CN108558823A - A kind of cyano-thiophene amide ROCK inhibitor, preparation method and its usage - Google Patents
A kind of cyano-thiophene amide ROCK inhibitor, preparation method and its usage Download PDFInfo
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- CN108558823A CN108558823A CN201711493475.9A CN201711493475A CN108558823A CN 108558823 A CN108558823 A CN 108558823A CN 201711493475 A CN201711493475 A CN 201711493475A CN 108558823 A CN108558823 A CN 108558823A
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- 0 C*c(c1ccc2)cccc1c2C(N)=O Chemical compound C*c(c1ccc2)cccc1c2C(N)=O 0.000 description 1
- HQMUNHDZIBTEMN-UHFFFAOYSA-N C=C(c1cccc2c1cccc2Br)N Chemical compound C=C(c1cccc2c1cccc2Br)N HQMUNHDZIBTEMN-UHFFFAOYSA-N 0.000 description 1
- XPWZELXBVDALQW-UHFFFAOYSA-N C=CCCCNC(c([s]1)cc(C#N)c1Br)=O Chemical compound C=CCCCNC(c([s]1)cc(C#N)c1Br)=O XPWZELXBVDALQW-UHFFFAOYSA-N 0.000 description 1
- JTECUOPQEJCHGT-UHFFFAOYSA-N C=CCCCNC(c1cc(C#N)c(-c2cccc3c2cccc3C(N)=O)[s]1)=O Chemical compound C=CCCCNC(c1cc(C#N)c(-c2cccc3c2cccc3C(N)=O)[s]1)=O JTECUOPQEJCHGT-UHFFFAOYSA-N 0.000 description 1
- CGHDIGFSJFEHKW-UHFFFAOYSA-N CC(C1C=CC=C2C(Br)=CC=CC12)=O Chemical compound CC(C1C=CC=C2C(Br)=CC=CC12)=O CGHDIGFSJFEHKW-UHFFFAOYSA-N 0.000 description 1
- LYYHJYTZUCDTHE-UHFFFAOYSA-N CC(c1cccc2c1cccc2-c([s]c(C(NCCCC(CO)O)=O)c1)c1C#N)N Chemical compound CC(c1cccc2c1cccc2-c([s]c(C(NCCCC(CO)O)=O)c1)c1C#N)N LYYHJYTZUCDTHE-UHFFFAOYSA-N 0.000 description 1
- LVZMNLDIMAXVDN-UHFFFAOYSA-N C[BrH]c([s]c(C(O)=O)c1)c1C#N Chemical compound C[BrH]c([s]c(C(O)=O)c1)c1C#N LVZMNLDIMAXVDN-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to ROCK inhibitor fields.Specifically, the present invention relates to a kind of cyano-thiophene amides ROCK inhibitor, preparation method and the applications in preparing the disease medicaments such as the treatment of sexual dysfunction.
Description
Technical field
The present invention relates to the fields of ROCK inhibitor.In particular it relates to generate treatment to inhibiting ROCK and make
A kind of ROCK inhibitor of nitrile group-containing thiophene-carboxamides analog derivative, preparation method, and preparing treatment sexual function barrier
Hinder the purposes in equal disease medicaments.
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.The molecular mass of the two
It is each about 160kD.There is the two (amino acid sequence) 65% homology, the homology in wherein kinases area to be up to 95%.To the greatest extent
The sequence for managing them is much like, 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 the one member-GTPase RhoA institutes shadow by Rho (Ras homologues) gtp binding protein
It rings and enhances.The RhoA of active form GTP reference states and the ROCK Rho protein binding domains (RBD) positioned at inhibition carboxyl terminal ring certainly
Generate interaction.After bonding, the interaction between ROCK negativity regulatory region and kinases area is destroyed.This process makes
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 structural domains of kinases carboxy-terminal domains.Also illustrate another activation machine in apoptosis process
System, and be related to through Caspase (caspase) -3 and -2 (or granzyme granzyme B) respectively to ROCK I and II progress
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 recombination 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
It plays 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 other inflammatory cytokines to generate.It was reported that
ROCK inhibitor can fight the generation of TNF-α and the IL-6 factors in lipopolysaccharides (LPS) stimulation 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 ingredient of the fibrosis and remodeling process of journey and many affected organs.There is apparent sign to show that ROCK is related 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.
Illustratively with gene knockout model and a large amount of academic research, 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) it combines, it is a real and significant medicine target to show 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 various and ROCK and activate relevant ROCK inhibitor, be especially considering that most of these current diseases are all controlled
It treats insufficient.Some unrestricted examples are glaucoma, asthma and chronic obstructive pulmonary disease.
Glaucoma, a kind of disease may result in hypopsia and blindness because of optic nerve injury are 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, ROCK inhibitor anti-inflammatory and nerve regneration at
Dividing will 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 will dramatically increase girder outflow when being applied topically to animal, cause advantageously to drop
Low intraocular pressure.
Allergic asthma is a kind of because heredity susceptible person is immune anti-to ubiquitous environment albumen generation non-habitual
It answers, to the respiratory tract chronic inflammatory diseases caused.Although there is the therapy of successful, illness rate because these therapies without
Method is effected a radical cure and be increased；Present situation is still being aggravated, and has more and more nonresponders.It can do with all factors of the disease
Novel, efficient, steroid-sparing be required.
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) is one group with slow
Irreversibility respiratory tract is restricted for property, reacted with abnormal inflammatory, the remodeling and damage of bronchoconstriction and lung tissue are characterized
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 therapy at urgent need.Due to glucocorticoid only have the function of it is limited or absolutely void, because
Bronchodilator is used only in this till now.Quote people's branch gas of the ROCK inhibitor energy diastole separation of such as Y-27632
Pipe prepared product inhibits the resistance of respiratory tract of anesthetized animal to increase, and reinforces the diastole effect of the beta-receptor agonist 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 fight the increasing across endothelial cell permeability of antiphlogistic mediation
By force, the inflow of the eosinophil after keeping the barrier integrity of blood vessel endothelium, the internal ovalbumin of inhibition to excite prevents lung
The formation of oedema and neutrophil migration inhibit anti-to the allergy of methacholine and serotonin in allergy Respiratory Tract of Mice
Answer and block tumor necrosis factor (TNF) release that LPS is induced.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 result from mouse (wherein the excalation of ROCK cause decaying myocardial fibrosis).Y-27632 obstructs cardiac muscle
Plug and Fasudil (fasudil) decay for the myocardial fibrosis of 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 male and female can be generated because of the interaction of physiology, psychology and Hormone Factors.Male and
One 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
It relaxes, to enable 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 erection.Impotence
(male erectile dysfunction) is generally defined as being unable to reach and maintaining the erectile ability for carrying out being satisfied with sex expression and sexual intercourse enough.
Impotence may be because mental handicape, nervous system abnormality or other include anhormonia physiological barrier or many reasons
In conjunction with causing.In the U.S., impotence estimation influences 40% 40 years old male, will be improved by 50 years old with age
To about 50%, 67% will be up to when by 70 years old.Women can also face sex dysfunction with the increase at age, and with climacteric
Breaking-out and the risk for increasing vascular diseases.Therefore, as male, the sexual arousal of women is at least part of can be with enabling clitoris
Congested blood flow increases.The blood flow of vagina also increases the degree of lubrication of vagina.Therefore, Female sexual dysfunction may be
Caused by being unable to reach or maintaining clitoral engorgement and/or vaginal lubrication in entire sexuality period.Currently, most of 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 flat
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 includes a kind of for treating sex
The method of dysfunction comprising to individuals in need local application include can weaken to sexual stimulus in organ subject
Rho kinase activities compound.
There are several known ROCK inhibitor types at present.Current emphasis is the application of tumour and angiocardiopathy.It arrives
Until now, the outstanding treatment potentiality of ROCK inhibitor is only limited in limited range.Its reason is that ROCK is such a
Effectively with extensive biochemical regulator, the systemic inhibiting effect of ROCK can bring powerful biological effect, but be also regarded as
The side effect of most of disease treatments.In fact, ROCK inhibitor with stronger anti-inflammatory component treat disease medical application by
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 drug of big deal.Therefore, local
Or the medicinal application of part is desired.Under normal conditions, the drug of topical application is for treating respiratory tract, eyes, property work(
It 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 treating or mitigate to be activated with ROCK
The seriousness of relevant various obstruction and illness.More specifically, the compound of the present invention is preferred for preventing and/or treat extremely
A kind of few disease or obstacle being related to ROCK, for example, with the function of smooth muscle cell, inflammation, fibrosis, excessive cell Proliferation,
Angiogenesis excessively, high response, barrier dysfunction, nerve degeneration lesion and the related disease of remodeling.For example, the present invention
Compound can be used for preventing and/or treat 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 nitrile group-containing thiophene-carboxamides structure, these compounds can be used for preparative
The medicine of dysfunction, diseases associated with inflammation, ophthalmology disease and respiratory disease etc..
Invention content
It is an object of the present invention to provide a kind of ROCK inhibitors with Formulas I.
It is a further object to provide the methods for preparing the compound with Formulas I.
It is also another object of the present invention to provide the compounds containing Formulas I in the treatment of sexual dysfunction, diseases associated with inflammation, eye
The application of section's disease and respiratory disease etc..
The content of present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the present 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 are condensed in the presence of DCC, generate amide IV；Naphthalene-carboxylic acid compound
II and VI is condensed in the presence of DCC, generates amide VII；Compound VII is in the presence of triisopropyl borate ester using at n-BuLi
Reason, obtains compound VIII；Compound IV is reacted with compound VIII 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 inhibiting effect, can be used as an active ingredient in the preparation of sexual function such as and hinders
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
It is verified by inhibiting ROCK experiments in vitro.
Specific implementation mode
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and is not intended to limit the present invention.General technical staff's training centre according to the present invention in the art is made various
Variation 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, is added 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
It pours into 200mL ice water, stirs, with 50mL × 3CH2Cl2Extraction, merge extraction phase, successively use 1% dilute hydrochloric acid of 100mL and
5% salt water washings of 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated on a rotary evaporator, residue
It is purified using silica gel column chromatography, obtains compound IV-I, 2.41g (yield 88%).ESI-MS, m/z=275 ([M+H]+)。
The synthesis of step 2. compound VII
2.51g (10mmol) compounds V is dissolved in the THF of 20mL dryings, is stirred at room temperature, and 2.48g (12mmol) is added
N, N'- dicyclohexyl carbodiimide (DCC) and 0.1g 4- dimethylamino pyridines (DMAP), after adding, reaction mixture is in room
The lower stirring of temperature 1 hour, then adds the NH of 5mL saturations3/ MeOH solution, then gained mixture be stirred at room temperature overnight,
TLC tracking finds that reaction is completed.Reaction mixture carefully pours into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction,
Merge extraction phase, uses 5% salt water washing of 1% dilute hydrochloric acid of 100mL and 100mL, anhydrous sodium sulfate drying successively.It filters 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, 2.28g (yield
91%).ESI-MS, m/z=251 ([M+H]+)。
The synthesis of step 3. compound VIII
2.00g (8mmol) compound VII and 3.76g (20mmol) B (i-PrO)3It is dissolved in 14mL dry toluenes and 7mL
In THF, stirring is cooled to -30 DEG C, 10mL (16mmol) 1.6M n- is then slowly added dropwise with syringe under nitrogen protection
The hexane solution of BuLi.After being added dropwise, compound of reaction stirs 3 hours at such a temperature, is 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, at room temperature stirring 1 hour, then
It pours into 200mL ice water, stirs, with 50mL × 3CH2Cl2Extraction merges extraction phase, anhydrous with 5% salt water washings of 100mL
Sodium sulphate is dried.It filters and removes drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, is obtained
To compound VIII, 1.38g (yield 80%).ESI-MS, m/z=216 ([M+H]+)。
The synthesis of step 4. compound IX-1
1.37g (5mmol) compound IV-1,1.08g (5mmol) compound VIII, 0.18g (0.25mmol) Pd (dppf)
Cl2It is added in 21mL Isosorbide-5-Nitraes-dioxane and 7mL water with 1.59g (15mmol) sodium carbonate, reaction mixture is in nitrogen atmosphere
In be stirred overnight at 80 DEG C, TLC tracking finds that reaction is completed.Reaction mixture pours into 200mL ice water, and 50mL is used in stirring
×3CH2Cl2Extraction merges extraction phase, with 5% salt water washings of 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filter
Liquid is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtains 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, and 0.70g is added
(6mmol) NMMO and 1.2mL (0.3mmol) 0.25M OsO4It is dissolved in solution made of 75% tertiary butanol aqueous solution, after adding,
Compound of reaction is stirred at room temperature overnight, and TLC tracking finds that reaction is completed.Reaction mixture pours into 200mL ice water, stirs
It mixes, with 50mL × 3CH2Cl2Extraction merges extraction phase, uses 100mL 5%Na successively2S2O3Aqueous solution and the washing of 5% salt of 100mL
It washs, anhydrous sodium sulfate drying.It filters and removes 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
2.32g (10mmol) compound II-2 and 0.85g (10mmol) compound III is dissolved in the THF of 20mL dryings, room
The lower stirring of temperature, is added 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
It pours into 200mL ice water, stirs, with 50mL × 3CH2Cl2Extraction, merge extraction phase, successively use 1% dilute hydrochloric acid of 100mL and
5% salt water washings of 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated on a rotary evaporator, residue
It is purified using silica gel column chromatography, obtains compound IV-2.ESI-MS, m/z=300 ([M+H]+)。
The synthesis of step 2. compound VII
2.51g (10mmol) compounds V is dissolved in the THF of 20mL dryings, is stirred at room temperature, and 2.48g (12mmol) is added
N, N'- dicyclohexyl carbodiimide (DCC) and 0.1g 4- dimethylamino pyridines (DMAP), after adding, reaction mixture is in room
The lower stirring of temperature 1 hour, then adds the NH of 5mL saturations3/ MeOH solution, then gained mixture be stirred at room temperature overnight,
TLC tracking finds that reaction is completed.Reaction mixture carefully pours into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction,
Merge extraction phase, uses 5% salt water washing of 1% dilute hydrochloric acid of 100mL and 100mL, anhydrous sodium sulfate drying successively.It filters 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.ESI-MS,m/z
=251 ([M+H]+)。
The synthesis of step 3. compound VIII
1.46g (8mmol) compound VII and 3.76g (20mmol) B (i-PrO)3It is dissolved in 14mL dry toluenes and 7mL
In THF, stirring is cooled to -30 DEG C, 10mL (16mmol) 1.6M n- is then slowly added dropwise with syringe under nitrogen protection
The hexane solution of BuLi.After being added dropwise, compound of reaction stirs 3 hours at such a temperature, is 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, at room temperature stirring 1 hour, then
It pours into 200mL ice water, stirs, with 50mL × 3CH2Cl2Extraction merges extraction phase, anhydrous with 5% salt water washings of 100mL
Sodium sulphate is dried.It filters and removes drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, is obtained
To compound VIII.ESI-MS, m/z=216 ([M+H]+)。
The synthesis of step 4. compound IX-2
1.55g (5mmol) compound IV-2,1.08g (5mmol) compound VIII, 0.18g (0.25mmol) Pd (dppf)
Cl2It is added in 21mL Isosorbide-5-Nitraes-dioxane and 7mL water with 1.59g (15mmol) sodium carbonate, reaction mixture is in nitrogen atmosphere
In be stirred overnight at 80 DEG C, TLC tracking finds that reaction is completed.Reaction mixture pours into 200mL ice water, and 50mL is used in stirring
×3CH2Cl2Extraction merges extraction phase, with 5% salt water washings of 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filter
Liquid is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtains compound IX-2, ESI-MS, m/z=390
([M+H]+)。
The synthesis of step 5. compound I-2
1.17g (3mmol) compounds IX-2 is dissolved in 7mL THF and 3mL water, is stirred at room temperature, and 0.70g is added
(6mmol) NMMO and 1.2mL (0.3mmol) 0.25M OsO4It is dissolved in solution made of 75% tertiary butanol aqueous solution, after adding,
Compound of reaction is stirred at room temperature overnight, and TLC tracking finds that reaction is completed.Reaction mixture pours into 200mL ice water, stirs
It mixes, with 50mL × 3CH2Cl2Extraction merges extraction phase, uses 100mL 5%Na successively2S2O3Aqueous solution and the washing of 5% salt of 100mL
It washs, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated on a rotary evaporator, and residue uses silica gel column chromatography
Purifying, obtains compound I-2, ESI-MS, m/z=424 ([M+H]+), pale solid.
3 Compound ira vitro of embodiment inhibits ROCK analyses
Using the ROCK IMAP kits (product identification R8093) from Molecular Devices companies markets, and
Inhibition test is executed with fluorescence polarization (FP) method essentially according to the scheme that manufacturer provides.S6 ribosomal proteins source property bottom used
Object 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
Close object and be placed into 384 orifice plates and screened to measure enzyme inhibition, 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 execute experiment.It 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 of 2 μ L is added to be 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
It incubates 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 total 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)
Wave 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, then uses XL-Fit algorithms to calculate again every
The IC of a matched curve50Value.
As a result it see the table below：
| Compound | IC50(nM) |
| Compound I-1 | 54.1 |
| Compound I-2 | 17.5 |
Can be seen that the compounds of this invention from upper table result has very strong inhibition to ROCK, can be used as preparative
The medicine of dysfunction, diseases associated with inflammation, ophthalmology disease etc..
Claims (3)
1. the compound with logical formula (I) structure,
2. the method for synthesizing compound described in claim 1：
Thiophene carboxylic acid's compound II and 4- amylene amine III are condensed in the presence of DCC, generate amide IV；Naphthalene-carboxylic acid compound II with
VI is condensed in the presence of DCC, generates amide VII；Compound VII is handled in the presence of triisopropyl borate ester using n-BuLi,
Obtain compound VIII；Compound IV is reacted with compound VIII under Suzuki reaction conditions, and coupling obtains compound IX；Change
It closes object IX and uses OsO4With N-methylmorpholine N- oxides (NMMO) processing, product I is obtained.
3. application of the compound described in claim 1 in terms of preparing medicaments for treating sexual disorder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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