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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Novel Drug Approvals for 2017, A Review/Compilation


CDSCOImage result for FDA EMA

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

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 (COPANLISIBto 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, BRIGATINIBTo 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 ALFATo 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 (enasidenibfor 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 (valbenazineto 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 (edaravoneto 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

No. Drug
Name
Active Ingredient Approval Date FDA-approved use on approval date
46. Giapreza angiotensin II 12/21/2017

Press Release
Drug Trials Snapshot

To increase blood pressure in adults with septic or other distributive shock
45. Macrilen macimorelin acetate 12/20/2017

Drug Trials Snapshot

For the diagnosis of adult growth hormone deficiency
44. Steglatro ertugliflozin 12/19/2017

Drug Trials Snapshot

To improve glycemic control in adults with type 2 diabetes mellitus
43. Rhopressa netarsudil 12/18/2017

Drug Trials Snapshot

To treat glaucoma or ocular hypertension
42. Xepi ozenoxacin 12/11/2017 To treat impetigo
Drug Trials Snapshot
41. Ozempic semaglutide 12/5/2017

Drug Trials Snapshot

To improve glycemic control in adults with type 2 diabetes mellitus
40. Hemlibra emicizumab 11/16/2017

Press Release
Drug Trials Snapshot

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.
39. Mepsevii vestronidase alfa-vjbk 11/15/2017

Press Release
Drug Trials Snapshot

To treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome.
38. Fasenra  benralizumab 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
37. Prevymis letermovir 11/8/2017 To prevent infection after bone marrow transplant
Drug Trials Snapshot
36. Vyzulta latanoprostene bunod ophthalmic solution 11/2/2017 To treat intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Drug Trials Snapshot
35. Calquence acalabrutinib 10/31/2017 To treat adults with mantle cell lymphoma
Press Release
Drug Trials Snapshot
34. Verzenio abemaciclib 9/28/2017 To treat certain advanced or metastatic breast cancers
Press Release
Drug Trials Snapshot
33. Solosec secnidazole 9/15/2017 To treat bacterial vaginosis
Drug Trials Snapshot
32. Aliqopa copanlisib 9/14/2017 To treat adults with relapsed follicular lymphoma
Press Release
Drug Trials Snapshot
31. benznidazole benznidazole 8/29/2017 To treat children ages 2 to 12 years old with Chagas disease
Press Release
Drug Trials Snapshot
30. Vabomere meropenem and vaborbactam 8/29/2017 To treat adults with complicated urinary tract infections
Press Release
Drug Trials Snapshot
29. Besponsa inotuzumab ozogamicin 8/17/2017 To treat adults with relapsed or refractory acute lymphoblastic leukemia
Press Release
Drug Trials Snapshot
28. Mavyret glecaprevir and pibrentasvir 8/3/2017 To treat adults with chronic hepatitis C virus
Press Release
Drug Trials Snapshot
27. Idhifa enasidenib 8/1/2017 To treat relapsed or refractory acute myeloid leukemia
Press Release
Drug Trials Snapshot
26. Vosevi sofosbuvirvelpatasvir and voxilaprevir 7/18/2017 To treat adults with chronic hepatitis C virus
Press Release
Drug Trials Snapshot
25. Nerlynx neratinib maleate 7/17/2017 To reduce the risk of breast cancer returning
Press Release
Drug Trials Snapshot
24. Tremfya guselkumab 7/13/2017 For the treatment of adult patients with moderate-to-severe plaque psoriasis
Drug Trials Snapshot
23. Bevyxxa betrixaban 6/23/2017 For the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness
Drug Trials Snapshot
22. Baxdela delafloxacin 6/19/2017 To treat patients with acute bacterial skin infections
Drug Trials Snapshot
21. Kevzara sarilumab 5/22/2017 To treat adult rheumatoid arthritis
Drug Trials Snapshot
20. Radicava edaravone 5/5/2017 To treat patients with amyotrophic lateral sclerosis (ALS)
Press Release
Drug Trials Snapshot
19. Imfinzi durvalumab 5/1/2017 To treat patients with locally advanced or metastatic urothelial carcinoma
Web Post
Drug Trials Snapshot
18. Tymlos abaloparatide 4/28/2017 To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot
17. Rydapt midostaurin 4/28/2017 To treat acute myeloid leukemia
Press Release Chemistry Review(s) (PDF)
Drug Trials Snapshot
16. Alunbrig brigatinib 4/28/2017 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
Drug Trials Snapshot
15. Brineura cerliponase alfa 4/27/2017 To treat a specific form of Batten disease
Press Release
Drug Trials Snapshot
14. Ingrezza valbenazine 4/11/2017 To treat adults with tardive dyskinesia
Press Release Chemistry Review(s) (PDF)Drug Trials Snapshot
13. Austedo deutetrabenazine 4/3/2017 For the treatment of chorea associated with Huntington’s disease
Drug Trials Snapshot,  Chemistry Review(s) (PDF)
12. Ocrevus ocrelizumab 3/28/2017 To treat patients with relapsing and primary progressive forms of multiple sclerosis
Press Release
Drug Trials Snapshot
11. Dupixent dupilumab 3/28/2017 To treat adults with moderate-to-severe eczema (atopic dermatitis)
Press Release
Drug Trials Snapshot
10. Zejula niraparib 3/27/2017 For the maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers
Press Release
Drug Trials Snapshot
9. Symproic naldemedine 3/23/2017

For the treatment of opioid-induced constipation
Drug Trials Snapshot

8. Bavencio avelumab 3/23/2017 To treat metastatic Merkel cell carcinoma
Press Release
Drug Trials Snapshot
7. Xadago safinamide 3/21/2017 To treat Parkinson’s disease
Press Release
Drug Trials SnapshotChemistry Review(s) (PDF)
6. Kisqali ribociclib 3/13/2017 To treat postmenopausal women with a type of advanced breast cancer
Drug Trials Snapshot
5. Xermelo telotristat ethyl 2/28/2017 To treat carcinoid syndrome diarrhea
Press Release
Drug Trials Snapshot
4. Siliq brodalumab 2/15/2017 To treat adults with moderate-to-severe plaque psoriasis
Press Release
Drug Trials Snapshot
3. Emflaza deflazacort 2/9/2017 To treat patients age 5 years and older with Duchenne muscular dystrophy (DMD)
Press Release
Drug Trials Snapshot
2. Parsabiv etelcalcetide 2/7/2017 To treat secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing dialysis
Drug Trials Snapshot
1. Trulance plecanatide 1/19/2017 To treat Chronic Idiopathic Constipation (CIC) in adult patients.
Press Release
Drug Trials Snapshot

* 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.

USFDA 2017
2017/12/21 Angiotensin II Giapreza La Jolla Pharmaceutical
2017/12/20 Ertugliflozin Steglatro Merck Sharp Dohme
2017/12/20 Macimorelin acetate Macrilen Aeterna Zentaris GmbH
2017/12/18 Netarsudil mesylate Rhopressa Aerie Pharmaceuticals
2017/12/11 Ozenoxacin Xepi Ferrer Internacional S.A.
2017/12/5 Semaglutide Ozempic Novo Nordisk Inc
2017/11/16 Emicizumab Hemlibra Genentech BLA
2017/11/15 Vestronidase alfa Mepsevii Ultragenyx Pharmaceutical BLA
2017/11/14 Benralizumab Fasenra AstraZeneca AB BLA
2017/11/8 Letermovir Prevymis Merck Sharp Dohme
2017/11/2 Latanoprostene bunod Vyzulta Bausch & Lomb Incorporated
2017/10/31 Acalabrutinib Calquence AstraZeneca Pharmaceuticals LP
2017/9/28 Abemaciclib Verzenio Eli Lilly
2017/9/15 Secnidazole Solosec Symbiomix Therapeutics
2017/9/14 Copanlisib Aliqopa Bayer Healthcare Pharmaceuticals
2017/8/29 Benznidazole Chemo Research
2017/8/29 Meropenem – Vaborbactam Vabomere Rempex Pharmaceuticals
2017/8/17 Inotuzumab ozogamicin Besponsa Wyeth Pharmaceuticals BLA
2017/8/3 Glecaprevir – Pibrentasvir Mavyret AbbVie
2017/8/1 Enasidenib Idhifa Celgene Corporation
2017/7/18 Sofosbuvir – Velpatasvir – Voxilaprevir Vosevi Gilead Sciences
2017/7/17 Neratinib maleate Nerlynx Puma Biotechnology
2017/7/13 Guselkumab Tremfya Janssen Biotech BLA
2017/6/23 Betrixaban Bevyxxa Portola Pharmaceuticals
2017/6/19 Delafloxacin meglumine Baxdela Melinta Therapeutics
2017/5/22 Sarilumab Kevzara Sanofi Synthelabo BLA
2017/5/5 Edaravone Radicava Mitsubishi Tanabe Pharma America
2017/5/1 Durvalumab Imfinzi AstraZeneca UK BLA
2017/4/28 Abaloparatide Tymlos Radius Health
2017/4/28 Midostaurin Rydapt Novartis Pharmaceuticals
2017/4/28 Brigatinib Alunbrig Ariad Pharmaceuticals
2017/4/27 Cerliponase alfa Brineura BioMarin Pharmaceutical BLA
2017/4/11 Valbenazine Ingrezza Neurocrine Biosciences
2017/4/3 Deutetrabenazine Austedo Teva Pharmaceuticals
2017/3/28 Ocrelizumab Ocrevus Genentech BLA
2017/3/28 Dupilumab Dupixent Regeneron Pharmaceuticals BLA
2017/3/27 Niraparib Zejula Tesaro
2017/3/23 Naldemedine tosylate Symproic Shionogi
2017/3/23 Avelumab Bavencio EMD Serono BLA
2017/3/23 Safinamide mesylate Xadago Newron Pharmaceuticals
2017/3/21 Ribociclib Kisqali Novartis Pharmaceuticals
2017/2/28 Telotristat ethyl Xermelo Lexicon Pharmaceuticals
2017/2/15 Brodalumab Siliq Valeant Pharmaceuticals BLA
2017/2/9 Deflazacort Emflaza Marathon Pharmaceuticals
2017/2/8 Etelcalcetide hydrochloride Parsavib KAI Pharmaceuticals
2017/1/19 Plecanatide Trulance Synergy Pharmaceuticals

