AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

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.

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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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