FDA approves new treatment Erleada (apalutamide) for a certain type of prostate cancer using novel clinical trial endpoint

The U.S. Food and Drug Administration today approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer. Continue reading.

//////////////fda 2018, Erleada, apalutamide, Priority Review, Janssen

CAS  946414-94-4

• BMS 936558
• MDX 1106
• NKTR 214
• ONO 4538
• Opdivio
• NIVOLUMAB

Pegylated engineered interleukin-2 (IL-2) with altered receptor binding

NKTR-214 is a cytokine (investigational agent) that is designed to target CD122, a protein which is found on certain immune cells (known as CD8+ T Cells and Natural Killer Cells) to expand these cells to promote their anti-tumor effects. Nivolumab is a full human monoclonal antibody that binds to a molecule called PD-1 (programmed cell death protein 1) on immune cells and promotes anti-tumor effects.

Protein Sequence

Sequence Length: 1308, 440, 440, 214, 214multichain; modified (modifications unspecified)

NKTR-214 is a CD122-biased cytokine in phase II clinical trials at the M.D. Anderson Cancer Center for the treatment of advanced sarcoma in combination with nivolumab.

M.D. Anderson Cancer Center, PHASE 2, SARCOMA

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO, Novel Drug Approvals for 2017, A Review Compilation (USFDA, EMA).

Any errors in this compilation, email  amcrasto@gmail.com, Call +919323115463

Some gaps will be filled up soon keep watching……………..

INDEX, NAME (click on the title,  it contains link)

SECTION A; USFDA Approvals

1 Abaloparatide

2 Abemaciclib

3 ACALABRUTINIB

4 ANGIOTENSIN II

5 AVELUMAB

6 BENRALIZUMAB

7 BENZNIDAZOLE

8 BETRIXABAN

9 BRIGATINIB

10 BRODALUMAB

11 CERLIPONASE ALPA

12 COPANLISIB

13 DEFLAZACORT

14 Delafloxacin

15 Deutetrabenazine

16DUPILUMAB

17 DURVALUMAB

18 EDAVARONE

19 EMICIZUMAB

20 Enasidenib

21 ERTUGLIFLOZIN

22 ETELCALCETIDE

23 GLECAPREVIR

24 GUSELKUMAB

25 INOTUZUMAB OZOGAMICIN

26 LATANOPROSTENE

27 LETERMOVIR

28 MACIMORELIN ACETATE

29 MEROPENEM

30 MIDOSTAURIN

31 NALDEMEDINE

32 NERATINIB

33 NETARSUDIL

34 NIRAPARIB

35 Ocrelizumab

36 OZENOXACIN

37 PIBRENTASVIR

38 PLECANATIDE

39 RIBOCICLIB

40  SARILUMAB

41 SECNIDAZOLE

42 SAFINAMIDE

43 SEMAGLUTIDE

44 SOFOSBUVIR

45 TELOTRISTAT ETHYL

46 VABORBACTAM

47 VALBENAZINE

48 VESTRONIDASE ALFA-VJBK

49 VELPATASVIR

50 VOXILAPREVIR

INDEX, FORMULATION NAME

USFDA

•Aliqopa (COPANLISIB) to treat adults with relapsed follicular lymphoma — a slow-growing type of nonHodgkin lymphoma (a cancer of the lymph system) — who have received at least two prior systemic therapies;

• ALUNBRIG, BRIGATINIB, To treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

• Austedo, Deutetrabenazine For the treatment of chorea associated with Huntington’s disease

• Bavencio (avelumab) for the treatment of patients 12 years and older with a rare and aggressive form of cancer called metastatic Merkel cell carcinoma, including those who have not received prior chemotherapy;

•BAXDELLA, Delafloxacin, BACTERIAL INFECTIONS

• Benznidazole to treat children ages 2 to 12 years with Chagas disease, a parasitic infection that can cause serious heart illness after years of infection, and can also affect swallowing and digestion. This is the first treatment approved in the United States for this rare disease;

• Besponsa (inotuzumab ozogamicin) for the treatment of adults with a type of cancer of the blood called relapsed or refractory B-cell precursor acute lymphoblastic leukemia;

•BEVYXXA, BETRIXABAN, For the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness

• BRINEURA, CERLIPONASE ALFA, To treat a specific form of Batten disease

• Calquence (ACALABRUTINIB) to treat adults with mantle cell lymphoma who have received at least one prior therapy. Mantle cell lymphoma is a particularly aggressive cancer;

• DUPIXENT, (DUPILUMAB) To treat adults with moderate-to-severe eczema (atopic dermatitis)

• Emflaza (deflazacort) to treat patients age 5 years and older with Duchenne muscular dystrophy, a rare genetic disorder that causes progressive muscle deterioration and weakness;

• FASENRA, BENRALIZUMAB, For add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype

• Giapreza (angiotensin II), for the treatment of hypotension in adults with distributive or vasodilatory shock (dangerously low blood pressure despite adequate heart function) whose blood pressure remains low despite receiving fluids and treatment with drugs called vasopressors;

•  HEMLIBRA EMICIZUMAB To prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

• Idhifa (enasidenib) for the treatment of adults with relapsed or refractory acute myeloid leukemia, a form of blood cancer, who have a specific genetic mutation;

• IMFINZI, DURVALUMAB To treat patients with locally advanced or metastatic urothelial carcinoma

• Ingrezza (valbenazine) to treat adults with tardive dyskinesia, a side effect of some antipsychotic medications whereby patients can experience uncontrollable stiff, jerky movements of their face and body, and other uncontrolled movements such as eye-blinking, sticking out the tongue, and arm-waving;

•  KEVZARA SARILUMAB, RHEUMATOID ARTHRITIS

• KISQALI, RIBOCICLIB, To treat postmenopausal women with a type of advanced breast cancer

• Macrilen  macimorelin acetate, For the diagnosis of adult growth hormone deficiency

• Mavyret (glecaprevir and pibrentasvir) to treat adults with chronic hepatitis C virus genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease, as well as those who are on hemodialysis;

• Mepsevii (vestronidase alfa-vjbk) to treat patients with Sly syndrome or mucopolysaccharidosis type 7 – a rare genetic disorder where an enzyme deficiency results in skeletal abnormalities, developmental delay, enlarged liver and spleen, and narrowed airways, which can lead to respiratory infections;

• Nerlynx (neratinib) for the extended adjuvant treatment — a form of therapy administered after an initial treatment to further lower the risk of the cancer coming back — of early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer;

• OCREVUS, OCRELIZUMAB, To treat patients with relapsing and primary progressive forms of multiple sclerosis

• OZEMPIC SEMAGLUTIDE To improve glycemic control in adults with type 2 diabetes mellitus

•PARSABIV, ETELCALCETIDE, To treat secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing dialysis

• Prevymis (letermovir) for prevention of an infection called cytomegalovirus (CMV) in patients who are receiving a bone marrow transplant. CMV disease can cause serious health issues in these patients;

• Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis, commonly referred to as Lou Gehrig’s disease, a rare disease that attacks and kills the nerve cells that control voluntary muscles;

• RHOPRESSA, NETARSUDIL,  To treat glaucoma or ocular hypertension

• Rydapt (midostaurin) to treat adults newly diagnosed with a form of blood cancer known as acute myeloid leukemia who have a specific genetic mutation called FLT3, in combination with chemotherapy;

• Siliq (brodalumab) to treat adults with moderate-to-severe plaque psoriasis, a chronic disorder in which the body’s immune system sends out faulty signals that speed growth of skin cells that then accumulate, causing red, flaky patches that can appear anywhere on the body;

•SOLOSEC, SECNIDAZOLE To treat bacterial vaginosis

•  STEGLATRO ERTUGLIFLOZIN To improve glycemic control in adults with type 2 diabetes mellitus

• Symproic (Naldemedine) for the treatment of opioid-induced constipation in adults with chronic noncancer pain; • Tremfya (guselkumab) for the treatment of adults with moderate-to-severe plaque psoriasis;

• Trulance (plecanatide) to treat adults with chronic idiopathic constipation, which is a persistent condition of constipation due to unknown origin;

• TYMLOS, Abaloparatide, To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies

• Vabomere (vaborbactam and meropenem) for treatment of adults with complicated urinary tract infections, including pyelonephritis (kidney infection) caused by bacteria;

• Verzenio (abemaciclib) to treat adults who have hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy);

• Vosevi (sofosbuvir/velpatasvir/voxilaprevir) to treat adults with chronic hepatitis C virus genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis;

• VYZULTA LATANOPROSTENE To treat intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

• Xadago (safinamide) as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes;

• XERMELO, TELOTRISTAT ETHYL combined with somatostatin analog (SSA) therapy to treat adults with carcinoid syndrome diarrhea that SSA therapy alone has inadequately controlled, and;

• XEPI OZENOXACIN TO TREAT IMPETIGO

•XERMELO, TELOTRISTAT ETHYL, To treat carcinoid syndrome diarrhea

• Zejula (niraparib) for the maintenance treatment (intended to delay cancer growth) of adults with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, whose tumors have completely or partially shrunk (complete or partial response, respectively) in response to platinum-based chemotherapy

USFDA

* This information is currently accurate. In rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME) designation or the status of its application as a novel new biologics license application (BLA).  For instance, new information may become available which could lead to a reconsideration of the original designation or status.  If changes must be made to a drug’s designation or the status of an application as a novel BLA, the Agency intends to communicate the nature of, and the reason for, any revisions as appropriate.

1 Abaloparatide

RADIUS

Tymlos

FDA 4/28/2017

To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot

link……..https://newdrugapprovals.org/2018/02/13/abaloparatide-%D0%B0%D0%B1%D0%B0%D0%BB%D0%BE%D0%BF%D0%B0%D1%80%D0%B0%D1%82%D0%B8%D0%B4-%D8%A3%D8%A8%D8%A7%D9%84%D9%88%D8%A8%D8%A7%D8%B1%D8%A7%D8%AA%D9%8A%D8%AF-%E5%B7%B4%E7%BD%97%E6%97%81/

2 Abemaciclib

ELI LILLY

LINK https://newdrugapprovals.org/2015/10/19/abemaciclib-bemaciclib/

3 Acalabrutinib

LINK……….https://newdrugapprovals.org/2018/02/02/acalabrutinib-acp-196-%D0%B0%D0%BA%D0%B0%D0%BB%D0%B0%D0%B1%D1%80%D1%83%D1%82%D0%B8%D0%BD%D0%B8%D0%B1-%D8%A3%D9%83%D8%A7%D9%84%D8%A7%D8%A8%D8%B1%D9%88%D8%AA%D9%8A%D9%86%D9%8A%D8%A8-%E9%98%BF/

4 Angiotensin II

LA JOLLA

LINK https://newdrugapprovals.org/2017/12/22/fda-approves-drug-giapreza-angiotensin-ii-to-treat-dangerously-low-blood-pressure/

5 AVELUMAB

MERCK

LINK…..https://newdrugapprovals.org/2017/03/24/fda-approves-first-treatment-bavencio-avelumabfor-rare-form-of-skin-cancer/

6 BENRALIZUMAB

ASTRA ZENECA

Fasenra benralizumab

FDA 11/14/2017

For add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype
Drug Trials Snapshot

7 Benznidazole

CHEMO RESEARCH

LINK…https://newdrugapprovals.org/2017/08/30/fda-approves-first-u-s-treatment-benznidazole-for-chagas-disease/

8 BETRIXABAN

PORTOLA PHARMA

LINK…….https://newdrugapprovals.org/2013/03/05/phase-3-portola-pharma-betrixaban-long-acting-oral-direct-factor-xa-inhibitor/

9 BRIGATINIB

TAKEDA

LINK..https://newdrugapprovals.org/2017/01/20/brigatinib-%D0%B1%D1%80%D0%B8%D0%B3%D0%B0%D1%82%D0%B8%D0%BD%D0%B8%D0%B1-%D8%A8%D8%B1%D9%8A%D8%BA%D8%A7%D8%AA%D9%8A%D9%86%D9%8A%D8%A8-%E5%B8%83%E6%A0%BC%E6%9B%BF%E5%B0%BC/

10 BRODALUMAB

VALEANT PHARMA

LINK ,,,,https://newdrugapprovals.org/2017/02/16/fda-approves-new-psoriasis-drug-siliq-brodalumab/

11 CERLIPONASE ALFA

LINK….https://newdrugapprovals.org/2017/04/28/fda-approves-first-treatment-for-a-form-of-batten-disease-brineura-cerliponase-alfa/

12 Copanlisib

LINK…..https://newdrugapprovals.org/2017/11/20/copanlisib/

13  DEFLAZACORT

MARATHON PHARMA

LINK……https://newdrugapprovals.org/2017/02/17/deflazacort/

14 DELAFLOXACIN

LINK……..https://newdrugapprovals.org/2018/01/25/delafloxacin/

15 Deutetrabenazine

TEVA

LINK……………https://newdrugapprovals.org/2015/08/15/sd-809-deutetrabenazine-nda-submitted-by-teva/

16 DUPILUMAB

SANOFI/REGENERON

LINK…….https://newdrugapprovals.org/2017/03/29/fda-approves-new-eczema-drug-dupixent-dupilumab/

17 DURVALUMAB

ASTRA ZENECA

Imfinzi

durvalumab FDA 5/1/2017To treat patients with locally advanced or metastatic urothelial carcinoma
Web Post
Drug Trials Snapshot

18 EDAVARONE

MITSUBISHI TANABE

LINK………https://newdrugapprovals.org/2017/05/06/fda-approves-drug-to-treat-als-radicava-edaravone-%D1%8D%D0%B4%D0%B0%D1%80%D0%B0%D0%B2%D0%BE%D0%BD-%D8%A5%D9%8A%D8%AF%D8%A7%D8%B1%D8%A7%D9%81%D9%88%D9%86-%E4%BE%9D%E8%BE%BE%E6%8B%89%E5%A5%89/

19 EMICIZUMAB

ROCHE

LINK https://newdrugapprovals.org/2017/11/17/fda-approves-new-treatment-hemlibra-emicizumab-kxwh-to-prevent-bleeding-in-certain-patients-with-hemophilia-a/

20 Enasidenib

LINK……https://newdrugapprovals.org/2017/08/02/enasidenib-%D1%8D%D0%BD%D0%B0%D1%81%D0%B8%D0%B4%D0%B5%D0%BD%D0%B8%D0%B1-%D8%A5%D9%8A%D9%86%D8%A7%D8%B3%D9%8A%D8%AF%D9%8A%D9%86%D9%8A%D8%A8-%E4%BC%8A%E9%82%A3%E5%B0%BC%E5%B8%83/

21 Ertugliflozin

MERCK

LINK https://newdrugapprovals.org/2014/02/10/ertugliflozin/

22 ETELCALCETIDE

Amgen

SYNTHESIS LINK……..https://cen.acs.org/articles/96/i4/the-year-in-new-drugs-2018.html

23 GLECAPREVIR

ABBVIE

LINK https://newdrugapprovals.org/2016/10/05/glecaprevir-abt-493/

24 GUSELKUMAB

JOHNSON AND JOHNSON

Tremfya

guselkumab

FDA 7/13/2017

For the treatment of adult patients with moderate-to-severe plaque psoriasis
Drug Trials Snapshot

25 Inotuzumab ozogamicin

PFIZER

LINK….https://newdrugapprovals.org/2015/10/23/fda-grants-breakthrough-status-for-pfizers-leukaemia-drug-inotuzumab-ozogamicin/

26 LATANOPROSTENE

VALEANT

latanoprostene bunod ophthalmic solution

FDA 11/2/2017

To treat intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Drug Trials Snapshot

LINK https://newdrugapprovals.org/2014/09/27/nicox-stock-leaps-on-positive-ph-iii-glaucoma-drug-data-%E8%8B%B1%E6%96%87%E5%90%8D%E7%A7%B0/

27 LETERMOVIR

MERCK

LINK https://newdrugapprovals.org/2016/05/16/letermovir-aic-246/

28 Macimorelin acetate

AETERNA ZENTARIS

LINK https://newdrugapprovals.org/2014/01/07/aeterna-zentaris-submits-new-drug-application-to-fda-for-macimorelin-acetate-aezs-130-for-evaluation-of-aghd-2/

29 MEROPENEM

30 MIDOSTAURIN

NOVARTIS

• Chemistry Review(s) (PDF)

LINK…….https://newdrugapprovals.org/2017/04/29/fda-approves-new-combination-treatment-for-acute-myeloid-leukemia-rydapt-midostaurin/

31 Naldemedine

FDA 3/23/2017, Symproic, For the treatment of opioid-induced constipation

LINK……..https://newdrugapprovals.org/2018/01/24/naldemedine-%E3%83%8A%E3%83%AB%E3%83%87%E3%83%A1%E3%82%B8%E3%83%B3%E3%83%88%E3%82%B7%E3%83%AB%E9%85%B8%E5%A1%A9/

32 NERATINIB MALEATE

PUMA BIOTECH

LINK…https://newdrugapprovals.org/2014/04/11/neratinib-hki-272-puma-presents-positive-results-from-phase-ii-trial-of-its-investigational-drug-pb272/

33 NETARSUDIL

LINK……https://newdrugapprovals.org/2018/01/29/netarsudil/

34 NIRAPARIB

TESARO

LINK…https://newdrugapprovals.org/2016/12/22/niraparib-mk-4827/

35 OCRELIZUMAB

ROCHE

LINK..https://newdrugapprovals.org/2017/03/30/fda-approves-new-drug-to-treat-multiple-sclerosis-ocrevus-ocrelizumab/

36 OZENOXACIN

MEDIMETRIX

LINK https://newdrugapprovals.org/2014/03/28/ozenoxacin-in-phase-3-topical-formulation-in-the-treatment-of-impetigo/

