBCNUBiCNU) is a medication used mainly for chemotherapy and sometimes for immunosuppression before organ transplantation. It is a nitrogen mustard β-chloro-nitrosourea compound used as an alkylating agent. As a dialkylating agent, BCNU is able to form interstrand crosslinks in DNA, which prevents DNA replication and DNA transcription.

Carmustine for injection was earlier marketed under the name BiCNU by Bristol-Myers Squibb[2] and now by Emcure Pharmaceuticals.[3] In India it is sold under various brand names, including Consium.

It is disclosed that carmustine is useful for treating brain tumor, multiple myolema, Hodgkin’s disease and non-Hodgkin’s lymphomas. In September 2017, Newport Premium™ reports that MSN laboratories is potentially interested in carmustine and holds an active US DMF for the drug. Represents new area of patenting to be seen from MSN lab on Carmustine . Supratek was investigating SP-1009C , carmustine formulated in the company’s Biotransport carrier technology, for the potential treatment of glioblastoma. However, no further development has been reported since 2000 , and as of February 2004, SP-1009C was no longer listed on Supratek’s pipeline.

Uses

It is used in the treatment of several types of brain cancer (including gliomaglioblastoma multiformemedulloblastoma and astrocytoma), multiple myeloma and lymphoma (Hodgkin’s and non-Hodgkin). BCNU is sometimes used in conjunction with alkyl guanine transferase (AGT) inhibitors, such as O6-benzylguanine. The AGT-inhibitors increase the efficacy of BCNU by inhibiting the direct reversal pathway of DNA repair, which will prevent formation of the interstrand crosslinkbetween the N1 of guanine and the N3 of cytosine.

It is also used as part of a chemotherapeutic protocol in preparation for hematological stem cell transplantation, a type of bone marrow transplant, in order to reduce the white blood cell count in the recipient (patient). Use under this protocol, usually with Fludarabine and Melphalan, was coined by oncologists at the University of Texas MD Anderson Cancer Center.

Implants

In the treatment of brain tumours, the U.S. Food and Drug Administration (FDA) approved biodegradable discs infused with carmustine (Gliadel).[4] They are implanted under the skull during a surgery called a craniotomy. The disc allows for controlled release of carmustine in the extracellular fluid of the brain, thus eliminating the need for the encapsulated drug to cross the blood-brain barrier.[5]

Image result for synthesis of carmustine

Image result for synthesis of carmustine

Image result for synthesis of carmustine

Image result for synthesis of carmustine

Reference:

Synthesis, , # 11 p. 1027 – 1029

Celaries, Benoit; Parkanyi, Cyril Synthesis, 2006 , # 14 p. 2371 – 2375

PAPER

Pharmaceutical Chemistry Journal, 2001, vol. 35, vol 2, pg. 108 – 111

10.1023/A:1010485224267

PATENT

EP 3214075

EP 902015

CA1082223

US 523334

SYNTHESIS

PATENT

http://www.google.co.in/patents/US4028410

The Urea. This material is used in good grades, preferably CP, and the amount of urea utilized is the base on which the amounts of nitrosating agent are calculated. The starting material 1,3-bis(2-chloroethyl)urea is commercially available and also may be prepared readily from phosgene and ethyleneimine.

Dinitrogen trioxide (N2 O3). Efficacy of reaction has been observed where this nitrosation agent was utilized in preference to the prior use of aqueous NaNO2. It has also been found for stoichiometric reasons that an excess of the nitrosating agent ranging from 10-200% and preferably 10-20% based on urea is necessary to force the reaction to the right and obtain satisfactory completion. Furthermore, it is known from the literature art, Cotton, Advanced Inorganic Chemistry, Interscience, 1972, page 357, that this oxide exists in a pure state only at low temperatures and, therefore, reaction is conducted at nitrosation temperatures of about 0° C. to -20° C.

The Solvent. In contrast to prior art methods, the present reaction is conducted in an organic milieu. The preferred non-aqueous solvent is of the chlorinated variety; i.e., methylene dichloride. Other preferred compounds include related halogenated compounds such as ethylene dichloride, nitro-compounds such as nitromethane, acetonitrile, and simple ethers such as ethyl ether. Other less preferred but operable compounds include esters such as ethyl acetate, simple ketones such as acetone, and chloroform. Solvents to be avoided are olefins, unsaturated ethers and other unsaturated compounds, amines, malonate esters, acid anhydrides, and solvents which would interact with the reactant N2 O3 and the urea as well as the product nitrosourea. In general, the solvent should be low boiling (b.p. less than 120° C. and preferably less than 100° C.).

BCNU 1,3-bis(2-chloroethyl)-1-nitrosourea is one of a group of relatively recent drugs used against cancer and since 1972 has been charted by the National Cancer Institute for utilization against brain tumors, colon cancer, Hodgkins disease, lung cancer, and multiple myeloma. The modus of action of BCNU (NSC 409962) is as an alkylating agent. Such an alkylating agent is injurious to rapidly proliferating cells such as are present in many tumors and this action is known as antineoplastic activity.

EXAMPLE 1 1,3-Bis(2-chloroethyl)-1-nitrosourea

A suspension of 1.11 mmole (0.205 g) of 1,3-bis(2-chloroethyl)urea in 8 ml methylene dichloride at -10° C. was saturated with dinitrogen trioxide in 20% excess of theoretical. The heterogeneous mixture gradually changed to a green homogeneous solution. The methylene dichloride was evaporated, and the residue was extracted with 3× 10 ml hexane. Evaporation of the hexane gave 0.1773 g of oil which was the crude BCNU (NSC 409962). The hexane insoluble portion, 0.0649 g, when treated with benzene, gave 0.020 g of 1,3-bis(2-chloroethyl)urea which was benzene insoluble. The benzene solubles were processed through a silica column (1× 10 cm) and 0.0245 g of crude BCNU was obtained. The combined fractions of crude product amounted to 0.2018 g (85.1%).

In order to evaluate the product, the above crude was recrystallized from hexane to yield a first crop and from this first crop the ir spectrum was identical to that of known BCNU. A tlc (benzene on sillica) gave a single spot Rf 0.35 (blue, 254 mμ).

EXAMPLE 2 Comparative

A cold solution of 0.2346 g (3.4 mmole) sodium nitrite in 2 ml water was slowly added to a stirred solution of 0.2727 g (1.47 mmole) 1,3-bis(2-chloroethyl)urea in 2 ml 88% formic acid at 0°. After 2 hours at 0°, 0.1449 g (46.0%) of an oil solid phase was removed. The ir spectrum of this fraction failed to agree with that of BCNU. After 2 days a small amount of crystalline BCNU slowly formed in this oil phase. A methylene dichloride extract of the aqueous phase yielded 0.0943 g (30.0%) of an amber oil whose ir spectrum agreed with that of a known sample of BCNU. Treatment of this oil with 5 ml hexane and cooling to 0° gave crystalline BCNU which formed an oil on warming to ambient temperature.

EXAMPLE 3

A cold slurry at -15° C. of the 1,3-bis(2-chloroethyl)urea (2.0 mmole) in 8 ml methylene dichloride was treated with a small excess of N2 O3. The 1,3-bis(2-chloroethyl)urea is almost insoluble in the cold methylene dichloride, whereas the BCNU product is quite soluble. Thus, treatment of the urea with the N2 O3 changed the slurry to a homogeneous solution. Evaporation of the methylene dichloride gave a quantitative yield of crude BCNU. Purification by silica column chromatography gave 93.4% yield and recrystallization from benzene-heptane gave 85.2% yield of pure BCNU.

PAPER

Journal of Medicinal Chemistry (1963), 6(6), 669-81.

SPECTROSCOPY

Chloroform-d, Nitrogen-15 NMR Spectrum,  Lown, J. William; Journal of Organic Chemistry 1981, V46(26), P5309-21

1H NMR

Open Babel bond-line chemical structure with annotated hydrogens.<br>Click to toggle size.

<sup>1</sup>H NMR spectrum of C<sub>5</sub>H<sub>9</sub>Cl<sub>2</sub>N<sub>3</sub>O<sub>2</sub> in CDCL3 at 400 MHz.<br>Click to toggle size.

WO-2017154019

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=103D413664C194D84095110F1084E521.wapp2nA?docId=WO2017154019&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for preparing 1,3-bis(2-chloroethyl)-1- nitrosourea (also known as carmustine) and its intermediate 1,3-bis(2-chloroethyl)urea is claimed. Also claimed are composition comprising them and novel crystalline polymorphic form of carmustine.

,3-bis(2-chloroethyl)-l -nitrosourea is known as Carmustine and is approved in USA under the brand names of BICNU for the treatment of chemotherapy of certain neoplastic diseases such as brain tumor, multiple myolema, Hodgkin’s disease and non-Hodgkin’s lymphomas & Gliadel for the treatment of newly-diagnosed high-grade-malignant glioma as an adjunct to surgery and radiation, recurrent glioblastoma multiforme as an adjunct to surgery.

Journal of Medicinal Chemistry 1963, 6, 669-681 firstly disclosed process for the preparation of l,3-bis(2-chloroethyl)-l-nitrosourea.

US2288178 patent disclosed the process for the preparation of the compound of formula-2 from aziridine and phosgene. J. Med. Chem., 1979, 22 (10), pp 1193-1198 disclosed the process for the preparation of the compound of formula-2 using 2-chloroethanamine and 2-chloroisocyanoethane.

Prior disclosed processes for the preparation of the compound of formula-2 are used hazardous reagents which were difficult to handle in the laboratory. The present inventors have developed an improved process for the preparation of the compound of formula-2 by using easily available raw materials and usage of that compound in the preparation of the compound of formula- 1 to get good yield and having high purity.

he present invention is schematically represented in the scheme- 1.

Scheme-1

Examples:

Example-1: Preparation of l,3-bis(2-chloroethyl)urea compound of formula-2

2-chloroethanamine hydrochloride (429.19 gm) was added to the mixture of carbonyldiimidazole (200 gm) and tetrahydrofuran (1000 ml) at 25-30°C and stirred the reaction mixture for 5 minutes. Heated the reaction mixture to 65-70°C and stirred for 14 hours at the same temperature. Cooled the reaction mixture to 25-30°C and water was added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with isopropanol. Isopropanol (100 ml) was added to the obtained compound and stirred the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred the reaction mixture for 10 minutes at the same temperature.

Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 1 10 gm; M.P: 121-125°C.

Example-2: Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (50 gm) was added to the mixture of dilute hydrochloric acid (16 ml) and acetic acid (205 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Sodium nitrite (46.6 gm) was added to the reaction mixture in lot-wise over the period of 3 hours at 0-5 °C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched into pre-cooled water at 0-5°C and stirred it for 30 minutes at the same temperature. Filtered the precipitated solid and washed with water. Dissolved the obtained compound in dichloromethane (100 ml) at 0-5°C. The reaction mixture was added to pre-cooled n-heptane (250 ml) at 0-5°C and stirred for 1 ½ hour at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 28 gm.

Example-3: Preparation of l,3-bis(2-chloroethyl)urea compound of formuIa-2

Carbonyldiimidazole (8 kg) was slowly added to the pre-cooled mixture of 2-chloroethanamine hydrochloride (14.31 kg) and tetrahydrofuran (40 lit) at 0-5°C in lot-wise under nitrogen atmosphere and stirred the reaction mixture for 5 minutes. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 36 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water was added to the obtained compound at 25-30°C and stirred it for I hour at the same temperature. Filtered the precipitated solid and washed with water. The obtained compound was slurried in water at 25-30°C, filtered and washed with water. Methanol was added to the obtained compound at 25-30°C and stirred it for 1 hour at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 6 kg; PXRD of the obtained compound is shown in figure-3.

Example-4: Preparation of l,3-bis(2-ch!oroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (6 kg) was added to the mixture of dilute hydrochloric acid (1.9 lit) and acetic acid (24.5 lit) at 25-30°C. Cooled the reaction mixture to 0-5°C, sodium nitrite (5.59 kg) was slowly added to the reaction mixture in lot-wise at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched with pre-cooled water at 0-5°C. Cooled the reaction mixture to -15 to -10°C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid and washed with water. Dissolved the obtained compound in dichloromethane (24 lit) at 5-10°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Silicagel (3 kg) was added to the organic layer at 5-10°C and stirred for 25 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tertiary butyl ether. Pre-cooled Methyl tertiary butyl ether (12 lit) was added to the obtained compound and stirred it for at 0-5°C. This reaction mixture was added to pre-cooled n-heptane (60 lit) at -15 to -10°C and stirred the reaction mixture for 1 hour at the same temperature. Filtered the precipitated solid and washed with chilled n-heptane. Dried the compound at 0-10°C under reduced pressure.

Yield: 4.5 kg; MR: 30-32°C;

Purity by HPLC: 99.97%; Impurity at RRT -0.08: 0.01%, Impurity at RRT -0.13: Not detected; l,3-bis(2-chloroethyl)urea: 0.02%

PXRD of the obtained compound is shown in figure- 1 and IR shown in figure-2.

Example-5: Preparation of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1 l,3-bis(2-chloroethyl)urea (150 gm) was added to the mixture of dilute hydrochloric acid (48 ml) and acetic acid (612 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C, sodium nitrite (139.8 gm) was slowly added to the reaction mixture in lot-wise at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was quenched with pre-cooled water at 0-5°C. Cooled the reaction mixture to -15 to -10°C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid and washed with water.

Purity by HPLC: 95.1 1%, Impurity at RRT -0.08: 4.17%, Impurity at RRT -0.13: 0.63%.

