CN109761958A - Fasudil complex salt and its preparation method and application - Google Patents
Fasudil complex salt and its preparation method and application Download PDFInfo
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- CN109761958A CN109761958A CN201910158848.XA CN201910158848A CN109761958A CN 109761958 A CN109761958 A CN 109761958A CN 201910158848 A CN201910158848 A CN 201910158848A CN 109761958 A CN109761958 A CN 109761958A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, more particularly to a kind of Fasudil complex salt, selected from Fasudil dichloroacetate, Fasudil trifluoroacetate, Fasudil trichloroacetate, Fasudil chloracetate, Fasudil chlorobromacetate, Fasudil tribromoacetic acid salt, Fasudil dichloroacetic acid condensation product, or its pharmaceutically acceptable salt, their preparation method, Pharmaceutical composition containing these compounds and their medical usage, especially in preparation prevention and/or treatment pulmonary hypertension, cerebral arterial thrombosis, application in the drug of the cardiovascular and cerebrovascular diseases such as subarachnoid hemorrhage.
Description
Technical field
The present invention relates to a kind of Fasudil complex salts, and in particular to a kind of Fasudil complex salt, their preparation side
Method, the Pharmaceutical composition containing these compounds and their medical usage, belong to pharmaceutical technology.
Background technique
Rho kinases (Rho associa ted kinase, ROCK) is to participate in cell mitogen adherency, cytoskeleton
A series of important enzyme of cell life phenomenons such as adjustment, muscle cell contraction, tumor cell invasion.Since nineteen ninety-six, it has sent out
Existing ROCK points are ROCK I (ROCK β) and ROCK II (ROCK α).The former be primarily present in non-nervous tissue for example heart, lung,
The cells such as skeletal muscle；The latter is primarily present in central nervous system, such as hippocampal pyramidal neurons, cerebral cortex, cerebellum Purkinje
Cell etc..Rho kinases (ROCK) is in multinomial cell functions such as vascular smooth muscle cells contraction, cell migration, proliferation and apoptosis
In have important intracellular signal transduction effect.Rho kinases abnormal activation has been had been found that in a variety of cardiovascular diseases, it is such as dynamic
Pulse atherosclerosis, restenosis, hypertension, pulmonary hypertension and myocardial hypertrophy etc..Studies have shown that chronic hypoxia and monocrotaline institute
Rho kinase activity in pulmonary hypertension model in rats and severe pulmonary hypertension patient lung tissue and pulmonary artery is caused significantly to increase
It is high.
Fasudil [hexahydro -1- (5- sulfonyl isoquinolin) -1 (H)-Isosorbide-5-Nitrae-diazepine, Fasudil, also known as
HA1077], it is a kind of novel isoquinoline of Japanese Asahi Kasei Corporation and the cooperative development of Nagoya University pharmaceutical research room
Sulphone amide derivative.As a kind of novel, efficient vasodilator agent, cerebral angiospasm can be effectively relieved in Fasudil, improved
The prognosis of Subarachnoid Hemorrhage (SAH) patient, from Fasudil in 1996 since Japan's listing, for pulmonary vascular work
With the extensive concern for being constantly subjected to researcher, a large amount of zoopery and clinical research show that Fasudil can be with: 1) activating
Endogenic neural stem cell promotes brain tissue reparation；2) increase astrocyte stimulating factor；3) inhibit intracellular Ca2+ from
The release of son；4) diastole cerebral vessels；5) nerve cell and improvement is protected to put in function；6) promote the regeneration of aixs cylinder.Therefore method
The ground that relaxes is also used for the treatment of cerebral arterial thrombosis.In addition, Fasudil also can safely and effectively treat pulmonary hypertension.
ROCK depressant Fasudil can infiltrate through vascular smooth muscle cells, can compete Rho with ATP under normal or pathologic condition
The ATP-binding site in kinase catalytic area specifically blocks Rho kinase activity.The anti-PAH of Fasudic hydrochloride is in the II phase and faces at present
Bed conceptual phase.
Summary of the invention
Purpose: the present invention provides a kind of Fasudil complex salt, preparation method and medical usage.
Technical solution: the technical solution adopted by the present invention are as follows:
A kind of compound, the compound are selected from Fasudil dichloroacetate, Fasudil trifluoroacetate, method and relax ground
That trichloroacetate, Fasudil chloracetate, Fasudil chlorobromacetate, Fasudil tribromoacetic acid salt, Fasudil
Dichloroacetic acid condensation product.
Compound 1: Fasudil dichloroacetate, structural formula are as follows:
Fasudil dichloroacetate the preparation method comprises the following steps:
Take appropriate Fasudil to be placed in reaction vessel, the mixing of appropriate reaction dissolvent be added, obtain Fasudil with react molten
The mixed liquor of agent；
Suitable dichloroacetic acid is added while stirring under reaction temperature 0-100 degree into above-mentioned mixed liquor, drips off subsequent
Continuous stirring a period of time, obtain reaction solution；
Then solvent is concentrated under reduced pressure away in reaction solution, washing recrystallizes to get Fasudil dichloroacetate.
In preferred preparation process, reaction temperature is room temperature, and reaction dissolvent is water, the Fasudil and dichloroacetic acid of addition
Molar ratio be 1:1.5, recrystallization solvent is isopropanol.
Compound 2: Fasudil trifluoroacetate, structural formula are as follows:
Compound 3: Fasudil trichloroacetate, structural formula are as follows:
Compound 4: Fasudil chloracetate, structural formula are as follows:
Compound 5: Fasudil chlorobromacetate, structural formula are as follows:
Compound 6: Fasudil tribromoacetic acid salt, structural formula are as follows:
Compound 7: Fasudil dichloroacetic acid condensation product (FD), structural formula is as follows:
On the other hand, the present invention also provides a kind of pharmaceutical compositions, wherein the above-mentioned compound containing therapeutically effective amount
Or its optical isomer, enantiomer, diastereomer, racemic modification or racemic mixture or its pharmaceutically acceptable salt and
Pharmaceutical carrier, adjuvant or mediator.
