CN86104681A - The cyclic amide and the imido diaza-phenyl piperidine derivative of treatment senile psychosis - Google Patents
The cyclic amide and the imido diaza-phenyl piperidine derivative of treatment senile psychosis Download PDFInfo
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Abstract
A series of short intelligent compounds with formula I:
X is ethylene chain or 1 in the formula, 2-benzo ring; Y is carbonyl or methylene radical; R
1Be hydrogen or low-carbon alkyl; Z is R
2, R
3-dibasic diaza phenyl ring by pyridazine, is selected in pyrimidine and the pyrazine ring system.Pharmacological testing proves: in diving tower passive avoidance response experiment, this series compound has the usefulness of the loss of memory that recovery causes by ECS.The result of these pharmacological evaluation shows to have the activity that strengthens cognitive power and memory as compound in structural formula I.
Description
This is that the series number of submission on July 8th, 1985 is a part continuation application of 753,006.
The present invention relates generally to have heterocycle carbon compound and the preparation and the purposes of medicine and biological action character.The present invention is special relevant with disubstituted piperidine derivatives, one of them substituting group is cyclic amide or imide ring, be connected to by an end of endo-methylene group on the carbocyclic ring position of piperidine ring, and another substituting group is a diazine ring system on the nitrogen-atoms that is connected in piperidines.Compound of the present invention is applicable to treatment the elderly's various senile dementias.
The clinical condition of various senile dementias reaches caused problem when handling the presbyatrics problem, is well-known for stager in this field.People also can be appreciated that, to the various pharmacological agenies of this elderly's disorder at present just under study for action.In these medicines, there is a class medicine to be called as short intellectual drug, or more generally is called the cognitive power toughener; The some of them medicine is carrying out clinical evaluation to the patient who suffers from Alzheimer's at present, and this disease is a kind of serious and quite common the elderly's central nervous system disorder.These are the medicine in clinical study just, chemically is the derivative that belongs to the 2-Pyrrolidone that N-that a class has structural formula 1 replaces.
a：X＝H;R＝-CH
2CONH
2（piracetam）
b：X＝OH;R＝-CH
2CONH
2（oxiracetam）
c：X＝H;R＝-CH
2CONH[CH
2]
2N[CH（CH
3）
2]
2
（pramiracetam）
d：X＝H;R＝
（aniracetam）
A representational reference of this test method and serial 1 compound property is described, referring to people such as Butler, " J.Med.chem. ", 27 volumes, 684～691 pages (1984).With structure 1a-d is example, and the preliminary clinical results of this class medicine shows may have some useful effectiveness for the senile dementia for the treatment of the elderly.
Relevant technology can be seen by following basic structure formula 2:
Wherein X is C
2-4Alkylidene group or 1,2-benzo ring; Y is carbonyl or methylene radical; A is a bridging part, alkylidene group for example, and alkanoyl, alkylidene group acid amides alkylidene group, or the like; W is nitrogen or CH; And B is an aryl or pyrimidine ring system.The most closely-related technology is in we the own U.S.S.N.799 that submits on November 11st, 1985, the content of delivering and requiring in 670 the part continuation application.Its related content is the compound about a series of structural formulas 2, and W is a nitrogen.The most closely-related compound of delivering in this application can be represented with structural formula 3.
R in the formula
1Be hydrogen or low-carbon alkyl; R
2Also can be hydrogen or low-carbon alkyl.As shown in the figure, these early stage compounds on chemical structure with the present invention in series of compounds have any different, these early stage compounds are piperazine ring derivative (W=N in formula 2), and the compound among the present invention then is piperidine ring derivative (W=CH in formula 2).
Other related content about the compound of formula 3 is delivered by people such as Malawska, see " the synthetic and pharmacological properties of being permitted alkali in some 2-Pyrrolidone is graceful ", " Polish Journal of Pharmacology ", 1982,34 volumes, 373-382, a series of compound that they describe have a class possible constructions formula 4 expressions, report this compounds and have analgesia character and weak anti-inflammatory action
X is hydrogen or chlorine in the formula.
Wu, Temple, New and theys' co-worker and the others have delivered a large amount of antipsychotic compounds with formula 2 structures, and Y is a carbonyl in the formula, and W is a nitrogen and A is C
2-4Alkylidene group, these compounds contain the cyclin imide ring, for example: succimide, glutarimide, phosphorus Phthalimide etc.The shortest chain that is defined by A in these compounds is an ethylene, and that A is the compound of methylene radical is too unstable in practicality, especially in acidic medium.To the more detailed expression of these compounds, referring to: people such as Wu, U.S.putent 3,717, and on February 20th, 634,1973 patented; Temple, U.S.patent 4,423,049, and patent December 27 nineteen eighty-three; And New and Yecich, U.S.patent 4,524, and on June 18th, 206,1985 patented.
Listed compound in above-mentioned patent application structurally has more difference with compound of the present invention.Generally speaking, the diaza-phenyl piperidine compounds of Miao Shuing is the cognitive power toughener of novel texture in the present invention, and the included specific compound of the present invention is not to be to rely on certain theory of this area to be predicted or clear.
A series of compounds with structural formula I:
X or be ethylene chain or be 1,2-benzo ring in the formula; Y is carbonyl or methylene radical; R
1Be hydrogen or low-carbon alkyl; Z is R
2, R
3-dibasic by pyridazine, the diaza phenyl ring of selecting in pyrimidine and the pyrazine ring system, R
2And R
3Independently be selected from hydrogen separately, low alkane carbon back, low-carbon alkoxy, low-carbon (LC) sulphur alkyl, cyano group, trifluoromethyl and fontanel element.This serial compound can participate in the medicament component, is used for the treatment of the senile dementia patient.Some representative compounds have carried out rat test, prove the loss of memory that can prevent that ECS from causing.
The present invention relates generally to N-methylene radical cyclic amide and the imido 1-(4-diaza-phenyl with senile psychosis effectiveness) piperidine derivative, can represent by the structural formula I:
In the formula I, X is C
2(ethylene) alkylidene chain or 1,2-benzo ring, X is connecting Y and carbonyl, for example, when Y also is carbonyl, then is the phthalic imidine part.Y be carbonyl (have only when X be 1, during 2-benzo ring) or CH
2In the formula I, R
1Can or be hydrogen or for low-carbon (LC) (C
1-4) alkyl; Z is R
2, R
3-dibasic by diaza phenyl ring selected in pyridazine, pyrimidine and the pyrazine ring system, R
2And R
3Be independently selected from hydrogen, low-carbon alkyl, the high fluoro-alkyl of low-carbon (LC) (refers to contain in these groups 1 to 4 carbon atom as trifluoro.The fontanel element means F, Cl, Br or I.In the preferred compound, X is an ethylene, and Y is a methylene radical, R
1Be hydrogen, R
2And R
3Be selected from hydrogen, trifluoromethyl and fontanel element, and most preferred fontanel element is a muriate.
