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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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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

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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.
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  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.
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  13. Jump up^ “Acerta Pharma B.V. – Company Profile – BioCentury”http://www.biocentury.com. Retrieved 2016-11-12.
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  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
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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


Netarsudil.png

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

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

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.

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
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  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
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    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
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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
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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
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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
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Delafloxacin
Delafloxacin.svg
Clinical data
Trade names Baxdela
Synonyms ABT-492; RX-3341; WQ-3034
Routes of
administration
Oralintravenous injection
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C18H12ClF3N4O4
Molar mass 440.76 g/mol
3D model (JSmol)

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

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

Naldemedine, ナルデメジントシル酸塩


str1

Naldemedine.svg

ChemSpider 2D Image | Naldemedine | C32H34N4O6

NALDEMEDINE.png

Naldemedine

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

FDA APPROVED 2017

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

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

Image result for naldemedineImage result for naldemedine

Image result for naldemedine

ナルデメジントシル酸塩

Commercialization

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

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

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

SYN

US 8084460

WO 2012063933

Manufacturer Finances

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

Intellectual Property

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

Preclinical Trials

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

Clinical Trials

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

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

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

Patent ID

Patent Title

Submitted Date

Granted Date

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

FDA Orange Book Patents

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

References

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

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

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

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


FDA approves drug to treat dangerously low blood pressure

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

 

December 21, 2017

Release

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

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

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

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

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

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

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

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

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


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

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

December 12, 2017

Release

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

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

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

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

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

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

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

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

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

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

The FDA granted approval of Nucala to GlaxoSmithKline.

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

FDA approves first two-drug regimen for certain patients with HIV, Juluca (dolutegravir and rilpivirine)


FDA approves first two-drug regimen for certain patients with HIV

The U.S. Food and Drug Administration today approved Juluca, the first complete treatment regimen containing only two drugs to treat certain adults with human immunodeficiency virus type 1 (HIV-1) instead of three or more drugs included in standard HIV treatment. Juluca is a fixed-dose tablet containing two previously approved drugs (dolutegravir and rilpivirine) to treat adults with HIV-1 infections whose virus is currently suppressed on a stable regimen for at least six months, with no history of treatment failure and no known substitutions associated with resistance to the individual components of Juluca. Continue reading.

 

 

November 21, 2017

Summary

FDA approved Juluca, the first complete treatment regimen containing only two drugs to treat certain adults with human immunodeficiency virus type 1 (HIV-1).

Release

The U.S. Food and Drug Administration today approved Juluca, the first complete treatment regimen containing only two drugs to treat certain adults with human immunodeficiency virus type 1 (HIV-1) instead of three or more drugs included in standard HIV treatment. Juluca is a fixed-dose tablet containing two previously approved drugs (dolutegravir and rilpivirine) to treat adults with HIV-1 infections whose virus is currently suppressed on a stable regimen for at least six months, with no history of treatment failure and no known substitutions associated with resistance to the individual components of Juluca.

“Limiting the number of drugs in any HIV treatment regimen can help reduce toxicity for patients,” said Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research.

HIV weakens a person’s immune system by destroying important cells that fight disease and infection. According to the Centers for Disease Control and Prevention, an estimated 1.1 million people in the United States are living with HIV, and the disease remains a significant cause of death for certain populations.

Juluca’s safety and efficacy in adults were evaluated in two clinical trials of 1,024 participants whose virus was suppressed on their current anti-HIV drugs. Participants were randomly assigned to continue their current anti-HIV drugs or to switch to Juluca. Results showed Juluca was effective in keeping the virus suppressed and comparable to those who continued their current anti-HIV drugs.

The most common side effects in patients taking Juluca were diarrhea and headache. Serious side effects include skin rash and allergic reactions, liver problems and depression or mood changes. Juluca should not be given with other anti-HIV drugs and may have drug interactions with other commonly used medications.

The FDA granted approval of Juluca to ViiV Healthcare.

 

/////////fda 2017, dolutegravir,  rilpivirine, Juluca,  ViiV Healthcare,

DISCLAIMER

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

Copanlisib


Copanlisib.svgChemSpider 2D Image | Copanlisib | C23H28N8O4

Copanlisib, BAY 80-6946, 

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

Cas 1032568-63-0 [RN]

1402152-26-4 MONO HCL

UNII-WI6V529FZ9

FDA Approved September 2017

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

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

Image result for copanlisib

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

Image result for copanlisib

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

Image result for copanlisib

1402152-46-8 CAS  X=4, 

1919050-77-3 CAS X=1

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

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

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

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

SYN

WO 2017049983

PATENTS

WO 2008070150

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

Example 13

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

Figure imgf000084_0001

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

Figure imgf000084_0002

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

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

Figure imgf000084_0003

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

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

Figure imgf000085_0001

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

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

Figure imgf000085_0002

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

Figure imgf000086_0001

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

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

Figure imgf000086_0002

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

PATENT

CN 105130998

TRANSLATED

Example VI:

