AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Difelikefalin

 Phase 3 drug  Comments Off on Difelikefalin
May 302016
 

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Difelikefalin, CR-845; MR-13A-9; MR-13A9

4-amino-1- (D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl) piperidine-4-carboxylic acid

Phase III

C36H53N7O6, 679.40573

Originator Ferring Pharmaceuticals
Developer Cara Therapeutics
Class Analgesic drugs (peptides)
Mechanism Of Action Opioid kappa receptor agonists
Who Atc Codes D04A-X (Other antipruritics), N02A (Opioids)
Ephmra Codes D4A (Anti-Pruritics, Including Topical Antihistamines, Anaesthetics, etc), N2A (Narcotics)
Indication Pain, Osteoarthritis, Pruritus

A kappa opioid receptor agonist potentially for treatment of post-operative pain and uremic pruritus.

Difelikefalin, also known CR845, is a novel and potent kappa opioid receptor agonist. CR845 exhibit low P450 CYP inhibition and low penetration into the brain. CR845 may be useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions .

No. CAS 1024828-77-0

2D chemical structure of 1024828-77-0

Difelikefalin ( INN ) (Developmental Code Names CR845 , FE-202845 ), Also Known As D -Phe- D -Phe- D -Leu- D -Lys- [Ganma- (4-N-Piperidinyl) Amino Carboxylic Acid] (As The Acetate Salt ), Is An Analgesic Opioid Peptide [2] Acting As A Peripherally-Specific , Highly Selective Agonist Of The kappa-Opioid Receptor (KOR). [1] [3] [4] [5] It Is Under Development By Cara Therapeutics As An Intravenous Agent For The Treatment Of Postoperative Pain . [1] [3] [5] An Oral Formulation Has Also Been Developed. [5] Due To Its Peripheral Selectivity, Difelikefalin Lacks The Central Side Effects Like Sedation , Dysphoria , And Hallucinations Of Previous KOR-Acting Analgesics Such As Pentazocine And Phenazocine . [1] [3] In Addition To Use As An Analgesic, Difelikefalin Is Also Being Investigated For The Treatment Of Pruritus (Itching). [1] [3] [4 ] Difelikefalin Has Completed Phase II Clinical Trials For Postoperative Pain And Has Demonstrated Significant And “Robust” Clinical Efficacy, Along With Being Safe And Well-Tolerated. [3] [5] It Is Also In Phase II Clinical Trials For Uremic Pruritus In Hemodialysis Patients. [4]

Difelikefalin Acts As An Analgesic By Activating KORs On Peripheral Nerve Terminals And KORs Expressed By Certain Immune System Cells . [1] Activation Of KORs On Peripheral Nerve Terminals Results In The Inhibition Of Ion Channels Responsible For Afferent Nerve Activity , Causing Reduced Transmission Of Pain Signals , While Activation Of KORs Expressed By Immune System Cells Results In Reduced Release Of Proinflammatory , Nerve-Sensitizing Mediators (Eg, Prostaglandins ). [1]

 

PATENT

WO 2015198505

κ opioid receptor agonists are known to be useful as therapeutic agents for various pain. Among, kappa opioid receptor agonist with high selectivity for peripheral kappa opioid receptors, are expected as a medicament which does not cause the central side effects. Such as peripherally selective κ opioid receptor agonist, a synthetic pentapeptide has been reported (Patent Documents 1 and 2).

 

　The following formula among the synthetic pentapeptide (A)

 

[Formula 1] Being Represented By Compounds Are Useful As Pain Therapeutics. The Preparation Of This Compound, Solid Phase Peptide Synthesis Methods In Patent Documents 1 And 2 Have Been Described.

Document 1 Patent: Kohyo 2010-510966 JP
Patent Document 2: Japanese Unexamined Patent Publication No. 2013-241447
　Compound (1) or a salt thereof and compound (A), for example as shown in the following reaction formula, 4-aminopiperidine-4-carboxylic acid, D- lysine (D-Lys), D- leucine (D-Leu) , it can be prepared by D- phenylalanine (D-Phe) and D- phenylalanine (D-Phe) sequentially solution phase peptide synthesis methods condensation.
[Of 4]

The present invention will next to examples will be described in further detail.
Example
1 (1) Synthesis of Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3)
to the four-necked flask of 2L, α-Boc-Pic- OMe · HCl [α-Boc-4 – aminopiperidine-4-carboxylic acid methyl hydrochloride] were charged (2) 43.7g (148mmol), was suspended in EtOAc 656mL (15v / w). To the suspension of 1-hydroxybenzotriazole (HOBt) 27.2g (178mmol), while cooling with Cbz-D-Lys (Boc) -OH 59.2g (156mmol) was added an ice-bath 1-ethyl -3 – (3-dimethylcarbamoyl amino propyl) was added to the carbodiimide · HCl (EDC · HCl) 34.1g (178mmol). After 20 minutes, stirring was heated 12 hours at room temperature. After completion of the reaction, it was added and the organic layer was 1 N HCl 218 mL of (5.0v / w). NaHCO to the resulting organic layer 3 Aq. 218ML (5.0V / W), Et 3 N 33.0 g of (326Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 218ML 1N (5.0V / W), NaHCO 3 Aq. 218mL (5.0v / w), NaClaq . Was washed successively with 218ML (5.0V / W), Na 2 SO 4　dried addition of 8.74g (0.2w / w). Subjected to vacuum filtration, was concentrated under reduced pressure resulting filtrate by an evaporator, and pump up in the vacuum pump, the Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3) 88.9g as a white solid obtained (96.5% yield, HPLC purity 96.5%).

[0033]
(2) D-Lys (Boc) Synthesis Of -Arufa-Boc-Pic-OMe (4)
In An Eggplant-Shaped Flask Of 2L, Cbz-D-Lys (Boc) -Arufa-Boc-Pic-OMe (3) 88.3g (142mmol) were charged, it was added and dissolved 441mL (5.0v / w) the EtOAc. The 5% Pd / C to the reaction solution 17.7g (0.2w / w) was added, After three nitrogen substitution reduced pressure Atmosphere, Was Performed Three Times A Hydrogen Substituent. The Reaction Solution Was 18 Hours With Vigorous Stirring At Room Temperature To Remove The Pd / C And After The Completion Of The Reaction Vacuum Filtration. NaHCO The Resulting Filtrate 3 Aq. 441ML And (5.0V / W) Were Added For Liquid Separation, And The Organic Layer Was Extracted By The Addition Of EtOAc 200ML (2.3V / W) In The Aqueous Layer. NaHCO The Combined Organic Layer 3 Aq. 441ML And (5.0V / W) Were Added for liquid separation, and the organic layer was extracted addition of EtOAc 200mL (2.3v / w) in the aqueous layer. NaClaq the combined organic layers. 441mL and (5.0v / w) is added to liquid separation, was extracted by the addition EtOAc 200ML Of (2.3V / W) In The Aqueous Layer. The Combined Organic Layer On The Na 2 SO 4　Dried Addition Of 17.7 g of (0.2W / W), Then The Filtrate Was Concentrated Under Reduced Pressure Obtained Subjected To Vacuum Filtration By an evaporator, and pump up in the vacuum pump, D-Lys (Boc) -α-Boc-Pic- OMe (4) to give 62.7g (90.5% yield, HPLC purity 93.6%).
(3) Cbz-D-Leu -D-Lys (Boc) -α-Boc-Pic-OMe synthesis of (5)
in the four-necked flask of 2L, D-Lys (Boc) -α-Boc-Pic-OMe (4) was charged 57.7 g (120 mmol), was suspended in EtOAc 576mL (10v / w). HOBt 19.3g (126mmol) to this suspension, was added EDC · HCl 24.2g (126mmol) while cooling in an ice bath added Cbz-D-Leu-OH 33.4g (126mmol). After 20 minutes, after stirring the temperature was raised 5 hours at room temperature, further the EDC · HCl and stirred 1.15 g (6.00 mmol) was added 16 h. After completion of the reaction, it was added liquid separation 1N HCl 576mL (10v / w) . NaHCO to the resulting organic layer 3 Aq. 576ML (10V / W), Et 3 N 24.3 g of (240Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 576ML 1N (10V / W), NaHCO 3 Aq. 576mL (10v / w), NaClaq . Was washed successively with 576ML (10V / W), Na 2 SO 4　dried addition of 11.5g (0.2w / w). After the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and pump up in the vacuum pump, the Cbz-D-Leu-D- Lys (Boc) -α-Boc-Pic-OMe (5) 85.8g It was obtained as a white solid (98.7% yield, HPLC purity 96.9%).
(4) D-Leu-D -Lys (Boc) -α-Boc-Pic-OMe synthesis of (6)
in an eggplant-shaped flask of 1L, Cbz-D-Leu- D-Lys (Boc) -α-Boc-Pic -OMe the (5) 91.9g (125mmol) were charged, was added and dissolved 459mL (5.0v / w) the EtOAc. The 5% Pd / C to the reaction solution 18.4g (0.2w / w) was added, After three nitrogen substitution reduced pressure atmosphere, was performed three times a hydrogen substituent. The reaction solution was subjected to 8 hours with vigorous stirring at room temperature to remove the Pd / C and after the completion of the reaction vacuum filtration. NaHCO the resulting filtrate 3 Aq. 200mL (2.2v / w) were added to separate liquid, NaHCO to the organic layer 3 Aq. 200mL (2.2v / w), NaClaq . It was sequentially added washed 200mL (2.2v / w). To the resulting organic layer Na 2 SO 4　dried added 18.4g (0.2w / w), to the filtrate concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and a pump-up with a vacuum pump. The resulting amorphous solid was dissolved adding EtOAc 200mL (2.2v / w), was crystallized by the addition of heptane 50mL (1.8v / w). Was filtered off precipitated crystals by vacuum filtration, the crystals were washed with a mixed solvent of EtOAc 120mL (1.3v / w), heptane 50mL (0.3v / w). The resulting crystal 46.1g to added to and dissolved EtOAc 480mL (5.2v / w), was crystallized added to the cyclohexane 660mL (7.2v / w). Was filtered off under reduced pressure filtered to precipitate crystals, cyclohexane 120mL (1.3v / w), and washed with a mixed solvent of EtOAc 20mL (0.2v / w), and 30 ° C. vacuum dried, D-Leu- as a white solid D-Lys (Boc) -α- Boc-Pic-OMe (6) to give 36.6 g (48.7% yield, HPLC purity 99.9%).
(5) Synthesis of Cbz-D-Phe-D- Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7)
to the four-necked flask of 1L, D-Leu-D- Lys (Boc) -α-Boc-Pic-OMe with (6) 35.8g (59.6mmol) was charged, it was suspended in EtOAc 358mL (10v / w). To this suspension HOBt 9.59g (62.6mmol), Cbz- D-Phe-OH 18.7g was cooled in an ice bath is added (62.6mmol) while EDC · HCl 12.0g (62.6mmol) It was added. After 20 minutes, a further EDC · HCl After stirring the temperature was raised 16 hours was added 3.09 g (16.1 mmol) to room temperature. After completion of the reaction, it was added and the organic layer was 1N HCl 358mL of (10v / w). NaHCO to the resulting organic layer 3 Aq. 358ML (10V / W), Et 3 N 12.1 g of (119Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 358ML 1N (10V / W), NaHCO 3 Aq. 358mL (10v / w), NaClaq . Was washed successively with 358ML (10V / W), Na 2 SO 4　dried addition of 7.16g (0.2w / w). After the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and pump up in the vacuum pump, Cbz-D-Phe-D -Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7) was obtained 52.5g as a white solid (yield quant, HPLC purity 97.6%).
(6) D-Phe-D -Leu-D-Lys (Boc) synthesis of -α-Boc-Pic-OMe ( 8)
in an eggplant-shaped flask of 2L, Cbz-D-Phe- D-Leu-D-Lys ( Boc) -α-Boc-Pic- OMe (7) the 46.9g (53.3mmol) were charged, the 840ML EtOAc (18V / W), H 2 added to and dissolved O 93.8mL (2.0v / w) It was. The 5% Pd / C to the reaction mixture 9.38g (0.2w / w) was added, After three nitrogen substitution reduced pressure atmosphere, was performed three times a hydrogen substituent. The reaction solution was subjected to 10 hours with vigorous stirring at room temperature to remove the Pd / C and after the completion of the reaction vacuum filtration. NaHCO the resulting filtrate 3 Aq. 235mL (5.0v / w) were added to separate liquid, NaHCO to the organic layer 3 Aq. 235mL (5.0v / w), NaClaq . It was added sequentially cleaning 235mL (5.0v / w). To the resulting organic layer Na 2 SO 4　dried addition of 9.38g (0.2w / w), then the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, pump up with a vacuum pump to D-Phe -D-Leu-D-Lys ( Boc) -α-Boc-Pic-OMe (7) was obtained 39.7g (yield quant, HPLC purity 97.3%).
351mL was suspended in (10v / w). To this suspension HOBt 7.92g (51.7mmol), Boc-D-Phe-OH HCl HCl
(8) D-Phe-D -Phe-D-Leu-D-Lys-Pic-OMe Synthesis Of Hydrochloric Acid Salt (1)
In An Eggplant-Shaped Flask Of 20ML Boc-D-Phe-D -Phe-D- Leu-D- lys (Boc) -α -Boc- Pic-OMe (9) and 2.00gg, IPA 3.3mL (1.65v / w), was suspended by addition of PhMe 10mL (5v / w). It was stirred at room temperature for 19 hours by addition of 6N HCl / IPA 6.7mL (3.35v / w). The precipitated solid was filtered off by vacuum filtration and dried under reduced pressure to a white solid of D-Phe-D-Phe- D- Leu-D-Lys-Pic- OMe 1.59ghydrochloride (1) (yield: 99 .0%, HPLC purity 98.2%) was obtained.
(9) D-Phe-D -Phe-D-Leu-D-Lys-Pic-OMe Purification Of The Hydrochloric Acid Salt (1)
In An Eggplant-Shaped Flask Of 20ML-D-Phe-D- Phe D-Leu -D-Lys- pic-OMe hydrochloride crude crystals (1) were charged 200mg, EtOH: MeCN = 1: after stirring for 1 hour then heated in a mixed solvent 4.0 mL (20v / w) was added 40 ° C. of 5 , further at room temperature for 2 was time stirring slurry. Was filtered off by vacuum filtration, the resulting solid was dried under reduced pressure a white solid ((1) Purification crystals) was obtained 161 mg (80% yield, HPLC purity 99.2% ).
(10) D-Phe-D -Phe-D-Leu-D-Lys-Pic Synthesis (Using Purified
(1)) Of (A) To A Round-Bottomed Flask Of 10ML D-Phe-D-Phe-D- -D-Lys Leu-Pic-OMe Hydrochloride Salt (1) Was Charged With Purified Crystal 38.5Mg (0.0488Mmol), H 2 Was Added And Dissolved O 0.2ML (5.2V / W). 1.5H Was Stirred Dropwise 1N NaOH 197MyuL (0.197mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 48.8μL (0.0488mmol), to obtain a D-Phe-D-Phe- D-Leu-D-Lys- Pic (A) (yield: quant , HPLC purity 99.7%).
D-Phe-D-Phe- D-Leu-D-Lys-Pic-OMe (1) physical properties 1 H NMR (400 MHz, 1M DCl) [delta] ppm by: 0.85-1.02 (yd,. 6 H), 1.34-1.63 ( m, 5 H), 1.65-2.12 ( m, 5 H), 2.23-2.45 (m, 2 H), 2.96-3.12 (m, 4 H), 3.19 (ddt, J = 5.0 & 5.0 & 10.0 Hz), 3.33-3.62 (m, 1 H), 3.68-3.82 (m, 1 H), 3.82-3.95 (m, 4 H), 3.95-4.18 (m, 1 H), 4.25-4.37 (m, 2 H), 4.61-4.77 (M, 2 H), 7.21-7.44 (M, 10 H) 13 C NMR (400MHz, 1M DCl) Deruta Ppm: 21.8, 22.5, 24.8, 27.0, 30.5, 30.8, 31.0, 31.2, 31.7, 37.2 , 37.8, 38.4, 39.0, 39.8, 40.4, 40.6, 41.8, 42.3, 49.8, 50.2, 52.2, 52.6, 54.6, 55.2, 57.7, 57.9, 127.6, 128.4, 129.2, 129.6, 129.7, 129.8 dp 209.5 ℃

Example 2
(Trifluoroacetic Acid (TFA)
Use) (1) D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe TFA Synthesis Of Salt (1)
TFA 18ML Eggplant Flask Of 50ML (18V / W) , 1- Dodecanethiol 1.6ML (1.6V / W), Triisopropylsilane 0.2ML (0.2V / W), H 2 Sequentially Added Stirring The O 0.2ML (0.2V / W) Did. The Solution To The Boc-D-Phe- D- Phe-D-Leu-D -Lys (Boc) -α-Boc-Pic-OMe the (9) 1.00g (1.01mmol) was added in small portions with a spatula. After completion of the reaction, concentrated under reduced pressure by an evaporator, it was added dropwise the resulting residue in IPE 20mL (20v / w). The precipitated solid was filtered off, the resulting solid was obtained and dried under reduced pressure to D-Phe-D-Phe- D-Leu -D-Lys-Pic-OMe · TFA salt as a white solid (1) (Osamu rate 93.0%, HPLC purity 95.2%).
(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic synthesis of (A)
to a round-bottomed flask of 10mL D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe TFA were charged salt (1) 83mg (0.0843mmol), was added and dissolved H2O 431μL (5.2v / w). Was 12h stirring dropwise 1N NaOH 345μL (0.345mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 84.3μL (0.0843mmol), to obtain a D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) ( yield: quant, HPLC purity 95.4%).
Example
3 (HCl / EtOAc
Use) (1) In An Eggplant-Shaped Flask Of 30ML Boc-D-Phe-D -Phe-D-Leu-D-Lys (Boc) -Arufa-Boc-Pic-OMe (9) 1. It was charged with 00g (1.01mmol ), was added and dissolved EtOAc7.0mL (7.0v / w). 4N HCl / EtOAc 5.0mL (5.0v / w) was added after 24h stirring at room temperature, the precipitated solid was filtered off by vacuum filtration, washed with EtOAc 2mL (2.0v / w). The resulting solid D-Phe-D-Phe- D-Leu-D-Lys-Pic-OMe hydrochloride (1) was obtained 781mg of a white solid was dried under reduced pressure (the 96.7% yield, HPLC purity 95.4%).
(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic (A) Synthesis of
eggplant flask of 10mL D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe hydrochloride were charged salt (1) 90 mg (0.112 mmol), H 2 was added and dissolved O 0.47mL (5.2v / w). Was 12h stirring dropwise 1N NaOH 459μL (0.459mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 0.112μL (0.112mmol), was obtained D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) ( yield: quant, HPLC purity 93.1%).
4 Example
Compound (1) Of The Compound By Hydrolysis Synthesis Of (The A) (Compound (1) Without
Purification) Eggplant Flask 10ML D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe (1) Charged Hydrochloride Were (Without Pre-Step Purification) 114.5Mg (0.142Mmol), H 2 Was Added And Dissolved O 595MyuL (5.2V / W). Was 14H Stirring Dropwise 1N NaOH 586MyuL (0.586Mmol) At Room Temperature. After Completion Of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 0.15μL (0.150mmol), was obtained D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) (yield: quant, HPLC purity 95.2 %).
Example 1 Comparative
Path Not Via The Compound (1) (Using Whole Guard Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -Alpha-Boc-Pic-OMe
(A)) (1) D–Boc Phe- D-Phe-D-Leu-D-Lys (Boc) -Arufa-Boc-Pic-OH Synthesis Of
Eggplant Flask Of 30ML Boc-D-Phe-D -Phe-D-Leu-D- Lys (Boc) -α- Boc-Pic -OMe (9) were charged 1.00g (1.00mmol), was added and dissolved MeOH 5.0mL (5.0v / w). After stirring for four days by the addition of 1N NaOH 1.1 mL (1.10mmol) at room temperature, further MeOH 5.0mL (5.0v / w), 1N NaOH 2.0mL the (2.0mmol) at 35 ℃ in addition 3h and the mixture was stirred. After completion of the reaction, 1 N HCl 6.1 mL was added, After distilling off the solvent was concentrated under reduced pressure was separated and the organic layer was added EtOAc 5.0mL (5.0mL) .NaClaq. 5.0mL (5.0v / w) Wash the organic layer was added, the organic layer as a white solid was concentrated under reduced pressure to Boc-D-Phe-D- Phe-D-Leu-D-Lys (Boc) – α-Boc-Pic-OH 975.1mg (99.3% yield, HPLC purity 80.8% )
(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic synthesis of (A)
to a round-bottomed flask of 20mL Boc-D-Phe-D -Phe-D-Leu-D-Lys (Boc) It was charged -α-Boc-Pic-OH ( 10) 959mg (0.978mmol), was added and dissolved EtOAc 4.9mL (5.0v / w). And 4h stirring at room temperature was added dropwise 4N HCl / EtOAc 4.9mL (5.0mL) at room temperature. After completion of the reaction, it was filtered under reduced pressure, a white solid as to give D-Phe-D-Phe- D-Leu-D-Lys-Pic the (A) (96.4% yield, HPLC purity 79.2%) .
　If not via the compound of the present invention (1), the purity of the compound obtained (A) was less than 80%.
PATENT
http://www.google.com/patents/US20110212882

References

  1.  S. Sinatra Raymond; Jonathan S. Jahr;. J. Michael Watkins-Pitchford (14 October 2010) The Essence Of Analgesia And Analgesics …. Cambridge University Press Pp 490-491 ISBN  978-1-139-49198-3 .
  2.  A Janecka, Perlikowska R, Gach K, Wyrebska A, Fichna J (2010) “Development Of Opioid Peptide Analogs For Pain Relief”.. Curr Pharm Des… 16 (9):. 1126-35 Doi : 10.2174 / 138161210790963869 . PMID  20030621 .
  3. Apfelbaum Jeffrey (8 September 2014). Ambulatory Anesthesia, An Issue Of Anesthesiology Clinics, . Elsevier Health Sciences. Pp. 190-. ISBN  978-0-323-29934-3 .
  4.  Cowan Alan;. Gil Yosipovitch (10 April 2015) Pharmacology Of Itch …. Springer Pp 307- ISBN  978-3-662-44605-8 .
  5.  Allerton Charlotte (2013). Pain Therapeutics: Current And Future Treatment Paradigms …. Royal Society Of Chemistry Pp 56- ISBN  978-1-84973-645-9 .

 

REFERENCES

1: Cowan A, Kehner GB, Inan S. Targeting Itch With Ligands Selective For kappa Opioid
. Receptors Handb Exp Pharmacol 2015; 226:.. 291-314 Doi:
.. 10.1007 / 978-3-662-44605-8_16 Review PubMed PMID: 25861786.

 

Difelikefalin
Difelikefalin.svg
Systematic (IUPAC) Name
Amino–4 1- ( D -Phenylalanyl- D -Phenylalanyl- D -Leucyl- D -Lysyl) Piperidine-4-Carboxylic Acid
Clinical data
Of Routes
Administration		 Intravenous
Pharmacokinetic Data
Bioavailability Pasento 100 ( IV ) [1]
Metabolism Metabolized Not [1]
Biological half-life Hours 2 [1]
Excretion As Unchanged Excreted
Drug Via Bile And Urine [1]
Identifiers
CAS Number 1024828-77-0
ATC code None
ChemSpider 44208824
Chemical data
Formula C 36 H 53 N 7 O 6
Molar mass 679.85 g / mol

///// Difelikefalin,  CR845 , FE-202845,  Phase III, PEPTIDES

CC (C) C [C @ H] (C (= O) N [C @ H] (CCCCN) C (= O) N1CCC (CC1) (C (= O) O) N) NC (= O) [ C @@ H] (Cc2ccccc2) NC (= O) [C @@ H] (Cc3ccccc3) N

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Rovatirelin Hydrate

 Phase 3 drug  Comments Off on Rovatirelin Hydrate
May 302016
 

2D chemical structure of 204386-76-5

img

Rovatirelin Hydrate, S-0373, 

Rovatirelin, RN: 204386-76-5
UNII: 9DL0X410PY

(4S,5S)-5-methyl-N-((2S)-1-((2R)-2-methylpyrrolidin-1-yl)-1-oxo-3-((1,3-thiazol-4-yl)methyl)propan-2-yl)-2-oxo-1,3-oxazolidine-4-carboxamide

(4S,5S)-5-methyl-N-((S)-1-((R)-2-methylpyrrolidin-1-yl)-1-oxo-4-(thiazol-4-yl)butan-2-yl)-2-oxooxazolidine-4-carboxamide4-Oxazolidinecarboxamide, 5-methyl-N-[2-(2-methyl-1-pyrrolidinyl)-2-oxo-1-(4-thiazolylmethyl)ethyl]-2-oxo-, [4S-[4α[R*(S*)],5α]]-

Phase III

A thyrotropin-releasing hormone potentially for the treatment of spinocerebellar ataxia.

CAS No.204386-76-5(Rovatirelin)

879122-87-9(Rovatirelin Hydrate)

C17H24N4O4S
Exact Mass: 380.1518

Rovatirelin is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). Rovatirelin increased locomotor activity. Rovatirelin may have an orally effective therapeutic potential in patients with SCD.

Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.

PATENT

WO 9808867

 

PATENT

WO 9945000 

 

PATENT

WO 2002017954

Example

Preparation of the compound represented by Example 1 set (IX)

The second step

Two

(First step)

Method described in the literature (Synth. Commun., 20, 3507 (1990)) synthesized N- in (tert- butoxide deer Lupo sulfonyl) one 3- (4 one-thiazolyl) one L Aranin (1, 21.79 g, 80 mmol) in Torifuruoro and the mixture was stirred acetic acid (80 ml) were added under ice-cooling for 2 hours and a half. Then stirred for 30 minutes at room temperature was added to the reaction mixture p- toluenesulfonic acid hydrate (15.22 g, 80 mmol). The reaction mixture was concentrated to dryness under reduced pressure. To remove excess Torifuruoro acetic acid by the obtained residue concentrated to dryness under reduced pressure by addition of water and methanol.Obtained obtained residue was collected by filtration crystals ether was added to precipitate the compound (2) 29.8 g (quantitative).

NMR (CD 3 OD): 9.01 (1H, d-, J = 1.8 Hz), 7.70 (2H ; yd), 7.46 (lH, d-, J = 1.8 Hz), 7.23 (2H, yd), 4.38 (1H, dd , J = 4.8 from and 3.8 from Hz), 3.45 (2H ; yd), 2.37 (3H, s).

(Second step)

I 匕合 product (2) 38.85 g E evening Nord (200 ml) of (112.8 mmol) – in THF (600 ml) solution, diphenyl di § zone methane while 攪袢 at room temperature (39 g, 201 mmol) in small portions over 30 minutes were added. The reaction mixture was stirred for 1 hour at room temperature, Ziv E sulfonyl di § zone methane (10 g, 51.5 mmol) was added and stirred for one hour. To the reaction mixture

After decomposing the excess reagent by the addition of acetic acid (0.1 ml), it was concentrated to dryness under reduced pressure and distilled off the solvent. The resulting residue (92 g) with ether (1 L) was crystallized to give compound (3) 49.05 g (96.1%).

mp: 139-140 ° C

[A] D = -34.7 ° (C = 1.006, CHC1 3) 23 ° C)

^ Cm IRCKB ” 1 : 1753, 1602, 1512, 1496, 1260, 1224, 1171, 1124, 1036, 1012. NMR (CD 3 0D): 8.92 (1H, D, J = 2 Hz), 7.70 (2H ; M ), 7.2-7.4 (13H, m) , 6.91 (1H, s), 4.62 (1H, t, J = 5.8 Hz), 3.47 (2H, d, J = 5.8 Hz), 2.36 (3H, s).

Elemental analysis (C 2E H 2S N 2 0 5 S 2 )

Calculated: C, 61.16; H, 5.13; N, 5.49; S, 12.56.

Measured value: C, 61.14; H, 5.32; N, 5.41; S, 12.46.

(Third step)

Cis-one L one 5-methyl-2-one O Kiso O Kisa ethylbenzthiazoline one 4-carboxylic acid 13.95 g (96.14 mmol), compound (3) 49.09 g (96.14 mmol ), N-hydroxybenzotriazole To Riazoru 2.6 g (19.23 mmol) and under ice-cooling in THF (1L) solution of Toryechiruamin 14.1 ml (lOlmmol), was added to the DCC (20.83g, 101 mmol). The cooling bath was removed after stirring for 10 minutes at the same temperature, and stirred for an additional 2 0 hours at room temperature. After removing the precipitated precipitate and the filtrate concentrated to dryness under reduced pressure an oily residue (82.7 g was obtained). The residue was filtered off and dissolved by heating to insoluble matter in acetic acid Echiru (700 ml). The filtrate was successively washed with sodium carbonate aqueous solution and water.After the addition of methanol (20 ml) the organic layer was dried with sulfuric acid mug Neshiumu, was concentrated to a small volume under reduced pressure.Precipitated collected by filtration and acetic acid E Ji Le crystals – ether (2: 3) washing to compound with a mixture (4) 35.69 g (79.8% ) was obtained. After addition was concentrated to dryness under reduced pressure of the mother liquor, and crystallized from acetic acid E Chiru ether mixture compound (4) 2.62 g (5.9% ) was obtained.

mp: 176-177 ° C

[A] D = -39.2 ° (C = 1.007, CHC1 3 , 24 ° C)

^ Cm IRiKB 1 : 1739, 1681, 1508, 1453, 1386, 1237, 1193, 1089.

NMR (CDC1 3 ): 8.71 (1H, d-, J = 1.8 Hz), 8.18 (lH, d-‘J = 3.9 from Hz), 7.2-7.4 (10H ; yd), 6.82 (1H, s), 6.66 (1H, d-, J = 1.8 Hz), 5.79 (1H, s), 5.12 (1H, yd), 4.94 (lH, yd), 4.35 (1H ; dd, J = 1.8 and 4.5 from Hz), 3.40 (1H ; dd, J 5.7 and 15 = Hz), 3.29 (1H ; dd, J = 4.5 of and 15 Hz), 1.27 (3H, d-, J = 6.3 Hz).

Elemental analysis (C 24 H 23 N 3 0 5 S)

Calculated: C, 61.92; H, 4.98; N, 9.03; S, 6.89.

Measured value: C ! 61.95; H, 5.01; N, 8.94; S ) 6.62.

(Fourth step)

Compound (4) 41.24 under ice-cooling to g (88.59 mmol), and the mixture was stirred Anisoru (240ml) and To Rifuruoro acetic acid (120 ml) and the mixture for 15 minutes. And the mixture was stirred for 2 hours 3 0 minutes further room temperature after removal of the cooling bath. The reaction mixture was added to the E one ether (500 ml) to the oily residue obtained by concentrated to dryness under reduced pressure was collected by filtration and pulverized. The resulting powder is water (50 ml) – was removed by filtration methanol (300 ml) warming dissolved insoluble matter in a mixture. The filtrate was concentrated to small volume under reduced pressure, and allowed to stand at room temperature for 3 days adding a seed crystal and methanol. The precipitated crystals were obtained Shi preparative filtration compound (5) 14.89 g (56.1%). The mother liquor was concentrated to dryness under reduced pressure, to give again further compound was crystallized from methanol one ether mixture of the (5) 10.3 g (38%). mp: 214-215 ° C

[]. -4.2 ° = (C = 0.5, H 2 0, 22 ° C)

^ Cm IRCKB 1 : 1753, 1707, 1655, 1548, 1529, 1409, 1343, 1264, 1236, 1102, 1092. NMR (DMS0-D6): 9.02 (1H, D, J = 1.8 Hz), 8.46 (1H, d- ; J = 3.9 from Hz), 7.74 (1H, s),

7.38 (1H, d, J = 1.8 Hz), 4.77 (1H, dq, J = 6.6 and 8.7 Hz), 4.66 (1H, m), 4.21 (1H, d,

J = 8.7 Hz), 3.24 (IH, dd, J = 5.1 and 15 Hz), 3.13 (1H, dd, J = 8.4 and 15 Hz),

1.13 (3H, d, J = 6.6 Hz).

Elemental analysis (C U H 13 N 3 0 5 S)

Calculated: C ; 44.14; H, 4.38; N, 14.04; S ) 10.71.

Measured value: C, 43.94; H, 4.478; N, 14.09; S, 10.58.

(Fifth step)

Compound (5) 12.1 g, (40.48 mmol) and N- hydroxysuccinimide (4.66 g, 40,48 mM) under ice-cooling to THF (242 ml) suspension of,: DCC (8.35 g, 40.48 mmol) was added to 3 and the mixture was stirred for 10 minutes. The cooling bath was removed, and the mixture was further stirred at room temperature for 2 hours. The resulting compound N- hydroxysuccinimide ester solution of (5) was synthesized in a way described in the literature (Tetrahedron, 27, 2599 (1971 )) (R) – (+) – 2- Mechirupiro lysine hydrochloride (5.42 g) and Toryechiruamin (8.46 ml, was added at room temperature to THF (121 ml) suspension of 60.72 mmol). The reaction mixture was stirred for an additional 1 5 hrs. The filtrate after removal of the insoluble matter that has issued analysis was concentrated to dryness under reduced pressure. Residue (24.6 Ga) the insoluble material was removed by filtration was dissolved in water (150 ml). The filtrate was purified by gel filtration column chromatography one (MCI Gel CHP-20P, 600 ml). 4 0% aqueous methanol solution compound of the collected crude eluted cut off fractionated (IX) was obtained 8.87 g. Then after purification by silica gel column chromatography (black port Holm one methanol mixture), to give the compound was freeze-dried (IX) 5.37 g (35.7% ).

mp: 192-194 ° C

[A] D = -1.9 ° (C = 1.005, H 2 0, 25 ° C)

KB Cm- IR 1 : 1755, 1675, 1625, 1541, 1516, 1448, 1232, 1097.

NMR (CD 3 0D): 8.97 (1H, t, J = 2.1 Hz), 7.34 (1H, t, J = 2.1 Hz), 5.19 and 5.04 (total the IH, the each t, J = 7.5 Hz), 4.92 (1H , Dq, J = 6.6 And 8.7 Hz), 4.36 And 4.35 (1H, D, J = 8.7 Hz), 4.07 And 3.92 (Total IH, Eac M), 3.78 (1H ; M), 3.42 (1¾ M), 3.22 (2H, m), 1.5-2.0 ( 4H, m), 1.28 and 1.22 (total 3H, each d, J = 6.6 Hz), 1.21 and 1.02 (total 3H, each d, J = 6.6 Hz).

Elemental analysis (C 16 H 22 N 4 0 4 S H 2 0)

Calculated: C, 49.99; H, 6.29; N, 14.57; S, 8.34.

Measured value: C, 49.99; H, 6.29; N, 14.79; S, 8.36.

PATENT

WO 2006028277

Example

Example 1

B

Figure imgf000007_0001

Step 1 l-N-[N<tert-butoxycarbonyl)-3-(^^^

N.N-dicyclohexylcarbodiimide (10.83 g, 52.5 mmol), N-hydroxybenzotriazole (2.03 g, 15 mmol) and triethylamine (7.7 ml, 55.2 mmol) were added to a solution (130 ml) of N-(tert-butoxycarbonyl)-3-(thiazol-4-yl)-L-alanine (1) (13.62 g, 50 mmol) obtained by the method described in literatures (J. Am. Chem. Soc. 73, 2935 (1951) and Chem. Pharm. Bull. 38, 103 (1950)) and 2(R)-2-methylpyrrolidine p-toluenesulfonic acid (2) (12.79 g, 50 mmol) obtained by the method described in a literature (HeIv. Chim. Acta, 34, 2202 (1951)) in tetrahydrofuran. The mixture was stirred for 20 hours at room temperature. After the precipitates are filtered off, the obtained filtrate was concentrated under reduced pressure. Thus-obtained residue was dissolved in ethyl acetate (200 ml) and the solution were washed with an aqueous solution of sodium hydrogencarbonate and water, successively. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give a title compound (3) (16.45 g, 100%) as oil.

NMR (CDCl3): OH 8.76 and 8.75 (1 H, each d, J=2.1Hz, Thia-H-2), 7.08 (1 H, d, J=2.fflz, thia-H-5), 5.45 (1 H, m, NH), 3.45-3.64 (1 H, m, AIa-CoH), 4.14 and 3.81 (1 H, each m, Pyr-CαH), 3.51 (1 H, m, PVr-NCH2), 3.1-3.4 (3 H, m, Pyr-CH2and AIa-CH2), 1.39 (9 H, s, BOC), 1.3-2.0 (4 H, m, PyT-CH2), 1.06 (3 H, d, J=6Hz, Pyr-Me)

Step 2 l-N-[3-(thiazol-4-yl)-L-alanyl]-(2R)-2-methylpyrroHdine di-p-toluenesulfcnate (4)

Compound (3) (33.77 g, 99.48 mmol) and p-toluenesulfonic acid hydrate (37.85 g, 199 mmol) were dissolved in ethyl acetate (101 ml) and the solution was cooled with ice. To the mixture, 4 mol/L solution of hydrogen chloride-ethyl acetate (125 ml) was added, and the mixture was stirred for 2 hours 45 minutes. After the mixture was concentrated under reduced pressure, methanol was added to the residue. The mixture was concentrated. Methanol-toluene (1: 1) was added to the residue and concentrated under reduced pressure to give crystalline residue. The residue was washed with acetone and filtered to give compound (4) as crystals (36 g, 62%). After the mother liquor was concentrated under reduced pressure, methanol and toluene were added to the residue and concentrated. Obtained crystalline residue was washed with acetone to give compound (4) (10.67 g, 18.4%). mp 188-189 0C [α]D 24 +2.2 (c, 1.0, MeOH) IR(KBr)Cm“1: 3431, 3125, 3080, 2963, 1667, 1598, 1537, 1497, 1451, 1364, 1229, 1198, 1170, 1123, 1035, 1011.

NMR (CD3OD): δH 9.04 and 9.03 (1 H, each d, J=2.1Hz, Thia-H-2), 7.70 (2 H, m, aromaticH), 7.46 (1H, d, J=2.1Hz, thia-H-5), 7.23 (2H, m, aromaticH), 4.49and4.46 (1 H, each d, J=6.9Hz, Ala-CαH), 4.14 and 3.75 (1 H, each m, Pyr-CαH), 3.51 (1 H, m, pyr-NCH2), 3.2-3.4 (3 H, m, PyT-CH2 and AIa-CH2), 2.36 (3 H, s, aromatic Me), 1.3-2.0 (4 H, m, pyr-CH2), 1.19 and 1.07 (3 H, each d, J=6.3Hz, Pyr-Me) Anal Calcd For C11H17N3OS 2C7H8O3S Calculated: C, 51.44%; H1 5.70%; N, 7.20%; S, 16.48%. Found: C, 51.36%; H, 5.69%; N, 7.23%; S, 16.31%.

Step 3 l-[N-[(4S,5S)-(5-methyl-2-oxooxazolidin-4-yl)carbonyl]-3-(thiazol-4-yl)-L-alanyl-(2R)-2- methylpyrrolidine trihydrate (I- 1) Step 3 (1) Method A

(4S, 5S)-5-methyl-2-oxooxazolidin-4-yl carboxylic acid (5) (1.368 g, 9.43 mmol) obtained by the method described in literatures (J. Chem. Soc. 1950, 62; Tetrahedron 48; 2507 (1992) and Angew. Chem. 101, 1392 (1989)), Compound (4) (5 g, 8.56 mmol) and N-hydiOxysuccinimide (217 mg, 1.89 mmol) were dissolved in N, N-dimethylformamide (10 ml), and tetrahydrofuran (65 ml) was added. After the mixture was cooled with ice in a cool bath, triethylamine (2.63 ml, 18.86 mmol) and N, N-dicyclohexylcarbodiimide (2.04 g, 9.89 mmol) were added with stirred and the mixture was stirred for additional 30 minutes. The cooling bath was removed and the mixture was stirred for 15 hours at room temperature. The precipitated were filtered off and the filtrate was concentrated under reduced pressure. Water (100 ml) was added to thus-obtained residue (9.95 g) and the mixture was stirred for 1.5 hours at room temperature. After insoluble substance was filtered off, the filtrate was concentrated until it was reduced to about half volume under reduced pressure. The small amount of insoluble substance was filtered off and the filtrate was concentrated until it was reduced to about 2O g under reduced pressure. After the mixture was allowed to stand in a refrigerator for 3 days, the precipitated crystals (2.98 g) were collected by filtration and washed with cold water. The filtrate was extracted twice with chloroform, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (5 ml) was added to oil residue (1.05 g) and the mixture was stirred to give crystals (136 mg). The obtained crystals were combined and dissolved in purified water (45 ml) with heating. After the solution was allowed to cool to room temperature, the precipitated insoluble substance was filtered off The filtrate was concentrated under reduced pressure and allowed to stand at room temperature overnight. The mixture was cooled with ice, and the crystals were collected by filtration to give Compound (1-1, 2.89 g, 80.3%). mp 194-196 0C

[α]D 22 -2.0 ± 0.4 ° (c, 1.008, H2O), [α]365 +33.1 ± 0.7 ° (c, 1.008, H2O)

IR(Nujor)cm”1: 3517, 3342, 3276, 3130, 3092, 3060, 1754, 1682, 1610, 1551, 1465, 1442,

1379, 1235, 1089. NMR(CD3OD): δH 8.97 and 8.96 (total 1 H, d, J=2.1Hz, Thia-H-2), 7.34 and 7.33 (total 1

H, d, J=2.1Hz, Thia-H-5), 5.18 and 5.04 (total 1 H, each t, J=7.5Hz, Ala-CαH), 4.92 (1

H, dq, J=6.6 and 8.7Hz, Oxa-H-5), 4.36 and 4.35 (total 1 H, d, J=8.7Hz, Oxa-H-4), 4.07 and 3.92 (total 1 H, each m, Pyr-Cα-H), 3.78 (1 H, m, Pyr-NCH2), 3.42 (1 H, m, Pyr- 5 NCH2), 3.22 (2 H, m, AIa-CH2), 1.5-2.0 (4 H, m, Pyr-CH2), 1.28 and 1.22 (total 3 H, each d, J=6.6Hz, Oxa-5-Me), 1.21 and 1.02 (total 3 H, each d, J=6.6Hz, Pyr-2-Me)

Anal. Calcd For C16H22N4O4S 3H2O

Calculated: C, 45.00%; H, 6.71%; N, 13.33%; S, 7.63%.

Found: C, 45.49%; H, 6.60%; N, 13.58%, S, 7.88%. 10

Step 3 (2)

Method B

After Compound (1-2) (410 g, 1.119 mmol) was dissolved in purified water (6.3 L) with heating, the solution was concentrated until the total weight of the mixture was 15 reduced to 1370 g under reduced pressure. The concentrated solution was allowed to stand at room temperature overnight. The solution was cooled with ice for 1 hour and filtered to give the precipitated crystals. The obtained crystals were washed with cold water to give

Compound (T- 1) (448 g, 95.2%) as colorless crystals. Mother liquor was mixed with purified water (300 mL) with heating and the solution was concentrated to 55 g under reduced pressure. 20 After the concentrated solution was allowed to stand at room temperature overnight, the solution was filtered to give the precipitated crystals (T-1, 16.3 g, 3.5%, total amount 464.3 g, 98.7%). mp 194-196 0C

[α]D 22 -0.9 ± 0.4 ° (c, 1.007, H2O), [α]365 + 35.4 ± 0.8 ° (c, 1.007, H2O)

IR(NuJOr)Cm“1: 3511, 3348, 3276, 3130, 3093, 3060, 1755, 1739, 1682, 1611, 1551, 1465, 25. 1442, 1379, 1235, 1089.

AnalCalcdFor: C16H22N4O4S 3H2O

Calculated: C, 45.00%;H, 6.71%;N, 13.33%; S, 7.63%.

Found: C, 45.56%; H, 6.66%; N, 13.43%, S, 7.69%.

30 Step 4 l-[N-[(4S)5S)-(5-methyl-2-oxooxazolidin-4-yl)carbonyl]-3-(thiazol-4-yl)-L-alanyl-(2R)-2- methylpyrrolidine (1-2)

Method A

After l-[N-[(4S,5S)-(5-methyl-2-oxooxazolidin-4-yl)carbonyl]-3-(thiazol-4-yl)-L- 35 alanyl-(2R)-2-methylpyrrolidine monohydrate (4.77 g) obtained by the method described in Patent Literature 8 was crushed in a mortar, it was dried under reduced pressure (66.5 Pa) at 100 0C for 15 hours to give 4.54 g of Compound (1-2). mp 194.5-196.5 0C [α]D 25 -2.1 +. 0.4 ° (c, 1.004, H2O), [α]365 +36.8 ± 0.8 ° (c, 1.004, H2O) Water measurement (Karl Fischer method): 0.27%

IR(NuJOr)Cm”1: 3276, 3180, 3104, 1766, 1654, 1626, 1548, 1517, 1457, 1380, 1235, 1102, 979. NMR(CD3OD):δH 8.97 and 8.96 (total 1 H, d, J 2.1 Hz, Thia-H-2), 7.34 and 7.33 (total 1 H, d, J 2.1 Hz, Thia-H-5), 5.19 and 5.04 (total 1 H, each t, J 7.5 Hz, Ala- CaH), 4.92 (1 H, dq, J 6.6 and 8.7 Hz, Oxa-H-5), 4.36 and 4.35 (total 1 H, d, J 8.7 Hz, Oxa-H-4), 4.07 and 3.92 (total 1 H, each m, Pyr-Cα-H), 3.78 (1 H, m, Pyr-NCH2), 3.42 (1 H, m, Pyr-NCH2), 3.22 (2 H, m, AIa-CH2), 1.5-2.0 (4 H, m, Pyr-CH2), 1.28 and 1.22 (total 3 H, each d, J 6.6 Hz, Oxa-5-Me), 1.21 and 1.02 (total 3 H, each d, J 6.6 Hz, Pyr-2-Me). Anal Calcd For: C16H22N4O4S

Calculated: C, 52.44%; H, 6.05%; N, 15.29%; S, 8.75%. Found: C, 52.24%; H, 5.98%; N, 15.27%, S, 8.57%.

Method B

After Compound (1-1) (17.89 g, 47.3 mmol) was crushed in a mortar, it was dried under reduced pressure (66.5 Pa) at 100 °C for 14 hours to give Compound (1-2, 17.31 g). mp 193-194 0C [α]D 25 -1.9 ± 0.4 ° (c, 1.002, H2O), [α]365 +37.2 ± 0.8 ° (c, 1.002, H2O)

Water measurement (Karl Fischer method): 0.22%

IR(NuJOr)Cm“1: 3273, 3180, 3111, 1765, 1685, 1653, 1626, 1549, 1516, 1456, 1346, 1331,

1277, 1240, 1097, 980.

Anal Calcd For C16H22N4O4S Calculated: C, 52.44%; H, 6.05%; N, 15.29%; S, 8.75%.

Found: C, 52.19%; H, 5.98%; N, 15.42%, S, 8.74%.

 

 

REFERENCES

1: Ijiro T, Nakamura K, Ogata M, Inada H, Kiguchi S, Maruyama K, Nabekura J,
Kobayashi M, Ishibashi H. Effect of rovatirelin, a novel thyrotropin-releasing
hormone analog, on the central noradrenergic system. Eur J Pharmacol. 2015 Aug
15;761:413-22. doi: 10.1016/j.ejphar.2015.05.047. Epub 2015 Jul 2. PubMed PMID:
26142830.

////////Rovatirelin Hydrate, S-0373, Rovatirelin, 204386-76-5, clinical, phase 3

C[C@@H]1CCCN1C(=O)[C@H](Cc2cscn2)NC(=O)[C@@H]3[C@@H](OC(=O)N3)C

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Oliceridine

 Phase 3 drug, Uncategorized  Comments Off on Oliceridine
May 042016
 

TRV130.svg

Oliceridine.png

Oliceridine

N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine

[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

Phase III

A mu-opioid receptor ligand potentially for treatment of acute postoperative pain.

TRV-130; TRV-130A

CAS No.1401028-24-7

Molecular Formula: C22H30N2O2S
Molecular Weight: 386.5508 g/mol
  • Originator Trevena

Trevena, Inc.

  • Class Analgesics; Small molecules
  • Mechanism of Action Beta arrestin inhibitors; Opioid mu receptor agonists
  • Orphan Drug Status No
  • On Fast track Postoperative pain
    • Phase III Postoperative pain
    • Phase II Pain

    Most Recent Events

    • 09 Mar 2016Trevena intends to submit NDA to US FDA in 2017
    • 22 Feb 2016Oliceridine receives Breakthrough Therapy status for Pain in USA
    • 19 Jan 2016Phase-III clinical trials in Postoperative pain in USA (IV) (NCT02656875)

Oliceridine (TRV130) is an opioid drug that is under evaluation in human clinical trials for the treatment of acute severe pain. It is afunctionally selective μ-opioid receptor agonist developed by Trevena Inc. Oliceridine elicits robust G protein signaling, with potencyand efficacy similar to morphine, but with far less β-arrestin 2 recruitment and receptor internalization, it displays less adverse effectsthan morphine.[1][2][3]

In 2015, the product was granted fast track designation in the U.S. for the treatment of moderate to severe acute pain. In 2016, the compound was granted FDA breakthrough therapy designation for the management of moderate to severe acute pain.

Oliceridine (TRV130) is an intravenous G protein biased ligand that targets the mu opioid receptor. Trevena is developing TRV130 for the treatment of moderate to severe acute pain where intravenous therapy is preferred, with a clinical development focus in acute postoperative pain

TRV 130 HCl is a novel μ-opioid receptor (MOR) G protein-biased ligand; elicits robust G protein signaling(pEC50=8.1), with potency and efficacy similar to morphine, but with far less beta-arrestin recruitment and receptor internalization.

NMR

STR1

Oliceridine (TRV130) – Mu Opioid Biased Ligand for Acute Pain

Target Indication Lead
Optimization Preclinical
Development Phase
1 Phase
2 Phase
3		 Ownership
Oliceridine (TRV130) Mu-receptor Moderate to
Severe Pain		 intravenous Trevena Logo

Oliceridine (TRV130) is an intravenous G protein biased ligand that targets the mu opioid receptor. Trevena is developing TRV130 for the treatment of moderate to severe acute pain where intravenous therapy is preferred, with a clinical development focus in acute postoperative pain.

Recent TRV130 News

Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically distinct opioid receptor types have been described: δ, κ and μ. Furthermore, each type is believed to have sub-types. All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, activation of the opioid receptors causes inhibition of adenylate cyclase, and recruits β-arrestin.

When therapeutic doses of morphine are given to patients with pain, the patients report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue.

There is a continuing need for new OR modulators to be used as analgesics. There is a further need for OR agonists as analgesics having reduced side effects. There is a further need for OR agonists as analgesics having reduced side effects for the treatment of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions, urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and/or agents for the treatment of respiratory diseases and cough.

 PAPER

Structure activity relationships and discovery of a g protein biased mu opioid receptor ligand, ((3-Methoxythiophen-2-yl)methyl)a2((9R)-9-(pyridin-2-y1)-6-oxaspiro-(4.5)clecan-9-yl)ethylpamine (TRV130), for the treatment of acute severe pain
J Med Chem 2013, 56(20): 8019

Structure–Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain

Trevena, Inc., 1018 West 8th Avenue, Suite A, King of Prussia, Pennsylvania 19406, United States
J. Med. Chem., 2013, 56 (20), pp 8019–8031
DOI: 10.1021/jm4010829
Publication Date (Web): September 24, 2013
Copyright © 2013 American Chemical Society
*Phone: 610-354-8840. Fax: 610-354-8850. E-mail: dchen@trevenainc.com.

Abstract

Abstract Image

The concept of “ligand bias” at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical μ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in β-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased μ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased μ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.

http://pubs.acs.org/doi/abs/10.1021/jm4010829

[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl] ethyl})amine ((R)-30)

Using a procedure described in method A, (R)-39e was converted to (R)-30 as a TFA salt. 1H NMR (400 MHz, CDCl3) δ 11.70 (brs, 1H), 9.14 (d, J = 66.6, 2H), 8.72 (d, J = 4.3, 1H), 8.19 (td,J = 8.0, 1.4, 1H), 7.70 (d, J = 8.1, 1H), 7.63 (dd, J = 7.0, 5.8, 1H), 7.22 (d, J = 5.5, 1H), 6.78 (d,J = 5.6, 1H), 4.08 (m, 2H), 3.80 (m, 4H), 3.69 (dd, J = 11.2, 8.7, 1H), 2.99 (d, J = 4.8, 1H), 2.51 (t, J = 9.9, 1H), 2.35 (m, 3H), 2.18 (td, J = 13.5, 5.4, 1H), 1.99 (d, J = 14.2, 1H), 1.82 (m, 2H), 1.65 (m, 1H), 1.47 (m, 4H), 1.14 (m, 1H), 0.73 (dt, J = 13.2, 8.9, 1H). LC-MS (API-ES) m/z = 387.0 (M + H).

Patent

WO 2012129495

http://www.google.com/patents/WO2012129495A1?cl=en

Scheme 1: Synthesis of Spirocyclic Nitrile

NCCH2C02CH3 AcOH, NH4OAc

Figure imgf000050_0001
Figure imgf000050_0002

1-5 1-6 1-7

Chiral HPLC separation n=1-2

R= phenyl, substituted phenyl, aryl,

Figure imgf000050_0003

s

Scheme 2: Converting the nitrile to the opioid receptor ligand (Approach 1)

Figure imgf000051_0001

2-4

 

Scheme 3: Converting the nitrile to the opioid receptor ligand (Approach 2)

Figure imgf000051_0002

1-8B 3-1 3-2 n=1-2

 

In some embodiments, the same scheme is applied to 1 -7 and 1 -8A. Scheme 4: Synthesis of Non-Spirocyclic Nitrile

Figure imgf000052_0001

4-1 4-2 4-3

KOH, ethylene glycol R= phenyl, substituted phenyl, aryl,

substituted aryl, pyridyl, substituted pyridyl, heat heteroaryl, substituted heteroaryl,

Figure imgf000052_0002

carbocycle, heterocycle and etc.

In some embodiments, 4-1 is selected from the group consisting of

Figure imgf000052_0003

4-1 A 4-1 B 4-1 C 4-1 D 4-1 E

 

Scheme 5: Synthesis of Other Spirocyclic Derived Opioid Ligands

Figure imgf000053_0001

5-1 5-2 5-3

 

Scheme 6: Allyltrimethylsilane Approach to Access the Quaternary Carbon Center

RMgX, or RLi

Figure imgf000053_0002

 

Scheme 7: N-linked Pyrrazole Opioid Receptor Ligand

Figure imgf000054_0001
Figure imgf000055_0001

[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

Figure imgf000144_0001

Into a vial were added 2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l -amine (500 mg, 1.92 mmole), 18 mL CH2C12 and sodium sulfate (1.3 g, 9.6 mmole). The 3- methoxythiophene-2-carboxaldehyde (354 mg, 2.4 mmole) was then added, and the misture was stirred overnight. NaBH4 (94 mg, 2.4 mmole) was added to the reaction mixture, stirred for 10 minutes, and then MeOH (6.0 mL) was added, stirred l h, and finally quenched with water. The organics were separated off and evaporated. The crude residue was purified by a Gilson prep HPLC. The desired fractions collected and concentrated and lyophilized. After lyophilization, residue was partitioned between CH2C12 and 2N NaOH, and the organic layers were collected. After solvent was concentrated to half of the volume, 1.0 eq of IN HC1 in Et20 was added,and majority of solvent evaporated under reduced pressure. The solid obtained was washed several times with Et20 and dried to provide [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine monohydrochloride (336 mg, 41% yield, m/z 387.0 [M + H]+ observed) as a white solid. The NMR for Compound 140 is described herein.

Example 15: Synthesis of [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine (Compound 140).

Methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (mixture of E and Z isomers)

Figure imgf000141_0001

A mixture of 6-oxaspiro[4.5]decan-9-one (13.74 g, 89.1 mmol), methylcyanoacetate (9.4 ml, 106.9 mmol), ammonium acetate (1.79 g, 26.17.mmol) and acetic acid (1.02 ml, 17.8 mmol) in benzene (75 ml) was heated at reflux in a 250 ml round bottom flask equipped with a Dean-Stark and a reflux condenser. After 3h, TLC (25%EtOAc in hexane, PMA stain) showed the reaction was completed. After cooling, benzene (50 ml) was added and the layer was separated, the organic was washed by water (120 ml) and the aqueous layer was extracted by CH2CI2 (3 x 120 ml). The combined organic was washed with sat’d NaHCCb, brine, dried and concentrated and the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 5% EtOAc, 2CV; 5-25%, 14CV; 25-40%,8 CV) gave a mixture of E and Z isomers: methyl 2-cyano-2-[6- oxaspiro[4.5]decan-9-ylidene]acetate ( 18.37 g, 87.8 % yield, m/z 236.0 [M + H]+ observed) as a clear oil. -cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate

Figure imgf000141_0002

A solution of 2-bromopyridine (14.4 ml, 150 mmo) in THF (75 ml) was added dropwise to a solution of isopropylmagnesium chloride (75 ml, 2M in THF) at 0°C under N2, the mixture was then stirred at rt for 3h, copper Iodide(2.59 g, 13.6 mmol) was added and allowed to stir at rt for another 30 min before a solution of a mixture of E and Z isomers of methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (16 g, 150 mmol) in THF (60 ml) was added in 30 min. The mixture was then stirred at rt for 18h. The reaction mixture was poured into a 200 g ice/2 N HC1 (100 ml) mixture. The product was extracted with Et20 (3×300 ml), washed with brine (200 ml), dried (Na2S04) and concentrated. The residual was purified by flash chromatography (100 g silica gel column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV gave methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.44 g, 72% yield, m/z 315.0 [M + H]+ observed) as an amber oil .

-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile

Figure imgf000142_0001

Ethylene glycol (300 ml) was added to methyl 2-cyano-2-[9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]acetate( 15.43 g, 49 mmol) followed by potassium hydroxide (5.5 g , 98 mmol), the resulting mix was heated to 120oC, after 3 h, the reaction mix was cooled and water (300 ml) was added, the product was extracted by Et20(3 x 400 ml), washed with water(200 ml), dried (Na2S04) and concentrated, the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV to give 2-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]acetonitrile (10.37 g, 82% yield, m/z 257.0 [M + H]+ observed).

-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile

Figure imgf000142_0002

racemic 2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile was separated by chiral HPLC column under the following preparative-SFC conditions: Instrument: SFC-80 (Thar, Waters); Column: Chiralpak AD-H (Daicel); column temperature: 40 °C; Mobile phase: Methanol /CO2=40/60; Flow: 70 g/min; Back pressure: 120 Bar; Cycle time of stack injection: 6.0min; Load per injection: 225 mg; Under these conditions, 2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (4.0 g) was separated to provide the desired isomer, 2-[(9R)-9-(Pyridin-2-yI)-6- oxaspiro[4.5]decan-9-yl]acetonitrile (2.0 g, >99.5% enantiomeric excess) as a slow- moving fraction. The absolute (R) configuration of the desired isomer was later determined by an X-ray crystal structure analysis of Compound 140. [0240] -[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l-amine

Figure imgf000143_0001

LAH (1M in Et20, 20ml, 20 mmol) was added to a solution of 2-[(9R)-9-(pyridin-2-yl)- 6-oxaspiro[4.5]decan-9-yl]acetonitrile (2.56 g, 10 mmol) in Et20 (100 ml, 0.1M ) at OoC under N2. The resulting mix was stirred and allowed to warm to room temperature. After 2 h, LCMS showed the reaction had completed. The reaction was cooled at OoC and quenched with water ( 1.12 ml), NaOH (10%, 2.24 ml) and another 3.36 ml of water. Solid was filtered and filter pad was washed with ether (3 x 20 ml). The combined organic was dried and concentrated to give 2-[(9R)-9-(Pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethan-l -amine (2.44 g, 94% yield, m/z 260.6 [M + H]+ observed) as a light amber oil.

Alternatively, 2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l -amine was prepared by Raney-Nickel catalyzed hydrogenation.

An autoclave vessel was charged with 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4,5]decan-9- yl] acetonitrile and ammonia (7N solution in methanol). The resulting solution was stirred at ambient conditions for 15 minutes and treated with Raney 2800 Nickel, slurried in water. The vessel was pressurized to 30 psi with nitrogen and agitated briefly. The autoclave was vented and the nitrogen purge repeated additional two times. The vessel was pressurized to 30 psi with hydrogen and agitated briefly. The vessel was vented and purged with hydrogen two additional times. The vessel was pressurized to 85-90 psi with hydrogen and the mixture was warmed to 25-35 °C. The internal temperature was increased to 45-50 °C over 30-60 minutes. The reaction mixture was stirred at 45-50 °C for 3 days. The reaction was monitored by HPLC. Once reaction was deemed complete, it was cooled to ambient temperature and filtered through celite. The filter cake was washed with methanol (2 x). The combined filtrates were concentrated under reduced pressure at 40-45 °C. The resulting residue was co-evaporated with EtOH (3 x) and dried to a thick syrupy of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l -amine.

References

  1.  Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS (October 2013). “Structure-Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain”. J. Med. Chem. 56 (20): 8019–31.doi:10.1021/jm4010829. PMID 24063433.
  2.  DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD (March 2013). “A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine”. J. Pharmacol. Exp. Ther. 344 (3): 708–17.doi:10.1124/jpet.112.201616. PMID 23300227.
  3.  Soergel DG, Subach RA, Sadler B, Connell J, Marion AS, Cowan C, Violin JD, Lark MW (October 2013). “First clinical experience with TRV130: Pharmacokinetics and pharmacodynamics in healthy volunteers”. J Clin Pharmacol 54(3): 351–7. doi:10.1002/jcph.207. PMID 24122908.

External links

Patent ID Date Patent Title
US2015246904 2015-09-03 Opioid Receptor Ligands And Methods Of Using And Making Same
US8835488 2014-09-16 Opioid receptor ligands and methods of using and making same
US2013331408 2013-12-12 Opioid Receptor Ligands and Methods of Using and Making Same
Oliceridine
TRV130.svg
Systematic (IUPAC) name
N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine
Clinical data
Routes of
administration		 IV
Legal status
Legal status
Identifiers
CAS Number 1401028-24-7
ATC code none
PubChem CID 66553195
ChemSpider 30841043
UNII MCN858TCP0
ChEMBL CHEMBL2443262
Synonyms TRV130
Chemical data
Formula C22H30N2O2S
Molar mass 386.55 g·mol−1

////////TRV-130; TRV-130A, Oliceridine, Phase III, Postoperative pain, trevena, mu-opioid receptor ligand, fast track designation, breakthrough therapy designation

COc1ccsc1CNCC[C@]2(CCOC3(CCCC3)C2)c4ccccn4

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Galunisertib

 Phase 3 drug, Uncategorized  Comments Off on Galunisertib
May 042016
 

Galunisertib

Phase III

A TGF-beta receptor type-1 inhibitor potentially for the treatment of myelodysplastic syndrome (MDS) and solid tumours.

LY-2157299

CAS No.700874-72-2

4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide
6-Quinolinecarboxamide, 4-[5,6-dihydro-2-(6-methyl-2-pyridinyl)-4H-pyrrolo[1,2-b]pyrazol-3-yl]-
700874-72-2
  • Molecular FormulaC22H19N5O
  • Average mass369.419 Da

Eli Lilly and Company

4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carboxamide

4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-6-carboxamide monohydrate 

Anal. Calcd for C22H19N5O·H2O: C, 68.20; H, 5.46; N, 18.08. Found: C, 68.18; H, 5.34; N, 17.90.

1H NMR (DMSO-d6: δ) 1.74 (s, 3H), 2.63 (m, 2H), 2.82 (br s, 2H), 4.30 (t, J = 7.2 Hz, 2H), 6.93 (m, 1H), 7.37 (s, 1H), 7.41 (d, J = 4.4 Hz, 1H), 7.56 (m, 1H), 7.58 (m, 1H), 8.04, (s, 1H), 8.04 (d, J = 4.4 Hz, 1H), 8.12 (dd, J = 8.8, 1.6 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 4.4 Hz, 1H).

13C NMR (DMSO-d6: δ) 22.56, 23.24, 25.58, 48.01, 109.36, 117.74, 121.26, 122.95, 126.73, 127.16 (2C), 129.01, 131.10, 136.68, 142.98, 147.20, 148.99, 151.08, 151.58, 152.13, 156.37, 167.47.

IR (KBr): 3349, 3162, 3067, 2988, 2851, 1679, 1323, 864, 825 cm–1.

HRMS (m/z M + 1): Calcd for C22H19N5O: 370.1653. Found: 370.1662.

GalunisertibAn orally available, small molecule antagonist of the tyrosine kinase transforming growth factor-beta (TGF-b) receptor type 1 (TGFBR1), with potential antineoplastic activity. Upon administration, galunisertib specifically targets and binds to the kinase domain of TGFBR1, thereby preventing the activation of TGF-b-mediated signaling pathways. This may inhibit the proliferation of TGF-b-overexpressing tumor cells. Dysregulation of the TGF-b signaling pathway is seen in a number of cancers and is associated with increased cancer cell proliferation, migration, invasion and tumor progression.

.

  • OriginatorEli Lilly
  • DeveloperEli Lilly; National Cancer Institute (USA); Vanderbilt-Ingram Cancer Center; Weill Cornell Medical College
  • ClassAntineoplastics; Pyrazoles; Pyridines; Pyrroles; Quinolines; Small molecules
  • Mechanism of ActionPhosphotransferase inhibitors; Transforming growth factor beta1 inhibitors
    • Phase II/IIIMyelodysplastic syndromes
    • Phase IIBreast cancer; Glioblastoma; Hepatocellular carcinoma
    • Phase I/IIGlioma; Non-small cell lung cancer; Pancreatic cancer
    • Phase ICancer; Solid tumours

    Most Recent Events

    • 26 Apr 2016Eli Lilly plans a pharmacokinetics phase I trial in Healthy volunteers in United Kingdom (PO) (NCT02752919)
    • 16 Apr 2016Pharmacodynamics data from a preclinical study in Cancer presented at the 107th Annual Meeting of the American Association for Cancer Research (AACR-2016)
    • 06 Apr 2016Eli Lilly and AstraZeneca plan a phase Ib trial for Pancreatic cancer (Second-line therapy or greater, Metastatic disease, Recurrent, Combination therapy) in USA, France, Italy, South Korea and Spain (PO) (NCT02734160)

Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.

Company Eli Lilly and Co.
Description Transforming growth factor (TGF) beta receptor 1 (TGFBR1; ALK5) inhibitor
Molecular Target Transforming growth factor (TGF) beta receptor 1 (TGFBR1) (ALK5)
Mechanism of Action Transforming growth factor (TGF) beta 1 inhibitor
Therapeutic Modality Small molecule

Bristol-Myers Squibb and Lilly Enter Clinical Collaboration Agreement to Evaluate Opdivo (nivolumab) in Combination with Galunisertib in Advanced Solid Tumors

Bristol-Myers Squibb and Lilly

NEW YORK & INDIANAPOLIS–(BUSINESS WIRE)– Bristol-Myers Squibb Company (NYSE:BMY) and Eli Lilly and Company (NYSE:LLY) announced today a clinical trial collaboration to evaluate the safety, tolerability and preliminary efficacy of Bristol-Myers Squibb’s immunotherapy Opdivo (nivolumab) in combination with Lilly’s galunisertib (LY2157299). The Phase 1/2 trial will evaluate the investigational combination of Opdivo and galunisertib as a potential treatment option for patients with advanced (metastatic and/or unresectable) glioblastoma, hepatocellular carcinoma and non-small cell lung cancer.

Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. Galunisertib (pronounced gal ue” ni ser’tib) is a TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system and increases the ability of tumors to spread in the body. This collaboration will address the hypothesis that co-inhibition of PD-1 and TGF beta negative signals may lead to enhanced anti-tumor immune responses than inhibition of either pathway alone.

“Advanced solid tumors represent a serious unmet medical need among patients with cancer,” said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. “Our clinical collaboration with Lilly underscores Bristol-Myers Squibb’s continued commitment to explore combination regimens from our immuno-oncology portfolio with other mechanisms of action that may accelerate the development of new treatment options for patients.”

“Combination therapies will be key to addressing tumor heterogeneity and the inevitable resistance that is likely to develop to even the most promising new tailored therapies,” said Richard Gaynor, M.D., senior vice president, Product Development and Medical Affairs, Lilly Oncology. “To that end, having multiple cancer pathways and technology platforms will be critical in an era of combinations to ensure sustainability beyond any single asset.”

The study will be conducted by Lilly. Additional details of the collaboration were not disclosed.

About Galunisertib

Galunisertib (pronounced gal ue” ni ser’tib) is Lilly’s TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumors growth, suppresses the immune system, and increases the ability of tumors to spread in the body.

Immune function is suppressed in cancer patients, and TGF beta worsens immunosuppression by enhancing the activity of immune cells called T regulatory cells. TGF beta also reduces immune proteins, further decreasing immune activity in patients

Galunisertib is currently under investigation as an oral treatment for advanced/metastatic malignancies, including Phase 2 evaluation in hepatocellular carcinoma, myelodysplastic syndromes (MDS), glioblastoma, and pancreatic cancer.

PATENT

WO 2004048382

The disclosed invention also relates to the select compound of Formula II:

Figure imgf000005_0001

Formula II

2-(6-methyl-pyridin-2-yI)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[l,2- bjpyrazole and the phannaceutically acceptable salts thereof.

