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Regeneron Pharmaceuticals and Sanofi’s dupilumab has received breakthrough therapy designation from US Food and Drug Administration (FDA) to treat adults with moderate-to-severe atopic dermatitis (AD).

http://www.pharmaceutical-technology.com/news/newsdupilumab-fda-breakthrough-therapy-4446953?WT.mc_id=DN_News

Dutogliptin tartrate
Syn name: 1-[N-[3(R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid L-tartrate
Cas number: 890402-81-0
Molecular Formula: C14H26BN3O9
Molecular Weight: 391.18

DUTOGLIPTIN

[1-[2-(Pyrrolidin-3-ylamino)acetyl]pyrrolidin-2-yl]boronic Acid; [(2R)-1-[2-[[(3R)-Pyrrolidin-3-yl]amino]acetyl]pyrrolidin-2-yl]boronic acid

C₁₀H₂₀BN₃O_3, 241.0951

852329-66-9

• Dutogliptin
• PHX1149
• UNII-38EAO245ZX

clinical trials

http://clinicaltrials.gov/search/intervention=Dutogliptin

PHX-1149 is a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor which had been in phase III clinical trials at Phenomix and Forest for the oral, once-daily treatment of type 2 diabetes.

In 2008, the compound was licensed to Forest by Phenomix in North America for development and commercialization; however this license agreement was terminated in 2010. In 2009, the compound was licensed to Chiesi by Phenomix for development and commercialization for the treatment of diabetes type 2 in Europe, Brazil, the Russian Federation and all other members of the Commonwealth of Independent States, Turkey and Northern Africa. Phenomix ceased operations in 2010.

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WO2010107809A2

http://www.google.com/patents/WO2010107809A2?cl=en

or

http://www.google.com/patents/US20100240611?cl=en

The enzyme dipeptidyl peptidase IV (DPP-IV) is a member of the dipeptidyl peptidase family, which cleaves N-terminal dipeptide residues from proteins, particularly where the dipeptide includes an N-terminal penultimate proline or alanine residue. DPP-IV is believed to be involved in glucose control, as its peptidolytic action inactivates the insulotropic peptides glucagon-like peptide I (GLP-I) and gastric inhibitory protein (GIP).

Inhibition of DPP- IV, such as with synthetic inhibitors in vivo, can serve to increase plasma concentrations of GLP-I and GIP, and thus improve glycemic control in the body. Such synthetic inhibitors would therefore be useful in the treatment of diabetes mellitus and related conditions. Certain such selective DPP-IV inhibitors have been developed, as are disclosed in U.S. Patent 7,317,109, U.S. Patent 7,576,121, U.S. Application Publication Nos. 2007/0060547, 2007/0185061, 2007/0299036, 2008/0182995, 2008/0300413, 2006/0264400, and 2006/0264401, and in International Applications WO2008/027273 and WO2008/144730, the contents of which are incorporated herein by reference. Inhibition of DPP-IV by compounds of the structure of formula (I) is disclosed therein:

Example 1 – Synthesis of (R)-N-( 1 , 1 -Dimethylethoxycarbonyl)(pyrrolidine-2-yl)boronic Acid.

An oven dried 1 L three neck round bottom flask equipped with an overhead stirrer, addition funnel and internal thermocouple was charged with (IS, 2S)-Dimethyl-bis(3,3- dimethylbutyl)cyclohexane-l,2-diamine (approx. 50 g, 161.23 mmol, 1.2 eq), BOC-pyrrolidine (approx. 23.55 ml, 134.35 mmol, 1 eq) and dry toluene (approx. 500 ml) under inert atmosphere. The clear colorless solution was cooled to ^“ 78° C and a solution of sec-BuLi (approx. 115.16 ml of a 1.4 solution in cyclohexane, 161.23 mmol, 1.2 eq) was added slowly via dropping funnel over approx. 10 minutes (the temperature of the reaction mixture was maintained between approx. – 78⁰C and -65⁰C). The light orange colored solution was stirred for 3.5 hours at approx. -78⁰C, which was then followed by the addition of a solution of trimethylborate (approx. 45.06 ml, 403.05 mmol, 3 eq) in toluene (approx. 75 ml) via dropping funnel over 30 minutes while maintaining the temperature below -65⁰C. The reaction mixture was warmed slowly to room temperature, and stirred for 16 hours at room temperature. The reaction mixture was added into an aqueous sodium hydroxide solution (approx. 670 ml of 2.0 M solution, 1340 mmol, 10 eq) and the resulting cloudy mixture was stirred for 30 minutes before allowing layers to separate. The aqueous phase (product) was transferred to a receiver and backwashed with toluene (approx. 100 ml). The organic phases (chiral amine ligand) were transferred to a receiver for later isolation. The aqueous phase was acidified to pH 5-6 by slow addition of HCl {cone), then extracted with EtOAc (approx. 3 x 500 ml). The organic extracts were combined, dried over Na₂SO₄ and concentrated until a final volume of approximately 100 ml. Heptane (approx. 300 ml) was added and the concentrated mixture was stirred at room temperature overnight (approx. 15 hours). The resulting white precipitate was filtered and the filter cake was washed with cold heptane. The product was dried at room temperature under vacuum to yield (R)- (pyrrolidine-2-yl)boronic acid (approx. 20.31 g, 94.44 mmol, 70.27 %) as a white solid. [α]²⁵D – 72.5 (c 1, DCM); 94-95 % ee (% ee was determined through chiral HPLC); ¹H NMR (400 MHz, D₂O) δ 3.40-3.50 (IH), 3.20- 3.30 (IH), 2.90-3.00 (IH), 2.10 (IH), 2.00 (IH), 1.85 (IH), 1.72 (IH), 1.45-1.48 (9H); m/z (ES+) 216.06.

Example 2 – Isolation of the chiral ligand ((1S, 2S)-Dimethyl-bis(3,3-dimethyl butyl) cyclohexane- 1 ,2-diamine)

Water (approx. 300 ml) was added to the first organic extract from the previous workup and cooled to 0° C the mixture was acidified to pH 3 by slow addition of HCl. The resulting cloudy mixture was stirred vigorously before allowing layers to separate. The aqueous phase (product) was transferred to a receiver and backwashed with toluene (approx. 100 ml). The aqueous phase was stirred at O⁰C and the pH of the solution was adjusted to 12-13 by the addition of sodium hydroxide. The mixture was extracted with toluene (approx. 3 x 500 ml) and the combined organic phases were concentrated under reduced pressure to give the crude chiral diamine (approx. 48.32 g, 155.57 mmol, 96.5%) as light yellow oil. Further purification by vacuum distillation (approx. 120-130⁰C, house vacuum) yielded the chiral diamine as a colorless oil (approx. 45.57 g, 146.72 mmol) in 91% recovery).Example 3 – Synthesis of (R)-N-(I, l-dimethylethoxycarbonyl)-pinanediol-(Pyrrolidin-2-yl) boronate

A solution of (R)-Pyrrolidine boronic acid (approx. 300 mg, 1.39 mmol) in isopropyl acetate (approx. 10 ml) was treated with (+)-pinanediol (approx. 236.35 mg, 1.39 mmol, 1 eq) and Na₂SO₄ (approx. 203.25 mg, 1.39 mmol, 1 eq). After 24 hr, the solvent was evaporated to give crude boronic ester (approx. 475.55 mg, 1.36 mmol, 98 %) as a clear oil: 98-99 % de via chiral HPLC; ¹U NMR (400 MHz, CDCl₃) δ 4.32 (IH), 3.47 (IH), 3.41-3.31 (2H), 3.22-3.05 (IH), 2.38- 2.30 (IH), 2.20-1.75 (8H), 1.45 (9H), 1.41 (3H), 1.28 (3H), .85 (3H); m/z (ES, M+l) 350.28.Example 4 – (R)-N-(Pyrrolidine-2-yl)-pinacol boronate

To a solution of pyrrolidine boronic acid (approx. 456 mg, 2.12 mmol) in isopropyl acetate

(approx. 15 ml) was added pinacol (approx. 251 mg, 2.12 mmol, 1 eq) and Na₂SO₄ (approx. 310 mg, 2.12 mmol, 1 eq). The mixture was stirred for 24 hr and the solvent was evaporated to yield crude pinacol boronate. The residue was triturated with EtOAc/hexane (approx. 1 : 10) at RT for 1 hr then filtered to give the pinacol boronate (approx. 611 mg, 2.06 mmol, 97 %) as a white solid: . ¹H NMR (400 MHz, CDCl₃) δ 3.40-2.95 (3H), 1.95-1.50 (4H), 1.40 (9H), 1.20 (12H); m/z (ES+) 298.21. Removal of the Boc-protecting group was achieved by dissolving the white solid pinacol boronate in dry ether (approx. 15 ml), cooling to 0° C in an ice bath followed with addition of 1.5 eq of HCl in dioxane After 8 hours, the solvent was evaporated then triturated in hexane for 1 hr. The white precipitate was filtered and dried to yield the acid salt (approx. 472 mg, 2.02 mmol, 98 %): ¹HNMR (CDCl₃) δ 3.48 (IH), 3.36 (IH), 3.21 (IH), 2.21 (IH), 2.03 (2H), 1.95 (IH), 1.35 (12H); m/z (ES M+l) 198.21.

Example 5 – Synthesis of (R)-3-(Benzyloxycarbonyl-{2-oxo-2-[(R)-2-((lS,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^'”]dec-4-yl)-pyrrolidin-l-yl]-ethyl}-amino)- pyrrolidine- 1-carboxylic acid benzyl ester

A mixture of (R)-3-(benzyloxycarbonyl-carboxymethyl-amino)-pyrrolidine- 1-carboxylic acid benzyl ester dicyclohexylamine salt) (approx. 300.Og, 0.505mol), water (approx. 1.5L), 2M aqueous sulfuric acid (approx. 0.75L, 1.5mol) and toluene (approx. 2L) was stirred in a 1OL reactor at room temperature for 15 min. After settling the layers were separated. The aqueous layer was stirred with toluene (approx. 1.0L) for 15 min, and the layers were separated. The combined organic layers were washed with water (approx. 1.5L), and concentrated under vacuum at 45⁰C to 1.5L. To this solution was added N-methylmorpholine (approx. 55.4 mL, 0.505mol) and this mixture was added to a cold solution (approx. 0°-5°C) of ethyl chloroformate (approx. 48.1 mL, 0.505mol) in toluene (approx. 1.0L). The reaction mixture was stirred at 0° – 5⁰C for 15 min and solid (2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidine hydrochloride) (approx. 144.4g, 0.505mol) was added in one portion followed by addition of N- Methylmorpholine (approx. 110.8 mL, l.Olmol). The mixture was stirred for 30 min at 0°-5°C, and allowed to warm to 20°-25°C. Stirring was continued for an additional 2.5 h. Water (approx. 2.0L) was then added, and the mixture was stirred for an additional 15 min. The layers were separated and the organic layer was subsequently washed with 0.85M aqueous sodium bicarbonate solution (approx. 1.2L), water (approx. 2.0L), and 0.065M citric acid solution (approx. 1.5L). Toluene solution was concentrated under vacuum at 45⁰C, to give 287.3 g (approx. 88.4%) of the title compound. ¹H NMR (400 MHz, CDCl₃, ppm): mixture of rotomers, 7.35-7.25 (10H,m); 5.22- 4.99 (4H,m); 4.60 (IH, d); 4.22 (IH, dd); 4.11-3.65 (3H, m); 3.60-3.00 (6H, m); 2.32-1.91 (8H, m); 1.89-1.67 (4H, m); 1.42-1.18 (6H, m); 0.84-0.72 (3H, m); m/z (M+H)=644. Example 6 – Synthesis of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.0 ‘ ]dec-4-yl)-pyrrolidin- 1 -yl]-ethanone

a) THF solvateA solution of (R)-3-(Benzyloxycarbonyl-{2-oxo-2-[(R)-2-((l S,2S,6R,8S)-2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.0²‘”]dec-4-yl)-pyrrolidin- 1 -yl] -ethyl }-amino)-pyrrolidine- 1 – carboxylic acid benzyl ester (approx. 4.76 g, 7.4 mmol) in toluene (approx. 60 mL) was diluted with methanol (approx. 60 mL). 10% Pd/C (wet, 500 mg) was added, and the mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through celite and washed with methanol (approx. 10 mL). The solution was then concentrated under vacuum to dryness. The residue was dissolved in THF (approx. 10 mL) at 4O⁰C and crystallized overnight at -1O⁰C to -15°C. Crystals were filtered, washed with cold THF (approx. 3 mL), and dried under vacuum for 5 h to yield 1.9 g (approx. 68.5%) of the title compound. ¹H NMR (400 MHz, D₂O, 1 drop TFA), 64.18 – 4.89 (m, IH), 3.93 – 3.85 (m, IH), 3.77 (s, 2H), 3.55 (dd, IH)₅ 3.45 -3.38 (m, 4H), 3.35 – 3.25 (m, 2H), 3.24 – 3.05 (m, 3H), 2.93 (t, IH), 2.33 – 2.24 (m, IH), 2.15 – 1.42 (m, 16H), 1.09 (s, 3H), 0.94 (s, 3H), 0.78 (d, IH), 0.50 (s, 3H). m/z (ES+) = 376.30.

Thermogravimetric analysis of THF solvate of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-

((lS,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidin-l-yl]- ethanone was performed as is shown in Figure 5.

X-Ray Diffractogram of THF solvate of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 6. b) Non-solvate

A solution of (3-(Benzyloxycarbonyl-{2-oxo-2-[2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidin-l-yl]-ethyl}-amino]-pyrrolidine-l-carboxylic acid benzyl ester) (approx. 20.Og, 31.Ommol) in toluene (approx. 8OmL) was diluted with methanol (approx. 20 mL). 10% Pd/C (2g, wet) was added, and the mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through celite and the filter bed was washed with a mixture of toluene (approx. 2OmL) and methanol (approx. 4 mL). The solution was concentrated to 8OmL at 30 -35 ⁰C under vacuum (approx. 90 to 120 mBar). THF (approx. 10OmL) was added and the solution was concentrated to 12OmL at 30 -35 ⁰C under vacuum (approx. 90 to 120 mBar). The mixture was stirred at 35 ⁰C for Ih, resulting in crystallization. The mixture was cooled to 0 ⁰C and held at that temperature for 2h. Crystals were isolated by filtration, washed with a cold mixture of toluene (approx. 20 mL) and THF (approx. 5 mL), and dried under vacuum at 35 ⁰C for 16 h to yield 9.11 g (approx. 24.3 mmol, 78%) of the title compound as a white solid.¹H NMR (400 MHz, D₂0, 1 drop TFA), δ 4.34 (dd, IH, J= 9, 2 Hz), 4.08 (m, IH), 3.99 (s, 2H), 3.74 (dd, IH, J= 13, 8 Hz), 3.52 -3.29 (m, 6H), 3.12 (t, IH, J= 8 Hz), 2.47 (m, IH), 2.27 (m, IH), 2.19 – 2.06 (m, 2H), 2.02 – 1.84 (m, 6H), 1.67 (m, 2H), 1.30 (s, 3H), 1.15 (s, 3H), 1.00 (d, IH, J= 11 Hz), 0.71 (s, 3H). m/z (ES+) = 376.30.

Thermogravimetric analysis of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^'”]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 7.

X-Ray Diffractogram of2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9-trimethyl-

3,5-dioxa-4-bora-tricyclo[6.1.1.0 ‘ ]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 8.

Example 7 – Synthesis of Dutogliptin Tartrate

A round bottom flask equipped with a magnetic stirrer was charged with 2-(Pyrrolidin-3- ylamino)- 1 -[2-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0]dec-4-yl)-pyrrolidin-l-yl]- ethanone (approx. l:l-Pinanediol borane / THF complex; 2.98 g, 6.67 mmol, leq), (L)-tartaric acid (approx. 1.00 g, 6.67 mmol, 1 eq), and H₂O (approx. 15 mL). The mixture was allowed to stir for 1 hour then tert-Butyl methyl ether (approx. 15 ml) and (i?)-N-(l,l- dimethylethoxycarbonyl)(pyrrolidine-2-yl)boronic acid (approx. 1.46 g, 6.80 mmol, 1.02 eq) were added. The bi-phasic mixture was allowed to stir for 20 hours at room temperature before separating the layers. The aqueous phase backwashed with tert-butyl methyl ether (approx. 15 ml) and the organic layers were combined. Lyophilization of the aqueous layer provided dutogliptin tartrate as a white solid (approx. 2.60 g, 6.65 mmol, 99.7%): ¹H NMR (400 MHz, D₂O, one drop of TFA) δ 4.48 (2H), 3.95-3.88 (IH), 3.81 (2H), 3.59-3.54 (IH), 3.37-3.28 (2H), 3.21-3.16 (2H), 3.11-3.07 (IH), 2.82-2.78 (IH), 2.37-2.28 (IH), 2.04-1.96 (IH), 1.88-1.78 (2H), 1.71-1.60 (IH), 1.50-1.42 (IH); m/z (ES+) 241.10 (-tartrate acid).

 

 

 

 

 

 

 

US20060069250 *	Sep 28, 2005	Mar 30, 2006	Xiaohu Deng	Synthesis by chiral diamine-mediated asymmetric alkylation
US20080182995 *	Oct 31, 2007	Jul 31, 2008	Phenomix Corporation	Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv
US20080300413 *	Jul 27, 2006	Dec 4, 2008	David Alan Campbell	Efficiently preparing boropyrrolidines and derivatives by coupling a (pyrrolidin3-yl-amino-)acetic acid and a 7,9,8-dioxaborotricyclic- (4,3,0,1(2,4))decane; protecting groups avert side reactions; antidiabetic agents

 

DENAGLIPTIN

(2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile

1-[2(S)-Amino-3,3-bis(4-fluorophenyl)propionyl]-4(S)-fluoropyrrolidine-2(S)-carbonitrile

GSK-823093, 823093
811432-66-3 CAS TOSYLATE

483369-58-0 (free base)

Denagliptin (GSK-823093) having the structural formula D below is (2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, also named (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile

(D) – A -

Denagliptin is specifically disclosed in US Patent No. 7,132,443 and in WO 03/002531. In one embodiment, denagliptin is in the form of its hydrochloride salt as disclosed in Example 2 of WO 03/002531 or its tosylate salt as disclosed in WO 2005/009956. A class of this embodiment refers to denagliptin tosylate. Crystalline anhydrous denagliptin tosylate is disclosed in WO 2005/009956.

Denagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor which entered phase III clinical trials in 2006 for the treatment of type 2 diabetes at GlaxoSmithKline. Development of this compound was put on hold due to unfavorable preliminary data from preclinical long-term toxicity trials.

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http://www.google.com/patents/US7132443

Example 2

(2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride

A. 3,3-Bis(4-fluorophenyl)-3-hydroxypropanoic acid.

To an anhydrous THF (80 mL) solution of n-butyl lithium (46 mL of 2.5 M, 115 mmol) at 0° C. was added dropwise diisopropylamine (11.13 g, 115 mmol) and the solution stirred for 10 minutes. Keeping the solution at 0° C., acetic acid (2.64 g, 44 mmol) was added dropwise and the mixture stirred for 10 min and it was then heated 50° C. After 30 min a heavy precipitate had formed and the solution was allowed to cool. A solution of 4,4′-diflurobenzophenone (9.6 g, 0.044 mol) in THF (50 mL, anhydrous) was added at 0° C., and the solution stirred at room temperature overnight. Water (100 mL) and diethyl ether (100 mL) were added and the aqueous layer was separated and acidified with 1M HCl to pH 3. The organics were extracted with ethyl acetate (3×200 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a crude white solid that could be washed with cold CHCl₃ to remove trace amounts of the benzophenone. The solid was dried under high vacuum yielding 5.63 g (20.2 mmol, 46% yield) of compound A as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.48–7.39 (m, 4H), 7.19–7.02 (m, 4H), 5.91 (s(br), 1H), 3.25 (s, 2H) ppm.

B. 3,3-Bis(4-fluorophenyl)acrylic acid.

To a 20% solution of sulfuric acid in acetic acid (50 mL, V/V) was compound A (5.6 g, 20.2 mmol) and the mixture stirred for 30 minutes at RT. To this solution was added H₂O (500 mL) and the organics were extracted with ethyl acetate (3×150 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a white solid. The solid was dried under high vacuum yielding 4.97 g (19.1 mmol, 95% yield) of compound B as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 7.27–7.21 (m, 2H), 7.19–7.13 (m, 2H), 7.10–6.95 (m, 4H), 6.26 (s, 1H) ppm.

C. 3,3-Bis(4-fluorophenyl)propanoic acid.

To a solution of compound B (2.5 g, 9.61 mmol) in ethyl acetate (250 mL) was added 10% palladium on carbon (50% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hours. The heterogeneous solution was filtered through celite and concentrated in vacuo to provide a yellow oil. The oil was dried under high vacuum yielding 2.40 g (9.16 mmol, 95% yield) of compound C as a yellow oil.

¹H NMR (d₆-DMSO) 400 MHz δ 12.08 (brs, 1H), 7.40–7.30 (m, 4H), 7.15–7.05 (m, 4H), 4.45 (t, 1H, J=8.1 Hz), 3.05(d, 2H, J=8.1 Hz) ppm.

D. (4S,5R)-3-[3,3-Bis(4-fluorophenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one.

To a THF (50 mL, anhydrous) containing compound C (2.0 g, 7.63 mmol) was added N,N-diisopropylethylamine (1.18 g, 9.16 mmol) and then the solution cooled to −78° C. To this solution was added trimethylacetyl chloride (0.97 g, 8.01 mmol) and the solution warmed to 0° C. over 1 hour. The cloudy mixture was filtered and the filtrate added slowly over 10 min to a solution of the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone at −78° C., which was prepared by the dropwise addition of n-butyl lithium (3.0 mL of 2.5 M, 7.63 mmol) to a THF (50 mL) solution of (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (1.35 g, 7.63 mmol) at −78° C. which had stirred for 10 min to provide the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone. The yellow mixture was warmed to 0° C. and quenched with H₂O (50 mL) and extracted with diethyl ether (3×250 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a solid. Flash chromatography (silica gel, 20% ethyl acetate/hexanes) provided compound D. The white solid was dried under high vacuum yielding 2.31 g (5.49 mmol, 72% yield) as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 7.40–7.25 (m, 9H), 7.18–7.02 (m, 4H), 5.76 (d, 1H, J=7.6 Hz), 4.65 (m, 1H), 4.58 (t, 1H, J=7.6 Hz), 3.72 (dd, 1H, J=16.8, 7.0 Hz) 3.57 (dd, 1H, J=16.8, 7.0 Hz), 0.58 (d, 3H, J=6.7 Hz) ppm.

E. (4S,5R)-3-[(2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoyl]-4-methyl-5-[(1E,3Z)-1-methylhexa-1,3,5-trienyl]-1,3-oxazolidin-2-one.

To a THF (50 mL anhydrous) solution containing compound D (2.0 g, 4.75 mmol) at −78° C. was added dropwise potassium bis(trimethylsilyl)amide (10.0 mL of 0.5 M toluene solution, 4.98 mmol). After stirring for 10 min 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) (1.84 g, 5.94 mmol) in THF (10 mL, anhydrous) was added in one portion. After 3 minutes acetic acid was added (1.31 g, 21.8 mmol) at −78° C. and then the reaction quickly warmed to 30° C. and stirred for 1 hr at that temperature generating a light yellow solution. To this solution was added H₂O (100 mL) and the organics were extracted with ethyl acetate (500 mL). After washing with sat NaHCO₃ (100 mL) and drying over MgSO₄ the solvent was reomved in vacuo yielding a yellow oil. Column chromatography (ethyl acetate/hexanes 1:9) provided compound E as a white solid. HPLC showed a single diastereoisomer. The white solid was dried under high vacuum yielding 1.71 g (3.70 mmol, 78% yield) as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 7.42–7.35 (m, H), 7.25–7.18 (m, H), 7.10–7.06 (m, 2H), 7.05–6.92 (m, 2H), 5.95 (d, 1H, J=10.8 Hz), 5.05 (d, 1H, J=7.1 Hz), 4.60 (d, 1H, J=10.8 Hz), 4.38 (m, 1H), 0.95 (d, 3H, J=6.8 Hz) ppm.

F. (2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoic acid.

To a THF/H₂O (4:1, 50 mL) solution of compound E (1.5 g, 3.25 mmol) at 0° C. was added a solution of lithium hydroxide (0.272 g, 6.49 mmol) in hydrogen peroxide (1.50 mL of 30% soln in H₂O, 48.75 mmol). The mixture was stirred at 0° C. for 1 hr and then quenched with Na₂SO₄ (6.3 g, 50 mL of 1.0 M solution in H₂O). The THF was removed in vacuo and the solution acidified to pH 1 with 6.0 M HCl at 0° C. The organics were extracted with ethyl acetate (2×200 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a clear oil. Column chromatography (EtOAc/hexanes/acetic acid 50:50:1) provided compound F as a white solid. The solid was dried under high vacuum yielding 0.78 g (2.60 mmol, 80% yield) as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 9.60(s(br), 1H), 7.25–7.10 (m, 4H), 7.10–6.95 (m, 4H), 4.50 (d, 2H, J=8.6 Hz) ppm.

G. (2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoic acid.

To an ethyl acetate (250 mL) solution of compound F (1.5 g, 4.95 mmol) was added 10% palladium on carbon (10% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hr. The heterogeneous solution was filtered through celite (1 g) and the filtrate concentrated in vacuo to provide a clear oil. The oil was dried under high vacuum yielding 1.30 g (4.70 mmol, 95% yield) of compound G as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 10.2(s(br), 1H), 7.38–7.27(m, 4H), 7.08–6.98 (m, 4H), 4.25 (d, 1H, J=8.3 Hz), 3.95 (d, 1H, J=8.3 Hz) ppm.

H. (2S)-2-[(tert-Butoxycarbonyl)amino]-3,3-bis(4-fluorophenyl)propanoic acid.

To a CH₂Cl₂ (150 mL) solution containing compound G (1.30 g, 4.69 mmol) was added triethylamine (2.37 g, 23.4 mmol) and di-tert-butyl dicarbonate (1.23 g, 5.63 mmol). After stirring for 12 hr H₂O (50 mL) and CH₂Cl₂ (300 mL) were added and the solution acidified to pH 3 with 1.0 M HCl. Separation of the ethyl acetate layer followed by drying over MgSO₄ and removal of the solvent in vacuo yielded a clear oil. The oil was dried under high vacuum yielding 1.68 g (4.4 mmol, 95% yield) of compound H as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.35–7.22 (m, 4H), 7.15–6.95 (m, 4H), 4.78 (t, 1H, J=8.9 Hz), 4.25 (d, 1H, J=8.9 Hz), 3.05 (m, 1H), 1.20 (s, 3H), 1.15 (s, 6H) ppm.

I. (2S,4S)-1-[(2S)-2-(tert-Butoxycarbonyl)amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile.

To a DMF solution (25 mL anhydrous) was compound H (1.0 g, 2.65 mmol) and HATU (1.0 g, 2.65 mmol). To this solution was added N,N-diisopropylethylamine (0.462 mL, 2.65 mmol) and after 30 min (2S, 4S)-4-fluoro-2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate (0.619 g, 2.12 mmol) and additional N,N-diisopropylethylamine (0.37 mL 2.12 mmol) were added. This solution was allowed to stir at RT for 12 hr and then saturated sodium bicarbonate (100 mL) was added. The resulting gummy mixture was extracted with ethyl acetate (3×100 mL) and the organics were washed with saturated NaCl (50 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a clear oil. The oil was chromatographed on silica gel (hexanes/EtOAc 4:1) to provide a white solid. The solid was dried under high vacuum yielding 815 mg (1.72 mmol, 65% yield) of compound I as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 7.38–7.32 (m, 2H), 7.21–7.15 (m, 2H), 7.12–6.98(m, 4H), 5.15 (d, 1H, J=51 Hz), 5.03 (d, 1H, J=8.9 Hz, 4.89 (d, 1H, J=11.2 Hz), 4.86 (d, 1H, J=8.9 Hz), 4.40 (d, 1H, J=11.2 Hz), 3.83 (ddd, 1H, J=36.8, 12.1, 3.7 Hz), 3.05 (d, 1H, J=12.2 Hz), 2.62 (t, 1H, J=15.3 Hz), 2.25 (m, 1H), 1.38 (s, 9H) ppm.

J. (2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride.

To compound I (0.5 g, 1.05 mmol) was added 4.0 N HCl in 1,4-dioxane (10 mL, 40 mmol) and after 3 hr diethyl ether (100 mL) was added. The resulting precipitate was collected by filtration and after drying under high vacuum 0.41 g (1.0 mmol, 95% yield) of compound J was obtained as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 8.42 (s(br), 3H), 7.72–7.66 (m, 2H), 7.38–7.32 (m, 2H), 7.25–7.19 (m, 2H), 7.06–7.0 (m, 2H), 5.38 (d, 1H, J=51 Hz), 4.91 (d, 2H, J=8.8 Hz), 4.82 (d, 1H, J=11.3 Hz), 4.41 (d, 1H, J=11.3 Hz), 3.86 (ddd, 1H, J=39.2, 12.4, 3.1 Hz), 3.45 (q, 1H, J=12.4 Hz), 2.38–2.20 (m, 2H) ppm.

…………………

PAPER

http://pubs.acs.org/doi/full/10.1021/op900178d

A recent paper from workers at GSK describes improvements to the synthesis of Denagliptin (12). The final chemical step is Boc deprotection of (11) with p-toluenesulphonic acid (p-TSA) in isopropanol (IPA).   Some isolated batches of final product contained impurities 12A (~1%), 12B (~1%), and 12C (~0.3%). Investigation showed that these three impurities were not produced during the reaction but were produced in the dryer if there was any excess p-TSA in the filter cake during drying. These impurities could be avoided by washing the filter cake with 2 volumes of IPA prior to drying.

D.E. Paterson,* J.D. Powers, M. LeBlanc, T. Sharkey, E. Boehler, E. Irdam, and M.H. Osterhout (GlaxoSmithKline), Org. Process. Res. Dev.,2009, 13(5), 900-906.

…………………………….

http://www.google.com.ar/patents/US7462641?cl=pt-PT

(2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt

EXAMPLE 1Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt, Form 1a) Preparation of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide

A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min.

The solid was collected by filtration, washed with heptane (260 mL, 2 vol), and then dried under vacuum at approximately 50° C. to constant weight. Yield: 88-90%.

b) Preparation of (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid

The reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide (116 g, 1 wt, 1 eq.), isopropyl acetate (578 mL, 5 vol), and pyridine (88 mL, 0.8 vol, 2.2 eq). The resulting slurry was stirred at approx. 20° C. Trifluoroacetic anhydride (77 mL, 1.0 wt, 1.1 eq.) was added over at least 30 minutes, maintaining the temperature at approx. 20° C. The reaction solution was stirred an additonal 1 hour at approx. 20° C. Water (578 mL, 5 vol) was added slowly, and the reaction mixture was stirred for 15 minutes. The stirring was stopped, the layers were allowed to separate, and the aqueous (lower) layer was discarded. The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume. The reaction was diluted back up to 5 volumes with isopropyl acetate. The reactor contents were cooled to 20° C., and the reactor was charged with p-toluenesulfonic acid (94 g, 0.8 wt, 1 eq). The reaction was stirred for 2 hours, and GC analysis at this point should show complete consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide. The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added. The reaction was concentrated to a final volume of 4 volumes. The reaction was cooled to 0° C. and held for 30 minutes. The solids were collected by filtration, washed with isopropyl alcohol (1 vol), and then dried under vacuum at approx. 50° C. to constant weight. Yield: 68-71%.

c) Preparation of tert-Butyl{(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate

A reactor was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (400 g, 1 wt, 1 eq.), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid (307.7 g, 0.77 wt, 1.01 eq.), O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexaflurophosphate [i.e. HATU] (408 g, 1.02 wt, 1.01 equiv.), and DMF (2.8L, 7 vol). The mixture was cooled to approximately 0° C. Hunig’s base (376 mL, 0.94 vol, 2.04 equiv.) was added over at least 30 minutes. The mixture was heated to approximately 25° C. and was stirred at this temperature until the reaction was complete (ca. 3 hours). MTBE (2.8L mL, 7 vol) was added, followed by water (2L, 5 vol) over at least 30 minutes to quench the reaction. The aqueous phase was extracted with MTBE (1.2L, 3 vol). The combined organic phases were washed with water (2L, 5 vol). The organic phase was concentrated under vacuum to 3 volumes, and ethanol (1.6L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes, and ethanol (1.6 L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes. Added ethanol (2L, 5 vol). The ethanol solution of tert-Butyl {(1 S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamatewas used directly in the next step.

d) Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt. Form 1

A 10L reactor equipped with overhead stirring was charged with a slurry of tert-Butyl {(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate (500 g, 1 wt, 1 eq) in ethanol (3.5L, 7 vol). To this solution was added para-toluenesulfonic acid (403g, 0.806 wt, 2 eq). This solution was heated to 60° C., and was allowed to stir at this temperature for 12 hours. The reaction mixture was cooled to 5° C. and was stirred at this temperature for 30 minutes. The solids were collected by filtration, washed with ethanol (2×1 L), and dried to constant weight in a 50° C. vacuum oven. Yield: 70-80% over 2 steps.

………………….

Augustyns, K. et al., “The Unique Properties of Dipeptidyl-Peptidase IV (DPP IV/CD26) and the Therapeutic Potential of DPP IV Inhibitors,” Current Medicinal Chemistry, V6, N4, 1999, pp. 311-327.