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

PATENT

WO 2016071435

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

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

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

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

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

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

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

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

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

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

Reaction Scheme 1 :

(I)

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

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

Reaction Scheme 2 :

Reaction Scheme 3

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

Step A1 1 : Easy purification of copanlisib via its dihydrochloride

(dihydrochloride is the final product)

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

Reaction Scheme 3 : 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PATENT

WO 2017049983

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

Synthetic route four:
Synthetic route five:

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

PAPER

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

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

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

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

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

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

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

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

References

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

Patent Title

Submitted Date

Granted Date

US2016303136 COMBINATION OF PI3K-INHIBITORS
2014-11-28
US2015141420 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR THE TREATMENT OF MYELOMA
2014-09-29
2015-05-21
Patent ID

Patent Title

Submitted Date

Granted Date

US2016058770 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR TREATING LYMPHOMAS
2014-04-04
2016-03-03
US2015254400 GROUPING FOR CLASSIFYING GASTRIC CANCER
2013-09-18
2015-09-10
US2011251191 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR THE TREATMENT OF MYELOMA
2011-10-13
US2013184270 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE-CONTAINING COMBINATIONS
2011-04-14
2013-07-18
US2014072529 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE SALTS
2012-03-29
2014-03-13
Patent ID

Patent Title

Submitted Date

Granted Date

US2014243295 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES
2012-03-29
2014-08-28
US2017056336 CO-TARGETING ANDROGEN RECEPTOR SPLICE VARIANTS AND MTOR SIGNALING PATHWAY FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER
2016-05-09
US2015320754 COMBINATION THERAPIES
2015-04-15
2015-11-12
US2015320755 COMBINATION THERAPIES
2015-04-15
2015-11-12
US2016113932 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2014-05-30
2016-04-28
Patent ID

Patent Title

Submitted Date

Granted Date

US8466283 Substituted 2, 3-dihydroimidazo[1, 2-c]quinazoline Derivatives Useful for Treating Hyper-Proliferative Disorders and Diseases Associated with Angiogenesis
2011-04-14
US9636344 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE SALTS
2016-01-07
2016-07-07
US2014377258 Treatment Of Cancers Using PI3 Kinase Isoform Modulators
2014-05-30
2014-12-25
US2015283142 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2013-11-01
2015-10-08
US2013261113 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
2013-06-03
2013-10-03
Copanlisib
Copanlisib.svg
Names
IUPAC name

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

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

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

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

 

DISCLAIMER

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

FDA approves new treatment Hemlibra (emicizumab-kxwh) to prevent bleeding in certain patients with hemophilia A


FDA approves new treatment to prevent bleeding in certain patients with hemophilia A

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.Continue reading.

 

 

November 16, 2017

Summary

FDA approves new treatment to prevent or reduce frequency of bleeding episodes in patients with hemophilia A who have Factor VIII inhibitors.

Release

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

“Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia. Today’s approval provides a new preventative treatment that has been shown to significantly reduce the number of bleeding episodes in patients with hemophilia A with Factor VIII inhibitors,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “In addition, patients treated with Hemlibra reported an improvement in their physical functioning.”

Hemophilia A is an inherited blood-clotting disorder that primarily affects males. According to the National Institutes of Health, hemophilia affects one in every 5,000 males born in the United States, approximately 80 percent of whom have hemophilia A. Patients with hemophilia A are missing a gene which produces Factor VIII, a protein that enables blood to clot. Patients may experience repeated episodes of serious bleeding, primarily into their joints, which can be severely damaged as a result. Some patients develop an immune response known as a FVIII inhibitor or antibody. The antibody interferes with the effectiveness of currently available treatments for hemophilia.

Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).

The safety and efficacy of Hemlibra was based on data from two clinical trials. The first was a trial that included 109 males aged 12 and older with hemophilia A with FVIII inhibitors. The randomized portion of the trial compared Hemlibra to no prophylactic treatment in 53 patients who were previously treated with on-demand therapy with a bypassing agent before enrolling in the trial. Patients taking Hemlibra experienced approximately 2.9 treated bleeding episodes per year compared to approximately 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment. This represents an 87 percent reduction in the rate of treated bleeds. The trial also included patient-reported Quality of Life metrics on physical health. Patients treated with Hemlibra reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking) compared to patients who did not receive prophylactic treatment.

The second trial was a single arm trial of 23 males under the age of 12 with hemophilia A with FVIII inhibitors. During the trial, 87 percent of the patients taking Hemlibra did not experience a bleeding episode that required treatment.

Common side effects of Hemlibra include injection site reactions, headache, and joint pain (arthralgia).

The labeling for Hemlibra contains a boxed warning to alert healthcare professionals and patients that severe blood clots (thrombotic microangiopathy and thromboembolism) have been observed in patients who were also given a rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Hemlibra also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Hemlibra to Genentech, Inc.

///////Hemlibra, emicizumab-kxwh, FDA 2017, hemophilia A, Priority Review and Breakthrough Therapy designation,  Orphan Drug designation

 

 

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

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