CN108129453A - A kind of ROCK inhibitor containing methyl naphthalene and propylene glycol thiophene-carboxamides class formation - Google Patents

Abstract

The invention belongs to pharmaceutical technology fields, specifically, the present invention relates to a kind of compounds containing methyl naphthalene and propylene glycol thiophene-carboxamides class formation, it can be used as ROCK inhibitor, preparation method and the application in the treatment of sexual dysfunction, diseases associated with inflammation, ophthalmology disease and respiratory disease etc. is prepared.

Description

A kind of ROCK inhibitor containing methyl naphthalene and propylene glycol thiophene-carboxamides class formation

Technical field

The invention belongs to pharmaceutical technology fields.In particular it relates to a kind of contain methyl naphthalene and propylene glycol thiophene acyl The compound of amine structure can be used as ROCK inhibitor, 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.The molecular mass of the two It is each about 160kD.The two (amino acid sequence) has 65% homology, and the homology in wherein kinases area is 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 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 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 structural 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 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 leading to Tumor necrosis factor TNF and the generation of other inflammatory cytokines.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.

With gene knockout model and a large amount 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) 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 the relevant ROCK inhibitor of various and ROCK activation, 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, one kind may result in the disease of hypopsia and blindness due to optic nerve injury, be 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 into 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 to be immunized instead because heredity susceptible person generates non-habitual to ubiquitous environment albumen Should, so as 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 have 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, inhibiting the resistance of respiratory tract of anesthetized animal increases, and strengthens 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 the barrier integrity of holding blood vessel endothelium, the internal ovalbumin of inhibition 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 It should and block tumor necrosis factor (TNF) release of LPS inductions.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.ROCK is for the internal card of Fibrosis parameters According to generally resulting from mouse (myocardial fibrosis that wherein excalation of ROCK causes attenuation).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 generate due to 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 It relaxes, so as 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 maintains to carry out the erectile ability for being satisfied with sex expression and sexual intercourse enough. Impotence may be because mental handicape, nervous system abnormality or other include the physiological barrier or many reasons of anhormonia With reference to 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%, by 70 years old when will be up to 67%.Women can also face sex dysfunction, and with climacteric with the increase at age 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.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, including including and weakening in organ subject to sexual stimulus to individuals in need local application The compound of Rho kinase activities and the composition of pharmaceutically acceptable carrier.

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 and 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, it is local Or the medicinal application of part is desired.Under normal conditions, the drug of topical application is used to treat 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 treatment or mitigate to activate 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 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 ROCK inhibitor of the one kind containing methyl naphthalene and propylene glycol thiophene-carboxamides class, these compounds can be used In the medicine for preparing sex 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 general formula I.

It is a further object to provide prepare the method with compounds of formula I.

It is also another object of the present invention to provide containing compounds of formula I the treatment of sexual dysfunction, diseases associated with inflammation, The application of ophthalmology 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 logical formula (I) is with following structural formula：

Logical formula (I) compound of the present invention can be synthesized by following route：

Thiophene carboxylic acid's compound II is condensed with allylamine III in the presence of DCC, generation amide IV；Bromination naphthalene V is in boric acid three It is handled in the presence of isopropyl ester using n-BuLi, obtains compound VI；Compound IV and compound VI is in Suzuki reaction conditions Lower reaction, coupling obtain compound VII；Compound VII uses OsO₄With N-methylmorpholine N- oxides (NMMO) processing, obtain Product I.

Compound of Formula I of the present invention has ROCK inhibiting effect, can be used as an active ingredient in the preparation of such as sexual function The medicine of obstacle, diseases associated with inflammation, ophthalmology disease and respiratory disease etc..The work of compound of Formula I of the present invention Property be by the way that ROCK experiments is in vitro inhibited to verify.

Specific 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 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 0.57g (10mmol) compound III is dissolved in the THF of 20mL dryings, room Temperature is lower to be stirred, and adds in 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 is carefully poured into 200mL ice water, stirring, with 50mL × 3CH₂Cl₂Extraction merges extraction phase, according to It is secondary to use 5% salt water washing of 1% dilute hydrochloric acid of 100mL and 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is being revolved Turn to be evaporated on evaporimeter, residue is purified using silica gel column chromatography, obtains compound IV-I, 2.22g (yield 90%).ESI- MS, m/z=247 ([M+H]⁺)。

The synthesis of step 2. compound VI-1

2.07g (10mmol) compound V-1 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, 6.25mL (10mmol) 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, stirs 1 hour at room temperature, then pours into 200mL ice water In, stirring, with 50mL × 3CH₂Cl₂Extraction merges extraction phase, with 5% salt water washings of 100mL, anhydrous sodium sulfate drying.It filters Drier is removed, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtains compound VI-I, 1.43g (yield 83%).ESI-MS, m/z=173 ([M+H]⁺)。

The synthesis of step 3. compound VII-1

1.23g (5mmol) compound IV-1,0.86g (5mmol) compound VI-1,0.18g (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 is poured into 200mL ice water, stirring, with 50mL × 3CH₂Cl₂Extraction merges extraction phase, uses 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 VII-I, 1.26g (yield 86%).ESI-MS, m/z=294 ([M+H]⁺)。

The synthesis of step 4. compound I-1

0.88g (3mmol) compounds VII-1 is dissolved in 7mL THF and 3mL water, is stirred at room temperature, adds in 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 ice water, stirring, with 50mL × 3CH₂Cl₂Extraction merges extraction phase, uses successively 100mL 5%Na₂S₂O₃5% salt water washing of aqueous solution and 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filtrate exists It is evaporated on Rotary Evaporators, residue is purified using silica gel column chromatography, obtains compound I-I, 0.83g (yield 84%).ESI- MS, m/z=328 ([M+H]⁺)。

The synthesis of 2 compound I-2 of embodiment

The synthesis of step 1. compound IV-2

2.52g (10mmol) compound II-1 and 0.57g (10mmol) compound III is dissolved in the THF of 20mL dryings, room Temperature is lower to be stirred, and adds in 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 merges extraction phase, successively with 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=292 ([M+H]⁺)。

The synthesis of step 2. compound VI-2

2.21g (10mmol) compound V-2 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, 6.25mL (10mmol) 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 VI-2.ESI-MS, m/z=187 ([M+H]⁺)。

The synthesis of step 3. compound VII-2

1.46g (5mmol) compound IV-2,0.93g (5mmol) compound VI-2,0.18g (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 is poured 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 VII-2.ESI-MS, m/z=353 ([M+H]⁺)。

The synthesis of step 4. compound I-2

1.06g (3mmol) compounds VII-2 is dissolved in 7mL THF and 3mL water, is stirred at room temperature, adds in 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 ice water, is stirred It mixes, with 50mL × 3CH₂Cl₂Extraction merges extraction phase, successively with 100mL 5%Na₂S₂O₃Aqueous 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=387 ([M+H]⁺), white 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 performed 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 perform 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 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 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, is then calculated again with XL-Fit algorithms every The IC of a matched curve₅₀Value.

As a result it see the table below.

Compound	IC50(nM)
		Compound I-1	138.3
Compound I-2	14.2

Can be seen that the compound of the present invention from upper table result has very high inhibition effect to ROCK, can be used as and prepare The medicine of sex dysfunction, diseases associated with inflammation, ophthalmology disease and respiratory disease etc..

Claims (3)

1. the compound with logical formula (I) structure,

2. synthesize the method for claim 1 compound：

Thiophene carboxylic acid's compound II is condensed with allylamine III in the presence of DCC, generation amide IV；Bromination naphthalene V is in three isopropyl of boric acid It is handled in the presence of ester using n-BuLi, obtains compound VI；Compound IV and compound VI is anti-under Suzuki reaction conditions Should, coupling obtains compound VII；Compound VII uses OsO₄With N-methylmorpholine N- oxides (NMMO) processing, product is obtained I。

3. application of claim 1 compound in terms of the treatment of sexual dysfunction disease medicament is prepared.