625115-55-1

Basic information

• Product Name: Riociguat
• Synonyms: Riociguat;N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methylcarbamic acid methyl ester;Bay 63-2521;Carbamic acid, (4,6-diamino-2-(1-((2-fluorophenyl)methyl)-1H-pyrazolo(3,4-B)pyridin-3-yl)-5-pyrimidinyl)methyl-, methyl ester;Riociguat (BAY 63-2521);Bay63-2521,Riociguat;[4,6-DiaMino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyriMidin-5-yl]MethylcarbaMic acid Methyl ester;Methyl (4,6-diaMino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyriMidin-5-yl)(Methyl)carbaMate
• CAS NO: 625115-55-1
• Molecular Formula: C20H19FN8O2
• Molecular Weight: 422.4156632
• EINECS: 1308068-626-2
• Product Categories: API
• Mol File: 625115-55-1.mol

Chemical Properties

• Boiling Point: 567.202 °C at 760 mmHg
• Flash Point: 296.833 °C
• Appearance: /
• Density: 1.51
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly, Heated)
• PKA: 1.51±0.50(Predicted)
• CAS DataBase Reference: Riociguat(CAS DataBase Reference)
• NIST Chemistry Reference: Riociguat(625115-55-1)
• EPA Substance Registry System: Riociguat(625115-55-1)

Safety Data

• Hazardous Substances Data: 625115-55-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Riociguat is used as a medication for the treatment of pulmonary hypertension, specifically targeting chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) in adults. Its dual mode of action helps restore the NO-sGC-cGMP pathway, leading to increased cGMP generation and vasodilation, which can alleviate the symptoms and complications associated with pulmonary hypertension.

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).

Originator

Bayer (Germany)

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.

Upstream product

• 74-88-4 methyl iodide 
• 370879-49-5 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazen-1-yl]pyrimidine-4,6-diamine 
• 6642-30-4 methyl N-methylcarbamate 
• 256499-19-1 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride 
• 256376-68-8 please input 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-formamidine 
• 1702271-98-4 2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-N-methylpyrimidine-4,5,6-triamine 
• 79-22-1 methyl chloroformate 
• 428854-23-3 C₂₃H₁₈FN₉ 
• 428854-24-4 2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6- triamine 

Relevant articles and documents

Synthesis method of riociguat

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.

PROCESS FOR THE PREPARATION OF METHYL 4,6-DIAMINO-2-[1-(2-FLUOROBENZYL)-1H-PYRAZOLO[3,4-B]PYRIDIN-3-YL]-5-PYRIMIDINYL(METHYL)CARBAMATE AND ITS POLYMORPHS THEREOF

The present invention relates to an improved process for the preparation of methyl 4,6-diamino-2-[ 1-(2-fluorobenzyl)-1 H -pyrazolo[3,4-b )pyridin-3 -yl]-5-pyrimidinyl(methyl)carbamatecompound of formula-1 and its polymorphs thereof, represented by the fo

Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure

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.

PROCESS FOR THE PREPARATION OF METHYL 4,6-DIAMINO-2-[L-(2-FHIOROBENZVR)-LH-PYRAZOLO I3,4-BLPVRIDIN-3-VN-5-PYRIMIDINYL(METHVL)CARBAMATE AND ITS POLYMORPHS THEREOF

The present invention relates to process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof compound of formula-1, represented by the following structur

Preparation method of riociguat

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

The preparation method of the west leo gua (by machine translation)

The invention discloses a method for preparation of west leo gua, its to 1 - (2 - fluorobenzyl) - 1 H - pyrazolo [3, 4 - b] pyridine - 3 - carboxamidine hydrochloride as the raw material, via the four-step reaction 2 - [1 - (2 - fluorobenzyl) - 1 H - pyra

A compound intermediate [...] and its as the application of the (by machine translation)

This invention relates to a kind of compound, can be used as intermediate [...] and its derivatives. Also disclosed are intermediates to a new method of preparing [...], [...] and the purity of the obtained high, effectively reducing the occurrence of the side reaction, the production cost is saved. (by machine translation)

Preparation method of riociguat

The invention discloses a preparation method of riociguat. The preparation method comprises the steps of firstly, taking 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride and 2-aminopropanediamide as basic raw materials, adding str

Compound and application thereof in preparation of riociguat

The present invention discloses compound 5-methylamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidine-4,6-diamine, which can be used as an intermediate of riociguat and riociguat derivatives. The present invention also discloses a new method for the preparation of the riociguat by use of the intermediate, and the obtained riociguat has high yield and purity, the occurrence of side effects can be effectively reduced, and production cost is saved.

A method for synthesizing [...]

The invention relates to a method for synthesizing riociguat. The method includes the following steps: 1, a compound 1-(2-fluorobenzyl)-1H-[3,4-b] pyridine derivative-3-formamidine hydrochloride (1) and a compound benzeneazomalononitrile (2) are reacted i