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LCB01-0371……..new oxazolidinone in phase 1 has improved activity against Gram-positive pathogens

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LCB01-0371

3-[3-Fluoro-4-(1-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-4-yl)phenyl]-5(R)-(hydroxymethyl)oxazolidin-2-one

LegoChem Biosciences (South Korea)

Phase I, Gram-positive

308.3082

C14 H17 F N4 O3

LCB01-0371 is being developed by LegoChem Bio. This new oxazolidinone has improved activity against Gram-positive pathogens and has good pharmacokinetic profiles in animals [103].

The compound is under Phase I clinical development to assess the safety and tolerability of the compound. The company is currently recruiting participants to be part of the trial [103,104].

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LCB01-0371 is a new oxazolidinone with cyclic amidrazone. In vitro activity of LCB01-0371 against 624 clinical isolates was evaluated and compared with those of linezolid, vancomycin, and other antibiotics. LCB01-0371 showed good activity against Gram-positive pathogens. In vivo activity of LCB01-0371 against systemic infections in mice was also evaluated. LCB01-0371 was more active than linezolid against these systemic infections. LCB01-0371 showed bacteriostatic activity against Staphylococcus aureus.

As examples of oxazolidinone compounds including an oxazolidinone ring, 3-phenyl-2-oxazolidinone derivatives having one or two substituent(s) are described in US Patent Nos. 4,948,801, 4,461,773, 4,340,606, 4,476,136, 4,250,318 and 4,128,654, and 3-[(mono-substituted)phenyl]-2-oxazolidinone derivatives represented by Chemical Formula A are described in EP 0312000, J. Med. Chem.32, 1673(1989), J. Med. Chem. 33, 2569 (1990), Tetrahedron Lett. 45,123(1989), and the like.

[Chemical Formula A]

 

Figure PCTKR2009005376-appb-I000002

And, oxazolidinone derivatives represented by Chemical Formula B and Chemical Formula C were synthesized by Pharmacia & Upjohn (WO 93/23384, WO 95/14684 and WO 95/07271). The compound of Chemical Formula B, “linezolid”, is the first oxazolidinone antibiotic and is marketed under the trade name “zyvox” for oral administration and injection, approved by the U.S. Food and Drug Administration (FDA). However, most of synthetic oxazolidinone compounds are associated with some limitations, such as toxicity, low in vivo efficacy and low solubility. As for linezolid, solubility in water is only about 3 mg/mL, which causes its use as injection limited.

[Chemical Formula B]

 

Figure PCTKR2009005376-appb-I000003

[Chemical Formula C]

 

Figure PCTKR2009005376-appb-I000004

WO 93/09103 discloses phenyl oxazolidinone derivatives having a heterocyclic ring, including pyridine, thiazole, indole, oxazole, quinol, etc., at the 4-position of the phenyl group. But, the substituents of the heterocyclic ring are merely simple alkyl or amino group, and the activities are not so excellent.

In order to solve these problems, WO 01/94342 discloses phenyloxazolidinone derivatives having various pyridine or phenyl derivatives at the 4-position of the phenyl group. The synthetic compounds have wide antibacterial spectrum and excellent antibacterial activity. Although the oxazolidinone compounds having various pyridine derivatives at the 4-position of the phenyl group of oxazolidinone have wider antibacterial spectrum and excellent antibacterial activity as compared to linezolid, most of them have aqueous solubility of 30 ㎍/mL or less, and thus have limitation in preparing injections.

TR-700 and TR-701, represented by Chemical Formula D, are developed by Dong-A Pharmaceutical and recently licensed to Trius Therapeutics. TR-701 is a prodrug of TR-700 and it is in the phase II clinical trial. TR-701 solves the solubility problem via formation of prodrug from TR-700, exhibits an antibacterial activity superior to that of linezolid. However, the compound shows higher toxicities (cytotoxicity, MAO profile, myelosuppression, etc.) than linezolid, and, thus, is expected to have many limitations.

[Chemical Formula D]

 

Figure PCTKR2009005376-appb-I000005

As described above, a compound having superior antibacterial activity, satisfactory solubility and lower toxicity is yet to be found.

