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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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AN 2898


An external file that holds a picture, illustration, etc. Object name is JRPS-8-145-g012.jpg

AN2898

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

1,2-Benzenedicarbonitrile, 4-((1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy)-, 

AN-2898
cas: 906673-33-4
UNII: 6O60L94RMB,

MW 276.0581, MF C15 H9 B N2 O3

A PDE4 inhibitor potentially for the treatment of fungal infection.

AN-2898, a novel topical anti-inflammatory compound that inhibits phosphodiesterase 4 and 7 enzyme activit

PHASE 2  FUNGAL INFECTION, Anacor Pharmaceuticals for the treatment of atopic dermatitis

Anacor Pharmaceuticals Inc.
Description Boron-containing small molecule phosphodiesterase-4 (PDE-4) inhibitor that reduces the production of tumor necrosis factor (TNF) alpha, IL-12 and IL-23
Molecular Target Phosphodiesterase-4 (PDE-4)
Mechanism of Action Phosphodiesterase-4 (PDE-4) inhibitor
Therapeutic Modality Small molecule

 

AN2898 (5-(3,4-dicyanophenoxy)-1-hydroxy -1,3-dihydro-2,1-benzoxaborole)  is a broad spectrum anti-inflammatory compound currently in development for the topical treatment of plaque and atopic psoriasis.

AN2898 inhibited phosphodiesterase 4 (PDE4) enzyme activity (IC50 0.060 μM) and the release of multiple cytokines including TNF-α (IC50 0.16 μM) from peripheral blood mononuclear cells (hPBMCs) stimulated by lipopolysaccharide (LPS) or phytohemag- glutinin.

Further, AN2898 was also found to inhibit IL-23 release (IC50 1.0 μM) from THP-1 cells stimulated by LPS and IFN-γ. Investigation of the structure-activity relation-ship around this compound was reported to identify a more potent dual TNF-α/IL-23 inhibitor

(  ref………. Akama T, Antunes J, Freund Y, Kimura R, Dong C, Sanders V, et al. Structure-activity studies of novel oxaborole dual inhibitors of PDE4 and IL-23 release. 69th Annu Meet Soc Invest Dermatol (May 6-9, Montreal) 2009 Abst 282.  ).

PATENT

WO 2007095638

https://www.google.co.in/patents/WO2007095638A2?cl=en

PATENT

WO 2006089067

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

 

US 7582621

http://www.google.co.in/patents/US7582621

 

WO 2009111676

http://www.google.im/patents/WO2009111676A2?cl=en

 

WO 2007078340

http://www.google.im/patents/WO2007078340A2?cl=en

US 20070286822

http://www.google.com/patents/US20070286822

REFERENCES

1 Structure-activity studies led to the discovery of AN2898 in development for topical treatment of psoriasis and atopic dermatitis, J Am Acad Dermatol 2009, 60(3, Suppl. 1): Abst P1317

2 FEBS Letters (2012), 586(19), 3410-3414

 

See all Bboroles at………http://apisynthesisint.blogspot.in/p/borole-compds.html

 

/////////AN2898, AN 2898, ANACOR, BOROLE

B1(c2ccc(cc2CO1)Oc3ccc(c(c3)C#N)C#N)O

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крисаборол , كريسابورول , Crisaborole, AN 2728


 

Crisaborole

Treatment for Inflammatory Skin Diseases, including Atopic Dermatitis and Psoriasis

C14H10BNO3, 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.

PDE4 inhibitors aiming at skin inflammatory 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

AN3

CKICK ON IMAGE FOR CLEAR VIEW

 

 

 

Originator
Therapeutic Claim
Class
Mechanism of action
WHO ATC code(s)
EPhMRA code(s)
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

 

  • 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

Image for unlabelled figure

Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6h ...

