CN1061963A - Be used as the croak pyridine class of the 4-replacement of medicine - Google Patents
Be used as the croak pyridine class of the 4-replacement of medicineDownload PDFInfo
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- CN1061963A CN1061963ACN91105945ACN91105945ACN1061963ACN 1061963 ACN1061963 ACN 1061963ACN 91105945 ACN91105945 ACN 91105945ACN 91105945 ACN91105945 ACN 91105945ACN 1061963 ACN1061963 ACN 1061963A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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Abstract
Description
The present invention relates to the 4-substituted piperidine derivative, their preparation method contains their pharmaceutical composition and the effect in their treatment.
For this reason, the present invention at first provides structure (I) compound and salt thereof:
Wherein:
R is C1-8Alkyl (phenyl) P, C2-8Alkenyl (phenyl) P, C2-8Alkynyl (phenyl) P, C3-8Cycloalkyl or C1-8Alkyl C3-8Cycloalkyl;
P is 0 to 2;
N is 0 to 6;
A is a key, oxygen, sulphur or NR1;
R1Be hydrogen, C1-8Alkyl or phenyl C1-4Alkyl;
M is 0 to 3;
Ar is aryl or heteroaryl, and wherein each can at random be substituted.
Aptly, R is C1-8Alkyl (phenyl) P, C2-8Alkenyl (phenyl) P, C2-8Alkynyl (phenyl) P, C3-8Cycloalkyl or C1-8Alkyl C3-8Cycloalkyl.
Certainly, alkyl-cycloalkyl, alkyl phenyl, alkenyl phenyl and alkynyl phenyl group pass through alkyl respectively, alkenyl, and the alkynyl part links to each other with the piperidines nitrogen-atoms.
Preferred R is C1-8Alkyl (phenyl) P, wherein P is 0 or 1, i.e. C1-8Alkyl, as the n-amyl group, or phenyl C1-8Alkyl such as phenyl propyl, or R is C2-8Alkenyl (phenyl) P, wherein P is 1, as cinnamyl.
Aptly, n is 0 to 6, and preferred n is 0 to 3; Most preferably n is 2 or 3.
Aptly, m is 0 to 3, and preferred m is 0 or 1, and most preferably m is 0.
Aptly, A is a key, oxygen, sulphur or NR1; Preferred A is oxygen or sulphur; Most preferably A is an oxygen.When A was oxygen, preferred n was 2 and m preferably 0.
Aptly, Ar is aryl or the heteroaryl that replaces arbitrarily; Preferred Ar is the aryl that replaces arbitrarily.
Suitable aryl comprises for example unsaturated monocycle of 10 carbon atoms of as many as and the bicyclic system of unsaturated or fractional saturation, phenyl for example, and naphthyl and tetrahydrochysene close naphthyl.The preferred benzyl ring that replaces arbitrarily.
Suitable substituted benzene basic ring comprises by C1-2Alkylenedioxy group is as 3, the benzyl ring that 4-methylene radical dioxy base is replaced, or by 1 to 3 benzyl ring that substituting group replaced that is selected from following radicals: halogen, C1-4Alkoxyl group, nitro, SC1-4Alkyl, NR2R2(each R wherein2Base can be H or C1-4Alkyl), OCF3, C1-6Alkyl, trifluoromethyl, CN, the phenyl that replaces, the phenyl C that replaces arbitrarily arbitrarily1-4Alkyl and the phenyl C that replaces arbitrarily1-4Alkoxyl group.Preferred benzyl ring is replaced by one or two substituting group, coverlet halogen especially, trifluoromethyl, unsubstituted phenyl or unsubstituted phenyl C1-4Alkoxyl group replaces, or is replaced by two chlorine atoms, especially on 3 and 4 of ring.
Suitable any substituted-phenyl C1-4Alkyl comprises for example benzyl.Suitable any substituted-phenyl C1-4Alkoxyl group comprises for example benzyloxy.
Above-mentioned any substituted-phenyl, phenyl C1-4Alkyl and phenyl C1-4The suitable substituting group of alkoxyl group comprises for example halogen, C1-4Alkyl, C1-4Alkoxyl group, nitro and trifluoromethyl.
Suitable hetero-aromatic ring comprises and for example contains at least one heteroatoms, the unsaturated monocycle of 10 carbon atoms of as many as and unsaturated or fractional saturation bicyclic system, for example pyridyl, thienyl, quinolyl, tetrahydric quinoline group and imidazoles basic ring.Hetero-aromatic ring by carbon atom or by heteroatoms for example nitrogen-atoms link on the residue position of structure (I).
The suitable substituting group of above-mentioned hetero-aromatic ring comprises and for example is selected from halogen, C1-4Alkyl and C1-41 to 3 substituting group of alkoxyl group.
Be present in the alkyl in the structure formula I compound, separately or as the part of another group, but straight or branched.
The salt that should be noted that compound (I) should be medicinal acceptable during as medicine.The example of medicinal acceptable salt comprises inorganic and organic acid addition salt adds hydrochloride, hydrobromide, vitriol, phosphoric acid salt, acetate, fumarate, maleate, Citrate trianion, lactic acid salt, tartrate, oxalate, or similarly medicinally accept inorganic or organic acid addition salt.Other non-medicinal acceptable salt for example can be used as intermediate, and are included in the scope of the present invention.
Special case compound of the present invention comprises:
The 4-[2-(4-4-trifluoromethylphenopendant) ethyl]-1-amyl piperidine oxalate,
The 4-[2-(3-4-trifluoromethylphenopendant) ethyl]-1-amyl piperidine hydrochloride,
The 4-[2-(4-fluorophenoxy) ethyl]-1-amyl piperidine hydrochloride,
4-[2-(3,4-methylenedioxyphenyl oxygen base) ethyl]-1-amyl piperidine hydrochloride,
4-(2-phenoxy group ethyl)-1-amyl piperidine hydrochloride,
4-[2-(4-phenyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride,
4-[2-(4-benzyloxy phenoxy group) ethyl]-1-amyl piperidine hydrochloride,
The 4-[2-(4-fluorophenoxy) ethyl]-1-cinnamyl piperidine oxalate salt,
4-(4-fluorine benzyloxy)-1-amyl piperidine oxalate,
4-[2-(3, the 4-dichlorophenoxy) ethyl]-1-amyl piperidine hydrochloride,
4-[2-(4-benzyl phenyl oxygen base) ethyl]-1-amyl piperidine oxalate,
4-[2-(3, the 4-dichlorophenoxy) ethyl]-1-cinnamyl piperidine oxalate salt,
The 4-[2-(4-fluorophenoxy) ethyl]-the 1-(3-phenyl propyl) the piperidines hydrochloride,
The 4-[2-(4-fluorophenoxy) ethyl]-1-heptyl piperidines hydrochloride,
1-(3, the 3-diphenyl propyl)-the 4-[2-(4-fluorophenoxy) ethyl] piperidine oxalate salt,
4-[2-(3,4-dichloro sulfo-phenoxy group) ethyl]-1-amyl piperidine hydrochloride,
4-[2-(4-tertiary butyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride,
4-[2-(4-sec.-propyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride,
4-[2-(3,4-two fluorophenoxies) ethyl]-the 1-(3-phenyl propyl) the piperidines hydrochloride,
1-cyclopropyl methyl-4-[2-(4-fluorophenoxy) ethyl] piperidine oxalate salt.
Should be noted that structure formula I compound can be from containing one or more asymmetric centers.Such compound exists with optical isomer (enantiomorph) form.
Pure enantiomorph, racemic mixture (each enantiomorph accounts for 50% respectively) and both mixtures that do not wait include within the scope of the present invention.Moreover all possible diastereomeric form (pure enantiomorph and its mixture) includes within the scope of the present invention.
The compounds of this invention can prepare with the currently known methods that is similar to the present technique field.Thereby, having the present invention further provides the method for preparing structure formula I compound, it comprises:
(a) be O to A in the formula, S or NR1Structure formula I compound, make the compound of structure formula II:
Wherein R and n be as described in the structure formula I, A1Be O, S or NR1, with formula L(CH2)mAr compound reaction, wherein m and Ar be as described in the structure formula I, and L is a leavings group;
(b) be O to A in the formula, S or NR1Structure formula I compound, make structure formula III compound:
Wherein n and R be as described in the structure formula I, L1Be the nucleophilic reagent displaceable group, with structural formula HA1(CH2)mAr compound reaction, wherein m and Ar be as described in the structure formula I, and A1As described in the structure formula II; Or
(c) be NR to A in the formula1Structure formula I compound, make the compound reduction of structure formula IV:
（Ⅳ）
N, m, R and Ar are as described in the structure formula I;
(d) be the structure formula I compound of key to A in the formula, make structural formula (V) compound:
(R wherein, L1, n and m as above define) and structural formula X1Ar compound reaction, wherein Ar is as described in the structure formula I, X1Be basic metal;
(e) the R group is introduced the formula VI compound:
Use and RL2The method of compound reaction, wherein L2It is leavings group;
(f) reduction-type (VII) compound:
R wherein5Be C1-7Alkyl (phenyl) P, C2-7Alkenyl (phenyl) P, C2-7Alkynyl (phenyl) P or1-7Alkyl C3-8Cycloalkyl;
(g) reduction structural formula (VIII) compound:
R wherein, A, Ar, m and n define as mentioned, X
Be counter ion;
And arbitrary shape salify after this.
