New Drug Approvals

Home » Posts tagged 'FDA 2017'

Tag Archives: FDA 2017

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

Blog Stats

  • 2,531,472 hits

Flag and hits

Flag Counter

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

Join 2,366 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 2,366 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

Macimorelin acetate


Macimorelin.svg

ChemSpider 2D Image | Macimorelin | C26H30N6O3

Macimorelin.png

Macimorelin

  • Molecular FormulaC26H30N6O3
  • Average mass474.555 Da

CAS  381231-18-1

Chemical Formula: C26H30N6O3

Exact Mass: 474.23794

Molecular Weight: 474.55480

Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11

2-Methylalanyl-N-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]-D-tryptophanamide
381231-18-1 [RN]
8680B21W73
9073
D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-
Thumb

CAS 945212-59-9 (Macimorelin acetate)

(2R)-2-(2-amino-2-methylpropanamido)-3-(1H-indol-3-yl)-N-[(1R)-2-(1H-indol-3-yl)-1-formamidoethyl]propanamide; acetic acid

AEZS-130
ARD-07
D-87875
EP-01572
EP-1572
JMV-1843

USAN (ab-26)
MACIMORELIN ACETATE

AQZ1003RMG
ARD 07
D-87575
D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1) [ACD/Index Name]
EP 1572

THERAPEUTIC CLAIM
Diagnostic agent for adult growth hormone deficiency (AGHD)
CHEMICAL NAMES
1. D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1)
2. N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]- D-tryptophanamide acetate

MOLECULAR FORMULA
C26H30N6O3.C2H4O2
MOLECULAR WEIGHT
534.6

SPONSOR
Aeterna Zentaris GmbH
CODE DESIGNATIONS
D-87575, EP 1572, ARD 07
CAS REGISTRY NUMBER
945212-59-9

Macimorelin (also known as AEZS-130, EP-1572) is a novel synthetic small molecule, acting as a ghrelin agonist, that is orally active and stimulates the secretion of growth hormone (GH). Based on results of Phase 1 studies, AEZS-130 has potential applications for the treatment of cachexia, a condition frequently associated with severe chronic diseases such as cancer, chronic obstructive pulmonary disease and AIDS. In addition to the therapeutic application, a Phase 3 trial with AEZS-130 as a diagnostic test for growth hormone deficiencies in adults has been completed.

http://www.ama-assn.org/resources/doc/usan/macimorelin-acetate.pdf

QUEBEC, Nov. 5, 2013 /PRNewswire/ – Aeterna Zentaris Inc. (the “Company”) today announced that it has submitted a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for its ghrelin agonist, macimorelin acetate (AEZS-130). Phase 3 data have demonstrated that the compound has the potential to become the first orally-approved product that induces growth hormone release to evaluate adult growth hormone deficiency (“AGHD”), with accuracy comparable to available intravenous and intramuscular testing procedures.  read at

http://www.drugs.com/nda/macimorelin_acetate_131105.html

http://www.ama-assn.org/resources/doc/usan/macimorelin-acetate.pdf

macimorelin (JMV 1843), a ghrelin-mimetic growth hormone secretagogue in Phase III for adult growth hormone deficiency (AGHD)

Macimorelin, a growth hormone modulator, is currently awaiting registration in the U.S. by AEterna Zentaris as an oral diagnostic test of adult growth hormone deficit disorder. The company is also developing the compound in phase II clinical trials for the treatment of cancer related cachexia. The compound was being codeveloped by AEterna Zentaris and Ardana Bioscience; however, the trials underway at Ardana were suspended in 2008 based on a company strategic decision. AEterna Zentaris owns the worldwide rights of the compound. In 2007, orphan drug designation was assigned by the FDA for the treatment of growth hormone deficit in adults.

Macimorelin (INN), or Macrilen (trade name) is a drug being developed by Æterna Zentaris for use in the diagnosis of adult growth hormone deficiency. Macimorelin acetate, the salt formulation, is a synthetic growth hormone secretagogue receptor agonist.[1]Macimorelin acetate is described chemically as D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-acetate.

As of January 2014, it was in Phase III clinical trials.[2] The phase III trial for growth hormone deficiency is expected to be complete in December 2016.[3]

As of December 2017, it became FDA-approved as a method to diagnose growth hormone deficiency.[4] Traditionally, growth hormone deficiency was diagnosed via means of insulin tolerance test (IST) or glucagon stimulation test (GST). These two means are done parenterally, whereas Macrilen boasts an oral formulation for ease of administration for patients and providers.