37 Pibrentasvir

ABBVIE

LINK https://newdrugapprovals.org/2016/06/08/abt-530-pibrentasvir/

38 PLECANATIDE

Plecanatide 普卡那肽 ليكاناتيد плеканатид

SYNERGY PHARMA

LINK ….https://newdrugapprovals.org/2016/04/21/plecanatide-%E6%99%AE%E5%8D%A1%E9%82%A3%E8%82%BD-%D9%84%D9%8A%D9%83%D8%A7%D9%86%D8%A7%D8%AA%D9%8A%D8%AF-%D0%BF%D0%BB%D0%B5%D0%BA%D0%B0%D0%BD%D0%B0%D1%82%D0%B8%D0%B4/

39 RIBOCICLIB

NOVARTIS

Structure..link for correct structure

LINK https://newdrugapprovals.org/2015/10/19/ribociclib/

40  SARILUMAB

SANOFI /REGENERON

LINK https://newdrugapprovals.org/2013/11/25/late-stage-success-for-sanofiregeneron-ra-drug-sarilumab/

41 SECNIDAZOLE

SYMBIOMIX

link….https://newdrugapprovals.org/2017/11/03/secnidazole-%D1%81%D0%B5%D0%BA%D0%BD%D0%B8%D0%B4%D0%B0%D0%B7%D0%BE%D0%BB-%D8%B3%D9%8A%D9%83%D9%86%D9%8A%D8%AF%D8%A7%D8%B2%D9%88%D9%84-%E5%A1%9E%E5%85%8B%E7%A1%9D%E5%94%91/

42 SAFINAMIDE

NEWRON PHARMA

• Chemistry Review(s) (PDF) for correct structure

LINK…https://newdrugapprovals.org/2017/03/22/fda-approves-drug-xadago-safinamide-%D1%81%D0%B0%D1%84%D0%B8%D0%BD%D0%B0%D0%BC%D0%B8%D0%B4-%D8%B3%D8%A7%D9%81%D9%8A%D9%86%D8%A7%D9%85%D9%8A%D8%AF-%E6%B2%99%E9%9D%9E%E8%83%BA-to-treat-parkins/

43 Semaglutide

NOVO NORDISK

LINK https://newdrugapprovals.org/2013/07/22/a-survey-of-promising-late-stage-diabetes-drugs/

44 SOFOSBUVIR

LINK https://newdrugapprovals.org/2013/12/11/us-approves-breakthrough-hepatitis-c-drug-sofosbuvir-all-about-drugs/

45 TELOTRISTAT ETHYL

LEXICON

46 VABORBACTAM

THE MEDICINES CO

LINK     https://newdrugapprovals.org/2017/09/05/vaborbactam-%D0%B2%D0%B0%D0%B1%D0%BE%D1%80%D0%B1%D0%B0%D0%BA%D1%82%D0%B0%D0%BC-%D9%81%D8%A7%D8%A8%D9%88%D8%B1%D8%A8%D8%A7%D9%83%D8%AA%D8%A7%D9%85-%E6%B3%95%E7%A1%BC%E5%B7%B4%E5%9D%A6/

47 VALBENAZINE

NEUROCRINE

• Chemistry Review(s) (PDF)

LINK…………..https://newdrugapprovals.org/2017/04/12/fda-approves-first-drug-ingrezza-valbenazine-to-treat-tardive-dyskinesia/

48 Vestronidase alfa-vjbk

ULTRAGENYX

LINK…https://newdrugapprovals.org/2017/11/16/fda-approves-mepsevii-vestronidase-alfa-vjbk-for-treatment-for-rare-genetic-enzyme-disorder/

49 VELPATASVIR

LINK https://newdrugapprovals.org/2016/07/30/velpatasvir-gs-5816-gilead-sciences-%D0%B2%D0%B5%D0%BB%D0%BF%D0%B0%D1%82%D0%B0%D1%81%D0%B2%D0%B8%D1%80-%D9%81%D8%A7%D9%84%D8%A8%D8%A7%D8%AA%D8%A7%D8%B3%D9%81%D9%8A%D8%B1-%E7%BB%B4%E5%B8%95/

50 VOXILAPREVIR

GILEAD

LINK https://newdrugapprovals.org/2017/07/19/voxilaprevir-%D9%81%D9%88%D9%83%D8%B3%D9%8A%D9%84%D8%A7%D8%A8%D8%B1%D9%8A%D9%81%D9%8A%D8%B1-%E4%BC%8F%E8%A5%BF%E7%91%9E%E9%9F%A6-%D0%B2%D0%BE%D0%BA%D1%81%D0%B8%D0%BB%D0%B0%D0%BF%D1%80%D0%B5%D0%B2/

SECTION B; EMA approvals

European Medicines Agency’s – Human medicines: Highlights of 2017

Advances in medicines authorizations are essential for public health as they have the potential to improve treatment of diseases. In 2017, EMA recommended 92 medicines for marketing authorization. Of these, 35 had a new active substance, which has never been authorized in the European Union (EU) before. Many of these medicines represent a significant improvement in their therapeutic areas; they include medicines for children, for rare diseases and advanced therapies42. Amongst the 35 new active substances (NAS) that EMA recommended, 11 were new drugs and biologics to treat cancer, 05 to treat neurological disorders, 04 for infectious diseases, 04 for immunology/rheumatology, 03 for endocrinology, 02 each for Uro-nephrology, haematology, and dermatology, 01 for Pneumonology, and 01 for hepatology/gastroenterology class of drugs.

SECTION B; EMA Approvals

KEEP WATCHING UNDER CONSTRUCTION AND WILL BE PASTED SOON………………………………………..

KEEP WATCHING UNDER CONSTRUCTION AND WILL BE PASTED SOON………………………………………..

KEEP WATCHING UNDER CONSTRUCTION AND WILL BE PASTED SOON………………………………………..

KEEP WATCHING UNDER CONSTRUCTION AND WILL BE PASTED SOON………………………………………..

REFERENCES

1 http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/01/news_detail_002886.jsp&mid=WC0b01ac058004d5c1

2 http://www.ema.europa.eu/docs/en_GB/document_library/Report/2018/01/WC500242079.pdf

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

Join me on Researchgate

amcrasto@gmail.com

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

////////EMA APPROVALS, USFDA Approvals, ACALABRUTINIB, AVELUMAB, BETRIXABAN, BRODALUMAB, COPANLISIB, DEFLAZACORT, Delafloxacin, Deutetrabenazine, DUPILUMAB, ETELCALCETIDE, Naldemedine, NETARSUDIL, NIRAPARIB, Ocrelizumab, PLECANATIDE, RIBOCICLIB, SAFINAMIDE, TELOTRISTAT ETHYL, VALBENAZINE, CERLIPONASE, BRIGATINIB, MIDOSTAURIN, Abaloparatide, BENZNIDAZOLE, NERATINIB, inotuzumab ozogamicin, Enasidenib, LETERMOVIR, GLECAPREVIR, PIBRENTASVIR, VOXILAPREVIR, SOFOSBUVIR, EDAVARONE, abemaciclib, ANGIOTENSIN II, VESTRONIDASE, macimorelin acetate, ERTUGLIFLOZIN, SEMAGLUTIDE, EMICIZUMAB, eu 2017, fda 2017, BENRALIZUMAB, DURVALUMAB, GUSELKUMAB, LATANOPROSTENE, OZENOXACIN, SARILUMAB, SECNIDAZOLE, BENRALIZUMAB, SARILUMAB

Entecavir

• Molecular FormulaC₁₂H₁₅N₅O₃
• Average mass277.279 Da

2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-9H-purin-6-ol

6H-Purin-6-one, 2-amino-1,9-dihydro-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl)-

6H-Purin-6-one, 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-

9H-purin-6-ol, 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-

Baraclude[Trade name]

CAS 142217-69-4

Entecavir monohydrate 209216-23-9

Baraclude (Entecavir) Film Coated Tablets & Oral Solution
Company:  Bristol-Myers Squibb Pharmaceutical Co.
Application No.:  021797 & 021798
Approval Date: 03/29/2005

Chemistry Review(s) (PDF)

BARACLUDE® is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C₁₂H₁₅N₅O₃•H₂O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:

Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° C ± 0.5° C.

BARACLUDE film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. BARACLUDE 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5 mg tablet only), and iron oxide red (1 mg tablet only). BARACLUDE Oral Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir per milliliter. BARACLUDE Oral Solution contains the following inactive ingredients: maltitol, sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.

 

Title: Entecavir

CAS Registry Number: 142217-69-4

CAS Name: 2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one

Molecular Formula: C12H15N5O3

Molecular Weight: 277.28

Percent Composition: C 51.98%, H 5.45%, N 25.26%, O 17.31%

Literature References: Deoxyguanine nucleoside analog; inhibits hepatitis B virus (HBV) DNA polymerase. Prepn: R. Zahler, W. A. Slusarchyk, EP481754; eidem,US5206244 (1992, 1993 both to Squibb); G. S. Bisacchi et al.,Bioorg. Med. Chem. Lett.7, 127 (1997). In vitro antiviral activity: S. F. Innaimo et al,Antimicrob. Agents Chemother.41, 1444 (1997). Review of pharmacology and clinical experience: P. Honkoop, R. A. de Man, Expert Opin. Invest. Drugs12, 683-688 (2003); T. Shaw, S. Locarnini, Expert Rev. Anti Infect. Ther.2, 853-871 (2004). Clinical comparisons with lamivudine in chronic hepatitis B: T.-T. Chang et al., N. Engl. J. Med.354, 1001 (2006); C.-L. Lai et al., ibid. 1011.

Derivative Type: Monohydrate

CAS Registry Number: 209216-23-9

Manufacturers’ Codes: BMS-200475; SQ-200475

Trademarks: Baraclude (BMS)

Molecular Formula: C12H15N5O3.H2O

Molecular Weight: 295.29

Percent Composition: C 48.81%, H 5.80%, N 23.72%, O 21.67%

Properties: White to off-white powder, mp >220°. [a]D +35.0° (c = 0.38 in water). Soly in water: 2.4 mg/ml. pH of saturated soln in water is 7.9 at 25°±0.5°.

Melting point: mp >220°

Optical Rotation: [a]D +35.0° (c = 0.38 in water)

Therap-Cat: Antiviral.

Keywords: Antiviral; Purines/Pyrimidinones.

Antiviral agents used against HBV

Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection. It is marketed under the trade name Baraclude (BMS).

Entecavir is a guanine analogue that inhibits all three steps in the viral replication process, and the manufacturer claims that it is more efficacious than previous agents used to treat hepatitis B (lamivudine and adefovir). It was approved by the U.S. Food and Drug Administration (FDA) in March 2005.

For the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection.^[1] In those with both HIV/AIDS and HBV antiretroviral medication should also be used.^[1] Entecavir is taken by mouth as a tablet or solution.^[1]

Common side effects include headache, nausea, high blood sugar, and decreased kidney function.^[1] Severe side effects include enlargement of the liver, high blood lactate levels, and liver inflammation if the medication is stopped.^[1] While there appears to be no harm from use during pregnancy, this use has not been well studied.^[4] Entecavir is in the nucleoside reverse transcriptase inhibitors(NRTIs) family of medications.^[1] It prevents the hepatitis B virus from multiplying by blocking reverse transcriptase.^[1]

Entecavir was approved for medical use in 2005.^[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[5] In the United States as of 2015 it is not available as a generic medication.^[6]The wholesale price is about 392 USD for a typical month supply as of 2016 in the United States.^[7]

Medical uses

Entecavir is mainly used to treat chronic hepatitis B infection in adults and children 2 years and older with active viral replication and evidence of active disease with elevations in liver enzymes.^[2] It is also used to prevent HBV reinfection after liver transplant^[8] and to treat HIV patients infected with HBV. Entecavir is weakly active against HIV, but is not recommended for use in HIV-HBV co-infected patients without a fully suppressive anti-HIV regimen^[9] as it may select for resistance to lamivudine and emtricitabine in HIV.^[10]

The efficacy of entecavir has been studied in several randomized, double-blind, multicentre trials. Entecavir by mouth is effective and generally well tolerated treatment.^[11]

Pregnancy and breastfeeding

It is considered pregnancy category C in the United States, and currently no adequate and well-controlled studies exist in pregnant women.^[12]

Side effects

The majority of people who use entecavir have little to no side effects.^[13] The most common side effects include headache, fatigue, dizziness, and nausea.^[2] Less common effects include trouble sleeping and gastrointestinal symptoms such as sour stomach, diarrhea, and vomiting.^[14]

Serious side effects from entecavir include lactic acidosis, liver problems, liver enlargement, and fat in the liver.^[15]

Laboratory tests may show an increase in alanine transaminase (ALT), hematuria, glycosuria, and an increase in lipase.^[16] Periodic monitoring of hepatic function and hematology are recommended.^[2]

Mechanism of action

Entecavir is a nucleoside analog,^[17] or more specifically, a deoxyguanosine analogue that belongs to a class of carbocyclic nucleosidesand inhibits reverse transcription, DNA replication and transcription in the viral replication process. Other nucleoside and nucleotide analogues include lamivudine, telbivudine, adefovir dipivoxil, and tenofovir.

Entecavir reduces the amount of HBV in the blood by reducing its ability to multiply and infect new cells.^[18]

Administration

Entecavir is take by mouth as a tablet or solution. Doses are based on a person’s weight.^[15] The solution is recommended for children more than 2 years old who weigh up to 30 kg. Entecavir is recommended on an empty stomach at least 2 hours before or after a meal, generally at the same time every day. It is not used in children less than 2 years old. Dose adjustments are also recommended for people with decreased kidney function.^[15]

History

• 1992: SQ-34676 at Squibb as part of anti-herpes virus program^[19]
• 1997: BMS 200475 developed at BMS pharmaceutical research institute as antiviral nucleoside analogue à Activity demonstrated against HBV, HSV-1, HCMV, VZV in cell lines & no or little activity against HIV or influenza^[20]
• Superior activity observed against HBV pushed research towards BMS 200475, its base analogues and its enantiomer against HBV in HepG2.2.15 cell line^[20]
• Comparison to other NAs, proven more selective potent inhibitor of HBV by virtue of being Guanine NA^[21]
• 1998: Inhibition of hepadnaviral polymerases was demonstrated in vitro in comparison to a number of NAs-TP^[22]
• Metabolic studies showed more efficient phosphorylation to triphosphate active form^[23]
• 3-year treatment of woodchuck model of CHB à sustained antiviral efficacy and prolonged life spans without detectable emergence of resistance^[24]
• Efficacy # LVD resistant HBV replication in vitro^[25]
• Superior activity compared to LVD in vivo for both HBeAg+ & HBeAg− patients^[26][27]
• Efficacy in LVD refractory CHB patients^[28]
• Entecavir was approved by the U.S. FDA in March 2005.

Patent information

Bristol-Myers Squibb was the original patent holder for Baraclude, the brand name of entecavir in the US and Canada. The drug patent expiration for Baraclude was in 2015.^[29][30]On August 26, 2014, Teva Pharmaceuticals USA gained FDA approval for generic equivalents of Baraclude 0.5 mg and 1 mg tablets;^[31] Hetero Labs received such approval on August 21, 2015;^[32] and Aurobindo Pharma on August 26, 2015.^[33]

Chronic hepatitis B virus infection is one of the most severe liver diseases in morbidity and death rate in the worldwide range. At present, pharmaceuticals for treating chronic hepatitis B (CHB) virus infection are classified to interferon α and nucleoside/nucleotide analogue, i.e. Lamivudine and Adefovir. However, these pharmaceuticals can not meet needs for doctors and patients in treating chronic hepatitis B virus infection because of their respective limitation. Entecavir (ETV) is referred to as 2′-cyclopentyl deoxyguanosine (BMS2000475) which belongs to analogues of Guanine nucleotide and is phosphorylated to form an active triple phosphate in vivo. The triple phosphate of entecavir inhibits HBV polymerase by competition with 2′-deoxyguanosine-5′-triphosphate as a nature substrate of HBV polymerase, so as to achieve the purpose of effectively treating chronic hepatitis B virus infection and have strong anti-HBV effects. Entecavir, [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-hydroxymethyl]-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate, and has the molecular formula of C₁₂H₁₅N₅O₃.H₂O and the molecular weight of 295.3. Its structural formula is as follows:

Entecavir was successfully developed by Bristol-Myers Squibb Co. of USA first and the trademark of the product formulation is Baraclude, including two types of formulations of tablet and oral solution having 0.5 mg and 1 mg of dosage. Chinese publication No. CN1310999 made by COLONNO, Richard, J. et al discloses a low amount of entecavir and uses of the composition containing entecavir in combination with other pharmaceutically active substances for treating hepatitis B virus infection, however, the entecavir is non-crystal. In addition, its oral formulations such as tablet and capsule are made by a boiling granulating process. The process is too complicated to control quality of products during humidity heat treatment even though ensuring uniform distribution of the active ingredients.

Entecavir, [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, is currently used for treating hepatitis B virus infection, whose structure is composed of a cyclopentane ring having purine, exomethylene, hydroxymethyl, and hydroxy substituents at the 1S-, 2-, 3R-, and 4S-positions, respectively. There have been conducted a number of studies to develop methods for preparing entecavir.

For example, U.S. Pat. No. 5,206,244 and WO 98/09964 disclose a method for preparing entecavir shown in Reaction Scheme 1:

The above method, however, has difficulties in that: i) the cyclopentadiene monomer must be maintained at a temperature lower than -30 °C in order to prevent its conversion to dicyclopentadiene; ii) residual sodium after the reaction as well as the sensitivity of the reaction toward moisture cause problems; iii) the process to obtain the intermediate of formula a) must be carried out at an extremely low temperature of below -70 °C in order to prevent the generation of isomers; iv) a decantation method is required when (-)-Ipc₂BH (diisopinocampheylborane) is used for hydroboration; v) the process of the intermediate of formula a) does not proceed smoothly; and, vi) separation by column chromatography using CHP-20P resin is required to purify entecavir.