1 Abaloparatide

RADIUS

str1

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

Image result for AbaloparatideImage result for Abaloparatide

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

Verzenio abemaciclib FDA 9/28/2017 To treat certain advanced or metastatic breast cancers
Press Release
Drug Trials Snapshot

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

Image result for abemaciclibImage result for abemaciclib

3 Acalabrutinib

Calquence FDA APPROVED

10/31/2017

To treat adults with mantle cell lymphoma
Press Release
Drug Trials Snapshot

Image result for AcalabrutinibImage result for AcalabrutinibImage result for 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

Giapreza angiotensin II 12/21/2017 To increase blood pressure in adults with septic or other distributive shock
Press Release
Drug Trials Snapshot

Image result for angiotensin IIImage result for GIAPREZA

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

5 AVELUMAB

MERCK

Image result for AVELUMABImage result for AVELUMAB

Bavencio FDA 3/23/2017 To treat metastatic Merkel cell carcinoma
Press Release
Drug Trials Snapshot

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

Image result for BENRALIZUMAB

7 Benznidazole

CHEMO RESEARCH

Image result for BENZNIDAZOLE

Image result for BENZNIDAZOLEImage result for BENZNIDAZOLE

benznidazole FDA

8/29/2017

To treat children ages 2 to 12 years old with Chagas disease
Press Release
Drug Trials Snapshot

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

8 BETRIXABAN

PORTOLA PHARMA

Image result for betrixaban

Bevyxxa FDA

6/23/2017

For the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness
Drug Trials Snapshot

Image result for betrixabanImage result for betrixaban

STR2STR1

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

9 BRIGATINIB

Figure imgf000127_0001

TAKEDA

Image result for BRIGATINIBImage result for BRIGATINIB

Alunbrig FDA

4/28/2017

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
Drug Trials Snapshot

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

Siliq FDA

2/15/2017

To treat adults with moderate-to-severe plaque psoriasis
Press Release
Drug Trials Snapshot

Image result for BRODALUMAB

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

11 CERLIPONASE ALFA

Image resultImage result for cerliponase alfaImage result for cerliponase alfa

Brineura FDA 4/27/2017 To treat a specific form of Batten disease
Press Release
Drug Trials Snapshot

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

12 Copanlisib

Aliqopa FDA APPROVED

9/14/2017

To treat adults with relapsed follicular lymphoma
Press Release
Drug Trials Snapshot

Copanlisib dihydrochloride.png

Image result for copanlisibImage result for copanlisib

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

13  DEFLAZACORT

MARATHON PHARMA

Image result for deflazacort

Emflaza FDA 2/9/2017 To treat patients age 5 years and older with Duchenne muscular dystrophy (DMD)
Press Release
Drug Trials Snapshot

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

14 DELAFLOXACIN

Baxdela FDA APPROVED

6/19/2017

To treat patients with acute bacterial skin infections

Image result for delafloxacin

Image result for delafloxacinImage result for delafloxacin

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

15 Deutetrabenazine

TEVA

Deutetrabenazine.svg

Image result for deutetrabenazineImage result for deutetrabenazineImage result for deutetrabenazine

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

Austedo FDA 4/3/2017 For the treatment of chorea associated with Huntington’s disease
Drug Trials Snapshot   Chemistry Review(s) (PDF)

STR1STR2str3

16 DUPILUMAB

SANOFI/REGENERON

Image result for DUPILUMABImage result for DUPILUMAB

Dupixent FDA 3/28/2017 To treat adults with moderate-to-severe eczema (atopic dermatitis)
Press Release
Drug Trials Snapshot

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

17 DURVALUMAB

ASTRA ZENECA

Image result for DURVALUMAB

Imfinzi

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

18 EDAVARONE

Image result for EDARAVONE

MITSUBISHI TANABE

Radicava FDA 5/5/2017 To treat patients with amyotrophic lateral sclerosis (ALS)
Press Release
Drug Trials Snapshot

Image result for EDARAVONEImage result for EDARAVONE

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

Image result for EMICIZUMAB

Hemlibra emicizumab FDA 11/16/2017 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.
Press Release

Drug Trials Snapshot

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

Image result for EMICIZUMAB

20 Enasidenib

Enasidenib.png

Image result for EnasidenibImage result for Enasidenib

Idhifa FDA

8/1/2017

To treat relapsed or refractory acute myeloid leukemia
Press Release
Drug Trials Snapshot

Image result for 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

Image result for ERTUGLIFLOZIN

Steglatro ertugliflozin FDA

12/19/2017

To improve glycemic control in adults with type 2 diabetes mellitus
Drug Trials Snapshot

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

Image result for ERTUGLIFLOZIN

22 ETELCALCETIDE

Amgen

Parsabiv FDA APPROVED

2/7/2017

To treat secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing dialysis
Drug Trials SnapshotSYNTHESIS LINK……..https://cen.acs.org/articles/96/i4/the-year-in-new-drugs-2018.html

Image result for ETELCALCETIDEImage result for ETELCALCETIDE

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

23 GLECAPREVIR

ABBVIE

Image result for GLECAPREVIR

Mavyret glecaprevir and pibrentasvir FDA 8/3/2017 To treat adults with chronic hepatitis C virus
Press Release
Drug Trials Snapshot

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

Image result for GLECAPREVIRImage result for GLECAPREVIRImage result for GLECAPREVIR

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

Image result for GUSELKUMABImage result for GUSELKUMAB

25 Inotuzumab ozogamicin

PFIZER

Image result for inotuzumab ozogamicin

Image result for inotuzumab ozogamicinImage result for inotuzumab ozogamicin

Besponsa FDA

8/17/2017

To treat adults with relapsed or refractory acute lymphoblastic leukemia
Press Release
Drug Trials Snapshot

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

26 LATANOPROSTENE

VALEANT

Image result for LATANOPROSTENE

latanoprostene bunod ophthalmic solution

FDA 11/2/2017

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

Image result for LATANOPROSTENE

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

Image result for LETERMOVIR

Prevymis FDA 11/8/2017 To prevent infection after bone marrow transplant
Drug Trials Snapshot

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

Image result for LETERMOVIRImage result for LETERMOVIR

 

28 Macimorelin acetate

AETERNA ZENTARIS

Macrilen macimorelin acetate FDA

12/20/2017

For the diagnosis of adult growth hormone deficiency
Drug Trials Snapshot

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/

 Image result for macimorelin acetate

29 MEROPENEM

Image result for MEROPENEM


30 MIDOSTAURIN

NOVARTIS

Image result for MIDOSTAURIN

Rydapt FDA

4/28/2017

To treat acute myeloid leukemia
Press Release
Drug Trials Snapshot

STR1 STR2

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

Image result for naldemedine

Image result for naldemedineImage result for naldemedine

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

Image result for NERATINIB

Image result for NERATINIBImage result for NERATINIBImage result for NERATINIB

Nerlynx FDA 7/17/2017 To reduce the risk of breast cancer returning
Press Release
Drug Trials Snapshot

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

Rhopressa FDA APPROVED

12/18/2017

To treat glaucoma or ocular hypertension

Image result for Netarsudil

Image result for Netarsudil

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

34 NIRAPARIB

TESARO

Zejula FDA 3/27/2017 For the maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers
Press Release
Drug Trials Snapshot

Figure imgf000023_0001Image result for TESARO

Image result for NIRAPARIB

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

35 OCRELIZUMAB

ROCHE

Ocrevus FDA 3/28/2017 To treat patients with relapsing and primary progressive forms of multiple sclerosis
Press Release
Drug Trials Snapshot

Image result for ocrelizumabImage result for ocrelizumab

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

36 OZENOXACIN

MEDIMETRIX

Image result for ozenoxacin

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

Image result for ozenoxacin

Xepi ozenoxacin FDA

12/11/2017

To treat impetigo
Drug Trials Snapshot

37 Pibrentasvir

ABBVIE

Image result for PIBRENTASVIR

Mavyret glecaprevir and pibrentasvir FDA 8/3/2017 To treat adults with chronic hepatitis C virus
Press Release
Drug Trials Snapshot

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

Image result for PIBRENTASVIRImage result for PIBRENTASVIR

38 PLECANATIDE

Plecanatide 普卡那肽 ليكاناتيد плеканатид

SYNERGY PHARMA

Image result for PLECANATIDEImage result for PLECANATIDE

Trulance FDA APPROVED

1/19/2017

To treat Chronic Idiopathic Constipation (CIC) in adult patients.
Press Release
Drug Trials Snapshot

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

2D chemical structure of 1374639-75-4

Structure..link for correct structure

Kisqali FDA 3/13/2017 To treat postmenopausal women with a type of advanced breast cancer
Drug Trials Snapshot

Image result for RIBOCICLIB

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

40  SARILUMAB

SANOFI /REGENERON

Kevzara sarilumab FDA 5/22/2017 To treat adult rheumatoid arthritis
Drug Trials Snapshot

