CN103467391B - One class contains diarylmethylpiperazine compound and the application thereof of saturated nitrogen heterocyclic acid amides - Google Patents
One class contains diarylmethylpiperazine compound and the application thereof of saturated nitrogen heterocyclic acid amides Download PDFInfo
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- 0 *c1cc(Cc(cc2)ccc2C(NCC*)=O)ccc1 Chemical compound *c1cc(Cc(cc2)ccc2C(NCC*)=O)ccc1 0.000 description 2
- IUXNYAQFUOGSBY-UHFFFAOYSA-N CC(CN(Cc1ccccc1)CC1)[N-]1=C Chemical compound CC(CN(Cc1ccccc1)CC1)[N-]1=C IUXNYAQFUOGSBY-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses the diarylmethylpiperazine compounds that a class replaces containing saturated nitrogen heterocyclic acid amides, or the acceptable ester of its pharmacy, or its pharmacologically acceptable salts, compound provided by the invention is delta opiate receptor agonist, can be used for the treatment of parkinsonism, relative to diarylmethylpiperazine class delta receptor agonists such as existing BW373U86 and SNC80, compound provided by the invention instead of original N-diethylamide with the good saturated nitrogen heterocyclic amide structure fragment of metabolic stability, expection can improve metabolic stability, play the result for the treatment of of compound better.
Description
Technical field
The present invention relates to a class diarylmethylpiperazine compound, particularly relate to the diarylmethylpiperazine compound replaced containing saturated nitrogen heterocyclic acid amides, and the application in the medicine of preparation treatment parkinsonism.
Background technology
Parkinsonism (Parkinson ' s disease) is a kind of common nerve degenerative diseases, is mainly in the elderly, and the sex change of pathological manifestations mainly dopaminergic neuron is dead, causes striatal dopamine significantly to reduce
[1].The treatment of parkinsonism is not enough mainly for Dopamine HCL at present, adopts the pharmacological agenies such as levodopa
[2].But patient's curative effect after treatment in 3 to five years weakens, and occurs side effect such as " switch " phenomenon, Abnormal involuntary movement etc., and increases the weight of gradually, have a strong impact on patients ' life quality
[2].As being aided with dopamine agonist when medication, the generation of above-mentioned phenomenon can be slowed down, but can not prevent.It should be noted that once the Abnormal involuntary movement that levodopa causes appears in patient, be also easy to cause even if use other dopaminergic agent instead.Therefore, the medicine researched and developed based on different mechanisms become current parkinsonism clinical treatment in the urgent need to.
δ acceptor is a kind of hypotype of opiate receptor, belongs to g protein coupled receptor, is distributed in central nervous system and unifies peripheral nervous system.It has been generally acknowledged that, delta opiate receptor and other opiate receptor such as μ and kappa receptor etc. participate in regulating the perception to pain jointly, and opium drug targeting, in μ, δ and kappa receptor, produces corresponding physiological action
[3,4].Traditional opioid drug, such as morphine, fentanyl, methadone etc., mainly act on the mu opioid receptor of central nervous system, Chang Zuowei analgesic is to treat severe pain.Research finds, selectivity delta receptor agonist is if BW373U86 etc. is without potent analgesic effect
[5-7], use with morphine simultaneously, dependency, respiration inhibition that morphine causes can be weakened, and improve the analgesic activity of morphine
[8,9].
Recent research shows, intracellular signaling and the dopamine system of Opioid Receptor System have close ties.In the Research of Animal Model for Study of the Abnormal involuntary movement caused at levodopa, find that the resultant quantity of endorphin in basal nuclei increases, also same phenomenon is found in the tissue examination of Parkinson's disease patients corpse, show that mu opioid receptor activation take part in developing of in chronic levodopa treatment Abnormal involuntary movement, and selectivity mu opioid receptor antagonists can suppress the generation of Abnormal involuntary movement completely
[10-12].On the other hand, in rat model research, the pallidum GABA that the endogenic ligand enkephalinergic reduction depolarize of delta opiate receptor causes discharges, and this phenomenon is relevant to anti-Parkinson disease
[13], thus activate δ acceptor and there is potential anti-Parkinson disease effect
[14-17].
The above results shows, has δ receptor agonist activity should can be used for parkinsonism simultaneously treatment without the compound of μ receptor agonist activity.Such as, by BW373U86
[5]the derivative SNC80 obtained
[18], experimentation on animals shows to have the effect of obvious anti-Parkinson disease
[16].Patent application US 2007/0066625 discloses a class N-diethylamide diarylmethylpiperazine class delta agonists, obviously can reduce Abnormal involuntary movement in the parkinsonism rat model that serpentine or haloperidol are induced.Therefore, this compounds possesses unique advantage, and obviously can alleviate the drug-induced side effect of traditional Dopamine HCL, be the antiparkinsonism drug thing had good prospects.
But existing delta receptor agonist contains N-diethylamide or the N-dimethylformamide structure fragment of easier metabolism mostly, limits clinical value.Such as SNC80
[18], experimentation on animals shows that its metabolic stability is poor, causes bioavailability low, can not oral administration.
Based on early-stage Study, the object of this invention is to provide the diarylmethylpiperazine class delta opiate receptor agonist that a class contains the replacement of saturated nitrogen heterocyclic acid amides, to improve the metabolic stability of compound.
reference
[1] Jankovic, J., Parkinson’s disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 2008, 79: 368-376.
[2] The National Collaborating Centre for Chronic Conditions, ed., Parkinson’s Disease, 2006, Royal College of Physicians, London.
[3] Chang, K. J., et al., Multiple opiate receptors: different regional distribution in the brain and differential binding of opiates and opioid peptides. Mol. Pharmacol. 1979, 16: 91-104.
[4] Chang, K. J., Multiple opiate receptors. Enkephalins and morphine bind to receptors of different specificity. J. Bio. Chem.1979, 254: 2610-2618.
[5] Chang, K. J., et al., A novel, potent and selective nonpeptidic delta opioid receptor agonist BW373U86. J. Pharmacol Exp Ther, 1993, 267: 852-857.
[6] Chang, K. J., et al., The Delta Receptor, 2004, Marcel Dekker, Inc. New York, Basel.
[7] 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.
[8] 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.
[9] 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.
[10] De Ceballos, M. L., et al., Parallel alterations in Met-enkephalin and substance P levels in medial globus pallidus in Parkinson's disease patients. Neurosci. Lett. 1993, 160: 163-166.
[11] Nisbet, A. P., et al., Preproenkephalin and preprotachykinin messenger RNA expression in normal human basal ganglia and in Parkinson's disease. Neurosci. 1995, 66: 361-376.
[12] Henry, B., et al., μ- and δ-Opioid receptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Exp. Neurol. 2001, 171: 139-146.
[13] Maneuf, Y. P., et al., On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus. Exp. Neurol. 1994, 125: 65-71.
[14] Henry, B., et al., Potent of opioid antagonists in the treatment of levodopa-induced dyskinesias in Parkinson’s disease. Drugs Aging 1996, 9: 149-158.
[15] Hill, M. P., et al., δ opioid receptor agonists as a therapeutic approach in Parkinson’s disease. Drug News Perspect. 2000, 13: 261-268.
[16] Hille, C. J., Antiparkinsonian action of a δ opioid agonist in rodent and primate models of Parkinson’s disease. Exp. Neurol. 2001, 172: 189-198.
[17] Silverdale, M. A., Potent nondopaminergic drugs for Parkinson’s disease. Adv. Neurol. 2003, 91: 271-291.
[18] Furness, M. S., et al., Probes for narcotic receptor-mediated phenomena. 27. Synthesis and pharmacological evaluation of selective δ-opioid receptor agonists from 4[(α-S)-α-(2S, 5R)-4-substituted-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamides and their enantiomers. J. Med. Chem. 2000, 43: 3193-3196。
Summary of the invention
The object of the present invention is to provide a kind of diarylmethylpiperazine compound, this compound is the diarylmethylpiperazine compound of structural formula shown in general formula (I) or the acceptable ester of its pharmacy or its pharmacologically acceptable salts,
Wherein: R
1be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl or C
1-C
2alkoxyl group; R
2be selected from hydrogen, fluorine, chlorine, bromine or iodine, the position of substitution is 2,3 or 4 of A ring; N represents 1,2,3,4 or 5, is 4-8 ring corresponding to B ring, is namely commonly referred to as the saturated nitrogen heterocyclic of azetidine, tetramethyleneimine, piperidines, azepan, Azacyclooctane.
Preferred the compounds of this invention comprises:
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-(α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-(3-hydroxybenzyl))-(piperidino)-benzamide;
4-((α R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane.
The acceptable ester of the pharmacy of compound described in the present invention, is selected from but is not limited to: manthanoate, acetic ester, propionic ester, butyric ester, trifluoro-acetate, oleic acid ester, stearate etc.
The pharmacologically acceptable salts of compound described in the present invention, is selected from but is not limited to: 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 for committed step with a Four composition cascade reaction, by aryl formaldehyde, chirality lupetazin and benzotriazole first condensation obtain unstable adducts, react with aryl grignard reagent generation Asymmetrical substitute again, then obtain corresponding target compound through aftertreatment.
Another object of the present invention is to provide a kind of the diarylmethylpiperazine compound or the acceptable ester of its pharmacy that contain structural formula shown in general formula (I), or the pharmaceutical composition of its pharmacologically acceptable salts, namely with the diarylmethylpiperazine compound of structural formula general formula (I) Suo Shi or the acceptable ester of its pharmacy, or its pharmacologically acceptable salts is as main effectively activeconstituents, also can add one or more pharmaceutically acceptable auxiliary materials, to improve drug absorption effect or to be convenient to take, as made capsule or pill, pulvis, tablet, granula, oral liquid and injection liquid etc., auxiliary material of the present invention comprises the weighting agent of pharmaceutical field routine, thinner, tackiness agent, vehicle, absorption enhancer, tensio-active agent and stablizer etc., also can add flavouring agent, pigment and sweeting agent etc. if desired.
The compounds of this invention using method comprises the medicine using significant quantity to described patient, any suitable administering mode can be adopted to use these treatment monomeric compounds or composition, such as, be selected from the administering mode of following manner: oral, rectum, locally, sublingual, mucous membrane, nose, eye, subcutaneous, intramuscular, intravenously, in skin, vertebra, sheath, under intraarticular, intra-arterial, arachnoid membrane, segmental bronchus, lymph and utero administration.
The compounds of this invention is delta opiate receptor agonist, can be used for the treatment of parkinsonism.Relative to diarylmethylpiperazine class delta receptor agonists such as existing BW373U86 and SNC80, compound provided by the invention instead of original N-diethylamide with the good saturated nitrogen heterocyclic amide structure fragment of metabolic stability, expection can improve metabolic stability, plays the result for the treatment of of compound better.
Embodiment
The present invention can be well understood to further by preparation embodiment of the present invention given below and pharmacological evaluation; but do not form limiting the scope of the present invention; method operating all according to a conventional method if no special instructions in the present embodiment, agents useful for same employing conventional reagent if no special instructions or the reagent configured according to a conventional method.
embodiment 1:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines
Concrete synthetic method is as follows:
The preparation of step one, (4-formyl radical) benzoyl-1-piperidines: get 4-formylbenzoate (50.0 g, 333.3 mmol), be dissolved in methylene dichloride (500 ml), ice bath is cooled to about 0 DEG C, slow dropping thionyl chloride (78.6 g, 666.6 mmol), stirs, dropwise the bath of recession deicing, be heated to backflow until reacted; Be down to room temperature, concentration of reaction solution obtains 4-formyl radical Benzoyl chloride, then, under condition of ice bath, piperidines (28.26 g, the 333.3 mmol) solution that will be dissolved in methylene dichloride (250 ml) proceeds in 4-formyl radical Benzoyl chloride, stir 1 h, add water (500 ml), separate organic phase, use anhydrous sodium sulfate drying organic phase, concentrate to obtain oily matter 50.0 g, productive rate 69%;
1H NMR (400 MHz, CDCl
3) δ 10.01(s, 1H), 7.89 (d,
J= 11.4 Hz, 2H), 7.51 (d,
J= 10.7 Hz 2H), 3.69 (s, 2H), 3.26 (s, 2H), 1.65-1.53 (m, 4H), 1.48-1.45 (m, 2H)；
Step 2, (2R, 5S)-1-(3-luorobenzyl)-2, the preparation of 5-lupetazin: take trans 2,5-lupetazin alkali (114.0 g, 1.0 mol) and its dihydrochloride (187.0 g, 1.0 mol) be placed in flask, add dehydrated alcohol (1000 ml), stir lower heating in water bath to 60-70
oc makes it fully dissolve the new distilled 3-fluorine benzyl chlorine (144.5 g, 1.0 mol) of rear slow dropping, vigorous stirring, about 1-3 hour drips off, continue insulation reaction and be cooled to room temperature after 1 hour, filter, filter cake dehydrated alcohol (200 ml) washs; Merging filtrate, steams except ethanol, adds water (500 ml), after being greater than 12, uses dichloromethane extraction under stirring by 10%NaOH solution adjust ph.Extraction liquid anhydrous magnesium sulfate drying, filters, and concentrates to obtain 1-(3-luorobenzyl)-2,5-lupetazin raceme 213.4 g, productive rate 96%; The chiral tartaric acid crystallization of raceme splits and obtains isomer (2R, 5S)-1-(3-luorobenzyl)-2,5-lupetazin 72.6 g, productive rate 34%;
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)；
The preparation of step 3,3-(bromo phenoxy group) t-butyldimethyl silane: by 3-bromophenol (30.1 g, 174 mmol) be dissolved in DMF (200 ml), TBSCl (26.2 g are added under room temperature, 174 mmol) and imidazoles (23.7 g, 348 mmol), stirring at room temperature 3 h.After completion of the reaction, saturated sodium bicarbonate solution cancellation is added.Petroleum ether extraction, water, salt solution wash successively, anhydrous magnesium sulfate drying, concentrate to obtain clear, yellowish 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 4, (3-t-butyldimethyl silane oxygen 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) t-butyldimethyl silane (14.4 g, 50.1 mmol) proceed in magnesium rod, be warming up to 45 DEG C of reactions, namely obtain the anhydrous tetrahydrofuran solution of (3-t-butyldimethyl silane oxygen base) phenyl-magnesium-bromide of light brown clear after magnesium rod dissolves completely, be cooled to room temperature for subsequent use;
Step 5, 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-piperidines: in the round-bottomed flask of an assembling condenser and Dean-Stark water trap, add (4-formyl radical) benzoyl-1-piperidines (6.70 g, 30.85 mmol), benzotriazole (3.67 g, 30.85 mmol), (2R, 5S)-1-(3-luorobenzyl)-2, 5-lupetazin (6.86 g, 30.85 mmol) and toluene (100 ml), reflux is to dewatering completely under nitrogen protection, then cool to room temperature, anhydrous tetrahydro furan (50 ml) is added under nitrogen protection, (the 3-t-butyldimethyl silane oxygen base) phenylmagnesium bromide solution prepared in step 4 is slowly added, continue stirring at room temperature again to reacting completely, add saturated aqueous ammonium chloride cancellation, extraction into ethyl acetate, organic layer is through anhydrous magnesium sulfate drying, filter, steaming desolventizes to obtain viscous brown oily thing, this oily matter is at room temperature dissolved in methyl alcohol (100 ml) and 1 N hydrochloric acid (50 ml) mixed solution, stir 1.5 hours, after completion of the reaction, add water (50 ml) dilution, after regulating pH to 9 with 10%NaOH, be extracted with ethyl acetate product, combining extraction liquid, respectively with water and saturated brine washing, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, crude on silica gel column chromatography purification obtains white solid 4.93 g, productive rate 31%,
1H NMR (400 MHz, CDCl
3) δ 7.44 (d,
J = 20.3 Hz, 3H), 7.26-7.20 (m, 3H), 7.13-7.11 (m, 2H), 7.02-7.05 (m, 2H), 6.93-6.88 (m, 2H), 5.00 (s, 1H), 3.88 (d,
J = 10.3 Hz, 2H), 3.69 (s, 2H), 3.37 (s, 2H), 3.19 (d,
J = 15.4 Hz, 1H), 2.66-2.56 (m, 4H), 2.01-1.85 (m, 3H), 1.50 (d,
J = 20.1 Hz, 6H), 1.07-1.04 (m, 6H)。
Synthetic method described in embodiment 1 is equally applicable to embodiment 2-8.
embodiment 2:the preparation of 4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines
Synthetic method is with embodiment 1, and difference is step 2, five:
The preparation of step 2, (2R, 5S)-1-benzyl-2,5-lupetazin: with benzyl chlorine for raw material, adopts method described in embodiment 1 step 2 to obtain 1-benzyl-2,5-lupetazin raceme, productive rate 93%; Chiral tartaric acid crystallization splits and obtains (2R, 5S)-1-benzyl-2,5-lupetazin, productive rate 37% again;
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)；
Step 5,4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-piperidines: with (2R, 5S)-1-benzyl-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 31%;
1H NMR (400 MHz, CDCl
3) δ 7.50-7.45 (m, 3H), 7.40-7.32 (m, 3H), 7.29-7.20 (m, 1H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 3.72 (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, 6H), 1.25-1.17 (m, 3H), 1.15-1.10 (m, 3H)。
embodiment 3:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines
Synthetic method is with embodiment 1, and difference is step 2, five:
Step 2, (2R, 5S) the preparation of-1-(3-chlorobenzyl)-2,5-lupetazins: with 3-benzyl chloride chlorine for raw material, adopts method described in embodiment 1 step 2 to obtain 1-(3-chlorobenzyl)-2,5-lupetazin raceme, productive rate 92%; Chiral tartaric acid crystallization splits and obtains (2R, 5S)-1-(3-chlorobenzyl)-2,5-lupetazins, productive rate 35% 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 5,4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-piperidines: with (2R, 5S)-1-(3-chlorobenzyl)-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 38%;
1H NMR (400 MHz, CDCl
3) δ 7.45-7.30 (m, 5H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 4H), 4.95 (s, 1H), 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), 1.60-1.51 (m, 6H), 1.25-1.17 (m, 3H), 1.15-1.10 (m, 3H)。
embodiment 4:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines
Synthetic method is with embodiment 1, and difference is step 2, five:
Step 2, (2R, 5S) the preparation of-1-(3-bromobenzyl)-2,5-lupetazins: with 3-bromobenzyl chlorine for raw material, adopts method described in embodiment 1 step 2 to obtain 1-(3-bromobenzyl)-2,5-lupetazin raceme, productive rate 95%; Chiral tartaric acid crystallization splits and obtains (2R, 5S)-1-(3-bromobenzyl)-2,5-lupetazins, productive rate 33% 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 5,4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-piperidines: with (2R, 5S)-1-(3-bromobenzyl)-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 32%;
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, 2H), 5.04 (s, 1H), 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), 1.24-1.23 (m, 6H), 1.11 (d,
J = 5.8 Hz, 6H)。
embodiment 5:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines
Synthetic method is with embodiment 1, and difference is step 2, five:
Step 2, (2R, 5S) the preparation of-1-(3-iodine benzyl)-2,5-lupetazins: with 3-bromobenzyl chlorine for raw material, adopts method described in embodiment 1 step 2 to obtain 1-(3-iodine benzyl)-2,5-lupetazin raceme, productive rate 96%; Chiral tartaric acid crystallization splits and obtains (2R, 5S)-1-(3-iodine benzyl)-2,5-lupetazins, productive rate 38% again;
1H NMR (400 MHz, CDCl
3) δ 7.26-7.22 (m, 3H), 7.06-7.04 (m,1H), 4.27 (d,
J = 13.7 Hz, 1H), 3.26 (d,
J = 10.1Hz, 1H), 2.88-2.82 (m, 1H), 2.79-2.68 (m, 1H), 2.64 (d,
J = 21.3 Hz, 2H), 2.24-2.20 (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 5,4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-piperidines: with (2R, 5S)-1-(3-iodine benzyl)-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 30%;
1H NMR (400 MHz, CDCl
3) δ 7.43-7.25 (m, 4H), 7.20-7.06 (m, 3H), 7.07-6.95 (m, 2H), 6.73-6.69 (m, 3H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 6H), 1.10 (d,
J = 5.8 Hz, 3H), 1.00-0.87 (m, 3H)。
embodiment 6:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-piperidines
Synthetic method is with embodiment 1, and difference is step 3, four, five, without step 3:
The preparation of step 4, phenyl-magnesium-bromide: take bromobenzene as raw material, adopts method described in embodiment 1 step 4 to obtain the anhydrous tetrahydrofuran solution of phenyl-magnesium-bromide, cools for subsequent use;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) preparation of benzoyl-1-piperidines: take phenyl-magnesium-bromide as raw material, method described in embodiment 1 step 5 is adopted to obtain, for white solid, productive rate 18%;
1H NMR (400 MHz, CDCl
3) δ 7.43-7.30 (m, 2H), 7.28 (m, 5H), 7.21 (m, 3H), 7.04 (m, 2H), 6.90 (br t,
J= 8.2 Hz, 1H), 3.87 (d,
J= 13.5 Hz, 2H), 3.53 (br, m, 2H), 3.28 (m, 2H), 3.18 (d,
J = 13.8 Hz, 1H), 2.67 (m, 2H), 2.57 (m, 2H), 2.02 (dd,
J= 8.2 Hz, 3H), 1.94 (dd,
J= 10.8, 8.1 Hz, 3H), 1.22 (m, 2H), 1.15 (d,
J = 6.1 Hz, 3H), 1.06 (d,
J = 6.1 Hz, 3H)。
embodiment 7:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-piperidines
Synthetic method is with embodiment 1, and difference is step 3, four, five, without step 3:
The preparation of step 4 3-flourophenyl magnesium bromide: with 3-bromofluorobenzene for raw material, adopts method described in embodiment 1 step 4 to obtain the anhydrous tetrahydrofuran solution of 3-flourophenyl magnesium bromide, cools for subsequent use;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) preparation of benzoyl-1-piperidines: with 3-flourophenyl magnesium bromide for raw material, method described in embodiment 1 step 5 is adopted to obtain, for white solid, productive rate 21%;
1H NMR (400 MHz, CDCl
3) δ 7.44 (m, 2H), 7.28 (d,
J = 8.2 Hz, 2H), 7.22 (m, 1H), 7.14 (t,
J= 7.8 Hz, 2H), 7.00 (m, 5H), 3.89 (d,
J= 13.9 Hz, 2H), 3.54 (br, m, 2H), 3.28 (m, 2H), 3.19 (d,
J = 13.6 Hz, 1H), 2.68 (m, 2H), 2.47 (m, 2H), 2.00 (dd,
J= 8.2 Hz, 3H), 1.90 (m, 3H), 1.32 (m, 2H), 1.20 (d,
J = 10.1 Hz, 3H), 1.10 (d,
J = 6.1 Hz, 3H)。
embodiment 8:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-piperidines
Synthetic method is with embodiment 1, and difference is step 3, four, five:
The preparation of step 3,3-bromoanisole: take 3-bromophenol (0.10 g, 1.0 mmol), methyl iodide (0.28 g, 2.0 mmol), sodium hydroxide (0.16 g, 4.0 mmol) dissolves in DMF (10 ml), stirring at room temperature.Add water (200 ml) after completion of the reaction, petroleum ether-ethyl acetate mixed solution extracts, and organic phase drying is filtered, and concentrates to obtain 3-bromoanisole 0.17 g, productive rate 91%;
1H NMR (400 MHz, CDCl
3) δ 7.26 (m, 3H), 7.10 (m, 1H), 3.57 (s, 3H)。
The preparation of step 4, (3-methoxyl group) phenyl-magnesium-bromide: with 3-bromoanisole for raw material, adopts the anhydrous tetrahydrofuran solution of obtained (3-methoxyl group) phenyl-magnesium-bromide of method described in embodiment 1 step 4, cools for subsequent use;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) preparation of benzoyl-1-piperidines: with (3-methoxyl group) phenyl-magnesium-bromide for raw material, method described in embodiment 1 step 5 is adopted to obtain, for white solid, productive rate 19%;
1H NMR (400 MHz, CDCl
3) δ 7.42 (d,
J= 8.0 Hz, 2H), 7.38 (m, 2H), 7.28 (m, 5H), 7.00 (m, 3H), 5.16 (s, 1H), 4.01 (s, 3H), 3.28 (m, 3H), 3.16 (dd,
J= 14.0, 5.2 Hz, 1H), 2.84 (dd,
J= 14.0, 7.0 Hz, 2H), 2.72 (dd,
J= 11.0, 2.8 Hz, 2H), 2.50 (m, 1H), 2.09 (m, 1H), 1.55 (m, 4H), 1.40 (m, 4H), 1.09 (m, 6H)。
The synthetic method of embodiment 1-8 is equally applicable to embodiment 9-32.
embodiment 9:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine:
Synthetic method is with embodiment 1, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azetidine: take azetidine as raw material, adopts method described in embodiment 1 step one to obtain, light yellow oil, productive rate 78%;
1H NMR (400 MHz, CDCl
3) δ 10.13 (s, 1H), 7.48 (d,
J= 9.7 Hz, 2H), 7.30 (d,
J= 15.6 Hz, 2H), 3.52-3.87 (m, 4H), 2.57-2.46 (m, 2H).
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azetidine: with (4-formyl radical) benzoyl-1-azetidine for raw material, method described in embodiment 1 step 5 is adopted to obtain, for white solid, productive rate 18%;
1H NMR (400 MHz, CDCl
3) δ 7.54-7.30 (m, 6H), 7.26-7.11 (m, 2H), 7.08-7.05 (m, 2H), 6.93-6.80 (m, 2H), 5.30 (s, 1H), 3.95 (d,
J = 15.3 Hz, 1H), 3.55 (s, 2H), 3.47 (s, 2H), 3.22 (d,
J = 20.4 Hz, 1H), 3.05-2.87 (m, 3H), 2.27-2.20 (m, 2H), 1.99 (d,
J = 20.1 Hz, 6H), 1.50-1.44 (m, 3H)。
embodiment 10:4-(the preparation of (α R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl benzoyl-1-azetidine
Synthetic method is with embodiment 6, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azetidine: with embodiment 9 step one;
Step 5,4-((α R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) preparation of benzyl benzoyl-1-azetidine: with (4-formyl radical) benzoyl-1-azetidine and phenyl-magnesium-bromide for raw material, method described in embodiment 1 step 5 is adopted to obtain, for white solid, productive rate 25%;
1H NMR (400 MHz, CDCl
3) δ 7.55-7.40 (m, 5H), 7.35-7.20 (m, 4H), 7.15-7.00 (m, 4H), 4.84 (s, 1H), 4.00-3.55 (m, 6H), 2.52-2.40 (m, 2H), 2.30-2.10 (m, 6H), 1.61-1.40 (m, 6H)。
embodiment 11:the preparation of 4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine
Synthetic method is with embodiment 2, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azetidine: with embodiment 9 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azetidine: with (4-formyl radical) benzoyl-1-azetidine and (2R, 5S)-1-benzyl-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 21%;
1H NMR (400 MHz, CDCl
3) δ 7.43-7.32 (m, 6H), 7.29-7.20 (m, 1H), 7.15-6.99 (m, 6H), 4.82 (s, 1H), 3.75-3.70 (m, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 2H), 2.73-2.60 (m, 2H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 5H), 1.25-1.17 (m, 3H)。
embodiment 12:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine
Synthetic method is with embodiment 3, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azetidine: with embodiment 9 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azetidine: with (4-formyl radical) benzoyl-1-azetidine and (2R, 5S)-1-(3-chlorobenzyl)-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 28%;
1H NMR (400 MHz, CDCl
3) δ 7.45-7.30 (m, 5H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 4H), 4.95 (s, 1H), 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), 1.60-1.51 (m, 5H), 1.15-1.10 (m, 2H)。
embodiment 13:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine
Synthetic method is with embodiment 4, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azetidine: with embodiment 9 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azetidine: with (4-formyl radical) benzoyl-1-azetidine and (2R, 5S)-1-(3-bromobenzyl)-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 19%;
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, 2H), 5.30 (s, 1H), 3.95 (d,
J = 15.3 Hz, 1H), 3.55 (s, 2H), 3.47 (s, 2H), 3.23 (d,
J = 20.4 Hz, 1H), 3.05-2.87 (m, 4H), 2.27-2.20 (m, 2H), 1.98 (d,
J = 20.1 Hz, 5H), 1.50-1.44 (m, 3H)。
embodiment 14:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine
Synthetic method is with embodiment 5, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azetidine: with embodiment 9 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azetidine: with (4-formyl radical) benzoyl-1-azetidine and (2R, 5S)-1-(3-iodine benzyl)-2,5-lupetazin is raw material, adopting method described in embodiment 1 step 5 to obtain, is white solid, productive rate 17%;
1H NMR (400 MHz, CDCl
3) δ 7.43-7.25 (m, 4H), 7.20-7.06 (m, 3H), 7.07-6.95 (m, 3H), 6.73-6.69 (m, 2H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 4H), 1.11 (d,
J = 5.8 Hz, 3H)。
embodiment 15:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine
Synthetic method is with embodiment 1, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-tetramethyleneimine: take tetramethyleneimine as raw material, adopts method described in embodiment 1 step one to obtain, colorless oil, productive rate 82%;
1H NMR (400 MHz, CDCl
3) δ 9.97 (s, 1H), 7.43 (d,
J= 19.7 Hz, 2H), 7.32 (d,
J= 30.6 Hz, 2H), 3.62-3.81 (m, 4H), 2.43-2.30 (m, 2H), 2.26-2.15 (m, 2H)；
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-tetramethyleneimine: with (4-formyl radical) benzoyl-1-tetramethyleneimine for raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 24%;
1H NMR (400 MHz, CDCl
3) δ 7.30-7.13 (m, 12H), 4.81 (s, 1H), 3.90 (d,
J= 13.2 Hz, 1H), 3.39 (s, 3H), 3.11-2.87 (m, 4H), 2.57 (dd,
J= 11.1, 2.6 Hz, 4H), 2.41 (s, 1H), 2.34 (m, 1H), 1.90-1.77 (m, 3H), 1.00 (d,
J= 6.1 Hz, 3H), 0.86 (d,
J= 6.1 Hz, 3H)。
embodiment 16:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-tetramethyleneimine
Synthetic method is with embodiment 6, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-tetramethyleneimine: with embodiment 15 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) preparation of benzoyl-1-tetramethyleneimine: with (4-formyl radical) benzoyl-1-tetramethyleneimine and phenyl-magnesium-bromide for raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 36%;
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, 2H), 6.64 (m, 3H), 5.13 (s, 1H), 3.95 (d,
J = 13 Hz, 2H), 3.55 (m, 2H), 3.29 (m, 2H), 2.65 (dd,
J= 9.0, 2.0 Hz, 2H), 1.99 (m, 2H), 1.24 (m, 4H), 1.12 (m, 3H), 1.09 (d,
J = 6.1 Hz, 3H), 1.03 (m, 3H)。
embodiment 17:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-tetramethyleneimine
Synthetic method is with embodiment 7, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-tetramethyleneimine: with embodiment 15 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) preparation of benzoyl-1-tetramethyleneimine: with (4-formyl radical) benzoyl-1-tetramethyleneimine and 3-flourophenyl magnesium bromide for raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 30%;
1H NMR (400 MHz, CDCl
3) δ 7.50 (m, 3H), 7.41 (m, 5H), 7.23 (m, 1H), 7.11 (d,
J= 10.0 Hz, 2H), 7.00 (m, 3H), 5.02 (s, 1H), 3.95 (m, 2H), 3.50 (m, 2H), 3.29 (m, 2H), 2.60 (dd,
J= 10.0, 5.0 Hz, 2H), 2.02 (m, 2H), 1.20 (m, 4H), 1.15 (m, 3H), 1.09 (d,
J = 8.3 Hz, 3H), 0.87 (m, 3H)。
embodiment 18:4-((α-R)-α-(2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-tetramethyleneimine
Synthetic method is with embodiment 2, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-tetramethyleneimine: with embodiment 15 step one;
Step 5,4-((α-R)-α-(2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-tetramethyleneimine: with (4-formyl radical) benzoyl-1-tetramethyleneimine and (2R, 5S)-1-benzyl-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 26%;
1H NMR (400 MHz, CDCl
3) δ 7.40-7.20 (m,7H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 3.72 (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, 6H), 1.20-1.11 (m, 4H)。
embodiment 19:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine
Synthetic method is with embodiment 3, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-tetramethyleneimine: with embodiment 15 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-tetramethyleneimine: with (4-formyl radical) benzoyl-1-tetramethyleneimine and (2R, 5S)-1-(3-chlorobenzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 32%;
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), 4.95 (s, 1H), 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), 1.60-1.51 (m, 4H), 1.15-1.10 (m, 4H), 0.90-0.78 (m, 2H)。
embodiment 20:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine
Synthetic method is with embodiment 4, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-tetramethyleneimine: with embodiment 15 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-tetramethyleneimine: with (4-formyl radical) benzoyl-1-tetramethyleneimine and (2R, 5S)-1-(3-bromobenzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 27%;
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), 5.04 (s, 1H), 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), 1.24-1.23 (m, 4H), 1.10 (d,
J = 5.8 Hz, 6H)。
embodiment 21:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine
Synthetic method is with embodiment 5, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-tetramethyleneimine: with embodiment 15 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-tetramethyleneimine: with (4-formyl radical) benzoyl-1-tetramethyleneimine and (2R, 5S)-1-(3-iodine benzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 22%;
1H NMR (400 MHz, CDCl
3) δ 7.55-7.25 (m, 4H), 7.20-7.11 (m, 2H), 7.07-6.95 (m, 3H), 6.73-6.69 (m, 3H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 4H), 1.11 (d,
J = 5.8 Hz, 3H), 1.00-0.87 (m, 3H)。
embodiment 22:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan
Synthetic method is with embodiment 1, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azepan: take azepan as raw material, adopts method described in embodiment 1 step one to obtain, colorless oil, productive rate 76%;
1H NMR (400 MHz, CDCl
3) δ 10.21 (s, 1H), 7.56-7.50 (m, 2H), 7.45-7.32 (m, 2H), 3.52-3.40 (m, 4H), 2.43-2.28 (m, 6H), 2.23-2.15 (m, 2H)；
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azepan: with (4-formyl radical) benzoyl-1-azepan for raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 21%;
1H NMR (400 MHz, CDCl
3) δ 7.26 (ddd,
J= 13.9, 5.2, 2.9 Hz, 8H), 7.14-7.02 (m, 4H), 5.10 (s, 1H), 4.05 (d,
J= 13.0 Hz, 3H), 3.58 (s, 1H), 3.09 (d,
J= 13.0 Hz, 2H), 2.72 (dd,
J= 11.5, 2.6 Hz, 1H), 2.64 (dd,
J= 11.2, 2.9 Hz, 2H), 2.51-2.36 (m, 2H), 2.03-1.90 (m, 4H), 1.13 (d,
J= 6.2 Hz, 6H), 1.06 (d,
J= 6.0 Hz, 6H)。
embodiment 23:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-azepan
Synthetic method is with embodiment 6, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azepan: with embodiment 22 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) preparation of benzoyl-1-azepan: with (4-formyl radical) benzoyl-1-azepan and phenyl-magnesium-bromide for raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 35%;
1H NMR (400 MHz, CDCl
3) δ 7.46 (d,
J = 8.1 Hz, 2H), 7.33 (m, 2H), 7.29 (d,
J= 9.4 Hz, 2H), 7.24 (m, 2H), 7.20 (d,
J= 7.3 Hz, 3H), 6.90 (t,
J = 8.2 Hz, 2H), 5.15 (s, 1H), 3.81 (d,
J = 13.1 Hz, 1H), 3.54 (m, 2H), 3.28 (m, 2H), 3.14 (d,
J= 13.1 Hz, 1H), 2.65 (m, 2H), 1.98 (m, 2H), 1.93 (m, 4H), 1.23 (m, 4H), 1.10 (d,
J= 6.3 Hz, 3H)。
embodiment 24:the preparation of 4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan
Synthetic method is with embodiment 2, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azepan: with embodiment 22 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azepan: with (4-formyl radical) benzoyl-1-azepan and (2R, 5S)-1-benzyl-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 32%;
1H NMR (400 MHz, CDCl
3) δ 7.50-7.45 (m, 3H), 7.40-7.32 (m, 3H), 7.29-7.20 (m, 1H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 3.73 (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, 6H), 1.34-1.28 (m, 2H), 1.25-1.17 (m, 3H), 1.15-1.10 (m, 3H)。
embodiment 25: the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan
Synthetic method is with embodiment 3, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azepan: with embodiment 22 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azepan: with (4-formyl radical) benzoyl-1-azepan and (2R, 5S)-1-(3-chlorobenzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 29%;
1H NMR (400 MHz, CDCl
3) δ 7.44-7.35 (m, 3H), 7.34-7.20 (m, 3H), 7.12-7.05 (m, 2H), 7.00-6.92 (m, 4H), 4.82 (s, 1H), 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, 6H), 1.35-1.11 (m, 6H), 1.05-0.88 (m, 2H)。
embodiment 26:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan
Synthetic method is with embodiment 4, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azepan: with embodiment 22 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azepan: with (4-formyl radical) benzoyl-1-azepan and (2R, 5S)-1-(3-bromobenzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 23%;
1H NMR (400 MHz, CDCl
3) δ 7.45-7.30 (m, 6H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 3H), 4.95 (s, 1H), 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), 1.60-1.51 (m, 6H), 1.25-1.17 (m, 3H), 1.16-1.11 (m, 2H), 0.98-0.70 (m, 3H)。
embodiment 27:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan
Synthetic method is with embodiment 5, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-azepan: with embodiment 22 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-azepan: with (4-formyl radical) benzoyl-1-azepan and (2R, 5S)-1-(3-iodine benzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 17%;
1H NMR (400 MHz, CDCl
3) δ 7.45-7.43 (d,
J = 20.3 Hz, 2H), 7.26-7.20 (m, 3H), 7.13-7.11 (m, 3H), 7.02-7.05 (m, 2H), 6.93-6.88 (m, 2H), 5.00 (s, 1H), 3.91-3.87 (d,
J = 10.3 Hz, 1H), 3.69 (s, 2H), 3.37 (s, 2H), 3.20-3.17 (d,
J = 15.4 Hz, 1H), 2.66-2.56 (m, 4H), 2.01-1.85 (m, 2H), 1.52-1.47 (d,
J = 20.1 Hz, 6H), 1.07-1.04 (m, 6H), 0.97-0.83 (m,3H)。
embodiment 28:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane
Synthetic method is with embodiment 1, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-Azacyclooctane: take Azacyclooctane as raw material, adopts method described in embodiment 1 step one to obtain, colorless oil, productive rate 67%;
1H NMR (400 MHz, CDCl
3) δ 10.01 (s,1H), 7.76-7.63 (m, 3H), 7.60 (m, 1H), 3.61-3.56 (m, 4H), 2.54-2.30 (m 5H), 2.28-2.15 (m, 3H), 2.05-1.90 (m, 2H)；
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-Azacyclooctane: with (4-formyl radical) benzoyl-1-Azacyclooctane for raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 18%;
1H NMR (400 MHz, CDCl
3) δ 7.27-7.22 (m, 4H), 7.07 (m, 3H), 6.95 (m, 5H), 5.90 (m, 1H), 5.36 (s, 1H), 3.48 (dd,
J= 13.5, 5.2 Hz, 4H), 2.85 (m, 3H), 2.68 (dd,
J= 11.5, 2.5 Hz, 4H), 2.58-2.37 (m, 4H), 2.31 (m, 3H), 2.14-1.94 (m, 4H), 1.21 (d,
J= 6.0 Hz, 3H), 1.04 (d,
J= 6.3 Hz, 3H)。
embodiment 29:the preparation of 4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane
Synthetic method is with embodiment 2, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-Azacyclooctane: with embodiment 28 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-Azacyclooctane: with (4-formyl radical) benzoyl-1-Azacyclooctane and (2R, 5S)-1-benzyl-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 20%;
1H NMR (400 MHz, CDCl
3) δ 7.43-32 (m, 6H), 7.29-7.20 (m, 1H), 7.15-6.99 (m, 6H), 4.82 (s, 1H), 3.75-3.70 (m, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.20-3.17 (m, 2H), 2.73-2.60 (m, 2H), 2.53-2.40 (m, 3H), 2.38-2.20 (m, 4H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 5H), 1.25-1.17 (m, 4H)。
embodiment 30:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane
Synthetic method is with embodiment 3, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-Azacyclooctane: with embodiment 28 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-Azacyclooctane: with (4-formyl radical) benzoyl-1-Azacyclooctane and (2R, 5S)-1-(3-chlorobenzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 17%;
1H NMR (400 MHz, CDCl
3) δ 7.45-7.30 (m, 6H), 7.25-7.05 (m, 3H), 7.00-6.92 (m, 3H), 4.95 (s, 1H), 3.70-3.62 (m, 4H), 3.42 (s, 2H), 3.20-3.17 (m, 1H), 2.73-2.65 (m, 4H), 2.55-2.34 (m, 3H), 2.33-2.21 (m, 3H), 2.01-1.85 (m, 3H), 1.60-1.51 (m, 6H), 1.15-1.10 (m, 3H)。
embodiment 31:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane
Synthetic method is with embodiment 4, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-Azacyclooctane: with embodiment 28 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-Azacyclooctane: with (4-formyl radical) benzoyl-1-Azacyclooctane and (2R, 5S)-1-(3-bromobenzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 13%;
1H NMR (400 MHz, CDCl
3) δ 7.50-7.30 (m, 4H), 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, 2H), 5.30 (s, 1H), 4.02-3.87 (d,
J = 15.3 Hz, 1H), 3.55 (s, 2H), 3.47 (s, 2H), 3.22 (d,
J = 20.4 Hz, 1H), 3.05-2.87 (m, 4H), 2.60-2.56 (m, 3H), 2.27-2.20 (m, 2H), 2.00 (d,
J = 20.1 Hz, 6H), 1.73-1.60 (m, 5H), 1.50-1.44 (m, 2H)。
embodiment 32:the preparation of 4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane
Synthetic method is with embodiment 5, and difference is step one, five:
The preparation of step one, (4-formyl radical) benzoyl-1-Azacyclooctane: with embodiment 28 step one;
Step 5,4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) preparation of benzoyl-1-Azacyclooctane: with (4-formyl radical) benzoyl-1-Azacyclooctane and (2R, 5S)-1-(3-iodine benzyl)-2,5-lupetazin is raw material, method described in embodiment 1 step 5 is adopted to obtain, white solid, productive rate 21%;
1H NMR (400 MHz, CDCl
3) δ 7.33-7.25 (m, 4H), 7.20-7.06 (m, 3H), 7.07-6.95 (m, 2H), 6.73-6.69 (m, 3H), 5.04 (s, 1H), 4.67 (br, 1H), 4.00-3.88 (m, 2H), 3.62-3.43 (m, 2H), 3.21 (s, 2H), 2.71-2.59 (m, 4H), 2.30-2.21 (m, 3H), 2.15-2.00 (m, 3H), 2.07-2.00 (m, 2H), 1.24-1.23 (m, 6H), 1.11-1.04 (m, 4H)。
embodiment 33:opiate receptor Binding experiment
The opiate receptor affinity of the compounds of this invention is undertaken measuring (with reference to Payza by opiate receptor Binding 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, method described in Basel), concrete steps are as follows:
Prepared by rat brain membrane: murine brain (brain of Male albino Sprague-Dawley rat or the cerebellum of Male albino guinea-pigs) adopts ice-cold Tris-HCl buffer solution for cleaning (pH 7.4,50 mM, 25 DEG C), 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 homogenizers containing tetrafluoroethylene granulated glass sphere (0.13-0.18 mm) to make brain tissue homogenate; Homogenate at 4 DEG C, centrifugal 15 min of 6000 g, collect supernatant liquor and under 41000 g centrifugal 30 min; Every 1 g weight in wet base cerebral tissue film precipitates 10 mM Tris-Sucrose buffer (0.32 M) Eddy diffusions with 10 times of volumes and adopts tissue grinder process (10s, low speed), and the homogenate after supersound process is at 4 DEG C, centrifugal 30 min of 41000 g; The 50 mM Tris damping fluid Eddy diffusions of film throw out containing proteinase inhibitor, final protein concentration is 40 ~ 50 μ g/ml; Membrane granule liquid nitrogen after suspension or-80 DEG C frozen, measure protein concentration by Bandford method before using.
Receptor Binding Assay: the rat brain membrane after resuspension and 0.1 nM [
3h] deltorphin II-δ-acceptor (Rate activity 38.5-40.6 Ci/mmol), 0.1 nM [
3h] DAMGO-μ-acceptor (Rate activity 50 Ci/mmol) or 0.1 nM [
3h] U69593-κ-acceptor contains 4 mM MgCl at 2 ml
2, proteinase inhibitor and testing compound (gradient concentration is set between 1.0 nM to 100 μMs) 10 mM Tris-HCl damping fluids in 25 DEG C of temperature bath 90 min, make radioligand and acceptor complete equipilibrium.Adopt cell harvestor (model M-48R, Brandel Instruments, Gaithersberg, MD) with the ice-cold 50 mM Tris damping fluid fast filterings of 5 ml by glass fiber filter twice to stop part and receptor response, combination rate employing 1 × 10
-6m naloxone replaces radioligand and defines, and specific binding rate liquid flash spectrum counting is determined, the external perimysium reference of mensuration is 40-45%.With combination rate data be ordinate zou, concentration maps for X-coordinate, calculates Receptor binding constants (K
ivalue).
Part of compounds of the present invention, namely compound 1-10,15,16,22,23 and 28(compound number is corresponding numbers with embodiment), detect its receptor affinity through above-mentioned steps, find its δ acceptor K
ivalue is all between 1-2000 nM, and μ and kappa receptor K
ivalue, between 100-5000 nM, is all obviously greater than δ acceptor K
ivalue, is shown as δ receptor selective ligand.
embodiment 34:people's opiate receptor intrinsic activity is tested
The opiate receptor intrinsic activity of the delta agonists that the present invention relates to is by GTP γ [S
35]/GDT exchange experiment is carried out measuring (according to Payza, 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).
Prepared by opiate receptor cytolemma: use clone can express the HEK-293 of people μ, δ or kappa receptor or the cytolemma of Chinese hamster ovary celI, and the preparation method of cytolemma is identical with above-mentioned rat brain membrane preparation method.
GTP γ [S
35]/GDT exchange is tested: the cytolemma of 100 micrograms is suspended in 50 mM Tris-HCl, (includes 100 mM NaCl, 5 nM MgCl in the damping fluid of pH 7.4
2, 1 mM EDTA, 100 μMs of [or 15 μMs] GTP γ S [Rate activity 1250 Ci/mmol]), add testing compound (gradient concentration is set between 1.0 nM to 100 μMs), 28 DEG C temperature bath 60 min, make radioactivity [
35s] GTP γ S and GDP exchange complete equipilibrium; Adopt the ice-cold 50 mM Tris-HCl of cell harvestor 5 ml, pH 7.4 damping fluid fast filtering by glass fiber filter twice with termination [
35s] GTP γ S and GDP exchange reaction; Specific binding rate adopts 40 × 10
-6m GTP γ S replacement radioactivity [
35s] GTP γ S defines; Positive control medicine is BW373U86(δ acceptor), DAMGO(μ acceptor) and U50488(kappa receptor), if it is 10
-6during M, agonist activity is 100%.
Part of compounds of the present invention, namely compound 1-10,15,16,22,23 and 28(numbering correspond to embodiment numbering), its receptor receptor intrinsic activity is detected through above-mentioned steps, find that the ratio of its δ acceptor intrinsic activity and μ acceptor intrinsic activity is all between 2-100 times, has δ receptor selective agonist active.Wherein, the intrinsic activity experimental result of compound 1 is as shown in the table.Compound 1 pair of δ receptor acting concentration is minimum, and activity is the highest, and action intensity (Emax value) is more than δ receptor positive control drug BW373U86, and kappa receptor activity is minimum, is partial agonist.Also the δ receptor agonist activity (EC of compound 1 can be found out from table
50be worth 31.1 nM, Emax value 156.5%) be about its μ receptor agonist activity (EC
50be worth 1000 nM, Emax value 100%) 33 times.
Table 1: part of compounds of the present invention is to the intrinsic activity detected result of μ and δ acceptor
embodiment 35:parkinsonism macaque model effect experiment
The drug effect of the compounds of this invention induces the experiment of parkinsonism monkey model to detect by MPTP.This experiment utilizes MPTP to induce rhesus monkey brain injury, and set up parkinsonism monkey model, intravenous injection subsequently gives medicine to be measured, and the Behavioral change of animal is observed in timing.
Prepared by parkinsonism macaque model: MPTP every per daily dose 0.2 mg/kg, drug solution is inserted in slow-releasing pump, is embedded in laboratory animal subcutaneous, and every day carries out animal behavioral study.With Bennazzouz Parkinson's disease clinical behavior Scale assessment animal model, the modeling success when integration arrival more than 8 or 8, and give pharmacological agent, madopar is as positive control.
Experimental program: intravenous administration 2.0 mg/kg treats the heavier parkinsonism model monkeys of symptom, the lighter parkinsonism model monkeys of symptom, as blank (not giving any medicine), observes animal daily behavior and meal situation.Within three days, be limited, as invalid, increase dosage successively; As effectively, reduce dosage successively.If desired compared with Treated with Madopar situation.
In compound of the present invention, when compound 1 dosage is 2.0 mg/kg, animal behavior has clear improvement, and Bennazzouz behavior rating scale integration drops to 6-7 from more than 8, and daily behavior and diet are all improved.Increase dosage to 4.0 mg/kg and 6.0 mg/kg, integration is down to less than 6, the animal behavior no significant difference of two dosage.Reduce dosage to 1.0 mg/kg and 0.5 mg/kg, animal behavior is slightly improved, but not obvious, and integration fluctuates 8.
The result for the treatment of of positive drug madopar (62.5 mg are oral) is suitable with compound 1 dosage 4.0 mg/kg.
Bennazzouz clinical behavior scale: nineteen ninety-five is proposed by French neuroscientist doctor Bennazzouz, is widely used at present in the behavior evaluation of Parkinson's disease macaque model.This scale is on the basis of Parkinsonian monkey behavior expression summarizing 5 years, formulate in conjunction with the immunohistochemical staining analytical results of substantia nigra of midbrain district dopamine neuron regression and various human Parkinson's disease clinical scale evaluation charter and form, its evaluation index comprises following 7 Parkinson's disease signs:
Tremble (0-3), and motion is slowed down (0-3), postural change (0-3), sounding change (0-2), dull (0-2), tetanic (each upper limbs 0-3), upper extremity exercise (ability of fruit of ingesting, each upper limbs 0-3), total score 0-25.
The score value of table 2:Bennazzouz scale projects is becoming the statistics under mould state
Illustrate: 4 modeling animal movements slow down and at least reach moderate (>=2), postural change at least reaches trunk severe bending (>=2), the motor capacity of both sides upper limbs at least reaches the degree (>=2) of exceptional hardship of searching for food, and the parkinsonism symptom such as to tremble, stiff, tetanic all has embodiment.
Table 3: animal Parkinson's disease behavior evaluation result before and after treatment
Illustrate: 4 modeling animal Bennazzouz scale integrations are all greater than 8, wherein 2 clinical symptom are obvious, reach clinical Pyatyi standard (namely animal is bilateral Parkinson disease model, must rely on to assist to obtain enough nutrition, but can also keep sitting posture).The clinical symptom of animal, diet and daily routines situation have improvement in various degree upon administration.
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 not departing from the inventive method, also can carry out some improvement and supplement, these possible improvement and supplement also should be considered as protection scope of the present invention.
Claims (4)
1. the compound as shown in general formula I,
Wherein: R
1be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl or C
1-C
2alkoxyl group; R
2be selected from hydrogen, fluorine, chlorine, bromine or iodine, the position of substitution is 2,3 or 4 of A ring; N represents 1,2,3,4 or 5, is 4-8 ring corresponding to B ring.
2. compound according to claim 1, is characterized in that: compound is selected from
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-(α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azetidine;
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-tetramethyleneimine;
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-piperidines;
4-((α-R)-α-(2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-azepan;
4-((α-R)-α-((2S, 5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(2-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl) benzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-luorobenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(4-luorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-bromobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane;
4-((α-R)-α-((2S, 5R)-4-(3-iodine benzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) benzoyl-1-Azacyclooctane.
3. a pharmaceutical composition, is characterized in that: containing the compound according to any one of claim 1-2, and pharmaceutically acceptable diluent or carrier.
4. the application of the compound according to any one of claim 1-2 in the medicine of preparation treatment parkinsonism.
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| WO2007027987A2 (en) * | 2005-09-02 | 2007-03-08 | Mount Cook Biosciences, Inc. | Method of treating parkinson's disease with diarylmethylpiperazine compounds exhibiting delta receptor agonist activity |
| CN101198330A (en) * | 2005-04-14 | 2008-06-11 | 蒙特库克生物科学公司 | Compositions of novel opioid compounds and method of use thereof |
| CN101318952A (en) * | 2008-06-04 | 2008-12-10 | 昆明贝尔吉科技有限公司 | Sigma Acceptor activator compound and uses thereof |
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| CN101198330A (en) * | 2005-04-14 | 2008-06-11 | 蒙特库克生物科学公司 | Compositions of novel opioid compounds and method of use thereof |
| WO2007027987A2 (en) * | 2005-09-02 | 2007-03-08 | Mount Cook Biosciences, Inc. | Method of treating parkinson's disease with diarylmethylpiperazine compounds exhibiting delta receptor agonist activity |
| CN101318952A (en) * | 2008-06-04 | 2008-12-10 | 昆明贝尔吉科技有限公司 | Sigma Acceptor activator compound and uses thereof |
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