WO 2004/52310 and U.S. Pat. Publication No. 2005/0272932 disclose a method for preparing entecavir using the intermediate of formula (66), which is prepared as shown in Reaction Scheme 2:

The above preparation method of the intermediate of formula (66) must be carried out at an extremely low temperature of -70 °C or less, and the yield of the desired product in the optical resolution step is less than 50%.

PATENT

https://patents.google.com/patent/EP2382217B1

(3-4) Preparation of [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purine-6-one (a compound of formula (1))

34 mg (0.115 mmol) of 4-(2-amino-6-chloro-purine-9-yl)-2-hydroxymethyl-3-methylene-cyclopentanol (a compound of formula (5)) obtained in (3-3) was added to 0.7 ml of 2N aqueous sodium hydroxide, and the resulting mixture was stirred. The solution thus obtained was heated to 72 °C and stirred for 3.5 hrs. After completion of the reaction, the resulting mixture was cooled to 0 °C, controlled to pH 6.3 by adding 2N aqueous hydrochloric acid and 1N aqueous hydrochloric acid, and condensed to obtain 24 mg of the title compound (yield: 70 %, purity: 99 %).

NMR(300MHz, DMSO-d6): δ 10.58 (s, 1H), 7.67 (s, 1H), 6.42 (s, 2H), 5.36 (t, 1H), 5.11 (s, 1H), 4.86 (d, 1H), 4.83 (t, 1H), 4.57 (s, 1H), 4.24 (s, 1H), 3.54 (t, 2H), 2.53(s, 1H), 2.27-2.18 (m, 1H), 2.08-2.01(m, 1H).

PAPER

https://www.sciencedirect.com/science/article/pii/S0040403911020144

PAPER

https://www.sciencedirect.com/science/article/pii/S0040402017313029

PAPER

Total Synthesis of Entecavir: A Robust Route for Pilot Production

Hua Xu‡, Fang Wang‡, Weicai Xue, Yunjie Zheng, Qi Wang, Fayang G. Qiu^*, and Yehua Jin^* 

Launch-Pharma Technologies, Ltd., 188 Kaiyuan Boulevard, Building D, Fifth Floor, The Science Park of Guangzhou, Guangzhou 510530, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00007

Publication Date (Web): February 12, 2018

Copyright © 2018 American Chemical Society

*E-mail: jinyehua@launch-pharma.com., *E-mail: qiufayang@launch-pharma.com.

A practical synthetic route for pilot production of entecavir is described. It is safe, robust, and scalable to kilogram scale. Starting from (S)-(+)-carvone, this synthetic route consists of a series of highly efficient reactions including a Favorskii rearrangement-elimination-epimerization sequence to establish the cyclopentene skeleton, the Baeyer–Villiger oxidation/rearrangement to afford the correct configuration of the secondary alcohol, and a directed homoallylic epoxidation followed by epoxide ring-opening to introduce the hydroxyl group suitable for the Mitsunobu reaction. In addition, the synthesis contains only four brief chromatographic purifications.

 1: white crystalline solid; HRMS (m/z) calcd for C₁₂H₁₆N₅O₃ [M + H]⁺ 278.1253, found 278.1255; [α]_D +27.2° [c 1.07, DMF/H₂O (1:1)];

¹H NMR (500 MHz, DMSO) δ 10.55 (s, 1H), 7.65 (s, 1H), 6.40 (s, 2H), 5.36 (dd, J = 10.3, 8.0 Hz, 1H), 5.10 (s, 1H), 4.85 (d, J = 3.1 Hz, 1H), 4.81 (t, J = 5.3 Hz, 1H), 4.56 (s, 1H), 4.23 (s, 1H), 3.54 (t, J = 6.1 Hz, 2H), 2.55–2.50 (m, 1H), 2.26–2.17 (m, 1H), 2.04 (dd, J = 12.5, 7.8 Hz, 1H);

¹³C NMR (126 MHz, DMSO) δ 156.8, 153.4, 151.4, 151.3, 135.9, 116.2, 109.2, 70.4, 63.0, 55.1, 54.1, 39.2.

Clips

EP 0481754; JP 1992282373; US 5206244, WO 9809964

The regioselective reaction of cyclopentadiene (I) and sodium or commercial sodium cyclopentadienide (II) with benzyl chloromethyl ether (III) by means of the chiral catalyst (-)-diisopinocampheylborane in THF, followed by hydroxylation with H2O2/NaOH, gives (1S-trans)-2-(benzyloxymethyl)-3-cyclopenten-1-ol (IV), which is regioselectively epoxidized with tert-butyl hydroperoxide and vanadyl acetylacetonate in 2,2,4-trimethylpentane, yielding [1S-(1alpha,2alpha,3beta,5alpha)-2-(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexan-3-ol (V). The protection of (V) with benzyl bromide and NaH affords the corresponding ether (VI), which is condensed with 6-O-benzylguanine (VII) by means of LiH in DMF to give the guanine derivative (VIII). The protection of the amino group of (VIII) with 4-methoxyphenyl(diphenyl)chloromethane (IX), TEA and DMAP in dichloromethane gives intermediate (X), which is oxidized at the free hydroxyl group with methylphosphonic acid, DCC and oxalic acid in DMSO or Dess Martin periodinane in dichloromethane, yielding the cyclopentanone derivative (XI). The reaction of (XI) with (i) Zn/TiCl4/CH2Br2 complex in THF/CH2Cl2, (ii) activated Zn/PbCl2/CH2I2/TiCl4 in THF/CH2Cl2 (2), (iii) Nysted reagent/TiCl4 in THF/CH2Cl2 or (iv) Tebbe reagent in toluene affords the corresponding methylene derivative (XII), which is partially deprotected with 3N HCl in hot THF, providing the dibenzylated compound (XI). Finally, this compound is treated with BCl3 in dichloromethane

PAPER

Bioorg Med Chem Lett 1997,7(2),127

BMS-200475, a novel carbocyclic 2′-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro

BMS-200475, a novel carbocyclic analog of 2′-deoxyguanosine, is a potent inhibitor of hepatitis B virus in vitro (ED₅₀ = 3nM) with relatively low cytotoxicity (CC₅₀ = 21–120 μM).

PATENT

https://patents.google.com/patent/US20140220120

Fourier transform infrared (FTIR) spectrogram: The range of wave numbers is measured by using the Nicolet NEXUS 670 FT-IR spectrometer with KBr pellet method, and the range of wave numbers is about 400 to 4000 cm⁻¹. FIG. 3 is a Fourier transform infrared spectrogram of the sample. The infrared spectrogram shows that there are groups in the molecular structure of the sample, such as NH, NH₂, HN—C═O, C═C, OH.

PAPER

Total Synthesis of Entecavir

Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron–aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp₂TiCl-catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.

2-Amino-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl)-1H-purin-6(9H)-one Monohydrate (1)

1 (2.102 g, 64% overall yield, 99.47% HPLC purity) with a 6.7% water content (as determined by Karl Fischer titration). Mp 248 °C. [α]_D²⁵ +35.0 (c 0.4, H₂O). IR (ATR): 3445, 3361, 3296, 3175, 3113, 2951, 2858, 2626, 1709 cm^–1.

¹H NMR (DMSO-d₆, 400 MHz) δ: 10.59 (s, 1H), 7.66 (s, 1H), 6.42 (bs, 2H), 5.36 (ddt, J = 10.6, 7.8, 2.7 Hz, 1H), 5.10 (dd, J = 2.7, 2.2 Hz, 1H), 4.87 (d, J = 3.1 Hz, 1H), 4.84 (t, J = 5.3 Hz, 1H), 4.56 (t, J = 2.4 Hz, 1H), 4.23 (m, 1H), 3.53 (m, 2H), 2.52 (m, 1H), 2.22 (ddd, J = 12.6, 10.8, 4.6 Hz, 1H), 2.04 (ddt, J = 12.6, 7.7, 1.9 Hz, 1H).

¹³C NMR (DMSO-d₆, 101 MHz) δ: 156.9, 153.5, 151.5, 151.3, 136.0, 116.2, 109.3, 70.4, 63.1, 55.2, 54.1, 39.2. HRMS (ESI): m/z calcd for C₁₂H₁₆N₅O₃⁺ [M + H]⁺ 278.1253; found 278.1262.

PATENTS

PublicationPublication DateTitle

References

External links

• PubMed Health page on Entecavir
• Baraclude U.S. website

Entecavir

Clinical data
Pronunciation	/ɛnˈtɛkəvɪər/ en-TEK-a-vir or en-TE-ka-veer
Trade names	Baraclude[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a605028
License data	EU EMA: by INN US FDA: Entecavir
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	by mouth
ATC code	J05AF10 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	n/a (≥70)[2]
Protein binding	13% (in vitro)
Metabolism	negligible/nil
Biological half-life	128–149 hours
Excretion	Renal 62–73%
Identifiers
IUPAC name[show]
CAS Number	209216-23-9
PubChem CID	153941
DrugBank	DB00442
ChemSpider	135679
UNII	5968Y6H45M
KEGG	D04008
ChEBI	CHEBI:59902
ChEMBL	CHEMBL713
ECHA InfoCard	100.111.234
Chemical and physical data
Formula	C12H15N5O3
Molar mass	277.279 g/mol
3D model (JSmol)	Interactive image
Melting point	220 °C (428 °F) value applies to entecavir monohydrate and is a minimum value[3]
SMILES[show]
InChI

///////////////Entecavir, энтекавир , إينتيكافير , 恩替卡韦 , BMS-200475,  SQ-200475, エンテカビル, 

NC1=NC(=O)C2=C(N1)N(C=N2)[C@H]1C[C@H](O)[C@@H](CO)C1=C

NMR PREDICT

1H NMR AND 13C NMR

13C PREDICT VALUES

The results are consistent with prior studies which have shown that consumption of 100% fruit juice is not linked to increasing risk of developing type 2 diabetes. It also supports a growing body of evidence that fruit juice has no significant impact on glycemic control.The study involved comprehensive data analysis that quantitatively evaluated the correlation between…

via One hundred percent fruit juice does not alter blood sugar levels — Med-Chemist

Tivozanib

• Molecular FormulaC₂₂H₁₉ClN₄O₅
• Average mass454.863 Da

Tivozanib (AV-951) is an oral VEGF receptor tyrosine kinase inhibitor. It has completed a pivotal Phase 3 investigation for the treatment of first line (treatment naive) patients with renal cell carcinoma.^[1] The results from this first line study did not lead to FDA approval, but Tivozanib was approved by the EMA in August 2017^[2]

Originally developed at Kirin Brewery, in January 2007 AVEO Pharmaceuticals acquired an exclusive license to develop and commercialize tivozanib in all territories outside of Asia.

In 2010, orphan drug designation was assigned in the E.U. for the treatment of renal cell carcinoma. In 2011, the compound was licensed to Astellas Pharma and AVEO Pharmaceuticals on a worldwide basis for the treatment of cancer

Tivozanib is an orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3 with potential antiangiogenic and antineoplastic activities. Tivozanib binds to and inhibits VEGFRs 1, 2 and 3, which may result in the inhibition of endothelial cell migration and proliferation, inhibition of tumor angiogenesis and tumor cell death. VEGFR tyrosine kinases, frequently overexpressed by a variety of tumor cell types, play a key role in angiogenesis.

Tivozanib was originally developed by Kyowa Hakko Kirin and in 2007 AVEO Pharmaceutical acquired all the rights of the compound outside Asia. In December 2015, AVEO reached an agreement with EUSA Pharma, which acquired exclusive rights to tivozanib for advanced renal cell carcinoma in Europe, South America, Asia, parts of the Middle East and South Africa.

Tivozanib is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 for first-line treatment of patients with advanced renal cell carcinoma in advanced disease or without VEGFR and mTOR inhibitors and progression after cytokine therapy Advanced renal cell carcinoma patients. Fotivda® is an oral capsule containing 890 μg and 1340 μg of Tivozanib per tablet. The recommended dose is 1 day, each 1340μg, taking three weeks, withdrawal for a week.

• CAS HCL HYDRATE 682745-41-1

ティボザニブ塩酸塩水和物;

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Fotivda is indicated for the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC.

Treatment of advanced renal cell carcinoma

Fotivda : EPAR -Product Information

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004131/WC500239035.pdf

Tivozanib is synthesized in three main steps using well defined starting materials with acceptable specifications.
Adequate in-process controls are applied during the synthesis. The specifications and control methods for intermediate products, starting materials and reagents have been presented. The critical process parameters are duly justified, methodology is presented and control is adequate.
The characterisation of the active substance and its impurities are in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities were well discussed with regards to their origin and characterised.
The active substance is packaged in a low-density polyethylene (LDPE) bag which complies with the EC
directive 2002/72/EC and EC 10/2011 as amended.

Product details

Publication details

Mechanism

An oral quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor.^[3] It was developed by AVEO Pharmaceuticals.^[4] It is designed to inhibit all three VEGF receptors.^[5]

Results

Phase III results on advanced renal cell carcinoma suggested a 30% or 3 months improvement in median PFS compared to sorafenibbut showed an inferior overall survival rate of the experimental arm versus the control arm.^[5][6] The Food and Drug Administration‘s Oncologic Drugs Advisory Committee voted in May 2013 13 to 1 against recommending approval of tivozanib for renal cell carcinoma. The committee felt the drug failed to show a favorable risk-benefit ratio and questioned the equipose of the trial design, which allowed control arm patients who used sorafenib to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition to sorafenib. The application was formally rejected by the FDA in June 2013, saying that approval would require additional clinical studies.^[6]

In 2016 AVEO Oncology published data in conjunction with the ASCO meeting showing a geographical location effect on Overall Survival in the Pivotal PhIII trial^[7]

In 2016 AVEO Oncology announced the start of a second Pivotal PhIII clinical study in Third Line advanced RCC patients. ^[8]

In 2016 EUSA Pharma and AVEO Oncology announced that Tivozanib had been submitted to the European Medicines Agency for review under the Centralised Procedure. ^[9]

In June 2017 the EMA Scientific Committee recommended Tivozanib for approval in Europe, with approval expected in September.^[10]

In August 2017 the European Commission (EC) formally approved Tivozanib in Europe.^[11]

SYNTHESIS

Heterocycles, 92(10), 1882-1887; 2016

CLIP

Paper

Heterocycles (2016), 92(10), 1882-1887

Short Paper | Regular issue | Vol 92, No. 10, 2016, pp. 1882 – 1887
Published online: 5th September, 2016

■ A New and Practical Synthesis of Tivozanib

Chunping Zhu, Yongjun Mao,* Han Wang, and Jingli Xu

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

New and improved synthetic route of tivozanib is described on a hectogram scale. An reduction cyclization process to prepare the key intermediate 6,7-dimethoxyquinolin-4-ol from the 3-(dimethylamino)-1-(2-nitrophenyl)prop-2- en-1-one compound at H2/Ni condition is adopted in good result. Commercial available materials, simple reaction and operation are used, including nitration, condensation, hydrogenation, chlorination and so on, to give the final product in 28.7% yield over six steps and 98.9% purity (HPLC).

PAPER

https://www.sciencedirect.com/science/article/pii/S0960894X15003054

Bioorganic & Medicinal Chemistry Letters

PAPER

J MED CHEM 2005 48 1359

PATENT

WO 2002088110

KUBO, Kazuo; (JP).
SAKAI, Teruyuki; (JP).
NAGAO, Rika; (JP).
FUJIWARA, Yasunari; (JP).
ISOE, Toshiyuki; (JP).
HASEGAWA, Kazumasa; (JP)

Scheme 1 and Scheme 2

Skiing

PATENT

WO 2004035572

MATSUNAGA, Naoki; (JP).
YOSHIDA, Satoshi; (JP).
YOSHINO, Ayako; (JP).
NAKAJIMA, Tatsuo; (JP)

Preparation example: Preparation of N- {2-chloro-1- [(6,7-dimethoxy- 14 1 quinolyl) oxyl] phenyI} – N, – (5-methyl- 3 -isoxazolyl) urea ) Nitration process:

3, 4-Dimethoxyacetophenone (1 500 g) was dissolved in 5:: L 0 ° C of 17% nitric acid (1400 g), and 67% nitric acid (843 0 g) and sodium nitrite g) at a temperature of 5 to 10 ° C. over a period of 2 to 3 hours. After completion of dropping, the mixture was stirred at 5 to 10 ° C. for 1 to 2 hours. Cold water (7. 5 L) was added and after stirring for 30 minutes, filtration and washing with water (30 L). The filtrate was added to water (7. 5 L), neutralized with sodium bicarbonate water, filtered, and washed with water (7 L). The filtrate was dried under reduced pressure to obtain 3, 4-dimethoxy-6-nitroacetophenone (2164 g) (yield = 87.9%).

‘H-NMR (400 MHz, CD C 1 ₃ / p pm); 62. 5 0 (s, 3 H), 3. 9 7 (s, 3H), 3. 9 9 (s, 3 H), 6. 76 (s, 1 H), 7.6 2 (s, 1 H)

(2) Reduction process:

Methanol (5. 4 L), acetic acid (433 g:), 5% palladium / power monobonn (162 g) was added to 3, 4-dimethoxy-6-nitroacetophenone (1082 g) and hydrogen gas The mixture was stirred for 8 hours under pressure (2 Kg / cm 2, 40 ° C. The reaction solution was filtered, washed with methanol (1 L), and the filtrate was neutralized with aqueous sodium hydroxide solution and concentrated under reduced pressure Water (10 L) was added to the concentrate, stirred overnight, filtered and washed with water (7 L) Toluene (4 L) was added to the filtrate, heated to 80 ° C., 1 After stirring for a while, the residue was concentrated under reduced pressure and the residue was filtered, washed with toluene (300 mL), dried under reduced pressure to give 2-amino-4,5-dimethoxa Cetophenone (576 g) was obtained (yield = 6.1%).

