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Fexinidazole Hoe-239

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Fexinidazole, Hoe-239

1-Methyl-2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole

cas59729-37-2 
Molecular formula C12H13N3O3S
Molar mass 279.31 g mol−1

Hoechst Aktiengesellschaft

Sanofi (Originator)
University of Dundee
Drugs for Neglected Diseases Initiative

Winkelmann, E.; Raether, W.
Chemotherapeutically active nitro compounds. 4,5-nitroimidazoles. Part III
Arzneim-Forsch Drug Res 1978, 28(5): 739

US 4042705, DE 2531303,

UPDATE 7/16/2021 FDA APPROVES

To treat human African trypanosomiasis caused by the parasite Trypanosoma brucei gambiense

600 MG TABLET ORAL, DRUGS FOR NEGLECTED DISEASES INITIATIVE

US FDA approves fexinidazole as the first all-oral treatment for sleeping sickness

POSTED ON JULY 19

The US Food and Drug Administration (FDA) has approved fexinidazole as the first all-oral treatment for both stages of the Trypanosoma brucei gambiense form of sleeping sickness (Human African trypanosomiasis) in patients 6 years of age and older and weighing at least 20 kg.
Fexinidazole was developed as part of an innovative partnership between the non-profit research and development organization Drugs for Neglected Diseases initiative (DNDi), which conducted the pivotal clinical trials for this treatment, in partnership with the National Sleeping Sickness Programs of the Democratic Republic of Congo (DRC) and Central African Republic (CAR), and Sanofi.

Sleeping sickness is a parasitic disease transmitted by the bite of an infected tse-tse fly. It affects mostly populations living in remote rural areas of sub-Saharan Africa, where about 65 million people are at risk of infection. Left untreated, sleeping sickness is almost always fatal. Through Sanofi’s collaboration the number of sleeping sickness cases reported to the WHO has been reduced by ~97% between 2001 and 2020. DNDiSanofi and partners are deeply committed to ensuring access to fexinidazole in all sleeping sickness-endemic countries.

Current treatment options for the disease are effective, but burdensome for patients and health workers due to the need for infusion or injection, requiring hospitalization, especially challenging for people living in remote areas.

“Having a simple, all-oral treatment for sleeping sickness is a dream come true for frontline clinicians,” said Dr Bernard Pécoul, DNDi Executive Director. “We are proud of this latest milestone in our long-term partnership with Sanofi, developed in close collaboration with researchers in countries hard-hit by sleeping sickness.”

Fexinidazole is indicated as a 10-day once-a-day treatment for Trypanosoma brucei gambiense sleeping sickness, the most common form of the disease found in West and Central Africa. Fexinidazole is the first all-oral treatment that works both for the first stage of the disease, as well as the second stage of the disease in which the parasites have crossed the blood-brain barrier, causing patients to suffer from neuropsychiatric symptoms.

This FDA approval is a key milestone in Sanofi’s long-term commitment to fight sleeping sickness, started 20 years ago alongside the WHO through an ambitious partnership to combat Neglected Tropical Diseases” said Luc Kuykens, Senior Vice President, Sanofi Global Health unit. “Following the positive scientific opinion granted by the European Medicines Agency end 2018, the FDA approval is an important step to revitalize efforts to support the sustainable elimination of the disease”.

As a result of FDA approval, a Tropical Disease Priority Review Voucher (PRV) has been awarded to DNDi. The FDA Tropical Disease PRV Program was established in 2007 to incentivize development of new treatments for neglected tropical diseases, including sleeping sickness. Any benefits from the PRV will be shared between Sanofi and DNDi, which will enable continued investments in innovating for and ensuring access to new health tools for sleeping sickness and other neglected diseases. Sanofi commits to continue to provide the drug free-of-charge to the World Health Organization for distribution to affected countries, as part of a long-term collaboration with WHO.

About Sleeping sickness
Sleeping sickness, or human African trypanosomiasis (HAT), is usually fatal without treatment. Transmitted by the bite of an infected tse-tse fly, following a period with nonspecific symptoms, it evolves to cause neuropsychiatric symptoms, including abnormal behaviour, and a debilitating disruption of sleep patterns that have given this neglected disease its name. About 65 million people in sub-Saharan Africa are at moderate to very high risk of infection.

About DNDi
The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patient needs-driven, not-for-profit research and development (R&D) organization that develops safe, effective, and affordable treatments for sleeping sickness, leishmaniasis, Chagas disease, filarial infections, mycetoma, paediatric HIV, hepatitis C, and covid-19. Since its inception in 2003, DNDi has delivered eight new treatments, including nifurtimox-eflornithine combination therapy (NECT) for late-stage sleeping sickness, and fexinidazole, the first all-oral drug for sleeping sickness.