Example 6: Purification of l,3-bis(2-chloroethyl)-l-nitrosourea compound of formula-1

Dissolved the compound of formula 1 obtained in example-5 in dichloromethane (600 ml) at 5-10°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Silicagel (75 gm) was added to the organic layer at 5-10°C and stirred for 25 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tertiary butyl ether. Pre-cooled Methyl tertiary butyl ether (300 ml) was added to the obtained compound and stirred it for 10-15 min at 0-5°C. This reaction mixture was added to pre-cooled n-heptane (1500 ml) at -15 to -10°C and stirred the reaction mixture for 1 hour at the same temperature. Filtered the precipitated solid and washed with chilled n-heptane. Dried the compound at 0-10°C under reduced pressure. Yield: HO gm; MR: 30-32°C;

Purity by HPLC: 99.96%, Impurity at RRT -0.08: 0.02%, Impurity at RRT -0.13: Not detected; l,3-bis(2-chloroethyl)urea: 0.02%

References

External links

  1.  Lown, J. William; Journal of Organic Chemistry 1981, V46(26), P5309-21 
  2.  Barcelo, Gerard; Synthesis 1987, (11), P1027-9 
  3.  Barcelo, Gerard; FR 2589860 A1 1987 
  4.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
  5.  Xu, Longji; International Journal of Pharmaceutics 2008, V355(1-2), P249-258 
  6.  Xu, Xiuling; Journal of Controlled Release 2006, V114(3), P307-316 
  7.  Lown, J. William; Journal of Organic Chemistry 1982, V47(5), P851-6 
  8. “PhysProp” data were obtained from Syracuse Research Corporation of Syracuse, New York (US)
US3465025 * 17 Nov 1966 2 Sep 1969 Allied Chem Process for the preparation of isocyanates
Reference
1 * Johnston et al., J. Med. Chem., vol, 18, No. 1, 1975, pp. 104-106.
2 * Montero et al., C. R. Acad. Sc. Paris, t. 279, Series C, 1974, pp. 809-811.
3 * Ryan et al., CA 17: 1792-1793 (1923).
Citing Patent Filing date Publication date Applicant Title
US4335247 * 23 Feb 1981 15 Jun 1982 Kowa Co., Ltd. Novel nitrosourea derivatives and process for their production
US4452814 * 12 Jan 1982 5 Jun 1984 Suami T Nitrosourea derivatives
US6096923 * 11 Sep 1998 1 Aug 2000 Johnson Matthey Public Limited Company Process for the preparation of nitrosourea compounds
US20040072889 * 16 Apr 2003 15 Apr 2004 Pharmacia Corporation Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
US20070196277 * 22 Jan 2007 23 Aug 2007 Levin Victor A Compositions and Methods for the Direct Therapy of Tumors
EP0902015A1 * 13 Aug 1998 17 Mar 1999 Johnson Matthey Public Limited Company Process for the preparation of nitrosourea compounds
Carmustine
Skeletal formula of carmustine
Ball-and-stick model of carmustine molecule
Names
IUPAC name

1,3-Bis(2-chloroethyl)-1-nitrosourea[1]
Other names

N,N’-Bis(2-chloroethyl)-N-nitrosourea
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
DrugBank
ECHA InfoCard 100.005.309
EC Number 205-838-2
KEGG
MeSH Carmustine
PubChem CID
RTECS number YS2625000
UNII
UN number 2811
Properties
C5H9Cl2N3O2
Molar mass 214.05 g·mol−1
Appearance Orange crystals
Odor Odourless
Melting point 30 °C (86 °F; 303 K)
log P 1.375
Acidity (pKa) 10.194
Basicity (pKb) 3.803
Pharmacology
L01AD01 (WHO)
Hazards
GHS pictograms The skull-and-crossbones pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) The health hazard pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
GHS signal word DANGER
H300H350H360
P301+310P308+313
Lethal dose or concentration (LDLC):
LD50 (median dose)
20 mg kg−1 (oral, rat)
Related compounds
Related ureas
Dimethylurea
Related compounds
Except where otherwise noted, data are given for materials in their standa

/////////////

ClCCNC(=O)N(CCCl)N=O

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Funapide, TV 45070, XEN-402, фунапид فونابيد 呋纳匹特


Image result for TV 450702D chemical structure of 1259933-16-8

ChemSpider 2D Image | Funapide | C22H14F3NO5Funapide.png

Funapide TV 45070,  XEN-402,  Funapide, (+)-

фунапид
فونابيد
呋纳匹特
  • Molecular FormulaC22H14F3NO5
  • Average mass429.345 Da

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one

Spiro(furo(2,3-F)-1,3-benzodioxole-7(6H),3′-(3H)indol)-2′(1’H)-one, 1′-((5-(trifluoromethyl)-2-furanyl)methyl)-, (3’S)-

(3’S)-1′-((5-(Trifluoromethyl)furan-2-yl)methyl)-2H,6H-spiro(furo(2,3-F)(1,3)benzodioxole-7,3′-indol)-2′(1’H)-one

Spiro[furo[2,3-f]-1,3-benzodioxole-7(6H),3′-[3H]indol]-2′(1’H)-one, 1′-[[5-(trifluoromethyl)-2-furanyl]methyl]-, (7S)-
TV-45070
UNII-A5595LHJ2L
XEN-401-S
XEN402
(3’S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2H-6H-spiro[furo[2,3-f]-1,3-benzodioxole-7,3′-indol]-2′(1’H)-one
(7S)-1′-{[5-(Trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1’H)-one
1259933-16-8 CAS
UNII-A5595LHJ2L

Phase II clinical trials for Postherpetic neuralgia (PHN)

Treatment of Neuropathic Pain

  • Originator Xenon Pharmaceuticals
  • Developer Teva Pharmaceutical Industries; Xenon Pharmaceuticals
  • Class Benzodioxoles; Fluorobenzenes; Furans; Indoles; Non-opioid analgesics; Small molecules; Spiro compounds
  • Mechanism of Action Nav1.7-voltage-gated-sodium-channel-inhibitors; Nav1.8 voltage-gated sodium channel inhibitors
  • Orphan Drug Status Yes – Erythromelalgia

Highest Development Phases

  • Phase II Erythromelalgia; Postherpetic neuralgia
  • No development reported Dental pain; Pain
  • Discontinued Musculoskeletal pain

Most Recent Events

  • 09 May 2017 Teva Pharmaceutical Industries completes a phase IIb trial for Postherpetic neuralgia in USA (Topical) (NCT02365636)
  • 26 Sep 2016 Adverse events data from a phase II trial in Musculoskeletal pain presented at the 16th World Congress on Pain (PAN – 2016)
  • 19 Aug 2015 No recent reports of development identified – Phase-I for Pain (In volunteers) in Canada (PO)

MP 100 – 102 DEG CENT EP2538919

S ROT  ALPHA 0.99 g/100ml, dimethyl sulfoxide, 14.04, US 20110087027

Funapide (INN) (former developmental code names TV-45070 and XEN402) is a novel analgesic under development by Xenon Pharmaceuticals in partnership with Teva Pharmaceutical Industries for the treatment of a variety of chronic pain conditions, including osteoarthritisneuropathic painpostherpetic neuralgia, and erythromelalgia, as well as dental pain.[1][2][3][4] It acts as a small-moleculeNav1.7 and Nav1.8 voltage-gated sodium channel blocker.[1][2][4] Funapide is being evaluated in humans in both oral and topicalformulations, and as of July 2014, has reached phase IIb clinical trials.[1][3]

Image result for TV 45070

Sodium channels play a diverse set of roles in maintaining normal and pathological states, including the long recognized role that voltage gated sodium channels play in the generation of abnormal neuronal activity and neuropathic or pathological pain. Damage to peripheral nerves following trauma or disease can result in changes to sodium channel activity and the development of abnormal afferent activity including ectopic discharges from axotomised afferents and spontaneous activity of sensitized intact nociceptors. These changes can produce long-lasting abnormal hypersensitivity to normally innocuous stimuli, or allodynia. Examples of neuropathic pain include, but are not limited to, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.

There have been some advances in treating neuropathic pain symptoms by using medications, such as gabapentin, and more recently pregabalin, as short-term, first-line treatments. However, pharmacotherapy for neuropathic pain has generally had limited success with little response to commonly used pain reducing drugs, such as NSAIDS and opiates. Consequently, there is still a considerable need to explore novel treatment modalities.

There remain a limited number of potent effective sodium channel blockers with a minimum of adverse events in the clinic. There is also an unmet medical need to treat neuropathic pain and other sodium channel associated pathological states effectively and without adverse side effects. PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708 discloses certain spiro-oxindole compounds. These compounds are disclosed therein as being useful for the treatment of sodium channel-mediated diseases, preferably diseases related to pain, central nervous conditions such as epilepsy, anxiety, depression and bipolar disease;

cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as restless leg syndrome; neuroprotection against stroke, neural trauma and multiple sclerosis; and channelopathies such as erythromelalgia and familial rectal pain syndrome.

Methods of preparing these compounds and pharmaceutical compositions containing them are also disclosed in PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT

Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708.

Postherpetic neuralgia (PHN) is a rare disorder that is defined as significant pain or abnormal sensation 120 days or more after the presence of the initial rash caused by shingles. This pain persists after the healing of the associated rash. Generally, this affliction occurs in older individuals and individuals suffering from immunosuppression. There are about one million cases of shingles in the US per year, of which 10–20% will result in PHN.
Topical analgesics such as lidocaine and capsaicin are traditionally used to treat this disorder. Both lidocaine and TV-45070 have a mechanism of action that involves the inhibition of voltage-gated sodium ion channels.
TV-45070 (formerly XEN-402) was in-licensed by Teva from Xenon Pharmaceuticals and is reported to be an antagonist of the Nav1.7 sodium ion channel protein.
It is currently in Phase II clinical trials for PHN. Interestingly, the loss of function of the Nav1.7 sodium ion channel was reported to result in the inability to experience pain as a hereditary trait in certain individuals.
Primary erythromelalgia is another rare disease where alterations in Nav1.7 or mutations in the corresponding encoding gene SCN9A have been reported to result in chronic burning pain that can last for hours or even days. Thus, compounds which regulate this protein have potential therapeutic value as analgesics for chronic pain.
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PATENT
US 20100331386
WO 2011106729
US 20110087027
US 20110086899
US 20130143941
US 20130210884
WO 2013154712
 US 20150216794
WO 2016127068
WO 2016109795
CN 106518886
US 20170239183
SYNTHESIS
WO 2013154712
 CONTD…….
Synthesis
CN 106518886
PATENT
US 20100331386
Preparation of the (S)-Enantiomer of the Invention
The (S)-enantiomer of the invention and the corresponding (R)-enantiomer are prepared by the resolution of the compound of formula (I), as set forth above in the Summary of the Invention, using either chiral high pressure liquid chromatography methods or by simulated moving bed chromatography methods, as described below in the following Reaction Scheme wherein “chiral HPLC” refers to chiral high pressure liquid chromatography and “SMB” refers to simulated moving bed chromatography:
Figure US20100331386A1-20101230-C00006
The compound of formula (I) can be prepared by the methods disclosed in PCT Published Patent Application No. WO 2006/110917, by methods disclosed herein, or by methods known to one skilled in the art.
One of ordinary skill in the art would recognize variations in the above Reaction Scheme which are appropriate for the resolution of the individual enantiomers.
Alternatively, the (S)-enantiomer of formula (I-S) and the (R)-enantiomer of formula (I-R), can be synthesized from starting materials which are known or readily prepared using process analogous to those which are known.
Preferably, the (S)-enantiomer of the invention obtained by the resolution methods disclosed herein is substantially free of the (R)-enantiomer or contains only traces of the (R)-enantiomer.
The following Synthetic Examples serve to illustrate the resolution methods disclosed by the above Reaction Schemes and are not intended to limit the scope of the invention.
Synthetic Example 1Synthesis of 1-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (Compound of formula (I))
Figure US20100331386A1-20101230-C00007
To a suspension of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.0 g, 3.6 mmol), which can be prepared according to the methods disclosed in PCT Published Patent Application No. WO 2006/110917, and cesium carbonate (3.52 g, 11 mmol) in acetone (50 mL) was added 2-bromomethyl-5-trifluoromethylfuran (1.13 g, 3.9 mmol) in one portion and the reaction mixture was stirred at 55-60° C. for 16 hours. Upon cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (1/9-1/1) to afford 1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1 ′H)-one, i.e., the compound of formula (I), (1.17 g, 76%) as a white solid: mp 139-141° C.;
1H NMR (300 MHz, CDCl3) δ 7.32-6.97 (m, 5H), 6.72 (d, J=3.3 Hz, 1H), 6.66 (s, 1H), 6.07 (s, 1H), 5.90-5.88 (m, 2H), 5.05, 4.86 (ABq, JAB=16.1 Hz, 2H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.9, 155.7, 153.5, 148.8, 142.2, 141.9, 140.8, 140.2, 139.7, 139.1, 132.1, 129.2, 124.7, 124.1, 123.7, 121.1, 120.1, 117.6, 114.5, 114.4, 110.3, 109.7, 103.0, 101.9, 93.8, 80.0, 57.8, 36.9;
MS (ES+) m/z 430.2 (M+1), 452.2 (M+23); Cal’d for C22H14F3NO5: C, 61.54%; H, 3.29%; N, 3.26%; Found: C, 61.51%; H, 3.29%; N, 3.26%.
Synthetic Example 2Resolution of Compound of Formula (I) by Chiral HPLC
The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by chiral HPLC under the following conditions:

Column: Chiralcel® OJ-RH; 20 mm I.D.×250 mm, 5 mic; Lot: OJRH CJ-EH001 (Daicel Chemical Industries, Ltd)

Eluent: Acetonitrile/Water (60/40, v/v, isocratic)

Flow rate: 10 mL/min

Run time: 60 min

Loading: 100 mg of compound of formula (I) in 1 mL of acetonitrileTemperature: Ambient

Under the above chiral HPLC conditions, the (R)-enantiomer of the compound of formula (I), i.e., (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one, was isolated as the first fraction as a white solid; ee (enantiomeric excess)>99% (analytical OJ-RH, 55% acetonitrile in water); mp 103-105° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.2 Hz, 2H), 5.13, 5.02 (ABq, JAB=16.4 Hz, 2H), 4.82, 4.72 (ABq, JAB=9.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]D−17.46° (c 0.99, DMSO).

The (S)-enantiomer of the compound of formula (I), i.e., (S)-1′-{[5-(trifluoromethypfuran-2-yl]methyl}spiro-[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was isolated as the second fraction as a white solid; ee >99% (analytical OJ-RH, 55% acetonitrile in water); mp 100-102° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.3 Hz, 2H), 5.12, 5.02 (ABq, JAB=16.4 Hz, 2H), 4.82, 4.72 (ABq, JAB=9.4 Hz, 2H); 13C NMR (75MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]D+14.04° (c 0.99, DMSO)

Synthetic Example 3Resolution of Compound of Formula (I) by SMB Chromatography

The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by SMB chromatography under the following conditions:

Extract: 147.05 mL/min, Raffinate: 76.13 mL/min Eluent: 183.18 mL/min Feed: 40 mL/min Recycling: 407.88 mL/min Run Time: 0.57 min Temperature: 25° C. Pressure: 46 bar

The feed solution (25 g of compound of formula (I) in 1.0 L of mobile phase (25:75:0.1 (v:v:v) mixture of acetonitrile/methanol/trifluoroacetic acid)) was injected continuously into the SMB system (Novasep Licosep Lab Unit), which was equipped with eight identical columns in 2-2-2-2 configuration containing 110 g (per column, 9.6 cm, 4.8 cm I.D.) of ChiralPAK-AD as stationary phase. The first eluting enantiomer (the (R)-enantiomer of the compound of formula (I)) was contained in the raffinate stream and the second eluting enantiomer (the (S)-enantiomer of the compound of formula (I)) was contained in the extract stream. The characterization data of the (S)-enantiomer and the (R)-enantiomer obtained from the SMB resolution were identical to those obtained above utilizing chiral HPLC.

