CN103467460A - Diaryl methyl piperazine compounds containing thiophene rings and benzyls and application thereof - Google Patents
Diaryl methyl piperazine compounds containing thiophene rings and benzyls and application thereof Download PDFInfo
- Publication number
- CN103467460A CN103467460A CN2013104353008A CN201310435300A CN103467460A CN 103467460 A CN103467460 A CN 103467460A CN 2013104353008 A CN2013104353008 A CN 2013104353008A CN 201310435300 A CN201310435300 A CN 201310435300A CN 103467460 A CN103467460 A CN 103467460A
- Authority
- CN
- China
- Prior art keywords
- dimethyl
- piperazinyl
- benzyl
- thiophene
- luorobenzyl
- 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
Links
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 title claims abstract description 110
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims abstract description 24
- -1 Diaryl methyl piperazine compounds Chemical class 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 230000000202 analgesic effect Effects 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 229930192474 thiophene Natural products 0.000 claims description 54
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000011630 iodine Substances 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229940095064 tartrate Drugs 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 235000019439 ethyl acetate Nutrition 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
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- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 2
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
The invention discloses diaryl methyl piperazine compounds containing thiophene rings and benzyls, or pharmaceutically acceptable esters, or pharmaceutically acceptable salts thereof. The compounds provided by the invention belong to delta, mu and kappa opiate receptor triple agonists which can be used for treating moderate to severe pain; compared with the existing diaryl methyl piperazine delta, mu and kappa opiate receptor triple agonists, such as DPI-3290 and DPI-125, the original N-allyl is substituted by N-benzyl structure fragments with better metabolic stability in the compounds provided by the invention; the metabolic stability of the compound can be increased expectedly; the analgesic activity can be well played.
Description
Technical field
The present invention relates to a class diaryl methylpiperazine compound, relate in particular to the diaryl methylpiperazine compound replaced containing thiphene ring and benzyl, and as the therepic use of analgesic.
Background technology
The pain sensation is the fundamental sensation of human body, at human body, avoids injury and maintain the aspect such as internal secretion environment having great importance
[1].Yet some has an intense pain for a long time, body is caused to a kind of insufferable torment
[2-4].Therefore, the research of analgesic is always in widespread attention.
Opiate receptor is the action target spot of opium kind analgesics thing, and the perception of pain is played to important neuroregulation effect.Opiate receptor belongs to g protein coupled receptor, be distributed in the central nervous system peripheral nervous system of unifying, mainly be divided into 3 kinds of hypotypes, i.e. μ, δ and kappa receptor, the endogenous opiatepeptide of answering in contrast is respectively endorphin (endorphin), enkephalin (enkephalins) and dynorphin
[5-8].In addition, opioid receptor 1(opioid receptor like 1, ORL1) have homology highly with classical μ, δ and kappa receptor, also belong to opiate receptor family, its endogenic ligand is orphanin FQ (orphanin FQ, OFQ) or nociceptin (nociceptin, NOP).Opioid drug acts on μ, δ and kappa receptor usually, produces corresponding physiological action.
Traditional opioid drug as Main Functions such as morphine, fentanyl, methadones in the mu opioid receptor of central nervous system, usually used as analgesic, with the treatment moderate and severe pain, but suppress and the side effects such as habituation with gastrointestinal motility inhibition, respiration inhibition, tolerance, dependency, the reaction of urinating
[8].The research discovery, the activation of δ and kappa receptor also shows analgesic activity in various degree.The BW373U86 of early discovery is the selectivity delta receptor agonist, can treat inflammation and neuropathic pain
[9,10].U50,488 alternative exciting kappa receptors, have analgesic activity, the dependency caused without the morphine class
[11,12].
Research finds that there is certain balance relationship in the stirring effect of different opiate receptor hypotypes.For example, BW373U86 and morphine are used simultaneously, can weaken dependency, respiration inhibition that morphine causes, and improve the analgesic activity of morphine
[13,14].The dual agonists of μ and delta opiate receptor has an analgesic activity preferably through μ is receptor-mediated, acts on δ simultaneously and is subject to physical efficiency to alleviate respiration inhibition and dependency
[15].In addition, exciting μ of while and kappa receptor, analgesic activity better also obviously alleviates habituation and tolerance
[16-18].
On this basis, the active δ of development opiate receptor > μ > triple agonists of κ become one of effective ways that alleviate the opioid drug side effect.Diaryl methylpiperazine Compound D PI-3290 has agonist activity to δ, μ and the triple acceptors of κ, and analgesic activity intensity is between morphine and fentanyl, and the respiration inhibition effect is relative with the physical dependence habituation to be weakened, and Medical security index increases greatly
[19,20].DPI-3290 enters phase ii clinical trial in the U.S., and the analgesic effect of Patients Undergoing Abdominal Surgery operation posterior vein drug administration by injection is tested and shown, analgesic effect is equivalent to morphine, but the respiration inhibition effect do not occur.Patent application WO 03/026660 has announced another kind of δ, μ, the triple agonist DPI-125 of κ, in the U.S., has also entered a clinical trial phase.Obvious reduction is compared in the respiration inhibition effect of clinical effectiveness proof δ, μ, the triple agonists of kappa receptor with fentanyl with morphine with habituation.Therefore, this compounds possesses unique advantage, can obviously alleviate the side effects such as respiration inhibition that traditional opium kind analgesics thing causes, dependency, habituation.Above-mentioned research and other report show, δ, μ, the triple agonists of kappa opioid receptor are the analgesics that have good prospects
[21].
Yet DPI-3290 and DPI-125 all contain the N-allylic structure fragment of easier metabolism, cause metabolic stability poor, bioavailability is low, can not oral administration, limited clinical value.Early-stage Study based on us, the purpose of this invention is to provide the novel diaryl methylpiperazine medicine of a class containing thiphene ring and benzyl, to improve the metabolic stability of compound.
reference
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[7]Yasuda,?K.,?et?al.,?Cloning?and?functional?comparison?of?kappa?and?delta?opioid?receptors?from?mouse?brain.?Proc.?Natl.?Acad.?Sci.?USA?1993,?90:?6736-6740。
[8]Eguchi,?M.;?Recent?advances?in?selective?opioid?receptor?agonists?and?antagonists.?Med.?Res.?Rev.?2004,?24:?182-212。
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[10]Wild,?K.?D.,?et?al.,?Binding?of?BW?373U86,?a?non-peptidic?delta?opioid?receptor?agonist,?is?not?regulated?by?guanine?nucleotides?and?sodium.?Eur.?J.?Pharmacol.?1993,?246:?289-292。
[11]Lahti,?R.?A.,?et?al.,?Properties?of?a?selective?kappa?agonist,?U-50,488H.?Life?Sci.?1982,?31:?2257-2260。
[12]Bown,?C.?A.,?et?al.,?Effects?of?mixed-Action?kappa/mu?opioids?on?cocaine?self-administration?and?cocaine?discrimination?by?rhesus?monkeys.?Neuropsychopharmacology?2003,?28:?1125-1139。
[13]O’Neill,?S.?J.,?et?al.,?Antagonistic?modulation?between?the?delta?opioid?agonist?BW373U86?and?the?mu?opioid?agonist?fentanyl?in?mice.?J.?Pharmacol.?Exp.?Ther.?1997,?282:?271-277。
[14]Negus,?S.?S.,?et?al.,?Role?of?delta?opioid?efficacy?as?a?determinant?of?mu/delta?opioid?interactions?in?rhesus?monkeys.?Eur.?J.?Pharmacol.?2009,?602:?92-100。
[15]Grundt,?P.,?et?al.,?14-Amino,?14-alkylamino,?and?14-acylamino?analogs?of?oxymorphindole.?Differential?effects?on?opioid?receptor?binding?and?functional?profiles.?J.?Med.?Chem.?2003,?46:?1563-1566。
[16]Wang,?Y.?J.,?et?al.,?Pharmacological?characterization?of?ATPM?[(-)-3-aminothiazolo[5,4-b]-N-?cyclopropylmethylmorphinan?hydrochloride],?a?novel?mixed?mu-agonist?and?delta-?agonist/antagonist?that?attenuates?morphine?antinociceptive?tolerance?and?heroin?self-administration?behavior.?J.?Pharmacol.?Exp.?Ther.?2009,?329:?306-313。
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[19]Gengo,?P.?J.,?et?al.,?DPI-3290?[(+)-3-((α?R)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-?piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide].?II.?A?mixed?opioid?agonist?with?potent?antinociceptive?activity?and?limited?effects?on?respiratory?function.?J.?Pharmacol.?Exp.?Ther.?2003,?307:?1227-1233。
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Summary of the invention
The object of the present invention is to provide a kind of diaryl methylpiperazine compound containing thiphene ring and benzyl, or the acceptable ester of its pharmacy or its pharmacologically acceptable salts,
In formula: R
1be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl or methoxyl group; R
2be selected from hydrogen, fluorine, chlorine, bromine or iodine, the position of substitution is 2,3 or 4 of A ring.
Preferred the compounds of this invention comprises:
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(4-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(4-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene.
Work as R described in the present invention
1during for hydroxyl, the pharmaceutically acceptable ester of compound, be selected from manthanoate, acetic ester, propionic ester, butyric ester, trifluoro-acetate, oleic acid ester, stearate etc.
The pharmacy acceptable salt of compound described in the present invention, be selected from vitriol, hydrochloride, hydrobromate, phosphoric acid salt, trifluoroacetate, mesylate, benzene sulfonate, tosilate, fluoroform sulphonate, camsilate, formate, acetate, propionic salt, hexanoate, adipate, tartrate, Citrate trianion, benzoate, fumarate, maleate, lactic acid salt, succinate etc.
The synthetic method of the compounds of this invention is that to take four component cascade reactions be committed step, by 3-thiophenecarboxaldehyde, chirality lupetazin and benzotriazole at first condensation obtain unsettled adducts, react with aryl grignard reagent generation Asymmetrical substitute again, through aftertreatment, obtain corresponding target compound.
Another object of the present invention is to provide a kind of diaryl methylpiperazine compound that contains structural formula shown in general formula (I) or the acceptable ester of its pharmacy, or the pharmaceutical composition of its pharmacologically acceptable salts, with diaryl methylpiperazine compound or the acceptable ester of its pharmacy of structural formula shown in general formula (I), or its pharmacologically acceptable salts is as main effectively activeconstituents, also can add one or more pharmaceutically acceptable auxiliary materials, to improve the drug absorption effect or to be convenient to take, as make capsule or pill, pulvis, tablet, granula, oral liquid and injection liquid etc., auxiliary material of the present invention comprises weighting agent, thinner, tackiness agent, vehicle, absorption enhancer, tensio-active agent and the stablizer etc. of pharmaceutical field routine, also can add flavouring agent, pigment and sweeting agent etc. in case of necessity.
The compounds of this invention using method comprises the medicine of using significant quantity to described patient, can adopt any suitable administering mode to use these treatment monomeric compound or compositions, for example be selected from the administering mode of following manner: oral, rectum, part, hypogloeeis, mucous membrane, nose, eye, subcutaneous, intramuscular, intravenously, in skin, vertebra, sheath, under intraarticular, intra-arterial, arachnoid membrane, segmental bronchus, lymph and uterus administration.
The compounds of this invention belongs to δ, μ, the triple agonists of kappa opioid receptor, can be used for treating the pain of moderate to severe.With respect to diaryl methylpiperazine class δ, μ, the triple agonists of kappa opioid receptor such as existing DPI-3290 and DPI-125, compound provided by the invention with metabolic stability preferably N-benzyl structure fragment substituted original N-allyl group, expection can improve the metabolic stability of compound, brings into play better analgesic activities.
Embodiment
Can further be well understood to the present invention by Preparation Example of the present invention given below and pharmacological testing; but do not form limiting the scope of the present invention; method all operations according to a conventional method if no special instructions, the conventional reagent of agents useful for same employing if no special instructions or the reagent configured according to a conventional method in the present embodiment.
embodiment 1:the preparation of 3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol
Particular content is as follows:
Step 1, (2R, 5S)-1-benzyl-2, the preparation of 5-lupetazin: take trans 2, 5-lupetazin alkali (114.0 g, 1.0 mol) with its dihydrochloride (187.0 g, 1.0 mol) be placed in flask, add 1000 ml dehydrated alcohols, stirring lower heating in water bath to 70 ℃ makes it fully dissolve rear slow dropping benzyl chlorine (126.5 g, 1.0 mol), vigorous stirring, approximately within 2 hours, drip off, continue insulation reaction and be cooled to room temperature after 1 hour, filter, the filter cake absolute ethanol washing, merging filtrate, steam except ethanol, add water, after being greater than 12 by 10%NaOH solution adjusting pH value under stirring, use dichloromethane extraction, the extraction liquid anhydrous magnesium sulfate drying, filter, concentrated 1-benzyl-2 that are, 5-lupetazin racemoid, then split and can obtain isomer (2R with the method for tartrate salify crystallization, 5S)-1-benzyl-2, 5-lupetazin 82.7 g, productive rate 81%,
1H?NMR?(400?MHz,?CDCl
3)?δ?7.22-7.32?(m,?5H),?4.10?(d,?
J?=?13.5?Hz,?1H),?3.09?(d,?
J?=?13.5?Hz,?1H),?2.91?(dd,?
J=?12.1,?3.1?Hz,?1H),?2.83-2.74?(m,?1H),?2.70-2.60?(m,?2H),?2.28-2.17?(m,?1H),?1.63?(dd,?
J=?11.0,?10.3?Hz,?1H),?1.49?(br,?1H),?1.14?(d,?
J?=?6.0?Hz,?3H),?0.94?(d,?
J?=?6.2?Hz,?3H)。
The preparation of step 2,3-(bromo phenoxy group) tertiary butyl dimethylsilane: by 3-bromophenol (30.1 g, 174 mmol) be dissolved in DMF(200 ml) in, add TBSCl(26.2 g under room temperature, 174 mmol) and imidazoles (23.7 g, 348 mmol), stirring at room 3 h, after completion of the reaction, add saturated NaHCO
3solution (200 ml) cancellation, petroleum ether extraction, water, salt solution wash successively, and anhydrous magnesium sulfate drying concentrates to obtain transparent light yellow liquid 38.6 g, productive rate 77%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.25-7.03?(m,?3H),?6.58-6.43?(m,?1H),?0.98?(s,?9H),?0.20?(s,?6H)。
The preparation of step 3,3-(tertiary butyl dimethyl-silicon alcoxyl base) phenyl-magnesium-bromide: take magnesium rod (1.5 g, 61.7 mmol) be placed in round-bottomed flask, add anhydrous tetrahydro furan (90 ml), by 3-(bromo phenoxy group) tertiary butyl dimethylsilane (14.4 g, 50.1 mmol) proceed in magnesium rod, be warming up to 45 ℃ of reactions, magnesium rod obtains the anhydrous tetrahydrofuran solution of the transparent 3-tertiary butyl dimethyl-silicon alcoxyl base phenyl-magnesium-bromide of light brown after dissolving fully, be cooled to after room temperature standby.
Step 4, 3-((α-S)-α-((2S, 5R)-4-benzyl-2, 5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) preparation of phenol: add 3-thiophenecarboxaldehyde (2.92 g in the round-bottomed flask of an assembling condenser and Dean-Stark water trap, 26 mmol), benzotriazole (3.10 g, 26 mmol), (2R, 5S)-1-luorobenzyl-2, 5-lupetazin (5.31 g, 26 mmol) and toluene (100 ml), this reaction mixture reflux under nitrogen protection is complete to dewatering, then cool to room temperature, add 50 ml anhydrous tetrahydro furans under nitrogen protection and constantly stir, the 3-tertiary butyl dimethyl-silicon alcoxyl base phenyl-magnesium-bromide solution of above-mentioned preparation is slowly added, continue again stirring at room to reacting completely, add the saturated aqueous ammonium chloride cancellation, the ethyl acetate extraction, anhydrous magnesium sulfate drying, filter, after desolventizing, steaming obtains brown thickness oily matter, this oily matter at room temperature is dissolved in methyl alcohol (100 ml) and 1 N hydrochloric acid (50 ml) mixed solution, stir 1.5 hours, after completion of the reaction, by 50 ml water diluting reaction systems, with after 2 M sodium hydroxide adjusting pH to 9, being extracted with ethyl acetate product, combining extraction liquid, water and saturated brine washing respectively, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, purified white solid 2.50 g, productive rate 81 % of obtaining of crude product.
1H?NMR?(400?MHz,?CDCl
3)?δ?7.26-7.18?(m,?8H),?7.14-7.02?(m,?4H),?5.10?(s,?1H),?4.05?(d,?
J?=?13.0?Hz,?1H),?3.09?(d,?
J?=?13.0?Hz,?1H),?2.72?(dd,?
J?=?11.5,?2.6?Hz,?1H),?2.64?(dd,?
J?=?11.2,?2.9?Hz,?1H),?2.51-2.36?(m,?2H),?2.03-1.90?(m,?3H),?1.13?(d,?
J?=?6.2?Hz,?3H),?1.06?(d,?
J?=?6.0?Hz,?3H)。
The described synthetic method of embodiment 1 is equally applicable to embodiment 2-12.
embodiment 2:the preparation of 3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol
Synthetic method is with embodiment 1, and difference is step 1, four:
Step 1, (2R, 5S)-1-(3-luorobenzyl)-2, the preparation of 5-lupetazin: the 3-fluorine benzyl chlorine of take is raw material, adopts the described method of embodiment 1 step 1 to make 1-(3-luorobenzyl)-2,5-lupetazin raceme, productive rate 86%; Split and obtain (2R, 5S)-1-(3-luorobenzyl)-2,5-lupetazin, productive rate 40% through the crystallization of chirality tartrate salify again;
1H?NMR?(400?MHz,?CDCl
3)?δ7.26-7.07?(m,?3H),?6.93-6.89?(m,?1H),?4.06?(d,
?J?=?13.7?Hz,1H),?3.05?(d,?
J?=?13.7?Hz,?1H),?2.90?(dd,?
J=?12.1,?3.0?Hz,?1H),?2.80-2.78?(m,?1H),?2.66-2.59?(m,?2H),?2.24-2.23?(m,?1H),?1.76?(br,?1H),?1.64?(t,?
J?=?10.8?Hz,?1H),?1.10?(d,
?J?=?6.1?Hz,?3H),?0.94?(d,?
J?=?6.4?Hz,?3H)。
Step 4,3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) preparation of phenol: with (2R, 5S)-1-(3-luorobenzyl)-2, the 5-lupetazin is raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 51%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.30-7.18?(m,?5H),?7.14-7.02?(m,?6H),?5.11?(s,?1H),?4.25?(d,?
J?=?10.5?Hz,?1H),?3.09?(d,?
J?=?13.0?Hz,?1H),?2.77?(dd,?
J?=?11.5,?2.6?Hz,?1H),?2.54?(dd,?
J?=?11.2,?2.9?Hz,?1H),?2.51-2.36?(m,?2H),?2.03-1.90?(m,?3H),?1.13?(d,?
J?=?6.2?Hz,?3H),?1.06?(d,?
J?=?6.0?Hz,?3H)。
embodiment 3:the preparation of 3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol
Synthetic method is with embodiment 1, and difference is step 1, four:
Step 1, (2R, 5S)-1-(4-luorobenzyl)-2, the preparation of 5-lupetazin: the 4-fluorine benzyl chlorine of take is raw material, adopts the described method of embodiment 1 step 1 to make 1-(4-luorobenzyl)-2,5-lupetazin raceme, productive rate 88%; Split and obtain (2R, 5S)-1-(4-luorobenzyl)-2,5-lupetazin, productive rate 37% through the crystallization of chirality tartrate salify again;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.22-7.17?(m,?2H),?6.90-6.99?(m,?2H),?4.04?(d,
?J?=?13.7?Hz,1H),?3.06?(d,?
J?=?13.7?Hz,?1H),?2.91?(dd,?
J=?12.1,?3.0?Hz,?1H),?2.80-2.77?(m,?1H),?2.66-2.60?(m,?2H),?2.25-2.23?(m,?1H),?1.77?(br,?1H),?1.63?(t,?
J?=?10.8?Hz,?1H),?1.10?(d,
?J?=?6.1?Hz,?3H),?0.93?(d,?
J?=?6.4?Hz,?3H)。
Step 4,3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) preparation of phenol: with (2R, 5S)-1-(4-luorobenzyl)-2, the 5-lupetazin is raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 51%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.31-7.20?(m,?4H),?7.12-6.98?(m,?7H),?5.13?(s,?1H),?4.25?(d,?
J?=?10.5?Hz,?1H),?3.07?(d,?
J?=?13.0?Hz,?1H),?2.80?(dd,?
J?=?11.5,?2.6?Hz,?1H),?2.53?(dd,?
J?=?11.2,?2.9?Hz,?1H),?2.50-2.37?(m,?2H),?2.01-1.90?(m,?3H),?1.13?(d,?
J?=?6.2?Hz,?3H),?1.03?(d,?
J?=?6.0?Hz,?3H)。
embodiment 4:the preparation of 3-((α-S)-α-((2S, 5R)-4-(4-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol
Synthetic method is with embodiment 1, and difference is step 1, four:
Step 1, (2R, 5S)-1-(4-chlorobenzyl)-2, the preparation of 5-lupetazin: the 4-benzyl chloride chlorine of take is raw material, adopts the described method of embodiment 1 step 1 to make 1-(4-chlorobenzyl)-2,5-lupetazin raceme, productive rate 92%; Split and obtain (2R, 5S)-1-(4-chlorobenzyl)-2,5-lupetazin, productive rate 32% through the crystallization of chirality tartrate salify again;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.26-7.22?(m,?2H),?7.06-7.04?(m,?2H),?4.07?(d,?
J?=?13.7?Hz,?1H),?3.06?(d,?
J?=?13.7?Hz,?1H),?2.91?(dd,
?J=?12.1,?3.0?Hz,?1H),?2.80-2.78?(m,?1H),?2.65-2.59?(m,?2H),?2.24-2.23?(m,?1H),?1.76?(br,?1H),?1.65?(t,?
J?=?10.7?Hz,?1H),?1.10?(d,?
J?=?6.1?Hz,?3H),?0.94?(d,?
J?=?6.4?Hz,?3H)。
Step 4,3-((α-S)-α-((2S, 5R)-4-(4-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) preparation of phenol: with (2R, 5S)-1-(4-chlorobenzyl)-2, the 5-lupetazin is raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 45%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.27-6.91?(m,?11H),?5.39?(s,?1H),?4.11?(d,?
J?=?8.5Hz,?1H),?3.19?(d,?
J?=?13.0?Hz,?1H),?2.77-2.52?(m,?2H),?2.51-2.36?(m,?2H),?2.00-1.90?(m,?3H),?1.21?(d,?
J?=?6.2?Hz,?3H),?1.16?(d,?
J?=?7.0?Hz,?3H)。
embodiment 5:the preparation of 3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol
Synthetic method is with embodiment 1, and difference is step 1, four:
Step 1, (2R, 5S)-1-(3-bromobenzyl)-2, the preparation of 5-lupetazin: the 3-bromobenzyl chlorine of take is raw material, adopts the described method of embodiment 1 step 1 to make 1-(3-bromobenzyl)-2,5-lupetazin raceme, productive rate 86%; Split and obtain (2R, 5S)-1-(3-bromobenzyl)-2,5-lupetazin, productive rate 37% through the crystallization of chirality tartrate salify again;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.36-7.05?(m,?4H),?4.27?(d,?
J?=?10.7?Hz,?1H),?3.26?(d,
?J?=?23.7?Hz,?1H),?2.91-2.82?(m,?1H),?2.80-2.78?(m,?1H),?2.65-2.59?(m,?2H),?2.24-2.23?(m,?1H),?1.86?(br,?1H),?1.65?(t,?
J?=?10.7?Hz,?1H),?1.10?(d,?
J?=?6.1?Hz,?3H),?0.94-0.85?(m,?3H)。
Step 4,3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) preparation of phenol: with (2R, 5S)-1-(3-bromobenzyl)-2, the 5-lupetazin is raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 35%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.53-7.52?(m,?2H),?7.27-7.30?(m,?2H),?7.14-7.16?(m,?1H),?7.13-7.10?(m,?2H),?7.07-7.05?(m,?1H),?6.95?(t,?2H),?6.73-6.69?(m,?1H),?5.04?(s,?1H),?3.30?(s,?2H),?2.69-2.59?(m,?4H),?2.07-1.99?(m,?3H),?1.24-1.23?(m,?3H),?1.11-1.10?(d,?
J?=?5.8?Hz,?3H)。
embodiment 6:the preparation of 3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl) benzyl) thiophene
Synthetic method is with embodiment 1, and difference is step 2, three, four, without step 2:
The preparation of step 3, phenyl-magnesium-bromide: take bromobenzene as raw material, adopt the described method of embodiment 1 step 3 to make the anhydrous tetrahydrofuran solution of phenyl-magnesium-bromide, be cooled to after room temperature standby;
Step 4,3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl) benzyl) preparation of thiophene: take phenyl-magnesium-bromide as raw material, adopt the described method of embodiment 1 step 4 to make, for white solid, productive rate 62%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.40-7.20?(m,?3H),?7.12-7.05?(m,?4H),?7.00-6.92?(m,?5H),?3.75-3.70?(d,?
J?=?21.3?Hz,?2H),?3.69?(s,?2H),?3.52?(s,?2H),?3.20-3.17?(m,?1H),?2.73-2.60?(m,?3H),?2.01-1.85?(m,?3H),?1.60-1.51?(m,?3H)。
embodiment 7:the preparation of 3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene
Synthetic method is with embodiment 5, and difference is step 1, four:
Step 1, (2R, 5S)-1-(2-luorobenzyl)-2, the preparation of 5-lupetazin: identical with embodiment 2 step 1;
Step 4,3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl) benzyl) preparation of thiophene: with (2R, 5S)-1-(2-luorobenzyl)-2, the 5-lupetazin is raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 70%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.55-7.46?(m,?3H),?7.40-7.30?(m,?3H),?7.25-7.05?(m,?3H),?7.00-6.92?(m,?3H),?3.70-3.62?(m,?4H),?3.42?(s,?2H),?3.20-3.17?(m,?1H),?2.73-2.65?(m,?3H),?2.01-1.85?(m,?3H),?1.15-1.10?(m,?2H)。
embodiment 8:the preparation of 3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene
Synthetic method is with embodiment 5, and difference is step 1, four:
Step 1, (2R, 5S)-1-(3-chlorobenzyl)-2, the preparation of 5-lupetazin: identical with embodiment 3 step 1;
Step 4,3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) preparation of thiophene: with (2R, 5S)-1-(3-chlorobenzyl)-2, the 5-lupetazin is raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 37%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.43-7.30?(m,?4H),?7.23-7.10?(m,?3H),?7.07-6.95?(t,?2H),?6.73-6.69?(m,?3H),?4.67?(br,?1H),?3.90-3.88?(m,?2H),?3.62-3.53?(m,?2H),?3.30?(s,?2H),?2.69-2.59?(m,?4H),?2.07-1.99?(m,?2H),?1.11-1.10?(d,?
J?=?5.8?Hz,?2H)。
embodiment 9: the preparation of 3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene
Synthetic method is with embodiment 1, and difference is step 2, three, four:
The preparation of step 2,3-bromoanisole: take 3-bromophenol (15 g, 0.15 mol) and be dissolved in dry DMF, add sodium hydroxide (23.5 g, 0.58 mol), drip methyl iodide (18.3 ml, 0.30 mol) after stirring 30 min, stirred overnight at room temperature, after reacting completely, thin up, be extracted with ethyl acetate, water, salt solution wash successively, and anhydrous magnesium sulfate drying is concentrated, purifying obtains colourless liquid 26.5 g, productive rate 96 %;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.11-6.90?(m,?1H),?6.80-6.72?(m,?1H),?3.72?(s,?1H)；
The preparation of step 3,3-p-methoxy-phenyl magnesium bromide: the 3-methoxyl group bromobenzene of take is raw material, adopts the described method of embodiment 1 step 3 to make the anhydrous tetrahydrofuran solution of 3-p-methoxy-phenyl magnesium bromide, is cooled to after room temperature standby;
Step 4,3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-the methoxy-benzyl)) preparation of thiophene: the 3-p-methoxy-phenyl magnesium bromide of take is raw material, adopt the described method of embodiment 1 step 4 to make, for white solid, productive rate 51%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.30-7.15?(m,?7H),?7.12-7.02?(m,?4H),?5.21?(s,?3H),?4.13?(d,?
J?=?13.0?Hz,?1H),?3.39?(d,?
J?=?13.0?Hz,?1H),?2.82?(dd,?
J?=?10.5,?2.6?Hz,?1H),?2.64?(dd,?
J?=?15.2,?2.1?Hz,?1H),?2.51-2.36?(m,?2H),?2.03-1.90?(m,?3H),?1.13?(d,?
J?=?6.2?Hz,?3H),?1.06?(d,?
J?=?6.0?Hz,?3H)。
embodiment 10:the preparation of 3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene
Synthetic method is with embodiment 8, and difference is step 1, four:
Step 1, (2R, 5S)-1-(2-luorobenzyl)-2, the preparation of 5-lupetazin: identical with embodiment 2 step 1;
Step 4,3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-the methoxy-benzyl)) preparation of thiophene: with (2R, 5S)-1-(2-luorobenzyl)-2,5-lupetazin and 3-p-methoxy-phenyl magnesium bromide are raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 43%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.44-7.32?(m,?3H),?7.27-7.10?(m,?3H),?7.00-6.91?(t,?2H),?6.80-6.69?(m,?3H),?4.67?(br,?1H),?3.90-3.88?(m,?2H),?3.62-3.53?(m,?2H),?3.30?(s,?3H),?2.69-2.59?(m,?4H),?2.07-1.99?(m,?4H),?1.10?(d,?
J?=?5.8?Hz,?2H)。
embodiment 11: the preparation of 3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene
Synthetic method is with embodiment 8, and difference is step 1, four:
Step 1, (2R, 5S)-1-(3-chlorobenzyl)-2, the preparation of 5-lupetazin: identical with embodiment 2 step 1;
Step 4,3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-the methoxy-benzyl)) preparation of thiophene: with (2R, 5S)-1-(3-chlorobenzyl)-2,5-lupetazin and 3-p-methoxy-phenyl magnesium bromide are raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 43%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.45?(d,?
J?=?8.1?Hz,?2H),?7.24?(m,?5H),?7.13?(m,?1H),?7.10?(t,?
J?=?7.7?Hz,?3H),?5.13?(s,?1H),?3.95?(d,
?J?=?13?Hz,?2H),?3.55?(s,?3H),?3.29-3.00?(m,?2H),?2.65?(dd,
?J?=?9.0,?2.0?Hz,?2H),?1.99?(m,?2H),?1.24?(m,?4H),?1.09?(d,?
J?=?6.1?Hz,?2H)。
embodiment 12:the preparation of 3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene
Synthetic method is with embodiment 8, and difference is step 2, three, four, without step 2:
The preparation of step 3,3-fluorophenyl magnesium bromide: take the 3-bromofluorobenzene as raw material, adopt the described method of embodiment 1 step 3 to make the anhydrous tetrahydrofuran solution of the fluorine-based phenyl-magnesium-bromide of 3-, be cooled to after room temperature standby;
Step 4,3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-the luorobenzyl)) preparation of thiophene: with (2R, 5S)-1-benzyl-2,5-lupetazin and 3-fluorophenyl magnesium bromide are raw material, adopting the described method of embodiment 1 step 4 to make, is white solid, productive rate 33%;
1H?NMR?(400?MHz,?CDCl
3)?δ?7.43-7.30?(m,?2H),?7.28-7.22?(m,?5H),?7.21-7.10?(m,?3H),?7.04?(m,?2H),?3.87?(d,?
J?=?13.5?Hz,?2H),?3.53-3.42?(m,?2H),?3.28-3.20?(m,?2H),?3.18?(d,?
J?=?13.8?Hz,?1H),?2.02?(dd,?
J?=?8.2?Hz,?3H),?1.15?(d,?
J?=?6.1?Hz,?3H),?1.06?(d,?
J?=?6.1?Hz,?3H)。
embodiment 13: opiate receptor is in conjunction with experiment
The opiate receptor affinity of the compounds of this invention is measured (according to Payza in conjunction with experiment by opiate receptor; K.; Binding and activity of opioid ligands at the cloned human delta; mu and kappa receptors. in The Delta Receptor; Chang, Porreca & Wood eds. 2004, Marcel Dekker, Inc. New York, method described in Basel), concrete steps are as follows.
The rat brain membrane preparation: murine brain (brain of male albefaction Sprague-Dawley rat or the cerebellum of male Albino guinea pig) adopts ice-cold Tris-HCl buffer solution for cleaning, and (pH 7.4,50 mM, 25 ℃), the Tris-HCl damping fluid comprises following proteinase inhibitor: 50 μ g/ml leucine enzyme inhibitorss, 200 μ g/ml bacitracins and 0.5 μ g/ml proteinase inhibitor (Aprotinin); Every 1 g weight in wet base cerebral tissue adds 10 times of above-mentioned ice-cold Tris-HCl damping fluids of volume, and adopts the mechanical refiner that contains tetrafluoroethylene granulated glass sphere (0.13-0.18 mm) to make brain tissue homogenate; Homogenate, at 4 ℃, centrifugal 15 min of 6000 g, is collected supernatant liquor and centrifugal 30 min under 41000 g; Every 1 g weight in wet base cerebral tissue film precipitates with 10 mM Tris-sucrose damping fluid (0.32 M) Eddy diffusions of 10 times of volumes and adopts tissue grinder to process (10 s, low speed).Homogenate after supersound process is at 4 ℃, centrifugal 30 min of 41000 g; The 50 mM Tris damping fluid Eddy diffusions that contain proteinase inhibitor for the film throw out, the protein final concentration is 40 ~ 50 μ g/ml; Membrane granule after suspension with liquid nitrogen or-80 ℃ frozen, measure protein concentration by the Bandford method before using.
The receptors bind experiment: the rat brain membrane after resuspension and 0.1 nM [
3h] deltorphin II-δ-acceptor (than vigor 38.5-40.6 Ci/mmol), 0.1 nM [
3h] DAMGO-μ-acceptor (than vigor 50 Ci/mmol) or 0.1 nM [
3h] U69593-κ-acceptor contains 4 mM MgCl at 2 ml
2, proteinase inhibitor and testing compound (between 1.0 nM to 100 μ M, gradient concentration being set) 10 mM Tris-HCl damping fluids in 25 ℃ of temperature bathe 90 min, make radioligand and acceptor complete equipilibrium.Adopt cell harvestor (model M-48R, Brandel Instruments, Gaithersberg, MD) with 5 ml ice-cold 50 mM Tris damping fluid fast filterings by twice of glass fiber filter, to stop part and receptor response, combination rate adopts 1 * 10
-6the M naloxone replaces radioligand and defines, and the specific binding rate is determined with liquid flash spectrum counting, the external perimysium reference 40-45% of mensuration.Take the combination rate data as ordinate zou, concentration as the X-coordinate mapping, calculate receptors bind constant (Ki value).
The compounds of this invention, i.e. compound
1-
12, through above-mentioned steps, detect, find that its μ, δ and kappa receptor Ki value all between 1-5000 nM, are shown as the mixed type part of δ, μ, kappa receptor.Compound
1,
3with
4the receptors bind experimental result as shown in the table.Wherein, compound
1receptors bind avidity to μ, δ and kappa receptor hypotype is quite approaching, and the Ki value is respectively 2.97 nM, 1.86 nM and 1.25 nM, is the mixed type part of μ, δ and kappa receptor.
Table 1: the affinity data results of the compounds of this invention to μ, δ and kappa receptor
embodiment 14:the experiment of people's opiate receptor intrinsic activity
The opiate receptor intrinsic activity of the compounds of this invention is by GTP γ [S
35(Payza is measured in]/GDT exchange experiment; K., Binding and activity of opioid ligands at the cloned human delta, mu and kappa receptors. in The Delta Receptor; Chang, Porreca & Wood eds. 2004, Marcel Dekker, Inc. New York, Basel), concrete steps are as follows:
The preparation of opiate receptor cytolemma: use clone's the HEK-293 that can express people μ, δ or kappa receptor or the cytolemma of Chinese hamster ovary celI, the preparation method of cytolemma is identical with above-mentioned rat brain membrane preparation method.
GTP γ [S
35]/GDT exchange experiment: the cytolemma of 100 micrograms is suspended in 50 mM Tris-HCl, in the damping fluid of pH 7.4, (includes 100 mM NaCl, 5 nM MgCl
2, 1 mM EDTA, 100 μ M [or 15 μ M] GTP γ S [than vigor 1250 Ci/mmol]), add testing compound (between 1.0 nM to 100 μ M, gradient concentration being set), 28 ℃ of temperature are bathed 60 min, make radioactivity [
35s] GTP γ S and GDP exchange complete equipilibrium.Adopt the cell harvestor 50 mM Tris-HCls ice-cold with 5 ml, pH 7.4 damping fluid fast filterings by twice of glass fiber filter with termination [
35s] GTP γ S and GDP exchange reaction.The specific binding rate adopts 40 * 10
-6m GTP γ S replacement radioactivity [
35s] GTP γ S defines.The positive control medicine is BW373U86(δ acceptor), DAMGO(μ acceptor) and the U50488(kappa receptor), establish it 10
-6during M, agonist activity is 100%.
The intrinsic activity experimental result of part of compounds of the present invention is as shown in the table.Compound
1μ, δ and kappa receptor hypotype are had to agonist activity, EC
50value is respectively 30.9 nM, 22.5 nM and 231 nM, and the Emax value is respectively 93.94%, 102.6% and 75.39%, so compound
1being the full agonist of μ and δ acceptor, is partial agonist to kappa receptor.This result proof compound
1δ, μ, the triple agonists of kappa receptor.
Table 2: part of compounds of the present invention to μ,
with
the inherent agonist activity data results of acceptor
embodiment 15: pressure analgesic experiment (pinching the tail experiment)
Measure each group test animal (10-12 only) reaction times to the pressure induced pain under each compound dosage.
Experimental technique: rat intravenous injection gives the compound of physiological saline (control group), morphine, various dose and in conjunction with different μ, δ, κ antagonist NTI, TREXUPONT or Nor-BNI.The 1st day 30 min(basic value before the first administration of rat respectively) 30 min measure the rat pain sensation reaction times and after administration, and before and after later every morning injection, 30 min measure the rat pain sensation reaction times.Artery forceps is clipped in to the top of rat tail, adopts stopwatch to record the time of large damaged by rats artery forceps, whipping or the reaction of other pain sensation.Before and after injectable drug, measure respectively three times, be 5 min the interval time of measurement, gets its average as the threshold of pain.For avoiding crushing, maximum duration is made as 20 seconds.According to dosage analgesic effect gradient relation, calculate median effective dose (ED
50).
The pressure analgesic experiment result of part of compounds of the present invention is as shown in the table.Compound
1,
2,
3with
4all have and approach with morphine or better analgesic activities, wherein compound
1activity best, be about 12 times of morphine.This result shows that the compounds of this invention is the good analgesic of drug effect.
Table 3: the pressure analgesic experiment result of part of compounds of the present invention
The above is only the preferred embodiment of the present invention.It should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the inventive method, also can carry out some improvement and supplement, the improvement that these are possible and supplement and also should be considered as protection scope of the present invention.
Claims (5)
1. the compound as shown in general formula I or the acceptable ester of its pharmacy or its pharmacologically acceptable salts,
In formula: R
1be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl or methoxyl group; R
2be selected from hydrogen, fluorine, chlorine, bromine or iodine, the position of substitution is 2,3 or 4 of A ring.
2. according to the compound shown in claim 1, it is characterized in that: compound is selected from
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α S)-α-((2S, 5R)-4-(4-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(4-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(2-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-thienyl) methyl) phenol;
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl) benzyl) thiophene;
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-methoxy-benzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene;
3-((α-S)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-(3-luorobenzyl)) thiophene.
3. according to the described compound of claim 1 or 2, it is characterized in that: work as R
1during for hydroxyl, the pharmaceutically acceptable ester of compound is selected from manthanoate, acetic ester, propionic ester, butyric ester, trifluoro-acetate, oleic acid ester, stearate.
4. according to the described compound of claim 1 or 2, it is characterized in that: the compound pharmacy acceptable salt is selected from vitriol, hydrochloride, hydrobromate, phosphoric acid salt, trifluoroacetate, mesylate, benzene sulfonate, tosilate, fluoroform sulphonate, camsilate, formate, acetate, propionic salt, hexanoate, adipate, tartrate, Citrate trianion, benzoate, fumarate, maleate, lactic acid salt, succinate.
5. the application of the described compound of any one in preparing analgesic in claim 1-4.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018204163A1 (en) * | 2017-04-30 | 2018-11-08 | Versi Group, Llc | An opioid for use to reduce and/or treat drug addiction |
| CN113979997A (en) * | 2021-11-12 | 2022-01-28 | 中国科学院昆明植物研究所 | N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, pharmaceutical composition and application thereof |
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|---|---|---|---|---|
| WO1993015062A1 (en) * | 1992-02-03 | 1993-08-05 | The Wellcome Foundation Limited | Opioid diarylmethylpiperazines and piperidines |
| US20020052007A1 (en) * | 1992-02-03 | 2002-05-02 | Chang Kwen Jen | Diarylmethylbenzylpiperazines and corresponding halobenzyl derivatives |
| CN1596113A (en) * | 2001-10-29 | 2005-03-16 | 安达制药公司 | Method of treating depression with delta receptor agonist compounds |
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2013
- 2013-09-23 CN CN2013104353008A patent/CN103467460A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993015062A1 (en) * | 1992-02-03 | 1993-08-05 | The Wellcome Foundation Limited | Opioid diarylmethylpiperazines and piperidines |
| US20020052007A1 (en) * | 1992-02-03 | 2002-05-02 | Chang Kwen Jen | Diarylmethylbenzylpiperazines and corresponding halobenzyl derivatives |
| CN1596113A (en) * | 2001-10-29 | 2005-03-16 | 安达制药公司 | Method of treating depression with delta receptor agonist compounds |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018204163A1 (en) * | 2017-04-30 | 2018-11-08 | Versi Group, Llc | An opioid for use to reduce and/or treat drug addiction |
| US11246865B2 (en) | 2017-04-30 | 2022-02-15 | Versi Group, Llc | Opioid for use to reduce and/or treat drug addiction |
| US11779581B2 (en) | 2017-04-30 | 2023-10-10 | Dmk Pharmaceuticals Corporation | Opioid for use to reduce and/or treat drug addiction |
| CN113979997A (en) * | 2021-11-12 | 2022-01-28 | 中国科学院昆明植物研究所 | N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, pharmaceutical composition and application thereof |
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