AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

GSK-2816126

 phase 1, Uncategorized  Comments Off on GSK-2816126
Jun 142016
 

STR1

GSK-2816126

N-[(1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide, GSK 126, GSK 2816126, GSK 2816126A

N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-((1S)-1-methylpropyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide

Phase I

Formula
C31H38N6O2
Formula Wt.
526.67

An histone-lysine n-methyltransferase EZH2 inhibitor potentially for the treatment of B-cell lymphoma.

Research Code GSK-2816126; GSK-126; 2816126

CAS No. 1346574-57-9

  • Originator GlaxoSmithKline
  • Class Antineoplastics
  • Mechanism of Action EZH2 enzyme inhibitors; Histone modulators
  • Phase I Diffuse large B cell lymphoma; Follicular lymphoma
  • Preclinical Acute myeloid leukaemia

Most Recent Events

  • 31 Mar 2014 Phase-I clinical trials in Follicular lymphoma (Second-line therapy or greater) in USA and United Kingdom (IV)
  • 31 Mar 2014 Phase-I clinical trials in Diffuse large B cell lymphoma (Second-line therapy or greater) in USA and United Kingdom (IV)
  • 16 Jan 2014 Preclinical trials in Diffuse large B cell lymphoma & Follicular lymphoma in United Kingdom (IV)

GSK-126 is an inhibitor of mutant EZH2, a histone methyltransferase (HMT) that exhibits point mutations at key residues Tyr641 and Ala677; this compound does not appreciably affect WT EZH2. EZH2 is responsible for modulating expression of a variety of genes. GSK-126 competes with cofactor S-adenylmethionine (SAM) for binding to EZH2. GSK-126 displays anticancer chemotherapeutic activity by inhibiting proliferation in in vitro and in vivo models of diffuse large B-cell lymphoma.

SYNTHESIS

 

STR1

 

 

STR1

 

 

PATENT

CN 105541801

https://www.google.com/patents/CN105541801A?cl=zh

Example 79: Add (S) in a three-necked flask 100 Qiu – bromo – Shu – (isobutyl) – N – ((4,6-dimethyl-2-oxo -l, 2- dihydropyridin-3-yl) methyl) -3-methyl-1 hydrogen – indole carboxamide (365mg, 0.82mmol), 2- (piperazin-1-yl) pyridine-5-boronic acid pinacol ester (309mg, 1.07mmol, 1 · 3eq), potassium phosphate (522mg, 2.46mmol, 3eq), water, and I, 4- diepoxy-hexadecane as the solvent. Then, under nitrogen was added [I, Γ- bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (53.9mg, 0.066mmo 1), and at 90 ° C reaction, to give the desired product after purification 400mg (92% yield). Goo NMR (500MHz, DMSO- (I6) JO.70-0 · 78 (ιή, 3H), 1.37-1.44 (m, 4H), 1.75-1.87 (m, 2H), 2.11 (s, 3H), 2.16 ( s, 3H), 2.22-2.27 (m, 3H), 2.77-2.85 (m, 4H), 3.41-3.49 (m, 4H), 4.35 (d, J = 5.31Hz, 2H), 4.56-4.68 (m, lH), 5.87 (s, 1H), 6.88 (d, J = 8.84Hz, 1H), 7.17 (d J = 1.52Hz, 1H), 7.26 (s, lH), 7.73 (d J = 1.26Hz, 1H) , 7.91 (dd, J = 8.84Hz, lH), 8.16 (t, J = 5.05Hz, lH), 8.50 (d, J = 2.53Hz, lH); 13C NMR (125MHz, DMSO- (I6) Sll .6 , 12.6,19.1, 19.9,21.7,30.4,35.9,46.3,46.9,52.4,107.6,108.2,108.5,110.6,116.9,122.6,123.8, 130.6,131.5,136.7,138.6,143.5,146.4,150.2,159.2,164.0 , 169.6.

 

PATENT

WO 2013067296

Examples 267 and 268

(S)-6-bromo-1 -(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3- methyl-1 H-indole-4-carboxamide (Ex 267) and (R)-6-Bromo-1 -(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (Ex 268)

Figure imgf000120_0001

6-Bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methy methyl-1 H-indole-4-carboxamide (racemic mixture, 1.9 g) was resolved by chiral HPLC (column : Chiralpak AD-H, 5 microns, 50 mm x 250 mm, UV detection :240 nM, flow rate: 100 mL/min, T = 20 deg C, eluent: 60:40:0.1 n-heptane:ethanol:isopropylamine

(isocratic)). For each run, 100 mg of the racemic compound was dissolved in 30 volumes (3.0 ml.) of warm ethanol with a few drops of isopropylamine added. A total of 19 runs were performed. Baseline resolution was observed for each run. The isomer that eluted at 8.3-10.1 min was collected (following concentration) as a white solid, which was dried at 50 °C (< 5 mm Hg) to afford 901 mg, and was determined to be the S isomer* (Ex. 267; chiral HPLC: >99.5% ee (no R isomer detected). The isomer that eluted at 10.8-13.0 min was collected as a white solid, which was dried at 50 °C (< 5 mm Hg) to afford 865 mg, and was determined to be the R isomer* (Ex. 268; chiral HPLC: 99.2% ee; 0.4% S isomer detected). 1H NMR and LCMS were consistent with the parent racemate.

* The absolute configuration was determined by an independent synthesis of each enantiomer from the corresponding commercially available homochiral alcohols via Mitsunobu reaction. The sterochemical assignments were also consistent by vibrational circular dichroism (VCD) analysis.

Example 269

1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 -indole-4-carboxamide

Figure imgf000120_0002

Added sequentially to a reaction vial were 6-bromo-1 -(sec-butyl)-N-((4,6-dimethyl- 2-OXO-1 , 2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (0.15 g, 0.338 mmol), 1-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.127 g, 0.439 mmol), and potassium phosphate (tribasic) (0.287 g, 1.350 mmol), followed by 1 ,4- Dioxane (3 mL) and water (0.75 mL). The suspension was stirred under N2 degassing for 10 min., and then added PdCI2(dppf)-CH2CI2adduct (0.028 g, 0.034 mmol). The reaction vial was sealed, placed into a heat block at 95 °C, and stirred for 1.5 h. The contents were removed from heating and allowed to cool to room temperature. The aq layer was removed from bottom of the reaction vial via pipette. The reaction mixture was diluted into EtOAc (20 mL) followed by addition of 0.2 g each of Thiol-3 silicycle resin and silica gel. The volatiles were removed in vacuo and the residue dried on hi-vac for 1 h. The contents were purified by silica gel chromatography (dry loaded, eluent : A:

Dichloromethane, B: 10% (2M Ammonia in Methanol) in Chloroform, Gradient B: 8- 95%). The obtained solid was concentrated from TBME and dried in vacuum oven at 45 °C for 18 h. The product was collected as 129 mg (70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (t, J=7.33 Hz, 3H), 1.40 (d, J=6.57 Hz, 3H), 1.80 (dq, J=10.07, 7.08 Hz, 2H), 2.1 1 (s, 3H), 2.14 – 2.19 (m, 3H), 2.24 (s, 3H), 2.76 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 – 4.67 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.26 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.53 Hz, 1 H), 1 1.48 (br. s.,1 H) ; LCMS MH+ =527.3.

Example 270

A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -[(1 S)-1 -methylpropyl]-6- [6-(1-piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide

Figure imgf000121_0001

To a 30 mL microwave vial were added (S)-6-bromo-1 -(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (100 mg, 0.225 mmol), 1 -(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCI2(dppf)-CH2CI2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H20, 0.1 % NH4OH to 60%

ACN/H20, 0.1 % NH4OH ) to give 91 mg of product as off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.70 – 0.78 (m, 3H), 1.37 – 1.44 (m, 3H), 1 .75 – 1.87 (m, 2H), 2.1 1 (s, 3H), 2.16 (s, 3H), 2.22 – 2.27 (m, 3H), 2.77 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.31 Hz, 2H), 4.56 – 4.68 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.52 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.53 Hz, 1 H); LCMS: 527.8 (MH+).

Example 271

A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -[(1 /?)-1-methylpropyl]- 6-[6-(1 -piperazinyl)-3-pyridinyl]-1 -indole-4-carboxamide

Figure imgf000122_0001

To a 30 mL microwave vial were added (R)-6-bromo-1-(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (100 mg, 0.225 mmol), 1 -(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCI2(dppf)-CH2Cl2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H20, 0.1 % NH4OH to 60%

ACN/H20, 0.1 % NH4OH ) to give 90 mg of product as off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.1 1 (s, 3H), 2.15 – 2.20 (m, 3H), 2.24 (s, 3H), 2.77 – 2.83 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 – 4.68 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.52 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.27 Hz, 1 H); LCMS: 527.7 (MH+)

PATENT

WO 2011140324

Example 270

N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l-[(15)-l-methylpropyl]-6-[6-(l-piperazinyl)-3-pyridinyl]-lH-indole-4-carboxamide

To a 30 niL microwave vial were added (S)-6-bromo-l-(sec-butyl)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3 -methyl- lH-indole-4-carboxamide (100 mg, 0.225 mmol), l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCi2(dppf)-CH2Ci2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H20, 0.1% NH4OH to 60% ACN/H20, 0.1% NH4OH ) to give 91 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 – 0.78 (m, 3H), 1.37 – 1.44 (m, 3H), 1.75 – 1.87 (m, 2H), 2.11 (s, 3H), 2.16 (s, 3H), 2.22 – 2.27 (m, 3H), 2.77 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.31 Hz, 2H), 4.56 – 4.68 (m, IH), 5.87 (s, IH), 6.88 (d, J=8.84 Hz, IH), 7.17 (d, J=1.52 Hz, IH), 7.26 (s, IH), 7.73 (d, J=1.26 Hz, IH), 7.91 (dd, J=8.84, 2.53 Hz, IH), 8.16 (t, J=5.05 Hz, IH), 8.50 (d, J=2.53 Hz, IH); LCMS: 527.8 (MH+).

Example 271

N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l-[(li?)-l-methylpropyl]-6-[6-(l-piperazinyl)-3-pyridinyl]-l -indole-4-carboxamide

To a 30 mL microwave vial were added (R)-6-bromo-l-(sec-butyl)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3 -methyl- lH-indole-4-carboxamide (100 mg, 0.225 mmol), l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCl2(dppf)-CH2Cl2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H20, 0.1% NH4OH to 60% ACN/H20, 0.1% NH4OH ) to give 90 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.11 (s, 3H), 2.15 – 2.20 (m, 3H), 2.24 (s, 3H), 2.77 – 2.83 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 -4.68 (m, 1H), 5.87 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 7.17 (d, J=1.52 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 8.16 (t, J=5.05 Hz, 1H), 8.50 (d, J=2.27 Hz, 1H); LCMS: 527.7 (MH+).

REF

Tian X, Zhang S, Liu HM, et al. Histone lysine-specific methyltransferases and demethylases in carcinogenesis: new targets for cancer therapy and prevention. Curr Cancer Drug Targets. 2013 Jun 10;13(5):558-79. PMID: 23713993.

McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012 Dec 6;492(7427):108-12. PMID: 23051747.

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/////////GSK-2816126,  GSK-126,  2816126, 1346574-57-9, GSK 126, GSK 126, GSK 2816126, GSK 2816126A

CC=5C=C(C)NC(=O)C=5CNC(=O)c1cc(cc2c1c(C)cn2[C@@H](C)CC)c3cnc(cc3)N4CCNCC4

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GSK-2838232

 phase 1, Uncategorized  Comments Off on GSK-2838232
Jun 132016
 

STR1

Figure imgf000135_0002

GSK-2838232

4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.

28-​Norlup-​18-​en-​21-​one, 3-​(3-​carboxy-​3-​methyl-​1-​oxobutoxy)​-​17-​[(1R)​-​2-​[[(4-​chlorophenyl)​methyl]​[2-​(dimethylamino)​ethyl]​amino]​-​1-​hydroxyethyl]​-​, (3β)​-

Phase I

Glaxosmithkline Llc INNOVATOR

Mark Andrew HATCHER, Brian Alvin Johns,Michael Tolar Martin, Elie Amine TABET, Jun Tang

A reverse transcriptase inhibitor potentially for the treatment of HIV infection.

GSK-2838232; GSK-8232; 2838232

CAS No. 1443460-91-0

C48H73ClN2O6,809.56

SYNTHESIS

PART 1

STR1

PART2

STR1

PART3

STR1

PART 4

STR1

AND UNWANTEDISOMER SHOWN BELOW

PART5

STR1

GSK2838232 is a novel human immune virus (HIV) maturation inhibitor being developed for the treatment of chronic HIV infection. GSK2838232 is a betulin derivative

Human immunodeficiency virus type 1 (HIV-1 ) leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus. Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which have been shown to greatly increase patient survival and quality of life.

However, additional therapies are still required because of undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; and drug resistance due to mutation of the enzyme target.

Currently, almost all HIV positive patients are treated with therapeutic regimens of antiretroviral drug combinations termed, highly active antiretroviral therapy (“HAART”). However, HAART therapies are often complex because a combination of different drugs must be administered often daily to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur. The emergence of multidrug-resistant HIV-1 isolates has serious clinical consequences and must be suppressed with a new drug regimen, known as salvage therapy.

Current guidelines recommend that salvage therapy includes at least two, and preferably three, fully active drugs. Typically, first-line therapies combine three to four drugs targeting the viral enzymes reverse transcriptase and protease. One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates.

However, the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class.

Alternative therapeutic strategies have recently become available with the development of fusion, entry, and integrase inhibitors. However, resistance to all three new drug classes has already been reported both in the lab and in patients. Sustained successful treatment of HIV-1 -infected patients with antiretroviral drugs will therefore require the continued development of new and improved drugs with new targets and mechanisms of action.

Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. To date, a number of approved drugs have been shown to greatly increase patient survival. However, therapeutic regimens known as highly active antiretroviral therapy (HAART) are often complex because a combination of different drugs must be administered to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur.

The HIV Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains – matrix (MA), capsid (CA), nucleocapsid (NC) and p6 – and two spacer peptides, SP1 and SP2, represents a new therapeutic target. Although the cleavage of the Gag polyprotein plays a central role in the progression of infectious virus particle production, to date, no antiretroviral drug has been approved for this mechanism.

In most cell types, assembly occurs at the plasma membrane, and the

MA domain of Gag mediates membrane binding. Assembly is completed by budding of the immature particle from the cell. Concomitant with particle release, the virally encoded PR cleaves Gag into the four mature protein domains, MA, CA, NC and p6, and the two spacer peptides, SP1 and SP2. Gag-Pol is also cleaved by PR, liberating the viral enzymes PR, RT and IN. Gag proteolytic processing induces a

morphological rearrangement within the particle, known as maturation. Maturation converts the immature, donut-shaped particle to the mature virion, which contains a condensed conical core composed of a CA shell surrounding the viral RNA genome in a complex with NC and the viral enzymes RT and IN. Maturation prepares the virus for infection of a new cell and is absolutely essential for particle infectivity.

Bevirimat (PA-457) is a maturation inhibitor that inhibits the final step in the processing of Gag, the conversion of capsid-SP1 (p25) to capsid, which is required for the formation of infectious viral particles. Bevirimat has activity against ART-resistant and wild-type HIV, and has shown synergy with antiretrovirals from all classes. Bevirimat reduced HIV viral load by a mean of 1.3 logi0/mL in patients who achieved trough levels of >= 20 μg/mL and who did not have any of the key baseline Gag polymorphisms at Q369, V370 or T371. However, Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag polymorphisms at these sites.

Other examples of maturation inhibitors can be found in PCT Patent

Application No. WO201 1/100308, “Derivatives of Betulin”; PCT Patent Application No. PCT/US2012/024288, “Novel Anti-HIV Compounds and Methods of Use Thereof ; Chinese PCT Application No. PCT/CN201 1/001302, “Carbonyl Derivatives of Betulin”; Chinese PCT Application No. PCT/CN201 1/001303, “Methylene Derivatives of Betulin”; Chinese PCT Application Nos. PCT/CN201 1/002105 and PCT/CN201 1/002159, “Propenoate Derivatives of Betulin”. Maturation inhibitors in the prior art leave open gaps in the areas of polymorphism coverage whereby potency against a broad range of clinically relevant gag sequences is extremely important, along with overall potency including the clinically relevant protein adjusted antiviral activity that will be required for robust efficacy in long term durability trials. To date, no maturation inhibitor has achieved an optimal balance of these properties.

PATENT

WO 2013090664

https://www.google.com/patents/WO2013090664A1?cl=en

Example 17: Compound 50

4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((S)-1-Acetoxy-2-((4- chlorobenzyl)amino)ethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

Figure imgf000134_0001

[00241] The title compound was made in a similar manner to Example 16 and isolated as a TFA salt. 1H NMR (400MHz ,CHLOROFORM-d) δ = 7.49 – 7.30 (m, 4 H), 5.85 – 5.71 (m, 1 H), 4.59 – 4.40 (m, 1 H), 4.31 – 4.03 (m, 2 H), 3.41 – 2.79 (m, 4 H), 2.79 – 2.50 (m, 2 H), 2.37 (d, J = 18.1 Hz, 2 H), 2.02 – 0.63 (m, 49 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1 )+.

Figure imgf000135_0001

Example 18: Compound 51

4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((4-Chlorobenzyl)(2- (dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8, 11a-pe

2-0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

Figure imgf000135_0002

[00242] To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (6.75 g, 54.6 mmol) in methanol (20 ml_) was added 4-

(((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-1 – hydroxyethyl)-1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,1 1 ,1 1 a,1 1 b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid , Trifluoroacetic acid salt (46) (9.5 g, 10.92 mmol). The pH was adjusted to 7-8 with Et3N. The reaction mixture was stirred at rt for 2 h. Sodium cyanoborohydride (0.686 g, 10.92 mmol) was then added and the mixture was stirred at rt overnight. After the reaction was complete, water (15 ml_) and EtOAc (15 ml_) were added, and then the organic phase was removed and concentrated under reduced presure. The product was extracted with EtOAc (80 ml_x3), the combined organic phase was washed with brine, dried, and concentrated. The product was purified by flash chromatography (DCM:EtOAc=2: 1 to 1 : 1 , then DCM:MeOH=100: 1 to 20: 1 ) to give 4- (((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)-1 -hydroxyethyl)-1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethyl- 2-0X0-3, 3a,4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1 , 1 1 a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (51 ) (6 g, 7.41 mmol, 67.9 % yield) as white solid. Multiple batches of this material (were combined 95 g), dissolved in 600 mL of dichloromethane and washed with NaHC03 (400 ml_*3) and the organic phase was dried over Na2S04, filtered and concentrated. The solids were washed with a mixture of EtOAc: petroleum ether (600 mL), and filtered followed by lyophilization to provide the final title compound 62 g as a white solid. 1H NMR (400MHz ,METHANOL-d4) δ = 7.47 – 7.29 (m, 4 H), 4.48 (dd, J = 5.8, 10.3 Hz, 1 H), 4.15 – 4.04 (m, 1 H), 3.80 (d, J = 13.8 Hz, 1 H), 3.57 (d, J = 14.1 Hz, 1 H), 3.21 – 2.82 (m, 5 H), 2.72 – 2.41 (m, 9 H), 2.37 – 2.05 (m, 4 H), 2.05 – 0.74 (m, 45 H);

LC/MS: m/z calculated 808.5, found 809.5 (M+1 )+.

Figure imgf000137_0001

REFERENCES

Hatcher, Mark Andrew; Johns, Brian Alvin; Martin, Michael Tolar; Tabet, Elie Amine; Tang, Jun.  Preparation of betulin derivatives for the treatment of HIV, PCT Int. Appl. (2013), WO 2013090664 A1 20130620.

 

 

Mark Hatcher

Director, US R&D Policy and Scientific Affairs at GlaxoSmithKline

https://www.linkedin.com/in/mark-hatcher-232b904

 

Jun Tang

Chief Scientist at GlaxoSmithKline

https://www.linkedin.com/in/jun-tang-2a50629

Brian Johns

Chemistry Director, GlaxoSmithKline

https://www.linkedin.com/in/brian-johns-26a5953

////////GSK-2838232, 1443460-91-0, GSK 2838232,  GSK-8232,  2838232,  treatment of HIV, phase1

O=C(C1)C(C(C)C)=C2[C@@]1([C@@H](O)CN(CCN(C)C)CC3=CC=CC(Cl)=C3)CC[C@]4(C)[C@]2([H])CC[C@@]5([H])[C@@]4(C)CC[C@]6([H])[C@]5(C)CC[C@H](OC(CC(C)(C)C(O)=O)=O)C6(C)C

Karl Landsteiner’s 148th birthday

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TD 1607

 phase 1, Uncategorized  Comments Off on TD 1607
Jun 132016
 

STR1

STR1

TD-1607

Phase I

A glycopeptide-cephalosporin heterodimer potentially for the treatment of gram-positive bacterial infection.

CAS No. 827040-07-3

C95 H109 Cl3 N18 O31 S2, 
Molecular Weight, 2169.47
Vancomycin, 29-​[[[2-​[[6-​[[[1-​[[(6R,​7R)​-​7-​[[(2Z)​-​2-​(2-​amino-​5-​chloro-​4-​thiazolyl)​-​2-​(methoxyimino)​acetyl]​amino]​-​2-​carboxy-​8-​oxo-​5-​thia-​1-​azabicyclo[4.2.0]​oct-​2-​en-​3-​yl]​methyl]​pyridinium-​4-​yl]​methyl]​amino]​-​1,​6-​dioxohexyl]​amino]​ethyl]​amino]​methyl]​-​, inner salt
Vancomycin, 29-[[[2-[[6-[[[1-[[(6R,7R)-7-[[(2Z)-(2-amino-5-chloro-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]pyridinium-4-yl]methyl]amino]-1,6-dioxohexyl]amino]ethyl]amino]methyl]-, inner salt
  • Originator Theravance
  • Developer Theravance Biopharma
  • Class Antibacterials; Cephalosporins; Glycopeptides
  • Mechanism of Action Cell wall inhibitors
    • Phase I Gram-positive infections

    Most Recent Events

    • 21 Apr 2016 Phase I development is ongoing in USA
    • 01 Jul 2014 Theravance completes a phase I trial in Healthy volunteers in in USA (NCT01949103)
    • 02 Jun 2014 Theravance Biopharma is formed as a spin-off of Theravance
    • Company Theravance Biopharma Inc.
      Description Glycopeptide cephalosporin heterodimer antibiotic
      Molecular Target
      Mechanism of Action
      Therapeutic Modality Small molecule: Combination
      Latest Stage of Development Phase I
      Standard Indication Gram-negative bacterial infection
      Indication Details Treat Gram-positive bacterial infections

PATENT
WO 2005005436
https://www.google.com/patents/WO2005005436A2?cl=en29

The present invention provides novel cross-linked glycopeptide – cephalosporin compounds that are useful as antibiotics. The compounds of this invention have a unique chemical structure in which a glycopeptide group is covalently linked to a pyridinium moiety of a cephalosporin group. Among other properties, compounds of this invention have been found to possess surprising and unexpected potency against Gram-positive bacteria including methicillin-resistant Staphylococci aureus (MRSA). Accordingly, in one aspect, the invention provides a compound of formula I:

Figure imgf000004_0001
////////Theravance Biopharma, TD 1607, phase 1, glycopeptide-cephalosporin heterodimer ,  gram-positive bacterial infection
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Temanogrel

 Phase 3 drug, Uncategorized  Comments Off on Temanogrel
Jun 122016
 

ChemSpider 2D Image | temanogrel | C24H28N4O4TEMANOGREL.pngimg

Temanogrel

APD 791

3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholinoethoxy)phenyl]benzamide
Benzamide,3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-
UNII:F42Z27575A
TEMANOGREL; APD791; CHEMBL1084617; UNII-F42Z27575A; 887936-68-7; 3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;
Molecular Formula: C24H28N4O4
Molecular Weight: 436.50352 g/mol
  • Originator Arena Pharmaceuticals
  • Developer Arena Pharmaceuticals; Ildong Pharmaceutical
  • Class Antithrombotics; Small molecules
  • Mechanism of Action Serotonin 2A receptor inverse agonists

Phase I Arterial thrombosis

Most Recent Events

  • 30 Mar 2016 Arena Pharmaceuticals has patents pending for Temanogrel in 12 regions, including Brazil (Arena Pharmaceuticals 10-K; march 2016)
  • 30 Mar 2016 Arena Pharmaceuticals has patent protection for Temanogrel in 87 regions, including USA, Japan, China, Germany, France, Italy, the United Kingdom, Spain, Canada, Russia, India, Australia and South Korea
  • 01 Mar 2015 Ildong Pharmaceutical initiates enrolment in a phase I trial for Arterial thrombosis in South Korea (NCT02419820)

A 5-HT2A inverse agonist potentially for the reduction of the risk of arterial thrombosis.

