625115-55-1 Usage
Pharmacological effects
Riociguat is a soluble guanylyl cyclase activator, developed by the German Bayer ,it is an important signaling enzyme, which can be activated by nitric oxide (NO) to catalyze guanosine triphosphate ( GTP) to convert into the second messenger cyclic guanosine monophosphate (cGMP). Soluble guanylate cyclase is currently the only known NO receptor. Damage of NO-sGC-cGMP signal pathway is believed to be the cause of the incidence of cardiovascular, lung, endothelium, kidney and liver diseases. NO synthesis in patients with pulmonary hypertension is not enough, NO donor drugs, although effective, short half-life, riociguat can directly activate sGC, stable NO-sGC combination so as to upregulate the second messenger cGMP. riociquat can significantly increase exercise tolerance in patients with hemodynamic parameters of cardiac function and prolong the time to reach clinical worsening (PATENT study), It may also be effective in treating CTEPH(CHEST study) .
October 8, 2013, the US FDA approved Riociguat for the treatment of chronic thromboembolic pulmonary hypertension and PAH (Pulmonary Arterial Hypertension).
At present, Riociguat is not yet sold in the domestic market ,in the United States it is sold by the Haoeyou Pharmacy , the pharmacy is subsidiary of California Healthcom Group, because the market ofRiociguat is in its infancy, its sales grow slowly.
Clinical evaluation
In clinical trials ,261 patients with chronic thromboembolic pulmonary hypertension (CTEPH) were divided into riociguat and placebo groups, a six-minute walk distance (6MWD) as the main clinical endpoint, after 16 weeks of treatment, 6MWD of riociguat group increased by 46 meters higher than the average in the placebo group. 443 cases of PAH were divided into riociguat and placebo groups,after 12 weeks of treatment, riociguat group increased 36 meters higher than the average 6MWD in the placebo group. Boxed warning suggests that the drug has a embryo toxicity, pregnant patients are forbidden.
Adempas is granted baseing on two global III studies CHEST-1 and PATENT-1, whose findings are published in the July 25, 2013"New England Journal of Medicine," (2013; 369: 330-40; 2013; 369: 319-29). Thomson Reuters released analysis report that it is expected that sales of the drug in 2017 will reach $ 679 million, while the market will face a potential threat constituted by the Swiss company Actelion bosentan and Gilead drug Imber bosentan tablets.
The above information is edited by the lookchem of Tian Ye.
Production Method
Synthetic key of Riociguat is the synthesis of three heterocyclic ring. Compounds 1 and 2 directly close the pyrazole ring to generate 3,3 and 4 and then close the pyrazole ring to obtain5, ethyl of 5 is dehydrated using trifluoroacetic anhydride to give a cyano group after amidation by the ammonia , the cyano group is treated with methanol sodium and chloride ammonium to get amidine 6. The two nitrogen atoms on Amidine 6 as dinucleophile, with two cyano on compound 7 as the electrophile ,directly close the pyrimidine ring to give 8. pyrimidine 5-position amino group on 8 with a strong nucleophilic, directly reacts with methyl chloride and then methylates to give riociguat.
Figure 1 is a chemical reactions road map of Riociguat production .
Patent cases
US7173037 (there is a deadline to April 25, 2023), US6743798 (valid until July 16, 2019).
Description
In September 2013, Health Canada approved riociguat (also referred to as BAY 63-2521), for the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment or inoperable CTEPH and for the treatment of adults with pulmonary arterial hypertension (PAH). Riociguat has a dual mode of action and works by (a) sensitizing sGC to the body’s NO by stabilizing NO–sGC binding and (b) an NO-independent, direct stimulation of sGC via a different binding site. This process restores the NO–sGC–cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.Headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation were the most common adverse events ( 3%) observed during riociguat clinical trials. Riociguat comes with a black box warning for embryo-fetal toxicity.
Originator
Bayer (Germany)
Uses
Different sources of media describe the Uses of 625115-55-1 differently. You can refer to the following data:
1. Riocguat is used in the treatment for pulmonary hypertension.
2. Riociguat is used in the treatment for pulmonary hypertension.
Definition
ChEBI: A carbamate ester that is the methyl ester of {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamic acid. It is used for treatment of chronic thromboembolic pulmonary hypertension an
pulmonary arterial hypertension
Brand name
Adempas
Clinical Use
Guanylate cyclase stimulator:
Treatment of chronic thromboembolic pulmonary
hypertension (CTEPH) and pulmonary arterial
hypertension (PAH)
Synthesis
The sequence began with condensation of commercial 2-fluorobenzylhydrazine
(136) with sodium ethyl cyanopyruvate (137),
which derives from diethyl oxalate to generate aminopyrazole
138. This was followed by the cyclocondensation with 3-dimethylaminoacrolein
(139) to access pyrazolopyridine 140 in 50% yield
for the two-step operation. Next, ester 140 was transformed to
the corresponding primary amide 141, which was subsequently
dehydrated upon treatment with trifluoroacetic acid anhydride
(TFAA) to construct nitrile 142 in quantitative yield from 140.
Subjection of cyanopyrazole 142 to Pinner conditions using
methoxide and ammonium chloride in refluxing acetic acid generated
amidine 143, and this was followed by condensation with the
malononitrile derivative 144 in base to provide pyrimidine 145 in
73% yield. Hydrogenative cleavage of the phenyldiazine converted 145 to the pyrimidyl triamine 146, which underwent carbamoylation
at the 40 position to produce the penultimate carbamate
147. This carbamate was then selectively methylated
through deprotonation of the carbamate N–H proton followed by
quench with methyl iodide. Sequential recrystallization from
warm DMSO and refluxing ethyl acetate produced riociguat (XIX)
in 64% yield from 147.
Drug interactions
Potentially hazardous interactions with other drugs
Avanafil, sildenafil, tadalafil, vardenafil: enhanced
hypotensive effect - avoid.
Nicorandil: possibly enhanced hypotensive effect -
avoid.
Nitrates: possibly enhanced hypotensive effect -
avoid.
Metabolism
N-demethylation, catalysed by CYP1A1, CYP3A4,
CYP2C8 and CYP2J2 is the major biotransformation
pathway leading to its major circulating active
metabolite M-1 (pharmacological activity: 1/10th to
1/3rd of riociguat) which is further metabolised to the
pharmacologically inactive N-glucuronide.
Riociguat and metabolites are excreted via both
renal (33-45%) and biliary/faecal routes (48-59%).
Approximately 9-44% of the administered dose was
found as unchanged riociguat in faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 625115-55-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,2,5,1,1 and 5 respectively; the second part has 2 digits, 5 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 625115-55:
(8*6)+(7*2)+(6*5)+(5*1)+(4*1)+(3*5)+(2*5)+(1*5)=131
131 % 10 = 1
So 625115-55-1 is a valid CAS Registry Number.
625115-55-1Relevant articles and documents
Synthesis method of riociguat
-
Paragraph 0033-0034; 0037-0040; 0041; 0044-0047, (2021/09/04)
The invention relates to the field of drug synthesis, in particular to a preparation method of riociguat. The preparation method comprises the steps that a compound 3 is taken as a raw material and is reacted with methyl chloroformate to obtain a hydrochloride of a compound 2, and the hydrochloride of the intermediate 2 is reacted with a methylation reagent under base catalysis to obtain riociguat. In the synthesis of the compound 2, pyridine used as a solvent and alkali is avoided; in the synthesis of the compound 1, the use of unsafe and expensive reagents such as NaH and LiHMDS is avoided. The riociguat synthesis method provided by the invention has the advantages of simplicity and convenience in operation, mild conditions, environmental friendliness, high total yield and purity, low cost and the like, and is suitable for large-scale industrial production.
Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure
Follmann, Markus,Ackerstaff, Jens,Redlich, Gorden,Wunder, Frank,Lang, Dieter,Kern, Armin,Fey, Peter,Griebenow, Nils,Kroh, Walter,Becker-Pelster, Eva-Maria,Kretschmer, Axel,Geiss, Volker,Li, Volkhart,Straub, Alexander,Mittendorf, Joachim,Jautelat, Rolf,Schirok, Hartmut,Schlemmer, Karl-Heinz,Lustig, Klemens,Gerisch, Michael,Knorr, Andreas,Tinel, Hanna,Mondritzki, Thomas,Trübel, Hubert,Sandner, Peter,Stasch, Johannes-Peter
, p. 5146 - 5161 (2017/06/28)
The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-Activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.
Preparation method of riociguat
-
Paragraph 0020; 0021; 0022; 0023; 0024; 0025; 0026-0040, (2017/08/29)
The invention relates to the field of medicinal chemistry, in particular to a preparation method of riociguat. According to the method, a compound of a formula 2 serves as a raw material, and reaction is conducted in a solvent under the existence of a met
