CN101318943A - Substituted diethylenediamine compounds, preparation method, uses and medicament composition containing the compounds - Google Patents

Substituted diethylenediamine compounds, preparation method, uses and medicament composition containing the compounds Download PDF

Info

Publication number
CN101318943A
CN101318943A CNA2007100416407A CN200710041640A CN101318943A CN 101318943 A CN101318943 A CN 101318943A CN A2007100416407 A CNA2007100416407 A CN A2007100416407A CN 200710041640 A CN200710041640 A CN 200710041640A CN 101318943 A CN101318943 A CN 101318943A
Authority
CN
China
Prior art keywords
compound
methyl
phenyl
piperazine
benzene base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2007100416407A
Other languages
Chinese (zh)
Inventor
沈竞康
谢欣
孟韬
王珏
彭红丽
朱婷
王昕�
熊兵
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CNA2007100416407A priority Critical patent/CN101318943A/en
Publication of CN101318943A publication Critical patent/CN101318943A/en
Pending legal-status Critical Current

Links

Images

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to substituted piperazines compounds shown in formula (I), a preparation method, an application thereof, and a drug composition containing the compounds. The compounds shown in the formula (I) can be antagonists and/or inverse agonists of cannabinoide-1 receptor (CB1), can be used for treating, preventing and inhibiting diseases mediated by the CB1 receptor, and can be used for preparing medicines for treating obesity, mental diseases and nerve diseases.

Description

Substituted piperazidine compounds, its preparation method, purposes and comprise the pharmaceutical composition of this compounds
Technical field
The present invention relates to the substituted piperazidine compounds, the preparation method of this compounds, and contain in these compounds one or more as the pharmaceutical composition of activeconstituents; The invention still further relates to this compounds and be used for the treatment of by the application in the medicine of the receptor-mediated disease of cannaboid-1, be specifically related to the application in the medicine of preparation treatment of obesity, mental disorder and sacred disease in preparation.
Background technology
Because fat incidence increases year by year, causes health risk constantly to increase, and has become important public health problem.Fatly and overweight generally define by weight index (BMI).BMI calculates (kg/m with body weight (kilogram is a unit) divided by height square (rice is unit) 2), relevant with total body fat, generally be used to estimate the relative risk that causes relative disease thus.General Definition, BMI25-29.9kg/m 2For overweight, BMI meets or exceeds 30kg/m 2Be obesity.[referring to NationalHeart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, TheEvidence Report, Washington, DC:U.S.Department of Health and HumanServices, NIH publication no.98-4083 (1998)].
The risk that fat and overweight increase numerous disease takes place comprises the cancer (for example carcinoma of endometrium, mammary cancer, prostate cancer and colorectal carcinoma) of coronary heart disease, apoplexy, hypertension, type ii diabetes, hyperlipemia, sleep apnea, osteoarthritis, cholecystopathy, depression and some form.Fat negative impact to health makes it become the second largest preventible reason that causes death of the U.S., and society is caused tangible economy and psychological impact.[referring to McGinnis M, Foege WH., " ActualCauses of Death in the United States, " JAMA, 270,2207-12 (1993)].
The cannabis material is the earliest by one of addicted substance of human knowledge, and its main active ingredient is a Δ 9-tetrahydrocannabinol (Δ 9-THC), and nearly millennial medicinal history, the cannabis material has multiple pharmacological effect such as pain relieving, calmness, spasmolytic, emesis, anti-glaucoma and hypertension, says Δ during the researchist of U.S. Scripps institute reports a few days ago 9The effect that the Alzheimer's disease that delays-THC worsens is better than existing market medicine (Eubanks, L.M., et al., A MolecularLink between the Active Component of Marijuana and Alzheimer ' s DiseasePathology.MOLECULAR PHARMACEUTICS, 2006.3:p.773-777.), but owing to easily produce tolerance and habituation, limited its use in the treatment field.The cannabis material mainly comprises three major types according to the source: the cannabis material that extract from natural phant (1): the plant hemp component is 60 several down, and its common trait is to contain a polynuclear plane.Purifying in 1964 and the Δ of illustrating structure 9-THC is first cannabis material (Gaoni that is identified, Y.and R.Mechoulam, Isolation, Structure, and Partial Synthesis of an ActiveConstituent of Hashish.J.Am.Chem.Soc., 1964.86 (8): p.1646-1647.); (2) after this, the part of many cannabinoid receptors is synthesized the research that is used to carry out 26S Proteasome Structure and Function, this class part shows rich diversity on chemical structure, as with CP55,940 for the dicyclo hemp derivative of representative, amino alkyl indole analog derivative with WIN55,212-2 is representative and optionally CB2 agonist HU-308, AM-1241, JWH-133; (3) similar with natural THC, (Anandamide AN) can regulate adenylate cyclase (AC) and Ca by G albumen to isolate the arachidonic acid thanomin from the pig brain 2+Channel function, and and THC between have cross tolerance, therefore be considered to first endogenous CBRs part (Devane, W.A., et al., Isolation andstructure of a brain constituent that binds to the cannabinoid receptor.Science, 1992.258 (5090): p.1946-1949.), other some polybasic unsaturated fatty acid derivatives in the body, also can exciting CBRs, as: 2-arachidonic acid glyceride (2-AG) (Mechoulam, R., et al., Identification of an Endogenous 2-Monoglyceride, Present in Canine Gut, That Binds to Cannabinoid Receptors.BiochemicalPharmacology, 1995.50 (1): p.83-90.), noladin ether and Virodhamine (Porter, A.C., et al., Characterization of a novel endocannabinoid, virodhamine, withantagonist activity at the CB1 receptor.Journal of Pharmacology andExperimental Therapeutics, 2002.301 (3): p.1020-1024.), be referred to as Endocannabinoids, they can see through hemato encephalic barrier fast, it is the important mediator in the nerve immunity system, wherein abundant with AN and 2-AG content in vivo, activity is also higher.
Cannabinoid receptors is meant cannabis material such as Δ 9-THC has the acceptor of replying.Now determined the hypotype of two kinds of cannabinoid receptors: CB1 acceptor and CB2 acceptor.The CB1 acceptor includes 473 amino acid, striding the film district by 17 forms, this receptor has high conservative (Matsuda in evolution, L.A., et al., Structure of a cannabinoid receptor and functional expression ofthe cloned cDNA.Nature, 1990.346 (6284): p.561-564.), the CB2 acceptor comprises 360 amino acid, different with the CB1 acceptor is, not strong (the Munro of its conservative property, S., K.L.Thomas, and M.Abu-Shaar, Molecular characterization of a peripheralreceptor for cannabinoids.Nature, 1993.365 (6441): p.61-65.).The CB1 acceptor mainly is present in central nervous system, and the CB2 acceptor mainly is present in peripheral neurons, and one of function all is to stop neural release.Their key distinction is: (1) aminoacid sequence: CB1 and CB2 acceptor all belong to the g protein coupled receptor Visual purple sample A of family guiding principle, be mainly Gi/o type g protein coupled receptor, gene clone discovers that these two kinds of complete aminoacid sequences of acceptor have 44% homology, stride the film region amino acid sequence 68% homology (Matsuda is arranged, L.A., et al., Structure of a cannabinoid receptor and functional expression of the clonedcDNA.Nature, 1990.346 (6284): p.561-564.); (2) signal transduction mechanism: the CB acceptor can activate leader's transduction path in the cell multiplex, comprises by suppressing adenylate cyclase, suppressing the generation that calcium channel, activating potassium channel and map kinase passage suppress cAMP; (3) organ distributes: the CB1 acceptor has another name called maincenter type cannabinoid receptors, mainly be arranged in brain, spinal cord and peripheral nervous system, the CB1 acceptor mainly is distributed in basal ganglion (black substance, pallidum, outside striatum), hippocampus CA pyramidal cell layer, cerebellum and pallium in the brain.This distribution of CB1 acceptor may be relevant to memory, adjusting cognitive, motion control with the cannabis material.The CB2 acceptor has another name called periphery type cannabinoid receptors, mainly is distributed in peripheral tissues, and as spleen marginarium, immunocyte, tonsilla etc., its this distribution then may be relevant with the immunosuppressive action of cannabis material.
Traditional nonselective cannabinoid receptors agonist such as CP-55,940, WIN55,212-2 and Δ 9-THC has the feed of stimulation, emesis, analgesia, anti-glaucoma (Drysdale, A.J.and B.Platt, Cannabinoids:Mechanisms and therapeutic applications in the CNS.Current Medicinal Chemistry, 2003.10 (24): p.2719-2732.), suppress tumor growth (Ligresti, A., et al., Possible endocannabinoid control of colorectal cancergrowth.Gastroenterology, 2003.125 (3): p.677-687.), and the treatment that is used for nerve degenerative diseases, comprise encephalitis periaxialis scleroticans (Croxford, J.L.and S.D.Miller, Towards cannabis and cannabinoid treatment of multiple sclerosis.Drugs ofToday, 2004.40 (8): p.663-676.) and alzheimer's disease (Eubanks, L.M., et al., A Molecular Link between the Active Component of Marijuana andAlzheimer ' s Disease Pathology.Molecular Pharmaceutics, 2006.3:p.773-777.), the agonist of these three nonselective cannabinoid receptors is widely used in the middle of the pharmacological research equally always, in addition, the endogenous agonist noladin ether of CB1 receptor-selective and the agonist AM-1241 of CB2 receptor-selective, HU-308 and JWH-133 will play a key effect for thoroughly understanding the effect in vivo of cannabinoid receptors different subtype.Studies show that, main and the immunomodulatory (Correa of CB2 receptor antagonist, F., et al., The role of cannabinoidsystem on immune modulation:Therapeutic implications on CNSinflammation.Mini-Reviews in Medicinal Chemistry, 2005.5 (7): p.671-675.) and nerve degenerative diseases (Carrier, E.J., et al., Cultured rat microglialcells synthesize the endocannabinoid 2-arachidonylglycerol, which increasesproliferation via a CB2 receptor-dependent mechanism.MolecularPharmacology, 2004.65 (4): p.999-1007.) relevant, but at present mechanism also is not very clear, therefore for CB1 optionally antagonist be exactly the focus that each big drugmaker is mainly studied.
Has a kind of CB1 conditioning agent that is characterized as being inverse agonist or antagonist at present at least, N-(piperidino)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methylpyrazole-3-methane amide (SR141716A) is being used for the treatment of eating disorder disease (Fernandez, J.R.and D.B.Allison, RimonabantSanofi-Synthelabo.Curr Opin Investig Drugs, 2004.5 (4): p.430-435.).
Research also shows, the quit smoking rate that SR141716A causes is significantly higher than placebo, have with market on the suitable effect of stop smoking medicine, compare with the patient who uses placebo, use the patient of this product also to obtain the effect (Cohen that loses weight, C., et al., SR141716, a central cannabinoid (CB (1)) receptor antagonist, blocks the motivational and dopamine-releasingeffects of nicotine in rats.Behav Pharmacol, 2002.13 (5-6): p.451-63.).Except smoking cessation, this product also is used for long term maintenance and gives up craving for tobacco being studied, and III phase clinical studies show, this product have very strong smoking cessation effect and good tolerability.Research is proof also, and the not only long-term quit smoking rate of this product is significantly higher than placebo, and can make the patient avoid putting on weight in smoking cessation, even can also lose weight.Further increase because smoking is dangerous for the obese person, normal non-smoker compares with body weight, the fat female life expectancy of smoking has reduced 13.3, and the obese males of smoking has then reduced 13.7, and therefore need working out more efficiently, the CB1 conditioning agent is used to give up craving for tobacco.
Except obesity, the demand that alcohol abuse is treated does not satisfy yet.Alcoholism is in about 1,090 ten thousand male sex of u.s. influence and 4,400,000 women.Annual about 100,000 examples are dead owing to alcohol abuse or dependence.Comprise motion control and impaired, the cancer of decision-making, hepatopathy, birth defect, heart trouble, medicine/drug interaction, pancreatitis and interpersonal problem with alcoholism associated health risk.Studies show that Endocannabinoids is adjusted in the control that alcohol takes in plays an important role.The voluntary alcohol that has shown CB1 receptor antagonist SR-141716A blocking-up rat and mouse is taken in.Treatment to alcohol abuse or dependence at present generally suffers not comply with or potential liver toxicity problem, therefore is not met to a great extent for the demand of more effectively treating alcohol abuse/dependence.
Though research is carried out, and still needs to be suitable for use as the more effective and safe lower molecular weight CB1 conditioning agent of human medicine, be used for reducing or preventing weight increase.In addition, such medicine needs long-term prescription, and therefore the medicine of desirability different structure same function is used alternatingly clinically, to reduce toxic side effect and to improve drug effect.
Summary of the invention
The object of the present invention is to provide the conditioning agent of class cannaboid-1 (CB1) acceptor, promptly by the substituted-piperazinyl compounds of general formula (I) expression or its acceptable salt pharmaceutically, it can be used for treatment, prevention and suppresses by the receptor-mediated disease of cannaboid-1 (CB1);
Another object of the present invention is to provide the method for the substituted-piperazinyl compounds of a kind of preparation general formula (I) expression;
An also purpose of the present invention is to provide a kind of and contains by the compound of general formula (I) expression or its pharmaceutical composition of acceptable salt pharmaceutically;
The compound of general formula of the present invention (I) expression is a CB1 cannabinoid receptors antagonist, thereby it can stop endogenous agonist and combining of cannabinoid receptors to block the biological activity of such endogenous agonist, therefore, of the present inventionly be to use on the one hand at least a compound of the present invention to block combining of cannabinoid agonist and CB1 cannabinoid receptors again, can be used for disease, illness and/or the obstacle of treatment by the adjusting of Cannabined receptor (particularly CB1 acceptor) antagonist.More specifically, the compound by general formula (I) expression be used for the treatment of cannabis abuse, obesity, schizophrenia, epilepsy, anxiety, dysmnesia, migraine, vomiting, thymus gland obstacle, dyskinesia, dyskinesis, anxiety disorder, mental disorder, cognitive disorder, limited appetite, emotional handicap, lose consciousness, disease and disease, illness and/or the obstacles such as ethanol, opium, Nicotine or cocaine addiction of neuropathy, Parkinson's disease, alzheimer disease, depression, neuroinduction.
According to purpose of the present invention, the substituted-piperazinyl compounds that provides a class to have following general structure (I), all steric isomers of this compound, its pharmacologically acceptable salt, solvate, hydrate or crystalline form:
Figure A20071004164000171
Wherein:
V in the general formula (I) is C=O, C=S or SO 2
W is the nitrogen-atoms of direct key, oxygen or replacement;
R 1And R 2Be independently selected from phenyl, naphthyl, furyl, thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl respectively, preferred especially phenyl or pyridyl, these groups can be replaced by 1-4 substituting group U, the U substituting group is identical or different, is selected from the C of branching or non-branching 1-8Alkyl or alkoxyl group, C 1-3Alkoxy methyl, list or two C 1-3Alkylamino, list or two C 1-3Alkylamidoalkyl, C 1-3Alkyl sulphonyl, C 1-3Alkoxy carbonyl, phenyl, phenoxy group, hydroxyl, methylol, methylthio group, hydroxyethyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoro-methoxy, trifluoromethoxy, trifluoromethylthio, trifyl, methyl sulphonyl, amino-sulfonyl, amino, nitro and cyano group etc., R 1Or R 2Last substituting group U combination is preferably: R 1Last substituting group is respectively 2,4-dichloro, 4-chlorine, 3,4-dichloro, 2-chloro-4-bromine, 2-bromo-4-chlorine, 2-fluoro-4-chlorine, 2-chloro-4-fluorine; R 2Last substituting group is respectively hydrogen, the optional position replaces on the aromatic ring chlorine, fluorine, bromine, trifluoromethyl, C 1-3Alkoxy methyl, C 1-8Alkyl.
R 3The C of expression hydrogen atom, branching or non-branching 1-10Alkyl, C 3-10Cycloalkyl, C 5-10Bicyclic alkyl, C 6-10Tricyclic alkyl, C 3-8Alkenyl, C 5-8Cycloalkenyl group or adamantyl, preferred especially C 4-6Alkyl, cyclohexyl, cyclohexenyl, adamantyl, these groups can be chosen the heteroatoms that contains one or more O of being selected from, N and S wantonly, and these groups can be by hydroxyl, C 1-8Alkyl or alkoxyl group or 1-3 halogen atom replaces; Perhaps R 3The expression aromatic nucleus can be by phenyl, benzyl, styroyl, naphthyl, anthryl, menaphthyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or the triazinyl etc. of 1-4 substituting group U replacement, and wherein substituting group U definition as above; Perhaps R 3Expression group NR 4R 5, R wherein 4And R 5With the nitrogen-atoms that they connected, formation has the saturated or undersaturated monocycle or the bicyclic heterocycle part of 4-10 annular atoms, this heterocyclic moiety contains 1 or 2 identical or different heteroatoms that is selected from N, O and S, and described heterocyclic moiety can be by branching or non-branching C 1-4Replacements such as alkyl, hydroxyl, trifluoromethyl or halogen atom are preferably formed the saturated monocyclic heterocycles of 6 annular atomses especially, and wherein this heterocyclic moiety does not preferably contain or contain the another one Sauerstoffatom;
R ' and R " identical or different and represent 1 or 2 to be substituted in hydrogen, methyl, ethyl, hydroxyl or the halogen atom etc. that the piperazine ring different positions replaces, 2,5 substituent methyls, 2,6 substituent methyls on the preferred especially piperazine ring.
In the preferred embodiment of the invention, preferred especially following combination: when V was C=O, W was direct key; When V was C=O, W was an oxygen; When V is C=O, the nitrogen-atoms of W for replacing; When V is C=S, the nitrogen-atoms of W for replacing; V is SO 2The time, W is direct key.
For substituted-piperazinyl compounds acceptable salt pharmaceutically, comprise the pharmaceutically acceptable acid additive salt, by handle the free alkali of general formula (I) compound with mineral acid or organic acid, can obtain its pharmacy acceptable salt.Described mineral acid, for example hydrochloric acid, Hydrogen bromide, phosphoric acid and sulfuric acid; Described organic acid, for example xitix, nicotinic acid, citric acid, tartrate, lactic acid, toxilic acid, propanedioic acid, fumaric acid, oxyacetic acid, succsinic acid, propionic acid, acetate, methylsulfonic acid etc.
The piperazine compounds of general formula (I) and their salt may have at least one chiral centre, therefore exist as steric isomer, comprise enantiomorph and diastereomer.The present invention includes the mixture of such enantiomorph of each R of aforementioned formula I compound and S enantiomorph and their salt and arbitrary proportion, comprise and contain the racemic mixture of two enantiomorphs of equivalent basically.
This area obtains the asymmetric synthesis of pure steric isomer or the method for chiral separation as everyone knows, as chromatography or Steppecd crystallization.Can pass through for example fractional crystallization, fractionation or HPLC separation of racemic thing and enantiomer separation.Can separate diastereomer by for example fractional crystallization, HPLC or flash chromatography separating isomerism body mixture.Perhaps, can under the condition that can not cause racemization or epimerization, synthesize the preparation steric isomer from the chiral raw material chirality, or by preparing with chiral reagent deutero-method.Comprise all steric isomers within the scope of the invention.
Compound of the present invention can with solvation not and exist with the form of pharmaceutically acceptable solvent (for example water, ethanol etc.) solvation.Usually, for purpose of the present invention, think that the form of solvation is equal to the not form of solvation.
Be applicable to whole specification sheets and additional claims to give a definition.Unless otherwise mentioned or point out, term " alkyl " expression straight or branched alkyl.The example of described alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Preferred alkyl is methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.
Unless otherwise mentioned or point out, term " alkoxyl group " expression group O-alkyl, wherein alkyl as above defines.
Unless otherwise mentioned or point out that term " halogen " is meant fluorine, chlorine, bromine or iodine.
Unless otherwise mentioned or point out, term " directly key " is meant that this group does not exist.
In the preferred embodiment of the present invention, preferred particular compound of the present invention is:
1) hexamethylene acyl group-4-benzhydryl piperazidine (compound 4d among the embodiment)
2) N-butyl-4-benzhydryl piperazidine-1-formyl ammonia (compound 6n among the embodiment)
3) N-benzyl-4-phenmethyl piperazine-1-sulfo-formyl ammonia (compound 6a among the embodiment)
4) 4-benzhydryl piperazidine-N-benzyl-1-sulfo-formyl ammonia (compound 5a among the embodiment)
5) 4-benzhydryl piperazidine-N-cyclohexyl-1-sulfo-formyl ammonia (compound 5b among the embodiment)
6) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(cyclobutyl acyl group) piperazine (Compound D a-1 among the embodiment)
7) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(cyclopentyl acyl group) piperazine (Compound D a-2 among the embodiment)
8) (2, the 4-chloro-phenyl-) methyl 1-[(4-chloro-phenyl-)]-4-(cyclohexyl acyl group) piperazine (Compound D a-3 among the embodiment)
9) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(diamantane acyl group) piperazine (Compound D a-4 among the embodiment)
10) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-piperidines-1-acyl piperazine (Compound D a-5 among the embodiment)
11) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-morpholine-4-acyl piperazine (Compound D a-6 among the embodiment)
12) (2,4 dichloro benzene base) methyl N-butyl-4-[(4-chloro-phenyl-)] piperazine-1-formyl ammonia (Compound D c-1 among the embodiment)
13) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-chloro-phenyl-)] piperazine-1-formyl ammonia (Compound D c-2 among the embodiment)
14) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-chloro-phenyl-)] piperazine-1-sulfo-formyl ammonia (Compound D b-1 among the embodiment)
15) (2, the 4-chloro-phenyl-) methyl 1-[(4-chloro-phenyl-)]-4-(4-Methyl benzenesulfonyl base) piperazine (Compound D a-20 among the embodiment)
16) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(cyclobutyl acyl group) piperazine (Compound D a-7 among the embodiment)
17) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(cyclopentyl acyl group) piperazine (Compound D a-8 among the embodiment)
18) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(cyclohexyl acyl group) piperazine (Compound D a-9 among the embodiment)
19) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(diamantane acyl group) piperazine (Compound D a-10 among the embodiment)
20) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-piperidines-1-acyl piperazine (Compound D a-11 among the embodiment)
21) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-morpholine-1-acyl piperazine (Compound D a-12 among the embodiment)
22) (2,4 dichloro benzene base) methyl N-butyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-3 among the embodiment)
23) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-4 among the embodiment)
24) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-sulfo-formyl ammonia (Compound D b-2 among the embodiment)
25) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-p-methoxy-phenyl)] piperazine-1-formyl ammonia (Compound D c-5 among the embodiment)
26) (2,4 dichloro benzene base) methyl 1-[(4-p-methoxy-phenyl)]-4-(cyclohexyl acyl group) piperazine (embodiment Compound D a-13)
27) (2,4 dichloro benzene base) methyl 1-[(4-trifluoromethyl)]-4-(cyclohexyl acyl group) piperazine (Compound D a-14 among the embodiment)
28) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-trifluoromethyl)] piperazine-1-formyl ammonia (Compound D c-6 among the embodiment)
29) (2,4 dichloro benzene base) methyl 1-[(4-Phenoxyphenyl)]-4-(cyclohexyl acyl group) piperazine (Compound D a-15 among the embodiment)
30) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-Phenoxyphenyl)] piperazine-1-formyl ammonia (Compound D c-7 among the embodiment)
31) (2,4 dichloro benzene base) methyl 1-[(3-chloro-phenyl-)]-4-(cyclohexyl acyl group) piperazine (Compound D a-16 among the embodiment)
32) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(3-chloro-phenyl-)] piperazine-1-formyl ammonia (Compound D c-8 among the embodiment)
33) (2,4 dichloro benzene base) methyl 1-[(4-aminomethyl phenyl)]-4-(cyclohexyl acyl group) piperazine (Compound D a-17 among the embodiment)
34) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-aminomethyl phenyl)] piperazine-1-formyl ammonia (Compound D c-9 among the embodiment)
35) (4-chloro-phenyl-) methyl 1-[(3-itrile group phenyl)]-4-(cyclohexyl acyl group) piperazine (Compound D a-18 among the embodiment)
36) (4-chloro-phenyl-) methyl N-cyclohexyl-4-[(3-itrile group phenyl)] piperazine-1-formyl ammonia (Compound D c-10 among the embodiment)
37) (4-chloro-phenyl-) methyl 1-[(2-trifluoromethyl)]-4-(cyclohexyl acyl group) piperazine (Compound D a-19 among the embodiment)
38) (3, the 4-dichlorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-11 among the embodiment)
39) (2, the 5-dichlorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-12 among the embodiment)
40) (2-fluoro-4-bromophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-13 among the embodiment)
41) (2, the 6-dichlorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-14 among the embodiment)
42) (2-chloro-4-fluorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-15 among the embodiment)
43) (2-fluoro-4-chloro-phenyl-) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia (Compound D c-16 among the embodiment)
44) (2,4 dichloro benzene base) methyl 1-[(4-fluorophenyl)]-4-(cyclohexyl acyl group) piperazine (Compound D c-17 among the embodiment)
45) (2,4 dichloro benzene base) methyl 4-[(phenyl)]-N-piperidyl-1-piperazine-1-methane amide (Compound D c-18 among the embodiment)
46) (2,4 dichloro benzene base) methyl 4-[(4-aminomethyl phenyl)]-N-piperidyl-1-piperazine-1-methane amide (Compound D c-19 among the embodiment)
47) (2,4 dichloro benzene base) methyl 4-[(4-chloro-phenyl-)]-N-piperidyl-1-piperazine-1-methane amide (Compound D c-20 among the embodiment)
48) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-aminomethyl phenyl)]-2,5-lupetazin-1-formyl ammonia (compound among the embodiment 5).
And optical isomer, tautomer, steric isomer and racemoid and pharmacologically acceptable salt, solvate and crystalline form under usable condition.
The invention provides the preparation method of the substituted-piperazinyl compounds of general formula (I) expression.
Compound with general formula (I) of the present invention can be synthetic by following route of synthesis, and this approach comprises and is similar to institute's well known in the chemical field, particularly states the method for bright part according to this.Initial substance generally can be obtained from commercial source such as Aldrich chemical company (the hot state of University of Wisconsin-Madison Milwaukee), or can prepare (as preparing by the method for being summarized in the following books: it " reagent that is used for the organic synthesis effect " 1-19 volume (the USA New York Wiley 1967-1999 of company version) of Louis F.Fieser and Mary Fieser by method well-known to those skilled in the art; Or " Beilsteins Handbuch der organischen Chemie " 1. editions the 4th of Auf and comprise supplement (Berlin, Germany Springer-Verlag company publish and also can obtain) via Beilstein online material storehouse.
Except as otherwise noted, in following reaction scheme, each symbol of described compound has identical implication.Compound in reaction scheme comprises its salt, for example, and the salt that those define as the compound with general formula (I) etc.
For the usefulness that illustrates, the reacting flow chart shown in following is provided for the possible approach of synthetic compound of the present invention and key intermediate species.The more detailed description of relevant indivedual reactions steps is asked for an interview embodiment part described later.Those skilled in the art will understand and can use other route of synthesis to synthesize compound of the present invention.Though in schema, show and in aftermentioned partly touch upon specific initial substance and reagent, alternative with other initial substances and reagent easily, and multiple derivative and/or reaction conditions is provided.In addition,, can use conventional chemical well-known to those skilled in the art, state the prepared numerous compounds of method by this and further modify in view of present disclosure.
Reaction scheme 1:
Compound with structural formula (I-a) can utilize the method for describing in following reaction scheme 1 to be prepared.R wherein 1, R 2, R 3And R ', R " definition as mentioned above; X is a halogen; Also can see structural formula (I-a) just the V in the general formula (I) be C=O, W is direct key.
Reaction scheme 1
Step a:
This is a step that is used for preparation by the compound of formula (A-3) expression, and step comprises to be made by the compound of formula (A-1) expression and the compound reaction of being represented by formula (A-2).
Examples for compounds by formula (A-1) expression comprises phenyl aldehyde, 2-chlorobenzaldehyde, 4-chlorobenzaldehyde, 2,4-dichlorobenzaldehyde, 3,4-dichlorobenzaldehyde, 2,5-dichlorobenzaldehyde, 2, aromatic aldehydes such as 6-dichlorobenzaldehyde, 2-chloro-4-fluorobenzaldehyde, 2-fluoro-4-chlorobenzaldehyde, 2-fluoro-4-bromobenzaldehyde, 3-itrile group phenyl aldehyde, 2-trifluoromethylated benzaldehyde.Examples for compounds by formula (A-2) expression comprises halogenated aromatic ring or aromatic heterocycles such as bromobenzene, 4-chloro-bromobenzene, 3-chloro-bromobenzene, 4-bromofluorobenzene, 4-methyl bromobenzene, 4-methoxyl group bromobenzene, 4-phenoxy group bromobenzene, 4-methyl bromobenzene trifluoride.In anhydrous non-protonic solvent, by formula (A-1) and formula (A-2) are passed through the grignard reaction coupling, the example of reaction solvent comprises anhydrous non-protonic solvent, as tetrahydrofuran (THF), ether, isopropyl ether etc., especially be preferably tetrahydrofuran (THF), the example of temperature of reaction comprises-10 ℃ to 200 ℃, especially be preferably the general condition of grignard reaction well-known to those skilled in the art, this step comprises that the product by formula (A-3) expression that obtains carries out purifying by organic compound purification process commonly used such as column chromatography or recrystallizations.
Step b:
This is a step that is used for preparation by the compound of formula (A-4) expression, and step is included under the existence of halogenating agent, makes the reaction that is converted into the compound of being represented by formula (A-4) by the compound of formula (A-3) expression.
The example of halogenating agent comprises sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride etc., especially is preferably sulfur oxychloride.The example of reaction solvent comprises ether, tetrahydrofuran (THF), methylene dichloride, trichloromethane, 1, and the 2-ethylene dichloride especially is preferably methylene dichloride, trichloromethane, 1, the 2-ethylene dichloride.The experiment of temperature of reaction comprises 20 ℃～150 ℃, especially is preferably room temperature～100 ℃.
Step c:
This is a step that is used for preparation by the compound of formula (A-5) expression, and step comprises the substituted-piperazinyl reaction with piperazine or the protection of nitrogen-atoms list.The example of reaction solvent comprises acetone, tetrahydrofuran (THF), acetonitrile, N, and dinethylformamide etc. especially are preferably acetonitrile.Temperature of reaction comprises 0～200 ℃, especially is preferably 70 ℃.The protecting group of piperazinyl comprises amino protecting groups commonly used such as tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl group, and step c comprises that equally the common methods that removes these blocking groups is to obtain the compound by formula (A-5) expression.
Steps d:
This is a step that is used for preparation by the compound of formula (I-a) expression.
Step comprises by the compound of formula (A-5) expression and the carboxylic acid (R of different replacements 3-COOH) condensation reaction, the example of reaction solvent is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its mixture; Condensing agent is 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDC), di-isopropyl carbodiimide (DIC), dicyclohexyl carbodiimide (DCC), phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP), O-benzotriazole-N, N, N, N '-tetramethyl--urine salt-hexafluorophosphate (HBTU) or 1-hydroxyl-benzo-triazole (HOBt); Used organic bases example is triethylamine, 4-dimethyl amine pyridine (DMAP) or diisopropyl ethyl amine (DIPEA) in the condensation reaction;
Step also comprises by the compound of formula (A-5) expression and the carboxylic acid halides (R of different replacements 3-COX) reaction, the example of reaction solvent is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its mixture especially are preferably methylene dichloride; Used organic bases example is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP) or diisopropyl ethyl amine (DIPEA) in the reaction, especially is preferably triethylamine; Temperature of reaction especially is preferably 0 ℃～room temperature for experiment comprises 0～200 ℃.
Reaction scheme 2:
Compound with structural formula (I-b) can utilize the method for describing in following reaction scheme 2 to be prepared.R wherein 1, R 2, R 3And R ', R " definition as mentioned above; X is a halogen; Also can see structural formula (I-b) just the V in the general formula (I) be C=O, the nitrogen-atoms of W for replacing.
Figure A20071004164000261
Reaction scheme 2
Step a-step c:
This is the synthesis step that a preparation has the intermediate of structural formula A-3, A-4, A-5, the described term harmonization of step a-step c in its description and the reaction scheme 1.
Steps d:
This is a step that is used for preparation by the compound of formula (I-b) expression.
Step comprises by the compound of formula (A-5) expression and the isocyanide ester (R of different replacements 3-NCO) reaction.The example of reaction solvent is tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, N, and dinethylformamide (DMF) or its mixture especially are preferably tetrahydrofuran (THF) and methylene dichloride; May use organic bases in the reaction and improve reaction efficiency as catalyzer, example is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP) or diisopropyl ethyl amine (DIPEA); Temperature of reaction especially is preferably room temperature～50 ℃ for experiment comprises 0～200 ℃.
Step also comprises by the compound of formula (A-5) expression and the organic amine (R of different replacements 3-NH 2) reaction, reaction is by phosgene or three surpalites, N, N '-carbonyl dimidazoles (CDI) and organic amine (R 3-NH 2) the generation active carbonyl compound, obtain product I-b with the compound reaction of representing by formula (A-5) again, the example of reaction solvent is tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its mixture especially are preferably tetrahydrofuran (THF) and methylene dichloride; Temperature of reaction especially is preferably room temperature～50 ℃ for experiment comprises 0～200 ℃.
Reaction scheme 3:
Compound with structural formula (I-c) can utilize the method for describing in following reaction scheme 3 to be prepared.R wherein 1, R 2, R 3And R ', R " definition as mentioned above; X is a halogen; Also can see structural formula (I-c) just the V in the general formula (I) be C=S, the nitrogen-atoms of W for replacing.
Reaction scheme 3
Step a-step c:
This is the synthesis step that a preparation has the intermediate of structural formula A-3, A-4, A-5, the described term harmonization of step a-step c in its description and the reaction scheme 1.
Steps d:
This is a step that is used for preparation by the compound of formula (I-c) expression.
Step comprises by the compound of formula (A-5) expression and the different sulphur nitrile acid esters (R of different replacements 3-NCS) reaction.The example of reaction solvent is tetrahydrofuran (THF), methylene dichloride, 1,2-monochloroethane, chloroform, N, and dinethylformamide (DMF) or its mixture especially are preferably tetrahydrofuran (THF) and methylene dichloride; May use organic bases in the reaction and improve reaction efficiency as catalyzer, example is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP) or diisopropyl ethyl amine (DIPEA); Temperature of reaction especially is preferably room temperature～50 ℃ for experiment comprises 0～200 ℃.
Step also comprises by the compound of formula (A-5) expression and the organic amine (R of different replacements 3-NH 2) reaction, N is passed through in reaction, N '-thiocarbonyldiimidazole (TCDI) and organic amine (R 3-NH 2) generate active thiocarbonyl compound, obtain product I-c with the compound reaction of representing by formula (A-5) again, the example of reaction solvent is tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its mixture especially are preferably tetrahydrofuran (THF) and methylene dichloride; Temperature of reaction especially is preferably room temperature～50 ℃ for experiment comprises 0～200 ℃.
Reaction scheme 4:
Compound with structural formula (I-d) can utilize the method for describing in following reaction scheme 4 to be prepared.R wherein 1, R 2, R 3And R ', R " definition as mentioned above; X is a halogen; Also can see structural formula (I-d) just the V in the general formula (I) be SO 2, W is direct key.
Figure A20071004164000291
Reaction scheme 4
Step a-step c:
This is the synthesis step that a preparation has the intermediate of structural formula A-3, A-4, A-5, the described term harmonization of step a-step c in its description and the reaction scheme 1.
Steps d:
This is a step that is used for preparation by the compound of formula (I-d) expression.
Step comprises by the compound of formula (A-5) expression and the SULPHURYL CHLORIDE reaction (R of different replacements 3-SO 2Cl) reaction.The reaction needed organic bases improves reaction yield, the example of the organic bases of using is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP) or diisopropyl ethyl amine (DIPEA), especially is preferably triethylamine, 4-dimethyl amine pyridine (DMAP) or diisopropyl ethyl amine (DIPEA); The example of reaction solvent is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, and dinethylformamide (DMF) or its mixture especially are preferably methylene dichloride; Temperature of reaction especially is preferably room temperature～50 ℃ for experiment comprises 0～200 ℃.
Reaction scheme 5:
The key intermediate A-5 of the compound of synthetic general formula (I) also can utilize the method for describing in following reaction scheme 5 to be prepared.R wherein 1, R 2And R ', R " definition as mentioned above, X is a halogen, Y represents halogen.
Figure A20071004164000292
Reaction scheme 5
Step a:
This is a step that is used for preparation by the compound of formula (B-3) expression, and step comprises makes compound of being represented by formula (B-1) and the compound of being represented by formula (B-2) obtain ketone (B-3) by friedel-crafts acylation reaction.
Examples for compounds by formula (B-1) expression comprises Benzoyl chloride, to aryl formyl halides such as methyl benzoyl chloride, 2-chloro-benzoyl chloride, 4-chloro-benzoyl chloride, 4-methoxy benzoyl chlorides, be preferably Benzoyl chloride especially and to methyl benzoyl chloride.Examples for compounds by formula (B-2) expression comprises substituted aromatic compounds such as 2,4 dichloro benzene, 2-chloro-4-fluorobenzene, 2-fluoro-4-chlorobenzene, 2-fluoro-4-bromobenzene, is preferably 2,4 dichloro benzene especially.The solvent of friedel-crafts acylation reaction comprises non-polar solvent, as dithiocarbonic anhydride, tetracol phenixin etc., or polar solvent, as Nitromethane 99Min. etc., or medium polar solvent, as methylene dichloride, or solvent-free reaction, be preferably solvent-free reaction in this example especially.The used catalyzer example of friedel-crafts acylation reaction comprises aluminum chloride, butter of antimony, iron trichloride etc., is preferably aluminum chloride especially.The example of temperature of reaction comprises 0～200 ℃, is preferable over 100 ℃ especially, and this step comprises that the product by formula (B-3) expression that obtains carries out purifying by organic compound purification process commonly used such as column chromatography or recrystallizations.
Step b:
This is a step that is used for preparation by the compound of formula (B-4) expression, step comprises makes the compound of being represented by formula (B-3) by generating two aryl carboxamides with formamide, temperature of reaction comprises 100～200 ℃, especially is preferably 180 ℃, and the reaction times is 24 hours.After handle through acidic alcohol again and obtain product B-4.
Step c:
This is a step that is used for preparation by the compound of formula (A-5) expression.
Step comprises intermediate (B-4) and N, N-two-(2-chloroethyl)-4-methyl benzenesulfonamide reaction generates product A-5, need organic bases in the reaction, example is triethylamine, pyridine or diisopropyl ethyl amine (DIPEA), especially be preferably diisopropyl ethyl amine (DIPEA), temperature of reaction comprises 100～200 ℃, especially is preferably 120 ℃.
Step also comprises and removes 4-Methyl benzenesulfonyl amine protecting group, the piperazine nitrogen-atoms that dissociates, and the reaction conditions that removes protecting group is 30%～45% Hydrogen bromide/acetic acid solution, and temperature of reaction comprises 0～100 ℃, especially is preferably room temperature, and the reaction times is 48 hours.
Reaction scheme 6:
The enantiomorph B-5 of the key intermediate A-5 of the compound of synthetic general formula (I) is prepared by the method for describing in the following reaction scheme 6.R wherein 1, R 2And R ', R " definition as mentioned above, X represents R 2On substituted radical, the definition as mentioned above, Y represents halogen.
Figure A20071004164000311
Reaction scheme 6
Step a～step b:
This is the synthesis step that a preparation has the intermediate of structural formula B-3, B-4, the described term harmonization of step a-step b in its description and the reaction scheme 5.
Step c:
This is a step that is used for preparation by the compound of formula (B-4a) expression.
Step comprises that the compound by formula (B-4) expression obtains the enantiomorph (B-4a) of optically pure (B-4) by the method for chiral separation, the chiral selectors example of using is chiral mandelic acid or L-(+) tartrate or D-(-) tartrate, especially preferred L-(+) tartrate or D-(-) tartrate carry out chiral separation, obtain the enantiomer of R and S configuration respectively.Used chiral separation method from but be not limited only to document Opalka CJ, Ambra JE.A novel synthesis of the enantiomersof an antihistamine drug by piperizine formation from a primary amine.Synthesis, 1995 (7): 766-768.
Steps d:
This is a step that is used for preparation by the compound of formula (B-5) expression.Its description is consistent with the step c in the reaction scheme 5.
Preliminary study shows, following disease, illness and/or obstacle are regulated by cannabinoid receptor antagonists: eating disorder (carousing property eating disorder for example, apositia and exessive appetite), lose weight or control (for example calorie or food intake minimizing and/or appetite inhibiting), fat, depressed, atypical depression, bipolar disorder, psychosis, schizophrenia, the behavior habituation, reward inhibition (for example conditionality position escape of related behavior, for example to the inhibition of the conditioned place preference of Cocaine and morphine induction), substance abuse, assuetude disturbance, impulsive action, alcoholism (alcohol abuse for example, habituation and/or dependence, comprise the treatment abstinence from alcohol, thirst for reducing and alcohol absorption recurrence prevention), tobacco abuse (the habituation of for example smoking, stop and/or relying on, comprise the recurrence prevention that is used to the treatment thirsting for reducing and smoking), dementia (comprises the loss of memory, Alzheimer, old and feeble dementia, vascular dementia, mild cognitive impairment, cognitive decline relevant and slight nervus cognition disorder) with the age, male sexual disorder (difficulty of for example erecing), the epileptic seizures obstacle, epilepsy, inflammation, gastrointestinal disorder (for example gastrointestinal motility or intestines propulsion functions obstacle), (ADD comprises distractibility hyperkinetic syndrome (ADHD) to attention deficit disorder (ADD), Parkinson's disease and type ii diabetes.Therefore, the compound (comprising wherein compositions for use and method) with general formula (I) structure disclosed herein can be used in the medicine of preparation treatment by Cannabined receptor (particularly CB1 acceptor) disease, illness and/or obstacle that antagonist mediated.
Cannabinoid receptor antagonists can be to its effective other disease, illness and/or obstacle comprise: premenstrual syndrome or corpus luteum syndromes in late period, migraine, panic disorder, anxiety, syndromes after the wound, social phobia, non-dull-witted individual cognitive impairment, non-memory disappearance mild cognitive impairment, operation back cognitive decline, the obstacle relevant (disruptive behaviour obstacle (anxiety/depression for example for example with impulsive action, the execution function is improved, tic disorder, conduct disorder and/or oppositional defiant disorder), adult's personality disorder (for example borderline personality disorder and dissocial personality disorder), with (for example substance abuse of impulsive action diseases associated, sexual desire example mistake and autotomy) and impulse control disorder (intermittent explosive disorder for example, the kleptomania, pyromania, pathological gambling and trichotillomania)), obsessive compulsive disorder, chronic tired syndrome, male sexual disorder (for example drought is let out), Female sexual dysfunction, somnopathy (for example sleep apnea), autism, mutism, the neurodegeneration dyskinesia, Spinal injury, central nervous system damage (for example wound), apoplexy, neurodegenerative disease or toxic or infectious CNS disease (for example encephalitis or meningitis), cardiovascular disorder (for example thrombosis) and diabetes.
Therefore, compound of the present invention is to be suitable for disease, the patient's condition and/or the dysfunction that treatment is regulated and control by cannabinoid receptor antagonists.
Another aspect of the present invention is a kind of method for the treatment of disease, illness and/or the obstacle regulated by cannabinoid receptor antagonists of animal, and described method comprises to the compound of the present invention of the animal administering therapeutic significant quantity of this treatment of needs or contains the compound of the present invention of significant quantity and the pharmaceutical composition of pharmaceutically acceptable vehicle, diluent or carrier.
Another embodiment of the present invention provides a kind of pharmaceutical composition, and it comprises compound of the present invention or its pharmacy acceptable salt for the treatment of significant quantity, and can further comprise vehicle, thinner or supporting agent.Be to be understood that, pharmaceutical composition of the present invention can comprise one or more compounds of the present invention, the i.e. arbitrary combination of 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47 or 48 these compounds.
Further, pharmaceutical composition of the present invention can also comprise: slimming agents, nicotine receptor partial agonist, dopaminergic or OPIOIDS antagonist.
Further, pharmaceutical composition of the present invention can also comprise at least a lipase inhibitor or have the medicine of effect for reducing fat; Wherein said lipase inhibitor can be orlistat or mud pool Si Tating etc.; Described medicine with effect for reducing fat can be nicotinic acid.
Typical prescription is to prepare it by mixing compound of the present invention and supporting agent, thinner or vehicle.Suitable supporting agent, thinner or vehicle are well-known to those skilled in the art, comprise the material such as carbohydrate, wax, water-soluble and/or swellability polymkeric substance, wetting ability or lyophobic dust, gelatin, oil, solvent, water etc.Used specific supporting agent, thinner or vehicle will be according to the mode of using compound of the present invention and purposes and decide.Generally think that based on those skilled in the art but safety offers medicine to the solvent of a mammal (GRAS), and selective solvent.Generally speaking, the solvent of safety be the nontoxicity water-containing solvent such as water, and other water solubles or the nontoxicity solvent miscible with water.Suitable water-containing solvent comprises water, ethanol, propylene glycol, polyoxyethylene glycol (as PEG400, PEG300) etc. and composition thereof.This prescription also can comprise one or more buffer reagent, tranquilizer, tensio-active agent, wetting agent, lubricant, emulsifying agent, suspension agent, sanitas, antioxidant, opalizer, glidant, processing aid, tinting material, sweetener, perfume agent, seasonings and other known additives, providing one of this medicine graceful appearance form (that is compound of the present invention or its pharmaceutical compositions), or assist the manufacturing of this pharmaceutical product (that is medicine).
This prescription can use conventional dissolving combination process and prepare it.For example, in the presence of one or more above-mentioned vehicle, with blocky drug substance (that is the stabilized form of compound of the present invention or this compound (as with the complex compound of a cyclodextrin derivative or other known recombiners) be dissolved in the suitable solvent.Typically compound of the present invention is mixed with pharmaceutical formulation, so that the easily dosage of control of this medicine to be provided, and provides a kind of grace of patient and easy to handle product.
The pharmaceutical compositions of Gong using (or prescription) can be complied with the dosing mode of this medicine, and packs in many ways.Generally speaking, the object that is used to distribute comprises a container, wherein deposits the pharmaceutical formulation of a suitable form.Suitable container is well-known to those skilled in the art, comprises the material such as bottle (plastics and vial), sachet, ampoule, plastics bag, metallic cylinder etc.This container also can comprise that a kind of anti-behaviour does device, to avoid contacting immodestly the content in this packing.In addition, on container, can be equipped with a sign, so that the content of this container to be described.This mark also can comprise suitable warning message.
Compound of the present invention can with between every day about 0.7 milligram of dosage level to about 7000 nanogram ranges offer medicine to the patient.With regard to the about 70 kilograms normal adult of body weight, typical full dose be between per kilogram of body weight about 0.01 milligram to about 100 milligrams scope.Yet, according to institute treat age of individuality and body weight, the dosing way of being planned, the specific compound of being offerd medicine etc. and deciding, this general dosage range may need some changes.Being used for the judgement of the dosage range and the optimal dose of a specific sufferer, is to be positioned within the those of ordinary skills' that benefit from present disclosure the limit of power.Also examine and know that compound of the present invention can be used for continuing in discharge type, control discharge type and the delay discharge type prescription, these forms also are well known to those of ordinary skill in the art.
According to method of the present invention, give a compound of the present invention for individual a throwing of this treatment of needs, or throw and give the combination of a compound of the present invention and at least a additional medicaments, be preferably the form of a pharmaceutical compositions.With regard to combined aspects of the present invention, compound of the present invention can separate and offer medicine with at least a other medicaments (as slimming agents, nicotine receptor partial agonist, dopaminergic or OPIOIDS antagonist), or to comprise the pharmaceutical compositions dispensing of the two simultaneously.Generally speaking, be preferably oral administration medicine supplying.Yet, if the individuality of being treated can't swallow, or oral administration medicine supplying be obstructed or non-other situations of desiring under, may suit to carry out parenteral or transdermal and offer medicine.According to method of the present invention, when a compound of the present invention is when offeing medicine with the combination of one of at least a other medicaments, this dispensing effect can be carried out in time in regular turn or simultaneously, and generally to carry out simultaneously to preferably.With regard to the dispensing effect of carrying out in regular turn, compound of the present invention and this additional medicaments can be with arbitrary order dispensings.Generally speaking, this dispensing effect is preferably oral administration medicine supplying.This dispensing effect is preferably dispensing oral and that carry out simultaneously especially.When compound of the present invention and this additional medicaments are when offeing medicine in regular turn, dispensing separately can be undertaken by identical or different method.
According to method of the present invention, the combination of a compound of the present invention or a compound of the present invention and at least a other medicaments (being referred to herein as " combination "), preferably offer medicine with the form of pharmaceutical compositions.Therefore, compound of the present invention or combination can with in arbitrary known oral, rectum, transdermal, parenteral (for example intravenously, intramuscular or subcutaneous) the brain pond, intravaginal, intraperitoneal, intravesical, part (for example powder, ointment or drop), cheek or nose formulation, and separate or offer medicine together to a sufferer.
Be applicable to non-composition, generally comprise pharmaceutically acceptable aseptic moisture or non-aqueous solution, dispersion liquid, suspension or emulsion, and be used to recombinate and become the aseptic syringeability solution or the sterilized powder of dispersion liquid through enteral administration.Suitable moisture or non-water ballast agent or thinner (comprising solvent and carrier) comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.) and suitable mixture thereof; Vegetables oil (such as sweet oil); And the syringeability organic ester is such as ethyl oleate.For example can under the situation of dispersion liquid, keep required particle size by using a coating such as Yelkin TTS, and by the use tensio-active agent, and keep suitable flowability properties.
These constituents also can contain vehicle, such as sanitas, wetting agent, emulsifying agent and dispersion agent.Can pass through various bactericide and mycocide, for example metagin, butylene-chlorohydrin, phenol, Sorbic Acid etc., and avoid the microbial contamination said composition.Comprising isoosmotic pressure agent such as carbohydrate, sodium-chlor etc., may also be what desired.Can pass through to use the medicament that can postpone absorption, such as aluminum monostearate and gelatin, and the absorption that prolongs the injection type pharmaceutical compositions.
The solid dosage that is used for oral administration medicine supplying can comprise capsule, tablet, powder and particle.In these solid dosage, compound of the present invention or combination are to mix with at least a inert excipient, thinner or supporting agent.Suitable vehicle, thinner or supporting agent comprises the material such as Trisodium Citrate or Lin Suanergai, or (a) filler or extender (as starch, lactose, sucrose, mannitol, silicic acid etc.); (b) tackiness agent (as carboxymethyl cellulose, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose, gum arabic etc.); (c) wetting agent (as glycerine etc.); (d) disintegrating agent (as agar, lime carbonate, potato or tapioca (flour), alginic acid, specific complex silicate, yellow soda ash etc.); (e) solution retarding agent (as paraffin etc.); (f) quicken absorption agent (as quaternary ammonium compound etc.); (g) wetting agent (as ethanoyl alcohol, glyceryl monostearate etc.); (h) sorbent material (as kaolin, wilkinite etc.); And/or i) lubricant (as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP etc.).Under the situation of capsule and tablet, this formulation also can comprise buffer reagent.The solid-state composition of similar type also can be used as the filler in the soft and rigid filling gelatine capsule, and it uses lactose and high molecular weight polyethylene glycol etc. as vehicle.
Can be with the solid dosage of coating or shell preparation such as tablet, dragee, capsule and particle, such as known enteric film in the pharmacy preparation field or other coatings.They also can contain opalizer, and can be this kind composition that delayed mode disengages compound of the present invention and/or additional medicaments.The example of the embedded composition that can use comprises polymerizability material and wax.If suitable, this medicine also also is the little encapsulated form with last mentioned one or more vehicle.
The liquid formulation that is used for oral administration medicine supplying comprises pharmaceutically acceptable emulsion, solution, suspension, liquid syrup and elixir.Except compound of the present invention or combination, this liquid state formulation can contain inert diluent commonly used in this area, such as water or other solvents; Solubilizing agent and emulsifying agent such as ethanol, isopropyl alcohol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3 butylene glycol, dimethyl formamide; Oils (as Oleum Gossypii semen, Peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C, sesame wet goods); Glycerine; Tetrahydrofurfuryl alcohol; The fatty acid ester of polyoxyethylene glycol and sorbitan; Or the mixture of these materials etc.
Except these inert diluents, said composition also can comprise vehicle, such as wetting agent, emulsifying agent and suspension agent, sweetener, seasonings and perfume agent.
With regard to suspension, except compound of the present invention or combination, can further contain supporting agent such as suspension agent, as ethoxylation isooctadecanol, polyoxyethylene pear oligose alcohol and dehydration pear oligose alcohol ester, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar and tragacanth gum, or the mixture of these materials etc.
The composition that is used for rectum or vaginal dosing preferably includes suppository, can prepare it by compound of the present invention or combination are mixed with non-irritating excipient that suits or supporting agent, vehicle or supporting agent such as cocoa butter, polyoxyethylene glycol or suppository wax, its general room temperature be solid-state and at body temperature for liquid, and therefore can in rectum or vagina, melt and disengage active compound.
The combination of The compounds of this invention and The compounds of this invention and diet pill is used for the formulation of topical administration, can comprise ointment, powder, spray and inhalation.This medicine can be under aseptic condition and pharmaceutically acceptable vehicle, thinner or supporting agent and needed arbitrary sanitas, buffer reagent or propellant mixing.Ophthalmic formulations, eye also are intended to be covered by in the scope of the present invention with ointment, powder and solution.
The following passage is the explanation exemplary prescription that is used for the animal beyond human, dosage etc.Can carry out the administration of the combination of The compounds of this invention or The compounds of this invention and diet pill with oral or non-oral way (as by injection).
The quantity of the combination of compound of the present invention or compound of the present invention and diet pill is given in throwing, reaches effective dose whereby.Generally speaking, offer medicine to dosage every day of animal with oral way, be between about 0.01 and about 1000 milligrams/kg body weight between, preferably between about 0.01 and about 300 milligrams/kg body weight between.
Known ground, compound of the present invention (or combination) can be inserted in the drinking-water, takes in this compound of therapeutic dose whereby in company with the drinking water supply of every day.This compound can directly measure and insert in the drinking-water, preferably with the form of liquid water-soluble concentrate (such as the aqueous solution of water-soluble salt).
Known ground, compound of the present invention (or combination) also can be added directly in the feed, or adds with the form of animal feed supplement, and also claims pre-adulterant or enriched material.Usually use the pre-adulterant or the enriched material of this compound in a vehicle, thinner or supporting agent, so that this medicament is included in the feed.According to required, suitable supporting agent is liquid or solid-state, such as water; Various meals such as root of Dahurian angelica Mu powder, analysis for soybean powder, the cottonseed dregs of fat, the Semen Lini dregs of fat, corn cob powder and Semen Maydis powder, molasses, urea, bone meal and mineral mixture are such as the dust head of institute in the poultry feed.The discrete animal-feed itself is effective especially carrier, that is a fraction of this feed.This carrier promotes this compound at this pre-adulterant uniform distribution in the final feed of fusion therewith.This compound preferably fully mixes in this pre-adulterant, mixes then in this feed.Thus, this compound can disperse or be dissolved in a kind of suitable oily supporting agent such as Oleum Glycines, Semen Maydis oil, the cottonseed wet goods; Or disperse or be dissolved in a kind of volatile organic solvent, then with this carrier fusion.To understand the ratio of this compound in this enriched material and can have difference widely, because can adjust the compound amount in this final feed by the pre-adulterant and the feed of fusion suitable proportion, and the compound level that acquisition is desired.
Feed manufacturer can be with potent enriched material and protein-based carrier such as the soya bean dregs of fat and other above-mentioned meal mixs, and produce the enriching substance that concentrates that is applicable to direct nutrition purposes, especially for feeding animals.Under these situations, the edible general diet of animal.Alternatively, can directly in feed, add these concentrated enriching substances,, wherein contain the compound of the present invention for the treatment of level of significance to produce final feed balanced in nutrition.This mixture is guaranteed uniformity by standard program such as twin shell blender mix up hill and dale.
If enriching substance is the topping or surface dressing as this feed, then to guaranteeing that the homogeneous of this compound on the surface of institute's flush coat feed distributes also for useful.
Usually a compound of the present invention is mixed with the animal-feed of capacity, in foodstuff or water, to provide about 10 -3To the compound of about 500ppm, and preparation can effectively increase the lean meat fraction of coverage and be used to promote drinking-water and the feed of lean meat with respect to the fat meat ratio.
The preferred medicated feed that is used for pig, ox, sheep and goat generally contains the compound of the present invention (or combination) of 1 to 400 gram of having an appointment in feed per ton, the optimum quantity that is used for these animals is generally about 50 to 300 grams of feed per ton.Preferred poultry and house feed for pet contain in feed per ton usually and have an appointment 1 to about 400 grams, preferred about 10 compounds of the present invention to about 400 grams (or combination).
Non-with regard to the intestines dispensings with regard to animal, compound of the present invention (or combination) can be prepared into the form of a mashed prod or a pellet and with implant form dispensing, seek to increase the lean meat fraction of coverage and promoting lean meat and implant under with respect to the head of the animal of fat meat ratio or ear skin usually.
Generally speaking, the non-dispensing through intestines relates to the compound of the present invention (or combination) that injects capacity, to provide this animal about 0.01 to about 20 milligrams of medicine/kg body weight/days.Being used for the preferred dose of poultry, pig, ox, sheep, goat and house pet, is between about 0.01 scope to about 10 milligrams of medicine/kg body weight/days.
Can be by medicine being scattered in a kind of pharmaceutically acceptable oil such as peanut oil, sesame oil, the corn wet goods, and preparation pasty state prescription.
Can pass through a compound of the present invention or combination are mixed such as carbowax, palm wax etc. with a kind of thinner, and preparation contains the pill of a compound of the present invention, pharmaceutical compositions or the combination of a significant quantity; Also can add a kind of lubricant such as Magnesium Stearate or calcium stearate, to promote the pill processing procedure.
Certainly should be appreciated that to throw for an animal and give more than one pill, will increase the lean meat fraction of coverage and promote the dosage level of being desired of lean meat with respect to the fat meat ratio to reach.Moreover, during treatment of animals, also can implant termly, to keep the intravital suitable drugs level of animal.
The present invention has several favourable veterinary science characteristics.The pet that increases the very lean degree of pet animals and/or remove too much fat meat for hope is raised main for the animal doctor, the invention provides the mode that can reach this target.With regard to raising of poultry, ox and pig is main, uses the present invention can make that the animal that is produced is comparatively very lean, and can obtain higher price from the meat industrial community.
The present invention is also contained through isotope-labeled The compounds of this invention, and except one or more atom is different from the fact that one of atomic mass common in the nature or total mass number atom replaces by atomic mass or total mass number, it is that not state the person therewith identical.Can include the isotropic substance example in the compound of the present invention in, comprise the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and chlorine, its respectively such as: 2Hydrogen, 3Hydrogen, 11Carbon, 13Carbon, 14Carbon, 13Nitrogen, 15Nitrogen, 15Oxygen, 17Oxygen, 18Oxygen, 31Phosphorus, 32Phosphorus, 35Sulphur, 18Fluorine, 123Iodine, 125Iodine reaches 36Chlorine.
Some isotope-labeled compound of the present invention (is for example used 3H and 14Those of C mark) be used for compound and/or substrate tissue distribution assays.Preferred especially tritiate (promptly 3H) and carbon-14 (promptly 14C) isotropic substance is because their preparation and detections easily.And heavier isotropic substance such as deuterium are (promptly 2H) replace some treatment advantage of being caused by bigger metabolic stability (for example the transformation period increases or the dosage demand reduces in the body) can be provided, thereby may be preferred in some cases.The positron radiation isotropic substance, for example 15O, 13N, 11C and 18F is used for positron emission tomography (PET) research, to check substrate acceptor occupancy.Isotope-labeled compound of the present invention generally can be followed and be similar in scheme and/or disclosed method among the embodiment hereinafter, prepares by substituting nonisotopically labelled reagent with isotope-labeled reagent.
Description of drawings
Fig. 1 a is the receptors bind graphic representation of Rimonabant (Rimonabant) and CB1 acceptor among Fig. 1, and Fig. 1 b is the receptors bind graphic representation of Rimonabant and CB2 acceptor;
Fig. 2 a is the receptors bind graphic representation of Compound D c-9 and CB1 acceptor among Fig. 2, and Fig. 2 b is the receptors bind graphic representation of Compound D c-9 and CB2 acceptor.
Embodiment
By the following example explanation embodiment of the present invention.Yet, should be appreciated that embodiment of the present invention are not subject to the specific detail among these embodiment, because in view of disclosure of the present invention, it is known and conspicuous making other change those of ordinary skills.
Provide following experimental example further to illustrate the present invention and will not constitute restriction to its scope.
Laboratory sample is analyzed used instrument and reagent
Nuclear magnetic resonance spectrum ( 1H NMR, 13C NMR) (solvent is CDCl by the Mercury-300 of Varian company or Mercury-400 type nmr determination 3, in be designated as TMS).LC-MS is measured by Thermo Finnigan LCQDECA * P type mass spectrograph.Fusing point is measured (thermometer reading is not calibrated) by the SGW X-4 type fusing point instrument of Shanghai Precision Scientific Apparatus Co., Ltd.The column chromatography for separation used silica gel is Haiyang Chemical Plant, Qingdao's product (200～300 order).The TLC silica-gel plate is the HSF-254 thin-layer chromatography precoated plate of Yantai Chemical Manufacture, adopts ultraviolet lamp, the colour developing of iodine cylinder.Ultraviolet lamp is the Shanghai ZF-1 of a Gu Cun electric light instrument plant type ultraviolet analysis instrument for three purposed.The raw materials used commercially available prod that is in synthetic.
Embodiment 1:
Figure A20071004164000421
A) preparation of compound 3
With sulfur oxychloride (2.5mL, 0.035mol) slowly splash into to benzhydrol (5.0g, 0.029mol) in the solution of methylene dichloride (30mL), stirring at room is after 2 hours, pressure reducing and steaming methylene dichloride and a small amount of excessive sulfur oxychloride obtain intermediate 2.This intermediate is not purified, is dissolved in 50 milliliters of acetonitriles, and (12.0g, 0.15mol), 70 ℃ of reactions are spent the night to add piperazine.Behind the pressure reducing and steaming acetonitrile, add 50 milliliters of the 1N NaOH aqueous solution, dichloromethane extraction, organic phase is after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, behind the pressure reducing and steaming solution product 3, be yellow solid 4.8g, yield 70.1%.
1H?NMR(300MHz，CDCl 3)δ7.37-7.43(m，4H)，7.13-7.29(m，6H)，4.21(s，1H)，2.90(t，J＝4.9Hz，4H)，2.38(m，4H)，2.17(br，1H)m.p.80-82℃
B) preparation of compound 4a
In parallel reactor, take by weighing compound 3 (0.20g respectively, 0.79mmol) in reaction tubes, after being dissolved in 3 milliliters of methylene dichloride, add triethylamine (0.11mL, 0.79mmol), be added dropwise to 111.4mg (0.79mmol) Benzoyl chloride under the ice bath, stirred overnight at room temperature, reaction solution is directly with 40 milliliters of dichloromethane extractions, organic layer is after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, behind the pressure reducing and steaming solvent crude product, crude product gets product through column chromatographic isolation and purification, elution requirement is a sherwood oil: ethyl acetate=10: 1～3: 1, getting compound 4a is white solid 221.3mg, yield 78.3%.
1H?NMR(300MHz，CDCl 3)δ7.16-7.43(m，15H)，4.25(s，1H)，3.79(m，2H)，3.41(m，2H)，2.48(m，2H)，2.32(m，2H)
ESI：m/z(relative?intensity)357.2(M+1，100％)，167.0m.p.140-143℃
C) preparation of compound 4b
The preparation of compound 4b is identical with the preparation method of compound 4a among the embodiment 1, and difference is in replacing Benzoyl chloride with 94mg (0.79mmol) cyclobutyl acyl chlorides, and getting compound 4b is amorphous solid 197.8mg, yield 74.6%.
1H?NMR(300MHz，CDCl 3)δ7.39-7.42(m，3H)，7.25-7.30(m，5H)，7.16-7.22(m，2H)，4.21(s，1H)，3.58-3.62(m，2H)，3.32-3.35(m，2H)，3.20(m，1H)，2.31-2.39(m，4H)，2.29(m，1H)，2.06-2.12(m，2H)，1.85-1.96(m，2H)
ESI：m/z(relative?intensity)334.9(M+1，100％)，167.0
D) preparation of compound 4c
The preparation of compound 4c is identical with the preparation method of compound 4a among the embodiment 1, and difference is in replacing Benzoyl chloride with 105mg (0.79mmol) cyclopentyl acyl chlorides, and getting compound 4c is amorphous solid 214.7mg, yield 77.7%.
1H?NMR(300MHz，CDCl 3)δ7.40-7.43(m，3H)，7.26-7.31(m，5H)，7.16-7.22(m，2H)，4.22(s，1H)，3.61-3.64(m，2H)，3.50-3.53(m，2H)，2.83(dt，J＝15.5，7.7Hz，1H)，2.35-2.39(m，4H)，1.68-1.83(m，6H)，1.51-1.60(m，2H)
ESI：m/z(relative?intensity)348.9(M+1，100％)，167.0
E) preparation of compound 4d
The preparation of compound 4d is identical with the preparation method of compound 4a among the embodiment 1, and difference is in replacing Benzoyl chloride with 116.2mg (0.79mmol) cyclohexyl acyl chlorides, and getting compound 4d is amorphous solid 226.1mg, yield 78.7%.
1H?NMR(300MHz，CDCl 3)δ7.40-7.43(m，3H)，7.25-7.31(m，5H)，7.16-7.22(m，2H)，4.21(s，1H)，3.59-3.63(m，2H)，3.47-3.51(m，2H)，2.34-2.40(m，4H)，1.60-1.79(m，6H)，1.43-1.54(m，2H)，1.21(m，2H)
ESI：m/z(relative?intensity)362.9(M+1，100％)，167.0
F) preparation of compound 4e
The preparation of compound 4e is identical with the preparation method of compound 4a among the embodiment 1, and difference is in replacing Benzoyl chloride with 116mg (0.70mmol) piperidine formyl chloro, and getting compound 4e is amorphous solid 223.60mg, yield 77.6%.
1H?NMR(300MHz，CDCl 3)δ7.40-7.42(m，3H)，7.25-7.30(m，5H)，7.16-7.20(m，2H)，4.22(s，1H)，3.23-3.26(m，4H)，3.14-3.17(m，4H)，2.36-2.39(m，4H)，1.47-1.58(m，6H)
ESI：m/z(relative?intensity)364.0(M+1，100％)，167.0
G) preparation of compound 4f
The preparation of compound 4f is identical with the preparation method of compound 4a among the embodiment 1, and difference is in replacing Benzoyl chloride with 118mg (0.70mmol) morpholine formyl chloride, and getting compound 4f is amorphous solid 215.5mg, yield 74.4%.
1H?NMR(300MHz，CDCl 3)δ7.39-7.42(m，3H)，7.25-7.31(m，5H)，7.16-7.21(m，2H)，4.23(s，1H)，3.63-3.66(m，4H)，3.27-3.30(m，4H)，3.21-3.24(m，4H)，2.37-2.40(m，4H)
ESI：m/z(relative?intensity)366.0(M+1，100％)，167.0。
Embodiment 2:
A) preparation of compound 5a
In parallel reactor, take by weighing the compound 3 (0.10g among the embodiment 1 respectively, 0.40mmol) in reaction tubes, be dissolved in 3 milliliters of tetrahydrofuran (THF)s after, add the different sulphur nitrile of 59.1mg (0.40mmol) benzyl acid esters, stirred overnight at room temperature, get crude product in the pressure reducing and steaming reaction solution behind the tetrahydrofuran (THF), crude product is through column chromatographic isolation and purification, and elution requirement is a sherwood oil: ethyl acetate=10: 1～3: 1, getting product is white solid 121.7mg, yield 76.5%.
1H?NMR(300MHz，CDCl 3)δ7.19-7.42(m，15H)，4.85(d，J＝4.4Hz，2H)，4.25(s，1H)，3.79-3.82(m，4H)，2.45(m，4H)
ESI：m/z(relative?intensity)402.1(M+1，100％)，167.1
m.p.141～143℃
B) preparation of compound 5b
The preparation of compound 5b is identical with the preparation method of compound 5a among the embodiment 2, and difference is in replacing the different sulphur nitrile of benzyl acid esters with the different sulphur nitrile of 56mg (0.40mmol) cyclohexyl acid esters, and getting product is white solid 116.4mg, yield 74.6%.
1H?NMR(300MHz，CDCl 3)δ7.17-7.42(m，10H)，4.34(m，1H)，4.24(s，1H)，3.75-3.79(m，4H)，2.42-2.46(m，4H)，2.05-2.11(m，2H)，1.66-1.72(m，2H)，1.34-1.46(m，2H)，1.10-1.17(m，4H)
ESI：m/z(relative?intensity)394.1(M+1，100％)，167.1
m.p.154～155℃
C) preparation of compound 5c
The preparation of compound 5c is identical with the preparation method of compound 5a among the embodiment 2, and difference is in replacing the different sulphur nitrile of benzyl acid esters with the different sulphur nitrile of 53.6mg (0.40mmol) phenyl acid esters, and getting product is white solid 126.5mg, yield 82.4%.
1H?NMR(300MHz，CDCl 3)δ7.05-7.41(m，15H)，4.24(s，1H)，3.81(m，4H)，2.44(m，4H)
ESI：m/z(relative?intensity)388.0(M+1，100％)，167.1
m.p.213-215℃
D) preparation of compound 5d
The preparation of compound 5d is identical with the preparation method of compound 5a among the embodiment 2, and difference is in 59.1mg (0.40mmol) the different sulphur nitrile of methylbenzene acid esters being replaced the different sulphur nitrile of benzyl acid esters, and getting product is white solid 124.2mg, yield 78.1%.
1H?NMR(300MHz，CDCl 3)δ6.96-7.41(m，14H)，4.24(s，1H)，3.79-3.82(m，4H)，2.43-2.46(m，4H)，2.31(s，3H)
ESI：m/z(relative?intensity)402.0(M+1，100％)，167.1
m.p.166～167℃
E) preparation of compound 5e
The preparation of compound 5e is identical with the preparation method of compound 5a among the embodiment 2, and difference is in using the different sulphur nitrile of the different sulphur nitrile of methylbenzene acid esters replacement benzyl acid esters between 59.1mg (0.40mmol), and getting product is white solid 128.8mg, yield 81%.
1H?NMR(300MHz，CDCl 3)δ6.87-7.41(m，14H)，4.24(s，1H)，3.78-3.81(m，4H)，2.42-2.46(m，4H)，2.31(s，3H)
ESI：m/z(relative?intensity)402.0(M+1，100％)，167.1
m.p.171～173℃
F) preparation of compound 5f
The preparation of compound 5f is identical with the preparation method of compound 5a among the embodiment 2, and difference is in replacing the different sulphur nitrile of benzyl acid esters with the different sulphur nitrile of 59.1mg (0.40mmol) o-methyl-benzene acid esters, and getting product is white solid 131.9mg, yield 82.9%.
1H?NMR(300MHz，CDCl 3)δ6.87-7.41(m，14H)，4.23(s，1H)，3.77(m，4H)，2.43(m，4H)，2.22(s，3H)
ESI：m/z(relative?intensity)402.0(M+1，100％)，167.1
m.p.208～210℃
G) preparation of compound 5g
The preparation of compound 5g is identical with the preparation method of compound 5a among the embodiment 2, and difference is in replacing the different sulphur nitrile of benzyl acid esters with the different sulphur nitrile of 71.4mg (0.40mmol) 4-oil of mirbane acid esters, and getting product is yellow solid 106.5mg, yield 62.1%.
1H?NMR(300MHz，CDCl 3)δ8.17(d，J＝8.8Hz，2H)，7.20-7.42(m，12H)，4.27(s，1H)，3.88(m，4H)，2.50(m，4H)
ESI：m/z(relative?intensity)432.9(M+1，100％)，167.1
m.p.111～113℃
H) preparation of compound 5h
The preparation of compound 5h is identical with the preparation method of compound 5a among the embodiment 2, and difference is in replacing the different sulphur nitrile of benzyl acid esters with the different sulphur nitrile of 65.5mg (0.40mmol) 4-anisole acid esters, and getting product is white solid 137.8mg, yield 83.3%.
1H?NMR(300MHz，CDCl 3)δ6.86-7.39(m，14H)，4.24(s，1H)，3.80(m，4H)，3.79(s，3H)，2.45(m，4H)
ESI：m/z(relative?intensity)417.0(M+1，100％)，167.1
m.p.160～161℃。
Embodiment 3:
Figure A20071004164000471
A) preparation of compound 6a
In parallel reactor, take by weighing compound 3 (0.10g respectively, 0.4mmol) in reaction tubes, be dissolved in 3 milliliters of tetrahydrofuran (THF)s after, add 52.8mg (0.4mmol) benzyl isocyanide ester after, stirred overnight at room temperature, pressure reducing and steaming reaction solution tetrahydrofuran (THF) gets crude product, and crude product is through column chromatographic isolation and purification, and elution requirement is a sherwood oil: ethyl acetate=10: 1～3: 1, getting product is white solid 116.4mg, yield 76.2%.
1H?NMR(300MHz，CDCl 3)δ7.16-7.43(m，15H)，4.42(d，J＝5.5Hz，2H)，4.22(s，1H)，3.38(m，4H)，2.38(m，4H)
ESI：m/z(relative?intensity)386.0(M+1，100％)，167.1
m.p.166-168℃
B) preparation of compound 6b
The preparation of compound 6b is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 57.1mg (0.4mmol) 4-itrile group benzene isocyanide ester, and getting product is white solid 93.6mg, yield 59.6%.
1H?NMR(300MHz，CDCl 3)δ7.14-7.56(m，19H)，4.27(s，1H)，3.49-3.53(m，4H)，2.43-2.47(m，4H)
ESI：m/z(relative?intensity)396.9(M+1，100％)，167.1
m.p.209-211℃
C) preparation of compound 6c
The preparation of compound 6c is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 54.3mg (0.4mmol) 3-fluorobenzene isocyanide ester, and getting product is white solid 114.0mg, yield 73.9%.
1H?NMR(300MHz，CDCl 3)δ7.15-7.43(m，14H)，4.26(s，1H)，3.47-3.51(m，4H)，2.43-2.46(m，4H)
ESI：m/z(relative?intensity)778.8(2M+1，100％)，389.9(M+1)，167.1
m.p.227-228℃
D) preparation of compound 6d
The preparation of compound 6d is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 60.9mg (0.4mmol) 2-chlorobenzene isocyanide ester, and getting product is white solid 99.1mg, yield 61.6%.
1H?NMR(300MHz，CDCl 3)δ6.91-7.44(m，14H)，4.27(s，1H)，3.53-3.56(m，4H)，2.45-2.49(m，4H)
ESI：m/z(relative?intensity)810.6(2M+1，100％)，405.9(M+1)，167.1
m.p.143-145℃
E) preparation of compound 6e
The preparation of compound 6e is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 60mg (0.4mmol) 2-methyl-5-fluorobenzene isocyanide ester, and getting product is white solid 101.2mg, yield 63.3%.
1H?NMR(300MHz，CDCl 3)δ7.04-7.44(m，13H)，4.26(s，1H)，3.49-3.52(m，4H)，2.44-2.47(m，4H)，2.15(s，3H)
ESI：m/z(relative?intensity)806.7(2M+1，100％)，404.0(M+1)，167.1
m.p.207-209℃
F) preparation of compound 6f
The preparation of compound 6f is identical with the preparation method of compound 6a among the embodiment 3, and difference is in using 64.6mg (0.4mmol) 3, and 4-methylenedioxy benzene isocyanide ester replaces the benzyl isocyanide ester, and getting product is white solid 120.7mg, yield 73.3%.
1H?NMR(300MHz，CDCl 3)δ7.03-7.44(m，13H)，5.92(s，2H)，4.26(s，1H)，3.45-3.48(m，4H)，2.42-2.45(m，4H)
ESI：m/z(relative?intensity)830.7(2M+1，100％)，416.0(M+1)，167.1
m.p.237-239℃
G) preparation of compound 6g
The preparation of compound 6g is identical with the preparation method of compound 6a among the embodiment 3, and difference is in using 58.3mg (0.4mmol) 2, and 3-dimethyl benzene isocyanide ester replaces the benzyl isocyanide ester, and getting product is white solid 103.3mg, yield 65.3%.
1H?NMR(300MHz，CDCl 3)δ6.92-7.44(m，13H)，4.26(s，1H)，3.47-3.50(m，4H)，2.43-2.46(m，4H)，2.27(s，3H)，2.11(s，3H)
ESI：m/z(relative?intensity)798.9(2M+1，100％)，400.0(M+1)，167.1
m.p.235-237℃
H) preparation of compound 6h
The preparation of compound 6h is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 59.1mg (0.4mmol) 3-anisole isocyanide ester, and getting product is white solid 119.8mg, yield 75.3%.
1H?NMR(300MHz，CDCl 3)δ7.12-7.44(m，14H)，4.26(s，1H)，3.78(s，3H)，3.47-3.51(m，2H)，2.43-2.46(m，2H)
ESI：m/z(relative?intensity)802.8(2M+1，100％)，402.0(M+1)，167.1
m.p.213-215℃
I) preparation of compound 6i
The preparation of compound 6i is identical with the preparation method of compound 6a among the embodiment 3, and difference is in using 54.7mg (0.4mmol) 3, and 5-dimethyl isoxazole-4-isocyanide ester replaces the benzyl isocyanide ester, and getting product is white solid 116.0mg, yield 75%.
1H?NMR(300MHz，CDCl 3)δ7.18-7.44(m，10H)，4.27(s，1H)，3.45-3.49(m，4H)，2.43-2.46(m，4H)，2.28(s，3H)，2.15(s，3H)
ESI：m/z(relative?intensity)390.9(M+1，100％)，167.1
m.p.232-233℃
J) preparation of compound 6j
The preparation of compound 6j is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 83.7mg (0.4mmol) 9H-2-fluorenes isocyanide ester, and getting product is white solid 124.2mg, yield 67.6%.
1H?NMR(300MHz，CDCl 3)δ7.20-7.71(m，17H)，4.27(s，1H)，3.86(s，2H)，3.52(m，4H)，2.46(m，2H)
ESI：m/z(relative?intensity)918.9(2M+1，100％)，460.0(M+1)，167.1
m.p.231-233℃
K) preparation of compound 6k
The preparation of compound 6k is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 78.8mg (0.4mmol) 1H-1-Methylimidazole-5-isocyanide ester, and getting product is white solid 94.9mg, yield 63.8%.
1H?NMR(300MHz，CDCl 3)δ7.19-7.40(m，12H)，4.33(s，1H)，3.22(m，4H)，2.72(m，4H)，1.58(s，3H)
ESI：m/z(relative?intensity)750.8(2M+1，100％)，375.9(M+1)，167.1
m.p.200-203℃
L) preparation of compound 6l
The preparation of compound 6l is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 47.6mg (0.4mmol) 3-pyridine isocyanide ester, and getting product is white solid 91.5mg, yield 62%.
1H?NMR(300MHz，CDCl 3)δ8.45(d，J＝2.2Hz，1H)，8.24(dd，J＝4.8，0.7Hz，1H)，8.02(m，1H)，7.18-7.44(m，11H)，4.27(s，1H)，3.51-3.55(m，4H)，2.44-2.47(m，4H)
ESI：m/z(relative?intensity)744.7(2M+1，100％)，373(M+1)，167.1
m.p.189-191℃
M) preparation of compound 6m
The preparation of compound 6m is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 63.9mg (0.4mmol) 5-indane isocyanide ester, and getting product is white solid 129.4mg, yield 79%.
1H?NMR(300MHz，CDCl 3)δ6.99-7.44(m，13H)，4.26(s，1H)，3.47-3.50(m，4H)，2.85(m，4H)，2.42-2.46(m，4H)，2.05(ddd，J＝14.5，7.1，7.0Hz，2H)
ESI：m/z(relative?intensity)822.9(2M+1，100％)，412.0(M+1)，167.1
m.p.221-223℃
N) preparation of compound 6n
The preparation of compound 6n is identical with the preparation method of compound 6a among the embodiment 3, and difference is in replacing the benzyl isocyanide ester with 39.3mg (0.4mmol) butyl isocyanide ester, and getting product is white solid 118.1mg, yield 84.8%.
1H?NMR(300MHz，CDCl 3)δ7.40-7.43(m，3H)，7.25-7.30(m，5H)，7.16-7.21(m，2H)，4.22(s，1H)，3.33-3.36(m，4H)，3.21(td，J＝7.0，5.6Hz，1H)，2.36-2.39(m，4H)，1.42-1.52(m，2H)，1.26-1.39(m，2H)，0.91(t，J＝7.3Hz，3H)
ESI：m/z(relative?intensity)352.0(M+1，100％)，167.0
Embodiment 4:
Present embodiment is as follows provide synthetic a series of have in general formula (I) structure unsubstituted on the piperazine ring (R '=R "=H) general synthetic route, wherein R 1, R 2, V, W described as defined above.
Figure A20071004164000521
The series A compound synthesizes general routes outlined:
In three-necked bottle, on prolong is housed, dropping funnel, insert under argon atmospher with respect to the aldehyde mol ratio with general formula 7 is 1.3 magnesium chips and a granule iodine, after to be added dropwise to respect to the aldehyde mol ratio with general formula 7 be 1.1 the bromo aromatic hydrocarbon with general formula 8 solution at anhydrous tetrahydro furan, grignard reaction causes back control reaction and slowly refluxes, drip to finish and to react reflux after 30 minutes, be added dropwise to the solution of aldehyde in tetrahydrofuran (THF) after the ice bath cooling with general formula 7, drip to finish and to react reflux after 30 minutes, add the reaction of going out of ammonium chloride saturated aqueous solution essence, reaction solution extracted with diethyl ether 3 times, ether layer is after water and saturated brine are respectively washed once respectively, it is the series A compound that anhydrous sodium sulfate drying, evaporated under reduced pressure get product, and product need not purifying can directly carry out next step reaction.
Compd A-1:1,1-(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2,4 dichloro benzene formaldehyde and para chlorobromobenzene, and experiment condition is with above-mentioned general synthetic route, down together;
1H?NMR(300MHz，CDCl 3)δ7.55(d，J＝8.4Hz，1H)，7.37(d，J＝2.2Hz，1H)，7.31(m，2H)，7.28-7.29(m，1H)，7.26(m，2H)，6.15(s，1H)
Compd A-2:1,1-phenyl (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2,4 dichloro benzene formaldehyde and bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.59(d，J＝8.4Hz，1H)，7.26-7.38(m，9H)，6.16(d，J＝3.7Hz，1H)
Compd A-3:1,1-(4-p-methoxy-phenyl) (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2,4 dichloro benzene formaldehyde and to the methoxyl group bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.62(d，J＝8.4Hz，1H)，7.33(d，J＝2.0Hz，1H)，7.25-7.31(m，3H)，6.84-6.86(m，2H)，6.09(d，J＝3.3Hz，1H)，3.78(s，3H)
Compd A-4:1,1-(4-trifluoromethyl) (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2,4 dichloro benzene formaldehyde and to methyl bromobenzene trifluoride;
1H?NMR(300MHz，CDCl 3)δ7.59-7.61(m，2H)，7.49-7.52(m，3H)，7.38(d，J＝2.0Hz，1H)，7.30(dd，J＝8.4，2.2Hz，1H)，6.24(d，J＝3.7Hz，1H)
Compd A-5:1,1-(4-Phenoxyphenyl) (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2,4 dichloro benzene formaldehyde and 4-phenoxy group bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.61(d，J＝8.3Hz，1H)，7.28-7.35(m，6H)，7.10(m，1H)，6.98-7.02(m，2H)，6.93-6.97(m，2H)，6.13(d，J＝3.3Hz，1H)
Compd A-6:1,1-(3-chloro-phenyl-) (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2,4 dichloro benzene formaldehyde and 3-chloro-bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.52(d，J＝8.4Hz，1H)，7.36(m，2H)，7.22-7.30(m，4H)，6.12(s，1H)
Compd A-7:1,1-(4-aminomethyl phenyl) (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2,4 dichloro benzene formaldehyde and 4-methyl bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.60(d，J＝8.4Hz，1H)，7.33(d，J＝2.1Hz，1H)，7.22-7.30(m，3H)，7.12-7.15(m，2H)，6.10(s，1H)，2.32(s，3H)
Compd A-8:1,1-(3-cyano-phenyl) (4-chloro-phenyl-) methyl alcohol
Reaction raw materials 7 and 8 is respectively 3-cyanobenzaldehyde and 4-chloro-bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.67(s，1H)，7.53-7.59(m，2H)，7.41-7.46(m，1H)，7.26-7.34(m，4H)，5.81(s，1H)
Compd A-9:1,1-(2-trifluoromethyl) (4-chloro-phenyl-) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2-trifluoromethylated benzaldehyde and 4-chloro-bromobenzene;
Compd A-10:1,1-phenyl (3, the 4-dichlorophenyl) methyl alcohol
Reaction raw materials 7 and 8 is respectively 3, the 4-dichlorobenzaldehyde and and bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.49(d，J＝1.6Hz，1H)，7.29-7.39(m，6H)，7.17(m，1H)，5.74(s，1H)
Compd A-11:1,1-phenyl (2, the 5-dichlorophenyl) methyl alcohol
Reaction raw materials 7 and 8 is respectively 2, the 5-dichlorobenzaldehyde and and bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.67(d，J＝2.5Hz，1H)，7.16-7.37(m，7H)，6.11(s，1H)
Compd A-12:1,1-phenyl (2-fluoro-4-bromophenyl) methyl alcohol
Reaction raw materials 7 and 8 be respectively 2-fluoro-4-bromobenzaldehyde and and bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.42(t，J＝8.1Hz，1H)，7.23-7.38(m，6H)，7.19(dd，J＝9.7，1.8Hz，1H)，6.06(s，1H)
Compd A-13:1,1-phenyl (2-chloro-6-chloro-phenyl-) methyl alcohol
Reaction raw materials 7 and 8 be respectively 2-chloro-6-chlorobenzaldehyde and and bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.25-7.35(m，7H)，7.21(dd，J＝8.5，7.4Hz，1H)，6.65(d，J＝10.6Hz，1H)
Compd A-14:1,1-phenyl (2-chloro-4-fluorophenyl) methyl alcohol
Reaction raw materials 7 and 8 be respectively 2-chloro-4-fluorobenzaldehyde and and bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.58(dd，J＝8.7，6.1Hz，1H)，7.25-7.37(m，5H)，7.08(dd，J＝8.4，2.6Hz，1H)，7.01(td，J＝8.3，2.6，1H)，6.16(d，J＝2.9Hz，1H)
Compd A-15:1,1-phenyl (2-fluoro-4-chloro-phenyl-) methyl alcohol
Reaction raw materials 7 and 8 be respectively 2-fluoro-4-chlorobenzaldehyde and and bromobenzene;
1H?NMR(300MHz，CDCl 3)δ7.47(t，J＝8.2Hz，1H)，7.25-7.38(m，6H)，7.14(dd，J＝8.2，2.3Hz，1H)，7.04(dd，J＝10.0，2.1Hz，1H)，6.07(s，1H)
Compd A-16:1,1-(4-fluorophenyl) (2,4 dichloro benzene base) methyl alcohol
Reaction raw materials 7 and 8 be respectively 2,4 dichloro benzene formaldehyde and and the 4-bromofluorobenzene;
1H?NMR(300MHz，CDCl 3)δ7.57(d，J＝8.4Hz，1H)，7.28-7.36(m，4H)，7.00-7.04(m，2H)，6.14(s，1H)
The synthetic general routes outlined of series B compound:
With the compound in the series A, be respectively compd A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, after A-16 is dissolved in methylene dichloride, the adding mol ratio is 1.2 sulfur oxychloride, room temperature or heated and stirred are after 2 hours, finish through the thin-layer chromatography detection reaction, behind pressure reducing and steaming methylene dichloride and the excessive chlorination sulfone product is a compound among the serial B, be respectively B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, product need not purifying can directly carry out next step reaction.
The synthetic general routes outlined of series C compound:
With each compound dissolution among the serial B in acetonitrile, it is behind 5.0 the Piperazine anhydrous that ice bath adds down mol ratio, spend the night in 70 ℃ of reactions, the pressure reducing and steaming acetonitrile, after residuum adds aqueous sodium carbonate, with ethyl acetate extraction 2 times, after the aqueous hydrochloric acid of 1mol/L is added in the above-mentioned ethyl acetate solution, make product be dissolved to water, after this water is washed 2 times with ethyl acetate again, with 6mol/L aqueous sodium hydroxide solution adjust pH is about 10, and water merges organic phase with behind the dichloromethane extraction 2 times, organic phase is after water and saturated brine are respectively washed once respectively, it is respective compound among the serial C that anhydrous sodium sulfate drying, pressure reducing and steaming solvent get product, and product need not purifying can directly carry out next step reaction.
Compound C-1:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, and 1-(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl chloride obtains with excessive piperazine reaction, and experiment condition is with above-mentioned general synthetic route, down together;
1H?NMR(400MHz，CDCl 3)δ7.71(d，J＝8.4Hz)，7.23-7.36(m，6H)，4.71(s，1H)，2.85-2.88(m，4H)，2.29-2.38(m，4H)
ESI：m/z(relative?intensity)354.9(M+1，100％)，269.0
Compound C-2:1-[phenyl (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-phenyl (2,4 dichloro benzene base) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.73(dd，J＝12.5，8.4Hz，1H)，7.17-7.39(m，7H)，4.83(s，1H)，3.10(m，2H)，2.60(m，2H)，2.49(m，2H)，2.37(m，2H)
ESI：m/z(relative?intensity)320.9(M+1，100％)，235.0
Compound C-3:1-[(4-p-methoxy-phenyl) (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(4-p-methoxy-phenyl) (2, the 4-chloro-phenyl-) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.72(dd，J＝17.1，8.3Hz，1H)，7.21-7.30(m，4H)，6.78-6.82(m，2H)，4.78(s，1H)，3.76(s，3H)，3.14(m，2H)，2.63(m，2H)，2.52(m，2H)，2.37(m，2H)
ESI：m/z(relative?intensity)350.8(M+1，100％)，265.0
Compound C-4:1-[(4-trifluoromethyl) (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(4-trifluoromethyl) (2,4 dichloro benzene base) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.70(dd，J＝8.4，6.2Hz，1H)，7.52-7.54(m，3H)，7.31(dd，J＝5.6，2.1Hz，1H)，7.23-7.27(m，2H)，4.84(s，1H)，2.92-2.95(m，2H)，2.36-2.49(m，4H)，2.00(m，2H)
ESI：m/z(relative?intensity)388.9(M+1，100％)，303.0
Compound C-5:1-[(4-Phenoxyphenyl) (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(4-Phenoxyphenyl) (2,4 dichloro benzene base) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.74(m，1H)，7.29-7.34(m，5H)，7.25(m，1H)，7.09(m，1H)，6.96-6.99(m，2H)，6.87-6.90(m，2H)，4.75(s，1H)，2.97-3.00(m，2H)，2.36-2.47(m，6H)
ESI：m/z(relative?intensity)412.8(M+1，100％)，327.1
Compound C-6:1-[(3-chloro-phenyl-) (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(3-chloro-phenyl-) (2,4 dichloro benzene base) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.67(dd，J＝8.5，4.8Hz，1H)，7.37(m，1H)，7.25-7.33(m，3H)，7.18-7.23(m，2H)，4.81(s，1H)，3.07(t，J＝4.9Hz，2H)，2.55(m，2H)，2.49(m，2H)，2.36(m，2H)
ESI：m/z(relative?intensity)354.9(M+1，100％)，271.0
Compound C-7:1-[(4-aminomethyl phenyl) (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(4-aminomethyl phenyl) (2,4 dichloro benzene base) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.73(dd，J＝13.5，8.4Hz，1H)，7.20-7.30(m，4H)，7.05-7.10(m，2H)，4.69(s，1H)，3.16(m，2H)，2.65(m，2H)，2.52(m，2H)，2.38(m，2H)
ESI：m/z(relative?intensity)334.9(M+1，100％)，249.0
Compound C-8:1-[(3-cyano-phenyl) (4-chloro-phenyl-) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(3-cyano-phenyl) (4-chloro-phenyl-) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.69(m，1H)，7.60(m，1H)，7.50(m，1H)，7.41(m，1H)，7.27-7.29(m，4H)，4.26(s，1H)，3.19(m，2H)，2.66(m，2H)，2.58(m，2H)，2.38(m，2H)
ESI：m/z(relative?intensity)311.9(M+1，100％)，226.0
Compound C-9:1-[(2-trifluoromethyl) (4-chloro-phenyl-) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(2-trifluoromethyl) (4-chloro-phenyl-) methyl chloride;
Compound C-10:1-[phenyl (3, the 4-dichlorophenyl) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-phenyl (3, the 4-dichlorophenyl) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.51(m，1H)，7.18-7.36(m，7H)，4.21(s，1H)，2.97-3.00(m，2H)，2.35-2.46(m，6H)
ESI：m/z(relative?intensity)320.9(M+1，100％)，235.0
Compound C-11:1-[phenyl (2, the 5-dichlorophenyl) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-phenyl (2, the 5-dichlorophenyl) methyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.83(d，J＝2.6Hz，1H)，7.40-7.42(m，2H)，7.26-7.30(m，3H)，7.19-7.23(m，2H)，7.09(dd，J＝8.5，2.7Hz，1H)，4.73(s，1H)，2.88-2.90(m，4H)，2.36(br，4H)
ESI：m/z(relative?intensity)320.9(M+1，100％)，234.9
Compound C-12:1-[phenyl (2-fluoro-4-bromophenyl) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-phenyl (2-fluoro-4-bromophenyl) methyl chloride methane;
1H?NMR(300MHz，CDCl 3)δ7.53(m，1H)，7.35-7.39(m，2H)，7.18-7.29(m，4H)，7.14(dd，J＝9.6，1.9Hz，1H)，4.60(s，1H)，2.88-2.91(m，4H)，2.37(br?s，4H)
ESI：m/z(relative?intensity)348.9(M+1，100％)，265.0
Compound C-13:1-[phenyl (2, the 6-dichlorophenyl) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-phenyl (2, the 6-dichlorophenyl) methyl chloride methane;
Compound C-14:1-[phenyl (2-chloro-4-fluorophenyl) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-phenyl (2-chloro-4-fluorophenyl) methyl chloride methane;
1H?NMR(300MHz，CDCl 3)δ7.79(dd，J＝8.8，6.4Hz，1H)，7.38-7.42(m，2H)，7.24-7.29(m，2H)，7.20(m，1H)，6.96-7.04(m，2H)，4.75(s，1H)，2.87-2.89(m，4H)，2.36(br?m，4H)
ESI：m/z(relative?intensity)304.9(M+1，100％)，219.0
Compound C-15:1-[phenyl (2-fluoro-4-chloro-phenyl-) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-phenyl (2-fluoro-4-chloro-phenyl-) methyl chloride methane;
1H?NMR(300MHz，CDCl 3)δ7.58(t，J＝8.1Hz，1H)，7.36-7.39(m，2H)，7.19-7.30(m，4H)，7.11(dd，J＝8.1，1.8Hz，1H)，7.00(dd，J＝9.9，2.2Hz，1H)，4.63(s，1H)，2.92-2.94(m，4H)，2.41(br?m，4H)
ESI：m/z(relative?intensity)304.9(M+1，100％)，219.0
Compound C-16:1-[(4-fluorophenyl) (2,4 dichloro benzene base) methyl] piperazine
Reaction raw materials is from 1 of serial B compound, 1-(4-fluorophenyl) (2,4 dichloro benzene base) methyl chloride methane;
1H?NMR(300MHz，CDCl 3)δ7.73(d，J＝8.4Hz，1H)，7.34-7.38(m，2H)，7.30(d，J＝2.2Hz，1H)，7.25(m，1H)，6.94-6.98(m，2H)，4.72(s，1H)，2.86-2.89(m，4H)，2.34(m，4H)
ESI：m/z(relative?intensity)338.9(M+1，100％)，253.0
The synthetic general routes outlined of series D compound:
According to the structure of serial D compound, following several situation is arranged respectively, when V is C=O, when W is direct key, or V is SO 2, when W is direct key, be the Da compounds; When V is C=O, when W is the nitrogen-atoms that replaces, be the Db compounds; When V is C=S, when W is the nitrogen-atoms that replaces, be the Dc compounds.
Respectively the synthetic of these several compounds is exemplified below:
The synthetic route of Da compounds:
In parallel reactor, compound among the weighing series C is in reaction tubes respectively, after being dissolved in 3 milliliters of methylene dichloride, adding and serial C compound mol ratio are 1.0 triethylamine respectively, be added dropwise to after serial C compound mol ratio is the acyl chlorides and urea chloride or SULPHURYL CHLORIDE of 1.0 different replacements stirred overnight at room temperature under the ice bath.Reaction solution is directly with 40 milliliters of dichloromethane extractions, organic layer is after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, behind the pressure reducing and steaming solvent crude product, crude product gets product through column chromatographic isolation and purification, and elution requirement is a sherwood oil: ethyl acetate=10: 1～3: 1.
Compound D a-1:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-(cyclobutyl acyl group) piperazine
Reaction raw materials is respectively Compound C-1 and cyclobutyl acyl chlorides, and experiment condition is with above-mentioned general synthetic route, down together;
1H?NMR(300MHz，CDCl 3)δ7.80(m，1H)，7.30-7.44(m，6H)，4.81(s，1H)，3.66(m，2H)，3.39(m，2H)，3.11(m，1H)，2.26-2.38(m，4H)，2.09-2.13(m，2H)，1.24-1.28(m，2H)，0.88(m，2H)
ESI：m/z(relative?intensity)436.9(M+1，100％)，269.0
Compound D a-2:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-(cyclopentyl acyl group) piperazine
Reaction raw materials is respectively Compound C-1 and cyclopentyl acyl chlorides;
1H?NMR(300MHz，CDCl 3)δ7.76(m，1H)，7.28-7.35(m，6H)，4.81(s，1H)，3.63(m，2H)，2.83(m，1H)，2.40(m，2H)，1.73-1.81(m，4H)，1.53-1.59(m，4H)，1.26(m，2H)，0.86(m，2H)
13C?NMR(CDCl 3)δ174.47，138.62，137.87，134.31，133.33×2，129.58×3，129.48，128.86×2，127.72，69.17，52.07(CH 2)，51.58(CH 2)，45.46(CH 2)，41.75(CH 2)，40.92，30.05(CH 2)，30.01(CH 2)，26.00(2×CH 2)
ESI：m/z(relative?intensity)450.9(M+1，100％)，271.0
Compound D a-3:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-1 and cyclohexyl acyl chlorides;
1H?NMR(300MHz，CDCl 3)δ7.71(m，1H)，7.28-7.35(m，6H)，4.74(s，1H)，3.59(m，2H)，3.48(m，2H)，2.36-2.40(m，5H)，1.79(m，2H)，1.62-1.70(m，2H)，1.45-1.57(m，4H)，1.22(m，2H)
13C?NMR(CDCl 3)δ174.49，138.58，137.84，134.29，133.32×2，129.57×3，129.47，128.86×2，127.70，69.16，52.18(CH 2)，51.59(CH 2)，45.35(CH 2)，41.50(CH 2)，40.37，29.33(2×CH 2)，29.29，25.80(2×CH 2)
ESI：m/z(relative?intensity)464.9(M+1，100％)，271.0
Compound D a-4:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-(diamantane acyl group) piperazine
Reaction raw materials is respectively Compound C-1 and diamantane acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ7.72(d，J＝8.5Hz，1H)，7.31-7.36(m，3H)，7.24-7.27(m，3H)，4.71(s，1H)，3.66-3.69(m，4H)，2.31-2.41(m，4H)，1.96-2.00(m，7H)，1.63-1.73(m，5H)，1.24-1.28(m，1H)，0.83-0.90(m，2H)
ESI：m/z(relative?intensity)517.0(M+1，100％)，271.1
Compound D a-5:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-piperidines-1-acyl piperazine
Reaction raw materials is respectively Compound C-1 and piperidine formyl chlorine;
1H?NMR(300MHz，CDCl 3)δ7.71(d，J＝8.1Hz，1H)，7.24-7.36(m，6H)，4.74(s，1H)，3.21-3.24(m，4H)，3.16-3.18(m，4H)，2.38(m，4H)，1.54(m，6H)
ESI：m/z(relative?intensity)466.0(M+1，100％)，269.0
Compound D a-6:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-morpholine-4-acyl piperazine reaction raw materials is respectively Compound C-1 and morpholine formyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.28-7.88(m，7H)，4.75(m，1H)，3.63-3.66(m，6H)，3.26(m，8H)，2.38(m，2H)
ESI：m/z(relative?intensity)467.9(M+1，100％)，271.0
Compound D a-7:1-[(phenyl) (2,4 dichloro benzene base) methyl]-4-(cyclobutyl acyl group) piperazine reaction raw materials is respectively Compound C-2 and cyclobutyl acyl chlorides;
1H?NMR(300MHz，CDCl 3)δ7.76(m，1H)，7.22-7.41(m，7H)，4.75(s，1H)，3.58(m，2H)，3.33(m，2H)，3.20(m，1H)，2.27-2.38(m，6H)，2.09-2.12(m，2H)，1.83-1.94(m，2H)
ESI：m/z(relative?intensity)402.9(M+1，100％)，235.0
Compound D a-8:1-[(phenyl) (2,4 dichloro benzene base) methyl]-4-(cyclopentyl acyl group) piperazine reaction raw materials is respectively Compound C-2 and cyclopentyl acyl chlorides;
1H?NMR(300MHz，CDCl 3)δ7.76(d，J＝8.0Hz，1H)，7.25-7.40(m，7H)，4.76(s，1H)，3.62(m，2H)，3.51(m，2H)，2.81-2.86(m，1H)，2.33-2.42(m，4H)，1.69-1.77(m，4H)，1.2-1.61(m，4H)
ESI：m/z(relative?intensity)416.9(M+1，100％)，235.0
Compound D a-9:1-[(phenyl) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine reaction raw materials is respectively Compound C-2 and cyclohexyl acyl chlorides;
1H?NMR(300MHz，CDCl 3)δ7.77(d，J＝8.1Hz，1H)，7.22-7.41(m，7H)，4.75(s，1H)，3.59(m，2H)，3.48(m，2H)，2.38(m，5H)，1.79(m，2H)，1.67-1.71(m，4H)，1.48-1.52(m，2H)，1.22(m，2H)
13C?NMR(CDCl 3)δ174.44，140.01，138.37，134.35，133.02，129.63，129.48，128.63×2，128.29×2，127.57×2，69.85，52.23(CH 2)，51.65(CH 2)，45.40(CH 2)，41.53(CH 2)，40.36，29.34(CH 2)，29.29(CH 2)，25.81(3×CH 2)
ESI：m/z(relative?intensity)430.9(M+1，100％)，235.0
LRMS(EI，70eV)：m/z?430[M +]，395，353，319，290，276，235，199，165，154，83，55
HRMS(EI)m/z?calcd?for?C 24H 28Cl 2N 2O，430.1579；found，430.1581.
Compound D a-10:1-[(phenyl) (2,4 dichloro benzene base) methyl]-4-(diamantane acyl group) piperazine
Reaction raw materials is respectively Compound C-2 and adamantyl acyl chlorides;
1H?NMR(400MHz，CDCl3)δ7.77(d，J＝8.2Hz，1H)，7.41-7.42(m，1H)，7.38-7.39(m，1H)，7.21-7.30(m，5H)，4.73(s，1H)，3.66-3.69(m，4H)，2.35-2.39(m，4H)，1.97-2.00(m，7H)，1.63-1.73(m，5H)，1.24-1.28(m，1H)，0.85-0.87(m，2H)
ESI：m/z(relative?intensity)483.0(M+1，100％)，234.9
Compound D a-11:1-[(phenyl) (2,4 dichloro benzene base) methyl]-4-piperidines-1-acyl piperazine reaction raw materials is respectively Compound C-2 and piperidine formyl chlorine;
1H?NMR(300MHz，CDCl 3)δ7.77(d，J＝8.4Hz，1H)，7.21-7.41(m，7H)，4.76(s，1H)，3.21-3.24(m，4H)，3.16-3.18(m，4H)，2.38(m，4H)，1.54(m，6H)
ESI：m/z(relative?intensity)432.0(M+1，100％)，235.0
Compound D a-12:1-[(phenyl) (2,4 dichloro benzene base) methyl]-4-morpholine-1-acyl piperazine reaction raw materials is respectively Compound C-2 and morpholine formyl chloride;
1H?NMR(300MHz，CDCl 3)δ7.76(d，J＝8.4Hz，1H)，7.21-7.41(m，7H)，4.77(s，1H)，3.63-3.66(m，4H)，3.22-3.28(m，8H)，2.39(m，4H)
ESI：m/z(relative?intensity)434.0(M+1，100％)，235.0
Compound D a-13:1-[(4-p-methoxy-phenyl) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-3 and cyclohexyl acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ7.77(d，J＝8.2Hz，1H)，7.24-7.30(m，4H)，6.80-6.83(m，2H)，4.67(s，1H)，3.76(s，3H)，3.58-3.61(m，2H)，3.46-3.48(m，2H)，2.30-2.40(m，4H)，1.76-1.80(m，2H)，1.67(m，3H)，1.45-1.52(m，2H)，1.19-1.25(m，2H)，0.85-0.87(m，2H)
ESI：m/z(relative?intensity)460.8(M+1，100％)，265.1
Compound D a-14:1-[(4-trifluoromethyl) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-4 and cyclohexyl acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ7.71(d，J＝8.2Hz，1H)，7.55(m，4H)，7.33(d，J＝2.1Hz，1H)，7.27(dd，J＝8.2，2.1Hz，1H)，4.84(s，1H)，3.58-3.64(m，2H)，3.48-3.50(m，2H)，2.35-2.44(m，4H)，1.76-1.78(m，2H)，1.67-1.71(m，3H)，1.22(m，2H)，0.86(m，2H)
ESI：m/z(relative?intensity)499.0(M+1，100％)，303.1
Compound D a-15:1-[(4-Phenoxyphenyl) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-5 and cyclohexyl acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ7.75(d，J＝8.5Hz，1H)，7.24-7.35(m，6H)，7.10(m，1H)，6.96-7.00(m，2H)，6.87-6.92(m，2H)，4.71(s，1H)，3.57-3.62(m，2H)，3.46-3.49(m，2H)，2.33-2.42(m，4H)，1.76-1.78(m，3H)，1.73(m，2H)，1.48-1.53(m，2H)，1.22(m，2H)，0.86(m，2H)
ESI：m/z(relative?intensity)522.8(M+1，100％)，327.1
Compound D a-16:1-[(3-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-6 and cyclohexyl acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ7.70(d，J＝8.5Hz，1H)，7.39(s，1H)，7.22-7.33(m，5H)，4.74(s，1H)，3.56-3.64(m，2H)，3.48-3.50(m，2H)，2.32-2.44(m，4H)，1.78(dd，J＝8.5，3.8Hz，2H)，1.69(m，3H)，1.52(m，2H)，1.22(m，2H)，0.86(m，2H)
ESI：m/z(relative?intensity)465.0(M+1，100％)，269.0
Compound D a-17:1-[(4-aminomethyl phenyl) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-7 and cyclohexyl acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ7.77(d，J＝8.2Hz，1H)，7.23-7.29(m，4H)，7.10(s，1H)，7.07(s，1H)，4.70(s，1H)，3.56-3.61(m，2H)，3.45-3.48(m，2H)，2.34-2.41(m，4H)，2.29(s，3H)，1.75-1.79(m，2H)，1.66-1.71(m，3H)，1.44-1.55(m，2H)，1.18-1.28(m，2H)，0.83-0.88(m，2H)
ESI：m/z(relative?intensity)445.0(M+1，100％)，249.0
Compound D a-18:1-[(3-itrile group phenyl) (4-chloro-phenyl-) methyl]-4-(cyclohexyl acyl group) piperazine reaction raw materials is respectively Compound C-8 and cyclohexyl acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ7.71(t，J＝1.6Hz，1H)，7.62(dt，J＝7.6，1.5Hz)，7.51(dt，J＝7.6，1.5Hz，1H)，7.40(t，J＝7.6Hz，1H)，7.29(m，4H)，4.26(s，1H)，3.61-3.64(m，2H)，3.49-3.53(m，2H)，2.33-2.38(m，4H)，1.76-1.80(m，2H)，1.62-1.71(m，3H)，1.44-1.56(m，2H)，1.19-1.27(m，4H)
ESI：m/z(relative?intensity)422.0(M+1，100％)，226.1
Compound D a-19:1-[(2-trifluoromethyl) (4-chloro-phenyl-) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-9 and cyclohexyl acyl chlorides;
1H?NMR(400MHz，CDCl 3)δ8.00(d，J＝7.9Hz，1H)，7.60(d，J＝7.9Hz，1H)，7.54(t，J＝7.8Hz，1H)，7.42-7.44(m，2H)，7.31-7.34(m，1H)，7.24-7.27(m，2H)，4.66(s，1H)，3.56-3.59(m，2H)，3.44-3.47(m，2H)，2.27-2.44(m，4H)，1.75-1.78(m，2H)，1.66-1.71(m，3H)，1.43-1.52(m，2H)，1.21(m，2H)，0.86(m，2H)
ESI：m/z(relative?intensity)465.0(M+1，100％)，269.1
Compound D a-20:1-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-4-(4-Methyl benzenesulfonyl base) piperazine
Reaction raw materials is respectively Compound C-1 and p-methyl benzene sulfonic chloride;
1H?NMR(400MHz，CDCl 3)δ7.62-7.64(m，2H)，7.52(d，J＝8.5Hz，1H)，7.34-7.36(m，2H)，7.15-7.30(m，6H)，4.73(s，1H)，2.97-3.00(m，4H)，2.46(s，3H)，2.42-2.45(m，4H)
ESI：m/z(relative?intensity)510.8(M+1，100％)，271.0
The synthetic route of Db compounds:
In parallel reactor, compound among the weighing series C is in reaction tubes respectively, after being dissolved in 3 milliliters of tetrahydrofuran (THF)s, adding and serial C compound mol ratio are 1.0 different sulphur nitrile acid esters respectively, stirred overnight at room temperature, pressure reducing and steaming reaction solution tetrahydrofuran (THF) gets crude product, and crude product gets product through column chromatographic isolation and purification, and elution requirement is a sherwood oil: ethyl acetate=10: 1～3: 1.
Compound D b-1:N-cyclohexyl-4-[(4-chloro-phenyl-) (2, the 4-chloro-phenyl-) methyl] piperazine-1-sulfo-formyl ammonia
Reaction raw materials is respectively Compound C-1 and the different sulphur nitrile of cyclohexyl acid esters, and experiment condition is with above-mentioned general synthetic route, down together;
1H?NMR(300MHz，CDCl 3)δ7.69(m，1H)，7.26-7.35(m，6H)，4.76(s，1H)，4.30(m，1H)，3.76(m，2H)，2.44(m，4H)，2.09(m，2H)，1.70(m，4H)，1.40(m，2H)，1.17(m，4H)
13C?NMR(CDCl 3)δ180.90，138.43，137.65，134.30，133.39×2，129.64，129.53×2，129.41，128.88×2，127.72，68.94，54.17，51.09(2×CH 2)，47.10(2×CH 2)，33.07(2×CH 2)，25.53(CH 2)，24.84(2×CH 2)
ESI：m/z(relative?intensity)495.9(M+1，100％)，269.0
LRMS(EI，70eV)：m/z?495[M +]，354，319，309，298，269，233，199，149，141，85，67，55
HRMS(EI)m/z?calcd?for?C 24H 28Cl 3N 3S，495.1070；found，495.1070.
Compound D b-2:N-cyclohexyl-4-[(phenyl) (2,4 dichloro benzene base) methyl] piperazine-1-sulfo-formyl ammonia
Reaction raw materials is respectively Compound C-2 and the different sulphur nitrile of cyclohexyl acid esters;
1H?NMR(300MHz，CDCl 3)δ7.76(d，J＝8.5Hz，1H)，7.38-7.41(m，2H)，7.19-7.32(m，5H)，4.77(s，1H)，4.33(m，1H)，3.69-3.83(m，4H)，2.42-2.45(m，4H)，2.05-2.11(m，2H)，1.61-1.73(m，4H)，1.35-1.46(m，2H)，1.14(m，2H)
13C?NMR(CDCl 3)δ180.83，139.84，138.16，134.35，133.10，129.57，129.50，128.64，128.25×2，127.63×2，127.58，69.62，54.14，51.12(2×CH 2)，47.15(2×CH 2)，33.07(2×CH 2)，25.53(CH 2)，24.84(2×CH 2)
ESI：m/z(relative?intensity)462.0(M+1，100％)，235.0
LRMS(EI，70eV)：m/z?461[M +]，320，275，264，235，199，185，165，141，85，55
HRMS(EI)m/z?calcd?for?C 24H 29Cl 2N 3S，461.1459；found，416.1456.
The synthetic route of Dc compounds:
In parallel reactor, compound among the weighing series C is in reaction tubes respectively, after being dissolved in 3 milliliters of tetrahydrofuran (THF)s, adding and serial C compound mol ratio are 1.0 isocyanide ester respectively, stirred overnight at room temperature, pressure reducing and steaming reaction solution tetrahydrofuran (THF) gets crude product, and crude product gets product through column chromatographic isolation and purification, and elution requirement is a sherwood oil: ethyl acetate=10: 1～3: 1 (the Compound D c-1 to Dc-17 among the embodiment adopts aforesaid method to synthesize).
This general synthetic route also provides the route of another kind of synthetic this compounds.In parallel reactor, difference weighing N, N '-carbonyl dimidazoles (CDI) is in reaction tubes, after being dissolved in tetrahydrofuran (THF), add with the mol ratio of the different replacements of serial C compound is 1.0 primary amine or the solution of secondary amine in tetrahydrofuran (THF), after the stirring at room 1.5 hours, after adding mol ratio and be the tetrahydrofuran solution of 0.83 serial C compound, reflux 18 hours, reaction solution evaporate to dryness, residuum are dissolved in 100 milliliters of methylene dichloride, after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets crude product, and the crude product column chromatography gets product (Compound D c-18 among the embodiment and Dc-19 adopt aforesaid method to synthesize).
Compound D c-1:N-butyl-4-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-1 and normal-butyl isocyanide ester, and experiment condition is with above-mentioned general synthetic route, down together;
1H?NMR(300MHz，CDCl 3)δ7.70(d，J＝8.8Hz，1H)，7.25-7.36(m，6H)，4.74(s，1H)，3.32-3.35(m，4H)，3.21(m，2H)，2.37(m，4H)，1.43-1.52(m，2H)，1.29-1.39(m，2H)，0.92(t，J＝7.3Hz，3H)
13C?NMR(CDCl3)δ157.74，138.68，137.95，134.28，133.26，129.58×3，129.50，128.83×2，127.69，69.14，51.36(2×CH 2)，43.77(2×CH 2)，40.60(CH 2)，32.31(CH 2)，20.05(CH 2)，13.80
ESI：m/z(relative?intensity)453.9(M+1，100％)，269.0
Compound D c-2:N-cyclohexyl-4-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-1 and cyclohexyl isocyanide ester;
1H?NMR(400MHz，CDCl 3)δ7.70(d，J＝8.2Hz，1H)，7.27-7.36(m，6H)，4.73(s，1H)，3.32(t，J＝5.0Hz，4H)，2.36(ddd，J＝20.2，11.2，4.4Hz，4H)，1.93(dd，J＝12.5，3.4Hz，2H)，1.57-1.72(m，3H)，1.26-1.43(m，2H)，1.05-1.15(m，2H)
13C?NMR(CDCl 3)δ156.99，138.70，137.96，134.28，133.26×2，129.58×2，129.51×2，128.82×2，127.68，69.14，51.35(2×CH 2)，49.35，43.76(2×CH 2)，33.93(2×CH 2)，25.62(CH 2)，25.00(2×CH 2)
ESI：m/z(relative?intensity)481.9(M+1，100％)，269.1
LRMS(EI，70eV)：m/z?479[M +]，354，312，269，233，210，199，169，125，85，67，56
HRMS(EI)m/z?calcd?for?C 24H 28Cl 3N 3O，479.1298；found，479.1296.
Compound D c-3:N-butyl-4-[(phenyl) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia react raw material is respectively Compound C-2 and normal-butyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.75(d，J＝9.2Hz，1H)，7.24-7.41(m，7H)，4.75(s，1H)，3.33(m，4H)，3.18-3.25(m，2H)，2.37(m，4H)，1.43-1.52(m，2H)，1.29-1.37(m，2H)，0.92(t，J＝7.3Hz，3H)
13C?NMR(CDCl 3)δ157.78，140.10，138.46，134.33，132.95，129.67，129.44，128.59×2，128.29×2，127.54×2，69.83，51.40(2×CH 2)，43.80(2×CH 2)，40.58(CH 2)，32.30(CH 2)，20.05(CH 2)，13.80
ESI：m/z(relative?intensity)405.0(M+1，100％)，235.0
Compound D c-4:N-cyclohexyl-4-[(phenyl) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia react raw material is respectively Compound C-2 and cyclohexyl isocyanide ester;
1H?NMR(400MHz，CDCl 3)δ7.75(d，J＝8.5Hz，1H)，7.38-7.41(m，2H)，7.18-7.30(m，5H)，4.75(s，1H)，3.31(m，4H)，2.37(m，4H)，1.93(dd，J＝12.5，3.1Hz，2H)，1.57-1.72(m，3H)，1.32-1.39(m，2H)，1.04-1.16(m，2H)
13C?NMR(CDCl 3)δ157.04，140.13，138.49，134.35，132.96，129.68，129.45，128.59×2，128.31×2，127.54×2，69.83，51.39(2×CH 2)，49.32，43.80(2×CH 2)，33.93(2×CH 2)，25.62(CH 2)，25.01(2×CH 2)
ESI：m/z(relative?intensity)446.0(M+1，100％)，235.0
LRMS(EI，70eV)：m/z?445[M +]，410，320，290，276，235，210，199，169，165，85，67，56
HRMS(EI)m/z?calcd?for?C 24H 29Cl 2N 3O，445.1688；found，445.1683.
Compound D c-5:N-cyclohexyl-4-[(4-p-methoxy-phenyl) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-3 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.76(d，J＝8.4Hz，1H)，7.24-7.29(m，4H)，6.80-6.82(m，2H)，4.67(s，1H)，3.76(s，3H)，3.62(m，1H)，3.30-3.32(m，4H)，2.34-2.37(m，4H)，1.91-1.95(m，2H)，1.58-1.71(m，4H)，1.31-1.40(m，2H)，1.05-1.14(m，2H)
ESI：m/z(relative?intensity)475.8(M+1，100％)，265.0
Compound D c-6:N-cyclohexyl-4-[(4-trifluoromethyl) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-4 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.70(d，J＝8.4Hz，1H)，7.54(s，4H)，7.33(d，J＝2.2Hz，1H)，7.26(dd，J＝8.4，2.2Hz，1H)，4.84(s，1H)，3.63(m，1H)，3.32-3.34(m，4H)，2.32-2.43(m，4H)，1.91-1.95(m，2H)，1.58-1.71(m，4H)，1.31-1.41(m，2H)，1.02-1.18(m，2H)
ESI：m/z(relative?intensity)513.9(M+1，100％)，303.0
Compound D c-7:N-cyclohexyl-4-[(4-Phenoxyphenyl) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-5 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.47(d，J＝8.4Hz，1H)，7.30-7.35(m，5H)，7.25-7.27(m，1H)，7.08-7.12(m，1H)，6.97-6.99(m，2H)，6.88-6.92(m，2H)，4.72(s，1H)，3.64(m，1H)，3.31-3.33(m，4H)，2.36-2.39(m，4H)，1.93(dd，J＝12.7，3.1Hz，2H)，1.58-1.71(m，4H)，1.31-1.41(m，2H)，1.05-1.15(m，2H)
ESI：m/z(relative?intensity)537.8(M+1，100％)，327.1
Compound D c-8:N-cyclohexyl-4-[(3-chloro-phenyl-) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-6 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.69(d，J＝8.4Hz，1H)，7.39(m，1H)，7.33(d，J＝2.2Hz，1H)，7.25-7.31(m，3H)，7.20(m，1H)，4.74(s，1H)，3.63(m，1H)，3.31-3.34(m，4H)，2.36-2.39(m，4H)，1.91-1.95(m，2H)，1.67-1.70(m，2H)，1.59-1.63(m，2H)，1.30-1.41(m，2H)，1.02-1.18(m，2H)
ESI：m/z(relative?intensity)481.9(M+1，100％)，269.0
Compound D c-9:N-cyclohexyl-4-[(4-aminomethyl phenyl) (2,4 dichloro benzene base) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-7 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.76(d，J＝8.4Hz，1H)，7.23-7.29(m，4H)，7.07-7.09(m，2H)，4.70(s，1H)，3.63(m，1H)，3.29-3.32(m，4H)，2.35-2.37(m，4H)，2.29(s，3H)，1.91-1.95(m，2H)，1.66-1.71(m，2H)，1.59-1.62(m，2H)，1.31-1.38(m，2H)，1.03-1.14(m，2H)
13C?NMR(CDCl 3)δ157.04，138.75，137.22，137.07，134.27，132.83，129.57，129.43，129.27×2，128.22×2，127.50，69.58，51.38(2×CH 2)，49.31，43.80(2×CH 2)，33.93(2×CH 2)，25.63(CH 2)，25.01(2×CH 2)，21.05
ESI：m/z(relative?intensity)459.9(M+1，100％)，249.0
LRMS(EI，70eV)：m/z?459[M +]，424，334，304，290，278，249，210，199，179，169，85，65，56
HRMS(EI)m/z?calcd?for?C 25H 31Cl 2N 3O，459.1844；found，459.1837.
Compound D c-10:N-cyclohexyl-4-[(3-itrile group phenyl) (4-chloro-phenyl-) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-8 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ1.71(m，1H)，7.61-7.63(m，1H)，7.51(ddd，J＝7.9，1.4，1.2Hz，1H)，7.40(t，J＝7.7Hz，1H)，7.29(m，4H)，4.26(s，1H)，3.34-3.36(m，4H)，2.31-2.39(m，4H)，1.91-1.94(m，2H)，1.59-1.71(m，4H)，1.30-1.41(m，2H)，1.05-1.14(m，2H)
ESI：m/z(relative?intensity)437.0(M+1，100％)，226.1
Compound D c-11:N-cyclohexyl-4-[(phenyl) (3, the 4-dichlorophenyl) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-10 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.52(d，J＝1.8Hz，1H)，7.20-7.36(m，7H)，4.19(s，1H)，3.62(m，1H)，3.32-3.35(m，4H)，2.35-2.37(m，4H)，1.92-1.95(m，2H)，1.58-1.71(m，4H)，1.31-1.40(m，2H)，1.05-1.14(m，2H)
ESI：m/z(relative?intensity)446.0(M+1，100％)，234.9
Compound D c-12:N-cyclohexyl-4-[(phenyl) (2, the 5-dichlorophenyl) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-11 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.81(d，J＝2.6Hz，1H)，7.39-7.41(m，2H)，7.20-7.31(m，4H)，7.10(dd，J＝8.5，2.7Hz，1H)，4.74(s，1H)，3.64(m，1H)，3.32-3.35(m，4H)，2.35-2.39(m，4H)，1.91-1.95(m，2H)，1.65-1.71(m，2H)，1.56-1.62(m，2H)，1.31-1.40(m，2H)，1.03-1.15(m，2H)
ESI：m/z(relative?intensity)446.0(M+1，100％)，235.0
Compound D c-13:N-cyclohexyl-4-[(phenyl) (2-fluoro-4-bromophenyl) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-12 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.52(t，J＝8.0Hz，1H)，7.37-7.39(m，2H)，7.19-7.30(m，4H)，7.15(dd，J＝9.5，1.8Hz，1H)，4.61(s，1H)，3.61(m，1H)，3.33(br?s，4H)，2.37-2.40(m，4H)，1.92-1.94(m，2H)，1.58-1.71(m，4H)，1.31-1.40(m，2H)，1.03-1.15(m，2H)
ESI：m/z(relative?intensity)445.9(M+1，100％)，265.0
Compound D c-14:N-cyclohexyl-4-[(phenyl) (2, the 6-dichlorophenyl) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-13 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.61(d，J＝7.3Hz，2H)，7.26-7.29(m，4H)，7.18-7.22(m，1H)，7.07(t，J＝8.1Hz，1H)，5.44(s，1H)，3.64(m，1H)，3.39-3.42(m，4H)，2.56-2.61(m，2H)，2.34-2.39(m，2H)，1.93-1.96(m，2H)，1.57-1.71(m，4H)，1.31-1.38(m，2H)，1.03-1.15(m，2H)
ESI：m/z(relative?intensity)446.0(M+1，100％)，235.0
Compound D c-15:N-cyclohexyl-4-[(phenyl) (2-chloro-4-fluorophenyl) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-14 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.78(dd，J＝8.7，6.3Hz，1H)，7.39-7.41(m，2H)，7.28-7.30(m，2H)，7.19-7.23(m，1H)，7.04(dd，J＝8.6，2.6Hz，1H)，6.99(td，J＝8.3，2.7Hz，1H)，4.76(s，1H)，3.64(m，1H)，3.30-3.33(m，4H)，2.36-2.39(m，4H)，1.92-1.95(m，2H)，1.58-1.70(m，4H)，1.31-1.40(m，2H)，1.05-1.14(m，2H)
ESI：m/z(relative?intensity)430.0(M+1，100％)，219.0
Compound D c-16:N-cyclohexyl-4-[(phenyl) (2-fluoro-4-chloro-phenyl-) methyl] piperazine-1-formyl ammonia
Reaction raw materials is respectively Compound C-15 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.57(t，J＝8.1Hz，1H)，7.37-7.39(m，2H)，7.26-7.30(m，2H)，7.19-7.23(m，1H)，7.11(dd，J＝8.4，1.8Hz，1H)，7.00(dd，J＝9.8，2.1Hz，1H)，4.62(s，1H)，3.62(m，1H)，3.30-3.37(m，4H)，2.37-2.40(m，4H)，1.91-1.95(m，2H)，1.58-1.71(m，4H)，1.30-1.41(m，2H)，1.03-1.14(m，2H)
ESI：m/z(relative?intensity)430.0(M+1，100％)，219.0
Compound D c-17:1-[(4-fluorophenyl) (2,4 dichloro benzene base) methyl]-4-(cyclohexyl acyl group) piperazine
Reaction raw materials is respectively Compound C-16 and cyclohexyl isocyanide ester;
1H?NMR(300MHz，CDCl 3)δ7.73(d，J＝8.4Hz，1H)，7.25-7.38(m，4H)，6.94-7.00(m，2H)，4.73(s，1H)，4.30(m，1H)，4.12(m，1H)，3.63(m，1H)，3.32(m，4H)，2.36(m，4H)，1.91-1.94(m，2H)，1.58-1.69(m，2H)，1.26-1.37(m，2H)，1.05-1.13(m，2H)
ESI：m/z(relative?intensity)464.0(M+1，100％)，253.0
Compound D c-18:4-[(phenyl) (2,4 dichloro benzene base) methyl]-N-piperidyl-1-piperazine-1-methane amide
N with 0.18g (1.13mmol), N '-carbonyl dimidazoles (CDI) is dissolved in 10 milliliters of tetrahydrofuran (THF)s, after adding the solution of 0.11g (1.13mmol) 1-amino piperidine in 10 milliliters of tetrahydrofuran (THF)s, stirring at room 1.5 hours, 0.30g (0.94mmol) the 1-[phenyl (2, the 4-dichlorophenyl) methyl] solution of piperazine in 10 milliliters of tetrahydrofuran (THF)s is added in the above-mentioned reaction solution, reflux 18 hours, the reaction solution evaporate to dryness, residuum is dissolved in 100 milliliters of methylene dichloride, after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets crude product, and crude product is with sherwood oil: ethyl acetate=2: 1～1: 2 is that the eluent column chromatography gets product 0.38g, yield 90.8%.
1H?NMR(300MHz，CDCl 3)δ7.77(d，J＝8.4Hz，1H)，7.38-7.42(m，2H)，7.19-7.31(m，5H)，4.97(s，1H，NH)，4.74(s，1H)，3.44-3.47(m，4H)，2.65(br?s，4H)，2.35-2.38(m，4H)，1.58-1.66(m，4H)，1.36(m，2H)
13C?NMR(CDCl 3)δ158.28，140.20，138.54，134.34，132.93，129.73，129.43，128.56×2，128.30×2，127.52，127.47，69.93，57.62(2×CH 2)，51.66(2×CH 2)，44.71(2×CH 2)，25.70(2×CH 2)，23.21(CH 2)
LRMS(EI，70eV)：m/z?446[M +]，276，235，211，199，165，125，99，85，56
Compound D c-19:4-[(4-aminomethyl phenyl) (2,4 dichloro benzene base) methyl]-N-piperidyl-1-piperazine-1-methane amide
N with 0.29g (1.79mmol), N '-carbonyl dimidazoles (CDI) is dissolved in 10 milliliters of tetrahydrofuran (THF)s, after adding the solution of 0.18g (1.79mmol) 1-amino piperidine in 10 milliliters of tetrahydrofuran (THF)s, stirring at room 1.5 hours, 0.50g (1.49mmol) 1-[(4-aminomethyl phenyl) (2, the 4-dichlorophenyl) methyl] solution of piperazine in 10 milliliters of tetrahydrofuran (THF)s is added in the above-mentioned reaction solution, reflux 18 hours, the reaction solution evaporate to dryness, residuum is dissolved in 100 milliliters of methylene dichloride, after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets crude product, and crude product is with sherwood oil: ethyl acetate=2: 1～1: 2 is that the eluent column chromatography gets product 0.61g, yield 89.1%.
1H?NMR(400MHz，CDCl 3)δ7.78(d，J＝8.4Hz，1H)，7.23-7.30(m，4H)，7.08-7.10(m，2H)，4.91(s，1H，NH)，4.70(s，1H)，3.43-3.47(m，4H)，2.64(m，4H)，2.34-2.37(m，4H)，2.29(s，3H)，1.58-1.66(m，4H)，1.36(m，2H)
13C?NMR(CDCl 3)δ158.29，138.80，137.18，137.14，134.27，132.81，129.62，129.40，129.26×2，128.22×2，127.49，69.69，57.60(2×CH2)，51.66(2×CH2)，44.71(2×CH2)，25.71(2×CH2)，23.22(CH2)，21.02
LRMS(EI，70eV)：m/z?460[M +]，289，249，211，179，165，125，99，85，56
Compound D c-20:4-[(4-chloro-phenyl-) (2,4 dichloro benzene base) methyl]-N-piperidyl-1-piperazine-1-methane amide
N with 0.27g (1.69mmol), N '-carbonyl dimidazoles (CDI) is dissolved in 10 milliliters of tetrahydrofuran (THF)s, after adding the solution of 0.17g (1.69mmol) 1-amino piperidine in 10 milliliters of tetrahydrofuran (THF)s, stirring at room 1.5 hours, 0.50g (1.41mmol) 1-[(4-chloro-phenyl-) (2, the 4-dichlorophenyl) methyl] solution of piperazine in 10 milliliters of tetrahydrofuran (THF)s is added in the above-mentioned reaction solution, reflux 18 hours, the reaction solution evaporate to dryness, residuum is dissolved in 100 milliliters of methylene dichloride, after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets crude product, and crude product is with sherwood oil: ethyl acetate=2: 1～1: 2 is that the eluent column chromatography gets product.
Embodiment 5:
As follows also the providing in synthetic a series of general formulas (I) structure of present embodiment has substituent general synthetic route on the piperazine ring, wherein R 1, R 2, V, W described as defined above.
Figure A20071004164000771
This example is only with synthetic N-cyclohexyl-4-[(4-aminomethyl phenyl) (2,4 dichloro benzene base) methyl]-2,5-lupetazin-1-formyl ammonia is example (R 1Be 2,4 dichloro benzene base, R 2Be the 4-aminomethyl phenyl, R ' and R " be respectively 2 of piperazine rings and 5 substituent methyls, V is C=O, W is a nitrogen-atoms), below be the reaction synthetic route of this compound.
Compd A-7 is synthetic with compd B-7:
Compd A-7 and compd B-7 are respectively A-7 in the series A compound among the embodiment 4 and the B-7 in the serial B compound among the embodiment 4.
Synthesizing of compound 9:
With (2.0g, 7.0mmol) compd B-7 is dissolved in the acetonitrile, ice bath adds 2 down, 5-lupetazin (4.0g, 28.0mmol) after, spend the night in 70 ℃ of reactions, the pressure reducing and steaming acetonitrile is after residuum adds aqueous sodium carbonate, with ethyl acetate extraction 2 times, after the aqueous hydrochloric acid of 1mol/L is added in the above-mentioned ethyl acetate solution, make product be dissolved to water, after this water is washed 2 times with ethyl acetate again, with 6mol/L aqueous sodium hydroxide solution adjust pH is about 10, water merges organic phase with behind the dichloromethane extraction 2 times, and organic phase is after water and saturated brine are respectively washed once respectively, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets compound 9, and (2.0g, yield: 77.8%), product need not purifying can directly carry out next step reaction for crude product.
1H?NMR(400MHz，CDCl 3)δ7.79(Ar-H，d，J＝9.2Hz，0.5Ha)，7.39(Ar-H，d，J＝2.2Hz，0.5Hb)，7.15-7.28(m，3H)，7.05-7.10(m，2H)，6.98(m，1H)，5.61(N-CH，s，0.5Ha)，5.25(N-CH，s，0.5Hb)，3.00(m，1H)，2.88(m，1H)，2.49-2.72(m，4H)，2.32(Ar-CH 3，s，1.5Ha)，2.31(Ar-CH 3，s，1.5Hb)，1.05(dd，J＝18.3，6.2Hz，3H)，0.97(t，J＝6.2Hz，3H)
ESI：m/z(relative?intensity)362.9(M+1，100％)，249.0
Synthesizing of compound 10:
With (0.30g, 0.83mmol) after compound 9 is dissolved in 10 milliliters of methylene dichloride, add the cyclohexyl isocyanide ester under the room temperature, stirred overnight at room temperature, boil off solvent, residuum is directly through column chromatographic isolation and purification, and with sherwood oil: ethyl acetate=2: 1～1: 2 is an eluent, get product 0.38g, yield: 95.2%.
1H?NMR(400MHz，CDCl 3)δ7.86(Ar-H，d，J＝8.2Hz，0.5Ha)，7.76(Ar-H，d，J＝8.4Hz，0.5Ha)，7.22-7.36(m，4H)，7.06-7.10(m，2H)，5.01(N-CH，s，0.5Ha)，4.93(N-CH，s，0.5Hb)，4.13(m，1H)，3.95(m，1H)，3.64(m，1H)，3.45(m，1H)，3.31(m，1H)，2.97(m，1H)，2.66(ddd，J＝25.9，11.9，4.0Hz，1H)，2.29(Ar-CH 3，s，1.5Ha)，2.28(Ar-CH 3，s，1.5Hb)，1.92-1.96(m，2H)，1.59-1.71(m，4H)，1.26-1.38(m，2H)，1.30(d，J＝7.3Hz，3H)，1.06-1.15(m，2H)，0.94(t，J＝6.6Hz，3H)
ESI：m/z(relative?intensity)488.0(M+1，100％)，249.0
Pharmacological testing embodiment
Some material can be specifically and receptors bind, thereby activate the signal path in downstream, causes a series of biologicallies of cell, and this species specific combination is called as the receptor-ligand keying action.The keying action of receptor-ligand has saturability equally, can cause the combination rate of part and acceptor to descend under the situation of existence and the competitive material of part, shows as the competition curve of S type, and the theoretical basis that this point is studied just.In experiment, adopt with isotope-labeled ligands specific as observation index, detect and to add at the same time under the situation of testing compound and isotropic substance part, with the variation of the amount of the isotropic substance part of receptors bind, with the combine activity of reflection testing compound with acceptor.
The pharmacological evaluation embodiment of the above compound of following demonstration the present invention.
Pharmacological testing embodiment 1: full cell is in conjunction with screening model (whole cell bindingscreening assay)
Cannabinoid receptors can combine with specific part.[ 3H]-CP55940 is with isotope-labeled specificity cannabinoid receptors agonist, if testing compound can combine with cannabinoid receptors, then can cause with its bonded [ 3H]-minimizing of CP55940 quantity, can quantitative this variation on suitable instrument.According to this principle, set up full cell in conjunction with screening model (whole cell bindingscreening assay).
(hCB1, hCB2) transfection Chinese hamster ovary cancer cells (CHO) are set up stably transfected cell line CHO-hCB1/hCB2 by microbiotic G418 screening to personnel selection source cannabinoid receptors.30,000/hole of the CHO-hCB1/hCB2 cell kind of surely changeing in 96 orifice plates, is spent the night, make the cell in every hole when detecting about 4～60,000/hole.Changed the substratum of serum-free in second day into, hungry 3 hours.Change the substratum of serum-free into contain 1%BSA substratum, testing compound is added in the nutrient solution, hatched 10 minutes for 37 ℃.Add isotropic substance, room temperature was placed 8 hours.Whole system finally is: according to the testing compound of experiment needs adjustment concentration, 1%DMSO, 1%BSA, 1.7nM[ 3H]-CP55940, final volume 100uL after 8 hours, goes the liquid suction, with phosphoric acid buffer PBS (NaCl 137mM, KCl 2.7mM, Na 2HPO 410mM, KH 2PO 41.76mM) 5 cells of flushing, add 50 μ L cell pyrolysis liquid (NaCl 137mM, KCl2.7mM, Na 2HPO 410mM, KH 2PO 41.76mM, 1%SDS), vibrated 5 minutes.In 96 hole microwell plates (isoplate) at the bottom of the 50uL liquid adding standard transparent, add 150uL scintillation solution Optiphase Supermix, vibrated 5 minutes, at Microbeta liquid scintillation ﹠amp; Reading on the luminescence counter instrument.(the results are shown in following table 1)
Pharmacological testing embodiment 2: calcium current screening model (Calcium current assay)
After cannabinoid receptors is activated, can cause the inhibition of intracellular Ca2+ stream.But after changing G Protein G α 16 over to, show as the calcium current in the activating cells, other physiologic function is unaffected.By having set up the clone of corotation CB1 and G α 16, can cause G α 16 proteic activation after making acceptor be activated, and then activate Phospholipase C (PLC) and produce IP 3And DAG, IP 3Can with the IP3 receptors bind on endoplasmic reticulum in the cell and the plastosome, thereby cause the release of cellular calcium.Therefore, the variation of mensuration cellular calcium can be used as the method that detects the CB1 active state.Fluo-4/AM is that a kind of calcium fluorescent probe indicator is used for measuring calcium ion, as nonpolar fat-soluble compound, enters behind the cell under the effect of cell lipolytic enzyme, and the AM group dissociates, and disengages Fluo-4; Because Fluo-4 is a polar molecule, be difficult for by bimolecular lipid membrane, it can make Fluo-4 be retained in the cell for a long time.Finally the amount of the photon that can be excited by measurement reflects the level that g is activated.According to this principle, set up calcium current screening model (Calcium current assay).
(hCB1 hCB2) with G α 16 while transfectional cell, sets up stably transfected cell line CHO-hCB1-G α 16 and CHO-hCB2-G α 16 by antibiotic-screening to personnel selection source cannabinoid receptors.CHO/CB1-G α 16 cells (about 20,000/hole) of 24h kind suitable density are in 96 porocyte plates before detecting, and the cell in every hole is about 4～60,000/hole when making detection.Fresh preparation calcium damping fluid (KCl 0.4g/L, Na before experiment 2HPO 40.09g/L, KH 2PO 40.06g/L, NaHCO 30.35g/L, CaCl 20.14g/L, MgCl 26H 2O 0.10g/L, Mg 2SO 47H 2O 0.10g/L, NaCl 8.0g/L), and, with the calcium damping fluid positive drug CP55940 is diluted to 100nM in addition with drug dilution and mixing that the calcium damping fluid of 50 μ L/well need detect 1 μ l.Kind being had training liquid in the hole of cell inhale goes, add freshly prepared dyestuff 40 μ L/well, being formulated as of every milliliter of dyestuff is first with the Fluo-4AM (2mM) of 1 μ L and the Cremophor EL of 5 μ L (3%in PBS, 100X) mixing, buffer dilution of usefulness 1ml calcium and mixing again.Place the interior constant temperature of 37 degree incubators to hatch 40min.Dyestuff exhausted discard, wash one time with the calcium damping fluid of 50ul after, change and dilute the damping fluid that medicine to be measured is arranged in the step 2 in advance.Detect with the Flextation instrument, beginning in the 15th second adds the 100nM CP55940 that 25ul prepares in advance automatically by instrument, finally reads the peak value RFU of calcium current.
Pharmacological testing embodiment 3: pharmacology data
To announce the pharmacology test result of one group of The compounds of this invention that part obtains with embodiment 1～embodiment 4 in the following table 1, the positive medicine Rimonabant of the contrast of adopting in the test (SR141716A):
Table 1
Figure A20071004164000821
The ratio of the Ki value of positive compound Rimonabant (Rimonabant) on CB2 and CB1 acceptor is 141.4, about 120 comparatively approaching with bibliographical information, this method can repeat literature method preferably, and resulting active result has higher confidence level on this system.In the table 1 in the listed compound selectivity of part of compounds on CB1 and CB2 acceptor be higher than the marketed drug Rimonabant, also list the calcium current activity of compound for CB1 and CB2 acceptor in the table 1, this compounds is all relatively good for the selectivity of CB1 acceptor and CB2 acceptor equally.It seems that totally affine experiment of acceptor and calcium current experimental data show that all The compounds of this invention has very strong combination activity to people source cannabinoid receptors, and acceptor type is had very high specificity, are cannabinoid receptors 1 specific antagonist or inverse agonists.
Fig. 1 a is the receptors bind graphic representation of Rimonabant (Rimonabant) and CB1 acceptor among Fig. 1, Rimonabant antagonism in the Chinese hamster ovary celI receptor-ligand combination model of CB1 high expression level [ 3H]-CP55940 (1.7nM); Fig. 1 b is the receptors bind graphic representation of Rimonabant and CB2 acceptor, Rimonabant antagonism in the Chinese hamster ovary celI receptor-ligand combination model of CB2 high expression level [ 3H]-CP55940 (1.7nM);
Fig. 2 a is the receptors bind graphic representation of Compound D c-9 and CB1 acceptor among Fig. 2, Compound D c-9 antagonism in the Chinese hamster ovary celI receptor-ligand combination model of CB1 high expression level [ 3H]-CP55940 (1.7nM), Fig. 2 b is the receptors bind graphic representation of Compound D c-9 and CB2 acceptor, Compound D c-9 antagonism in the Chinese hamster ovary celI receptor-ligand combination model of CB2 high expression level [ 3H]-CP55940 (1.7nM).
Above picture is illustrated under the situation that has the positive drug Rimonabant, [ 3H]-curve of CP55940 and receptors bind is S-type, shows tangible competition-keying action, and half-inhibition concentration IC 50With suppress all very approaching with bibliographical information of constant K i, the illustrative experiment method is reliable.Compound D c-9 shows the characteristic similar with the positive drug Rimonabant, illustrates that Compound D c-9 is the same with Rimonabant, can both cause [ 3H]-bonded of CP55940 and acceptor descends, illustrate compound and Rimonabant can both with the ground combination of CB1 receptor-specific.
Above-mentioned example is as an illustration purpose only, and scope of the present invention is not so limited.It is conspicuous making amendment to one skilled in the art, and the present invention only is subjected to the restriction of claims scope.

Claims (20)

1, a class is by the substituted-piperazinyl compounds of following general formula (I) expression and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof:
Wherein:
V is C=O, C=S or SO 2
W is the nitrogen-atoms of direct key, Sauerstoffatom or replacement;
R 1And R 2Be independently selected from phenyl, naphthyl, furyl, thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl respectively, these groups can be replaced by 1-4 substituting group U, the U substituting group is identical or different, is selected from the C of branching or non-branching 1-8Alkyl or alkoxyl group, C 1-3Alkoxy methyl, list or two C 1-3Alkylamino, list or two C 1-3Alkylamidoalkyl, C 1-3Alkyl sulphonyl, C 1-3Alkoxy carbonyl, phenyl, phenoxy group, hydroxyl, methylol, methylthio group, hydroxyethyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoro-methoxy, trifluoromethoxy, trifluoromethylthio, trifyl, methyl sulphonyl, amino-sulfonyl, amino, nitro and cyano group;
R 3The C of expression hydrogen atom, branching or non-branching 1-10Alkyl, C 3-10Cycloalkyl, C 5-10Bicyclic alkyl, C 6-10Tricyclic alkyl, C 3-8Alkenyl, C 5-8Cycloalkenyl group or adamantyl, these groups can be chosen the heteroatoms that contains one or more O of being selected from, N and S wantonly, and these groups can be by hydroxyl, C 1-8Alkyl or alkoxyl group or 1-3 halogen atom replaces; Perhaps R 3The expression aromatic nucleus can be by phenyl, benzyl, styroyl, naphthyl, anthryl, menaphthyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or the triazinyl of 1-4 substituting group U replacement, and wherein the U definition as above; Perhaps R 3Expression group NR 4R 5, R wherein 4And R 5With the nitrogen-atoms that they connected, formation has the saturated or undersaturated monocycle or the bicyclic heterocycle part of 4-10 annular atoms, this heterocyclic moiety contains 1 or 2 identical or different heteroatoms that is selected from N, O and S, and described heterocyclic moiety can be by branching or non-branching C 1-4Alkyl, hydroxyl, trifluoromethyl or halogen atom replace;
R ' and R " identical or different and represent 1 or 2 to be substituted in hydrogen, methyl, ethyl, hydroxyl or the halogen atom that the piperazine ring different positions replaces.
2. substituted-piperazinyl compounds as claimed in claim 1 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof is characterized in that described R 1And R 2Be phenyl or pyridyl independently respectively, described phenyl or pyridyl can be replaced by 1-4 substituting group U, and the U substituting group is identical or different, is selected from the C of branching or non-branching 1-8Alkyl or alkoxyl group, C 1-3Alkoxy methyl, list or two C 1-3Alkylamino, list or two C 1-3Alkylamidoalkyl, C 1-3Alkyl sulphonyl, C 1-3Alkoxy carbonyl, phenyl, phenoxy group, hydroxyl, methylol, methylthio group, hydroxyethyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, difluoro-methoxy, trifluoromethoxy, trifluoromethylthio, trifyl, methyl sulphonyl, amino-sulfonyl, amino, nitro and cyano group.
3, substituted-piperazinyl compounds as claimed in claim 1 or 2 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof is characterized in that,
For R 1, R 1On substituting group be 2,4-dichloro, 4-chlorine, 3,4-dichloro, 2-chloro-4-bromine, 2-bromo-4-chlorine, 2-fluoro-4-chlorine or 2-chloro-4-fluorine;
For R 2, R 2On substituting group be chlorine, fluorine, bromine, trifluoromethyl, the C that the optional position replaces on the aromatic ring 1-3Alkoxy methyl or C 1-8Alkyl.
4, substituted-piperazinyl compounds as claimed in claim 1 or 2 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof is characterized in that R 3Be C 4-6Alkyl, cyclohexyl, cyclohexenyl or adamantyl, these groups can be by hydroxyl, C 1-8Alkyl or alkoxyl group or 1-3 halogen atom replaces; Perhaps R 3Expression group NR 4R 5, R wherein 4And R 5With the nitrogen-atoms that they connected, form the saturated monocyclic heterocycles of 6 annular atomses, wherein this heterocyclic moiety is chosen wantonly and is contained a Sauerstoffatom.
5, substituted-piperazinyl compounds as claimed in claim 1 or 2 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof, it is characterized in that R ' and R " identical, it is on the piperazine ring 2; 5 substituent methyls or 2,6 substituent methyls.
6, substituted-piperazinyl compounds as claimed in claim 1 or 2 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof is characterized in that described V is C=O; W is the nitrogen-atoms of direct key, Sauerstoffatom or replacement.
7, substituted-piperazinyl compounds as claimed in claim 1 or 2 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof is characterized in that described V is C=S; The nitrogen-atoms of W for replacing.
8, substituted-piperazinyl compounds as claimed in claim 1 or 2 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof is characterized in that described V is SO 2W is direct key.
9, substituted-piperazinyl compounds as claimed in claim 1 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof is characterized in that described compound is selected from one of following compound:
1) hexamethylene acyl group-4-benzhydryl piperazidine
2) N-butyl-4-benzhydryl piperazidine-1-formyl ammonia
3) N-benzyl-4-benzhydryl piperazidine-1-sulfo-formyl ammonia
4) 4-benzhydryl piperazidine-N-benzyl-1-sulfo-formyl ammonia
5) 4-benzhydryl piperazidine-N-cyclohexyl-1-sulfo-formyl ammonia
6) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(cyclobutyl acyl group) piperazine
7) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(cyclopentyl acyl group) piperazine
8) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(cyclohexyl acyl group) piperazine
9) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(diamantane acyl group) piperazine
10) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-piperidines-1-acyl piperazine
11) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-morpholine-4-acyl piperazine
12) (2,4 dichloro benzene base) methyl N-butyl-4-[(4-chloro-phenyl-)] piperazine-1-formyl ammonia
13) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-chloro-phenyl-)] piperazine-1-formyl ammonia
14) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-chloro-phenyl-)] piperazine-1-sulfo-formyl ammonia
15) (2,4 dichloro benzene base) methyl 1-[(4-chloro-phenyl-)]-4-(4-Methyl benzenesulfonyl base) piperazine
16) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(cyclobutyl acyl group) piperazine
17) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(cyclopentyl acyl group) piperazine
18) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(cyclohexyl acyl group) piperazine
19) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-(diamantane acyl group) piperazine
20) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-piperidines-1-acyl piperazine
21) (2,4 dichloro benzene base) methyl 1-[(phenyl)]-4-morpholine-1-acyl piperazine
22) (2,4 dichloro benzene base) methyl N-butyl-4-[(phenyl)] piperazine-1-formyl ammonia
23) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia
24) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-sulfo-formyl ammonia
25) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-p-methoxy-phenyl)] piperazine-1-formyl ammonia
26) (2,4 dichloro benzene base) methyl 1-[(4-p-methoxy-phenyl)]-4-(cyclohexyl acyl group) piperazine
27) (2,4 dichloro benzene base) methyl 1-[(4-trifluoromethyl)]-4-(cyclohexyl acyl group) piperazine
28) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-trifluoromethyl)] piperazine-1-formyl ammonia
29) (2,4 dichloro benzene base) methyl 1-[(4-Phenoxyphenyl)]-4-(cyclohexyl acyl group) piperazine
30) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-Phenoxyphenyl)] piperazine-1-formyl ammonia
31) (2,4 dichloro benzene base) methyl 1-[(3-chloro-phenyl-)]-4-(cyclohexyl acyl group) piperazine
32) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(3-chloro-phenyl-)] piperazine-1-formyl ammonia
33) (2,4 dichloro benzene base) methyl 1-[(4-aminomethyl phenyl)]-4-(cyclohexyl acyl group) piperazine
34) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-aminomethyl phenyl)] piperazine-1-formyl ammonia
35) (4-chloro-phenyl-) methyl 1-[(3-itrile group phenyl)]-4-(cyclohexyl acyl group) piperazine
36) (4-chloro-phenyl-) methyl N-cyclohexyl-4-[(3-itrile group phenyl)] piperazine-1-formyl ammonia
37) (4-chloro-phenyl-) methyl 1-[(2-trifluoromethyl)]-4-(cyclohexyl acyl group) piperazine
38) (3, the 4-dichlorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia
39) (2, the 5-dichlorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia
40) (2-fluoro-4-bromophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia
41) (2, the 6-dichlorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia
42) (2-chloro-4-fluorophenyl) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia
43) (2-fluoro-4-chloro-phenyl-) methyl N-cyclohexyl-4-[(phenyl)] piperazine-1-formyl ammonia
44) (2,4 dichloro benzene base) methyl 1-[(4-fluorophenyl)]-4-(cyclohexyl acyl group) piperazine
45) (2,4 dichloro benzene base) methyl 4-[(phenyl)]-N-piperidyl-1-piperazine-1-methane amide
46) (2,4 dichloro benzene base) methyl 4-[(4-aminomethyl phenyl)]-N-piperidyl-1-piperazine-1-methane amide
47) (2,4 dichloro benzene base) methyl 4-[(4-chloro-phenyl-)]-N-piperidyl-1-piperazine-1-methane amide
48) (2,4 dichloro benzene base) methyl N-cyclohexyl-4-[(4-aminomethyl phenyl)]-2,5-lupetazin-1-formyl ammonia.
10, as claim 1 or 9 described substituted-piperazinyl compounds and all steric isomer, pharmacologically acceptable salt, solvate, hydrate or crystal formations thereof, it is characterized in that described pharmacologically acceptable salt is the substituted-piperazinyl compounds of general formula (I) expression and the salt that hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, xitix, nicotinic acid, citric acid, tartrate, lactic acid, toxilic acid, propanedioic acid, fumaric acid, oxyacetic acid, succsinic acid, propionic acid, acetate or methylsulfonic acid form.
11, the preparation method of the substituted-piperazinyl compounds of a kind of general formula (I) expression is characterized in that this method comprises:
With the following A-5 compound of structural formula is raw material,
The carboxylic acid R of A-5 compound and different replacements 3-COOH is by condensation reaction, perhaps the carboxylic acid halides R of A-5 compound and different replacements 3-COX reaction, making V is that C=O, W are general formula (I) compound of direct key
Figure A2007100416400007C2
R wherein 1, R 2, R ', R " and R 3Definition according to claim 1, X is a halogen;
Perhaps
The isocyanide ester R of A-5 compound and different replacements 3-NCO reaction; Perhaps, by phosgene, three surpalites or N, N '-carbonyl dimidazoles and organic amine R 3-NH 2Reaction generates active carbonyl compound, this active carbonyl compound and the reaction of A-5 compound, and making V is that C=O, W are general formula (I) compound of NH
Figure A2007100416400007C3
R wherein 1, R 2, R ', R " and R 3Definition according to claim 1;
Perhaps
The different sulphur nitrile acid esters R of A-5 compound and different replacements 3-NCS reaction; Perhaps, by N, N '-thiocarbonyldiimidazole and organic amine R 3-NH 2Reaction generates active thiocarbonyl compound, this activity thiocarbonyl compound and the reaction of A-5 compound, and making V is that C=S, W are general formula (I) compound of NH
Figure A2007100416400007C4
R wherein 1, R 2, R ', R " and R 3Definition according to claim 1;
Perhaps
The SULPHURYL CHLORIDE R of A-5 compound and different replacements 3-SO 2The Cl reaction, making V is SO 2, W is general formula (I) compound of direct key
Figure A2007100416400008C1
R wherein 1, R 2, R ', R " and R 3Definition according to claim 1.
12, preparation method as claimed in claim 11 is characterized in that, the A-5 compound makes as follows:
Figure A2007100416400008C2
Step a, by the grignard reaction coupling, temperature of reaction-10 ℃～200 ℃ obtains the A-3 compound with A-1 compound and A-2 compound;
A-3 compound that step b, step a obtain and halogenating agent reaction make A-4 compound, 20 ℃～150 ℃ of temperature of reaction;
The substituted-piperazinyl reaction of A-4 compound that step c, step b obtain and piperazine or the protection of nitrogen-atoms list makes A-5 compound, 0～200 ℃ of temperature of reaction;
Wherein X is a halogen, R 1, R 2, R ', R " definition as claim 1.
13, preparation method as claimed in claim 11 is characterized in that, the A-5 compound makes as follows:
Figure A2007100416400008C3
Step a obtains ketone B-3 by B-1 compound and B-2 compound by friedel-crafts acylation reaction, 0～200 ℃ of temperature of reaction;
Step b, the B-3 ketone that step a is obtained be by generating two aryl carboxamides with formamide, and then handle through acidic alcohol and to obtain the B-4 compound;
Step c, with B-4 compound and the N that step b obtains, N-two-(2-chloroethyl)-4-methyl benzenesulfonamide reaction after removing 4-Methyl benzenesulfonyl amine protecting group, obtains formula A-5 compound;
Wherein, R 1, R 2, R ', R " definition according to claim 1; X, Y are halogen.
14, as each described substituted-piperazinyl compounds in the claim 1～10 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formation purposes in the medicine of disease, illness and/or obstacle that the preparation treatment is regulated by cannabinoid receptor antagonists thereof.
15, purposes as claimed in claim 14 is characterized in that, described Cannabined receptor is the CB1 acceptor.
16, as claim 14 or 15 described purposes, it is characterized in that described disease is a cannabis abuse, obesity, schizophrenia, epilepsy, nervous, dysmnesia, migraine, vomiting, the thymus gland obstacle, dyskinesia, dyskinesis, anxiety disorder, mental disorder, cognitive disorder, limited appetite, emotional handicap, lose consciousness, neuropathy, Parkinson's disease, alzheimer disease, depressed, the disease of neuroinduction, ethanol, opium, Nicotine or cocaine addiction or with the excessive relevant feed disease of picked-up of food, wherein with food excessively the relevant feed disease of picked-up be selected from: obesity, teenager's obesity, drug-induced obesity, bulimia and mandatory feed illness.
17, a kind of pharmaceutical composition, it comprises as each described substituted-piperazinyl compounds in the claim 1～10 and all steric isomer, its pharmacologically acceptable salt, solvate, hydrate or crystal formation thereof as activeconstituents, and further comprises pharmaceutically acceptable vehicle, diluent or carrier.
18, pharmaceutical composition as claimed in claim 17 is characterized in that, said composition further comprises slimming agents, nicotine receptor partial agonist, dopaminergic or OPIOIDS antagonist.
19, pharmaceutical composition as claimed in claim 17 is characterized in that, said composition further comprises at least a lipase inhibitor or has the medicine of effect for reducing fat.
20, pharmaceutical composition as claimed in claim 19 is characterized in that, described lipase inhibitor is orlistat or mud pool Si Tating; Described medicine with effect for reducing fat is a nicotinic acid.
CNA2007100416407A 2007-06-05 2007-06-05 Substituted diethylenediamine compounds, preparation method, uses and medicament composition containing the compounds Pending CN101318943A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNA2007100416407A CN101318943A (en) 2007-06-05 2007-06-05 Substituted diethylenediamine compounds, preparation method, uses and medicament composition containing the compounds

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNA2007100416407A CN101318943A (en) 2007-06-05 2007-06-05 Substituted diethylenediamine compounds, preparation method, uses and medicament composition containing the compounds

Publications (1)

Publication Number Publication Date
CN101318943A true CN101318943A (en) 2008-12-10

Family

ID=40179245

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2007100416407A Pending CN101318943A (en) 2007-06-05 2007-06-05 Substituted diethylenediamine compounds, preparation method, uses and medicament composition containing the compounds

Country Status (1)

Country Link
CN (1) CN101318943A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603678A (en) * 2011-01-25 2012-07-25 中国科学院上海药物研究所 Diphenyl-methyl piperazine compound, preparation and use of the diphenyl-methyl piperazine compound
CN115611855A (en) * 2022-05-11 2023-01-17 西北大学 Nicotinamide type compound and application thereof in preparation of weight-losing medicine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603678A (en) * 2011-01-25 2012-07-25 中国科学院上海药物研究所 Diphenyl-methyl piperazine compound, preparation and use of the diphenyl-methyl piperazine compound
CN115611855A (en) * 2022-05-11 2023-01-17 西北大学 Nicotinamide type compound and application thereof in preparation of weight-losing medicine
CN115611855B (en) * 2022-05-11 2023-11-24 西北大学 Nicotinamide compound and application thereof in preparation of weight-losing medicines

Similar Documents

Publication Publication Date Title
CN102803269B (en) Thieno-[2,3-B] the pyrimidine dione activator of AMPK and therepic use thereof
CN103209704B (en) Organic compound
CN101356169A (en) Pyrazine derivatives
CN105517989A (en) Mixtures of cannabinoid compounds, and production and use thereof
CA3169679A1 (en) Methods of treating estrogen receptor-associated diseases
US9221781B2 (en) Synthesis of polyhydroxy chromenone compounds and their anti-tumor effects
CN104395319A (en) Thienopyridone derivatives useful as activators of ampk
TW200400037A (en) 5Ht2c receptor modulators
TWI579277B (en) A substituted cinnamamide derivative, a method for preparing the same, use thereof and a pharmaceutical composition
CN101522685A (en) Tricyclic spiro-oxindole derivatives and their uses as therapeutic agents
CN101636385B (en) Naphthalene and quinoline sulfonylurea derivatives as EP4 receptor antagonists
RU2557235C1 (en) Substituted 2-thioxo-imidazolidin-4-one, and spiroanalogues thereof, anticancer active ingredient, pharmaceutical composition, medicinal product, method of treating prostate cancer
CN105837562A (en) Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament
CN112654616A (en) 3-aryloxy-3-aryl-propylamine compounds and application thereof
BRPI0706992A2 (en) compound, pharmaceutical formulation, and use of a compound, salt or stereoisomer
CN107007587A (en) For inducing chondrogenetic Compounds and methods for
EP3617195A1 (en) Novel tetrahydronaphthyl urea derivatives
CN103391932B (en) For suppressing the heterogeneous ring compound of PASK
JP2020537667A (en) Antagonist of muscarinic acetylcholine receptor M4
CN101415707B (en) Heterobicyclic amide derivatives
AU2016302755A1 (en) 5-HT2C receptor agonists and compositions and methods of use
CN101801187A (en) heterocyclic modulators of cannabinoid receptors
JP2004535413A (en) Cinnamide derivatives as KCNQ potassium channel modulators
JP2011201777A (en) Optically active heterocyclidene-n-arylacetamide derivative
CN109415295A (en) α-truxillic acid derivative and its pharmaceutical composition

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20081210