CN1190390A - Nitric oxide synthase inhibitors derived from cyclic amidines - Google Patents

Nitric oxide synthase inhibitors derived from cyclic amidines Download PDF

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CN1190390A
CN1190390A CN96195400A CN96195400A CN1190390A CN 1190390 A CN1190390 A CN 1190390A CN 96195400 A CN96195400 A CN 96195400A CN 96195400 A CN96195400 A CN 96195400A CN 1190390 A CN1190390 A CN 1190390A
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hydrogen
low
alkyl group
group
amino
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小D·W·汉森
T·J·哈根
S·W·克拉梅尔
S·梅茨
K·B·佩特尔森
D·P·斯潘格勒尔
M·V·托思
K·F·霍克
R·K·维贝尔
F·S·乔思
B·S·皮泽勒
E·A·哈利南
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GD Searle LLC
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Abstract

Compounds having formula (I) wherein R<1>, R<5>, R<6> and R<7> are hydrogen or certain specified substituents; R<8> and R<9> are independently hydrogen, hydroxy or alkoxy; and X, A and B are independently NR<2>, O, S, SO, SO2, CH=CH or (CH2)p, p being 0-6; are useful as nitric oxide synthase inhibitors.

Description

By ring-type amidine deutero-inhibitors of nitric oxide synthase
The application is the subsequent application of the U. S. application serial number 08/438,321 submitted May 10 nineteen ninety-five, and the content of above-mentioned U. S. application is incorporated this paper into as a reference.Invention field
The present invention relates to the amidino groups derivative compound, contain the medicinal compositions of these compounds, and relate to their application in treatment, particularly they are as the application of inhibitors of nitric oxide synthase.
Background of invention
Just know that at the beginning of the 1980's by the loose existence of depending on endothelium of blood vessel of vagusstoff initiation, and this activity gives the credit to the variable humoral factor that is known as endothelium derivation relaxation factor (EDRF).Nitrogen oxide (NO) exceedes a century as the active well known of vasodilator, and NO is the active ingredient of amyl nitrite, trinitrin and other nitro vasodilator.EDRF identifies recently with the identity of NO and can be consistent from synthetic this biochemical route of NO of amino acid L-arginine by the NO synthetic enzyme with discovery.
NO is the endogenous stimulant of soluble guanylate cyclase, and rely on the relaxation effect except relating to endothelium, also relate to many biological actions, the cell pair cell that comprises phagocytal cytotoxicity and central nervous system transmits (referring to Moncada etc., " biological pharmacology (Biochemical Pharmacology) 38,1709-1715 (1989) and Moncada etc., " pharmacology comment " (Pharmacological Reuiews) 43,109-142 (1991)).
Think that now excessive N O generation can cause many illnesss, particularly relate to systemic ypotension such as toxic shock and with the illness of some cytokine therapy.
By the synthetic NO of L-arginine can be that L-N-monomethyl arginine (L-NMMA) suppresses by the L-arginine analog, and once advises L-NMMA is used to handle the systemic hypotensive treatment (WO 91/04024 and GB-A-2240041) of toxic shock and other type.Once advised also in WO 91/04024 and EP-A-0446699 that some other NO synthetase inhibitors except that L-NMMA was used for the treatment application of same purpose.
The NO synthetic enzyme that has three kinds of following types at least, this point has become clearly recently:
(i) composing type, Ca ++/ calmodulin relies on enzyme, is arranged in endothelium, and it is replied acceptor or physical stimulation and discharges NO.
(ii) composing type, Ca ++/ calmodulin relies on enzyme, is positioned at brain, and it is replied acceptor or physical stimulation and discharges NO.
(iii) Ca ++Independent enzyme, it is by behind intracellular toxin and cytokine activation vascular smooth muscle, scavenger cell, endotheliocyte and many other cells and derivative.In case express, this NO synthetic enzyme of inducing will synthesize NO in a segment length period.
Work to support the transduction mechanism of several physiological responses by the NO of composing type enzyme release.But by the NO that inducible enzyme produces is born of the same parents' poison molecule to tumour cell and invading micro-organism.But it seems the side effect, particularly pathological angiogenesis diastole and tissue injury that excessive NO produces, mainly is owing to caused by the influence that can induce NO synthetic enzyme synthetic NO.
More and more evidences shows that it is rotten that NO may relate to the cartilage that takes place in some illness such as the sacroiliitis, and also know, NO is synthetic in rheumatoid arthritis increases.Therefore, inhibition can bring other illness of benefit to comprise the inflammation (for example sacroiliitis) of the autoimmunization and/or the infection of joint by the NO that the L-arginine produces, enteritis, heart lobe local asphyxia, diabetes, people's hyperpathia disease (allodynia), cerebral ischemia (focus local asphyxia, thrombus apoplexy and sphere local asphyxia, the ischemic of cardiempharaxis secondary) and other CNS disorder by NO mediation, the opium tolerance that comprises the patient who needs long-term opioid analgesics, take for example Nicotine of patient's the benzodiazepine tolerance of benzodiazepine and other Addictive Behaviors, and the feed imbalance etc.
Inhibition produces NO by the L-arginine can comprise the sepsis that is induced by medicament various in style and/or the relevant systemic ypotension of shock of poisoning to it other favourable situation, with the treatment of cytokine (as TNF, IL-1, IL-2), and be used for organ transplantation short-term immunosuppressant therapy with adjuvant.Inhibition produces NO by the L-arginine can comprise that autoimmune disease and/or those influence the inflammation in joint as (for example sacroiliitis or acquired immune deficiency syndrome (AIDS) or enteritis) or asthma, cardiovascular local asphyxia, congested blood heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhoea, irritated enteron aisle syndromes, tumour fibrosis, pulmonary emphysema and diabetes to it other favourable illness.
Some suggestions at present are nonselective as the NO synthetase inhibitors, particularly L-NMMA of therepic use, its non-selective being, but they had not only suppressed composing type but also NO synthetic enzyme that suppress induction type.The application of this non-selective NO synthetase inhibitors needs the minimum heart, to avoid excessively suppressing the possible serious consequence of composing type NO synthetic enzyme, comprises hypertension and possible thrombosis and tissue injury.Specifically, in the treatment application of suffering a shock is poisoned in the L-NMMA treatment, recommended already, in the entire treatment process, the patient must carry out the successive monitoring of blood pressure.Therefore, though if take suitable preventive measures, non-selective NO synthetase inhibitors has treatment effectiveness, but selective N O synthetase inhibitors is with regard on its meaning that the rejection ratio that can induce the NO synthetic enzyme is suppressed to want much higher to the composing type isoforming body of NO synthetic enzyme, this selective N O synthetase inhibitors has bigger treatment advantage, and easier use.
WO 94/12165, WO 94/14780, WO 93/13055, EP0446699A1 and USP 5,132,453 disclose the compound that inhibited oxidation nitrogen synthesizes and preferentially inhibited oxidation nitrogen synthetic enzyme can be induced the isoforming body.These open texts are as described herein incorporates this paper into as a reference in full with it.
Summary of the invention
The invention provides novel amidino derivatives.These novel inhibitor compounds and its salt, its medicinal upward acceptable ester and prodrug thereof can be represented by following chemical formula: Wherein:
R 1Be selected from hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, alkoxyl group, thio alkoxy, cycloalkyl, heterocyclic radical and aryl, they can be chosen wantonly by following groups and replace: low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, heterocyclic radical, aryl, hydroxyl, lower alkoxy, aryloxy, thiol, rudimentary thio alkoxy, halogen, cyano group, nitro, amino, alkylamino, dialkyl amido, aminoalkyl group, dialkyl aminoalkyl, arylamino, aminoaryl, alkylamino aryl, acyl amino, carboxyl, carboxyalkyl, CONR 10R 11, S (O) R 10, S (O) 2R 10, SO 2NR 10R 11, PO (OR 10) (OR 11), amidino groups, guanidine radicals; Wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: halogen, low alkyl group, amino, alkylamino, dialkyl amido, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonylic alkyl aryloxy, hydroxyl, lower alkoxy, S (O) R 10, S (O) 2R 10, amidino groups, guanidine radicals;
X＝NR 2、O、S、SO、SO 2、(CH 2) p、CH＝CH；
P=0 to 6;
A＝NR 3、O、S、SO、SO 2、(CH 2) q、CH＝CH；
Q=0 to 6;
B＝NR 4、O、S、SO、SO 2、(CH 2) v、CH＝CH；
V=0 to 6;
R 2=hydrogen, low alkyl group, aryl, heterocyclic radical;
R 3=hydrogen, low alkyl group, aryl, heterocyclic radical;
R 4=hydrogen, low alkyl group, aryl, heterocyclic radical;
R 5, R 6, R 7Be independently selected from hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, heterocyclic radical, hydroxyl, lower alkoxy, thiol, rudimentary thio alkoxy, S (O) R 9, S (O) 2R 9, halogen, nitro, amino, alkylamino, dialkyl amido, aminoalkyl group, dialkyl aminoalkyl, arylamino, aminoaryl, alkylamino aryl, acyl amino, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonyl alkoxy aryl, cyano group, aminocarboxyl alkoxyl group, amino carbonyl amino, amino carbonyl amino alkyl, haloalkyl, SO 2NR 10R 11, wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: low alkyl group, amino, alkylamino, dialkyl amido, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonylic alkyl aryloxy, hydroxyl, lower alkoxy;
R 5, R 6Can choose wantonly connects together forms alicyclic hydrocarbon, heterocyclic radical or aromatic hydrocarbons, and the ring of described optional formation can be chosen wantonly by one or more following groups replacement:
Low alkyl group, low-grade alkenyl, low-grade alkynyl, they can be chosen wantonly by following groups and replace: carboxyl, carbonylic alkoxy, carbonyl aryloxy, carboxyalkyl aryloxy and lower alkoxy;
R 8=hydrogen, hydroxyl, O-alkyl;
R 9=hydrogen, hydroxyl, O-alkyl;
R 10=hydrogen, low alkyl group, alkylaryl, aryl;
R 11=hydrogen, low alkyl group, alkylaryl, aryl;
R 10And R 11Connecting together can be alkylidene group, thereby produces nitrogenous heterocycle;
Its precondition is to work as R 1When being low alkyl group, low-grade alkenyl or low-grade alkynyl, R 1Can not choose wantonly by cycloalkyl, heterocyclic radical and aryl and replace, unless A or B are NR 2, O, S, SO, SO 2
Its precondition is, when A and B are (CH 2) pOr CH=CH, and R 1When being low alkyl group, low-grade alkenyl or low-grade alkynyl, R 1Can't help cycloalkyl, heterocyclic radical or aryl replaces, and R 5And R 6Not H;
Its precondition is to have only one of X, A and B can be selected from NR respectively 2, NR 3, NR 4, or be selected from O, S, SO or SO 2
Its precondition further is, as X=(CH 2) pA=(CH 2) qB=(CH 2) vDuring p+q+v=3, then maximum R 1, R 5, R 6And R 7One of can be alkyl, alkoxyl group, cycloalkyl or cycloalkyloxy on the 5-position;
Another precondition is, as X=(CH 2) pA=(CH 2) qB=(CH 2) vP+q+v=3, and R 1, R 5, R 6And R 7One of be alkyl, cycloalkyl or aryl on the 5-position, Yu Xia R then 1, R 5, R 6And R 7None can be the cyano group on the 5-position, amino, alkoxyl group or the thio alkoxy of replacement;
Another precondition is to work as X=CH=CH; A=(CH 2) qB=(CH 2) vAnd during q+v=2, R then 1, R 5, R 6And R 7None can be the carboxyl on the 6-position; And
Another precondition is to work as X=NH; A=(CH 2) qB=(CH 2) vAnd during q+v=4, R then 1, R 5, R 6And R 7None can be the carboxyl on the 7-position.
Another wider aspect, it is synthetic to the present invention relates in the patient inhibited oxidation nitrogen, this inhibition of described needs of patients or treatment, promptly with formula (I) compound administration of the synthetic amount of suppression of nitrogen oxide in the patient, the induced isoforming body of the preferred inhibited oxidation nitrogen of this compound synthetic enzyme but not nitric oxide synthase composing type isoforming body.
The invention still further relates to the medicinal compositions that comprises formula (I) compound.
Compound defined above and composition have the function of inhibitors of nitric oxide synthase.These compounds also preferentially suppress to induce this enzyme of form.
In disorder by the nitrogen oxide mediation, can be because suppress by the NO of L-arginine generation to it other favourable situation, comprise by the medicament inductive septicemia various in style and/or the relevant systemic ypotension of shock of poisoning, with the treatment of cytokine (as TNF, IL-1 and IL-2) with at the auxiliary of transplantation treatment immunosuppressant therapy a middle or short term.Inhibition produces NO by the L-arginine can comprise that autoimmune disease and/or those influence inflammation in joint (for example sacroiliitis) or enteritis to it other favourable illness, cardiovascular local asphyxia, diabetes, congestive heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhoea, irritable bowel trace integration disease, the tumour fibrosis, pulmonary emphysema, sick feel irritated (allodynia), cerebral ischemia (focus local asphyxia, thrombus apoplexy and sphere local asphyxia, the ischemic of cardiempharaxis secondary) and other CNS disorder by NO mediation, the opium tolerance that comprises the long-term opioid analgesics patient of needs, take benzodiazepine tolerance and other Addictive Behaviors of the patient of benzodiazepine , as Nicotine, and the feed imbalance.
The present invention includes salt form, particularly the formula of acid salt form (I) compound.The salt that is fit to comprises the salt that forms with organic or inorganic acid.Though non-medicinal acceptable salt is perhaps useful on the preparation of the compound of being discussed and purifying, above-mentioned acid salt is often referred to medicinal acceptable salt.Therefore, preferred salt comprises those and the salt of following acid formation: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, acetate, succsinic acid, fumaric acid, toxilic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Phenylsulfonic acid etc. are (for example referring to S.M.Berge etc., " Pharmaceutical Salts ", " pharmaceutical science magazine " (J.Pharm.Sci.), 1977,66,1-19).The salt of formula (I) compound can make with the acid-respons that suits by the suitable compound of free alkali form.
Though formula (I) compound can be with the form administration of starting compound, preferably the form with medicinal compositions exists.On the other hand, the invention provides a kind of medicinal preparations, this medicinal preparations comprises formula (I) compound or its medicinal acceptable salt, or solvate and one or more its medicinal acceptable carrier, and chooses any one kind of them or multiple other therapeutic component.These carriers must be that " acceptable " meaning is that carrier need be compatible with other composition of preparation, and harmful to its acceptor.
Preparation comprises the preparation that is suitable for oral, suction, non-enteron aisle (comprising subcutaneous, intracutaneous, intramuscular, intravenously and intraarticular), rectum and part (comprising skin, mouth, hypogloeeis and intraocular) administration, but optimal approach depends on the symptom of acceptor and illness etc.The preparation routine exists with unit dosage form, and can be by the known either party's method preparation of technical field of pharmaceuticals.All methods comprise formula (I) compound or its medicinal acceptable salt or solvate (activeconstituents) this step that combines with one or more carriers that constitute ancillary components.Usually, formulation preparation is as follows: activeconstituents and liquid vehicle or finely divided solid carrier or the two evenly and will closely be combined, afterwards, if desired, product is shaped and required preparation.
Being suitable for oral preparation of the present invention can exist with isolating unit, and as capsule, flat capsule or sheet, they respectively contain the activeconstituents of predetermined amount; Exist with powder or particle; Exist with liquid, aqueous or not liquid, aqueous solution or suspension; Or exist with oil-in-water liquid emulsion or water-in-oil liquid emulsion.Activeconstituents also can exist with bolus, electuary or paste.
Tablet can be suppressed or molded forming with one or more ancillary components by optional.The tablet of compacting can be made with tackiness agent, lubricant, inert diluent, wetting agent, tensio-active agent or dispersant by the activeconstituents of stranglehold liquid form (as powder or particle) in the machine that is fit to is also optional.Molded tablet can will make with the mixture pressing mold of the moistening powder compound of inert liquid diluent by in the machine that is fit to.Optional dressing of these tablets or marking, and can formulated and make wherein that activeconstituents slowly or controlledly discharges.
The preparation that is used for parenterai administration comprises moisture and non-aqueous disinfecting injection solution, can contain oxidation inhibitor, damping fluid, sterilant in this injection solution and make preparation and the isoosmotic solute of blood of desiring the patient; Moisture and non-aqueous disinfecting suspension, this suspension can comprise suspension agent and thickening material.These preparations may reside in unitary dose or the multiple-unit container, and for example Mi Feng ampoule and phial, and can preserve under lyophilisation condition only need before being about to use adding sterilised liq carrier for example salt solution, the water that is used to inject.Pei Zhi injection solution and suspension can be by disinfecting powder, particle and the tablet preparation of type described above then and there.
The preparation that is used for rectal administration can exist with the suppository that has common carrier such as theobroma oil or polyoxyethylene glycol.
The preparation that is suitable in the mouth (for example per os, through the hypogloeeis) administration comprises lozenge and pastille.Active ingredient is contained in fragrance matrix such as sucrose and kordofan gum or the tragacanth gum in the lozenge.Active ingredient is contained in matrix such as gelatin and glycerine or sucrose and the kordofan gum in the pastille.
The preparation that is used for inhalation, activeconstituents be with aerosol or with the together administration and sucking in the lung of inert support reagent.
Preferred unit dose formulations be those contain hereinafter described effective dose or the preparation of the activeconstituents of its suitable component.
Should be appreciated that except the composition of above specifically mentioning preparation of the present invention can also comprise that this area is thought the preparation discussed is belonged to other conventional reagent that the preparation that for example is suitable for oral administration can comprise flavouring agent.
The compounds of this invention can be oral or by injection with 0.001 to 2500 milligram/kilogram dosed administration every day.For the adult, dosage range normally 0.005 milligram to 10 gram/skies.With tablet or other existence form that separation unit provides, can contain compound routinely in the effective amount of this dosage or its many multiple dose subordinate, for example per unit contains 5 milligrams to 500 milligrams, usually about 10 milligrams to 200 milligrams.
Formula (I) compound preferred oral or by the injection (intravenously or subcutaneous) administration.Granting patient's the accurate amount of compound should be responsible for by attending upon one's elder and betters the doctor.Yet the dosage that is adopted will depend on many factors, comprise patient's age and sex, be intended to handle diagnose a disease really disease and severity thereof.Equally, route of administration can be according to symptom and severity thereof and difference.
As used herein, term " low alkyl group " (separately or with other word combination time) meaning is to contain 1 to about 10, and preferred 1 to about 8 carbon atoms, and the more preferably 1 acyclic alkyl group to about 6 carbon atoms.These examples of groups comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, octyl group or the like.
Term " low-grade alkenyl " is meant the unsaturated acyclic hydrocarbon base that contains at least one two key.These alkyl contain has an appointment 2 to about 10 carbon atoms, preferably contains about 2 to 8 carbon atoms and more preferably 2 to about 6 carbon atoms.The non-limiting examples of alkenyls that is fit to is propenyl, butene-1-Ji, isobutenyl, amylene-1-base, 2-2-methyl butene-1-base, 3-methyl butene-1-base, hexene-1-base, heptene-1-base and octene-1-Ji or the like.
Term " low-grade alkynyl " is meant the unsaturated acyclic hydrocarbon base that contains one or more three key, and these hydrocarbon groups contain and have an appointment 2 to about 10 carbon atoms, preferably have about 2 to 8 carbon atoms, and more preferably have 2 to about 6 carbon atoms.The example of the alkynyl that is fit to comprises ethynyl, proyl, butine-1-base, crotonylene-Ji, pentyne-1-base, pentyne-2-base, 3-methyl butine-1-base, hexin-1-base, hexin-2-base, hexin-3-base, 3,3-dimethyl butine-1-base or the like.
Term " alicyclic hydrocarbon " or " cycloalkyl " meaning is that 3 alicyclic radicals to the ring of about 10 carbon atoms are arranged, and preferred 3 to about 6 carbon atoms.The example of the alicyclic group that is fit to comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl or the like.
Term " aromatic hydrocarbon " meaning is to have 4 to about 16 carbon atoms, and preferred 6 to about 12 carbon atoms, more preferably 6 aromatic groups to about 10 carbon atoms.The example of the aromatic hydrocarbyl that is fit to comprises phenyl, naphthyl or the like.
The term that this paper uses " aryl " meaning is the single aromatic group of 5-and 6-unit, and it can comprise zero to four heteroatomss, and representational aryl comprises phenyl, thienyl, furyl, pyridyl, (different) oxazolyl or the like.
The term DCM meaning is a methylene dichloride.
The term DEAD meaning is the diethylazodicarboxylate.
The term DIBAL-H meaning is a diisobutyl aluminium hydride.
The term DMAP meaning is a dimethyl aminopyridine.
The term DMSO meaning is a dimethyl sulfoxide (DMSO).
The term EDC meaning is hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide.
Term " heterocyclic group " meaning is saturated or unsaturated cyclic hydrocarbon group, and described cyclic hydrocarbon group comprises and have 4 to about 10 carbon atoms, the aromatics ring system of preferred about 5 to 6 carbon atoms, wherein 1 substituted by nitrogen, oxygen, sulphur or carbonyl to about 4 carbon atoms.Described " heterocyclic group " can condense with aromatic hydrocarbon radical.The example that is fit to comprises pyrryl, pyridyl, pyrazolyl, triazolyl, pyrimidyl, pyridazinyl oxazolyl isoxazolyl, thiazolyl, imidazolyl, indyl, thienyl, furyl, tetrazyl, the 2-pyrrolinyl, the 3-pyrrolinyl, pyrrolidyl, 1, the 3-dioxolanyl, the 2-imidazolinyl, imidazolidyl, the 2-pyrazolinyl, pyrazolidyl isoxazoline-3-yl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, the 2H-pyranyl, the 4H-pyranyl, piperidyl, 1, the 4-alkyl dioxin, morpholinyl, 1,4-dithiane base, thio-morpholinyl, pyrazinyl, piperazinyl, triazinyl, 1,3,5-trithian base, benzo (b) thienyl, benzimidazolyl-, quinolyl or the like.
The term HOBT meaning is the N-hydroxybenzotriazole.
Term " lower alkoxy " (separately or with other word combination) meaning is an alkyl ether groups, and wherein the term alkyl and most preferably contains 1 to about 4 carbon atoms as defined above.The example of the alkyl ether groups that is fit to comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy or the like.
Term " rudimentary thio alkoxy " (separately or with other word combination) meaning is the alkyl thioether group, and wherein the term alkyl and most preferably contains 1 to about 4 carbon atoms as defined above.The example of the alkyl thioether that is fit to comprises sulfo-methoxyl group, thio ethoxy, sulfo-positive propoxy, sulfo-isopropoxy, sulfo-n-butoxy, sulfo-isobutoxy, sulfo-sec-butoxy, sulfo-tert.-butoxy or the like.
The term alkoxy carbonyl meaning used herein is the alkoxy base with as above definition of the carbonyl (C=O) that is attached thereto.
Term " halogen " meaning is fluorine, chlorine, bromine or iodine.
The term MCPBA meaning is a metachloroperbenzoic acid.
The term NMM meaning is a N-methylmorpholine.
The term NMMO meaning is a 4-methylmorpholine N oxide compound.
Term " prodrug " is meant the active bigger compound that can become in vivo.
The term sulfinyl meaning is SO.
The term alkylsulfonyl meaning is SO 2
The term TEA meaning is a triethylamine.
Term TMSN 3The meaning is a TMSA.
As adopting herein, patient " processing " tends to also comprise prevention.
No matter the reference of being quoted among the application is patent or application, the U.S. or other country, it is for referencial use all to incorporate this paper into, writes this paper as it.
The compounds of this invention can exist with geometry or stereoisomer form.The present invention considers these all compounds, comprise cis-and trans-geometrical isomer, E-and Z-type geometrical isomer, R-and S-enantiomer, diastereomer, d-isomer, L-isomer, its racemic mixture and other mixture, they all fall into scope of the present invention.
11 kinds of useful common synthetic methods in the preparation The compounds of this invention are hereinafter disclosed.
Reaction formula 1: A) Mg, THF; B) CuI ,-30 ℃; C)-30 ℃ to 0 ℃ or r.t.; D) DMSO, oxalyl chloride, CH 2Cl 2,-70 ℃; E) Et 3N ,-70 ℃ to 0 ℃; F) NH 2OH, NaOAc, EtOH; G) PhSO 2Cl, NaOH, H 2O, acetone; H) Me 3O +BF 4 -I) NH 4Cl; J) K 2CO 3Or NaH, DMF; K) NaCN, DMSO, H 2O, heat l) DMF, L-R 1(L '-R wherein 1Be CH 2=CHCO-R 1); M) 1N LiOH, MeOH.Reaction formula 2: (Y=CN, COO alkyl, NO 2, SO 2Alkyl, SO 2NH 2, SO 2NR 10R 11, heteroaryl) and R m=H, alkyl, cycloalkyl, aryl, heterocycle R n=H, alkyl, aryl, heterocycle R mAnd R nCan connect together and form a) solvent (benzene) of ring; B) NH 2OH, NaOAc, EtOH; C) PhSO 2Cl, NaOH, H 2O, acetone; D) Me 3O +BF 4 -, CH 2Cl 2E) NH 4Cl, MeOH.Reaction formula 3: A) alkali, R 1CH 2NO 2B) H 2/ RaNi, 55 ℃ of c) Me 3O +BF 4 -, CH 2Cl 2D) NH 4Cl, MeOH.Reaction formula 4:
Figure A9619540000212
A) R 5COR 6Alkali; B) alkali, R 7CH 2CO 2Me; C) H 2/ RaNi, 55 ℃; D) Me 3O +BF 4 -, CH 2Cl 2E) NH 4Cl, MeOH.Reaction formula 5:
Figure A9619540000221
A) DBU, Z-α-phosphonoglycine trimethylammonium ester; B) H 2/ [Rh[(COD) (R, R-DIPAMP)] +BF 4 -(can use the enantiomorph catalyzer); C) Me 3O +BF 4 -, CH 2Cl 2D) NH 4Cl, MeOH; E) H 2, Pd/C.Reaction formula 6:
Figure A9619540000231
A) (tertiary butyl OCO) 2O, DMAP, THF; B) LiHMDS, HMPA, THF, (1S)-(+)-(10-camphor sulfonyl) oxa-aziridine or (1R)-(-)-(10-camphor sulfonyl) oxa-aziridine; C) tert-butyldimethylsilyl chloride, imidazoles, DMF; D) Mg (ClO 4) 2(20%), CH 3CN; E) Me 3O +BF 4 -, CH 2Cl 2F) NH 4Cl, MeOH; G) (butyl) 4N +F -, MeOH.Reaction formula 7: A) NaH/THF; B) BrCH 2CN/THF; C) ethylene glycol/tosic acid/toluene; D) LiAlH 4/ Et 2O; E) carbonyl benzyloxy chlorine/butanol/water/NaOH; F) Tosyl chloride/CH 2Cl 2/ pyridine; G) KCN/ acetonitrile; H) KOH/ ethylene glycol; I) MeI/DMF/NaHCO 3J) H 2/ Pd/MeOH; K) B 2H 6/ THF; M) HCl/AcOH/H 2O; N) NH 2OH; P) benzene sulfonyl chloride/H 2O/ acetone NaOH; Q) Tetrafluoroboric acid trimethylammonium oxonium salt; R) NH 4Cl/MeOH.Reaction formula 8:
Figure A9619540000251
A) (tertiary butyl OCO) 2O, DMAP, THF; B) LiHMDS, HMPA, THF; (1S)-(+)-(10-camphor sulfonyl) oxa-aziridine or (1R)-(-)-(10-camphor sulfonyl) oxa-aziridine; C) tert-butyldimethylsilyl chloride, imidazoles, DMF; D) Mg (ClO 4) 2(20%), CH 3CN; E) Me 3O +BF 4 -, CH 2Cl 2F) NH 4Cl, MeOH; G) (butyl) 4N +F -, MeOH; H) H 2, Pd/C.Reaction formula 9:
Figure A9619540000271
Reaction formula 9 (continuing)
Figure A9619540000281
A) NaH/THF; B) BrCH 2CN/THF; C) ethylene glycol/tosic acid/toluene; D) LiAlH 4/ Et 2O; E) carbonyl benzyloxy chlorine/butanol/water/NaOH; F) Tosyl chloride/CH 2Cl 2/ pyridine; G) KCN/ acetonitrile; H) KOH/ ethylene glycol; I) MeI/DMF/NaHCO 3J) H 2/ Pd/MeOH; K) B 2H 6/ THF; M) HCl/AcOH/H 2O; N) NH 2OH; P) benzene sulfonyl chloride/H 2O/NaOH; Q) Tetrafluoroboric acid trimethylammonium oxygen; R) NH 4Cl/MeOH; S) H 2/ Pd/C.Reaction formula 10:
Figure A9619540000291
A) (tertiary butyl OCO) 2O, DMAP, THF; B) LiHMDS, HMPA, THF; (1S)-(+)-(10-camphor sulfonyl) oxa-aziridine or (1R)-(-)-(10-camphor sulfonyl) oxa-aziridine; C) tert-butyldimethylsilyl chloride, imidazoles, DMF; D) Mg (ClO 4) 2(20%), CH 3CN; E) Me 3O +BF 4 -, CH 2Cl 2F) NH 4Cl, MeOH; G) (butyl) 4N +F -, MeOH; H) H 2, Pd/C.Reaction formula 11: A) catalytic hydrogenation; B) RCHO; C) reduction; D) CH 2=C (NHZ) CO 2Me; E) reduction; F) hydrolysis
Need not to be described in further detail, can be sure of that those skilled in the art adopt the description of front, can utilize the present invention extremely at utmost.Therefore preferred specific embodiments is only with explaining below, but not by any way remaining part disclosed herein imposed any restrictions.
All experiments are all carried out under dry nitrogen or argon gas.All solvents and the reagent that adopt all need not to be further purified, unless otherwise.The conventional processing of reaction relates to reaction mixture is joined in neutrality or acid or alkaline aqueous solution and the organic solvent.The waterbearing stratum is with indicated organic solvent extraction n time (x).The organic extract liquid that merges is with indicated solution washing n time (x), through anhydrous Na 2SO 4Drying, filtration, vacuum concentration, and purifying in addition as specified.Column chromatography is separated the condition of describing with Still and is obtained (Still, W.C.; Kahn.M.; Mitra, A.Rapid.Chromatographic Technique for Preparative SeparationWith Moderate Resolution " organic chemistry magazine " (J.Org.Chem.) 1978,43,2923-2925).Make its hydrochloride by ethanol (EtOH) solution of 1N HCl, HCl, MeOH solution or the 6N HCl De dioxane solution of 2N.Thin-layer chromatography carries out on 0.25 millimeter EM precoating plate of silica gel 60F 254.High performance liquid chromatography (HPLC) is obtained by C-8 or C-18 reversed-phase column.And C-8 or C-18 reversed-phase column are buied from manufacturer of a few family.Analytic sample is dry in the Abderhalden device under 56 ℃ or 78 ℃.The 1HNMR spectrum is by General Electric QE-300 or Varian VXR 400MHz spectrometer, with marking and obtain in the tetramethylsilane work. 13C NMR, is marked and obtains with the tetramethylsilane work is interior under 125.8MHz by the Varian spectrometer.
Embodiment 12,2,6-3-methyl cyclohexanol ketoxime
With 2,2,6-trimethylcyclohexanone sample (Aldrich, 4.9 grams, 39.0 mmoles) and the hydroxylamine hydrochloride (NH in ethanol (EtOH, 35 milliliters) and water (25 milliliters) mixture 2OHHCl, 3.6 grams, 52.4 mmoles) and sodium acetate (NaOAc, 5.2g, 62.9mmol) merging.This mixture was refluxed 5 hours under nitrogen atmosphere.After this reaction was cooled to room temperature and stirs 5 days, all solvents were removed in decompression.Residue distributes between ethyl acetate (EtOAc) and water, and organic phase is with 1 * 75 milliliter of saturated NaCl (salt solution) washing, through Na 2SO 4Drying, all solvents of decompression stripping.5.0 gram (91%) title compounds are provided thus, are white solid.The retention time of this material on Shimadzu GC-14A gas-chromatography (GC) is 9.6 minutes (by peak district integral and calculating, purity is 100%).The gas-chromatography operational condition is: 0.25mm * 25M methyl, and 5% phenyl siloxane post, carrier gas is a helium, and temperature programming originates in 55 ℃, and per minute improves 10 °, until reaching 200 ℃.NMR and IR spectrum also match with the structure of setting.Ultimate analysis: C 9H 17NO0.1H 2O (MW=157.04)
C H N calculated value: 68.83 11.04 8.92 measured values: 69.00 11.00 8.85
Embodiment 2 isomer A: six hydrogen-3,3,7-trimethylammonium-2H-azatropylidene-2-ketone isomer B: six hydrogen-3,7,7-trimethylammonium-2H-azatropylidene-2-ketone
Figure A9619540000321
4.9 gram (34.3 mmole) embodiment 1 title substance samples are joined contain 6 milliliters of 80%H 2SO 4Addition funnel in.Behind stirring rod acquisition turbid solution, this mixture is added dropwise to 5 milliliters of 80%H that is stirring to magnetic (10 minutes) 2SO 4In, and remain on 120 ℃ with outside oil bath.The adding beginning heat release occurred in 5 minutes, and temperature of reaction rises to 160 ℃, afterwards it is cooled to 120 ℃ again.After 10 minutes flask is removed from bathe, and made it to be cooled to room temperature.Product mixtures water (20 milliliters) dilution, and use dense NH 4OH transfers to pH6.This solution is with 75 ml water redilution, and with 3 * 75 milliliters of CH 2Cl 2Extraction.The organic phase that merges is washed with 1 * 50 mL of saline, dry (Na 2SO 4), filter, and all solvents of decompression stripping.By the HPLC on silica gel oily residue (2.9 grams, 56%) is separated, provide title product.
Embodiment 33,4,5,6-tetrahydrochysene-7-methoxyl group-2,6,6-trimethylammonium-2H-azatropylidene
Under argon gas (Ar), Tetrafluoroboric acid trimethylammonium oxonium salt that is stirring to magnetic (Lancaster, 0.30 gram, 2.0 mmoles) and 3 molecular sieves (2 restrain) are in CH 2Cl 2The isomer A product (0.31 gram, 1.5 mmoles) that adds embodiment 2 in the slurry (15ml).After this mixture at room temperature stirs 3 days, with it with 10 milliliters of CH 2Cl 2Dilution, and at 40 milliliters of saturated KHCO 3And distribute between 50 milliliters of EtOAc.Organic phase is separated, through Na 2SO 4Drying is filtered, and all solvents of decompression stripping.Provide the title product crude product, be faint yellow oily thing.This material is carried out chromatography with EtOAc/ normal hexane (1: 1) wash-out on short distance Merck flash silica gel column.Weak yellow liquid title product (308 milligrams, 93%) is carried out the GC retention time under the condition of embodiment 1 be 15.5 minutes (100%), and NMR and IR spectrum matches with specified product.
Embodiment 43,4,5,6-tetrahydrochysene-7-methoxyl group-2,2,6-trimethylammonium-2H-azatropylidene
Figure A9619540000331
With the method for embodiment 3,, produce title substance with isomer-B product and the reaction of Tetrafluoroboric acid trimethylammonium oxonium salt of embodiment 2.
Embodiment 5 six hydrogen-3,3,7-trimethylammonium-2H-azatropylidene-2-imines mono-hydrochloric salts
Under nitrogen atmosphere, with title compound (0.30 gram, 1.4 mmoles) and 0.06 gram (1.1 mmole) ammonium chloride (NH of embodiment 3 4Cl) in 13 ml methanol (MeOH), refluxed 19 hours.After being cooled to room temperature, with it filtration, all solvents of decompression stripping, and at 15 ml waters and 7 milliliter CH 2Cl 2Between distribute.With organic phase and aqueous phase separation, water with it freeze-drying, provides 0.24 gram (92%) title substance with after a 25 milliliters of EtOAc washing, is white solid.
Embodiment 6 six hydrogen-3,7,7-trimethylammonium-2H-azatropylidene-imines mono-hydrochloric salts
Figure A9619540000341
With of method and the ammonium chloride reaction of 4 products of the embodiment among the MeOH, produce title substance with embodiment 5.
Embodiment 73,3,5,5-tetramethyl-ring hexanone oxime
Figure A9619540000342
By the method for embodiment 1, use 5.6 gram (80.0 mmole) hydroxylamine hydrochlorides and 6.7 gram (82.0 mmole) NaOAc in the mixture of 60 milliliters of EtOH and 60 ml waters, with 3,3,5,5-tetramethyl-ring hexanone (Aldrich, 6.2 gram, 40.0 mmoles) change into title compound.This method produces the title compound of 7.5 grams (100%), is white solid.
Embodiment 8 six hydrogen-4,4,6,6-tetramethyl--2H-azatropylidene-2-ketone
By the method for embodiment 2, use 11 milliliters of 80%H 2SO 4, the product sample (7.5 grams, 44.4 mmoles) of embodiment 7 is changed into title compound.This method produces 5.6 gram (75%) title substances, is faint yellow viscous solid.
Embodiment 93,4,5,6-tetrahydrochysene-7-methoxyl group-3,3,5,5-tetramethyl--2H-azatropylidene
By the method for embodiment 3, title product (845 milligrams, 5.0 mmoles) and Tetrafluoroboric acid trimethylammonium oxonium salt (962 milligrams, 5.0 mmoles) reaction with embodiment 8 produce 815 milligrams of (100%) title substances.
Embodiment 10 6 hydrogen-4,4,6,6-tetramethyl--2H-azatropylidene-2-imines mono-hydrochloric salts
Figure A9619540000352
By the method for embodiment 5, product (110 milligrams, 0.6 mmole) and ammonium chloride (32 milligrams, 0.6 mmole) reaction with the embodiment 9 among 3.5 milliliters of MeOH produce 90 milligrams of (67%) title substances.C 10H 20N 2HRMS (EI) calculated value: m/e 168.163, measured value: m/e 168.162. 1H?NMR(CD 3OD)：δ3.21(s，2H)，2.62(s，2H)，1.54(s，2H)，1.1(s，6H)，1.01(s，6H)。Ultimate analysis: C 10H 20N 2HCl0.3H 2O0.25NH 4Cl (MW=223.52)
C H N Cl calculated value: 53.74 10.19 14.10 19.83 measured values: 53.71 9.66 13.99 19.59
Embodiment 11 tetrahydrochysenes-4H-pyrans-4-ketoxime
Figure A9619540000361
With tetrahydrochysene-4H-pyrans-4-ketone (5.0 gram, 0.05 mole), hydroxylamine hydrochloride (5.2 grams, 0.075 mole) and sodium acetate (13.6 restrain 0.1 mole) at ethanol (30 milliliters)/H 2Reflux among the O (20 milliliters) and spend the night.Allow mixture cool off, and vacuum concentration is to remove ethanol.Last aqueous solution CH 2Cl 2Extraction, dry (MgSO 4) and vacuum concentration, stay title compound, be white solid (5.4 gram).1H?NMR(CDCl 3)：δ9.15(br，1H)；3.85-3.70(m，4H)；?2.72-2.60(m，2H)；2.40-2.35(m，2H).
Embodiment 12 tetrahydrochysenes-1,4-oxa-azatropylidene-5 (2H)-ketone
Figure A9619540000362
Under 0 ℃, add 1N sodium hydroxide in embodiment 11 title substances in acetone (30 milliliters) (5.4 grams, 0.047 mole).Follow the magnetic agitation and dropping to go into benzene sulfonyl chloride (6 milliliters, 0.047 mole) in the acetone (10 milliliters).Mixture was stirred 72 hours, and vacuum concentration is removed acetone.Aqueous solution CH 2Cl 2(2 * 150 milliliters) extraction, dry (MgSO 4) and vacuum concentration, stay amber oily/solid (2.2 gram).Residue provides title substance by the hexane recrystallization, is white solid (1.37 gram).1H?NMR(CDCl 3)：δ6.90(br，1H)；3.82-3.70(m，4H)；3.38-3.30(m，2H)；2.75-2.65(m，2H).
Embodiment 13 tetrahydrochysenes-1,4-oxa-azatropylidene-5 (2H)-imines trifluoroacetate
Figure A9619540000371
With the title substance (960 milligrams, 0.008 mole) of embodiment 12 and Tetrafluoroboric acid trimethylammonium oxonium salt (1.5 grams, 0.01 mole) at CH 2Cl 2(50 milliliters) middle mixing was also stirred 72 hours.With the mixture vacuum concentration, and residue is dissolved in methyl alcohol (50 milliliters).The anhydrous ammonia gas bubbling was fed 15 minutes.The good stopper stirring of mixture bottle cap is spent the night.Behind the vacuum concentration, with residue at CH 2Cl 2And distribute between water.Water 100%H 2The C-18 reverse-phase chromatography purifying of O (0.05%TFA) wash-out provides title substance, is white solid (730 milligrams).1H?NNR(D 2O)：δ3.78-3.72(m，2H)；3.68-3.63(m，2H)；3.49-3.44(m，2H)；2.85-2.80(m，2H).
Embodiment 141-(5,6-dihydro-2H-pyrans-4-yl) tetramethyleneimine
Figure A9619540000372
Collect water with Dean Stark trap, tetrahydrochysene-4H-pyrans-4-ketone (5.0 grams, 0.05 mole) and tetramethyleneimine (4.6 milliliters, 0.055 mole) were refluxed 2 hours in benzene (50ml).With this mixture vacuum concentration, stay heavy-gravity amber oil (7.6 gram), it is distilled on the kugelrohr device under 40 ℃ (0.1mm), provide title substance.Be limpid water white oil (5.9 gram).1H?NMR(CDCl 3)：δ4.28-4.20(m，2H)；4.20-4.13(m，1H)；3.88-3.78(m，2H)；3.07-2.95(m，4H)；2.35-2.22(m，2H)；1.90-1.80(m，4H).
Embodiment 153-(crotyl) tetrahydrochysene-4H-pyrans-4-ketone
The title substance of embodiment 14 (23 grams, 0.15 mole) and crotyl bromide (15.4 milliliters, 0.15 mole) are mixed in benzene (200 milliliters) and stirred 72 hours.Add entry (50 milliliters) and stirred 2 hours.Shift out the benzene layer, water extracts with EtOAc (150 milliliters).Organic extract liquid is merged dry (MgSO 4) and vacuum concentration, stay oily matter (20.8 gram).This oily matter is chromatography on the silica gel of 5%EtOAc/ hexane wash-out, provides title substance, is colorless oil (12.3 gram).1H?NMR(CDCl 3)：δ5.52-5.25(m，2H)；4.20-4.07(m，2H)；3.82-3.70(m，1H)；3.50-3.40(m，1H)；2.68-2.40(m，4H)；2.03-1.90(m，1H)；1.65(d.J＝6Hz.3H).
Embodiment 163-(crotyl) tetrahydrochysene-4H-pyrans-4-ketoxime
Be added dropwise to the anhydrous pyridine (8.1 milliliters, 0.1 mole) in the methyl alcohol (50 milliliters) in embodiment 15 title substances in methyl alcohol (100 milliliters) (13.0 grams, 0.084 mole) and the hydroxylamine hydrochloride (6.5 grams, 0.093 mole).The mixture stirring is spent the night.Vacuum concentrated mixture, and with residue at CH 2Cl 2And distribute between water.With CH 2Cl 2Dry (the MgSO of layer 4) and vacuum concentration, stay title substance, be oily matter (19.5 gram).
1H NMR (CDCl 3) mixture of cis and anti-oxime: δ (9.0,8.85 (br, 1H)]; [5.80-5.25,5.20-4.85 (m, 2H)]; 4.20-2.90 (m, 5H); 2.80-2.00 (m, 4H); [1.63 (d, J=6Hz), 1.20-0.90 (m) is (3H)].
Embodiment 173-(crotyl) tetrahydrochysene-1,4-oxa-azatropylidene-5 (2H)-ketone
Under 0 ℃, add 1N sodium hydroxide (30 milliliters) in embodiment 16 title substances in acetone (30 milliliters) (5.0g, 0.03 mole).Be added dropwise to the benzene sulfonyl chloride (3.8 milliliters, 0.03 mole) in the acetone (10 milliliters), after room temperature is got back in reaction, it stirring spent the night.With the mixture vacuum concentration to remove acetone, last aqueous solution CH 2Cl 2(2 * 150 milliliters) extraction.With CH 2Cl 2Extraction liquid merges, dry (MgSO 4), and vacuum concentration, stay oily matter.Add hexane in this oily matter, gained white solid thing is filtered, and, provide title substance, be white solid (812 milligrams) with EtOAc/ hexane recrystallization.From mother liquor, isolate the other title substance again and add other regional isomer---6-(crotyl) tetrahydrochysene-1,4-oxa-azatropylidene-5 (2H)-ketone comes out by chromatographic separation.1H?NMR(CDCl 3)：δ5.75(br，1H)；5.70-5.50(m，1H)；5.40-5.23(m，1H)；4.00-3.80(m，2H)；3.72-3.52(m，2H)；3.40-3.30(m，1H)；2.95-2.80(m，1H)；2.60-2.55(m，1H)；2.30-2.15(m，1H)；2.10-1.95(m，1H)；1.70(d，J＝6Hz，3H).
Embodiment 183-(crotyl) tetrahydrochysene-1,4-oxa-azatropylidene-5 (2H)-imines trifluoroacetate
Figure A9619540000401
To CH 2Cl 2Add Tetrafluoroboric acid trimethylammonium oxonium salt (540 milligrams, 3.6 mmoles) in embodiment 17 title substances in (25 milliliters) (612 milligrams, 3.6 mmoles), and the mixture stirring is spent the night.Behind the vacuum concentration, residue is dissolved in the methyl alcohol (25 milliliters), and bubbling feeds anhydrous ammonia gas in this solution.The mixture bottle stopper is good and stirred 72 hours.Vacuum concentrated mixture, residue passes through CH 3CN/H 2O gradient liquid (0.05%TFA) wash-out provides title substance with C-18 reverse-phase chromatography purifying, is white solid (404 milligrams).C 9H 16N 2The mass spectroscopy of O: M +H=169.1H?NMR(CDCl 3)：δ9.7(br，2H)；8.9(br，1H)；?5.70-5.54(m，1H)；5.40-5.25(m，1H)；4.03-3.92(m，1H)；3.90-3.80(m，1H)；3.76-3.58(m，2H)；3.46-3.32(m，1H)；3.04-2.76(m，2H)；2.42-2.18(m，2H)；1.67(d，J＝6Hz，3H).
Embodiment 191-methyl-4-piperidin-4-one-oxime mono-hydrochloric salts
Figure A9619540000402
In methyl alcohol (100 milliliters) slurry of 1-methyl-4-pyridone (10 milliliters, 0.08 mole) and hydroxylamine hydrochloride (6.1 grams, 0.088 mole), be added dropwise to the anhydrous pyridine (7.8 milliliters, 0.097 mole) in methyl alcohol (50 milliliters).The mixture stirring being spent the night, leach title substance, is white solid (9.2 gram).Another part title substance reclaims (7.7 gram) from methyl alcohol filtrate.1H?NMR(D 2O)：δ3.70-2.90(m，5H)；2.80(s，3H)；2.60-2.45(m，2H)；2.40-2.10(m，1H).
Embodiment 20 6 hydrogen-1-methyl-5H-1,4-diaza -5-ketone
Figure A9619540000411
Under 0 ℃, embodiment 19 title substances in acetone (50 milliliters) (9.2 grams, 0.056 mole) are added dropwise to 1N sodium hydroxide, stir after 5 minutes, are added dropwise to the benzene sulfonyl chloride (7.1 milliliters) in acetone (5 milliliters).Mixture was stirred 72 hours.Get back to room temperature, and vacuum concentration makes the aqueous solution be alkaline to remove acetone with 1N sodium hydroxide, and freeze-drying, stay solids.With this solids CH 2Cl 2Grind and filtration vacuum concentration CH 2Cl 2, stay title substance, be solids (4.9 gram).1H?NMR(CDCl 3)：δ6.85(br，1H)；3.30-3.20(m，2H)；2.65-2.40(m，6H)；2.35(s，3H).
Embodiment 21 6 hydrogen-1-methyl-5H-1,4-diaza -5-imines trifluoroacetate With the product 5-oxo-2,3,4,5,6 of embodiment 20,7-six hydrogen-1,4-diaza is used to handle CH 2Cl 2In Me 3O +BF 4 -, and stir and spend the night.Behind the vacuum concentration, residue is dissolved in the methyl alcohol, and bubbling feeds anhydrous ammonia gas in solution.Mixture is stirred the also vacuum concentration that spends the night.Residue provides title product with C-18 reverse-phase chromatography purifying.C 6H 13N 3Mass spectroscopy: M +H=128. 1H?NMR(DMSO-d6)：δ9.80-9.40(s，1H)；9.40(s，1H)；9.10(s，1H)；8.60(s，1H)；3.70-2.85(m，8H)；?2.80(s，3H).
Embodiment 22 tetrahydrochysenes-3-(2-methoxy ethyl)-4H-pyrans-4-ketone
Figure A9619540000421
With the method for embodiment 15, title compound and bromo-ethyl-methyl ether reaction with embodiment 14 produce title compound.
Embodiment 23 tetrahydrochysenes-3-(2-methoxy ethyl)-4H-pyrans-4-ketoxime
With the method for embodiment 16,, produce title compound with title compound and the azanol reaction of embodiment 22.
Embodiment 24 isomer-A: tetrahydrochysene-3-(2-methoxy ethyl)-1,4-oxa-azatropylidene-5 (2H)-ketone isomer-B: tetrahydrochysene-6-(2-methoxy ethyl)-1,4-oxa-azatropylidene-5 (2H)-ketone
Figure A9619540000431
With the method for embodiment 17, title compound and benzene sulfonyl chloride reaction with embodiment 23 produce title compound.Isomer separates by column chromatography.
Embodiment 252,3,6,7-tetrahydrochysene-3-(2-methoxy ethyl)-5-methoxyl group-1,4-oxa-azatropylidene
Figure A9619540000432
With the method for embodiment 3,, produce title compound with the isomer A of embodiment 24 and the reaction of the Tetrafluoroboric acid trimethylammonium oxonium salt in methylene dichloride.
Embodiment 262,3,6,7-tetrahydrochysene-6-(2-methoxy ethyl)-5-methoxyl group-1,4-oxa-azatropylidene
With the method for embodiment 3,, produce title compound with the isomer B of embodiment 24 and the reaction of the Tetrafluoroboric acid trimethylammonium oxonium salt in the methylene dichloride.
Embodiment 27 tetrahydrochysenes-3-(2-methoxy ethyl)-1,4-oxa-azatropylidene-5 (2H)-imines mono-hydrochloric salts
Figure A9619540000441
With the method for embodiment 4, with product and the reaction of the ammonium chloride in the methyl alcohol of embodiment 25, product title compound.
Embodiment 28 tetrahydrochysenes-6-(2-methoxy ethyl)-1,4-oxa-azatropylidene-5 (2H)-imines mono-hydrochloric salts
Figure A9619540000442
With the method for embodiment 4, with product and the reaction of the ammonium chloride in the methyl alcohol of embodiment 26, product title compound.
Embodiment 294,4-dimethyl-5-amyl group tetramethyleneimine-2-imines mono-hydrochloric salts
Figure A9619540000443
Embodiment 29A) with 3,3-dimethyl ethyl (4.9 grams, 38 mmoles) mixes with nitro hexane (5.0 grams, 38 mmoles), 1M tetrabutyl ammonium fluoride (in THF, 38 milliliters), and 40 ℃ of heating 24 hours.Reaction mixture is diluted with ether, use salt solution, then wash with water.Chromatogram purification on silica gel produces product 3,3-dimethyl-4-nitro methyl pelargonate (6.6 grams, 67%).
Embodiment 29B) under 55 ℃ and 60psi, will be in the product (5.6 grams, 24 mmoles) of the embodiment 29A among the anhydrous MeOH through RaNi hydrogenation 24 hours.With reaction product column chromatography purifying, produce 4,4-dimethyl-5-amyl group pyrrolidin-2-one (2.63 grams, 60%).
Embodiment 29C) method by embodiment 3, product (2.63 grams with embodiment 29B, 14.3 mmole) with (2.56 grams of the Tetrafluoroboric acid trimethylammonium oxonium salt among the DCM (20 milliliters), 17.4 mmole) handle, produce 3,4-dihydro-5-methoxyl group-3,3-dimethyl-2-amyl group-2H-pyrroles (2.0 grams, 71%).
Embodiment 29) by the method for embodiment 5,, then compose in the enterprising circumstances in which people get things ready for a trip of reversed-phase HPLC with MeOH (30 milliliters) solution and ammonium chloride (529 milligrams, the 9.9 mmoles) reaction of embodiment 29C title product (2.0 grams, 10 mmoles).
Embodiment 305-phenyl-4, two (trifluoromethyl) tetramethyleneimine of 4--2-imines mono-hydrochloric salts
Embodiment 30A) with 4,4,4-three fluoro-3-(trifluoromethyl) ethyl crotonates (9.0 grams, 38 mmoles) mix with nitro hexane (5.0 grams, 38 mmoles), salt of wormwood (5.3 grams, 38 mmoles) and Aliquat 336 (20).With mixture sonication at room temperature.Reaction is monitored with G.C, when reaction finishes, and mixture HCl (1N) acidifying, water extracted with diethyl ether.Purify by chromatogram on silica gel, produce product 4-nitro-3, two (trifluoromethyl) methyl pelargonates of 3-(3 grams, 21%).
Embodiment 30B) under 55 ℃ and 60psi, with the product of the embodiment 30A among the anhydrous MeOH through RaNi hydrogenation 24 hours.Reaction product produces 5-amyl group-4 by the column chromatography purifying, two (trifluoromethyl) pyrrolidin-2-ones of 4-.
Embodiment 30C) method by embodiment 3, the Tetrafluoroboric acid trimethylammonium oxonium salt that the product of embodiment 30B is used for DCM (20 milliliters) is handled, and produces 3,4-dihydro-5-methoxyl group-2-amyl group-3, two (the trifluoromethyl)-2H-pyrroles of 3-.
Embodiment 30) method by embodiment 5, with MeOH (30 milliliters) solution and ammonium chloride reaction of the title product of embodiment 30C, then chromatography on reversed-phase HPLC, generation title substance.
Embodiment 312-imino--4-methyl-5-amyl group tetramethyleneimine-3-carboxylic acid, ethyl ester mono-hydrochloric salts
Embodiment 31A) ethylidene diethyl malonate (6.4 grams, 33 mmoles) is mixed with nitro hexane (5 grams, 38 mmoles), salt of wormwood (2 gram) and Aliquat 336 (10).Mixture is at room temperature used sonication.Reaction is monitored with G.C, when reaction finishes, with mixture HCl (1N) acidifying, water extracted with diethyl ether.Chromatogram purification on silica gel produces product 2-(1-methyl-2-nitro heptyl) the third-1,3-two diethyl phthalates.
Embodiment 31B) under 55 ℃ and 60psi, will be in the product of the embodiment 31A among the anhydrous EtOH through RaNi hydrogenation 24 hours.Reaction product produces 4-methyl-2-oxo-5-amyl group tetramethyleneimine-3-carboxylic acid, ethyl ester by the column chromatography purifying.
Embodiment 31C) by the method for embodiment 3, the 31B material is handled with Tetrafluoroboric acid trimethylammonium oxonium salt, produced 3,4-dihydro-5-methoxyl group-2-amyl group-2H-pyrazoles-3-carboxylic acid, ethyl ester.
Embodiment 31) method by embodiment 5, the MeOH solution of the title substance of embodiment 31C is handled with ammonium chloride, then chromatography on reversed-phase HPLC produces title substance.
Embodiment 322-imino--4-methyl-5-amyl group tetramethyleneimine-3-carboxylic acid mono-hydrochloric salts
Embodiment 32A) with the MeOH/2N NaOH solution stirring of embodiment 31B title product 6 hours, then ice was done.The gained solid is soluble in water, and add the EtOAc that contains bromotoluene.Mixture is shaken in separatory funnel.Organic phase is separated dry and evaporation.Residue column chromatography purifying produces 4-methyl-2-oxo-5-amyl group tetramethyleneimine-3-carboxylic acid benzene methyl.
Embodiment 32B) method by embodiment 3, the Tetrafluoroboric acid trimethylammonium oxonium salt that the product of embodiment 32A is used for DCM is handled, and produces 3,4-dihydro-5-methoxyl group-3-methyl-2-amyl group-2H-pyrroles-4-carboxylic acid benzene methyl.
Embodiment 32C) by the method for embodiment 5, with the MeOH solution and the ammonium chloride reaction of embodiment 32B title product, then chromatography on reversed-phase HPLC produces 2-imino--4-methyl-5-amyl group-3-carboxylic acid benzene methyl.
Embodiment 32) with the anhydrous MeOH solution of embodiment 32C product through Pd/C hydrogenation.Reaction product is purified by chromatogram on reversed-phase HPLC, produces title substance.
Embodiment 33 alpha-amino groups-4-hydroxyl-5-imino--3-(trifluoromethyl) tetramethyleneimine-2-butyric acid mono-hydrochloric salts
Figure A9619540000472
Embodiment 33A) method by embodiment 14, with 4,4,4-trifluoromethyl ethyl crotonate (10 mmole) and 2-(2-nitro-ethyl)-1,3-dioxolane (12 mmole) reacts with salt of wormwood (5 mmole) and Aliquat 336 (3).Chromatogram purification on silica gel provides γ-nitro-β-(trifluoromethyl)-1,3-dioxolane-2-Valeric acid ethylester.
Embodiment 33B) under 55 ℃ and 60psi, embodiment 33A product that will be in MeOH was through RaNi hydrogenation 6 hours.Reaction product produces 5-((1,3-dioxolane-2-yl) methyl)-4-(trifluoromethyl) pyrrolidin-2-one by the column chromatography purifying, is non-enantiomer mixture.
Embodiment 33C) product of embodiment 33B is handled with di-tert-butyl dicarbonic acid ester among the THF and DMAP, and refluxed 2 hours.Remove solvent, product produces 2-((1,3-dioxolane-2-yl) methyl)-5-oxo-3-(trifluoromethyl) tetramethyleneimine-1-carboxylic acid (1, the 1-dimethyl ethyl) ester by the column chromatography purifying.
Embodiment 33D) under-70 ℃, the embodiment 33C product that has HMPA (1 equivalent) in THF is handled with hexamethyl second silicon Lithium Azide (1.2 equivalents, the THF solution of 1M).Allow solution be warming up to-40 ℃, be cooled to-70 ℃ afterwards, and be incorporated in the camphor sulphonyl oxa-aziridine among the THF.Solution after 2 hours, is joined saturated NH-40 ℃ of stirrings 4Quick stoppage reaction among the Cl.Use the EtOAc extraction solution afterwards.Organism is merged.Remove solvent, product produces 2-((1,3-dioxolane-2-yl) methyl)-4-hydroxyl-5-oxo-3-(trifluoromethyl) tetramethyleneimine-1-carboxylic acid (1, the 1-dimethyl ethyl) ester by the column chromatography purifying.
Embodiment 33E) NaH and the bromotoluene that the product of embodiment 33D is used for THF handled.Product produces 2-((1,3-dioxolane-2-yl) methyl)-5-oxo-4-(phenyl methoxyl group)-3-(trifluoromethyl) tetramethyleneimine-1-carboxylic acid (1, the 1-dimethyl ethyl) ester by the column chromatography purifying.
Embodiment 33F) product of the embodiment 33E among the MeOH is handled with HCl (1N), produced 5-oxo-4-(phenyl methoxyl group)-3-(trifluoromethyl) tetramethyleneimine-2-acetaldehyde, it is directly used in the next step reaction.
Embodiment 33G) to the CH of embodiment 33F and Z-α-phosphono glycine trimethyl 2Cl 2Add DBU in the solution.With solution stirring 2 hours.Remove solvent, product produces 4-(5-oxo-4-(phenyl methoxyl group)-3-(trifluoromethyl) tetramethyleneimine-2-yl)-2-[[(phenyl methoxyl group by the column chromatography purifying) carbonyl] amino]-the 2-methyl-butyrate.
Embodiment 33H) product of embodiment 33G is used [Rh (COD) (R, R-DIPAMP)] +BF 4 -Hydrogenation.Remove solvent, product produces 5-oxo-α-[[(phenyl methoxyl group) carbonyl] amino]-4-(phenyl methoxyl group)-3-(trifluoromethyl) tetramethyleneimine-2-methyl-butyrate by the column chromatography purifying.
Embodiment 33I) method by embodiment 3, the product of embodiment 33H is handled with the Tetrafluoroboric acid trimethylammonium oxonium salt among the DCM, produce 3,4-dihydro-5-methoxyl group-α-[[(phenyl methoxyl group) carbonyl] amino]-4-(phenyl methoxyl group)-3-(trifluoromethyl)-2H-pyrroles-2-methyl-butyrate.
Embodiment 33J) method by embodiment 5, MeOH solution and ammonium chloride reaction with embodiment 33I title product, then chromatography on reversed-phase HPLC produces 5-imino--α-[[(phenyl methoxyl group) carbonyl] amino]-4-(phenyl methoxyl group)-3-(trifluoromethyl) tetramethyleneimine-2-methyl-butyrate mono-hydrochloric salts.
Embodiment 33) with the embodiment 33J product among the anhydrous MeOH through Pd/C hydrogenation 24 hours.Reaction product is chromatogram purification on reversed-phase HPLC, produces 33.
Embodiment 34 6 hydrogen-2-imino--4-methyl-7-(2-propenyl)-1H-azatropylidene-3-alcohol
Figure A9619540000491
Embodiment 34A) with the THF solution of six hydrogen-4-methyl-7-(2-propenyl)-2H-azatropylidene-2-ketone with di-t-butyl carbonic ether and dimethyl aminopyridine (DMAP; 1 equivalent) handles; produce lactan-six hydrogen-4-methyl-2-oxo-7-(2-propenyl)-1H-azatropylidene-1-carboxylic acid (1, the 1-dimethyl ethyl) ester of Boc protection.
Embodiment 34B) adds hexamethylphosphoramide (HMPA, 1 equivalent) to being dissolved in THF and being cooled to cryogenic embodiment 34A product, then add hexamethyldisilane base Lithium Azide (LHMDS, 1.1 equivalents).To wherein adding 1.2 normal (1S)-(+)-(camphor sulfonyl)-oxa-aziridine or (1R)-(-)-(camphor sulfonyl)-oxa-aziridine, but produce following two kinds of non-enantiomer mixtures of chromatographic separation; Isomer-A six hydrogen-3R-hydroxy-4-methyl-2-oxo-7-(2-propenyl)-1H-azatropylidene-1-carboxylic acid (1, the 1-dimethyl ethyl) ester or isomer B six hydrogen-3S-hydroxy-4-methyl-2-oxo-7-(2-propenyl)-1H-azatropylidene-1-carboxylic acid (1, the 1-dimethyl ethyl) ester.
Embodiment 34C) the product or the product mixtures from the foregoing description 34B that will be dissolved in DMF handled with imidazoles (2 equivalent) and tert-butyldimethylsilyl chloride, produce 3-((1, the 1-dimethyl ethyl) six hydrogen-4-methyl-2-oxo-7-(2-propenyl)-1H-azatropylidene-1-carboxylic acid (1, the 1-dimethyl ethyl) ester dimethylsilane oxygen base).
Embodiment 34D) adds magnesium perchlorate (Mg (ClO to being dissolved in acetonitrile and being warming up to about 50 ℃ in from the product of the foregoing description 34C or product mixtures 4) 2, 0.2 equivalent), produce 3-((1, the 1-dimethyl ethyl) dimethylsilane oxygen base) six hydrogen-4-methyl-2-oxo-7-(2-propenyl)-2H-azatropylidene-ketone.
Embodiment 34E) will be from product or the product mixtures of the foregoing description 34D, the method by embodiment 3 is used in CH 2Cl 2In Tetrafluoroboric acid trimethylammonium oxonium salt handle, produce 6-((1, the 1-dimethyl ethyl) dimethylsilane oxygen base)-3,4,5,6-tetrahydrochysene-7-methoxyl group-5-methyl-2H-azatropylidene.
Embodiment 34F) method by embodiment 5, MeOH solution and ammonium chloride reaction with embodiment 34E title product or product mixtures, produce 3-((1, the 1-dimethyl ethyl) dimethylsilane oxygen base) six hydrogen-4-methyl-7-(2-propenyl)-2H-azatropylidene-2-imines mono-hydrochloric salts.This material is handled with fluoride sources, and, produced title substance crude product chromatography on reversed-phase HPLC.
Embodiment 356-butyl-3-hydroxy-4-methyl piperidines-2-imines mono-hydrochloric salts
Figure A9619540000501
Embodiment 35A) with the THF solution of 6-butyl-4-methyl piperidine-2-ketone with di-t-butyl carbonic ether and dimethyl aminopyridine (DMAP; 1 equivalent) handles; the lactan that produces the Boc protection is 2-butyl-4-methyl-6-oxo-piperidine-1-carboxylic acid (1, the 1-dimethyl ethyl) ester.
Embodiment 35B) adds hexamethylphosphoramide (HMPA, 1 equivalent) in cryogenic the foregoing description 35A product to being dissolved in THF and being cooled to, then add hexamethyldisilane base Lithium Azide (LHMDS, 1.1 equivalents).To wherein adding 1.2 equivalents (1S)-(+)-(camphor sulfonyl)-oxa-aziridine or (1R)-(-)-(camphor sulfonyl)-oxa-aziridine, but produce following two kinds of non-enantiomer mixtures of chromatographic separation; Isomer-A6-butyl-3R-hydroxy-4-methyl-2-oxo-piperidine-1-carboxylic acid (1, the 1-dimethyl ethyl) ester or isomer B6-butyl-3S-hydroxy-4-methyl-2-oxo-piperidine-1-carboxylic acid (1, the 1-dimethyl ethyl) ester.
Embodiment 35C) the product or the product mixtures from the foregoing description 35B that will be dissolved in DMF handled with imidazoles (2 equivalent) and tert-butyldimethylsilyl chloride, produce 6-butyl-3-((1, the 1-dimethyl ethyl) dimethylsilane oxygen base)-4-methyl-2-oxo-piperidine-1-carboxylic acid (1, the 1-dimethyl ethyl) ester.
Embodiment 35D) to be dissolved in acetonitrile and be warming up to about 50 ℃ from the foregoing description 35C product or product mixtures in add magnesium perchlorate (Mg (ClO 4) 2, 0.2 equivalent), produce 6-butyl-3-((1, the 1-dimethyl ethyl) dimethylsilane oxygen base)-4-methyl piperidine-2-ketone.
Embodiment 35E) will be used in CH from the product of the foregoing description 35D or the product mixtures method by embodiment 3 2Cl 2In Tetrafluoroboric acid trimethylammonium oxonium salt handle, produce 2-butyl-5-((1, the 1-dimethyl ethyl) dimethylsilane oxygen base)-6-oxyethyl group-2,3,4,5-tetrahydrochysene-4-picoline.
Embodiment 35F) with the methanol solution of embodiment 35E title product or product mixtures method and ammonium chloride reaction, generation 6-butyl-3-((1, the 1-dimethyl ethyl) dimethylsilane oxygen base)-4-methyl piperidine-2-imines by embodiment 5.This material is handled with fluoride sources and with crude product chromatography on reversed-phase HPLC, is produced title substance.
Embodiment 366-imino--2,4-lupetidine-3-methylamine dihydrochloride
With the 6-amino-2 in ethanol (30 milliliters) and the concentrated hydrochloric acid (1 milliliter), 4-lutidine-3-nitrile (1.5 gram) and platinum oxide (500 milliliters) vibrate 48 hours down 55psi hydrogen pressure and 55 ℃ in the Parr hydrogenation apparatus.Mixture is filtered, and vacuum concentrated filtrate, remaining wax sample solid.Grind with ethanol, provide title substance, be white solid (191 milligrams).C 8H 17N 3Mass spectroscopy: M +H=156. 1H?NMR(D 2O)：3.63-3.40(m，2H)；3.20-3.07(m，1H)；2.72-2.60(m，1H)；2.40-2.25(m，1H)；2.05-1.90(m，2H)；1.25(d，J＝6Hz，3H)；1.00(d，J＝6Hz，3H).
Embodiment 374,6,6-trimethyl-piperidine-2-imines trifluoroacetate
Embodiment 37A) under nitrogen atmosphere, with 2,2,4-trimethylammonium cyclopentanone (5.5 grams, 44 mmoles) 35 milliliters of EtOAc/25 ml water solution and hydroxylamine hydrochloride (4.6 grams, 66 mmoles) and sodium acetate trihydrate (10.8 restrain 79 mmoles) refluxed 4 hours together.Behind the evaporative removal solvent, residue is dissolved among 100 milliliters of EtOAc again, with the saturated sodium-chloride water solution washing, through dried over sodium sulfate, and all solvents of stripping, provide 5.6 gram white powders, 2,2,4-trimethylammonium cyclopentanone oxime.FAB/MS：(MH +)＝142。
Embodiment 37B) under 0 ℃, the product of embodiment 37A is dissolved in 50 milliliters of acetone and the 50 milliliters of 1N sodium hydroxide.Times adding benzene sulfonyl chloride (7.8 grams, 44 mmoles) with 5 minutes.Allow reaction mixture heat up, and stirred 18 hours, until determining that with the displacement of HPLC retention time (Vydac C-18,5% to 75% acetonitrile/0.05%TFA water liquid/0.05%TFA linear gradient liquid, 20 minutes consuming time) reaction finishes.Evaporative removal solution, and residue is dissolved in 100 milliliters of EtOAc again with the saturated sodium-chloride water solution washing, through dried over mgso, and goes out all solvents by the evaporation stripping.On Waters Deltapak C-18, adopt water (0.05%TFA) the solution linear gradient liquid of 10% to 15% acetonitrile (0.05%TFA), 20 minutes times spent are with the semi-solid material purifying crude.Freeze dried product, 4,6,6-trimethyl-piperidine-2-ketone is pale brown look semisolid, 0.47 gram.FAB/MS：(MH +)＝142。
Embodiment 37C) to 10 milliliters of CH 2Cl 2In embodiment 37B product (3.3 mmole) add Tetrafluoroboric acid trimethylammonium oxonium salt (0.6 gram, 4.0 mmoles).Stir after 18 hours, reaction mixture is with another part 10 milliliters of CH 2Cl 2The saturated potassium carbonate solution washing is used in dilution, through dried over mgso, and all solvents of stripping, produce 2,3,4,5-tetrahydrochysene-6-methoxyl group-2,2,4-trimethylpyridine.
Embodiment 35) product of embodiment 37C is dissolved in 25 ml methanol, and refluxed 3 hours with ammonium chloride.All solvents of evaporative removal, and residual oily matter is dissolved among 25 milliliters of EtOAc wash with water, and the decompression stripping goes out all solvents, produce crude product.On WatersDeltapak C-18, use water (0.05%TFA) the solution linear gradient liquid of 5% to 70% acetonitrile (0.05%TFA), 30 minutes times spent, the above-mentioned crude product of purifying, and freeze-drying provide 0.075 gram white powder title substance.FAB/MS：(MH +)＝141。 1H?NMR(CDCl 3)：δ10.4(bs，1H)；9.7(bs，1H)；7.5(bs，1H)；2.6(q，1H)；2.0(q，2H)；1.8(d，2H)；1.4(s，3H)；1.3(s，3H)；1.1(d，3H).
Embodiment 384,4,6-trimethyl-piperidine-2-imines trifluoroacetate
Embodiment 38A) under nitrogen atmosphere, with 2,4,4-trimethylammonium cyclopentanone (5.5 grams, 44 mmoles) 35 milliliters of ethyl acetate/25 ml water solution and hydroxylamine hydrochloride (4.6 grams, 66 mmoles) and sodium acetate trihydrate (10.8 grams, 79 mmoles) refluxed 4 hours together.The evaporative removal solvent, and be dissolved in again in 100 milliliters of ethyl acetate, with the saturated sodium-chloride water solution washing,, remove solvent afterwards through dried over mgso, provide 6.2 grams 2,4,4-trimethylammonium cyclopentanone oxime is white powder.FAB/MS：(MH +)＝142。
Embodiment 38B) under 0 ℃, the product of embodiment 38A is dissolved in 50 milliliters of acetone and the 50 milliliters of 1N sodium hydroxide.Times adding benzene sulfonyl chloride (7.8 grams, 44 mmoles) with 5 minutes.Allow reaction mixture heat up, and stir and finished until reaction in 18 hours, whether reaction finishes and determines (Vydac C-18,5% to 75% acetonitrile/0.05%TFA water/0.05%TFA solution gradient liquid, 20 minutes times spent) by the skew of HPLC retention time.The evaporative removal solvent, and residue is dissolved among 100 milliliters of EtOAc again, with the saturated sodium-chloride water solution washing, strip all solvents through dried over mgso and evaporation.On Waters Deltapak C-18, use water (0.05%TFA) the solution gradient liquid of 10% to 15% acetonitrile (0.05%TFA), the semi-solid product of 20 minutes times spent purifying.Freeze dried product, 6,4,4-trimethyl-piperidine-2-ketone is pale brown look semisolid, 0.75 gram.FAB/MS：(MH +)＝142。
Embodiment 38C) to 15 milliliters of CH 2Cl 2In embodiment 38B product (5.3 mmole) in add Tetrafluoroboric acid trimethylammonium oxonium salt (0.9 gram, 6.0 mmoles).Stir after 18 hours, with reaction mixture with another part 15 milliliters of CH 2Cl 2The saturated potassium carbonate solution washing is used in dilution, through dried over mgso, and strips all solvents, provides 0.69 gram 2,3,4,5-tetrahydrochysene-6-methoxyl group-2,4, and the 4-trimethyl-piperidine is oily matter.
Embodiment 38) will be dissolved in embodiment 38C product in 25 ml methanol and ammonium chloride (0.25 gram, 4.6 mmoles) refluxed 3 hours together.The evaporative removal solvent, and residual oily matter is dissolved in 25 milliliters of EtOAc, wash with water, and strip all solvents.On WatersDeltapak C-18, use water (0.05%TFA) the solution gradient liquid of 5% to 70% acetonitrile (0.05%TFA), the above-mentioned residue of 30 minutes times spent purifying, and freeze-drying provide 0.66 gram title substance, are white powder.FAB/MS：(MH +)＝141。 1H?NMR(CDCl 3)：δ10.4(bs，1H)；9.5(bs，1H)；8.1(bs，1H)；3.8(m，1H)；2.3(q，2H)；1.75(d，2H)；1.3(d，3H)；1.1(s，3H)；1.0(s，3H).
Embodiment 393-(crotyl) six hydrogen-5-imines-1,4-oxa-azatropylidene-6-alcohol trifluoroacetate
Figure A9619540000551
Isomer-A
Embodiment 39A) with embodiment 17 product 3-(2-butylene-1-yl)-5-oxo-2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene (6.6 grams, 39 mmoles), di-t-butyl carbonic ether (17.5 grams, 80 mmoles) and 4-dimethylaminopyridine (200 milligrams) reflux in anhydrous THF (80 milliliters) and spend the night.Allow this mixture cool off,, and use 5%NaHCO with the EtOAc dilution 3Solution washing, through dried over mgso, and vacuum concentration, remaining oily matter (12.9 gram).This oily matter is purified with 10%EtOAc/ hexane elution chromatography on silica gel, provide 4-N-Boc-3-(2-butylene-1-yl)-5-oxo-2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene is colorless oil (3.7 gram).
Embodiment 39B) under-78 ℃, embodiment 39A product 4-N-Boc-3-(2-butylene-1-yl)-5-oxo-2 among the anhydrous THF (60 milliliters), 3,4,5,6,7-six hydrogen-1 are added dropwise to two (trimethyl silyl) lithamide (1M THF liquid in the 4-oxa-azatropylidene (3.1 grams, 12 mmoles), 12 milliliters), and keep temperature to be lower than-70 ℃.Allow this mixture be warming up to-40 ℃, reduce to-78 ℃ afterwards.Be added dropwise to THF (30 milliliters) solution of (1S)-(+)-(10-camphor sulfonyl) oxa-aziridine (3.0 grams, 13 mmoles).Mixture is warming up to-25 ℃, and stirred 3 hours, pour saturated NH afterwards into 4Among the Cl, and extract with EtOAc.The EtOAc layer is through MgSO 4Drying, and vacuum concentration.Provide 4-N-Boc-3-(2-butylene-1-yl)-6-hydroxyl-5-oxo-2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene is wax sample solid.
Embodiment 39C) with product 4-N-Boc-3-(2-butylene-1-yl)-6-hydroxyl-5-oxo-2 of embodiment 39B, 3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene (600 milligrams), tert-butyldimethylsilyl chloride (2.0 gram), imidazoles (1.6 gram) and anhydrous THF (50 milliliters) stir together and spend the night.Mixture is distributed between EtOAc and water.The EtOAc layer is through MgSO 4Drying, and vacuum concentration provide oily matter.This oily matter is used 25%EtOAc/ hexane wash-out on silica gel, carry out chromatography, provide 4-N-Boc-3-(2-butylene-1-yl)-6-(t-butyldimethylsilyloxy base)-5-oxo-2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene is oily matter (400 milligrams).
Embodiment 39D) under 50 ℃, with product 4-N-Boc-3-(2-butylene-1-yl)-6-(t-butyldimethylsilyloxy base)-5-oxo-2,3 of embodiment 39C, 4,5,6,7-six hydrogen-1,4-oxa-azatropylidene, (400 milligrams, 1 mmole) and magnesium perchlorate (45 milligrams) are in CH 3Heating is 3 hours among the CN (25 milliliters).Allow mixture cooling and between EtOAc and water, distributing.The EtOAc layer is through MgSO 4Drying, and vacuum concentration, remaining 3-(2-butylene-1-yl)-6-(t-butyldimethylsilyloxy base)-5-oxo-2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene is oily matter (300 milligrams).
Embodiment 39) with product 3-(2-butylene-1-yl)-6-(t-butyldimethylsilyloxy base)-5-oxo-2,3,4,5,6 of embodiment 39D, 7-six hydrogen-1,4-oxa-azatropylidene (300 milligrams, 1 mmole) and Me 3O +BF 4 -(150 milligrams, 1 mmole) are in CH 2Cl 2The middle stirring spent the night.With the mixture vacuum concentration, residue is dissolved in the methyl alcohol, and feeds anhydrous ammonia gas to this solution bubbling.It is good and stir and spend the night to react plug.Vacuum concentrated mixture, a remaining yellow oil (366 milligrams).This oily matter CH 3CN/H 2The C-18 reverse-phase chromatography purifying of O wash-out provides the title product (isomer A, 16 milligrams) of embodiment 39 and the title product (isomer B, 11 milligrams) of embodiment 40, is oily matter.C 9H 16N 2O 2Mass spectroscopy: M +H=185. 1H?NMR(D 2O)：δ5.60-5.42(m，1H)；5.35-5.20(m，1H)；4.75-4.60(m，1H)；3.95-3.50(m，5H)；2.35-2.20(m，2H)；1.60-1.45(m，3H)
Embodiment 403-(crotyl) six hydrogen-5-imines-1,4-oxa-azatropylidene-6-alcohol trifluoroacetate
Isomer-B
Crude product oil CH with embodiment 39 3CN/H 2The C-18 reverse-phase chromatography purifying of O wash-out provides the title product of embodiment 39 and the title product of embodiment 40 (isomer B, 11 milligrams).C 9H 16N 2O 2Mass spectroscopy: M +H=185. 1H?NMR(D 2O)：δ5.65-5.45(m，1H)；5.35-5.20(m，1H)；4.90-4.75(m，1H)；3.90-3.45(m，4H)；3.35-3.20(m，1H)；2.25-2.05(m，2H)；1.60-1.45(m，3H).
Embodiment 416-(crotyl) six hydrogen-1,4-oxa-azatropylidene-5-imines trifluoroacetate
Figure A9619540000571
According to the method for embodiment 18, use isolating 6-(crotyl) tetrahydrochysene-1 among the embodiment 17,4-oxa-azatropylidene-5 (2H)-ketone is prepared title substance.C 9H 16N 2The mass spectroscopy of O: M +H=169. 1H?NMR(D 2O)：δ5.65-5.50(m，1H)；5.40-5.20(m，1H)；3.95-3.25(m，6H)；2.80-2.60(m，1H)；2.50-2.30(m，2H)；1.60-1.50(m，3H).
Embodiment 423-butyl six hydrogen-1,4-oxa-azatropylidene-5-imines trifluoroacetate
The product of embodiment 18 (1.3 grams, 4.6 mmoles), 5% rhodium/carbon (400 milligrams), ethanol (30 milliliters) and glacial acetic acid (30 milliliters) vibrated under the 55psi hydrogen pressure in the Parr hydrogenator spend the night.Reaction mixture is filtered, and with the filtrate vacuum concentration, remaining oily matter (1.1 gram).This oily matter is by using CH 3CN/H 2The C-18 reverse-phase chromatography purifying of O wash-out provides title product, is oily matter (701 milligrams, yield 54%).C 9H 16N 2The mass spectroscopy of O: M +H=171. 1H?NMR(CDCl 3)：δ9.90(s，1H)；9.50(s，1H)；8.90(s，1H)；4.00-3.40(m，6H)；3.00-2.70(m，2H)；1.80-1.20(m，6H)；1.00-0.80(m，3H).
Embodiment 43 6 hydrogen-5-imino--1, two (trifluoroacetic acid) salt of 4-oxa-azatropylidene-3-ethamine
Figure A9619540000581
Embodiment 43A) at CH 2Cl 22-nitroethyl alcohol in (50 milliliters) (Aldrich, 50 milliliters, 0.7 mole) is added dropwise to CH 2Cl 2Acetyl Chloride 98Min. in (50 milliliters) (53.2 milliliters, 0.75 mole).The mixture stirring being spent the night, wash with water, through dried over mgso and vacuum concentration, provide 1-ethanoyl-2-nitroethyl alcohol, is faint yellow oily thing (86 gram).
Embodiment 43B) collects water with Dean Stark trap, the tetrahydrofuran (THF)-4-ketone (Aldrich, 30 grams, 0.3 mole) and the sample of morpholine (Aldrich, 30.5 milliliters, 0.35 mole) were refluxed in benzene 3 hours.Allow mixture cooling, and vacuum concentration it.Residue is dissolved in the acetonitrile (250 milliliter), and is added dropwise under-20 ℃ in acetonitrile (250 milliliters) solution of embodiment 48A product 1-ethanoyl-2-nitroethyl alcohol (46.6 grams, 0.35 mole).Reaction mixture stirred to spend the night rise to room temperature and vacuum concentration.Residue is in Et 2Distribute between O and water.Ether layer is through dried over mgso and vacuum concentration.Remaining oily matter.This oily matter being distilled down in 100 ℃ (0.1mm) in the Kugelrohr device, provide 2-nitro-ethyl tetrahydrofuran (THF)-4-ketone, is partly solidified oily matter (20.9 gram).
Embodiment 43C) product 2-nitro-ethyl tetrahydrofuran (THF)-4-ketone, hydroxylamine-o-sulfonic acid and the formic acid (98%) with embodiment 43B refluxed 0.5 hour together.Allow mixture cool off, and vacuum concentration.Residue is in CH 2Cl 2And distribute between water.CH 2Cl 2Layer is through MgSO 4Drying, and vacuum concentration.Residue C-18 reverse-phase chromatography provides 3-(2-nitro-ethyl)-5-oxo-2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene.
Embodiment 43D) in CH 2Cl 2The product 3-of embodiment 43C in (25 milliliters) (2-nitro-ethyl)-5-oxo-2,3,4,5,6,7-six hydrogen-1 add Me in the 4-oxa-azatropylidene 3O +BF 4 -, and mixture stirred spend the night.Behind the vacuum concentration, residue is dissolved in the methyl alcohol (25 milliliters), and bubbling feeds anhydrous ammonia gas through solution.The mixture plug is good and stirred 72 hours.Vacuum concentrated mixture, and with residue by using CH 3CN/H 2The C-18 reverse-phase chromatography purifying of O gradient liquid (0.05%TFA) wash-out provides 3-(2-nitro-ethyl)-5-imino--2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene.
Embodiment 43) in the Parr hydrogenator under the 55psi hydrogen pressure, with product 3-(2-nitro-ethyl)-5-imino--2,3,4,5,6 of embodiment 43C, 7-six hydrogen-1,4-oxa-azatropylidene and palladium black shaken over night in ethanol.Mixture is filtered, and with the filtrate vacuum concentration.Residue provides title compound by C-18 reverse-phase chromatography purifying.
Embodiment 44 (±) 3 α-methoxyl group-4 Alpha-Methyl-5 α-amyl group tetramethyleneimine-2-imines mono-hydrochloric salts
Embodiment 44 is by embodiment 45e, and methyl iodide and sodium hydride prepare.The synthetic of embodiment 44 finished in the mode of describing among the embodiment 45.
Embodiment 45 (±) 2-imino--4 Alpha-Methyl-5 α-amyl group-3 α-pyrrolidinol mono-hydrochloric salts
Figure A9619540000592
Embodiment 45A) to 20 milliliters of CH of methyl crotonate that is stirring (3.28 gram, 32.8 mmoles) and Nitromethane 99Min. (1.08 restrain 16.0 mmoles) 3Add DBU (2.39 milliliters, 16.0 mmoles) in the CN solution.After 72 hours, with the reactant concentrating under reduced pressure.Residue digests with EtOAc.EtOAc solution is with 0.5N HCl washing, through anhydrous Na 2SO 4Drying is filtered and concentrating under reduced pressure.Crude product column chromatography purifying provides 3.05 gram products.
Embodiment 45B.C) embodiment 45A (34 grams, 0.15 mole) reduces under the catalytic hydrogenation condition with Ni in Ruan in methyl alcohol.In that down heating is after 16 hours in 55 ℃ with reaction mixture, vacuum is removed solvent.The lactan crude product is isolated along (45B) and anti-(45C) lactan by column chromatography.
The embodiment 45B that embodiment 45D) will stir (20 grams, 0.12 mole), (BocO) 2500 milliliters of THF solution reflux of O (38.7 grams, 0.18 mole), DMAP (14.4 grams, 0.12 mole) 3 hours.After the vacuum concentration reaction, residue digests with EtOAc, and uses KHSO 4With the salt water washing.Organic layer is through anhydrous sodium sulfate drying, filtration and stripping.Crude product produces 31 gram products by the column chromatography purifying.
Embodiment 45E) adds hexamethyldisilane base Lithium Azide (1.7 grams, 10.0 mmoles) to being cooled to-70 ℃ the embodiment 45D that is stirring (2.7 grams, 9.9 mmoles) and 15 milliliters of THF solution of HMPA (1.8 grams, 10.0 mmoles).After 20 minutes, reaction is warming up to-40 ℃, and is cooled to-70 ℃ again.7 milliliters of THF solution that in the reactant that is stirring, add (R)-(-)-(camphor sulfonyl) oxa-aziridine (2.4 grams, 10.4 mmoles)., reaction is warming up to-30 ℃, and stirred other 2.5 hours after 30 minutes-70 ℃ of stirrings.In reaction, add saturated NH 4Cl solution then adds EtOAc.Organic layer salt water washing is through anhydrous Na 2SO 4Drying is filtered, and stripping.Crude product provides 1.3 gram 3-hydroxyl lactams by the column chromatography purifying.
Embodiment 45F) to the CH of embodiment 45E (1.3 gram) 2Cl 2Add TFA (6 milliliters) in the solution.After 2 hours, will react vacuum concentration, provide 0.85 gram product.
Embodiment 45G) in 15 ml solns of embodiment 45F that is stirring (0.85 gram, 4.6 mmoles) and imidazoles (0.35 gram, 4.6 mmoles), adds tert-butyldimethylsilyl chloride (0.70 gram, 4.6 mmoles).After 18 hours, reaction mixture is concentrated under high vacuum.Add EtOAc to residue.Organic layer KHCO 3Solution, H 2O and salt water washing, through anhydrous Na 2The SO drying is filtered and stripping, produces 1.1 gram products.
Embodiment 45H) at room temperature with the 30 ml solns stirring of embodiment 45G (1.1 gram, 3.7 mmoles) and Tetrafluoroboric acid trimethylammonium oxonium salt (0.6 gram, 4.7 mmoles) 72 hours.Vacuum is dissolved in residue among the EtOAc after removing solvent.Organic layer KHCO 3Solution and salt water washing are through anhydrous Na 2SO 4Drying is filtered and stripping, produces 1 gram product.
Embodiment 45I) under 12 kilobar pressure, the embodiment 45H product (1 gram) in MeOH is used NH 4Cl (0.3g) handles.Reactant is concentrated under vacuum.Residue CH 2Cl 2Digestion is filtered and stripping, provides 0.8 gram product.
Embodiment 45) in 40 milliliters of MeOH solution of embodiment 45I (0.8 gram), add 10 milliliters of 1N HCl.1.5 after hour, reaction mixture is concentrated under vacuum.Residue is in 0.05N HCl and CH 2Cl 2Between distribute.The stripping water layer.Residue is chromatogram purification on anti-phase C-18 post, provides two kinds of alcohol.Elder generation's wash-out goes out, and that be that embodiment 46, the second wash-outs go out is embodiment 45.Ultimate analysis: C 10H 20N 2O1HCl0.2H 2O (MW=224.35)
C H N Cl calculated value: 53.80 9.61 12.49 15.80 measured values: 53.80 9.47 12.14 15.46
Embodiment 46 (±) 2-imino--4 Alpha-Methyl-5 α-amyl group-3 β-pyrrolidinol mono-hydrochloric salts
The synthetic of embodiment 46 is described among the embodiment 45 with separating.Ultimate analysis: C 10H 20N 2O1HCl0.2H 2O (MW=224.35)
C H N Cl calculated value: 53.80 9.61 12.49 15.80 measured values: 53.78 9.37 12.14 15.78
Embodiment 47 (±) 2-imino--5 α-amyl group-4 β-(trifluoromethyl)-3 α-pyrrolidinol mono-hydrochloric salts
Embodiment 47A) with 4,4,4-trifluoroacetic ethyl crotonate (10.0 grams, 59 mmoles), 1-nitro hexane (7.86 grams, 60 mmoles), K 2CO 3The suspension sonication of (4.1 gram) and Aliquot 336 (6) 5 hours.In this reaction, add Et 2O (200 milliliters).Reaction mixture is filtered, with the salt solution extraction, through anhydrous Na 2SO 4Drying is filtered, and concentrating under reduced pressure, provides yellow liquid, and this product obtains 13.8 grams (77%) by the column chromatography purifying.
Embodiment 47B, C) methanol solution with embodiment 47A (13.0 gram) reduces down in catalytic hydrogenation condition (60psi, 55 ℃) with Raney nickel.Behind nitroreduction, reactant is heated 8 hours to implement cyclisation.Behind the concentrating under reduced pressure reaction mixture, residue column chromatography purifying provides 9.0 gram weak yellow liquids.Cross post for the second time, will separate along (47B) and anti-lactan (47C).
Embodiment 47D) embodiment 47C handles with the described mode of embodiment 45D, then prepares embodiment 47.Ultimate analysis: C 10H 17N 2F 3O1HCl (MW=274.71)
C H N Cl calculated value: 43.72 6.60 10.20 12.91 measured values: 43.62 6.44 10.15 12.73
Embodiment 48 6 hydrogen-5-imino--beta-phenyl-1, two (trifluoroacetic acid) salt of 4-oxa-azatropylidene-3-methylamine
Figure A9619540000622
According to the method for embodiment 43, use beta-nitrostyrene to replace 1-ethanoyl-2-nitroethyl alcohol, prepare title compound.
Embodiment 49N-(3,4-dihydro-2 h-pyrrole-5-yl) six hydrogen-5-imino--1, two (trifluoroacetic acid) salt of 4-oxa-azatropylidene-3-ethamine
Figure A9619540000631
Make embodiment 43 and the reaction of 2-methoxyl group pyrroline, provide title compound.
Embodiment 503-[[2-(six hydrogen-5-imino--1,4-oxa-azatropylidene-3-yl) ethyl] fluorine-based] L-Ala three (trifluoroacetic acid) salt
Figure A9619540000632
Embodiment 50A) makes embodiment 43 and the reaction of N-CBZ-dehydroalanine methyl esters, provide title product through protection.
Embodiment 50) by the CBZ blocking group of hydrogenation removal from embodiment 50A, then acid hydrolysis provides title product.
Embodiment 513-[[2-(six hydrogen-5-imino--1,4-oxa-azatropylidene-3-yl)-2-phenylethyl] amino] L-Ala three (trifluoroacetic acid) salt
Figure A9619540000641
Embodiment 51A) makes embodiment 48 and the reaction of N-CBZ-dehydroalanine methyl esters, provide title compound through protection.
Embodiment 51) by the CBZ protecting group of hydrogenation removal from embodiment 51A, then acid hydrolysis provides title compound.
Two (trifluoroacetic acid) salt of embodiment 522-(six hydrogen-5-imino--1,4-oxa-azatropylidene-3-yl) hexahydroaniline
Use 2-nitrocyclohex alcohol to replace the 2-nitroethyl alcohol, prepare title compound by the method for embodiment 43.
Embodiment 53 β-cyclopropyl six hydrogen-5-imino--1, two (trichoroacetic acid(TCA)) salt of 4-oxa-azatropylidene-3-ethamine
Embodiment 53A) through the Henry reaction, goes out 2-nitro-2-cyclopropyl ethanol by the cyclopropyl prepared formaldehyde.
Embodiment 53) with product 2-nitro-2-cyclopropyl ethanol replacement 2-nitroethyl alcohol of embodiment 53A, adopt the method for embodiment 43 to prepare title product.
Embodiment 54 α-ethyl six hydrogen-5-imino--Beta-methyl-1, two (trifluoroacetic acid) salt of 4-oxa-azatropylidene-3-ethamine
Use 3-nitro-4-hydroxyl amyl group to replace the 2-nitroethyl alcohol, prepare title product by the method for embodiment 43.
Two (trifluoroacetic acid) salt of embodiment 552-(six hydrogen-5-imino--1,4-oxa-azatropylidene-3-yl) hexahydroaniline
Figure A9619540000652
Embodiment 55A) under alkaline condition, make tetrahydrofuran (THF)-4-ketone and adjacent nitrobenzyl bromine reaction, provide 2-(adjacent nitrobenzyl) Tetrahydro-pyran-4-one.
Embodiment 55B) product 2-(adjacent nitrobenzyl) Tetrahydro-pyran-4-one of embodiment 55A is carried out the same step with embodiment 43c-d, provide 3-(adjacent nitrobenzyl)-5-imino--2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene.
Embodiment 55) under nitrogen atmosphere, utilize platinum-oxide catalyst reduction embodiment 55A product 3-(adjacent nitrobenzyl)-5-imino--2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene provides title product.
Embodiment 56 6 hydrogen-5-imino--β-(2-thienyl)-1, two (trifluoroacetic acid) salt of 4-oxa-azatropylidene-3-ethamine
Figure A9619540000661
According to the method for embodiment 48, use 1-nitro-2-(2-thienyl) ethene, prepare title substance.
Embodiment 57 alpha-amino groups six hydrogen-5-imino--β-(2-thienyl)-1,4-oxa-azatropylidene-3-propionic acid two (trifluoroacetic acid) salt
Figure A9619540000662
Embodiment 58 α-(amino methyl) six hydrogen-5-imino--1, two (trifluoroacetic acid) salt of 4-oxa-azatropylidene-3-methyl alcohol
Embodiment 598-imino--3,7-phenodiazine spiral shell [5.6] dodecane-9-alcohol dihydrochloride
(hexanolactam of spiral shell-4-piperidyl-N-Z) is handled with embodiment 34 described methods, provides title compound with 7-.
Embodiment 603-(2-amino-ethyl) six hydrogen-5-imino--1,4-oxa-azatropylidene-two (trifluoroacetic acid) salt of 6-alcohol
Figure A9619540000672
Embodiment 60A) method of the product of embodiment 43C being pressed among the embodiment 39 is handled, and provides 3-(2-nitro-ethyl) six hydrogen-5-imino--1,4-oxa-azatropylidene-6-alcohol.
Embodiment 60) with 3-(2-nitro-ethyl) six hydrogen-5-imino--1,4-oxa-azatropylidene-6-alcohol is pressed the method reduction among the embodiment 43, provides title compound.
Embodiment 61 6 hydrogen-5-imino--3-(2-((2-pyrrolidyl subunit) amino) ethyl)-1,4-oxa-azatropylidene-two (trifluoroacetic acid) salt of 6-alcohol
Figure A9619540000681
The method that the method for embodiment 60 is pressed among the embodiment 49 is reacted, provide title compound.
Embodiment 623-(2-amino-1-phenylethyl) six hydrogen-5-imino--1,4-oxa-azatropylidene-two (trifluoroacetic acid) salt of 6-alcohol
Figure A9619540000682
Embodiment 62A) presses method among the embodiment 43, use beta-nitrostyrene to replace 1-ethanoyl-2-nitroethyl alcohol, prepare 3-(2-nitro-1-phenylethyl)-5-oxo-2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene.
Embodiment 62B) presses method among the embodiment 39, with 3-(2-nitro-1-phenylethyl)-5-oxo-2,3,4,5,6,7-six hydrogen-1, the reaction of 4-oxa-azatropylidene provides 3-(2-nitro-1-phenylethyl)-6-hydroxyl-5-imino--2,3,4,5,6,7-six hydrogen-1,4-oxa-azatropylidene.
Embodiment 62) press the method among the embodiment 43, with 3-(2-nitro-1-phenylethyl)-6-hydroxyl-5-imino--2,3,4,5,6,7-six hydrogen-1, the reduction of 4-oxa-azatropylidene provides title compound.
Embodiment 63 (±) 2-imino--4 α-(trifluoromethyl)-5 β-amyl group tetramethyleneimine-3 α-alcohol
Figure A9619540000691
Embodiment 63 is synthesized by embodiment 47 and separates.
Embodiment 64 (±) 2-imino--4 β-(trifluoromethyl)-5 β-amyl group tetramethyleneimine-3 α-alcohol
Figure A9619540000692
In the mode of describing among the embodiment 47, prepare embodiment 64 compounds by embodiment 47B.
Embodiment 65 (±) 2-imino--4 α-(trifluoromethyl)-5 α-amyl group tetramethyleneimine-3 α-alcohol
Figure A9619540000693
In the mode of describing among the embodiment 47, prepare embodiment 65 compounds by embodiment 47B.
Embodiment 66 (±) 2-imino--4 Beta-methyl-5 α-amyl group tetramethyleneimine-3 α-alcohol
Prepare embodiment 66 in the mode of describing among the embodiment 45 by embodiment 45C.
Embodiment 67 (±) 2-imino--4 Alpha-Methyl-5 β-amyl group tetramethyleneimine-3 α-alcohol
Figure A9619540000702
Prepare embodiment 67 in the mode of describing among the embodiment 45 by embodiment 45C.
Embodiment 68 (±) 5 α-(3-aminopropyl)-2-imino--4 Alpha-Methyl tetramethyleneimine-3 α-pure dihydrochloride
Figure A9619540000703
Embodiment 69 (±) 5 α-(the amino butyl of 3-)-2-imino--4 Alpha-Methyl tetramethyleneimine-3 α-pure dihydrochloride
Embodiment 70 (±) alpha-amino group-4 Alpha-hydroxies-5-imino--3 Alpha-Methyl tetramethyleneimine-2 α-butanols dihydrochloride
Embodiment 71 (±) alpha-amino group-4 Alpha-hydroxies-5-imino--3 Alpha-Methyl tetramethyleneimine-2 iophenoxic acid methyl esters dihydrochloride
Figure A9619540000713
Embodiment 72 (±) 2-imino--4 Alpha-Methyl-5 α-amyl group tetramethyleneimine-3 α-amine dihydrochloride
Figure A9619540000714
Adopt the Mitsunobu reaction conditions, by embodiment 45E and Boc 2NH prepares embodiment 72 compounds.The synthetic of embodiment 72 finished in the mode of describing among the embodiment 45.
Embodiment 73 (±) 5-imino--4 alpha-methyl-2 α-amyl group tetramethyleneimine-3 α-pure mono-hydrochloric salts
Embodiment 74 (±) 5-imino--3 α, 4 alpha-alpha-dimethyl tetramethyleneimine-2 α-propylamine dihydrochloride
Embodiment 75 (±) 2-imino--4 Alpha-Methyl-5 α-amyl group tetramethyleneimine-3 α-carboxylic acid mono-hydrochloric salts
Figure A9619540000723
Embodiment 76 (±) 2-imino--4 Alpha-Methyl-5 α-amyl group tetramethyleneimine-3 α-methyl alcohol mono-hydrochloric salts
Figure A9619540000731
Embodiment 77 (±) 5 α-(3-(4,5-dihydro-1H-imidazoles-2-yl) propyl group)-2-imino--4 Alpha-Methyl tetramethyleneimine-3 α-pure dihydrochloride
Embodiment 78 (±) 5 α-(3-(1H-imidazoles-2-yl) propyl group)-2-imino--4 Alpha-Methyl tetramethyleneimine-3 α-pure dihydrochloride
Embodiment 79 (±) 5 α-(3-amino-3-(1H-imidazoles-2-yl) propyl group)-2-imino--4 Alpha-Methyl tetramethyleneimine-3 α-pure tri hydrochloride
Embodiment 80 (±) 2-imino--4 Alpha-Methyl-5 α-(3-((phenmethyl) amino) propyl group) tetramethyleneimine-3 α-pure dihydrochloride
Figure A9619540000741
Embodiment 80A) uses R.Ohrlein, W.Schwab, R.Ehrler, V.Jager is at " synthesizing " (Synthesis) 1986, the mode of describing 535-538), with 1,1-dimethoxy-3-nitropropane and methyl crotonate are initiator, prepare genial anti--5-((1,3-dioxolane-2-yl) methyl)-4-(methyl) pyrrolidin-2-one.
Embodiment 80B, C) under the catalytic hydrogenation condition, the interior Ni of Ruan that is used in the methyl alcohol reduces embodiment 80A.In that down heating is after 16 hours in 55 ℃ with reaction mixture, vacuum is removed solvent.The lactan crude product is separated into along (80B) and anti-(80C) lactan by column chromatography.
The embodiment 80B that embodiment 80D) will stir, (BocO) 2The THF solution reflux of O, DMAP 3 hours, behind the concentration response, residue digests with EtOAc under the vacuum, uses KHSO 4With the salt water washing.Organic layer is through anhydrous Na 2SO 4Drying is filtered and stripping.Crude product is by the column chromatography purifying.
Embodiment 80E) in the THF solution that is cooled to-70 ℃ embodiment 80D that is stirring and HMPA, adds hexamethyl dimethyl silanyl Lithium Azide.After 20 minutes reaction is warming up to-40 ℃, and is cooled to-70 ℃ again.In the reactant that this is stirring, be incorporated in (R)-(-)-(camphor sulfonyl) oxa-aziridine among the THF.-70 ℃ stir 30 minutes after, reaction is warming up to-30 ℃, and restir 2.5 hours.In this reaction, add saturated NH 4Cl solution then adds EtOAc.Organic layer salt water washing is through anhydrous Na 2SO 4Drying, filtration and stripping.Crude product produces 1.3 gram 3-hydroxyl lactams through the column chromatography purifying.
Embodiment 80F) to the CHCl of the embodiment 80E that is stirring 3Solution adds H 2O and TFA.Stir after 2 hours, with the reaction mixture concentrating under reduced pressure.Residue dissolves with EtOAc.Organic layer is with a small amount of saturated NaHCO 3Washing is through MgSO 4Drying, filtration and concentrating under reduced pressure are to reclaim the aldehyde crude product.
Embodiment 80G) methanol solution to the embodiment 80F that is stirring adds NaBH 3CN.Make reaction remain on pH4 by adding HOAc.Stir after 3 days, with the reaction mixture vacuum concentration.Add 1N HCl and EtOAc to this residue.After different layer separation, water NaHCO 3Neutralize, and extract with EtOAc.After organic layer concentrated, residue was handled and freeze-drying with 1N HCl.The gained solid passes through the reversed-phase column chromatography purifying on the C-18 post.
Embodiment 80H) with the product of embodiment 80G by embodiment 45 described method CH 2Cl 2In Tetrafluoroboric acid trimethylammonium oxonium salt handle.
Embodiment 80) methanol solution of embodiment 80H product is handled with ammonium chloride by the method for embodiment 5, then chromatography on reversed-phase HPLC produces title substance.
Embodiment 814 Alpha-Methyls-5 α-amyl group-3 α-(methylthio group) tetramethyleneimine-2-imines mono-hydrochloric salts
Figure A9619540000751
Biological data
Above listed compound used following test determination as the activity of NO synthetase inhibitors.The citrulline test of nitric oxide synthase
The activity of nitric oxide synthase (NOS) changes into [3H]-citrulline by monitoring [3H]-arginine and measures (Bredt and Snyder, Proc.Natl.Acad.Sci.U.S.A., 87,682-685,1990 and Misko etc., " European medicine magazine " (Eur.J.Pharm.) 233,119-125,1993).The people can induce NOS (hiNOS), people's endothelium composing type NOS (hecNOS) and each freedom of human neure composing type NOS (hncNOS) RNA clone from people's tissue extraction.The people can induce the cDNA people of NOS (hiNOS) to extract from the λ cDNA storehouse separation that the RNA of colon sample forms, and the colon sample derives from the patient who suffers from ulcerative colitis.The cDNA of people's endothelium composing type NOS (hecNOS) separates from extracting from the λ cDNA storehouse that the RNA of Human umbilical vein endothelial cells (HUVEC) forms, and the cDNA of human neure composing type NOS (hncNOS) separates from extracting from the λ cDNA storehouse that people's cerebellum RNA of corpse acquisition forms.These recombinases use baculovirus vector at Sf9 expressed in insect cells (Rodi etc., The Biology of Nitric Oxide, Pt.4:Enzymology, Biochemistry and Immunology; Moncada, S., Feelisch, M., Busse, R., Higgs, E., Eds; Portland Press Ltd.: London, 1995; Pp447-450).Enzymic activity is separated by the soluble cell extraction liquid, and by DEAE-Sepharose chromatographic fraction purifying.When measuring the NOS activity, 10 μ L enzymes are joined or do not have among the 50mM Tris (pH7.6) of 40 μ L of test compound, reaction is initial by adding 50 μ L reaction mixtures, and reaction mixture contains 50mM Tris (pH7.6), 2.0mg/ml bovine serum albumin(BSA), 2.0mM DTT, 4.0mM CaCl 2, 20 μ M FAD, 100 μ M tetrahydrobiopterins, 0.4-2.0mM NADPH and 60 μ M contain 0.9 μ Ci L-(2,3-3H)-arginic L-arginine.L-arginine final concentration in test is 30 μ M.For hecNOS and hncNOS, comprise Calmodulin during for 40-100nM in final concentration.After 15 minutes, make reaction terminating 37 ° of cultivations by the cold damping fluid that stops that contains 10mM EGTA, 100mMHEPES, pH5.5 and 1mM citrulline that adds 300 μ L.[3H]-citrulline passes through chromatographic separation on Dowex 50W X-8 Zeo-karb, and measures radioactivity with liquid scintillation counter.The result is with the IC of compound to hiNOS, hecNOS and hncNOS 50Value is listed in the table 1.When 100 μ M, provide the compound that is lower than 50% inhibition and be recorded as IC 50Value＞100 μ M are recorded as IC and provide the compound that is higher than 50% inhibition when 100 μ M 50Value＜100 μ M.
The following example test draws following result.
Table I
IC 50[μM]
Embodiment hiNOS hecNOS hncNOS
10 ＞100
13 ＜100 ＜100 ＜100
18 ＜100 ＞100 ＞100
21 ＞100 ＞100 ＞100
36 ＞100
37 ＜100 ＜100 ＜100
38 ＞100 ＜100 ＜100
39 ＜100 ＞100 ＜100
40 ＜100 ＞100 ＜100
41 ＞100 ＞100 ＞100
42 ＜100 ＞100 ＜100
44 ＞100 ＞100 ＞100
45 ＜100 ＞100 ＜100
46 ＜100 ＞100 ＜100
47 ＜100 ＞100 ＜100
HiNOS is meant that the people can induce NOS
HecNOS is meant people's endothelium composing type NOS
HncNOS is meant human neure composing type NOS
By the description of front, those skilled in the art can determine essential characteristic of the present invention at an easy rate, and on the basis of the spirit and scope that do not depart from the present invention, can make various changes and improvements of the present invention, to make it to be adapted to various uses and condition.

Claims (11)

  1. The compound of following formula and its salt, with and medicinal acceptable ester,
    Figure A9619540000021
    Wherein:
    R 1Be selected from hydrogen; hydroxyl; low alkyl group; low-grade alkenyl; low-grade alkynyl; alkoxyl group; thio alkoxy; cycloalkyl; heterocyclic radical and aryl, they can be chosen wantonly by following groups and replace: low alkyl group; low-grade alkenyl; low-grade alkynyl; cycloalkyl; heterocyclic radical; aryl; hydroxyl; lower alkoxy; aryloxy; halogen; thiol; rudimentary thio alkoxy; halogen; cyano group; nitro; amino; alkylamino; dialkyl amido; aminoalkyl group; dialkyl aminoalkyl; arylamino; aminoaryl; the alkylamino aryl; acyl amino; carboxyl; carboxyalkyl; CONR 10R 11, S (O) R 10, S (O) 2R 10, SO 2NR 10R 11, PO (OR 10) (OR 11), amidino groups, guanidine radicals;
    Wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: halogen, low alkyl group, amino, alkylamino, dialkyl amido, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonylic alkyl aryloxy, hydroxyl, lower alkoxy, S (O) R 10, S (O) 2R 10, amidino groups, guanidine radicals;
    X＝NR 2、O、S、SO、SO 2、(CH 2) p、CH＝CH；
    P=0 to 6;
    A＝NR 3、O、S、SO、SO 2、(CH 2) q、CH＝CH；
    Q=0 to 6;
    B＝NR 4、O、S、SO、SO 2、(CH 2) v、CH＝CH；
    V=0 to 6;
    R 2=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 3=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 4=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 5, R 6, R 7Be independently selected from hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, heterocyclic radical, hydroxyl, lower alkoxy, thiol, rudimentary thio alkoxy, S (O) R 9, S (O) 2R 9, halogen, nitro, amino, alkylamino, dialkyl amido, aminoalkyl group, dialkyl aminoalkyl, arylamino, aminoaryl, alkylamino aryl, acyl amino, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonyl alkoxy aryl, cyano group, aminocarboxyl alkoxyl group, amino carbonyl amino, amino carbonyl amino alkyl, haloalkyl, SO 2NR 10R 11, wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: low alkyl group, halogen, amino, alkylamino, dialkyl amido, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonylic alkyl aryloxy, hydroxyl, lower alkoxy;
    R 5, R 6Can choose wantonly connects together forms alicyclic hydrocarbon, heterocyclic radical or aromatic hydrocarbon, and the ring of described optional formation can be chosen wantonly by one or more following groups replacement:
    Low alkyl group, low-grade alkenyl, low-grade alkynyl, they can be chosen wantonly by following groups and replace: carboxyl, carbonylic alkoxy, carbonyl aryloxy, carboxyalkyl aryloxy and lower alkoxy;
    R 8=hydrogen, hydroxyl, alkoxyl group;
    R 9=hydrogen, hydroxyl, alkoxyl group;
    R 10=hydrogen, low alkyl group, alkylaryl, aryl;
    R 11=hydrogen, low alkyl group, alkylaryl, aryl;
    R 10And R 11Connecting together can be alkylidene group, thereby produces nitrogenous heterocycle;
    Its precondition is to work as R 1When being low alkyl group, low-grade alkenyl or low-grade alkynyl, R 1Can not choose wantonly by cycloalkyl, heterocyclic radical and aryl and replace, unless A or B are NR 2, O, S, SO, SO 2
    Its precondition is, when A and B are (CH 2) pOr CH=CH, and R 1When being low alkyl group, low-grade alkenyl or low-grade alkynyl, R 1Can't help cycloalkyl, heterocyclic radical or aryl replaces, and R 5And R 6Not H;
    Its precondition is that X, A and B have only one can be selected from NR respectively 2, NR 3, NR 4, or be selected from O, S, SO or SO 2
    Its precondition is, as X=(CH 2) pA=(CH 2) qB=(CH 2) vDuring p+q+v=3, then maximum R 1, R 5, R 6And R 7One of can be alkyl, alkoxyl group, cycloalkyl or cycloalkyloxy on the 5-position;
    Another precondition is, as X=(CH 2) pA=(CH 2) qB=(CH 2) vP+q+v=3, and R 1, R 5, R 6And R 7One of be alkyl, cycloalkyl or aryl on the 5-position, Yu Xia R then 1, R 5, R 6And R 7None can be the cyano group on the 5-position, amino, alkoxyl group or the thio alkoxy of replacement;
    Another precondition is to work as X=CH=CH; A=(CH 2) qB=(CH 2) vAnd during q+v=2, R then 1, R 5, R 6And R 7None can be the carboxyl on the 6-position; And
    Another precondition is to work as X=NH; A=(CH 2) qB=(CH 2) vAnd during q+v=4, R then 1, R 5, R 6And R 7None can be the carboxyl on the 7-position.
  2. 2. the described compound of claim 1, wherein:
    R 1Be selected from hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxyl group, thio alkoxy, cycloalkyl, heterocyclic radical and aryl, they can be chosen wantonly by following groups and replace: low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, heterocyclic radical, aryl, hydroxyl, lower alkoxy, aryloxy, halogen, thiol, rudimentary thio alkoxy, amino, alkylamino, aminoalkyl group, aminoaryl, carboxyl, carboxyalkyl, CONR 10R 11, SO 2NR 10R 11, amidino groups, guanidine radicals;
    Wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: halogen, low alkyl group, amino, alkylamino, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonylic alkyl aryloxy, hydroxyl, lower alkoxy, amidino groups, guanidine radicals;
    X＝NR 2、O、S、(CH 2) p、CH＝CH；
    P=0 to 4;
    A＝NR 3、O、S、SO、SO 2、(CH 2) q、CH＝CH；
    Q=0 to 4;
    B＝NR 4、O、S、SO、SO 2、(CH 2) v、CH＝CH；
    V=0 to 4;
    R 2=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 3=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 4=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 5, R 6, R 7Be independently selected from hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, heterocyclic radical, hydroxyl, lower alkoxy, thiol, rudimentary thio alkoxy, amino, alkylamino, aminoalkyl group, arylamino, aminoaryl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, aminocarboxyl alkoxyl group, amino carbonyl amino, amino carbonyl amino alkyl, haloalkyl, SO 2NR 10R 11, wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: low alkyl group, halogen, amino, alkylamino, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, carbonylic alkyl aryloxy, hydroxyl, lower alkoxy;
    R 5, R 6Can choose wantonly connects together forms alicyclic hydrocarbon or heterocyclic radical;
    R 8=hydrogen or hydroxyl;
    R 9=hydrogen;
    R 10=hydrogen or low alkyl group; And
    R 11=hydrogen or low alkyl group.
  3. 3. the described compound of claim 1, wherein:
    R 1Be selected from hydrogen, hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, alkoxyl group, thio alkoxy, cycloalkyl, heterocyclic radical and aryl, they can be chosen wantonly by following groups and replace: low alkyl group, low-grade alkenyl, low-grade alkynyl, halogen, cycloalkyl, heterocyclic radical, aryl, hydroxyl, lower alkoxy, aryloxy, amino, alkylamino, aminoalkyl group, aminoaryl, carboxyl, carboxyalkyl, SO 2NR 10R 11, amidino groups, guanidine radicals;
    Wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: halogen, low alkyl group or amino, alkylamino, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, hydroxyl, lower alkoxy, amidino groups, guanidine radicals;
    X＝(CH 2) p、CH＝CH；
    P=0 to 3;
    A＝NR 3、O、S、(CH 2) q、CH＝CH；
    Q=0 to 3;
    B＝NR 4、O、S、(CH 2) v、CH＝CH；
    V=0 to 3;
    R 3=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 4=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 5, R 6, R 7Be independently selected from hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, heterocyclic radical, hydroxyl, lower alkoxy, amino, alkylamino, aminoalkyl group, arylamino, aminoaryl, carboxyl, carbonylic alkoxy, carbonyl aryloxy, amino carbonyl amino, SO 2NR 10R 11, wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: low alkyl group, halogen, amino, alkylamino, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, hydroxyl, lower alkoxy;
    R 8=hydrogen or hydroxyl;
    R 9=hydrogen or hydroxyl;
    R 10=hydrogen or low alkyl group; And
    R 11=hydrogen or low alkyl group.
  4. 4. the described compound of claim 1, wherein:
    R 1Be selected from hydrogen, hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, alkoxyl group, thio alkoxy, cycloalkyl, heterocyclic radical and aryl, they can be chosen wantonly by following groups and replace: low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, heterocyclic radical, aryl, hydroxyl, lower alkoxy, aryloxy, amino, alkylamino, aminoalkyl group, aminoaryl, carboxyl, carboxyalkyl, SO 2NR 10R 11, amidino groups, guanidine radicals;
    Wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: halogen, low alkyl group, amino, alkylamino, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, hydroxyl, lower alkoxy, amidino groups, guanidine radicals;
    X＝(CH 2) p；
    P=0 to 3;
    A＝NR 3、O、(CH 2) q、CH＝CH；
    Q=0 to 3;
    B＝O、(CH 2) v、CH＝CH；
    V=0 to 3;
    R 3=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 5, R 6, R 7Be independently selected from hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, heterocyclic radical, hydroxyl, lower alkoxy, amino, alkylamino, aminoalkyl group, arylamino, aminoaryl, carboxyl, carbonylic alkoxy, amino carbonyl amino, SO 2NR 10R 11, wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: low alkyl group, amino, alkylamino, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, hydroxyl, lower alkoxy;
    R 8=hydrogen or hydroxyl;
    R 9=hydrogen or hydroxyl;
    R 10=hydrogen or low alkyl group; And
    R 11=hydrogen or low alkyl group.
  5. 5. the described compound of claim 1, wherein:
    R 1Be selected from hydrogen, hydroxyl, low alkyl group, low-grade alkenyl, alkoxyl group, thio alkoxy, cycloalkyl, heterocyclic radical and aryl, they can be chosen wantonly by following groups and replace: low alkyl group, low-grade alkenyl, halogen, aryl, hydroxyl, lower alkoxy, aryloxy, amino, alkylamino, aminoalkyl group, aminoaryl, carboxyl, carboxyalkyl, SO 2NR 10R 11, amidino groups, guanidine radicals;
    X＝(CH 2) p；
    P=0 to 3;
    A＝NR 3、O、(CH 2) q、CH＝CH；
    Q=0 to 3;
    B＝(CH 2) v、CH＝CH；
    V=0 to 3;
    R 3=hydrogen, low alkyl group, aryl, heterocyclic radical;
    R 5, R 6, R 7Be independently selected from hydrogen, low alkyl group, low-grade alkenyl, heterocyclic radical, hydroxyl, lower alkoxy, amino, alkylamino, aminoalkyl group, arylamino, aminoaryl, carboxyl, carbonylic alkoxy, amino carbonyl amino, SO 2NR 10R 11, wherein all described substituting groups can be chosen wantonly by one or more following groups and replace: low alkyl group, halogen, amino, alkylamino, aminoalkyl group, aminoacyl, carboxyl, carbonylic alkoxy, hydroxyl, lower alkoxy;
    R 8=hydrogen or hydroxyl;
    R 9=hydrogen or hydroxyl;
    R 10=hydrogen or low alkyl group; And
    R 11=hydrogen or low alkyl group.
  6. 6. as the defined compound of claim 1, wherein compound is selected from following one group: six hydrogen-3,3,7-trimethylammonium-2H-azatropylidene-2-imines mono-hydrochloric salts; Six hydrogen-3,7,7-trimethylammonium-2H-azatropylidene-2-imines mono-hydrochloric salts; Six hydrogen-4,4,6,6-tetramethyl--2H-azatropylidene-2-imines mono-hydrochloric salts; Tetrahydrochysene-1,4-oxa-azatropylidene-5 (2H)-imines trifluoroacetate; 3-(crotyl) tetrahydrochysene-1,4-oxa-azatropylidene-5 (2H)-imines trifluoroacetate; Six hydrogen-1-methyl-5H-1,4-diaza -5-imines trifluoroacetate; Tetrahydrochysene-3-(2-methoxy ethyl)-1,4-oxa-azatropylidene-5 (2H)-imines mono-hydrochloric salts; Tetrahydrochysene-6-(2-methoxy ethyl)-1,4-oxa-azatropylidene-5 (2H)-imines mono-hydrochloric salts; 4,4-dimethyl-5-amyl group tetramethyleneimine-2-imines mono-hydrochloric salts; 5-amyl group-4, two (trifluoromethyl) tetramethyleneimine of 4--2-imines mono-hydrochloric salts; 2-imino--4-methyl-5-amyl group tetramethyleneimine-3-carboxylate methyl ester mono-hydrochloric salts; 2-imino--4-methyl-5-amyl group tetramethyleneimine-3-carboxylic acid mono-hydrochloric salts; Alpha-amino group-4-hydroxyl-5-imino--3-(trifluoromethyl) tetramethyleneimine-2-butyric acid mono-hydrochloric salts; Six hydrogen-2-imino--4-methyl-7-(2-propenyl)-1H-azatropylidene-3-alcohol; 6-butyl-3-hydroxy-4-methyl piperidines-2-imines mono-hydrochloric salts; 6-imino--2,4-lupetidine-3-methylamine dihydrochloride; 4,6,6-trimethyl-piperidine-2-imines trifluoroacetate; 4,4,6-trimethyl-piperidine-2-imines trifluoroacetate.
  7. 7. inhibited oxidation nitrogen synthetic method in needs inhibited oxidation nitrogen synthetic patient, described method be to patient's administering therapeutic significant quantity according to claim 1,2,3,4,5 or 6 compound.
  8. 8. one kind in needs selectivity inhibited oxidation nitrogen synthetic method among the inhibited oxidation nitrogen synthetic patient optionally, described method be to the patient treat significant quantity come optionally to suppress to exceed the nitrogen oxide that can induce nitric oxide synthase to produce is synthetic that the nitrogen oxide that endothelium composing type nitric oxide synthase is produced is synthetic suppresses according to claim 1,2,3,4,5 or 6 compound.
  9. 9. method that in needs reduce the patient of nitric oxide levels, reduces nitric oxide levels, described method be to patient's administering therapeutic significant quantity according to claim 1,2,3,4,5 or 6 compound.
  10. 10. method that in needs reduce the patient of nitric oxide levels, reduces nitric oxide levels, described method is the medicinal compositions to patient's administering therapeutic significant quantity, and this medicinal compositions comprises according to claim 1,2,3,4,5 or 6 compound and at least a nontoxic medicinal carrier of accepting.
  11. 11. a medicinal compositions, it comprises according to claim 1,2,3,4,5 or 6 compound and at least a nontoxic medicinal carrier of accepting.
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