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крисаборол , كريسابورول , Crisaborole, AN 2728

October 30, 2015 8:59 am / 1 Comment on крисаборол , كريسابورول , Crisaborole, AN 2728

Crisaborole

Treatment for Inflammatory Skin Diseases, including Atopic Dermatitis and Psoriasis

C₁₄H₁₀BNO_3,Average mass251.045 Da

4-[(1-Hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile ,

4-((1-Hydroxy-1,3-dihydrobenzo(c)(1,2)oxaborol-6-yl)oxy)benzonitrile

CAS 906673-24-3, AN-2728

Benzonitrile, 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]-

1,3-Dihydro-1-hydroxy-5-(4-cyanophenoxy)-2,1-benzoxaborole

5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole

crisaborol, crisaborole, Crisaborole, crisaborolum

UNII-Q2R47HGR7P

крисаборол

كريسابورول

In phase 3 for treatment of mild to moderate atopic dermatitis……Anacor Pharmaceuticals, Inc.

Psoriasis is a chronic skin disorder caused by inflammatory cell infiltration into the dermis and epidermis, and is accompanied by keratinocyte hyperproliferation. Once triggered, a strong T-cell response is mounted, and a cascade of cytokine and chemokine production is induced.

Down-regulation of certain cytokines and chemokines is considered to be a good approach to treatment, and indeed, the biologics targeting TNF-α demonstrate the effectiveness of this approach.However, biologics have intrinsic challenges, such as limited administration route, side effects, quality control and production cost.

Small molecule approaches to treat psoriasis include systemic or topical steroids, cyclosporine, psoralen plus UVA (PUVA), retinoids, methotrexete, and vitamin D₃ analogs.Atopic dermatitis is an allergic skin disorder, which is typically treated with topical steroids, antihistamines, and calcineurin inhibitors.

However, there is still a need for new treatment with improved safety profile. Recently phosphodiesterase 4 (PDE4) inhibitors have been in development for such skin diseases. CC-10004 is in development as an oral treatment for psoriasis and atopic dermatitis. AWD-12-281 was, until recently, in development for the topical treatment of atopic dermatitis. In addition, roflumilast is under Phase 1 development for both diseases.

Figure 1.

PDE4 inhibitors aiming at skin inflammatory diseases.

Anacor’s lead product candidate is crisaborole, an investigational non-steroidal topical PDE-4 inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis

crisaborole is an investigational topical antiinflammatory drug in phase III clinical development by Anacor Pharmaceuticals for the treatment of mild to moderate atopic dermatitis and in phase II clinical trials in mild to moderate psoriasis

A novel boron-containing small molecule, Crisaborole inhibits the release of pro-inflammatory cytokines including TNF-alpha, IL-12, and IL-23, known mediators of the inflammation associated with psoriasis.

Synthesis

CKICK ON IMAGE FOR CLEAR VIEW

Originator

Anacor Pharmaceuticals

Therapeutic Claim

Inflammatory skin diseases

Atopic dermatitis

Psoriasis

Class

Nonsteroidal anti-inflammatories

Mechanism of action

Tumour necrosis factor alpha inhibitors

Type 4 cyclic nucleotide phosphodiesterase inhibitors

WHO ATC code(s)

D05A-X (Other antipsoriatics for topical use)

D11A-H (Agents for atopic dermatitis excluding corticosteroids)

EPhMRA code(s)

D5A (Topical Antipsoriasis Products)

D5X (Other Nonsteroidal Products for Inflammatory Skin Disorders)

Clinical trial(s)

Conditions	Phases	Interventions	Status
Dermatitis, Atopic	Phase 3	AN-2728	Active, not recruiting
Psoriasis	Phase 2	AN-2728	Completed
Plaque-Type Psoriasis	Phase 1	AN-2728	Completed

PAPER

Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis
Bioorg Med Chem Lett 2009, 19(8): 2129

http://www.sciencedirect.com/science/article/pii/S0960894X09002996

Tsutomu Akama ^,,

Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis

Scheme 1.

Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6 h (quant.); (b) K₂CO₃, DMF, 100 °C, overnight (82–96%); (c) 3 M HCl, THF, reflux, 2 h (80–100%); (d) NaBH₄, MeOH, rt, 1 h (quant.); (e) 3,4-dihydro-2H-pyran, camphorsulfonic acid, CH₂Cl₂, rt, 2 h (quant.); (f) (i-PrO)₃B, n-BuLi, THF, −78 °C to rt, 3 h; (g) 6 M HCl, THF, rt, 3 h (37–44%); (h) 6 M NaOH, MeOH, 1,4-dioxane, reflux, 6 days (79%); (i) diethylamine (for 5f) or morpholine (for 5g), EDCI, HOBt, DMAP, DMF, rt, overnight (41–70%).

PATENT

http://www.google.co.in/patents/WO2006089067A2?cl=en

4.2. q 5-(4-Cyanophenoxy)-l, 3-dihydro-l-hydroxy-2, 1-benzoxaborole (C17) [0264] ¹H-NMR (300 MHz,

δ ppm 4.95 (s, 2H), 7.08 (dd, J= 7.9, 2.1 Hz, IH), 7.14 (d, J= 8.8 Hz, IH), 7.15 (d, J= 2.1 Hz, IH), 7.78 (d, J= 7.9 Hz, IH), 7.85 (d, J= 9.1 Hz, 2H), 9.22 (s, IH).

PATENT

EXAMPLE 15

http://www.google.com/patents/WO2007095638A2?cl=en

4-(4-Cvanophenoxy)phenylboronic acid (C97)

(a) (4-cyanophenyl) (4-bromophenyl) ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100⁰C for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with IN NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4- bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. ¹H NMR (300 MHz, DMSO-de): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.

(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p.l94-198°C. MS: m/z = 239 (M+), 240 (M+ 1) (ESI+) and m/z = 238 (M-I) (ESI-). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. ¹H NMR (300 MHz, DMSO-d₆ + D₂O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.

FURTHER METHOD

2-Bromo-5-(4-cvanophenoxy)benzyl Alcohol

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J= 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).

PATENT

http://www.google.im/patents/EP1976536A2?cl=en

2.2.a 2-Bromo-5-(4-cyanophenoxy)benzyl Alcohol

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 2.00 (br s, IH), 4.75 (s, 2H), 6.88 (dd, J= 8.5, 2.9 Hz, IH), 7.02 (d, J= 8.8 Hz, IH), 7.26 (d, J- 2.6 Hz, IH), 7.56 (d, J = 8.5 Hz, IH), 7.62 (d, J= 8.8 Hz, 2H).

2.2.b 2-Bromo-4-(4-cyanophenoxγ)benzyl Alcohol

¹H NMR (300 MHz, DMSO-d₆): δ 7.83 (d, 2H), 7.58 (d, IH), 7.39 (d, IH), 7.18 (dd, IH), 7.11- (d, 2H), 5.48 (t, IH) and 4.50 (d, 2H) ppm.

2.2.c 5- (4-Cyanophenoxy) -1 -Indanol

M.p.50-53°C. MS (ESI+): m/z = 252 (M+l). HPLC: 99.7% purity at 254 nm and 99.0% at 220 nm. ¹H NMR (300 MHz, DMSOd₆): δ 7.80 (d, 2H), 7.37 (d, IH), 7.04 (d, 2H), 6.98-6.93 (m, 2H), 5.27 (d, IH)₅ 5.03 (q, IH), 2.95-2.85 (m, IH), 2.75-2.64 (m, IH), 2.39-2.29 (m, IH) and 1.85-1.74 (m, IH) ppm.

2.2. d 2-Bromo-5-(tert-butyldimethylsiloxy)benzyl Alcohol [0429] ¹H-NMR (300 MHz, CDCl₃) δ (ppm) 0.20 (s, 6H), 0.98 (s, 9H), 4.67 (br s,lH), 6.65 (dd, J= 8.2, 2.6 Hz, IH), 6.98 (d, J= 2.9 Hz, IH), 7.36 (d, J= 8.8 Hz, IH).

3.2.k 2-Bromo-5-(2-cyanophenoχy)-l-(methoxymethoxymethyl)benzene [0443] ¹H-NMR (300 MHz, CDCl₃) δ (ppm) 3.41 (s, 3H), 4.64 (s, 2H), 4.76 (s, 2H), 6.8-6.9 (m, 2H), 7.16 (td, J= 7.6, 0.9 Hz, IH), 7.28 (d, J= 2.9 Hz, IH), 7.49 (ddd, J= 8.8, 7.6, 1.8 Hz, IH)₅ 7.56 (d, J= 8.5 Hz, IH), 7.67 (dd, J= 7.9, 1.8 Hz, IH).

EXAMPLE 32

Alternative Preparation of C17 -Intermediate

The procedure described in Example II I was followed for ¹H NMR characterization of the current alcohol-borate intermediate. ¹H NMR determination indicated there were 72.7 mol% of the desired alcohol-borate intermediate [2-bromo- 5-(4-cyanophenoxy)benzyl] diisopropyl borate, 20.7 mol% of an unknown intermediate and 6.5 mol% of unreacted alcohol. ¹H NMR (CDCl₃, 300 MHz) of [2- bromo-5-(4-cyanophenoxy)benzyl] diisopropyl borate: δ= 7.61 (d, J= 9.0 Hz, 2H), 7.52 (d, J= 8.4 Hz, IH), 7.15 (d, J= 3.0 Hz, IH), 7.03 (d, J= 8.7 Hz, 2H), 6.84 (dd, J= 8.7 Hz, J= 3.0 Hz, IH), 4.85 (s, 2H), 4.35 (septet, J= 6.1 Hz, 2H), 1.11 (d, J= 6.1 Hz, 12H) ppm.

PATENT

http://www.google.com/patents/US20090291917

(a) (4-cyanophenyl)(4-bromophenyl)ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100° C. for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with 1N NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p. 194-198° C. MS: m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M−1) (ESI−). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. ¹H NMR (300 MHz, DMSO-d₆+D₂O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.

see

http://www.google.co.in/patents/WO2006089067A2?cl=en

see

http://www.google.com/patents/US20090291917

US5688928 *	Jun 7, 1995	Nov 18, 1997	Prolinx, Inc.	Phenylboronic acid complexing reagents derived from aminosalicylic acid
US5880188 *	May 26, 1995	Mar 9, 1999	Zeneca Limited	Oxaboroles and salts thereof, and their use as biocides
US5962498 *	Dec 2, 1994	Oct 5, 1999	Procyon Pharmaceuticals, Inc.	Protein kinase C modulators. C. indolactam structural-types with anti-inflammatory activity
US6369098 *	Oct 4, 2000	Apr 9, 2002	Bethesda Pharmaceuticals, Inc.	Dithiolane derivatives
US20030032673 *	Jul 19, 2002	Feb 13, 2003	Isis Innovation Limited	Therapeutic strategies for prevention and treatment of alzheimer’s disease
US20050239170 *	Jul 16, 2001	Oct 27, 2005	Hedley Mary L	Alpha-MSH related compounds and methods of use
US20060009386 *	May 12, 2005	Jan 12, 2006	The Brigham And Women’s Hospital, Inc.	Use of gelsolin to treat infections

Boron-containing small molecules as anti-inflammatory agents

US Pat. US8501712

Methods of treating anti-inflammatory conditions through the use of boron- containing small molecules are disclosed.

Boron-containing small molecules

US Pat. US8461336

… Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … Francisco, CA Mar. 6-10, 2009. 7 , “AN2728 … Kyoto, Japan, May 14-18, 2008. 10, “AN2728 …

Compounds and Methods for Treating Pain

US Pat. US20130252924

AN2728, 5-(4-cyanophenoxy)-2,3- dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).

Boron-containing small molecules

US Pat. US8440642

… Dermatology Annual Meeting, San Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … 7, “AN2728 … Francisco, CA May 6-10, 2009. 10, “AN2728 …

Phenylethylpyridine derivatives as pde4-inhibitors

US Pat. WO2014086855A1

… from the group consisting of AN-2728, AN-2898, CBS- 3595, apremilast, ELB- 353, KF-66490, K-34, LAS-37779, IBFB-211913, AWD-12-281, …

A method of inhibiting the expression of il-22 in activated t-cells

US Pat. WO2014083099A1

“AN2728” is the compound 4-(l-hydroxy-l,3-dihydro-2 … GSK256066, oglemilast, tetomilast, apremilast, AN2728, Compound A, Compound B, …

FMO3 inhibitors for treating pain

US Pat. EP2674161A1

AN2728, 5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).

Compounds and methods for treating pain

US Pat. CN103415286A

85.用于治疗疼痛的UK-500，001。 85. for the treatment of pain UK-500,001. 86.用于治疗疼痛的AN2728。 86. for the treatment of pain AN2728.

see full series on boroles

http://apisynthesisint.blogspot.in/p/borole-compds.html

do not miss out

///////////crisaborole, AN 2728, PHASE 3, Anti-inflammatory, Phosphodiesterase, Oxaborole, Psoriasis, Atopic dermatitis, borole

GSK 2251052, Epetraborole, AN3365

October 30, 2015 5:18 am / 1 Comment on GSK 2251052, Epetraborole, AN3365

(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro- 2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gramnegative infections

(S)-3-aminomethylbenzoxaborole; ABX; AN-3365; GSK ‘052; GSK-052; GSK-2251052, GSK2251052, Epetraborole

[(S)-3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy- 1,3-dihydro-2,1-benzoxaborole hydrochloride],

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride

1-Propanol, 3-(((3S)-3-(aminomethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborol-7-yl)oxy)-

AN3365,

MW 237.0614,

cas 1093643-37-8
UNII: 6MC93Z2DF9

Anacor Pharmaceuticals, Inc., INNOVATOR

Glaxosmithkline Llc DEVELOPER

Biomedical Advanced Research and Development Authority (BARDA)

GSK 2251052 • $38.5M over the 1st two years; up to $94M……..http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Bad_Bugs_No_Drugs/Press_Releases/FIS%20Slides.pdf

Originally came from Anacor about ten years ago, then was picked up by GlaxoSmithKline, and it’s an oxaborole heterocycle that inhibits leucyl tRNA synthetase

GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development
Authority (BARDA), a US government preparedness organization , The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option.

The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis).

Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesizedbortezomib, a boronic acid peptide, in 1995.

Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell.

Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases. Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various fungi.

Boron-containing molecules such as benzoxaboroles that are useful as antimicrobials have been described previously, see e.g. “Benzoxaboroles – Old compounds with new applications” Adamczyk-Wozniak, A. et al., Journal of Organometallic Chemistry Volume 694, Issue 22, 15 October 2009, Pages 3533-3541 , and U.S. Pat. Pubs. US20060234981 and US20070155699. Generally speaking, a benzoxaborole has the following structure and substituent numbering system:

Certain benzoxaboroles which are monosubstituted at the 3-, 6-, or 7-position, or disubstituted at the 3-/6- or 3-/7- positions are surprisingly effective antibacterials, and they have been found to bind to the editing domain of LeuRS in association with tRNA^Leu Such compounds have been described in US7, 816,344. Using combinations of certain substituted benzoxaboroles with norvaline and/or other amino acid analogs and their salts to: (a) reduce the rate of resistance that develops; and/or (b) decrease the frequency of resistance that develops; and/or (c) suppress the emergence of resistance, in bacteria exposed to compounds

2D chemical structure of 1234563-15-5

Epetraborole R-mandelate
1234563-15-5

2D chemical structure of 1234563-16-6

Epetraborole hydrochloride
1234563-16-6

Image result for GSK 2251052

GSK2251052

Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.

Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets.

Lucy Shapiro is a Professor in the Department of Developmental Biology at Stanford University School of Medicine where she holds the Virginia and D. K. Ludwig Chair in Cancer Research and is the Director of the Beckman Center for Molecular and Genetic Medicine. She is a member of the Scientific Advisory Board of Ludwig Institute for Cancer Research and is a member of the Board of Directors of Pacific Biosciences, Inc. She founded the anti-infectives discovery company, Anacor Pharmaceuticals, and is a member of the Anacor Board of Directors. Professor Shapiro has been the recipient of multiple honors, including: election to the American Academy of Arts and Sciences, the US National Academy of Sciences, the US Institute of Medicine, the American Academy of Microbiology, and the American Philosophical Society. She was awarded the FASEB Excellence in Science Award, the 2005 Selman Waksman Award from the National Academy of Sciences, the Canadian International 2009 Gairdner Award, the 2009 John Scott Award, the 2010 Abbott Lifetime Achievement Award, the 2012 Horwitz Prize and President Obama awarded her the National Medal of Science in 2012. Her studies of the control of the bacterial cell cycle and the establishment of cell fate has yielded valuable paradigms for understanding the bacterial cell as an integrated system in which the transcriptional circuitry is interwoven with the three-dimensional deployment of key regulatory and morphological proteins, adding a spatial dimension to the systems biology of regulatory networks.

Stephen J. Benkovic

Evan Pugh University Professor and Eberly Chair in Chemistry

Office:
414 Wartik Laboratory
University Park, PA 16802
Email: sjb1@psu.edu
(814) 865-2882

http://chem.psu.edu/directory/sjb1

Websites,Benkovic Research Group

Naeja was a three-year-old contract research firm run by Ronald Micetich and his son Christopher Micetich. Based in Edmonton, Alberta, the firm is staffed by chemists and biologists from a variety of nations who have found Canada welcoming to highly educated immigrants.

GSK. Last July, the British firm paid Anacor $15 million and exercised its option to take over development of AN3365. David J. Payne, vice president of GSK’s antibacterial drug discovery unit, lauded the compound, now renamed GSK2251052, as having “the potential to be the first new-class antibacterial to treat serious hospital gram-negative infections in 30 years.” GSK chemists have since developed a stereospecific synthesis for commercial-scale production

david.j.payne@gsk.com

David J. Payne, vice president of GSK’s antibacterial drug discovery unit

David J Payne Dr Payne holds a BSc in Biochemistry from Brunel University, UK, and a PhD and DSc from The Medical School, University of Edinburgh, UK. Dr Payne has 20 years of experience in antibacterial drug discovery and is currently Vice President and Head of the Antibacterial Discovery Performance Unit (DPU) within the Infectious Diseases Centre of Excellence in Drug Discovery (ID CEDD) where he is responsible for GSK’s antibacterial research effort from discovery to clinical proof of concept (up to Phase II clinical trials). At GSK, Dr Payne has played a leading role in redesigning the strategy for antibacterial research and has helped create long-term alliances with innovative biotechnology companies which has expanded GSK’s discovery pipeline. Furthermore, he has created industry-leading partnerships with the Wellcome Trust and the Defense Threat Reduction Agency (US Department of Defense) to accelerate GSK’s antibacterial programmes. To date, Dr Payne has been involved with the progression of a broad diversity of novel mechanism antibacterial agents into development. Dr Payne has authored more than 190 papers and conference presentations.

PATENT

http://www.google.com/patents/US20090227541

4-[2-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid ethyl ester

A mixture of 4-(2-bromo-3-formyl-phenoxy)-butyric acid ethyl ester (5.50 g, 17.5 mmol), bis(neopentyl glucolato)diboron (6.80 g, 30.1 mmol), PdCl₂(dppf).CH₂Cl₂(1.30 g, 1.79 mmol), and KOAc (5.30 g, 54.1 mmol) in anhydrous THF (600 mL) was heated with stirring at 80° C. (bath temp) O/N under an atmosphere of N2. The mixture was then filtered through Celite and concentrated in vacuo to approximately one quarter of the original volume. The resulting precipitate was isolated by filtration. The precipitate was washed with THF and EtOAc and the combined filtrate was concentrated in vacuo to give an oily residue which was used directly in the next reaction without further purification.
¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.95 (s, 1H), 7.47-7.39 (m, 2H), 7.09-7.07 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 4.09-4.01 (m, 2H), 3.83 (s, 3H), 3.66 (s, 3H), 2.53 (t, J=8.0 Hz, 2H), 2.19-2.07 (m, 2H), 1.32-1.22 (m, 3H), 0.98 (s, 6H).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester

MeNO₂(1.3 mL, 25 mmol) was added dropwise to a stirred solution of crude 4-[2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid methyl ester (9.4 g), NaOH (1.0 g, 25 mmol) and H₂O (35 mL) in MeCN (90 mL) at rt. The mixture was stirred at rt O/N and then acidified (pH 2) using 4 M HCl. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated in vacuo. The residue was purified by flash chromatography (10% to 30% EtOAc in hexane) to give the title compound as a yellow oil: yield 2.52 g (45% over 2 steps).
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.04 (s, 1H), 7.46-7.42 (m, 1H), 7.07-7.05 (m, 1H), 6.88-6.86 (m, 1H), 5.87 (d, J=8.2 Hz, 1H), 5.69 (dd, J=9.2, 2.5 Hz, 1H), 5.29 (dd, J=13.3, 2.7 Hz, 1H), 4.14-3.94 (m, 5H), 2.55-2.44 (m, 2H), 2.02-1.88 (m, 2H), 1.16 (t, J=7.2 Hz, 3H); MS (ESI) m/z=322 (M−1, negative).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid

A mixture of 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester (2.51 g, 7.78 mmol), 10% NaOH (17 mL), and 1:1 MeOH/H₂O (70 mL) was stirred at rt for 5 h. The MeOH was removed in vacuo and the remaining aqueous layer was acidified to pH 1 using 2 M HCl. The aqueous layer was then extracted with EtOAc. The organic fractions were washed with brine, dried (MgSO₄), and concentrated in vacuo to give the title compound as a pale yellow foam: yield 1.85 g (81%).
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.08 (bs, 1H), 9.01 (bs, 1H), 7.46-7.41 (m, 1H), 7.06-7.04 (m, 1H) 6.89-6.87 (m, 1H), 5.70 (dd, J=7.0, 2.3 Hz, 1H), 5.30 (dd, J=13.3, 2.3 Hz, 1H), 4.55 (dd, J=13.6, 4.2 Hz, 1H), 4.03 (t, J=6.6 Hz, 2H), 2.40 (t, J=7.5 Hz, 2H), 1.95-1.89 (m, 2H); MS (ESI) m/z=296 (M+1, positive).

