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SUTEZOLID for Treatment of tuberculosis

April 1, 2014 12:37 pm / 1 Comment on SUTEZOLID for Treatment of tuberculosis

Sutezolid

168828-58-8

N-({(5S)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-2-oxo-oxazolidin-5-yl}methyl) acetamide

(S)—N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide

Sutezolid, PNU-100480, U-100480, NSC742407, PNU 100480, 168828-58-8, Sutezolid [INN]

Molecular Formula: C₁₆H₂₀FN₃O₃S Molecular Weight: 353.41170

http://www.ama-assn.org/resources/doc/usan/sutezolid.pdf

Sutezolid (PNU-100480, PF-02341272) is an oxazolidinone antibiotic currently in development as a treatment for extensively drug-resistant tuberculosis.

Rapid evaluation in whole blood culture of regimens for XDR-TB containing PNU-100480 (sutezolid), TMC207, PA-824, SQ109, and pyrazinamide

Sutezolid, an antimicrobial oxazolidinone and the thiomorpholine analogue of linezolid, had been in early clinical development for the treatment of tuberculosis. However, development was discontinued.

The compound had been found to be active against Gram-positive bacteria such as multiresistant staphylococci, streptococci and enterococci. It was being developed by Pfizer. In 2011, orphan drug designation was assigned in the U.S. and the E.U. for the treatment of tuberculosis.

In 2013, Sequella acquired an exclusive worldwide license for the development and commercialization of sustezolid.

US2011190199

8-5-2011

Combination Therapy for Tuberculosis

http://www.google.com/patents/US20110190199

Scheme 1 illustrates a general synthetic sequence for preparing compounds of the present invention.

Example 3 Preparation of (5S)-5-{[(4-chlorobenzylidene)amino]methyl}-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-1,3-oxazolidin-2-one

The title compound in Example 2 (194 g, 0.56 mole), and the title compound of Example 1 (195 g, 0.84 mole), and lithium tert-butoxide (116 g, 1.4 mole) were charged into a 3000 mL three neck round bottom flask under nitrogen. The reactants were slurried with methyl tert-butyl ether (1200 mL) and the mixture was warmed to 56° C. and stirred for 2 h as a yellow solid gradually formed. The reaction was cooled to room temperature, and diluted with 1200 mL water. The mixture was then stirred vigorously over 60 min as the solid changed from dark yellow to a more pale yellow solid. The mixture was cooled to 10° C., filtered, and the filter cake was washed with ice cold methyl tert-butyl ether (450 mL). The resulting light yellow solid was dried in air for 30 min, then placed in a vacuum oven and dried at 40° C. overnight to afford the title compound (243 g, 99% yield). ¹H NMR (400 MHz, CDCl₃): δ 2.8 (m, 4H), 3.2 (m, 4H), 3.9 (m, 2H), 4.1 (m, 2H), 5.0 (m, 1H), 6.9 (m, 1H), 7.2 (m, 1H), 7.4 (m, 3H), 7.6 (m, 2H), 8.4 (s, 1H).

Example 4 Preparation of N-{[(5S)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide

The title compound in Example 3 (243 g, 0.56 mole) was combined with EtOAc (1300 mL) and water (1300 mL) in a 5000 mL three neck round bottom flask equipped with a mechanical stirrer. The mixture was treated drop-wise with 12N HCl (140 mL, 1.68 moles) and the mixture was stirred vigorously for 1 hour at room temperature. The layers were separated and the aqueous layer was washed with EtOAc (1×500 mL). The resulting aqueous solution containing (S)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one hydrochloride was combined with a mixture of dichloromethane (1800 mL) and MeOH (120 mL), and the vigorously stirred mixture was charged with acetic anhydride (132 mL, 1.4 mole) in one portion and subsequently treated drop-wise with 10 N NaOH (200 mL, 2.0 mole) over 15 min. An extremely thick reaction mixture resulted from addition of the base, which gradually thinned as the pH rose and the acylation rapidly progressed. The reaction was stirred vigorously for 1 hour after the mixture resolved to two phases. At that time, 10 M NaOH (160 mL, 1.6 mole) was added drop-wise to the mixture until the pH was stable at 7. The layers were separated, the aqueous layer was extracted with dichloromethane (250 mL), and the combined organic layers were dried over anhydrous potassium carbonate. The volatiles were removed in vacuo to give an off-white solid which was titrated with methyl tert-butyl ether (250 mL), collected, and dried in vacuo to give title compound (5) (186.1 g, 94% yield) as a fine white solid with greater than 98% HPLC purity (retention time=3.93 minutes, HPLC conditions reported below).

The crude solid was dissolved in warm 6% methanol in dichloromethane (1250 mL) in a 5000 mL three neck round bottom flask equipped with a mechanical stirrer. The solution was warmed to reflux, diluted by the portion-wise (500 mL) addition of 2500 mL isopropanol (IPA), and, in order to maintain reflux, the temperature was ramped to 50-70° C. On completion of this addition of IPA, the reflux condenser was replaced with a short-path distillation head and distillation was continued into a cooled flask. During distillation, a 500 mL portion of fresh IPA was added after 500 mL of distillate was collected to maintain between 2000 and 2500 mL IPA present at all times. After this addition (internal flask temperature dropped to 60° C.) the mixture became slightly cloudy and remained so for the balance of the distillation, becoming increasingly cloudy as the distillate temperature exceeded 70° C.; particulate matter appeared as the distillate temperature exceeded 75° C. The temperature controller was ramped to 85° C. and held there until the conclusion of the distillation. When the distillate was clearly isopropanol alone (82-83° C.) the volume was reduced to 2500 mL hot IPA, the heating mantle was removed, stirring was discontinued, and the paddle was removed from the flask. The mixture was allowed to continue to crystallize as the flask cooled. The white crystalline solid was then collected by filtration, washed with methyl tert-butyl ether (250 mL), and dried in vacuo at 40° C. to afford 180 g (91% yield) of the title compound in greater than 99% HPLC purity (retention time=3.93 minutes, HPLC conditions reported below). ¹H NMR (400 MHz, DMSO-d₆): δ 1.8 (s, 3H), 2.7 (m, 4H), 3.2 (m, 4H), 3.4 (m, 2H), 3.7 (m, 1H), 4.7 (m, 1H), 7.1 (m, 1H), 7.15 (m, 1H), 7.2 (m, 1H), 8.2 (m, 1H). Mass Spec. C₁₆H₂₀FN₃O₃S: m/z 354.1 (M+1).

HPLC conditions for analyses mentioned in the text: HP Series 1100; Column: Symmetry C8 5 uM 4.6×50 mm; Flow rate 1.2 mL/min; Solvent A: water with 0.1% formic acid, Solvent B: acetonitrile with 0.1% formic acid; Injection volume=10 uL of 1 mg/mL (acetonitrile); Gradient: Solvent B 0-100% over 7 minutes then 100% B for 1 minute; wavelength=254 nm.

Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity
J Med Chem 1996, 39(3): 680

http://pubs.acs.org/doi/full/10.1021/jm950956y

(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5–oxazolidinyl]methyl]acetamide (6, U-100480). A solution of (R)-[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl azide (19.662 g, 58.28 mmol) in dry THF (290 mL) was treated with triphenylphosphine (16.815 g, 64.11 mmol) over 10 min. After 2.0 h, TLC analysis (10% MeOH/CHCl₃) revealed the conversion to iminophosphorane was complete. H₂O (2.10 mL, 116.56 mmol) was added and the reaction mixture heated to 40 °C (internal temperature) for 5 h and then allowed to cool to ambient temperature overnight. At this point, TLC analysis (10% MeOH/CHCl₃) indicated incomplete hydrolysis of the iminophosphorane intermediate. More H₂O (8.40 mL) was added, and the reaction was heated to 40 °C for 5 h. At this time, TLC indicated complete conversion to the 5-(aminomethyl)oxazolidinone intermediate. The reaction mixture was first concentrated by rotary evaporation (benzene was added several times to azeotrope off the H₂O) and then under high vacuum to give the crude amine as an off-white solid. This material was dissolved in CH₂Cl₂ (250 mL), treated with pyridine (46.099 g, 47.10 mL, 582.79 mmol) and acetic anhydride (29.749 g, 27.49 mL, 291.40 mmol), and then stirred overnight at ambient temperature. TLC analysis (10% MeOH/CHCl₃) showed complete conversion to 6. The reaction mixture was diluted with CH₂Cl₂, transferred to a separatory funnel, and then washed with 1 N HCl until the washings were acidic. The organic layer was then washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give crude 6 (U-100480) as a cream-colored solid. The crude product was triturated with hot CHCl₃; most but not all of the solids dissolved. After cooling to ambient temperature, the solids were filtered off (cold CHCl₃ wash) and dried in vacuo to furnish 13.174 g of analytically pure title compound as a white solid. A second crop of 3.478 g, also analytically pure, afforded a combined yield of 81%:

mp 186.5−187.0 ^oC; [α]_D −8° (c 1.00, CHCl₃);

IR (mull) 1749, 1746, 1641, 1656, 1518, 1448, 1419, 1225, 1215, 1158, 1106, 1083, 867 cm^-1;

¹H NMR (300 MHz, CDCl₃) δ 7.42 (dd, 1H, J = 2.6, 14.0 Hz), 7.06 (ddd, 1H, J = 1.0, 2.6, 8.8 Hz), 6.95 (dd, 1H, J = 9.0, 9.0 Hz), 6.61 (br t, 1H, J = 6.0 Hz), 4.81−4.72 (m, 1H), 4.02 (dd, 1H, J = 9.0, 9.0 Hz), 3.75 (dd, 1H, J = 6.7, 9.1 Hz), 3.71−3.55 (m, 2H), 3.32−3.27 (m, 4H), 2.84−2.79 (m, 4H), 2.02 (s, 3H);

MS m/z (rel intensity) 353 (M⁺, 100), 309 (31), 279 (5), 250 (17), 235 (14), 225 (20), 212 (7), 176 (19), 138 (18), 42 (28);

HRMS calcd for C₁₆H₂₀N₃O₃FS 353.1209, found 353.1200. Anal. (C₁₆H₂₀N₃O₃FS) C, H, N.

Repurposed drugs for tuberculosis treatment.

http://www.nature.com/nrd/journal/v12/n5/fig_tab/nrd4001_F1.html

Repurposed drugs for tuberculosis treatment.

EPEREZOLID

April 1, 2014 8:08 am / Leave a comment

EPEREZOLID

pfizer.originator

CAS NO 165800-04-4

Eperezolid [USAN], PNU 100592, U-100592,

Molecular Formula: C₁₈H₂₃FN₄O₅

Molecular Weight: 394.397423

(S)-N-[[3-[3-Fluoro-4-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide

(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]- phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide

Oxazolidinones are a new class of Gram-positive antibacterial agents which are known to those skilled in the art, see for example US 5,688,792. (S)-N-[[3-[3- fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, known as linezolid, the compound of Example 5 of US Patent 5,688,792 is known and has the following chemical formula:

(S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]-phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide, known as eperezolid, the compound of

Example 8 of US Patent 5,837,870 is known and has the following chemical formula:

Linezolid and eperezolid can be produced by the processes set forth in US Patents 5,688,791 and 5,837,870 as well as that of International Publication WO99/24393. It is preferably produced by the process of US Patent 5,837,870.

