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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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USFDA approval to Lumoxiti (moxetumomab pasudotoxtdfk) a new treatment for hairy cell leukemia


Image result for moxetumomab pasudotox tdfk

USFDA approval to Lumoxiti is a new treatment for hairy cell leukemia

On September 13, 2018, the U.S. Food and Drug Administration approved Lumoxiti (moxetumomab pasudotoxtdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory Hairy Cell Leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog 1. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL. The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent. The FDA granted this application Fast Track and Priority Review designations. Lumoxiti 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 Lumoxiti to AstraZeneca Pharmaceuticals. About Hairy Cell Leukemia HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cells that fight infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

About Lumoxiti2 Lumoxiti (moxetumomab pasudotox) is a CD22-directed cytotoxin and a first-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min). It comprises the CD22 binding portion of an antibody fused to a truncated bacterial toxin; the toxin inhibits protein synthesis and ultimately triggers apoptotic cell death.

September 13, 2018

Release

The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent.

Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Women who are breastfeeding should not be given Lumoxiti.

The FDA granted this application Fast Track and Priority Review designations. Lumoxiti 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 Lumoxiti to AstraZeneca Pharmaceuticals.

1 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620448.htm

2 https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-approves-lumoxiti-moxetumomab-pasudotox-tdfk-for-certain-patientswith-relapsed-or-refractory-hairy-cell-leukaemia.html

/////////// Lumoxiti, moxetumomab pasudotoxtdfk, FDA 2018, Fast Track,  Priority Review ,  Orphan Drug, AstraZeneca

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AZD 9567


SCHEMBL17643955.png

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AZD 9567

CAS 1893415-00-3

1893415-64-9  as MONOHYDRATE

2,2-Difluoro-N-[(1R,2S)-3-methyl-1-[[1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl]oxy]-1-phenylbutan-2-yl]propanamide

Propanamide, N-[(1S)-1-[(R)-[[1-(1,6-dihydro-1-methyl-6-oxo-3-pyridinyl)-1H-indazol-5-yl]oxy]phenylmethyl]-2-methylpropyl]-2,2-difluoro-

2,2-difluoro-N-[(1R,2S)-3-methyl-1-[1-(1-methyl-6-oxopyridin-3-yl)indazol-5-yl]oxy-1-phenylbutan-2-yl]propanamide

2,2-difluoro- V-[(lR,25)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide

MF C27 H28 F2 N4 O3, MF 494.533

AstraZeneca INNOVATOR

AZD-9567, a glucocorticoid receptor modulator, is in early clinical development at AstraZeneca in healthy male volunteers.

Phase I Rheumatoid arthritis

  • Originator AstraZeneca
  • Class Antirheumatics
  • Mechanism of Action Glucocorticoid receptor modulators
    • 01 Sep 2016 AstraZeneca completes a phase I trial (In volunteers) in Germany (NCT02512575)
    • 24 May 2016 Phase-I clinical trials in Rheumatoid arthritis (In volunteers) in United Kingdom (PO) (NCT02760316)
    • 24 May 2016 AstraZeneca initiates a phase I trial in Rheumatoid arthritis (In volunteers) in Germany (PO) (NCT02760316)
     
Inventors Lena Elisabeth RIPA, Karolina Lawitz, Matti Juhani Lepistö, Martin Hemmerling, Karl Edman, Antonio Llinas
Applicant Astrazeneca

Warning: Chancellor George Osborne told Scotland it could be forced to give up the pound if it became independent of the rest of the UK. He is pictured yesterday with Jan Milton-Edwards during a visit to the Macclesfield AstraZeneca site in Cheshire

Macclesfield AstraZeneca site in Cheshire

Image result

Glucocorticoids (GCs) have been used for decades to treat acute and chronic inflammatory and immune conditions, including rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (“COPD”), osteoarthritis, rheumatic fever, allergic rhinitis, systemic lupus erythematosus, Crohn’s disease, inflammatory bowel disease, and ulcerative colitis. Examples of GCs include dexamethasone, prednisone, and

prednisolone. Unfortunately, GCs are often associated with severe and sometimes irreversible side effects, such as osteoporosis, hyperglycemia, effects on glucose metabolism (diabetes mellitus). skin thinning, hypertension, glaucoma, muscle atrophy. Cushing’s syndrome, fluid homeostasis, and psychosis (depression ). These side effects can particularly limit the use of GCs in a chronic setting. Thus, a need continues to exist for alternative therapies that possess the beneficial effects of GCs, but with a reduced likel ihood of side effects.

GCs form a complex with the GC receptor ( GR ) to regulate gene transcription. The GC-GR complex translocates to the cell nucleus, and then binds to GC response elements (GREs) in the promoter regions of various genes. The resulting GC-GR- GRE complex, in turn, activates or inhibits transcription of proximally located genes. The GC-GR complex also (or alternatively) may negatively regulate gene transcription by a process that does not involve DNA binding. In this process, termed transrepression, the GC-GR complex enters the nucleus and directly interacts (via protein-protein interaction) with other transcription factors, repressing their ability to induce gene transcription and thus protein expression.

Some of the side effects of GCs are believed to be the result of cross-reactivity with other steroid receptors (e.g., progesterone, androgen, mineralocorticoid, and estrogen receptors), which have somewhat homologous ligand binding domains; and/or the inability to selectively modulate gene expression and downstream signaling. Consequently, it is believed that an efficacious selective GR modulator (SGRM), which binds to GR with greater affinity relative to other steroid hormone receptors, would provide an alternative therapy to address the unmet need for a therapy that possesses the beneficial, effects of GCs, while, at the same time, having fewer side effects.

A range of compounds have been reported to have SGRM activity. See, e.g., WO2007/0467747, WO2007/114763, WO2008/006627, WO2008/055709, WO2008/055710, WO2008/052808, WO2008/063116, WO2008/076048,

WO2008/079073, WO2008/098798, WO2009/065503, WO2009/142569,

WO2009/142571, WO2010/009814, WO2013/001294, and EP2072509. Still, there continues to be a need for new SGRMs that exhibit, for example, an improved potency, efficacy, effectiveness in steroid-insensitive patients, selectivity, solubility allowing for oral administration, pharmacokinetic profile allowing for a desirable dosing regimen, stability on the shelf {e.g., hydro lytic, thermal, chemical, or photochemical stability), crystallinity, tolerability for a range of patients, side effect profile and/or safety profile.

PATENT

WO 2016046260

Scheme 1 below illustrates a general protocol for making compounds described in this specification, using either an Ullman route or an aziridine route.

Scheme 1

In Scheme 1, Ar is

[182] The amino alcohol reagent used in Scheme 1 may be made using the below Scheme 2.

Scheme 2

The Grignard reagent (ArMgBr) used in Scheme 2 can be obtained commercially, or, if not, can generally be prepared from the corresponding aryl bromide and Mg and/or iPrMgCl using published methods.

[183] The iodo and hydroxy pyridone indazole reagents used in Scheme 1 may be made using the below Scheme 3A or 3B, respectively.

Scheme 3A

[184] Scheme 4 below provides an alternative protocol for making compounds described in this specification.

Scheme 4

Example 1. Preparation of 2,2-difluoro- V-[(lR,2S)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide.

[199] Step A. Preparation of 5-[5-[(te^butyldimethylsilyl)oxy]-lH-indazol-l-yl]-l-methyl-l,2-dihydropyridin-2-one.

Into a 2 L 4-necked, round-bottom flask, purged and maintained with an inert atmosphere of N2, was placed a solution of 5-[(tert-butyldimethylsilyl)oxy]-lH-indazole (805 g, 3.2 mol) in toluene (8 L), 5 -iodo-1 -methyl- 1 ,2-dihydropyridin-2-one (800 g, 3.4 mol) and

K3PO4 (1.2 kg, 5.8 mol). Cyclohexane-l,2-diamine (63 g, 0.5 mol) was added followed by the addition of Cul (1.3 g, 6.8 mmol) in several batches. The resulting solution was stirred overnight at 102°C. The resulting mixture was concentrated under vacuum to yield 3.0 kg of the title compound as a crude black solid. LC/MS: m/z 356 [M+H]+.

[200] Step B. Preparation of 5-(5-hydroxy-lH-indazol-l-yl)-l-methylpyridin-2(lH)-one.

Into a 2 L 4-necked, round-bottom flask was placed 5-[5-[(fert-butyldimethylsilyl)oxy]-lH-indazol-l-yl]-l-methyl-l,2-dihydropyridin-2-one (3.0 kg, crude) and a solution of HCl (2 L, 24 mol, 36%) in water (2 L) and MeOH (5 L). The resulting solution was stirred for 1 hr at 40°C and then evaporated to dryness. The resulting solid was washed with water (4 x 5 L) and ethyl acetate (2 x 0.5 L) to afford 480 g (61%, two steps) of the title product as a brown solid. LC/MS: m/z 242 [M+H]+. 1HNMR (300 MHz, DMSO-d6): δ 3.52 (3H, s),6.61 (lH,m),7.06 (2H,m),7.54 (lH,m), 7.77 (lH,m), 8.19 (2H, m) 9.35 (lH,s).

[201] Ste C. Preparation of tert-butyl((lR,25)-l-hydroxy-3-methyl-l-phenylbutan-2-yl)carbamate.

(S)-tert-butyl 3 -methyl- l-oxo-l-phenylbutan-2-ylcarbamate (1.0 kg, 3.5 mol) was dissolved in toluene (4 L). Afterward, 2-propanol (2 L) was added, followed by triisopropoxyaluminum (0.145 L, 0.73 mol). The reaction mixture was heated at 54-58°C for 1 hr under reduced pressure (300-350 mbar) to start azeothropic distillation. After the collection of 0.75 L condensate, 2-propanol (2 L) was added, and the reaction mixture was stirred overnight at reduced pressure to afford 4 L condensate in total. Toluene (3 L) was added at 20°C, followed by 2M HC1 (2 L) over 15 min to keep the temperature below 28°C. The layers were separated (pH of aqueous phase 0-1) and the organic layer was washed successively with water (3 L), 4% NaHCCte (2 L) and water (250 mL). The volume of the organic layer was reduced from 6 L at 50°C and 70 mbar to 2.5 L. The resulting mixture was heated to 50°C and heptane (6.5 L) was added at 47-53°C to maintain the material in solution. The temperature of the mixture was slowly decreased to 20°C, seeded with the crystals of the title compound at 37°C (seed crystals were prepared in an earlier batch made by the same method and then evaporating the reaction mixture to dryness, slurring the residue in heptane, and isolating the crystals by filtration), and allowed to stand overnight. The product was filtered off, washed with heptane (2 x 1 L) and dried under vacuum to afford 806 g (81%) of the title compound as a white solid. 1HNMR (500 MHz, DMSO-d6): δ 0.81 (dd, 6H), 1.16 (s, 8H), 2.19 (m, 1H), 3.51 (m, 1H), 4.32 (d, 1H), 5.26 (s, 1H), 6.30 (d, 1H), 7.13 – 7.2 (m, 1H), 7.24 (t, 2H), 7.3 – 7.36 (m, 3H).

[202] Step D. Preparation of (lR,2S)-2-amino-3-methyl-l-phenylbutan-l-ol hydrochloride salt.

To a solution of HC1 in propan-2-ol (5-6 N, 3.1 L, 16 mol) at 20°C was added tert-butyl((li?,25)-l-hydroxy-3-methyl-l-phenylbutan-2-yl)carbamate (605 g, 2.2 mol) in portions over 70 min followed by the addition of MTBE (2 L) over 30 min. The reaction mixture was cooled to 5°C and stirred for 18 hr. The product was isolated by filtration and dried to afford 286 g of the title compound as an HC1 salt (61% yield). The mother liquor was concentrated to 300 mL. MTBE (300 mL) was then added, and the resulting precipitation was isolated by filtration to afford additional 84 g of the title compound as a HC1 salt (18% yield). Total 370 g (79%). 1HNMR (400 MHz, DMSO-d6): δ 0.91 (dd, 6H), 1.61 – 1.81 (m, 1H), 3.11 (s, 1H), 4.99 (s, 1H), 6.08 (d, 1H), 7.30 (t, 1H), 7.40 (dt, 4H), 7.97 (s, 2H).

