CN107973777A - One kind contains methyl naphthalene and propane diols thiophene-carboxamides class ROCK inhibitor and application thereof - Google Patents

Abstract

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

Description

One kind contains methyl naphthalene and propane diols thiophene-carboxamides class ROCK inhibitor and application thereof

Technical field

The invention belongs to pharmaceutical technology field.In particular it relates to a kind of contain methyl naphthalene and propane diols thiophene acyl The compound of amine structure, 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 to be influenced by the one member-GTPaseRhoA of Rho (Ras homologues) gtp binding protein And strengthen.The RhoA of active form GTP reference states positioned at from the ROCK Rho protein binding domains (RBD) for suppressing carboxyl terminal ring with producing Raw interaction.After bonding, the interaction between ROCK negativity regulatory region and kinases area is destroyed.This process to swash Enzyme obtains the opening conformation for being completely in activated state.The opening conformation also by lipid activity factor (such as arachidonic acid) with The PH domains of kinases carboxy-terminal domains with reference to caused by.Another activation mechanism in apoptosis process is also illustrated, And it is related to the carboxyl carried out respectively to ROCK I and II through Caspase (caspase) -3 and -2 (or granzyme granzyme B) End check solution.

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, one kind may result in the disease of hypopsia and blindness because of 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, 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 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.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 ROCK inhibitor of the one kind containing methyl naphthalene and propane diols thiophene-carboxamides class, these compounds can use In the medicine for preparing sex dysfunction, 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 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..

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 acid amides IV；Bromination naphthalene V is in boric acid three Handled in the presence of isopropyl ester using n-BuLi, obtain 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 inhibitory action, can be used to prepare as active ingredient 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 to be 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 0.57g (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 is carefully poured into 200mL frozen 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.Filter and remove 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 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 In, stirring, with 50mL × 3CH₂Cl₂Extraction, merges extraction phase, with 5% salt water washings of 100mL, anhydrous sodium sulfate drying.Filter 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 to 1.59g (15mmol) sodium carbonate in 21mL Isosorbide-5-Nitraes-dioxane and 7mL water, 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 frozen water, stirring, with 50mL × 3CH₂Cl₂Extraction, merges extraction phase, uses 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 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 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, stirring, with 50mL × 3CH₂Cl₂Extraction, merges extraction phase, uses successively 100mL 5%Na₂S₂O₃5% salt water washing of aqueous solution and 100mL, anhydrous sodium sulfate drying.Filter and remove 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

2.07g (10mmol) compound II-1 and 0.57g (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=247 ([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 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 VI-2.ESI-MS, m/z=187 ([M+H]⁺)。

The synthesis of step 3. compound VII-2

1.23g (5mmol) compound IV-2,0.94g (5mmol) compound VI-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 atmosphere In be stirred overnight at 80 DEG C, TLC tracking finds that reaction is completed.Reaction mixture is poured into 200mL frozen water, and stirring, uses 50mL ×3CH₂Cl₂Extraction, merges extraction phase, with 5% salt water washings of 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=308 ([M+H]⁺)。

The synthesis of step 4. compound I-2

0.92g (3mmol) compounds VII-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.ESI-MS, m/z=342 ([M+H]⁺), white solid.

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	138.3
Compound I-2	86.2

The compound that can be seen that the present invention from upper table result acts on ROCK with very high inhibition, 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 acid amides IV；Bromination naphthalene V is in three isopropyl of boric acid Handled in the presence of ester using n-BuLi, obtain 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.