4-(2-Benzyloxy propoxy-2-bromobenzaldehyde

A mixture of 2-bromo-4-fluoro-benzaldehyde (30.0 g, 148 mmol), Na2CO3 (78.31 g, 738.8 mmol) and 2-benzyloxy propanol (24.56 g, 147.8 mmol) in anhydrous DMSO (300 mL) was heated with stirring at 130° C. (bath temp) for 72 h under N₂. The reaction mixture was cooled to rt and diluted with H₂O and extracted with EtOAc. The organic layer was washed with H₂O then brine, dried (MgSO₄), and concentrated in vacuo. The residue was purified by flash chromatography (hexane to 30% EtOAc in hexane) to give the title compound: yield 3.84 g (7%).
¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.22 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.42-7.20 (m, 5H), 7.12 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.8, 2.2 Hz, 1H), 4.52 (s, 2H), 4.16 (t, J=6.2 Hz, 2H), 3.65 (t, J=6.1 Hz, 2H), 2.10 (q, J=6.2 Hz, 2H).

4-(2-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde

General procedure 5: 4-(2-benzyloxy propoxy-2-bromobenzaldehyde (4.84 g, 13.9 mmol), B₂pin₂(5.27 g, 20.8 mmol), KOAc (4.08 g, 41.6 mmol), PdCl₂(dppf).CH₂Cl₂(811 mg, 8 mol %), and 1,4-dioxane (50 mL). Purification: Biotage (gradient from 2% EtOAc/hexane to 20% EtOAc/hexane): yield 4.0 g (70%).
¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.36 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.43-7.14 (m, 6H), 7.01 (dd, J=8.6, 2.7 Hz, 1H), 4.53 (s, 2H), 4.18 (t, J=6.2 Hz, 2H), 3.66 (t, J=6.1 Hz, 2H), 2.11 (q, J=6.1 Hz, 2H), 1.40 (s, 12H).

6-(2-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol

General procedure 8: 4-(2-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.0 g, 7.6 mmol), MeNO₂(924 mg, 15.1 mmol), NaOH (605 mg, 15.1 mmol), and H₂O (10 mL). Purification: flash chromatography (10% EtOAc/hexane to 40% EtOAc): yield 820 mg (30%).
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.46 (bs, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.41-7.18 (m, 6H), 7.09 (dd, J=8.6, 2.3 Hz, 1H), 5.71 (dd, J=9.2, 2.5 Hz, 1H), 5.31 (dd, J=13.3, 2.7 Hz, 1H), 4.58-4.40 (m, 3H), 4.08 (t, J=6.2 Hz, 2H), 3.60 (t, J=6.2 Hz, 2H), 2.08-1.94 (m, 2H).

3-Aminomethyl-6-(2-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol acetate salt (A31)

General procedure 13: 6-(2-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (820 mg, 2.29 mmol), 20% Pd(OH)₂(850 mg, 1 equiv w/w), and AcOH (40 mL). Purification: preparative HPLC: yield 120 mg (22%).
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.32 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.98 (bs, 1H), 4.04 (t, J=6.2 Hz, 2H), 3.56 (t, J=6.2 Hz, 2H), 3.03-2.85 (m, 1H), 2.61 (dd, J=12.9, 7.0 Hz, 1H), 1.89 (s, 3H), 1.97-1.67 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 97.44% (MaxPlot 200-400 nm), 97.77% (220 nm).
3-(3-Benzyloxy-propoxy)-2-hydroxy-benzaldehyde
3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde
7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)
Alternative synthesis of 3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A46)
- General procedure 13: A47 (0.50 g, 1.4 mmol), 20% Pd(OH)₂/C (0.5 g, 1:1 w/w), AcOH (20 mL), and H₂O (0.24 mL). The filtrate was concentrated and treated with 4 N HCl to give the title compound as a colorless solid: yield 0.22 g (47%).
- ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.42 (t, J=7.8 Hz, 1H), 6.97-6.90 (m, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.20 (dd, J=9.2, 2.5 Hz, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 3.40 (dd, J=13.3, 2.7 Hz, 1H), 2.68 (dd, J=13.1, 9.2 Hz, 1H), 1.88-1.78 (m, 2H); MS (ESI): m/z=238 (M+1, positive).

Synthesis of 3-(3-Benzyloxy-propoxy)-2-bromo-benzaldehyde (C)

To a 5° C. solution of compound A (15.0 g, 0.075 mol), B (12.0 ml, 0.075 mol) and triphenylphosphine (19.6 g, 0.075 mol) in 200 ml of anhydrous THF was added DIAD (14.8 ml, 0.075 mol) drop by drop over a period of 15 minutes. The resulting solution was warmed to room temperature over a period of 5 h and the solvent was evaporated in vacuo. The residue was dissolved in 150 ml of EtOAc and the organic layer washed with water, brine and dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) generating 13.0 g (50% yield) of C [3-(3-benzyloxy-propoxy)-2-bromo-benzaldehyde].
¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.41 (s, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.32-7.25 (m, 6H), 7.08 (d, J=8.0 Hz, 1H), 4.54 (s, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.19-2.14 (m, 2H).

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (D)

Compound C (8.9 g, 0.025 mol), KOAc (7.5 g, 0.076 mol), and bis(pinacolato)diboron (12.9 g, 0.051 mol) were dissolved in 50 ml of dry DMF and degassed for 30 minutes. To this was added PdCl₂(dppf).DCM (0.56 g, 0.76 mmol) and the contents were again degassed for 10 minutes and then heated to 90° C. for 4 h. An additional quantity of PdCl₂(dppf).DCM (0.2 g, 0.27 mmol) was added and heating was continued for an additional 2 h. The reaction was cooled to RT, filtered through celite and the solvent evaporated in vacuo. The residue was dissolved in DCM, washed with brine and the organic layer dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) provided 5.4 g (53% yield) of D [3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde].
¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 9.91 (s, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.32-7.27 (m, 5H), 7.06 (d, J=8.4 Hz, 1H), 4.49 (s, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H), 2.11-2.08 (m, 2H), 1.44 (s, 12H). ESI+MS m/z, 397 (M+H)⁺.

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (E)

To an ice cold solution of NaOH (0.68 g, 0.017 mol) in 10 ml of water was added a solution of compound D (6.8 g, 0.017 mol) dissolved in 5 ml of THF. After 15 minutes, nitromethane (0.93 ml, 0.017 mol) was added drop by drop and the content stirred at RT overnight. The THF was evaporated under reduced pressure and the contents acidified to pH-3 with 2N HCl. The aqueous layer was extracted with EtOAc several times, and the combined ethyl acetate layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of 10% EtOAc/hexane to 30% EtOAc/hexane) provided 3.7 g (55% yield) of E [7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol] 3.7 g.
¹H NMR (400 MHz, DMSO-d₆+D₂O (0.01 ml)) δ (ppm) 7.49 (t, J=7.8 Hz, 1H), 7.34-7.25 (m, 5H), 7.08 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 5.23 (dd, J=13.2, 2.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.47 (s, 2H), 4.12 (t, J=6.2 Hz, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.04-2.00 (m, 2H). ESI-MS m/z, 356 [M−H]⁻. HPLC purity: 97.12% (MaxPlot 200-400 nm).

Compound E (6.0 g, 0.016 mol) was dissolved in 50 ml of glacial acetic acid and to it was added Pd(OH)₂on Carbon (20% metal content, 50% weight-wet) (5.2 g) and the content set for hydrogenation in a Parr shaker at 45 psi for 2 h. The reaction was checked for completion and the contents were filtered through Celite. The solvent was evaporated under reduced pressure at ambient temperature to yield a gummy material. To this three times was added 15 ml of dry toluene and evaporated yielding a fluffy solid. Purification was accomplished by preparative HPLC (C18 column, using acetonitrile and 0.1% AcOH/water solution) provided 1.5 g (45% yield) of compound A46 [3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol] with 0.33 mol % acetic acid (by HNMR).
¹H NMR (400 MHz, DMSO-d₆+D₂O (0.01 ml)) δ (ppm) 7.52 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.29 (dd, J=9.2, 2.4, 1H), 4.12 (t, J=6.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.48 (dd, J=13.2, 2.8 Hz, 1H), 2.80-2.74 (m, 1H), 1.92 (t, J=6.2 Hz, 2H). ESI+MS m/z, 238 [M+H]⁺. HPLC purity: 95.67% (MaxPlot 200-400 nm) and 96.22% (220 single wavelength).

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A49)

A solution of 1 (160 g, 962.58 mmol) and triphenylphosphine (277.72 g, 1.1 eq, 1058.83 mmol) was dissolved in dichloromethane (800 mL) and cooled to 0° C. (ice/water). A solution of carbon tetrabromide (351.16 g, 1.1 eq, 1058.83 mmol) in dichloromethane (200 mL) was added dropwise and the mixture was left to stir at rt for 18 h. The dichloromethane solvent was evaporated to obtain a white solid. The solid was treated with an excess of hexanes, stirred for 1 h, filtered off and the solvent was evaporated to yield a crude product. The crude product was purified by silica gel column chromatography using 5-10% ethyl acetate and hexane to obtain 2 (199 g, 91%) as a colorless liquid.

3-(3-Benzyloxy-propoxy)-2-hydroxy-benzaldehyde (4)

To a solution of aldehyde 3 (27.47 g, 1 eq, 198.88 mmol) in 0.5 L of anhydrous DMSO was added sodium tertiary-butoxide (42.3 g, 2.2 eq, 440.31 mmol) portionwise. The reaction mixture was stirred at rt for 30 minutes. A brown color solution was formed. The reaction mixture was cooled to 0° C. and added bromide (56 g, 1.2 eq, 244.41 mmol) dropwise. The mixture was stirred at rt O/N. 90% of aldehyde 3 was converted to product. The reaction mixture was acidified to pH-3 and then extracted into EtOAc and washed with water. The organic layer was concentrated, the product was purified on silica gel column (EtOAc:hexane 80:20), to yield as compound 4 (48 g, 84.31% yield) (viscous oil).

Trifluoro-methanesulfonic acid 2-(3-benzyloxy-propoxy)-6-formyl-phenyl ester (5)

To an ice cold solution of 4 (48 g, 1.0 eq, 167.72 mmol) in 200 mL of dry DCM was added pyridine (22 mL, 1.62 eq, 272.11 mmol). To the reaction mixture trifluoromethanesulfonic anhydride (33 mL, 1.16 eq, 196.14 mol) was added drop by drop. The mixture was stirred for 3 h at 0° C. The mixture was quenched with 500 mL of 1N HCl. The compound was then extracted into DCM (300 mL) and passed through a small silica gel column and concentrated to give compound 5 (57 g, 82% yield) as a pale yellow thick oil.

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (6)

Compound 5 (65 g, 1.0 eq, 155.5 mmol), bis(pinacolato)diboron (86.9 g, 2.2 eq, 342.11 mmol), KOAc (45.7 g, 3.0 eq, 466.5 mmol) were mixed together and 600 mL of dioxane was added. The mixture was degassed with N₂for 30 minutes and PdCl₂(dppf).DCM (5.7 g, 0.05 eq, 7.77 mmol) was added. The resulting slurry was heated to 90° C. overnight. The solvent was evaporated, EtOAc was added and then filtered through a pad of Celite. The organic layer was then washed with water (2×150 mL) and the solvent was evaporated. Column chromatography using 15% EtOAc/hexanes gave compound 6 (37.1 g, 61% yield).

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

A solution of compound 6 (36 g, 1.0 eq, 90.91 mmol) in 50 mL of THF was cooled to 0° C. Nitromethane (16.6 g, 3.0 eq, 272.72 mmol) was added, followed by an aqueous solution of NaOH (3.64 g in 180 mL of H₂O). The reaction mixture was stirred at room temperature overnight. The starting material disappeared. The cyclization was afforded by adding 1N HCl until the solution was acidified and then extracted into EtOAc. The EtOAc was evaporated and the mixture was triturated with water and decanted. Column chromatography using 50% EtOAc/hexanes gave compound A47 (15.9 g, 50% yield).

(R) and (S) 7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol

4.82 g of (A47) was resolved via chiral HPLC using CHIRALPAK ADH column and CO₂:methanol (86:14) as eluent (25° C. UV detection was monitored at 230 nm. Two peaks, (S)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol and (R)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol were collected and evaporated to yellow oils. Analysis of the pooled fractions using a CHIRALPAK ADH 4.6 mm ID×250 mm analytical column and the same mobile phase provided the (S) enantiomer [0.7 g (29% yield)] with a retention time of 6.11 min and a 98.2% ee. The (R) enantiomer [1.0 g (41% yield)] had a retention time of 8.86 min and a 99.6% ee.

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A49)

(A47) (550 mg, 1.57 mmol) was dissolved in 15 mL of glacial acetic acid. 280 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 128 mg of the acetate salt of (A49). The acetate salt was treated with 10 mL of 2N HCl and stirred for 3 hours. The material was lyophilized overnight to obtain 93 mg of the hydrochloride salt of (A49) (Yield 22%).
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.82 (dd, J=13.3, 9.0 Hz, 1H), 1.95-1.83 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 98.74% (MaxPlot 200-400 nm), 98.38% (220 nm); Chiral HPLC=95.14% ee.

OTHER ISOMER

(R)-7-(3-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (0.70 g, 2.0 mmol) was dissolved in 20 mL of glacial acetic acid. 350 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 65 mg of pure compound. After purification, this acetate salt was combined with material from another reaction. This product was treated with 2N HCl (10 mL) and stirred for 3 h at rt. The material was lyophilized overnight to obtain 74 mg of the hydrochloride salt of (A50) (Yield 14%).
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.83 (dd, J=13.3, 8.6 Hz, 1H), 1.94-1.82 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 99.12% (MaxPlot 200-400 nm), 98.74% (220 nm); Chiral HPLC=98.82% ee.

REFERENCES

https://pubs.acs.org/cen/coverstory/89/8912cover3.html

https://www.yumpu.com/en/document/view/34463506/the-discovery-of-gsk2251052-a-first-in-class-boron-anacor

US20040203094 *	Sep 20, 2002	Oct 14, 2004	Martinis Susan A.	Eucyl-tRNA synthetases and derivatives thereof that activate and aminoacylate non-leucine amino acids to tRNA adaptor molecules
US20070155699 *	Aug 16, 2006	Jul 5, 2007	Anacor Pharmaceuticals	Boron-containing small molecules
US20090227541 *	Jun 19, 2008	Sep 10, 2009	Anacor Pharmaceuticals, Inc.	Boron-containing small molecules

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters. Anacor

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters.

RONALD G. MICETICH

Dr. R. G. Micetich’s research career began in 1963 as a Research Scientist with R & L Molecular Research Ltd. (established by Dr. R. U. Lemieux). This company later became Raylo Chemicals Ltd. Dr. Micetich served as the Research Director (Pharmaceutical Research) of Raylo. During the period from 1963 to 1980 Dr. Micetich’s group was involved in pharmaceutical research and process development work in antibiotics and in NSAI’s (non-steroidal anti-inflammatory agents). This work produced a drug “Mofezolac” – a NSAI which is now marketed in Japan by the Japanese company “Yoshitomi”. Market ~ U.S. $60 million.

In 1980, Dr. R. G. Micetich joined the Faculty of Pharmacy, University of Alberta as an Adjunct Professor working on projects for international big Pharma companies. The work with Taiho Pharmaceutical Company in Japan has produced another drug – a beta-lactamase inhibitor – “TAZOBACTAM” which is now marketed worldwide. This drug now produces annual sales of over US$ 1 billion.

In 1987, Dr. Micetich established a joint venture research company with Taiho, Japan called SynPhar. SynPhar had numerous patents worldwide in various therapeutic areas and many compounds and classes of compounds at various stages of development up to late preclinical.

In view of the significant growth opportunities for SynPhar and in response to the changing international market place for pharmaceuticals, Dr. Micetich acquired and transferred all the assets including intellectual property, equipment and fixtures from SynPhar to NAEJA Pharmaceutical Inc. in 1999. NAEJA is a private Albertan company, founded by the Micetich family which from an initial staff in August 1999 of 40, has grown to 130 and is still growing. NAEJA is a completely self-supporting private company with no venture capital, nor private, nor government funding. The majority of NAEJA employees hold Ph.D.’s. NAEJA has collaborative agreements with pharmaceutical companies around the world. Based on its own intellectual property, NAEJA also has a number of co-development agreements with biotech companies worldwide. Dr. Micetich laid the seeds of foundation for NAEJA and the company continues after his passing, building his legacy.

Dr. R. G. Micetich boasted over 100 publications in well know scientific journals and composed over 100 patents taken out in many countries…………..http://www.bioalberta.com/ron-micetich

more……….

RONALD G. MICETICH (1931-2006): A Scientific Career Ronald Micetich was born in Podanur, Coimbatore (South India). Following receipt of B.Sc. Honors (Chemistry, Loyola College, Madras) and M.A. (Chemistry, Madras University) degrees in India, Ron obtained a Ph.D. (Organic Chemistry, University of Saskatchewan, Canada) in 1962. Ron initiated his interest in microbiology while he was a postdoctoral fellow at the National Research Council of Canada. During the period 1963-1980, Ron held a number of industrial appointments where he rapidly advanced his industrial scientific career (research scientist → associate research director → acting research director → director pharmaceutical / agricultural research) at Raylo Chemicals in Edmonton, Alberta. In 1981 Ron joined the Faculty of Pharmacy & Pharmaceutical Sciences at the University of Alberta as an Adjunct Professor at which time a highly successful drug development program was established with Taiho Pharmaceuticals. This joint industrial collaboration led to the birth of SynPhar with Dr. Micetich as Chairman of the Board, President, CEO and Research Director (1987-1999). Ron, again as Chairman of the Board, CEO and Research Director, established NAEJA (North America, Europe, Japan, Asia) Pharmaceuticals in 1999 with a rollover of assets, including staff, equipment and intellectual property, from SynPhar Laboratories. What began as a full fledged pharmaceutical company with an extensive intellectual property portfolio and a proven track record evolved into an internationally respected pharmaceutical outsource service provider. NAEJA has carved a unique niche in the outsource industry offering extensive discovery experience and expertise. Today, NAEJA has over 120 staff that consists of over 90% scientists holding PhD degrees.,………….see link below

[PDF]RONALD G. MICETICH – University of Alberta – Journal …

https://ejournals.library.ualberta.ca/index.php/JPPS/article/…/4173

by T Yajima – ‎2008

Dr.Muhammed Majeed with Dr. Ronald Micetich, CEO, Naeja Pharmaceuticals, Edmonton Canada’.

Christopher Micetich

https://ca.linkedin.com/pub/christopher-micetich/5/b4a/6a7

Founder, President & CEO, Board Chairman

Fedora Pharmaceuticals Inc.

January 2012 – Present (3 years 10 months)Edmonton, Alberta, Canada

See us at: http://www.fedorapharma.com

Fedora Pharmaceuticals has developed a family of beta-lactamase inhibitors designed to have activity against pathogens containing all four classes of beta-lactamases. These promising novel beta-lactamase inhibitors, used in combination with various beta-lactam antibiotics to treat those antibiotic infections currently resistant to therapy, have recently been licensed to Swiss-based pharmaceutical giant, Hoffman La Roche Ltd. in what is being touted as one of the largest biotech licensing deals ever signed in Canadian history!

Fedora Pharmaceuticals in Canada and Meiji Seika in Japan, with shared world-wide rights, have teamed and jointly entered into this significant tripartite agreement with Roche. Under the terms of the agreement, Roche will obtain exclusive rights from both companies to develop and commercialize the agent worldwide excluding Japan. Fedora and Meiji will receive from Roche; an upfront payment, development, regulatory and sales event milestone payments in addition to royalties on sales of products. While the details of the amounts have not been disclosed a total deal value of US$750 Million in addition to royalties has been announced.

Fedora was founded in 2012 and is headquartered in Edmonton, Alberta, Canada.

President & CEO, Founder

Naeja

August 1999 – Present (16 years 3 months)

NAEJA Pharmaceuticals Inc. is a privately controlled pharmaceutical CRO specializing in early stage drug discovery research with particular expertise in the area of Medicinal Chemistry. NAEJA employs highly skilled PhD scientists recruited from around the globe.

The company boasts a very long and successful track record of rapidly advancing drugs through discovery into the clinic. Several drugs in latter stages of clinical development and on the market today have originated from NAEJA. Most recently is Fedora Pharmaceuticals US $750M licensing deal to Hoffman La Roche Ltd that originated from the laboratories of NAEJA.

As a privately controlled company, NAEJA are very responsive to client’s needs offering many years of drug discovery experience to successfully find ways to advance research programs in a timely, cost effective and efficient manner. NAEJA’s longstanding track record is a testimony in itself!