Macimorelin is a growth hormone secretagogue receptor (ghrelin receptor) agonist causing release of growth hormone from the pituitary gland.[5][6][7]

Macimorelin, a novel and orally active ghrelin mimetic that stimulates GH secretion, is used in the diagnosis of adult GH deficiency (AGHD). More specifically, macimorelin is a peptidomimetic growth hormone secretagogue (GHS) that acts as an agonist of GH secretagogue receptor, or ghrelin receptor (GHS-R1a) to dose-dependently increase GH levels [3]. Growth hormone secretagogues (GHS) represent a new class of pharmacological agents which have the potential to be used in numerous clinical applications. They include treatment for growth retardation in children and cachexia associated with chronic disease such as AIDS and cancer.

Growth hormone (GH) is classically linked with linear growth during childhood. In deficiency of this hormone, AGHD is commonly associated with increased fat mass (particularly in the abdominal region), decreased lean body mass, osteopenia, dyslipidemia, insulin resistance, and/or glucose intolerance overtime. In addition, individuals with may be susceptible to cardiovascular complications from altered structures and function [5]. Risk factors of AGHD include a history of childhood-onset GH deficiency or with hypothalamic/pituitary disease, surgery, or irradiation to these areas, head trauma, or evidence of other pituitary hormone deficiencies [3]. While there are various therapies available such as GH replacement therapy, the absence of panhypopituitarism and low serum IGF-I levels with nonspecific clinical symptoms pose challenges to the detection and diagnosis of AGHD. The diagnosis of AGHD requires biochemical confirmation with at least 1 GH stimulation test [3]. Macimorelin is clinically useful since it displays good stability and oral bioavailability with comparable affinity to ghrelin receptor as its endogenous ligand. In clinical studies involving healthy subjects, macimorelin stimulated GH release in a dose-dependent manner with good tolerability [3].

Macimorelin, developed by Aeterna Zentaris, was approved by the FDA in December 2017 under the market name Macrilen for oral solution.

New active series of growth hormone secretagogues
J Med Chem 2003, 46(7): 1191

WO 2001096300

WO 2007093820

PAPER

J Med Chem 2003, 46(7): 1191

http://pubs.acs.org/doi/full/10.1021/jm020985q

Abstract Image

Figure

Synthetic Pathway for JMV 1843 and Analoguesa

a Reagents and conditions:  (a) IBCF, NMM, DME, 0 °C; (b) NH4OH; (c) H2, Pd/C, EtOH, HCl; (d) BOP, NMM, DMF, Boc-(d)-Trp-OH; (e) Boc2O, DMAP cat., anhydrous CH3CN; (f) BTIB, pyridine, DMF/H2O; (g) 2,4,5-trichlorophenylformate, DIEA, DMF; (h) TFA/anisole/thioanisole (8:1:1), 0 °C; (i) BOP, NMM, DMF, Boc-Aib-OH; (j) TFA/anisole/thioanisole (8:1:1), 0 °C; (k) RP preparative HPLC.

TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO (7). 6 (1 g, 1.7 mmol) was dissolved in a mixture of trifluoroacetic acid (8 mL), anisole (1 mL), and thioanisole (1 mL) for 30 min at 0 °C. The solvents were removed in vacuo, the residue was stirred in ether, and the precipitated TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO was filtered. 7 was purified by preparative HPLC and obtained in 52% yield. 1H NMR (400 MHz, DMSO-d6) + correlation 1H−1H:  δ 1.21 (s, 3H, CH3 (Aib)), 1.43 (s, 3H, CH3(Aib)), 2.97 (m, 2H, (CH2)β), 3.1 (m, 2H, (CH2)β), 4.62 (m, 1H, (CH)αA and (CH)αB), 5.32 (q, 0.4H, (CH)α‘B), 5.71 (q, 0.6H, (CH)α‘A), 7.3 (m, 4H, H5 and H6(2 indoles)), 7.06−7.2 (4d, 2H, H2A and H2B (2 indoles)), 7.3 (m, 2H, H4 or H7 (2 indoles)), 7.6−7.8 (4d, 2H, H4A and H4B or H7A and H7B), 7.97 (s, 3H, NH2 (Aib) and CHO (formyl)), 8.2 (d, 0.4H, NH1B (diamino)), 8.3 (m,1H, NHA and NHB), 8.5 (d, 0.6H, NH1A (diamino)), 8.69 (d, 0.6H, NH2A (diamino)), 8.96 (d, 0.4H, NH2B(diamino)), 10.8 (s, 0.6H, N1H1A (indole)), 10.82 (s, 0.4H, N1H1B (indole)), 10.86 (s, 0.6H, N1H2A (indole)), 10.91 (s, 0,4H, N1H2B (indole)). MS (ES), m/z:  475 [M + H]+, 949 [2M + H]+. HPLC tR:  16.26 min (conditions A).