‘H-NM (400 MHz, CD C 1 ₃ / p pm); 62. 5 6 (s, 3 H), 3. 84 (s, 3H), 3. 88 (s, 3 H), 6. 10 ( s, 1 H), 7.11 (s, 1 H)

(3) Cyclization step:

Tetrahydrofuran (THF) (5. 3 L) and sodium methoxide (3 1 3 g) were added to 2-amino-4, 5-dimethoxyacetophenone (33 7 g) and the mixture was stirred at 20 ° C for 30 minutes. At 0 ° C, ethyl formate (858 g) was added and stirred at 20 ° C for 1 hour. Water (480 mL) was added at 0 ° C. and neutralized with 1 N hydrochloric acid. After filtering the precipitate, the filtrate was washed with slurry with water (2 L). After filtration, the filtrate was dried under reduced pressure to obtain 6, 7-dimethoxy-141 quinolone (3 52 g) (yield = 8.15%).

‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 63. 8 1 (s, 3 H), 3. 84 (s, 3 H), 5. 94 (d, 1 H), 7. 0 1 (s, 1 H), 7. 43 (s, 1 H), 7. 76 (d, 1 H)

(4) Clovalization process

Toluene (3 L) and phosphorus oxychloride (1300 g) were added to 6, 7-dimethoxy-1-quinolone (105 g), and the mixture was stirred under heating reflux for 1 hour. It was neutralized with aqueous sodium hydroxide solution at 0 ° C. The precipitate was filtered, and then the filtrate was washed with water (10 L) for slurry. After filtering, the filtrate was dried under reduced pressure to obtain 4 1 -chloro- 16, 7-dimethoxyquinoline (928 g) (yield – 87.6 %) _c ‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 63. 9 5 (s, 3 H), 3. 9 6 (s, 3 H), 7. 3 5 (s, 1 H), 7. 43 (s, 1 H) , 7. 54 (d, 1 H), 8. 59 (d, 1 H)

(5) Phenol site introduction step:

4-Amino-3-chlorophenol · HC 1 (990 g) was added to N, N-dimethylacetamide (6. 6 L). Potassium t-butoxide (145 2 g) was added at 0 ° C. and the mixture was stirred at 20 ° C. for 30 minutes. 4-Chloro-6, 7-dimethoxyquinoline (82 5 g) was added thereto, followed by stirring at 115 ° C for 5 hours. After cooling the reaction solution to room temperature, water (8. 3 L) and methanol (8.3 L) were added and the mixture was stirred for 2 hours. After filtration of the precipitate, the filtrate was washed with slurry with water (8. 3 L), filtered, and the filtrate was dried under reduced pressure to give 4- [(4-amino-3-chlorophenol) 6, 7-Dimethoxyquinoline (8 52 g) was obtained (yield = 6 9. 9%).

‘H-NMR (400MH z, DMS 0 – d ₆ / ppm); 63. 9 2 (s, 3 H), 3. 93 (s, 3 H), 5. 4 1 (s, 2 H), 6 (D, 1 H), 6. 89 (d, 1 H), 6. 98 (dd, 1 H), 7. 19 (d, 1 H), 7. 36 (s, 1 H) , 7. 48 (s, 1 H), 8. 43 (d, 1 H)

(6) Ureaization process:

To 3 – amino – 5 – methylisoxazole (377 g), pyridine (1 2 1 5:), N, N – dimethylacetamide (4 L) at 0 ° C was added chlorobutyl carbonate phenyl

(60 1 g) was added dropwise and the mixture was stirred at 20 ° C. for 2 hours. 4- [(4-amino-1-chlorophenol) oxy] -6, 7-dimethoxyquinoline (84 7 g) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 5 hours. The reaction solution was cooled to 5 ° C, then added with MeOH (8. 5 L) and water (8. 5 L) and neutralized with aqueous sodium hydroxide solution. After filtering the precipitate, the filtrate was washed with water (8. 5 L) for slurry. After filtration, the filtrate was dried under reduced pressure to give N- {2-chloro-4- [(6,7-dimethoxy-4-quinolyl) oxy] phenyl] – N, 1- -isoxazolyl) urea (1002 g) was obtained (yield = 86.1%).

‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 62.37 (s, 3 H), 3. 92 (s, 3 H), 3. 94 (s, 3 H), 6. 7 (s, 1 H), 7. 48 (s, 1 H), 7 (s, 1 H), 6. 54 (d, . 5 1 (d, 1 H), 8. 2 3 (d, 1 H), 8. 49

(d, 1 H), 8. 77 (s, 1 H), 1 0.16 (s, 1 H)

PATENT

WO 2011060162

WO 2017037220

CN 106967058

CN 104072492

CN 102532116

CN 102408418

PAPER

Advanced Materials Research Vols. 396-398 (2012) pp 1490-1492

Synthesis of the compounds

The synthesis of 6,7-Dimethoxy-4-quinolinone (2a) The 33.7g (0.173mol) of 2-amino-4,5-dimethoxy acetophenone, 150 ml of methanol and 95.5g (0.69mol) of anhydrous potassium carbonate were added to the 500 ml flask and stirred about 1 h at room temperature. Then, the ethyl formate (75.8g, 0.861mol) was dropped the admixture and reactioned about 2 h in the same temperature. The admixture was filtrated and the 35.2 g white powder compound 2a (C11H11NO3) was obtained with the yield of 81.5% and m.p. 124-125. 1H-NMR (DMSO-d6/ppm): δ 3.81 (s, 3H), 3.84 (s,3H), 5.94 (d,1H), 7.01 (s,1H), 7.43 (s,1H), 7.76 (d,1H). ESI-MS: 206 (M+ +1).

The synthesis of 4-chloro-6,7-dimethoxy-quinoline (2b)The 100 ml of toluene, 15 g (0.103 mol) of phosphorus trichloride and 10.6 g (0.52 mol) compound 2a were added to the 250 ml of three bottles, the obtained mixture was refluxed about 2 h. Then, the reaction mixture was cooled to the room temperature, filtrated and the solid was dried. The 9.3 g similar white powder compound 2b (C11H10ClNO2 ) was obtained with the yield of 96.9% and m.p.138-140 ℃ . 1H-NMR (DMSO-d6/ppm): δ 3.95 (s,3H) , 3.96 (s,3H), 7.35 (s,1H), 7.43 (s,1H), 7.54 (d,1H), 8.59(d,1H). ESI-MS: 225 (M+ +1).

The synthesis of 4-[(4-Amino-3-phenol) oxy]-6,7-dimethoxy-quinoline (2c) The 60 ml of N, N-dimethylformamide, 8.9g (0.05 mol) of 4-amino-3-chlorophenol hydrochloride, 14.5g (0.105 mol) of potassium carbonate and 8.3 g (0.037 mol) compounds 2b were added to the 250 ml of three bottles, the obtained mixture was refluxed about 2 h. Then, the reaction mixture was cooled to the room temperature and the 100 ml of anhydrous ethanol was added. The obtained mixture was stirred about 1 h and filtrated. The filtered product was then dried under the reduced pressure to give the 8.5 g similar white powder compound 2c (C17H15ClN2O3) with the yield of 69.9%. 1H-NMR (DMSO-d6/ppm): δ 3.92 (s,3H), 3.93 (s,3H), 5.41 (s,2H), 6.41 (d,1H), 6.89 (d,1H), 6.98 (dd,1H), 7.19 (d,1H), 7.36 (s,1H), 7.48 (s,1H), 8.43(d,1H). ESI-MS: 331 (M+ +1).

The synthesis of N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl} -N’- (5-methyl-3- isoxazole-yl) urea (2d) The 100 ml of N,N-dimethylformamide, 5.0g (0.051mol) of 3-amino-5- methylisoxa -zole, 7.98 g (0.051mol) of phenyl chloroformate and 17g (0.051mol) compound 2c were added to the 250 ml of three bottles. The mixture was refluxed about 5 h, cooled to room temperature, added the 100 ml of anhydrous ethanol. The obtained mixture was stirred 1 h and filtrated. The filtered product was slurried in water for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give the 20.0g white crystal compound 2d (C22H19ClN4O5) with the yield of 86.1% and the purity of more than 98.5 %. 1H-NMR (DMSO-d6/ppm): δ 2.37 (s,3H), 3.92 (s,3H), 3.94 (s,3H), 6.50 (s,1H), 6.54 (d,1H), 7.26 (dd,1H), 7.39 (s,1H), 7.48 (s,1H), 7.51 (d,1H), 8.23 (d,1H), 8.49 (d,1H), 8.77 (s,1H), 10.16(s,1H). ESI-MS: 456 (M+ +1).

Conclusions Tivozanib was synthesized through the cyclization, chlorinated, condensation reaction with 2-amino-4,5-dimethoxy acetophenone as the starting material. The total yield was 47.5% and the product purity of more than 98.5 %. The synthetic routs and methods of tivozanib are feasible to industrial production owing to the cheap raw materials, mild reaction conditions, stable technology and high yield.

PATENT

https://patents.google.com/patent/CN102532116B/en

Example

[0035] In 250ml three-neck flask, 80ml of chloroform and 22. 0g (0. 16mol) of anhydrous aluminum chloride at room temperature were successively added dropwise l〇.2g (0. 13mol) acetyl chloride, 13.8g (0. i mole) phthalic dimethyl ether, dropwise, stirred at room temperature until the reaction end point (GLC trace). The reaction solution was poured into 500ml diluted hydrochloric acid, with stirring, the organic phase was separated, the aqueous phase was extracted with chloroform and the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 15. Og of white powder Compound Ia (CltlH12O3), mp 48-52 ° C, 83% yield. HKcnT1): 1673,1585,1515,1418 1H-NMR (CDCl3 / ppm):! S 2. 55 (s, 3H), 3.73 (s, 3H), 3.73 (s, 3H), 6.77 (s, lH) , 7.26 (s, lH), 7.31 (s, lH).

[0036] The two 3 Synthesis of 4-dimethoxy-6-nitroacetophenone (Compound lb) Example

[0037] CN 102532116 B specification 4/6

[0038] In 500ml three-neck flask, was added IOOml formic acid and 18g (0 • lmol) compound la, KTC hereinafter 60ml of concentrated nitric acid was added dropwise, dropwise, warmed to 60-70 ° C, stirred for 30min. The reaction mixture was poured into 500ml ice water bath and stirred, suction filtered to give a pale yellow powder 36.9g Compound lb (CltlH11NO5), mp 135-137 ° C, in 82% yield. 1H-NMR (CDCl3 / ppm): S 2. 50 (s, 3H), 3 97 (s, 3H), 3 99 (s, 3H), 6 76 (s, 1H), 7. 62 (… s, 1H).

Example tri-2-amino-4, Synthesis of 5-dimethoxy acetophenone (Compound Ic), [0039] Embodiment

[0041] In 250ml three-neck flask, 36ml of water was added and 7g (0. 125mol) of reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g (0. 025mol) LB compound, stirred for 3h, filtered off with suction, the filtrate is cooled, to give a yellow powder 7g compound Ic (C10H13NO3), mp 106-108 ° C, in 96% yield.1H-NMR (CDCl3Zppm): S 2. 56 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 6.10 (s, lH), 7.11 (s, lH).

Synthesis of four 6, 7-dimethoxy-4-quinolinone (Compound Id), [0042] Example

[0045] A 33. 7g (0 • 173mol) Compound lc, 150ml methanol and 95. 5g (0 • 69mol) of anhydrous potassium carbonate were added to a 500ml three-necked flask, LH stirred at room temperature, was added dropwise 75. 8g (0. 861mol) ethyl, the reaction incubated 2h. Suction filtration and dried, to give 35. 2g of a white powder compound Id (C11H11NO3), mp 124-125 ° C, yield 81.5%. 1H-NMR (DMSO-Cl6Zppm): 8 3.81 (s, 3H), 3.84 (s, 3H), 5.94 (d, 1H), 7.01 (s, 1H), 7.43 (s, lH), 7.76 (d, lH ).

[0046] Example 4- five-chloro-6, 7-dimethoxy-quinoline (compound Ie) Synthesis of

[0047] CN 102532116 B specification 5/6

[0049] The IOOml toluene, 10. 6g (0 • 52mol) Compound Id and 15g (0 • 103mol) phosphorus trichloride force the opening into a 250ml three-necked flask and heated at reflux for 2h, cooled suction filtration and dried to give 9 . 3g white powder compound Ie (C11H10ClNO2), mp 138-14 (TC, yield 87. 6% .1H-NMR (DMS〇-d6 / ppm): 8 3. 95 (s, 3H), 3.96 ( s, 3H), 7.35 (s, lH), 7.43 (s, lH), 7.54 (d, lH), 8.59 (d, lH).

Six 4 [0050] Example – [(4-amino-phenol) oxy] -6, 7-dimethoxy-quinoline (compound If) Synthesis of

[0053] In 250ml three-neck flask, was added 60ml of N, N- dimethylformamide, 8. 9g (0 • 05mol) 4- amino-3-chlorophenol hydrochloride, 14.5g (0.105mol) of potassium carbonate and (0.037 mol) compound le 8.3g, was heated refluxed for 2h. Cooled to room temperature, IOOml ethanol, stirred, filtered off with suction, and dried to give compound 8. 5g If (C17H15ClN2O3), a yield of 69. gQ / jH-NMlUDMSO-dyppm): S 3.92 (s, 3H), 3.93 ( s, 3H), 5.41 (s, 2H), 6.41 (d, 1H), 6.89 (d, 1H), 6.98 (dd, 1H), 7.19 (d, 1H), 7.36 (s, 1H), 7.48 (s , 1H), 8.43 (d, 1H).

-N’- (5- methyl-3-isobutyl – [0054] Example seven N- {[(6,7- dimethoxy-4-quinolyl) oxy] phenyl} -42- chloro oxazolyl) urea (compound Ig) synthesis of

[0056] The IOOml of N, N- dimethylformamide, 5. Og (0.051mol) of 3-amino-5-methylisoxazole, 7. 98g (0 • 051mol) and phenyl chloroformate 17g (0 • 051mol) If a compound was added to 250ml three-necked flask, the reaction was heated at reflux for 5h, cooled to room temperature, ethanol was added IOOml, stirring, filtration, and dried to give 20. Og compound Ig (C22H19ClN4O5), yield 86 . 1%. 1H-NMR (DMS0-d6 / ppm): S 2.37 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 6.50 (s, lH), 6.54 (d, lH), 7.26 (dd , lH), 7.39 (s, lH), 7.48 (s, lH), 7.51 (d, lH), 8.23 ​​(d, lH), 8.49 (d, lH), 8.77 (s, lH), 10.16 (s, lH).

Claims (3)

translated from Chinese

1. An antitumor drugs Si tivozanib to synthesis, the method as follows: The lOOmL of N, N- dimethylformamide, 5 Og of 3-amino-5-methylisoxazole, 7 . 98g phenyl chloroformate and 17g 4- [(4- amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline was added to 250mL three-necked flask, the reaction was heated at reflux for 5h, cooled to rt, lOOmL ethanol was added, stirred, filtered off with suction, and dried to give 20. Og tivozanib, yield 86.1%, the reaction is:

Wherein the 4- [(4-amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline is obtained by the following synthesis method: in 250mL three-neck flask, was added 60mL of N, N- dimethylformamide, 8. 9g 4- amino-3-chloro-phenol hydrochloride, 14. 5g of potassium carbonate and 8. 3g 4- chloro-6, 7-dimethoxy quinoline, was heated at reflux for 2h cooled to room temperature, 100mL of absolute ethanol was added, stirred, filtered off with suction, and dried to obtain 8. 5g 4 – [(4_-amino-3-chlorophenol) oxy] -6, 7-dimethoxy quinoline, close was 69.9%, the reaction is:

Said 4-chloro-6, 7-dimethoxy-quinoline is obtained by the following synthesis method: A mixture of 100mL of toluene, 10 6g 6, 7- dimethoxy-4-quinolone and 15g trichloride phosphorus is added to 250mL three-necked flask and heated at reflux for 2h, cooled suction filtration, and dried to give an off-white powder 9. 3g 4- chloro-6, 7-dimethoxy quinoline, a yield of 87.6%, the reaction formula:

6, 7-dimethoxy-4-quinolone was synthesized by the following method: 33. 7g 2- amino-4, 5-dimethoxy acetophenone, 150 mL of methanol, and 95. 5g anhydrous potassium carbonate was added to the 500mL three-necked flask, stirred at room temperature LH, 75. 8g of ethyl dropwise, the reaction incubated 2h, filtered off with suction, and dried to give 35. 2g of white powder 6, 7-dimethoxy-4 – quinolinone, a yield of 81.5%, the reaction is:

The 2-amino-4,5-dimethoxy acetophenone is synthesized by the following method: In the 250mL three-neck flask, was added 36mL of water and 7g reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g 3, 4-dimethoxy-6-nitroacetophenone, stirred for 3h, filtered off with suction, the filtrate was cooled to give a yellow powder 7g of 2-amino-4,5-dimethoxy acetophenone, yield 96 %, the reaction is:

2. The synthesis method according to claim 1, wherein: said 3,4-dimethoxy-6-nitroacetophenone is 3, 4-dimethoxy acetophenone nitration obtained by a reaction of reaction formula:

3. The method of synthesis according to claim 2, wherein: said 3,4-dimethoxy acetophenone in the catalyst, to give the phthalimido ether is reacted with acetyl chloride by Friedel The reaction is:

References

ivozanib

Names
IUPAC name 1-{2-Chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea
Other names AV-951
Identifiers
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL1289494
ChemSpider	8087481
IUPHAR/BPS	6058
KEGG	D09683
PubChem CID	9911830
UNII	172030934T
InChI[show]
SMILES[show]
Properties
Chemical formula	C22H19ClN4O5
Molar mass	454.87 g·mol−1
Pharmacology
ATC code	L01XE34 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////Tivozanib, ema 2017, ASP-4130, AV-951, KRN-951, Kil-8951, Fotivda, Tivopath, orphan drug, ティボザニブ塩酸塩水和物,

CC1=CC(=NO1)NC(=O)NC2=C(C=C(C=C2)OC3=C4C=C(C(=CC4=NC=C3)OC)OC)Cl

SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

WO-2018032356, Pharmaresources (Shanghai) Co Ltd

CHEN, Ping; (CN).
PENG, Shaoping; (CN).
LI, Yinqiang; (CN).
LI, Dafeng; (CN).
DONG, Xuejun; (CN)

Process for the preparation of lactone derivatives and their intermediates are important precursors for the synthesis of anti-hepatitis C virus agents, including sofosbuvir . Represents a first filing from Pharmaresources (Shanghai) Co Ltd and the inventors on this API. Gilead Sciences , following its acquisition of Pharmasset , has developed and launched sofosbuvir, a pure chiral isomer of PSI-7851, a next-generation HCV uracil nucleotide analog polymerase inhibitor prodrug for once-daily oral use.