APD-791

CAS No. 887936-68-7

ChemSpider 2D Image | Temanogrel hydrochloride | C24H29ClN4O4

Temanogrel hydrochloride

  • Molecular FormulaC24H29ClN4O4
  • Average mass472.965
957466-27-2 CAS
Benzamide, 3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-, hydrochloride (1:1) [ACD/Index Name]
Temanogrel hydrochloride [USAN]
UNII:5QEY8NZP3T

Temanogrel, also known as APD791, is a highly selective 5-hydroxytryptamine2A receptor inverse agonist under development for the treatment of arterial thrombosis. APD791 displayed high-affinity binding to membranes (K(i) = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC(50) = 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT(2A) receptor. APD791 was greater than 2000-fold selective for the 5-HT(2A) receptor versus 5-HT(2C) and 5-HT(2B) receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC(50) = 8.7 and 23.1 nM, respectively)

Arterial thrombosis is the formation of a blood clot or thrombus inside an artery or arteriole that restricts or blocks the flow of blood and, depending upon location, can result in acute coronary syndrome or stroke. The formation of a thrombus is usually initiated by blood vessel injury, which triggers platelet aggregation and adhesion of platelets to the vessel wall. Treatments aimed at inhibiting platelet aggregation have demonstrated clear clinical benefits in the setting of acute coronary syndrome and stroke. Current antiplatelet therapies include aspirin, which irreversibly inhibits cyclooxygenase (COXa

Abbreviations: COX, cyclooxygenase; ADP, adenosine diphosphate; SAR, structure−activity relationship; hERG, human ether-a-go-go-related gene; CNS, central nervous system; 5-HT, serotonin; AUC, area under the plasma concentration time curve, iv, intravenous; IP, inositol phosphate.

) and results in reduced thromboxane production, clopidogrel and prasugrel, which inhibit platelet adenosine diphosphate (ADP) P2Y12 receptors, and platelet glycoprotein IIb/IIIa receptor antagonists. Another class of antiplatelet drugs, protease-activated thrombin receptor (PAR-1) antagonists, are also being evaluated in the clinic for the treatment of acute coronary syndrome. The most advanced candidate in this class, N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1-methyl-3-oxoperhydro-naphtho[2,3-c]furan-6-yl]-carbamic acid ethyl ester (SCH-530348), is currently in phase 3 trials for the prevention of arterial thrombosis.

The 5-HT2A receptor is one of 15 different serotonin receptor subtypes.
 In the cardiovascular system, modulation of 5-HT2A receptors on vascular smooth muscle cells and platelets is thought to play an important role in the regulation of cardiovascular function. Platelets are activated by a variety of agonists such as ADP, thrombin, thromboxane, serotonin, epinephrine, and collagen. Upon platelet activation at the site of blood vessel injury, a number of factors including serotonin (5-HT) are released. Although by itself serotonin is a weak activator of platelet aggregation, in vitro it can amplify aggregation induced by other agonists as mentioned above. Therefore, serotonin released from activated platelets may induce further platelet aggregation and enhance thrombosis.
The 5-HT2A receptor antagonist ketanserin  was shown in clinical studies to reduce early restenosis(7) and decrease myocardial ischemia during coronary balloon angioplasty.(8)However, in another study, ketanserin did not significantly improve clinical outcomes, and the rate of adverse events was higher than that observed in the control group.(9) Some of the adverse events reported in the latter study could be specific to ketanserin and resulted from its lack of 5-HT2A receptor selectivity. Other 5-HT2A antagonists with improved selectivity profiles have shown promise in clinical studies. For example, sarpogrelate  was shown to inhibit restenosis following coronary stenting.

Figure

Figure 1. Serotonin and known 5-HT2A receptor antagonists.

Because the 5-HT2A receptor is expressed both in peripheral tissues and in the central nervous system (CNS), compounds with limited CNS partitioning would be preferred to maximize cardiovascular and blood platelet pharmacological activity while minimizing CNS effects. In addition, because 5-HT2A receptor inverse agonists are thought to reduce thrombus formation via inhibition of serotonin-mediated amplification of platelet aggregation without inhibiting agonist driven aggregation per se, it is possible that this class of inhibitors will have an improved bleeding risk side effect profile compared to what has been observed with other classes of antithrombotic drugs.

SYNTHESIS 

PAPER

Journal of Medicinal Chemistry (2010), 53(11), 4412-4421.

http://pubs.acs.org/doi/abs/10.1021/jm100044a

Abstract Image

Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121
J. Med. Chem., 2010, 53 (11), pp 4412–4421
DOI: 10.1021/jm100044a
Publication Date (Web): May 10, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: +1 858-453-7200. Fax: +1 858-453-7210. E-mail:yxiong@arenapharm.com.
3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (10k)

10k was prepared in a manner similar to that described for 10c, using 9d (120 mg, 0.40 mmol) and 3-methoxybenzoyl chloride (81 mg, 0.48 mmol) to give the TFA salt of 10k as a white solid (88 mg, 51%); mp (HCl salt, recrystallized from iPrOH) 214−216 °C. 1H NMR (acetone-d6, 400 MHz) δ: 2.99−3.21 (m, 2H), 3.22−3.45 (m, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79−3.89 (m, 4H), 4.58 (t, J = 4.8 Hz, 2H), 6.29 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.5, 8.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.52 (t, J = 1.7 Hz, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.80−7.83 (m, 1H), 7.91−7.96 (m, 1H), 9.54 (s, 1H). LCMSm/z = 437.5 [M + H]+.

Additional Information

Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT(2A) receptor antagonist with potent activity on platelets and vascular smooth muscle.(http://www.ncbi.nlm.nih.gov/pubmed/19628629).

 

PATENT

WO 2006055734

https://google.com/patents/WO2006055734A2?cl=en

Example 1.88: Preparation of 3-methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin~

4-yl-ethoxy)-phenyl]-benzamide (Compound 733).

Figure imgf000151_0002

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole), and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 88 mg, 51 %). 1H NMR ( Acetone-^, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, J= 4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t, J= 4.80 Hz, 2H), 6.29 (d, J= 2.02 Hz IH), 7.13 (dd, J= 8.34, 2.53 Hz, IH), 7.22 (d, J= 8.84 Hz, IH), 7.42 (t, J= 7.83 Hz, IH), 7.47 (d, J= 1.77 Hz, IH), 7.52 (t, J= 1.77 Hz, IH), 7.56 (d, J= 7.07 Hz, IH), 7.80-7.83 (m, IH), 7.91-7.96 (m, IH), 9.54 (s, NH). Exact mass calculated for C24H28N4O4 436.2, found 437.5 (MH+).

References

1: Xiong Y, Teegarden BR, Choi JS, Strah-Pleynet S, Decaire M, Jayakumar H, Dosa
PI, Casper MD, Pham L, Feichtinger K, Ullman B, Adams J, Yuskin D, Frazer J,
Morgan M, Sadeque A, Chen W, Webb RR, Connolly DT, Semple G, Al-Shamma H.
Discovery and structure-activity relationship of
3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide
(APD791): a highly selective 5-hydroxytryptamine2A receptor inverse agonist for
the treatment of arterial thrombosis. J Med Chem. 2010 Jun 10;53(11):4412-21.
doi: 10.1021/jm100044a. PubMed PMID: 20455563.

2: Przyklenk K, Frelinger AL 3rd, Linden MD, Whittaker P, Li Y, Barnard MR, Adams
J, Morgan M, Al-Shamma H, Michelson AD. Targeted inhibition of the serotonin
5HT2A receptor improves coronary patency in an in vivo model of recurrent
thrombosis. J Thromb Haemost. 2010 Feb;8(2):331-40. doi:
10.1111/j.1538-7836.2009.03693.x. Epub 2009 Nov 17. PubMed PMID: 19922435; PubMed
Central PMCID: PMC2916638.

3: Adams JW, Ramirez J, Shi Y, Thomsen W, Frazer J, Morgan M, Edwards JE, Chen W,
Teegarden BR, Xiong Y, Al-Shamma H, Behan DP, Connolly DT. APD791,
3-methoxy-n-(3-(1-methyl-1h-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide,
a novel 5-hydroxytryptamine 2A receptor antagonist: pharmacological profile,
pharmacokinetics, platelet activity and vascular biology. J Pharmacol Exp Ther.
2009 Oct;331(1):96-103. doi: 10.1124/jpet.109.153189. Epub 2009 Jul 23. PubMed
PMID: 19628629.

Patent ID Date Patent Title
US2015361031 2015-12-17 STAT3 INHIBITOR
US8785441 2014-07-22 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US2013296321 2013-11-07 CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF PHENYL-PYRAZOLES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
US2012252813 2012-10-04 CRYSTALLINE FORMS OF CERTAIN 3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148417 2012-04-03 PRIMARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148418 2012-04-03 ETHERS, SECONDARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US2011105456 2011-05-05 3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US7884101 2011-02-08 3-Phenyl-pyrazole derivatives as modulators of the 5-HT2a serotonin receptor useful for the treatment of disorders related thereto
US2010234380 2010-09-16 CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF PHENYL-PYRAZOLES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
US2007244086 2007-10-18 3-Phenyl-Pyrazole Derivatives as Modulators of the 5-Ht2A Serotonin Receptor Useful for the Treatment of Disorders Related Thereto

///////////APD-791 , 887936-68-7, Temanogrel , PHASE 1, ARENA,

CN1C(=CC=N1)C2=C(C=CC(=C2)NC(=O)C3=CC(=CC=C3)OC)OCCN4CCOCC4

C(=O)(c1cc(ccc1)OC)Nc1ccc(c(c1)c1n(ncc1)C)OCCN1CCOCC1

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DR ANTHONY’S ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS

 Uncategorized  Comments Off on DR ANTHONY’S ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS
Jun 112016
 

str1

ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS

LINK https://orgspectroscopyint.blogspot.in/

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ORGANIC SPECTROSCOPY INTERNATIONAL

Organic Chemists from Industry and academics to Interact on Spectroscopy Techniques for Organic Compounds ie NMR, MASS, IR, UV Etc. Starters, Learners, advanced, all alike, contains content which is basic or advanced, by Dr Anthony Melvin Crasto, Worlddrugtracker.

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Genistein

 Uncategorized  Comments Off on Genistein
Jun 102016
 

Genistein.svg

Genistein

5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; Baichanin A; Bonistein; 4’,5,7-Trihydroxyisoflavone; GeniVida; Genisteol; NSC 36586; Prunetol; Sophoricol;

CAS Number: 446-72-0
 BIO-300; G-2535; PTI-G-4660; SIPI-9764-I; PTIG-4660; SIPI-9764I
Molecular form.: C₁₅H₁₀O₅
Appearance: Light Tan to Light Yellow Solid
Melting Point: >277°C (dec.)
Mol. Weight: 270.24

Genistein , an isoflavone found in many Fabaceae plants and important non-nutritional constituent of soybeans (Glycine max Merill), is a well-known plant metabolite from phenylpropanoid pathway, chiefly because of its presence in numerous phytoestrogenic dietary supplements. In fact, the compound also strives for higher medicinal status, undergoing dozens of clinical trials for various ailments, from osteoporosis to cancer

IR (KBr, cm–1; inter alia): 3411, 3104, 1651, 1615, 1570, 1519, 1504, 1424, 1361, 1309, 1202, 1179, 1145, 1043, 911, 840, 790.
1H NMR (200 MHz, THF-d8), δ (ppm): 6.17 (d, J = 2,2 Hz, 1H); 6.26 (d, J = 2,2 Hz, 1H); 6.78 (m, 2H); 7.41 (m, 2H); 8.02 (s, 1H); 8.50 (bs, 1H); 9.34 (bs, 1H); 13.02 (s, 1H).
13C NMR (THF-d8), δ (ppm): 94.13; 99.73; 106.20; 115.82; 122.95; 124.17; 130.84; 153.78; 158.73; 159.08; 164.24; 165.16; 181.46.
 

An EGFR/DNA topoisomerase II inhibitor potentially for the treatment of bladder cancer and prostate cancer.

NMR

Genistein; CAS: 446-72-0

REF http://www.wangfei.ac.cn/nmrspectra/7/1/30

SEE https://www.google.com/patents/EP2373326A1?cl=en

Genistein is an angiogenesis inhibitor and a phytoestrogen and belongs to the category of isoflavones. Genistein was first isolated in 1899 from the dyer’s broom, Genista tinctoria; hence, the chemical name. The compound structure was established in 1926, when it was found to be identical with prunetol. It was chemically synthesized in 1928.[1]

Natural occurrences

Isoflavones such as genistein and daidzein are found in a number of plants including lupin, fava beans, soybeans, kudzu, andpsoralea being the primary food source,[2][3] also in the medicinal plants, Flemingia vestita[4] and F. macrophylla,[5][6] and coffee.[7] It can also be found in Maackia amurensis cell cultures.[8]

Extraction and purification

Most of the isoflavones in plants are present in a glycosylated form. The unglycosylated aglycones can be obtained through various means such as treatment with the enzyme β-glucosidase, acid treatment of soybeans followed by solvent extraction, or by chemical synthesis.[9] Acid treatment is a harsh method as concentrated inorganic acids are used. Both enzyme treatment and chemical synthesis are costly. A more economical process consisting of fermentation for in situ production of β-glucosidase to isolate genistein has been recently investigated.[10]

 

Biological effects

Besides functioning as antioxidant and anthelmintic, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen. Isoflavones also produce non-hormonal effects.

Molecular function

Genistein influences multiple biochemical functions in living cells:

Activation of PPARs

Isoflavones genistein and daidzein bind to and transactivate all three PPAR isoforms, α, δ, and γ.[18] For example, membrane-bound PPARγ-binding assay showed that genistein can directly interact with the PPARγ ligand binding domain and has a measurable Ki of 5.7 mM.[19] Gene reporter assays showed that genistein at concentrations between 1 and 100 uM activated PPARs in a dose dependent way in KS483 mesenchymal progenitor cells, breast cancer MCF-7 cells, T47D cells and MDA-MD-231 cells, murine macrophage-like RAW 264.7 cells, endothelial cells and in Hela cells. Several studies have shown that both ERs and PPARs influenced each other and therefore induce differential effects in a dose-dependent way. The final biological effects of genistein are determined by the balance among these pleiotrophic actions.[18][20][21]

Tyrosine kinase inhibitor

The main known activity of genistein is tyrosine kinase inhibitor, mostly of epidermal growth factor receptor (EGFR). Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades.

Redox-active — not only antioxidant

Genistein may act as direct antioxidant, similar to many other isoflavones, and thus may alleviate damaging effects of free radicals in tissues.[22][23]

The same molecule of genistein, similar to many other isoflavones, by generation of free radicals poison topoisomerase II, an enzyme important for maintaining DNA stability.[24][25][26]

Human cells turn on beneficial, detoxyfying Nrf2 factor in response to genistein insult. This pathway may be responsible for observed health maintaining properities of small doses of genistein.[27]

Anthelmintic

The root-tuber peel extract of the leguminous plant Felmingia vestita is the traditional anthelmitic of the Khasi tribes of India. While investigating its anthelmintic activity, genistein was found to be the major isoflavone responsible for the deworming property.[4][28] Genistein was subsequently demonstrated to be highly effective against intestinal parasitessuch as the poultry cestode Raillietina echinobothrida,[28] the pork trematode Fasciolopsis buski,[29] and the sheep liver fluke Fasciola hepatica.[30] It exerts its anthelmintic activity by inhibiting the enzymes of glycolysis and glycogenolysis,[31][32] and disturbing the Ca2+ homeostasis and NO activity in the parasites.[33][34] It has also been investigated inhuman tapeworms such as Echinococcus multilocularis and E. granulosus metacestodes that genistein and its derivatives, Rm6423 and Rm6426, are potent cestocides.[35]

Atherosclerosis

Genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte–endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis.[36]

Cancer links

Genistein and other isoflavones have been identified as angiogenesis inhibitors, and found to inhibit the uncontrolled cell growth of cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival (growth factors). Various studies have found that moderate doses of genistein have inhibitory effects on cancersof the prostate,[37][38] cervix,[39] brain,[40] breast[37][41][42] and colon.[16] It has also been shown that genistein makes some cells more sensitive to radio-therapy.;[43] although, timing of phytoestrogen use is also important. [43]

Genistein’s chief method of activity is as a tyrosine kinase inhibitor. Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades. Inhibition of DNA topoisomerase II also plays an important role in the cytotoxic activity of genistein.[25][44] Genistein has been used to selectively target pre B-cells via conjugation with an anti-CD19 antibody.[45]

Studies on rodents have found genistein to be useful in the treatment of leukemia, and that it can be used in combination with certain other antileukemic drugs to improve their efficacy.[46]

Estrogen receptor — more cancer links

Due to its structure similarity to 17β-estradiol (estrogen), genistein can compete with it and bind to estrogen receptors. However, genistein shows much higher affinity towardestrogen receptor β than toward estrogen receptor α.[47]

Data from in vitro and in vivo research confirms that genistein can increase rate of growth of some ER expressing breast cancers. Genistein was found to increase the rate of proliferation of estrogen-dependent breast cancer when not cotreated with an estrogen antagonist.[48][49][50] It was also found to decrease efficiency of tamoxifen and letrozole – drugs commonly used in breast cancer therapy.[51][52] Genistein was found to inhibit immune response towards cancer cells allowing their survival.[53]

Effects in males

Isoflavones can act like estrogen, stimulating development and maintenance of female characteristics, or they can block cells from using cousins of estrogen. In vitro studies have shown genistein to induce apoptosis of testicular cells at certain levels, thus raising concerns about effects it could have on male fertility;[54] however, a recent study found that isoflavones had “no observable effect on endocrine measurements, testicular volume or semen parameters over the study period.” in healthy males given isoflavone supplements daily over a 2-month period.[55]

Carcinogenic and toxic potential

Genistein was, among other flavonoids, found to be a strong topoisomerase inhibitor, similarly to some chemotherapeutic anticancer drugs ex. etoposide and doxorubicin.[24][56]In high doses it was found to be strongly toxic to normal cells.[57] This effect may be responsible for both anticarcinogenic and carcinogenic potential of the substance.[26][58] It was found to deteriorate DNA of cultured blood stem cells, what may lead to leukemia.[59] Genistein among other flavonoids is suspected to increase risk of infant leukemia when consumed during pregnancy.[60][61]

Sanfilippo syndrome treatment

Genistein decreases pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by adequate dose of genistein.[62] Genistein was found to also possess toxic properties toward brain cells.[57] Among many pathways stimulated by genistein, autophagy may explain the observed efficiency of the substance as autophagy is significantly impaired in the disease.[63][64]

Related compounds

Glycosides

Genistin is the 7-O-beta-D-glucoside of genistein.

Acetylated compounds

Wighteone is the 6-isopentenyl genistein (6-prenyl-5,7,4′-trihydroxyisoflavone)[citation needed]

Pharmaceutical derivatives

  • KBU2046 under investigation for prostate cancer.[65][66]
  • B43-genistein, an anti-CD19 antibody linked to genistein e.g. for leukemia.[67]
  • Genistein has two known synthesis routes: deoxybenzoin route and chalcone route. Deoxybenzoin route uses friedel-craft reaction, and chalcone route uses aldol condensation as shown in figure 2. Developing synthesis of genistein allows the access to the affordable therapy as well as mass production of commercial genistein supplements. However, it would be recommended to consult with the health care provider and discuss the pros and cons before the use since the effects of genistein on human body are not fully understood yet as discussed above.


MEDIUM_10555_2010_9238_Fig2_HTML.jpg
Figure 2. Synthesis of genistein via deoxybenzoin route or chalcone route. 10

https://chemprojects263sp11.wikispaces.com/genistein

Paper

Identification of Benzopyran-4-one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors
ChemMedChem (2011), 6, (8), 1340-1346

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201100120/abstract

 

PATENT

By Achmatowicz, Osman et al

From Pol., 204473

STR1

 

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  61. Jump up^ Azarova, Anna M.; Lin, Ren-Kuo; Tsai, Yuan-Chin; Liu, Leroy F.; Lin, Chao-Po; Lyu, Yi Lisa (2010). “Genistein induces topoisomerase IIbeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia”. Biochemical and Biophysical Research Communications 399 (1): 66–71. doi:10.1016/j.bbrc.2010.07.043.PMC 3376163. PMID 20638367.
  62. Jump up^ Piotrowska, Ewa; Jakóbkiewicz-Banecka, Joanna; Barańska, Sylwia; Tylki-Szymańska, Anna; Czartoryska, Barbara; Węgrzyn, Alicja; Węgrzyn, Grzegorz (2006). “Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses”. European Journal of Human Genetics 14(7): 846–52. doi:10.1038/sj.ejhg.5201623. PMID 16670689.
  63. Jump up^ Ballabio, A. (2009). “Disease pathogenesis explained by basic science: Lysosomal storage diseases as autophagocytic disorders”. International Journal of Clinical Pharmacology and Therapeutics 47 (Suppl 1): S34–8. doi:10.5414/cpp47034.PMID 20040309.
  64. Jump up^ Settembre, Carmine; Fraldi, Alessandro; Jahreiss, Luca; Spampanato, Carmine; Venturi, Consuelo; Medina, Diego; de Pablo, Raquel; Tacchetti, Carlo; Rubinsztein, David C.; Ballabio, Andrea (2007). “A block of autophagy in lysosomal storage disorders”. Human Molecular Genetics 17 (1): 119–29. doi:10.1093/hmg/ddm289. PMID 17913701.
  65. Jump up^ Xu, Li; Farmer, Rebecca; Huang, Xiaoke; Pavese, Janet; Voll, Eric; Irene, Ogden; Biddle, Margaret; Nibbs, Antoinette; Valsecchi, Matias; Scheidt, Karl; Bergan, Raymond (2010). “Abstract B58: Discovery of a novel drug KBU2046 that inhibits conversion of human prostate cancer to a metastatic phenotype”. Cancer Prevention Research 3 (12 Supplement): B58. doi:10.1158/1940-6207.PREV-10-B58.
  66. Jump up^ “New Drug Stops Spread of Prostate Cancer” (Press release). Northwestern University. April 3, 2012. Retrieved September 27, 2014.
  67. Jump up^ Chen, Chun-Lin; Levine, Alexandra; Rao, Asha; O’Neill, Karen; Messinger, Yoav; Myers, Dorothea E.; Goldman, Frederick; Hurvitz, Carole; Casper, James T.; Uckun, Fatih M. (1999). “Clinical Pharmacokinetics of the CD19 Receptor-Directed Tyrosine Kinase Inhibitor B43-Genistein in Patients with B-Lineage Lymphoid Malignancies”. The Journal of Clinical Pharmacology 39 (12): 1248–55. doi:10.1177/00912709922012051. PMID 10586390.

External links

 

 

Abstract Image

Development and scale-up of the synthetic process for genistein preparation are described. The process was designed with consideration for environmental and economical aspects and optimized in a laboratory scale. In a scale up, on every step quantity of the environmentally unfriendly substrates or solvents was reduced without compromising the quality of the final product, and the waste load was significantly diminished. The optimal duration times of the individual stages were determined, and the number of operations was reduced, leading to lowering of energy consumption. Elaborated process secures good yield and quality expected for pharmaceutical substances.

Technical Process for Preparation of Genistein

Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00425
Publication Date (Web): June 03, 2016
Copyright © 2016 American Chemical Society

 

Genistein
Genistein.svg
Genistein molecule
Names
IUPAC name

5,7-Dihydroxy-3-(4-hydroxyphenyl)chromen-4-one
Other names

4′,5,7-Trihydroxyisoflavone
Identifiers
446-72-0 Yes
ChEBI CHEBI:28088 Yes
ChEMBL ChEMBL44 Yes
ChemSpider 4444448 Yes
DrugBank DB01645 Yes
2826
Jmol 3D model Interactive image
KEGG C06563 Yes
PubChem 5280961
UNII DH2M523P0H Yes
Properties
C15H10O5
Molar mass 270.24 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Akiyama, T., et al.: J. Biol. Chem., 262, 5592 (1987), O’Dell, T.J., et al.: Nature, 353, 588 (1991), Aharonovits, O., et al.: Biochim Biophys. Acta, 1112, 181 (1992), Platanias, L.C., et al.: J. Biol. Chem., 267, 24053 (1992), Yoshida, H., et al.: Biochim. Biophys. Acta, 1137, 321 (1992), Uckun, F.M., et al.: Science, 267, 886 (1995), Merck Index 12th ed. 4395, Huang, R.Q.; Fang, M.J.; Dillon, G.H., Mol. Brain Res. 67: 177-183 (1999)

 

//////BIO-300,  G-2535,  PTI-G-4660,  SIPI-9764-I,  PTIG-4660,  SIPI-9764I, Genistein, phase 2, national cancer institute

Oc1ccc(cc1)C\3=C\Oc2cc(O)cc(O)c2C/3=O

Supporting Info

 

Start of the Euro 2016

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ND 630, NDI 010976

 Uncategorized  Comments Off on ND 630, NDI 010976
Jun 102016
 

str1

 

ndi molecul
str1
ND 630, NDI 010976,  ND-630, NDI-010976
1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid
2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid
2-[1-[(2R)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2-methylpropanoic acid
CAS 1434635-54-7
Thieno[2,​3-​d]​pyrimidine-​3(2H)​-​acetic acid, 1,​4-​dihydro-​1-​[(2R)​-​2-​(2-​methoxyphenyl)​-​2-​[(tetrahydro-​2H-​pyran-​4-​yl)​oxy]​ethyl]​-​α,​α,​5-​trimethyl-​6-​(2-​oxazolyl)​-​2,​4-​dioxo-
Molecular Formula: C28H31N3O8S
Molecular Weight: 569.62604 g/mol
Company Nimbus Therapeutics LLC
Description Small molecule allosteric inhibitor of acetyl-coenzyme A carboxylase alpha (ACACA; ACC1) and acetyl-coenzyme A carboxylase beta (ACACB; ACC2)
Molecular Target Acetyl-Coenzyme A carboxylase alpha (ACACA) (ACC1) ; Acetyl-Coenzyme A carboxylase beta (ACACB) (ACC2)
Mechanism of Action Acetyl-coenzyme A carboxylase alpha (ACACA) (ACC1) inhibitor; Acetyl-coenzyme A carboxylase beta (ACACB) (ACC2) inhibitor
Therapeutic Modality Small molecule
Preclinical Diabetes mellitus; Hepatocellular carcinoma; Metabolic syndrome; Non-alcoholic steatohepatitis; Non-small cell lung cancer
CHEMBL3407547.png

Acetyl CoA carboxylase 1/2 allosteric inhibitors – Nimbus Therapeutics

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting, San Francisco, CA, USA

Nimbus compounds targeting liver disease in rat models

Data were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND-630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively, EC50 values in HepG2 serum free and 10% serum of 9 and 66 nM, respectively, and 2-fold C2C12 fatty acid oxidation (FAOxn) stimulation at 200 nM. Rat FASyn (synthase), malonyl-CoA (liver) and malonyl-COA (muscle) respective ED50 values were 0.14 mg/kg po, 0.8 and 3 mg/kg. The rat respiratory quotient (RQ) MED was 3 mg/kg po. ADME data showed low multispecies intrinsic clearance (human, mouse, rat, dog, monkey). NDI-010976 was eliminated predominantly as the parent drug. Additionally, P450 inhibition was > 50 microM. In liver and muscle, NDI-010976 modulated key metabolic parameters including a dose-dependent reduction in the formation of the enzymatic product of acetyl coA carboxyloase malonyl coA; the ED50 value was lower in muscle. The drug also decreased FASyn dose dependently and increased fatty acid oxidation in the liver (EC50 = 0.14 mg/kg). In 28-day HS DIO rats, NDI-010976 favorably modulated key plasma and liver lipids, including decreasing liver free fatty acid, plasma triglycerides and plasma cholesterol; this effect was also seen in 37-day ZDF rats

 PATENT

http://www.google.com/patents/WO2013071169A1?cl=en

 

Example 76: Synthesis of 2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid (1-181).

Figure imgf000193_0001

Synthesis of compound 76.1. Into a 250-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed oxan-4-ol (86 g, 842.05 mmol, 2.01 equiv) and FeCl3 (10 g). This was followed by the addition of 57.2 (63 g, 419.51 mmol, 1.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 500 mL of H20. The resulting solution was extracted with 3×1000 mL of ethyl acetate and the organic layers combined. The resulting solution was extracted with 3×300 mL of sodium chloride (sat.) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 22 g (21%) of 76.1 as a white solid.

Synthesis of compound 76.2. The enantiomers of 76.1 (22g) were resolved by chiral preparative HPLC under the following conditions (Gilson Gx 281): Column: Venusil Chiral OD-

H, 21.1 *25 cm, 5 μιη; mobile phase: hexanes (0.2% TEA) and ethanol (0.2% TEA) (hold at 10% ethanol (0.2%TEA) for 13 min); detector: UV 220/254 nm. 11.4 g (52%) of 76.2 were obtained as a white solid.

Synthesis of compound 76.3. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 70.1 (12 g, 20.49 mmol, 1.00 equiv), tetrahydrofuran (200 mL), 76.2 (6.2 g, 24.57 mmol, 1.20 equiv) and DIAD (6.5 g, 32.18 mmol, 1.57 equiv). This was followed by the addition of a solution of triphenylphosphane (8.4 g, 32.03 mmol, 1.56 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at 0 °C in 60 min. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 17 g (crude) of 76.3 as a white solid.

Synthesis of compound 76.4. Into a 500-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 76.3 (17 g, crude), toluene (300 mL), Pd(PPh3)4 (1.7 g, 1.47 mmol, 0.07 equiv) and 2-(tributylstannyl)-l,3-oxazole (8.6 g, 24.02 mmol, 1.16 equiv). The resulting solution was stirred overnight at 110 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). Purification afforded 6 g of 76.4 as a white solid.

Synthesis of compound 1-181. Into a 250-mL 3-necked round-bottom flask, was placed 76.4 (6 g, 7.43 mmol, 1.00 equiv), tetrahydrofuran (100 mL), TBAF (2.3 g, 8.80 mmol,

I .18 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50: 1). This resulted in 3.4 g (80%) of Compound 1-181 as a white solid.

Purification: MS (ES): m/z 570 (M+H)+, 592 (M+Na)+.

1H NMR (300 MHz, DMSO- d6): δ 1.22-1.36 (m, 2H), 1.62 (m, 8H), 2.75 (s, 3H), 3.20-3.39 (m, 3H), 3.48-3.58 (m, 2H), 3.80 (s, 3H), 3.85-4.20 (m, 2H), 5.30 (m, 1H), 7.03 (m, 2H), 7.33-7.50 (m, 3H), 8.2 (s, 1H).

Figure imgf000193_0001

ndi molecul

Preparation of ND-630.1,4-dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-3(2H)-acetic acid, ND-630, was prepared as described (49)…….http://www.pnas.org/content/113/13/E1796.full.pdf
Harriman GC, Masse CE, Harwood HJ, Jr, Baht S, Greenwood JR (2013) Acetyl-CoA
carboxylase inhibitors and uses thereof. US patent publication US 2013/0123231.
CLIPS

The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting,  San Francisco, CA, USA

Conference: 66th Annual Meeting of the American Association for the Study of Liver Diseases Conference Start Date: 13-Nov-2015

…candidates for minimizing IR injury in liver transplantation.Nimbus compounds targeting liver disease in rat modelsData were presented by Geraldine Harriman, from Nimbus Therapeutics, from rat models using acetyl-CoA carboxylase (ACC) inhibitors NDI-010976 (ND–630) and N-654, which improved metabolic syndrome endpoints, decreased liver steatosis, decreased expression of inflammatory markers and improved fibrosis. The hepatotropic ACC inhibitor NDI-010976 had IC50 values of 2 and 7 nM for ACC1 and 2, respectively…

REFERENCES

November 13-17 2015
The Liver Meeting 2015 – American Association for the Study of Liver Diseases (AASLD) – 2015 Annual Meeting  San Francisco, CA, USA ,
WO-2014182943

WO-2014182951 

WO-2014182945

WO-2014182950 

Patent ID Date Patent Title
US2015203510 2015-07-23 ACC INHIBITORS AND USES THEREOF
US2013123231 2013-05-16 ACC INHIBITORS AND USES THEREOF

/////// ND 630, NDI 010976,  ND-630, NDI-010976, NIMBUS, GILEAD, 1434635-54-7

O=C(O)C(C)(C)N4C(=O)c1c(C)c(sc1N(C[C@H](OC2CCOCC2)c3ccccc3OC)C4=O)c5ncco5

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Pexidartinib

 orphan status, Phase 3 drug, Uncategorized  Comments Off on Pexidartinib
Jun 102016
 

Pexidartinib

PLX-3397

5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine

N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine

Phase III

A Multi-targeted tyrosine kinase inhibitor potentially for the treatment of tenosynovial giant cell tumor (TGCT).

CAS No.: 1029044-16-3
Mol. Formula: C20H15ClF3N5
Mol. Weight: 417.81
  • Pexidartinib; 1029044-16-3; PLX-3397; 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine; 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine; 5-[(5-Chloro-1h-Pyrrolo[2,3-B]pyridin-3-Yl)methyl]-N-{[6-(Trifluoromethyl)pyridin-3-Yl]methyl}pyridin-2-Amine;
  • Originator Plexxikon
  • Developer Barbara Ann Karmanos Cancer Institute; Columbia University; Merck & Co; National Cancer Institute (USA); Plexxikon; University of California at San Francisco
  • Class 2 ring heterocyclic compounds; Antineoplastics; Fluorine compounds; Pyridines; Pyrroles; Small molecules
  • Mechanism of Action Fms-like tyrosine kinase 3 inhibitors; Immunomodulators; Macrophage colony stimulating factor receptor antagonists; Proto oncogene protein c-akt inhibitors; Proto oncogene protein c-kit inhibitors
  • Orphan Drug Status Yes – Giant cell tumour of tendon sheath; Pigmented villonodular synovitis
  • Phase III Pigmented villonodular synovitis
  • Phase II Glioblastoma; Malignant melanoma; Prostate cancer
  • Phase I/II Breast cancer; Leukaemia; Peripheral nervous system diseases; Sarcoma; Solid tumours
  • Phase I Gastrointestinal stromal tumours
  • No development reported Neurological disorders; Rheumatoid arthritis
  • Discontinued Acute myeloid leukaemia; Hodgkin’s disease

Most Recent Events

  • 25 May 2016 Plexxikon and AstraZeneca plan the MEDIPLEX phase I trial for Solid tumours (Combination therapy, Metastatic disease) in France (NCT02777710)
  • 05 Apr 2016 Daiichi Sankyo plans a phase I trial for Solid tumours (Late-stage disease, Second-line therapy or greater) in Taiwan (PO) (NCT02734433)
  • 11 Mar 2016 Plexxikon re-initiates enrolment in a phase Ib trial in Solid tumours and Gastrointestinal stromal tumours in USA (NCT02401815)

 

Multi-targeted receptor tyrosine kinase inhibitor of CSF1R, c-Kit, and FLT3 (IC50 values 13 nM, 27 nM, and 11 nM, respectively) Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

Plexxikon is conducting phase III clinical studies with PLX-3397 for the treatment of pigmented villonodular synovitis. Phase II clinical studies are ongoing for the oral treatment of melanoma and glioblastoma multiforme. Additional early clinical trials are underway for the treatment of metastatic breast cancer, for the treatment of prostate cancer (adenocarcinoma), and for the treatment of malignant peripheral nerve sheath tumor. No recent development has been reported from preclinical studies for the treatment of systemic lupus erythematosus and for the treatment of multiple sclerosis. Prior to patient enrollment, a phase I clinical trial by Plexxikon for the treatment of rheumatoid arthritis was withdrawn. Daiichi Sankyo (parent of Plexxikon) decided to discontinue phase II trials of the product for the treatment of castration-resistant prostate cancer and for the treatment of Hodgkin’s lymphoma after reviewing its clinical study results and also have discontinued phase II studies for the treatment of acute myeloid leukemia due to strategic reasons.

Pexidartinib.png

In 2014, orphan drug designation was assigned to the compound in the US for the treatment of pigmented villonodular synovitis andf giant cell tumor of the tendon sheath. In 2015, the compound was granted orphan designation in the E.U. for the treatment of tenosynovial giant cell tumor, localised and diffuse type. In the same year, the product was granted breakthrough therapy designation for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity.

C-fms and c-kit arc both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.

c-Fms
C-fms is a member of the family of genes originally isolated from the Susan McDonough strain ot teline sarcoma viruses, The cellular proto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes for the receptor for the macrophage colony-stimuktmg tactor (M- CSF) C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage, and upon binding of Vf-CSF to the extracellular domain of c-fms, the receptor dimeπzes and trans- autophosphorylates cytoplasmic tyrosine residues

M-CSF, first described by Robinson and co-workers (Blood 1969, 33 396-9), is a cytokine that controls the production, differentiation, and function of macrophages M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemota\is, and secondary cytokine production of additional factors in monocytes and macrophages Examples of such additional factors include granulocyte colony stimulating lactor (G-CSF) interleukin-6 (IL-6), and mterleukm-8 (IL-8) M-CSF stimulates hematopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism Furthermore, M-CSF is important in pregnancy Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, lnt J Hematol 1998, 67 109-22) l hc elevated semm levels of M-CSF m early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opm Hematol 1998, 5 181-5)

Related to c-fms and c-kit are two p_latelet -derived growth factor receptors, alpha (i e , pdgfra) and beta (pdgfrb) (PDGF) 1 he gene coding for pdgfra is located on chromosome 4ql 1 -q!2 in the same region of chromosome 4 as the oncogene coding for c-kit The genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5 They are oriented head to tail with the 5-pnme exon of the c-fms gene located only 500 bp from the last 3-pπme exon of the gene coding for pdgfra Most gastrointestinal stromal tumors (GIST) have activating mutations in c-kit and most patients with GISTs respond well to Gleevec, which inhibits c-kit Hemπch et al (Science 2003, 299 “OS-IO) have shown that approximately 35% of GISTs lacking c-krt mutations, have intragenic activation mutations m tht gene encoding pdgfra, and that tumors expressing c-kit or pdgfrd are indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression Thus, c kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms m GISTs [0007} Similarly, the observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation points out a role for c-frns in diseases, such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of c-fms can ameliorate disease associated with increased levels of M-CSF.

c-Kit
The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of melanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded by the Sl locus, and has also been called “kit ligand” (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol 1997, 153:337-344; Vliagoftis, et al,, Clin Immunol 1997, 100:435-440; Broudy, Blood 1997, 90: 1345-1364; Pignon, Hermatol Cell Ther 1997, 39: 1 14-1 16; and Lyman, et al., Blood 1998, 91 : 1 101 -1 134.). Herein the abbreviation SCF refers to the physiological ligand for c-kit.

SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form, a soluble, glycosylated protein which noncovalently dimerizcs. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-kit on germ cells.

 

 

STR1

PATENT

WO 2008063888

 

PATENT

WO 2008064265

 

PATENT

WO 2008064255

PATENT

WO 2012158957

Fragments in the clinic: PLX3397

Practical Fragments covers a wide variety of journals. J. Med. Chem., Bioorg. Med. Chem. Lett., Drug Disc. Today, and ACS Med. Chem. Lett. are all well-represented, but we also range further afield, from biggies such asNature and Science to more niche titles such as ChemMedChem, Acta. Cryst. D., and Anal. Chim. Acta. The increasingly clinical relevance of fragment-based approaches is highlighted by a recent paper by William Tap and a large group of collaborators appearing in the New England Journal of Medicine. This reports on the results of the Daiichi Sankyo (née Plexxikon) drug PLX3397 in a phase I trial for tenosynovial giant-cell tumor, a rare but aggressive cancer of the tendon sheath.

The story actually starts with a 2013 paper by Chao Zhang and his Plexxikon colleagues in Proc. Nat. Acad. Sci. USA. The researchers were interested in inhibiting the enzymes CSF1R (or FMS) and KIT; both kinases are implicated in cancer as well as inflammatory diseases. The team started with 7-azaindole, the same fragment they used to discover vemurafenib. Structural studies of an early derivative, PLX070, revealed a hydrogen bond between the ligand oxygen and a conserved backbone amide. Further building led to PLX647, with good activity against both CSF1R and KIT. Selectivity profiling against a panel of 400 kinases revealed only two others with IC50values < 0.3 µM. The molecule was active in cell-based assays, had good pharmacokinetics in mice and rats, and was active in rodent models of inflammatory disease.

The new paper focuses on the results of a clinical trial with PLX3397, a derivative of PLX647. Despite its close structural similarity to PLX647, it binds to CSF1R in a slightly different manner. Both inhibitors bind to the inactive form of the kinase, but PLX3397 also recruits the so-called juxtamembrane domain of the kinase to stabilize this autoinhibited conformation. Pharmacokinetic and pharmacodynamics studies in animals were also positive.

http://practicalfragments.blogspot.in/2015/10/fragments-in-clinic-plx3397.html

Tenosynovial giant-cell tumor seems to be dependent on CSF1R, so the researchers performed a phase 1 dose-escalation study with an extension in which patients treated with the chosen phase 2 dose were treated longer. Of the 23 patients in this extension, 12 had a partial response and 7 had stable disease. A quick search ofclinicaltrials.gov reveals that PLX3397 is currently in multiple trials for several indications, including a phase 3 trial for giant cell tumor of the tendon sheath.

Several lessons can be drawn from these studies. First, as the authors note, one fragment can give rise to multiple different clinical candidates. Indeed, in addition to vemurafenib, 7-azaindole was also the starting point forAZD5363. This is a good counterargument to those who believe that novelty is essential in fragments.

A second, related point is that selectivity is also not necessary for a fragment. The fact that 7-azaindole comes up so frequently as a kinase-binding fragment has not prevented researchers from growing it into remarkably selective inhibitors. An obvious corollary is that even subtle changes to a molecule can have dramatic effects: the added pyridyl nitrogen in PLX3397 is essential for stabilizing a unique conformation of the enzyme.

 

Patent ID Date Patent Title
US2015265586 2015-09-24 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US2014243365 2014-08-28 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR
US8722702 2014-05-13 Compounds modulating c-fms and/or c-kit activity and uses therefor
US2014045840 2014-02-13 COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
US2013274259 2013-10-17 KINASE MODULATION AND INDICATIONS THEREFOR
US8404700 2013-03-26 Compounds modulating c-fms and/or c-kit activity and uses therefor
US2011230482 2011-09-22 COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY
US7893075 2011-02-22 Compounds modulating c-fms and/or c-kit activity and uses therefor

//////1029044-16-3, Pexidartinib , PLX-3397, PHASE3

FC(F)(F)c1ccc(cn1)CNc2ccc(cn2)Cc4cnc3ncc(Cl)cc34

Start of the Euro 2016

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Gilteritinib for Treatment of Acute Myeloid Leukemia

 Phase 3 drug, Uncategorized  Comments Off on Gilteritinib for Treatment of Acute Myeloid Leukemia
Jun 102016
 

Gilteritinib

ASP-2215

Treatment of Acute Myeloid Leukemia

6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine-2-carboxamide

C29H44N8O3, 552.71

Phase III

A FLT3/AXL inhibitor potentially for the treatment of acute myeloid leukemia.

CAS No. 1254053-43-4

Astellas Pharma  INNOVATOR
Mechanism Of Action Axl receptor tyrosine kinase inhibitors, Fms-like tyrosine kinase 3 inhibitors, Proto oncogene protein c-kit inhibitors
Who Atc Codes L01X-E (Protein kinase inhibitors)
Ephmra Codes L1H (Protein Kinase Inhibitor Antineoplastics)
Indication Cancer, Hepatic impairment

Gilteritinib(ASP-2215) is a potent FLT3/AXL inhibitor with IC50 of 0.29 nM/<1 nM respectively; shows potent antileukemic activity against AML with either or both FLT3-ITD and FLT3-D835 mutations.
IC50 value: 0.29 nM(FLT3); <1 nM(Axl kinase)
Target: FLT3/AXL inhibitor
ASP2215 inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. ASP2215 decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells. ASP2215 may have potential use in treating AML.

SYNTHESIS

STR1

PATENT

WO 2010128659

 

Patent

WO 2015119122

Compound A is 6-ethyl-3 – ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- a (tetrahydro -2H- pyran-4-ylamino) pyrazine-2-carboxamide, its chemical structure is shown below.
[Formula 1]

Gilteritinib fumarate

1254053-84-3.png

2D chemical structure of 1254053-84-3

Gilteritinib fumarate [USAN]

RN: 1254053-84-3

UNII: 5RZZ0Z1GJT

2-Pyrazinecarboxamide, 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-, (2E)-2-butenedioate (2:1)

  • ASP-2215 hemifumarate
  • Molecular Formula, 2C29-H44-N8-O3.C4-H4-O4, Molecular Weight, 1221.5108

Astellas Inititaties Phase 3 Registration Trial of gilteritinib (ASP2215) in Relapsed or Refractory Acute Myeloid Leukemia Patients

gilteritinib-ASP2215

TOKYO, Japan I October 28, 2015 I Astellas Pharma Inc. (TSE:4503) today announced dosing of the first patient in a randomized Phase 3 registration trial of gilteritinib (ASP2215)versus salvage chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The primary endpoint of the trial is overall survival (OS).

Gilteritinibis a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinibhas demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML.

The gilteritinib Phase 3 trial follows a Phase 1/2 trial, which evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in the dose escalation phase. Preliminary data from the Phase 1/2 trial presented at the 2015 American Society of Clinical Oncology annual meeting demonstrated a 57.5 percent overall response rate and a 47.2 percent composite Complete Response (CR) rate (CR + CR with incomplete platelet recovery + CR with incomplete hematologic recovery) in 106 patients with FLT3 mutations who received 80 mg and higher doses. Median duration of response was 18 weeks across all doses and median OS was approximately 27 weeks at 80 mg and above in FLT3 mutation positive patients. Common drug-related adverse events (> 10%) observed in the study were diarrhea (13.4%), fatigue (12.4%) and AST increase (11.3%). At the 450 mg dose, two patients reached dose-limiting toxicity (grade 3 diarrhea and ALT/AST elevation) and the maximum tolerated dose was determined to be 300 mg.

On October 27, 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for SAKIGAKE.

About the Phase 3 Study

The Phase 3 trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in patients with Acute Myeloid Leukemia (AML). The study will enroll 369 patients with FLT3 activating mutation in bone marrow or whole blood, as determined by central lab, AML who are refractory to or have relapsed after first-line AML therapy. Subjects will be randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy consisting of LoDAC (low-dose cytarabine), azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin). The primary endpoint of the trial is OS. For more information about this trial go to www.clinicaltrials.gov, trial identifier NCT02421939.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib.

About Acute Myeloid Leukemia

Acute myeloid leukemia is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the//www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf” target=”_blank” rel=”nofollow”>American Cancer Society, in 2015, there will be an estimated 20,830 new cases of AML diagnosed in the United States, and about 10,460 cases will result in death.

About SAKIGAKE

The SAKIGAKE designation system can shorten the review period in the following three approaches: 1.) Prioritized Consultation 2.) Substantial Pre-application Consultation and 3.) Prioritized Review. Also, the system will promote development with the following two approaches: 4.) Review Partner System (to be conducted by the Pharmaceuticals and Medical Devices Agency) and 5.) Substantial Post-Marketing Safety Measures.

About Astellas

Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. We focus on Urology, Oncology, Immunology, Nephrology and Neuroscience as prioritized therapeutic areas while advancing new therapeutic areas and discovery research leveraging new technologies/modalities. We are also creating new value by combining internal capabilities and external expertise in the medical/healthcare business. Astellas is on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at www.astellas.com/en.

SOURCE: Astellas Pharma

////////1254053-43-4, Gilteritinib, ASP-2215, PHASE 3, ASP 2215, Astellas Pharma, Acute Myeloid Leukemia

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.C(=C/C(=O)O)\C(=O)O

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Ponesimod

 Phase 3 drug, Uncategorized  Comments Off on Ponesimod
Jun 092016
 

Ponesimod.svg

Ponesimod

Phase III

MW 460.97, C23 H25 Cl N2 O4 S

A sphingosine-1-phosphate receptor 1 (S1P1) agonist potentially for the treatment of multiple sclerosis.

  • (2Z,5Z)-5-[[3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylene]-3-(2-methylphenyl)-2-(propylimino)-4-thiazolidinone
  • 5-[3-Chloro-4-[((2R)-2,3-dihydroxypropyl)oxy]benz-(Z)-ylidene]-2-((Z)-propylimino)-3-(o-tolyl)thiazolidin-4-one
  • ACT 128800

ACT-128800; RG-3477; R-3477

CAS No. 854107-55-4

SYNTHESIS

STR1

Ponesimod

str1

str1

 

NMR CDCL3 FROM NET

 

 

STR1

 

 

STR1

 

 

STR1

 

STR1

 

STR1

SEE……http://www.slideserve.com/truda/discovery-of-the-novel-orally-active-s1p-1-receptor-agonist-act-128800-ponesimod

Ponesimod (INN, codenamed ACT-128800) is an experimental drug for the treatment of multiple sclerosis (MS) and psoriasis. It is being developed by Actelion.

The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod’s side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Biology and pharmacology of sphingosine-1-phosphate receptor 1

The past decades have witnessed major advances in the treatment of autoimmune and chronic inflammatory diseases. A plethora of novel therapies targeting specific molecules involved in the inflammatory or immune system activation cascades have become available. These have significantly increased our understanding of disease pathogenesis and improved the management of immune-mediated disorders. However, most of the targeted therapies are biological drugs which need to be injected, are eliminated slowly (e.g. over several weeks) and can lose efficacy or tolerability due to their potential immunogenicity. In an attempt to overcome these hurdles, pharmaceutical research has made considerable efforts to develop novel oral targeted therapies for autoimmune and chronic inflammatory diseases.

Sphingosine-1-phosphate receptor 1 (S1P1R) is one of five known G protein-coupled receptors with nanomolar affinity for the lysophospholipid sphingosine-1-phosphate (S1P), which is generated through physiologic metabolism of the cell membrane constituent sphingomyelin by all cells [Brinkmann, 2007]. S1P receptors, including S1P1R, are widely expressed in many tissues [Chun et al. 2010]. S1P1R expression on lymphocytes controls their egress from thymus and secondary lymphoid organs [Cyster and Schwab, 2012]. Lymphocyte egress requires a gradient of S1P concentration, which is established by a high S1P concentration in blood and lymph compared with a low concentration in the interstitial fluid of lymphoid organs [Grigorova et al. 2009].

Synthetic S1P1 receptor modulators disrupt the interaction of the physiologic S1P ligand with S1P1R by promoting initial activation followed by sustained internalization and desensitization of S1P1R [Hla and Brinkmann, 2011; Pinschewer et al. 2011]. Experiments conducted in animal models of transplant rejection, multiple sclerosis, lupus erythematosus, arthritis and inflammatory bowel disease with the first-generation, nonselective S1P receptor modulator, fingolimod, have demonstrated the potential efficacy of this mode of action across several immune-mediated chronic inflammatory conditions [Brinkmann, 2007]. Fingolimod is a structural analog of sphingosine that is phosphorylated in the body by a sphingosine kinase to generate the bioactive form of the drug, fingolimod phosphate, which binds to multiple S1P receptors [Brinkmann, 2007]. Clinical trials in multiple sclerosis (MS) have confirmed the efficacy of fingolimod in relapsing MS, but not in primary progressive disease, and led to the approval of the first oral medication for the treatment of relapsing forms of MS in 2010 [Kappos et al. 2010].

The mechanism of action of fingolimod has increased our understanding of MS pathogenesis. T and B cells, but not natural killer (NK) cells, express functional S1P1R and are affected by fingolimod [Cyster and Schwab, 2012]. Furthermore, S1P1R is differentially expressed and regulated in functionally distinct subsets of lymphocytes and fingolimod has been shown to predominantly affect naïve T cells and central memory T cells (TCM) while sparing effector memory T cells (TEM), and terminally differentiated effector T cells (TE) in patients with relapsing MS [Mehling et al. 2008, 2011]. This has raised the possibility that, at least in MS, retention of TCM cells, which include pro-inflammatory T helper 17 (Th17) cells, by fingolimod may prevent their accumulation in the cerebrospinal fluid (CSF) and subsequent differentiation to TE cells in the central nervous system (CNS) [Hla and Brinkmann, 2011]. The effects of S1P1R modulation on B cells are less well defined. Recent data from patients with relapsing MS have shown predominant reduction of memory B cells and recently activated memory B cells (CD38int-high) in peripheral blood after treatment with fingolimod [Claes et al. 2014; Nakamura et al. 2014]. As memory B cells are implicated in the pathogenesis of MS and other autoimmune diseases, these observations suggest another potential mechanism underlying the therapeutic effects of S1P1R modulators.

Astrocytes, microglia, oligodendrocytes and neurons express various S1P receptors including S1P1R, S1P3R and S1P5R. Fingolimod has been shown to penetrate the CNS tissues and in vitro studies have shown activation of astrocytes and oligodendrocytes by fingolimod [Foster et al. 2007]. Conditional deletion of S1P1R on neural cells in mice reduced the severity of experimental autoimmune encephalomyelitis (EAE) and reductions in the clinical scores were paralleled by decreased demyelination, axonal loss and astrogliosis [Choi et al. 2011]. Unfortunately, there was no beneficial effect in a recently completed, large study of fingolimod in patients with primary progressive MS [Lublin et al. 2015], suggesting that the direct effect on CNS cells alone may not be sufficient. Taken together, these data suggest the possibility of a direct beneficial effect of S1P1R modulation in the brain of patients with relapsing MS [Dev et al. 2008]; however, its contribution to efficacy relative to the immunological effects remains unclear.

Initial studies in rodents suggested that modulation of S1P3R on cardiac myocytes by fingolimod was associated with a reduction of heart rate (HR) by activation of G-protein-coupled inwardly rectifying potassium channels (GIRK) that regulate pacemaker frequency, and the shape and duration of action potentials [Koyrakh et al. 2005; Camm et al. 2014]. Modulation of S1P2R and S1P3R on myofibroblasts by fingolimod was also shown to stimulate extracellular matrix synthesis [Sobel et al. 2013]. Modulation of these receptors on vascular smooth muscle cells appeared to be associated with vasoconstriction, leading to the slight increase in blood pressure observed with fingolimod treatment [Salomone et al. 2003; Watterson et al. 2005; Hu et al. 2006; Lorenz et al. 2007; Kappos et al. 2010]. These observations raised the possibility that some side effects associated with fingolimod treatment could be avoided by more selective S1P1R modulators, thus triggering the search for novel compounds.

Currently, there are several selective S1P1R modulators in clinical development [Gonzalez-Cabrera et al.2014; Subei and Cohen, 2015]. Here we review data and the development status of ponesimod, a selective S1P1R modulator developed by Actelion Pharmaceuticals Ltd.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Ponesimod, a selective, rapidly reversible, orally active, sphingosine-1-phosphate receptor modulator

Ponesimod (ACT-128800 (Z,Z)-5-[3-chloro-4-(2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolylthiazolidin-4-one) is a selective, rapidly reversible, orally active, S1P1R modulator. Ponesimod emerged from the discovery of a novel class of S1P1R agonists based on the 2-imino-thiazolidin-4-one scaffold (Figure 1) [Bolli et al. 2010]. Ponesimod activates S1P1R with high potency [half maximal effective concentration (EC50) of 5.7 nM] and selectivity. Relative to the potency of S1P, the potency of ponesimod is 4.4 higher for S1P1R and 150-fold lower for S1P3R, resulting in an approximately 650-fold higher S1P1R selectivity compared with the natural ligand.

Figure 1.

Chemical structure of ponesimod, C23H25N2O4CIS (molecular weight 460.98).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707431/

Clinical trials

In a 2009–2011 Phase II clinical trial including 464 MS patients, ponesimod treatment resulted in fewer new active brain lesions thanplacebo, measured during the course of 24 weeks.[3][4]

In a 2010–2012 Phase II clinical trial including 326 patients with psoriasis, 46 or 48% of patients (depending on dosage) had a reduction of at least 75% Psoriasis Area and Severity Index (PASI) score compared to placebo in 16 weeks.[3][5]

SEE https://clinicaltrials.gov/ct2/show/NCT02425644

Adverse effects

Common adverse effects in studies were temporary bradycardia (slow heartbeat), usually at the beginning of the treatment,dyspnoea (breathing difficulties), and increased liver enzymes (without symptoms). No significant increase of infections was observed under ponesimod therapy.[3] QT prolongation is detectable but was considered to be too low to be of clinical importance in a study.[6]

Mechanism of action

Like fingolimod, which is already approved for the treatment of MS, ponesimod blocks the sphingosine-1-phosphate receptor. This mechanism prevents lymphocytes (a type of white blood cells) from leaving lymph nodes.[3] Ponesimod is selective for subtype 1 of this receptor, S1P1.[7]

 

PAPER

Bolli, Martin H.; Journal of Medicinal Chemistry 2010, V53(10), P4198-4211 CAPLUS

2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1Receptor Agonists

Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
J. Med. Chem., 2010, 53 (10), pp 4198–4211
DOI: 10.1021/jm100181s
Publication Date (Web): May 06, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: + 41 61 565 65 70. Fax: + 41 61 565 65 00. E-mail:martin.bolli@actelion.com.
Abstract Image

Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P1 through S1P5. Agonists of the S1P1 receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure−activity relationships of a novel class of S1P1 receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P1 receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.

(Z,Z)-5-[3-Chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one (8bo)

…………..DELETED…………… column chromatography on silica gel eluting with heptane:ethyl acetate 1:4 to give the title compound (1.34 g, 37%) as a pale-yellow foam.
1H NMR (CDCl3): δ 0.94 (t, J = 7.3 Hz, 3 H), 1.58−1.70 (m, 2 H), 2.21 (s, 3 H), 3.32−3.48 (m, 2 H), 3.82−3.95 (m, 3 H), 4.12−4.27 (m, 4 H), 7.07 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 7.0 Hz, 1 H), 7.31−7.39 (m, 3 H), 7.49 (dd, J = 8.5, 2.0 Hz, 1 H), 7.64 (d, J= 2.0 Hz, 1 H), 7.69 (s, 1 H).
13C NMR (CDCl3): δ 11.83, 17.68, 23.74, 55.42, 63.46, 69.85, 70.78, 133.48, 120.75, 123.71, 127.05, 128.25, 128.60, 129.43, 130.06, 131.13, 131.50, 134.42, 136.19, 146.98, 154.75, 166.12. LC-MS (ES+): tR 0.96 min. m/z: 461 (M + H).
HPLC (ChiralPak AD-H, 4.6 mm × 250 mm, 0.8 mL/min, 70% hexane in ethanol): tR 11.8 min. Anal. (C23H25N2O4SCl): C, H, N, O, S, Cl.

PATENT

WO 2014027330

https://www.google.com/patents/WO2014027330A1?cl=3Den

The present invention relates inter alia to a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (hereinafter also referred to as the “COMPOUND” or “compound (2)”), especially in crystalline form C which form is described in WO 2010/046835. The preparation of COMPOUND and its activity as immunosuppressive agent is described in WO 2005/054215. Furthermore, WO 2008/062376 describes a new process for the preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one which can be used as an intermediate in the preparation of COMPOUND.

Example 1 a) below describes such a process of preparing (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one according to WO 2008/062376. According to WO 2008/062376 the obtained (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one can then be transformed into COMPOUND by using standard methods for the alkylation of phenols. Such an alkylation is described in Example 1 b) below. Unfortunately, this process leads to the impurity (2Z,5Z)-5-(3-chloro-4-((1 ,3-dihydroxypropan-2-yl)oxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one which is present in about 2% w/w in the crude product (see Table 1 ) and up to 6 recrystallisations are necessary in order to get this impurity below 0.4% w/w (see Tables 1 and 2) which is the specified limit based on its toxicological qualification.

the obtained (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one to form (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (2):


.

The reaction of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ) with 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one can be performed under conditions which are typical for a Knoevenagel condensation. Such conditions are described in the literature for example in Jones, G., Knoevenagel Condensation in Organic Reaction, Wiley: New York, 1967, Vol. 15, p 204; or Prout, F. S., Abdel-Latif, A. A., Kamal, M. R., J. Chem. Eng. Data, 2012, 57, 1881-1886.

2-[(Z)-Propylimino]-3-o-tolyl-thiazolidin-4-one can be prepared as described in WO 2008/062376, preferably without the isolation and/or purification of intermediates such as the thiourea intermediate that occurs after reacting o-tolyl-iso-thiocyanate with n-propylamine. Preferably 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one obtained according to WO 2008/062376 is also not isolated and/or purified before performing the Knoevenagel condensation, i.e. before reacting 2-[(Z)-propylimino]-3-o-tolyl-thiazolidin-4-one with (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde (1 ), i.e. in a preferred embodiment compound (2) is prepared in a one-pot procedure analogous to that described in WO 2008/062376.

 

Example 1 : (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one

a) Preparation of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one:

Acetic acid solution: To acetic acid (149.2 mL) are added sodium acetate (1 1 .1 1 g, 2.00 eq.) and 3-chloro-4-hydroxybenzaldehyde (10.60 g, 1.00 eq.) at 20 °C. The mixture is stirred at 20 °C until complete dissolution (2 to 3 h).

n-Propylamine (4.04 g, 1.00 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 40 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (13.53 g, 1.00 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). 70 mL of dichloromethane are distilled off under atmospheric pressure and jacket temperature of 60 °C. The temperature is adjusted to 42 °C and the acetic acid solution is added to the reaction mixture. The resulting solution is heated to 58 °C and stirred at this temperature for 15 h before IPC (conversion specification≥ 95 %). 25 mL of solvents are distilled off under vacuum 900 – 500 mbars and jacket temperature of 80 °C. The temperature is adjusted to 60 °C and water (80.1 mL) is added to the reaction mixture over 1 h. The resulting yellow suspension is stirred at 60 °C for 30 min. The suspension is cooled to 20 °C over 1 h and stirred at this temperature for 30 min.

The product is filtered and washed with a mixture of acetic acid (30 mL) and water (16 mL) and with water (50 mL) at 20 °C. The product is dried under vacuum at 50 °C for 40 h to afford a pale yellow solid; yield 25.93 g (78 %).

b) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

To a suspension of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one (10.00 g, 1.00 eq.) in ethanol (47.2 mL) is added (R)-3-chloro-1 ,2-

propanediol (3.37 g, 1.18 eq.) at 20 °C. Potassium tert-butoxide (3.39 g, 1.13 eq.) is added in portions at 20 °C. The resulting fine suspension is stirred at 20 °C for 25 min before being heated to reflux (88 °C). The reaction mixture is stirred at this temperature for 24 h before IPC (conversion specification≥ 96.0 %). After cooling down to 60 °C, acetonitrile (28.6 mL) and water (74.9 mL) are added. The resulting clear solution is cooled from 60 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.010 g, 0.001 eq.; crystalline form C can be prepared as described in WO 2010/046835) are added at 50 °C. The suspension is heated from 0 °C to 50 °C, cooled to 0 °C over 6 h and stirred at this temperature for 12 h.

The product is filtered and washed with a mixture of acetonitrile (23.4 mL) and water (23.4 mL) at 0 °C. The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield 1 1.91 g (84 %).

c) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

Recrystallisation I: The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in acetonitrile (30 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 12.8 mL).

Recrystallisation II: The wet product is dissolved in acetonitrile (27.0 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 1 1.3 mL).

Recrystallisation III: The wet product is dissolved in acetonitrile (24.3 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4- one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 10.1 mL).

Recrystallisation IV: The wet product is dissolved in acetonitrile (21.9 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 9.1 mL).

Recrystallisation V: The wet product is dissolved in acetonitrile (19.7 mL) at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10 °C (2 x 8.2 mL).