[203] Step E. Preparation of (2S,35)-2-isopropyl-l-(4-nitrophenylsulfonyl)-3-phenylaziridine.

(li?,25)-2-Amino-3-methyl-l-phenylbutan-l-ol hydrochloride (430 g, 2.0 mol) was mixed with DCM (5 L) at 20°C. 4-Nitrobenzenesulfonyl chloride (460 g, 2.0 mol) was then added over 5 min. Afterward, the mixture was cooled to -27°C. Triethylamine (1.0 kg, 10 mol) was slowly added while maintaining the temperature at -18°C. The reaction mixture was cooled to -30°C, and methanesulfonyl chloride (460 g, 4.0 mol) was added slowly while maintaining the temperature at -25 °C. The reaction mixture was then stirred at 0°C for 16 hr before adding triethylamine (40 mL, 0.3 mol; 20 mL ,0.14 mol and 10 mL, 0.074 mol) w at 0°C in portions over 4 hr. Water (5 L) was subsequently added at 20°C, and the resulting layers were separated. The organic layer was washed with water (5 L) and the volume reduced to 1 L under vacuum. MTBE (1.5 L) was added, and the mixture was stirred on a rotavap at 20°C over night and filtered to afford 500 g (70%) of the title product as a solid. 1HNMR (400 MHz, CDCls): δ 1.12 (d, 3H), 1.25 (d, 3H), 2.23 (ddt, 1H), 2.89 (dd, 1H), 3.84 (d, 1H), 7.08 – 7.2 (m, 1H), 7.22 – 7.35 (m, 4H), 8.01 – 8.13 (m, 2H), 8.22 – 8.35 (m, 2H)

[204] Step F. Preparation of V-((lR,2S)-3-methyl-l-(l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yloxy)-l-phenylbutan-2-yl)-4-nitrobenzenesulfonamide.

[205] (25′,35)-2-Isopropyl-l-(4-nitrophenylsulfonyl)-3-phenylaziridine (490 g, 1.3 mol) was mixed with 5-(5-hydroxy-lH-indazol-l-yl)-l-methylpyridin-2(lH)-one (360 g, 1.4 mol) in acetonitrile (5 L) at 20°C. Cesium carbonate (850 g, 2.6 mol) was added in portions over 5 min. The reaction mixture was then stirred at 50°C overnight. Water (5 L) was added at 20°C, and the resulting mixture was extracted with 2-methyltetrahydrofuran (5L and 2.5 L). The combined organic layer was washed successively with 0.5 M HC1 (5 L), water (3 x 5L) and brine (5L). The remaining organic layer was concentrated to a thick oil, and then MTBE (2 L) was added. The resulting precipitate was filtered to afford 780 g (purity 71% w/w) of the crude title product as a yellow solid, which was used in the next step without further purification. 1HNMR (400 MHz, DMSO-d6): δ 0.93 (dd, 6H), 2.01 -2.19 (m, 1H), 3.50 (s, 3H), 3.74 (s, 1H), 5.00 (d, 1H), 6.54 (d, 1H), 6.78 (d, 1H), 6.95 -7.15 (m, 4H), 7.23 (d, 2H), 7.49 (d, 1H), 7.69 (dd, 1H), 7.74 (d, 2H), 8.00 (s, 1H), 8.08 (d, 2H), 8.13 (d, 2H).

[206] Step G. Preparation of 2,2-difluoro- V-[(lR,25)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide.

[207] N-((lR,2S)-3-Methyl- 1 -(1 -(1 -methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)- \H-indazol-5-yloxy)-l-phenylbutan-2-yl)-4-nitrobenzenesulfonamide (780 g, 71%w/w) was mixed with DMF (4 L). DBU (860 g, 5.6 mol) was then added at 20°C over 10 min. 2-Mercaptoacetic acid (170 g, 1.9 mol) was added slowly over 30 min, keeping the temperature at 20°C. After 1 hr, ethyl 2,2-difluoropropanoate (635 g, 4.60 mol) was added over 10 min at 20°C. The reaction mixture was stirred for 18 hr. Subsequently, additional ethyl 2,2-difluoropropanoate (254 g, 1.8 mol) was added, and the reaction mixture was stirred for an additional 4 hr at 20°C. Water (5 L) was then slowly added over 40 min, maintaining the temperature at 20°C. The water layer was extracted with isopropyl acetate (4 L and 2 x 2 L). The combined organic layer was washed with 0.5M HC1 (4 L) and brine (2 L). The organic layer was then combined with the organic layer from a parallel reaction starting from 96 g of N-((li?,25)-3-methyl-l-((l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)- lH-indazol-5-yl)oxy)- 1 -phenylbutan-2-yl)-4-nitrobenzenesulfonamide, and concentrated to approximate 1.5 L. The resulting brown solution was filtered. The filter was washed twice with isopropyl acetate (2 x 0.5 L). The filtrate was evaporated until a solid formed. The solid was then co evaporated with 99.5% ethanol (1 L), affording 493 g (77%, two steps) of an amorphous solid.

[208] The solid (464 g, 0.94 mol) was dissolved in ethanol/water 2: 1 (3.7 L) at 50°C. The reaction mixture was then seeded with crystals () of the title compound (0.5 g) at 47°C, and a slight opaque mixture was formed. The mixture was held at that temperature for 1 hr. Afterward, the temperature was decreased to 20°C over 7 hr, and kept at 20°C for 40 hr. The solid was filtrated off, washed with cold (5°C) ethanol/water 1 :2 (0.8 L), and dried in vacuum at 37°C overnight to afford 356 g (0.70 mol, 74%, 99.9 % ee) of the title compound as a monohydrate. LC/MS: m/z 495 [M+H]+. ‘HNMR (600 MHz, DMSO-d6) δ 0.91 (dd, 6H), 1.38 (t, 3H), 2.42 (m, 1H), 3.50 (s, 3H), 4.21 (m, 1H), 5.29 (d, 1H), 6.53 (d, 1H), 7.09 (d, 1H), 7.13 (dd, 1H), 7.22 (t, 1H), 7.29 (t, 2H), 7.47 (d, 2H), 7.56 (d, 1H), 7.70 (dd, 1H), 8.13 (d, 1H), 8.16 (d, 1H), 8.27 (d, 1H).

[209] The seed crystals may be prepared from amorphous compound prepared according to Example 2 using 2,2-difluoropropanoic acid, followed by purification on HPLC. The compound (401 mg) was weighed into a glass vial. Ethanol (0.4 mL) was added, and the vial was shaken and heated to 40°C to afford a clear, slightly yellow solution. Ethanol/Water (0.4 mL, 50/50% vol/vol) was added. Crystallization started to

occur within 5 min, and, after 10 min, a white thick suspension formed. The crystals were collected by filtration

/////////////AZD 9567, AstraZeneca, lucocorticoid receptor modulator, Rheumatoid arthritis, phase 1, Lena Elisabeth RIPA, Karolina Lawitz, Matti Juhani Lepistö, Martin Hemmerling, Karl Edman, Antonio Llinas

3rd speaker this afternoon in 1st time disclosures is Lena Ripa of @AstraZeneca on a glucocorticoid receptor modulator

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CC(F)(F)C(=O)N[C@@H](C(C)C)[C@H](Oc1cc2cnn(c2cc1)C=3C=CC(=O)N(C)C=3)c4ccccc4

AZD 7594


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Picture credit….

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AZD 7594

‘s asthma candidate

AZ13189620; AZD-7594

Bayer Pharma Aktiengesellschaft, Astrazeneca Ab

Molecular Formula: C32H32F2N4O6
Molecular Weight: 606.616486 g/mol

3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-(oxolan-3-yl)benzamide

Benzamide, 3-​[5-​[(1R,​2S)​-​2-​[(2,​2-​difluoro-​1-​oxopropyl)​amino]​-​1-​(2,​3-​dihydro-​1,​4-​benzodioxin-​6-​yl)​propoxy]​-​1H-​indazol-​1-​yl]​-​N-​[(3R)​-​tetrahydro-​3-​furanyl]​-
Cas 1196509-60-0

AZD-7594 is in phase II clinical trials by AstraZeneca for the treatment of mild to moderate asthma.

It is also in phase I clinical trials for the treatment of chronic obstructive pulmonary disorder (COPD).

https://clinicaltrials.gov/ct2/show/NCT02479412

Company AstraZeneca plc
Description Inhaled selective glucocorticoid receptor (GCCR) modulator
Molecular Target Glucocorticoid receptor (GCCR)
  • Phase II Asthma
  • Phase I Chronic obstructive pulmonary disease
  • 01 Feb 2016 AstraZeneca completes a phase II trial in Asthma in Bulgaria and Germany (Inhalation) (NCT02479412)
  • 09 Jan 2016 AstraZeneca plans to initiate a phase I trial in Healthy volunteers in USA (IV and PO) (NCT02648438)
  • 01 Jan 2016 Phase-I clinical trials in Chronic obstructive pulmonary disease (In volunteers) in USA (PO, IV, Inhalation) (NCT02648438)

PATENT

http://www.google.com/patents/WO2009142569A1

PATENT

US20100804345

UNWANTED ISOMER

str1

str1

WANTED COMPD

str1

str1

str1

PATENT

WO 2009142571

Example 6

WANTED ISOMER

Figure imgf000053_0002

3-(5- { TC 1 R,2SV2-r(2,2-difluoropropanoyl)aminol- 1 -(2,3-dihydro-l ,4-benzodioxin-6-5 yDpropylioxy) – 1 H-indazol- 1 -ylVN-[(3R)-tetrahydrofuran-3-vnbenzamide. APCI-MS: m/z 607 [MH+] 1H NMR ^OO MHz, DMSOd6) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d). LC (method A) rt = 12.03 min LC (method B) rt = 11.13 min Chiral SFC (method B) rt = 4.71 min M.p. = 177 °C

UNWANTED

Figure imgf000053_0001

o 3-(5- { IY 1 R,2S V2-r(2,2-difluoropropanoyl)amino|- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6- yl)propyl]oxy } – 1 H-indazol- 1 -yP-N-IO S)-tetrahydrofuran-3 -yl|benzamide

APCI-MS: m/z 607 [MH+]

1H NMR (400 MHz, DMSO-J6) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s),

7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H,s m), 5.17 (IH, d), 4.48 (IH, m), 4.24 – 4.11 (5H, m), 3.90 – 3.81 (2H, m), 3.72 (IH, td), 3.61

(IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (Method A) rt = 12.02 min

LC (Method B) rt = 11.12 min

Chiral SFC (method B) rt = 5.10 min o M.p. = 175 0C

PATENT

WO 2011061527

http://www.google.com/patents/WO2011061527A1?cl=en

Intermediate 12

( 1 R,2S)-2-amino- 1 -(2,3 -dihydrobenzo b [ 1 ,41dioxin-6-yl)propan- 1 -ol hydrochloride. (12)

Figure imgf000036_0001

5-6 N HC1 in 2-propanol (8 mL, 40-48 mmol) was added to tert-butyl (lR,2S)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxypropan-2-ylcarbamate (I2a) (3.1 g, 10.02 mmol) in ethyl acetate (40 mL) at 40°C and stirred for 3 hours. The reaction mixture was allowed to reach r.t. and was concentrated by evaporation. Ether was added and the salt was filtered off and washed with ether. The salt was found to be hygroscopic. Yield 2.10 g (85%)

APCI-MS: m/z 210 [MH+-HC1]

1H-NMR (300 MHz, DMSO-^): δ 8.01 (brs, 3H), 6.87-6.76 (m, 3H), 5.93 (brd, 1H), 4.79 (brt, 1H), 4.22 (s, 4H), 3.32 (brm, 1H), 0.94 (d, 3H).

tert-butyl (1R,2S)- 1 -(2,3-dihvdrobenzorbl Γ 1 ,41dioxin-6-yl)- 1 -hvdroxypropan-2-ylcarbamate.

Figure imgf000036_0002

The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction was made by the method described by Jingjun Yin et. al. J. Org. Chem. 2006, 71, 840-843.

