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| | Ripasudil hydrochloride dihydrate Basic information |
| Product Name: | Ripasudil hydrochloride dihydrate | | Synonyms: | K-115 HCL;Ripasudil free base;RipasudilHCl Hydrate;K115 HCl Dihydrate;RIPASUDIL HYDROCHLORIDE HYDRATE;(2S)-1-[(4-Fluoro-5-isoquinolinyl)sulfonyl]hexahydro-2-methyl-1H-1,4-diazepine monohydrochloride dihydrate;K-115 (HCl H2O);Ripasudil HCl Dihydrate | | CAS: | 887375-67-9 | | MF: | C15H21ClFN3O3S | | MW: | 377.86 | | EINECS: | | | Product Categories: | | | Mol File: | 887375-67-9.mol |  |
| | Ripasudil hydrochloride dihydrate Chemical Properties |
| storage temp. | Store at -20°C | | solubility | insoluble in EtOH; ≥123.2 mg/mL in DMSO; ≥41.7 mg/mL in H2O | | form | solid | | color | White to off-white | | Stability: | Hygroscopic |
| | Ripasudil hydrochloride dihydrate Usage And Synthesis |
| Description | Ripasudil hydrochloride hydrate (Glanatec®) was approved in
Japan in 2014 for the treatment of glaucoma and ocular hypertension.
Originally discovered by D. Western Therapeutics Institute,
Inc. and licensed by the Kowa Company, Ltd, ripasudil
functions as a selective Rho-kinase inhibitor and reduces intraocular
pressure by stimulation of aqueous humour drainage of the
trabecular meshwork. While this recent approval allows
for use of ripasudil as a twice-daily monotherapy treatment when
other drugs cannot be used or are not effective, clinical trials
using ripasudil as a combination therapy with other glaucoma
drugs have shown promising results in the treatment of primary
open-angle glaucoma or ocular hypertension. Currently, the
Kowa Company is also pursuing trials focused on the use of
ripasudil for the treatment of diabetic retinopathy and diabetic
macular edema. | | Uses | Ripasudil (Glanatec TM, Kowa Pharmaceutical), a close derivative of fasudil, is another Rho kinase inhibitor approved in Japan at the end of 2014 for the treatment of glaucoma and ocular hypertensionwhen other therapeutic agents are not effective or cannot be administered. Additionally, ripasudil has been tested in diabetic retinopathy clinical trials and shown to promote corneal endothelial cell proliferation, endothelium regeneration, and wound healing. | | Uses | Ripasudil Hydrochloride Dihydrate is a derivative of fasudil and a rho kinase inhibitor (1,2). It is used for the treatment of glaucoma and ocular hypertension. | | Synthesis | While initial synthetic routes to ripasudil were carried out via a
stepwise functionalization of 4-fluoroisoquinoline-5-sulfonyl
chloride (238), more recent reports describe an efficient
route to ripasudil employing a late stage-coupling of Boc-diazepane
(237) with 4-fluoroisoquinoline-5-sulfonyl chloride (238),
enabling synthesis on multi-kilogram scale and isolation of the
drug in high purity. This optimized route
to ripasudil begins with 2-nitrobenzene sulfonyl chloride (NsCl)-
mediated protection of (S)-2-amino-1-propanol (234) in 82% yield.
In this case, use of the NaHCO3/THF/H2O conditions were essential
for preventing bis-nosylation.228 Alcohol activation with methanesulfonyl
chloride (MsCl) in N-methyl morpholine (NMM) took
place smoothly to give the corresponding mesylate 235 in 91%
yield. Direct mesylate displacement with 3-aminopropanol and
subsequent amine protection as the carbamate ((Boc)2O) in a
one-pot fashion provided the corresponding Boc-amino propanol
product 236 in 95% yield over 2 steps. With the acyclic diazepane
precursor 236 in hand, employment of the intramolecular
Fukuyama-Mitsunobu N-alkyl cyclization conditions (diisopropyl
azodicarboxylate (DIAD)/PPh3) allowed generation of the diazepane
in 75% yield. Nosyl group cleavage with thiophenol/K2CO3
provided the Boc-diazepane 237 in 65% overall yield and 98% purity
following a pH-controlled aqueous workup. Finally, 4-fluoroisoquinoline-
5-sulfonyl chloride (238)?aprepared via subjection of 4-
fluoroisoquinoline (239) to sulfur trioxide and sulfuric
acid followed by treatment with thionyl chloride and finally 4 N
HCl in ethyl acetate?awas involved in a 1-pot, two-step procedure
in which this sulfonyl chloride was coupled with diazepane 237
(TEA/MeCN) to access the ripasudil framework in quantitative
yield. Synthesis of the final drug target by deprotection with 4 M
HCl in ethyl acetate followed by neutralization with aqueous
sodium hydroxide provided the free base of ripasudil in 93% yield
and 99.8% purity. Conversion to the more stable hydrochloride
dihydrate form could be performed by treatment of the free base
with 1 M HCl/EtOH and subsequent heating of the hydrochloride
in H2O/acetone to provide ripasudil hydrochloride dihydrate XXIX
in 83% yield. 
| | in vivo | in optic nerve crush (nc) c57bl/6 mice model, oral administration of k-115 (1 mg/kg/d) increased 34 ± 3% survival of rgcs after nc [2]. | | references | shimokawa h, takeshita a. rho-kinase is an important therapeutic target in cardiovascular medicine[j]. arteriosclerosis, thrombosis, and vascular biology, 2005, 25(9): 1767-1775.yamamoto k, maruyama k, himori n, et al. the novel rho kinase (rock) inhibitor k-115: a new candidate drug for neuroprotective treatment in glaucomanovel rho kinase inhibitor[j]. investigative ophthalmology & visual science, 2014, 55(11): 7126-7136.tanihara h, inoue t, yamamoto t, et al. phase 1 |
| | Ripasudil hydrochloride dihydrate Preparation Products And Raw materials |
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