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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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BMS-986118, for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)


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BMS-986118
BMS compd for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)
Cas 1610562-74-7
1H-Pyrazole-5-acetic acid, 1-[4-[[(3R,4R)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)-
Molecular Weight, 540.96, C25 H28 Cl F3 N4 O4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid

(-)-[(4S,5S)-1-(4-[[(3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid

  • (4S,5S)-1-[4-[[(3R,4R)-1-(5-Chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-1H-pyrazole-5-acetic acid
  • 2-[(4S,5S)-1-[4-[[1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl]-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid isomer 2

BMS-986118 is a GPR40 full agonist. GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia

Image result for bms

NOTE CAS OF , 1H-Pyrazole-5-acetic acid, 1-[4-[[(3S,4S)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)- IS 1610562-73-6

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SYNTHESIS

WO 2014078610

PAPER

https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00982

Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

Abstract

Abstract Image

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitroIn vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

Compound 4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (4)

To a stirred solution of methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (5.5 g, 9.9 mmol) in THF (90 mL) and water (9 mL) at room temperature was added 2 N LiOH solution (12 mL, 24 mmol). The reaction mixture was stirred at room temperature for 16 h, and 1 N HCl (25 mL, 25 mmol) was added at 0 °C to pH = 4–5. The solvent was evaporated, and the residue was extracted three times with EtOAc. The organic extracts were dried over Na2SO4; the solution was filtered and concentrated. The residue was recrystallized from isopropanol to give 4(neutral form) as white solid (4.3 g, 7.7 mmol, 78% yield).
1H NMR (500 MHz, DMSO-d6) δ ppm 12.52 (br s, 1H), 8.01 (s, 1H), 7.05 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 6.40 (s, 1H), 4.49–4.33 (m, 1H), 4.02 (td, J = 8.8, 4.1 Hz, 1H), 3.80 (s, 3H), 3.56–3.39 (m, 2H), 3.37–3.29 (m, 1H), 2.94–2.85 (m, 1H), 2.72–2.66 (m, 1H), 2.64 (dd, J = 16.1, 2.9 Hz, 1H), 2.49–2.41 (m, 1H), 2.22–2.05 (m, 1H), 2.01–1.86 (m, 1H), 1.68–1.50 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H).
 
13C NMR (126 MHz, DMSO-d6) δ 171.5, 163.7, 157.1, 152.5, 146.3, 139.7 (q, J = 34.7 Hz), 136.2, 121.7 (q, J = 269.3 Hz), 117.3, 117.2, 116.0, 100.4, 78.9, 65.6, 54.2, 53.4, 47.8, 44.2, 36.0, 34.9, 29.5, 17.4, 15.3. 19F NMR (471 MHz, DMSO-d6) δ −61.94 (s, 3F).
 
Optical rotation: [α]D(20)−11.44 (c 2.01, MeOH).
 
HRMS (ESI/HESI) m/z: [M + H]+ Calcd for C25H29ClF3N4O4 541.1824; Found 541.1813. HPLC (Orthogonal method, 30% Solvent B start): RT = 11.9 min, HI: 97%. m/zobs 541.0 [M + H]+.
 
Melting point = 185.5 °C.
PAPER

Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

Chemical and Synthetic DevelopmentBristol-Myers Squibb CompanyOne Squibb Drive, New Brunswick, New Jersey08903, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00022

Abstract

Abstract Image

The final two steps used to prepare greater than 1 kg of a compound evaluated as a treatment for type 2 diabetes are reported. The application of a palladium-catalyzed C–O coupling presented significant challenges due to the nature of the reactants, impurities produced, and noncrystalline coupling intermediate. Process development was able to address these limitations and enable production of kilogram quantities of the active pharmaceutical ingredient (API) in greater efficiency than a Mitsunobu reaction for formation of the key bond. The development of a sequence that telescopes the coupling with the subsequent ester hydrolysis to yield the API and the workup and final product crystallization necessary to produce high-quality drug substance without the need of column chromatography are discussed.

Bruce Ellsworth

Bruce Ellsworth, Director, Head of Fibrosis Discovery Chemistry at Bristol-Myers Squibb

Rick EwingRick Ewing, Head, External Partnerships, Discovery Chemistry and Molecular Technologies at Bristol-Myers Squibb
str1 str2
PATENT
WO 2014078610
Original Assignee Bristol-Myers Squibb Company
Patent
Patent ID

Patent Title

Submitted Date

Granted Date

US9133163 DIHYDROPYRAZOLE GPR40 MODULATORS
2013-11-15
2014-05-22
US9604964 Dihydropyrazole GPR40 modulators
2013-11-15
2017-03-28
REF
1: Li Z, Qiu Q, Geng X, Yang J, Huang W, Qian H. Free fatty acid receptor
agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II
clinical development. Expert Opin Investig Drugs. 2016 Aug;25(8):871-90. doi:
10.1080/13543784.2016.1189530. PubMed PMID: 27171154.
2
Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
248th Am Chem Soc (ACS) Natl Meet (August 10-14, San Francisco) 2014, Abst MEDI 31
MEDI John Macor Sunday, August 10, 2014
Oral Session
General Oral Session – PM Session
Organizers: John Macor
Presiders: John Macor
Duration: 1:30 pm – 5:15 pm
1:55 pm 31 Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
Bruce A Ellsworth, Jun Shi, Elizabeth A Jurica, Laura L Nielsen, Ximao Wu, Andres H Hernandez, Zhenghua Wang, Zhengxiang Gu, Kristin N Williams, Bin Chen, Emily C Cherney, Xiang-Yang Ye, Ying Wang, Min Zhou, Gary Cao, Chunshan Xie, Jason J Wilkes, Heng Liu, Lori K Kunselman, Arun Kumar Gupta, Ramya Jayarama, Thangeswaran Ramar, J. Prasada Rao, Bradley A Zinker, Qin Sun, Elizabeth A Dierks, Kimberly A Foster, Tao Wang, Mary Ellen Cvijic, Jean M Whaley, Jeffrey A Robl, William R Ewing.

///////////BMS-986118, Preclinical, BMS, Bruce A. Ellsworth,  Jun Shi,  William R. Ewing,  Elizabeth A. Jurica,  Andres S. Hernandez,  Ximao Wu, DIABETES,

COc1cc(c(Cl)cn1)N4CCC(Oc2ccc(cc2)N3N=C([C@@H](C)C3CC(=O)O)C(F)(F)F)[C@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@H](C)C4

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LY 3104607


imgChemSpider 2D Image | LY3104607 | C27H25N3O3
FDIWCHYTKOPHPS-QFIPXVFZSA-N.png
 LY3104607
(3S)-3-[4-[[2-(2,6-Dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoic Acid
(3S)-3-[4-[[2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoic acid
CAS: 1795232-22-2
Chemical Formula: C27H25N3O3
Molecular Weight: 439.515
(3S)-3-(4-{[2-(2,6-Dimethylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methoxy}phenyl)-4-hexinsäure
Benzenepropanoic acid, 4-[[2-(2,6-dimethylphenyl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methoxy]-β-1-propyn-1-yl-, (βS)-

[+]Enlarge

Structure of LY3104607.
Credit: Tien Nguyen/C&EN

Presented by: Chafiq Hamdouchi, founder at Hamdouchi Pharmaceutical Consulting

Target: G-protein-coupled receptor 40 (GPR40), a receptor that modulates insulin secretion in cells

Disease: Type 2 diabetes

Reporter’s notes: Developed by Eli Lilly, LY3104607 joins the handful of GPR40 agonists recently offered by the company. The compound is not exactly a first disclosure as its structure was revealed in a January publication that describes its discovery and pharmacokinetic properties (J. Med. Chem. 2018, DOI: 10.1021/acs.jmedchem.7b01411). Hamdouchi, who worked on the molecule while at Eli Lilly, presented what the team learned about GPR40 and suggested that allosteric binding, binding which happens at a location other than the active site, may be a viable mode of action for GPR40 agonists.

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Chafiq Hamdouchi

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STR OF TITLE LY 3104607

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Paper

Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus

 Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, DC: 0540, Indianapolis, Indiana 46285, United States
 Jubilant Biosys Research Center, Bangalore, India
J. Med. Chem.201861 (3), pp 934–945
DOI: 10.1021/acs.jmedchem.7b01411
Publication Date (Web): December 13, 2017
Copyright © 2017 American Chemical Society
*E-mail: hamdouchi_chafiq@lilly.comchafiq.hamdouchi@gmail.com. Phone: 317-797-4751.

Abstract

Abstract Image

As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 12, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.

(3S)-3-[4-[[2-(2,6-Dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoic Acid (4)

Compound 4 (LY3104607)

title compound as white solid (35.76 kg, 91%). LCMS m/z [M + H]+: calcd, 439.5; found, 439.2.
1H NMR (399.80 MHz, DMSO, δ): 12.22 (s, 1H), 9.13 (dd, J = 0.8, 1.5 Hz, 1H), 7.88 (dd, J = 0.8, 9.2 Hz, 1H), 7.75 (dd, J = 1.7, 9.2 Hz, 1H), 7.29–7.24 (m, 3H), 7.14–7.12 (m, 2H), 7.01–6.99 (m, 2H), 5.18 (s, 2H), 3.96–3.91 (m, 1H), 2.58 (d, J = 7.7 Hz, 2H), 2.06 (s, 6H), 1.75 (d, J = 2.4 Hz, 3H).
PATENT
WO 2015088868
Applicants: ELI LILLY AND COMPANY [US/US]; Lilly Corporate Center Indianapolis, Indiana 46285 (US)
Inventors: HAMDOUCHI, Chafiq; (US)

A Novel Triazolo-Pyridine Compound

This invention relates to triazolo-pyridine compounds or pharmaceutically acceptable salts thereof, and for use of compounds in therapy. Triazolo-pyridine compounds of this invention are activators of GPR-40.

GPR-40, also known as Free Fatty Acid Receptor 1 (FFA1 or FFAR1), is reported as predominately expressed at high levels in rodent pancreatic beta cells, insulinoma cell lines, and human islets. The glucose modulation of insulin secretion is an important feature of activating GPR-40. Compounds that effectuate GPR-40 activation are associated with stimulation of insulin secretion in a patient with type II diabetes (T2D). Compounds that are GPR-40 activators are desired for use in treatment of GPR-40 mediated conditions.

WO2004/041266 discloses GPR-40 receptor function regulators comprising a compound having an aromatic ring and a group capable of releasing a cation.

The present invention rovides compounds of the Formula la below:

la

Example 1

(3S)-3-[4-[[2-(2,6-Dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6- yl]methoxy]phenyl]hex-4-ynoic acid

To a solution of ethyl (3S)-3-[4-[[2-(2,6-dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoate (0.22 g, 0.47 mmol) in EtOH (20 mL) is added 5 N NaOH (0.3 mL) and the reaction mixture is stirred at 80 °C in a microwave instrument for 30 minutes. The reaction mixture is evaporated to dryness, diluted with water, and acidified with 6 N HC1 solution to pH ~ 3. The precipitated solid is filtered, washed with n-pentane, and dried to give the title compound as a white solid (0.155 g, 75%). LCMS m/z 440 (M+H)+.

Alternate Preparation, Example 1

To a solution of ethyl (3S)-3-[4-[[2-(2,6-dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoate (16 g, 34.22 mmol) in ethanol (160 mL) is added aqueous 5 N NaOH (2.73 g, 68.44 mmol in 16 mL water) drop wise at room temperature and the reaction mixture is stirred for 16 hours. The reaction mixture is evaporated to dryness, the residue is dissolved in water (300 mL), washed with diethyl ether (2 χ 200 mL), and the organic extract is discarded. The aqueous layer is cooled to 10 °C- 15 °C, acidified with saturated citric acid solution to pH~5, and extracted with DCM (2 x 300 mL). The combined organic extracts are washed with water (2 x 500 mL), brine solution (500 mL), dried over Na2S04, filtered, and evaporated to dryness to give the title compound as an off-white solid (14 g, 93%). LCMS m/z 440 (M+H)+.

The products from other batches, prepared as in Alternate Preparation of Example 1, are mixed with the product from Alternate Preparation Example 1 DCM (5 L) and warmed to 40 °C to get a clear solution. Then the solvent is evaporated to give an off-white solid. The possibility of trapped DCM is a concern, thus EtOAc (7.5 L) is charged and the resulting mixture is warmed to 65 °C to get a clear solution (-30 minutes). The solvent is evaporated and the resulting solid is dried under vacuum at 50 °C to obtain the desired product as an off-white solid. LCMS m/z 440 (M+H)+.

Form II Seed Crystal, Example 1

A saturated ethanol solution of (3S)-3-[4-[[2-(2,6-Dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoic acid is filtered through 0.22 μιη nylon syringe filter into a clean vessel. Slow solvent evaporation at 25°C results in Form II seed crystals of Example 1.

Crystalline Form II (3S)-3-[4-[[2-(2,6-Dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin- 6-yl] methoxy] phenyl] hex-4-ynoic acid

(3S)-3-[4-[[2-(2,6-Dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoic acid can be prepared as a crystalline anhydrous Form II by dissolving (3S)-3-[4-[[2-(2,6-Dimethylphenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methoxy]phenyl]hex-4-ynoic acid (580 mg, 132 mmol) in EtOH (1.2 mL) while stirring the mixture at 80 °C for 10 minutes. The solution is filtered and cooled to 70 °C at which point seeds of Form II are introduced. The mixture is then slowly cooled to ambient temperature while stirring overnight. The resulting solid plug is loosened with the addition of heptane (600 μΐ.) and the solids are recovered by vacuum filtration and dried under vacuum at 60 °C to give the crystalline title product (438 mg, 75.5%).

Patent ID

Patent Title

Submitted Date

Granted Date

US9120793 Triazolo-pyridine compound
2014-12-04
2015-09-01
US2015166535 NOVELTRIAZOLO-PYRIDINE COMPOUND
2014-12-04
2015-06-18

/////////LY3104607, LY-3104607, LY 3104607, PRECLINICAL

CC#C[C@H](C1=CC=C(OCC2=CN3C(C=C2)=NC(C4=C(C)C=CC=C4C)=N3)C=C1)CC(O)=O

Pfizer’s Monobactam PF-?


STR1

Pfizer’s monobactam PF-?

1380110-34-8, C20 H24 N8 O12 S2, 632.58

Propanoic acid, 2-​[[(Z)​-​[1-​(2-​amino-​4-​thiazolyl)​-​2-​[[(2R,​3S)​-​2-​[[[[[(1,​4-​dihydro-​1,​5-​dihydroxy-​4-​oxo-​2-​pyridinyl)​methyl]​amino]​carbonyl]​amino]​methyl]​-​4-​oxo-​1-​sulfo-​3-​azetidinyl]​amino]​-​2-​oxoethylidene]​amino]​oxy]​-​2-​methyl-

2-((Z)-1-(2-Aminothiazol-4-yl)-2-((2R,3S)-2-((((1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methoxy)carbonylamino)methyl)-4-oxo-1-sulfoazetidin-3-ylamino)-2-oxoethylideneaminooxy)-2-methylpropanoic Acid

2-[[(Z)-[1-(2-Amino-4-thiazolyl)-2-[[(2R,3S)-2-[[[[[(1,4-dihydro-1,5-dihydroxy-4-oxo-2-pyridinyl)methyl]amino]carbonyl]amino]methyl]-4-oxo-1-sulfo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid

Monobactams are a class of antibacterial agents which contain a monocyclic beta-lactam ring as opposed to a beta-lactam fused to an additional ring which is found in other beta-lactam classes, such as cephalosporins, carbapenems and penicillins. The drug Aztreonam is an example of a marketed monobactam; Carumonam is another example. The early studies in this area were conducted by workers at the Squibb Institute for Medical Research, Cimarusti, C. M. & R.B. Sykes: Monocyclic β-lactam antibiotics. Med. Res. Rev. 1984, 4, 1 -24. Despite the fact that selected

monobacatams were discovered over 25 years ago, there remains a continuing need for new antibiotics to counter the growing number of resistant organisms.

