105628-07-7

Basic information

• Product Name: Fasudil hydrochloride
• Synonyms: 1-(5-ISOQUINOLINESULFONYL)HOMOPIPERAZINE HYDROCHLORIDE;(5-ISOQUINOLINESULFONYL)HOMOPIPERAZINE, 2HCL;5-(1,4-DIAZEPAN-1-YLSULFONYL)ISOQUINOLINE HYDROCHLORIDE;HEXAHYDRO-1-(5-ISOQUINOLINYLSULFONYL)-MONOHYDROCHLORIDE;HA-1077;HA-1077 DIHYDROCHLORIDE;FASUDEL;FASUDIL DIHYDROCHLORIDE
• CAS NO: 105628-07-7
• Molecular Formula: C₁₄H₁₇N₃O₂S*ClH
• Molecular Weight: 327.83
• EINECS: 1308068-626-2
• Product Categories: APIs;API;Inhibitor;Cardiovascular & Blood System Agents;Inhibitors
• Mol File: 105628-07-7.mol
• Article Data: 10

Chemical Properties

• Melting Point: 220.5°; mp 219.3° (Shirotani)
• Boiling Point: 506.2 °C at 760 mmHg
• Flash Point: 259.9 °C
• Appearance: white/solid
• Storage Temp.: Inert atmosphere,Store in freezer, under -20°C
• Solubility: H2O: >200 mg/mL
• Water Solubility: Soluble in water and dimethyl sulfoxide. Insoluble in ethanol.
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20° for up to 1 month.
• Merck: 14,3942
• CAS DataBase Reference: Fasudil hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Fasudil hydrochloride(105628-07-7)
• EPA Substance Registry System: Fasudil hydrochloride(105628-07-7)

Safety Data

• Statements: 22
• Safety Statements: 36-60
• WGK Germany: 3
• RTECS: HM4031166
• Hazardous Substances Data: 105628-07-7(Hazardous Substances Data)

Usage

Description

Fasudil hydrochloride, also known as Fasudil monohydrochloride, is a novel calcium antagonistic vasodilator that was marketed for the treatment of cerebral vasospasm following subarachnoid hemorrhage (SAH). It is a potent inhibitor of myosin light chain kinase and protein kinase C, and it serves as a selective Rho-associated protein kinase (ROCK) inhibitor. Fasudil hydrochloride is used in the prevention and treatment of cardiovascular and cerebrovascular diseases, as well as in the inhibition of proliferation of vascular smooth muscle cells. It has an intracellular mode of action in relaxing vascular smooth muscle, which makes it distinct from other calcium channel blockers. Additionally, it protects against methyl mercury-induced axonal degeneration.

Uses

Used in Cardiovascular and Cerebrovascular Applications:
Fasudil hydrochloride is used as a vasodilator for the prevention and treatment of cardiovascular and cerebrovascular diseases. It acts as a potent Rho-kinase inhibitor, which helps in the inhibition of proliferation of vascular smooth muscle cells.
Used in Cerebral Vasospasm Treatment:
Fasudil hydrochloride is used as a treatment for cerebral vasospasm following subarachnoid hemorrhage (SAH). It helps in decreasing the occurrence of angiographic severe and symptomatic vasospasm and cerebral infarction without decreasing systemic blood pressure.
Used in Neurological Deficits:
Fasudil hydrochloride is used as a treatment for patients with neurological deficits due to vasospasm, providing relief and improving their condition.
Used in Clinical Trials:
Fasudil hydrochloride is reportedly in clinical trials for acute ischemic stroke, sequelae of cerebral vascular diseases, and angina pectoris, indicating its potential in treating a range of conditions related to blood flow and vascular health.
Brand Name:
Eril is the brand name under which Fasudil hydrochloride is marketed.

Indications and Usage

Fasudil Hydrochloride is a new drug with a wide range of pharmacological effects, developed by Asahi Kasei Corporation (Japan.) It is a cardiovascular and cerebrovascular drug which improves symptoms of ischemic cerebrovascular disease such as cerebral vasospasm following subarachnoid hemorrhage. It has significant neuroprotective and therapeutic effects for ischemic cerebrovascular disease, and is suited for clinical use, particularly at the grassroots level to reduce mortality and improve quality of life.

Mechanisms of Action

Fasudil Hydrochloride is an isoquinoline sulfonamide derivative which can relax separated cerebral blood vessels, inhibit the shrinkage of separated blood vessels caused by calcium influx, inhibit different mechanisms of brain blood vessel contraction from contractile agents, and inhibit intracellular calcium ion activity without reducing calcium ion concentration. Fasudil Hydrochloride is an RHO kinase inhibitor which dilates vessels, reduces tension of endothelial cells, and improves microcirculation of brain tissue without producing or exacerbating diversion of blood to the brain, by increasing activity of myosin light chain phosphatase. At the same time, it can protect nerves against apoptosis and promote their regeneration. Fasudil Hydrochloride promotes recovery of neural function and reduces clinical symptoms.

Adverse reactions

Adverse reactions after use can include intracranial hemorrhage, gastrointestinal bleeding, pulmonary hemorrhage, nasal bleeding, subcutaneous bleeding, and loss of consciousness, etc., as well as abnormal liver function. Low blood pressure, anemia, leukopenia, renal dysfunction, polyuria, rashes, and fever, etc. occur occasionally.

Warnings and Precautions

Patients with intracranial hemorrhage or possibility thereof, or low blood pressure, should not use. Patients with diabetes mellitus, cerebral arterial sclerosis, severe disturbance of consciousness, subarachnoid hemorrhages with cerebrovascular disorders, and liver or kidney dysfunction, or those over 70 years old, pregnant, or children should use with caution. Breastfeeding women should stop while using the drug. Fasudil Hydrochloride can only be administered via intravenous drip.

Originator

Asahi Chemical (Japan)

References

1) Davies et al. (2000), Specificity and mechanism of action of some commonly used protein kinase inhibitors; Biochem. J., 351 95 2) Anwar et al. (2013), Signal transduction and modulating pathways in tryptamine-evoked vasopressor responses of the rat isolated perfused mesenteric bed; Vascul. Pharmacol., 58 140 3) Jiang et al. (2012), Fasudil, a rho-kinase inhibitor, attenuates bleomycin-induced pulmonary fibrosis in mice; Int. J. Mol. Sci., 13 8293

InChI:InChI=1/C14H17N3O2S.ClH/c18-20(19,17-9-2-6-15-8-10-17)14-4-1-3-12-11-16-7-5-13(12)14;/h1,3-5,7,11,15H,2,6,8-10H2;1H

Synthetic route

1,4-Diazacycloheptane (505-66-8) + isoquinoline-5-sulfonyl chloride hydrochloride (105627-79-0) → fasudil hydrochloride (105628-07-7)

Conditions	Yield
In dichloromethane at 0 - 50℃; for 2h; Temperature;	89%

1,4-Diazacycloheptane (505-66-8) + isoquinoline-5-sulfonic acid (27655-40-9) + 1-chloro-3,5-dimethoxybenzene (7051-16-3) → fasudil hydrochloride (105628-07-7)

Conditions	Yield
Stage #1: isoquinoline-5-sulfonic acid; 1-chloro-3,5-dimethoxybenzene With 4-methyl-morpholine In chloroform at 10℃; for 4h; Reflux; Stage #2: 1,4-Diazacycloheptane In chloroform at 30℃; for 3.5h; Reagent/catalyst; Solvent; Reflux; Further stages;	84.4%

fasudil (103745-39-7) → fasudil hydrochloride (105628-07-7)

Conditions	Yield
With hydrogenchloride; pyrographite In methanol; water at 30℃; pH=4.5 - 5;	34.9%

1,4-Diazacycloheptane (505-66-8) + 5-isoquinolinesulfonyl chloride (84468-15-5) → fasudil hydrochloride (105628-07-7)

Conditions	Yield
With water; sodium hydrogencarbonate 2.) CH2Cl2, RT, 1 h; Yield given. Multistep reaction;

isoquinoline-5-sulfonic acid (27655-40-9) → fasudil hydrochloride (105628-07-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: thionyl chloride / N,N-dimethyl-formamide / 2 h / Reflux; Large scale 2: ammonia / dichloromethane / 10 °C / Large scale 3: pyrographite; hydrogenchloride / methanol; water / 30 °C / pH 4.5 - 5 View Scheme

fasudil dihydrogen phosphate → fasudil hydrochloride (105628-07-7)

Conditions	Yield
Stage #1: fasudil dihydrogen phosphate With sodium hydroxide In water pH=10 - 10.5; Stage #2: With hydrogenchloride In methanol; water at 50 - 60℃; pH=5 - 5.1;	16.3 g

1,3-dioxoisoindolin-2-yl N2,N6-bis(tert-butoxycarbonyl)lysinate + fasudil hydrochloride (105628-07-7) → C30H46N4O6S

Conditions	Yield
With 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate; [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate In N,N-dimethyl acetamide; water at 20℃; for 5h; Schlenk technique; Irradiation; Inert atmosphere;	91%

4-nitrophenyl 2-(2-(pyridin-2-yl)disulfanyl)ethyl carbonate (874302-76-8) + fasudil hydrochloride (105628-07-7) → 2-(pyridin-2-yldisulfanyl)ethyl 4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylate

Conditions	Yield
With triethylamine In dichloromethane	90%

4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (1539-59-9) + fasudil hydrochloride (105628-07-7) → 5‐((1,4‐diazepan‐1‐yl)sulfonyl)‐1‐cyclohexylisoquinoline

Conditions	Yield
With sodium persulfate; trifluoroacetic acid In water; acetonitrile at 20℃; for 18h; Inert atmosphere;	84%

fasudil hydrochloride (105628-07-7) → C14H17N3O3S

Conditions	Yield
Stage #1: fasudil hydrochloride With sodium hydrogencarbonate for 0.5h; pH=5 - 6; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 30℃; for 1h;	82.17%

O-(4-nitrophenyl)-O’-propargylcarbonate (228111-40-8) + fasudil hydrochloride (105628-07-7) → prop-2-yn-1-yl 4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylate

Conditions	Yield
With triethylamine In dichloromethane at 20℃;	73.5%

diethyl 4-((benzyloxy)methyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate + fasudil hydrochloride (105628-07-7) → 5-((1,4-diazepan-1-yl)sulfonyl)-1-((benzyloxy)methyl)isoquinoline

Conditions	Yield
With sodium persulfate; trifluoroacetic acid In water; acetonitrile at 20℃; for 18h; Inert atmosphere;	51%

2-oxo-2-(piperidin-1-yl)acetic acid (4706-33-6) + fasudil hydrochloride (105628-07-7) → (5-((1,4-diazepan-1-yl)sulfonyl)isoquinoline-1-yl)(piperidin-1-yl)methanone

Conditions	Yield
With ammonium peroxydisulfate In water; dimethyl sulfoxide at 50℃; for 16h;	50%

fasudil hydrochloride (105628-07-7) + Cyclohexanecarboxylic acid (98-89-5) → 5‐((1,4‐diazepan‐1‐yl)sulfonyl)‐1‐cyclohexylisoquinoline

Conditions	Yield
With dipotassium peroxodisulfate In water; dimethyl sulfoxide at 40℃; for 16h; Minisci Aromatic Substitution; Inert atmosphere; Schlenk technique; Sealed tube;	44%

fasudil hydrochloride (105628-07-7) → 6H-1-(5-isoquinolinesulfonyl)-4-(β-hydroxyethyl)-1,4-diazepane

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water / 0.5 h / pH 5 - 6 2: triethylamine / dichloromethane / 30 h / 20 °C View Scheme

fasudil hydrochloride (105628-07-7) → fasudil (103745-39-7)

Conditions	Yield
With sodium hydrogencarbonate In water for 0.5h; pH=5 - 6;

fasudil hydrochloride (105628-07-7) → 4-(isoquinoline-5-sulfonyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (612483-90-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water / 0.5 h / pH 5 - 6 2: triethylamine / dichloromethane / 2 h / 0 - 5 °C View Scheme

fasudil hydrochloride (105628-07-7) → fasudil dihydrogen phosphate

Conditions	Yield
With potassium dihydrogenphosphate In methanol; water at 25 - 30℃; Reagent/catalyst; Temperature;	30.1 g

fasudil hydrochloride (105628-07-7) → C21H29N3O5S

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 0 °C 2: [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; trifluoroacetic acid / N,N-dimethyl acetamide / 24 h / 20 °C / Inert atmosphere; Irradiation View Scheme

fasudil hydrochloride (105628-07-7) → 5-((4-acetyl-1,4-diazepan-1-yl)sulfonyl)isoquinoline-1-carbaldehyde

Conditions

Yield

Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 2 h / 0 °C 2: [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; trifluoroacetic acid / N,N-dimethyl acetamide / 24 h / 20 °C / Inert atmosphere; Irradiation 3: hydrogenchloride / N,N-dimethyl acetamide; 1,4-dioxane / 6 h View Scheme

acetic anhydride (108-24-7) + fasudil hydrochloride (105628-07-7) → 1-(4-((1-cyclohexylisoquinolin-5-yl)sulfonyl)-1,4-diazepan-1-yl)ethan-1-one (1422972-00-6)

Conditions	Yield
With triethylamine In dichloromethane at 0℃; for 2h;	897 mg

Upstream product

• 103745-39-7 fasudil 
• 27655-40-9 isoquinoline-5-sulfonic acid 
• 105627-79-0 isoquinoline-5-sulfonyl chloride hydrochloride 
• 186544-80-9 C₂₂H₂₃N₃O₄S 
• 117009-97-9 benzyl 1,4-diazepane-1-carboxylate 
• 18158-16-2 benzyl 5-oxo-1,4-diazepane-1-carboxylate 
• 1208098-44-5 benzyl 4-(hydroxyimino)piperidine-1-carboxylate 
• 19099-93-5 benzyl 4-oxo-1-piperidinecarboxylate 
• 651309-72-7 tert-butyl (N-(2-aminoethyl)-5-isoquinolinesulfonamide)carbamate 
• 41979-39-9 4-piperidone hydrochloride 
• 5769-35-7 N,N'-di-p-toluenesulfonylhomopiperazine 
• 116700-36-8 H-9 
• 116970-50-4 N-(2-aminoethyl)-5-isoquinoline-sulphonamide hydrochloride 
• 84468-15-5 5-isoquinolinesulfonyl chloride 

Downstream Products

• 103745-39-7 fasudil 

Relevant articles and documents

Unconventional Synthetic Process of Fasudil Hydrochloride: Costly Homopiperazine Was Avoided

An efficient, robust, and cost-effective synthetic process of fasudil hydrochloride 1 was developed. Starting from readily available ethylenediamine and 5-isoquinoline sulfonyl chloride, the target product 1 was prepared through a six-step reaction, including sulfonamidation, protection, nucleophilic substitution, deprotection, cyclization, and salification. The process afforded 1 in 67.1% overall yield (based on 5-isoquinoline sulfonyl chloride) with 99.94% purity. Compared to the earlier published methodologies, the use of homopiperazine or its derivatives as intermediates was avoided. The salient features of this environmentally friendly synthetic route include easily available starting materials and operational simplicity, which could be suitable for large-scale industrial production.

Preparation method of fasudil hydrochloride

The invention belongs to the technical field of medicines, and relates to a preparation method of fasudil hydrochloride. The specific process of the method comprises the following steps: firstly reacting isoquinoline-5-sulfonic acid with 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine in an organic solvent under the action of organic alkali, then reacting the obtained reaction product with homopiperazine, washing the obtained reaction product with water, washing the obtained reaction product with alkali, and salifying and recrystallizing the obtained reaction product to obtain the high-purity fasudilhydrochloride. The impurity content of the fasudil hydrochloride prepared by the method is lower than 0.1%, and the purity of the fasudil hydrochloride reaches 99.5% or above. The preparation methodcompletely avoids the problem of product pigments caused by acyl chloride corrosion and hydrolysis, has the advantages of safety, environmental protection, low production cost, high product quality, convenience in operation and the like, and is suitable for industrial production.

Preparation method of Fasudil hydrochloride

The invention belongs to the technical field of preparation of heterocyclic compounds, and particularly relates to a preparation method of Fasudil hydrochloride. The preparation method includes the following steps: 1) reacting isoquinoline-5-sulfonyl chloride hydrochloride, homopiperazine and liquid ammonia in an organic solvent at the temperature of 10-15 DEG C for 2-4 hours, subjecting a reactedreaction system to water extraction separation, and concentrating an oil-phase separation product to obtain an intermediate; 2) subjecting the intermediate obtained in the step 1) and hydrochloric acid to a salt formation reaction to obtain the Fasudil hydrochloride. The preparation method has the advantages that the isoquinoline-5-sulfonyl chloride hydrochloride as a raw material directly reactswith the homopiperazine to obtain the intermediate, so that the operation steps are reduced and the preparation process is simple.