……………………..

DIABETES

MURAGLITAZAR(CAS-No. 331741-94-7), ROSIGLITAZONE (CAS-NO. 122320-73-4), PIOGLITAZONE (CAS-No. 111025-46-8), RAGAGLITAZAR(CAS-No. 222834-30-2), FARGLITAZAR(CAS-No. 196808-45-4), TESAGLITAZAR(CAS-No. 251565-85-2), NAVEGLITAZAR(CAS-No. 476-436-68-7), NETOGLITAZONE (CAS-NO. 161600-01-7), RIVOGLITAZONE (CAS-No. 185428-18-6), K-111 (CAS-No. 221564-97-2), GW-677954 (CAS-No. 622402-24-8), FK-614 (CAS-No 193012-35-0) and (−)-Halofenate (CAS-No. 024136-23-0).

TABLE 1
INN or Research
Code	Structure/Chemical Name
BIM-51077	L-histidyl-2-methylalanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-
	aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L-
	alanyl-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-
	lysyl-2-methylalanyl-L-argininamide
EXENATIDE	L-histidylglycyl-L-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-leucyl-
	L-seryl-L-lysyl-glutaminyl-L-methionyl-L-glutamyl-L-glutamyl-L-glutamyl-L-alanyl-L-valyl-L-
	arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-
	asparaginylglyclglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-
	serinamide
CJC-1131	L-histidyl-D-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-
	aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L-
	alanyl-L-lysyl-L-alpha-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-
	L-lysylglycyl-L-arginyl-N6-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-
	yl)propionamido]ethoxy]ethoxy]acetyl]-L-lysin-amide
LIRAGLUTIDE	L-histidyl-L-alanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-
	valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L-alanyl-Nepsilon-
	(Nalpha-hexadecanoyl-gamma-L-glutamyl)-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-
	L-tryptophyl-L-leucyl-L-valyl-L-arginyl-glycyl-L-arginyl-glycine
ZP-10	H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-
	Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2
TOLBUTAMIDE
TOLAZAMIDE
GLIPIZIDE
CARBUTAMIDE
GLISOXEPIDE
GLISENTIDE
GLIBORNURIDE
GLIBENCLAMIDE
GLIQUIDONE
GLIMEPIRIDE
GLICLAZIDE
METFORMIN
ACARBOSE
MIGLITOL
VOGLIBOSE
MURAGLITAZAR
ROSIGLITAZONE
PIOGLITAZONE
RAGAGLITAZAR
FARGLITAZAR
TESAGLITAZAR
NAVEGLITAZAR
NETOGLITAZONE
RIVOGLITAZONE
K-111
GW-677954
FK-614
(−)-Halofenate
REPAGLINIDE
NATEGLINIDE
MITIGLINIDE
SITAGLIPTIN
SAXAGLIPTIN
VILDAGLIPTIN
DENAGLIPTIN
P32/98
NVP-DPP-728
SILDENAFIL
VARDENAFIL
TADALAFIL
PRAMLINTIDE	L-lysyl-L-cysteinyl-L-asparaginyl-L-threonyl-L-alanyl-L-threonyl-L-cysteinyl-L-alanyl-L-threonyl-
	L-glutaminyl-L-arginyl-L-leucyl-L-alanyl-L-asparaginyl-L-phenylalanyl-L-leucyl-L-valyl-L-histidyl-
	L-seryl-L-seryl-L-asparaginyl-L-asparaginyl-L-phenylalanylglycyl-L-prolyl-L-isoleucyl-L-leucyl-L-
	prolyl-L-prolyl-L-threonyl-L-asparaginyl-L-valylglycyl-L-seryl-L-asparaginyl-L-threonyl-L-
	tyrosinamide, cyclic (2−>7)disulfide
ETOMOXIR
HMR-1426
CETILISTAT
SIBUTRAMINE

Additional information with regard to the preparation, suitable dosage forms and dose ranges of the glucagon-like-peptide-1 receptor agonists listed in Table 1 can be found in the following patents/patent applications: WO0334331, EP0981611, EP1180121, WO9808871 and WO0104156.

NAVEGLITAZAR

2(S)-Methoxy-3-[4-[3-(4-phenoxyphenoxy)propoxy]phenyl]propionic acid

476436-68-7

C25 H26 O6, 422.4703

• CCRIS 9448
• LY 519818
• LY 9818
• LY519818
• LY9818
• Naveglitazar
• UNII-Y995M7GM0G

http://clinicaltrials.gov/search/intervention=NAVEGLITAZAR

Naveglitazar, a peroxisome proliferator-activated receptor (PPAR) modulator, had been in phase II clinical trials for the once-daily oral treatment of type 2 diabetes, however, no recent development for this indication has been reported. The compound was originally discovered through an ongoing research collaboration between Lilly and Ligand, but, in 2006, Lilly discontinued the development program.

Naveglitazar [LY519818; benzenepropanoic acid, alpha-methoxy-4-[3-(4-phenoxyphenoxy)propoxy], (alpha-S)-] is a nonthiozolidinedione peroxisome proliferator-activated receptor alpha-gamma dual, gamma-dominant agonist that has shown glucose-lowering potential in animal models and in the clinic.

Studies have been conducted to characterize the disposition, metabolism, and excretion of naveglitazar in mice, rats, and monkeys after oral and/or i.v. bolus administration.

………………………………

2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents.

Martín JA, Brooks DA, Prieto L, González R, Torrado A, Rojo I, López de Uralde B, Lamas C, Ferritto R, Dolores Martín-Ortega M, Agejas J, Parra F, Rizzo JR, Rhodes GA, Robey RL, Alt CA, Wendel SR, Zhang TY, Reifel-Miller A, Montrose-Rafizadeh C, Brozinick JT, Hawkins E, Misener EA, Briere DA, Ardecky R, Fraser JD, Warshawsky AM.

Bioorg Med Chem Lett. 2005 Jan 3;15(1):51-5.

………………………………………..

http://www.google.im/patents/US20050020684?cl=un

EXAMPLE 153

′2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid

The title compound was prepared from 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example 152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a manner analogous as in Example 152, Step E. MS (ES) for C₂₅H₂₆O₆[M+NH₄]⁺: 440.2, [M+Na]⁺: 445.2. ¹H-NMR (CDCl₃, 200.15 MHz): 7.33-7.17 (m, 3H), 7.07-6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.25 (qui, 2H, J=5.9)ppm.

NETOGLITAZONE, isaglitazone

161600-01-7

1. 5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl)-2,4-thiazolidinedione
2. MCC 555
3. MCC-555
4. netoglitazone
5. RWJ-241947

Netoglitazone (MCC-555) is a hypoglycemic agent.

Synthesis

US 5594016

http://www.google.co.in/patents/US5594016

Reaction of aldehyde (III) with 2-fluorobenzyl alcohol (VIII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF furnishes 6-(2-fluorobenzyloxy)naphthalene-2-carbaldehyde (IX) , which is then reduced with NaBH4 in ethanol/THF to give the naphthalenemethanol derivative (X). Halogenation of (X) by means of iodide, triphenylphosphine and imidazole in THF yields the naphthylmethyl iodide derivative (XI), which is finally condensed with thiazolidine-2,4-dione (IV) by means of HMPA and butyl lithium in THF.

Ueno, H.; Oe, T.; Suehiro, I.; Nakamura, F. (Mitsubishi Chemical Corp.); Naphthalene derivs.. EP 0604983; JP 1994247945; US 5594016 .

http://www.google.co.in/patents/EP0604983B1?cl=en

References

Sorbera, L.A.; Castañer, J.; Del Fresno, M.; Silvestre, J. (2002). “Netoglitazone”. Drugs of the Future 27 (2): 132.doi:10.1358/dof.2002.027.02.657482.

Netoglitazone

Systematic (IUPAC) name
5-[(6-[(2-fluorophenyl)methoxy]naphthalen-2-yl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Legal status	Uncontrolled
Identifiers
CAS number	161600-01-7
ATC code	?
PubChem	CID 204109
UNII	QOV2JZ647A
KEGG	D05150
Chemical data
Formula	C21H16FNO3S
Mol. mass	381.420 g/mol

Regulators in Europe have given the green light to Eli Lilly’s Trulicity, its once-weekly glucagon-like peptide-1 receptor agonist for type 2 diabetes.

Read more at: http://www.pharmatimes.com/Article/14-11-25/EU_approves_Lilly_diabetes_drug_Trulicity.aspx

Dulaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 agonist) for the treatment of type 2 diabetes that can be used once weekly.^[1][2]GLP-1 is a hormone that is involved in the normalization of level of glucose in blood (glycemia). The FDA approved dulaglutide for use in the United States in September 2014.^[3] The drug is manufactured by Eli Lilly under the brand name Trulicity.^[3]

Mechanism of action

Dulaglutide binding to glucagon-like peptide 1 receptor, slows gastric emptying and increases insulin secretion by beta cells in the pancreas. Simultaneously the compound reduces the elevated glucagon secretion by alpha cells of the pancreas, which is known to be inappropriate in the diabetic patient. GLP-1 is normally secreted by L cells of the gastrointestinal mucosa in response to a meal.^[4]

Medical uses[

The compound is indicated for adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control. Dulaglutide is not indicated in the treatment of subjects with type 1 diabetes mellitus or patients with diabetic ketoacidosis. Dulaglutide can be used either stand-alone or in combination with other medicines for type 2 diabetes, in particular metformin, sulfonylureas, thiazolidinediones, and insulin taken concomitantly with meals.^[5]

Side effects

The most common side effects include gastrointestinal disorders, such as dyspepsia, decreased appetite, nausea, vomiting, abdominal pain, diarrhea.^[6] Some patients may experience serious adverse reactions: acute pancreatitis (symptoms include persistent severe abdominal pain, sometimes radiating to the back and accompanied by vomiting),hypoglycemia, renal impairment (which may sometimes require hemodialysis). The risk of hypoglycemia is increased if the drug is used in combination with sulfonylureas orinsulin.^[7][8]

Contraindications

The compound is contraindicated in subjects with hypersensitivity to active principle or any of the product’s components. As a precautionary measure patients with a personal or family history of medullary thyroid carcinoma or affected by multiple endocrine neoplasia syndrome type 2 should not take dulaglutide, because for now it is unclear whether the compound can increase the risk of these cancers.^[9]

References

Kebuzone (or ketophenylbutazone) is a non-steroidal anti-inflammatory drug.

Structural formula

UV – range

Conditions : Concentration – 1 mg / 100 ml
The solvent designation graphics	Methanol	Water	0.1М HCl	0.1M NaOH
Maximum absorption	244 nm	-	237 nm	262 nm
	448	-	404	617
e	14440	-	13020	19890

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

Reference

Brief background information

Salt	ATC	Formula	MM	CAS
-	M01AA06	C 19 H 18 N 2 O 3	322.36 g / mol	853-34-9

4-(3-oxobutyl)-1,2-di(phenyl)pyrazolidine-3,5-dione
Clinical data
Legal status	?
Identifiers
CAS number	853-34-9
ATC code	M01AA06
PubChem	CID 3824
ChemSpider	3692
UNII	4VD83UL6Y6
KEGG	D01567
ChEBI	CHEBI:31749
Chemical data
Formula	C19H18N2O3
Mol. mass	322.35782 g/mol

 

Application

Synthesis of a)
Synthesis b)

Trade names

Formulations

Reference

Scheme 1: Synthesis of ibuprofen using Silica-Supported Preyssler Nanoparticles (H14[NaP5W30O110]/SiO2) (SPNPs) using ethanol and pyridine in their reactions.

Synthesis of Ibuprofen Using Silica-Supported Preyssler Nanoparticles as an Eco-Friendly, Inexpensive, and Efficient Catalyst,

Organic Chemistry International
Volume 2014 (2014), Article ID 906801, 6 pages

http://dx.doi.org/10.1155/2014/906801

http://www.hindawi.com/journals/oci/2014/906801/

Ali Gharib,1,2 Nader Noroozi Pesyan,3 Leila Vojdani Fard,4 and Mina Roshani1

1Department of Chemistry, Islamic Azad University, Mashhad, Iran
2Agricultural Researches and Services Center, Mashhad, Iran
3Department of Chemistry, Faculty of Science, Urmia University, Urmia 57159, Iran
4Education Organization of Razavi Khorasan, Education Ministry, Mashhad, Iran
Received 5 January 2014; Revised 15 February 2014; Accepted 31 March 2014; Published 6 May 2014
Academic Editor: Jonathan White

Copyright © 2014 Ali Gharib et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This paper describes an alternative and simple procedure for the synthesis of Ibuprofen using Silica-Supported Preyssler Nanoparticles (H14[NaP5W30O110]/SiO2) (SPNPs), as an eco-friendly, inexpensive, and efficient catalyst. High yields, simplicity of operation, and easy work-up procedure are some advantages of this protocol. Silica-Supported Preyssler Nanoparticles (H14[NaP5W30O110]/SiO2) (SPNPs) offer the advantages of a higher hydrolytic and thermal stability. The salient features of Preyssler’s anion are availability, nontoxicity and reusability. We believe this methodology can find usefulness in organic synthesis.

Synthesis of Ibuprofen (6)

To a solution of ethyl-2-(4-isobutylphenyl) propanoate (1 g, 4.27 mmol) in 6 mL of CH3OH a solution of KOH was added (479 mg, 8.55 mmol) in 5 mL of H2O. The resultant solution was stirred at room temperature for 4 h. Methanol was removed under reduced pressure and the resulting solution was extracted with ethyl acetate and the organic extracts were washed with H2O, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 6.

M.P (°C) 130-133,

IR (KBr, cm−1): 3100, 2920, 2870, 1716, 1408, 1419, 1321, 1230, 1184, 935, 779, 668, 583. 1H NMR (400 MHz, CDCl3) 7.15 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 3.64 (q, J = 7.2 Hz, 1H), 2.37 (d, J = 7.1 Hz, 2H), 1.75 (m, 1H), 1.43 (d, J = 7.1 Hz, 3H), 0.82 (d, J = 6.6 Hz, 6H).

13C NMR (100 MHz, CDCl3): 22.81, 22.82, 29.07, 42.64, 44.50, 128.80, 128.93, 128.95, 132.22, 140.23, 181.26. Anal. Calcd. for C13H18O2: C, 75.69; H, 8.80%. Found: C, 75.61; H, 8.70%.

HRMS (EI) Calcd. for C26H25FN4O6 [M]+, 206.1600, Found 206.1009.

ET-743, Yondelis (trabectedin)

Trabectedin, Ecteinascidin 743, NSC-684766, ET-743, Yondelis, ID0YZQ2TCP

cas 114899-77-3

(-)-(1’R,6R,6aR,7R,13S,14S,16R)-5-Acetoxy-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-1′,2′,3′,4′,6a,7,12,13,14,16-decahydro-6H-spiro[6,16-(epithiopropanoxymethano)-7,13-epimino-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′-isoquinolin]-19-one

Janssen seeks FDA approval for Yondelis drug to treat advanced STS

Janssen Research & Development is seeking approval from US Food and Drug Administration (FDA) for its Yondelis (trabectedin) to treat patients with advanced soft tissue sarcoma (STS).

http://www.pharmaceutical-technology.com/news/newsjanssen-yondelis-sts-4451060?WT.mc_id=DN_News

Trabectedin, also referred as ET-743 during its development, is a marine derived antitumoral agent discovered in the Carribean tunicate _Ecteinascidia turbinata_ and now produced synthetically. Trabectedin has a unique mechanism of action. It binds to the minor groove of DNA interfering with cell division and genetic transcription processes and DNA repair machinery.It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.

Trabectedin (also known as ecteinascidin 743 or ET-743) is an anti-tumor drug. It is sold by Zeltia and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.

Discovery and development

The ecteinascidins (herein abbreviated ETs) are exceedingly potent antitumor agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature. See, for example U.S. Pat. No. 5,089,273, which describes novel compounds of matter extracted from the tropical marine invertebrate Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumor agents in mammals. U.S. Pat. No. 5,478,932 describes other novel ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo antitumor activity against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX- I human lung and MX- 1 human mammary carcinoma xenografts.

One of the ETs, ecteinascidin 743 (ET-743), is a tetrahydroisoquinoline alkaloid with considerable in vitro and in vivo antitumor activity in murine and human tumors, and potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma, ovarian and breast carcinoma.

ET-743 is a natural compound with the following structure:

ET-743 is also known with the generic name trabectedin and the trademark Yondelis^®, and it is currently approved in Europe for the treatment of soft tissue sarcoma. The clinical development of trabectedin continues in phase 11/ III clinical trials in breast, ovarian and prostate cancer. A clinical development program of ET-743 in cancer patients was started with phase I studies investigating 1- hour, 3-hour, 24-hour, and 72-hour intravenous infusion schedules and a 1 hour daily x 5 (dx5) schedule. Promising responses were observed in patients with sarcoma, breast and ovarian carcinoma.