Fexinidazole is an antiparasitic agent.[1] It has activity against Trypanosoma cruziTritrichomonas foetusTrichomonas vaginalis,Entamoeba histolytica,[1] Trypanosoma brucei,[2] and Leishmania donovani.[3] The biologically relevant active metabolites in vivo are the sulfoxide and sulfone [3][4]

Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s.[5] Fexinidazole is now being studied through a collaboration between Sanofi and the Drugs for Neglected Diseases Initiative for the treatment of Chagas disease and human African trypanosomiasis (sleeping sickness).[6][7] Fexinidazole is the first drug candidate for the treatment of advanced-stage sleeping sickness in thirty years.[8]

Fexinidazole is currently in phase II/III clinical development at Drugs for Neglected Diseases Initiative for the oral treatment of African trypanosomiasis (sleeping sickness). In May 2009, Sanofi (formerly known as sanofi-aventis) licensed the drug candidate to Drugs for Neglected Diseases Initiative for the development, manufacturing and distribution as a treatment of human African trypanosomiasis. Once approved, the companies plan to make the drug available on a nonprofit basis.

Fexinidazole was originally developed by a German pharmaceutical company called Hoechst, now part of Sanofi; however, its development was abandoned in the 1980s when the company gave up its tropical disease programs. Fexinidazole is one of a class of drugs known as azoles, like fluconazole, that work against fungi and may work against cancer.

  • Onset of trypanosomiasis is caused by Trypanosoma protozoa and it is said that every year 200,000 to 300,000 of new patients of African sleeping sickness fall sick. At present the number of patients of African sleeping sickness cannot be confirmed due to the low reliability of the investigative data. According to the WHO, at least 150,000 people died of African sleeping sickness in 1996 and it is said that its aftereffect remains in not less than 100,000 people. Beyond that, enormous is the damage to domestic animals caused by a disease called as nagana, and several hundred thousands of cattle which are to be protein sources for people die every year. Further, in the area of about 10,000,000 km2of savanna equal to the United States of America, cattle-breeding is impossible due to Trypanosoma. Thus, African sleeping sickness remarkably damages the health and the economical development of African people, and this is the reason why the WHO adopts the trypanosomiasis as one of the infectious diseases that should be controlled.
  • African sleeping sickness is a protozoal infectious disease by Trypanosoma transmitted through tsetse flies and the protozoa appear in the blood stream in about 10 days after infection. In the initial period of infection the protozoa multiply in the blood stream and give fever, physical weakness, headache, a pain of muscles and joints and a feeling of itching to proceed. On entering the chromic period, the central nerve is affected to show symptoms such as mental confusion and systemic convulsion, and finally the patients lapse into lethargy and are led to death.
  • The trypanosomiasis of domestic animals has Trypanosoma brucei brucei, Trypanosoma evansi, Trypanosoma congolense and Trypanosoma vivax as pathogens and is a communicable disease which affects domestic animals such as horses, cattle, pigs and dogs and, in addition, mice, guinea pigs, rabbits and the like. Particularly, the loss of cattle and horses is greatest and almost fetal, and they are led to anemia, edema, weakening and the like and fall dead in one month after infection.
  • In treating trypanosomiasis, pentamidine, melarsoprol, eflornithine and the like are used and there was a feeling in the 1960s that its eradication might be possible. However, these drugs are old and are gradually losing their efficacy. Particularly, the resistance to melarsoprol of an arsenic agent causes a big problem and the situation is so dire that patients with no efficacy only await death and the development of novel antitrypanosoma agents are strongly desired.
  • Trypanosoma mainly lives in the blood stream of the human body. This bloodstream energy metabolism depends on the glycolytic pathway localized in the organelle characteristic of the protozoa which is called as glycosome and the so-called oxidative phosphorylation does not function. However, in order to efficiently drive this glycolytic pathway, the produced NADH has to be reoxidized, and the glycerol-3-phosphate oxidation system of mitochondria plays an important role in this reoxidation. The terminal oxidase of this oxidation system functions as a quinol oxidase having a reduced ubiquinone as an electron donor and has properties greatly different from those of cytochrome oxidase of an aerobic respiration system which the host has. Particularly, a remarkable point is that the terminal oxidase of the oxidation system is non-sensitive to the cyanide which quickly inhibits the cytochrome oxidase of the host. Then, many researchers centered around Western countries have tried to develop drugs targeting this cyanide resistant oxidase but effective drugs having a selective toxicity have not been obtained.
  • Under these circumstances the present inventors et al. found that isoprenoid based physiologically active substances of ascochlorin, ascofuranone and derivatives thereof, particularly ascofuranone specifically inhibits the glycerol-3-phosphate oxidation system of trypanosome at a very low concentration of the order of nM and filed a patent application (Japanese Patent Publication A No. : H09-165332). They also clarified that acofuranone exhibits a very strong multiplication inhibition effect in the copresence of glycerin (Molecular and Biochemical Parasitology, 81: 127-136, 1996).
    In consideration of practical use of ascofuranone, it was found essential to discover agents which replace glycerin and exhibit an effect of the combined use in a small amount, and by using an alkaloid compound having an indole skeleton existing in a plant of the family Simaroubaceae together with ascofuranone, the prolongation of life and recovery effect in African seeping sickness was found and a patent application was filed (Japanese Patent Application No.: 2003-24643, Japanese Patent Publication A No.: 2004-23601).

