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(3S)-3-[(2-amino-5-methoxypyrimidin-4-yl)amino]heptan-1-ol for the treatment of viral infections

September 18, 2016 10:32 am / Leave a comment

(3S)-3-[(2-amino-5-methoxypyrimidin-4-yl)amino]heptan-1-ol

JNJ ?

cas 1402802-45-2

WO 2012136834, WO 2014053595

for the treatment of viral infections

Molecular Formula:	C₁₂H₂₂N₄O₂
Molecular Weight:	254.32868 g/mol

Inventors	Gowan David Mc, Pierre Jean-Marie Bernard Raboisson, Werner Embrechts, Tim Hugo Maria Jonckers, Stefaan Julien Last, Serge Maria Aloysius Pieters, Jaromir Vlach,
Applicant	Janssen R&D Ireland

(3S)-3-[(2-amino-5-methoxypyrimidin-4-yl)amino]heptan-1-ol

Mark Hicken, Managing Director UK & Ireland, Janssen Ltd; Maggie Throup MP, Health Select Committee; Richard Mason, Head of Innovation, Johnson and Johnson; Dr Mark Lloyd Davies, Senior Director Government Affairs and Policy UK and Ireland, Johnson & Johnson

To the use of pyrimidine derivatives in the treatment of viral infections, immune or inflammatory disorders, whereby the modulation, or agonism, of toll-like-receptors (TLRs) is involved. Toll-Like Receptors are primary transmembrane proteins characterized by an extracellular leucine rich domain and a cytoplasmic extension that contains a conserved region. The innate immune system can recognize pathogen-associated molecular patterns via these TLRs expressed on the cell surface of certain types of immune cells. Recognition of foreign pathogens activates the production of cytokines and upregulation of co-stimulatory molecules on phagocytes. This leads to the modulation of T cell behaviour.

It has been estimated that most mammalian species have between ten and fifteen types of Toll-like receptors. Thirteen TLRs (named TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which are represented in humans. Other mammals may express TLRs which are not found in humans. Other non-mammalian species may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the process of using experimental animals as models of human innate immunity.

For detailed reviews on toll-like receptors see the following journal articles. Hoffmann, J. A., Nature, 426, p 33-38, 2003; Akira, S., Takeda, K., and Kaisho, T., Annual Rev. Immunology, 21, p 335-376, 2003; Ulevitch, R. J., Nature Reviews: Immunology, 4, p 512-520, 2004.

Compounds indicating activity on Toll-Like receptors have been previously described such as purine derivatives in WO 2006/117670, adenine derivatives in WO 98/01448 and WO 99/28321, and pyrimidines in WO 2009/067081. However, there exists a strong need for novel Toll-Like receptor modulators having preferred selectivity, higher potency, higher metabolic stability, and an improved safety profile compared to the compounds of the prior art.

In the treatment of certain viral infections, regular injections of interferon (IFNα) can be administered, as is the case for hepatitis C virus (HCV), (Fried et. al. Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82). Orally available small molecule IFN inducers offer the potential advantages of reduced immunogenicity and convenience of administration. Thus, novel IFN inducers are potentially effective new class of drugs for treating virus infections. For an example in the literature of a small molecule IFN inducer having antiviral effect see De Clercq, E.; Descamps, J.; De Somer, P. Science 1978, 200, 563-565.

IFNα is also given in combination with other drugs in the treatment of certain types of cancer (Eur. J. Cancer 46, 2849-57, and Cancer Res. 1992, 52, 1056). TLR 7/8 agonists are also of interest as vaccine adjuvants because of their ability to induce pronounced Th1 response (Hum. Vaccines 2010, 6, 1-14; Hum. Vaccines 2009, 5, 381-394).

SYNTHESIS

50d

patent

WO 2014053595

https://www.google.com/patents/WO2014053595A1?cl=en

Experimental Section.

Into a 50 ml_ vial equipped with a magnetic stir bar was placed 2,4-dichloro-5- methoxypyrimidine (2.0 g, 1 1.7 mmol), and acetonitrile (20 ml_), diisopropylethylamine (3.02 g, 23.4 mmol) and (S)-3-aminoheptanol (4.59 g, 35.1 mmol). The reaction mixture was allowed to stir 15 hours at room temperature. The solvents were removed under reduced pressure. The crude was purified via silica gel column chromatography using a dichloromethane to 10% methanol in dichloromethane gradient. The best fractions were pooled and the solvents were removed under reduced pressure to afford a white solid, B.

B C

To a thick wall glass vial equipped with a magnetic stir bar was added B (1 g, 3.66 mmol), NH₃ (10 ml_, aq.), ammonium bicarbonate (3.34 g, 42.3 mmol) and copper(l) oxide (121 mg, 0.85 mmol). The vial was sealed and placed into an oil bath and heated to 150°C for 15 hours. The reaction mixture was extracted with dichloro- methane (3 x 25 ml_), the organic layers were pooled and dried over magnesium sulfate. The solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure. Crude C was purified via HPLC.

c 1

C (463 mg, 1.82 mmol) was dissolved in THF (13 ml_) and cooled to -78°C. NaH (145 mg, 3.64 mmol, a 60% dispersion in mineral oil) was added in one portion and stirred at -78°C for 30 minutes. Isobutyryl chloride (389 μΙ_, 3.64 mmol) was added dropwise at -78°C and stirred for 10 minutes. The cooling bath was removed and the mixture was allowed to reach room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water and concentrated in vacuo. The residue was purified by HPLC (RP Vydac Denali C18 10 μηι, 200 g, 5 cm, mobile phase 0.25% NH4HCO₃ solution in water, acetonitrile), the desired fractions were collected, and the solvents were removed under reduced pressure to afford the pure product.

LC-MS m/z = 395 (M+H), Retention time 1.1 minutes, LC method A.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.83 (t, J=6.90 Hz, 3 H) 0.98 – 1.07 (m, 12 H) 1.16 – 1.35 (m, 4 H) 1.44 – 1.62 (m, 2 H) 1.84 (q, J=6.78 Hz, 2 H) 2.45 (spt, J=7.00 Hz, 1 H) 2.96 (br. s., 1 H) 3.80 (s, 3 H) 3.92 – 4.07 (m, 2 H) 4.18 – 4.31 (m, 1 H) 6.69 (d, J=9.03 Hz, 1 H) 7.60 (s, 1 H) 9.49 (s, 1 H).

Synthetic scheme for the preparation of A

Preparati

valeraldehyde A2

To a solution of valeraldehyde (43 g, 500 mmol) in THF (1 L) was added A1 (200 g, 532 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvents were evaporated and the residue was diluted in petroleum ether and filtered. The solvents of the filtrate were removed under reduced pressure and the residue was purified by silica chromatography using a petroleum ether to 3% ethyl acetate in petroleum ether gradient to give A2 (90 g) as a colorless oil.

¹H NMR (400 MHz, CDCI₃): δ ppm 6.81 -6.77 (m, 1 H), 5.68-5.64 (td, J=1.2Hz, 15.6 Hz, 1 H), 2.11-2.09 (m, 2H), 1.41 (s, 9H), 1.38-1.26 (m, 4H), 0.85-0.81 (t, J=7.2Hz, 3H).

/7-butyl lithium (290 mL, 725 mmol) was added to a stirred solution of A3 (165 g, 781 mmol) in THF (800 mL) at -78°C. The reaction mixture was stirred for 30 minutes then A2 (90 g, 488.4 mmol) in THF (400 mL) was added and the reaction was stirred for 2 hours at -78°C. The mixture was quenched with sat., aq. NH₄CI solution and warmed to room temperature. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by column chromatography eluting with 5% ethyl acetate in petroleum ether to afford a colorless oil, A4 (132 g).

¹H NMR (400 MHz, CDCI₃): δ ppm 7.36-7.16 (m, 10H), 3.75-3.70 (m, 2H), 3.43-3.39 (d, J=15.2Hz, 1 H), 3.33-3.15 (m, 1 H), 1.86-1.80 (m, 2H), 1.47-1.37 (m, 2H), 1.32 (s, 9H), 1.26-1.17 (m, 7H), 0.83-0.79 (t, J=7.2Hz, 3H).

Preparatio

A4 (130 g, 328 mmol) was dissolved in THF (1.5 L) and LAH (20 g, 526 mmol) was added at 0°C in small portions. The resulting mixture was stirred at the same temperature for 2 hours and then allowed to warm to room temperature. The mixture was quenched with a sat. aq. NH₄CI solution. The product was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. The combined organic layers were dried over sodium sulfate, the solids were removed via filtration and concentrated to afford crude A5 (100 g), which was used in the next step without further purification.

¹H NMR (400 MHz, CDCI₃): δ ppm 7.33-7.14 (m, 10H), 3.91 -3.86 (m, 1 H), 3.80-3.77 (d, J=13.6Hz, 1 H), 3.63-3.60 (d, J=13.6Hz, 1 H), 3.43-3.42 (m, 1 H), 3.15-3.10 (m, 1 H), 2.70-2.63 (m, 2H), 1.65-1.28 (m, 10H), 0.89-0.81 (m, 3H).

Preparation of A

A5 A

A solution of A5 (38 g, 116.75 mmol) and 10% Pd/C in methanol (200 ml_) was hydrogenated under 50 PSI hydrogen at 50°C for 24 hours. The reaction mixture was filtered and the solvent was evaporated to give A.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.04 (s, 3H), 3.60-3.49 (m, 2H), 3.16-3.15 (m, 1 H), 1.71-1.67 (m, 2H), 1.60-1.55 (m, 2H), 1.33-1.26 (m, 4H), 0.90-0.87 (t, J=6.8Hz, 3H).

Analytical Method.

Compounds 1-8 in the table below were characterized by LC-MS according to the following LC-MS method.

Reverse phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μηι, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (10 mM ammonium acetate in H₂0/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.7 minutes. An injection volume of 0.75 μΙ_ was used. Cone voltage was 30 V for positive ionization mode and 30 V for negative ionization mode.

Paper

Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure–activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.

Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus

David McGowan ^*^†, Florence Herschke ^*^†, Frederik Pauwels^†, Bart Stoops^†, Stefaan Last^†, Serge Pieters^†, Annick Scholliers^†, Tine Thoné^†, Bertrand Van Schoubroeck^†, Dorien De Pooter^†, Wendy Mostmans^†, Mourad Daoubi Khamlichi^‡, Werner Embrechts^†, Deborah Dhuyvetter^†, Ilham Smyej^†, Eric Arnoult^†, Samuël Demin^†, Herman Borghys^†, Gregory Fanning^†, Jaromir Vlach^†, and Pierre Raboisson^†

^†Janssen Infectious Diseases Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium

^‡Villapharma Research S.L., Parque Tecnológico de Fuente Álamo. Ctra. El Estrecho-Lobosillo, Km. 2.5, Av. Azul 30320 Fuente Álamo de Murcia, Murcia, Spain

J. Med. Chem., 2016, 59 (17), pp 7936–7949

DOI: 10.1021/acs.jmedchem.6b00747, http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.6b00747

*For D.M.: phone, +32 6414 1019; E-mail, dmcgowan@its.jnj.com., *For F.H.: phone, +32 6414 1644; E-mail, fherschk@its.jnj.com.

(S)-3-((2-Amino-5-methoxypyrimidin-4-yl)amino)heptan-1-ol (50d)

¹H NMR (360 MHz, DMSO-d₆) δ 7.34 (s, 1H), 6.16 (d, J = 9.15 Hz, 1H), 5.48 (s, 2H), 4.42 (t, J = 5.12 Hz, 1H), 4.04–4.20 (m, 1H), 3.66 (s, 3H), 3.36–3.44 (m, 2H), 1.37–1.73 (m, 4H), 1.11–1.35 (m, 4H), 0.84 (t, J = 6.95 Hz, 3H).

¹³C NMR (101 MHz, DMSO-d₆) δ 158.0, 154.6, 135.5, 133.2, 58.0, 56.7, 46.1, 37.5, 34.0, 27.9, 22.1, 14.0.

ESI-HRMS (TOF) m/z: 255.1816 [M + H]⁺ (calcd for C₁₂H₂₂N₄O₂: 254.1743).

[α]_D²⁰ + 25.2 (c 0.81, DMF).

PATENT

http://www.google.com.na/patents/US20140045849

David McGowan, Pierr Jeane-Marie Bernar Raboisson, Werner Embrechts, Tim Hugo Maria Jonckers, Stefaan Julien Last, Serge Maria Aloysius Pieters, Jaromir Vlach,

Preparation of Compounds.

Compounds of formula (I), where R₁is hydrogen atom are prepared according to scheme 1

Compounds of formula (I), when R₁is alkyl, cycloalkyl, trifluoromethyl, or alkoxy and where R₂is aromatic or aliphatic, can be prepared according scheme 4. This reaction scheme begins with a crossed-Claisen reaction where an acyl chloride reacts with ester intermediate A (shown in scheme 1) to form intermediates (G) as in scheme 3. From intermediate G, the reaction scheme follows the same pathway to the products as in scheme 3. This is a general scheme using methods known to a skilled person, see for instance The Journal of American Chemical Society volume 127, page 2854 (2005).

Synthetic Scheme for the Preparation of AA-9

A solution of AA-6 (38 g, 116.75 mmol) and 10% Pd/C in methanol (200 mL) was hydrogenated under 50 PSI hydrogen at 50° C. for 24 hours. The reaction mixture was filtered and the solvent was evaporated to give crude product AA-7 (17 g).

The crude product was dissolved in dichloromethane (200 mL), triethylamine (26.17 g, 259.1 mmol) and di-tert-butyl dicarbonate (84.7 g, 194.4 mmol) was added at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in petroleum ether to give AA-8 (13 g) as colorless oil.

¹H NMR (400 MHz, CDCl₃): δ ppm 4.08-4.03 (br, 1H), 3.68 (m, 1H), 3.58-3.55 (m, 2H), 3.20-2.90 (br, 1H), 1.80-1.73 (m, 1H), 1.42-1.17 (m, 15H), 0.85-0.82 (t, J=6.8 Hz, 3H).

AA-8 (42 g, 0.182 mol) was dissolved in dioxane (200 mL) and dioxane/HCl (4M, 200 mL) was added at 0° C. The resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated to afford the crude product. A dichloromethane/petroleum ether mixture (50 mL, 1:1, v/v) was added to the crude product, and the supernatant was decanted. This procedure was repeated two times to obtain an oil, AA-9 (26.6 g).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.04 (s, 3H), 3.60-3.49 (m, 2H), 3.16-3.15 (m, 1H), 1.71-1.67 (m, 2H), 1.60-1.55 (m, 2H), 1.33-1.26 (m, 4H), 0.90-0.87 (t, J=6.8 Hz, 3H)

Procedure for Preparation of Intermediate C-1.Reaction Scheme:

A suspension of intermediate B-1 (160 g, 0.74 mol) in POCl₃(900 mL) was heated to 100° C. under N₂with stirring for 5 hours. The reaction mixture was cooled to room temperature. The excess POCl₃was removed under reduced pressure, the oil residue was poured into cold, sat. aq. NaHCO₃(2 L) that was stirred for 30 minutes. The mixture was extracted with ethyl acetate (3×1.5 L). The combined organic layers were separated and washed with brine (1 L), dried over sodium sulfate, the solids were removed via filtration, and the solvents of the filtrate were concentrated to afford intermediate C-1 (70 g) as a yellow solid. The product was used in the next step without further purification.