In method (a), structure formula II compound and compound L (CH2)mThe condition of reacting between the Ar depends on the character of group L.For example, when L is halogen or sulfonic acid (as toluenesulphonic acids or methylsulfonic acid) residue, react under the standard conditions in solvent, at random in the presence of alkali, carry out.When fluorinated aryl F-Ar is used for method (a), be reflected at highly basic such as sodium hydride and exist down, in inert organic solvents such as dimethyl formamide, finish.Preferred aryl groups is by active group such as CF3Or NO2Replace.
Structure formula III compound and structural formula HA1(CH2)mThe condition of reacting between the Ar compound depends on L1Character with A.For example, work as L1Be hydroxyl, m is O and A1When being oxygen or sulphur, being reflected under the existence of diethylazodicarboxylate and triphenylphosphine and carrying out.Such reaction is known as Mitsunobu reaction (as Synthesis1981,1, described in).On the other hand, leavings group L1Can for example be halogen atom or sulfonyloxy, for example mesyloxy or P-tosyloxy.In this case, reaction can be finished under 0 to 200 ℃ of temperature range in the solvent existence or not.
The available methods known in the art of reduction of structure formula IV compound are finished, and for example use reductive agent such as lithium aluminum hydride.Structure formula IV compound can prepare (for example as described below) and reduction in " still " reaction easily, does not need separating compound (IV) itself.
Structural formula (V) compound and structural formula X1Carry out under the standard conditions that are reflected at formation C-C well known in the art between the Ar compound.
According to method (e), structure formula VI compound and RL2Between the available general method of reaction, as in organic solvent such as dimethyl formamide, carrying out.Leavings group L2Can be halogenide for example, as bromide or muriate, acyloxy be as acetoxyl group or chloroethene acyloxy or sulfonyloxy, as mesyloxy or P-tosyloxy.Work as L2When being halogenide, reaction is preferably carried out in the presence of weak base such as salt of wormwood, works as L2When being sulfonyloxy, can use highly basic such as sodium hydride or t-butanols potassium.
The reduction available standards reductive agent such as the lithium aluminum hydride of formula (VII) compound are finished.
Formula (VIII) compound for example can reduce by hydrogenation, uses noble metal catalyst, and as platinum, palladium or platinum oxide, reaction suits for example pure at solvent, as carrying out in the ethanol.
Structure formula II compound can be that the respective compound of hydrogen prepares by R in the alkanisation formula under standard conditions.For example R is that the structure formula II compound of n-amyl group can R be the corresponding precursor preparation of hydrogen from formula in the formula, and its method is in appropriate solvent, as methyl ethyl ketone, or C1-4Alkanol, in ethanol, at alkali, as salt of wormwood, or the dimethyl formamide existence down, makes precursor and n-amyl halide in the presence of alkane iodide, as the n-amyl bromide, reacts.
R is that the compound of corresponding construction formula II of hydrogen is known in the literature in the formula, can obtain by commodity, perhaps with the standard technology preparation, for example reduces corresponding 4-hydroxyalkyl piperidines.
On the other hand, A in the formula1The structure formula II compound that is oxygen can prepare by reduction structural formula (IX) compound:
R and n be as described in the structure formula I in the formula, X
Be counter ion.
L in the formula1The structure formula III compound that is OH can be by as preparing L in the formula as described in structure formula II compound1Be halogen atom, the structure formula III compound of mesyloxy or tosyloxy can prepare from corresponding alcohol with general method.
R in the formula4Be
Structure formula IV compound can be by making A in the formula1Represent NR1Structure formula II compound with corresponding to-(CH2)mThe acylating agent of Ar base, for example chloride of acid ClOC(CH2)M-1Ar, reaction prepares.
R in the formula4Be
The structure formula IV compound of base for example can be by making R in the formula4Representative-(CH2)N-1CO2The respective compound of H or its activated derivatives such as acyl halide, ester or acid anhydride and formula HN(R1) (CH2)mThe amine of Ar reacts and prepares.Should be noted that when using acid itself, should in the presence of coupler, finish with the reaction of amine.Carboxylic acid itself can be for example pure accordingly by oxidation, i.e. A in the formula1Be the structure formula II compound of oxygen, prepare.
Structural formula (V) compound can be used the method preparation of the compound of similar structures formula III, when using the prior art known method, increases necessary chain length possibly.
The intermediate of similar structures formula II to (IV) used in the preparation of the either party's method in (a) to (d) for example according to the method described above of structure formula VI compound, and wherein R is replaced by the N-protected base, then is removed with the prior art known method.Suitable protecting group comprises aralkyl, and as benzyl, diphenyl-methyl or trityl, acyl group is as ethanoyl, trifluoroacetyl group, benzoyl, methoxycarbonyl, ethoxycarbonyl or carbobenzoxy-(Cbz).But aralkyl such as benzyl hydrogenolysis disconnect, and acyl group such as benzoyl hydrolyzable disconnect.Should be noted that when the N-protected base was aralkyl, compound had the structure formula I, this reaction sequence thereby the method that a kind of formula I compound is converted into different formula I compounds is provided.
Formula (VII) compound can be by making formula VI compound and a kind of suitable acid derivative, for example chloride of acid or acid anhydride, and reaction prepares.
Use the general method described in the aforesaid method (a) to (e) can prepare structural formula (VIII) compound.In addition, in the formula A represent key structural formula (VIII) compound can by in the presence of highly basic such as sodium amide in liquefied ammonia or lithium alkylide with formula in L and Ar defines as mentioned and q is the formula L(CH of (m+n-1)2)qThe reaction of Ar compound prepares from 4-picoline (picoline).Then, make gained substituted pyridines and compound R L2(definition as mentioned) reaction obtains formula (VIII) season pyridine compounds.Reduce this compound according to method (g), provide A in a kind of easy preparation formula to represent the method for the structure formula I compound of key.
Have found that The compounds of this invention demonstrates high calcium and injects blocking activity, and be desirably in treatment and relate to calcium Mammals, special people, brain cell in therepic use is arranged in the caused symptom of accumulation and the disease.For example, expect that these compounds are used for the treatment of anoxia, local asphyxia, comprise for example apoplexy, migraine, epilepsy, traumatic brain damage are with the sick now relevant dementia of love, neurodegenerative disease such as senile dementia (Alzheimer) and the dysmnesia relevant with the age, and be used for the dopy de-addiction, as the de-addiction of ethanol addiction.
Further purpose of the present invention thereby provide the symptom or the treatment of diseases method of being drawn or being increased the weight of by the accumulation institute of the calcium in the Mammals brain cell, it comprises to the patient and imposes its required significant quantity structure formula I compound or its medicinal acceptable salt.In addition, the present invention also provides a kind of method for the treatment of following disease: anoxia, and local asphyxia comprises for example apoplexy, migraine, epilepsy, the traumatic brain damage is with the sick now relevant dementia of love, neurodegenerative disease such as senile dementia and the dysmnesia relevant with the age, and the dopy de-addiction is provided, as the method for ethanol addiction de-addiction, this method comprises to the patient and imposes its required significant quantity structure formula I compound or its medicinal acceptable salt.The present invention also provides with structure formula I compound or its medicinal acceptable salt and has removed to prepare the medicine that is used for the treatment of above mentioned symptom or disease.
Be treatment usefulness, The compounds of this invention is usually with the administration of standard drug composition mode.Thereby further aim of the present invention provides and contains structure formula I compound or its medicinal acceptable salt and the medicinal pharmaceutical composition of accepting carrier or vehicle.
When oral administration, the medicinal acceptable salt with active structures formula I compound and they can be prepared and become liquid, syrup for example, suspension or emulsion, tablet, capsule and lozenge.
Liquid agent shape will comprise The compounds of this invention or suspension or the solution of medicinal acceptable salt in suitable liquid vehicle that contains suspension agent, preservatives, spices or tinting material or water usually, liquid vehicle for example comprises ethanol, glycerine, non-aqueous solvent (for example polyoxyethylene glycol, oil).
The pharmaceutical carrier that sheet-like composition can use any suitable usually being used to prepare solid formulation shape prepares.The example of carrier comprises Magnesium Stearate like this, starch, lactose, sucrose and Mierocrystalline cellulose.
Use usual sealing technology can make capsule shape state combination thing.For example, use the carrier of standard can prepare the bead that contains active ingredient, in the glutoid capsule of packing into then; On the other hand, use any suitable pharmaceutical carrier, as water-soluble natural gum, Mierocrystalline cellulose, silicate or oil can prepare dispersion or suspensoid, in the soft ' Yanming ' capsules for clearing of then this dispersion or suspensoid being packed into.
The compounds of this invention also can use the method administered parenterally that concentrates injection or inject continuously.Typical parenteral composition comprises compound or medicinal acceptable salt at aseptic aqueous carrier or the acceptable oil of parenteral, polyoxyethylene glycol for example, Polyvinylpyrolidone (PVP), Yelkin TTS, solution in peanut oil or the sesame oil or suspension.On the other hand, this solution freeze-drying can be prepared with appropriate solvent before administration then again.
Preferred this composition is for example sheet or a capsule of unit dosage form.
The every dose unit of oral administration preferably contains 1 to 250mg(and preferably contains 0.1 to 60mg for administered parenterally) press formula I compound or its medicinal acceptable salt that free alkali calculates.
