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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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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, 

Copanlisib


Copanlisib.svgChemSpider 2D Image | Copanlisib | C23H28N8O4

Copanlisib, BAY 80-6946, 

  • BAY 84-1236
  • Molecular FormulaC23H28N8O4
  • Average mass480.520 Da

Cas 1032568-63-0 [RN]

1402152-26-4 MONO HCL

UNII-WI6V529FZ9

FDA Approved September 2017

2-Amino-N-{7-methoxy-8-[3-(4-morpholinyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-5-pyrimidinecarboxamide
5-Pyrimidinecarboxamide, 2-amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy]imidazo[1,2-c]quinazolin-5-yl]-

Copanlisib (BAY 80-6946), developed by Bayer, is a selective Class I phosphoinositide 3-kinase inhibitor[1] which has shown promise in Phase I/II clinical trials for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia.[2]

Image result for copanlisib

Copanlisib is a selective pan-Class I phosphoinositide 3-kinase (PI3K/Phosphatidylinositol-4,5-bisphosphate 3-kinase/phosphatidylinositide 3-kinase) inhibitor that was first developed by Bayer Healthcare Pharmaceuticals, Inc. The drug targets the enzyme that plays a role in regulating cell growth and survival. Copanlisib was granted accelerated approval on September 14, 2017 under the market name Aliqopa for the treatment of adult patients with relapsed follicular lymphoma and a treatment history of at least two prior systemic therapies. Follicular lymphoma is a slow-growing type of non-Hodgkin lymphoma that is caused by unregulated proliferation and growth of lymphocytes. The active ingredient in Aliquopa intravenous therapy is copanlisib dihydrochloride.

Image result for copanlisib

Copanlisib dihydrochloride.pngCopanlisib dihydrochloride; UNII-03ZI7RZ52O; 03ZI7RZ52O; 1402152-13-9; BAY 80-6946 dihydrochloride;

Image result for copanlisib

1402152-46-8 CAS  X=4, 

1919050-77-3 CAS X=1

The FDA awarded copanlisib orphan drug status for follicular lymphoma in February 2015.[3]

Phase II clinical trials are in progress for treatment of endometrial cancer,[4] diffuse large B-cell lymphoma,[5] cholangiocarcinoma,[6]and non-Hodgkin lymphoma.[7] Copanlisib in combination with R-CHOP or R-B (rituximab and bendamustine) is in a phase III trial for relapsed indolent non-Hodgkin lymphoma (NHL).[8] Two separate phase III trials are investigating the use of copanlisib in combination with rituximab for indolent NHL[9] and the other using copanlisib alone in cases of rituximab-refractory indolent NHL.[10]

Copanlisib hydrochloride, a phosphatidylinositol 3-Kinase inhibitor developed by Bayer, was first approved and launched in 2017 in the U.S. for the intravenous treatment of adults with relapsed follicular lymphoma who have received at least two prior treatments.

In 2015, orphan drug designation was assigned in the U.S. for the treatment of follicular lymphoma. In 2017, additional orphan drug designations were granted in the U.S. for the treatment of splenic, nodal and extranodal marginal zone lymphoma.

SYN

WO 2017049983

PATENTS

WO 2008070150

Inventors Martin HentemannJill WoodWilliam ScottMartin MichelsAnn-Marie CampbellAnn-Marie BullionR. Bruce RowleyAniko RedmanLess «
Applicant Bayer Schering Pharma Aktiengesellschaft

Example 13

Preparation of 2-amino-N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazori^-clquinazolin-S-vHpvrimidine-S-carboxamide.

Figure imgf000084_0001

Step 1 : Preparation of 4-hvdroxy-3-methoxy-2-nitrobenzonitrile

Figure imgf000084_0002

4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (200 g, 1.01 mol) was dissolved in THF (2.5 L) and then ammonium hydroxide (2.5 L) was added followed by iodine (464 g, 1.8 mol). The resulting mixture was allowed to stir for 2 days at which time it was concentrated under reduced pressure. The residue was acidified with HCI (2 N) and extracted into diethyl ether. The organic layer was washed with brine and dried (sodium sulfate) and concentrated under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to provide the title compound (166 g, 84%): 1H NMR (DMSO-cfe) δ: 11.91 (1 H, s), 7.67 (1 H, d), 7.20 (1 H, d), 3.88 (3H, s)

Step 2: Preparation of 3-methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile

Figure imgf000084_0003

To a solution of 4-hydroxy-3-methoxy-2-nitrobenzonitrile (3.9 g, 20.1 mmol) in DMF (150 mL) was added cesium carbonate (19.6 g, 60.3 mmol) and Intermediate C (5.0 g, 24.8 mmol). The reaction mixture was heated at 75 0C overnight then cooled to room temperature and filtered through a pad of silica gel and concentrated under reduced pressure. The material thus obtained was used without further purification

Step 3: Preparation of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile

Figure imgf000085_0001

3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile (7.7 g, 24.1 mmol) was suspended in acetic acid (170 ml_) and cooled to 0 °C. Water (0.4 ml_) was added, followed by iron powder (6.7 g, 120 mmol) and the resulting mixture was stirred at room temperature for 4 h at which time the reaction mixture was filtered through a pad of Celite and washed with acetic acid (400 ml_). The filtrate was concentrated under reduced pressure to 100 mL and diluted with EtOAc (200 ml.) at which time potassium carbonate was added slowly. The resulting slurry was filtered through a pad of Celite washing with EtOAc and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and passed through a pad of silica gel. The resultant solution was concentrated under reduced pressure to provide the title compound (6.5 g, 92%): 1H NMR (DMSO-Cf6) δ: 7.13 (1 H1 d), 6.38 (1 H, d), 5.63 (2H1 br s), 4.04 (2H, t), 3.65 (3H, s), 3.55 (4H1 br t), 2.41 (2H, t), 2.38 (4H1 m), 1.88 (2H1 quint.).

Step 4: Preparation of 6-(4.5-dihvdro-1 H-imidazol-2-v0-2-methoxy-3-(3-morpholin- 4-ylpropoxy)aniline

Figure imgf000085_0002

To a degassed mixture of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (6.5 g, 22.2 mmol) and ethylene diamine (40 mL) was added sulfur (1.8 g, 55.4 mmol). The mixture was stirred at 100 °C for 3 h at which time water was added to the reaction mixture. The precipitate that was formed was collected and washed with water and then dried overnight under vacuum to provide the title compound (3.2 g, 43%): HPLC MS RT = 1.25 min, MH+= 335.2; 1H NMR (DMSO-Cf6) δ: 7.15 (1H, d), 6.86 (2H, br s), 6.25 (1 H, d), 4.02 (2H, t), 3.66 (3H, s), 3.57 (8H, m), 2.46 (2H, t), 2.44 (4H, m), 1.89 (2H, quint.). Step 5: Preparation of 7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazof1.2-clquinazolin-5-amine

Figure imgf000086_0001

Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture of 6-(4,5-dihydro-1 H- imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline (17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200 ml_) precooled to 0 0C. After 1 h the reaction mixture was concentrated under reduced pressure and the resulting residue stirred with EtOAc (300 mL) overnight at rt. The resulting slurry was filtered to generate the title compound contaminated with triethylamine hydrobromide (26.2 g, 71%): HPLC MS RT = 0.17 min, MH+= 360.2.

Step 6: Preparation of 2-amino-N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazori ^-clquinazolin-S-vnpyrimidine-δ-carboxamide.

Figure imgf000086_0002

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 mL), and Intermediate B (46 mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give the title compound (42.7 mg, 40%): HPLC MS RT = 1.09 min, MH+= 481.2; 1H NMR (DMSO-Cf6 + 2 drops TFA-tf) δ: 9.01 (2H, s), 8.04 (1 H, d), 7.43 (1 H, d), 4.54 (2H, m), 4.34 (2H, br t), 4.23 (2H, m), 4.04 (2H, m), 4.00 (3H, s), 3.65 (2H, br t), 3.52 (2H, m), 3.31 (2H, m), 3.18 (2H, m), 2.25 (2H, m).

PATENT

CN 105130998

TRANSLATED

Example VI:

[0053] a nitrogen atmosphere, the reaction flask was added 7-methoxy-8- (3-morpholin-4-yl-propoxy) -2,3-dihydro-imidazo [l, 2-c] quinoline tetrazol-5-amine (V) (0 • 36g, lmmol), 2- amino-5-carboxylic acid (0 • 15g, l.lmmol) and acetonitrile 25mL, condensing agent added benzotriazole-1-yl yloxy-tris (dimethylamino) phosphonium hexafluorophosphate key (0.49g, 1. lmmol) and the base catalyst 1,5_-diazabicyclo [4. 3.0] – non-5-ene (0 . 50g, 4mmol), at room temperature for 12 hours.Then heated to 50-60 ° C, the reaction was stirred for 6-8 hours, TLC the reaction was complete. The solvent was distilled off under reduced pressure, cooled to room temperature, ethyl acetate was added solid separated. Filter cake washed with cold methanol and vacuum dried to give an off-white solid Kupannixi (1) 0.278, showing a yield of 56.3% -] \ ^ 111/2: 481 [] \ 1+ buckle + 1 111 bandit ? (square) (: 13). 5 2.05 (111,211), 2.48 (111,411), 2. 56 (m, 2H), 3 72 (t, 4H), 4 02 (s, 3H),. 4. 16 (m, 7H), 5. 36 (s, 2H), 6. 84 (d, 1H), 7. 08 (d, 1H), 9. 10 (s, 2H) square

PATENT

WO 2016071435

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (10), (which is hereinafter referred to as„copanlisib”), is a proprietary cancer agent with a novel mechanism of action, inhibiting Class I phosphatidylinositol-3-kinases (PI3Ks). This class of kinases is an attractive target since PI3Ks play a central role in the transduction of cellular signals from surface receptors for survival and proliferation. Copanlisib exhibits a broad spectrum of activity against tumours of multiple histologic types, both in vitro and in vivo.

Copanlisib may be synthesised according to the methods given in international patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004, (which is incorporated herein by reference in its entirety), on pp. 26 et seq.

Copanlisib is published in international patent application PCT/US2007/024985, published as WO 2008/070150 A1 on June 12, 2008, (which is incorporated herein by reference in its entirety), as the compound of Example 13 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.

Copanlisib may be synthesized according to the methods given in WO 2008/070150, pp. 9 et seq., and on pp. 42 et seq. Biological test data for said compound of formula (I) is given in WO 2008/070150 on pp. 101 to 107.

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (1 1 ), (which is hereinafter referred to as „copanlisib dihydrochloride”) is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 1 1 , 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dinydrochloride : it may be synthesized according to the methods given in said Examples 1 and 2.

Copanlisib may exist in one or more tautomeric forms : tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the migration of one or more single bonds and one or more adjacent double bonds.

Copanlisib may for example exist in tautomeric form (la), tautomeric form (lb), or tautomeric form (Ic), or may exist as a mixture of any of these forms, as depicted below. It is intended that all such tautomeric forms are included within the scope of the present invention.

Copanlisib may exist as a solvate : a solvate for the purpose of this invention is a complex of a solvent and copanlisib in the solid state. Exemplary solvates include, but are not limited to, complexes of copanlisib with ethanol or methanol.

Copanlisib and copanlisib dihydrochloride may exist as a hydrate. Hydrates are a specific form of solvate wherein the solvent is water, wherein said water is a structural element of the crystal lattice of copanlisib or of copanlisib dihydrochloride. It is possible for the amount of said water to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric hydrates, a hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, or penta-hydrate of copanlisib or of copanlisib dihydrochloride is possible. It is also possible for water to be present on the surface of the crystal lattice of copanlisib or of copanlisib dihydrochloride. The present invention includes all such hydrates of copanlisib or of copanlisib dihydrochloride, in particular copanlisib dihydrochloride hydrate referred to as “hydrate I”, as prepared and characterised in the experimental section herein, or as “hydrate II”, as prepared and characterised in the experimental section herein.

As mentioned supra, copanlisib is, in WO 2008/070150, described on pp. 9 et seq., and may be synthesized according to the methods given therein on pp. 42 et seq., viz. :

Reaction Scheme 1 :

(I)

In Reaction Scheme 1 , vanillin acetate can be converted to intermediate (III) via nitration conditions such as neat fuming nitric acid or nitric acid in the presence of another strong acid such as sulfuric acid. Hydrolysis of the acetate in intermediate (III) would be expected in the presence of bases such as sodium

hydroxide, lithium hydroxide, or potassium hydroxide in a protic solvent such as methanol. Protection of intermediate (IV) to generate compounds of Formula (V) could be accomplished by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Conversion of compounds of formula (V) to those of formula (VI) can be achieved using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. Reduction of the nitro group in formula (VI) could be accomplished using iron in acetic acid or hydrogen gas in the presence of a suitable palladium, platinum or nickel catalyst. Conversion of compounds of formula (VII) to the imidazoline of formula (VIII) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur with heating. The cyclization of compounds of formula (VIII) to those of formula (IX) is accomplished using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine in a halogenated solvent such as DCM or dichloroethane. Removal of the protecting group in formula (IX) will be dependent on the group selected and can be accomplished by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol in formula (X) can be achieved using a base such as cesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group. Lastly, amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.

Reaction Scheme 2 :

Reaction Scheme 3

Step A9: N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride (“EDCI”) is used as coupling reagent. Copanlisib is isolated by simple filtration.

Step A1 1 : Easy purification of copanlisib via its dihydrochloride

(dihydrochloride is the final product)

Hence, in a first aspect, the present invention relates to a method of preparing copanlisib (10) via the following steps shown in Reaction Scheme 3, infra :

Reaction Scheme 3 : 

Example 1 : Step A1 : Preparation of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2)

3.94 kg of nitric acid (65 w%) were added to 5.87 kg of concentrated sulfuric acid at 0°C (nitrating acid). 1 .5 kg of vanillin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app. 8.0 mL/min (nitrating acid) and app. 4.0 mL/min (vanillin acetate solution) at 5°C. The reaction mixture was directly dosed into 8 kg of water at 3°C. After 3h flow rates were increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After additional 9 h the flow reaction was completed. The layers were separated at r.t., and the aqueous phase was extracted with 2 L of dichloromethane. The combined organic phases were washed with 2 L of saturated sodium bicarbonate, and then 0.8 L of water. The dichloromethane solution was concentrated in vacuum to app. 3 L, 3.9 L of methanol were added and app. the same volume was removed by distillation again. Additional 3.9 L of methanol were added, and the solution concentrated to a volume of app. 3.5 L. This solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) was directly used in the next step.

Example 2 : Step A2 : Preparation of 4-hydroxy -3-methoxy-2-nitrobenzaldehyde (2-nitro-vanillin) (3)

To the solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) prepared as described in example 1 (see above) 1 .25 kg of methanol were added, followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30°C for 3h. 7.3 kg of dichloromethane and 12.8 kg of aqueous hydrochloric acid (10 w%) were added at < 30°C (pH 0.5 – 1 ). The mixture was stirred for 15 min, and the layers were separated. The organic layer was filtered, and the filter cake washed with 0.5 L of dichloromethane. The aqueous layer was extracted twice with 4.1 kg of

dichloromethane. The combined organic layers were concentrated in vacuum to app. 4 L. 3.41 kg of toluene were added, and the mixture concentrated to a final volume of app. 4 L. The mixture was cooled to 0°C. After 90 min the suspension was filtered. The collected solids were washed with cold toluene and dried to give 0.95 kg (62 %).

1H-NMR (400 MHz, de-DMSO): δ =3.84 (s, 3H), 7.23 (d, 1 H), 7.73 (d, 1 H), 9.74 (s, 1 H), 1 1 .82 (brs, 1 H).

NMR spectrum also contains signals of regioisomer 6-nitrovanillin (app. 10%): δ = 3.95 (s, 3H), 7.37 (s, 1 H), 7.51 (s, 1 H), 10.16 (s, 1 H), 1 1 .1 1 (brs, 1 H).

Example 3 : Step A3 : Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (4) :

10 g of 3 were dissolved in 45 mL DMF at 25 °C. This solution was charged with 14 g potassium carbonate and the temperature did rise to app. 30 °C. Into this suspension 7.1 mL benzyl bromide was dosed in 15minutes at a temperature of 30 °C. The reaction mixture was stirred for 2 hours to complete the reaction. After cooling to 25 °C 125 mL water was added. The suspension was filtered, washed twice with 50 mL water and once with water / methanol (10 mL / 10 mL) and tried at 40 °C under reduced pressure. In this way 14.2 g (97% yield) of 4 were obtained as a yellowish solid.

1 H-NMR (500 MHz, d6-DMSO): 3.86 (s, 3H); 5.38 (s, 2 H); 7.45 (m, 5H); 7.62 (d, 2H); 7.91 (d, 2H); 9.81 (s, 1 H).

Example 4a : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5-dihydro-1 H-imidazole (5) : Method A

10 g of 4 were dissolved in 100 mL methanol and 2.5 g ethylenediamine were added at 20-25 °C. The reaction mixture was stirred at this temperature for one hour, cooled to 0°C and a solution of N- bromosuccinimide (8.1 g) in 60 mL

acetonitrile was added. Stirring was continued for 1 .5 h and the reaction mixture was warmed to 20 °C and stirred for another 60 minutes. The reaction was quenched with a solution of 8.6 g NaHCO3 and 2.2 g Na2SO3 in 100 mL water. After 10 minutes 230 mL water was added, the product was filtered, washed with 40 mL water and tried at 40 °C under reduced pressure. In this way 8.9 g (78% yield) of 5 was obtained as an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.31 (s, 4H); 3.83 (s, 3H); 5.29 (s, 2 H); 6.88 (s, 1 H); 7.37 (t, 1 H); 7.43 (m, 3H); 7.50 (m, 3H).

Example 4b : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5-dihydro-1 H-imidazole (5) : Method B

28.7 kg of compound 4 were dissolved in 231 kg dichloromethane at 20 °C and 8.2 kg ethylenediamine were added. After stirring for 60 minutes N-bromosuccinimide was added in 4 portions (4 x 5.8 kg) controlling that the temperature did not exceed 25°C. When the addition was completed stirring was continued for 90 minutes at 22 °C. To the reaction mixture 9 kg potassium carbonate in 39 kg water was added and the layers were separated. From the organic layer 150 kg of solvent was removed via distillation and 67 kg toluene was added. Another 50 kg solvent was removed under reduced pressure and 40 kg toluene was added. After stirring for 30 minutes at 35-45 °C the reaction was cooled to 20 °C and the product was isolated via filtration. The product was washed with toluene (19 kg), tried under reduced pressure and 26.6 kg (81 % yield) of a brown product was obtained.

Example 5 : Step A5 : 3-(benzyloxy)-6-(4,5-dihydro-1 H-imidazol-2-yl)-2-methoxyaniline (6) :

8.6 g of compound 5 were suspended in 55 mL THF and 1 .4 g of 1 %Pt/0.2% Fe/C in 4 mL water was added. The mixture was heated to 45 °C and hydrogenated at 3 bar hydrogen pressure for 30 minutes. The catalyst was

filtered off and washed two times with THF. THF was removed via distillation and 65 mL isopropanol/water 1/1 were added to the reaction mixture. The solvent remaining THF was removed via distillation and 86 mL isopropanol/water 1/1 was added. The suspension was stirred for one hour, filtered, washed twice with isopropanol/water 1/1 and dried under reduced pressure to yield 7.8g (99% yield) of an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.26 (t, 2H); 3.68 (s, 3H); 3.82 (t, 2H); 5.13 (s, 2 H); 6.35 (d, 1 H); 6.70 (s, 1 H); 6.93 (bs, 2 H); 7.17 (d, 1 H); 7.33 (t, 1 H); 7.40 (t, 2H); 7.45 (d, 2H).

Example 6a : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (7) : Method A

10 g of 6 were suspended in 65 mL acetonitrile and 6.1 mL triethylamine were added. At 5-10 °C 8.4 mL bromocyanide 50% in acetonitrile were added over one hour and stirring was continued for one hour. 86 mL 2% NaOH were added and the reaction mixture was heated to 45 °C and stirred for one hour. The suspension was cool to 10 °C, filtered and washed with water/acetone 80/20. To further improve the quality of the material the wet product was stirred in 50 mL toluene at 20-25 °C. The product was filtered off, washed with toluene and dried under reduced pressure. In this way 8.8 g (81 % yield) of 7 was isolated as a white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.73 (s, 3H); 3.87 (m, 4H); 5.14 (s, 2 H); 6.65 (bs, 2 H); 6.78 (d, 1 H); 7.33 (m, 1 H); 7.40 (m, 3 H); 7.46 (m, 2H).

Example 6b : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (8) : Method B

20 kg of compound 6 were dissolved in 218 kg dichloromethane at 20 °C and the mixture was cooled to 5 °C. At this temperature 23.2 kg triethylamine was dosed in 15 minutes and subsequently 25.2 kg bromocyanide (3 M in

dichloromethane) was dosed in 60 minutes to the reaction mixture. After stirring for one hour at 22 °C the reaction was concentrated and 188 kg of solvent were removed under reduced pressure. Acetone (40 kg) and water (50 kg) were added and another 100 kg of solvent were removed via distillation. Acetone (40 kg) and water (150 kg) were added and stirring was continued for 30 minutes at 36°C. After cooling to 2 °C the suspension was stirred for 30 minutes, isolated, washed with 80 kg of cold water and tried under reduced pressure. With this procedure 20.7 kg (95% yield) of an off-white product was obtained.

Example 7a : Step A7 : Method A: preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (8) :

A mixture of 2 kg of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine, 203 g of 5% Palladium on charcoal (50% water wetted) and 31 .8 kg of Ν,Ν-dimethylformamide was stirred at 60°C under 3 bar of hydrogen for 18 h. The mixture was filtered, and the residue was washed with 7.5 kg of Ν,Ν-dimethylformamide. The filtrate (38.2 kg) was concentrated in vacuum (ap. 27 L of distillate collected and discarded). The remaining mixture was cooled from 50°C to 22°C within 1 h, during this cooling phase 14.4 kg of water were added within 30 min. The resulting suspension was stirred at 22°C for 1 h and then filtered. The collected solids were washed with water and dried in vacuum to yield 0.94 kg (65 %).

1H-NMR (400 MHz, de-DMSO): δ = 3.72 (s, 3H), 3.85 (m, 4H), 6.47 (d, 1 H), 6.59 (bs, 1 H), 7.29 (d, 1 H), 9.30 (bs, 1 H).

Example 7b : Step A7 Method B : preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (8) :

222.8 g of trifluroacetic acid were added to a mixture of 600 g of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine and 2850 g of DMF. 18 g of 5% Palladium on charcoal (50% water wetted) were added. The mixture

was stirred at under 3 bar of hydrogen overnight. The catalyst was removed by filtration and washed with 570 g of DMF. The filtrate was concentrated in vacuum (432 g of distillate collected and discarded). 4095 ml of 0.5 M aqueous sodium hydroxide solution was added within 2 hours. The resulting suspension was stirred overnight. The product was isolated using a centrifuge. The collected solids were washed with water. The isolated material (480.2g; containing app. 25 w% water) can be directly used in the next step (example 8b).

Example 8a : Step A8 : Method A : preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (9) :

2.5 kg of potassium carbonate were added to a mixture of 1 .4 kg of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol, 14 L of n-butanol, 1 .4 L of Ν,Ν-dimethylformamide and 1 .4 L of water. 1 .57 kg of 4-(3-chloropropyl)morpholine hydrochloride were added. The resulting suspension was heated to 90°C and stirred at this temperature for 5 h. The mixture was cooled to r.t.. At 50°C 8.4 kg of water were added. The mixture was stirred at r.t. for 15 min. After phase separation the aqueous phase was extracted with 12 L of n-butanol. The combined organic phases were concentrated in vacuum to a volume of ap. 1 1 L. 10.7 L of terf-butyl methyl ether were added at 50°C. The resulting mixture was cooled within 2 h to 0°C and stirred at this temperature for 1 h. The suspension was filtered, and the collected solids were washed with tert-butyl methyl ether and dried to give 1 .85 kg (86 %).

The isolated 1 .85 kg were combined with additional 0.85 kg of material produced according to the same process. 10.8 L of water were added and the mixture heated up to 60°C. The mixture was stirred at this temperature for 10 min, then cooled to 45°C within 30 min and then to 0°C within 1 h. The suspension was stirred at 0°C for 2 h and then filtered. The solids were washed with cold water and dried to yield 2.5 kg.

1H-NMR (400 MHz, de-DMSO): δ = 1 .88 (m, 4H), 2.36 (m, 4H), 2.44 (t, 2H), 3.57 (m, 4H), 3.70 (s, 3H), 3.88 (m, 4H), 4.04 (t, 2H), 6.63 (s, 2H), 6.69 (d, 1 H), 7.41 (d, 1 H).

HPLC: stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 μιτι particle size): mobile phase A: 0.5 ml_ trifluoro acetic acid / 1 L water; mobile phase B: 0.5 ml_ trifluoro acetic acid / L acetonitrile; UV detection at 256 nm; oven temperature: 40°C; injection volume: 2.0 μΙ_; flow 1 .0 mL/min; linear gradient in 4 steps: 0% B -> 6% B (20 min), 6 % B -> 16% B (5 min), 16% B -> 28 % B (5 min), 28 % B -> 80 % B (4 min), 4 minutes holding time at 80% B; purity: >99,5 % (Rt=1 1 .0 min), relevant potential by-products: degradation product 1 at RRT (relative retention time) of 0.60 (6.6 min) typically <0.05 %, 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol RRT 0.71 (7.8 min): typically <0.05 %, degradation product 2 RRT 1 .31 (14.4 min): typically <0.05 %, 7-methoxy-5-{[3-(morpholin-4-yl)propyl]amino}-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol RRT 1 .39 (15.3 min): typically <0.05 %, 9-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 1 .43 (15.7 min): typically <0.05 %, degradation product 3 RRT 1 .49 (16.4 min): typically <0.05 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 1 .51 (16.7 min): typically <0.10 %, 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 2.56 (28.2 min): typically <0.05 %, 8-(benzyloxy)-7-methoxy-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 2.59 (28.5 min): typically <0.05 %.

Example 8b: : Step A8 (Method B): preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (9) :

13.53 g of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (containing app. 26 w% of water) were suspended in 1 10 g of n-butanol. The mixture was concentrated in vacuum (13.5 g of distillate collected and discarded). 17.9 g of potassium carbonate and 1 1 .2 g of 4-(3-chloropropyl)morpholine hydrochloride were added. The resulting mixture was heated to 90°C and stirred at this temperature for 4 hours. The reaction mixture was cooled to to 50°C, and 70 g of water were added. The layers were separated. The organic layer was concentrated in vacuum (54 g of distillate collected and discard). 90 g of terf-butyl methyl ether were added at 65°C. The resulting mixture was cooled to 0°C. The mixture was filtered, and the collected solids washed with terf-butyl methyl ether and then dried in vacuum to yield 13.4 g (86%).

13.1 g of the isolated material were suspended in 65.7 g of water. The mixture was heated to 60°C. The resulting solution was slowly cooled to 0°C. The precipitated solids were isolated by filtration, washed with water and dried in vacuum to yield 12.0 g (92%).

Example 9: Step A10 : Preparation of 2-aminopyrimidine-5-carboxylic acid (9b)

1 kg of methyl 3,3-dimethoxypropanoate was dissolved in 7 L of 1 ,4-dioxane. 1 .58 kg of sodium methoxide solution (30 w% in methanol) were added. The mixture was heated to reflux, and ap. 4.9 kg of distillate were removed. The resulting suspension was cooled to r.t., and 0.5 kg of methyl formate was added. The reaction mixture was stirred overnight, then 0.71 kg of guanidine hydrochloride was added, and the reaction mixture was stirred at r.t. for 2 h. The reaction mixture was then heated to reflux, and stirred for 2 h. 13.5 L of water were added, followed by 0.72 kg of aqueous sodium hydroxide solution (45 w%). The reaction mixture was heated at reflux for additional 0.5 h, and then cooled to 50°C. 0.92 kg of aqueous hydrochloric acid (25 w%) were added until pH 6 was reached. Seeding crystals were added, and additional 0.84 kg of aqueous hydrochloric acid (25 w%) were added at 50°C until pH 2 was reached. The mixture was cooled to 20°C and stirred overnight. The suspension was filtered, the collected solids washed twice with water, then twice with methanol, yielding 0.61 kg (65%).

Four batches produced according to the above procedure were combined (total 2.42 kg). 12 L of ethanol were added, and the resulting suspension was stirred at r.t. for 2.5 h. The mixture was filtered. The collected solids were washed with ethanol and dried in vacuum to yield 2.38 kg.

To 800 g of this material 2.5 L of dichloromethane and 4 L of water were added, followed by 1375 ml_ of dicyclohexylamine. The mixture was stirred for 30 min. at r.t. and filtered. The collected solids are discarded. The phases of the filtrate are separated, and the organic phase was discarded. 345 ml_ of aqueous sodium hydroxide solution (45 w%) were added to the aqueous phase. The aqueous phase was extracted with 2.5 L of ethyl acetate. The phases were separated and the organic phase discarded. The pH value of the aqueous phase was adjusted to pH 2 using app. 500 ml_ of hydrochloric acid (37 w%). The mixture was filtered, and the collected solids were washed with water and dried, yielding 405 g.

The 405 g were combined with a second batch of comparable quality (152 g). 2 L of ethyl acetate and 6 L of water were added, followed by 480 ml_ of aqueous sodium hydroxide solution (45 w%). The mixture was stirred at r.t. for 30 min.. The phases were separated. The pH of the aqueous phase was adjusted to pH 2 with ap. 770 ml_ of aqueous hydrochloric acid (37 w%). The mixture was filtered, and the collected solids washed with water and dried to yield 535 g.

1H-NMR (400 MHz, de-DMSO): δ = 7.46 (bs, 2H); 8.66 (s, 2H), 12.72 (bs, 1 H).

Example 10 : Step A9 : preparation of copanlisib (10)

A mixture of 1250 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydro-imidazo[1 ,2-c]quinazolin-5-amine, 20.3 kg of N,N-dimethylformamide, 531 g of 2-aminopyrimidine-5-carboxylic acid, 425 g of Ν,Ν-dimethylaminopyridine and 1000 g of N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride was stirred at r.t. for 17 h. The reaction mixture was filtered. The collected solids were washed with Ν,Ν-dimethylformamide, then ethanol, and dried at 50°C to yield 1 .6 kg (96%). The isolated material was directly converted into the dihydrochloride.

Example 11 : Step A11 : preparation of copanlisib dihydrochloride (11)

To a mixture of 1 .6 kg of copanlisib and 4.8 kg of water were added 684 g of aqueous hydrochloric acid (32 w%) while maintaining the temperature between 20 to 25°C until a pH of 3 to 4 was reached. The resulting mixture was stirred for 10 min, and the pH was checked (pH 3.5). The mixture was filtered, and the filter cake was washed with 0.36 kg of water. 109 g of aqueous hydrochloric acid were added to the filtrate until the pH was 1 .8 to 2.0. The mixture was stirred for 30 min and the pH was checked (pH 1 .9). 7.6 kg of ethanol were slowly added within 5 h at 20 to 25°C, dosing was paused after 20 min for 1 h when crystallization started. After completed addition of ethanol the resulting suspension was stirred for 1 h. The suspension was filtered. The collected solids was washed with ethanol-water mixtures and finally ethanol, and then dried in vacuum to give 1 .57 kg of copansilib dihydrochloride (85 %).

1H-NMR (400 MHz, de-DMSO): δ = 2.32 (m, 2H), 3.1 1 (m, 2H), 3.29 (m, 2H),

3.47 (m, 2H), 3.84 (m, 2H), 3.96 (m, 2H), 4.01 (s, 3H), 4.19 (t, 2H), 4.37 (t, 2H),

4.48 (t, 2H), 7.40 (d, 1 H), 7.53 (bs, 2H), 8.26 (d, 1 H), 8.97 (s, 2H), 1 1 .28 (bs, 1 H), 12.75 (bs, 1 H), 13.41 (bs, 1 H).

HPLC: stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 μιτι particle size): mobile phase A: 2.0 ml_ trifluoro acetic acid / 1 L water; mobile phase B: 2.0 ml_ trifluoro acetic acid / L acetonitrile; UV detection at 254 nm switch after 1 minute to 282 nm; oven temperature: 60°C; injection volume: 2.0 μΙ_; flow 1 .7 mL/min; linear gradient after 1 minute isocratic run in 2 steps: 0% B -> 18% B (9 min), 18 % B -> 80% B (2.5 min), 2.5 minutes holding time at 80% B; purity: >99.8% (Rt=6.1 min), relevant potential by-products: 2-Aminopyrimidine-5-carboxylic acid at RRT (relative retention time) of 0.10 (0.6 min) typically <0.01 %, 4-dimethylaminopyrimidine RRT 0.26 (1 .6 min): typically <0.01 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 0.40 (2.4 min): typically <0.03 %, by-product 1 RRT 0.93 (5.7 min): typically <0.05 %, by-product 6 RRT 1 .04 (6.4 min): typically <0.05 %, 2-amino- N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamicle RRT 1.12 (8.9 min); typically <0.10 %, 5-{[(2-aminopyrimidin-5-yl)carbonyl]amino}-7-methoxy-2,3-dihydroimidazo[ ,2-c]quinazolin-8-yl 2-aminopyrimidine-5-carboxylate RRT 1.41 (8.6 min): typically <0.01 %

Example 15 : Step A11 : further example of preparation of copanlisib dihydrochloride (11)

7.3 g of hydrochloric acid were added to a mixture of 12 g of copanlisib and 33 g of water at maximum 30°C. The resulting mixture was stirred at 25°C for 15 min, and the filtered. The filter residue was washed with 6 g of water. 1 1 .5 g of ethanol were added to the filtrate at 23°C within 1 hour. After the addition was completed the mixture was stirred for 1 hour at 23°C. Additional 59 g of ethanol were added to the mixture with 3 hours. After the addition was completed the mixture was stirred at 23°C for 1 hour. The resulting suspension was filtered. The collected crystals were washed three times with a mixture of 1 1 .9 g of ethanol and 5.0 g of water and the air dried to give 14.2 g of copanlisib dihydrochloride as hydrate I.

Purity by HPLC: > 99.8%; < 0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7- [3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide

Example 16 : Step A11 : further example of preparation of copanlisib dihydrochloride (11 )

9.1 kg of hydrochloric acid (25 w%) were added to a mixture of 14,7 kg of copanlisib and 41.9 kg of water at maximum temperature of 28°C. The resulting mixture was stirred at 23°C for 80 minutes until a clear solution was formed. The solution was transferred to a second reaction vessel, and the transfer lines rinsed with 6 kg of water, 14.1 kg of ethanol were slowly added within 70 minutes at 23°C. After the addition of ethanol was completed the mixture was stirred at 23°C for 1 hour. Additional 72.3 kg of ethanol were slowly added within 3.5 hours at 23°C, and resulting mixture stirred at this temperature for 1 hour. The suspension is filtered, and the collected solids were washed twice with 31 kg of an ethanol-water mixture (2.4: 1 (w w)). The product was dried in vacuum with a maximum jacket temperature of 40°C for 3.5 hours to yield 15.0 kg of copanlisib dihydrochloride as hydrate I.

Purity by HPLC: > 99.9 %; < 0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]^-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamideLoss on drying: 14.7 w%

PATENT

WO 2017049983

Copanlisib is a novel oral phosphoinositide 3 kinase (PI3K) inhibitor developed by the German company Bayer. Existing clinical studies have shown that the drug inhibits the growth of cancer cells in patients with leukemia and lymphoma by blocking the PI3K signaling pathway. To further prove the promise of the drug, Bayer also conducted two more Phase III clinical studies in 2015: treating a rare non-Hodgkin’s lymphoma (NHL) by itself or in combination with Rituxan and using it alone The effect of Rituxan is compared. In addition, Bayer also plans to conduct a Phase II clinical trial of Copanlisib in the treatment of diffuse large B-cell lymphoma, a malignant NHL subtype. Because the drug does not yet have a standard Chinese translation, the applicant here transliterates “Kupanisi”.
The chemical name of Copanisibib (I) is 2-amino-N- [2,3-dihydro-7-methoxy- 8- [3- (4- morpholinyl) propoxy] Imidazo [1,2-c] quinazolin-5-yl] -5-pyrimidinecarboxamide of the formula:
PCT patent WO2008070150 from the original company discloses the preparation of cupanatinib and its analogs. The document altogether refers to the following five possible synthetic routes.
Synthetic Route 1:
Synthetic route two:
Synthetic route three:

Synthetic route four:
Synthetic route five:

Example 6:
In a nitrogen atmosphere, 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [1,2-c] quinazoline- (V) (0.36 g, 1 mmol), 2-aminopyrimidine-5-carboxylic acid (0.15 g, 1.1 mmol) and acetonitrile were added 25 mL of a condensing agent benzotriazol- (0.49 g, 1.1 mmol) and base catalyst 1,5-diazabicyclo [4.3.0] -non-5-ene (0.50 g, 4 mmol) were added and the mixture was stirred at room temperature for 12 hours . Then warmed to 50-60 ℃, the reaction was stirred for 6-8 hours, TLC detection reaction was completed. The solvent was evaporated under reduced pressure, cooled to room temperature, ethyl acetate was added and a solid precipitated. Filter cake washed with cold methanol, and dried in vacuo to give an off-white solid Kupannixi (I) 0.27g, yield% 56.3; the MS-EI m / Z: 481 [M + H] + , . 1 H NMR (CDCl3 3 ) 62.05 (m, 2H), 2.48 (m, 4H), 2.56 (m, 2H), 3.72 (t, 4H), 4.02 (s, 3H), 4.16 (m, , 6.84 (d, 1H), 7.08 (d, 1H), 9.10 (s, 2H).

PAPER

http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=1&sid=49a5a4d4-00a3-4f4a-8630-0277f78d630f%40sessionmgr4010

 ChemMedChem (2016), 11(14), 1517-1530.

2-Amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide (BAY 80-6946, 39i):

Amine 36 (80% purity; 100 mg, 0.22 mmol) was dissolved in DMF (5 mL), and acid 39i’ (46 mg, 0.33 mmol) was added. PyBOP (173 mg, 0.33 mmol) and DIPEA (0.16 mL, 0.89 mmol) were sequentially added, and the mixture was stirred at RT overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give 39i (42.7 mg, 40%):

1H NMR ([D6 ]DMSO+ 2 drops [D]TFA): d=2.25 (m, 2H), 3.18 (m, 2H), 3.31 (m, 2H), 3.52 (m, 2H), 3.65 (brt, 2H), 4.00 (s, 3H), 4.04 (m, 2H), 4.23 (m, 2H), 4.34 (brt, 2H), 4.54 (m, 2H), 7.43 (d, 1H), 8.04 (d, 1H), 9.01 (s, 2H);

1H NMR of the bis-HCl salt (500 MHz, [D6 ]DMSO): d=2.30–2.37 (m, 2H), 3.11 (brs, 2H), 3.25–3.31 (m, 2H), 3.48 (d, J=12.1 Hz, 2H), 3.83–3.90 (m, 2H), 3.95–4.00 (m, 2H), 4.01 (s, 3H), 4.17–4.22 (m, 2H), 4.37 (t, J=6.0 Hz, 2H), 4.47 (t, J=9.7 Hz, 2H), 7.40 (d, J= 9.2 Hz, 1H), 7.54 (s, 2H), 8.32 (d, J=9.2 Hz, 1H), 8.96 (s, 2H), 11.46 (brs, 1H), 12.92 (brs, 1H), 13.41 (brs, 1H);

13C NMR (125 MHz, [D6 ]DMSO): d=23.09, 45.22, 46.00, 51.21, 53.38, 61.54, 63.40, 67.09, 101.18, 112.55, 118.51, 123.96, 132.88, 134.35, 148.96, 157.25, 160.56, 164.96, 176.02 ppm;

MS (ESI+) m/z: 481 [M+H]+ .

References

  1. Jump up^ “Phase II Data of Bayer’s Novel Cancer Drug Candidate Copanlisib to be Presented”. Retrieved 3 March 2015.
  2. Jump up^ Loguidice, Christina (8 December 2014). “Copanlisib Continues to Show Promise for Treating Indolent Lymphomas”. Rare Disease Report. Retrieved 3 March 2015.
  3. Jump up^ HealthCare, Bayer. “Bayer Advances Clinical Development Program for Investigational Cancer Drug Copanlisib”http://www.prnewswire.com.
  4. Jump up^ “Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer – Full Text View – ClinicalTrials.gov”.
  5. Jump up^ “Phase II Copanlisib in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) – Full Text View – ClinicalTrials.gov”.
  6. Jump up^ “Copanlisib (BAY 80-6946) in Combination With Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma – Full Text View – ClinicalTrials.gov”.
  7. Jump up^ “Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin’s Lymphomas – Full Text View – ClinicalTrials.gov”.
  8. Jump up^ “Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin’s Lymphoma (iNHL) – Full Text View – ClinicalTrials.gov”.
  9. Jump up^ “Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin’s Lymphoma (iNHL) – Full Text View – ClinicalTrials.gov”.
  10. Jump up^ “Phase III Copanlisib in Rituximab-refractory iNHL – Full Text View – ClinicalTrials.gov”.
Patent ID

Patent Title

Submitted Date

Granted Date

US2016303136 COMBINATION OF PI3K-INHIBITORS
2014-11-28
US2015141420 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR THE TREATMENT OF MYELOMA
2014-09-29
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Patent ID

Patent Title

Submitted Date

Granted Date

US2016058770 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR TREATING LYMPHOMAS
2014-04-04
2016-03-03
US2015254400 GROUPING FOR CLASSIFYING GASTRIC CANCER
2013-09-18
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2011-10-13
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2011-04-14
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2012-03-29
2014-03-13
Patent ID

Patent Title

Submitted Date

Granted Date

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2012-03-29
2014-08-28
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Patent ID

Patent Title

Submitted Date

Granted Date

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2016-01-07
2016-07-07
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2014-05-30
2014-12-25
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2013-11-01
2015-10-08
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2013-06-03
2013-10-03
Copanlisib
Copanlisib.svg
Names
IUPAC name

2-Amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide
Other names

BAY 80-6946
Identifiers
3D model (JSmol)
ChemSpider
KEGG
MeSH 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo(1,2-c)quinazolin-4-yl)pyrimidine-5-carboxamide
UNII
Properties
C23H28N8O4
Molar mass 480.53 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////copanlisib, BAY 80-6946, BAYER, orphan drug status,  follicular lymphoma, FDA 2017, BAY 84-1236

COC1=C(C=CC2=C1N=C(N3C2=NCC3)NC(=O)C4=CN=C(N=C4)N)OCCCN5CCOCC5

 

DISCLAIMER

“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

Copanlisib (BAY 80-6946), Bayer’s novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor


Copanlisib (BAY 80-6946)

1032568-63-0, cas no

MW: 480.5262

In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.

PI3K inhibitor BAY 80-6946
A phosphoinositide 3-kinase (PI3K) inhibitor with potential antineoplastic activity. PI3K inhibitor BAY 80-6946 inhibits the activation of the PI3K signaling pathway, which may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

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