The inventors of the present invention have synthesized novel oxazolidinone derivatives in order to develop antibiotics having superior antibacterial activity as compared to existing antibiotics and having higher solubility for easier preparation into oral administration and injection formulations. The novel oxazolidinone derivatives according to the present invention have been confirmed to have superior antibacterial activity and significantly improved antibacterial spectrum.

Especially, the cyclic amidoxime or cyclic amidrazone compound presented by the present invention has not been studied before. Whereas acyclic amidoxime or amidrazone is relatively well known, the cyclic amidoxime or cyclic amidrazone compound like those disclosed in the present invention is hardly known. Introduction of the cyclic form results in remarkably improved absorptivity and allows the formation of a salt having an adequate basicity, thereby greatly increasing solubility in water. The increased solubility in water makes it possible to prepare injections without using a prodrug and with little toxicity.

watch outfor synthesis…will be updated

WO 2010036000

http://www.google.com/patents/WO2010036000A2?cl=en

[Scheme 1]

 

Figure PCTKR2009005376-appb-I000029

[Scheme 2]

 

Figure PCTKR2009005376-appb-I000030

[Scheme 3]

 

Figure PCTKR2009005376-appb-I000031

[Scheme 4]

 

Figure PCTKR2009005376-appb-I000032

[Scheme 5]

 

Figure PCTKR2009005376-appb-I000033

*[Scheme 6]

 

Figure PCTKR2009005376-appb-I000034

http://www.google.com/patents/WO2010036000A2?cl=en

[Example 94] Preparation of Compound 94

 

Figure PCTKR2009005376-appb-I000145

Compound 93 (150 mg, 0.51 mmol) was dissolved in methanol (5 mL), formaldehyde (37% aqueous solution, 0.21 mL, 2.55 mmol) and stirred for 1 hour at room temperature after adding acetic acid (0.03 mL, 0.51 mmol) and NaBH3CN (48 mg, 0.77 mmol). The solution was distilled under reduced pressure, dissolved in dichloromethane (100 mL), sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution (brine), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain Compound 94(71 mg, 0.23 mmol, 45%).

1H NMR (600 MHz, DMSO-d6) δ= 7.59 (dd, J 1 13.8 Hz, J 2 = 2.4 Hz, 1H), 7.33-7.30 (m, 2H), 6.84 (s, 1H), 5.23 (t, J = 5.4 Hz, 1H), 4.70 (m, 1H), 4.07 (t, J = 9.0 Hz, 1H), 3.82 (m, 1H), 3.71 (t, J = 4.8 Hz, 2H), 3.69-3.54 (m, 2H), 2.87 (t, J = 4.8 Hz, 2H), 2.61 (s, 3H).

LCMS: 309 (M + H+) for C14H17-FN4O3.

[Example 93] Preparation of Compound 93

 

Figure PCTKR2009005376-appb-I000144

Compound 93 (190 mg, 0.65 mmol, 74%) was obtained from Compound 92 as in Example 2.

1H NMR (600 MHz, DMSO-d6) δ= 7.73 (dd, J 1 13.8 Hz, J 2 = 2.4 Hz, 1H), 7.60 (t, J = 9 Hz, 1H), 7.45 (dd, J 1 9.0 Hz, J2 = 2.4 Hz, 1H), 4.75 (m, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.88 (m, 1H), 3.78 (t, J = 4.8 Hz, 2H), 3.70-3.55 (m, 2H), 3.36 (t, J =4.8 Hz, 2H).

LCMS: 295 (M + H+) for C13H15-FN4O3.

[Example 92] Preparation of Compound 92

 

Figure PCTKR2009005376-appb-I000143

Compound 92 (240 mg, 0.75 mmol, 32%) was obtained from Compound XXIII as in Preparation Example 10.

1H NMR (600 MHz, CDCl3) δ= 8.55 (s, 1H), 7.61 (dd, J 1 13 Hz, J 2 = 2.4 Hz, 1H), 7.25 (dd, J 1 9.0 Hz, J 2 = 2.7 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 6.90 (s, 1H), 4.79 (m, 1H), 4.04-3.99 (m, 5H), 3.79-3.73 (m, 3H), 2.58 (br, s, 1H).

LCMS: 323 (M + H+) for C14H15-FN4O4.

 

[Preparation Example 17] Preparation of Compound XXIII

 

Figure PCTKR2009005376-appb-I000051

Compound V (26 g, 0.053 mol) was dissolved in dichloromethane (180 mL) and stirred for 10 minutes after slowly adding diisopropylethylamine (DIPEA, 13 mL, 0.079 mol) and benzoyl chloride (Bz-Cl, 7.4 mL, 0.064 mol) sequentially dropwise at 0℃. After heating to room temperature, followed by adding a small amount of DMAP, the solution was stirred for 2 hours. The solution was concentrated under reduced pressure, dissolved in ethyl acetate, sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution (brine), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtain Compound XXII (31 g, 0.053 mol), which was treated with hydrochloric acid as in Preparation Example 9 to quantitatively obtain Compound XXIII.

[Preparation Example 5] Preparation of Compound V

 

Figure PCTKR2009005376-appb-I000039

Compound IV (116 g, 0.22 mol) was dissolved in THF (400 mL) and stirred for 20 minutes after slowly adding n-butyllithium (2.5 M solution in n-hexane, 90 mL, 0.23 mol) dropwise at -78℃. After adding (R)-glycidyl butyrate (31.5 mL, 0.23 mol), followed by stirring for 3 hours while slowly heating to room temperature, the solution was adjusted to pH ~6 with aqueous ammonium chloride solution, and concentrated under reduced pressure. The concentrate was dissolved in 80% ethyl acetate/hexane solution, sequentially washed with water and saturated aqueous sodium chloride solution (brine), dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated by column chromatography using 40% ethyl acetate/hexane solution to obtain Compound V (45 g, 0.093 mol, 42%) as a colorless oil.

1H NMR (600 MHz, CDCl3) δ 7.50-7.48 (m, 1H), 7.30-7.28 (m, 1H), 7.17-7.16 (m, 1H), 4.74-4.70 (m, 1H), 4.03-4.02 (m, 1H), 3.98 (m, 2H), 3.75 (m, 3H), 3.65 (m, 2H), 1.51 (s, 3H), 1.36 (s, 6H), 0.85 (s, 9H), 0.02 (s, 6H).

 

 

[Preparation Example 1] Preparation of Compound I

 

Figure PCTKR2009005376-appb-I000035

After dissolving 3,4-difluoronitrobenzene (158 g, 0.99 mol) in acetonitrile (800 mL) and adding ethanolamine (117 g, 1.9 mol), the mixture was stirred for 4 hours under reflux. The reaction solution was cooled to room temperature, concentrated under reduced pressure, triturated with diethyl ether, and filtered to obtain yellow Compound I (199 g, 0.99 mol, 100%).

1H NMR (400 MHz, chloroform-d1) δ 7.97 (d, 1H, J = 8.8 Hz), 7.87 (dd, 1H, J 1 = 11.6 Hz, J 2 = 2.4 Hz), 6.65 (t, 1H, J = 8.8 Hz), 5.10-4.87 (bs, 1H), 3.97-3.83 (m, 2H), 3.43-3.37 (m, 2H).

 

[Preparation Example 2] Preparation of Compound II

 

Figure PCTKR2009005376-appb-I000036

Compound I (100 g, 0.5 mol), t-butyldimethylsilyl chloride (TBS-Cl, 97 g, 0.65 mol) and imidazole (51 g, 0.75 mol) were dissolved in dichloromethane (700 mL) at 0℃ and stirred overnight after slowly heating to room temperature. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate and washed with 0.5 N HCl, washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution (brine), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtain a compound with a tbs group attached to alcohol. This compound was dissolved in THF (500 mL) and 1.2 equivalents of Boc2O and 0.1 equivalent of 4-dimethylaminopyridine (DMAP) were added. After stirring for 3 hours at room temperature, ammonia water (30 mL) was added. After stirring further for 20 minutes, the solution was concentrated under reduced pressure. The concentrate was dissolved again in ethyl acetate, sequentially washed with 0.5 N HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution (brine), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtain Compound II.

1H NMR (600 MHz, chloroform-d1) δ 8.06-7.98 (m, 1H), 7.95 (dd, 1H, J 1 = 10.2 Hz, J 2 = 2.4 Hz), 7.57 (t, 1H, J = 7.8 Hz), 3.80 (t, 2H, J = 5.4 Hz), 3.73 (t, 2H, J = 4.8 Hz), 1.42 (s, 9H), 0.81 (s, 9H), 0.01 (s, 6H).

 

[Preparation Example 3] Preparation of Compound III

 

Figure PCTKR2009005376-appb-I000037

Compound II (92 g, 0.22 mol) was dissolved in methanol (600 mL) and stirred for 4 hours under hydrogen balloon after adding Pd/C (6 g). The reaction mixture was filtered using celite and concentrated under reduced pressure to quantitatively obtain Compound III (86 g) as a colorless oil.

1H NMR (400 MHz, chloroform-d1) δ 6.99 (t, 1H, J = 12.0 Hz), 6.44-6.30 (m, 2H), 3.81-3.63 (m, 4H), 3.63-3.52 (m, 2H), 1.50 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H), 0.03 (s, 6H).

 

[Preparation Example 4] Preparation of Compound IV

 

Figure PCTKR2009005376-appb-I000038

Compound III (86 g, 0.22 mol) was dissolved in dichloromethane (300 mL). After adding aqueous 1 N NaOH solution (300 mL), benzyl chloroformate (Cbz-Cl, 38 mL, 0.27 mol) was slowly added dropwise while stirring. After stirring for 1 hour at room temperature, the organic layer was separated, washed twice with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtain Compound IV (116 g) as a yellow oil.

1H NMR (600 MHz, chloroform-d1) δ 7.44-7.32 (m, 6H), 7.18 (t, 1H, J = 8.1 Hz), 6.96 (d, 1H, J = 8.4 Hz), 6.84-6.66 (bs, 1H), 5.20 (s, 2H), 3.82-3.63 (m, 2H), 3.63-3.58 (m, 2H), 1.51 (s, 3H), 1.35 (s, 6H), 0.86 (s, 9H), 0.02 (s, 6H).

  1. 103         Jeong, J.-W.; Jung, S.-J.; Lee, H.-H.; Kim, Y.-Z.; Park, T.-K.; Cho, Y.-L.; Chae, S.-E.; Baek, S.-Y.; Woo, S.-H.; Lee, H.-S.; et alIn vitro and In vivo activities of LCB01–0371, a new oxazolidinone. Antimicrob. Agents Chemother. 201054, 5359–5362, doi:10.1128/AAC.00723-10.
  2. 104          LegoChem Biosciences. Multiple ascendoing dose study for LCB01–0371. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01842516 (accessed on 15 August 2013).
  3. http://clinicaltrials.gov/ct2/show/NCT01842516
  4. http://www.pubfacts.com/author/Yong+Zu+Kim
  5. New oxazolidinones with cyclic amidrazone (I): Structure activity relationship of cyclic amidrazone antibiotics
    49th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 12-15, San Francisco) 2009, Abst F1-1508
  6. [PDF]

    7. 레고켐(임상).cdr

    New oxazolidinone LCB010371 for MRSA and VRE infection. Young Lag Cho. Company : LegoChem Biosciences, Inc. Website : http://www.legochembio.com.

 

KR100674096B1 * Title not available
KR100713170B1 * Title not available
KR20040035207A * Title not available
US7157456 * Dec 11, 2000 Jan 2, 2007 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
WO2011111971A2 * Mar 8, 2011 Sep 15, 2011 Legochem Biosciences,Inc. Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives
WO2012121424A1 * Mar 4, 2011 Sep 13, 2012 (주)레고켐바이오사이언스 Novel oxazolidinone derivative having cyclic amidrazone group and pharmaceutical composition containing same

 

Eperezolid.pngEperezolid

 

Skeletal formula of radezolidradezolid

 

Ranbezolid structure.svg

Ranbezolid

 

Sutezolid structure.svgSutezolid

Skeletal formula of linezolidlinezolid

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DR ANTHONY CRASTO

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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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