Scheme 1

In a similar process reported in CN105418547A (Scheme 2) , the Witting product was epoxidized followed by ring-opening fluorolation by HF-Et₃N or other fluoro-containing reagents, significant amount of regioisomer was observed which was difficult to remove from the oily mixture.

Scheme 4

Examples

Example 1： preparation of 2-fluoropropanoyl chloride (3)

Chlorosulfonic acid (660 mL, 10 mol, 20 eq) was added to a solution of phthaloyl dichloride (1.4 L, 10 mol, 20 eq) and ethyl-2-fluoropropanoate (600 g, 5 mol) at room temperature. The solution was heated at 120 ℃ for 4 hs. 2- (R) -fluoropropanoyl chloride was distilled from the reaction mixture under reduced pressure and recovered as a colourless oil (320 g, 58.2％) . ¹H-NMR (CDCl₃， 400 MHz) ： δ 5.08 (dq, J ＝ 48.8, 6.8 Hz, 1 H) , 1.63 (dd, J ＝22.8, 6.8 Hz, 3 H) .

Example 2： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (4)

n-Butyl lithium (2.5 M in hexane, 30 mL, 75 mmol, 1.1 eq) was added to a solution of 4-(R) -4-isopropyl-2-oxazolidinone (8.8 g, 68.2 mmol, 1 eq) in dry THF (80 mL) at -50 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (6.8 mL, 0.9 eq) was added, and the solution was stirred for 4 hs at -50 ℃. The reaction was then quenched with a saturated solution of NH₄Cl (50 mL) , extracted with MTBE (80 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (Hexane/EtOAc＝ 10/1) and recovered as a brown oil (9 g, 74.8％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 6.00 (dm, J ＝ 49.2Hz, 1 H) , 4.27 -4.53 (m, 3 H) , 2.43 (dm, J ＝ 52.6 Hz, 1 H) , 1.63 (td, J ＝ 23.2Hz, 3 H) , 0.92 (dq, J ＝ 17.8 Hz, 6 H) .

[0206]

Example 3： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (5)

[0207]

n-Butyl lithium (2.5 M in hexane, 75 mL, 187 mmol, 1.1eq) was added to a solution of 4- (S) -4-isopropyl-2-oxazolidinone (22 g, 170 mmol, 1 eq) in dry THF (200 mL) at -50 ℃ under N₂ atomosphere. After 30 min 2-fuoropropanoyl chloride (17 mL, 153 mmol, 0.9 eq) was added, and the solution was stirred for 1 h at -50 ℃. After the starting material was completely consumed, the reaction was then quenched with a saturated solution of NH₄Cl (125 mL) , extracted with MTBE (200 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc＝ 10/1) and recovered as a brown oil (34 g, 83.3％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 5.93 (dm， J ＝ 48.8 Hz, 1 H) , 4.19 -4.17 (m, 3H) , 2.35 (dm, J ＝ 52.8 Hz , 1 H) , 1.55 (td, J ＝ 23.6 Hz, 3 H) , 0.85 (dq, J ＝ 18 Hz, 6 H) .

Example 4： preparation of (4R) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (6)

n-Butyl lithium (2.5 M in hexane, 13.5 mL, 33.74 mmol, 1.1 eq) was added to a solution of (R) -4-phenyloxazolidin-2-one (5 g, 30.67 mmol, 1 eq) in dry THF (75 mL) at -50 ℃ under N₂ atomosphere. After 30 minutes, 2-fuoropropanoyl chloride (3.75 g, 33.74 mmol) was added, and the solution was stirred for 1 h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃(sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (4 g, 55％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.35-7.21 (m, 5 H) , 5.99-5.84 (md, 1 H) , 5.42-5.33 (dd, 1 H) , 4.72 (dd, 1 H) , 4.31 (m, 1 H) , 1.50 (m, 3 H) .

Example 5： preparation of (4s) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7)

n-Butyl lithium (2.5 M in hexane, 67.5 mL, 169 mmol, 1.1 eq) was added to a solution of (s) -4-phenyloxazolidin-2-one (25 g, 153 mmol, 1 eq) in dry THF (375 mL) at -60 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (18.7 g, 169 mmol) was added, and the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (16.5 g, 45.4％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.36-7.20 (m, 5 H) , 5.95-5.80 (md, 1 H) , 5.42-5.30 (dd, 1 H) , 4.71 (dd, 1 H) , 4.30 (m, 1 H) , 1.51 (m, 3 H) .

Example 6： preparation of (4S) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (8)

n-Butyl lithium (2.5 M in hexane, 54.7 mL, 137 mmol, 1.1eq) was added to a solution of (S) -4-benzyloxazolidin-2-one (22 g, 124 mmol, 1eq) in dry THF (220 mL) at -60 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (15.2 g, 137 mmol) was added dropwisely below -50 ℃ , after adding the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc) and recovered as a brown oil (25.8 g, 82.7％) . ¹H-NMR(400 MHz, CDCl₃ ) ： δ 7.29-7.13 (m, 5 H) , 6.01-5.81 (qd, 1 H) , 4.71-4.58 (md, 1 H) , 4.29-4.04 (m, 2 H) , 3.32-3.16 (dd, 1 H) , 2.79-2.74 (m, 1 H) , 1.51 (m, 3 H) .

Example 7： preparation of (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (9)

Use the procedure described in Example 6, (R) -4-benzyloxazolidin-2-one as the start material to give the desired compound (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (yield: 85％) . ¹H-NMR (400 MHz, CDCl₃ ) ： δ 7.27 -7.12 (m, 5 H) , 6.00-5.83 (qd, 1 H) , 4.72-4.55 (md, 1 H) , 4.27-4.03 (m, 2 H) , 3.32 -3.16 (dd, 1 H) , 2.79 -2.72 (m, 1 H) , 1.53 (m, 3 H) .

[0221]

Example 8： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (10)

[0222]

[0223]

n-Butyl lithium (2.5 M in hexane, 48 mL) was added to a solution of (R) -4-isopropyl-5,5-diphenyloxazolidin-2-one (28.1 g) in dry THF (150 mL) at -65 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (16.4 g, 1.5 eq) was added dropwisely below -60 ℃. After adding the solution was stirred for 2 h at -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The crude product was recrystalized in (DCM/PE) to give (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (30 g, 85％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.50 -7.26 (m, 10 H) , 5.89 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.37 (dd, J ＝ 70.8, 3.4 Hz, 1 H) , 2.00 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.70 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.12 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.83 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0224]

Example 9： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11)

[0225]

[0226]

Use the procedure described in Example 8 and (S) -4-isopropyl-5, 5-diphenyloxazolidin-2-one as the start material to give the desired compound (4S) -3- (2-fluoropropanoyl) -4-isopropyl- 5,5-diphenyl oxazolidin-2-one (yield: 82％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.51 -7.27 (m, 10 H) , 5.90 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.38 (dd, J ＝ 70.8, 3.4 Hz, 1H) , 2.01 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.71 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.13 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.84 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0227]

Example 10： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12)

[0228]

[0229]

Method A: TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (10.3 mL, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.2 g, yield: 80％, purity: 97.2％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.89 (dddd, J ＝ 17.1, 10.5, 6.5, 0.8 Hz, 1 H) , 5.42 (d, J ＝17.2 Hz, 1 H) , 5.30 (d, J ＝ 10.1 Hz, 1 H) , 4.68 (dd, J ＝ 14.8, 6.5 Hz, 1 H) , 4.44 (d, J ＝ 4.0 Hz, 1 H) , 4.32 (t, J ＝ 8.5 Hz, 1 H) , 4.24 (dd, J ＝ 9.1, 3.4 Hz, 1 H) , 3.61 (d, J ＝ 6.5 Hz, 1 H) , 2.37 (dd, J ＝ 7.0, 4.1 Hz, 1 H) , 1.73 (s, 1.5 H) , 1.67 (s, 1.5 H) , 0.92 (ddd, J ＝ 7.8, 5.6, 2.4 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) : -158.3 ppm.

[0230]

Method B: TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, (-) -spartein (14.5 g, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with NH₄Cl (sat 50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (9.4 g, yield: 75％, purity: 96.5％) .

[0231]

Example 11： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (13)

[0232]

[0233]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.4 g, yield: 83％, purity: 92.8％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.92 (d， J ＝ 1.1 Hz， 1 H) ， 5.44 (d, J ＝ 17.2 Hz, 1 H) , 5.34 -5.28 (m, 1 H) , 4.73 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.43 (m, 1 H) , 4.37 -4.30 (m, 1H) , 4.27 -4.21 (m, 1 H) , 2.43 -2.31 (m, 1H) , 1.77 (s, 1.5 H) , 1.71 (s, 1.5 H) , 0.91 (dd, J ＝ 12.1, 7.0 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -159.1ppm.

[0234]

Example 12： preparation of (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one

[0235]

[0236]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4S) -4-benzyl-3-(2-fluoro propanoyl) oxazolidin-2-one (8) (12.3 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, TMEDA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at -78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL*2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (13 g, yield: 86％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 7.38 -7.27 (m, 3 H) , 7.22 (d, J ＝ 6.8 Hz, 2 H) , 5.96 (dddd, J ＝ 17.0, 10.5, 6.2, 1.2 Hz, 1 H) , 5.47 (d, J ＝ 17.2 Hz, 1 H) , 5.35 (d, J ＝ 10.5 Hz, 1 H) , 4.75 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.66 (td, J ＝ 7.1, 3.6 Hz, 1 H) , 4.23 (dd, J ＝ 16.3, 5.0 Hz, 2 H) , 3.33 (dd, J ＝ 13.3, 3.3 Hz, 1 H) , 2.76 (dd, J ＝13.3, 10.0 Hz, 1 H) , 1.81 (s, 1.5 H) , 1.76 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0237]

Example 13： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0238]

[0239]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, Et₃N (12.5 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (12 g, yield: 83％, purity: 90.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.43 -7.30 (m, 5 H) , 5.81 (dddd, J ＝ 17.0, 10.5, 6.3, 1.1 Hz, 1 H) , 5.46 (dd, J ＝ 8.4, 5.1 Hz, 1 H) , 5.37 (dt, J ＝ 17.2, 1.2 Hz, 1 H) , 5.23 (d, J ＝ 10.4 Hz, 1 H) , 4.74 (t, J ＝ 8.7 Hz, 1 H) , 4.64 (dd, J ＝ 13.5, 6.3 Hz, 1 H) , 4.31 (dd, J ＝ 8.9, 5.2 Hz, 1 H) , 1.60 (s, 1.5H) , 1.55 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0240]

Example 14： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0241]

[0242]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoro propan oyl) -4-phenyloxazolidin-2-one (6) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, DIPEA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (11.1 g, yield: 77％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.44 -7.29 (m, 5 H) , 5.74 -5.63 (m, 1 H) , 5.48 (dd, J ＝ 8.4, 5.3 Hz, 1 H) , 5.35 -5.26 (m, 1 H) , 5.15 (d, J ＝ 10.5 Hz, 1 H) , 4.73 (t, 1 H) , 4.52 (dd, J ＝ 14.8, 6.2 Hz, 1 H) , 4.28 (dd, J ＝ 8.9, 5.3 Hz, 1 H) , 1.68 (s, 1.5 H) , 1.63 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -161.93 ppm.

[0243]

Example 15： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one

[0244]

[0245]

Method 1: LiHMDS (1 M in THF, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry THF (100 mL) at -20 ℃ under N₂ atomosphere. After 1.5 hs, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -20 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step. m/z (ES+) : 412 [M+H] +.

[0246]

Method 2: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5g, 2eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (40 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (17.82 g, yield: 88％ (Internal standard yield) .

[0247]

Method 3: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, DIPEA (13 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (16.2 g, yield: 80％ (Internal standard yield ) .

[0248]

Method 4: (C₆H₁₂) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (14.6 g, yield: 80％ (Internal standard yield ) .

[0249]

Example 16： preparation of (3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydro furan-2 (3H) -one

[0250]

Method 1:

[0251]

[0252]

N-Bromosuccinimide (19.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in DME/H₂O (4: 1, 130ml) at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (bromomethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18a) . ¹H-NMR (400 MHz, CDCl₃) : δ 4.62 -4.53 (m, 1 H) , 4.37 (dd, J ＝ 3.0, 1.9 Hz, 1 H) , 3.73 (dd, J ＝ 10.1, 8.7 Hz, 1 H) , 3.60 (ddd, J ＝ 10.1, 5.8, 1.9 Hz, 1 H) , 2.59 (dd, J ＝ 2.5, 1.7 Hz, 1 H) , 1.67 (d, J ＝ 22.7 Hz, 3 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -172.248 ppm.

[0253]

Alternative Method 1a: Br₂ (17.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in MeCN/H₂O (4: 1, 130 mL) between -5 ℃ to -10 ℃ and stirred for 2 hs . After the reaction was complete, Na₂S₂O₃ (10％, 20 ml) was added and stirred for 0.5 h at rt then separated . The water phase was re-extracted by DCM (50 mL *2) , the combine organic phase was concentrated, dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to used in the next step.

[0254]

Alternative Method 1b: N-chlorosuccinimide (13.3 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in 100ml CH3CN at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (chloromethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18b) , m/z (ES+) : 183 [M+H] +.

[0255]

The related lactone 18a or 18b (0.14eq) was dissolved in EtOH (104 mL) , then KOH (30％in H₂O, 50 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into the mixture and reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (yield: 80～85％) . m/z (ES+) : 165 [M+H] +. ¹H-NMR (400 MHz, MeOD) : δ 4.34 (ddd， J ＝ 8.0， 4.2， 2.3 Hz， 1 H) , 4.02 (ddd, J ＝ 17.6, 15.2, 5.1 Hz, 2 H) , 3.74 (dd, J ＝ 13.0, 4.2 Hz, 1 H) , 1.60 (s, 1.5 H) , 1.54 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, MeOD) : -172.47 ppm.

[0256]

Method 2:

[0257]

[0258]

Osmium tetroxide (OsO4) (0.1 equiv) was added in one portion to a stirring solution of the (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in acetone/water (8: 1 ratio) under nitrogen. After 5 min, NMO (N-methylmorpholine N-oxide, 60％by weight in water, 1.1 equiv) was added in one portion and stirred for 24 h. The resulting reaction mixture was concentrated under reduced pressure and immediately purified via column chromatography to obtain the desired lactone (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (21) , yield: 87％, m/z (ES+) : 165 [M+H] +.

[0259]

15.1 g (92.3 mmol) (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydrofuran-2 (3H) -one (21) was dissolved in 25 mL pyridine and 11.1 g (96.9 mmol) methanesulfonyl chloride was slowly added dropwise at -25 degC. It was stirred for a day at -25 deg and a day at -10 deg. After adding 20 mL of ethyl acetate and 20 mL water, the solvent was removed on a rotary evaporator. After neutralization with dilute sodium hydrogen carbonate solution, the solvent was removed in vacuo again, the residue was digested with ethyl acetate, the eluate was dried with magnesium sulfate and concentrated in vacuo to dryness. Recrystallization from ethyl acetate/diethyl ether gave a colorless crystalline product ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate (18c) . Yield: 31 ％.

[0260]

33.8g of ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate was disslolved in EtOH (104 mL) , then KOH (16.8 g , 3 eq) in H₂O (52 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into, the mixture was reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (10.5 g, yield: 45％) .

[0261]

Alternative reagents and reactions to those disclosed above can also be employed. For example, 4-methylbenzene-1-sulfonyl chloride can be used instead of methanesulfonyl chloride. Moreover, primary alcohol can be converted to chloro or bromo by using Ph₃P/CCl4, PPh₃P/CBr₄, PPh₃/NCS, PPh₃/NBS, or PPh₃/C₂Cl₆ as a halogenation reagent. The desired product can be obtained in good yields using these reagents and reactions.

