CN100488510C

CN100488510C - Morpholine derivatives for use as dopamine agonists in the treatment of I.A. sexual dysfunction

Info

Publication number: CN100488510C
Application number: CNB2003801056771A
Authority: CN
Inventors: C·M·N·阿勒顿; A·D·巴克斯特; A·S·库克; D·赫普沃思; S·K-F·翁
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd; Pfizer Inc
Priority date: 2002-12-10
Filing date: 2003-12-02
Publication date: 2009-05-20
Anticipated expiration: 2023-12-02
Also published as: CN101117335A; GT200300277A; ZA200504727B; GB0228787D0; CN1723023A; TNSN05159A1

Abstract

The present invention provides for compounds of formula (I), (la) and (lb) Wherein: A is selected from C-X and N, B is selected from C-Y and N, R<1> is selected from H and (C1-C6)alkyl R<2 >is selected from H and (C1-C6)alkyl, X is selected from H, HO, C(O)NH2, NH2 Y is selected from H HO,, NH2, Br, Cl and F Z is selected from H, HO, F, CONH2 and CN; And pharmaceutically acceptable salts, solvates and prodrugs thereof; With the provisos that: for a compound of formula (I), (la) or (lb), when A is C-X, B is C-Y, at least one of X, Y and Z must be OH; for a compound of formula (I), when A is C-X and B is C-Y, Y is H, Z is H, R<1> is H and R<2> is H, then X cannot be OH; these compounds are useful as dopamine agonists for the treatment of i.a. secual dysfunction.

Description

In treatment of sexual dysfunctions, be used as the morpholine derivative of dopamine agonist

The present invention relates to a class dopamine agonist, more definite is that a class is to the selective agonist that is better than D2 of D3.These chemical compounds can be used for treating and/or preventing sexual dysfunction, female sexual disorder (FSD), particularly female sexual arousal disorder (FSAD) for example, and male sexual disorder, particularly male erectile dysfunction (MED).The alleged male sexual disorder of this paper comprises defective ejaculation, for example premature ejaculation, frigidity (can not come to orgasm), perhaps dysaphrodisia, for example very few disease (HSDD of libido; Shortage is to the interest of property).These chemical compounds also can be used for treating methanone derivatives and neural degeneration obstacle.

The invention provides formula (I), (Ia) and (Ib) chemical compound

Wherein:

A is selected from C-X and N,

B is selected from C-Y and N,

R ¹Be selected from H and (C ₁-C ₆) alkyl,

R ²Be selected from H and (C ₁-C ₆) alkyl,

X is selected from H, HO, C (O) NH ₂, NH ₂,

Y is selected from H, HO, NH ₂, Br, Cl and F,

Z is selected from H, HO, F, CONH ₂And CN;

And pharmaceutically acceptable salt, solvate and prodrug;

Its condition is:

With regard to formula (I), (Ia) or (Ib) with regard to the chemical compound, if A is C-X, B is C-Y, R ¹Be H or (C ₁-C ₆) alkyl, R ²Be H or (C ₁-C ₆) alkyl, then having one among X, Y and the Z at least must be OH;

With regard to formula (I) chemical compound, if A is C-X, B is C-Y, and Y is H, and Z is H, R ¹Be H, R ²Be H, then X can not be OH.

The pharmaceutically acceptable salt of formula (I) chemical compound comprises its acid-addition salts and alkali salt.

The pharmaceutically acceptable salt of formula (I) chemical compound can be by suitably mixing the solution of formula (I) chemical compound and required acid or alkali and preparation easily.Salt can be precipitated out from solution, filters and collects, and perhaps can reclaim by evaporating solvent.

The acid-addition salts that is fit to is to generate from the acid that generates non-toxic salts, and example has hydrochlorate, hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphate, hydrophosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate (saccharate), benzoate, mesylate, esilate, benzene sulfonate, right-toluene fulfonate and pamoate.

The alkali salt that is fit to can generate from the alkali that generates non-toxic salts, and example has the salt of sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine.

About the commentary of suitable salt, referring to Berge et al, J.Pharm.Sci., 66,1-19,1977.

The pharmaceutically acceptable solvate of formula (I) chemical compound comprises its hydrate.

In the scope of formula (I) chemical compound, also comprise its polymorphic.

Formula (I) chemical compound contains one or more asymmetric carbon atoms, therefore has two or more stereoisomeric forms in any ratio.The separation of diastereomer can realize like this that promptly the stereoisomer mixture to formula (I) chemical compound or its salt that is fit to or derivant adopts routine techniques to handle for example fractional crystallization, chromatograph or H.P.L.C..The single enantiomer of formula (I) chemical compound also can be from the pure intermediate preparation of the optically-active of correspondence, perhaps utilize the chiral support that is fit to split corresponding racemate, H.P.L.C. for example, perhaps make corresponding racemate and optically active acid that is fit to or alkali (depending on the circumstances) reaction, the diastereoisomeric salt that is generated is carried out fractional crystallization.

Preferred The compounds of this invention is formula (Ia) and (Ib) chemical compound.

Particularly preferably be formula (Ia) chemical compound.

Preferably, A is C-X or N, and B is C-Y.More preferably, A is N, and B is C-Y.More preferably, A is C-X, and B is C-Y.

Preferably, R ¹Be selected from H and (C ₁-C ₄) alkyl.More preferably, R ¹Be H, methyl and ethyl.And then more preferably, R ¹Be H or methyl.Most preferably, R ¹Be H.

Preferably, R ²Be selected from H and (C ₁-C ₄) alkyl.More preferably, R ²Be selected from H, methyl and ethyl.Most preferably, R ²Be selected from H and methyl.

In particularly preferred embodiments, R ²Be H.In other particularly preferred embodiment, R ²It is methyl.

Preferably, X is selected from H, OH and NH ₂Most preferably, X is selected from H and OH.

In particularly preferred embodiments, X is H.In other particularly preferred embodiment, X is OH.

Preferably, Y is selected from H, NH ₂, Cl and F.Most preferably, Y is selected from H and NH ₂

In particularly preferred embodiments, Y is H.In other particularly preferred embodiment, Y is NH ₂

Preferably, Z is selected from H, HO and F.Most preferably, Z is selected from H or HO.

In particularly preferred embodiments, Z is H.In other particularly preferred embodiment, Z is HO.

Particularly preferably be The compounds of this invention (and salt) as this paper institute illustration; More preferably:

R-(-)-3-(phenol (embodiment 7A) of 4-propyl group morpholine-2-yl)

S-(+)-3-(phenol (embodiment 7B) of 4-propyl group morpholine-2-yl)

R-(-)-3-(the phenolate hydrochlorate (embodiment 8) of 4-propyl group morpholine-2-yl)

R-5-(benzene-1 of 4-propyl group morpholine-2-yl), 3-diphenol (embodiment 15A)

S-5-(benzene-1 of 4-propyl group morpholine-2-yl), 3-diphenol (embodiment 15B)

R-(+)-2-fluoro-5-(phenol (embodiment 23A) of 4-propyl group morpholine-2-yl)

S-(-)-2-fluoro-5-(phenol (embodiment 23B) of 4-propyl group morpholine-2-yl)

The 2-bromo-4-(phenol (embodiment 30) of 4-propyl group morpholine-2-yl)

2-hydroxyl-5-(Benzoylamide (embodiment 35) of 4-propyl group morpholine-2-yl)

2-nitro-4-(phenol (embodiment 36) of 4-propyl group morpholine-2-yl)

2-amino-4-(phenol (embodiment 37) of 4-propyl group morpholine-2-yl)

5-(the pyridine of 4-propyl group morpholine-2-yl)-2-base amine (embodiment 44A and 44B)

The 2-chloro-5-(phenol (embodiment 54) of 4-propyl group morpholine-2-yl)

3-[(5S)-and 5-methyl-4-propyl group morpholine-2-yl] phenol (embodiment 60)

5-[(2S, 5S)-5-methyl-4-propyl group morpholine-2-yl] pyridine-2-amine (embodiment 66)

5-[(2R, 5S)-5-methyl-4-propyl group morpholine-2-yl] pyridine-2-amine (embodiment 67)

Most preferably:

R-(-)-3-(phenol (embodiment 7A) of 4-propyl group morpholine-2-yl)

S-(+)-3-(phenol (embodiment 7B) of 4-propyl group morpholine-2-yl)

R-5-(benzene-1 of 4-propyl group morpholine-2-yl), 3-diphenol (embodiment 15A)

S-5-(benzene-1 of 4-propyl group morpholine-2-yl), 3-diphenol (embodiment 15B)

R-(+)-2-fluoro-5-(phenol (embodiment 23A) of 4-propyl group morpholine-2-yl)

S-(-)-2-fluoro-5-(phenol (embodiment 23B) of 4-propyl group morpholine-2-yl)

The 2-chloro-5-(phenol (embodiment 54) of 4-propyl group morpholine-2-yl)

The compounds of this invention can be according to known way, number of ways preparation.Following approach is set forth the method for synthesis type (I) chemical compound; The technical staff will figure out can separate type (Ia) and (Ib) chemical compound with suitable disassemble technique.

Can prepare such formula (I) chemical compound according to reaction process 1, wherein A is C-X, and B is C-Y, R ¹Be H or (C ₁-C ₆) alkyl, R ²Be H, wherein X, Y and Z are as described herein.

Flow process 1

Formula (III) chemical compound can prepare like this, even formula (II) aldehyde and i) cyanide source or Nitrocarbol. reaction, succeeded by ii) reducing with borine, lithium aluminium hydride reduction or hydrogenization.Some formulas (II) and (III) chemical compound also be commercial available.

Formula (IV) chemical compound can prepare like this, promptly in the presence of the alkali (for example triethylamine or 4-methyl morpholine) that is fit to, makes formula (III) chemical compound and iii) acyl chloride reaction.Typical reaction condition comprises 1.0 equivalent amine (III), 1.2-2.0 equivalent alkali (preferred triethylamine), 1.1-1.3 equivalent acyl chlorides, in dichloromethane, under 25 ℃.

The formula V chemical compound can prepare like this, is about to iv) Reducing agent (for example borine or the lithium aluminium hydride reduction) reduction of formula (IV) chemical compound.Typical condition comprises 1.0 equivalent amide (IV), 1.2-3.0 equivalent borine, in THF, under refluxing.The formula V chemical compound also can prepare like this, promptly in the presence of sodium cyanoborohydride, formula (III) chemical compound is used the aldehyde reductive amination that is fit to.

Formula (VI) chemical compound can prepare like this, promptly in the presence of alkali (for example triethylamine, sodium carbonate and potassium hydroxide), the formula V chemical compound and the chloracetyl chloride (for example 2-chlorpromazine chloride or 2-chlorobutanoylchloride) of v) chloracetyl chloride or 2-replacement is reacted.Typical condition comprises 1.0 equivalent amine (IV), 1.0-1.3 equivalent acyl chlorides, 1.2-2.0 equivalent triethylamine, in dichloromethane, under 25 ℃, then crude product mixture is dissolved among the IPA that contains 1.2-3.0 equivalent aqueous potassium hydroxide.

Formula (I) chemical compound can prepare like this, even formula (VI) chemical compound and vi) Reducing agent (for example borine or lithium aluminium hydride reduction) reaction.Typical condition comprises 1.0 equivalent amide (VI), 1.2-3.0 equivalent borine, in THF, under refluxing.

The technical staff will figure out, because one of X, Y or Z are hydroxyls, protect this hydroxyl with the blocking group that is fit to being necessary during the transformation of flow process 1, remove blocking group then.Blocking group is depended in the guard method of going of phenolic group group.About protecting/go the example of guard method, referring to ＂ Protective groups in Organic synthesis ＂, TW Greene and PGMWutz.For example,, then go protective condition to be included among the 48% moisture HBr backflow 1-24 hour, perhaps in dichloromethane, stirred 1-24 hour with the tribromide borine if hydroxyl is protected with the form of methyl ether.Perhaps, if hydroxyl is protected with the form of benzylic ether, then goes protective condition to be included in and use palladium catalyst hydrogenation under the nitrogen atmosphere.

Can prepare such formula (I) chemical compound according to reaction process 2, wherein one of A or B are N, R ¹Be H or (C ₁-C ₆) alkyl, R ²Be H, X, Y and Z are as described herein, and its condition is that one of X, Y or Z are NH ₂This flow process has been set forth wherein, and B is that C-Y, Y are NH ₂Situation; The technical staff will understand, and other chemical compounds can be realized equally.

Flow process 2

Formula (VII) chemical compound can utilize the prepared of describing among the JP2001048864.

Formula (VIII) chemical compound can prepare by making epoxide (VII) and the reaction of vii) propylamine.Typical reaction condition comprises and stirs epoxide and excess amine, carry out separately in this stirring or in dimethyl sulfoxide, carry out.

Formula (IX) chemical compound can prepare like this, promptly in the presence of alkali (for example triethylamine, sodium carbonate and potassium hydroxide), formula (VIII) chemical compound and the chloracetyl chloride (for example 2-chlorpromazine chloride or 2-chlorobutanoylchloride) of v) chloracetyl chloride or 2-replacement is reacted.Typical condition comprises 1.0 equivalent amine (VIII), 1.2-2.0 equivalent triethylamine, in dichloromethane, under 25 ℃, then crude product mixture is dissolved among the IPA that contains 1.2-3.0 equivalent aqueous potassium hydroxide.

Formula (X) chemical compound can by make formula (IX) chemical compound and Reducing agent for example lithium aluminium hydride reduction reaction prepare.Typical condition comprises 1.0 equivalent amide (X), 1.2 equivalent lithium aluminium hydride reductions, in THF, under refluxing.

Formula (I) chemical compound can be by ix) go protective effect and prepare.Typical condition comprises 1.0 equivalent chemical compounds (X) and 5 equivalent oxammonium hydrochloride .s, in ethanol, under refluxing.

Can prepare such formula (I) chemical compound according to reaction process 3, wherein A is C-X, and B is C-Y, R ¹Be H, R ²Be H or (C ₁-C ₆) alkyl, wherein X, Y and Z are as described herein.

Flow process 3

Formula (XII) chemical compound can prepare like this, promptly in the presence of the alkali (for example triethylamine and 4-methyl morpholine) that is fit to, makes formula (XI) amino-acid ester and x) acyl chloride reaction.Typical reaction condition comprises 1 equivalent amino-acid ester (XI), 1 equivalent acyl chlorides and 3 equivalent alkali, in dichloromethane, under 25 ℃.Some formulas (XI) chemical compound is commercial available.

Formula (XIII) chemical compound can prepare like this, even formula (XII) chemical compound and xi) borine-THF coordination compound reaction, decompose boron-nitrogen complex with acid subsequently, the amine that is generated carries out the tertbutyloxycarbonyl protection.Typical reaction condition comprises 1 equivalent amide (XII) and 3 equivalent BH ₃-THF, in THF, under refluxing, cooling adds the moisture HCl of 6M carefully, and being heated to refluxes reaches other 6 hours.Evaporating solvent subsequently is dissolved in methanol: water (8:1) mixture, add 5 equivalent alkali, and for example potassium hydroxide, and 1.5 equivalent Bis(tert-butoxycarbonyl)oxides stirs mixture 72 hours.

Formula (XIV) chemical compound can be by making formula (XIII) chemical compound and xii) the organic solution reaction of HCl prepares.Typical reaction condition comprises 1 equivalent carbamate (XIII) and 1-10 equivalent 4M HCl De dioxane solution, in the Zai diox, under 25 ℃.

Formula (XV) chemical compound can be by making formula (XIV) chemical compound and xiii in the presence of alkali (for example triethylamine or 4-methyl morpholine)) reaction of 2-bromoacetophenone prepares.The 2-bromoacetophenone can obtain from commercial source, and perhaps variable earthing can be prepared by standard bromination process well known to those skilled in the art from the parent 1-Phenylethanone..Typical condition comprises 1 equivalent amino alcohol (XIV) and 1-3 equivalent triethylamine and 1 equivalent 2-bromoacetophenone, under 65 ℃.

Formula (I) chemical compound can be by making formula (XV) chemical compound and xiv) triethyl group silicon and trimethylsilyl triflate (trimethylsilyltriflate) reaction prepare.Typical condition is included in the dichloromethane, under-78 ℃, adds 5-10 equivalent triethyl silicane to 1 equivalent morpholine alcohol (XV), succeeded by adding 2 equivalent trimethylsilyl triflate.

The technical staff will figure out, because one of X, Y or Z are hydroxyls, protect this hydroxyl with the blocking group that is fit to being necessary during the transformation of flow process 3, remove blocking group then.Blocking group is depended in the guard method of going of phenolic group group.About protecting/go the example of guard method, referring to ＂ Protective groups in Organic synthesis ＂, TW Greene and PGMWutz.For example,, then go protective condition to be included among the 48% moisture HBr backflow 1-24 hour, perhaps in dichloromethane, stirred 1-24 hour with the tribromide borine if hydroxyl is protected with the methyl ether form.Perhaps, if hydroxyl is protected with the benzylic ether form, then goes protective condition to be included in and use palladium catalyst hydrogenation under the nitrogen atmosphere.

The three-dimensional center that wherein is positioned at morpholine nitrogen α position has formula (I) chemical compound of absolute definition can be from formula (XI) homochiral chemical compound, and this formula (XI) chemical compound can be commercial available or prepare by the Chemistry Literature method that obtains for the technical staff easily.Gained formula (I) chemical compound will contain the mixture of diastereomer, can separate on the HPLC post.Typical condition comprises the post by Chiralcel OJ-H, with 100% MeOH mobile phase eluting.

Can prepare such general formula (I) chemical compound according to reaction process 4, wherein one of A or B are N, R ¹Be H, R ²Be H or (C ₁-C ₆) alkyl, X, Y and Z are as described herein, its condition is that one of X, Y or Z are NH ₂This flow process is set forth wherein, and B is that C-Y, Y are NH ₂Situation; The technical staff will understand, and other chemical compounds can be suitable for equally.

Flow process 4

Formula (XVIII) chemical compound can be by making formula (XVI) chemical compound and xv in the presence of alkali (for example triethylamine or 4-methyl morpholine)) reaction of formula (XIV) amino alcohol prepares.Typical condition comprises 1 equivalent amino alcohol (XIV) and 1-3 equivalent triethylamine and 1 equivalent formula (XVI) chemical compound, uses toluene as solvent, under room temperature or higher temperature.Formula (XVI) chemical compound is commercial available.

Formula (IXX) chemical compound can be by making formula (XVIII) chemical compound and xvi) the organometallic reagent reaction that generates from formula (XVII) bromide prepares.The organometallic reagent that is fit to comprises Ge Liya (organic-magnesium) or organolithium reagent, and they can prepare by the halogen metal metathesis from bromide.Typical condition is included in the absolute ether solvent for example in the oxolane, at room temperature, adds isopropylmagnesium chloride (carrying out the halogen metal displacement reaction) to bromide (XVII), succeeded by adding morpholone (XVIII).Bromide (XVII) can utilize prepared described in the WO 99/32475.

For example in the methanol, morpholine alcohol (IXX) and xvii) for example sodium borohydride reaction of hydride reducer can be reduced to glycol (XX) at alcoholic solvent.

Formula (XXI) chemical compound can by from glycol (XX) by ix) go protective effect to prepare.Typical condition comprises 1.0 equivalent chemical compounds (XX) and 5 equivalent oxammonium hydrochloride .s, in ethanol, under refluxing.

Formula (I) chemical compound can pass through xviii) cyclisation of carrying out formula (XXI) chemical compound with acid treatment prepares.Typical condition adopts concentrated sulphuric acid and dichloromethane solvent, under room temperature or higher temperature.

All above-mentioned reactions and the preparation that is used in the new raw material in the preceding method all are conventional, with reference to document and the following examples and the preparation example quoted, the technology that those skilled in the art know the reagent that is suitable for reacting or prepares and reaction condition and separate required product.

The compounds of this invention can be used as selective d 3 agonist and uses in the treatment of morbid state.Exist and to have the two the chemical compound of agonist activity of D2 and D3 in a large number; But, the use of this compounds is relevant with a large amount of side effect, comprises nauseating, vomiting, faintness, hypotension and bradycardia, and some of them can cause serious problems.

Thought in the past that the effect of prior art chemical compound was from the ability of their exciting D2; But, the D2 agonism reason of above-mentioned side effect just.

The invention provides a class selective d 3 agonist.Chancing on them is effectively, has reduced simultaneously and the relevant side effect of nonselective prior art chemical compound.

The compounds of this invention can be used for the therapeutic dysfunction, female sexual disorder (comprises the very few disease of libido, sexual arousal dysfunction, orgasm disorder and sexual anhedonia disease), male erectile dysfunction, hypertension, neural degeneration, psychosis, depressed (cancer patient's depression for example, parkinsonian's depression, the myocardial infarction retarded depression, the symptomatic depression of inferior syndrome, the SF depression, child's depression (paediatric depression), the serious symptom depression, single ictal depression, the recurrent depression, malaria is treated the depression (child abuse induceddepression) that the child brings out, postpartum depression and the old man syndrome of having a fiery temperament), generalized anxiety disorder, terrified (for example agoraphobia, social phobia and simple terrified), psychentonia syndrome after the wound, escape personality disorder, premature ejaculation, eating disorders (for example anorexia nervosa and bulimia nervosa), fat, chemicals relies on (for example to ethanol, cocaine, heroin, phenobarbital, nicotine and benzodiazepine

The class addiction), bunch headache, migraine, pain, Alzheimer, obsession, Panic disorder, dysmnesia are (for example dull-witted, amnesia and age related cognitive decline (ARCD)), parkinson (parkinson dementia for example, Parkinsonism that nerous sedative brings out (neuroleptic-induced parkinsonism) and tardive dyskinesia), dyshormonia (for example high prolactin hyperandrogenism), vasospasm (particularly in the brain vascular system), cerebellar ataxia, gastrointestinal tract disorder (involving motility and excretory change), schizoid negative symptom, premenstrual tension syndrome, fibromyalgia syndrome, the tonicity urinary incontinence, Tourette's syndrome, trichotillomania, kleptomania, impotence, attention-deficit hyperactivity disease (ADHD), chronic paroxysmal hemicrania, headache (relevant) with angiopathy, emotional instability, pathologic is cry and shout, sleep disorder (dampinging off) and shock.

The compounds of this invention is particularly suitable for treating female sexual disorder, male erectile dysfunction, neural degeneration, depression and psychiatric disturbance.

The compounds of this invention can be used for male sexual disorder, particularly male erectile dysfunction.Male erectile dysfunction (MED) also claim male erectile disorder, is defined as:

" erection can not reach and/or keep gratifying sex expression " (NIHConsensus Development Panel on Impotence, 1993)

According to estimation, the prevalence of the erection disturbance (ED) of various degree (slight, medium and complete sexual impotence) at 40 to 70 years old among the male be the philtrum prevalence more than 52%, 70 years old higher (Melman et al 1999, J.Urology, 161, p5-11).This disease has significant negative effect to individual and companion's quality of life, often causes anxiety and nervous increasing, and causes that depression and sense of personal worth reduce.And before 20 years, MED mainly is regarded as a kind of psychology obstacle, and (Benet et al 1994 Comp.Ther., 20:669-673), there is organic reason in known most of individuals now.As a result, on the pathophysiology of the mechanism of differentiating normal erection and MED, obtained huge progress.

Erection is a kind of hematodinamics incident, it depend on the contraction of cavernous body of penis smooth muscle and penis vascular system and tension and relaxation balance (Lerner et al 1993, J.Urology, 149,1256-1255).The cavernous body of penis smooth muscle also claims spongy body smooth muscle or cavernous body of penis in this article.The lax of cavernous body of penis smooth muscle causes that entering the spatial blood flow of trabeculae of cavernous body of penis shape increases, and causes their peripherad tunicles to expand, the compressing draining vein.This causes that blood pressure greatly raises, cause erecing (Naylor, 1998, J.Urology, 81,424-431).

The variation that occurs in during the erection process is complicated, needs the coordination control of height, involve periphery and central nervous system unify hormonal system (Naylor, 1998, J.Urology, 81,424-431).The spongy body smooth muscle contraction is subjected to the regulation and control of sympathetic noradrenergic nerve domination via the activation of postsynaptic α 1 adrenoceptor.MED may increase relevant with the inherent smooth muscle tension force of spongy body.But, the process of spongy body smooth muscle loosening is subjected to the mediation of non-adrenergic non-cholinergic (NANC) neurotransmission on the part degree.In penis, find a large amount of other NANC neurotransmitteies except that NO, for example calcitonin gene dependency peptide (CGRP) and vasoactive intestinal peptide (VIP).The main relaxation factor of being responsible for this relexation of mediation is nitric oxide (NO), it be from the L-arginine by nitric oxide synthetase (NOS) synthetic (Taub et al1993 Urology, 42,698-704).It is believed that reducing spongy body smooth muscle tension force has and help NO and induce the lax of spongy body.During male's sexual arousal, NO discharges from neuron and endothelium, in conjunction with also activating the sGC (sGC) that is arranged in smooth muscle cell and endothelium, causes the rising of cyclic guanosine 3 ', 5 '-one phosphoric acid (cGMP) level in the cell.This cGMP rises can be because intracellular calcium concentration ([Ca ²⁺] _i) reduce and cause that spongy body is lax, its mechanism is unknown, but it is believed that relevant with the activation of protein kinase G (may be owing to Ca ²⁺The activation of pump and Ca ²⁺Activated K ⁺Passage).

In the central nervous system, differentiated the position of a plurality of potential control behaviors.Crucial neurotransmitter it is believed that it is serotonin, norepinephrine, oxytocin, nitric oxide and dopamine.By simulating the effect of one of these crucial neurotransmitteies, can adjusting sexual function.Dopamine D 3 receptor is almost only expressed in brain edge zone, and these zones involve repayment emotion and cognitive process.

As if be not subjected to the limitation of any theory, " because its role in motor activity control, the integrity of nigrostriatum dopaminergic approach also is that the performance mounting is necessary.Somehow, specifically for sexual function, dopamine can cause erection by the short erection rumpbone parasympathetic nuclear that acts on the oxytocinergic neuron that is arranged in necleus of hypothalamus,paraventricular, perhaps also acts on spinal cord probably ".Now, seeming significant position is D3, rather than the former D2 that thinks.

In fact, D3 is the occasioner of sexual behaviour.

Therefore, the invention provides the purposes of formula (I) chemical compound in the medicine of preparation treatment or prevention erection disturbance.

Slightly should adopt compounds for treating of the present invention and be benefited to moderate MED patient, serious MED patient also has response.But, early stage research prompting, slight, medium and serious MED patient's responsiveness may be bigger in selective d 3 agonist/PDE5 inhibitor combination.Slightly, medium and serious MED will be the known terms of those skilled in the art, but relevant knowledge can be referring to The Journal of Urology, vol.151,54-61 (Jan1994).

Early stage research is pointed out, and following MED patient's group should adopt selective d 3 agonist and PDE5 inhibitor (perhaps other combinations hereinafter described) treatment and be benefited.These patient's groups are at Clinical Andrology vol.23, no.4, the book ＂ Erectile Dysfunction-Current Investigation andManagement ＂ of p773-782 and I.Eardley and K.Sethia, have a detailed description in the 3rd chapter of published by Mosby-Wolfe, as follows: spirituality, organic, vascular, incretion, nerve, arterialness, drug-induced sexual dysfunction (newborn originality) and the sexual dysfunction relevant, particularly veins reason with the spongy body factor.

Therefore, the invention provides formula (I), (Ia) or (Ib) purposes in the medicine that is combined in preparation treatment erection disturbance of chemical compound and PDE5 inhibitor.

The PDE5 inhibitor that is fit to is as described herein.

The compounds of this invention can be used for treatment or prevention female sexual disorder (FSD), particularly FSAD.

According to the present invention, FSD can be defined as that the women is difficult to or can not find satisfied in the property expression.FSD is general name (Leiblum, S.R. (1998)-Definition and classification of female sexualdisorders.Int.J.Impotence Res., 10, the S104-S106 of multiple different women's sexual disorders; Berman, J.R., Berman, L.﹠amp; Goldstein, I. (1999)-Female sexual dysfunction:Incidence, pathophysiology, evaluations and treatment options.Urology, 54,385-391).The women may have hyposexuality, arouse or the combination of orgasm difficulty, sexual anhedonia or these problems.The disease of some types, Drug therapy, damage or psychological problems can both cause FSD.Being in developing Therapeutic Method and being to treat concrete FSD hypotype is target, mainly is libido and arouses obstacle.

The classification of FSD is preferably according to stage of normal women's reaction: libido, arouse with orgasm and define (Leiblum, S.R. (1998)-Definition and classificationof female sexual disorders.Int.J.Impotence Res., 10, S104-S106).Libido or libido are the power of property expression.Its performance often comprises the property thought when interested companion accompanies or when being exposed to other sexual stimuluses.Arousing is vascular reaction to sexual stimulus, and its important component is genitals hyperemia, comprises vaginal lubrication increase, vagina elongation and the increase of genitals sensation/sensitivity.Orgasm is the tensile release of property that has reached a climax during arousing.

Therefore, insufficient or satisfied when the reaction of women in any these stages (be generally libido, arouse or orgasm), FSD will take place.The FSD classification comprises the very few disease of libido, sexual arousal dysfunction, orgasm disorder and sexual anhedonia disease.Although The compounds of this invention will improve the reaction (as in female sexual arousal disorder) of genitals to sexual stimulus, but meanwhile it can also improve the pain relevant with sexual intercourse, anxiety and uncomfortable, therefore also treat other women's sexual disorders.

If the women does not have or the desire of rare property, and do not have or the thought or the illusion of rare property, have the very few disease of libido so.Such FSD may since the testosterone levels that causes because of natural menopause or operation menopause low due to.Other reasons comprises disease, Drug therapy, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) be insufficient to the reaction of sexual stimulus with genitals be feature.Genitals can not experience normality and arouse peculiar hyperemia.The lubricity of vaginal wall is very poor, so that sexual intercourse is a pain.Orgasm also may be hindered.Arousing obstacle may or divide the puerperium and between age of sucking due to the estrogen decrease by menopause, also may be owing to have due to the disease of vascular factor, for example diabetes and atherosclerosis.Other reasons comprises with diuretic, hydryllin, antidepressant (for example selective serotonin reuptake inhibitor (SSRI)) or hypotensive agent treatment.

Sexual anhedonia disease (comprising dyspareunia and vulvismus) may be by due to the medicine, endometriosis, pelvis inflammatory diseases, inflammatory bowel or the urethra problem that reduce lubricity with because of insertion pain is feature.

Discussed as former, D3 is considered to the occasioner of sexual behaviour.Clitoris be regarded as with penis be homologous (Levin, R.J. (1991), Exp.Clin.Endocrinol., 98,61-69); Same mechanism provides erectile response in the male, provide genital blood flow to increase in the women, and FSD is had related effect.In addition, proceptivity and susceptibility also change.

Thereby, according to preferred aspect of the present invention, formula (I), (Ia) or (Ib) purposes of chemical compound in the medicine of preparation treatment or prevention female sexual disorder are provided, and described dysfunction is more definite is the very few disease of libido, sexual arousal dysfunction, orgasm disorder and sexual anhedonia disease.

Preferably, formula (I) chemical compound can be used for treatment or prevention sexual arousal dysfunction, orgasm disorder and the very few disease of libido, most preferably is used for the treatment of or prevents sexual arousal dysfunction.

In preferred embodiment, formula (I), (Ia) and (Ib) chemical compound can be used for treating and suffer from female sexual arousal disorder and with the individuality of the very few disease of libido.

The Diagnostic and Statistical Manual (DSM) IV of American Psychiatric Association is defined as female sexual arousal disorder (FSAD):

" ... continue or can not reach repeatedly or the sufficient lubrication-swelling of maintenance excitement is reacted to sexual activity and finishes.This disorder causes tangible misery or dyspareunia certainly ... ".

Arousal response is made up of the congestion of blood vessel, vaginal lubrication and the expansion of pelvis and the swelling of external genitalia.Disorder causes tangible misery and/or dyspareunia.

FSAD is very general sexual disorders, influence menopause before, the women of (± Hormone Replacement Therapy (HRT)) after menopause and the menopause.It is relevant with the obstacle that occurs together, for example depression, cardiovascular disease, diabetes and urogenital (UG) obstacle.

The preliminary consequence of FSAD is the shortage of hyperemia/swelling, lubricated shortage and the shortage of genitals pleasant sensation.The secondary consequence of FSAD is that libido reduces, the pain and the difficulty that comes to orgasm during the sexual intercourse.

There is hypothesis to think recently, there is problem (the Goldstein et al. on blood vessel basis in the patient that at least a portion has a FSAD symptom, Int.J.Impot.Res., 10, S84-S90,1998), animal data has been supported this viewpoint (Park et al., Int.J.Impot.Res., 9,27-37,1997).

R.J.Levin instructs us, because " ... the masculinity and femininity genitals is grown from the common original hase of organizing in fetology, and masculinity and femininity genitals structure it is said it is homologous each other.Thereby clitoris is the congener of penis, and labia and scrotum are homologous ... " (Levin, R.J. (1991), Exp.Clin.Endocrinol., 98,61-69).

Effect still under study for action the drug candidate scheme of treatment FSAD mainly is the erection disturbance therapy, and this therapy promotes the blood circulation of male genital organ.

The compounds of this invention is for recovering the normality arousal response---and just increase genital blood flow, cause that vagina, clitoris and labia hyperemia provide a kind of means, thereby be favourable.This will ooze out via mucus, the vagina compliance increases and genitals sensitivity increases and cause the vaginal lubrication increase.Therefore, the invention provides the means of recovering or strengthening the normality arousal response.

Thereby, according to preferred aspect of the present invention, provide formula (I), (Ia) or (Ib) purposes of chemical compound in the medicine of treatment or prevention female sexual arousal disorder.

In this article, female sex organs mean: " genitals is made up of inside and outside.The internal is positioned at pelvis, is made up of ovary, uterus pipe, uterus and vagina.Outward sense is positioned at the outer harmony in the exterior arcus pelvicus of urogenital diaphragm below.They comprise mons pubes, labium majus and nympha, clitoris, vestibule, vestibule bulb and big vestibular gland " (Gray ' s Anatomy, C.D.Clemente, 13th American Edition).

The compounds of this invention can be applicable to following FSD patient subgroups: before young, old, the menopause, menopause, postmenopausal women, accept or do not have a Hormone Replacement Therapy.

The compounds of this invention can be used in the patient who suffers from FSD because of following reason:

I) the vascular cause of disease, for example traumatic damage of cardiovascular or atheromatosis, hypercholesteremia, smoking, diabetes, hypertension, radiation, perineum wound, ilium lower abdomen pudendal vein guard system.

The ii) nerve cause of disease, for example spinal cord injury or central nervous system disease comprise multiple sclerosis, diabetes, Parkinsonism, cerebrovascular accident, peripheral neurophaty, wound or radical-ability pelvic surgery.

Iii) hormone/endocrinopathy because of, for example dysfunction of the dysfunction of the dysfunction of hypothalamus/hypophysis/gonadal axis, ovary, pancreas, operation or chemical castration, androgen defective, the high cyclical level of prolactin antagonist (for example high prolactin hyperandrogenism), natural menopause, premature ovarian failure, hyperthyroidism and go down.

The iv) spirituality cause of disease, for example depression, obsession, anxiety neurosis, postpartum depression/" baby's melancholy ", emotionality and relation property problem, behavior anxiety, marriage are discord, dysfunction sexual attitude, genophobia, religious taboo or traumatic the past experience.

V) drug-induced sexual dysfunction is caused by selective serotonin reuptake inhibitor (SSRis) and other antidepressant therapies (tricyclic antidepressants and main calm tranquilizer), resisting hypertension therapy, sympatholytic, long-term pill therapy.

It is depressed that The compounds of this invention also can be used for treatment.

Dopamine D 3 receptor is almost only expressed in brain edge district, and these zones relate to repayment, emotion and cognitive process.Can increase the expression of D3 in the edge district with some class antidepressant treatments are known for a long time, the antidepressant effect of desipramine can be blocked by sulpiride (D2/D3 antagonist), but will be expelled to volt nuclear (zone of enrichment D3) but not caudate putamen (zone of enrichment d2 dopamine receptor).In addition, in patient who treats with pramipexole (agonist of a kind of D3 of preference) and preclinical phase depression model, observe antidepressant effect.The information available prompting, the receptor-mediated antidepressant activity of D3, the class antidepressants that the representative of selective d 3 receptor stimulating agents is new.Because antidepressant is known effective to other psychiatric disorders, so the D3 agonist will have antipsychotic potentiality.

The invention provides the purposes of selective d 3 agonist in the medicine of preparation treatment depression and psychiatric disorders.

Preferably, described D3 agonist shows function to the D3 receptor and renders a service, and its EC50 is lower than 1000nM, more preferably less than 100nM, even more preferably less than 50nM, most preferably is lower than 10nM.

Preferably, described D3 agonist is better than D2 to the selectivity of D3, and wherein said dopamine D 3 receptor agonist is compared the d2 dopamine receptor height at least about 15 times, preferably at least about 27 times to the functionally selective of dopamine D 3 receptor, more preferably at least about 30 times, most preferably at least about 100 times.

The disease that is fit to comprises depression (cancer patient's depression for example, parkinsonian's depression, the myocardial infarction retarded depression, the symptomatic depression of inferior syndrome, the depression of SF, child's depression, the serious symptom depression, single ictal depression, the recurrent depression, malaria is treated the depression that the child brings out, postpartum depression and the old man syndrome of having a fiery temperament), generalized anxiety disorder, terrified (for example agoraphobia, social phobia and simple terrified), psychentonia syndrome after the wound, escape personality disorder, eating disorders (for example anorexia nervosa and bulimia nervosa), fat, chemicals relies on (for example to ethanol, cocaine, heroin, phenobarbital, nicotine and benzodiazepine

The class addiction), Alzheimer, obsession, Panic disorder, dysmnesia are (for example dull-witted, amnesia and age related cognitive decline (ARCD)), parkinson (parkinson dementia for example, Parkinsonism that nerous sedative brings out and tardive dyskinesia), dyshormonia (for example high prolactin hyperandrogenism), vasospasm (particularly in the brain vascular system), cerebellar ataxia, schizoid negative symptom, the tonicity urinary incontinence, Tourette's syndrome, trichotillomania, kleptomania, attention-deficit hyperactivity disease (ADHD), chronic paroxysmal hemicrania, emotional instability, pathologic is cry and shout, sleep disorder (dampinging off) and shock.

In preferred embodiment, the invention provides formula (I), (Ia) and (Ib) purposes of chemical compound in the medicine of preparation treatment depression or psychiatric disturbance.

The depressibility disease and the psychiatric disturbance that are fit to are aforesaid.

The compounds of this invention also has practicality in neurodegenerative treatment; Neurodegenerative source comprises the neurotoxin poisoning; By visual loss due to the visual pathway neural degeneration, the apoplexy in the visual pathway (for example retina, optic nerve and/or occipital lobe) for example; Epilepsy; The glucose of brain and/or oxygen supply are lowered.

Therefore, the invention provides the purposes of selective d 3 agonist in the neurodegenerative medicine of preparation treatment.

Preferably, described D3 agonist is renderd a service the function that the D3 receptor shows, and represents with EC50, for being lower than 1000nM, more preferably less than 100nM, and then more preferably less than 50nM, most preferably is lower than 10nM.

In preferred embodiment, the D3 agonist is formula (I), (Ia) or (Ib) chemical compound.

Except their effects in therapeutic dysfunction, depression, neural degeneration and psychiatric disturbance, The compounds of this invention might be also effective to a large amount of other indications.

Therefore, the invention provides formula (I), (Ia) or (Ib) purposes of chemical compound in the preparation medicine, described medicine can be used for treating hypertension, premature ejaculation, obesity, bunch headache, migraine, pain, dyshormonia (for example high prolactin hyperandrogenism), vasospasm (particularly in the brain vascular system), cerebellar ataxia, gastrointestinal tract disorder (involving motility and excretory change), premenstrual tension syndrome, fibromyalgia syndrome, tonicity urinary incontinence, trichotillomania, chronic paroxysmal hemicrania, headache (relevant with angiopathy).

D3/D2 agonist binding assay

Gonazalez et al (Eup.J Pharmacology 272 (1995) R1-R3) discloses and has measured chemical compound to the binding ability of D3 and/or D2 dopamine receptor thereby the combination of measuring this compounds algoscopy optionally.Therefore, this algoscopy is referred to herein as binding assay.

D3/D2 agonist functional examination method

Describe in detail below and be suitable for the active algoscopy of functional assays chemical compound D3 and/or D2 dopamine receptor.

Observe the GH4C1 of expressing human D2 and D3 receptor and the cAMP level in the Chinese hamster ovary celI system respectively, chemical compound is evaluated as the agonist or the antagonist of dopamine D 2 and D3 receptor.

Experimental technique

The adenylate cyclase activity that suppresses forskolin-stimulation via dopamine D 3 receptor

Material

Cell culture medium:

hD ₃The CHO culture medium
hD ₃The CHO culture medium	DMEM, high glucose (Sigma D5671)
2mM L-glutaminate (Sigma G7513)	DMEM, high glucose (Sigma D5671)
2mM L-glutaminate (Sigma G7513)	10% FBS that dialysed (Sigma F0392)

The hD of expressing human dopamine D 3 receptor ₃CHO (Chinese hamster ovary) cell generates in laboratory.These cells are dihydrofolate reductase gene defectives.

Followingly prepare fresh culture medium weekly, filter by 0.22 μ M filter before using.Nutrient media storage under 4 ℃, was warmed to 37 ℃ before adding cell.

The cell dispersion soln (Cell Dissociation Solution, CDS): (SigmaC-5914)

Use 5mL from 225cm ²Harvesting in the flask (37 ℃, 5min with regard to the hD2LGH4C1 cell, with regard to the hD3CHO cell 10 minutes).

Phosphate-buffered saline (PBS): (Gibco 14040-091)

Trypan blue: (Sigma T8154)

Forskolin (Calbiochem 344273)

Be dissolved in distilled water to concentration 20mM (this storing solution is stored in+4 ℃ under).Carry out 500 times of dilutions in the PBS buffer, the 4x for preparing 40 μ M measures storing solution.The 40 μ M storing solutions that add 25 μ L are finally measured concentration 10 μ M to the final volume 100 μ L that measure.

Test compound

Be dissolved in 100% DMSO, obtain storing solution concentration 10mM.

The pramipexole standard

Be dissolved in 100% DMSO, obtain storing solution concentration 10mM.

Cyclase activating Flashplate algoscopy (NEN SMP004B)

By Perkin-Elmer Life Sciences, Inc provides.

[125I]-3'5'-AMP (cAMP) (NEX 130)

By Perkin-Elmer Life Sciences, Inc provides.

Concrete equipment

Dull and stereotyped shaking table/the incubator of Westbart microtitration

Packard Topcount NXT (ECADA compatibility program)

Tecan?Genesis

Labsystems?Multi-drop?DW

Use hD ₃The active scheme of Chinese hamster ovary celI test compounds

Diluted chemical compound liquid

● comprise that pramipexole is as reference standard.By 10 semilog plots of per 4 dull and stereotyped generations.The chemical compound result standard is changed into minimum (0nM pramipexole) and maximum (100nM pramipexole) reaction that generates by cell.Also can test whole test compounds via 10 point (semilog) curves.

● test compound is dissolved in 100% DMSO, obtains storing solution concentration 10mM.Further they are diluted to 1mM (the required final mensuration concentration of 1000x, for example 1mM will obtain the top concentration of 1 μ M) in 100% DMSO via 10 times of dilutions.

● pramipexole is dissolved in 100% DMSO, obtains concentration 10mM.Further pramipexole is diluted to 0.1mM in 100% DMSO via 100 times of dilutions.

● further utilize suitable Tecan Genesis scheme to dilute in 0.4% DMSO/PBS and add, this scheme can be carried out serial dilution (semilog unit) by 3.159 times.

TECAN GENESIS diluent

● 1st hurdle dull and stereotyped to trace adds 10 μ L test compounds.To 0.4% DMSO/PBS that wherein adds 240 μ L, obtain 25 times of diluents (0.04mM).The 0.04mM diluent of 20 μ L is transferred to the aperture on the 2nd hurdle,, obtains further 10 times of diluents, reach the 4x top and measure concentration (0.004mM) to 0.4% DMSO/PBS that wherein adds 180 μ L.

● carry out serial dilution (3.159 times), realize half-log series: 4 μ M, 1.27 μ M, 400nM, 127nM, 40nM, 13nM, 4nM, 1.27nM, 0.4nM, 0.1nM

● 25 μ L (in duplicate) serial dilutions are transferred to the 2-11 hurdle (referring to appendix) of Flashplate.Because final mensuration volume is 100 μ L, so the final concentration of measuring will be: 1000 μ M, 317nM, 100nM, 32nM, 10nM, 3.2nM, 1nM, 0.3nM, 0.1nM, 0.03nM

● minimum contrast (low contrast): add 25 μ L, 0.4% DMSO/PBS (carrier) to the 1st hurdle aperture E-H and the 2nd hurdle aperture A-D.Add cell+forskolin after a while.

● maximum contrast (high contrast): via 250 times of dilutions the 10mM pramipexole is diluted in (10 μ L+2490 μ L PBS) among the PBS, generates 40 μ M pramipexoles.Further 40 μ M pramipexoles are diluted in (100 μ L+9900 μ L carrier) among 0.4% DMSO/PBS, generate 400nM (4x of standard pramipexole measures concentration) via 100 times of dilutions.400nM pramipexole to the 1st hurdle aperture A-D and the 12nd hurdle aperture E-H of Flashplate add 25 μ L obtains final 100nM pramipexole.Add cell+forskolin after a while.

Cyclase activating Flashplate algoscopy (NEN SMP004B)

● as described in material one joint, forskolin is dissolved in distilled water, reaches storing solution concentration 20mM.Further be diluted to 40 μ M (4x measures concentration) with PBS.Utilize Multi-drop to add the 40 μ M storing solutions of 25 μ L, obtain ultimate density 10 μ M to whole apertures.With the flat board sealing, in 37 ℃ of Westbart incubators, cultivate, again harvesting then.

● harvesting from flask, their fusion rate is between 70%-80%.The whole components that are necessary to join in the aperture are warmed to 37 ℃.Add 5mLCDS to every T225 flask, cultivated 5 minutes down, then with 5mL PBS neutralization at 37 ℃.Then cell was descended centrifugal 5 minutes at 160g (1000rpm).Discard the gained supernatant, cell is suspended in again to stimulate in the buffer (being warmed to 37 ℃), reaches 5 x 10 ⁵Cell/mL.Then 50 μ L cell suspension are assigned in whole apertures of Flashplate.

● immediately flat board was cultivated 15 minutes on 37 ℃ of wave and culture casees.Detect mixture with 100 μ L and stop reaction (each dull and stereotyped 100 μ L in whole apertures ¹²⁵I cAMP:11mL detects buffer).

● flat board is resealed, in the dark cultivated 3 hours, so that resisting-cAMP antibody (bag is by each hole), [ ¹²⁵I]-reach balance between cAMP tracer and the cell cAMP.

● utilize suitable ECADA compatibility scheme (Protocol 75) on PackardTopcount NXT to plate count.

The recovery of freezing ampoule

Gas that is captured or liquid from liquid nitrogen, takes out ampoule, made their balances 2 minutes, because may cause ampoule to expand rapidly and explode.Also can before melting, they be placed-20 ℃ following 2 minutes.

In 37 ℃ of water-baths, make the quick and complete thawing of ampoule.

Cell suspension is transferred to the 75cm that contains the 10mL growth medium ²In the flask, at 37 ℃ of 5% CO ₂Under cultivated 24 hours.(3-6 hour) removes culture medium after the cell attachment, changes to fresh culture (to remove DMSO).After 24 hours, if near merging, then with cell transfer to 225cm ²In the flask.Reach the 70%-80% fusion if no, then continue cultured cell until them.

Cell harvesting and branch bottle

Divide bottle on Friday with cell, to be provided at the cell of measuring usefulness on Monday and Tuesday.One all required cells of all the other times divide bottle at Monday.

Be necessary not make hD ₃The Chinese hamster ovary celI growth surpasses 80% merges, and perhaps divides the bottle ratio〉1:20, because this breeder reaction to them has adverse effect, and will influence the ability that cell is measured subsequently.

Make cell be grown in 225cm ²In the flask (Jumbos).The every kind of component that adds to cell must be warmed to 37 ℃ before use.

Cell harvesting

From flask, remove growth medium, cell with warm PBS (Gibco.14040-091) washing, is removed.

● add the 5mL cell to cell and disperse buffer, placed incubator about 5 minutes.

● pat flask sharp, to take all remaining cells from tissue culturing plastic.

● add 5mL PBS to cell, be used to wash substrate and flask.Cell was descended centrifugal 5 minutes at 160g (1000rpm), make cell precipitation.

● abandoning supernatant, cell is suspended in 5mL again to stimulate in the buffer.Carry out trypan blue and get rid of algoscopy, to measure the quantity of living cells.

● cell dilution in stimulating buffer, is obtained concentration 5 x 10 ⁵Cell/mL.

● during with passage, omit centrifugation step, cell suspension is assigned in the new T225 flask that contains the 50mL culture medium.

Divide the bottle ratio

HD ₃The branch bottle ratio of CHO is between 1:5 to 1:10.Cultivation can not continue above 30 generations, because along with the increase cell line feature of algebraically can be lost.

The low-temperature preservation of cell line

Be necessary to set up the cell bank of yourselves cell, use for further with recovery.

● as harvesting as described in the prosthomere.After trypan blue is got rid of algoscopy, cell dilution in the culture medium that contains 10% DMSO, is reached 2 to 4 x 10 ⁶Cell/mL.

● cell is divided into the 1mL aliquot, is chilled in immediately among the ＂ Mr Frosty ＂ (containing fresh IPA), be cooled to-80 ℃ gradually, be transferred to then (cell can be stored in ＂ Mr Frosty ＂ and reach 2 days) in the gas phase liquid nitrogen storage container.

Had better after freezing, melt an ampoule and come the test cell vigor.It is 70% may be because of cell quantity low and exist chip to cause the problem of the response rate that vigor is lower than.

Data analysis

Utilize the ECADA analytical data.

Obtain the standardization % (with respect to pramipexole) of whole chemical compounds via following formula:

Standardization %=(X-B0)/(Max-B0) x 100

Wherein

The average clean cell number of X=with regard to the test compound of given concentration,

The average clean cell number of the minimum contrast of B0=(0nM pramipexole),

The average clean cell number of the maximum contrast of Max=(100nM pramipexole).

Standardization % (y) is mapped formation curve to agonist concentration nM (x).Utilize the nonlinear regression and fitting data, slope is decided to be 1 approximately.Measure the EC50 and the %Emax of test compound thus.

Assay plate layout (10 EC50):

	1	2	3	4	5	6	7	8	9	10	11	12
	1	2	3	4	5	6	7	8	9	10	11	12	A	MAX	C1	MIN
B	MAX	C1										MIN	A	MAX	C1	MIN
B	MAX	C1										MIN	C	MAX	C2	MIN
D	MAX	C2										MIN	C	MAX	C2	MIN
D	MAX	C2										MIN	E	MIN	C3	MAX
F	MIN	C3										MAX	E	MIN	C3	MAX
F	MIN	C3										MAX	G	MIN	C4	MAX
H	MIN	C4										MAX	G	MIN	C4	MAX

The 1st hurdle: aperture A-D=MAX: high contrast (cell+forskolin+100nM pramipexole)

Aperture E-H=MIN: low contrast (cell+forskolin+carrier)

The 12nd hurdle: aperture A-D=MIN: low contrast (cell+forskolin+carrier)

Aperture E-H=MAX: high contrast (cell+forskolin+100nM pramipexole)

2-11 hurdle: 10 serial dilutions (in duplicate) of test compound.Concentration successively decrease from 11 hurdles, the 2nd hurdle to the (1000nM to 0.03nM).In first flat board, use pramipexole replaced C 1.

The adenylate cyclase activity that suppresses forskolin-stimulation via d2 dopamine receptor

Material

Cell culture medium:

HD2?GH4C1/hD ₂The L culture medium
HD2?GH4C1/hD ₂The L culture medium	Hams?F-12(Sigma?N6013)
2mM L-glutaminate (Sigma G7513)	Hams?F-12(Sigma?N6013)
2mM L-glutaminate (Sigma G7513)	10％?FBS(Gibco?10106-169)
700 μ g/mL heredity rhzomorph (Gibco 10131-019)	10％?FBS(Gibco?10106-169)

GH4C1/hD _2LIt is the expressing human dopamine D 2 _LongThe rat pituitary cell of receptor.

Cell dispersion soln (CDS): (Sigma C-5914)

Use 5mL from 225cm ²Harvesting in the flask.

Phosphate buffered saline (PBS) (PBS): (Gibco 14040-091)

Trypan blue: (Sigma T8154)

Forskolin (Calbiochem 344273)

Be dissolved in distilled water to concentration 20mM (this storing solution is stored in+4 ℃ under).Carry out 1000 times of dilutions in the PBS buffer, the 4x for preparing 20 μ M measures storing solution.The 20 μ M storing solutions that add 25 μ L are finally measured concentration 5 μ M to the final volume 100 μ L that measure.

Test compound

Be dissolved in 100% DMSO, obtain storing solution concentration 10mM.

The pramipexole standard

Be dissolved in 100% DMSO, obtain storing solution concentration 10mM.

Cyclase activating Flashplate algoscopy (NEN SMP004B)

By Perkin-Elmer Life Sciences, Inc provides.

[ ¹²⁵I]-3'5'-AMP (cAMP) (NEX 130)

By Perkin-Elmer Life Sciences, Inc provides.

Concrete equipment

Dull and stereotyped shaking machine/the cultivating container of Westbart microtitration

Packard Topcount NXT (ECADA compatibility program)

Tecan?Genesis

Labsystems?Multi-drop?DW

Scheme

Diluted chemical compound liquid

● comprise that pramipexole is as reference standard.10 semilog plots of per 4 dull and stereotyped generations.The chemical compound result standard is turned to minimum (0nM pramipexole) and maximum (1000nM pramipexole) reaction that generates by cell.Also can test whole test compounds via 10 point (semilog) curves.

● test compound is dissolved in 100% DMSO, obtains storing solution concentration 10mM (the required final mensuration concentration of 1000x, for example 10mM will obtain the top concentration of 10000nM).

● pramipexole is dissolved in 100% DMSO, obtains concentration 10mM.Further pramipexole is diluted to 1mM in 100% DMSO via 10 times of dilutions.

TECAN GENESIS diluent

● 1st hurdle dull and stereotyped to trace adds 10 μ L test compounds.To 0.4% DMSO/PBS that wherein adds 240 μ L, obtain 25 times of diluents (0.4mM).The 0.4mM diluent of 20 μ L is transferred to the aperture on the 2nd hurdle,, obtains further 10 times of diluents, reach the 4x top and measure concentration (0.04mM) to 0.4% DMSO/PBS that wherein adds 180 μ L.

● carry out serial dilution (3.159 times), realize half-log series: 40 μ M, 12.7 μ M, 4 μ M, 1.27 μ M, 400nM, 130nM, 40nM, 13nM, 4nM, 1.3nM

● 25 μ L (in duplicate) serial dilutions are transferred to the 2-11 hurdle (referring to appendix) of Flashplate.Because final mensuration volume is 100 μ L, finally measures concentration and will be: 10,000 μ M, 3170nM, 1000nM, 320nM, 100nM, 32nM, 10nM, 3nM, 1nM, 0.3nM

● maximum contrast (high contrast): via 250 times of dilutions the 10mM pramipexole is diluted in (10 μ L+2490 μ L PBS) among the PBS, generates 40 μ M pramipexoles.Further 40 μ M pramipexoles are diluted in (100 μ L+990 μ L carrier) among 0.4% DMSO/PBS, generate 4000nM (4x of standard pramipexole measures concentration) via 10 times of dilutions.4000nM pramipexole to the 1st hurdle aperture A-D and the 12nd hurdle aperture E-H of Flashplate add 25 μ L obtains final 1000nM pramipexole.Add cell+forskolin afterwards.

Cyclase activating Flashplate algoscopy (NEN SMP004B)

● as described in material one joint, forskolin is dissolved in distilled water, reaches storing solution concentration 20mM.Further be diluted to 20 μ M (4x measures concentration) with PBS.Utilize Multi-drop to add 25 μ L, obtain ultimate density 5 μ M to whole apertures.With the flat board sealing, in 37 ℃ of Westbart cultivating containers, cultivate then, simultaneously harvesting.

● harvesting from the flask of fusion rate between 70%-80%.The whole components that are necessary to join in the cell are warmed to 37 ℃.To every 225cm ²Flask adds 5mL CDS, cultivates 5 minutes down at 37 ℃, then with 5mL PBS neutralization.Then cell was descended centrifugal 5 minutes at 160g (1000rpm).Discard the gained supernatant, cell is suspended in again to stimulate in the buffer (being warmed to 37 ℃), reaches 1 x 10 ⁵Cell/mL.Then 50 μ L cell suspension are assigned in whole apertures of Flashplate.

● immediately flat board was cultivated 15 minutes on 37 ℃ of wave and culture casees.Detect mixture with 100 μ L and stop reaction (every flat board 100 μ L in whole apertures ¹²⁵I cAMP:11mL detects buffer).

● flat board is resealed, in the dark cultivated 3 hours, so that resisting-cAMP antibody (bag is by aperture), [ ¹²⁵I]-reach balance between cAMP tracer and the cell cAMP.

● it is dull and stereotyped to utilize suitable ECADA compatibility scheme (Protocol 75) to count on PackardTopcount NXT.

The recovery of freezing ampoule

In 37 ℃ of water-baths, make the quick and complete thawing of ampoule.

Cell suspension is transferred to the 75cm that contains the 10mL growth medium ²In the flask, at 37 ℃ of 5% CO ₂Under cultivated 24 hours.(3-6 hour) removes culture medium after the cell attachment, changes to fresh culture (to remove DMSO).After 24 hours, if near merging, then with cell transfer to 225cm ²In the flask.If no, then cultured cell is 60% until their fusion rate.

Cell harvesting and branch bottle

At pair cell branch bottle on Friday, to be provided at the cell of measuring on Monday and Tuesday.One all required cells of all the other times divide bottle at Monday.

Be necessary that being sure not to make the cell growth to surpass 60% merges, because this breeder reaction to them has adverse effect, and will influence the ability that cell is measured subsequently.

Cell harvesting

● add the 5mL cell to cell and disperse buffer, placed cultivating container about 5 minutes.

● pat flask sharp, from tissue culturing plastic's bottle, to take all remaining cells.

● cell dilution in stimulating buffer, is obtained concentration 1 x 10 ⁵Cell/mL.

● in order to make passage, omit centrifugation step, cell suspension is assigned in the new T225 flask that contains the 50mL culture medium.

Divide the bottle ratio

The branch bottle of GH4C1/D2 is than between 1:3 to 1:5.

The low-temperature preservation of cell line

Data analysis

Utilize the ECADA analytical data.

Via following formula whole chemical compounds are carried out standardization % (with respect to pramipexole):

Standardization %=(X-B0)/(Max-B0) x 100

Wherein

The average clean cell number of X=with regard to given concentration test compound,

The average clean cell number of the minimum contrast of B0=(0nM pramipexole),

Assay plate layout (10 EC50):

Aperture E-H=MIN: low contrast (cell+forskolin+carrier)

The 12nd hurdle: aperture A-D=MIN: low contrast (cell+forskolin+carrier)

Aperture E-H=MAX: high contrast (cell+forskolin+100nM pramipexole)

Utilize the said determination method, The compounds of this invention all has function to the D3 receptor and renders a service (represent with EC50, be lower than 1000nM), and the selectivity of D3 is higher than 10 times of D2.

The function that embodiment 8 described chemical compounds have the D3 receptor is renderd a service and is expressed as 7.6nM with EC50, and the selectivity of D3 is higher than 1315.8 times of D2.Selectivity is by calculating D2 EC50 value divided by D3 EC50 value.If, then getting 10000 greater than 10000, D2 EC50 is used for calculating.

Self-evident, this paper comprises healing, alleviates and preventive disposal all appellation of treatment.

The auxiliary activity composition that is suitable for use in the present invention's combination comprises:

1) natural existence or synthetic prostaglandin or its ester.The prostaglandin that is applicable to this comprises following chemical compound, for example Alprostadil, prostaglandin E ₁, prostaglandin E ₀, 13,14-dihydro prostaglandin E ₁, prostaglandin E ₂, eprostinol, natural, synthetic and semisynthetic prostaglandin and derivant thereof comprise the US 6,037 that WO 00/33825 and/or on March 14th, 2000 issue, those described in 346 (these documents are all quoted at this as a reference), PGE ₀, PGE ₁, PGA ₁, PGB ₁, PGF ₁α, 19-hydroxyl-PGA ₁, 19-hydroxyl-PGB ₁, PGE ₂, PGB ₂, 19-hydroxyl-PGA ₂, 19-hydroxyl-PGB ₂, PGE ₃α, romethamine, dinoprost trometamol, dinoprostone, lipoprost, gemeprost, meteneprost (metenoprost), sulprostone (sulprostune), tiaprost and thymoxamine;

2) alpha-adrenergic aceptor antagonist chemical compound is also referred to as alpha-2-adrenoceptor or alpha-receptor or α-Zu Zhiji.The chemical compound that is applicable to this comprises: as alpha-adrenergic receptor blocker (disclosure that wherein relates to alpha-adrenergic receptor is quoted at this as a reference) as described in the PCT application WO 99/30697 that announced on June 14th, 1998, comprise selectivity α ₁-adrenoceptor or α ₂-adrenoceptor blocker, and non-selective adrenoceptor blocker, suitable α ₁-adrenoceptor blocker comprises: fragrant appropriate amine, phentolamine methanesulfonate, trazodone, alfuzosin, indoramine, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaroxan, Yohimbine, rauwolfia alkaloid, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abanoquil and prazosin; From US 6,037, the α in 346 (on March 14th, 2000) ₂-blocker dibenamine, tolazoline, trimazosin and dibenamine; As alpha-adrenergic receptor as described in the following United States Patent (USP): 4,188,390,4,026,894,3,511,836,4,315,007,3,527,761,3,997,666,2,503,059,4,703,063,3,381,009,4,252,721 and 2,599,000, each self reference at this as a reference; α ₂-adrenoceptor blocker comprises: clonidine, papaverine, papaverin hydrochloride, alternatively cardiac tonic for example pirxamine in the presence of;

3) NO-donor (NO-agonist) chemical compound.The NO-compound donator that is applicable to this comprises organic nitrate, for example single-, two-or three-nitrate, perhaps organic nitrates, comprise glyceryl trinitrate (also claiming nitroglycerin), isosorbide 5-Mononitrate, Iso-bid, pentaerythritol tetranitrate, cardilate, sodium nitroprusside (SNP), 3-morpholino sydnonimine, molsidomine, S-nitroso-group-N-acetyl group penicillamine (SNAP), S-nitroso-group-N-glutathione (SNO-GLU), N-hydroxyl-L-arginine, nitric acid amyl group ester, linsidomine, linsidomine chloride hydrate (SIN-1), S-nitroso-group-N-cysteine, diazonium glycol acidulants (diazenium diolates) (NONO acid esters), 1,5-pentane dinitrate, the L-arginine, Radix Ginseng, Fructus Jujubae, molsidomine, Re-2047, nitrosylation thymoxamine derivant, for example NMI-678-11 and NMI-937 are as described in the PCT application WO 00/12075 that has announced;

4) potassium channel openers or adjusting control agent.Potassium channel openers/the adjusting control agent that is applicable to this comprises nicorandil, cromakalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glibenclamide, 4-aminopyridine, BaCl ₂

5) vasodilation.The vasodilation that is applicable to this comprises nimodipine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, haloperidol, Rec15/2739, trazodone;

6) TXA2. agonist;

7) CNS activating agent;

8) peptide.Suitable peptide is described in the United States Patent (USP) 6 of promulgation on March 14th, 2000,037, in 346, comprise acetergamine, brazergoline, bromerguride, cianergoline, delergotrile (delorgotrile), disulergine, Cornocentin, gynergen, etisulergine, Lergotrile, Lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride;

9) chemical compound, particularly atrial natriuretic peptide (also satisfactory room natriuretic peptide) of the effect of the regulation and control natriuresis factor, Type B and the C type natriuresis factor, for example neutral endopeptidase or inhibitor;

10) chemical compound of inhibition angiotensin converting enzyme, for example combined depressant of enalapril and angiotensin converting enzyme and neutral endopeptidase, for example omapatrilat;

11) angiotensin receptor antagonist, for example losartan;

12) NO synzyme substrate, for example L-arginine;

13) calcium channel blocker, for example amlodipine;

14) endothelin-receptor antagonists and endothelin-converting enzyme inhibitor;

15) cholesterol reducing agent, for example special class (fibrates) of Statins (for example atorvastatin/Lipitor-trade mark) and shellfish;

16) anti-platelet agents and antithrombotic agents, for example tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, tissue thromboplastin's activation factor inhibitor;

17) insulin sensitizers, for example Rezulin, and Hypoylycemic agents, for example glipizide;

18) L-DOPA or carbidopa;

19) acetylcholinesteraseinhibitors inhibitors, for example donezipil;

20) steroid or non-steroidal anti-inflammatory agents;

21) estrogen receptor adjusting control agent and/or estrogen agonist and/or estrogen antagonist, preferred raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-tetrahydrochysene Betanaphthol and pharmaceutically acceptable salt thereof, their preparation are described among the WO 96/21656;

22) PDE inhibitor, more definite is PDE 2,3,4,5,7 or 8 inhibitor, preferred PDE2 or PDE5 inhibitor, PDE5 inhibitor (as follows) most preferably, described inhibitor preferably to the IC50 of corresponding enzyme less than 100nM (its condition be PDE3 and 4 inhibitor only be local or to the penis drug administration by injection);

23) vasoactive intestinal peptide (VIP), VIP analogies, VIP analog, more properly be subjected to the mediation of following material: one or more VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activation peptide), one or more VIP receptor stimulating agents or VIP analog (for example Ro-125-1553) or VIP fragment, the alpha-2-adrenoceptor antagonists (for example Invicorp, Aviptadil) that one or more and VIP unite;

24) the plain reinforcing agent of casting skin element (melanocortin) receptor stimulating agent or adjusting control agent or casting skin, for example melanotan II, PT-14, PT-141 or as WO 99/64002, WO00/74679, WO 99/55679, WO 01/05401, WO 00/58361, WO 01/14879, WO 01/13112, WO 99/54358 claimed compounds;

25) serotonin receptor agonist, antagonist or adjusting control agent, more definite is agonist, antagonist or the adjusting control agent of 5HT1A (comprising VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptor, comprises described in WO 99/02159, WO 00/02550 and/or the WO 00/28993 those;

26) testosterone substituting agent (comprising the dehydrogenation androstanedione), testosterone (Tostrelle), dihydrotestosterone or testosterone implant;

27) estrogen, estrogen and medroxyprogesterone or Medroxyprogesterone Acetate (MPA) (just as combination) or estrogen and methyltestosterone hormone replacement therapy agent (for example HRT, especially Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone);

28) adjusting control agent of norepinephrine, dopamine and/or serotonin transport protein, for example amfebutamone, GW-320659;

29) purinergic receptor agonists and/or adjusting control agent;

30) neurokinin (NK) receptor antagonist comprises described in the WO 99/64008 those;

31) opioid receptor agonists, antagonist or adjusting control agent, the agonist of preferred ORL-1 receptor;

32) oxytocin/vasopressin receptor agonist or adjusting control agent, preferred selectivity oxytocin agonists or adjusting control agent;

33) Cannabined receptor adjusting control agent;

34) SEP inhibitor (SEPi), for example IC50 less than 100nM, be more preferably less than the SEPi of 50nM.Preferably, SEP inhibitor according to the present invention have greater than 30 times, be better than the selectivity that neutral endopeptidase NEP EC 3.4.24.11 and angiotensin converting enzyme (ACE) are selected SEP more preferably greater than 50 times.Preferably, SEPi also has the selectivity that is better than endothelin converting enzyme (ECE) greater than 100 times.

To carrying out cross reference according to the chemical compound that is contained in patent of the present invention and the patent application, we are defined in therapeutical active compound in claims (particularly claim 1) and the specific embodiment (all quoting at this as a reference) by this paper.

If give the combination of active component, they can be simultaneously, separate or the order administration so.

Auxiliary element-PDE5 inhibitor

Utilize literature method to estimate its effectiveness and selectivity,, can easily determine the fitness of any specific cGMP PDE5 inhibitor succeeded by estimating its toxicity, absorption, metabolism, pharmacokinetics etc. according to the standard pharmaceutical practice.

Utilize the PDE5 algoscopy can measure the IC50 value (as follows) of cGMP PDE5 inhibitor.

Preferably, according to the cGMP PDE5 inhibitor that uses in the drug regimen of the present invention the PDE5 enzyme had selectivity.Preferably (when oral use), they have and are better than PDE3, more preferably are better than the selectivity of PDE3 and PDE4.The selectivity ratio that preferably (when oral), cGMPPDE5 inhibitor of the present invention be better than PDE3, more preferably be better than PDE3 and PDE4 is greater than 100, more preferably greater than 300.

The technical staff can easily measure the selectivity ratio.Utilize set literature method can measure IC50 value to PDE3 and PDE4 enzyme, referring to SABallard et al, Journal ofUrology, 1998, vol.159, pages 2164-2171 and hereinafter described.

Be applicable to that cGMP PDE5 inhibitor of the present invention comprises:

Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones among the EP-A-0463756; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones among the EP-A-0526004; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones in the International Patent Application WO of having announced 93/06104; Be disclosed in isomery pyrazolo [3, the 4-d] pyrimidin-4-one in the International Patent Application WO of having announced 93/07149; Be disclosed in the quinazoline-4-one in the International Patent Application WO of having announced 93/12095; Be disclosed in pyrido [3, the 2-d] pyrimidin-4-one in the International Patent Application WO of having announced 94/05661; Be disclosed in the purine-6-one in the International Patent Application WO of having announced 94/00453; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones in the International Patent Application WO of having announced 98/49166; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones in the International Patent Application WO of having announced 99/54333; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-4-one among the EP-A-0995751; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones in the International Patent Application WO of having announced 00/24745; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-4-one among the EP-A-0995750; Be disclosed in the chemical compound in the International Application No. WO of having announced 95/19978; Be disclosed in the chemical compound in the International Application No. WO of having announced 99/24433; Be disclosed in the chemical compound in the International Application No. WO of having announced 93/07124; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones in the International Application No. WO of having announced 01/27112; Be disclosed in pyrazolo [4, the 3-d] pyrimidin-7-ones in the International Application No. WO of having announced 01/27113; Be disclosed in the chemical compound among the EP-A-1092718; Be disclosed in the chemical compound among the EP-A-1092719.

Be applicable to that further PDE5 inhibitor of the present invention comprises:

5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil), also claim 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] sulfonyl]-4-methyl piperazine (referring to EP-A-0463756); 5-(2-ethyoxyl-5-morpholino acetylphenyl)-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to EP-A-0526004); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 98/49166); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 99/54333); (+)-3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxyl group-1 (R)-methyl ethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, also claim 3-ethyl-5-{5-[4-ethyl piperazidine-1-base sulfonyl]-2-([(1R)-and 2-methoxyl group-1-Methylethyl] the oxygen base) pyridin-3-yl }-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 99/54333); 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, also claim 1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-4-ethyl piperazidine (referring to WO 01/27113, embodiment 8); 5-[2-isobutoxy-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(1-methyl piperidine-4-yl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27113, embodiment 15); 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27113, embodiment 66); 5-(5-acetyl group-2-propoxyl group-3-pyridine radicals)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2, and 6-dihydro-7H-pyrazolo [4,3-d1 pyrimidin-7-ones (referring to WO 01/27112, embodiment 124); 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27112, embodiment 132); (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1,4-diketone (IC-351), embodiment 78 in the International Application No. WO of just having announced 95/19978 and 95 chemical compounds, and embodiment 1,3,7 and 8 chemical compounds; 2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil), also claim 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-as-triazine-2-yl also)-the 4-ethoxyl phenenyl] sulfonyl]-the 4-ethyl piperazidine, embodiment 20,19,337 in the International Application No. WO of just having announced 99/24433 and 336 chemical compounds; Embodiment 11 chemical compounds (EISAI) in the International Application No. WO of having announced 93/07124; With from Rotella D P, J.Med.Chem., 2000,43,1257 chemical compound 3 and 14.

And then other PDE5 inhibitor that are fit to comprise:

4-bromo-5-(pyridylmethyl amino)-6-[3-(4-chlorphenyl)-propoxyl group]-3 (2H) 2H-Pyridazin-3-one; 1-[4-[(1,3-benzodioxole-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-4-piperidines-carboxylic acid, a sodium salt; (+)-cis-5,6a, 7,9,9,9a-six hydrogen-2-[4-(trifluoromethyl)-phenyl methyl-5-methyl-cyclopent[4,5] imidazo [2,1-b] purine-4 (3H) ketone; Furazlocillin; Cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydro cyclopent[4,5]-imidazo [2,1-b] purine-4-ketone; 3-acetyl group-1-(2-benzyl chloride base)-2-propyl indole-6-carboxylate; 3-acetyl group-1-(2-benzyl chloride base)-2-propyl indole-6-carboxylate; 4-bromo-5-(3-pyridylmethyl amino)-6-(3-(4-chlorphenyl) propoxyl group)-3-(2H) 2H-Pyridazin-3-one; 1-methyl-5-(5-morpholino acetyl group-2-positive propoxy phenyl)-3-n-pro-pyl-1, and 6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones; 1-[4-[(1,3-benzodioxole-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-the 4-piperidine carboxylic acid, a sodium salt; Pharmaprojects No.4516 (GlaxoWellcome); Pharmaprojects No.5051 (Bayer); Pharmaprojects No.5064 (Kyowa Hakko; Referring to WO 96/26940); Pharmaprojects No.5069 (Schering Plough); GF-196960 (GlaxoWellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 ﹠amp; 38-9456 (Bayer) and Sch-51866.

Formula (I) chemical compound can be individually dosed, but generally will with the drug excipient, diluent or carrier the mixings administration that are fit to, these excipient, diluent or carrier are put into practice according to expection route of administration and standard pharmaceutical and are selected.

Therefore, the invention provides compositions, wherein comprise formula (I), (Ia) or (Ib) chemical compound and pharmaceutically acceptable diluent or carrier.

For example, formula (I), (Ia) or (Ib) chemical compound can by oral, through cheek or sublingual administration, dosage form is tablet, capsule, the agent of ovum shape body, elixir, solution or suspension, wherein can contain correctives or coloring agent, be used for immediately, delay, modification, continue, the application of pulse or sustained release.

This class tablet can contain excipient, for example microcrystalline Cellulose, lactose, sodium citrate, calcium carbonate, Bibasic Calcium Phosphate and glycine, disintegrating agent, for example starch (preferred corn, Rhizoma Solani tuber osi or tapioca), primojel, cross-linking sodium carboxymethyl cellulose and some composition silicate, and Granulating Bonding Agent, for example polyvinylpyrrolidone, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and arabic gum.In addition, can comprise lubricant, for example magnesium stearate, stearic acid, Gan You behenic acid ester and Talcum.

The solid composite that also can adopt similar type is as the filler in the gelatine capsule agent.Preferred in this excipient comprises lactose, starch, cellulose, toffee or high molecular weight polyethylene glycol.With regard to aqueous suspension and/or elixir, formula (I), (Ia) or (Ib) chemical compound can mix with various sweeting agents or correctives, painted thing or stain, mix with emulsifying agent and/or suspending agent, mix with diluent (for example water, ethanol, propylene glycol and glycerol), and combination.

Formula (I), (Ia) or (Ib) chemical compound also can be by parenteral, for example in intravenous, intra-arterial, intraperitoneal, the sheath, in the ventricle, in the urethra, in the breastbone, intracranial, intramuscular or subcutaneous, perhaps they can be by the infusion techniques administration.With regard to this class parenteral, they preferably adopt the form of aseptic aqueous solution, wherein can contain other materials, and for example enough salt or glucose ooze solution and blood etc.If necessary, aqueous solution should suitably be cushioned (preferably buffered is to pH 3-9).By standard pharmaceutical technology well known to those skilled in the art, realize the preparation of parenteral administration under aseptic condition that is fit to easily.

Formula (I), (Ia) or (Ib) chemical compound also can be by intranasal administration or inhalation, common form (self with dry powder, the perhaps drying composite that forms with lactose, perhaps blending ingredients particle, for example mix with phospholipid) from pressurizing vessel, pump, aerosol apparatus or nebulizer, discharge (preferred nebulizer with Foradil Aerolizer formoterol fumarate or aerosol spray form, wherein utilize electronics hydraulics to produce mist), the wherein propellant that utilizes or need not be fit to, for example dichlorofluoromethane.

Pressurizing vessel, pump, aerosol apparatus or nebulizer contain the solution or the suspension of reactive compound, the agent that substitutes that wherein for example comprises ethanol (aquiferous ethanol alternatively) or be fit to supplies active component, discharges as the propellant of solvent and dispersion, dissolving or the time-delay of optional surfactant, and described surfactant is sorbitan trioleate or few lactic acid for example.

Before being used for dry powder or suspension preparation, drug products is ground into is suitable for sucking the size (usually less than 5 microns) of sending.This can realize that for example spiral spray is ground, fluidised-bed spray grinds, supercritical fluid is processed into nanoparticle, high pressure homogenizing or spray drying by any suitable breaking method.

Be suitable for use in pharmaceutical solutions in the nebulizer that utilizes electronics hydraulics to produce mist and can whenever press and contain 1 μ g to 10mg The compounds of this invention, whenever press volume and can not wait from 1 μ L to 100 μ L.Typical formulation can comprise formula (I), (Ia) or (Ib) chemical compound, propylene glycol, sterilized water, ethanol and sodium chloride.Can use to substitute solvent replacement propylene glycol, comprise glycerol and Polyethylene Glycol.

Be used in capsule in inhaler or the insufflator, bubble eye and cartridge case (for example making) and can be formulated into the mixture of powders that contains The compounds of this invention, suitable powder substrate (for example lactose or starch) and modifier (for example 1-leucine, mannitol or magnesium stearate) by gelatin or HPMC.

Suction/intranasal administration preparation can be formulated into immediately and/or modification discharges.

Select as an alternative, formula (I), (Ia) or (Ib) chemical compound can be with the form administration of suppository or vaginal suppository, perhaps they can be with the form local application of gel, hydrogel, lotion, solution, cream, ointment or spreading powder.Formula (I), (Ia) or (Ib) chemical compound can also for example be utilized skin patch by percutaneous or transdermal administration.They can also pass through lung or rectum administration.

They can also pass through the eye administration.With regard to eye with regard to, chemical compound can be formulated into the micronization suspension in isoosmotic, pH regulator, Sterile Saline, the perhaps preferred solution in isoosmotic, pH regulator, Sterile Saline, its alternatively with antiseptic coupling, for example benzalkonium chloride.Select as an alternative, they can be formulated in ointment, for example vaseline.

With regard to the local skin medication, formula (I), (Ia) or (Ib) chemical compound can be formulated into suitable ointment, wherein contain and suspend or be dissolved in reactive compound in following one or more the mixture: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene chemical compound, emulsifing wax and water.Select as an alternative, they can be formulated into suitable lotion or cream, suspend or are dissolved in following one or more the mixture: mineral oil, Arlacel-60, Polyethylene Glycol, liquid paraffin, polysorbate 60, spermaceti ester type waxes, spermol, 2-octyldodecanol, benzyl alcohol and water.

Formula (I), (Ia) or (Ib) chemical compound can also unite use with cyclodextrin.Known cyclodextrin and drug molecule form the complex of embedding and non-embedding.The formation of drug-cyclodextrin complex can change dissolubility, rate of dissolution, bioavailability and/or the stability of drug molecule.The drug-cyclodextrin complex generally can be used for most of dosage forms and route of administration.As with the direct compound alternative of medicine, cyclodextrin can be used as complementary additive, for example carrier, diluent or solubilizing agent.α-, β-with gamma-cyclodextrin be the most frequently used, the case description that is fit to is in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

The further illustration the present invention of following non-limiting examples.

Set forth the present invention with following non-limiting examples, wherein use following abbreviation and definition:

Optical rotation under the α D 587nm

Filtering agent

The b broad peak

The Boc tertbutyloxycarbonyl

CDCl ₃Chloroform-d1

CD ₃OD methanol-d4

The δ chemical drifting

D is bimodal

The dd doublet of doublet

The DCM dichloromethane

DMF N, dinethylformamide

The DMSO dimethyl sulfoxide

H hour

HCl hydrogen chloride

LRMS low resolution mass spectrum

The m multiplet

The m/z mass spectra peak

Min minute

The Mpt fusing point

The NaOH sodium hydroxide

The NMR nuclear magnetic resonance, NMR

The q quartet

S is unimodal

The t triplet

The Tf trifyl

The TFA trifluoroacetic acid

The THF oxolane

The TLC thin layer chromatography

Fusing point utilizes Perkin Elmer DSC7 to measure, and the rate of heat addition is 20 ℃/minute.

The X-ray diffraction data are at room temperature, utilize Bruker Axs Smart-Apex CCD area detection of diffracted meter (MO K α radiation) to write down.Ask the intensity integration from some series of exposures.Each exposure covers 0.3 ° of IN ω, and time of exposure is 60 seconds, and the burn-out data set is more than a sphere.

Embodiment 1

2-amino-1-(3-methoxyphenyl) ethanol

At room temperature, (27.2g, THF 0.2mol) (150ml) solution add the 3N HCl (aq) that is stirring, and (150ml is 0.3mol) with sodium sulfite (37.8g, 0.3mol) solution with the 3-methoxybenzaldehyde.After 10 minutes, add potassium cyanide (19.53g 0.3mol), stirs reactant mixture 30 minutes then in batches.Add diethyl ether (800ml) and water (300ml), layering subsequently.Water layer is stripped with diethyl ether (500ml), merges organic layer, through anhydrous magnesium sulfate drying, filters, and concentrates in a vacuum then, obtains the cyanalcohol intermediate, for colourless oil (35.57g, 0.22mol, 100%).(400ml 0.4mol) joins in the THF solution (100ml) of cyanalcohol carefully with borine-oxolane coordination compound (1M THF solution) then.In case effervescent stops, continuing under blanket of nitrogen, under refluxing, stirred 1.5 hours.With the reactant mixture cooling, use methanol (40ml) quencher then, concentrate in a vacuum again, obtain colourless oil.Add 6M HCl (aq) (200ml), reactant was stirred 2 hours under refluxing, concentrate in a vacuum then, obtain white solid.Its preadsorption to silicon dioxide, is passed through the column chromatography purification then, use dichloromethane: methanol: ammonia (90:10:1) eluting, obtain title compound, be colourless oil (31.3g, 0.19mol, 94%). ¹H NMR (CDCl ₃, 400MHz) δ: 1.60 (bs, 2H), 2.80 (dd, 1H), 3.02 (dd, 1H), 3.46 (s, 1H), 3.81 (s, 3H), 4.60 (dd, 1H), 6.81 (d, 1H), 6.91 (d, 1H), 6.93 (s, 1H), 7.22 (t, 1H) .LRMS:m/z 168 (M-H ⁺). analyze measured value C, 56.66; H, 8.28; N, 6.91%.C ₉H ₁₃NO ₂1.33H ₂O theoretical value C, 56.33; H, 8.27; N, 7.30%.

Embodiment 2

N-[2-hydroxyl-2-(3-methoxyphenyl) ethyl] propionic acid amide.

(52ml, (31.3g 0.19mol) in the solution in dichloromethane (400ml), stirs reactant mixture 10 minutes under 0 ℃ of blanket of nitrogen 0.37mol) to join the amine of embodiment 1 with triethylamine.(16.3ml 0.19mol), stirred 30 minutes then, made reaction temperature rise to room temperature and reached other 5 hours to add propionyl chloride.Reactant mixture with (100ml) quencher of 1N HCl (aq), is used dichloromethane extraction (2 x 50ml) then.Merge organic moiety, through anhydrous magnesium sulfate drying, filter, concentrate in a vacuum, obtain title compound, be colourless oil, the placement post crystallization is white crystal (28g, 0.13mol, 67%).

¹H NMR (CDCl ₃, 400MHz) δ: 1.18 (t, 3H), 2.22 (q, 2H), 2.51 (bs, 1H), 3.31 (m, 1H), 3.71 (dd, 1H), 3.80 (s, 3H), 4.81 (m, 1H), 5.95 (bs, 1H), 6.80 (d, 1H), 6.90 (d, 1H), 6.91 (s, 1H), 7.22 (t, 1H) .LRMS:m/z224.Mpt:77-78 ℃. analyze measured value C, 63.86; H, 7.82; N, 6.28%.C ₁₂H ₁₇NO ₃0.1H ₂O theoretical value C, 64.04; H, 7.70; N, 6.22%.

Embodiment 3

1-(3-methoxyphenyl)-2-propyl group ethylaminoethanol

(376ml, (28g 0.13mol) in the solution of anhydrous THF (100ml), makes the reaction mixture refluxed that stirs under nitrogen reach 2.5 hours then 0.4mol) to join the amide of embodiment 2 with borine-oxolane coordination compound (1M THF solution).With the reactant mixture cooling, use methanol (40ml) quencher then, concentrate in a vacuum again, obtain the oil of opaque white color.Add 6N HCl (aq) (200ml), reactant mixture was stirred 2 hours under refluxing.With the reactant mixture cooling, add dichloromethane (200ml) then, separate each layer.Add potassium carbonate to water layer and make it to be alkalescence, use dichloromethane extraction (2 x 200ml) then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be colourless oil, place post crystallization, obtain clear crystal (15.3g, 0.07mol, 59%) through anhydrous magnesium sulfate drying.

¹HNMR (CDCl ₃, 400MHz) δ: 0.93 (t, 3H), 1.62 (q, 2H), 2.71 (q, 2H), 2.81 (t, 2H), 3.00 (d, 1H), 3.80 (s, 3H), 4.30 (bs, 1H), 4.89 (d, 1H), 6.81 (d, 1H), 6.91 (d, 1H), 6.93 (s, 1H), 7.22 (t, 1H) .LRMS:m/z 210.Mpt:50-51 ℃. analyze measured value C, 67.47; H, 9.02; N, 6.45%.C ₁₂H ₁₉NO ₂0.2H ₂O theoretical value C, 67.70; H, 9.19; N, 6.58%.

Embodiment 4

2-chloro-N-[2-hydroxyl-2-(3-methoxyphenyl) ethyl]-the N-propyl acetamide

(15.1g, water 0.38mol) (180ml) solution join the amine of embodiment 3, and (15.8g is 0.08mol) in the solution of dichloromethane (500ml), with solution vigorous stirring at room temperature with sodium hydroxide.(7.22ml 0.09mol), stirs reactant mixture other 30 minutes to add chloracetyl chloride then.Separate each layer, water layer is stripped with dichloromethane (200ml).Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be colourless oil (17.8g, 0.06mol, 83%) through anhydrous magnesium sulfate drying. ¹H NMR (CDCl ₃, 400MHz) δ: 0.96 (t, 3H), 1.62 (q, 2H), 3.21 (q, 2H), 3.57-3.71 (m, 2H), 3.82 (s, 3H), 4.01-4.21 (bq, 1H), 4.16 (s, 2H), 5.00 (m, 1H), 6.82 (m, 1H), 6.91-6.99 (m, 2H), 7.22 (m, 1H) .LRMS:m/z 286. analyzes measured value C, 57.38; H, 6.95; N, 4.67%.C ₁₄H ₂₀NO ₃Cl0.33H ₂O theoretical value C, 57.64; H, 7.14; N, 4.80%.

Embodiment 5

6-(3-methoxyphenyl)-4-propyl group morpholine-3-ketone

With potassium hydroxide (4.2g, 0.07mol), (17.8g 0.06mol) stirs into opaque solution with water (15ml) together and reaches 2 hours for the amide of isopropyl alcohol (500ml) and embodiment 4.Concentrated reaction mixture is dissolved in ethyl acetate (200ml) with yellow residue in a vacuum.Its water (200ml), reuse saline (200ml) are distributed.Organic moiety through anhydrous magnesium sulfate drying, is filtered, concentrate in a vacuum, obtain title compound, be xanchromatic oil (15.8g, 0.06mol, 100%). ¹H NMR (CDCl ₃, 400MHz) δ: 0.96 (t, 3H), 1.62 (m, 2H), 3.36 (m, 2H), 3.51 (q, 2H), 3.81 (s, 3H), 4.30-4.62 (bq, 2H), 4.79 (d, 1H), 6.85 (d, 1H), 6.91 (d, 1H), 6.95 (s, 1H), 7.29 (t, 1H) .LRMS:m/z 272. analyzes measured value C, 66.80; H, 7.78; N, 5.52%.

C ₁₄H ₁₉NO ₃0.1H ₂O theoretical value C, 66.96; H, 7.71; N, 5.58%.

Embodiment 6

2-(3-methoxyphenyl)-4-propyl group morpholine

Under blanket of nitrogen, (200ml 0.19mol) goes through and was added drop-wise to embodiment 5 described morpholine-3-ketone in 30 minutes (15.8g is in anhydrous THF (100ml) solution 0.06mol) with borine-oxolane coordination compound (1M THF solution).Reaction mixture refluxed is reached 3 hours, and cooling then adds methanol (30ml) quencher.Concentrated reaction mixture in a vacuum then, with colourless residue be suspended in carefully 4N HCl (aq) (400ml) in, refluxed then 2.5 hours.With the reactant mixture cooling, add dichloromethane (200ml).Separate each layer, add potassium carbonate to water layer and make it to be alkalescence, use dichloromethane extraction (3 x 100ml) then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be colourless oil (12.51g, 0.05mol, 84%) through anhydrous magnesium sulfate drying.

¹H NMR (CDCl ₃, 400MHz) δ: 0.95 (t, 3H), 1.59 (q, 2H), 2.05 (t, 1H), 2.23 (t, 1H), 2.40 (t, 2H), 2.81 (d, 1H), 2.98 (d, 1H), 3.80 (s, 3H), 3.85 (t, 1H), 4.05 (d, 1H), 4.60 (d, 1H), 6.81 (d, 1H), 6.91 (d, 1H), 7.21 (t, 1H), 7.23 (s, 1H) .LRMS:m/z 236. analyzes measured value C, 68.94; H, 8.80; N, 5.79%.C ₁₄H ₂₁NO ₂0.5H ₂O theoretical value C, 68.82; H, 9.08; N, 5.73%.

Embodiment 7A

R-(-)-3-(phenol of 4-propyl group morpholine-2-yl)

Embodiment 7B

S-(+)-3-(phenol of 4-propyl group morpholine-2-yl)

(8.62g 0.03mol) is heated to together to reflux and reaches 1 hour with the methoxybenzene of hydrobromic acid (250ml) and embodiment 6.After the cooling,, add NH then with reactant mixture water (100ml) dilution ₄OH (20ml) neutralization.Use the yellow opaque solution of dichloromethane extraction (2 x 100ml) then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain the racemic mixture of title compound, be xanchromatic oil (7.78g, 0.03mol, 96%) then through anhydrous magnesium sulfate drying.By chiral chromatogram enantiomer separation (Chiralpak AD 250*20mm post), use hexane: isopropyl alcohol: diethylamine (70:30:0.05) eluting obtains enantiomer 1 (ee〉99.5%) and enantiomer 2 (ee〉99%).Every kind of enantiomer is used dichloromethane through the silica column chromatogram purification: methanol (95:5) eluting, obtain enantiomer 1 (7a) (3.02g, 0.014mol, 39%) and enantiomer 2 (7b) (3.15g, 0.014mol, 40%), and be colourless oil.Enantiomer 1 (7a): ¹H NMR (CDCl ₃, 400MHz) δ: 0.96 (t, 3H), 1.60 (q, 2H), 2.13 (t, 1H), 2.31 (t, 1H), 2.41 (t, 2H), 2.85 (d, 1H), 3.02 (d, 1H), 3.90 (t, 1H), 4.02 (dd, 1H), 4.60 (d, 1H), 6.78 (d, 1H), 6.80 (s, 1H), 6.91 (d, 1H), 7.20 (t, 1H) .LRMS:m/z 222 (M-H ⁺). enantiomer 2 (7b): ¹H NMR (CDCl ₃, 400MHz) δ: 0.96 (t, 3H), 1.60 (q, 2H), 2.13 (t, 1H), 2.31 (t ,-1H), 2.41 (t, 2H), 2.85 (d, 1H), 3.02 (d, 1H), 3.90 (t, 1H), 4.02 (dd, 1H), 4.60 (d, 1H), 6.78 (d, 1H), 6.80 (s, 1H), 6.91 (d, 1H), 7.20 (t, 1H) .LRMS:m/z 222 (M-H ⁺).

Embodiment 8

R-(-)-3-(the phenolate hydrochlorate of 4-propyl group morpholine-2-yl)

(3.00g 0.014mol) is dissolved in diethyl ether (180ml), adds hydrogen chloride (2.0M diethyl ether solution) (10ml) with the enantiomer 1 (7a) of embodiment 7.Reactant mixture was at room temperature stirred 30 minutes, and the decantation solvent is dry in a vacuum then, obtains title compound, is white solid (3.115g, 0.012mol, 90%).

¹H NMR (CD ₃OD, 400MHz) δ: 1.06 (t, 3H), 1.81 (m, 2H), 3.02 (t, 1H), 3.16 (t, 2H), 3.20 (t, 1H), 3.60 (t, 2H), 4.01 (t, 1H), 4.26 (d, 1H), 4.71 (d, 1H), 6.78 (d, 1H), 6.82 (s, 1H), 6.83 (d, 1H), 7.21 (t, 1H) .LRMS:m/z 222 (M-H ⁺). analyze measured value C, 59.74; H, 7.98; N, 5.25%.C ₁₃H ₁₉NO ₂0.18H ₂O theoretical value C, 59.82; H, 7.86; N, 5.37%. α _D=-5.66 ° (Methanol 10.6mg/10ml).

Make the title compound sample by diffusion of vapor from methanol: recrystallization the diethyl ether mixture obtains the X-ray crystal structure.By Flack ¹Method determine the absolute stereo chemistry of title compound from diffraction data, show to have the R configuration.

List of references 1:H.D.FLACK, ACTA CRYST.1983,439,876-881

Embodiment 9

2-amino-1-(3, the 5-Dimethoxyphenyl) ethanol

Follow the method identical with embodiment 1, from 3, (5.00g 0.03mol) begins preparation to the 5-dimethoxy benzaldehyde.After in 6M HCl (aq), refluxing, with the reactant mixture cooling, with diethyl ether extraction (2 x 80ml).Discard organic layer, add the potassium carbonate alkalization to water layer.The aqueous residue is used ethyl acetate extraction (3 x 70ml) then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be light yellow oil (3.47g, 0.018mol, 59%) through anhydrous magnesium sulfate drying. ¹H?NMR(CD ₃OD，400MHz)δ：2.77-2.86(m，2H)，3.78(s，6H)，4.60(m，1H)，6.38(s，1H)，6.52(s，2H).LRMS：m/z?198(M-H ⁺).

Embodiment 10

N-[2-(3, the 5-Dimethoxyphenyl)-2-hydroxyethyl] propionic acid amide.

Follow the method identical with embodiment 2, (3.41g 0.017mol) begins preparation from embodiment 9 described amine.Crude product mixture is used dichloromethane through the silica column chromatogram purification: methanol (95:5) eluting, obtain title compound, and be light yellow oil (3.08g, 0.012mol, 70%).

¹HNMR(CDCl ₃，400MHz)δ：1.18(m，3H)，2.24(m，2H)，3.34(m，1H)，3.68(m，1H)，3.81(s，6H)，4.80(dd，1H)，5.95(bs，1H)，6.39(s，1H)，6.51(s，2H).LRMS：m/z?252(M-H ^-).

Embodiment 11

1-(3, the 5-Dimethoxyphenyl)-2-propyl group ethylaminoethanol

Follow the method for embodiment 3, (3.06g 0.012mol) begins preparation, obtains title compound, is orange oil (2.72g, 0.011mol, 94%) from embodiment 10 described amide.

¹H?NMR(CD ₃OD，400MHz)δ：0.95(t，3H)，1.56(m，2H)，2.61(m，2H)，2.77(d，2H)，3.78(s，6H)，4.70(t，1H)，6.38(s，1H)，6.51(s，2H).LRMS：m/z?240(M-H ⁺).

Embodiment 12

2-chloro-N-[2-(3, the 5-Dimethoxyphenyl)-2-hydroxyethyl]-the N-propyl acetamide

Follow the method identical with embodiment 4, (2.70g 0.011mol) begins preparation, obtains title compound, is xanchromatic oil (3.56g, 0.011mol, 100%) from embodiment 11 described amine. ¹H?NMR(CDCl ₃，400MHz)δ：0.92(t，3H)，1.61(m，2H)，3.20(m，2H)，3.51-3.64(m，2H)，3.80(d，6H)，4.13(s，2H)，4.95(m，1H)，6.40(m，1H)，6.55(s，2H).LRMS：m/z?316(M-H ⁺).

Embodiment 13

6-(3, the 5-Dimethoxyphenyl)-4-propyl group morpholine-3-ketone

Follow the method identical with embodiment 5, (3.54g 0.011mol) begins preparation, obtains title compound, is xanchromatic oil (2.44g, 0.009mol, 78%) from embodiment 12 described amide. ¹H?NMR(CDCl ₃，400MHz)δ：0.94(t，3H)，1.61(m，2H)，3.30(m，2H)，3.49(m，2H)，3.80(s，6H)，4.30(d，1H)，4.42(d，1H)，4.73(dd，1H)，6.42(s，1H)，6.53(s，2H).LRMS：m/z?280(M-H ⁺).

Embodiment 14

2-(3, the 5-Dimethoxyphenyl)-4-propyl group morpholine

Follow the method for embodiment 6, (2.42g 0.009mol) begins preparation from embodiment 13 described amide.After in 6M HCl (aq), refluxing, chilled reactant mixture is extracted (2 x 80ml) with diethyl ether.Discard organic layer, add the potassium carbonate alkalization to water layer.The aqueous residue is used ethyl acetate extraction (3 x 80ml) then, merges organic extract liquid, through anhydrous magnesium sulfate drying, filters, and concentrates in a vacuum then, obtains title compound, is light orange oil (2.14g, 0.008mol, 93%). ¹H?NMR(CD ₃OD，400MHz)δ：0.95(t，3H)，1.58(m，2H)，2.01(m，1H)，2.22(dt，1H)，2.38(t，2H)，2.83(d，1H)，2.93(d，1H)，3.78(m，7H)，4.01(dd，1H)，4.45(dd，1H)，6.39(s，1H)，6.49(s，2H).LRMS：m/z?266(M-H ⁺).

Embodiment 15A

R-5-(benzene-1 of 4-propyl group morpholine-2-yl), 3-diphenol

Embodiment 15B

S-5-(benzene-1 of 4-propyl group morpholine-2-yl), 3-diphenol

Follow the approach identical with embodiment 7, described 3 from embodiment 14, (1.00g 0.004mol) begins preparation to 5-dimethoxy benzene based compound, obtains racemic compound shown in the title, is the oil (145mg, 0.61mmol, 16%) of brown.By chiral chromatogram enantiomer separation (Chiralpak AD 250*20mm post), use hexane: isopropyl alcohol (80:20) eluting, obtain enantiomer 1 (15a) (5.2mg) (ee〉98.94%) and enantiomer 2 (15b) (5.1mg) (ee〉96.46%), be the oil of brown.Enantiomer 1 (15a):

¹H NMR (CD ₃OD, 400MHz) δ: 0.96 (t, 3H), 1.58 (m, 2H), 2.01 (t, 1H), 2.20 (dt, 1H), 2.37 (t, 2H), 2.81-2.92 (m, 2H), 3.89 (dt, 1H), 3.99 (dd, 1H), 4.38 (dd, 1H), 6.18 (t, 1H), 6.26 (s, 2H) .LRMS:m/z 238 (M-H ⁺). enantiomer 2 (15b): ¹H NMR (CD ₃OD, 400MHz) δ: 0.95 (t, 3H), 1.58 (m, 2H), 2.01 (t, 1H), 2.20 (dt, 1H), 2.38 (t, 2H), 2.80-2.92 (q, 2H), 3.78 (dt, 1H), 3.98 (dd, 1H), 4.38 (dd, 1H), 6.18 (s, 1H), 6.25 (s, 2H) .LRMS:m/z 238 (M-H ⁺).

Embodiment 16

4-fluoro-3-methoxybenzaldehyde

Under blanket of nitrogen, with (4-fluoro-3-methoxyphenyl) methanol (5.00g, 0.03mol) and manganese dioxide (33.4g, 0.38mol) in dichloromethane (100ml), under gentle reflux, stirred 16 hours.Then chilled reactant mixture is filtered by arbacel, concentrate in a vacuum, obtain title compound, be white solid (4.18g, 0.027mol, 85%).

¹H NMR (CDCl ₃, 400MHz) δ: 3.96 (s, 3H), 7.23 (d, 1H), 7.43 (m, 1H), 7.50 (d, and 1H) 9.91 (s, 1H) .Mpt:61-63 ℃. analyze measured value C, 62.18; H, 4.54%, C ₈H ₇FO ₂Theoretical value C, 62.34; H, 4.58%.

Embodiment 17

2-amino-1-(4-fluoro-3-methoxyphenyl) ethanol

Follow the method identical with embodiment 1, (4.17g 0.03mol) begins preparation from 4-fluoro-3-methoxybenzaldehyde.After in 6M HCl (aq), refluxing, with the reactant mixture cooling, with diethyl ether extraction (2 x 60ml).Discard organic layer, add the potassium carbonate alkalization to water layer.The aqueous residue is used ethyl acetate extraction (3 x 80ml) then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be orange oil (2.36g, 0.013mol, 47%) through anhydrous magnesium sulfate drying.

¹H?NMR(CD ₃OD，400MHz)δ：2.80-2.91(m，2H)，3.86(s，3H)，4.64(m，1H)，6.89(m，1H)，7.03(t，1H)，7.11(dd，1H).LRMS：m/z?186(M-H ⁺).

Embodiment 18

N-[2-(4-fluoro-3-methoxyphenyl)-2-hydroxyethyl] propionic acid amide.

Follow the method identical, begin preparation from embodiment 17 described amine (1.32g, 0.007mo l) with embodiment 2.Crude product mixture is used ethyl acetate through the silica column chromatogram purification: pentane (2:1) eluting, obtain title compound, and be xanchromatic oil, place post crystallization (0.59g, 0.002mol, 35%).

¹H?NMR(CDCl ₃，400MHz)δ：1.18(t，3H)，2.24(q，2H)，2.58(bs，1H)，3.34(m，1H)，3.63(m，1H)，3.88(s，3H)，4.82(dd，1H)，5.98(bs，1H)，6.82(m，1H)，7.01(m，2H).LRMS：m/z?242(M-H ⁺).

Embodiment 19

1-(4-fluoro-3-methoxyphenyl)-2-propyl group ethylaminoethanol

Follow the method identical with embodiment 3, (585mg 2.42mmol) begins preparation from embodiment 18 described amide.After in 6M HCl (aq), refluxing, with the reactant mixture cooling, with diethyl ether extraction (2 x 50ml).Discard organic layer, add the potassium carbonate alkalization to water layer.The aqueous residue is used ethyl acetate extraction (3 x 50ml) then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be light yellow oil (448mg, 1.97mmol, 81%) through anhydrous magnesium sulfate drying. ¹H?NMR(CD ₃OD，400MHz)δ：0.96(t，3H)，1.58(m，2H)，2.63(m，2H)，2.79(d，2H)，3.96(s，3H)，4.77(t，1H)，6.90(m，1H)，7.03(t，1H)，7.11(d，1H).LRMS：m/z?228(M-H ⁺).

Embodiment 20

2-chloro-N-[2-(4-fluoro-3-methoxyphenyl)-2-hydroxyethyl]-the N-propyl acetamide

Follow the method identical with embodiment 4, (0.84g 4.00mmol) begins preparation, obtains title compound, is xanchromatic oil (0.97g, 3.00mmol, 87%) from embodiment 19 described amine.LRMS：m/z?304(M-H ⁺)。Crude product can use.

Embodiment 21

6-(4-fluoro-3-methoxyphenyl)-4-propyl group morpholine-3-ketone

Follow the method identical with embodiment 5, (0.96g 3.00mmol) begins preparation, obtains title compound, is xanchromatic oil (0.64g, 2.40mmol, 75%) from embodiment 20 described amide. ¹H?NMR(CDCl ₃，400MHz)δ：0.94(t，3H)，1.62(m，2H)，3.33(m，2H)，3.48(m，2H)，3.91(s，3H)，4.34(d，1H)，4.43(d，1H)，4.76(dd，1H)，6.85(m，1H)，7.01-7.08(m，2H).LRMS：m/z?268(M-H ⁺).

Embodiment 22

2-(4-fluoro-3-methoxyphenyl)-4-propyl group morpholine

Follow the method identical with embodiment 6, (633mg 2.37mmol) begins preparation from embodiment 21 described morpholine-3-ketone.After in 6M HCl (aq), refluxing, with the reactant mixture cooling, with diethyl ether extraction (2 x 20ml).Discard organic layer, add the potassium carbonate alkalization to water layer.The aqueous residue is used ethyl acetate extraction (3 x 20ml) then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be xanchromatic oil (552mg, 2.18mmol, 92%) through anhydrous magnesium sulfate drying. ¹H?NMR(CD ₃OD，400MHz)δ：0.95(t，3H)，1.58(m，2H)，2.02(t，1H)，2.22(dt，1H)，2.38(t，2H)，2.85(d，1H)，2.93(d，1H)，3.80(m，1H)，3.84(s，3H)，4.01(dd，1H)，4.50(dd，1H)，6.88(m，1H)，7.02(t，1H)，7.09(d，1H).LRMS：m/z?254(M-H ⁺).

Embodiment 23A

R-(+)-2-fluoro-5-(phenol of 4-propyl group morpholine-2-yl)

Embodiment 23B

S-(-)-2-fluoro-5-(phenol of 4-propyl group morpholine-2-yl)

Follow the method preparation identical with embodiment 7, (200mg 0.789mmol) begins preparation from embodiment 22 described methoxybenzene.Crude product mixture is used dichloromethane through the silica column chromatogram purification: methanol (90:10) eluting, obtain racemic compound shown in the title, and be buff viscous oil (149mg, 0.62mmol, 79%).By chiral chromatogram enantiomer separation (ChiralpakAD 250*20mm post), use hexane: isopropyl alcohol (90:10) eluting, obtain enantiomer 1 (23a), be opaque oil (15mg) (ee〉99.5%), with enantiomer 2 (23b), be crystalline solid (16mg) (ee〉99%).Enantiomer 1 (23a):

¹H NMR (CD ₃OD, 400MHz) δ: 0.95 (t, 3H), 1.58 (m, 2H), 2.01 (t, 1H), 2.21 (dt, 1H), 2.37 (t, 2H), 2.82-2.97 (bq, 2H), 3.78 (dt, 1H), 3.99 (dd, 1H), 4.43 (d, 1H), 6.78 (m, 1H), 6.89-7.01 (m, 2H) .LRMS:m/z 240 (M-H ⁺). α _D=+0.91 (Ethanol 1.10mg/ml). enantiomer 2 (23b): ¹H NMR (CD ₃OD, 400MHz) δ: 0.96 (t, 3H), 1.58 (m, 2H), 2.01 (t, 1H), 2.22 (dt, 1H), 2.38 (t, 2H), 2.78 (dd, 2H), 3.78 (dt, 1H), 4.00 (dd, 1H), 4.43 (dd, 1H), 6.78 (m, 1H), 6.91 (d, 1H), 6.98 (t, 1H) .LRMS:m/z 240 (M-H ⁺). α _D=-0.40 (Ethanol 1.00mg/ml).

Embodiment 24

2-amino-1-(4-benzyloxy phenyl) ethanol

With potassium cyanide (20.15g, 0.31mol) and ammonium chloride (16.4g, 0.31mol) water-soluble (60ml), to wherein add 4-benzyloxy benzaldehyde (32.9g, 0.155mol), succeeded by diethyl ether (100ml).With reactant mixture vigorous stirring 48 hours at room temperature, use ethyl acetate extraction (2 x 200ml) then.Merge organic layer,, filter, concentrate in a vacuum, obtain the cyanalcohol intermediate, be yellow solid (34.2g, 0.14mol, 90%) through anhydrous magnesium sulfate drying.Then cyanalcohol is dissolved in anhydrous THF (300ml), and adding borine-methyl sulfur coordination compound (26.6ml, 0.28mol).With reaction mixture refluxed 2 hours, use methanol (50ml) quencher then.Add entry (50ml),, the reactant mixture stirring was stopped until heat release in 2 hours succeeded by dense HCl (40ml).Concentrated reaction mixture in a vacuum then, residue water (100ml) dilution.Add NH to aqueous solution then ₄OH (30ml) alkalization is with ethyl acetate extraction (3 x 150ml).Organic extract liquid through anhydrous magnesium sulfate drying, is filtered, concentrate in a vacuum, obtain title compound, be white solid (24.8g, 0.10mol, 73%).

¹H?NMR(CDCl ₃，400MHz)δ：1.62(bs，3H)，2.81(dd，1H)，2.99(d，1H)，4.61(q，1H)，5.07(s，2H)，6.95(d，2H)，7.22-7.45(m，7H)LRMS：m/z?244(M-H ⁺).

Embodiment 25

N-[2-(4-benzyloxy phenyl)-2-hydroxyethyl] propionic acid amide.

With embodiment 24 described amine (24.8g 0.10mol) is dissolved in dichloromethane (700ml), to wherein add triethylamine (20.86ml, 0.15mol).Reactant mixture is stirred, is cooled to 0 ℃, drip then propionyl chloride (7.12ml, 0.082mol).Reactant mixture is gone through be warmed to room temperature in 16 hours, use 3M HCl (aq) (20ml) and water (100ml) quencher then.Reactant mixture merges organic layer with dichloromethane extraction (3 x 200ml), through anhydrous magnesium sulfate drying, filters, and concentrates in a vacuum, obtains title compound, is clarification viscosity natural gum (27.5g, 0.092mol, 90%). ¹H?NMR(CDCl ₃，400MHz)δ：1.10(t，3H)，2.19(q，2H)，3.32-3.43(m，4H)，4.81(s，2H)，5.11(m，1H)，6.99(d，2H)，7.25-7.42(m，7H).LRMS：m/z?298(M-H ^-).

Embodiment 26

1-(4-benzyloxy phenyl)-2-propyl group ethylaminoethanol

(27.5g, anhydrous THF (100ml) solution 0.092mol) add borine-methyl sulfur coordination compound, and (17.5ml 0.18mol), stirs reactant mixture 2 hours under refluxing to embodiment 25 described amide.Make the reactant mixture cooling, use methanol (30ml) quencher then.Add entry (50ml) and dense HCl (35ml), reactant mixture is stirred until no longer bubbling, concentrate in a vacuum then.Add entry (250ml) to residue, add NH then ₄OH (30ml) alkalization.Water layer merges organic extract liquid with ethyl acetate extraction (3 x 200ml), through anhydrous magnesium sulfate drying, filters, and concentrates in a vacuum, obtains title compound, is white solid (26.1g, 0.09mol, 99%). ¹H?NMR(CD ₃OD，400MHz)δ：0.95(t，3H)，1.58(q，2H)，2.62(m，2H)，2.81(m，2H)，4.72(dd，1H)，5.05(s，2H)，6.95(d，2H)，7.24(m，3H)，7.35(t，2H)，7.41(d，2H).LRMS：m/z?286(M-H ⁺).

Embodiment 27

6-(4-benzyloxy phenyl)-4-propyl group morpholine-3-ketone

(22.5g, water 0.56mol) (100ml) solution join embodiment 26 described amine, and (26.0g is in dichloromethane 0.09mol) (400ml) solution, with solution vigorous stirring at room temperature with sodium hydroxide.(8.6ml 0.11mol), stirs reactant mixture other 60 minutes to add chloracetyl chloride then.Separate each layer, water layer extracts with dichloromethane (200ml) again.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain colourless oil through anhydrous magnesium sulfate drying.With potassium hydroxide (15.0g, 0.27mol), isopropyl alcohol (400ml) and colourless oily residue stir into opaque solution with water (30ml) together and reach 2 hours.Concentrated reaction mixture is dissolved in ethyl acetate (200ml) with yellow residue in a vacuum.Its water (200ml), reuse saline (200ml) are distributed.Organic moiety through anhydrous magnesium sulfate drying, is filtered, concentrate in a vacuum, obtain title compound, be white solid (19.9g, 0.06mol, 67%).

¹H?NMR(CDCl ₃，400MHz)δ：0.95(t，3H)，1.62(m，2H)，3.34(m，2H)，3.51(m，2H)，4.32(d，1H)，4.41(d，1H)，4.72(dd，1H)，5.04(s，2H)，6.98(d，2H)，7.31-7.43(m，7H).LRMS：m/z?326(M-H ⁺).

Embodiment 28

2-(4-benzyloxy phenyl)-4-propyl group morpholine

Follow the method identical with embodiment 26, (19.9g 0.061mol) begins preparation, obtains title compound, is colourless oil (17g, 0.055mol, 90%) from embodiment 27 described morpholine-3-ketone.

¹H?NMR(CDCl ₃，400MHz)δ：0.95(t，3H)，1.55(q，2H)，2.06(t，1H)，2.21(dt，1H)，2.35(dd，2H)，2.80(d，1H)，2.91(d，1H)，3.82(dt，1H)，4.02(dd，1H)，4.52(dd，1H)，5.05(s，2H)，6.98(t，2H)，7.24-7.42(m，7H).LRMS：m/z?312(M-H ⁺).

Embodiment 29

4-(the phenol of 4-propyl group morpholine-2-yl)

(3.0g 9.64mmol) is dissolved in methanol (150ml), adds 10% palladium on carbon (800mg) with embodiment 28 described benzylic ethers.Reactant mixture is stirred a few minutes, add then in batches ammonium formate (6.17g, 96.4mmol).Reactant mixture is heated to 80 ℃ carefully, until no longer emitting gas.After the cooling, reactant mixture is filtered by arbacel,, concentrate in a vacuum, obtain title compound, be white crystalline solid (1.51g, 6.83mmol, 71%) with methanol (50ml) washing.

¹H?NMR(CDCl ₃，400MHz)δ：0.91(t，3H)，1.58(q，2H)，2.10(t，1H)，2.22(t，1H)，2.40(dd，2H)，2.81(d，1H)，2.93(d，1H)，3.85(t，1H)，4.02(dd，1H)，4.57(d，1H)，6.79(d，2H)，7.21(d，2H).LRMS：m/z?222(M-H ⁺).

Embodiment 30

The 2-bromo-4-(phenol of 4-propyl group morpholine-2-yl)

To embodiment 29 described phenol (200mg, dichloromethane 0.9mmol) (5ml) solution add N-bromine butanimide (161mg, 0.9mmol).Reactant mixture was at room temperature stirred 55 minutes, concentrate in a vacuum then.Crude product is used dichloromethane through the silica column chromatogram purification: methanol (95:5) eluting, obtain title compound, and be white foam (117.5mg, 0.39mmol, 44%). ¹H?NMR(CDCl ₃，400MHz)δ：0.96(t，3H)，1.59(q，2H)，2.03(t，1H)，2.23(t，1H)，2.40(t，2H)，2.81(d，1H)，2.98(d，1H)，3.82(t，1H)，4.01(d，1H)，4.56(d，1H)，6.96(d，1H)，7.20(d，1H)，7.49(s，1H).LRMS：m/z?302(M-H ⁺，Br?isotope).

Embodiment 31

2-(4-benzyloxy-3-bromophenyl)-4-propyl group morpholine

Under blanket of nitrogen, to embodiment 30 described phenol (117.5mg, dry DMF 0.39mmol) (10ml) solution add potassium carbonate (75mg, 0.54mmol) and benzyl bromide a-bromotoluene (0.07ml, 0.54mmol).Reactant mixture is heated to 150 ℃ reaches 48 hours.After the cooling, concentrated reaction mixture distributes residue between ethyl acetate (50ml) and water (50ml) in a vacuum.Extract (2 x 20ml) water layer again with ethyl acetate then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain crude product, be the oil of brown through anhydrous magnesium sulfate drying.Through the silica column chromatogram purification, use dichloromethane: methanol (98:2) eluting, obtain title compound, be colourless oil (153mg, 0.39mmol, 100%).

¹H?NMR(CDCl ₃，400MHz)δ：0.93(t，3H)，1.56(q，2H)，2.05(t，1H)，2.25(t，1H)，2.37(t，2H)，2.82(d，1H)，2.92(d，1H)，3.85(t，1H)，4.02(d，1H)，4.52(d，1H)，5.15(s，2H)，6.87(d，1H)，7.20(d，1H)，7.30(d，1H)，7.37(t，2H)，7.45(d，2H)，7.58(s，1H).LRMS：m/z?392(M-H ⁺).

Embodiment 32

2-benzyloxy-5-(benzoic acid methyl ester of 4-propyl group morpholine-2-yl)

To embodiment 31 described bromides (153mg, dry DMF 0.39mmol) (4ml) solution add triethylamine (2.1ml, 0.78mmol) and methanol (2ml), with reactant mixture stirring 5 minutes.(16mg 0.02mmol), feeds carbon monoxide (g) (3 aerating gasbags) to reactant mixture to the coordination compound (1:1) of adding [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II) and dichloromethane then.Under carbon monoxide atmosphere, reactant mixture is heated to 100 ℃ and reaches 16 hours.After the cooling, concentrated reaction mixture distributes residue between ethyl acetate (25ml) and water (20ml) in a vacuum.Separate organic layer,,, filter, concentrate in a vacuum, obtain black solid through anhydrous magnesium sulfate drying with saline (20ml) washing.Through the silica column chromatogram purification, use dichloromethane: methanol: ammonia (90:10:1) eluting, obtain title compound, be colourless oil (105mg, 0.28mmol, 73%).

¹H?NMR(CDCl ₃，400M?Hz)δ：0.94(t，3H)，1.60(m，2H)，2.18(s，4H)，2.43(m，2H)，3.00(m，2H)，3.90(s，3H)，4.04d，1H)，5.18(s，2H)，5.97(d，1H)，7.26-7.47(m，6H)，7.82(s，1H).LRMS：m/z?370(M-H ⁺).

Embodiment 33

2-benzyloxy-5-(benzoic acid of 4-propyl group morpholine-2-yl)

(105mg, methanol 0.28mmol) (5ml) solution adds 10% sodium hydroxide (aq) (15ml), and milky suspension was refluxed 2 hours to embodiment 32 described methyl ester.With now being colourless reactant mixture cooling, add 2M HCl (aq) (several) neutralization then.Concentrated reaction mixture in a vacuum obtains title compound then, is pale solid (99mg, 0.28mmol, 100%).LRMS：m/z?355(M-H ⁺)。This material is directly used in embodiment 34 with the crude product form.

Embodiment 34

2-benzyloxy-5-(Benzoylamide of 4-propyl group morpholine-2-yl)

(99mg 0.28mmol) adds thionyl chloride (5ml), reactant mixture is heated to 50 ℃ reaches 2 hours to embodiment 33 described crude benzol formic acid.With the reactant mixture cooling, remove excessive thionyl chloride in a vacuum.Then residue is dissolved in dichloromethane (10ml), feeds ammonia (g) to reactant mixture and reach 10 minutes.The gained suspension was at room temperature stirred 1 hour, concentrate in a vacuum then.Crude product is used dichloromethane: methanol through the silica column chromatogram purification: ammonia (95:5:0.5) eluting, obtain title compound, and be pale solid (88mg, 0.25mmo l, 90%). ¹H?NMR(CDCl ₃，400MHz)δ：0.94(t，3H)，1.59(m，2H)，2.15-2.42(m，4H)，2.87(m，1H)，3.03(m，1H)，3.96(m，1H)，4.02(d，1H)，4.67(m，1H)，5.19(s，2H)，5.72(m，1H)，7.04(d，1H)，7.41(m，5H)，7.50(d，1H)，7.70(m，1H)，8.21(s，1H).LRMS：m/z?355(M-H ⁺).

Embodiment 35

2-hydroxyl-5-(Benzoylamide of 4-propyl group morpholine-2-yl)

Utilize the method identical with embodiment 29, (80mg 0.22mmol) begins to prepare, and obtains title compound, is pale solid (56mg, 0.21mmol, 96%) from embodiment 34 described benzyl esters. ¹H?NMR(CD ₃OD，400MHz)δ：0.95(t，3H)，1.55(m，2H)，2.13(t，1H)，2.29(t，1H)，2.42(m，2H)，2.88(d，1H)，2.97(d，1H)，3.81(t，1H)，4.00(d，1H)，4.49(d，1H)，6.87(d，1H)，7.42(d，1H)，7.78(s，1H).LRMS：m/z?265(M-H ⁺).

Embodiment 36

2-nitro-4-(phenol of 4-propyl group morpholine-2-yl)

(100mg 0.45mmol) is dissolved in nitric acid: water (1:3) (2ml) at room temperature stirred 10 minutes with embodiment 29 described phenol.With reactant mixture water (5ml) dilution, use NH then ₄Ethyl acetate extraction (3 x 10ml) is used in OH (1ml) alkalization then.Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be yellow solid (95mg, 0.35mmol, 79%) through anhydrous magnesium sulfate drying.

¹H?NMR(CDCl ₃，400MHz)δ：0.97(t，3H)，1.33(t，2H)，1.43-1.79(bm，4H)，2.02(d，3H)，4.06(m，2H)，7.17(d，1H)，7.60(d，1H)，8.16(s，1H)，10.55(bs，1H).LRMS：m/z?267(M-H ⁺).

Embodiment 37

2-amino-4-(phenol of 4-propyl group morpholine-2-yl)

To embodiment 36 described nitro compounds (95mg, ethanol 0.35mmol) (10ml) solution add 10% palladium on carbon (50mg) and ammonium formate (100mg, XS).With reactant mixture mild heat to 70 ℃, under this temperature, kept 1 hour, be cooled to room temperature then.Reactant mixture is filtered by arbacel, earlier with ethanol (20ml), reuse dichloromethane (20ml) washing.Be associated with the machine cleaning mixture, concentrate in a vacuum, obtain title compound, be yellow solid (65mg, 0.28mmol, 78%).

¹H?NMR(CDCl ₃，400MHz)δ：0.91(t，3H)，1.55(m，2H)，2.12(t，1H)，2.25(dt，1H)，2.40(t，2H)，2.81-2.92(dd，2H)，3.82(t，1H)，4.00(d，1H)，4.42(d，1H)，6.60(m，2H)，6.71(s，1H).LRMS：m/z?237(M-H ⁺).

Embodiment 38

5-bromo-2-(2,5-dimethyl pyrrole-1-yl) pyridine

With 5-bromopyridine-2-base-amine (13.8g, 0.08mol), acetonyl acetone (14.1ml, 0.12mol) and right-toluenesulfonic acid (100mg) be dissolved in toluene (180ml), under Dean Stark condition, refluxed 14 hours.After the cooling, brown solution is poured in the water (200ml), with toluene extraction (2 x 200ml).Merge organic extract liquid,,, filter, concentrate in a vacuum, obtain crude product then through anhydrous magnesium sulfate drying with saline (50ml) washing.Through the silica column chromatogram purification, use ethyl acetate: pentane (1:3) eluting, obtain title compound, be the oil (18.4g, 0.073mol, 92%) of brown.

¹H?NMR(CDCl ₃，400MHz)δ：2.18(s，6H)，5.90(s，2H)，7.11(d，1H)，7.92(d，1H)，8.62(s，1H).LRMS：m/z?253(M-H ⁺，Br?isotope).

Embodiment 39

2-chloro-1-[6-(2,5-dimethyl pyrrole-1-yl) pyridin-3-yl] ethyl ketone

Under-78 ℃, to embodiment 38 described pyridine bromides (2g, anhydrous THF (30ml) solution 8.0mmol) go through dripped in 20 minutes butyl lithium (2.5M hexane solution) (3.5ml, 8.8mmol).Reactant mixture was stirred 30 minutes, and (keeping temperature is-78 ℃ for 1.2g, anhydrous THF (20ml) solution 8.8mmol) to drip 2-chloro-N-methoxyl group-N-methylacetamide then.Continuation was stirred 30 minutes under this temperature, added 1M HCl (aq) then (50ml), made reactant mixture be warmed to room temperature.Separate organic layer, water layer washs with ethyl acetate (56ml).Merge organic layer, use 3M NaOH (aq) (10ml) and saline (10ml) washing then,, filter again through anhydrous magnesium sulfate drying, concentrated in a vacuum, obtain thick title compound, be the oil (1.34g, 5.4mmol, 67%) of brown.

¹H?NMR(CDCl ₃，400MHz)δ：2.20(s，6H)，4.68(s，2H)，5.92(s，2H)，7.32(d，1H)，8.38(d，1H)，9.16(s，1H).LRMS：m/z?249(M-H ⁺).

Embodiment 40

2-(2,5-dimethyl pyrrole-1-yl)-5-oxirane yl pyridines

To be cooled to 0 ℃, embodiment 39 described ketone (1.34g, 5.4mmol) solution that is dissolved in anhydrous THF (20ml) add in batches sodium borohydride (308mg, 8.1mmol).Reactant mixture was stirred 2 hours, add 3M NaOH (aq) then (10ml), continue to stir other 16 hours.Reactant mixture merges organic extract liquid with ethyl acetate extraction (2 x 20ml), with saline (5ml) washing, through anhydrous magnesium sulfate drying, filters, and concentrates in a vacuum.Residue is used ethyl acetate through the silica column chromatogram purification: pentane (1:5) eluting, obtain title compound, and be colourless oil (900mg, 4.2mmol, 78%). ¹H?NMR(CDCl ₃，400MHz)δ：2.13(s，6H)，2.91(dd，1H)，3.25(t，1H)，3.98(t，1H)，5.90(s，2H)，7.20(d，1H)，7.62(dd，1H)，8.58(s，1H).LRMS：m/z?215(M-H ⁺)，

Embodiment 41

1-[6-(2,5-dimethyl pyrrole-1-yl) pyridin-3-yl]-2-propyl group ethylaminoethanol

(900mg, DMSO 4.2mmol) (5ml) solution add propylamine, and (4ml 4.8mmol), is heated to 40 ℃ with reactant mixture and reaches 4 days to embodiment 40 described epoxide.Then with reactant mixture cooling, add 3M HCl (aq) (10ml) and water (10ml), the reuse diethyl ether washs (2 x 10ml).Discard this organic layer.Water layer NH ₄OH (5ml) alkalization is with ethyl acetate extraction (3 x 10ml).Merge organic extract liquid,, filter, concentrate in a vacuum, obtain title compound, be oil (1.15g, 4.2mmol, 100%) through anhydrous magnesium sulfate drying.

¹H?NMR(CDCl ₃，400MHz)δ：0.93(t，3H)，1.62(m，2H)，2.11(s，6H)，2.69-2.82(m，3H)，3.06(dd，1H)，3.60(bs，2H)，4.92(dd，1H)，5.84(s，2H)，7.20(d，1H)，7.88(d，1H)，8.61(s，1H).LRMS：m/z?274(M-H ⁺).

Embodiment 42

6-[6-(2,5-dimethyl pyrrole-1-yl) pyridin-3-yl]-4-propyl group morpholine-3-ketone

Follow the method identical with embodiment 27, (1.15g 4.2mmol) begins preparation from embodiment 41 described amine.Through the silica column chromatogram purification, use dichloromethane: methanol (98:2) eluting, obtain title compound, be the film (191mg, 0.61mmol, 14%) of brown.

¹H?NMR(CDCl ₃，400MHz)δ：0.97(t，3H)，1.65(m，2H)，2.13(s，6H)，3.38(m，1H)，3.42-3.56(m，2H)，6.61(t，1H)，4.35(d，1H)，4.45(d，1H)，4.91(dd，1H)，6.91(s，2H)，7.22(d，1H)，7.89(d，1H)，8.61(s，1H).LRMS：m/z?314(M-H ⁺).

Embodiment 43

6-[6-(2,5-dimethyl pyrrole-1-yl) pyridin-3-yl]-4-propyl group morpholine

(191mg, anhydrous THF (5ml) solution 0.61mmol) add lithium aluminium hydride reduction (1M diethyl ether solution), and (1.25ml 0.61mmol), is warmed to backflow with reactant mixture and reaches 2.5 hours to embodiment 42 described morpholine-3-ketone.Reactant mixture is cooled to room temperature, adds 1MNaOH (1.25ml) then, obtain white precipitate.Reactant mixture is filtered, concentrate in a vacuum.Discard white solid.Concentrated filtrate, through the silica column chromatogram purification, use dichloromethane: methanol (95:5) eluting, obtain title compound, be the film (108mg, 0.36mmol, 59%) of white. ¹H?NMR(CDCl ₃，400MHz)δ：0.92(t，3H)，1.61(q，2H)，2.10(s，6H)，2.15(m，1H)，2.29(dt，1H)，2.40(t，2H)，2.82(d，1H)，3.02(d，1H)，3.90(t，1H)，4.08(d，1H)，4.71(d，1H)，5.89(s，2H)，7.20(d，1H)，7.81(d，1H)，8.60(s，1H).LRMS：m/z?300(M-H ⁺).

Embodiment 44A and 44B

5-(the pyridine of 4-propyl group morpholine-2-yl)-2-base amine

Described 2 to embodiment 43, (45mg, ethanol 0.15mmol) (3ml) solution add oxammonium hydrochloride., and (52mg 0.75mmol), is heated to 80 ℃ with reactant mixture and reaches 20 hours the 5-dimethyl pyrrole.Reactant mixture is cooled to room temperature, concentrates in a vacuum.Residue is used dichloromethane: methanol through the silica column chromatogram purification: ammonia (90:10:1) eluting, obtain racemic compound, and be colourless film (31mg, 0.14mmol, 94%).

¹H?NMR(CDCl ₃，400MHz)δ：0.92(t，3H)，1.60(m，2H)，2.11(t，1H)，2.25(dt，1H)，2.41(t，2H)，2.82-2.91(dd，2H)，3.89(dt，1H)，4.01(dd，1H)，4.57(bd，3H)，6.49(d，1H)，7.42(d，1H)，8.02(s，1H).LRMS：m/z?222(M-H ⁺).

This racemic product sample (580mg) is separated into its enantiomer by chirality HPLC.Used condition: Chiralpak AD post (250 x 21.2mm), eluant methanol: ethanol (1:1), flow velocity 15mL/min.

Obtain the enantiomer embodiment 44A (retention time 8.3min) of very fast eluting,〉99%ee. ¹H NMR (CDCl ₃, 400MHz) identical .LRMS:m/z 222. with racemate analyzes actual measurement C, 63.54; H, 8.60; N, 18.38%.C ₁₂H ₁₉N ₃O.3H ₂O theoretical value C, 63.58; H, 8.71; N, 18.53%.[α] ²⁵ ₅₄₆-2.1 (c=0.12, MeOH); [α] ²⁵ ₄₃₆-8.9 (c=0.12, MeOH).

Obtain the enantiomer embodiment 44B (retention time 9.4min) of slow eluting,〉98.9% ee. ¹H NMR (CDC l ₃, 400MHz) identical .LRMS:m/z 222. with racemate analyzes actual measurement C, 63.53; H, 8.57; N, 18.36%.C ₁₂H ₁₉N ₃O.3H ₂O theoretical value C, 63.58; H, 8.71; N, 18.53%.[α] ²⁵ ₅₄₆+ 2.4 (c=0.12, MeOH); [α] ²⁵ ₄₃₆+ 7.2 (c=0.12, MeOH).

Embodiment 45

2-ethyl-6-(3-methoxyl group-phenyl)-4-propyl group-morpholine-3-ketone

(0.48g, water 12.0mmol) (2ml) solution join embodiment 3 described products, and (0.50g in dichloromethane 2.4mmol) (5ml) solution, at room temperature stirs mixture with sodium hydroxide.(0.28ml 2.87mmol), stirs reactant mixture 60 hours to drip the 2-chlorobutanoylchloride then.Reactant mixture separates water layer with dichloromethane (10ml) dilution.Organic layer through anhydrous magnesium sulfate drying, is filtered, concentrates in a vacuum, obtain crude product, for clarifying oil (contain cyclisation with not the mixture of cyclisation product) (0.57g).LRMS:m/z 314 (the M-H of cyclisation product not ⁺), the 296 (M-H of low amounts of water ⁺), the 278 (M-H of cyclisation product ⁺).((0.57g is in isopropyl alcohol 1.83mmol) (5ml) solution to join crude product for 0.13g, 2.20mmol) water-soluble (1ml) with potassium hydroxide.Reactant mixture at room temperature stirred spend the night, evaporate organic solvent then in a vacuum.Residue is dissolved in ethyl acetate (10m1), separates water layer.Organic layer through anhydrous magnesium sulfate drying, is filtered, concentrate in a vacuum, obtain crude product, be oil.Residue is used ethyl acetate through the silica column chromatogram purification: pentane (1:5 to 1:1) eluting, obtain title compound, and for clarifying oil (326mg, 1.17mmol, 49%), be non-enantiomer mixture.

¹H?NMR(CDCl ₃，400MHz)δ：0.90(t，3H)，1.00(t，3H)，1.60(m，2H)，2.00(bm，2H)，3.10-3.60(m，4H)，3.80(s，3H)，4.20(d，0.5H)，4.25(d，0.5H)，4.75(d，-0.5H)，4.90(d，0.5H)，6.80(d，1H)，6.90(m，2H)，7.25(m，1H).LRMS(APCl)：m/z?278(MH ⁺)，276(MH ^-).

Embodiment 46A and 46B

2-ethyl-6-(3-methoxyl group-phenyl)-4-propyl group-morpholine

Under blanket of nitrogen, (3ml, (0.33g is in anhydrous THF (4ml) solution 1.18mmol) 3mmol) to be added drop-wise to embodiment 45 described products with borine-oxolane coordination compound (1M THF solution).Reactant mixture was heated 3 hours down at 85 ℃, and cooling then adds methanol (1ml) quencher.Concentrated reaction mixture in a vacuum then, with residue be suspended in 6N HCl (aq) (10ml) in, be heated to 60 ℃ and reach 1.5 hours.With the reactant mixture cooling, with diethyl ether extraction (2 x 10ml).Add solid carbonic acid potassium to water layer and make it to be alkalescence (pH 9-10), extract (2 x 15ml) again with dichloromethane then.Dichloromethane extraction liquid through anhydrous magnesium sulfate drying, is filtered, concentrate in a vacuum, obtain crude product, be clarifying oil.Through the silica column chromatogram purification, use ethyl acetate: pentane (1:10) eluting, obtain two kinds of title compounds, be single diastereomer.

Embodiment 46A: clarifying oil (0.10g, 0.38mmol, 32%):

¹H?NMR(CDCl ₃，400MHz)δ：1.00(m6H)，1.60(bm，3H)，1.85(m，1H)，2.25(bt，2H)，2.35(s，1H)，2.45(m，1H)，2.60(m，1H)，2.65(m，1H)，3.70(s，1H)，3.80(s，3H)，4.80(s，1H)，6.80(d，1H)，7.00(m，2H)，7.25(m，1H).LRMS(APCl)：m/z?264(M-H ⁺).

Embodiment 46B: clarifying oil (0.10g, 0.38mmol, 32%):

¹H?NMR(CDCl ₃，400MHz)δ：0.90(t，3H)，1.00(t，3H)，1.60(bm，4H)，1.80(bs，1H)，2.00(bs，1H)，2.35(bs，2H)，2.85(bd，1H)，2.95(bd，1H)，3.60(s，1H)，3.80(s，3H)，4.60(s，1H)，6.80(d，1H)，6.95(s，2H)，7.25(t，1H).LRMS(APCl)：m/z?264(MH ⁺).

Embodiment 47A

3-(6-ethyl-4-propyl group-morpholine-2-yl)-phenol

(48% aq., 5ml) (0.10g 0.38mmol) heated 16 hours down at 80 ℃ with the described product of embodiment 46A with hydrobromic acid.After the cooling, concentrated reaction mixture in a vacuum.Make residue ammonia (0.880, distribute 15ml) and between the dichloromethane (15ml), separate each layer, water layer extracts (2 x 15ml) again with dichloromethane.Merge the organic layer extract,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is used dichloromethane, reuse dichloromethane through the silica column chromatogram purification: methanol (99:1 to 95:5) eluting, obtain title compound, and for clarifying oil (65mg, 0.26mmol, 69%), be single diastereomer.

¹H NMR (CDCl ₃, 400MHz) δ: 0.95 (m 6H), 1.60 (m, 3H), 1.85 (m, 1H), 2.25 (m, 2H), 2.45 (m, 2H), 2.55 (q, 1H), 2.75 (d, 1H), 3.75 (s, 1H), 4.80 (m, 1H), 6.70 (d, 1H), 6.90 (s, 1H), 7.00 (1H, d), 7.25 (t, 1H) .LRMS (APCl): m/z 250 (MH ⁺). analyze measured value C, 70.94%; H, 9.16%; N, 5.53%.C ₁₅H ₂₃NO ₂.0.3H ₂O theoretical value C, 70.72%; H, 9.34%; N, 5.50%.

Embodiment 47B

3-(6-ethyl-4-propyl group-morpholine-2-yl)-phenol

Follow the method identical with embodiment 47A, (0.10g 0.38mmol) begins preparation from the described product of embodiment 46B.Need not through the silica column chromatogram purification.Obtain title compound,, be single diastereomer for xanchromatic oil (57mg, 0.23mmol, 60%).

¹H NMR (CDCl ₃, 400MHz) δ: 0.90 (t, 3H), 1.00 (t, 3H), 1.60 (m, 4H), 1.85 (t, 1H), 2.00 (t, 1H), 2.35 (m, 2H), 2.90 (d, 1H), 3.00 (d, 1H), 3.65 (m, 1H), 4.60 (m, 1H), 6.75 (d, 1H), 6.80 (s, 1H), 6.90 (1H, d), 7.20 (t, 1H) .LRMS (ESI): m/z 250 (MH ⁺), 248 (M-H ^-). analyze measured value found C, 71.63%; H, 9.19%; N, 5.55%.C ₁₅H ₂₃NO ₂.0.1H ₂O theoretical value C, 71.73%; H, 9.31%; N, 5.58%.

Embodiment 48

2-methyl-6-(3-methoxyl group-phenyl)-4-propyl group-morpholine-3-ketone

Follow the method identical with embodiment 45, from embodiment 3 described products (0.44g, 2.10mmol) and the 2-chlorpromazine chloride (0.25ml 2.50mmol) begins preparation.Title compound be need not through the silica column chromatogram purification.Obtain title compound,, be the mixture of diastereomer for clarifying oil (0.42g, 1.60mmol, 76%). ¹H?NMR(CDCl ₃，400MHz)δ：0.95(t，3H)，1.60(m，5H)，3.30(bm，2H)，3.50(bm，2H)，3.80(s，3H)，4.40(q，0.5H)，4.55(q，0.5H)，4.80(dd，0.5H)，4.95(dd，0.5H)，6.85(d，1H)，6.95(s，2H)，7.25(m，1H).LRMS(APCl)：m/z?264(MH ⁺)，262(MH ^-).

Embodiment 49A and 49B

2-methyl-6-(3-methoxyl group-phenyl)-4-propyl group-morpholine

Follow the method identical with embodiment 46, (0.42g 1.6mmol) begins preparation from embodiment 48 described products.Through the silica column chromatogram purification, use ethyl acetate: pentane (1:6) eluting, obtain two kinds of title compounds, be single diastereomer.

Embodiment 49A: clarifying oil (0.10g, 0.40mmol, 25%):

¹H?NMR(CDCl ₃，400MHz)δ：0.95(t?3H)，1.30(d，3H)，1.60(m，2H)，2.20-2.35(m，3H)，2.50(d，1H)，2.60(m，1H)，2.65(d，1H)，3.80(s，3H)，4.00(s，1H)，4.85(s，1H)，6.80(d，1H)，7.05(m，2H)，7.25(m，1H).LRMS(APCl)：m/z?250(MH ⁺).

Embodiment 49B: clarifying oil (0.10g, 0.40mmol, 25%):

¹H?NMR(CDCl ₃，400MHz)δ：0.90(t?3H)，1.25(m，3H)，1.60(m，2H)，1.80(m，1H)，2.00(bm，1H)，2.35(s，2H)，2.80(d，1H)，2.90(d，1H)，3.80(s，3H)，3.85(s，1H)，4.60(s，1H)，6.80(d，1H)，7.00(m，2H)，7.25(m，1H).LRMS(APCl)：m/z?250(MH ⁺).

Embodiment 50A

3-(6-methyl-4-propyl group-morpholine-2-yl)-phenol

Follow the method identical with embodiment 47A, (0.10g 0.4mmol) begins preparation from embodiment 49A product.Through the silica column chromatogram purification, use dichloromethane, reuse dichloromethane: methanol (99:1) eluting, obtain title compound, for clarifying oil (70mg, 0.30mmol, 74%), be single diastereomer.

¹H NMR (CDCl ₃, 400MHz) δ: 0.95 (t, 3H), 1.35 (d, 3H), 1.55 (m, 2H), 2.25 (m, 2H), 2.35 (m, 1H), 2.50 (m, 1H), 2.55 (m, 1H), 2.75 (d, 1H), 4.05 (s, 1H), 4.85 (m, 1H), 6.70 (d, 1H), 6.90 (s, 1H), 7.00 (1H, d), 7.20 (t, 1H) .LRMS (APCl): m/z 236 (MH ⁺). analyze measured value C, 70.62%; H, 8.89%; N, 5.95%.C ₁₄H ₂₁NO ₂.0.1H ₂O theoretical value C, 70.91%; H, 9.01%; N, 5.91%.

Embodiment 50B

3-(6-methyl-4-propyl group-morpholine-2-yl)-phenol

Follow the method identical with embodiment 47A, (0.10g 0.4mmol) begins preparation from the described product of embodiment 49B.Need not through the silica column chromatogram purification.Obtain title compound,, be single diastereomer for xanchromatic oil (100mg, 0.42mmol, 103%-contain 3% raw material). ¹H NMR (CDCl ₃, 400MHz) δ: 0.90 (t, 3H), 1.25 (d, 3H), 1.60 (m, 2H), 1.85 (m, 1H), 2.00 (m, 1H), 2.35 (m, 2H), 2.85 (d, 1H), 3.00 (d, 1H), 3.85 (s, 1H), 4.60 (d, 1H), 6.75 (d, 1H), 6.80 (s, 1H), 6.90 (1H, d), 7.20 (m, 1H) .LRMS (APCl): m/z 236 (MH ⁺). analyze measured value C, 69.38%; H, 8.86%; N, 5.73%.C ₁₄H ₂₁NO ₂.0.45H ₂O theoretical value C, 69.33%; H, 9.06%; N, 5.78%.

Embodiment 51

1-(4-chloro-3-methoxyl group-phenyl)-2-propyl group amino-ethanol

With sodium triacetoxy borohydride (1.25g, 5.89mmol) join 2-amino-1-(4-chloro-3-methoxyl group-phenyl)-ethanol (J.Med.Chem. carefully, 30 (10), 1887, (1987)) (600mg, 2.98mmol) (0.22ml in dichloromethane 2.96mmol) (10ml) solution, at room temperature stirred reactant mixture 1 hour with propionic aldehyde.(saturated aqueous solution 10ml), dilutes further water of reactant mixture (20ml) and dichloromethane (20ml) then to drip sodium bicarbonate solution.Separate water layer, extract (2 x 20ml) again with dichloromethane.Merge organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is used dichloromethane: methanol through the silica column chromatogram purification: 0.880 ammonia (95:5:0.5 to 92:8:0.8) eluting, obtain title compound, and be solid (320mg, 1.31mmol, 44%).

¹H?NMR(CDCl ₃，400MHz)δ：0.90(t，3H)，1.50(q，2H)，2.50-2.70(m，5H)，2.90(dd，1H)，3.80(s，3H)，4.65(dd，1H)，6.85(d，1H)，7.00(1H，d)，7.30(bd，1H).LRMS(APCl)：m/z?244(MH ⁺)，226(MH ⁺?less?H ₂O).

Embodiment 52

6-(4-chloro-3-methoxyl group-phenyl)-4-propyl group-morpholine-3-ketone

(0.11ml, (0.31g, 1.27mmol) (0.19ml in dichloromethane 1.36mmol) (10ml) solution, at room temperature stirred 60 hours with triethylamine 1.33mmol) to join embodiment 51 described products with chloracetyl chloride.With reactant mixture with dichloromethane (20ml) dilution, with hydrochloric acid (aq.1N, 10ml), water (10ml) and sodium bicarbonate solution (saturated aqueous solution, 10ml) washing.Organic layer through anhydrous magnesium sulfate drying, is filtered, concentrate in a vacuum, obtain not cyclisation product, be oil (0.40g).LRMS (APCI): the m/z 320 (MH of cyclisation product not ⁺), the 302 (MH of low amounts of water ⁺), the 284 (MH of cyclisation product ⁺).(0.75g 1.33mmol) joins not cyclisation product and (among the 0.40g, isopropyl alcohol 1.23mmol) (10ml) and water (0.4ml) solution, at room temperature stirred 16 hours with potassium hydroxide.Concentrated reaction mixture distributes between dichloromethane (30ml) and water (30ml) in a vacuum.Separate each layer, water layer extracts (2 x 20ml) again with dichloromethane.Merge organic layer, water (30ml) washing through anhydrous magnesium sulfate drying, is filtered, and concentrates in a vacuum, obtains title compound, is oil (0.34g, 1.19mmol, 94%). ¹H?NMR(CDCl ₃，400MHz)δ：0.95(t，3H)，1.60-1.70(m，2H)，3.30-3.40(m，2H)，3.40-3.55(m，2H)，3.95(s，3H)，4.35(bd，1H)，4.42(bd，1H)，4.78(dd，1H)，6.85(dd，1H)，7.00(s，1H)，7.38(dd，1H).LRMS(APCl)：m/z?284(MH ⁺).

Embodiment 53

6-(4-chloro-3-methoxyl group-phenyl)-4-propyl group-morpholine

Under blanket of nitrogen, (3.5ml, (0.33g is in anhydrous THF (3ml) solution 1.16mmol) 3.5mmol) to be added drop-wise to embodiment 52 described products with borine-oxolane coordination compound (1M THF solution).With reaction mixture refluxed 2.5 hours, cooling then added methanol (1ml) quencher.Concentrated reaction mixture in a vacuum, with residue be suspended in 4N HCl (aq., 8ml) in, refluxed 2 hours.With the reactant mixture cooling, with dichloromethane extraction (2 x 10ml).Discard organic layer.Add solid carbonic acid potassium to water layer and make it to be alkalescence (pH 9-10), extract (2 x 15ml) again with dichloromethane then.With dichloromethane extraction liquid water (10ml) washing, through anhydrous magnesium sulfate drying, filter, concentrate in a vacuum, obtain title compound, be oil (0.31g, 1.15mmol, 99%). ¹H?NMR(CDCl ₃，400MHz)δ：0.95(t，3H)，1.45-1.60(m，2H)，2.00(t，1H)，2.20(t，1H)，2.35(t，2H)，2.80(d，1H)，2.90(d，1H)，3.80(t，1H)，3.90(s，3H)，4.03(dd，1H)，4.55(d，1H)，6.85(dd，1H)，7.00(s，1H)，7.30(dd，1H).LRMS(APCl)：m/z?270(MH ⁺).

Embodiment 54

2-chloro-5-(4-propyl group-morpholine-2-yl)-phenol

Follow the method identical with embodiment 7b (continuing 2.5 hours but not 1 hour but reflux), (0.28g 1.02mmol) begins preparation from embodiment 53 described products.Need not through the silica column chromatogram purification.Obtain title compound, be filbert natural gum (0.21g, 0.82mmol, 81%). ¹HNMR (CDCl ₃, 400MHz) δ: 0.93 (t, 3H), 1.55 (q, 2H), 2.0 (t, 1H), 2.20 (dt, 1H), 2.30-2.40 (m, 2H), 2.80 (bd, 1H), 2.90 (bd, 1H), 3.80 (dt, 1H), 4.0 (dd, 1H), 4.30 (d, 1H), 6.87 (dt, 1H), 7.02 (fd, 1H), 7.25 (s, 1H) .LRMS (APCl): m/z 256 (MH ⁺). analyze measured value C, 60.71%; H, 7.10%; N, 5.45%.C ₁₃H ₁₈NO ₂Cl theoretical value C, 61.05%; H, 7.09%; N, 5.48%.

Embodiment 55

(2S)-2-(propionamido) methyl propionate

(14g 0.1mol) is dissolved in dichloromethane (150ml), and (30.45g 0.3mmol) handles with triethylamine with L-methyl lactamine hydrochlorate.Stir this solution, drip propionyl chloride.After stirring is spent the night, add 1M hydrochloric acid (200ml) quencher, separate organic layer to mixture.Water layer extracts (3 x 200ml) again with dichloromethane, merges organic layer, uses dried over mgso, filters, and evaporation obtains clarifying oil (16.0g, quantitative).

¹H?NMR(DMSO-d6，400MHz)δ：0.95(t，3H)，1.25(d，3H)，2.1(q，2H)，3.6(s，3H)，4.2(quin，1H)，8.2(bd，1H).LRMS(ESI+)m/z?160(MH ⁺)

Embodiment 56

(1S)-2-hydroxyl-1-Methylethyl (propyl group) carbamic acid tertiary butyl ester

Embodiment 55 described products are dissolved in oxolane (200ml), at room temperature to the solution that stirring add borine-oxolane coordination compound (300ml, 0.3mol).Then with mixture heated overnight under refluxing.After being cooled to room temperature, add 6M hydrochloric acid (100ml) carefully with the quencher reaction to reactant, being heated to then refluxes reaches 6 hours.Make reactant mixture be cooled to ambient temperature overnight, be evaporated to dried (11.77g) then.The m/z of crude mixture is 118, and is consistent with required amino alcohol intermediate.Then crude mixture is dissolved in methanol (50ml) and water (400ml), add again potassium hydroxide (28.22g, 0.5mol).(32.87g 0.15mol), continues to stir 3 days to add Bis(tert-butoxycarbonyl)oxide to mixture.Reactant mixture is distributed between DCM (500ml) and water (100ml), separate organic layer, water layer is with DCM extracting twice again.Merge organic moiety, use dried over mgso, filter, evaporation obtains crude product.Through SiO ₂Purification by flash chromatography is used dichloromethane: methanol: 880 NH ₃(97:3:0.3) eluting obtains required product (for clarifying oil (4.5g, 21%)), and the other partially purified product of 10g.

¹H?NMR(DMSO-d6，400MHz)δ：0.8(t，3H)，1.05(bs，3H)，1.4(m，11H)，2.95(bs，2H)，3.35(bm，3H)，4.6(bs，1H)LRMS(ESI+)m/z?240(MNa ⁺)

Embodiment 57

(2S)-2-(propyl group amino) third-1-alcohol hydrochloride

(4.2g 0.021mol) is dissolved in diox (10ml), handles with 4M HCl De dioxane solution (30ml) with embodiment 56 described pure products.Mixture was at room temperature stirred 16 hours, and evaporation obtains white solid (2.74g, 92%) then.

¹H?NMR(DMSO-d6，400MHz)δ：0.9(t，3H)，1.15(d，3H)，1.6(m，2H)，2.8(m，2H)，3.15(m，1H)，3.5(bm，1H)，3.6(m，1H)，5.4(bs，1H)，8.8(bd，2H).LRMS(APCl+)118(MH ⁺)

Embodiment 58

(5S)-2-(3-methoxyphenyl)-5-methyl-4-propyl group morpholine-2-alcohol

With embodiment 57 described products (1.0g 6.6mmol) is dissolved in toluene (10ml), with triethylamine (1.38g 14mmol) handles, add then 2-bromo-3 '-methoxyacetophenone (1.5g, 6.6mmol).With mixture heated to 65 ℃, stirred 3 days.After being cooled to room temperature, mixture is distributed between saline and ethyl acetate, separate organic layer, use dried over mgso, filter, evaporation.Residue is through SiO ₂Purification by flash chromatography is used eluent ethyl acetate, obtains required morpholine alcohol (morpholinol) chemical compound, is the mixture of stereoisomer, light yellow oil (1.0g, 58%).

¹H?NMR(DMSO-d6，400MHz)δ：0.8(m，3H)，0.95(d，3H)，1.35(m，2H)，2.1(m，2H)，2.4(bm，1H)，2.6(m，1H)，2.75(m，1H)，3.5(d，1H)，3.75(m，4H)，6.0(s，0.75H)，6.1(s，0.25H)，6.85(d，1H)，7.05(m，2H)，7.25(t，1H).LRMS(ESI+)m/z?248(M-H2O)，266(MH ⁺)，288(MNa+)

Embodiment 59

(5S)-2-(3-methoxyphenyl)-5-methyl-4-propyl group morpholine

(770mg 2.9mmol) is dissolved in dichloromethane (20ml), is cooled to-78 ℃ under blanket of nitrogen with embodiment 58 described products.To the mixture that stirring add triethyl silicane (3.7ml, 23mmol), add then the trimethylsilyl triflate (1.1ml, 5.8mmol).Continue to stir and spend the night, make reactant mixture reach room temperature.Add saturated sodium bicarbonate aqueous solution to reactant and react, with dichloromethane extraction (three times) with quencher.Merge organic layer, use dried over mgso, filter, evaporation.Crude product is through SiO ₂Purification by flash chromatography, use dichloromethane: methanol: 880 ammonia (97:3:0.3) eluting obtains required morpholinium compound (600mg, 83%).

¹H?NMR(CDCl ₃，400MHz)δ：0.95(m，3H)，1.1(b，d，3H)，1.6(bm，2H)，2.2-3.1(5H)，3.5(bm，1H)，4.85(m，4H)，4.6(b，1H)，6.8(d，1H)，6.95(m，2H)，7.25(m，1H+CHCl ₃)

LRMS(APCl+)m/z?250(MH ⁺)

Analyze measured value C, 71.53%; H, 9.21%; N, 5.55%.C ₁₅H ₂₃NO ₂.0.15H ₂O theoretical value C, 71.48%; H, 9.32%; N, 5.56%.

Embodiment 60

3-[(5S)-and 5-methyl-4-propyl group morpholine-2-yl] phenol

(400mg 1.6mmol) is dissolved in 48% hydrobromic acid aqueous solution (8ml), and mixture heated to 80 ℃ is spent the night with embodiment 59 described products.After being cooled to room temperature, add saturated sodium bicarbonate aqueous solution quencher reaction, mixture dichloromethane extraction (three times) to mixture.Merge organic layer, use dried over mgso, filter, evaporation obtains product, is white solid (285mg, 76%).

¹H?NMR(CDCl ₃，400MHz)δ：0.9(m，3H)，1.1+1.2(2xd，3H)，1.5(m，2H)，2.3(m，2H)，2.5(bm，1H)，2.8(bm，1H)，3.1(d，1H)，3.5(bm，1H)，3.85(bm，1H)，4.6(d，1H)，6.8(m，2H)，6.95(m，1H)，7.2(t，1H)

LRMS(APCl+)，236(MH ⁺)

Analyze measured value C, 70.61%; H, 9.00%; N, 5.86%.C ₁₄H ₂₁NO ₂.0.1H ₂O theoretical value C, 70.91%; H, 9.01%; N, 5.91%.

On Chiralcel 0J-H (250*21.2mm) HPLC post, separate this non-enantiomer mixture.Mobile phase 100% MeOH, flow velocity 15ml/min.200mg is dissolved in 4ml MeOH, and the preparation sample is injected 250 μ L.Obtain two main peaks, retention time is 5.822min (embodiment 60A, 57mg 28%) and 7.939min (embodiment 60B, 12mg, 6%).

Embodiment 60A: ¹HNMR (CDCl ₃, 400MHz) δ: 0.85 (t, 3H), 1.05 (d, 3H), 1.5 (m, 2H+H ₂O), 2.2 (m, 2H), 2.4 (m, 1H), 2.8 (m, 1H), 3.0 (d, 1H), 3.4 (t, 1H), 3.9 (dd, 1H), 4.55 (d, 1H), 5.6 (bs, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 6.95 (d, 1H), 7.2 (t, 1H)

HRMS?m/z?236.1643(MH ⁺)

Embodiment 60B: ¹H NMR (CDCl ₃, 400MHz) δ: 0.95 (t, 3H), 1.15 (d, 3H), 1.55 (m, 2H), 2.4 (m, 2H), 2.55 (t, 1H), 2.65 (dd, 1H), 2.95 (bm, 1H), 3.8 (d, 1H), 3.95 (d, 1H), 4.55 (dd, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 6.95 (d, 1H), 7.2 (t, 1H)

HRMS?m/z?236.1643(MH ⁺)

Embodiment 61

(S)-2-propyl group amino-third-1-alcohol hydrochloride

(19.6g, dichloromethane 0.26mol) (500ml) solution add propionic aldehyde, and (20.9ml 0.28mol), adds 4A molecular sieve (40g) pre-dried, through pulverizing then, mixture is at room temperature stirred spend the night to (S)-(+)-2-amino-1-propanol.Mixture is filtered by the celite pad, use the washed with dichloromethane mat, evaporating solvent obtains clarifying oil.This oil is dissolved in methanol (200ml), goes through and added NaBH in 15 minutes in batches ₄Mixture at room temperature stirred spend the night, add (200ml) quencher reaction of 2M HCl (aq) then carefully, add 2M NaOH (200ml) alkalization, methanol is removed in evaporation.(115g 0.52mol), adds 1 then, and 4-diox (200ml) at room temperature stirs mixture and to spend the night to add Bis(tert-butoxycarbonyl)oxide.Evaporation removes 1, and the 4-diox obtains clarifying oil.Add 1 of 4M HCl to this oil, 4-dioxane solution (200ml) at room temperature stirs mixture and to spend the night.Evaporation removes and desolvates, and obtains white solid (24g).

¹H?NMR(DMSO，400MHz)δ：0.95(t，3H)，1.2(d，3H)，1.6(m，2H)，2.8(m，2H)，3.15(m，1H)，3.5(bm，1H)，3.6(m，1H)，5.4(b，1H)，8.6-8.9(bd，2H)

LRMS(APCl+)，118(MH ⁺)

Embodiment 62

(5S)-4-propyl group-5-methyl morpholine-2-ketone

With embodiment 61 products (4g 26mmol) is dissolved in benzene, succeeded by add the N-ethyl diisopropylamine (9.07ml, 52mmol) and methyl bromoacetate (2.4ml, 26mmol).Mixture heated is spent the night to refluxing, simultaneously azeotropic removal of water.Evaporation removes and desolvates, and crude product is dissolved in methanol, and preadsorption is to SiO ₂On, through SiO ₂Flash chromatography is handled, and with 40% EtOAc/ pentane eluting, obtains morpholone shown in the title, is clarifying oil (1.78g).

¹H?NMR(CDCl ₃，400MHz)δ：0.9(t，3H)，1.1(d，3H)，1.5(m，2H)，2.25(m，1H)，2.6(m，1H)，2.8(m，1H)，3.2(d，1H)，3.6(d，1H)，4.05(dd，1H)，4.3(dd，1H)t.l.c.Rf＝0.18(50％?EtOAc/Pentane，UV?visualisation)

Embodiment 63

(5S)-2-[6-(2,5-dimethyl-1H-pyrroles-1-yl) pyridin-3-yl]-4-propyl group-5-methyl morpholine-2-alcohol

With 5-bromo-2-(2,5-dimethyl-pyrroles-1-yl)-pyridine (1.5g5.9mmol) and methylbenzene azeotropic, be dissolved in THF (20ml).This mixture is cooled to-78 ℃, and (11.9mmol), holding temperature is lower than-70 ℃ simultaneously for 1.7M pentane solution, 7ml to add tert-butyl lithium.Embodiment 62 products are dissolved in THF (20ml), join in the mixture immediately after adding tert-butyl lithium.Mixture was stirred 30 minutes down at-78 ℃, add NH this moment ₄(10% aq 150ml), with EtOAc (200ml) extraction, uses dried over mgso with mixture to Cl, filters evaporation.Through SiO ₂Flash chromatography is handled, and with 25% EtOAc/ pentane to 50% EtOAc/ pentane substep gradient elution, obtains title compound, is the mixture of diastereomer, and the about 3.5:1 of ratio is xanchromatic oil (480mg).

¹H NMR (CDCl ₃, 400MHz) (diastereomer) δ: 0.95 (m, 3H), 1.1,1.2 (2xd, 3H) 1.5 (m, 2H), 2.15 (s, 6H), 2.4 (m, 1H), 2.5 (d, 1H), 2.6 (m, 1H), 2.75 (m, 1H) 3.85-3.95 (m, 1H), 3.6,3.75,4.4 (3xm, 2H), 5.15 (bs, 1H), 5.9 (s, 2H), 7.2 (d, 1H), 8.05 (dd, 1H), 8.8 (s, 1H)

LRMS(ES+)，330(MH ⁺)，352(MNa+)

LRMS(ES-)，328(M-H)

Embodiment 64

(2S)-2-[{ (2RS)-2-[6-(2,5-dimethyl-1H-pyrroles-1-yl) pyridin-3-yl]-the 2-hydroxyethyl } propyl group] amino] third-1-alcohol

With (5S)-2-[6-(2,5-dimethyl-1H-pyrroles-1-yl) pyridin-3-yl]-(480mg 1.45mmol) is dissolved in ethanol (5ml) and water (2ml) to 4-propyl group-5-methyl morpholine-2-alcohol, and (220mg 5.8mmol) handles with sodium borohydride.Reactant mixture at room temperature stirred spend the night, add saturated NH then ₄Cl aqueous solution (50ml) quencher reaction is with ethyl acetate extraction (2 x100ml).Merge organic extract liquid, use MgSO ₄Drying, evaporation obtains 400mg fine hair shape white solid, need not to be further purified and can use.

¹H NMR (CDCl ₃, 400MHz) diastereomer δ: 0.8-1.1 (m, 6H), 1.15,1.35 (2xd, 3H), 1.6-2.0 (m, 2H) 2.1 (s, 6H), 2.5-4.05 (m, 7H), 4.8-5.2 (m, 1H), 5.9 (s, 2H), 7.2 (m, 1H), 7.8-8.1 (m, 1H), 8.55 (m, 1H).

LRMS(ES+)，332(MH ⁺)

Embodiment 65

(2S)-2-[[(2RS)-and 2-(6-aminopyridine-3-yl)-2-hydroxyethyl] (propyl group) amino] third-1-alcohol

With (2S)-2-[[(2RS)-2-(6-aminopyridine-3-yl)-2-hydroxyethyl] (propyl group) amino] (400mg 1.2mmol) is dissolved in EtOH (5ml) to third-1-alcohol, and (419mg 6mmol), ℃ spends the night mixture heated to 80 to add oxammonium hydrochloride..Remove under vacuum and desolvate, residue is through SiO ₂Purification by flash chromatography with methylene chloride/880 ammonia (95:5:0.5, polarity increases to 93:7:1) eluting, obtains title compound, is the mixture (300mg, 98%) of diastereomer.

¹H NMR (CDCl ₃, 400MHz) (2 kinds of diastereomers) δ: 0.82-0.97 (6H, m), 2.40-2.77 (2H, m), 3.27-3.51 (2H, m), 4.51 (1H, m), 6.58 (1H, m), 7.49 (1H, m), 7.86 (1H, m)

LRMS(APCl+)，254(MH ⁺)

Embodiment 66 and 67

5-[(2S, 5S)-5-methyl-4-propyl group morpholine-2-yl] pyridine-2-amine

With

5-[(2R, 5S)-5-methyl-4-propyl group morpholine-2-yl] pyridine-2-amine

(300mg 1.2mmol) is dissolved in dichloromethane (3ml), adds concentrated sulphuric acid (3ml) with embodiment 65 " glycol ".Mixture was at room temperature stirred 3 hours.Reactant is cooled to 0 ℃, adds 6M sodium hydroxide solution quencher reaction carefully, use dichloromethane extraction (4 x50ml) then.Combining extraction liquid, dry (MgSO ₄), evaporation obtains the brown colloidal solid.Through SiO ₂Purification by flash chromatography, with the eluent ethyl acetate that contains 10% methanol, obtain the 5mg enrichment product of low pole diastereomer (about 80% d.e.), 12mg enrichment about 1:1 mixture (total recovery 167mg, 59%) of the product of low pole diastereomer (about 80% d.e.) and 150mg diastereomer.Make latter 1:1 mixture through Chiralpak OD-H post (250 x 21.2mm) HPLC purification, with methanol/ethanol (1:1) eluting.

Obtain the diastereomer (retention time 8.1min) of very fast eluting,〉99% d.e. (60mg, 21%).

¹H?NMR(CDCl ₃，400MHz)0.88(3H，t)，1.01(3H，d)，1.26(3H，t)，1.37-1.58(2H，m)，2.18-2.28(2H，m)，2.36-2.47(1H，m)，2.69-2.77(1H，m)，2.90(1H，m)，3.38(1H，m)，3.72(2H，d)，3.82(1H，m)，4.40(2H，brs)，4.45(1H，dd)，6.48(1H，d)，7.45(1H，dd)，8.04(1H，d)

LRMS(ES ⁺)：m/z236(MH ⁺)

46.28(c0.13，MeOH)

Obtain the diastereomer (retention time 10.5min) of slow eluting,〉99% d.e. (62mg, 22%). ¹H?NMR(CDCl ₃，400MHz)0.93(3H，t)，1.11(3H，d)，1.49(2H，m)，2.38(2H，m)，2.50-2.56(2H，m)，2.89(1H，m)，3.75(1H，m)，3.89(1H，m)，4.40(2H，brs)，4.46(1H，m)，6.50(1H，d)，7.50(1H，dd)，8.07(1H，d)

LRMS(ES ⁺)：m/z?236(MH ⁺)

22.58(c?0.13，MeOH)

Claims

1, formula (I), (Ia) or (Ib) chemical compound

Wherein:

A is N,

B is selected from C-Y and N,

R ¹Be selected from H and (C ₁-C ₆) alkyl,

R ²Be selected from H and (C ₁-C ₆) alkyl,

Y is selected from H, HO, NH ₂, Br, Cl and F,

Z is selected from H, HO, F, CONH ₂And CN;

Or its pharmaceutically acceptable salt or solvate.

2, as claim 1 formula required for protection (I), (Ia) or (Ib) chemical compound, wherein B is C-Y.

3, as claim 1 or 2 formulas required for protection (I), (Ia) or (Ib) chemical compound, wherein R ¹Be H, methyl or ethyl.

4, as claim 1 or 2 formulas required for protection (I), (Ia) or (Ib) chemical compound, wherein R ²Be H or methyl.

5, as claim 1 or 2 formulas required for protection (I), (Ia) or (Ib) chemical compound, wherein Y is H, NH ₂, Cl or F.

6, as claim 1 or 2 formulas required for protection (I), (Ia) or (Ib) chemical compound, wherein Z is H, HO or F.

7, according to the chemical compound of claim 1, it is

5-(the pyridine of 4-propyl group morpholine-2-yl)-2-base amine;

5-[(2S, 5S)-5-methyl-4-propyl group morpholine-2-yl] pyridine-2-amine;

5-[(2R, 5S)-5-methyl-4-propyl group morpholine-2-yl] pyridine-2-amine;

Or its pharmaceutically acceptable salt or solvate.

8; as each formula required for protection (I) of claim 1-7; (Ia) or (Ib) purposes of chemical compound in the sanatory medicine of preparation, described disease is selected from: sexual dysfunction; hypertension; neural degeneration; depressed; generalized anxiety disorder; phobia; psychentonia syndrome after the wound; escape personality disorder; eating disorders; fat; chemicals relies on; pain; Alzheimer; obsession; Panic disorder; dysmnesia; parkinson; dyshormonia; vasospasm; cerebellar ataxia; gastrointestinal tract disorder; schizoid negative symptom; premenstrual tension syndrome; fibromyalgia syndrome; the tonicity urinary incontinence; Tourette's syndrome; trichotillomania; kleptomania; attention-deficit hyperactivity disease; emotional instability; pathologic is cry and shout; sleep disorder; and shock.

9, as claim 8 purposes required for protection, wherein said sexual dysfunction is female sexual disorder or male erectile dysfunction.

10, as claim 9 purposes required for protection, wherein said sexual dysfunction is a male erectile dysfunction.

11, as claim 9 purposes required for protection, wherein said female sexual disorder is the very few disease of women's libido, sexual arousal dysfunction, orgasm disorder and sexual anhedonia disease.

12, as claim 9 purposes required for protection, wherein said female sexual disorder is female sexual arousal disorder and the very few disease of following of libido.

13, as claim 8 purposes required for protection, wherein said disease is neural degeneration and depression.

14, as claim 8 purposes required for protection, wherein said disease is a pain.

15, as claim 14 purposes required for protection, wherein said pain is chronic paroxysmal hemicrania.

16, as claim 8 purposes required for protection, wherein said sleep disorder is for dampinging off.

17, a kind of compositions wherein contains just like each formula required for protection (I) of claim 1-7, (Ia) or (Ib) chemical compound and pharmaceutically acceptable diluent or carrier.