The compound of formula (I) was resolved into its constituent enantiomers on a Waters preparative LCMS autopurification system. The first-eluting enantiomer from the chiral column was brominated (at a site well-removed from the stereogenic centre) to give the corresponding 5′-bromo derivative, which was subsequently crystallized to generate a single crystal suitable for X-ray crystallography. The crystal structure of this brominated derivative of the first-eluting enantiomer was obtained and its absolute configuration was found to be the same as the (R)-enantiomer of the invention. Hence, the second-eluting enantiomer from the chiral column is the (S)-enantiomer of the invention. Moreover, the material obtained from the extract stream of the SMB resolution had a specific optical rotation of the same sign (positive, i.e. dextrorotatory) as that of the material obtained from the aforementioned LC resolution.

Patent

WO 2013154712

EXAMPLE 8

Synthesis of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yllmethylJspirotfurop.S-flll .Sl enzoclioxole-y.S’-indoll-Zil ‘Wi-one

Compound of formula (ia1 )

Figure imgf000095_0001

To a cooled (0 °C) solution of (3S)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 7 (16.4 mmol) and 2- (diphenylphosphino)pyridine (5.2 g, 20 mmol) in anhydrous tetrahydrofuran (170 mL) was added di-ferf-butylazodicarboxylate (4.5 g, 20 mmol). The mixture was stirred for 2 h at 0 °C, then the reaction was diluted with ethyl acetate (170 mL), washed with 3 N hydrochloric acid (7 x 50 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (80 mL), decolorizing charcoal (15 g) was added and the mixture was heated at reflux for 1 h. The mixture was filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated in a mixture of diethyl ether/hexanes to afford (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3-/][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (1.30 g) as a colorless solid in 18% yield. The mother liquor from the trituration was concentrated in vacuo, trifluoroacetic acid (20 mL) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride (100 mL), 3 N hydrochloric acid (4 x 60 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of ethyl acetate in hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (2.6 g) as a colorless solid (37% yield, overall yield 55% over 2 steps): H NMR (300 MHz, CDCI3) £7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert- butyl ether).

EXAMPLE 9

Synthesis of 1-(diphenylmethyl)-1 H-indole-2,3-dione

Compound of formula (15a)

Figure imgf000096_0001

A. To a suspension of hexanes-washed sodium hydride (34.0 g, 849 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) at 0 °C was added a solution of isatin (99.8 g, 678 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) dropwise over 30 minutes. The reaction mixture was stirred for 1 h at 0 °C and a solution of benzhydryl bromide (185 g, 745 mmol) in anhydrous N-dimethylformamide (100 mL) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 h and heated at 60 °C for 2 h. The mixture was cooled to 0 °C and water (500 mL) was added. The mixture was poured into water (2 L), causing a precipitate to be deposited. The solid was collected by suction filtration and washed with water (2000 mL) to afford 1-(diphenylmethyl)-1H-indole-2,3- dione (164 g) as an orange solid in 77% yield.

B. Alternatively, to a mixture of isatin (40.0 g, 272 mmol), cesium carbonate (177 g, 543 mmol) and A/./V-dimethylformamide (270 mL) at 80 °C was added dropwise a solution of benzhydryl bromide (149 g, 544 mmol) in N,N- dimethyiformamide (200 mL) over 30 minutes. The reaction mixture was heated at 80 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was rinsed with ethyl acetate (1000 mL). The filtrate was washed with saturated aqueous ammonium chloride (4 x 200 mL), 1 N

hydrochloric acid (200 mL) and brine (4 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 1 -(diphenylmethyl)-1 H-indole-2,3-dione (59.1 g) as an orange solid in 69% yield. The mother liquor from the trituration was concentrated in vacuo and the residue triturated in diethyl ether to afford a further portion of 1-(diphenylmethyl)-1 H- indole-2,3-dione (8.2 g) in 10% yield: 1H NMR (300 MHz, CDCI3) £7.60 (d, J = 7.4 Hz, 1 H), 7.34-7.24 (m, 1 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

C. Alternatively, a mixture of isatin (500 g, 3.4 mol) and anhydrous N,N- dimethylformamide (3.5 L) was stirred at 15-35 °C for 0.5 h. Cesium carbonate (2.2 kg, 6.8 mol) was added and the mixture stirred at 55-60 °C for 1 h. A solution of benzhydryl bromide (1.26 kg, 5.1 mol) in anhydrous N, A/-dimethylformamide (1.5 L) was added and the resultant mixture stirred at 80-85 °C for 1 h, allowed to cool to ambient temperature and filtered. The filter cake was washed with ethyl acetate (12.5 L). To the combined filtrate and washes was added 1 N hydrochloric acid (5 L). The phases were separated and the aqueous phase was extracted with ethyl acetate (2.5 L). The combined organic extracts were washed with 1 N hydrochloric acid (2 * 2.5 L) and brine (3 χ 2.5 L) and concentrated in vacuo to a volume of approximately 750 mL. Methyl ferf-butyl ether (2 L) was added and the mixture was cooled to 5-15 °C, causing a solid to be deposited. The solid was collected by filtration, washed with methyl ferf- butyl ether (250 mL) and dried in vacuo at 50-55 °C for 16 h to afford 1- (diphenylmethyl)-1 H-indole-2,3-dione (715 g) as an orange solid in 67% yield: 1H NMR (300 MHz, CDCI3) 7.60 (d, J = 7.4 Hz, H), 7.34-7.24 (m, 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

EXAMPLE 10

Synthesis of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3- dihydro-2H-indol-2-one

Compound of formula (16a1 )

Figure imgf000097_0001

A. To a solution of sesamol (33.1 g, 239 mmol) in anhydrous

tetrahydrofuran (500 mL) at 0 °C was added dropwise a 2 M solution of

isopropylmagnesium chloride in tetrahydrofuran (104 mL, 208 mmol), followed by 1 – (diphenylmethyl)-1H-indole-2,3-dione (50.0 g, 160 mmol) and tetrahydrofuran (100 mL). The reaction mixture was stirred at ambient temperature for 5 h, diluted with ethyl acetate (1500 mL), washed with saturated aqueous ammonium chloride (400 mL) and brine (2 x 400 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford 1- (diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-in

2- one (70.7 g) as a colorless solid in 98% yield: 1H NMR (300 MHz, CDCI3) <59.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56- 6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

B. Alternatviely, a mixture of sesamol (0.99 kg, 7.2 mol) and anhydrous tetrahydrofuran (18 L) was stirred at 15-35 °C for 0.5 h and cooled to -5-0 °C.

Isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 3.1 L, 6.2 mol) was added, followed by 1-(diphenylmethyl)-1 H-indole-2,3-dione (1.50 kg, 4.8 mol) and further anhydrous tetrahydrofuran (3 L). The mixture was stirred at 15-25 °C for 5 h. Ethyl acetate (45 L) and saturated aqueous ammonium chloride (15 L) were added. The mixture was stirred at 15-25 °C for 0.5 h and was allowed to settle for 0.5 h. The phases were separated and the organic phase was washed with brine (2.3 L) and concentrated in vacuo to a volume of approximately 4 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 4 L. Heptane (6 L) was added and the mixture was stirred at 15-25 °C for 2 h, causing a solid to be deposited. The solid was collected by filtration, washed with methyl tert- butyl ether (0.3 L) and dried in vacuo at 50-55 °C for 7 h to afford 1-(diphenylmethyl)-3- hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.12 kg) as an off-white solid in 98% yield: 1H NMR (300 MHz, CDCI3) 9.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56-6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

EXAMPLE 1 1

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one

Compound of formula (17a1)

Figure imgf000098_0001

A. A mixture of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (30.0 g, 66.5 mmol), benzyl bromide (8.3 mL, 70 mmol), and potassium carbonate (18.4 g, 133 mmol) in anhydrous N,N- dimeihylformamide (100 mL) was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the solid was washed with /V,A/-dimethylformamide (100 mL). The filtrate was poured into water (1000 mL) and the resulting precipitate was collected by suction filtration and washed with water to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol- 5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g) as a beige solid in 83% yield: 1H NMR (300 MHz, CDCI3) 7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10- 6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1), 523.9 (M – 17).

B. Alternatively, to a solution of 1-(diphenylmethyl)-3-hydroxy-3-(6- hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.1 kg, 4.6 mol) in anhydrous A/,A/-dimethylformamide (8.4 L) at 20-30 °C was added potassium carbonate (1.3 kg, 9.2 mol), followed by benzyl bromide (0.58 L, 4.8 mol). The mixture was stirred at 20-30 °C for 80 h and filtered. The filter cake was washed with

A/,/V-dimethylformamide (0.4 L) and the filtrate was poured into water (75 L), causing a solid to be deposited. The mixture was stirred at 15-25 °C for 7 h. The solid was collected by filtration, washed with water (2 L) and dried in vacuo at 50-60 °C for 48 h to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one (2.1 1 kg) as an off-white solid in 84% yield; 1H NMR (300

MHz, CDCI3) £7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10-6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1 ).

EXAMPLE 12

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H- indol-2-one

Compound of formula (18a1 )

Figure imgf000099_0001

A. To a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g, 57.7 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (50 mL) followed by triethylsilane (50 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in ethyi acetate (250 mL), washed with saturated aqueous ammonium chloride (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5- yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (19.0 g) as a colorless solid in 61 % yield: 1H NMR (300 MHz, CDCI3) 7.31 -7.23 (m, 15H), 7.10-6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

B. Alternatively, to a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (2.0 kg, 3.7 mol) in

dichloromethane (7 L) at 20-30 °C was added trifluoracetic acid (2.5 L), followed by triethylsilane (3.1 L). The mixture was stirred at 15-35 °C for 4 h and concentrated in vacuo to dryness. To the residue was added ethyl acetate (16 L) and the mixture was stirred at 15-35 °C for 0.5 h, washed with saturated aqueous ammonium chloride (3 x 7 L) and brine (3 χ 7 L) and concentrated in vacuo to a volume of approximately 7 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 9 L and stirred at 10-20 °C for 2.5 h, during which time a solid was deposited. The solid was collected by filtration, washed with methyl te/t-butyl ether (0.4 L) and dried in vacuo at 50-55 °C for 7 h to afford 3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1 .26 kg) as an off-white solid in 65% yield: 1H NMR (300 MHz, CDCI3) £7.31 -7.23 (m, 15H), 7.10- 6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

EXAMPLE 13

Synthesis of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 –

(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one

Compound of formula (19a1 )

Figure imgf000100_0001

A. To a nitrogen-degassed mixture of 50% w/w aqueous potassium hydroxide (69.6 mL, 619 mmol), toluene (100 mL), and (9S)-1 -(anthracen-9- ylmethyl)cinchonan-1 -ium-9-ol chloride (0.50 g, 0.95 mmol) cooled in an ice/salt bath to an internal temperature of -18 °C was added a nitrogen-degassed solution of 3-[6- (benzyloxy)-l ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H-indol-2-one (10.0 g, 19.0 mmol) and benzyl chloromethyl ether (2.9 mL, 21 mmol) in

toluene/tetrahydrofuran (1 :1 v/v, 80 mL) dropwise over 1 h. The reaction mixture was stirred for 3.5 h and diluted with ethyl acetate (80 mL). The organic phase was washed with 1 N hydrochloric acid (3 x 150 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (3S)-3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (12.6 g) as a colorless solid in quantitative yield: 1H NMR (300 MHz, CDCI3) 7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83- 5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17-4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, a mixture of 50% w/v aqueous potassium hydroxide (4.2 kg), toluene (12 L) and (9S)-1 -(anthracen-9-ylmethyl)cinchonan-1 -ium-9-ol chloride (0.06 kg, 0.1 mol) was degassed with dry nitrogen and cooled to -18 to -22 °C. To this mixture was added a cold (-18 to -22 °C), nitrogen-degassed solution of 3-[6-

(benzyloxy)-l ,3-benzodioxol-5-yl]-1 ~(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.2 kg, 2.3 mol) and benzyl chloromethyl ether (0.43 kg, 2.8 mol) in toluene (10 L) and tetrahydrofuran (10 L) at -18 to 22 °C over 3 h. The mixture was stirred at -18 to -22 °C for 5 h, allowed to warm to ambient temperature and diluted with ethyl acetate (10 L). The phases were separated and the organic layer was washed with 1 N

hydrochloric acid (3 χ 8 L) and brine (2 χ 12 L) and concentrated in vacuo to dryness to afford (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1- (diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.5 kg) as a colorless solid in quantitative yield: 1H NMR (300 MHz, CDCI3) £7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83-5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17- 4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, ChiralPak IA). EXAMPLE 14

Synthesis of (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1 ,3-dihydro-2/-/-indol-2-one

Compound of formula (20a1)

Figure imgf000102_0001

A. A mixture of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3- [(benzyloxy)methyl]-1 -(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (8.8 g, 14 mmol), 10% w/w palladium on carbon (50% wetted powder, 3.5 g, 1.6 mmol), and acetic acid (3.9 ml_, 68 mmol) in a nitrogen-degassed mixture of ethanol/tetrahydrofuran (1 : 1 v/v, 140 mL) was stirred under hydrogen gas (1 atm) at ambient temperature for 4 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to afford (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3- dihydro-2H-indol-2-one as a colorless solid that was carried forward without further purification: H NMR (300 MHz, CDCI3) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15- 7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 93% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl ie t-butyl ether).