[0262]

Method 3: Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methyl pent-4-enoyl) -4-isopropyloxazolidin-2-one (13) as starting material provides the desired compound 19 (yield: 63.2％)

[0263]

Method 4： Using a method analogous to that described as hereinabove and (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one (14) as starting material provides the desired compound 19 (yield: 71.8％)

[0264]

Method 5： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one (15) as the start material gives the desired compound 19 (yield: 65.7％)

[0265]

Method 6： Using a method analogous to that described as hereinabove and (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-oneas (16) starting material provides the desired compound 19 (yield: 59.5％)

[0266]

Method 7： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (17) as starting material gives the desired compound 19 (yield: 66.7％)

[0267]

Example 17: preparation of ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetra hydro fur an-2-yl) methyl benzoate

[0268]

[0269]

(3R, 4R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (19) (25.4 g, 0.154 mol) obtained from example 3 was dissolved in 200 ml of THF. 4- (Dimethylamino) -pyridine (8.2 g, 0.066 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixture was cooled to 0 ℃. Benzoyl chloride (46.0 g, 0.33 mol) was added, and the mixture was warmed to 35-40 ℃ in the course of 2 hs. Upon completion of the reaction, water (100 mL) was charged and the mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tert-butyl ether (100 mL) was added and the mixture was stirred for 30 min. Phases were separated and the organic phase was washed with saturated NaCl solution (100 mL) . The combined organic phases were dried over Na₂SO₄ (20 g) filtered and the filtrate was evaporated to dryness. The residue was taken up in iso-propanol (250 mL) and the mixture was warmed to 50 ℃ and stirred for 60 min, then cooled down to 0 ℃ and further stirred for 60 min. The solid was filtered and the wet cake was washed with i-propanol (50 mL) and then dried under vacuum. The title compound ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methyl benzoate (47.5 g, 82.6 ％yield) was obtained. ‘H-NMR (CDCl₃, 400 MHz) : 8.10 (d, 7＝7.6 Hz, 2H) , 8.00 (d, 7＝7.6 Hz, 2H) , 7.66 (t, 7＝7.6 Hz, IH) , 7.59 (t, 7＝7.6 Hz, IH) , 7.50 (m, 2H) , 7.43 (m, 2H) , 5.53 (dd, 7＝17.6, 5.6 Hz, IH) , 5.02 (m, IH) , 4.77 (dd, 7＝12.8, 3.6 Hz, IH) , 4.62 (dd, 7＝12.8, 5.2 Hz, IH) , 1.77 (d, 7＝23.2 Hz, 3H) .

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

PADELIPORFIN

759457-82-4; 457P824,

RN: 759457-82-4
UNII: EEO29FZT86

3-[(2S,3S,12R,13R)-8-acetyl-13-ethyl-20-(2-methoxy-2-oxoethyl)-3,7,12,17-tetramethyl-18-(2-sulfoethylcarbamoyl)-2,3,12,13-tetrahydroporphyrin-22,24-diid-2-yl]propanoic acid;palladium(2+)

 (SP-4-2)-[(7S,8S,17R,18R)-13-acetyl-18-ethyl-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato (4-)-kN21,kN22,kN23,kN24] palladate(2-)

Chemical Formula: C37H41K2N5O9PdS
Molecular Weight: 916.43

cas 698393-30-5

WST11; WST-11; WST 11; Stakel; padeliporfin; palladiumbacteriopheophorbide monolysine taurine.

Palladate(2-​)​, [(7S,​8S,​17R,​18R)​-​13-​acetyl-​18-​ethyl-​7,​8-​dihydro-​5-​(2-​methoxy-​2-​oxoethyl)​-​2,​8,​12,​17-​tetramethyl-​3-​[[(2-​sulfoethyl)​amino]​carbonyl]​-​21H,​23H-​porphine-​7-​propanoato(4-​)​-​κN²¹,​κN²²,​κN²³,​κN²⁴]​-​, potassium (1:2)​, (SP-​4-​2)​-

Tookad : EPAR -Product Information

Product details

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Tookad is indicated as monotherapy for adult patients with previously untreated, unilateral, low risk, adenocarcinoma of the prostate with a life expectancy ≥ 10 years and:

• Clinical stage T1c or T2a;
• Gleason Score ≤ 6, based on high-resolution biopsy strategies;
• PSA ≤ 10 ng/mL;
• 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0.15 ng/mL/cm³.

Photodynamic therapy (PDT) is a non-surgical treatment of tumors in which non-toxic drugs and non-hazardous photosensitizing irradiation are combined to generate cytotoxic reactive oxygen species in situ. This technique is more selective than the commonly used tumor chemotherapy and radiotherapy. To date, porphyrins have been employed as the primary photosensitizing agents in clinics. However, current sensitizers suffer from several deficiencies that limit their application, including mainly: (1) relatively weak absorption in the visible spectral range which limits the treatment to shallow tumors; (2) accumulation and long retention of the sensitizer in the patient skin, leading to prolonged (days to months) skin phototoxicity; and (3) small or even no differentiation between the PDT effect on illuminated tumor and non-tumor tissues. The drawbacks of current drugs inspired an extensive search for long wavelength absorbing second-generation sensitizers that exhibit better differentiation between their retention in tumor cells and skin or other normal tissues.

In order to optimize the performance of the porphyrin drugs in therapeutics and diagnostics, several porphyrin derivatives have been proposed in which, for example, there is a central metal atom (other than Mg) complexed to the four pyrrole rings, and/or the peripheral substituents of the pyrrole rings are modified and/or the macrocycle is dihydrogenated to chlorophyll derivatives (chlorins) or tetrahydrogenated to bacteriochlorophyll derivatives (bacteriochlorins).

Due to their intense absorption in favorable spectral regions (650-850 nm) and their ready degradation after treatment, chlorophyll and bacteriochlorophyll derivatives have been identified as excellent sensitizers for PDT of tumors and to have superior properties in comparison to porphyrins, but they are less readily available and more difficult to handle.

Bacteriochlorophylls are of potential advantage compared to the chlorophylls because they show intense near-infrared bands, i.e. at considerably longer wavelengths than chlorophyll derivatives.

The spectra, photophysics, and photochemistry of native bacteriochlorophylls (Bchls) have made them optimal light-harvesting molecules with clear advantages over other sensitizers presently used in PDT. In particular, these molecules have a very high extinction coefficient at long wavelengths (λ_max=760-780 nm, ε=(4-10)xl0⁴ M^-1cm^-1), where light penetrates deeply into tissues. They also generate reactive oxygen species (ROS) at a high quantum yield (depending on the central metal).

Under normal delivery conditions, i.e. in the presence of oxygen at room temperature and under normal light conditions, the BChl moieties are labile and have somewhat lower quantum yields for triplet state formation, when compared with, e.g., hematoporphyrin derivative (HPD). However, their possible initiation of biological redox reactions, favorable spectral characteristics and their ready degradation in vivo result in the potential superiority of bacteriochlorophylls over other compounds, e.g. porphyrins and chlorophylls, for PDT therapy and diagnostics and for killing of cells, viruses and bacteria in samples and in living tissue. Chemical modification of bacteriochlorophylls is expected to further improve their properties, but this has been very limited due to lack of suitable methods for the preparation of such modified bacteriochlorophylls .

The biological uptake and PDT efficacy of metal-free derivatives of Bchl have been studied with the objective to manipulate the affinity of the sensitizers to the tumor cellular compartment. Cardinal to this approach is the use of highly lipophilic drugs that may increase the accumulation of the drug in the tumor cells, but also renders its delivery difficult. In addition, the reported biodistribution shows significant phototoxic drug levels in non-tumor tissues over prolonged periods (at least days) after administering the drug.

In applicant’s previous Israel Patent No. 102645 and corresponding EP 0584552, US 5,726,169, US 5,726,169, US 5,955,585 and US 6,147,195, a different approach was taken by the inventors. Highly efficient anti- vascular sensitizers that do not extravasate from the circulation after administration and have short lifetime in the blood were studied. It was expected that the inherent difference between vessels of normal and abnormal tissues such as tumors or other tissues that rely on neovessels, would enable relatively selective destruction of the abnormal tissue. Hence, it was aimed to synthesize Bchl derivatives that are more polar and, hence, have better chance to stay in the vascular compartment, where they convey the primary photodynamic effect. To this end, the geranylgeranyl residue at the C-17 position of Bchl a (Compound 1, depicted in Scheme 1 herein) has been replaced by various residues such as amino acids, peptides, or proteins, which enhance the sensitizer hydrophilicity. One particular derivative, Bchl-Ser (Scheme 1, Compound 1, wherein R is seryl), was found to be water-soluble and highly phototoxic in cell cultures. Following infraperitoneal injection, the Bchl-Ser cleared from the mouse blood and tissues bi-exponentially in a relatively short time (t_1/2~2 and 16 h, respectively). Clearance from the circulation was even faster following intravenous injection. Under the selected treatment protocol (light application within minutes after drug injection), phototoxicity was predominantly conferred to the tumor vasculature (Rosenbach-

Belkin et al., 1996; Zilberstein et al., 2001 and 1997). However, unfortunately, like native Bchl, the Bchl-Ser derivative undergoes rapid photo-oxidation, forming the corresponding 2-desvinyl-2-acetyl-chlorophyllide ester and other products.

To increase the stability of the Bchl derivatives, the central Mg atom was replaced by Pd in the later applicant’s PCT Publication WO 00/33833 and US 6,569,846. This heavy atom was previously shown to markedly increase the oxidation potential of the Bchl macrocycle and, at the same time, to greatly enhance the intersystem-crossing (ISC) rate of the molecule to its triplet state. The metal replacement was performed by direct incorporation of Pd²⁺ ion into a Bpheid molecule, as described in WO 00/33833. Based on the pigment biodistribution and pharmacokinetics, it was assumed that the derivative Pd-Bpheid remained in the circulation for a very short time with practically no extravasation to other tissues, and is therefore a good candidate for vascular-targeting PDT that avoids skin phototoxicity. The treatment effect on the blood vessels was demonstrated by intravital microscopy of treated blood vessels and staining with Evans-Blue. Using a treatment protocol with a minimal drug-to-light interval, Pd-Bpheid (also designated Tookad) was found to be effective in the eradication of different tumors in mice, rats and other animal models and is presently entering Phase I/II clinical trials in patients with prostate cancer that failed radiation therapy (Chen et al, 2002; Schreiber et al., 2002; Koudinova et al., 2003).

Because of its low solubility in aqueous solutions, the clinical use of Pd-Bpheid requires the use of solubilizing agents such as Cremophor that may cause side effects at high doses. It would be highly desirable to render the Pd-Bpheid water-soluble while retaining its physico-chemical properties. Alternatively, it would be desirable to prepare Bchl derivatives that are cytophototoxic and, at the same time, more water-soluble than Pd-Bpheid itself. Such water solubility is expected to further enhance the drug retention in the circulation and, thereby, the aforementioned selectivity. In addition, having no need to use carriers such as detergents or lyposomes, may prevent side effects.

SYNTHESIS

START FROM CAS 17499-98-8, Phorbine, magnesium deriv., Bacteriochlorophyll a_P

PADELIPORFIN

Paper

Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: Synthesis, solubility, phototoxicity and the effect of serum proteins
Photochemistry and Photobiology (2005), 81, (July/Aug.), 983-993

PAPER

Journal of Medicinal Chemistry (2014), 57(1), 223-237

With the knowledge that the dominant photodynamic therapy (PDT) mechanism of 1a (WST09) switched from type 2 to type 1 for 1b (WST11) upon taurine-driven E-ring opening, we hypothesized that taurine-driven E-ring opening of bacteriochlorophyll derivatives and net-charge variations would modulate reactive oxygen species (ROS) photogeneration. Eight bacteriochlorophyll a derivatives were synthesized with varying charges that either contained the E ring (2a–5a) or were synthesized by taurine-driven E-ring opening (2b–5b). Time-dependent density functional theory (TDDFT) modeling showed that all derivatives would be type 2 PDT-active, and ROS-activated fluorescent probes were used to investigate the photogeneration of a combination of type 1 and type 2 PDT ROS in organic- and aqueous-based solutions. These investigations validated our predictive modeling calculations and showed that taurine-driven E-ring opening and increasing negative charge generally enhanced ROS photogeneration in aqueous solutions. We propose that these structure–activity relationships may provide simple strategies for designing bacteriochlorins that efficiently generate ROS upon photoirradiation.

Modulation of Reactive Oxygen Species Photogeneration of Bacteriopheophorbide a Derivatives by Exocyclic E-Ring Opening and Charge Modifications

REFERENCES

1: Kessel D, Price M. Evaluation of DADB as a Probe for Singlet Oxygen Formation during Photodynamic Therapy. Photochem Photobiol. 2012 Feb 2. doi: 10.1111/j.1751-1097.2012.01106.x. [Epub ahead of print] PubMed PMID: 22296586.

2: Betrouni N, Lopes R, Puech P, Colin P, Mordon S. A model to estimate the outcome of prostate cancer photodynamic therapy with TOOKAD Soluble WST11. Phys Med Biol. 2011 Aug 7;56(15):4771-83. Epub 2011 Jul 13. PubMed PMID: 21753234.

3: Chevalier S, Anidjar M, Scarlata E, Hamel L, Scherz A, Ficheux H, Borenstein N, Fiette L, Elhilali M. Preclinical study of the novel vascular occluding agent, WST11, for photodynamic therapy of the canine prostate. J Urol. 2011 Jul;186(1):302-9. Epub 2011 May 20. PubMed PMID: 21600602.

4: Dandler J, Wilhelm B, Scheer H. Photochemistry of bacteriochlorophylls in human blood plasma: 1. Pigment stability and light-induced modifications of lipoproteins. Photochem Photobiol. 2010 Mar-Apr;86(2):331-41. Epub 2009 Nov 23. PubMed PMID: 19947966.

5: Dandler J, Scheer H. Inhibition of aggregation of [Pd]-bacteriochlorophyllides in mesoporous silica. Langmuir. 2009 Oct 20;25(20):11988-92. PubMed PMID: 19772311.

6: Ashur I, Goldschmidt R, Pinkas I, Salomon Y, Szewczyk G, Sarna T, Scherz A. Photocatalytic generation of oxygen radicals by the water-soluble bacteriochlorophyll derivative WST11, noncovalently bound to serum albumin. J Phys Chem A. 2009 Jul 16;113(28):8027-37. PubMed PMID: 19545111.

7: Moore CM, Pendse D, Emberton M. Photodynamic therapy for prostate cancer–a review of current status and future promise. Nat Clin Pract Urol. 2009 Jan;6(1):18-30. Review. PubMed PMID: 19132003.

8: Preise D, Oren R, Glinert I, Kalchenko V, Jung S, Scherz A, Salomon Y. Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity. Cancer Immunol Immunother. 2009 Jan;58(1):71-84. Epub 2008 May 17. PubMed PMID: 18488222.

9: Fleshker S, Preise D, Kalchenko V, Scherz A, Salomon Y. Prompt assessment of WST11-VTP outcome using luciferase transfected tumors enables second treatment and increase in overall therapeutic rate. Photochem Photobiol. 2008 Sep-Oct;84(5):1231-7. Epub 2008 Apr 8. PubMed PMID: 18399928.

10: Berdugo M, Bejjani RA, Valamanesh F, Savoldelli M, Jeanny JC, Blanc D, Ficheux H, Scherz A, Salomon Y, BenEzra D, Behar-Cohen F. Evaluation of the new photosensitizer Stakel (WST-11) for photodynamic choroidal vessel occlusion in rabbit and rat eyes. Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1633-44. PubMed PMID: 18385085.

11: Fabre MA, Fuseau E, Ficheux H. Selection of dosing regimen with WST11 by Monte Carlo simulations, using PK data collected after single IV administration in healthy subjects and population PK modeling. J Pharm Sci. 2007 Dec;96(12):3444-56. PubMed PMID: 17854075.

12: Brandis A, Mazor O, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: synthesis, solubility, phototoxicity and the effect of serum proteins. Photochem Photobiol. 2005 Jul-Aug;81(4):983-93. PubMed PMID: 15839743.

13: Mazor O, Brandis A, Plaks V, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. WST11, a novel water-soluble bacteriochlorophyll derivative; cellular uptake, pharmacokinetics, biodistribution and vascular-targeted photodynamic activity using melanoma tumors as a model. Photochem Photobiol. 2005 Mar-Apr;81(2):342-51. PubMed PMID: 15623318.

14: Plaks V, Posen Y, Mazor O, Brandis A, Scherz A, Salomon Y. Homologous adaptation to oxidative stress induced by the photosensitized Pd-bacteriochlorophyll derivative (WST11) in cultured endothelial cells. J Biol Chem. 2004 Oct 29;279(44):45713-20. Epub 2004 Aug 31. PubMed PMID: 15339936.

////////PADELIPORFIN,  WST11, WST-11, WST 11, Stakel, padeliporfin, palladiumbacteriopheophorbide monolysine taurine, EU 2017, EMA 2017

CCC1C(C2=NC1=CC3=C(C(=C([N-]3)C(=C4C(C(C(=N4)C=C5C(=C(C(=C2)[N-]5)C(=O)C)C)C)CCC(=O)O)CC(=O)OC)C(=O)NCCS(=O)(=O)O)C)C.[Pd+2]

ALOFISEL

darvadstrocel

Cx-601

On 14 December 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Alofisel, intended for the treatment of complex perianal fistulas in patients with Crohn’s disease. As Alofisel is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. Alofisel was designated as an orphan medicinal product on 8 October 2009. The applicant for this medicinal product is Tigenix, S.A.U.

Alofisel will be available as a suspension for injection (5 million cells/ml). The active substance of Alofisel is darvadstrocel. Darvadstrocel contains expanded adipose stem cells which, once activated, impair proliferation of lymphocytes and reduce the release of pro-inflammatory cytokines at inflammation sites. This immunoregulatory activity reduces inflammation and may allow the tissues around the fistula tract to heal.

The benefits with Alofisel are its ability to improve the healing process of complex perianal fistulas in patients with Crohn’s disease. The most commonly reported side effects include anal abscess and fistula, as well as procedural pain and proctalgia.

The full indication is: “Alofisel is indicated for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy. Alofisel should be used after conditioning of fistula, see section 4.2.”

It is proposed that Alofisel be administered by specialist physicians experienced in the diagnosis and treatment of conditions for which Alofisel is indicated.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

New medicine to treat perianal fistulas in patients with Crohn’s disease

CHMP summary of positive opinion for Alofisel

Cx601

Cx601 is a local administration of expanded adipose-derived stem cells (eASCs) for the treatment of complex perianal fistulas in Crohn’s disease patients. The treatment is administered as a single dose and has been proven to have long-term efficacy in the healing of complex perianal fistulas in Crohn’s disease patients (ADMIRE-CD study completed in 2015 with positive 2 year follow-up data). The 24-week results of this trial were published in The Lancet in July 2016.

