868540-17-4

Basic information

• Product Name: Carfilzomib
• Synonyms: Carfilzomib;N-{(2S)-2-[(Morpholin-4-ylacetyl)aMino]-4-phenylbutanoyl}-L-leucyl-N-{(2S)-4-Methyl-1-[(2R)-2-Methyloxiran-2-yl]-1-oxopentan-2-yl}-L-phenylalaninaMide;CarfilzoMib salt;CarfilzoMib/PR 171;PR-171 (CarfilzoMib);(alphaS)-alpha-[(4-Morpholinylacetyl)amino]benzenebutanoyl-L-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-L-phenylalaninamide;CarfilzoMib, Free Base, >99%;(S)-4-Methyl-N-((S)-1-((S)-4-Methyl-1-((R)-2- Methyloxiran-2-yl)-1 -oxopentan-2-ylaMino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-MorpholinoacetaMido)-4-phenylbutanaMido)pentanaMide
• CAS NO: 868540-17-4
• Molecular Formula: C40H57N5O7
• Molecular Weight: 719.90988
• EINECS: 1592732-453-0
• Product Categories: Inhibitor;peptides;API;Inhibitors
• Mol File: 868540-17-4.mol
• Article Data: 10

Chemical Properties

• Boiling Point: 975.627 °C at 760 mmHg
• Flash Point: 543.8℃
• Appearance: /
• Density: 1.161
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.551
• Storage Temp.: -20°
• Solubility: Soluble in DMSO (up to 80 mg/ml) or in Ethanol (up to 25 mg/ml).
• PKA: 13.17±0.46(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 week.
• CAS DataBase Reference: Carfilzomib(CAS DataBase Reference)
• NIST Chemistry Reference: Carfilzomib(868540-17-4)
• EPA Substance Registry System: Carfilzomib(868540-17-4)

Safety Data

• Hazardous Substances Data: 868540-17-4(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Carfilzomib is used as a treatment for relapsed and refractory multiple myeloma, a type of blood cancer. It is particularly effective in patients who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression within 60 days of completion of the last therapy. The proteosome inhibition induced by Carfilzomib results in cell cycle arrest and apoptosis in a variety of hematologic and solid tumor cell lines, such as MM, acute myeloid leukemia (AML), pancreatic cancer, and lung cancer.

Mechanism

Carfilzomib is a tetrapeptide-based epoxy-proteasome inhibitor that irreversibly binds to the 20S proteasome containing the threonine N-terminal active site and the in vivo proteolysis core particle of 26S proteasome. In animal, carfilzomib has antiproliferative and apoptosis activity in vitro in solid and hematological granulocytes. In animals, carfilzomib inhibits proteasome activity in blood and tissue and delays tumor growth in multiple myeloma, hematological and solid tumor models.

Side effects

The most common adverse events observed in clinical trials (incidence ≥30%) were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea and fever; the most common serious adverse events (overall incidence 45%) include pneumonia, acute renal failure, fever and congestive heart failure.

Efficacy and Safety

To assess the safety and efficacy of the drug, one study included 266 patients who had received at least two prior therapies, including bortezomib and thalidomide. It was assessed of the complete or partial disappearance of the tumor in the treated patient (overall response rate). The overall response rate was 23% and the median response time was 7.8 months. Common adverse effects of carfilzomib were observed in more than 30% of the subjects include fatigue, low blood cell counts and platelet counts, dyspnea, diarrhea and fever. Severe adverse reactions include heart failure and dyspnea. Upon the occurrence of serious adverse reactions, the patient should be closely monitored and stop the drug treatment. Information regarding the pharmacological effects, indications, mechanism of action, indications and side effects of Carfilzomib, a drug for treating multiple myeloma (MM), were compiled and edited by Xiao Nan of lookchem.

