923604-59-5 Usage
Description
Simeprevir, also known as TMC435, is a potent NS3/4A protease inhibitor (PI) used for the treatment of genotype 1 hepatitis C virus (HCV) infection. It was approved in Japan, the United States, and Canada under the trade names Sovriad, Olysio, and Galexos, respectively. Simeprevir is the third HCV PI to receive approval and was discovered through the optimization of a novel series of cyclopentane-core macrocyclic HCV PIs. It gains binding affinity through a large P2 quinoline substituent that occupies an extended S2 subsite of HCV protease by induced fit, unlike earlier PIs that rely on the formation of a covalent intermediate. Key features of simeprevir include truncation of the P3 capping group, use of an acylsulfonamide as an acid isostere, and incorporation of an isopropylthiazole group for improved permeability. It exhibits potent antiviral activity against genotype 1 HCV with Ki=0.36 nM and EC50 values of 7.8 nM for genotype 1b and 28.4 nM for genotype 1a.
Uses
Used in Pharmaceutical Industry:
Simeprevir is used as an antiviral agent for the treatment of genotype 1 hepatitis C virus (HCV) infection. It is administered in combination with pegylated interferon and ribavirin (PR) to enhance the therapeutic efficacy and provide a more effective treatment option for patients suffering from this viral infection.
Originator
Tibotec and Medivir (Ireland and Sweden)
Clinical Use
HCV NS3/4A serine protease inhibitor:
Treatment of hepatitis C in combination with other
treatment
Synthesis
Commercial 2-methyl-3-methoxybenzoic acid (153) was treated
with diphenylphosphorylazide (DPPA) and triethylamine to
affect a Curtius rearrangement and the resulting isocyanate was
trapped with t-butanol to produce the Boc-protected aniline 154
in quantitative yield. Upon removal of the Boc protecting group
with TFA, the resulting aniline was reacted with boron trichloride
followed by the addition of acetonitrile and aluminum trichloride
to affect Friedel–Crafts acylation to give aminoacetophenone 155
in 40% yield. Acylation of the amino group with 4-isopropylthiazole-
2-carbonyl chloride (156) gave ketoamide 157 in 90% yield,
which was treated with potassium tert-butoxide in t-butanol at
100 ℃ to furnish quinolinol 158 in 88% yield.
Use of a ring closing metathesis approach, enabling the synthesis
of the macrocyclic portion of the drug and ultimately simeprevir,
is described. Hydrogenation of commercial
trans-cyclopentanone-3,4-dicarboxylic acid (159) over Raney Ni in
the presence of triethylamine followed by cyclization to the
lactone using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and
N-methylmorpholine (NMM), and subsequent cinchonidine salt
formation gave lactone acid 160 in 26% yield over the 3 steps in
97% ee. Next, amide coupling with N-methylhexenylamine using
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), Fischer
esterification, and subsequent introduction of the quinolinol fragment
158 under Mitsunobu conditions using triphenylphosphine
(PPh3) and diisopropyl azodicarboxylate (DIAD) provided methyl
ester 161 in 65% overall yield for the three steps. Saponification
of the ester with lithium hydroxide followed by EEDQ-promoted
coupling to (1R,2S)-1-amino-2-vinyl-cyclopropane ethyl ester
(162) and Boc protection of the resulting amide gave the RCM
substrate, diene 163 in 95% yield for the two steps.
Macrocyclization of 163 using the second generation M2 catalyst
under dilute concentration in refluxing toluene followed
by acidic removal of the amide protecting group gave cycloalkene
ester 164 in high yield. Saponification of the ester, activation of the
resulting acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI), and coupling with cyclopropylsulfonamide led to
simeprevir (XXI) in high overall yield.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: possible increased risk of
bradycardia with amiodarone.
Antibacterials: concentration possibly increased by
clarithromycin - avoid; concentration of both drugs
increased with erythromycin - avoid; concentration
reduced by rifampicin and possibly rifabutin - avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, oxcarbazepine,
phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration possibly increased by
fluconazole, itraconazole, ketoconazole, posaconazole
and voriconazole - avoid.
Antivirals: concentration of both drugs increased
with darunavir - avoid; concentration reduced
by efavirenz; avoid with etravirine; concentration
possibly reduced by nevirapine - avoid;
concentration increased by ritonavir - avoid.
Ciclosporin: avoid concomitant use, increased
simeprevir concentration.
Cobicistat: concentration possibly increased by
cobicistat - avoid.
Metabolism
Hepatically metabolised. In vitro experiments with human
liver microsomes indicated that simeprevir primarily
undergoes oxidative metabolism by the hepatic CYP3A4
system.
Elimination of simeprevir occurs via biliary excretion.
Following a single oral administration of 200 mg
[14C]-simeprevir to healthy subjects, on average 91% of
the total radioactivity was recovered in faeces. Unchanged
simeprevir in faeces accounted for on average 31% of the
administered dose. Renal clearance plays an insignificant
role in its elimination.
Check Digit Verification of cas no
The CAS Registry Mumber 923604-59-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,2,3,6,0 and 4 respectively; the second part has 2 digits, 5 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 923604-59:
(8*9)+(7*2)+(6*3)+(5*6)+(4*0)+(3*4)+(2*5)+(1*9)=165
165 % 10 = 5
So 923604-59-5 is a valid CAS Registry Number.
923604-59-5Relevant articles and documents
HCV inhibitors of HCV inhibitors and intermediates prepared by the method of
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Paragraph 0058; 0059, (2019/06/11)
The invention relates to the drug synthesis technical field, specifically discloses compounds represented by the formula IV and the formula V and used for preparation of an HCV inhibitor Simeprevir and a preparation method thereof, and at the same time, also discloses a method for preparation of the HCV inhibitor Simeprevir with the compounds. In the process of preparation of the HCV inhibitor Simeprevir, during synthesis of a 14-membered macro ring, an amidation reaction is adopted for replacing a conventional double decomposition reaction, and the efficiency of the amidation reaction is much higher than that of the double decomposition reaction, and a step of synthesis of olefins is carried out in advance, so that the reaction steps of the whole synthesis are greatly shortened in the synthetic process, the operations are simple, expensive hydroxyl cycloglutaric acid and heterocyclic phenol have no need of consumption, and the production cost is greatly reduced.
Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350
Raboisson, Pierre,de Kock, Herman,Rosenquist, Asa,Nilsson, Magnus,Salvador-Oden, Lourdes,Lin, Tse-I,Roue, Natalie,Ivanov, Vladimir,Waehling, Horst,Wickstroem, Kristina,Hamelink, Elizabeth,Edlund, Michael,Vrang, Lotta,Vendeville, Sandrine,Van de Vreken, Wim,McGowan, David,Tahri, Abdellah,Hu, Lili,Boutton, Carlo,Lenz, Oliver,Delouvroy, Frederic,Pille, Geert,Surleraux, Dominique,Wigerinck, Piet,Samuelsson, Bertil,Simmen, Kenneth
scheme or table, p. 4853 - 4858 (2009/05/11)
SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]- 13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamid e (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (Ki = 0.36 nM) and viral replication (replicon EC50 = 7.8 nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics.
MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
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Page/Page column 76-77, (2008/06/13)
Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is -OR7, -NH-SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het; R6 is C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents ; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