B. Alternatively, a glass-lined hydrogenation reactor was charged with (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 -(diphenylmethyl)- 1 ,3-dihydro-2H-indol-2-one (0.1 kg, 0.15 mol), tetrahydrofuran (0.8 L), ethanol (0.4 L), acetic acid (0.02 L) and 20% w/w palladium (li) hydroxide on carbon (0.04 kg). The reactor was purged three times with nitrogen. The reactor was then purged three times with hydrogen and was then pressurized to 50-55 lb/in2 with hydrogen. The mixture was stirred at 20-30 °C for 5 h under a 50-55 lb/in2 atmosphere of hydrogen. The reactor was purged and the mixture was filtered. The filtrate was concentrated in vacuo to a volume of approximately 0.2 L and methyl te/t-butyl ether (0.4 L) was added. The mixture was concentrated in vacuo to a volume of approximately 0.2 L and methyl ie/t-butyl ether (0.2 L) was added, followed by heptane (0.25 L). The mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.05 L) and dried in vacuo at a temperature below 50 °C for 8 h to afford (3S)-1 -(diphenylmethyl)-3-(6-hydroxy- 1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one (0.09 kg) as a colorless solid in 95% yield: 1H NMR (300 MHz, CDCI3) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15-7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 91% (HPLC, ChiralPak IA).

EXAMPLE 15

Synthesis of (7S)-1′-(diphenylmethyl)spiro[furo[2,3-/][1 ,3]benzodioxole-7,3′-indol]-

2′(1 ‘tf)-one

Compound of formula (21 a1 )

Figure imgf000103_0001

A. To a cooled (0 °C) solution of (3S)-1 -(diphenylmethyl)-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 14 (13.6 mmol) and 2-

(diphenylphosphino)pyridine (4.3 g, 16 mmol) in anhydrous tetrahydrofuran (140 mL) was added di-tert-butylazodicarboxylate (3.8 g, 17 mmol). The reaction mixture was stirred at 0 °C for 3 h, diluted with ethyl acetate (140 mL), washed with 3 N

hydrochloric acid (6 * 50 mL) and brine (2 χ 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (4.55 g) as a colorless solid in a 75% yield over 2 steps: 1H NMR (300 MHz, CDCI3) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99-6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1); ee

(enantiomeric excess) 93% (HPLC, Chiraipak IA, 2.5% acetonitrile in methyl te/f-butyl ether).

B. Alternativel, to a cooled (0-5 °C) solution of (3S)-1-(diphenylmethyl)-3- (6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2 -/-indol-2-one (1 .0 kg, 2.1 mol) and 2-(diphenylphosphino)pyridine (0.66 kg, 2.5 mol) in anhydrous tetrahydrofuran (20 L) was added over 2 h a solution of di-terf-butylazodicarboxylate (0.62 kg, 2.7 mmol) in anhydrous tetrahydrofuran (5 L). The mixture was stirred for 4 h at 0-5 °C and was allowed to warm to ambient temperature. The mixture was diluted with ethyl acetate (20 L), washed with 3 N hydrochloric acid (6 * 8 L) and brine (2 x 12 L) and concentrated in vacuo to a volume of approximately 1.5 L. Methyl rert-butyl ether (4 L) was added and the mixture concentrated in vacuo to a volume of

approximately 1.5 L. Methyl terf-butyl ether (2 L) and heptane (2 L) were added and the mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.5 L) and dried in vacuo below 50 °C for 8 h to afford (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (0.76 kg) as a colorless solid in 79% yield: 1H NMR (300 MHz, CDCI3) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99- 6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1 ); ee (enantiomeric excess) 92% (HPLC, ChiralPak IA).

EXAMPLE 16

Synthesis of (7S)-spiro[furo[2,3-f][1 ,3]benzodioxole-7,3′-indol]-2′(1 ‘H)-one

Compound of formula (22a1)

Figure imgf000104_0001

A. To a solution of (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (4.55 g, 10.2 mmol) in trifluoroacetic acid (80 ml_) was added triethylsilane (7 ml_). The reaction mixture was heated at reflux for 2.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford

(7S)-spiro[furo[2,3-/][1 ,3]benzodioxole-7,3,-indol]-2′(1’W)-one (2.30 g) as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCI3) £8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1 ); ee (enantiomeric excess) 99% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl fert-butyl ether). B. Alternatively, a mixture of (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- /Kl^benzodioxole^-indol^ r^-one (0.70 kg, 1.6 mol), trifluoroacetic acid (12 L) and triethylsilane (1.1 L) was heated at reflux under nitrogen atmosphere for 3 h, allowed to cool to ambient temperature and concentrated in vacuo to dryness. To the residue was added ethyl acetate (0.3 L), methyl fert-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration, taken up in dichloromethane (3 L), stirred at ambient temperature for 1 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was taken up in ethyl acetate (0.3 L), methyl ferf-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration and dried in vacuo below 50 °C for 8 h to afford (7S)-spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘ -/)-one (0.40 kg) as a colorless solid in 91 % yield: 1H NMR (300 MHz, CDCI3) 8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1); ee (enantiomeric excess) 98.6% (HPLC, ChiralPak IA).

EXAMPLE 17

Synthesis of of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yl]methyl}spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(rH)-one

Compound of formula (Ia1)

Figure imgf000105_0001

A. To a mixture of (7S)-6H-spiro[[1 ,3]dioxolo[4,5-f]benzofuran-7,3′-indolin]- 2′-one (1.80 g, 6.41 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)furan (1.47 g, 6.41 mmol) in acetone (200 mL) was added cesium carbonate (3.13 g, 9.61 mmol). The reaction mixture was heated at reflux for 2 h and filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford (7S)-1′-{[5- (trifluoromethyOfuran^-yllmethy^spiroIfurop.S- ltl .Slbenzodioxole^.S’-indol^ rH)- one (2.71 g) as a colorless solid in quantitative yield (97% purity by HPLC). The product was crystallized from a mixture of methanol and hexanes to afford (7S)-1 ‘-{[5- (trifluoromethy furan^-yllmethylJspirotfuro^.S- lfl .Slbenzodioxole^.S’-indoll^ rH)- one (1.46 g) as colorless needles in 53% yield. The mother liquor was concentrated in vacuo and subjected to a second crystallization in methanol and hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-/][1 ,3]benzodioxole- 7,3’-indol]-2′(1 ‘H)-one (0.469 g) as a colorless solid in 17% yield (total yield 70%): 1H NMR (300 MHz, CDCI3) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, to a solution of (7S)-spiro[furoI2,3-f][1 ,3]benzodioxole-7,3′- indol]-2′(1’H)-one (0.40 kg, 1.4 mol) in anhydrous N, W-dimethylformamide (5 L) was added cesium carbonate (1.2 kg, 3.4 mol), followed by 2-(bromomethyl)-5- (trifluromethyl)furan (0.24 L, 1.7 mol). The mixture was heated at 80-85 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was washed with ethyl acetate (8 L). The combined filtrate and washes were washed with water (4 L), saturated aqueous ammonium chloride (2 * 4 L) and brine (2 * 4 L) and concentrated in vacuo to dryness. The residue was purified by recrystallization from te/t-butyl methyl ether (0.4 L) and heptane (0.8 L), followed by drying of the resultant solid in vacuo at 40-50 °C for 8 h to afford (7S)-1 ‘-{[5- (trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)- one (0.37 kg) as a colorless solid in 61% yield: 1H NMR (300 MHz, CDCI3) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz,1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) > 99% (HPLC, Chiralpak IA).

PATENT
CadieuxJ.-J.ChafeevM.ChowdhuryS.FuJ.JiaQ.AbelS.El-SayedE.HuthmannE.IsarnoT. Synthetic Methods For Spiro-Oxindole Compounds. U.S. Patent 8,445,696, May 21, 2013.
PATENT
SunS.FuJ.ChowdhuryS.HemeonI. W.GrimwoodM. E.MansourT. S. Asymmetric Syntheses of Spiro-Oxindole Compounds Useful As Therapeutic Agents. U.S. Patent 9,487,535, Nov 08, 2016.
PAPER
Abstract Image

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Nav1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

The First Asymmetric Pilot-Scale Synthesis of TV-45070

Chemical Process Research and Development, Analytical Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00237
Publication Date (Web): September 8, 2017
Copyright © 2017 American Chemical Society

*E-mail: jasclafan@yahoo.com.

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one (1)

1H NMR (DMSO, 400 MHz) δ 7.32 (t, J = 7.7 Hz, 1H), 7.20 (m, 3H), 7.07 (t, J = 7.3 Hz, 1H), 6.77 (d, J= 3.3 Hz, 1H), 6.72 (s, 1H), 6.10 (s, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.13 (d, J = 16.5 Hz, 1H), 5.02 (d, J = 16.5 Hz, 1H), 4.82 (d, J = 9.5 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H).
13C NMR (100 MHz, DMSO-d6): 176.48, 155.28, 153.02, 148.40, 141.80, 141.51, 139.54 (q, JCF = 41.9 Hz), 131.63, 128.79, 123.64, 123.29, 119.69, 118.92 (q, JCF = 266.4 Hz), 114.01 (q, JCF = 2.9 Hz) 109.86, 109.21, 102.55, 101.44, 93.31, 79.52, 57.41, 36.44.

References

  1. Jump up to:a b c Bagal, Sharan K.; Chapman, Mark L.; Marron, Brian E.; Prime, Rebecca; Ian Storer, R.; Swain, Nigel A. (2014). “Recent progress in sodium channel modulators for pain”. Bioorganic & Medicinal Chemistry Letters24 (16): 3690–9. ISSN 0960-894XPMID 25060923doi:10.1016/j.bmcl.2014.06.038.
  2. Jump up to:a b Stephen McMahon; Martin Koltzenburg; Irene Tracey; Dennis C. Turk (1 March 2013). Wall & Melzack’s Textbook of Pain: Expert Consult – Online. Elsevier Health Sciences. p. 508. ISBN 0-7020-5374-0.
  3. Jump up to:a b Xenon Pharma. “TV-45070: A Small Molecule for the Treatment of the Orphan Disease EM and Other Pain Disorders”.
  4. Jump up to:a b Xenon Pharma (2012). “Teva and Xenon Announce Teva’s World Wide License of Xenon’s Pain Drug XEN402”.

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US8445696 SYNTHETIC METHODS FOR SPIRO-OXINDOLE COMPOUNDS 2011-04-14
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WO2011047174A1 14 Oct 2010 21 Apr 2011 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
WO2011106729A2 25 Feb 2011 1 Sep 2011 Xenon Pharmaceuticals Inc. Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents
Reference
1 * DEHMLOW E V ET AL: “Monodeazacinchona alkaloid derivatives: synthesis and preliminary applications as phase-transfer catalysts“, EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY – V C H VERLAG GMBH & CO. KGAA, DE, vol. 13, 1 January 2002 (2002-01-01), pages 2087 – 2093, XP002399953, ISSN: 1434-193X, DOI: 10.1002/1099-0690(200207)2002:13<2087::AID-EJOC2087>3.0.CO;2-Z
2 E.J. COREY; M.C. NOE, ORG. SYNTH., vol. 80, 2003, pages 38 – 45
3 GARST, J. F.; UNGVARY, F.: “Grignard Reagents”, 2000, JOHN WILEY & SONS, article “Mechanism of Grignard reagent formation“, pages: 185 – 275
4 GREENE, T.W.; P.G.M. WUTS: “Greene’s Protective Groups in Organic Synthesis, 4th Ed.,“, 2006, WILEY
5 GREENE, T.W.; WUTS, P.G.M.: “Greene’s Protective Groups in Organic Synthesis, 4th Ed.“, 2006, WILEY
6 HUGHES, D.L., ORG. PREP., vol. 28, 1996, pages 127 – 164
7 KUMARA SWAMY, K.C. ET AL.: “Mitsunobu and Related Reactions: Advances and Applications“, CHEM. REV., vol. 109, 2009, pages 2551 – 2651, XP055023394, DOI: doi:10.1021/cr800278z
8 MERSMANN, A.: “Crystallization Technology Handbook; 2nd ed.“, 2001, CRC
9 SMITH, M.; BAND J. MARCH: “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition“, December 2000, WILEY
10 SMITH, M.B.; J. MARCH: “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition“, December 2000, WILEY
11 * TAKASHI OOI ET AL: “Recent Advances in Asymmetric Phase-Transfer Catalysis“, ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 46, no. 23, 4 June 2007 (2007-06-04), pages 4222 – 4266, XP055060024, ISSN: 1433-7851, DOI: 10.1002/anie.200601737
Citing Patent Filing date Publication date Applicant Title
WO2016109795A1 31 Dec 2015 7 Jul 2016 Concert Pharmaceuticals, Inc. Deuterated funapide and difluorofunapide
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US9504671 25 Feb 2011 29 Nov 2016 Xenon Pharmaceuticals Inc. Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents
US9682033 5 Feb 2016 20 Jun 2017 Teva Pharmaceuticals International Gmbh Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound
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Funapide
Funapide.svg
Clinical data
Routes of
administration
By mouthtopical
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C22H14F3NO5
Molar mass 429.34547 g/mol
3D model (JSmol)
//////////TV 45070,  XEN 402, TEVA, XENON, Postherpetic neuralgia, PHN, PHASE 2, Funapide, фунапид , فونابيد , 呋纳匹特 , Orphan Drug Status
C1C2(C3=CC=CC=C3N(C2=O)CC4=CC=C(O4)C(F)(F)F)C5=CC6=C(C=C5O1)OCO6

2,5-Bis(ethoxymethyl)furan


ORGANIC CHEMISTRY SELECT

2,5-Bis(ethoxymethyl)furan, 6

1H NMR (CDCl3) = 6.20 (s, 2H), 4.36 (s, 4H), 3.47 (q, 4H, J = 7.1 Hz), 1.16 (t, 6H, J = 7.1 Hz);

13C NMR (CDCl3) = 150.9, 109.7, 65.7, 64.7, 15.1 ppm

PREDICTS

Green Chem., 2017, Advance Article

DOI: 10.1039/C7GC02211E, Paper

F. A. Kucherov, K. I. Galkin, E. G. Gordeev, V. P. Ananikov

Efficient one-pot synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described using a [4 + 2] cycloaddition reaction.