Method for the preparation of fexinidazole, useful for the treatment of parasitic diseases, visceral leishmaniasis, chagas disease and human African trypanosomiasis. Family members of the product patent, WO2005037759, are expected to expire from October 2024. This to be the first application from Drugs for Neglected Diseases Initiative (DNDi) on this API. DNDi in collaboration with Sanofi, the Swiss Tropical & Public Health Institute and the University of Dundee, is developing fexinidazole, an antiparasitic agent, for treating human African trypanosomiasis (HAT) and visceral Leishmaniasis (VL). By June 2013, phase I clinical studies had been completed and at that time, DNDi was planning to initiate a phase II proof-of-concept study in VL patients in early 2013.

fexinidazole[inn], 59729-37-2, 1-Methyl-2-((4-(methylthio)phenoxy)methyl)-5-nitro-1H-imidazole, Fexinidazol, Fexinidazolum

Chemotherapeutically active nitro compounds. 4,5-Nitroimidazoles. Part III
Synthesis
By condensation of 4 – (methylmercapto) phenol (II) with 1-mehtyl-2-chloromethyl-5-nitroimidazole (I) by means of K2CO3 in DMF (1,2) Description:. Crystals, mp 116 C. References: 1) Raether, W., Winkelman, E.; Chemotherapeutically active nitro compounds 4,5-Nitroimidazoles Part III Arzneim-Forsch 1978, 28 (5):. 739 2) Winkelmann,… E., Raether, W. (Hoechst AG); DE 2531303.
Winkelman, E.; Raether, W.;… Chemotherapeutically active nitro compounds 4,5-Nitroimidazoles Part III Arzneim-Forsch 1978, 28, 5, 739
Arzneim-Forsch1978, 28, (5): 739

………………..

http://www.google.com/patents/EP1681280A1?cl=en

…………..

US 4042705

http://www.google.co.in/patents/US4042705

…………

new patent june 2014

WO-2014079497

Process for preparing fexinidazole – comprising the reaction of 1-methyl-2-hydroxymethyl-5-nitro-imidazole with methanesulfonyl chloride, followed by reaction with 4-methylmercapto-phenol, and further manipulative steps.

1-Methyl-2-hydroxymethyl-5-nitro-imidazole is (I) and 1-methyl-2-(4-methylmercapto-phenyloxymethyl)-5-nitro-imidazole (fexinidazole) is (II) (claim 1, page 12).

The synthesis of (II) via intermediate (I) is described (example 1, pages 6-8).

A process for preparing fexinidazole comprising the reaction of 1-methyl-2-hydroxymethyl-5-nitro-imidazole with methanesulfonyl chloride in the presence of a suspension of powdered alkaline carbonate (eg potassium carbonate) in an anhydrous organic solvent (eg acetone), followed by reaction with 4-methylmercapto-phenol, removal of hydrochloride salt, and isolation and purification is claimed. Also claimed is their use for treating parasitic diseases, visceral leishmaniasis, chagas disease, and human African trypanosomiasis. Fexinidazole is known to be an antiparasitic agent.