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,

Figure imgf000077_0001

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)

Figure imgf000097_0002

(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

Figure imgf000048_0003

 

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

Figure imgf000223_0001

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

    Example 154-(4-Cyanophenoxy)phenylboronic acid (C97)

  • Figure US20090291917A1-20091126-C00195
  • (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
Methods of treating anti-inflammatory conditions through the use of boron- containing small molecules are disclosed.
… Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … Francisco, CA Mar. 6-10, 2009. 7 , “AN2728 … Kyoto, Japan, May 14-18, 2008. 10, “AN2728 …
AN2728, 5-(4-cyanophenoxy)-2,3- dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).
… Dermatology Annual Meeting, San Francisco, CA Mar. 6-10, 2009. 6, “AN2728 … 7, “AN2728 … Francisco, CA May 6-10, 2009. 10, “AN2728 …
… 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, …
AN2728” is the compound 4-(l-hydroxy-l,3-dihydro-2 … GSK256066, oglemilast, tetomilast, apremilast, AN2728, Compound A, Compound B, …
AN2728, 5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1- …. UK-500,001, AN2728, DE-103, Tofisopam, Dextofisopam, Levotofisopam (USAN).
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

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

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

AN 3485


Figure imgf000092_0002

 

AN 3485

image

AN3485,

6-(4-(aminomethyl)-2-chlorophenoxyl)benzo[c][1,2]oxaborol-1(3H)-ol,
was synthesized at Anacor Pharmaceuticals as described in patent application WO 2010028005
A1

6-[4-(Aminomethyl)-2-chlorophenoxy]-2,1-benzoxaborol-1(3H)-ol hydrochloride

Anacor Pharmaceuticals, Inc.

http://jpet.aspetjournals.org/content/early/2012/11/28/jpet.112.200030.full.pdf

Pro-inflammatory cytokines play a critical role in the development of autoimmune and
inflammatory diseases. Targeting the cytokine environment has proven efficient for averting
inflammation. In this study, we reported that 6-(4-(aminomethyl)-2-
chlorophenoxyl)benzo[c][1,2]oxaborol-1(3H)-ol (AN3485), a benzoxaborole analog, inhibited
TLR2-, TLR3-, TLR4- and TLR5-mediated TNF-α, IL-1β and IL-6 release from human PBMCs
and isolated monocytes with IC50s ranging from 18 to 580 nM, and the inhibition was mediated
at the transcriptional level. Topical administration of AN3485 significantly reduced PMAinduced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice,
indicating its capability of penetrating skin and potential topical application in skin
inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPSinduced TNF-α and IL-6 production in mice with an ED90 of 30 mg/kg. Oral AN3485, 35
mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The
potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an
attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases

A new class of boron-containing small molecules has been developed over the past several
years as potential drugs. Different from carbon, boron contains an electrophilic empty p-orbital
which can form transient bonds with nucleophiles in an enzyme active site, which mimics a
tetrahedral transition state of peptide bond cleavage in an enzymatic reaction (Baker et al., 2011).
The benzoxaboroles, in which the boron atom is incorporated into a heteroaromatic ring system,
are able to inhibit a number of important enzymes, including bacterial and fungi Leucyl-tRNA
synthetase (Rock et al., 2007), human phosphodiesterase-4 (PDE4) (Akama et al., 2009) and
HCV NS3/4A protease (Li et al., 2010). Three benzoxaboroles, AN2690 (Tavaborole), AN2728
and AN3365 (GSK’052) are in clinical trials for treatment of onychomycosis, psoriasis/atopic dermatitis and Gram-negative bacterial infection, and have been proven safe in human when
applied topically or systemically

……………………………………………………….

Structure-activity relationships of 6-(aminomethylphenoxy)-benzoxaborole derivatives as anti-inflammatory agent
Bioorg Med Chem Lett 2013, 23(6): 1680

http://www.sciencedirect.com/science/article/pii/S0960894X13001054

Full-size image (12 K)

Scheme 2.

Synthesis of compounds 9ae. Reagents and conditions: (a) K2CO3, DMSO, 80–90 °C, overnight (33–61%); (b) LAH, THF, 0 °C to rt, 1 h, then 4 M HCl in 1,4-dioxane (43–68%); (c) aq NaOH, MeOH, 50 °C, 2 h (61%), (d) Ac2O, pyridine, rt (79%).

 

  • Synthesis of 6-(4-(aminomethyl)-2-chlorophenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (9e): To a solution of 3H-benzo[c][1,2]oxaborole-1,6-diol (8) (300 mg, 2.00 mmol) in DMSO (30 mL) were added K2CO3(828 mg, 6.00 mmol) and 3-chloro-4-fluoro-benzonitrile (7b) (933 mg, 6.00 mmol). The reaction was heated at 90 °C for 7 h. After cooling the reaction mixture to room temperature, EtOAc (50 mL) was added. The organic layer was washed with water (5 × 50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-benzonitrile (9b) (190 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1H), 8.22 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 4.99 (s, 2H); ESIMS (m/z): 284 (M−H); HPLC: 96.4% (220 nm), 96.0% (maxplot).

  • To a solution of compound 9b (136 mg, 0.480 mmol) in anhydrous THF (60 mL) was added lithium aluminum hydride (1 M/ether, 1.19 mL, 1.19 mmol) at 0 °C. The reaction was stirred for 2 h. Then the reaction was quenched with 1 M HCl (30 mL). MeOH (50 mL) was added and the solution was filtered. The filtrate was evaporated under vacuum. The residue was purified by reverse phase chromatography (biotage, gradient MeOH/H2O from 10% to 100%). To a suspension of 9e free base in MeOH (5 mL) was added 4 M HCl in 1,4-dioxane (0.2 mL). The mixture became a clear solution then precipitates formed, which were collected by filtration to afford 9e (106 mg, 68%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (s, 1H), 8.18 (br s, 3H), 7.75 (s, 1H), 7.44–7.39 (m, 2H), 7.19–7.10 (m, 3H), 4.98 (s, 2H), 4.03 (q, J = 5.5 Hz, 2H); ESIMS (m/z): 290 (M+H)+; HPLC: 95.9% (220 nm), 96.9% (maxplot).

…………………………………………………………

Patent

https://www.google.com/patents/WO2010028005A1?cl=en

 

Figure imgf000092_0001
Figure imgf000092_0002

(X) IS AN 3485

Compound 2:

To a solution of 2-hydroxy-4-methoxy-benzaldehyde (30 g, 197 mmol) in DCM (anhydrous, 120 rnL) was added pyridine (79 mL, 986 mmol) at room temperature. After the mixture was cooled to -10 0C, the Tf2O (50 mL, 296 mmol) was slowly added to the reaction between -10 0C to 0 0C. The addition took about 2.5 hours. After the addition, the stirring was kept for 30 minutes. The EtOAc (200 mL) was added. The organic layer was washed with 1 M HCl (3 X 80 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified over silica gel, eluting with 5% EtOAc / hexanes to give trifluoro-methanesulfonic acid 2- formyl-5-methoxy-phenyl ester (2) 46 g in 82% yield. 1H NMR (400 MHz,

CHLOROFORM-^) δ ppm 10.13 (s, 1 H), 7.95 (d, J=8.99 Hz, 1 H), 7.03 (dd, J=8.60, 2.34 Hz, 1 H), 6.88 (d, J=2.34 Hz, 1 H), 3.93 (s, 3 H)

Compound 3:

To a solution of trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (2) (46 g, 160 mmol) in 1,4-dioxane (anhydrous, 360 rnL) were added bis(pinacolato)diboron (82.3 g, 320 mmol), [l,l ‘-bis(diphenylphosphino)ferrocene] palladium(II)chloride (23.7 g, 32 mmol) and KOAc (47.6 g, 480 mmol). The mixture was stirred at room temperature with N2bubbling for 30 minutes. Then the reaction was heated at 100 0C for 3 hours. The solution was filtered, evaporated under vacuum. The residue was purified over silica gel, eluting with 20% EtOAc / hexanes to afford 4-methoxy-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzaldehyde (3) 37.8 g in 90% yield. 1H NMR (400 MHz, CHLOROFORM- d) δ ppm 10.34 (s, 1 H), 7.90 (d, J=8.60 Hz, 1 H), 7.26 (s, 1 H), 6.99 (d, J=8.60 Hz, 1 H), 3.86 (s, 3 H), 1.36 (s, 12 H)

Compound 4:

To a clear solution of 4-methoxy-2-(4,4,5,5-tetramethyl-

[l,3,2]dioxaborolan-2-yl)-benzaldehyde (3) (48 g, 180 mmol) in MeOH (anhydrous, 300 mL) was slowly added NaBH4 (6.96 g, 180 mmol). The reaction was stirred at room temperature for 2 hours. Then IM HCl (100 mL) was slowly added. After stirring for overnight, the MeOH was evaporated under vacuum. The solid was filtered, washed with water and air-dried to afford 6-methoxy-3H- benzo[c][l,2]oxaborol-l-ol (4) 23 g in 77% yield. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.11 (s, 1 H), 7.29 (d, J=8.21 Hz, 1 H), 7.23 (d, J=2.34 Hz, 1 H), 7.03 (dd, J=8.40, 2.54 Hz, 1 H), 4.90 (s, 2 H), 3.75 (s, 3 H).

Compound 5:

To a clear solution of 6-methoxy-3H-benzo[c][l,2]oxaborol-l-ol (4) (600 mg, 3.66 mmol) in DCM (anhydrous, 60 mL) was slowly added BBr3 (1M/DCM, 8.05 mL, 8.05 mmol) at -10 0C. The reaction was stirred for 3 hours, with monitoring by NMR. After all 4 had gone, 30 mL of cold water was added. Then 50 mL of EtOAc was added to extract all organic compounds. The organic layer was washed with cold brine, until the pH of aqueous layer changed to pH 7. The organic layer was dried over Na2SO4, filtered, evaporated under vacuum. The residue (-85% HPLC purity) was used directly for the next step reaction without further purification. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.29 (s, 1 H), 9.04 (s, 1 H), 7.17 (d, J=8.21 Hz, 1 H), 7.07 (d, J=2.34 Hz, 1 H), 6.85 (dd, J=8.21, 2.34 Hz, 1 H), 4.85 (s, 2 H). ESMS (m/z): 149 (M- H). HPLC: 88.31% (220 nm), 85.02% (maxplot).

Compound 6:

To a solution of 3H-benzo[c][l,2]oxaborole-l,6-diol (5) (300 mg, 2 mmol) in DMSO (30 mL) were added K2CO3 (828 mg, 6 mmol) and 3-chloro-4-fiuoro- benzonitrile (933 mg, 6 mmol). The reaction was heated at 90 0C for 7 hours. After the cooling of reaction solution, EtOAc (50 mL) was added. The organic layer was washed with water (5 X 50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(l- hydroxy-l,3-dihydro-benzo[c][l,2]oxaborol-6-yloxy)-benzonitrile (6) 190 mg in 33.3% yield. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.24 (s, 1 H), 8.22 (s, 1 H), 7.77 (d, J=7.81 Hz, 1 H), 7.50 (d, J=8.20 Hz, 1 H), 7.34 (s, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.01 (d, J=8.59 Hz, 1 H), 4.99 (s, 2 H). ESMS (m/z): 284 (M-H). HPLC: 96.41% (220 nm), 96.0% (maxplot).

(X): IS AN 3485

To a clear solution of 3-chloro-4-(l-hydroxy-l,3-dihydro- benzo[c][l,2]oxaborol-6-yloxy)-benzonitrile (6) (136 mg, 0.48 mmol) in THF

(anhydrous, 60 mL) was added lithium aluminum hydride (lM/ether, 1.19 mL, 1.19 mmol) at 0 0C. The reaction was stirred for 2 hours. Then the reaction was quenched with IM HCl (30 mL). MeOH (50 mL) was added and the solution was filtered. The filtrate was evaporated under vacuum. The residue was purified by reverse phase chromatography (biotage, gradient MeOH / H2O from 10% to 100%) to afford (X) 106 mg (white solid) in 68% yield. 1H NMR (400 MHz, DMSO-J6) δ ppm 9.19 (s, 1 H), 8.18 (br, s, 3 H), 7.75 (s, IH), 7.44-7.39 (m, 2 H), 7.19-7.10 (m, 3 H), 4.98 (s, 2 H), 4.03 (q, J=5.50 Hz, 2 H).

ESMS (m/z): 290 (M+H)+.

HPLC: 95.9% (220 nm), 96.85% (maxplot).

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