Efficient route for the construction of polycyclic systems from bioderived HMF

 Author affiliations

//////

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Riamilovir, Triazavirin


Image result for riamilovirChemSpider 2D Image | Triazavirin | C5H4N6O3S[1,2,4]Triazolo[5,1-c][1,2,4]triazin-4(1H)-one, 7-(methylthio)-3-nitro-.png

Riamilovir, Triazavirin

Riamilovir sodium dihydrate, CAS 928659-17-0,
Riamilovir CAS: 123606-06-4
Chemical Formula: C5H4N6O3S
Molecular Weight: 228.19

[1,2,4]Triazolo[5,1-c][1,2,4]triazin-4(1H)-one, 7-(methylthio)-3-nitro- (9CI)

7-(Methylthio)-3-nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin-4(6H)-one

1,2,4]Triazolo[5,1-c][1,2,4]triazin-4(6H)-one, 7-(methylthio)-3-nitro-

7-(methylsulfanyl)-3-nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin- 4(1H)-one

7-thio-substituted-3-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4(1H)-one

Riamilovir sodium CAS 116061-59-7

Riamilovir sodium dihydrate, CAS 928659-17-0, Triazavirin

Flavivirus infection; Zika virus infection

Image result for Zika virus

Zika virus

Image result for Flavivirus

Flavivirus

Anti-viral drug

http://apps.who.int/medicinedocs/documents/s23256en/s23256en.pdf

Image result for Ural Federal University

Triazavirin (TZV) is a broad-spectrum antiviral drug developed in Russia through a joint effort of Ural Federal UniversityRussian Academy of Sciences, Ural Center for Biopharma Technologies and Medsintez Pharmaceutical.

Image result for Medsintez Pharmaceutical

It has an azoloazine base structure, which represents a new structural class of non-nucleoside antiviral drugs.[1]

It was originally developed as a potential treatment for pandemic influenza strains such as H5N1, and most of the testing that has been done has focused on its anti-influenza activity.[2][3][4]

However triazavirin has also been found to have antiviral activity against a number of other viruses including tick-borne encephalitis,[5]and is also being investigated for potential application against Lassa fever and Ebola virus disease.[6][7][8][9][10]

Image result for Ebola virus

Ebola virus

Yunona Holdings, was investigating riamilovir sodium dihydrate (triazavirin), a novel nucleoside inhibitor of human influenza virus A and B replication, for the potential oral treatment of influenza virus infection.

In November 2009, the company was seeking to outlicense the drug for development in the EU, presumed to be for use as a prescription medicine .

The Ural Branch of the Russian Academy of Sciences had previously developed, and Yunona Holdings registered and launched, triazavirinin in Russia as an OTC product .

Negative-sense, single-stranded RNA viruses (ssRNA), such as ssRNA viruses belonging to the Order Mononegavirales such as viruses in the Rhabdoviridae family, in particular the Rabies virus, the Filoviridae family, in particular the Ebolavirus, and the Paramyxoviridae family, in particular the Measles virus, other ssRNA viruses belonging to unassigned families such as notably the

Arenaviridae family, the Bunyaviridae family and the Orthomyxoviridae family and other unassigned ssRNA viruses such as notably the Deltavirus, cause many diseases in wildlife, domestic animals and humans. These ssRNA viruses belonging to different families are genetically and antigenically diverse, exhibiting broad tissue tropisms and a wide pathogenic potential.

For example, the Filoviridae viruses belonging to the Order

Mononegavirales, in particular the Ebolaviruses and Marburgviruses, are among the most lethal and most destructive viruses in the world. Filoviridae viruses are of particular concern as possible biological weapons since they have the potential for aerosol dissemination and weaponization.

The Ebolavirus includes five species: the Zaire, Sudan, Reston, Tai Forest and Bundibugyo Ebolaviruses. In particular the Zaire, Sudan and Bundibugyo Ebolavirus cause severe, often fatal, viral hemorraghic fevers in humans and nonhuman primates.

For more than 30 years, the Ebolavirus has been associated with periodic episodes of hemorrhagic fever in Central Africa that produce severe disease in

infected patients. Mortality rates in outbreaks have ranged from 50% for the Sudan species of the Ebolavirus to up to 90% for the Zaire species of the Ebolavirus ((Sanchez et al., Filoviridae: Marburg and Ebola Viruses, in Fields Virology, pages 1409-1448 (Lippincott Williams & Wilkins, Philadelphia)). In November 2007, during an outbreak in the Bundibugyo district of Uganda, near the border with the Democratic Republic of the Congo the fifth species of the Ebolavirus was discovered, the Bundibugyo species. Said outbreak resulted in a fatality rate of about 25% (Towner et al., PLoS Pathog., 4(11 ) :e1000212 (2008)). The Zaire species of the Ebolavirus has also decimated populations of wild apes in this same region of Africa (Walsh et al., Nature, 422:611-614 (2003)).

When infected with the Ebolavirus, the onset of illness is abrupt and is characterized by high fever, headaches, joint and muscle aches, sore throat, fatigue, diarrhea, vomiting, and stomach pain. A rash, red eyes, hiccups and internal and external bleeding may be seen in some patients. Within one week of becoming infected with the virus, most patients experience chest pains and multiple organ failure, go into shock, and die. Some patients also experience blindness and extensive bleeding before dying.

Another example of a negative sense single-stranded RNA envelope virus is the Morbilllivirus such as the Measles virus which is associated with Measles and the Lyssavirus such as the Rabies virus.

The Lyssavirus, belonging to the family Rhabdoviridae, includes eleven recognized species, in particular the Rabies virus which is known to cause Rabies. Rabies is an ancient disease with the earliest reports possibly dated to the Old World before 2300 B.C and remains a world health threat due to remaining lack of effective control measures in animal reservoir populations and a widespread lack of human access to vaccination. The Rabies virus is distributed worldwide among mammalian reservoirs including carnivores and bats. Each year there are many reported cases of transmission of the Rabies virus from animals to humans (e.g. by an animal bite). More than 50,000 people annually die of Rabies, particularly in Asia and Africa.

Thus, there remains a need for antiviral compounds which are effective for use in the treatment of the ssRNA virus infections different from the Influenza A and Influenza B virus infections

SYNTHESIS CONTRUCTED WITH 3 ARTICLES AS BELOW

RU 2340614 C2 20081210,

e-EROS Encyclopedia of Reagents for Organic Synthesis, 1-7; 2009,

European Journal of Medicinal Chemistry, 113, 11-27; 2016

Khimiya Geterotsiklicheskikh Soedinenii (1989), (2), 253-7.

Khimiya Geterotsiklicheskikh Soedinenii (1992), (11), 1555-9.

Zhurnal Organicheskoi Khimii (1996), 32(5), 770-776

PAPER

Russian Journal of Organic Chemistry (Translation of Zhurnal Organicheskoi Khimii) (2002), 38(2), 272-280.

https://link.springer.com/article/10.1023%2FA%3A1015538322029

Russian Journal of Organic Chemistry

Volume 38, Issue 2pp 272–280

Adamantylation of 3-Nitro- and 3-Ethoxycarbonyl-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4-ones

Abstract

Reaction of 3-nitro- and 3-ethoxycarbonyl-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4-ones with 1-adamantanol (or 1-adamantyl nitrate) in concentrated sulfuric acid or with 1-bromoadamantane in sulfolane affords N-adamantyl derivatives. The adamantylation of 3-nitro-1,4-dihydro-7H-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4-one yields a mixture of N8– and N1-isomers that undergo interconversion in concentrated sulfuric acid along intermolecular mechanism.

PATENT

RU 2340614 C2 20081210,

PAPER

Russian Chemical Bulletin (2010), 59(1), 136-143.

Synthesis and antiviral activity of nucleoside analogs based on 1,2,4-triazolo[3,2-c][1,2,4]triazin-7-ones

Abstract

Nucleoside analogs containing hydroxybutyl, hydroxyethoxymethyl, allyloxymethyl, and propargyloxymethyl fragments were synthesized based on 1,2,4-triazolo[3,2-c][1,2,4]triazin-7-ones isosteric to purine bases. Some of the compounds obtained inhibit in vitro reproduction of influenza and respiratory syncytial virus infection.

PATENT

WO 2015117016

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015117016&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PAPER

Chemistry of Heterocyclic Compounds (New York, NY, United States) (2015), 51(3), 275-280.

https://link.springer.com/article/10.1007%2Fs10593-015-1695-4

The nucleophilic susbstitution of nitro group in [1,2,4]triazolo[5,1-c][1,2,4]triazinones upon treatment with cysteine and glutathione was studied as a model for the interaction with thiol groups of virus proteins, which mimics the metabolic transformations of antiviral drug Triazavirin® and its derivatives.

Chemistry of Heterocyclic Compounds

Volume 51, Issue 3pp 275–280

Nucleophilic substitution of nitro group in nitrotriazolotriazines as a model of potential interaction with cysteine-containing proteins

  1. 1.Ural Federal University named after the First President of Russia Boris YeltsinYekaterinburgRussia
  2. 2.Institute of Organic SynthesisUral Branch of the Russian Academy of SciencesYekaterinburgRussia
  3. 3.Research Institute of InfluenzaMinistry of Healthcare of the Russian FederationSaint-PetersburgRussia

PATENT

WO 2017144709

Example 1 : One pot synthesis of the sodium salt of 7-methylthio-3-nitro [1 ,

2, 4] triazolo [5,1 -c] [1, 2, 4] triazin -4 (1H)-one

Step 1 : Diazotization of compound (B): A solution (solution [1], herein after) was prepared of 5.8 g (0.05 ) of 5-amino-3-mercapto-1 ,2,4-triazole in 6.7 ml of nitric acid (15 M) and 12 ml of water. Said solution [1] was refrigerated to -7°C . Then a 40% sodium nitrite solution was added to the solution [1] in portions of 0.5 mL to obtain a total amount of sodium nitrite equal to 3.8 g in the mixture.

Step 2: Condensation of diazonium compound with an a-nitroester:

To the resulting diazonium salt of step 1 , 8.54 ml of diethyl nitromaionate was added. After holding for five minutes, a cooled solution of sodium hydroxide was slowly added dropwise to the reaction mixture until the pH was between pH 9 and pH 10 (solution [2], herein after). The resulting solution [2] was stirred at 0°C for 1 hour and at room temperature for 2 hours.

Step 3: alkylation: To the solution [2] of step 2, 6.23 ml (0.1 moi) of methyl iodide was added. The mixture was stirred for 1 hour at room temperature and filtered. The resulting precipitate was successively crystallized from water and dried in air. The reaction scheme is depicted below in Scheme 1.

SCHEME 1

The yield was 9.87 g (69%).

Physical and chemical characteristics of the sodium salt of 7-methylthio-3-nitro

[1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt: yellow crystalline powder, soluble in water, acetone, dimethylsulfoxide, dimethylformamide. insoluble in chloroform; Tmelt = 300°C, H NMR spectrum, δ, ppm, solvent DMSO-d6: 2.62 (3H, s, SCH3); IR spectrum, n, cm“1: 3535 (OH), 1649 (C=0), 1505 (N02), 1367 (N02); found.. %: C – 20.86, H 2.51 , N 29.28;

C5H;N6Na05S; Calculated, %: C – 20.98, H 2.47, N 29.36.

Example 2: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt

In this example the synthesis comprises 3 steps: in the first step 5-amino-3-mercapto-1.2,4-triazole (i.e. compound (B)) was prepared by condensation of aminoguanidine with a thio-derivative (thio ester) of formic acid, HC(=0)S-R, wherein -R was: methyl. In the second step 5-amino-3-mercapto-1 , 2,4-triazole was converted to the corresponding diazonium salt. In the third step this diazonium salt was reacted with an a-nitroester, 2-nitroacetoacetic ester, to form the 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one. The different steps are explained in more detail below.

Step 1 : Synthesis of compound (B): In a reaction flask equipped with a stirrer, reflux condenser, under inert gas (nitrogen, argon), 20 g (0.1 mol) of aminoguanidine and 7.6 g (0.1 mol) methylthio-formate was added to 400 ml of absolute pyridine. The reaction mixture was boiled for 4 hours at 115°C.

Subsequently the reaction mixture was transferred into distilled water and washed several times with water. The washed mixture was dried over a Nutsche filter under vacuum. Recrystallization was carried out from ethanol. The reaction scheme is depicted below in Scheme 2.

SCHEME 2

The yield was 19.3 g (70%)

Step 2: Diazotation of compound (B): A solution (solution [3], herein after) was prepared of 26 g (0.1 mol) of 5-amino-3-mercapto-1 ,2,4-triazole (as obtained in step 1) in 32 ml of nitric acid (0.1 mol) and 200 ml of water. The solution was mixed and cooled to -5°C. In a separate recipient, a 0.1 M solution of sodium nitrite was prepared by dissolving 16 g of sodium nitrite in 100 ml of water. The sodium nitrite solution was put in the freezer until there was ice formation and subsequently the ice was crushed. Thereafter, the solution [3] and the sodium nitrite crushed ice were transferred into a 1 L reactor and stirred for 1 hour while the reactor temperature was kept at 0°C. The low temperature and the fact that the two reaction components are in different phases (i.e. liquid and solid) ensured a slow gradual progress of diazotization reaction at the phase interface. The end of the diazotization process was controlled by a iodine starch test (proof of the absence of sodium nitrite in a free state).

The rea

SCHEME 3

Step 3: Condensation of the diazonium compound with an α-nitroester: A solution (solution [4], herein after) was prepared by mixing 17.5 g of methyl 2- nitro-acetoacetate in 300 mL of isopropanoi. The solution [4] was mixed with the diazonium salt of step 2. The mixture was cooled to 0°C. At 0°C, a 10% sodium hydroxide solution was added to the reaction mixture (to neutralize residual nitrite and acetate) until there was a marked alkaline reaction (pH between 8 and 9). The temperature was controlled and was kept below +5°C. The resulting mixture was stirred for 1 hour. The precipitate was filtered off and dried in air. The yield was 78%.

The reaction scheme is depicted in Scheme 4

SCHEME 4

Example 3: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one

The synthesis of the sodium salt of 7-methylthio-3-nitro-1 ,2,4-triazolo [5,1-c]-1 ,2,4-triazin-7-one may be carried out as in Example 2, only in step 2 the aqueous alcohol solution is replaced by an alcohol with alkali (such as sodium hydroxide). The yield of the antiviral compound (A) (sodium salt of 7-methylthio-3-nitro [1 2, 4] triazolo [5,1-c] [1 , 2. 4] triazin -4 (1 H)-one) may increase to 83%. The reaction scheme is depicted below in Scheme 5:

SCHEME 5

PATENT

WO2017144708

Process for the preparation of 7-thio-substituted-3-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4(1H)-one i.e. riamilovir sodium dihydrate is claimed. Also claimed are use of triazolo compounds for the treatment of ssRNA virus infections such as Zika virus and flavivirus, ssRNA viruses different from the Influenza A and Influenza B viruses and compositions comprising them. Along with concurrently published WO2017144709 claiming similar derivatives. Represents new area of interest from Doring International Gmbh and the inventors on this moiety.