It is preferred that the linezolid produced be used in crystal form π, which has the characteristics set forth in CHART A. Once linezolid is synthesized, crystal Form π is prepared by starting with linezolid of high enantiomeric purity. It is preferred that the linezolid be more than 98% enantiomerically pure, it is more preferred that the linezolid be more than 99% pure and it is even more preferred that the linezolid be 99.5% pure. The linezolid of greater than 98% enantiomeric purity to be used to form crystal form II can either be in solution or be a solid. The linezolid starting material, solid or solution, is mixed with a solvent selected from the group consisting of compounds of the formula: water, acetonitrile, chloroform, methylene chloride, R OH where R_\ is Cι-C₆ alkyl; Rι-CO-R₂ where R₂ is Cι-C alkyl and Ri is as defined above; phenyl substituted with 1 thru 3 Ri where Ri is as defined above; Rι-CO-O-R₂ where Ri is -C alkyl and Ri is as defined above; Rι-O-R₂ where

is Cι-C₆ alkyl and Ri is as defined above. It is preferred that the solvent be selected from the group consisting of water, ethyl acetate, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, methylene chloride, toluene, xylene, diethyl ether, or methyl-t-butyl ether. It is more preferred that the solvent be ethyl acetate, acetone, acetonitrile, propanol, or isopropanol. It is most preferred that the solvent be ethyl acetate. The mixture of linezolid in the solvent is agitated at a temperature below 80° until crystals of Form II are formed and crystals of other solid forms, such as Form I, disappear. It is preferred to dissolve the linezolid in ethyl acetate at a temperature near the boiling point of the solvent. This mixture is cooled to a temperature of about 70°. The mixture may be seeded with crystals of Form II to facilitate crystallization. It is preferred that the solid product is cooled and agitated at a temperature between about 45° and about 60° until the solids consist only of Form II crystals. It is most preferred to maintain the slurry at a temperature of about 55°. It is preferred to mix the linezolid and solvent for at least 10 min, it is even more preferred to mix the linezolid and solvent for at least 20 min and it is most preferred to mix the linezolid and solvent for at least 30 min. The time and temperature will vary depending on the solvent selected. With ethyl acetate it is preferred to mix for not less that 60 minutes. The crystalline slurry may be further cooled to improve yield, and the solid Form II product may be isolated. The mixture may be further cooled and agitated. Other measures which can be used to facilitate crystallization include, but are not limited to, cooling, concentration of the solution by evaporation or distillation, or through addition of other solvents. The crystals are isolated by procedures known to those skilled in the art.

It is well known to those skilled in the art that the oxazolidinones are useful as anti-bacterial agents especially against Gram-positive organisms. US Patent 5,688,792 discloses that oxazolidinones can be administered IV. The preferred formulation for linezolid IV solution is: Linezolid 2.0 mg mL

Sodium Citrate Dihydrate (USP) 1.64 mg/mL

Citric Acid Anhydrous (USP) 0.85 mg/mL

Dextrose Monohydrate (USP) 50.24 mg/mL

Hydrochloric Acid ( 10%) q.s. to pH 4.8 (pH 4.6 to 5.0) Sodium hydroxide (10%) q.s. to pH 4.8 (pH 4.6 to 5.0)

Water for Injection (USP) q.s. ad 1.0 mL

The linezolid IV solution is formulated by heating water for injection from about 50 to about 65°. Next the sodium citrate, citric acid and dextrose are added and stirred until dissolved. An aqueous slurry of linezolid is added to the previous mixture and stirred until dissolved. The mixture is cooled to 25° with stirring. The pH is measured and adjusted if necessary. Last the mixture is brought to volume, if necessary, with water for injection. The mixture is filtered, filled into infusion containers, over wrapped and terminally moist heat sterilized.

The aqueous solution for IV administration can be placed in the container which is selected from the group consisting of a bag, a bottle, a vial, a large volume parenteral, a small volume parenteral, a prefilled syringe and a cassette. It is realized that a vial is a bottle. However, those skilled in the art use the term “bottle” to refers to larger bottles and “vials” to refer to smaller bottles. It is preferred that the container be a bag, a bottle, a vial or a prefilled syringe. It is more preferred that the container be a bag or bottle. It is most preferred that the container be a bag. The shape and/or size of the container is unimportant. It is preferred that the container be a bag sufficient to hold 25 to 2,000 mL of IV solution. It is preferred that the linezolid mixture be put in bags in amounts of 100, 200 or 300 mL of solution however smaller or larger volumes are acceptable.

……………..

http://www.google.com/patents/WO2007138381A2?cl=en

. Scheme 2. Synthesis of eperezolid

RR==IH-

Et₃N,

17 (eperezolid)

1-(2-Fluoro-4-nitrophenyl)piperazine (8). To 3,4-difluoronitrobenzene (20.5 g, 129 mmol) in acetonitrile (290 mL) was added triethylamine (36 mL) and piperazine (32 g, 387 mmol). The mixture was stirred at reflux for 18 h, after which it was cooled to room temperature and partitioned between H₂O (500 mL) and EtOAc (400 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 300 mL). The organic layers were combined and washed with saturated NaCI solution (400 mL). The saturated NaCI layer was extracted again with EtOAc (2 x 200 mL). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated to yield 8 as a yellow solid (29 g, quant.). ¹H NMR (400 MHz, CDCI₃) δ 1.63 (s, 1 H), 3.04-3.06 (m, 4H), 3.25-3.28 (m, 4H), 6.91 (t, J=8.7, 1 H), 7.90 (dd, J=13.2, 2.5, 1 H), 7.97- 8.00 (m, 1H).

3-Fluoro-4-(piperazin-1-yl)benzenamine (9). Compound 8 (10.0 g, 44.4 mmol) was dissolved in anhydrous EtOH (222 mL) and placed in a Parr pressure flask. PtO₂ catalyst (31 mg) was added and the mixture was agitated under 50-60 psi of H₂ on a Parr apparatus for 30 min, after which the reaction mixture was vented, more catalyst was added (78 mg) and the reaction mixture was submitted to 50-60 psi of H₂ for another 30 min. The reaction mixture was filtered on Celite, the solid was washed with MeOH₁ and the combined filtrates were concentrated to give 9 as a yellow solid (8.7 g, quant.). ¹H NMR (400 MHz, CDCI₃) δ 1.64 (bs,

1 H), 2.92-2.94 (m, 4H), 3.02-3.04 (m, 4H), 5.53 (bs, 2H)₁ 6.38-6.45 (m, 2H), 6.80 (t, J=8.5, 1 H).

Benzyl 4-(4-((benzyloxy)carbonyl)piperazin-1 -yl)-3-fluorophenylcarbamate (10).

Compound 10 was obtained in 78% yield (light yellow solid) using the protocol described in J. Med. Chem. 1996, 39, 673-679. ¹H NMR (400 MHz, CDCI₃) δ 2.98 (bs, 4H), 3.65-3.68 (m, 4H),

5.16 (s, 2H), 5.19 (s, 2H), 6.59 (bs, 1H), 6.85 (t, J=9.1 , 1 H), 6.94-6.97 (m, 1 H), 7.27-7.41 (m,

11H).

Benzyl 4-(2-fluoro-4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl)phenyl) piperazine-1-carboxylate (11). Compound 11 was obtained in 66% yield (off-white solid) using the protocol described in J. Med. Chem. 1996, 39, 673-679. ¹H NMR (400 MHz, CDCI₃) δ 3.01

(bs, 4H), 3.66-3.69 (m, 4H), 3.74-3.79 (m, 1H)₁ 3.92-4.03 (m, 3H), 4.71-4.77 (m, 1H), 5.16 (s,

2H), 6.91 (t, J=9.1 , 1 H), 7.11-7.14 (m, 1H), 7.91-7.38 (m, 5H), 7.46 (dd, J=14.2, 2.5, 1 H).

Benzyl 4-(2-fluoro-4-((/?)-5-(methanesulfonyloxymethyl)-2-oxo-oxazolidin-3- yl)phenyl) piperazine-1-carboxylate (12). Compound 12 was obtained in quantitative yield (off- white foam) using the protocol described in J. Med. Chem. 1996, 39, 673-679. ¹H NMR (400 MHz, CDCI₃) δ 3.02 (bs, 4H), 3.10 (s, 3H), 3.67-3.69 (m, 4H), 3.92 (dd, J=9.1 , 6.1 , 1 H), 4.12 (t, J=QA, 1H), 4.44 (dd, J=11.7, 3.8, 1H), 4.49 (dd, J=11.7, 3.8, 1H), 4.88-4.94 (m, 1H), 5.16 (s, 2H), 6.93 (t, J=9.1 , 1 H), 7.08-7.12 (m, 1 H), 7.30-7.38 (m, 5H), 7.44 (dd, J=14.0, 2.6, 1 H).

Benzyl 4-(4-((S)-5-(aminomethyl)-2-oxo-oxazolidin-3-y!)-2-fluorophenyl) piperazine- 1-carboxylate (13). Compound 13 was obtained in 70% yield from 12 (4.4 g, 8:67 mmol), following the same procedure as for compound 6. After work-up, crude 13 was purified by flash chromatography using a gradient of 0-2-5-10% MeOH / CHCI₃ as eluent. ¹H NMR (400 MHz,

CDCI₃) δ 1.33 (bs, 2H), 2.94-3.03 (m, 5H), 3.11 (dd, J=13.7, 4.1 , 1 H), 3.66-3.69 (m, 4H)₁ 3.82

(dd, J=8.6, 6.7, 1 H), 4.00 (t, J=8.7, 1 H)₁4.63-4.69 (m, 1 H), 5.16 (s, 2H), 6.91 (t, J=9.1 , 1 H)₁7.12- 7.15 (m, 1 H)₁ 7.30-7.38 (m, 5H)₁ 7.47 (dd, J=14.3, 2.6, 1 H).

Benzyl 4-(4-((S)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl)-2-fluorophenyl) piperazine-1-carboxylate (14). Compound 14 was obtained in 90% yield from 13 (5.3 g, 12.4 mmol), following the same procedure as for compound 7. After work-up, the compound was used without any further purification. ¹H NMR (400 MHz, CDCI₃) δ 2.02 (s, 3H), 3.01 (bs, 4H), 3.57-3.77 (m, 7H)₁4.01 (t, J=9.0, 1 H)₁4.73-4.79 (m, 1 H)₁ 5.16 (s, 2H)₁6.05 (t, J=6.2, 1H)₁6.91 (t, J=9.2, 1H), 7.05-7.08(m, 1 H)₁ 7.32-7.38 (m, 5H)₁ 7.44 (dd, J=14.2, 2.62, 1 H).

Λ/-[((S)-3-(3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-oxazolidin-5-yl)methyl)acetamide (15). To a solution of 14 (748 mg, 1.59 mmol) in abs. ethanol (40 ml.) was added cyclohexene (1 ml.) and 10% Pd / C (400 mg). The mixture was refluxed for 2 h, when TLC indicated complete reaction. The reaction mixture was filtered through celite and concentrated to give 15 as an off-white solid (520 mg, 97%). The product was essentially pure, but could be purified by chromatography (90:10:1.5 CH₂CI₂:MeOH:conc. NH₄OH). ¹H NMR (400 MHz, CDCI₃) 52.01 (s, 3H), 3.02 (d, J=Al, 8H), 3.57-3.76 (m, 3H), 4.01 (t, J=9.0, 1H), 4.73-4.79 (m, 1H), 6.29 (m, 1H)₁ 6.92 (t, J=9.1 , 1 H), 7.04-7.07(m, 1 H), 7.39-7.43 (m, 1 H).

Λ/-(((S)-3-(4-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)-3-fluorophenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide (16). To a solution of 15 (537 mg, 1.60 mmol) and triethylamine (0.22 mL, 3.53 mmol) in CH₂CI₂ (35 mL) at 0 ⁰C was added benzyloxyacetyl chloride (0.30 ml_, 1.92 mmol). The mixture was stirred at 0 ⁰C for 1 h, then 15 min at room temperature when TLC indicated complete reaction. The reaction mixture was washed with water (2 x 30 mL), and saturated sodium bicarbonate (2 x 30 mL), and dried over MgSO₄. After chromatography (gradient elution 5-10% MeOH / CH₂CI₂) the product was obtained as a white foam (709 mg, 91%). ¹H NMR (400 MHz, CDCI₃) δ 2.02 (s, 3H), 2.98-3.14 (m, 4H), 3.56-3.86 (m, 7H), 4.02 (t, J=9.0, 1 H), 4.22 (S, 2H), 4.62 (s, 2H), 4.73-4.80 (m, 1H)₁ 6.02 (t, J=5.9,1 H), 6.96-7.10 (m, 2H), 7.28-7.40 (m, 5H), 7.45-7.53 (m, 1 H).

Λ/-(((S)-3-(3-fluoro-4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)-2-oxooxazoiidin-5- yl)methyl)acetamide (17, eperezolid). To a solution of 16 (709 mg, 1.46 mmol) in abs. ethanol (40 mL) was added cyclohexene (1 mL) and 10% Pd / C (250 mg). The mixture was refluxed for 15 h, when TLC indicated complete reaction. The reaction mixture was filtered through Celite™ and concentrated to give 17 (470 mg, 82% yield). The product was essentially pure, but could be purified by chromatography. ¹H NMR (400 MHz, CDCI₃) δ 2.02 (s, 3H), 3.06-3.10 (m, 4H), 3.45-3.50 (m, 2H), 3.58-3.77 (m, 3H), 3.85-3.87 (m, 2H), 4.02 (t, J=9.0, 1 H), 4.21 (s, 2H), 4.74- 4.80 (m, 1H), 6.09 (t, J=6.0, 1 H), 6.97 (t, J=QA , 1 H), 7.07-7.10 (m, 1 H), 7.46-7.50 (m, 1 H). LCMS : 96.1% (254 nm), 95.1% (220 nm), 94.5% (320 nm). MS : 395 (MH)⁺.

……………….

http://www.google.com/patents/WO1997037980A1

EXAMPLE 8 (S)-N-[[3-[3-fluoro-4- 4-(hydro3ζyacetyl)-l-piperazinyl]-phenyl]-2- oxo-5-oxazoHdinyl]methylJ-acetamide sesquihydrate (VIII) To a stirred mixture of (S)-N-[[3-[3-fluoro-4-(l-piperazinyl)phenyl]-2-oxo-5- oxazoHdinyl]methyl]acetamide hydrochloride (EXAMPLE 7, 16.2 kg, 43.5 moles), tetrahydrofuran (205 kg) and triethylamine (10.1 kg, 100 moles) is added acetoxyacetyl chloride (6.5 kg, 47.8 moles) in tetrahydrofuran (11.1 kg) over 35 minutes keeping the temperature at 22-23°. After 40 minutes, at which time TLC and HPLC analysis indicated complete formation of the acetoxyacetamide intermediate, the mixture is concentrated under reduced pressure to 30 1, diluted with methanol (100 1) and concentrated to 30 1. To the residue is added methanol (25 1) and an aqueous solution of potassium carbonate (5.6 kg in 56 1). The resulting mixture is stirred 20 hr at 22-25° at which time TLC and HPLC analysis indicates the reaction is complete. The pH is adjusted to 7-7.5 with hydrochloric acid (4 N, 14.3 1). The mixture is stirred 18 hr at 15-22° then 3 hrs at 2-5°. The soHds are collected on a filter, washed with water (68 1) and dried at 20-25° with recycled nitrogen to give the desired product. The crude product is dissolved in water (225 1) at 60-70°, clarified through a 0.6 micron filter, diluted with water rinse (55 1) and stirred 17 hrs. at 15°. The solids are collected on a filter, washed with water at 15° and dried at 45° with recycled nitrogen to a water content of 0.33%. These soHds are dissolved in a solution of ethyl acetate (143 1), methanol (65 1) and water (1.95 1) at 60-65°. The solution is cooled to 15-25° and stirred 16 hrs for crystallization. The soHds are coUected on a filter, washed with ethyl acetate (75 1) and dried with 45° nitrogen to give the desired product. The product is recrystallized two more times from water (147 1 then 133 1) at 60-70°, clarified each time through a 0.6 micron filter and rinsed with water (40 1 and 30 1). The soHds are dried on the filter at 30° with recycled nitrogen to give, after deagglomeration through a mill, the title compound as the sesquihydrate (6.45% water), TLC (siHca gel; methanol/methylene chloride, 5/95) Rf = 0.45; [α]_D = -20° (c = 1.0, ethanol).

pamidronate eperezolid

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US6770664	8-4-2004	BICYCLIC HETEROCYCLIC SUBSTITUTED PHENYL OXAZOLIDINONE ANTIBACTERIALS, AND RELATED COMPOSITIONS AND METHODS
US2003171366	9-12-2003	Bicyclic heterocyclic substituted phenyl oxazolidinone antibacterials, and related compositions and methods
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Tuberculosis: the drug development pipeline at a glance.

April 1, 2014 5:21 am / 1 Comment on Tuberculosis: the drug development pipeline at a glance.

Tuberculosis: The drug development pipeline at a glance

Review Article
Pages 1-16
Baptiste Villemagne, Céline Crauste, Marion Flipo, Alain R. Baulard, Benoit Déprez, Nicolas Willand

Graphical Abstract

Highlights

► This review presents anti-tuberculosis compounds currently in clinical trials. ► Promising strategies in preclinical development are described. ► The chemical synthesis, target and mechanism of action are highlighted. ► Activities observed in preclinical and clinical studies are reported.

Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60’s of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.

Eur J Med Chem. 2012 May;51:1-16. doi: 10.1016/j.ejmech.2012.02.033. Epub 2012 Feb 25.

Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A.R.; Déprez, B.; Willand, N. Tuberculosis: Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A.R.; Déprez, B.; Willand, N. Tuberculosis: The drug development pipeline at a glance. . Eur. J. Med. Chem. 2012, 51, 1–16, doi:10.1016/j.ejmech.2012.02.033.

MicuRx Pharmaceuticals (USA) has MRX I IN PHASE 1 for resistant Gram-positive bacteria

April 1, 2014 4:20 am / Leave a comment

Figure imgf000071_0001 MRX I

MRX-I

1112968-42-9 cas no

C₁₈ H₁₅ F₃ N₄ O₄

4(1H)-Pyridinone, 2,3-dihydro-1-[2,3,6-trifluoro-4-[(5S)-5-[(3-isoxazolylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]-

IN phase 1 FOR GRAM POSITIVE BACTERIA

MicuRx Pharmaceuticals (USA)

MicuRx Pharmaceuticals is developing two oxazolidinone compounds MRX-I and MRX-II. MRX-I is an oral oxazolidinone antibiotic that targets infections due to resistant Gram-positive bacteria, including MRSA and vancomycin-resistant enterococci (VRE). The company announced the completion of a double-blinded, placebo-controlled Phase 1 clinical study, and that the compound has been shown to be safe and well-tolerated at all doses tested with no evidence of myelosuppression.

In October 2012, the company announced the establishment of Shanghai MengKe Pharmaceuticals, a joint venture with Shanghai Zhangjiang Biomedical Industry Venture Capital formed to fund the development and commercialization of MRX-I for the Chinese market. MRX-II is currently under pre-clinical development [1,2].

Figure US08178683-20120515-C00084

MRX-I: A Potent and Safe Oxazolidinone Antibiotic

MRX-I is a next-generation oral oxazolidinone antibiotic for treating Gram-positivebacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In April 2012, MicuRx announced positive Phase I clinical results demonstrating that MRX-I is safe and well tolerated in human subjects, with no signs of myelosuppression, a major toxicity concern for most oxazolidinone agents, including linezolid.In preclinical studies, MRX-I cures in vivoinfections due to Gram-positive bacteria including MRSA and VRE effectively. In addition, MRX-I exhibits 2-fold improved activity against MRSA strains as compared to linezolid.

WO 2009020616 OR

http://www.google.fm/patents/US20090048305?cl=ja

Example 1 Compound of Structure

Scheme for the Compound of Example 1

Intermediate 17. 2,3,4,5-Tetrafluoronitrobenzene (1.17 g, 6.0 mmol) in N-methylpiperidone (NMP; 25 mL) was added dropwise with stirring to 4-piperidone hydrochloride (0.84 g, 6.2 mmol) and N,N-diisopropyl-N-ethylamine (DIEA; 2.45 mL, 14.0 mmol) in NMP (20 mL) at ca.-10 to −5° C. under nitrogen. The mixture was allowed to warm up to r.t. and stirred o.n. The mixture was taken into EtOAc (ca. 100 mL), washed with 2% aq. citric acid (2×50 mL), water (10×50 mL), brine, and dried (Na₂SO₄). Solvent was removed under vacuum, and the crude product was washed with hexanes (4×20 mL) and dried. Yellow crystals.¹H NMR (400 MHz): 7.74 (m, 1H); 3.73 (t, J=6.0 Hz, 4H); 2.66 (t, J=6.0 Hz, 4H). MS (m/z): 275 [M+H].

Intermediate 18. Triethylamine (TEA; 5.6 mL, 43.87 mmol) was added to the Intermediate 17 (8.1 g, 29.56 mmol) in THF (120 mL) at 0° C., followed by triisopropylsilyl triflate (TIPSOTf; 10.7 g, 34.97 mmol). The mixture was allowed to warm up to r.t. over ca. 40 min, and stirred for another 2 h. Solvent was removed on a rotary evaporator. EtOAc (180 mL) was added, and the solution washed with 10% aq. NaHCO₃(40 mL), brine (60 mL) and dried (Na₂SO₄). Solvent was removed under vacuum and to afford the product as a red-brownish oil. This was directly used at the next step without purification.

Intermediate 19. Ceric ammonium nitrate (CAN, 19.0 g, 34.65 mmol) was added portionwise with stirring to a solution of the Intermediate 18 (12.4 g, 28.80 mmol) in dry DMF (100 mL) at 0° C. The reaction mixture was allowed to warm up to r.t. and stirred for another 4 h. Most of solvent was removed under vacuum. Water (ca. 75 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried (Na₂SO₄). Solvent was removed and the residue purified by column chromatography (gradient 20% to 30% EtOAc in petroleum ether). The product was obtained as a yellow solid. ¹H NMR (400 MHz): 7.84 (m, 1H); 7.14 (m, 1H); 5.43 (d, J=8.2 Hz, 1H); 4.06 (t, J=7.2 Hz, 2H); 2.74 (t, J=7.2 Hz, 2H). MS (m/z): 273 [M+H].

Intermediate 20. NH₄Cl (0.33 g, 6.2 mmol) in water (5 mL) was added to a hot solution of the Intermediate 19 (0.170 g, 0.62 mmol) in EtOH (10 mL). Iron powder (0.173 g, 3.1 mmol) was added portionwise with stirring, and the mixture at ca. 100-105° C. for 50 min. The solution was filtered, and the precipitate washed with EtOH (5×10 mL). EtOH was removed under vacuum, and residue distributed between EtOAc (ca. 50 mL) and water (10 mL). Aq. layer was washed with EtOAc (3×20 mL), and combined organic layers were washed with water (3×7 mL), brine, and dried (MgSO₄). Solvent was removed under vacuum to afford the product as yellow crystals. ¹H NMR (400 MHz): 7.03 (m, 1H); 6.36 (m, 1H); 5.19 (d, J=8.0 Hz, 1H); 4.12 (d, J=7.2 Hz, 2H); 3.80 (t, J=7.2 Hz, 2H); 2.66 (t, J=7.2 Hz, 2H). MS (m/z): 243 [M+H].

Intermediate 21.60% NaH in mineral oil (1.4 g, 36.0 mmol) was added portionwise with stirring to the Intermediate 20 (2.9 g, 11.94 mmol) in THF (20 mL) at 0° C. under Ar, and the mixture was stirred at this temperature for 30 min. Benzyl chloroformate (4.1 g, 24.03 mmol) was added dropwise with stirring. The reaction mixture was allowed to warm up to r.t. and stirred o.n. The reaction was carefully quenched with water (10 mL), and THF was removed under vacuum. The residue was taken in DCM (80 mL). Organic layer was washed with brine (50 mL) and dried (Na₂SO₄). Solvent was removed under vacuum, and the residue dissolved with MeOH (40 mL). Aq. NH₃(25 mL) was added with stirring, and the mixture was stirred at r.t. for 2 h. Solvent was removed under vacuum, and EtOAc (100 mL) was added. The organic layer was washed with brine and dried (Na₂SO₄). Solvent was removed under vacuum, and the residue purified by column chromatography (gradient 25% to 100% DCM/petroleum ether). White solid. ¹H NMR (400 MHz): 7.95 (m, 1H); 7.41 (m, 6H); 7.07 (m, 2H); 5.28 (s, 2H); 3.88 (t, J=7.6 Hz, 2H); 2.69 (t, J=7.6 Hz, 2H). MS (m/z): 377 [M+H].