Patent ID	Date	Patent Title
US2015274676	2015-10-01	ACYLAMINOPYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS AND FURTHER DISEASES
US2014045849	2014-02-13	PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS

WO2006053109A1 *	Nov 10, 2005	May 18, 2006	Synta Pharmaceuticals Corp.	Heteroaryl compounds
WO2012136834A1 *	Apr 10, 2012	Oct 11, 2012	Janssen R&D Ireland	Pyrimidine derivatives for the treatment of viral infections
US5434157 *	Jan 21, 1993	Jul 18, 1995	The Upjohn Company	6-aryl pyrimidine compounds and method for treating viral infections and inducing interferon production

Reference
1	*	ANGELICA M BELLO ET AL: “De Novo Design of Nonpeptidic Compounds Targeting the Interactions between Interferon-a and its Cognate Cell Surface Receptor“, JOURNAL OF MEDICINAL CHEMISTRY,, vol. 51, no. 9, 1 January 2008 (2008-01-01), pages 2734 – 2723, XP008157384, DOI: 10.1021/JM701182Y
2		DE CLERCQ, E.; DESCAMPS, J.; DE SOMER, P., SCIENCE, vol. 200, 1978, pages 563 – 565
3		FRIED: “Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection“, N ENGL J MED, vol. 347, 2002, pages 975 – 82

/////////////// treatment of viral infections, Pyrimidine Toll-like Receptor 7, Toll-like Receptor 8 Dual Agonists, Treat Hepatitis B Virus, PRECLINICAL, 1402802-45-2, JNJ ?

n1c(nc(c(c1)OC)N[C@@H](CCCC)CCO)N

ORM 10921

September 16, 2016 11:08 am / Leave a comment

ORM 10921

UNII-D26C95A960; D26C95A960; ORM-12741; ORM12741; ORM 12741; ORM-10921;

(1S,12bS)-1-(Methoxymethyl)-1-methyl-2,3,4,6,7,12b-hexahydro-1H-[1]benzofuro[2,3-a]quinolizine

(1S,12bS)-1-(methoxymethyl)-1-methyl-2,3,4,6,7,12b-hexahydro-[1]benzofuro[2,3-a]quinolizine

285.38, C₁₈ H₂₃ N O₂

2H-Benzofuro[2,3-a]quinolizine, 1,3,4,6,7,12b-hexahydro-1-(methoxymethyl)-1-methyl-, (1S,12bS)-

cas 610782-82-6

Belle David Din, Reija Jokela, Arto Tolvanen,Antti Haapalinna, Arto Karjalainen, Jukka Sallinen, Jari Ratilainen
Applicant	Orion Corporation

David Din Belle

Senior research scientist at Orion Corporation

https://fi.linkedin.com/in/david-din-belle-a2594115

Jari Ratilainen

https://fi.linkedin.com/in/jari-ratilainen-6a566218

Image result for Reija Jokela

Reija Jokela

https://fi.linkedin.com/in/reija-jokela-06499a1a

The basic drug substance candidate ORM10921 (MW = 285.38),

IUPAC name [1R*,12bR*)-(−)-1,3,4,6,7,12b-hexahydro-1-methoxymethyl-1-methyl-2H-benzofuro [2,3-a]quinolizine],

and its hydrochloric salt were synthesized by Orion Pharma, Finland.

The absolute configuration was assigned by optical rotation and later by single-crystal X-ray diffraction (see Supporting Information). The optical purity of the material was >97%.

Originator Juvantia Pharma (CEASED); Orion
Class Neuropsychotherapeutics
Mechanism of Action Alpha 2c adrenergic receptor antagonists

Highest Development Phases

Discontinued Major depressive disorder; Schizophrenia

Most Recent Events

10 May 2006 Discontinued – Phase-I for Schizophrenia in Finland (unspecified route)
10 May 2006 Discontinued – Preclinical for Depression in Finland (unspecified route)
15 Nov 2002 Preclinical trials in Schizophrenia in Finland (unspecified route)

Figure 1: Chemical structure of the study compound. Molecular Formula: C18H23NO2 · HCl · ½ H2O; Molecular Weights: 285.39 (free base), 321.85 (hydrochloride) 330.86 (hydrochloride hemihydrate). ORM-10921 · HCl is a single stereoisomer with the (1R*,12bR*) configuration.

The alpha adrenergic receptors can be divided on a pharmacological basis into alphal- and alpha2-adrenoceptors, which can both be further divided into subtypes. Three genetically encoded subtypes, namely alpha2A-, alpha2B- and alpha2C-adrenoceptors, have been discovered in human. Accordingly, alpha2- adrenoceptors in humans have been subdivided into three pharmacological subtypes known as alpha2A-, alpha2B- and alpha2C-adrenoceptors. A fourth, pharmacologically defined subtype, alpha2D, is known in rodents and in some other mammals, and it corresponds to the genetically defined alpha2A-adrenoceptors.

The alpha2-adrenoceptor subtypes have distinct tissue distributions and functional roles. For instance, while alpha2A-adrenoceptors are widely expressed in various tissues, alpha2C-adrenoceptors are concentrated in the CNS, and they appear to play a role in the modulation of specific CNS-mediated behavioural and physiological responses. Compounds that are non-specific to any of the above-mentioned alpha2 subtypes, and compounds that are specific to certain alpha2 subtypes, are already known. For example, atipamezole is a non-specific alpha2 antagonist. Atipamezole has been described in, for example, EP-A-183 492 (cf. p.13, compound XV) and Haapalinna, A. et al., Naunyn-Schmiedeberg’s Arch. Pharmacol. 356 (1997) 570-582. U.S. Patent No. 5,902,807 describes compounds that are selective antagonists for the alpha2C subtype and may be used in the treatment of mental illness, e.g. mental disturbance induced by stress. Such compounds include, for example, MK-912 and BAM- 1303. Furthermore, WO-A-99 28300 discloses substituted imidazole derivatives having agonist-like activity for alpha2B- or 2B/2C-adrenoceptors. hi addition, WO 01/64645 relates to derivatives of quinoline useful as alpha2 antagonists, as well as to selective alpha2C antagonist agents. The disclosures of all documents cited above in this paragraph are incorporated by reference herein.

Several arylquinolizine derivatives and related compounds have been described in the literature, some of which possess valuable pharmaceutical effects. For example, U.S. Patents No. 4,806,545 and 4,044,012 describe 1,1-disubstituted indolo[2,3-«]quinolizidines useful as vasodilators and antihypoxic agents. Further, substituted arylquinolizine derivatives, described for example in U.S. Patent No. 4,686,226 possessing alpha2-adrenoceptor antagonistic activity are useful for example as antidepressant, antihypertensive, or antidiabetic agents or platelet aggregation inhibitors. In addition, U.S. Patent No. 3,492,303 relates to indolo[2,3- α]quinolizidines useful as central nervous system depressants.

PATENT

WO 2003082866

https://www.google.com/patents/WO2003082866A1?cl=en

///////////

CC1(CCCN2C1C3=C(CC2)C4=CC=CC=C4O3)COC

How to document a Product Transfer? Example templates!

September 15, 2016 12:57 pm / 1 Comment on How to document a Product Transfer? Example templates!

DRUG REGULATORY AFFAIRS INTERNATIONAL

All participants of the GMP training course “Product Transfer” will receive a special version of the Guideline Manager CD including documents and templates useable for site change projects.

Click

http://www.gmp-compliance.org/eca_mitt_05359_15221,Z-PEM_n.html

According to the European GMP-Rules, written procedures for tranfser activities and their documentation are required. For example, a Transfer SOP, a transfer plan and a report are now mandatory and will be checked during inspections.

As participant of the GMP education course “Product Transfer” in Berlin, from 25-27 October 2016 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.

Regulatory Guidance Documents like the WHO guideline on transfer of technology in pharmaceutical manufacturing and the EU/US…

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Analytical Lifecycle: USP “Statistical Tools”, Analytical Target Profile and Analytical Control Strategy

September 15, 2016 12:57 pm / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Image result for statistical tools Analytical Lifecycle: USP <1210> “Statistical Tools”, Analytical Target Profile and Analytical Control Strategy

The United States Pharmacopeia (USP) is currently undertaking further steps towards a comprehensive analytical lifecycle approach by publishing a draft of a new General Chapter <1210> Statistical Tools for Procedure Validation and two Stimuli Articles regarding Analytical Target Profile and AnalyticalControl Strategy in Pharmacopeial Forum. Read more about the life cycle concept for analytical procedures.

http://www.gmp-compliance.org/enews_05565_Analytical-Lifecycle–USP–1210–%22Statistical-Tools%22–Analytical-Target-Profile-and-Analytical-Control-Strategy_15438,15608,Z-PDM_n.html

Following the recently announced elaboration of a new general chapter <1220> “The Analytical Procedure Lifecycle” the United States pharmacopeia (USP) is now proceeding in its approach for a comprehensive analytical lifecycle concept. A further step towards this approach is the draft of a new USP General Chapter <1210> Statistical Tools for Procedure Validation which has been published in Pharmacopeial Forum (PF) 42(5) in September 2016. Comment deadline is November 30, 2016.

Additionally, two Stimuli Articles regarding “Analytical Control Strategy” and “Analytical…

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Ibipinabant Revisited

September 15, 2016 6:43 am / Leave a comment

Ibipinabant

cas 464213-10-3; UNII-O5CSC6WH1T; BMS-646256; SLV-319;

Molecular Formula:	C₂₃H₂₀Cl₂N₄O₂S
Molecular Weight:	487.4015 g/mol

(4S)-5-(4-chlorophenyl)-N-(4-chlorophenyl)sulfonyl-N’-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide

1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N’-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N-methyl-4-phenyl-, (4S)-

(4S)-3-(4-Chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N’-methyl-4-phenyl-1H-pyrazole-1-carboximidamide

1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N‘-methyl-4-phenyl-, (4S)-

(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine

4S)-(−)-3-(4-Chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

It was originally developed by Solvay, which was acquired by Abbott in 2010.

SLV 319, UNII:O5CSC6WH1T, (S)-SLV 319, BMS 646256, JD 5001

Originator Solvay
Class Antipsychotics; Imides; Obesity therapies; Pyrazoles; Small molecules; Sulfonamides
Mechanism of ActionCannabinoid receptor CB1 antagonists

Ibipinabant, also known as BMS-646256, JD-5001 and SLV-319, is a potent and highly selective CB1 antagonist. It has potent anorectic effects in animals, and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists

Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB₁ antagonist.^[1] It has potent anorectic effects in animals,^[2] and was researched for the treatment of obesity, although CB₁ antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB₁ antagonists.^[3]^[4]^[5]

Image for figure Chart 1

Inventors	Josephus H.M. Lange, Cornelis G Kruse,Jacobus Tipker, Jan Hoogendoorn
Applicant	Solvay Pharmaceuticals B.V.

PATENT

WO 2002076949

https://www.google.com/patents/WO2002076949A1?cl=en

Example IV

(-)-(4S)-N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine

(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (7.16 gram, 0.0147 mol)) ([α²⁵ _D] = -150°, c = 0.01 , MeOH) (melting point: 169-170 °C) was obtained via chiral chromatographic separation of racemic N-methyl-N’-((4-chlorophenyl)sulfonyl)-3- (4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (18 gram, 0.037 mol) using a Chiralpak AD, 20 μm chiral stationary phase. The mobile phase consisted of a mixture of hexane/ethanol (80/20 (v/v)) and 0.1 % ammonium hydroxide (25 % aqueous solution).

Example III N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine

Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 ml) in 1 ,4-dioxane (20 ml) is added 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100 °C After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCI and water, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to a volume of 20 ml. Methyl-tert-butyl ether (60 ml) is added and the resulting solution is concentrated to a volume of 20 ml. The formed crystals are collected by filtration and recrystallised from methyl-te/τ-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1-carboxamide (4J5 gram, 76 % yield) Melting point: 211-214 °C

Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamide (3.67 gram, 7J5 mmol) and phosphorus pentachloride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour. After thorough concentration in vacuo, the formed N-((4- chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1- carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo. The residue is crystallised from diethyl ether to give N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole-1 -carboxamidine (2.29 gram, 61 % yield). Melting point: 96-98 °C(dec).

PATENT

WO 2008074816

https://google.com/patents/WO2008074816A1?cl=en

PAPER

An expedient atom-efficient synthesis of the cannabinoid CB₁receptor inverse agonist ibipinabant

Abbott Healthcare Products B.V., Chemical Design & Synthesis Unit, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands

http://www.sciencedirect.com/science/article/pii/S0040403911000955

http://dx.doi.org/10.1016/j.tetlet.2011.01.068

Image for unlabelled figure

A novel synthetic route to the highly selective and orally active cannabinoid CB₁ receptor inverse agonist ibipinabant is described which combines the use of inexpensive, commercially available reagents and mild reaction conditions with a high degree of atom-efficiency. The method is expected to enable the rapid synthesis of a variety of sulfonylguanidines.

PAPER

JD-5006 and JD-5037: Peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities

Jenrin Discovery, 2515 Lori Lane North, Wilmington, DE 19810, USA

http://dx.doi.org/10.1016/j.bmcl.2012.08.004

http://www.sciencedirect.com/science/article/pii/S0960894X12009936

Scheme 1.

Reagents and conditions: (a) ArylSO₂NHCO₂CH₃, toluene, reflux, 3–6 h, 30–95%; (b) PCl₅, chlorobenzene, reflux, 2–4 h, 50–90%; (c) NH₂Me.HCl, Et₃N, CH₂Cl₂, ice-bath to rt, 16–20 h, 30–70%; (d) X = CO₂Et/X′ = CO₂H: LiOH, H₂O/THF(1:3), 50%; X′ = CO₂H/X′ = CONH₂, (1) IBCF, NMM, CH₂Cl₂, (2) NH₃/THF, 60%; X′ = CO₂H/X′ = CONHOH, (1) IBCF, NMM, CH₂Cl₂, (2) NH₂OH·HCl, NMM, CH₂Cl₂, 40%; X = OCH₂CO₂Et/OCH₂CO₂H: LiOH, H₂O/THF(1:3), rt, 50%; X′ = OCH₂CO₂H/X′ = OCH₂CONH₂: (1) IBCF, NMM, CH₂Cl₂, (2) NH₃/THF, 30%; X = NO₂:/X′ = NHCOCH₃: (1) Fe/HCl, EtOH, H₂O, reflux 1–2 h, 90%; (2) Ac₂O, pyr, CH₂Cl₂, rt, 8 h, 90%; X = NO₂:/X′ = NHCO₂Et: (1) Fe/HCl, EtOH, H₂O, reflux 1–2 h, 90%; (2) ClCO₂Et, pyr, CH₂Cl₂, 0 °C to rt, 8 h, 90%

Clip

http://molpharm.aspetjournals.org/content/87/2/197.full.pdf

Paper

Lange et al (2005) Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity. Bioorg.Med.Chem.Lett. 15 4794. PMID: 16140010.

http://www.sciencedirect.com/science/article/pii/S0960894X05010139

http://dx.doi.org/10.1016/j.bmcl.2005.07.054

Paper

Lange et al (2004) Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB₁ cannabinoid receptor antagonists. J.Med.Chem. 47 627. PMID:14736243.

A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB₁ and hCB₂) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitroCB₁ antagonistic activities and in general exhibited high CB₁ vs CB₂ receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C₄ position as 4S. Bioanalytical studies revealed a high CNS−plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB₁ receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH₂ moiety with a -NHCH₃ group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80

Abstract Image

4S)-(−)-3-(4-Chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (80) and (4R)-(+)-3-(4-chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (81). Chiral preparative HPLC separation of racemic 67 (18 g, 0.037 mol) using a Chiralpak AD, 20 μm chiral stationary phase yielded 80 (7.16 g, 0.0147 mol) and 81 (7.46 g, 0.0153 mol), respectively. The mobile phase consisted of a mixture of n-hexane/ethanol (80/20 (v/v)) and 0.1% NH₄OH (25% aqueous solution).