Example 1 : One pot synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1 -cj [1, 2, 4] triazin -4 (1H)-one

Step 1: Diazotization of compound (B): A solution (solution [1], herein after) was prepared of 5.8 g (0.05 M) of 5-amino-3-mercapto-1 ,2,4-triazole in 6.7 ml of nitric acid (15 M) and 12 ml of water. Said solution [1] was refrigerated to -7°C . Then a 40% sodium nitrite solution was added to the solution [1] in portions of 0.5 mL to obtain a total amount of sodium nitrite equal to 3.8 g in the mixture.

Step 2: Condensation of diazonium compound with an a-nitroester: To the resulting diazonium salt of step 1 , 8.54 ml of diethyl nitromalonate was added. After holding for five minutes, a cooled solution of sodium hydroxide was slowly added dropwise to the reaction mixture until the pH was between pH 9 and pH 10 (solution [2], herein after). The resulting solution [2] was stirred at 0°C for 1 hour and at room temperature for 2 hours.

Step 3: alkylation: To the solution [2] of step 2, 6.23 ml (0.1 mol) of methyl iodide was added. The mixture was stirred for 1 hour at room temperature and

filtered. The resulting precipitate was successively crystallized from water and dried in air. The reaction scheme is depicted below in Scheme 1.

SCHEME 1

The yield was 9.87 g (69%).

Physical and chemical characteristics of the sodium salt of 7-methylthio-3-nitro

[1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt: yellow crystalline powder, soluble in water, acetone, dimethylsulfoxide, dimethylformamide, insoluble in chloroform; Tmei, = 300°C, 1H NMR spectrum, δ, ppm, solvent DMSO-d6: 2.62 (3H, s, SCH3); IR spectrum, n, cm“1: 3535 (OH), 1649 (CO), 1505 (N02), 1367 (N02); found, %: C – 20.86, H 2.51 , N 29.28; C5H7N6Na05S; Calculated, %: C – 20.98, H 2.47, N 29.36.

Example 2: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2,

4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one sodium salt

In this example the synthesis comprises 3 steps: in the first step 5-amino-3-mercapto-1 ,2,4-triazole (i.e. compound (B)) was prepared by condensation of aminoguanidine with a thio-derivative (thio ester) of formic acid, HC(=0)S-R, wherein -R was: methyl. In the second step 5-amino-3-mercapto-1 ,2,4-triazole was converted to the corresponding diazonium salt. In the third step this diazonium salt was reacted with an a-nitroester, 2-nitroacetoacetic ester, to form the 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one. The different steps are explained in more detail below.

Step 1 : Synthesis of compound (B): In a reaction flask equipped with a stirrer, reflux condenser, under inert gas (nitrogen, argon), 20 g (0.1 mo!) of

aminoguanidine and 7.6 g (0.1 mol) methylthio-formate was added to 400 ml of absolute pyridine. The reaction mixture was boiled for 4 hours at 115°C. Subsequently the reaction mixture was transferred into distilled water and washed several times with water. The washed mixture was dried over a Nutsche filter under vacuum. Recrystallization was carried out from ethanol. The reaction scheme is depicted below in Scheme 2.

SCHEME 2

The yield was 19.3 g (70%)

Step 2: Diazotation of compound (B): A solution (solution [3], herein after) was prepared of 26 g (0.1 mol) of 5-amino-3-mercapto-1 ,2,4-triazole (as obtained in step 1 ) in 32 ml of nitric acid (0.1 mol) and 200 ml of water. The solution was mixed and cooled to -5°C. In a separate recipient, a 0.1 M solution of sodium nitrite was prepared by dissolving 16 g of sodium nitrite in 100 ml of water. The sodium nitrite solution was put in the freezer until there was ice formation and subsequently the ice was crushed. Thereafter, the solution [3] and the sodium nitrite crushed ice were transferred into a 1 L reactor and stirred for 1 hour while the reactor temperature was kept at 0°C. The low temperature and the fact that the two reaction components are in different phases (i.e. liquid and solid) ensured a slow gradual progress of diazotization reaction at the phase interface. The end of the diazotization process was controlled by a iodine starch test (proof of the absence of sodium nitrite in a free state).

The rea

SCHEME 3

Step 3: Condensation of the diazonium compound with an a-nitroester: A solution (solution [4], herein after) was prepared by mixing 17.5 g of methyl 2-nitro-acetoacetate in 300 mL of isopropanol. The solution [4] was mixed with the diazonium salt of step 2. The mixture was cooled to 0°C. At 0°C, a 10% sodium hydroxide solution was added to the reaction mixture (to neutralize residual nitrite and acetate) until there was a marked alkaline reaction (pH between 8 and 9). The temperature was controlled and was kept below +5°C. The resulting mixture was stirred for 1 hour. The precipitate was filtered off and dried in air. The yield was 78%.

The reaction scheme is depicted in Scheme 4

SCHEME 4

Example 3: Synthesis of the sodium salt of 7-methylthio-3-nitro [1, 2, 4] triazolo [5,1-c] [1, 2, 4] triazin -4 (1H)-one

The synthesis of the sodium salt of 7-methy I th io-3-nitro- 1 ,2, 4-triazolo [5,1-c]-1 ,2,4-triazin-7-one may be carried out as in Example 2, only in step 2 the aqueous alcohol solution is replaced by an alcohol with alkali (such as sodium hydroxide). The yield of the antiviral compound (A) (sodium salt of 7-methylthio-3-nitro [1 2, 4] triazolo [5,1-c] [1 , 2, 4] triazin -4 (1 H)-one) may increase to 83%.

The reaction scheme is depicted below in Scheme 5:

SCHEME 5

References

  1. Jump up^ Rusinov VL, Sapozhnikova IM, Ulomskii EN, Medvedeva NR, Egorov VV, Kiselev OI, Deeva EG, Vasin AV, Chupakhin ON. Nucleophilic substitution of nitro group in nitrotriazolotriazines as a model of potential interaction with cysteine-containing proteins. Chemistry of Heterocyclic Compounds 2015;51(3):275-280. doi 10.1007/s10593-015-1695-4
  2. Jump up^ Loginova SIa, Borisevich SV, Maksimov VA, Bondarev VP, Kotovskaia SK, Rusinov VL, Charushin VN. Investigation of triazavirin antiviral activity against influenza A virus (H5N1) in cell culture. (Russian) Antibiotiki i Khimioterapiia. 2007;52(11-12):18-20. PMID 19275052
  3. Jump up^ Karpenko I, Deev S, Kiselev O, Charushin V, Rusinov V, Ulomsky E, Deeva E, Yanvarev D, Ivanov A, Smirnova O, Kochetkov S, Chupakhin O, Kukhanova M. Antiviral properties, metabolism, and pharmacokinetics of a novel azolo-1,2,4-triazine-derived inhibitor of influenza A and B virus replication. Antimicrobial Agents and Chemotherapy. 2010 May;54(5):2017-22. doi: 10.1128/AAC.01186-09 PMID 20194696
  4. Jump up^ Kiselev OI, Deeva EG, Mel’nikova TI, Kozeletskaia KN, Kiselev AS, Rusinov VL, Charushin VN, Chupakhin ON. A new antiviral drug Triazavirin: results of phase II clinical trial. (Russian). Voprosy Virusologii. 2012 Nov-Dec;57(6):9-12. PMID 23477247
  5. Jump up^ Loginova SIa, Borisevich SV, Rusinov VL, Ulomskiĭ UN, Charushin VN, Chupakhin ON. Investigation of Triazavirin antiviral activity against tick-borne encephalitis pathogen in cell culture. (Russian). Antibiotiki i Khimioterapiia. 2014;59(1-2):3-5. PMID 25051708
  6. Jump up^ “Target: Ebola”. Pravda. Retrieved 18 January 2015.
  7. Jump up^ “Yekaterinburg pharmacies to sell domestic antiviral drug”. Retrieved 18 January 2015.
  8. Jump up^ “Ebola crisis: Vaccine ‘too late’ for outbreak. BBC News, 17 October 2014”BBC News.
  9. Jump up^ Kukil Bora. Russia Will Begin Testing Triazavirin, Used For Lassa Fever, And Other Drugs On Ebola: Health Ministry. International Business Times, 12 November 2014
  10. Jump up^ Darya Kezina. New antiviral drug from Urals will help fight Ebola and other viruses. Russia Beyond the Headlines, 12 November 2014
Triazavirin
Triazavirin.svg
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
ECHA InfoCard 100.217.074
Chemical and physical data
Formula C5H4N6O3S
Molar mass 228.189
3D model (JSmol)

///////////riamilovir sodium dihydrate, Riamilovir , ANTIVIRAL, Triazavirin, Flavivirus infection,  Zika virus infection

O=C1N2C(NN=C1[N+]([O-])=O)=NC(SC)=N2

Vaborbactam, Ваборбактам , فابورباكتام , 法硼巴坦 ,


Vaborbactam.svg

 Image result for VaborbactamImage result for Vaborbactam
Vaborbactam 
RN: 1360457-46-0
UNII: 1C75676F8V
Molecular Formula. C12-H16-B-N-O5-S
Molecular Weight. 297.1374
1,2-Oxaborinane-6-acetic acid, 2-hydroxy-3-((2-(2-thienyl)acetyl)amino)-, (3R,6S)-
B1([C@H](CC[C@H](O1)CC(=O)O)NC(=O)Cc2cccs2)O
RPX7009
A beta-lactamase inhibitor.
Treatment of Bacterial Infection
{(3R,6S)-2-Hydroxy-3-[(2-thienylacetyl)amino]-1,2-oxaborinan-6-yl}acetic acid
2-[(3R,6S)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid
1,2-Oxaborinane-6-acetic acid, 2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-, (3R,6S)-
Ваборбактам [Russian]
فابورباكتام [Arabic]
法硼巴坦 [Chinese]
  • Originator Rempex Pharmaceuticals
  • Developer The Medicines Company; US Department of Health and Human Services
  • Class Antibacterials; Pyrrolidines; Small molecules; Thienamycins
  • Mechanism of Action Beta lactamase inhibitors; Cell wall inhibitors

Highest Development Phases

  • Registered Urinary tract infections
  • Phase III Bacteraemia; Gram-negative infections; Pneumonia; Pyelonephritis

Most Recent Events

  • 29 Aug 2017 Registered for Urinary tract infections (Treatment-experienced, Treatment-resistant) in USA (IV) – First global approval
  • 29 Aug 2017 Updated efficacy and safety data from a phase III trial in Gram-negative infections released by The Medicines Company
  • 09 Aug 2017 Planned Prescription Drug User Fee Act (PDUFA) date for Urinary tract infections (Treatment-experienced, Treatment-resistant) in USA (IV) is 2017-08-29
 
Rapidly rising resistance to multiple antimicrobial agents in Gram-negative bacteria, commonly related to healthcare-associated infections, is an emerging public health concern in U.S. hospitals. While the cephalosporin class of β-lactams was the mainstay of treatment in the 1980s, the dissemination of extended-spectrum β-lactamases (ESBLs) over the past 2 decades has dramatically weakened the utility of this class and brought about a corresponding reliance on the carbapenems.(1) Although carbapenems are widely recognized as a safe and effective class of antimicrobials, carbapenem-resistant Enterobacteriaceae (CRE) due to the Klebsiella pneumoniaecarbapenemase (KPC) and other β-lactamases now threatens the usefulness of all β-lactam antibiotics.(2) The Centers for Disease Control (CDC) considers CRE to be an urgent antimicrobial resistance threat that now has been detected in nearly every U.S. state, with an alarming increase in incidence over the past 5 years.(3) The failure to develop antimicrobial agents to manage CRE threatens to have a catastrophic impact on the healthcare system.(4)
A proven strategy to overcome resistance to β-lactam antibiotics has been to restore their activity by combining them with an inhibitor of the β-lactamase enzymes responsible for their degradation. Examples of clinically important β-lactamase inhibitors (Figure 1) include clavulanic acid (combined with amoxicillin), sulbactam (with ampicillin), and tazobactam (with piperacillin). The KPC β-lactamase is poorly inhibited by these β-lactamase inhibitors, and thus, they have no usefulness in the treatment of infections due to CRE. More recently, the diazabicyclooctane inhibitors avibactam (NXL-104)(5) and relebactam (MK-7655)(6) have entered clinical development, in combination with ceftazidime and imipenem, respectively. Both compounds display a broad spectrum of β-lactamase inhibition that includes the KPC enzyme.

Image result for VaborbactamNext generation β-lactamase inhibitors recently approved or in clinical trials. A. Avibactam. B. Relebactam. C. Vaborbactam.

Vaborbactam (INN)[1] is a non-β-lactam β-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an antibiotic by itself, it restores potency to existing antibiotics by inhibiting the beta-lactamase enzymes that would otherwise degrade them. When combined with an appropriate antibiotic it can be used for the treatment of gram-negative bacterial infections.[2]

According to a Medicines Company press release, as of June 2016 a combination of vaborbactam with the carbapenem antibiotic meropenem had met all pre-specified primary endpoints in a phase III clinical trial in patients with complicated urinary tract infections.[3] The company planned to submit an NDA to the FDAin early 2017.

Biochemistry

Carbapenemases are a family of β-lactamase enzymes distinguished by their broad spectrum of activity and their ability to degrade carbapenem antibiotics, which are frequently used in the treatment of multidrug-resistant gram-negative infections.[4] Carbapenemases can be broadly divided into two different categories based on the mechanism they use to hydrolyze the lactam ring in their substrates. Metallo-β-lactamases contain bound zinc ions in their active sites and are therefore inhibited by chelating agents like EDTA, while serine carbapenemases feature an active site serine that participates in the hydrolysis of the substrate.[4] Serine carbapenemase-catalyzed hydrolysis employs a three-step mechanism featuring acylation and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral transition state.[4][5]

Boronic acids are unusual in their ability to reversibly form covalent bonds with alcohols such as the active site serine in a serine carbapenemase. This property enables them to function as transition state analogs of serine carbapenemase-catalyzed lactam hydrolysis and thereby inhibit these enzymes. Based on data from Hecker et al., vaborbactam is a potent inhibitor of a variety of β-lactamases, exhibiting a 69-nanomolar {\displaystyle K_{i}}K_{i} against the KPC-2 carbapenemase and even lower inhibition constants against CTX-M-15 and SHV-12.[2]

Given their mechanism of action, the possibility of off-target effects brought about through inhibition of endogenous serine hydrolases is an obvious possible concern in the development of boronic acid β-lactamase inhibitors, and in fact boronic acids like bortezomib have previously been investigated or developed as inhibitors of various human proteases.[2] Vaborbactam, however, is a highly specific β-lactamase inhibitor, with an IC50 >> 1 mM against all human serine hydrolases against which it has been tested.[2] Consistent with its high in vitro specificity, vaborbactam exhibited a good safety profile in human phase I clinical trials, with similar adverse events observed in both placebo and treatment groups.[6] Hecker et al. argue this specificity results from the higher affinity of human proteases to linear molecules; thus it is expected that a boron heterocycle will have zero effect on them.

