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

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

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

• 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 
• 505-66-8 1,4-Diazacycloheptane 
• 27655-40-9 isoquinoline-5-sulfonic acid 

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 compound fasudil hydrochloride

The invention relates to a novel efficient and economical method for synthesizing fasudil hydrochloride. The method comprises the following steps: carrying outsulfonamide and Boc protection on cheap and easily available ethylenediamine serving as a starting raw material in a synthesis route to obtain an intermediate tert-butyl-(N-(2-aminoethyl)-5-isoquinoline sulfonamide) carbamate (5), and carrying out collapse condensation to obtain fasudil hydrochloride. The method comprises four steps of nucleophilic substitution, deprotection, cyclization and salification. The total yield of the fasudil hydrochloride (1) is 67.1%, and the purity of the fasudil hydrochloride (1) is as high as 99.94%. Compared with a traditional process, high-price homopiperazine and derivatives thereof are prevented from being used as synthesis intermediates in the route, so the method has the advantages that raw materials are cheap and easy to obtain, operation is easy, cost is low, and the process is environmentally friendly and suitable for industrial production.

Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chlorination system

The invention discloses a method for preparing an isoquinoline hydrochloride intermediate and an Rho kinase inhibitor by using a BTC/Ph3PO chlorination system, which comprises the following steps: putting an isoquinoline 5-sulfonic acid compound, BTC and a catalytic amount of Ph3PO into a reaction bottle, adding an organic solvent A, uniformly mixing all the components, and heating the mixture toreact; after the reaction is finished, carrying out suction filtration and drying to obtain a white solid isoquinoline hydrochloride intermediate, which is the isoquinoline 5-sulfonylchloride hydrochloride compound; concentrating a mother liquor part of the filtrate for separating out Ph3PO at a low temperature, and washing Ph3PO with a low-polarity solvent for recycling use. The method has the advantages of few side reactions, high product quality, less three-waste pollution, high atom economy and the like, the invention also provides a method for further preparing the Rho kinase inhibitor byutilizing the prepared isoquinoline hydrochloride intermediate; the impurities in the Rho kinase inhibitor prepared by the method are obviously lower than those in medicines obtained by a traditionalmethod.

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.

Method for purifying fasudil hydrochloride

The invention provides a method for purifying fasudil hydrochloride. According to the method, diffluent fasudil hydrochloride is converted into slightly soluble fasudil dihydrogen phosphate in a water-methanol solution, so that high-content piperazine impurities, most pigment and other water-soluble impurities which are easily dissolved in water and methanol are removed. The method has controllable process parameters, convenient operation and a mild reaction.

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.

FASUDIL-CONTAINING PREPARATION AND METHOD OF IMPROVING STABILITY THEREOF

Fasudil-containing preparations that despite the use of a container excelling in the visibility of contents without particularly blocking of light, exhibit high stability against light; and a method of improving the stability of the preparations against light, or storing the same. By regulating the pH value of aqueous solution of fasudil charged in a colorless transparent container to ≦ 5.5, there can be provided fasudil-containing preparations excelling in stability against light; and can be provided a method of improving the stability of the aqueous solution of fasudil against light, or storing the same.

5-Isoquinolinesulfonamide derivatives. III. Synthesis and vasodilatory activity of 1-(5-isoquinolinesulfonyl)piperazine derivatives

On the basis of a hypothesis that cyclization and alkylation of the diamine part in formula 1 may give highly active compounds, a new series of 5-isoquinolinesulfonamide derivatives, shown as formula 2, were prepared from cyclic diamines. Their vasodilatory effects were subsequently evaluated in vivo according to the increase in arterial blood flow after the formulas were injected locally to the femoral and/or vertebral arteries of dogs. Cyclization of the diamine structure in formula 1 gave very potent vasodilators: 6 and 14. Acylation and sulfonylation of terminal amino nitrogen afforded much less potent compounds. In contrast to the hypothesis, alkylation on the ring carbon and the terminal nitrogen of the cyclic amine afforded less active compounds except for compound 11. The most active compounds, 6, 11 and 14, showed more potent vasodilatory effects and more selective activity to the vertebral artery than either trapidil or diltiazem.

Substituted isoquinolinesulfonyl compounds

An isoquinolinesulfonyl compound represented by the formula (I): STR1 wherein R1 : H, Cl, OH A : unsubstituted or substituted ethylene or alkylene R2, R3 : H, alkyl, jointly forming unsubstituted or substituted ethylene or trimethylene R4 : H, alkyl, amidino or an acid salt thereof. They can be prepared, for example, by converting 1-R1 substituted-5-isoquinolinesulfonic acid to the corresponding sulfonyl chloride and subsequently reacting the chloride with a compound of formula STR2 They can be advantageously utilized as vasodilator, cerebral circulation ameliorator, antihypertensive agent and drugs for prevention and treatment of various circulatory organ diseases.