- Synthesis and biological activity evaluation of novel fasudil derivatives
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A series of isoquinoline Rho kinase inhibitors were designed and synthesized based on the ligand-binding pocket model with fasudil as the lead compound. Their biological activity including Rho kinsase inhibitory activity, cell viability were systematically evaluated on (3-[4,5-dimethyltyhiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) assay and lactate deyhydrogenase (LDH) assay. Among these analogues, compounds 2, 3 and 6 not only exhibited Rho kinase inhibitory activity, but also promoted better cell viability. Therefore, they are potential candidates for the future drug discovery. Keywords: (3-[4,5-Dimethyltyhiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) assay and lactate deyhydrogenase (LDH) assay.
- Li, Hang,Duan, Yifan,Jiang, Shende,Chen, Ligong,Yan, Xilong
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- Design, Synthesis, and Biological Evaluations of Several Fasudil Analogues
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In our previous work, (S)-6H-1-(5-isoquinolinesulfonyl)-2-hydroxymethyl-1-pyrrolidine and (S)-6H-1-(5-isoquinolinesulfonyl)-2-chloromethyl-1-pyrrolidine displayed potent inhibitory activity. Therefore, with these two substances as lead compounds, we designed and synthesized their enantiomers to reveal the inhibitory effects of chirality on Rho kinase. It is found that their enantiomers exhibited much better Rho kinase inhibitory activity and strongly promoted synapse formation. Experimental autoimmune encephalomyelitis is a murine autoimmune disease used to study multiple sclerosis. With added antigens, the changes from C57BL/6 mice's limbs and tail was observed and scored by clinical evaluation. The synthetic compounds may simultaneously reduce symptoms of experimental autoimmune encephalomyelitis and inhibit inflammatory infiltration of the central nervous system. Thus, these compounds may be potential candidates for inhibition of Rho kinase and should be considered for further experimental study in relation to multiple sclerosis.
- Li, Hang,Zhou, Xueyong,Ye, Hang,Sun, Xi,Zhang, Pingping
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- Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis
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Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.
- Martín-Cámara, Olmo,Arribas, Marina,Wells, Geoffrey,Morales-Tenorio, Marcos,Martín-Requero, ángeles,Porras, Gracia,Martínez, Ana,Giorgi, Giorgio,López-Alvarado, Pilar,Lastres-Becker, Isabel,Menéndez, J. Carlos
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p. 1867 - 1882
(2022/01/20)
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- Refining method of Fasudil hydrochloride
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The invention discloses a synthetic refining method of Fasudil hydrochloride. The method includes: taking 5-isoquinolinesulfonic acid as the raw material, adopting DMF as the catalyst, using thionyl chloride as the chlorinating agent and solvent, conducting reflux concentration, then performing dichloromethane pulping to obtain isoquinoline-5-sulfonyl chloride hydrochloride, conducting neutralization and extraction to obtain a dichloromethane solution of isoquinoline-5-sulphonyl chloride, adding the dichloromethane solution of isoquinoline-5-sulphonyl chloride dropwise into a dichloromethane solution of homopiperazine, carrying out low temperature reaction to obtain 1-(5-isoquinoline sulfonyl)homopiperazine, adding dilute hydrochloric acid dropwise into the reaction solution, performing cooling to precipitate a solid Fasudil hydrochloride crude product 1, neutralizing the aqueous solution of the crude product 1, then conducting dichloromethane extraction, using an HCl-ethanol solutionto adjust acid to obtain a Fasudil hydrochloride crude product 2, and carrying out ethanol aqueous solution refining and drying so as to obtain a high purity final product meeting the requirements. The method provided by the invention can remove thionyl chloride in large quantities, facilitates subsequent operation and enlarged production, also precipitates the Fasudil hydrochloride crude product1 in a two-phase solvent directly by cooling, and can remove a large number of pigment impurities.
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Paragraph 0025; 0026; 0029-0031
(2019/10/02)
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- Preparation method of Fasudil hydrochloride
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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.
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- Isoquinoline derivative as well as preparation method and application thereof
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The invention relates to an isoquinoline derivative expressed by a general formula (I) or pharmaceutically acceptable salts thereof, wherein Y represents for carbonyl or sulfonyl. The invention also relates to a preparation method of the compound and application to preparation of medicines for treating NK/T cell malignant tumor. The formula is as shown in the description.
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Paragraph 0053
(2017/05/13)
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- THERAPEUTIC AGENT FOR OCULAR FUNDUS DISEASE
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Disclosed herein is a prophylactic or therapeutic agent for ocular fundus disease, especially diabetic retinopathy or age-related macular degeneration. The prophylactic or therapeutic agent for ocular fundus disease comprising: (S)-(?)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine, a salt thereof, or a solvate thereof, as an active ingredient.
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Paragraph 0077; 0078
(2015/01/07)
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- FASUDIL-CONTAINING PREPARATION AND METHOD OF IMPROVING STABILITY THEREOF
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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.
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Page/Page column 5-6
(2008/06/13)
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- 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates
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Disclosed is a 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrate having a water content of from 2.5 to 15.5% by weight represented by the following formula (I): STR1 wherein n means a number in the range of from 1/2 to 3. Since the 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrate of the present invention has excellent shapeability as compared to a 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride anhydride, a tablet having satisfactory hardness can be obtained even with a relatively low compression pressure in a tableting process. Further, due to a reduction in the compression pressure needed for tableting, various advantages are brought about, such as improved disintegratability of the resultant tablet when the tablet is orally taken, so that good dissolution of 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride from the tablet can be achieved, as well as suppression of abrasion of the die and punch used in producing tablets by compression, and the like.
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- Substituted isoquinolinesulfonyl compounds
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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.
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