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

Image result for SARILUMABImage result for SARILUMAB

41 SECNIDAZOLE

SYMBIOMIX

Secnidazole.svg

Solosec FDA 9/15/2017 To treat bacterial vaginosis
Drug Trials Snapshot

Image result for SECNIDAZOLE

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

Image result for safinamide

Image result for safinamideImage result for safinamide

STR1

Xadago FDA 3/21/2017 To treat Parkinson’s disease
Press Release
Drug Trials Snapshot

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

Image result for SEMAGLUTIDE

Ozempic semaglutide FDA

12/5/2017

To improve glycemic control in adults with type 2 diabetes mellitus
Drug Trials Snapshot

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

Image result for SEMAGLUTIDE

44 SOFOSBUVIR

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

45 TELOTRISTAT ETHYL

LEXICON

LX1606 Hippurate.png

Xermelo FDA

2/28/2017

To treat carcinoid syndrome diarrhea
Press Release
Drug Trials Snapshot

Image result for Lexicon Pharmaceuticals, Inc.STR1

46 VABORBACTAM

THE MEDICINES CO

Image result for Vaborbactam

Vabomere meropenem and vaborbactam FDA

8/29/2017

To treat adults with complicated urinary tract infections
Press Release
Drug Trials Snapshot

Image result for VABOMERE

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

Image result for valbenazine

Image result for VALBENAZINEImage result for VALBENAZINEImage result for VALBENAZINE

Ingrezza FDA

4/11/2017

To treat adults with tardive dyskinesia
Press Release
Drug Trials Snapshot

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

48 Vestronidase alfa-vjbk

ULTRAGENYX

Mepsevii vestronidase alfa-vjbk FDA 11/15/2017 To treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome.
Press Release
Drug Trials Snapshot

Image result for vestronidase alfa-vjbkImage result for vestronidase alfa-vjbk

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

Image result for VOXILAPREVIR

Image result for VOXILAPREVIR

Vosevi sofosbuvir, velpatasvir and voxilaprevir FDA 7/18/2017 To treat adults with chronic hepatitis C virus
Press Release
Drug Trials Snapshot

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.

STR1 STR2 str3 str4 str5

STR1 STR2

EUROPE

2017/11/16 Niraparib Zejula Tesaro UK Limited O NME
2017/11/10 Adalimumab Cyltezo Boehringer Ingelheim International GmbH B
2017/11/10 Miglustat Miglustat Gen.Orph Gen.Orph G
2017/11/10 Ritonavir Ritonavir Mylan MYLAN S.A.S G
2017/11/10 Padeliporfin Tookad STEBA Biotech S.A
2017/11/10 Guselkumab Tremfya Janssen-Cilag International N.V. BLA
2017/9/27 Dupilumab Dupixent sanofi-aventis groupe BLA
2017/9/21 Darunavir / Cobicistat / Emtricitabine / Tenofovir alafenamide Symtuza Janssen-Cilag International N.V.
2017/9/21 Atezolizumab Tecentriq Roche Registration Limited BLA
2017/9/18 Avelumab Bavencio Merck Serono Europe Limited O BLA
2017/9/18 Entecavir Entecavir Mylan Mylan S.A.S G
2017/9/18 Lacosamide Lacosamide Accord Accord Healthcare Ltd G
2017/9/18 Midostaurin Rydapt Novartis Europharm Ltd O NME
2017/9/18 Telotristat ethyl Xermelo Ipsen Pharma O NME
2017/9/5 Trientine Cuprior GMP-Orphan SA
2017/9/5 Efavirenz / Emtricitabine / Tenofovir disoproxil Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan Mylan S.A.S G
2017/8/24 Tivozanib hydrochloride monohydrate Fotivda EUSA Pharma (UK) Limited NME
2017/8/24 Adalimumab Imraldi Samsung Bioepis UK Limited (SBUK) B
2017/8/24 Nitisinone Nitisinone MDK (previously Nitisinone MendeliKABS) MendeliKABS Europe Ltd G
2017/8/22 Ribociclib Kisqali Novartis Europharm Ltd NME
2017/8/22 Cladribine Mavenclad Merck Serono Europe Limited
2017/7/26 Glecaprevir / Pibrentasvir Maviret AbbVie Limited NME
2017/7/26 Sofosbuvir / Velpatasvir / Voxilaprevi Vosevi Gilead Sciences International Ltd NME
2017/7/19 Insulin lispro Insulin lispro Sanofi sanofi-aventis groupe B
2017/7/19 Patiromer sorbitex calcium Veltassa Vifor Fresenius Medical Care Renal Pharma France NME
2017/7/17 Efavirenz / Emtricitabine / Tenofovir disoproxil Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva Zentiva k.s. G
2017/7/17 Brodalumab Kyntheum LEO Pharma A/S BLA
2017/7/17 beclometasone / formoterol / glycopyrronium bromide Trimbow Chiesi Farmaceutici S.p.A.
2017/7/13 Rituximab Blitzima Celltrion Healthcare Hungary Kft. B
2017/7/13 Cariprazine Reagila Gedeon Richter
2017/7/10 Spheroids of human autologous matrix-associated chondrocytes Spherox CO.DON AG
2017/7/6 Cenegermin Oxervate Dompe farmaceutici s.p.a. O BLA
2017/6/29 Inotuzumab ozogamicin Besponsa Pfizer Limited O BLA
2017/6/23 Etanercept Erelzi Sandoz GmbH
2017/6/23 Sarilumab Kevzara Sanofi-Aventis Groupe NME
2017/6/23 Dimethyl fumarate Skilarence Almirall S.A
2017/6/23 Carglumic acid Ucedane Lucane Pharma G
2017/6/15 Rituximab Rixathon, Riximyo B Sandoz GmbH
2017/6/2 Pentosan polysulfate sodium Elmiron bene-Arzneimittel GmbH
2017/6/2 Nonacog beta pegol Refixia Novo Nordisk A/S BLA
2017/5/30 Cerliponase alfa Brineura BioMarin International Limited O E BLA
2017/5/30 Nusinersen Spinraza Biogen Idec Ltd O NME
2017/5/24 Meningococcal group b vaccine (recombinant, adsorbed) Trumenba Pfizer Limited
2017/5/22 Ivabradine Ivabradine Accord Accord Healthcare Ltd G
2017/5/8 Dinutuximab beta Dinutuximab beta Apeiron Apeiron Biologics AG O E
2017/4/28 Emtricitabine – tenofovir disoproxil mixt Emtricitabine/Tenofovir disoproxil Krka d.d. KRKA, d.d., Novo mesto G
2017/4/24 Parathyroid hormone Natpar Shire Pharmaceuticals Ireland Ltd O C BLA
2017/4/20 Edoxaban Roteas Daiichi Sankyo Europe GmbH
2017/3/22 Tofacitinib citrate Xeljanz Pfizer Limited NME
2017/3/20 Umeclidinium Rolufta GlaxoSmithKline Trading Services Limited
2017/3/3 Chlormethine Ledaga Actelion Registration Ltd. O
2017/2/27 Pregabalin Pregabalin Zentiva Zentiva k.s. G
2017/2/17 Rituximab Truxima Celltrion Healthcare Hungary Kft. B
2017/2/13 Etanercept Lifmior Pfizer Limited
2017/2/13 Baricitinib Olumiant Eli Lilly Nederland B.V. NME
2017/1/19 Mercaptamine Cystadrops Orphan Europe S.A.R.L. O
2017/1/18 Bezlotoxumab Zinplava Merck Sharp & Dohme Limited NME
2017/1/11 Teriparatide Movymia STADA Arzneimittel AG B
2017/1/11 Insulin glargine / lixisenatide Suliqua Sanofi-Aventis Groupe
2017/1/9 Insulin aspart Fiasp Novo Nordisk A/S
2017/1/9 Tadalafil Tadalafil Mylan S.A.S G
2017/1/9 Tenofovir alafenamide Vemlidy Gilead Sciences International Ltd
2017/1/4 Lonoctocog alfa Afstyla CSL Behring GmbH BLA
2017/1/4 Darunavir Darunavir Mylan Mylan S.A.S. G
2017/1/4 Insulin glargine Lusduna Merck Sharp & Dohme Limited B
2017/1/4 Teriparatide Terrosa Gedeon Richter Plc. B

SECTION B; EMA Approvals

Combined drugs  USFDA+EMA +PMDA  list are listed below. trying to simplify search