Cx601 has been designated as an orphan drug by the EMA and SwissMedic, in Switzerland.

On 4th July 2016, Takeda Pharmaceuticals acquired an exclusive right to develop and commercialize Cx601 for complex perianal fistulas in Crohn’s disease patients outside of the U.S. Takeda is a leading pharmaceutical company in the gastroenterology space. TiGenix retains full rights to the product in the US as well as to the development of Cx601 in other indications.

• OriginatorCellerix
• DeveloperLa Fundacion para la Investigacion Biomedica del Hospital Universitario La Paz; Takeda; TiGenix
• ClassStem cell therapies
• Mechanism of ActionCell replacements

• Orphan Drug StatusYes – Rectal fistula
• New Molecular EntityNo

Highest Development Phases

• PreregistrationRectal fistula
• No development reportedRectovaginal fistula

Most Recent Events

• 15 Dec 2017Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) recommend approval for darvadstrocel for Rectal fistula in European Union
• 14 Dec 2017TiGenix in-licenses patents related to adipose-derived mesenchymal stem cells from Mesoblast
• 16 Nov 2017Cx 601 is now called darvadstrocel

/////////////////ALOFISEL, darvadstrocel, Cx-601, eu 2017, ema 2017

All my hard work gets International recognition and makes me feel to work more
Bestowed on me an International award for Outstanding contribution in Pharma at World Health and wellness Congress award, 14th Feb, 2018, at Taj Lands ends, Bandra, Mumbai, India

My family Shobha Crasto Lionel crastoAishal Crasto too get all credit for sacrifices done to help me achieve this honour.

DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent

CRYSTAL FORM OF ANDROGEN RECEPTOR ANTAGONIST MEDICATION, PREPARATION METHOD THEREFOR, AND USE

一种式(I)所示ODM-201的晶型B，其特征在于，其X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°处有特征峰。

Novel crystalline forms of an androgen receptor antagonist medication, particularly ODM-201 (also known as darolutamide; designated as Forms B and C), processes for their preparation and compositions comprising them are claimed. Represents a first filing from Crystal Pharmaceutical Co Ltd and the inventors on this API.

Orion and licensee Bayer are codeveloping darolutamide, an androgen receptor antagonist, for treating castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer.

专利CN102596910B公开了ODM-201的制备方法，但并未公开任何的晶型信息。专利WO2016120530A1公开了式(I)(CAS号：1297538-32-9)所示的晶型I，式(Ia)(CAS号：1976022-48-6)所示的晶型I’和式(Ib)(CAS号：1976022-49-7)所示的晶型I”。文献Expert Rev.Anticancer Ther.15(9),(2015)已报道：ODM-201是由1:1比例的(Ia)和(Ib)两种非对应异构体组成，即为式(I)所示结构。因此，现有关于ODM-201的晶型只有晶型I报道。

Prostate cancer has become an important disease threatening the health of men. Its incidence is higher in western countries and shows a year-by-year upward trend. In the past, Asian countries with a lower incidence of the disease have also seen an increase in the number of patients in recent years. Clinical treatment of prostate cancer commonly used methods are surgical resection, radiation therapy and blocking androgen endocrine therapy. Androgen is closely related to the growth of prostate and the occurrence of prostate cancer. Therefore, endocrine therapy has become an effective way to treat prostate cancer. The method includes orchidectomy, estrogen therapy, gonadotropin-releasing hormone analog therapy, gonadotropin-releasing hormone antagonist therapy, androgen antagonistic therapy, etc., wherein androgen antagonist therapy can be both early treatment of prostate cancer can also be combined Surgery for adjuvant therapy is currently one of the main clinical treatment of prostate cancer. Androgen receptor as a biological target of androgen play an important role in the field of biomedical research.

Clinical trials have shown that exogenous androgen administration to patients with prostate cancer can lead to an exacerbation of the patient’s condition; conversely, if the testicles are removed and the level of androgens in the patient is reduced, the condition is relieved, indicating that androgens contribute to the development of prostate cancer Significant influence. According to receptor theory, androgen must bind with androgen receptor (AR) to cause subsequent physiological and pathological effects, which is the basis for the application of androgen receptor (AR) antagonist in the treatment of prostate cancer. In vitro experiments have shown that AR antagonists can inhibit prostate cell proliferation and promote apoptosis. Depending on the chemical structure of AR antagonists, they can be divided into steroidal AR antagonists and non-steroidal AR antagonists. Non-steroidal anti-androgen activity is better, there is no steroid-like hormone-like side effects, it is more suitable for the treatment of prostate cancer.

ODM-201 (BAY-1841788) is a non-steroidal oral androgen receptor (AR) antagonist used clinically to treat prostate cancer. The binding affinity of ODM-201 to AR was high, with Ki = 11nM and IC50 = 26nM. Ki was the dissociation constant between ODM-201 and AR complex. The smaller the value, the stronger the affinity. half maximal inhibitory concentration “refers to the half-inhibitory concentration measured, indicating that a certain drug or substance (inhibitor) inhibits half the amount of certain biological processes. The lower the value, the stronger the drug’s inhibitory ability. In addition, ODM-201 does not cross the blood-brain barrier and can reduce neurological related side effects such as epilepsy. Bayer Corporation has demonstrated in clinical trials the effectiveness and safety of ODM-201, demonstrating its potential for treating prostate cancer.

The chemical name of ODM-201 is: N – ((S) -l- (3- (3- chloro-4-cyanophenyl) -lH-pyrazol-l-yl) -propan- The chemical name contains the tautomer N – ((S) -1- (3- (3- 4-cyanophenyl) -1H-pyrazol- 1 -yl) -propan-2-yl) -5- (1 -hydroxyethyl) 1297538-32-9, the structural formula is shown in formula (I) :

The different crystalline forms of solid chemical drugs can lead to differences in their solubility, stability, fluidity and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compounds (see K. Knapman, Modern Drug Discovery, 3, 53 -54,57,2000.), Resulting in differences in clinical efficacy. It has been found that new crystalline forms (including anhydrates, hydrates, solvates, etc.) of the active ingredients of the medicinal product may give rise to more processing advantages or provide substances with better physical and chemical properties such as better bioavailability, storage stability, ease Processed, purified or used as an intermediate to promote conversion to other crystalline forms. The new crystalline form of the pharmaceutical compound can help improve the performance of the drug and broaden the choice of starting material for the formulation.

Patent CN102596910B discloses the preparation of ODM-201, but does not disclose any crystal form information. Patent WO2016120530A1 discloses a crystalline form I represented by the formula (I) (CAS number: 1297538-32-9), a crystalline form I ‘represented by the formula (Ia) (CAS number: 1976022-48-6) and a compound represented by the formula (CAS No. 1976022-49-7). Document Expert Rev. Anticancer Ther. 15 (9), (2015) It has been reported that ODM-201 is composed of a 1: 1 ratio of (Ia) And (Ib), which is the structure shown in Formula (I), so the only existing crystal form I for ODM-201 is reported.

However, the lower solubility of Form I and the high hygroscopicity, and the preparation of Form I requires the use of highly toxic acetonitrile solvents, which are carcinogenic in animals and are the second class of solvents that should be controlled during the process development stage. Form I preparation method is more complex, long preparation cycle, the process needs heating, increasing the cost of industrial preparation, is not conducive to industrial production. In order to overcome the above drawbacks, there is still a need in the art for a systematic and comprehensive development of other polymorphs of ODM-201 of formula (I), simplifying the preparation thereof, enabling its pharmacological development and releasing its potential, Preparation of a better formulation of the drug ingredients.

The inventors found through experiments that Form B and Form C of the present invention, and found that Form B and Form C of the present invention have more excellent properties than the prior art. Dissolution is a prerequisite for drug absorption, and increased solubility will help to increase the bioavailability of the drug and thereby improve the drug’s druggability. Compared with the prior art, the crystalline forms B and C of the invention have higher solubility and provide favorable conditions for drug development. Compared with the prior art, the crystalline forms B and C of the invention also have lower hygroscopicity. Hydroscopic drug crystal form due to adsorption of more water lead to weight changes, so that the raw material crystal component content is not easy to determine. In addition, the crystalline form of the drug substance absorbs water and lumps due to high hygroscopicity, which affects the particle size distribution of the sample in the formulation process and the homogeneity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample. The crystal form B and the crystal form C have the same moisture content under different humidity conditions, and overcome the disadvantages caused by high hygroscopicity, which is more conducive to the long-term storage of the medicine, reduces the material storage and the quality control cost.

In addition, the present invention provides Form B and Form C of ODM-201 represented by formula (I), which have good stability, excellent flowability, suitable particle size and uniform distribution. The solvent used in the preparation method of crystal form B and crystal form C of the invention has lower toxicity, is conducive to the green industrial production, avoids the pharmaceutical risk brought by the residue of the toxic solvent, and is more conducive to the preparation of the pharmaceutical preparation. The novel crystal type provided by the invention has the advantages of simple operation, no need of heating, short preparation period and cost control in industrialized production. Form B and Form C of the present invention provide new and better choices for the preparation of pharmaceutical formulations containing ODM-201, which are of great significance for drug development.

The problem to be solved by the invention

The main object of the present invention is to provide a crystal form of ODM-201 and a preparation method and use thereof.

//////////DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent, CRYSTAL

Forodesine

• Molecular FormulaC₁₁H₁₄N₄O₄
• Average mass266.253 Da

CAS No. : 284490-13-7

Forodesine (INN; also known as Immucillin H; trade names Mundesine and Fodosine) is a transition-state analog inhibitor of purine nucleoside phosphorylase^[1] studied for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and for treatment of B-cell acute lymphocytic leukemia (B-ALL).

Forodesine was originally discovered by Vern Schramm‘s laboratory at the Albert Einstein College of Medicine in New York and Industrial Research Limited in New Zealand.

Forodesine is being developed by BioCryst Pharmaceuticals. As of 2008, it is currently in phase II clinical trials.^[2].

In 2006, BioCryst entered into a licensing agreement with Mundipharma International Holdings Limited to develop and commercialize forodesine in markets across Europe, Asia, and Australasia for use in oncology.^[3]

In April 2017, forodesine was approved in Japan for the treatment of relapsed/refractory peripheral T-cell lymphoma.^[4]

ema

On 20 September 2010, orphan designation (EU/3/10/780) was granted by the European Commission to Mundipharma Research Limited, United Kingdom, for forodesine for the treatment of chronic lymphocytic leukaemia

EU/3/10/780: Public summary of opinion on orphan designation: Forodesine for the treatment of chronic lymphocytic leukaemia

P/69/2010: European Medicines Agency decision on the granting of a product specific waiver for forodesine hydrochloride (EMEA-000785-PIP01-09)

On 20 September 2010, orphan designation (EU/3/10/780) was granted by the European Commission to Mundipharma Research Limited, United Kingdom, for forodesine for the treatment of chronic lymphocytic leukaemia.

What is chronic lymphocytic leukaemia?

Chronic lymphocytic leukaemia (CLL) is cancer of a type of white blood cell called B lymphocytes. In this disease, the lymphocytes multiply too quickly and live for too long, so that there are too many of them circulating in the blood. The cancerous lymphocytes look normal, but they are not fully developed and do not work properly. Over a period of time, the abnormal cells replace the normal white blood cells, red blood cells and platelets (components that help the blood to clot) in the bone marrow (the spongy tissue inside the large bones in the body). CLL is the most common type of leukaemia and mainly affects older people. It is rare in people under the age of 40 years. CLL is a long-term debilitating and life-threatening disease because some patients develop severe infections. What is the estimated number of patients affected by the condition? At the time of designation, CLL affected approximately 3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 152,000 people, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

What treatments are available? Treatment for CLL is complex and depends on a number of factors, including the extent of the disease, whether it has been treated before, and the patient’s age, symptoms and general state of health. Patients whose CLL is not causing any symptoms or is only getting worse very slowly may not need

Forodesine Hydrochloride was originally developed by BioCryst Pharmaceuticals and then licensed to Mundipharma and in particular is marketed in Japan under the trade name Mundesine®. Forodesine Hydrochloride is a transitional analogue inhibitor of purine nucleoside phosphorylase (PNP). Mundesine® is approved for the treatment of peripheral T-cell lymphoma (PTCL).

Mundesine® is a capsule that contains 100mg of free Forodesine per capsule. The recommended dose is 300mg orally, twice daily.

In 2004, the compound was eligible for orphan drug treatment for non-Hodgkin’s lymphoma (NHL), chronic myelogenous leukemia (CLL) and hairy cell leukemia, respectively. In 2007, the compound was eligible for the EU orphan drug for the treatment of acute lymphoblastic leukemia (ALL) and cutaneous T-cell lymphoma (CTCL). In 2010, the compound was eligible for EU orphan drug for treatment of CLL. In 2006, the compound obtained Japanese orphan drug eligibility for CTCL treatment.

Forodesine, or 7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-pyrrolidinyl]-l,5-dihydropyrrolo[2,3-e]pyrimidin-4-one, is an inhibitor of purine nucleoside phosphorylase. It is currently in development as a treatment for peripheral T-Cell Lymphoma .

W099/19338 describes a compound genus as a new class of inhibitors of nucleoside metabolism, including Forodesine. The compounds effect as inhibitors of purine nucleoside phosphorylase is taught as efficacious to suppress T-cell function and to treat infections caused by protozoan parasites.

WO00/61783 describes a number of processes for preparing molecules described in W099/19338. Reaction scheme 3 on page 23 of the published application describes a synthesis of Forodesine, characterised by the removal of two acid labile protecting groups in the final step to yield the hydrochloride salt.

Forodesine is a particularly difficult molecule to make on a commercial scale. The current process for manufacture requires a coupling reaction under cryogenic temperature conditions of -55C. Subsequent steps involve the use of a high pressure hydrogenation reaction. Such extreme reaction conditions provide for safety concerns, particularly when conducted on a bulk scale. Further the products of the reaction were extremely challenging to purify. The effect of all this is to require more sophisticated and expensive equipment at the manufacturing plant; all of which add up to an increased cost of goods for patients. Accordingly a new manufacturing process was sought.

Surprisingly a new route has been invented which is shorter, cheaper, less dangerous and provides an increased overall yield whilst still conforming to the required purity profile.

The current manufacturing process is described in Fig 1.

5C

, MeOH, reflux xchange

tallisation

Fig l

Within the diagram, the following acronyms are used, wherein NCS is N-Chlorosuccinimide, OTBDMS is t-butyldimethylsiloxy protecting group, MtBE is methyl t-butyl ether, (BOC)₂0 is di-t-butyldicarbonate and BOC is t-butyloxycarbonyl protecting group,

Particularly problematic in this process is the requirement to conduct the coupling of process step (iii) at exceptionally low temperature. Further challenges are provided by process step (v) the hydrogenation reaction to remove the benxylyoxymethyl (BOM) protecting group, before removing the other acid labile protecting groups.

Conducting hydrogenation reactions with their need for a high pressure environment requires specialist equipment. Such apparatus is expensive, adding to the cost of the materials produced. Despite the use of specialist equipment, safety concerns can never be eradicated. Whilst BOM can, in certain circumstances, be acid labile, treatment of analogues of the molecules described in Fig 1 with acid has always resulted in incomplete removal of the protecting group, leading to a large number of partially deprotected impurities. This makes purification exceptionally difficult as well as reducing the overall yield for the step.

A new improved process has been developed as described in Fig 2:

Toluene

Fig 2

The new route has a number of clear advantages. The coupling reaction (ix) is conducted at a warmer -15°C, rather than the challenging cryogenic conditions of -55°C required previously. It eradicates the hydrogenation step, avoiding the need for dangerous high pressure conditions. It also makes the overall process much quicker and cheaper; not only are the conditions challenging, but the reagents used in large quantities such as palladium are expensive and environmentally challenging.

The classical method to remove a BOM protecting group is by catalytic hydrogenation. It is however known to be unstable in acid conditions. For this reasons there have been previous attempts to remove BOM at the same time as the three acid labile protecting groups. This has always been unsuccessful as treatment with acid typically resulted in incomplete deprotection, leading to a mixture of products. This made for a tricky purification and a reduced yield. Surprisingly under the particular conditions described herein it has been possible to effect the transformation in greater yield and without a difficult purification. The final product is obtained in equal or greater purity than material obtained from the previous route.

PATENT

WO2013158746A1 *

Scheme 13

HO _OH 1 . HCI/Acetone, MeOH OCH,

2. PPh₃, imidazole I

HO (EtO)₂POCH₂CN

OH O O

Ribose Λ 13a

References for preparation of compound 13a:

1. Mishra, Girija Prasad; Rao, Batchu Venkateswara; Tetrahedron: Asymmetry (2011), 22(7), 812-817.

2. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson,

James E; Organic Letters (2011), 13(7), 1594-1597.

3. WO 2010/085377 A2 (incorporated by reference).

4. Yadav, J. S.; Reddy, P. Narayana; Reddy, B. V. Subba; Synlett (2010), (3), 457- 461.

5. Song, Kai; Zheng, Guo-jun; Huaxue Shiji (2010), 32(2), 171-172.

6. Prabhakar, Peddikotla; Rajaram, Singanaboina; Reddy, Dorigondla Kumar;

Shekar, Vanam; Venkateswarlu, Yenamandra; Tetrahedron: Asymmetry (2010), 21(2), 216-221.

7. CN 101182342 A.

8. Baird, Lynton J.; Timmer, Mattie S. M.; Teesdale-Spittle, Paul H.; Harvey, Joanne

E; Journal of Organic Chemistry (2009), 74(6), 2271-2277.