DESIRED

80: [ ] = −150°, c = 0.01, MeOH; mp 171−172 °C;

¹H NMR (400 MHz, DMSO-d₆) δ 2.94 (d, J = 4 Hz, 3H), 3.96 (dd, J = 11 and 4 Hz, 1H), 4.46 (t, J = 11 Hz, 1H), 5.05 (dd, J = 11 and 4 Hz, 1H), 7.20−7.35 (m, 5H), 7.45 (dt, J = 8 and 2 Hz, 2H), 7.53 (dt, J = 8 and 2 Hz, 2H), 7.77 (dt, J = 8 and 2 Hz, 2H), 7.82 (dt, J = 8 and 2 Hz, 2H), 8.19 (br d, J = 4 Hz, 1H);

HRMS (C₂₃H₂₁Cl₂N₄O₂S) [M+H]⁺: found m/z 487.0768, calcd 487.0762. Anal. (C₂₃H₂₀Cl₂N₄O₂S) C, H, N.

UNDESIRED

81: [ ] = + 150°, c = 0.01, MeOH; mp 171−172 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.94 (d, J = 4 Hz, 3H), 3.96 (dd, J = 11 and 4 Hz, 1H), 4.46 (t, J = 11 Hz, 1H), 5.05 (dd, J = 11 and 4 Hz, 1H), 7.20−7.35 (m, 5H), 7.45 (dt, J = 8 and 2 Hz, 2H), 7.53 (dt, J = 8 and 2 Hz, 2H), 7.77 (dt,J = 8 and 2 Hz, 2H), 7.82 (dt, J = 8 and 2 Hz, 2H), 8.19 (br d, J = 4 Hz, 1H); HRMS (C₂₃H₂₁Cl₂N₄O₂S) [M+H]⁺: found m/z 487.0749, calcd 487.0762. Anal. (C₂₃H₂₀Cl₂N₄O₂S) C, H, N.

Paper

Org. Process Res. Dev., 2012, 16 (4), pp 567–576

DOI: 10.1021/op2003024, http://pubs.acs.org/doi/full/10.1021/op2003024

Modeling-Based Approach Towards Quality by Design for the Ibipinabant API Step

This work presents a process modeling-based methodology towards quality by design that was applied throughout the development lifecycle of the ibipinabant API step. By combining mechanistic kinetic modeling with fundamental thermodynamics, the degradation of the API enantiomeric purity was described across a large multivariate process knowledge space. This knowledge space was then narrowed down to the process design space through risk assessment, target quality specifications, practical operating conditions for scale-up, and plant control capabilities. Subsequent analysis of process throughput and yield defined the target operating conditions and normal operating ranges for a specific pilot-plant implementation. Model predictions were verified via results obtained in the laboratory and at pilot-plant scale. Future efforts were focused on increasing fundamental process knowledge, improving model confidence, and using a risk-based approach to reevaluate the design space and selected operating conditions for the next scale-up campaign.

API process at the time of the first pilot-plant campaign

changed to

Process for the second pilot-plant implementation

Process parameter ranges and typical results from approximately 20 lab experiments conducted on the process shown in Scheme

Figure 3. Ishikawa diagram for the API step, highlighting factors that potentially affect the enantiomeric purity of the product. Factors shown in blue were accounted for in the sulfonylation reaction and distillative crystallization models. Factors shown in red were not included in the models

table 3. Process parameter ranges and number of parameter levels utilized for model-based prediction of sulfonylation reaction conversion and degradation of API enantiopurity during the distillative crystallization

process parameter	min. value	max. value	# of “levels”
sulfonylation reaction model
temp. (°C)	5	35	7
4-chlorobenzenesulfonyl chloride (equiv)	1.0	1.2	6
conc. (mL/g)	5	10	6
reaction time (h)	2	5	4
distillative crystallization model
pressure (mbar)	300	1013	6
residual 2(AP)	0.05	2.0	6
distillation time (h)	8	48	4
distillation end point (wt % EtOH)	90	98	3

REFERENCES

1: Schirris TJ, Ritschel T, Herma Renkema G, Willems PH, Smeitink JA, Russel FG. Mitochondrial ADP/ATP exchange inhibition: a novel off-target mechanism underlying ibipinabant-induced myotoxicity. Sci Rep. 2015 Sep 29;5:14533. doi: 10.1038/srep14533. PubMed PMID: 26416158; PubMed Central PMCID: PMC4586513.

2: Chorvat RJ, Berbaum J, Seriacki K, McElroy JF. JD-5006 and JD-5037: peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6173-80. doi: 10.1016/j.bmcl.2012.08.004. Epub 2012 Aug 20. PubMed PMID: 22959249.

3: Tomlinson L, Tirmenstein MA, Janovitz EB, Aranibar N, Ott KH, Kozlosky JC, Patrone LM, Achanzar WE, Augustine KA, Brannen KC, Carlson KE, Charlap JH, Dubrow KM, Kang L, Rosini LT, Panzica-Kelly JM, Flint OP, Moulin FJ, Megill JR, Zhang H, Bennett MJ, Horvath JJ. Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic-adipic aciduria in beagle dogs. Toxicol Sci. 2012 Oct;129(2):268-79. doi: 10.1093/toxsci/kfs217. Epub 2012 Jul 21. PubMed PMID: 22821849.

4: Dawes J, Allenspach C, Gamble JF, Greenwood R, Robbins P, Tobyn M. Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations. Pharm Dev Technol. 2013 Feb;18(1):246-56. doi: 10.3109/10837450.2012.705299. Epub 2012 Jul 20. PubMed PMID: 22813432.

5: Leane MM, Sinclair W, Qian F, Haddadin R, Brown A, Tobyn M, Dennis AB. Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant. Pharm Dev Technol. 2013 Mar-Apr;18(2):359-66. doi: 10.3109/10837450.2011.619544. Epub 2012 Jan 23. PubMed PMID: 22268601.

6: Rohrbach K, Thomas MA, Glick S, Fung EN, Wang V, Watson L, Gregory P, Antel J, Pelleymounter MA. Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight. Diabetes Obes Metab. 2012 Jun;14(6):555-64. doi: 10.1111/j.1463-1326.2012.01563.x. Epub 2012 Feb 24. PubMed PMID: 22268426.

7: Lynch CJ, Zhou Q, Shyng SL, Heal DJ, Cheetham SC, Dickinson K, Gregory P, Firnges M, Nordheim U, Goshorn S, Reiche D, Turski L, Antel J. Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels. Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E540-51. doi: 10.1152/ajpendo.00258.2011. Epub 2011 Dec 13. PubMed PMID: 22167524; PubMed Central PMCID: PMC3311290.

8: Gamble JF, Leane M, Olusanmi D, Tobyn M, Supuk E, Khoo J, Naderi M. Surface energy analysis as a tool to probe the surface energy characteristics of micronized materials–a comparison with inverse gas chromatography. Int J Pharm. 2012 Jan 17;422(1-2):238-44. doi: 10.1016/j.ijpharm.2011.11.002. Epub 2011 Nov 10. PubMed PMID: 22100516.

9: Sinclair W, Leane M, Clarke G, Dennis A, Tobyn M, Timmins P. Physical stability and recrystallization kinetics of amorphous ibipinabant drug product by fourier transform raman spectroscopy. J Pharm Sci. 2011 Nov;100(11):4687-99. doi: 10.1002/jps.22658. Epub 2011 Jun 16. PubMed PMID: 21681752.

10: Gamble JF, Tobyn M, Dennis AB, Shah T. Roller compaction: application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics. Pharm Dev Technol. 2010 Jun;15(3):223-9. doi: 10.3109/10837450903095342. PubMed PMID: 22716462.

11: Zhang H, Patrone L, Kozlosky J, Tomlinson L, Cosma G, Horvath J. Pooled sample strategy in conjunction with high-resolution liquid chromatography-mass spectrometry-based background subtraction to identify toxicological markers in dogs treated with ibipinabant. Anal Chem. 2010 May 1;82(9):3834-9. doi: 10.1021/ac100287a. PubMed PMID: 20387806.

12: Lange JH, van der Neut MA, den Hartog AP, Wals HC, Hoogendoorn J, van Stuivenberg HH, van Vliet BJ, Kruse CG. Synthesis, SAR and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles as potent cannabinoid CB(1) receptor antagonists. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1752-7. doi: 10.1016/j.bmcl.2010.01.049. Epub 2010 Jan 20. PubMed PMID: 20137935.

References

Lange, JH; Coolen, HK; Van Stuivenberg, HH; Dijksman, JA; Herremans, AH; Ronken, E; Keizer, HG; Tipker, K; et al. (2004). “Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists”. Journal of Medicinal Chemistry. 47 (3): 627–43. doi:10.1021/jm031019q. PMID 14736243.
Need, AB; Davis, RJ; Alexander-Chacko, JT; Eastwood, B; Chernet, E; Phebus, LA; Sindelar, DK; Nomikos, GG (2006). “The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats”.Psychopharmacology. 184 (1): 26–35. doi:10.1007/s00213-005-0234-x. PMID 16328376.
Lange, JH; Van Stuivenberg, HH; Veerman, W; Wals, HC; Stork, B; Coolen, HK; McCreary, AC; Adolfs, TJ; Kruse, CG (2005). “Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity”. Bioorganic & Medicinal Chemistry Letters. 15 (21): 4794–8. doi:10.1016/j.bmcl.2005.07.054. PMID 16140010.
Srivastava, BK; Joharapurkar, A; Raval, S; Patel, JZ; Soni, R; Raval, P; Gite, A; Goswami, A; et al. (2007). “Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: synthesis, biological evaluation, and molecular modeling in the homology model”. Journal of Medicinal Chemistry. 50 (24): 5951–66. doi:10.1021/jm061490u. PMID 17979261.
Srivastava, BK; Soni, R; Joharapurkar, A; Sairam, KV; Patel, JZ; Goswami, A; Shedage, SA; Kar, SS; et al. (2008). “Bioisosteric replacement of dihydropyrazole of 4S-(−)-3-(4-chlorophenyl)-N-methyl-N’-(4-chlorophenyl)-sulfonyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole”. Bioorganic & Medicinal Chemistry Letters. 18 (3): 963–8. doi:10.1016/j.bmcl.2007.12.036. PMID 18207393.

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Ibipinabant
Systematic (IUPAC) name

4S-(−)-3-(4-chlorophenyl)-N-methyl-N’-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine
Identifiers
CAS Number	464213-10-3
ATC code	none
PubChem	CID 9826744
ChemSpider	24765166
UNII	O5CSC6WH1T
KEGG	D09349
ChEMBL	CHEMBL158784
Chemical data
Formula	C₂₄H₂₂Cl₂N₄O₂S
Molar mass	501.427

///////// 464213-10-3, UNII-O5CSC6WH1T, BMS-646256, SLV-319, Ibipinabant, JD 5001, solvay, abbott

c2cc(Cl)ccc2C1=NN(C(NC)=NCS(=O)(=O)c3ccc(Cl)cc3)CC1c4ccccc4

IPI-549

September 14, 2016 2:55 pm / Leave a comment

IPI-549

CAS 1693758-51-8
MF : C30H24N8O2
Molecular Weight: 528.576

(S)-2-amino-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Company	Infinity Pharmaceuticals Inc.
Description	Small molecule inhibitor of phosphoinositide 3-kinase (PI3K) gamma
Molecular Target	Phosphoinositide 3-kinase (PI3K) gamma
Mechanism of Action	Phosphoinositide 3-kinase (PI3K) gamma inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase I
Standard Indication	Solid tumors
Indication Details	Treat solid tumors

Originator Intellikine
Developer Infinity Pharmaceuticals
ClassAntineoplastics; Small molecules
Mechanism of ActionPhosphatidylinositol 3 kinase delta inhibitors; Phosphatidylinositol 3 kinase gamma inhibitors

Phase I Solid tumours

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Most Recent Events

18 Apr 2016 Pharmacodynamics data from a preclinical study in Solid tumours presented at the 107^th Annual Meeting of the American Association for Cancer Research (AACR-2016)
01 Dec 2015 Phase-I clinical trials in Solid tumours (Monotherapy, Combination therapy, Late-stage disease, Second-line therapy or greater) in USA (PO)

IPI-549 is a potent and selective phosphoinositide-3-kinase (PI3Kγ) Inhibitor as an Immuno-Oncology Clinical Candidate (Kd = 0.29 nM). Bioactivity data of IPI-549: biochemcial IC50 (nM) for PI3K isoform: 3200 (α); 3500 (β); 16 (γ); and >8400 (δ) respectively. Cellar IC50 (nM) of IPI549 for PI3K isoform: 250 (α); 240 (β); 1.6 (γ); and 180 (δ) respectively. IPI-549 shows >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Image result for IPI-549

Patent

WO 2015051244

https://www.google.co.in/patents/WO2015051244A1?cl=en

Scheme 1

Scheme 2

Example 1

[00657] Compound 4 was prepared in 3 steps from compound A according to the following procedures:

Compound A was prepared according to Method A. It was coupled to 2-((tert-butoxycarbonyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid according to the following procedure: Compound A (27.4 mmol, 1.0 equiv), HOBt hydrate (1.2 equiv), 2-((tert-butoxycarbonyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (1.05 equiv) and

EDC (1.25 equiv) were added to a 200 mL round bottomed flask with a stir bar. N,N-Dimethylformamide (50 mL) was added and the suspension was stirred at RT for 2 min. Hunig’s base (4.0 equiv) was added and after which the suspension became homogeneous and was stirred for 22h resulting in the formation of a solid cake in the reaction flask. The solid mixture was added to water (600 mL) and stirred for 3h. The resulting cream colored solid was filtered and washed with water (2 x 100 mL) and dried. The solid was then dissolved in methylene chloride (40 mL) after which trifluoroacetic acid (10 equiv, 20 mL) was added and the reaction was stirred for 30 min at RT after which there is no more starting material by LC/MS analysis. The solution was then concentrated and coevaporated with a mixture of methylene choride/ethanol (1 : 1 v/v) and then dried under high vacuum overnight. The resulting solid was triturated with 60 mL of ethanol for lh and then collected via vacuum filtration. The beige solid was then neutralized with sodium carbonate solution (100 mL) and then transferred to a separatory funnel with methylene chloride (350 mL). The water layer was extracted with an additional 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to provide a pale yellow solid that was purified using flash silica gel chromatography (Combiflash, 24g column, gradient of 0-5% methanol/methylene chloride) to provide amide B. ESI-MS m/z: 459.4 [M+H]+.

[00658] Amide B was placed in a sealed tube (0.67 mmol, 1.0 equiv) followed by dichlorobis(acetonitrile)palladium (15 mol%), X-Phos (45 mol%), and cesium carbonate (3.0 equiv) Propionitrile (5 mL) was added and the mixture was bubbled with Ar for 1 min. 4-Ethynyl-l -methyl- lH-pyrazole (1.24 equiv) was added and the resulting orange mixture was sealed and stirred in an oil bath at 85 oC for 1.5h. The resulting brownish-black mixture was allowed to cool at which point there was no more SM by LC/MS analysis. The mixture was then filtered through a short plug of cotton using acetonitrile and methylene chloride. The combined filtrates were concentrated onto silica gel and purified using flash silica gel chromatography (Combiflash, 4g column, gradient of 0-5% methylene chloride/methanol). The resulting material was further purified by reverse phase HPLC (15-90%o acetonitrile with 0.1%o formic acid/water with 0.1%o formic water) to provide desired compound 4. ESI-MS m/z: 529.5 [M+H]+.

PAPER

WO 2015143012

https://www.google.com/patents/WO2015143012A1?cl=en

PAPER

IPI-549 NMR 1H

IPI-549 13C NMR

IPI-549 ASSAY

Compound 1 is coupled to 4-ethynyl-1-methyl-1H-pyrazole using the general procedure outlined above to provide compound 26 IPI-549, in 70% yield with >98% enantiomeric purity.

IPI-549

1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 6.8, 1.7 Hz, 1H), 8.55 (dd, J = 4.5, 1.7 Hz, 1H), 8.00 (d, J=6.8 Hz, 1H), 8.00 (s, 1H), 7.69 – 7.54 (m, 5H), 7.53 – 7.43 (m, 3H), 7.41 – 7.35 (m, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 6.74 (s, 1H), 6.42 (s, 2H), 4.56 (quin, J = 6.8 Hz, 1H).), 3.82 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H).