1 Abaloparatide   USFDA

2 Abemaciclib  USFDA

3 ACALABRUTINIB USFDA

3A ALOFISEL        EMA

3B AMENAMEVIR  JAPAN

4 ANGIOTENSIN II USFDA

4A Atezolizumab            EMA

5 AVELUMAB      USFDA+EMA

6 BENRALIZUMAB     USFDA+EMA

6A BARICITINIB   JAPAN

7 BENZNIDAZOLE USFDA

8 BETRIXABAN USFDA

9 BRIGATINIB USFDA

10 BRODALUMAB    USFDA+EMA

10A BUROSUMAB           EMA

10B CARIPRAZINE HYDROCHLORIDE        EMA

11 CERLIPONASE ALPA    USFDA+EMA

12 COPANLISIB USFDA

13 DEFLAZACORT USFDA

14 Delafloxacin USFDA

15 Deutetrabenazine USFDA

16DUPILUMAB    USFDA+EMA

17 DURVALUMAB   USFDA

18 EDAVARONE   USFDA

19 EMICIZUMAB USFDA

20 Enasidenib USFDA

21 ERTUGLIFLOZIN USFDA

22 ETELCALCETIDE USFDA

22A FORODESINE   JAPAN

22B FLUCICLOVINE  EMA

23 GLECAPREVIR    USFDA+EMA

24 GUSELKUMAB    USFDA+EMA

25 INOTUZUMAB OZOGAMICIN     USFDA+EMA

26 LATANOPROSTENE USFDA

27 LETERMOVIR    USFDA+EMA

27A Utetium lu 177 dotatate        EMA

28 MACIMORELIN ACETATE USFDA

29 MEROPENEM USFDA

30 MIDOSTAURIN     USFDA+EMA

31 NALDEMEDINE USFDA

32 NERATINIB USFDA

33 NETARSUDIL USFDA

34 NIRAPARIB    USFDA+EMA

34A NONACOG        EMA

34B NUCINERSEN        EMA   +Japan

35 Ocrelizumab    USFDA+EMA

35A OXERVATE         EMA

36 OZENOXACIN USFDA

36A PATIROMER        EMA

36B PADELIPORFIN        EMA

36C PEMAFIBRATE  JAPAN

37 PIBRENTASVIR     USFDA+EMA

38 PLECANATIDE USFDA

38A PRALATREXATE    JAPAN

39 RIBOCICLIB      USFDA+EMA

39A ROLAPITANT         EMA

39BRURLOCTOCOG        EMA

40  SARILUMAB    USFDA+EMA

41 SECNIDAZOLE USFDA

42 SAFINAMIDE USFDA

43 SEMAGLUTIDE    USFDA+EMA

43A SODIUM ZIRCONIUM CYCLOCYLICATE        EMA

44 SOFOSBUVIR    USFDA+EMA

44A SPHEROX       EMA

45 TELOTRISTAT ETHYL    USFDA+EMA

45A TIVOZANIB        EMA

45B TOFACITINIB      EMA

45C TRUMENBA        EMA

46 VABORBACTAM USFDA

47 VALBENAZINE  USFDA

48 VESTRONIDASE ALFA-VJBK USFDA

49 VELPATASVIR    USFDA+EMA

50 VOXILAPREVIR     USFDA+EMA

Drugs EMA list missed out in usfda list

3A ALOFISEL

link………https://newdrugapprovals.org/2018/03/02/alofisel-darvadstrocel-cx-601/

4A Atezolizumab

WILL BE UPDATED

10A BUROSUMAB

WILL BE UPDATED

10B CARIPRAZINE HYDROCHLORIDE

WILL BE UPDATED

22B FLUCICLOVINE

Image result for FLUCICLOVINE

LINK https://newdrugapprovals.org/2016/05/28/fda-approves-new-diagnostic-imaging-agent-fluciclovine-f-18-to-detect-recurrent-prostate-cancer/

SEE EMA

Axumin : EPAR – Summary for the public EN = English 06/07/2017

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004197/human_med_002100.jsp&mid=WC0b01ac058001d124

Marketing-authorisation holder Blue Earth Diagnostics Ltd
Revision 0
Date of issue of marketing authorisation valid throughout the European Union 22/05/2017

Contact address:

Blue Earth Diagnostics Ltd
215 Euston Road
London NW1 2BE
United Kingdom

27A Lutetium lu 177 dotatate

WILL BE UPDATED

34A NONACOG

WILL BE UPDATED

34B NUCINERSEN

EMA AND JAPAN 2017 APPROVED

Nusinersen sodium colored.svg

Image result for Nusinersen sodium

LINK …….https://newdrugapprovals.org/2018/03/14/nusinersen-sodium-%E3%83%8C%E3%82%B7%E3%83%8D%E3%83%AB%E3%82%BB%E3%83%B3%E3%83%8A%E3%83%88%E3%83%AA%E3%82%A6%E3%83%A0/

35A OXERVATE

WILL BE UPDATED

36A PATIROMER

WILL BE UPDATED

36B PADELIPORFIN

img

NAME Tookad
AGENCY PRODUCT NUMBER EMEA/H/C/004182
ACTIVE SUBSTANCE padeliporfin di-potassium
INTERNATIONAL NON-PROPRIETARY NAME(INN) OR COMMON NAME padeliporfin
THERAPEUTIC AREA Prostatic Neoplasms
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CODE L01XD07
ADDITIONAL MONITORING This medicine is under additional monitoring. This means that it is being monitored even more intensively than other medicines. For more information, see medicines under additional monitoring.
MARKETING-AUTHORISATION HOLDER STEBA Biotech S.A
REVISION 0
DATE OF ISSUE OF MARKETING AUTHORISATION VALID THROUGHOUT THE EUROPEAN UNION 10/11/2017

Contact address:

STEBA Biotech S.A
7 place du theatre
L-2613 Luxembourg
Luxembourg

Image result for PADELIPORFIN

38A PRALATREXATE 

Pralatrexate.png

Japan approved 2017

2017/7/3 PMDA JAPAN Pralatrexate Difolta Mundipharma NME

LINK https://newdrugapprovals.org/2018/03/16/pralatrexate-%E3%83%97%E3%83%A9%E3%83%A9%E3%83%88%E3%83%AC%E3%82%AD%E3%82%B5%E3%83%BC%E3%83%88/

39A ROLAPITANT

WILL BE UPDATED

39B RURLOCTOCOG

WILL BE UPDATED

 43A SODIUM ZIRCONIUM

WILL BE UPDATED

 44A SPHEROX

WILL BE UPDATED

45A TIVOZANIB

Image result for TIVOZANIB EMAImage result for TIVOZANIB EMA

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

str6

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

Name Fotivda
Agency product number EMEA/H/C/004131
Active substance tivozanib
International non-proprietary name(INN) or common name tivozanib hydrochloride monohydrate
Therapeutic area Carcinoma, Renal Cell
Anatomical therapeutic chemical (ATC) code L01XE

Publication details

Marketing-authorisation holder EUSA Pharma (UK) Limited
Revision 0
Date of issue of marketing authorisation valid throughout the European Union 24/08/2017

Contact address:

EUSA Pharma (UK) Limited
Breakspear Park, Breakspear Way
Hemel Hempstead, HP2 4TZ
United Kingdom

LINK………https://newdrugapprovals.org/2018/02/26/tivozanib-%E3%83%86%E3%82%A3%E3%83%9C%E3%82%B6%E3%83%8B%E3%83%96%E5%A1%A9%E9%85%B8%E5%A1%A9%E6%B0%B4%E5%92%8C%E7%89%A9/

45B TOFACITINIB

WILL BE UPDATED

45C TRUMENBA

WILL BE UPDATED

SECTION C JAPANFORODOS

STR1

SECTION C  New Drugs JAPAN

https://www.pmda.go.jp/english/review-services/reviews/approved-information/drugs/0002.html

STR1

STR1

STR2

JAPAN 2017

2017/9/27 Avelumab (genetical recombination) Bavencio Merck Serono BLA
2017/9/27 Glecaprevir – pibrentasvir mixt Maviret Abbvie NME
2017/9/27 Daratumumab (genetical recombination) Darzalex Janssen Pharmaceutical BLA
2017/9/27 Belimumab (genetical recombination) Benlysta GlaxoSmithKline BLA
2017/9/27 Bezlotoxumab (genetical recombination) Zinplava MDS BLA
2017/9/27 Palbociclib Ibrance Pfizer NME
2017/9/27 Lonoctocog alfa (genetical recombination) Afstyla CSL Behring BLA
2017/9/27 Rupatadine fumarate Rupafin Teikoku seiyaku NME
2017/9/27 Sarilumab (genetical receombination) Kevzara Sanofi BLA
2017/9/27 Flutemetamol (18F) Vizamyl Nihon Medi-Physics NME
2017/7/3 Nusinersen sodium Spinraza Biogen Japan
2017/7/3 Romidepsin Istodax Celgene NME
2017/7/3 Pralatrexate Difolta Mundipharma NME
2017/7/3 Amenamevir Amenalief Maruho NME
2017/7/3 Baricitinib Olumiant Lilly NME
2017/7/3 Pemafibrate Parmodia Kowa NME
2017/3/30 Human prothrombin complex, freeze-dried concentrated Kcentra CSL Behring
2017/3/30 Ixazomib citrate Ninlaro Takeda NME
2017/3/30 Forodesine hydrochloride Mundesine Mundipharma
2017/3/30 Aflibercept beta (genetical recombination) Zaltrap Sanofi
2017/3/30 Hydromorphone hydrochloride Narusus, Narurapid DaiichiSankyo-pp
2017/3/30 Naldemedine tosylate Symproic Shionogi NME
2017/3/30 Guanfacine hydrochloride Intuniv Shionogi

3B AMENAMEVIR

Originally developed by Astellas, the drug was licensed to Maruho. Amenamevir treats herpes zoster by inhibiting the activity of the helicase-primer enzyme during viral DNA replication and blocking the virus’s proliferation.

Amenalief® is an oral film-coated tablet containing 200 mg of amenamevir per tablet. Recommended dose of 1 day, 400mg each time, after meals.

LINK https://newdrugapprovals.org/2018/03/12/amenamevir-%E3%82%A2%E3%83%A1%E3%83%8A%E3%83%A1%E3%83%93%E3%83%AB/

22A FORODESINE HYDROCHLORIDE

LINK  https://newdrugapprovals.org/2018/03/06/forodesine-hydrochloride/

6A BARICITINIB   JAPAN

Originally developed by Incyte, Baricitinib was later licensed to and for sale by Lilly under the trade name Olumiant®. Baricitinib is an irreversible inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2). Olumiant® is approved for the treatment of mild to moderate rheumatoid arthritis in adult patients who are not responsive or intolerant to other anti-arthritic drugs. This product can be used alone or in combination with methotrexate.

Olumiant® is a film-coated tablet containing 2 mg or 4 mg per tablet. Recommended oral dose is 4mg daily, with meals or fasting food, you can take any time period.

2017/7/3PMDA   Baricitinib Olumiant Lilly

LINK https://newdrugapprovals.org/2013/06/17/lilly-and-partner-incyte-corp-have-presented-more-promising-data-on-their-investigational-jak-inhibitor-baricitinib-for-rheumatoid-arthritis/

36C PEMAFIBRATE 

LINK   https://newdrugapprovals.org/2016/04/24/pemafibrate/

SECTION D

CDSCO INDIA


http://www.cdsco.nic.in/forms/list.aspx?lid=2034&Id=11 http://www.cdsco.nic.in/forms/list.aspx?lid=2034&Id=11

str1


 

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

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

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

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Anthony Melvin Crasto Dr.

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, ACALABRUTINIBAVELUMABBETRIXABANBRODALUMABCOPANLISIBDEFLAZACORTDelafloxacinDeutetrabenazineDUPILUMABETELCALCETIDENaldemedineNETARSUDILNIRAPARIBOcrelizumabPLECANATIDERIBOCICLIBSAFINAMIDETELOTRISTAT ETHYL, VALBENAZINE, CERLIPONASE, BRIGATINIB, MIDOSTAURIN, Abaloparatide, BENZNIDAZOLENERATINIBinotuzumab ozogamicinEnasidenib, 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, TIVOZANIB, SARILUMAB, FLUCICLOVINE, 

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Niraparib; MK 4827


ChemSpider 2D Image | Niraparib | C19H20N4ONiraparib.svgNiraparib.png

MK-4827,(S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxaMide

Niraparib; MK 4827; MK4827
UNII:HMC2H89N35
Antineoplastic, Poly(ADP-ribose) Polymerase Inhibitors

1038915-60-4 CAS, free form

str1

1038915-64-8 CAS HYDROCHLORIDE

1613220-15-7 cas TOSYLATE MONOHYDRATE

Figure imgf000023_0001

1038915-73-9  TOSYLATE

str1

MK-4827(Niraparib) tosylate is a selective inhibitor of PARP1/PARP2 with IC50 of 3.8 nM/2.1 nM; with great activity in cancer cells with mutant BRCA-1 and BRCA-2; >330-fold selective against PARP3, V-PARP and Tank1.
IC50 value: 3.8 nM/2.1 nM( PARP1/2) [1]
Target: PARP1/2
in vitro: MK-4827 displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibits PARP activity with EC(50) = 4 nM and inhibits proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range [1].
in vivo: MK-4827 is well tolerated in vivo and demonstrates efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer [1]. In addition, MK-4827 strongly enhances the effect of radiation on a variety of human tumor xenografts, both p53 wild type and p53 mutant. The enhancement of radiation response is observed in clinically relevant radiation-dose fractionation schedules. The therapeutic window during which time MK-4827 interacts with radiation lasts for several hours. These biological attributes make translation of this therapeutic combination treatment feasible for translation to the treatment of a variety of human cancers [2].

[1]. Jones P, et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.

[2]. Wang L, et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs. 2012 Dec;30(6):2113-20.

MERCK

Image result for MERCK

TESARO

Image result for TESARO

An inhibitor of poly (ADP-ribose) polymerase (PARP) with potential antineoplastic activity. PARP Inhibitor MK4827 inhibits PARP activity, enhancing the accumulation of DNA strand breaks and promoting genomic instability and apoptosis. The PARP family of proteins detect and repair single strand DNA breaks by the base-excision repair (BER) pathway. The specific PARP family member target for PARP inhibitor MK4827 is unknown. (NCI Thesaurus)

Niraparib (originally MK-4827)[1] is an orally active[2] small molecule PARP inhibitor being developed (by Tesaro) to treat ovarian cancer.

It is an inhibitor of PARP1 and PARP2.[3]

Niraparib is due to be submitted for FDA approval (for maintenance therapy in ovarian cancer) later in 2016.[4]

Chemically, MK-4827 is C19H20N4O[5] (ignoring a possible tosylate group).[6]

A 2012 study found that PARP inhibitors exhibit cytotoxic effects not based solely on their enzymatic inhibition of PARP, but by their trapping of PARP on damaged DNA, and the strength of this trapping activity was ordered niraparib >> olaparib >> veliparib.[7]

MEDICINAL CHEMISTRY APPROACH

Figure

The Medicinal Chemistry approach to compound 1 is shown in Scheme ABOVE. The racemic piperidine 2 was accessed by reduction of the 3-aryl pyridine 3 and then resolved by salt formation with tartaric acid. Protection of the piperidine nitrogen in enantiomerically upgraded piperidine 2 and condensation with aldehyde 4 afforded imine 5 which, after displacement of the nitro group with sodium azide, underwent a thermally promoted cyclisation to afford the 2-aryl indazole 6. Conversion of the ester functionality to a primary amide and deprotection afforded the active pharmaceutical ingredient (API) as the hydrochloride salt. A final chiral HPLC purification was then required to upgrade the enantiomeric purity to >98% ee, followed by lyophilization to give the desired compound 1 as an amorphous HCl salt.

str1NMR CD3OD

Clinical trials

It has undergone a phase III trial for ovarian cancer.[8] It is reported that the primary endpoint (progression-free survival, PFS) was met.[4] Patients with and without a BRCA mutation both showed longer PFS.[4]

As of June 2016 seven clinical trials have been registered for MK-4827.[9]

PAPER

http://pubs.acs.org/doi/abs/10.1021/op400233z

Process Development of C–N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib

Department of Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Department of Medicinal Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States
§ Department of Chemical Process Development and Commercialization, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Org. Process Res. Dev., 2014, 18 (1), pp 215–227
DOI: 10.1021/op400233z
This article is part of the Transition Metal-Mediated Carbon-Heteroatom Coupling Reactions special issue.

Abstract

Abstract Image

Process development of the synthesis of the orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed N-arylation of an indazole derivative as the late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions of racemic aldehyde surrogates provided enantioselective syntheses of the 3-aryl-piperidine coupling partner. Conversion of the C–N cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form.

PAPER

http://pubs.acs.org/doi/full/10.1021/op2000783

Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor

Global Process Chemistry, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K.
Global Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States
Department of Chemical Process Development and Commercialization, Merck and Co., Rahway, New Jersey, 07065, USA
WuXi APPTec (Shanghai) Pharmaceutical Co. Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
Org. Process Res. Dev., 2011, 15 (4), pp 831–840
DOI: 10.1021/op2000783

Abstract

Abstract Image

Compound (1) a poly(ADP-ribose)polymerase (PARP) inhibitor has been made by a fit-for-purpose large-scale synthesis using either a classical resolution or chiral chromatographic separation. The development and relative merits of each route are discussed, along with operational improvements and extensive safety evaluations of potentially hazardous reactions.

str1 str2

str1 as tosylate H20

1613220-15-7 cas

Free form 1038915-60-4

(S)-2-(4-(Piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide Tosylate Monohydrate 1

………………. The solid was collected and dried in vacuo at 40 °C to afford 1 as the tosylate monohydrate salt (797 g, 86%, >99 wt %, >99%ee) as a tan-coloured solid.
Mp = 144 °C. 1H NMR (600 MHz, CD3OD) δ 8.95 (1H, s), 8.15 (1H, dd, J = 7.1, 1.2 Hz), 8.02 (2H, m), 8.00 (1H, dd, J = 8.3, 1.2 Hz), 7.72 (2H, m), 7.49 (2H, m), 7.25 (1H, dd, J = 8.3, 7.1 Hz), 7.22 (2H, d, J = 8.0 Hz), 3.49–3.43 (2H, m), 3.16–3.04 (3H, m), 2.34 (3H, s), 2.09–2.05 (2H, m), 1.96–1.82 (2H, m).
13C NMR (150.9 MHz, CD3OD) δ 169.7, 148.1, 143.7, 143.0, 141.9, 140.5, 131.8, 130.0, 129.8, 127.3, 127.1, 125.4, 124.2, 123.3, 122.4, 50.2, 45.2, 41.1, 30.9, 24.0, 21.4.
 PAPER

Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors

IRBM/Merck Research Labs Rome, Via Pontina km 30,600, 00040 Pomezia, Italy
J. Med. Chem., 2009, 52 (22), pp 7170–7185
*To whom correspondence should be addressed. Current address: Department of Medicinal Chemistry, Merck Research Labs Boston, Avenue Louis Pasteur 33, Boston, MA 02115-5727. Phone: +1-617-992-2292. Fax: +1-617-992-2405. E-mail: philip_jones@merck.com.

Abstract

Abstract Image

We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10−100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

PATENT

https://www.google.com/patents/WO2014088983A1?cl=en

Image result for niraparib

EXAMPLE 1

The following Example 1 describes synthesis of the compound 2-{4-[(3S)-Piperidin enyl}-2H-indazole-7-carboxamide:

Figure imgf000023_0001

2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate 1

Scheme

Figure imgf000024_0001

1.1 Acylation

Figure imgf000024_0002

2- crystalline

10

A mixture of succinic anhydride 1 (110 g) and bromobenzene (695 mL) was cooled to below 5°C then added A1C13 (294 g). The slurry was allowed to warm to RT and then aged until the reaction was complete judged by HPLC. The reaction mixture was then transferred slowly into a cold HC1 solution resulting in the formation of a white precipitate. The white slurry was filtered through a fritted funnel rinsing with H20. To the off-white product was added MTBE and extracted with aq. NaOH. The aqueous layer was cooled in an ice bath. Concentrated HC1 was added drop wise to adjust the solution pH to 1 , resulting in the formation of a white slurry. The slurry was collected on a fritted funnel, rinsed with H20, and dried under vacuum with a N2 sweep at RT to give the target compound (265 g, 93% corrected yield) as a white powder.

1.2 Esterification

Figure imgf000025_0001

A mixture of the acid 2 (205 g), IPA (4 L) and cone. H2S04 (2.13 mL / 3.91 g) was heated to a gentle reflux until the reaction was complete judged by HPLC. The solution was then cooled to RT and concentrated to a volume of 350-400 mL. The residue was dissolved in

MTBE (1.2 L), washed with aq. Na2C03 followed by water. After dried over MgS04 , the filtrate was solvent-switched into heptane. The slurry was then filtered, and the cake was washed with cold heptane. After drying under vacuum, the target compound (223.5 g, 93% corrected yield) was obtained as a white powder.

1.3 Epoxidation

Figure imgf000025_0002

A mixture of Me3SOI (230 g) and DMSO (300 mL) was added KOt-Bu (113 g) followed by DMSO (300 mL). The mixture was aged for a further 1.5 hr. In a separate flask, ketone 3 (230 g) was dissolved in a mixture of THF (250 mL) and DMSO (150 mL), and the resulting solution was added drop wise to the ylide solution. The mixture was aged for 2 hr at RT, added hexanes (1 L), and then quenched by the addition of ice-water (600 mL). The layers were cut, and the organic layer was washed with water then with brine. The slightly cloudy yellow organic layer was dried over Na2S04 and filtered through a fritted funnel. Product solution assay was 176.1 g (76%> assay yield). This solution was carried forward into the rearrangement step. 1.4 Epoxide rearrangement and bisulfite formation

Figure imgf000026_0001

5 – not isolated

Figure imgf000026_0002

A solution of crude epoxide 4 (assay 59.5 g) in hexanes was solvent switched into PhMe, and added ZnBr2 (10.7 g). When the rearrangement was complete judged by HPLC, the slurry was filtered through a fritted funnel. The clear filtrate was washed with 10% aq. NaCl and then stirred with a solution of sodium bisulfite (NaHS03, 24.7 g) in H20 (140 mL) vigorously at RT for 3 hr. The cloudy aqueous layer was separated and washed with heptanes. By 1H-NMR assay, the aqueous solution contained 71.15 g bisulfite adduct 6 (30.4 wt % solution, 90%) yield from crude epoxide 4). This solution was used directly in the subsequent transaminase step.

1.5 Transaminase DKR

Figure imgf000026_0003

45 C, inert, 40-46 hrs 7

100 g/L as 17.16 wt % aq solution 99.3% ee

85-87% yield

To a cylindrical Labfors reactor was charged pyridoxal-5 -phosphate (1.4 g, 5.66 mmol), 452 ml 0.2 M borate buffer pH 10.5 containing 1M iPrNH2, 52 g transaminase (SEQ ID NO: 180), and 75 ml DMSO, and the resulting mixture was warmed to 45°C. The pH was controlled at pH 10.5 using 8 M aq iPrNH2. To this was added dropwise a mixture of 17.16 wt% aq solution of ester bi-sulfite 6 (147.2 g, 353 mmol) and 219 ml DMSO under N2 atmosphere. When the reaction was complete judged by HPLC, the reaction mixture was cooled and extracted with 1 volume of 3:2 IPA:IPAc. The aq/rag layer was extracted again with 1 volume of 3:7 IPATPAc. The organic layer was washed with brine at pH >9. Assay yield in solution was 78 g (87%); 99.3% ee. After dried over MgS04, and filtered through a fritted funnel, the crude solution was concentrated under vacuum flushing with IP Ac to remove IPA. The resulting slurry was concentrated to a final volume of -200 mL, cool to below 0°C, and filtered to collect the solid. The cake was washed with ice-cold IPAc and dried at RT under vacuum to give the desired product (84% corrected yield, 99.3 LCAP) as a white powder. 1.6. Reduction of amide

Figure imgf000027_0001

(S)-3-(4-bromophenyl)piperidine

The lactam 7 can be reduced to form the i eridine 8 as described below:

Figure imgf000027_0002

7 – crystalline

A mixture of lactam 7 (10.25 g at 97.5 wt %) in THF (100 mL) was cooled to < 10°C, and added NaBH4 (4.47 g). EtOH (6.89 mL) was then added slowly over 20 min. The slurry was aged for an additional 1 hr at 2°C after which BF3 THF (13.03 mL) was added over 1 hr. The slurry was slowly warmed to RT and aged until complete conversion judged by HPLC. The reaction was then cooled to < 5°C then slowly quenched with MeOH (7.96 mL), added HC1 (9.69 mL), then the reaction was heated to 45°C until decomplexation of product-borane complex was complete, as indicated by LC assay. The reaction was cooled, diluted with IPAc (75 mL) and water (80 mL), and then pH was adjusted with aqueous NH4OH to pH 8. The organic layer was separated, added 75 mL water, then pH adjusted to 10.5 with 50 wt % NaOH. The layers were separated and the organic layer was washed with brine. After solvent-switched to IPAc, LC Assay yield was 9.1g; 95.9%.

1.7 Tosylate salt formation The tosylate salt of the piperidine 8 can be formed as described below:

Figure imgf000028_0001

The crude piperidine 8 free base in IPA was heated to ~40°C. TsOH H20 solids was added portion-wise. The slurry was warmed to 50°C and held at that temperature for 2 h, and then slowly cooled to RT and aged overnight. Supernatant concentration was measured to be 2.5 g/ml (free base concentration). The solids were filtered and washed with IP Ac (3×15 mL) and dried at RT. Isolated solides: 14.85 g, 96% corrected isolated yield.

1.8 Boc protection

The piperi ine 8 tosylate salt can be protected as described below:

Figure imgf000028_0002

To a stirred slurry of the tosylate salt of piperidine 8 (25.03 g, 60.6 mmol) in MTBE (375 ml) was added NaOH (aq. 1.0 N, 72.7 ml, 72.7 mmol) at RT. To the mixture, (BOC)20 (13.36 ml, 57.6 mmol) was added slowly over 3 min. The resulting mixture was stirred for 4.5 hr at RT, and then the aqueous layer was separated. The MTBE layer was washed with water (100 ml X 2). The organic layer was filtered, and DMAC (100 ml) was added to the filtrate and

concentrated under vacuum. Product assay: 21.86 g, quantitative yield.

1.9 Terf-Butylamide Formation

Figure imgf000028_0003

N-(tert-butyl)- 1 H-indazole-7-carboxamide

Figure imgf000029_0001

10 11

Indazole-7-carboxylic acid 10 (50.3 g, 295 mmol) was dissolved in DMF, and added CDI (59.1 g, 354 mmol) at RT. After 1.5hr, tert-butylamine (62.5 ml, 589 mmol) was added to the reaction mixture. The resulting reaction mixture was warmed to 40 °C until complete

conversion, then cooled to RT. Water (600 ml) was added dropwise causing the mixture to form a thick slurry. Solid was collected by filtration and washed with 10% DMF in water (250 ml) followed by water. The solid was dried under vacuum. Beige solid: 55.31 g, 86%> isolated yield.

1.10 Carbon-Nitrogen Coupling

Figure imgf000029_0002

(S)-tert-butyl 3-(4-(7-(tert-butylcarbamoyl)-2H-indazol-2-yl)phenyl)piperidine- 1 -carboxylate

Figure imgf000029_0003

A mixture of the protected piperidine 9 (113 g, 18.23 wt%, 60.6 mmol) in DMAc (160 mL), compound 11 (13.82 g, 63.6 mmol), and K2CO3 (25.6 g, 182 mmol) was degassed by bubbling nitrogen. To the mixture was added CuBr (0.444 g, 3.03 mmol) and 8- hydroxyquinoline 12 (0.889 g, 6.06 mmol), and the resulting mixture was warmed to 110°C until complete conversion. The reaction mixture was then cooled, filtered through a pad of Celite, and rinsed with DMAc (100 ml). The filtrate was warmed to 35°C and added citric acid aqueous solution (10%) dropwise to form a light green slurry. After cooled to room temperature, the slurry was filtered, and the cake was washed with DMAc/Water (2/1, 150ml) followed by copious amount of water. The solid was dried under vacuum with nitrogen. Net weight: 27.24g. LC assay: 26.77g, 98.3 wt %. Assay yield: 93.6%.

1.11 Double deprotection

Figure imgf000030_0001

To compound 13 (20.0 g, 41.2 mmol) was added MSA (60 ml) and o-xylene (40 ml), and the the reaction mixture was warmed to 40°C until the complete conversion judged by HPLC. The reaction mixture was cooled to RT and added water (140 ml) slowly maintaining the temperature < 25°C. When the water addition was completed, the organic layer was removed, and the aq. layer was washed with toluene. The aqueous layer was filtered through a glass funnel, and the filtrate was added an aqueos solution of TsOH (11.77g in 23.5 ml) slowly at RT causing a thick slurry to form. Solid was collected by filtration, washed with water, and dried under vacuum. The titled compound was obtained as a white powder. Net weight: 20.6 g. LC assay: 20.0 g, 97.3 wt %. Assay yield: 95.2%.

EXAMPLE 2

The following Example 2 describes synthesis of the trifluoromethylacetate salt of compound 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide:

2.1 Cumylamide Formation

Figure imgf000031_0001

N-(2-phenylpropan-2-yl)- 1 H-indazole-7-carboxamide

Figure imgf000031_0002

10 1 5

10

To the indazole-7-carboxylic acid 10 (400 mg, 2.47 mmol) in tetrahydrofuran (9.9 mL), was sequentially added HATU (1.13 g, 2.96 mmol), DIPEA (2.15 mL, 12.3 mmol), and cumylamine (500 mg, 3.70 mmol) at 50°C. The reaction was stirred overnight before being concentrated and loaded directly onto a silica column, eluting with 10-30% EtOAc/hexane. The product was collected and concentrated to afford the desired product as a colorless solid (557 mg, 81% yield).

2.2 Carbon-Nitrogen Coupling

Figure imgf000031_0003

-butyl 3-(4-(7-((2-phenylpropan-2-yl)carbamoyl)-2H-indazol-2-yl)phenyl)piperidine- carboxylate

Figure imgf000031_0004

15 16

A sealed vial containing the indazole-7-carboxamide 15 (50 mg, 0.18 mmol), copper(I) iodide (2.6 mg, 0.014 mmol), potassium phosphate tribasic (80 mg, 0.38 mmol), and aryl bromide 9 (73.1 mg, 0.215 mmol) was evacuated and backfilled with argon (x3). Trans-N,N’- dimethylcyclohexane-l,2-diamine (11.3 μΐ,, 0.072 mmol), and toluene (179 μΐ) were then added successively and the sealed vial was heated at 110 °C overnight. The vial was then cooled and toluene (0.30 mL) was added to the slurry. Crude LC/MS indicated >20: 1 selectivity for the desired indazole isomer. The crude product was purified by loading directly onto a Biotage Snap 10G silica column, eluting with 5-50% EtOAc/hexane. The product was collected and concentrated to afford the desired product as a colorless solid (78 mg, 81% yield).

2.3 Double deprotection

Figure imgf000032_0001

(5)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide trifluoromethylacetate salt

Figure imgf000032_0002

16 17

To the piperidine-l-carboxylate 16 (45 mg, 0.084 mmol), was added triethylsilane (267 μί, 1.67 mmol) and TFA (0.965 mL, 12.5 mmol) at 25°C. The reaction was stirred for 4 hours and the reaction was concentrated in vacuo, and purified by mass triggered reverse phase HPLC (acetonitrile: water, with 0.1% TFA modifier). Lyphilization gave the desired product as the TFA salt and as a white solid (31 mg, 85% yield). HRMS (ESI) calc’d for Ci9H2iN40 [M+H]+: 321.1710, found 321.1710.

EXAMPLE 3

Following the conditions used in sections 2.1 and 2.2 of Example 2, this Example 3 shows regioselective N2 arylation of compound 9 using various amide protecting groups. The indazole-7-carboxylic acid 10 was reacted with various amines to generate a protected amide.

The amide protecting groups are indicated by the R group in Table 2. The amide coupling yield is provided in Table 2. The Cu-mediated carbon-nitrogen coupling of this indazole to compound 9 was then tested to determine if regioselective N2 arylation was possible. The arylation yield is also provided in Table 2. The data shows that various amide protecting groups on the indazole intermediate are suitable to generate efficient regioselective N2 arylation of compound 9.

Figure imgf000033_0001
Figure imgf000033_0002
PATENT
 WO 2008084261

The present invention relates to amide substituted indazoles which are inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), previously known as poly(ADP-ribose)synthase and poly(ADP-ribosyl)transferase. The compounds of the present invention are useful as monotherapies in tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA-damaging agents such as anticancer agents and radiotherapy. Further, the compounds of the present invention are useful for reducing cell necrosis (in stroke and myocardial infarction), down regulating inflammation and tissue injury, treating retroviral infections and protecting against the toxicity of chemotherapy.
Poly(ADP-ribose) polymerase (PARP) constitute a super family of eighteen proteins containing PARP catalytic domains (Bioessays (2004) 26:1148). These proteins include PARP-1, PARP-2, PARP-3, tankyrase-1, tankyrase-2, vaultPARP and TiPARP. PARP-I, the founding member, consists of three main domains: an amino (N)-terminal DNA-binding domain (DBD) containing two zinc fingers, the automodification domain, and a carboxy (C)-terminal catalytic domain.
PARP are nuclear and cytoplasmic enzymes that cleave NAD+ to nicotinamide and ADP-ribose to form long and branched ADP-ribose polymers on target proteins, including
topoisomerases, histones and PARP itself (Biochem. Biophys. Res. Commun. (1998) 245:1-10).

Poly(ADP-ribosyl)ation has been implicated in several biological processes, including DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability.
The catalytic activity of PARP-I and PARP-2 has been shown to be promptly stimulated by DNA strand breakages (see Pharmacological Research (2005) 52:25-33). In response to DNA damage, PARP-I binds to single and double DNA nicks. Under normal physiological conditions there is minimal PARP activity, however, upon DNA damage an immediate activation of PARP activity of up to 500-fold occurs. Both PARP-I and PARP-2 detect DNA strand interruptions acting as nick sensors, providing rapid signals to halt transcription and recruiting the enzymes required for DNA repair at the site of damage. Since radiotherapy and many chemotherapeutic approaches to cancer therapy act by inducing DNA damage, PARP inhibitors are useful as chemo- and radiosensitizers for cancer treatment. PARP inhibitors have been reported to be effective in radio sensitizing hypoxic tumor cells (US 5,032,617, US
5,215,738 and US 5,041,653).
Most of the biological effects of PARP relate to this poly (ADP-ribosyl)ation process which influences the properties and function of the target proteins; to the PAR oligomers that, when cleaved from poly(ADP-ribosyl)ated proteins, confer distinct cellular effects; the physical association of PARP with nuclear proteins to form functional complexes; and the lowering of the cellular level of its substrate NAD+ (Nature Review (2005) 4:421-440).
Besides being involved in DNA repair, PARP may also act as a mediator of cell death. Its excessive activation in pathological conditions such as ischemia and reperfusion injury can result in substantial depletion of the intercellular NAD+, which can lead to the impairment of several NAD+ dependent metabolic pathways and result in cell death (see Pharmacological Research (2005) 52:44-59). As a result of PARP activation, NAD+ levels significantly decline. Extensive PARP activation leads to severe depletion OfNAD+ in cells suffering from massive DNA damage. The short half-life of poly(ADP-ribose) results in a rapid turnover rate, as once poly(ADP-ribose) is formed, it is quickly degraded by the constitutively active poly(ADP-ribose) glycohydrolase (PARG). PARP and PARG form a cycle that converts a large amount OfNAD+ to ADP-ribose, causing a drop OfNAD+ and ATP to less than 20% of the normal level. Such a scenario is especially detrimental during ischemia when deprivation of oxygen has already drastically compromised cellular energy output. Subsequent free radical production during reperfusion is assumed to be a major cause of tissue damage. Part of the ATP drop, which is typical in many organs during ischemia and reperfusion, could be linked to NAD+ depletion due to poly(ADP-ribose) turnover. Thus, PARP inhibition is expected to preserve the cellular energy level thereby potentiating the survival of ischemic tissues after insult. Compounds which are inhibitors of PARP are therefore useful for treating conditions which result from PARP mediated cell death, including neurological conditions such as stroke, trauma and Parkinson’s disease.
PARP inhibitors have been demonstrated as being useful for the specific killing of BRCA-I and BRCA-2 deficient tumors {Nature (2005) 434:913-916 and 917-921; and Cancer Biology & Therapy (2005) 4:934-936).
PARP inhibitors have been shown to enhance the efficacy of anticancer drugs
{Pharmacological Research (2005) 52:25-33), including platinum compounds such as cisplatin and carboplatin {Cancer Chemother Pharmacol (1993) 33:157-162 and MoI Cancer Ther (2003) 2:371-382). PARP inhibitors have been shown to increase the antitumor activity of
topoisomerase I inhibitors such as Irinotecan and Topotecan (MoI Cancer Ther (2003) 2:371-382; and Clin Cancer Res (2000) 6:2860-2867) and this has been demonstrated in in vivo models (J Natl Cancer Inst (2004) 96:56-67).
PARP inhibitors have been shown to restore susceptibility to the cytotoxic and antiproliferative effects of temozolomide (TMZ) (see Curr Med Chem (2002) 9:1285-1301 and Med Chem Rev Online (2004) 1:144-150). This has been demonstrated in a number of in vitro models (Br J Cancer (1995) 72:849-856; Br J Cancer (1996) 74:1030-1036; MoI Pharmacol (1997) 52:249-258; Leukemia (1999) 13:901-909; GUa (2002) 40:44-54; and Clin Cancer Res (2000) 6:2860-2867 and (2004) 10:881-889) and in vivo models (Blood (2002) 99:2241-2244; Clin Cancer Res (2003) 9:5370-5379 and J Natl Cancer Inst (2004) 96:56-67). PAPR inhibitors have also been shown to prevent the appearance of necrosis induced by selective Λ3 -adenine methylating agents such as MeOSC>2(CH2)-lexitropsin (Me-Lex) {Pharmacological Research (2005) 52:25-33).
PARP inhibitors have been shown to act as radiation sensitizers. PARP inhibitors have been reported to be effective in radiosensitizing (hypoxic) tumor cells and effective in preventing tumor cells from recovering from potentially lethal {Br. J. Cancer (1984) 49(Suppl. VI):34-42; and Int. J. Radial Bioi. (1999) 75:91-100) and sub-lethal {Clin. Oncol. (2004) 16(l):29-39) damage of DNA after radiation therapy, presumably by their ability to prevent DNA strand break rejoining and by affecting several DNA damage signaling pathways.
PARP inhibitors have also been shown to be useful for treating acute and chronic myocardial diseases (see Pharmacological Research (2005) 52:34-43). For instance, it has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of 3-amino-benzamide (10 mg/kg), either one minute before occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32-42%) while 1,5-dihydroxyisoquinoline (1 mg/kg), another PARP inhibitor, reduced infarct size by a comparable degree (38-48%). These results make it reasonable to assume that PARP inhibitors could salvage previously ischemic heart or reperfusion injury of skeletal muscle tissue {PNAS (1997) 94:679-683). Similar findings have also been reported in pigs {Eur. J. Pharmacol. (1998) 359:143-150 and Ann. Thorαc. Surg. (2002) 73:575-581) and in dogs (Shock. (2004) 21:426-32). PARP inhibitors have been demonstrated as being useful for treating certain vascular diseases, septic shock, ischemic injury and neurotoxicity {Biochim. Biophys. Actα (1989) 1014:1-7; J Clin. Invest. (1997) 100: 723-735). Oxygen radical DNA damage that leads to strand breaks in DNA, which are subsequently recognized by PARP, is a major contributing factor to such disease states as shown by PARP inhibitor studies (J Neurosci. Res. (1994) 39:38-46 and PNAS (1996) 93:4688-4692). PARP has also been demonstrated to play a role in the
pathogenesis of hemorrhagic shock {PNAS (2000) 97:10203-10208).
PARP inhibitors have been demonstrated as being useful for treatment of inflammation diseases (see Pharmacological Research (2005) 52:72-82 and 83-92).
It has also been demonstrated that efficient retroviral infection of mammalian cells is blocked by the inhibition of PARP activity. Such inhibition of recombinant retroviral vector infections has been shown to occur in various different cell types (J Virology, (1996)
70(6): 3992-4000). Inhibitors of PARP have thus been developed for use in anti- viral therapies and in cancer treatment (WO 91/18591).
In vitro and in vivo experiments have demonstrated that PARP inhibitors can be used for the treatment or prevention of autoimmune diseases such as Type I diabetes and diabetic complications {Pharmacological Research (2005) 52:60-71).
PARP inhibition has been speculated as delaying the onset of aging characteristics in human fibroblasts {Biochem. Biophys. Res. Comm. (1994) 201(2):665-672 and Pharmacological Research (2005) 52:93-99). This may be related to the role that PARP plays in controlling telomere function (Nature Gen., (1999) 23(l):76-80).
The vast majority of PARP inhibitors to date interact with the nicotinamide binding domain of the enzyme and behave as competitive inhibitors with respect to NAD+(Expert Opin. Ther. Patents (2004) 14:1531-1551). Structural analogues of nicotinamide, such as benzamide and derivatives were among the first compounds to be investigated as PARP inhibitors.
However, these molecules have a weak inhibitory activity and possess other effects unrelated to PARP inhibition. Thus, there is a need to provide potent inhibitors of the PARP enzyme.
Structurally related PARP inhibitors have previously been described. WO 1999/59973 discloses amide substituted benzene rings fused to 5 membered heteroaromatic rings;
WO2001/85687 discloses amide substituted indoles; WO 1997/04771, WO 2000/26192, WO 2000/32579, WO 2000/64878, WO 2000/68206, WO 2001/21615, WO 2002/068407, WO 2003/106430 and WO 2004/096793 disclose amide substituted benzo imidazoles; WO
2000/29384 discloses amide substituted benzoimidazoles and indoles; and EP 0879820 discloses amide substituted benzoxazoles.
It has now surprisingly been discovered that amide substituted indazoles of the present invention exhibit particularly high levels of inibition of the activity of poly(ADP-ribose)polymerase (PARP). Thus the compounds of the present invention are particularly useful as inhibitors of PARP-I and/or PARP-2. They also show particularly good levels of cellular activity, demonstrating good anti-proliferative effects in BRCAl and BRCA2 deficient cell lines.

The present invention provides compounds of formula I:

Scheme 1

A procedure to synthesize derivatives of those compounds of this invention is shown in scheme 1, whereby the substituted 2H-indazoles are prepared using a synthetic route similar to that described in WO 2005/066136. Following initial conversion of the 2-nitro-3-methyl-benzoic acid derivative into the corresponding ester, radical bromination of the methyl group using reagents like N-bromosuccinimide and benzoyl peroxide yields the key benzyl bromide derivative. Oxidation of this benzylic bromide to the corresponding benzaldehyde can be accomplished for instance using 7V-methylmorpholine-7V-oxide and molecular sieves. Following the condensation of the aldehyde with an amine, ring closure can be accomplished by treating the key intermediate with sodium azide at elevated temperature to introduce the final nitrogen atom and the resultant extrusion of nitrogen to furnish the indazole ring. A base such as lutidine can also be added to this reaction. Final conversion of the ester to the primary amide yields the desired derivatives. This can be accomplished either by heating the ester in an ammonia solution or by conversion to the corresponding carboxylic acid and then amide coupling.

Rx = C1-6alkyl
Oxidation
e.g. NMMO, mol sieves

NH3, THF or MeOH,
700C sealed tube, or
NaOH or KOH, NH3, HATU
or TBTU, DIPEA, DMF, RT
Scheme 1

Scheme 2
A variation of schemes 1 is shown below in scheme 2 and allows the introduction of substituents onto the indazole cores. When the required nitrobenzoic acid derivatives are not commercial available they can be prepared through nitration of the corresponding benzoic acid derivatives, for instance using potassium nitrate in concentrated sulphuric acid. Synthetic manipulations as decribed above allow the formation of the corresponding aniline which can either be cyclised to the indazole by firstly acetylation of the indazole and cyclisation with sodium nitrite in concentrated HCl acid at O0C. Alternatively, the aniline can be diazonitised with nitrosium tetrafluoroborate and the corresponding diazonium tetrafluoroborate salt decomposed at elevated temperatures to the corresponding dilfluorobenzene derivative by a Schiemann reaction
(Caution). Following the synthetic sequence as described in scheme 1 allows oxidation of the benzylic methyl group to the corresponding aldehyde and elaboration of the desired indazole derivatives by coupling with a (hetero)anilide and cyclisation with sodium azide.

Nitration Esterifi cation
KNO3, cone. e.g. AcCI, MeOH,



Reduction
H2, Pd/C

Scheme 2 Scheme 3
An alternative procedure involves functionalisation of the indazole at a late stage as shown in scheme 3. Here the indazole ester is first converted to the corresponding carboxamide and the subjected to nucleophilic aromatic substitution of the appropriate fluoro(hetero)aromatic bromide. This allows the preparation of a bromide derivative that can be cross coupled under Suzuki coupling conditions, for instance using tri(tert-butyl)phosphine and Pd2(dba)3 as catalysts in the presence of a base, such as sodium carbonate. Conversion to the desied piperidine moiety is then accomplished by a Fowler reaction using an acyl chloride, such as CBz-Cl and a reducing agent such as NaBH4. Final hydrogenation reaction can yield the corresponding piperidine derivatives.

Suzuki coupling

Scheme 3

PATENT
WO 2009087381
PATENT CITATIONS
Cited Patent Filing date Publication date Applicant Title
US8071623 * Jan 8, 2008 Dec 6, 2011 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors
US8129377 * Sep 29, 2005 Mar 6, 2012 Mitsubishi Tanabe Pharma Corporation 6-(pyridinyl)-4-pyrimidone derivates as tau protein kinase 1 inhibitors
US20100286203 * Jan 8, 2009 Nov 11, 2010 Foley Jennifer R Pharmaceutically acceptable salts of 2–2h-indazole-7-carboxamide
NON-PATENT CITATIONS
Reference
1 * CHUNG ET AL.: “Process Development of C-N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib.“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 18, no. 1, 2014, pages 215 – 227, XP055263728
2 * JONES ET AL.: “Discovery of 2-(4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ( MK -4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors.“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 22, 2009, pages 7170 – 7185, XP055263725
3 * WALLACE ET AL.: “Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor.“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 15, no. 4, 2011, pages 831 – 840, XP055263721
REFERENCED BY
Citing Patent Filing date Publication date Applicant Title
WO2016025359A1 * Aug 10, 2015 Feb 18, 2016 Merck Sharp & Dohme Corp. Processes for the preparation of a bace inhibitor

References

Further reading

1 to 6 of 6
Patent ID Patent Title Submitted Date Granted Date
US2015299167 Regioselective N-2 Arylation of Indazoles 2013-12-03 2015-10-22
US8889707 Treatment of addiction 2013-02-07 2014-11-18
US2013184342 METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASE 2013-03-13 2013-07-18
US2012035244 PARP1 TARGETED THERAPY 2012-02-09
US8071623 Amide substituted indazoles as poly(ADP-ribose)polymerase(PARP) inhibitors 2008-07-10 2011-12-06
US2010286203 PHARMACEUTICALLY ACCEPTABLE SALTS OF 2–2H-INDAZOLE-7-CARBOXAMIDE 2010-11-11
Niraparib
Niraparib.svg
Clinical data
Routes of
administration
By mouth
Legal status
Legal status
  • US: Investigational
Identifiers
CAS Number 1038915-60-4 Yes
PubChem (CID) 24958200
ChemSpider 24531930 Yes
UNII HMC2H89N35 Yes
ChEMBL CHEMBL1094636 Yes
Chemical and physical data
Formula C19H20N4O
Molar mass 320.394 g/mol
3D model (Jmol) Interactive image

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.

//////////1613220-15-7, 1038915-60-4, 2-[4-(3S)-3-Piperidinylphenyl]-2H-indazole-7-carboxamide, Niraparib, mk 4827, Antineoplastic, Poly(ADP-ribose) Polymerase Inhibitors
c1(cccc2c1nn(c2)c1ccc(cc1)[C@H]1CNCCC1)C(=O)N
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