879085-55-9

Usage

Uses

Used in Oncology:
2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide is used as a potent Hedgehog inhibitor for the treatment and prevention of many types of human cancers. By inhibiting the Hh signaling pathway, 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide can effectively reduce the downstream production of proliferation factors, thereby suppressing tumor growth and progression.
Used in the Treatment of Basal Cell Carcinoma:
In January 2012, the US FDA approved vismodegib (Erivedge) for the treatment of adults with metastatic basal cell carcinoma (BCC) or locally advanced BCC that has recurred following surgery or for those who are not candidates for surgery or radiation. As an antagonist of SMO, vismodegib inhibits the activation of Hedgehog target genes, resulting in decreased tumor growth and progression.
Used in Drug Synthesis:
A synthesis of vismodegib starting from 2-chloro-5-nitro aniline and employing a Negishi coupling with 2-pyridyl zinc iodide as a key step has been reported. This synthesis process highlights the potential of 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide as a key intermediate in the development of novel therapeutic agents targeting the Hedgehog signaling pathway.

Originator

Curis/Genentech (United States)

Clinical Use

Antineoplastic agent: Treatment of basal cell carcinoma which is inappropriate for surgery or radiotherapy

Synthesis

The synthesis began with selective iodination of commercial carboxylic acid 179, affording trisubstituted arene 180 in 73% yield. A Curtius reaction then converted 180 to carbamate 181 in 84% 52 yield, and this was followed by a palladium(0)-catalyzed borylation of 181 which furnished Suzuki coupling partner 182 in 91% yield. Pinacol borane 182 was exposed to commercial 2-bromopyridine under conventional cross-coupling conditions to furnish biaryl 183, which underwent Boc-deprotection in quantitative conversion to generate 184. Amide bond formation with acid chloride 185 (readily available from the corresponding commercial acid) produced vismodegib (XXVIII) in 99% yield.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration possibly reduced by rifampicin - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

Metabolism

Vismodegib is hepatically metabolised by CYP2C9 and CYP3A4, however more than 98% of total systemic vismodegib is not metabolised. Metabolic pathways of vismodegib include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in faeces are produced in vitro by recombinant CYP2C9 and CYP3A4/5. Vismodegib is slowly eliminated by a combination of metabolism and excretion of parent drug, the majority is recovered in the faeces (82%). Vismodegib and its metabolites are eliminated mainly by the hepatic route.

References

1) Rominger et al. (2009), Evidence for allosteric interactions of antagonist binding to the smoothened receptor; J. Pharmacol. Exp. Therap., 329 995 2) Tian et al. (2012), The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells; Anticancer Res., 32 89 3) Zhang et al. (2009), Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp; Neoplasia, 11 96 4) Cirrone and Harris (2012), Vismodegib anf the hedgehog pathway: a new treatment for basal cell carcinoma; Clin. Ther., 34 2039 5) Wu et al. (2017), Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines; Exp. Ther. Med., 13 2529 6)Singh et al. (2011) Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms; PLoS One 6?e27306 7) Rudin et al. (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449; N. Engl. J. Med., 361?1173 8) Von Hoff et al. (2009) Inhibition of the hedgehog pathway in advanced basal-cell carcinoma; N. Engl. J. Med., 361?1164

InChI:InChI=1/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)

Upstream product

• 879088-40-1 2-(2-chloro-5-nitrophenyl)-pyridine 
• 879088-41-2 4-chloro-3-(pyridin-2-yl)benzeneamine 
• 106904-10-3 2-chloro-4-(methylsulphonyl)benzoyl chloride 
• 110-86-1 pyridine 
• 694-59-7 pyridine N-oxide 
• 645-00-1 m-iodonitrobenzene 
• 103985-13-3 2-(3-nitrophenyl)pyridine 1-oxide 
• 53250-83-2 2-chloro-4-(methanesulfonyl)benzoic acid 
• 23082-50-0 2'-chloro-5'-nitroacetophenone 
• 2516-96-3 2-chloro-5-nitrobenzoic acid 
• 25784-91-2 2-chloro-5-nitrobenzoylchloride 
• 6283-25-6 H₂NC₆H₃(Cl)NO₂ 
• 74534-15-9 1-chloro-2-iodo-4-nitrobenzene 
• 99-03-6 1-(3-aminophenyl)ethanone 

Downstream Products

• 1616666-78-4 C₂₁H₁₆Cl₂N₂O₅S 
• 1616666-79-5 C₂₁H₁₅Cl₂FN₂O₅S 

Relevant academic research and scientific papers

Preparation method of vimodegil

The invention provides a preparation method of vimodegil. 2-chloro-5-nitroacetophenone is used as a raw material; 5-oxo-5-(2-chloro-5-nitrophenyl) n-valeraldehyde is prepared through an addition reaction between 2-chloro-5-nitroacetophenone and acrolein,

Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones

Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross-coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross-couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five- to twelve-membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO2-insertion reductive cross-coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late-stage SO2 insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.

Selective Late-Stage Oxygenation of Sulfides with Ground-State Oxygen by Uranyl Photocatalysis

Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late-stage oxygenation of sulfur-containing complex molecules with ground-state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+) enabled the efficient synthesis of sulfones. The ligand-to-metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late-stage oxygenation in an atom- and step-efficient manner.

A [...] synthesis of intermediates method and application

The invention relates to a method for synthesizing intermediate [...] and application, which belongs to the field of organic synthesis, in particular to intermediate 2 - (2 - chloro - 5 - nitrophenyl) pyridine (i.e. compound A) preparation process, compri

Preparation methods of Vismodegib and intermediate of Vismodegib

The invention provides preparation methods of Vismodegib and an intermediate of the Vismodegib, namely, preparation methods of 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide and an intermediate of the 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide. According to the preparation methods, the intermediate, namely 2-chloro-4-methylsulfonyl-N-(3-(2-pyridinyl)phenyl)benzamide is prepared firstly, and then the 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide is prepared through a chlorination reaction. The preparation methods have the characteristics that the steps are short, operation is easy, starting materials are cheap and easy to obtain, no palladium reagent is used, the reaction condition has the low requirements for the anhydrous and oxygen-free condition, and the production cost can be effectively lowered.

Sulfoxide and sulfone compounds, as well as selective synthesis method and application thereof

The invention discloses a method for selectively synthesizing a sulfoxide compound shown as a formula (II) and a sulfone compound shown as a formula (III). In a reaction solvent, thioether (I) is usedas a reaction raw material and oxygen as an oxidation reagent, under the catalytic action of visible light and a photosensitive reagent; under the assistance of an additive, when a large-polarity proton-containing additive such as an acid and an alcohol or a solvent or an additive with excellent electron donating ability is used, a sulfoxide compound (II) is selectively generated; and when a small-polarity aprotic additive or a solvent is used, a sulfone compound (III) is selectively generated. The synthesis method has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and excellent functional group tolerance. According to the invention, synthesis and modification of some medicines are realized, and an efficient method for selectively constructing sulfoxide and sulfone compounds is provided for medicinal chemistry research.

Aryl alkyl sulfone compound and reducing coupling method for constructing sulfone compounds

The invention discloses an aryl alkyl sulfone compound shown as a formula (1) and a synthetic method thereof. The aryl alkyl sulfone compound is prepared by taking an aromatic iodide, an inorganic sulfur reagent and an alkyl bromide as reaction raw materials to carry out reacting in a solvent under action of alkali, a catalyst, a ligand, a reducing agent and an additive. According to the invention, an inorganic sulfur reagent is used as a sulfur source to construct the aryl alkyl sulfone compound in one step under catalysis and reduction conditions, so that the defect in synthesizing the arylalkyl sulfone compound by conventional oxidation of thioether is avoided. The aryl alkyl sulfone compound developed by the invention can be used for synthesizing aryl alkyl sulfone medicines.

A Pyridine–Pyridine Cross-Coupling Reaction via Dearomatized Radical Intermediates

A pyridine–pyridine coupling reaction has been developed between pyridyl phosphonium salts and cyanopyridines using B2pin2 as an electron-transfer reagent. Complete regio- and cross-selectivity are observed when forming a range of valuable 2,4′-bipyridines. Phosphonium salts were found to be the only viable radical precursors in this process, and mechanistic studies indicate that the process does not proceed through a Minisci-type coupling involving a pyridyl radical. Instead, a radical–radical coupling process between a boryl phosphonium pyridyl radical and a boryl-stabilized cyanopyridine radical explains the C?C bond-forming step.

Design, synthesis and biological evaluation of deuterated Vismodegib for improving pharmacokinetic properties

Vismodegib is an oral and high selective hedgehog (Hh) inhibitor used for the treatment of basal cell carcinoma (BCC). In this work, analogs of Vismodegib with deuterium-for-hydrogen replacement at certain metabolically active sites were prepared and found to have a better pharmacokinetic properties in mice. In particular, deuterated compound SKLB-C2211 obviously altered the blood circulation behavior compared to its prototype, which was demonstrated by significantly prolonged blood circulation half-life time (t1/2) and increased AUC0→∞. These results suggested SKLB-C2211 had the potential to be a long-acting inhibitor against Hh signaling pathway, and laid the foundation for the further research of its druggability.

Synthetic Path To Pharmaceutically Acceptable Vismodegib

The present invention relates to a new route of synthesis to obtain pharmaceutically acceptable Vismodegib. In addition, besides the synthesis also suitable pharmaceutical compositions and the use of the compound for the treatment of basal-cell carcinomas