13C NMR (101 MHz, DMSO-d6) δ 162.73, 161.19, 160.93, 150.06, 147.51, 146.74, 141.05, 138.09, 137.81, 135.42, 133.66, 132.56, 131.90, 129.51, 129.24, 129.20, 129.17, 128.50, 126.16, 123.41, 123.31, 107.88, 102.44, 101.15, 90.40, 87.06, 85.94, 44.88, 38.62, 20.69.

ESI-HRMS: calcd for 529.2095 C30H25N8O2 (M+H)+ , found 529.2148.

[]D 22: +447.8o (c 1.007, DMSO)

COMPD1

compound 1 in 95% yield.

1H NMR (400 MHz, CDCl3) 8.41 (dd, J = 6.8, 1.7 Hz, 1H), 8.37 (dd, J = 4.4, 1.7 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.50-7.34 (m, 5H), 7.34-7.27 (m, 2H), 6.76 (dd, J = 7.1, 4.9 Hz, 1H), 6.57 (s, 1H), 5.54 (broad s, 2H), 4.79 (quin, J = 6.9 Hz, 1H), 1.36 (d, J = 6.5 Hz, 3H);

ESI-HRMS: calcd for C24H20ClN6O2 459.1331 (M+H)+ , found 459.1386. HPLC Purity: 96% AUC.

Abstract Image

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

Infinity Pharmaceuticals, Inc., 784 Memorial Drive, Cambridge, Massachusetts 02139, United States

ACS Med. Chem. Lett., 2016, 7 (9), pp 862–867

DOI: 10.1021/acsmedchemlett.6b00238

*E-mail: catherine.evans@infi.com., *E-mail: alfredo.castro@infi.com.

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00238

Image result for IPI-549

CLIP

Infinity Expands Pipeline with Addition of IPI-549, an Immuno-Oncology Development Candidate for the Treatment of Solid Tumors

– IPI-549, a Selective PI3K-Gamma Inhibitor, Targets the Immune-Suppressive Tumor Microenvironment –

– Preclinical Data for IPI-549 Presented at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference –

September 18, 2015 07:41 AM Eastern Daylight Time

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) today announced the expansion of its pipeline with the addition of IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), for the treatment of solid tumors. Preclinical data demonstrating the potential of IPI-549 to disrupt the immune-suppressive tumor microenvironment and enable a heightened anti-tumor immune response are being presented today at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival Meeting in New York City. IPI-549 was discovered at Infinity and is expected to enter Phase 1 clinical development in early 2016.

“Infinity is committed to developing first-in-class and best-in-class medicines, and the expansion of our pipeline with the addition of IPI-549 represents an important step toward fulfilling our vision of building a sustainable biopharmaceutical company that brings meaningful medicines to patients”

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“Infinity is committed to developing first-in-class and best-in-class medicines, and the expansion of our pipeline with the addition of IPI-549 represents an important step toward fulfilling our vision of building a sustainable biopharmaceutical company that brings meaningful medicines to patients,” stated Vito Palombella, Ph.D., Infinity’s chief scientific officer. “Infinity’s ability to internally develop a selective PI3K-gamma inhibitor provides us with a unique opportunity to explore the impact that PI3K-gamma inhibition has on disrupting the tumor microenvironment. We look forward to initiating the first clinical study of IPI-549 in patients with solid tumors.”

“I have had the pleasure of collaborating with Infinity’s discovery team and am excited to have worked with IPI-549 in my laboratory,” Jedd Wolchok, M.D., Ph.D., chief of Melanoma and Immunotherapeutics Service, Lloyd J. Old/Ludwig Chair in Clinical Investigation Department of Medicine and Ludwig Center, at Memorial Sloan Kettering Cancer Center and the principal investigator for the planned Phase 1 clinical study of IPI-549. “IPI-549 is a novel, small molecule immuno-oncology agent, and I am looking forward to leading the Phase 1 study for this program.”

IPI-549 inhibits immune suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

Preclinical Data for IPI-549 Presented at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference

Today at the AACR meeting in New York City Infinity researchers are presenting preclinical data for IPI-549 in a poster entitled, “The potent and selective phosphoinositide-3-kinase-gamma inhibitor, IPI-549, inhibits tumor growth in murine syngeneic solid tumor models through alterations in the immune suppressive microenvironment.”

In vitro data showed that IPI-549 blocks both the migration of murine myeloid cells and the differentiation of myeloid cells to the M2 phenotype, which is a type of myeloid cell known to promote cancer growth and suppress anti-tumor immune responses. In vivo data in murine solid tumor models demonstrated that IPI-549 treatment also decreased tumor-associated myeloid cells found in the immune suppressive microenvironment. Additionally, IPI-549 treatment increased the number of intratumoral CD8⁺T-cells, which are known to play a role in inhibiting tumor growth.

IPI-549 has demonstrated dose-dependent, single-agent, anti-tumor activity in multiple solid tumor models, including murine models of lung, colon and breast cancer. Additionally, mice treated with IPI-549 in combination with checkpoint inhibitors showed greater tumor growth inhibition than either treatment as a monotherapy. Preclinical in vivo data also demonstrated that T-cells are required for the anti-tumor activity of IPI-549, which is a hallmark of immunotherapy.

Further details about the IPI-549 development program will be provided at Infinity’s R&D Day on Tuesday, October 6, 2015. R&D Day will be held in New York City from 7:30 a.m. to 12:00 p.m. ET. The event will be webcast beginning at 8:00 a.m. ET and can be accessed in the Investors/Media section of Infinity’s website, www.infi.com. A replay of the event will also be available.

Infinity is also developing duvelisib, an investigational, oral, dual inhibitor of PI3K-delta and PI3K-gamma. The PI3K pathway is also known to play a critical role in regulating the growth and survival of certain types of blood cancers. The investigational agent is being evaluated in registration-focused studies, including DYNAMO^TM, a Phase 2 study in patients with refractory indolent non-Hodgkin lymphoma, DYNAMO+R, a Phase 3 study in patients with previously treated follicular lymphoma, and DUO^TM, a Phase 3 study in patients with relapsed/refractory chronic lymphocytic leukemia. Duvelisib is an investigational compound and its safety and efficacy have not been evaluated by the U.S. Food and Drug Administration or any other health authority.

About Infinity Pharmaceuticals, Inc.

Infinity is an innovative biopharmaceutical company dedicated to discovering, developing and delivering best-in-class medicines to people with difficult-to-treat diseases. Infinity combines proven scientific expertise with a passion for developing novel small molecule drugs that target emerging disease pathways. For more information on Infinity, please refer to the company’s website at www.infi.com.

Clip

IPI-549-01-A phase 1/1b first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors.

Subcategory:

Other

Category:

Developmental Therapeutics—Immunotherapy

Meeting:

2016 ASCO Annual Meeting

Session Type and Session Title:

Poster Session, Developmental Therapeutics—Immunotherapy

Abstract Number: TPS3111

Poster Board Number:

Board #425a

Citation:

J Clin Oncol 34, 2016 (suppl; abstr TPS3111)

Author(s):

Anthony W. Tolcher, David S. Hong, Ryan J. Sullivan, James Walter Mier, Geoffrey Shapiro, Joseph Pearlberg, Les H. Brail, Jahnavi Kharidia, Lixin Han, Claudio Dansky Ullmann, Howard Marvin Stern, Jedd D. Wolchok; START San Antonio, San Antonio, TX; Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, TX; Massachusetts General Hospital, Boston, MA; Department of Medicine, Dana-Farber/Harvard Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Infinity Pharmaceuticals, Inc., Cambridge, MA; Infinity Pharmaceuticals Inc., Cambridge, MA; Infinity Pharmaceuticals, Cambridge, MA; Memorial Sloan Kettering Cancer Center, New York, NY

Abstract Disclosures

Abstract:

Background: IPI-549 is a potential first-in-class potent and selective PI3K-γ inhibitor being developed as a novel orally administered immuno-oncology therapeutic in multiple cancer indications. Preclinical studies demonstrate a role for PI3K-γ in polarization of immune suppressive myeloid cells in the tumor microenvironment. Inhibition of PI3K-γ by IPI-549 enhanced antitumor immune responses and inhibited tumor growth in syngeneic solid tumor preclinical models. In addition, IPI-549 in combination with immune checkpoint inhibitors showed increased tumor growth inhibition compared to each single agent in multiple pre-clinical models. These data served as the scientific foundation for initiating a clinical trial testing IPI-549 as a potential immuno-oncology therapy. This first-in-human clinical study will evaluate the safety and tolerability, and determine the recommended Phase 2 dose (RP2D) of IPI-549 when administered as a monotherapy and in combination with pembrolizumab (NCT02637531) in solid tumors. Methods: This multi-part Phase 1/1b open-label trial will initiate with monotherapy dose escalation cohorts consisting of an accelerated dose escalation phase followed by a standard phase with a 3+3 design. Evaluation of the PK, PD, and safety data in these cohorts will lead to the determination of the maximum tolerated dose (MTD) and RP2D of IPI-549 monotherapy. Subsequently, combination dose escalation cohorts will be initiated in which the combination of IPI-549 and pembrolizumab will be evaluated. Expansion cohorts evaluating the safety, PK, PD, and preliminary clinical activity of IPI-549 as a monotherapy and in combination with pembrolizumab will occur following the dose escalation phase. All subjects in the trial will have advanced and/or metastatic carcinoma or melanoma, and will have failed to respond to standard therapies. Combination expansion cohorts will recruit subjects with non-small cell lung cancer or melanoma who must have received an anti-PD-1 or anti-PD-L1 antibody as their most recent treatment. This trial is currently enrolling patients in the US. Clinical trial information: NCT02637531

REFERENCES

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate
Catherine A. Evans, Tao Liu, André Lescarbeau, Somarajan J. Nair, Louis Grenier, Johan A. Pradeilles, Quentin Glenadel, Thomas Tibbitts, Ann M. Rowley, Jonathan P. DiNitto, Erin E. Brophy, Erin L. O’Hearn, Janid A. Ali, David G. Winkler, Stanley I. Goldstein, Patrick O’Hearn, Christian M. Martin, Jennifer G. Hoyt, John R. Soglia, Culver Cheung, Melissa M. Pink, Jennifer L. Proctor, Vito J. Palombella, Martin R. Tremblay, and Alfredo C. Castro
Publication Date (Web): July 22, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00238

Patent ID	Date	Patent Title
US2015290207	2015-10-15	HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015225410	2015-08-13	HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015111874	2015-04-23	HETEROCYCLIC COMPOUNDS AND USES THEREOF

///////immuno-oncology, IPI-549, isoform selectivity, neutrophil migration, phosphoinositide-3-kinase, PI3K-gamma inhibitor, IPI 549, IPI549. PRECLINICAL

O=C1N(C2=CC=CC=C2)C([C@@H](NC(C3=C(N=CC=C4)N4N=C3N)=O)C)=CC5=CC=CC(C#CC6=CN(C)N=C6)=C51

PF-04745637

September 13, 2016 6:29 am / Leave a comment

Graphical abstract: The discovery of a potent series of carboxamide TRPA1 antagonists

PF-04745637

cas 1917294-46-2

MW 509.00, MF C₂₇ H₃₂ Cl F₃ N₂ O₂

Cyclopentanecarboxamide, 1-(4-chlorophenyl)-N-[2-[4-hydroxy-4-(trifluoromethyl)-1-piperidinyl]-3-phenylpropyl]-

rac-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyDcyclopentanecarboxamide

PRODUCT PATENT WO-2016067143-A1

Applicants:	PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US)
Inventors:	SWAIN, Nigel Alan; (GB). PRYDE, David Cameron; (GB). RAWSON, David James; (GB). RYCKMANS, Thomas; (GB). SKERRATT, Sarah Elizabeth; (GB). AMATO, George Salvatore; (US). MARRON, Brian Edward; (US). REISTER, Steven Michael; (US).

TrpA1 is a member of the Transient Receptor Potential (Trp) family of ion channels. It was first described as being activated in response to noxious cold. It is activated by a number of exogenous chemical compounds and some endogenous inflammatory mediators. It has also been reported to be activated in response to mechanical stress.

There is substantial evidence for the involvement of TrpA1 in the physiology of pain, including neuropathic and inflammatory pain, and in pruritus (itch). For example, see:

Bautista, D.M. et al., “TRPA 1: A Gatekeeper for Inflammation” , Annu. Rev. Physiol.2013, 75, 181-200;

Bishnoi, M. & Premkumar, L.S., “Changes in TRP Channels Expression in Painful

Conditions”, Open Pain Journal 2013, 6(Suppl. 1), 10-22;Brederson, J.-D. et al., “Targeting TRP channels for pain relief, Eur. J. Pharmacol.2013, 716, 61-76;

Radresa, O. et al., “Roles of TRPAI in Pain Pathophysiology and Implications for the Development of a New Class of Analgesic Drugs”, Open Pain Journal 2013, 6(Suppl. 1), 137-153; and Toth, B.I. & Biro, T., “TRP Channels and Pruritus” , Open Pain Journal 2013, 6(Suppl.1), 62-80.

There is a continuing interest in finding new compounds that interact with TrpA1.

Nigel Swain

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016067143&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

E8 that is 1-(4-chlorophenyl)-/V-[2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3-phenylpropyl]-cyclopentanecarboxamide, or a pharmaceutically acceptable salt thereof. This compound is represented by formula (l^E).

Example 1

rac-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyDcyclopentanecarboxamide

Method 1

To a solution of rac-1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 2, 50 mg, 0.214 mmol) in DMF (1 mL) was added 1-(4-chlorophenyl)cyclopentanecarboxylic acid (37 mg, 0.165 mmol), DIPEA (0.035 mL, 0.198 mmol) and EDCI (38 mg, 0.198 mmol), followed by HOBt (30 mg, 0.198 mmol) and the reaction was stirred at room temperature for 18 hours. Water was added and the reaction stirred for a further 2 hours. DCM was added with further stirring for 1 hour followed by elution through a phase separation cartridge. The organic filtrate was concentrated in vacuo. The residue was dissolved in MeOH and treated with ethereal HCI with standing for 18 hours. The resulting suspension was filtered and triturated with EtOAc, heptanes and TBME to afford the title compound as the hydrochloride salt (69 mg, 82%).

¹H NMR (400MHz, DMSO-d₆): δ ppm 1.50-1.60 (m, 4H), 1.70-1.90 (m, 4H), 2.15-2.25 (m, 2H), 2.40-2.48 (m, 2H), 2.70-2.80 (m, 1 H), 3.05-3.25 (m, 6H), 3.47-3.62 (m, 2H), 6.38 (br s, 1 H), 7.20-7.40 (m, 9H), 7.80 (br m, 1 H).

MS m/z 509 [M+H]⁺

Example 1 may also be prepared according to the following method:

A mixture of 1-(4-chlorophenyl)cyclopentanecarboxylic acid (25.7 g, 114 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluoro phosphate (49.4 g, 130 mmol) and N,N-diisopropylethylamine (40 mL, 229 mmol) in DMF (475 mL) was stirred at room temperature for 15 minutes. To this mixture was added a solution of 1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 2, 31.4 g, 104 mmol) in DMF (200 mL). The reaction was stirred at room temperature for 18 hours before partitioning between EtOAc (600 mL) and saturated aqueous sodium hydrogen carbonatesolution (600 mL). The aqueous layer was washed with EtOAc (2 x 600 mL). The combined organic layers were washed with water (600 mL), brine (600 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0: 1 to 1 : 1 EtOAc: heptanes to afford the title compound (44 g, 76%).

¹H NMR (400MHz, CDCI₃): δ ppm 1.35 (br s, 1 H), 1.49-1.85 (m, 6H), 1.90-1.99 (m, 2H), 2.25-2.55 (m, 7H), 2.56-2.70 (m, 1 H), 2.75-3.00 (m, 4H), 3.23-3.31 (m, 1 H), 5.87 (br s, 1 H), 7.07 (d, 2H), 7.16-7.30 (m, 7H).

MS m/z 509 [M+H]⁺

Examples 2 and 3

IS) and (R)-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyl)cyclopentanecarboxamide

Example 2

To a suspension of (S)-1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 3, 70 mg, 0.232 mmol) and 1-(4-chlorophenyl)cyclopentanecarboxylic acid (57.3 mg, 0.255 mmol) in acetonitrile (0.8 mL) was added triethylamine (0.133 mL, 0.928 mmol) followed bypropylphosphonic anhydride (50% wt solution in EtOAc, 0.21 mL, 0.35 mmol). The reaction was stirred at room temperature for 1.5 hours after which the solution was purified directly by silica gel column chromatography eluting with 0-30% EtOAc in heptanes to afford the title compound (75 mg, 64%).

[a]_D²⁰ = +9.6 in DCM [20 mg/mL]

ee determination:

Column: ChiralTech AD-H, 250×4.6 mm, 5 micron.

Mobile phase A: CO2; Mobile phase B: MeOH with 0.2% ammonium hydroxide Gradient: 5% B at 0.00 mins, 60% B at 9.00 mins; hold to 9.5 mins and return to 5% B at 10 mins. Flow rate 3 mL/min.

Rt = 5.047 minutes, ee = 95%

Example 2 may also be prepared from rac-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4- (trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide(Example 1).

The racemate was separated into two enantiomers using preparative chiral chromatography as described below:

Chiralpak IA, 4.6x250mm, 5 micron.

Mobile phase: Hexane:DCM:EtOH:DEA 90:8:2:0.1

Flow rate: 1 mL/min

Rt = 8.351 minutes and Rt = 10.068 minutes

The first eluting isomer is Example 2: (S)-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide. ee = 100% The second eluting isomer is Example 3: (R)-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide. ee = 99.62% The compound of Example 2 prepared from the chiral separation method is identical by a-rotation and retention time to the compound of Example 2 prepared as the single enantiomer described above.

MS m/z 509 [M+H]⁺

¹H NMR (400MHz, DMSO-d₆): δ 1.30-1.80 (m, 10H), 2.20-2.30 (m, 1 H), 2.35-2.60 (m, 6H), 2.65-2.85 (m, 4H), 3.00-3.15 (m, 1 H), 5.50 (br s, 1 H), 6.95-7.00 (m, 1 H), 7.05-7.15 (m, 2H), 7.20-7.35 (m, 6H) ppm

PAPER

The discovery of a potent series of carboxamide TRPA1 antagonists

D. C. Pryde,*^a B. Marron,^b C. G. West,^b S. Reister,^b G. Amato,^b K. Yoger,^b K. Padilla,^b J. Turner,^c N. A. Swain,^a P. J. Cox,^c S. E. Skerratt,^a T. Ryckmans,^d D. C. Blakemore,^a J. Warmus^e and A. C. Gerlach^b

*Corresponding authors

^aPfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, UK

^bIcagen, Inc., 4222 Emperor Boulevard, Suite 350, Durham, USA

^cNeuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, UK

^dPfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich, UK

^ePfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Groton, USA

Med. Chem. Commun., 2016, Advance Article

DOI: 10.1039/C6MD00387G, http://pubs.rsc.org/en/Content/ArticleLanding/2016/MD/C6MD00387G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

. Please note PF-6667294 is Compound 4 and PF-4746537 is Compound 8.

A series of potent and selective carboxamide TRPA1 antagonists were identified by a high throughput screen. Structure–activity relationship studies around this series are described, resulting in a highly potent example of the series. Pharmacokinetic and skin flux data are presented for this compound. Efficacy was observed in a topical cinnamaldehyde flare study, providing a topical proof of pharmacology for this mechanism. These data suggest TRPA1 antagonism could be a viable mechanism to treat topical conditions such as atopic dermatitis.

Graphical abstract: The discovery of a potent series of carboxamide TRPA1 antagonists

hydrochloride salt (69 mg, 82%). 1 H NMR (400 MHz, DMSO-d6): δ ppm 1.50–1.60 (m, 4H), 1.70– 1.90 (m, 4H), 2.15–2.25 (m, 2H), 2.40–2.48 (m, 2H), 2.70–2.80 (m, 1H), 3.05–3.25 (m, 6H), 3.47–3.62 (m, 2H), 6.38 (br s, 1H), 7.20–7.40 (m, 9H), 7.80 (br m, 1H). MS m/z 509 [M + H]+ .

Image result for The discovery of a potent series of carboxamide TRPV1 antagonists

Discovery and development of TRPV1 antagonists

https://en.wikipedia.org/wiki/Discovery_and_development_of_TRPV1_antagonists

/////////////PF-04745637, PF 04745637, PF04745637, PFIZER, PRECLINICAL, TRPV1 antagonists, atopic dermatitis, 1917294-46-2

c1(ccccc1)CC(CNC(=O)C3(c2ccc(cc2)Cl)CCCC3)N4CCC(CC4)(O)C(F)(F)F

DDD 107498

September 13, 2016 4:04 am / Leave a comment

DDD 107498, DDD 498

PATENT WO 2013153357, US2015045354

6-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide

6-Fluoro-2-[4-(4-morpholinylmethyl)phenyl]-N-[2-(1-pyrrolidinyl)ethyl]-4-quinolinecarboxamide

4-Quinolinecarboxamide, 6-fluoro-2-[4-(4-morpholinylmethyl)phenyl]-N-[2-(1-pyrrolidinyl)ethyl]-

CAS 1469439-69-7

CAS 1469439-71-1 SUCCINATE

MF C₂₇H₃₁FN₄O₂
MW	462.559043 g/mol

6-fluoro-2-[4-(morpholin-4-ylmethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide

Originator Medicines for Malaria Venture; University of Dundee
Class Small molecules
Mechanism of Action Protein synthesis inhibitors

Highest Development Phases

No development reported Malaria

Most Recent Events

16 Jul 2016 No recent reports of development identified for preclinical development in Malaria in United Kingdom
01 Apr 2015 DDD 498 licensed to Merck Serono worldwide for the treatment of Malaria

Inventors	Ian Hugh Gilbert, Neil Norcross, Beatriz Baragana Ruibal, Achim Porzelle
Original Assignee	University Of Dundee

Prof Ian Gilbert:

Head of Biological Chemistry and Drug Discovery

BCDD, College of Life Sciences, University of Dundee, DD1 5EH, UK
Tel: +44 (0) 1382-386240

University of Dundee

School of Life Sciences

Image result for School of Life Sciences University of Dundee

DDD498

Merck Serono and MMV sign agreement to develop potential antimalarial therapy

Agreement further diversifies MMV’s partner base, strengthening our antimalarial research and development portfolio

01 April 2015

Photo © Merck Serono

Merck Serono, the biopharmaceutical business of Merck, and MMV announced today that an agreement has been signed for Merck Serono to obtain the rights to the investigational antimalarial compound DDD107498 from MMV. This agreement underscores the commitment of Merck Serono to provide antimalarials for the most vulnerable populations in need.

“This agreement strengthens our Global Health research program and our ongoing collaboration with Medicines for Malaria Venture,” said Luciano Rossetti, Executive Vice President, Global Head of Research & Development at Merck Serono. “MMV is known worldwide for its major contribution to delivering innovative antimalarial treatments to the most vulnerable populations suffering from this disease, and at Merck Serono we share this goal.”

DDD107498 originated from a collaboration between MMV and the University of Dundee Drug Discovery Unit, led by Prof. Ian Gilbert and Dr. Kevin Read. The objective of the clinical program is to demonstrate whether the investigational compound exerts activity on a number of malaria parasite lifecycle stages, and remains active in the body long enough to offer potential as a single-dose treatment against the most severe strains of malaria.

While development and commercialization of the compound is under Merck Serono’s responsibility, MMV will provide expertise in the field of malaria drug development, including its clinical and delivery expertise, and provide access to its public and private sector networks in malaria-endemic countries.

Merck Serono has a dedicated Global Health R&D group working to address key unmet medical needs related to neglected diseases, such as schistosomiasis and malaria, with a focus on pediatric populations in developing countries. Its approach is based on public-private partnerships and collaborations with leading global health institutions and organizations in both developed and developing countries.

“Working with partners like Merck Serono is critical to the progress of potential antimalarial compounds, like DDD107498, through the malaria drug pipeline,” said Dr. Timothy Wells, Chief Scientific Officer at MMV. “Their Global Health Program is gaining momentum and we need more compounds to tackle malaria, a disease that places a huge burden on the world’s most vulnerable populations. DDD107498 holds great promise and we look forward to working with the Merck Serono team through the development phase.”

According to the World Health Organization, there were an estimated 198 million cases of malaria worldwide in 2013, and an estimated 584,000 deaths, primarily in young children from the developing world. The launch of the not-for-profit research foundation, MMV, in 1999 and a number of collaborations and partnerships, including those with Merck Serono, has contributed to reducing the major gap in malaria R&D investment and subsequent dearth of new medicines.

“It’s hugely encouraging to see the German pharmaceutical industry increasing their engagement in the development of novel antimalarials,” said global malaria expert Prof. Dr. Peter Kremsner, Director of the Institute for Tropical Medicine at the University of Tübingen, Germany. “The Merck Serono and MMV collaboration to develop DDD107498 is a great step. It’s a compound that offers lots of promise so I’m excited to see how it progresses.

Scots scientists in ‘single dose’ malaria treatment breakthrough

STV17 June 2015

An antimalarial drug that could treat patients was discovered by Dundee university scientists

Scientists have discovered an antimalarial compound that could treat malaria patients in a single dose and help prevent the spread of the disease from infected people.

The compound DDD107498 also has the potential to treat patients with malaria parasites resistant to current medications, researchers say.

Scientists hope it could lead to treatments and protection against the disease, which claimed almost 600,000 lives amid 200 million reported cases in 2013.

The compound was identified through a collaboration between the University of Dundee’s drug discovery unit (DDU) and the Medicines for Malaria Venture (MMV), a separate organisation.

The compound is now undergoing further safety testing with a view to entering human clinical trials within the next year.

Details of the discovery have been published in the journal Nature.

Professor Ian Gilbert, head of chemistry at the DDU, who led the team that discovered the compound, said: “The publication describes the discovery and profiling of this exciting new compound.

“It reveals that DDD107498 has the potential to treat malaria with a single dose, prevent the spread of malaria from infected people and protect a person from developing the disease in the first place.

“There is still some way to go before the compound can be given to patients. However, we are very excited by the progress that we have made.”

The World Health Organisation reports that there were 200 million clinical cases of malaria in 2013, with 584,000 people dying from the disease. Most of these deaths were children under the age of five and pregnant women.

MMV chief executive officer Dr David Reddy said: “Malaria continues to threaten almost half of the world’s population – the half that can least afford it.

“DDD107498 is an exciting compound since it holds the promise to not only treat but also protect these vulnerable populations.

“The collaboration to identify and progress the compound, led by the drug discovery unit at the University of Dundee, drew on MMV’s network of scientists from Melbourne to San Diego.”The publication of the research is an important step and a clear testament to the power of partnership.”

MMV selected DDD107498 to enter preclinical development in October 2013 following the recommendation of its expert scientific advisory committee.

Since then, with MMV’s leadership, large quantities of the compound have been produced and it is undergoing further safety testing with a view to entering human clinical trials within the next year.

Merck Serono has recently obtained the right to develop and, if successful, commercialise the compound, with the input of MMV’s expertise in the field of malaria drug development and access and delivery in malaria-endemic countries.

Dr Michael Chew from the Wellcome Trust, which provides funding for the DDU and MMV, said: “The need for new antimalarial drugs is more urgent than ever before, with emerging strains of the parasite now showing resistance against the best available drugs.

“These strains are already present at the Myanmar-Indian border and it’s a race against time to stop resistance spreading to the most vulnerable populations in Africa.

“The discovery of this new antimalarial agent, which has shown remarkable potency against multiple stages of the malaria lifecycle, is an exciting prospect in the hunt for viable new treatments.”

PAPER

Abstract Image

Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy

Beatriz Baragaña^†, Neil R. Norcross^†, Caroline Wilson^†, Achim Porzelle^†, Irene Hallyburton^†, Raffaella Grimaldi^†,Maria Osuna-Cabello^†, Suzanne Norval^†, Jennifer Riley^†, Laste Stojanovski^†, Frederick R. C. Simeons^†, Paul G. Wyatt^†, Michael J. Delves^‡, Stephan Meister^§, Sandra Duffy^∥, Vicky M. Avery^∥, Elizabeth A. Winzeler^§, Robert E. Sinden^‡, Sergio Wittlin^⊥^#, Julie A. Frearson^†, David W. Gray^†, Alan H. Fairlamb^†, David Waterson^∇, Simon F. Campbell^∇, Paul Willis^∇, Kevin D. Read^*^†, and Ian H. Gilbert^*^†

^† Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, U.K.

^‡ Cell and Molecular Biology, Department of Life Sciences, Imperial College, London, SW7 2AZ, U.K.

^§ School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States

^∥ Eskitis Institute, Griffith University, Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia

^⊥ Swiss Tropical and Public Health Institute, Swiss TPH, Socinstrasse 57, 4051 Basel, Switzerland

^#University of Basel, CH-4003 Basel, Switzerland

^∇Medicines for Malaria Venture, International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.6b00723

*K.D.R.: phone, +44 1382 388 688; e-mail, k.read@dundee.ac.uk., *I.H.G.: phone, +44 1382 386 240; e-mail,i.h.gilbert@dundee.ac.uk.

http://pubs.acs.org/doi/full/10.1021/acs.jmedchem.6b00723

Conditions: (a) morpholine, Et₃N, DCM, 16 h, 72% yield; (b) MeMgBr, toluene, reflux, 4 h and then a 10% aqueous HCl, reflux, 1 h, 70% yield; (c) NBS, benzoyl peroxide, dichlorobenzene, 140 °C, 16 h, 70% yield; (d) morpholine, K₂CO₃, acetonitrile, 40 °C, 16 h, 64% yield; (e) 5-fluoroisatin, KOH, EtOH, 120 °C, microwave, 20 min, 30–76% yield; (f) amine, CDMT, N-methylmorpholine, DCM, 20–61% yield.

// https://tpc.googlesyndication.com/pagead/js/r20160906/r20110914/abg.js//

A single-dose treatment against malaria worked in mice to cure them of the disease. The drug also worked to block infection in healthy mice and to stop transmission, according to a study published in Nature today. The fact that the drug can act against so many stages of malaria is pretty new, but what’s even more exciting is the compound’s mode of action: it kills malaria in a completely new way, researchers say. The feature would make it a welcome addition to our roster of antimalarials — a roster that’s threatened by drug resistance.

RESEARCHERS SIFTED THROUGH A LIBRARY OF ABOUT 4,700 COMPOUNDS TO FIND THIS ONE

Malaria is an infectious disease that’s transmitted through mosquito bites; it’s also a leading cause of death in a number of developing countries. Approximately 3.4 billion people live in areas where malaria poses a real threat. As a result, there were 207 million cases of malaria in 2012 — and 627,000 deaths. There are drugs that can be used to prevent malaria, and even treat it, but drug resistance is halting the use of certain treatments in some areas.

A long search

Searching for a new drug is all about trial and error. To find this particular compound, researchers sifted through a library of about 4,700 compounds, testing them to see if they were capable of killing the malaria parasite in a lab setting. When they found something that worked, they tweaked the drug candidate to see if it could perform more effectively. “We went through a lot of these cycles of testing and designing new compounds,” says Ian Gilbert, a medicinal chemist at the University of Dundee in the UK, and a co-author of the study. “Eventually we optimized to the compound which is the subject of the paper.” For now, that compound’s unwieldy name is DDD107498.