The compound above is genetically disclosed and claimed in PCT patent application PCT/US02/11884, filed 13 May 2002, which claims priority from U.S. patent application U. S . S .N. 60/293 ,464, filed 24 May 2001 , and incorporated herein by reference. The above compound has been selected for having a surprisingly superior toxicology profile over the compounds specifically disclosed in application cited above.

 

The following scheme illustrates the preparation of the compound of Formula II.

Scheme II

Figure imgf000007_0001

Cs2C03

Figure imgf000007_0002

The following examples further illustrate the preparation of the compounds of this invention as shown schematically in Schemes I and II. Example 1

Preparation of 7-(2-morpholin-4-yI-ethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H- pyrroIo[l,2-b]pyrazol-3-yl)-q inoline

A. Preparation of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)- 7-[2-(tetrahydropyran-2-yIoxy)ethoxy]quinoIine

Heat 4-(2-pyridm-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-quinolin-7-ol (376 mg, 1.146 mmol), cesium carbonate (826 mg, 2.54 mmol), and 2-(2- bromoethoxy)tetrahydro-2H-pyran (380 μL, 2.52 mmol) in DMF (5 mL) at 120 °C for 4 hours. Quench the reaction with saturated sodium chloride and then extract with chloroform. Dry the organic layer over sodium sulfate and concentrate in vacuo. Purify the reaction mixture on a silica gel column eluting with dichloromethane to 10% methanol in dichloromethane to give the desired subtitled intermediate as a yellow oil (424 mg, 81%). MS ES+m/e 457.0 (M+l).

 

EXAMPLE 2

Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazole

A. Preparation of 6-bromo-4-methyI-quinoline

Stir a solution of 4-bromo-phenylamine (1 eq), in 1,4-dioxane and cool to approximately 12 °C. Slowly add sulfuric acid (2 eq) and heat at reflux. Add methyl vinyl ketone (1.5 eq) drop wise into the refluxing solution. Heat the solution for 1 hour after addition is complete. Evaporate the reaction solution to dryness and dissolve in methylene chloride. Adjust the solution to pH 8 with 1 M sodium carbonate and extract three times with water. Chromatograph the residue on SiO (70/30 hexane/ethyl acetate) to obtain the desired subtitled inteπnediate. MS ES+ m e = 158.2 (M+l). B. Preparation of 6-methyl-pyridine-2-carboxylic acid methyl ester

Suspend 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL). Cool to 0 °C. Add methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)

(18.2 g, 94.8 mmol). Stir the mixture at room temperature for 6 hours, wash with water and brine, and dry over sodium sulfate. Filter the mixture and concentrate in vacuo.

Chromatograph the residue on SiO2 (50% ethyl acetate/hexanes) to obtain the desired subtitled intermediate, 9.66 g (92%), as a colorless liquid. 1H NMR (CDC13) 6 7.93-7.88 (m, IH), 7.75-7.7 (m, IH), 7.35-7.3 (m, IH), 4.00 (s, 3H), 2.60 (s, 3H).

C. Preparation of 2-(6-bromo-quinoIin-4-yl)-l-(6-methyl-pyridin-2-yl)-ethanone Dissolve 6-bromo-4-methyl-quinoline (38.5 g, 153 mmol) in 600 mL dry THF.

Cool to -70° C and treat with the dropwise addition of 0.5 M potassium hexamethyldisilazane (KN(SiMe )2 (400 mL, 200 mmol) over 2 hours while keeping the temperature below -65 °C. Stir the resultant solution at -70°C for 1 hour and add a solution of 6-methylpyridine-2-carboxylic acid methyl ester (27.2, 180 mmol) in 100 mL dry THF dropwise over 15 minutes. During the addition, the mixture will turn from dark red to pea-green and form a precipitate. Stir the mixture at -70°C over 2 hours then allow it to warm to ambient temperature with stirring for 5 hours. Cool the mixture then quench with 12 N HC1 to pH=l . Raise the pH to 9 with solid potassium carbonate. Decant the solution from the solids and extract twice with 200 mL ethyl acetate. Combine the organic extracts, wash with water and dry over potassium carbonate. Stir the solids in 200 mL water and 200 mL ethyl acetate and treat with additional potassium carbonate. Separate the organic portion and dry with the previous ethyl acetate extracts. Concentrate the solution in vacuo to a dark oil. Pass the oil through a 300 mL silica plug with methylene chloride then ethyl acetate. Combine the appropriate fractions and concentrate in vacuo to yield an amber oil. Rinse the oil down the sides of the flask with methylene chloride then dilute with hexane while swirling the flask to yield 38.5 g (73.8 %) of the desired subtitled intermediate as a yellow solid. MS ES+ = 341 (M+l)v D. Preparation of l-[2-(6-bromo-quinolin-4-yI)-l-(6-methyl-pyridin-2-yl)- ethylideneamino]-pyrrolidin-2-one

Stir a mixture of 2-(6-bromo-quinolin-4-yl)-l-(6-methyl-pyridin-2-yl)-ethanone (38.5 g, 113 mmol) and 1-aminopyrrolidinone hydrochloride (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g 4 A unactivated sieves. Continue stirring an additional 13 h and add 10-15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid. MS ES+ = 423 (M+l).

E. Preparation of 6-bromo-4-[2-(6-methyl-pyridin-2-yι)-5,6-dihydro-4H- pyrrolo[l,2-b]pyrazol-3-yl]-quinoline

To a mixture of (1.2 eq.) cesium carbonate and l-[2-(6-bromo-qumolin-4-yl)-l- (6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one (33.3 g, 78.7 mmol) add 300 mL dry N,N-dimethylformamide. Stir the mixture 20 hours at 100°C. The mixture may turn dark during the reaction. Remove the N,N-dimethylformamide in vacuo. Partition the residue between water and methylene chloride. Extract the aqueous portion with additional methylene chloride. Filter the organic solutions through a 300 mL silica plug, eluting with 1.5 L methylene chloride, 1.5 L ethyl acetate and 1.5 L acetone. Combine the appropriate fractions and concentrate in vacuo. Collect the resulting precipitate by filtration to yield 22.7 g (71.2%) of the desired subtitled intermediate as an off-white solid. MS ES+ = 405 (M+l).

F. Preparation of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl]-quinoline-6-carboxylic acid methyl ester

Add 6-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl]-quinoline (22.7 g, 45 mmol) to a mixture of sodium acetate (19 g, 230 mmol) and the palladium catalyst [1,1 ‘- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (850 mg, 1.04 mmol) in 130 mL methanol. Place the mixture under 50 psi carbon monoxide atmosphere and stir while warming to 90° C over 1 hour and with constant charging with additional carbon monoxide. Allow the mixture to cool over 8 hours, recharge again with carbon monoxide and heat to 90 °C. The pressure may rise to about 75 PSI. The reaction is complete in about an hour when the pressure is stable and tic (1 : 1 toluene/acetone) shows no remaining bromide. Partition the mixture between methylene chloride (600 mL) and water (1 L). Extract the aqueous portion with an additional portion of methylene chloride (400 mL.) Filter the organic solution through a 300 mL silica plug and wash with 500 mL methylene chloride, 1200 mL ethyl acetate and 1500 mL acetone. Discard the acetone portion. Combine appropriate fractions and concentrate to yield 18.8 g (87.4%) of the desired subtitled intermediate as a pink powder. MS ES+ = 385 (M+l).

G. Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yι)-5,6- dihydro-4H-pyrrolo[l,2-b]pyrazole

Figure imgf000012_0001

Warm a mixture of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl]-quinolme-6-carboxylic acid methyl ester in 60 mL 7 N ammonia in methanol to 90 °C in a stainless steel pressure vessel for 66 hours. The pressure will rise to about 80 PSI. Maintain the pressure for the duration of the reaction. Cool the vessel and concentrate the brown mixture in vacuo. Purify the residual solid on two 12 g Redi- Pak cartridges coupled in series eluting with acetone. Combine appropriate fractions and concentrate in vacuo. Suspend the resulting nearly white solid in methylene chloride, dilute with hexane, and filter. The collected off-white solid yields 1.104 g (63.8%) of the desired title product. MS ES+ = 370 (M+l).

PAPER

http://pubs.acs.org/doi/abs/10.1021/op4003054

Application of Kinetic Modeling and Competitive Solvent Hydrolysis in the Development of a Highly Selective Hydrolysis of a Nitrile to an Amide

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
Org. Process Res. Dev., 2014, 18 (3), pp 410–416
DOI: 10.1021/op4003054
Publication Date (Web): February 11, 2014
Copyright © 2014 American Chemical Society
*Telephone: (317) 276-2066. E-mail: niemeier_jeffry_k@lilly.com (J.K.N.)., *Telephone: (317) 433-3769. E-mail: rrothhaar@lilly.com(R.R.R.).

Abstract

Abstract Image

A combination of mechanism-guided experimentation and kinetic modeling was used to develop a mild, selective, and robust hydroxide-promoted process for conversion of a nitrile to an amide using a substoichiometric amount of aqueous sodium hydroxide in a mixed water and N-methyl-2-pyrrolidone solvent system. The new process eliminated a major reaction impurity, minimized overhydrolysis of the product amide by selection of a solvent that would be sacrificially hydrolyzed, eliminated genotoxic impurities, and improved the intrinsic safety of the process by eliminating the use of hydrogen peroxide. The process was demonstrated in duplicate on a 90 kg scale, with 89% isolated yield and greater than 99.8% purity.

Patent ID Date Patent Title
US2015289795 2015-10-15 METHODS AND KITS FOR THE PROGNOSIS OF COLORECTAL CANCER
US2014348889 2014-11-27 Compositions and Methods for Treating and Preventing Neointimal Stenosis
US2014328860 2014-11-06 METHODS FOR STIMULATING HEMATOPOIETIC RECOVERY BY INHIBITING TGF BETA SIGNALING
US2014127228 2014-05-08 INHIBITION OF TGFBETA SIGNALING TO IMPROVE MUSCLE FUNCTION IN CANCER
US2014128349 2014-05-08 ADMINISTERING INHIBITORS OF TGFBETA SIGNALING IN COMBINATION WITH BENZOTHIAZEPINE DERIVATIVES TO IMPROVE MUSCLE FUNCTION IN CANCER PATIENTS
US2013071931 2013-03-21 PROCESS FOR HEPATIC DIFFERENTIATION FROM INDUCED HEPATIC STEM CELLS, AND INDUCED HEPATIC PROGENITOR CELLS DIFFERENTIATED THEREBY
US7872020 2011-01-18 TGF-[beta] inhibitors
US7834029 2010-11-16 QUINOLINYL-PYRROLOPYRAZOLES
US7265225 2007-09-04 Quinolinyl-pyrrolopyrazoles

REFERENCES

1: Rodón J, Carducci M, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J, Braña I, Sicart E, Gueorguieva I, Cleverly A, Pillay NS, Desaiah D, Estrem ST, Paz-Ares L, Holdhoff M, Blakeley J, Lahn MM, Baselga J. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs. 2014 Dec 23. [Epub ahead of print] PubMed PMID: 25529192.

2: Kovacs RJ, Maldonado G, Azaro A, Fernández MS, Romero FL, Sepulveda-Sánchez JM, Corretti M, Carducci M, Dolan M, Gueorguieva I, Cleverly AL, Pillay NS, Baselga J, Lahn MM. Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study. Cardiovasc Toxicol. 2014 Dec 9. [Epub ahead of print] PubMed PMID: 25488804.

3: Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, Brana I, Sicart E, Gueorguieva I, Cleverly AL, Sokalingum Pillay N, Desaiah D, Estrem ST, Paz-Ares L, Holdoff M, Blakeley J, Lahn MM, Baselga J. First-in-Human Dose Study of the Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma. Clin Cancer Res. 2014 Nov 25. pii: clincanres.1380.2014. [Epub ahead of print] PubMed PMID: 25424852.

4: Huang C, Wang H, Pan J, Zhou D, Chen W, Li W, Chen Y, Liu Z. Benzalkonium Chloride Induces Subconjunctival Fibrosis Through the COX-2-Modulated Activation of a TGF-β1/Smad3 Signaling Pathway. Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):8111-22. doi: 10.1167/iovs.14-14504. PubMed PMID: 25406285.

5: Cong L, Xia ZK, Yang RY. Targeting the TGF-β receptor with kinase inhibitors for scleroderma therapy. Arch Pharm (Weinheim). 2014 Sep;347(9):609-15. doi: 10.1002/ardp.201400116. Epub 2014 Jun 11. PubMed PMID: 24917246.

6: Gueorguieva I, Cleverly AL, Stauber A, Sada Pillay N, Rodon JA, Miles CP, Yingling JM, Lahn MM. Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol. 2014 May;77(5):796-807. PubMed PMID: 24868575; PubMed Central PMCID: PMC4004400.

7: Oyanagi J, Kojima N, Sato H, Higashi S, Kikuchi K, Sakai K, Matsumoto K, Miyazaki K. Inhibition of transforming growth factor-β signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor. Exp Cell Res. 2014 Aug 15;326(2):267-79. doi: 10.1016/j.yexcr.2014.04.009. Epub 2014 Apr 26. PubMed PMID: 24780821.

8: Giannelli G, Villa E, Lahn M. Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma. Cancer Res. 2014 Apr 1;74(7):1890-4. doi: 10.1158/0008-5472.CAN-14-0243. Epub 2014 Mar 17. Review. PubMed PMID: 24638984.

9: Dituri F, Mazzocca A, Peidrò FJ, Papappicco P, Fabregat I, De Santis F, Paradiso A, Sabbà C, Giannelli G. Differential Inhibition of the TGF-β Signaling Pathway in HCC Cells Using the Small Molecule Inhibitor LY2157299 and the D10 Monoclonal Antibody against TGF-β Receptor Type II. PLoS One. 2013 Jun 27;8(6):e67109. Print 2013. PubMed PMID: 23826206; PubMed Central PMCID: PMC3694933.

10: Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, Stanford J, Cook RS, Arteaga CL. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013 Mar 1;123(3):1348-58. doi: 10.1172/JCI65416. Epub 2013 Feb 8. PubMed PMID: 23391723; PubMed Central PMCID: PMC3582135.

11: Bhattachar SN, Perkins EJ, Tan JS, Burns LJ. Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus,™ simulations to predict absorption. J Pharm Sci. 2011 Nov;100(11):4756-65. doi: 10.1002/jps.22669. Epub 2011 Jun 16. PubMed PMID: 21681753.

12: Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S, Trocóniz IF. Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer. 2008 Jan;44(1):142-50. Epub 2007 Nov 26. PubMed PMID: 18039567.

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539082/

http://www.ncbi.nlm.nih.gov/pubmed/26057634

https://clinicaltrials.gov/ct2/show/NCT0242334

Bhattachar, Shobha N.; Journal of Pharmaceutical Sciences 2011, 100(11), 4756-4765 

Investigational new drugs (2015), 33(2), 357-70.

//////////TGF-β, TGF-βRI kinase inhibitor, ALK5, galunisertib, LY2157299, cancer, clinical trials, PHASE 3

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Elpamotide

 PEPTIDES, Phase 3 drug, Uncategorized  Comments Off on Elpamotide
May 032016
 

STR1

STR1

Elpamotide str drawn bt worlddrugtracker

Elpamotide

L-Arginyl-L-phenylalanyl-L-valyl-L-prolyl-L-alpha-aspartylglycyl-L-asparaginyl-L-arginyl-L-isoleucine human soluble (Vascular Endothelial Growth Factor Receptor) VEGFR2-(169-177)-peptide

MF C47 H76 N16 O13
Molecular Weight, 1073.2164
L-​Isoleucine, L-​arginyl-​L-​phenylalanyl-​L-​valyl-​L-​prolyl-​L-​α-​aspartylglycyl-​L-​asparaginyl-​L-​arginyl-
  • 10: PN: WO2008099908 SEQID: 10 claimed protein
  • 14: PN: WO2009028150 SEQID: 1 claimed protein
  • 18: PN: JP2013176368 SEQID: 18 claimed protein
  • 1: PN: WO2009028150 SEQID: 1 claimed protein
  • 2: PN: WO2010027107 TABLE: 1 claimed sequence
  • 6: PN: WO2013133405 SEQID: 6 claimed protein
  • 8: PN: US8574586 SEQID: 8 unclaimed protein
  • 8: PN: WO2004024766 SEQID: 8 claimed sequence
  • 8: PN: WO2010143435 SEQID: 8 claimed protein

Phase III

A neoangiogenesis antagonist potentially for the treatment of pancreatic cancer and biliary cancer.

OTS-102

CAS No.673478-49-4, UNII: S68632MB2G

Company OncoTherapy Science Inc.
Description Angiogenesis inhibitor that incorporates the KDR169 epitope of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1; VEGFR-2)
Molecular Target Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2) (KDR/Flk-1)
Mechanism of Action Angiogenesis inhibitor; Vaccine
Therapeutic Modality Preventive vaccine: Peptide vaccine
  • Originator OncoTherapy Science
  • Class Cancer vaccines; Peptide vaccines
  • Mechanism of Action Cytotoxic T lymphocyte stimulants
  • 16 Jun 2015 No recent reports on development identified – Phase-II/III for Pancreatic cancer (Combination therapy) and Phase-II for Biliary cancer in Japan (SC)
  • 09 Jan 2015 Otsuka Pharmaceutical announces termination of its license agreement with Fuso Pharmaceutical for elpamotide in Japan
  • 01 Feb 2013 OncoTherapy Science and Fuso Pharmaceutical Industries complete a Phase-II trial in unresectable advanced Biliary cancer and recurrent Biliary cancer (combination therapy) in Japan (UMIN000002500)

STR1

Elpamotide str drawn bt worlddrugtracker

Elpamotide , credit kegg

Elpamotide is a neoangiogenesis inhibitor in phase II clinical trials at OncoTherapy Science for the treatment of inoperable advanced or recurrent biliary cancer. Phase III clinical trials was also ongoing at the company for the treatment of pancreas cancer, but recent progress report for this indication are not available at present.

Consisting of VEGF-R2 protein, elpamotide is a neovascular inhibitor with a totally novel mechanism of action. Its antitumor effect is thought to work by inducing strong immunoreaction against new blood vessels which provide blood flow to tumors. The drug candidate only act against blood vessels involved in tumor growth and is associated with few adverse effects.

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival

The vaccine candidate was originally developed by OncoTherapy Science. In January 2010, Fuso Pharmaceutical, which was granted the exclusive rights to manufacture and commercialize elpamotide in Japan from OncoTherapy Science, sublicensed the manufacturing and commercialization rights to Otsuka Pharmaceutical. In 2015, the license agreement between Fuso Pharmaceutical and OncoTherapy Science, and the license agreement between Fuso Pharmaceutical and Otsuka Pharmaceutical terminated.

 

 

 

WO 2010143435

US 8574586

WO 2012044577

WO 2010027107

WO 2013133405

WO 2009028150

WO 2008099908

WO 2004024766

 

PATENT

WO2013133405

The injectable formulation containing peptides, because peptides are unstable to heat, it is impossible to carry out terminal sterilization by autoclaving. Therefore, in order to achieve sterilization, sterile filtration step is essential. Sterile filtration step is carried out by passing through the 0.22 .mu.m following membrane filter typically absolute bore is guaranteed. Therefore, in the stage of pre-filtration, it is necessary to prepare a peptide solution in which the peptide is completely dissolved. However, peptides, since the solubility characteristics by its amino acid sequence differs, it is necessary to select an appropriate solvent depending on the solubility characteristics of the peptide. In particular, it is difficult to completely dissolve the highly hydrophobic peptide in a polar solvent, it requires a great deal of effort on the choice of solvent. It is also possible to increase the solubility by changing the pH, or depart from the proper pH range as an injectable formulation, in many cases the peptide may become unstable.

 

　In recent years, not only one type of peptide, the peptide vaccine formulation containing multiple kinds of peptides as an active ingredient has been noted. Such a peptide vaccine formulation is especially considered to be advantageous for the treatment of cancer.

 

　The peptide vaccine formulation for the treatment of cancer, to induce a specific immune response to the cancer cells, containing the T cell epitope peptides of the tumor-specific antigen as an active ingredient (e.g., Patent Document 1). Tumor-specific antigens these T-cell epitope peptide is derived, by exhaustive expression analysis using clinical samples of cancer patients, for each type of cancer, specifically overexpressed in cancer cells, only rarely expressed in normal cells It never is one which has been identified as an antigen (e.g., Patent Document 2). However, even in tumor-specific antigens identified in this way, by a variety of having the cancer cells, in all patients and all cancer cells, not necessarily the same as being highly expressed. That is, there may be a case in which the cancer in different patients can be an antigen that is highly expressed cancer in a patient not so expressed. Further, even in the same patient, in the cellular level, cancer cells are known to be a heterogeneous population of cells (non-patent document 1), another even antigens expressed in certain cancer cells in cancer cells may be the case that do not express. Therefore, in one type of T-cell epitope peptide vaccine formulations containing only, there is a possibility that the patient can not be obtained a sufficient antitumor effect is present. Further, even in patients obtained an anti-tumor effect, the cancer cells can not kill may be present. On the other hand, if the vaccine preparation comprising a plurality of T-cell epitope peptide, it is likely that the cancer cells express any antigen. Therefore, it is possible to obtain an anti-tumor effect in a wider patient, the lower the possibility that cancer cells can not kill exists.

 

　The effect of the vaccine formulation containing multiple types of T-cell epitope peptide as described above, the higher the more kinds of T-cell epitope peptides formulated. However, if try to include an effective amount of a plurality of types of T cell peptide, because the peptide content of the per unit amount is increased, to completely dissolve the entire peptide becomes more difficult. Further, because it would plurality of peptides having different properties coexist, it becomes more difficult to maintain all of the peptide stability.

 

　For example, in European Patent Publication No. 2111867 (Patent Document 3), freeze-dried preparation of the vaccine formulation for the treatment of cancer comprising a plurality of T-cell epitope peptides have been disclosed. This freeze-dried preparation, in the preparation of peptide solution before freeze drying, each peptide depending on its solubility properties, are dissolved in a suitable solvent for each peptide. Furthermore, when mixing the peptide solution prepared in order to prevent the precipitation of the peptide, it is described that mixing the peptide solution in determined order. Thus, to select a suitable solvent for each peptide, possible to consider the order of mixing each peptide solution is laborious as the type of peptide increases.

In order to avoid difficulties in the formulation preparation, as described above, a vaccine formulation comprising one type of T-cell epitope peptides, methods for multiple types administered to the same patient is also contemplated. However, when administering plural kinds of vaccine preparation, it is necessary to vaccination of a plurality of locations of the body, burden on a patient is increased. Also peptide vaccine formulation, the DTH (Delayed Type Hypersensitivity) skin reactions are often caused called reaction after inoculation. Occurrence of skin reactions at a plurality of positions of the body, increases the discomfort of the patient. Therefore, in order to reduce the burden of patients in vaccination is preferably a vaccine formulation comprising a plurality of T-cell epitope peptide. Further, even when the plurality of kinds administering the vaccine formulation comprising a single type of epitope peptides, when manufacturing each peptide formulation is required the task of selecting an appropriate solvent for each peptide.

Patent Document 1: International Publication No. WO 2008/102557
Patent Document 2: International Publication No. 2004/031413 Patent
Patent Document 3: The European Patent Publication No. 2111867
PATENT
https://www.google.com/patents/US8574586
PATENT

///////////Elpamotide, Phase III,  A neoangiogenesis antagonist, pancreatic cancer and biliary cancer, OTS-102, OncoTherapy Science Inc, peptide

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Tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE)

 Phase 3 drug, Uncategorized  Comments Off on Tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE)
Mar 312016
 

Gly-Pro-Glu

Synonym: GPE, Glycyl-prolyl-glutamic acid, (1-3)IGF-1

Pfizer (Originator)
Neuren Pharmaceuticals (Originator)

Glypromate; glycine-proline-glutamate (neuroprotectant), Neuren

  • CAS Number 32302-76-4
  • Empirical Formula C12H19N3O6
  • Molecular Weight 301.30
  • Psychiatric Disorders (Not Specified)
    Neurologic Drugs (Miscellaneous)
    Cognition Disorders, Treatment of
    Antiepileptic Drugs
    Antidepressants Biochem/physiol Actions

Gly-Pro-Glu is a neuroprotective compound and the N-terminal tripeptide of IGF-1. Gly-Pro-Glu is neuroprotective after central administration in animal models of neurodegenerative processes, such as Huntington’s, Parkinson’s, Alzheimer’s diseases, and varies acute brain injury animal models. The neuroprotective activity is not related to its affinity to glutamate receptor. Findings indicate that GPE mimics insulin-like growth factor I effects on the somatostatin system through a mechanism independent of β-amyloid clearance that involves modulation of calcium and glycogen synthase kinase 3β signaling.

GPE is a naturally occurring peptide fragment which had been in phase III clinical trials at Neuren Pharmaceuticals for use as prophylactic neuroprotection for patients undergoing coronary artery bypass graft (CABG) and valvuloplasty surgery. Although clinical evaluation in Australia continues, phase III trials evaluating the compound in the U.S. were discontinued based on negative results. The compound is found in normal brain tissue and, when injected intravenously, has been shown to act by multiple pathways to protect brain tissue from injury. The drug was originally developed by Pfizer, but rights were transferred to Neuren pursuant to a proprietary agreement between the companies.

When amino acids join together (forming short groups called polypeptides, or much longer chains called proteins) the amine group of one amino acid joins with the carboxyl group of the next, making a peptide bond. These bonds don’t ionise at different pHs, but can be hydrolised — broken — reforming the amino acids. GPE is formed from the amino acids glycine, proline and glutamic acid:

This tripeptide has 3 pH-sensitive groups, each with its own pKa. What the university chemists needed to do was work out what form GPE is in when it is active in the brain, what parts of the molecule are critical to its effectiveness, and how to ‘tweak’ the molecule (by changing the side chains) so that it will remain in the brain for longer than the naturally-occurring substance.   They also needed to make sure the final compound passes through the blood-brain barrier (that prevents most substances in the blood from entering and affecting the brain). If possible, they also wanted a compound that could be taken in pill form without being broken down in the stomach. It was also essential that the compound was safe for people to take!

 

Neuren Pharmaceuticals

After initial work on GPE at the university, the research was passed to a spin-off research group called Neuren Pharmaceuticals Ltd, which takes compounds discovered by the University of Auckland and develops them into medicines. Neuren developed GPE intoGlypromate® and are working with researchers in the US (including the US Military, who have a keen interest in a medicine that will reduce brain damage after head injuries) to test the compound on patients. There is considerable interest in Glypromate® world-wide, because at present there is nothing that reduces cell death after brain injuries. The chances of winning a race are pretty high when you’re the only competitor!Glypromate® is being tested on heart-bypass patients because up to 70% of bypass patients are affected mentally after their surgery. It’s thought that tiny clots form after the heart is restarted, and that these travel to the brain and cause mini-strokes. Unlike naturally-occurring strokes, or the brain damage caused by accident or war, the bypass surgery is planned, so before and after tests can be done on the patients to see exactly what effect the treatment has. Early results look very promising.

Glypromate is just one of the compounds Neuren is working on. Others may develop into treatments for Multiple Sclerosis, Parkinson’s Disease or Alzheimer’s Disease as well as various kinds of cancer. The company’s links with overseas research groups mean that compounds developed in New Zealand are able to be tested in the US and gain the FDA approval which will allow them to be used in most countries in the world.

 

The tripeptide Glycyl-L-Prolyl-L-Glutamate (Gly-Pro-Glu or GPE) is a naturally occurring peptide, which is proteolytically cleaved from insulin-like growth factor-1 (IGF-1). IGF-1 is a potent neurotrophic factor produced endogenously in damaged regions of the brain. It has been postulated that some of the neuroprotective actions of IGF-1 are mediated by GPE although the precise mechanism of action remains unclear. GPE has a different mode of action to IGF-1 as GPE does not bind to the IGF-1 receptor. Rather, GPE has been shown to bind with low affinity to the N-methyl-D-aspartate (NMDA) receptor and also elicit a biological response via other mechanisms. GPE facilitates the release of dopamine through interaction with the NMDA receptor but GPE stimulated acetylcholine release is via an unknown, non-NMDA pathway.

It has been demonstrated that GPE can act as a neuronal rescue agent following brain injury or disease, including hypoxic-ischemic brain injury, NMDA challenge, chemical toxins and in animal models of Parkinson’s and Alzheimer’s disease. Analogs of GPE are thus of interest in the development of novel pharmaceutical agents for the treatment of central nervous system (CNS) injuries and neurodegenerative disorders among others.

CURRENT STATUS

Neuren Pharmaceuticals was developing Glypromate (glycine-proline glutamate), a naturally occurring small-molecule neuroprotectant derived from IGF-1 which inhibits caspase III dependent apoptosis, for the potential treatment of neurodegenerative diseases by iv infusion. By June 2008, a phase III trial had begun . However, in December 2008, the company discontinued further development of the drug after it failed to show an observable effect [972907]. In November 2005, the company was seeking to outlicense the drug [771417].

Neuren is also investigating the Glypromate analog, NNZ-2566 for similar indications.

In August 2006, Neuren expected Glypromate to be eligible for Orphan Drug status for neurodegenerative diseases and planned to apply for Fast Track status for the drug.

SYDNEY, Australia, Sept. 4 /PRNewswire-FirstCall/ — Neuren Pharmaceuticals today announced that physicians from Madigan Army Medical Center (Madigan) in Tacoma, Washington, will conduct an investigator- initiated Phase 2 trial to determine the safety and efficacy of Glypromate(R) in reducing brain injury caused by out of hospital cardiac arrest. The trial will start in mid-2007 and will be managed by The Henry M. Jackson Foundation for the Advancement of Military Medicine (Jackson Foundation) in consultation with the clinical investigators at Madigan.

The proposed study will be an investigator-initiated study which means that the Investigational New Drug (IND) application will be submitted to the FDA by the Army investigators rather than by Neuren. Neuren will provide the drug product as well as access to preclinical, clinical and regulatory documents related to Glypromate(R). The Company’s only financial commitment will be compensation to the Jackson Foundation for administrative costs incurred in coordinating the study. Neuren will retain all commercial rights to Glypromate(R) in these indications.

Cardiac arrest involves the sudden, complete cessation of heart function and circulation leading rapidly to neurological and other organ system damage. Among patients who survive, the consequences of neurological damage resulting from lack of blood flow and oxygen to the brain represent the primary adverse outcomes. This occurs in up to 80% of survivors and causes cognitive impairment such as occurs in patients undergoing major cardiac surgery, the focus for Neuren’s upcoming Phase 3 study with Glypromate(R). However recovery without residual neurological damage after cardiac arrest is rare.

There are no drugs approved to reduce the neurological damage caused by cardiac arrest. Neuren believes that Glypromate(R) for this indication will be eligible for Orphan Drug designation. Orphan Drug designation provides for a period of market exclusivity following approval as well as possible access to US government grants. In addition, because of the serious nature of neurological impairment resulting from cardiac arrest and the lack of available drug therapy, Neuren intends to apply for Fast Track designation which provides for accelerated clinical development and review.

While the Army’s investigator-initiated trial will focus on out of hospital cardiac arrest, if this trial is successful, Neuren, the Jackson Foundation and the Army investigators are considering additional trials of Glypromate(R) to reduce brain damage resulting from related conditions including in-hospital cardiac arrest and treatment of patients with ventricular fibrillation, the heart rhythm disturbance associated with more than 75% of cardiac arrests.

Under the agreement, the Jackson Foundation will provide support to the Army investigators in clinical trial preparations, protocol development, obtaining human subjects clearance, coordination of patient enrolment, data management and analysis, and preparation of study reports.

Mr David Clarke, CEO of Neuren said: “This is a very important development for Neuren in that it reflects a growing appreciation of the potential for Glypromate(R) to reduce neurological damage. It also, of course, reinforces the value and strength of Neuren’s relationship with the US Army physicians and scientists. Cardiac arrest is a devastating clinical event and one for which a drug to reduce the neurological consequences is clearly needed. The addition of this trial will now give Neuren a very strong and cost effective portfolio of clinical trials in 2007 — a Phase 3 and a Phase 2 for Glypromate(R) and the two Phase 2 trials with NNZ-2566.”

Approximately 300,000 deaths result from cardiac arrest in the US each year, making cardiac arrest one of the leading causes of death. According to the American Heart Association, each year approximately 160,000 people in the US experience sudden cardiac arrest outside of a hospital or in a hospital emergency department.

Neuren estimates that the number of patients in the US that could be treated for out of hospital cardiac arrest and related indications is approximately 400,000 which could represent a potential market of US$800 million.

About Madigan Army Medical Center

Madigan Army Medical Center, located in Tacoma, Washington, is one of the major US Army medical centers, providing clinical care to over 120,000 active, reserve and retired military personnel and dependents. The hospital has a medical staff of more than 1,000 with 200 physicians and nurses in training. Madigan’s Department of Clinical Investigations, which is dedicated to writing, performing, and regulating clinical research, is conducting approximately 200 clinical trials across a wide spectrum of indications from Phase I to IV.

About the Jackson Foundation

The Jackson Foundation is a private, not-for-profit organisation that supports the US military in conducting medical research and clinical trials and has established relationships with more than 160 military medical organisations worldwide. It was founded in 1983, in part, to foster cooperative relationships between the military medical community and the private sector, including pharmaceutical sponsors. The Jackson Foundation manages Phase I – IV clinical trials utilizing an established network of military medical centers across the United States.

About Glypromate(R)

Glypromate(R) is a peptide fragment of IGF-1 and is being developed by Neuren as a potential therapeutic candidate for diseases caused by some forms of chronic or acute brain injury. Glypromate(R) has been shown to act by multiple pathways to protect brain tissue from injury. Neuren has successfully completed a Phase I safety study and a Phase IIa safety and pharmacokinetics study and plans to initiate a Phase III study in late 2006.

About Neuren Pharmaceuticals

Neuren Pharmaceuticals is a biotechnology company developing novel therapeutics in the fields of brain injury and diseases and metabolic disorders. The Neuren portfolio consists of six product families, targeting markets with large unmet needs and limited competition. Neuren has three lead candidates, Glypromate(R) andNNZ-2566, presently in the clinic in development to treat a range of acute neurological conditions, and NNZ-2591, in preclinical development for Parkinson’s and other chronic conditions. Neuren has commercial and development partnerships with the US ArmyWalter Reed Army Institute of Research, Metabolic Pharmaceuticals,UCLA Medical Center and the National Trauma Research Institute in Melbourne.

For more information, please visit Neuren’s website at http://www.neurenpharma.com

Company David Clarke CEO of Neuren T: 1800 259 181 (Australia) T: +64 9 3 367 7167 ext 82308 (New Zealand) M: +64 21 988 052 Media and investor relations Rebecca Piercy Buchan Consulting T: +61 9827 2800 M: +61 422 916 422

CONTACT: David Clarke, CEO of Neuren, 1-800-259-181(Australia), or
+64-9-3-367-7167 ext 82308 (New Zealand), or +64-21-988-052 (mobile); or
Media and investor relations – Rebecca Piercy of Buchan Consulting,
+61-9827-2800, +61-422-916-422 (mobile)

Web site: http://www.neurenpharma.com/

REFERENCES

1 EP 0366638

2 WO 2005042000

3 WO 2008153929

4 WO 2009033805

5 WO 2009033806

Synthesis off isotopically labelled glycyl-L-prolyl-L-glutamic acid (Glypromate(R)) and derivatives
J Label Compd Radiopharm 2006, 49(6): 571

An efficient fmoc solid-phase synthesis of an amphiphile of the neuroprotective agent glycyl-prolyl-glutamic acid
Synlett (Stuttgart) 2014, 25(15): 2221

Intracellular pathways activated by Insulin-like growth factor 1 and its derivates
40th Annu Meet Soc Neurosci (November 13-17, San Diego) 2010, Abst 167.13

 

EP2667715A1 * Jan 27, 2012 Dec 4, 2013 Neuren Pharmaceuticals Limited Treatment of autism spectrum disorderes using glycyl-l-2-methylprolyl-l-glutamic acid
EP2667715A4 * Jan 27, 2012 Jul 23, 2014 Neuren Pharmaceuticals Ltd Treatment of autism spectrum disorderes using glycyl-l-2-methylprolyl-l-glutamic acid
US8940732 Jan 15, 2010 Jan 27, 2015 Massachusetts Institute Of Technology Diagnosis of autism spectrum disorders and its treatment with an antagonist or inhibitor of the 5-HT2c receptor signaling pathway
US9212204 Jan 26, 2015 Dec 15, 2015 Neuren Pharmaceuticals Limited
WO2005042000A1 * 22 Oct 2004 12 May 2005 David Charles Batchelor Neuroprotective effects of gly-pro-glu following intravenous infusion
WO2005097161A2 * 30 Mar 2005 20 Oct 2005 Peter D Gluckman Gpe and g-2mepe, caffeine and alkanol for treatment of cns injury
WO2006127702A2 * 23 May 2006 30 Nov 2006 Neuren Pharmaceuticals Ltd Analogs of glycyl-prolyl-glutamate
EP0366638A2 * 24 Oct 1989 2 May 1990 KabiGen AB Neuromodulatory peptide
US20020151522 * 13 Mar 2002 17 Oct 2002 Tajrena Alexi Regulation of weight
Reference
1 * ALONSO DE DIEGO, SERGIO A. ET AL: “New Gly-Pro-Glu (GPE) analogues: Expedite solid-phase synthesis and biological activity” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, no. 5, 2006, – 1392 page 1396, XP002527092
2 * SARA V R ET AL: “IDENTIFICATION OF GLY-PRO-GLU (GPE), THE AMINOTERMINAL TRIPEPTIDE OF INSULIN-LIKE GROWTH FACTOR 1 WHICH IS TRUNCATED IN BRAIN, AS A NOVEL NEUROACTIVE PEPTIDE” BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 165, no. 2, 15 December 1989 (1989-12-15), pages 766-771, XP000992688 ISSN: 0006-291X

//////Gly-Pro-Glu, GPE, Glycyl-prolyl-glutamic acid,  32302-76-4, Tripeptide,  Glycyl-L-Prolyl-L-Glutamate, Glypromate®, (1-3)IGF-1 , PHASE 3, Glypromate,  glycine-proline-glutamate, neuroprotectant, Neuren

 

 

Neuren’s NNZ-2566 shows clinical benefit in Rett syndrome trial

FRAXA Research Foundation Logo

Promising results in Phase 2 clinical trial

by Michael Tranfaglia, MD
FRAXA Medical Director

nnz-2566This isn’t a Fragile X trial, but the Neuren compound, NNZ-2566, that is in trials now for Fragile X has shown significant positive effects in a Phase 2 trial for Rett syndrome.

The results of the trial are interesting, in that improvement was seen a Rett syndrome-specific rating scale compared to placebo, and there was also improvement noted on the CGI-I (Clinical Global Impression of Improvement) and Caregiver Top 3 Concerns. However, there was no effect seen on ABC scores (Aberrant Behavior Checklist) compared to placebo. Many in the Fragile X field have noted the inadequacies of the ABC; indeed, it was never designed or intended to be an outcome measure for clinical trials. In this case, a Rett-specific rating scale called the Motor-Behavior Assessment (MBA) showed a statistically significant and clinically meaningful treatment effect at the highest dose of the Neuren compound compared to placebo.

This is great news for those of us in the Fragile X community for several reasons:

  • It shows that this compound really does something—it seems to have useful properties in actual patients, and that’s not trivial.
  • It demonstrates that disease-specific symptoms can improve significantly on the drug, and that improvement can be measured in a relatively short clinical trial.
  • It shows that a drug can have beneficial effects on core features of a genetically based developmental disorder, even if the more general rating scales (like the ABC) show no change.

–
This last point is strongly reminiscent of the experience of many families and clinicians in recent Fragile X clinical trials, where the drugs showed no advantage compared to placebo based on rating scales, but genuine improvement was noted in many subjects, with significant deterioration upon discontinuation of the drugs. Thus the calls for improved rating scales which can “capture” these core, disease-specific therapeutic effects. The NeurenFragile X trial is using some Fragile X-specific outcome measures which will hopefully lead to similar positive results.

The fact that this result is good news for Neuren also means that the company should remain financially viable for longer, so that they can continue the development of this compound for a number of indications—more “shots on goal”.

Of course, the usual caveats apply: this was a small study, and these results need to be replicated in a larger Phase 3 trial. Still, there’s a realistic possibility that we may see a similar result in Fragile X!

 

 

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Lusutrombopag….Oral thrombopoietin (TPO) mimetic

 Phase 3 drug, Uncategorized  Comments Off on Lusutrombopag….Oral thrombopoietin (TPO) mimetic
Aug 202015
 

 

 LUSUTROMBOPAG.png

Lusutrombopag

(E)-3-[2,6-dichloro-4-[[4-[3-[(1S)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid

(S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid

(2E)-3-{2,6-Dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylacrylic acid

UNII 6LL5JFU42F,  CAS 1110766-97-6,

D10476, MW591.546 , [US2010267783], MF C29H32Cl2N2O5S, S-888711

Shionogi & Co., Ltd., 塩野義製薬株式会社 INNOVATOR

Optically active compound (C-3B)  Melting point: 142-145°C…………….EP2184279B1

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)………….EP2184279B1

Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C), NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)………EP2184279B1

 

Thrombopoietin receptor agonist, Oral thrombopoietin (TPO) mimetic

  • 24 Mar 2015 Shionogi plans a phase III trial in Thrombocytopenia (in patients with chronic liver disease) in USA (NCT02389621)
  • 31 Dec 2014 Preregistration for Thrombocytopenia in Japan (PO)
  • 08 Nov 2013 Phase II development is ongoing in the US and the Europe

Process for preparing intermediates of an optically active 1,3-thiazole containing thrombopoietin receptor agonist  Also claims crystalline forms of lusutrombopag intermediates and a process for preparing lusutrombopag. Shionogi is developing lusutrombopag, a small-molecule thrombopoietin mimetic, as an oral tablet formulation for treating thrombocytopenia.

In December 2014, an NDA was submitted in Japan. In May 2015, the drug was listed as being in phase III development for thrombocytopenia in the US and Europe.

  

 

The lusutrombopag, a low molecular-human thrombopoietin receptor agonist, its chemical formula, “(E) -3- [2,6-Dichloro-4- [4- [3 – [(S) -1-hexyloxyethyl] – 2-methoxyphenyl] -thiazol- 2-ylcarbamoyl] -phenyl] is a -2-methylacrylic acid “. lusutrombopag is represented by the following chemical structural formula.

 

Figure JPOXMLDOC01-appb-C000001

 

Eltrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000002

 

Avatrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000003

 

 

Totrombopag choline is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000004
C 3B IS THE COMPD OF ROT (-) AND S, E  FORM
Figure imgb0009
      Example 2 Synthesis of (R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3A) (not included in the present invention) and (S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3B)

    • According to the same method as in Example 1, an optically active compound (C-3A) and an opticallly active compound (C-3B) were synthesized from (RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (B-3) obtained in Reference Example 3.

Optically active compound (C-3A)Melting point: 139-141°C   UNDESIRED

    • NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82 – 0.87 (m, 3H) Optical rotaion +4.5 degrees (DMSO, c = 1.001, 25°C)

Optically active compound (C-3B)Melting point: 142-145°C  DESIRED

  • NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)
      Example 4: Synthesis of (C-3B)

    • Figure imgb0021

First step: Synthesis of (S)-1-(3-bromo-2-methyloxyphenyl)ethane-1-ol (17)

    • Using the same method as that of the first step of Example 3, the compound (17) was obtained from the compound (16) at a yield 77%.
      Optical rotation: -23.5 ± 0.6 degrees (CHCl3, c = 1.050, 21°C)
      NMR (CDCl3) θ ppm: 1.49 (3H, d, J = 6.6 Hz), 2.33 (1H, brs), 3.88 (3H, s), 5.19 (1H, q, J = 6.4 Hz), 7.01 (1H, t, J = 7.9 Hz), 7.40 (1H, dd, J = 7.7 Hz, J = 1.1 Hz), 7.46 (1H, dd, J = 8.0 Hz, J = 1.4 Hz)

Second step: Synthesis of (S)-1-bromo-3-(1-hexyloxyethyl)-2-methyloxybenzene (18)

    • Using the same method as that of the second step of Example 3, the compound (18) was obtained from the compound (17) at a yield of 96%.
      Optical rotation: -29.8 ± 0.6 degrees (CHCl3, c = 1.055, 21°C)
      NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.42 (3H, d, J = 6.5 Hz), 1.54 (2H, m), 3.29 (2H, m), 3.85 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 7.02 (1H, t, J = 7.9 Hz), 7.39 (1H, dd, J = 7.8 Hz, J = 1.7 Hz), 7.45 (1H, dd, J = 7.9 Hz, J = 1.7 Hz)

Third step and fourth step: Synthesis of (S)-4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazole-2-amine (20)

    • Using the same method as that of the fourth step of Example 3, the compound (19) was obtained from the compound (18), subsequently according to the same method as that of the fourth step, the compound (20) was obtained.

Compound (19)

    • NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2-1.4 (6H, m), 1.45 (3H, d, J = 6.6 Hz), 1.55 (2H, m), 3.29 (2H, m), 3.78 (3H, s), 4.73 (2H, m), 4.80 (1H, q, J = 6.4 Hz), 7.24 (1H, t, J = 7.8Hz), 7.52 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.65 (1H, dd, J = 7.7 Hz, J = 1.8 Hz)

Compound (20)

  • Optical rotation: -4.2 ± 0.4 degrees (DMSO, c = 1.025, 21°C)
    NMR (CDCl3) δ ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, m), 1.35 (3H, d, J = 6.5 Hz), 1.48 (2H, m), 3.25 (2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)

 

      Fifth step: Synthesis of ethyl (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate (21)

    • Using the same method as that of the fifth step of Example 3, the compound (21) was obtained from the compound (20) at a yield of 94%.
      Optical rotation: +4.7 ± 0.4 degrees (CHCl3, c = 1.07, 21°C)
      NMR (CDCl3 ) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2 – 1.35 (6H, m), 1.38 (3H, t, J = 7.1
      Hz), 1.44 (3H, d, J = 6.4 Hz), 1.57 (2H, m), 1.77 (3H, d, J = 1.4 Hz), 3.30 (2H, m), 3.59 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 4.83 (1H, q, J = 6.4 Hz), 7.17 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J = 1.7 Hz), 7.42 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.51 (1H, s), 7.67 (1H, dd, J = 7.6 Hz, J = 1.7 Hz), 7.89 (2H, s), 10.30 (1H, brs)

Sixth step: Synthesis of (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-3B)

  • Using the same method as that of the sixth step of Example 3, the compound (C-3B) was obtained from the compound (21) at a yield of 80%.
    Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C)
    NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)
  • Results of powder X-ray deffraction are shown in Fig. 5.
  • Diffraction angle of main peak: 2θ = 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4 degrees

WO2005014561/EP1655291A1

 https://www.google.co.in/patents/EP1655291A1?cl=en

 

 

WO2014003155, claiming a composition comprising lusutrombopag, useful for treating thrombocytopenia.

https://www.google.co.in/patents/US20150148385?cl=en

.

WO  2015093586

Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound 

 

(Step 1) Synthesis of compound (VII ‘) 　under a nitrogen atmosphere, it was dissolved compound 1 (2.00kg) in 1,2-dimethoxyethane (28.0kg). 25% LDA tetrahydrofuran – heptane – ethyl benzene solution (13.20kg) was added dropwise over 1 hour at -55 ℃, and stirred for 30 minutes. It was added dropwise over 40 minutes to 1,2-dimethoxyethane (3.0kg) solution of N- formyl morpholine (3.74kg) at -55 ℃, and stirred for 1 hour. 1,2-dimethoxyethane (3.0kg) solution of 2-phosphono-propanoic acid triethyl (3.74kg) was added dropwise over 45 minutes at 0 ℃, and stirred for 2 hours. 35% aqueous solution of sulfuric acid (15.8kg) was added dropwise over 40 minutes to the reaction solution. Water (16.0kg) was added and extracted. The resulting organic layer was washed with water (8.0kg), and the solvent was evaporated under reduced pressure. Acetonitrile (16.0kg) was added, and the mixture was stirred for 1 hour at 25 ℃, and the mixture was stirred and cooled to 0 ℃ 5 hours and 30 minutes. The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (16.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Over 1 hour and then cooled to 30 ℃, and the mixture was stirred for 45 minutes. Over 40 minutes and then cooled to 5 ℃, and the mixture was stirred for 3 hours.The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (13.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Furthermore, up to 30 ℃ over 1 hour and then cooled and stirred for 70 minutes. Over 30 minutes and then cooled to 5 ℃, and the mixture was stirred for 4 hours. I precipitated crystals were collected by filtration. Washed with 5 ℃ acetonitrile (3.2kg), and dried to give the compound (VII ‘) (1.63kg, 51.2% yield). NMR (CDCl 3 ) delta ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (Q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz) 　Results of powder X-ray diffraction and I shown in Figure 1 and Table 3. [Table 3] 　In the powder X-ray diffraction spectrum, diffraction angle (2θ): 8.1 ± 0.2 °, 16.3 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0. 2 °, the peak was observed at 24.8 ± 0.2 °, and 39.0 ± 0.2 ° degrees.

 

(Synthesis of Compound (XI ‘))

(Step 2) Synthesis of Compound 4 　under a nitrogen atmosphere over Compound 3 (3.00kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (11.40kg) 1 hour at 25 ℃ in The dropped, and stirred for 2 hours. 1mol / L isopropylmagnesium chloride in tetrahydrofuran solution (0.56kg) was added at 25 ℃, and stirred for 2 hours. To the reaction mixture N- methoxymethyl -N- methylacetamide the (1.45kg) was added dropwise over at 25 ℃ 40 minutes, and stirred for 80 minutes. 7% hydrochloric acid (9.7kg) was added to the reaction mixture, and the mixture was extracted with toluene (11.0kg). The resulting organic layer twice with water (each 7.5kg) washed, the solvent was evaporated under reduced pressure to give Compound 4 (2.63kg). NMR (CDCl 3 ) delta ppm: 7.69 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.55 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.05 (t, 1H, J = 7.7 Hz), 3.88 (s, 3H), 2.64 (s, 3H) ppm:

(Step 3) Synthesis of Compound 5 　Under a nitrogen atmosphere, chloro [(1S Compound 4 (2.63kg), 2S) -N- ( p- toluenesulfonyl) -1,2-diphenyl-ethane diamine] (p- cymene) ruthenium (II) (28.6g), it was added to tetrahydrofuran (1.3kg) and triethylamine (880.0g). Formic acid (570.0g) was added dropwise over 6 hours at 40 ℃, and stirred for 1 hour. In addition 3.5% hydrochloric acid (14.4kg) to the reaction mixture, and the mixture was extracted with toluene (13.0kg).The organic layer was washed with 3.5% hydrochloric acid (14.4kg) and water (7.5kg), the solvent was concentrated under reduced pressure to obtain a toluene solution of Compound 5 (4.44kg).

(Step 4) Synthesis of Compound 6 　under a nitrogen atmosphere, it was a potassium hydroxide (6.03kg) was dissolved in water (6.0kg). To the solution, it added tetrabutylammonium bromide (182.0g) and toluene solution of Compound 5 (4.44kg). 1-bromo-hexane (2.79kg) was added dropwise over 1 hour at 60 ℃, and the mixture was stirred for 4 hours. And extracted by adding water (4.4kg) to the reaction solution. The resulting organic layer was filtered through powdered cellulose and extracted with toluene (3.0kg) and water (7.6kg) to the filtrate. The solvent it was evaporated under reduced pressure from the organic layer. Toluene operation of evaporated under reduced pressure and the solvent by the addition of a (7.8kg) was repeated five times to obtain a toluene solution of Compound 6 (10.0kg).

(Step 5) Synthesis of Compound 7 　under a nitrogen atmosphere, magnesium powder (301.0g), in tetrahydrofuran (1.3kg), the compound in toluene (6.4kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (432.0g) 6 In addition of the toluene solution (0.50kg) at 30 ℃, and the mixture was stirred for 2 hours. Toluene solution of Compound 6 (9.50kg) was added dropwise over 3 hours at 50 ℃, and stirred for 2 hours. 1-bromo-hexane (746.0g) was added at 50 ℃, and the mixture was stirred for 1 hour. It was added dropwise over 1 hour at 5 ℃ toluene (5.3kg) solution of 2-chloro -N- methoxy -N- methyl-acetamide (1.78kg), and stirred for 1 hour. 3.7% hydrochloric acid (16.7kg) was added to the reaction mixture, and the mixture was extracted. The obtained organic layer was washed with water (15.0kg), and concentrated under reduced pressure to give a toluene solution of Compound 7 (8.25kg).

 

(Step 6) Synthesis of Compound (II ‘) 　under a nitrogen atmosphere, thiourea (1.03kg), in ethanol (1.2kg) and 65 ℃ toluene solution of compound 7 (8.25kg) in toluene (6.3kg) over 3 hours was added dropwise and stirred for 2 hours. The reaction solution was extracted by adding 0.7% hydrochloric acid (30.6kg), and washed twice with water (30.0kg). Ethanol in the organic layer (9.5kg), and extracted by addition of heptane (10.0kg) and 3.5% hydrochloric acid (5.9kg). The resulting aqueous layer with 4% hydrochloric acid (1.5kg) and ethanol (3.5kg) merged the aqueous layer was extracted from the organic layer, the ethanol was washed with heptane (10.0kg) (3.1kg) It was added. 8% aqueous sodium hydroxide (6.0kg) was added dropwise over at 5 ℃ 30 minutes, and stirred for 20 minutes. 8% aqueous sodium hydroxide (5.8kg) was added dropwise over a period at 5 ℃ 15 minutes.The precipitated crystals were collected by filtration, washed with 45% aqueous ethanol (10.9kg) and water (15.0kg) (crude crystals of Compound (II ‘)). The resulting crude crystals were dissolved in 50 ℃ in ethanol (8.1kg), over a period of 1 hour and then cooled to 10 ℃, and the mixture was stirred for 30 minutes. Water (10.0kg) over 2 hours was added dropwise and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with 50% aqueous ethanol (7.5kg) and water (10.0kg) (crystals of the compound after recrystallization from ethanol / water system (II ‘)). The resulting crystals were dissolved at 55 ℃ in toluene (1.6kg) and heptane (1.3kg), over 1 hour and cooled to 20 ℃, and stirred for 30 minutes. Heptane (6.3kg) over a period of 30 minutes was added dropwise and stirred for 15 minutes. The obtained crystals precipitated were collected by filtration, washed with a mixed solvent of toluene (0.3kg) and heptane (2.3kg), and dried to give compound (II ‘) (1.67kg, 44.5% yield) a (crystalline compound after recrystallization from toluene / heptane system (II ‘)).

NMR (CDCl 3 ) delta ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, M), 1.35 (3H, D, J = 6.5 Hz), 1.48 (2H, M), 3.25 ( 2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz) 　it is shown in Figure 2 and Table 4 the results of powder X-ray diffraction. [Table 4] 　In the powder X-ray diffraction spectrum, diffraction angle (2θ): 12.5 ± 0.2 °, 13.0 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0. 2 °, 23.0 ± 0.2 °, a peak was observed at 24.3 ± 0.2 ° degrees. 　Above, each of the compounds (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) crystallographic purity of the results of the , Fig. 3, I 4 and 5 as well as Table 5. [Table 5](HPLC was measured by the above method A.) 　As shown in the results of the above table, as compared to recrystallization from ethanol / water, recrystallized with toluene / heptane system, compounds having a high optical purity it is possible to manufacture a crystal of (II ‘). 　Next, the above-mentioned compound (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) results of crystals of HPLC of the respectively, Fig. 6, I 7 and 8 and Table 6. [Table 6] (units, .N.D shows the peak area of the (%). is, .HPLC to indicate not detected was measured by the above method B.) 　As shown in the results of Table, with ethanol / water system Compared to recrystallization, recrystallization from toluene / heptane system is found to be efficiently remove organic impurities A and organic impurities B.

(Step 7) Compound ‘Synthesis of DMSO adduct of (VIII) 　Under a nitrogen atmosphere, the compound (II ‘) (1.50kg) and compound (VII’) (1.43kg) in ethyl acetate (17.6kg) and triethylamine (1.09kg) were sequentially added, was dissolved.Diphenyl phosphorochloridate the (1.46kg) was added dropwise over 1 hour at 50 ℃, and the mixture was stirred for 3 hours. The reaction mixture was cooled to 25 ℃, after the addition of 2.6% hydrochloric acid (8.1kg), and extracted. The resulting organic layer to 6.3% aqueous solution of sodium hydroxide (3.2kg) and 14% aqueous sodium carbonate (5.2kg) was added and stirred for 20 minutes. Adjusted to pH7.5 with 8.3% hydrochloric acid and extracted. The organic layer it was washed with 4.8% sodium chloride aqueous solution (11.0kg). DMSO and (16.5kg) was added, and the mixture was concentrated under reduced pressure.DMSO and (5.8kg) was added, over a period at 40 ℃ 30 minutes was added dropwise water (0.9kg), and stirred for 1 hour. Over a period of 30 minutes, cooled to 25 ℃, and the mixture was stirred for 30 minutes. Over at 25 ℃ 30 minutes was added dropwise water (1.4kg), and the precipitated crystals were collected by filtration. After washing with 90% DMSO solution (10.0kg) and water (27.0kg), to obtain crystals of DMSO adduct and dried to Compound (VIII ‘) (2.98kg, 95.2% yield).

1H-NMR (CDCl 3 ) delta: 0.87 (t, J = 6.8 Hz, 3H), 1.20-1.34 (M, 6H), 1.37 (t, J = 7.1 Hz, 3H), 1.44 (D, J = 6.5 Hz , 3H), 1.52-1.59 (m, 2H), 1.77 (d, J = 1.3Hz, 3H), 2.62 (s, 6H), 3.28-3.34 (m, 2H), 3.59 (s, 3H), 4.31 ( q, J = 7.1Hz, 2H), 4.83 (q, J = 6.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (s, 1H), 7.68 (dd, J = 7.7, 1.8Hz, 1H), 7.92 (d, J = 1.3Hz, 2H), 10.58 (s, 1H). 　The results of the powder X-ray diffraction and I are shown in Figure 9 and Table 7. [Table 7]

In the powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° peak was observed to ± 0.2 ° and 24.1 ° ± 0.2 °. 　TG / DTA analysis result it is shown in Figure 10. 　Then, each result of HPLC of concentrated dry solid and the above DMSO adduct crystals described in the following Reference Examples 1, 11 and 12, 13 and 14, and I are shown in Table 8. [Table 8] (unit, .HPLC showing peak areas of (%) was measured by the above methods C.) 　As shown in the results of the above Table, when compared with the extract, DMSO adduct of the compound (VIII ‘) The in the crystal, less residual organic impurities D, and it found to be about 56% removal.

(Step 8) 　under nitrogen atmosphere, DMSO adduct of the compound (VIII ‘) and (2.50kg) it was dissolved in ethanol (15.8kg). 24% sodium hydroxide aqueous solution (1.97kg) was added dropwise over a period at 45 ℃ 30 minutes to the solution and stirred for 3 hours. The reaction mixture was cooled to 25 ℃, water was added (20.0kg) and ethanol (7.8kg). 18% hydrochloric acid (2.61kg) was added dropwise over at 25 ℃ 30 minutes, followed by addition of seed crystals prepared according to the method described in Patent Document 23. After stirring for 3 hours and allowed to stand overnight. Thereafter, the precipitated crystals were collected by filtration, to give after washing with 50% aqueous ethanol solution (14.2kg), and dried to a compound (XI ‘) (1.99kg, 93.9% yield).

NMR (CDCl 3 ) delta ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, M), 1.48 (3H, D, J = 6.4 Hz), 1.52 – 1.64 (2H, M), 1.86 (3H, d, J = 1.4Hz), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs) 　I is shown in Figure 15 the results of powder X-ray diffraction.

 

Patent Document 1: JP-A-10-72492 JP
Patent Document 2: WO 96/40750 pamphlet
Patent Document 3: JP-A-11-1477 JP
Patent Document 4: Japanese Unexamined Patent Publication No. 11-152276
Patent Document 5: International Publication No. 00/35446 pamphlet
Patent Document 6: JP-A-10-287634 JP
Patent Document 7: WO 01/07423 pamphlet
Patent Document 8: International Publication WO 01/53267 pamphlet
Patent Document 9: International Publication No. 02 / 059 099 pamphlet
Patent Document 10: International Publication No. 02/059100 pamphlet
Patent Document 11: International Publication No. 02/059100 pamphlet
Patent Document 12: International Publication No. 02/062775 pamphlet
Patent Document 13: International Publication No. 2003/062233 pamphlet
Patent Document 14: International Publication No. 2004/029049 pamphlet
Patent Document 15: International Publication No. 2005/007651 pamphlet
Patent Document 16: International Publication No. 2005/014561 pamphlet
Patent Document 17: JP 2005-47905 Japanese
patent Document 18: Japanese Patent Publication No. 2006-219480
Patent Document 19: Japanese Patent Publication No. 2006-219481
Patent Document 20: International Publication No. 2007/004038 pamphlet
Patent Document 21: International Publication No. 2007/036709 pamphlet
Patent Document 22: International Publication No. 2007/054783 pamphlet
Patent Document 23: International Publication No. 2009/017098 pamphlet

Non-Patent Document 1: Proceedings of the National Akademyi of Science of the United State of America (…. Proc Natl Acad Sci USA) 1992, Vol. 89, p 5640-5644.
Non-Patent Document 2: Journal of Organic (.. J. Org Chem) Chemistry 1984, Vol. 49, p 3856-3857.
Non-Patent Document 3: (.. J. Org Chem). Journal of Organic Chemistry, 1992, Vol. 57, p 6667-6669
Non-Patent Document 4:. Shinretto (Synlett) 2004 year Vol. 6, p 1092-1094

 

 

 

 

 

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CCCCCCOC(C)C1=CC=CC(=C1OC)C2=CSC(=N2)NC(=O)C3=CC(=C(C(=C3)Cl)C=C(C)C(=O)O)Cl

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EVOGLIPTIN

 diabetes, Phase 3 drug, Uncategorized  1 Response »
Jul 032015
 

 

ChemSpider 2D Image | Evogliptin | C19H26F3N3O3

 

EVOGLIPTIN
CAS: 1222102-29-5 FREE

HCL……

Dong-A Pharmaceutical. Co., Ltd, 동아제약 주식회사
2-Piperazinone, 4-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-3-((1,1-dimethylethoxy)methyl)-, (3R)-
R)-4-((R)-3-Amino-4-(2,4,5-trifluorophenyl)-butanoyl)-3-(t-butoxymethyl)-piperazin-2-one

4-[3(R)-Amino-4-(2,4,5-trifluorophenyl)butyryl]-3(R)-(tert-butoxymethyl)piperazin-2-one hydrochloride

DA-1229

DA-1229 is a dipeptidyl peptidase IV (CD26) inhibitor currently being developed in phase III clinical studies at Dong-A for the treatment of type 2 diabetes.

In 2014, Eurofarma aquired rights for product development and commercialization in Brazil.

Evogliptin Tartrate

 

 

86…………H. J. Kim, W. Y. Kwak, J. P. Min, J. Y. Lee, T. H. Yoon, H. D. Kim, C. Y. Shin, M. K.
Kim, S. H. Choi, H. S. Kim, E. K. Yang, Y. H. Cheong, Y. N. Chae, K. J. Park, J. M.
Jang, S. J. Choi, M. H. Son, S. H. Kim, M. Yoo and B. J. Lee, Bioorg. Med. Chem. Lett.,
2011, 21 (12), 3809-3812.
[87] …………K. S. Lim, J. Y. Cho, B. H. Kim, J. R. Kim, H. S. Kim, D. K. Kim, S. H. Kim, H. J. Yim,
S. H. Lee, S. G. Shin, I. J. Jang and K. S. Yu, Br. J. Clin. Pharmacol., 2009, 68 (6), 883-
890.

  • Originator Dong-A Pharmaceutical
  • Developer Dong-A ST
  • Class Amides; Antihyperglycaemics; Fluorobenzenes; Piperazines; Small molecules
  • Mechanism of Action CD26 antigen inhibitors
  • Orphan Drug Status No
  • On Fast track No
  • New Molecular Entity Yes
  • Available For Licensing Yes – Type 2 diabetes mellitus

Highest Development Phases

  • Phase III Type 2 diabetes mellitus

Most Recent Events

  • 01 Sep 2014 Phase-I clinical trials in Type-2 diabetes mellitus (In volunteers) in United Kingdom (PO)
  • 31 Jul 2014 Phase-III clinical trials in Type-2 diabetes mellitus in South Korea (PO)
  • 31 Jul 2014 Dong-A ST initiates enrolment in a phase I trial in patients with renal impairment in South Korea (NCT02214693)

Evogliptin Tartrate

…………………………………..

WO 2010114291

http://www.google.co.in/patents/WO2010114291A2?cl=en

Formula 1

Figure PCTKR2010001947-appb-C000001

 

 

Korea Patent Publication No. 2008-0094604 the call to the scheme, as indicated by A Ⅰ) of formula (II) beta-compound of formula 3 is already substituted heterocyclic compound having 1-hydroxy-benzotriazole group (HOBT) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and reacting with a tertiary amine to prepare a compound of formula (4) connected by peptide bonds; Ⅱ) beta comprises the step of reacting under acidic conditions a compound of the formula (4) – a method of manufacturing the heterocyclic compounds of the formula I having an amino group is disclosed.

– Scheme A]

 

Figure PCTKR2010001947-appb-I000001

(Wherein, PG is a protecting group.)

In this case, the beta of the formula (2) of Scheme A – a compound having an amino group is prepared in addition to the DPP-IV inhibitor International Publication represented by Formula 1 WO03 / 000181, WO03 / 004498, WO03 / 082817, WO04 / 007468, WO04 / 032836, WO05 / 011581, WO06 / 097175, WO07 / 077508, WO07 / 063928, WO08 / 028662 WO08 / it may be used for the production of different DPP-IV inhibitors according 087,560 and can be prepared in a number of ways.

To, the compound of Formula 2 is an example as shown in Scheme J. Med.Chem. 2005; 141, and Synthesis 1997; it can be produced by the known method described in 873.

 

Figure PCTKR2010001947-appb-I000002

Specifically, (2S) – (+) – 2,5- dihydro-3,6-dimethoxy-2-isopropyl-pyrazine 2,4,5-trifluoro-react with benzyl bromide and acid treatment, and then the amine an ester compound obtained by the protection reaction. Ester compounds are hydrolyzed to re-3- (2,4,5-trifluoro-phenyl) -2-amino-propionic acid tert such as isobutyl chloroformate, triethylamine or diisopropylethylamine to give the amine, and then using diazomethane to form a diazo ketone, and then may be prepared by reaction with silver benzoate. However, the reaction can be performed at low temperature (-78 ℃) or high alpha-amino acid to purchase and use, and may have a risk of problems such as the need to use large diazomethane.

 

To a different process for preparing a compound of Formula 2 as shown in scheme Tetrahedron: Asymmetry 2006; It is known in 2622; 205 or similarly Bioorganic & Medicinal Chemistry Letters 2007.

 

Figure PCTKR2010001947-appb-I000003

That is, a 1,1′-carbonyl-2,4,5 which the phenyl trifluoroacetic acid activated using the following imidazole mono-methyl words potassium carbonate is reacted with the beta-keto ester compound is prepared. This produced an enamine ester using ammonium acetate and ammonium solution, the ester compound chloro (1,5-cyclooctadiene) rhodium (I) dimer using a chiral ferrocenyl ligands I the reaction of the high-pressure hydrogen with a chiral primary amine with a beta-amino ester compound after production and can lead to hydrolysis to prepare a compound of formula (2). However, use of expensive metal catalyst has a problem that must be performed in high pressure hydrogenation.

 

The method for preparing a compound of Formula 2 is disclosed in International Publication No. WO 04/87650.

 

Figure PCTKR2010001947-appb-I000004

Specifically, 2,4,5-fluorophenyl reagent is oxalyl chloride, the acid activated acid with 2,2-dimethyl-1,3-dioxane-4,6-dione, and after the reaction of methanol and the resulting material at reflux to prepare a corresponding compound. With a selective reducing reagents which enantiomers (S) -BINAP-RuCl 2 and hydrogen through a reaction (S) – producing a compound having coordinated to each other, it again after the decomposition, and the singer O- benzyl hydroxyl amine and the coupling reaction and the intermediate is prepared. To do this, the resulting intermediate tree azodicarboxylate and diisopropyl azodicarboxylate presence ring condensation reaction, treated with an aqueous solution of lithium hydroxide to (R) – while having the formula (II) coordinated to the amine group protected with a benzyl-O- the compound can be produced. However, the method has a problem as a whole to be prepared by the reaction yield to be low and a long processing time to perform the reaction.

 

Thus, the conventional known method for producing a compound of the general formula (2) has the disadvantage of using expensive reagents, or not suitable for commercial mass-production method by a long synthesis time yield is also low.

 

In addition, the compound represented by General Formula (3), as described in Korea Patent Publication No. 2008-0094604 call, can be prepared by way of reaction schemes.

 

Figure PCTKR2010001947-appb-I000005

Specifically, the starting material D- serine methyl ester is substituted by a hydroxy group when reflux again substituted by trityl chloride as methoxy groups converted to the aziridine compound.

[Scheme 3]

 

Figure PCTKR2010001947-appb-I000008

<Example 3> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) Preparation of the hydrochloride

Step 1: t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소 – 1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트(화학식 Preparation of 4)

2 L flask, prepared in Example 1 (R) -3-t- butoxycarbonyl-4- (2,4,5-trifluoro-phenyl) butanoate acid (Formula 2) 10.0 g of toluene was dissolved in 450 mL of bis (2,2′-benzothiazolyl) disulfide 13.0 g, was cooled and then 10.2 g triphenylphosphine was added to the reaction solution at 0 ℃. While stirring the reaction mixture was added to a solution of 0.8 mL of triethylamine in 20 mL of toluene was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0 ℃ and prepared in Example 2 (R) -3- (t- butoxymethyl) piperazin-2-one (Formula 3) was dissolved in 5.6 g of toluene and 40 mL pyridine a 2.4 mL was added slowly. After 30 minutes the reaction mixture was heated to room temperature and stirred for 1 hour. Saturated sheet to be the aqueous acid solution to a pH of 2.5 and then diluted with ethyl acetate 400 mL. Washed twice with brine and the organic layer was dehydrated with magnesium sulfate and concentrated. The residue was purified by column chromatography to give the title compound 838 mg.

1 H NMR (400 MHz, CDCl 3) δ 7.03 (m, 1H), 6.88 (m, 1H), 5.97 (m, 1H), 5.48 (m, 1H), 4.16 ~ 4.07 (m, 1H), 4.02 ~ 3.91 (m, 1H), 3.74 (m, 2H) 3.37 (m, 2H), 3.24 (m, 1H), 2.92 (m, 2H), 2.80 (m, 1H), 2.59 (m, 2H), 1.34 ( d, 9H), 1.13 (s, 9H)

 

Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- on the production of (I) hydrochloride

Prepared in Step 1 t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소-1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트 97 mg was dissolved in methanol was added 3 mL 2N- hydrochloric acid / diethyl ether 2 mL was stirred at room temperature for 3 hours. The reaction mixture was concentrated and dried under reduced pressure to give 64 mg of the title compound as a foaming solid.

1 H NMR (400 MHz, CD 3 OD) δ 7.37 (m, 1H), 7.23 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H), 1.18 (s, 3H ), 1.11 (s, 6H)

Mass (M + 1): 402

 

<Example 4> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) tartaric acid salts

Step 1: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- Preparation of one (I)

Example 3 to give a compound of formula I in hydrochloride 60 mg 5% sodium hydrogen carbonate in dichloromethane was added to 10 mL of an aqueous solution / 2-propanol (4/1 (v / v)) was added to the mixed solution and extracted two times 10 mL The organic layer was dried under reduced pressure to give 55 mg of the title compound as a solid.

1 H NMR (400 MHz, CD 3 OD) δ 7.27 (m, 1H), 7.14 (m, 1H), 4.56 ~ 4.39 (m, 1H), 3.96 ~ 3.81 (m, 3H), 3.70 (m, 1H) , 3.46 (m, 1H), 3.43 ~ 3.32 (m, 1H), 2.83 ~ 2.65 (m, 3H), 2.58 ~ 2.40 (m, 2H), 1.16 (s, 3H), 1.11 (s, 6H)

Mass (M + 1): 402

 

Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- (t- butoxymethyl) piperazin-2- one (I) tartaric acid salt [

Was dissolved 55 mg of the compound of step 1 in 0.56 mL of acetone, L- tartrate 26 mg ethanol / water (9/1 (v / v)) was added slowly to a solution of 0.35 mL was stirred for 30 minutes. Here was added 0.56 mL of 2-propanol was stirred for 10 minutes and re-filtered to give 77 mg of the title compound as a solid.

1 H NMR (400 MHz, CD 3 OD) δ 7.38 (m, 1H), 7.22 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 4.40 (s, 2H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H ), 1.15 (s, 3H), 1.11 (s, 6H)

Mass (M + 1): 402

………………………………

WO 2010114292

http://www.google.com/patents/WO2010114292A2?cl=en

…………………………………

Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
Bioorg Med Chem Lett 2011, 21(12): 3809

http://www.sciencedirect.com/science/article/pii/S0960894X11004859

Full-size image (3 K)

A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.

About evogliptin tartrate tablets
Evogliptin tartrate tablets is a dipeptidyl peptidase IV inhibitor, in tablet form. Evogliptin tartrate
tablets is expected to be approved for the treatment of type 2 diabetes mellitus. The Group holds
an exclusive intellectual property licence from Dong-A Pharmaceutical Co. Ltd. to develop
and commercialise evogliptin tartrate tablets in China, including the exclusive right to develop
evogliptin tartrate tablets for manufacturing and sale in the Group’s name. The new drug certificate
to be issued by the CFDA will be approved and registered under the Group’s name.
Evogliptin is a patented new molecular entity in the United States and other international markets.
Evogliptin tartrate tablets is being concurrently developed by Dong-A Pharmaceutical Co. Ltd.
for the Korean market. Based on information released from a multi-centre, phase II, randomised,
double-blind, placebo-controlled, therapeutic exploratory clinical trial conducted in Korea by
Dong-A Pharmaceutical Co. Ltd. to investigate the efficacy and safety of evogliptin, evogliptin
was proven to be effective in significantly lowering blood glucose levels in patients with type
2 diabetes. Data also show that the body weights of patients remain stable over the treatment
period. In addition, evogliptin was proven to be safe and well tolerated with no severe adverse
drug reactions observed during those phase II clinical trials. The Company believes evogliptin
tartrate tablets will help reduce the burden of patients with moderate-to-severe renal impairment
as pharmacokinetic study in animal model and healthy human volunteers showed low renal
elimination.
2
According to the statistics of IMS Health Incorporated, the market size of products for the
treatment of diabetes in China in 2013 was approximately RMB7.8 billion, and grew at a
compound annual growth rate of 23.4% from 2011 to 2013.

 http://www.luye.cn/en/uploads//2014-07/21/_1405936452_zr21xh.pdf

Dong-A ST
SEOUL, SOUTH KOREA
14 April 2015 – 5:45pm
Oh Seung-mock

Dong-A ST has licensed its new diabetes drug Evogliptin to 17 Latin American countries including Mexico, Venezuela, Argentina, Chile, Colombia, Ecuador, Peru, the Dominican Republic, and Uruguay, Jung Jae-wook, Dong-A ST’s PR manager, told Business Korea.

Dong-A ST and Eurofarma, a Brazilian pharmaceutical company, concluded the licensing contract at Dong-A ST’s headquarters on April 13 in Seoul.

Eurofarma will be responsible for Evogliptin’s product development and sales in the 17 Latin American countries, Dong-A ST said. Dong-A ST will receive royalties from Eurofarma, and export the raw material of the medicine.

Dong-A ST has been developing Evogliptin with the support of the Ministry of Health & Welfare of South Korea as an innovative new medicine research project since May 2008. Evogliptin is a DPP-4 remedy based on the inhibition mechanism which is “excellent” at reducing blood sugar, whilst “less likely” to cause weight increases and hypoglycemia, the company said.

Park Chan-il, president of Dong-A ST, said that Dong-A ST will pursue further out-licensing “over the globe,” through continuous investment in research and development.

Maurizio Billi, Eurofarma’s president, wished to expand both companies’ partnership in the innovative new remedy development sector, according to Dong-A ST.

Last July, Dong-A ST and Eurofarma concluded a contract out-licensing Evogliptin to Brazil itself, the company said.

– See more at: http://www.businesskorea.co.kr/article/10115/southern-strategy-dong-st-licenses-new-diabetes-drug-evogliptin-17-latin-american#sthash.liqwFTWU.dpuf

see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

 

see gliptins at…..http://drugsynthesisint.blogspot.in/p/gliptin-series.html

see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

Dong-A Pharm. Co., Ltd, Yongin-si, Gyeonggi-do, Republic of Korea.

 

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Ragaglitazar ……..Dr. Reddy’s Research Foundation

 diabetes, Phase 3 drug  Comments Off on Ragaglitazar ……..Dr. Reddy’s Research Foundation
Nov 202014
 

Ragaglitazar

NNC-61-0029, (-) – DRF-2725, NN-622,

(−)DRF 2725

cas   222834-30-2

222834-21-1 (racemate)

Hyperlipidemia; Hypertriglyceridemia; Lipid metabolism disorder; Non-insulin dependent diabetes

PPAR alpha agonist; PPAR gamma agonist

(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID,

(2S)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid, DRF, 1nyx

Molecular Formula: C25H25NO5
Molecular Weight: 419.4697 g/mol
Dr. Reddy’s Research Foundation (Originator), Novo Nordisk (Licensee)
Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists
Phase III
…………………..
EP 1049684; JP 2001519422; WO 9919313
Several related procedures have been described for the synthesis of the title compound. The Horner-Emmons reaction of 4-benzyloxybenzaldehyde (I) with triethyl 2-ethoxyphosphonoacetate (II) afforded the unsaturated ester (IIIa-b) as a mixture of E/Z isomers. Simultaneous double-bond hydrogenation and benzyl group hydrogenolysis in the presence of Pd/C furnished phenol (IV). Alternatively, double-bond reduction by means of magnesium in MeOH was accompanied by transesterification, yielding the saturated methyl ester (V). Further benzyl group hydrogenolysis of (V) over Pd/C gave phenol (VI). The alkylation of phenols (IV) and (VI) with the phenoxazinylethyl mesylate (VII) provided the corresponding ethers (VIII) and (IX), respectively. The racemic carboxylic acid (X) was then obtained by hydrolysis of either ethyl- (VIII) or methyl- (IX) esters under basic conditions.
…………………………………………
……………………………………………………..
The synthesis of ragaglitazar (Scheme 1) was commenced by treating substrate 2 under optimized phase-transfer catalyzed conditions, using solid cesium hydroxide monohydrate as the base, a pivalate protected benzyl bromide and the Park and Jew triflurobenzyl-hydrocinchonidinium bromide salt 1. We were delighted to find that this reaction produced 3 in good yield with good selectivity. Subsequent removal of the diphenylmethyl (DPM) group under Lewis acidic conditions followed by a Baeyer-Villager like oxidation yielded the - hydroxy aryl ester 4. At this point, we were again pleased to find that this ester could be recrystalized from warm ether to give essentially enantiomerically pure products (~95% ee). The free hydroxyl was then alkylated using triethyloxonium tetrafluoroborate, and then transesterification under catalytic basic conditions produced 5. A mesylated phenoxazine alcohol reacted with 5 to yield the methyl ester of 6, which was obtained by treatment with sodium hydroxide in methanol. The overall synthesis proceeds with 47% overall yield (41% from commercially available reagents) and is eight linear steps from the alkoxyacetophenone substrate 2, including a recrystalization.

……………………………………………………………..

J Med Chem 2001,44(16),2675

http://pubs.acs.org/doi/abs/10.1021/jm010143b

 

Abstract Image

(−)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPARα and PPARγ. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.

Figure

Scheme 1 a

 

a (a) NaH, DMF, 0−25 °C, 12 h; (b) triethyl 2-ethoxy phosphosphonoacetate, NaH, THF, 0−25 °C, 12 h; (c) Mg/CH3OH, 25 °C, 12 h; (d) 10% aq NaOH, CH3OH, 25 °C, 6 h; (e) (1) pivaloyl chloride, Et3N, DCM, 0 °C, (2) (S)-2-phenyl glycinol/Et3N; (f) 1 M H2SO4, dioxane/water, 90−100 °C, 80 h.

Compound 6 is prepared from phenoxazine using a synthetic route shown in Scheme 1. Phenoxazine 7 upon reaction with p-bromoethoxy benzaldehyde 89 gave benzaldehyde derivative 9. Reacting 9 with triethyl 2-ethoxy phosphonoacetate afforded propenoate 10 as a mixture of geometric isomers. Reduction of 10 using magnesium methanol gave propanoate 11, which on hydrolysis using aqueous sodium hydroxide gave propanoic acid 12 in racemic form. Resolution of 12 using (S)(+)-2-phenyl glycinol followed by hydrolysis using sulfuric acid afforded the propanoic acid 6 in (−) form.

Nate, H.; Matsuki, K.; Tsunashima, A.; Ohtsuka, H.; Sekine, Y. Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. II. 2-(phenylpiperazinoalkoxyphenyl)thiazolidine-3-thiocarboxyamides and corresponding carboxamides. Chem. Pharm. Bull. 1987, 35, 2394−2411

(S)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-eth-oxypropanoic Acid (6).  as a white solid, mp: 89−90 °C.

[α]D 25 = − 12.6 (c = 1.0%, CHCl3).

1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J = 7.0 Hz, 3H), 1.42−1.91 (bs, 1H, D2O exchangeable), 2.94−3.15 (m, 2H), 3.40−3.65 (m, 2H), 3.86−4.06 (m, 3H), 4.15 (t, J = 6.6 Hz, 2H), 6.63−6.83 (m, 10H), 7.13 (d, J = 8.5 Hz, 2H). Mass m/z (relative intensity):  419 (M+, 41), 197 (15), 196 (100), 182 (35), 167 (7), 127 (6), 107 (19).

Purity by HPLC: chemical purity: 99.5%; chiral purity: 94.6% (RT 27.5).

…………………………………

http://www.google.com/patents/US6608194?cl=zh

EXAMPLE 23 (−) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid:

 

Figure US06608194-20030819-C00052

 

The title compound (0.19 g, 54%) was prepared as a white solid from diastereomer [(2S-N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenyl)ethylpropanamide (0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example 22. mp: 89-90° C.

[α]D 25=−12.6 (c=1.0% CHCl3)

1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J=7.02 Hz, 3H), 1.42-1.91 (bs, 1H, D2O exchangeable), 2.94-3.15 (complex, 2H), 3.40-3.65 (complex, 2H), 3.86-4.06 (complex, 3H), 4.15 (t, J=6.65 Hz, 2H), 6.63-6.83 (complex, 10H), 7.13 (d, J=8.54 Hz, 2H).

………………………..

http://www.google.com/patents/EP1049684A1?cl=en

Example 23

(S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid :

 

Figure imgf000051_0002

The title compound (0.19 g, 54 %) was prepared as a white solid from diastereomer [(2S- N(lS)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-l- phenyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21b by an analogous procedure to that described in example 22. mp : 89 – 90 °C. [α]D 25 = – 12.6 (c = 1.0 %, CHC13)

*H NMR (CDC13, 200 MHz) : δ 1.16 (t, J = 7.02 Hz, 3H), 1.42 – 1.91 (bs, IH, D20 exchangeable), 2.94 – 3.15 (complex, 2H), 3.40 – 3.65 (complex, 2H), 3.86 – 4.06 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.63 – 6.83 (complex, 10H), 7.13 (d, J = 8.54 Hz, 2H).

Patent Submitted Granted
Benzamides as ppar modulators [US2006160894] 2006-07-20
Novel tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US2002077320] 2002-06-20
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US7119198] 2006-07-06 2006-10-10
Tricyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them [US6440961] 2002-08-27
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6548666] 2003-04-15
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6608194] 2003-08-19
CRYSTALLINE R- GUANIDINES, ARGININE OR (L) -ARGININE (2S) -2- ETHOXY -3-{4- [2-(10H -PHENOXAZIN -10-YL)ETHOXY]PHENYL}PROPANOATE [WO0063189] 2000-10-26
Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds [US6897199] 2002-11-14 2005-05-24
Tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them [US6939988] 2005-09-06

WO-2014181362

  1. wo/2014/181362 a process for the preparation of 3 … – WIPO

    patentscope.wipo.int/search/en/WO2014181362

    Nov 13, 2014 – (WO2014181362) A PROCESS FOR THE PREPARATION OF 3-ARYL-2-HYDROXY PROPANOIC ACID COMPOUNDS …

A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds

ragaglitazar; saroglitazar

Council of Scientific and Industrial Research (India)

Process for preparing enantiomerically pure 3-aryl-2-hydroxy propanoic acid derivatives (eg ethyl-(S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate), using S-benzyl glycidyl ether as a starting material. Useful as intermediates in the synthesis of peroxisome proliferator activated receptor agonist such as glitazars (eg ragaglitazar or saroglitazar). Appears to be the first filing on these derivatives by the inventors; however see WO2014181359 (for a concurrently published filing) and US8748660 (for a prior filing), claiming synthesis of enantiomerically pure compounds.

  1. Dolling, U. H.; Davis, P.; Grabowski, E. J. J. Efficient Catalytic Asymmetric Alkylations. 1. Enantioselective Synthesis of (+)-Indacrinone via Chiral Phase-Transfer Catalysis. J. Am. Chem. Soc. 1984, 106, 446–447.
  2. Andrus, M. B.; Hicken, E. J.; Stephens, J. C. Phase-Transfer Catalyzed Asymmetric Glycolate Alkylation. Org. Lett. 2004, 6, 2289–2292.
  3. Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. Asymmetric Phase-Transfer Catalyzed Glycolate Alkylation, Investigation of the Scope, and Application to the Synthesis of (-)-Ragaglitazar. J. Org. Chem. 2005, ASAP.
  4. Henke, B. R. Peroxisome Proliferator-Activated Receptor  Dual Agonists for the Treatment of Type 2 Diabetes. J. Med. Chem. 2004, 47, 4118–4127.
  5. Wilson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 2000, 46, 1306–1317.
  6. Uchida, R.; Shiomi, K.; Inokoshi, J.; Masuma, R.; Kawakubo, T.; Tanaka, H.; Iwai, Y.; Omura, A. Kurasoins A and B, New Protein Farnesyltrasferase Inhibitors Produced by Paecilomyces sp. FO-3684. J. Antibio. 1996, 49, 932–934.
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Etirinotecan pegol (NKTR-102) エチリノテカンペゴル: A Next-Generation Topoisomerase I Inhibitor

 Phase 3 drug, Uncategorized  Comments Off on Etirinotecan pegol (NKTR-102) エチリノテカンペゴル: A Next-Generation Topoisomerase I Inhibitor
Aug 222014
 

Chemical structure for etirinotecan pegol

Etirinotecan pegol (NKTR-102)

848779-32-8

PEG-irinotecan

Also known as: NKTR-102; UNII-LJ16641SFT; 848779-32-8

Molecular Formula: C161H192N20O40   Molecular Weight: 3047.35718

Nektar Therapeutics innovator

http://www.acsmedchem.org/mediabstractf2013.pdf

CAS:  1193151-09-5

Synonym:   NKTR102; NKTR 102; NKTR-102; pegylated irinotecan NKTR 102; Etirinotecan pegol.

IUPAC/Chemical name: (1). Tetrakis{(4S)-9-[([1,4′-bipiperidinyl]-1′-carbonyl)oxy]-4,11-diethyl-3,14-dioxo-3,4,12,14- tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl} N,N’,N”,N”’- {methanetetrayltetrakis[methylenepoly(oxyethylene)oxy(1-oxoethylene)]}tetraglycinate tetrahydrochloride

(2). Poly(oxy-1,2-ethanediyl), α-hydro-ω-[2-[[2-[[(4S)-9-[([1,4′-bipiperidin]-1′-ylcarbonyl)oxy]- 4,11-diethyl-3,4,12,14-tetrahydro-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2- b]quinolin-4-yl]oxy]-2-oxoethyl]amino]-2-oxoethoxy]-, ether with 2,2-bis(hydroxymethyl)- 1,3-propanediol, hydrochloride (4:1:4)

Etirinotecan pegol tetratriflutate [USAN]

RN: 1193151-12-0

2D chemical structure of 1193151-12-0

MF and MW

  • 3503.4754

Tetrakis((4S)-9-(((1,4′-bipiperidinyl)-1′-carbonyl)oxy)-4,11-diethyl-3,14-dioxo-3,4,12,14- tetrahydro-1H-pyrano(3′,4′:6,7)indolizino(1,2-b)quinolin-4-yl) N,N’,N”,N”’- (methanetetrayltetrakis(methylenepoly(oxyethylene)oxy(1-oxoethylene)))tetraglycinate tetrakis(trifluoroacetate)

NKTR-102 is currently being developed by Nektar. According to the company’s news release, this agent exhibits a very high response rate and excellent clinical benefit rate in patients with metastatic breast cancer, and importantly, this anti-tumor activity is maintained in each of the poor prognosis subsets within the study. The data from the Phase 2 study also shows highly promising PFS of 5.3 months and OS of 13.1 months in the every three week dose schedule, which was also very well-tolerated.   As a novel topoisomerase I inhibitor in breast cancer, NKTR-102 holds great therapeutic potential and allows us to address the challenge of resistance in this setting

NKTR-102 (PEG-irinotecan), a PEGylated form of irinotecan, is in clinical development by Nektar Therapeutics for the treatment of multiple solid tumors, including colorectal cancer, metastatic or locally advanced breast cancer, metastatic or locally advanced ovarian cancer and gastrointestinal cancer. No recent development has been reported for phase I clinical trials for the treatment of gastrointestinal cancer.

In preclinical studies, NKTR-102 resulted in significantly higher reduction in tumor growth than irinotecan in colon, lung and breast tumors. The company believes that following intravenous administration of NKTR-102, irinotecan will be released slowly, resulting in prolonged systemic exposure of irinotecan. Irinotecan is a cytotoxic anticancer agent used extensively to treat colorectal, lung, esophageal and other solid tumors. In 2011, orphan drug designation was assigned to the compound in the U.S. for the treatment of ovarian cancer.

In 2011, orphan drug designation was assigned in the E.U. for the treatment of ovarian cancer. In 2012, fast track designation was assigned by the FDA for the treatment of locally recurrent or metastatic breast cancer progressing after treatment with an anthracycline, a taxane and capecitabine.

Therapeutic Area Nektar
Discovered		 Indication Phase
Oncology
Etirinotecan pegol (NKTR-102)
Metastatic Breast Cancer
Phase 3
Platinum-Resistant Ovarian Cancer
Phase 2 Completed
Second-Line Colorectal Cancer
Phase 2 Completed
Bevacizumab (Avastin)-refractory high-grade glioma
Phase 2
Non-Small Cell Lung Cancer (NSCLC)
Phase 2
Small Cell Lung Cancer (SCLC)
Phase 2
GI and solid tumors
In combination with 5-FU
Phase 1 Completed

http://www.nektar.com/product_pipeline/all_phases.html#BAX855

Market Overview

Etirinotecan pegol is in Phase 3 clinical development for patients with metastatic or locally recurrent breast cancer and Phase 2 clinical development for patients with solid tumor malignancies, including ovarian, colorectal, glioma, small cell and non-small cell lung cancers. Each year, approximately 5.3 million patients worldwide are diagnosed with one of these types of cancer.1

Etirinotecan Pegol Clinical Data and Product Profile

Etirinotecan pegol (NKTR-102) is the first long-acting topoisomerase I-inhibitor (Topo I) designed to concentrate in tumor tissue, provide sustained tumor suppression throughout the entire chemotherapy cycle, and to reduce the peak exposures that are associated with toxicities of other cytotoxics. Etirinotecan pegol was invented by Nektar using its advanced polymer conjugate technology platform, and is the first oncology product candidate to leverage Nektar’s releasable polymer technology platform.

Topo I-inhibitors are important chemotherapeutic agents used to treat cancer. Immediately after dosing, however, standard topo I-inhibitors reach high peak concentrations and diffuse quickly throughout the body—penetrating and damaging healthy tissue, such as bone marrow, as well as tumor tissue. Subsequent rapid metabolism limits topo I exposure in tumor cells, reducing the duration of their effect and resulting in a much lower tumor exposure to the active metabolite that may limit their efficacy.

Etirinotecan pegol is a novel chemotherapeutic designed to enhance the anti-cancer effects of topo I-inhibition while minimizing its toxicities. Unlike first generation topo I-inhibitors that exhibit a high initial peak concentration and short half-life, etirinotecan pegol’s unique pro-drug design results in a lowered initial peak concentration of active topo I inhibitor in the blood. The large etirinotecan pegol molecule is inactive when administered. Over time, the body’s natural enzymatic processes slowly metabolize the linkers within the molecule, continuously freeing active drug that then works to stop tumor cell division through inhibition of topo I.

Clinical and preclinical studies have shown that the half-life of active drug generated from etirinotecan pegol is greatly extended to 50 days (compared to 48 hours for irinotecan) and that active drug remains in circulation throughout the entire chemotherapy cycle, providing sustained exposure to topo I inhibition. In preclinical models, etirinotecan pegol achieved a 300-fold increase in tumor concentration as compared to a first generation topo I-inhibitor. Because etirinotecan pegol is a large molecule, it is believed to penetrate the leaky vasculature within the tumor environment more readily than normal vasculature, concentrating and trapping etirinotecan pegol in tumor tissue.

Etirinotecan pegol is currently in development for the treatment of breast, ovarian, colorectal, glioma, small cell and non-small cell lung cancers.

Ongoing clinical development for etirinotecan pegol:

  • In metastatic breast cancer, a Phase 3 randomized, head to head study (The BEACON Study) of etirinotecan pegol compared to Treatment of Physician’s Choice (TPC) completed enrollment of 864 patients in August 2013. Data from the study on the primary endpoint of overall survival is expected by the end of 2014 or early 2015.
  • In ovarian cancer, an expanded Phase 2 study of single-agent etirinotecan pegol in platinum refractory/resistant ovarian cancer in 177 women who failed prior Doxil therapy was completed at the end of 2012.
  • In colorectal cancer, a 174-patient Phase 2 randomized, head-to-head study of etirinotecan pegol compared to irinotecan in patients with second-line colorectal cancer with the KRAS gene mutation is in progress.
  • Etirinotecan pegol is also being evaluated in glioma, small cell and non-small cell lung cancers.

Highlighted Data Presentations:

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were published in the November 2013 issue of The Lancet Oncology (click here to view manuscript) These data were previously presented at the 2011 ASCO Annual meeting (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in platinum-resistant/refractory ovarian cancer were published in the September 30, 2013 online edition of the Journal of Clinical Oncology (click here to view abstract). These data were previously presented at the 2010 ASCO Meeting (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were presented in an oral abstract session at the 2011 ASCO Breast Cancer Symposium by Agustin Garcia, MD. View presentation slides.

Data from a Phase 2 clinical study of NKTR-102 in a subpopulation of patients with platinum-resistant/refractory ovarian cancer and prior Doxil® (pegylated liposomal doxorubicin or PLD) treatment were presented at the 2011 ASCO Annual Meeting by Agustin Garcia, MD. (click here to download this presentation).

Data from a Phase 2 clinical study of etirinotecan pegol in metastatic breast cancer were presented at the 2010 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium by Amad Awada, MD. (click here to download this presentation).

January 16-18, 2014 2014 Gastrointestinal Cancers SymposiumPoster C55: “A phase I study of etirinotecan pegol in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.” January 18, 2014 San Francisco, CA
February 22, 2014 26.2 with Donna Marathon sponsored by Mayo Clinic Jacksonville, FL
March 5-7, 2014 TAT 2013: International Congress on Targeted Anticancer Therapies Washington, DC
April 5-9, 2014 AACR Annual Meeting 2013 San Diego, CA
May 19-21, 2014 10th International Symposium on Polymer Therapeutics Valencia, Spain
May 30-June 3, 2014 2014 ASCO 50th Annual MeetingPoster Presentation: “Combination Immunotherapy: Synergy of a Long-Acting Engineered Cytokine (NKTR-214) and Checkpoint Inhibitors Anti-CTLA-2 or Anti-PD-1 in Murine Tumor Models,” Kantak et al.
Abstract Number: 3082
Session Title/Track: Developmental Therapies – Immunotherapy
Date: June 1, 2014, 8:00 a.m. – 11:45 a.m. Central Time		 Chicago, Illinois
September 4-6, 2014 ASCO Breast Cancer Symposium San Francisco, CA
September 26-30, 2014 ESMO 2014 Congress Madrid, Spain
December 9-13, 2014 San Antonio Breast Cancer Symposium San Antonio, TX

 

……………………….

http://www.google.com.ar/patents/US7744861?cl=pt-PT

Example 1 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-20K

A. Synthesis of t-Boc-Glycine-Irinotecan

 

In a flask, 0.1 g Irinotecan (0.1704 mmoles), 0.059 g t-Boc-Glycine (0.3408 mmoles), and 0.021 g DMAP (0.1704 mmoles) were dissolved in 13 mL of anhydrous dichloromethane (DCM). To the solution was added 0.070 g DCC (0.3408 mmoles) dissolved in 2 mL of anhydrous DCM. The solution was stirred overnight at room temperature. The solid was removed through a coarse frit, and the solution was washed with 10 mL of 0.1N HCL in a separatory funnel. The organic phase was further washed with 10 mL of deionized H2O in a separatory funnel and then dried with Na2SO4. The solvent was removed using rotary evaporation and the product was further dried under vacuum. 1H NMR (DMSO): δ 0.919 (t, CH2CH 3), 1.34 (s, C(CH3)3), 3.83 (m, CH2), 7.66 (d, aromatic H).

B. Deprotection of t-Boc-Glycine-Irinotecan

 

0.1 g t-Boc-Glycine-Irinotecan (0.137 mmoles) was dissolved in 7 mL of anhydrous DCM. To the solution was added 0.53 mL trifluoroacetic acid (6.85 mmoles). The solution was stirred at room temperature for 1 hour. The solvent was removed using rotary evaporation. The crude product was dissolved in 0.1 mL MeOH and then precipitated in 25 mL of ether. The suspension was stirred in an ice bath for 30 minutes. The product was collected by filtration and dried under vacuum. 1H NMR (DMSO): δ 0.92 (t, CH2CH 3), 1.29 (t, CH2CH 3), 5.55 (s, 2H), 7.25 (s, aromatic H).

C. Covalent Attachment of a Multi-Armed Activated Polymer to Glycine Irinotecan.

 

0.516 g Glycine-Irinotecan (0.976 mmoles), 3.904 g 4arm-PEG(20K)-CM (0.1952 mmoles), 0.0596 g 4-(dimethylamino)pyridine (DMAP, 0.488 mmoles), and 0.0658 g 2-hydroxybenzyltriazole (HOBT, 0.488 mmoles) were dissolved in 60 mL anhydrous methylene chloride. To the resulting solution was added 0.282 g 1,3-dicyclohexylcarbodiimide (DCC, 1.3664 mmoles). The reaction mixture was stirred overnight at room temperature. The mixture was filtered through a coarse frit and the solvent was removed using rotary evaporation. The syrup was precipitated in 200 mL of cold isopropanol over an ice bath. The solid was filtered and then dried under vacuum. Yield: 4.08 g. 1H NMR (DMSO): δ 0.909 (t, CH2CH 3), 1.28 (m, CH2CH 3), 3.5 (br m, PEG), 3.92 (s, CH2), 5.50 (s, 2H).

Example 2 ANTI-TUMOR ACTIVITY OF PENTAERYTHRITOLYL-4-ARM-(PEG -1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-20K, “4-ARM-PEG-GLY-IRINO-20K” IN A COLON CANCER MOUSE XENOGRAFT MODEL

Human HT29 colon tumor xenografts were subcutaneously implanted in athymic nude mice. After about two weeks of adequate tumor growth (100 to 250 mg), these animals were divided into different groups of ten mice each. One group was dosed with normal saline (control), a second group was dosed with 60 mg/kg of irinotecan, and the third group was dosed with 60 mg/kg of the 4-arm PEG-GLY-Irino-20K (dose calculated per irinotecan content). Doses were administered intraveneously, with one dose administered every 4 days for a total of 3 administered doses. The mice were observed daily and the tumors were measured with calipers twice a week. FIG.1 shows the effect of irinotecan and PEG-irinotecan treatment on HT29 colon tumors in athymic nude mice.

As can be seen from the results depicted in FIG. 1, mice treated with both irinotecan and 4-arm-PEG-GLY-Irino-20K exhibited a delay in tumor growth (anti-tumor activity) that was significantly improved when compared to the control. Moreover, the delay in tumor growth was significantly better for the 4-arm-PEG-GLY-Irino-20K group of mice when compared to the group of animals administered unconjugated irinotecan.

Example 3 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-IRINOTECAN)-40K, “4-ARM-PEG-GLY-IRINO-40K”

4-arm-PEG-GLY-IRINO-40K was prepared in an identical fashion to that described for the 20K compound in Example 1, with the exception that in step C, the multi-armed activated PEG reagent employed was 4 arm-PEG(40K)-CM rather than the 20K material.

Example 4 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-SN-38)-20K, “4-ARM-PEG-GLY-SN-38-20K”

4-arm PEG-GLY-SN-38-20K was prepared in a similar fashion to its irinotecan counterpart as described in Example 1, with the exception that the active agent employed was SN-38, an active metabolite of camptothecin, rather than irinotecan, where the phenolic-OH of SN-38 was protected with MEMCI (2-methoxyethoxymethyl chloride) during the chemical transformations, followed by deprotection with TEA to provide the desired multi-armed conjugate.

Example 5 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-1-METHYLENE-2 OXO-VINYLAMINO ACETATE LINKED-SN-38)-40K, “4-ARM-PEG-GLY-SN-38-40K”

4-arm PEG-GLY-SN-38-40K was prepared in a similar fashion to the 20K version described above, with the exception that the multi-armed activated PEG reagent employed was 4 arm-PEG(40K)-CM rather than the 20K material.

Example 8 SYNTHESIS OF PENTAERYTHRITOLYL-4-ARM-(PEG-2-{2-[2-1-HYDROXY-2-OXO-VINYLOXY)-ETHOXY]-ETHYLAMINO}-PROPEN-1-ONE LINKED-IRINOTECAN)-20K AND -40K

 

A. 2-(2-t-Boc-aminoethoxy)ethanol (1)

2-(2-Aminoethoxy)ethanol (10.5 g, 0.1 mol) and NaHCO3 (12.6 g, 0.15 mol) were added to 100 mL CH2Cl2 and 100 mL H2O. The solution was stirred at RT for 10 minutes, then di-tert-butyl dicarbonate (21.8 g, 0.1 mol) was added. The resulting solution was stirred at RT overnight, then extracted with CH2Cl2 (3×100 mL). The organic phases were combined and dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was subjected to silica gel column chromatography (CH2Cl2:CH3OH=50:1˜10:1) to afford 2-(2-t-Boc-aminoethoxy)ethanol (1) (16.0 g, 78 mmol, yield 78%)

B. 2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-Irinotecan (2)

2-(2-t-Boc-aminoethoxy)ethanol (1) (12.3 g, 60 mmol) and 4-dimethylaminopyridine (DMAP) (14.6 g, 120 mmol) were dissolved in 200 ml anhydrous CH2Cl2. Triphosgene (5.91 g, 20 mmol) was added to the solution while stirring at room temperature. After 20 minutes, the solution was added to a solution of irinotecan (6.0 g, 10.2 mmol) and DMAP (12.2 g, 100 mmol) in anhydrous CH2Cl2 (200 mL). The reaction was stirred at RT for 2 hrs, then washed with HCI solution (pH=3, 2L) to remove DMAP. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was evaporated under vacuum and subjected to silica gel column chromatography (CH2Cl2:CH3OH=40:1˜10:1) to afford 2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-irinotecan (2) (4.9 g, 6.0 mmol, yield 59%).

C. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3)

2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-irinotecan (2) (4.7 g, 5.75 mmol) was dissolved in 60 mL CH2Cl2, and trifluoroacetic acid (TFA) (20 mL) was added at RT. The reaction solution was stirred for 2 hours. The solvents were removed under vacuum and the residue was added to ethyl ether and filtered to give a yellow solid as product 3 (4.3 g, yield 90%).

D. 4-arm-PEG20k-carbonate-inotecan (4)

4-arm-PEG20k-SCM (16.0 g) was dissolved in 200 mL CH2Cl2. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3) (2.85 g, 3.44 mmol) was dissolved in 12 mL DMF and treated with 0.6 mL TEA, then added to a solution of 4-arm-PEG20k-SCM. The reaction was stirred at RT for 12 hrs then precipitated in Et2O to yield a solid product, which was dissolved in 500 mL IPA at 50° C. The solution was cooled to RT and the resulting precipitate collected by filtration to give 4-arm-PEG20k-glycine -irinotecan (4) (16.2 g, drug content 7.5% based on HPLC analysis). Yield: 60%.

E. 4-arm-PEG40k-carbonate-irinotecan (5)

4-arm-PEG40k-SCM (32.0 g) was dissolved in 400 mL CH2Cl2. 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan TFA salt (3) (2.85 g, 3.44 mmol) was dissolved in 12 mL DMF and treated with 0.6 mL TEA, then added to the solution of 4-arm -PEG40k-SCM. The reaction was stirred at RT for 12 hrs and then precipitated in Et2O to get solid product, which was dissolved in 1000 mL isopropyl alcohol (IPA) at 50° C. The solution was cooled to RT and the precipitate collected by filtration to gave 4-arm-PEG40k-glycine-irinotecan (4) (g, drug content 3.7% based on HPLC analysis). Yield: 59%.

 

References

1: Iwase Y, Maitani Y. Dual functional octreotide-modified liposomal irinotecan leads to high therapeutic efficacy for medullary thyroid carcinoma xenografts. Cancer Sci. 2011 Oct 24. doi: 10.1111/j.1349-7006.2011.02128.x. [Epub ahead of print] PubMed PMID: 22017398.

2: Matsuzaki T, Takagi A, Furuta T, Ueno S, Kurita A, Nohara G, Kodaira H, Sawada S, Hashimoto S. Antitumor activity of IHL-305, a novel pegylated liposome containing irinotecan, in human xenograft models. Oncol Rep. 2012 Jan;27(1):189-97. doi: 10.3892/or.2011.1465. Epub 2011 Sep 20. PubMed PMID: 21935577.

3: Cobleigh MA. Other options in the treatment of advanced breast cancer. Semin Oncol. 2011 Jun;38 Suppl 2:S11-6. Review. PubMed PMID: 21600380.

4: Li C, Cui J, Wang C, Li Y, Zhang L, Xiu X, Li Y, Wei N, Zhang L, Wang P. Novel sulfobutyl ether cyclodextrin gradient leads to highly active liposomal irinotecan formulation. J Pharm Pharmacol. 2011 Jun;63(6):765-73. doi: 10.1111/j.2042-7158.2011.01272.x. Epub 2011 Apr 7. PubMed PMID: 21585373.

5: Iwase Y, Maitani Y. Octreotide-targeted liposomes loaded with CPT-11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma. Mol Pharm. 2011 Apr 4;8(2):330-7. Epub 2011 Jan 18. PubMed PMID: 21166471.

6: Xenidis N, Vardakis N, Varthalitis I, Giassas S, Kontopodis E, Ziras N, Gioulbasanis I, Samonis G, Kalbakis K, Georgoulias V. Α multicenter phase II study of pegylated liposomal doxorubicin in combination with irinotecan as second-line treatment of patients with refractory small-cell lung cancer. Cancer Chemother Pharmacol. 2011 Jul;68(1):63-8. Epub 2010 Sep 10. PubMed PMID: 20830475.

7: Pastorino F, Loi M, Sapra P, Becherini P, Cilli M, Emionite L, Ribatti D, Greenberger LM, Horak ID, Ponzoni M. Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor. Clin Cancer Res. 2010 Oct 1;16(19):4809-21. Epub 2010 Aug 11. PubMed PMID: 20702613.

8: Morgensztern D, Baggstrom MQ, Pillot G, Tan B, Fracasso P, Suresh R, Wildi J, Govindan R. A phase I study of pegylated liposomal doxorubicin and irinotecan in patients with solid tumors. Chemotherapy. 2009;55(6):441-5. Epub 2009 Dec 8. PubMed PMID: 19996589.

9: Meckley LM, Neumann PJ. Personalized medicine: factors influencing reimbursement. Health Policy. 2010 Feb;94(2):91-100. Epub 2009 Oct 7. PubMed PMID: 19815307.

10: Skak K, Søndergaard H, Frederiksen KS, Ehrnrooth E. In vivo antitumor efficacy of interleukin-21 in combination with chemotherapeutics. Cytokine. 2009 Dec;48(3):231-8. Epub 2009 Aug 25. PubMed PMID: 19709902.

11: Murphy CG, Seidman AD. Evolving approaches to metastatic breast cancer previously treated with anthracyclines and taxanes. Clin Breast Cancer. 2009 Jun;9 Suppl 2:S58-65. Review. PubMed PMID: 19596644.

12: Fox ME, Guillaudeu S, Fréchet JM, Jerger K, Macaraeg N, Szoka FC. Synthesis and in vivo antitumor efficacy of PEGylated poly(l-lysine) dendrimer-camptothecin conjugates. Mol Pharm. 2009 Sep-Oct;6(5):1562-72. PubMed PMID: 19588994; PubMed Central PMCID: PMC2765109.

13: Atyabi F, Farkhondehfai A, Esmaeili F, Dinarvand R. Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice. Acta Pharm. 2009 Jun;59(2):133-44. PubMed PMID: 19564139.

14: Liu Z, Robinson JT, Sun X, Dai H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J Am Chem Soc. 2008 Aug 20;130(33):10876-7. Epub 2008 Jul 29. PubMed PMID: 18661992; PubMed Central PMCID: PMC2597374.

15: Scott LC, Yao JC, Benson AB 3rd, Thomas AL, Falk S, Mena RR, Picus J, Wright J, Mulcahy MF, Ajani JA, Evans TR. A phase II study of pegylated-camptothecin (pegamotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma. Cancer Chemother Pharmacol. 2009 Jan;63(2):363-70. Epub 2008 Apr 9. PubMed PMID: 18398613.

16: Almubarak M, Newton M, Altaha R. Reinduction of bevacizumab in combination with pegylated liposomal Doxorubicin in a patient with recurrent glioblastoma multiforme who progressed on bevacizumab/irinotecan. J Oncol. 2008;2008:942618. Epub 2008 Sep 2. PubMed PMID: 19259336; PubMed Central PMCID: PMC2648641.

17: Krauze MT, Noble CO, Kawaguchi T, Drummond D, Kirpotin DB, Yamashita Y, Kullberg E, Forsayeth J, Park JW, Bankiewicz KS. Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts. Neuro Oncol. 2007 Oct;9(4):393-403. Epub 2007 Jul 24. PubMed PMID: 17652269; PubMed Central PMCID: PMC1994096.

18: Li YF, Fu S, Hu W, Liu JH, Finkel KW, Gershenson DM, Kavanagh JJ. Systemic anticancer therapy in gynecological cancer patients with renal dysfunction. Int J Gynecol Cancer. 2007 Jul-Aug;17(4):739-63. Epub 2007 Feb 16. Review. PubMed PMID: 17309673.

19: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2006 Dec;28(10):719-40. PubMed PMID: 17235418.

20: Lokich J. Same-day pegfilgrastim and chemotherapy. Cancer Invest. 2005;23(7):573-6. PubMed PMID: 16305982.

21: Honig A, Rieger L, Sutterlin A, Kapp M, Dietl J, Sutterlin MW, Kämmerer U. Brain metastases in breast cancer–an in vitro study to evaluate new systemic chemotherapeutic options. Anticancer Res. 2005 May-Jun;25(3A):1531-7. PubMed PMID: 16033055.

Irinotecan
Irinotecan.svg
Irinotecan ball-and-stick.png
Systematic (IUPAC) name
(S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-
3,14-dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-
9-yl-[1,4’bipiperidine]-1’-carboxylate
Clinical data
Trade names Camptosar
AHFS/Drugs.com monograph
MedlinePlus a608043
Pregnancy cat. D (Australia, United States)
Legal status POM (UK), ℞-only (U.S.)
Routes Intravenous
Pharmacokinetic data
Bioavailability NA
Metabolism Hepatic glucuronidation
Half-life 6 to 12 hours
Excretion Biliary and renal
Identifiers
CAS number 100286-90-6 Yes
ATC code L01XX19
PubChem CID 60838
DrugBank DB00762
ChemSpider 54825 Yes
UNII 7673326042 Yes
KEGG D08086 Yes
ChEMBL CHEMBL481 Yes
Chemical data
Formula C33H38N4O6 e 
Mol. mass 586.678 g/mol (Irinotecan)
623.139 g/mol (Irinotecan hydrochloride)
677.185 g/mol (Irinotecan hydrochloride trihydrate))

…………..

Irinotecan (Camptosar, Pfizer; Campto, Yakult Honsha) is a drug used for the treatment of cancer.

Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1.[1] In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin.

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan.

Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996[2] and full approval in 1998.[3] During development, it was known as CPT-11.

Mechanism

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:

IrinotecanPathway_WP46359

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IrinotecanPathway_WP46359

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Irinotecan Pathway edit

  1. The interactive pathway map can be edited at WikiPathways: “IrinotecanPathway_WP46359”.

Side-effects

The most significant adverse effects of irinotecan are severe diarrhea and extreme suppression of the immune system.

Diarrhea

Irinotecan-associated diarrhea is severe and clinically significant, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or Lomotil with the first loose bowel movement.

Immunosuppression

The immune system is adversely impacted by irinotecan. This is reflected in dramatically lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience a period of neutropenia (a clinically significant decrease of neutrophils in the blood) while the bone marrow increases white cell production to compensate.

Pharmacogenomics

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.

*28 variant patients

People with variants of the UGT1A1 called TA7, also known as the “*28 variant”, express fewer UGT1A1 enzymes in their liver and often suffer from Gilbert’s syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.[4]

In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.[4]

In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses.[5] Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient’s genotype.[6]

Research

Recently it was shown that antitumor activity of irinotecan against glioblastoma can be enhanced by co-treatment with statins.[7] Similarly, it was shown that berberine may enhance chemosensitivity to irinotecan in colon cancercells. [8]

 

 

References

  1. Pommier, Y., Leo, E., Zhang, H., Marchand, C. 2010. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17: 421-433.
  2. New York Times Article http://www.nytimes.com/1996/06/18/science/new-cancer-drug-approved.html
  3. FDA Review Letter http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20571s8ltr.pdf
  4. Innocenti F, Undevia SD, Iyer L, et al. (April 2004). “Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan”. J. Clin. Oncol. 22 (8): 1382–8. doi:10.1200/JCO.2004.07.173. PMID 15007088.
  5. Camptosar® irinotecan hydrochloride injection August 2010 http://labeling.pfizer.com/ShowLabeling.aspx?id=533
  6. O’Dwyer PJ, Catalano RB (October 2006). “Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy”. J. Clin. Oncol. 24 (28): 4534–8. doi:10.1200/JCO.2006.07.3031. PMID 17008691.
  7. Jiang PF (Jan 2014). “Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs.”. J Transl Med. 12. doi:10.1186/1479-5876-12-13. PMC 3898565. PMID 24433351.
  8. Yu M (Jan 2014). “Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF-κB”. J Mol Med Rep 9 (1): 249–54. doi:10.3892/mmr.2013.1762. PMID 24173769.
  9. DNA Topoisomerases and Cancer. Yves Pommier, Editor. Human Press. 2012

External links

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