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

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.

Description

Fasudil hydrochloride, a novel calcium antagonistic vasodilator, was marketed for the treatment of cerebral vasospasm following subarachnoid hemorrhage (SAH). Fasudil is also a potent inhibitor of myosin light chain kinase and protein kinase C. In contrast to other calcium channel blockers, which regulate the influx of calcium ions through the cell membrane but not involved in the intracellular regulatory mechanism of the calcium, fasudil was suggested to have an intracellular mode of action in relaxing vascular smooth muscle. In patients with neurological deficits due to vasospasm, fasudil decreased the occurrence of angiographic severe and symptomatic vasospasm and cerebral infarction without decreasing systemic blood pressure. Fasudil is reportedly in clinical trials for acute ischemic stroke, sequelae of cerebral vascular diseases and angina pectoris.

Originator

Asahi Chemical (Japan)

Uses

Fasudil monohydrochloride is used in the prevention and treating cardiovascular and cerebrovascular diseases. It is also used in the inhibition of proliferation of vascular smooth muscle cells. It serves as a selective Rho-associated protein kinase (ROCK) inhibitor. Further, it protects against methyl mercury-induced axonal degeneration.

Uses

vasodilator, potent Rho-kinase inhibitor

Brand name

Eril

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

• 105628-00-0 5-[(6-benzyl-1,4-diazepan-1-yl)sulfonyl]isoquinoline 
• 105627-90-5 5-[(3-methyl-1,4-diazepan-1-yl)sulfonyl]isoquinoline 
• 105627-85-8 2-PHENYL-[1,4]DIAZEPANE 
• 105627-81-4 1-Chloroisoquinoline-5-sulfonyl chloride Hydrochloride 
• 105627-80-3 1-Chloro-5-isoquinolinesulfonic Acid 
• 105627-79-0 Isoquinoline-5-sulphonyl chloride hydrochloride 
• 105627-73-4 N-({2-acetyl-7-[(4-chlorobenzyl)oxy]-1-benzofuran-4-yl}sulfonyl)-N-(4-chlorobenzyl)glycine 
• 105627-67-6 N-{[2-acetyl-7-(benzyloxy)-1-benzofuran-4-yl]sulfonyl}glycine 
• 105627-63-2 N-{[2-acetyl-7-(2-oxopropoxy)-1-benzofuran-4-yl]sulfonyl}glycine 
• 105627-59-6 N-[(2-ethyl-5-nitro-1-benzofuran-3-yl)sulfonyl]glycine 
• 105627-56-3 N-({2-acetyl-7-[(4-nitrobenzyl)oxy]-1-benzofuran-4-yl}sulfonyl)glycine 
• 105626-87-7 4-{[3-Chloro-5-(trifluoromethyl)-pyridin-2-yl]oxy}benzoic acid 
• 105626-86-6 3-CHLORO-2-[4-(ETHOXYCARBONYL)PHENOXY]-5-(TRIFLUOROMETHYL)PYRIDINE 
• 10562-68-2 4-ETHYNYL-2,6-DIMETHYL-4-HEPTANOL 

Downstream Products

• 105628-33-9 1-chloro-N-{2-[(diaminomethylidene)amino]ethyl}isoquinoline-5-sulfonamide 
• 105628-45-3 N-{2-[(diaminomethylidene)amino]ethyl}-1-oxo-1,2-dihydroisoquinoline-5-sulfonamide 
• 105628-63-5 (2-AMINO-ETHYL)-ETHYL-CARBAMIC ACID TERT-BUTYL ESTER 
• 105628-64-6 (2-AMINO-ETHYL)-PROPYL-CARBAMIC ACID TERT-BUTYL ESTER 
• 105628-70-4 1-[(1-Chloro-5-isoquinolinyl)sulfonyl]hexahydro-1H-1,4-diazepine 
• 105628-72-6 1-[(1,2-DIHYDRO-1-OXO-5-ISOQUINOLINYL)SULFONYL]HEXAHYDRO-1H-1,4-DIAZEPINE 
• 105629-49-0 Cefyl 
• 10563-01-6 CH2=C=CHCH=CH2 
• 10563-10-7 bicyclo[3.2.0]hept-1(5)-ene 
• 10563-11-8 bicyclo[4.2.0]oct-1(6)-ene 
• 105632-19-7 1,4,6-Trioxaspiro[4.4]nonane, 2-methyl-7-methylene- 
• 10563-23-2 N-Ethyl-1,3-propanediamine 
• 105632-52-8 1-tert-butyl 2-ethyl 5-formyl-1H-pyrrole-1,2-dicarboxylate 
• 10563-26-5 N,N'-BIS(3-AMINOPROPYL)ETHYLENEDIAMINE 

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