PATENTS

http://www.google.com/patents/US8192719

The inventors have now found that the oral administration of growth hormone secretagogues (GHSs) EP 1572 and EP 1573 can be used effectively and reliably to diagnose GHD.

EP 1572 (Formula I) or EP 1573 (Formula II) are GHSs (see WO 01/96300, Example 1 and Example 58 which are EP 1572 and EP 1573, respectively) that may be given orally.

Figure US08192719-20120605-C00001

EP 1572 and EP 1573 can also be defined as H-Aib-D-Trp-D-gTrp-CHO and H-Aib-D-Trp-D-gTrp-C(O)NHCH2CH3. Wherein, His hydrogen, Aib is aminoisobutyl, D is the dextro isomer, Trp is tryptophan and gTrp is a group of Formula III:

Figure US08192719-20120605-C00002

PATENT

http://www.google.com/patents/US6861409

H-Aib-D-Trp-D-gTrp-CHO: Figure US06861409-20050301-C00007

Example 1 H-Aib-D-Trp-D-gTrp-CHO

Total synthesis (percentages represent yields obtained in the synthesis as described below):

Figure US06861409-20050301-C00010

Z-D-Tr-NH2

Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml) and placed in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF (4.1 ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were added successively. The mixture was diluted with water (100 ml), and the product Z-D-Trp-NHprecipitated. It was filtered and dried in vacuo to afford 8.58 g of a white solid.

Yield=98%.

C19H19N3O3, 337 g.mol−1.

Rf=0.46 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

1H NMR (250 MHZ, DMSO-d6): δ 2.9 (dd, 1H, Hβ, Jββ′=14.5 Hz; Jβα=9.8 Hz); 3.1 (dd, 1H, Hβ′, Jβ′β=14.5 Hz; Jβ′α=4.3 Hz); 4.2 (sextuplet, 1H, Hα); 4.95 (s, 2H, CH2(Z); 6.9-7.4 (m, 11H); 7.5 (s, 1H, H2); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N1H).

Mass Spectrometry (Electrospray), m/z 338 [M+H]+, 360 [M+Na]+, 675 [2M+H]+, 697 [2M+Na]+.

Boc-D-Trp-D-Trp-NH2

Z-D-Trp-NH(3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal (95 mg, 0.1 eq.) were added to the stirred mixture. The solution was bubbled under hydrogen for 24 hr. When the reaction went to completion, the palladium was filtered on celite. The solvent was removed in vacuo to afford HCl, H-D-Trp-NH2as a colorless oil.

In 10 ml of DMF, HCl, H-D-Trp-NH(8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NHas a white solid.

Yield=85%.

C27H31N5O4, 489 g.mol−1.

Rf=0.48 {Chloroform/Methanol/Acetic Acid (85/10/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.28 (s, 9H, Boc); 2.75-3.36 (m, 4H, 2 (CH2)β; 4.14 (m, 1H, CHα); 4.52 (m, 1H, CHα′); 6.83-7.84 (m, 14H, 2 indoles (10H), NH2, NH (urethane) and NH (amide)); 10.82 (d, 1H, J=2 Hz, N1H); 10.85 (d, 1H, J=2 Hz, N1H).

Mass Spectrometry (Electrospray), m/z 490 [M+H]+, 512 [M+Na]+, 979 [2M+H]+.

Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH2

Boc-D-Trp-D-Trp-NH(3 g; 6.13 mmol; 1 eq.) was dissolved in acetonitrile (25 ml).

To this solution, di-tert-butyl-dicarbonate (3.4 g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) were successively added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.53 g of Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NHas a white solid.

Yield=60%.

C37H47N5O8, 689 g.mol−1.

Rf=0.23 {ethyl acetate/hexane (5/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH2)β); 4.2 (m, 1H, CHα′); 4.6 (m, 1H, CHα); 7.06-8 (m, 14H, 2 indoles (10H), NH (urethane), NH and NH(amides)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]+, 712 [M+Na]+, 1379 [2M+H]+, 1401 [2M+Na]+.

Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-H

Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.) was dissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772 μl; 2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) were added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturated sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Boc-D-NiBoc)Trp-D-g(NiBoc)Trp-H was used immediately for the next reaction of formylation.

Rf=0.14 {ethyl acetate/hexane (7/3)}.

C36H47N5O7, 661 g.mol−1.

1H NMR (200 MHZ, DMSO-d6): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2 Boc); 2.13 (s, 2H, NH(amine)); 3.1-2.8 (m, 4H, 2 (CH2)β); 4.2 (m, 1H, CHα′); 4.85 (m, 1H, CHα); 6.9-8 (m, 12H, 2 indoles (10H), NH (urethane), NH (amide)).

