CN107973776A - A kind of thiophene-carboxamides type of structured compound and application thereof - Google Patents
A kind of thiophene-carboxamides type of structured compound and application thereof Download PDFInfo
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- CN107973776A CN107973776A CN201711493517.9A CN201711493517A CN107973776A CN 107973776 A CN107973776 A CN 107973776A CN 201711493517 A CN201711493517 A CN 201711493517A CN 107973776 A CN107973776 A CN 107973776A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention relates to field of medicaments, and specifically, the present invention relates to a kind of compound thing of class formation containing thiophene-carboxamides, its preparation method and the application in treatment diseases associated with inflammation, ophthalmology disease and respiratory disease etc. is prepared.
Description
Technical field
The present invention relates to field of medicaments, in particular it relates to produce one kind of therapeutic effect to suppressing ROCK
The compound of type of structured containing thiophene-carboxamides, can be used as ROCK inhibitor, its preparation method, and the purposes in pharmacy.
Background technology
Serine/threonine protein kitase ROCK is made of in human body two kinds of hypotype ROCK I and ROCK II.ROCK I
It is encoded in No. 18 chromosomes, and ROCK II (also referred to as Rho kinases) are then located at No. 12 chromosomes.Both molecular masses
It is each about 160kD.Both (amino acid sequences) have 65% homology, and the homology in wherein kinases area is up to 95%.To the greatest extent
It is much like to manage their sequence, but Tissue distribution is had nothing in common with each other.The expression of ROCK I highest levels can be from heart, lung and bone
Structure observation arrives, and ROCK II are then mainly expressed in brain.Nearest data show that both isomers have the function of part rich
Yu Xing, ROCK I are more related in immunocompetence, and ROCK II are then related in smooth muscle function.
ROCK activity has been demonstrated one member-GTPase RhoA institutes shadow by Rho (Ras homologues) gtp binding protein
Ring and strengthen.The RhoA of active form GTP reference states and the ROCK Rho protein binding domains (RBD) positioned at suppression carboxyl terminal ring certainly
Produce interaction.After bonding, the interaction between ROCK negativity regulatory region and kinases area is destroyed.This process causes
Kinases obtains the opening conformation for being completely in activated state.The opening conformation is also by lipid activity factor (such as arachidonic acid)
And caused by the combination of the PH domains of kinases carboxy-terminal domains.Also illustrate another activation machine in apoptosis process
System, and it is related to ROCK I and II are carried out respectively through Caspase (caspase) -3 and -2 (or granzyme granzyme B)
C-terminus cracks.
ROCK plays an important role in various cell functions, such as smooth muscle contraction, the group of actin cytoskeleton
Knit, platelet activation, the downward of myosin phosphatase cell adherence, the migration of aortic smooth muscle cell, hyperplasia, survival and
Thrombin induction reaction, cardiac myocyte hypertrophy, bronchial smooth muscle contraction, smooth muscle contraction and the restructuring of nonmuscle cells skeleton,
Capacity regulates and controls activation, neural process retraction, wound healing, cell transformation and the gene expression of anion channel.ROCK is also being related to
Play a role in many signal pathways of autoimmunity and aspect of inflammation.ROCK has been demonstrated to play in terms of the activation of NF- κ B
Effect, the NF- κ B are a kind of key molecules for causing Tumor necrosis factor TNF and the generation of other inflammatory cytokines.It was reported that
ROCK inhibitor, which can resist lipopolysaccharides (LPS), stimulates the generation of TNF-α and the IL-6 factors in THP-1 macrophages.Therefore, ROCK
Inhibitor provides beneficial therapy to treat autoimmune disease, diseases associated with inflammation and response to oxidative stress.
Generally speaking, ROCK is the major control point of smooth muscle cell function, and is the inflammation mistake of various inflammatory cells
The crucial signaling component of the fibrosis and remodeling process of journey and many affected organs.There is obvious sign to show that ROCK relate to
The pathogenesis of many diseases, includes asthma, chronic obstructive pulmonary disease and glaucoma in the middle.In addition, ROCK involve it is various
Disease and obstacle, include eye illness, breathing problem, angiocardiopathy and vascular diseases, diseases associated with inflammation, nervous system in the middle
With central nervous system disease, proliferative disease, kidney trouble, sex dysfunction, disease in the blood system, skeletal diseases, glycosuria
Disease, benign prostate hyperplasia, graft-rejection, liver diseases, systemic loupus erythematosus, spasm, hypertension, chronic obstruction
Property bladder disease, premature labor, infection, allergy, obesity, pancreatic disease and AIDS.
With gene knockout model and substantial amounts of academic research illustratively, ROCK looks like the target spot of a safety.This
The data of a little knock out mice and the post-market surveillance research of Fasudil (Fasudil) (go out for treating cavum subarachnoidale
The strong ROCK inhibitor of appropriateness of cerebral angiospasm after blood) combine, it is a real and significant medicine target to indicate ROCK
Mark.ROCK inhibitor can be used as the curative drug that treatment is related to the obstacle of ROCK approach.Therefore, we extremely need exploitation one
Kind can be used for treating the relevant ROCK inhibitor of various and ROCK activation, be especially considering that most of these current diseases are all controlled
Treat deficiency.Some unrestricted examples are glaucoma, asthma and chronic obstructive pulmonary disease.
Glaucoma, a kind of disease that may result in hypopsia and blindness because of optic nerve injury, is because of intraocular pressure
Caused by increase.This is the common cause of adult's blindness, is a kind of chronic disease for needing to control all the life after making a definite diagnosis mostly.
Due to current treatment can only control and can not radical curing of disease, and further by stimulate, side effect locally and systemically, the disease
Disease needs the cure of an improvement.In addition, other positive influences, that is, the anti-inflammatory of ROCK inhibitor and nerve regneration into
Dividing to be prioritized.The ROCK inhibitor of reference such as Y-27632 can change cellular morphology and the TM mankind of reduction incubation are thin
Tonofibrils, Focal adhesions and the MLC phosphorylations of born of the same parents；The human trabecular meshwork shape tissue of their diastole in vitro cultures, diastole are external
Mankind's Schlemm pipeline endothelial cells, can dramatically increase girder outflow when being applied topically to animal, cause advantageously to drop
Low intraocular pressure.
Allergic asthma is a kind of to be immunized instead because heredity susceptible person produces non-habitual to ubiquitous environment albumen
Should, so that the respiratory tract chronic inflammatory diseases triggered.Although there is the treatment method of successful, illness rate because these therapies without
Method is effected a radical cure and increased；Present situation is still being aggravated, and has more and more nonresponders.It can do with all factors of the disease
New, efficient, steroid-sparing be required.
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) is one group with slow
Property irreversibility respiratory tract is restricted, is characterized with abnormal inflammatory reaction, the remodeling and infringement of bronchoconstriction and lung tissue
Disease.One of the main reason for it is human death, illness rate just steadily increase.Since current therapy is not enough to cure disease
Disease, we seek new treatment method at urgent need.Due to glucocorticoid only have the function that it is limited or absolutely void, because
Bronchodilator is used only in this till now.Quote the separated people's branch gas of ROCK inhibitor energy diastole of such as Y-27632
Pipe prepared product, suppresses the resistance of respiratory tract increase of anesthetized animal, strengthens the diastole effect of the beta-receptor activator of in vitro and in vivo,
And rapid bronchiectasis is given after inhalation.In addition, ROCK inhibitor can block H2O2The tracheal smooth muscle of induction is shunk
(clinical marker of response to oxidative stress).
Relevant with respiratory inflammation to be, ROCK inhibitor can resist the increasing across endothelial cell permeability of antiphlogistic mediation
By force, the barrier integrity of blood vessel endothelium is kept, suppresses the inflow of the eosinophil after internal ovalbumin excites, prevent lung
The formation of oedema and neutrophil migration, suppress anti-to the allergy of methacholine and serotonin in allergy Respiratory Tract of Mice
Tumor necrosis factor (TNF) release of LPS inductions and should be blocked.In terms of respiratory tract fibrosis and remodeling, ROCK inhibitor
The migration that asm cell can be blocked to induce.ROCK is found in the mankind's for the external evidence that Airway Remodeling acts on
Lung cancer cell line, the airway smooth muscle cells of calf and human airway smooth muscle.Internal cards of the ROCK for Fibrosis parameters
According to generally resulting from mouse (myocardial fibrosis that wherein excalation of ROCK causes decay).Y-27632 obstructs for cardiac muscle
The myocardial fibrosis decay of plug and Fasudil (fasudil) for the congestive heart failure of chronic hypertension rat model
Other indication is brought for the importance of remodeling for ROCK.Finally, the apoptosis of ROCK inhibitor increase smooth muscle cell is thin
Born of the same parents lose.
The human sexual response of masculinity and femininity can be produced because of the interaction of physiology, psychology and Hormone Factors.Male and
One of them of female body reaction is common that blood vessel function response, it can be loose because of the vascular smooth muscle that sexual stimulus is brought
Relax, so as to make phallic property tissue congested.Therefore, when the smooth muscle of perineum blood vessel loosens, the blood pressure in penis and clitoris
It is consequently increased with blood flow.The inflow of arterial blood will cause penis or corpora cavernosa clitoridis to expand, so as to cause to erect.Impotence
(male erectile dysfunction) is generally defined as being unable to reach and maintains to carry out the erectile ability for being satisfied with sex expression and sexual intercourse enough.
Impotence be probably because mental handicape, nervous system abnormality or other include the physiological barrier of anhormonia, or many reasons
With reference to causing to form.In the U.S., impotence estimation influences 40% 40 years old male, will be improved by 50 years old with age
To about 50%, by 70 years old when will be up to 67%.Women can also face sex dysfunction with the increase at age, and with climacteric
Breaking-out and the risk of increase vascular diseases.Therefore, as male, the sexual arousal of women is at least part of can be with making clitoris
Congested blood flow increase.The blood flow of vagina also increases the degree of lubrication of vagina.Therefore, Female sexual dysfunction is probably
Caused by being unable to reach or maintaining clitoral engorgement and/or vaginal lubrication in whole sexuality period.At present, it is most of to use
The signal transduction pathway for reducing calcium ion can be targeted in the vasodilator for the treatment of erectile dysfunction, this needs startup blood vessel to put down
The contraction movement of sliding flesh.However, from the point of view of physiological angle, vasoconstrictive startup is a very acute activity, when continuing
Between only from the several seconds to several minutes.Erectile tissue is maintained at by the long-term vessel retraction of calcium dependent/non-dependent signal transduction pathway
Relaxed state.It is RhoA/Rho kinase pathways to keep the vasoconstrictive signal pathway of calcium dependent/non-dependent.ROCK inhibitor is for controlling
It is also corresponding useful to treat erectile dysfunction.Therefore, from the point of view of on the one hand, the present invention is used to treat male or female comprising a kind of
The method of dysfunction, it, which includes including to individuals in need local application, to weaken in organ subject to sexual stimulus
Rho kinase activities compound.
There are several known ROCK inhibitor types at present.Current emphasis is the application of tumour and angiocardiopathy.Arrive
Untill now, the outstanding treatment potentiality of ROCK inhibitor is only limited in limited scope.Its reason is that ROCK is such a
Effectively with extensive biochemical regulator, the systemic inhibitory action of ROCK can bring powerful biological effect, but be also regarded as
The side effect of most of disease treatments.In fact, ROCK inhibitor is subject to the medical application of stronger anti-inflammatory component treatment disease
ROCK key effects adjust smooth muscle cell contraction nourish the stage when obstruction.The ROCK inhibitor of systemic applications can lure
Hair blood pressure is decreased obviously.Therefore, we have ROCK inhibitor of different nature high demand.
In order to specifically be treated by the specific aim for adjusting smooth muscle function and/or inflammatory process and/or remodeling expansion disease,
We can target target organ at high expectations ROCK inhibitor, enter other organs to avoid the medicine of big deal.Therefore, it is local
Or local medicinal application is desired.Under normal conditions, the medicine of topical application is used to treat respiratory tract, eyes, property work(
Can obstacle and dermatopathy.
To sum up, we still have lasting necessary design and exploitation ROCK inhibitor at present, it is wide for therapeutic domain
General morbid state.Compound described herein and pharmaceutically acceptable composition can be used for treatment or mitigate to activate with ROCK
The seriousness of relevant various obstruction and illnesses.More specifically, compound of the invention is preferred for preventing and/or treats extremely
A kind of few disease or obstacle for being related to ROCK, for example, with the function of smooth muscle cell, inflammation, fibrosis, excessive cell Proliferation,
The disease that angiogenesis is excessive, high response, barrier dysfunction, nerve degeneration lesion and remodeling are related.For example, the present invention
Compound can be used for preventing and/or treating following disease and illness：Ophthalmology disease or illness, breathing problem, throat, nose and
It is disease, skin disease, intestines problem, cardiovascular and the vascular diseases of ear, diseases associated with inflammation, the nervous system disease, Hypertrophic
Disease, kidney trouble, sex dysfunction, etc..
The invention discloses a kind of ROCK inhibitor of structure containing thiophene-carboxamides, these compounds can be used for preparing sexual function
The medicine of obstacle, diseases associated with inflammation, ophthalmology disease and respiratory disease etc..
The content of the invention
It is an object of the present invention to provide a kind of ROCK inhibitor with Formulas I.
It is a further object to provide the method for preparing the compound with Formulas I.
It is also another object of the present invention to provide the compound containing Formulas I in the treatment of sexual dysfunction, diseases associated with inflammation, eye
The application of section's disease and respiratory disease etc..
Present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the invention with formula (I) is with following structural formula：
Formula (I) compound of the present invention can be synthesized by following route：
Thiophene carboxylic acid's compound II and 4- amylene amine III is condensed in the presence of DCC, generation acid amides IV；Naphthalene-carboxylic acid compound
II and VI is condensed in the presence of DCC, generation acid amides VII；Compound VII is in the presence of triisopropyl borate ester using at n-BuLi
Reason, obtains compound VIII；Compound IV and compound VIII reacts under Suzuki reaction conditions, and coupling obtains compound
IX；Compound IX uses OsO4With N-methylmorpholine N- oxides (NMMO) processing, product I is obtained.
Compound of formula I of the present invention has ROCK inhibitory action, and sexual function such as can be used to prepare as active ingredient and is hindered
Hinder, the medicine of diseases associated with inflammation, ophthalmology disease and respiratory disease etc..The activity of compound of formula I of the present invention is
Verified by vitro suppressing ROCK experiments.
Embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.General technical staff's training centre according to the present invention in the art is made various
Change should all be within the protection domain required by the application claim.
The synthesis of 1 compound I-1 of embodiment
The synthesis of step 1. compound IV-1
2.07g (10mmol) compound II-1 and 0.85g (10mmol) compound III is dissolved in the THF of 20mL dryings, room
The lower stirring of temperature, adds 2.48g (12mmol) N, N'- dicyclohexyl carbodiimides (DCC) and 0.1g 4- dimethylamino pyridines
(DMAP), after adding, reaction mixture is stirred at room temperature overnight, and TLC tracking finds that reaction is completed.Reaction mixture carefully inclines
Pour into 200mL frozen water, stir, with 50mL × 3CH2Cl2Extraction, merges extraction phase, successively with 1% dilute hydrochloric acid of 100mL and
5% salt water washings of 100mL, anhydrous sodium sulfate drying.Filter and remove drier, filtrate is evaporated on a rotary evaporator, residue
Purified using silica gel column chromatography, obtain compound IV-I, 2.41g (yield 88%).ESI-MS, m/z=275 ([M+H]+)。
The synthesis of step 2. compound VII-1
2.51g (10mmol) compounds V is dissolved in the THF of 20mL dryings, is stirred at room temperature, adds 2.48g (12mmol)
N, N'- dicyclohexyl carbodiimide (DCC) and 0.1g 4- dimethylamino pyridines (DMAP), after adding, reaction mixture is in room
When the lower stirring 1 of temperature is small, the NH of 5mL saturations is then added3/ MeOH solution, then gained mixture be stirred at room temperature overnight,
TLC tracking finds that reaction is completed.Reaction mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction,
Merge extraction phase, successively with 5% salt water washing of 1% dilute hydrochloric acid of 100mL and 100mL, anhydrous sodium sulfate drying.Filter to remove and do
Drying prescription, filtrate are evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtain compound VII-1,2.28g and (receive
Rate 91%).ESI-MS, m/z=251 ([M+H]+)。
The synthesis of step 3. compound VIII-1
2.00g (8mmol) compound VII-1 and 3.76g (20mmol) B (i-PrO)3It is dissolved in 14mL dry toluenes and 7mL
THF in, stirring, be cooled to -30 DEG C under nitrogen protection, 10mL (16mmol) 1.6M n- be then slowly added dropwise with syringe
The hexane solution of BuLi.After being added dropwise, compound of reaction stir at such a temperature 3 it is small when, be then stirred for 3 at room temperature
Hour, TLC tracking finds that reaction is completed.1mL concentrated hydrochloric acids are slowly added into reaction mixture, when stirring 1 is small at room temperature, then
Pour into 200mL frozen water, stir, with 50mL × 3CH2Cl2Extraction, merges extraction phase, anhydrous with 5% salt water washings of 100mL
Sodium sulphate is dried.Filter and remove drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, is obtained
To compound VIII-1,1.38g (yield 80%).ESI-MS, m/z=216 ([M+H]+)。
The synthesis of step 4. compound IX-1
1.37g (5mmol) compounds IV-1,1.08g (5mmol) compound VIII-1,0.18g (0.25mmol) Pd
(dppf)Cl2It is added to 1.59g (15mmol) sodium carbonate in 21mL Isosorbide-5-Nitraes-dioxane and 7mL water, reaction mixture is in nitrogen
It is stirred overnight in gas atmosphere at 80 DEG C, TLC tracking finds that reaction is completed.Reaction mixture is poured into 200mL frozen water, stirring,
With 50mL × 3CH2Cl2Extraction, merges extraction phase, with 5% salt water washings of 100mL, anhydrous sodium sulfate drying.Filter and remove drying
Agent, filtrate are evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtain compound IX-I, 1.51g (yield
83%).ESI-MS, m/z=365 ([M+H]+)。
The synthesis of step 5. compound I-1
1.09g (3mmol) compounds IX-1 is dissolved in 7mL THF and 3mL water, is stirred at room temperature, adds 0.70g
(6mmol) NMMO and 1.2mL (0.3mmol) 0.25M OsO4Solution made of 75% tertiary butanol aqueous solution is dissolved in, after adding,
Compound of reaction is stirred at room temperature overnight, and TLC tracking finds that reaction is completed.Reaction mixture is poured into 200mL frozen water, is stirred
Mix, with 50mL × 3CH2Cl2Extraction, merges extraction phase, successively with 100mL 5%Na2S2O3Aqueous solution and the washing of 5% salt of 100mL
Wash, anhydrous sodium sulfate drying.Filter and remove drier, filtrate is evaporated on a rotary evaporator, and residue uses silica gel column chromatography
Purifying, obtains compound I-I, 1.05g (yield 88%).ESI-MS, m/z=399 ([M+H]+)。
The synthesis of 2 compound I-2 of embodiment
The synthesis of step 1. compound IV-2
2.07g (10mmol) compound II-2 and 0.85g (10mmol) compound III is dissolved in the THF of 20mL dryings, room
The lower stirring of temperature, adds 2.48g (12mmol) N, N'- dicyclohexyl carbodiimides (DCC) and 0.1g 4- dimethylamino pyridines
(DMAP), after adding, reaction mixture is stirred at room temperature overnight, and TLC tracking finds that reaction is completed.Reaction mixture carefully inclines
Pour into 200mL frozen water, stir, with 50mL × 3CH2Cl2Extraction, merges extraction phase, successively with 1% dilute hydrochloric acid of 100mL and
5% salt water washings of 100mL, anhydrous sodium sulfate drying.Filter and remove drier, filtrate is evaporated on a rotary evaporator, residue
Purified using silica gel column chromatography, obtain compound IV-2.ESI-MS, m/z=275 ([M+H]+)。
The synthesis of step 2. compound VII-2
2.51g (10mmol) compounds V is dissolved in the THF of 20mL dryings, is stirred at room temperature, adds 2.48g (12mmol)
N, N'- dicyclohexyl carbodiimide (DCC) and 0.1g 4- dimethylamino pyridines (DMAP), after adding, reaction mixture is in room
When the lower stirring 1 of temperature is small, 10mmol VI-2 are then added, then gained mixture is stirred at room temperature overnight, TLC tracking hairs
Now reaction is completed.Reaction mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction
Phase, successively with 5% salt water washing of 1% dilute hydrochloric acid of 100mL and 100mL, anhydrous sodium sulfate drying.Filter and remove drier, filter
Liquid is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtains compound VII-2.ESI-MS, m/z=293
([M+H]+)。
The synthesis of step 3. compound VIII-2
2.34g (8mmol) compound VII-2 and 3.76g (20mmol) B (i-PrO)3It is dissolved in 14mL dry toluenes and 7mL
THF in, stirring, be cooled to -30 DEG C under nitrogen protection, 10mL (16mmol) 1.6M n- be then slowly added dropwise with syringe
The hexane solution of BuLi.After being added dropwise, compound of reaction stir at such a temperature 3 it is small when, be then stirred for 3 at room temperature
Hour, TLC tracking finds that reaction is completed.1mL concentrated hydrochloric acids are slowly added into reaction mixture, when stirring 1 is small at room temperature, then
Pour into 200mL frozen water, stir, with 50mL × 3CH2Cl2Extraction, merges extraction phase, anhydrous with 5% salt water washings of 100mL
Sodium sulphate is dried.Filter and remove drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, is obtained
To compound VIII-2.ESI-MS, m/z=258 ([M+H]+)。
The synthesis of step 4. compound IX-2
1.38g (5mmol) compound IV-2,1.29g (5mmol) compound VIII-2,0.18g (0.25mmol) Pd
(dppf)Cl2It is added to 1.59g (15mmol) sodium carbonate in 21mL Isosorbide-5-Nitraes-dioxane and 7mL water, reaction mixture is in nitrogen
It is stirred overnight in gas atmosphere at 80 DEG C, TLC tracking finds that reaction is completed.Reaction mixture is poured into 200mL frozen water, stirring,
With 50mL × 3CH2Cl2Extraction, merges extraction phase, with 5% salt water washings of 100mL, anhydrous sodium sulfate drying.Filter and remove drying
Agent, filtrate are evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtain compound IX-2, ESI-MS, m/z
=408 ([M+H]+)。
The synthesis of step 5. compound I-2
1.22g (3mmol) compounds IX-2 is dissolved in 7mL THF and 3mL water, is stirred at room temperature, adds 0.70g
(6mmol) NMMO and 1.2mL (0.3mmol) 0.25M OsO4Solution made of 75% tertiary butanol aqueous solution is dissolved in, after adding,
Compound of reaction is stirred at room temperature overnight, and TLC tracking finds that reaction is completed.Reaction mixture is poured into 200mL frozen water, is stirred
Mix, with 50mL × 3CH2Cl2Extraction, merges extraction phase, successively with 100mL 5%Na2S2O3Aqueous solution and the washing of 5% salt of 100mL
Wash, anhydrous sodium sulfate drying.Filter and remove drier, filtrate is evaporated on a rotary evaporator, and residue uses silica gel column chromatography
Purifying, obtains compound I-2, white solid, ESI-MS, m/z=442 ([M+H]+)。
3 Compound ira vitro of embodiment suppresses ROCK analyses
Using the ROCK IMAP kits (product identification R8093) from Molecular Devices companies markets, and
Inhibition test is performed with fluorescence polarization (FP) method essentially according to the scheme that manufacturer provides.S6 ribosomal proteins source property bottom used
Thing is (Fl)-AKRRRLSSLRA, also from Molecular Devices companies (product identification R7184).ROCKα/
The enzymatic mixture of ROCKII comes from Upstate Biotechnology companies (product identification 14-451).In brief, Suo Youhua
Compound is placed into 384 orifice plates and is screened to measure enzyme suppression, concentration used between 100 μM between 0.1nM, using in proper order gradually
Into 3 times of dilution methods.Y-27632 is used as reference (0.4 μM) (by Tocris companies markets) to perform experiment.Will be
The 1 μ L compound solutions (each concentration) tested in DMSO be put into 10mM Tris-HCl, 10mM MgCl2,0.1%BSA,
In 0.05%NaN3, the 2 μ L enzyme solutions that pH value is 7.2.The ultimate density of enzyme is 2.6nM.After incubating 30 minutes at room temperature, add
The ATP for adding 2 μ L is in 10mM Tris-HCl, 10mM MgCl2,0.1%BSA, 0.05%NaN3, pH value with protein substrate
Mixture in 7.2 solution.Final concentration of 10 μM of ATP, and the ultimate density of protein substrate is then 0.2 μM.At room temperature
Incubate after sixty minutes, (IMAP combination buffers A (1x) and IMAP binding reagents (come from the IMAP binding solns of 12 μ L of addition
ROCK IMAP kits) mixture).Mixture (the cumulative volume so obtained is incubated at room temperature：17 μ L) 60 minutes, make
Fluorescence polarization degree, wherein FP filters are measured with automatic flat-plate reader (Perkin Elmer, Envision 2100-0010HTS types)
Ripple device is given out light optical filter using FITC FP480 exciter filters and FITC FP P-pol535 and FITC FP S-pol535
(Perkin-Elmer).Result is fitted to a curve using XL-Fit algorithms, is then calculated again with XL-Fit algorithms every
The IC of a matched curve50Value.
As a result see the table below：
| Compound | IC50(nM) |
| Compound I-1 | 54.1 |
| Compound I-2 | 17.2 |
Can be seen that the compounds of this invention from upper table result has very strong inhibition to ROCK, can be controlled as preparation
Treat the application in the disease medicaments such as diseases associated with inflammation, ophthalmology disease and respiratory disease.
Claims (3)
1. the compound with logical formula (I) structure,
2. synthesize the method for compound described in claim 1：
Thiophene carboxylic acid's compound II and 4- amylene amine III is condensed in the presence of DCC, generation acid amides IV；Naphthalene-carboxylic acid compound II with
VI is condensed in the presence of DCC, generation acid amides VII；Compound VII is handled in the presence of triisopropyl borate ester using n-BuLi,
Obtain compound VIII；Compound IV and compound VIII reacts under Suzuki reaction conditions, and coupling obtains compound IX；Change
Compound IX uses OsO4With the processing of 3 quinoline N- oxides (NMMO) of N- methyl, product I is obtained.
3. compound described in claim 1 is preparing answering for diseases associated with inflammation, ophthalmology disease and medicament for treating respiratory system object space face
With.
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| CN101166734A (en) * | 2005-02-28 | 2008-04-23 | 日本烟草产业株式会社 | Novel aminopyridine compounds having Syk inhibitory activity |
| WO2008049919A2 (en) * | 2006-10-26 | 2008-05-02 | Devgen N.V. | Rho kinase inhibitors |
| CN102159547A (en) * | 2008-09-18 | 2011-08-17 | 安斯泰来制药株式会社 | Heterocyclic carboxamide compounds |
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