On the other hand, the present invention also provides above-mentioned compounds in preparation prevention and/or treatment pulmonary hypertension, arachnoid
Cavity of resorption bleeding, the medium cardiovascular and cerebrovascular disease of ischemic cerebral apoplexy drug in application.
In the present invention, mammal above compound and its pharmaceutically acceptable salt and these compounds are being given
Solvate (collectively referred to here in as " therapeutic agent ") when, can be used alone, or preferably according to specification pharmaceutical methods
By its be suitable for medicinal carrier or diluent cooperation after use.Administration mode can be through various approach, including take orally, is non-gastrointestinal
Canal drug administration or local administration.Parenteral administration referred herein includes but is not limited to intravenous injection, intramuscular injection, abdominal cavity note
It penetrates, be subcutaneously injected and cutaneous penetration.
The present invention discloses Fasudil dichloroacetate and preparation method thereof first, comprising the following steps: free method
The ground that relaxes is mixed with water first, is slowly added dropwise to dichloroacetic acid, is continued after stirring 5min, pure water is concentrated away, residue adds
After entering ether washing 3 times, then the Fasudil dichloroacetic acid of high-purity is obtained after being recrystallized with isopropanol or other solvents
Salt.And by composing through hydrogen, carbon spectrum, mass spectrum confirms its structure.Operation of the present invention is simple, and production cost is low, and product is received
Rate is high, and environmental pollution is small, is conducive to industrialized production.
Meanwhile the invention discloses Fasudil dichloroacetate, Netarsudil dichloroacetate and Ripasudil bis-
Inhibitory activity of the chloracetate to ROCK I and ROCK II.As a result, it has been found that dichloroacetate and ROCK inhibitor are improved at salt
Its ROCK inhibitory activity.
Therapeutic effect the invention discloses Fasudil dichloroacetate (FDCA) to pulmonary hypertension.Firstly, cell
Fasudil dichloroacetate (FDCA) can significantly inhibit Platelet-derived growth factor BB (PDGF-BB) in experiment and hypoxemia lures
Tumor necrosis factor-α in the arteria pulmonalis smooth muscle cells (PASMCs) and pulmonary artery endothelial cell (PAECs) led
The expression of (TNF-α) and interleukin-6 (IL-6)；Further progress zoopery, it is dynamic in the induced lung of monocrotaline induction
In the treatment model of arteries and veins high pressure, the average lung that FDCA (43.3mg/kg) gastric infusion can obviously reduce Rats of Pulmonary Hypertension is dynamic
Pulse pressure, right ventricular systolic pressure and right ventricle plumpness index, and body circulation pressure is had no significant effect；By by rat lung and heart
Tissue carries out pathological examination discovery, and FDCA significantly reduces the ratio of Pulmonary Arterioles of Rat Exposed vessel wall thickness and lung arteriolar diameter
(PAMT) and lung parteriole degree of fibrosis；FDCA significantly reduces myocardium of right ventricle cell area (CSA) and degree of fibrosis.Value
It obtains it is to be noted that the activity of FDCA anti-pulmonary hypertension is better than the Fasudil dihydrochloride (F) of equimolar dosage, dichloroacetic acid
The administering drug combinations of sodium (DCA) and the two, prompting FDCA is a kind of drug candidate of effective anti-pulmonary hypertension, is worth further
Research.
Meanwhile the invention discloses Fasudil dichloroacetate (FDCA) prevention and/or treatment subarachnoid hemorrhages
Effect.(the intravascular perforation modeling of cavum subarachnoidale, 0.5h and 6h respectively give after modeling in rat model of subarachnoid hemorrhage
Medicine is primary, the indices of rat after evaluation for 24 hours), FDCA significantly reduces cerebral arteries after subarachnoid hemorrhage in rats spasm damage
Wound improves brain edema and animal nerve scoring, hence it is evident that improve basal arteries caliber, Lumen Area and pipe thickness and top
Regional cortex blood flow amount (rCBF) is better than F, the administering drug combinations of DCA and the two.As a result prompt FDCA is a kind of effective anti-
The drug candidate of subarachnoid hemorrhage is worth further research.
Meanwhile the invention discloses Fasudil dichloroacetate (FDCA) prevention and/or treating cerebral arterial thrombosis
Effect.(ischemic 2h is filled again, and ischemic 4h is administered once, and is administered for 24 hours, the rat after evaluating 48h in rat transient ischemia model
Indices), FDCA is effectively reduced brain infarction area, is significantly better than marketed drug butylbenzene peptide (NBP) group, is significantly better than method and relaxes
The administering drug combinations group of ground your dihydrochloride group (F) and dichloroacetate sodium (DCA) group and F and DCA；Furthermore FDCA is also significantly
Improve the neurobehavioral dysfunction of ischemic induction, hence it is evident that be better than F, the administering drug combinations of DCA and the two are slightly better than NBP group.
As a result prompt FDCA is a kind of drug candidate of effective anti-cerebral arterial thrombosis, is worth further research.
As the inhibitor of ROCK, Fasudil can with vasodilator, reduce blood pressure, inhibit the increasing of vascular smooth muscle cells
It grows, inhibits vascular remodeling；And dichloroacetate is the inhibitor of pyruvic dehydrogenase kinase, and pyruvic dehydrogenase can be improved
Activity promotes the aerobic metabolism of glucose, reduces the generation of lactic acid；It can also promote potassium-channel especially Kv1.5 simultaneously
Expression, inhibit the proliferation of smooth muscle cell and promote its apoptosis.Therefore, Fasudil and the administering drug combinations of dichloroacetate can
To treat pulmonary hypertension, the cardiovascular and cerebrovascular diseases such as cerebral arterial thrombosis and subarachnoid hemorrhage from multiple mechanism.And connection
It closes administration to compare, the molecule of Fasudil dichloroacetate (FDCA) as a whole may be in drug absorption, distribution and generation
Thank etc. has difference with what is be administered in combination, therefore shows better activity.
Detailed description of the invention
Fig. 1 be in embodiment 9 compound to PASMCs and PAECs at PDGF-BB and hypoxemia condition of culture TNF-α and
The influence of IL-6 expression；PASMs: arteria pulmonalis smooth muscle cells；PAECs: pulmonary artery endothelial cell；PDGF-BB: platelet-derived
Growth factor B B；IL-6；Interleukin-6；CON: blank control group；Hypoxia: hypoxemia；FDCA: two chloroethene of Fasudil
Hydrochlorate；F: Fasudil dihydrochloride；DCA: dichloroacetic acid sodium salt；F+DCA: Fasudil dihydrochloride and dichloroacetic acid sodium salt
Administering drug combinations group.
Fig. 2 is influence of the compound to the MCT PAH rat model haemodynamics induced in embodiment 9；MPAP: average
Pulmonary arterial pressure, RVSP: right ventricular systolic pressure；MSAP: average body circulation pressure；RV/LV+S: Right ventricular hypertrophy index；Control: right
According to group, MCT: monocrotaline；FDCA: Fasudil dichloroacetate；F: Fasudil dihydrochloride；DCA: dichloroacetate sodium
Salt；F+DCA: Fasudil dihydrochloride and dichloroacetic acid sodium salt administering drug combinations group.
Fig. 3 be in embodiment 9 each administration group to the ratio of Pulmonary Arterioles of Rat Exposed vessel wall thickness and lung arteriolar diameter
(PAMT) and the influence of degree of fibrosis；PAMT: the ratio of Pulmonary Arterioles of Rat Exposed vessel wall thickness and lung arteriolar diameter；
Fibrosis: fibrosis；Control: control group, MCT: monocrotaline；FDCA: Fasudil dichloroacetate；F: method relaxes ground
That dihydrochloride；DCA: dichloroacetic acid sodium salt；F+DCA: Fasudil dihydrochloride and dichloroacetic acid sodium salt administering drug combinations group.
Fig. 4 is influence of each administration group to myocardium of right ventricle cell area and degree of fibrosis in embodiment 9；
CAS: cardiac muscle cell's cross sectional area；Fibrosis: fibrosis；Control: control group, MCT: monocrotaline；
FDCA: Fasudil dichloroacetate；F: Fasudil dihydrochloride；DCA: dichloroacetic acid sodium salt；F+DCA: Fasudil two
Hydrochloride and dichloroacetic acid sodium salt administering drug combinations group.
Fig. 5 A is influence of the different compounds to SAH cerebral edema in embodiment 10；Fig. 5 B is different in embodiment 10
The influence that compound scores to SAH rat spontaneous activity.
Fig. 6 is tMCAO rat model brain tissue TTC colored graph in embodiment 11.
Fig. 7 is tMCAO rat model brain infarction area statistical chart in embodiment 11.
Fig. 8 is tMCAO rat model Neuroscore in embodiment 11.
Fig. 9 is tMCAO rat model brain infarction area and rat nerve function score figure in embodiment 11.
Specific embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it
Only be used to the present invention specifically describe, be not construed as limitation of the present invention.
Embodiment 1
Fasudil dichloroacetate
Compound synthesis and structural identification:
At room temperature, 10g Fasudil is placed in 100mL eggplant-shape bottle, 20mL tap water is added or pure water is stirred,
Then 4.87g dichloroacetic acid is weighed, is slowly added dropwise in above-mentioned suspension, finds Fasudil or gradually molten during being added dropwise
Solution, drop finish.Continue that 10min is stirred at room temperature.Reaction solution is concentrated under reduced pressure afterwards, residue is added ether and carries out washing 3 times, discards second
Ether, then recrystallized with organic solvent, white solid is obtained by filtration, postposition is dried to obtain 13.95g mesh in a vacuum drying oven
Mark compound, yield 96.9%.Mp:141-143 DEG C of1H NMR (300MHz, D2O, TMS) δ 9.20 (s, 1H), 8.49 (d, J
=6.2,1H), 8.21-8.29 (m, 3H), 7.72 (t, J=7.7,1H), 6.03 (s, 1H), 3.72 (t, J=5.0,2H), 3.53
(t, J=6.1,2H), 3.35-3.41 (m, 4H), 2.09-2.17 (m, 2H)13C NMR (75MHz, D2O) 170.25 δ,
152.36,142.97,134.17,133.01,131.0,130.25,128.10,126.03,116.69,68.07,46.76,
46.22,44.41,43.46,24.99.ESI-MS (70eV) m/z:292.2 [M+H]+。
Embodiment 2
Fasudil trifluoroacetate
Compound synthesis and structural identification:
At room temperature, 100mg Fasudil is placed in 50mL eggplant-shape bottle, 10mL acetone is added and is stirred, then weighs
40mg trifluoroacetic acid is slowly added dropwise in above-mentioned suspension, and Fasudil is found during being added dropwise or is gradually dissolved, drop finishes.After
It is continuous that 10min is stirred at room temperature.Reaction solution is concentrated under reduced pressure afterwards, residue filters after ether stirring is added, and filter cake is washed with ether
It washs 3 times, obtains white solid, postposition is dried to obtain 130.8mg target compound, yield 94% in a vacuum drying oven.1H
NMR (500MHz, D2O, TMS) δ 9.72 (s, 1H), 8.84 (d, J=5.2,1H), 8.64-8.72 (m, 3H), 8.10 (t, J=
7.7,1H), 3.84 (t, J=4.7,2H), 3.65 (t, J=5.9,2H), 3.44-3.52 (m, 4H), 2.23-2.26 (m, 2H)
.ESI-MS (70eV) m/z:292.2 [M+H]+。
Embodiment 3
Fasudil trichloroacetate
Compound synthesis and structural identification:
At room temperature, 100mg Fasudil is placed in 50mL eggplant-shape bottle, 10mL acetone is added and is stirred, then weighs
66.76mg trichloroacetic acid is slowly added dropwise in above-mentioned suspension, and Fasudil is found during being added dropwise or is gradually dissolved, drop finishes.
Continue that 10min is stirred at room temperature.Reaction solution is concentrated under reduced pressure afterwards, residue filters after ether stirring is added, and filter cake is carried out with ether
Washing 3 times, obtains white solid, postposition is dried to obtain 135mg target compound, yield 87% in a vacuum drying oven.1H
NMR (300MHz, D2O, TMS) δ 9.89 (s, 1H), 9.08 (d, J=6.8,1H), 8.75-8.81 (m, 3H), 8.20 (t, J=
7.1,1H), 3.85 (t, J=4.8,2H), 3.67 (t, J=5.8,2H), 3.48-3.62 (m, 4H), 2.22-2.26 (m, 2H)
.ESI-MS (70eV) m/z:292.2 [M+H]+。
Embodiment 4
Fasudil chloracetate
Compound synthesis and structural identification:
At room temperature, 100mg Fasudil is placed in 50mL eggplant-shape bottle, 10mL acetone is added and is stirred, then weighs
38.76mg monoxone is slowly added dropwise in above-mentioned suspension, and Fasudil is found during being added dropwise or is gradually dissolved, drop finishes.After
It is continuous that 10min is stirred at room temperature.Reaction solution is concentrated under reduced pressure afterwards, residue filters after ether stirring is added, and filter cake is washed with ether
It washs 3 times, obtains white solid, postposition is dried to obtain 121mg target compound, yield 91.5% in a vacuum drying oven.1H
NMR (300MHz, D2O, TMS) δ 9.21 (s, 1H), 8.49 (d, J=6.1,1H), 8.24-8.30 (m, 3H), 7.74 (t, J=
8.0,1H), 4.06 (s, 2H), 3.74 (t, J=3.9,2H), 3.54 (t, J=5.7,2H), 3.41-3.43 (m, 4H), 2.15-
2.18 (m, 2H) .ESI-MS (70eV) m/z:292.2 [M+H]+。
Embodiment 5
Fasudil chlorobromacetate
Compound synthesis and structural identification:
At room temperature, 100mg Fasudil is placed in 50mL eggplant-shape bottle, 10mL acetone is added and is stirred, then weighs
70.88mg chlorobromoacetic acid is slowly added dropwise in above-mentioned suspension, and Fasudil is found during being added dropwise or is gradually dissolved, drop finishes.
Continue that 10min is stirred at room temperature.Reaction solution is concentrated under reduced pressure afterwards, residue filters after ether stirring is added, and filter cake is carried out with ether
Washing 3 times, obtains white solid, postposition is dried to obtain 140mg target compound, yield 88% in a vacuum drying oven.1H
NMR (300MHz, D2O, TMS) δ 9.63 (s, 1H), 8.74 (d, J=6.5,1H), 8.58-8.68 (m, 3H), 8.02 (t, J=
7.5,1H), 6.07 (s, 1H), 3.81 (t, J=4.5,2H), 3.62 (t, J=6.0,2H), 3.43-3.47 (m, 4H), 2.17-
2.21 (m, 2H) .ESI-MS (70eV) m/z:292.2 [M+H]+。
Embodiment 6
Fasudil tribromoacetic acid salt
Compound synthesis and structural identification:
At room temperature, 100mg Fasudil is placed in 50mL eggplant-shape bottle, 10mL acetone is added and is stirred, then weighs
121mg tribromoacetic acid is slowly added dropwise in above-mentioned suspension, and Fasudil is found during being added dropwise or is gradually dissolved, drop finishes.After
It is continuous that 10min is stirred at room temperature.Reaction solution is concentrated under reduced pressure afterwards, residue filters after ether stirring is added, and filter cake is washed with ether
It washs 3 times, obtains white solid, postposition is dried to obtain 164.5mg target compound, yield 82% in a vacuum drying oven.1H
NMR (300MHz, D2O, TMS) δ 9.18 (s, 1H), 8.49 (d, J=5.8,1H), 8.22-8.26 (m, 3H), 7.71 (t, J=
7.8,1H), 3.61 (t, J=3.9,2H), 3.50 (t, J=6.1,2H), 3.14-3.16 (m, 4H), 1.98-2.0 (m, 2H)
.ESI-MS (70eV) m/z:292.2 [M+H]+。
Embodiment 7
Fasudil dichloroacetic acid condensation product (FD)
Compound synthesis and structural identification: at room temperature, by 200mg Fasudil, the DIEA of 227 μ L, the HBUT of 522mg and
68 μ L dichloroacetic acid are placed in the eggplant-shape bottle of 50mL, and 20mL anhydrous methylene chloride is added and is stirred to react overnight.It afterwards will be in reaction solution
10mL water washing is added, dichloromethane layer is concentrated again, sand processed, and column chromatography (petrol ether/ethyl acetate=1:1) obtains target product
175mg, yield 61.4%.1H-NMR(300MHz,CDCl3,TMS)δ9.36(s,1H),8.69-8.72(m,1H),8.32-
8.36 (m, 2H), 8.22 (d, J=8.1,1H), 7.67-7.74 (m, 1H), 6.21 (s, 1H), 3.91 (s, 1H), 3.75-3.84
(m,3H),3.61(s,1H),3.43-3.49(m,3H),2.05-2.11(m,2H).ESI-MS(70eV)m/z:416.1[M+H]+。
Embodiment 8
Compound is to ROCK-I and II inhibitory activity:
Inhibitory activity (nM) of 1. compound of table to ROCK-I and ROCK-II
Embodiment 9
Prevention and/or treatment pulmonary hypertension
One, FDCA is in PDGF-BB and hypoxemia culture model to inflammatory factor TNF-α in PASMCs and PAECs cell
With the influence of IL-6 expression
The relevant pulmonary hypertension of pulmonary hypertension especially connective tissue disease often with the generation of inflammation, inflammation because
Sub- tumor necrosis factor-alpha (TNF-α) can activate inflammatory factor interleukin-6 (IL-6), promote smooth muscle cell proliferation,
The fibrosis of blood vessel and the reconstruct of lung parteriole.Fasudil dichloroacetate (FDCA) has been investigated by cell experiment first
The arteria pulmonalis smooth muscle cells (PASMCs) that hypoxemia condition of culture and Platelet-derived growth factor BB (PDGF-BB) are induced
The influence expressed with TNF-α in pulmonary artery endothelial cell (PAECs) and IL-6.Cell grouping: 1. normal cell group
(Control)；2. PDGF-BB or the model group of hypoxemia culture；3. model group+Fasudil dichloroacetate (FDCA)；④
Model group+fasudil hydrochloride (F) treatment group；5. model group+dichloroacetic acid sodium salt (DCA) treatment group；6. model group+F with
DCA administering drug combinations group.Experimental method is as follows.PGDFBB model group: first cell is passaged to 3-6 generation, adds PDGFBB after culture afterwards for 24 hours
(5 microlitres are matched 10 milliliters) supports for 24 hours, then starvation 48h, dosing, and each administration group concentration is 50 μM, is counted after cultivating 72h by ELISA
The expression of TNF-α and IL-6 in group of cells；Anoxia model group: first cell is passaged to 3-6 generation, then starvation lacks after 24 hours
Oxygen culture 24 hours, administration, each administration group concentration be 50 μM, cultivate 72h after by ELISA count group of cells in TNF-α with
The expression of IL-6).As shown in Figure 1, hypoxemia condition of culture and PDGF-BB are remarkably improved in PASMCs and PAECs
The expression of TNF-α and IL-6 prompts hypoxemia condition of culture and PDGF-BB to be remarkably improved inflammation；And each administration group is at two plants
The expression for inhibiting TNF-α and IL-6 in cell to some extent, mitigates inflammation.Wherein the inhibition Inflammatory effects of FDCA group are most
It is good, better than F, DCA and the administering drug combinations group of the two.Prompt F and DCA has certain synergistic effect at anti-inflammatory aspect, may
The reason of be FDCA as a whole molecule compared to F and DCA have preferably across the ability of cell membrane.
Two, influence of the FDCA compound to the MCT PAH rat model haemodynamics induced
It further studies in P of Rats AH model caused by monocrotaline (MCT), the treatment of FDCA and related compound is made
With.Animal packet: 1. Normal group；2. Normal group+FDCA；3. MCT model group；4. Fasudil dihydrochloride (F)
Treatment group；5. DCA treatment group；6. F+DCA combination therapy group；7. FDCA administration group.The foundation of rat model: animal model group and
Treatment group's disposable celiac injects monocrotaline (MCT) 60mg/kg, and Normal group injects same amount of normal saline.Experiment process:
In the 14th day of injection monocrotaline, each administration group started to be administered with equimolar dosage, and administration mode is gastric infusion, and daily one
Secondary, F group 37.5mg/kg, DCA group 15.5mg/kg, F+DCA combination therapy group includes F (37.5mg/kg) and DCA15.5mg/kg,
Normal group+FDCA organizes 43.3mg/kg；FDCA group 43.3mg/kg.The physiological saline that normal group and model group give equivalent is fed
It supports.Each group is in the 28th day progress mean pulmonary arterial pressure power (mPAP), right ventricular systolic pressure (RVSP) and average body circulation pressure
(mSAP) measurement, then puts to death rat and lung tissue and heart is taken to carry out Right ventricular hypertrophy index (RV/LV+S), and PCNA detection is exempted from
Epidemic disease histochemical stain, hematoxylin eosin staining, the processing such as Masson dyeing, it is dynamic in haemodynamics, lung to evaluate each administration group
Arteries and veins average thickness, pulmonary fibrosis degree, the activity of right heart function etc..As a result as shown in Fig. 2, being compared with Normal group,
It is little directly to give influence of the FDCA to mPAP, RVSP and the RV/LV+S of normal rat, illustrates that the safety of FDCA is higher.And
MCT model group can apparent increase mPAP, RVSP and RV/LV+S.Each administration group can be effectively reduced mPAP, RVSP and RV/LV+
S, wherein FDCA group reduces the active most strong of mPAP, RVSP and RV/LV+S, is better than F, the administering drug combinations of DCA and the two.Separately
Outside, influence of each administration group to mSAP is smaller.
Three, influence of the FDCA compound to the MCT PAH rat model pulmonary artery induced
As shown in figure 3, ratio of the different dosing group to Pulmonary Arterioles of Rat Exposed vessel wall thickness and lung arteriolar diameter
(PAMT) and the influence of degree of fibrosis slightly excellent, it can be found that FDCA can effectively reduce PAMT and lung parteriole degree of fibrosis
In F, the administering drug combinations of DCA and the two.
Four, influence of the FDCA compound to the MCT PAH rat model right ventricle induced
As shown in figure 4, influence of each administration group to myocardium of right ventricle cell area and degree of fibrosis, as a result prompt and sky
White control is compared, and MCT model group dramatically increases rat right ventricular cardiomyocyte surface area and degree of fibrosis.And administration group, especially
It is that FDCA can significantly reduce myocardium of right ventricle cell area and degree of fibrosis, is better than F, DCA and the two administering drug combinations group, as a result
The proliferation and reconstruct of myocardium of right ventricle cell can be effectively suppressed in prompt FDCA.
Embodiment 10
Prevention and/or treatment subarachnoid hemorrhage
Experimental animal
SPF grades of SD rats, weight 260-340g, male and female half-and-half, purchased from Beijing tie up the limited public affairs of tonneau China experimental animal technology
Department raises in SPF grade feeding environments, room temperature control at 23 ± 2 DEG C, free diet with take the photograph water.Animal number 32.It is false
Operation group: isometric physiological saline contains 1% DMSO (n=8)；
Experimental method
Test grouping situation and drug concentration selection:
SAH model group: isometric physiological saline contains 1% DMSO (n=8)；Fasudil dihydrochloride (F) group:
(26.0mg/kg) (n=8)；Dichloroacetate sodium (DCA) group: (10.7mg/kg) (n=8): Fasudil dihydrochloride joint two
Sodium chloroacetate (F+DDCA) group: (F:26.0mg/kg；DCA:10.7mg/kg) (n=8)；FDCA group: (30mg/kg) (n=8)；
All drugs are made into the normal saline solution containing 1%DMSO, and administration mode is tail vein injection administration.Respectively in SAH (rat spider
The modeling of net film lower cavity hemorrhage) it is administered after 0.5h and 6h afterwards each primary, sham-operation group and model group are contained using isometric physiological saline
1%DMSO is replaced.
Model and medication
Bibliography (Stroke, 1995,26,1086-1092) the intravascular perforation model for carrying out SAH.It will be big
Mouse anesthesia, is intubated and keeps artificial ventilation in 70%/30% medical air/oxygen with 3% isoflurane during operation.Pass through
Rectal prob monitors body temperature, and maintains normal heat by heating lamp.The 4-0 nylon suture of sharpening is introduced into left internal carotid
(ICA) until feeling resistance (away from arteria carotis communis bifurcated about 18mm).Then suture is pushed further into pierce through forebrain and move
The bifurcated of arteries and veins and arteria cerebri media, until overcoming resistance and being recalled immediately after perforation.In sham-operation animal, suture is inserted into
Left ICA, but do not perforate.After suture removes, notch is closed, rat is housed individually in the cage of heating until extensive
It is multiple.
Spontaneous activity scoring: by rat be placed in it is one spacious, can move freely, carried out in the cage that four walls are accessible it is spontaneous
Activity score.Experimental rat is evaluated and recorded with double-blind study respectively by 2 experimenters for 24 hours after SAH modeling, takes 2 groups
Mean value is final score, puts to death rat immediately after spontaneous activity observation.Spontaneous activity is scored according to animal mental state and movement
Situation is divided into 4 grades: 1 grades, and activities in rats is normal, non-activity obstacle, tries to explore surrounding environment, at least touches the upper of three face cage walls
Edge；2 grades, gentle activity obstacle, i.e. rat spirit are poor, drowsiness, and action has certain delay, do not reach all cage walls, but
He at least touches the upper limb of a face cage wall；3 grades, moderately active obstacle, i.e. rat can hardly stand, in cage almost without
Activity；4 grades, severe moving obstacle, i.e. mouse are not moved, and show the paralysis of limbs.As a result see Fig. 5 A.
Brain water content measurement: putting to death rat after SAH modeling for 24 hours, takes out brain and cerebellum rapidly, is sucked with filter paper
Surface blood.Then brain tissue is placed in oven by the quality (weight in wet base) for weighing brain and cerebellum respectively with electronic balance, and 105
DEG C it is baked to constant weight, weighs the quality (dry weight) of brain and cerebellum again.The calculation formula of brain water content are as follows: brain tissue contains
Water (%)=(weight in wet base-dry weight)/weight in wet base × 100%.Wherein the tissue water content of cerebellum is as normal control.As a result see figure
5B。
The measurement of basal arteries caliber, Lumen Area and pipe thickness: by the histotomy of above-mentioned each group basal arteries into
Row HE dyeing after optical microphotograph is taken a picture under the microscope, measures basal arteries using image pro-plus6.0 image analysis system
Caliber, Lumen Area and pipe thickness.The measurement method of Lumen Area is as follows: measuring its lumen week along basal arteries inner surface
Long (L), according to formula: diameter (d)=L/ π calculates lumen diameter, and radius (r)=L/2 π calculates lumen radius, Lumen Area
(S) according to formula: S=π r2It acquires.The measurement method of pipe thickness is as follows: measurement basal arteries inner surface to middle film outer rim it
Away from not including outer membrane.Every blood vessel chooses 4 different test points and measures pipe thickness, takes its average value as the blood vessel
Measured value.It the results are shown in Table 1.
Top skin local cerebral blood flow (rCBF) measurement: being opened seam window at the top of postal with the small-sized trepan of diameter 5mm, centre bit
The 1mm after Bergma point, rear foreign side 3mm.LDF3 type laser Doppler flowmetry probe is fixed on direction finder micro-thruster,
Before preparing SAH and 1 after SAH, 4,12, for 24 hours in time observation rCBF.It the results are shown in Table 2.
Statistical method: spontaneous activity score data indicates that remainder data is indicated with means ± SD using scatter plot；From
It sends out activity score and is examined and Mann-Whitney U inspection, remainder data according to statistical difference between group using Kruskal-Wallis
Statistical difference is examined using one-way ANOVA and Tukey ' s between group, and P value thinks there is significant difference less than 0.05.
2.3 experimental result
As shown in figs. 5 a-b, compared with SAH model control group, giving different test-compound F and FDCA can be bright
It is aobvious to improve animal nerve scoring, hence it is evident that rat brain water content caused by SAH is reduced, wherein FDCA shows strongest activity,
It is significantly better than F and DCA, is slightly better than F+DCA.
In addition, FDCA group is obviously improved basal arteries caliber, Lumen Area and pipe thickness (table 1) and top skin part
Cerebral blood flow (CBF) (rCBF) (table 2), is significantly better than F, DCA and F+DCA group.The above results show that FDCA has significant anti-spider web
The activity of film lower cavity hemorrhage, better than marketed drug Fasudil dihydrochloride and Fasudil dihydrochloride and dichloroacetic acid
The administering drug combinations of sodium.
The measurement of table 1. each administration group Rat Basilar lumen diameter, Lumen Area and lumen thickness
| Group | Lumen diameter (μm) | Lumen Area (μm2) | Lumen thickness (μm) |
| Sham | 180.66±20.64 | 25912.41±6017.4 | 5.94±0.20 |
| Model | 122.11±17.00 | 11903.30±3367.5 | 11.67±0.61 |
| F | 153.73±18.87** | 18796.09±4730.3** | 8.13±0.80** |
| DCA | 129.10±9.87* | 13092.20±1788.6* | 10.12±1.21* |
| F+DCA | 160.78±12.65** | 20.7162±2987.76** | 8.01±0.41** |
| FDCA | 175.91±25.70**# | 24745.73±7235.4**## | 6.62±0.80**## |
Note: P < 0.01 * P < 0.05 compared with model, * *, #P < 0.05 compared with F+DCA group, ##P < 0.01.
The influence that 2 compound of table changes SAH rat local cerebral blood flow
Note: P < 0.01 * P < 0.05 compared with model, * *, #P < 0.05 compared with F+DCA group, ##P < 0.01
Embodiment 11
Prevention and/or treatment cerebral arterial thrombosis
Whether there is neuroprotection in vivo for research FDCA, selects transience rat cerebral ischemia model (tMCAO)
It is tested.
Model and medication: after 10% chloraldurate of rats by intraperitoneal injection (350mg/kg) anesthesia, dorsal position is fixed
On experimental bench, neck median incision, scalpel cuts skin, each layer tissue of blunt separation, according to rat neck vascular anatomy figure,
Left common carotid (CCA) is separated under stereomicroscope, sets in the spare upward separation left external carotid artery (ECA) of line and neck and moves
Two External Carotid Artery Branchs of superior thyroid artery and occipital artery are cut in arteries and veins, dual ligation, double at nearly CCA bifurcated about 5mm-8mm
ECA is ligatured again, is closed respectively with arteriole folder folder in ICA and CCA proximal part, is accomplished fluently unijunction but not in the nearly crotch indwelling one of ECA
The silk thread of tightening does the V-type micro-incision of a diameter about 0.2mm, by Buddhist nun at the ligation of the proximal end ECA between arteria carotis communis crotch
Imperial the end of a thread is gently inserted into from incision, gently tightens knot, and internal carotid is cut between two ligatures, is allowed to and internal carotid
Artery clamp is unanimously unclamped in direction, and nylon wire is sent into encephalic through ICA along ECA, when the micro- power of being hampered of insertion depth about 18mm~20mm
Stop, nylon wire head end is made to be located at MCA section start, blocks the blood flow of MCA to tighten silk thread, sew up the incision, indwelling nylon wire tail end
In external.
After ischemic 2h, with 10% chloraldurate anesthetized rat again, gently pull nylon wire that its head end is made to return to micro-incision
Locate (slightly resistance sense), arteria cerebri media is made to restore blood supply, carries out Reperfu- sion.Rats in sham-operated group only carries out anesthesia and blood vessel point
From art, blood vessel and lead-in wire bolt, postoperative animal heat-preservation are not ligatured.Administration mode: ischemic 4h, for 24 hours rear rat difference tail vein note
Penetrate administration.After ischemic 48h, Neuroscore, then put to death rat.
Grouping: sham-operation group (Sham)；Blank solvent group (Vehicle)；Fasudil dihydrochloride group (F, 30mg/kg,
Tail vein injection)；FDCA group (30mg/kg, tail vein injection)；Butylphenyl phthaleine group (NBP, 5mg/kg, tail vein injection).
TTC dyeing: at full brain optic chiasma and its each 2mm in front and back, do it is coronal cut four knives, be cut into brain piece after five rapidly
It sets 5ml to contain in the phosphate buffer solution of 2%TTC, 37 DEG C are protected from light temperature and incubate 10min, turn over during temperature is incubated every 7~8 minutes
Dynamic primary, temperature takes out brain piece after incubating 10min, is taken pictures with digital camera (Olympus C-4000, Japan), uses ophthalmic tweezers later
Pale area (infarct) and non-pale area (normal area) are separated, infarct percent is calculated such as by Image pro-plus 6.0
Under:
Infarct percent (%)=pale area weight/(pale area's weight+non-pale area's weight) × 100%
Nervous function grading: it after ischemic 48h, is classified according to neurological deficit of Longa ' the s method to animal
Scoring, standard are as follows:
0 point: not observing nervous symptoms；
1 point: mention tail it is hanging when, the operation opposite side forelimb of animal shows as wrist elbow buckling, shoulder inward turning, elbow outreach, is close to chest
Wall；
2 points: animal being placed in smooth flat, when pushing hands art side shoulder is mobile to opposite side, resistance is reduced；
3 points: side ring being turned or turn-taked to operation when animal freely walks；
4 points；It collapses from physical exhaustion, limbs are without spontaneous activity.
Statistical method: neurological deficit rank scores data indicate that remainder data is with means ± SD using median
It indicates；Statistical difference is using Kruskal-Wallis inspection and Mann- between neurological deficit rank scores data group
Whitney U is examined, and statistical difference is examined using one-way ANOVA and Tukey ' s between remainder data group, and P value is less than
0.05 thinks there is significant difference.
The result shows that giving rat FDCA (30mg/kg) after ischemic 4h and being effectively reduced brain infarction area (infarct face
Product percentage: 7.48%), hence it is evident that be lower than blank solvent group (31.4%) and marketed drug NBP group (21.1%), be significantly better than
Fasudil dihydrochloride (30mg/kg) group (13.6%) (as shown in Figure 6, Figure 7)；In addition, FDCA improve also significantly it is scarce
The neurobehavioral dysfunction of blood induction, hence it is evident that be better than fasudil hydrochloride, be slightly better than NBP (Fig. 8).
Further investigate the Fasudil dihydrochloride (F) of FDCA and equimolar dosage, two in rat tMCAO model
The activity that monoxone sodium salt (DCA) and the two equimolar are administered in combination.Modeling method and administration time point are same as above.As a result table
It is bright, after ischemic 4h, give rat FDCA (30mg/kg) be effectively reduced brain infarction area (infarct size percentage:
6.78%) F (26.0mg/kg, infarct size percentage: 22.8%) DCA (10.7mg/kg, infarct size percentage, are significantly better than
Than: 23.4%) and and the two administering drug combinations group (infarct size percentage: 15.2%) (Fig. 9).In addition, FDCA is also significant
Ground improves the neurobehavioral dysfunction of ischemic induction, better than F, DCA and the administering drug combinations (Fig. 9) of the two.
The above is only a preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of compound, which is characterized in that the compound is Fasudil complex salt, is selected from Fasudil dichloroacetic acid
Salt, Fasudil trifluoroacetate, Fasudil trichloroacetate, Fasudil chloracetate, Fasudil chlorobromacetate,
Fasudil tribromoacetic acid salt.
2. compound according to claim 1, which is characterized in that the compound is Fasudil dichloroacetate, knot
Structure formula is as follows:
3. compound according to claim 2, which is characterized in that Fasudil dichloroacetate the preparation method comprises the following steps:
It takes appropriate Fasudil to be placed in reaction vessel, the mixing of appropriate reaction dissolvent is added, obtain Fasudil and reaction dissolvent
Mixed liquor；
Suitable dichloroacetic acid is added while stirring under reaction temperature 0-100 degree into above-mentioned mixed liquor, continues to stir after dripping off
A period of time is mixed, reaction solution is obtained；
Then solvent is concentrated under reduced pressure away in reaction solution, washing recrystallizes to get Fasudil dichloroacetate.
4. compound according to claim 3, which is characterized in that in preparation process, reaction temperature is room temperature, reaction dissolvent
For water, the Fasudil of addition and the molar ratio of dichloroacetic acid are 1:1.5, and recrystallization solvent is isopropanol.
5. compound according to claim 1, which is characterized in that the compound is Fasudil trifluoroacetate, knot
Structure formula is as follows:
Or, the compound is Fasudil trichloroacetate, structural formula is as follows:
6. compound according to claim 1, which is characterized in that the compound is Fasudil chloracetate, structure
Formula is as follows:
Or, the compound is Fasudil chlorobromacetate, structural formula is as follows:
Or, the compound is Fasudil tribromoacetic acid salt, structural formula is as follows:
7. a kind of pharmaceutical composition, wherein the compound described in any one of claims 1-6 containing therapeutically effective amount or its rotation
Photoisomer, enantiomer, diastereomer, racemic modification or racemic mixture or its pharmaceutically acceptable salt and pharmaceutically acceptable
Carrier, adjuvant or mediator.
8. compound described in any one of claims 1-6 is in the drug of preparation prevention and/or treatment pulmonary hypertension disease
Application.
9. compound described in any one of claims 1-6 is in preparation prevention and/or the medicine for the treatment of subarachnoid hemorrhage disease
Application in object.
10. compound described in any one of claims 1-6 is in preparation prevention and/or the drug for the treatment of cerebral arterial thrombosis disease
In application.
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| WO2020177291A1 (en) * | 2019-03-04 | 2020-09-10 | 中国药科大学 | Fasudil compound salt, preparation method therefor and use thereof |
| CN113262226A (en) * | 2021-04-19 | 2021-08-17 | 浙江大学 | Application of lisuridil in preparation of medicament for treating bacterial infection |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092413A (en) * | 2006-06-23 | 2007-12-26 | 黄振华 | Hydrate of medicinal salt of Fasudil |
| CN101925367A (en) * | 2007-11-26 | 2010-12-22 | 鲁汶天主教大学 | Targeted radiotherapy |
| CN102276442A (en) * | 2011-07-07 | 2011-12-14 | 赵永俊 | Synthetic method of dichloroacetate |
| CN108779093A (en) * | 2016-03-29 | 2018-11-09 | 默克专利股份公司 | N1- (tri- fluoro- 2- hydroxy-2-methyls propionos of 3,3,3-)-piperidine derivative of inhibitor as pyruvic dehydrogenase kinase |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004106325A1 (en) * | 2003-05-29 | 2004-12-09 | Schering Aktiengesellschaft | Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine |
| CN102633779B (en) * | 2012-04-26 | 2014-01-22 | 齐鲁制药有限公司 | Fasudil acetate as well as preparation method and application thereof |
| CN109761958B (en) * | 2019-03-04 | 2020-04-28 | 中国药科大学 | Fasudil composite salt and preparation method and application thereof |
| CN109734701B (en) * | 2019-03-04 | 2020-07-14 | 中国药科大学 | ROCK inhibitor-dichloroacetic acid complex salt and preparation method and application thereof |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092413A (en) * | 2006-06-23 | 2007-12-26 | 黄振华 | Hydrate of medicinal salt of Fasudil |
| CN101925367A (en) * | 2007-11-26 | 2010-12-22 | 鲁汶天主教大学 | Targeted radiotherapy |
| CN102276442A (en) * | 2011-07-07 | 2011-12-14 | 赵永俊 | Synthetic method of dichloroacetate |
| CN108779093A (en) * | 2016-03-29 | 2018-11-09 | 默克专利股份公司 | N1- (tri- fluoro- 2- hydroxy-2-methyls propionos of 3,3,3-)-piperidine derivative of inhibitor as pyruvic dehydrogenase kinase |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020177291A1 (en) * | 2019-03-04 | 2020-09-10 | 中国药科大学 | Fasudil compound salt, preparation method therefor and use thereof |
| CN113262226A (en) * | 2021-04-19 | 2021-08-17 | 浙江大学 | Application of lisuridil in preparation of medicament for treating bacterial infection |
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