Obviously, the present invention is believed to comprise various steric isomers, and for example: optically active isomer comprises single enantiomorph, the mixture of enantiomorph, the mixture of diastereomer and diastereomer.The generation of these isomer is that structure is asymmetric to be caused thereby cause owing to introduced one or two unsymmetrical carbon in some compound in the series of the present invention.The whole bag of tricks that the professional was familiar with that the separation of each isomer can be applied as in this field is realized.For medicinal purpose, first-selected in some cases is to be suitable for medicinal acid and salify, and negatively charged ion wherein can toxigenicity or to the not influence of organic cations pharmacologically active.The acquisition of those acid salt or by a kind of organic bases and a kind of organic or inorganic acid-respons of structure I compound is preferably reacted in solution; Perhaps adopt any standard method that elaborates in the document, these methods are that each professional who is familiar with this field can find.Useful organic acid example is: carboxylic acid, and toxilic acid for example, acetate, tartrate, propionic acid, fumaric acid, hydroxyethylsulfonic acid, Succinic Acid, methylene-two (hydroxynaphthoic acid), Cyclamen persicum acid, trimethylacetic acid, or the like.The available mineral acid has the acid of hydrogen fontanel, HCl for example, HBr, HI; Sulfuric acid, phosphoric acid, or the like.In addition, the present invention also comprise any with solvent with the thing structural formula I compound that exists of hydrate forms for example.
Compound of the present invention can adopt as flow process general method shown in Figure 1 and prepare easily:
Schema 1
General building-up process
In schema 1, symbol X, Y and Z such as preceding definition.Basically be piperidine carboxylic acid ester (IX) and suitable fontanel diazine (VIII) reaction.Compound IX and VIII are respectively ethyl ester and muriate in the schema 1, also can be with other group of equal value, for example, alkyl carboxylic acid ester, and/or a kind of different fontanel element.These select for being proficient in the synthetic organic chemist of compound is very familiar.Representational reaction is IX and VIII (for example salt of wormwood) in the presence of alkali, carries out in reaction solvent (for example acetonitrile), generates product (VII).The reduction of product VII can with the lithium aluminum hydride reaction, generate intermediate product VI (R in appropriate solvent (for example tetrahydrofuran (THF))
1=H), perhaps use another kind of approach, adopt ester group to be transformed into the standard method of aldehyde radical, VII can be transformed into the aldehyde X, uses organometallic reagent R then
1M represents proper metal positively charged ion or the processing of Ge Shi complex compound in the M(formula, generation intermediate product VI '.Primary alconol intermediate (VI) or secondary alcohol (VI ') are handled with thionyl chloride, generate corresponding chlorinated thing (V), with cyclic amide of selecting or imide (VI) reaction, generate the expection product with structural formula I then.The response class of this linked reaction and IX and VIII seemingly, in this case, first-selected reaction solvent is a dimethyl formamide, and adds alkali, for example salt of wormwood.The people who is familiar with this technology can understand, the conversion reaction that other also can the reaction intermediate VI takes place is about to hydroxyl and changes into different leavings groups effectively, (for example, tosylate or methanesulfonates part) is beneficial to the nitrogen-atoms alkylation in cyclic amide/imide.
Another process also can be used for producing the product as the structural formula I, and this process such as flow process are shown in Figure 2.
Schema 2
Building-up process when X is the dimethylene chain
In schema 2, R
1, X, Y and Z are as defined above.Though generalized method has higher yield than the structure I product that in general the logical method of schema 1 produces in schema 2, it does not have the general applicability as Fig. 1 process.Because the cause (changing into II by III) of catalytic reduction has only those not can be used by catalytic reduction interferential cyclic amide imide.For example, when X is 1,2-benzo ring, for example IV is a phthalic imidine, then the benzo loop section is reduced into 1 immediately, the 2-cyclohexyl derivatives, thus generate hexahydro-phthalic imidine ring system.
In sum, the compound of formula I
R in the formula
1, X, Y and Z as defined above, its preparation process can be by selecting in the following serial of methods, this serial of methods comprises:
(a) coupling of (1) compound IX and VIII
R is C in the formula
1-6Alkyl, Q be for being suitable for the metathetical group, muriate for example, bromide, iodide, sulfuric ester, phosphoric acid ester, tosylate, methanesulfonates, or the like the intermediate product of production VII:
(2) use metal reagent R
1M handles the intermediate product VII, and M is proper metal ion or complex compound, and for example lithium aluminum hydride or Grignard reagent complex compound generate the reaction intermediate suc as formula VI.
(3), be about to the leavings group Q in the OH groups converted accepted way of doing sth V compound of VI with suitable agent treated intermediate VI.
(4) make the cyclic amide/imide compound of midbody product V and formula IV react the product of production I.
(b) cyclic amide/imide compound of (1) formula IV
X is not 1 in the formula, 2-benzo ring, and with the pyridine intermediate reaction of formula X,
Production is the intermediate compound of III:
(2) compound of catalytic reduction formula III, the piperidines intermediate compound of production II:
(3) compound of formula II and compound Z-Q coupling reflection, the product of production I.
It is active that compound of the present invention has been estimated short intelligence, is that assessing compound reverses the loss of memory effect that is caused by ECS with the experiment of diving tower passive avoidance response as the method for primary dcreening operation.(referring to: Banfis, etc., 255 pages (1982) of " J.pharmacol.Meth. " 8 volumes, Janvik, " Ann.Rev.psychol. " 23 volumes, 457 pages (1971); Mc Gaugh and Petrinovich, " Int.Rev.Neurobiology ", 8 volumes, 139 pages (1965)) reference compound such as pramiracetam, piracetam, aniracetam or the like, this respect activity that has, roughly be to influence the memory process, and may be effective to treatment senile dementia and alzheimer's disease.In this experiment, 12 animals administers trained it to keep motionless to avoid foot's electric shock after 30 minutes.After the training, make these animal ECSs immediately.After 24 hours, measure the memory of these animals to the behavior learned.Be considered to still remain with passive avoidance response and rest on the animal that platform do not jump off last 300 second.Two animals of control group are used for comparison: give vehicle and ECS for one group, another group is given vehicle and false ECS.If both the numerical value than ECS control group (placebo group) was big on the mean residence time statistics on the platform for animal, with the numerical value no difference of science of statistics of false ECS control group, think that then tested compound is activated on the dosage level of being given again.