2-1-1983
The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica.
Annals of tropical medicine and parasitology
1-1-1983
The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice.
Zeitschrift für Parasitenkunde (Berlin, Germany)
5-1-2011
1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis.
European journal of medicinal chemistry
2-1-2011
Compounds containing 2-substituted imidazole ring for treatment against human African trypanosomiasis.
Bioorganic & medicinal chemistry letters
1-1-2011
Trypanocidal activity of nitroaromatic prodrugs: current treatments and future perspectives.
Current topics in medicinal chemistry
12-1-2010
Potential new drugs for human African trypanosomiasis: some progress at last.
Current opinion in infectious diseases
7-1-2010
Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis.
Antimicrobial agents and chemotherapy
1-1-2010
Fexinidazole–a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.
PLoS neglected tropical diseases
1-1-1999
[Use of megazol for the treatment of trypanosomiasis].
Médecine tropicale : revue du Corps de santé colonial
11-1-1998
A method to assess invasion and intracellular replication of Trypanosoma cruzi based on differential uracil incorporation.
Journal of immunological methods
10-1-1996
Topical chemotherapy for experimental murine African CNS-trypanosomiasis: the successful use of the arsenical, melarsoprol, combined with the 5-nitroimidazoles, fexinidazole or MK-436.
Tropical medicine & international health : TM & IH
6-1-1991
Chemotherapy of CNS-trypanosomiasis: the combined use of the arsenicals and nitro-compounds.
11-15-2013
Targeting the human parasite Leishmania donovani: discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series.
Bioorganic & medicinal chemistry
10-1-2013
The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral Leishmaniasis.
Antimicrobial agents and chemotherapy
2-1-2013
Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation.
Antimicrobial agents and chemotherapy
9-1-2012
Genotoxicity profile of fexinidazole–a drug candidate in clinical development for human African trypanomiasis (sleeping sickness).
Mutagenesis
7-15-2012
Discovery of nitroheterocycles active against African trypanosomes. In vitro screening and preliminary SAR studies.
Bioorganic & medicinal chemistry letters
2-1-2012
The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis.
Science translational medicine
1-1-2012
Fexinidazole: a potential new drug candidate for Chagas disease.
PLoS neglected tropical diseases
1-1-2012
Management of trypanosomiasis and leishmaniasis.
British medical bulletin
12-1-2011
Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness.
Antimicrobial agents and chemotherapy
6-1-2011
Development of novel drugs for human African trypanosomiasis.
Future microbiology
US3682951 * 2 Nov 1970 8 Aug 1972 Searle & Co 1-{8 {62 -(1-adamantyloxy)halophenethyl{9 {0 imidazoles and congeners
US3714179 * 8 Sep 1970 30 Jan 1973 Searle & Co 1-alkyl-2-furfurylthioimidazoles and congeners
US3796704 * 16 Aug 1971 12 Mar 1974 Bayer Ag Phenyl-imidazolylalkanyl derivatives
US3828065 * 11 Dec 1972 6 Aug 1974 Searle & Co 2-methyl-5-nitro-1-(2-phenylthioethyl)imidazoles
US3842097 * 22 Jan 1973 15 Oct 1974 Searle & Co 2-(phenoxyalkylthio)imidazoles and congeners
US3910925 * 24 May 1974 7 Oct 1975 Searle & Co {8 2-(2-Methyl-5-nitro-1-imidazolyl)ethyl{9 benzo(b)pyridyloxy ethers
US3922277 * 14 Nov 1974 25 Nov 1975 Hoechst Ag (1-Alkyl-5-nitro-imidazolyl-2-alkyl)-pyridyl compounds
DE2124103A1 * 14 May 1971 25 Nov 1971 Title not available

References

  1.  Raether, W; Seidenath, H (1983). “The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica”. Annals of Tropical Medicine and Parasitology 77 (1): 13–26. PMID 6411009.
  2.  Jennings, FW; Urquhart, GM (1983). “The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice”. Zeitschrift für Parasitenkunde 69 (5): 577–581. doi:10.1007/bf00926669PMID 6636983.
  3.  Wyllie, S; Patterson, S; Stojanovski, FRC; Norval, S; Kime, R; Read, RD; Fairlamb, AH (2012). “The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis”Science Translational Medicine 4 (119): 119re1.doi:10.1126/scitranslmed.3003326PMC 3457684PMID 22301556.
  4.  Sokolova, AY; Wyllie, S; Patterson, S; Oza, SL; Read, RD; Fairlamb, AH (2010). “Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis”. Antimicrobial Agents and Chemotherapy 54 (7): 2893–900. doi:10.1128/AAC.00332-10.PMID 20439607.
  5.  “Jump-Start on Slow Trek to Treatment for a Disease”New York Times. January 8, 2008.
  6.  “Fexinidazole Progresses into Clinical Development”. DNDi Newsletter. November 2009.
  7.  “Sanofi-aventis and DNDi enter into a Collaboration Agreement on a New Drug for Sleeping Sickness, Fexinidazole”. DNDi. May 18, 2009.
  8.  Torreele, E; Bourdin Trunz, B; Tweats, D; Kaiser, M; Brun, R; Mazué, G; Bray, MA; Pécoul, B (2010). “Fexinidazole–a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness”. In Boelaert, Marleen. PLOS Neglected Tropical Diseases 4 (12): e923. doi:10.1371/journal.pntd.0000923PMC 3006138PMID 21200426.


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DR ANTHONY CRASTO

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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 LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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