Mass Spectrometry (Electrospray), m/z 662 [M+H]+, 684 [M+Na]+.

Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-CHO

Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-H (4.3 mmol; 1 eq.) was dissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1 eq.) and 2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added. After 30 minutes, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.07 g of Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-CHO as a white solid.

Yield=70%.

C37H47N5O8, 689 g.mol−1.

Rf=0.27 {ethyl acetate/hexane (5/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH2)β); 4.25 (m, 1H, (CH)αA&B); 5.39 (m, 0.4H, (CH)α′B); 5.72 (m, 0.6H, (CH)α′A); 6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO (formyl)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]+, 712 [M+Na]+, 1379 [2M+H]+.

Boc-Aib-D-Trp-D-gTrp-CHO

Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-CHO (1.98 g; 2.9 mmol; 1 eq.) was dissolved in a -mixture of trifluoroacetic acid (16 ml), anisole (2 ml) and thioanisole (2 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-D-Trp-D-gTrp-CHO was filtered.

TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1 eq.), NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successively added in 10 ml of DMF. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a white solid.

Yield=70%.

C31H38N6O5, 574 g.mol−1.

Rf=0.26 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.21 (s, 6H, 2 CH3(Aib)); 1.31 (s, 9H, Boc); 2.98-3.12 (m, 4H, 2 (CH2)β); 4.47 (m, 1H, (CH)αA&B); 5.2 (m, 0.4H, (CH)α′B); 5.7 (m, 0.6H, (CH)α′A); 6.95-8.37 (m, 15H, 2 indoles (10H), 3 NH (amides), 1 NH (urethane) CHO (formyl)); 10.89 (m, 2H, 2 N1H (indoles)).

Mass Spectrometry (Electrospray), ml/z 575 [M+H]+, 597 [M+Na]+, 1149 [2M+H]+, 1171 [2M+Na]+.

H-Aib-D-Trp-D-gTrT-CHO

Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 nmmol) was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Aib-D-Trp-D-gTrp-CHO was filtered.

The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

Yield=52%.

C26H30N6O3, 474 g.mol−1.

1H NMR (400 MHZ, DMSO-d6)+1H/1H correlation: δ 1.21 (s, 3H, CH(Aib)); 1.43 (s, 3H, CH(Aib)); 2.97 (m, 2H, (CH2)β); 3.1 (m, 2H, (CH2)β′); 4.62 (m, 1H, (CH)αA&B); 5.32 (q, 0.4H, (CH)α′B); 5.71 (q, 0.6H, (CH)α′A); 7.3 (m, 4Hand H6(2 indoles)); 7.06-7.2 (4d, 2H, H2A et H2B (2 indoles)); 7.3 (m, 2H, Hor H(2 indoles)); 7.6-7.8 (4d, 2H, H4A and H4B or H7A et H7B); 7.97 (s, 3H, NH(Aib) and CHO (Formyl));8.2 (d, 0.4H, NH1B (diamino)); 8.3 (m,1H, NHA&B); 8.5 (d, 0.6H, NH1A (diamino)); 8.69 (d, 0.6H, NH2A (diamino)); 8.96 (d, 0.4H, NH2B (diamino)); 10.8 (s, 0.6H, N1H1A (indole)); 10.82 (s, 0.4H, N1H1B (indole)); 10.86 (s, 0.6H, N1H2A (indole)); 10.91 (s, 0.4, N1H2B (indole)).

Mass Spectrometry (Electrospray), m/z 475 [M+H]+, 949 [2M+H]+.

CLIP

CLIP

CLIP

UPDATED INFO AS ON JAN 6 2014

Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

Quebec City, Canada, January 6, 2014 – Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) (the “Company”) today announced that the U.S. Food and Drug Administration (“FDA”) has accepted for filing the Company’s New Drug Application (“NDA”) for its ghrelin agonist, macimorelin acetate, in Adult Growth Hormone Deficiency (“AGHD”). The acceptance for filing of the NDA indicates the FDA has determined that the application is sufficiently complete to permit a substantive review.

The Company’s NDA, submitted on November 5, 2013, seeks approval for the commercialization of macimorelin acetate as the first orally-administered product that induces growth hormone release to evaluate AGHD. Phase 3 data have demonstrated the compound to be well tolerated, with accuracy comparable to available intravenous and intramuscular testing procedures. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (“PDUFA”) date of November 5, 2014. The PDUFA date is the goal date for the FDA to complete its review of the NDA.

David Dodd, President and CEO of Aeterna Zentaris, commented, “The FDA’s acceptance of this NDA submission is another significant milestone in our strategy to commercialize macimorelin acetate as the first approved oral product for AGHD evaluation. We are finalizing our commercial plan for this exciting new product. We are also looking to broaden the commercial application of macimorelin acetate in AGHD for use related to traumatic brain injury victims and other developmental areas, which would represent significant benefit to the evaluation of growth hormone deficiency, while presenting further potential revenue growth opportunities for the Company.”

About Macimorelin Acetate

Macimorelin acetate, a ghrelin agonist, is a novel orally-active small molecule that stimulates the secretion of growth hormone. The Company has completed a Phase 3 trial for use in evaluating AGHD, and has filed an NDA to the FDA in this indication. Macimorelin acetate has been granted orphan drug designation by the FDA for use in AGHD. Furthermore, macimorelin acetate is in a Phase 2 trial as a treatment for cancer-induced cachexia. Aeterna Zentaris owns the worldwide rights to this novel patented compound.

About AGHD

AGHD affects about 75,000 adults across the U.S., Canada and Europe. Growth hormone not only plays an important role in growth from childhood to adulthood, but also helps promote a hormonally-balanced health status. AGHD mostly results from damage to the pituitary gland. It is usually characterized by a reduction in bone mineral density, lean mass, exercise capacity, and overall quality of life.

About Aeterna Zentaris

Aeterna Zentaris is a specialty biopharmaceutical company engaged in developing novel treatments in oncology and endocrinology. The Company’s pipeline encompasses compounds from drug discovery to regulatory approval.

References

  1. ^ “Macrilen Prescribing Information” (PDF). Retrieved 2018-07-25.
  2. ^ “Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA”. Wall Street Journal. January 6, 2014.
  3. ^ https://clinicaltrials.gov/ct2/show/NCT02558829
  4. ^ Research, Center for Drug Evaluation and. “Drug Approvals and Databases – Drug Trials Snapshots: Marcrilen”http://www.fda.gov. Retrieved 2018-07-25.
  5. ^ “Macimorelin”NCI Drug Dictionary. National Cancer Institute.
  6. ^ Koch, Linda (2013). “Growth hormone in health and disease: Novel ghrelin mimetic is safe and effective as a GH stimulation test”. Nature Reviews Endocrinology9 (6): 315. doi:10.1038/nrendo.2013.89.
  7. ^ Garcia, J. M.; Swerdloff, R.; Wang, C.; Kyle, M.; Kipnes, M.; Biller, B. M. K.; Cook, D.; Yuen, K. C. J.; Bonert, V.; Dobs, A.; Molitch, M. E.; Merriam, G. R. (2013). “Macimorelin (AEZS-130)-Stimulated Growth Hormone (GH) Test: Validation of a Novel Oral Stimulation Test for the Diagnosis of Adult GH Deficiency”Journal of Clinical Endocrinology & Metabolism98 (6): 2422. doi:10.1210/jc.2013-1157PMC 4207947.
Patent ID

Title

Submitted Date

Granted Date

US2015099709 GHRELIN RECEPTOR AGONISTS FOR THE TREATMENT OF ACHLORHYDRIA
2013-05-27
2015-04-09
US2013060029 QUINAZOLINONE DERIVATIVES USEFUL AS VANILLOID ANTAGONISTS
2012-09-12
2013-03-07
US8835444 Cyclohexyl amide derivatives as CRF receptor antagonists
2011-01-31
2014-09-16
US8163785 PYRAZOLO[5, 1B]OXAZOLE DERIVATIVES AS CRF-1 RECEPTOR ANTAGONISTS
2011-08-04
2012-04-24
Patent ID

Title

Submitted Date

Granted Date

US7297681 Growth hormone secretagogues
2004-11-18
2007-11-20
US2018071367 METHODS OF TREATING COGNITIVE IMPAIRMENTS OR DYSFUNCTION
2016-03-08
US2012295942 Pyrazolo[5, 1b]oxazole Derivatives as CRF-1 Receptor Antagonists
2011-01-28
2012-11-22
US8349852 Quinazolinone Derivatives Useful as Vanilloid Antagonists
2010-08-05
US2017266257 METHODS OF TREATING TRAUMATIC BRAIN INJURY
2015-08-18
Patent ID

Title

Submitted Date

Granted Date

US2015265680 THERAPEUTIC AGENT FOR AMYOTROPHIC LATERAL SCLEROSIS
2013-10-23
2015-09-24
US2011201629 CYCLOHEXYL AMIDE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS
2011-08-18
US8614213 Organic compounds
2011-06-23
US7994203 Organic compounds
2010-02-11
2011-08-09
US8273900 Organic compounds
2010-02-11
Patent ID

Title

Submitted Date

Granted Date

US6861409 Growth hormone secretagogues
2002-11-07
2005-03-01
US8192719 Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds
2009-12-10
2012-06-05
US2017121385 METHODS OF TREATING NEURODEGENERATIVE CONDITIONS
2016-10-28
US2017281732 METHODS OF TREATING MILD BRAIN INJURY
2015-08-18
US2014088105 Cyclohexyl Amide Derivatives and Their Use as CRF-1 Receptor Antagonists
2013-11-22
2014-03-27
Macimorelin
Macimorelin.svg
Names
IUPAC name

2-Amino-N-[(2R)-1-[[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]amino]-3-1H-indol-3-yl)-1-oxopropan-2-yl]-2-methylpropanamide
Other names

Aib-Trp-gTrp-CHO; AEZS-130; JMV 1843; Macimorelin acetate
Identifiers
3D model (JSmol)
ChemSpider
KEGG
PubChem CID
UNII
Properties
C26H30N6O3
Molar mass 474.565 g·mol−1
Pharmacology
V04CD06 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/205598Orig1s000ChemR.pdf

///////////macimorelin, FDA 2017, Aeterna Zentaris, AEZS-130, ARD-07, D-87875, EP-01572, EP-1572, JMV-1843, USAN (ab-26), MACIMORELIN ACETATE, orphan drug designation

CC(O)=O.CC(C)(N)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)NC=O

Advertisements

Voretigene neparvovec , ボレチジーンネパルボベック;


Voretigene neparvovec
Voretigene neparvovec-rzyl;
Luxturna (TN)

ボレチジーンネパルボベック;

DNA (synthetic adeno-associated virus 2 vector AAV2-hRPE65v2)

CAS: 1646819-03-5
2017/12/19, FDA  Luxturna, SPARK THERAPEUTICS

Vision loss treatment, Retinal dystrophy

AAV2-hRPE65v2
AAV2.RPE65
LTW-888
SPK-RPE65
rAAV.hRPE65v2
rAAV2-CBSB-hRPE65
2SPI046IKD (UNII code)

melting point (°C) 72-90ºC Rayaprolu V. et al. J. Virol. vol. 87. no. 24. (2013)

FDA

https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM592766.pdf

LUXTURNA

STN: 125610
Proper Name: voretigene neparvovec-rzyl
Trade Name: LUXTURNA
Manufacturer: Spark Therapeutics, Inc.
Indication:

  • Is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients must have viable retinal cells as determined by the treating physician(s).

Product Information

Related Information

Voretigene neparvovec (Luxturna) is a novel gene therapy for the treatment of Leber’s congenital amaurosis.[1] It was developed by Spark Therapeutics and Children’s Hospital of Philadelphia.[2][3] It is the first in vivo gene therapy approved by the FDA.[4]

Leber’s congenital amaurosis, or biallelic RPE65-mediated inherited retinal disease, is an inherited disorder causing progressive blindness. Voretigene is the first treatment available for this condition.[5] The gene therapy is not a cure for the condition, but substantially improves vision in those treated.[6] It is given as an subretinal injection.

It was developed by collaboration between the University of Pennsylvania, Yale University, the University of Florida and Cornell University. In 2018, the product was launched in the U.S. by Spark Therapeutics for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The same year, Spark Therapeutics received approval for the product in the E.U. for the same indication.

Chemistry and production

Voretigene neparvovec is an AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence. The virus is grown in HEK 293 cells and purified for administration.[7]

History

Married researchers Jean Bennett and Albert Maguire, among others, worked for decades on studies of congenital blindness, culminating in approval of a novel therapy, Luxturna.[8]

It was granted orphan drug status for Leber congenital amaurosis and retinitis pigmentosa.[9][10] A biologics license application was submitted to the FDA in July 2017 with Priority Review.[5] Phase III clinical trial results were published in August 2017.[11] On 12 October 2017, a key advisory panel to the Food and Drug Administration (FDA), composed of 16 experts, unanimously recommended approval of the treatment.[12] The US FDA approved the drug on December 19, 2017. With the approval, Spark Therapeutics received a pediatric disease priority review voucher.[13]

The first commercial sale of voretigene neparvovec — the first for any gene therapy product in the US — occurred in March 2018.[14][14][4] The price of the treatment has been announced at $425,000 per eye.[15]

INDICATION

LUXTURNA (voretigene neparvovec-rzyl) is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Patients must have viable retinal cells as determined by the treating physicians.

IMPORTANT SAFETY INFORMATION FOR LUXTURNA

Warnings and Precautions

  • Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering LUXTURNA, and monitor for and advise patients to report any signs or symptoms of infection or inflammation to permit early treatment of any infection.

  • Permanent decline in visual acuity may occur following subretinal injection of LUXTURNA. Monitor patients for visual disturbances.