Although not limiting to the present invention, it is believed that monobactams of the present invention exploit the iron uptake mechanism in bacteria through the use of siderophore-monobactam conjugates. For background information, see: M. J. Miller, et al. BioMetals (2009), 22(1 ), 61-75.

The mechanism of action of beta-lactam antibiotics, including monobactams, is generally known to those skilled in the art and involves inhibition of one or more penicillin binding proteins (PBPs), although the present invention is not bound or limited by any theory. PBPs are involved in the synthesis of peptidoglycan, which is a major component of bacterial cell walls.

WO 2012073138

https://www.google.com/patents/WO2012073138A1?cl=en

Inventors Matthew Frank BrownSeungil HanManjinder LallMark. J. Mitton-FryMark Stephen PlummerHud Lawrence RisleyVeerabahu ShanmugasundaramJeremy T. Starr
Applicant Pfizer Inc.

Example 4, Route 1

2-({[(1Z)-1 -(2-amino-1 ,3-thiazol-4-yl)-2-({(2f?,3S)-2-[({[(1 ,5-dihydroxy-4-oxo-1 ,4- dihydropyridin-2-yl)methyl]carbamoyl}amino)methyl]-4-oxo-1 -sulfoazetidin-3- yl}amino)-2-oxoethylidene]amino}oxy)-2-methylpropanoic acid, bis sodium salt

(C92-Bis Na Salt).

Figure imgf000080_0001

C92-bis Na salt

Step 1 : Preparation of C90. A solution of C26 (16.2 g, 43.0 mmol) in tetrahydrofuran (900 mL) was treated with 1 , 1 ‘-carbonyldiimidazole (8.0 g, 47.7 mmol). After 5 minutes, the reaction mixture was treated with a solution of C9 (15 g, 25.0 mmol) in anhydrous tetrahydrofuran (600 mL) at room temperature. After 15 hours, the solvent was removed and the residue was treated with ethyl acetate (500 mL) and water (500 mL). The layers were separated and the aqueous layer was back extracted with additional ethyl acetate (300 mL). The organic layers were combined, washed with brine solution (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via chromatography on silica gel (ethyl acetate / 2-propanol) to yield C90 as a yellow foam. Yield: 17.44 g, 19.62 mmol, 78%. LCMS m/z 889.5 (M+1 ). 1H NMR (400 MHz, DMSO-d6) 1 1 .90 (br s, 1 H), 9.25 (d, J=8.7 Hz, 1 H), 8.40 (br s, 1 H), 7.98 (s, 1 H), 7.50-7.54 (m, 2H), 7.32-7.47 (m, 8H), 7.28 (s, 1 H), 6.65 (br s, 1 H), 6.28 (br s, 1 H), 5.97 (s, 1 H), 5.25 (s, 2H), 5.18 (dd, J=8.8, 5 Hz, 1 H), 4.99 (s, 2H), 4.16-4.28 (m, 2H), 3.74-3.80 (m, 1 H), 3.29-3.41 (m, 1 H), 3.13-3.23 (m, 1 H), 1.42 (s, 9H), 1.41 (s, 3H), 1.39 (br s, 12H).

Step 2: Preparation of C91. A solution of C90 (8.5 g, 9.6 mmol) in anhydrous N,N- dimethylformamide (100 mL) was treated sulfur trioxide /V,/V-dimethylformamide complex (15.0 g, 98.0 mmol). The reaction was allowed to stir at room temperature for 20 minutes then quenched with water (300 mL). The resulting solid was collected by filtration and dried to yield C91 as a white solid. Yield: 8.1 g, 8.3 mmol, 87%. LCMS m/z 967.6 (M-1 ). 1H NMR (400 MHz, DMSO-d6) δ 1 1.62 (br s, 1 H), 9.29 (d, J=8.8 Hz, 1 H), 9.02 (s, 1 H), 7.58-7.61 (m, 2H), 7.38-7.53 (m, 9H), 7.27 (s, 1 H), 7.07 (s, 1 H), 6.40 (br d, J=8 Hz, 1 H), 5.55 (s, 2H), 5.25 (s, 2H), 5.20 (dd, J=8.8, 5.6 Hz, 1 H), 4.46 (br dd, half of ABX pattern, J=17, 5 Hz, 1 H), 4.38 (br dd, half of ABX pattern, J=17, 6 Hz, 1 H), 3.92-3.98 (m, 1 H), 3.79-3.87 (m, 1 H), 3.07-3.17 (m, 1 H), 1.40 (s, 9H), 1 .39 (s, 3H), 1 .38 (s, 12H).

Step 3: Preparation of C92. A solution of C91 (8.1 g, 8.3 mmol) in anhydrous dichloromethane (200 mL) was treated with 1 M boron trichloride in p-xylenes (58.4 mL, 58.4 mmol) and allowed to stir at room temperature for 15 minutes. The reaction mixture was cooled in an ice bath, quenched with 2,2,2-trifluoroethanol (61 mL), and the solvent was removed in vacuo. A portion of the crude product (1 g) was purified via reverse phase chromatography (C-18 column; acetonitrile / water gradient with 0.1 % formic acid modifier) to yield C92 as a white solid. Yield: 486 mg, 0.77 mmol. LCMS m/z 633.3 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J=8.7 Hz, 1 H), 8.15 (s, 1 H), 7.26-7.42 (br s, 2H), 7.18-7.25 (m, 1 H), 6.99 (s, 1 H), 6.74 (s, 1 H), 6.32-6.37 (m, 1 H), 5.18 (dd, J=8.7, 5.7 Hz, 1 H), 4.33 (br d, J=4.6 Hz, 2H), 3.94-4.00 (m, 1 H), 3.60-3.68 (m, 1 H), 3.19-3.27 (m, 1 H), 1.40 (s, 3H), 1.39 (s, 3H).

Step 4: Preparation of C92-Bis Na Salt. A flask was charged with C92 (388 mg, 0.61 mmol) and water (5.0 mL). The mixture was cooled in an ice bath and treated dropwise with a solution of sodium bicarbonate (103 mg, 1.52 mmol) in water (5.0 mL). The sample was lyophilized to yield C92-Bis Na Salt as a white solid. Yield: 415 mg, 0.61 mmol, quantitative. LCMS m/z 633.5 (M+1 ). 1H NMR (400 MHz, D20) δ 7.80 (s, 1 H), 6.93 (s, 1 H), 6.76 (s, 1 H), 5.33 (d, J=5.7 Hz, 1 H), 4.44 (ddd, J=6.0, 6.0, 5.7 Hz, 1 H), 4.34 (AB quartet, JAB=17.7 Hz, ΔνΑΒ=10.9 Hz, 2H), 3.69 (dd, half of ABX pattern, J=14.7, 5.8 Hz, 1 H), 3.58 (dd, half of ABX pattern, J=14.7, 6.2 Hz, 1 H), 1.44 (s, 3H), 1.43 (s, 3H).

Alternate preparation of C92

Figure imgf000082_0001

Step 1 : Preparation of C93. An Atlantis pressure reactor was charged with 10% palladium hydroxide on carbon (0.375 g, John Matthey catalyst type A402028-10), C91 (0.75 g, 0.77 mmol) and treated with ethanol (35 mL). The reactor was flushed with nitrogen and pressurized with hydrogen (20 psi) for 20 hours at 20 °C. The reaction mixture was filtered under vacuum and the filtrate was concentrated using the rotary evaporator to yield C93 as a tan solid. Yield: 0.49 g, 0.62 mmol, 80%. LCMS m/z 787.6 (M-1 ). 1H NMR (400 MHz, DMSO-d6) δ 1 1.57 (br s, 1 H), 9.27 (d, J=8.5 Hz, 1 H), 8.16 (s, 1 H), 7.36 (br s, 1 H), 7.26 (s, 1 H), 7.00 (s, 1 H), 6.40 (br s, 1 H), 5.18 (m, 1 H), 4.35 (m, 2H), 3.83 (m, 1 H), 3.41 (m, 1 H), 3.10 (m, 1 H), 1.41 (s, 6H), 1.36 (s, 18H).

Step 2: Preparation of C92. A solution of C93 (6.0 g, 7.6 mmol) in anhydrous dichloromethane (45 mL) at 0 °C was treated with trifluoroacetic acid (35.0 mL, 456 mmol). The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cannulated into a solution of methyl ferf-butyl ether (100 mL) and heptane (200 mL). The solid was collected by filtration and washed with a mixture of methyl ferf-butyl ether (100 mL) and heptane (200 mL) then dried under vacuum. The crude product (~5 g) was purified via reverse phase chromatography (C-18 column; acetonitrile / water gradient with 0.1 % formic acid modifier) and lyophilized to yield C92 as a pink solid. Yield: 1.45 g, 2.29 mmol. LCMS m/z 631.0 (M-1). 1H NMR (400 MHz, DMSO-de) δ 9.20 (d, J=8.7 Hz, 1H), 8.13 (s, 1H), 7.24-7.40 (br s, 2H), 7.16-7.23 (m, 1H), 6.97 (s, 1H), 6.71 (s, 1H), 6.31-6.35 (m, 1H), 5.15 (dd, J=8.7, 5.7 Hz, 1H), 4.31 (br d, J=4.6 Hz, 2H), 3.92-3.98 (m, 1H), 3.58-3.67 (m, 1H), 3.17-3.25 (m, 1H), 1.37 (s, 3H), 1.36 (s, 3H).

Example 4, route 2

2-({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-({(2 ?,3S)-2-[({[(1,5-dihydroxy-4-oxo-^ dihydropyridin-2-yl)methyl]carbamoyl}amino)methyl]-4-oxo-1-sulfoazetidin-3- yl}amino)-2-oxoethylidene]amino}oxy)-2-methylpropanoic acid (C92).

lt

Figure imgf000083_0001

single

enantiomer

Figure imgf000083_0002

Step 1. Preparation of C95. A solution of C94 (50.0 g, 189.9 mmol) in

dichloromethane (100 mL) was treated with trifluoroacetic acid (50.0 mL, 661.3 mmol). The reaction mixture was stirred at room temperature for 24 hours. The dichloromethane and trifluoroacetic acid was displaced with toluene (4 x 150 mL) using vacuum, to a final volume of 120 mL. The solution was added to heptane (250 mL) and the solid was collected by filtration. The solid was washed with a mixture of toluene and heptane (1 : 3, 60 mL), followed by heptane (2 x 80 mL) and dried under vacuum at 50 °C for 19 hours to afford C95 as a solid. Yield: 30.0 g, 158 mmol, 84%. 1H NMR (400 MHz, CDCI3) δ 9.66 (s, 1 H), 7.86 – 7.93 (m, 2H), 7.73 – 7.80 (m, 2H), 4.57 (s, 2H). HPLC retention time 5.1 minutes; column: Agilent Extended C-18 column (75 mm x 3 mm, 3.5 μηη); column temperature 45 °C; flow rate 1.0 mL / minute; detection UV 230 nm; mobile phase: solvent A = acetonitrile (100%), solvent B = acetonitrile (5%) in 10 mM ammonium acetate; gradient elusion: 0-1.5 minutes solvent B (100%), 1.5-10.0 minutes solvent B (5%), 10.0-13.0 minutes solvent B (100%); total run time 13.0 minutes.

Step 2: Preparation of C96-racemic. A solution of C95 (32.75 g; 173.1 mmol) in dichloromethane (550 mL) under nitrogen was cooled to 2 °C. The solution was treated with 2,4-dimethoxybenzylamine (28.94 g, 173.1 mmol) added dropwise over 25 minutes, maintaining the temperature below 10 °C. The solution was stirred for 10 minutes at 2 °C and then treated with molecular sieves (58.36 g, UOP Type 3A). The cold bath was removed and the reaction slurry was stirred for 3 hours at room temperature. The slurry was filtered through a pad of Celite (34.5 g) and the filter cake was rinsed with dichloromethane (135 mL). The dichloromethane filtrate (imine solution) was used directly in the following procedure.

A solution of A/-(ferf-butoxycarbonyl)glycine (60.6 g, 346.1 mmol) in

tetrahydrofuran (622 mL) under nitrogen was cooled to -45 °C and treated with triethylamine (38.5 g, 380.8 mmol). The mixture was stirred for 15 minutes at -45 °C and then treated with ethyl chloroformate (48.8 g, 450 mmol) over 15 minutes. The reaction mixture was stirred at -50 °C for 7 hours. The previously prepared imine solution was added via an addition funnel over 25 minutes while maintaining the reaction mixture temperature below -40 °C. The slurry was treated with triethylamine (17.5 g, 173 mmol) and the reaction mixture was slowly warmed to room temperature over 5 hours and stirred for an additional 12 hours. The reaction slurry was charged with water (150 mL) and the volatiles removed using a rotary evaporator. The reaction mixture was charged with additional water (393 mL) and the volatiles removed using a rotary evaporator. The mixture was treated with methyl ferf-butyl ether (393 mL) and vigorously stirred for 1 hour. The solid was collected by vacuum filtration and the filter cake was rinsed with a mixture of methyl ferf-butyl ether and water (1 : 1 , 400 mL). The solid was collected and dried in a vacuum oven at 50 °C for 16 hours to afford C96- racemic. Yield: 55.8 g, 1 13 mmol, 65%. 1H-NMR (400 MHz, DMSO-d6) δ 7.85 (s, NH), 7.80 (s, 4H), 6.78 (d, J=7.8 Hz, 1 H), 6.25 (m, 1 H), 6.10 (m, 1 H), 4.83 (m, 1 H), 4.38 (d, J=9.5 Hz, 1 H), 3.77-3.95 (m, 3H), 3.62 (s, 3H), 3.45 (m, 1 H), 3.40 (s, 3H), 1.38 (s, 9H). HPLC retention time 6.05 minutes; XBridge C8 column (4.6 x 75 mm, 3.5 μηη); column temperature 45 °C; flow rate 2.0 mL/minute; detection UV 210 nm, 230 nm, and 254 nm; mobile phase: solvent A = methanesulfonic acid (5%) in 10 mmol sodium octylsulfonate, solvent B = acetonitrile (100%); gradient elusion: 0-1.5 minutes solvent A (95%) and solvent B (5%), 1.5-8.5 minutes solvent A (5%) and solvent B (95%), 8.5- 10.0 minutes solvent A (5%) and solvent B (95%), 10.01 -12.0 minutes solvent A (95%) and solvent B (5%); total run time 12.0 minutes.

Step 3: Preparation of C97-racemic. A solution of C96-racemic (15.0 g, 30.3 mmol) in ethyl acetate (150 mL) under nitrogen was treated with ethanolamine (27.3 mL, 454.1 mmol). The reaction mixture was heated at 90 °C for 3 hours and then cooled to room temperature. The mixture was charged with water (150 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (75 mL) and the combined organic layers washed with water (2 x 150 mL) followed by saturated aqueous sodium chloride (75 mL). The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated to a volume of 38 mL. The filtrate was treated with heptane (152 mL) and the solid was collected by filtration. The solid was washed with heptane and dried at 50 °C in a vacuum oven overnight to yield C97-racemic as a solid. Yield: 9.68 g, 26.5 mmol, 88%. LCMS m/z 967.6 (M-1 ). 1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J=9.4 Hz, 1 H), 7.14 (d, J=8.2 Hz, 1 H), 6.56 (s, 1 H), 6.49 (dd, J=8.20, 2.3 Hz, 1 H), 4.78 (dd, J=9.37, 5.1 Hz, 1 H), 4.30 (d, J=14.8 Hz, 1 H), 4.14 (d, J=14.8 Hz, 1 H), 3.77 (s, 3H), 3.75 (s, 3H), 3.45 – 3.53 (m, 1 H), 2.65 – 2.75 (m, 1 H), 2.56 – 2.64 (m, 1 H), 1.38 (s, 9H), 1.30 – 1.35 (m, 2H). HPLC retention time 5.1 minutes; column: Agilent Extended C-18 column (75 mm x 3 mm, 3.5 μΐη); column temperature 45 °C; flow rate 1.0 mL / minute;

detection UV 230 nm; mobile phase: solvent A = acetonitrile (100%), solvent B = acetonitrile (5%) in 10 mM ammonium acetate; gradient elusion: 0-1 .5 minutes solvent B (100%), 1 .5-10.0 minutes solvent B (5%), 10.0-13.0 minutes solvent B (100%); total run time 13.0 minutes. Step 4: Preparation of C97-(2R,3S) enantiomer. A solution of C97-racemic (20.0 g, 54.7 mmol) in ethyl acetate (450 mL) was treated with diatomaceous earth (5.0 g) and filtered through a funnel charged with diatomaceous earth. The filter cake was washed with ethyl acetate (150 mL). The filtrate was charged with diatomaceous earth (20.0 g) and treated with (-)-L-dibenzoyltartaric acid (19.6 g, 54.7 mmol). The slurry was heated at 60 °C for 1.5 hours and then cooled to room temperature. The slurry was filtered and the solid washed with ethyl acetate (90 mL). The solid was collected and dried at 50 °C in a vacuum oven for 17 hours to yield C97-(2R,3S) enantiomer as a solid (mixed with diatomaceous earth). Yield: 17.3 g, 23.9 mmol, 43.6%, 97.6% ee. 1H NMR (400 MHz, DMSO-de) δ 7.89 – 7.91 (m, 4H), 7.59 – 7.65 (m, 3H), 7.44 – 7.49 (m, 4H), 7.09 (d, J=8.3 Hz, 1 H), 6.53 (d, J=2.3 Hz, 1 H), 6.49 (dd, J=8.3, 2.3 Hz, 1 H), 5.65 (s, 2H), 4.85 (dd, J=9.3, 4.9 Hz, 1 H), 4.30 (d, J=15.3 Hz, 1 H), 4.10 (d, J=15.3 Hz, 1 H), 3.74 (s, 3H), 3.72 (s, 3H), 3.68 – 3.70 (m, 1 H), 2.92 – 2.96 (dd, J=13.6, 5.4 Hz, 1 H), 2.85 – 2.90 (dd, J=13.6, 6.3 Hz, 1 H), 1.36 (s, 9H). HPLC retention time 5.1 minutes; column: Agilent Extended C-18 column (75 mm x 3 mm, 3.5 μηη); column temperature 45 °C; flow rate 1.0 mL / minute; detection UV 230 nm; mobile phase: solvent A = acetonitrile (100%), solvent B = acetonitrile (5%) in 10 mM ammonium acetate; gradient elusion: 0-1 .5 minutes solvent B (100%), 1.5-10.0 minutes solvent B (5%), 10.0-13.0 minutes solvent B (100%); total run time 13.0 minutes. Chiral HPLC retention time 9.1 minutes; column: Chiralcel OD-H column (250 mm x 4.6 mm); column temperature 40 °C; flow rate 1 .0 mL / minute; detection UV 208 nm; mobile phase: solvent A = ethanol (18%), solvent B = heptane (85%); isocratic elusion; total run time 20.0 minutes.

Step 5: Preparation of C98-(2R,3S) enantiomer. A solution of C97-(2R,3S) enantiomer. (16.7 g, 23.1 mmol) in ethyl acetate (301 mL) was treated with diatomaceous earth (18.3 g) and 5% aqueous potassium phosphate tribasic (182 mL). The slurry was stirred for 30 minutes at room temperature, then filtered under vacuum and the filter cake washed with ethyl acetate (2 x 67 mL). The filtrate was washed with 5% aqueous potassium phosphate tribasic (18 mL) and the organic layer dried over magnesium sulfate. The solid was filtered and the filter cake washed with ethyl acetate (33 mL). The filtrate was concentrated to a volume of 42 mL and slowly added to heptane (251 mL) and the resulting solid was collected by filtration. The solid was washed with heptane and dried at 50 °C in a vacuum oven for 19 hours to yield C98- (2R,3S) enantiomer as a solid. Yield: 6.4 g, 17.5 mmol, 76%, 98.8% ee. 1H NMR (400 MHz, DMSO-de) δ 7.64 (d, J=9.4 Hz, 1 H), 7.14 (d, J=8.2 Hz, 1 H), 6.56 (s, 1 H), 6.49 (dd, J=8.20, 2.3 Hz, 1 H), 4.78 (dd, J=9.37, 5.1 Hz, 1 H), 4.30 (d, J=14.8 Hz, 1 H), 4.14 (d, J=14.8 Hz, 1 H), 3.77 (s, 3H), 3.75 (s, 3H), 3.45 – 3.53 (m, 1 H), 2.65 – 2.75 (m, 1 H), 2.56 – 2.64 (m, 1 H), 1.38 (s, 9H), 1.30 – 1.35 (m, 2H). HPLC retention time 5.2 minutes; column: Agilent Extended C-18 column (75 mm x 3 mm, 3.5 μηη); column temperature 45 °C; flow rate 1.0 mL / minute; detection UV 230 nm; mobile phase: solvent A = acetonitrile (100%), solvent B = acetonitrile (5%) in 10 mM ammonium acetate; gradient elusion: 0-1 .5 minutes solvent B (100%), 1.5-10.0 minutes solvent B (5%), 10.0-13.0 minutes solvent B (100%); total run time 13.0 minutes. Chiral HPLC retention time 8.7 minutes; column: Chiralcel OD-H column (250 mm x 4.6 mm); column temperature 40 °C; flow rate 1.0 mL / minute; detection UV 208 nm; mobile phase: solvent A = ethanol (18%), solvent B = heptane (85%); isocratic elusion; total run time 20.0 minutes.

Step 6: Preparation of C99. A solution of potassium phosphate tribasic N-hydrate (8.71 g, 41 .05 mmol) in water (32.0 mL) at 22 °C was treated with a slurry of C26- mesylate salt (12.1 g, 27.4 mmol, q-NMR potency 98%) in dichloromethane (100.00 mL). The slurry was stirred for 1 hour at 22 °C. The reaction mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was back extracted with dichloromethane (50.0 mL). The organic layers were combined, dried over magnesium sulfate, filtered under vacuum and the filter cake washed with

dichloromethane (2 x 16 mL). The filtrate (-190 mL, amine solution) was used directly in the next step.

A solution of 1 ,1 ‘-carbonyldiimidazole (6.66 g, 41 .0 mmol) in dichloromethane (100 mL) at 22 °C under nitrogen was treated with the previously prepared amine solution (-190 mL) added dropwise using an addition funnel over 3 hour at 22 °C with stirring. After the addition, the mixture was stirred for 1 hour at 22 °C, then treated with C98-(2R,3S) enantiomer. (10.0 g, 27.4 mmol) followed by /V,/V-dimethylformamide (23.00 mL). The reaction mixture was stirred at 22 °C for 3 hours and then heated at 40 °C for 12 hours. The solution was cooled to room temperature and the dichloromethane was removed using the rotary evaporator. The reaction mixture was diluted with ethyl acetate (216.0 mL) and washed with 10% aqueous citric acid (216.0 mL), 5% aqueous sodium chloride (2 x 216.0 mL), dried over magnesium sulfate and filtered under vacuum. The filter cake was washed with ethyl acetate (3 x 13 mL) and the ethyl acetate solution was concentrated on the rotary evaporator to a volume of (-1 10.00 mL) providing a suspension. The suspension (~1 10.00 mL) was warmed to 40 °C and transferred into a stirred solution of heptane (22 °C) over 1 hour, to give a slurry. The slurry was stirred for 1 hour and filtered under vacuum. The filter cake was washed with heptane (3 x 30 mL) and dried under vacuum at 50 °C for 12 hours to afford C99 as a solid. Yield: 18.1 g, 24.9 mmol, 92%. LCMS m/z 728.4 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1 H), 7.62 (d, J=9.4 Hz, 1 H), 7.33-7.52 (m, 10H), 7.07 (d, J=8.3 Hz, 1 H), 6.51 (d, J=2.3 Hz, 1 H), 6.50 (m, 1 H), 6.44 (dd, J=8.3, 2.3 Hz, 1 H), 6.12 (m, 1 H), 6.07 (s, 1 H), 5.27 (s, 2H), 5.00 (s, 2H), 4.73 (dd, J=9.4, 5.2 Hz, 1 H), 4.38 (d, J=15.0 Hz, 1 H), 4.19 (m, 2H), 3.99 (d, J=15.0 Hz, 1 H), 3.72 (s, 3H), 3.71 (s, 3H), 3.48 (m, 1 H), 3.28 (m, 1 H), 3.12 (m, 1 H), 1 .37 (s, 9H).

Step 7: Preparation of C100. A solution of C99 (46.5 g, 63.9 mmol) in acetonitrile (697 mL and water (372 mL) was treated with potassium persulfate (69.1 g, 255.6 mmol) and potassium phosphate dibasic (50.1 g, 287.5 mmol). The biphasic mixture was heated to 75 °C and vigorously stirred for 1.5 hours. The pH was maintained between 6.0-6.5 by potassium phosphate dibasic addition (-12 g). The mixture was cooled to 20 °C, the suspension was filtered and washed with acetonitrile (50 mL). The filtrate was concentrated using the rotary evaporator and treated with water (50 mL) followed by ethyl acetate (200 mL). The slurry was stirred for 2 hours at room temperature, filtered and the solid dried under vacuum at 40 °C overnight. The solid was slurried in a mixture of ethyl acetate and water (6 : 1 , 390.7 mL) at 20 °C for 1 hour then collected by filtration. The solid was dried in a vacuum oven to yield C100. Yield: 22.1 g, 38.3 mmol, 60%. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (br s, 1 H), 7.96 (s, 1 H), 7.58 (d, J=9.6 Hz, 1 H), 7.29-7.50 (m, 10H), 6.49 (dd, J=8.0, 6.0 Hz, 1 H), 6.08 (dd, J=5.6, 5.2 Hz, 1 H), 5.93 (s, 1 H), 5.22 (s, 2H), 4.96 (s, 2H), 4.77 (dd, J=9.6, 5.0 Hz, 1 H), 4.16 (m, 2H), 3.61 (m, 1 H), 3.1 1 (m, 2H), 1.36 (s, 9H). HPLC retention time 6.17 minutes; XBridge C8 column (4.6 x 75 mm, 3.5 μηη); column temperature 45 °C; flow rate 2.0 mL/minute; detection UV 210 nm, 230 nm, and 254 nm; mobile phase: solvent A = methanesulfonic acid (5%) in 10 mmol sodium octylsulfonate, solvent B = acetonitrile (100%); gradient elusion: 0-1 .5 minutes solvent A (95%) and solvent B (5%), 1.5-8.5 minutes solvent A (5%) and solvent B (95%), 8.5-10.0 minutes solvent A (5%) and solvent B (95%), 10.01- 12.0 minutes solvent A (95%) and solvent B (5%); total run time 12.0 minutes.

Step 8: Preparation of C101. A solution of trifluoroacetic acid (120 mL, 1550 mmol) under nitrogen was treated with methoxybenzene (30 mL, 269 mmol) and cooled to -5 °C. Solid C100 (17.9 g, 31.0 mmol) was charged in one portion at -5 °C and the resulting mixture stirred for 3 hours. The reaction mixture was cannulated with nitrogen pressure over 15 minutes to a stirred mixture of Celite (40.98 g) and methyl ferf-butyl ether (550 mL) at 10 °C. The slurry was stirred at 16 °C for 30 minutes, then filtered under vacuum. The filter cake was rinsed with methyl ferf-butyl ether (2 x 100 mL). The solid was collected and slurried in methyl ferf-butyl ether (550 mL) with vigorous stirring for 25 minutes. The slurry was filtered by vacuum filtration and washed with methyl ferf-butyl ether (2 x 250 mL). The solid was collected and dried in a vacuum oven at 60 °C for 18 hours to afford C101 on Celite. Yield: 57.6 g total = C101 + Celite; 16.61 g C101 , 28.1 mmol, 91%. 1H NMR (400 MHz, DMSO-d6) δ 8.75-8.95 (br s, 2H), 8.65 (s, 1 H), 8.21 (s, 1 H), 7.30-7.58 (m, 10H), 6.83 (br s, 1 H), 6.65 (br s, 1 H), 6.17 (s, 1 H), 5.30 (s, 2H), 5.03 (s, 2H), 4.45 (br s, 1 H), 4.22 (br s, 2H), 3.77 (m, 1 H), 3.36 (m, 1 H), 3.22 (m, 1 H). 19F NMR (376 MHz, DMSO-d6) δ -76.0 (s, 3F). HPLC retention time 5.81 minutes; XBridge C8 column (4.6 x 75 mm, 3.5 μηη); column temperature 45 °C; flow rate 2.0 mL/minute; detection UV 210 nm, 230 nm, and 254 nm; mobile phase: solvent A = methanesulfonic acid (5%) in 10 mmol sodium octylsulfonate, solvent B = acetonitrile (100%); gradient elusion: 0-1.5 minutes solvent A (95%) and solvent B (5%), 1.5-8.5 minutes solvent A (5%) and solvent B (95%), 8.5-10.0 minutes solvent A (5%) and solvent B (95%), 10.01-12.0 minutes solvent A (95%) and solvent B (5%); total run time 12.0 minutes.

Step 9: Preparation of C90. A suspension of C101 (67.0 g, 30% activity on Celite = 33.9 mmol) in acetonitrile (281 .4 mL) was treated with molecular sieves 4AE (40.2 g), C5 (17.9 g, 33.9 mmol), 4-dimethylaminopyridine (10.4 g, 84.9 mmol) and the mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to 20 °C, filtered under vacuum and the filter cake washed with acetonitrile (2 x 100 mL). The filtrate was concentrated under vacuum to a volume of -50 mL. The solution was diluted with ethyl acetate (268.0 mL) and washed with 10% aqueous citric acid (3 x 134 mL) followed by 5% aqueous sodium chloride (67.0 mL). The organic layer was dried over magnesium sulfate and filtered under vacuum. The filter cake was washed with ethyl acetate (2 x 50 mL) and the filtrate was concentrated to a volume of -60 mL. The filtrate was added slowly to heptane (268 mL) with stirring and the slurry was stirred at 20 °C for 1 hour. The slurry was filtered under vacuum and the filter cake washed with a mixture of heptane and ethyl acetate (4: 1 , 2 x 27 mL). The solid was collected and dried under vacuum for 12 hours at 50 °C to afford a solid. The crude product was purified via chromatography on silica gel (ethyl acetate / 2-propanol), product bearing fractions were combined and the volume was reduced to -60 mL. The solution was added dropwise to heptane (268 mL) with stirring. The slurry was stirred at room temperature for 3 hours, filtered and washed with heptane and ethyl acetate (4: 1 , 2 x 27 mL). The solid was collected and dried under vacuum for 12 hours at 50 °C to afford C90 as a solid. Yield: 16.8 g, 18.9 mmol, 58%. LCMS m/z 889.4 (M+1 ). 1H NMR (400 MHz, DMSO-cfe) 1 1.90 (br s, 1 H), 9.25 (d, J=8.7 Hz, 1 H), 8.40 (br s, 1 H), 7.98 (s, 1 H), 7.50-7.54 (m, 2H), 7.32- 7.47 (m, 8H), 7.28 (s, 1 H), 6.65 (br s, 1 H), 6.28 (br s, 1 H), 5.97 (s, 1 H), 5.25 (s, 2H), 5.18 (dd, J=8.8, 5 Hz, 1 H), 4.99 (s, 2H), 4.16-4.28 (m, 2H), 3.74-3.80 (m, 1 H), 3.29-3.41 (m, 1 H), 3.13-3.23 (m, 1 H), 1 .42 (s, 9H), 1 .41 (s, 3H), 1.39 (br s, 12H).

Step 10: Preparation of C91. A solution of C90 (14.5 g, 16.3 mmol) in anhydrous N,N- dimethylformamide (145.0 mL) was treated with sulfur trioxide /V,/V-dimethylformamide complex (25.0 g, 163.0 mmol). The reaction mixture was stirred at room temperature for 45 minutes, then transferred to a stirred mixture of 5% aqueous sodium chloride (290 mL) and ethyl acetate (435 mL) at 0 °C. The mixture was warmed to 18 °C and the layers separated. The aqueous layer was extracted with ethyl acetate (145 mL) and the combined organic layers washed with 5% aqueous sodium chloride (3 x 290 mL) followed by saturated aqueous sodium chloride (145 mL). The organic layer was dried over magnesium sulfate, filtered through diatomaceous earth and the filter cake washed with ethyl acetate (72 mL). The filtrate was concentrated to a volume of 36 mL and treated with methyl ferf-butyl ether (290 mL), the resulting slurry was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with methyl ferf- butyl ether (58 mL) and dried at 50 °C for 2 hours followed by 20 °C for 65 hours in a vacuum oven to yield C91 as a solid. Yield: 15.0 g, 15.4 mmol, 95%. LCMS m/z 967.6 (M-1 ). 1H NMR (400 MHz, DMSO-d6) δ 1 1.62 (br s, 1 H), 9.29 (d, J=8.8 Hz, 1 H), 9.02 (s, 1 H), 7.58-7.61 (m, 2H), 7.38-7.53 (m, 9H), 7.27 (s, 1 H), 7.07 (s, 1 H), 6.40 (br d, J=8.0 Hz, 1 H), 5.55 (s, 2H), 5.25 (s, 2H), 5.20 (dd, J=8.8, 5.6 Hz, 1 H), 4.46 (br dd, half of ABX pattern, J=17.0, 5.0 Hz, 1 H), 4.38 (br dd, half of ABX pattern, J=17.0, 6.0 Hz, 1 H), 3.92- 3.98 (m, 1 H), 3.79-3.87 (m, 1 H), 3.07-3.17 (m, 1 H), 1.40 (s, 9H), 1.39 (s, 3H), 1.38 (s, 12H).

Step 11 : Preparation of C92. A solution of C91 (20.0 g, 20.6 mmol) in

dichloromethane (400 mL) was concentrated under reduced pressure (420 mmHg) at 45 °C to a volume of 200 mL. The solution was cooled to -5 °C and treated with 1 M boron trichloride in dichloromethane (206.0 mL, 206.0 mmol) added dropwise over 40 minutes. The reaction mixture was warmed to 15 °C over 1 hour with stirring. The slurry was cooled to -15 °C and treated with a mixture of 2,2,2-trifluoroethanol (69.2 mL) and methyl ferf-butyl ether (400 mL), maintaining the temperature at -15 °C. The reaction mixture was warmed to 0 °C over 1 hour. The suspension was filtered using nitrogen pressure and the solid washed with methyl ferf-butyl ether (2 x 200 mL).

Nitrogen was passed over the solid for 2 hours. The solid was collected and suspended in methyl ferf-butyl ether (400 mL) for 1 hour with stirring at 18 °C. The suspension was filtered using nitrogen pressure and the solid washed with methyl ferf-butyl ether (2 x 200 mL). Nitrogen was passed over the resulting solid for 12 hours. A portion of the crude product was neutralized with 1 M aqueous ammonium formate to pH 5.5 with minimal addition of /V,/V-dimethylformamide to prevent foaming. The feed solution was filtered and purified via reverse phase chromatography (C-18 column; acetonitrile / water gradient with 0.2% formic acid modifier). The product bearing fractions were combined and concentrated to remove acetonitrile. The solution was captured on a GC-161 M column, washed with deionized water and blown dry with nitrogen pressure. The product was released using a mixture of methanol / water (10: 1 ) and the product bearing fractions were added to a solution of ethyl acetate (6 volumes). The solid was collected by filtration to afford C92 as a solid. Yield: 5.87 g, 9.28 mmol. LCMS m/z 633.3 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J=8.7 Hz, 1 H), 8.15 (s, 1 H), 7.26-7.42 (br s, 2H), 7.18-7.25 (m, 1 H), 6.99 (s, 1 H), 6.74 (s, 1 H), 6.32-6.37 (m, 1 H), 5.18 (dd, J=8.7, 5.7 Hz, 1 H), 4.33 (br d, J=4.6 Hz, 2H), 3.94-4.00 (m, 1 H), 3.60-3.68 (m, 1 H), 3.19-3.27 (m, 1 H), 1.40 (s, 3H), 1.39 (s, 3H).

PAPER

Journal of Medicinal Chemistry (2014), 57(9), 3845-3855

Siderophore Receptor-Mediated Uptake of Lactivicin Analogues in Gram-Negative Bacteria

Medicinal Chemistry, Computational Chemistry, §Antibacterials Research Unit, and Structural Biology, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
J. Med. Chem.201457 (9), pp 3845–3855
DOI: 10.1021/jm500219c
Publication Date (Web): April 2, 2014
Copyright © 2014 American Chemical Society
*Phone: (860)-686-1788. E-mail: seungil.han@pfizer.com.

Abstract

Abstract Image

Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug–target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and β-lactam core structures. Results from drug sensitivity studies with β-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.

PAPER

Pyridone-Conjugated Monobactam Antibiotics with Gram-Negative Activity

Worldwide Medicinal Chemistry, Computational Chemistry, §Antibacterials Research Unit, Pharmacokinetics, Dynamics & Metabolism, Structural Biology, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
J. Med. Chem.201356 (13), pp 5541–5552
DOI: 10.1021/jm400560z
Publication Date (Web): June 11, 2013
Copyright © 2013 American Chemical Society
*Phone: 860-441-3522. E-mail: matthew.f.brown@pfizer.com.
Abstract Image

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosaKlebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.

STR1

17 as a solid. Yield: 5.87 g, 9.28 mmol. LCMS m/z 633.3 (M+1). 1H NMR (400 MHz, DMSOd6) δ 9.22 (d, J=8.7 Hz, 1H), 8.15 (s, 1H), 7.26-7.42 (br s, 2H), 7.18-7.25 (m, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 6.32-6.37 (m, 1H), 5.18 (dd, J=8.7, 5.7 Hz, 1H), 4.33 (br d, J=4.6 Hz, 2H), 3.94-4.00 (m, 1H), 3.60-3.68 (m, 1H), 3.19-3.27 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H).

Nc1nc(cs1)\C(=N\OC(C)(C)C(=O)O)C(=O)N[C@@H]3C(=O)N([C@@H]3CNC(=O)NCC2=CC(=O)C(O)=CN2O)S(=O)(=O)O

PAPER

Process Development for the Synthesis of Monocyclic β-Lactam Core 17

Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00359
Publication Date (Web): January 4, 2018
Copyright © 2018 American Chemical Society
Abstract Image

Process development and multikilogram synthesis of the monocyclic β-lactam core 17 for a novel pyridone-conjugated monobactam antibiotic is described. Starting with commercially available 2-(2,2-diethoxyethyl)isoindoline-1,3-dione, the five-step synthesis features several telescoped operations and direct isolations to provide significant improvement in throughput and reduced solvent usage over initial scale-up campaigns. A particular highlight in this effort includes the development of an efficient Staudinger ketene–imine [2 + 2] cycloaddition reaction of N-Boc-glycine ketene 12 and imine 9 to form racemic β-lactam 13 in good isolated yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution of racemic amine 15 to afford single enantiomer salt 17 in excellent isolated yield (45%) with high enantiomeric excess (98%).

Figure

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00359/suppl_file/op7b00359_si_001.pdf

Nc1nc(cs1)\C(=N\OC(C)(C)C(=O)O)C(=O)N[C@@H]3C(=O)N([C@@H]3CNC(=O)NCC2=CC(=O)C(O)=CN2O)S(=O)(=O)O

////////////////////////////////////////////////////////////////////////

J. Med. Chem.201356 (13), pp 5541–5552
DOI: 10.1021/jm400560z

OXYGEN ANALOGUE…………..

STR2
 1380110-45-1, C20 H23 N7 O13 S2, 633.57
Propanoic acid, 2-​[[(Z)​-​[1-​(2-​amino-​4-​thiazolyl)​-​2-​[[(2R,​3S)​-​2-​[[[[(1,​4-​dihydro-​1,​5-​dihydroxy-​4-​oxo-​2-​pyridinyl)​methoxy]​carbonyl]​amino]​methyl]​-​4-​oxo-​1-​sulfo-​3-​azetidinyl]​amino]​-​2-​oxoethylidene]​amino]​oxy]​-​2-​methyl-
2-[[(Z)-[1-(2-Amino-4-thiazolyl)-2-[[(2R,3S)-2-[[[[(1,4-dihydro-1,5-dihydroxy-4-oxo-2-pyridinyl)methoxy]carbonyl]amino]methyl]-4-oxo-1-sulfo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid

STR2

18 as a light yellow solid. Yield: 43 mg, 0.068 mmol, 51%. LCMS m/z 634.4 (M+1). 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 9.29 (d, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.04-7.10 (m, 1H), 7.00 (s, 1H), 6.75 (s, 1H), 5.05-5.30 (m, 3H), 4.00-4.07 (m, 1H), 1.42 (s, 3H), 1.41 (s, 3H).

Nc1nc(cs1)\C(=N\OC(C)(C)C(=O)O)C(=O)N[C@@H]3C(=O)N([C@@H]3CNC(=O)OCC2=CC(=O)C(O)=CN2O)S(=O)(=O)O

Step 4: Preparation of 18-Bis Na salt. A suspension of 5 (212 mg, 0.33 mmol) in water (10 mL) was cooled to 0 oC and treated with a solution of sodium bicarbonate (56.4 mg, 0.67 mmol) in water (2 mL), added dropwise. The reaction mixture was cooled to -70 oC (frozen) and lyophilized to afford 18-Bis Na salt as a white solid. Yield: 210 mg, 0.31 mmol, 93%. LCMS m/z 632.5 (M-1). 1H NMR (400 MHz, D2O) δ 7.87 (s, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 5.35 (d, J=5 Hz, 1H), 5.16 (s, 2H), 4.46-4.52 (m, 1H), 3.71 (dd, half of ABX pattern, J=14.5, 6 Hz, 1H), 3.55 (dd, half of ABX pattern, J=14.5, 6 Hz, 1H), 1.43 (s, 3H), 1.42 (s, 3H).

WO 2012073138

Inventors Matthew Frank BrownSeungil HanManjinder LallMark. J. Mitton-FryMark Stephen PlummerHud Lawrence RisleyVeerabahu ShanmugasundaramJeremy T. Starr
Applicant Pfizer Inc.

Example 5

disodium 2-({[(1Z)-1 -(2-amino-1 ,3-thiazol-4-yl)-2-({(2R,3S)-2-[({[(1 ,5-dihydroxy-4- oxo-1 ,4-dihydropyridin-2-yl)methoxy]carbonyl}amino)methyl]-4-oxo-1 – sulfonatoazetidin-3-yl}amino)-2-oxoethylidene]amino}oxy)-2-methylpropanoate

(C104-Bis Na salt).

Figure imgf000092_0001

Step 1 : Preparation of C102. A solution of C28 (300 mg, 0.755 mmol) in

tetrahydrofuran (10 mL) was treated with 1 , 1 ‘-carbonyldiimidazole (379 mg, 2.26 mmol) at room temperature and stirred for 20 hours. The yellow reaction mixture was treated with a solution of C9 (286 mg, 0.543 mmol) in tetrahydrofuran (25 mL). The mixture was stirred for 6 hours at room temperature, then treated with water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via chromatography on silica gel (heptane / ethyl acetate / 2-propanol) to afford C102 as a light yellow solid. Yield: 362 mg, 0.381 mmol, 62%. LCMS m/z 950.4 (M+1 ). 1H NMR (400 MHz, DMSO-de), characteristic peaks: δ 9.31 (d, J=8.4 Hz, 1 H), 8.38 (s, 1 H), 8.00 (s, 1 H), 7.41 (br d, J=8.2 Hz, 2H), 7.36 (br d, J=8.8 Hz, 2H), 7.26 (s, 1 H), 6.10 (s, 1 H), 5.20 (s, 2H), 4.92 (br s, 4H), 3.77 (s, 3H), 3.76 (s, 3H), 1.45 (s, 9H), 1.38 (s, 9H). Step 2: Preparation of C103. A solution of C102 (181 mg, 0.191 mmol) in anhydrous /V,/V-dimethylformamide (2.0 mL) was treated with sulfur trioxide pyridine complex (302 mg, 1.91 mmol). The reaction mixture was allowed to stir at room temperature for 6 hours, then cooled to 0 °C and quenched with water. The resulting solid was collected by filtration and dried in vacuo to yield C103 as a white solid. Yield: 145 mg, 0.14 mmol, 74%. APCI m/z 1028.5 (M-1 ). 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 1 1.65 (br s, 1 H), 9.37 (d, J=8.6 Hz, 1 H), 8.87 (s, 1 H), 7.49 (br d, J=8.6 Hz, 2H), 7.43 (br d, J=8.6 Hz, 2H), 7.26 (s, 1 H), 7.01 (br d, J=8.9 Hz, 2H), 7.00 (br d, J=8.8 Hz, 2H), 5.43 (s, 2H), 5.20 (dd, J=8.4, 6 Hz, 1 H), 4.01-4.07 (m, 1 H), 3.78 (s, 3H), 3.77 (s, 3H), 3.50- 3.58 (m, 1 H), 3.29-3.37 (m, 1 H), 1.44 (s, 9H), 1.37 (s, 9H). Step 3: Preparation of C104. A solution of C103 (136 mg, 0.132 mmol) in anhydrous dichloromethane (5 mL) was treated with 1 M boron trichloride in p-xylenes (0.92 mL, 0.92 mmol) and allowed to stir at room temperature for 40 minutes. The reaction mixture was cooled in an ice bath, quenched with water (0.4 mL), and transferred into a solution of methyl ferf-butyl ether: heptane (1 :2, 12 mL). The solvent was removed in vacuo and the crude product was purified via reverse phase chromatography (C-18 column; acetonitrile / water gradient with 0.1 % formic acid modifier) to yield C104 as a light yellow solid. Yield: 43 mg, 0.068 mmol, 51 %. LCMS m/z 634.4 (M+1 ). 1H NMR (400 MHz, DMSO-de), characteristic peaks: δ 9.29 (d, J=8.5 Hz, 1 H), 8.10 (s, 1 H), 7.04- 7.10 (m, 1 H), 7.00 (s, 1 H), 6.75 (s, 1 H), 5.05-5.30 (m, 3H), 4.00-4.07 (m, 1 H), 1 .42 (s, 3H), 1 .41 (s, 3H).

Step 4: Preparation of C104-Bis Na salt. A suspension of C104 (212 mg, 0.33 mmol) in water (10 mL) was cooled to 0 °C and treated with a solution of sodium bicarbonate (56.4 mg, 0.67 mmol) in water (2 mL), added dropwise. The reaction mixture was cooled to -70 °C (frozen) and lyophilized to afford C104-Bis Na salt as a white solid. Yield: 210 mg, 0.31 mmol, 93%. LCMS m/z 632.5 (M-1 ). 1H NMR (400 MHz, D20) δ 7.87 (s, 1 H), 6.94 (s, 1 H), 6.92 (s, 1 H), 5.35 (d, J=5 Hz, 1 H), 5.16 (s, 2H), 4.46-4.52 (m, 1 H), 3.71 (dd, half of ABX pattern, J=14.5, 6 Hz, 1 H), 3.55 (dd, half of ABX pattern, J=14.5, 6 Hz, 1 H), 1.43 (s, 3H), 1 .42 (s, 3H).

////////////Pfizer,  monobactam,  PF-?, 1380110-34-8, pfizer, pf, 1380110-45-1, WO 2012073138, Matthew Frank BrownSeungil HanManjinder LallMark. J. Mitton-FryMark Stephen PlummerHud Lawrence RisleyVeerabahu ShanmugasundaramJeremy T. Starr, preclinical

Design, synthesis and biological evaluation of novel 5-hydroxy-2-methyl-4H-pyran-4-one derivatives as antiglioma agents


Med. Chem. Commun., 2018, Advance Article
DOI: 10.1039/C7MD00551B, Research Article
Yi-Bin Li, Wen Hou, Hui Lin, Ping-Hua Sun, Jing Lin, Wei-Min Chen
Two series of 5-hydroxy-2-methyl-4H-pyran-4-one derivatives were synthesized and their antiglioma activities were evaluated.

Design, synthesis and biological evaluation of novel 5-hydroxy-2-methyl-4H-pyran-4-one derivatives as antiglioma agents

Author affiliations

Abstract

D-2-Hydroxyglutarate (D-2HG) is frequently found in human brain cancers. Approximately 50–80% of grade II glioma patients have a high level of D-2HG production, which can lead to cancer initiation. In this study, a series of novel 5-hydroxy-2-methyl-4H-pyran-4-one derivatives were designed and synthesized as antiglioma agents, and their related structure–activity relationships are discussed. Among these novel compounds, 4a exhibited promising anti-proliferative activity against glioma HT1080 cells and U87 cells with an IC50 of 1.43 μM and 4.6 μM, respectively. Further studies found that the most active compound (4a) shows an 86.3% inhibitory rate against the intracellular production of D-2HG at 1 μM, and dramatic inhibitory effects, even at 1 μM on the colony formation and migration of U87 and HT1080 cells.

STR1 STR2 str3 str4
6,6′-((4-(Benzyloxy)phenyl)methylene)bis(5-hydroxy-2-methyl-4H-pyran-4- one) (4a) The reaction was performed according to the general procedure C, using 1 (1.00 g, 7.90 mmol) and 4-(benzyloxy)benzaldehyde (0.84 g, 3.95 mmol).2 The crude product was recrystallized from isopropanol affording a white powder 4a (1.53 g, 87%): mp 261.4-262.1oC; 1HNMR (300 MHz, DMSO-d6)  2.22 (s, 6H, CH3), 5.08 (s, 3H, OCH2- Ph), 5.96 (s, 1H, CH-Ar), 6.25 (s, 2H, C=CH), , 7.01 (d, J = 9.0 Hz, 2H, Ar-H3’/H5’), 7.22 (d, J = 9.0 Hz, 2H, Ar-H2’/H6’), 7.31-7.45 (m, 5H, Ph-H); 13CNMR (75 MHz, DMSO-d6)  173.95, 165.08, 158.12, 151.20, 147.68, 142.19, 140.77, 137.42, 129.87, 128.91, 128.16, 127.69, 115.46, 114.97, 111.74, 69.69, 19.63; ESI-MS m/z: 447.1 [M+H]+ ; ESI-HRMS m/z: 447.1438 [M+H]+ , calcd for C26H23O7 447.1438.

The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents


ST50238235.png

str1

CAS  74102-02-6

Molecular Formula: C15H17NO3
Molecular Weight: 259.305 g/mol

2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (39): White solid; m.p. 249 o C; TLC Rf value, 0.48 (in EtOAc:Hexane,60:40);

IR (neat) 2980, 2950, 1678, 1040 cm-1;

1 H NMR (400 MHz, CD3OD) δ 9.86 (1H, bs), 8.66 (1H, d, J = 16.0 Hz), 7.46- 7.34 (1H, m), 7.07-6.84 (3H, m), 2.46 (2H, s), 2.41 (2H, s), 1.10 (3H, s), 1.09 (3H, s);

13C NMR (101 MHz, CDCl3) δ 199.8, 197.2, 149.6, 149.3, 147.8, 127.2, 126.6, 120.6, 120.3, 108.

The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents

 Author affiliations

Abstract

The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against Mycobacterium tuberculosis H37Rv (M. tuberculosis) and identified the cyclohexane-1,3-dione-based structures 5 and 6 as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against M. tuberculosis lead to the identification of three lead antituberculosis agents (3739 and 41). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (39) showed an MIC of 2.5 μg mL−1, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 μM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria and even against M. smegmatis; thereby reflecting its highly specific antituberculosis activity.

Graphical abstract: The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents
http://pubs.rsc.org/en/Content/ArticleLanding/2017/MD/C7MD00350A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract
Background Image

Muzafar Ahmad Rather

Ph.D Research Scholar

CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Srinagar

Clinical Microbiology and PK/PD Division, Clinical Microbiology PK/PD/Laboratory, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, India-190005

Image result for Zahoor Ahmad CSIR

CSIR-Indian Institute of Integrative Medicine

(Council of Scientific & Industrial Research)

Dr. Zahoor Ahmad Parry

Clinical Microbiology Division
CSIR – Indian Institute of Integrative Medicine,Canal Road, Jammu – 180001
Email: zahoorap@iiim.ac.in
Positions Held
Position Held Date Organization
Sr. Scientist   2010 – Present CSIR-IIIM

Dr. Bilal Ahmad Bhat

Medicinal Chemistry Division
CSIR – Indian Institute of Integrative Medicine,Canal Road, Jammu – 180001
Email: bilal@iiim.ac.in
Positions Held
Position Held Date Organization
Scientist 2010 – Present CSIR-IIIM

Image result for Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar,

Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar,

A small Drug Research Laboratory working under the Government of Jammu & Kashmir was taken over by CSIR in 1957 and named as Regional Research Laboratory, Jammu. Col. Sir Ram Nath Chopra, who is acclaimed the father of modern Pharmacology in India, was the Director of Drug Research Laboratory, continued as the first Director of Regional Research Laboratory. Having significant expertise in the area of medicinal & aromatic plants, Col. Chopra started its related R&D activities such as collection of plants from north & north-west and study the chemistry & pharmacology of the plant extracts and the new molecules isolated from these plants. Thus the initial mandate of this laboratory was mainly focused on screening the flora of north India for new molecules and to study the biological activity of these molecules. Gradually the activities of the institute increased, many more disciplines were introduced, that were important for the exploitation of regional resources such as mineral technology division, paper & pulp, fur technology division, sericulture, food technology division and mycology division. The main stream department such as chemistry, botany and pharmacology were strengthened by the introduction of a small animal house, instrumentation and chemical engineering & design division. The activity of the institute gradually increased which showed up in its publications and technology developments.

With the progress of time, the institute developed high quality expertise and infrastructure for working in the area of plant based products & drugs to explore new botanicals for new molecules and new activity. The institute specialized for working in the area of chemistry of natural products, synthesis of new & nature like molecules. These were studied for their use on various indication such as Oncology, hepatoprotection, anti-bacterial, bio-enhancers, anti-diabetes, anti-inflammation, aphrodisiac, hypertension, immunomodulation, anti-oxidants, oral care and beauty care. Some of the areas which did not progress to the satisfaction level gradually became redundant and were dropped.

Keeping in view the expertise developed in the area of natural products and revised mandate of the institute to explore and exploit natural, nature like and synthetic products with modern scientific tools to reduce the burden of disease, the institute became more focused towards integrative medicine hence was renamed as Indian Institute of Integrative Medicine in 2007 by the governing body of CSIR

////////////////// synthesis, biological evaluation, structure–activity relationship, 2-phenylaminomethylene-cyclohexane-1,3-diones, anti-tuberculosis agents

O=C2CC(C)(C)CC(=O)/C2=C\Nc1ccccc1O

 

DISCLAIMER

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

Takeda’s Peripherally selective noradrenaline reuptake inhibitor


str1

SCHEMBL1279856.png

ChemSpider 2D Image | 1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxylic acid | C18H18ClFN2O4

1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydro-3-pyridinecarboxylic acid

  • Molecular Formula C18H18ClFN2O4
  • Average mass 380.798 Da

CAS 1372185-97-1

CAS 1372180-09-0 hydrochloride

Peripherally selective noradrenaline reuptake inhibitor

Image result for takeda pharmaceuticals1-([(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid monohydrochloride

3-Pyridinecarboxylic acid, 1-[[(6S,7R)-7-(4-chloro-3-fluorophenyl)hexahydro-1,4-oxazepin-6-yl]methyl]-1,2-dihydro-2-oxo-, hydrochloride (1:1)

1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic Acid Hydrochloride (1:1) (1·HCl)

TAKEDA PHARMACEUTICAL COMPANY LIMITED [JP/JP]; 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP)

ISHICHI, Yuji; (JP).
YAMADA, Masami; (US).
KAMEI, Taku; (JP).
FUJIMORI, Ikuo; (US).
NAKADA, Yoshihisa; (JP).
YUKAWA, Tomoya; (JP).
SAKAUCHI, Nobuki; (JP).
OHBA, Yusuke; (JP).
TSUKAMOTO, Tetsuya; (JP)

Paper

Development of a Practical Synthesis of a Peripherally Selective Noradrenaline Reuptake Inhibitor Possessing a Chiral 6,7-trans-Disubstituted-1,4-oxazepane as a Scaffold

Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00313

Abstract

Abstract Image

A practical synthesis of a peripherally selective noradrenaline reuptake inhibitor that has a chiral 6,7-trans-disubstituted-1,4-oxazepane as a new class of scaffold is described. The amino alcohol possessing the desired stereochemistry was obtained with excellent dr and ee, starting from a commercially available aldehyde via a Morita–Baylis–Hillman reaction, Michael addition, isolation as maleic acid salt, reduction, and diastereomeric salt formation with (+)-10-camphorsulfonic acid. The desired single stereoisomer obtained at an early stage of the synthesis was used for seven-membered ring formation in fully telescoped processes, providing the chiral 6,7-trans-disubstituted-1,4-oxazepane efficiently. In addition to controls of dr and ee of the chiral 1,4-oxazepane, and control of N,O-selectivity in SN2 reaction of the intermediate mesylate with a pyridone derivative, finding appropriate intermediates that were amenable to isolation and upgrade of purity enabled a practical chiral HPLC separation-free, column chromatograph-free synthesis of the drug candidate with excellent chemical and optical purities in a higher overall yield.

Mp 261–262 °C;
1H NMR (600 MHz, DMSO-d6) δ 3.09–3.18 (m, 1H), 3.20–3.43 (m, 4H), 3.77–3.88 (m, 1H), 3.96 (br dd, J = 13.2, 5.7 Hz, 1H), 4.04 (dt, J = 13.8, 4.2 Hz, 1H), 4.17 (br dd, J = 13.6, 7.6 Hz, 1H), 4.59 (br d, J = 9.1 Hz, 1H), 6.66 (t, J = 7.0 Hz, 1H), 7.27 (br dd, J = 8.3, 1.1 Hz, 1H), 7.47 (br dd, J = 10.4, 1.3 Hz, 1H), 7.54 (br t, J = 8.1 Hz, 1H), 8.10 (dd, J = 6.4, 1.9 Hz, 1H), 8.26 (dd, J = 7.2, 1.9 Hz, 1H), 9.59 (br s, 2H), 14.2 (br s, 1H);
 13C NMR (151 MHz, DMSO-d6) δ 40.5, 44.9, 46.5, 50.0, 63.9, 82.1, 108.4, 116.0 (2JCF = 21.1 Hz), 116.7, 119.3 (2JCF = 18.1 Hz), 125.1 (3JCF = 4.5 Hz), 130.4, 140.9 (3JCF = 7.6 Hz), 145.1, 145.2, 156.8 (1JCF = 247.6 Hz), 163.6, 164.4;
IR (ATR) 2925, 2693, 1725, 1625, 1563, 1484, 1445, 1379, 1293, 1206, 1126, 1097, 1064, 1003, 934, 868, 856, 820, 783, 771, 627, 538, 521, 459, 411 cm–1;
HRMS (ESI): [M + H]+ calcd for C18H19ClFN2O4 (1), 381.1017; found, 381.1009.

PATENT

https://www.google.com/patents/WO2012046882A1?cl=zh

PAPER

Volume 24, Issue 16, 15 August 2016, Pages 3716–3726

http://www.sciencedirect.com/science/article/pii/S0968089616304382

Abstract

Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety. The resulting compound 9exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.


Graphical abstract

Image for unlabelled figure

REFERNCES

(a) IshichiY.YamadaM.KameiT.FujimoriI.NakadaY.YukawaT.SakauchiN.OhbaY.TsukamotoT. WO 2012/046882 A1, Apr 12, 2012.

(b) FujimoriI.YukawaT.KameiT.NakadaY.SakauchiN.YamadaM.OhbaY.TakiguchiM.KunoM.KamoI.NakagawaH.HamadaT.IgariT.OkudaT.YamamotoS.TsukamotoT.IshichiY.UenoH. Bioorg. Med. Chem. 2015235000– 5014 DOI: 10.1016/j.bmc.2015.05.017

(c) YukawaT.FujimoriI.KameiT.NakadaY.SakauchiN.YamadaM.OhbaY.UenoH.TakiguchiM.KunoM.KamoI.NakagawaH.FujiokaY.IgariT.IshichiY.TsukamotoT. Bioorg. Med. Chem. 2016243207– 3217 DOI: 10.1016/j.bmc.2016.05.038

(d) YukawaT.NakadaY.SakauchiN.KameiT.YamadaM.OhbaY.FujimoriI.UenoH.TakiguchiM.KunoM.KamoI.NakagawaH.FujiokaY.IgariT.IshichiY.TsukamotoT. Bioorg. Med. Chem. 2016243716– 3726 DOI: 10.1016/j.bmc.2016.06.014

//////////////////1372185-97-1, 1372180-09-0, Peripherally selective,  noradrenaline reuptake inhibitor,  TAKEDA

O=C(O)C3=CC=CN(C[C@@H]1CNCCO[C@H]1c2ccc(Cl)c(F)c2)C3=O

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
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PF 06821497


str1

PF 06821497

Cas 1844849-11-1

Designed to treat lymphoma

1(2H)-Isoquinolinone, 5,8-dichloro-2-[(1,2-dihydro-4-methoxy-6-methyl-2-oxo-3-pyridinyl)methyl]-3,4-dihydro-7-[(S)-methoxy-3-oxetanylmethyl]-

MF C22 H24 Cl2 N2 O5, 

MW 467.34

ChemSpider 2D Image | 5,8-Dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-7-[methoxy(3-oxetanyl)methyl]-3,4-dihydro-1(2H)-isoquinolinone | C22H24Cl2N2O5PF 06821497

5,8-Dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-7-[methoxy(3-oxetanyl)methyl]-3,4-dihydro-1(2H)-isoquinolinone

1(2H)-Isoquinolinone, 5,8-dichloro-2-[(1,2-dihydro-4-methoxy-6-methyl-2-oxo-3-pyridinyl)methyl]-3,4-dihydro-7-(methoxy-3-oxetanylmethyl)-

  • Molecular Formula C22H24Cl2N2O5
  • Average mass 467.342 Da

SCHEMBL17330377.pngPF 06821497

5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[(S)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1-one

US2015361067

Inventors Michael Raymond Collins, Robert Steven Kania, Robert Arnold Kumpf, Pei-Pei Kung, Daniel Tyler Richter, Scott Channing Sutton, Martin James Wythes
Original Assignee Pfizer Inc.Image result
  • Epigenetic alterations play an important role in the regulation of cellular processes, including cell proliferation, cell differentiation and cell survival. The epigenetic silencing of tumor suppressor genes and activation of oncogenes may occur through alteration of CpG island methylation patterns, histone modification, and dysregulation of DNA binding protein. Polycomb genes are a set of epigenetic effectors. EZH2 (enhancer of zeste homolog 2) is the catalytic component of the Polycomb Repressor Complex 2 (PRC2), a conserved multi-subunit complex that represses gene transcription by methylating lysine 27 on Histone H3 (H3K27). EZH2 plans a key role in regulating gene expression patterns that regulate cell fate decisions, such as differentiation and self-renewal. EZH2 is overexpressed in certain cancer cells, where it has been linked to cell proliferation, cell invasion, chemoresistance and metastasis.
  • High EZH2 expression has been correlated with poor prognosis, high grade, and high stage in several cancer types, including breast, colorectal, endometrial, gastric, liver, kidney, lung, melanoma, ovarian, pancreatic, prostate, and bladder cancers. See Crea et al., Crit. Rev. Oncol. Hematol. 2012, 83:184-193, and references cited therein; see also Kleer et al., Proc. Natl. Acad. Sci. USA 2003, 100:11606-11; Mimori et al., Eur. J. Surg. Oncol. 2005, 31:376-80; Bachmann et al., J. Clin. Oncol. 2006, 24:268-273; Matsukawa et al., Cancer Sci. 2006, 97:484-491; Sasaki et al. Lab. Invest. 2008, 88:873-882; Sudo et al., Br. J. Cancer 2005, 92(9):1754-1758; Breuer et al., Neoplasia 2004, 6:736-43; Lu et al., Cancer Res. 2007, 67:1757-1768; Ougolkov et al., Clin. Cancer Res. 2008, 14:6790-6796; Varambally et al., Nature 2002, 419:624-629; Wagener et al., Int. J. Cancer 2008, 123:1545-1550; and Weikert et al., Int. J. Mol. Med. 2005, 16:349-353.
    Recurring somatic mutations in EZH2 have been identified in diffuse large B-cell lymphoma (DLBCL) and follicular lymphomas (FL). Mutations altering EZH2 tyrosine 641 (e.g., Y641C, Y641F, Y641N, Y641S, and Y641H) were reportedly observed in up to 22% of germinal center B-cell DLBCL and 7% of FL. Morin et al. Nat. Genetics 2010 February; 42(2):181-185. Mutations of alanine 677 (A677) and alanine 687 (A687) have also been reported. McCabe et al., Proc. Natl. Acad. Sci. USA 2012, 109:2989-2994; Majer et al. FEBS Letters 2012, 586:3448-3451. EZH2 activating mutations have been suggested to alter substrate specificity resulting in elevated levels of trimethylated H3K27 (H3K27me3).
    Accordingly, compounds that inhibit the activity of wild type and/or mutant forms of EZH2 may be of interest for the treatment of cancer.

SYNTHESIS

Steps

1 COUPLING, Ag2CO3

2 Alkylation, K2CO3

3 LiAlH4 REDUCTION

4 THIONYL CHLORIDE

5 N-Alkylation of Amides, t-BuOK

6 A GRIGNARD REACTION

7 AN ALKYLATION , METHYL IODIDE, t-BuOK

8 HYDROGENATION, DE BENZYLATION,  PLATINUM OXIDE

9 LAST STEP separation by chiral preparative, SFC on (R,R) Whelk O1 column, TO GET PF 06821497

PATENT

US 20150361067

///////////////PF 06821497, 1844849-11-1, PFIZER, lymphoma, Pei-Pei Kung,  @pfizer, #ACSSanFran, Michael Raymond Collins, Robert Steven Kania, Robert Arnold Kumpf, Pei-Pei Kung, Daniel Tyler Richter, Scott Channing Sutton, Martin James Wythes

Next up in #MEDI 1st time disclosures Pei-Pei Kung from @pfizer presenting a molecule designed to treat lymphoma #ACSSanFran

str0

CO[C@H](c2cc(Cl)c3CCN(CC1=C(OC)C=C(C)NC1=O)C(=O)c3c2Cl)C4COC4

CC1=CC(=C(C(=O)N1)CN2CCC3=C(C=C(C(=C3C2=O)Cl)C(C4COC4)OC)Cl)OC

ABBV 2222


str1

ABBV 2222

Benzoic acid, 4-[(2R,4R)-4-[[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]-

4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}- amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid

CAS  1918143-53-9

MF C28 H21 F4 N O7
MW 559.46
1H NMR (400 MHz, CDCl.sub.3) .delta. 8.17-8.03 (m, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.16-6.99 (m, 4H), 6.73-6.67 (m, 2H), 6.38 (d, J=73.6 Hz, 1H), 5.48 (td, J=10.4, 6.1 Hz, 1H), 5.36 (d, J=8.8 Hz, 1H), 5.31-5.21 (m, 1H), 2.52 (ddd, J=13.3, 6.0, 2.2 Hz, 1H), 1.86-1.71 (m, 2H), 1.68-1.60 (m, 1H), 1.10 (q, J=3.7, 2.4 Hz, 2H);
 
MS (ESI-) m/z=558 (M-H).sup.-.

Image result

DESCRIPTION

Cystic fibrosis (CF), one of the most common autosomal recessive genetic diseases in the Caucasian population, is caused by loss of function mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which is located on chromosome 7 (http://www.cff.org/AboutCF/; Rowe S. M et al. (2005); N Eng J Med. (352), 1992-2001). Approximately 1:3500 and 1:3000 infants born in the United States and in Europe, respectively, are affected by CF, resulting in ˜75,000 cases worldwide, ˜30,000 of which are in the United State. Approximately 1,000 new cases of CF are diagnosed each year, with more than 75% of patients being diagnosed by 2 years of age. Nearly half the CF population is currently 18 years of age and older. The CFTR protein (Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362; Riordan, J. R. et al. (1989) Science 245:1066-1073) is a cAMP/ATP-mediated ion channel expressed in a variety of cell types, including secretory and absorptive epithelial cells. CFTR regulates chloride and bicarbonate anion flux across the cell membrane, maintaining electro neutrality and osmolarity across the epithelial membrane (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). CFTR is also responsible for regulating the activity of other ion channels and proteins (Guggino, W. B. et al. (2006), Nat Revs Molecular Cell Biology 7, 426-436).

Aberrations in CFTR function result in imbalance of the airway surface liquid, leading to mucus dehydration, inflammation, recurrent bacterial infection and irreversible lung damage, which lead to premature death in affected patients. Besides respiratory disease, CF patients suffer from gastrointestinal problems and pancreatic insufficiency. The majority of males (95%) with cystic fibrosis are infertile as a result of azoospermia caused by altered vas deferens; which may be absent, atrophic, or fibrotic. Fertility is also decreased among females with cystic fibrosis due to abnormal cervical mucus.

The F508del mutation, the most common of the approximately 1900 identified polymorphisms in CFTR, results in defective processing of CFTR in the endoplasmic reticulum (ER) (http://www.cftr2.org/index.php). Approximately 90% of the CF patients carry at least one copy of the F508del mutation (deletion of a phenylalanine on position 508), and 50%-60% of the patients are homozygous for this mutation. The defective processing of CFTR results in early CFTR degradation, which leads to reduced trafficking or absence of the protein on the membrane. As there have been over 100 CF disease-causing mutations identified, they have been classified according to their phenotypic consequences and belong to synthesis, maturation, regulation, conductance, reduced number due to quantity and reduced number due to stability classifications.

Current CF drug discovery efforts focus upon developing two classes of compounds to modulate CFTR. One class, called Correctors, helps to overcome the folding defects of the mutated CFTR protein to promote its maturation resulting in higher cell surface expression. The other classes of compounds, called Potentiators, help overcome the defective regulation and/or conductance of the protein by increasing the probability of channel opening on the membrane surface.

In addition, as the modulation of CFTR protein mutations to promote proper protein folding is beneficial for CF, there are other diseases mediated by CFTR. For example, Sjögren’s Syndrome (SS), an autoimmune disorder that results in symptoms of xerostomia (dry mouth) and keratoconjunctivitis sicca (KCS, dry eyes) may result from dysregulation of moisture producing glands throughout the body. Chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD), which is a progressive and irreversible airflow limitation in the airways is result of several physiologic abnormalities, including mucus hyper secretion and impaired mucociliary secretion. Increasing the anion secretion by CFTR potentiators have been suggested to overcome these phenotypic complexities with Sjögren’s Syndrome by increasing the corneal hydration and by overcoming the impaired mucociliary secretion in COAD (Bhowmik A, et al. (2009) Vol. 103(4), 496-502; Sloane P, et al. PLOS One (2012) Vol 7(6), 239809 (1-13)).

STEP 1

(R)-methyl 4-(7-hydroxy-4-oxochroman-2-yl)benzoate

RXN……….By reacting  7-hydroxy-4H-chromen-4-one AND  (4-(methoxycarbonyl)phenyl)boronic acid

STEP 2

(R)-methyl 4-(7-hydroxy-4-(methoxyimino)chroman-2-yl)benzoate

Reacting ABOVE compd  and O-methylhydroxylamine,

STEP 3

Methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate

reacting ABOVE  compd with 5% platinum (0.05 equivalent) on carbon in acetic acid. The reaction was stirred at room temperature under hydrogen

THEN STEP 4

Methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate isolated AS  trifluroroacetic acid salt

STEP 5
methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-hydroxychroman-2-yl)benzoate

by reacting  1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid  and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, the ABOVE compound AND  N-ethyl-N-isopropylpropan-2-amine

STEP 6

Methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-(difluoromethoxy)chroman-2-yl)benzoate

by reacting ABOVE compound  and diethyl(bromodifluoromethyl)phosphonate

AND FINAL STEP7  is ESTER HYDROLYSIS USING lithium hydroxide to get ABBV 2222

PATENT
US 20160120841

str1

Example 122

4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}- amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid

[1880] To Example 123E (130 mg, 0.227 mmol) in methanol (2 mL) and water (0.5 mL) was added lithium hydroxide (32.6 mg, 1.360 mmol). The mixture was stirred at 35.degree. C. for 4 hours, LC/MS showed the conversion was complete. Solvent was removed under reduced pressure and water (2 mL) was added. The pH of the mixture was adjusted to pH 1-2 with the addition of 2 M HCl. The precipitated white solid was collected by filtration, and dried to provide the title compound (110 mg, 0.197 mmol, 87% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.17-8.03 (m, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.16-6.99 (m, 4H), 6.73-6.67 (m, 2H), 6.38 (d, J=73.6 Hz, 1H), 5.48 (td, J=10.4, 6.1 Hz, 1H), 5.36 (d, J=8.8 Hz, 1H), 5.31-5.21 (m, 1H), 2.52 (ddd, J=13.3, 6.0, 2.2 Hz, 1H), 1.86-1.71 (m, 2H), 1.68-1.60 (m, 1H), 1.10 (q, J=3.7, 2.4 Hz, 2H); MS (ESI-) m/z=558 (M-H).sup.-.

Example 123

methyl 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca- rbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate

Example 123A

(R)-methyl 4-(7-hydroxy-4-oxochroman-2-yl)benzoate

[1881] A mixture of bis(2,2,2-trifluoroacetoxy)palladium (271 mg, 0.816 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (200 mg, 0.979 mmol), ammonium hexafluorophosphate(V) (798 mg, 4.90 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2203 mg, 12.24 mmol) and dichloroethane (8 mL) in a 20 mL vial was stirred for 5 minutes at room temperature, followed by the addition of 7-hydroxy-4H-chromen-4-one (CAS 59887-89-7, MFCD00209371, 1323 mg, 8.16 mmol) and water (256 mg, 14.19 mmol). The vial was capped and the mixture was stirred at 60.degree. C. overnight. The reaction gradually turned black, with Pd plated out on the sides of the vial. The mixture was filtered through a plug of celite and eluted with ethyl acetate to give a red solution which was washed with brine. The solvent was removed in vacuo and the crude material was chromatographed using a 100 g silica gel cartridge and eluted with a gradient of 5-40% ethyl acetate in heptane to provide the title compound (1.62 g, 66.6% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15-8.04 (m, 2H), 7.87 (d, J=8.7 Hz, 1H), 7.60-7.49 (m, 2H), 6.62-6.45 (m, 2H), 5.87 (s, 1H), 5.53 (dd, J=12.8, 3.2 Hz, 1H), 3.94 (s, 3H), 3.07-2.80 (m, 2H); MS (ESI+) m/z=299 (M+H).sup.+.

Example 123B

(R)-methyl 4-(7-hydroxy-4-(methoxyimino)chroman-2-yl)benzoate

[1882] The mixture of Example 123A (960 mg, 3.22 mmol), sodium acetate (528 mg, 6.44 mmol) and O-methylhydroxylamine, hydrochloric acid (538 mg, 6.44 mmol) in methanol (10 mL) was stirred at 60.degree. C. overnight. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layers was dried over MgSO.sub.4, filtered, and concentrated. The residue was washed with ether to provide the title compound (810 mg, 2.475 mmol, 77% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15-8.03 (m, 2H), 7.81 (d, J=8.7 Hz, 1H), 7.58-7.43 (m, 2H), 6.50 (dd, J=8.6, 2.5 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.21 (d, J=3.0 Hz, 1H), 5.12 (dd, J=12.2, 3.2 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.45 (dd, J=17.2, 3.2 Hz, 1H), 2.63 (dd, J=17.2, 12.2 Hz, 1H); MS (ESI+) m/z 328 (M+H).sup.+.

Example 123C

Methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate

[1883] A mixture of Example 123B (570 mg, 1.741 mmol) was treated with 5% platinum (0.05 equivalent) on carbon in acetic acid (5 mL). The reaction was stirred at room temperature under hydrogen (1 atmosphere) for 24 hours, LC/MS showed conversion over 95%. The mixture was filtered through a celite pad and solvent removed under reduced pressure. The residue was purified by preparative LC method TFA2 to provide the trifluroroacetic acid salt of the title compound (300 mg, 44% yield). LC/MS m/z 283 (M-NH.sub.2).sup.+.

Example 123D

methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-hydroxychroman-2-yl)benzoate

[1884] A mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (162 mg, 0.668 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 380 mg, 1.0 mmol) in DMF (2 mL) was stirred for 5 minutes at room temperature, followed by the addition of Example 123C (200 mg, 0.334 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.466 ml, 2.67 mmol). The mixture was stirred at room temperature for 2 hours, LC/MS showed reaction complete. The mixture was loaded on to a 25 g silica gel cartridge eluting with 5-50% ethyl acetate in heptane provide the title compound (204 mg, 58.3% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11-7.90 (m, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.16-7.02 (m, 2H), 6.94 (dd, J=37.7, 8.3 Hz, 2H), 6.49-6.32 (m, 2H), 5.67 (s, 1H), 5.36 (dt, J=15.3, 8.7 Hz, 2H), 5.18 (d, J=10.7 Hz, 1H), 3.93 (s, 3H), 2.56-2.36 (m, 1H), 1.80-1.70 (m, 2H), 1.26 (d, J=2.2 Hz, 1H), 1.10-1.04 (m, 2H); MS (ESI-) m/z=521.9 (M-H).sup.-.

Example 123E

Methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-(difluoromethoxy)chroman-2-yl)benzoate

[1885] To Example 123D (190 mg, 0.363 mmol) and diethyl(bromodifluoromethyl)phosphonate (0.129 ml, 0.726 mmol) in a mixture of acetonitrile (2 mL) and water (1 mL) was added 50% aqueous potassium hydroxide (244 mg, 2.178 mmol) drop wise via syringe while stirring vigorously. After the addition was completed, LC/MS showed conversion was complete with a small by-product peak. Additional water was added to the mixture and the mixture was extracted with ethyl acetate (3.times.20 mL). The combined organic extracts were washed with 1 M HCl (5 mL) and water, dried over MgSO.sub.4, filtered, and concentrated. The residue was purified by preparative LC method TFA2 to provide the title compound (150 mg, 72% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09-8.00 (m, 2H), 7.49-7.41 (m, 2H), 7.15-6.99 (m, 4H), 6.75-6.66 (m, 2H), 5.50-5.40 (m, 1H), 5.33 (d, J=8.9 Hz, 1H), 5.25 (dd, J=11.3, 2.0 Hz, 1H), 3.93 (s, 3H), 2.50 (ddd, J=13.4, 6.1, 2.1 Hz, 1H), 1.84-1.71 (m, 2H), 1.65 (d, J=2.8 Hz, 1H), 1.11-1.06 (m, 2H); MS (ESI-) m/z=572 (M-H).sup.-.

REFERENCE

Next up is Xueqing Wang of @abbvie speaking about a collaboration with @GalapagosNV on a different cystic fibrosis treatment

str0

///////////ABBV 2222

O=C(O)c1ccc(cc1)[C@@H]3Oc2cc(OC(F)F)ccc2C(C3)NC(=O)C4(CC4)c5ccc6OC(F)(F)Oc6c5

BMS 986158


SCHEMBL16861831.png

str1

BMS 986158

MF C30H33N5O2, MW495.627 g/mol

CAS 1800340-40-2

5H-Pyrido[3,2-b]indole-7-methanol, 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-α,α-dimethyl-5-[(S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl]-

MOA:Bromodomain and extraterminal domain protein inhibitor

Indication:Solid tumoursStatus:

Phase II :Bristol-Myers Squibb (Originator)

Phase I/IISolid tumours

  • Originator Bristol-Myers Squibb
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Bromodomain and extraterminal domain protein inhibitors
  • 01 Jun 2015 Phase-I/II clinical trials for Solid tumours (Late-stage disease, Metastatic disease) in Canada (NCT02419417)
  • 02 Apr 2015 Bristol-Myers Squibb plans a phase I/IIa trial for Solid tumours (Late-stage disease) in USA, Australia and Canada (NCT02419417)

The genomes of eukaryotic organisms are highly organized within the nucleus of the cell. The long strands of duplex DNA are wrapped around an octomer of histone proteins to form a nucleosome. This basic unit is then further compressed by the aggregation and folding of nucleosomes to form a highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of this structure varies during the cell cycle, being most compact during the process of cell division. There has been appreciation recently that chromatin templates form a fundamentally important set of gene control mechanisms referred to as epigenetic regulation. By conferring a wide range of specific chemical modifications to histones and DNA (such as acetylation, methylation, phosphorylation, ubiquitinylation and SUMOylation) epigenetic regulators modulate the structure, function and accessibility of our genome, thereby exerting a huge impact in gene expression.

Histone acetylation is most usually associated with the activation of gene transcription, as the modification loosens the interaction of the DNA and the histone octomer by changing the electrostatics. In addition to this physical change, specific proteins bind to acetylated lysine residues within histones to read the epigenetic code. Bromodomains are small (-110 amino acid) distinct domains within proteins that bind to acetylated lysine residues commonly but not exclusively in the context of histones. There is a family of around 50 proteins known to contain bromodomains, and they have a range of functions within the cell. The BET family of bromodomain containing proteins

comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-T) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction.

BRD2 and BRD3 are reported to associate with histones along actively

transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008 30(1):51-60), while BRD4 appears to be involved in the recruitment of the pTEF-I3 complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Cell, 2009 138(1): 1294145). All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division – suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al., Cell, 2004 117(3):349-60).

Recent articles relating to this target include Prinjha et al., Trends in

Pharmacological Sciences, March 2012, Vol. 33, No. 3, pp. 146-153; Conway, ACS Med. Chem. Lett., 2012, 3, 691-694 and Hewings et al, J. Med. Chem., 2012, 55, 9393-9413.

Small molecule BET inhibitors that are reported to be in development include GSK-525762A, OTX-015, TEN-010 as well as others from the University of Oxford and Constellation Pharmaceuticals Inc.

Hundreds of epigenetic effectors have been identified, many of which are chromatin-binding proteins or chromatin-modifying enzymes. These proteins have been associated with a variety of disorders such as neurodegenerative disorders, metabolic diseases, inflammation and cancer. Thus, these compounds which inhibit the binding of a bromodomain with its cognate acetylated proteins, promise new approaches in the treatment of a range of autoimmune and inflammatory diseases or conditions and in the treatment of various types of cancer.

 
Inventors Derek J. Norris, George V. Delucca, Ashvinikumar V. Gavai, Claude A. Quesnelle, Patrice Gill, Daniel O’MALLEY, Wayne Vaccaro, Francis Y. Lee, Mikkel V. DEBENEDETTO, Andrew P. Degnan, Haiquan Fang, Matthew D. Hill, Hong Huang, William D. Schmitz, JR John E. STARRETT, Wen-Ching Han, John S. Tokarski, Sunil Kumar MANDAL
Applicant Bristol-Myers Squibb Company

PATENT

WO 2015100282

Examples 54 & 55

2-[3-(Dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2- b] indol-7-yl] pr opan-2-ol

Enantiomer A, Example 54 Enantiomer B, Example 55

Step 1 : 2-C hloro-5-(l ,4-dimethyl- 1H- 1 ,2,3-triazol-5-yl)pyridin-3-amine

To a 100 mL round bottom flask containing 5-bromo-2-chloropyridin-3-amine (2.90 g, 14.0 mmol), l,4-dimethyl-5-(tributylstannyl)-lH-l,2,3-triazole (2.70 g, 6.99 mmol) [Seefeld, M.A. et al. PCT Int. AppL, 2008, WO2008098104] and Pd(PPh3)4 (0.61 g, 0.52 mmol) in DMF (20 mL) was added cuprous iodide (0.20 g, 1.05 mmol) and Et3N (1.9 mL, 14.0 mmol). The reaction mixture was purged with N2 for 3 min and then heated at 100 °C for 1 h. After cooling to room temperature, the mixture was diluted withl0% LiCl solution and extracted with EtOAc (2x). The combined organics were washed with sat. NaCl, dried over MgS04, filtered and concentrated. CH2C12 was added, and the resulting precipitate was collected by filtration. The mother liquor was concentrated and purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 100% EtOAc/CH2Cl2). The resulting solid was combined with the precipitate and triturated with cold EtOAc to give the title compound (740 mg, 47%) as a light tan solid. LCMS (M+H) = 224.1; HPLC RT = 1.03 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH: water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2: Methyl 3-((2-chloro-5-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Following a procedure analogous to that described in Step 2 of Example 1, 2-chloro-5-(l ,4-dimethyl-lH-l,2,3-triazol-5-yl)pyridin-3-amine (740 mg, 3.31 mmol) was converted to the title compound (644 mg, 54%). 1H NMR (400 MHz, CDC13) δ 7.94 (t, J=1.9 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.83 (dt, J=7.8, 1.3 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.36 (ddd, J=8.0, 2.3, 0.9 Hz, 1H), 6.38 (s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 2.34 (s, 3H); LCMS (M+H) = 358.2; HPLC RT = 2.34 min (Column:

Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 3: Methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-6]indole-7-carboxylate

Following a procedure analogous to that described in Step 3 of Example 1 , methyl 3-((2-chloro-5-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate (2.82 g, 7.88 mmol) was converted to the title compound (1.58 g, 62%). 1H NMR (500 MHz, DMSO-de) δ 11.93 (s, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.36 (dd, J=8.2, 0.6 Hz, 1H), 8.29 -8.22 (m, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.2, 1.4 Hz, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 2.31 (s, 3H); LCMS (M+H) = 322.3; HPLC RT = 1.98 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Alternate synthesis of Methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-b] indole-7-carboxylate

A mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (Step 2 of Example 40, 3.000 g, 9.83 mmol), l,4-dimethyl-5-(tributylstannyl)-lH-l,2,3-triazole (4.18 g, 10.82 mmol), copper (I) iodide (0.281 g, 1.475 mmol), Pd(Ph3P)4 (0.738 g, 0.639 mmol) and triethylamine (2.74 mL, 19.66 mmol) in DMF (25 mL) was purged under a nitrogen stream and then heated in a heating block at 95 °C for 2 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted into ethyl acetate. Washed with water, NH4OH, brine and concentrated. The residue was triturated with 100 mL CHC13, filtered off the solid and rinsed with CHC13 to give. 1.6 g of product. The filtrate was loaded unto the ISCO column (330 g column, A: DCM; B:

10%MeOH/DCM, 0 to 100% gradient) and chromatographed to give an additional 0.7 g. of methyl 3 -( 1 ,4-dimethyl- 1 H- 1 ,2,3 -triazol-5 -yl)-5H-pyrido [3 ,2-b]indole-7-carboxylate (2.30 g total, 7.16 mmol, 72.8 % yield).

Step 4: Methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in Step 4 of Example 1 , methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-¾]indole-7-carboxylate (80 mg, 0.25 mmol) was converted to the title compound (65 mg, 53%) after purification by prep HPLC (Column: Phen Luna C 18, 30 x 100 mm, 5 μιη particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B : 95 : 5 acetonitrile: water with 0.1% TFA; Gradient: 10-100% B over 14 min, then a 2-min hold at 100% B; Flow: 40 mL/min). 1H NMR (400 MHz, CDC13) δ 8.51 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 8.10 (dd, J=8.1, 1.1 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.40 – 7.30 (m, 3H), 5.62 (d, J=10.6 Hz, 1H), 4.11 – 4.03 (m, 4H), 3.92 – 3.83 (m, 4H), 3.56 (td, J=l 1.9, 1.8 Hz, 1H), 3.35 (td, J=l 1.9, 1.9 Hz, 1H), 3.18 – 3.05 (m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.0 Hz, 1H), 1.71 – 1.58 (m, 1H), 1.50 – 1.37 (m, 1H), 1.09 (d, J=12.8 Hz, 1H); LCMS (M+H) = 496.3; HPLC RT = 2.93 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 5 : 2- [3-(Dimethyl- lH-1 ,2,3-triazol-5-yl)-5- [oxan-4-yl(phenyl)methyl] -5H-pyrido [3,2-6] indol-7-yl] pr opan-2-ol,

Following a procedure analogous to that described in Step 5 of Example 1 , methyl 3-(l ,4-dimethyl- IH- 1 ,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (65 mg, 0.13 mmol) was converted to racemic 2-[3-(dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-¾]indol-7-yl]propan-2-ol, which was separated by chiral prep SFC (Column: Chiralpak IB 25 x 2 cm, 5 μιη; Mobile Phase: 70/30 C02/MeOH; Flow: 50 mL/min);to give Enantiomer A (24 mg, 36%) and Enantiomer B (26 mg, 38%). Enantiomer A: 1H NMR (500 MHz, CDC13) 5 8.44 (d, J=1.8 Hz, IH), 8.36 (d, J=8.2 Hz, IH), 7.98 (s, IH), 7.56 (d, J=1.7 Hz, IH), 7.47 – 7.41 (m, 3H), 7.37 – 7.32 (m, 2H), 7.31 – 7.28 (m, IH), 5.59 (d, J=10.5 Hz, IH), 4.06 (dd, J=11.8, 2.8 Hz, IH), 3.90 – 3.84 (m, 4H), 3.55 (td, J=11.9, 2.0 Hz, IH), 3.35 (td, J=11.9, 2.0 Hz, IH), 3.15 – 3.04 (m, IH), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, IH), 1.92 (s, IH), 1.75 (s, 6H), 1.69 – 1.58 (m, IH), 1.47 – 1.38 (m, IH), 1.12 (d, J=13.4 Hz, IH); LCMS (M+H) = 496.4; HPLC RT = 2.46 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0- 100% B over 4 min; Flow: 4 mL/min). SFC RT = 5.50 min (Column: Chiralpak IB 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C02/MeOH; Flow: 2 mL/min); SFC RT = 1.06 min (Column:

Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 50/50 C02/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min); [a]D2° = -117.23 (c = 0.08, CHC13). Enantiomer B: 1H NMR (500 MHz, CDC13) δ 8.44 (d, J=l .8 Hz, IH), 8.36 (d, J=8.2 Hz, IH), 7.98 (s, IH), 7.56 (d, J=1.7 Hz, IH), 7.47 – 7.41 (m, 3H), 7.37 – 7.32 (m, 2H), 7.31 – 7.28 (m, IH), 5.59 (d, J=10.5 Hz, IH), 4.06 (dd, J=11.8, 2.8 Hz, IH), 3.90 – 3.84 (m, 4H), 3.55 (td, J=11.9, 2.0 Hz, IH), 3.35 (td, J=l 1.9, 2.0 Hz, IH), 3.15 – 3.04 (m, IH), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, IH), 1.92 (s, IH), 1.75 (s, 6H), 1.69 – 1.58 (m, IH), 1.47 – 1.38 (m, IH), 1.12 (d, J=13.4 Hz, IH); LCMS (M+H) = 496.4; HPLC RT = 2.46 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min). SFC RT = 8.30 min (Column: Chiralpak IB 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C02/MeOH; Flow: 2 mL/min); SFC RT = 2.83 min (Column: Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 50/50 C02/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min); [a]D2° = +88.78 (c = 0.10, CHC13).

Alternate Synthesis of Examples 54

2-[3-(Dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2- b] indol-7-yl] propan-2-ol.

Enantiomer A, Example 54

Step 1: (S)-methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

The enantiomers of phenyl(tetrahydro-2H-pyran-4-yl)methanol ( 2.0 g, 10.4 mmol) [Orjales, A. et al. J. Med. Chem. 2003, 46, 5512-5532], were separated on preperative SFC. (Column: Chiralpak AD 5 x 25 cm, 5 μιη; Mobile Phase: 74/26

C02/MeOH; Flow: 270 mL/min; Temperature 30°C). The separated peaks were concentrated and dried under vacuum to give white solids. Enantiomer A: (S)-phenyl(tetrahydro-2H-pyran-4-yl)methanol: (0.91 g, 45.5%) SFC RT = 2.32 min

(Column: Chiralpac AD 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C02/MeOH; Flow: 3 mL/min); Temperature 40°C. Enantiomer B: (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol. (0.92 g, 46%) SFC RT = 3.09 min (Column: Chiralpac AD 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C02/MeOH; Flow: 3 mL/min); Temperature 40°C.

Following a procedure analogous to that described in Step 4 of Example 1 except using toluene (120mL) as the solvent, methyl 3-(l ,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (4 g, 12.45 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (Enantiomer B above, 5.86 g, 30.5 mmol) was converted to the title compound (5.0 g, 81%). HPLC RT = 2.91 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOFLwater with 0.1% TFA; Mobile Phase B: 90: 10 MeOFLwater with 0.1% TFA; Temperature: 40 °C; Gradient: 0- 100% B over 4 min; Flow: 4 mL/min).

Step 2. (S)-2-[3-(Dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b] indol-7-yl] propan-2-ol

A 500 mL round bottom flask containing (S)-methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (5.0 g, 10.09 mmol) in THF (150 mL) was cooled in an ice/MeOH bath. MeMgBr, (3M in Et20, 17.0 mL, 51.0 mmol) was added slowly over 4 min. The resulting solution was stirred for 2 h and then quenched carefully with sat. NH4C1. The reaction mixture was diluted with 10% LiCl solution extracted with EtOAc. The organic layer was dried over MgS04, filtered and concentrated. The crude material was purified using ISCO silica gel chromatography (120 g column, gradient from 0%> to 6%>

MeOH/CH2Cl2). The product was collected and concentrated then dissolved in hot MeOH(35mL). To the mixture was added 15mL water and the mixture was cooled to room temperature. The resulting white precipitate was collected by filtration with 2: 1 MeOH/water rinse then dried under vacuum to give the title compound (3.2 g, 62%>). 1H

NMR (500 MHz, CDC13) δ 8.40 (d, J=1.8 Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.53 (d, J=l .8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.42 (dd, J=8.2, 1.4 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.30 – 7.28 (m, 1H), 5.56 (d, J=10.5 Hz, 1H), 4.06 (d, J=8.9 Hz, 1H), 3.89 – 3.83 (m, 1H), 3.55 (td, J=11.9, 2.1 Hz, 1H), 3.35 (td, J=11.9, 2.1 Hz, 1H), 3.10 (q, J=10.8 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H), 2.03 (d, J=14.2 Hz, 1H), 1.89 (s, 1H), 1.74 (s, 6H), 1.68 -1.59 (m, 1H), 1.46 – 1.36 (m, 1H), 1.12 (d, J=12.2 Hz, 1H); LCMS (M+H) = 496.3; HPLC RT = 2.44 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH: water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH: water with 0.1%

TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFC RT = 2.01 min (Column: Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 60/40 C02/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min). SFC RT = 1.06 min (Column: Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 50/50 C02/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min).

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CC(C)(O)c2cc3n(c1cc(cnc1c3cc2)c4c(C)nnn4C)[C@@H](C5CCOCC5)c6ccccc6

Process Development and Good Manufacturing Practice Production of a Tyrosinase Inhibitor via Titanium-Mediated Coupling between Unprotected Resorcinols and Ketones


(S)-4-(2,4-Dihydroxyphenyl)-N-(1-phenylethyl)piperidine-1-carboxamide (1)

In a………………….. to yield crude 1 (3.51 kg, 77%, 97.7 A% purity). Recrystallization: In a 100 L double jacketed reactor were charged crude 1 (3.51 kg, 10.31 mol, 1.0 equiv), iPrOH (27.0 L, 7.5 vol), AcOH (74.1 g), and water (27.0 L, 7.5 vol). The suspension was warmed to reflux and turned to a solution after 30 min of reflux. Heating was stopped, and the reaction medium was allowed to cool to 23 °C over 20 h. The suspension was filtered through a 25 μm filter medium; the cake was washed with a mixture of water (3.6 L) and AcOH (7.3 g) and the solid collected and dried under vacuum at 45 °C for 48 h to yield 1 (2.86 kg, 81%, 98.5 A% purity).
1H NMR (400 MHz, DMSO-d6): δ 9.11 (s, 1H), 8.96 (s, 1H), 7.30–7.31 (m, 4), 7.19–7.20 (m, 1H), 6.79 (d, J = 8.3 Hz, 2H), 6.7 (d, J = 7.9 Hz, 2H), 6.28 (d, J = 2.4 Hz, 1H), 6.16 (dd, J = 8.3, 2.4 Hz, 1H), 4.85–4.87 (m, 1 H), 4.13 (d, J = 12.9 Hz, 2H), 2.85 (t, J = 11.9 Hz, 1H), 2.70 (t, J = 12.7 Hz, 2H), 1.64 (d, J = 12.1 Hz, 2H), 1.40–1.41 (m, 5H).
13C NMR (101 MHz, DMSO-d6) δ 156.6, 156.0, 155.2, 146.3, 127.9, 126.7, 126.1, 125.9, 122.5, 106.0, 102.4, 49.3, 44.4, 34.7, 31.8, 31.7, 22.9;
mp: 200–201 °C;
HRMS (m/z, ES+) for C20H25N2O3 (M + H)+ calcd. 341.1865, measd. 341.1859.

Process Development and Good Manufacturing Practice Production of a Tyrosinase Inhibitor via Titanium-Mediated Coupling between Unprotected Resorcinols and Ketones

Nestlé Skin Health R&D, 2400 Route des colles BP 87, 06902 Sophia-Antipolis Cedex, France
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00036

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Thibaud Gerfaud

Thibaud Gerfaud

Team Leader Process Chemistry

Nestlé Skin Health Logo

Boiteau Jean-Guy

Boiteau Jean-Guy

Head of Process Research & Development

Nestlé Skin Health

Nestlé Skin Health Logo

Abstract

Abstract Image

A concise and economically attractive process for the synthesis of a novel tyrosinase inhibitor has been developed and implemented on a multikilogram scale under GMP. A major achievement to the success of the process is the development of a direct coupling between free resorcinol and ketone. First developed under basic conditions, this coupling has been turned to a novel titanium(IV) mediated process allowing good selectivity, easy isolation, and high atom efficiency. Other key steps feature an alkene reduction by palladium catalyzed transfer hydrogenation and a urea formation using N,N′-disuccinimidyl carbonate as the carbonyl source. This route allowed us to produce kilogram batches of the candidate to support preclinical and clinical studies.

Figure

Boiteau, J.-G.; Bouquet, K.; Talano, S.; Millois-Barbuis, C. Patent WO 2010/063774 A1, 2010.

More………………

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Cas 1228342-28-6
MF C20 H24 N2 O3,
MW  340.42
1-Piperidinecarboxamide, 4-(2,4-dihydroxyphenyl)-N-[(1S)-1-phenylethyl]-
  • 4-(2,4-Dihydroxyphenyl)-N-[(1S)-1-phenylethyl]-1-piperidinecarboxamide
  • 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid N-((S)-1-phenylethyl)amide
Inventors Jean-Guy Boiteau , Karine Bouquet , Sandrine Talano , Barbuis Corinne Millois
Applicant Galderma Research & Development

Hyperpigmentation disorders such as melasma are characterized by an increase in melanin synthesis which accumulates in the epidermis and is responsible for a darkening of the skin. Melanogenesis occurs in the basal layer of the epidermis into specific organelles of the melanocytes called melanosomes.

A detailed analysis of the biosynthetic pathway reveals that tyrosinase is a key enzyme in melanogenesis and is responsible for the oxidation of tyrosine into DOPA (3,4-dihydroxyphenylalanine) and DOPA quinone.

It is a melanogenesis inhibitor working through the inhibition of tyrosinase (IC50 = 0.1 μM on normal human epidermal melanocytes) currently under development at Nestlé Skin Health R&D for the topical treatment of hyperpigmentation disorders. REF 1-5

WO 2010063774

Novel 4- (azacycloalkyl)benzene-l ,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and in cosmetics

The invention relates to novel 4- (azacycloalkyl) benzene-1, 3-diol compounds as industrial and useful products. It also relates to the process for the preparation thereof and to the use thereof, as tyrosinase inhibitors, in pharmaceutical or cosmetic compositions for use in the treatment or prevention of pigmentary disorders.

Skin pigmentation, in particular human skin pigmentation, is the result of melanin synthesis by dendritic cells, melanocytes. Melanocytes contain organelles called melanosomes which transfer melanin into the upper layers of keratinocytes which are then transported to the surface of the skin through differentiation of the epidermis (Gilchrest BA, Park HY, Eller MS, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing VJ, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909) .

Among the enzymes of melanogenesis, tyrosinase is a key enzyme which catalyses the first two steps of melanin synthesis. Homozygous mutations of tyrosinase cause oculocutaneous albinism type I characterized by a complete lack of melanin synthesis (Toyofuku K, Wada I, Spritz RA, Hearing VJ, The molecular basis of oculocutaneous albinism type 1 (OCAl) : sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem J 2001; 355: 259-269) .

In order to treat pigmentation disorders resulting from an increase in melanin production, for which there is no treatment that meets all the expectations of patients and dermatologists, it is important to develop new therapeutic approaches.

Most of the skin-lightening compounds that are already known are phenols or hydroquinone derivatives.

These compounds inhibit tyrosinase, but the majority of them are cytotoxic to melanocytes owing to the formation of quinones. There is a risk of this toxic effect causing a permanent depigmentation of the skin. The obtaining of compounds that can inhibit melanogenesis while at the same time being very weakly cytotoxic or devoid of toxicity to melanocytes is most particularly sought.

Among the compounds already described in the literature, patent application WO 99/15148 discloses the use of 4-cycloalkyl resorcinols as depigmenting agents .

Patent FR2704428 discloses the use of 4-halo-resorcinols as depigmenting agents.

Patent applications WO 2006/097224 and WO 2006/097223 disclose the use of 4-cycloalkylmethyl resorcinols as depigmenting agents.

Patent application WO 2005/085169 discloses the use of alkyl 3- (2, 4-dihydroxyphenyl) propionate as a depigmenting agent.

Patent application WO 2004/017936 discloses the use of 3- (2, 4-dihydroxyphenyl) acrylamide as a depigmenting agent.

Patent application WO 2004/052330 discloses the use of 4- [ 1, 3] dithian-2-ylresorcinols as depigmenting agents .

More particularly, patent EP0341664 discloses the use of 4-alkyl resorcinols as depigmenting agents, among which 4-n-butyl resorcinol, also known as rucinol, is part of the composition of a depigmenting cream sold under the name Iklen®.

The applicant has now discovered, unexpectedly and surprisingly, that novel compounds of 4- (azacycloalkyl) benzene-1, 3-diol structure have a very good tyrosinase enzyme-inhibiting activity and a very low cytotoxicity. Furthermore, these compounds have a tyrosinase enzyme-inhibiting activity that is greater than that of rucinol while at the same time being less cytotoxic with respect to melanocytes than rucinol.

These compounds find uses in human medicine, in particular in dermatology, and in the cosmetics field.

FR 2939135

References

  1. Briganti, S.; Camera, E.; Picardo, M. Pigm. Cell Res. 2003, 16, 101, DOI: 10.1034/j.1600-0749.2003.00029.x

  2. 2.

    Brenner, M.; Hearing, V. J. Photochem. Photobiol. 2008, 84, 539, DOI: 10.1111/j.1751-1097.2007.00226.x

  3. 3.

    (a) Schallreuter, K. U.; Kothari, S.; Chavan, B.; Spencer, J. D. Exp. Dermatol. 2008, 17, 395, DOI: 10.1111/j.1600-0625.2007.00675.x

    (b) Cooksey, C. J.; Garratt, P. J.;Land, E. J.; Pavel, S.; Ramsden, C. A.; Riley, P. A.; Smit, N. P.J. Biol. Chem. 1997, 272, 26226, DOI: 10.1074/jbc.272.42.26226

    (c) Stratford, M. R. L.; Ramsden, C. A.; Riley, P. A.Bioorg. Med. Chem. 2013, 21, 1166, DOI: 10.1016/j.bmc.2012.12.031

  4. 4.

    Chang, T. S. Int. J. Mol. Sci. 2009, 10, 2440, DOI: 10.3390/ijms10062440

  5. 5.

    Hypopigmentation effect have already been demonstrated for resorcinols; see:

    (a) Kim, D. S.; Kim, S. Y.;Park, S. H.; Choi, Y. G.; Kwon, S. B.; Kim, M. K.; Na, J. I.; Youn, S. W.; Park, K. C. Biol. Pharm. Bull. 2005,28, 2216, DOI: 10.1248/bpb.28.2216

    (b) Khemis, A.; Kaiafa, A.;Queille-Roussel, C.; Duteil, L.; Ortonne, J. P. Br. J. Dermatol.2007, 156, 997, DOI: 10.1111/j.1365-2133.2007.07814.x

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O=C(N[C@@H](C)c1ccccc1)N2CCC(CC2)c3ccc(O)cc3O

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