SYN

WO 2015171430

 

 

PATENT

Image result for Rempex Pharmaceuticals, Inc.

Inventors Gavin HirstRaja ReddyScott HeckerMaxim TotrovDavid C. GriffithOlga RodnyMichael N. DudleySerge BoyerLess «
Applicant Rempex Pharmaceuticals, Inc.
WO 2012021455

Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of antibacterial therapy. The increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs

[0003] Various bacteria have evolved β-lactam deactivating enzymes, namely, β-lactamases, that counter the efficacy of the various β-lactams. β-lactamases can be grouped into 4 classes based on their amino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes in classes A, C, and D include active-site serine β-lactamases, and class B enzymes, which are encountered less frequently, are Zn-dependent. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β-lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi- resistant strains severely limits β-lactam treatment options available.

[0004] The increase of class D β-lactamase-expressing bacterium strains such as Acinetobacter baumannii has become an emerging multidrug-resistant threat. A. baumannii strains express A, C, and D class β-lactamases. The class D β-lactamases such as the OXA families are particularly effective at destroying carbapenem type β-lactam antibiotics, e.g., imipenem, the active carbapenems component of Merck’s Primaxin® (Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This has imposed a pressing threat to the effective use of drugs in that category to treat and prevent bacterial infections. Indeed the number of catalogued serine-based β- lactamases has exploded from less than ten in the 1970s to over 300 variants. These issues fostered the development of five “generations” of cephalosporins. When initially released into clinical practice, extended- spectrum cephalosporins resisted hydrolysis by the prevalent class A β-lactamases, TEM-1 and SHV-1. However, the development of resistant strains by the evolution of single amino acid substitutions in TEM-1 and SHV-1 resulted in the emergence of the extended- spectrum β-lactamase (ESBL) phenotype.

[0005] New β-lactamases have recently evolved that hydrolyze the carbapenem class of antimicrobials, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other β-lactam antibiotics. These carbapenemases belong to molecular classes A, B, and D. Class A carbapenemases of the KPC-type predominantly in Klebsiella pneumoniae but now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. The KPC carbapenemase was first described in 1996 in North Carolina, but since then has disseminated widely in the US. It has been particularly problematic in the New York City area, where several reports of spread within major hospitals and patient morbidity have been reported. These enzymes have also been recently reported in France, Greece, Sweden, United Kingdom, and an outbreak in Germany has recently been reported. Treatment of resistant strains with carbapenems can be associated with poor outcomes.

[0006] Another mechanism of β-lactamase mediated resistance to carbapenems involves combination of permeability or efflux mechanisms combined with hyper production of beta-lactamases. One example is the loss of a porin combined in hyperproduction of ampC beta-lactamase results in resistance to imipenem in Pseudomonas aeruginosa. Efflux pump over expression combined with hyperproduction of the ampC β-lactamase can also result in resistance to a carbapenem such as meropenem.

[0007] Because there are three major molecular classes of serine-based β- lactamases, and each of these classes contains significant numbers of β-lactamase variants, inhibition of one or a small number of β-lactamases is unlikely to be of therapeutic value. Legacy β-lactamase inhibitors are largely ineffective against at least Class A carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases. Therefore, there is a need for improved β-lactamase inhibitors.

The following compounds are prepared starting from enantiomerically pure (R)-tert-butyl 3-hydroxypent-4-enoate (J. Am. Chem. Soc. 2007, 129, 4175-4177) in accordance with the procedure described in the above Example 1.

5

[0192] 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-l,2-oxaborinan-6-yl)acetic acid 5. 1H NMR (CD3OD) δ ppm 0.97-1.11 (q, IH), 1.47-1.69 (m, 2H), 1.69-1.80 (m, IH), 2.21-2.33 (td, IH), 2.33-2.41 (dd, IH), 2.58-2.67 (m, IH), 3.97 (s, 2H), 4.06-4.14 (m, IH), 6.97-7.04 (m, IH), 7.04-7.08 (m, IH), 7.34-7.38 (dd, IH); ESIMS found for Ci2Hi6BN05S m/z 28 -H20)+.

PATENT
WO 2013122888

The following compounds are prepared starting from enantiomerically pure (R)-tert-butyl 3-hydroxypent-4-enoate (J. Am. Chem. Soc. 2007, 129, 4175-4177) in accordance with the procedure described in the above Example 1.

Figure imgf000091_0001

5

[0175] 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-l,2-oxaborinan-6- yl)acetic acid 5. 1H NMR (CD3OD) δ ppm 0.97-1.11 (q, 1H), 1.47-1.69 (m, 2H), 1.69-1.80 (m, 1H), 2.21-2.33 (td, 1H), 2.33-2.41 (dd, 1H), 2.58-2.67 (m, 1H), 3.97 (s, 2H), 4.06-4.14 (m, 1H), 6.97-7.04 (m, 1H), 7.04-7.08 (m, 1H), 7.34-7.38 (dd, 1H); ESIMS found for Ci2Hi6BN05S m/z 280 (100%) (M-H20)+.

 PATENT
WO 2015171430 

EXAMPLES

Example 1 – Synthesis of Intermediate Compound 10

[0191] The compound of Formula 10 was synthesized as shown in Scheme 3, below:

Scheme 3

95%

80% for 2 steps

(i?)-t-butyl 3-(trimethysilyloxy)-pent-4-enoate (7)

[0192] Chlorotrimethylsilane (4.6 mL, 36.3 mmol, 1.25 eq) was added to a solution of (R)-t-butyl 3-hydroxy-pent-4-enoate (1, 5 g, 29 mmol) and triethylamine (5.3 mL, 37.3 mmol, 1.3 eq) in dichloromethane (25 mL) keeping the temperature below 30 °C. After completion of the addition, the white heterogeneous mixture was stirred at rt for 20 minutes (TLC, GC, note 2) then quenched with MeOH (352 μί, 0.3 eq). After stirring at rt for 5 minutes, the white heterogeneous reaction mixture was diluted with heptane (25 mL). The salts were filtered off and rinsed with heptane (2 x 10 mL). The combined turbid filtrates were washed with a saturated solution of NaHC03 (2 x 25 mL) and concentrated to dryness. The residual oil was azeotroped with heptane (25 mL) to give a colorless oil that was used immediately.

QSVt-butyl 3-(trimethylsilyloxy)-5-(4,4,5,5-tetramethyl-[L3,21dioxaborolan-2-yl)-pentanoate (8)

[0193] A solution of bis-diphenylphosphino-ethane (46.3 mg, 0.2 mol%) and [Ir(COD)Cl]2 (39 mg, 0.1 mol%) in CH2C12 (5 mL) was added to a refluxing solution of crude TMS-protected pentenoate 7. Pinacol borane (9.3 mL,l .l eq) was added to the

refluxing solution. After stirring at reflux for 3 h, the reaction mixture was cooled to room temperature, concentrated to dryness and taken up in heptane (50 mL). The insolubles were filtered over Celite and rinse with heptane (10 mL).

Ethanolamine-boronic acid salt (10)

[0194] A mixture of fully protected boronate 8 (5.0 g, 13.4 mmol), 0.5 N HC1 (5 mL) and acetone (0.5 mL) was stirred vigorously at room temperature, providing intermediate 9. After complete consumption of the starting material, a solution of NaI04 (3.44 g, 1.2 eq) in water (15 mL) was added slowly keeping the temperature <30 °C. Upon the completion of the addition (30 min), the reaction mixture was allowed to cool to room temperature. After consumption of all pinacol, MTBE (5 mL) was added. After stirring at room temperature for 10 min, the white solids were filtered off and rinsed with MTBE (2 x 5 mL). The filtrate was partitioned and the aqueous layer was extracted with MTBE (10 mL). The combined organic extracts were washed sequentially with a 0.1 M NaHS03 solution (2 x 5 mL), a saturated NaHC03 solution (5 mL) and brine (5 mL). The organic layer was concentrated to dryness. The residue was taken up in MTBE (15 mL) and the residual salts filtered off. The filtrate was concentrated to dryness and the residue was taken up in MTBE (10 mL) and acetonitrile (1.7 mL). Ethanolamine (0.99 mL, 1.1 eq) was added. After stirring at room temperature for 1 hour, the heterogeneous mixture was stirred at 0 °C. After stirring at 0 °C for 2 hours, the solids were collected by filtration, rinsed with MTBE (2 x 5 mL), air dried then dried under high vacuum to give Compound 10 as a white granular powder.

Example 2 – Preparation of Beta-Lactamase Inhibitor (15)

[0195] The compound of Formula 15 was synthesized as shown in Scheme 4 below:

Scheme 4

Synthesis of pinanediol boronate (12)

[0196] Ethanolammonium boronate 11 (15 g, 61.7 mmol) and pinanediol (10.5 g, 61.7 mmol, 1 eq) were suspended in MTBE (75 mL). Water (75 mL) was added and the yellow biphasic heterogeneous mixture was stirred at room temperature. After stirring for 2 hours at room temperature, some pinanediol was still present and stirring was continued overnight. The layers were separated and the organic layer was washed with brine, concentrated under reduced pressure and azeotroped with MTBE (2 x 30 mL). The residual oil was taken up in dichloromethane (40 mL). In another flask, TBSC1 (1 1.6 g, 77.1 mmol, 1.25 eq) was added to a solution of imidazole (9.66 g, 141.9 mmol, 2.3 eq) in dichloromethane (25 mL). The white slurry was stirred at room temperature. After 5 minutes, the solution of pinanediol boronate was added to the white slurry and the flask was rinsed with dichloromethane (2 x 5 mL). The heterogeneous reaction mixture was heated at reflux temeprature. After stirring at reflux for 8 hours, the reaction mixture was cooled to 30 °C and TMSC1 (330 \JL) was added. After stirring 30 minutes at 30 °C, MeOH (15 mL) was added. After stirring at room temperature overnight, the reaction mixture was washed sequentially with 0.5 N HC1 (115 niL), 0.5 N HC1 (60 n L) and saturated NaHC03 (90 niL). The organic layer was concentrated under reduced pressure and azeotroped with heptane (150 n L) to give 12 as a yellow oil (27.09 g, 94.1%) which was used without purification.

Synthesis of chloroboronate (13)

[0197] A solution of n-butyllithium (2.5 M in hexane, 29.6 niL, 74.1 mmol, 1.3 eq) was added to THF (100 mL) at -80 °C. The resulting solution was cooled to -100 °C. A solution of dichloromethane (14.6 mL, 228 mmol, 4 eq) in THF (25 mL) was added via syringe pump on the sides of the flask keeping the temperature < -95 °C. During the second half of the addition a precipitate starts to appear which became thicker with the addition of the remaining dichloromethane solution. After stirring between -100 and -95 °C for 30 min, a solution of 12 (26.59 g, 57 mmol) in THF (25 mL) was added by syringe pump on the sides of the flask while maintaining the batch temperature < -95 °C to give a clear yellow solution. After stirring between -100 and -95 °C for 30 min, a solution of zinc chloride (1 M in ether, 120 mL, 120 mmol, 2.1 eq) was added keeping the temperature < -70 °C. The reaction mixture was then warmed to room temperature (at about -18 °C the reaction mixture became turbid/heterogeneous). After stirring at room temperature for 2 hours, the reaction mixture was cooled to 15 °C and quenched with 1 N HC1 (100 mL). The layers were separated and the organic layer was washed sequentially with 1 N HC1 (100 mL) and water (2 x 100 mL), concentrated to oil and azeotroped with heptane (3 x 150 mL) to provide 13 as a yellow oil (30.03 g, 102%) which was used without purification.

Synthesis of (14)

[0198] LiHMDS (1 M in THF, 63 mL, 62.7 mmol, 1.1 eq) was added to a solution of 13 (29.5 g, 57 mmol) in THF (60 mL) while maintaining the batch temperature at < -65 °C. After stirring at -78 °C for 2 hours, additional LiHMDS (5.7 mL, 0.1 eq) was added to consume the remaining starting material. After stirring at -78 °C for 30 minutes, the tan reaction mixture was warmed to room temperature. After stirring at room temperature for one hour, the solution of silylated amine was added via cannula to a solution of HOBT ester of 2-thienylacetic acid in acetonitrile at 0 °C (the solution of HOBT ester was prepared by adding EDCI (16.39 g, 85.5 mmol, 1.5 eq) to a suspension of recrystallized 2-thienylacetic acid (9.73 g, 68.4 mmol, 1.2 eq) and HOBT.H20 (11.35 g, 74.1 mmol, 1.3 eq) in acetonitrile (10 mL) at 0 °C. The clear solution was stirred at 0 °C for 30 minutes prior to the addition of the silylated amine). After stirring at 0 °C for one hour, the heterogeneous reaction mixture was placed in the fridge overnight. Saturated aqueous sodium bicarbonate (80 mL) and heptane (80 mL) were added, and after stirring 30 minutes at room temperature, the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate (2 x 80 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and the tan oil was azeotroped with heptane (3 x 1 10 mL). The residue was taken up in heptane (60 mL) and seeds were added. After stirring at room temperature for one hour, the reaction mixture became heterogeneous. After stirring 4 hours at 0 °C, the solids were collected by filtration and washed with ice cold heptane (3 x 20 mL), air dried then dried under high vacuum to give 14 as an off white powder (10.95 g, 31%).