9. Wang, Xiang-cheng; Wang, Gang; Qu, Gang-lian; Huaxue Shijie (2008), 49(4), 226-228.

10. Ivanova, N. A.; Valiullina, Z. R.; Shitikova, O. V.; Miftakhov, M. S; Russian

Journal of Organic Chemistry (2007), 43(5), 742-746.

11. Braga, Fernanda Gambogi; Coimbra, Elaine Soares; Matos, Magnum de Oliveira;

Lino Carmo, Arturene Maria; Cancio, Marisa Damato; da Silva, Adilson David; European Journal of Medicinal Chemistry (2007), 42(4), 530-537.

12. Wender, Paul A.; Bi, F. Christopher; Buschmann, Nicole; Gosselin, Francis; Kan, Cindy; Kee, Jung-Min; Ohmura, Hirofumi; Organic Letters (2006), 8(23), 5373- 5376.

13. Fei, Xiangshu; Wang, Ji-Quan; Miller, Kathy D.; Sledge, George W.; Hutchins, Gary D.; Zheng, Qi-Huang; Nuclear Medicine and Biology (2004), 31(8), 1033- 1041.

14. Abdel-Rahman, Adel A.-H.; Abdel-Megied, Ahmed E.-S.; Goda, Adel E.-S.; Zeid,

Ibrahim F.; El Ashry, El Sayed H; Nucleosides, Nucleotides & Nucleic Acids (2003), 22(11), 2027-2038.

15. Palmer, Andreas M.; Jager, Volker; European Journal of Organic Chemistry

(2001), (7), 1293-1308.

16. Paquette, Leo A.; Bailey, Simon; Journal of Organic Chemistry (1995), 60(24),

7849-56.

17. Classon, Bjoern; Liu, Zhengchun; Samuelsson, Bertil; Journal of Organic

Chemistry (1988), 53(26), 6126-30.

18. Kissman, Henry M.; Baker, B. R; Journal of the American Chemical Society

(1957), 79 5534-40.

References for cyclizations related to preparation of compounds of type 13d:

1. Davies, Stephen G.; Durbin, Matthew J.; Goddard, Euan C; Kelly, Peter M.;

Kurosawa, Wataru; Lee, James A.; Nicholson, Rebecca L.; Price, Paul D.;

Roberts, Paul M.; Russell, Angela J.; Scott, Philip M.; Smith, Andrew D; Organic & Biomolecular Chemistry (2009), 7(4), 761-776.

2. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul M.;

Russell, Angela J.; Savory, Edward D.; Smith, Andrew D.; Thomson, James E; Tetrahedron: Asymmetry (2009), 20(6-8), 758-772.

3. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul. M.;

Smith, Andrew D; Synlett (2004), (5), 901-903.

4. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson, James E; Organic Letters (2011), 13(7), 1594-1597.

5. Gary B. Evans, Richard H. Furneaux, Andrzej Lewandowicz, Vern L. Schramm, and Peter C. Tyler, Journal of Medicinal Chemistry (2003), 46, 3412-3423.

PATENT

WO 2016110527

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016110527

The invention also provides for the synthesis of a compound of formula (II)

By reacting a compound of Formula (VII)

With di-t-butyldicarbonate.

Preferably the reaction is conducted at -10 to -20°C, in methyl t-butyl ether & heptane

The invention also provides for the synthesis of a compound of formula (VII)

By reacting a compound of Formula (IV)

With a suitable base to form

Before reacting with a compound of Formula (III)

Example 1

Stage 1 Manufacture of (III)

Compound of formula (III) (approx. 130g) in toluene solution is added to a suspension of N-Chlorosuccinimide in toluene at 20°C over a period of 90min. The reaction mixture is stirred at 20°C for 1 hour then chilled to 0°C and stirred for a further hour. The precipitated succinimide by-product is removed by filtration and the filtered solution charged directly to a 45% potassium hydroxide solution (aq) containing

tetrabutylammonium bromide. The reaction mixture is stirred at 0°C and completion of reaction is confirmed by GC analysis. Water is then added to the two-phase mixture to dissolve inorganic precipitates and the toluene product solution is washed with a 28% ammonium hydroxide/acetic acid buffer mixture with sodium chloride added. After phase separation the organic phase solution is stabilised with triethylamine. Magnesium sulfate is added to dry the solution. After filtration, the yield of (III) is determined by R.O.E. and GC purity.

Stage 2 Manufacture of (II)

Stage 2a Lithiation

A suspension of compound of formula (IV) (approx. 200g) in MtBE is chilled to -15°C and treated with /7-Hexyl lithium (2.5M in hexanes) added over 2h, maintaining the reaction mixture at -15°C. The mixture is then stirred for 3h at -15°C.

Stage 2b Coupling with (IV)

After lithiation is complete, a compound formula (III) in toluene solution is added to the reaction mixture maintaining the contents at -15°C. The reaction mixture is then stirred at this temperature for 1.5h.

Stage 2c Boc anhydride quench

A solution of di-t-butyldicarbonate in MtBE is added to the above reaction mixture at -15°C. The solution is stirred for a further 30min.

Workup and Purification

The reaction mixture is quenched by addition of RO water, then filtered. The aqueous layer is separated and run to waste. The organic layer is again washed with water. The organic layer is concentrated to a low volume and solvent replaced by heptane. The mix is stirred for 16h and filtered again.

The solution is passed through a silica gel column and eluted with heptane. The resulting solution is treated with charcoal – stirred for 3h, then filtered. The product (II) is progressed as a solution in heptane to the next stage.

Stage 3 Manufacture of Crude Forodesine (la)

Stage 3 Deprotection with cone. HCI

Concentrated hydrochloric acid is added to (II) in heptane and the mixture stirred. The acid phase is separated off and stirred for 16h at ambient temperature. The solution is then heated to 40°C for 6h. The water is then distilled off under reduced pressure to a minimum volume.

Ethanol is then added to precipitate the crude Forodesine (la) which is isolated by filtration after cooling 0-5°C. It is washed with ethanol and dried in a vacuum oven at 75°C to a constant weight.

Stage 4a Decolourization of crude Forodesine (la) using Ion-Exchange Column

Crude Forodesine (la) is dissolved in water and loaded onto a freshly prepared ion-exchange column containing Dowex 50WX4 resin in the Na⁺ form activated with 30% sodium hydroxide solution. The ion-exchange column is eluted with 4 x lOOmL water followed by 4 x lOOmL 2M HCI. The HCI fractions are collected separately as they contain the desired product. The 2M HCI fractions are combined and concentrated under vacuum with minimum RO water added to dissolve the residue. 1,4-Dioxane is added to the aqueous solution to precipitate the product. The mixture is stirred at 20°C for 1.5h. The product is filtered, washed with 1,4-dioxane and dried in a vacuum oven at 35°C to a constant weight to give decolourised BCX1777.

Stage 4b Recrystallization of Forodesine

Decolourised Forodesine is added to in 0.6M dilute hydrochloric acid and heated to 45°C to dissolve. The resulting solution is hot filtered and washed through with some RO Water. The solution is cooled to 20°C and ethanol added over at least lh. The mixture is then seeded with Forodesine HCI. The resulting slurry is stirred for 8h at 20°C, then cooled to 2°C for a further 1.5h. The product is isolated by filtration, washed twice with cold ethanol then dried in a vacuum oven at 75°C to a constant weight to give a white crystalline Forodesine HCI (approx. 50g).

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one of skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Moreover, all embodiments described herein are considered to be broadly applicable and combinable with any and all other consistent embodiments, as appropriate.

PAPER

 Journal of Medicinal Chemistry (2009), 52(4), 1126-1143.

Third-Generation Immucillins: Syntheses and Bioactivities of Acyclic Immucillin Inhibitors of Human Purine Nucleoside Phosphorylase

References

External links

• “From cell biology to therapy: forodesine”. Hematology Meeting Reports. 2 (5): 106–111. 2008.
• Gore, L; Stelljes, M; Quinones, R (2007). “Forodesine treatment and post-transplant graft-versus-host disease in two patients with acute leukemia: Facilitation of graft-versus-leukemia effect?”. Seminars in Oncology. 34 (6 Suppl 5): S35–9. doi:10.1053/j.seminoncol.2007.11.005. PMID 18086346.
• 18 December 2006 Fodosine orphan designation by the European Commission for acute lymphoblastic leukaemia.
• BioCryst Pharmaceuticals, Inc. have entered into an exclusive license agreement with Mundipharma for develop and commercialize BioCryst’s lead compound, Forodesine.
• Birmingham, Alabama – February 2, 2006 Mundipharma will obtain rights in markets across Europe, Asia and Australasia to Forodesine in the field of oncology in exchange for a $10 million up-front payment. Furthermore, Mundipharma will commit up to an additional $15 million to assist in the evaluation of Forodesine’s therapeutic safety and efficacy profile. BioCryst may also receive future event payments totalling $155 million in addition to royalties on product sales of Forodesine by Mundipharma.
• News BioCryst provides Fodosine update March 27, 2007. “Voluntarily Placed on Hold by BioCryst (…) we don’t think the final response rate will be as high as 18%”.
• The European Commission granted a marketing authorisation valid throughout the European Union for Atriance on 22 August 2007 for acute lymphoblastic leukaemia. What benefit has Atriance shown during the studies? Atriance was shown to be effective in a proportion of the patients in both studies. In the first study, among the 39 children and young adults who se cancer had not responded to two or more previous treatments, five (13%) had a complete response to treatment after a month, with no evidence of disease and normal blood counts. In the second study, among the 28 adults and adolescents with cancer that had not responded to two or more previous tre atments, five (18%) had a complete response to treatment. In both studies, more patients had a partial response to Atriance treatment, with blood counts returning towards normal levels.
• Lino Berton collects all the information on Forodesine in www.linoberton.com site, putting them in a row. In 2014 he published the book Qualcosa che non muore where he tells his incredible experience in the closed trial early in 2007.
• Il Giornale.it (in Italian). “Come si boicotta un farmaco che funziona”. Dated 08-01-2016.

Forodesine

Clinical data
Trade names	Mundesine and Fodosine
Routes of administration	oral
Identifiers
IUPAC name[show]
CAS Number	209799-67-7
PubChem CID	444499
ChemSpider	392417
UNII	426X066ELK
KEGG	D06596
ChEMBL	CHEMBL218291
Chemical and physical data
Formula	C11H14N4O4
Molar mass	266.26 g·mol−1
3D model (JSmol)	Interactive image

/////////Forodesine Hydrochloride, Forodesine, BCX 1777, Immucillin-H, FOSODINE, JAPAN 2017

FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk),for patients who have limited treatment options

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Continue reading.

•  First HIV treatment approved with a new mechanism of action in more than 10 years
• Infused every two weeks, only antiretroviral treatment (ART) that does not require daily dosing
• Trogarzo has no drug-drug interactions and no cross-resistance with other ARTs

MONTREAL, March 6, 2018 /PRNewswire/ – Theratechnologies Inc. (Theratechnologies) (TSX: TH) and its partner TaiMed Biologics, Inc. (TaiMed) today announced that the U.S. Food and Drug Administration (FDA) has granted approval of Trogarzo (ibalizumab-uiyk) Injection. In combination with other ARTs, Trogarzo is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.¹

Trogarzo represents a critical new treatment advance as the first HIV therapy with a new mechanism of action approved in 10 years and proven effectiveness in difficult-to-treat patients with limited options. Unlike all other classes of ARTs, Trogarzo is a CD4-directed post-attachment HIV-1 inhibitor that binds to CD4+ receptors on host cells and blocks the HIV virus from infecting the cells.¹

“Today’s approval of Trogarzo by the FDA is great news for people infected with difficult-to-treat multidrug resistant HIV. We look forward to bringing this much-needed therapy to patients in the U.S within six weeks,” said Luc Tanguay, President and Chief Executive Officer, Theratechnologies Inc. “We are grateful to the patients, investigators, as well as the FDA who supported the clinical development of Trogarzo, and are helping address this critical unmet medical need.”

Trogarzo previously received Breakthrough Therapy and Orphan Drug designations as well as Priority Review status from the FDA, underscoring the significance of the treatment for this patient population.

“I witnessed some of the earliest cases of HIV and AIDS, at a time when the diagnosis was terrifying to patients because in many cases it was a death sentence,” said David Ho, M.D., chief scientific advisor of TaiMed and scientific director and CEO of the Aaron Diamond AIDS Research Center. “Since then, treatment advances and the discovery that combinations of ARTs was the best way to bring viral load below the level of detection have allowed most people to manage HIV like a chronic condition and live long, healthy lives. However, this is not the reality for people whose HIV is resistant to multiple drugs and whose viral load is not controlled, which is why TaiMed dedicated the past decade to advancing ibalizumab in the clinic. For these patients, it represents the next breakthrough.”

Up to 25,000 Americans with HIV are currently multidrug resistant, of which 12,000 are in urgent need of a new treatment option because their current treatment regimen is failing them and their viral load has risen to detectable levels, jeopardizing their health and making HIV transmittable.^2-13 The best way to prevent the transmission of multidrug resistant HIV is to control the virus in those living with it. According to new guidance from the Centers for Disease Control and Prevention (CDC), the HIV virus cannot be transmitted if it is being fully suppressed.¹³

“I’ve struggled with multidrug resistant HIV for almost 30 years and it was completely debilitating to feel like I had run out of options – I made no long-term plans,” said Nelson Vergel, founder of the Program for Wellness Restoration (PoWeR) and Trogarzo patient. “Since starting treatment with Trogarzo six years ago and getting my viral load to an undetectable level, I have been my happiest, most productive self. Trogarzo is a new source of hope and peace of mind for people whose treatments have failed them, and I feel incredibly lucky to have been able to participate in the clinical trial program.”

TaiMed and Theratechnologies partnered on the development of Trogarzo so patients who can benefit from the treatment have access to it. For patients who need assistance accessing Trogarzo or who face challenges affording medicines, Theratechnologies has a team of patient care coordinators available to help. Patients can get assistance and expert support by contacting THERA patient support at 1-833-23-THERA (84372).

“In Phase 3 ibalizumab trials, we saw marked improvements in patients’ health who not only were heavily treatment-experienced and had limited remaining treatment options, but in cases they also had extremely high viral loads and significantly impaired immune systems,” said Edwin DeJesus, M.D., Medical Director for the Orlando Immunology Center. “As an investigator for ibalizumab clinical trials over nearly 10 years, it was remarkable and inspiring to see the dramatic effect ibalizumab had on such vulnerable patients. As a clinician, I am excited that we will now have another option with a different mechanism of action for our heavily pretreated patients who are struggling to keep their viral load below detection because their HIV is resistant to multiple drugs.”

Clinical Trial Findings

Clinical studies show that Trogarzo, in combination with other ARTs, significantly reduces viral load and increases CD4+ (T-cell) count among patients with multidrug resistant HIV-1.

The Phase 3 trial showed:¹

• Trogarzo significantly reduced viral load within seven days after the first dose of functional monotherapy and maintained the treatment response when combined with an optimized background regimen that included at least one other active ART for up to 24 weeks of treatment, while being safe and well tolerated.
• More than 80% of patients achieved the study’s primary endpoint – at least a 0.5 log₁₀ (or 70%) viral load reduction from baseline seven days after receiving a 2,000 mg loading dose of Trogarzo and no adjustment to the failing background regimen.
• The average viral load reduction after 24 weeks was 1.6 log₁₀ with 43% of patients achieving undetectable viral loads.

Patients experienced a clinically-significant mean increase in CD4+ T-cells of 44 cells/mm³, and increases varied based on T-cell count at baseline. Rebuilding the immune system by increasing T-cell count is particularly important as people with multidrug resistant HIV-1 often have the most advanced form of HIV.¹

The most common drug-related adverse reactions (incidence ≥ 5%) were diarrhea (8%), dizziness (8%), nausea (5%) and rash (5%). No drug-drug interactions were reported with other ARTs or medications, and no cross-resistance with other ARTs were observed.¹

About Trogarzo (ibalizumab-uiyk) Injection

Trogarzo is a humanized monoclonal antibody for the treatment of multidrug resistant HIV-1 infection. Trogarzo binds primarily to the second extracellular domain of the CD4+ T receptor, away from major histocompatibility complex II molecule binding sites. It prevents HIV from infecting CD4+ immune cells while preserving normal immunological function.

IMPORTANT SAFETY INFORMATION

Trogarzo is a prescription HIV medicine that is used with other antiretroviral medicines to treat human immunodeficiency virus-1 (HIV-1) infections in adults.

Trogarzo blocks HIV from infecting certain cells of the immune system. This prevents HIV from multiplying and can reduce the amount of HIV in the body.

Before you receive Trogarzo, tell your healthcare provider if you:

• are pregnant or plan to become pregnant. It is not known if Trogarzo may harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Trogarzo passes into breast milk.

Tell your healthcare provider about all the medicines you take, including all prescription and over-the-counter medicines, vitamins, and herbal supplements.

Trogarzo can cause serious side effects, including:

Changes in your immune system (Immune Reconstitution Inflammatory Syndrome) can happen when you start taking HIV-1 medicines.  Your immune system might get stronger and begin to fight infections that have been hidden in your body for a long time.  Tell your health care provider right away if you start having new symptoms after starting your HIV-1 medicine.

The most common side effects of Trogarzo include:

• Diarrhea
• Dizziness
• Nausea
• Rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Trogarzo. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.  You may also report side effects to at 1-833-23THERA (1-833-238-4372).

 

About Theratechnologies

Theratechnologies (TSX: TH) is a specialty pharmaceutical company addressing unmet medical needs to promote healthy living and an improved quality of life among HIV patients. Further information about Theratechnologies is available on the Company’s website at www.theratech.com and on SEDAR at www.sedar.com.

/////Trogarzo, ibalizumab-uiyk, fda 2018, Fast Track, Priority Review, Breakthrough Therapy designations,  Orphan Drug designation

Elobixibat

• Molecular FormulaC₃₆H₄₅N₃O₇S₂
• Average mass695.888 Da