Compound of Example 1. 1.06M Lithium hexamethyldisilylamide (LHMDS; 3.0 mL, 3.18 mmol) in THF was added dropwise with stirring to a solution of the Intermediate 21 (1.0 g, 2.66 mmol) in THF (8.0 mL) at −78° C., and the mixture was stirred at this temperature for 30 min. (R)-Glycidyl butyrate (0.8 mL, 5.55 mmol) was added dropwise, and the mixture was allowed to warm up to r.t. and stirred o.n. The reaction was quenched with 10% aq. NH₄Cl (15 mL), and THF was removed under vacuum. The residue was extracted with EtOAc (2×30 mL). Combined organic layers were washed with brine and dried (Na₂SO₄). Solvent was removed under vacuum. MeOH (5 mL) and 20% aqueous Cs₂CO₃(5 mL) were added, and the mixture was stirred at r.t. for 20 min. The mixture was taken into EtOAc (50 mL), washed with water (2×15 mL), brine, and dried (Na₂SO₄). Solvent was removed under vacuum and the crude product was purified by column chromatography (2% methanol/DCM). Off-white solid. ¹H NMR (400 MHz): 7.44 (m, 1H); 7.10 (d, J=7.6 Hz, 1H); 5.33 (d, J=8.0 Hz, 1H); 4.84 (m, 1H); 4.19 (m, 1H); 4.08 (m, 2H); 3.92 (t, J=7.4 Hz, 2H); 3.81 (dd, J=12.4, 3.2 Hz, 1H); 2.71 (t, J=7.4 Hz, 2H); 2.14 (br, 1H). MS (m/z): 343 [M+H].

………………………………..

WO2010091272A1

http://www.google.com/patents/WO2010091272A1?cl=en

Scheme 4 below.

Scheme 4. Example for synthesis of (isoxazole-3-yl)amino compounds of formula I.

a) Piperidin-4-one hydrochloride, DIEA, NMP, -5 ⁰C to r.t; b) TMSOTf,

TEA, THF, 0 ⁰C to r.t.; c) O-allyl-0′ -methyl carbonate, Pd(OAc)₂, DMSO, 2,3,4,5-tetrafluoronitrobenzene, 60 ⁰C; d) Fe, NH₄Cl, EtOH, 95 ⁰C; e) isobutyl chloroformate, Py, DCM, 0 ⁰C to r.t.; f) two steps: 1) (Λ)-glycidyl butyrate or chlorohydrine, Bu¹OLi, THF, MeCN, 0-30 ⁰C; 2) 10% aq. K₂CO₃; g) MsCl, TEA, THF, 0 ⁰C; h) 3-[N-(/er/-butoxycarbonyl)amino]isoxazole, Bu¹OK, DMF, 20-40 ⁰C; i) aq. HCl, EtOH, EtOAc, 0 ⁰C to r.t.

Select innovative steps pertaining to the particular utility of Scheme 4 for an efficient synthesis and production of the compounds of formula I (illustrated by structure 26 in the Scheme 4) are summarized in paragraphs (i-iv) below:

i) The novel efficient method for an installation of the dihydropyridone ring into an ortho-F compound of formula I provided herein involve the use of an alkoxide (e.g, methoxide) capture reagent (e.g., 2,3,4,5-tetrafluoronitrobenzene). The dihydropyri done-forming step for a transformation of the compounds 19 to compounds 20 performed in absence of the methoxide-capture reagent(s) is accompanied by formation of the hard-to-remove ort/zo-methoxy impurity (e.g., l-(2,6-difluoro-3-methoxy-4-nitrophenyl)-2,3-dihydropyridone) resulted from undesired substitution of ortho-F atom with MeOH, AIkOH, or anion thereof. This is a serious problem specific for the synthesis of ortho-F dihydropyridone compounds, arising from the unique reactivity of ortho-F substrates 19 and may not be encountered in synthesis of des-ortho-F compounds lacking the key ortho-F substitution. The methods disclosed herein involve the use of a methoxide-capture nitrobenzene additive to eliminate or minimize above methoxy-aryl by-product to allow for a high-yielding preparation and manufacture of precursors 19 and compounds of formula I, with a purity suitable for pharmaceutical applications (generally, better than 90-95%). Additional MeO-capture additives may include acylating, alkylating, or arylating agents (e.g., carboxylic acid anhydride or an active ester capable of methoxide acylation). Optionally, one or more alkoxide-capture reagent(s), or a combination thereof can be used.

ii) New practical method for the key oxazolidinone-forming step (from

22 to 23) provided herin involves the use of an alkali metal alkoxide (e.g., LiOBu- 1) instead of the conventionally used BuLi (as more generally described, e.g., in J. Med. Chem., 1988, vol. 41, pp. 3727-3735). The procedure provided herein thus eliminates the use of a highly flammable and unstable organometallic chemical. Moreover, the new processes provided herein also eliminates the need for costly cryogenic (-78 ⁰C) conditions impractical for the industrial manufacture of the reagents 23 and of the compounds of formula I. [00111] iii) Novel process for the preparation of 5-[(isoxazole-3-yl)amino]methyl derivatives 25 that employs an alkali metal alkoxide ( e.g., KOBu-t) in place of previously used NaH (as more generally described, e.g., in International Patent Publication No. WO 00/21960, incorporated herein by reference in its entirety). This eliminates the use of an extremely flammable base and allows for an efficient preparation and manufacture of the precursors 25 and the compounds of formula I.

iv) New practical method for the synthesis of the compounds of formula I

(Ri = (isoxazole-3-yl)amino; structure 26 in Scheme 4) employing aq. HCl – organic solvent(s) system for deprotection of acid-cleavable protective groups (PG; e.g., PG = tert-butoxycarbonyl or Boc group). The method provided herein eliminates the use of highly toxic and expensive reagents conventionally employed for des-ortho-F 1-phenyldihydropyridone compounds (the method as described, for example, in International Patent Publication No. WO 2004/033449, advocating the use of trifluoroacetic acid and 1 ,2-dichloroethane Boc-deprotection system). The efficiency of the new deprotection method invented herein is particularly surprising in view of the fact that enamino ketones (such as dihydropyridones) are generally degradable by a strong aqueous acids, such as aq. HCl (as more generally described, e.g., by Katritzky et al. in J. Chem. Research, Miniprint, 1980, pp. 3337-3360).

……………………………….

US8178683

https://www.google.com/patents/US8178683

Example 5 Compound of Structure

Scheme for Compound of Example 5

Intermediate 25.

Method A. A solution of tert-butyl isoxazol-3-ylcarbamate (187 mg, 1.00 mmol) in DMF (1 mL) was added dropwise with stirring to a suspension of NaH (60% in mineral oil, 48 mg, 1.20 mmol) in DMF (2 mL). The mixture was stirred under N₂for 15 min. at 35° C. The Intermediate 22 (357 mg, 0.85 mmol) in DMF (1 mL) was added, and the mixture was stirred at 50° C. for 1.5 h. The reaction mixture was taken into EtOAc (30 mL), washed with 10% aq. NH₄Cl (2×15 mL), brine, and dried (Na₂SO₄). Solvent was removed under vacuum and the crude material was purified by column chromatography (2% MeOH/DCM) to afford the product as a light yellow solid.

Method B. A solution of tert-butyl isoxazol-3-ylcarbamate (694 mg, 3.8 mmol) in DMF (3 mL) was added dropwise with stirring to Bu^tOK (439 mg, 3.8 mmol) in DMF (3 mL) at 0° C. The mixture was warmed up to r.t. and stirred for 30 min. The Intermediate 22 (1.34 g, 3.2 mmol) in DMF (6 mL) mL) was added, and the mixture was stirred at 35° C. for 2 h. The reaction was quenched with saturated aq. NH₄Cl solution (10 mL), and isolation performed just as described above for Method A to afford the product as a light yellow solid. ¹H NMR (400 MHz): 8.28 (s, 1H), 7.44 (m, 1H), 7.09 (d, J=7.6 Hz, 1H), 7.00 (s, 1H, 5.32 (d, J=7.6 Hz, 1H), 5.15 (m, 1H), 4.44 (m, 1H), 4.20 (m, 2H, 3.94 (m, 3H), 2.70 (t, J=7.4 Hz, 2H), 1.45 (s, 9H). MS (m/z): 509 [M+H].

Compound of Example 5

Method A. TFA (2.0 mL) was added dropwise to the solution of the Intermediate 25 (310 mg, 0.61 mmol) in 1,2-dichloroethane (DCE; 2 mL) at 0° C., and the solution was stirred at 0° C. for 30 min. Volatiles were removed under vacuum, and the residue taken into EtOAc (30 mL). The solution was washed with saturated NaHCO₃solution (2×15 mL), brine, and dried (Na₂SO₄). Solvent was removed under vacuum and the crude product was purified by column chromatography (3% MeOH/DCM). Light-yellow solid.

Method B. 4M HCl in THF (56 mL) was added dropwise to the Intermediate 25 (3.0 g, 5.9 mmol) at 0° C. Water (0.59 mL) was added, and the solution was stirred at r.t. for 2 h. Most of volatiles were removed under vacuum, the residue taken into water (30 mL) and sat. aq. NaHCO₃(15 mL), and pH adjusted to ca. 8. After stirring for 15 min, the mixture was extracted with EtOAc (3×60 mL). Combined organic layers were washed with brine (2×30 mL), and dried (Na₂SO₄). Solvent was removed under vacuum. The residue was re-dissolved in 2% MeOH in DCM (3 mL), and passed through a short pad of silica, eluting the product with 2% MeOH in DCM. Light-yellow solid. ¹H NMR (400 MHz, DMSO-d₆): 8.41 (d, J=1.6 Hz, 1H); 7.57 (m, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.58 (t, J=5.8 Hz, 1H), 6.02 (d, J=1.6 Hz, 1H), 5.08 (d, J=8.0 Hz, 1H), 4.90 (m, 1H), 4.17 (t, J=8.6 Hz, 1H), 3.86 (m, 3H), 3.48 (t, J=5.6 Hz, 2H), 2.49 (m, overlapped with DMSO-d₆, 2H). MS (m/z): 409 [M+H].

pick up int 22

from below

Example 3 Compound of Structure

Scheme for Compound of Example 3

Intermediate 22. Methylsulfonyl chloride (MsCl; 79 uL, 1.00 mmol) was added dropwise with stirring to the compound of Example 1 (290 mg, 0.85 mmol) and TEA (177 uL, 1.27 mmol, 1.50 equiv.) in DCM (5 mL) at ca. 0° C. The mixture was stirred for 20 min and allowed to warm up to r.t. The reaction mixture distributed between water and the DCM. Aq. layer was extracted with DCM (2×10 mL), and the combined organic layers washed with brine and dried (Na₂SO₄). Solvent was removed under vacuum to afford the product that was used for the next step without purification.

Intermediate 23. A mixture of the Intermediate 22 (567 mg, 1.35 mmol) and NaN₃(438 mg, 6.75 mmol) in DMF (5 mL) was stirred at 55° C. o.n. After cooling to r.t., water (15 mL) was added, and the reaction mixture was extracted with DCM (3×30 mL). Combined organic layers were washed with brine (30 ml) and dried (Na₂SO₄). Solvent was removed under vacuum to afford the product as a light yellow solid. This was used directly for the next step without further purification.

Compound of Example 3. A mixture of the Intermediate 23 (785 mg, 2.14 mmol) and bicyclo[2.2.1]hepta-2,5-diene (2.2 mL, 21.4 mmol) in 1,4-dioxane (22 mL) under N₂was heated at 100° C. for 3 h. Most of volatiles were removed under vacuum, and the residue was purified by column chromatography (1% MeOH/DCM). Thus isolated product was recrystallized from MeOH. White solid. ¹H NMR (400 MHz): 7.83 (s, 2H), 7.05 (m, 2H), 5.30 (d, J=8 Hz, 1H), 5.16 (m, 1H), 4.83 (d, J=3.6 Hz, 2H), 4.33 (m, 1H), 4.06 (m, 1H), 3.91 (t, J=14.8 Hz, 2H), 2.69 (t, J=14.8 Hz, 2H). MS (m/z): 394 [M+H].