  • Retinal abnormalities may occur during or following the subretinal injection of LUXTURNA, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer LUXTURNA in the immediate vicinity of the fovea. Retinal abnormalities may occur during or following vitrectomy, including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay.

  • Increased intraocular pressure may occur after subretinal injection of LUXTURNA. Monitor and manage intraocular pressure appropriately.

  • Expansion of intraocular air bubbles Instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination.

  • Cataract Subretinal injection of LUXTURNA, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.

Adverse Reactions

  • In clinical studies, ocular adverse reactions occurred in 66% of study participants (57% of injected eyes), and may have been related to LUXTURNA, the subretinal injection procedure, the concomitant use of corticosteroids, or a combination of these procedures and products.

  • The most common adverse reactions (incidence ≥5% of study participants) were conjunctival hyperemia (22%), cataract (20%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma) (7%), macular hole (7%), subretinal deposits (7%), eye inflammation (5%), eye irritation (5%), eye pain (5%), and maculopathy (wrinkling on the surface of the macula) (5%).

Immunogenicity

Immune reactions and extra-ocular exposure to LUXTURNA in clinical studies were mild. No clinically significant cytotoxic T-cell response to either AAV2 or RPE65 has been observed.

In clinical studies, the interval between the subretinal injections into the two eyes ranged from 7 to 14 days and 1.7 to 4.6 years. Study participants received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye, which may have decreased the potential immune reaction to either AAV2 or RPE65.

Pediatric Use

Treatment with LUXTURNA is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and LUXTURNA would potentially be diluted or lost during the cell proliferation. The safety and efficacy of LUXTURNA have been established in pediatric patients. There were no significant differences in safety between the different age subgroups.

Please see US Full Prescribing Information for LUXTURNA.

References:

1. LUXTURNA [package insert]. Philadelphia, PA: Spark Therapeutics, Inc; 2017. 2. Gupta PR, Huckfeldt RM. Gene therapy for inherited retinal degenerations: initial successes and future challenges. J Neural Eng. 2017;14(5):051002. 3. Kay C. Gene therapy: the new frontier for inherited retinal disease. Retina Specialist. March 2017. http://www.retina-specialist.com/CMSDocuments/2017/03/RS/rs0317I.pdf. Accessed November 14, 2017 4. Polinski NK, Gombash SE, Manfredsson FP, et al. Recombinant adeno-associated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging. 2015;36(2):1110-1120. 5. Moore T. Restoring retinal function in a mouse model of hereditary blindness. PLoS Med. 2005;2(11):e399. 6. McBee JK, Van Hooser JP, Jang GF, Palczewski K. Isomerization of 11-cis-retinoids to all-trans-retinoids in vitro and in vivo. J Biol Chem. 2001;276(51):48483-48493. 7. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4(5):346-358. 8. Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res. 2014;43:108-128. 9. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860.

Illustration of the RPE65 gene delivery method

Illustration of the RPE65 protein production cycle

PAPERS

Progress in Retinal and Eye Research (2018), 63, 107-131

Lancet (2017), 390(10097), 849-860.