Recrystallisation VI: The wet product is dissolved in acetonitrile (23.9 mL) at 70 °C. Water (20 mL) is added at 70 °C. The reaction mixture is cooled from 70 °C to 0 °C over 2 h.

During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2- (propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50 °C. The suspension is heated up to 52 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h. The product is filtered and washed twice with a mixture of acetonitrile (4.5 mL) and water (4.5 mL) at -10 °C.

The product is dried under vacuum at 45 °C for 24 h to afford a pale yellow solid; yield: 7.0 g (70 %).

Example 2: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde

Potassium tert-butoxide (1 18 g, 1.20 eq.) is added to n-propanol (963 mL) followed by 3-chloro-4-hydroxybenzaldehyde (137 g, 1.00 eq.). To the mixture is added (R)-3-chloro-1 ,2-propanediol (126 g, 1.30 eq.). The suspension is heated to 90 °C and stirred at this temperature for 17 h. Solvent (500 mL) is distilled off at 120 °C external temperature and reduced pressure. Water is added (1.1 L) and solvent (500 mL) is removed by distillation. The turbid solution is cooled to 20 °C. After stirring for one hour a white suspension is obtained. Water (500 mL) is added and the suspension is cooled to 10 °C. The suspension is filtered and the resulting filter cake is washed with water (500 mL). The product is dried at 50 °C and reduced pressure to yield 149 g of a white solid (73%), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.

Example 3: (R)-3-Chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde

Potassium tert-butoxide (8.60 g, 1.20 eq.) is added to n-propanol (70 mL) below 15 °C, the temperature is allowed to rise. After the addition the temperature is corrected again to below 15 °C before addition of 3-chloro-4-hydroxybenzaldehyde (10 g, 1 .00 eq.). The suspension is heated to 40 °C and stirred for 30 min. (R)-3-Chloro-1 ,2-propanediol (9.18 g, 1.30 eq.) is added at 40 °C. The resulting suspension is heated to 60 °C and stirred at this temperature for 15 h then heated to 94 °C till meeting the IPC-specification (specification conversion≥ 90.0 %). The mixture is cooled to 30 °C and n-propanol is partially distilled off (-50 mL are distilled off) under reduced pressure and a maximum temperature of 50 °C, the jacket temperature is not allowed to raise above 60 °C.

Water (81 mL) is added and a second distillation is performed under the same conditions (24 mL are distilled off). The mixture is heated till homogeneous (maximum 54 °C) and then cooled to 24 °C. At 24 °C the mixture is seeded with crystalline (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of form A (0.013 g, 0.00085 eq.). How to obtain the crystalline seeds is described in Examples 2 and 5. The reaction mixture is cooled to 0 °C over 7.5 h.

The product is filtered and washed with water (2 x 35 mL) and once with methyl tert-butyl ether (20 mL) at 5 °C. The product is dried under vacuum at 40 °C for 20 h to afford an off-white solid; yield: 10.6 g (72 %), which is (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde in crystalline form A.

Example 4: (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)- 3-(o-tolyl)thiazolidin-4-one

a) Preparation of crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

n-Propylamine (5.23 g, 1.32 eq.) is added to a solution of o-tolyl-iso-thiocyanate (10 g, 1.00 eq.) in dichloromethane (100 mL) at 20 °C. The resulting pale yellow solution is agitated for 15 min at 20 °C before IPC (conversion specification≥ 99.0 %). The reaction is cooled to -2 °C. Bromoacetyl bromide (14.88 g, 1.10 eq.) is added and the resulting solution is stirred for 15 min at -2 °C. Pyridine (10.92 g, 2.05 eq.) is then added slowly at -2 °C. The intensive yellow reaction mixture is stirred for 15 min at -2 °C before IPC (conversion specification≥ 93.0 %). Dichloromethane is partially distilled off (66 mL are distilled off) under atmospheric pressure and jacket temperature of 60 °C. Ethanol (1 1 1.4 mL), sodium acetate (12.75 g, 2.30 eq.) and (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde from Example 3 (14.38 g, 0.93 eq.) are added. The remaining dichloromethane and a part of ethanol are distilled off (49.50 mL are distilled off) under atmospheric pressure and jacket temperature up to 85 °C. The reaction mixture (orange suspension) is stirred for 3 – 5 h under reflux (78 °C) before IPC (conversion specification≥ 97.0 %).

Water (88.83 mL) is added and the temperature adjusted to 40 °C before seeding with micronized (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.075 g, 0.0024 eq.). The reaction mixture is cooled to 0 °C over 5 h, heated up to 40 °C, cooled to 0 °C over 6 h and stirred at this temperature for 2 h.

The product is filtered and washed with a 1 :1 ethanohwater mixture (2 x 48 mL) at 0 °C. The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 24.71 g (86 %).

b) Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one:

The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in ethanol (40 mL) at 70 °C. The temperature is adjusted at 50 °C for seeding with micronised (2Z,5Z)-5-(3-chloro-4-((R)-2,3- dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one in crystalline form C (0.016 g, 0.0016 eq.). The reaction mixture is cooled from 50 °C to 0 °C over 4 h, heated up to 50 °C, cooled to 0 °C over 6 h and agitated at this temperature for 2 h.

The product is filtered and washed with ethanol at 0 °C (2 x 12.8 mL). The product is dried under vacuum at 45 °C for 10 h to afford a pale yellow solid; yield: 9.2 g (92 %).

Example 5: Preparation of crystalline seeds of (R)-3-chloro-4-(2,3-dihydroxypropoxy)- benzaldehyde

10 mg of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde of at least 99.5% purity by 1 H-NMR assay is dissolved in a 4 mL vial by adding 1 mL of pure ethanol (puriss p. a.). The solvent is allowed to evaporate through a small hole in the cap (approx. 2 mm of diameter) of the vial until complete dryness. The white solid residue is crystalline (R)-3-chloro-4-(2,3- dihydroxypropoxy)-benzaldehyde in crystalline form A. Alternatively, methanol or methylisobutylketone (both in puriss p. a. quality) is used. This procedure is repeated until sufficient seeds are made available.

PATENT

WO 2005054215

SEE https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005054215

 

 

 

 

WO2005054215A1 Nov 16, 2004 Jun 16, 2005 Actelion Pharmaceuticals Ltd 5-(benz- (z) -ylidene) -thiazolidin-4-one derivatives as immunosuppressant agents
WO2008062376A2 Nov 22, 2007 May 29, 2008 Actelion Pharmaceuticals Ltd New process for the preparation of 2-imino-thiazolidin-4-one derivatives
WO2010046835A1 Oct 19, 2009 Apr 29, 2010 Actelion Pharmaceuticals Ltd Crystalline forms of (r) -5- [3-chloro-4- ( 2, 3-dihydroxy-propoxy) -benz [z] ylidene] -2- ( [z] -propylimino) -3-0-tolyl-thiazolidin-4-one
Reference
1 * BOLLI, M.H. ET AL.: “2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1 Receptor Agonists“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 10, 2010, pages 4198-4211, XP55090073, ISSN: 0022-2623, DOI: 10.1021/jm100181s

References

  1. “Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: Favorable impact of dose up-titration”. The Journal of Clinical Pharmacology 54: 179–88. Feb 2014. doi:10.1002/jcph.244. PMID 24408162.
  2.  “Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans”. Xenobiotica 45: 139–49. Feb 2015. doi:10.3109/00498254.2014.955832. PMID 25188442.
  3. H. Spreitzer (29 September 2014). “Neue Wirkstoffe – Ponesimod”. Österreichische Apothekerzeitung (in German) (20/2014): 42.
  4.  “Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial”. Journal of Neurology, Neurosurgery 85: 1198–208. Nov 2014. doi:10.1136/jnnp-2013-307282. PMC 4215282. PMID 24659797.
  5.  “Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial”. The Lancet 384: 2036–45. Dec 2014. doi:10.1016/S0140-6736(14)60803-5. PMID 25127208.
  6. “Effect of Ponesimod, a selective S1P1 Receptor Modulator, on the QT Interval in Healthy Subjects”. Basic 116: 429–37. May 2015.doi:10.1111/bcpt.12336. PMID 25287214.
  7.  “Ponesimod”. Actelion. Retrieved 31 October 2014.

ABOUT PONESIMOD

Ponesimod is a potent orally active, selective sphingosine-1-phosphate receptor 1 (S1P1) immunomodulator.

Ponesimod prevents lymphocytes from leaving lymph nodes, thereby reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. The lymphocyte count reduction is rapid, dose-dependent, sustained upon continued dosing, and quickly reversible upon discontinuation. Initial data suggest that ponesimod does not cause lymphotoxicity by destroying/depleting lymphocytes or interfering with their cellular function. Other blood cells e.g. cells of the innate immune system are largely unaffected. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.

CURRENT STATUS

OPTIMUM (Oral Ponesimod versus Teriflunomide In relapsing MUltiple sclerosis) is a Phase III multi-center, randomized, double-blind, parallel-group, active-controlled superiority study to compare the efficacy and safety of ponesimod to teriflunomide in patients with relapsing multiple sclerosis (RMS). The study aims to determine whether ponesimod is more efficacious than teriflunomide in reducing relapses. The study is expected to enroll approximately 1’100 patients, randomized in 2 groups in a 1:1 ratio to receive ponesimod 20 mg/day or teriflunomide 14 mg/day, and is expected to last a little over 3 years. An additional study to further characterize the utility and differentiation of ponesimod in multiple sclerosis is being discussed with Health Authorities.

Ponesimod is also evaluated in a Phase II open-label, single-arm, intra-subject dose-escalation study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ponesimod in patients suffering from moderate or severe chronic graft versus host disease (GvHD)inadequately responding to first- or second-line therapy. The study will also investigate the clinical response to ponesimod treatment in these patients. Approximately 30 patients will be enrolled to receive ponesimod in escalating doses of 5, 10, and 20 mg/day over the course of 24 weeks. The study is being conducted at approximately 10 sites in the US and is expected to last approximately 18 months.

AVAILABLE CLINICAL DATA

The decision to move into Phase III development was based on the Phase IIb dose-finding study with ponesimod in patients with relapsing-remitting multiple sclerosis. A total of 464 patients were randomized into this study and the efficacy, safety and tolerability of three ponesimod doses (10, 20, and 40 mg/day) versus placebo, administered once daily for 24 weeks.

The primary endpoint of this study was defined as the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans at weeks 12, 16, 20, and 24 after study drug initiation. A key secondary endpoint of this study was the annualized relapse rate over 24 weeks of treatment. Patients who completed 24 weeks of treatment were offered the opportunity to enter into an extension study. This ongoing trial is investigating the long-term safety, tolerability, and efficacy of 10 and 20 mg/day of ponesimod in patients with relapsing-remitting multiple sclerosis, in a double-blind fashion. The study continues to provide extensive safety and efficacy information for ponesimod in this indication, with some patients treated for more than 6 years.

The safety database from all studies with ponesimod now comprises more than 1,300 patients and healthy volunteers.

MILESTONES

2015 – Phase III program in multiple sclerosis initiated
2011 – Phase IIb dose-finding study in multiple sclerosis successfully completed
2006 – Entry-into-man
2004 – Preclinical development initiated

KEY SCIENTIFIC LITERATURE

Olsson T et al. J Neurol Neurosurg Psychiatr. 2014 Nov;85(11):1198-208. doi: 10.1136/jnnp-2013-307282. Epub 2014 Mar 21

Freedman M.S, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 420 (P923).

Fernández Ó, et al. Multiple Sclerosis Journal, 2012; 18 (4 suppl): 417 (P919).

Piali L, Froidevaux S, Hess P, et al. J Pharmacol Exp Ther 337(2):547-56, 2011

Bolli MH, Abele S, Binkert C, et al. J Med Chem. 53(10):4198-211, 2010

Kappos L et al. N Engl J Med. 362(5):387-401, 2010

Ponesimod
Ponesimod.svg
Ponesimod ball-and-stick model.png
Systematic (IUPAC) name
(2Z,5Z)-5-{3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one
Clinical data
Routes of
administration		 Oral
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Metabolism 2 main metabolites
Biological half-life 31–34 hrs[1]
Excretion Feces (57–80%, 26% unchanged), urine (10–18%)[2]
Identifiers
CAS Number 854107-55-4
ATC code none
PubChem CID 11363176
ChemSpider 9538103
ChEMBL CHEMBL1096146
Synonyms ACT-128800
Chemical data
Formula C23H25ClN2O4S
Molar mass 460.974 g/mol

////Ponesimod, Phase III , A sphingosine-1-phosphate receptor 1, S1P1 agonist, multiple sclerosis.  ACT-128800; RG-3477; R-3477, autoimmune disease, lymphocyte migration, multiple sclerosis, psoriasis, transplantation

CCC/N=C\1/N(C(=O)/C(=C/C2=CC(=C(C=C2)OC[C@@H](CO)O)Cl)/S1)C3=CC=CC=C3C

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