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B1(c2c(cccc2OCCCO)[C@H](O1)CN)O

TRAMADOL

October 29, 2015 4:25 am / 7 Comments on TRAMADOL

2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol

Tramadol (marketed as Ultram, and as generics) is an opioid pain medication used to treat moderate to moderately severepain.^[1] When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.^[5]It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin andnorepinephrine.^[6]^[7]

Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Common side effects include: constipation, itchiness and nausea, among others. A change in dosage may be recommended in those with kidney or liver problems. Its use is not recommended in women who are breastfeeding or those who are at risk of suicide.^[1]

Tramadol is marketed as a racemic mixture of both R– and S–stereoisomers.^[2] This is because the two isomers complement each other’s analgesic activity.^[2] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.^[2] Tramadol is metabolised to O-desmethyltramadol, which is a more potent opioid.^[8] It is of the benzenoid class.

Tramadol was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 inWest Germany, and 20 years later it was launched in countries such as the UK, U.S., and Australia.^[7]

Developed (from 1962) by the German company Grünenthal, and is marketed through much of the world under various trade names, including Acugersic (Malaysia), Mabron (some Eastern European countries as well as parts of the Middle and Far East), Ultram (USA), Zaldiar (France and much of Europe, as well as Russia) and Zydol (UK and Ireland).

CONFUSION ON CIS TRANS

There is some confusion within the literature as to what should be called cis and what should be called trans. For purposes of this disclosure, what is referred to herein as the trans form of Tramadol includes the R,R and S,S isomers as shown by the following two structures:

The cis form of Tramadol, as that phrase is used herein, includes the S,R and the R,S isomers which are shown by the following two structures:

Tramadol is marketed as a racemic mixture of both R and S stereoisomers. It is a μ-opioid receptor agonist, like morphine, but much less active. It inhibits reuptake of the neurotransmitters serotonin and norepinephrine, suggesting that it lifts mood and thereby may dull the brain’s perception of pain.


1R,2R-Tramadol	1S,2S-Tramadol

In the body, tramadol undergoes demethylation to several metabolites by a Cytochrome P450 enzyme (CYP2D6) in the liver, the most important of these products being O-desmethyltramadol. O-desmethyltramadol has a much stronger (200x) affinity for the μ-opioid receptor than tramadol, so in effect tramadol is a prodrug.


1R,2R–O-desmethyltramadol	1S,2S–O-desmethyltramadol

Not everyone’s liver works identically. Around 6% of the Caucasian population has a reduced CYP2D6 activity (hence reducing metabolism), so there is a reduced analgesic effect with Tramadol. These people require a dose increase of 30% to get the same pain relief as the norm. A case has been reported of a patient where, following an overdose, their ultrarapid tramadol metabolism led to excessive norepinephrine levels, with near-fatal consequences.

However, it has recently been discovered at relatively high concentrations in the roots of the African peach or pin cushion tree (Nauclea latifolia), which has a long tradition as a folk remedy. As usual, Nature got there first.

The African pin-cushion tree -from:http://upload.wikimedia.org/wikipedia/commons/4/49/Nauclea_latifolia_.jpg
The African pin-cushion tree (Nauclea latifolia)

In the area of “legal highs”, a disturbing development is a drug blend known as “Krypton”. This isn’t the noble gas, but a mixture of O-desmethyltramadol withKratom (Mitragyna speciosa, a medicinal plant that originates in SE Asia, seemingly the local equivalent of khat), which contains an alkaloid mitragynine which is also a μ-receptor agonist. Several fatalities have been linked with its use, notably in Sweden.

SYNTHESIS

(1R,2R)-Tramadol (1S,2S)-Tramadol

(1R,2S)-Tramadol (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.^[35] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at thecyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

(1R,2R)-isomer
(1S,2S)-isomer
(1R,2S)-isomer
(1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described^[36] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects^[37] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals^[38] and in humans.^[39]

Synthesised by chemists at the German company Grünenthal and brought to the market in 1977. It can readily be made by nucleophilic attack of a Grignard or RLi species upon a carbonyl group.

Synthesis of tramadol

ALSO

Paper

http://www.jmcs.org.mx/PDFS/V49/N4/04-Alvarado.pdf

Tramadol hydrochloride (1). To a solution of 3-bromoanisol 13 (0.823 g, 4.4 mmol) in dry THF (10 mL), 1.75 M n-BuLi (2.5 mL, 4.4 mmol) was added dropwise at -78°C under argon atmosphere. The mixture was stirred at the same temperature during 45 minutes and a solution of 2-dimethylaminomethylcyclohexanone 6a (0.62 g, 4mmol) in dry THF was added dropwise. The resulting mixture was stirred at -78°C for 2 h. and the solvent was removed in vacuo. Water (30 mL) was added and the product was extracted with ethyl ether (3X30 mL). The extracts were dried over sodium sulfate, filtered and evaporated in vacuum. The residue was treated with 5mL of ethyl ether saturated with hydrogen chloride; the ethyl ether was evaporated in vacuo and the resulting solid was purified by crystallization from acetone. Tramadol hydrochloride 1 was obtained as white crystals (0.94 g, 78.6%),

MP 168- 175°C.

IR (KBr): 3410, 3185, 2935, 2826, 2782, 1601, 1249, 702 cm-1;

1H NMR (CDCl3, 300 MHz) δ 1.2-1.9 (10H, m), 2.15 (6H, s), 2.45 (1H, dd, J = 15.1, 4.4 Hz), 3.82 (3H, s), 6.76 (1H, dd, J = 8, 2.4 Hz), 7.04 (1H, d, 7.6 Hz), 7.14 (1H, s), 7.26 (1H, t, 3.9 Hz), 11.4 (1H, bs);

MS (EI): m/z 263 M+ (28), 58 (100).

PATENT

http://www.google.com.ar/patents/WO1999003820A1?cl=en

Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-l-(3- methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic

Tramadol means the racemic mixture of cis-Tramadol as shown by the following chemical structures:

(1 R, 2R) (1S. 2S) cis-Tramadol

Step l Formation of Dimethylaminomethyl Cyclohexanone Hydrochloride

Dimethylaminomethyl Cyclohexanone Hydrochloride

Step 2 Formation of Tramadol Mannich Base

NaOH, Water

Toluene, TBME

Tramadol Mannich Base

Step 3 Formation of Tramadol Base Hydrate

Tramadol Base Hydrate (crude) Step 4 Purification of Tramadol Base Hydrate

Tramadol Base Hydrate (pure)

Step 5 Formation of Tramadol Hydrochloride

Tramadol Hydrochloride

Example 1

To produce the Tramadol base hydrate, a reaction vessel is charged successively with 69 Kg of Magnesium, 400 1 of dry Tetrahydrofuran (THF) and 15 1 of 3- bromoanisole.

With careful heating, the reactor temperature is brought up to ca. 30°C. The Grignard initiates at this point and exotherms to approximately 50°C. A further 5 1 of bromoanisole are added which maintains reflux. 400 1 of THF are then added before the remainder of the bromoanisole. This addition of the remainder of the bromoanisole is carried out slowly so as to sustain a gentle reflux. The reaction is refluxed after complete addition of 3-bromoanisole. The vessel is cooled and Mannich base is added. When addition is complete, the vessel is reheated to reflux for 30 minutes to ensure complete reaction. After cooling to ca. 10°C, 2,300 1 of water are added to quench the reaction. When complete, part of the solvents are distilled under vacuum. Approximately 260 1 of concentrated HC1 is added at a low temperature until a pH of 0 – 1 is reached. This aqueous phase is extracted with toluene. The toluene phases are discarded and ethyl acetate is added to the aqueous phase. 30% Ammonia solution is then charged to reach pH 9 – 10 and the phases are separated. The aqueous phases are extracted again with ethyl acetate and finally all ethyl acetate layers are combined and washed twice with water. Ethyl acetate is then distilled from the reaction solution at atmospheric pressure. Process water is added and the solution cooled to 20°C and seeded. After crystallisation, the vessel is cooled to -5 to 0°C and stirred for one hour.

The product is centrifuged at this temperature and washed with cold ethyl acetate 5 x 50 1. Approximately 310 – 360 Kg of moist cis-Tramadol base hydrate are obtained.

Purification

A reactor vessel is charged successively with cis-Tramadol base hydrate (crude) 200 Kg and ethyl acetate 300 1 and the contents of the vessel heated to 50°C until all solids are in solution. The vessel is then cooled to -5 to 0°C and the product crystallises. Stirring is continued for two hours and the product is then centrifuged and washed with cold ethyl acetate, 2 x 25 1. Approximately 165 – 175 Kg (moist) of cis(+/-) Tramadol base hydrate are obtained from this procedure.

The overall process produced high yields of cis-Tramadol with a trans isomer content of less than 0.03%. Analytical data of the base hydrate of cis-Tramadol

Melting point: 79 – 80°C (in comparison cis-Tramadol base anhydrous is an oil). Water content (KF) : 6.52% (= monohydrate) IR-spectrum of the base hydrate of cis-Tramadol (see Fig. 1).

IR-spectrum (=cis-Tramadol base anhydrous, see Fig. 2).

The invention provides a unique process in which a base hydrate of cis-Tramadol is selectively crystallised without impurities. The base hydrate is processed to readily form cis-Tramadol hydrochloride. The process is substantially simpler than known processes and does not require the use of potentially toxic solvents. Thus the process is environmentally friendly.

The base hydrate of cis-Tramadol prepared may also be used in various formulations.

The base hydrate of cis-Tramadol may be formulated in the form of a solid with a slow release profile. For example, slow release pellets may be prepared by coating a suitable core material with a coating, for example, of ethylcellulose/schellack solution (4:1) and suitable pharmaceutical excipients. The pellets have typical average diameter of 0.6 to 1.6 mm. The pellets may be readily converted into gelatine capsules or pressed into tablet form using well-known techniques.

Alternatively the base hydrate of cis-Tramadol may be formulated into effervescent tablets by forming granules of the base hydrate with acidity/taste modifiers and a suitable effervescent base such as sodium hydrogen carbonate /anhydrous sodium carbonate (12:1). The ingredients are typically blended in a mixer /granulator and heated until granulation occurs. The resulting granules may be pressed into tablet form, on cooling. Of particular interest is the use of the base hydrate of cis-Tramadol in a form for parenteral use/injectables. The base hydrate is typically dissolved in water together with suitable excipients (as necessary). The solution is filtered through a membrane to remove solid fibres or particles. The filtered solution may then be filled into ampoules, typically containing 10.0 mg of the active compound. Usually the formulation is prepared for intramuscular injection.

PATENT

http://www.google.com/patents/EP1346978A1?cl=en

Various processes for the synthesis of tramadol hydrochloride have been described in the prior art. For example, US 3 652 589 and British patent specification no. 992 399 describe the preparation of tramadol hydrochloride. In this method, Grignard reaction of 2-dimethylaminomethyl cyclohexanone (Mannich base) with metabromo-anisole gives an oily mixture of tramadol and the corresponding cis isomer, along with Grignard impurities. This oily reaction mixture is subjected to high vacuum distillation at high temperature to give both the geometric isomers of the product base as an oil. This oil, on acidification with hydrogen chloride gas, furnishes insufficiently pure tramadol hydrochloride as a solid. This must then be purified, by using a halogenated solvent and 1,4-dioxane, to give sufficiently pure tramadol hydrochloride. The main drawback of this process is the use of large quantities of 1,4-dioxane and the need for multiple crystallizations to get sufficiently pure trans isomer hydrochloride (Scheme – 1).
[0004]

The use of dioxane for the separation of tramadol hydrochloride from the corresponding cis isomer has many disadvantages, such as safety hazards by potentially forming explosive peroxides, and it is also a category 1 carcinogen (Kirk and Othmer, 3^rd edition, 17, 48). Toxicological studies of dioxane show side effects such as CNS depression, and necrosis of the liver and kidneys. Furthermore, the content of dioxane in the final tramadol hydrochloride has been strictly limited; for example, the German Drug Codex (Deutscher Arzneimittel Codex, DAC (1991)) restricts the level of dioxane in tramadol hydrochloride to 0.5 parts per million (ppm).
In another process, disclosed in US patent specification no. 5 414 129, the purification and separation of tramadol hydrochloride is undertaken from a reaction mixture containing the trans and cis isomers, and Grignard reaction side products, in which the reaction mixture is diluted in isopropyl alcohol and acidified with gaseous hydrogen chloride to yield (trans) tramadol hydrochloride (97.8%) and its cis isomer (2.2%), which is itself crystallized twice with isopropyl alcohol to give pure (trans) tramadol hydrochloride (Scheme – 2). This process relies on the use of multiple solvents to separate the isomers (ie butylacetate, 1-butanol, 1-pentanol, primary amyl alcohol mixture, 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol and anisole). The main drawback of this process is therefore in using high boiling solvents; furthermore, the yields of tramadol hydrochloride are still relatively low and the yield of the corresponding cis hydrochloride is relatively high in most cases.
PCT patent specification no. WO 99/03820 describes a method of preparation of tramadol (base) monohydrate, which involves the reaction of Mannich base with metabromo-anisole (Grignard reaction) to furnish a mixture of tramadol base with its corresponding cis isomer and Grignard impurities. This, on treatment with an equimolar quantity of water and cooling to 0 to -5°C, gives a mixture of tramadol (base) monohydrate with the corresponding cis isomer (crude). It is further purified with ethyl acetate to furnish pure (trans) tramadol (base) monohydrate, which is again treated with hydrochloric acid in the presence of a suitable solvent to give its hydrochloride salt (Scheme – 2). The drawback of this method is that, to get pure (trans) tramadol hydrochloride, first is prepared pure (trans) tramadol (base) monohydrate, involving a two-step process, and this is then converted to its hydrochloride salt. The overall yield is low because of the multiple steps and tedious process involved.
More recently, a process for the separation of tramadol hydrochloride from a mixture with its cis isomer, using an electrophilic reagent, has been described in US patent specification no. 5 874 620. The mixture of tramadol hydrochloride with the corresponding cis isomer is reacted with an electrophilic reagent, such as acetic anhydride, thionyl chloride or sodium azide, using an appropriate solvent (dimethylformamide or chlorobenzene) to furnish a mixture of tramadol hydrochloride (93.3 to 98.6%) with the corresponding cis isomer (1.4 to 6.66%), (Scheme – 3). The product thus obtained is further purified in isopropyl alcohol to give pure (trans) tramadol hydrochloride. However, the drawback of this process is that a mixture of tramadol base with its cis isomer is first converted into the hydrochloride salts, and this is further reacted with toxic, hazardous and expensive electrophilic reagents to get semi-pure (trans) tramadol hydrochloride. The content of the cis isomer is sufficiently high to require further purification, and this therefore results in a lower overall yield.
Therefore, all the known methods require potentially toxic solvents and/or reagents, and multiple steps to produce the desired quality and quantity of tramadol hydrochloride. By contrast, the present invention requires a single step process (or only two steps when tramadol hydrochloride is made via the tramadol (base) monohydrate route) using a natural solvent (ie water) in the absence of carcinogenic solvents (such as the category 1 carcinogen, 1,4-dioxane) to produce pure tramadol hydrochloride, so it is ‘ecofriendly’ and easily commercialized to plant scale without any difficulties.

PATENT

http://www.google.co.in/patents/US6399829

EXAMPLE 8 Hydrochloride Formed without Improvement of the Trans:Cis Ratio

Whether a recrystallization step improves the trans:cis ratio of Tramadol depends upon the solvent composition from which the recrystallization is performed. When the hydrochloride form of Tramadol is produced and then crystallized in the presence of a solvent with a high toluene concentration, the ratio of trans:cis remains essentially unchanged. This is in contrast to the recrystallization from a solvent which has a high acetonitrile concentration as was the case in Examples 5-7.

A 21 mL solution of 1.8 g of HCl gas (bubbled at 5° C.) in acetonitrile (yielding a 2.0 M solution), was added to 10.2 g of Grignard product C (90/10 of trans/cis) in 30 mL of toluene and stirred mechanically for 3 hours. The mixture was filtered and washed with toluene. Drying in vacuo yielded 11.2 g (96% recovery). The resulting hydrochloride had a trans/cis ratio of 92:8, essentially the same trans:cis ratio as did the 10.2 g of Grignard product C.

Recrystallization from 90 mL of acetonitrile yielded 8.83 g, which was 96.6/3.4 of trans/cis by HPLC. Of this, 8.6 g was recrystallized from 75 mL of acetonitrile to give 7.44 g, trans/cis ratio of 99.6/0.4.

This example shows that the formation of the hydrochloride in the presence of a relatively large amount of toluene (here about 60%) and crystallization from toluene-acetonitrile does not improve the trans:cis ratio. As the percentage of toluene present in the mixture of toluene and acetonitrile in a crystallization step is decreased, the trans:cis ratio of the recovered product will increase. Steps in which the hydrochloride is recrystallized from acetonitrile do yield an improved trans:cis ratio.

PATENT

https://www.google.com/patents/EP0831082A1

The synthesis of Tramadol is described in U.S. Patent No. 3,652,589 and in British Patent No. 992,399. The synthesis of Tramadol consists of a Grignard reaction between 2-dimethylaminomethylcyclohexanone and 3-methoxyphenyl magnesium bromide (Equation 1). From the reaction scheme, it is clear that both isomers (RR,SS) (Structure 1) and (RS, SR) (Structure 2) are obtained in variable ratios, depending on the reaction conditions.

The original patents assigned to Gruenenthal GmbH describe the isolation of the (RR,SS) isomer, as follows:

The complex mixture of products containing both isomers of Tramadol obtained from the Grignard reaction is distilled under reduced pressure. The isomers are distilled together at 138-140°C (0.6 mm Hg). The distillate is dissolved in ether and is reacted with gaseous HCl. The resulting mixture of both isomers of Tramadol is precipitated as hydrochlorides and filtered. The resulting mixture contains about 20% of the (RS,SR) isomer. The isomer mixture is then refluxed twice with five volumes of moist dioxane, and filtered. The cake obtained consists of pure (RR,SS) isomer. The residual solution consists of “a mixture of about 20-30% of the cis (i.e. RS,SR), which cannot be further separated by boiling dioxane” [U.S. Patent 3,652,589, Example 2].

Dioxane, used in large quantities in this process, possesses many undesirable properties. It has recently been listed as a Category I carcinogen by OSHA [Kirk & Othmer, 3rd Ed., Vol. 9, p. 386], and it is known to cause CNS depression and liver necrosis [ibid., Vol. 13, p. 267]; in addition, it tends to form hazardous peroxides [ibid., Vol 17, p. 48]. As a result, the concentration of dioxane in the final product has been strictly limited to several ppb’s, and the DAC (1991) restricted the level of dioxane in Tramadol to 0.5 ppm.

A different separation method, described in Israeli Specification No. 103096, takes advantage of the fact that the precipitation of the (RR,SS) isomer of Tramadol from its solution in medium chained alcohols (C₄-C₈) occurs faster than the precipitation of the (RS,SR) isomer, which tends to separate later. The main disadvantage of this method is, that the time interval between the end of separation of the (RR,SS) isomer and the beginning of the (RS,SR) isomer separation is variable, and seems to depend sharply on the composition of the crude mixture. Therefore, variations in the yield and the quality of the product often occur. Furthermore, about 40% of the (RR,SS) isomer does not separate and remains in solution, along with the (RS,SR) isomer. This remaining mixture cannot be further purified by this method.

Another method, described in Israeli Specification No. 116281, relies on the fact that the (RS,SR) isomer of Tramadol undergoes dehydration much faster then the (RR,SS) isomer, when treated with 4-toluenesulfonic acid, or sulfuric acid; furthermore, when the reaction is carried out in an aqueous medium, a certain amount (up to 50%) of the (RS,SR) isomer is converted to the (RR,SS) isomer. This may, of course increase the efficiency of the process.

The unreacted (RR, SS) isomer is then separated from the dehydrated products and from other impurities by simple crystallization.

While further examining the results of the latter process, it was surprisingly found that the hydroxyl group of the (RS,SR) isomer of Tramadol reacts faster than the same group of the (RR,SS) with various reagents. A plausible explanation for this observation can be supplied by comparing the structures of both isomers, and their ability to form hydrogen bonds.

Looking closely at Fig. 1 [(RR,SS) Tramadol hydrochloride] and at Fig. 2 [(RS,SR) Tramadol hydrochloride], one can provide a plausible explanation for the difference in the OH group’s activity, as follows: The proton attached to the nitrogen atom of the protonated (RR,SS) isomer of Tramadol is capable of forming a stable hydrogen bonding with the oxygen atom of the hydroxyl group (see Fig. 1). Thus, any reaction involving protonation of the hydroxyl group (such as dehydration), or any reaction in which the hydroxyl group reacts as a nucleophile (such as a nucleophilic substitution or esterification process) is less favored to occur.

In the (RS,SR) isomer, on the other hand, there is no possible way of forming a stable intramolecular hydrogen bond, and therefore, any of the above-mentioned types of reactions can easily occur, considering the fact that this particular hydroxyl group is tertiary and benzyllic.

The general purification procedure of the present invention consists of reacting a mixture of both geometrical isomers of Tramadol hydrochloride with a potential electrophile under such conditions that the (RS,SR) isomer reacts almost exclusively, while the (RR,SS) isomer remains practically intact. The resulting mixture is evaporated and the resulting solid substance is then recrystallized from isopropanol or any other suitable solvent.