Adult patients per daily dose scope can be for example between the oral dosage 1mg to 500mg, preferred 1mg to 250mg, for example 5 to 200mg, or intravenously, subcutaneous, or between the intramuscular dosage 0.1mg to 100mg, preferred 0.1mg to 60mg for example 1 to 40mg presses formula I compound or its medicinal acceptable salt that free alkali calculates, and uses this compound every day 1 to 4 time.On the other hand, The compounds of this invention can be by the mode administration of continuous intravenously injection, reaches 100mg dosage preferred every day.In The compounds of this invention was suitable for during treating continuously, for example one is all or more, administration.
Ca2+The mensuration of stream
The preparation of cell
Made from 1 day mouse separate the responsive neurocyte of dorsal root ganglion (Forda etc., Developmental Brain Research, 22(1985), 55-65).Be applied to cell on the cover slip and use in 3 days, allow Ca2+Stream virtual voltage folder.
Solution
Suction pipe (interior solution) contains the CsCl in mM, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2, be buffered to PH7.2 with CsOH.
As the soak solution separable Ca that becomes2+During stream, before all cellular replication is set up, cell is immersed in the standard Tyrode solution.
Record Ca2+The outer solution of passage stream contains the BaCl in mM2, 10; TEA-Cl, 130; Glucose, 10; HEPES, 10; MgCl2, 1, be buffered to PH7.3 with TEA-OH.With barium as charged particle carrier because this help flow point from and can avoid the inactivation that depends on calcium that flows.
Compound is dissolved among the DMSO, makes the liquid storage of 20mM.When the working concentration of medicine, not remarkably influenced of carrier (0.1%) Ca2+Stream.
Total Test is finished under 21 to 24 ℃.Use List EPC-7 enlarger to write down whole stream of cells and store, digitizing is used based on the PC base software of similar above-mentioned scheme and below it is analyzed (Benham ﹠amp; Tsien, Journal of physiology(1988), 404,767-784).
The result
Ca2+Stream
Use 10mMBa2+Make charged particle carrier, the Ca that reaches 10nA of record dorsal root ganglion neurocyte2+The peak pressure of passage current control.In per 15 seconds, make the fixed voltage-80mv of stream move to trial voltage 0 or 10mv.This pressure testing voltage is on the current-voltage characteristics peak, in this some assessment blocking-up, deducts any error due to the fixedly piezoelectricity drift.Some cells show stream to be weakened, as at Ca2+That sees usually during stream is the same.Under collating condition, measure and weaken speed, in dispenser, infer to obtain and the relevant control value of the affected stream of medicament.The barrier effect of 3 minutes assessment 20 μ M medicines after the dispenser.
The compounds of this invention is to Ca2+Levelling platform inhibiting rate is 30% to 100%.
Toxicology
When to rat during with the 10mg/kg intravenous administration, embodiment 9 compounds do not show any deleterious toxicology influence.
Embodiment
Intermediate preparation
(ⅰ) 4-(2-hydroxyethyl)-the 1-amyl piperidine
With the 4-(2-hydroxyethyl) piperidines (20g), 1-bromo pentane silane (19.2g), the mixture of salt of wormwood (21.42g) and ethanol (400ml) is in the heating down 3 days that refluxes.Filter this solution and following to desolvating in decompression.Use the acetone treatment resistates, filter, remove and desolvate, obtain oily title compound (30.2g), just need not be further purified and to use.
(ⅱ) 4-(2-hydroxyethyl)-1-cinnamyl piperidines
With the 4-(2-hydroxyethyl) piperidines (16.4g), cinnamyl bromine (25.0g), the mixture of salt of wormwood (17.55g) and ethanol (350ml) is in the heating down 3 days that refluxes.Filter this solution and removal of solvent under reduced pressure.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, use the ethanol/methylene wash-out, obtain pure solid title compound (12.0g), just need not be further purified and to use.
(ⅲ) bromination 4-(3-hydroxypropyl)-the 1-pentyl pyridine
With the 4-(3-hydroxypropyl) pyridine (27.43g), the solution of 1-bromo pentane silane (37.76g) and acetone (50ml) refluxed 24 hours, in its cooling and impouring ether (200ml).The oil that the decant collecting precipitation goes out, (5 * 100ml) carry out decantate, dry down in 50 ℃ of 0.1mmHg, obtain title compound, just need not be further purified and can use to use ether then.
(ⅳ) 4-(3-hydroxypropyl)-the 1-amyl piperidine
With bromination 4-(3-hydroxypropyl)-1-pentyl pyridine (8.65g), the mixture of platinum oxide (0.5g) and ethanol (120ml) stirred under nitrogen atmosphere 3 hours.Filter this mixture also except that desolvating.Resistates is dissolved in the diluted sodium hydroxide solution (70ml) also with methylene dichloride (3 * 75ml) extractions.Combining extraction liquid, dry on sal epsom, remove and desolvate, obtain oily title compound (4.68g).
(ⅴ) bromination 4-methylol-1-pentyl pyridine
With 4-4-hydroxymethylpiperidine (25g), the solution of 1-bromo pentane silane (43.2g) and acetone (50ml) refluxed 24 hours, in cooling and the impouring ether (200ml).The oil that the decant collecting precipitation goes out, (5 * 100ml) carry out decantate, dry down in 50 ℃ of 0.1mmHg, obtain title compound, just need not be further purified and can use to use pentane then.
(ⅵ) 4-methylol-1-amyl piperidine
With bromination 4-(3-hydroxypropyl)-1-pentyl pyridine (5.2g), the mixture of platinum oxide (0.4g) and ethanol (100ml) stirred under nitrogen atmosphere 3 hours.Filter this mixture also except that desolvating.Resistates is dissolved in the sodium hydroxide solution (70ml) of dilution and with methylene dichloride (3 * 75ml) extractions.Combining extraction liquid, dry also removing desolvated on sal epsom.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column,, obtain oily title compound (1.35g) with methyl alcohol/ammonia/methylene dichloride wash-out.
(ⅶ) 4-hydroxyl-1-amyl piperidine
With 4-hydroxy piperidine (25g), 1-bromo pentane silane (37.33g), the mixture reflux of salt of wormwood (34.13g) and ethanol (400ml) 3 days.Filter this solution and removal of solvent under reduced pressure.Use the acetone treatment resistates, filter, remove the also oil of underpressure distillation gained that desolvates, obtain oily title compound (18.00g, b.p.100 ℃).
(ⅷ) 4-(2-hydroxyethyl)-1-propyl group piperidines
With the 4-(2-hydroxyethyl) piperidines (5g), 1-N-PROPYLE BROMIDE (4.87g), the mixture reflux of salt of wormwood (5.5g) and ethanol (100ml) 1 day.Filter this solution, removal of solvent under reduced pressure.Use the acetone treatment resistates, filter, remove and desolvate, obtain oily title compound (5.1g), just need not be further purified and to use.
(ⅸ) 4-(2-hydroxyethyl)-and the 1-(3-phenyl) the propyl group piperidines
With the 4-(2-hydroxyethyl) piperidines (10g), 1-bromo-3-(phenyl) propane (15.8g), the mixture reflux of salt of wormwood (10.69g) and ethanol (200ml) 24 hours.Filter this solution, removal of solvent under reduced pressure.Use the acetone treatment resistates, filter, remove and desolvate and distillation residue, obtain oily title compound (14.52g) (b.p.141 ℃).
(ⅹ) 4-(2-hydroxyethyl)-1-heptyl piperidines
With the 4-(2-hydroxyethyl) piperidines (20g), 1-heptyl bromide (27.73g), the mixture reflux of salt of wormwood (21.39g) and ethanol (400ml) 24 hours.Filtering solution, removal of solvent under reduced pressure.Use the acetone treatment resistates, filter, remove and desolvate and distillation residue, obtain oily title compound (10.01g) (b.p.110 ℃).
(ⅹ ⅰ) 4-(2-hydroxyethyl)-and the 1-(2-ethyl) butyl piperidine
With the 4-(2-hydroxyethyl) piperidines (20g), the mixture heating up of 1-bromo-2-ethyl butane (17.9g) salt of wormwood (26g) and ethanol (400ml) refluxed 4 days.Filtering solution, removal of solvent under reduced pressure.Distillation residue obtain oily title compound (29.61g) (b.p.102 ℃ @0.3mmHg).
(ⅹ ⅱ) 1-cyclohexyl methyl-4-(2-hydroxyethyl) piperidines
With 4-(2-hydroxyl hexyl) piperidines (20g), cyclohexyl methyl bromine (27.41g), the mixture heating up of salt of wormwood (26g) and ethanol (400ml) refluxed 4 days.Filtering solution, removal of solvent under reduced pressure.Distillation residue obtain oily title compound (27g) (b.p.165 ℃ @0.5mmHg).
(ⅹ ⅲ) 4-(2-hydroxyethyl)-and the 1-(3-methyl butyl) piperidines
With the 4-(2-hydroxyethyl) piperidines (20g), 1-bromo-3-methylbutane (25.57g), salt of wormwood (26g) and ethanol (400ml) reflux 4 days.Filtering solution, removal of solvent under reduced pressure.Distillation residue obtain oily title compound (23.21g) (b.p.98 ℃ @0.1mmHg).
(ⅹ ⅳ) 1-benzyl-4-(2-hydroxyethyl) piperidines
With the 4-(2-hydroxyethyl) piperidines (5g), bromotoluene (6.15g), salt of wormwood, (5.35g) and the mixture heating up of ethanol (50ml) refluxed 24 hours.With in this mixture impouring water (200ml) and use extracted with diethyl ether.Dry organic phase on sodium sulfate is filtered removal of solvent under reduced pressure.Distillation residue obtain oily title compound (5.13g) (b.p.120-130 ℃ @0.1mmHg).
(ⅹ ⅴ) 4-[2-(4-fluorophenyl) ethyl] pyridine
4-picoline (30g) was joined in the suspension of sodium amide (12.56g) in liquefied ammonia (150ml) in 30 minutes, the gained mixture was stirred 1.5 hours.Then 4-fluorobenzyl chloride (40ml) was added in 15 minutes, this mixture was stirred 3 hours.Add ammonium chloride (50g), and evaporating solvent.Resistates is dissolved in chloroform (300ml) and the dilute sodium hydroxide (300ml), separates organic phase, dry also removing desolvated on sal epsom.With resistates recrystallization from sherwood oil, obtain white needles title compound (25.3g), m.p.69-70.5 ℃.
(ⅹ ⅵ) bromination 4-[2-(4-fluorophenyl) ethyl]-the 1-pentyl pyridine
With the 4-[2-(4-fluorophenyl) ethyl] pyridine (5g), the mixture reflux of 1-bromo pentane silane (7.0g) and acetone (10ml) 18 hours.Removal of solvent under reduced pressure and with resistates recrystallization from ethyl acetate/methanol obtains title compound (7.32g), m.p.130-131 ℃.
(ⅹ ⅶ) 4-[2-(4-fluorophenoxy) ethyl] the piperidines hydrochloride
With 1-benzyl-4-[2-(4-fluorophenoxy) ethyl] piperidines (1.50g), the mixture of 10% palladium/carbon (0.6g) and ethanol (120ml) vibrates 24 hours down in nitrogen atmosphere (50p.s.i).Filter this mixture and use the washing with alcohol resistates.Merging filtrate removes and desolvates, and is used in the hydrogenchloride processing resistates in the ether, obtains solid.Recrystallization from ethyl acetate obtains title compound (0.45g), m.p.122-123 ℃.C13H18FNOHCl's:
Measured value: C, 59.58; H, 7.37; N, 5.35; Cl, 13.33%
Calculated value: C, 60.11; H, 7.37; N, 5.39; Cl, 13.65%
Embodiment 1
The 4-[2-4 fluorophenoxy) ethyl]-1-amyl piperidine hydrochloride
With the 4-(2-hydroxyethyl)-1-amyl piperidine (2.0g), the nitrine diethyl dicarboxylate 1.74g that tetrahydrofuran (THF) (40ml) solution of 4-fluorophenol (1.12g) and triphenylphosphine (2.62g) is used in the tetrahydrofuran (THF) (10ml) handles.With gained solution stirring 18 hours, remove and desolvate under the room temperature, resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, use the ethanol/methylene wash-out.Be dissolved in the ethyl acetate (50ml) oil of gained and the processing of usefulness ether hydrogenchloride, filter collecting precipitation and recrystallization (methanol/ethyl acetate), obtain title compound (1.1g), m.p.167-169 ℃.
C18H28FNOHCl's:
Measured value: C, 65.45; H, 8.90; N, 4.16; Cl, 10.75; F, 5.76%
Calculated value: C, 65.54; H, 8.86; N, 4.25; Cl, 10.75; F, 5.77%
Embodiment 2
4-[2-(3,4-methylenedioxyphenyl oxygen base) ethyl]-1-amyl piperidine hydrochloride
With the 4-(2-hydroxyethyl)-1-amyl piperidine (2.0g), the nitrine diethyl dicarboxylate (1.74g) that tetrahydrofuran (THF) (40ml) solution of sesamol (1.39g) and triphenylphosphine (2.62g) is used in the tetrahydrofuran (THF) (10ml) handles.With gained solution stirring 18 hours, remove and desolvate under the room temperature, resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, use the ethanol/methylene wash-out.The oil of gained is dissolved in the ethyl acetate (50ml) also with the processing of ether hydrogenchloride.Filter collecting precipitation and recrystallization (methanol/ethyl acetate), obtain title compound (0.45g), m.p.134-136 ℃.
C19H29NO3HCl's
Measured value: C, 64.12; H8.52; N4.03; Cl, 10.00%
Calculated value: C, 64.12; H8.50; N3.93; Cl, 9.96%
Embodiment 3
4-(2-benzene oxygen ethyl)-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (2.0g), phenol (0.94g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.74g) preparation title compound.Handle this compound with hydrogenchloride, recrystallization from methanol/ethyl acetate (0.88g) obtains white solid, m.p.158-159 ℃.
C18H29NOHCl's
Measured value: C, 69.10; H, 9.80; N, 4.61; Cl, 11.34%
Calculated value: C, 69.32; H, 9.69; N, 4.49; Cl, 11.37%
Embodiment 4
The 4-[2-(3-4-trifluoromethylphenopendant) ethyl]-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (2.0g), α, α, α-three fluoro-m-cresols (1.62g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.74g) preparation title compound.Handle this product with hydrogenchloride, recrystallization from methanol/ethyl acetate obtains white solid (0.44g), m.p.154 ℃.
C19H28F3NOHCl's:
Measured value: C, 59.51; H, 7.62; N, 3.80; Cl, 9.49%
Calculated value: C, 60.07; H, 7.69; N, 3.69; Cl, 9.33%
Embodiment 5
4-[2-(4-phenyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (2.0g), 4-phenylphenol (1.70g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.74g) preparation title compound.Handle this product with hydrogenchloride, recrystallization from methanol/ethyl acetate obtains white solid (0.4g), m.p.205-206 ℃.
C24H33NOHCl's:
Measured value: C, 73.77; H, 8.88; N, 3.66; Cl, 9.14%
Calculated value: C, 74.2; H, 8.8; N, 3.6; Cl, 9.27%
Embodiment 6
4-[2-(4-benzyloxy phenoxy group) ethyl]-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (1.0g), 4-benzyloxy phenol (1.00g), triphenylphosphine (1.31g) and nitrine diethyl dicarboxylate (0.87g) preparation title compound.Handle this product with hydrogenchloride, recrystallization from methanol/ethyl acetate obtains white solid (0.1g), m.p.168-169 ℃.
C25H35NO2HCl0.5H2O's:
Measured value: C, 70.42; H, 8.59; N, 3.50; Cl, 8.29%
Calculated value: C, 70.31; H, 8.73; N, 3.28; Cl, 8.20%
Embodiment 7
4-[2-(3-dimethylamino phenoxy group) ethyl]-1-amyl piperidine dioxalic acid salt
Method with similar embodiment 1 prepares title compound, m.p.128-130 ℃.
C20H34N2O2C2H2O4:
Measured value: C, 57.82; H, 7.63; N, 5.62%
Calculated value: C, 57.83; H, 7.63; N, 5.62%
Embodiment 8
4-[2-(4-methoxyl group phenoxy group) ethyl]-1-amyl piperidine oxalate
Method with similar embodiment 1 prepares title compound, m.p.119-121 ℃.
C19H31NO2C2H2O4:
Measured value: C, 63.54; H, 8.47; N, 3.69%
Calculated value: C, 63.79; H, 8.35; N, 3.54%
Embodiment 9
4-[2-(3, the 4-dichlorophenoxy) ethyl]-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (2.0g), 3 4-chlorophenesic acid (1.63g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.76g) preparation title compound.Handle this product with hydrogenchloride, from methanol/ethyl acetate, obtain white prism title compound (1.02g), m.p.177-178 ℃.
C18H27Cl2NOHCl's:
Measured value: C, 57.05; N, 7.43; N, 3.85; Cl, 27.93%
Calculated value: C, 56.78; H, 7.41; N, 3.68; Cl, 27.93%
Method with similar embodiment 1 makes following compounds:
Embodiment 10
The 4-[2-(4-cyano-benzene oxygen) ethyl]-1-amyl piperidine hydrochloride
m.p.173-174℃
C19H28N2OHCl's:
Measured value: C, 67.69; H, 8.84; N, 8.28; Cl, 10.85%
Calculated value: C, 67.74; H, 8.68; N, 8.31; Cl, 10.52%
Embodiment 11
The 4-[2-(4-chlorophenoxy) ethyl]-1-amyl piperidine hydrochloride
m.p.185-186℃
C18H28ClNOHCl's:
Measured value: C, 62.14; H, 8.48; N, 4.44; Cl, 20.63%
Calculated value: C, 62.42; H, 8.44; N, 4.04; Cl, 20.47%
Embodiment 12
4-[2-(5,6,7,8-tetrahydrochysene-2-naphthyloxy) ethyl]-1-amyl piperidine oxalate
m.p.147℃
C22H35NOC2H2O4:
Measured value: C, 68.88; H, 9.07; N, 3.40%
Calculated value: C, 68.71; H, 8.89; N, 3.34%
Embodiment 13
4-[2-(5,6,7,8-tetrahydrochysene-1-naphthyloxy) ethyl]-1-amyl piperidine oxalate
m.p.162℃
C22H35NOC2H2O40.25H2O's:
Measured value: C, 68.03; H, 8.73; N, 3.40%
Calculated value: C, 67.97; H, 8.84; N, 3.30%
Embodiment 14
4-[2-(4-nitro-3-4-trifluoromethylphenopendant) ethyl]-1-amyl piperidine hydrochloride
m.p.139-141℃
C19H27N2O3HCl's:
Measured value: C, 53.80; H, 6.50; N, 6.45; Cl, 8.30%
Calculated value: C, 53.71; H, 6.64; N, 6.59; Cl, 8.34%
Embodiment 15
The 4-[2-(3-fluorophenoxy) ethyl]-1-amyl piperidine hydrochloride
m.p.157-159℃
C18H28FNOHCl's:
Measured value: C, 65.27; H, 8.67; N, 4.61; Cl, 10.75%
Calculated value: C, 65.54; H, 8.86; N, 4.25; Cl, 10.75%
Embodiment 16
The 4-[2-(4-methylphenoxy) ethyl]-1-amyl piperidine hydrochloride
m.p.164-166℃
C19H31NOHCl's:
Measured value: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82%
Calculated value: C, 70.02; H, 9.90; N, 4.30; Cl, 10.88%
Embodiment 17
4-[2-(4-benzyl phenoxy group) ethyl]-1-amyl piperidine oxalate
Method with similar embodiment 1 prepares title compound, m.p.166-168 ℃.
C25H35NOC2H2O4:
Measured value: C, 70.86; H, 8.02; N, 3.07%
Calculated value: C, 71.18; H, 8.19; N, 3.07%
Embodiment 18
The 4-[2-(3-chlorophenoxy) ethyl]-1-amyl piperidine hydrochloride
Method with similar embodiment 1 prepares title compound, m.p.151-153 ℃
C18H28ClNOHCl's:
Measured value: C, 62.13; H, 8.30; N, 4.05; Cl-, 10.20%
Calculated value: C, 62.42; H, 8.44; N, 4.04; Cl-, 10.23%
Embodiment 19
4-benzyl-1-amyl piperidine hydrochloride
With 4-benzyl piepridine (3.0g), amyl bromide (2.84g), the mixture reflux of salt of wormwood (4.72g) and ethanol (40ml) 48 hours.Filtering solution and removal of solvent under reduced pressure.Resistates in Kugel rohr apparatusto distillation, is obtained a kind of oily b.p.150 ℃ @0.1mmHg, it is handled with hydrogenchloride, from methanol/ethyl acetate, obtain white solid title compound (2.06g).
m.p.188-190℃
C19H31NOHCl's:
Measured value: C, 70.00; H, 9.69; N, 4.15; Cl, 10.82%
Calculated value: C, 70.02; H, 9.90; N, 4.30; Cl, 10.88%
Embodiment 20
The 4-[2-(4-fluorophenoxy) ethyl]-1-cinnamyl piperidine oxalate salt
With the 4-(2-hydroxyethyl)-1-cinnamyl piperidines (2.94g), tetrahydrofuran (THF) (50ml) solution of 4-fluorophenol (1.31g) and triphenylphosphine (3.15g) is handled with nitrine diethyl dicarboxylate (2.09g).Gained solution in stirring at room 18 hours, is removed and desolvates, and resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, use the ethanol/methylene wash-out.Gained oil is dissolved in the ethyl acetate (50ml) also with oxalic acid (1.1 molar equivalent) processing.Filter collecting precipitation and recrystallization (methanol/ethyl acetate) and obtain title compound (1.10g), m.p.180 ℃.
C22H26FNOC2H2O4:
Measured value: C, 67.14; H, 6.60; N, 3.56%
Calculated value: C, 67.11; H, 6.57; N, 3.26%
Embodiment 21
4-[2-(3, the 4-dichlorophenoxy) ethyl]-1-cinnamyl piperidine oxalate salt
With the 4-(2-hydroxyethyl)-1-cinnamyl piperidines (2.02g), 3, tetrahydrofuran (THF) (50ml) solution of 4-chlorophenesic acid (1.34g) and triphenylphosphine (2.16g) is handled with nitrine diethyl dicarboxylate (1.44g).With gained solution stirring 18 hours, remove and desolvate and resistates is dissolved in the ethyl acetate under the room temperature, extract with dilute hydrochloric acid.Alkalization extraction water liquid is also used ethyl acetate extraction.The gained organic layer is dry on sal epsom, filter and remove and desolvate.Resistates is dissolved in the ethyl acetate (50ml) also with oxalic acid (1.1 molar equivalent) processing.Filter collecting precipitation and recrystallization (methanol/ethyl acetate) and obtain m.p.179-180 ℃ of title compound (0.3g).
C22H25Cl2NOC2H2O4:
Measured value: C, 60.07; H, 5.67; N, 2.92; Cl, 14.79%
Calculated value: C, 60.01; H, 5.67; N, 2.92; Cl, 14.76%
Method with similar embodiment 1 prepares following compounds:
Embodiment 22
The 4-[3-(4-fluorophenoxy) propyl group]-1-amyl piperidine hydrochloride
m.p.148-150℃
C19H30FNOHCl's:
Measured value: C, 65.94; H, 9.29; N, 4.15; Cl, 10.32%
Calculated value: C, 66.36; H, 9.09; N, 4.07; Cl, 10.31%
Embodiment 23
4-[3-(4-benzyloxy phenoxy group) propyl group]-1-amyl piperidine hydrochloride
m.p.163-164℃
C26H37NO2HCl's:
Measured value: C, 72.43; H, 8.91; N, 3.31; Cl, 8.06%
Calculated value: C, 72.28; H, 8.86; N, 3.24; Cl, 8.21%
Embodiment 24
The 4-(4-fluorophenoxy) methyl-1-pentene phenylpiperidines hydrochloride
m.p.111-112℃
C17H26FNOC2H2O40.5H2O's:
Measured value: C, 60.25; H, 7.56; N, 3.88%
Calculated value: C, 60.3; H, 7.72; N, 3.70%
Embodiment 25
4-(4-fluorine benzyloxy)-1-amyl piperidine oxalate
Dimethyl formamide (25ml) solution of 4-hydroxyl-1-amyl piperidine (2.0g) is handled with sodium hydride (0.012mole), stirred then 1 hour,, mixture was stirred 3 days when 4-fluorobenzyl chloride (1.43ml) adds fashionablely.Water (100ml) is added and separate organic layer with methylene dichloride (100ml), and (2 * 100ml) washings are also dry on sal epsom for water.Except that desolvating and on silicagel column, resistates being carried out chromatographic separation, use the ethanol/methylene wash-out.The oil of gained is dissolved in the ethyl acetate also with oxalic acid (1.1 molar equivalent) processing.Filter collecting precipitation thing and recrystallization (methanol/ethyl acetate), obtain m.p.124-125 ℃ of title compound (0.2g).
C17H26FNOC2H2O4:
Measured value: C, 61.71; H, 7.69; N, 3.94%
Calculated value: C, 61.77; H, 7.64; N, 3.79%
Embodiment 26
4-benzyloxy-1-amyl piperidine oxalate
With the 4-fluorobenzyl chloride in bromotoluene (2.0g) the replacement embodiment 25 described technological processs, recrystallization from methanol/ethyl acetate obtains white solid title compound (0.2g), m.p.119-121 ℃.
C17H27NOC2H2O4:
Measured value: C, 64.63; H, 8.11; N, 4.14%
Calculated value: C, 64.98; H, 8.32; N, 3.99%
Method with similar embodiment 1 prepares following compounds:
Embodiment 27
The 4-(4-fluorophenoxy)-1-amyl piperidine oxalate
m.p.164℃
C16H24FNOC2H2O4:
Measured value: C, 60.91; H, 7.56; N, 4.06%
Calculated value: C, 60.83; H, 7.37; N, 3.94%
Embodiment 28
4-(3,4-methylenedioxyphenyl oxygen base)-1-amyl piperidine oxalate
m.p.164℃
C17H25NO3C2H2O4:
Measured value: C, 59.76; H, 7.22; N, 3.72%
Calculated value: C, 59.83; H, 7.14; N, 3.67%
Embodiment 29
The 4-[2-(4-fluorophenoxy) ethyl]-1-propyl group piperidine oxalate salt
m.p.109-122℃
C16H24FNOC2H2O4.0.5H2O's:
Measured value: C, 59.66; H, 7.46; N, 3.80%
Calculated value: C, 59.50; H, 7.43; N, 3.86%
Embodiment 30
The 4-[2-(4-fluorophenoxy) ethyl]-the 1-(3-phenyl propyl) the piperidines hydrochloride
With the method for similar embodiment 1 from the 4-(2-hydroxyethyl)-the 1-(3-phenyl propyl) piperidines (2.47g), 4-fluorophenol (1.12g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.74g) preparation title compound.Handle this product with hydrogenchloride, obtain white solid (0.65g), m.p.111-113 ℃ from the methanol/ethyl acetate recrystallization.
C22H28FNOHCl0.5H2O's:
Measured value: C, 68.04; H, 7.72; N, 3.83; Cl, 9.11%
Calculated value: C, 68.23; H, 7.75; N, 3.60; Cl, 9.04%
Embodiment 31
The 4-[2-(4-fluorophenoxy) ethyl]-1-heptyl piperidines hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-heptyl piperidines (2.27g), 4-fluorophenol (1.12g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.74g) preparation title compound.Handle this product with hydrogenchloride,, obtain white solid (1.1g), m.p.139-141 ℃ from the methanol/ethyl acetate recrystallization.
C20H32FNOHCl's:
Measured value: C, 66.71; H, 9.32; N, 4.05; Cl, 10.08%
Calculated value: C, 67.10; H, 9.29; N, 3.91; C19.90%;
Method with similar embodiment 1 prepares following compounds:
Embodiment 32
4-[2-(3,4-methylenedioxyphenyl oxygen base) ethyl]-1-heptyl piperidines hydrochloride
m.p.129-131℃
C21H33NO3HCl's:
Measured value: C, 65.61; H, 8.85; N, 3.71; Cl, 9.26%
Calculated value: C, 65.69; H, 8.93; N, 3.65; Cl, 9.23%
Embodiment 33
The 4-[2-(4-fluorophenoxy) ethyl]-the 1-(2-ethyl) the butyl piperidine oxalate
m.p.137-138℃
C19H30FNOC2H2O4:
Measured value: C, 63.24; H, 8.26; N, 3.58%
Calculated value: C, 63.46; H, 8.11; N, 3.52%
Embodiment 34
4-[2-(3,4-methylenedioxyphenyl oxygen base) ethyl]-the 1-(2-ethyl) the butyl piperidine oxalate
m.p.133-134℃
C20H31NO3C2H2O4:
Measured value: C, 62.05; H, 7.88; N, 3.39%
Calculated value: C, 62.39; H, 7.85; N, 3.31%
Embodiment 35
1-cyclohexyl methyl-4-[2-(3,4-methylenedioxyphenyl oxygen base) ethyl] the piperidines hydrochloride
m.p.177-178℃
C21H31NO3HCl's:
Measured value: C, 66.01; H, 8.44; N, 3.85; Cl, 9.39%
Calculated value: C, 66.04; H, 8.44; N, 3.67; Cl, 9.28%
Embodiment 36
The 4-[2-(4-fluorophenoxy) ethyl]-1-cyclohexyl methyl piperidines hydrochloride
m.p.178-180℃
C20H30FNOHCl's:
Measured value: C, 67.68; H, 8.85; N, 4.12; Cl, 9.87%
Calculated value: C, 67.68; H, 8.78; N, 3.94; Cl, 9.96%
Embodiment 37
The 1-(3-methyl butyl)-and 4-[2-(3,4-methylenedioxyphenyl oxygen base) ethyl] the piperidines hydrochloride
m.p.168-169℃
C19H29NO3HCl's:
Measured value: C, 63.95; H, 8.50; N, 4.05; Cl, 10.17%
Calculated value: C, 64.12; H, 8.50; N, 3.94; Cl, 9.96%
Embodiment 38
1-benzyl-4-[2-(4-fluorophenoxy) ethyl]-1-piperidines hydrochloride
m.p.175-176℃
C20H26FNOHCl's:
Measured value: C, 68.48; H, 7.22; N, 3.92; Cl, 10.07%
Calculated value: C, 68.66; H, 7.20; N, 4.00; Cl, 10.13%
Embodiment 39
The 4-[2-(4-fluorophenoxy) ethyl]-the 1-(2-phenylethyl) the piperidines hydrochloride
With the 4-[2-(4-fluorophenoxy) ethyl] piperidines hydrochloride (0.57g) and the sodium hydride in dimethyl formamide (10ml) (80%, in the oil) mixture (0.146g) be stirred to bubble in nitrogen and go down.Add 2-phenylethyl bromine (0.3ml) and mixture was stirred 48 hours.With in the mixture impouring water (50ml) and use extracted with diethyl ether.With dilute hydrochloric acid washing ether phase, filter and collect the gained precipitation.Recrystallization obtains title compound (0.228g), m.p.210-212 ℃ from water
C21H26FNOHCl's:
Measured value: C, 69.61; H, 7.48; N, 3.96; Cl, 9.77%
Calculated value: C, 69.12; H, 7.73; N, 3.84; Cl, 9.72%
Embodiment 40
The 4-[2-(4-fluorophenoxy) ethyl]-the 1-(4-phenyl butyl) the piperidines hydrochloride
Method with similar embodiment 39, from the 4-[2-(4-fluorophenoxy) ethyl piperidine hydrochloride (1.0g), sodium hydride (80%, in oil) (0.3g) and the 4-phenyl butyl chlorine (0.649g) in dimethyl formamide (20ml) begin to prepare title compound, and with products obtained therefrom ethyl acetate/methanol recrystallization, output (0.39g), m.p.166-168 ℃
C23H30FNOHCl's:
Measured value: C, 70.20; H, 8.00; N, 3.87; Cl, 8.91%
Calculated value: C, 70.48; H, 7.97; N, 3.57; Cl, 9.05%
Embodiment 41
1-(3, the 3-diphenyl propyl)-the 4-[2-(4-fluorophenoxy) ethyl] piperidine oxalate salt
With the 4-[2-(4-fluorophenoxy) ethyl] piperidines hydrochloride (2.0g), first
Measured value: C, 71.80; H, 10.57; N, 3.88; Cl-, 9.67%
Calculated value: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%
Embodiment 53
4-[2-(2-phenyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride
m.p.175-177℃
Embodiment 54
1-amyl group-4-[2-(4-4-trifluoromethylphenopendant) ethyl] piperidine oxalate salt
With the 4-(2-hydroxyethyl)-1-amyl piperidine (2.0g), sodium hydride (60%, in oil) (0.4g) and the mixture of dimethyl formamide (20ml) refluxed 1.5 hours.Add 4-fluoro-trifluoromethylbenzene (1.64g) and mixture was refluxed 18 hours.Cool off this mixture, extract in the impouring water and with ether.Ether extraction liquid dry also removing on sal epsom desolvated.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, make elutriant,, obtain solid with this product of oxalic acid treatment with ethanol/methylene.With its recrystallization from ethyl acetate/methanol, obtain title compound (0.5g), m.p.101-103 ℃.
C19H28F3NO.C2H2O40.1H2O's:
Measured value: C, 57.76; H, 7.00; N, 3.27%
Calculated value: C, 57.9; H, 6.9; N, 3.2%
Embodiment 55
4-[2-(3, the 5-dichlorophenoxy) ethyl]-1-amyl piperidine hydrochloride
Method with similar embodiment 1 prepares title compound, m.p.168-170 ℃
C18H27Cl2NOHCl's:
Measured value: C, 56.80; H, 7.40; N, 3.64; Cl-, 9.33; Cl, 27.92
Calculated value: C, 56.78; H, 7.41; N, 3.68; Cl-, 9.30; Cl, 27.93%
Embodiment 56
4-[2-(3, the 4-dichlorophenoxy) ethyl]-1-heptyl piperidines hydrochloride sulfonic acid 3, under 3-diphenyl propane-1-base ester (2.23g) and the sodium hydride in dimethyl formamide (40ml) (80%, in oil) the mixture nitrogen atmosphere (0.58g), stirred 48 hours in 60 ℃.With in the mixture impouring water (200ml) and use extracted with diethyl ether.Handle the ether phase and precipitate fuel-displaced with dilute hydrochloric acid.Separating oil, and be dissolved in the methylene dichloride.Wash dichloromethane solution with diluted sodium hydroxide solution, dry also removing desolvated on sodium sulfate.When the crystallization title compound, be dissolved in resistates in the ethyl acetate and use oxalic acid treatment.Output 0.963g, m.p.160-161 ℃
C28H32FNOC2H2O4:
Measured value: C, 70.96; H, 6.75; N, 2.83%
Calculated value: C, 70.98; H, 6.90; N, 2.66%
Embodiment 42
4-[2-(4-fluorine sulfo-phenoxy group) ethyl]-1-amyl piperidine hydrochloride
Method with similar embodiment 1 prepares title compound, m.p.164-165 ℃.
C18H28FNSHCl's:
Measured value: C, 62.41; H, 8.47; N, 4.09; Cl, 10.17%
Calculated value: C, 62.49; H, 8.45; N, 4.05; Cl, 10.25%
Embodiment 43
4-[2-(3,4-dichloro sulfo-phenoxy group) ethyl]-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (2.00g), 3,4-dichloro thiophenol (1.79g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.74g) preparation title compound.Handle this product with hydrogenchloride, obtain white solid,, obtain white crystalline solid title compound (0.77g), m.p.158-159 ℃ its recrystallization from ethyl acetate.
C18H27Cl2NSHCl's:
The dry methylene chloride extraction liquid also removes and desolvates on sal epsom.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, make elutriant, handle this product with hydrogenchloride and obtain yellow solid, its recrystallization from ethyl acetate is obtained m.p.174-176 ℃ of yellow crystalline solid title compound (0.937g) with ethanol/methylene.
C18H28NO3HCl's:
Measured value: C, 60.35; H, 8.15; N, 7.85; Cl-, 9.70%
Calculated value: C, 60.58; H, 8.19; N, 7.85; Cl-, 9.93%
Embodiment 47
The 4-[2-(2-fluorophenoxy) ethyl]-1-amyl piperidine hydrochloride
Method with similar embodiment 1 prepares title compound m.p.150-152 ℃.
C18H28FNOHCl's:
Measured value: C, 65.14; H, 8.87; N, 4.30; Cl-, 10.82%
Calculated value: C, 65.54; H, 8.86; N, 4.25; Cl-, 10.75%
Embodiment 48
4-[2-(4-tertiary butyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (1.5g), 4-tert.-butyl phenol (1.127g), triphenylphosphine (1.96g) and nitrine diethyl dicarboxylate (1.19g) preparation title compound.Handle this product with hydrogenchloride and obtain white solid,, obtain white crystalline solid title compound (1.23g), m.p.189-191 ℃ its recrystallization from ethyl acetate/methanol.
C22H37NOHCl's:
Measured value: C, 71.67; H, 10.50; N, 3.88; Cl-, 9.68%
Calculated value: C, 71.8; H, 10.41; N, 3.81; Cl, 9.63%
Embodiment 49
1-amyl group-4-[2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl] the piperidines hydrochloride
Measured value: C, 54.41; H, 7.11; N, 3.48; Cl-, 8.89%
Calculated value: C, 54.48; H, 7.11; N, 3.53; Cl-, 8.93%
Embodiment 44
1-amyl group-4-(3-phenyl propyl) piperidines hydrochloride
With the 4-(3-phenyl propyl) piperidines (5g), 1-bromo pentane silane (7.42g), the mixture heating up of salt of wormwood (10g) and ethanol (125ml) refluxed 18 hours.Filter this solution and removal of solvent under reduced pressure.Resistates is dissolved in the methylene dichloride and with diluted sodium hydroxide solution washs this dichloromethane solution, dry and remove and desolvate on sodium sulfate.The hydrogenchloride that resistates is used in the ether is handled, obtained solid.Obtain m.p.188-189 ℃ of title compound (4.19g) from re-crystallizing in ethyl acetate.
C19H31NCl0.25H2O's:
Measured value: C, 72.56; H, 10.29; N, 4.58; Cl, 11.44%
Calculated value: C, 72.56; H, 10.36; N, 4.45; Cl, 11.27%
Embodiment 45
The 4-[2-(4-fluorophenyl) ethyl]-1-amyl piperidine hydrobromide
With bromination 4-[2-(4-fluorophenyl) ethyl]-1-amyl piperidine (3.0g), the mixture of oxidation of primary (0.6g) and ethanol (100ml) was in nitrogen atmosphere vibration 15 minutes.Filter this mixture and filtrate is evaporated to dried.With resistates recrystallization from methanol/ethyl acetate, obtain title compound, m.p.173-174 ℃.
Embodiment 46
The 4-[2-(4-nitro-phenoxy) ethyl]-1-amyl piperidine hydrochloride
With the 4-(2-hydroxyethyl)-1-amyl piperidine (2.5g), sodium hydride (60%, in oil) (0.42g) and the mixture of dimethyl formamide (20ml) in 50 ℃ the heating 1.5 hours.Add 1-fluoro-4-oil of mirbane (2.14ml) and this mixture was stirred 5 hours in 50 ℃.Cool off this mixture, in the impouring water and use dichloromethane extraction.
Method with similar embodiment 1 prepares title compound, m.p.154-156 ℃
C19H28F3NO2HCl's:
Measured value: C, 57.29; H, 7.31; N, 3.52; Cl-, 8.59%
Calculated value: C, 57.64; H, 7.38; N, 3.54; Cl, 8.96%
Embodiment 50
4-[2-(4-sec.-propyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-1-amyl piperidine (1.5g), 4-isopropyl-phenol (1.02g), triphenylphosphine (1.96g) and nitrine diethyl dicarboxylate (1.19ml) preparation title compound.Handle this product with hydrogenchloride and obtain white solid,, obtain white crystalline solid title compound (1.21g), m.p.185-187 ℃ its recrystallization from ethyl acetate/methanol.
C21H35NOHCl's:
Measured value: C, 71.35; H, 10.23; N, 4.05; Cl-, 10.08%
Calculated value: C, 71.26; H, 10.25; N, 3.96; Cl, 10.02%
Method with similar embodiment 1 prepares following compounds:
Embodiment 51
4-[2-(3-sec.-propyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride
m.p.166-168℃
C21H35NOHCl's:
Measured value: C, 71.40; H, 10.30; N, 3.97; Cl, 10.00%
Calculated value: C, 71.26; H, 10.25; N, 3.96; Cl, 10.02%
Embodiment 52
4-[2-(3-tertiary butyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride
m.p.171-173℃
C22H37NOHCl's:
Method with similar embodiment 1 prepares title compound, m.p.138-139 ℃
C20H31Cl2NOHCl's:
Measured value: C, 58.87; H, 7.88; N, 3.50; Cl-, 8.68; Cl, 26.00%
Calculated value: C, 58.76; H, 7.89; N, 3.43; Cl, 8.68; Cl, 26.01%
Embodiment 57
4-[2-(3, the 4-dichlorophenoxy) ethyl]-the 1-(3-phenyl propyl) the piperidines hydrochloride
With the method for similar embodiment 1, from the 4-(2-hydroxyethyl)-the 1-(3-phenyl propyl) piperidines (2.47g), 3,4-chlorophenesic acid (1.63g), triphenylphosphine (2.62g) and nitrine diethyl dicarboxylate (1.74g) preparation title compound.Handle this product with hydrogenchloride and obtain white solid,, obtain white crystalline solid title thing (0.75g), m.p.137-138 ℃ its recrystallization from ethyl acetate/methanol.
C22H27Cl2NOHCl0.1H2O's:
Measured value: C, 61.24; H, 6.45; N, 3.36; Cl-, 8.7%
Calculated value: C, 61.56; H, 6.34; N, 3.27; Cl, 8.30%
Embodiment 58
1-cyclopropyl methyl-4-[2-(4-fluorophenoxy) ethyl] piperidine oxalate salt
Method with similar embodiment 41, from the 4-[2-(4-fluorophenoxy) ethyl] piperidines hydrochloride (2.0g), brooethyl cyclopropane (2.0ml) and the sodium hydride in dimethyl formamide (40ml) (80%, in oil) (0.58g) prepare title compound.In ethyl acetate, obtain solid, its recrystallization from ethyl acetate is obtained title compound with this product of oxalic acid treatment.Output 0.963gm., m.p129-132 ℃.
C17H24FNOC2H2O4:
Measured value: C, 61.95; H, 7.05; N, 3.91%
Calculated value: C, 62.11; H, 7.13; N, 3.81%
Embodiment 59
1-(3,3-diphenylprop-2-thiazolinyl)-the 4-[[2-(4-fluorophenoxy) ethyl] piperidine oxalate salt
Methylsulfonyl chloride (0.46ml) is added 1, in tetrahydrofuran (THF) (20ml) solution of 1-phenylbenzene-2-methylol ethylidene (1.14g).When the 4-[2-(4-fluorophenoxy) ethyl] piperidines (1.42g) and triethylamine (0.8ml) add fashionablely, mixture stirred 1 hour.Under the nitrogen atmosphere mixture was stirred 48 hours, reflux is 8 hours then.To extract in the mixture impouring water (200ml) and with ether.Ether is carried out drying on sal epsom, filter and remove and desolvate.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, make elutriant,, obtain solid with this product of oxalic acid treatment with ethanol/methylene.Its recrystallization from ethyl acetate/methanol is obtained title compound (0.687g), m.p.174-176 ℃.
C28H30FNOC2H2O4:
Measured value: C, 70.84; H, 6.34; N, 2.93%
Calculated value: C, 71.27; H, 6.38; N, 2.77%
Embodiment 60
4-[2-(2-benzyl phenoxy group) ethyl]-1-amyl piperidine hydrochloride
Method with similar embodiment 1 prepares title compound, m.p.119-120 ℃.
C25H35NOHCl0.3H2O's:
Measured value: C, 73.32; H, 8.94; N3.61; Cl, 8.70%
Calculated value: C, 73.59; H, 8.89; N, 3.43; Cl, 8.69%
Claims (10)
1, the method for preparing structure formula I compound or its salt
Wherein
R is C1-8Alkyl (phenyl) P, C2-8Alkenyl (phenyl) P,
C2-8Alkynyl (phenyl) P, C3-8Cycloalkyl or C1-8Alkyl C3-8Cycloalkyl;
P is 0 to 2;
N is 0 to 6;
A is a key, oxygen, sulphur or NR1
R1Be hydrogen, C1-8Alkyl or phenyl C1-4Alkyl;
M is 0 to 3;
Ar is aryl or heteroaryl, and wherein each can be optionally substituted, and present method comprises:
(a) be O to A in the formula, S or NR1Structure formula I compound, make structure formula II compound:
Wherein R and n be as described in the structure formula I, and A1Be O, S or NR1, with structural formula L (CH2)mAr compound reaction, wherein m and Ar are as described in the structure formula I;
(b) be O to A in the formula, S or NR1Structure formula I compound, make structure formula III compound:
Wherein n and R are as described in the structure formula I and L1Be can be by nucleophilic reagent metathetical group, with structural formula HA1(CH2)mAr compound reaction, wherein m and Ar be as described in the structure formula I, A1As described in the structure formula II; Or
(c) be NR to A in the formula1Structure formula I compound, structure formula IV compound is reduced:
Group, n, m, R and Ar are as described in the structure formula I;
(d) be the structure formula I compound of key to A in the formula, make structural formula (V) compound:
(Ⅴ)
(R wherein, L1, n and m are as hereinbefore defined) and structural formula x1Ar compound reaction, wherein Ar is as described in the structure formula I, x1Be basic metal;
(e) the R group is introduced the formula VI compound:
Use and RL2The method of compound reaction, wherein L2It is leavings group;
(f) reduction-type (VII) compound:
R wherein5Be C1-7Alkyl (phenyl) P, C2-7Alkenyl (phenyl) P, C2-7Alkynyl (phenyl) P or C1-7Alkyl C3-8Cycloalkyl;
(g) reduction structural formula (VIII) compound:
R wherein, A, Ar, m and n define as mentioned, X
Be counter ion;
And arbitrary shape salify after this.
2, according to the process of claim 1 wherein that R is C1-8Alkyl, phenyl (C1-8) alkane itself or phenyl (C2-8) alkenyl.
3, according to the method for claim 1 or claim 2, wherein A is an oxygen.
4, according to the method for one of claim 1 to 3, wherein n is 0 to 3.
5, according to the method for one of claim 1 to 4, wherein m is 0 to 3.
6, according to the method for one of claim 1 to 5, wherein Ar is the phenyl that replaces arbitrarily.
7, be selected from down compound or its medicinal acceptable salt of group according to the method preparation of claim 1:
The 4-[2-(4-4-trifluoromethylphenopendant) ethyl]-the 1-amyl piperidine,
The 4-[2-(3-4-trifluoromethylphenopendant) ethyl]-the 1-amyl piperidine,
The 4-[2-(4-fluorophenoxy) ethyl]-the 1-amyl piperidine,
4-[2-(3,4-methylenedioxyphenyl oxygen base) ethyl]-the 1-amyl piperidine,
4-(2-benzene oxygen ethyl)-the 1-amyl piperidine,
4-[2-(4-phenyl phenoxy group) ethyl]-the 1-amyl piperidine,
4-[2-(4-benzyloxy phenoxy group) ethyl]-the 1-amyl piperidine,
The 4-[2-(4-fluorophenoxy) ethyl]-1-cinnamyl piperidines,
4-(4-fluorine benzyloxy)-the 1-amyl piperidine,
4-[2-(3, the 4-dichlorophenoxy) ethyl]-the 1-amyl piperidine,
4-[2-(4-benzyl phenoxy group) ethyl]-the 1-amyl piperidine,
4-[2-(3, the 4-dichlorophenoxy) ethyl]-1-cinnamyl piperidines,
The 4-[2-(4-fluorophenoxy) ethyl]-the 1-(3-phenyl propyl) piperidines,
The 4-[2-(4-fluorophenoxy) ethyl]-1-heptyl piperidines,
1-(3, the 3-diphenyl propyl)-the 4-[2-(4-fluorophenoxy) ethyl] piperidines,
4-[2-(3,4-dichloro sulfo-phenoxy group) ethyl]-the 1-amyl piperidine,
4-[2-(4-tertiary butyl phenoxy group) ethyl]-the 1-amyl piperidine,
4-[2-(4-sec.-propyl phenoxy group) ethyl]-the 1-amyl piperidine,
4-[2-(3, the 4-dichlorophenoxy) ethyl]-the 1-(3-phenyl propyl) piperidines, or
1-cyclopropyl methyl-4-[2-(4-fluorophenoxy) ethyl] piperidines.
8, preparation contains the method as the pharmaceutical composition of one of claim 1 to 7 defined structure formula I compound or its medicinal acceptable salt, comprises said compound is combined with medicinal acceptable carrier.
9, will be used for the treatment of according to structure formula I compound or its medicinal acceptable salt of one of claim 1 to 7.
10, be used for preparing a medicine for the treatment of a Mammals brain cell calcium accumulation disease that causes or increase the weight of as one of claim 1 to 7 defined structure formula I compound or its medicinal acceptable salt.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9017224.8 | 1990-08-06 | ||
| GB909017224AGB9017224D0 (en) | 1990-08-06 | 1990-08-06 | Compounds |
| GB919107757AGB9107757D0 (en) | 1991-04-12 | 1991-04-12 | Compounds |
| GB9107757.8 | 1991-04-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1061963Atrue CN1061963A (en) | 1992-06-17 |
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ID=26297463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91105945APendingCN1061963A (en) | 1990-08-06 | 1991-08-05 | Be used as the croak pyridine class of the 4-replacement of medicine |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0542846A1 (en) |
| JP (1) | JPH06500093A (en) |
| KR (1) | KR930701402A (en) |
| CN (1) | CN1061963A (en) |
| AP (1) | AP279A (en) |
| AU (1) | AU8327191A (en) |
| CA (1) | CA2088491A1 (en) |
| IE (1) | IE912759A1 (en) |
| IL (1) | IL99073A0 (en) |
| MA (1) | MA22250A1 (en) |
| MX (1) | MX9100513A (en) |
| NZ (1) | NZ239268A (en) |
| PT (1) | PT98574A (en) |
| TW (1) | TW267164B (en) |
| WO (1) | WO1992002502A1 (en) |
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| ZA9610738B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
| ZA9610736B (en) | 1995-12-22 | 1997-06-27 | Warner Lambert Co | 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists |
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| AR042628A1 (en)* | 2002-12-20 | 2005-06-29 | Astrazeneca Ab | PIPERIDINE DERIVATIVES AS CCR5 RECEIVER MODULATORS |
| SE0203828D0 (en)* | 2002-12-20 | 2002-12-20 | Astrazeneca Ab | Chemical compounds |
| SE0301369D0 (en) | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Chemical compounds |
| PT1641775E (en) | 2003-07-03 | 2009-04-23 | Euro Celtique Sa | 2-pyridine alkyne derivatives useful for treating pain |
| TW200610761A (en) | 2004-04-23 | 2006-04-01 | Astrazeneca Ab | Chemical compounds |
| SE0401656D0 (en)* | 2004-06-24 | 2004-06-24 | Astrazeneca Ab | Chemical compounds |
| FR2872416B1 (en)* | 2004-07-01 | 2006-09-22 | Oreal | USE OF PIPERIDINE DERIVATIVES TO COMBAT WRINKLES |
| WO2008096189A2 (en) | 2005-09-23 | 2008-08-14 | M's Science Corporation | Piperidine and piperazine derivatives |
| NZ570078A (en)* | 2006-01-27 | 2011-10-28 | Ms Science Corp | Piperidine and piperazine derivatives |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4031221A (en)* | 1974-06-17 | 1977-06-21 | American Hoechst Corporation | Method of treating pain and hypertension |
| EP0077427B1 (en)* | 1981-10-15 | 1985-05-22 | Synthelabo | Piperidine derivatives, their preparation and use in medicine |
| US4546105A (en)* | 1984-09-04 | 1985-10-08 | Hoechst-Roussel Pharmaceuticals Inc. | Pyrrolylaminopiperidines, compositions thereof and methods of use |
| DE3441929A1 (en)* | 1984-11-16 | 1986-05-28 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING SUBSTITUTED PIPERIDINES |
| DE3529994A1 (en)* | 1985-08-22 | 1987-02-26 | Hoechst Ag | INDOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THEM AND THE USE THEREOF |
| DK623586A (en)* | 1985-12-27 | 1987-06-28 | Eisai Co Ltd | PIPERIDE INGREDIENTS OR SALTS THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE COMPOUNDS |
| MY104343A (en)* | 1987-11-23 | 1994-03-31 | Janssen Pharmaceutica Nv | Novel pyridizinamine deravatives |
| FR2636946B1 (en)* | 1988-09-23 | 1990-11-02 | Lipha | ((DIARYLMETHOXY) ALCOYL) -1 PYRROLIDINES AND PIPERIDINES, METHODS OF PREPARATION AND MEDICAMENTS CONTAINING THEM |
| US5153206A (en)* | 1988-12-02 | 1992-10-06 | Pfizer Inc. | Arylpiperidine derivatives |
- 1991
- 1991-08-02IEIE275991Apatent/IE912759A1/enunknown
- 1991-08-02MXMX9100513Apatent/MX9100513A/enunknown
- 1991-08-04ILIL99073Apatent/IL99073A0/enunknown
- 1991-08-05WOPCT/GB1991/001340patent/WO1992002502A1/ennot_activeApplication Discontinuation
- 1991-08-05EPEP91914558Apatent/EP0542846A1/ennot_activeWithdrawn
- 1991-08-05JPJP3513952Apatent/JPH06500093A/enactivePending
- 1991-08-05NZNZ239268Apatent/NZ239268A/enunknown
- 1991-08-05AUAU83271/91Apatent/AU8327191A/ennot_activeAbandoned
- 1991-08-05KRKR1019930700352Apatent/KR930701402A/ennot_activeWithdrawn
- 1991-08-05MAMA22529Apatent/MA22250A1/enunknown
- 1991-08-05PTPT98574Apatent/PT98574A/ennot_activeApplication Discontinuation
- 1991-08-05TWTW080106121Apatent/TW267164B/zhactive
- 1991-08-05CACA002088491Apatent/CA2088491A1/ennot_activeAbandoned
- 1991-08-05CNCN91105945Apatent/CN1061963A/enactivePending
- 1991-08-06APAPAP/P/1991/000313Apatent/AP279A/enactive
Also Published As
| Publication number | Publication date |
|---|---|
| KR930701402A (en) | 1993-06-11 |
| JPH06500093A (en) | 1994-01-06 |
| TW267164B (en) | 1996-01-01 |
| IE912759A1 (en) | 1992-02-12 |
| PT98574A (en) | 1992-06-30 |
| NZ239268A (en) | 1994-06-27 |
| MA22250A1 (en) | 1992-04-01 |
| EP0542846A1 (en) | 1993-05-26 |
| WO1992002502A1 (en) | 1992-02-20 |
| AP9100313A0 (en) | 1991-10-31 |
| IL99073A0 (en) | 1992-07-15 |
| CA2088491A1 (en) | 1992-02-07 |
| AP279A (en) | 1993-08-01 |
| AU8327191A (en) | 1992-03-02 |
| MX9100513A (en) | 1992-04-01 |
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| C06 | Publication | ||
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| SE01 | Entry into force of request for substantive examination | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |