CN100435796C - Cardioprotective delta opioid receptor agonists and methods of using same - Google Patents

Cardioprotective delta opioid receptor agonists and methods of using same Download PDF

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CN100435796C
CN100435796C CNB2004800000129A CN200480000012A CN100435796C CN 100435796 C CN100435796 C CN 100435796C CN B2004800000129 A CNB2004800000129 A CN B2004800000129A CN 200480000012 A CN200480000012 A CN 200480000012A CN 100435796 C CN100435796 C CN 100435796C
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chemical compound
alkyl
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aryl
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CN1697657A (en
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张宽仁
威廉·彭德格斯特
彼得·J·真戈
马欣
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Mount Cook Biosciences Inc
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Abstract

The present invention relates to compositions and methods of treatment for cardioprotection through the use of non-peptidic delta opioid receptor agoni st compound(s) that mediate cardioprotective effects of ischemic preconditionin g. The compounds are used to reduce injury associated with ischemia and reperfusion of cardiac tissue. Further, the compounds may be used in solutio ns preserving the viability of an isolated organ.

Description

The application in the preparation medicine of the δ opioid receptor agonist of protection heart and this agonist
Background of invention
Invention field
The present invention relates to be used for the compositions and the method for Cardioprotective treatment, more particularly, relate to the non-peptide δ opioid receptor agonist compound of the pretreated Cardioprotective effect of mediation ischemia.
Description of Related Art
The tissue that loses blood and oxygen can suffer ischemic necrosis or infraction, and with possible irreversible organ injury.In surviving the patient of myocardial infarction,, reduces ischemic damage owing to showing efficient myocardium.Yet,, have the people of angor before heart attack, to demonstrate less myocardium histologic lesion owing to the oxygen that flows to cardiac muscle reduces with respect to those people who does not have angor.Therefore, of short duration ischemia has the effect that the protection cardiac muscle is avoided ischemic damage.
Ischemia pretreatment (PC) is a kind ofly to comprise the phenomenon that is generally confirmed among the mankind at a lot of species, thus by of short duration in advance ischemia or anoxia, pour into again subsequently and again oxygenation protect cardiac muscle not to be subjected to the influence of severe ischemic accident.Use short persistent period, of short duration ischemia to avoid the infringement of the ischemia accident of longer time subsequently by people such as Murry. confirm (Circulation, 1986:74:1124-1136).Result of the test shows, carried out with the short-term ischemia before serious long-term ischemia accident that tissue necrosis has reduced about 30% in the pretreated dog class heart.Ischemia pretreatment phenomenon has caused great clinical concern aspect the patient who suffers from ischemic heart desease being used for the treatment of.
The ischemia pretreatment needs blood supply minimizing on the health, and this is difficulty or unpractical to most patient.Have been found that to take exercise to have about 24 hours ischemia effects of pretreatment of continuing, but can not reach the required cardiac output level of from the ischemia pretreatment, being benefited on a lot of patient body.The ischemia at intermittence that was caused by the large artery trunks bridging before coronary artery frame bypass surgery has been used as the pretreated clinical practice of ischemia.Have been found that after operation process had myocardium pretreated patient's cardiac output significantly higher.With respect to there not being pretreated patient, the operation bleeding from anus that pretreated patient also the demonstrates improvement mechanical behavior that surges.Yet a plurality of potential problems are relevant to realize to the blood supply minimizing of cardiac muscle with the large artery trunks bridging, therefore, need have a kind of by the pretreated treatment of pharmacological method reinforcement ischemia.
Determined that many membrane receptors are relevant with pretreatment, comprise opioid receptor.Three main opioid receptor hypotypes are μ, κ and δ.Even the δ opioid receptor stimulate in the animal of not hibernation also can natural imitation hibernation, being in the news can be to organizing oxygen supply hour to improve tissue survival.Similarly, it is relevant with the ischemia pretreatment to have proved that also the δ opioid receptor stimulates.Utilize peptide and non-peptide δ opioid receptor agonist induction ischemia effects of pretreatment to carry out big quantity research.Schultz and Gross (U.S.Patent No.6,103,722) tested many non-peptide δ opioid receptor chemical compounds that show the ischemia pretreating effect, comprised (-)-2-methyl-4a. α-(3-hydroxyphenyl)-1,2,3,4,4a, 5,12,12a. β-octahydro quino [2,3] isoquinolin (TAN67 (-)); (±)-4-((α R *)-α-((2S *, 5R *)-4-pi-allyl-2,5-dimethyl-1-piperazinyl)-the 3-acrinyl)-N, N diethylbenzene Methanamide (BW373U86); And (+)-4-[(α R)-α-((2S, 5R)-4-pi-allyl-2,5-dimethyl-1-piperazinyl)-the 3-methoxy-benzyl]-N, N-diethylbenzene Methanamide (SNC80).
Yet these non-peptide compounds are not no problem, especially because these chemical compounds are considered to analgesic, and known several chemical compounds since these chemical compounds by blood brain barrier cause the taking medicine outbreak of object.
Similarly, need have and a kind ofly strengthen the pretreated treatment of ischemia by pharmacological method, this treatment has been avoided and has been reduced relevant problem and use the potential outbreak that some δ opioid receptor agonist compounds cause to blood supply of cardiac muscle.
Summary of the invention
On the one hand, the present invention relates to treat ischemic damage and/or realize the pretreated therapeutic combination of ischemia, said composition comprises diaryl methyl piperazine chemical compound or its pharmaceutically acceptable ester or the salt of the following formula of effective dose:
Figure C20048000001200081
Wherein:
Z is selected from by following group:
Hydrogen;
Halogen;
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl;
C 1-C 6Haloalkyl;
C 1-C 6Alkoxyl;
C 3-C 6Cycloalkyloxy;
Has formula SR 8Sulfide, R wherein 8Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 3-C 6Cycloalkyl, has C 5-C 10Aryl moiety and C 1-C 6The aryl alkyl of moieties or C 5-C 10Aryl;
Has formula SOR 8Sulfoxide, R wherein 8Same as above;
Has formula SO 2R 8Sulfone, R wherein 8Same as above;
Nitrile;
C 1-C 6Acyl group;
Has formula NHCO 2R 8Alkoxycarbonyl amido (carbamyl), R wherein 8Same as above;
Carboxylic acid or its ester, amide or salt;
Has formula CH 2NR 9R 10Aminomethyl, R wherein 9And R 10Can be identical or different, and can be hydrogen, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 2-C 6Hydroxyalkyl, C 2-C 6Methoxy alkyl, C 3-C 6Cycloalkyl or C 5-C 10Aryl, perhaps R 9And R 10The common ring that forms 5 or 6 atoms, the atom on the ring are selected from the group of N and C composition;
Has formula CONR 9R 10Carbamyl, R wherein 9And R 10Same as above, or its C 2-C 30Peptide conjugates; With
Has formula SO 2NR 9R 10Sulfonamide, R wherein 9And R 10Same as above; With
X is selected from the group of being made up of hydrogen, hydroxyl, halogen and alkoxyl.
Another aspect of the present invention relates to the method for ischemic damage among a kind of patient of alleviating, and this method comprises: use the therapeutic combination of effective dose, this therapeutic combination comprises the diaryl methyl piperazine chemical compound of following formula:
Figure C20048000001200091
Or acceptable salt of its pharmacy or ester.
Of the present inventionly also relate in one aspect among a kind of patient of alleviating ischemic damage and/or realize the pretreated method of ischemia, this method comprises: use the δ opioid receptor of the following formula of effective dose for described patient:
Figure C20048000001200092
Or acceptable salt of its pharmacy or ester.
Preferably, diaryl methyl piperazine chemical compound of the present invention is for mainly acting on the non-analgesic compounds of periphery δ opioid receptor.Diaryl methyl piperazine chemical compound can be used in several different effective time sections, comprising: with the ischemia accident outbreak while; At the ischemic episode previous crops is that preventive therapy prevents that those are in the patient's in ischemic heart disease symptoms stage advancing of disease; Before having patient's the operation of clot or other type heart ischemia danger; Or after the outbreak of ischemia accident;
The non-invasive clinical imaging method that the effect of The compounds of this invention can adopt involved area for example nuclear magnetic resonance, NMR (MRI) imaging is estimated with the size of determining the infringement area.
On the other hand, the present invention relates to keep the solution of isolated organ survival ability, this solution comprises the chemical compound of following formula:
Figure C20048000001200101
Or acceptable salt of its pharmacy or ester, and concentration effectively armour avoid ischemic injuries.Isolated organ can include but not limited to heart, liver, kidney, cornea and/or lung.
Therapeutic combination can be used by any suitable administering mode, for example, be selected from down the form of medication of group: comprise that oral, rectum, part, Sublingual, mucosa, nose, eye, subcutaneous, intramuscular, intravenous, transdermal, vertebra, sheath are interior, under the intraarticular, intra-arterial, arachnoidea, bronchus, lymph and intrauterine administration.
Another aspect of the present invention relates to the method that resists long-term ischemic episode and reperfusion injury in the mammal, and this method comprises the δ opioid receptor agonist of the following formula of using effective dose:
Figure C20048000001200111
Or acceptable ester of its pharmacy or salt; With second kind of chemical compound, comprise being used to resist arginine hydrochloride and other the potential source of nitric oxide that plays similar effect that cardiac function descends after the ischemia accident with ischemia resisting effect.
It is more abundant obvious that various others of the present invention, feature and embodiment will become in ensuing disclosure and accessory claim.
The accompanying drawing summary
Fig. 1 has shown the histological specimens of infraction size in contrast and treatment animal.
Detailed Description Of The Invention and preferred embodiment thereof
Of the present invention main aspect, the diaryl methyl piperazine chemical compound that is applied in hereinafter more abundant description to the patient to be to be in harmonious proportion the ischemia pretreatment, reach thus that tissue necrosis reduces, ischemia after-contraction function is improved and ischemia after dysrhythmia reduce.Can advantageously comprise the monotherapy treatment according to treatment of the present invention; wherein with chemical compound of the present invention as the single therapy pharmacy application in the therapeutic combination; or conjoint therapy treatment, wherein can be applied to be in harmonious proportion cardiac treatment medicament same period of corrective or protectiveness cardiac response with other as simultaneously or in turn use according to compositions of the present invention.Other cardiac treatment medicament can include but not limited to nitrate, beta-adrenaline blocker, calcium-channel antagonists, ACE inhibitor, non-peptide angiotonin II antagonist, IIb/IIIa antagonist and aspirin.
According to the present invention, term used herein " alkyl " is intended to be comprised by being interpreted as widely: the alkyl that (i) has straight chain and side chain feature; The alkyl that does not (ii) replace and replace, wherein the substituent group of substituted alkyl can comprise any and this alkyl fit and can not hinder on the space of curative effect of diaryl methyl piperazine chemical compound intended purpose acceptable substituent group that (the substituent group example of substituted alkyl comprises halogen (as fluorine, chlorine, bromine and iodine), amino, acylamino-, C 1-C 4Alkyl, C 1-C 4Alkoxyl, nitro, hydroxyl etc.); (iii) saturated alkyl and unsaturated alkyl, the latter comprises the alkyl of alkyl (as pi-allyl, methylallyl, the third generation pi-allyl (propallyl), cyclobutenyl methyl etc.), alkynyl substituted of group such as alkenyl substituted and any other and this alkyl fit and can not hinder the containing to have living space and go up the alkyl of acceptable degree of unsaturation of curative effect of diaryl methyl piperazine chemical compound intended purpose; (iv) comprise for example alkyl of hetero atom such as nitrogen, oxygen, sulfur etc. of bonding or bridging part.
According to the present invention, term used herein " aryl " is intended to be interpreted as widely and is meant carbocyclic ring (as phenyl, naphthyl) and heterocyclic aromatic base (as pyridine radicals, thienyl, furyl etc.), and comprise the aryl that does not replace and replace, wherein the substituent group of substituted aryl can comprise with this aryl fit and can not hinder acceptable substituent group on any space of curative effect of diaryl methyl piperazine δ opioid receptor agonist intended purpose.The substituent group example of substituted aryl comprises hydrogen, one or more halogens (as fluorine, chlorine, bromine and iodine), amino, acylamino-, C 1-C 4Alkyl, C 1-C 4Alkoxyl, nitro, trifluoromethyl, hydroxyl, comprise C 1-C 4The hydroxyalkyl of moieties etc.
The example of the pharmaceutically acceptable ester of the chemical compound of formula (1), (2) and (3) comprises the carboxylate of hydroxyl in the chemical compound of X=OH in the formula (1), and the carboxylate of hydroxyl in formula (2) and (3) chemical compound, wherein the non-carbonyl moiety of carboxylic moiety is selected from straight or branched alkyl (as n-pro-pyl, the tert-butyl group, normal-butyl), alkoxyalkyl (as methoxy), aryl alkyl (as benzyl), aryloxy alkyl (as phenoxymethyl) and aryl (as phenyl) in the ester group; Alkyl sulphonyl, aryl sulfonyl or aryl alkylsulfonyl (as methyl sulphonyl); Amino-acid ester (as L-valyl or L-isoleucyl-); Dicarboxylic ester (as the hemisuccinic acid ester); Carbonic ester (as carbethoxyl group); Carbamate (as dimethyl formamide, (2-aminoethyl) Methanamide); And inorganic ester (as Monophosphate-, bisphosphate or triguaiacyl phosphate).
The example of the pharmaceutically acceptable salt of the chemical compound of formula (1), (2) and (3) comprises the salt that derives from suitable alkali, described alkali such as alkali metal (for example sodium, potassium), alkaline-earth metal (for example calcium, magnesium), ammonium and NR ' 4 +(wherein R ' is C 1-C 4Alkyl).Amino pharmaceutically acceptable salt comprises the salt of following material: organic carboxyl acid such as acetic acid, lactic acid, tartaric acid, malic acid, lactobionic acid, fumaric acid and succinic acid; Organic sulfonic acid such as pyrovinic acid, ethylsulfonic acid, isethionic acid, benzenesulfonic acid and p-methyl benzenesulfonic acid; With mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sulfamic acid.The pharmaceutically acceptable salt of chemical compound with hydroxyl by the anion of described chemical compound in conjunction with suitable cation such as Na +, NH 4 +Or NR ' 4 +(wherein R ' is for example C 1-4Alkyl) forms.
The present invention considers that also the veterinary uses and the medical pharmaceutical preparation of people, and this pharmaceutical preparation comprises one or more diaryl methyl piperazine chemical compounds of the present invention as activating agent.
In this pharmaceutical preparation, activating agent preferably uses with one or more pharmaceutically acceptable carriers that use and optional any other therapeutic component for this reason.From with preparation the matched meaning of other composition, carrier must be pharmaceutically acceptable, can't be excessively harmful to its receiver.As mentioned above, the activating agent that effective dose is provided to be obtaining best pharmacotoxicological effect, and provides suitable amount to obtain best daily dose.
Preparation comprises those that are suitable for parenteral and parenteral external administration, that concrete administering mode comprises is oral, in rectum, part, Sublingual, mucosa, nose, eye, subcutaneous, intramuscular, intravenous, transdermal, vertebra, the sheath, under the intraarticular, intra-arterial, arachnoidea, bronchus, lymph and intrauterine administration.
When using diaryl methyl piperazine chemical compound in the preparation that is comprising liquid solution, can be advantageously at the parenteral administration said preparation.When in the liquid suspension liquid formulation or as the powder in the physiologically acceptable carrier preparation, using diaryl methyl piperazine chemical compound, advantageously oral administration, rectum or bronchus administered formulation.
When directly using diaryl methyl piperazine chemical compound with the form of powdery solid, can be advantageously Orally administered.Selectively,, use, can disperse thing by the gaseous state that patient sucks from the breathing circuit that comprises suitable sprayer device to form through bronchus by powder atomization in the carrier gas.
In some applications, can advantageously use diaryl methyl piperazine chemical compound with " vectorization " form, as in liposome or other capsule sealing medium, sealing activating agent, or for example fix activating agent on as those molecules that are selected from protein, lipoprotein, glycoprotein and polysaccharide by covalent bond, chelation or associating coordination in suitable biomolecule.
Can provide the preparation that comprises diaryl methyl piperazine chemical compound of the present invention with the unit dosage form form expediently, and can prepare by well-known any method in the pharmaceutics field.These methods generally include carries out associating step with diaryl methyl piperazine chemical compound and the carrier that constitutes one or more auxiliary agents.Typically, by evenly and nearly diaryl methyl piperazine chemical compound and liquid-carrier, solid carrier in small, broken bits or the two being associated, then, as required, the dosage form that product is configured as required preparation prepares preparation.
The preparation that is suitable for oral administration of the present invention can be provided with the form of dispersal unit such as capsule, cachet, tablet or lozenge, and the diaryl methyl piperazine chemical compound of its each self-contained scheduled volume is as powder or granule; Or provide with the suspension of aqueous solution or on-aqueous liquid, as syrup, elixir, Emulsion or Haust.
Can make tablet by compression or mold pressing, randomly add one or more auxiliary agents.Can prepare compressed tablets by compression on suitable machine, wherein diaryl methyl piperazine chemical compound is free-flowing form such as powder or granule, and randomly mixes with binding agent, disintegrating agent, lubricant, inert diluent, surfactant or discharging agent.Can make the mold pressing tablet of the mixture that comprises powdery diaryl methyl piperazine chemical compound and suitable carrier by mold pressing on suitable machine.
Can by to sugar as the concentrated aqueous solution of sucrose in the adding chemical compound of the present invention make syrup, also can in this syrup, add any auxiliary agent.This analog assistant can comprise flavoring agent, suitable antiseptic, prevent sugared crystallizing agent and improve the medicament of any other composition dissolubility, as polyhydroxy-alcohol, and for example glycerol or Sorbitol.
The preparation that is suitable for parenteral comprises the sterilized water preparation of The compounds of this invention expediently, said preparation preferably with receiver's haemoconcentration identical (as normal saline solution).This class preparation can comprise that suspending agent, thickening agent and liposome or other are designed to make chemical compound to reach the microparticle system of blood constituent or one or more organs.Can provide preparation with unit dose or multiple dose form.
The nose spray agent comprises the purification of aqueous solutions of the The compounds of this invention with antiseptic and isotonic agent.Preferably this class preparation is adjusted to the pH that adapts with nasal mucosa and waits and ooze state.
Can be provided for the preparation of rectally with suppository form with suitable carrier such as cocoa butter, hydrogenated fat or hydrogenated fat carboxylic acid.
By preparing ophthalmic preparation, except preferably with pH with wait and ooze the factor and adjust to and the eye coupling with the similar method of nasal spray.
Topical preparation comprises The compounds of this invention or other main component that is used for topical pharmaceutical formulation that is dissolved in or is suspended in one or more media such as mineral oil, oil, polyhydroxy-alcohol.
By for example sneaking into The compounds of this invention in methylcellulose or the hydroxyethyl-cellulose at thixotroping or gel carrier such as cellulose family medium, prepare preparation capable of permeating skin, the preparation that obtains at transdermal equipment intermediate package then, the safety when guaranteeing to contact with wearer skin.
Except mentioned component, preparation of the present invention also can comprise one or more auxiliary agents, and it is selected from diluent, buffer agent, flavoring agent, binding agent, disintegrating agent, surfactant, thickening agent, lubricant, antiseptic (comprising antioxidant) etc.
Sometimes, in order to prolong the effect of diaryl methyl piperazine chemical compound of the present invention, the absorption of diaryl methyl piperazine chemical compound in the time of need slowing down from subcutaneous or intramuscular injection.This can realize by the crystal of use water-soluble difference or the liquid suspension of amorphous materials.So the absorption rate of diaryl methyl piperazine chemical compound depends on its rate of dissolution, it depends on crystal size and crystal form again.Selectively, the time-delay of the diaryl methyl piperazine chemical compound of parenteral administration absorbs by dissolving or suspended drug in oiliness vehicle and realizes.
Can prepare injectable storage form by the microcapsule substrate that in biodegradable polymers such as polyactide-poly-Acetic acid, hydroxy-, bimol. cyclic ester, forms at least a The compounds of this invention.According to the characteristic of the ratio of active component and polymer and the concrete polymer that adopted, can control the rate of release of active component.The example of other biodegradable polymers comprises poly-(ortho esters) and poly-(acid anhydride).Storing injectable formulation also prepares by active component being contained in liposome compatible with bodily tissue or the microemulsion.Injectable materials can be sterilized by for example filtering with antibacterial reservation filter.
According to the concrete condition of treatment, can use chemical compound of the present invention to animal patient with effective in any suitable treatment and safe dosage, this can easily be determined by the one skilled in the art, not need over-drastic test.
Usually, although according to related actual conditions, in main enforcement of the present invention, can change the effective dose of the The compounds of this invention of treatment use largely, this can easily be determined by the one skilled in the art, but for each attached compositions described herein, and for obtaining the treatment benefit in the treatment under every kind of condition described herein, the suitable therapeutic dose of The compounds of this invention is in the scope of 10 micrograms (μ g) to 100 milligrams (mg)/kilogram receiver body weight/day, preferably in the scope in 50 μ g to 75mg/ kg body weight/skies, most preferably in the scope in 100 μ g to 50mg/ kg body weight/skies.The mode that can use secondary, three times, four times, five times, six times or more times sub-dosage in the suitable interval of whole day provides required dosage, when especially soon performing the operation.In addition, the selection of single dose time preferably behind the ischemic episode in 4 hours.The dosage that needs can repeat repeatedly to think that cardiac muscle provides more resistance to any follow-up longer time ischemic episode.
Following examples have illustrated the building-up process that can be advantageously used in synthetic The compounds of this invention.
Embodiment 1
4-{ (2R, 5S)-4-[(R)-(4-diethylamino formoxyl phenyl) (3-hydroxy phenyl) methyl]-2,5-dimethyl-1-piperazinyl methyl } benzoic acid
Figure C20048000001200171
At room temperature with the 3-bromophenol (400g, 2.31mol), tertiary butyl chloride for dimethylsilane (391mg, 2.54mol) and imidazoles (346g, 5.08mol) 5000mL dichloromethane solution stir and spend the night.Reaction solution is poured in the 2000mL water into layering.Preceding by silica filler (400g, silicon dioxide 60,230-400 order), with the 1N sodium hydrate aqueous solution (3 * 1500mL) and water (2 * 1500mL) wash organic layers.(2 * 500mL) washing silica gel, merging filtrate, and under reduced pressure remove and desolvate obtain the 3-bromo phenoxy group-tert-butyl group dimethylsilane of the transparent light yellow liquid shape of 669g (98.4%) with dichloromethane. 1H NMR(300MHz，CDCl3)：7.1(m，2H)；7.0(br s，1H)；6.75(m，1H)；1.0(s，9H)；δ0.2(s，6H)。
Under refluxing with 3-bromo phenoxy group-tert-butyl group dimethylsilane (45.97g, 160mmol) with 1,2-Bromofume (6.01g, 32mmol) anhydrous tetrahydrofuran solution of the 150mL unrestraint agent of mixture slowly joins magnesium chips mixture (4.28g, in the anhydrous tetrahydrofuran solution of 400mL unrestraint agent 176mmol), form 3-t-butyldimethylsilyloxy phenyl-magnesium-bromide.Under refluxing, stir after 1 hour, transparent light brown solution cool to room temperature.
(100.3g 0.67mol) dissolves/is suspended in the toluene (1200mL), adds N, dinethylformamide (0.15mL), and at thionyl chloride (53.5mL, 87.2g, stirred suspension in the time of 0.73mol) with the 4-carboxyl benzaldehyde.The reacting by heating mixture to be refluxing under nitrogen, and stirs 2 hours, therebetween in a large number but be not that whole aldehydic acid enter solution.(0.27mol) also backflow continues to spend the night for 20mL, 32.6g to add a certain amount of thionyl chloride again.Evaporate transparent reactant mixture, and residue is dissolved in the anhydrous tetrahydro furan (1500mL).Cooling solution in ice/water-bath, and in the solution that stirs, drip diethylamine (173mL, 122g, 1.67mol (2.5 equivalent)).Remove ice bath and continue and stirred 2.5 hours.Filter reaction mixture is to remove white crystals diethylamine hydrochloride by-product with ethyl acetate (2 * 600mL) washing crystals, and stay washings.Evaporate the oxolane filter liquor, and residue is dissolved in the ethyl acetate washings.Use successively 1M hydrochloric acid (2 * 600mL), water (2 * 300mL), the dilution sodium carbonate liquor (saturated solution: H 2O/1:1,2 * 600mL), water (2 * 300mL) and saturated nacl aqueous solution (300mL) wash solution.Separate organic layer, dry also evaporation produces the 4-formyl-N of filbert oily on anhydrous sodium sulfate, and N-diethylbenzene Methanamide uses to need not at that time to be further purified.(yield 115.7g, 84%)
In the 3L round-bottomed flask that condenser and Dean-Stark catcher are housed, with 4-formyl-N, and N-diethylbenzene Methanamide (20.53g, 100mmol), benzotriazole (11.91g, 100mmol) with (2R, 5S)-and 1-pi-allyl-2,5-lupetazin (15.43g, 100mmol, ChirotechTechnology, Ltd., Cambridge England) mixes with 1000mL toluene.The reacting by heating thing is to reflux, up to do not observe extra water (about 3 hours) in catcher under nitrogen.Reactant is cooled to room temperature, and under vacuum, concentrates the volume that stays about 300mL.Under nitrogen, in the benzotriazole adduct, add anhydrous tetrahydro furan (500mL) and stir and obtain solution completely.At room temperature this solution is joined in the solution of bromination 3-t-butyldimethylsilyloxy phenyl magnesium (above-mentioned) by double needle.Stir after 1.5 hours, finish reaction by adding saturated aqueous ammonium chloride (50mL), and stirred 15 minutes.Add anhydrous magnesium sulfate (50g), stirred 1.5 hours, and the filtering reaction thing.Under reduced pressure except that desolvating and residue being dissolved in the ethyl acetate (1000mL).With the 1M sodium hydroxide (5 * 400mL), water (4 * 400mL) and saturated sodium-chloride water solution (400mL) washing ethyl acetate solution.Dry organic layer on anhydrous magnesium sulfate, and remove to desolvate and obtain dark oil.Oil is dissolved in 500mL oxolane and the 300mL3M hydrochloric acid, and at room temperature stirred 1.5 hours.Water (300mL) diluting reaction, and under vacuum, be concentrated into half of about original volume.With pentane (2 * 500mL) extraction solutions.With the 5M sodium hydroxide aqueous layer is adjusted to PH8-9 and uses ethyl acetate (250Ml) extraction.Stratum disjunctum, and contain water section with other ethyl acetate (250mL) extraction.With the organic extract that the saturated sodium-chloride water solution washing merges, dry on anhydrous sodium sulfate, and under reduced pressure obtain brown oil except that desolvating.This residue is dissolved in (25mL) in the ethyl acetate, crystal with reliable chemical compound connects crystal seed, and crystallization (the Michael J.Bishop and Robert W.McNutt that spends the night, Seed Crystals Obtained From Hot 2-propanol With Addition of Water, Bioorg.Med.Chem.Lett. (1995), 5,1311-14).Crystal is filtered, with a small amount of cold ethyl acetate washing solid.Under 5mmHg and room temperature, carry out the dry 4-[(R that produces the white crystal shape)-((2S, 5R)-4-pi-allyl-2,5-dimethyl-1-piperazinyl) (3-hydroxyphenyl) methyl]-N, N-diethylbenzene Methanamide.Product shows on HPLC unimodal (Zorbax RX C8,4.6mm * 25cm, 40%0.01 M NH of MeOH intermediate concentration 4OAc, 3 minutes; Linear gradient to 100% MeOH, 45 minutes; Isocyatic MeOH, 5 minutes; 1.0mL/min; Obs=210nm, Rt=32.21min).C 27H 37N 3O 2Value of calculation: %C, 74.45; H, 8.56; N, 9.65. measured value: %C, 74.48; H, 8.60; N, 9.62. 1H NMR (CDCl 3, 300MHz): δ 7.42 (d, J=8.1Hz, 2H); 7.28 (d, J=8.4Hz, 2H); 7.08 (t, J=7.8Hz, 1H); 6.64-6.57 (m, 3H); 5.94-5.83 (m, 1H); 5.22 (d, J=8.7Hz, 1H); 5.18 (s, 1H); 5.14 (br s, 1H); 3.60-3.47 (m, 2H); 3.42 (dd, J=5.2,13.7Hz, 1H); 3.37-3.20 (br m, 2H); 2.91 (dd, J=8.1,13.5Hz, 1H); 2.85 (dd, J=2.6,11.4Hz, 1H); 2.70-2.47 (m, 3H); 2.17 (t, J=10.7Hz, 1H); 1.98 (t, J=11.1Hz, 1H); 1.23 (m, 3H); 1.14 (d, J=6.1Hz, 3H, with m, 3H is overlapping); 1.02 (d, J=6.2Hz, 3H).
Under nitrogen and room temperature, use catalyst solution with 4-[(R)-((2S, 5R)-4-pi-allyl-2,5-dimethyl-1-piperazinyl) (3-hydroxyphenyl)-methyl]-N, N-diethylbenzene Methanamide (10.89g, 25mmol) and thiosalicylic acid (4.63g, anhydrous tetrahydro furan 30mmol) (50mL) solution stirring 1.5 hours, this catalyst solution is by two (dibenzalacetone) palladium (0.718g of dissolving in oxolane (10mL), 1.25mmol) and 1, (0.533mg 1.25mmol) prepares two (diphenylphosphino) butane of 4-.(J.P.Genet，S.Lemaire-Audoire，M.Savignac，Tetrahedron Letters， 36，1267-1270(1995))。Under reduced pressure concentrated reaction mixture distributes residue between ethyl acetate (150mL) and aqueous sodium carbonate.Stratum disjunctum adds diethyl ether (250mL) in organic layer.With 5% sodium carbonate liquor (2 * 150mL) extraction organic layers.Dilute organic layer with pentane (500mL), and (6 * 30mL) extract with 3M hydrochloric acid.Use saturated aqueous sodium carbonate that this aqueous solution is adjusted to pH9-10, and (3 * 100mL) extract with dichloromethane.The dry organic extract that merges on anhydrous sodium sulfate, and under reduced pressure remove and desolvate, obtain the 4-[(R of frangible light yellow foams shape)-((2S, 5R)-2,5-dimethyl-1-piperazinyl) (3-hydroxyphenyl) methyl]-N, N-diethylbenzene Methanamide (10.24g).Product shows on HPLC unimodal (Zorbax C-8,40%0.01 M NH of MeOH intermediate concentration 4OAc, 3 minutes; Linear gradient is to 100%MeOH, 45 minutes; Isocyatic MeOH, 5 minutes; 1.0mL/min; Obs=210nm, Rt=19.24min).C 24H 33N 3O 20.1 EtOAc0.4 CH 2Cl 2Value of calculation: %C, 67.96; H, 7.96; N, 9.59. measured value: %C, 67.90; H, 8.03; N, 9.54. 1HNMR (CDCl 3, 300MHz): δ 7.42 (d, J=8.1Hz, 2H); 7.26 (d, J=8.3Hz, 2H); 7.11 (t, J=7.8Hz, 1H); 6.72 (d, J=8.1Hz, 1H); 6.65 (s, 1H); 6.59 (d, J=7.6Hz, 1H); 5.16 (s, 1H); 4.93 (v br s, 2H); 3.51 (br m, 2H); 3.27 (br m, 2H); 3.02-2.97 (m, 1H); 2.92 (d, J=10.5Hz, 1H); 2.66 (br d, J=8.5Hz, 2H); 2.60-2.45 (m, 1H); 1.84 (dd, J=11.3,8.3Hz, 1H); 1.27-1.15 (m, 3H); 1.10 (d, J=6.1Hz, 3H and m, 3H is overlapping); 1.02 (d, J=6.1Hz, 3H).
4-{ (2R, 5S)-4-[(R)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-dimethyl-1-piperazine methyl } benzoic acid
Method A: standard reductive alkylation
With glacial acetic acid (0.635 mL, 11.1mmol) join 4-[(R)-((2S, 5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl) methyl]-N, N-diethylbenzene Methanamide (1.98g, 5mmol) (1.50g is in anhydrous tetrahydro furan 10mmol) (35mL) solution with the 4-carboxyl benzaldehyde.Under stirring gently, (2.12g 10mmol), allows to bubble behind each the interpolation and disappears to add the triacetic acid sodium borohydride with the 50-100mg portioning.There is not raw material with the HPLC detection reaction.After at room temperature stirring 16 hours, add other 4-carboxyl benzaldehyde (0.75g, 5mmol), acetic acid (0.318mL, 5mmol) and the triacetic acid borohydride sodium (1.06g, 5mmol).Behind the restir 4 hours, under reduced pressure concentrated reaction mixture distributes residue between ethyl acetate (50mL) and 3M hydrochloric acid (10mL).Stratum disjunctum, (5 * 10mL) extract organic layer once more with 3M hydrochloric acid.Use saturated aqueous sodium carbonate that this aqueous solution is adjusted to pH4.5-5, and (3 * 50mL) extract with dichloromethane.The dry organic extract that merges on anhydrous sodium sulfate; and under reduced pressure remove and desolvate; obtain frangible white foam body shape 4-{ (2R, 5S)-4-[(R)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-dimethyl-1-piperazinyl-methyl } benzoic acid (2.34g).Product shows on HPLC unimodal (Zorbax RX-C8,4.6mm * 25cm, 40%0.01 M NH of MeOH intermediate concentration 4OAc, 3 minutes; Linear gradient is to 100%MeOH, 45 minutes; Isocyatic MeOH, 5 minutes; 1.0mL/min; Obs=210nm, Rt=13.75min).
With 4-{ (2R, 5S)-4-[(R)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-dimethyl-1-piperazinyl-methyl } (2.09g 3.5mmol) is dissolved in the ethanol (6mL) benzoic acid, and adds 0.986N hydrochloric acid (3.60mL).(30mL) dilutes this solution with distilled water, filter, and quick freezing, and lyophilizing obtains white solid (2.17g) C 32H 39N 3O 41.6HCl1.6H 2O value of calculation: %C, 62.31; H, 7.16; N, 6.81; Cl, 9.20. measured value: %C, 62.32; H, 7.19; N, 6.74; Cl, 9.28. 1H NMR (D 2O+50%v/v 1-M NaOD in D 2O, 300MHz): δ 7.57 (d, J=8.1Hz, 2H); 7.17 (d, J=8.0Hz, 2H); 7.11 (d, J=8.1Hz, 2H); 6.99 (d, J=8.1Hz, 2H); 6.81 (t, J=7.8Hz, 1H); 6.30 (s, 1H); 6.29 (d of overlapping, J=7.5,1H); 6.13 (d, J=7.5Hz, 1H); 4.89 (s, 1H); 3.78 (d, J=12.7Hz, 1H); 3.22 (q, J=7.2Hz, 2H); 3.05 (d, J=12.9Hz, 1H); 2.95 (q, J=7.2Hz, 2H); 2.60 (d, J=11.2Hz, 1H); 2.35 (d, J=11.4Hz, 1H); 2.31-2.19 (m, 2H); 1.87-1.74 (m, 2H); 0.94 (t, J=7.3 Hz, 3H); 0.87 (t, J=7.3Hz, 3H); 0.77 (d, J=6.3Hz, 3H); 0.75 (d, J=6.3Hz, 3H; The two doublet is overlapping).
Method B: directly alkylation
With the 4-[(R in the acetonitrile (15mL))-((2S, 5R)-2,5-dimethyl-1-piperazinyl) (3-hydroxyphenyl) methyl]-N, N-diethylbenzene Methanamide (1.41g, 3.56mmol) be added to sodium iodide (80mg, 0.53mmol) in, and (2.0mL 14.3mmol) and during 4-(bromomethyl) essence of Niobe stirs to add triethylamine in priority.At nitrogen lower seal reactant mixture, stirred at ambient temperature 20 hours.Under reduced pressure concentrated reaction mixture distributes residue between ethyl acetate (50mL) and water (25mL).Separate organic layer, (3 * 20mL) extract with ethyl acetate in the water-bearing layer.With 5% sodium carbonate liquor (2 * 50mL) organic extracts that merge of water (50mL) extraction then.Organic layer dilutes with pentane (100mL), and (5 * 30mL) extract with 1M hydrochloric acid.Use saturated aqueous sodium carbonate that this aqueous solution is adjusted to pH8.5-9, and (3 * 50mL) extract with dichloromethane.The dry organic extract that merges on anhydrous sodium sulfate and magnesium sulfate.Under reduced pressure remove and desolvate, obtain faint yellow solid (1.90g).Residue is dissolved in the dichloromethane (5mL), is coated in filling in advance and (also carries out eluting [A=ethyl acetate and 2%NH on 4 * 7cm) the Biotage silicagel column with 20% to 60% solution gradient of A in B 4OH, the B=dichloromethane].Under reduced pressure concentrate required fraction [silica gel t.l.c. (EtOAc and the 2%NH that comprises product 4OH: CH 2Cl 2/ 1: 1) R f=0.39]; and it is further dry under 2mmHg and room temperature; the 4-{ of generation Off-white solid shape (2R, 5S)-4-[(R)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-dimethyl-1-piperazinyl methyl } essence of Niobe (1.34g).C 33H 41N 3O 4Value of calculation: %C, 72.90; H, 7.60; N, 7.73. measured value: %C, 72.68; H, 7.57; N, 7.64. 1H NMR (CDCl 3, 300 MHz): δ 7.95 (d, J=8.4Hz, 2H); 7.44 (d, J=8.1Hz, 2H); 7.37 (d, J=8.2Hz, 2H); 7.28 (d, J=8.2Hz, 2H); 7.14 (t, J=7.8Hz, 1H); 6.73-6.69 (m, 2H); 6.64 (s, 1H); 6.05 (br s, 1H); 5.00 (s, 1H); 3.94 (d, J=14Hz, 1H part and s, 3H is overlapping); 3.89 (s, 3H); 3.54 (br m, 2H); 3.29 (br m, 2H); 3.24 (d, J=14Hz, 1H); 2.68-2.53 (m, 4H); 2.05-1.94 (m, 2H); 1.26 (br m, 3H); 1.23 (br m, 3H); 1.06 (overlapping d, J=5.9Hz, 3H); 1.04 (overlapping d, J=5.9Hz, 3H).
With this solid (0.88g 1.62mmol) is dissolved in the ethanol (10mL), with the aliquot of about 1mL add the 2.5M sodium hydroxide solution (6.4mL, 16mmol).After in the end adding, muddy slightly reactant mixture clarification 5 minutes produces yellow solution, stirs this solution at ambient temperature 16 hours.Dilute this solution with isopyknic water, remove ethanol and be estimated as 50% water volume by evaporation.With 3M hydrochloric acid solution is adjusted to pH4.The cotton-shaped white solid that obtains is collected by filtration, uses a small amount of cold water washing.After air drying, further dry this solid produces title compound (0.90g, 85.9%) under 5mmHg vacuum and room temperature.Prove that by HPLC this material is identical with the chemical compound that method A makes.C 32H 39N 3O 41.5NaCl1.6 H 2The value of calculation of O: %C, 59.48; H, 6.58; N, 6.50. measured value: %C, 59.50; H, 6.45; N, 6.32. 1H NMR ((d 6-DMSO+20%v/v 1-M NaOD inD 2O, 300MHz); δ 0.93 (d, J=6.0Hz, 3H); 0.98 (d, J=5.9Hz, 3H; The overlapping br m of the two doublet, 6H); 1.9 (m, 2H); (2.54 m, 2H is because of the DMSO part is blured); 3.13 (br m, 2H); 3.22 (d, J=14.2Hz, 1H); 3.34 (br m, 2H); 3.71 (d, J=14.0Hz, 1H); 4.66 (s, 1H); 5.97 (d, J=6.9Hz, 1H); 6.16 (d, J=7.9,1H); 6.23 (s, 1H); 6.72 (t, J=7.7Hz, 1H); 7.16 (d, J=7.8Hz, 4H); 7.38 (d, J=8.1Hz, 2H); 7.72 (d, J=8.1Hz, 2H). mass spectrum: (ESI-, DP-120V, MeOH); M/z:529.0, (M+, 100%); 528, ((M-1)+, 57%); 512.6, ((M-17)+, 95%).
Embodiment 2
4-{ (2R, 5S)-4-[(S)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-dimethyl-1-piperazine methyl } benzoic acid
Figure C20048000001200231
(100g 666mmol), and stirs in 1200mL toluene under nitrogen weighing 4-carboxyl benzaldehyde in the three neck round-bottomed flasks of 2000mL.(53.5mL 733mmol), adds the 0.15mL dimethyl formamide then to add thionyl chloride in mixture.The reflux condenser that calcium chloride tube is housed is placed on the flask.Reactant placed oil bath and in the bath relaxing the bowels with purgatives of warm nature heating that keeps below 120 ℃.After obtaining clear solution, mixture was refluxed 1 hour, be cooled to room temperature then.Use the dry toluene dilute solution, and under vacuum, remove all volatile matters.
Thick acid chloride is dissolved in the 1500mL dry tetrahydrofuran, and in ice/water-bath, cools off.Dropwise add diethylamine (173mL, 1.67mol, 2.5 equivalents) by addition funnel.Make turbid solution in 1 hour, be warming up to room temperature, and stir and spend the night.Filter reaction mixture is to remove white crystals diethylamine hydrochloride by-product.With ethyl acetate (2 * 600mL) washing crystals.Evaporation oxolane filtrate is dissolved in residue in the ethyl acetate washings.Use successively 1M hydrochloric acid (2 * 600mL), water (2 * 300mL), the dilution sodium carbonate liquor (saturated solution: H 2O, 1: 1,2 * 600mL), water (2 * 300mL) and saturated nacl aqueous solution (300mL) wash solution.Separate organic layer, dry on sodium sulfate, under vacuum, remove and desolvate.Obtain the 4-formyl-N of faint yellow oily, N-diethylbenzene Methanamide (117.14g) uses and need not at that time to be further purified (85% not the yield of chromatogram purification). 1H NMR(300MHz，CDCl 3)：δ1.09-1.25(m，6H)；3.19-3.31(d，J＝6.4Hz，2H)；3.54-3.56(d，J＝6.6Hz，2H)；7.49-7.52(d，J＝8.1Hz，2H)；7.89-7.92(d，J＝8.2Hz，2H)；9.98(s，1H).
With the 3-iodophenol (110g, 500mmol) and imidazoles (93.6g, 1735mmol, 2.75 equivalents) place the 1150mL dry dichloromethane of 2000mL flask, and under nitrogen, in ice/water-bath, be cooled to 15 ℃.(82.9g 550mmol) dropwise joins in the reactant by addition funnel with the chlorination tert-butyl group dimethyl silane in the 200mL dry dichloromethane.Under nitrogen, the reactant mixture stirring is spent the night, filter, use washed with dichloromethane.Water (400mL), 0.4N NaOH solution (600mL) and the water (extract that 2 * 300mL) washings merge.Use Na 2SO 4The dry organic layer of/NaCl, evaporation produces light yellow oil (166g).
(48.85g 146mmol) puts into the 250mL flask that the 180mL dry tetrahydrofuran is housed with 3-iodo phenoxy group-tert-butyl group dimethylsilane under room temperature and nitrogen.Add isopropylmagnesium chloride (73mL, 146mmol, 2.0M solution in the oxolane) to form lurid solution by addition funnel.At room temperature reaction stirred is 1 hour.During this time, with 30g 4-formyl-N, N-diethylbenzene Methanamide is dissolved in the 300mL dry tetrahydrofuran in another 1000mL flask, and is cooled to-72 ℃ under nitrogen.Freshly prepd 3-phenoxy group-tert-butyl group-dimethylsilane magnesium chloride is slowly joined in the 1000mL flask.The monitoring transfer rate is to keep reaction temperature below-70 ℃.Make reactant when stirring is spent the night, be warming up to room temperature.With 24mL saturated aqueous ammonium chloride termination mix, and with the dilution of 600mL diethyl ether, successively with 600mL water and the washing of 150mL saturated nacl aqueous solution.Use the dried over sodium sulfate ethereal solution, remove thick 4-{[3-(the tert-butyl group dimethyl-silicon alcoxyl) phenyl that desolvates and obtain yellow oily] methylol }-N, N-diethylbenzene Methanamide.Thick productive rate is～100%.Thick product forms serosity in 20% ethyl acetate pentane solution.The white precipitate that obtains is collected by filtration, with pentane washing, dried overnight (30mmHg, 40 ℃).
With 4-{[3-(tert-butyl group dimethyl-silicon alcoxyl base) phenyl] methylol }-N, (50g 120.9mmol) is dissolved in the 800mL dichloromethane N-diethylbenzene Methanamide, dropwise adds 13.23mL (181.3mmol) thionyl chloride.At room temperature reaction stirred solution is 5 hours, removes under vacuum and desolvates.With the yellow oil of chromatography, obtain the required product 22.58g (52.26mmol) of yellow oily in the last purification remnants of silica gel (17%EtOAc in the pentane, 17%EtOAc in the pentane then).
With pure 4-{[3-(tert-butyl group dimethyl-silicon alcoxyl base) phenyl] the chloro methyl }-N, (22.58g 52.26mmol) is dissolved in the 350mL dry acetonitrile N-diethylbenzene Methanamide.Add sodium iodide (7.83g, 52.26mmol), diisopropylethylamine (13.69mL, 78.39mmol) and (2R, 5S)-1-pi-allyl-2, the 5-lupetazin (8.06g, 52.26mmol).Under refluxing and under the nitrogen, stirred the mixture 3 hours.Under reduced pressure remove acetonitrile, reactant mixture is poured in ethyl acetate (400mL) and the solution of potassium carbonate (150mL 2M aqueous solution).Separate organic layer, water and salt water washing, dry on solid carbonic acid potassium, and under vacuum, concentrate.Obtain the buttery thick product of dark brown (30g), thick productive rate is～100%.
Obtain two kinds of benzhydryl epimers with chromatography purifying crude product on silica gel.Pentane with 20%EtOAc carries out eluting earlier, progressively adopt in the pentane 30% then, 40%, 50% and 80% EtOAc eluting, obtain 4-{ (the R)-((2S of 11.00g (20.00mmol) yellow oily, 5R)-4-pi-allyl-2,5-lupetazin-1-yl) [3-(tert-butyl group dimethyl-silicon alcoxyl base) phenyl] methyl }-N, N-diethylbenzene Methanamide and 9.27g 4-{ (S)-((2S, 5R)-4-pi-allyl-2,5-lupetazin-1-yl) [3-(tert-butyl group dimethyl-silicon alcoxyl base)-phenyl] methyl }-N, N-diethylbenzene Methanamide (16.86mmol, yellow oil).Utilize the known pure isomer of describing among thin layer chromatography (TLC) and the embodiment 1 relatively to discern these isomers.
With 4-{ (S)-(2S, 5R)-4-pi-allyl-2,5-lupetazin-1-yl) [3-(tert-butyl group dimethyl-silicon alcoxyl base) phenyl] methyl }-N, N-diethylbenzene Methanamide (9.27g, 16.86mmol) successively be dissolved in the 35mL dry acetonitrile and fluoridize triethylammonium tetrakis dihydrate (4.69g, 25.29mmol) in, stirring is spent the night.Reaction solution is concentrated into drying, and residue is dissolved in the 40mL ethyl acetate, uses 2%NaHCO 3Aqueous solution (3 * 40mL) and water (40mL) extraction.Organic layer is dry on sodium sulfate, and evaporation obtains 4-{ (S)-(2S, 5R) 4-pi-allyl-2,5-lupetazin-1-yl) [3-hydroxyphenyl] methyl of the red amorphous solid shape of 8.55g }-N, N-diethylbenzene Methanamide.
Under the thiosalicylic acid existence condition, adopt the method Pd (dba) of the Genet that discusses among the embodiment 1 2/ DPPB removes pi-allyl.The concentration response thing is poured residue in 200mL ethyl acetate and the 300mL diethyl ether into.After the 340mL water washing, with 10% citric acid (5 * 80mL) extraction organic solutions.The acid extract thing that filters merging is adjusted to 8-8.5 with 15%NaOH solution with pH to remove a spot of suspended solid.With dichloromethane (the oily suspension that 3 * 300mL) extractions obtain.Dry (Na 2SO 4/ MgSO 4) organic solution that merges, under reduced pressure concentrate.Residue is the solid of light orange.
With 4-[(S)-((2S, 5R)-2,5-lupetazin-1-yl) (3-hydroxyphenyl) methyl]-N, (0.51g 1.29mmol) is dissolved in the 10mL dry acetonitrile N-diethylbenzene Methanamide.Add sodium iodide (20mg, 0.13mmol), successively add triethylamine (0.72mL, 5.16mmol) and 4-(bromomethyl) essence of Niobe (0.59g, 2.58mmol) in the process under nitrogen and room temperature reaction stirred.Under nitrogen, the reactant mixture stirring is spent the night.Except that desolvating, between ethyl acetate and saturated sodium bicarbonate solution, distribute residue by evaporation.Wash organic layer with water, at Na 2SO 4/ MgSO 4Last dry, under reduced pressure concentrate.With the color popularize law at silica gel (CH 2Cl 2Middle 50%EtOAc) light yellow oil of last purification remnants; obtain the 4-{ (2R of the white amorphous solid shape of 0.45g (0.83mmol); 5S)-4-[(S)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-dimethyl-1-piperazinyl methyl }-essence of Niobe.
With the above-mentioned ester of 1mL10%NaOH solution hydrolysis in the 3mL ethanol.Evaporation reaction mixture adds 2mL water to dry.Use 2mL EtOAc/Et 2Twice of O extraction solution dropwise adds the set point of 1M HCl to pH4-4.5 then to remove impurity.Form white gels, collect, use a small amount of cold water washing by filtering.Dry 4-{ in vacuum drying oven (30mmHg, 40 ℃) (2R, 5S)-4-[(S)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-lupetazin-1-ylmethyl } benzoic acid obtains the 180mg white solid. 1H NMR(300MHz，d 6-DMSO)：δ0.98-1.16(m，12H)；1.89-2.05(m，2H)；2.48-2.65(m，5H)；3.10-3.50(m，5H)；3.76-3.80(d，J＝13.9Hz，1H)；4.94(s，1H)；6.53-6.95(d，J＝8.0Hz，1H)；6.75-6.85(m，2H)；7.02-7.09(t，1H)；7.29-7.40(m，6H)；7.80-7.84(d，J＝8.3Hz，2H)；9.29(s，1H).
Embodiment 3
3-{ (2R, 5S)-4-[(R)-(4-diethylamino formoxyl phenyl) (3-hydroxyphenyl) methyl]-2,5-dimethyl-1-piperazinyl methyl } benzoic acid
Figure C20048000001200271
With 4-{ (R)-(2S, 5R)-4-pi-allyl-2,5-dimethyl-piperazine-1-yl)-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-phenyl] methyl }-N, N-diethylbenzene Methanamide (11.00g, 20.0mmol embodiment 2) be dissolved in the 40mL dry acetonitrile, add and fluoridize triethylammonium tetrakis dihydrate (5.56g, 30.00mmol), stirring is spent the night.Reaction solution is concentrated into drying, residue is dissolved in the 40mL ethyl acetate, use 2%NaHCO 3Aqueous solution (3 * 40mL) and water (40mL) wash.Organic layer is dry on sodium sulfate, and evaporation obtains the 4-{ (R) of the red amorphous solid shape of 8.55g-(2S, 5R)-4-pi-allyl-2,5-dimethyl-piperazine-1-yl) [3-hydroxyphenyl] methyl }-N, N-diethylbenzene Methanamide (10.30g).
Under the thiosalicylic acid existence condition, adopt the method for the Genet that discusses among the embodiment 1, with Pd (dba) 2/ DPPB removes pi-allyl.The concentration response thing is poured residue in 200mL ethyl acetate and the 300mL diethyl ether into.After the 340mL water washing, with 10% citric acid (5 * 80mL) extraction organic solutions.The acid extract thing that filters merging is adjusted to 8-8.5 with 15%NaOH solution with pH to remove a spot of suspended solid.With dichloromethane (the oily suspension that 3 * 300mL) extractions obtain.Dry (Na 2SO 4/ MgSO 4) organic extract that merges, under reduced pressure concentrate.Residue is the solid of light orange.
With 4-[(R)-((2S, 5R)-2,5-lupetazin-1-yl) (3-hydroxyphenyl) methyl]-N, N-diethylbenzene-Methanamide (2.50g, 6.32mmol) and the 3-carboxyl benzaldehyde (1.90g 12.64mmol) places the 250mL flask that 60mL oxolane and 0.80mL (13.91mmol) acetic acid are housed.At room temperature reaction stirred is 20 minutes, add in batches the triacetic acid sodium borohydride (2.68g, 12.64mmol).It is very muddy that reaction solution becomes, and at the nitrogen lower seal, stirring is spent the night.Reactant mixture is evaporated to drying, between ethyl acetate (60mL) and 3M HCl (12mL), distributes.With other 5 * 12mL 3M HCl extraction organic layer.With 0.5M NaOH solution and Na 2CO 3The aqueous extract that the solid adjustment merges is to pH4-4.5.The gel that obtains is collected by filtering, and it is dissolved in the 30mL 0.5M NaOH solution, uses 20mL EtOAc/Et 2The O extracting twice is to remove impurity.The set point that in aqueous solution, dropwise adds 1M HCl to pH4.5-5.The leucosol that obtains is collected by filtering, and uses a small amount of cold water washing.Dry 3-{ in vacuum drying oven (30mmHg, 40 ℃) (2R, 5S)-4-[(R)-(4-diethylamino formoxyl phenyl)-(3-hydroxyphenyl) methyl]-2,5-lupetazin-1-ylmethyl } benzoic acid obtains the 1.55g white solid. 1H NMR(300MHz，d 6-DMSO)：δ0.99-1.20(m，12H)；1.89-2.05(m，2H)；2.48-2.65(m，5H)；3.06-3.57(m，5H)；3.78-3.83(d，J＝12.5Hz，1H)；4.94(s，1H)；6.63-6.84(m，3H)；7.09-7.91(m，9H)；9.36(s，1H).
Embodiment 4
At mouse vas deferens (Mouse Vas Deferens ED 50) estimate the external opioid receptor activity of the chemical compound of as above being discerned with formula (3) (hereinafter referred to as chemical compound 1) in the receptor system.The analytic process of the definite receptor active that is adopted is as described below.
Vitro bioassay: remove the deferent duct (MVD) of mice, (Harlan, Raleigh NC), and are being equipped with the Mg of improvement in the CD-1 strain ++In the organ bathroom of free Krebs buffer it is suspended between the platinum electrode, pulling force is 0.5g, and buffer composition (mM) is as follows: NaCl, 117.5; KCl, 4.75; CaCl 2, 2.6; KH 2PO 4, 1.20; NaHCO 3, 24.5; And glucose, 11.Use 95%O 2/ 5%CO 2Make buffer saturated, and remain on 37 ℃.Under super large voltage, stimulate 400 milliseconds in tissue with the 10-Hz train of pulse; That goes here and there is spaced apart 10 seconds; In the following pulse duration of maximum voltage is 1.0 milliseconds.At 1uM CTOP (a kind of μ class antagonist of high selection type; K.Gulya, J.T.Pelton, V.J.Hruby and H.I.Yamamura, Life Sci.38:2221-2229, (1986)) and 15nM non--BNI (a kind of selectivity κ class antagonist; P.S.Portoghese, A.W.Lipkowski, and A.E.Takemori, Life Sci.40,1287 (1987)) by in organ bath, adding suitable concn under the condition that exists test compounds and before adding next time higher concentration, obtain peak response and measure δ receptoroid activity.The μ receptoroid is active to adopt similar mode to measure, but at 3M TIPP (a kind of δ class antagonist of high selection type; P.W.Schiller, T.M.-D.Nguyen, G.Weltrowska, B.C.Wilkes, B.J.Marsden, C.Lemieux, and N.N.Chung, Proc.Natl.Acad.Sci.89,11871 (1992)) and 15nM selectivity κ class antagonist non--condition that BNI exists under.
The kappa receptor activity is measured under the condition of 1uM high selectivity μ class antagonist CTOP and 3uM high selectivity δ class antagonist TIPP existence.
Under variation accumulative total concentration, measure the inhibition percentage ratio that the chemical compound electricity is induced muscle contraction.ED extrapolates from the curve of show dose concentration to response 50Value (J.A.H.Lord, A.A.Waterfield, J.Hughes, H.W.Kosterlitz, Nature 267,495, (1977)).The result lists in following table 1.
Table 1
Figure C20048000001200291
Embodiment 5
The external opioid receptor affinity of assessing compound 1 in rat meninges (μ and δ OPIOIDS) and in Cavia porcellus cerebellum (κ opioid receptor).Preparation is used for the bonded film of radioligand from whole brain of rat or Cavia porcellus cerebellum, and (Rogers AR.) provides by Pel-Freeze Biological Inc. for rat and Cavia porcellus.To be organized in homogenize in 50mM TRIS (three [methylol] aminomethane) buffer (pH 7.4), this buffer comprises 50 μ g/ml Semen sojae atricolor insulin inhibitors, 1mM EDTA (ethylenediaminetetraacetic acid) and 100 μ M PMSF (fluoridizing the phenyl methyl sulfonyl).With the cerebral tissue of homogenize under 500xg centrifugal 30 minutes (4 ℃) to remove big fragment.To supernatant polytronically sonicated 10 seconds (P.E. is provided with 2,4 ℃).Add sucrose solution to final concentration 0.35M with 10mM TRIS-sucrose buffer (pH 7.4), then with meninges 40, under the 000xg centrifugal 30 minutes (4 ℃).Wash the film bead twice with the 10mM TRIS buffer (pH 7.4) that comprises 50 μ g/ml Semen sojae atricolor insulin inhibitors, 1mM EDTA and 100 μ MPMSF.
Comprising 50 μ g/ml Semen sojae atricolor insulin inhibitors, 1mM EDTA, 5mM MgCl 2With carry out radioligand-binding assay in the 10mM TRIS buffer (pH 7.4) of 100 μ M PMSF.Part (2-3 * 10 tritium-labeled DAMGO (μ), Deltorphin II (δ) that employing is bought from New England Nuclear or U69593 (κ) test in contrast -10The M final concentration), the non-specific binding of control experiment is by 0.5 * 10 -6MM naloxone (buying) definition from SIGMAChemical Co..All binding analysis all at room temperature carried out 90 minutes, use semi-automatic cell harvestor (the model M48 of Brandel then, Brandel, Gaithersburg, MD) with (4 ℃ of 50mM TRIS buffer, pH 7.4) (OR) going up fast, filtration stops for Whatman, Hillsboro at the GF/C glass fiber filter.With 50mM TRIS buffer (4 ℃, pH 7.4) washing filter twice, filter is placed in the liquid scintillation radioactive substance (cocktail), with Beckman LS 6500 scintillation counters counting binding radioactivity.The chemical compound (1) of (3) suppresses DAMGO (μ), Deltorphin II (δ) or the bonded ability of U69593 (κ) of radiolabel to determine to have formula from complete concentration-effect curve.(GraphPad Software Inc., San Diego CA), adopt monobasic (one-site) nonlinear regression analysis of radioligand binding data to determine IC to the program that uses a computer Prism 50Value.Adopt Cheng-Prusoff equation (Cheng Y and Prusoff WH (1973), Relationshipbetween the inhibition constant (Ki) and the concentration of inhibitorwhich causes 50 percent inhibition (I then 50) of a enzymatic reaction; BiochemPharm., 22:3099-3108.) with IC 50Value converts K to iValue.
The result of radioligand-binding assay lists in following table 2.
Table 2
Figure C20048000001200311
The result: obviously, the chemical compound (1) with formula (3) has shown unique and different binding affinities to different types of receptor of being tested.In conjunction with the low-down concentration of needs the strong affinity of this chemical compound to the δ receptoroid has been described by suppressing labelled compound.
Embodiment 6
With analgesia in the folder tail test analysis rat.Adopt vein mode administered compound 1.Obtain the pain reaction value during 1-2 hour.Place a bulldog clamp at afterbody (from terminal 1 inch of tail) and continue a bit of time, up to escape reaction (promptly wagging the tail or sounding) takes place.With the response time of stopwatch record escape reaction.The deadline of adopting 20 seconds is to prevent unnecessary tissue injury.Observe the sounding of rat or the pain reaction of body kinematics.Cause that to write down second the pain reaction required time is as the folder end reaction time.
Dosage when in 20 seconds, bulldog clamp compressing not shown any pain and react bitterly by half animal determine analgesia ability in the pain relieving ability the ED50 value (half of maximum effective dose, ED50).As shown in table 3, chemical compound 1 does not show analgesic activity, and this shows that tested chemical compound not by blood brain barrier, is considered to a kind of non-analgesic chemical compound.And this chemical compound mainly acts on periphery δ opioid receptor.The more important thing is,, also do not observe the outbreak of any test animal, show that chemical compound (1) mainly is limited to periphery δ receptor even under the high dose of 50mg/kg.
Table 3
Figure C20048000001200321
Embodiment 7
Inaccessible Sprague-Dawley isolated rat heart left anterior descending branch (LAD) coronary artery precontract 15 minutes, with the concentration administered compound 1 of 1nM, 2nM and 10nM.By large artery trunks in the Langendorff mode with oxygenation Krebs-Henseleit buffer retroperfusion isolated heart.Bring out infraction by 35 minutes ischemia and 120 minutes and reperfusion subsequently.Make the 6-0 stitching thread pass through (LAD) main split coronarius to form lasso.
Cause ischemia by the lasso around the tension LAD.After 35 minutes Ischemia Time, unclamp lasso, with the physiological buffer of oxygenation perfused hearts 120 minutes again.Retighten LAD occluder is injected the saline that contains 0.125% routine train of thought indigo plant by large artery trunks, with visual non-ischemic area in heart when perfusion finishes again.With the heart tissue section, with the size of the physiological buffer dyeing estimation infraction after 15 minutes that contains 1.5% RT (TTC).After in 10% buffered formalin, fixing, section is installed between the wave carrier piece, obtains image with the scanner digitized.Handle image with Adobe Photoshop 5.0.Adopt Optimas 6.2 image analysis software, measure non-ischemic area, the zone of being at stake and infraction with the computerization planimetry.
Fig. 1 has shown a result of group like this, and the big or small histological stain of infraction is cut into slices in contrast after its 1nM chemical compound 1 emergency treatment of illustrating use by oneself and the isolated heart tissue of treatment animal.Discovery is with respect to the infraction of matched group, and pretreatment makes the infraction size reduce 71%.
Table 4 has shown the minimizing of the ischemic lesions that the percentage ratio (%IS/AAR) in the zone of being at stake that causes with chemical compound in this preparation 1 is represented.
Table 4
Concentration (nM chemical compound 1) ％IS/AAR
Contrast 12 10 55±1 18±5 9±2 20±6
Under collating condition, 35 minutes locality ischemias, 54.7 ± 1.2% the cell injury in zone that causes being at stake.2nM chemical compound 1 produces maximum protection, has prevented almost 90% the damage that occurs in the matched group.
Listed the hemodynamic parameter of measuring after locality ischemia 35 minutes and 120 minutes and reperfusion in the table 5.
Table 5
The amount of chemical compound 1 (nM) HRXDP % suppresses + dP/dt % suppresses -dP/dt % suppresses CF % suppresses
Contrast 61.8 54.2 54.8 59.7
0.1nM 32 26 19 43
1.0nM 17 7 10 13
10nM 32 21 18 38
HRXDP, heart rate x forms pressure; + dP/dt shrinks variable force (inotropy);-dP/dt, lustitropy; CF, coronary flow
Hemodynamic parameter is the result show, 61.8% inhibition is arranged in the HRXDP parameter when not carrying out pharmacology's pretreatment, has 50% inhibition at least in contraction and diastolic pressure, reduces with coronary flow.On the contrary, if animal is carried out pretreatment with The compounds of this invention 1, cardiac parameters is greatly improved.In general, the function of heart tissue is normally at least 75%, and some parameter reaches 90%.These results show that when using, chemical compound 1 can play cardioprotection before the ischemia accident.
Embodiment 8
Make test animal (rat) anesthesia by the peritoneal injection pentobarbital sodium.Along opisthotonos skin on the crura intermedium bone line, produce a midline incision.Provide ventilating air by rodent respiratory organ (Harvard rodent respiratory organ) with the air that is mixed with oxygen.Notice and see the same normal thoracic expansion on one's body sentient rat.Need accurate dissection, wear rib and cut to the side of about gladiolus and open the thoracic cavity by cutting along the breastbone left side with shears with the sternotomy.Need accurate dissection to conflux in the foremost of breastbone to avoid big bilateral vein.With 5-0 silk or monofilament stitching thread the thoracic cavity is shunk.With the taper pin 7-0 silk stitching thread is passed below the LAC of the most advanced and sophisticated 1-3mm of the normal localized left auricle of distance and carry out colligation.The 1-mm of PE-10 pipe partly is placed on the top of container, is that a knot is with inaccessible coronary artery on the top of pipe.After inaccessible 35 minutes, manage vertical knot by knife blade cut-out PE-10 and pour into again with label 11.At colligation LAD coronary artery preceding 15 minutes, with the dosage intravenous administration chemical compound 1 of 0.1mg/kg or 1.0mg/kg.By measuring the infraction size in 2 hours, 24 hours and 167 hours with azovan blue and TTC dyeing at ischemia with after pouring into again.
Chemical compound 1 is dissolved in 0.9% the saline, and is expelled in the test animal.Make the LAD coronary artery inaccessible again, the patent blue dyestuff is expelled in the venous duct heart is normally poured into zone dyeing.The excision heart is removed left ventricle, and is cut into the section of transverse section.This process can make normal region, non-ischemic area, the zone of being at stake and infraction size visual.With TTC as indicator with separately living tissue and non-living tissue (Klein, H.H., etc., VirchowsArch (1981) 393:287-297).To be organized in store overnight in 10% formalin.Next day, will block the percentage ratio (%) that size (IS) is calculated as the zone of being at stake with the Digital image technology described in the embodiment 7.
Discovery is with respect to matched group, and the infraction size is obviously less, as shown in table 6 in chemical compound 1 pretreated rat.
Table 6
Measure the time of infraction size Big or small the reducing of matched group infraction with respect to non-treatment
Promptly using 1mg/kg chemical compound 1 back measures 48％
Using the 1mg/kg chemical compound measured after 1156 hours 43％
Carry out pretreatment with chemical compound 1 and show,, promptly using back infraction size minimizing 48% with respect to matched group.After about 7 days, with respect to the matched group that does not have treatment, the infraction size still shows minimizing 43% in initial therapy.
Embodiment 9
With Inactin (sulfuration butabarbital sodium salt, 178mg/kg i.p.) or urethanes (1.2g/kg i.p.) anesthesia male rat.Flat then when reaching operation, carry out tracheotomy (pe-240 pipe), this animal is inserted the pe-50 pipe at jugular vein (being used for i.v. chemical compound and dye application) and carotid artery (being used to measure blood pressure), then animal is placed the respirator (Harvard that links to each other with source of oxygen, model 683), under 36-42bpm, practice artificial respiration.Carotid duct is connected to the PT300 pressure transducer by the threeway injector valve, is used to measure arteriotony and heart rate.After animal is stable, from carotid duct, extract a small amount of blood sample (150 microlitre) out, be used for blood gas analysis.
Carry out left thoracotomy at interval at the 5th intercostal, carry out pericardiotomy then and adjust left auricle to show the position of left coronary artery.Make binder (6-0 prolene) by the right half of left auricle bottom to left ventricle.The stitching thread end passes and flange at one end is housed to form the polyethylene tube of snare.By tension stitching thread and employing mosquito forceps snare is clipped in the inaccessible coronary artery of epicardial surface.Reduce by visceral pericardium cyanosis and blood pressure and to examine obturation coronarius.Kept inaccessible 30 minutes, and began to pour into again, confirm by showing the congested reaction of visceral pericardium by Xie Jiataoquan.The dabbling again time is 1.5-2 hour.At last between flush phase again, with the inaccessible once more coronary artery of lasso, by i.v. tube injection patent blue dyestuff (.4Ml 10%w/v saline).After dyestuff disperses by circulation, remove heart immediately.Remove atrium and right ventricle fast, remaining left ventricle is cut into 4-5 section.Separate the regional same deathtrap (AAR does not dye blueness) that will be defined as normal (dying blueness), and tissue put into fill 100mMKH 2PO 4With 0.187% chlorination 2,3, in the bottle of the independent 20mL of 5-triphenyltetrazolium (TTC), under 37 ℃, hatched 5 to 10 minutes.Then tissue is placed in the independent bottle that 10% buffering formalin is housed, it is fixing to spend the night.Be partitioned into infarct area from non-infarct area, measure normal with gravimetric method; AAR, non-infraction; And blocking tissue.
Inject chemical compound 1 with scope from the dosage of 0.01mg/kg to 1.0mg/kg by the i.v. conduit at inaccessible LAD preceding 5 minutes (pre-ischemia is used).
The result who is obtained by two independent experiments is provided in following table 7.
Table 7
Drug therapy (mg/kg chemical compound 1) Research 1 (%IS/AAR) Research 2 (%IS/AAR)
Contrast 0.01 0.03 0.1 0.3 1.0 54±10 56±5 44±10 35±11 40±8 54±3 40±3 39±3 38±3
Chemical compound 1 uses until the dosage of 1.0mg/kg has all produced the significant protection effect in two testing researches.Matched group has shown the ischemic injuries of the zone of being at stake (AAR)～50-55%.Be higher than 0.1 chemical compound of using 1 with dosage and in two researchs, prevented about 30 to 40% of this damage.
Embodiment 10
Adopt and identical experimental technique described in the embodiment 9, just administered compound 1 (promptly using immediately behind the initial ischemia injury and before pouring into again) immediately before the binder of unblocking LDA.In this model, chemical compound 1 is tested, shown the significant protection effect with 0.3mg/kg.
The contrast ischemia injury is regional～50% in the danger, as the matched group among the embodiment 9.Yet, when when infringement perfusion again administered compound 1 prevented from before ischemia injury, to form contrast described in damage that 30-40% is such and the embodiment 9.
**********
Although described the present invention according to concrete aspect of the present invention, feature and illustrative embodiments here, it will be understood that application of the present invention is not limited thereto, but can expand to and comprise a large amount of others, feature and embodiment.Therefore, the claims that after this propose are intended to can be in view of the above extensively be thought and are included in all these aspects, feature and embodiment in its spirit and scope.

Claims (10)

1. therapeutic combination for the treatment of ischemia injury, said composition comprises diaryl methyl piperazine chemical compound or its pharmaceutically acceptable ester or the salt of the following formula of effective dose:
Figure C2004800000120002C1
Wherein:
Z is selected from following groups:
Hydrogen;
Halogen;
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl;
C 1-C 6Haloalkyl;
C 1-C 6Alkoxyl;
C 3-C 6Cycloalkyloxy;
Has formula SR 8Sulfide, R wherein 8Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 3-C 6Cycloalkyl, has C 5-C 10Aryl moiety and C 1-C 6The aryl alkyl of moieties or C 5-C 10Aryl;
Has formula SOR 8Sulfoxide, R wherein 8Same as above;
Has formula SO 2R 8Sulfone, R wherein 8Same as above;
Nitrile;
C 1-C 6Acyl group;
Has formula NHCO 2R 8Alkoxycarbonyl amido, R wherein 8Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl;
Carboxylic acid or its ester, amide or salt;
Has formula CH 2NR 9R 10Aminomethyl, R wherein 9And R 10Identical or different, and be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 2-C 6Hydroxyalkyl, C 2-C 6Methoxy alkyl, C 3-C 6Cycloalkyl or C 5-C 10Aryl, perhaps R 9And R 10The common ring that forms 5 or 6 atoms, the atom on the ring is selected from N and C;
Has formula CONR 9R 10Carbamyl, R wherein 9And R 10Identical or different, and be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 2-C 6Hydroxyalkyl, C 2-C 6Methoxy alkyl, C 3-C 6Cycloalkyl or C 5-C 10Aryl; With
Has formula SO 2NR 9R 10Sulfonamide, R wherein 9And R 10Identical or different, and be selected from hydrogen, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 2-C 6Hydroxyalkyl, C 2-C 6Methoxy alkyl, C 3-C 6Cycloalkyl or C 5-C 10Aryl; With
X is selected from hydrogen, hydroxyl, halogen and alkoxyl.
2. the compositions of claim 1 is used for alleviating the application of the medicine of patient's ischemic lesions in preparation.
3. the compositions of claim 1, wherein diaryl methyl piperazine chemical compound is the following formula structure:
Or acceptable ester of its pharmacy or salt.
4. the non-pain relieving diaryl methyl piperazine chemical compound of following formula or the acceptable salt of its pharmacy or ester are used for alleviating the application of the medicine of patient's ischemic lesions in preparation:
5. the compositions of claim 1, wherein diaryl methyl piperazine chemical compound is the following formula structure:
Figure C2004800000120004C2
Or acceptable ester of its pharmacy or salt.
6. according to each compositions in the claim 1,3 and 5, wherein compositions also comprises pharmaceutically acceptable carrier.
7. according to the application of claim 4, wherein diaryl methyl piperazine chemical compound is used to the patient as preventive therapy, with the disease progression of the individuality that prevents to be in the ischemic heart disease symptoms stage.
8. according to the application of claim 4, wherein diaryl methyl piperazine chemical compound is to be selected from following acceptable form of medication: parenteral and parenteral external administration.
9. preservation solution that isolated organ is used, this solution comprises the chemical compound of following formula:
Or acceptable salt of its pharmacy or ester.
10. the solution of claim 9, wherein isolated organ is selected from heart, liver, kidney, cornea and/or lung.
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US5658908A (en) * 1992-02-03 1997-08-19 Delta Pharmaceuticals, Inc. Opioid diarylmethylpiperazines and piperdines
WO1999001438A1 (en) * 1997-07-02 1999-01-14 Astra Aktiebolag (Publ) New compounds
US6103722A (en) * 1997-07-23 2000-08-15 The Medical College Of Wisconsin Research Foundation Inc. Ischemic preconditioning

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Publication number Priority date Publication date Assignee Title
US5658908A (en) * 1992-02-03 1997-08-19 Delta Pharmaceuticals, Inc. Opioid diarylmethylpiperazines and piperdines
WO1999001438A1 (en) * 1997-07-02 1999-01-14 Astra Aktiebolag (Publ) New compounds
US6103722A (en) * 1997-07-23 2000-08-15 The Medical College Of Wisconsin Research Foundation Inc. Ischemic preconditioning

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