Example 1

11.1 g of a mixture consisting of 77% (RR,SS) Tramadol hydrochloride and 23% of the corresponding (RS,SR) isomer were dissolved in 30 ml DMF. 1.3 g acetic anhydride were added and the reaction mixture was stirred at room temperature for 12 hours. The solvent was partly evaporated under reduced pressure and 15 ml toluene were added. The suspension obtained was filtered and washed with 5 ml toluene. 5.8 g of crystals were obtained, in which the (RR,SS):(RS,SR) isomer ratio was 70:1. The product obtained was crystallized from 12 ml isopropanol and 4 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 2

19.5 g of a mixture consisting of 60.5% (RR,SS) Tramadol hydrochloride and 40.5% of the corresponding (RS,SR) isomer were suspended in 55 ml chlorobenzene. A solution of 4 ml thionyl chloride in 15 ml chlorobenzene was added dropwise for two hours. The suspension was partly evaporated, the residue was filtered and rinsed with toluene, and 8.1 g of crystals were obtained, in which the (RR,SS):(RS, SR) isomer ratio was 14:1. The product obtained was recrystallized from isopropanol, and 6.7 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 3

33.4 g of a mixture consisting of 45% (RR,SS) Tramadol hydrochloride and 55% of the corresponding (RS,SR) isomer was immersed in 50 ml trifluoroacetic acid, 5.2 g of sodium azide was added, and the reaction mixture was stirred for 24 hours. The reaction mixture was then evaporated under reduced pressure, 50 ml water was added, and the solution was brought to pH 12 with solid potassium carbonate. The suspension was extracted with 50 ml toluene, the solvent was evaporated and 25 ml hydrogen chloride solution in isopropanol were added. The solution was cooled and filtered. 9.5 g of crude (RR,SS) Tramadol were obtained, and the crude product was purified by recrystallization from isopropanol.

The hitherto unknown (RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride was isolated from the reaction mixture, recrystallized from isopropanol and characterized as follows:

(RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride

ms : 288 m⁺
IR : 2050 cm^-1 (N₃)

¹H-NMR (DMSO): 10.42 ppm: (acidic proton); 1H; 7.40-6.90 ppm: (aromatic protons) 4H; 3.79 ppm; (OCH₃ ), 3H; 2.78, 2.42 ppm: NCH₂ ; 2H; 2.58, 2.37 ppm: [N(CH₃ )₂], 6H; 2.30-1.40 ppm: cyclohexane ring protons, 9H.

¹³C-NMR (DMSO): 159.74 ppm: C₁; 144.12 ppm: C₅; 130.08 ppm: C₃; 117.36 ppm: C₄; 112.97, 111.35 ppm: C₂, C₆; 69.61 ppm: C₈; 59.29 ppm: C₁₄; 55.21 ppm: C₇; 44.6 ppm: C₁₅; 40.12 ppm: C₁₃; 35.94, 27.02, 23.56, 21.63 ppm: cyclohexane ring carbon nucleii.

AZIDE COMPD

Bibliography

Synthesis of Tramadol

http://www.nioch.nsc.ru/icnpas98/pdf/posters1/156.pdf

http://www.opioids.com/tramadol/synthesis/index.html
Patents to Grünenthal G.m.b.H.:- K. Flick and E. Frankus, U.S. Patent 3,652,589, March 28, 1972; Chem. Abs., 1972, 76, 153321; K. Flick and E. Frankus, U.S. Patent. 3,830,934, August 20, 1974; Chem. Abs., (1974), 82, 21817 (synth)
C. Alvarado, Á. Guzmán, E. Díaz and R. Patiño, J. Mex. Chem. Soc., 49, (2005) 324-327 (synth)
G. Venkanna, G. Madhusudhan, K. Mukkanti, A. Sankar, V. M. Kumar and S. A. Ali, J. Chem. Pharm. Res., 4 (2012) 4506-4513 (synth)
A. Boumendjel, G. S.Taïwe, E. N. Bum, T. Chabrol, C. Beney, V. Sinniger, R. Haudecoeur, L. Marcourt, S. Challal, E. F. Queiroz, F. Souard, M. Le Borgne, T. Lomberget, A. Depaulis, C. Lavaud, R. Robins, J.-L. Wolfender, B. Bonaz and M. De Waard, Angew. Chem. Int. Ed., 52 (2013) 11780 –11784 (Tramadol in nature)

Action

R. B. Raffa, E. Friderichs, W. Reimann, R. P. Shank, E. E. Codd and J. L. Vaught, J. Pharmacol. Exp. Ther., 260 (1992) 275-285 (means of action)
P. Dayer, L. Collart and J. Desmeules, Drugs (Suppl. 1), (1994) 3-7.
T. A. Bamigbade, C. Davidson, R. M. Langford and J. A. Stamford, Br. J. Anaesthes., 79 (1997) 352-356. (action of enantiomers)
P. W. Keeley, G. Foster and L. Whitelaw, BMJ, 321 (2000) 1608 (auditory hallucinations with tramadol)
U. M. Stamer, F. Musshoff, M. Kobilay, B. Madea, A. Hoeft and F. Stuber, Clin. Pharmacol. Ther., 82 (2007) 41-47 (different CYP2D6 Genotypes and metabolism)
W. Leppert, Pharmacology, 87 (2011)274–285 (metabolism of tramadol to O-desmethyltramadol by CYP2D6)
A. Elkalioubie, D. Allorge, L. Robriquet, J.-F. Wiart, A. Garat, F. Broly and F. Fourrier, Eur. J. Clin. Pharmacol., 67 (2011) 855–858 (ultrarapid metabolism of tramadol)
C. F. Samer, K. I. Lorenzini, V. Rollason, Y. Daali and J. A. Desmeules, Molecular Diagnosis & Therapy, 17 (2013), 165–84 (variations in tramadol response)

Tramadol abuse

M. K. Wedge, Can. Pharm. J., 142 (2009) 71-73. (tramadol and antidepressants)
ACMD advice on O-desmethyltramadol
Y. Progler, J. Res. Med. Sci., 15 (2010) 185-188 (Tramadol abuse and smuggling into Gaza)
M. M. Fawzi, Egypt. J. Forensic Sci., 1 (2011) 99–102 (Tramadol abuse in Egypt)
I. Giraudon, K. Lowitz, P. I. Dargan, D. M. Wood and R. C. Dart, Br. J. Clin. Pharmacol., 76, (2013) 823–824 (prescription opioid abuse in the UK)
C. Stannard, BMJ, 347 (2013) f5108 (tramadol problem)
N. Hawkes, BMJ, 347 (2013) f5336 (deaths from tramadol and legal highs)
A. Winstock, J. Bell and R. Borschmann, BMJ 347 (2013) f5599 (monitoring Tramadol abuse)
S. H. Park, R. C. Wackernah and G. L. Stimmel, J. Pharm. Pract., 27 (2014) 71-78.
Unemployment in Gaza and Tramadol addiction.

Tramadol in “highs”

T. Arndt, U. Claussen, B. Güssregen, S. Schröfel, B. Stürzer, A. Werle and G. Wolf, For. Sci. Int., 208 (2011) 47-52. (Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer)
R. Kronstrand, M. Roman, G. Thelander and A. Eriksson, J. Anal. Toxicol., 35 (2011) 242–247. (fatalities from mitragynine and O-desmethyltramadol combinations in Krypton herbal mixture)
C. D. Rosenbaum, S. P. Carreiro and K. M. Babu, J. Med. Toxicol., 8 (2012) 15-32 (review of herbal marijuana alternatives, including Kratom)

Tramadol in cycling

Michael Barry, “Shadows on the Road: Life at the Heart of the Peloton, from US Postal to Team Sky”, Faber 2014.
Chris Froome, “The Climb: The Autobiography”, Viking, 2014.
http://cyclingtips.com.au/2014/05/wada-proposes-tramadol-remains-a-monitored-rather-than-a-banned-substance-in-2015/
Tramadol blamed for crashes
Tramadol use for pain in cycling

EP0778262A2 *	19 Nov 1996	11 Jun 1997	Chemagis Ltd.	Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts
EP0787715A1 *	21 Dec 1996	6 Aug 1997	Grünenthal GmbH	Process for the optical resolution of tramadol
EP0831082A1 *	19 Aug 1997	25 Mar 1998	Chemagis Ltd.	Process for the purification of (RR-SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride
US5414129 *	8 Sep 1993	9 May 1995	Chemagis, Ltd.	Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts

Reference
1	*	CHEMICAL ABSTRACTS, vol. 126, no. 26, 30 June 1997 Columbus, Ohio, US; abstract no. 343383v, page 597; column 1; XP002079824 & IL 103 096 A (CHEMAGIS LTD) 5 December 1996
2	*	CHEMICAL ABSTRACTS, vol. 127, no. 20, 17 November 1997 Columbus, Ohio, US; abstract no. 278028n, QIAO, BEN-ZHI ET AL.: “Synthesis and structure of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl )cyclohexanol.” page 683; column 2; XP002079825 & GAODENG XUEXIAO HUAXUE XUEBAO , vol. 18, no. 6, 1997, pages 902-905,

Citing Patent	Filing date	Publication date	Applicant	Title
WO1999036389A1 *	14 Jan 1999	22 Jul 1999	Nicholas Archer	Purification of tramadol
WO2000078705A1 *	22 Jun 1999	28 Dec 2000	Bernhard Akteries	Method for separating the diastereomer bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol
WO2003078380A2 *	20 Mar 2003	25 Sep 2003	Shahid Akhtar Ansari	Process for preparing tramadol hydrochloride and/or tramadol momohydrate
WO2004020390A1 *	7 Aug 2003	11 Mar 2004	Bernhard Akteries	Method for the production of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
EP1346978A1 *	21 Mar 2002	24 Sep 2003	Jubilant Organosys Limited	Process for preparing tramadol hydrochloride and/or tramadol monohydrate
US6521792 *	21 Dec 2001	18 Feb 2003	Gruenenthal Gmbh	Process for separating the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cylohexanol
US6649783	3 Oct 2001	18 Nov 2003	Euro-Celtique, S.A.	Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US6784319	15 Sep 2003	31 Aug 2004	Euro-Celtique, S.A.	Synthesis of (±)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US7030276	9 Feb 2005	18 Apr 2006	Gruenenthal Gmbh	Process for preparing 2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol
US8221792	7 Jul 2006	17 Jul 2012	Farnam Companies, Inc.	Sustained release pharmaceutical compositions for highly water soluble drugs

EP0940385A1 *	Mar 3, 1999	Sep 8, 1999	Dinamite Dipharma S.p.A.	Process for the separation of the (RR,SS)-2-(dimethylamino)methyl-1-(3-methoxyphenyl)-cyclohexanol isomer from the (RS,SR) isomer by selective precipitation
WO1999003820A1 *	Jun 26, 1998	Jan 28, 1999	Nikolopoulos Angelo	Tramadol, salts thereof and process for their preparation
WO1999036390A1 *	Jan 14, 1999	Jul 22, 1999	Nicholas Archer	Purification of tramadol
WO2000078705A1 *	Jun 22, 1999	Dec 28, 2000	Bernhard Akteries	Method for separating the diastereomer bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol

Citing Patent	Filing date	Publication date	Applicant	Title
US7470816	Nov 13, 2006	Dec 30, 2008	Ipac Laboratories Limited	Tramadol recovery process

US3652589 *	27 Jul 1967	28 Mar 1972	Gruenenthal Chemie	1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US5414129 *	8 Sep 1993	9 May 1995	Chemagis, Ltd.	Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts
EP0778262A2 *	19 Nov 1996	11 Jun 1997	Chemagis Ltd.	Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts

Citing Patent	Filing date	Publication date	Applicant	Title
US6828345 *	31 Mar 2003	7 Dec 2004	Gruenenthal Gmbh	O-substituted 6-methyltramadol derivatives
US7030276	9 Feb 2005	18 Apr 2006	Gruenenthal Gmbh	Process for preparing 2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol
US7470816	13 Nov 2006	30 Dec 2008	Ipac Laboratories Limited	Tramadol recovery process
US20050215821 *	9 Feb 2005	29 Sep 2005	Gruenenthal Gmbh	Process for preparing 2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol
US20070112074 *	13 Nov 2006	17 May 2007	Ashok Kumar	Tramadol recovery process

EP0778262A2 *	Nov 19, 1996	Jun 11, 1997	Chemagis Ltd.	Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts
US3652589 *	Jul 27, 1967	Mar 28, 1972	Gruenenthal Chemie	1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US5414129 *	Sep 8, 1993	May 9, 1995	Chemagis, Ltd.	Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts

* Cited by examiner

Referenced by

Citing Patent	Filing date	Publication date	Applicant	Title
EP0940385A1 *	Mar 3, 1999	Sep 8, 1999	Dinamite Dipharma S.p.A.	Process for the separation of the (RR,SS)-2-(dimethylamino)methyl-1-(3-methoxyphenyl)-cyclohexanol isomer from the (RS,SR) isomer by selective precipitation
DE10218862A1 *	Apr 26, 2002	Nov 6, 2003	Gruenenthal Gmbh	Verfahren zur Chlorierung tertiärer Alkohole
US6169205	Mar 4, 1999	Jan 2, 2001	Dipharma S.P.A.	Process for the purification of (RR,SS)-2-(dimethylamino) methyl-1-(3-methoxyphenyl)-cyclohexanol from (RS,SR)-2-(dimethylamino)methyl-1-(3-methoxyphenyl) cyclohexanol
US6469213	Jan 14, 2000	Oct 22, 2002	Russinsky Limited	Tramadol, salts thereof and process for their preparation
US6649783	Oct 3, 2001	Nov 18, 2003	Euro-Celtique, S.A.	Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US6784319	Sep 15, 2003	Aug 31, 2004	Euro-Celtique, S.A.	Synthesis of (±)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US7235693	Oct 26, 2004	Jun 26, 2007	Gruenenthal Gmbh	Process for chlorinating tertiary alcohols
US7470816	Nov 13, 2006	Dec 30, 2008	Ipac Laboratories Limited	Tramadol recovery process
WO1999003820A1 *	Jun 26, 1998	Jan 28, 1999	Nikolopoulos Angelo	Tramadol, salts thereof and process for their preparation

Systematic (IUPAC) name
2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Clinical data
Trade names	Ryzolt, Tramal, Ultram
AHFS/Drugs.com	monograph
MedlinePlus	a695011
Licence data	US FDA:link
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: Class C US: Schedule IV ℞ (Prescription only)
Dependence liability	Present^[1]
Routes of administration	Oral, IV, IM, rectal
Pharmacokinetic data
Bioavailability	70–75% (oral), 77% (rectal), 100% (IM)^[2]
Protein binding	20%^[3]
Metabolism	Liver-mediated demethylation andglucuronidation via CYP2D6 &CYP3A4^[2]^[3]
Biological half-life	6.3 ± 1.4 hr^[3]
Excretion	Urine (95%)^[4]
Identifiers
CAS Registry Number	27203-92-5
ATC code	N02AX02
PubChem	CID: 33741
DrugBank	DB00193
ChemSpider	31105
UNII	39J1LGJ30J
KEGG	D08623
ChEBI	CHEBI:9648
ChEMBL	CHEMBL1066
Chemical data
Formula	C₁₆H₂₅N O₂
Molecular mass	263.4 g/mol

DMF

TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH INDIA – Drug Master File submitted 3Q 2009

… 23121 A II 9 / 21 / 2009 RAKSHIT DRUGS PVT LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH INDIA Status: P = Pending A = Active I …

TRAMADOL HYDROCHLORIDE USP (NON STERILE DRUG SUBSTANCE)AS MANUFACTURED IN ANDHRA PRADESH INDIA – Drug Master File submitted 4Q 2010

… 24285 A II 10 / 29 / 2010 AUROBINDO PHARMA LTD TRAMADOL HYDROCHLORIDE USP (NON STERILE DRUG SUBSTANCE) AS MANUFACTURED IN ANDHRA PRADESH INDIA Status: P …

TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH, INDIA – Drug Master File submitted 2Q 2011

… 24954 A II 5 / 6 / 2011 PIRAMAL HEALTHCARE LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH, INDIA Status: P = Pending A = Active I …

TRAMADOL HYDROCHLORIDE USP API (PROCESS-2) (ESUB) AS MANUFACTURED IN ANDHRA PRADESH, INDIA – Drug Master File submitted 2Q 2013

… Holder Subject 27159 A II 5 / 21 / 2013 RAKS PHARMA PVT LTD TRAMADOL HYDROCHLORIDE USP API (PROCESS-2) (ESUB) AS MANUFACTURED IN ANDHRA PRADESH, …

TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA – Drug Master File submitted 1Q 2009

… 22687 A II 3 / 31 / 2009 CADILA HEALTHCARE LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA Status: P = Pending A = Active I = Inactive …

TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA – Drug Master File submitted 2Q 2009

… 22687 A II 3 / 31 / 2009 CADILA HEALTHCARE LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA Status: P = Pending A = Active I = Inactive …

TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ZHEJIANG, CHINA – Drug Master File submitted 1Q 2008

… 21249 A II 12 / 6 / 2007 ZHEJIANG HISOAR PHARMACEUTICAL CO LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ZHEJIANG, CHINA Status: P = Pending A = Active …

TRAMADOL HYDROCHLORIDE BP AS MANUFACTURED IN MAHARASHTRA, INDIA – Drug Master File submitted 3Q 2008

… 21915 A II 8 / 27 / 2008 KAMUD DRUGS PVT LTD TRAMADOL HYDROCHLORIDE BP AS MANUFACTURED IN MAHARASHTRA, INDIA Status: P = Pending A = Active …

TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN HEBEI, CHINA – Drug Master File submitted 3Q 2008

… 21805 A II 7 / 15 / 2008 HEBEI ZHONGSHENG PHARMACEUTICAL CO LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN HEBEI, CHINA Status: P = Pending A = Active …

TRAMADOL HYDROCHLORID EP AS MANUFACTURED IN MAHARASHTRA, INDIA – Drug Master File submitted 1Q 2009

… 22531 A II 2 / 11 / 2009 SEQUEL PHARMACHEM PRIVATE LTD TRAMADOL HYDROCHLORID EP AS MANUFACTURED IN MAHARASHTRA, INDIA Status: P = Pending A = Active …

Drug Master Files Submitted 1Q 2007

… 20204 A II 23-Jan-2007 TONIRA PHARMA LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA Status: P = Pending A = Active I = Inactive A | B | …

Drug Master Files Submitted or Reviewed during 4Q 2013

… ASSIGNED NUMBER 27159 A II 5 / 21 / 2013 RAKS PHARMA PVT LTD TRAMADOL HYDROCHLORIDE USP API (PROCESS-2) (ESUB) AS MANUFACTURED IN ANDHRA PRADESH, …

Drug Master Files Submitted or Reviewed during 3Q 2013

… ASSIGNED NUMBER 27159 A II 5 / 21 / 2013 RAKS PHARMA PVT LTD TRAMADOL HYDROCHLORIDE USP API (PROCESS-2) (ESUB) AS MANUFACTURED IN ANDHRA PRADESH, …

Tramadol hydrochloride..CEP

Product Name	Country	Manufacture	Chemical formula	CAS #	CEP	DMF
Tramadol hydrochloride	India	IPCA Laboratories Ltd	C16H26ClNO2	22204-88-2	R0-CEP 2008-189-Rev 00	– – –
Tramadol hydrochloride	India	Dishman Pharmaceuticals and Chemicals Ltd.	C16H26ClNO2	22204-88-2	R0-CEP 2003-148-Rev 01	– – –
Tramadol hydrochloride	India	Sun Pharmaceutical Industries Ltd.	C16H26ClNO2	22204-88-2	R1-CEP 2002-232-Rev 02	– – –
Tramadol hydrochloride	China	CSPC OUYI PHARMACEUTICAL CO., LTD.	C16H26ClNO2	22204-88-2	R0-CEP 2005-227-Rev 02	– – –
Tramadol hydrochloride	India	JUBILANT LIFE SCIENCES LIMITED	C16H26ClNO2	22204-88-2	R1-CEP 2002-199-Rev 03	– – –
Tramadol hydrochloride	India	Cadila Pharmaceuticals Ltd.	C16H26ClNO2	22204-88-2	R1-CEP 2004-098-Rev 01	– – –
Tramadol hydrochloride	Germany	AREVIPHARMA GMBH	C16H26ClNO2	22204-88-2	R0-CEP 2005-020-Rev 02	– – –
Tramadol hydrochloride New process	India	Inogent Laboratories Private Limited	C16H26ClNO2	22204-88-2	R0-CEP 2007-129-Rev 00	– – –
Tramadol hydrochloride	India	SPIC Limited, Pharmaceuticals Division	C16H26ClNO2	22204-88-2	R0-CEP 2004-245-Rev 00	– – –
Tramadol hydrochloride	Switzerland	Cilag AG CH	C16H26ClNO2	22204-88-2	R0-CEP 2006-262-Rev 00	– – –
Tramadol hydrochloride	Italy	Dipharma Francis S.r.l.	C16H26ClNO2	22204-88-2	R0-CEP 2002-105-Rev 01	– – –
Tramadol hydrochloride	Israel	Chemagis Ltd	C16H26ClNO2	22204-88-2	R1-CEP 2003-146-Rev 00	– – –
Tramadol hydrochloride	India	Wanbury LTD	C16H26ClNO2	22204-88-2	R0-CEP 2005-151-Rev 01	– – –
Tramadol hydrochloride	Germany	Excella GmbH	C16H26ClNO2	22204-88-2	R0-CEP 2003-137-Rev 02	– – –
Tramadol hydrochloride	Switzerland	Proto Chemicals AG	C16H26ClNO2	22204-88-2	R1-CEP 2002-204-Rev 01	– – –
Tramadol hydrochloride	Czech Republic	ZENTIVA K.S.	C16H26ClNO2	22204-88-2	R0-CEP 2009-214-Rev 00	– – –
Tramadol hydrochloride	United States	Noramco, Inc.	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	Germany	GRUNENTHAL GMBH	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	Ireland	IROTEC LABORATORIES	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	Switzerland	HELSINN CHEMICALS SA	C16H26ClNO2	22204-88-2		US – –
TRAMADOL HYDROCHLORIDE	Israel	Chemagis Ltd				US – –
Tramadol hydrochloride	Slovakia	“ZENTIVA, A.S.”	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	United States	WYCKOFF CHEMICAL CO INC	C16H26ClNO2	22204-88-2		US – –
TRAMADOL HYDROCHLORIDE	Germany	Excella GmbH				US – –
Tramadol hydrochloride USP (BULK)	China	SHIJIAZHUANG PHARMACEUTICAL GROUP CO LTD	C16H26ClNO2	22204-88-2		US – –
TRAMADOL HYDROCHLORIDE	Germany	EVONIK DEGUSSA GMBH				US – –
Tramadol hydrochloride	Italy	RECORDATI S.p.A.	C16H26ClNO2	22204-88-2		US – –
TRAMADOL HYDROCHLORIDE	India	Dishman Pharmaceuticals and Chemicals Ltd.				US – –
TRAMADOL HYDROCHLORIDE	India	Sun Pharmaceutical Industries Ltd.				US – –
TRAMADOL HYDROCHLORIDE	India	Cadila Pharmaceuticals Ltd.	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	Switzerland	PROTO CHEMICALS AG	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride EP	India	DAI ICHI KARKARIA LTD	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	India	PEARL ORGANICS LTD	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride EP	China	SHIJIAZHUANG PHARMACEUTICAL GROUP HUASHENG PHARMA CO LTD	C16H26ClNO2	22204-88-2		US – –
TRAMADOL HYDROCHLORIDE	India	JUBILANT LIFE SCIENCES LIMITED				US – –
TRAMADOL HYDROCHLORIDE	Germany	AREVIPHARMA GMBH				US – –
Tramadol hydrochloride	India	TONIRA PHARMA LTD	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	India	INOGENT LABORATORIES PRIVATE LIMITED	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	China	ZHEJIANG HISOAR PHARMACEUTICAL CO LTD	C16H26ClNO2	22204-88-2		US – –
TRAMADOL HYDROCHLORIDE	India	IPCA Laboratories Ltd				US – –
Tramadol hydrochloride	China	HEBEI ZHONGSHENG PHARMACEUTICAL CO LTD	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride BP	India	KAMUD DRUGS PVT LTD	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	India	Raks Pharma Pvt Ltd.	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride USP n/sterile	India	Aurobindo Pharma Ltd.	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride (YT3 PROCESS)	India	IPCA Laboratories Ltd	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	India	PIRAMAL HEALTHCARE LTD	C16H26ClNO2	22204-88-2		US – –
Tramadol hydrochloride	India	Asence Pharma Private Ltd	C16H26ClNO2	22204-88-2		– – –

SYNOPSIS FOR M. PHARM DISSERTATION

K RAMARAO – rguhs.ac.in

… PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION. … 9. Shaikh AC et al.,
Formulated and Optimized Hydrodynamically balanced Oral Controlled release Bioadhesive
Tablets of Tramadol Hydrochloride using different polymers like Carbopol 971P (CP) and …

////////TRAMADOL,

Ivermectin

October 29, 2015 4:01 am / 2 Comments on Ivermectin

IVERMECTIN

MK933

22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b

70288-86-7 71827-03-7

C₉₅H₁₄₆O₂₈
Molecular Weight:	1736.15894 g/mol

Ivermectin Chemical Structure C₄₈H₇₄O_14, 875.09

Ivermectin is a macrocyclic lactone derived from Streptomyces avermitilis with antiparasitic activity. Ivermectin exerts its anthelmintic effect via activating glutamate-gated chloridechannels expressed on nematode neurons and pharyngeal muscle cells. Distinct from the channel opening induced by endogenous glutamate transmitter, ivermectin-activated channels open very slowly but essentially irreversibly. As a result, neurons or muscle cells remain at either hyperpolarisation or depolarization state, thereby resulting in paralysis and death of the parasites. Ivermectin does not readily pass the mammal blood-brain barrier to the central nervous system where glutamate-gated chloride channels locate, hence the hosts are relatively resistant to the effects of this agent.

This drug, ivermectin, was developed by William C. Campbell of Drew University and Satoshi Ōmura of Japan’s Kitasato University. They were awarded the Nobel Prize in Physiology or Medicine. Originally, the drug was used to treat parasites in livestock and pets before becoming the mainstay of the global campaigns to combat lymphatic filariasis and onchocerciasis.

A workhorse of a drug that a few weeks ago earned its developers a Nobel prize for its success in treating multiple tropical diseases is showing early promise as a novel and desperately needed tool for interrupting malaria transmission, according to new findings presented today at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting.

At ASTMH annual meeting, new studies explore advances in using ivermectin in ‘mass drug administration’ campaigns to reduce infections in Africa and slow spread of drug resistance in Asia…http://www.pharmpro.com/news/2015/10/nobel-prize-winning-drug-could-also-fight-malaria?et_cid=4908183&et_rid=577220619&type=cta

http://www.forbes.com/sites/zackomalleygreenburg/2015/10/27/the-13-top-earning-dead-celebrities-of-2015/

This new finding was presented today at the American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting by researchers from Colorado State University.

Ivermectin has been used for decades, given once per year as a part of Mass Drug Administration (MDA) programs, to reduce the disabling worm infections onchocerciasis, which causes river blindness, and filariasis, the cause of the hugely swollen legs (elephantiasis). Merck has generously donated the entire supply of drug; other companies have followed suit with different drugs for other neglected tropical diseases.

Ivermectin (22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b) is a broad-spectrum antiparasitic drug in theavermectin family. It is sold under brand names Heartgard, Sklice^[1] and Stromectol^[2] in the United States, Ivomecworldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT^[3] in Nepal by Alive Pharmaceutical and Ivextermin Mexico by Valeant Pharmaceuticals International. In Southeast Asian countries, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. While in development, it was assigned the code MK-933 by Merck.^[4]

It is taken internally or used topically, depending on the treated condition.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basichealth system.^[5]

It is a drug for the treatment of Onchocerciasis.

The disease is also known as river blindness. It is sometimes called Robles’ disease, after the Guatemalan doctor Rodolfo Robles, who first linked the blindness with an insect a century ago (1915).

Medical uses

Ivermectin is a broad-spectrum antiparasitic agent, traditionally against parasitic worms. It is mainly used in humans in the treatment of onchocerciasis (river blindness), but is also effective against other worm infestations (such as strongyloidiasis,ascariasis, trichuriasis, filariasis and enterobiasis), and some epidermal parasitic skin diseases, including scabies.

Ivermectin is currently being used to help eliminate river blindness (onchocerciasis) in the Americas, and to stop transmissionof lymphatic filariasis and onchocerciasis around the world in programs sponsored by the Carter Center using ivermectin donated by Merck.^[6]^[7]^[8] The disease is endemic in 30 African countries, six Latin American countries, and Yemen, according to studies conducted by the World Health Organization.^[9] The drug rapidly kills microfilariae, but not the adult worms. A single oral dose of ivermectin, taken annually for the 10- to 15-year lifespan of the adult worms, is all that is needed to protect the individual from onchocerciasis.^[10]

An Ivermectin cream called Soolantra has been approved by the FDA for treatment of rosacea.^[11]^[12]

SOOLANTRA (ivermectin) cream, 1% is a white to pale yellow hydrophilic cream. Each gram of SOOLANTRA cream contains 10 mg of ivermectin. It is intended for topical use.

Ivermectin is a semi-synthetic derivative isolated from the fermentation of Streptomyces avermitilis that belongs to the avermectin family of macrocyclic lactones.

Ivermectin is a mixture containing not less than 95.0 % and not more than 102.0 % of 5-O-demethyl-22,23-dihydroavermectin A1a plus 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b or H2B1a and H2B1b, respectively; and the ratio (calculated by area percentage) of component H2B1a/(H2B1a + H2B1b)) is not less than 90.0 %.

The respective empirical formulas of H2B1a and H2B1b are C₄₈H₇₄O₁₄and C₄₇H₇₂O₁₄ with molecular weights of 875.10 and 861.07 respectively.

The structural formulas are:

SOOLANTRA™ (ivermectin) Structural Formula Illustration

Component H2B1a: R = C2H5, Component H2B1b: R = CH3.SOOLANTRA cream contains the following inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol.

River blindness?

The disease is also known as river blindness. It is sometimes called Robles’ disease, after the Guatemalan doctor Rodolfo Robles, who first linked the blindness with an insect a century ago (1915).

A sufferer of river blindness

The infection is associated with a nematode worm Onchocerca volvulus, which are transmitted by Simulium blackflies which live and breed near fast-flowing streams and rivers. The worms carry parasitic Wolbachia bacteria. The bite of the flies enables the worm larvae to enter the human’s body; after maturing into adults, followed by breeding, the larvae (microfilariae) formed move towards the skin, and release the bacteria when they die. The bacteria trigger an immune response which leads to lesions on the eye and possible blindness (the “river blindness”).

Lifecycle of Onchocerciasis volvulus
Left: the Simulium fly (from http://flipper.diff.org/app/items/6730). Right: Simplified life cycle of Onchocerciasis volvulus, modified from the original at: http://emedicine.medscape.com/article/224309-overview#a0104.

Arthropod

More recent evidence supports its use against parasitic arthropods and insects:

Mites such as scabies:^[13]^[14]^[15] It is usually limited to cases that prove to be resistant to topical treatments or that present in an advanced state (such as Norwegian scabies).^[15]

Lice:^[16]^[17] Ivermectin lotion (0.5%) is FDA-approved for patients six months of age and older.^[18] After a single, 10-minute application of this formulation on dry hair, 78% of subjects were found to be free of lice after two weeks.^[19] This level of effectiveness is equivalent to other pediculicide treatments requiring two applications.^[20]

Bed bugs:^[21] Early research shows that the drug kills bed bugs when taken by humans at normal doses. The drug enters the human bloodstream and if the bedbugs bite during that time, they will die in a few days.

Contraindications

Ivermectin is contraindicated in children under the age of five, or those who weigh less than 15 kg (33 lb);^[22] and those who are breastfeeding, and have a hepatic or renal disease.^[23]

Side effects

The main concern is neurotoxicity, which in most mammalian species may manifest as central nervous system depression, and consequent ataxia, as might be expected from potentiation of inhibitory GABA-ergic synapses.

Dogs with defects in the P-glycoprotein gene (MDR1), often collie-like herding dogs, can be severely poisoned by ivermectin.

Since drugs that inhibit CYP3A4 enzymes often also inhibit P-glycoprotein transport, the risk of increased absorption past the blood-brain barrier exists when ivermectin is administered along with other CYP3A4 inhibitors. These drugs include statins, HIV protease inhibitors, many calcium channel blockers, and glucocorticoids such as dexamethasone, lidocaine, and the benzodiazepines.^[24]

For dogs, the insecticide spinosad may have the effect of increasing the potency of ivermectin.^[25]

Pharmacology

Pharmacodynamics

Ivermectin and other avermectins (insecticides most frequently used in home-use ant baits) are macrocyclic lactones derived from the bacterium Streptomyces avermitilis. Ivermectin kills by interfering with nervous system and muscle function, in particular by enhancing inhibitory neurotransmission.

The drug binds and activates glutamate-gated chloride channels (GluCls).^[26] GluCls are invertebrate-specific members of the Cys-loop family of ligand-gated ion channelspresent in neurons and myocytes.

Pharmacokinetics

Ivermectin can be given either by mouth or injection. It does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein,^[27] (the MDR1 gene mutation affects function of this protein). Crossing may still become significant if ivermectin is given at high doses (in which case, brain levels peak 2–5 hr after administration). In contrast to mammals, ivermectin can cross the blood–brain barrier in tortoises, often with fatal consequences.

Ecotoxicity

Field studies have demonstrated the dung of animals treated with ivermectin supports a significantly reduced diversity of invertebrates, and the dung persists longer.^[28]

History

The discovery of the avermectin family of compounds, from which ivermectin is chemically derived, was made by Satoshi Ōmura of Kitasato University, Tokyo and William C. Campbell of the Merck Institute for Therapeutic research. Ōmura identified avermectin from the bacterium Streptomyces avermitilis. Campbell purified avermectin from cultures obtained from Ōmura and led efforts leading to the discovery of ivermectin, a derivative of greater potency and lower toxicity.^[29] Ivermectin was introduced in 1981.^[30] Half of the 2015 Nobel Prize in Physiology or Medicine was awarded jointly to Campbell and Ōmura for discovering avermectin, “the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases”.^[31]

It started with the avermectins. In 1974, a group of researchers headed by Professor Satoshi Ōmura of the Kitasato Institute, isolated an organism with promising antimicrobial properties in a soil sample (sample OS-3153) picked up near a golf course at Kawana, Ito City, Shizuoka Prefecture, Japan. This was passed on to researchers at the Merck, Sharpe and Dohme (MSD) research laboratories in the USA, who isolated a small family of natural products that became known as avermectins. For many years, scientists have looked in soil samples for the source of potential medicines, like the tetracyclines or streptomycin . There are 8 avermectins, molecules with closely related structures. They are made by fermentation from the bacterium Streptomyces avermitilis.

Omura Professor Satoshi Ōmura

the avermectins
The 8 different avermectins, with the differences between them shown in the table below.

Name	R1	R2	X-Y
Avermectin A_1a	Me	Et	CH=CH
Avermectin A_1b	Me	Me	CH=CH
Avermectin A_2a	Me	Et	CH₂CH(OH)
Avermectin A_2b	Me	Me	CH₂CH(OH)
Avermectin B_1a	H	Et	CH=CH
Avermectin B_1b	H	Me	CH=CH
Avermectin B_2a	H	Et	CH₂CH(OH)
Avermectin B_2b	H	Me	CH₂CH(OH)

The avermectins proved to be have biocidal activity against a wide range of parasites – such as roundworms, lungworms, mites, lice and arachnids; one of these parasites is the tick Rhipicephalus (Boophilus) microplus, one of the most important cattle parasites in tropical regions. Those with the -CH=CH- function are the more active; the most potent was Avermectin B₁, occurring as an 80:20 mixture of the similar molecules B_1a and B_1b, particularly the B_1a component. Commercially it is known as Abamectin.

Veterinary use

In veterinary medicine ivermectin is used against many intestinal worms (but not tapeworms), most mites, and some lice. Despite this, it is not effective for eliminating ticks, flies, flukes, or fleas. It is effective against larval heartworms, but not against adult heartworms, though it may shorten their lives. The dose of the medicine must be very accurately measured as it is very toxic in over-dosage. It is sometimes administered in combination with other medications to treat a broad spectrum of animal parasites. Some dog breeds (especially the Rough Collie, the Smooth Collie, the Shetland Sheepdog, and the Australian Shepherd), though, have a high incidence of a certain mutation within the MDR1 gene (coding for P-glycoprotein); affected animals are particularly sensitive to the toxic effects of ivermectin.^[32]^[33] Clinical evidence suggests kittens are susceptible to ivermectin toxicity.^[34] A 0.01% ivermectin topical preparation for treating ear mites in cats (Acarexx) is available.

Ivermectin is sometimes used as an acaricide in reptiles, both by injection and as a diluted spray. While this works well in some cases, care must be taken, as several species of reptiles are very sensitive to ivermectin. Use in turtles is particularly contraindicated.

IVERMECTIN

Chlorotris(triphenylphosphine)rhodium(I), [RhCl(PPh₃)₃]

http://www.chm.bris.ac.uk/motm/wilcat/wilcath.htm

Such selectivity found an important application in the synthesis of Ivermectin (MectizanTM). Avermectin is a naturally-occurring molecule with anthelmintic and insecticidal properties; selectively reducing one double bond using Wilkinson’s catalyst afforded Ivermectin. The resultant small change in molecular shape makes Ivermectin a much more effective drug to combat onchocerciasis (river blindness), a disease which affects many millions of people, mainly in poor African communities.

Avermectin

You need to add just two hydrogen atoms to reduce a C=C bond in avermectin.

Notes and references

“SKLICE- ivermectin lotion (NDC Code(s): 49281-183-71)”. DailyMed. February 2012. Retrieved 2015-09-09.
“STROMECTOL- ivermectin tablet (NDC Code(s): 0006-0032-20)”. DailyMed. May 2010. Retrieved 2015-09-09.
Adhikari, Santosh (2014-05-27). “ALIVE PHARMACEUTICAL (P) LTD.: Iver-DT”. ALIVE PHARMACEUTICAL (P) LTD. Retrieved 2015-10-07.
Pampiglione S, Majori G, Petrangeli G, Romi R (1985). “Avermectins, MK-933 and MK-936, for mosquito control”. Trans R Soc Trop Med Hyg 79 (6): 797–9. doi:10.1016/0035-9203(85)90121-X. PMID 3832491.
“WHO Model List of Essential Medicines” (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
The Carter Center. “River Blindness (Onchocerciasis) Program”. Retrieved2008-07-17..
The Carter Center. “Lymphatic Filariasis Elimination Program”. Retrieved 2008-07-17..
WHO. “African Programme for Onchocerciasis Control”. Retrieved 2009-11-12..
United Front Against Riverblindness. “Onchocerciasis or Riverblindness”..
United Front Against Riverblindness. “Control of Riverblindness”..
Galderma Receives FDA Approval of Soolantra (Ivermectin) Cream for Rosacea“
“SOOLANTRA- ivermectin cream (NDC Code(s): 0299-3823-30, 0299-3823-45, 0299-3823-60)”. DailyMed. December 2014. Retrieved 2015-09-09.
Brooks PA, Grace RF (August 2002). “Ivermectin is better than benzyl benzoate for childhood scabies in developing countries”. J Paediatr Child Health 38 (4): 401–4.doi:10.1046/j.1440-1754.2002.00015.x. PMID 12174005.
Victoria J, Trujillo R (2001). “Topical ivermectin: a new successful treatment for scabies”. Pediatr Dermatol 18 (1): 63–5. doi:10.1046/j.1525-1470.2001.018001063.x.PMID 11207977.
^ Jump up to:^a ^b Strong M, Johnstone PW (2007). Strong, Mark, ed. “Interventions for treating scabies”. Cochrane Database of Systematic Reviews (Online) (3): CD000320.doi:10.1002/14651858.CD000320.pub2. PMID 17636630.
Dourmishev AL, Dourmishev LA, Schwartz RA (December 2005). “Ivermectin: pharmacology and application in dermatology”. International Journal of Dermatology 44(12): 981–8. doi:10.1111/j.1365-4632.2004.02253.x. PMID 16409259.
Strycharz JP, Yoon KS, Clark JM (January 2008). “A new ivermectin formulation topically kills permethrin-resistant human head lice (Anoplura: Pediculidae)”. Journal of Medical Entomology 45 (1): 75–81. doi:10.1603/0022-2585(2008)45[75:ANIFTK]2.0.CO;2.ISSN 0022-2585. PMID 18283945.
“Sklice lotion”.
David M. Pariser, M.D., Terri Lynn Meinking, Ph.D., Margie Bell, M.S., and William G. Ryan, B.V.Sc. (November 1, 2012). “Topical 0.5% Ivermectin Lotion for Treatment of Head Lice”. New England Journal of Medicine 367: 1687–1693.doi:10.1056/NEJMoa1200107.
Study shows ivermectin ending lice problem in one treatment, Los Angeles Times, Nov 5, 2012
DONALD G. MCNEIL JR. (2012-12-31). “Pill Could Join Arsenal Against Bedbugs”. The New York Times. Retrieved 2013-04-05.
Jump up^ Dourmishev AL, Dourmishev LA, Schwartz RA (December 2005). “Ivermectin: pharmacology and application in dermatology”. International Journal of Dermatology 44(12): 981–988. doi:10.1111/j.1365-4632.2004.02253.x. PMID 16409259.
Huukelbach J, Winter B, Wilcke T, et al. (August 2004). “Tratmient masivo selectivo con ivermectina contra las helmintiasis intestinales y parasitos cutáneas en una población gravemente afectada”. Bull World Health Organ 82 (7): 563–571. doi:10.1590/S0042-96862004000800005.
Goodman and Gilman’s Pharmacological Basis of Therapeutics, 11th edition, pages 122, 1084-1087.
Jump up^ “COMFORTIS® and ivermectin interaction Safety Warning Notification”. U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM).
Yates DM, Wolstenholme AJ (August 2004). “An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis”. Int. J. Parasitol. 34 (9): 1075–81.doi:10.1016/j.ijpara.2004.04.010. PMID 15313134.
Borst P, Schinkel AH (June 1996). “What have we learnt thus far from mice with disrupted P-glycoprotein genes?”. European Journal of Cancer 32 (6): 985–990.doi:10.1016/0959-8049(96)00063-9.
Iglesias LE, Saumell CA, Fernández AS, et al. (December 2006). “Environmental impact of ivermectin excreted by cattle treated in autumn on dung fauna and degradation of faeces on pasture”. Parasitology Research 100 (1): 93–102. doi:10.1007/s00436-006-0240-x. PMID 16821034.
Fisher MH, Mrozik H (1992). “The chemistry and pharmacology of avermectins”. Annu. Rev. Pharmacol. Toxicol. 32: 537–53. doi:10.1146/annurev.pa.32.040192.002541.PMID 1605577.
W. C. CAMPBELL; R. W. BURG, , M. H. FISHER, and , R. A. DYBAS (June 26, 1984).“The Discovery of Ivermectin and Other Avermectins”. American Chemical Society. pp. 5–20. ISBN 9780841210837. |chapter= ignored (help)
“The Nobel Prize in Physiology or Medicine 2015” (PDF). Nobel Foundation. Retrieved7 October 2015.
“MDR1 FAQs”, Australian Shepherd Health & Genetics Institute, Inc.
“Multidrug Sensitivity in Dogs”, Washington State University’s College of Veterinary Medicine
Frischke H, Hunt L (April 1991). “Suspected ivermectin toxicity”. Canadian Veterinary Journal 32 (4): 245. PMC 1481314. PMID 17423775.

External links

Stromectol
The Carter Center River Blindness (Onchocerciasis) Control Program
Mectizan Donation Program
American NGDO Treating River Blindness
MERCK. 25 Years: The MECTIZAN® Donation Program
Trinity College Dublin. Prof William Campbell – The Story of Ivermectin
“IVERMECTIN- ivermectin tablet (NDC Code(s): 42799-806-01)”. DailyMed. November 2014. Retrieved 2015-09-09

Bibliography

Chapman and Hall Combined Chemical Dictionary compound code number CMD99-Y (Ivermectin); CLF13-X (Avermectin).
The World Health Organisation page on Onchocerciasis
“Organic Chemists Fighting Blindness” – the Mectizan story from the RSC Organic Division
A. Crump and K. Otoguro, Trends in Parasitology, 2005, 21, 126-132. (Ōmura’s work)
Nobel committee’s announcement.

Avermectin

R. W. Burg, B. M. Miller, E. E. Baker, J. Birnbaum, S. A. Currie, R. Hartman, Y.-L. Kong, R. L. Monaghan, G. Olson, I. Putter, J. B. Tunac, H. Wallick, E. O. Stapley, R. Oiwa, and S. Ōmura, Antimicrob. Agents Chemother., 1979, 15, 361-367 (production of avermectins)
T. W. Miller, L. Chaiet, D. J. Cole, L. J. Cole, J. E. Flor, R. T. Goegelman, V. P. Gullo, H. Joshua, A. J. Kempf, W. R. Krellwitz, R. L. Monaghan, R. E. Ormond, K. E. Wilson, G. Albers-Schönberg and I. Putter., Antimicrob. Agents Chemother., 1979, 15, 368-371 (isolation of avermectins)
J. R. Egerton, D. A. Ostlind, L. S. Blair, C. H. Eary, D. Suhayda, S. Cifelli, R. F. Riek and W. C. Campbell, Antimicrob. Agents Chemother., 1979, 15, 372-378 (efficacy of avermectins)
M. H. Fisher, Pure Appl. Chem., 1990, 62, 1231-1240 (avermectin review)
Y. J. Yoon, E.-S. Kim, Y.-S. Hwang and C.-Y. Choi, Appl. Microbiol. Biotechnol., 2004, 63, 626–634 (biosynthesis)

Ivermectin

J. C. Chabala, H. Mrozik, R. L. Tolman, P. Eskola, A. Lusi, L. H. Peterson, M. F. Woods, M. H. Fisher and W. C. Campbell, J. Med. Chem., 1980, 23, 1134-1136 (synth)
W. C. Campbell, M. H. Fisher, E. O. Stapley, G. Albers-Schönberg and T. A. Jacob, Science, 1983, 221, 823–828 (ivermectin as a new antiparasitic agent)
S. Ōmura and A. Crump, Nat. Rev. Microbiol., 2004, 2, 984-989. (“The life and times of ivermectin – a success story”).
K. Collins, Perspect. Biol. Med., 2004, 47, 100-109. (History of the Merck Mectizan donation program)
A. D. Hopkins, Eye, 2005, 19, 1057–1066 (improvements upon ivermectin treatment)
T. G. Geary, Trends in Parasitology, 2005, 21, 530–532 (20 years of ivermectin)
S. Ōmura, Int. J. Antimicrob. Ag., 2008, 31, 91–98 (25 years of Ivermectin)
A. G. Canga, A. M. S. Prieto, M. J. D. Liébana, N. F. Martínez, M. S.Vega and J. J. G. Vieitez, Vet. J., 2009, 179, 25–37 (pharmacokinetics and metabolism of ivermectin in domestic animal species)
A. Crump and S. Ōmura, Proc. Jpn. Acad., Ser. B., 2011, 87, 13-28 (ivermectin review)
I. Farrell, Education in Chemistry, November 2013. (“One in the eye for river blindness”), online.
The Mectizan donation program
Colombia eliminates river blindness

Doramectin

K. Stutzman-Engwall, S. Conlon, R. Fedechko, H. McArthur, K. Pekrun, Y. Chen, S. Jenne, C. La, N. Trinh, S. Kim, Y.-X. Zhang, R. Fox, C. Gustafsson and A. Krebber, Metabolic Engineering, 2005, 7, 27–37 (synth.)
J.-B. Wang, H.-X. Pan and G.-L. Tang, Bioorg. Med. Chem. Lett., 2011, 21, 3320–3323 (synth.)

Ivermectin
Systematic (IUPAC) name

22,23-dihydroavermectin B_1a + 22,23-dihydroavermectin B_1b
Clinical data
Trade names	Stromectol
AHFS/Drugs.com	monograph
MedlinePlus	a607069
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral, topical
Pharmacokinetic data
Protein binding	93%
Metabolism	Liver (CYP450)
Biological half-life	18 hours
Excretion	Feces; <1% urine
Identifiers
CAS Registry Number	70288-86-7 71827-03-7
ATC code	D11AX22 P02CF01 QP54AA01QS02QA03
PubChem	CID: 9812710
DrugBank	DB00602
ChemSpider	7988461
UNII	8883YP2R6D
KEGG	D00804
ChEMBL	CHEMBL341047
PDB ligand ID	IVM (PDBe, RCSB PDB)
Chemical data
Formula	C 48H 74O 14 (22,23-dihydroavermectin B_1a) C 47H 72O 14 (22,23-dihydroavermectin B_1b)
Molecular mass	875.10 g/mol

SIMILAR

Doramectin is a similar molecule, used to treat parasites in animals, such as cattle, horses, sheep and pigs.

doramectin

/////////////////ivermectin, MALARIA

Study Demonstrates Efficacy of New Tumor Treatment

October 29, 2015 3:35 am / Leave a comment

Study Demonstrates Efficacy of New Tumor Treatment

The results of a study demonstrate the efficacy of this drug in treating nonfunctional neuroendocrine tumors of lung or gastrointestinal origin.

FULL STORY

http://www.pharmpro.com/news/2015/10/study-demonstrates-efficacy-new-tumor-treatment?et_cid=4908183&et_rid=577220619&type=cta

What are “complex manufacturing processes”? A recent reply from the EMA

October 29, 2015 3:04 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Sometimes a clear definition of terms is crucial in the communication between authorities and pharmaceutical companies. Find out what the European Medicines Agency EMA defines as “complex manufacturing steps” and what authorisation holders providing a variation application need to consider.

http://www.gmp-compliance.org/enews_05072_What-are-%22complex-manufacturing-processes%22-A-recent-reply-from-the-EMA_9371,15219,S-RGL_n.html

The Variations Regulation (EC) no. 1234/2008 of the European Commission defines the procedure for variations of existing marketing authorisations. The “detailed guidelines for the various categories of variations“, which were published in the consolidated version in August 2013 in the European Official Journal, explain the interpretation and application of this Variations Regulation.

Although the “detailed guidelines” describe a number of scenarios of possible variations in some detail, there are formulations in the Guideline text which require clarification due to their blur. The EMA adopted such a case in a recent update of itsquestions and answers collection “Quality of Medicines Questions and Answers: Part 1”…

View original post 258 more words

Voxtalisib, SAR-245409, XL-765

October 28, 2015 5:22 am / 1 Comment on Voxtalisib, SAR-245409, XL-765

Voxtalisib

SAR-245409, XL-765

2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

2-Amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride

C13 H14 N6 O . Cl H, 306.751

934493-76-2

INNOVATOR Exelixis Inc,, LICENSE SANOFI

PHASE 2, Malignant neoplasms

0.2H₂O

Mol. Formula:C₁₃H₁₄N₆O∙0.2H₂O, MW:273.9
NMR………http://www.chemietek.com/Files/Line2/CHEMIETEK,%20XL765,%20Lot%2001,%20NMR%20in%20CD3OD.pdf
Mechanism of Action:selective oral inhibitor of PI3K and mTOR Indication:Cancer Treatment Stage of Development: phase ll study in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). A phase I/II trial is assessing SAR245409 in combination with letrozole in ER/PR+ HER2- breast cancer.

SAR245409 (XL765)

SAR245409 (XL765) is an orally available inhibitor of PI3K and the mammalian target of rapamycin (mTOR), which are frequently activated in human tumors and play central roles in tumor cell proliferation. Exelixis discovered SAR245409 internally and out-licensed the compound to Sanofi. SAR245409 is being evaluated by Sanofi as a single agent and in multiple combination regimens in a variety of cancer indications. Clinical trials have included a single agent phase 2 trial in Non-Hodgkin’s lymphoma, combination phase 1b/2 trials with temozolomide in patients with glioblastoma, with letrozole in hormone receptor positive breast cancer, with bendamustine and/or rituximab in lymphoma or leukemia, and a phase 1 trial in combination with a MEK inhibitor.

SAR-245409 is an investigational drug originated by Exelixis that dually inhibits mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K).

Sanofi is also evaluating the compound in phase I/II clinical trials for the treatment of malignant neoplasm as monotherpay or in combination regimen. It has also completed phase I clinical trials as an oral treatment for brain cancer.

In 2009, the drug candidate was licensed to Sanofi (formerly known as sanofi-aventis) by Exelixis worldwide for the treatment of solid tumors.

XL765 (Voxtalisib, SAR245409, Sanofi)*, a PYRIDOPYRIMIDINONE-derivative, is a highly selective, potent and reversible ATP-competitive inhibitor of pan-Class I PI3K (α, β, γ, and δ) and mTORC1/mTORC2. It is orally active, highly selective over 130 other protein kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway.

In mouse xenograft models, oral administration of XL-765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects

PATENT

WO 2014058947

http://www.google.co.in/patents/WO2014058947A1?cl=en

Example 1. Synthesis of Compound (1)

Compound (1) can be synthesized as described in WO 07/044813, which is hereby incorporated in its entirety.

Briefly, a base and an intermediate, compound (a), are added to solution of commercially available 2-metfiyl-2-thiopseudourea sulfate in a solvent such as water and stirred overnight at room temperature. After neutralization, compound (b) is collected by filtration and dried under vacuum. Treatment of compound (b) with POCI₃ and heating at reflux for 2 hours yields compound (c) which can be concentrated under vacuum to dryness. Compound (c) can be used directly in the following reaction with ethylamine carried out in a solvent such as water with heating to give compound (d). Compound (d) is then treated with iodine monochloride in a solvent such as methanol to form compound (e). Compound (e) is then dissolved in DMA, to which ethyl acrylate, Pd(OAc)₂ and a base are added. This reaction mixture is heated and reacted overnight until completion of the reaction to give compound (f), which can be purified via column chromatography.

Compound (f) is then be treated with DBU in the presence of a base, such as DIEA, and heated at reflux for 15 hours. Upon completion of the reaction, the solvent is evaporated and the residue triturated with acetone to yield compound (g). Bromination of compound (g) can be achieved through drop-wise addition of Br₂ to compound (g) in CH₂C1₂, followed by stirring overnight at room temperature. Next, filtration is carried out, and triethylamine is added so that, upon washing and drying, the product, compound (h) is obtained. A Suzuki coupling between compound (h) and lH-pyrazol-5-yl boronic acid is carried out using a Pd- catalyst such as [1,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of a base to yield compound (i). Finally, compound (i) can be converted to compound (1) of the instant invention through 1) oxidation of the methylthio group with m-CPBA, carried out at room temperature with stirring and 2) treatment of the resulting product dissolved in dioxane, with liquid ammonia. Stirring at room temperature overnight followed by purification by column chromatography gives the desired product, 2-amino-8-ethyl-4-methyl- 6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, compound (1).

PATENT

WO 2007044813

http://www.google.co.in/patents/WO2007044813A1?cl=en

Example 1 2-amino-8-ethyl-4-methyl-6-(lJΪ-pyrazol-5-yl)pyrido[2,3-</]pyrimidin-7(8J?)-one

To a solution of 2-methyl-2-thiopseudourea sulfate (Aldrich, 58.74 g, 0.422 mol) in water (1000 mL) were added sodium carbonate (81.44 g, 0.768 mol) and ethyl acetoacetate (50 g, 0.384 mol) at room temperature. The reaction mixture was stirred overnight. After neutralizing to pH = 8, the solid was collected through filtration followed by drying under vacuum overnight to afford 6-methyl-2-(methylthio)pyrimidin-4(3H)-one (57.2 g, 95% yield) of product. ¹H NMR (400 MHz, DMSO-d6): δ 12.47 (bs, IH), 5.96 (bs, lH), 2.47(s, 3H), 2.17 (s, 3H).

To the round bottom flask containing 6-methyl-2-(methylthio)pyrimidin-4(3H)- one (19 g, 121.6 mmol) was added POCl₃ (30 mL). The reaction mixture was heated to reflux for 2 h and then concentrated on a rotary evaporator to dryness. The crude 4-chloro- 6-methyl-2-(methylthio)pyrimidine was used directly in the next reaction without further purification.

To the 4-chloro-6-methyl-2-(methylthio)pyrimidine from above was added 30 mL of a solution of 70% ethylamine in water. The reaction mixture was heated to 50 ⁰C for 3 h. After completion, excess ethylamine was evaporated on rotary evaporator under vacuum. The solid was filtered and dried under vacuum to afford 7V-ethyl-6-methyl-2- (methylthio)pyrimidin-4-amine (20 g, 90% yield).

To the solution of N-emyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 121.6 mmol) in methanol was added iodine monochloride (26.58 g, 163.7 mmol) in small portions at 0 °C. Then the reaction mixture was stirred overnight. After evaporation of solvent, the residue was triturated with acetone. The product iV-ethyl-5-iodo-6-methyl-2- (methylthio)pyrimin-4-amine (25.2 g, 75% yield) was collected by filtration. ¹H NMR (400 MHz, CDCl₃): δ 5.37 (bs, IH), 3.52 (q, J = 7.2 Hz, IH), 2.50 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).

To the solution of N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimin-4-amine (25.2 g, 81.48 mmol) in DMA (260 mL) were added ethyl acrylate (12.23 g, 122.2 mmol), Pd(OAc)₂ (3.65 g, 16.25 mmol), (+)BINAP and triethyl amine (24.68 g, 244.4 mmol). Then the reaction mixture was heated to 100 ⁰C and reacted overnight. After evaporation of solvent, the residue was diluted with water and the aqueous layer was extracted with ethyl acetate. The product (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5- yl)acrylate (16.8 g, 73% yield) was isolated by silica gel column chromatography with 6-8% ethyl acetate in hexane as eluent. ¹H NMR (400 MHz, CDCl₃): δ 7.65 (d, J = 16.4Hz, IH), 6.20 (d, J = 16.4Hz, IH), 5.15 (bs, IH), 4.28(q, J = 7.2 Hz, 2H), 3.54 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).

To a solution of (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin- 5-yl)acrylate (16.8 g, 59.8 mmol) in DIPEA was added l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 15 h. After evaporation of solvent, the residue was triturated with acetone. The product 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77 g, 77% yield) was collected by filtration. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 9.6 Hz, IH), 6.63 (d, J = 9.6 Hz₅ IH), 4.5(q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[00187] To a solution of 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (6.31 g, 26.84 mmol) in DCM was added Br₂ (4.79 g, 29.52 mmol) dropwise at room temperature. Then the reaction mixture was stirred at room temperature overnight. After filtration the solid was suspended in DCM (100 mL), and triethylamine (20 mL) was added. The mixture was washed with water and dried with Na₂SO₄, and the product 6-bromo-8- ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.96 g, 83 % yield) was obtained after evaporation of DCM. ¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, IH), 4.56 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 2.62 (s, 3H), 1.34 (t, J = 7.2Hz, 3H).

To a solution of 6-bromo-8-ethyl-4-methyl-2-(methylthio)ρyrido[2,3- d]pyrimidin-7(8H)-one (0.765 g, 2.43 mmol) in DME-H₂O (10:1 11 mL) was added IH- pyrazol-5-ylboronic acid (Frontier, 0.408 g, 3.65 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH₂Cl₂ (Pd(dρρρf),0.198 g, 0.243 mmol) and triethylamine (0.736 g, 7.29 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 4 h. After cooling down to room temperature, the reaction mixture was partitioned with water and ethyl acetate. After separation, the. organic layer was dried with Na₂SO₄, and the product 8- ethyl-4-methyl-2-(methylthio)-6-(lH-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.567 g, 77% yield) was obtained by silica gel column chromatography. ¹H NMR (400 MHz, CDCl₃): δ 13.3 (bs, IH), 8.54 (s, IH), 7.82-7.07 (m, 2H), 4.45 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 2.60 (s, 3H), 1.26 (t, J = 7.2Hz, 3H).

To the solution of 8-ethyl-4-methyl-2-(methylthio)-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.123 g, 0.41mmol) in DCM (2 mL) was added MCPBA (0.176 g, 77%, 0.785 mmol) in a small portion at room temperature. Then the reaction mixture was stirred for 4 h. After evaporation of DCM, dioxane (1 mL) and liquid ammonia (1 mL) were introduced. The reaction was stirred at room temperature overnight. The product 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3-(/lpyrimidin-7(8H)- one (50.4 mg) was obtained by silica gel column chromatography. ¹H NMR (400 MHz, CD₃OD): δ 8.41 (s, IH), 7.62 (d, J – 2.0 Hz, IH), 6.96 (d, J = 2.0Hz₅ IH), 4.51 (q, J = 7.2Hz, 2H), 2.64 (s, 3H), 1.29 (t, J = 7.2Hz, 3H); MS (EI) for C₁₃H₁₄N₆O: 271.3 (MH⁺)

References:

1. P. W. Yu, et al., Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway, Mol Cancer Ther, May 2014 13; 1078-91

2. K. P. Papadopoulos, et al., Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors, Clin Cancer Res, May 1, 2014 20; 2445

3 WO 2014058947

4 WO 2013040337

5 WO 2012065019

6 WO 2009017838

7 WO 2008127678

8 WO 2008124161

9 WO 2007044698

10 WO 2007044813

WO2007044813A1	9 Oct 2006	19 Apr 2007	Exelixis Inc	PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kα
WO2012054748A2 *	20 Oct 2011	26 Apr 2012	Seattle Genetics, Inc.	Synergistic effects between auristatin-based antibody drug conjugates and inhibitors of the pi3k-akt mtor pathway
WO2012065019A2 *	11 Nov 2011	18 May 2012	Exelixis, Inc.	Pyridopyrimidinone inhibitors of p13k alpha
US7811572	14 Aug 2006	12 Oct 2010	Immunogen, Inc.	Process for preparing purified drug conjugates
US20040235840	20 May 2004	25 Nov 2004	Immunogen, Inc.	Cytotoxic agents comprising new maytansinoids

Exelixis, Inc.

210 East Grand Avenue
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(650) 837-7000 phone
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////////////Voxtalisib hydrochloride, Exelixis, SANOFI, PHASE 2, Malignant neoplasms, SAR-245409, XL-765

New “mTOR” inhibitor from Exelixis, Inc., XL 388

October 28, 2015 4:18 am / 3 Comments on New “mTOR” inhibitor from Exelixis, Inc., XL 388

XL 388

A Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)

Benzoxazepine-Containing Kinase Inhibitor

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone

[7-(6-amino-3-pyridinyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]-Methanone,

(7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone

MW 455.50, CAS 1251156-08-7, MF C₂₃ H₂₂ F N₃ O₄ S

Exelixis, Inc. INNOVATOR, IND Filed

½H2O

C23H22FN3O4S.½H2O , Molecular Weight: 464.51

MONO HYDROCHLORIDE…..CAS 1777807-51-8, [7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)

TLC Rf = 0.33 (Dichloromethane:Methanol [95:5])

Potent and selective mTOR inhibitor (IC₅₀ = 9.9 nM). Inhibits mTOR activity in an ATP-competitive manner. Exhibits >300-fold selectivity for mTOR over PI 3-K and a range of other kinases. Displays antitumor activity in athymic nude mice implanted with tumor xenografts.

SYNTHESIS

CLICK ON IMAGE FOR CLEAR VIEW……………..

Tyrosine kinases are important enzymes for signal transduction in cells. Therefore, they are often targets for the treatment of diseases that are caused by dysregulation of cellular processes, such as cancers. Mammalian target of rapamycin (mTOR) is a kinase in the phosphatidylinositol-3-kinase (PI3K) family of enzymes and is implicated in the regulation of cell growth and proliferation. Various inhibitors of mTOR have been explored as possible agents for treatment of various cancers

The mammalian target of rapamycin (mTOR) is a large protein kinase that integrates both extracellular and intracellular signals of cellular growth, proliferation, and survival. Both extracellular mitogenic growth factor signaling from cell surface receptors and intracellular signals that convey hypoxic stress, energy, and nutrient status converge at mTOR. mTOR exists in two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

mTORC1 is a key mediator of translation and cell growth, via its substrates p70S6 kinase (p70S6K) and eIF4E binding protein 1 (4E-BP1), and promotes cell survival via the serum and glucocorticoid-activated kinase (SGK), whereas mTORC2 promotes activation of prosurvival kinase AKT. mTORC1, but not mTORC2, can be inhibited by an intracellular complex between rapamycin and FK506 binding protein (FKBP). However, rapamycin–FKBP may indirectly inhibit mTORC2 in some cells by sequestering mTOR protein and thereby inhibiting assembly of mTORC2.

Given the role of mTOR signaling in cellular growth, proliferation, and survival as well as its frequent deregulation in cancers, several rapamycin analogues (rapalogues) that are selective allosteric mTORC1 inhibitors have been extensively evaluated in a number of cancer clinical trials.

Demonstrated clinical efficacy for rapalogues is currently limited to patients with advanced, metastatic renal cell carcinoma (RCC) despite extensive development efforts.

This result is likely attributed not only to a lack of inhibition of mTORC2 by rapalogues that leads to upregulation of Akt through a negative feedback loop, but also to only partial inhibition of mTORC1.Therefore, ATP-competitive mTOR inhibitors that should simultaneously inhibit both mTORC1 and mTORC2 may offer a clinical advantage over rapalogues.

As a key component of the phosphoinositide 3-kinase-related kinase (PIKK) family, which is comprised of phosphoinositide 3-kinases (PI3Ks), DNA-PK, ATM, and ATR, mTOR shares the highly conserved ATP binding pockets of the PI3K family with sequence similarity of 25% in the kinase catalytic domain.

In light of this fact, it is not surprising that many of the first reported ATP-competitive mTOR inhibitors such as BEZ235 and GDC-0980 also inhibited PI3Ks. PI3Ks are responsible for the production of 3-phosphoinositide lipid second messengers such as phosphatidylinositol 3,4,5-triphosphate (PIP3), which are involved in a number of critical cellular processes, including cell proliferation, cell survival, angiogenesis, cell adhesion, and insulin signaling.

Therefore, the development of ATP-competitive mTOR inhibitors that are selective over PI3Ks may offer an improved therapeutic potential relative to rapalogues as well as dual PI3K/mTOR inhibitors. Recently, several selective ATP-competitive mTOR inhibitors such as Torin 2 and AZD8055 have been reported with sufficient promise to warrant clinical trials.

PATENT

WO 2010118208

http://www.google.com.ar/patents/WO2010118208A1?cl=en

Example 2:

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl] [3-fluoro- 2-methyl-4-(methylsulfonyl)phenyl]methanone

tørt-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/] [l,4]oxazepine-4(5H)- carboxylate. To a mixture of 4-(te/t-butoxycarbonyl)-2,3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1 ,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol%) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77 %) as an off-white solid. MS (EI) for Ci₉H₂₃N₃O₃: 342 (MH⁺).

5-(2,3,4,5-Tetrahydrobenzo[/] [l,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/][l,4]oxazepine- 4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1 ,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5 % methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96 %). MS (EI) for Ci₄Hi₅N₃O: 242 (MH⁺).

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl][3-fluoro-2- methyl-4-(methylsulfonyl)phenyl]methanone.

To a stirred suspension of 5-(2, 3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4- (methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0 ⁰C for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.24-8.03 (dd, IH), 7.79-7.71 (m, IH), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, IH), 7.05-7.01 (dd, IH), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, IH), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36(d, 3H), 2.12-1.77 (d, 3H).

MS (EI) C₂₃H₂₂FN₃O₄S: 456 (MH⁺).

PAPER

Journal of Medicinal Chemistry (2013), 56(6), 2218-2234.

J. Med. Chem., 2013, 56 (6), pp 2218–2234

DOI: 10.1021/jm3007933

http://pubs.acs.org/doi/abs/10.1021/jm3007933

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

(7-(6-Aminopyridin-3-yl)-2,3-dihydrobenz[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone (28)

¹H NMR (400 MHz, DMSO-d₆): δ (rotamers are observed) 8.24 and 8.03 (d, J = 2.4 Hz, 1H), 7.77 and 7.72 (t, J = 7.6 Hz, 1H), 7.71–7.39 (m, 2H), 7.57 and 6.63 (d, J = 2.4 Hz, 1H), 7.28 and 7.19 (d, J = 7.6 Hz, 1H), 7.04 and 7.02 (d, J = 8.0 Hz, 1H), 6.52 and 6.46 (d, J = 8.8 Hz, 1H), 6.05 (br s, 2H), 4.93–4.31 (m, 2H), 4.28–3.56 (m, 4H), 3.37 and 3.34 (s, 3H), 2.12 and 1.77 (d,J = 1.6 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 167.3, 167.2, 166.6, 166.6, 158.9, 158.9, 158.4, 158.4, 157.4, 157.2, 155.9, 155.8, 145.4, 145.1, 145.1, 144.0, 143.9, 135.0, 134.7, 132.9, 132.8, 129.4, 129.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 125.9, 125.6, 125.4, 123.6, 123.5, 123.3, 123.1, 122.8, 122.0, 122.0, 121.9, 121.9, 121.2, 120.7, 107.8, 107.8, 70.9, 70.8, 51.1, 51.1, 47.4, 46.5, 43.5, 43.5, 43.5, 43.4, 11.0, 10.9, 10.7, 10.6. IR (KBr pellet): 1623, 1487, 1457, 1423, 1385, 1314, 1269, 1226, 1193, 1144, 1133, 1054, 1031, 962, 821, 768 cm^–1. Mp: 204–205 °C. MS (EI): m/z for C₂₃H₂₂FN₃O₄S, 456.0 (MH⁺). High-resolution MS (FAB MS using glycerol as the matrix): m/z calcd for C₂₃H₂₂FN₃O₄S 456.13878, found 456.13943.

PATENT

US20100305093

http://www.google.com/patents/US20100305093

SYNTHETIC EXAMPLES

1-Bromo-3,4-difluoro-2-methylbenzene. To a stirred mixture of 2,3-difluorotoluene (1.9 g, 14.8 mmol) and iron (82.7 mg, 1.48 mmol) in chloroform (10 mL) at rt was added bromine (76 μL, 14.8 mmol) over 2 h. The resulting mixture was stirred at rt overnight. Excess water (10 mL) was added and the reaction mixture was diluted with ether (20 mL). The separated organic layer was washed with aqueous sodium thiosulfate, brine, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was distilled to give the desired product (2.49 g, 81%) as a colorless oil.
3,4-Difluoro-2-methylbenzoic acid. To a stirred solution of 1-bromo-3,4-difluoro-2-methylbenzene (940 mg, 4.54 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium bromide (3.0 mL, 6.0 mmol) over 1 h at 0° C. The resulting mixture was stirred at rt for 24 h. Carbon dioxide (CO₂), generated from dry ice, was introduced to the reaction mixture over 2 h and the resulting mixture was stirred for an additional 30 min. The reaction mixture was quenched with addition of an excess amount of water (5 mL) and the tetrahydrofuran was removed on a rotary evaporator. The resulting aqueous layer was diluted with water (5 mL) and acidified with concentrated hydrochloric acid to pH 1-2. The white precipitate was filtered and washed with water and cold hexanes and dried under high vacuum to give the desired product (630 mg, 81%) as a white powder. MS (EI) for C₈H₆F₂O₂: 171 (MH⁻).
3-Fluoro-2-methyl-4-(thiomethyl)benzoic acid. To a stirred solution of acid 3,4-difluoro-2-methylbenzoic acid (700 mg, 4.1 mmol) in dimethylsulfoxide (5 mL) was added powdered potassium hydroxide (274 mg, 4.9 mmol) and the mixture was stirred at rt for 30 min. Sodium thiomethoxide (342 mg, 4.9 mmol) was added to the mixture and the resulting mixture was stirred at 55-60° C. for 4 h. Additional powdered potassium hydroxide (70 mg, 1.2 mmol), sodium thiomethoxide (60 mg, 0.8 mmol), and dimethylsulfoxide (2 mL) were added to the reaction mixture. After stirring for 4 h, the mixture was cooled to 0° C. and quenched with excess water (10 mL). The resulting suspension was acidified at 0° C. with concentrated hydrochloric acid to pH 1-2. The white precipitate was collected by suction filtration, washed with water and dried under vacuum overnight to give the desired product (870 mg, 100%). The intermediate sulfide was used in the next step without further purification. MS (EI) for C₉H₉FO₂S: 199.1 (MH⁻).
3-Fluoro-2-methyl-4-(methylsulfonyl)benzoic acid. To a stirred suspension of 3-fluoro-2-methyl-4-(thiomethyl)benzoic acid in an acetone/water (1 mL/10 mL) mixture was added sodium hydroxide (330 mg, 8.25 mmol) and sodium bicarbonate (680 mg, 8.1 mmol). Oxone (˜4 g) was added portionwise to the reaction mixture at 0° C. over 2 h. The reaction was monitored by LC/MS. Concentrated hydrochloric acid was added to adjust the pH 2-3 and the white precipitate was collected by suction filtration, washed with water, and dried under vacuum. Dried precipitate was suspended in water (10 mL), stirred vigorously at rt for 1 h, filtered, washed with water, and hexanes and dried under vacuum to give the desired product (886 mg, 94%) as a white powder. MS (EI) for C₉H₉FO₄S: 231 (MH⁻).
3-Fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride. A mixture of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (860 mg, 3.7 mmol) in thionyl chloride (10 mL) was heated to reflux for 3 h. (the reaction mixture became homogenous). The reaction mixture was concentrated on a rotary evaporator to give the crude acid chloride. This acid chloride was triturated with dichloromethane (2 mL) and concentrated under reduced pressure. The trituration process was repeated 3 times until the product (900 mg, 98%) was obtained as a white powder.

Reference Example 2Ethyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate hydrochloride salt

4-(ethoxycarbonyl)phenylboronic acid (22.16 g, 114 mmol), tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-carboxylate (34.08 g, 104 mmol), prepared as described in Reference Example 4, Pd(dppf)Cl₂and TEA (21 g, 208 mmol) were combined in a mixture of dioxane (200 mL) and water (20 mL). The reaction mixture was heated to 90° C. for 2 h, then cooled and the solvent removed. Purification of the residue by silica chromatography gave the desired product ester (31.3 g, 69% yield).
To the solution of tert-butyl 7-(4-(ethoxycarbonyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10.3 g, 25.93 mmol) in MeOH (120 mL) was added a solution of 4 N HCl in dioxane (50 mL). The reaction mixture was heated to 50° C. for 3 h (monitored by LC/MS). The reaction mixture was allowed to cool to rt. Ethyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate as the hydrochloride salt (8.8 g, 99% yield) was collected by suction filtration.

tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate. Commercially-available 5-bromo-2-hydroxybenzaldehyde (4.0 g, 10 mmol) and 2-aminoethanol were combined in THF/MeOH (100 mL, 10:1) and sodium borohydride (0.76 g, 2.0 mmol) was added with stirring. The resulting reaction mixture was stirred at 40° C. for 4 h, concentrated on a rotary evaporator then diluted with EtOAc (50 mL) and saturated NaHCO₃(30 mL). To this suspension was added di-tert-butyl dicarbonate (2.83 g, 13 mmol). The mixture was stirred at rt overnight. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was filtered to obtain the desired product (6.8 g, 98%) as a white solid. MS (EI) for C₁₄H₂₀BrNO₄, found 346 (MH+).
tert-Butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. tert-Butyl-5-bromo-2-hydroxybenzyl(2-hydroxyethyl)carbamate (3.46 g, 10 mmol) and triphenylphosphine (3.96 g, 15 mmol) were combined in DCM (100 mL) and diisopropyl azodicarboxylate (3.03 g, 15 mmol) was added. The resulting reaction mixture was stirred at rt for 12 h. The reaction mixture was washed with water, dried, filtered, and concentrated on a rotary evaporator. The resulting crude product was purified via silica gel chromatography eluting with 8:2 hexane/ethyl acetate to give the desired product (1.74 g, 53%) as a white solid. MS (EI) for C₁₄H₁₈BrNO₃, found 328 (MH+).

Reference Example 54-(tert-Butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid

To a stirred solution of tert-butyl-7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (10 g, 30.5 mmol), prepared as described in Reference Example 4, and triisopropylborate (9.1 mL, 40 mmol) in dry tetrahydrofuran (100 mL) was added dropwise n-butyllithium in tetrahydrofuran (1.6 M, 25 mL, 40 mmol) while maintaining the temperature below −60° C. Upon completion of addition, the reaction mixture was stirred for 30 min, then quenched with 1 N aqueous hydrochloric acid (35 mL) and allowed to warm to rt. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator. Hexane was subsequently added to the crude reaction product which resulted in the formation of a white solid. This slurry was stirred for 1 h and filtered to obtain 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (8.6 g, 95%) as a white solid. MS (EI) for C₁₄H₂₀BNO₅: 194 (M-Boc).

tert-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate. To a mixture of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol %) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77%) as an off-white solid. MS (EI) for C₁₉H₂₃N₃O₃: 342 (MH⁺).
5-(2,3,4,5-Tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5% methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96%). MS (EI) for C₁₄H₁₅N₃O: 242 (MH⁺).
[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone. To a stirred suspension of 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4-(methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0° C. for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.24-8.03 (dd, 1H), 7.79-7.71 (m, 1H), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, 1H), 7.05-7.01 (dd, 1H), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, 1H), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36 (d, 3H), 2.12-1.77 (d, 3H). MS (EI) C₂₃H₂₂FN₃O₄S: 456 (MH⁺).

PAPER

Org. Process Res. Dev., 2015, 19 (7), pp 721–734

DOI: 10.1021/acs.oprd.5b00037

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00037

The benzoxazepine core is present in several kinase inhibitors, including the mTOR inhibitor 1. The process development for a scalable synthesis of 7-bromobenzoxazepine and the telescoped synthesis of 1 are reported. Compound 1 consists of three chemically rich, distinct fragments: the tetrahydrobenzo[f][1,4]oxazepine core, the aminopyridyl fragment, and the substituted (methylsulfonyl)benzoyl fragment. Routes were developed for the preparation of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (17) and tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2). The processes for the two compounds were scaled up, and over 15 kg of each starting material was prepared in overall yields of 42% and 58%, respectively.

A telescoped sequence beginning with compound 2 afforded 7.5 kg of the elaborated intermediate 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-2-amine dihydrochloride (6) in 63% yield. Subsequent coupling with benzoic acid 17 gave 7.6 kg of the target compound 1 in 84% yield. The preferred hydrochloride salt was eventually prepared. The overall yield for the synthesis of inhibitor 1 was 21% over eight isolated synthetic steps, and the final salt was obtained with 99.7% HPLC purity.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone (1)

Compound 1 was observed as a mixture of two rotational isomers in the ¹H and ¹³C NMR spectra.

¹H NMR (400 MHz, DMSO-d₆): δ 8.24–8.03 (dd, 1H), 7.79–7.71 (m, 1H), 7.71–7.69 (dd, 0.5H), 7.57–7.57 (d, 0.5H), 7.44–7.40 (m, 1.5H), 7.29–7.19 (dd, 1H), 7.05–7.01 (dd, 1H), 6.64–6.63 (d, 0.5H), 6.54–6.45 (dd, 1H), 6.06 (s, 2H), 4.93–4.31 (m, 2H), 4.31–3.54 (m, 4H), 3.37–3.36 (d, 3H), 2.12–1.77 (d, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 167.3, 167.2, 166.6, 166.6, 158.9, 158.9, 158.4, 158.4, 157.4, 157.2, 155.9. 155.8, 145.4, 145.1, 145.1, 144.0, 143.9, 135.0, 134.7, 132.9, 132.8, 129.4, 129.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 125.9, 125.6, 125.4, 123.6, 123.5, 123.3, 123.1, 122.8, 122.0, 122.0, 121.9, 121.9, 121.2, 120.7, 107.8, 107.8, 70.9, 70.8, 51.1, 51.1, 47.4, 46.5, 43.5, 43.5, 43.5, 43.4, 11.0, 10.9, 10.7, 10.6. IR (KBr pellet): 1623, 1487, 1457, 1423, 1385, 1314, 1269, 1226, 1193, 1144, 1133, 1054, 1031, 962, 821, 768 cm^–1. MS (EI) C₂₃H₂₂FN₃O₄S: found 456.2 ([M + H]⁺). High-resolution MS (FAB-MS using glycerol as a matrix) for C₂₃H₂₂FN₃O₄S: found 456.13943 ([M + H]⁺), calcd 456.13878.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)

1·HCl as a white solid (7.81 kg, 95%, 99.7% purity by AN-HPLC).

Analyses: OVI: DMF < 100 ppm, DMC < 100 ppm, acetone = 3081 ppm, MTBE < 100 ppm, iPAc < 100 ppm, THF < 100 ppm. Heavy metals: Pd ≤ 0.2 ppm, others < 20 ppm (USP ⟨231⟩). ¹H NMR (400 MHz, DMSO-d₆), equimolar amounts of two rotamers: δ 8.20–8.40 (br s, 2H), 8.33 (s, 0.5H), 8.31 (d, J = 2.8 Hz, 0.5H), 8.15 (d, J = 2.0 Hz, 0.5H), 7.96 (dd, J = 9.7, 2.0 Hz, 0.5H), 7.70–7.78 (m, 1.5H), 7.55–7.57 (m, 0.5H), 7.51–7.55 (m, 0.5H), 7.28 (d, J = 8.6 Hz, 0.5H), 7.17 (d, J = 3.1 Hz, 0.5H), 7.15 (d, J = 5.1 Hz, 0.5H), 7.05–7.11 (m, 1.5H), 6.83 (d, J = 2.7 Hz, 0.5H), 4.86–4.99 (m, 1H), 4.29–4.56 (m, 1H), 4.10–4.27 (m, 2H), 3.93–4.04 (m, 0.5H), 3.45–3.65 (m, 1.5H), 3.37 (s, 1.5 H), 3.35 (s, 1.5H), 2.12 (d, J = 2.0 Hz, 1.5H), 1.76 (d, J = 2.0 Hz, 1.5H). ¹³C NMR (100 MHz, DMSO-d₆), equimolar amounts of two rotamers: δ 168.1, 167.5, 159.4, 159.2, 159.1, 156.6, 153.9, 153.8, 144.6, 142.9, 142.3, 133.0, 132.7, 130.0, 129.9, 129.7, 129.5, 129.1, 129.0, 128.9, 128.8, 128.5, 127.7, 127.6, 127.5, 127.1, 126.9, 124.4, 124.3, 124.1, 122.7, 122.1, 121.6, 114.4, 71.2, 51.7, 51.3, 47.9, 46.9, 44.3, 44.2, 11.7, 11.4.

REFERENCES

Anand, N.; Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of their Use and Manufacture. U.S. Patent 8,648,066, Feb 11, 2014.

Aay, N.; Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of their Use and Manufacture. U.S. Patent 8,637,499, Jan 28,2014.

US20100305093

US8637499 *	May 25, 2010	Jan 28, 2014	Exelixis, Inc.	Benzoxazepines as inhibitors of PI3K/mTOR and methods of their use and manufacture
US20120258953 *	May 25, 2010	Oct 11, 2012	Exelixis, Inc.	Benzoxazepines as Inhibitors of PI3K/mTOR and Methods of Their Use and Manufacture

PROFILE

Sriram Naganathan

Senior Director

Chemical Development at Dermira, Inc.

Lives San jose caifornia

Sriram Naganathan, S.N.: Dermira, Inc., 275 Middlefield Road, Suite 150, Menlo Park, CA 94025.

E-mail: sriram.naganathan@dermira.com.

LINKS

https://www.linkedin.com/pub/sriram-naganathan/3/50a/5b6

https://www.facebook.com/sriram.naganathan.5

snaganat@exelixis.com, sriramrevathi@yahoo.com

sriram.naganathan@dermira.com

Summary

Chemical process-development and CMC professional offering 20 years of experience from preclinical development through commercialization of small molecules and peptides.

Hands-on experience in multi-step synthesis, route-scouting, process development, scale-up, tech transfer to CRO/CMO, including manufacture under cGMP and process validation.

Extensive knowledge of CMC regulatory landscape (FDA, EMEA) including preparation of CMC sections of IND, IMPD, NDA and MAA

Experience

Senior Director, Chemical Development

Dermira, Inc.

January 2015 – Present (10 months)Menlo Park, CA

Consultant

Intarcia Therapeutics

December 2014 – January 2015 (2 months)

Senior Director

Exelixis

March 2013 – November 2014 (1 year 9 months)South San Francisco, CA

Exelixis , Inc.

210 E. Grand Ave

South San Francisco , California 94080
United States

Company Description: Exelixis, Inc. (Exelixis) is developing therapies for cancer and other serious diseases. Through its drug discovery and development activities, the Company is… more

Director

Exelixis, Inc

July 2008 – February 2013 (4 years 8 months)

Senior Scientist II

Exelixis

August 2004 – January 2008 (3 years 6 months)

Associate Director

CellGate, Inc.

2000 – 2004 (4 years)

Research Scientist

Roche Bioscience

1997 – 2000 (3 years)

Research Scientist

Cultor

1995 – 1997 (2 years)

Research Scientist

Pfizer

1994 – 1997 (3 years)

Research Assistant Professor

University of Pittsburgh

April 1992 – October 1994 (2 years 7 months)

Worked on Vitamin K mechanism in the labs of (Late) Prof Paul Dowd

Education

University at Albany, SUNY

Ph.D., Organic Chemistry (Organosulfur)

1988 – 1992

The University of Kansas

MS, Organic Chemistry

1983 – 1988

Vivekananda College (University of Madras), India

Bachelor of Science (B.Sc.), Chemistry

1980 – 1983

Shri Nehru Vidyalaya

(Above) Former Group members join Professor Block at the National ACS Meeting in San Francisco, March 2010: from left, Dr. Shuhai Zhao, Dr. Sherida Johnson, Professor Block, Dr. Sriram Naganathan.

Sriram Naganathan, Ph.D. 1992, snaganat@exelixis.com, sriramrevathi@yahoo.com

snaganathan

As many things change, many things remain constant. One such constant is the frequent reminder that “You can take the boy out of sulfur chemistry but you cannot take sulfur chemistry out of the boy”. At every stage of my professional career organic chemistry of sulfur and sulfur-containing compounds have followed me (or is it the other way around?). Not many can point to the cover of an Angewandte Chemie issue as a synopsis of his/her thesis work – I will be forever grateful for that opportunity received in the Block Group.

As a post-doc in the late Prof. Paul Dowd’s lab at the University of Pittsburgh we used sulfur-containing analogs of vitamin K to probe the mechanism of action. I was then hired at Pfizer Central Research in Groton, CT in the Specialty Chemicals Division to investigate possible decomposition pathways of sulfur-containing high-intensity artificial sweeteners.

At Roche Bioscience (Palo Alto, CA) and Exelixis (South San Francisco, CA – my current job………CHANGED……Dermira) I was involved in process development for the preparation of therapeutic agents, several of them sulfur-containing molecules. Between those two positions I was a Senior Scientist at CellGate (Sunnyvale, CA).

We attempted to exploit the chemistry of sulfur-containing linkers to target the delivery active pharmaceutical agents, using the transport properties of polyarginines. Although I thought I was only training to become a synthetic organic chemist, I did not realize that my passion was really organic reaction mechanisms until I arrived in the Block lab – the two arms of the science are truly inseparable.

I realize after many years that the seed was really sown and nurtured during the many friendly and sometimes-fiery discussions in the lab, and further solidified in my post-doc years. I learned that every “blip-in-the-baseline” cannot to be ignored, and is part of the whole story.

As a process chemist in the pharma industry, I can attribute much of my success to lessons about careful and critical evaluation of primary data and thorough knowledge of reaction mechanisms. I am currently Director, Chemical Development, at Exelixis.NOW DERMIRA.

My primary responsibility involves the manufacture and potential commercialization of our primary product, cabozantinib. It was only natural that I developed a strong interest in the science of cooking and food. I have been pursuing this avenue since moving to Northern California.

I am also an avid gardener, experimenting with growing interesting varieties of chilies, tomatoes and then combining those with all sorts of alliums. It does help that I live close enough to Gilroy, CA, that I can often smell what they are famous for as I walk out of the front door!! I have shared my knowledge in several lectures at the Tech Museum (San Jose, CA) where I was a volunteer exhibit explainer.

My family (my wife Revathi and our two high-school-age daughters Swetha and Sandhya) like to travel and also enjoy the outdoor recreation so abundant in Northern California. We try to take in a new country each year and accomplish personal challenges. After many interesting years in the tech-industry, Revathi is a full-time mom. She is also a fitness instructor at the Y. Swetha and Sandhya are part of the water polo and swim teams at their school.

Swetha is very active in a leadership role for the robotics team, and Sandhya belongs to the quiz team. Revathi and I climbed Half Dome (Yosemite) a few years ago and I just completed a 100-mile bicycle ride around Lake Tahoe.

I remain a highly-opinionated baseball and college basketball fan (favorite teams: in order, Kansas, North Carolina and whoever happens to be playing Missouri and Duke). I am still an avid photographer, although I spend no money on film (I thought I was going to be the last guy on the planet still shooting film!!). I greatly value the many friendships developed during my stay in Albany and keep in touch with many.

In fact, one of my roommates from the SUNY days was instrumental in me getting my present position. Of course, this also means that I have lost touch with several friends during the past decades. If you are reading this and haven’t contacted me in a few years, please do, via e-mail.

We enjoy entertaining guests who drop by – so now you have no excuse not to contact us, especially when you visit the SF Bay Area.

OLD PROFLE……Dr Sriram Naganathan received his Ph.D. from SUNY-Albany where he studied organosulfur chemistry. He is currently an Associate Director at CellGate, Inc. located in Sunnyvale, California. CellGate is involved in the commercialization of novel medicines by utilizing proprietary transporter technology, based on oligomers of arginine, to enhance the therapeutic potential of existing drugs. His responsibilities include process development, scale-up and GMP production of clinical candidates, as well some basic research. He previously held positions at Pfizer Central Research and Roche Bioscience.

Dermira

Thomas G. Wiggans | Founder & Chief Executive Officer……..http://dermira.com/about-us/management-team/

CEO TOM WIGGANS, LEFT AND CMO GENE GAUER, RIGHT

Map of Dermira

Exelixis, Inc.

210 East Grand Avenue
So. San Francisco, CA 94080
(650) 837-7000 phone
(650) 837-8300 fax

Directions to Exelixis, Inc.

101 Northbound from San Francisco Airport:

Take 101 North toward San Francisco.
Take the Grand Avenue exit, exit 425A, toward So San Francisco.
Turn right onto East Grand Ave.
210 East Grand Ave is on your right-hand side.

101 Southbound from San Francisco:

Take 101 South.
Take the Grand Avenue exit. Turn left at the first light.
Immediately turn left at the first light onto Grand Avenue (which will become East Grand Avenue)
210 East Grand Ave is on your right-hand side.

////////////mTOR inhibitor, Exelixis, Inc., PI3K, phosphatidylinositol-3-kinase, XL 388, XL388, IND Filed

IPI 504, Retaspamycin, Retaspimycin

October 27, 2015 4:55 am / Leave a comment

IPI 504, Retaspamycin, Retaspimycin

CAS 857402-63-2

Cas 857402-23-4 ( Retaspimycin); 857402-63-2 ( Retaspimycin HCl).

MF C31H45N3O8 BASE

MW: 587.32067 BASE

Infinity Pharmaceuticals Inc, INNOVATOR

[(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-6,20,22-trihydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16-oxo-21-(prop-2-enylamino)-17-azabicyclo[16.3.1]docosa-1(22),8,12,14,18,20-hexaen-10-yl] carbamate;hydrochloride

17-Allylamino-17-demethoxygeldanamycin Hydroquinone Hydrochloride

UNII-928Q33Q049
SEE………http://www.biotechduediligence.com/retaspamycin-hcl-ipi-504.html

Retaspimycin hydrochloride; 8,21-didehydro-17-demethoxy-18,21-dideoxo-18,21-dihydroxy-17-(2-propenylamino)-geldanamycin monohydrochloride
Application:	A novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90)
Molecular Weight:	624.17 ……….HCl salt
Molecular Formula:	C₃₁H₄₆ClN₃O_{8……….HCl salt}

Introduction

IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90).

Orphan drug designation was assigned to the compound by the FDA for the treatment of gastrointestinal stromal cancer (GIST).

Retaspimycin Hydrochloride is the hydrochloride salt of a small-molecule inhibitor of heat shock protein 90 (HSP90) with antiproliferative and antineoplastic activities. Retaspimycinbinds to and inhibits the cytosolic chaperone functions of HSP90, which maintains the stability and functional shape of many oncogenic signaling proteins and may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which may result in the induction of apoptosis.

Phase I study of Retaspimycin: A phase 1 study of IPI-504 (retaspimycin hydrochloride) administered intravenously twice weekly for 2 weeks at 22.5, 45, 90, 150, 225, 300 or 400 mg/m(2) followed by 10 days off-treatment was conducted to determine the safety and maximum tolerated dose (MTD) of IPI-504 in patients with relapsed or relapsed/refractory multiple myeloma (MM). Anti-tumor activity and pharmacokinetics were also evaluated. Eighteen patients (mean age 60.5 years; median 9 prior therapies) were enrolled. No dose-limiting toxicities (DLTs) were reported for IPI-504 doses up to 400 mg/m(2).

The most common treatment-related adverse event was grade 1 infusion site pain (four patients). All other treatment-related events were assessed as grade 1 or 2 in severity. The area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2-4 h for IPI-504 and its metabolites. Four patients had stable disease, demonstrating modest single-agent activity in relapsed or relapsed/refractory MM. (source: Leuk Lymphoma. 2011 Dec;52(12):2308-15.)

Figure Hsp90 protein partners and clients destabilized by Hsp90 inhibition (Jackson et al., 2004).

In a different approach, Infinity Pharmaceuticals has developed IPI504 (retaspimycin or 17-AAG hydroquinone, Figure 4) (Adams et al., 2005; Sydor et al., 2006), a new GA analogue, in which the quinone moiety was replaced by a dihydroquinone one. Indeed, the preclinical data suggested that the hepatotoxicity of 17-AAG was attributable to the ansamycin benzoquinone moiety, prone to nucleophilic attack.

Furthermore, it was recently reported that the hydroquinone form binds Hsp90 with more efficiency than the corresponding quinone form (Maroney et al., 2006). In biological conditions, the hydroquinone form can interconvert with GA, depending on redox equilibrium existing in cell. It has been recently proposed, that NQ01 (NAD(P)H: quinone oxidoreductase) can produce the active hydroquinone from the quinone form of IPI504 (Chiosis, 2006).

However, Infinity Pharmaceuticals showed that if the overexpression of NQ01 increased the level of hydroquinone and cell sensitivity to IPI504, it has no significant effect on its growth inhibitory activity. These results suggest that NQ01 is not a determinant of IPI504 activity in vivo (Douglas et al., 2009).

Figure 4: GA, 17-AAG, 17-DMAG and IPI504.

PATENT

http://www.google.com/patents/EP2321645A1?cl=en

Geldanamycin (IUPAC name ([18S-(4E,5Z,8R*.9R*.10E,12R*.13S*,14R*,l6S*)]- 9- [(aminocarbonyl)oxy]- 13- hydroxy- 8,14,19- trimetoxy- 4,10,12,16- tetramethyl- 2- azabicyclo[16.3.1.]docosa- 4,6.10,18,21- pentan- 3.20,22trion) is a benzoquinone ansamycin antibiotic which may be produced by the bacterium Streptorayces hygroscopicus. Geldanamycin binds specifically to HSP90 (Heat Shock Protein 90) and alters its function.

While Hsp90 generally stabilizes folding of proteins and, in particular in tumor cells, folding of overexpressed/mutant proteins such as v-Src. Bcr-Abl and p53. the Hsp90 inhibitor Geldanamycin induces degradation of such proteins.

The respectiv e formula of geldanamycin is given herein below:

E\en though geldanamycin is a potent antitumor agent, the use of geldanamycin also shows some negathe side-effects (e.g. hepatotoxicity) which led to the dev elopment of geldanamycin analogues/derivatives, in particular analogues/deriv atives containing a derivatisation at the 17 position. Without being bound by theory , modification at the 17 position of geldanamycin may lead to decreases hepatotoxicity.

Accordingly geldanamycin analogues/derivatives which are modified at the 17 position, such as 17-AAG (17-N-Allylamino-17-demethoxygeldanamycin), are preferred in context of the present invention. Also preferred herein are geldanamycin derivatives to be used in accordance with the present invention which are water-soluble or which can be dissoh ed in water completely (at least 90 %. more preferably 95 %. 96 %. 97 %, 98 % and most preferably 99 %). 17-AAG ([QS.5S,6RJS$EΛ0R,l \SΛ2E,14E)-2\- (allylamino)-6-hydroxy-5.11-diraethoxy-

3.7.9,15-tetramethyl-16.20.22-trioxo-17-azabicyclo[16.3.1]docosa-8,12.14,18,21-pentaen-10- yl] carbamate) is. as mentioned above a preferred derivative of geldanamycin. 17- AAG is commercially available under the trade name “Tanespimycin^“ (also known as KOS-953) for example from Kosan Biosciences Incorporated (Acquired by Bristol-Myers Squibb Company). Tanespimycin is presently studied in phase II clinical trials for multiple myeloma and breast cancer and is usually administered intravenously.

The respective formula of 17- AAG is given herein below:

Preferred geldanamycin-derh ative (HSP90 inhibitor) to be used in context of the present invention are IPI-504 (also known as retaspiimcin or Mcdi-561 : lnfinin Pharmaceuticals (Medlmmunc/ Astra Zeneca)). Clinical trials on the use of IPI-504 (which is usually administered intravenously) in the treatment of non-small cell lung cancer (NSCLC) and breast cancer are performed. Also alvespimycin hy drochloride (Kosan Biosciences Incorporated Acquired By : Bristol-Myers Squibb Company) is a highly potent, water-soluble and orally acti\e derivative of geldanamycin preferably used in context of the present invention.

IPI-504

PATENT

WO 2005063714

http://www.google.co.ug/patents/WO2005063714A1?cl=en

Example 24

Preparation of Air-stable Hydroquinone Derivatives of the Geldanamycin Family of Molecules

17-Allylamino-17-Demethoxygeldanamycin (10.0 g, 17.1 mmol) in ethyl acetate

(200 mL) was stirred vigorously with a freshly prepared solution of 10% aqueous sodium hydrosulfite (200 mL) for 2 h at ambient temperature. The color changed from dark purple to bright yellow, indicating a complete reaction. The layers were separated and the organic phase was dried with magnesium sulfate (15 g). The drying agent was rinsed with ethyl acetate (50 mL). The combined filtrate was acidified with 1.5 M hydrogen chloride in ethyl acetate (12 mL) to pH 2 over 20 min. The resulting slurry was stirred for 1.5 h at ambient temperature. The solids were isolated by filtration, rinsed with ethyl acetate (50 mL) and dried at 40 °C, 1 mm Hg, for 16 h to afford 9.9 g (91%) of off-white solid. Crude hydroquinone hydrochloride (2.5 g) was added to a stirred solution of 5% 0.01 N aq. hydrochloric acid in methanol (5 mL). The resulting solution was clarified by filtration then diluted with acetone (70 mL). Solids appeared after 2-3 min. The resulting slurry was stirred for 3 h at ambient temperature, then for 1 h at 0-5 °C. The solids were isolated by filtration, rinsed with acetone (15 mL) and dried

PAPER

J. Med. Chem., 2006, 49 (15), pp 4606–4615

DOI: 10.1021/jm0603116

http://pubs.acs.org/doi/abs/10.1021/jm0603116

17-Allylamino-17-demethoxygeldanamycin (17-AAG)¹ is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.

17-Allylamino-17-demethoxygeldanamycin Hydroquinone Hydrochloride Ia

17-AAG hydroquinone hydrochloride (1a) as an off-white solid (11 g, 18 mmol, 80% yield). HPLC purity: 99.6%;

IR (neat): 3175, 2972, 1728, 1651, 1581, 1546, 1456, 1392, 1316, 1224, 1099, 1036 cm^-1;

¹H NMR (CDCl₃:d₆-DMSO, 6:1, 400 MHz):

δ 10.20 (1H, br), 9.62 (2H, br), 8.53 (1H, s), 8.47 (1H, s), 7.74 (1H, s), 6.72 (1H, d, J= 11.6 Hz), 6.28 (1H, dd, J = 11.6, 11.2 Hz), 5.73 (1H, dddd, J = 17.2, 10.0, 3.2, 2.4 Hz), 5.53 (1H, d, J = 10.4 Hz), 5.49 (1H, dd, J = 10.8, 10.0 Hz), 5.32 (2H, s), 5.04 (1H, d, J = 4.8 Hz), 5.02 (1H, d, J = 16.0 Hz), 4.81 (1H, s), 4.07 (1H, d, J = 9.6 Hz), 3.67 (2H, d, J = 6.4 Hz), 3.31 (1H, d,J = 8.8 Hz), 3.07 (3H, s), 3.07−3.04 (1H, m), 2.99 (3H, s), 2.64 (1H, m), 2.52−2.49 (1H, m), 1.76 (3H, s), 1.61−1.39 (3H, m), 0.78 (3H, d, J = 6.4 Hz), 0.64 (3H, d, J = 7.2 Hz);

¹³C NMR (CDCl₃:d₆-DMSO, 6:1, 100 MHz): δ 167.3, 155.8, 143.3, 136.3, 135.0, 134.2, 132.9, 132.1, 128.8, 127.6, 125.9, 125.3, 123.7, 123.0, 115.1, 104.5, 80.9, 80.7, 80.1, 72.5, 56.2, 56.2, 52.4, 34.6, 33.2, 31.1, 27.2, 21.6, 12.1, 12.1, 11.7;

HRMS calculated for C₃₁H₄₅N₃O₈ (M⁺ + H): 588.3285, Found 588.3273.

POSTER

Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90

MEDI 210

James R. Porter, jporter@ipi.com, Jie Ge, Emmanuel Normant, Janid Ali, Marlene S. Dembski, Yun Gao, Asimina T. Georges, Louis Grenier, Roger Pak, Jon Patterson, Jens R. Sydor, Jim Wright, Julian Adams, and Jeffrey K. Tong.

Infinity Pharmaceuticals, Inc, 780 Memorial Drive, Cambridge, MA 02139

IPI-504 is the hydroquinone hydrochloride salt of 17-allylamino-17-demethoxy-geldanamycin (17-AAG), an Hsp90 inhibitor that is currently in clinical trials for the treatment of cancer.

IPI-504 demonstrates high aqueous solubility (>200 mg/mL). Interestingly, in vitro and in vivo IPI-504 interconverts with 17-AAG and exists in a pH and enzyme-mediated redox equilibrium. This occurs due to oxidation of the hydroquinone (IPI-504) to the quinone (17-AAG) at physiological pH and the reduction of 17-AAG by quinone reductases such as NQO1 to IPI-504.

Here we report the design and synthesis of the stabilized hydroquinone IPI-504 and its inhibitory effect against Hsp90 and Grp94. Although IPI-504 was originally designed to be a soluble prodrug of 17-AAG, the hydroquinone is more potent than the quinone in the biochemical Hsp90 binding assay.

Various hydroquinone analogs have been prepared to investigate the structure activity relationship of hydroquinone binding to Hsp90. Hydroquinone and quinone forms of 17-AAG metabolites show comparable binding affinities for Hsp90 and in cancer cell lines, hydroquinone analogs elicit specific responses consistent with Hsp90 inhibition.

The desirable pharmacological properties as well as in vitro and in vivo activity of our lead compound, IPI-504, has led to the initiation of Phase I clinical trials in multiple myeloma.

http://oasys2.confex.com/acs/231nm/techprogram/P945016.HTM

Geldanamycin and Beyond: Progress Toward the Development of HSP90 Inhibitors
8:30 AM-12:05 PM, Wednesday, 29 March 2006 Georgia World Congress Center — Georgia Ballroom 1, OralDivision of Medicinal Chemistry The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006

References

Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90
231st Am Chem Soc (ACS) Natl Meet (March 26-30, Atlanta) 2006, Abst MEDI 210

Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90
J Med Chem 2006, 49(15): 4606

http://www.biotechduediligence.com/retaspamycin-hcl-ipi-504.html

///////////////////Hsp90, IPI-504, infinity pharma, Retaspamycin, Retaspimycin

MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan

October 26, 2015 2:04 pm / Leave a comment

MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved MARIZEV^® (omarigliptin) 25 mg and 12.5 mg tablets, an oral, once-weekly DPP-4 inhibitor indicated for the treatment of adults with type 2 diabetes. Japan is the first country to have approved omarigliptin……….http://www.mercknewsroom.com/news-release/prescription-medicine-news/marizev-omarigliptin-mercks-once-weekly-dpp-4-inhibitor-type

syn…….https://newdrugapprovals.org/2014/04/18/omarigliptin-mk-3102-in-phase-3-for-type-2-diabetes/

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

/////////////MARIZEV, (Omarigliptin), Merck’s, Once-Weekly, DPP-4 Inhibitor, Type 2 Diabetes, Approved, Japan

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4-((1-Hydroxy-1,3-dihydrobenzo(c)(1,2)oxaborol-6-yl)oxy)benzonitrile

CAS 906673-24-3, AN-2728

Benzonitrile, 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]-

crisaborol, crisaborole, Crisaborole, crisaborolum

UNII-Q2R47HGR7P

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1-Propanol, 3-(((3S)-3-(aminomethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborol-7-yl)oxy)-

Stephen J. Benkovic

Websites,Benkovic Research Group

[PDF]RONALD G. MICETICH – University of Alberta – Journal …

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Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-l-(3- methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic

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River blindness?

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Chlorotris(triphenylphosphine)rhodium(I), [RhCl(PPh3)3]

You need to add just two hydrogen atoms to reduce a C=C bond in avermectin.

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Avermectin

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Exelixis, Inc.

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Chlorotris(triphenylphosphine)rhodium(I), [RhCl(PPh₃)₃]