New Drug Approvals

Home » FDA 2017

Category Archives: FDA 2017

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,263,298 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,308 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,308 other followers

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

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

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

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

Join me on Researchgate

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, 

Advertisements

Abaloparatide, абалопаратид , أبالوباراتيد , 巴罗旁肽 ,


Chemical structure for Abaloparatide

Abaloparatide

BA058
BIM-44058
UNII-AVK0I6HY2U

BA058; BIM-44058; CAS  247062-33-5

MW 3960.5896, MF C174 H300 N56 O49

абалопаратид [Russian] [INN]
أبالوباراتيد [Arabic] [INN]
巴罗旁肽 [Chinese] [INN]
str1

NAME………C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

  1. C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide

Biologic Depiction

Abaloparatide biologic depiction
IUPAC Condensed

H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

Sequence

AVSEHQLLHDKGKSIQDLRRRELLEKLLXKLHTA

HELM

PEPTIDE1{A.V.S.E.H.Q.L.L.H.D.K.G.K.S.I.Q.D.L.R.R.R.E.L.L.E.K.L.L.[Aib].K.L.H.T.A.[am]}$$$$

IUPAC

(N-(L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysyl-glycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl)-2-aminoisobutyryl)-L-lysyl-L-leucyl-L-histidyl-L-threonyl-L-alaninamide

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

2D chemical structure of 247062-33-5

Image result for AbaloparatideImage result for Abaloparatide

CLINICAL……….https://clinicaltrials.gov/search/intervention=Abaloparatide%20OR%20BA058%20OR%20BIM-44058

BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.

Abaloparatide (brand name Tymlos; formerly BA058) is a parathyroid hormone-related protein (PTHrP) analog drug used to treat osteoporosis. Like the related drug teriparatide, and unlike bisphosphonates, it is an anabolic (i.e., bone growing) agent.[1] A subcutaneous injection formulation of the drug has completed a Phase III trial for osteoporosis.[2] This single study found a decrease in fractures.[3] In 28 April 2017, it was approved by Food and drug administration (FDA) to treat postmenopausal osteoporosis.

Image result for Abaloparatide

Therapeutics

Medical use

Abaloparatide is indicated to treat postmenopausal women with osteoporosis who are more susceptible to bone fractures.[2]

Dosage

The dose recommended is 80mcg subcutaneous injection once a day, administered in the periumbilical area using a prefilled pen device containing 30 doses.[4]

Warnings and Precautions

Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[5] However, whether abaloparatide-SC will cause osteosarcoma in humans is unknown. Thus, the use of abaloparatide is not recommended for individuals at increased risk of osteosarcoma. Additionally, its use is not advised for more than 2 years during a patient’s lifetime.[4][6]

Image result for Abaloparatide

Side Effects

The most common side effects reported by more than 2% of clinical trials subjects are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo.[4]

Pharmacology

Abaloparatide is 34 amino acid synthetic analog of PTHrP. It has 41% homology to parathyroid hormone (PTH) (1-34) and 76% homology to parathyroid hormone-related protein (PTHrP) (1-34).[7] It works as an anabolic agent for the bone, through selective activation of the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor (GPCR) expressed in the osteoblasts and osteocytes. Abaloparatide preferentially binds the RG conformational state of the PTH1R, which in turn elicits a transient downstream cyclic AMP signaling response towards to a more anabolic signaling pathway.[8][9]

History

Preclinical studies

Abaloropatide was previously known as BA058 and BIM-44058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovarectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term[10] and long-term[11] daily subcutaneous injection of abaloparatide compared to controls. Recent studies indicated a dose-dependent increased in bone mass and strength in long-term abalorapatide treatment.[12] However, it was also indicated that prolonged abalorapatide-SC treatment leads to increased incidence of osteosarcoma.[5] To date, there is no yet evidence for increased risk of bone tumors due to prolonged abalorapatide systemic administration in humans. Based on this preclinical data, the FDA does not advised the use of abaloparatide-SC for more than 2 years, or in patients with history of Paget disease and/or other conditions that exacerbates the risk of developing osteosarcoma.[4]

Clinical Trials

Phase II trials were initiated in 2008. A 24-week randomized trial was conducted in postmenopausal women with osteoporosis (n=222) assessing bone mass density (BMD) changes as the primary endpoint.[13] Significant BMD increase at doses of 40 and 80 mcg were found in the lumbar spine, femur and hips of abaloparatide-treated participants compared to placebo. Additionally, abaloparatide showed superior anabolic effects on the hips compared to teriparatide.[14]

In the phase III (2011-2014) Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, a 18-months randomized, multicenter, double-blinded, placebo-controlled study evaluated the long-term efficacy of abaloparatide compared to placebo and teriparatide in 2,463 postmenopausal women (± 69 years old).[2] Women who received daily injections of abaloparatide experienced substantial reduction in the incidence of fractures compared to placebo. Additionally, greater BMD increase at 6, 12 and 18 months in spinal, hips and femoral bones was observed in abaloparatide compared to placebo and teriparatide-treated subjects.[3]

Participants who completed 18 months of abaloparatide or placebo in the ACTIVE study were invited to participate in an extended open-labeled study – ACTIVExtend study (2012-2016).[15] Subjects (n=1139) received additional 2 years of 70 mg of alendronate, Vitamin D (400 to 800 IU), and calcium (500–1000 mg) supplementation daily. Combined abaloparatide and alendronate therapy reduced significantly the incidence of vertebral and nonvertebral fractures.[16]

A clinical trial assessing the effectiveness of abaloparatide in altering spinal bone mineral density (BMD) in male subjects is expected to start in the first quarter of 2018. If successful, Radius Health aims to submit a sNDA to expand the use of abaloparatide-SC to treat men with osteoporosis.[17]

In addition to the injectable form of abaloparatide, a transdermal patch is also in development.[1]

Commercialization

As previously noted, abaloparatide-SC is manufactured by Radius Health, Inc. (Nasdaq: RDUS), a biomedical company based in Waltham, Massachusetts. This company is focused on the development of new therapeutics for osteoporosis, cancer and endocrine diseases. Abaloparatide is the only drug currently marketed by Radius Health. RDUS reported that sales for abaloparatide were $3.5million for the third quarter of 2017.[17] The company announced a net loss of $57.8 million, or $1.31 per share for the third quarter of 2017, compared to $19.2 million for the same quarter of 2016.[18] The net loss most likely reflects the substantial expenses associated with the preparation and launching of abaloparatide into the US market in May 2017.

In July 2017, Radius Health licensed rights to Teijin Limited for abaloparatide-SC manufacture and commercialization in Japan. Teijin is developing abaloparatide-SC under agreement with Ipsen Pharma S.A.S., and is conducting a phase III clinical trial in Japanese patients with osteoporosis.[19]

Regulatory Information

Radius Health filed a Marketing Authorization Application (MAA) in November 2015,[20] which was validated in December, 2015, and still under regulatory assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). As in July 2017, the CHMP issued a second Day-180 List of Outstanding Issues, which Radius is addressing with the CHMP.[17]

In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May, 2016.[21] A Prescription Drug User Fee Act (PDUFA) date was initially granted in March 30, 2016, but then extended to June 30, 2017.[22] As previously stated, abaloparatide injection was approved for use in postmenopausal osteoporosis on April 28, 2017.[6]

Intellectual Property

Radius Health currently holds three patents on abaloparatide-SC, with expiration dates from 2027-2028.[23] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2).

As previously mentioned, Teijin Limited was granted use of Radius Health intellectual property in July 2017, for the development, manufacture and commercialization of abaloparatide-sc in Japan.

PATENT

http://www.google.com/patents/EP2206725A1?cl=en

  1. A peptide of the formula:

    [Glu22, 25, Leu23, 2831, Lys26, Aib29, Nle30]hPTHrP(1-34)NH2;
    [Glu22, 25, Leu23, 28, 3031, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25,29, Leu23, 28, 30, 31, Lys26]hpTHrP(1-34)NH2; [Glu22, 25, 29, Leu23, 28, 31, Lys26, Nle30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11, 23, 28, 31, His14, Cha15, Glu22, 25, Lys26, 30, Aib29]hPTHrP (1-34)NH2; [Cha22, Leu23, 28, 31, Glu25, 29, Lys26, Nle30]hPTHrP(1-34)NH2; [Cha7, 1115]hPTHrP(1-34)NH2; [Cha7, 8, 15]hPTHrP(1-34)NH2; [Glu22, Leu23, 28, Aib25, 29, Lys26]hpTHrP(1-34)NH2; [Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29, 30]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Aib26, 29, Lys30] hPTHrP(1-34)NH2; or [Leu27, Aib29]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.

PATENT

SEE……http://www.google.com.ar/patents/US8148333?cl=en

PATENT

SEE…………http://www.google.im/patents/US20090227498?cl=pt

EP5026436A Title not available
US3773919 Oct 8, 1970 Nov 20, 1973 Du Pont Polylactide-drug mixtures
US4767628 Jun 29, 1987 Aug 30, 1988 Imperial Chemical Industries Plc Polylactone and acid stable polypeptide
WO1994001460A1* Jul 13, 1993 Jan 20, 1994 Syntex Inc Analogs of pth and pthrp, their synthesis and use for the treatment of osteoporosis
WO1994015587A2 Jan 5, 1994 Jul 21, 1994 Steven A Jackson Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
WO1997002834A1* Jul 3, 1996 Jan 30, 1997 Biomeasure Inc Analogs of parathyroid hormone
WO1997002834A1* 3 Jul 1996 30 Jan 1997 Biomeasure Inc Analogs of parathyroid hormone
WO2008063279A2* 3 Oct 2007 29 May 2008 Radius Health Inc A stable composition comprising a bone anabolic protein, namely a pthrp analogue, and uses thereof
US5695955 * 23 May 1995 9 Dec 1997 Syntex (U.S.A.) Inc. Gene expressing a nucleotide sequence encoding a polypeptide for treating bone disorder
US20030166836 * 6 Nov 2002 4 Sep 2003 Societe De Conseils De Recherches Et D’application Scientefiques, S.A.S., A France Corporation Analogs of parathyroid hormone
US20050282749 * 14 Jan 2005 22 Dec 2005 Henriksen Dennis B Glucagon-like peptide-1 (GLP-1); immunotherapy; for treatment of obesity
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
Abaloparatide
Clinical data
Trade names Tymlos
Synonyms BA058, BIM-44058
Routes of
administration
Subcutaneous injection
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C174H299N56O49
Molar mass 3,959.65 g·mol−1
3D model (JSmol)

/////////FDA 2017, Abaloparatide, TYMLOS, RADIUS HEALTH, PEPTIDE, BA058, BIM 44058; 247062-33-5, абалопаратид أبالوباراتيد 巴罗旁肽 

CCC(C)C(C(=O)NC(CCC(=O)N)C(=O)NC(CC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C)(C)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC1=CN=CN1)C(=O)NC(C(C)O)C(=O)NC(C)C(=O)N)NC(=O)C(CO)NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CC(=O)O)NC(=O)C(CC2=CN=CN2)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCC(=O)N)NC(=O)C(CC3=CN=CN3)NC(=O)C(CCC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(C)N

Acalabrutinib, ACP-196, Акалабрутиниб , أكالابروتينيب , 阿可替尼 ,


ChemSpider 2D Image | acalabrutinib | C26H23N7O2

Acalabrutinib.png

Image result for Acalabrutinib

Acalabrutinib

  • Molecular FormulaC26H23N7O2
  • Average mass465.507 Da

AcalabrutinibrINN, ACP-196,

FDA 2017 APPROVED, Lymphoma, mantle cell, ACERTA PHARMA

Orphan Drug, breakthrough therapy designation,

CAS 1420477-60-6 [RN]

(S)-4-[8-Amino-3-[1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(pyridin-2-yl)benzamide

(S)-4-(8-amino-3-n-but-2-vnoylpyrrolidin-2-vnimidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

4-{8-Amino-3-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide
Benzamide, 4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-
Calquence [Trade name]
UNII:I42748ELQW
Акалабрутиниб [Russian] [INN]
أكالابروتينيب [Arabic] [INN]
阿可替尼 [Chinese] [INN]
4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-benzamide
4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide
I42748ELQW
Image result for Acalabrutinib
Image result for Acalabrutinib
 Acalabrutinib, also known as ACP-196, is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, ACP-196 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.
Image result for Acalabrutinib

Acalabrutinib (rINN,[1] ACP-196) is a novel experimental anti-cancer drug and a 2nd generation Bruton’s tyrosine kinase (BTK) inhibitor[2][3] developed by Acerta Pharma.[4] It is more potent and selective (fewer side-effects) than ibrutinib, the first-in-class BTK inhibitor.[2][3][5]

The compound was granted orphan drug designation for the treatment of chronic lymphocytic leukemia, Waldenström’s macroglobulinemia and mantle cell lymphoma in the U.S. and the E.U. in 2015 and 2016, respectively. In 2017, the product was granted breakthrough therapy designation in the U.S. for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Acalabrutinib is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, acalabrutinib inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosinekinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.

Acalabrutinib is a Bruton’s Tyrosine Kinase (BTK) inhibitor developed at Acerta Pharma launched in 2017 in the U.S. for the oral treatment of adults with mantle cell lymphoma who have received at least one prior therapy.

Image result for Acalabrutinib

Image result for Acalabrutinib

To date, acalabrutinib has been used in trials studying the treatment of B-All, Myelofibrosis, Ovarian Cancer, Multiple Myeloma, and Hodgkin Lymphoma, among others. As of October 31, 2017 the FDA approved Astra Zeneca’s orally administered Calquence (acalabrutinib) medication as a Bruton Tyrosine Kinase (BTK) inhibitor indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have already received at least one prior therapy, marking the company’s first entry into the treatment of blood cancers. Also known as ACP-196, acalabrutinib is also considered a second generation BTK inhibitor because it was rationally designed to be more potent and selective than ibrutinib, theoretically expected to demonstrate fewer adverse effects owing to minimized bystander effects on targets other than BTK. Nevertheless, acalabrutinib was approved under the FDA’s accelerated approval pathway, which is based upon overall response rate and faciliates earlier approval of medicines that treat serious conditions or/and that fill an unmet medical need based on a surrogate endpoint. Continued approval for acalabrutinib’s currently accepted indication may subsequently be contingent upon ongoing verification and description of clinical benefit in confimatory trials. Furthermore, the FDA granted this medication Priority Review and Breakthrough Therapy designations. It also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. At this time, more than 35 clinical trials across 40 countries with more than 2500 patients are underway or have been completed with regards to further research into better understanding and expanding the therapeutic uses of acalabrutinib [L1009].
Image result for Acalabrutinib

Clinical and Regulatory Status

Pre-clinical

Relative to ibrutinib, acalabrutinib demonstrated higher selectivity and inhibition of the targeted activity of BTK, while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.[3] In addition, in platelets treated with ibrutinib, thrombus formation was clearly inhibited while no impact to thrombus formation was identified relative to controls for those treated with acalabrutinib.[3] These findings strongly suggest an improved safety profile of acalabrutinib with minimized adverse effects relative to ibrutinib.[3]

As was conducted in the development of ibrutinib, pre-clinical studies of acalabrutinib included in vitro and in vivo pharmacodynamic evaluation in a canine lymphoma model.[6] A dose-dependent relationship resulting in cyto-toxicity and anti-proliferative effects was first demonstrated in a canine lymphoma cell line in vitro.[6] In vivo, the compound was found to be generally safe and well tolerated in the dosage range of 2.5–20 mg/kg every 12 or 24 hours, with clinical benefit observed in 30% of canine patients while observed adverse events consisted primarily of gastrointestinal effects such as anorexia, weight loss, vomiting, diarrhea and lethargy.[6]

Image result for Acalabrutinib

Clinical

The interim results of the still on-going first human phase 1/2 clinical trial (NCT02029443) with 61 patients for the treatment of relapsed chronic lymphocytic leukemia (CLL) are encouraging, with a 95% overall response rate demonstrating potential to become a best-in-class treatment for CLL.[2][7] Notably, a 100% response rate was achieved for those patients which were positive for the 17p13.1 gene deletion – a subgroup of patients that typically results in a poor response to therapy and expected outcomes.[3]

The most common adverse events were headache, diarrhea and weight gain.[3] Despite the appearance of a greater occurrence of transient headaches, the pre-clinical data suggests a preferred advantage of acalabrutinib over ibrutinib due to expected reduced adverse events of skin rash, severe diarrhea, and bleeding risk.[3] An additional clinical trial is currently in progress to directly compare the safety and efficacy performance of acalabrutinib to ibrutinib to better elucidate the differences in the therapeutic agents.[3]

While the primary indication is for CLL, as of late 2016, acalabrutinib is under evaluation for multiple indications in 20+ clinical trials (alone and in combination with other interventions) for various blood cancers, solid tumors, and rheumatoid arthritis.[7][8] Approximately 1,000 patients have been treated with acalabrutinib in clinical trials so far, including more than 600 on acalabrutinib alone and almost 400 on additional therapies in combination with acalabrutinib.[9]

Regulatory

As of February 2016, acalabrutinib had received orphan designation in the United States for CLL only,[10] and was similarly designated as an orphan medicinal product by the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) for treatment of three indications – chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and lymphoplasmacytic lymphoma (Waldenström’s macroglobulinaemia, MG).[11] If the drug is ultimately approved, this designation will result in a 10-year period of market exclusivity for the stated indications within Europe.[12]

Commercial Aspects

Acerta Pharma, the innovator responsible for the discovery and development of acalabrutinib, is a clinical stage biopharmaceutical company recently founded in 2012 in Oss, the Netherlands.[13] A combined $13 Million in Series A funding was secured March 14, 2013 from various investor sources including the venture capital firms of BioGeneration Ventures and OrbiMed Advisors, the Dutch State and Province of Brabant through the Brabant Development Agency, and the private US equity firm Frazier Healthcare.[14] Further undisclosed amounts of Series B funding was secured May 2015 from the mutual fund company T. Rowe Price.[15]

After the promising results for the treatment of CLL in initial clinical trials,[2] Astra Zeneca purchased a 55% stake in Acerta Pharma for $4 billion in December 2015, with an option to acquire the remaining 45% stake for an additional $3 billion, conditional on the first approval in both the US and Europe and the establishment of commercial opportunity.[16]

Intellectual Property

Several patents have been filed by Acerta Pharma through the World Intellectual Property Organization (WIPO) for the use of acalabrutinib (and structurally similar derivatives) either alone or in combination with additional therapeutic agents for the treatment of various hematological and solid tumor cancers as well as inflammatory and autoimmune diseases.[17][18][19][19][20][21][22][23][24][25][26][27]

Notably, patents filed through WIPO still need to be filed appropriately for each individual nation on the path to commercialization. For example, one related United States patent application is US2014155385, which was filed July 11, 2012 and approved June 5th, 2014 for the use of 6-5 membered fused pyridine ring compounds (including acalabrutnib and its structurally similar derivatives) in the treatment of BTK mediated disorders.[28]

SYNTHESIS

Inventors Tjeerd A. BarfChristiaan Gerardus Johannes Maria Jansde Adrianus Petrus Antonius MANArthur A. OubrieHans C.A. RaaijmakersJohannes Bernardus Maria RewinkelJan-Gerard SterrenburgJacobus C.H.M. Wijkmans
Applicant Msd Oss B.V.

WO 2013010868

Synthesis of acalabrutinib, using 3-chloropyrazine-2-carbonitrile as the starting material, is described. The method comprises reduction of the starting material, condensation with N-Cbz-L-proline, intramolecular cyclization, bromination, Suzuki coupling with (4-(2-pyridylcarbamoyl)phenyl)boronic acid and condensation with 2-butynoic acid. WO 2013010868

Reduction of 3-chloropyrazine-2-carbonitrile  with H2 over Raney-Ni in AcOH, followed by treatment with aqueous HCl in Et2O gives (3-chloro-2-pyrazinyl)methylamine hydrochloride , which upon condensation with N-Cbz-L-proline  in the presence of HATU and Et3N in CH2Cl2 affords amide .

Intramolecular cyclization of intermediate  by means of DMI and POCl3 in acetonitrile at 63 °C provides N-Cbz-8-chloro-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazine , which is brominated with NBS in DMF to yield N-Cbz-1-bromo-8-chloro-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazine .

Reaction of chloro compound  with NH3 in i-PrOH at 110 °C produces N-Cbz-1-bromo-3-[2(S)-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine , which upon Suzuki coupling with (4-(2-pyridylcarbamoyl)phenyl)boronic acid in the presence of PdCl2(dppf) and K2CO3 in dioxane at 140 °C under microwave irradiation furnishes diaryl derivative .

Removal of the benzyloxycarbonyl moiety in intermediate  using HBr in AcOH generates pyrrolidine derivative , which is condensed with 2-butynoic acid  in the presence of HATU and Et3N in CH2Cl2 to afford the target acalabrutinib 

PATENT

WO 2013010868

https://www.google.com/patents/WO2013010868A1?cl=en

scheme I

Figure imgf000026_0001

 scheme II

Figure imgf000027_0001

Intermediate 1

Figure imgf000032_0001

(S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-alpyrazin-3-vnpyrrolidine-1-carboxylate

(a) (3-Chloropyrazin-2-yl)methanamine. hydrochloride

To a solution of 3-chloropyrazine-2-carbonitrile (160 g, 1 .147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50°C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1 .14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C. The product brown solid obtained was dissolved in methanol at 60°C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40°C to give 153.5 g of (3-chloropyrazin-2- yl)methanamine. hydrochloride as a brown solid (74.4 %, content 77 %).

(b) (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate

To a solution of (3-chloropyrazin-2-yl)methanamine.HCI (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21 .26 mmol) in dichloromethane (250 mL) was added triethylamine (1 1.85 mL, 85 mmol) and the reaction mixture was cooled to 0°C. After 15 min stirring at 0°C, HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0°C and then overnight at room temperature. The mixture was washed with 0.1 M HCI-solution, 5% NaHC03, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%).

(c) (S)-Benzyl 2-(8-chloroimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

(S)-Benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (20.94 mmol, 7.85 g) was dissolved in acetonitrile (75 ml), 1 ,3-dimethyl-2-imidazolidinone (62.8 mmol, 6.9 ml, 7.17 g) was added and the reaction mixture was cooled to 0°C before POCI3 (84 mmol, 7.81 ml, 12.84 g) was added drop wise while the temperature remained around 5°C. The reaction mixture was refluxed at 60-65°C overnight. The reaction mixture was poured carefully in ammonium hydroxide 25% in water (250 ml)/crushed ice (500 ml) to give a yellow suspension (pH -8-9) which was stirred for 15 min until no ice was present in the suspension. Ethyl acetate was added, layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The organic layers were combined and washed with brine, dried over sodium sulfate, filtered and evaporated to give 7.5 g crude product. The crude product was purified using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 6.6 g of (S)-benzyl 2-(8- chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (88%).

(d) (S)-Benzyl 2-(1-bromo-8-chloroimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

N-Bromosuccinimide (24.69 mmol, 4.4 g) was added to a stirred solution of (S)-benzyl 2-(8- chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (24.94 mmol, 8.9 g) in DMF (145 mL). The reaction was stirred 3 h at rt. The mixture was poored (slowly) in a stirred mixture of water (145 mL), ethyl acetate (145 mL) and brine (145 mL). The mixture was then transferred into a separating funnel and extracted. The water layer was extracted with 2×145 mL ethyl acetate. The combined organic layers were washed with 3×300 mL water, 300 mL brine, dried over sodium sulfate, filtered and evaporated. The product was purified using silica gel chromatography (ethyl acetate/heptane = 3/1 v/v%) to give 8.95 g of (S)-benzyl 2-(1-bromo-8-chloroimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (82.3%).

(e) (S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-alpyrazin-3-yl)pyrrolidine-1-carboxylate

(S)-Benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (20.54 mmol, 8.95 g) was suspended in 2-propanol (1 13 ml) in a pressure vessel. 2-propanol (50 ml) was cooled to -78°C in a pre-weighed flask (with stopper and stirring bar) and ammonia gas (646 mmol, 1 1 g) was lead through for 15 minutes. The resulting solution was added to the suspension in the pressure vessel. The vessel was closed and stirred at room temperature and a slight increase in pressure was observed. Then the suspension was heated to 1 10 °C which resulted in an increased pressure to 4.5 bar. The clear solution was stirred at 1 10 °C, 4.5 bar overnight. After 18h the pressure remained 4 bar. The reaction mixture was concentrated in vacuum, the residue was suspended in ethyl acetate and subsequent washed with water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 7.35 g of (S)-benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1- carboxylate (86%).

Intermediate 2

Figure imgf000034_0001

(S)-4-(8-Amino-3-(pyrrolidin-2-v0im^

(a) (S)-Benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamov0

carboxylate

(S)-benzyl 2-(8-amino-1-bromoimidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1 -carboxylate (0.237 mmol, 98.5 mg) and 4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid (0.260 mmol, 63.0 mg) were suspended in a mixture of 2N aqueous potassium carbonate solution (2.37 mmol, 1 .18 mL) and dioxane (2.96 mL). Nitrogen was bubbled through the mixture, followed by the addition of 1 , 1 ‘- bis(diphenylphosphino)ferrocene palladium (ii) chloride (0.059 mmol, 47.8 mg). The reaction mixture was heated for 20 minutes at 140°C in the microwave. Water was added to the reaction mixture, followed by an extraction with ethyl acetate (2x). The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The product was purified using silicagel and dichloromethane/methanol = 9/1 v/v% as eluent to afford 97.1 mg of (S)-benzyl 2-(8-amino-1-(4-(pyridin- 2-ylcarbamoyl)phenyl)imidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1 -carboxylate (77%).

(b) (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

To (S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1 ,5-a]pyrazin-3-yl)pyrrolidine-1- carboxylate (0.146 mmol, 78 mg) was added a 33% hydrobromic acid/acetic acid solution (1 1.26 mmol, 2 ml) and the mixture was left at room temperature for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The aqueous phase was neutralized using 2N sodium hydroxide solution, and then extracted with dichloromethane. the organic layer was dried over magnesium sulfate, filtered and evaporated to give 34 mg of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1 ,5-a]pyrazin-1-yl)-N- (pyridin-2-yl)benzamide (58%).

Example 6

Figure imgf000038_0001

(S)-4-(8-amino-3-n-but-2-vnoylpyrrolidin-2-vnimidazo[1 ,5-alpyrazin-1-yl)-N-(pyridin-2-yl)benzamide

This compound was prepared, in an analogues manner as described in Example 2, from the compound described in intermediate 2b and 2-butynoic acid, to afford the title compound (10.5 mg, 18.0%). Data: LCMS (B) Rt : 2.08 min; m/z 466.1 (M+H)+.

PATENT

WO 2016024228

https://www.google.com/patents/WO2016024228A1?cl=en

PATENT

CN 107056786

Step SI:

[0029] The pressure in the reactor was added 3-chloro-2-carboxaldehyde l-yl P ratio of (II) (0.71g, 5mmol) and dioxane (20mL), under stirring ammonia gas (I. 7g, 0 . Imol), was added 4- (pyridin-2-yl – aminocarbonyl) phenylboronic acid (III) (2.42g, lOmmol), Ming dicarbonyl acetylacetonate (0.26g, lmmol), and water 4mL. The reactor was sealed, gradually warmed to 80~90 °, the reaction 16-18 hours, TLC detection, the reaction was complete. Concentrated under reduced pressure, the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and water successively, dried over anhydrous sodium sulfate. Concentrated to give brown oil, ethyl acetate and petroleum ether (volume ratio 1: 2) column chromatography to give an off-white solid 4- [amino (3-chloro-2-pyrazinyl) methyl] -N- (2-pyridyl) benzamide (IV) 1.38g, yield 81 · 2%; ESI-MS (m / z): 340 (m + H).

[0030] Step S2:

[0031] added in the reactor [1- (1-oxo-2-butyn-1-yl)] – L- proline (1.09g, 6mmol) and thionyl chloride (IOmL), was added dropwise 4mL of triethylamine and heated to 30 to 40 degrees, after the reaction for 2-4 hours under reduced pressure to remove excess thionyl chloride, the residue that is [I- (1- oxo-2-butyn-1-yl )] – L- proline acid chloride (V). The resulting [I- (1- oxo-2-butynyl -1_ yl)] _ L_ proline acid chloride (V) dissolved in 20mL dichloromethane burning, to a solution of 4- [amino (3-chloro -2-P ratio piperazinyl) methyl] -N- (2- pyridinyl) benzamide (IV) (1.35g, 4mmol) and triethylamine (0.6g, 6mmol) in dichloromethane (30mL) solution of in. Dropwise, warmed to 30-50 °, the reaction was stirred for 6 ~ 8 hours, TLC detection, the reaction was complete. Cooled to room temperature, washed with saturated sodium bicarbonate solution, brine and water, dried over anhydrous sodium sulfate. Concentrated to give a beige solid of 4- [1- (1-acyl-2-yne-2-yl) carboxamido (3-chloro-2-pyrazinyl) methyl] -N- (2- pyridinyl) benzamide (VI) 1.8g, yield 89.6% C3ESI-MS (m / z): 503 (m + H).

[0032] Step S3:

[0033] in a reaction flask was added 4- [I- (1- but-2-yn-acyl-2-yl) carboxamido (3-chloro-2-pyrazinyl) methyl] -N- ( 2-P ratio piperidinyl) benzamide (VI) (1 · 0g, 2mmol), phosphorus oxychloride (1 · 53g, IOmmol) and acetonitrile (25 mL), warmed to 80 ~ 100 ° with stirring, maintaining the temperature reaction 6 ~ 8 h, TLC the reaction was complete. Cooled to room temperature, the reaction solution was poured into 50mL concentration of 8% aqueous ammonia was added ethyl acetate, and the organic phase was separated, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine and water, dried over anhydrous over sodium sulfate. Concentrated and the resulting residue with ethyl acetate and petroleum ether (volume ratio 2: 1) column chromatography to give an off-white solid 4- [8-Chloro -3- [(2S) -I- (1- oxo-2 – butyn-1-yl) -2-pyrrolidinyl] imidazo [I, 5-a] pyrazin-1-yl] -N-2- pyridinyl benzamide (VII) 0.85g, yield 87.8 %; EI-MS m / z: 485 [m + H] + square

[0034] Step S4:

[0035] The pressure reactor was added to 4- [8-Chloro -3- [(2S) -I- (1- oxo-2-butyn-1-yl) -2-pyrrolidinyl] imidazo [ I, 5-a] pyrazin – Buji] -N-2- pyridinyl benzamide (VII) (0.48g, lmmol) and isopropanol (15 mL), cooled to 0 degrees, by controlling the dose into ammonia gas (0.51g, 30mmol), the reactor is closed, warmed up to room temperature for 1 hour, and then continuously increasing the reaction temperature to 110~120 °, maintained at the reaction temperature and pressure 20~24 h, TLC the reaction was complete. Cooled to room temperature, slowly vented, and concentrated under reduced pressure, the resulting residue was dissolved with ethyl acetate, water and saturated brine, dried over anhydrous sodium sulfate. Concentrated and the resulting residue with ethyl acetate and petroleum ether (volume ratio 2: 1) column chromatography to give an off-white solid Acre imatinib ⑴ 0.40g, yield 86 · 0%; 1Η bandit R (DMS0-d6) 1.63 (m, lH), 1.97 (s, 3H), 2.02 ~2.12 (m, lH), 2 · 28~2.35 (m, 2H); 3.36~3.85 (m, 2H), 5 · 47~5.49 (m , lH), 6 · 17~6.23 (m, 2H), 7.12~7.20 (m, 2H), 7 · 73~7.86 (m, 4H), 8 · 16~8.25 (m, 3H), 8 · 41 ( dd, lH), 10.86 (s, lH); EI-MS m / z: 466 [m + H] +.

[0036] 3-chloro starting material employed in the method above relates to the present invention yl pyrazin-2-carbaldehyde (II) and 4- (pyridin-2-yl – aminocarbonyl) phenylboronic acid (III), respectively, refer to methods for their preparation Document “Tetrahedron Letters, 47 (l), 31-34; 2006” international Patent W02013010868 and method for preparing the same compound. Raw [1- (1-oxo-2-butyn-1-yl)] – L- proline acid chloride (V), in one embodiment, the compound may be made [the I-(1-oxo-known -2-yn-1-yl)] – L- proline acylation.

PATENT

US 20170224688

PATENT

CN 107522701

 Example I

[0030] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0031] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (10g, 28mmol) was dissolved in N- methylpyrrolidone ( SOML), the mass concentration was added 28% aqueous ammonia (168mm〇l), the reaction mixture was placed in a sealed stainless steel autoclave at 85 ° C, stirring the reaction under a pressure of 2.5 atm 6h, after the completion of the reaction, was cooled to 40 ° C and delivery system pressure, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin – 3- yl) -1-pyrrolidine-carboxylate, an off-white solid (8.5 g of), yield 90%, reaction formula of this step is as follows:

Figure CN107522701AD00091

[0033] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5_a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0034] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (8g, 24mmol) was dissolved in dichloromethane (IOOmL) was added tert-butyl dicarbonate (5.7g, 26mmol), reaction mixture was stirred 3h at 25 ° C, after completion of the reaction, post-treatment and purification to give ⑸-2- (8- tert-butoxycarbonyl-amino-imidazole and [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (IoG), 96% yield, this step follows the reaction formula:

Figure CN107522701AD00092

[0036] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0037] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (IOg, 23mmol) was dissolved in tetrahydrofuran ( 80mL), was slowly added N- bromosuccinimide (4.5g, 25mmol), the reaction mixture was 25 ° C the reaction was stirred for 4h. The mixture was then slowly added water (80 mL), cooled to -10 ° C crystallization 3h, filtered, and recrystallized from isopropanol to give (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [ I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (I I. Ig), a yield of 94.5%, the reaction formula of this step is as follows:

Figure CN107522701AD00093

[0039] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0040] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (I Ig, 2lmmol ), 4- (2-pyridyl-carbamoyl) phenylboronic acid (5.7g, 23.4mmol), [1, Γ – bis (diphenylphosphino) ferrocene] dichloropalladium cesium (〇.78g, the I · lmmol), potassium carbonate (4.0g, 29mmol), N, N- dimethylformamide (120 mL) and water (50mL) added to the reaction flask, the reaction mixture was heated to 90 ° C the reaction was stirred for 20 h, the reaction solution was reduced at room temperature, was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give (S) -2- {8- tert butoxycarbonyl group -I- [4- (2-P of pyridine-ylcarbamoyl) phenyl] imidazole and sat Jie [I, 5_a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, class as a white solid (10.3 g of), a yield of 76.5%, the reaction formula of this step is as follows:

Figure CN107522701AD00101

[0042] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} pyrrolidine:

[0043] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- [1-carboxylic acid than the burning section slightly ester (10g, 15.8mmol) was dissolved in methanol (80mL), was added cesium charcoal (0.5g), under a hydrogen pressure into 35 ° C the reaction 8h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (7.6 g of), 96% yield, this step follows the reaction formula:

Figure CN107522701AD00102

[0045] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0046] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } ratio slightly burning Jie (7g, 14mmol) was dissolved in tetrahydrofuran (75 mL), with stirring, was added 2-butyne chloride (I. 7g, 16.6mmol), was added dropwise N, N- diisopropylethylamine (2.7 g, 21 mmol), the reaction mixture was 50 ° C the reaction was stirred for 8h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give ⑸ -2_ {8-tert-butoxycarbonyl-amino -1- [4- (2-P of pyridine-ylcarbamoyl) phenyl] imidazole and sat Jie [I, 5_a] [! than 3-yl} -1 – (2_ butynoyl) pyrrolidine-white solid (7g), in 88% yield, this step follows the reaction formula:

Figure CN107522701AD00111

[0048] ⑺ prepared Acalabrutinib:

[0049] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- (2-butynoyl) pyrrolidine (7g, 12.4mmol) and dissolved in methanol (70 mL), trifluoroacetic acid (1.55g, 13.6mmol), 65 ° C until the reaction was complete the reaction was stirred for 6h, the reaction was added dropwise to a stirred solution of water (150 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors Acalabrut inib, as a white solid (5.3 g of), 92% yield, this step is the following reaction formula:

Figure CN107522701AD00112

[0051] Example 2:

[0052] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0053] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (15g, 42mmol) was dissolved in N- methylpyrrolidone ( 75 mL), aqueous ammonia (273_〇1) was added mass percent concentration of 28%, the reaction mixture was placed in a sealed stainless steel autoclave at 70 ° C, stirring the reaction under a pressure of 3 atm 8h, after the completion of the reaction, was cooled to 40 ° C and releasing the pressure in the system, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazine 3-yl) pyrrolidine-carboxylic acid benzyl ester, off-white solid (12.9 g of), yield 91% ,, this step reaction scheme in Example 1.

[0054] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5_a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0055] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (12g, 35.6mmol) was dissolved in chloroform (80mL), was added tert-butyl dicarbonate (7.8g, 35.6mmol), the reaction mixture was stirred for lh the reaction at 35 ° C, after completion of the reaction, post-treatment and purification to give ⑸-2- (8- tert-butoxycarbonyl-amino-imidazole and [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (14.8 g of), in 95% yield, this step is the same reaction scheme as in Example 1.

[0056] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0057] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (Hg, 32mmol) was dissolved in 1, 1,2-dichloroethane (90mL), was slowly added bromine (6g, 37.8mmol), the reaction mixture was 20 ° C the reaction was stirred for 6h. After the reaction, water was slowly added (I5mL), cooled to -5 ° C crystallization 4h, filtered and recrystallized from isopropanol to give ⑸-2- (8- tert-butoxycarbonyl-amino-1-bromo-imidazo [1, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (15.8 g), yield 95.5%, the reaction of the present step is the same formula as in Example 1.

[0058] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0059] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (15g, 29mmol) , 4- (2-pyridyl-carbamoyl) phenylboronic acid (34 · 7mmol 8 · 4g,), tetrakis (triphenylphosphine) palladium (0 · 84g, 0.73mmol), sodium carbonate (6.9g, 65mmol), tetrahydrofuran (IOOmL) and water (40 mL) was added a reaction flask, the reaction mixture was heated to 80 ° C the reaction was stirred for 24h, the reaction was cooled to room temperature, and concentrated by rotary evaporation to dryness, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazole and [I, 5-a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, an off-white solid (14.4g), 78% yield, this step is the same reaction scheme as in Example 1.

[0060] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} pyrrolidine:

[0061] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-yl _3- it is slightly burned} -1-carboxylic acid ester section (14g, 22mmol) dissolved in isopropanol (85mL), was added Raney nickel (0.5g), under a hydrogen pressure into the reaction 60 ° C 12h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (10.4 g of), 94% yield, this step is the same reaction scheme as in Example 1.

[0062] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0063] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } pyrrolidine (10g, 20mmo 1) was dissolved in N, N- dimethylformamide (SOML), with stirring, was added 2-butyne chloride (3. lg, 30mmol), dropwise addition of triethylamine (2.2g, 22mmol ), the reaction mixture was 60 ° C the reaction was stirred for 4h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give ⑸- 2- {8-tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -l- (2- butynoyl) pyrrolidine-white solid (10.2 g of), a yield of 90.2%, the same reaction scheme of the present embodiment step 1〇

[0064] ⑺ prepared Acalabrutinib:

[0065] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1- (2-butynoyl) pyrrolidine (IOg, 17.7mmol) was dissolved in ethanol, and (IOOmL), trifluoroacetic acid (2.6g, 23mmol), 50 ° C with stirring until the reaction was complete IOh reaction, the reaction solution was added dropwise to a stirred solution of water (70 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors AcaIabrut inib, as a white solid (7.5 g of), yield 91%, reaction of this step formula same as in Example 1.

[0066] Example 3:

[0067] (1) Preparation of ⑸-2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0068] (S) -2- (8- chloro-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (4.5g, 12.6mmol) was dissolved in N- methyl pyrrolidinone (70 mL), was added mass percent concentration of 28% aqueous ammonia (69.4 mmol), the reaction mixture was placed in the autoclave 90 ° C, the reaction was stirred under atmospheric pressure of 4h, after the completion of the reaction, it was cooled to 35 ° C a sealed stainless steel reactor and releasing the pressure in the system, slow addition of water (50 mL), cooled to 10 ° C, crystallization 3h, filtered, and recrystallized from isopropanol to give ⑸-2- (8- amino-imidazo [I, 5-a] pyrazine 3-yl) pyrrolidine-carboxylic acid benzyl ester, off-white solid (3.9 g of), 92% yield, this step is the same reaction scheme as in Example 1.

[0069] (2) Preparation of (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0070] (S) -2- (8- amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester (3 · 5g, 10 · 4mmol) was dissolved in 1, 4- dioxane (50 mL), was added tert-butyl dicarbonate (2.7g, 12.4mmol), the reaction mixture was stirred at 10 ° C the reaction 6h, after the completion of the reaction, workup and purification, to give (S) 2- (8-tert-butoxycarbonyl-amino-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (4.3 g of), in 95% yield, according to the present step reaction scheme in Example 1.

[0071] (3) Preparation of (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylic acid benzyl ester:

[0072] (S) -2- (8- tert-butoxycarbonyl-amino-imidazo [l, 5_a] pyrazin-3-yl) -1_ pyrrolidine-carboxylate (4g, 9.6mmol) was dissolved in toluene (50 mL ), was slowly added N- bromosuccinimide (I. 8g, 10. lmmol), the reaction mixture was 35 ° C the reaction was stirred for 2h. The mixture was then slowly added water (25 mL), cooled to -10 ° C crystallization 3h, filtered, and recrystallized from isopropanol to give (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [ I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate, an off-white solid (4.7 g), 94% yield, this step is the same reaction scheme as in Example 1.

[0073] (4) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} 1-pyrrolidine-carboxylic acid benzyl ester:

[0074] (S) -2- (8- tert-butoxycarbonyl-1-bromo-imidazo [I, 5-a] pyrazin-3-yl) -1-pyrrolidine-carboxylate (4g, 7 · 7mmol), 4_ (2- piperidinyl than Jie carbamoyl) phenylboronic acid (2 · 4g, IOmmol), bis (triphenylphosphine) dichloride Leba (0.41g, 0.58mmol), potassium phosphate (I. 9g, 8.9mmol), methyl tert-butyl ether (IOOmL) and water (40 mL) was added a reaction flask, the reaction mixture was heated to 100 ° C the reaction was stirred for 12h, the reaction was cooled to room temperature, and concentrated by rotary evaporation to dryness, was added acetic acid extracted with ethyl, brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2 – pyridin-ylcarbamoyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -1-pyrrolidine-carboxylate, an off-white solid (3.9 g of), in 79% yield, this step the reaction scheme in Example 1.

[0075] (5) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5_a] pyrazin-3 -} pyrrolidine:

[0076] (S) -2- {8- tert-butoxycarbonyl group -I- [4- (2- carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } -1 Jie section than slightly burning acid ester (3.5g, 5.5mmol) was dissolved in ethanol (50mL), was added cesium charcoal (0.2g), under a hydrogen pressure into 45 ° C the reaction 6h. Concentrated suction through Celite to remove the catalyst and the filtrate was rotary evaporated to dryness to afford ⑸-2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [ I, 5-a] pyrazin-3-yl} pyrrolidine as a white solid powder (2.6 g of), in 95% yield, this step is the same reaction scheme as in Example 1.

[0077] (6) Preparation of (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [1, 5-a] pyrazine 3-yl} -1- (2-butynoyl) pyrrolidine:

[0078] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl } ratio slightly burning Jie (2.5g, 5mmol) was dissolved in toluene (50 mL), with stirring, was added 2-butyne chloride (0.62g, 6mmol), was added dropwise N, N- dimethylaniline (Ig, 8.5mmo 1), The reaction mixture was 40 ° C the reaction was stirred for 12h, the reaction solution was concentrated by rotary evaporation to dryness, dilute hydrochloric acid was added was adjusted to neutral, extracted with ethyl acetate was added, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, and recrystallized from methanol to give ⑸-2- {8-tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-3-yl} -1- (2-butyn acyl) pyrrolidine-white solid (2.5g), 88% yield, this step is the same reaction scheme as in Example 1.

[0079] ⑺ prepared Acalabrutinib:

[0080] (S) -2- {8- tert-butoxycarbonyl-amino-1- [4- (2-carbamoyl-pyridyl) phenyl] imidazo [I, 5-a] pyrazin-yl _3_ } -1- (2-block group) ratio slightly burning Jie (2.5g, 4.4mmol) was dissolved in dichloromethane and burned (IOmL), two gas was added acetic acid (0.76g, 6.6mmol), 80 ° C The reaction was stirred 4h until the reaction was complete, the reaction was added dropwise to a stirred solution of water (25 mL), cooled to 0 ° C crystallization 3h, filtered to give the treatment of chronic lymphocytic leukemia BTK inhibitors AcaIabrut inib, as a white solid (1.8 g of), the yield of 89%, this step is the same reaction scheme as in Example 1.

PATENT

US 20170035881

References

  1. Jump up^ “WHO Drug Information – recommended INN” (PDF). WHO Drug Information. World Health Oorganisation. Retrieved 24 December 2015.
  2. Jump up to:a b c d Byrd; et al. (2015). “Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia”doi:10.1056/NEJMoa1509981.
  3. Jump up to:a b c d e f g h i Wu, Jingjing; Zhang, Mingzhi; Liu, Delong (2016-01-01). “Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor”Journal of Hematology & Oncology9: 21. doi:10.1186/s13045-016-0250-9ISSN 1756-8722PMC 4784459Freely accessiblePMID 26957112.
  4. Jump up^ “AstraZeneca to buy Acerta for blood cancer drug”http://www.rsc.org. Chemistry World – Royal Society of Chemistry. Retrieved 24 December 2015.
  5. Jump up^ Wu, Jingjing; Zhang, Mingzhi; Liu, Delong (2016-03-09). “Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor”Journal of Hematology & Oncology9 (1). doi:10.1186/s13045-016-0250-9ISSN 1756-8722PMC 4784459Freely accessiblePMID 26957112.
  6. Jump up to:a b c Harrington, Bonnie K.; Gardner, Heather L.; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R.; Covey, Todd; Kaptein, Allard; Gulrajani, Michael (2016-07-19). “Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma”PLOS ONE11 (7): e0159607. doi:10.1371/journal.pone.0159607ISSN 1932-6203PMC 4951150Freely accessiblePMID 27434128.
  7. Jump up to:a b Acerta Pharma Announces Study Published in New England Journal of Medicine Demonstrates Acalabrutinib (ACP-196) Shows Marked Activity in Relapsed Chronic Lymphocytic Leukemia
  8. Jump up^ 21 studies found for: ACP-196
  9. Jump up^ “Acerta Investor Conference Call – 17 December 2015” (PDF). http://www.astrazeneca.com. Retrieved 2016-11-20.
  10. Jump up^ “Public summary of opinion on orphan designation” (PDF). European Medicines Agency. 2016-04-27. Retrieved 2016-11-20.
  11. Jump up^ “azn201602256k.htm”http://www.sec.gov. Retrieved 2016-11-21.
  12. Jump up^ House, SA Editor Douglas W. (2016-02-25). “AstraZeneca and Acerta Pharma’s acalabrutinib tagged an Orphan Drug in Europe for three indications”Seeking Alpha. Retrieved 2016-11-21.
  13. Jump up^ “Acerta Pharma B.V. – Company Profile – BioCentury”http://www.biocentury.com. Retrieved 2016-11-12.
  14. Jump up^ “Log in to CB Insights”http://www.cbinsights.com. Retrieved 2016-11-12.
  15. Jump up^ “This is The Most Valuable Startup You’ve Never Heard Of”Fortune. 2015-12-17. Retrieved 2016-11-12.
  16. Jump up^ Walker, Ian; Roland, Denise (2015-12-17). “AstraZeneca to Buy Stake in Acerta Pharma”Wall Street JournalISSN 0099-9660. Retrieved 2016-11-19.
  17. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Nov 26, 2015), Btk inhibitor for the treatment of chronic lymphocytic and small lymphocytic leukemia, retrieved 2016-11-19
  18. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Jun 11, 2015), Therapeutic combination of a pi3k inhibitor and a btk inhibitor, retrieved 2016-11-19
  19. Jump up to:a b IZUMI, Raquel; SALVA, Francisco; HAMDY, Ahmed (Feb 4, 2016), Methods of blocking the cxcr-4/sdf-1 signaling pathway with inhibitors of bruton’s tyrosine kinase, retrieved 2016-11-19
  20. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Aug 4, 2016), Therapeutic combinations of a btk inhibitor, a pi3k inhibitor and/or a jak-2 inhibitor, retrieved 2016-11-19
  21. Jump up^ Lannutti, Brian; Covey, Todd; Kaptein, Allard; Johnson, David; STAMATIS, Jay; Krejsa, Cecile M.; Slatter, John Gregory (Feb 11, 2016), Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on btk occupancy and btk resynthesis rate, retrieved 2016-11-19
  22. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Feb 18, 2016), Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment, retrieved 2016-11-19
  23. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Feb 18, 2016), Therapeutic combinations of a btk inhibitor, a pi3k inhibitor, a jak-2 inhibitor, and/or a bcl-2 inhibitor, retrieved 2016-11-19
  24. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Feb 18, 2016), Therapeutic combinations of a btk inhibitor, a pi3k inhibitor, a jak-2 inhibitor, a pd-1 inhibitor and/or a pd-l1 inhibitor, retrieved 2016-11-19
  25. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Feb 18, 2016), Therapeutic combinations of a btk inhibitor, a pi3k inhibitor, a jak-2 inhibitor and/or a cdk 4/6 inhibitor, retrieved 2016-11-19
  26. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Jul 28, 2016), Compositions and methods for treatment of chronic lymphocytic leukemia and small lymphocytic leukemia using a btk inhibitor, retrieved 2016-11-19
  27. Jump up^ HAMDY, Ahmed; Rothbaum, Wayne; IZUMI, Raquel; Lannutti, Brian; Covey, Todd; ULRICH, Roger; Johnson, Dave; Barf, Tjeerd; Kaptein, Allard (Aug 18, 2016), Therapeutic combinations of a btk inhibitor, a pi3k inhibitor, a jak-2 inhibitor, a pd-1 inhibitor, and/or a pd-l1 inhibitor, retrieved 2016-11-19
  28. Jump up^ Barf, Tjeerd A.; Jans, Christian Gerardus Johannes Maria; Man, Petrus Antonius De Adrianus; Oubrie, Arthur A.; Raaijmakers, Hans C. A.; Rewinkel, Johannes Bernardus Maria; Sterrenburg, Jan-Gerard; Wijkmans, Jacobus C. H. M. (5 June 2014), United States Patent Application: 0140155385 – 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS, retrieved 2016-11-19

ADDITIONAL INFORMATION

Acalabrutinib is a potent and selective BTK (Bruton’s tyrosine kinase) inhibitor. BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. BTK inhibitors targeting B cell receptor signaling and other survival mechanism showed great promise for the treatment of chronic lymphocytic leukemia (CLL)s holds great promise.

As of 2015 it is in late stage clinical trials for relapsed chronic lymphocytic leukemia. Interim results are encouraging : 95% overall response rate. It is also in another 20 clinical trials (alone and in combination) for various cancers.

REFERENCES

1: Maly J, Blachly JS. Chronic Lymphocytic Leukemia: Exploiting Vulnerabilities with Targeted Agents. Curr Hematol Malig Rep. 2016 Feb 11. [Epub ahead of print] PubMed PMID: 26893063.

2: Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7. PubMed PMID: 26641137.

Patent ID

Patent Title

Submitted Date

Granted Date

US2017231995 BTK Inhibitors to Treat Solid Tumors Through Modulation of the Tumor Microenvironment
2015-08-11
US2017095471 Methods of Treating Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia Using a BTK Inhibitor
2015-01-21
Patent ID

Patent Title

Submitted Date

Granted Date

US2017231986 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor
2015-08-11
US2017035756 METHODS OF BLOCKING THE CXCR-4/SDF-1 SIGNALING PATHWAY WITH INHIBITORS OF BRUTON’S TYROSINE KINASE
2015-04-10
US2017266191 Therapeutic Combination of PI3K Inhibitor and a BTK Inhibitor
2014-12-05
US2016159810 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2016-02-09
2016-06-09
US2017143712 Methods of Treating Cancers, Immune and Autoimmune Diseases, and Inflammatory Diseases Based on BTK Occupancy and BTK Resynthesis Rate
2017-02-07
Patent ID

Patent Title

Submitted Date

Granted Date

US2017035881 Therapeutic Combinations of an IRAK4 Inhibitor and a BTK Inhibitor
2016-10-19
US2017071962 Therapeutic Combinations of a Proteasome Inhibitor and a BTK Inhibitor
2016-09-12
US9717745 PHARMACEUTICAL COMPOSITIONS AND THEIR USE FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASES
2016-06-15
US9758524 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2016-02-09
2016-06-02
US2017224819 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a CDK 4/6 Inhibitor
2015-08-11
Patent ID

Patent Title

Submitted Date

Granted Date

US2017029428 Solid Forms and Formulations of Imidazopyrazine Compound
2016-07-01
US2017239351 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, a PD-1 Inhibitor, and/or a PD-L1 Inhibitor
2015-08-11
US2017136014 Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor and/or a JAK-2 Inhibitor
2015-06-17
US9290504 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES AS BTK INHIBITORS
2012-07-11
2014-06-05
US2017224688 Methods of Using BTK Inhibitors to Treat Dermatoses
2017-02-03
Acalabrutinib
Acalabrutinib.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C26H23N7O2
Molar mass 465.507 g/mol
3D model (JSmol)

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID)
Patent 9290504
Expiration Jul 11, 2032
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)
FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID)
Patent 9758524
Expiration Jul 11, 2032
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)
FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID)
Patent 9796721
Expiration Jul 1, 2036
Applicant ASTRAZENECA
Drug Application N210259 (Prescription Drug: CALQUENCE. Ingredients: ACALABRUTINIB)

////////////AcalabrutinibrINNACP-196, fda 2017, Акалабрутиниб , أكالابروتينيب , 阿可替尼 , Orphan Drug, breakthrough therapy designation, Lymphoma, mantle cell, ACERTA PHARMA

CC#CC(=O)N1CCC[C@H]1c2nc(c3n2ccnc3N)c4ccc(cc4)C(=O)Nc5ccccn5

CC#CC(=O)N1CCCC1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)C(=O)NC5=CC=CC=N5

Netarsudil, Нетарсудил , نيتارسوديل , 奈舒地尔 , ネタルスジル ,


Netarsudil.pngChemSpider 2D Image | netarsudil | C28H27N3O3

Netarsudil

Molecular Formula: C28H27N3O3
Molecular Weight: 453.542 g/mol

Netarsudil; UNII-W6I5QDT7QI; W6I5QDT7QI; 1254032-66-0; Netarsudil [USAN]; AR-11324 free base

1422144-42-0 (mesylate)   1254032-66-0 (free base)   1253952-02-1 (HCl)

[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate

4-[(2S)-3-Amino-1-(6-isoquinolinylamino)-1-oxo-2-propanyl]benzyl 2,4-dimethylbenzoate [ACD/IUPAC Name]
Benzoic acid, 2,4-dimethyl-, [4-[(1S)-1-(aminomethyl)-2-(6-isoquinolinylamino)-2-oxoethyl]phenyl]methyl ester
W6I5QDT7QI
Нетарсудил [Russian] [INN]
نيتارسوديل [Arabic] [INN]
奈舒地尔 [Chinese] [INN]
ネタルスジル;
Inventor – Aerie Pharmaceuticals, Inc. 
Approved by US-FDA in December-2017 for dimesylate salt

Image result for NetarsudilImage result for Netarsudil

Netarsudil Mesylate
CAS: 1422144-42-0 (mesylate)
Chemical Formula: C30H35N3O9S2

Molecular Weight: 645.742

1422144-42-0 [RN]
4-[(2S)-3-Amino-1-(6-isoquinolinylamino)-1-oxo-2-propanyl]benzyl 2,4-dimethylbenzoate methanesulfonate (1:2)
Benzoic acid, 2,4-dimethyl-, [4-[(1S)-1-(aminomethyl)-2-(6-isoquinolinylamino)-2-oxoethyl]phenyl]methyl ester, methanesulfonate (1:2)

Netarsudil dimesylate is a light yellow-to-white powder that is freely soluble in water, soluble in methanol, sparingly soluble in dimethyl formamide, and practically insoluble in dichloromethane and heptane.

Netarsudil ophthalmic solution 0.02% is supplied as a sterile, isotonic, buffered aqueous solution of netarsudil dimesylate with a pH of approximately 5 and an osmolality of approximately 295 mOsmol/kg. It is intended for topical application in the eye. Each mL of netarsudil contains 0.2 mg of netarsudil (equivalent to 0.28 mg of netarsudil dimesylate). Benzalkonium chloride, 0.015%, is added as a preservative. The inactive ingredients are: boric acid, mannitol, sodium hydroxide to adjust pH, and water for injection

Netarsudil, also known as AR-11324, is a Rho-associated protein kinase inhibitor. Netarsudil is potential useful for treating glaucoma and/or reducing intraocular pressure. Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large reductions in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia observed as the only adverse effect.

Netarsudil (trade name Rhopressa) is a drug for the treatment of glaucoma. In the United States, the Food and Drug Administrationhas approved a 0.02% ophthalmic solution for the lowering of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.[1]

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton. ROCK signaling plays an important role in many diseases including diabetes, neurodegenerative diseases such as Parkinson´s disease and amyotrophic lateral sclerosis, pulmonary hypertension and cancer. It has been shown to be involved in causing tissue thickening and stiffening around tumours in a mouse model of skin cancer, principally by increasing the amount of collagen in the tissue around the tumour.

WO 2014144781Image result for Netarsudil

SYNTHESIS

WO2010127329

 

 

CONTINUED………..

PATENT

WO 2014144781

CN 107434780

https://www.google.com/patents/CN107434780A?cl=en

Synthesis of Compound 12

Figure CN107434780AD00153

[0091] The 2,4-dimethyl benzoic acid (1.5g, IOmmol) and a catalytic amount of DMF was added to the toluene and cooled to 2-5 ° C, was added dropwise oxalyl chloride (I.64g, 13_〇1 ), warmed to room temperature after dropwise, stirred overnight, during which a solid gradually dissolved to give a clear solution, evaporated to dryness under reduced pressure to give a yellow oil with dichloromethane (IOml) was dissolved in dichloromethane to give the acid chloride ;

[0092] Compound 11 (3.2g, 7.7mmo 1) and triethylamine (2ml) were added 20ml of dichloromethane, nitrogen, the above prepared acid chloride solution in dichloromethane dropwise at 0-5 ° C the increases after mixing, overnight; TLC (dichloromethane: methanol = 20: 1) to monitor the reaction, completion of the reaction, evaporated to dryness under reduced pressure, and then stirred with saturated sodium carbonate solution, filtered, the filter cake was washed with water 3 times, dried to give 3.9g white solid, i.e. compound 12; purity: 991%, optical purity: 100% (CHIRALPAK AS-H, 0.46cm IDX15cm L, Me0H + 0.1DEA) / C02 = 20/80 (V / V, 2.0ml / min), R-type, Rt = 3 · 253min; S type Rt = 4.3min).

Compound 12 (3.9g) in DCM was added, with stirring to obtain clear solution, was then added dropwise I, a solution of hydrogen chloride in dioxane 15ml 4_ (concentration 4mol / L, 4mol HCl gas dissolved in two IL oxygen six ring), and then stirred for 4 hours at room temperature, rotary evaporated under reduced pressure, and filtered to give 3.65g product as a white solid, was obtained HNMR detectable substance is the AR-13324 hydrochloride, which IHNMR spectrum Referring to FIG. 1 , MS, purity, 99.4%, lHNMR (400MHz, DMS0,300) S (Ppm) c3Il .773 (s, 1H), 9.702 (s, lH), 8.740 (d, lH), 8.560 (d, 1H), 8.469 (d, 1H), 8.360 (d, 1H), 8.280 (s, 3H), 8.158 (dd, lH), 7.777 (d, lH), 7.577 (d, 2H), 7.496 (d, 2H), 7.134 (s, lH), 7.111 (d, lH), 5.281 (s, 2H), 4.504 (q, lH), 3.609 (q, lH), 3.139 (q, lH), 2.483 (s, 3H), 2.302 ( s, 3H).

Example 2

[0097] In this embodiment, the same processing steps except that Compound 12, the other the same as in Example 1.

[0098] Compound 12 processing steps are as follows: The compound is dissolved in 12 (3.9g) 40ml of dichloromethane, followed by dropwise addition of methanesulfonic acid (2g, 21.6mmol), stirred at room temperature overnight, rotary evaporated under reduced pressure, IOOml diethyl ether was added thereto, followed by stirring, a large amount of white solid was filtered, dried to give a white solid (4.54 g of), yield 97.8%, purity 98.2%, the resulting substance was detected IHNMR AR-13324 is the mesylate salt.

CN 107434780
Figure CN107434780AD00171

References

Patent ID

Patent Title

Submitted Date

Granted Date

US9643927 Process for the preparation of kinase inhibitors and intermediates thereof
2015-11-17
2017-05-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2016346269 COMBINATION THERAPY
2016-08-15
US2014275160 COMBINATION THERAPY
2014-03-14
2014-09-18
US2016243105 COMBINATION THERAPY
2016-04-29
2016-08-25
US9415043 COMBINATION THERAPY
2014-03-14
2014-09-18
US2017204065 PROCESS FOR THE PREPARATION OF KINASE INHIBITORS AND INTERMEDIATES THEREOF
2017-03-31
Netarsudil
Netarsudil.svg
Clinical data
Trade names Rhopressa
Synonyms AR-11324
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C28H27N3O3
Molar mass 453.54 g·mol−1

REFERENCES

1: Sturdivant JM, Royalty SM, Lin CW, Moore LA, Yingling JD, Laethem CL, Sherman B, Heintzelman GR, Kopczynski CC, deLong MA. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg Med Chem Lett. 2016 May 15;26(10):2475-80. doi: 10.1016/j.bmcl.2016.03.104. Epub 2016 Apr 1. PubMed PMID: 27072905.

2: Ren R, Li G, Le TD, Kopczynski C, Stamer WD, Gong H. Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6197-6209. doi: 10.1167/iovs.16-20189. PubMed PMID: 27842161; PubMed Central PMCID: PMC5114035.

3: Li G, Mukherjee D, Navarro I, Ashpole NE, Sherwood JM, Chang J, Overby DR, Yuan F, Gonzalez P, Kopczynski CC, Farsiu S, Stamer WD. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur J Pharmacol. 2016 Sep 15;787:20-31. doi: 10.1016/j.ejphar.2016.04.002. Epub 2016 Apr 13. PubMed PMID: 27085895; PubMed Central PMCID: PMC5014700.

4: Lin CW, Sherman B, Moore LA, Laethem CL, Lu DW, Pattabiraman PP, Rao PV, deLong MA, Kopczynski CC. Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma. J Ocul Pharmacol Ther. 2017 Jun 13. doi: 10.1089/jop.2017.0023. [Epub ahead of print] PubMed PMID: 28609185.

5: Lu LJ, Tsai JC, Liu J. Novel Pharmacologic Candidates for Treatment of Primary Open-Angle Glaucoma. Yale J Biol Med. 2017 Mar 29;90(1):111-118. eCollection 2017 Mar. Review. PubMed PMID: 28356898; PubMed Central PMCID: PMC5369028.

/////////////Netarsudil, fda 2017, Rhopressa, AR-11324, AR 11324 

CC1=CC(=C(C=C1)C(=O)OCC2=CC=C(C=C2)C(CN)C(=O)NC3=CC4=C(C=C3)C=NC=C4)C

Delafloxacin


Delafloxacin.svg

ChemSpider 2D Image | Delafloxacin | C18H12ClF3N4O4

Delafloxacin.png

Delafloxacin

  • Molecular FormulaC18H12ClF3N4O4
  • Average mass440.760 Da

Delafloxacin, ABT-492, RX-3341, WQ-3034, A-319492

1-(6-Amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-7-(3-hydroxy-1-azetidinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
189279-58-1 [RN]
3-Quinolinecarboxylic acid, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-
T66 BN EVJ DVQ HF JG B- BT6NJ CF EF FZ& I- AT4NTJ CQ [WLN]
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid
MOA:DNA gyrase enzyme inhibitor; DNA topoisomerase Ⅳ inhibitor
Indication:Community-acquired pneumonia (CAP); Complicated skin and soft tissue infections
Status:FDA 2017
Company:Wakunaga (Originator) , Melinta Therapeutics

Delafloxacin is a Fluoroquinolone Antibacterial. The chemical classification of delafloxacin is Fluoroquinolones.

Image result for delafloxacin

Delafloxacin is a fluoroquinolone antibiotic which has been used in trials studying the treatment and basic science of Gonorrhea, Hepatic Impairment, Bacterial Skin Diseases, Skin Structure Infections, and Community Acquired Pneumonia, among others. It was approved in June 2017 under the trade name Baxdela for use in the treatment of acute bacterial skin and skin structure infections.
Image result for delafloxacin
Delafloxacin meglumine; 352458-37-8; UNII-N7V53U4U4T; Delafloxacin (meglumine); Delafloxacin meglumine [USAN]; N7V53U4U4T, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxoquinoline-3-carboxylic acid;(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol
D-Glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (1:1)

Delafloxacin (INN) (trade name Baxdela) is a fluoroquinolone antibiotic used to treat acute bacterial skin and skin structure infections.[1] It was developed and marketed by Melinta Therapeutics (formerly Rib-X Pharmaceuticals),[1] which subsequently merged with Cempra.[2]

Image result for delafloxacin

syn

CN 104876911

Medical use

Delafloxacin is used to treat acute bacterial skin and skin structure infections caused by designated susceptible bacteria.[1]

Susceptible bacteria are:[1]

  • Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Staphylococcus haemolyticusStaphylococcus lugdunensisStreptococcus agalactiaeStreptococcus anginosus group, Streptococcus pyogenes, and Enterococcus faecalis
  • Gram-negative organisms: Escherichia coliEnterobacter cloacaeKlebsiella pneumoniae, and Pseudomonas aeruginosa.

It has not been tested in pregnant women.[1]

Adverse effects

Like other drugs in the fluoroquinolone class, delafloxacin contains a black box warning about the risk of tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of myasthenia gravis. The label also warns against the risk of hypersensitivity reactions and Clostridium difficile-associated diarrhea.[1]

Adverse effects occurring in more than 2% of clinical trial subjects included nausea, diarrhea, headache, elevated transaminases, and vomiting.[1]

Image result for delafloxacin

Interactions

Like other fluoroquinolones, delafloxacin chelates metals including aluminum, magnesium, sucralfate, iron, zinc, and divalent and trivalent cations like didanosine; using this drugs with antacids, some dietary supplements, or drugs buffered with any of these ions will interfere with available amounds of delafloxacin.[1]

Pharmacology

The half-life varies in around 8 hours at normal doses. Excretion is 65% through urine, mostly in unmetabolized form, and 28% via feces. Clearance is reduced in people with severe kidney disease.[3]

Delafloxacin is more active (lower MIC90) than other quinolones against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In contrast to most approved fluoroquinolones, which are zwitterionic, delafloxacin has an anionic character, which results in a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH. This property is believed to confer to delafloxacin an advantage for the eradication of Staphylococcus aureus in acidic environments, including intracellular infections.[3]

Chemistry

The chemical name is 1-Deoxy-1 (methylamino)-D-glucitol, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl) 4-oxo-1,4-dihydroquinoline-3-carboxylate (salt).[1]

The injectable form of delafloxacin is sold as the meglumine salt of the active ingredient and its United States Adopted Name, delafloxacin meglumine, reflects that; the injection formulation also includes EDTA and sulfobutylether-β-cyclodextrin. The tablet is made of delafloxacin, citric acid anhydrous, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, sodium bicarbonate, and sodium phosphate monobasic monohydrate.[1]

History

Delafloxacin was known as ABT-492, RX-3341, and WQ-3034 while it was under development.[4]

Rib-X Pharmaceuticals acquired delafloxacin from Wakunaga Pharmaceutical in 2006.[5] Rib-X was renamed to Melinta Therapeutics in 2013.[6]

Key clinical trials for delafloxacin have been performed by Melinta regarding indications for skin and skin structure infections as well as complicated bacterial infections and uncomplicated gonorrhea. The trial on gonorrhea was terminated before data was released.[7]

Delafloxacin was approved by the FDA in June 2017, after it was noninferior to vancomycin plus aztreonam in two trials on 1042 patients with acute bacterial skin and skin structure infection.[8] New Drug Applications (NDA) for delafloxacin (Baxdela) 450 mg tablets and 300 mg injections were approved by the FDA in June 2017.[9]

The FDA obligated Melinta to conduct further studies as follows:[9]

  • a 5-year surveillance study to determine if resistance emerges, with the final report due in December 2022
  • a study of the IV form in pregnant rats to determine distribution to the reproductive tract, due June 2018, with further studies required if there is significant distribution.

Melinta merged with Cempra in August, 2017.[2]

Melinta has entered into commercialization and distribution agreements with both Menarini Therapeutics (March 2017) and Eurofarma Laboratórios (January 2015) for international commercialization of delafloxacin. The agreement with Menarini allows them to commercialize and distribute in 68 countries, including Europe, China, and South Korea among others. A similar agreement with Eurofarma allows for commercialization in Brazil.[7]

PATENT

CN103936717A

 de Iaf Ioxacin Preparation

Figure CN103936717BD00132

[0101] was added to the S-neck flask resultant product of Example 11 (3.5 Yap, dirty 〇1 0.76) implemented 01. (35 blood) milky white suspension, was added glacial acetic acid (3. OmL), stirred at room temperature to embrace completely clear solution was added dropwise distilled water 70 fed blood, filter, wash coating, evaporated to dryness to give a pale yellow powder 3. Og, purity 99.8% (HPLC), m / z (MH + M41.03, IH NMR (400MHz, DMSO) S4.20 (m, 2H), 4.45 (m, lH), 4.61 (m, 2H), 5.63 (d, lH), 6.69 (s, 2H), 7.81 (d, lH), 7.95 (dd, lH), 8.69 (d, lH), 14.34 (brs, lH).

PAPER

Org. Process Res. Dev. 200610, 803-807.

Chlorination at the 8-Position of a Functionalized Quinolone and the Synthesis of Quinolone Antibiotic ABT-492

GPRD Process Research and Development, Abbott Laboratories, Bldg. R8/1, 1401 Sheridan Road, North Chicago, Illinois 60064-6285, U.S.A.
Org. Process Res. Dev.200610 (4), pp 803–807
DOI: 10.1021/op0600557
Abstract Image

The total synthesis of quinolone antibiotic ABT-492 has been achieved in 67% yield over nine steps from 2,4,5-trifluorobenzoic acid. The highlights of this synthesis include a novel chemoselective chlorination at the 8-position of a highly elaborated quinolone core. In addition, a Lewis acid promoted cyclization reaction to form the quinolone heterocycle was developed which was incorporated into a one-pot, three-step cyclization/coupling/protection sequence that proceeds in 93% yield.

1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid (ABT-492), NCS Process: . Mp:  238−241 °C. 1H NMR (CDCl3) δ 14.63 (brs, 1H), 8.70 (d, J = 0.7 Hz, 1H), 7.95 (dd, J = 9.9, 0.7 Hz, 1H), 7.83 (d, J = 13.6 Hz, 1H), 6.75 (s, 2H), 5.75 (d, J = 5.8 Hz, 1H), 4.61 (m, 12H), 4.47 (m, 1H), 4.18 (m, 2H). Anal. Calcd for C18H12ClF3N4O4:  C, 49.05; H, 2.74; N, 12.71. Found:  C, 48.90; H, 2.48; N, 12.62.

PATENT

WO2006015194A2.

EXAMPLE 5
A solution of 2,4,5-trifluorobenzoic acid (139.5Kg) in DMF (8.4Kg) and toluene (613Kg) was treated with thionyl chloride (139.4Kg), stirred at 60°C for 3.5 hours, cooled to 250C, concentrated to 20% of its original volume, treated with toluene (600Kg), distilled and stored at ambient temperature.

EXAMPLE 6
A suspension of potassium ethyl malonate (50.8Kg) and magnesium chloride
(34.5Kg) in toluene (130Kg) below 00C was treated with THF (265L), cooled to 0°C, treated with triethylamine (75Kg), warmed to 5O0C, stirred for 1-5 hours, cooled to 00C, treated with 22% (w/w) of EXAMPLE 5 in toluene (163Kg), warmed to ambient temperature, stirred for 2 hours, added to 2M HCl (407Kg), stirred for 30 minutes, separated from the water layer and washed with water. This procedure was repeated, and the organic layers were combined, concentrated with an ethanol (150L) azeotrope, treated with water (30% by weight of the organic layer), stirred for 3 hours at 00C, and filtered. The andfiltrant was washed with 3:1 ethanol/water and dried under vacuum at 35-45°C to provide 86Kg of product. H NMR (CDCl3) (keto) δ 7.75 (ddd, J=10.8, 10.8, 6.0Hz, IH), 7.02 (ddd, IH), 4.27 (q, J=7.2Hz, 2H), 3.95 (d, 4.2Hz, 2H), 1.35 (t, J=7.3Hz, 3H); (enol) δ 12.72 (s, IH), 7.85 (ddd, J=10.5, 9.6, 6.6Hz, IH), 6.96 (ddd, J=10.5, 10.5, 6.6Hz, IH), 5.84 (s, IH), 4.23 (q, J=7.2Hz, 2H), 1.27 (t, J=7.4Hz, 3H).

EXAMPLE 7A
A solution of EXAMPLE 6 (83.2Kg) in triethyl orthoformate (80.1Kg) at reflux was stirred for 0.5-1 hour, treated with acetic anhydride (103.5Kg), stirred for 12 hours and cooled to ambient temperature to provide a solution that was used immediately.

EXAMPLE 7B
The solution of EXAMPLE 7A was treated with N-methylpyrrolidinone (210Kg), acetonitrile (161Kg) and water (3Kg), added to a suspension of EXAMPLE 4 (57.4Kg) in 1 : 1 N-methylpyrrolidinone (210Kg) and acetonitrile (161Kg), stirred for 2 hours, added to water (662Kg) and filtered. The fϊltrant was washed with (2:1) acetonitrile/water and water and dried under vacuum at 600C to provide 119.5Kg of product. Mp 157-16O0C; 1H NMR (CDCl3, 300 MHz) (E) δ 1.15 (t, 3H), 4.16 (q, 2H), 4.64 (br s, 2H), 6.90 (m, IH), 7.22 (t, IH), 7.32 (m, IH), 9.03 (d, IH), 12.44 (bd, IH); (Z) δ 1.03 (t, 3H), 4.11 (q, 2H), 4.60 (br s, 2H), 6.90 (m, IH), 7.20 (t, IH), 7.48 (m, IH), 8.90 (d, IH), 11.17 (bd, IH).

EXAMPLE 8A
A mixture of EXAMPLE 7 (115Kg) and lithium chloride (24.3Kg) in
N-methylpyrrolidinone (769Kg) below 350C was treated with DBU (946.1Kg) and stirred for 2 hours to provide a solution of EXAMPLE 8 A that was used immediately.

EXAMPLE 8B
The solution of EXAMPLE 8A below 4O0C was treated with EXAMPLE 2 (33.9Kg) and DBU (109Kg) and stirred for 2-5 hours to provide a solution of EXAMPLE 8B that was used immediately.

EXAMPLE 8C
The solution of EXAMPLE 8B was treated with isobutyric anhydride (99.7Kg), stirred at 350C for 1-2 hours, cooled to 20-300C, treated with ethyl acetate (104Kg) and 10% aqueous citric acid (570Kg) and filtered. The filtrant was washed with water and dried under vacuum at 500C to provide 136Kg of product. 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (s, IH), 8.00 (dd, J=9.0, 9.3 Hz, IH), 7.75 (d, J=12.8 Hz, IH), 6.79 (br s, 2H), 5.95 (dd, J=I.5, 7.6 Hz, IH), 5.21 (m, IH), 4.36 (t, J=7.4 Hz, 2H), 4.02 (q, J=7.0 Hz, 2H), 3.95 (dd, J=3.7, 9.2 Hz, 2H), 2.58 (hept, J=7.0 Hz, IH), 1.26 (t, J=7.0 Hz, 3H), 1.11 (d, J=7.0 Hz, 6H).

EXAMPLE 10
A solution of N-chlorosuccinimide (25.3Kg) in methyl acetate (419Kg) at 170C was treated with sulfuric acid (560 g), transferred to a slurry of EXAMPLE 8 (92.7Kg) in ethyl acetate (244Kg) at 17°C while maintaining the reaction temperature at 17°C,
quenched/washed with 1.5% aqueous sodium bicarbonate (370Kg), washed with
10% aqueous sodium sulfite (200Kg) and concentrated. The concentrate was dissolved in isopropanol, treated with 4% (w/w) aqueous potassium hydroxide (750Kg), stirred at 5O0C until hydrolysis was complete, passed through a polishing filter, treated with 12% aqueous acetic acid (410Kg) and filtered. The filtrant was washed with water and dried at 5O0C to provide 73Kg of product. 1H NMR (CDCl3) δ 14.63 (brs, IH), 8.70 (d, J=0.7Hz, IH), 7.95 (dd, J=9.9, 0.7Hz, IH), 7.83 (d, J=13.6Hz, IH), 6.75 (s, 2H), 5.75 (d, J=5.8Hz, IH), 4.61 (m, 12H), 4.47 (m, IH), 4.18 (m, 2H).

PATENT

https://www.google.com/patents/CN104876911A?cl=en

Image result for delafloxacin

 Currently, 德拉沙 star for the synthesis mainly in the following two ways:

[0004] 1, Chinese patent CN1201459A _2,4,5_ trifluorobenzoyl from 3-chloro-ethyl ester synthesis De Lasha star. Used in this reaction is N, N- dimethylformamide high temperature and potassium carbonate cyclization, prone to impurities, after cyclization is hydrolyzed required, increase the reaction step, a low yield. Reaction scheme is as follows:

[0005]

Figure CN104876911AD00031

[0006] 2, published in the Journal of Organic Chemistry (Org Process Res & Dev2006,4, 751) provides a new synthesis method 德拉沙 star from 2,4,5_ trifluoroacetic acid as the starting material, synthetic Germany Lassa star. This reaction because of the need in eight selective chlorination, so 7-hydroxy need protection, reaction step increase. And when eight were chlorinated 7 substituent easily broken, harsh reaction conditions, the reaction yield is low, is not suitable for mass production. Reaction scheme is as follows:

[0007]

Figure CN104876911AD00041

Example: 8_-Chloro-6-fluoro-1- (6-amino-3,5-difluoro-2-yl) -7- (3-hydroxy-1-azetidinyl) – 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Dela Sha star) Synthesis of

[0025] 3-chloro-2,4,5-trifluoro-benzoyl acetate (78,0.025111〇1) in 501,111 flask, triethylorthoformate (5. 9g, 0. 04mol) and vinegar anhydride, heated at reflux for 3h ~ 5h, evaporated under reduced pressure excess triethyl orthoformate and acetic anhydride, was added N- methylpyrrolidone was diluted, and then 2,6-diamino-3,5-difluoro-pyridine was suspended ( 3. 8g, 0. 026mol) and N- methylpyrrolidone were suspended, was added dropwise to the above solution, after completion of the reaction was added anhydrous lithium chloride (2. 6g) and DBU (4.6g, 0.03mol) (1 1,8-diazabicyclo [5.4.0] undec-ene _7_) was heated with stirring, HPLC monitored the reaction was complete. Then 3-hydroxy-azetidine hydrochloride (3. 52g) was added to the above solution was added dropwise DBU, the reaction was continued to completion. In the aqueous solution of isopropanol and potassium hydroxide, heating the hydrolysis, the hydrolysis is completed after adjusting PH = 3 solid precipitated. Filtering, washing, to give a yellow solid (7. 82g), yield 71%.

[0026] MP: 238-241 ° C

[0027] Tuen bandit 1 (square)?! (: 13) 14.32 0 ^ 8,1 1), 8.51 ((1, J = 0.7Hz, lH), 7.96 (dd, J = 9 · 9,0 · 7Ηζ , 1H), 7 · 64 (d, J = 13. 6Hz, 1H), 6 · 92 (s, 2H), 5 · 86 (d, J = 5. 8Hz, 1H), 4 · 89 (m, 12H ), 4 · 32 (m, 1H), 4 · 18 (m, 2H).

References

  1. Jump up to:a b c d e f g h i j “Delafloxacin tablets US label” (PDF). FDA. June 2017. Retrieved July 9,2017.  This article incorporates text from this source, which is in the public domain. For label updates, see FDA index page for NDA 208610 for tablets, and see FDA index page for NDA 208611 for injectable form.
  2. Jump up to:a b “Cempra Press Releases”.
  3. Jump up to:a b Candel, FJ; Peñuelas, M (2017). “Delafloxacin: design, development and potential place in therapy”Drug design, development and therapy11: 881–891. doi:10.2147/DDDT.S106071PMC 5367733Freely accessiblePMID 28356714.
  4. Jump up^ “Delafloxacin”. AdisInsight. Retrieved 10 July 2017.
  5. Jump up^ Cartwright, Heather (12 July 2011). “Rib-X Pharmaceuticals Signs Global Antibiotic Research Collaboration with Sanofi”PharmaDeals Review (7). doi:10.3833/pdr.v2011i7.1494. Archived from the original on 25 April 2012.
  6. Jump up^ Stearns, John (August 1, 2016). “Melinta Therapeutics takes aim at deadly drug-resistant bacteria”Hartford Business Journal.
  7. Jump up to:a b Markham, Anthony (July 2017). “Delafloxacin: First Global Approval” Check |url=value (help)Drugs77: 1481–1486 – via Springer.
  8. Jump up^ Osborne, Randy (20 June 2017). “Melinta’s I.V., oral delafloxacin wins FDA nod in skin infections”BioWorld.
  9. Jump up to:a b “NDA Approval Letter: NDA 208610 and NDA 208611” (PDF). FDA. June 19, 2017.
  10. Cited Patent Filing date Publication date Applicant Title
    CN1201459A * Sep 20, 1996 Dec 9, 1998 涌永制药株式会社 Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising same as active ingredient
    JP2005097116A * Title not available
    WO2006015194A2 * Jul 29, 2005 Feb 9, 2006 Abbott Laboratories Preparation of pyridonecarboxylic acid antibacterials
  11. FDA Orange Book Patents

    FDA Orange Book Patents: 1 of 8 (FDA Orange Book Patent ID)
    Patent 8871938
    Expiration Sep 23, 2029
    Applicant MELINTA
    Drug Application N208610 (Prescription Drug: BAXDELA. Ingredients: DELAFLOXACIN MEGLUMINE)
    FDA Orange Book Patents: 2 of 8 (FDA Orange Book Patent ID)
    Patent 9539250
    Expiration Oct 7, 2025
    Applicant MELINTA
    Drug Application N208611 (Prescription Drug: BAXDELA. Ingredients: DELAFLOXACIN MEGLUMINE)
    FDA Orange Book Patents: 3 of 8 (FDA Orange Book Patent ID)
    Patent 7728143
    Expiration Nov 20, 2027
    Applicant MELINTA
    Drug Application N208611 (Prescription Drug: BAXDELA. Ingredients: DELAFLOXACIN MEGLUMINE)

    View All 8 FDA Orange Book Patents

Patent ID

Patent Title

Submitted Date

Granted Date

US9199026 Modular Extracorporeal Systems and Methods for Treating Blood-Borne Diseases
2012-01-09
2012-07-26
US2011281839 COMBINATION THERAPY FOR THE TREATMENT OF BACTERIAL INFECTIONS
2011-05-06
2011-11-17
US2012082627 OTIC FOAM FORMULATIONS
2010-06-08
2012-04-05
US2017073329 SALT AND CRYSTALLINE FORMS THEREOF OF A DRUG
2016-11-23
US2016046603 Crystalline Forms of D-Glucitol, 1-Deoxy-1-(Methylamino)-, 1-(6-Amino-3, 5-Difluoropyridine-2-Yl)-8-Chloro-6-Fluoro-1, 4-Dihydro-7-(3-Hydroxyazetidin-1-Yl)-4-Oxo-3-Quinolinecarboxylate
2014-03-07
2016-02-18
Patent ID

Patent Title

Submitted Date

Granted Date

US2012309740 Pharmaceutical Compositions Having Improved Dissolution Profiles For Poorly Soluble Drugs
2012-08-14
2012-12-06
US2010324018 PHARMACEUTICAL COMPOSITIONS HAVING IMPROVED DISSOLUTION PROFILES FOR POORLY SOLUBLE DRUGS
2010-06-02
2010-12-23
US8299254 PREPARATION OF PYRIDONECARBOXYLIC ACID ANTIBACTERIALS
2010-02-18
US8648196 Preparation of pyridonecarboxylic acid antibacterials
2012-10-30
2014-02-11
US2012058936 COMPOSITIONS AND METHODS FOR ELIMINATION OF GRAM NEGATIVE BACTERIA
2010-03-12
2012-03-08
Patent ID

Patent Title

Submitted Date

Granted Date

US2007238720 Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
2007-10-11
US2007148235 PHARMACEUTICAL COMPOSITION
2007-06-28
US2005152975 Pharmaceutical composition
2005-07-14
US2006228411 Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs
2006-04-11
2006-10-12
US2004022848 Medicinal composition
2004-02-05
Patent ID

Patent Title

Submitted Date

Granted Date

EP0911327 NOVEL PYRIDONECARBOXYLIC ACID DERIVATIVES OR THEIR SALTS AND ANTIBACTERIAL AGENT COMPRISING THE SAME AS THE ACTIVE INGREDIENT
1999-04-28
2001-12-05
US2012065186 ANTIMICROBIAL COMPOSITIONS
2011-05-11
2012-03-15
US2012156259 Biodegradable Polyethylene Glycol Based Water-Insoluble Hydrogels
2010-07-30
2012-06-21
US2007249577 Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
2007-10-25
US2007238719 Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
2007-10-11
Patent ID

Patent Title

Submitted Date

Granted Date

US6156903 Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
2000-12-05
US6133284 Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
2000-10-17
EP0992501 Pyridonecarboxylic acid derivatives as antibacterial agents
2000-04-12
2002-08-28
US5998436 Pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient
1999-12-07
EP0952151 Intermediates for use in preparing novel pyridonecarboxylic acid derivatives or their salts
1999-10-27
2003-05-28
Patent ID

Patent Title

Submitted Date

Granted Date

US8535655 BIODEGRADABLE POLYMER – BIOACTIVE MOIETY CONJUGATES
2011-10-06
US2012202756 USE OF PRODRUGS TO AVOID GI MEDIATED ADVERSE EVENTS
2011-10-05
2012-08-09
US8563598 BETA-LACTONES AS ANTIBACTERIAL AGENTS
2011-08-11
US2010040548 HIGH PENETRATION PRODRUG COMPOSITIONS OF ANTIMICROBIALS AND ANTIMICROBIAL-RELATED COMPOUNDS
2010-02-18
US6586420 Quinolinecarboxylic acid derivative or its salt
2003-07-01
Patent ID

Patent Title

Submitted Date

Granted Date

US9439888 Tetrazolones as a carboxylic acid bioisosteres
2016-01-25
2016-09-13
US8809286 CONJUGATED ANTIMICROBIAL AGENTS
2012-01-26
US2012157371 HIGH PENETRATION PRODRUG COMPOSITIONS OF ANTIMICROBIALS AND ANTIMICROBIAL-RELATED COMPOUNDS
2011-12-12
2012-06-21
US8962786 CHAIN EXTENDERS
2011-11-24
US9409896 Sustained release pharmaceutical compositions comprising an antibacterial agent
2011-11-01
2016-08-09
Patent ID

Patent Title

Submitted Date

Granted Date

US8252813 Salt and crystalline forms thereof of a drug
2010-02-05
2012-08-28
US9539250 Salt and Crystalline Forms Thereof of a Drug
2015-02-03
2015-07-16
US8273892 Salt and crystalline forms thereof of a drug
2010-04-20
2012-09-25
US8895033 SUSTAINED RELEASE FORMULATIONS USING NON-AQUEOUS CARRIERS
2011-09-01
US9701647 Tetrazolones as a carboxylic acid bioisosteres
2016-08-10
2017-07-11
Patent ID

Patent Title

Submitted Date

Granted Date

US8871938 Process for making quinolone compounds
2013-07-09
2014-10-28
US8497378 Process for making quinolone compounds
2009-09-23
2013-07-30
US7728143 Salt and crystalline forms thereof of a drug
2005-10-07
2010-06-01
US8969569 Salt and crystalline forms thereof of a drug
2014-02-07
2015-03-03
US8648093 Salt and crystalline forms thereof of a drug
2012-08-27
2014-02-11
Delafloxacin
Delafloxacin.svg
Clinical data
Trade names Baxdela
Synonyms ABT-492; RX-3341; WQ-3034
Routes of
administration
Oralintravenous injection
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C18H12ClF3N4O4
Molar mass 440.76 g/mol
3D model (JSmol)

/////////////Delafloxacin, ABT-492, RX-3341, WQ-3034, FDA 2017, A-319492

C1C(CN1C2=C(C=C3C(=C2Cl)N(C=C(C3=O)C(=O)O)C4=NC(=C(C=C4F)F)N)F)O

Naldemedine, ナルデメジントシル酸塩


str1

Naldemedine.svg

ChemSpider 2D Image | Naldemedine | C32H34N4O6

NALDEMEDINE.png

Naldemedine

  • Molecular FormulaC32H34N4O6
  • Average mass570.636 Da
CAS 916072-89-4 [RN]
CAS Number

FDA APPROVED 2017

Morphinan-7-carboxamide, 17-(cyclopropylmethyl)-6,7-didehydro-4,5-epoxy-3,6,14-trihydroxy-N-[1-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-, (5α)-
(5α)-17-(Cyclopropylmethyl)-3,6,14-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-propanyl]-6,7-didehydro-4,5-epoxymorphinan-7-carboxamide
(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,7,9-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide
S-297,995
S-297995
UNII:03KSI6WLXH
Naldemedine is an opioid receptor antagonist [FDA Label]. It is a modified form of [DB00704] to which a side chain has been added to increase molecular weight and polar surface area resulting in restricted transport across the blood brain barrier. Naldemedine was approved in 2017 in both the US and Japan for the treatment of Opioid-induced Constipation.
Naldemedine, also known as S 297995, is a peripherally-selective μ-opioid receptor antagonist under development by Shionogi for the treatment of opioid-induced adverse effects including constipation, nausea, and vomiting. Clinical studies have thus far found it to possess statistically significant effectiveness for these indications and to be generally well-tolerated with predominantly mild to moderate gastrointestinal side effects. No effects indicative of central opioid withdrawal or impact on the analgesic or mydriatic effects of co-administered opioids have been observed.
Image result for naldemedine

Naldemedine (INNUSANS-297,995Symproic) is a peripherallyselective μ-opioid receptor antagonist developed by Shionogi which is approved for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.[1] Clinical studies have thus far found it to possess statistically significant effectiveness for these indications and to be generally well-tolerated with predominantly mild to moderate gastrointestinal side effects.[2][3] No effects indicative of central opioid withdrawal or impact on the analgesic or mydriatic effects of co-administered opioids have been observed.[2]

Image result for naldemedineImage result for naldemedine

Image result for naldemedine

ナルデメジントシル酸塩

Commercialization

Naldemedine is manufactured by Shionogi Inc., a U.S. based subsidiary of Shionogi & Co., Ltd. Shionogi & Co., Ltd. (SGIOF) is a Japanese pharmaceutical company founded in 1878 based in Osaka, Japan. Shionogi Inc. is fully funded by its parent company, Shionogi & Co., Ltd. The parent company specializes in pharmaceuticals, diagnostic reagents and medical devices in Japan and internationally. Naldemedine is their only gastroenterology product in the United States.

In the US market, Shionogi Inc. has partnered with Purdue Pharma in a joint venture for US commercialization of Symproic.[4] Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders.[5]

Purdue Pharma appealed to remove the Class II scheduling of Symproic as accordant to the Controlled Substances Act. The appeal was posted to the Federal Register on July 12, 2017.[6] The Drug Enforcement Administration officially removed the Class II scheduling in September 2017.[7]

SYN

US 8084460

WO 2012063933

Manufacturer Finances

Since 2015, Shionogi & Co., Ltd. has produced increasing net income. At the end of fiscal year 2016, Shionogi & Co., Ltd. had a net income of $66,687,000. At the end of fiscal year 2017, they increased their net income to $83,879,000.[8] How much of this is attributed to sales of Symproic is unknown. Shionogi & Co., Ltd. ends their fiscal year on March 31 of each year. Considering the drug was only FDA approved on March 23 of 2017, the true valuation of the drug is yet to be seen. Purdue Pharma has begun advertising for the medication to be available by October 2017.[9]

Intellectual Property

There are currently three patents issued for naldemedine tosylate by the United States Patent and Trademark Office. All patents are owned by Shionogi Inc. and will expire from 2026-2031.[10] Naldemedine tosylate has 46 other patents in 18 different countries.[11]

Preclinical Trials

12 Phase I clinical trials were reported for the use of naldemedine in healthy volunteers.[12] In a single ascending dose study, subjects received one dose of naldemedine (0.1–100 mg) or one dose of a placebo. In a multiple ascending dose study, subjects received once daily naldemedine (3–30 mg) or placebo for 10 days. Maximum plasma concentrations were reached within 0.5-0.75 hours. There were no reported major safety concerns, even at doses 150-500 times the available dose of 0.2 mg. In both studies, gastrointestinal events occurred more frequently with naldemedine, but researchers concluded these to be treatment related.[13]

Clinical Trials

The approval of naldemedine came from the results of the COMPOSE program, a phase three clinical studies program conducted in adults 18–80 years of age with chronic non-cancer pain opioid induced constipation. COMPOSE-I and COMPOSE-II were 12-week double blind randomized controlled trials comparing the use of naldemedine to placebo in the patient population. COMPOSE-I began in August 2013 until January 2015 in 68 outpatient clinic in seven countries. COMPOSE-II began in November 2013 until June 2015 taking place in 69 outpatient clinics in six countries. In both trials, patients were randomly assigned to receive either naldemedine 0.2 mg or placebo once daily for 12 weeks. A responder had at least three spontaneous bowel movements per week with an increase of one spontaneous bowel movement for nine of the 12 weeks, including three of the final four weeks of the study. In COMPOSE-I and COMPOSE-II, the proportion of responders were significantly higher in the naldemedine group than the placebo group. Adverse events were similar in both trials, however, patients in the naldemedine group had slightly higher rates of adverse events.[14]

COMPOSE-III was a 52 week clinical trial examining the long term safety with naldemedine in patients with non cancer chronic pain. Results from this trial showed statistical significance for increased weekly bowel movements and no opioid withdrawal symptoms. The study also concluded adverse effects were more similar between two groups.[12]

All trials were conducted following Good Clinical Practice guidelines.[12]

Patent ID

Patent Title

Submitted Date

Granted Date

US9108975 CRYSTAL OF 6, 7-UNSATURATED-7-CARBAMOYL MORPHINAN DERIVATIVE AND METHOD FOR PRODUCING THE SAME
2011-11-11
2013-09-05
US9315512 Crystal of 6, 7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
2015-08-04
2016-04-19
US8536192 6, 7-unsaturated-7-carbamoyl substituted morphinan derivative
2011-11-30
2013-09-17
US8084460 6, 7-unsaturated-7-carbamoyl substituted morphinan derivative
2009-08-13
2011-12-27
US2015216804 PREPARATION CONTAINING 6, 7-UNSATURATED-7-CARBAMOYL MORPHINAN DERIVATIVES
2013-05-13
2015-08-06

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID)
Patent 9108975
Expiration Nov 11, 2031
Applicant SHIONOGI INC
Drug Application N208854 (Prescription Drug: SYMPROIC. Ingredients: NALDEMEDINE TOSYLATE)
FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID)
Patent RE46375
Expiration Oct 5, 2026
Applicant SHIONOGI INC
Drug Application N208854 (Prescription Drug: SYMPROIC. Ingredients: NALDEMEDINE TOSYLATE)
FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID)
Patent RE46365
Expiration Jan 11, 2028
Applicant SHIONOGI INC
Drug Application N208854 (Prescription Drug: SYMPROIC. Ingredients: NALDEMEDINE TOSYLATE)

References

  1. Jump up^ “FDA Approves Symproic (naldemedine) for the Treatment of Opioid-Induced Constipation – Chemdiv”Chemdiv. 2017-03-27. Retrieved 2017-04-05.
  2. Jump up to:a b De Sarro, Giovambattista; Kelly S. Sprawls; Egilius L.H. Spierings; Dustin Tran (2012-03-07). “Drugs in Development for Opioid-Induced Constipation” (PDF). In Catto-Smith G., Anthony. Constipation – Causes, Diagnosis and Treatment. p. 7. doi:10.5772/30377ISBN 978-953-51-0237-3. Retrieved 12 May 2012.
  3. Jump up^ Shionogi (2009-03-27). “Research and Development at Shionogi (as of March 2009)”(PDF). Retrieved 2012-05-12.
  4. Jump up^ “SHIONOGI AND PURDUE PHARMA ESTABLISH ALLIANCE FOR JOINT U.S. COMMERCIALIZATION OF NALDEMEDINE”Purdue Pharma. Purdue Pharma. Retrieved 31 October 2017.
  5. Jump up^ “FDA Approves Symproic® (naldemedine) Once-Daily Tablets C-II for the Treatment of Opioid-Induced Constipation in Adults with Chronic Non-Cancer Pain”Purdue Pharma. Purdue Pharma. Retrieved 31 October 2017.
  6. Jump up^ “Schedules of controlled substances: removal of naldemedine from control” (PDF). Federal Register. Federal Register. Retrieved 1 November 2017.
  7. Jump up^ “Symproic Now Available for Opioid-Induced Constipation”MPR. 2017-10-12. Retrieved 2017-11-08.
  8. Jump up^ “Shionogi & Co., Ltd”Yahoo Finance. Yahoo Finance. Retrieved 31 October 2017.
  9. Jump up^ “Opioid Induced Constipation”Opioid Induced Constipation. Purdue Pharma. Retrieved 31 October 2017.
  10. Jump up^ “Generic Symproic Availability”Drugs.com. Drugs.com. Retrieved 31 October 2017.
  11. Jump up^ “Naldemedine tosylate – generic drug details”Drug Patent Watch. Drug Patent Watch. Retrieved 31 October 2017.
  12. Jump up to:a b c “Center for Drug Evaluaiton and Research Medication Review” (PDF). FDA. FDA. Retrieved 31 October 2017.
  13. Jump up^ Fukumura, K; Yokota, T; Baba, Y; Arjona Ferreira, JC (27 September 2017). “Phase 1, Randomized, Double-Blind, Placebo-Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers”. Clinical pharmacology in drug developmentdoi:10.1002/cpdd.387PMID 28960888.
  14. Jump up^ Hale, M; Wild, J; Reddy, J; Yamada, T; Arjona Ferreira, JC (August 2017). “Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials”. The Lancet. Gastroenterology & Hepatology2 (8): 555–564. doi:10.1016/S2468-1253(17)30105-XPMID 28576452.
Naldemedine
Naldemedine.svg
Clinical data
Routes of
administration
Oral
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C32H34N4O6
Molar mass 570.63556 g/mol
3D model (JSmol)

//////////S-297995, Naldemedine, FDA 2017, ナルデメジントシル酸塩 ,  Symproic

CC(C)(C1=NC(=NO1)C2=CC=CC=C2)NC(=O)C3=C(C4C56CCN(C(C5(C3)O)CC7=C6C(=C(C=C7)O)O4)CC8CC8)O

FDA approves drug Giapreza (angiotensin II) to treat dangerously low blood pressure


FDA approves drug to treat dangerously low blood pressure

The U.S. Food and Drug Administration today approved Giapreza (angiotensin II) injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock. Continue reading.

 

December 21, 2017

Release

The U.S. Food and Drug Administration today approved Giapreza (angiotensin II) injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock.

“Shock, the inability to maintain blood flow to vital tissues, can result in organ failure and death,” said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “There is a need for treatment options for critically ill hypotensive patients who do not adequately respond to available therapies.”

Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Hypotension is abnormally low blood pressure. Shock is a critical condition in which blood pressure drops so low that the brain, kidneys and other vital organs can’t receive enough blood flow to function properly.

In a clinical trial of 321 patients with shock and a critically low blood pressure, significantly more patients responded to treatment with Giapreza compared to those treated with placebo. Giapreza effectively increased blood pressure when added to conventional treatments used to raise blood pressure.

Giapreza can cause dangerous blood clots with serious consequences (clots in arteries and veins, including deep venous thrombosis); prophylactic treatment for blood clots should be used.

This application received a Priority Review, under which the FDA’s goal is to take action on an application within six months when the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted the approval of Giapreza to La Jolla Pharmaceutical Company.

///////////Giapreza ,  La Jolla Pharmaceutical Company, fda 2017,  low blood pressure, angiotensin II

FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome


FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA. Continue reading.

December 12, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA.

According to the National Institutes of Health, EGPA (formerly known as Churg-Strauss syndrome) is a condition characterized by asthma, high levels of eosinophils (a type of white blood cell that helps fight infection), and inflammation of small- to medium-sized blood vessels. The inflamed vessels can affect various organ systems including the lungs, gastrointestinal tract, skin, heart and nervous system. It is estimated that approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year, with an overall prevalence of 10.7 to 14 per 1,000,000 adults.

“Prior to today’s action, patients with this challenging, rare disease did not have an FDA-approved treatment option,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded indication of Nucala meets a critical, unmet need for EGPA patients. It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”

The FDA granted this application Priority Review and Orphan Drug designations. Orphan Drug designation provides incentives to assist and encourage the development of drugs for rare diseases.

Nucala was previously approved in 2015 to treat patients age 12 years and older with a specific subgroup of asthma (severe asthma with an eosinophilic phenotype) despite receiving their current asthma medicines. Nucala is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells.

Nucala is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.

The safety and efficacy of Nucala was based on data from a 52-week treatment clinical trial that compared Nucala to placebo. Patients received 300 milligrams (mg) of Nucala or placebo administered subcutaneously once every four weeks while continuing their stable daily oral corticosteroids (OCS) therapy. Starting at week four, OCS was tapered during the treatment period. The primary efficacy assessment in the trial measured Nucala’s treatment impact on disease remission (i.e., becoming symptom free) while on an OCS dose less than or equal to 4 mg of prednisone. Patients receiving 300 mg of Nucala achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of Nucala achieved remission at both week 36 and week 48 compared with placebo. In addition, significantly more patients who received 300 mg of Nucala achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with patients who received the placebo.

The most common adverse reactions associated with Nucala in clinical trials included headache, injection site reaction, back pain, and fatigue.

Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or one of its ingredients. It should not be used to treat acute bronchospasm or status asthmaticus. Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash, have occurred. Patients should discontinue treatment in the event of a hypersensitivity reaction. Patients should not discontinue systemic or inhaled corticosteroids abruptly upon beginning treatment with Nucala. Instead, patients should decrease corticosteroids gradually, if appropriate.

Health care providers should treat patients with pre-existing helminth infections before treating with Nucala because it is unknown if Nucala would affect patients’ responses against parasitic infections. In addition, herpes zoster infections have occurred in patients receiving Nucala. Health care providers should consider vaccination if medically appropriate.

The FDA granted approval of Nucala to GlaxoSmithKline.

//////////////Nucala, mepolizumab, fda 2017, gsk,  Eosinophilic Granulomatosis, Polyangiitis, Churg-Strauss Syndrome, Priority Review, Orphan Drug

FDA approves Admelog, the first short-acting “follow-on” insulin product to treat diabetes


FDA approves Admelog, the first short-acting “follow-on” insulin product to treat diabetes

 

The U.S. Food and Drug Administration today approved Admelog (insulin lispro injection), a short-acting insulin indicated to improve control in blood sugar levels in adults and pediatric patients aged 3 years and older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. Admelog is the first short-acting insulin approved as a “follow-on” product (submitted through the agency’s 505(b)(2) pathway). Continue reading.

 

December 11, 2017

Release

The U.S. Food and Drug Administration today approved Admelog (insulin lispro injection), a short-acting insulin indicated to improve control in blood sugar levels in adults and pediatric patients aged 3 years and older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. Admelog is the first short-acting insulin approved as a “follow-on” product (submitted through the agency’s 505(b)(2) pathway).

According to the Centers for Disease Control and Prevention, more than 30 million people in the U.S. have diabetes, a chronic disease that affects how the body turns food into energy and the body’s production of natural insulin. Over time, diabetes increases the risk of serious health complications, including heart disease, blindness, and nerve and kidney damage. Improvement in blood sugar control through treatment with insulin, a common treatment, can reduce the risk of some of these long-term complications.

“One of my key policy efforts is increasing competition in the market for prescription drugs and helping facilitate the entry of lower-cost alternatives. This is particularly important for drugs like insulin that are taken by millions of Americans every day for a patient’s lifetime to manage a chronic disease,” said FDA Commissioner Scott Gottlieb, M.D. “In the coming months, we’ll be taking additional policy steps to help to make sure patients continue to benefit from improved access to lower cost, safe and effective alternatives to brand name drugs approved through the agency’s abbreviated pathways.”

Admelog was approved through an abbreviated approval pathway under the Federal Food, Drug, and Cosmetic Act, called the 505(b)(2) pathway. A new drug application submitted through this pathway may rely on the FDA’s finding that a previously approved drug is safe and effective or on published literature to support the safety and/or effectiveness of the proposed product, if such reliance is scientifically justified. The use of abbreviated pathways can reduce drug development costs so products can be offered at a lower price to patients. In the case of Admelog, the manufacturer submitted a 505(b)(2) application that relied, in part, on the FDA’s finding of safety and effectiveness for Humalog (insulin lispro injection) to support approval. The applicant demonstrated that reliance on the FDA’s finding of safety and effectiveness for Humalog was scientifically justified and provided Admelog-specific data to establish the drug’s safety and efficacy for its approved uses. The Admelog-specific data included two phase 3 clinical trials which enrolled approximately 500 patients in each.

Admelog is a short-acting insulin product, which can be used to help patients with diabetes control their blood sugar. Short-acting insulin products are generally, but not always, administered just before meals to help control blood sugar levels after eating. These types of insulin products can also be used in insulin pumps to meet both background insulin needs as well as mealtime insulin needs. This is in contrast to long-acting insulin products, like insulin glargine, insulin degludec and insulin detemir, which are generally used to provide a background level of insulin to control blood sugars between meals, and are administered once or twice a day. While both types of insulin products can play important roles in the treatment of types 1 and 2 diabetes mellitus, patients with type 1 diabetes require both types of insulin while patients with type 2 diabetes may never need a short-acting insulin product.

“With today’s approval, we are providing an important short-acting insulin option for patients that meets our standards for safety and effectiveness,” said Mary T. Thanh Hai, M.D., deputy director of the Office of New Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research.

Admelog can be administered by injection under the skin (subcutaneous), subcutaneous infusion (i.e., via insulin pump), or intravenous infusion. Dosing of Admelog should be individualized based on the route of administration and the patient’s metabolic needs, blood glucose monitoring results and glycemic control goal.

The most common adverse reactions associated with Admelog in clinical trials was hypoglycemia, itching, and rash. Other adverse reactions that can occur with Admelog include allergic reactions, injection site reactions, and thickening or thinning of the fatty tissue at the injection site (lipodystrophy).

Admelog should not be used during episodes of hypoglycemia (low blood sugar) or in patients with hypersensitivity to insulin lispro or one of its ingredients. Admelog SoloStar prefilled pens or syringes must never be shared between patients, even if the needle is changed.

Patients or caregivers should monitor blood glucose in all patients treated with insulin products. Insulin regimens should be modified cautiously and only under medical supervision. Admelog may cause low blood sugar (hypoglycemia), which can be life-threatening. Patients should be monitored more closely with changes to insulin dosage, co-administration of other glucose-lowering medications, meal pattern, physical activity and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness.

Accidental mix-ups between insulin products can occur. Patients should check insulin labels before injecting the insulin product.

Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur.

Health care providers should monitor potassium levels in patients at risk of hyperkalemia, a serious and potentially life-threatening condition in which the amount of potassium in the blood is too high.

Admelog received tentative approval from the FDA on Sept. 1, 2017 and is now being granted final approval.

The approval of Admelog was granted to Sanofi-Aventis U.S.

///////////////FDA2017,  Admelog, insulin,  diabetes, insulin lispro, Sanofi-Aventis

FDA approves first biosimilar Herceptin (trastuzumab) for the treatment of certain breast and stomach cancers


FDA approves first biosimilar for the treatment of certain breast and stomach cancers

Ogivri, a biosimilar to the cancer drug Herceptin, is approved for HER2+ breast cancer and metastatic stomach cancers

The U.S. Food and Drug Administration today approved Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer. Continue reading.

December 1, 2017

Release

The U.S. Food and Drug Administration today approved Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer.

As with any treatment, health care professionals should review the prescribing information in the labeling for detailed information about the approved uses.

“The FDA continues to grow the number of biosimilar approvals, helping to promote competition that can lower health care costs. This is especially important when it comes to diseases like cancer, that have a high cost burden for patients,” said FDA Commissioner Scott Gottlieb, M.D. “We’re committed to taking new policy steps to advance our biosimilar pathway and promote more competition for biological drugs.”

Biological products are generally derived from a living organism and can come from many sources, such as humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on data showing that it is highly similar to a biological product already approved by the FDA (reference product) and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

The FDA’s approval of Ogivri is based on review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Ogivri is biosimilar to Herceptin. Ogivri has been approved as a biosimilar, not as an interchangeable product.

Common expected side effects of Ogivri for the treatment of HER2+ breast cancer include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, difficulty sleeping (insomnia), cough and rash. Common expected side effects of Ogivri for the treatment of HER2+ metastatic stomach cancer include low levels of certain white blood cells (neutropenia), diarrhea, fatigue, low levels of red blood cells (anemia), inflammation of the mouth (stomatitis), weight loss, upper respiratory tract infections, fever, low levels of blood platelets (thrombocytopenia), swelling of the mucous membranes (mucosal inflammation), common cold (nasopharyngitis) and unusual taste sensation (dysgeusia). Serious expected side effects of Ogivri include worsening of chemotherapy-induced neutropenia.

Like Herceptin, the labeling for Ogivri contains a Boxed Warning to alert health care professionals and patients about increased risks of heart disease (cardiomyopathy), infusions reactions, lung damage (pulmonary toxicity) and harm to a developing fetus (embryo-fetal toxicity). Patients should stop taking Ogivri if cardiomyopathy, life-threatening allergic reactions (anaphylaxis), swelling below the skin (angioedema), inflammation of the lungs (interstitial pneumonitis) or fluid in the lungs (acute respiratory distress syndrome) occur. Patients should be advised of the potential risk to a developing fetus and to use effective contraception.

The FDA granted approval of Ogivri to Mylan GmbH. Herceptin was approved in September 1998 and is manufactured by Genentech, Inc.

/////////////Ogivri, biosimilar , cancer, Herceptin, Trastuzumab, FDA 2017

%d bloggers like this: