CN1243723C - N-phenylpropylcyclopentyl substituted glutaramide derivatives as NEP inhibitors of FSAD - Google Patents

N-phenylpropylcyclopentyl substituted glutaramide derivatives as NEP inhibitors of FSAD Download PDF

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CN1243723C
CN1243723C CNB028054091A CN02805409A CN1243723C CN 1243723 C CN1243723 C CN 1243723C CN B028054091 A CNB028054091 A CN B028054091A CN 02805409 A CN02805409 A CN 02805409A CN 1243723 C CN1243723 C CN 1243723C
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methyl
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alkyl
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CN1492852A (en
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S·夏伦戈
A·S·库克
A·T·吉尔莫
D·S·米德勒顿
D·C·普瑞德
A·斯托比
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Pfizer Inc
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Abstract

The present invention relates to compounds of formula wherein R is1Is optionally substituted C1-6Alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, hydrogen, C1-6Alkoxy, -NR2R3or-NR4SO2R5(ii) a X is a linker- (CH)2)n-or- (CH)2)q-O- (wherein Y is attached to oxygen); wherein one or more hydrogen atoms in the linker X may be independently replaced by C1-4Alkoxy, hydroxy (C)1-3Alkyl group), C3-7Cycloalkyl, carbocyclyl, heterocyclyl, or C optionally substituted by one or more fluoro or phenyl groups1-4Alkyl substitution; n is 3, 4, 5, 6 or 7; q is 2, 3, 4, 5 or 6; y is phenyl or pyridyl, each of which may be substituted, or two R on adjacent carbon atoms8The radicals together with the interconnecting carbon atomsA fused, optionally substituted 5 or 6 membered carbocyclic or heterocyclic ring may be formed.

Description

The glutaramide derivatives that replaces as the N-hydrocinnamyl cyclopentyl of the nep inhibitor of FSAD
The present invention relates to intermediate that uses in neutral endopeptidase (NEP) inhibitor, its application, its preparation method, its preparation and the composition that contains this inhibitor.These inhibitor have effectiveness in multiple treatment field, these treatment fields comprise masculinity and femininity sexual dysfunction, particularly Female sexual dysfunction (FSD), wherein FSD female sexual arousal disorder (FSAD) especially.
Nep inhibitor is disclosed among WO 91/07386 and the WO 91/10644.
EP1 097 719-A1 discloses the purposes that nep inhibitor is used for the treatment of FSD.
According to first aspect, the invention provides available salt, solvate, polymorphic form or prodrug on the compound of molecular formula (I) and its medicine;
Figure C0280540900091
Wherein
R 1Be the C that can be replaced by one or more substituting groups 1-6Alkyl, substituting group can be for being selected from down the identical or different group that compiles a name list: halogen, hydroxyl, C 1-6Alkoxyl group, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkoxyl group, carbocylic radical (C preferably 3-7Cycloalkyl, C 3-7Cycloalkenyl group (cycloalkenyl) or phenyl), carbon epoxy group(ing) (preferably phenoxy group), C 1-4Alcoxyl carbon epoxy group(ing) (C preferably 1-4The alcoxyl phenoxy group), heterocyclic radical, heterocyclic oxy group ,-NR 2R 3,-NR 4COR 5,-NR 4SO 2R 5,-CONR 2R 3,-S (O) pR 6,-COR 7With-CO 2(C 1-4Alkyl); Perhaps R 1Be carbocylic radical (C preferably 3-7Cycloalkyl or phenyl) or heterocyclic radical, wherein each can be replaced by one or more substituting groups that are selected from above-mentioned list, and its substituting group can be identical or different, and above-mentioned list further comprises C 1-6Alkyl; Perhaps R 1Be hydrogen, C 1-6Alkoxyl group ,-NR 2R 3Or-NR 4SO 2R 5
Wherein
R 2And R 3(they can be identical or different) is carbocylic radical (C preferably 3-7Cycloalkyl or phenyl) or heterocyclic radical (wherein each can be by C 1-4Alkyl, hydroxyl or C 1-4Alkoxyl group replaces); Perhaps be hydrogen or C 1-4Alkyl; Perhaps R 2And R 3Form pyrrolidyl, piperidino-(1-position only), morpholino, piperazinyl or N-(C with the nitrogen that they connected 1-4Alkyl) piperazinyl;
R 4Be hydrogen or C 1-4Alkyl;
R 5Be C 1-4Alkyl, CF 3, carbocylic radical (preferably phenyl), C 1-4Alkyl carbocylic radical (C preferably 1-4Alkyl phenyl), C 1-4Alkoxyl group carbocylic radical (C preferably 1-4Alkoxyl phenyl), heterocyclic radical, C 1-4Alkoxyl group or-NR 2R 3
R 6Be C 1-4Alkyl, carbocylic radical (preferably phenyl), heterocyclic radical or NR 2R 3With
R 7Be C 1-4Alkyl, carbocylic radical (C preferably 3-7Cycloalkyl or phenyl) or heterocyclic radical;
P is 0,1,2 or 3;
X is linker-(CH 2) n-or-(CH 2) q-O-(wherein Y is connected on the oxygen); Wherein the one or more hydrogen atoms among the linker X can be independently by C 1-4Alkoxyl group, hydroxyl, hydroxyl C 1-3Alkyl, C 3-7Cycloalkyl, carbocylic radical, heterocyclic radical replace, perhaps by the C by one or more fluorine-based or optional replacements of phenyl 1-4Alkyl replaces; N is 3,4,5,6 or 7; Q is 2,3,4,5 or 6; With
Y is phenyl or pyridyl, and wherein each can be by one or more radicals R that can be identical or different 8Replace, wherein R 8Be hydroxyl, sulfydryl, halogen, cyano group, acyl group, amino, list (C 1-4Alkyl) amino, two (C 1-4Alkyl) (any in this two can be by C for amino, carbocylic radical or heterocyclic radical 1-6Alkyl, halo C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkoxyl group, C 1-6The optional replacement of alkyl sulfenyl or halogen), C 1-6Alkoxyl group, phenoxy group, C 1-6Alkyl sulfenyl, thiophenyl or by C 1-6Alkoxyl group, halo C 1-6Alkoxyl group, C 1-6The alkyl of alkyl sulfenyl, halogen or the optional replacement of phenyl; Perhaps
Two R on the adjacent carbons 8Group can form condensed 5 or 6 yuan of carbocyclic rings or heterocycle with interconnective carbon atom, and this carbocyclic ring or heterocycle are by C 1-6Alkyl, halo C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkoxyl group, C 1-6The optional replacement of alkyl sulfenyl or halogen.
R 1Be preferably hydrogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkoxy C 1-3Alkyl, C 1-6Alkoxy C 1-6Alkoxy C 1-3Alkyl or the C that is replaced by phenyl 1-6Alkyl.
R 1More preferably be hydrogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkoxy C 1-3Alkyl (methoxyl group C preferably 1-3Alkyl) or C 1-6Alkoxy C 1-6Alkoxy C 1-3Alkyl (preferably methoxy ethoxy methyl).
R 1More preferably be C 1-4Alkyl (preferably propyl group) or C 1-6Alkoxy C 1-3Alkyl (methoxyl group C preferably 1-3Alkyl is more preferably methoxy ethyl).
One group of preferred compound has molecular formula Ia:
N is preferably 3 or 4, more preferably is 3.
Q is preferably 2 or 3, more preferably is 2.
X is preferably-(CH 2) n-, wherein the one or more hydrogen atoms among the linker X can be replaced for the specified group of X in first aspect by one or more.
R 8Be preferably C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl, sulfydryl, halogen, cyano group, carbocylic radical or heterocyclic radical; Perhaps two R on the adjacent carbons 8Group can form condensed 5 or 6 yuan of carbocyclic rings or heterocycle with interconnective carbon atom, and this carbocyclic ring or heterocycle are by C 1-6Alkyl, halo C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkoxyl group, C 1-6The optional replacement of alkyl sulfenyl or halogen.
Work as R 8During for carbocylic radical, preferred group is cyclopentyl, cyclopropyl, cyclohexyl or phenyl.
Work as R 8During for heterocyclic radical, preferred group is pyridyl, oxadiazole base, pyrazolyl or triazolyl.
When Y is two R on phenyl and the adjacent carbons 8When group forms condensed 5 or 6 yuan of carbocyclic rings or heterocycle with interconnective carbon atom, preferred fused rings system is naphthyl, quinolyl, isoquinolyl, indyl, indazolyl, benzimidazolyl-, benzoisoxazole base, dihydro benzo furyl, benzoxazolyl, 2,3-indanyl, benzisothiazole base and benzothiazolyl.
Preferred compound of the present invention is:
(2R)-and 2-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] methyl } valeric acid (embodiment 16),
3-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] propionic acid (embodiment 18),
3-{[1-({ [3-(2,3-dihydro-1-cumarone-5-yl) propyl group] amino } carbonyl) cyclopentyl] propionic acid (embodiment 21),
2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 15),
2-{[1-({ [3-(4-fluorophenyl) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 4),
4-methoxyl group-2-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] methyl } butyric acid (embodiment 1),
2-{[1-({ [3-(2,3-dihydro-1-cumarone-5-yl) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 11),
(2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl-4-methoxyl group butyric acid (embodiment 22) and
(2S)-and 2-{[1-({ [3-(2,3-dihydro-1-cumarone-5-yl) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 25).
Particularly preferred compound is (2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 22).
Unless otherwise indicated, any alkyl can be straight chain or branched, and has 1-6 carbon atom, preferably has 1-4 carbon atom, especially has 1-3 carbon atom.
Unless otherwise indicated, any carbon ring group contains 3-8 annular atoms, and can be saturated, undersaturated or aromatic.Preferred saturated carbon ring group is cyclopropyl, cyclopentyl or cyclohexyl.Preferred unsaturated carbon cyclic group contains 3 two keys at the most.Preferred aromatic carbon ring group is a phenyl.Term " isocyclic " should make an explanation similarly.In addition, term " carbocylic radical " comprises any condensing property combination of carbon ring group, for example naphthyl, phenanthryl, 2,3-indanyl and indenyl.
Unless otherwise indicated, any heterocyclic group contains 5-7 annular atoms, and 4 atoms at the most wherein can be heteroatoms, and as nitrogen, oxygen and sulphur, and heterocyclic group can be saturated, undersaturated or aromatic.The example of heterocyclic group is a furyl, thienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, dioxolanyl oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazoles, pyranyl, pyridyl, piperidyl alkyl dioxin, morpholino, the dithiane base, thiomorpholine generation, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, the tetramethylene sulfone base, tetrazyl, triazinyl, the azepine base, oxygen azepine (oxazepinyl), sulphur azepine (thiazepinyl), diaza and thiazolinyl.In addition, term " heterocyclic radical " comprises the condensed heterocycle group, for example benzimidazolyl-, benzoxazolyl, imidazopyridyl, benzoxazinyl, benzothiazine Ji, oxazole and pyridyl (oxazolopyridinyl), benzofuryl, quinolyl, quinazolyl, quinoxalinyl, dihydroquinazoline base, benzothiazolyl, phthalimido, benzofuryl, benzodiazepine, indyl and pseudoindoyl.Term " heterocyclic " should make an explanation similarly.
Halogen is represented fluorine, chlorine, bromine or iodine.
For fear of doubt, unless stated otherwise, term " replacement " expression is replaced by the group of one or more qualifications.May be selected from group under the situation of many alternative groups, the group of picking out can be identical or different.
For fear of doubt, term " independently " expression is when selecting to surpass one substituting group from many possible substituting groups, and these substituting groups can be identical or different.
The compound of molecular formula I contains a basic center, on its medicine or veterinarily available salt is for example to form with mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid, the non-toxic acid addition salt that forms with carboxylic acid or form with organic sulfonic acid.Example comprises HCl salt, HBr salt, HI salt, vitriol or hydrosulfate, nitrate, phosphoric acid salt or hydrophosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactic acid salt, Citrate trianion, tartrate, gluconate, camsilate (camsylate), mesylate, esilate, benzene sulfonate, tosilate and embonate (pamoate).Compound of the present invention also can provide on the medicine or available metal-salt veterinarily with alkali, particularly avirulent basic metal and alkaline earth salt.Example comprises sodium salt, sylvite, aluminium salt, calcium salt, magnesium salts, zinc salt, glycol amine salt, pure amine salt, ethylenediamine salt, tromethane salt (tromethamine), chloine salt, megulamine salt and diethanolamine salt.In order to consult suitable pharmaceutical salts, people such as visible Berge, J.Pharm.Sci., 66,1-19,1977; P L Gould, InternationalJournal of Pharmaceutics, 33 (1986), 201-217; With people such as Bighley, Encyclopedia of Pharmaceutical Technology, MarcelDekker Inc, New York 1996, the 13 volumes, 453-497 page or leaf.
Hereinafter, available salt, their solvate and polymorphic form (the midbody compound in chemical process) on defined compound in any aspect of the present invention or the preferred embodiment, their medicine are called " compound of the present invention ".
The available solvate comprises its hydrate on the medicine of The compounds of this invention.
Compound of the present invention and intermediate may have one or more chiral centres, therefore have many heterogeneous types.All steric isomers and its miscellany comprise within the scope of the present invention.
Single enantiomer can obtain by the known various technology of skilled chemist, appropriate means is as carrying out the high pressure liquid chromatography (HPLC) of corresponding racemoid with suitable chirality upholder, perhaps form diastereoisomeric salt, then this salt is carried out fractional crystallization by corresponding racemoid and suitable optically-active alkali reaction.Preferred optically-active alkali is pseudo-ephedrine (seeing preparation 69).
The separation of diastereomer can be finished by the technology of routine, for example fractional crystallization, chromatography or H.P.L.C..
Compound of the present invention can exist by one or more tautomerism types.All tautomers and its miscellany comprise within the scope of the present invention.For example, the claim for the 2 hydroxy pyrimidine base will also comprise its tautomerism type α-pyriconyl.
One skilled in the art will appreciate that can be at the final derivative of making some shielded The compounds of this invention before going the protection stage; so they may not have pharmaceutical activity; but can carry out oral or parenteral administration in some cases, and form The compounds of this invention through metabolism in vivo subsequently with pharmaceutical activity.Therefore, this derivative is described as " prodrug ".In addition, some compound of the present invention can serve as the prodrug of other compounds of the present invention.
The derivative and the prodrug of all shielded The compounds of this invention all comprise within the scope of the present invention.Example for the suitable precursor medicine of The compounds of this invention is described in the following document: Drugs of Today, the 19th volume, No.9,1983, pp499-538; Topics in Chemistry, the 31st chapter, pp306-316; " the Design of Prodrugs " that H.Bundgaard showed, Elsevier, 1985, the 1 chapters (herein quote in these public publications document as a reference).
Those skilled in the art it will be further appreciated that, when having suitable functional group (functionalities) in the The compounds of this invention, some part of being thought " precursor portions " by those skilled in the art can place on this functional group, and for example H.Bundgaard has described this " precursor portions " (quote in the disclosure publication document as a reference) herein in " Design of Prodrugs ".
The prodrug of preferred The compounds of this invention comprises: ester, carbonic ether, half ester, phosphoric acid ester, nitro ester, sulfuric ester, sulfoxide, acid amides, carbamate, azo-compound, phosphamide, glucosides, ether, acetal and ketal.
Drug metabolism study shows that in vivo, it also is the following compounds of nep inhibitor that the compound of molecular formula I may form:
Figure C0280540900161
Especially work as R 1For methoxy ethyl and-when XY is 3-(4-chloro-phenyl-) propyl group, can form these metabolites.
The present invention also comprises all suitable isotopic variations of The compounds of this invention.Isotopic variations is defined as a kind of like this variant, and promptly wherein at least one atom is had identical ordination number but atomic mass is different from the atom of the atomic mass that common occurring in nature finds substitutes.Can be integrated into the isotropic substance that isotopic example in the The compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, respectively as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36Cl.Some isotopic variations of the present invention, for example those wherein contain radio isotope (as 3H or 14C) variant can be used for medicine and/or the research of substrate tissue distribution.Tritium (promptly 3H) and carbon-14 (promptly 14C) isotropic substance is easy to preparation owing to them and detects, thereby is particularly preferred.In addition, use isotropic substance (as tritium, promptly 2H) replace some treatment advantage can be provided, for example increase in the body half life or reduce the dosage requirement, these advantages are from higher metabolic stability, so they may be preferred in some cases.The isotopic variations of The compounds of this invention generally can prepare by conventional procedure, as adopting embodiment and the method described in the preparation or preparation hereinafter and preparing with the suitable isotopic variations of suitable agent.
Compound of the present invention is the inhibitor of the neutral endopeptidase EC.3.4.24.11 of zinc dependence, plans to use compounds for treating of the present invention to list in following disease.This enzyme is at the amino side cutting peptide bonds of hydrophobic amino acid residue, thereby participated in the decomposition of several biological activity oligopeptides.Comprise Natriuretic factor, atrial (ANP), bombesin, bradykinin, calcitonin-gene-related peptide, endothelin, enkephalin, neurotensin, P material and vasoactive intestinal peptide through metabolic peptide.In these peptides some have effective vasorelaxation and neurohormone function, diuretic(s) and natriuretic are active or the behavior of adjusting effectiveness.
Therefore, compound of the present invention can strengthen the biological effectiveness of biologically active peptides by suppressing neutral endopeptidase EC.3.4.24.11.Therefore, this compound can be used for the treatment of numerous disease especially, comprises hypertension, pulmonary hypertension, peripheral vascular disease, heart failure, stenocardia, renal insufficiency, acute renal failure, cyclic edema, meniere's (M é niere ' s) disease, high aldosterone disease (first phase and second phase) and hypercalciuria.In addition, because they can strengthen the effectiveness of ANF, so these compounds can be used for treating glaucoma.Can suppress the further result of neutral endopeptidase EC.3.4.24.11 as them, compound of the present invention can play a role in the other treatment field, for example comprises menoxenia, premature labor, preeclampsia, endometriosis and dysgenesia (particularly sterile, the polycystic ovary syndrome of masculinity and femininity, graft failure (implantation failure)).Compound of the present invention in addition can also be treated asthma, inflammation, leukemia, pain, epilepsy, affective disorder, dementia and senile confusion of consciousness, obesity and gastrointestinal dysfunction (particularly diarrhoea and irritable bowel syndrome), wound healing (particularly diabetic and venous ulcer and bedsore), septic shock, the adjusting of gastric acid secretion, treatment, cystic fibrosis, restenosis, diabetic complication and the atherosclerosis of high-renin mass formed by blood stasis.In preferred embodiments, compound of the present invention is used for the treatment of the masculinity and femininity sexual dysfunction.
Compound of the present invention is particularly conducive to treatment FSD (especially FSAD) and male sexual disorder (especially male erectile dysfunction (MED)).
According to the present invention, FSD can be defined as the women and in the property expression, find satisfied difficulty or can not.FSD is the common terminology (Leiblum for several different women's sexual dysfunctions, S.R. (1998), the definition of women's sexual dysfunction and classification (Definition andclassification of female sexual disorders), Int.J.Impotence Res., 10, S104-S106; Berman, J.R., Berman, L.﹠amp; Goldstein, I. (1999), Female sexual dysfunction: (Female sexual dysfunction:Incidence is selected in generation, physiopathology, assessment and treatment, pathophysiology, evaluations and treatment options), Urology, 54,385-391).The women may lack desire, and has and arouse or the difficulty and the dyspareunia of organism the combination that perhaps has these problems.The disease of several types, medicine, wound or psychological problems may cause FSD.With the special hypotype that developing therapy is positioned to treat FSD, mainly be desire and arouse obstacle.
The kind of FSD is preferably by with them and normal women's step of reaction (desire, arouse and organism) (Leiblum, S.R. (1998), the definition of women's sexual dysfunction and classification (Definition and classification of female sexual disorders), Int.J.Impotence Res., 10, S104-S106) compare and define.Desire or sexual desire are the motivating forces of property expression.Its manifestation usually comprises when with interested companion together the time or the property idea that is occurred when being subjected to other erotic stimuluses.Arousing is vascular reaction for sexual stimulus, and its important integral part is sexual organ hyperemia, and comprises the elongation of the lubricated and vagina that increases vagina and increase phallic sensation/susceptibility.Organism discharges for the property tensile that culminates during arousing.
Therefore, when the women has inadequate or ungratified reaction among any of these stages (be generally desire, arouse and organism) FSD will appear.The FSD kind comprises hyposexuality, sexual arousal dysfunction, orgasm disorder and property pain obstacle.Though compound of the present invention can improve the genital response (as in female sexual arousal disorder) for sexual stimulus, it also can improve pain, the worries and uncomfortable that link together with sexual intercourse like this, thereby can treat other women's sexual dysfunctions.
If the women is not for property or desire is seldom arranged and not or seldom property idea or illusion are arranged, just there is not hyposexuality in explanation.Such FSD can be caused by low testosterone levels, and this causes owing to natural menopause or operation menopause.Other reasons comprises disease, medicine, fatigue, depression and anxiety.
Female sexual arousal disorder (FSAD) characterizes by the inadequate genital response for sexual stimulus.Sexual organ do not experience the hyperemia of the feature of arousing as normality.The vaginal wall lack of lubrication, so sexual intercourse will pain.This may hinder the acquisition of organism.Arouse obstacle can be by menopause the time or between the puerperium of branch and lactation estrogenic minimizing cause, and caused by the disease (as diabetes and atherosclerosis) of blood vessel integral part.The use by oneself treatment of diuretic(s), antihistaminic agent, antidepressive (for example SSRI) or antihypertensive drug of other reasons.
Property pain obstacle (for example dyspareunia and vulvismus) characterizes by the pain that is caused by insertion, and it may be caused by alleviating lubricated medicine, endometriosis, pelvic inflammatory disease, inflammatory bowel or urinary tract problem.
The sickness rate of FSD is difficult to evaluate and test, because this term comprises the problem of several types, wherein some are difficult to measure, and because of for the interest for the treatment of FSD being relative appearance recently.Many women's property problem directly and female aging process or link together with chronic disease (as diabetes and hypertension).
Because FSD by several in the independent stage of sexual response cycle the hypotype of reveal any symptoms form, so there is not single therapy.The treatment of FSD at present concentrates on psychology or concerns on the problem.The treatment of FSD more clinicalization that becoming gradually, basic scientific research contributes for the research of this medical problem.Women's disease not all is psychogenic in physiopathology, especially has the individuality of a kind of obstacle in the angiogenic dysfunction (for example FSAD) that causes whole women's diseases for those.There is not medicine to obtain permitting the treatment that is used for FSD at present.Experiential pharmacological agent comprises estrogenic using (local or as hormone replacement therapy), male sex hormone or changes the medicine (as buspirone or trazodone) of mood.These treatments are selected owing to hanging down curative effect or unacceptable side-effects usually unsatisfactory,
Because for the interest of treatment FSD on pharmacology is to occur recently relatively, so therapeutic process is made up of following part: the property lubricant of psychological consultation, OTC (over-the-counter) and research material standed for comprise the medicine that is used for other illnesss through approval.These medicines are made up of the combination and the verified blood vessel drug eluting that effectively upgrades for male erectile dysfunction of hormonal medicaments, testosterone or oestrogenic hormon and testosterone.Do not have a kind of verified very effective in these medicines for treatment FSD.
Diagnostic and statistical manual (DSM) IV of APA (American Psychiatric Association) defines female sexual arousal disorder (FSAD) like this: " can not reach or keep the lubricated-expansion reaction of sufficient heat constantly or periodically when sexual behaviour is finished.This obstacle is certain to cause tangible worries or interpersonal difficulty.”
Arousal response is made up of the expansion lubricated and expansion and genitalia of the congestion of blood vessel in the pelvic cavity, vagina.This obstacle can cause tangible worries and/or interpersonal difficulty.
FSAD be influence before climacteric, climacteric with climacteric after (± HRT) women's very general sexual dysfunction.It links together as depression, cardiovascular disorder, diabetes and UG disease with the illness of following.
The main result of FSAD is that to lack hyperemia/expand, lack lubricated and lack happy sexual organ sensation.The less important result of FSAD is the difficulty of the sexual desire, the pain during the sexual intercourse and the acquired climax that have reduced.
Recently hypothesis has basis (people such as Goldstein, Int.J.Impot.Res., 10, the S84-S90 of blood vessel at least a portion has the patient of FSAD symptom, 1998), animal data has been supported this viewpoint (people such as Park, Int.J.Impot.Res., 9,27-37,1997).
The drug candidates that is used for the treatment of FSAD of studying its curative effect mainly is to be used to promote the sanguimotor treatment of erectile dysfunction of male genital organ.They are made up of two class ingredients (formulation), promptly oral or hypogloeeis medicine (apomorphine, phentolamine, phosphodiesterase type 5 (PDE5) inhibitor such as Virga) and prostaglandin(PG) (PGE 1), prostaglandin(PG) can be injected or use and be locally applied to sexual organ for the women for male sex's per urethra.
Compound of the present invention is favourable, because it provides method to recover normal sexual arousal reaction, causes vagina, clitoris and labia hyperemia thereby promptly increase phallic volume of blood flow.This will cause oozing out lubricating, increase the conformability of vagina and increasing phallic susceptibility of increase vagina by blood plasma.Therefore, compound of the present invention provides the method for recovering or strengthen the normality arousal response.
Be not limited by theory, we believe that neuropeptide such as vasoactive intestinal peptide (VIP) are the main neurotransmitter material standed fors in women's sexual arousal reaction control (especially genital blood flow amount control).VIP and other neuropeptides are degraded/metabolism by NEP EC3.4.24.11.Therefore, nep inhibitor can strengthen the endogenous vasodilator effect of the VIP that is discharged during arousing.This will cause the treatment of FSAD, as also causing sexual organ hyperemia to treat FSAD thus by increasing the genital blood flow amount.We illustrate, the selective depressant of NEP EC.3.4.24.11 can strengthen the pelvic cavity nerve stimulation and increase VIP inductive vagina and clitoral blood flow amount.In addition, selective N EP inhibitor can strengthen the VIP of separation vaginal wall and the diastole of neural mediation.
Therefore compound of the present invention is favourable, because it helps to provide method to recover normal sexual arousal reaction, causes vagina, clitoris and labia hyperemia thereby promptly increase phallic volume of blood flow.This will cause oozing out the conformability of lubricating, increase vagina that increases vagina and the susceptibility that increases vagina by blood plasma.Therefore, the invention provides the method for recovering or strengthening the normality arousal response.
Male sexual disorder comprises male erectile dysfunction, defective ejaculation such as premature ejaculation (PE), ahedonia (can not acquired climax) and desire obstacle such as hyposexuality (lacking the interest to property).
Will appreciate that all treatments herein comprise therapeutic, the property alleviated and prophylactic treatment.
Compound of the present invention can be applicable to following FSD patient's subgroup: the women after before young, old, climacteric, climacteric, climacteric, they can carry out or not carry out hormone replacement therapy.
Compound of the present invention can be applicable to have the patient of the FSD that is caused by underlying cause:
I) the angiogenic cause of disease, the traumatic injury of private parts vascular system under for example cardiovascular or atherosclerotic disease, hypercholesterolemia, smoking, diabetes, hypertension, radiation and perineum wound, the ilium abdomen.
The ii) neurogenic cause of disease, for example Spinal injury or comprise central nervous system disease, diabetes, Parkinson's disease, cerebrovascular accident, peripheral neuropathy, wound or the radical-ability pelvic surgery of multiple sclerosis disease.
Iii) hormone/incretopathy because of, the high cyclical level of for example castrating of the dysfunction of the dysfunction of the dysfunction of hypothalamus/hypophysis/gonadal axis or ovary, pancreas, surgery or internal medicine, hypoandrogenism, prolactin such as hyperprolactinemia, natural menopause, ovarian failure too early, hyperthyroidism and hypothyroidism.
Iv) psychological source venereal disease because of, for example depression, obsession, anxiety disorder, postpartum depression/" Baby Blues ", mood and concern the inhibition or the traumatic experience of problem, workability anxiety, impediment to marriage, handicapped attitude, sex dread disease, religion.
V) drug-induced sexual dysfunction, this is owing to treatment and other anti depressant therapies (tricyclic antidepressant and major tranquilizer), antihypertensive therapy, sympathicolytic, long-term oral contraception pill for curing with selectivity serotonin reuptake inhibitor (SSRi) produce.
Having slight patient to medium MED should benefit from compound of the present invention, and the patient with serious MED also has reaction., the early stage response rate that studies show that the patient who has slight, medium and serious MED when uniting use with the PDE5 inhibitor is higher.Slightly, medium and serious MED is the term of knowing to those skilled in the art, but can be at The Journal of Urology, vol 151,54-61 finds guidance in (Jan 1994).
Compound of the present invention can be applicable to following MED patient's subgroup: psychological source property, incretion, neurogenic, artery source property, drug-induced sexual dysfunction (lactogenesis) and relate to the sexual dysfunction of cavernous body factor (particularly vein source property reason).These patient groups have been described in following document in more detail: Clinical Andrology, vol 23, no.4, p773-782; The 3rd chapter of the book " ErectileDysfunction-Current Investigation and Management " of I.Eardley and K.Sethia work, Mosby-Wolfe publishes.
Compound of the present invention can adopt the mode of knowing to prepare according to number of ways.After this, unless otherwise indicated, R in the reacting flow chart below 1, specified the same in n, X and Y and the first aspect.These methods have formed further aspect of the present invention.
In whole detailed description, general formula Roman number I, II, III, IV or the like mark.With the subset definition of these general formulas is Ia, Ib, Ic or the like ... IVa, IVb, IVc or the like.
The preparation method of the compound of general formula I is, with the compound (wherein Prot is suitable blocking group) of molecular formula II thus obtain the compound of molecular formula IV with the amine reaction of molecule formula III, go protection (seeing schema 1) subsequently.Preferred reaction conditions for this acid/amine coupling step comprises: under the condition of activating reagent (alternatively for catalyzer) and the existence of excess acid acceptor and in suitable solvent II and III (or its amine salt) are reacted.Particularly preferred reaction conditions comprises: II (1-1.5 equivalent) and III (or its salt, the 1-1.5 equivalent) react; Have 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (WSCDI) or N, N '-dicyclohexylcarbodiimide (DCC) (1.1-1.3 equivalent), hydration I-hydroxybenzotriazole (HOBT) or Dimethylamino pyridine (DMAP) (1.05-1.2 equivalent), N-methylmorpholine (NMM) or triethylamine (2.3-3 equivalent); Solvent is dimethyl formamide or methylene dichloride; Temperature is a room temperature to 90 ℃; Reaction times is 16-18 hour.
More particularly preferred reaction conditions comprises: with II (1-1.5 equivalent) and 1,1 '-phosphinylidyne diimidazole (1-1.5 equivalent) temperature of reaction in room temperature to 90 ℃ in suitable solvent (as tetrahydrofuran (THF), isopropyl acetate or toluene) reacts, add III (or its amine salt, have organic bases such as triethylamine or Hunig ' s alkali in this case) subsequently.
Schema 1
Select as another kind, acid/amine coupling step can and be undertaken by chloride of acid in suitable solvent under the condition that the excess acid acceptor exists.Chloride of acid can separate and obtains or it can produce in position.Preferred reaction conditions comprises: with the chloride of acid of II (1-1.1 equivalent), III (or its salt, 1-1.5 equivalent), triethylamine or N-methylmorpholine (1.4-10 equivalent) in methylene dichloride in room temperature reaction 24 hours.The compound of molecular formula II can be transformed into chloride of acid in position, and this is to realize in 2 hours by handling with oxalyl chloride in room temperature under the condition that exists at the dimethyl formamide of catalytic quantity and in methylene dichloride.
Be used for the de-protected method of acidic-group and depend on blocking group." Protective groups inOrganic synthesis " for visible TW Greene of the example of protecting/go guard method and PGM Wutz.
For example; when blocking group is the tertiary butyl; go protective condition to comprise: with IV and trifluoroacetic acid/dichloromethane (volume ratio 1:, selectively under the condition of carbonium ion scavenging agent such as methyl-phenoxide (10 equivalent) existence, react 1-2.5) in room temperature reaction 2-18 hour.When X and Y contained hydroxyl, the basic hydrolysis of intermediate trifluoro-acetate may be essential.Another kind when blocking group is the tertiary butyl go guard method comprise with hydrochloric acid in methylene dichloride in room temperature treatment IV 3 hours.For fear of doubt, as an example blocking group is given as the tertiary butyl, but is not to want it is confined to the tertiary butyl.
Method according to schema 1 has formed further aspect of the present invention.
The intermediate of general formula I V is new.Therefore according to further aspect, the invention provides the compound of molecular formula IV.
The compound of many molecular formula II is well known in the art (seeing EP274234-B1 and WO9113054).The compound of other molecular formula II can prepare in a similar fashion.
The compound of general formula I and II (R wherein 1Be not hydrogen) with R 1Has a chiral centre on the carbon atom that connects.Single enantiomer can obtain by the known the whole bag of tricks of skilled chemist, for example obtains from corresponding optically pure intermediate or by splitting.The preferred method that splits is by (+)-pseudo-ephedrine salt (seeing WO9113054, embodiment 10 wherein).
The compound of molecular formula IIa, the i.e. chipal compounds of molecular formula II, wherein R 1Be the optional C that replaces 1-6(wherein Q is for R in first aspect to alkyl 1Specified C 1-6Substituting group on the alkyl), can also prepare by the asymmetric hydrogenation of the compound of molecular formula XI, XII or XIII according to reacting flow chart 1a.
Schema 1a
Figure C0280540900251
Common hydrogenation conditions be included in the suitable solvent and in the hydrogen pressure that has increased down with suitable asymmetric hydrogenation catalyst treatment molecular formula XI, XII or the compound of XIII (perhaps its organic or inorganic salt (as sodium salt)).Preferred catalyzer contains one or more chiral ligands (preferably chiral phosphine ligand), this part and suitable transition-metal coordination (for example rhodium, ruthenium, iridium, palladium).Preferred catalyzer is:
[(R)-(+)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl chlorine (p-cymene)] and the ruthenium muriate (J.Org.Chem.1994,59,3064-76);
[(S)-3,3 ', 4,4 ', 5,5 '-hexamethyl (6,6 '-phenylbenzene)-2,2 '-two bases] the two trifluoroacetates (seeing WO 01/94359) of two (diphenylphosphino) ruthenium;
[(R)-(-)-4, adjacent formyl radical-(1, the 5-cyclooctadiene) of two (di-isopropyl phosphino-)-[2.2]-two polyphenylene ethyls of 12-] rhodium (I) a tetrafluoro borate (J.Am.Chem.Soc.1997,119,6207-6208);
[two-((2S, 5S)-2,5-dimethyl-1-phenylphospholano) (1, the 5-cyclooctadiene)] rhodium (I) a tetrafluoro borate (Tetrahedron:Asymm.1991,2,569-92); With
[(R)-(6,6 '-dimethoxy phenylbenzene-2,2 '-two bases) two (diphenylphosphino)] ruthenium two (trifluoroacetate) is (EP398132).
Preferred reaction conditions comprises: height is to the temperature of reaction of hydrogen pressure and 0-100 ℃ (preferably 50-60 ℃) of 150psi.Preferred solvent is a protonic solvent, for example methyl alcohol or ethanol.
In schema 1a, the compound of molecular formula (XIII) is preferred initial substance.
The method of schema 1a forms further aspect of the present invention.
Select as another kind, the compound of molecular formula I and IV can be directly prepares by the asymmetric hydrogenation corresponding to the unsaturated compound of XI, XII and XIII.
The compound of molecular formula IIIa, promptly wherein X is-(CH 2) 3-the compound of molecule formula III, can prepare according to reaction process Fig. 2.At first, the compound of molecular formula V under the condition that appropriate catalyst system (as palladium) and excessive alkali (as triethylamine or 4-methylmorpholine) exist with vinyl cyanide experience Heck reaction, thereby obtain the compound of molecular formula VI.Common reaction conditions comprises: the normal aryl halide of 1.0-1.5,3 normal alkali, 0.1 normal palladium catalyst (preferably acid chloride (II)), 0.2 normal phosphine part (preferably tri-o-tolyl phosphine); In 1, react among 4-diox, acetonitrile or the DMF (preferably acetonitrile); And reflux.Thereby the compound with molecular formula VI carries out the compound that catalytic hydrogenation obtains molecular formula IIIa then.Common hydrogenation conditions comprises: handle VI with Raney nickel in ethanol or methyl alcohol under the pressure of 15-150psig and 25 and 80 ℃.Preferably in ethanol, under 30psig and 25 ℃, react.
Schema 2
Figure C0280540900261
Select as another kind, the compound of molecular formula VI can prepare by the compound of molecular formula VII and diethyl cyano methyl phosphoric acid ester are reacted according to reaction process Fig. 3.Common reaction conditions comprises: in suitable solvent (for example methylene dichloride, tetrahydrofuran (THF) or ether) in room temperature with diethyl cyano methyl phosphoric acid ester and the reaction of suitable alkali (for example sodium hydride, lithium chloride/Hunig ' s alkali or sodium ethylate), add the compound of molecular formula VII subsequently.
Schema 3
Select as another kind, the compound of molecular formula IIIa can prepare according to schema 4.
Schema 4
Other molecular formula (III), (V), (VI) and compound (VII) can obtain from commercial source well known in the prior art, perhaps can prepare from compound well known in the prior art by using method well known in the prior art or method described herein (seeing embodiment and preparation part).
The reaction that all are above-mentioned and in preceding method the preparation of employed new initial substance be conventional.After document precedent and hereinafter embodiment and preparation, the suitable reagent that those skilled in the art will know the implementation that is used for them or preparation is with reaction conditions and the program that is used to separate desired product.
Suitably, on the medicine of the compound of molecular formula (I) available salt can be easily by the solution of the compound of molecular formula (I) and desired acid or alkali are mixed in the preparation of coming together.The salt of gained can be precipitated out from solution and collect by filtering, and perhaps can reclaim by the evaporation of solvent.
Compound of the present invention (particularly (2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 22)) can further be selected from down the activeconstituents associating that compiles a name list with one or more:
1) one or more naturally occurring or synthetic prostaglandin(PG) or its esters.The suitable prostaglandin(PG) of Shi Yonging comprises following compound herein: Prostaglandin E1, PGE 1, PGE 0, 13,14-dihydro PGE 1, PGE 2, eprostinol, natural synthetic and semisynthetic prostaglandin(PG) and its derivative (comprise those at WO-00033825 and/or the US 6,037 that published on March 14th, 2000, the compound described in 346 is all quoted as a reference herein), 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, Prostaglin F2, Trometamol, rostaglin E2, fat prostatitis element (lipo prost), gemeprost, meteneprost (metenoprost), sulprostone, tiaprost and Thymoxamine (moxisylate).
2) one or more alpha-adrenergic receptor antagonist compounds are also referred to as alpha-2-adrenoceptor or alpha-receptor or alpha block agent.The suitable compound of Shi Yonging comprises herein: the alpha-adrenergic receptor blocker described in the PCT application WO99/30697 that announced on June 14th, 1998, quote herein wherein relate to alpha-adrenergic receptor disclosure as a reference, this content comprises selectivity α 1-adrenoceptor or α 2-adrenoceptor blocker and non-selective adrenoceptor blocker, suitable α 1-adrenoceptor blocker comprises phentolamine, phentolamine mesilate, trazodone, alfuzosin, Indoramine, naftopidil, Tamsulosin, dapiprazole, phenoxybenzamine, Racemic idazoxan, efaroxan, Yohimbine, rauwolfine, Recordati 15/2739, SNAP 1069, SNAP 5089, RS 17053, SL 89.0591, Doxazosin, terazosin, Abanoquil and Prazosin; From US 6,037, the α in 346 (on March 14th, 2000) 2-blocker blocker comprises dibenarnine, tolazoline, trimazosin and dibenarnine; US patent 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, the alpha-adrenergic receptor described in 000 is quoted each herein as a reference; α 2-adrenoceptor blocker comprises clonidine, Papaverine, papaverin hydrochloride, alternatively under the condition of cariotonic medicament such as pirxamine existence.
3) one or more NO-donors (NO-agonist) compound.The suitable NO-compound donator of Shi Yonging comprises herein: organic nitrate is (as list, two or trinitrate) or organic nitrates (comprise glyceryl brinitrate, be also referred to as nitroglycerine), Isosorbide 5-Mononitrate, Iso-bid, trinitrol, erythrol tetranitrate, sodium nitroprusside (SNP), 3-Sydnonimine-1 molsidomine (3-morpholinosydnonimine molsidomine), S-nitroso-group-N-ethyl penicillanate amine (SNAP), S-nitroso-group-N-gsh (SNO-GLU), N-hydroxyl-L-arginine, amyl nitrate, Sydnonimine-1, the Sydnonimine-1 chloride hydrate, (SIN-1) S-nitroso-group-N-halfcystine, diazenium diolate, (NONOate), 1,5-dinitric acid penta diester, the L-arginine, genseng, zizphi fructus, molsidomine, Re-2047, the maxisylyte derivative of nitrosylation is as NMI-678-11 and NMI-937 described in the PCT application WO 0012075 that announces.
4)-kind or multiple potassium channel openers or modulator.Suitable potassium channel openers/the modulator of Shi Yonging comprises herein: Nicoril, cromokalim, levcromakalim, lemakalim, Pinacidil, cliazoxide, minoxidil, charybdotoxin, Glyburide, 4-aminopyridine, BaCl 2
5) one or more dopaminergic medicaments are preferably apomorphine or selective d 2, D 3Or D 2/ D 3Agonist is as pramipexole and ropirinol (requiring among the WO-0023056), PNU95666 (requiring among the WO-0040226).
6) one or more vasodilators.The suitable vasodilator of Shi Yonging comprises herein: nimodipine, Pinacidil, Cyclelate, isoxsuprine, chloroprumazine, haloperidol, Rec 15/2739, trazodone.
7) one or more thromboxane A2 agonists.
8) one or more CNS active agents.
9) one or more ergot alkaloids.The US patent 6 that on March 14th, 2000 published, 037, described suitable ergot alkaloid in 346, it comprises: acetergamine, brazergoline, Bromlisuride, cianergoline, delorgotrile, Soz 29-717, Ergometrini Maleats, gynergen, etisulergine, Lergotrile, lysergsure diethylamid, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride, terguride.
10) one or more regulate the compound of the effect of the sharp natriuresis factor of the sharp natriuresis factor (particularly atrial natriuretic factor is also referred to as Natriuretic factor, atrial), Type B and C type, as inhibitor or neutral endopeptidase.
11) one or more suppress the compound of angiotensin converting enzyme such as the combined depressant such as the omapatrilat of enalapril and angiotensin converting enzyme and neutral endopeptidase.
12) one or more angiotensin receptor antagonists such as losartan.
13) substrate of one or more NO synthetic enzyme such as L-arginine.
14) one or more calcium channel blockers such as amlodipine.
15) inhibitor of the antagonist of one or more endothelin-receptors and endothelin-converting enzyme.
16) medicament of one or more reducing cholesterol such as statin (for example atorvastatin/Lipitor-trade mark) and fibrate.
17) one or more antiplatelets and antithrombotic agent, for example tPA, uPA, warfarin, r-hirudin and other thrombin inhibitorss, heparin, thromboplastin activation factor inhibitor.
18) one or more insulin sensitizers such as Rezulin and hypoglycemic medicament such as Glipizide.
19) L-DOPA or carbidopa.
20) one or more acetylcholinesterase depressant such as donezipil.
21) one or more steroid or on-steroidal anti-inflammatory agent.
22) one or more estrogen receptor modulators and/or estrogen agonist and/or estrogen antagonist, be preferably raloxifene, tibolone, Lasofoxifene, (-)-suitable-6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, available salt (its preparation is described in detail among the WO 96/21656) on pure and mild its medicine of 8-naphthane-2-.
23) modulator of one or more Cannabined receptors.
24) one or more NPY (neuropeptide tyrosine) inhibitor more particularly is NPY1 or NPY5 inhibitor, is preferably the NPY1 inhibitor, and this NPY inhibitor (comprising NPY Y1 and NPY Y5) preferably has the IC50 that is lower than 100nM (more preferably being lower than 50nM).Have the test that is used to identify the NPY inhibitor among the WO-A-98/52890 (see 96 pages, 2-28 is capable).
25) one or more vasoactive intestinal peptides (VIP), VIP stand-in, VIP analogue, more particularly mediated by one or more VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide), one or more VIP receptor stimulants or VIP analogue (for example Ro-125-1553) or VIP fragment, one or more and VIP bonded alpha-2-adrenoceptor antagonists (for example Invicorp, aviptadil).
26) one or more melanocortin-4 receptor agonists or modulator or melanocortin toughener are as the compound that requires among melanotan II, PT-14, PT-141 or WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, the WO-09954358.
27) one or more 5-hydroxytryptamine receptor agonists, antagonist or modulator, more particularly, comprise the compound that those are described in WO-09902159, WO-00002550 and/or WO-00028993 for agonist, antagonist or the modulator of 5HT1A (comprising VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 acceptor.
28) one or more male sex hormones, for example androsterone, dehydroandrosterone, testosterone, androstanedione and synthetic male sex hormone.
29) one or more oestrogenic hormon, for example estradiol, oestrone, trihydroxy-oestrin and synthetic oestrogenic hormon such as phenylformic acid oestrogenic hormon.
30) modulator of the translocator of one or more norepinephrines, Dopamine HCL and/or serotonin, for example Bupropion, GW-320659.
31) one or more purinergic receptor agonists and/or modulator.
32) one or more neurokinins (NK) receptor antagonist comprises those compounds described in the WO-09964008.
33) one or more opioid receptor agonists, antagonist or modulator are preferably the agonist of ORL-1 acceptor.
34) agonist of one or more pitocin/II/vasopressin receptors or modulator are preferably selectivity oxytocin agonists or modulator.
35) one or more PDE inhibitor, more particularly be PDE2,3,4,5,7 or 8 inhibitor, be preferably PDE2 or PDE5 inhibitor, be most preferably PDE5 inhibitor (seeing below), these inhibitor preferably have the anti-IC50 of enzyme separately that is lower than 100nM.
Comprise according to suitable cGMP PDE5 inhibitor used in the present invention: disclosed pyrazolo among the EP-A-0463756 [4,3-d] pyrimidin-7-ones; Disclosed pyrazolo among the EP-A-0526004 [4,3-d] pyrimidin-7-ones; Disclosed pyrazolo [4,3-d] pyrimidin-7-ones in the International Patent Application WO of announcing 93/06104; Pyrazolo [3, the 4-d] pyrimidin-4-one of disclosed isomery in the International Patent Application WO of announcing 93/07149; Disclosed quinazoline-4-one in the International Patent Application WO of announcing 93/12095; Disclosed pyrido [3,2-d] pyrimidin-4-one in the International Patent Application WO of announcing 94/05661; Disclosed purine-6-one in the International Patent Application WO of announcing 94/00453; Disclosed pyrazolo [4,3-d] pyrimidin-7-ones in the International Patent Application WO of announcing 98/49166; Disclosed pyrazolo [4,3-d] pyrimidin-7-ones in the International Patent Application WO of announcing 99/54333; Disclosed pyrazolo among the EP-A-0995751 [4,3-d] pyrimidin-4-one; Disclosed pyrazolo [4,3-d] pyrimidin-7-ones in the International Patent Application WO of announcing 00/24745; Disclosed pyrazolo among the EP-A-0995750 [4,3-d] pyrimidin-4-one; Disclosed compound in the International Patent Application WO of announcing 95/19978; Disclosed compound in the International Patent Application WO of announcing 99/24433; With disclosed compound in the International Patent Application WO of announcing 93/07124.Disclosed pyrazolo [4,3-d] pyrimidin-7-ones in the International Patent Application WO of announcing 01/27112; Disclosed pyrazolo [4,3-d] pyrimidin-7-ones in the International Patent Application WO of announcing 01/27113; Disclosed compound among the EP-A-1092718; With disclosed compound among the EP-A-1092719.
In addition, comprise according to suitable PDE5 inhibitor used in the present invention: 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Virga), be also referred to as 1-[[3-(6,7-dihydro-1-methyl-7-oxygen-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] alkylsulfonyl]-4-methylpiperazine (seeing EP-A-0463756); 5-(2-oxyethyl group-5-morpholino ethylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (seeing EP-A-0526004); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base alkylsulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (seeing WO 98/49166); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base alkylsulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (seeing WO 99/54333); (+)-3-ethyl-5-[5-(4-ethyl piperazidine-1-base alkylsulfonyl)-2-(2-methoxyl group-1 (R)-methyl ethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, be also referred to as 3-ethyl-5-{5-[4-ethyl piperazidine-1-base alkylsulfonyl]-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 (seeing WO 99/54333); 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, be also referred to as 1-{6-oxyethyl group-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxygen-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-4-ethyl piperazidine (see WO 01/27113, embodiment 8); 5-[2-isobutoxy-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-(1-methyl piperidine-4-yl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (see WO 01/27113, embodiment 15); 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (see WO01/27113, embodiment 66); 5-(5-ethanoyl-2-propoxy--3-pyridyl)-3-ethyl-2-(1-sec.-propyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (see WO 01/27112, embodiment 124); 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (see WO 01/27112, embodiment 132); (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (IC-351), i.e. the embodiment 78 of the International Patent Application WO 95/19978 of Gong Buing and 95 compound, and the compound of embodiment 1,3,7 and 8; 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil), be also referred to as 1-[[3-(3,4-dihydro-5-methyl-4-oxygen-7-propyl imidazole is [5,1-f]-as-triazine-2-yl also)-the 4-ethoxyl phenenyl] alkylsulfonyl]-4-ethyl piperazidine, the i.e. embodiment 20,19,337 of the International Patent Application WO 99/24433 of Gong Buing and 336 compound; The compound of the embodiment 11 of the International Patent Application WO of announcing 93/07124 (EISAI); With from Rotella D P, J.Med.Chem., 2000,43,1257 compound 3 and 14.
Also have other suitable PDE5 inhibitor to comprise: 4-bromo-5-(pyridyl methylamino-)-6-[3-(4-chloro-phenyl-)-propoxy-]-3 (2H) pyridazinone; 1-[4-[(1,3-benzo dioxole-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-the 4-piperidine carboxylic acid, a sodium salt; (+)-suitable-5,6a, 7,9,9,9a-six hydrogen-2-[4-(trifluoromethyl)-phenyl methyl-5-methyl-cyclopenta-4,5] imidazo [2,1-b] purine-4 (3H) ketone; Fuzlocillin; Suitable-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydro cyclopenta [4,5]-imidazo [2,1-b] purine-4-ketone; 3-ethanoyl-1-(2-chloro-phenyl-)-2-propyl indole-6-carboxylicesters; 3-ethanoyl-1-(2-chloro-phenyl-)-2-propyl indole-6-carboxylicesters; 4-bromo-5-(3-pyridyl methylamino-)-6-(3-(4-chloro-phenyl-) propoxy-)-3-(2H) pyridazinone; 1-methyl-5 (5-morpholinyl ethanoyl-2-positive propoxy phenyl)-3-n-propyl-1, and 6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones; 1-[4-[(1,3-benzo dioxole-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-the 4-piperidine carboxylic acid, a sodium salt; Pharmaprojects No.4516 (Glaxo Wellcome); Pharmaprojects No.5051 (Bayer); Pharmaprojects No.5064 (Kyowa Hakko; See WO 96/26940); Pharmaprojects No.5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 ﹠amp; 38-9456 (Bayer) and Sch-51866.
For treatment FSD, compound of the present invention (particularly (2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 22)) can preferably be selected from down the activeconstituents associating that compiles a name list with one or more:
A) PDE5 inhibitor more preferably is 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Virga); (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (IC-351); 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil); 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; And 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones with and medicine on available salt;
B) NPY Y1 inhibitor;
C) dopamine agonist such as apomorphine, perhaps selective d 2, D 3Or D 2/ D 3Agonist such as pramipexole and ropirinol;
D) melanocortin-4 receptor agonists or modulator or melanocortin toughener are preferably melanotan II, PT-14, PT-141;
E) agonist of 5HT2C, antagonist or modulator;
F) estrogen receptor modulator, estrogen agonist and/or estrogen antagonist are preferably raloxifene, tibolone, Lasofoxifene;
G) male sex hormone, for example androsterone, dehydroandrosterone, testosterone, androstanedione and synthetic male sex hormone; With
H) oestrogenic hormon, for example estradiol, oestrone, trihydroxy-oestrin and synthetic oestrogenic hormon such as phenylformic acid oestrogenic hormon.
For treatment MED, compound of the present invention (particularly (2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid (embodiment 22)) can preferably be selected from down the activeconstituents associating that compiles a name list with one or more:
A) PDE5 inhibitor more preferably is 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Virga); (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (IC-351); 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil); 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; And 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones with and medicine on available salt;
B) NPY Y1 inhibitor;
C) dopamine agonist (being preferably apomorphine), perhaps selective d 2, D 3Or D 2/ D 3Agonist such as pramipexole and ropirinol;
D) melanocortin-4 receptor agonists or modulator or melanocortin toughener are preferably melanotan II, PT-14, PT-141; With
E) agonist of 5HT2C, antagonist or modulator.
FSD is particularly preferred is combined as (2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl for treatment] methyl-4-methoxyl group butyric acid (embodiment 22)) and one or more be selected from down the activeconstituents that compiles a name list:
5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Virga);
(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (IC-351);
2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil);
5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Apomorphine;
melanotan II；
PT-141；
Lasofoxifene;
Raloxifene;
Tibolone;
Male sex hormone, for example androsterone, dehydroandrosterone, testosterone, androstanedione and synthetic male sex hormone; With
Oestrogenic hormon, for example estradiol, oestrone, trihydroxy-oestrin and synthetic oestrogenic hormon such as phenylformic acid oestrogenic hormon.
MED is particularly preferred is combined as (2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl for treatment] methyl-4-methoxyl group butyric acid (embodiment 22)) and one or more be selected from down the activeconstituents that compiles a name list:
5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Virga);
(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (IC-351);
2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil);
5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;
Apomorphine;
Melanotan II; With
PT-141。
If use the combination of active agents, so can be side by side, use respectively or in turn.
Compound of the present invention can be used separately, but in people's treatment, generally to use with suitable drug excipient, the miscellany of diluent or carrier, these drug excipients, diluent or carrier are to select according to the medicine operation of route of administration of being wanted and standard for it.
For example, compound of the present invention can tablet, capsule (comprising soft gel capsule), pill, elixir, solution or form of suspension carry out oral, contain clothes or sublingual administration, they can contain seasonings or tinting material, and applicable to immediately, that postpone, modify, that continue, dual, the release of control or the application form of beating and sending.Compound of the present invention also can be used by quick dispersion or rapid-dissolve dosage form.
Release of modifying and the release dosage form of beating can contain just like for immediately those vehicle that release dosage form described in detail, also contain the additional vehicle as the rate of release instrumentality simultaneously, these additional vehicle can cover on the medicine body and/or be included in the medicine body.The rate of release instrumentality comprise Vltra tears, methylcellulose gum, Xylo-Mucine, ethyl cellulose, rhodia, polyethylene oxide,, xanthan gum, carbomer (carbomer), ammonio methacrylate copolymer, hydrogenant Viscotrol C, carnauba wax, paraffin, Cellacefate, Hydroxypropyl Methylcellulose Phathalate, methacrylic acid copolymer and its miscellany, but be not limited in this.Release of modifying and the release dosage form of beating can contain a kind of rate of release regulates vehicle or its combination.It is within the matrix that rate of release regulates that vehicle may reside within the formulation, and/or is present on the formulation promptly on the formulation surface or the parcel formulation.
Disperse or dissolve formulation (FDDF) fast and can comprise following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, polyvinylpolypyrrolidone, two xitix, ethyl propenoate, ethyl cellulose, gelatin, Vltra tears, Magnesium Stearate, N.F,USP MANNITOL, methyl methacrylate, the peppermint seasonings, polyoxyethylene glycol, pyrogenic silica, silicon-dioxide, sodium starch glycollate, sodium stearyl fumarate, sorbyl alcohol, Xylitol.Be used to describe the term " dispersion " of FDDF or the solvability that " dissolving " depends on used drug substance herein, promptly when drug substance is soluble, can prepare the fast-dispersing type, when drug substance is solvable, can prepare rapid-dissolve dosage form.
Composition of the present invention can be used by direct injection.Composition can be according to preparing for parenteral, mucous membrane, intramuscular, intravenously, subcutaneous, eye, intraocular or endermic using.As required, the dosage that medicament can the 0.01-30mg/kg body weight is used, and as the dosage of 0.1-10mg/kg body weight, more preferably is the dosage of 0.1-1mg/kg body weight.
Term administering " comprise by the technology of virus or non-virus and sending.The virus delivery mechanism comprises adenovirus carrier, adeno associated virus (AAV) carrier, herpesvirus vector, retrovirus vector, lentiviral vectors and baculovirus vector, but is not limited to this.Non-viral delivery mechanism comprises transfection, liposome, immunoliposome, lipofection reagent, cationic surface amphipath (CFA) and its combination of lipid mediation.Approach for this delivery mechanism comprises mucous membrane, nose, mouth, parenteral, stomach and intestine, part or hypogloeeis approach, but is not limited to this.
Additionally or selectively, composition of the present invention (or its composition) can be used by direct injection.Additionally or selectively, composition of the present invention (or its composition) can topical application (preferably being applied to sexual organ).Additionally or selectively, composition of the present invention (or its composition) can be used by sucking.Additionally or selectively, composition of the present invention (or its composition) also can be used by one or more following approach: the approach of mucous membrane for example is used to the nasal spray or aerosol or the absorbable solution (as the through port approach) that suck; The parenteral route of sending with injectable form, for example rectum, eye (comprise in the vitreum or in the eye-chamber), nose, part (comprise mouthful and hypogloeeis), intrauterine, vagina or parenteral (comprising in subcutaneous, intraperitoneal, intramuscular, intravenously, intracutaneous, encephalic, the tracheae and epidural) approach; In skin, intraperitoneal, encephalic, Intraventricular, brain, intravaginal, intrauterine or parenteral (for example in intravenously, the backbone, subcutaneous, through skin or intramuscular) approach.
As an example, pharmaceutical composition of the present invention can be used according to 1-10 time the system of taking every day, as every day 1 time or 2 times.For any specific patient, specific dosage level and administration frequency can change, it depends on multiple factor, comprises the severity and the individual treatment of just carrying out of the metabolic stability of activity, this compound of employed specific compound and acting duration, age, body weight, general healthy state, sex, diet, the mode of using and time, excretion rate, drug regimen, particular disorder.
Therefore, term administering " comprise by following approach and sending that promptly mucosal route for example is used to the nasal spray or aerosol or the absorbable solution that suck; The parenteral route of sending with injectable form, for example intravenously, intramuscular or subcutaneous route, but be not limited to this.
This tablet can comprise following vehicle: Microcrystalline Cellulose, lactose, Trisodium Citrate, lime carbonate, secondary calcium phosphate and glycine, decomposition agent (as starch, being preferably corn, potato or tapioca (flour)), sodium starch glycollate, croscarmellose sodium and some composition silicate, particle form tackiness agent (as polyvinylpyrrolidone, Vltra tears (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and Sudan Gum-arabic).Can also comprise lubricant in addition, for example Magnesium Stearate, stearic acid, Gan You docosoic ester and talcum.
The solids composition of similar type also can be used as weighting material in gelatine capsule.Preferred in this respect vehicle comprises lactose, starch, Mierocrystalline cellulose, toffee (milk sugar) or high-molecular weight polyoxyethylene glycol.For aqueous suspension and/or elixir, compound of the present invention can be united with following material: promptly various sweeteners or seasonings, coloring material or staining agent; Emulsifying agent and/or suspension agent; Thinner such as water, ethanol, propylene glycol and glycerine; With and the combination.
Compound of the present invention also can parenteral administration, for example intravenously, intra-arterial, intraperitoneal, sheath are interior, indoor, in the urethra, in the breastbone, encephalic, intramuscular or subcutaneous, perhaps they can be used by infusion techniques.In addition, the form that they can implant is used.For this parenteral administration, preferably use, thereby aseptic aqueous solution can contain for example enough salt of other materials or glucose forms and the isoosmotic solution of blood with the form of aseptic aqueous solution.If desired, the aqueous solution should suitably cushion (preferably to 3-9 pH).Can easily finish the preparation of parenteral ingredients suitable under the aseptic condition by standard pharmaceutical technology well-known to those skilled in the art.The parenteral ingredients can immediately, that postpone according to being applicable to, modification, that continue, dual, control the release or the form of sending of beating be prepared.
Following dosage level and other dosage levels are herein for the common human subject with about 65-70kg body weight.Those skilled in the art can easily determine the required dosage level of curee (as children and the elderly) that exceeds this scope for body weight.
When oral and parenteral administration during in human patients, the dosage level of The compounds of this invention or its salt or solvate is generally 10-1000mg (single or separate dosage).
Therefore, for example the tablet of The compounds of this invention or its salt or solvate or capsule can contain the active compound of 5-1000mg (as 5-500mg), and this compound is used for every receipt time or twice or repeatedly uses, if this is suitable.The physician can both determine the optimal actual dose for any discrete patient in any case, and this dosage can change along with age, body weight and the reaction of particular patient.Above-mentioned dosage can be used as the example of normal conditions.Certainly, may have the discrete situation, at this moment should use higher or lower dosage level, these are also included within the scope of the present invention.Those skilled in the art also will appreciate that in the treatment of (comprising FSD and MED) of some illness, and compound of the present invention can use with single dose based on needs (promptly need or expect).
Compound of the present invention also can adopt intranasal administration or use by suction, this moment, they suited to send with Diskus or the aerosol spray form of presenting, (for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, hydrofluoroalkane are as 1 from using suitable propelling agent for these medicaments, 1,1,2-Tetrafluoroethane (HFA 134A, trade mark) or 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227EA, trade mark), carbonic acid gas or other suitable gas) pressurizing vessel, pump, atomizer or spraying gun.Under the situation of pressurised aerosol, dose unit can come to determine as follows, promptly provides a valve to send quantity through metering.Pressurizing vessel, pump, atomizer or spraying gun can contain the solution or the suspension of active compound, and the miscellany of for example using ethanol and propelling agent can contain lubricant such as sorbitan trioleate as solvent in solution or the suspension in addition.Capsule that uses in sucker or insufflator and cartridge case (for example making from gelatin) can contain the powder mixture of compound of the present invention and suitable powder matrix (as lactose or starch) through preparation.
Aerosol or dry powder ingredients are preferably through arrangement, so that each contains the 1-50mg that is delivered to patient compound of the present invention through dosage or " the aerosol group " of metering.Total per daily dose of aerosol is 1-50mg, and it can single dose in whole one day or more generally uses with the dosage that separates.
Select as another kind, compound of the present invention can suppository or the form of vaginal suppository use, perhaps they can gel, the form of hydrogel, washing lotion, solution, emulsifiable paste, ointment or dusting carries out topical application (preferably being applied to sexual organ).Compound of the present invention also can be applied to skin.Compound of the present invention also can for example use skin patch through dermal administration.They also can be used by eye, lung or rectum approach.
For using of eye, compound can be mixed with the littleization suspension in isoosmotic, that adjusted pH, aseptic salt solution, perhaps preferably be mixed with the solution in isoosmotic, that adjusted pH, aseptic salt solution, they also unite sanitas alternatively such as benzyl alkane positively charged ion muriate is prepared.Select as another kind, they can be formulated in ointment such as the vaseline.
For being applied topically to skin (preferably being applied to sexual organ), compound of the present invention can be mixed with the suitable ointment that contains active compound, and this active compound suspends or is dissolved in the miscellany that for example has one or more following materials: mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsive wax and water.Select as another kind, they can be mixed with suitable washing lotion or emulsifiable paste, and they suspend or are dissolved in the miscellany that for example has one or more following materials: mineral oil, Arlacel-60, polyoxyethylene glycol, whiteruss, Polysorbate 60, spermaceti ester type waxes, spermaceti aryl alcohol (ceteary alcohol), 2-Standamul G, phenylcarbinol and water.
Compound of the present invention also can be united use with cyclodextrin.Known cyclodextrin can form inclusion and non-inclusion complex with drug molecule.The formation of drug-cyclodextrin mixture can change solvability, dissolution rate, bioavailability and/or the stability characteristic of drug molecule.The drug-cyclodextrin mixture generally can be used for most formulation and route of administration.As the direct and another kind of selection of medicine compound, cyclodextrin can be used as auxiliary additive and uses, for example as carrier, thinner or solubilizing agent.α-, β-, γ-Huan Hujing is the most frequently used, suitable example is described among WO-A-91/11172, WO-A-94/02518 and the WO-A-98/55148.
In a preferred embodiment, compound general of the present invention ground (as oral, contain clothes and hypogloeeis) send, more preferably send with oral.(most preferred for oral) of this general used and is preferably used for treating Female sexual dysfunction (preferably FSAD).
Therefore in particularly preferred embodiment, provide compound of the present invention to be used for the treatment of or to prevent purposes in systemic delivery (preferably oral delivery) medicine of FSD (being more preferably FSAD) in production.
Preferred oral ingredients is used release tablet immediately, perhaps disperses or dissolves dosage ingredients (FDDF) fast.
In further preferred embodiment, compound of the present invention carries out topical application, preferably directly is applied to female sex organs (especially vagina).
Because NEP spreads all over whole body, so be very unexpectedly, compound of the present invention can be used to general and acquisition therapeutic response and do not cause intolerable (opposite) side effect in female sex organs.In EP 1097719-A1 and animal model hereinafter, we have shown phallic volume of blood flow (by pelvic cavity nerve stimulation simulation) when nep inhibitor that general ground has been applied to rabbit model (in the body) has increased sexual arousal, but do not influence cardio-vascular parameters unfriendly, as cause tangible ypotension or hypertension.
Preferably, compound of the present invention is used the FSD among patient's (we represent to comprise vision, the sense of hearing or tactile stimulation with sexual stimulus) with therapeutic stimulation.Stimulation can be before this be used, afterwards or during.
Therefore, compound of the present invention has strengthened the approach/mechanism as the basis of sexual arousal in the female sex organs, and its recovery or the sexual arousal that has improved for sexual stimulus react.
Therefore, preferred embodiment provides the purposes of compound of the present invention in the preparation medicine, and this medicine is used at patient's treatment of irriate or prevention FSD.
For veterinary application, compound of the present invention is used with acceptable ingredients according to general veterinary science convention, and the structive sursery doctor can determine for the optimal system of taking medicine and the approach of using of particular animals.
Following preparation example just is used for illustrating, rather than wants to limit the scope of the invention." activeconstituents " represents compound of the present invention.
Ingredients 1: prepare tablet with following composition:
Weight/mg
Activeconstituents 250
Mierocrystalline cellulose, crystallite 400
Silicon-dioxide, pyrolysis method 10
Stearic acid 5
Amount to 665
Component is through the mixed tablet that forms with compression.
Ingredients 2: can prepare the intravenously ingredients with following:
Activeconstituents 100mg
Isotonic saline solution 1,000ml
Followingly compound of the present invention is locally applied to phallic common ingredients for being used for:
Ingredients 3: sprays
Activeconstituents (1.0%) is arranged in Virahol (30%) and water.
Ingredients 4: foam
Activeconstituents, Glacial acetic acid, phenylformic acid, hexadecanol, methyl p-hydroxybenzoate, phosphoric acid, polyvinyl alcohol, propylene glycol, Xylo-Mucine, stearic acid, diethyl stearylamide, van Dyke spices No.6301, pure water and Trimethylmethane.
Ingredients 5: gel
Activeconstituents, Docusate Sodium BP, Virahol BP, propylene glycol, sodium hydroxide, carbomer 934 P, phenylformic acid and pure water.
Ingredients 6: emulsifiable paste
Activeconstituents, phenylformic acid, hexadecanol, lavandula angustifolia, compound 13091, methyl p-hydroxybenzoate, propylparaben, propylene glycol, Xylo-Mucine, sodium lauryl sulphate, stearic acid, trolamine, Glacial acetic acid, Viscotrol C, potassium hydroxide, Sorbic Acid and pure water.
Ingredients 7: vaginal suppository
Activeconstituents, cetomacrogol 1000 BP, citric acid, PEG 1500 and 1000 and pure water.
The present invention comprises in addition:
(i) pharmaceutical composition, it comprises available vehicle, diluent or carrier on compound of the present invention and the medicine.
(ii) be used as the compound of the present invention of medicine.
Compound (iii) of the present invention is as the purposes of medicine, and it is used for the treatment of or prevents can be by suppressing the illness that neutral endopeptidase obtains useful therapeutic response.
Compound (iv) of the present invention is as the purposes of medicine, and it is used for the treatment of or prevents hyposexuality, sexual arousal dysfunction, orgasm disorder or property pain obstacle, and preferably sexual arousal dysfunction, orgasm disorder or property pain obstacle are more preferably sexual arousal dysfunction.
(v) treat the method for FSD or MED in Mammals, it comprises with the The compounds of this invention of effective dose treats this Mammals.
(pharmaceutical composition that vi) is used for the treatment of FSD or MED, it contains available vehicle, diluent or carrier on compound of the present invention and the medicine.
(the compound of the present invention that vii) is used for the treatment of FSD or MED.
(compound viii) of the present invention is used for the treatment of or prevents purposes in the medicine of FSD or MED in production.
The present invention illustrates by following non-limiting example, has used following abbreviation and definition in these embodiments:
Arbacel _Filtering medium
Br broad peak (broad)
The Boc tert-butoxycarbonyl
CDI phosphinylidyne diimidazole
The δ chemical shift
D is bimodal
The Δ heating
The DCCI dicyclohexylcarbodiimide
The DCM methylene dichloride
The DMA N,N-DIMETHYLACETAMIDE
DMF N, dinethylformamide
The DMSO methyl-sulphoxide
ES +Electrospray ionization just scans
ES -The negative scanning of electrospray ionization
Ex embodiment
H hour
The HOBt I-hydroxybenzotriazole
The HPLC high pressure liquid chromatography
The m/z mass spectra peak
Min minute
The MS mass spectrum
The NMR nucleus magnetic resonance
The Prec parent
The Prep preparation
The q quartet
S is unimodal
The t triplet
The Tf trifluoromethane sulfonyl group
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
The TLC tlc
TS +Heat atomizing ionization just scans
WSCDI 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride
1H nucleus magnetic resonance (NMR) spectrum is consistent with the structure that is proposed in all cases.Distinctive chemical shift (δ) provides with the form of " ppm of tetramethylsilane downfield ", and indicates main peak with conventional abbreviation: s for example, and unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; Br, broad peak.Following abbreviation is used for common solvent: CDCl 3, deuteriochloroform; DMSO, methyl-sulphoxide.Abbreviation " psi " expression pound/square inch, LRMS represents the low resolution mass spectroscopy.When using tlc (TLC), refer to and use silica gel 60F 254The silica gel tlc of plate, R fThe distance that the distance that moves for compound on the TLC plate moves divided by the solvent front.Fusing point is measured with Perkin Elmer DSC7 by the heating rate with 20 ℃/minute.
The available SIEMENS D5000 powder x-ray diffraction meter of powder x-ray diffraction (PXRD) figure is measured, and this powder x-ray diffraction meter is equipped with automatic sample transmodulator, θ-θ goniometer, automatic beam divergence slit, secondary monochromator and scintillometer.By being installed to, powder prepares sample on the silicon chip sample slide glass to be used for analysis.When using copper K-α 1X ray (wavelength=rotary sample when 1.5406_) shining sample, work under 40kV/40mA by X-ray tube.Analyze with the goniometer that operates under the setting of fractional scanning pattern, it is set at the mode of carrying out counting for 5 seconds with per 0.02 ° of step-length and analyzes in two whole 3 °-40 ° θ scopes.In table as a result, " angle 2-θ " is meant that crystalline spacing, given intensity are the per-cent (I/I with maximum peak 1).
Skilled crystallographer will appreciate that the relative intensity at peak may be owing to many factors change, and as crystalline orientation effect in X-ray beam, perhaps is used to the purity of the material analyzed, perhaps the degree of crystallinity of sample.The position at peak may change with specimen height, but the position at peak basically with table in listed the same.In addition, according to Bragg equation-n λ=2dsin θ, use different wavelength measurements may cause the variation of displacement.These by the variation using other wavelength and produce also within the scope of the invention.
Embodiment 1
4-methoxyl group-2-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] Methyl } butyric acid
Figure C0280540900471
(its condition is 0 ℃ of ventilation 30 minutes for 302mg, methylene dichloride 0.72mmol) (5ml) solution with the tertiary butyl ester of hydrogen chloride gas by coming self-preparing agent 1.Reaction mixture is concentrated in a vacuum, thereby then residuum and methylene dichloride azeotropic are obtained the title compound (233mg, 0.6mmol, 82%) of yellow oily; 1H NMR (CDCl 3400MHz), and δ: 1.4-1.55 (m, 2H), 1.6-1.75 (m, 6H), 1.75-1.85 (m, 2H), 2.4-2.5 (m, 1H), 2.6 (t, 2H), 3.2 (s, 3H), 3.2-3.3 (m, 2H), 3.4 (t, 2H), 3.8 (s, 3H), 5.9 (t, 1H), 6.8 (d, 2H), 7.1 (d, 2H); LRMS:m/z 390 (M-H +); With HRMS:m/z 392.2430 (C 22H 33NO 5Required value 392.2432).
The compound of following molecular formula I (seeing Table 1) can adopt the method that is similar among the embodiment 1 to prepare from specified tertiary butyl ester parent.
Figure C0280540900481
Table 1
Figure C0280540900482
Figure C0280540900491
Figure C0280540900531
Figure C0280540900541
Figure C0280540900551
Figure C0280540900581
Figure C0280540900591
Embodiment 22 also can prepare according to the methods below:
(2S)-and 2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4- The methoxyl group butyric acid
Always the product of self-preparing agent 22 (9.6g, add in methylene dichloride 21.2mmol) (52ml) solution trifluoroacetic acid (16.3ml, 212mmol), then with the solution of gained as a result at N 2In the environment in stirring at room 3.75 hours.Adding aqueous sodium carbonate (the 10%w/v solution of 95ml) in reaction system then when stirring, is 2-3 until the pH of water layer.Then layer is separated, and extract organic layer with aqueous sodium carbonate (the 10%w/v solution of 2 * 20ml).Water layer is merged, add saturated brine (80ml) then, add 2-butanone (40ml) subsequently.Layer is separated, and (2 * 50ml) extract water layer once more with 2-butanone.Organic layer is merged,,, use 2-butanone (70ml) dilution miscellany subsequently so formed crystallization then under atmospheric pressure by the volume of component distillation to 70ml.Then by filter collecting product, thereby and obtained the rough sodium salt (5.76g) of the title compound of white solid in a vacuum in 65 hours in 50 ℃ of dryings, subsequently it is come purifying by recrystallize according to the methods below.In rough product, add ethyl acetate (87ml) and ethanol (13ml), and by removing by filter remaining insoluble material.Remove ethanol (removing the solvent of 110ml) by component distillation under atmospheric pressure then and substitute, so form crystallization with ethyl acetate (145ml).Collect the crystallized product of gained as a result by filtering in a vacuum then, thereby obtain the pure sodium salt (4.51g, 10.8mmol, 51%) of the title product of white crystalline solid; M.p. (ethyl acetate) 214-216 ℃; 1H NMR (DMSO-d 6300MHz), and δ: 1.26-1.58 (m, 8H), 1.62-1.74 (m, 3H), 1.74-1.86 (m, 1H), 1.91-2.07 (m, 3H), 2.57 (t, 2H), 3.03 (q, 2H), 3.10 (s, 3H), 3.13-3.27 (m, 2H), 7.22 (d, 2H), 7.29 (d, 2H), 9.16 (t, br, 1H); LRMS (ES is negative); 789[2M-H] -( 35Cl), 394[M-H] -( 35Cl).For analysis purposes, title product (being free acid) can obtain by following method: dissolve this sodium salt in water, use the 5M hcl acidifying again, use dichloromethane extraction then.Come to remove and to desolvate by stream of nitrogen gas being blown over sample, thereby obtain title product; 1H NMR (DMSO-d 6300MHz), and δ: 1.22-1.80 (m, 11H), 1.81-1.96 (m, 2H), 1.96-2.08 (m, 1H), 2.93-2.27 (m, 1H), 2.53 (t, 2H), 3.03 (q, 2H), 3.11 (s, 3H), 3.16-3.25 (m, 2H), 7.20 (d, 2H), 7.30 (d, 2H), 7.51 (t, 1H); LRMS (ES is negative); 789[2M-H] -( 35Cl), 394[M-H] -( 35Cl); HPLC (post: ChiralPak AS (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (95/5/0.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: UV @ 220nm; Sample solution concentration: prepare 1.0mg/ml in moving phase), retention time: less important enantiomer is 11.4 minutes (5.7%), and main enantiomer is 14.3 minutes (94.3%).
The sodium salt of embodiment 22
A) Monohydrate
The aqueous isopropanol that in the sodium salt (200mg) of embodiment 22, adds 1ml moisture 3.9%.The soup compound of gained was as a result stirred 12 days, then by filtering to isolate product.PXRD figure below product has provided.
Angle 2-θ ° Intensity % % Angle 2-θ ° Intensity % % Angle 2-θ ° Intensity % % Angle 2-θ ° Intensity % %
3.552 30.8 17.708 13.5 22.881 35 30.672 15
7.154 8 17.93 29 23.141 23.2 30.952 17.5
9.526 3.1 18.313 12 23.478 15.1 31.437 15.7
10.359 15.7 18.545 23.9 24.088 13.9 31.788 13.9
10.608 14.3 18.811 14 24.313 12.6 32.114 24.6
11.03 5 19.7 34.2 24.588 22.7 32.998 13.3
12.369 3.7 19.978 100 25.013 25.8 33.375 18.8
12.939 13.2 20.273 90.6 25.514 29.9 33.815 14
13.233 12.3 20.627 51.9 25.987 25.5 34.266 14.4
13.835 14.2 20.829 29.4 27.107 18.2 35.705 15.7
14.345 37.9 20.926 28.4 27.395 30.6 35.989 14.1
14.887 16 21.443 52.7 27.869 19.2 36.514 16.7
15.16 16.8 21.611 41.6 28.716 21 38.151 14.6
16.372 24.9 21.881 21.2 28.788 19 38.925 17
16.813 6.9 22.174 24.3 28.989 27.2 39.091 19
17.203 22.1 22.472 47.1 30.232 13.4 39.961 13
17.408 32.7
Carry out dsc (DSC) with the Perkin Elmer DSC-7 instrument that the automatic sample transmodulator is installed.The sample that accurately takes by weighing about 3mg places 50 mul alumina dishes, curls then and with the lid seal that punches.Sample speed with 20 ℃/minute in 40 ℃-300 ℃ scope is heated, carry out nitrogen purge simultaneously.At 50-150 ℃ dehydrogenation reaction takes place, main thaw process occurs in 212-225 ℃.Those skilled in the art will appreciate that fusing point may change and exceeds this scope, and this is because the impure result of sample.
B) Anhydrous salt
PXRD figure below the sodium salt of embodiment 22 has provided.
Angle 2-θ ° Intensity % % Angle 2-θ ° Intensity % % Angle 2-θ ° Intensity % % Angle 2-θ ° Intensity % %
5.463 12.2 17.714 95.6 22.735 30 28.926 23.8
6.654 100 18.083 31.7 23.36 56.5 29.802 23.5
7.546 66 18.64 28.8 24.126 31.9 30.454 30.7
9.336 31.3 18.902 82.4 24.388 45.2 30.885 29.2
10.953 9.7 19.696 40.1 24.72 25.8 31.48 21
11.571 55.9 20.406 33.9 25.298 26.7 32.66 16.8
12.56 10.9 20.502 31.8 25.579 20.4 34.027 23.1
13.287 22.9 20.683 45.4 26.718 17.6 34.494 17.6
15.125 33.6 20.942 31.5 27.151 24.2 36.011 19
15.667 60.3 21.559 92.6 27.46 22.7 36.997 17.4
16.403 17.2 21.898 66.2 27.737 20.2 38.704 21.2
17.024 62.2 22.274 36.6 28.56 27.1 39.961 18.7
Preparation
Preparation 1
4-methoxyl group-2-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] Methyl } the butyric acid tertiary butyl ester
In methylene dichloride (5ml) in the room temperature product (325mg of self-preparing agent 68 in the future, 1.08mmol), the product of preparation 73 (178mg, 1.08mmol), HOBt (146mg, 1.08mmol), WSCDI (207mg, 1.08mmol) and triethylamine (0.3ml 2.16mmol) stirs 14 hours together.Reaction mixture is diluted with methylene dichloride (10ml), and water (2 * 20ml) washings.Organic layer by dried over mgso, is filtered then and concentrates in a vacuum.Adopt column chromatography (to use earlier methylene dichloride; Use methylene dichloride then: methyl alcohol 99: 1; Use methylene dichloride then: 98: 2 (R of methyl alcohol f0.2)) thereby purified product obtain yellow oily product (267mg, 0.6mmol); 1H NMR (CDCl 3400MHz), δ: 1.4 (s, 9H), 1.6 (m, 5H), 1.8 (m, 4H), 2.0 (m, 1H), 2.3 (m, 1H), 2.6 (t, 2H), 3.2 (s, 3H), 3.3 (m, 2H), 3.7 (s, 3H), 5.7 (t, 1H), 6.8 (d, 2H), 7.0 (d, 2H); LRMS:m/z 448 (M-H +).
The embodiment of following molecular formula (IVa) (being that blocking group is the compound of the general formula I V of the tertiary butyl) can adopt the method that is similar in the preparation 1 to prepare from specified parent (seeing Table 2).
Figure C0280540900641
Table 2
Figure C0280540900642
Figure C0280540900661
Figure C0280540900671
Figure C0280540900681
Figure C0280540900691
Figure C0280540900701
Figure C0280540900711
Figure C0280540900731
Figure C0280540900741
Preparation 22 also can prepare according to the methods below:
To 1,1 '-(73.9g 0.45mol) adds to come the isopropyl acetate solution of the product of self-preparing agent 69, simultaneously at N to the phosphinylidyne diimidazole in formed solution in the isopropyl acetate (339ml) of azeotropic drying 2Under the environment in the time of 60 ℃ of stirrings through 1.5 hours.Use anhydrous isopropyl acetate (50ml) washing transfer limes then.Then with the solution of gained as a result 60 ℃ of restir 4.5 hours, be cooled to room temperature and it stirred 15 hours with the relief reaction mixture.In the solution of gained as a result, add then triethylamine (46.1g, 0.46mol), add subsequently 3-(4-chloro-phenyl-) propylamine hydrochloride (J.Med.Chem., 1996,39,4942-51) (94.3g, 0.46mol).Then the miscellany of gained as a result is heated to 60 ℃ and kept 7 hours, is cooled to room temperature subsequently.Then add deionized water (100ml) in reaction mixture when stirring, adding aqueous hydrochloric acid (the 5M solution of 190ml) subsequently is 2-3 until the pH of water layer.Separate water layer then, and wash organic layer with wet chemical (the 0.5M solution of 50ml).Water phase separated, and with saturated brine solution (100ml) washing organic phase.Separate water layer then, thereby and organic phase concentrated the title compound (200.3g, 443mmol, 98% productive rate) that obtains yellow oily by distillation in a vacuum; 1H NMR (CDCl 3300MHz), δ: 1.45 (s, 9H), 1.45-1.56 (m, 1H), 1.56-1.74 (m, 6H), 1.74-2.11 (m, 7H), 2.32-2.43 (m, 1H), 2.64 (t, 2H), 3.22-3.30 (m, 2H), 3.27 (s, 3H), 3.30-3.38 (m, 2H), and 5.75-5.85 (m, br, 1H), 7.13 (d, 2H), 7.26 (d, 2H); LRMS (ES just): m/z 452[M+H] +( 35Cl).
3-(4-chloro-phenyl-) propylamine also can prepare according to the methods below:
Will be from the initial substance (11.3g of following stage b), 62mmol) be dissolved in the tetrahydrofuran (THF) (500ml), in this solution that stirs, add borine dimethyl sulphide mixture (boranedimethylsulphide complex) (30ml), and whole system was refluxed 12 hours.Reaction mixture carries out cancellation with methyl alcohol (100ml), concentrates in a vacuum then, and refluxes 4 hours in 3M HCl (200ml).Water layer is concentrated into 50ml in a vacuum, filtering precipitate then, thereby and under the pressure that lowers the dry title product (10.1g, 59.7mmol, 96%) that obtains white powder; 1H NMR (400MHz, MeOD), δ: 1.9 (quin, 2H), 2.65 (t, 2H), 2.9 (t, 2H), 7.2 (d, 2H), 7.25 (d, 2H).
The preparation of initial substance
A) 3-(4-chloro-phenyl-) methyl propionate
(14.5g adds Acetyl Chloride 98Min. (50ml) in methyl alcohol 77.1mmol) (400ml) solution, and reaction mixture was refluxed 20 hours to 3-(4-chloro-phenyl-) propionic acid that stirs (be purchased from Maybridge).Allow reaction mixture cool off after this, under the pressure that lowers, concentrate then.Residuum is dissolved among the DCM (200ml) then, and washs with 1M sodium hydroxide solution (100ml).Organic layer carries out drying with sal epsom, thereby and concentrate in a vacuum and obtain brown buttery title product (15.7g, 77mmol, 100%); 1H NMR (400MHz, CDCl 3), δ: 2.55 (t, 2H), 2.9 (t, 2H), 3.6 (s, 3H), 7.1 (d, 2H), 7.2 (d, 2H).
B) 3-(4-chloro-phenyl-) propionic acid amide
Will (15g 75.7mmol) be dissolved in the methyl alcohol (400ml), is cooled to 0 ℃ then from product a) of above-mentioned stage.Allow ammonia pass through reaction mixture in the mode that froths then, this continues 4 hours, subsequently reaction mixture is stirred 3 days.Under the pressure that lowers, remove and desolvate, then the pentane of residuum with heat ground.The dry in a vacuum title product (11.32g, 61.8ml, 82%) that just obtains white powder of remaining solid; 1H NMR (400MHz, CDCl 3), δ: 2.45 (t, 2H), 2.9 (t, 2H), 5.3 (bs, 1H), 5.5 (bs, 1H), 7.1 (d, 2H), 7.2 (d, 2H).
Preparation 67
[1-({ [3-(4-cyano-phenyl) propyl group] amino } carbonyl) cyclopentyl] ra-butyl acetate
Figure C0280540900771
In the future the product of self-preparing agent 45 (44mg, 0.1mmol) and Cu (I) CN (13.4mg 0.15mmol) is dissolved under nitrogen environment among the DMF (0.5ml), and in about 130 ℃ of stirrings 16 hours.After this, add Cu (I) CN of 13mg once more, then temperature is increased to 145 ℃ and lasting 16 hours.After this, in solution, add Cu (I) CN of last 26mg, and whole system was heated 24 hours in 160 ℃.Come the cancellation reaction by adding entry, use EtOAc (50ml) to extract organic phase subsequently and also use the salt water washing, through super-dry (MgSO 4) and evaporation and obtain xanchromatic oil.This oil process is with just obtaining title product (6mg, 16%) after the preparation type TLC purifying of 7: 3 pentanes: EtOAc as eluent; 1H NMR (400MHz, CDCl 3), δ: 1.40 (s, 9H), 1.45-1.49 (m, 2H), 1.62-1.64 (m, 4H), 1.79-1.83 (m, 4H), 1.94-2.00 (m, 2H), 2.12-2.17 (m, 2H), 2.65 (t, 2H), 3.22-3.35 (m, 2H), 5.65 (brs, 1H), 7.23 (d, 2H), 7.54 (d, 2H); LRMS:m/z (ES +) 407[M+Na].
Preparation 68
1-[2-(tert-butoxycarbonyl)-4-methoxyl group butyl] Cyclopentane carboxylic acid
Figure C0280540900781
LDA (130ml) is dissolved in the miscellany of hexane (52ml) and tetrahydrofuran (THF) (200ml) and forms solution, under nitrogen environment, in this solution that stirs, add 3-(1-carboxyl cyclopentyl) propionic acid tertiary butyl ester (12g in-78 ℃, 49.5mmol) anhydrous tetrahydro furan (100ml) solution of (see EP274234B1, embodiment 35).After 1 hour, add tetrahydrofuran (THF) (100ml) solution of 2-bromo-ethyl-methyl ether, keep temperature in-78 ℃ simultaneously.Allow reaction mixture through being warming up to room temperature whole night.Miscellany water (100ml) quenches, and with the 2M hcl acidifying to pH1, use ethyl acetate (2 * 150ml) extractions then.Merge organic extraction and with it by dried over mgso, concentrate in a vacuum then and obtain rough acid, should acid separate at the enterprising circumstances in which people get things ready for a trip spectrometry of silicon-dioxide.Be eluted in the ratio (absolute dichloromethane to 1: carry out under the condition 50), thereby obtain oily mater (7.7g, 25.6mmol, 52%) R that increases methyl alcohol in the methylene dichloride f0.3 methyl alcohol, methylene dichloride 1: 20; 1H NMR (CDCl 3400MHz), δ: 1.4 (s, 9H), 1.4-1.7 (m, 7H), 1.75-1.95 (m, 2H), 2.0-2.15 (m, 3H), 2.3-2.4 (m, 1H), 3.3 (s, 3H), 3.3-3.4 (m, 2H); LRMS:m/z 299 (M-H +).
The compound of preparation 68 also can prepare according to the methods below:
In the miscellany of heptane (41.2L) and water (30.9L), add product from following stage b) (5.15g, 12.9mol).The aqueous hydrochloric acid (the 5M solution of 2.6L) that adds dilution then when stirring is 2-3 until the pH of water layer.Separating layer then, and extract water with heptane (20.6L).The merging organic layer is used saturated brine solution (15.5L) washing then, and is under atmospheric pressure concentrated by distillation, thereby obtains the n-heptane solution (total solution weight is 44.0kg) of title compound (3.90kg, 13.0mol, 100% productive rate).Can take out a aliquots containig, and remove in a vacuum and desolvate, thereby obtain analytical sample; 1H NMR (CDCl 3300MHz), δ: 1.42 (s, 9H), 1.45-1.58 (m, 2H), 1.58-1.70 (m, 5H), 1.70-1.90 (m, 2H), 2.03-2.18 (m, 3H), 2.32-2.46 (m, 1H), 3.27 (s, 3H), 3.35 (t, 2H); LRMS (EI): m/z 244[M-C 4H 8] +, 227[M-C 4H 9O] +, 199[M-C 4H 9O 2C] +GC (syringe program: 0 ℃ of starting temperature, 150 ℃/minute of speed, 230 ℃ of outlet temperatures; Baking oven program: 100 ℃ of starting temperatures, 10 ℃/minute of speed, 230 ℃ of outlet temperatures, final 10 minutes time; Post, BP-2125m * 0.25mm ID * 0.25um FT; Detector FID), RT is 16.1 minutes.
The preparation of initial substance
A) Rough 1-[2-(tert-butoxycarbonyl)-4-methoxyl group butyl] Cyclopentane carboxylic acid
At N 2Under the environment in-10 ℃ of LDAs that provide to commerce (2M thf/n-heptane/ethylbenzene solution of 9.63kg, 23.7mol) 1, add 1-(3-tert.-butoxy-3-oxygen propyl group) Cyclopentane carboxylic acid (EP274234B1 in 2-glycol dimethyl ether (25L) solution, see embodiment 35) (2.5kg, 10.3mol) 1,2-glycol dimethyl ether (12.5L) solution, and stir time through 4 hours, keeping temperature of reaction simultaneously is-10 ℃.With 1,2-glycol dimethyl ether (2.5L) washing header tank, and with in its adding reaction system.Allow reaction mixture stir 1.75 hours then in-10 ℃.In the solution of gained as a result, add in during whole 1.75 hours 2-iodine ethyl-methyl ether (2.73kg, 14.4mol) 1,2-glycol dimethyl ether (10L) solution.Then reaction mixture was stirred 4 hours in this temperature, be warming up to 20 ℃ and be incubated 4 hours time subsequently.After this temperature stirs 8 hours, come the cancellation reaction by adding aqueous ammonium chloride solution (the 2.8M solution of 25L), add ethyl acetate (12.5L) then.When stirring, add aqueous hydrochloric acid (the 5M solution of 10L) then thereby adjusting pH to 2-3.Two-phase is mixed, separate then.Organic phase is with wet chemical (0.3M solution then; 37.5L 12.5L is 6.25L then) extract three times.Merge water, adding normal heptane (15.6L) then and add aqueous hydrochloric acid (the 5M solution of 14.5L) when stirring is 2-3 until the pH of water layer.Separating layer then, and extract water with normal heptane (15.6L).Merge organic phase, and wash, thereby concentrate the n-heptane solution (total solution weight is 21.8kg) that obtains rough title compound (2.50kg, 8.32mol, 81% productive rate) in a vacuum then with saturated brine (3.1L).
B) Hexamethylene ammonium 1-[2-(tert-butoxycarbonyl)-4-methoxyl group butyl] cyclopentane carboxylate
Under atmospheric pressure pass through the concentrated n-heptane solution (5.51kg, 18.3mol, the solution of gross weight 41.4kg) of distillation, thereby remove the normal heptane of 20L from crude product a) of above-mentioned stage.In the solution of gained as a result, add hexahydroaniline (1.82kg, normal heptane 18.4mol) (9.9L) solution in during whole 0.5 hour.Use normal heptane (1.1L) washing transfer limes then, and it is added in the reaction system.Allow as a result in 22 ℃ of stirrings the soup compound of gained becomes particle then, this process will continue 19.5 hours time.By filter to collect product and with normal heptane (2 * 11.0L) washings, then with the solid of gained as a result in a vacuum in 50 ℃ of dryings 20 hours.(6.2kg 15.5mol) is suspended in the isopropyl acetate (37.2L), then the suspension of gained as a result is heated to 80 ℃ until obtaining clear soln with the pale solid of gained as a result.Then the solution of gained as a result is cooled to 50 ℃, and the sample (1.0g) that adds real crystallization title compound forms to promote crystalline as crystal seed.Will be just be cooled to 20 ℃ and kept 4 hours, carried out granulating 0.5 hour in this temperature then at the crystalline soup compound.Then by filter collecting product and (2 * 6.2L) washings are subsequently in a vacuum in 45 ℃ of dryings 11 hours with normal heptane.(5.5kg 13.8mol) is suspended in the isopropyl acetate (55.0L), and is heated to 80 ℃ until obtaining clear soln with the white solid of gained as a result then.Then the solution of gained as a result is cooled to 50 ℃, and the sample (1.0g) that adds real crystallization title compound forms to promote crystalline as crystal seed.Will be just be cooled to 20 ℃ and kept 4 hours, carried out granulating 22.5 hours in this temperature then at the crystalline soup compound.Also (2 * 5.5L) wash, thereby obtain title product (5.15kg, 12.9mol, 94% productive rate) in 16.5 hours in 45 ℃ of dryings in a vacuum subsequently with normal heptane to pass through to filter the collection product then; M.p. (heptane) 121 ℃; 1H NMR (CDCl 3300MHz), δ: 1.06-1.37 (m, 7H), 1.42 (s, 9H), 1.50-1.67 (m, 5H), 1.67-1.86 (m, 5H), and 1.86-2.18 (m, 5H), 2.30-2.58 (m, 1H), 2.80-2.93 (m, 1H), 3.29 (s, 3H), 3.35 (q, 2H), 7.29 (s, br, 3H); Analytical value C, 66.20; H, 10.26; N, 3.50; C 22H 41NO 5Required value C, 66.13; H, 10.34; N, 3.51%.
Preparation 69
1-[(2S)-and 2-(tert-butoxycarbonyl)-4-methoxyl group butyl] Cyclopentane carboxylic acid
In the future the product of self-preparing agent 68 and (+) thereby-pseudo-ephedrine recrystallize from hexane obtains the solid of white crystals for 9 times.This salt is dissolved in the ethyl acetate also with 0.5M salt acid elution, pass through dried over mgso then, and concentrate in a vacuum, thereby obtaining (the S)-acid of light yellow oily with 31% yield, its NMR analysis by δ 3.3 peaks of (+)-pseudo-ephedrine salt has＞90%ee; 1H NMR (CDCl 3400MHz), δ: 1.4 (s, 9H), 1.4-1.7 (m, 7H), 1.75-1.9 (m, 2H), 2.0-2.15 (m, 3H), 2.35-2.45 (m, 1H), 3.3 (s, 3H), 3.3-3.4 (m, 2H); [α] D-5.2 (EtOH, c 1.2).
Preparation 69 also can prepare according to the methods below:
Under nitrogen environment in 20 ℃ always the product of self-preparing agent 68 (3.90kg, add in heptane 13.0mol) (58.5L, total solution weight the are 44.0kg) solution (1S, 2S)-(+)-pseudo-ephedrine (2.13kg, 12.9mol).When stirring, suspension is heated to 70 ℃ until obtaining clear soln then.Solution is cooled to 40 ℃ then, and the sample (0.8g) that adds real crystallization title compound forms to promote crystalline as crystal seed.The temperature of miscellany was kept 2 hours in 40 ℃, then soup compound is cooled to 20 ℃ and kept 6 hours.Collect product by filtering then, and with heptane (2 * 2.3L) washing, thereby obtained (1S in 22 hours in 50 ℃ of dryings in a vacuum subsequently, 2S)-1-hydroxy-n-methyl isophthalic acid-phenyl-2-third ammonium 1-[(2S)-2-(tert-butoxycarbonyl)-4-methoxyl group butyl] cyclopentane carboxylate (3.20kg, 6.87mol, 53% yield), warp 1H NMR measures its form with 86: 14 miscellanys of diastereo-isomerism salt and exists.(3.20kg 6.87mol) is suspended in the heptane (30L), and is heated to 70 ℃ until obtaining clear soln with product then.Then the solution of gained as a result is cooled to 58 ℃, and the sample (1.0g) that adds real crystallization title compound forms to promote crystalline as crystal seed.Solution was kept 1 hour in 58 ℃, be cooled to 20 ℃ and kept 6 hours then.Then with soup compound in 20 ℃ of granulatings 12 hours.Collect product by filtering, and (2 * 2L) wash with heptane.Thereby in vacuum drying oven, obtained the solid (1S of white crystals in 22.5 hours in 50 ℃ of dryings, 2S)-1-hydroxy-n-methyl isophthalic acid-phenyl-2-third ammonium 1-[(2S)-2-(tert-butoxycarbonyl)-4-methoxyl group butyl] cyclopentane carboxylate (2.35kg, 5.0mol, 73% yield); M.p. (heptane) 95 ℃; 1H NMR (CDCl 3300MHz), δ: 1.08 (d, 3H), 1.48 (s, 10H), 1.56-1.74 (m, 4H), 1.74-1.90 (m, 2H), 1.90-2.03 (m, 2H), and 2.03-2.27 (m, 2H), 2.4-2.53 (m, 1H), 2.66 (s, 3H), 3.08 (dq, 1H), 3.24 (s, 3H), 3.38 (q, 2H), 4.58 (d, 1H), 7.27-7.45 (m, 5H), 7.70 (s, br, 3H); Analytical value C, 67.06; H, 9.35; N, 3.04; C 26H 43NO 6Required value C, 67.07; H, 9.31; N, 3.01%.Title compound obtains by salt decomposition according to the methods below.With (1S, 2S)-1-hydroxy-n-methyl isophthalic acid-phenyl-2-third ammonium 1-[(2S)-2-(tert-butoxycarbonyl)-4-methoxyl group butyl] cyclopentane carboxylate (210g, 0.45mol) place deionized water (1.26L) and isopropyl acetate (1.47L) to form suspension, (the 5M solution of 99.5ml is 2-3 until the pH of water layer 0.50mol) to add aqueous hydrochloric acid in the suspension of this stirring.Then layer is separated, and extract water with isopropyl acetate (630ml).Merge organic extraction then, and wash with saturated brine solution (420ml).Under atmospheric pressure concentrate (isopropyl acetate of removing 1.4L) then by distillation thus obtain the isopropyl acetate solution of title compound, it is directly used in next step.Can take out a aliquots containig, thereby and remove to desolvate and obtain analytical sample; 1HNMR (CDCl 3300MHz), δ: 1.44 (s, 9H), 1.48-1.59 (m, 2H), 1.59-1.72 (m, 5H), 1.72-1.93 (m, 2H), 2.03-2.18 (m, 3H), 2.35-2.46 (m, 1H), 3.31 (s, 3H), 3.38 (t, 2H); LRMS (EI): m/z 244[M-C 4H 8] +, 227[M-C 4H 9O] +, 199[M-C 4H 9O 2C] +GC (syringe program: 0 ℃ of starting temperature, 150 ℃/minute of speed, 230 ℃ of outlet temperatures; Baking oven program: 100 ℃ of starting temperatures, 10 ℃/minute of speed, 230 ℃ of outlet temperatures, final 20 minutes time; Post, BP-2125m * 0.25mm ID * 0.25um FT; Detector FID), retention time is 16.0 minutes.HPLC (post: ChiralPak AD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1 v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: less important enantiomer is 15.5 minutes (3.3%), and main enantiomer is 17.5 minutes (96.7%).
Come the product of self-preparing agent 69 also can prepare by asymmetric hydrogenation, it uses many following catalyzer and conditions:
I) Hydrogenation 1
Will be from the initial substance (62mg of following stage c), 0.21mmol) and [(R)-(+)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl chlorine (p-cymene)] ruthenium muriate (J.Org.Chem.1994,59,3064-76) (2.0mg 0.0021mmol) packs in the pressurized vessel.Container cleans emptying then with the nitrogen that is forced into 10bar.Then this wash procedure is repeated 4 times again.Add degassing methyl alcohol (2ml) then.Container pressurizes with hydrogen (10bar), and hydrogen (10bar) pressurization is also used in emptying once more then.Miscellany was stirred 18 hours in 65 ℃ (oil bath temperature).After being cooled to room temperature, relief pressure also removes under the pressure that lowers and desolvates, thereby obtains the buttery title compound; HPLC (post: ChiralPak AD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: the R enantiomer is 15.5 minutes, and the S enantiomer is 17.5 minutes; 91% transforms, the S enantiomer, and ee 97%.
Ii) Hydrogenation 2
Will be from the initial substance (82mg of following stage c), 0.27mmol), sodium tert-butoxide (25mg, 0.26mmol) and [(S)-3,3 ', 4,4 ', 5,5 '-hexamethyl (6,6 '-phenylbenzene)-2,2 '-two bases] (2.5mg's two trifluoroacetates (seeing WO 01/94359) of two (diphenylphosphino) ruthenium 0.0027mmol) packs in the pressurized vessel.Container cleans emptying then with the nitrogen that is forced into 10bar.Then this wash procedure is repeated 4 times again.Add degassing methyl alcohol (2ml) then.Container pressurizes with hydrogen (10bar), and hydrogen (10bar) pressurization is also used in emptying once more then.Miscellany was stirred 18 hours in 65 ℃.Allow container be cooled to room temperature, then relief pressure.In reaction mixture, add then ethyl acetate/heptane (1: 1,10ml) and hydrochloric acid (1M, 5ml).Separate organic phase, and, obtain the buttery title compound thereby under the pressure that lowers, remove to desolvate then by dried over mgso; HPLC (post: ChiralPak AD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: the R enantiomer is 15.5 minutes, and the S enantiomer is 17.5 minutes;＞98% transforms, the R enantiomer, and ee 91%.
Iii) Hydrogenation 3
By use with on regard to hydrogenation 2 described same methods, but be to use [(R)-(6,6 '-dimethoxy phenylbenzene-2,2 '-two bases) two (diphenylphosphino)] the two trifluoroacetates (EP398132) of ruthenium are as pre-catalyst (pre-catalyst), can obtain the buttery title compound; HPLC (post: ChiralPak AD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1 v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: the R enantiomer is 15.5 minutes, and the S enantiomer is 17.5 minutes; 57% transforms S enantiomer, ee＞98%.
Iv) Hydrogenation 4
Will be from the initial substance (80mg of following stage i); 0.25mmol) and [(R)-(-)-4; the adjacent formyl radical-(1 of two (di-isopropyl phosphino-)-[2.2]-two polyphenylene ethyls of 12-; the 5-cyclooctadiene)] rhodium (I) a tetrafluoro borate (J.Am.Chem.Soc.1997; 119; 6207-6208) (1.8mg 0.0025mmol) packs in the pressurized vessel.Container cleans emptying then with the nitrogen that is forced into 10.5bar.Then this wash procedure is repeated 4 times again.Add degassing methyl alcohol (2ml) then.Container pressurizes with hydrogen (10.5bar), and hydrogen (10.5bar) pressurization is also used in emptying once more then.With miscellany in stirring at room 18 hours, relief pressure then.In reaction mixture, add t-butyl methyl ether and 2M hydrochloric acid, and two-phase is mixed.Separate organic phase, and, obtain the buttery title compound thereby under the pressure that lowers, remove to desolvate then by dried over mgso; HPLC (post: ChiralPak AD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1 v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: the R enantiomer is 15.5 minutes, and the S enantiomer is 17.5 minutes;＞98% transforms, the R enantiomer, and ee 91%.
V) Hydrogenation 5
Will be from the initial substance (80mg of following stage i), 0.25mmol) and [(S)-3,3 ', 4,4 ', 5,5 '-hexamethyl (6,6 '-phenylbenzene)-2,2 '-two bases] (2.3mg's two trifluoroacetates (seeing WO 01/94359) of two (diphenylphosphino) ruthenium 0.0025mmol) packs in the pressurized vessel.Container cleans emptying then with the nitrogen that is forced into 10.5bar.Then this wash procedure is repeated 4 times again.Add degassing methyl alcohol (2ml) then.Container pressurizes with hydrogen (10.5bar), and hydrogen (10.5bar) pressurization is also used in emptying once more then.In 45 ℃ of stirrings 18 hours, allow it be cooled to room temperature then miscellany.Relief pressure adds t-butyl methyl ether and 2M hydrochloric acid then in reaction mixture, and two-phase is mixed.Separate organic phase, and, obtain the buttery title compound thereby under the pressure that lowers, remove to desolvate then by dried over mgso; HPLC (post: ChiralPak AD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1 v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: the R enantiomer is 15.5 minutes, and the S enantiomer is 17.5 minutes;＞98% transforms, the R enantiomer, and ee 97%.
Vi) Hydrogenation 6
Will be from the initial substance (80mg of following stage i), 0.25mmol) and [(R)-(+)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl] the two trifluoroacetates of ruthenium (2.4mg, 0.0025mmol) or [(R)-(+)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl chlorine (p-cymene)] ruthenium muriate (J.Org.Chem.1994,59,3064-76) (2.4mg 0.0025mmol) packs in the pressurized vessel.Can obtain the buttery title compound by the same program described in use and the preparation 6; HPLC (post: ChiralPakAD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1 v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: the R enantiomer is 15.5 minutes, and the S enantiomer is 17.5 minutes;＞98% transforms S enantiomer, ee＞98%.
Vii) Hydrogenation 7
Will be from the initial substance (80mg of following stage i), 0.25mmol) and [(R)-(6,6 '-dimethoxy phenylbenzene-2,2 '-two bases) two (diphenylphosphino)] (2.3mg's two trifluoroacetates (EP398132) of ruthenium 0.0025mmol) packs in the pressurized vessel.Can obtain the buttery title compound by the same program described in use and the hydrogenation 6; HPLC (post: ChiralPak AD (25 * 0.46cm); Moving phase: hexane/IPA/ acetate (98/2/0.1v/v/v); Rinsing moving phase: hexane/IPA/DEA (80/20/.5 v/v/v); Flow velocity: 1.0ml/ minute; Temperature: envrionment temperature; Volume injected: 20 μ l; Detect: ELSD), working time: 20 minutes, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently, use hexane/IPA/ acetate (98/2/0.1 v/v/v) to carry out rinsing in 10 minutes subsequently; Retention time: the R enantiomer is 15.5 minutes, and the S enantiomer is 17.5 minutes;＞98% transforms S enantiomer, ee＞98%.
The preparation of initial substance
A) 1-(2-tert-butoxycarbonyl-4-methoxyl group-3-oxygen-butyl)-Cyclopentane carboxylic acid
(35.0ml, THF 250mmol) (70ml) solution is cooled to-15 ℃ in nitrogen environment with Diisopropylamine.(2.5M, 100ml 250mmol), keep temperature to be lower than-10 ℃ simultaneously dropwise to add n-Butyl Lithium then.(27.52g, THF 113.6mmol) (50ml) solution stir reaction system 1 hour in-10 to-15 ℃ then to add 1-(3-tert.-butoxy-3-oxygen propyl group) Cyclopentane carboxylic acid (see EP274234B1, embodiment 35) in the solution of gained as a result.THF (20ml) solution that adds methoxyimino acetic acid methyl esters (18.0ml) in reaction mixture allows then as a result the miscellany of gained is warming up to room temperature, stirs subsequently 19 hours.In reaction mixture, add t-butyl methyl ether (300ml) and deionized water (300ml), when stirring, use 2M hcl acidifying water then to pH3.Separate two-phase, use t-butyl methyl ether (250ml) to extract water then.Merge organic phase and water (250ml) and salt solution (250ml) washing successively,, under the pressure that lowers, remove then and desolvate again by dried over mgso.Then by using ethyl acetate/heptane (1: 2-1: 1) come the title compound of purification of crude as the flash chromatography on the silica gel of eluent, thereby obtain title compound (17.35g, 55.2mmol, 49% productive rate); 1H NMR (400MHz, CDCl 3), δ: 1.43 (s, 9H), 1.69-1.47 (m, 6H), 2.17-2.05 (m, 2H), 2.18 (dd, 1H), 2.32 (dd, 1H), 3.42 (s, 3H), 3.59 (t, 1H), 4.17 (q, 2H); 13C NMR (100MHz, CDCl 3), δ: 24.7,27.8,34.9,35.8,36.7,53.2,53.3,59.2,82.3,168.3,183.4,203.2.
B) 8-methoxymethyl-6-oxygen-7-oxa--spiral shell [4.5] decane-9-carboxylic acid tertiary butyl ester
Will (10.50g, methanol solution 33.4mmol) (100ml) be cooled to 0 to-5 ℃ in nitrogen environment from product a) of above-mentioned stage.Gradation adds sodium borohydride (2.02g 53.4mmol), keeps temperature to be lower than 0 ℃ simultaneously in the solution of gained as a result then.Then reaction system was stirred 1 hour.Add ethyl acetate (150ml) and water (150ml) subsequently, and when stirring, come the acidifying water by adding hydrochloric acid (the 2M solution of 50ml).Separate two-phase then, and extract water with ethyl acetate (100ml).Merge organic phase and water (50ml) and salt solution (50m1) washing successively.Merge the aqueous solution of washing and use ethyl acetate (100ml) to extract.The combined ethyl acetate extract also passes through dried over mgso, removes under the pressure that lowers then and desolvates, thereby obtain lurid oil (11.29g), and it does not need further purifying and is used for next step.The part that this is oily (10.89g 34.4mmol) is dissolved under nitrogen environment among the THF (100ml), and in the solution of gained as a result, add dicyclohexylcarbodiimide (7.10g, 34.4mmol).Then with miscellany in stirring at room 19 hours.In reaction system, add methyl alcohol (5ml) and acetate (2ml) then, and miscellany was stirred 30 minutes.Under the pressure that lowers, remove subsequently and desolvate.Then rough product is suspended in the ethyl acetate (50ml), and by removing by filter byproduct of reaction.With ethyl acetate (50ml) washing leaching cake, then filtrate is concentrated under the pressure that lowers.Then by using ethyl acetate/heptane (1: 3-2: 3) come the title compound of purification of crude as the flash chromatography on the silica gel of eluent, thereby obtain the title compound (8.19g that exists with 2: 1 diastereoisomer miscellany form, 27.4mmol, 80%); For analysis purposes, come the purifying sample as the flash chromatography on the silica gel of eluent by using EtOAc/ heptane (1: 2); I) point of higher rf (single diastereoisomer); 1H NMR (400MHz, CDCl 3), δ: 1.47 (s, 9H), 1.50-2.15 (m, 9H), 2.30 (m, 1H), 2.90 (td, 1H), 3.38 (s, 3H), 3.58 (d, 2H), 4.62 (dt, 1H); 13C NMR (100MHz, CDCl 3), δ ppm 25.5,25.8,28.0,36.9, and 38.3,39.6,40.4,47.8,59.5,73.1,79.5,81.8,171.3,176.5; Ii) hang down the point (non-isolating fully, 3.5: 1 diastereoisomer miscellany) of rf; 1H NMR (400MHz, CDCl 3), δ: (main isomer) 1.47 (s, 9H), 1.49-2.10 (m, 8H), 2.18 (dd, 1H), 2.43 (m, 1H), 3.03 (m, 1H), 3.35 (s, 3H), 3.60-3.67 (m, 2H), 4.72 (q, 1H).
C) 1-(2-tert-butoxycarbonyl-4-methoxyl group-Ding-2E-thiazolinyl)-Cyclopentane carboxylic acid
To product (6.11g from above-mentioned stage b), 20.49mmol) toluene (50ml) solution in add 1,8-diaza-dicyclo [5.4.0] 11-7-alkene (3.7ml, 24.58mmol), then with the solution of gained as a result reflux 5 hours under nitrogen environment.Then solution is cooled to room temperature, and under the pressure that lowers, removes and desolvate.Residuum to gained as a result adds deionized water (100ml), uses t-butyl methyl ether (30ml) to extract miscellany then.Separate two-phase then, and with hydrochloric acid (the 2M solution of 15ml) acidifying water to pH2, (2 * 30ml) extract to use t-butyl methyl ether subsequently.Merge organic extraction and water (30ml) and salt solution (30ml) washing successively, pass through dried over mgso again.Under the pressure that lowers, remove then and desolvate, thereby obtain rough title compound (6.29g), subsequently it is crystallized out from heptane (15ml) in 0 ℃.By filter collecting the solid of gained as a result, and ice-cold then heptane (2 * 5ml) washings, thus the title compound (29%, the E-isomer is determined according to chemical shift for 1.79g, 6.0mmol) of white solid obtained; 1H NMR (400MHz, CDCl 3), δ: 1.47 (s, 9H), 1.45-1.70 (m, 6H), 2.05-2.10 (m, 2H), 2.74 (s, 2H), 3.36 (s, 3H), 4.09 (d, 2H), 6.75 (t, 1H); 13C NMR (100MHz, CDCl 3), δ: 23.9,28.0,34.1,35.0,55.0,58.6,69.2,80.8,132.7,139.1,167.1,183.3.
Thereby filtrate concentrating obtained xanchromatic oil (4.02g).By using ethyl acetate/heptane (1: 2+0.5% acetate) come this miscellany of purifying, thereby obtain more title compound and colourless oil (2.43g, 1.1: 1 E/Z ratios) as the flash chromatography on the silica gel of eluent; 1-(2-tert-butoxycarbonyl-4-methoxyl group-Ding-2Z-thiazolinyl)-Cyclopentane carboxylic acid: 1H NMR (400MHz, CDCl 3), δ: (crucial signal) 1.48 (s, 9H), 2.65 (s, 2H), 3.33 (s, 3H), 4.29 (d, 2H), 5.99 (t, 1H).
Also can separating ethene ether 1-[(3E by flash chromatography)-2-(tert-butoxycarbonyl)-4-methoxyl group-3-butenyl] sample (the E geometry is determined according to coupling constant) of Cyclopentane carboxylic acid: 1H NMR (400MHz, CDCl 3), δ: 1.42 (s, 9H), 1.40-1.70 (m, 6H), 2.03 (d, 2H), 2.06 (m, 1H), 2.17 (m, 1H), 2.83 (s, 1H), 3.49 (s, 3H), 4.66 (dd, 1H), 6.35 (d, 1H); 13C NMR (100MHz, CDCl 3), δ: 24.9,25.2,28.4,34.7,38.8,41.7,44.3,53.5,56.1,80.9,101.9,149.2,174.5,184.5.
D) The 3-tertiary butyl-2-(2-methoxy ethyl) propanedioic acid 1-benzyl ester
(60% dispersion in the 14.4g mineral oil, THF 360mmol) (300ml) suspension is cooled to 0 ℃ under nitrogen environment with the sodium hydride that stirs.During whole 45 minutes, in the soup compound of gained as a result, add the tertiary butyl-propanedioic acid benzyl ester (90.0g, THF 360mmol) (500ml) solution.Allow reaction mixture be warming up to room temperature, stirred then 1 hour.Reaction mixture is cooled to 0 ℃ once more, adds 2-bromo-ethyl-methyl ether (50.0g, THF 360mmol) (100ml) solution in then during whole 0.5 hour.Allow reaction system be warming up to room temperature then, and stirred 19 hours.Reaction system was refluxed 24 hours, be cooled to room temperature then.Add deionized water (500ml) in reaction mixture, (3 * 500ml) extract product to use ethyl acetate then.Merge organic phase and pass through dried over mgso, under the pressure that lowers, concentrate then, thereby obtain rough buttery product (100g) by distillation.Come purified product by the column chromatography on the silica gel (eluent is the n-heptane solution of 10% ether, is the n-heptane solution of 20% ether then) then, thereby obtain buttery title compound (37.1g, 120mmol, 33% productive rate); TLC (ether/heptane 3: 7 is used Dragendorff ' s immersion liquid colour developing) R f0.25; 1H NMR (300MHz, CDCl 3), δ: 1.4 (s, 9H), 2.13 (dt, 2H), 3.30 (s, 3H), 3.43 (t, 2H), 3.51 (t, 1H), 5.20 (d, 2H), 7.29-7.40 (m, 5H).
E) 2-(tert-butoxycarbonyl)-4-methoxyl group butyric acid
Will from the product of above-mentioned stage d) (37.1g 120mmol) is dissolved in diox (740ml) and the water (111ml), when stirring, in this solution, add potassium hydroxide (6.73g, 120mmol).Then with the solution of gained as a result in stirring at room 19 hours.Under the pressure that lowers, desolvate, then with the concentrated solution of gained deionized water (300ml) dilution as a result by distilling to remove.Use ether (3 * 400ml) wash water solution then.Adding 1M hydrochloric acid to aqueous phase subsequently is 2 until pH.(3 * 400ml) extract acidifying solution, merge organic layer then and pass through dried over mgso with ethyl acetate.Under the pressure that lowers, desolvate, thereby obtain buttery title compound (14.7g, 67.4mmol, 56% productive rate) by distilling to remove; TLC (ether/heptane 3: 7 is used Dragendorff ' s immersion liquid colour developing) R f0.20; 1H NMR (300MHz, CDCl 3), δ: 1.48 (s, 9H), 2.16 (dt, 2H), 3.16 (s, 3H), 3.27-3.51 (m, 3H).
F) 2-(2-methoxy ethyl) vinylformic acid tertiary butyl ester
To from the product of above-mentioned stage e) (20.8g, add in pyridine 95.3mmol) (170ml) solution piperidines (1.70ml, 19.1mmol), add subsequently paraformaldehyde (3.89g, 130mmol).Then with the miscellany of gained as a result in 63 ℃ of heating 3.5 hours.Allow reaction mixture be cooled to room temperature then and stirred 19 hours.Under the pressure that lowers, desolvate subsequently by distilling to remove.In concentrated solution, add deionized water (250ml), add hydrochloric acid (the 2M solution of 200ml) subsequently.(1 * 350ml 2 * 400ml) extracts water subsequently to use ether then.Merge organic extraction, use hydrochloric acid (the 2M solution of 400ml) washing then, and pass through dried over mgso.Thereby under the pressure that lowers, remove to desolvate and obtain the buttery title compound. 1H NMR(300MHz，CDCl 3)，δ：1.50(s，9H)，2.56(t，2H)，3.35(s，3H)，3.46-3.53(m，2H)，5.54(s，1H)，6.13(s，1H)；LRMS(EI)：m/z 130[M-C 4H 8] +，113[M-C 4H 9O] +。
G) (2E)-and 2-(2-methoxy ethyl)-3-[(4-aminomethyl phenyl) alkylsulfonyl]-the 2-propylene The acid tertiary butyl ester
Under nitrogen environment in room temperature to tolysulfonyl iodine (the J.Chem.Soc.Perkin Trans. that stirs, 1,1988,1029) (11.4g, 40.2mmol) methylene dichloride (25.0ml) solution in add product (5.0g, methylene dichloride 26.8mmol) (10ml) solution from above-mentioned stage f).Then with the solution stirring of gained as a result 60 hours.Compound of reaction is cooled to 0 ℃, and (5.4g, 53.4mmol), keeping temperature simultaneously is 0 ℃ to add triethylamine in then during whole 15-20 minute.The miscellany of gained was as a result stirred 0.5 hour in 0 ℃, be warming up to room temperature and restir then 5 hours.React by adding deionized water (100ml) cancellation then, and separating layer.Extract water with methylene dichloride (100ml), merge organic extraction then and use hydrochloric acid (the 1M solution of 50ml) washing.Then successively with sodium thiosulfate solution (the 5%w/v solution of 100ml) and deionized water (100ml) washing organic layer.Organic layer is passed through dried over mgso, and under the pressure that lowers, remove and desolvate, thereby obtain dark-coloured buttery crude product (7.5g, 22.0mmol, 82% productive rate).Repeat twice this reaction again with same condition, merge crude product (74.6g) then and come purifying as the flash chromatography on the silica gel of eluent, thereby obtain the title compound (48.0g) of white crystalline solid by use heptane/ethyl acetate (4: 1); M.p. (heptane/ethyl acetate) 84-86 ℃; TLC (ethyl acetate/heptane 1: 4 develops the color with UV @ 254nm) R f0.20; 1HNMR (300MHz, CDCl 3), δ ppm 1.45 (s, 9H), 2.48 (s, 3H), 3.14 (t, 2H), 3.30 (s, 3H), 3.51 (t, 2H), 7.10 (s, 1H), 7.35 (d, 2H), 7.83 (d, 2H).
H) 1-[(1E)-and 2-(tert-butoxycarbonyl)-4-methoxyl group-1-butylene base] Cyclopentane carboxylic acid
In anhydrous THF (200ml) solution of the LDA (2M THF/ heptane/ethylbenzene solution of 64.6ml) that stirs, add Cyclopentane carboxylic acid (7.0ml in 0 ℃, 58.7mmol) anhydrous THF (100ml) solution, this process under nitrogen environment through whole 10 minutes time.Allow reaction system be warming up to room temperature then, stirred simultaneously 2.5 hours.Then the soup compound of gained as a result is cooled to 0 ℃, adds zinc chloride (the 1M diethyl ether solution of 38.2ml) in subsequently during whole 1 minute.Reaction mixture was stirred 10 minutes, then during whole 5 minutes in the solution of gained as a result adding from product (20.0g, anhydrous THF (160ml) solution 58.7mmol) of above-mentioned stage g).Then reaction mixture was stirred 2 hours, keeping temperature simultaneously is 0-5 ℃.Allow reaction system be warming up to room temperature then and stirred 19 hours.Come the cancellation reaction by adding Virahol (120ml), subsequently miscellany was stirred 1 hour.Reaction mixture is filtered, and wash solid by-product with THF (10ml).In filtrate, add deionized water (400ml), aqueous sodium hydroxide solution (the 1M solution of 200ml) and ethyl acetate (600ml) then.Add more deionized water (600ml) then, and by removing by filter resultant solid.Separating layer then, and to add hydrochloric acid (1M solution) to aqueous phase be 2 until pH.(2 * 700ml) extract water, merge organic layer then, and by dried over mgso, desolvate by distilling to remove under the pressure that lowers subsequently, thereby obtain the crude product (16.7g) of yellow oily with ethyl acetate.Come purified product by use methylene chloride (9: 1) as the flash chromatography on the silica gel of eluent then, thereby obtain the title compound (15.2g, 50.9mmol, 87% productive rate) of yellow oily; TLC (methylene chloride 9: 1 develops the color with UV @ 254nm) R f0.70; 1H NMR (300MHz, CDCl 3), δ ppm 1.48 (s, 9H), 1.67-1.90 (m, 6H), 2.37-2.48 (m, 2H), 2.58 (t, 2H), 3.32 (s, 3H), 3.48 (t, 2H), 6.83 (s, 1H); LRMS (ES is negative): m/z 253[M-CO 2H] -
I) 1-[(1E)-and 2-(tert-butoxycarbonyl)-4-methoxyl group-1-butylene base] the pentamethylene carboxylic Acid sodium
To the product that stirs from above-mentioned stage h) (15.0g, add in isopropyl acetate 50.3mmol) (300ml) solution sodium methylate (3.0g, 55.6mmol).Then with the suspension of gained as a result in stirring at room 19 hours.In a vacuum by solid collected by filtration and with isopropyl acetate washing, then in 50 ℃ in vacuum drying oven dry 19 hours, thereby obtain the title compound (10.0g, 31.2mmol, 62% productive rate) of white solid; M.p. (isopropyl acetate) 195-198 ℃; 1H NMR (300MHz, CDCl 3), δ ppm 1.48 (s, 9H), 1.51-1.72 (m, 6H), 2.21-2.37 (m, 2H), 2.61 (t, 2H), 3.34 (s, 3H), 3.51 (t, 2H), 6.86 (s, 1H); LRMS (ES is negative): m/z 253[M-CO 2Na] -
Preparation 70
1-[(2R)-and 3-tert.-butoxy-2-methyl-3-oxygen propyl group] Cyclopentane carboxylic acid
According to preparing title compound with preparation 68 and 69 similar methods (replacing the 2-bromo-ethyl-methyl ether) with methyl iodide.With its (+)-pseudo-ephedrine salt recrystallize three times from hexane.Yield with 28% obtains the title compound of light yellow oily, and its NMR by δ 1.4 peaks of (+)-pseudo-ephedrine salt analyzes to have＞95%ee; 1H NMR (CDCl 3400MHz), δ 1.13 (d, 3H), 1.40-1.60 (m, 11H), 1.60-1.78 (m, 5H), 2.14 (m, 3H), 2.38 (m, 1H); [α] D-24.2 (EtOH, c 1.2).
Preparation 71
1-[(2R)-2-(tert-butoxycarbonyl)-4-amyl group]-Cyclopentane carboxylic acid
Figure C0280540900941
With (R)-1-[2-(tert-butoxycarbonyl)-4-pentenyl]-Cyclopentane carboxylic acid (WO9113054, embodiment 10) (10g, 35.4mmol) and palladium-charcoal (600mg) of 10% place dehydrated alcohol (25ml), the miscellany of gained carried out hydrogenation 18 hours under 1 normal atmosphere and room temperature.Pass through Arbocel _Reaction mixture is filtered, thereby filtrate is evaporated the title compound (9.6g, 95%) that obtains yellow oily under the pressure that lowers; 1HNMR (CDCl 3, 0.86 (t, 3H), 1.22-1.58 (m, 15H), 1.64 (m, 4H), 1.78 (dd, 1H), 2.00-2.18 (m, 3H), 2.24 (m, 1H); [α] D=-3.3 ° (c=0.09, ethanol).
Preparation 72
3-(4-p-methoxy-phenyl)-2-vinyl cyanide
Figure C0280540900942
With 4-phenyl-iodide methyl ether (1g, 4.2mmol), vinyl cyanide (0.3ml, 4.7mmol), the tri-o-tolyl phosphine (243mg, 0.4mmol), acid chloride (II) (90mg, 0.4mmol) and triethylamine (1.78ml, acetonitrile 12mmol) (20ml) solution refluxed in nitrogen environment 14 hours.Also wash with EtOAc (50ml) diluting reaction miscellany, then organic layer is also filtered by dried over mgso with 2M sodium bicarbonate (100ml).Filtrate evaporated in a vacuum and (use pentane by column chromatography, 95: 5 pentanes then: ethyl acetate, 90: 10 pentanes then: ethyl acetate) carry out purifying, thereby obtain yellow crystals the title compound that exists with form suitable, the trans isomer miscellany (414mg, 2.5mmol). 1H NMR (CDCl 3400MHz), δ: 3.8 (s, 3H), 5.7 (d, 1H), 6.9 (d, 1H), 7.2 (d, 1H), 7.4 (d, 2H); LRMS:m/z 176 (M+NH 4 +); Analytical value C, 74.44; H, 5.66; N, 8.36; C 10H 39NO0.1H 2O required value C, 74.42; H, 5.65; N, 8.41%.
Preparation 73
3-(4-p-methoxy-phenyl)-1-propylamine
Figure C0280540900951
(414mg 2.6mmol) is dissolved in solution of ammonium hydroxide (10ml) and the ethanol (10ml) product of self-preparing agent 72, then formed solution is shaken 12 hours with Ra-Ni (100mg) under the hydrogen environment of 40p.s.i. in the future.Reaction mixture filtered by arbocel and with ethanol (20ml) washing, thus then filtrate is evaporated in a vacuum the title compound that obtains yellow oily (183mg, 1.1mmol); 1H NMR (CDCl 3400MHz), δ: 1.7 (bs, 2H), 2.0 (bs, 2H), 2.5 (t, 2H), 2.7 (bs, 2H), 3.7 (s, 3H), 6.7 (d, 2H), 7.0 (d, 2H); LRMS:m/z 376 (M+H +).
The compound of following molecular formula (IIIa) (is that X is-(CH 2) 3-the compound of general formula III) can adopt the method that is similar to described in preparation 72 and 73 to prepare from specified parent.
Table 3
Figure C0280540900953
Figure C0280540900961
Preparation 93
3-(4-chloro-3-fluorophenyl)-2-vinyl cyanide
Figure C0280540900981
In nitrogen environment in 0 ℃ with diethyl cyano methyl phosphoric acid ester (3.2ml 18.9mmol) is dissolved among the anhydrous THF (20ml), when stirring, in about 10 minutes time, add in batches 60%NaH oil dispersion (756mg, 18.9mmol).Then the grey suspension of gained was as a result stirred 1 hour in 0 ℃, dropwise add 4-chloro-3-fluorobenzaldehyde (Lancaster Synthesis) (3g, THF 18.9mmol) (5ml) solution subsequently.Allow whole reaction system be warming up to room temperature then, and kept 60 hours.Add entry (5ml), (3 * 50ml) extract miscellany to use EtOAc then.Merge organic extraction and carry out drying (MgSO 4), thereby evaporation obtains xanchromatic oil then, and this oil is carried out purifying by the pentane solution that uses 5%EtOAc as the column chromatography of eluent, thus obtain the title product (2.4g, 70%) that the form with the geometrical isomer miscellany exists; 1HNMR (400MHz, CDCl 3), δ: 5.82 (d, 1H), 7.19 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.42 (app.t, 1H); LRMS TS +199.1 (M+NH 4 +).
Preparation 94
3-(4-chloro-3-fluorophenyl)-1-propylamine
(500mg 2.75mmol) is dissolved in ethanol (36ml) and 0.88NH to the vinyl cyanide of self-preparing agent 93 in the future 3In the solution (18ml), and at the H of 15psi 2Pressure descends the 30%w/w RaNi shaken over night with 150mg.Remove by filter catalyzer by short Arbocel plug, then filtrate is evaporated in a vacuum, and by using 90: 10: 1 (DCM, MeOH, NH 3) carry out purifying as the column chromatography of eluent, thus title product (320mg, 62%) obtained; 1H NMR (400MHz, CDCl 3) 1.65-1.78 (m, 2H), 2.53-2.70 (m, 4H), 6.85 (d, 1H), 6.90 (d, 1H), 7.22 (s, 1H); LRMS:m/z (TS +) 188 (M+H).
The compound of following molecular formula (IIIa) (is that X is-(CH 2) 3-the compound of general formula III) can adopt the method that is similar to described in preparation 93 and 94 to prepare from specified parent.
Figure C0280540900991
Preparation 102
Quinoline-6-formaldehyde
With 6-methyl-quinoline (Aldrich Chemical Co.) (1g, 7.0mmol) and tin anhydride (2.32g 21.0mmol) combines under the situation that does not have solvent, and under nitrogen environment in 100 ℃ the heating 16 hours.Allow reaction mixture be cooled to room temperature, be dissolved in then among the MeOH and preadsorption to silica gel.Use 3: 1 miscellanys of pentane: EtOAc to carry out the chromatography separation, thereby obtain title product (236mg, 21%); 1H NMR (400MHz, CDCl 3), δ: 7.46-7.52 (m, 2H), 7.98 (d, 1H), 8.33-8.37 (m, 2H), 9.03 (d, 1H), 10.18 (s, 1H); M/z (ES +) 315 (2MH +).
Preparation 103
4-(4-p-methoxy-phenyl)-butyramide
With 4-(4-p-methoxy-phenyl)-butyric acid (Aldrich Chemical Co.) (2g 10.4mmol) is dissolved among the 50ml DCM, and when stirring, dropwise add thionyl chloride (1.85g, 15.5mmol).After interpolation is finished, miscellany was refluxed 4 hours.Remove in a vacuum and desolvate, add more solvent again, evaporation is done then, and the circulation that continues this interpolation/evaporation is until removing all thionyl chloride from rough miscellany.This miscellany is dissolved among the 20ml DCM, and in 0 ℃ of 0.88NH that dropwise joins stirring 3In the solution.After interpolation is finished, whole system was stirred 4 hours, separate organic layer then and through super-dry (Na 2CO 3) and evaporation, thereby obtaining the title product (1.5g) that the form with the white solid acid amides exists, it does not need further purifying and comes into operation.
Preparation 104
4-(4-hydroxy phenyl)-butylamine
Figure C0280540901011
(38g 0.20mol) adds the LiAlH that stirs to the product of self-preparing agent 103 in batches in the future 4(15g in THF 0.40mol) (1L) solution, refluxes whole system 16 hours then.Destroy excessive hydride by adding EtOAc (400ml), under the pressure that lowers, remove most solvent then.(note by the 2N NaOH solution that adds 30ml! ) decompose hydride fully, then the solution of gained is as a result carried out acidifying with 1N HCl, and (2 * 200ml) extract and dissolve by water.Then by with 2N NaOH alkalization solution of extract, with EtOAc extract, dry (MgSO 4) and evaporate and the rough amine of acquisition yellow oily.Should in the 160ml HBr aqueous solution, reflux 4 hours by oil, pour into then in the 100ml water.Add solid Na 2CO 3Until the pH that obtains 9-10.(3 * 100ml) extract completely, and dry (MgSO with DCM with miscellany 4Thereby) and evaporate the solid that obtains white, this white solid recrystallize from benzene is just obtained title product (6.4g, 35%); M.p.114-116 ℃.
Preparation 105
4-(4-hydroxy phenyl) butyl carboxylamine tertiary butyl ester
Figure C0280540901012
Product (the 400mg of self-preparing agent 104 in the future, 2.4mmol) water-soluble (10ml) is with in the miscellany of diox (10ml), under nitrogen environment, in this solution that stirs, once add then two dimethyl dicarbonate butyl esters (di-tert-butyl dicarbonate) (1.06g, 4.8mmol).Reaction system was stirred 72 hours, after this once add salt of wormwood (2.0g, 14.4mmol), then with miscellany restir 23 hours with any ester that during reaction forms of complete hydrolysis.Miscellany is transferred in the separating funnel, separated organic layer then, pass through MgSO 4Dry and evaporation just obtains xanchromatic oil.Should oil by using 2 of pentane: EtOAc: thereby 1 miscellany obtains title product (555mg, 86%) as the chromatography of eluent; 1H NMR (400MHz, CDCl 3), δ: 1.41-1.62 (m, 13H), 2.53 (t, 2H), 3.12 (m, 2H), 4.48 (1H, brs), 4.80 (s, 1H), 6.74 (d, 2H), 7.01 (d, 2H).
Preparation 106
4-(4-p-methoxy-phenyl) butyl carboxylamine tertiary butyl ester
Figure C0280540901021
(88mg, (555mg is in THF 2.1mmol) (7ml) solution 2.2mmol) to join the product that comes self-preparing agent 105 of stirring with the mineral oil dispersion of 60%NaH in room temperature under nitrogen environment.Miscellany was stirred 15 minutes, once add then MeI (0.14ml, 2.2mmol), and in room temperature restir 16 hours.With EtOAc (20ml) diluting reaction system, and use 3%NaHCO 3Solution (15ml) washing.Organic layer is passed through MgSO 4Drying, thereby and obtain title compound (500mg, 85%) by using DCM to carry out purifying as the chromatography of eluent; 1H NMR (400MHz, CDCl 3), δ: 1.40-1.63 (m, 13H), 2.57 (t, 2H), 3.13 (m, 2H), 3.78 (s, 3H), 4.46 (1H, brs), 6.82 (d, 2H), 7.06 (d, 2H).
Preparation 107
4-(4-p-methoxy-phenyl) butylamine
(500mg 1.8mmol) is dissolved among 3ml DCM and the 3ml TFA product of self-preparing agent 106, stirs 16 hours under nitrogen environment then in the future.Miscellany is poured into the 10%Na of 50ml 2CO 3In the aqueous solution, (2 * 50ml) extract organic phase to use EtOAc then.Merge organic layer, and carry out drying (MgSO 4) and evaporation, thereby obtaining title product (300mg, 94%), it does not need further purifying and comes into operation.
Preparation 108
3-(2-pyridyl)-1-propylamine
Figure C0280540901031
2-vinyl pyridine (105g) and diacetyl oxide (204g) are merged in room temperature, in the solution of this stirring, dropwise add water (250ml) solution of KCN (130g) then.The backflow of regulating interpolation speed and keeping easing up.After interpolation is finished, miscellany was refluxed 22 hours, use Na then 2CO 3The aqueous solution is with the pH regulator to 8 of solution.Extract miscellany with DCM (600ml), and pass through MgSO 4Drying, thus evaporation obtains brown oil then.Should approximately carry out vacuum distilling under the 0.6mmHg pressure by oil then.Distill out clarifying oily product in 100-107 ℃, its yield is 56%.(200mg 1.5mmol) is dissolved among the 6ml EtOH, and uses 2ml 0.88NH with buttery 2-(2-cyano ethyl)-pyridine 3Solution and 50mg RaNi handle.With miscellany at 30psi H 2Hydrogenation is 16 hours under the pressure, and through filtering and evaporation and obtain title product (approximately 200mg), it does not need further purifying and comes into operation then.
Preparation 109
2-ethanoyl-2H-indazole
With indazole (3.5g, 29.6mmol) and diacetyl oxide (35ml) under nitrogen environment in 60 ℃ the heating 3 hours.Excessive acetic anhydride via is removed in evaporation, then with remaining oily residuum at 3%NaHCO 3Distribute between the aqueous solution (20ml) and the EtOAc (30ml).Separate organic layer, then through super-dry (MgSO 4Thereby) and evaporation obtain title product (4.5g, 96%); 1H NMR (400MHz, CDCl 3), δ: 2.80 (s, 3H), 7.37 (t, 1H), 7.58 (t, 1H), 7.75 (d, 1H), 8.46 (d, 1H).
Preparation 110
5-bromo-2H-indazole and 5-bromo-1H-indazole
Figure C0280540901041
Under nitrogen environment in room temperature in the future the product of self-preparing agent 109 (450mg 2.8mmol) is dissolved in the acetate (0.5ml) and stirs.In whole about 1 minute time, add bromine (0.5ml), then with reaction system restir 16 hours.Nitrogen is passed through solution in the mode that froths, and this process continues 30 minutes to remove excessive bromine, so produce the heavy-gravity solid in flask.Add 5ml toluene, then whole system is evaporated in a vacuum, and residuum is ground with pentane (5ml).Remaining solid filtering come out and dry in a vacuum, each 1M NaOH and EtOH with 6ml handle then.Miscellany is heated to 50 ℃ and kept 1 hour, allows it be cooled to room temperature then.EtOH is removed in evaporation, and (2 * 10ml) extract residuum, then through super-dry (MgSO with DCM 4Thereby) and evaporation obtain title 1-H: 3: 1 inseparable 400mg miscellanys of 2-H indazole isomer; 1H NMR (400MHz, CDCl 3), δ: 7.41 (d, 1H), 7.49 (d, 1H), 7.92 (s, 1H), 8.02 (s, 1H).
Preparation 111
2-methyl-5-bromo-2H-indazole and 1-methyl-5-bromo-1H-indazole
Figure C0280540901042
Under nitrogen environment in room temperature in the future the isomer miscellany of self-preparing agent 110 (400mg 2.0mmol) is dissolved among the MeOH (8ml), once add then NaOMe (223mg, 4.0mmol).Dropwise add MeI (0.32ml, 5mmol), then with miscellany reflux 4 hours.Allow reaction system be cooled to room temperature, be concentrated into small volume (approximately 3ml) then, subsequently with it at EtOAc (20ml) and 3%NaHCO 3Distribute between the aqueous solution.Separate organic layer and dry (MgSO 4), carry out purifying by use 99: 1 DCM: MeOH as the chromatography of eluent then, thereby obtain 1-Me isomer (100mg, 23%) and 2-Me isomer (112mg, 26%); 1-methyl isomer; 1H NMR (400MHz, CDCl 3), δ: 4.08 (s, 3H), 7.30-7.50 (m, 2H), 7.82 (s, 1H), 7.92 (s, 1H); 2-methyl isomer; 1H NMR (400MHz, CDCl 3), δ: 4.13 (s, 3H), 7.35 (d, 1H), 7.59 (d, 1H), 7.81 (s, 1H), 7.85 (s, 1H).
Preparation 112
3-(1-methyl isophthalic acid H-indazole-5-yl)-2-vinyl cyanide
In the future the 1-methyl isomer of self-preparing agent 111 (100mg 0.47mmol) is dissolved in the diox (6ml), add in turn then salt of wormwood (72mg, 0.52mmol), vinyl cyanide (0.035ml, 0.52mmol), Pd 2(dba) 3(43mg, 0.047mmol) and PtertBu 3(0.038ml, 0.16mmol).Reaction system was refluxed 3 hours under nitrogen environment, be cooled to room temperature then, fill in row by short arbocel again and filter, and evaporated filtrate in a vacuum.Then residuum is used the chromatography of 99: 1 DCM: MeOH to separate, thereby obtain the title product (57mg, 66%) that the form with suitable, anti-geometrical isomer miscellany exists; 1H NMR (300MHz, CDCl 3), δ: 4.11 (s, 3H), 5.40 and 5.84 (d, 1H), 7.37-8.18 (m, 5H).
Preparation 113
3-(1-methyl isophthalic acid H-indazole-5-yl)-1-propylamine
(55mg 0.29mmol) is dissolved in ethanol (4ml) and 0.88NH to the product of self-preparing agent 112 in the future 3In the solution (1ml), under the condition that has 10mg 30%w/w RaNi, carried out hydrogenation 2 hours then in 30psi and room temperature.Miscellany is filled in row by short Arbocel filter, thereby then the filtrate evaporation is obtained title product, it does not need further purifying and comes into operation.
Preparation 114
2-(4-bromophenyl)-pyridine
Figure C0280540901061
Will in-60 ℃ n(hexane solution of 1.6M, 34.4ml 55mmol) dropwise join 1 of stirring to BuLi, and (11.8g is in anhydrous THF (100ml) solution 50mmol) for the 4-dibromobenzene.Miscellany was stirred 15 minutes in this temperature, dropwise add ZnCl then 2(the THF solution of 0.5M, 100ml, THF solution 50mmol).Allow miscellany be warming up to room temperature and kept 90 minutes, add Pd (PPh then 3) 4(200mg), immediately add the 2-bromopyridine (4.8ml, 50mmol).Whole system in stirred overnight at room temperature, is evaporated to small volume (10ml) then and uses EtOAc (400ml) dilution.With EDTA (32g) in water (200ml) and salt solution (200ml) the above-mentioned solution of the solution washing that forms, then through super-dry (MgSO 4) and evaporation just obtain the yellow/green solid.This solid carries out purifying by using 1: 1 hexane: DCM as the column chromatography of eluent, thereby obtains title product (8.3g, 71%); M/z MH +234 (TS +); Measured value C 56.61%, H 3.37%, and N 5.90%; Calculated value C 56.44%, H 3.44%, and N 5.98%.
Preparation 115
3-(2.3-dihydro-1H-indenes-5-yl)-propionic acid
(500mg 2.66mmol) (can obtain from Aldrich) to be dissolved in the ethanol (40ml), and at 15psi H with 3-(2,3-dihydro-1H-indenes-5-yl)-vinylformic acid 2Under the pressure with the 10%Pd/C hydrogenation of 40mg 4 hours.Miscellany is filled in row by short Arbocel filter, thereby then the filtrate evaporation is obtained title product (560mg, about quantity), it does not need further purifying and comes into operation; 1H NMR (400MHz, CDCl 3), δ: 1.98-2.07 (m, 2H), 2.75 (t, 2H), 2.80-2.90 (m, 6H), 6.95 (d, 1H), 7.03 (s, 1H), 7.08 (d, 1H); LRMS:m/z ES -189 (M-H).
Preparation 116
3-(2,3-dihydro-1H-indenes-5-yl)-propionic acid amide
Figure C0280540901071
Under nitrogen environment in room temperature in the future the product of self-preparing agent 115 (190mg 1mmol) is dissolved among the DCM (2ml), at first adds 132 μ l (1.5mmol) oxalyl chlorides then, adds 1 DMF subsequently.After effervesce is calmed down, miscellany in stirring at room 3 hours, is concentrated then in a vacuum.Be dissolved in residuum among the 2ml THF again and add 0.6ml 0.88NH 3Solution stirs whole system 4 days then.The reaction system water quenches, and (2 * 10ml) extract with EtOAc.Merge organic phase, and through super-dry (MgSO 4Thereby) and evaporation obtain title product (190mg, 99%); 1H NMR (400MHz, CDCl 3), δ: 1.96-2.05 (m, 2H), 2.49 (t, 2H), 2.81-2.92 (m, 6H), 5.32 (brs, 2H), 6.93 (d, 1H), 7.05 (s, 1H), 7.08 (d, 1H); LRMS:m/z (ES -) 189 (M-H).
Preparation 117
3-(2,3-dihydro-1H-indenes-5-yl)-propylamine
Figure C0280540901072
Under nitrogen environment in 0 ℃ in the future the acid amides of self-preparing agent 116 (170mg 0.9mmol) is dissolved among the anhydrous THF (3ml), dropwise adds LiAlH when stirring 4THF solution (1M, 0.9ml 0.9mmol), have sizable effervesce in this process.Reaction system is warming up to 60 ℃, and under this temperature, stirs and spend the night.Miscellany water (1ml) quenches, and adds 1N NaOH solution (1ml), and (2 * 50ml) extract solution, again through super-dry (MgSO with EtOAc then 4), filter and concentrate and just obtain lurid oil.This oil is by using 90: 10: 1 (DCM, MeOH, NH 3Thereby) carry out purifying as the column chromatography of eluent and obtain title product (30mg, 35%); 1H NMR (400MHz, CDCl 3), δ: 1.72-1.77 (m, 2H), 1.96-2.03 (m, 4H), 2.57 (t, 2H), 2.70 (t, 2H), 2.80-2.85 (m, 4H), 6.90 (d, 1H), 7.02 (s, 1H), 7.09 (d, 1H); LRMS:m/z (TS +) 176 (M+H).
Preparation 118
3-(4-bromophenyl)-2-vinyl cyanide
(2.16g 54.1mmol) is suspended among the THF (50ml), and is cooled to 0 ℃ with the mineral oil suspension of 60%NaH under nitrogen environment.(8.74ml 54.1mmol), stirs whole system 30 minutes in 0 ℃ then dropwise to add diethyl cyanogen methyl phosphorodithioate.(10g, THF 54.1mmol) (20ml) solution allows miscellany be warming up to room temperature again and maintenance is spent the night dropwise to add the 4-bromobenzaldehyde then.The reaction system water quenches, and (3 * 50ml) extract, dry again (MgSO with EtOAc 4), just obtain xanchromatic oil through filtering and evaporating then.This oil is dissolved in pentane: in 9: 1 miscellanys of EtOAc, title product is from wherein crystallizing out (5.8g, 52%); 1H NMR (400MHz, CDCl 3), δ: 5.82 (d, 1H), 7.21-7.28 (m, 3H), 7.50 (d, 2H).
Preparation 119
3-(4-bromophenyl)-1-propylamine
Figure C0280540901082
This title compound prepares by the program of revising according to people such as Iddon (J.C.S.Perkin I, 1977,2357) described method.Under nitrogen environment with solid LiAlH 4(1.2g 31.6mmol) is suspended in the ether (35ml), and when stirring this suspension is heated to about 50 ℃.(2.06g, ether 9.88mmol) (20ml) solution is then with miscellany heating 90 minutes dropwise to add the vinyl cyanide of self-preparing agent 118.After this, stop heating, with reaction system in stirring at room 16 hours.Add entry, add 1N NaOH (30ml) and EtOAc (60ml) subsequently, then with whole system vigorous stirring 30 minutes.Separate organic layer, and through super-dry (MgSO 4) and evaporation just obtain xanchromatic oil, should oil by using 90: 10: 1 (DCM, MeOH, NH 3Thereby) carry out purifying as the column chromatography of eluent and obtain title product (740mg, 35%); 1H NMR (400MHz, CDCl 3), δ: 1.65-1.74 (m, 2H), 2.52 (t, 2H), 2.66 (t, 2H), 7.02 (d, 2H), 7.35 (d, 2H); LRMS:m/z (TS +) 214 (M+H).
Preparation 120
1-(2-chlorophenoxy)-2-propylamine
Under nitrogen environment in the future the product of self-preparing agent 121 (11g, ether 55.2mmol) (41ml) solution dropwise join lithium aluminum hydride, and (4.1g is in ether 108mmol) (110ml) suspension.With reaction mixture refluxed 4 hours, successively add ethyl acetate and water then.With 4N hcl acidifying water layer and shake, separate then, alkalize with 40% sodium hydroxide solution again.(3 * 100ml) extract water layer, merge organic extraction and pass through dried over mgso to use ether then.With hydrogenchloride acidifying ether extract, then the throw out of gained is as a result filtered.Recrystallize goes out solid from ethanol/sherwood oil (b.p.60-80 degC), thereby obtains title product (2.5g, 20%), m.p.126-127 ℃; 1H NMR (CDCl 3400MHz), δ: 1.55 (d, 3H), 3.80 (q, 1H), 4.20 (d, 2H), 6.90-7.00 (m, 2H), 7.15 (t, 1H), 7.30 (d, 1H), 8.60 (bs, 3H); Analytical value C, 48.9; H, 6.0; N, 6.5.C 9H 13NOCl 2Required value C, 48.7; H, 5.9; N, 6.3%.
Preparation 121
1-(2-chlorophenoxy)-2-acetoxime
With 1-(2-chlorophenoxy) acetone (106.6g, 0.58mol) (J.Am.Chem.Soc., 75,1953,1134) (27.8g is 4mol) in 2N sodium hydroxide solution (420ml) among the formed solution to join oxammonium hydrochloride, add enough ethanol then, thereby obtain clear soln.Reaction mixture was refluxed 30 minutes, concentrate in a vacuum then, and (3 * 200ml) extract rough residuum with ether.Merge organic layer, then by dried over mgso and concentrated in a vacuum.Residuum through the distillation just obtain title product (134-136 ℃/1.35mmHg) (4.5g, 3.9%); 1H NMR (CDCl 3400MHz), δ: 2.05 (s, 3H), 5.00 (s, 2H), 6.90-7.00 (m, 2H), 7.10 (t, 1H), 7.30 (d, 1H), 7.60 (s, 1H); Analytical value C, 54.95; H, 5.05.C 9H 10NO 2Cl required value C, 54.15; H, 5.05%.
Preparation 122
3-(4-methoxyl group-3-chloro-phenyl-)-1-propylamine
Figure C0280540901102
With 4-methoxyl group-phenyl aldehyde (Aldrich) (42g, 0.31mol) and pyridine (0.6ml, catalysis) under nitrogen environment, stir together, in 30 minutes time, add SULPHURYL CHLORIDE (51g then, 0.37mol), the internal temperature that keeps reaction system simultaneously is 25-30 ℃.Having violent gas emits.Miscellany in room temperature restir 30 minutes, is warming up to 70 ℃ and kept 4 hours then.Remove excessive reagent by evaporation in a vacuum, residuum is dissolved in is poured in the 50ml diisopropyl ether and in vigorous stirring in the 500ml hexane then, product is from wherein being precipitated out.Cross filter solid and use hexane wash, dry in a vacuum then, thus obtain title product (40.3g, 77%), m.p.55-56 ℃; 1H NMR (400MHz, CDCl 3), δ: 3.99 (s, 3H), 7.05 (dd, 1H), 7.91 (d, 1H), 9.86 (s, 1H); Analytical value C, 56.13; H, 4.14%.C 8H 7ClO 2Required value C, 56.33; H, 4.14%.
Preparation 123
3-(4-methoxyl group-3-chloro-phenyl-)-1-propylamine
Figure C0280540901111
Change into the non-mapping miscellany of corresponding ethene nitrile (vinylnitrile) according to the product of preparation self-preparing agent 122 in 93 future.With miscellany (300mg 1.55mmol) is dissolved among the DCM (6ml) in room temperature under nitrogen environment, in 5 minutes time, add then in batches tetra-n-butyl ammonium hydroborate (1.6g, 6.2mmol).Miscellany was refluxed 4 hours, be evaporated to dried then.Residuum is dissolved among the 10%HCl (aqueous solution) of about 6ml, and then refluxed 1 hour.Reaction system is cooled off, and (3 * 30ml) extract, then through super-dry (MgSO with EtOAc 4) and evaporation just obtain xanchromatic oil.With this oil successively in 95/5/0.5 and 95/5/1 DCM/MeOH/NH 3Middle post excessively, thus title product (75mg, 24%) obtained; 1H NMR (400MHz, CDCl 3), δ: 1.60-1.74 (m, 2H), 2.56 (t, 2H), 2.67 (t, 2H), 3.82 (s, 3H), 6.79 (d, 1H), 6.98 (d, 1H), 7.15 (s, 1H).
Preparation 124
Chroman
Figure C0280540901112
(2.77g, (3.5ml 36.9mmol) and in the acetate (30ml), and refluxed 3 hours, allowed it be cooled to room temperature then and kept 16 hours 18.4mmol) to be dissolved in diacetyl oxide with 4-chroman alcohol (Aldrich).In solution, add 10%w/w Pd/C, then with the hydrogenation 16 hours under the 40p.s.i. hydrogen pressure of whole system.Filter out catalyzer by the Arbocel pad, then filtrate is evaporated to small volume (5ml).Remaining liquid is dissolved among the EtOAc (30ml), and priority water and NaHCO 3Solution (each 100ml) washing.Organic layer is passed through MgSO 4Drying, evaporation just obtains lurid oil then.This oil is crossed post in 10% EtOAc/ pentane, thereby obtain title product (2.1g, 85%); 1HNMR (400MHz, CDCl 3), δ: 1.93-2.04 (m, 2H), 2.79 (t, 2H), 4.18 (t, 2H), 6.78-6.83 (m, 2H), 7.00-7.10 (m, 2H).
Preparation 125
6-bromobenzene and dihydropyrane
Figure C0280540901121
(1g 7.5mmol) is dissolved among the DCM (10ml) product of self-preparing agent 124, adds bromine (403 μ l, DCM 7.8mmol) (3ml) solution then in the time of several minutes in the future.When finishing near interpolation, solution continues to present brown.In stirring at room 3 hours, organic layer was isolated in water (20ml) and salt solution (20ml) washing then with miscellany, and through super-dry (MgSO 4) and evaporation just obtain thick yellow oil, obtain title product (1.3g, 82%) thereby the column chromatography of the pentane solution of this oil by using 5%EtOAc is carried out purifying; 1H NMR (400MHz, CDCl 3), δ: 1.90-1.98 (m, 2H), 2.73 (t, 2H), 4.14 (t, 2H), 6.61 (d, 1H), 7.08-7.15 (m, 2H).
Preparation 126
5-bromo-2,2-dimethyl-2,3-dihydrobenzo [b] furans
Figure C0280540901122
With 2,2-dimethyl-2,3-dihydrobenzo [b] furans (according to Baker and Shulgin, J.Org.Chem., 28, the preparation of 1963,2468 method) (500mg 3.38mmol) is dissolved in the ethylene dichloride (5.5ml), and under nitrogen environment in stirring at room, once add then N-bromine succinimide (661mg, 3.72mmol).Then reaction system was refluxed 2 hours, add ether (10ml), after the white precipitate that leaches succinimide.Filtrate is evaporated to dried, and carries out purifying as the column chromatography of eluent, thereby obtain title product (604mg, 79%) by the pentane solution that uses 5% ether; 1H NMR (400MHz, CDCl 3), δ: 1.43 (s, 6H), 2.92 (s, 2H), 6.54 (d, 1H), 7.16 (d, 1H), 7.19 (s, 1H); LRMS:M+H, 227. (TS +).
Preparation 127
5-bromo-2-methyl-2,3-dihydro-1-benzo [b] furans
Use and the same program that is used for preparation 126, from 2-methyl-2,3-dihydro-1-benzo [b] furans (being obtained commercially from TCI (Japan)) prepares title product (87%); 1H NMR (400MHz, CDCl 3), δ: 1.43 (d, 3H), 2.80 (dd, 1H), 3.29 (dd, 1H), 4.94 (m, 1H), 6.61 (d, 1H), 7.18 (d, 1H), 7.22 (s, 1H).
Preparation 128
2,3-dihydrobenzo [b] furans-7-formaldehyde
Figure C0280540901132
Under nitrogen environment in 0 ℃ with 2, (25g 0.21mol) is dissolved among the DCM (500ml) and stirs 3-dihydrobenzo [b] furans (MaybridgeChemicals).Once add SnCl 4(36.5ml 0.3mol), thereby produces lurid solution.(18.8ml 0.21mol), and with solution stirring 30 minutes, removes cooling bath after this and reaction system is poured in the frozen water (1000ml) to add the dichloromethyl methyl ether then.Separate organic layer, and water (2 * 100ml), 2N HCl (100ml) and salt solution (50ml) washs, and adds charcoal (30g) and Na then in solution 2SO 4Filter and evaporate the oil that just obtains black by Celite, this oil is used the flash chromatography of the pentane solution of 7-10%EtOAc, thereby obtain title product (190mg, 0.01%); 1H NMR (400MHz, CDCl 3), δ: 3.24 (t, 2H), 4.75 (t, 2H), 6.93 (t, 1H), 7.40 (d, 1H), 7.59 (d, 1H), 10.2 (s, 1H); LRMS:(M+H) 149, TS +Analytical value C, 72.98; H, 5.46%.C 9H 8O 2Required value C, 72.96; H, 5.44%.
Preparation 129
1-cumarone-3-base acetonitrile
Figure C0280540901141
((1.1ml 6.7mmol), stirs whole system 45 minutes more dropwise to add diethyl cyanogen methyl phosphorodithioate then for 268mg, 6.7mmol) furnishing slurry in anhydrous THF (10ml) with sodium hydride in 0 ℃ under nitrogen environment.Dropwise add then 3-coumaranone (Lancaster) (900mg, 6.7mmol), and with whole system in stirring at room 45 minutes.With EtOAc (15ml) and water (15ml) diluting reaction system, separate organic layer then, and through super-dry (MgSO 4) and evaporation, again residuum is used the flash chromatography of the pentane solution of 0-5%EtOAc, thereby obtain title product (940mg, 91%); 1H NMR (400MHz, CDCl 3), δ: 3.77 (s, 2H), 7.25-7.40 (m, 2H), 7.52 (dd, 1H), 7.58 (dd, 1H), 7.67 (s, 1H); LRMS:M+NH 4 +, 175. (TS +).
Preparation 130
2-(1-cumarone-3-yl)-ethamine
In the future the product of self-preparing agent 129 (400mg, 2.55mmol) with solution of ammonium hydroxide (10ml), ethanol (20ml) and 30wt%Ra-Ni (120mg, catalysis) merging, then under the 30p.s.i. hydrogen pressure in room temperature hydrogenation 16 hours.Remove by filter catalyzer by the Arbocel plug, then the filtrate of yellowish brown is separated by the chromatography of the DCM solution of use 0-5%MeOH, thereby obtain title product (380mg, 93%); 1H NMR (400MHz, CDCl 3), δ: 1.20 (brs, 2H), 2.80 (t, 2H), 3.02 (t, 2H), 7.15-7.25 (m, 2H), 7.43 (dd, 2H), 7.55 (dd, 1H); LRMS:M+H, 162. (ES +).
Preparation 131
2-(2,3-dihydro-1-cumarone-3-yl)-ethamine
Figure C0280540901151
In the future (200mg, 1.24mmol) 10wt%Pd/C with ethanol (20ml) and 20mg mixes the product of self-preparing agent 130, hydrogenation 48 hours under the 40p.s.i. hydrogen pressure then.The catalyzer that adds 20mg again, then with whole system under 60p.s.i. pressure in 40 ℃ of hydrogenations 72 hours again.Remove by filter catalyzer by short Arbocel plug, then filtrate is evaporated to dried.Residuum is passed through to use 90/10/1 DCM/MeOH/NH 3Column chromatography as eluent is carried out purifying, thereby obtains title product (11mg, 55%); 1H NMR (400MHz, CDCl 3), δ: 1.81 (m, 1H), 1.98 (m, 1H), 2.75-2.83 (m, 2H), 3.50 (m, 1H), 4.22 (t, 1H), 4.60 (t, 1H), 6.72 (d, 1H), 6.85 (t, 1H), 7.10 (t, 1H), 7.20 (d, 1H); LRMS:M+H, 164. (ES +).
Preparation 132
(2E and 2Z)-3-(2,3-dihydro-1-cumarone-5-yl)-2-butylene nitrile
Figure C0280540901152
(247mg, (0.98ml, THF 6.16mmol) (2ml) solution stir whole system 1 hour in 0 ℃ then to add diethyl cyanogen methyl phosphorodithioate in anhydrous THF (6ml) suspension 6.16mmol) to the sodium hydride that stirs in 0 ℃ under nitrogen environment.Dropwise add 5-ethanoyl-2,3-dihydro [b] cumarone (Aldrich) (1g, THF 6.16mmol) (2ml) solution, then with whole system in stirring at room 16 hours.Add entry (20ml) and EtOAc (20ml), separate organic layer, (2 * 20ml) extract water layer to use EtOAc then.Merge organic extraction, pass through MgSO then 4Drying, thereby and through filtering and evaporation obtains amber oil, subsequently it is left standstill and solidifies.This solid is carried out purifying by the pentane solution that uses 20-30%EtOAc as the column chromatography of eluent, thereby obtain title product (789mg, 69%); 1H NMR (400MHz, CDCl 3), δ: 2.4 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 5.5 (s, 1H), 6.7 (d, 1H), 7.2 (d, 1H), 7.3 (s, 1H); LRMS:M+NH 4203 (ES +).
Preparation 133
3-(2,3-dihydro-1-cumarone-5-yl)-butylamine
Figure C0280540901161
In the future the product of self-preparing agent 132 is dissolved in ethanol (20ml) and the solution of ammonium hydroxide (5ml), then whole system is passed through the 30wt%Ra-Ni hydrogenation 16 hours of 200mg under the 30p.s.i. hydrogen pressure.And then the catalyzer of adding 100mg, and continued hydrogenation again 16 hours.Reaction mixture is filled in row by short Arbocel filter, then filtrate is evaporated to small volume in a vacuum.(2 * 20ml) coevaporations to be removing the water of last trace, thereby obtain title product (780mg, 96%), and it does not need further purifying and comes into operation from toluene with residuum then; 1H NMR (400MHz, CDCl 3), δ: 1.2 (d, 3H), 1.7 (q, 2H), 2.5 (m, 2H), 2.65 (m, 1H), 3.1 (t, 2H), 4.45 (t, 2H), 6.6 (d, 1H), 6.9 (d, 1H), 7.0 (s, 1H); LRMS:M+H 192. (ES +).
Preparation 134
7-methyl-2,3-dihydro-1-cumarone-3-alcohol
Figure C0280540901171
(3.78g, (1.16g 0.03mol), refluxes whole architecture heat preservation 1 hour then to add sodium hydride in anhydrous THF (60ml) suspension 0.03mol) to the chlorination trimethylammonium sulfoxonium that stirs.(4g, THF 0.03mol) (30ml) solution reflux the orange suspension of gained as a result and stirred 5 hours then to add 2-hydroxy-3-methyl-phenyl aldehyde (Lancaster) by syringe.Add entry (50ml), and (3 * 50ml) extract organic layer with ether.Merge organic extraction, and through super-dry (MgSO 4), filter and in a vacuum evaporation just obtain orange oil, then should oil the column chromatography of pentane solution by using 15-25%EtOAc carry out purifying, thereby obtain title product (2g, 45%); 1H NMR (400MHz, CDCl 3), δ: 2.2 (s, 3H), 4.45 (m, 2H), 5.3 (m, 1H), 6.8 (t, 1H), 7.1 (d, 1H), 7.2 (d, 1H); LRMS:M+H 151. (ES +).
Preparation 135
7-methyl-2,3-dihydro-1-cumarone
Figure C0280540901172
To the product (500mg that comes self-preparing agent 134 that stirs, 3.3mmol) acetate (5ml) solution in add diacetyl oxide (0.63ml, 6.7mmol), then whole system refluxing under nitrogen environment and stirred 2 hours, it is warming up to room temperature and kept 16 hours with relief.In solution, directly add 10wt%Pd/C (30mg), then under the 40p.s.i. hydrogen pressure in room temperature hydrogenation 16 hours.Remove by filter catalyzer by Arbocel plug, filtrate is concentrated in a vacuum obtain light yellow residuum then, this residuum is dissolved among the EtOAc (20ml), and water (3 * 20ml) and NaHCO 3(20ml) washing is then through super-dry (MgSO 4) and evaporation just obtain lurid oil.This oil is carried out purifying by the pentane solution that uses 3%EtOAc as the column chromatography of eluent, thereby obtain title product (261mg, 58%); 1H NMR (400MHz, CDCl 3), δ: 2.2 (s, 3H), 3.2 (t, 2H), 4.55 (t, 2H), 6.75 (t, 1H), 6.9 (d, 1H), 7.05 (d, 1H).
Preparation 136
5-bromo-7-methyl-2,3-dihydro-1-cumarone
(200mg, (318mg 1.79mmol), refluxes whole system then and stirred 16 hours under nitrogen environment to add N-bromine succinimide in ethylene dichloride 1.49mmol) (2.5ml) solution to the product that comes self-preparing agent 135 that stirs.Miscellany concentrated in a vacuum just obtain greenish orange brown solid, this solid is carried out purifying by the pentane solution that uses 1%EtOAc as the column chromatography of eluent, thereby obtain title product (112mg, 35%); 1H NMR (400MHz, CDCl 3), δ: 2.1 (s, 3H), 3.15 (t, 2H), 4.5 (t, 2H), 7.0 (s, 1H), 7.1 (s, 1H).
Preparation 137
2-hydroxy-4-methyl-phenyl aldehyde
(1g adds SnCl in toluene 9.2mmol) (5ml) solution to the 3-methyl-phenol that stirs in room temperature under nitrogen environment 4(241mg, 0.92mmol) and tri-n-butyl amine (0.6ml, 2.77mmol).After 20 minutes, (611mg 20.3mmol), stirs whole system 16 hours in 100 ℃ then to add paraformaldehyde.Water (20ml) diluting reaction miscellany, and be acidified to pH2 with 2N HCl.Extract solution with ether (25ml), use salt solution (20ml) washing then, again through super-dry (MgSO 4), filter and evaporation just obtains brown oil.This oil is carried out purifying by the pentane solution that uses 5%EtOAc as the column chromatography of eluent, thereby obtain title product (319mg, 25%); 1H NMR (400MHz, CDCl 3), δ: 2.3 (s, 3H), 6.75 (m, 2H), 7.35 (d, 1H), 9.75 (s, 1H), 11.00 (s, 1H).
Preparation 138
5-bromo-6-methyl-2, the 3-Dihydrobenzofuranes
Figure C0280540901191
In the future the product of self-preparing agent 137 is by just becoming title compound with same 3-sequence of steps described in the preparation 134-136; 1H NMR (400MHz, CDCl 3), δ: 2.3 (s, 3H), 3.55 (t, 2H), 4.5 (t, 2H), 6.7 (s, 1H), 7.3 (s, 1H); LRMS:M+H, 214. (ES +).
Preparation 139
(3E)-4-(2,3-dihydro-1-cumarone-5-yl)-3-butene-2-ketone
Figure C0280540901192
With 2,3-dihydrobenzo [b] furans-5-formaldehyde (Aldrich Chemicals) (2g, 13.5mmol), acetone (2.73ml, 37.1mmol), water (1.35ml) and 10%NaOH (aqueous solution) (0.34ml) be added on together, then with whole system in stirring at room 16 hours.The xanchromatic solid is dissolved among about 15ml DCM again, adds 2N HCl then and obtain the solution of pH2.Add entry (10ml), and (2 * 20ml) extract organic layer with DCM.Separate water layer, and (2 * 15ml) extract again with DCM.Merge organic extraction, and through super-dry (MgSO 4) and the concentrated in a vacuum xanchromatic oil that just obtains, this oil is carried out purifying by the pentane solution that uses 15-30%EtOAc as the column chromatography of eluent, thereby obtain title product (2.13g, 84%); 1H NMR (400MHz, CDCl 3), δ: 2.3 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.45 (d, 1H); LRMS:M+H, 189. (ES +).
Preparation 140
4-(2,3-dihydro-1-cumarone-5-yl)-2-butanone
Figure C0280540901201
(2.12g 11.3mmol) is dissolved in the ethanol (40ml) product of self-preparing agent 139, and the 10wt%Pd/C by 200mg carried out hydrogenation 4 hours under the 15p.s.i. hydrogen pressure then in the future.Miscellany is filled in row by short Arbocel filter, filtrate is evaporated in a vacuum just obtain colourless oil then, the column chromatography of the pentane solution of this oil by using 15-25%EtOAc is carried out purifying, thereby obtain title product (1.53g, 71%); 1H NMR (400MHz, CDCl 3), δ: 2.1 (s, 3H), 2.7 (t, 2H), 2.8 (t, 2H), 3.1 (t, 2H), 4.5 (t, 2H), 6.65 (d, 1H), 6.9 (d, 1H), 7.0 (s, 1H); LRMS:M+NH 4, 208. (ES +).
Preparation 141
4-(2,3-dihydro-1-cumarone-5-yl)-2-butylamine
Figure C0280540901202
To the product that comes self-preparing agent 140 that stirs (500mg, add in methyl alcohol 2.6mmol) (25ml) solution ammonium acetate (4.05g, 52.6mmol) and sodium cyanoborohydride (661mg, 10.5mmol), then with whole system in stirred overnight at room temperature.Reaction mixture is concentrated in a vacuum, between EtOAc (20ml) and water (20ml), distribute then.(2 * 20ml) extract organic layer and washing to water, then through super-dry (MgSO 4) and evaporation just obtain clarifying oil.This oil carries out purifying by the DCM solution that uses 5%MeOH as the column chromatography of eluent, thereby obtains title product (187mg, 37%); 1H NMR (400MHz, CDCl 3), δ: 1.3 (d, 3H), 1.8 (m, 2H), 2.6 (m, 2H), 3.1 (t, 2H), 3.2 (m, 1H), 4.45 (t, 2H), 6.6 (d, 1H), 6.9 (d, 1H), 7.05 (s, 1H); LRMS:M+H, 192. (ES +).
Preparation 142
(2E)-2-cyano group-3-(2,3-dihydro-1-cumarone-5-yl)-2-butylene acid methyl esters
Figure C0280540901211
To the 5-ethanoyl-2 that stirs; 3-dihydrobenzo [b] furans (Aldrich) (1g; 6.17mmol) toluene (60ml) solution in add methyl-cyanacetate (O.60ml; 6.78mmol), benzylamine (0.07ml; 0.61mmol) and acetate (0.3ml; 5.3mmol), then whole system was refluxed 16 hours in the Dean-Stark instrument.With reaction mixture cooling, and with 2N HCl (30ml), NaHCO 3(30ml), salt solution (30ml) washing, then through super-dry (MgSO 4) and evaporation just obtain the xanchromatic residuum.This residuum is carried out purifying by the pentane solution that uses 15-20%EtOAc as the column chromatography of eluent, thereby obtain title product (902mg, 60%); 1H NMR (400MHz, CDCl 3), δ: 2.65 (s, 3H), 3.25 (t, 2H), 3.9 (s, 3H), 4.6 (t, 2H), 6.8 (d, 1H), 7.25 (d, 1H), 7.8 (s, 1H); LRMS:M+NH 4 +, 261. (ES +).
Preparation 143
2-cyano group-3-(2,3-dihydro-1-cumarone-5-yl)-3-methyl-methyl-butyrate
Figure C0280540901221
(109mg, (ethereal solution of 1.4M, 0.76ml is in ether 1.07mmol) (2ml) miscellany 0.57mmol) to join the MeLi of stirring with cupric iodide (I) in-25 ℃ under nitrogen environment.After stirring 10 minutes, dropwise add to come self-preparing agent 142 product (100mg, ether 0.4lmmol) (2ml) solution stir whole system 2 hours in-25 ℃ then, and when being warming up to 0 ℃ restir 2 hours.Add salt solution (10ml), use EtOAc (10ml) to extract organic layer then, and through super-dry (MgSO 4), filter and evaporation.Residuum carries out purifying by the column chromatography of the pentane solution of use 20%EtOAc then, thereby obtains title product (92mg, 86%); 1H NMR (400MHz, CDCl 3), δ: 1.55 (d, 6H), 3.2 (m, 2H), 3.59 (s, 3H), 3.62 (s, 1H), 4.5 (t, 2H), 6.7 (d, 1H), 7.1 (d, 1H), 7.2 (s, 1H); LRMS:M+NH 4 +, 277. (ES +).
Preparation 144
3-(2,3-dihydro-1-cumarone-5-yl)-3-methylbutyronitrile
In the future (400mg, (1.5ml) is with in the diox (1.5ml), and (87mg 1.54mmol), refluxes whole system then and stirred 6 hours to add solid KOH again in this solution that stirs 1.54mmol) to be dissolved in ethanol for the product of self-preparing agent 143.Reaction mixture is concentrated in a vacuum, be dissolved in again in the water (15ml).With toluene (15ml) washing water layer, be acidified to pH1 with 2N HCl then, and (2 * 20ml) therefrom extract product with EtOAc.Merge organic layer and use salt solution (20ml) washing, then through super-dry (MgSO 4), filter and concentrate in a vacuum and just obtain orange oil, it does not need further purifying and comes into operation; 1H NMR (400MHz, CDCl 3), δ: 1.6 (d, 6H), 3.15 (t, 2H), 3.7 (s, 1H), 4.5 (t, 2H), 6.7 (d, 1H), 7.1 (d, 1H), 7.22 (s, 1H); LRMS:M+NH 4 +, 263. (ES +).This oil is dissolved among the DMA (2ml), and in 150 ℃ of heating 2 hours, allows it be cooled to room temperature and stir and spend the night then.Reaction mixture is concentrated in a vacuum, be dissolved in then among the EtOAc (10ml).With salt solution (10ml) washing organism, pass through MgSO then 4Dry and filter and concentrate in a vacuum and just obtain orange oil.This oil is carried out purifying by the pentane solution that uses 15%EtOAc as the column chromatography of eluent, thereby obtain title product (100mg, 32%); 1HNMR (400MHz, CDCl 3), δ: 1.45 (s, 6H), 2.55 (s, 2H), 3.2 (t, 2H), 4.5 (t, 2H), 6.7 (d, 1H), 7.1 (d, 1H), 7.2 (s, 1H); LRMS:M+NH 4 +, 219. (ES +).
Preparation 145
3-(2,3-dihydro-1-cumarone-5-yl)-3-methyl butyl carboxylamine tertiary butyl ester
Figure C0280540901231
Under nitrogen environment in 0 ℃ in the future the product of self-preparing agent 144 (250mg 1.24mmol) is dissolved in the methyl alcohol (12ml), again with two dimethyl dicarbonate butyl esters (542mg, 2.48mmol), NiCl 2(161mg 1.24mmol) stirs together, adds NaBH then in batches 4(329mg, 8.69mmol).Allow the solution of this black be warming up to room temperature and keep spending the night, concentrate in a vacuum then.With residuum at EtOAc (20ml) and NaHCO 3Distribute between the solution (20ml), then miscellany is filtered to remove all solids, (2 * 20ml) extract filtrate to use EtOAc again.Merge organic extraction, pass through MgSO then 4Dry and filter and evaporate and just obtain title product (366mg, 96%), it does not need further purifying and comes into operation; 1H NMR (400MHz, CDCl 3), δ: 1.25 (s, 6H), 1.35 (s, 9H), 1.7 (t, 2H), 2.9 (brs., 2H), 3.1 (t, 2H), 4.2 (brs., 1H), 4.5 (t, 2H), 6.65 (d, 1H), 7.0 (d, 1H), 7.1 (s, 1H); LRMS:M-BOC, 206. (ES +).
Preparation 146
3-(2,3-dihydro-1-cumarone-5-yl)-3-methylbutylamine
Figure C0280540901241
In 0 ℃ in the future the product of self-preparing agent 145 (366mg 1.20mmol) is dissolved among the DCM (15ml), stirs 15 minutes in by solution in the mode that froths at hydrogen chloride gas then.Stop the HCl air-flow, allow reaction mixture be warming up to room temperature then and stirred 2 hours.(20ml) makes solution exuberant with ether, thereby forms the precipitation of white.Filter out this solid, and wash with ether, drying just obtains title product (177mg, 61%) in a vacuum then; 1H NMR (400MHz, MeOD), δ: 1.3 (s, 6H), 1.9 (m, 2H), 2.6 (m, 2H), 3.1 (m, 2H), 4.5 (m, 2H), 6.6 (s, 1H), 7.01 (s, 1H), 7.2 (s, 1H); LRMS:M+H, 207. (ES +).
Preparation 147
2-(4-chloro-phenyl-)-3-cyanopropionic acid methyl esters
Figure C0280540901242
(8.65ml dropwise adds 2.5M in anhydrous THF (100ml) solution 61.8mmol) to the Diisopropylamine that stirs in-20 ℃ under nitrogen environment nThe hexane solution of BuLi (23.7ml, 59.2mmol).Allow solution be warming up to 0 ℃ and kept 20 minutes, be cooled to-70 ℃ then.(9.5g, THF 51.5mmol) (5ml) solution stir whole system 30 minutes then dropwise to add 2-(4-chloro-phenyl-) methyl acetate in 5 minutes time.(5.03ml 69.5mmol), allows the solution of this merging be warming up to room temperature again and kept 72 hours to add iodomethyl cyanide then lentamente.Add saturated NaHCO 3The aqueous solution (20ml) is concentrated into about 50ml with miscellany again in vacuum, use 1N HCl (100ml) to handle then.Extract miscellany with EtOAc (120ml), then through super-dry (MgSO 4) and evaporation just obtain the oil of burgundy, should oil by 2: 1 DCM of use: pentane carries out purifying as the column chromatography of eluent, thereby obtains title product (8.6g, 75%); 1H NMR (400MHz, CDCl 3), δ: 2.80 (dd, 1H), 3.00 (d, 1H), 3.73 (s, 3H), 3.92 (dd, 1H), 7.22 (d, 2H), 7.37 (d, 2H).
Preparation 148
4-amino-2-(4-chloro-phenyl-) butanols
Figure C0280540901251
In the future the product of self-preparing agent 147 (235mg 1.05mmol) is dissolved among the 1ml THF, then with its under nitrogen environment in 0 ℃ of LiAlH that dropwise joins stirring 4(2.1ml, the THF solution of 1M is in THF solution 2.1mmol).Then with miscellany in stirring at room 2 hours, be cooled to 0 ℃ again.Add entry (0.08ml), add the 3NNaOH aqueous solution (0.08ml) subsequently, use THF (2ml) and water (0.24ml) to dilute whole system then.Suspension was stirred 5 minutes, filter then and the filtrate evaporation is just obtained xanchromatic natural gum.This natural gum is dissolved among the EtOAc (5ml), and extracts, use Na then with 0.5N HCl solution (0.3ml) 2CO 3Solution alkalizes to pH10, and (5 * 3ml) extract to use EtOAc again.Merge organic extraction, then through super-dry (MgSO 4) and evaporation, thereby obtain title product (60mg, 29%); 1H NMR (400MHz, CDCl 3), δ: 1.62-1.95 (m, 2H), 2.58-3.00 (m, 3H), 3.58-3.80 (m, 2H), 7.02-7.39 (m, 4H).
Preparation 149
(4-chloro-phenyl-) ra-butyl acetate
Figure C0280540901252
To N, (25ml, (5.94g 34.8mmol), heats whole system 1 hour in 80 ℃ N-dimethyl-methane amide-di-t-butyl acetal then to add rubigan acetate in dry toluene 104.4mmol) (90ml) suspension.With EtOAc (50ml) dilution miscellany, and water (50ml), 3%NaHCO 3MgSO is passed through in the aqueous solution (50ml) and salt solution (20ml) washing then 4Dry and evaporation just obtains oily matter.With this oil successively with 35%, the pentane solution of 50%DCM carries out purifying, thereby obtains title product (2.4g, 30%); 1H NMR (400MHz, CDCl 3), δ: 1.42 (s, 9H), 3.44 (s, 2H), 7.20 (d, 2H), 7.28 (d, 2H).
Preparation 150
2-(4-chloro-phenyl-) propionic acid tertiary butyl ester
Figure C0280540901261
In the future the product of self-preparing agent 149 is according to carrying out alkylation with the same program described in the preparation 147, and it is to use methyl iodide as alkylating reagent.After carrying out purifying by the pentane solution that uses 25%DCM as the column chromatography of eluent, the yield with 95% obtains title product; 1H NMR (400MHz, CDCl 3), δ: 1.39 (s, 9H), 1.41 (d, 3H), 3.59 (q, 1H), 7.20 (d, 2H), 7.25 (d, 2H).
Preparation 151
The product of self-preparing agent 150 is according to carrying out alkylation with the same program described in the preparation 137 in the future.By successively use 35%, after the pentane solution of 70%DCM carries out purifying as the column chromatography of eluent, the yield with 82% obtains title product; 1H NMR (400MHz, CDCl 3), δ: 1.40 (s, 9H), 1.74 (s, 3H), 2.80 (d, 1H), 2.95 (d, 1H), 7.24 (d, 2H), 7.35 (d, 2H).
Preparation 152
4-amino-2-(4-chloro-phenyl-)-2-methyl butanol
Figure C0280540901271
The product of self-preparing agent 151 is according to the program LiAlH of preparation 148 in the future 4Reduce, thereby obtain title product (35%).The product of this reduction reaction is enough pure, so that it does not need to guarantee further purifying; 1H NMR (400MHz, CDCl 3), δ: 1.22 (s, 3H), 1.71 (ddd, 1H), 2.01 (ddd, 1H), 2.60 (ddd, 1H), 2.83 (ddd, 1H), 3.60 (d, 1H), 3.82 (d, 1H), 7.27 (d, 2H), 7.38 (d, 2H).
Biological test
Adopt method described in [0368]-[0376] section of disclosed patent application EP 1097719-A1 to measure the IC50 value of anti-NEP of The compounds of this invention and ACE.The IC50 value that occurs below is to use the NEP from the dog kidney to measure.In addition, the IC50 value of of the present invention-a little compounds is to use the NEP from people's kidney to measure; These values are similar to the value with the NEP mensuration of dog.
Compound of the present invention is effective inhibitor of NEP, and it has optionally anti-ACE activity.
The title compound of embodiment demonstrates the IC50 of the anti-NEP that is lower than 400nM herein.
The title compound of embodiment 1-25,27-37,39-41,43-48,50-53 and 55-67 demonstrates the IC50 of the anti-NEP of being less than or equal to 150nM and greater than 300 times the selectivity for ACE.
Especially, the title compound of embodiment 3 demonstrates the IC50 of the anti-NEP of 22nM; The title compound of embodiment 4 demonstrates the IC50 of the anti-NEP of 4nM; The title compound of embodiment 21 demonstrates the IC50 of the anti-NEP of 3nM; The title compound of embodiment 33 demonstrates the IC50 of the anti-NEP of 47nM; The title compound of embodiment 43 demonstrates the IC50 of the anti-NEP of 29nM; The title compound of embodiment 51 demonstrates the IC50 of the anti-NEP of 9nM.Embodiment 3,4,21,33,43 and 51 title compound all have the selectivity greater than 300 times anti-ACE.
The animal model of women's sexual arousal reaction
Use the title compound (hereinafter being called " compound of picking out ") of embodiment 22 according to the scheme described in [0495] of EP 1097719-A1-[0499] section.The compound of picking out is formulated in 5% the salt solution.Compound and the vehicle contrast picked out are carried out infusion with Harvard 22 pumps, and this process is to be infused in the femoral vein by the three-dimensional plug with 500 μ l/ minutes.After infusion,, so do not stay in the conduit with regard to there being the compound of picking out with salt solution (Hepsaline) flushing line of heparinization.
When testing with clinical corresponding dosage, the compound of picking out has strengthened the increase (see figure 1) of the genital blood flow amount of pelvic cavity nerve stimulation significantly.Compare with the contrast increase of same time, the compound of picking out has strengthened the peak value of vaginal blood flow amount with the ratio of height to 56% (n=3) and has strengthened the peak value of clitoral blood flow amount with the ratio of height to 50% (n=3).
Fig. 1 has shown used the compound the picked out effect for the genital blood flow amount in rabbit.The compound of picking out has strengthened the increase of (PNS) genital blood flow amount of pelvic cavity nerve stimulation in the anesthetized rabbit model of sexual arousal.Carry out multiple PNS with 15 minutes intervals and caused the reproducible increase of genital blood flow amount (drawing hatched).Compare with viewed increase in the contrast of control stimulation or vehicle at one time (drawing hatched), using the peak value that the compound of picking out (gray) strengthened by inferior terminal stimulus frequency (for example 4Hz) caused clitoris and vaginal blood flow amount increases.After the about 0.5mg/kg of intravenous injection, observe following the time and strengthen: the clitoral blood flow amount has 50% increase, and the vaginal blood flow amount has 56% increase (n=3).Data are represented with mean value ± sem; Monitor all variations with laser doppler technique.
Do not have effect that bigger NEP suppresses or bigger for the basis/influence of non-stimulated genital blood flow amount.
With Medetomidine (Domitor _) (0.5ml/kg, intramuscular injection) and Ketamine (Vetalar _) (0.25ml/kg, intramuscular injection) combination to female new zealand rabbit (～2.5kg) carry out premedicate, keep oxygen to take in by face shield simultaneously.Rabbit is used Portex TMDo not have cover endotracheal tube 3 ID. and carry out tracheotomy, this endotracheal tube is connected on the respirator and keeps the air change rate of 30-40 breathing of per minute, has Tidal volume and the 10cm H of about 18-20ml simultaneously 2The maximum airway pressure of O.Be transformed into isoflurane then and anaesthetize, ventilation was with 2L/ minute O 2Soakage is proceeded.With 23G or 24G conduit the right hand edge ear vein is implemented intubation, and with 0.5ml/ minute perfusion lactic acid Ringer solution.Rabbit is kept in 3% isoflurane during invasive surgical, then reduces to 2% for keeping anesthesia.
Scrape the left inguinal region territory of clean rabbit, and cut the vertical incision of about 5cm that grows up along thigh.Exposure is also isolated femoral vein and femoral artery, uses PVC conduit (17G) to carry out intubation to be used for infused drug and compound then.Repeat to implement intubation for femoral artery, conduit is inserted 10cm deeply to guarantee that conduit arrives aorta abdominalis.This ductus arteriosus is connected in the Gould system with recording blood pressure.The sample that is used for blood gaseous analysis also obtains by ductus arteriosus.Measure systolic pressure and diastolic pressure, use formula (diastolic pressure * 2+ systolic pressure) ÷ 3 to calculate average arterial pressure then.Heart rate obtains software system (Ponemah Physiology Platform, Gould InstrumentSystems Inc) by pulse oxymeter and Po-ne-mah data and measures.
Make a ventrimeson otch that enters the abdominal cavity.The about 5cm of this otch is long and just in time above pubis.Directly fat and muscle are dissected the hypogastric nerve that comes and stretch into body cavity to expose.The edge line that the pubis wall is close in maintenance is very important, and this is femoral vein and the femoral artery that is positioned at the pubis top for fear of destruction.Sciatic nerve and pelvic cavity nerve are in more depths, can find their position after the dorsal part of rabbit is done further to dissect.In case identified sciatic nerve, pelvic cavity is neural has just located easily.Term " pelvic cavity nerve " is not strictly used; For this point, the anatomy book fails enough at length to differentiate this nerve., the stimulation of this nerve causes the increase of vagina and clitoral blood flow amount and the innervation in pelvic cavity zone.The pelvic cavity nerve is dissociated out, then at neural placed around Harvard bipolar stimulation electrode from surrounding tissue.Nerve is lifted slightly to obtain some tension force, go up electrode fixing in position then.The pumice wax oil of about 1ml is placed around neural and the electrode.These paraffin oils serve as neural protectiveness lubricant and prevent that electrode is by blood contamination.Electrode is connected on the Grass S88 stimulator.Stimulate the pelvic cavity nerve with following parameters :-0.5-5V, the pulse width of 0.5ms, 10 seconds stimulus duration, the range of frequency of 2-16Hz.When exciting nerve, can obtain reproducible reaction with every 15-20 minute.Each experiment begin to measure the frequency response curve, this is to it typically is 4Hz in order to determine as the optimum frequency of inferior limit reaction.Testing compound is carried out infusion by femoral vein with Harvard 22 infusion pumps, allow 15 minutes stimulation cycle of successive simultaneously.
Make a ventrimeson otch to expose the pubis zone at the tail end of pubis.Remove reticular tissue exposing the tunicle of clitoris, and definite wall separates with little blood vessel.Also expose outer vaginal wall by removing all reticular tissue.Laser-Doppler flow probe is inserted vagina 3cm, so half of probe rod remains visible.Settle another probe to allow it just in time be positioned at the top of outer clitoris wall.The position of adjusting these probes then is until picked up signal.Another probe just in time is placed on the top of blood vessel surface on the outer vaginal wall.All probes are clamped in position.Vagina and clitoral blood flow amount are carried out record in the following manner: directly to come record from the numeral of using the Po-ne-mah data to obtain the flow instrument of software system (Ponemah PhysiologyPlatform, Gould Instrument Systems Inc); Perhaps to come record from the numeral of Gould chart recorder track indirectly.Begin to be provided with scale (calibration) (0-125ml/ minute/100g tissue) in experiment.
The animal model of male erectile reaction
The anesthetized rabbit method
According to following scheme; will from the title compound (" compound of picking out ") of embodiment 22 separately or with selectivity and effective PDE5 inhibitor 3-ethyl-5-[5-(4-ethyl piperazidine-1-base alkylsulfonyl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones is united and is used.The compound of picking out is prepared among salt solution+5%1M NaOH.Compound and the vehicle contrast picked out are carried out infusion with Harvard 22 pumps, and this process is to be infused in the femoral vein by the three-dimensional plug with 500 μ l/ minutes.After infusion,, so do not stay in the conduit with regard to there being the compound of picking out with salt solution (Hepsaline) flushing line of heparinization.The PDE5 inhibitor is prepared among salt solution+5%1M HCl, and compound and vehicle contrast are carried out infusion with the speed of 0.1ml/s and were kept 15 minutes before the pelvic cavity nerve stimulation.
Carry out following two experiments: the compound of picking out carries out a) using separately and b) and the co-administered influence for intracavernous pressure power (ICP) of PDE5 inhibitor.Influence for ICP is presented among Fig. 2.Data are represented with average increase percentage ratio (%) ± s.e.mean.* P＜0.01, with contrast increase compare " student " (student) the t-check be azygous.
Using the compound of picking out separately causes observing intracavernous pressure power through inferior terminal stimulus and strengthens 37 ± 7% and (see Fig. 2, grayish post; N=4).
The combination of using the compound picked out and selectivity PDE5 inhibitor (1mg/kg, intravenous injection) causes the intracavernous pressure power through inferior terminal stimulus to strengthen 70 ± 4% (seeing Fig. 2, dimmed post; N=3).
Not bigger for the basis/NEP of the intracavernous pressure power that stimulates suppresses or the property followed NEP/PDE5 restraining effect.
With Medetomidine (Domitor _) (0.5ml/kg, intramuscular injection) and Ketamine (Vetalar _) (0.25ml/kg, intramuscular injection) combination to male new zealand rabbit (～2.5kg) carry out premedicate, keep oxygen to take in by face shield simultaneously.Rabbit is used Portex TMDo not have cover endotracheal tube 3ID. and carry out tracheotomy, this endotracheal tube is connected on the respirator and keeps the air change rate of 30-40 breathing of per minute, has Tidal volume and the 10cm H of about 18-20ml simultaneously 2The maximum airway pressure of O.Be transformed into isoflurane then and anaesthetize, ventilation was with 2L/ minute O 2Soakage is proceeded.With 23G or 24G conduit the right hand edge ear vein is implemented intubation, and to pour into newborn acidifying Ringer solution in 0.5ml/ minute.Rabbit is kept in 3% isoflurane during invasive surgical, then reduces to 2% for keeping anesthesia.Exposure is also isolated left jugular vein, uses PVC conduit (17G) to carry out compound or its combination that intubation is picked out to be used for infusion then.
Scrape the left inguinal region territory of clean rabbit, and cut the vertical incision of about 5cm that grows up along thigh.Exposure is also isolated femoral vein and femoral artery, uses PVC conduit (17G) to carry out compound or its combination that intubation is picked out to be used for infusion then.Repeat to implement intubation for femoral artery, conduit is inserted 10cm deeply to guarantee that conduit arrives aorta abdominalis.This ductus arteriosus is connected in the Gould system with recording blood pressure.The sample that is used for blood gaseous analysis also obtains by ductus arteriosus.Measure systolic pressure and diastolic pressure, use formula (diastolic pressure * 2+ systolic pressure) ÷ 3 to calculate average arterial pressure then.Heart rate obtains software system (Ponemah Physiology Platform, GouldInstrument Systems Inc) by pulse oxymeter and Po-ne-mah data and measures.
Make a ventrimeson otch that enters the abdominal cavity.The about 5cm of this otch is long and just in time above pubis.Directly fat and muscle are dissected the hypogastric nerve that comes and stretch into body cavity to expose.The edge line that the pubis wall is close in maintenance is very important, and this is femoral vein and the femoral artery that is positioned at the pubis top for fear of destruction.Sciatic nerve and pelvic cavity nerve are in more depths, can find their position after the dorsal part of rabbit is done further to dissect.In case identified sciatic nerve, pelvic cavity is neural has just located easily.Term " pelvic cavity nerve " is not strictly used; For this point, the anatomy book fails enough at length to differentiate this nerve., the stimulation of this nerve causes the increase of intracavernous pressure power and cavernous body volume of blood flow and the innervation in pelvic cavity zone.The pelvic cavity nerve is dissociated out, then at neural placed around Harvard bipolar stimulation electrode from surrounding tissue.Nerve is lifted slightly to obtain some tension force, go up electrode fixing in position then.The pumice wax oil of about 1ml is placed around neural and the electrode.These paraffin oils serve as neural protectiveness lubricant and prevent that electrode is by blood contamination.Electrode is connected on the Grass S88 stimulator.Stimulate the pelvic cavity nerve with following parameters :-0.5-5V, the pulse width of 0.5ms, 20 seconds stimulus duration, the frequency of 2-16Hz.When exciting nerve, can obtain reproducible reaction with every 15-20 minute.Carry out several stimulations with above-mentioned parameter and just can set up average control reaction.Compound or its combination picked out are carried out infusion by jugular vein with Harvard 22 infusion pumps, allow 15 minutes stimulation cycle of successive simultaneously.Remove skin around the penis and reticular tissue to expose penis.(Insyte-W, Becton-Dickinson 20Gauge 1.1 * 48mm) inserts left cavenae corporis spongiosi (corpus cavernosal space) by tunica albuginea, removes pin then, thereby stays the softish conduit with conduit set.Conduit is connected in the Gould system with record intracavernous pressure power by pressure transducer (Ohmeda 5299-04).In case determined intracavernous pressure power, used Vetbond (tissue adhesive, 3M) sealing duct in position.Heart rate obtains software system (Ponemah Physiology Platform, GouldInstrument Systems Inc) by pulse oxymeter and Po-ne-mah data and measures.
Volume of blood flow carries out record in the following manner in the cavernous body: directly to come record from the numeral of using the Po-ne-mah data to obtain the flow instrument of software system (Ponemah Physiology Platform, GouldInstrument Systems Inc); Perhaps to come record from the numeral of Gould chart recorder track indirectly.Begin to be provided with scale (0-125ml/ minute/100g tissue) in experiment.

Claims (31)

1. available salt, solvate, polymorphic form or prodrug on the compound of molecular formula (I), its medicine;
Wherein
R 1Be the C that can be replaced by one or more substituting groups 1-6Alkyl, substituting group can be for being selected from down the identical or different group that compiles a name list: hydroxyl, C 1-6Alkoxyl group, hydroxyl C 1-6Alkoxyl group and C 1-6Alkoxy C 1-6Alkoxyl group; Perhaps R 1Be hydrogen or C 1-6Alkoxyl group;
X is linker-(CH 2) n-or-(CH 2) q-O-, this moment, Y was connected on the oxygen; Wherein the one or more hydrogen atoms among the linker X can be independently by C 1-4Alkoxyl group, hydroxyl, hydroxyl C 1-3Alkyl, C 3-7Cycloalkyl substituted is perhaps by the C by one or more fluorine-based optional replacements 1-4Alkyl replaces; N is 3,4,5,6 or 7; Q is 2,3,4,5 or 6; With
Y is phenyl or pyridyl, and wherein each can be by one or more radicals R that can be identical or different 8Replace, wherein R 8For: hydroxyl; Sulfydryl; Halogen; Cyano group; Carbocylic radical or heterocyclic radical, wherein any can be by C 1-6Alkyl, C 1-6The optional replacement of alkoxyl group or halogen; C 1-6Alkoxyl group; Phenoxy group; C 1-6The alkyl sulfenyl; Thiophenyl; Perhaps by C 1-6Alkoxyl group, C 1-6The C of alkyl sulfenyl, halogen or the optional replacement of phenyl 1-6Alkyl; Perhaps
Two R on the adjacent carbons 8Group can form condensed 5 or 6 yuan of carbocyclic rings or heterocycle with interconnective carbon atom, and this carbocyclic ring or heterocycle are by C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6The optional replacement of alkyl sulfenyl or halogen.
2. available salt, solvate, polymorphic form or prodrug, wherein R on compound according to claim 1, its medicine 1Be hydrogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkoxy C 1-3Alkyl or C 1-6Alkoxy C 1-6Alkoxy C 1-3Alkyl.
3. available salt, solvate, polymorphic form or prodrug, wherein R on compound according to claim 2, its medicine 1Be C 1-4Alkyl or C 1-6Alkoxy C 1-3Alkyl.
4. according to available salt, solvate, polymorphic form or prodrug on each described compound, its medicine among the claim 1-3, it has molecular formula Ia:
5. according to available salt, solvate, polymorphic form or prodrug on each described compound, its medicine among the claim 1-3, wherein X is-(CH 2) n-and linker X in one or more hydrogen atoms can be replaced by defined group in one or more claims 1.
6. according to available salt, solvate, polymorphic form or prodrug on each described compound, its medicine among the claim 1-3, wherein when having n, n is 3 or 4.
7. according to available salt, solvate, polymorphic form or prodrug, wherein R on each described compound, its medicine among the claim 1-3 8Be C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl, C 1-6Alkyl sulfenyl, halogen, cyano group or heterocyclic radical; Perhaps two R on the adjacent carbons 8Group can form condensed 5 or 6 yuan of carbocyclic rings or heterocycle with interconnective carbon atom, and this carbocyclic ring or heterocycle are by C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6The optional replacement of alkyl sulfenyl or halogen.
8. according to available salt, solvate, polymorphic form or prodrug on any one described compound of claim 1-3, its medicine, wherein work as R 8During for heterocyclic radical, R 8Be pyridyl, oxadiazole base, pyrazolyl or triazolyl.
9. according to available salt, solvate, polymorphic form or prodrug on any one described compound of claim 1-3, its medicine, wherein when Y be two R on phenyl and the adjacent carbons 8When group forms condensed 5 or 6 yuan of carbocyclic rings or heterocycle with interconnective carbon atom, this condensed ring is naphthyl, quinolyl, isoquinolyl, indyl, indazolyl, benzimidazolyl-, benzoisoxazole base, dihydro benzo furyl, benzoxazolyl, 2,3-indanyl, benzisothiazole base and benzothiazolyl.
10. available salt, solvate, polymorphic form or prodrug on compound according to claim 1, its medicine, wherein this compound is:
(2R)-and 2-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] methyl } valeric acid,
3-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] propionic acid,
3-{[1-({ [3-(2,3-dihydro-1-cumarone-5-yl) propyl group] amino } carbonyl) cyclopentyl] propionic acid,
2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid,
2-{[1-({ [3-(4-fluorophenyl) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid,
4-methoxyl group-2-{[1-({ [3-(4-p-methoxy-phenyl) propyl group] amino } carbonyl) cyclopentyl] methyl } butyric acid,
2-{[1-({ [3-(2,3-dihydro-1-cumarone-5-yl) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid,
(2S)-2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl-4-methoxyl group butyric acid and
(2S)-and 2-{[1-({ [3-(2,3-dihydro-1-cumarone-5-yl) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid.
11. (2S)-and 2-{[1-({ [3-(4-chloro-phenyl-) propyl group] amino } carbonyl) cyclopentyl] methyl }-4-methoxyl group butyric acid.
12. available salt, solvate, polymorphic form or the prodrug purposes in producing medicine on each defined compound, its medicine in the aforementioned claim, this medicine is used for the treatment of or prevents can obtain by suppressing neutral endopeptidase the illness of useful reaction.
13. purposes according to claim 12, wherein this illness is Female sexual dysfunction or male erectile dysfunction.
14. purposes according to claim 13, wherein this illness is a female sexual arousal disorder.
15., wherein use to general this compound according to any one described purposes of claim 12-14.
16. purposes according to claim 15, wherein Orally administered this compound.
17. according to any one described purposes of claim 12-14, wherein this compound of topical application.
18. available salt, solvate, polymorphic form or prodrug on defined compound, its medicine in any one of claim 1-11, they are as medicine.
19. pharmaceutical composition, it comprises on compound specified in any one of claim 1-11, its medicine available vehicle, diluent or carrier on available salt, solvate, polymorphic form or prodrug and the medicine.
20. defined compound is selected from down the combination of the activeconstituents that compiles a name list with one or more in any one of claim 1-11:
A) PDE5 inhibitor;
B) NPY Y1 inhibitor;
C) dopamine agonist, perhaps selective d 2, D 3Or D 2/ D 3Agonist;
D) melanocortin-4 receptor agonists or modulator or melanocortin toughener;
E) agonist of 5HT2C, antagonist or modulator;
F) estrogen receptor modulator, estrogen agonist and/or estrogen antagonist;
G) male sex hormone; With
H) oestrogenic hormon.
21. the combination of claim 20, wherein said PDE5 inhibitor are 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (IC-351); 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone; 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; And 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones with and medicine on available salt.
22. the combination of claim 20, wherein dopamine agonist is an apomorphine.
23. the combination of claim 20, wherein selective d 2, D 3Or D 2/ D 3Agonist is pramipexole and ropirinol.
24. the combination of claim 20, wherein melanocortin-4 receptor agonists or modulator or melanocortin toughener are melanotan II, PT-14, PT-141.
25. the combination of claim 20, wherein estrogen receptor modulator, estrogen agonist and/or estrogen antagonist are raloxifene, tibolone or Lasofoxifene.
26. the combination of claim 20, wherein male sex hormone is androsterone, dehydroandrosterone, testosterone, androstanedione and synthetic male sex hormone.
27. the combination of claim 20, wherein oestrogenic hormon is estradiol, oestrone, trihydroxy-oestrin and synthetic oestrogenic hormon.
28. the combination of claim 27, wherein synthetic oestrogenic hormon is phenylformic acid oestrogenic hormon.
29. be used to prepare the compound of general formula I
Or the method for its salt, wherein R 1, X and Y and claim 1-11 any one in defined the same, this method comprises the following steps:
A) with the compound of molecular formula II
Figure C028054090007C1
Compound with the molecule formula III
Y-X-NH 2(III) react, thereby obtain the compound of molecular formula IV
Figure C028054090007C2
Wherein prot is suitable blocking group, then
B) compound with molecular formula IV reacts under the suitable condition of removing blocking group, thereby obtains the compound of molecular formula I; Then
C) form salt alternatively.
30. method according to claim 29, it further comprises any one asymmetric hydrogenation in the compound of molecular formula XI, XII or XIII
Figure C028054090008C1
Wherein Q is for R in the claim 1 1Defined C 1-6Substituting group on the alkyl, thus the compound of molecular formula IIa obtained
31. the compound of molecular formula IV
Figure C028054090008C3
R wherein 1, X and Y and claim 1-11 any one in defined the same, Prot is suitable blocking group.
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