If all be different from two control groups on the statistics as a result of administration group, think that then tested compound has medium activity on the dosage level of being given.For the ease of comparing, all medicines are subcutaneous administration all.But preferred compound shows in this series, and what variation is the active result with subcutaneous administration in oral back do not have.In this, following compounds is particularly preferred:
1-((1-(2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone,
1-((1-(2-chloro-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone,
1-((1-(6-chloro-2-pyrazinyl)-4-piperidyl) methyl)-2-Pyrrolidone,
1-((1-(2-trifluoromethyl-4-pyrimidyl)-4-piperidyl) methyl particularly)-2-Pyrrolidone.Compound of the present invention is changed into oral by subcutaneous administration, drug effect still keeps similar level, and this is a tangible medication advantage, and this has any different the medicament in compound of the present invention and the above-mentioned technical literature.In addition, compound of the present invention is not instability in acidic medium, and this prepares for preparation, and transportation and storage and medication are another advantages.
Summarize above the discussion, compound of the present invention has the intelligent character of promotion, is specially adapted to strengthen cognitive power and memory.Another aspect of the present invention is when Mammals need be treated, to the enhancement of its cognitive power and memory.This treatment is that the formula I compound of certain effective dose for oral administration or its are suitable for medicinal acid salt.The administration of the compound of formula I is disposed and can be undertaken by the mode identical with reference compound piracetoam with formulation.About piracetam, referring to: Recsberg etc., " Drug Develapment Reseacch ", 2 volumes, 475～480 pages (1982); Weng etc., " Rational Drug Thrapy " 17(5) volume, 1～4 page (1983); Rersberg etc., " Psychopathology in the Aged ", Editors, Cole and Barrett, Raven press, New York, 243～245 pages (1980); About pramiracetam, referring to: Butler etc., " J.Med.Chem ", 27 volumes, 684～691 pages (1984).
The compound of formula I is also found to can be used for preventing because the loss of memory that ECS causes except the central nervous system stimulant as cognitive power toughener and gentleness.The memory that this activity not only relates in the normal old process keeps, and the loss of memory of using clinically that ECS caused is had provide protection.ECS is used for treating some mental patient, and particularly those are with the very obstinate depressive type patient of traditional pharmacological agent.A large amount of records show that the ECS therapeutics can cause undesirable side effect to the patient: the loss of memory.And the pharmacological evaluation of compound of the present invention shows, the loss of memory that ECS is caused has provide protection.This is useful to the clinical application meeting of assisting ECS on psychiatric treatment.
Though each disease is split dosage and dosage place system must be adjusted modestly, uses correct professional judgement and consider age of patient, body weight and situation, administration footpath and psychotic nature and extent, but in general, oral dosage is approximately 0.1 every day and restrains 10 grams, preferably 0.5 restrains 5 grams.In some case, use lower dosage that sufficient result of treatment is promptly arranged, and other cases then need bigger dosage.For the doctor who is proficient in clinical pharmacology, obviously can understand according to them with treatment in the principle that must observe, the compound of formula I every day dosage can single administration or gradation administration.
The term of Shi Yonging " whole body administration " is meant herein: oral, and hypogloeeis, oral cavity, nose, skin, rectum, muscle, vein and the mode that gives such as subcutaneous.Usually can prove, when as best oral compound of administering mode, need bigger slightly effective dose with produce with non-when the enteral administration with slightly low dose of same effect.According to the requirement of effect clinical practice preferably, preferably control The compounds of this invention concentration level in vivo and be and to produce effectively short intelligence effect and do not cause any deleterious or unfavorable side effect.
On actual therapeutic, compound of the present invention generally is with the administration of medicament component, and the medicament component comprises the compound of the formula I of effectively urging intelligent dosage or their the effectively short intelligent dosage that is suitable for medicinal acid salt, and is suitable for medicinal carrier.In order to reach effective treatment, the major part of medicament component or small part (for example: by 95% to 0.5%) will be a kind of compound of the present invention and pharmaceutical carrier at least, and carrier comprises that one or more are nontoxic, inertia and be suitable for medicinal solid, semisolid or liquid diluent, weighting agent and prescription auxiliary.It is unitary form that these medicament components are preferably made with dosage, promptly according to the mark or the multiple of the good dosage of the calculating that is equivalent to produce desirable medical effect, makes the physics dispersal unit that contains pre-selected amount of medication.In general being suitable for, dosage device contains 1 times an of medicine, and 1/2,1/3 or still less.The dose of administration preferably contains the dose that is enough to produce desirable medical effect.According in advance fixed dosage range, once use one or more dosage devices, normally every day dosage whole, half, 1/3rd or still less, be administered once every day, secondary, three times or repeatedly.Can imagine that other healing potion also may reside in the said components.It is preferably that per unit dosage has the medicament component of the effective constituent of 0.1 to 1 gram, conventionally is to make tablet, sugar-pill, capsule, pulvis, suspension liquid, syrup, the elixir of water or oil, and the aqueous solution.First-selected oral dosage form is tablet, capsule, and (for example: syrup, Sudan Gum-arabic, gelatin, sorbyl alcohol, tragakanta can contain conventional vehicle such as tackiness agent, or polyvinylpyrrolidone), weighting agent (for example: lactose, sugar, W-Gum, calcium phosphate, sorbyl alcohol or Padil), lubricant (for example Magnesium Stearate, talcum, polyoxyethylene glycol or silicon-dioxide), (for example: starch), and wetting agent (for example: sodium lauryl sulphate) for disintegrating agent.The solution of formula I compound or suspension liquid are used for non-ly giving formulation through intestines, and conventional vehicle has the oily suspension liquid that for example is used for the intravenous aqueous solution and is used for intramuscular injection.These non-clarity that should have through the enteral administration formulation, stable and parenteral suitability, its preparation can be by being that 0.1% to 10% active compound is soluble in water or be dissolved in the vehicle that contains multi-hydroxy fat alcohol such as glycerol, propylene glycol and polyoxyethylene glycol or their mixture with weight ratio.This polyoxyethylene glycol is nonvolatile, the mixture of the polyoxyethylene glycol of molecular weight 200 to 1500.This mixture is generally liquid, the promptly water-soluble organic liquid that is dissolved in again.
Constitute compound of the present invention, its preparation method, and their biological activity will be described fully by investigating the following example.The purpose that provides these embodiment only is not think restriction the field of the invention and scope for explanation.If adding special indicating, all temperature all are not interpreted as degree centigrade.The eigenwert of nucleus magnetic resonance (NMR) spectrum is meant the chemical shift (δ) with respect to marker tetramethylsilane (TMS), with hundred value (PPM) expressions very much.In proton (PMR) spectrum data, the relative area at each peak of record is corresponding to the number of hydrogen atoms of each particular functional type in the molecule.Because its diversity, each displacement is recorded as wide unimodal (bs), unimodal (s), multiplet (m), doublet (d), the doublet of doublet (dd), triplet (t), or quartet (g).That uses is abbreviated as: DMSO-d
6(many deuteriums dimethyl sulfoxide (DMSO)), CDCl
3; (deuterium trichloromethane), other then follows convention.Infrared (IR) spectrographic is described and is included only the absorption wavenumber that those have functional group's identification value.Infrared identification is to make thinner with Potassium Bromide (KBr).All compounds have all carried out satisfactory ultimate analysis.
Embodiment 1
2-((1-(2-pyrimidyl)-4-piperidyl) methyl)-1H-isoindole-1,3-(2H)-diketone
This composition sequence is the embodiment of aforementioned flow process general synthetic method shown in Figure 1.
A.1-(2-piperidines-4-carboxylic acid, ethyl ester (VII) pyrimidyl).-isonipecotic acid ethyl ester (IX; 31.44 gram, 0.2 mole), 2-Chloropyrimide (VIII; 22.91 gram, 0.2 mole) and the mixture of salt of wormwood (27.69 gram, 0.2 mole) in acetonitrile (250 milliliters), refluxed 24 hours.Mixture filters, and concentrates in the filtrate vacuum.Residue distills the clarification oily product that (130～170 °, 0.32 torr) obtain 44.1 grams (94%).
B.2-piperidines (VI) methylol-1-(2-pyrimidyl).-ester (VII; 20 grams, 0.085 mole) be cooled to 0～5 ° in the solution of tetrahydrofuran (THF) (200 milliliters), lithium aluminum hydride (3.23 grams, 0.085 mole) is slowly added in during 10 minutes.This mixture at room temperature stirred 30 minutes.Excessive lithium aluminum hydride removes with acetone, and mixture adds earlier 3.2 milliliters water, adds 3.2 milliliters 15% sodium hydroxide solution then, adds 9.7 milliliters water dilution at last again.The mixture that generates is filtered, and filtrate concentrates in a vacuum and obtains a kind of oil, obtains 15 gram (91%) clarifying oily products after distillation, and boiling point is 140～190 ° when 0.3 torr.
C.4-piperidines (V) chloromethyl-1-(2-pyrimidyl).One methylol compound (VI; 7.73 gram, 0.04 mole) be cooled to 0～5 ° in the solution of methylene dichloride (40 milliliters), slowly add thionyl chloride (25 milliliters).Solution stirred under room temperature 12 hours, concentrated in vacuum then.Residue is dissolved in the methylene dichloride, and with the sodium bicarbonate aqueous solution extraction, dichloromethane layer concentrates in a vacuum.Residue separates with chromatography on silica gel, and ethyl acetate is an elutriant, obtains the oily product of 7.7 grams (91%).
D. the reaction of intermediate V and phthalic imidine.One salt of wormwood (2.76 grams; 0.02 phthalic imidine (1.47 grams mole); 0.01 mole) and 4-chloromethyl-1-(2-pyrimidyl) piperidines (V; 2.12 gram, 0.01 mole) in the mixture heating up of dimethyl formamide (50 moles) to about 50 °, 24 hours.Remove solvent dimethylformamide in a vacuum, residuum is dissolved in acetone and filters.Filtrate obtains crude product after concentrating in vacuum.Crude product is that elutriant separates with chromatography with 30% ethyl acetate-hexane on silica gel.Product is recrystallization in ethyl acetate, generates 0.95 gram (20.5%) white crystals shape product, and fusing point is 109～111 °.
Analyze C
18H
18N
4O
2: calculated value: C, 67.06; H, 5.64; N, 17.38.Measured value: C, 66.95; H, 5.68; N, 17.17.
NMR（CDCl
3）：1.35（2，m）;1.74（2，m）;2.10（1，m）;2.85（2，m）;3.61（2，d，7.0Hz）;4.76（2，m）;6.40（1，t，4.8Hz）;7.79（4，m）;8.27（2，d，4.8Hz）。
IR（KBr）：730，800，1360，1400，1515，1540，1590，1710，1750，2930cm
-1。
Embodiment 2
1-((1-(2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone
This experiment sequence is the embodiment (referring to schema 2) of building-up process used when the compounds X of formula I is alkylidene chain.
A.1-the hydrate (II) of ((4-pyrimidyl) methyl)-2-Pyrrolidone.-1-(4-picolyl-2-Pyrrolidone hydrochloride (III; 15.05 gram, 0.0707 mole; Produce by 2-Pyrrolidone and 4-picolyl chlorination thing), the raw spirit solution of HCl(10 milliliter 8N) and the solution of raw spirit (100 milliliters) at 60 pounds/inch
2Pressure under, with platinum dioxide catalysis (PtO
2; 1.0 gram) hydrogenation is 72 hours.Mixture filters; The filtrate vacuum concentration obtains white solid.Crude product is recrystallization in Virahol, obtains the white powder product of 13.03 grams (83%), and fusing point is 212～214 °.
B. the reaction of intermediate compound II and 2-chlorinated pyrimidines-piperidine methyl pyrrolidone (II; 5.08 gram, 0.0232 mole), 2-Chloropyrimide (2.67 grams, 0.0233 mole) and salt of wormwood (7.09 grams, 0.0513 mole) place 50～100 ° oil bath to heat 14 hours in the mixed solution of dimethyl formamide (60 milliliters).The mixture cooled and filtered.Vacuum is removed solvent then, and residuum is that elutriant separates with chromatography with ethyl acetate-acetone mixture on silica gel, obtains the white crystals product of 4.7 grams (78%), and fusing point is 144～147 °.
Analyze C
14H
20N
4O: calculated value: C, 64.59; H, 7.74; N, 21.52, measured value: C, 64.26; H, 7.78; N, 21.20.
NMR（CDCl
3）：1.29（2，m）;1.71（2，m）;2.01（3，m）;2.34（2，t，7.4Hz）;2.84（2.m）;3.16（2，d，7.0Hz）;3.39（2，t，6.8Hz）;4.73（2，m）;6.40（1，t，4.7Hz）;8.26（2，d，4.7Hz）
IR（KBr）：800，1360，1440，1515，1540，1585，1675，2930cm
-1）。
Embodiment 3
1-((1-(2-chloro-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone
1-((4-piperidyl) methyl)-2-Pyrrolidone hydrochloride (II; Press embodiment 2 preparations; 20.1 gram, 0.0922 mole), 2,4-dichloro-pyrimidine (14.90 grams, 0.1 mole) salt of wormwood (26.5 grams, 0.25 mole), the mixed solution that reaches 200 milliliters of dimethyl formamides at room temperature stirred 14 hours, then in 70 ° of heating 1 hour.Mixed solution filters final vacuum and concentrates, and thick residuum is that elutriant separates with chromatography with ethyl acetate/methanol (95: 5) on silicon-dioxide, thereby makes the product separated into two parts.The major portion that obtains is the linen powder of 16 grams (59%), and fusing point is 110～114 °, is desired 2-chloro-4-pyrimidyl isomer.Analyze: C
14H
19ClN
4O, calculated value: C, 57.04; H, 6.50;
N, 19.01; Measured value: C, 56.73; H, 6.44; N, 18.97.
NMR（CDCl
3）：1.30（2，m）;1.78（2，m）;2.03（3，m）;2.39（2，t，7.4Hz）;2.92（2，m）;3.17（2，d，7.0Hz）;3.40（2，t 6.8Hz）;4.35（2，m）;6.39（1，d，6.0Hz）;7.98（1，d，6.0Hz）
IR（KBr）：965，1150，1350，1360，1490，1590，1685，2860，2950cm
-1
Embodiment 4
1-((1-(4-chloro-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone
Another isomer, 4-chloro-2-pyrimidyl compounds, be by reaction product in the foregoing description 3 through chromatography separate and in ethyl acetate recrystallization and obtaining in the less component that obtains, obtain the white crystals of 1.1 grams (4%), fusing point is 143.5～145.5 °.
Analyze: C
14H
19ClN
4O, calculated value: C, 56.04; H, 6.50; N, 19.01.Measured value: C, 56.66; H, 6.49; N19.81.
NMR（CDCl
3）：0.9-2.1（5，m）;2.25（2，t，5Hz）;2.75（2，t，8Hz）;3.10（2，d，5Hz）;3.30（2，t，5Hz）;4.5-4.8（2，d）;6.45（1，d，4Hz）;8.13（1，d，4Hz）。
IR（KBr）：1275，1350，1419，1512，1525，1588，1688cm
-1。
Embodiment 5
1-((1-(6-chloro-2-pyrazine)-4-piperidyl) methyl)-2-Pyrrolidone
With method, with 1-((4-piperidyl) methyl)-2-Pyrrolidone hydrogen salt hydrochlorate (II as describing in front embodiment 2 and 3; 12.5 gram, 0.0556 mole); 2,6-dichloro-pyrazine (8.37 gram, 0.0556 mole), salt of wormwood (19.2 grams, 0.139 mole) and DMF(150 milliliter) mixture after stirring 14 hours under the room temperature in 70 ° of heating 1 hour.Mixture filters, the filtrate vacuum concentration.Crude product through twice recrystallization, obtains the brown crystallization of 11.16 grams (68%) in ethyl acetate, fusing point is 139～142 °.
Analyze: C
14H
19ClN
4O, calculated value: C, 57.04; H, 6.50; N, 19.01.Measured value: C, 57.02; H, 6.40; N, 19.03.
NMR（CDCl
3）：1.34（2，m），1.77（2，m）;2.05（3，m）;2.40（2，t，7.2Hz）;2.91（2，m）;3.18（2，d，7.0Hz）;3.40（2，t，6.8Hz）;4.30（2，m）;7.74（1，s）;7.96（1，s）。
IR（KBr）：835，1140，1275，1415，1460，1490，1500，1565，1685，2840，2945cm
-1。
Embodiment 6
1-((1-(2-(trifluoromethyl)-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone
The method of describing among the application of aforementioned embodiment 2 and 3, with 1-((4-piperidyl) methyl)-2-Pyrrolidone hydrochloride (II, 21.85 grams, 0.1 mole) and yellow soda ash (26.5 restrain 0.25 mole) in the mixed-liquor return of methyl alcohol (150 milliliters) 1 hour.Vacuum is removed methyl alcohol then, adds acetonitrile (150 milliliters) in the residuum.The mixed solution cooling is also stirred adding 4-chloro-2-(trifluoromethyl down)-mixed solution at room temperature stirs 18 hours after-filtration to pyrimidine (18.28 grams, 0.1 mole), is dense residuum behind the filtrate vacuum concentration, makes curing through hexane (100 milliliters) washing.The light brown powder that obtains (23.8 grams, 73%) is separated the white crystals that (5% methanol/ethyl acetate is on silicon-dioxide) obtains 19.8 grams, 118.5～120.5 ° of fusing points through chromatography.
Analyze: C
15H
19F
3N
4O, calculated value: C, 54.87; H, 5.83; N, 17.07, measured value: C, 54.50; H, 5.86; N, 16.80.
Use similar mode, prepared formula I other compound and be listed in the table 1
Table 1
Has compound of formula I
Piperidine ring
Embodiment R
1X Y coupling position Z molecular formula * fusing point (degree)
5 7 H -C
2H
4- CH
23-
C
14H
20N
4O 105.5-
107.5
8 H -C
2H
4- CH
22-
C
14H
20N
4O 110-113
9 H -C
2H
4- CH
24-
C
14H
19ClN
4O 138-
139.5
10 10 H -C
2H
4- CH
24-
C
15H
21FN
4OS 96-100
11 H -C
2H
4- CH
24-
C
14H
19FN
4O 134-136
12 H -C
2H
4- CH
24-
C
14H
18Cl
2N
4O 140-144
13 H -C
2H
4- CH
24-
C
14H
18Cl
2N
4O 111-
114.5
15 14 H -C
2H
4- CH
24-
C
14H
19ClN
4O 141-
142.5
Table I-continuous
Piperidine ring
Embodiment R
1X Y coupling position Z molecular formula * fusing point (degree)
15 H -C
2H
4- CH
24-
C
15H
21ClN
4O 133-135
5 16 H -C
2H
4- CH
24-
C
15H
21ClN
4O 104-107
17 H -C
2H
4- CH
24-
C
14H
19BrN
4O 143-146
18 H -C
2H
4- CH
24-
C
14H
19ClN
4O 130-133
19 H -C
2H
4- CH
24-
C
14H
19IN
4O 129.5-
131.5
10 20 H -C
2H
4- CH
24-
C
15H
21ClN
4OS 134-137
21 H -C
2H
4- CH
24-
C
14H
18Cl
2N
4O 135-138
22 H -C
2H
4- CH
24-
C
14H
18BrClN
4O 105-115
23 H -C
2H
4- CH
24-
C
15H
22N
4O
2116-121
24 H -C
2H
4- CH
24-
C
15H
19N
5O 139.5-
15 0.2H
3O 142
Table I-continuous
Piperidine ring
Embodiment R
1X Y coupling position Z molecular formula * fusing point (degree)
25 H 1，2-C
6H
4CH
24-
C
18H
20N
4O 176-178
26 H -C
2H
4- CH
24-
C
16H
19F
5N
4O 105-107.5
27 H -C
2H
4- CH
24-
C
15H
18ClF
3N
4O 102-
104.5
28 H -C
2H
4- CH
24-
C
16H
18F
6N
4O 132.5-
0.075H
2O 134
* C, the analysis of H and N all calculated value+0.4% in.
Embodiment 29
Measure the reverse of the loss of memory that compound causes ECS with the diving tower passive avoidance response.
In diving tower passive avoidance experimental arrangement, the rat training is become avoidance foot electric shock and keeps motionless.Two control groups (every group of n=36/) that need, one group is the ECS control group, another group is false ECS control group.The rat of ECS control group individually is placed on the platform on the electric shock grid (0.8 milliampere) that places energising, puts 30 minutes after the energising of electric shock grid.These rats are easy to be jumped off by platform, and foot shocks by electricity and very fast association avoids on the platform but experienced immediately.If rat rests on last 2 minute of platform and do not jump off after being subjected to foot's electric shock, think that then rat has obtained passive avoidance response.The rat that has obtained passive avoidance response ECS control group afterwards gives ECS by saturating Corneal electrode (transcomeal.electrodes) at once, and intensity is 400 milliseconds of 50 nanoamperes.The rat of false ECS control group is also handled according to the mode identical with above-mentioned ECS control group, and just electric current is not very by saturating Corneal electrode.After 24 hours, two control groups all impose memory and keep test.Rat is placed on the platform by one, and writes down it by by the residence time on platform before the grid that jumps to not energising on the platform; Do not jumped off if try rat to rest on last 300 second of platform, think that then it has kept passive avoidance response.The rat of false ECS control group rests on the platform at experimental session, demonstrates normal memory; The rat of ECS control group jumps off on then being easy to by platform within 300 seconds, shows the infringement (being the loss of memory) of memory.
The residence time divides and to be converted into percentage memory score on the platform, is that 100% memory keeps with 300 seconds.The percentage memory score of all each administration groups is all relatively estimated with Du Naite test method and ECS control group and false ECS control group.In experiment, if the average memory score of at least one dosage group of certain compound significantly greater than the score of ECS control group and with the score of false ECS control group do not have significantly different, then think this compound be have active.This expression test-compound has reversed the loss of memory of the passive avoidance response that causes because of ECS.If tried treated animal improve on the proportion by subtraction ECS control group score statistics, but the degree that improves again with the score of false ECS control group indifference statistically, then this compound is decided to be " medium activity ".These compounds have improved the memory of animal statistically really, but are not enough to prevent fully the loss of memory.
Press embodiment 29 described experiments,, list in table 2 evaluated biological activity that the compound of the formula I selected for use carries out.
Table 2
The biological activity of the reverse of the loss of memory that selected formula I compound causes ECS in the diving tower passive avoidance response experiment.
The reverse of the loss of memory that embodiment compound title causes ECS
-Pramiracetam has 10 milligrams of/kilogram subcutaneous administrations of active *
(reference compound)
1.2-((1-(2-pyrimidyl)-4-piperidyl) has active 10 milligrams of/kilogram subcutaneous administrations
Methyl)-and 1H-isoindole-1,3-
(2H)-ketone
2.1-((1-(2-pyrimidyl)-4-piperidyl) has active 10 milligrams of/kilogram subcutaneous administrations
Methyl)-2-Pyrrolidone and oral
3.1-((1-(2-chloro-4-pyrimidyl)-4-has active 0.5 milligram of/kilogram subcutaneous administration
Piperidyl) methyl)-2-Pyrrolidone and oral
5.1-((1-(6-chloro-2-pyrazine)-4-has active 0.5 milligram of/kilogram subcutaneous administration
Piperidyl) methyl)-2-Pyrrolidone
6.1-((1-(2-(trifluoromethyl)-4-has that active the 0.25-10 milligram/kilogram is oral
Piperidyl) methyl)-2-Pyrrolidone has active 0.5-10 milligram/kilogram subcutaneous administration
7.1-((1-(2-pyrimidyl)-3-piperidyl) has active 25 milligrams of/kilogram subcutaneous administrations
Methyl)-2-Pyrrolidone
8.1-((1-(2-pyrimidyl)-2-piperidyl) has active 25 milligrams of/kilogram subcutaneous administrations
Methyl)-2-Pyrrolidone
9.1-((1-(6-chloro-3-pyridazinyl)-4-has active 25 milligrams of/kilogram subcutaneous administrations
Piperidyl) methyl)-2-Pyrrolidone
10.1-((1-(5-fluoro-4-(methylthio group)-2-medium activity 10 and 25 milligrams of/kilogram subcutaneous administrations
-pyrimidyl)-and the 4-piperidyl) methyl)
-2-Pyrrolidone
11.1-((1-(5-fluoro-2-pyrimidyl)-4 has active 10 milligrams of/kilogram subcutaneous administrations
-pyrimidyl) methyl)-2-Pyrrolidone
The reverse of the loss of memory that embodiment compound title causes ECS
12.1-((1-(2,6-two chloro-4-have active 1.0 milligrams of/kilogram subcutaneous administrations
Pyrimidyl)-and the 4-piperidyl) methyl)
-2-Pyrrolidone
13.1-((1-(4,10 milligrams of/kilogram subcutaneous administrations of 6-two chloro-2-medium activity
Pyrimidyl)-and the 4-piperidyl) methyl)-2-
Pyrrolidone
14.1-((1-(6-chloro-4-pyrimidyl) 10 milligrams of/kilogram subcutaneous administrations of medium activity
-4-piperidyl) methyl)-2-pyrroles
Alkane ketone
15.1-((1-(2-chloro-6-methyl-10 milligrams of/kilogram subcutaneous administrations of 4-medium activity
Pyrimidyl)-and the 4-piperidyl) methyl)-2-
Pyrrolidone
17.1-((1-(5-bromo-2-pyrimidyl) has 10 and 25 milligrams/kilogram of activity oral
-4-piperidyl) methyl)-2-pyrroles
Alkane ketone
18.1-((1-(5-chloro-2-pyrimidyl)-4 has 10 milligrams/kilogram of activity oral
-piperidyl) methyl)-2-Pyrrolidone
19.1-((1-(5-iodo-2-pyrimidyl)-4 has 25 milligrams/kilogram of activity oral
-piperidyl) methyl)-2-Pyrrolidone
22.1-((1-(5-bromo-2-chloro-4-has that active the 0.5-1.0 milligram/kilogram is oral
Pyrimidyl)-and the 4-piperidyl) methyl)-2-
Pyrrolidone
The reverse of the loss of memory that embodiment compound title causes ECS
23.1-((1-(2-methoxyl group-10 milligrams/kilogram of 4-pyrimidine medium activity are oral
Base)-and the 4-piperidyl) methyl)-2-
Pyrrolidone
24.4-(((2-oxo-pyrrolidine-1-has 25 milligrams/kilogram of activity oral to 4-
Base) methyl)-piperidino)-2-
The pyrimidine nitrile
26.1-((10 milligrams/kilogram of 1-(2-(pentafluoroethyl group)-4-medium activity
Pyrimidyl)-and the 4-piperidyl) methyl)
-2-Pyrrolidone
27.1-((10 milligrams/kilogram of medium activity of 1-(5-chloro-2-(trifluoromethyl) are oral
-4-pyrimidyl)-and the 4-piperidyl) first
Base)-2-Pyrrolidone
28.1-(((2,6-is two, and (trifluoromethyl has that active the 1-milligram/kilogram is oral to 1-
-4-pyrimidyl)-the 4-piperidyl)
Methyl)-2-Pyrrolidone
* " activity is arranged " and be meant that those have reversed the compound of the loss of memory that is caused by ECS fully, and " medium activity " then is meant to be not enough to prevent fully the loss of memory.
Claims (35)
1, the medicinal acid salt that is suitable for that has the compound of formula I and they.
In the formula: X is ethylene chain or 1,2-benzo ring;
Y be carbonyl or-CH
2-, but just thinking that X is 1, Y is a carbonyl during 2-benzo ring;
R
1Be selected from hydrogen or C
1-4Alkyl;
Z is R
2-, R
3-dibasic diaza phenyl ring is by selecting in pyridazine, pyrimidine and the pyrazine ring system; And R
2And R
3Be selected from hydrogen independently of one another, low-carbon (LC) (C
1-4) alkyl, low-carbon alkoxy, lower alkanes sulfenyl, cyano group, trifluoromethyl, pentafluoroethyl group and fontanel element;
2, the compound of claim 1, X is an ethylene in the formula, R
1Be hydrogen.
3, the compound of claim 1, R in the formula
2And R
3Be selected from hydrogen independently of one another, fontanel element, and trifluoromethyl.
4, the compound of claim 2, R in the formula
2And R
3Be selected from hydrogen independently of one another, fontanel element, and trifluoromethyl.
5, the compound of claim 1,2-((1-(2-pyrimidyl)-4-piperidyl) methyl)-1H-isoindole-1,3-(2H)-diketone.
6, the compound of claim 1,1-((1-(2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
7, the compound of claim 1,1-((1-(2-chloro-4-pyrimidine)-4-piperidyl) methyl)-2-Pyrrolidone.
8, the compound of claim 1,1-((1-(4-chloro-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
9, the compound of claim 1,1-((1-(6-chloro-2-pyrazinyl)-4-piperidyl) methyl)-2-Pyrrolidone.
10, the compound of claim 1,1-((1-(2-(trifluoromethyl)-4-pyrimidyl) methyl)-2-Pyrrolidone.
11, the compound of claim 1,1-((1-(2-pyrimidyl)-3-piperidyl) methyl)-2-Pyrrolidone.
12, the compound of claim 1,1-((1-(2-pyrimidyl)-2-piperidyl) methyl)-2-Pyrrolidone.
13, the compound of claim 1,1-((1-(6-chloro-3-pyridazinyl)-4-piperidyl) methyl)-2-Pyrrolidone.
14, the compound of claim 1,1-((1-(5-chloro-4-(methylthio group)-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
15, the compound of claim 1,1-((1-(5-fluoro-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
16, the compound of claim 1,1-((1-(2,6-two chloro-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
17, the compound of claim 1,1-((1-(4,6-two chloro-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
18, the compound of claim 1,1-((1-(6-chloro-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
19, the compound of claim 1,1-((1-(2-chloro-6-methyl-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
20, the compound of claim 1,1-((1-(4-chloro-6-methyl-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
21, the compound of claim 1,1-((1-(5-bromo-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
22, the compound of claim 1,1-((1-(5-chloro-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
23, the compound of claim 1,1-((1-(5-iodo-2-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
24, the compound of claim 1,1-((1-(6-chloro-2-(methylthio group)-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
25, the compound of claim 1,1-((1-(5,6-two chloro-4-pyridazinyls)-4-piperidyl) methyl)-2-Pyrrolidone.
26, the compound of claim 1,1-((1-(5-bromo-2-chloro-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
27, the compound of claim 1,1-((1-(2-methoxyl group-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
28, the compound of claim 1,4-(4-((2-oxo-pyrrolidine-1-yl) methyl)-piperidino)-2-pyrimidine nitrile.
29, the compound of claim 1,1-((1-(2-(pentafluoroethyl group)-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
30, the compound of claim 1,1-((1-(5-chloro-2-(trifluoromethyl)-4-pyrimidyl)-4-piperidyl) methyl)-2-Pyrrolidone.
31, the compound of claim 1,1-((1-(2, two (the trifluoromethyl)-4-pyrimidyl of 6-)-4-piperidyl) methyl)-2-Pyrrolidone.
32, the compound of claim 1,1-((1-(6-chloro-3-pyridazinyl)-4-piperidyl) methyl)-2-Pyrrolidone.
When 33, the Mammals whole body is given the effective dose of compound of claim 1, improve the method for mammiferous insight and memory;
34, the method for preparation
In the formula, X be the ethylene chain or, 1,2-benzo ring; Y is carbonyl or methylene radical; R
1Be hydrogen or low-carbon alkyl; Z is R
2, R
3-dibasic diaza phenyl ring is by selecting in the group that comprises pyridazine, pyrimidine and pyrazine; R
2And R
3Independently of one another by comprising hydrogen, low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) sulphur alkyl, cyanogen is selected in the group of trifluoromethyl and fontanel element; This method comprises following selective method:
(A) make a kind of compound of following formula:
R is C in the formula
1To C
6Alkyl is with a kind of compound reaction of following formula
Z definition as above-mentioned and Q is a suitable substituents group in the formula
(B) make a kind of metal reagent reaction of the product and the following formula of (A)
R is described as defined above and M is metallicity ion or complex compound in the formula;
(C) make product and a kind of reagent react that hydroxyl in the product of (B) can be changed into substituting group Q of (B);
(D) make the product of (C) and a kind of cyclic amide/imide reaction of following formula:
(X and Y definition as above-mentioned in the formula) generates the compound with formula I; Or generate a kind of compound with formula I and wherein X be methylene radical, Y, R
1, R
2, R
3Described as defined above with Z;
(A ') makes a kind of cyclic amide/imide of following formula
A kind of compound reaction with following formula
R in the formula
1Described as defined above with Q;
The product of (B ') catalytic reduction (A ');
A kind of compound reaction of product that (C ') makes (B ') and following formula
Z and Q are described as defined above in the formula, generate a kind of compound with formula I.
35, the described method of claim 34, wherein Q is a substituted radical, by comprising muriate, bromide, iodide, sulfuric ester, phosphoric acid ester is selected in the group of tosylate and methanesulfonates.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75300685A | 1985-07-08 | 1985-07-08 | |
| US753,006 | 1985-07-08 | ||
| US86846886A | 1986-05-30 | 1986-05-30 | |
| US868,468 | 1986-05-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86104681A true CN86104681A (en) | 1987-05-27 |
| CN1012364B CN1012364B (en) | 1991-04-17 |
Family
ID=27115677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86104681A Expired CN1012364B (en) | 1985-07-08 | 1986-07-08 | Preparation for dinitrogen heterobenzopiperidine derivatives of cyclic amide and imide for curing elder mental patient |
Country Status (28)
| Country | Link |
|---|---|
| KR (1) | KR940003756B1 (en) |
| CN (1) | CN1012364B (en) |
| AT (1) | AT395850B (en) |
| AU (1) | AU595215B2 (en) |
| BE (1) | BE905061A (en) |
| CA (1) | CA1272725A (en) |
| CH (1) | CH671579A5 (en) |
| CY (1) | CY1630A (en) |
| DE (1) | DE3622842C2 (en) |
| DK (1) | DK170441B1 (en) |
| EG (1) | EG18310A (en) |
| ES (1) | ES2000476A6 (en) |
| FI (1) | FI88300C (en) |
| FR (1) | FR2584408B1 (en) |
| GB (1) | GB2177692B (en) |
| GR (1) | GR861765B (en) |
| HK (1) | HK11292A (en) |
| HU (1) | HU199455B (en) |
| IE (1) | IE59424B1 (en) |
| IL (1) | IL79351A (en) |
| IT (1) | IT1196467B (en) |
| NL (1) | NL8601763A (en) |
| NO (1) | NO167389C (en) |
| NZ (1) | NZ216720A (en) |
| PT (1) | PT82942B (en) |
| SE (1) | SE462491B (en) |
| SG (1) | SG111091G (en) |
| YU (2) | YU45017B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188039A (en) * | 2016-06-30 | 2016-12-07 | 广东工业大学 | A kind of derovatives and preparation method and application |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2634208B1 (en) * | 1988-07-12 | 1990-11-23 | Synthelabo | ((PIPERIDINYL-4) METHYL) -2 DIHYDRO-2,3 1H-ISOINDOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| EP0351283A1 (en) * | 1988-07-12 | 1990-01-17 | Synthelabo | 2-[(4-Piperidinyl)methyl]-2,3-dihydro-1H-isoindole and 2,3,4,5-tetrahydro-1H-benzazepine derivatives, their preparation and therapeutical use |
| US4963678A (en) * | 1989-10-27 | 1990-10-16 | Bristol-Myers Squibb Co. | Process for large-scale production of BMY 21502 |
| US5356906A (en) * | 1989-10-27 | 1994-10-18 | The Du Pont Merck Pharmaceutical Company | (N-phthalimidoalkyl) piperidines useful as treatments for psychosis |
| WO1991006297A1 (en) * | 1989-10-27 | 1991-05-16 | The Du Pont Merck Pharmaceutical Company | (n-phthalimidoalkyl) piperidines |
| US5098904A (en) * | 1990-06-27 | 1992-03-24 | Bristol-Myers Squibb Company | Cerebral function enhancing pyrimidinyl derivatives |
| US5240934A (en) * | 1990-10-19 | 1993-08-31 | Ss Pharmaceutical Co., Ltd. | Quinoline derivatives |
| US5190951A (en) * | 1990-10-19 | 1993-03-02 | Ss Pharmaceutical Co., Ltd. | Quinoline derivatives |
| US5401744A (en) * | 1993-10-04 | 1995-03-28 | Bristol-Myers Squibb Company | Useful hemi-hydrate form of a cerebral function enhancing agent |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE759371A (en) * | 1969-11-24 | 1971-05-24 | Bristol Myers Co | HETEROCYCLICAL AZASPIRODECANEDIONES AND METHODS FOR THEIR PREPARATION |
| ZA76475B (en) * | 1975-03-10 | 1977-08-31 | Ciba Geigy Ag | Indolyalkylpiperidines |
| EP0009465A1 (en) * | 1978-09-20 | 1980-04-02 | Ciba-Geigy Ag | N-(1-(4-amino-2-quinazolinyl)-3 or 4-piperidyl lactames, process for their preparation and pharmaceutical compositions containing them |
| US4423049A (en) * | 1981-12-28 | 1983-12-27 | Mead Johnson & Company | 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyrimidines |
| US4524206A (en) * | 1983-09-12 | 1985-06-18 | Mead Johnson & Company | 1-Heteroaryl-4-(2,5-pyrrolidinedion-1-yl)alkyl)piperazine derivatives |
-
1986
- 1986-07-01 NZ NZ216720A patent/NZ216720A/en unknown
- 1986-07-03 YU YU1186/86A patent/YU45017B/en unknown
- 1986-07-03 FR FR8609666A patent/FR2584408B1/en not_active Expired
- 1986-07-03 FI FI862830A patent/FI88300C/en not_active IP Right Cessation
- 1986-07-07 CA CA000513196A patent/CA1272725A/en not_active Expired - Lifetime
- 1986-07-07 CH CH2740/86A patent/CH671579A5/de not_active IP Right Cessation
- 1986-07-07 GB GB8616504A patent/GB2177692B/en not_active Expired
- 1986-07-07 NO NO862729A patent/NO167389C/en not_active IP Right Cessation
- 1986-07-07 HU HU862835A patent/HU199455B/en unknown
- 1986-07-07 NL NL8601763A patent/NL8601763A/en active Search and Examination
- 1986-07-07 DK DK323986A patent/DK170441B1/en not_active IP Right Cessation
- 1986-07-07 SE SE8603026A patent/SE462491B/en not_active IP Right Cessation
- 1986-07-07 GR GR861765A patent/GR861765B/en unknown
- 1986-07-07 IL IL79351A patent/IL79351A/en not_active IP Right Cessation
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- 1986-07-08 CN CN86104681A patent/CN1012364B/en not_active Expired
- 1986-07-08 PT PT82942A patent/PT82942B/en unknown
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- 1986-07-08 KR KR1019860005480A patent/KR940003756B1/en not_active IP Right Cessation
- 1986-07-08 EG EG416/86A patent/EG18310A/en active
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188039A (en) * | 2016-06-30 | 2016-12-07 | 广东工业大学 | A kind of derovatives and preparation method and application |
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