Originator

Proteolix Inc. (United States)

Clinical Use

Carfilzomib is an irreversible inhibitor of the chymotrypsin-like protease in the proteasome and was approved in the U.S. for the treatment of multiple myeloma. Carfilzomib was discovered by Proteolix which was later acquired by Onyx Therapeutics who completed the development of this drug. Carfilzomib is also undergoing clinical evaluation for additional oncology indications such as relapsed solid tumors, lymphoma, prolymphocytic leukemia, acute myeloid leukemia and acute lymphocytic leukemia.

Synthesis

Carfilzomib is an analog of the natural product epoxomicin which was first synthesized in the laboratories of Professor Crews at Yale University. Subsequent development of the SAR led to the discovery of YU-101 in which 3 of the amino acids of this pentapeptide were modified to improve the potency of the molecule. After licensing the molecule to Proteolix, the introduction of the morpholino group was found to improve the solubility of the drug while maintaining efficient interaction with the target. The most scalable route to carfilzomib closely resembles the original route developed toward epoximicin and is described herein.The synthesis was initiated with the amide coupling of phenyl alanine methyl ester (53) and N-Boc leucine (54) using standard coupling reagents to afford dipeptide 55 in high yield the Scheme below. Acidic removal of the amine protecting group followed by a second amide coupling reaction with N-Boc homophenyl alanine provided tripeptide 56 in 85% yield for the two steps. Acidic removal of the amine protecting group followed by acylation with chloroacetyl chloride provided β-chloro amide 57 in 67% yield. Reaction of 57 with morpholine in the presence of catalytic amounts of potassium iodide followed by saponification of the methyl ester with lithium hydroxide provided acid 58 in 87% yield for the two steps. Amide coupling between acid 58 and keto-epoxyamine 59 (whose preparation is described in the scheme below) using HOBT as the coupling reagent followed by recrystallization of the resulting product ultimately gave carfilzomib (IX) in 75% yield. Keto-epoxyamine 59 was prepared from N-Boc leucine (54) as described in the Scheme below. Reaction of 54 with isobutyl chloroformate followed by N,O-dimethylhydroxylamine provided Weinreb amide 60 in 94% yield. Grignard addition of isopropenylmagnesium bromide 60 provided enone 62 in 81% yield. Epoxidation of 62 with calcium hypochlorite provided a mixture of epoxides giving 41% yield of the desired isomer (presumably isolated by chromatography), and subsequent treatment with TFA liberated the amine, providing the TFA salt of ketoepoxy amine 59 in 92% yield.

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.

Metabolism

Carfilzomib was rapidly and extensively metabolised by mainly peptidase cleavage and epoxide hydrolysis. Cytochrome P450 mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity.

References

1) Bennett and Kirk (2008)?Development of proteasome inhibitors in oncology and autoimmune diseases; Curr. Opin. Drug Disc. Dev.?11?616 2) Hanada?et al.?(1992),?Epoxomicin, a new antitumor agent of microbial origin; J. Antibiot. (Tokyo),?45?174 3) Demo?et al. (2007)?Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome; Cancer Res.?67?6383 4) Kuhn?et al. (2007),?Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma; Blood,?110?328

InChI:InChI=1/C40H57N5O7/c1-27(2)22-32(36(47)40(5)26-52-40)42-39(50)34(24-30-14-10-7-11-15-30)44-38(49)33(23-28(3)4)43-37(48)31(17-16-29-12-8-6-9-13-29)41-35(46)25-45-18-20-51-21-19-45/h6-15,27-28,31-34H,16-26H2,1-5H3,(H,41,46)(H,42,50)(H,43,48)(H,44,49)/t31-,32-,33-,34-,40+/m0/s1

Upstream product

• 868540-16-3 (S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenyipropanoic acid 
• 247068-84-4 (2S)-2-amino-4-methyl-1-[(2R)-2-methyloxiran-2-yl]pentan-1-one 
• 110-91-8 morpholine 
• 83079-77-0 (S)-α-(2-phenylethyl)glycine, tert-butyl ester 
• 89531-58-8 N-(carboxymethyl)morpholine hydrochloride 
• 7087-68-5 N-ethyl-N,N-diisopropylamine 
• 140834-91-9 (S)-benzyl 2-((S)-2-(tert-butoxycarbonylamino)-4-methylpentanamido)-3-phenylpropanoate 
• 2462-32-0 L-phenylalanine benzyl ester hydrochloride 
• 1609959-45-6 tert-butyl N-[(4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl]carbamate 
• 875309-92-5 (S)-benzyl 2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido) pentanamido)-3-phenylpropanoate 

Relevant articles and documents

Water-removable ynamide coupling reagent for racemization-free syntheses of peptides, amides, and esters

A novel ynamide coupling reagent, the by-product of which can be removed by water, was reported. It promotes the direct coupling between carboxylic acids and amines, alcohols or thiols to provide amides, peptides, esters and thioesters, respectively. No detectable racemization was observed for all the coupling reactions of carboxylic acids containing an α-chiral center. Importantly, a simple acidic aqueous work-up removed the by-product readily to afford pure coupling products in good to excellent yields without the use of column chromatography, thus making this method more environmentally benign, user friendly and cost-effective. The robustness of the water-removable ynamide coupling reagent was further exemplified by the racemization/epimerization-free synthesis of carfilzomib, in which no column chromatography purification was involved for the entire 12-step synthesis.

Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis

Allenone has been identified as a highly effective peptide coupling reagent for the first time. The peptide bond was formed with an α-carbonyl vinyl ester as the key intermediate, the formation and subsequent aminolysis of which proceed spontaneously in a racemization-/epimerization-free manner. The allenone coupling reagent not only is effective for the synthesis of simple amides and dipeptides but is also amenable to peptide fragment condensation and solid-phase peptide synthesis (SPPS). The robustness of the allenone-mediated peptide bond formation was showcased incisively by the synthesis of carfilzomib, which involved a rare racemization-/epimerization-free N to C peptide elongation strategy. Furthermore, the successful synthesis of the model difficult peptide ACP (65-74) on a solid support suggested that this method was compatible with SPPS. This method combines the advantages of conventional active esters and coupling reagents, while overcoming the disadvantages of both strategies. Thus, this allenone-mediated peptide bond formation strategy represents a disruptive innovation in peptide synthesis.

PURIFICATION METHOD OF CARFILZOMIB

The present invention relates to a process for purification of carfilzomib free from its impurities using preparative high performance liquid chromatography (prep-HPLC).

PROCESSES FOR THE PREPARATION OF CARFILZOMIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.

PROCESS FOR MAKING CARFILZOMIB

The present invention relates to a process for preparation of Carfilzomib of formula (I).

AN IMPROVED PROCESSES FOR THE PREPARATION OF CARFILZOMIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.

PROCESS FOR THE PREPARATION OF (2S)-N-((S)-1-((S)-4-METHYL-1-((R)-2-METHYL OXIRAN-2-YL)-1-OXOPENTAN-2-YLCARBAMOYL)-2-PHENYLETHYL)-2-((S)-2-(2-MORPHOLINO ACETAMIDO)-4-PHENYLBUTANAMIDO)-4-METHYLPENTANAMIDE

The present invention relates to process for the preparation of (2S)-N-((S)-l -((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4 -methylpentanamide represented by the following structural formula-1.

METHODS OF MAKING CARFILZOMIB AND INTERMEDIATES THEREOF

Racemization-free methods are disclosed for the synthesis of carfilzomib. Novel intermediates and methods of making carfilzomib employing fragment condensation using the novel intermediates are disclosed. Amorphous carfilzomib and methods of making same are disclosed.

CRYSTALLINE PEPTIDE EPOXY KETONE PROTEASE INHIBITORS AND THE SYNTHESIS OF AMINO ACID KETO-EPOXIDES

The invention relates to crystalline peptide keto epoxide compounds, methods of their preparation, and related pharmaceutical compositions. This invention also relates to methods for the preparation of amino acid keto-epoxides. Specifically, allylic ketones are stereoselectively converted to the desired keto epoxides.

Compounds for enzyme inhibition

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.