To make sure DDD107498 really had potential, the researchers tested it on mice that had already been infected with malaria. A single dose was enough to provoke a 90 percent reduction in the number of parasites in their blood. The scientists also gave the compound to healthy mice that were subsequently exposed to malaria. DDD107498 helped the mice evade infection with a single dose, but it’s unclear how long that effect would last in humans. Finally, the researchers looked at whether the compound could prevent the transmission from an infected mouse to a mosquito. A day after receiving the treatment, mice were put in contact with mosquitoes. The scientists noted a 91 percent reduction in infected mosquitoes.

“IT HAS THE ABILITY TO BE A ONE-DOSE [DRUG], IN COMBINATION WITH ANOTHER MOLECULE.”

“What’s exciting about this molecule is obviously the fact that it has the ability to be a one-dose [drug], in combination with another molecule to cure blood stage malaria,” says Kevin Read, a drug researcher also at the University of Dundee and a co-author of the study. The fact that the compound has the ability to block transmission and protect against infection is equally thrilling. But the way in which DDD107498 kills malaria might be its most interesting feature. It halts the production of proteins — which are necessary for the parasite’s survival. No other malaria drug does that right now, Read says. “So, in principle, there’s no resistance out there already to this mechanism.”

The drug hasn’t been tested in humans yet, so it may not be nearly as good in the field. But Read says DDD107498 looks promising. “From all the pre-clinical or non-clinical data we’ve generated, it is comparable or better than any of the current marketed anti-malarials in those studies.” And at $1 per treatment, the price of the drug should fall “within the range of what’s acceptable,” he says.

“It looks like an excellent study, and the results look very important,” says Philip Rosenthal, a malaria drug researcher at The University of California-San Francisco who didn’t participate in the study. This is a big shift for Rosenthal’s field. Five years ago, “we had very little going on in anti-malarial drug discovery,” he says. Now, there’s quite a bit going on for malaria researchers, and a number of promising compounds are moving along. DDD107498 “is another player, and it’s got a number of positive features,” he says.

OTHER TREATMENTS HAVE TO BE TAKEN FOR A FEW DAYS

One of the features is the drug’s potency. It’s very active against cultured malaria parasites, Rosenthal says. But what’s perhaps most intriguing about DDD107498 is that the drug works against the mechanism that enables protein synthesis the malaria parasite’s cells. No other malaria drug does that right now, Read says. “Considering challenges of treating malaria, which is often in rural areas and developing countries, a single dose would be a big plus,” he says. “In addition, because of it’s long half life, it may also work to prevent malaria with once a week dosing, which is also a benefit.”

Still, no drug is perfect. The data suggests that DDD107498 doesn’t kill malaria as quickly as some other drugs, Rosenthal says. And when the researchers tested it to see how long it might take for resistance to develop, the results weren’t as promising as he would like. The parasites figured out a way to become resistant to the compound “relatively easily,” he says. That shouldn’t be “deal-killer,” however. “Its slow onset of action probably means it should be combined with a faster-acting drug,” he says.

BUT IT’S SLOW-ACTING

The compound is going through safety testing now. If everything goes well, it should hit human trials within the next year, Read says. Chances are, it will have to be used in combination with other malaria drugs, Gilbert says. “All anti-malarials are given in combination because it slows down resistance.”

“When you’re treating infectious diseases, you know that drug resistance is always a potential problem, so having a number of choices to treat malaria is a good thing,” Rosenthal says. In this case, the drug’s new mode of action may hold lead to an entirely new weapon against malaria. “Obviously it’s got a long way to go,” Read says. But the compound is “very exciting,” nonetheless.

// https://tpc.googlesyndication.com/pagead/js/r20160906/r20110914/abg.js//

PATENT

https://www.google.com/patents/US20150045354

Example 16-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1 in Scheme 2

In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4-(morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130° C. under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHCO₃saturated aqueous solution (2×100 ml). The organic layer was separated, dried over MgSO₄and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10% B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60-200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50° C. for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).

¹H NMR (500 MHz; CDCl₃) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J=5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J=5.4 Hz, J=11.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J=8.2 Hz), 8.21 (dd, 1H, J=5.5 Hz, J=9.2 Hz) ppm. ¹⁹F NMR (407.5 MHz; CDCl₃) δ−111.47 ppm.

Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.7 min, m/z 463 (M+H)⁺ HRMS (ES+) found 463.2501 [M+H]⁺, C27H32F1N4O2 requires 463.2504.

Example 26-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide; fumaric acid salt, compound (IB) in Scheme 2

The starting free base (example 1) (0.58 g, 1 mmol) was dissolved in dry ethanol (10 ml) and added dropwise to a stirred solution of fumaric acid (0.15 g, 1 mmol) in dry ethanol (9 ml). The mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with ethanol (20 ml) and then dissolved in 10 ml of water and freeze dried to obtain the desired salt as a white solid (0.601 g, 1 mmol, Yield 82%).

¹H NMR (500 MHz; d6-DMSO) δ 1.83-1.86 (m, 4H), 2.41 (brs, 4H), 2.94 (brs, 4H), 3.03 (t, 2H, J=6.2 Hz), 3.57 (s, 2H), 3.60-3.65 (m, 6H), 6.47 (s, 2H), 7.51 (d, 2H, J=8.25), 7.74-7.78 (m, 1H), 8.06 (dd, 1H, J=2.9 Hz, J=10.4 Hz), 8.17 (dd, 1H, J=5.7 Hz, J=9.3 Hz), 8.24-8.26 (m, 3H), 9.24 (t, 1H, J=5.5 Hz) ppm. ¹⁹F NMR (407.5 MHz; d6-DMSO) δ-112.30 ppm.

Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.3 min, m/z 463 (M+H)⁺

Example 1AAlternative synthesis of 6-fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1A in Scheme 4

To a stirred suspension of 6-fluoro-2-[4-(morpholinomethyl)phenyl]quinoline-4-carboxylic acid (preparation 7) (2.20 g, 6 mmol) in DCM (100 ml) at room temperature, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (1.26 g, 7 mmol) and 4-methylmorpholine (NMO) (1.33 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then 2-pyrrolidin-1-ylethanamine (0.77 ml, 6 mmol) was added and stirred at room temperature for further 3 h. The reaction mixture was washed with NaHCO₃saturated aqueous solution (2×100 ml) and the organic phase was separated, dried over MgSO₄and concentrated under reduced pressure. The resulting residue was absorbed on silica gel and purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 2 min hold 100% A followed by a 30 min ramp to 10% B and then 15 min hold at 10% B. The desired fractions were concentrated to dryness under vacuum to obtain the crude product as a yellow solid (95% purity by LCMS). The sample was further purified by a second column chromatography using a 40 g silica gel cartridge, eluting with DCM (Solvent A) and 10% NH₃-MeOH in DCM (Solvent B) and the following gradient: 2 min hold 100% A, followed by a 10 min ramp to 23% B and then 15 min hold at 23% B. The desired fractions were concentrated to dryness under vacuum to obtain product as a white solid (1 g). Re-crystallisation form acetonitrile (18 ml) yielded the title compound as a white solid (625 mg, 1.24 mmol, 20%).

¹H NMR (500 MHz; d6-DMSO) δ 1.72-1.75 (m, 4H), 2.41 (brs, 4H), 2.56 (brs, 4H), 2.67 (t, 2H, J=6.6 Hz), 3.49-3.52 (m, 2H), 3.56 (s, 2H), 3.60-3.61 (m, 4H), 7.52 (d, 2H, J=8.3 Hz), 7.73-7.77 (m, 1H), 8.07 (dd, 1H, J=2.9 Hz, J=10.4 Hz), 8.18-8.21 (m, 2H), 8.26 (d, 2H, J=8.3 Hz), 8.85 (t, 1H, J=6.6 Hz) ppm.

¹³C NMR (125 MHz; d⁶-DMSO₃) δ 23.2, 38.4, 53.2, 53.5, 54.5, 62.1, 66.2, 109.0, 109.1, 117.3, 120.1, 120.3, 124.1, 124.2, 127.1, 129.4, 132.2, 132.3, 136.8, 139.9, 142.8, 145.2, 155.3, 159.0, 161.0, 166.1 ppm.

¹⁹F NMR (500 MHz; d⁶-DMSO) δ-112.47 ppm.

Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.0 min, m/z 463 (M+H)⁺

PATENT

WO 2016033635

http://google.com/patents/WO2016033635A1?cl=en

Patent

WO 2013153357

https://www.google.com/patents/WO2013153357A1?cl=en

SCHEME 1

SCHEME 2

Preparation 4Yield: 54% Preparation 3

Yield: 27%

SCHEME 4 B

Yield: 72% Yield: 70% Preparation 6

Example 1 : 6-Fluoro-2-r4-(morpholinomethyl)phenyll-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide, Example compound 1 in Scheme 2

In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1- ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4- (morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130°C under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHC0₃ saturated aqueous solution (2 x 100 ml). The organic layer was separated, dried over MgS0₄and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10 % B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60- 200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50°C for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).

¹ H NMR (500 MHz; CDCI₃) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J = 5.4 Hz, J = 1 1.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1 H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J = 8.2 Hz), 8.21 (dd, 1 H, J = 5.5 Hz, J = 9.2 Hz) ppm . ¹⁹ F NMR (407.5 MHz; CDCI₃) δ -11 1.47 ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.7 min, m/z 463 (M+H)⁺ HRMS (ES+) found 463.2501 [M+H]⁺, C27H32F1 N402 requires 463.2504.

Example 2: 6-Fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide; fumaric acid salt, compound (IB) in Scheme 2

1 H NMR (500 MHz; d6-DMSO) δ 1.83-1.86 (m, 4H), 2.41 (brs, 4H), 2.94 (brs, 4H), 3.03 (t, 2H, J = 6.2 Hz), 3.57 (s, 2H), 3.60-3.65 (m, 6H), 6.47 (s, 2H), 7.51 (d, 2H, J = 8.25), 7.74-7.78 (m, 1 H), 8.06 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.17 (dd, 1 H, J = 5.7 Hz, J = 9.3 Hz), 8.24-8.26 (m, 3H), 9.24 (t, 1 H, J = 5.5 Hz) ppm. ¹⁹ F NMR (407.5 MHz; d6- DMSO) δ -112.30 ppm.

Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.3 min, m/z 463 (M+H)⁺

Example 1A: Alternative synthesis of 6-fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2- pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1A in Scheme 4

To a stirred suspension of 6-fluoro-2-[4-(morpholinomethyl)phenyl]quinoline-4-carboxylic acid (preparation 7) (2.20 g, 6 mmol) in DCM (100 ml) at room temperature, 2-chloro- 4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.26 g, 7 mmol) and 4-methylmorpholine (NMO) (1.33 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then 2-pyrrolidin-1-ylethanamine (0.77 ml, 6 mmol) was added and stirred at room temperature for further 3 h. The reaction mixture was washed with NaHC0₃ saturated aqueous solution (2x 100 ml) and the organic phase was separated, dried over MgS0₄ and concentrated under reduced pressure. The resulting residue was absorbed on silica gel and purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 2 min hold 100% A followed by a 30 min ramp to 10 %B and then 15 min hold at 10%B. The desired fractions were concentrated to dryness under vacuum to obtain the crude product as a yellow solid (95% purity by LCMS). The sample was further purified by a second column chromatography using a 40 g silica gel cartridge, eluting with DCM (Solvent A) and 10% NH₃-MeOH in DCM (Solvent B) and the following gradient: 2 min hold 100% A, followed by a 10 min ramp to 23 % B and then 15 min hold at 23% B. The desired fractions were concentrated to dryness under vacuum to obtain product as a white solid (1 g). Re-crystallisation form acetonitrile (18 ml) yielded the title compound as a white solid (625 mg, 1.24 mmol, 20%).

¹ H NMR (500 MHz; d6-DMSO) δ 1.72-1.75 (m, 4H), 2.41 (brs, 4H), 2.56 (brs, 4H), 2.67 (t, 2H, J = 6.6 Hz), 3.49-3.52 (m, 2H), 3.56 (s, 2H), 3.60-3.61 (m, 4H), 7.52 (d, 2H, J = 8.3 Hz), 7.73-7.77 (m, 1 H), 8.07 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.18-8.21 (m, 2H), 8.26 (d, 2H , J = 8.3 Hz), 8.85 (t, 1 H, J = 6.6 Hz) ppm.

¹³C NMR (125 MHz; d⁶-DMS0₃) 5 23.2, 38.4, 53.2, 53.5, 54.5, 62.1 , 66.2, 109.0, 109.1 , 1 17.3, 120.1 , 120.3, 124.1 , 124.2, 127.1 , 129.4, 132.2, 132.3, 136.8, 139.9, 142.8, 145.2, 155.3, 159.0, 161 .0, 166.1 ppm.

¹⁹ F NM R (500 MHz; d⁶-DMSO) δ -1 12.47 ppm.

Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.0 min, m/z 463 (M+H)⁺

PAPER

A Quinoline Carboxamide Antimalarial Drug Candidate Uniquely Targets Plasmodia at Three Stages of the Parasite Life Cycle
Angewandte Chemie, International Edition (2015), 54, (46), 13504-13506

http://onlinelibrary.wiley.com/doi/10.1002/anie.201507264/abstract

Putting a stop to malaria: Phenotypic screening against malaria parasites, hit identification, and efficient lead optimization have delivered the preclinical candidate antimalarial DDD107498. This molecule is distinctive in that it has potential for use as a single-dose cure for malaria and shows a unique broad spectrum of activity against the liver, blood, and mosquito stages of the parasite life cycle.

Prof. P. M. O’Neill Department of Chemistry, University of Liverpool Liverpool, L69 7ZD (UK) E-mail: pmoneill@liverpool.ac.uk Prof. S. A. Ward Liverpool School of Tropical Medicine, Pembroke Place Liverpool, L3 5QA (UK)

Professor Ian Gilbert FRSC

Design and synthesis of potential therapeutic agents

Position:

Professor of Medicinal Chemistry and Head of the Division of Biological Chemistry and Drug Discovery

Affiliation:

Biological Chemistry and Drug Discovery

Address:

College of Life Sciences, University of Dundee, Dundee

Full Telephone:

+44 (0) 1382 386240, int ext 86240

Email:

i.h.gilbert@dundee.ac.uk

Website:

Gilbert Lab Group

Medicinal Chemistry

I am a medicinal chemist and my research interests are in the design and synthesis of potential drugs. The mainstay of my work is synthetic medicinal chemistry as part of the Drug Discovery Unit (DDU). Where possible we make extensive use of molecular modeling to guide our synthetic efforts. I have a particular interests in the following aspects of drug discovery:

Neglected diseases such as human African trypanosomiasis, leishmaniasis and malaria.
Chemical validation of drug targets, including novel targets for which there is little or no precedence for drug discovery.
Novel approaches to and paradigms for drug discovery.
Mode of action studies and target identification.

I am Head of Chemistry in the DDU. Our main focuses are on neglected diseases and novel drug targets. The neglected diseases we are tackling are malaria, tuberculosis and the kinetoplastid diseases. We use both target-based approaches and phenotypic approaches (whole parasite screening). We have had particular success in validating the enzyme N-myristoyltransferase as a drug target in human African trypanosomiasis, and in identifying and optimising phenotypic hits. In our novel targets area, we aim to validate novel areas of biology as potential drug targets.

Dr Neil Norcross

Position:

Medicinal Chemist

Affiliation:

Biological Chemistry and Drug Discovery

Address:

College of Life Sciences, University of Dundee, Dundee

Full Telephone:

(0) , int ext

Email:

n.norcross@dundee.ac.uk

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La investigadora asturiana Beatriz Baragaña, en La Pola. / PABLO NOSTI

Achim Porzelle

REFERENCES

http://www.mmv.org/sites/default/files/uploads/docs/publications/annual_report_2013/Annual_Report_2013_Chapter_5.pdf

///////////DDD107498, DDD 107498, PRECLINICAL, DUNDEE, MALARIA, DDD 498, Achim Porzelle, Ian Gilbert, MERCK SERENO, Beatriz Baragaña, Medicines for Malaria Venture, University of Dundee, Neil Norcross, 1469439-69-7, 1469439-71-1 , SUCCINATE

Fc1ccc2nc(cc(c2c1)C(=O)NCCN1CCCC1)-c1ccc(cc1)CN1CCOCC1

1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone for androgen sensitive prostatic disorders

September 13, 2016 3:29 am / Leave a comment

1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone

Molecular Formula:	C₂₂H₂₆N₆O₅
Molecular Weight:	454.47904 g/mol

CAS 330633-91-5

CDRI-?

For treatment of androgen sensitive prostatic disorders

1,2-bis[4-(4-nitrophenyl)piperazin-1-yl]ethanone.png

1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone

Graphical abstract: Design, synthesis and biological profiling of aryl piperazine based scaffolds for the management of androgen sensitive prostatic disorders

In the quest for novel scaffolds for the management of androgen sensitive prostatic disorders like prostate cancer and benign prostatic hyperplasia, a series of twenty-six aryl/heteroaryl piperazine derivatives have been described. Three compounds, 8a, 8c and 9a, exhibited good activity profiles against an androgen sensitive prostate cancer cell line (LNCaP) with EC₅₀values of 9.8, 7.6 and 11.2 μM, respectively. These compounds caused a decrease in luciferase activity and a decline in PSA and Ca²⁺ levels, which are indicative of their anti-androgenic and α_1A-adrenergic receptor blocking activities, respectively.

Compound 9a reduced the prostate weight of rats (47%) and in pharmacokinetic analysis at 10 mg kg⁻¹ it demonstrated an MRT of ∼14 h post dose, exhibiting high levels in prostate. Compound 9a docked in a similar orientation to hydroxyflutamide on an androgen receptor and showed strong π–π interactions. These findings reveal that compound 9a is a promising candidate for management of prostatic disorders with anti-androgenic and α_1A-blocking activities.

Design, synthesis and biological profiling of aryl piperazine based scaffolds for the management of androgen sensitive prostatic disorders

Sonal Gupta,^a^e Deepti Pandey,^b Dhanaraju Mandalapu,^a Veenu Bala,^a^e Vikas Sharma,^b Mahendra Shukla,^c^e Santosh K. Yadav,^b Nidhi Singh,^d Swati Jaiswal,^c^e Jagdamba P. Maikhuri,^b Jawahar Lal,^c^e Mohammad I. Siddiqi,^d Gopal Gupta^b and Vishnu L. Sharma*^a^e

*Corresponding authors

^aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram ext., Lucknow-226031, India
E-mail: vl_sharma@cdri.res.in, vlscdri@gmail.com
Fax: +91 522 2771941
Tel: +91 522 2772450 Ext. 4671

^bEndocrinology Division, CSIR-Central Drug Research Institute, Lucknow-226031, India

^cPharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow-226031, India

^dMolecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow-226031, India

^eAcademy of Scientific and Innovative Research (AcSIR), New Delhi-110001, India

Med. Chem. Commun., 2016, Advance Article

DOI: 10.1039/C6MD00426A, http://pubs.rsc.org/en/Content/ArticleLanding/2016/MD/C6MD00426A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone (9a) To the mixture of 8a (0.3 g, 1.06 mmol) and Et3N (0.3 mL, 2.12 mmol) in CHCl3 (5 mL) was added 1-(4-nitrophenyl)piperazine (7a, 0.320 g, 1.59 mmol) in 5 mL CHCl3 dropwise within 1 h. After complete addition reaction mixture was further stirred in an oil bath at 80-85 °C for 15 h. The reaction mixture was cooled, washed with water (5 mL × 3) and the organic layer was separated. Combined organic layer was dried (anhyd. Na2SO4 and concentrated under reduced pressure in rotavapor. The solid obtained was purified by recrystallization using EtOAc/Hexane which furnished yellow crystals (yield 81%);

mp: 156-157 °C; IR (KBr)  (cm-1): 3019, 2399, 1640, 1597, 1506, 1423, 1330;

1H NMR (400 MHz, CDCl3):  8.14-8.09 (4H, m), 6.84-6.81 (4H, m), 3.84-3.83 (4H, m), 3.49-3.44 (8H, m), 3.33 (2H, s), 2.72 (4H, t, J = 5.0 Hz);

13C NMR (75.4 MHz, CDCl3):  167.7, 154.7, 154.3, 138.8, 138.4, 125.9, 125.8, 112.9, 112.7, 60.8, 52.5, 46.9, 46.7, 44.6;

HRMS (ESI positive) m/z calcd. for C22H26N6O5 [M+H]+ : 455.2043, found: 455.2034;

Anal calcd. for C22H26N6O5: C, 58.14; H, 5.77; N, 18.49, found: C, 58.31; H, 5.92; N, 18.66.

SONAL GUPTA

Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram ext., Lucknow-226031, India

Image result for Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute

Dr. VISHNU LAL SHARMA

http://www.cdriindia.org/VL_Sharma.htm

Dr. VISHNU LAL SHARMA

Senior Principal Scientist (CSIR-CDRI ) / Professor (AcSIR)
Lab No. CSS-SF-201, Medicinal and Process Chemistry Division
Central Drug Research Institute,
B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road
Lucknow- 226031

Educational Qualifications	M.Sc (Organic Chemistry, Lucknow University, Lucknow, Uttar Pradesh, 1978) Ph.D. (Chemistry, Lucknow University, Lucknow, Uttar Pradesh, 1985)
Date of Birth	February 7th, 1958
E- Mail	vl_sharma@cdri.res.in, vlscdri@gmail.com
Phone No.	+91-0522-2772450/550, Ext. 4671.
Mobile No.	+91-9415074195
Fax No.	+91-522-2771941
Research Experience (Area)	Medicinal chemistry, Organic chemistry.
Google Scholar	https://scholar.google.co.in/citations?user=cAsQaiYAAAAJ&hl=en
Research gate	https://www.researchgate.net/profile/Vishnu_Sharma13

POST-DOCTORAL RESEARCH (ABROAD)

University of Dusseldorf, Dusseldorf, Germany, Oct., 1994 to Dec., 1994

CURRENT AREAS OF INTEREST

	Medicinal Chemistry, Synthetic organic chemistry and Process chemistry.
	The research focused in my group is related to design and synthesis of small molecule libraries of biomedical importance and development of new methodologies and process developments of candidate drugs.

From left to right upper row: Dr. S.T.V.S. Kiran Kumar, Dr. Lalit Kumar, Dr. V.L. Sharma, Dr. Nand Lal, Dr. Amit Sarswat
Lower row: Dhanaraju Mandalapu, Sonal Gupta, Mrs. Tara Rawat (S.T.O.), Dr. Veenu bala, Dr. Santosh Jangir

THESIS SUPERVISED

	Seven (7) students for their Ph.D.
	Twenty two (22) students for their Post Graduation degrees

FORMER Ph.D. STUDENTS

	Dr. S.T.V.S. Kiran Kumar, 2006,Research Scientist at University of Virginia Charlottesville, Virginia.
	Dr. Lalit Kumar, 2011, KIMIA Biosciences Pvt.Ltd., Rajasthan, India .
	Dr. Amit Sarswat, 2011, Postdoctoral Fellow, University Health Network, Toronto, Ontario, Canada.
	Dr. Nand Lal, 2012, Scientist E1 at HLL-Lifecare Limited, Thiruvananthapuram, Kerala, India.
	Dr. Santosh Jangir, 2014.
	Dr. Veenu bala, 2014, Assistant Professor at Mohan Lal Sukhdia University, Rajasthan, India.
	Ms. Sonal Gupta, 2015.

FORMER PROJECT ASSISTANTS

Ms. Mala Singh (2014-2016)

PRESENT Ph.D. STUDENTS

Mr. Dhanaraju Mandalapu (CSIR-SRF; 2012-present)

FORMER POSTGRADUATE STUDENTS

	M. Jay Kothari (1997)
	A.N. Misra (1997)
	Ritu Chadda (1998)
	Arun Kumar Misra (2000)
	S.Nitya (2003)
	Vishwanath Pratap Gupta (2004)
	Divya (2006)
	Charu Mahawar (2007)
	Desh Deepak Pandey (2008)
	Priyanka Pandey (2010)
	Sumit Kumar (2010)
	Sourabh Maheswari (2011)
	Kartheek Nandikonda (2012)
	Naveen Gupta (2012)
	Pallavi Nayak (2012)
	Neetika (2013)
	Vikas Kumar (2013)
	Neha Yadav (2013)
	Subhadra Thakur (2014)
	Jitendra Kumar (2015)
	Suyash Tewari (2015)
	Anjali Misra (2015)

MEMBERSHIP OF SOCIETES :

1.	The Uttar Pradesh Association for Advancement of Science, Lucknow (India)
2.	Indian Chemical Society (Calcutta)
3.	Chemical Research Society of India, (Bangalore)

PROJECTS:

Reproductive Health Research: Male Reproductive Health and Contraception

1	Co – Principal Investigator: “Designed synthesis, evaluation and identification of novel, dually-effective spermicidal agents with anti-Trichomonal activity for ‘prophylactic’ contraception” (July 2014 – ongoing ), Funded by DHR, Indian council of Medical Research (ICMR), New Delhi.
2	Co-Principal Investigator: “Preclinical development of S,S’-Disulfanediylbis(pyrrolidinopropane-2,1-diyl) bis (piperidinothiocarbamate) as a vaginal contraceptive” (July 2011 – June 2013), Funded by Indian council of Medical Research (ICMR), New Delhi.
3	Principal Investigator: “Designed synthesis and biological evaluation of novel agents for management of benign prostatic hyperplasia” (November 2012 – October 2015), Funded by Indian council of Medical Research (ICMR), New Delhi.

PUBLICATIONS & PATENTS-

Total number of peer reviewed publications- 69 (Sixty Nine )

Total number of patents: (1 World patent and 4 National patents) – 5 (Five)

Citations to all publications: -Sum of times cited – 486, h-index- 12

SELECTED PUBLICATIONS

•	Dhanaraju Mandalapu, Deependra Kumar Singh, Sonal Gupta, Vishal M. Balaramnavar, Mohammad Shafiq, Dibyendu Banerjee, Vishnu Lal Sharma. Discovery of monocarbonyl curcumin hybrids as a novel class of human DNA ligase I inhibitors: in silico design, synthesis and biology. *RSC Advances*, 2016, 6, 26003.
•	Subhashis Pal, Kainat Khan, Shyamsundar Pal China, MonikaMittal, Konica porwal, Richa Shrivastava, Isha Taneja, Zakir Hossain, Dhanaraju Mandalapu, Jiaur R. Gayen, Muhammad Wahajuddin, Vishnu Lal Sharma, Arun K. Trivedi, Sabyasachi Sanyal, Smrati Bhadauria, Madan M. Godbole , Sushil K. Gupta, Naibedya Chattopadhyay. Theophylline, a methylxanthine drug induces osteopenia and alters calciotropic hormones and prophylactic vitamin D treatment protects against these changes in rats. *Toxicology and Applied Pharmacology, 2016, 295*, 12-25.
•	Bhavana Kushwaha, Dhanaraju Mandalapu, Veenu Bala, Lokesh Kumar, Aastha Pandey, Deepti Pandey, Santosh Kumar Yadav, Pratiksha Singh, P.K. Shukla, Jagdamba P. Maikhuri, Satya N. Sankhwar, Vishnu L. Sharma, Gopal Gupta. Ammonium salts of carbamodithioic acid as potent vaginal trichomonacides and fungicides. International Journal of Antimicrobial Agents, 2016, 47, 36-47.
•	Dhanaraju Mandalapu, Nand Lal, Lokesh Kumar, Bhavana Kushwaha, Sonal Gupta, Lalit Kumar, Veenu Bala, Santosh K. Yadav, Pratiksha Singh, Nidhi Singh, Jagdamba P. Maikhuri, Satya N. Sankhwar, Praveen K. Shukla, Imran Siddiqi, Gopal Gupta, Vishnu L. Sharma. Innovative Disulphide Esters of Dithiocarbamic acid as Women Controlled Contraceptive Microbicides: A Bioisosterism Approach. *ChemMedChem,* 2015, 10, 1739-1753.
•	Rachumallu Ramakrishna, Santosh kumar Puttrevu, Manisha Bhateria,Veenu Bala,Vishnu L. Sharma, Rabi Sankar Bhatta. Simultaneous determination of azilsartan and chlorthalidone in rat and human plasma by liquid chromatography-electrospray tandemmass spectrometry. *Journal of Chromatography B, 2015,990*, 185–197.
•	Hardik Chandasana, Yashpal S. Chhonkera, Veenu Bala, Yarra D. Prasad ,Telaprolu K. Chaitanya, Vishnu L. Sharma, Rabi S. Bhatta. Pharmacokinetic bioavailability, metabolism and plasma proteinbinding evaluation of NADPH-oxidase inhibitor apocynin using LC–MS/MS. Journal of Chromatography B, 2015, 985, 180–188.
•	Rajeev Kumar, Vikas Verma, Vikas Sharma, Ashish Jain, Vishal Singh, Amit Sarswat , Jagdamba P. Maikhuri, Vishnu L. Sharma, Gopal Gupta. A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors. *Toxicology and Applied Pharmacology, 2015, 283*, 187-197.
•	Nand Lal, Amit Sarswat, Lalit Kumar, Karthik Nandikonda, Santosh Jangir, Veenu Bala, Vishnu Lal Sharma. Synthesis of Dithiocarbamates Containing Disulfide Linkage Using Cyclic Trithiocarbonate and Amines under Solvent–Catalyst Free Condition. *Journal of Heterocyclic Chemistry*, 2015, 52, 156-162.
•	Veenu Bala, Santosh Jangir, Dhanaraju Mandalapu, Sonal Gupta, Yashpal S. Chhonker, Nand Lal, Bhavana Kushwaha, Hardik Chandasana, Shagun Krishna, Kavita Rawat, Jagdamba P. Maikhuri, Rabi S. Bhatta, Mohammad I. Siddiqi,Rajkamal Tripathi, Gopal Gupta, Vishnu L. Sharma. Dithiocarbamate- Thiourea Hybrids Useful as Vaginal Microbicides Also Show Reverse Transcriptase Inhibition: Design, Synthesis, Docking and Pharmacokinetic studies. Bioorganic & Medicinal Chemistry Letters, 2015, 25, 881-886.
•	Gopal Gupta, Santosh Jangir and Vishnu Lal Sharma. Targeting post-ejaculation sperm for value-added contraception. *Current Molecular Pharmacology*, 2014, 7, 167-174.
•	Veenu Bala, Santosh Jangir, Vikas Kumar, Dhanaraju Mandalapu, Sonal Gupta, Lalit Kumar, Bhavana Kushwaha, Yashpal S. Chhonker, Atul Krishna, Jagdamba P. Maikhuri, Praveen K. Shukla, Rabi S. Bhatta, Gopal Gupta, Vishnu L. Sharma. Design and synthesis of substituted morpholin/piperidin-1-yl-carbamodithioates as promising vaginal microbicides with spermicidal potential. *Bioorganic & Medicinal Chemistry Letters*, 2014, 24, 5782-5786.
•	Veenu Bala, Gopal Gupta, Vishnu Lal Sharma. Chemical and Medicinal Versatility of Dithiocarbamates: An Overview. Mini Review Medicinal Chemistry, 2014, 14, 1021–1032.
•	Rakesh Kumar Asthana, Rasna Gupta, Nidhi Agrawal, Atul Srivastava, Upma Chaturvedi, Sanjeev Kanojiya, Ashok Kumar Khanna, Gitika Bhatia, Vishnu Lal Sharma. Evaluation of antidyslipidemic effect of mangiferin and amarogentin from swertia chirayita extract in hfd induced charles foster rat model and in vitroantioxidant activity and their docking studies. *International Journal of Pharmaceutical Sciences and Research*, 2014, 5(9), 3734-3740.
•	Santosh Jangir, Veenu Bala, Nand Lal, Lalit Kumar, Amit Sarswat, Amit Kumar, Hamidullah, Karan S. Saini, Vikas Sharma, Vikas Verma, Jagdamba P. Maikhuri, Rituraj Konwar, Gopal Gupta, Vishnu L. Sharma. Novel alkylphospholipid-DTC hybrids as promising agents against endocrine related cancers acting via modulation of Akt-pathway. *European Journal of Medicinal Chemistry*, 2014,85, 638-647.
•	Hardik Chandasana, Yashpal S. Chhonker, Veenu Bala, Yarra Durga Prasad,Vishnu L. Sharma, Rabi S. Bhatta. A rapid and sensitive LC-MS/MS analysis of diapocynin in rat plasma to investigate in vitro and in vivo pharmacokinetics.Analytical Methods 2014, 6, 7075-82.
•	Yashpal S. Chhonker, Hardik Chandasanaa, Veenu Bala, Lokesh Kumar,Vishnu Lal Sharma, Gopal Gupta, Rabi S. Bhatta. Quantitative determination of microbicidal spermicide ‘nonoxynol-9’ in rabbit plasma and vaginal fluid using LC–ESI–MS/MS: Application to pharmacokinetic. Journal of Chromatography B, 2014, 965, 127–132.
•	Mittal M, Khan K, Pal S, Porwal K, China SP, Barbhuyan TK, Bhagel KS, Rawat T, Sanyal S, Bhaduria S, Sharma VL, Chattopadhyay N. The Thiocarbamate Disulphide Drug, Disulfiram Induces Osteopenia in Rats by Inhibition of Osteoblast Function Due to Suppression of Acetaldehyde Dehydrogenase Activity.Toxicological Sciences, 2014, 239, 257-270.
•	Santosh Jangir, Veenu Bala, Nand Lal, Lalit Kumar, Amit Sarswat, Lokesh Kumar, Bhavana Kushwaha, Pratiksha Singh, Praveen K. Shukla, Jagdamba P. Maikhuri, Gopal Gupta, Vishnu L. Sharma. A unique dithiocarbamate chemistry during design & synthesis of novel sperm-immobilizing agents. *Organic & Biomolecular Chemistry*, 2014, 12 , 3090-3099.
•	Amit Anthwal, U. Chinna Rajesh, M.S.M. Rawat, Bhavana Kushwaha, Jagdamba P. Maikhuri, Vishnu L. Sharma, Gopal Gupta, Diwan S. Rawat. Novel metronidazole-chalcone cojugates with potential to counter drug resistance inTrichomona vaginalis. *European Journal of Medicinal Chemistry*, 2014, 79, 89-94.
•	Ashish Jain, Lokesh Kumar, Bhavana Kushwaha, Monika Sharma, Aastha Pandey, Vikas Verma, Vikas Sharma, Vishal Singh, Tara Rawat, Vishnu L. Sharma, Jagdamba P. Maikhuri, Gopal Gupta. Combining a synthetic spermicide with a natural trichomonacide for safe, prophylactic contraception. *Human Reproduction*, 2014, 29, 242-252.
•	Lalit Kumar, Nand Lal, Vikash Kumar, Amit Sarswat, Santosh Jangir, Veenu Bala, Lokesh Kumar, Bhavana Kushwaha, Atindra K. Pandey, Mohammad I. Siddiqi, Praveen K. Shukla, Jagdamba P. Maikhuri, Gopal Gupta, Vishnu L. Sharma. Azole-carbodithioate hybrids as vaginal anti-Candida contraceptive agents: design, synthesis and docking studies. *European Journal of Medicinal Chemistry*, 2013,70, 68-77.
•	Monika Sharma, Lokesh Kumar, Ashish Jain, Vikas Verma, Vikas Sharma, Bhavna Kushwaha, Nand Lal, Lalit Kumar, Tara Rawat, AK Dwivedi, JP Maikhuri, VL Sharma, Gopal Gupta. Designed chemical intervention with thiols for prophylactic contraception. *PLOS-One*, 2013, 8 (6), page 67365.
•	Lalit Kumar, Ashish Jain, Nand Lal, Amit Sarswat, Santosh Jangir, Lokesh Kumar, Priyanka Shah, Swatantra K. Jain, Jagdamba P. Maikhuri, Mohammad I. Siddiqi, Gopal Gupta, Vishnu L. Sharma. Potentiating metronidazole scaffold against resistant trichomonas: Design, synthesis, biology and 3D–QSAR analysis. *ACS Medicinal Chemistry Letters*, 2012, 3 (2), 83-87.
•	Kumar R, Verma V, Sarswat A, Maikhuri JP, Jain A, Jain RK, Sharma VL, Dalela D, Gupta G. Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms-action of two new agents. *Investigational New Drugs*, 2012, 30, 582-593.
•	Ashish Jain, Nand Lal, Lokesh Kumar, Vikas Verma, Rajiv Kumar, Lalit Kumar, Vishal Singh, Raghav K. Mishra, Amit Sarswat, S. K. Jain, J. P. Maikhuri, V. L. Sharma, Gopal Gupta. Novel trichomonacidal spermicides. *Antimicrobial Agents and Chemotherapy*, 2011, 55 (9), 4343-4351.
•	Nand Lal, Lalit Kumar, Amit Sarswat, Santosh Jangir, Vishnu Lal Sharma. Synthesis of S-(2-thioxo-1,3-dithiolan-4-yl)methyl-dialkylcarbamothioate and S-thiiran-2-ylmethyl-dialkylcarbamothioate via Intermolecular O−S Rearrangement in Water. *Organic Letters*, 2011, 13 (9), 2330-2333.
•	Amit Sarswat, Rajeev Kumar, Lalit Kumar, Nand Lal, Smiriti Sharma, Yenamandra S. Prabhakar, Shailendra K. Pandey, Jawahar Lal, Vikas Verma, Ashish Jain, Jagdamba P. Maikhuri, Diwakar Dalela, Kirti, Gopal Gupta, Vishnu L. Sharma. Arylpiperazines for Management of Benign Prostatic Hyperplasia: Design, Synthesis, Quantative Structure – Activity Relationships, and Parmacokinetic Studies. *Journal of Medicinal Chemistry*, 2011, 54 (1), 302-311.
•	Lalit Kumar, Amit Sarswat, Nand Lal, Ashish Jain, Sumit Kumar, S.T.V.S. Kiran Kumar, Jagdamba P. Maikhuri, Atindra K. Pandey, Praveen K. Shukla, Gopal Gupta, Vishnu L. Sharma. Design and Synthesis of 3-(azol-1-yl)phenylprapanes as spermicide for prophylactic contraception . *Bioorganic & Medicinal Chemistry Letters, 2011, 21(1)*, 176-181.

LIST OF PATENTS

1	Kalpana Bhandari, V.L. Sharma and S. Ray. “An improved process for the synthesis of 3,4-disubstituted-1,5-dihydro-2H-3-pyrrolin-2-one” Indian PatentAppl. 323/Del/01 dt 23.3.2001.
2	A.K.Dwivedi, V.L.Sharma, N.Kumaria, Kiran Kumar, G.Gupta, J.P.Maikhuri, J.D.Dhar, Pradeep Kumar, A.H.Ansari, P.K.Shukla, M.Kumar, Raja Roy , K.P.Madhusudanan, R.C.Gupta, Pratima Srivastava, R.Pal, and S.Singh. “Novel spermicidal and antifungal agents” Indian Patent 245815 dt 25.01.2011 ; Appl. No.1792/Del/04 dt 22.09.2004.
3	Vishanu Lal Sharma, Nand Lal, Amit Sarswat, Santosh Jangir, Veenu Bala, Lalit Kumar, Tara Rawat, Ashish Jain, Lokesh Kumar, Jagdamba Prasad Maikhuri, Gopal Gupta. “ Carbodithioates and process for preparation thereof ” NF No. 0030/NF2013/IN, Indian Patent Appl. no.0373/DEL/2013 dated 08.02.2013.
4	Vishanu Lal Sharma, Nand Lal, Amit Sarswat, Santosh Jangir, Veenu Bala, Lalit Kumar, Tara Rawat, Ashish Jain, Lokesh Kumar, Jagdamba Prasad Maikhuri, Gopal Gupta, “ Carbodithioates with spermicidal activity and process for preparation thereof ” PCT Patent no. WO 2014122670 August 14, 2014.
5	Dhanaraju Mandalapu, Rajesh K. Arigela, Tara Rawat, and Vishnu L. Sharma, “An Improved Process For Preparation Of 4-Substituted amino-2,3-polymethylenequinoline hydrochloride ” Indian Patent IN 201611003055 dated: 28.01.2016.

Image result for Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute

///////////aryl piperazine, androgen sensitive prostatic disorders, 330633-91-5, CDRI-?

c1(ccc(cc1)[N+]([O-])=O)N2CCN(CC2)C(=O)CN3CCN(CC3)c4ccc(cc4)[N+]([O-])=O

ALMOREXANT REVISITED

September 11, 2016 11:48 am / Leave a comment

Almorexant; ACT-078573; (R)-2-((S)-6,7-Dimethoxy-1-(4-(trifluoromethyl)phenethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-2-phenylacetamide;

Almorexant (INN, codenamed ACT-078573) is an orexin antagonist, functioning as a competitive receptor antagonist of the OX₁ and OX₂ orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treatment of insomnia. Development of the drug was abandoned in January 2011.^[1]

Development

Originally developed by Actelion, from 2007 almorexant was being reported as a potential blockbuster drug, as its novel mechanism of action (orexin receptor antagonism) was thought to produce better quality sleep and fewer side effects than the traditionalbenzodiazepine and z drugs which dominated the multibillion-dollar insomnia medication market.^[2]^[3]

In 2008, pharmaceutical giant GlaxoSmithKline bought the development and marketing rights for almorexant from Actelion for an initial payment of $147 million.^[4] The deal was worth a potential $3.2billion if the drug were to successfully complete clinical development and obtain FDA approval.^[5] GSK and Actelion continued to develop the drug together, and completed a Phase III clinical trial in November 2009.^[6]

However, in January 2011 Actelion and GSK announced they were abandoning the development of almorexant because of its side effect profile.^[1]^[7]

Mechanism of action

Almorexant is a competitive, dual OX₁ and OX₂ receptor antagonist and selectively inhibits the functional consequences of OX₁ and OX₂ receptor activation, such as intracellular Ca²⁺ mobilization.

Image result for ACTELION

Image result for ALMOREXANT

PAPER

http://pubs.rsc.org/en/content/articlelanding/2013/ob/c3ob40655e#!divAbstract

An enantioselective synthesis of almorexant, a potent antagonist of human orexin receptors, is presented. The chiral tetrahydroisoquinoline core structure was prepared via iridium-catalysed asymmetric intramolecular allylic amidation. Further key catalytic steps of the synthesis include an oxidative Heck reaction at room temperature and a hydrazine-mediated organocatalysedreduction.

Graphical abstract: Enantioselective synthesis of almorexant via iridium-catalysed intramolecular allylic amidation

Image result for ALMOREXANT

PATENT

https://www.google.com/patents/EP2227454A2?cl=en

Reaction scheme 5:

7*CH₃COOH

Step 11 : synthesis of (2R)-2-{(-/S)-6,7-dimethoxy-1 -[2-(4-thfluoromethyl-phenyl)- ethyl]-3,4-dihydro-1 /-/-isoquinolin-2-yl}-Λ/-methyl-2-phenyl-acetamide (compound 8)

To the solution of the compound 7 in MIBK are added 1.2 equivalents of the compound 6, 1.1 equivalents caustic soda and 1.1 equivalents potassium carbonate and heated to 70-90 ⁰C. After full conversion the solution is cooled to RT and water is added. Phase separation is followed by a second washing of the organic phase with water and again phase separation. Step 12: synthesis of (2R)-2-{(-/S)-6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)- ethyl]-3,4-dihydro-1 /-/-isoquinolin-2-yl}-/\/-nnethyl-2-phenyl-acetannide hydrochloride acid (compound I)

To the organic phase of step 11 is added 1 equivalent aqueous hydrochloric acid and then the water removed by azeotropic distillation in vacuo. The precipitate is dissolved by addition of 2-propanol at 75 ⁰C. Concentration of the solution leads to crystallisation and the suspension is then cooled to RT. To ensure complete crystallisation, the suspension is aged at RT, then filtered and washed with a MIBK-2-propanol mixture. The product is dried in vacuo at 50 ⁰C.

PAPER

Abstract Image

Several methods are presented for the enantioselective synthesis of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a dual orexin receptor antagonist. Initial clinical supplies were secured by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori ATH) of the dihydroisoquinoline precursor. Both the yield and enantioselectivity eroded upon scale-up. A broad screening exercise identified TaniaPhos as ligand for the iridium-catalyzed asymmetric hydrogenation with a dedicated catalyst pretreatment protocol, culminating in the manufacture of more than 6 t of the acetate salt of the tetrahydroisoquinoline. The major cost contributor was TaniaPhos. By switching the dihydroisoquinoline substrate of the Ru-Noyori ATH to its methanesulfonate salt, the ATH was later successfully reduced to practice, delivering several hundreds of kilograms of the tetrahydroisoquinoline, thereby reducing the catalyst cost contribution significantly. The two methods are compared with regard to green and efficiency metrics.

Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?

Gerard K. M. Verzijl†, André H. M. de Vries†, Johannes G. de Vries†, Peter Kapitan‡, Thomas Dax‡, Matthias Helms‡, Zarghun Nazir‡, Wolfgang Skranc‡, Christoph Imboden∥, Juergen Stichler∥, Richard A. Ward§, Stefan Abele *∥, and Laurent Lefort *†

^† DSM Innovative Synthesis BV, P.O. Box 18, 6160 MD Geleen, The Netherlands

^‡ DSM Fine Chemicals Austria, St. Peter Strasse 25, 4021 Linz, Austria

^§ GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom

^∥ Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123 Allschwil, Switzerland

Org. Process Res. Dev., 2013, 17 (12), pp 1531–1539

DOI: 10.1021/op400268f, http://pubs.acs.org/doi/abs/10.1021/op400268f

Image result for ALMOREXANT

References

GSK and Actelion discontinue clinical development of almorexant – GSK press release, 28 Jan 2011
Sleeping Beautifully – CBS Business Network 24 Sep 2007
Is this FINALLY a cure for insomnia? The new pill which blocks the brain’s ‘stay awake’ messages – Daily Mail, 28 July 2008
Actelion Sells Glaxo Almorexant Sleep Medicine Rights – Bloomberg, 14 July 2008
Actelion’s top dollar deal leaves doubts, and little on the horizon – EP Vantage, 14 July 2008
Almorexant in Adult Subjects With Chronic Primary Insomnia (RESTORA 1). ClinicalTrials.gov (February 3, 2010). Retrieved on May 6, 2010.
Actelion and GSK Discontinue Clinical Development of Almorexant – Actelion press release, 28 Jan 2011

External links

Actelion’s official website

Almorexant
Systematic (IUPAC) name

(2R)-2-[(1S)- 6,7-dimethoxy- 1-{2-[4-(trifluoromethyl)phenyl]ethyl}- 3,4-dihydroisoquinolin-2(1H)-yl]- N-methyl- 2-phenylacetamide
Clinical data
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hepatic
Identifiers
CAS Number	871224-64-5
ATC code	none
PubChem	CID 23727689
IUPHAR/BPS	2886
ChemSpider	21377865
UNII	9KCW39P2EI
ChEMBL	CHEMBL455136
Chemical data
Formula	C₂₉H₃₁F₃N₂O₃
Molar mass	512.6 g/mol (free base)

///////Almorexant, ACT-078573

CNC(=O)C(C1=CC=CC=C1)N2CCC3=CC(=C(C=C3C2CCC4=CC=C(C=C4)C(F)(F)F)OC)OC

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