MicuRx Pharmaceuticalsresistant Gram-positive bacteria, Inc. MicuRx and Shanghai Zhangjiang biomedical industry venture capital partner to develop next-generation antibiotic MRX-I for Chinese market. Available online: http://www.micurx.com/doc/10-24-12%20JV-FINAL.doc (accessed on 11 April 2013).
MicuRx Pharmaceuticals. Discovery and development. Available online: http://www.micurx.com/d1.htm(accessed on 12 December 2012).
CN 102206213
CN 102485224
CN 102485225

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Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro

April 1, 2014 3:26 am / 10 Comments on Moringa Oleifera Kills 9710 of Pancreatic Cancer Cells in Vitro

Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro:

A hot-water extract of moringa leaves was shown to kill up to 97% of human pancreatic cancer cells (Panc-1) after 72 hours in this study. Moringa, also called the “miracle tree,” has a long history of use in traditional and Ayurvedic medicine due to its many beneficial properties as an anti-fungal, anti-bacterial, antidepressant, anti-diabetes, pain and fever reducer and even relief from asthma. But it also contains numerous powerful anti-cancer compounds such as kaempferol, rhamnetin, isoquercetin and others.

Latest research is now proving out moringa’s anti-cancer potential with positive results so far against ovarian cancer, liver cancer, lung cancer, and melanoma. Moringa is now extensively cultivated throughout Southeast Asia, Oceania, the Caribbean and Central America, but the largest crop in the world is produced by India – where it grows natively.

That may be one reason why the death rate from pancreatic cancer in India is a stunning 84% lower than in the United States.
‪
http://www.ncbi.nlm.nih.gov/pubmed/23957955

Posizolid in phase 2 for tuberculosis

March 31, 2014 12:23 pm / Leave a comment

POSIZOLID

252260-02-9 CAS NO

(5R)-3-[4-[1-[(2S)-2,3-Dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluorophenyl]-5-(1,2-oxazol-3-yloxymethyl)-1,3-oxazolidin-2-one

AstraZeneca (Originator)

AZD-2563, AZD-5847

Posizolid, Posizolid [INN], SureCN374786, AC1L4U5J, AC1Q6O1X, CHEMBL131854, AZD-2563, AZD-5847 AR-1H7626, A820111

Molecular Formula: C₂₁H₂₁F₂N₃O₇ Molecular Weight: 465.404146

Posizolid is an oxazolidinone antibiotic under investigation by AstraZeneca for the treatment of bacterial infections. At a concentration of 2 mg/L it inhibited 98% of all Gram-positive bacteria tested in vitro.^[1]

Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtu), which in 1990 was declared a global epidemic by the World Health Organisation (WHO). It affects more than one third of the world’s population resulting in 8 million new patients and 2 million deaths every year. Also there exists a scenario called “Latent TB”, which occurs when germs remain in the body in a quiescent state but without any apparent effect on the health of the individual. In many cases this stage may last for many years or decades. In case of normal human being the chance of activation is 2-23% in a lifetime. However in case of immuno-compromised patients (like HIV) the chances of activation rise to 10% every year.

The current treatment of drug sensitive tuberculosis is at least six months long and requires a combination of isoniazid, rifampicin, pyrazinamide and ethambutol in the first two months followed by isoniazid and rifampicin for a period of four months. In recent years, drug resistance to these drugs has increased and the last of drugs for tuberculosis was introduced into clinical practice in the late 1960’s. The evolution of resistance could result in strains against which currently available antitubercular agents will be ineffective and treatment in such cases may last two years with no guarantee of cure. So there is an urgent need to introduce new drugs particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups and new treatment regimens to overcome not only rising drug resistance but also improve the overall treatment duration.

R. Sood et al (Infectious Disorders—Drug Targets 2006, 343-354) report that “Oxazolidinones are a new class of totally synthetic antibacterial agents with wide spectrum of activity against a variety of clinically significant susceptible and resistant bacteria. These compounds have been shown to inhibit translation at the initiation phase of protein synthesis. DuP-721, the first oxazolidinone showed good activity against M. tuberculosis when given orally or parenterally to experimental animals but was not developed further due to lethal toxicity in animal models. Later two oxazolidinones, PNU-100480 and Linezolid, demonstrated promising antimycobacterial activities in the murine model. While Linezolid has been approved for clinical use for broad spectrum area, PNU-100840 was not developed further. DA-7867 showed good in vitro and better in vivo efficacy than Linezolid but was poorly tolerated in rat toxicology studies. The antimycobacterial activity of AZD2563 has not been explored. RBx 7644 had modest antimycobacterial activity whilst RBx 8700 has potent antibacterial and concentration dependent activity against all slow growing mycobacteria. It demonstrated better activity than RBx 7644 against MDR strains of M. tuberculosis along with intracellular activity”.

In published patent application WO-99/64417 we disclose the compound

ie. (5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one also known as AZD2563. As reported by R. Sood et al (op cit) the antimycobacterial activity of AZD2563 has not been explored.

In a first aspect of the invention we now provide (5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, for use in the treatment of Mycobacterium tuberculosis.

The compound can form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following.

Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, α-glycerophosphate. fumarate, hydrochloride, citrate, maleate, tartrate and hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. In one aspect of the invention the pharmaceutically-acceptable salt is the sodium salt.

Synthesis of 5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one (AZD 2563) is disclosed in our published patent application WO-99/64417.

……………….

http://www.google.com/patents/WO1999064417A2?cl=en

Example 22: 5(R)-IsoxazoI-3-yloxymethyl-3-(4-(l-(2(S)-hvdroxy-3-phosphoryl- propanovD-l^_^S^-tetrahvdropyrid^-vπ^^-difluorophenvDoxazolidin^-one

To a stiπed solution of the starting material Reference Example 15 (lOOmg, 0.15mmol) in dioxan (1ml) was added 4M HCl / dioxan (3ml). The solution was stiπed at ambient temperature for 30 mins. and then evaporated. The residue was triturated well with ether giving the title compound as a white powder (80mg, 96%).

NMR (300Mz. DMS0-d6): 2.43 (m, partially obscured), 3.6 – 4.35 (m, 8H), 4.35 – 4.60 (m, 3H), 5.09 (m, IH), 5.85 (s, IH), 6.30 (s, IH), 7.31 (d, 2H), 8.60 (s, IH). MS: ESP+ (M+H) = 546.

…………………….

EP 1082323; JP 2002517498; WO 9964417

The condensation of the protected 3,5-difluoroaniline (I) with 1-benzyl-4-piperidone (II) by means of BuLi in THF gives 4-(1-benzyl-4-hydroxypiperidin-4-yl)-3,5-difluoroaniline (III), which is dehydrated with refluxing conc. HCl to yield the tetrahydropyridine (IV). The reaction of (IV) with benzyl chloroformate in acetone/water affords the carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) by means of BuLi in THF to provide the oxazolidinone (VII). The condensation of (VII) with isoxazol-3-ol (VIII) by means of PPh3 and DIAD in THF gives the expected ether adduct (IX), which is debenzylated by reaction with 1-chloroethyl chloroformate in dichloromethane, yielding the free tetrahydropyridine derivative (X). The condensation of (X) with (S)-2,3-O-isopropylideneglyceric acid (XI) by means of DEC or DCC and TEA in dichloromethane affords the corresponding acyl tetrahydropyridine (XII), which is finally deprotected with HCl in THF to provide the target dihydroxy compound.

………………..

WO 0140236

References

Wookey, A.; Turner, P. J.; Greenhalgh, J. M.; Eastwood, M.; Clarke, J.; Sefton, C. (2004). “AZD2563, a novel oxazolidinone: definition of antibacterial spectrum, assessment of bactericidal potential and the impact of miscellaneous factors on activity in vitro”. Clinical Microbiology and Infection 10 (3): 247–254. doi:10.1111/j.1198-743X.2004.00770.x. PMID 15008947.

AstraZeneca. New tuberculosis drug trial begins in South Africa. Available online: http://www.astrazeneca.com/Research/news/Article/20121210–new-tuberculosis-drug-trial-begins-in-south-africa (accessed on 12 April 2013).
Working Group on New TB Drugs. AZD5847 oxazolidinone. Available online: http://www.newtbdrugs.org/project.php?id=174 (accessed on 12 April 2013).
National Institute of Allergy and Infectious Diseases (NIAID). Phase 2a EBA trial of AZD5847. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01516203 (accessed on 12 April 2013).
Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A.R.; Déprez, B.; Willand, N. Tuberculosis: The drug development pipeline at a glance. Eur. J. Med. Chem. 2012, 51, 1–16, doi:10.1016/j.ejmech.2012.02.033.

US2012035219

2-10-2012

Compound for the Treatment of Tuberculosis

WO1993022298A1 *	Apr 28, 1993	Nov 11, 1993	Hiroyuki Kawamura	Oxazolidine derivative and pharmaceutically acceptable salt thereof
WO1993023384A1 *	Apr 21, 1993	Nov 25, 1993	Michael Robert Barbachyn	Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials
WO1994022857A1 *	Apr 7, 1994	Oct 13, 1994	Masakazu Fukushima	Thiazolidine derivative and pharmaceutical composition containing the same
WO1997006791A1 *	Aug 13, 1996	Feb 27, 1997	Scripps Research Inst	METHODS AND COMPOSITIONS USEFUL FOR INHIBITION OF αvβ5 MEDIATED ANGIOGENESIS
WO1997009328A1 *	Aug 13, 1996	Mar 13, 1997	David J Anderson	Phenyloxazolidinones having a c-c bond to 4-8 membered heterocyclic rings
EP0645376A1 *	Sep 15, 1994	Mar 29, 1995	MERCK PATENT GmbH	Substituted 1-phenyl-oxazolidin-2-one derivatives, their preparation and their use as adhesion-receptor antagonists
EP0710657A1 *	Oct 19, 1995	May 8, 1996	MERCK PATENT GmbH	Antagonists of adhesion receptors

Radezolid in phase 2, Rib-X Pharmaceuticals

March 31, 2014 8:41 am / Leave a comment

Antibiotics 02 00500 i017

Radezolid

869884-78-6 cas no

http://www.ama-assn.org/resources/doc/usan/radezolid.pdf

869884-78-6, RX-103, RX-1741, RX-O1_667, Radezolid (USAN/INN), UNII-53PC6LO35W

Molecular Formula: C₂₂H₂₃FN₆O₃

Molecular Weight: 438.454823

Rib-X Pharmaceuticals

Phase II completed

N-{[(5S)-3-(2-fluoro-4′-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide

(5S)-N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide

Rib-X Pharmaceuticals has completed two Phase II clinical trials of radezolid for the treatment of pneumonia and uncomplicated skin infections. The trial completion dates were in 2008 and 2009, but to date the Phase III trials have not been initiated [1-6].

Radezolid (INN, codenamed RX-1741) is a novel oxazolidinone antibiotic being developed by Rib-X Pharmaceuticals, Inc. for the treatment of serious multi-drug–resistant infections. Radezolid has completed two phase-II clinical trials. One of these clinical trials was for uncomplicated skin and skin-structure infections (uSSSI) and the other clinical trial was for community acquired pneumonia (CAP).

Oxazolidinone antibiotics are a relatively new class of antibacterial agents with activity against a broad spectrum of gram-positive pathogens. The first member of this new class to be commercialized, linezolid, was approved in 2000. Since that time the development of linezolid resistant organisms has prompted efforts to discover more effective members of the oxazolidinone class.

A new family of biaryl oxazolidinone antibacterials with activity against both linezolid-susceptible and -resistant Gram-positive bacteria, as well as certain Gram-negative bacteria has been reported (see Bioorganic & Medicinal Chemistry Letters, 2008, 18, 6175-6178, and PCT Patent Publication WO 2005/019211).

Among the known biaryloxazolidinones is N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-bipheny- l-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide, more commonly known as radezolid (RX-1741), currently being developed for multi-drug-resistant infections.

Although a monohydrochloride salt of radezolid was disclosed in PCT Patent Publication WO 2006/133397, there is a continuing need for new salts and polymorphs thereof having improved properties such as solubility to optimize bioavailability on therapeutic administration.

Radezolid

Synthesis 1

http://www.google.co.il/patents/WO2005019211A2?hl=iw&cl=en

Scheme A

Scheme B illustrates the synthesis of intermediates 7 and 8 of the present invention using Suzuki coupling chemistry between boronic acids and aryl triflates. Boronic ester 6 is treated with an appropriate aryl triflate to yield the BOC-protected biaryl 7. The BOC group of 7 is removed to provide amine 8, an intermediate useful in the synthesis of certain compounds of the present invention.

Scheme B

8, R = NH₂-HCI Scheme C depicts the synthesis of intermediates 9-13, which are useful in producing certain methoxy-substituted biaryl derivatives of the present invention. Suzuki coupling of boronic ester 6 produces biaryl aldehyde 9, which can be reduced to alcohol 10. Mesylation of 10 yields 11 that can be converted to azide 12. Reduction of azide 12 yields amine 13.

Scheme C

Scheme D depicts the synthesis of pyridyl intermediates, which are useful for the synthesis of compounds of the present invention, via similar chemistry to that shown in Scheme C. Coupling of boronic ester 6 to a halopyridine aldehyde produces biaryl aldehyde 14. Aldehyde 14 serves as the precursor to intermediates 15-18 via chemistry described above.

Scheme D

Biaryl aldehyde 19 (Scheme E) can be synthesized from a Suzuki coupling of iodide 1 and 4-formylphenylboronic acid. Scheme E illustrates how intermediate aldehydes of type 19, 9, and 14 can be converted via reductive amination chemistry to other amines, such as amines 20-22, which are useful as intermediates for the synthesis of certain compounds of the invention.

Scheme E

Scheme F depicts the general synthesis of compounds of type la and lb from amines of type 5, 13, 18, and 20-22. Compounds of type la and lb are synthesized via acylation of amines 5, 13 and 18 and 20-22 with the appropriate acids using, for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as the coupling agent. Compounds 4001-4007 were specifically synthesized from amine 5 and the appropriate carboxylic acids. Scheme F

Scheme G highlights the synthesis of compounds of general structure II from amines of type 5 and 18. The amine can be acylated with carboxylic acids using EDCI (or other commonly employed peptide coupling reagents known in the art) to afford amides II.

Acid chlorides can be purchased or synthesized and allowed to react with amines 5 and 18, in the presence of bases such as triethylamine, to also produce amides II.

Alternatively, carboxylic acids can be pre-loaded onto a solid polymeric support, such as a tetrafluorophenol containing resin (TFP resin), and reacted with amines to yield amide products of general structure II (such as compounds 4008-4015).

Scheme G

Scheme H illustrates the synthesis of compounds of general structure Ilia from amines of type 5, 13, and 18 using reductive amination chemistry. For example, biaryl amine compounds 4016-4028 are synthesized in this manner. Scheme H

Scheme I depicts the synthesis of general structure Illb of the present invention from amine intermediate 8. For example, compounds 4029-4031 are synthesized using this reductive amination chemistry.

Scheme I

Scheme J shows the synthesis of compounds of general structure IVa and IVb. Amines 20, 21, and 22 can be converted to tertiary amines IVa, such as compounds 4032-4034 and 4036, using standard reductive amination chemistry employed earlier for other derivatives.

This reductive amination chemistry can be employed on biaryl aldehyde intermediates such as 19, 9, and 14 to yield optionally substituted amines of general structure IVb, illustrated by compound 4037.

Scheme J

producing compounds of the present invention. Known iodoaryl oxazolidinone intermediate 50 (see U.S. Patent Nos. 5,523,403 and 5,565,571) is coupled to a substituted aryl boronic acid (the Suzuki reaction) to produce biaryl alcohol 51. Mesylate 52, azide 53, and amine 54 are then synthesized using chemistry well known to those skilled in the art. Scheme 1

NaN₃, DMF, 70 °C

http://www.google.co.il/patents/WO2005019211A2?hl=iw&cl=en

……………….

NO 2

http://www.google.com/patents/US20100234615

TABLE 1

Compound
Number	Structure


1

Example 1 Synthesis of Compound 1

Compound 1 and its hydrochloride salt are synthesized according to the following Scheme:

4-Methoxybenzyl Azide

1001.

A solution of 4-methoxybenzyl chloride 1000 (51.8 g, 331.0 mmol) in anhydrous DMF (200 mL) was treated with solid sodium azide (21.5 g, 331.0 mmol, 1.0 equiv) at 25° C., and the resulting mixture was stirred at 25° C. for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H₂O (400 mL) and ethyl acetate (EtOAc, 400 mL) at room temperature.

The two layers were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic extracts were washed with H₂O (2×200 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO₄, and concentrated in vacuo. The crude 4-methoxybenzyl azide (51.2 g, 53.95 g theoretical, 94.9% yield) was obtained as colorless oil, which by HPLC and ¹H NMR was found to be essentially pure and was directly used in the subsequent reaction without further purifications. For 4-methoxybenzyl azide 1001:

¹H NMR (300 MHz, CDCl₃) δ 3.84 (s, 3H, ArOCH₃), 4.29 (s, 2H, Ar—CH₂), 6.96 (d, 2H, J=8.7 Hz), 7.28 (d, 2H, J=7.8 Hz).

C-[1-(4-Methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-Methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine

(1003 and 1004).

A solution of 4-methoxybenzyl azide 1001 (61.2 g, 375.5 mmol) in toluene (188 mL) was heated with propargylamine 1002 (commercially available, 30.97 g, 38.6 mL, 563.0 mmol, 1.5 equiv) at 25° C., and the resulting reaction mixture was warmed up to gentle reflux at 100-110° C. for 21 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being concentrated in vacuo to remove the excess amount of propargylamine and solvent.

The oily residue was then treated with 30% ethyl acetate-hexane (v/v, 260 mL), and the resulting mixture was warmed up to reflux and stirred at reflux for 30 min before being cooled down to room temperature for 1 h. The pale-yellow solids were then collected by filtration, washed with 30% ethyl acetate-hexane (v/v, 2×100 mL), and dried in vacuo at 40° C. for overnight to afford the crude, cycloaddition product (78.8 g, 81.75 g theoretical, 96.4%) as a mixture of two regioisomers, C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and 1004), in a ratio of 1.2 to 1 by ¹H NMR.

The crude cycloaddition product was found to be essentially pure and the two regioisomers were not separated before being used directly in the subsequent reaction without further purification. For 1003 and 1004:

¹H NMR (300 MHz, DMSO-d₆) δ 1.82 (br. s, 2H, NH₂), 3.72 and 3.73 (two s, 3H, Ar—OCH₃), 5.47 and 5.53 (two s, 2H, ArCH₂), 6.89 and 6.94 (two d, 2H, J=8.7 Hz, Ar—H), 7.17 and 7.29 (two d, 2H, J=8.7 Hz, Ar—H), 7.58 and 7.87 (two br. s, 1H, triazole-CH); C₁₁H₁₄N₄O, LCMS (EI) m/e 219 (M⁺+H) and 241 (M⁺+Na).

4-({tert-Butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-Butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009).

Method A. A solution of the regioisomeric C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and 1004, 20.0 g, 91.74 mmol) in 1,2-dichloroethane (DCE, 280 mL) was treated with 4-formylphenylboronic acid 1005 (commercially available, 12.39 g, 82.57 mmol, 0.9 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (NaB(OAc)₃H, 29.2 g, 137.6 mmol, 1.5 equiv) was then added to the reaction mixture in three portions over the period of 1.5 h at room temperature, and the resulting reaction mixture was stirred at room temperature for an additional 3.5 h.

When TLC and HPLC/MS showed that the reductive animation reaction was complete, the reaction mixture was concentrated in vacuo. The residue, which contained a regioisomeric mixture of 4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid as the reductive animation products (1006 and 1007), was then treated with tetrahydrofuran (THF, 100 mL) and water (H₂O, 100 mL).

The resulting solution was subsequently treated with solid potassium carbonate (K₂CO₃, 37.98 g, 275.2 mmol, 3.0 equiv) and di-tert-butyl dicarbonate (BOC₂O, 20.02 g, 91.74 mmol, 1.0 equiv) at room temperature and the reaction mixture was stirred at room temperature for 2 h. When TLC and HPLC/MS showed that the N-BOC protection reaction was complete, the reaction mixture was treated with ethyl acetate (EtOAc, 150 mL) and water (H₂O, 100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with H₂O (50 mL), 1.5 N aqueous HCl solution (2×100 mL), H₂O (100 mL), and saturated aqueous NaCl solution (100 mL), dried over MgSO₄, and concentrated in vacuo.

The crude, regioisomeric 4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009, 35.98 g, 37.32 g, 96.4%) was obtained as a pale-yellow oil, which solidified upon standing at room temperature in vacuo.

This crude material was directly used in the subsequent reaction without further purification. For 1008 and 1009:

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 and 1.37 (two br. s, 9H, COOC(CH₃)₃), 3.70, 3.73 and 3.74 (three s, 3H, Ar—OCH₃), 4.07-4.39 (m, 4H), 5.49 and 5.52 (two s, 2H), 6.70-8.04 (m, 9H, Ar—H and triazole-CH); C₂₃H₂₉BN₄O₅, LCMS (EI) m/e 453 (M⁺+H) and 475 (M⁺+Na).

Method B. A solution of the regioisomeric C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine and C-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and 1004, 20.06 g, 92.0 mmol) in tetrahydrofuran (THF, 300 mL) was treated with 4-formylphenylboronic acid (13.11 g, 87.4 mmol, 0.95 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (NaB(OAc)₃H, 29.25 g, 138.0 mmol, 1.5 equiv) was then added to the reaction mixture in three portions over the period of 1.5 h at room temperature, and the resulting reaction mixture was stirred at room temperature for an additional 3.5 h.

When TLC and HPLC/MS showed that the reductive animation reaction was complete, the reaction mixture, which contained a regioisomeric mixture of 4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid as the reductive animation products (1006 and 1007), was then treated with water (H₂O, 200 mL).

The resulting aqueous solution was subsequently heated with solid potassium carbonate (K₂CO₃, 38.0 g, 276 mmol, 3.0 equiv) and di-tert-butyl dicarbonate (BOC₂O, 20.08 g, 92 mmol, 1.0 equiv) at room temperature and the reaction mixture was stirred at room temperature for 2 h. When TLC and HPLC/MS showed that the N-BOC protection reaction was complete, the reaction mixture was treated with ethyl acetate (EtOAc, 150 mL) and water (H₂O, 100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL).

The combined organic extracts were washed with H₂O (50 mL), 1.5 N aqueous HCl solution (2×100 mL), H₂O (100 mL), and saturated aqueous NaCl solution (100 mL), dried over MgSO₄, and concentrated in vacuo. The crude, 4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009, 38.45 g, 39.50 g, 97.3%) was obtained as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. This crude material was found to be essentially identical in every comparable aspect as the material obtained from Method A and was directly used in the subsequent reaction without further purification.

(5S)-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamic acid tert-butyl ester and (5S)-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamic acid tert-butyl ester

(1011 and 1012).

A suspension of the crude regioisomeric mixture of 4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid and 4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronic acid (1008 and 1009, 37.62 g, 83.23 mmol) and N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1010, 28.32 g, 74.9 mmol, 0.90 equiv) in toluene (150 mL) was treated with powder K₂CO₃(34.45 g, 249.7 mol, 3.0 equiv), EtOH (50 mL), and H₂O (50 mL) at 25° C.,

and the resulting mixture was degassed three times under a steady stream of Argon at 25° C. Pd(PPh₃)₄(866 mg, 0.749 mmol, 0.01 equiv) was subsequently added to the reaction mixture, and the resulting reaction mixture was degassed three times again under a stead stream of Argon at 25° C. before being warmed up to gentle reflux for 18 h. When TLC and HPLC/MS showed the coupling reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H₂O (100 mL) and ethyl acetate (100 mL). The two layers were then separated, and the aqueous layer was extracted with EtOAc (100 mL).