Therefore this new drug is currently under intense investigation in several phase 11/ III clinical trials in cancer patients with a variety of neoplastic diseases. Further information regarding the dosage, schedules, and administration of ET-743 for the treatment of cancer in the human body, either given alone or in combination is provided in WO 00/69441 , WO 02/36135, WO 03/39571 , WO 2004/ 105761 , WO 2005/039584, WO 2005/049031 , WO 2005/049030, WO 2005/049029, WO 2006/046080, WO 2006/005602, and PCT/US07/98727, which are incorporated by reference herein in their entirety.

A review of ET-743, its chemistry, mechanism of action and preclinical and clinical development can be found in Kesteren, Ch.

Van et al., Anti-Cancer Drugs, 2003, 14 (7), 487-502: “ET-743 (trabectedin, ET-743): the development of an anticancer agent of marine origin”, and references therein.

During the past 30 years medical oncologists have focused to optimise the outcome of cancer patients and it is just now that the new technologies available are allowing to investigate polymorphisms, gene expression levels and gene mutations aimed to predict the impact of a given therapy in different groups of cancer patients to tailor chemotherapy. Representative examples include the relationship between the Thymidylate Synthase (TS) mRNA expression and the response and the survival with antifolates, beta tubulin III mRNA levels and response to tubulin interacting agents, PTEN gene methylation and resistance to CPT- I l and, STAT3 over expression and resistance to Epidermal Growth Factor (EGF) interacting agents.

A molecular observation of potential clinical impact relates to the paradoxical relation between the efficiency of the Nucleotide Excision Repair (NER) pathway and the cytotoxicity of ET-743. In fact, tumour cells that are efficient in this DNA repair pathway appear to be more sensitive to ET-743. This evidence is in contrast with the pattern noted with platin based therapeutic regimens which are highly dependent on the lack of activity of this repair pathway (ie. an increase in ERCCl expression has been associated to clinical resistance to platinum-based anti-cancer therapy).

There are evidences on the key role of NER pathways on the cytotoxicity of ET-743 in cell lines. ET-743 binds to G residues in the minor groove of DNA forming adducts that distort the DNA helix structure and they are recognised by NER mechanisms (Pourquier, P. et al., 2001 , Proceedings of the American Association for Cancer Research Annual Meeting, Vol. 42, pp. 556. 92nd Annual Meeting of the American Association for Cancer Research. New Orleans, LA, USA. March 24-28, 2001. ISSN: 0197-016X). Takebayasi et al. (Nature Medicine, 2001 , 7(8), 961-966) have proposed that the presence of these DNA adducts in transcribed genes, blocks the Transcription Coupled NER (TC-NER) system by stalling the cleavage intermediates and producing lethal Single Strand Breaks (SSBs). It is known from Grazziotin et al (Proc.Natl.Acad.Sic.USA, 104: 13062- 13067) that the DNA adducts formed by exposure to ET-743 are transformed into double strand DNA breaks.

The fact that NER mediates ET-743 ‘s cytotoxicity has also been found in the yeast Saccharomyces cerevisae by Grazziotin et al. (Biochemical Pharmacology, 2005, 70, 59-69) and in the yeast Schizosaccharomyces pombe by Herrero et al. (Cancer Res. 2006, 66(16), 8155-8162).

In addition, Bueren et al. (Proceedings AACR Annual Meeting 2007, Abstract no. 1965) have been shown that ET-743 induces double-strand breaks in the DNA in early S phase that are detected and repaired by the Homologous Recombination Repair (HRR) pathway. In addition, Erba et al (Eur. J. Cancer, 2001 , 37(1), 97- 105) and Bueren et al (Proceedings AACR Annual Meeting 2007, Abstract no. 1965) have shown that inactivation/ mutations of genes related to the Double Strand Break detection such as DNA-PK, ATM and ATR and of genes related to Homologous Recombination Repair pathway, such as Fanconi Anemia genes, BRCAl , BRCA2 and RAD51 make cells more sensitive to trabectedin. Such unique finding is the opposite to the pattern with conventional DNA interacting agents, like in the case of microtubule poisons such as taxanes and vinorelbine.

Finally, pharmacogenomic studies prior have demonstrated that increased expression of the NER genes ERCCl and XPD in the tumor tissue does not impact the outcome of patients treated with

ET-743. However, the low expression of BRCAl in the tumor tissue is correlated with a better outcome in cancer patents treated with

ET-743. Further information can be found in WO 2006/005602, which is incorporated by reference herein in its entirety.

Three rare, autosomal recessive inherited human disorders are associated with impaired NER activity: xeroderma pigmentosum (XP), Cockayne Syndrome (CS), and trichothiodystrophy (Bootsma et al. The Genetic Basis of Human Cancer. McGraw-Hill, 1998, 245- 274). XP patients exhibit extreme sensitivity to sunlight, resulting in a high incidence of skin cancers (Kraemer et al. Arch. Dermatol. 123, 241-250, and Arch. Dermatol. 130, 1018- 1021). About 20% of XP patients also develop neurologic abnormalities in addition to their skin problems. These clinical findings are associated with cellular defects, including hypersensitivity to killing and mutagenic effects of UV, and inability of XP cells to repair UV-induced DNA damage (van Steeg et al. MoI. Med. Today, 1999, 5, 86-94).

Seven different NER genes, which correct seven distinct genetic XP complementation groups (XPA-XPG), have been identified (Bootsma et al. The Genetic Basis of Human Cancer. McGraw-Hill, 1998, 245-274). The human gene responsible for XP group G was identified as ERCC5 (Mudgett et al. Genomics, 1990, 8, 623-633; O’Donovan et al. Nature, 1993, 363, 185- 188; and Nouspikel et al. Hum. MoI. Genet. 1994, 3, 963-967). The XPG gene codes for a structure-specific endonuclease that cleaves damaged DNA ~5 nt 3′ to the site of the lesion and is also required non-enzymatically for subsequent 5′ incision by the XPF/ ERCCl heterodimer during the NER process (Aboussekhra et al. Cell, 1995, 80, 859-868; Mu et al. J. Biol. Chem. 1996, 271 , 8285-8294; and Wakasugi et al. J. Biol. Chem. 1997, 272, 16030- 16034). There is also evidence suggesting that XPG is also involved in transcription-coupled repair of oxidative DNA lesions (Le Page et al. Cell, 101 , 159- 171).

Takebayashi et al. (Cancer Lett., 2001 , 174: 1 15- 125) have observed an increase in heterozygosity loss and microsatellite instability in a substantial percentage of samples of ovarian, lung and colon carcinoma. Le Moirvan et al, (Int.J. Cancer, 2006,1 19: 1732- 1735) have described the presence of polymorphisms in the XPG gene in sarcoma patients. It is also known from Takebayashi et al. (Proceedings of the American Association forCancer Research Annual Meeting, March, 2001 , Vol. 42, pp. 813.92nd Annual Meeting of the American Association for Cancer

Research. New Orleans, LA, USA. March 24-28, 2001) that cells deficient in the NER system are resistant to treatment with ET-743 (Zewail-Foote, M. et al., 2001 , Chemistry and Biology, 8: 1033- 1049 and Damia, G. et al., 2001 , Symposium AACR NCI EORTC) and that the antiproliferative effects of ET-743 require a functional XPG gene.

Since cancer is a leading cause of death in animals and humans, several efforts have been and are still being undertaken in order to obtain an antitumor therapy active and safe to be administered to patients suffering from a cancer. Accordingly, there is a need for providing additional antitumor therapies that are useful in the treatment of cancer.

Trabectedin is a tetrahydroisoquinoline, a novel marine-derived antitumor agent isolated from the colonial tunicate Ecteinascidia turbinate. The drug binds to the minor groove of the DNA, bending the DNA towards the major groove, blocking the activation of genes in a unique way via several pathways, including selective inhibition of the expression of key genes (including oncogenes) involved in cell growth and drug resistance, inhibition of genetic repair pathways and inhibition of cell cycle progression leading to p53-independent programmed cell death.

In July 2003, the European Committee of Proprietary Medicinal Products (CPMP) recommended against granting marketing authorization to trabectedin for soft tissue sarcoma. PharmaMar appealed the decision in September 2003. Later that year, the CPMP rejected the company’s appeal. In 2006, the company filed another regulatory application for this indication and, finally, in 2007, a positive opinion was received in the E.U. for the treatment of metastatic soft tissue sarcoma. First commercialization of the product in the E.U. took place in October 2007 in the U.K. and Germany.

The compound is also available in several other countries. In 2008, the compound was filed for approval in the U.S. and the E.U. for the treatment of relapsed advanced ovarian cancer in combination with liposomal doxorubicin, and in 2009 approval was received in both countries. Trabectedin is available in several European countries, including the U.K. and Germany. Also in 2009 the drug candidate was approved in Philippines for the ovarian cancer indication.

The compound had been in phase II development by Johnson & Johnson for the treatment of prostate cancer; however, no recent development has been reported for this research. PharmaMar is evaluating the compound in phase II trials for the treatment of breast cancer. Additional early clinical trials are ongoing at the National Cancer Institute (NCI) to evaluate trabectedin for potential use in the treatment of advanced, persistent or recurrent uterine leiomyosarcomas and solid tumors.

In 2011, a regulatory application that had been filed in the U.S. seeking approval for the treatment of relapsed advanced disease in combination with liposomal doxorubicin was withdrawn by the company based on the FDA’s recommendation that an additional phase III study be conducted to obtain approval. In 2014, Janssen Research & Development, LLC submitted an NDA for trabectedin to the FDA for the treatment of patients with advanced soft tissue sarcoma (STS), including liposarcoma and leiomyosarcoma subtypes, who have received prior chemotherapy including an anthracycline.

Trabectedin was developed by PharmaMar, a subsidiary of Zeltia. The drug was being codeveloped and comarketed in partnership with Ortho Biotech, a subsidiary of Johnson & Johnson pursuant to an agreement signed in 2001. However, in 2008 the license agreement between the two companies was terminated.

The compound was granted orphan drug designation for the treatment of soft tissue sarcoma and for the treatment of ovarian cancer by the FDA and the EMEA. In 2011, orphan drug designation was granted in Japan for the treatment of malignant soft tissue tumor accompanied with chromosomal translocation. In 2009, the product was licensed to Taiho by PharmaMar in Japan for the treatment of cancer.

During the 1950s and 1960s, the National Cancer Institute carried out a wide ranging program of screening plant and marine organism material. As part of that program extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.^[1] Separation and characterisation of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984.^[2] Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.^[3]

Recently, the biosynthetic pathway responsible for producing the drug, has been determined to come from Candidatus Endoecteinascidia frumentensis, a microbial symbiont of the tunicate.^[4] The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994 and attempted to farm the sea squirt with limited success.^[3]

Yields from the sea squirt are extremely low – it takes 1 tonne of animals to isolate 1 gram of trabectedin – and about 5 grams were believed to be needed for a clinical trial^[5] so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996.^[6] This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.^[3] The current supply is based on a semisynthetic process developed by PharmaMar starting from Safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens.^[7] PharmaMar have entered into an agreement with Johnson and Johnson to market the compound outside Europe.

Trabectedin was first dosed in humans in 1996.In 2007, the EMEA gave authorisation for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The agency’s evaluating committee, the CHMP observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized trial against current best care, and that the clinical efficacy data was mainly based on patients with liposarcoma and leiomyosarcoma. However the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease the CHMP considered that marketing authorisation could be granted under exceptional circumstances.^[8] As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.^[9] Trabectedin is also approved in South Korea^[10] and Russia.

In 2008 the submission was announced of a registration dossier to the European Medicines Agency (EMEA) and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson&Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional Phase III study to be done in support of the submission.^[11]

Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.^[12]

Structure

Trabectedin is composed of 3 tetrahydroisoquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cysteine residue, and 7 chiral centers.

Biosynthesis

The biosynthesis of Trabectedin in Candidatus Endoecteinascidia frumentensis starts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids. A tyrosine residue is modified by the enzymes EtuH, EtuM1, and EtuM2 to add a hydroxyl at the meta position of the phenol, and adding two methyl groups at the para-hydroxyl and the meta carbon position. This modified tyrosine reacts with the original substrate via a Pictet-Spangler reaction, where the amine group is converted to an imine by deprotonation, then attacks the free aldehyde to form a carbocation that is quenched by electrons from the methyl-phenol ring. This is done in the EtuA2 T-domain. This reaction is done a second time to yeid a dimer of modified tyrosine residues that have been further cyclized via Pictet-spangler reaction, yielding a bicyclic ring moiety. The EtuO and EtuF3 enzymes continue to post-translationally modify the molecule, adding several functional groups and making a sulfide bridge between the original cysteine residue and the beta-carbon of the first tyrosine to form ET-583, ET-597, ET-596, and ET-594 which have been previously isolated.^[4] A third o-methylated tyrosine is added and cyclized via Pictet-Spangler to yield the final product.^[4]

Synthesis

The total synthesis by E.J. Corey used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine-catalyzed enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.

Org Lett 2000,2(7),993

The previously reported synthesis of 139221 (scheme 13922101a) has been investigated in order to find a more efficient, reproducible and economical route to work in the mutikilogram scale. Herein it is reported a new process which is simpler and proceeds with an overall yield of 54% (the original process, 35%). The condensation of intermediate aminolactone (I) (scheme 13922101a, intermediate (VII)) with acid (XLII) (the acid derived from scheme 13922101a, intermediate ester (IX)) by means of 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), and 1-hydroxy-7-azabenzotriazole (HOAt) in THF/dichloromethane gives the coupling product (XLIII), which is allylated with allyl bromide (XLIV) and Cs2CO3 in DMF yielding the allyl ether (XLV). The reduction of the lactone group of (XLV) with LiAlH2(OEt)2 in ethyl ether affords the lactol (XLVI), which is desilylated with KF in methanol to provide the phenolic compound (XLVII). The opening of the lactol ring of (XLVII) with simultaneous cyclization by means of Tf-OH in water/trifluoroethanol gives the hexacyclic intermediate (XLVIII), which is finally reductocondensed with KCN by means of LiAlH2(OEt)2 in THF to furnish the previously reported pentacyclic intermediate (XI) (scheme 13922101a, intermediate (XI)).

……………………………………………

Reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino-protected compound (II), which is treated with methoxymethyl bromide (MOM-Br), DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF to provide compound (V). Reaction of (V) with allyl bromide (VI) and Cs2CO3 in DMF gives the allyl ether (VII), which first is treated with TFA, phenyl isothiocyanate and HCl to yield the primary amine (VIII) and then protected at the free NH2 group with Troc-Cl and pyridine, to afford the amino protected compound (IX).Org Lett 2000,2(16),2545

……………………………….

Reaction of (IX) with MOM-Br and DIEA as before affords the ether (X), which is treated with Zn/HOAc in order to regenerate the primary amino group giving (XI). The reaction of (XI) with NaNO2 and HOAc eliminates the NH2 group, affording the primary alcohol (XII), which is esterified with the protected (S)-cysteine (XIII) by means of EDC and DMAP in dichloromethane furnishing the cysteine ester (XIV). Reaction of (XIV) with Bu3SnH and PdCl2(PPh3)2, followed by oxidation with (PhSeO)2O in dichloromethane gives the hydroxyketone (XV), which is cyclized with Tf2O and Ac2O yielding the heptacyclic compound (XVI). Elimination of the MOM protecting group with TMSCl and NaI in CH3CN/CH2Cl2 affords the phenolic compound (XVII).

…………………….

Intermediate (XVII) by a treatment with Zn and HOAc eliminates the Troc protecting group, giving the primary amine (XVIII). This compound by treatment with 4-formyl-1-methylpyridinium iodide (NMPC), DBU and oxalic acid in order to convert the nitrile group into an alcohol, provides compund (XIX), which is finally cyclized with 2-(3-hydroxy-4-methoxyphenyl)ethylamine (XX) by means of SiO2 / EtOH, followed treatment with and AgNO3 in acetonitrile/water.

……………………….

The reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino protected compound (II), which is treated with Mom-Br, DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF providing the methylenedioxy compound (V). The reaction of (V) with acetyl chloride and pyridine in dichloromethane gives the acetate (VI), which is treated with TFA, phenyl isothiocyanate and HCl yielding the primary amine (VII). Finally, this compound is treated with phthalic anhydride (VIII) and CDI in dichloromethane to afford the target phthalimide (phthalascidin Pt-650)

………………………………

http://pubs.acs.org/doi/abs/10.1021/ol0056729

Mechanism of action

The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes ‘activated’ into its reactive oxazolidine form.

Schematic of the unique and complex mode of action of trabectedin. The antitumor effects of trabectedin are due to multiple mechanisms involving DNA binding in the minor groove, interactions with DNA repair mechanisms, modulation of transcription regulation, and induction of microenvironment changes.

References

Trabectedin

Systematic (IUPAC) name
(1′R,6R,6aR,7R,13S,14S,16R)-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-19-oxo-3′,4′,6,7,12,13,14,16-octahydrospiro[6,16-(epithiopropano-oxymethano)-7,13-imino-6aH-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′(2′H)-isoquinolin]-5-yl acetate
Clinical data
AHFS/Drugs.com	International Drug Names
Licence data	EMA:Link
Legal status	UK: POM
Routes	Intravenous
Pharmacokinetic data
Bioavailability	Not applicable (IV only)
Protein binding	94 to 98%
Metabolism	Hepatic (mostly CYP3A4-mediated)
Half-life	180 hours (mean)
Excretion	Mostly fecal
Identifiers
CAS number	114899-77-3
ATC code	L01CX01
PubChem	CID 108150
IUPHAR ligand	2774
DrugBank	DB05109
ChemSpider	16736970
UNII	ID0YZQ2TCP
Chemical data
Formula	C39H43N3O11S
Mol. mass	761.84 g/mol

……..

1  Corey, “Enantioselective Total Synthesis of Ecteinascidin 743“, J. Am. Chem. Soc. 1996, vol. 118, 9202-9203.

Cefditoren pivoxil

ME-1207, Spectracef, Meiact

117467-28-4

1. (-)-(6R,7R)-2,2-dimethylpropionyloxymethyl 7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido)-3-((Z)-2-(4-methylthiazol-5-yl)ethenyl)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylate
2. 7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-(2-(4-methylthiazol-5-yl)ethenyl)cephem-4-carboxylic acid pivaloyloxymethyl ester
3. CDTR-PI
4. cefditoren pivoxil
5. ME 1207
6. ME-1207
7. Spectracef

Novel crystalline form of cefditoren pivoxil (first disclosed in EP175610). Represents Yungjin Pharma’s first interest in this API, which was developed and launched by Meiji Seika and previous licensee TAP Pharmaceuticals, and now marketed by Merus Labs, for treating chronic bronchitis and community acquired pneumonia caused by bacterial infections

Cefditoren is a third-generation cephalosporin antibiotic for oral use. It is commonly marketed under the trade name Spectracef by Vansen Pharma Inc.

Cefditoren is also marketed under the name Meiact by Meiji Seika Pharma Co., Ltd.^[1]

Spectrum of bacterial susceptibility

Cefditoren has a broad spectrum of activity and has been used to treat bacterial infections of the skin and respiratory tract, including bronchitis, pneumonia, and tonsillitis. The following represents MIC susceptibility data for a few medically significant microorganisms.

• Haemophilus influenzae: ≥0.063 – 0.25 μg/ml
• Staphylcoccus aureus: 0.25 – >128 μg/ml (includes MRSA)
• Streptococcus pyogenes: ≤0.004 – 2 μg/ml^[2]

Cefditoren is a broad-spectrum antibiotic against Gram-negative and Gram-positive bacteria, but does not have antibacterial activity against Pseudomonas aeruginosa.^[3]

Clinical use

Indications

Cefditoren is used to treat uncomplicated skin and skin structure infections, community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, pharyngitis, and tonsillitis.

Formulations

Cefditoren is available as 200- and 400-mg tablets. It can be formulated as the prodrug cefditoren pivoxil.

Chemical structure of cefditoren pivoxil

References

External links

• Manufacturer’s Product website
• Manufacturer’s prescribing information for Spectracef

Cefditoren

Systematic (IUPAC) name
(7R)-7-((Z)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Clinical data
Trade names	Spectracef
AHFS/Drugs.com	monograph
MedlinePlus	a605003
Legal status	?
Identifiers
CAS number	104145-95-1
ATC code	J01DD16
PubChem	CID 9870843
DrugBank	DB01066
ChemSpider	8046534
UNII	81QS09V3YW
Chemical data
Formula	C19H18N6O5S3
Mol. mass	506.58 g/mol

NEW PATENT

WO-2014189308, Yungjin Pharmaceutical Co Ltd

A novel, practical, and efficient synthesis of (−)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate (YM758 monophosphate, (R)-1·H₃PO₄ (Figure 1) is described. The target molecule (R)-1 has a potent I_f current channel inhibitor. Medicinal chemistry synthetic routes were very long and suffered from extensive use of chlorinated solvents and silica-gel column chromatography. A number of steps in the medicinal chemistry route were also unattractive for large-scale synthesis due to some reasons for example the use of unstable intermediates.

An important objective of a new synthetic route was avoidance of such a use of unstable intermediate, and it was achieved by the discovery of an important 4,5-dihydrooxazole intermediate 19 and ring-opening N-alkylation of chiral amine with 19 under acidic condition. The new procedure does not require any purification by column chromatography for all steps.

The overall yield was significantly improved from 14% or 34% to 49% compared to that of the medicinal synthetic routes. This highly efficient process was successfully demonstrated at a pilot-scale operation, yielding 36.5 kg of (R)-1·H₃PO₄.

(−)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide Monophosphate (YM758 Monophosphate, (R)-1·H₃PO₄)

((2R,3aR,6aR)-2-((3R,4R)-3-Methoxytetrahydro-2H-pyran-4-ylamino)octahydropentalen-3a-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

((2R,3aR,6aR)-2-((3R,4R)-3-Methoxytetrahydro-2H-pyran-4-ylamino)octahydropentalen-3a-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone Semisuccinate

D-​erythro-​Pentitol, 1,​5-​anhydro-​3,​4-​dideoxy-​3-​[[(2R,​3aR,​6aR)​-​3a-​[[7,​8-​dihydro-​3-​(trifluoromethyl)​-​1,​6-​naphthyridin-​6(5H)​-​yl]​carbonyl]​octahydro-​2-​pentalenyl]​amino]​-​2-​O-​methyl-​, rel-

cas 1416178-01-2

Abbott Laboratories, Abbott Laboratories Trading (Shanghai) Company, Ltd.

Antagonists of the CC-chemokine receptor 2 (CCR-2) have been vigorously pursued by a number of pharmaceutical companies as a target for drug discovery, in that compounds could have the potential for use in the acute and chronic conditions of inflammatory and autoimmune diseases associated with infiltration of monocytes, macrophages, lymphocytes, dendritic cells, NK cells, eosinophils, basophils, natural killer (NK cells), and memory T-cells. A compound of interest that was discovered in the Janssen laboratories that met the initial criteria set out during the in vitro screening phase of drug discovery was bicyclic 1

Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract leukocytes, as illustrated by macrophages, T cells, B cells, eosinophils, basophils, and neutrophils to and from sites of inflammation or within specific compartments, as illustrated by lymph nodes (reviewed in Schall, Cytokine 1991 ; 3: 165- 183; Schall, et al., Curr. Opin. Immunol. 1994; 6:865- 873; and Murphy, Rev. Immun. 1994; 12:593-633). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca²⁺]), granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes), and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early modulators of inflammatory response, effecting inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.

There are four classes of chemokines, CXC (a), CC (β), C (γ), and CX₃C (δ), depending on whether the first two cysteines are separated by a single amino acid (C-X- C), are adjacent (C-C), have a missing cysteine pair (C), or are separated by three amino acids (CX₃C). The a-chemokines, such as interleukin-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-1) are chemotactic primarily for neutrophils and lymphocytes, whereas β-chemokines, such as RANTES, ΜΙΡ-Ια, ΜΙΡ- Ι β, monocyte chemotactic protein- 1 (MCP-1), MCP-2, MCP-3, and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Naturel996; 381 :661-666). The C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al., Science 1994; 266: 1395-1399) while the CX₃C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al., Nature 1997; 385:640-644).

Chemokines bind specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends

Pharm. Sci. 1994; 15: 159-165) termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated heterotrimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least twelve human chemokine receptors that bind or respond to β-chemokines with the following characteristic pattern: CCR1 (or “CKR-1 ” or “CC- CKR-1 “) ΜΙΡ-Ια, ΜΙΡ-Ι β, MCP-3, RANTES (Ben-Barruch, et al., J. Biol. Chem. 1995; 270:22123-22128; Neote, et al., Cell 1993; 72:415425); CCR2A and CCR2B (or “CKR- 2A’7″CKR-2A” or “CC-CKR-2A”/”CC-CKR2A”) MCP-1, MCP-2, MCP-3, MCP-4; CCR3 (or “CKR-3″ or “CC-CKR-3″) eotaxin, RANTES, MCP; (Ponath, et al., J. Exp. Med. 1996; 183:2437-2448); CCR4 (or “CKR-4″ or “CC-CKR-4″) TARC, MDC (Imai, et al., J. Biol. Chem. 1998; 273: 1764- 1768); CCR5 (or “CKR-5″ or “CC-CKR-5″) MIP- la, RANTES, MIP-Ι β; (Sanson, et al., Biochemistry 1996; 35:3362-3367); CCR6 MIP-3a (Greaves, et al., J. Exp. Med. 1997; 186:837-844); CCR7 ΜΙΡ-3β and 6Ckine (Campbell, et al., J. Cell. Biol. 1998; 141 : 1053- 1059); CCR8 I- 309, HHV8 vMIP-I, HHV-8 vMIP-II, MCV vMCC-I (Dairaghi, et al., J. Biol. Chem. 1999; 274:21569-21574); CCR9 TECK (Zaballos, et al., J. Immunol. 1999; 162:5671-5675), D6 MIP-1 beta, RANTES, and MCP-3 (Nibbs, et al., J. Biol. Chem. 1997; 272:32078-32083), and the Duffy blood-group antigen RANTES, MCP-1 (Chaudhun, et al., J. Biol. Chem. 1994; 269:7835-7838).

Chemokine receptors, such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX₃CR1, and XCRl have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

The CCR2 chemokine receptor is expressed primarily in monocytes and activated T lymphocytes, and its functional activity can be measured by cytosolic calcium elevation or chemotaxis. CCR2 exists in two isoforms, CCR2A and CCR2B. These two isoforms are alternatively spliced variants of a single MCP- 1 receptor gene and differ only in the carboxyl-terminal tails. The chromosomal location of the CCR2 gene is localized to

3p21. The CC chemokines, MCP-1, MCP-2, MCP-3, and MCP-4, have been identified as the ligands that are selective and of high affinity to the CCR2 receptor.

The highly selective expression of CCR2 makes it an ideal target for intervention to interrupt inappropriate monocyte and T cell trafficking. The clinical indications for such intervention are in inflammatory diseases and T-cell mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, asthma, allergy, chronic obstructive pulmonary disease, atherosclerosis, restinosis, type I and type II diabetes, metabolic syndrome, and pain. Ectopic expression of MCP-1 and CCR2 in certain tumors indicates that selective modulation (such as antagonism or inhibition) of CCR2 can have value in tumor immunotherapy, particularly attenuation of metastasis.

The native peptide ligand of CCR2 is monocyte chemoattractant protein- 1 (MCP- 1 or CCL2) containing two adjacent disulfied bonds. Ample evidence exists for the role of the CCR2/MCP-1 system in preclinical animal models of pain (White F.A., Jung F., and Miller R.J., Proc. Natl. Acad. Sci. USA 2007; 51 :20151). Although CCR2 and MCP- 1 have limited expression levels in the CNS tissues under normal conditions, significant upregulation of CCR2 and MCP- 1 has been observed following a neuropathic injury in tissue relevant to pain, including neurons and glia in the spinal cord, rostroventromedial medulla (RVM) and DRG (Wang H., Zou S., Wei F., Dubner R., and Ren K., Soc for Neurosci Poster 2009; 72.3). MCP- 1 has been shown to increase the excitability of neurons acutely dissociated from the DRG tissue (Sun J.H., Yang B., Donnelly D.F., Ma C, and LaMotte R.H., J Neurophysiol. 2006; 96:2189). In addition, direct injection of MCP- 1 in the spinal cord induces thermal hyperalgesia and mechanical allodynia (Dansereau et al. Neurochem. 2008; 106:7), and the MCP- 1 induced pronociception can be blocked by a CCR2 antagonist, INCB3344. Similarly, the hyperalgesia induced by MCP-1 injection in the RVM is reversed by another CCR2 antagonist, RS I 02895 (Wang H., Zou S., Wei F., Dubner R. and Ren K., Soc for Neurosci Poster 2009; 72.3). In addition, CCR2 knock out mice exhibit significantly reduced mechanical allydonia following nerve injury and reduced nocifensive behavior in the second phase of the formalin model, whereas they exhibit normal sensitivity to acute pain stimulation in the hot plate model (Abbadie C, Lindia J.A., Cumiskey A.M., Peterson L.B., Mudgett J.S., Bayne E.K., DeMartino J.A., Maclntyre D.E., and Forrest M.J., Proc Natl Aca Sci USA 2003; 100:7947). Treatment with AZ889 (Serrano A., Pare M., Mcintosh F., Elmes S.J.R. Martino G., Jomphe C, Lessard E., Lembo P.M.C., Vaillancourt F., Perkins M.N., and Cao C.Q., Mol. Pain 2010; 6:90), a CCR2 antagonist, abolished CCL2-evoked neuronal excitation, confirming that this activity is CCR2 -mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. In vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in chronic constriction injury rats (Serrano A., Pare M., Mcintosh F., Elmes S.J.R., Martino G., Jomphe C, Lessard E., Lembo P.M.C., Vaillancourt F., Perkins M.N., and Cao C.Q., Mol. Pain 2010; 6:90). Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. In view of the clinical importance of CCR2, the identification of compounds that modulate CCR2 function represents an attractive avenue into the development of new therapeutic agents that can be used to treat diseases such as inflammatory, autoimmune disease, cancer, and pain, that are associated with chemokine receptor expression or activity. Such compounds are provided herein.

……………………………………………………….

51   cas  1421063-65-1

succinate cas  1421065-31-7

52 cas 1416178-01-2

…………………………………..

http://www.google.com/patents/WO2013010453A1?cl=en

Example 74

1 -phenyl-4-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was obtained from the procedure of Example 63. Ή NMR

(400 MHz, CDCI₃) δ ppm 8.70 (s, 1 H), 7.65 (s, 1 H), 7.35 (m, 2 H), 7.20 (m, 3 H), 4.60 – 4.90 (m, 2 H), 3.85 (m, 2H), 3.65 (m, 2H), 3.30 – 3.45 (m, 3H), 3.09 (m, 2H), 2.90 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 2.15 (m, 1H), 1.92 (m, 1H), 1.45 – 1.82 (m, 6H), 1.25 (m, 1H); MS (ESI) nVz 513 (M+H)⁺.

Example 75 C

l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L-threo- pentitol

The title compound was prepared according to method A of Example 79G, substituting Example 75B for Example 79F, and isolated as the major isomer. Ή NMR (400 MHz, CDC1₃) δ 8.68 (s, 1H), 7.66 (s, 1H), 4.75 (m, 2H), 4.10 (m, 1H), 3.78 – 3.95 (m, 3H), 3.52 (m, 2H), 3.40 (s, 3H), 3.30 (m, 2H), 3.02 – 3.16 (m, 3H), 2.96 (m, 1H), 2.00 – 2.17 (m, 3H), 1.55 – 1.95 (m, 8H), 1.30 (m, 2H); MS (ESI) m/z 468 (M+H)⁺.

Example 76

l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitol

The title compound was prepared and purified according to the method A described in Example 79G, and was isolated as the major product. Ή NMR (400 MHz, CDC1₃) δ 8.70 (s, 1H), 7.70 (s, 1H), 4.70 – 4.90 (m, 2H), 4.10 (m, 1H), 3.80 – 3.95 (m, 3H), 3.35 – 3.50 (m, 2H), 3.42 (s, 3H), 3.30 (m, 2H), 3.15 (m, 2H), 3.05 (m, 1H), 2.75 (m, lH), 2.35 (m, lH), 2.15 (m, 1H), 1.50 – 2.00 (m, 9H), 0.90-1.10 (m, 2H). MS (ESI) m/z 468 (M+H)⁺.

Example 78

l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{methyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D- erythro-pentitol

To the solution of Example 79G (10 mg, 0.03 mmol) in dioxane (1 mL) was added formic acid (0.6 mL) and aqueous formalin solution (37%, 0.6 mL ). The mixture was heated at 80 °C overnight under nitrogen. The reaction mixture was concentrated in vaccum and was purified by HPLC to afford title compound as white solid (8.0 mg). Ή NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.06 (s, 1H), 4.75 – 4.90 (m, 2H), 4.30 (m, 1H), 3.90 – 4.10 (m, 4H), 3.50 – 3.72 (m, 4H), 3.45 (s, 3H), 3.15 (m, 2H), 2.78 (s, 3H), 2.60 (m, 1H), 1.85 – 2.20 (m, 9H), 1.80 (m, 1H), 1.58 (m, 1H), 1.42 (m, 1H); MS (ESI) m/z 482 (M+H)⁺.

To a solution of Example 78 (400 mg, 0.83 mmol) in MeOH (20 mL) was added succinic acid (98 mg 0.83 mmol) then the mixture was heated to 80 °C for 4 hours, then the solvent was concentrated under in vacuum to give the corresponding succinate salt (480 mg, 0.81 mmol, 96%). ‘H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.85 (m, 2H), 4.25 (m, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.70 (s, 1H), 3.50 (m, 2H), 3.42 (s, 3H), 3.33 (m, 1H), 3.12 (m, 2H), 2.70 (s, 3H), 2.55 (m, 1H), 2.50 (s, 4H), 2.15 (m, 3H), 1.70 – 2.02 (m, 7H), 1.55 (m, 1H), 1.40 (m, 1H).

ABS

Example 79l,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitolMethod A

Example 79A

4,4-dimethoxytetrahydro-2H-pyran

To the solution of dihydro-2H-pyran-4(3H)-one (50 g, 0.5 mol) in MeOH (500 mL) was added TiCl₄ (1 g, 5 mmol) and Et₃N (500 mg, 5 mmol), and the mixture stirred at room temperature for 10 hours, followed by the addition of Et₃N (2 g, 20 mmol). The mixture was concentrated to 100 mL, diluted by methyl tert-butyl ether (1.5 L) and washed with ¾0 (500 mL), and brine. The organic layer was dried over Na2S0₄, filtered, and concentrated to yield Example 79A (60 g, 84% yield). Example 79B

4,4-dimethoxytetrahydro-2H-pyran compound with 4-methoxy-3,6-dihydro-2H-pyran To the solution of Example 79A (60 g, 0.42 mol) in dichloromethane (800 mL) at -78 °C was added TiCl₄ (84 g, 0.42 mol). The mixture was stirred at -78 °C for 1 hour, followed by the addition of pyridine (66 g, 0.84 mol) and KOH (47 g, 0.84 mol). The mixture was stirred at -78 °C for additional 0.5 hour then warmed to room temperature and stirred overnight. The mixture was filtered. The filtrate was washed with water (1 L), dried over MgS0₄, filtered, and concentrated to yield Example 79B (52 g, 100%).

Example 79C

4,4-dimethoxytetrahydro-2H-pyran-3-ol

To the solution of Example 79B (2 g, 17.5 mmol) in MeOH (50 mL) was added meta-chloroperoxy benzoic acid (6 g, 35 mmol) in MeOH (6 mL) at 0 – 6 °C via addition funnel. After addition, the mixture was stirred at 0 °C for 4 hours. Upon reaction completion, the mixture was concentrated to yield white solid, which was then dissolved in dichloromethane (40 mL). Calcium hydroxide (14.8 g, 200 mmol) was added to the solution, and the solution was stirred for an additional 2 hours. The mixture was filtered and the filtrate was concentrated to yield crude title compound (2 g, 66.7%), which was used into next step without further purification.

Example 79D 3-methoxydihydro-2H-pyran-4(3H)-one

To the mixture of NaH (60%, 5.04 g, 12.6 mmol) in THF (200 mL) was added Example 79C (20 g, 12.6 mmol) in THF (150 mL). The mixture was stirred at 0 °C for 0.5 hour, followed by addition of iodomethane (200 g, 15.5 mmol), and was stirred overnight. HC1 (12 M, 12 mL) was added to the mixture, stirred at room temperature for additional 1.5 hours and concentrated. The residue was purified by column

chromatography to Example 79D (20 g, 100%).

Example 79E

(3S,4S)-3-methoxy-N-((S)-l-phenylethyl)tetrahydro-2H-pyran-4-amine To the solution of Example 79D (20 g, 153.8 mmol) and (S)- 1 -phenylethanamine

(18.6 g, 153.8 mmol) in dichloromethane (200 mL) was added Ti(i-OPr)₄ (87.7 g, 310 mmol) and diisopropylethyl amine (40 g, 310 mmoL). The mixture was then stirred at room temperature for 18 hours, following by addition of sodium triacetoxyborohydride (65.1 g, 310 mmol), and MeOH (15 mL). The mixture was stirred for additional 4 hours, then poured into saturated NaHC(¾ solution, stirred for 1.5 hours and filtered. The filtrate was extracted with dichloromethane (2 x 200 mL) and concentrated. The residue was purified by preparative HPLC followed by chiral SFC separation to yield title compound (10 g, 27.7%).

Example 79F

(3S,4S)-3-methoxytetrahydro-2H-pyran-4-amine

To the solution of Example 79E (5.8 g, 21.3 mmol) in EtOH (100 mL) was added Pd/C (6 g), and the mixture was then submitted to hydrogenolysis at 50 °C (¾, 50 Psi) for 48 hours. The mixture was filtered and the filtrate was concentrated to yield 1.5 g (55%) of Example 79F which was used into next step directly without further purification.

Example 79G

l,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitol

To the mixture of Example 1H (4.8 g, 13.6 mmol), Example 79F (1.5 g, 0.87 mmol) in dichloroethane (120 mL) was added Ti(i-OPr)₄ (974 mg, 3.48 mmol), N,N- diisopropylethyl amine (1.2 g, 10 mmol). The mixture was then stirred overnight followed by addition of NaBH₄ (132 mg, 3.48 mmol) and MeOH (5 mL). The mixture was stirred for another 12 hours before it was poured into saturated NaHC(¾, stirred at room temperature for 2 hours, filtered, and the filtrate was extracted by dichloromethane (3 x 200 mL). The organic layer was concentrated and the residue was purified by preparative HPLC to afford a mixture of two diastereomers. This mixture was purified by chiral SFC to yield Exmaple 76 as the first eluent, as well as the title compound (600 mg) as the second eluent. Ή NMR (400 MHz, CDC1₃) δ 8.70 (s, 1H), 7.70 (s, 1H), 4.68 – 4.85 (m, 2H), 4.22 (m, 1H), 4.05 (m, 1H), 3.70 – 3.90 (m, 3H), 3.55 (m, 2H), 3.35 – 3.45 (m, 2H), 3.40 (s, 3H), 3.30 (m, 1H), 3.10 (m, 2H), 2.45 (m, 1H), 2.30 (m, 1H), 2.00 – 2.20 (m, 3H), 1.55 – 1.95 (m, 6H), 1.30 (m, 2H); MS (ESI) m/z 468 (M+H)⁺.

The succinate salt of the above compound was prepared as follows: A mixture of free base of Example 79G (600 mg, 1.25 mmol), succinic acid (152 mg, 1.25 mmol) in EtOH (50 mL) was heated at 65 °C for 2 hours and then concentrated. The residue was washed with Et₂0 (25 mL) to yield white solid (610 mg, 86.4%). Ή NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.85 (m, 2H), 4.22 (d, J= 14.8 Hz, 1H), 3.95 (m, 3H), 3.70 (m, 1H), 3.30 – 3.53 (m, 4H), 3.38 (s, 3H), 3.12 (m, 2H), 2.55 (m, 1H), 2.52 (s, 4H), 2.15 (m, 1H), 1.70 – 2.05 (m, 9H), 1.55 (m, 1H), 1.38 (m, 1H).

Method B

Example 79H

( 1 R,4S)-methyl 4-aminocyclopent-2-enecarboxylate To a cooled mixture of (lR,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (13 g, 1 19 mmol) in MeOH (150 mL) was added SOCI₂ (20 mL) dropwise to keep the temperature of the reaction under 15 °C. Upon completion of addition, the mixture was stirred at 5 °C for 3 hours. The solvent was removed under reduced pressure to yield liquid, which was dried under high vacuum to give Example 79H as white solid (23 g).

Example 791

(lR,4S)-methyl 4-(2,5 -dimethyl- lH-pyrrol-l-yl)cyclopent-2-enecarboxylate To a mixture of Example 79H (23 g, 163 mmol) in MeOH (100 ml) was added diisopropylethyl amine (23 g, 179 mmol) and acetyl acetone (20 g, 170 mmol), then the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (S1O2, petroleum ethenEtOAc = 20: 1) to give Example 791 as yellow oil (20 g).

Example 79J (lR,4S)-methyl 1 -(3-bromopropyl)-4-(2,5-dimethyl- lH-pyrrol- 1 -yl)cyclopent-2- enecarboxylate

To a solution of Example 791 (16.5 g, 74.4 mmol) in THF (200 ml) was added dropwise lithium hexamethyl bis(trimethylsilyl)amide (1 M, 1 19 mL) at -50 °C, stirredd for 1 hour, allowed to warm to -20 °C, followed by the dropwise addition of 1,3- dibromopropane (150 g, 744 mmol) over 1 hour. The reaction mixture was stirred at -20 °C for 1 hour, quenched with aqueous NH₄C1 solution (6%, 600 mL), and extracted with ethyl acetate. The organic layer was washed with NH4CI solution, brine, dried over Na2S0₄, filtered, and concentrated. The residued was purified by silica gel column chromatography (petroleum ethenEtOAc = 80: 1) to give Example 79J (16 g).

Example 79K

(2R,3aR,6aR)-methyl 2-(2,5-dimethyl- lH-pyrrol- 1 -yl)octahydropentalene-3a-carboxylate To a solution of compound 79 J (16 g, 47 mmol) and azobisisobutyronitrile (1.6 g, 10 mmol) in toluene (1.8 L) was added a solution of tributyl tin hydride (32 mL) in toluene (200 mL) at 1 10 °C over 1 hour. After refluxing for 3 hours, the reaction mixture was quenched by saturated aqueous KF (200 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂S0_4;filtered, and concentrated. The residue was purified by column chromatography (S1O₂, petroleum ethenEtOAc = 50: 1) to give compound Example 79K (8 g) as white solid.

Example 79L

(2R,3aR,6aR)-2-(2,5-dimethyl-lH-pyrrol-l-yl)octahydropentalene-3a-carboxylic acid To a solution of Example 79K (5.3 g, 20.3 mmol) in MeOH (33 mL) and water (15 mL) was added a aqueous solution of NaOH (3.2 g, 80 mmol in 4 mL water) and the mixture was heated at 65 °C for 16 hours. The mixture was cooled to room temperature, adjusted the pH to about 4 with HC1 solution (4 N) and filtered to collect Example 79L (4.5 g) as yellow solid and used in next step without purification.

Example 79M

((2R,3aR,6aR)-2-(2,5-dimethyl- lH-pyrrol- 1 -yl)octahydropentalen-3a-yl)(3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)methanone To a solution of compound Example 79L (5 g, 20.2 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (4.2 g, 30.9 mmol), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (5.8 g, 30.4 mmol), and Et₃N (6.0 g, 59.4 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was suspended in water and extracted with dichloromethane (3 x 300 mL). The combined organic layer was washed with brine, dried over Na₂S0₄, filtered, and concentrated to result in the title compound (8 g), which was used in the next step without purification.

Example 79N

((2R,3aR,6aR)-2-aminooctahydropentalen-3a-yl)(3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl)methanone

To a solution of Example 79M (8.0 g, 18.6 mmol) in MeOH (100 mL) was added hydroxylamine hydrochloride (8.0 g, 1 15.9 mmol), 50% hydroxylamine hydrate (12 mL) and ¾0 (40 mL). The mixture was heated at reflux for 13 hours and cooled to room temperature. The mixture was treated with NaOH (10 N) to adjust the pH to about 1 1, and extracted with dichloromethane (3 x 300 mL). The combined organic layer was washed with brine, dried over MgS0₄, filtered, and concentrated. A solution of HCl in EtOAc (30 mL) was added to the residue with stirring at room temperature for 1 hour. The solvent was removed and the HCl salt of Example 79N (6.5 g) was used for next step without purification.

Example 790

tert-butyl(3,6-dihydro-2H-pyran-4-yloxy)dimethylsilane To a mixture of the tetrahydro-4H-pyran-4-one (38.9 g, 0.38 mol) and Et₃N (76.8 g, 0.76 mol) in dichloromethane (800 mL) was added trimethyl trifluoromethanesulfonate (105.5 g, 0.399 mol) dropwise over 3 hours. After addition, the reaction was allowed to warm to room temperature and stirred overnight. Water was added and the resulting solution was extracted with dichloromethane (2 x 500 mL). The combined organic phase was washed with water (2 x 500 mL) and brine (2 x 200 mL), dried over Na₂S0₄, filtered, and concentrated to give Example 790 (78 g, 85%) as an oil.

Example 79P

sodium (3R)-3,4-dihydroxytetrahydro-2H-pyran-4-sulfonate To a solution of (DHQD^PHAL (hydroquinidein 1 ,4-phthalazinediyl diether) (3.06 g, 3.93 mol), K₂0s0₄ (723 mg, 1.96 mol) and N-methylmorpholine-N-oxide (58.4 g, 0.432 mol) in acetone/H₂0 (700 mL, 10/1) at 0 °C was added slowly a solution of Example 790 (84 g, 0.393 mol) in acetone (100 mL) for 5 hours. The resulting solution was stirred at 10-20 °C overnight. A freshly prepared solution of Na₂S₂0s (44.8 g, 0.236 mol) in water (315 mL) was added followed by acetic acid (67.3 mL). After stirring for 16 hours at room temperature, the solid was filtered and washed with isopropanol (400 mL) and dried to provide Example 79P (60 g, 73%) as a white solid.

Example 79Q

(R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol To a solution of Example 79P (60 g, 0.294 mol) and HC(OCH₃)₃ (69.3 g, 0.647 mol) in MeOH (500 mL) at 50 °C was added HCl/MeOH (68 mL, 5-6 N) slowly over 30 minutes. Then the slurry was cooled to 5 °C and 50% of NaOH (100 mL in water) was added over 1 hour. The solid was filtered and the filtrate was concentrated. The resulting solution was washed with toluene for several times and then concentrated to give Example 79Q (38 g, yield: 88%) as an oil.

Example 79R

(R)-3-methoxydihydro-2H-pyran-4(3H)-one To a solution of Example 79Q (9.5 g, 64.68 mol) in THF (300 mL) was added sodium tert-butoxide (9.3 g, 97.02 mmol) at ice bath. Then dimethyl sulfate (13.4 g, 106 mmol) was added over 20 minutes, maintaining an interal temp below 36 °C. After addition, the reaction mixture was stirred for 4 hours at room temperature. Water (200 mL) was added followed by addition of 2N HC1 (100 mL). The apparent pH is below 1. After 16 hours of reaction, NaHC(¾ (20 g) was added and the mixture was extracted with EtOAc (4 x 300 mL), dried over Na2S0₄, filtered, and concentrated to give Example 79R (6 g, yield: 71 %) as an oil.

Example 79G

l,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitol

A solution of Example 79N (3.2 g, 9.0 mmol) in isopropyl acetate (80 mL) was cooled with ice bath and tributylamine (3.3 g, 20.7 mmol) was added dropwise, followed by the addition of isopropyl alcohol (1.6 ml, 20.7 mmol). Sodium triacetoxyborohydride (4.4 g, 20.7 mmol) was added. After 1 hour at room temperature, a solution of Exampole 79R (1.75 g, 13 mmol) in isopropyl acetate (10 mL) was added to the mixture at 1 °C. Then the mixture was stirred at room temperature for 15 hours and partitioned between satureated aqueous NaHC(¾ (80 mL), water (50 mL) and EtOAc (400 mL). The aqueous phase was further extracted with EtOAc (200 mL). The combined organic phase was washed with saturated.aqeous NaHC0₃ solution, dried with Na₂S0₄, filtered, concentrated. The residue was purified by column chromatography (S1O2,

dichloromethane:MeOH = 20: 1) to give Example 79G as a mixture of diastereomers, which was then further purified by chiral SFC to yield title compound as the first eluent and white solid upon concentration, as well as Example 80 as the second eluent.

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Bioorganic & Medicinal Chemistry Letters, 23(1), 351-354; 2013

http://www.sciencedirect.com/science/article/pii/S0960894X12013601

 

TREANDA contains bendamustine hydrochloride, an alkylating drug, as the active ingredient. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride. Its empirical molecular formula is C₁₆H₂₁Cl₂N₃O₂ • HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula:

TREANDA (bendamustine hydrochloride) for Injection is intended for intravenous infusion only after reconstitution with Sterile Water for Injection, USP, and after further dilution with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. It is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-use vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 -3.5.

Bendamustine hydrochloride, 4-{5-[Bis(2-chloroethyl) amino]- l-methyl-2- benzimidazolyl} butyric acid hydrochloride, of the formula (VI) :

was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there, as the hydrochloride salt, under the trade name Cytostasan®. Since that time, it has been marketed in Germany under the trade name Ribomustin®. Bendamustine Hydrochloride as injection is available in the United States under the tradename Treanda®. Bendamustine hydrochloride is an alkylating agent that is approved for the treatment of non-Hodgkin’s lymphoma, multiple myeloma and chronic lymphocytic leukemia.

Bendamustine hydrochloride is a benzimidazole analog. While bendamustine has been demonstrated as efficacious, it is known to be unstable, especially in aqueous solutions, leading to formation of non-bendamustine products (i.e. “degradation impurities”) which leads to technical difficulties in its preparation and administration. In light of its instability in aqueous solution, bendamustine is supplied as a lyophilized cake of bendamustine hydrochloride salt. US2006/159713, US 2006/128777 and WO2010/036702 disclose various impurities of Bendamustine hydrochloride which are as follows:

PC-1 PC-2

Jena et al. were the first to disclose the synthesis of Bendamustine hydrochloride in German (GDR) Patent No. 34727. Krueger et al. in German (GDR) Patent No. 159877 recite a method as summarized in scheme-1, for the synthesis of bendamustine hydrochloride comprising the reaction of the 4-[l-methyl-5-bis-(2- hydroxyethyl)-benzimidazolyl-2]butyric acid ethyl ester (4) (or the corresponding methyl, propyl or butyl ester) with thionyl chloride in chloroform at 0-5°C to form 4-[l- methyl-5-bis-(2-chloroethyl)-benzimidazolyl-2]butyric acid ethyl ester (5). Excess of thionyl chloride is destroyed by stirring the reaction mixture in aqueous HCl. Finally chloroform is distilled off and stirred at 95°C for 3 hours. The reaction mixture is partially concentrated and the residue is diluted with water and stirred upto crystallization. Further purification is done by recrystallization from water.

Scheme-1: Method disclosed by Krueger et al. in DD159877 for the synthesis of Bendamustine hydrochloride

Bendamustine hydrochloride (6)

Ozegowski et al in Zentralblatt fuer Pharmazie, Pharmakotherapie und Laboratoriumsdiagnostik 1 10 (10), 1013-1019 (1971) discloses a process for the preparation of bendamustine hydrochloride monohydrate. The Chinese journal “Chinese journal of New Drugs “, 2007, No. 23, Vol. 16, 1960-61 and J. Prakt. Chem. 20, 178-186 (1963) disclose another method for the synthesis of Bendamustine hydrochloride monohydrate starting from 2,4-dinitrochlorobenzene as summarized in scheme-2.

The crucial conversions are reaction of l-methyl-2-(4′-ethyl butyrate)-5- amino]-lH-benzimidazole 6 with ethylene oxide in the presence of water, sodium acetate and acetic acid, by maintaining at 5°C for 5 hours and overnight at 20°C to give 4-{5-[bis-(2-hydroxy-ethyl)-amino]-l-methyl-lH-benzimidazol-2-yl}-butyric acid ethyl ester (dihydroxy ester) 7 as a jelly mass, which on chlorination using thionyl chloride in chloroform and subsequent in situ hydrolysis with concentrated HCI gave bendamustine hydrochloride. It also discloses a process for the recrystallization of bendamustine hydrochloride from water and the product obtained is a monohydrate with a melting point of 148-151°C.

IP.com Journal 2009, 9(7B), 21 discloses another process as shown below for the preparation of ethyl-4-[5-[bis(2-hydroxyethyl) amino]- l-methylbenzimidazol-2- yl]butanoate (III) wherein ethyl-4-(5 -amino- 1 -methyl- lH-benzo[d]imidazol-2-yl) butanoate (II) is reacted with 2-halo ethanol in the presence of an inorganic base selected from the group consisting potassium carbonate, potassium bicarbonate, sodium

The PCT application WO 2010/042568 assigned to Cephalon discloses the synthesis of Bendamustine hydrochloride as summarized in schem-3 starting from 2,4- dintroaniline in six steps. The crucial step is reductive alkylation of Il-a, using borane- tetrahydrofuran and chloroacetic acid at ambient temperature, producing compound of formula I-a. Acid mediated hydrolysis of I-a using concentrated hydrochloric acid at reflux produced bendamustine hydrochloride which has a purity of 99.1%. The above PCT Patent application also discloses a method of purification of Bendamustine hydrochloride by agitating the Bendamustine hydrochloride in a mixture of DMF and THF at 75°C for about 30 minutes followed by cooling to ambient temperature and isolating the solid by filtration.

Scheme-3:

iil-a

Bemdamuatine hydrochloride

The PCT application WO 2011/079193 assigned to Dr. Reddy’s Laboratories discloses the synthesis of Bendamustine hydrochloride as summarized in schem-4 starting from compound of formula (II). The crucial step is alkylation of compound of formula II with 2-haloethanol in the presence of an organic base to give a compound of formula (III) which on chlorination with a chlorinating agent affords a compound of formula (IV). Compound of formula (IV) on hydrolysis in acidic medium gives bendamustine hydrochloride. It further discloses purification of bendamustine hydrochloride using aqueous hydrochloric acid and acetonitrile.

Scheme-4:

Bendamustine hydrochloride (Pure)

The most of the prior art processes described above involve

• The use of ethylene oxide for the preparation of bendamustine hydrochloride, which is often not suitable for industrial scale processes due to difficulty in handling ethylene oxide, since it is shipped as a refrigerated liquid.

• Further, the known processes involve the use of strongly acidic conditions and high temperatures for the hydrolysis of ethyl ester of bendamustine and subsequent in-situ formation of bendamustine hydrochloride, thereby resulting in increased levels of various process-related impurities IMP. -A (RRT-0.46), IMP. -B (RRT-1.27) and IMP. -C (RRT-1.31) whose removal is quite difficult and make the process less economically viable.

IMP.-B

International Application Publication No. WO 2009/120386 describes various solid forms of bendamustine hydrochloride designated as bendamustine hydrochloride Form 1, bendamustine hydrochloride Form 2, bendamustine hydrochloride Form 3, bendamustine hydrochloride Form 4, amorphous bendamustine hydrochloride or a mixture thereof, processes for their preparation and lyophilized composition comprising the solid forms. According to the disclosure, monohydrate of bendamustine hydrochloride has been prepared previously. The monohydrate has a reported melting point of 152-156°C which is similar to that of the observed melting point of bendamustine hydrochloride Form 2.

It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in Bendamustine hydrochloride or any active pharmaceutical ingredient (API) are undesirable and might be harmful.

Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible. The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the active pharmaceutical ingredient, the product is analyzed for purity, typically, by HPLC, TLC. or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities are limited to less than 0.1 percent.

Generally, impurities are identified spectroscopically and by other physical methods, and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the “retention time” (“RT”). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use “relative retention time” (“RRT”) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.

It is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.

Therefore, there remains a need for improved process for the preparation of bendamustine hydrochloride, producing high yield and purity, and well-suited for use on an industrial scale. Despite the existence of various polymorphic forms of bendamustine hydrochloride, there exists a need for a simple process for the preparation of the stable form of bendamustine hydrochloride which is amenable to scale up and results in high yield and purity.

Bendamustine (INN, trade names Treakisym, Ribomustin, Levact and Treanda; also known as SDX-105) is a nitrogen mustardused in the treatment of chronic lymphocytic leukemia^[1] and lymphomas. It belongs to the family of drugs called alkylating agents. It is also being studied for the treatment of sarcoma.^[2] It is also being investigated in phase II trials for the non-cancer treatment of AL Amyloidosis.

Bendamustine hydrochloride,  initially synthesized in 1963 in the German Democratic Republic, is an alkylating agent that has been shown to have therapeutic utility in treating diseases such as chronic lymphocytic leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, and breast cancer.It was available from 1971 to 1992 under the trade name Cytostasanand, since that time, has been marketed in Germany as Ribomustin.In March 2008 the FDA approved bendamustine hydrochloride under the trade name Treanda for the treatment of chronic lymphocytic leukemia (CLL). Approval for use in indolent B-cell non-Hodgkin’s lymphoma (NHL) was received in 2009.

History

Bendamustine was first synthesized in 1963 by Ozegowski and Krebs in East Germany (the former German Democratic Republic). Until 1990 it was available only in East Germany. East German investigators found that it was useful for treating chronic lymphocytic leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma and lung cancer.

Bendamustine received its first marketing approval in Germany, where it is marketed under the tradename Ribomustin, by Astellas Pharma GmbH’s licensee, Mundipharma International Corporation Limited. It is indicated as a single-agent or in combination with other anti-cancer agents for indolent non-Hodgkin’s lymphoma, multiple myeloma, and chronic lymphocytic leukemia. SymBio Pharmaceuticals Ltd holds exclusive rights to develop and market bendamustine HCl in Japan and selected Asia Pacific Rim countries.

In March 2008, Cephalon received approval from the United States Food and Drug Administration to market bendamustine in the US, where it is sold under the tradename Treanda, for treatment of chronic lymphocytic leukemia.^[3]

In October 2008, the FDA granted further approval to market Treanda for the treatment of indolent B-cell non-Hodgkin’s lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.^[4]

Pharmacology

Bendamustine is a white, water soluble microcrystalline powder with amphoteric properties. It acts as an alkylating agent causing intra-strand and inter-strand cross-links between DNA bases.

After intravenous infusion it is extensively metabolised in the liver by cytochrome p450. More than 95% of the drug is bound to protein – primarily albumin. Only free bendamustine is active. Elimination is biphasic with a half-life of 6–10 minutes and a terminal half-life of approximately 30 minutes. It is eliminated primarily through the kidneys. This paragraph is inconsistent with sidebar for primary excretion pathway.

Chemotherapeutic uses

Bendamustine has been used both as sole therapy and in combination with other agents including etoposide, fludarabine,mitoxantrone, methotrexate, prednisone, rituximab, vincristine and ⁹⁰Y-ibritumomab tiuxetan.

Lymphomas

One combination for stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL), with or without prior rituximab-containing chemoimmunotherapy treatment, is bendamustine with mitoxantrone and rituximab.^[5] In Germany in 2012 it has become the first line treatment of choice for indolent lymphoma.^[6] after Trial results released in June 2012 showed that it more than doubled disease progression-free survival when given along with rituximab. The combination also left patients with fewer side effects than the older R-CHOP treatment.^[7]

Adverse effects

Common adverse reactions are typical for the class of nitrogen mustards, and include nausea, fatigue, vomiting, diarrhea, fever, constipation, loss of appetite, cough, headache, unintentional weight loss, difficulty breathing, rashes, and stomatitis, as well as immunosuppression, anemia, and low platelet counts. Notably, this drug has a low incidence of hair loss (alopecia) unlike most other chemotherapy drugs.^[8]

……………………

http://www.google.com/patents/WO2013046223A1?cl=en

First aspect of the present invention provides an improved process for the preparation of Bendamustine hydrochloride of the formula (VI)

comprising the steps of:

a) reacting a compound of the formula (II), wherein R is Ci-C₆ alkyl

with a 2-haloethanol in the presence of a base to give a compound of formula (III);

b) reacting the compound of formula (III) with a chlorinating agent to provide a compound of formula (IV);

c) hydrolyzing the compound of formula (IV) with Lithium source to give a compound of formula (V); and

d) converting the compound of formula (V) to bendamustine or bendamustine hydrochloride of Formula VI .

Reference Example- 1

Preparation of Bendamustine Hydrochloride as per Patent No. DD159877

Ethyl 4-[l-methyl-5-bis-(2-hydroxyethyl)-amino-benzimidazolyl- 2]butanoate (4, 4.305g) was added to chloroform (36mL) and agitated till clear solution is formed. The solution was cooled to 0°C. Thionyl chloride (2.175g) was added to the above solution within 40 minutes maintaining the temperature of the solution to 0-5°C by cooling. The reaction mixture was agitated at 0-5°C for 1 hour. The temperature was raised slowly to room temperature by removing cooling within 2.5 to 3 hrs and subsequently agitated at room temperature for 15 to 16 hrs. The solution was dispersed by agitating in 37.5mL concentrated hydrochloric acid whereby the excessive thionyl chloride was decomposed under increased hydrochloric acid and S0₂development. The chloroform was distilled away and further stirred for 3 hrs at around 95°C. Activated carbon (0.78g) was added to the solution and stirred for further 30 minutes at around 95 °C. The solution was concentrated to almost 8mL under vacuum and the residue was diluted with 24mL of water and stirred up to crystallization. The further purification was done by recrystallization from water.

Example-4

Preparation of Bendamustine hydrochloride (VI) through Lithium 4-[l-methyl-5- bis-(2-chloroethyl)-benzimidazoIyl-2] butanoate (V)

Activated charcoal (11. Og) was added to Cone. HC1 (165.0 mL) under stirring and cooled to 5-10°C. Lithium 4-[l-methyl-5-bis-(2-chloroethyl)- benzimidazolyl-2] butanoate (V, HO.Og, 0.302 mol) was added below 65°C under agitation and agitated for 30-45 minutes. The reaction mass was filtered on celite bed prewashed with cone. HC1 and the celite bed was washed with cone. HC1 (27.5mL). The filtrate and washings were combined. DM water (550.0mL) was added to combined filtrate and washings and agitated for 15 minutes. DM water (1.1L) was added and stirred at 20-30°C for 30 minutes. The resulting mass was cooled to 0-5°C and maintained at a temperature of 0 to 5°C for 30 minutes under agitation. The solid was filtered, washed with chilled (0-5°C) DM water twice (220.0 mL each X 2 = 440.0mL) followed by with chilled acetone (0-5°C) (55. OmL) and sucked dried for 1 hour. The solid cake was agitated with acetone (1 lOO.OmL) for 10 minutes and filtered. The solid material was dried at 20-25°C under 100-200 mbar vacuum for one hour till moisture content is between 4.4-6.0% w/w to give the title compound (VI, 80.0g; 67.10%), with a purity of 99.86%.

…………………………..

………………………………..

1. 1.

   (a) Chen, J., Przyuski, K., and Roemmele, R. U.S. Patent 8,420,829, April 16, 2013;

   Chem. Abstr. 2010, 152, 454105.

   (b) Chen, J.; Przyuski, K.; Roemmele, R.; Bakale, R. P.Org. Process Res. Dev. 2011, 15, 1063

   ………………………………………

   Org. Process Res. Dev., 2011, 15 (5), pp 1063–1072

   DOI: 10.1021/op200176f

   http://pubs.acs.org/doi/abs/10.1021/op200176f

   Process Research and Development activities leading to a new and efficient route to bendamustine hydrochloride, 1, the active ingredient in Treanda, a treatment for blood cancers, are disclosed. Two key features of this new process include a one-pot hydrogenation/dehydration sequence to construct the benzimidazole moiety and a novel reductive alkylation using chloroacetic acid and borane to install the bischloroethyl side chain. The number of synthetic steps has been significantly reduced to five from the eight in the current commercial process. The overall yield has been improved from 12% to 45%. Additionally, this new route eliminates chloroform, ethylene oxide, and sodium sulfide. Scale-up of the new route has been successfully demonstrated to prepare kilogram quantities of bendamustine hydrochloride.

   …………………………

   http://pubs.acs.org/doi/full/10.1021/op200176f

   Org. Process Res. Dev., 2011, 15 (5), pp 1063–1072

   DOI: 10.1021/op200176f

   Preparation of Bendamustine Hydrochloride (1)

   A……../…………..purity of 99.9 A%.

   ¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (br s, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 9.3, 2.3 Hz, 1H), 3.90 (s, 3H), 3.80 (m, 8H), 3.14 (t, J = 7.6 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 2.01 (quint, J = 7.6 Hz, 2H);

   LC/MS (ESI, m/z) 358.2 Da (M + 1).

   ……………………..

   http://www.google.com/patents/WO2013150020A1?cl=en

   Bendamustine, 4-[5-[bis(2-chloroethyl)amino]-l-methyl-2-benzimidazolyl]butyric acid of formula (1)

   , is a cytostatic agent currently approved, in a form of a hydrochloride salt, for treatment of various cancer diseases, e.g. chronic lymphocytic leukemia. It is marketed in the form of a lyophilized powder for intravenous injection, e.g., under the brand name Ribomustin.

   Bendamustine, including bendamustine hydrochloride, was first disclosed in DD 34727. Bendamustine hydrochloride may exist, in solid state, in various polymorphic forms, which are disclosed, e.g. in WO 2009/120386. The hydrochloride product disclosed in DD 34727 is a monohydrate. The original process for making bendamustine in DD 34727 comprises the following synthetic pathway:

   The group R in the above process is an ethyl group.

   The last step of the above process was subsequently technologically improved in DD 159877.

   Without providing any experimental detail, DD 34727 also teaches that the starting compound of formula (4) for the above process may be prepared from 2-methylamino-5-nitro- aniline of formula (2) and glutaric acid anhydride. The obtained anilide of formula (3) is cyclized in diluted hydrochloric acid.

   Li-Mei et al, in Zhongguo Xinyao Zazhi, Chinese Journal of New Drugs (2007), 16(23), 1960-1961, disclose a process for the preparation of bendamustine hydrochloride in a total yield of 33.5%, which also involves reacting the compound of formula (10) with ethylene oxide to give compound (11). Starting from 2,4-dinitro-l-chlorobenzene, compound (11) is obtained in an overall yield of about 40%.IP.com Journal 2009, 9(7B), 21 discloses a process for the preparation of ethyl-4-[5-[bis(2- hydroxyethyl)amino]-l-methylbenzimidazol-2-yl]butanoate (11) [R=Et], wherein the corresponding compound of formula (10) reacts, instead of ethylene oxide, with 2-halo ethanol in the presence of an inorganic base.

   A similar process has been disclosed in WO 2011/079193, wherein the base employed in the reaction of the compound of formula (10) with the 2-haloethanol is an organic base, which is advantageous over inorganic base. The preferred ester group R in the compounds (10) and (11) is the 2-propyl group.

   WO 2010/042568 discloses a second basic process for making bendamustine, which is based on providing the compound of formula (5)

   (5)

   , wherein R is typically a methyl group, by a two step synthesis starting from 2,4- dinitroaniline of formula (6) via the dinitroanilide of formula (7)

   This compound of formula (5) is subjected, at reductive conditions (preferably hydrogenation over a platinum catalyst), to a cyclization reaction forming a compound of formula (8)

   (8)

   , which subsequently may be dehydrated by a strong acid to yield the compound of formula

   (10) above. The substituent R in both formulas is a methyl group.

   The compound of formula (10) is advantageously subjected to a reductive alkylation with a chloroacetic acid or chloroacetylaldehyde. The reductive agent in the alkylation is suitably a borane or a borohydride. This way, the bendamustine ester of formula (la)

   , wherein R is a methyl group, is made directly, without need of forming an intermediate bis-hydroxyethyl compound (11). In the last step of the overall process, the ester (la) is hydrolyzed by a strong acid.

   In any process of making bendamustine, various impurities are formed due to various reactive groups in the molecule.

   The subject of the present invention is a novel synthetic route to intermediates involved in the synthesis of bendamustine of formula (1) as well as of salts and esters thereof. The approach is based on a novel use of a compound of formula (13) below as the starting material in a synthetic transformation leading to bendamustine, or a pharmaceutically acceptable salt thereof.

   In a first aspect, the invention provides a process for making a compound of formula (11), or a salt thereof,

   wherein R is hydrogen or a C1-C4 alkyl group,

   said process comprising the following steps:

   a] providing the compound of formula (13), preferably by reaction of the compound of formula (12) with methylamine,

   (12) (13)b] reduction of the compound of formula (13), preferably by hydrogen under catalysis by a transition metal, to an amino compound of formula (14),

   c] condensation of the compound of formula (14) with glutaric acid anhydride, or a functional analogue thereof, providing a tertiary alcohol compound of formula (15)

   and/or any tautomeric forms thereof according to formula (14A) or (14B)

   (14A), (14B),

   d] dehydratation and, optionally, esterification of the product of the step c) , preferably in the presence of a strong acid, to yield the compound of formula (11).

   In a particular aspect, the above process sequence leading to a compound of formula (11) further comprises a subsequent step of converting the compound of formula (11) to

   bendamustine, a salt thereof or an ester thereof, conventionally by reaction with thionyl chloride, followed by ester hydrolysis and salt formation using hydrochloric acid. In yet another aspect, the process sequence of the above steps a) to c) or, optionally, of the above steps a) to d), is performed without isolation or purification of intermediates.

   The compounds of formula (14), (14A), (14B) and (15), the above processes of making them, and the use thereof as a starting material for making compounds of formula (11) and/or bendamustine of formula (1), or a pharmaceutically acceptable salt thereof, form next particular aspects of the present invention.

    

   Example 3

   A solution of [11, R = Me] (4.0 g, 12 mmol) in dichloromethane (40.0ml) was prepared.

   A 100 ml, three -necked, round -bottomed flask equipped with a magnetic stirring bar and a reflux condenser was charged with thionyl chloride (3.60 g, 2.20 ml, 30 mmol) and dichloromethane (12.0 ml) to produce a clear solution. The latter was stirred at 500 rpm at 23 °C and the solution of [11 , R = Me] was added over 15 min via a syringe pump. The resulting mixture was stirred at 500 rpm at 23 °C for 15 min and then at 35 °C for 3.0 h. An aqueous solution of hydrochloric acid (19.4 %) was prepared by mixing of concentrated hydrochloric acid (4.7 g, 4.0 ml) with water (4.0 g, 4.0 ml) and the solution was charged to the reaction mixture. The mixture was further stirred at 500 rpm at 60 °C for 2.0 h under reduced pressure of 100 mbar and the escaping volatiles were condensed and collected outside the reaction vessel. An aqueous solution of hydrochloric acid (4.0 ml, 5 M) was charged in order to dilute the reaction mixture. The mixture was filtered through diatomaceous earth and the filter cake was washed with aqueous solution of hydrochloric acid (2x 1.0 ml, 5 M). The collected filtrate was treated with activated carbon, the used carbon was filtered off, washed with aqueous solution of hydrochloric acid (2x 1.0 ml, 5M), and the filtrate was collected to a 100 ml, round -bottomed flask equipped with a magnetic stirring bar. The filtrate was stirred and diluted with water (40.0 g, 40.0 ml). The slurry was filtered and the filter cake was washed with water (2x 1.0 ml). The filter cake (3.8 g) was charged to a 25 ml, round-bottomed flask equipped with a magnetic stirring bar containing an aqueous solution of hydrochloric acid (8.5 ml, 5M). The mixture was stirred at 60 °C until the solids were dissolved and activated carbon (0.38 g) was charged. The mixture was stirred at 40 °C for additional 5 min and the suspension was filtered through a diatomaceous earth pad. The filter cake was washed with aqueous solution of hydrochloric acid (2x 1.0 ml, 5M) and the filtrate was collected to a 100 ml, round -bottomed equipped with a magnetic stirring bar. The filtrate was stirred at 23 °C and water (42.0 g, 42.0 ml) was added and the mixture was stirred at 23 °C for additional 1 h. The slurry of crystals was filtered and the filter cake was washed with aqueous solution of hydrochloric acid (2x 3.0 ml, 5M). The filtrate was discarded and the filter cake was dried to produce Bendamustine hydrochloride monohydrate (3.3 g) with an overall isolated yield of 67 % and with a chemical purity of 99.9 % by HPLC peak area normalization.

   Characteriz ation

   lU NMR (400 MHz, DMSO-J<5): δ (ppm) = 2.05 (q, J = 7.51 Hz, 2H), 2.41 (t, J = 7.19 Hz, 2H), 3.18 (t, / = 7.63 Hz, 2H), 3.79 (m, 8H), 3.90 (s, 3H), 6.95 (d, J = 2.31 Hz, 1H), 7.11 (dd, J_x = 2.40 Hz, J₂ = 9.20 Hz, 1H), 7.80 (d, J = 9.20 Hz, 1H).

   Assay H₂0 (Karl-Fisher titration): 4.7 %

   Assay HC1 (argentometric titration): 8.8 %

   Bendamustine

   Systematic (IUPAC) name
   4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid
   Clinical data
   Trade names	Treanda
   AHFS/Drugs.com	Consumer Drug Information
   MedlinePlus	a608034
   Licence data	US FDA:link
   Pregnancy cat.	US: D
   Legal status	US: ℞-only
   Routes	Intravenous infusion
   Pharmacokinetic data
   Bioavailability	NA (intravenous only)
   Protein binding	94–96%
   Metabolism	Hydrolyzed to inactive metabolites. Two minor metabolites (M3 and M4) formed by CYP1A2
   Half-life	40 min (bendamustine), 3 h (M3), 30 min (M4)
   Excretion	Mostly fecal
   Identifiers
   CAS number	16506-27-7
   ATC code	L01AA09
   PubChem	CID 65628
   ChemSpider	59069
   UNII	9266D9P3PQ
   ChEMBL	CHEMBL487253
   Chemical data
   Formula	C16H21Cl2N3O2
   Mol. mass	358.262 g/mol

   References

   1.  Kath R, Blumenstengel K, Fricke HJ, Höffken K (January 2001). “Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia”. J. Cancer Res. Clin. Oncol. 127(1): 48–54. doi:10.1007/s004320000180. PMID 11206271.
   2.  Bagchi S (August 2007). “Bendamustine for advanced sarcoma”. Lancet Oncol. 8 (8): 674. doi:10.1016/S1470-2045(07)70225-5. PMID 17726779.
   3.  “Cephalon press release – Cephalon Receives FDA Approval for TREANDA, a Novel Chemotherapy for Chronic Lymphocytic Leukemia”. Retrieved 2008-03-23.
   4.  “Cephalon press release -Cephalon Receives FDA Approval for TREANDA to Treat Patients with Relapsed Indolent Non-Hodgkin’s Lymphoma”. Retrieved 2008-11-03.
   5.  Weide R, Hess G, Köppler H, et al. (2007). “High anti–lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A muticenter phase II study of the German Low Grade Lymphoma Study Group (GLSG)”. Leuk. Lymphoma. 48 (7): 1299–1306. doi:10.1080/10428190701361828.PMID 17613757.
   6.  New Combo Replaces CHOP for Lymphoma. Dec 2012
   7.  “‘Rediscovered’ Lymphoma Drug Helps Double Survival: Study”. June 3, 2012.
   8.  Tageja, Nishant; Nagi, Jasdeepa; “Bendamustine: something old, something new”; Cancer Chemotherapy and Pharmacology, 2010 Aug;66(3):413-23. doi: 10.1007/s00280-010-1317-x.

   External links

   • Manufacturer’s official website intended for US patients

   References:

   Bifunctional alkylating agent. Prepn: W. Ozegowski, D. Krebs, J. Prakt. Chem. 20, 178 (1963); eidem,Zentralbl. Pharm. Pharmakother. Laboratoriumsdiagn. 110, 1013 (1971). Antitumor activity: W. Jungstand et al., ibid. 1021.

   Capillary GC determn in plasma: H. Weber et al., J. Chromatogr. 525, 459 (1990).

   Toxicity study: U. Horn et al., Arch. Toxicol.Suppl. 8, 504 (1985).

   Clinical evaluation in non-Hodgkin’s lymphomas: K. Bremer, J. Cancer Res. Clin. Oncol. 128, 603 (2002); in chronic lymphocytic leukemia: T. Lissitchkov et al., ibid. 132, 99 (2006); with prednisone in multiple myeloma: W. Pönisch et al.,ibid 205.

   Review of pharmacology and clinical development: K. Bremer, W. Roth, Tumordiagn. Ther. 17, 1-6 (1996); J. A. Barman Balfour, K. L. Goa, Drugs 61, 631-638 (2001).

   WO2009120386A2	Mar 26, 2009	Oct 1, 2009	Cephalon, Inc.	Novel solid forms of bendamustine hydrochloride
   WO2010036702A1	Sep 23, 2009	Apr 1, 2010	Cephalon, Inc.	Liquid formulations of bendamustine
   WO2010042568A1	Oct 7, 2009	Apr 15, 2010	Cephalon, Inc.	Processes for the preparation of bendamustine
   WO2011079193A2	Dec 22, 2010	Jun 30, 2011	Dr. Reddy’s Laboratories Ltd.	Preparation of bendamustine and its salts
   DD34727A				Title not available
   DD159877A1				Title not available
   US20060128777	Nov 4, 2005	Jun 15, 2006	Bendall Heather H	Cancer treatments
   US20060159713	Jan 12, 2006	Jul 20, 2006	Cephalon, Inc.	Bendamustine pharmaceutical compositions

French drug maker Sanofi  Tuesday said it has received approval from the U.S. Food and Drug Administration for its Priftin (rifapentine) tablets to treat latent tuberculosis infection, or LTBI.

Following a priority review, FDA has approved Priftin in combination with isoniazid, or INH, for a new indication for treatment of LTBI in patients two years of age and older at high risk of progression to tuberculosis or TB disease.

http://www.rttnews.com/2424574/sanofi-gets-us-fda-approval-for-priftin-tablets-to-treat-latent-tb-infection.aspx#.VH4RHVxo9iA.linkedin

Rifapentine

Antibiotic DL 473IT;Cyclopentylrifampicin;DL 473;KTC 1;MDL 473;Prifitin;Priftin;R 77-3;Rifamycin AF/ACPP;

Rifapentine is an antibiotic drug used in the treatment of tuberculosis. It inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.

For the treatment of pulmonary tuberculosis

3-(((4-Cyclopentyl-1-piperazinyl)imino)methyl)rifamycin

Rifapentine

Systematic (IUPAC) name
(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z,26E)-26-{[(4-cyclopentylpiperazin-1-yl)amino]methylidene}-2,15,17,29-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,27-trioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29)-heptaen-13-yl acetate
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a602026
Legal status	?
Pharmacokinetic data
Bioavailability	increases when administered with food
Identifiers
CAS number	61379-65-5
ATC code	J04AB05
PubChem	CID 5462354
DrugBank	DB01201
ChemSpider	10482075
UNII	XJM390A33U
KEGG	D00879
ChEBI	CHEBI:45304
ChEMBL	CHEMBL1660
NIAID ChemDB	007686
Synonyms	3{[(4-cyclopentyl-1-piperazinyl)imino]methyl}rifamycin
Chemical data
Formula	C47H64N4O12
Mol. mass	877.031 g/mol

Rifapentine (INN, marketed under the brand name Priftin by Sanofi-Aventis) is an antibiotic drug used in the treatment of tuberculosis.

Rifapentine was first synthesized in 1965 by the same company that produced rifampin. The drug was approved by the Food and Drug Administration (FDA) in June 1998.

 

Medical uses

A review of alternative regimens for prevention of active tuberculosis in HIV-negative individuals with latent TB found that a weekly, directly observed regimen of rifapentine with isoniazid for three months was as effective as a daily, self -administered regimen of isoniazid for nine months. But the rifapentine-isoniazid regimen had higher rates of treatment completion and lower rates of hepatotoxicity. However, the rate of treatment-limiting adverse events was higher in the rifapentine-isoniazid regimen. ^[1]

PRIFTIN (rifapentine) for oral administration contains 150 mg of the active ingredient rifapentine per tablet.

The 150 mg tablets also contain, as inactive ingredients: calcium stearate, disodium EDTA, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose, hypromellose USP, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide.

Rifapentine is a rifamycin derivative antibiotic and has a similar profile of microbiological activity to rifampin (rifampicin). The molecular weight is 877.04.

The molecular formula is C₄₇H₆₄N₄O₁₂.

The chemical name for rifapentine is rifamycin, 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]-or 3-[N-(4-Cyclopentyl – 1-piperazinyl)formimidoyl] rifamycin or 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-cyclopentyl-l-piperazinyl)-formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate. It has the following structure:

Use in special populations

Pregnancy

Rifapentine has been assigned a Pregnancy Category C by the FDA. Rifapentine in pregnant women has not been studied, but animal reproduction studies have resulted in fetal harm and were teratogenic. If rifapentine and rifampin are used together in pregnancy, coagulation should be monitored due to a possible increased risk of maternal postpartum hemorrhage and infant bleeding. ^[2]

Adverse effects

Common side effects are hyperuricemia, pyuria, hematuria, urinary tract infection, proteinuria, neutropenia, anemia, and hypoglycemia. ^[2]

Contraindications

Rifapentine should be avoided in patients with an allergy to the rifamycin class of drugs. ^[2] This drug class includes rifampin and rifabutin. ^[3]

Interactions

Rifapentine induces metabolism by CYP3A4, CYP2C8 and CYP2C9 enzymes. It may be necessary to adjust the dosage of drugs metabolized by these enzymes if they are taken with rifapentine. Examples of drugs that may be affected by rifapentine include warfarin, propranolol, digoxin, protease inhibitors and oral contraceptives.^[2]

History

Rifapentine was first synthesized in 1965 by the same company that produced rifampin. The drug was approved by the Food and Drug Administration (FDA) in June 1998. It is synthesized in one step from rifampicine.

Rifapentine was first synthesized in 1965 by the same company that produced rifampin. The drug was approved by the Food and Drug Administration (FDA) in June 1998.

(7S,11S,12S,13S,14R,15S,16R,17R,18R,26E)-26-{[(4-Cyclopentyl-1-piperazinyl)amino]methylene}-2,15,17,29-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,27-trioxo-8,30-dioxa-24-azatetracyclo [23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29)-heptaen-13-yl acetate. Rifapentine is an antibiotic drug used in the treatment of tuberculosis.

Preparation of Rifapentine: this chemical can be prepared by 3-aldehyde rifamycin SV with 1-Amino-4-cyclopentylpiperazine. This reaction needs reagent tetrahydrofuran. The yield is 55 %

References

 

I (Dr Anthony) seated with Dr Vijay Kirpalani CEO of Pi-Process Intensification Experts LLP

at CPhI Mumbai India 3rd Dec 2014

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Vijay Kirpalani
CEO
Pi-Process Intensification Experts LLP
Plot-W-33,  M.I.D.C. Industrial Area
TALOJA – 410208, Navi Mumbai, INDIA
email : vk@pi-inc.co
www.pi-inc.co
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some pics from hall 5 -H-47 at cphi mumbai india dec 3 2014