Synthesis of (15)

[0199] A mixture of 14 (10 g, 16.1 mmol), boric acid (1.3 g, 20.9 mmol, 1.3 eq), dioxane (20 mL), and 1 M sulfuric acid (10 mL) was heated at 75 °C. After stirring 7 hours at 75 °C, the cooled reaction mixture was diluted with water (10 mL) and MTBE (30 mL) and the residual mixture was cooled to 0 °C. The pH was adjusted to 5.0 with a solution of 2 N NaOH (14 mL). The layers were separated and the aqueous layer was extracted with MTBE (2 x 30 mL) then concentrated to dryness. The residue was taken up in water (10 mL) and the solution was filtered through a 0.45 μηι GMF syringe filter. The flask and filter were rinsed with water (7.5 mL). The pH of the filtrate was lowered to 4.0 with 2 M H2SO4 and seeds (5 mg) were added. After stirring at room temperature for 10 minutes, the pH was lowered to 1.9 over 1 hour with 2 M H2S04 (total volume 3.5 mL). After stirring at room temperature for 2 hours, the solids were collected by filtration. The filtrate was recirculated twice to rinse the flask and the cake was washed with water (2 x 12 mL), air dried then dried under high vacuum to give 15 as a white powder (3.63 g, 76%).

PAPER
 
Journal of Medicinal Chemistry (2015), 58(9), 3682-3692
Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases
 Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States
 Molsoft L.L.C., 11199 Sorrento Valley Road, San Diego, California 92121, United States
§ Beryllium, 3 Preston Court, Bedford, Massachusetts 01730, United States
J. Med. Chem.201558 (9), pp 3682–3692
DOI: 10.1021/acs.jmedchem.5b00127
Publication Date (Web): March 17, 2015
Copyright © 2015 American Chemical Society
*Phone: 858-875-6678. E-mail: scott.hecker@themedco.com.
Abstract
The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine β-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.
 
 
1 to 4 of 4
Patent ID
Patent Title
Submitted Date
Granted Date
CYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF
2013-07-29
2013-12-26
Cyclic boronic acid ester derivatives and therapeutic uses thereof
2011-08-08
2014-03-25
CYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF
2013-03-15
2013-12-12
METHODS OF TREATING BACTERIAL INFECTIONS
2013-02-11
2015-04-30
from PubChem
 
 

References

  1. Jump up^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75” (PDF). World Health Organization. pp. 161–2.
  2. Jump up to:a b c d Hecker, SJ; Reddy, KR; Totrov, M; Hirst, GC; Lomovskaya, O; Griffith, DC; King, P; Tsivkovski, R; Sun, D; Sabet, M; Tarazi, Z; Clifton, MC; Atkins, K; Raymond, A; Potts, KT; Abendroth, J; Boyer, SH; Loutit, JS; Morgan, EE; Durso, S; Dudley, MN (14 May 2015). “Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases”Journal of Medicinal Chemistry58 (9): 3682–92. ISSN 0022-2623doi:10.1021/acs.jmedchem.5b00127.
  3. Jump up^ “The Medicines Company Announces Positive Top-Line Results for Phase 3 TANGO 1 Clinical Trial of CARBAVANCE®. Business Wire, Inc.
  4. Jump up to:a b c Queenan, AM; Bush, K (13 July 2007). “Carbapenemases: the Versatile β-Lactamases”Clinical Microbiology Reviews20 (3): 440–58. ISSN 0893-8512PMC 1932750Freely accessiblePMID 17630334doi:10.1128/CMR.00001-07.
  5. Jump up^ Lamotte-Brasseur, J; Knox, J; Kelly, JA; Charlier, P; Fonzé, E; Dideberg, O; Frère, JM (December 1994). “The Structures and Catalytic Mechanisms of Active-Site Serine β-Lactamases”. Biotechnology and Genetic Engineering Reviews12 (1): 189–230. ISSN 0264-8725PMID 7727028doi:10.1080/02648725.1994.10647912.
  6. Jump up^ Griffith, DC; Loutit, JS; Morgan, EE; Durso, S; Dudley, MN (October 2016). “Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects”Antimicrobial Agents and Chemotherapy60 (10): 6326–32. ISSN 0066-4804PMC 5038296Freely accessiblePMID 27527080doi:10.1128/AAC.00568-16.
Vaborbactam
Vaborbactam.svg
Clinical data
Routes of
administration
IV
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C12H16BNO5S
Molar mass 297.13 g·mol−1
3D model (JSmol)

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FDA approves new antibacterial drug Vabomere (meropenem, vaborbactam)

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Meropenem

Beta-lactamase inhibitor vaborbactam
08/29/2017
The U.S. Food and Drug Administration today approved Vabomere for adults with complicated urinary tract infections (cUTI), including a type of kidney infection, pyelonephritis, caused by specific bacteria. Vabomere is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

The U.S. Food and Drug Administration today approved Vabomere for adults with complicated urinary tract infections (cUTI), including a type of kidney infection, pyelonephritis, caused by specific bacteria. Vabomere is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

“The FDA is committed to making new safe and effective antibacterial drugs available,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “This approval provides an additional treatment option for patients with cUTI, a type of serious bacterial infection.”

The safety and efficacy of Vabomere were evaluated in a clinical trial with 545 adults with cUTI, including those with pyelonephritis. At the end of intravenous treatment with Vabomere, approximately 98 percent of patients treated with Vabomere compared with approximately 94 percent of patients treated with piperacillin/tazobactam, another antibacterial drug, had cure/improvement in symptoms and a negative urine culture test. Approximately seven days after completing treatment, approximately 77 percent of patients treated with Vabomere compared with approximately 73 percent of patients treated with piperacillin/tazobactam had resolved symptoms and a negative urine culture.

The most common adverse reactions in patients taking Vabomere were headache, infusion site reactions and diarrhea. Vabomere is associated with serious risks including allergic reactions and seizures. Vabomere should not be used in patients with a history of anaphylaxis, a type of severe allergic reaction to products in the class of drugs called beta-lactams.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of antibacterial drugs, Vabomere should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Vabomere was designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of its QIDP designation, Vabomere received a priority review.

The FDA granted approval of Vabomere to Rempex Pharmaceuticals.

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Latamoxef (or moxalactam)

http://www.wikiwand.com/en/Latamoxef

////////////////RPX7009, RPX 7009, VABORBACTAM, Vaborbactam, Ваборбактам ,   فابورباكتام ,   法硼巴坦 , FDA 2017

Happy Teacher's Day 2017!

FDA approves Mylotarg (gemtuzumab ozogamicin) for treatment of acute myeloid leukemia


09/01/2017
The U.S. Food and Drug Administration today approved Mylotarg (gemtuzumab ozogamicin) for the treatment of adults with newly diagnosed acute myeloid leukemia whose tumors express the CD33 antigen (CD33-positive AML). The FDA also approved Mylotarg for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory).

The U.S. Food and Drug Administration today approved Mylotarg (gemtuzumab ozogamicin) for the treatment of adults with newly diagnosed acute myeloid leukemia whose tumors express the CD33 antigen (CD33-positive AML). The FDA also approved Mylotarg for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory).

Mylotarg originally received accelerated approval in May 2000 as a stand-alone treatment for older patients with CD33-positive AML who had experienced a relapse. Mylotarg was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns, including a high number of early deaths. Today’s approval includes a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population.

“We are approving Mylotarg after a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment.”

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. The National Cancer Institute of the National Institutes of Health estimates that approximately 21,380 people will be diagnosed with AML this year and that 10,590 patients with AML will die of the disease.

Mylotarg is a targeted therapy that consists of an antibody connected to an anti-tumor agent that is toxic to cells. It is thought to work by taking the anti-tumor agent to the AML cells that express the CD33 antigen, blocking the growth of cancerous cells and causing cell death.

The safety and efficacy of Mylotarg in combination with chemotherapy for adults were studied in a trial of 271 patients with newly diagnosed CD33-positive AML who were randomized to receive Mylotarg in combination with daunorubicin and cytarabine or to receive daunorubicin and cytarabine without Mylotarg. The trial measured “event-free survival,” or how long patients went without certain complications, including failure to respond to treatment, disease relapse or death, from the date they started the trial.  Patients who received Mylotarg in combination with chemotherapy went longer without complications than those who received chemotherapy alone (median, event-free survival 17.3 months vs. 9.5 months).

The safety and efficacy of Mylotarg as a stand-alone treatment were studied in two, separate trials. The first trial included 237 patients with newly diagnosed AML who could not tolerate or chose not to receive intensive chemotherapy. Patients were randomized to receive treatment with Mylotarg or best supportive care. The trial measured “overall survival,” or how long patients survived from the date they started the trial. Patients who received Mylotarg survived longer than those who received only best supportive care (median overall survival 4.9 months vs. 3.6 months). The second trial was a single-arm study that included 57 patients with CD33-positive AML who had experienced one relapse of disease. Patients received a single course of Mylotarg. The trial measured how many patients achieved a complete remission. Following treatment with Mylotarg, 26 percent of patients achieved a complete remission that lasted a median 11.6 months.

Common side effects of Mylotarg include fever (pyrexia), nausea, infection, vomiting, bleeding, low levels of platelets in the blood (thrombocytopenia), swelling and sores in the mouth (stomatitis), constipation, rash, headache, elevated liver function tests, and low levels of certain white blood cells (neutropenia). Severe side effects of Mylotarg include low blood counts, infections, liver damage, blockage of the veins in the liver (hepatic veno-occlusive disease), infusion-related reactions, and severe bleeding (hemorrhage). Women who are pregnant or breastfeeding should not take Mylotarg, because it may cause harm to a developing fetus or a newborn baby. Patients with hypersensitivity to Mylotarg or any component of its formulation should not use Mylotarg.

The prescribing information for Mylotarg includes a boxed warning that severe or fatal liver damage (hepatotoxicity), including blockage of veins in the liver (veno-occlusive disease or sinusoidal obstruction syndrome), occurred in some patients who took Mylotarg.

Mylotarg received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Mylotarg to Pfizer Inc.

 

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Gemtuzumab ozogamicin
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target CD33
Clinical data
Trade names Mylotarg
AHFS/Drugs.com Monograph
MedlinePlus a607075
Pregnancy
category
  • D
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
KEGG
ChEMBL
Chemical and physical data
Molar mass 151–153 g/mol

Gemtuzumab ozogamicin (marketed by Wyeth as Mylotarg) is a drug-linked monoclonal antibody (an antibody-drug conjugate) that was used to treat acute myelogenous leukemia from 2000 to 2010. It was withdrawn from market in June 2010 when a clinical trial showed the drug increased patient death and added no benefit over conventional cancer therapies.

Mechanism and side effects

Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins. CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells.

Common side effects of administration included shiveringfevernausea and vomiting. Serious side effects included severe myelosuppression (suppressed activity of bone marrow, which is involved in formation of various blood cells [found in 98% of patients]), disorder of the respiratory systemtumor lysis syndromeType III hypersensitivity, venous occlusion, and death.

History

Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991.[1][2] The same collaboration later produced inotuzumab ozogamicin.[3] Celltech was acquired by UCB in 2004[4] and Wyeth was acquired by Pfizer in 2009.[5]

In the United States, it was approved under an accelerated-approval process by the FDA in 2000 for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy.[6] The accelerated approval was based on the surrogate endpoint of response rate.[7] It was the first antibody-drug conjugate to be approved.[8]

Within the first year after approval, the FDA required a black box warning be added to Gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation.[9] Later the onset of VOD was shown to occur at increased frequency in Gemtuzumab patients even following bone marrow transplantation.[10] The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents.[11]

A randomized phase 3 comparative controlled trial (SWOG S0106) was initiated in 2004 by Wyeth in accordance with the FDA accelerated-approval process. The study was stopped[when?] prior to completion due to worrisome outcomes. Among the patients evaluated for early toxicity, fatal toxicity rate was significantly higher in the gemtuzumab combination therapy group vs the standard therapy group. Mortality was 5.7% with gemtuzumab and 1.4% without the agent (16/283 = 5.7% vs 4/281 = 1.4%; P = .01).[7]

In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA.[12][13] However, some other regulatory authorities did not agree with the FDA decision, with Japan’s Pharmaceuticals and Medical Devices Agency stating in 2011 that the “risk-benefit balance of gemtuzumab ozogamicin has not changed from its state at the time of approval”.[14]

In early 2017 Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML. [8]

References

  1. Jump up^ “Mylotarg”. Informa Biomedtracker. Retrieved 19 August 2017.
  2. Jump up^ Niculescu-Duvaz, I (December 2000). “Technology evaluation: gemtuzumab ozogamicin, Celltech Group.”. Current opinion in molecular therapeutics2 (6): 691–6. PMID 11249747.
  3. Jump up^ Damle, NK; Frost, P (August 2003). “Antibody-targeted chemotherapy with immunoconjugates of calicheamicin.”. Current opinion in pharmacology3 (4): 386–90. PMID 12901947doi:10.1016/S1471-4892(03)00083-3.
  4. Jump up^ “Celltech sold to Belgian firm in £1.5bn deal”The Guardian. 18 May 2004.
  5. Jump up^ Sorkin, Andrew Ross; Wilson, Duff (25 January 2009). “Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth”The New York Times.
  6. Jump up^ Bross PF, Beitz J, Chewn G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R (2001). “Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.”. Clin Cancer Res7 (6): 1490–6. PMID 11410481.
  7. Jump up to:a b Gemtuzumab Voluntarily Withdrawn From US Market. June 2010
  8. Jump up to:a b Stanton, Dan (February 1, 2017). “Pfizer resubmits US and EU application for withdrawn ADC Mylotarg”BioPharma Reporter.
  9. Jump up^ Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA, David CL, Phan AT, Colburn DE, Rashid A, Estey EH (2001). “Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation.”. Cancer92 (2): 406–13. PMID 11466696doi:10.1002/1097-0142(20010715)92:2<406::AID-CNCR1336>3.0.CO;2-U.
  10. Jump up^ Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, Antin JH, Stone RM, Soiffer RJ, DeAngelo DJ (2003). “Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation.”. Blood102 (5): 1578–82. PMID 12738663doi:10.1182/blood-2003-01-0255.
  11. Jump up^ The Research on Adverse Drug Events and Reports (RADAR) Project, JAMA
  12. Jump up^ Mylotarg (gemtuzumab ozogamicin): Market Withdrawal, US FDA
  13. Jump up^ Pfizer pulls leukemia drug from U.S. marketReuters
  14. Jump up^ Pharmaceuticals and Medical Devices Safety Information, No. 277, February 2011 (PDF) (Technical report). Pharmaceuticals and Medical Devices Agency of Japan. 2011.
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