The combined organic extracts were washed with H₂O (50 mL), 1.5 N aqueous HCl solution (2×150 mL), H₂O (100 mL), and the saturated aqueous NaCl solution (100 mL), dried over MgSO₄, and concentrated in vacuo. The residual oil was solidified upon standing at room temperature in vacuo to afford the crude, (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-y]methyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamic acid tert-butyl ester (1011) and (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamic acid tert-butyl ester (1012) as a regioisomeric mixture.

This crude product (43.36 g, 49.28 g theoretical, 88%) was used directly in the subsequent reaction without further purification. For the mixture of 1011 and 1012: ¹H NMR (300 MHz, DMSO-d₆) δ 1.35 and 1.38 (two br. s, 9H, COO(CH₃)₃), 1.85 (s, 3H, COCH₃), 3.45 (t, 2H, J=5.4 Hz), 3.73 and 3.76 (two s, 3H, Ar—OCH₃), 3.79 (dd, 1H, J=6.6, 9.1 Hz), 4.18 (t, 1H, J=9.1 Hz), 4.35-4.43 (m, 4H), 4.73-4.81 (m, 1H), 5.50 (br. s, 2H), 6.90 and 6.98 (two d, 2H, J=8.7 Hz), 7.28 and 7.32 (two d, 2H, J=8.7 Hz), 7.35 (dd, 2H, J=2.2, 8.6 Hz), 7.42 (dd, 1H, J=2.2, 8.6 Hz), 7.49-7.63 (m, 4H, aromatic-H), 7.90 and 7.99 (two br. s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH₃); C₃₅H₃₉FN₆O₆, LCMS (EI) m/e 659 (M⁺+H) and 681 (M⁺+Na).

(5S)-N-{3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide Hydrochloride (1013)

and

(5S)-N-{3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H–[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide Hydrochloride (1014).

A solution of a regioisomeric mixture of (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamic acid tert-butyl ester and (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamic acid tert-butyl ester (1011 and 1012, 37.28 g, 56.65 mmol) in ethyl acetate (EtOAc, 150 mL) and methanol (MeOH, 30 mL) was treated with a solution of 4 N hydrogen chloride in 1,4-dioxane (113.3 mL, 453.2 mmol, 8.0 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 12 h. When TLC and HPLC/MS showed that the N-BOC deprotection reaction was complete,

the solvents were removed in vacuo. The residue was then suspended in 250 mL of 5% methanol (MeOH) in acetonitrile (CH₃CN), and the resulting slurry was stirred at room temperature for 1 h. The solids were then collected by filtration, washed with toluene (2×100 mL) and 5% methanol in acetonitrile (2×50 mL), and dried in vacuo to afford a regioisomeric mixture of the crude, (5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride and (5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride (1013 and 1014, 30.0 g, 33.68 g theoretical, 89.1% yield) as off-white crystals in a ratio of 1.2 to 1.

This material was found by ¹H NMR and HPLC/MS to be essentially pure and was directly used in the subsequent reactions without further purification. For the regioisomeric mixture of 1013 and 1014:

¹H NMR (300 MHz, DMSO-d₆) δ 1.84 (s, 3H, COCH₃), 3.44 (t, 2H, J=5.4 Hz), 3.71 and 3.74 (two s, 3H, Ar—OCH₃), 3.80 (dd, 1H, J=6.6, 9.1 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.23-4.30 (m, 4H), 4.73-4.80 (m, 1H), 5.58 and 5.70 (two s, 2H), 6.88 and 6.93 (two d, 2H, J=8.7 Hz), 7.15 and 7.32 (two d, 2H, J=8.7 Hz), 7.43 (dd, 2H, J=2.2, 8.6 Hz), 7.52-7.62 (m, 6H, aromatic-H), 8.28 (s, 1H, triazole-CH), 8.32 (t, 1H, J=5.8 Hz, NHCOCH₃), 9.91 and 10.32 (two br. s, 2H, ArCH₂N⁺H₂); C₃₀H₃₁FN₆O₄, LCMS (EI) m/e 559 (M⁺+H) and 581 (M⁺+Na).

(5S)-N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide hydrochloride (1 hydrochloride salt).

A solution of the crude regioisomeric mixture of (5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride and (5S)-1H-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride (1013 and 1014, 29.17 g, 49.07 mmol) in trifluoroacetic acid(TFA, 150 mL) was warmed up to 65-70° C., and the resulting reaction mixture was stirred at 65-70° C. for 12 h. When TLC and HPLC/MS showed that the deprotection reaction was complete, the solvents were removed in vacuo.

The residual solids were then treated with ethyl acetate (EtOAc, 100 mL) and H₂O (150 mL) before being treated with a saturated aqueous solution of sodium carbonate (30 mL) at room temperature. The resulting mixture was then stirred at room temperature for 1 h before the solids were collected by filtration, washed with EtOAc (2×50 mL) and H₂O (2×50 mL), and dried in vacuo at 40-45° C. to afford the crude, (5S)-N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl)-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1 as the free base, 18.9 g, 21.49 g theoretical, 87.9%) as off-white powders, which by HPLC/MS and ¹H NMR was found to be one pure regioisomer and this regioisomer was found to be identical as the material obtained from deprotection of 1013 alone by the same method.

For 1 as the free base: ¹H NMR (300 MHz, DMSO-d₆) δ 1.85 (s, 3H, COCH₃), 3.44 (t, 2H, J=5.4 Hz), 3.74 (s, 2H), 3.77 (s, 2H), 3.79 (dd, 1H, J=6.4, 9.2 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.72-4.81 (m, 1H), 7.39-7.62 (m, 7H, aromatic-H), 7.73 (s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH₃), 9.72 (br. s, 2H, ArCH₂N⁺H₂), 15.20 (br. s, 1H, triazole-NH); C₂₂H₂₃FN₆O₃, LCMS (EI) m/e 439 (M⁺+H) and 461 (M⁺+Na).

A suspension of 1 free base (18.0 g, 41.1 mmol) in ethyl acetate (EtOAc, 80 mL), and methanol (MeOH, 20 mL) was treated with a solution of 4.0 N hydrogen chloride in 1,4-dioxane (41.1 mL, 164.4 mmol, 4.0 equiv) at room temperature, and the resulting mixture was stirred at room temperature for 8 h. The solvents were then removed in vacuo, and the residue was further dried in vacuo before being treated with a mixture of 10% methanol in acetonitrile (80 mL). The solids were collected by filtration, washed with 10% MeOH/acetonitrile (2×40 mL), and dried in vacuo to afford 1 hydrochloride salt (18.13 g, 19.50 g theoretical, 93% yield) as off-white crystals.

The crude 1 hydrochloride salt can be recrystallized from acetonitrile and water, if necessary, according to the following procedure: A suspension of the crude 1 hydrochloride salt (50.0 g) in acetonitrile (1250 mL) was warmed up to reflux before the distilled water (H₂O, 280 mL) was gradually introduced to the mixture. The resulting clear yellow to light brown solution was then stirred at reflux for 10 min before being cooled down to 45-55° C. The solution was then filtered through a Celite bed at 45-55° C., and the filtrates were gradually cooled down to room temperature before being further cooled down to 0-5° C. in an ice bath for 1 h. The solids were then collected by filtration, washed with acetonitrile (2×50 mL), and dried in vacuo at 40° C. for 24 h to afford the recrystallized 1 hydrochloride salt (42.5 g, 50.0 g theoretical, 85% recovery) as off-white crystals.

For 1: ¹H NMR (300 MHz, DMSO-d₆) δ 1.86 (s, 3H, COCH₃), 3.45 (t, 2H, J=5.4 Hz), 3.84 (dd, 1H, J=6.4, 9.2 Hz), 4.19 (t, 1H, J=9.1 Hz), 4.24 (br. s, 2H), 4.31 (br. s, 2H), 4.74-4.79 (m, 1H), 7.44 (dd, 1H, J=2.2, 8.6 Hz), 7.57-7.66 (m, 6H, aromatic-H), 8.17 (s, 1H, triazole-CH), 8.30 (t, 1H, J=5.8 Hz, NHCOCH₃), 9.72 (br. s, 2H, ArCH₂N⁺H₂), 15.20 (br. s, 1H, triazole-NH);

¹³C NMR (75 MHz, DMSO-d₆) δ 22.57, 40.69, 41.50, 47.36, 49.23, 71.85, 105.70 (d, J=28.5 Hz), 114.14 (d, J=2.9 Hz), 122.29 (d, J=13.3 Hz), 128.82 (d, J=3.0 Hz), 130.70, 130.94, 131.0, 131.22, 135.30, 137.92 (br. s), 139.66 (d, J=11.2 Hz), 154.11, 159.13 (d, J=243.5 Hz), 170.19;

C₂₂H₂₃FN₆O₃—HCl, LCMS (EI) m/e 439 (M⁺+H) and 461 (M⁺+Na).

……………………………..

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 23, 1 December 2008, Pages 6175–6178

http://www.sciencedirect.com/science/article/pii/S0960894X0801192X

Full-size image (49 K)

References

Zhou J, Bhattacharjee A, Chen S, et al. (December 2008). “Design at the atomic level: design of biaryloxazolidinones as potent orally active antibiotics”.Bioorg. Med. Chem. Lett. 18 (23): 6175–8. doi:10.1016/j.bmcl.2008.10.011. PMID 18947996.
Skripkin E, McConnell TS, DeVito J, et al. (October 2008). “Rχ-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance”.Antimicrob. Agents Chemother. 52 (10): 3550–7. doi:10.1128/AAC.01193-07. PMC 2565890. PMID 18663023.
Lawrence L, Danese P, DeVito J, Franceschi F, Sutcliffe J (May 2008). “In vitro activities of the Rχ-01 oxazolidinones against hospital and community pathogens”. Antimicrob. Agents Chemother. 52 (5): 1653–62. doi:10.1128/AAC.01383-07. PMC 2346622. PMID 18316525.
Hanselmann R, Job G, Johnson G, Lou R, Martynow JG, Reeve MM (2009). “Synthesis of an antibacterial compound containing a 1,4-substituted 1H-1,2,3-triazole- a scaleable alternative to the “click” reaction””. Organic Process Research and Development 14: 152–158. doi:10.1021/op900252a.
Franceschi F, Duffy EM (March 2006). “Structure-based drug design meets the ribosome”. Biochem. Pharmacol. 71 (7): 1016–25.doi:10.1016/j.bcp.2005.12.026. PMID 16443192.
Ohlsen K (November 2009). “Novel antibiotics for the treatment of Staphylococcus aureus“. Expert Rev. Clin. Pharmacol. 2 (6): 661–72.doi:10.1586/ecp.09.26.

Radezolid at Rib-X Pharmaceuticals
http://www.unil.ch/webdav/site/cnfmi/shared/abstracts_and_lectures/2009/3__F_van_Bambeke.pdf

Sutcliffe, J.A. Antibiotics in development targeting protein synthesis. Ann. NY Acad. Sci. 2011, 1241, 122–152, doi:10.1111/j.1749-6632.2011.06323.x.
Rib-X. Radezolid. Available online: http://www.rib-x.com/pipeline/radezolid.php#development (accessed on 14 April 2013).
Rib-X Pharmaceuticals, Inc. Safety and efficacy study of oxazolidinone to treat pneumonia. Available online: http://www.clinicaltrials.gov/ct2/show/NCT00640926 (accessed on 14 April 2013).
Rib-X Pharmaceuticals, Inc. Safety and efficacy study of oxazolidinones to treat uncomplicated skin infections. Available online: http://www.clinicaltrials.gov/ct2/show/NCT00646958 (accessed on 14 April 2013).
Shaw, K.J.; Barbachyn, M.R. The oxazolidinones: Past, present, and future. Ann. NY Acad. Sci. 2011, 1241, 48–70, doi:10.1111/j.1749-6632.2011.06330.x.
Skripkin, E.; McConnell, T.S.; DeVito, J.; Lawrence, L.; Ippolito, J.A.; Duffy, E.M.; Sutcliffe, J.; Franceschi, F. Rχ-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance.Antimicrob. Agents Chemother. 2008, 52, 3550–3557, doi:10.1128/AAC.01193-07.

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October 10, 2012

QIDP Designation for Radezolid for Acute Bacterial Skin and Skin Structure Infections, Community-acquired Bacterial Pneumonia

Rib-X Pharmaceuticals announced that the FDA designated radezolid as a Qualified Infectious Disease Product (QIDP) for the indications of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

The QIDP designation will enable Rib-X to benefit from certain incentives for the development of new antibiotics, including an additional five years of market exclusivity, priority review and eligibility for fast-track status, provided under the new Generating Antibiotic Incentives Now (GAIN) program. GAIN was included in the FDA Safety and Innovation Act (FDASIA), formerly known as PDUFA V, which received bipartisan Congressional support and was signed into law by President Obama in July 2012.

Radezolid has completed two Phase 2 clinical trials with an oral formulation in uncomplicated skin and skin structure infections (uSSSI) and in CABP. A Phase 1 study with an IV formulation was recently completed in healthy subjects. Rib-X recently announced data from a positive Phase 1 IV dosing study conducted in healthy subjects and an in vivo long-term safety study vs. linezolid (Zyvox; Pfizer).

Radezolid is a next-generation oxazolidinone with a safety profile permitting long-term treatment of resistant infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

For more information call (203) 624-5606 or visit www.rib-x.com

BC-3781, LEFAMULIN……A Pleuromutilin by Nabriva (Austria) in phase 2

March 31, 2014 5:49 am / 2 Comments on BC-3781, LEFAMULIN……A Pleuromutilin by Nabriva (Austria) in phase 2

Antibiotics 02 00500 i025

BC-3781

Topical pleuromutilin antibiotic agent

Gram-positive, including MRSA, PHASE 2 COMPLETED

Nabriva (Austria)

SEE UPDATED POST AT https://newdrugapprovals.org/2014/10/10/nabrivas-lefamulin-bc-3781-receives-fda-fast-track-status-to-treat-cabp-and-absssi/ ………….C0NTAINS SYNTHESIS

BC-3781
The pleuromutilin BC-3781 belongs to the first generation of pleuromutilins to combine excellent oral
bioavailability with substantial activity against Gram-positive pathogens and atypicals as well as some
Gram-negative pathogens. In particular, BC-3781 is highly active against multi-drug resistant (MDR)
pathogens including methicillin resistant Staphylococcus aureus (MRSA), MDR Streptococcus pneumonia
(i.e. macrolide and quinolone resistance), and vancomycin resistant Enterococcus faecium. It is
characterized by excellent in vivo activities (e.g. pneumonia model), outstanding PK/PD parameters,
allowing once a day dosing, and a novel mode of action. BC-3781 is being developed for both oral and IV
administration and is intended for the treatment of serious multi-drug resistant skin & skin structure
infections (CSSI) and moderate to severe pneumonia (CAP, HAP etc).

Pleuromutilins have been known since 1951, but only entered the market in 2007 with the approval of retapamulin for topical use. Until today, there are no pleuromutilins for systemic use approved in human clinical practice.

Nabriva is currently working on the development of new compounds is this class. The lead compound, BC-3781, if approved, will be the first pleuromutilin for systemic use in humans.

The compound shows potent in vitro activity against a large collection of staphylococci, streptococci, andE. faecium. When compared to linezolid and vancomycin, the compound shows greater overall potency againstS. aureus [121]. BC-3781 shows improved activity against most bacteria commonly associated with community-acquired respiratory tract infections, the compound is especially potent against S. pneumoniaincluding penicillin resistant strains. It also shows improved activity against H. influenza, M. catarrhalis, M. pneumoniae and C. pneumoniae.

BC-3781 is undergoing Phase I clinical trials for CAP and in March of 2011 has completed a Phase II clinical study comparing it to vancomycin for treatment of aBSSSI [119,120,121,122,123]. Nabriva Therapeutics AG announced that the cooperation with Forest Laboratories to develop the compound had elapsed, and that Nabriva retained all rights in BC-3781. The company informed that the product was Phase III ready and that it was seeking partners to continue further development [203].

Nabriva is also developing BC-7013 for topical use against Gram-positive infections and working on the discovery of new pleuromutilins [119,124].

Dr William Prince, CMO Nabriva Therapeutics commented:
“This is the first patient study with a systemic pleuromutilin. It will be an important proof of concept
for an exciting new class of antibiotics. The phase II study builds on our extensive preclinical and
phase I data which have demonstrated that BC-3781 can achieve therapeutically relevant blood and
tissue levels in man with excellent tolerability when administered by either oral or intravenous
routes.”

Dr. David Chiswell, CEO Nabriva Therapeutics commented:
“With a worldwide problem due to antibiotic resistant bacteria, there is a very significant need for
new classes of antibiotics with unique modes of action such as the pleuromutilins. The commercial
prospects for BC-3781 as the leading compound of an exciting new class are excellent, especially as it
has an ideal anti-bacterial spectrum for both skin and respiratory infections and is being developed
with both oral and intravenous formulations”

BC-3781 is highly active against key pathogens, including MRSA, associated with skin infections and
community and hospital acquired pneumonia and is more potent than Linezolid and vancomycin. The
compound’s novel mode of action ensures that it overcomes resistance mechanisms affecting all
approved classes of antibiotics. BC-378

About Nabriva Therapeutics
Nabriva Therapeutics is a biotechnology company focused on developing a new class of antibiotics for
the treatment of serious infections caused by resistant pathogens. Nabriva’s lead systemic product,
BC-3781, is being developed for the treatment of serious skin infections and bacterial pneumonia
caused by S. aureus, , S. pneumoniae, H. influenza, Mycoplasma, Legionella and other bacteria,
including drug resistant strains such as MRSA and vancomycin resistant E. faecium. In addition,
Nabriva Therapeutics’ topical pleuromutilin product candidate, BC-7013, is in clinical phase I. Nabriva
Therapeutics has a proven track record in world-class medicinal chemistry, clinical expertise, a
seasoned management team and solid IP. Nabriva Therapeutics is located in Vienna, Austria.

For more information on Nabriva please visit http://www.nabriva.com.

REF

http://www.phase4-partners.com/wp-content/uploads/2013/09/100412.pdf

http://www.glsv-vc.com/downloads/2010-06-02_First%20Patient_PressRelease.pdf

119

Nabriva. Pleuromutilins. Available online: http://www.nabriva.com/programs/pleuromutilins/ (accessed on 7 December 2012).
120

Forest Laboratories. Our pipeline: Solid, and set for further growth. Available online: http://www.frx.com/research/pipeline.aspx (accessed on 13 April 2013).
121

Sader, H.S.; Biedenbach, D.J.; Paukner, S.; Ivezic-Schoenfeld, Z.; Jones, R.N. Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother. 2012,56, 1619–1623, doi:10.1128/AAC.05789-11.

122
Sader, H.S.; Paukner, S.; Ivezic-Schoenfeld, Z.; Biedenbach, D.J.; Schmitz, F.J.; Jones, R.N. Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs). J. Antimicrob. Chemother. 2012, 67, 1170–1175, doi:10.1093/jac/dks001.

123
Nabriva Therapeutics AG. Study comparing the safety and efficacy of two doses of BC-3781 vs. vancomycin in patients with acute bacterial skin and skin structure infection (ABSSSI). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01119105 (accessed on 13 April 2013).

124
Novak, R. Are pleuromutilin antibiotics finally fit for human use? Ann. NY Acad. Sci. 2011, 1241, 71–81, doi:10.1111/j.1749-6632.2011.06219.x.

valnemulin

retapamulin

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

March 31, 2014 2:27 am / 1 Comment on LCB01-0371……..new oxazolidinone in phase 1 has improved activity against Gram-positive pathogens

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].

read

[PDF]

7. 레고켐(임상).cdr

http://www.kddf.org/common/file/?idx=1669&fname=7._레고켐(임상)…‎

New oxazolidinone LCB01–0371 for MRSA and VRE infection. Young Lag Cho. Company : LegoChem Biosciences, Inc. Website : http://www.legochembio.com.

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]

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]

[Chemical Formula C]

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]

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]

[Scheme 2]

[Scheme 3]

[Scheme 4]

[Scheme 5]

*[Scheme 6]

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

[Example 94] Preparation of Compound 94

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

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

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

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

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

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

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

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

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).

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 al. In vitro and In vivo activities of LCB01–0371, a new oxazolidinone. Antimicrob. Agents Chemother. 2010, 54, 5359–5362, doi:10.1128/AAC.00723-10.
104 LegoChem Biosciences. Multiple ascendoing dose study for LCB01–0371. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01842516 (accessed on 15 August 2013).
http://clinicaltrials.gov/ct2/show/NCT01842516
http://www.pubfacts.com/author/Yong+Zu+Kim
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
[PDF]

7. 레고켐(임상).cdr

http://www.kddf.org/common/file/?idx=1669&fname=7._레고켐(임상)…‎

New oxazolidinone LCB01–0371 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

radezolid

Ranbezolid

Sutezolid

linezolid

A safe, cheap and effective method for slow-freezing human stem cells

March 31, 2014 2:13 am / Leave a comment

Lyra Nara Blog

Human pluripotent stem cells (hPSCs) show great potential and versatility in regenerative medicine and new therapeutic approaches to fight disease. Patient-specific, individualized treatments using stem cells have even been generated for a number of diseases. Although further research into hPSCs is needed in order to harness their full potential, preserving the stem cells and storing them in the large numbers required for research has proved difficult.

Teruo Akuta and colleagues at the RIKEN Center for Developmental Biology, together with scientists from the Foundation for Biomedical Research and Innovation, have now developed a cost-effective, efficient and reliable slow-freezing method for preserving hPSCs in large numbers with a high survival rate.

Vitrification, which involves the use of cryoprotectants to chill cells to low temperatures without freezing, and conventional slow-freezing techniques are currently used for the cryopreservation of hPSCs. “Vitrification using liquid nitrogen is a highly skilled task,” notes Akuta, “and is not…

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Author Archives: DR ANTHONY MELVIN CRASTO Ph.D

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Repurposed drugs for tuberculosis treatment.

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1112968-42-9 cas no

C18 H15 F3 N4 O4

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Scheme G highlights the synthesis of compounds of general structure II from amines of type 5 and 18. The amine can be acylated with carboxylic acids using EDCI (or other commonly employed peptide coupling reagents known in the art) to afford amides II.

Acid chlorides can be purchased or synthesized and allowed to react with amines 5 and 18, in the presence of bases such as triethylamine, to also produce amides II.

Alternatively, carboxylic acids can be pre-loaded onto a solid polymeric support, such as a tetrafluorophenol containing resin (TFP resin), and reacted with amines to yield amide products of general structure II (such as compounds 4008-4015).

Scheme H illustrates the synthesis of compounds of general structure Ilia from amines of type 5, 13, and 18 using reductive amination chemistry. For example, biaryl amine compounds 4016-4028 are synthesized in this manner. Scheme H

Scheme I depicts the synthesis of general structure Illb of the present invention from amine intermediate 8. For example, compounds 4029-4031 are synthesized using this reductive amination chemistry.

Scheme J shows the synthesis of compounds of general structure IVa and IVb. Amines 20, 21, and 22 can be converted to tertiary amines IVa, such as compounds 4032-4034 and 4036, using standard reductive amination chemistry employed earlier for other derivatives.

This reductive amination chemistry can be employed on biaryl aldehyde intermediates such as 19, 9, and 14 to yield optionally substituted amines of general structure IVb, illustrated by compound 4037.

……………….

References

QIDP Designation for Radezolid for Acute Bacterial Skin and Skin Structure Infections, Community-acquired Bacterial Pneumonia

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C₁₈ H₁₅ F₃ N₄ O₄