(S)-tert-butyl 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)- 1 -oxopropan-2-ylcarbamate (I2b) (3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and 2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) were stirred at 50°C under argon for 16 hours. The reaction mixture was poured into 1M HC1 (150 mL) and the mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with water (2×50 mL) and brine (100 mL), dried over Na2SC”4, filtered and concentrated. The crude product was purified by flash- chromatography on silica using ethyl acetate/hexane (1/2) as eluent. Fractions containing product were combined. Solvent was removed by evaporation to give the desired product as a colourless solid. Yield 3.19 g (84%) APCI-MS: m/z 236, 210, 192 [MH -tBu-18, MH -BOC, MH -BOC- 18]

1H NMR (300 MHz, DMSO-^): δ 6.80-6.70 (m, 3H), 6.51 (d, IH), 5.17 (d, IH), 4.36 (t, IH),

4.19 (s, 4H), 3.49 (m, IH), 1.31 (s, 9H), 0.93 (d, 3H).

(S)-tert-butyl 1 -(2,3-dihydrobenzo[bl [ 1 ,41dioxin-6-yD- 1 -oxopropan-2-ylcarbamate. (I2b)

Figure imgf000037_0001

A suspension of (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) was placed under a protective atmosphere of argon and cooled down to -15 to -20°C. Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol), was added keeping the temperature below -10°C. The temperature was allowed to reach 0°C. A freshly prepared solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature was allowed to reach r.t. overnight. The reaction mixture was poured into ice cooled IN HC1 (300 mL). TBME (300 mL) was added and the mixture was transferred to a separation funnel. The water phase was back extracted with TBME (200 mL). The ether phases were washed with water, brine and dried (Na2S04). The crude product was purified by flash chromatography using TBME /Heptane 1/2 as eluent. Fractions containing the product were combined and solvents were removed by evaporation to give the subtitle compound as a slightly yellow sticky oil/gum. Yield 3.76g

(95%)

APCI-MS: m/z 208 [MH+ – BOC]

1H NMR (300 MHz, DMSO-^): δ 7.50 (dd, IH), 7.46 (d, IH), 7.24 (d, IH), 6.97 (d, IH), 4.97 (m, IH), 4.30 (m, 4H), 1.36 (s, 9H), 1.19 (d, 3H).

Intermediate 13

(lR,2S)-2-amino-l-(4H-benzo[dl[l,31dioxin-7- l)propan-l-ol hydrochloride (13)

Figure imgf000037_0002

Tert-butyl ( 1 R,2S)- 1 -(4H-benzo[d] [ 1 ,3]dioxin-7-yl)- 1 -hydroxypropan-2-ylcarbamate (I3b) (403 mg, 1.30 mmol) was dissolved in ethyl acetate (5 mL) and 5-6 N HC1 solution in 2- propanol (1.5 mL, 7.5-9 mmol) was added. The mixture was stirred at 50 °C for 1.5 hours. The solvents was removed by evaporation. The residual sticky gum was treated with ethyl acetate and evaporated again to give a solid material that was suspended in acetonitrile and stirred for a few minutes. The solid colourless salt was collected by filtration and was found to be somewhat hygroscopic. The salt was quickly transferred to a dessicator and dried under reduced pressure. Yield 293 mg (92%)

APCI-MS: m/z 210 [MH+ -HC1]

1H NMR (300 MHz, DMSO-^) δ 8.07 (3H, s), 7.05 (IH, d), 6.92 (IH, dd), 6.85 (IH, d), 6.03 (IH, d), 5.25 (2H, s), 4.87 (3H, m), 3.42 – 3.29 (IH, m), 0.94 (3H, d).

(4S.5R -5-(4H-benzordiri.31dioxin-7-vn- -methyloxazolidin-2-one (I3a

Figure imgf000038_0001

A mixture of (lR,2S)-2-amino-l-(4H-benzo[d][l,3]dioxin-7-yl)propan-l-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at r.t. for 2 hours. The reaction mixture was concentrated by evaporation and the residual material was partitioned between ethyl acetate and water. The organic phase was washed with 10% NaHS04, dried over MgS04, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)

The relative cis conformation of the product was confirmed by comparing the observed 1H- NMR with the literature values reported for similar cyclised norephedrine (Org. Lett. 2005 (07), 13, 2755-2758 and Terahedron Assym. 1993, (4), 12, 2513-2516). In a 2D NOESY experiment a strong NOE cross-peak was observed for the doublet at 5.64 with the multiplet at 4.19 ppm. This also confirmed the relative czs-conformation.

APCI-MS: m/z 236 [MH+]

1H NMR (400 MHz, CDC13) δ 6.99 (d, J= 8.0 Hz, IH), 6.88 (dd, J= 8.0, 1.4 Hz, IH), 6.83 (s, IH), 5.81 (brs,lH), 5.64 (d, J= 8.0 Hz, IH), 5.26 (s, 2H), 4.91 (s, 2H), 4.19 (m, IH), 0.85 (d, J = 6.4 Hz, 3H). Tert-butyl ( 1 R,2S)- 1 -(4H-benzord1 Γ 1 ,31dioxin-7-yl)- 1 -hvdroxypropan-2-ylcarbamate (I3b)

Figure imgf000039_0001

A mixture (S)-tert-butyl l-(4H-benzo[d][l,3]dioxin-7-yl)-l-oxopropan-2-ylcarbamate (I3c) (680 mg, 2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3 mL, 38.9 mmol) in toluene (3 mL) was stirred at 65 °C for 15 hours. The reaction mixture was allowed to cool down, poured into 1M HC1 (50 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was washed with water, brine, dried over MgS04, filtered and solvents were removed by evaporation to afford a colourless solid. The crude product was purified by flash chromatography, (solvent A = Heptane, solvent B = EtOAc + 10% MeOH. A gradient of 10%B to 50%B in A was used). The obtained product was crystallised from DCM / heptane to afford the subtitle compound as colourless needles. Yield 414 mg (60%)

APCI-MS: m/z 210 [MH+ -BOC]

1H NMR (400 MHz, DMSO- ¾ δ 6.97 (1H, d), 6.88 (1H, d), 6.77 (1H, s), 6.56 (1H, d), 5.27 (1H, d), 5.22 (2H, s), 4.83 (2H, s), 4.44 (1H, t), 3.53 (1H, m), 1.32 (9H, s), 0.93 (3H, d). (S)-Tert-butyl 1 -(4H-benzord1 Γ 1 ,31dioxin-7-vD- 1 -oxopropan-2-ylcarbamate (I3c)

Figure imgf000039_0002

7-Bromo-4H-benzo[d][l,3]dioxine (1 g, 4.65 mmol) was dissolved in THF (5 mL) and added to magnesium (0.113 g, 4.65 mmol) under a protective atmosphere of argon. One small iodine crystal was added. The coloured solution was heated with an heat gun in short periods to initiate the Grignard formation. When the iodine colour vanished the reaction was allowed to proceed at r.t. for 1.5 hours.

In a separate reaction tube (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2- ylcarbamate (1 g, 4.31 mmol) was suspended in THF (5 mL) and cooled in an ice/acetone bath to below -5 °C. Isopropylmagnesium chloride, 2M solution in THF (2.5 mL, 5.00 mmol) was slowly added to form a solution. To this solution was added the above freshly prepared Grignard reagent. The mixture was allowed to reach r.t. and stirred for 4 hours. The reaction mixture was slowly poured into ice-cold 150 mL 1M HC1. Ethyl acetate (150 mL) was added and the mixture was stirred for a few minutes and transferred to a separation funnel. The organic phase was washed with water and brine, dried over MgS04, filtered and concentrated. The obtained crude product was further purified by flash chromatography using a prepacked 70g silica column with a gradient of 10% TBME to 40% TBME in heptane as eluent. The subtitle compound was obtained as a colourless solid. Yield 790 mg (59%>)

APCI-MS: m/z 208 [MH+ -BOC]

1H NMR (400 MHz, DMSO-^) δ 7.53 (IH, dd), 7.39 (IH, s), 7.30 (IH, d), 7.22 (IH, d), 5.30 (2H, s), 4.98 (IH, m), 4.95 (2H, s), 1.35 (9H, s), 1.20 (3H, d).

Preparation 4

3-(5-([(lR,2S)-2-[(2,2-difluoropropanoyl)aminol-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy| – 1 H-indazol- 1 -yl)-N-[(3R)-tetrahydrofuran-3-yllbenzamide

Figure imgf000051_0001

TEA (2.0 g, 20.65 mmol) was added to a mixture of 3-(5-((lR,2S)-2-(2,2- difluoropropanamido)- 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)propoxy)-l H-indazol-1 – yl)benzoic acid (14) (3.6 g, 6.70 mmol), (R)-tetrahydrofuran-3 -amine hydrochloride (0.99 g, 8.0 mmol) and HBTU (2.65 g, 6.99 mmol) in DCM (15 mL). The reaction was stirred at r.t. for 3h, then quenched by addition of a mixture of water and ethyl acetate. The mixture was shaken and the organic layer was collected. The water phase was extracted twice with ethyl acetate. The combined organic layers were washed with a small portion of water and dried over magnesium sulphate. The product was purified by flash chromatography (silica, eluent: a gradient of ethyl acetate in heptane). The residue was crystallized by dissolving in refluxing acetonitrile (50 mL) and then allowing to cool to r.t. over night. The solid was collected by filtration, washed with a small volume of acetonitrile and dried at 40°C in vaccum to give the title compound (2.5 g, 61%).

APCI-MS: m/z 607 [MH+]

1H NMR (400 MHz, DMSO-d6) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (method A) rt = 12.03 min

LC (method B) rt = 11.13 min

Chiral SFC (method B) rt = 4.71 min

M.p. = 177 °C

Patent ID Date Patent Title
US2015080434 2015-03-19 PHENYL AND BENZODIOXINYL SUBSTITUTED INDAZOLES DERIVATIVES
US8916600 2014-12-23 Phenyl and benzodioxinyl substituted indazoles derivatives
US8211930 2012-07-03 Phenyl and Benzodioxinyl Substituted Indazoles Derivatives

REFERENCES

https://www.astrazeneca.com/content/dam/az/press-releases/2014/Q2/Pipeline-table.pdf

////////AZD 7594, AZ13189620, AZD-7594 , phase 2, astrazeneca, 1196509-60-0

c21cc(ccc1n(nc2)c3cc(ccc3)C(=O)NC4COCC4)O[C@H](c5cc6c(cc5)OCCO6)[C@@H](NC(=O)C(F)(F)C)C

CC(C(C1=CC2=C(C=C1)OCCO2)OC3=CC4=C(C=C3)N(N=C4)C5=CC=CC(=C5)C(=O)NC6CCOC6)NC(=O)C(C)(F)F

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AZD 2716


str1

AZD2716

CAS 1845753-81-2
MF C24 H23 N O3,   MW 373.44
[1,1′-Biphenyl]-3-propanoic acid, 2′-(aminocarbonyl)-α-methyl-5′-(phenylmethyl)-, (αR)-
Antiplaque candidate drug

AstraZeneca INNOVATOR

(R)-7(AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Chiral HPLC using a Chiralcel OJ 5 μm 20×250 mm
column with heptane/EtOH/formic acid ((10:90:0.1; 15 ml/min, 40 °C, 260 nm) as mobile
phase to yield (S)-7 and (R)-7

(R)-7:tR=5.8 min [α]D20 15.4 (c 0.5, ACN), 99.7 %ee. desired

(S)-7: tR=9.2 min. 99.0 % ee. undesired

LINK

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00188

SYNTHESIS

 

op-2015-00382y_0007.gif

1H NMR (400 MHz, DMSO-d6): δ 1.04 (d, J = 6.6 Hz, 3H), 2.55–2.68 (m, 2H), 2.95 (dd, J = 6.1, 12.8 Hz, 1H), 4.00 (s, 2H), 7.13–7.37 (m, 13H), 7.49–7.54 (m, 1H), 12.2 (s, br, 1H).

13C NMR (151 MHz, DMSO): δ 16.7, 39.1, 40.7, 41.0, 126.3, 126.4, 127.3, 127.8, 128.0, 128.2, 128.7, 128.9, 129.2, 130.3, 135.3, 139.2, 139.5, 140.5, 141.2, 142.7, 171.3, 177.1.

HRMS (ESI): [M + H]+ m/z calcd for C24H24NO3 374.1751, found 374.1748.

1H NMR

 

str1

str1

13C NMR

An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

CVMD iMed, Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden
SP Process Development, Box 36, SE-151 21 Södertälje, Sweden
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00382………..http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00382
STR1

A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

 

Paper

Abstract Image

Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7(AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease

Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit Departments of Medicinal Chemistry, Bioscience, §DMPK, Discovery Sciences Departments of Structure & Biophysics, Reagents and Assay Development, and #Screening Sciences and Sample Management, Astrazeneca, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00188
*(F.G.) Phone: +1-212-4780-822. E-mail: fabrizio.giordanetto@deshawresearch.com., *(D.P.) Phone: +46 31 7065 663. E-mail:daniel.pettersen@astrazeneca.com.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00188

STR1

str2

akenoic acid as a key step in the sysnthesis of AZD2716. Org. Proc. Res. Dev. 2016, 20(2),
262-269).

/////////atherosclerosis,  coronary artery disease,  fragment screening,  fragment-based drug discovery,   Secreted phospholipase A2,  sPLA2,  AZD2716, AZD-2716, AZD 2716, PRECLINICAL

c1c(cc(c(c1)C(=O)N)c2cccc(c2)CC(C(=O)O)C)Cc3ccccc3

Vandetanib


 

 

Vandetanib2DACS.svg

 

Vandetanib; 443913-73-3; Zactima; ZD6474; Caprelsa; ZD 6474; ch 331, azd 6474

cas 338992-00-0 free form
338992-48-6 HCl
338992-53-3 monotrifluoroacetate

N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-amine

Vandetanib (INN, trade name Caprelsa) is an anti-cancer drug that is used for the treatment of certain tumours of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), theepidermal growth factor receptor (EGFR), and the RET-tyrosine kinase.[1][2] The drug was developed by AstraZeneca.

Orphan drug designation has been assigned in the E.U. for the treatment of medullary thyroid carcinoma. In 2005, orphan drug designation was also assigned in the U.S. for several indications, including treatment of patients with follicular thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, and locally advanced and metastatic papillary thyroid carcinoma. In 2013, orphan drug designation has been assigned in Japan as well for the treatment of thyroid cancer.

 

Vandetanib.png

Approvals and indications

Vandetanib was the first drug to be approved by FDA (April 2011) for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.[3] Vandetanib was first initially marketed without a trade name,[4] and is being marketed under the trade name Caprelsa since August 2011.[5]

Vandetanib is an orally active vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) tyrosine kinase inhibitor, originally developed by AstraZeneca, which was filed for approval in the U.S. and the E.U. for the treatment of non-small cell lung cancer (NSCLC) in combination with chemotherapy, in patients previously treated with one prior anticancer therapy.

However, in late 2009 the company withdrew both the U.S and the EU applications. In 2010, AstraZeneca discontinued development of this compound for the treatment of NSCLC. In 2011, the FDA approved vandetanib for the treatment of medullary thyroid cancer. Also in 2011, a positive opinion was assigned to the regulatory application filed in the E.U. for this indication and in Japan was filed for approval.

Final EMA approval was granted in February 2012 and first E.U. launch took place in the U.K. in 2012.

2011 年 4 月 6 by the FDA-approved surgical resection can not be used for locally advanced or metastatic medullary thyroid cancer (medullary thyroid cancer, MTC) of the drug. Vandetanib is vascular endothelial growth factor receptors (vascular endothelial growth factor receptor, VEGFR) and epidermal growth factor receptor (epidermal growth factor receptor, EGFR) antagonists, tyrosine kinase inhibitors (tyrosine kinase inhibitor). Produced by AstraZeneca.

The synthetic route is as follows:

 

………………

 

 

………………………..

 ……….

Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors
J Med Chem 1999, 42(26): 5369

http://pubs.acs.org/doi/abs/10.1021/jm990345w

 

 

………………………

Radiosynthesis of [(11)C]Vandetanib and [(11)C]chloro-Vandetanib as new potential PET agents for imaging of VEGFR in cancer
Bioorg Med Chem Lett 2011, 21(11): 3222

Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors
J Med Chem 2002, 45(6): 1300

A novel approach to quinazolin-4(3H)-one via quinazoline oxidation: An improved synthesis of 4-anilinoquinazolines
Tetrahedron 2010, 66(4): 962

………………………………

CN 104098544

http://www.google.com/patents/CN104098544A?cl=en

Vandetanib is a synthetic Anilinoquinazoline, advanced medullary thyroid cancer can not be used for the treatment of surgical treatment (medullary thyroid cancer), chemical name: 4- (4-bromo-2- fluoroanilino) _6_ methoxy -7 – [(l- methylpiperidin-4-yl) methoxy] quinazoline, having the following structural formula I:

 

Figure CN104098544AD00031

[0004] The present method of synthesizing the compound are as follows:

[0005] US Patent US7173038 AstraZeneca announced the following methods:

[0006] Method One:

[0007]

Figure CN104098544AD00032

Method two:

 

Figure CN104098544AD00041

 A structure in which the synthesis of compounds of formula as follows:

 

Figure CN104098544AD00042

the process is cumbersome, long synthetic route, therefore a need to provide a new synthetic way to overcome these problems.

An aspect provides a compound having the structure of formula II:

 

Figure CN104098544AD00043

 Another aspect provides a process for preparing a compound of the structural formula II, a compound of formula III with a compound of formula IV in the presence of a base to give a compound of the structural formula II,

 

Figure CN104098544AD00051

where Μ for methylphenylsulfonyl, methylsulfonyl.

Example: 4- (4-bromo-2-fluoroanilino) -6_ methoxy-7 – [(1-formyl-4-yl) methoxy] quinazoline preparation

[0026] in 50mL two-neck flask was added 4- (4-bromo-2-fluoroanilino) -6-methoxy-7-hydroxy-quinazoline (3. 64g, 0 · Olmol), 1- formyl- 4-p methylsulfonyloxy- methylpiperazine steep (3. 56g, 0 · 012mol) and potassium carbonate (4. 14g, 0.03mol), yellow turbid solution was stirred and heated to 100 ° C, TLC detection to feed completion of the reaction. Down to room temperature, the reaction mixture was slowly poured into l〇〇mL water, stirred, filtered, then the filter cake was washed with 50mL water, 15mL of ethyl acetate and then slurried, filtered and dried to give a pale green solid 4- (4- bromo-2-fluoroanilino) -6-methoxy -7 – [(l- carboxylic acid piperidin-4-yl) methoxy] quinazoline 3. 9g, 80% yield.

[0027] ^ NMR (400Mz, DMS0): δ = 1 1〇-1 29 (m, 2H), δ = 1 40-1 43 (m, 2H), δ = 2 15 (s,….. 1H), δ = 2. 64-2. 73 (m, 1H), δ = 3. 06-3. 12 (m, 1H), δ = 3. 71-3. 74 (d, 1H), δ = 3. 95 (s, 3H), δ = 4 • 03-4. 05 (d, 2H), δ = 4. 20-4. 23 (d, 1H), δ = 7. 20 (s, 1H), δ = 7. 46-7. 48 (m, 1H), δ = 7. 51-7 • 53 (m, 1H), δ = 7. 65-7. 67 (d, 1H), δ = 7. 80 (s, 1H), δ = 8. 01 (s, 1H), δ = 8. 35 (s, 1H), δ = 9. 54 (s, 1H).

[0028] Example 2: Preparation of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7 – [(1-methyl-piperidin-4-yl) methoxy] quinazoline preparation

[0029] 4- (4-bromo-2-fluoroanilino) in 100mL three-necked flask, 6-methoxy-7 – [(1-formyl-4-yl) methoxy] quinoline oxazoline (0 · 98g, 2. Ommol), zinc (0 · 6g, 4. 4mmol) and tetrahydrofuran (20mL), stirred pale yellow turbid liquid. At room temperature was added portionwise sodium borohydride (0. 15g, 4. OmmoL), little change in the temperature. Heating
……………………………….

CN 104211649

http://www.google.com/patents/CN104211649A?cl=en

Pharmacokinetics

Vandetanib is well absorbed from the gut, reaches peak blood plasma concentrations 4 to 10 hours after application, and has a half-life of 120 hours days on average, per Phase I pharmacokinetic studies. It has to be taken for about three months to achieve a steady-state concentration. In the blood, it is almost completely (90–96%) bound to plasma proteins such as albumin. It is metabolised to N-desmethylvandetanib via CYP3A4 and to vandetanib-N-oxide via FMO1 and 3. Both of these are active metabolites. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites.[2][9][10]

Metabolites of vandetanib (top left): N-desmethylvandetanib (bottom left, via CYP3A4), vandetanib-N-oxide (bottom right, via FMO1 andFMO3), both pharmacologically active, and a minor amount of aglucuronide.[10]

Clinical trials

Non-small cell lung cancer

The drug underwent clinical trials as a potential targeted treatment for non-small-cell lung cancer. There have been some promising results from a phase III trial withdocetaxel.[11] There have also been ambivalent results when used with pemetrexed.[12] Another trial with docetaxel was recruiting in July 2009.[13]

AstraZeneca withdrew EU regulatory submissions for vandetanib (under the proposed trade name Zactima) in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy.[14]

References

  1.  “Definition of vandetanib”. NCI Drug Dictionary. National Cancer Institute.
  2.  “Vandetanib Monograph”. Drugs.com. Retrieved 29 August 2012.
  3. “FDA approves new treatment for rare form of thyroid cancer”. Retrieved 7 April 2011.
  4.  “FDA approves orphan drug vandetanib for advanced medullary thyroid cancer” (Press release). AstraZeneca. Retrieved 2011-08-17.
  5.  “AstraZeneca announces trade name CAPRELSA® for vandetanib” (Press release). AstraZeneca. Retrieved 2011-08-17.
  6.  Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.”. Drug Metabol Drug Interact.0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID 24643910.
  7. Haberfeld, H, ed. (2012). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  8.  Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11.doi:10.1515/dmdi-2014-0014. PMID 24807167.
  9.  Martin, P.; Oliver, S.; Kennedy, S. J.; Partridge, E.; Hutchison, M.; Clarke, D.; Giles, P. (2012). “Pharmacokinetics of Vandetanib: Three Phase I Studies in Healthy Subjects”.Clinical Therapeutics 34 (1): 221–237. doi:10.1016/j.clinthera.2011.11.011.PMID 22206795.
  10. “Clinical Pharmacology Review: Vandetanib” (PDF). US Food and Drug Administration, Center for Drug Evaluation and Research. 20 August 2010. Retrieved29 August 2012.
  11.  “Vandetanib Shows Clinical Benefit When Combined With Docetaxel For Lung Cancer”. ScienceDaily. 3 June 2009.
  12.  “IASLC: Vandetanib Fails to Improve NSCLC Outcomes with Pemetrexed”. Medpage today. 5 Aug 2009.
  13.  Clinical trial number NCT00687297 for “Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer” at ClinicalTrials.gov
  14.  “Zactima”. European Medicines Agency.

External links

 

 

Vandetanib
Vandetanib2DACS.svg
Systematic (IUPAC) name
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
Clinical data
Trade names Caprelsa
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a611037
Licence data US FDA:link
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Protein binding 90–96%
Metabolism CYP3A4, FMO1, FMO3
Biological half-life 120 hours (mean)
Excretion 44% faeces, 25% urine
Identifiers
CAS Registry Number 443913-73-3 
ATC code L01XE12
PubChem CID: 3081361
IUPHAR/BPS 5717
DrugBank DB08764 Yes
ChemSpider 2338979 Yes
UNII YO460OQ37K Yes
ChEBI CHEBI:49960 Yes
ChEMBL CHEMBL24828 Yes
Synonyms ZD6474
Chemical data
Formula C22H24BrFN4O2
Molecular mass 475.354 g/mol

//////

AZD 3264 an IKK2 Inhibitor from Astra Zeneca


 

 

 

Figure

AZD 3264

MW 441.50

CAS 1609281-86-8

MF C21 H23 N5 O4 S
3-​Thiophenecarboxamide​, 2-​[(aminocarbonyl)​amino]​-​5-​[4-​(3,​5-​dimethyl-​4-​isoxazolyl)​-​2-​[(3S)​-​3-​pyrrolidinyloxy]​phenyl]​-
2-(Carbamoylamino)-5-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(3S)-pyrrolidin-3-yloxy]phenyl]thiophene-3-carboxamide

Inhibition of IkB-kinase IKK2 has been identified as one of the novel pathways to treat inflammatory conditions such as asthma, chronic pulmonary obstructive disorder (COPD) and rheumatoid arthritis

Astrazeneca Ab,

……………………..

PATENT

WO 2003010158

https://www.google.com/patents/WO2003010158A1?cl=en

 

Figure

 

The synthesis began with the aromatic nucleophilic substitution reaction of 2-fluorobromobenzene (2) with (S)-N-Boc-3-pyrrolidinol 3 to give the bromo intermediate 4, which was borylated via halogen metal exchange using n-hexLi in THF followed by treatment with triisopropyl borate and acidic work-up to give the boronic acid intermediate 5. Suzuki coupling of the boronic acid 5 with bromothiophene 6(2)afforded the intermediate 7. Intermediate 7 was subjected to regioselective bromination using bromine in acetic acid. This reaction was nonregioselective and yielded 17% of the required isomer 8. The bromo compound 8 was coupled with isoxazole boronate ester 9 by another Suzuki reaction to get the title compound. The overall yield of the synthesis was <6%.

 

 

………………………..

PAPER

Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op500105n

http://pubs.acs.org/doi/full/10.1021/op500105n

 

Abstract Image

An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially available fragments.

AZD3264 (1)

A stirred solution of tert-butyl (3S)-3-[2-(4-carbamoyl-5-methyl-2-thienyl)-5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-carboxylate (16) (2.65 kg, 4.63 mol) in tetrahydrofuran (25 L) w……………………………………………………title compound in 91% yield.
Purification

To a stirred suspension of crude AZD3264 (1) (1.75 kg, 3.98 mol) in methanol (23.75 L) and water (2.64 L) was added formic acid (0.24 kg, 5.18 mol), and the mixture was heated to 40 °C for 1.5 h, cooled to 25 °C, and basified with aqueous ammonia (12.29 M in water, 1.62 L, 19.92 mol). The product was isolated by filtration.
 1H NMR (DMSO-d6, 400 MHz): δ 1.92–2.10 (m, 2H), 2.28 (s, 3H), 2.46 (s, 3H), 2.75–2.82 (m, 1H), 3.00–3.12 (m, 3H), 5.11–5.12 (m, 1H), 6.90 (br, 2H), 7.00–7.03 (m, 2H), 7.30 (br, 1H), 7.70–7.72 (m, 2H), 7.83 (s, 1H), 10.93 (s, 1H).
 13C NMR (DMSO-d6, 100.6 MHz): δ 10.54, 11.42, 32.94, 45.51, 53.00, 79.37, 111.76, 114.17, 115.66, 120.70, 121.20, 122.77, 125.39, 126.92, 128.84, 150.12, 152.54, 154.50, 158.13, 165.14, 167.06.
DEPT NMR (DMSO-d6, 100.6 MHz): δ 10.54, 11.43, 32.94, 45.51, 53.01, 79.35, 114.17, 120.70, 121.20, 126.92.
HRMS calcd for C21H24N5O4S (M + H)+: 442.1543, found 442.1554.
[α]25D −13.80 (c 0.5, DMSO)
 
Journal of Medicinal Chemistry (2013), 56(18), 7232-7242 reports similar analogues

Daiichi partners with AZ to sell Movantik in US…….Pharmatimes, Selina McKee


Naloxegol.svg
Naloxegol
Daiichi partners with AZ to sell Movantik in US 
March 19, 2015

Selina McKee

News editor, Selina McKee

Selina McKee

Qualified from King’s College London with BSc (hons) in Human Biology in 1999 with an interest in medical journalism. Has since held positions as a database analyst managing a portfolio of companies at Evaluate Pharma, and as news editor at Pharma Marketletter. Fluent German speaker, interests include music, piano, reading, astronomy, photography and Formula 1.

Daiichi partners with AZ to sell Movantik in US

AstraZeneca has chosen Daiichi Sankyo to help sell its novel constipation drug Movantik (naloxegol) in the US, as the firm gears up for its launch in April.

First-in-class Movantik was cleared in the US last September for the treatment of opioid-induced constipation in adults with chronic non-cancer pain, for which there is still significant unmet need.

PharmaTimes Magazine and Digital offer a unique blend of news stories, interviews, features, case studies, analysis and comment on the critical issues facing the pharma and healthcare sectors. Our wide editorial lens combined with our editorial philosophy to deliver sharp, informed and entertaining coverage from the perspective of the industry, the payer and the patient, allows PharmaTimes to help kickstart conversations that matter most to our audience of decision makers within pharma and the healthcare profession.PharmaTimes Competitions are a critical facet of our business, providing a unique opportunity for industry to showcase its most talented people in marketing, communications, sales and clinical research. No other competitions offer entrants the chance to compete head-to-head in real-life challenges devised by independent industry and healthcare experts, to test their skill sets against their peers in real time, and receive feedback to ensure the whole experience is a valuable learning process.

 Selina McKee

Selina McKee

Editor, UK News at PharmaTimes

London, United Kingdom
Pharmaceuticals
uk.linkedin.com/pub/selina-mckee/4/174/339/en

Experience

Editor, UK News

PharmaTimes

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Evaluate Pharma

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King’s College London, U. of London

BSc (Hons) Human Biology

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Selina McKee

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Registered in England & Wales at:
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more………….

LINKEDIN

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Authors – PharmaTimes

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EMA approves AstraZeneca’s lesinurad to treat gout patients


EMA approves AstraZeneca’s lesinurad to treat gout patients
British-Swedish drugmaker AstraZeneca has received approval from European Medicines Agency (EMA) for its lesinurad 200mg tablets to treat gout patients. READ AT…..[LINK]

 

 

SYNTHESIS………..https://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/

“The company submitted a MAA based on data from the Clear1, Clear2 and Crystal pivotal Phase III combination therapy studies.”

AstraZeneca’s subsidiary Ardea Biosciences carried out Clear1, Clear2 and Crystal trials.

 

LESINURAD

SYNTHESIS………..https://newdrugapprovals.org/2013/03/13/phase-3-ongoing-lesinurad-monotherapy-in-gout-subjects-intolerant-to-xanthine-oxidase-inhibitors-light/

Lesogaberan


Lesogaberan.svg

Lesogaberan

AZD-3355, AZD3355, [(2R)-3-amino-2-fluoropropyl]phosphinic acid, 344413-67-8
Molecular Formula: C3H8FNO2P+
Molecular Weight: 140.073285 g/mol
[(2R)-3-amino-2-fluoropropyl]-hydroxy-oxophosphanium

Lesogaberan (AZD-3355) was[1] an experimental drug candidate developed by AstraZeneca for the treatment of gastroesophageal reflux disease (GERD).[2] As a GABAB receptor agonist,[3] it has the same mechanism of action as baclofen, but is anticipated to have fewer of the central nervous system side effects that limit the clinical use of baclofen for the treatment of GERD.[4]

http://pubs.acs.org/doi/abs/10.1021/jm701425k

J. Med. Chem., 2008, 51 (14), pp 4315–4320
DOI: 10.1021/jm701425k
Abstract Image

We have previously demonstrated that the prototypical GABAB receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABAB agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABAB agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABAB agonists devoid of classical GABAB agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (R)-7 (AZD3355) that is presently being evaluated in man.

(2R)-(3-Amino-2-fluoropropyl)phosphinic Acid ((R)-7)

(R)-7 as a white solid (3.12 g, 24%):
mp = 183−185 °C;
1H NMR (300 MHz, D2O) δ 7.90 (s, 0.5 H), 6.15 (s, 0.5 H), 5.12−5.29 (m, 0.5 H), 4.92−5.10 (m, 0.5 H), 3.12−3.42 (m, 2H), 1.74−2.26 (m, 2H);
[α]D25 −4.0° (c 1.0, H2O);
APIMS m/z 142 [M + H]+. Anal. (C3H9FNO2P·0.25H2O) C, H, N.

Lesogaberan.png

References

  1. AstraZeneca. “AZD3355”. Retrieved 30 December 2011.
  2. Bredenoord, Albert J. (2009). “Lesogaberan, a GABAB agonist for the potential treatment of gastroesophageal reflux disease”. IDrugs 12 (9): 576–584. PMID 19697277.
  3. Alstermark, et al.; Amin, K; Dinn, SR; Elebring, T; Fjellström, O; Fitzpatrick, K; Geiss, WB; Gottfries, J et al. (2008). “Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors”. Journal of Medicinal Chemistry 51 (14): 4315–4320. doi:10.1021/jm701425k. PMID 18578471.
  4. Brian E. Lacy, Robert Chehade, and Michael D. Crowell (2010). “Lesogaberan”. Drugs of the Future 35 (12): 987–992. doi:10.1358/dof.2010.035.012.1540661.
Lesogaberan
Lesogaberan.svg
Identifiers
CAS number 344413-67-8 Yes=  Yes
PubChem 9833984
ChemSpider 23254384 
UNII 4D6Q6HGC7Z Yes
ChEMBL CHEMBL448343 
Jmol-3D images Image 1
Properties
Molecular formula C3H9FNO2P
Molar mass 141.08 g mol−1

Olaparib オラパリブ 奥拉帕尼 (AZD-2281, trade name Lynparza) AZ’ first-in-class PARP inhibitor wins EU nod


Olaparib.png

Olaparib

オラパリブ

奥拉帕尼

Women suffering from advanced relapsed BRCA-mutated ovarian cancer could gain access to a new treatment option after European regulators waved through AstraZeneca’s Lynparza (olaparib).

The European Commission has approved the first-in-class PARP inhibitor for the maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete response or partial response to platinum-based chemotherapy.

read at……http://www.pharmatimes.com/Article/14-12-18/AZ_first-in-class_PARP_inhibitor_Lynparza_wins_EU_nod.aspx


Olaparib.png
4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one, cas  763113-22-0

Kudos Pharmaceuticals Limited

Olaparib, AZD2281,  AZD2281

KU-0059436
KU-59436

Olaparib (AZD-2281, trade name Lynparza) is an experimental chemotherapeutic agent, developed by KuDOS Pharmaceuticalsand later by AstraZeneca, that is currently undergoing clinical trials. It is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.[1] It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers.

Olaparib is an oral poly-ADP-ribose polymerase (PARP) enzyme inhibitor developed by AstraZeneca. The product is awaiting registration in the E.U. and US as a maintenance treatment of patients with BRCA mutated platinum-sensitive relapsed serous ovarian cancer. In 2014, positive opinion was received in the E.U. recommending Lynparza approval for the maintanance treatment of BRCA mutated platinum-sensitive relapsed serous ovarian cancer.

An oral poly (ADP ribose) polymerase (PARP) inhibitor being investigated by British drug company AstraZeneca, is seeking approval from the U.S. Food and Drug Administration (FDA) for the treatment of BRCA mutated platinum-sensitive relapsed ovarian cancer. AstraZeneca filed the US regulatory submission for olaparib in February 2014.  Olaparib, one of several cancer drugs AstraZeneca flagged as having strong potential in its defense of a $118 billion take-over bid by Pfizer,was accepted for priority review on April 30, 2014  by the U.S.  Food and Drug Administration (FDA). The NDA filing was based on Phase II study 19 data, a randomized, double-blind, placebo-controlled, Phase II study.

On June 25, 2014, FDA Oncologic Drugs Advisory Committee (ODAC), an advisory panel to the U.S. Food and Drug Administration (FDA),  voted 11 to two against the accelerated approval of the PARP inhibitor olaparib as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer who have the germline BRCA (gBRCA) mutation, and who are in complete or partial response to platinum-based chemotherapy. By voting no, the committee recommended waiting for results from the larger confirmatory phase III SOLO-2 trial, which began enrolling in September 2013. According to clincialtrials.gov, the SOLO-2 study (NCT01874353) is slated to wrap in July 2015.

In terms of clinical development, phase III trials are ongoing at AstraZeneca for the treatment of gastric cancer and metastatic breast cancer. Olaparib is also in phase II clinical studies for several indications, including breast cancer, pancreatic cancer and castration-resistant prostate cancer. In March 2014, a phase II was also initiated in GB for the treatment of patients with stage IIIB or stage IV NSCLC that is not amenable to curative therapy. A phase I clinical trial for the treatment of melanoma has been completed. Phase II clinical trials are ongoing at General Hospital Corp. for the treatment of sarcoma. The drug had been in phase II clinical trials for the treatment of colorectal cancer; however no recent developments have been reported.

Discovered by KuDOS Pharmaceuticals, has experienced several twists and turns during its clinical development. Promising results for the drug were reported at the 2011 ASCO Annual Meeting, based on impressive early phase II results, only to have clinical development discontinued later that year after disappointing phase II trial results in a more generalized group of ovarian cancer patients. However, a re-analysis of the data in BRCA-positive patients – coupled with a reformulation of the drug – convinced the British drugmaker to think again and keep it going. AstraZeneca initiates Phase III clinical studies (SOLO 1 and SOLO 2) for olaparib in the U.S. in September 2013. AstraZeneca has filed Marketing Authorisation Application (MAA) for olaparib in EU in September 2013 based on Phase II study 19 data. The U.S. Food and Drug Administration has already granted olaparib orphan drug status for ovarian cancer and will hold an advisory panel hearing on the company’s application on June 25, 2014.

In 2013, orphan drug designation in the U.S. was assigned to the compound for the treatment of ovarian cancer. The compound was originally developed by Kudos Pharmaceuticals, which was acquired by AstraZeneca in 2006.

Early Phase I trials were promising, and olaparib underwent Phase II trials. However, in December 2011, AstraZeneca announced following interim analysis of a phase-II study which indicated that the previously reported progression free survival benefit was unlikely to translate into an overall survival benefit, that it would not progress into Phase III development for the maintenance treatment of serous ovarian cancer,[2] and took a charge of $285 million. The decision to discontinue development of the drug was reversed in 2013,[3] with AstraZeneca posting a new Phase III trial of Olaparib for patients with BRCA mutated ovarian cancer in April 2013.[4]

Mechanism of action

Olaparib acts as an inhibitor of the enzyme Poly ADP ribose polymerase (PARP) and is one of the first PARP inhibitors. Patients with BRCA1/2 mutations may be genetically predisposed to developing some forms of cancer, and are often resistant to other forms of cancer treatment, but this also sometimes gives their cancers a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of significant benefit in patients whose cancers are susceptible to this treatment.[5][6][7][8][9][10]

Trial results

Phase I clinical trials, in patients with BRCA-mutated tumors including ovarian cancer, were encouraging.[11] In one of these studies, it was given to 19 patients with inherited forms of advanced breast, ovarian and prostate cancers caused by mutations of the BRCA1 and BRCA2 genes. In 12 of the patients, none of whom had responded to other therapies, tumours shrank or stabilised.[12] One of the first patients to be given the treatment (who had castration-resistant prostate cancer) was as of July 2009 still in remission after two years.

In 2009 Phase II clinical trials examining the efficacy of Olaparib in treating breast, ovarian and colorectal cancer were initiated.[13][14] A phase II trial that included 63 cases of ovarian cancer concluded that olaparib is promising for women with ovarian cancer. [7 responses in 17 patients with BRCA1 or BRCA2 mutations and 11 responses in the 46 who did not have these mutations.][15]

Side effects

Olaparib is generally well tolerated, the side effects consist mainly of fatigue, somnolence, nausea, loss of appetite and thrombocytopenia.

………………………

Synthesis of Investigational Ovarian Cancer Drug Olaparib_PAPP Inhibitor_AstraZeneca 阿斯利康卵巢癌试验药物奥拉帕尼的化学合成

…………….

LOU Xi-yu, YANG Xuan, DING Yi-li, WANG Jian-jun, YAN Qing-yan, HUANG Xian-gui, GUO Yang-hui, WANG Xiang-jing, XIANG Wen-sheng
Synthesis of Olaparib Derivatives and Their Antitumor Activities
2013 Vol. 29 (2): 231-235 [摘要] ( 390 ) [HTML 1KB] [PDF 0KB] ( 22 )
doi: 10.1007/s40242-013-2448-5

……………………….

…………………

4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1
J Med Chem 2008, 51(20): 6581

…………………………..

http://www.google.co.in/patents/WO2004080976A1?cl=en

Synthesis of Key Intermediates

3- (4-0x0-3 , 4-dihydrophthalazin-l -ylmethyl) benzoic a cid (A)

Figure imgf000046_0001

A mixture of 27% sodium methoxide solution in methanol (400 g, 2 mol) and methanol (150 ml) was added dropwise between ambient temperature and 30°C over 15 minutes to a stirred mixture of phthalide (67 g, 0.5 mol), 3-formylbenzonitrile (65.5 g, 0.5 mol) and ethyl propionate (250 ml) , the mixture was stirred at ambient temperature for 40 minutes and at reflux temperature for 1 hour, then it was allowed to cool to ambient temperature. The resulting red solid was collected by filtration, washed with ethyl acetate (2 x 50 ml) and dissolved in water (1800 ml) . The solution was acidified by the addition of acetic acid (60 ml) and the resulting red solid was collected by filtration, washed with water (2 x 200 ml) and dried in vacuo to give 3- (1,3- dioxoindan-2-yl) benzonitrile (83.2 g) as a dark red solid, m.pt. 179- 182°C, m/z (M+H)+‘ 248, which was used without further purification.

3- (1, 3-Dioxoindan-2-yl) benzonitrile (74.18 g, 0.3 mol) was added in portions to a solution of sodium hydroxide (36 g, 0.9 mol) in water (580 ml), the resulting dark red suspension was stirred at reflux temperature for 5 hours, then it was cooled to ambient temperature and washed with ethyl acetate (3 x 300 ml) . The aqueous solution was acidified by the dropwise addition of concentrated hydrochloric acid (110 ml), the mixture was stirred at ambient temperature for 1 hour, then the resulting solid was collected by filtration, washed with water (2 x 200 ml) and dried in vacuo to give a 1:1 mixture of 3- (1,3- dioxoindan-2-yl)benzoic acid, (M+H)+” 267, and 2- [2- (3- carboxyphenyl) acetyl] benzoic acid, (M+H)+‘ 285, (69.32 g) , which was used without further purification.

The mixture obtained in the previous step (52.8 g) was added to a solution of triethylamine (37.55 g, 0.372 mol) in industrial methylated spirit (500 ml) and the resulting cloudy solution was filtered through a pad of filter-aid to give a clear solution. Hydrazine monohydrate (9.3 g, 0.186 mol) was added in one portion at ambient temperature, the stirred mixture was heated under reflux for 1 hour, then it was concentrated in vacuo to approximately 250 ml and added to a solution of sodium acetate (41 g, 0.5 mol) in water (500 ml) . The mixture was brought to pH 7 by the dropwise addition of concentrated hydrochloric acid, then it was stirred at ambient temperature for 3 hours. The resulting solid was collected by filtration, washed with water (50 ml) and dried in va cuo to give a white solid (15.62 g) . The combined filtrate and washings were acidified to pH 6 by the addition of hydrochloric acid, then the mixture was stirred at ambient temperature for 3 hours. The resulting solid was collected by filtration, washed with water (50 ml) and dried in va cuo to give a second crop of off-white solid (17.57 g) . The combined filtrate and washings from the second crop were readjusted to pH 6 and treated as before to give a third crop of pale orange solid (6.66 g) . The three crops were combined to give essentially pure 3- (4-oxo-3, 4-dihydrophthalazin-l-ylmethyl) benzoic acid (A), (M+H)+‘ 281, δH 4.4 (2H, s), 7.2-7.4 (IH, m) , 7.5-7.6 (IH, ) , 7.7-8.0 (5H, m) , 8.1- 8.2 (IH, m) , 12.6 (IH, s)

b . 2-Fluoro-5- (4-oxo-3 , 4-dihydro-phthalazin -l -ylmethyl) benzoi c a cid (B)

Figure imgf000048_0001

Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0°C. 2- Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5°C. The resulting pale yellow solution was warmed to 20°C over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in va cuo . The white residue was quenched with water and extracted into chloroform (3 x 100 ml) . The combined organic extracts were washed with water (2 x 100 ml) , dried over MgS04, and evaporated in va cuo to yield (3-oxo-l, 3-dihydro-isobenzofuran-l-yl) phosphonic acid dimethyl ester as a white solid (32.0 g, 95 %, 95 % purity) . This was then used without further purification in the next stage.

To a mixture of (3-oxo-l, 3-dihydro-isobenzofuran-l-yl) phosphonic acid dimethyl ester (35.0 g, 0.14 mol) in tetrahydrofuran (200 ml) and 2- fluoro-5-formylbenzonitrile (20.9 g, 0.14 mol) in tetrahydrofuran (130 ml) was added triethylamine (14 ml, 0.14 mol) drop-wise over 25 min, with the temperature kept below 15°C. The reaction mixture was warmed slowly to 20°C over 1 hour and concentrated in vacuo . The white residue was slurried in water (250 ml) for 30 minutes, filtered, washed with water, hexane and ether, and dried to yield 2-fluoro-5- (3- oxo-3H-isobenzofuran-l-ylidenemethyl) benzonitrile as a 50:50 mixture of E and Z isomers (37.2 g, 96 %); m/z [M+l]+ 266 (98 % purity) To a suspension of 2-fluoro-5- (3-oxo-3H-isobenzofuran-l- ylidenemethyl) benzonitrile in water (200 ml) was added aqueous sodium hydroxide (26.1 g in 50 ml water) solution and the reaction mixture was heated under nitrogen to 90 °C for 30 minutes. The reaction mixture was partially cooled to 70°C, and hydrazine hydrate (100 ml) was added and stirred for 18 hours at 70°C. The reaction was cooled to room temperature and acidified with 2M HC1 to pH 4. The mixture was stirred for 10 min and filtered. The resulting solid was washed with water, hexane, ether, ethyl acetate and dried to yield 2-fluoro-5- (4-oxo-3, 4- dihydrophthalazin-l-ylmethyl)benzoic acid as a pale pink powder (30.0 g, 77 %) . m/z [M+l]+ 299 (96 % purity), δH 4.4 (2H, s) , 7.2-7.3 (IH, m) , 7.5-7.6 (IH, m) , 7.8-8.0 (4H, m) , 8.2-8.3 (IH, m) , 12.6 (IH, s).

c . 1 – [3- (4-Oxo-S , 4-dihydrophthalazin-l -ylmethyl) benzoyl]piperidine-4- carboxylic a cid (C)

Figure imgf000049_0001undesried????????

(A) (C)

3- (4-Oxo-3, 4-dihydrophthalazin-l-ylmethyl)benzoic acid (A) (7.0 g, 0.25 mol), ethyl isonipecotate (5 ml, 0.32 mol), 2- (lH-benzotriazol-1-yl) – 1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HBTU) (12.3 g, 0.32 mol) and N, N, -diisopropylethylamine (10.0 ml, 0.55 mol) were added to dimethylacetamide (40 ml) and stirred for 18 h. Water (100 ml) was added to the reaction mixture and the product was extracted into dichloromethane (4 x 50 ml) . The combined organic layers were washed with water (3 x 100 ml), dried over MgS0, filtered and evaporated in va cuo to yield an oil. To a solution of the oil in tetrahydrofuran (100 ml) was added 10 % aqueous sodium hydroxide solution (20 ml) and the reaction was stirred for 18 hours. The reaction was concentrated, washed with ethyl acetate (2 x 30 ml) and acidified with 2M HCl to pH 2. The aqueous layer was extracted with dichloromethane (2 x 100 ml), then the extracts were dried over MgS04, filtered and evaporated to yield 1- [3- (4-oxo-3, 4-dihydrophthalazin-l-ylmethyl)benzoyl]piperidine- 4-carboxylic acid (C) as a yellow solid (7.0 g, 65 %), m/z [M+l]+ 392

(96 % purity), δH 1.3-1.8 (5H, m) , 2.8-3.1 (4H, m) , .4 (2H, s), 7.2- 7.3 (IH, m) , 7.3-7.4 (IH, ) , 7.7-8.0 (5H, m) , 8.2-E 3 (IH, m) , 12.6 (IH, s) .

d . 1 – [2-Fluoro-5- (4 -oxo-3 , 4-dihydrophthala zin-l – ylmethyl) benzoyl]piperidine-4~carboxylic a cid (D)

Figure imgf000050_0001

(B) (D)

2-Fluoro-5- ( -oxo-3, 4-dihydrophthalazin-l-ylmethyl) benzoic acid (B) (3.1 g, 0.14 mol), ethyl isonipecotate (1.7 ml, 0.11 mol), 2-(lH- benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HBTU) (5.1 g, 0.13 mol) and N,N, -diisopropylethylamine (10.0 ml, 0.55 mol) were added to dimethylacetamide (15 ml) and stirred for 18 hours. Water (100 ml) was added to the reaction mixture and the product was extracted into dichloromethane (4 x 50 ml) . The combined organic layers were, filtered, washed with water (3 x 100 ml), dried over MgS04, filtered and evaporated in vacuo to yield an orange oil. The oil was purified by flash chromatography (ethyl acetate) to yield l-[2- fluoro-5- (4-oxo-3, 4-dihydrophthalazin-l-ylmethyl) benzoyl] piperidine-4- carboxylic acid as the methyl ester (1.5 g, 33 %, 96 % purity) . To a solution of the methyl ester in tetrahydrofuran: water (2:1, 40 ml) was added sodium hydroxide (0.3 g, 0.075 mol) and the reaction was stirred for 18 h. The reaction was concentrated, washed with ethyl acetate (2 x 20 ml) and acidified with 2M HC1 to pH 2. The aqueous layer was extracted with dichloromethane (2 x 20 ml) , and the combined extracts were dried over MgS04 and evaporated to yield 1- [3- ( 4-oxo-3, 4- dihydrophthalazin-1-ylmethyl) benzoyl] piperidine- -carboxylic acid (D) as a yellow solid (0.6 g, 65 %), m/z [M+l]+ 392 (96 % purity) Example 1 – Synthesis of Key Compounds

a. Synthesis of 4- [3- (piperazine-1-carfoonyl)benzyl] -2H-phthalasin-l- one (1)

Figure imgf000051_0001undesired????????

(A) (1)

3- (4-0xo-3, 4-dihydrophthalazin-l-ylmethyl) benzoic acid (A) (5.0g, 0.17mol), tert-butyl 1-piperazinecarboxylate (3.9 g, 0.21 mol), 2-(lH- benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HBTU) (8.6 g, 0.22 mol) and N, , -diisopropylethylamine (6.7 ml, 0.38 mol) were added to dimethylacetamide (40 ml) and stirred for 18 hours. Water (100 ml) was added and the reaction mixture was heated to 100°C for 1 hour. The suspension was cooled to room temperature, filtered and dried to yield a white solid. The solid was dissolved in a solution of 6M HC1 and ethanol (2:1, 50 ml) and stirred for 1 hour. The reaction was concentrated, basified with ammonia to pH 9, and the product was extracted into dichloromethane (2 x 50 ml). The combined organic layers were washed with water (2 x 50 ml), dried over MgS04, and evaporated in va cuo to yield 4- [3- (piperazine-1-carbonyl) benzyl] – 2H-phthalazin-l-one (1) as a yellow crystalline solid (4.0 g, 77 %); m/z [M+l]+ 349 (97 % purity), δH 2.6-3.8 (8H, ) , 4.4 (2H, s), 7.2-7.5 (4H, m) , 7.7-8.0 (3H, m) , 8.2-8.3 (IH, m) , 12.6 (IH, s)

b . Synthesis of 4 – [4-Fluoro-3- (piperazine-1 -carbonyl) benzyl ] -2H- phthala zin ~l -one (2)

Figure imgf000051_0002desired……

(β) (2)

The synthesis was carried out according to the method described in (a) above using 2-fluoro-5- (4-oxo-3, -dihydrophthalazin-l-ylmethyl) benzoic acid (B) to yield 4- [4-fluoro-3- (piperazine-1-carbonyl) benzyl] -2H- phthalazin-1-one (2) as a white crystalline solid (4.8 g, 76 %); m/z [M+l]+ 367 (97 % purity), δH 2.6-3.8 (8H, m) , 4.4 (2H, s), 7.2-7.5 (3H, m) , 7.7-8.0 (3H, m) , 8.2-8.3 (IH, m) , 12.6 (IH, s) .

…………………………..

US 8183369

http://www.google.co.in/patents/US8183369

4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (compound A) disclosed in WO 2004/080976:

Figure US08183369-20120522-C00001

is of particular interest.

A crystalline form of compound A (Form A) is disclosed in co-pending applications, which claim priority from U.S. 60/829,694, filed 17 Oct. 2006, entitled “Phthalazinone Derivative”, including U.S. Ser. No. 11/873,671 and WO 2008/047082.

Form A

Figure US08183369-20120522-C00002

References(a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)

2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (I)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. 0-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).

Mass Spectrum: MH+ 435

1H NMR (400 MHz, DMSO-d6) δ: 0.70 (m, 4H), 1.88 (br s, 1H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1H), 7.34 (dd, 1H), 7.41 (m, 1H), 7.77 (dt, 1H), 7.83 (dt, 1H), 7.92 (d, 1H), 8.25 (dd, 1H), 12.53 (s, 1H).

………………………..

http://www.google.co.in/patents/US8247416

4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (compound A) disclosed in WO 2004/080976:

Figure US08247416-20120821-C00001

is of particular interest.

In WO 2004/080976, compound A was synthesised as one of a number of library compounds from 4-[4-fluoro-3-(piperazine-1-carbonyl)-benzyl]-2H-phthalazin-1-one (compound B):

Figure US08247416-20120821-C00002

by the addition of cyclopropanecarbonyl chloride:

Figure US08247416-20120821-C00003

to a solution of (B) in dichloromethane, followed by Hünig’s base (N,N-diisopropylethyl amine). This reaction is carried out with stirring at room temperature for 16 hours, and the resulting compound being purified by preparative HPLC.

The piperazine derivative (B) was prepared by deprotecting 4-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (compound C):

Figure US08247416-20120821-C00004

by the use of 6M HCl and ethanol for 1 hour, followed by basification with ammonia to pH 9, and extraction into dichloromethane.

The Boc-protected piperazine derivative (C) was prepared from 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid (compound D):

Figure US08247416-20120821-C00005

by the addition of piperazine-1-carboxylic acid tert-butyl ester:

Figure US08247416-20120821-C00006

2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and N,N,-diisopropylethylamine in dimethylacetamide, followed by stirring for 18 hours.

In WO 2004/080976, the following route to compound D is disclosed:

Figure US08247416-20120821-C00007

The method of synthesising compound D may further comprise the step of:

(c) synthesising 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (ED):

Figure US08247416-20120821-C00008

from compound E by reaction with hydrazine hydrate; and

(d) synthesising compound D from compound ED by reaction with sodium hydroxide.

Step (c) may be achieved by using between 1.1 and 1.3 equivalents of hydrazine hydrate in tetrahydrofuran followed by neutralisation of the excess hydrazine hydrate using acetic acid.

A sixth aspect of the present invention provides the compound ED:

Figure US08247416-20120821-C00009

and its use in the synthesis of compound D.

EXAMPLES

Example 1Synthesis of Compound A

Figure US08247416-20120821-C00010

Starting material (D) was synthesised by the method disclosed in WO 2004/080976

Methods

Preparative HPLC

Samples were purified with a Waters mass-directed purification system utilising a Waters 600 LC pump, Waters Xterra C18 column (5 μm 19 mm×50 mm) and Micromass ZQ mass spectrometer, operating in positive ion electrospray ionisation mode. Mobile phases A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile) were used in a gradient; 5% B to 100% over 7 min, held for 3 min, at a flow rate of 20 ml/min.

Analytical HPLC-MS

Analytical HPLC was carried out with a Spectra System P4000 pump and Jones Genesis C18 column (4 μm, 50 mm×4.6 mm). Mobile phases A (0.1% formic acid in water) and B (acetonitrile) were used in a gradient of 5% B for 1 min rising to 98% B after 5 min, held for 3 min at a flow rate of 2 ml/min. Detection was by a TSP UV 6000LP detector at 254 nm UV and range 210-600 nm PDA. The Mass spectrometer was a Finnigan LCQ operating in positive ion electrospray mode.

(a) 4-[2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (C)

To a stirred solution of the starting material D (850 g) in dimethylacetamide (DMA) (3561 ml) at room temperature under nitrogen was added HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (1402 g) in one portion. Hünig’s base (iPr2NEt, 1096 ml) was then added with the temperature kept between 15 to 25° C. followed by a solution of 1-Boc-piperazine (637 g) in DMA (1428 ml) with the temperature kept between 15 to 25° C.

The solution was stirred at room temperature for 2 hours and sampled for completion (HPLC). Upon completion the solution was added to vigorously stirred water (17085 ml) with the temperature kept between 15 to 25° C. and the solid filtered off, washing with water (2×7131 ml), hexane (2×7131 ml) and methyl tert-butyl ether (MTBE) (2×3561 ml). The solid was then dried overnight and then sampled for water content and chemical purity.

This reaction was then repeated, see table:

Purity Water Content
Batch Yield (g) (HPLC Area %) (K.F.) Corrected yield
1 1571.3 86.80 24.3 1032.5 g (78%)
2 2781.6 85.00 40.3 1411.5 g (106%)
a. Greater than 100% yield attributed to non-representative sampling

(b) 4-[4-Fluoro-3-(piperazine-1-carbonyl)-benzyl]-2H-phthalazin-1-one (B)

To a stirred solution of industrial methylated spirits (IMS) (2200 ml) and concentrated HCl (4400 ml) was added compound C (2780.2 g) in portions at room temperature under nitrogen, the foaming was controlled by the addition rate. The solution was then stirred at 15 to 25° C. for 30 minutes and sampled for completion (HPLC).

Upon completion the solution was evaporated to remove any IMS and the aqueous extracted with CH2Cl2 (2×3500 ml) before the pH was adjusted to >8 using concentrated ammonia. The resultant slurry was then diluted with water (10000 ml) and extracted with CH2Cl2 (4×3500 ml), washed with water (2×2000 ml), dried over MgSO4 (250 g) and evaporated. The crude product was then slurried in CH2Cl2 (3500 ml) and added to MTBE (5000 ml). The resultant suspension was filtered and dried at 50° C. overnight yielding 611.0 g (58.5% yield) of material with a purity of 94.12%

(c) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (A)

To a stirred suspension of compound B (1290 g) in CH2Cl2 (15480 ml) under nitrogen was added a pre-mixed solution of triethylamine (470 ml) and cyclopropane carbonyl chloride (306 ml) in CH2Cl2 (1290 ml) dropwise with the temperature kept below 20° C. The solution was then stirred at 10-15° C. for 15 minutes and sampled for completion. The reaction mixture was found to contain only 1.18% of starting material B and so the reaction was deemed complete and the batch was then worked-up.

The reaction mixture was washed with water (7595 ml), 5% citric acid solution (7595 ml), 5% sodium carbonate solution (7595 ml) and water (7595 ml). The organic layer was then dried over magnesium sulfate (500 g).

The CH2Cl2 containing product layer was then isolated, filtered through Celite and charged to a 251 vessel. CH2Cl2 (8445 ml) was then distilled out at atmospheric pressure and ethanol (10000 ml) added. Distillation was then continued with every 4000 ml of distillate that was removed being replaced with ethanol (4000 ml) until the head temperature reached 73.7° C. The reaction volume was then reduced (to 7730 ml) by which time the head temperature had reached 78.9° C. and the solution was allowed to cool to 8° C. overnight. The solid was then filtered off, washed with ethanol (1290 ml) and dried at 70° C. overnight. Yield=1377.3 g (90%). HPLC purity (99.34% [area %]). Contained 4.93% ethanol and 0.45% CH2Cl2 by GC.

(d) Water Treatment of Compound A

A suspension of compound A (1377.0 g), as produced by the method of Example 1, in water (13770 ml) was heated to reflux for 4 hours, cooled to room temperature and filtered. The solid was washed with water (2754 ml) and dried at 70° C. overnight. Yield=1274.8 g (92.6%). HPLC purity (99.49% [area %]). Contained 0.01% ethanol and 0.01% CH2Cl2 by GC.

1H NMR spectrum of compound A (DMSO-d6) following the water treatment is shown in FIG. 1.

The powder XRD pattern of Compound A following the water treatment is shown in FIG. 2, which shows the compound is as Form A.

Example 2

Alternative Synthesis of Compound A Using 1-(cyclopropylcarbonyl) piperazine

Figure US08247416-20120821-C00011

Methods (also for Examples 3 & 4)

NMR

1H NMR spectra were recorded using Bruker DPX 400 spectrometer at 400 MHz. Chemical shifts were reported in parts per million (ppm) on the δ scale relative to tetramethylsilane internal standard. Unless stated otherwise all samples were dissolved in DMSO-d6.

Mass Spectra

Mass spectra were recorded on an Agilent XCT ion trap mass spectrometer using tandem mass spectrometry (MS/MS) for structural confirmation. The instrument was operated in a positive ion elctrospray mode.

(a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)

2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (1)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).

Mass Spectrum: MH+435

1H NMR (400 MHz. DMSO-d6) δ: 0.70 (m, 4H), 1.88 (br s, 1H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1H), 7.34 (dd, 1H), 7.41 (m, 1H), 7.77 (dt, 1H), 7.83 (dt, 1H), 7.92 (d, 1H), 8.25 (dd, 1H), 12.53 (s, 1H).

Example 3Alternative Synthesis of Compound A Using 1-(cyclopropylcarbonyl) piperazine HCl salt

Figure US08247416-20120821-C00012

(a) 1-(Cyclopropylcarbonyl)piperazine HCl salt (I′)

Acetic acid (700 ml) was treated with piperazine (50.00 g, 0.581 mol) portionwise over 15 minutes with stirring under nitrogen The reaction mixture was warmed to 40° C. and maintained at this temperature until a complete solution was obtained. Cyclopropanecarbonyl chloride 59.2 ml, 0.638 mol) was added over 15 minutes. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate distilled under reduced pressure until ˜430 ml of distillates had been collected. Toluene (550 ml) was charged to the reaction mixture and reduced pressure distillation continued until a further 400 ml of distillates were collected. A further charge of toluene (550 ml) was added and reduced pressure distillation continued until 350 ml of distillates were collected. The resulting slurry was diluted with toluene (200 ml) and stirred overnight. Further toluene (500 ml) was added in order to mobilise the slurry. The slurry was filtered, washed with toluene (100 ml) and dried in vacuo at 40° C. to give the title compound as an off white solid (86.78 g).

Mass Spectrum: MH+155

1H NMR (400 MHz. D2O) δ: 0.92 (m, 4H), 1.98 (m, 1H), 3.29 (m, 2H), 3.38 (m, 2H), 3.84 (m, 2H), 4.08 (m, 2H).

(b) Compound A

2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(0.95 g, 3.19 mmol) was suspended with stirring under nitrogen in acetonitrile (4 ml). 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.45 g, 3.83 mmol) was added followed by 1-cyclopropylcarbonylpiperazine HCl salt (I′)(0.73 g, 3.83 mmol). Diisopropylethylamine (1.39 ml, 7.98 mmol) was added over 3 minutes and the reaction mixture was stirred for overnight at room temperature. The reaction mixture was cooled to 5° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (2 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (0.93 g).

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  9.  Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O’Connor MJ, Martin NM, Borst P, Jonkers J (November 2008). “High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs”. Proceedings of the National Academy of Sciences of the United States of America 105 (44): 17079–84. doi:10.1073/pnas.0806092105. PMC 2579381. PMID 18971340.
  10.  Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O’Connor M, Clarke AR (May 2009). “Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin”. Cancer Research 69 (9): 3850–5. doi:10.1158/0008-5472.CAN-08-2388. PMID 19383921.
  11. http://www.ncri.org.uk/ncriconference/archive/2007/abstracts/pdf/LB57.pdf “A Phase I trial of AZD2281 (KU-0059436), a PARP inhibitor with single agent anticancer activity in patients with BRCA deficient tumours, particularly ovarian cancer”
  12.  Fong PC, Boss DS, Yap TA, et al. (July 2009). “Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers”. N. Engl. J. Med. 361 (2): 123–34.doi:10.1056/NEJMoa0900212. PMID 19553641.
  13.  http://www.cancercompass.com/cancer-news/1,15869,00.htm “Phase II Trials Investigating Oral PARP Inhibitor, Olaparib, In BRCA-Deficient Advanced Breast And Ovarian Cancer” June 2009
  14.  http://clinicaltrials.gov/ct2/show/NCT00912743 Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status
  15.  “Olaparib Looks Promising in Treatment of Non-BRCA Ovarian Cancer”. 26 Aug 2011.
Patent Submitted Granted
Phthalazinone Derivatives [US2012010204] 2012-01-12
PARP1 TARGETED THERAPY [US2012035244] 2012-02-09
Phthalazinone derivatives [US7449464] 2005-03-17 2008-11-11
4- [3- (4-CYCLOPROPANECARBONYL-PIPERAZINE-I-CARBONYL) -4 -FLUORO-BENZYL] -2H-PHTHALAZ IN-1-ONE [US8183369] 2010-11-11 2012-05-22
PHTHALAZINONE DERIVATIVES [US7692006] 2008-06-19 2010-04-06
PHTHALAZINONE DERIVATIVES [US7981889] 2008-08-21 2011-07-19
PHARMACEUTICAL FORMULATION 514 [US2010098763] 2010-04-22
PHTHALAZINONE DERIVATIVE [US8247416] 2009-10-29 2012-08-21
WO2002036576A1 * 25 Oct 2001 10 May 2002 Kudos Pharm Ltd Phthalazinone derivatives
WO2002090334A1 * 30 Apr 2002 14 Nov 2002 Kudos Pharm Ltd Isoquinolinone derivatives as parp inhibitors
WO2003093261A1 * 29 Apr 2003 13 Nov 2003 Kudos Pharm Ltd Phthalazinone derivatives

extras…………..

Olaparib
Olaparib.png
Systematic (IUPAC) name
4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-1-one
Clinical data
Trade names Lynparza
Legal status
  • Investigational
Routes Oral
Identifiers
CAS number 763113-22-0 
ATC code None
PubChem CID 23725625
ChemSpider 23343272 Yes
UNII WOH1JD9AR8 Yes
ChEMBL CHEMBL521686 Yes
Chemical data
Formula C24H23FN4O3 
Mol. mass 435.08 g/mol
Research Area
Cancer
Biological Activity
Description Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1 and PARP2 with IC50 of 5 nM and 1 nM, respectively.
Targets PARP1 PARP2
IC50 5 nM 1 nM [1]
In Vitro Olaparib would act against BRCA1 or BRCA2 mutations. AZD2281 is not sensitive to tankyrase-1 (IC50 >1 μM). Olaparib could ablate the PARP-1 activity at concentrations of 30-100 nM in SW620 cells. Olaparib is hypersensitive to BRCA1-deficient cell lines (MDA-MB-463 and HCC1937), compared with BRCA1- and BRCA2-proficient cell lines (Hs578T, MDA-MB-231, and T47D). [1] Olaparib is strongly sensitive to KB2P cells due to suppression of base excision repair by PARP inhibition, which may result in the conversion of single-strand breaks to double-strand breaks during DNA replication, thus activating BRCA2-dependent recombination pathways. [2]
In Vivo Combining with temozolomide, Olaparib (10 mg/kg, p.o.) significantly suppresses tumor growth in SW620 xenografts. [1] Olaparib shows great response to Brca1-/-;p53-/- mammary tumors (50 mg/kg i.p. per day), while no responses to HR-deficient Ecad-/-;p53-/- mammary tumors. Olaparib even does not show dose-limiting toxicity in tumor-bearing mice. [3] Olaparib has been used to treat with BRCA mutated tumors, such as ovarian, breast and prostate cancers. Moreover, Olaparib shows selectively inhibition to ATM (Ataxia Telangiectasia Mutated)-deficient tumor cells, which indicates to be a potential agent for treating ATM mutant lymphoid tumors. [4]
Clinical Trials Combining with cediranib, Olaparib is currently in Phase I/II study for treatment of recurrent papillary-serous ovarian, fallopian tube or peritoneal cancer or treatment of recurrent triple-negative breast cancer.
Features Olaparib is one of the first PARP inhibitors.
Protocol
Kinase Assay [1]
FlashPlate assay (96-well screening assay) To columns 1 through 10, 1 μL of Olaparib (in DMSO) is added, and 1 μL DMSO only is added to the positive (POS) and negative (NEG) control wells (columns 11 and 12, respectively) of a pretreated FlashPlate. PARP-1 is diluted 1:40 in buffer (buffer B: 10% glycerol (v/v), 25 mM HEPES, 12.5 mM MgCl2,50 mM KCl, 1 mM DTT, 0.01% NP-40 (v/v), pH 7.6) and 40 μL added to all 96 wells (final PARP-1 concentration in the assay is ~1 ng/μL). The plate is sealed and shaken at RT for 15 min. Following this, 10 μL of positive reaction mix (0.2 ng/μL of double-stranded oligonucleotide [M3/M4] DNA per well, 5 μM of NAD+ final assay concentration, and 0.075 μCi 3H-NAD+ per well) is added to the appropriate wells (columns 1-11). The negative reaction mix, lacking the DNA oligonucleotide, is added to column 12 (with the mean negative control value used as the background). The plate is resealed and shaken for a further 60 min at RT to allow the reaction to continue. Then, 50 μL of ice-cold acetic acid (30%) is added to each well to stop the reaction, and the plate is sealed and shaken for a further 60 min at RT. Tritiated signal bound to the FlashPlate is then determined in counts per minute (CPM) using the TopCount plate reader.
In vitro isolated enzyme assay PARP-2 activity inhibition uses a variation of the PARP-1 assay in which PARP-2 protein (recombinant) is bound down by a PARP-2 specific antibody in a 96-well white-walled plate. PARP-2 activity is measured following 3H-NAD+ DNA additions. After washing, scintillant is added to measure 3H-incorporated ribosylations. For tankyrase-1, a α-Screen assay is developed in which HIS-tagged recombinant TANK-1 protein is incubated with biotinylated NAD+in a 384-well ProxiPlate assay. Alpha beads are added to bind the HIS and biotin tags to create proximity signal, whereas the inhibition of TANK-1 activity is directly proportional to the loss of this signal.
Cell Assay [1]
Cell lines Breast cancer cell lines including SW620 colon, A2780 ovarian, HCC1937, Hs578T, MDA-MB-231, MDA-MB-436, and T47D
Concentrations 1-300 nM
Incubation Time 7-14 days
Method The cytotoxicity of Olaparib is measured by clonogenic assay. Olaparib is dissolved in DMSO and diluted by culture media before use. The cells are seeded in six well plates and left to attach overnight. Then Olaparib is added at various concentrations and the cells are incubated for 7-14 days. After that the surviving colonies are counted for calculating the IC50.
Animal Study [3]
Animal Models Brca1-/-;p53-/- mammary tumors are generated in K14cre;Brca1F/F;p53F/F mice.
Formulation 50 mg/mL stocks in DMSO with 10% 2-hydroxyl-propyl-β-cyclodextrine/PBS
Doses 50 mg/kg
Administration Administered via i.p. injection at 10 μL/g of body weight
References
[1] Menear KA, et al. J Med Chem, 2008, 51(20), 6581-6591.
[2] Evers B, et al, Clin Cancer Res, 2008, 14(12), 3916-3925.
[3] Rottenberg S, et al, Proc Natl Acad Sci U S A, 2008, 105(44), 17079-17084.
[4] Weston VJ, et al, Blood, 2010, 116(22), 4578-4587.

 nmr

H-NMR spectral analysis
olaparib NMR spectra analysis, Chemical CAS NO. 763113-22-0 NMR spectral analysis, olaparib H-NMR spectrum
CAS NO. 763113-22-0, olaparib H-NMR spectral analysis
C-NMR spectral analysis
olaparib NMR spectra analysis, Chemical CAS NO. 763113-22-0 NMR spectral analysis, olaparib C-NMR spectrum
CAS NO. 763113-22-0, olaparib C-NMR spectral analysis

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