References

  1. ^ “Luxturna (voretigene neparvovec-rzyl) label” (PDF). FDA. December 2017. Retrieved 31 December 2017. (for label updates, see FDA index page)
  2. ^ “Spark’s gene therapy for blindness is racing to a historic date with the FDA”Statnews.com. 9 October 2017. Retrieved 9 October 2017.
  3. ^ Clarke,Reuters, Toni. “Gene Therapy for Blindness Appears Initially Effective, Says U.S. FDA”Scientific American. Retrieved 2017-10-12.
  4. Jump up to:a b “First Gene Therapy For Inherited Disease Gets FDA Approval”NPR.org. 19 Dec 2017.
  5. Jump up to:a b “Press Release – Investors & Media – Spark Therapeutics”Ir.sparktx.com. Retrieved 9 October 2017.
  6. ^ McGinley, Laurie (19 December 2017). “FDA approves first gene therapy for an inherited disease”Washington Post.
  7. ^ Russell, Stephen; Bennett, Jean; Wellman, Jennifer A.; Chung, Daniel C.; Yu, Zi-Fan; Tillman, Amy; Wittes, Janet; Pappas, Julie; Elci, Okan; McCague, Sarah; Cross, Dominique; Marshall, Kathleen A.; Walshire, Jean; Kehoe, Taylor L.; Reichert, Hannah; Davis, Maria; Raffini, Leslie; George, Lindsey A.; Hudson, F Parker; Dingfield, Laura; Zhu, Xiaosong; Haller, Julia A.; Sohn, Elliott H.; Mahajan, Vinit B.; Pfeifer, Wanda; Weckmann, Michelle; Johnson, Chris; Gewaily, Dina; Drack, Arlene; et al. (2017). “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial”The Lancet390 (10097): 849–860. doi:10.1016/S0140-6736(17)31868-8PMC 5726391PMID 28712537.
  8. ^ “FDA approves Spark’s gene therapy for rare blindness pioneered at CHOP – Philly”Philly.com. Retrieved 2018-03-24.
  9. ^ “Voretigene neparvovec – Spark Therapeutics – AdisInsight”adisinsight.springer.com.
  10. ^ Ricki Lewis, PhD (October 13, 2017). “FDA Panel Backs Gene Therapy for Inherited Blindness”Medscape.
  11. ^ Lee, Helena; Lotery, Andrew (2017). “Gene therapy for RPE65 -mediated inherited retinal dystrophy completes phase 3”. The Lancet390 (10097): 823–824. doi:10.1016/S0140-6736(17)31622-7PMID 28712536.
  12. ^ “Landmark Therapy to Treat Blindness Gets One Step Closer to FDA Approval”Bloomberg.com. 2017-10-12. Retrieved 2017-10-12.
  13. ^ “Spark grabs FDA nod for Luxturna, a breakthrough gene therapy likely bearing a pioneering price”FiercePharma.
  14. Jump up to:a b “The anxious launch of Luxturna, a gene therapy with a record sticker price”STAT. 2018-03-21. Retrieved 2018-03-24.
  15. ^ Tirrell, Meg (3 January 2018). “A US drugmaker offers to cure rare blindness for $850,000”. CNBC. Retrieved 3 January 2018.

Further reading

Voretigene neparvovec
Gene therapy
Vector Adeno-associated virusserotype 2
Nucleic acid type DNA
Editing method RPE65
Clinical data
Trade names Luxturna
Pregnancy
category
  • US: N (Not classified yet)
Routes of
administration
subretinal injection
ATC code
Legal status
Legal status
Identifiers
KEGG

//////////FDA 2017, Voretigene neparvovec , Voretigene neparvovec-rzyl, Luxturna, ボレチジーンネパルボベック, 1646819-03-5 , FDA  Luxturna, SPARK THERAPEUTICS, Vision loss treatment, Retinal dystrophy., AAV2-hRPE65v2, LTW-888, SPK-RPE65, Orphan drug,

FDA approves new treatment Xeljanz (tofacitinib) for moderately to severely active ulcerative colitis


The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

May 30, 2018

Release

The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

“New treatments are needed for patients with moderately to severely active ulcerative colitis,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “Today’s approval provides an alternative therapy for a debilitating disease with limited treatment options.”

Ulcerative colitis is a chronic, inflammatory bowel disease affecting the colon. Patients experience recurrent flares of abdominal pain and bloody diarrhea. Other symptoms include fatigue, weight loss and fever. More than 900,000 patients are affected in the U.S., many of them experiencing moderately to severely active ulcerative colitis, and there is currently no cure.

The efficacy of Xeljanz for the treatment of moderately to severely active ulcerative colitis was demonstrated in three controlled clinical trials. This included two 8-week placebo-controlled trials that demonstrated that 10 mg of Xeljanz given twice daily induces remission in 17 to 18 percent of patients by week eight. In a placebo-controlled trial among patients who achieved a clinical response by week eight, Xeljanz, at a 5 mg or 10 mg dose given twice daily, was effective in inducing remission by week 52 in 34 percent and 41 percent of patients, respectively. Among patients who achieved remission after 8 weeks of treatment, 35 percent and 47 percent achieved sustained corticosteroid-free remission when treated with 5 mg and 10 mg, respectively.

The safety of chronic use of Xeljanz for ulcerative colitis was studied in the 52-week placebo- controlled trial. Additional supportive safety information was collected from patients who received treatment in an open-label long-term study.

The most common adverse events associated with Xeljanz treatment for ulcerative colitis were diarrhea, elevated cholesterol levels, headache, herpes zoster (shingles), increased blood creatine phosphokinase, nasopharyngitis (common cold), rash and upper respiratory tract infection.

Less common serious adverse events included malignancy and serious infections such as opportunistic infections. Xeljanz has a boxed warning for serious infections and malignancy. Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Lymphoma and other malignancies have been observed in patients treated with Xeljanz.

Use of Xeljanz in combination with biological therapies for ulcerative colitis or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

Xeljanz, made by Pfizer Labs, was previously approved in 2012 for rheumatoid arthritis and in 2017 for psoriatic arthritis.

/////////////Xeljanz, tofacitinib, pfizer, fda 2017, psoriatic arthritis, ulcerative colitis

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

%d bloggers like this: