CN109232549A - It is a kind of to treat schizoid compound and its application - Google Patents

It is a kind of to treat schizoid compound and its application Download PDF

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Publication number
CN109232549A
CN109232549A CN201710559306.4A CN201710559306A CN109232549A CN 109232549 A CN109232549 A CN 109232549A CN 201710559306 A CN201710559306 A CN 201710559306A CN 109232549 A CN109232549 A CN 109232549A
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base
piperidyl
benzo
isoxazole
fluoro
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CN109232549B (en
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窦飞
陈寅
靖鹏
邱印利
于民权
张桂森
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Nhwa Pharmaceutical Corp
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Nhwa Pharmaceutical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention provides a kind of H3 acceptor compound and its application, and Compound ira vitro experiment provided by the invention shows high with H3 affinity, and prompt can improve negative symptoms and cognitive disorder；Weak to the affinity of H1 compared with Risperidone, the side effect possibility for generating weight gain is smaller.

Description

It is a kind of to treat schizoid compound and its application
Technical field:
The invention belongs to field of medicaments, and in particular to a kind of to treat schizoid compound and its application
Background technique
Psychotic disorder is to seriously endanger one of frequently-occurring disease and major disease of common disease of people's health, with social ring The deterioration in border and life stress it is growing day by day, such disease incidence is in obvious ascendant trend.Become and has seriously endangered people Health and social development a kind of important diseases.Current anti-schizophrenia drug is effective to positive symptom, but to yin Property symptom and cognitive disorder curative effect are very poor, while having more serious blood glucose rise, hyperprolactinemia and weight gain etc. no Good reaction.Therefore, novel anti-phrenoblabia drug is treated in research and development, is clinical eager demand.
By the research of decades, D is found2, 5-HT1A, 5-HT2AAnd H1It is extremely important to schizophrenia Deng five receptors Effect.With D2Receptor acting can effectively treat schizophrenia positive symptom.Forehead leaf skin of the serotonin system in adjusting It plays an important role in the function of layer, including emotion control, cognitive behavior and working memory.The cone neurone of prefrontal cortex It include 5-hydroxytryptamine receptor 5-HT with GABA intrerneuron1AAnd 5-HT2A.Prefrontal cortex of the serotonin system in adjusting Function in play an important role, including emotion control, cognitive behavior and working memory]。5-HT1AWith atypical antipsychotic agents Object treatment is related, can improve negative symptoms and cognitive disorder.5-HT2AReceptor is related to perception, mood regulation and motion control Various aspects, block 5-HT2AReceptor can make the release normalization of dopamine, and play antipsycholic action.
Histamine (Histamine) is a kind of critical biogenic amine, and in central nervous system and peripheral nervous system As important neurotransmitter.Histamine receptor is under the jurisdiction of g protein coupled receptor family (G-Protein-Coupled- Receptors, GPCRs), share 4 hypotypes: H1, H2, H3, H4.Sequence homology is not high between each hypotype of histamine receptor, For 20-38%, wherein H1 and H2 are found earliest, and H3 and the opposite discovery of H4 are later, it has recently been found that H4 receptor takes part in inflammatory tune Section and immunoregulatory process.Histamine H 3 receptor is widely distributed in central nervous system and peripheral nervous system.Research hair Existing, H3 receptor is not only receptor (presynaptic receptor) before a kind of protrusion, histaminergic mind on adjustable neuron Synthesis and release through mediator；While a kind of heteroreceptor (heteroreceptor) on H3 receptor or neuron, activation Under state H3 receptor by release histamine, the release of a variety of neuron mediators can be induced, as acetylcholine, dopaminergic, The neurotransmitters such as GABA, tryptamines energy and norepinephrine energy.Therefore, by the adjustable various neurotransmitters of H3 receptor, To carrying out the treatment of a variety of spirit/neural class disease, as antagonism H3 receptor can treat epilepsy, schizophrenia, old silly The diseases such as slow-witted disease, sleep disturbance, obesity, neuralgia and attention-deficit hyperactivity disease.
Therefore, positive disease can be treated and improve schizoid negative symptoms and cognitive disorder by finding to have, together When lose weight increased side effect noval chemical compound.
Summary of the invention:
In order to solve the above-mentioned technical problem, the relevant solution of the present invention:
On the one hand, the present invention provides a kind of compound, is the solid of compound shown in compound shown in Formulas I or Formulas I Isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug
In above-mentioned general formula,
n1It is 3 or 4,
n2It is 1 or 2；
Z is CH or N
R1, R2Or R3Separately represent hydrogen, halogen, C1-C5Alkyl, substituted C1-C5Alkyl or C1-C5 alkane Oxygroup；
W is CH, N or O；W is upper can be unsubstituted or can further to be replaced by Y；Wherein Y is hydrogen, and Formula II or formula III take Generation；
Q is O or S；
R4、R5Or R6It is separately hydrogen, halogen, C1-C5Alkyl, substituted C1-C5Alkyl or C1-C5Alcoxyl Base；
RaAnd RbIt is separately the linear or branched alkyl group containing 1~5 carbon atom optionally replaced, the substitution Substituent group be selected from alkyl, cyano, hydroxyl, halogen ,-CN ,-N (CN)2With-C (CN)3In it is one of few,
Or five~heptatomic ring containing at least one O, N or carbonyl, institute is collectively formed together with coupled Ra and Rb in N It states the alkyl containing 1~5 carbon atom that five~heptatomic ring is optionally optionally substituted, the aryl that optionally replaces, optionally replace Thiophene, the alkyl formate ester group of C1~10 replace, the substituted substituent group be selected from alkyl, cyano, hydroxyl, halogen ,-CN ,-N (CN) 2 and-C (CN) at least one of 3.
Further, the unsubstituted C1-5Alkyl is selected from methyl, ethyl, propyl, butyl, amyl or isopentyl, takes The C in generation1-5Alkyl is selected from C1-5Halogenated alkyl.
Further, the N in foregoing invention is together with coupled RaAnd RbFormula IV or Formula V compound is collectively formed,
R9For substituted or unsubstituted C1-5Alkyl；For methyl or ethyl；
M is 0,1 or 2；
X is O, one of N or CH；X is upper can be unsubstituted or can further to be replaced by R8, wherein R8For hydrogen, take Generation or unsubstituted C1-5Alkyl, hydroxyl, substitution or unsubstituted phenyl, formula III compound, Formula IV compound, wherein described Phenyl substituent group be halogen；Wherein, the substituent R 10 on Formula IV compound, R11 are halogen.
Further, the unsubstituted C1-5Alkyl is selected from methyl, ethyl, propyl, butyl, amyl or isopentyl, takes The C in generation1-5Alkyl is selected from C1-5Halogenated alkyl.
Further, the halogen is fluorine, chlorine, bromine, iodine.
Further, the C1-C5Alkoxy be methoxyl group, ethyoxyl.
Further, above-mentioned substituted phenyl is benzyl, phenethyl, phenylpropyl, aminomethyl phenyl, methoxyphenyl, first Oxy-benzyl, fluorophenyl, luorobenzyl.
Further, general formula I compound represented of the present invention or its pharmaceutically acceptable salt are selected from following It anticipates a kind of compound or its pharmaceutically acceptable salt:
(1) the fluoro- 3- of 5- (1- (3- (4- (morpholinomethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole；
(2) the fluoro- 3- of 6- (1- (3- (4- (piperidyl -1- ylmethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] is different Oxazole；
(3) the fluoro- 3- of 6- (1- (3- (4- ((4- methyl piperidine base -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) Benzo [d] isoxazole；
(4) the fluoro- 3- of 6- (1- (3- (4- (pyrrolidin-1-yl methyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] is different Oxazole；
(5) 3- (1- (3- (4- ((3,5- lupetidine base -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) - 5- fluorobenzene simultaneously [d] isoxazole；
(6) 1- (4- (3- (4- (5- fluorobenzene simultaneously [d] isoxazole purine -3- base) piperidyl -1- base) propoxyl group) benzyl) piperazine Piperidinyl -4- alcohol；
(7) N- ethyl-N- (4- (3- (4- (5- fluorobenzene simultaneously [d] isoxazole purine -3- base) piperidyl -1- base) propoxyl group) benzene Methyl) ethamine；
(8) 3- (1- (3- (4- ((2,6- thebaine generation) methyl) phenoxy group) propyl) piperidyl -4- base) -6- fluorobenzene And [d] isoxazole；
(9) the fluoro- 3- of 6- (1- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenoxy group) propyl) piperidyl -4- base) benzene And [d] isoxazole；
(10) 3- (1- (3- (4- ((4- ethyl piperazidine -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) -6- fluorobenzene And [d] isoxazole；
(11) the fluoro- 3- of 6- (1- (3- (4- ((4- phenylpiperazine -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) benzene And [d] isoxazole；
(12) 4- (4- (3- (4- (benzo [d] isothiazole -3- base) piperazine -1- base) propoxyl group) benzyl) morpholine；
(13) the fluoro- 3- of 6- (1- (4- (3- morpholino propoxyl group) benzyl) piperidyl -4- base) benzo [d] isoxazole；
(14) the fluoro- 3- of 6- (1- (4- (3- (piperidyl -1- base) propoxyl group) benzyl) piperidyl -4- base) benzo [d] is different Oxazole；
(15) the fluoro- 3- of 6- (1- (4- ((1- methyl piperidine base -4- base) oxygroup) benzyl) piperidyl -4- base) benzo [d] Isoxazole；
(16) the fluoro- 3- of 6- (1- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperidyl -4- base) benzo [d] is different Oxazole；
(17) the fluoro- 3- of 6- (1- (4- (3- morpholino propoxyl group) phenethyl) piperidyl -4- base) benzo [d] isoxazole；
(18) the fluoro- 3- of 6- (1- (4- (3- (4- methylpiperazine-1-yl) propoxyl group) phenethyl) piperidyl -4- base) benzo [d] isoxazole；
(19) the fluoro- 3- of 6- (1- (4- (3- (4- methyl piperidine base -1- base) propoxyl group) phenethyl) piperidyl -4- base) benzo [d] isoxazole；
(20) 4- (3- (4- (2- (4- (2,3- dichlorophenyl) piperazine -1- base) ethyl) phenoxy group) propyl) morpholine；
(21) 1- (2,3- dichlorophenyl) -4- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperazine；
(22) 1- (2,3- dichlorophenyl) -4- (4- (3- (4- methylpiperazine-1-yl) propoxyl group) phenethyl) piperazine；
(23) 1- (2,3- dichlorophenyl) -4- (4- (3- (4- methyl piperidine base -1- base) propoxyl group) phenethyl) piperazine；
(24) (2,4 difluorobenzene base) (1- (4- (3- morpholino propoxyl group) phenethyl) piperidyl -4- base) ketone；
(25) (2,4 difluorobenzene base) (1- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperidyl -4- base) first Ketone；
(26) the fluoro- 3- of 6- (1- (3- (4- (2- morpholinoethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] different evil Azoles；
(27) the fluoro- 3- of 6- (1- (3- (4- (2- (piperidyl -1- base) ethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole；
(28) the fluoro- 3- of 6- (1- (3- (4- (2- (4- methyl piperidine base -1- base) ethyl) phenoxy group) propyl) piperidyl -4- Base) benzo [d] isoxazole；
(29) the fluoro- 3- of 6- (1- (3- (4- (2- (4- methylpiperazine-1-yl) ethyl) phenoxy group) propyl) piperidyl -4- base) Benzo [d] isoxazole；
(30) 4- (3- (4- (2- (piperidyl -1- base) ethyl) phenoxy group) propyl) morpholine；
(31) N, N- diethyl -2- (4- (3- morpholino propoxyl group) phenyl) ethamine.
On the other hand, the present invention provides a kind of pharmaceutical composition, contains the described in any item compounds of the present invention, optionally Ground further includes pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination.
On the other hand, the purposes of compound of the present invention or the pharmaceutical composition in medicine preparation, it is described Drug is used to treat the purposes in individual by the receptor-mediated disease of H3 or illness.
Further, it is of the present invention it is described by the receptor-mediated disease of H3 or illness be epilepsy, schizophrenia, One of senile dementia, sleep disturbance, obesity, neuralgia and attention-deficit hyperactivity disease.
Detailed description of the invention:
Terms used herein " pharmaceutically acceptable salt " refer to the relative nontoxic of the compounds of this invention, inorganic acid or have Machine acid-addition salts.For example, with reference to S.M.Berge et al., " Pharmaceutical Salts, " J.Pharm.Sci.1977,66, 1-19。
The pharmaceutically acceptable salt of the compounds of this invention includes but is not limited to selected from the salt in the following group: oxalates, salt Hydrochlorate, hydrobromate, hydriodate, nitrate, sulfate, disulfate, phosphate, acid phosphate, acetate, lactic acid Salt, citrate, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoate, second Sulfonate, benzene sulfonate or tosilate.
On the other hand, the present invention relates to the acceptable optical isomers of compound of formula I.
On the other hand, the invention further relates to a kind of pharmaceutical compositions, containing any compound of the present invention, optionally Further include pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination.
On the other hand, the purposes of pharmaceutical composition of the present invention in medicine preparation, the drug for prevent or Mental disorder is treated, the optionally described mental disorder is neuralgia.Pharmaceutical composition of the present invention is also used to prepare Other central nervous system disease drugs, for example, for schizophrenia, control depression, memory disorders and with intelligence, study The drug of relevant functional disorder disease.
The effective dose of the compounds of this invention can take orally together with such as inert diluent or certain carrier.It can be wrapped in bright It is in glue capsule or tabletted.For the purpose of oral medication, the compounds of this invention can be used together with excipient and with tablet, ingot The forms such as agent, capsule, suspension, syrup use.These preparations should contain the active ingredient of the invention of at least 0.5wt% Object, but can be changed according to specific dosage form, account for Unit Weight 4% to about 70% is convenient.It is living in such composition The amount of property compound should reach dosage appropriate.The oral dosage of the preferential composition of the present invention and preparation contains 1.0- 300 milligrams of reactive compound of the present invention.
Compound and its pharmaceutically acceptable salt provided by the invention, solvate and hydrate can with pharmaceutically may be used Pharmaceutical preparation is formed with the carrier of receiving or diluent use in conjunction.Pharmaceutically acceptable carrier appropriate includes inert solid Filler or diluent and aseptic aqueous solution or organic solution.
The dosage of the compounds of this invention depends on the type and seriousness of disease or illness, additionally depends on the feature of object, Such as general health, age, gender, weight and drug tolerance.Technical staff can determine according to these or other factors Dosage appropriate.The effective dose of conventionally used medicine for central nervous system is known to technical staff.Every total daily dose is logical Between Chang Yue 0.05mg to 2000mg.
The present invention relates to pharmaceutical composition, per unit dose can provide about 0.01 active constituent for arriving 1000mg.Combination Object can be applied by any approach appropriate, such as capsules per os, the parenteral administration in the form of injection, with paste or The form local application of lotion, the rectal administration in the form of suppository, the transdermal administration in the form of the transmission system of patch.
Compound provided by the invention can be combined with solid appropriate or liquid-carrier or diluent to be formed capsule, tablet, Pill, powder, syrup, solution etc..Tablet, pill, capsule etc. include about 0.01 to about 99 weight percent it is active at Divide and adhesive such as gelatin, cornstarch, gum arabic；Excipient such as calcium monohydrogen phosphate；Disintegrating agent such as cornstarch, Potato starch or alginic acid；Lubricant such as magnesium stearate；With Sweetening agents such as sucrose, lactose.When dosage form is capsule, It also may include liquid-carrier, such as grease in addition to the raw material of the above-mentioned type.
For parenteral administration, compound provided by the invention can combine to form injectable with sterile water or organic media Solution or suspension.
The utility model has the advantages that
Compound ira vitro experiment provided by the invention shows that negative symptoms and cognition can be improved with H3 affinity height, prompt Obstacle；Weak to the affinity of H1 compared with Risperidone, the side effect possibility for generating weight gain is smaller.
Specific embodiment
The following examples are only for the purpose of description and not as limitation of the invention.
A, the embodiment of synthesis aspect
The fluoro- 3- of embodiment 1,6- (1- (4- (3- morpholino propoxyl group) benzyl) piperidyl -4- base) benzo [d] isoxazole (1)
Reaction equation 1
1) acetone 50ml, heating is added in disubstituted-4-hydroxy benzaldehyde 6.1g, 1,3- dibromopropane 15.0g, potassium carbonate 20.7g Back flow reaction 6 hours.TLC detection, end of reaction are cooled to room temperature, and q. s. methylene chloride is added in solvent evaporated, and washing divides and removes water Layer, organic layer add anhydrous magnesium sulfate dry, solvent evaporated, give light yellow oil, and column chromatographs to obtain white solid 9.4g, fusing point 186-188 DEG C, yield 78.3%.
2) first step product 4.7g, Anhydrous potassium carbonate 8.0g, the fluoro- 3- of acetonitrile 50ml, 6- (piperidyl -4- base) benzo are taken [d] isoxazole hydrochloride 5.5g, heating reflux reaction 6 hours, is cooled to room temperature, filtering, solvent evaporated, with eluent petroleum ether: Ethyl acetate 2:1 crosses column give light yellow oil 6.1g, yield 82.4%.
3) second step product 0.7g is taken, morpholine 0.35g, sodium triacetoxy borohydride 0.84g and methylene chloride is added 30ml is reacted at room temperature 12 hours, is washed with 1mol/ml sodium hydroxide solution, branch vibration layer, and organic layer adds anhydrous magnesium sulfate dry, Solvent evaporated, give light yellow oil, column chromatograph to obtain yellow solid 0.62g, fusing point: 96-98 DEG C, yield 68.6%.1H NMR (600MHz,CDCl3) δ 7.40 (dd, J=18.0,12.0Hz, 1H), 7.20 (dd, J=19.2,3.6Hz, 1H), 7.15-7.06 (m, 3H), 6.92-6.83 (m, 2H), 4.04 (t, J=17.9Hz, 2H), 3.65 (s, 2H), 3.56 (t, J=9.4Hz, 4H), 2.78 (p, J=15.8Hz, 1H), 2.57-2.34 (m, 10H), 1.90-1.64 (m, 4H), 1.42-1.55 (m, 2H) .MS (ESI) m/z 454.2([M+H]+).
The fluoro- 3- of embodiment 2,6- (1- (3- (4- (piperidyl -1- ylmethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] is different
Oxazole (2)
It changes morpholine into piperidines, prepares target compound as described in Example 1, structural formula is as numbered (2) institute in table 1 Show.1H-NMR(600MHz,CDCl3) δ 7.42 (dd, J=18.0,11.9Hz, 1H), 7.21 (dd, J=19.2,3.6Hz, 1H), 7.16-7.05 (m, 3H), 6.94-6.81 (m, 2H), 4.05 (t, J=11.6Hz, 2H), 3.66 (s, 2H), 2.77 (p, J= 19.0Hz,1H),2.60–2.30(m,10H),2.00-1.64(m,4H),1.62-1.18(m,8H).MS(ESI)m/z 452.3 ([M+H]+).
The fluoro- 3- of embodiment 3,6- (1- (3- (4- ((4- methyl piperidine base -1- base) methyl) phenoxy group) propyl) piperidyl - 4- yl) benzo [d] isoxazole (3)
It changes morpholine into 4- methyl piperidine, prepares target compound as described in Example 1, numbered in structural formula such as table 1 (3)。1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=18.0,12.1Hz, 1H), 7.21 (dd, J=19.2,3.6Hz, 1H), 7.18-7.05 (m, 3H), 6.95-6.82 (m, 2H), 4.05 (t, J=18.1Hz, 2H), 3.66 (s, 2H), 2.77 (p, J= 19.0Hz,1H),2.63-2.31(m,10H),1.94-1.58(m,6H),1.58-1.41(m,3H),1.27-1.37(m,2H), 0.86 (d, J=14.4Hz, 3H) .MS (ESI) m/z 466.3 ([M+H]+).
The fluoro- 3- of embodiment 4,6- (1- (3- (4- (pyrrolidin-1-yl methyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole (4)
It changes morpholine into pyrrolidines, prepares target compound as described in Example 1, number (4) in structural formula such as table 1.1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=18.0,12.1Hz, 1H), 7.21 (dd, J=19.2,3.6Hz, 1H), 7.17-7.03 (m, 3H), 6.96-6.75 (m, 2H), 4.05 (t, J=17.6Hz, 2H), 3.66 (s, 2H), 2.76 (p, J= 19.0Hz,1H),2.60-2.27(m,10H),1.92-1.61(m,8H),1.55-1.42(m,2H).MS(ESI)m/z 438.6 ([M+H]+).
Embodiment 5,3- (1- (3- (4- ((3,5- lupetidine base -1- base) methyl) phenoxy group) propyl) piperidyl -4- Base) -5- fluorobenzene simultaneously [d] isoxazole (5)
It changes morpholine into 3,5- lupetidine, prepares target compound as described in Example 1, in structural formula such as table 1 It numbers (5).1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=18.0,12.1Hz, 1H), 7.22 (dd, J=19.2,3.6Hz, 1H), 7.12 (m, 3H), 6.89 (m, 2H), 4.05 (t, J=18.1Hz, 2H), 3.59 (s, 2H), 2.71 (m, 3H), 2.47 (m, 6H), 2.05 (dd, J=29.7,17.8Hz, 2H), 1.78 (m, 7H), 1.51 (d, J=19.0Hz, 2H), 0.95 (d, J= 15.1Hz,6H),0.84(m,1H).MS(ESI)m/z 480.6([M+H]+).
Embodiment 6,1- (4- (3- (4- (5- fluorobenzene simultaneously [d] isoxazole purine -3- base) piperidyl -1- base) propoxyl group) benzene first Base) piperidyl -4- alcohol (6)
It changes morpholine into 4- hydroxy piperidine, prepares target compound as described in Example 1, numbered in structural formula such as table 1 (6)。1H-NMR(600MHz,CDCl3) δ 7.43 (dd, J=17.9,12.0Hz, 1H), 7.25 (dd, J=19.2,3.6Hz, 1H), 7.15-7.05 (m, 3H), 6.93-6.82 (m, 2H), 4.04 (t, J=18.2Hz, 2H), 3.70-3.54 (m, 3H), 2.76 (t, J =19.0Hz, 1H), 2.59-2.33 (m, 10H), 1.97-1.81 (m, 3H), 1.81-1.59 (m, 5H), 1.55-1.42 (m, 2H).MS(ESI)m/z 468.6([M+H]+).
Embodiment 7, N- ethyl-N- (4- (3- (4- (5- fluorobenzene simultaneously [d] isoxazole purine -3- base) piperidyl -1- base) third oxygen Base) benzyl) ethamine (7)
It changes morpholine into diethylamide, prepares target compound as described in Example 1, numbered in structural formula such as table 1 (7)。1H-NMR(600MHz,CDCl3) δ 7.37 (dd, J=15.0,9.9Hz, 1H), 7.18 (dd, J=15.9,2.9Hz, 1H), 7.15-6.95 (m, 3H), 6.92-6.71 (m, 2H), 4.03 (t, J=15.1Hz, 2H), 3.64 (s, 2H), 2.74 (dd, J= 31.5,15.8Hz, 1H), 2.59-2.25 (m, 10H), 1.96-1.62 (m, 4H), 1.54-1.42 (m, 2H), 1.01 (t, J= 12.6Hz,6H).MS(ESI)m/z 439.6([M+H]+).
Embodiment 8,3- (1- (3- (4- ((2,6- thebaine generation) methyl) phenoxy group) propyl) piperidyl -4- base) - 6- fluorobenzene simultaneously [d] isoxazole (8)
It changes morpholine into 2,6- thebaine, prepares target compound as described in Example 1, in structural formula such as table 1 It numbers (8).1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.22 (dd, J=16.0,3.0Hz, 1H), 7.16-6.99 (m, 3H), 6.98-6.73 (m, 2H), 4.05 (t, J=15.1Hz, 2H), 3.79-3.40 (m, 4H), 2.85-2.67 (m, 3H), 2.60-2.20 (m, 8H), 1.96-1.63 (m, 4H), 1.50-1.42 (m, 2H), 1.12 (d, J= 11.5Hz,6H).MS(ESI)m/z 482.3([M+H]+).
The fluoro- 3- of embodiment 9,6- (1- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenoxy group) propyl) piperidyl -4- Base) benzo [d] isoxazole (9)
It changes morpholine into 4- methyl piperazine, prepares target compound as described in Example 1, numbered in structural formula such as table 1 (9)。1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.21 (dd, J=16.0,3.0Hz, 1H), 7.17-7.03 (m, 3H), 6.96-6.72 (m, 2H), 4.05 (t, J=15.2Hz, 2H), 3.66 (s, 2H), 2.77 (p, J= 15.8Hz,1H),2.57-2.40(m,10H),2.39-2.27(m,4H),2.14(s,3H),1.95-1.64(m,4H),1.54- 1.43(m,2H).MS(ESI)m/z 467.3([M+H]+).
Embodiment 10,3- (1- (3- (4- ((4- ethyl piperazidine -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) - 6- fluorobenzene simultaneously [d] isoxazole (10)
It changes morpholine into 4- ethyl piperazidine, prepares target compound as described in Example 1, numbered in structural formula such as table 1 (10)。1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.21 (dd, J=16.0,3.0Hz, 1H), 7.17-7.03 (m, 3H), 6.93-6.76 (m, 2H), 4.05 (t, J=15.1Hz, 2H), 3.66 (s, 2H), 2.77 (p, J =15.8Hz, 1H), 2.57-2.33 (m, 12H), 2.32-2.18 (m, 4H), 1.97-1.62 (m, 4H), 1.56-1.43 (m, 2H), 1.03 (t, J=12.6Hz, 3H) .MS (ESI) m/z 481.3 ([M+H]+).
The fluoro- 3- of embodiment 11,6- (1- (3- (4- ((4- phenylpiperazine -1- base) methyl) phenoxy group) propyl) piperidyl -4- Base) benzo [d] isoxazole (11)
It changes morpholine into 4- phenylpiperazine, prepares target compound as described in Example 1, numbered in structural formula such as table 1 (11)。1H-NMR(600MHz,CDCl3) δ 7.36 (dd, J=14.9,10.0Hz, 1H), 7.22-7.12 (m, 3H), 7.12-7.03 (m, 3H), 6.94-6.81 (m, 4H), 6.81-6.62 (m, 1H), 4.02 (t, J=15.1Hz, 2H), 3.64 (s, 2H), 3.17 (t, J=10.3Hz, 4H), 2.75 (p, J=15.8Hz, 1H), 2.60 (t, J=10.3Hz, 4H), 2.56-2.26 (m, 6H), 1.96-1.61(m,4H),1.56-1.43(m,2H).MS(ESI)m/z429.3([M+H]+).
Embodiment 12,6-4- (4- (3- (4- (benzo [d] isothiazole -3- base) piperazine -1- base) propoxyl group) benzyl) Quinoline (12) changes the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole into 4- (benzo [d] isothiazole -3- base) piperazine, by real The method for applying example 1 prepares target compound, numbers (12) in structural formula such as table 1.1H-NMR(600MHz,CDCl3)δ8.40(dd,J =14.9,3.0Hz, 1H), 8.11-8.05 (m, 1H), 7.86 (dd, J=15.0,3.1Hz, 1H), 7.75-7.69 (m, 1H), 7.22-6.99 (m, 2H), 6.98-6.37 (m, 2H), 4.04 (t, J=15.1Hz, 2H), 3.87 (t, J=10.3Hz, 4H), 3.65 (s, 2H), 3.56 (t, J=9.4Hz, 4H), 3.43 (t, J=10.3Hz, 4H), 2.51-2.40 (m, 6H), 1.94-1.64 (m,2H).MS(ESI)m/z 454.2([M+H]+).
The fluoro- 3- of embodiment 13,6- (1- (4- (3- morpholino propoxyl group) benzyl) piperidyl -4- base) benzo [d] different evil Azoles (13) changes morpholine into the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole, the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] Isoxazole changes morpholine into, prepares target compound as described in Example 1, prepares target compound as described in Example 1, knot (13) are numbered in structure formula such as table 1.1H-NMR(600MHz,CDCl3) δ 7.39 (dd, J=14.9,10.0Hz, 1H), 7.19 (dd, J =15.9,2.9Hz, 1H), 7.16-7.03 (m, 3H), 6.93-6.69 (m, 2H), 4.04 (t, J=15.1Hz, 2H), 3.65 (s, 2H),3.59-3.38(m,5H),2.66-2.36(m,6H),2.36-2.25(m,4H),2.00-1.63(m,4H),1.55-1.42 (m,2H).MS(ESI)m/z 453.2([M+H]+).
The fluoro- 3- of embodiment 14,6- (1- (4- (3- (piperidyl -1- base) propoxyl group) benzyl) piperidyl -4- base) benzo [d] isoxazole (14)
Change morpholine into the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole, the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole changes morpholine into, prepares target compound as described in Example 1, numbers (14) in structural formula such as table 1.1H-NMR (600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.21 (dd, J=15.9,2.9Hz, 1H), 7.17-7.03 (m, 3H), 6.96-6.63 (m, 2H), 4.05 (t, J=14.9Hz, 2H), 3.66 (s, 2H), 3.49 (p, J=16.0Hz, 1H), 2.68-2.12(m,10H),1.97-1.61(m,4H),1.58-1.44(m,6H),1.44-1.21(m,2H).MS(ESI)m/z 452.3([M+H]+).
The fluoro- 3- of embodiment 15,6- (1- (4- ((1- methyl piperidine base -4- base) oxygroup) benzyl) piperidyl -4- base) benzene And [d] isoxazole (15)
1) the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole 13.2g, three second are added in disubstituted-4-hydroxy benzaldehyde 6.1g Triacetoxyborohydride 21.2g and methylene chloride 100ml is reacted at room temperature 12 hours, is washed with 1mol/ml sodium hydroxide solution, point Water layer is removed, organic layer adds anhydrous magnesium sulfate dry, solvent evaporated, give light yellow oil, and column chromatographs to obtain yellow solid 8.4g, melts Point: 122-123 DEG C, yield 51.5%.
2) first step product 1.2g is taken, N- methyl -4- piperidine alcohols 0.84g, triphenyl phosphorus 2.2g and 20ml tetrahydro furan is added It mutters, 1.3gDEAD is slowly added dropwise thereto under ice bath cooling condition, reacted at room temperature 8 hours after being added dropwise.Use saturated sodium-chloride Solution is washed, branch vibration layer, and organic layer adds anhydrous magnesium sulfate dry, solvent evaporated, give light yellow oil, and column chromatographs to obtain yellow oil Shape object 0.85g, yield 54.8%.1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.21 (dd, J =16.0,3.0Hz, 1H), 7.17-7.00 (m, 3H), 6.97-6.71 (m, 2H), 3.76 (p, J=14.7Hz, 1H), 3.66 (s, 2H), 3.49 (p, J=15.9Hz, 1H), 2.56-2.36 (m, 8H), 2.18 (s, 3H), 2.16-2.01 (m, 2H), 1.96-1.82 (m,2H),1.81-1.68(m,2H),1.55-1.42(m,2H).MS(ESI)m/z424.2([M+H]+).
The fluoro- 3- of embodiment 16,6- (1- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperidyl -4- base) benzo [d] isoxazole (16)
1) acetone 50ml, heating is added in disubstituted-4-hydroxy benzyl carbinol 6.9g, 1,3- dibromopropane 14.9g, potassium carbonate 20.7g Back flow reaction 6 hours.TLC detection, end of reaction are cooled to room temperature, and q. s. methylene chloride is added in solvent evaporated, and washing divides and removes water Layer, organic layer add anhydrous magnesium sulfate dry, solvent evaporated, give light yellow oil, and column chromatographs to obtain white solid 9.3g, fusing point 102-104 DEG C, yield 72.3%.
2) first step product 5.2g, Anhydrous potassium carbonate 8.0g, acetonitrile 50ml are taken, piperidines 3.4g, heating reflux reaction 6 is small When, it is cooled to room temperature, filters, solvent evaporated, with eluent petroleum ether: ethyl acetate 1:2 crosses column give light yellow oil 4.3g, receives Rate 81.8%.
3) second step product 2.6g is taken to be dissolved in 30ml methylene chloride, room temperature agitation instills down the 2.8g dissolved with 10ml to first Base benzene sulfonyl chloride drips room temperature reaction 12 hours, is washed with 1mol/ml sodium hydroxide solution, branch vibration layer, organic layer adds anhydrous Magnesium sulfate is dry, solvent evaporated, give light yellow oil, and column chromatographs to obtain yellow oil 3.8g, yield 91.5%.
4) third step product 2.1g, Anhydrous potassium carbonate 2.1g, the fluoro- 3- of acetonitrile 50ml, 6- (piperidyl -4- base) benzo are taken [d] isoxazole hydrochloride 1.3g, heating reflux reaction 6 hours, is cooled to room temperature, filtering, solvent evaporated, with eluant, eluent dichloromethane Alkane: methanol 30:1 crosses column and obtains light yellow solid 1.9g, fusing point 123-124, yield 83.2%.1H NMR(600MHz,CDCl3)δ 7.40 (dd, J=15.0,9.9Hz, 1H), 7.20 (dd, J=15.9,2.9Hz, 1H), 7.15-7.05 (m, 3H), 6.93-6.66 (m, 2H), 4.04 (t, J=14.3Hz, 2H), 2.90-2.60 (m, 5H), 2.59-2.28 (m, 10H), 1.98-1.63 (m, 4H), 1.63-1.43(m,6H),1.43-1.18(m,2H).MS(ESI)m/z 466.3([M+H]+).
The fluoro- 3- of embodiment 17,6- (1- (4- (3- morpholino propoxyl group) phenethyl) piperidyl -4- base) benzo [d] different evil Azoles (17) changes piperidines into morpholine, prepares target compound as described in Example 16, numbers (17) in structural formula such as table 1.1H- NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.22 (dd, J=16.0,3.0Hz, 1H), 7.16- 7.07 (m, 3H), 6.96-6.65 (m, 2H), 4.05 (t, J=15.2Hz, 2H), 3.55 (t, J=9.4Hz, 4H), 2.86-2.60 (m,5H),2.56-2.31(m,10H),1.96-1.63(m,4H),1.55-1.42(m,2H).MS(ESI)m/z 468.3([M+ H]+).
The fluoro- 3- of embodiment 18,6- (1- (4- (3- (4- methylpiperazine-1-yl) propoxyl group) phenethyl) piperidyl -4- base) Benzo [d] isoxazole (18)
It changes piperidines into N methyl piperazine, prepares target compound as described in Example 16, numbered in structural formula such as table 1 (18)。1H-NMR(600MHz,CDCl3) δ 7.39 (dd, J=15.0,10.0Hz, 1H), 7.20 (dd, J=16.0,3.1Hz, 1H), 7.16-7.05 (m, 3H), 6.92-6.79 (m, 2H), 4.04 (t, J=15.2Hz, 2H), 2.86-2.60 (m, 5H), 2.57-2.33(m,6H),2.28(s,8H),2.13(s,3H),1.91-1.66(m,4H),1.55-1.43(m,2H).MS(ESI) m/z 481.3([M+H]+).
The fluoro- 3- of embodiment 19,6- (1- (4- (3- (4- methyl piperidine base -1- base) propoxyl group) phenethyl) piperidyl -4- Base) benzo [d] isoxazole (19)
It changes piperidines into 4- methyl piperidine, prepares target compound as described in Example 16, numbered in structural formula such as table 1 (19)。1H-NMR(600MHz,CDCl3) δ 7.39 (dd, J=14.9,10.0Hz, 1H), 7.20 (dd, J=16.0,3.0Hz, 1H), 7.14-7.05 (m, 3H), 6.96-6.70 (m, 2H), 4.06 (t, J=15.2Hz, 2H), 2.86-2.59 (m, 5H), 2.58-2.26 (m, 10H), 1.96-1.58 (m, 6H), 1.58-1.17 (m, 5H), 0.86 (d, J=12.3Hz, 3H) .MS (ESI) m/z 480.3([M+H]+).
Embodiment 20,4- (3- (4- (2- (4- (2,3- dichlorophenyl) piperazine -1- base) ethyl) phenoxy group) propyl) morpholine (20) piperidines is changed into morpholine, the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride changes 2,3- dichlorophenyl piperazine into Piperazine hydrochloride prepares target compound as described in Example 16, numbers (20) in structural formula such as table 1.1H-NMR(600MHz, CDCl3) δ 7.25-7.05 (m, 2H), 7.02-6.86 (m, 2H), 6.86-6.71 (m, 2H), 6.52 (dd, J=14.6,3.4Hz, 1H), 4.03 (t, J=15.1Hz, 2H), 3.53 (t, J=9.4Hz, 4H), 3.42 (s, 8H), 2.81-2.59 (m, 4H), 2.47 (t, J=15.4Hz, 2H), 2.32 (t, J=9.4Hz, 4H), 478.2 ([M+H of 1.93-1.61 (m, 2H) .MS (ESI) m/z ]+).
Embodiment 21,1- (2,3- dichlorophenyl) -4- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperazine (21)
Change the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride into 2,3- dichlorophenylpiperazine hydrochloride, Target compound is prepared as described in Example 16, numbers (21) in structural formula such as table 1.1H-NMR(600MHz,CDCl3)δ 7.18-7.08 (m, 2H), 7.07-6.76 (m, 4H), 6.55 (dd, J=14.7,3.5Hz, 1H), 4.05 (t, J=15.2Hz, 2H),3.44(s,8H),2.81-2.60(m,4H),2.51-2.40(m,6H),2.02-1.69(m,2H),1.58-1.43(m, 4H),1.42-1.25(m,2H).MS(ESI)m/z 476.2([M+H]+).
Embodiment 22,1- (2,3- dichlorophenyl) -4- (4- (3- (4- methylpiperazine-1-yl) propoxyl group) phenethyl) piperazine (22) piperidines is changed into N methyl piperazine, the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride changes 2,3- dichloro into Phenylpiperazine hydrochloride prepares target compound as described in Example 16, numbers (22) in structural formula such as table 1.1H-NMR (600MHz,CDCl3) δ 7.25-7.09 (m, 2H), 7.02 (dd, J=14.9,3.4Hz, 1H), 6.98-6.78 (m, 3H), 6.55 (dd, J=14.7,3.5Hz, 1H), 4.05 (t, J=15.2Hz, 2H), 3.44 (s, 8H), 2.88-2.57 (m, 4H), 2.48 (t, J=15.3Hz, 2H), 2.29 (s, 8H), 2.14 (s, 3H), 1.94-1.68 (m, 2H) .MS (ESI) m/z 491.2 ([M+H]+).
Embodiment 23,1- (2,3- dichlorophenyl) -4- (4- (3- (4- methyl piperidine base -1- base) propoxyl group) phenethyl) piperazine Piperazine (23) changes piperidines into 4- methyl piperidine, and the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride changes 2,3- bis- into Chlorophenylpiperazine hydrochloride prepares target compound as described in Example 16, numbers (23) in structural formula such as table 1.1H-NMR (600MHz,CDCl3) δ 7.18-7.07 (m, 2H), 7.05-6.88 (m, 2H), 6.87-6.78 (m, 2H), 6.53 (dd, J= 14.7,3.3Hz, 1H), 4.04 (t, J=15.1Hz, 2H), 3.43 (s, 8H), 2.83-2.59 (m, 4H), 2.57-2.25 (m, 6H), 1.99-1.42 (m, 5H), 1.39-1.27 (m, 2H), 0.86 (d, J=12.3Hz, 2H) .MS (ESI) m/z, 490.2 ([M+ H]+).
Embodiment 24, (2,4 difluorobenzene base) (1- (4- (3- morpholino propoxyl group) phenethyl) piperidyl -4- base) ketone (24) piperidines is changed into morpholine, the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride changes (2,4- difluorophenyl) into (piperidyl -4- base) methanone hvdrochloric acid salt prepares target compound as described in Example 16, numbers (24) in structural formula such as table 1 。1H-NMR(600MHz,CDCl3)δ7.85-7.78(m,1H),7.23-7.07(m,3H),6.99-6.92(m,1H),6.91- 6.79 (m, 2H), 4.05 (t, J=15.2Hz, 2H), 3.55 (t, J=9.4Hz, 4H), 3.33 (p, J=16.1Hz, 1H), 2.81-2.60(m,4H),2.56-2.31(m,10H),2.16-2.04(m,2H),1.94-1.68(m,4H).MS(ESI)m/z 473.3([M+H]+).
Embodiment 25, (2,4 difluorobenzene base) (1- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperidyl -4- Base) ketone (25)
Change the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride into (2,4 difluorobenzene base) (piperidyl -4- Base) methanone hvdrochloric acid salt, target compound is prepared as described in Example 16, numbers (25) in structural formula such as table 1.1H-NMR (600MHz,CDCl3)δ7.85-7.78(m,1H),7.24-7.07(m,3H),7.00-6.93(m,1H),6.90-6.74(m, 2H), 4.05 (t, J=15.1Hz, 2H), 3.33 (p, J=16.1Hz, 1H), 2.84-2.61 (m, 4H), 2.58-2.32 (m, 10H),2.16-2.04(m,2H),1.94-1.71(m,4H),1.59-1.43(m,4H),1.41-1.32(m,2H).MS(ESI) m/z 471.3([M+H]+).
The fluoro- 3- of embodiment 26,6- (1- (3- (4- (2- morpholinoethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole (26)
Change piperidines into the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride, the fluoro- 3- of 6- (piperidyl -4- Base) benzo [d] isoxazole hydrochloride changes morpholine into, and target compound is prepared as described in Example 16, is compiled in structural formula such as table 1 Number (26).1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.21 (dd, J=15.9,2.9Hz, 1H), 7.17-7.03 (m, 3H), 6.96-6.74 (m, 2H), 4.05 (t, J=15.1Hz, 2H), 3.56 (t, J=9.4Hz, 4H), 2.85-2.61(m,5H),2.61-2.27(m,10H),1.94-1.60(m,4H),1.55-1.42(m,2H).MS(ESI)m/z 468.3([M+H]+).
The fluoro- 3- of embodiment 27,6- (1- (3- (4- (2- (piperidyl -1- base) ethyl) phenoxy group) propyl) piperidyl -4- Base) benzo [d] isoxazole (27)
Change piperidines into the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride, the fluoro- 3- of 6- (piperidyl -4- Base) benzo [d] isoxazole hydrochloride changes piperidines into, and target compound is prepared as described in Example 16, is compiled in structural formula such as table 1 Number (27).1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.21 (dd, J=16.0,3.0Hz, 1H), 7.17-7.02 (m, 3H), 6.93-6.59 (m, 2H), 4.05 (t, J=15.1Hz, 2H), 2.90-2.60 (m, 5H), 2.61-2.27(m,10H),1.96-1.61(m,4H),1.62-1.08(m,8H).MS(ESI)m/z 466.3([M+H]+).
The fluoro- 3- of embodiment 28,6- (1- (3- (4- (2- (4- methyl piperidine base -1- base) ethyl) phenoxy group) propyl) piperidines Base -4- base) benzo [d] isoxazole (28)
Change piperidines into the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride, the fluoro- 3- of 6- (piperidyl -4- Base) benzo [d] isoxazole hydrochloride changes 4- methyl piperidine into, target compound is prepared as described in Example 16, and structural formula is such as (28) are numbered in table 1.1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.1Hz, 1H), 7.21 (dd, J=16.0, 3.0Hz, 1H), 7.15-7.06 (m, 3H), 6.95-6.78 (m, 2H), 4.05 (t, J=15.0Hz, 2H), 3.48 (p, J= 16.0Hz,1H),2.85-2.60(m,4H),2.60-2.24(m,10H),1.91-1.59(m,6H),1.58-1.20(m,5H), 0.86 (d, J=12.1Hz, 3H) .MS (ESI) m/z480.3 ([M+H]+).
The fluoro- 3- of embodiment 29,6- (1- (3- (4- (2- (4- methylpiperazine-1-yl) ethyl) phenoxy group) propyl) piperidyl- 4- yl) benzo [d] isoxazole (29)
Change piperidines into the fluoro- 3- of 6- (piperidyl -4- base) benzo [d] isoxazole hydrochloride, the fluoro- 3- of 6- (piperidyl -4- Base) benzo [d] isoxazole hydrochloride changes N methyl piperazine into, target compound is prepared as described in Example 16, and structural formula is such as (29) are numbered in table 1.1H-NMR(600MHz,CDCl3) δ 7.41 (dd, J=15.0,10.0Hz, 1H), 7.21 (dd, J=16.0, 3.0Hz, 1H), 7.17-7.03 (m, 3H), 6.96-6.61 (m, 2H), 4.05 (t, J=14.9Hz, 2H), 3.47 (dd, J= 32.0,16.0Hz,1H),2.79-2.61(m,4H),2.58-2.33(m,6H),2.29(s,8H),2.14(s,3H),1.92- 1.65(m,4H),1.55-1.42(m,2H).MS(ESI)m/z481.3([M+H]+).
The compound number and its structural formula of 1 Examples 1 to 31 of table preparation
B, the embodiment in terms of pharmacology
Embodiment 32
5-HT1AThe preparation of film
Rat broken end, operates on ice, takes cortex rapidly, and 3ml buffer is added, and (the Tris-HCl buffer of 0.05M, contains 0.1% ascorbic acid, 10um pargyline and 4mM CaCl2) be homogenized in 4 grades of 3-4s, it is homogenized 4 times, 5ml buffer is then added (the Tris-HCl buffer of 0.05M, containing 0.1% ascorbic acid, 10um pargyline and 4mM CaCl2), hatch in 37 DEG C 10min, test tube balance adjustment weight abandons supernatant in 12000r, 4 DEG C of centrifugation 20min after having hatched, and 3ml buffering is added Liquid is mixed with vortex mixer, adds 5ml buffer, and centrifugation is centrifuged in triplicate, and centrifugation finishes, and is abandoned supernatant, will be sunk It forms sediment and is stored for future use in -80 DEG C.
Receptor Binding Assay material:
Isotope aglucon3H-8-OH-DPAT (67.0Ci/mmol) is purchased from PerkinElmer company；5-HT is purchased from RBI Company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP are purchased from Shanghai Reagent One Plant； Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental method:
(1) first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes is mixed into In the container of 100ml, the suspension that suitable buffer is in 50ml film is added, it is spare.
(2) each reaction tube is separately added into 100 μ L of film preparation object, 100 μ L of buffer.
(3) 100 μ L buffers are added in total binding pipe (TB), and 5-HT100 μ L (final concentration is added in non-specific binding pipe (NB) 10-5M), 100 μ L test-compound (final concentrations 10 are added in each test-compound specific binding pipe (SB)-5M)；
(4) each reaction tube is separately added into radioligand310 μ L of H-8-OH-DPAT (each reaction tube is all provided with 2 parallel pipes, Each pipe is placed on ice when sample-adding).
(5) 37 DEG C of temperature of each reaction tube are incubated into 10min, end of reaction, in conjunction with aglucon by decompression, quickly filtering, use are ice-cold Test buffer sufficiently wash, by filter disc taking-up be put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；
(6) scintillation vial liquid scintillation counter is put into count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2
Embodiment 33
5-HT2AThe preparation of film
Rat broken end, operates on ice, takes cortex rapidly, and 3ml buffer is added and (the Tris-HCl buffer of 0.05M: takes 6.05gTris is dissolved in 1000ml distilled water, is 7.5) to be homogenized in 4 grades of 3-4s with dense HCl tune PH, is homogenized 4 times, is then added 5ml buffer, in 37 DEG C of hatching 10min, test tube balance adjustment weight is abandoned in 12000r, 4 DEG C of centrifugation 20min after having hatched Supernatant is added 3ml buffer, is mixed with vortex mixer, add 5ml buffer, is centrifuged, (being centrifuged in triplicate), from The heart finishes, and abandons supernatant, will be deposited in -80 DEG C and store for future use.
Receptor Binding Assay material:
Isotope aglucon [3H]-Ketanserin (67.0Ci/mmol), it is purchased from PerkinElmer company； Methysergide is purchased from RBI company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP is purchased from Shanghai Reagent One Plant；Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental method:
(1) first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes is mixed into In the container of 100ml, the suspension that suitable buffer is in 50ml film is added, it is spare.
(2) each reaction tube is separately added into 100 μ L of film preparation object, 100 μ L of buffer.
(3) 100 μ L buffers are added in total binding pipe (TB), and Methysergide 100 is added in non-specific binding pipe (NB) μ L (final concentration 10-5M), 100 μ L test-compound (final concentrations 10 are added in each test-compound specific binding pipe (SB)-5M)；
(4) each reaction tube is separately added into radioligand3(each reaction tube is all provided with 2 in parallel to 10 μ L of H-Ketanserin Pipe, when sample-adding, each pipe was placed on ice).
(5) 37 DEG C of temperature of each reaction tube are incubated into 15min, end of reaction, in conjunction with aglucon by decompression, quickly filtering, use are ice-cold Test buffer sufficiently wash, by filter disc taking-up be put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；
(6) scintillation vial liquid scintillation counter is put into count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2
Embodiment 34
D2The preparation of film
Rat broken end, operates on ice, takes brain striatum rapidly, be added 3ml buffer (the Tris-HCl buffer of 0.05M, 120mM containing NaCl, KCl 5mM, MgCl2 1mM, CaCl2 1mM), it is homogenized in 4 grades of 3-4s, is homogenized 4 times, it is slow that 5ml is then added The test tube being homogenized balance is adjusted weight, in 12000r, 4 DEG C of centrifugation 20min, abandons supernatant, 3ml buffering is added by fliud flushing Liquid is mixed with vortex mixer, adds 5ml buffer, and centrifugation is centrifuged in triplicate, and centrifugation finishes, and is abandoned supernatant, will be sunk It forms sediment and is stored for future use in -80 DEG C.
Receptor Binding Assay material:
Isotope aglucon3H-Spiperone (67.0Ci/mmol) is purchased from PerkinElmer company；Butaclamol, purchase From RBI company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP are purchased from Shanghai reagent One factory；Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental method:
(1) first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes is mixed into In the container of 100ml, the suspension that suitable buffer is in 50ml film is added, it is spare.
(2) each reaction tube is separately added into 100 μ L of film preparation object, 100 μ L of buffer.
(3) 100 μ L buffers are added in total binding pipe (TB), and 100 μ LButaclamol are added in non-specific binding pipe (NB) (final concentration 10-5M), 100 μ L test-compound (final concentrations 10 are added in each test-compound specific binding pipe (SB)-5M)；
(4) each reaction tube is separately added into radioligand310 μ L of H-Spiperone (each reaction tube is all provided with 2 parallel pipes, Each pipe is placed on ice when sample-adding).
(5) 37 DEG C of temperature of each reaction tube are incubated into 20min, end of reaction, in conjunction with aglucon by decompression, quickly filtering, use are ice-cold Test buffer sufficiently wash, by filter disc taking-up be put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；
(6) scintillation vial liquid scintillation counter is put into count
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2.
Embodiment 35
Histamine H1The preparation of receptor membrane
Cavy broken end, operates on ice, takes guinea pig cerebellum rapidly, be added 3mL buffer (1.36 grams of potassium dihydrogen phosphate, The sodium hydroxide 79mL of 0.1mol/L, is diluted to 200mL with distilled water), it is mixed with vortex mixer, in 48000g, 4 DEG C of centrifugations 10min abandons supernatant, takes precipitating, adds buffer washing, is centrifuged in triplicate, and centrifugation finishes, and abandons supernatant, will precipitate It is stored for future use in -80 DEG C.
Receptor Binding Assay material:
Isotope aglucon3H-pyrilamine (67.0Ci/mmol) is purchased from PerkinElmer company； Promethazine is purchased from RBI company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP is purchased from Shanghai Reagent One Plant；Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental method:
Step 1: first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes are mixed into In the container of 100ml, the suspension that suitable homogenate is in 50ml film is added, it is spare.
Step 2: each reaction tube is separately added into 100 μ L of film preparation object.
Step 3: 100 μ L buffers are added in total binding pipe (TB), 100 μ L are added in non-specific binding pipe (NB) Promethazine (final concentration 10-5M), it is (dense eventually that 100 μ L test-compounds are added in each test-compound specific binding pipe (SB) Degree 10-5M)；
Step 4: each reaction tube is separately added into radioligand3(each reaction tube is all provided with 2 and puts down 10 μ L of H-pyrilamine Row pipe, when sample-adding, each pipe was placed on ice).
Step 5: 30 DEG C of temperature of each reaction tube are incubated 60min, end of reaction, in conjunction with aglucon by decompression quickly filtering, use Ice-cold test buffer sufficiently washs, and filter disc taking-up is put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；
It is counted step 6: scintillation vial is put into liquid scintillation counter
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2.
Ki of 2 compound of table to each receptor
Above-mentioned Vitro Experimental Results show 9,10,26 and 27 couples of four kinds of receptor (D of compound2,5-HT1A,5-HT2AAnd H3) have Stronger affinity；High with H3 affinity, prompt can improve negative symptoms and cognitive disorder；Compared with Risperidone, to the parent of H1 Weak with power, the side effect possibility for generating weight gain is smaller.
Anti- schizophrenia activity in the high activity compound body that embodiment 36, MK-801 are induced
Experimental animal and reagent
Healthy Kunming mouse, half male and half female, weight (20 ± 2) g are provided by Nanjing Qinglongshan animal-breeding center.
Ascorbic acid, Sinopharm Chemical Reagent Co., Ltd.；
MK-801 is produced by Sigma Co., USA, preparation method: the solution of 1mg/ml is made into 0.1% vitamin C；
Tested positive drug: haloperidol, Clozapine, Risperidone, Olanzapine, Aripiprazole, Ziprasidone, kui gentle ziprasidone；
Tween 80, concentration 10%.
Experimental method
The re-qualified mouse of selective body is randomly divided into blank group, model group, positive controls (Risperidone group), medicine group. Risperidone 0.1mg/kg, medicine group difference are given in blank group, 10% tween 0.1ml/10g of model group stomach-filling, positive controls stomach-filling Stomach-filling gives corresponding dosage drug.0.1% ascorbic acid 0.1ml/10g, model group, the positive is injected intraperitoneally in 1h blank group after administration MK-801 solution 0.1mg/kg is injected intraperitoneally in control group (30min), medicine group.Thereafter spontaneous work in each group mouse 90 minutes is measured It is dynamic.It the results are shown in Table 3.
Embodiment 37, the climbing experiment of apomorphine inducing mouse
Experimental animal
Healthy KM mouse, male, 18~22g of weight are provided by Nanjing Qinglongshan animal-breeding center.
Main agents
Tested positive drug: haloperidol, Clozapine, Risperidone, Olanzapine, Aripiprazole, Ziprasidone, kui gentle ziprasidone；
Apomorphine, Sigma company provide, and 0.9%NaCl (containing 0.1% vitamin C) dissolution, ready-to-use before use；
Vitamin C, F20061113, Sinopharm Chemical Reagent Co., Ltd.；
Sodium chloride injection, H32026305, the 5th pharmacy Co., Ltd., Factory of Xuzhou City.
Instrument: self-control climbing cage, stopwatch.
Experimental method: apomorphine inducing mouse climbing experiment
KM mouse, male, 18~22g of weight are randomly divided into each dosage group of negative control group, model group, positive drug (benefit Train ketone, Aripiprazole, Ziprasidone, kui gentle ziprasidone, Olanzapine, haloperidol, Clozapine) and each dosage group of compound is (specifically Dosage see the table below), every group 10.Coordinative solvent distilled water, positive drug group are given in negative control group and model group stomach-filling Corresponding positive drug (first adding micro-acetic acid, then plus distilled water when dissolution) is given in stomach-filling, and phase is given in each dosage group stomach-filling of compound Doses of compound is answered, stomach-filling volume is 0.1ml/10g.Apomorphine (1mg/kg) is subcutaneously injected after gastric infusion 1 hour, volume For 0.1ml/10g.After injecting apomorphine, it is immediately placed in climbing cage, adapts to 5 minutes, 10- after observation injection apomorphine Behavior in 11,20-21,30-31 minutes is simultaneously scored, and standards of grading: four-footed is scored at 0 on floor；Two front foots are in cylinder mould On be scored at 1；Four foots are scored at 2 on cylinder mould.It the results are shown in Table 3.
Embodiment 38, catalepsy experimental method
Experimental animal
Healthy Kunming mouse, half male and half female, (22 ± 2) g are provided by Nanjing Qinglongshan animal-breeding center.
Main agents:
Test drug, haloperidol, Clozapine, Risperidone, Olanzapine, Aripiprazole, Ziprasidone
Instrument:
Stick equipment is grabbed in self-control: diameter 0.3cm is placed in mouse box, higher than the stainless steel bar of workbench 5cm.
Experimental method:
KM mouse, half male and half female, 20~24g of weight are randomly divided into each dosage of negative control group, model group, positive drug Group (Risperidone, Aripiprazole, Ziprasidone, kui gentle ziprasidone, Olanzapine, haloperidol, Clozapine) and each dosage group of compound, Every group 10.Coordinative solvent distilled water is given in negative control group and model group stomach-filling, and the corresponding positive is given in positive drug group stomach-filling Drug (first adds micro-acetic acid, then plus distilled water) when dissolution, corresponding dosage compound, stomach-filling are given in each dosage group stomach-filling of compound Volume is 0.1ml/10g.When gastric infusion 30min, 60min, 90min, two fore paws of mouse are gently placed on long 20cm, directly Diameter 0.3cm on the spillikin higher than workbench 5.5cm, then animal hind leg is put down gently in cassette bottom face, records two fore paws of mouse in stick It is the upper duration for keeping posture, stiff motionless for positive reaction with 30s.It is whole when 60s if mouse fore paw is never put down Only observe.Each compound dosage group positive reaction number of animals is counted, the results are shown in Table 3.
Embodiment 39, studies on acute toxicity
The limit experiment of sequential method takes KM mouse, and half male and half female is randomly divided into several groups, every group 2-5, respectively eachization Object 2000mg/kg group and solvent group are closed, by 0.2ml/10g gastric infusion.Death condition in observation animal 3 days.If (animal There are 3 or 3 or more to survive in three days, when life state Non Apparent Abnormality, continue to observe, until testing after 7 days terminates.Such as Fruit animal at dead 3 or 3 or more, measured its LD50 using median lethal dose method in three days.)
The test of median lethal dose method takes KM mouse, half male and half female, divides several groups at random, and every group 4, respectively each compound 1500mg/kg, 1000mg/kg, 500mg/kg group and solvent group, by 0.2ml/10g gastric infusion, in observation animal 1-3 days Death condition.
As a result: the LD that mouse single gavages50Greater than 2000mg/kg, there is lesser acute toxicity.
Animal model test result in 3. preferred compound body of table
The result shows that compound 9,10,26 and 27 is small in animal model middle dosage, safety coefficient is higher than positive drug.

Claims (10)

1. a kind of compound is stereoisomer, tautomer, the nitrogen of compound shown in compound shown in Formulas I or Formulas I Oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug
In above-mentioned general formula,
n1It is 3 or 4,
n2It is 1 or 2；
Z is CH or N
R1, R2Or R3Separately represent hydrogen, halogen, C1-C5Alkyl, substituted C1-C5Alkyl or C1-C5 alkoxy；
W is CH, N or O；W is upper can be unsubstituted or can further to be replaced by Y；Wherein Y is hydrogen, and Formula II or formula III replace；
Q is O or S；
R4、R5Or R6It is separately hydrogen, halogen, C1-C5Alkyl, substituted C1-C5Alkyl or C1-C5Alkoxy；
RaAnd RbIt is separately the linear or branched alkyl group containing 1~5 carbon atom optionally replaced, described substituted takes Dai Ji is selected from alkyl, cyano, hydroxyl, halogen ,-CN ,-N (CN)2With-C (CN)3In it is one of few,
Or five~heptatomic ring containing at least one O, N or carbonyl is collectively formed together with coupled Ra and Rb in N, described five The alkyl containing 1~5 carbon atom that~heptatomic ring is optionally optionally substituted, the aryl optionally replaced, the thiophene optionally replaced Pheno, C1~10Alkyl formate ester group replaces, and the substituted substituent group is selected from alkyl, cyano, hydroxyl, halogen ,-CN ,-N (CN)2 With-C (CN)3At least one of.
2. compound according to claim 1, which is characterized in that N is together with coupled RaAnd RbBe collectively formed formula IV or Formula V compound,
R9For substituted or unsubstituted C1-5Alkyl；For methyl or ethyl；
M is 0,1 or 2；
X is O, one of N or CH；X is upper can be unsubstituted or can further to be replaced by R8, wherein R8For hydrogen, replace or Unsubstituted C1-5Alkyl, hydroxyl, substitution or unsubstituted phenyl, formula III compound, Formula IV compound, wherein the benzene The substituent group of base is halogen；Wherein, the substituent R 10 on Formula IV compound, R11 are halogen.
3. according to claim 1 or the 2 any compounds or pharmaceutically acceptable salt, it is characterised in that: it is described not Substituted C1-5Alkyl is selected from methyl, ethyl, propyl, butyl, amyl or isopentyl, substituted C1-5Alkyl is selected from C1-5Alkyl halide Base.
4. according to claim 1 or the 2 any compounds or pharmaceutically acceptable salt, it is characterised in that: the halogen Element is fluorine, chlorine, bromine, iodine.
5. compound according to claim 1 or pharmaceutically acceptable salt, which is characterized in that the C1-C5Alcoxyl Base is methoxyl group, ethyoxyl.
6. compound according to claim 1 or pharmaceutically acceptable salt, which is characterized in that the substituted phenyl For benzyl, phenethyl, phenylpropyl, aminomethyl phenyl, methoxyphenyl, methoxy-benzyl, fluorophenyl, luorobenzyl.
7. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that shown in the general formula I Compound or its pharmaceutically acceptable salt be selected from any one following compound or its pharmaceutically acceptable salt:
(1) the fluoro- 3- of 5- (1- (3- (4- (morpholinomethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole；
(2) the fluoro- 3- of 6- (1- (3- (4- (piperidyl -1- ylmethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] different evil Azoles；
(3) the fluoro- 3- of 6- (1- (3- (4- ((4- methyl piperidine base -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole；
(4) the fluoro- 3- of 6- (1- (3- (4- (pyrrolidin-1-yl methyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] different evil Azoles；
(5) 3- (1- (3- (4- ((3,5- lupetidine base -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) -5- fluorine Benzo [d] isoxazole；
(6) 1- (4- (3- (4- (5- fluorobenzene simultaneously [d] isoxazole purine -3- base) piperidyl -1- base) propoxyl group) benzyl) piperidyl - 4- alcohol；
(7) N- ethyl-N- (4- (3- (4- (5- fluorobenzene simultaneously [d] isoxazole purine -3- base) piperidyl -1- base) propoxyl group) benzyl) Ethamine；
(8) -6- fluorobenzene is simultaneously by 3- (1- (3- (4- ((2,6- thebaine generation) methyl) phenoxy group) propyl) piperidyl -4- base) [d] isoxazole；
(9) the fluoro- 3- of 6- (1- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] Isoxazole；
(10) -6- fluorobenzene is simultaneously by 3- (1- (3- (4- ((4- ethyl piperazidine -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) [d] isoxazole；
(11) the fluoro- 3- of 6- (1- (3- (4- ((4- phenylpiperazine -1- base) methyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole；
(12) 4- (4- (3- (4- (benzo [d] isothiazole -3- base) piperazine -1- base) propoxyl group) benzyl) morpholine；
(13) the fluoro- 3- of 6- (1- (4- (3- morpholino propoxyl group) benzyl) piperidyl -4- base) benzo [d] isoxazole；
(14) the fluoro- 3- of 6- (1- (4- (3- (piperidyl -1- base) propoxyl group) benzyl) piperidyl -4- base) benzo [d] isoxazole；
(15) the fluoro- 3- of 6- (1- (4- ((1- methyl piperidine base -4- base) oxygroup) benzyl) piperidyl -4- base) benzo [d] different evil Azoles；
(16) the fluoro- 3- of 6- (1- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperidyl -4- base) benzo [d] isoxazole；
(17) the fluoro- 3- of 6- (1- (4- (3- morpholino propoxyl group) phenethyl) piperidyl -4- base) benzo [d] isoxazole；
(18) the fluoro- 3- of 6- (1- (4- (3- (4- methylpiperazine-1-yl) propoxyl group) phenethyl) piperidyl -4- base) benzo [d] is different Oxazole；
(19) the fluoro- 3- of 6- (1- (4- (3- (4- methyl piperidine base -1- base) propoxyl group) phenethyl) piperidyl -4- base) benzo [d] Isoxazole；
(20) 4- (3- (4- (2- (4- (2,3- dichlorophenyl) piperazine -1- base) ethyl) phenoxy group) propyl) morpholine；
(21) 1- (2,3- dichlorophenyl) -4- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperazine；
(22) 1- (2,3- dichlorophenyl) -4- (4- (3- (4- methylpiperazine-1-yl) propoxyl group) phenethyl) piperazine；
(23) 1- (2,3- dichlorophenyl) -4- (4- (3- (4- methyl piperidine base -1- base) propoxyl group) phenethyl) piperazine；
(24) (2,4 difluorobenzene base) (1- (4- (3- morpholino propoxyl group) phenethyl) piperidyl -4- base) ketone；
(25) (2,4 difluorobenzene base) (1- (4- (3- (piperidyl -1- base) propoxyl group) phenethyl) piperidyl -4- base) ketone；
(26) the fluoro- 3- of 6- (1- (3- (4- (2- morpholinoethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole；
(27) the fluoro- 3- of 6- (1- (3- (4- (2- (piperidyl -1- base) ethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] Isoxazole；
(28) the fluoro- 3- of 6- (1- (3- (4- (2- (4- methyl piperidine base -1- base) ethyl) phenoxy group) propyl) piperidyl -4- base) benzene And [d] isoxazole；
(29) the fluoro- 3- of 6- (1- (3- (4- (2- (4- methylpiperazine-1-yl) ethyl) phenoxy group) propyl) piperidyl -4- base) benzo [d] isoxazole；
(30) 4- (3- (4- (2- (piperidyl -1- base) ethyl) phenoxy group) propyl) morpholine；
(31) N, N- diethyl -2- (4- (3- morpholino propoxyl group) phenyl) ethamine.
8. a kind of pharmaceutical composition, it is characterised in that containing the described in any item compounds of claim 1~7, optionally into one Step includes pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination.
9. the described in any item compounds of claim 1~7 or pharmaceutical composition according to any one of claims 8 are in medicine preparation Purposes, the drug is used to treat purposes in individual by the receptor-mediated disease of H3 or illness.
10. purposes according to claim 9, which is characterized in that described by the receptor-mediated disease of H3 or illness is insane One of epilepsy, schizophrenia, senile dementia, sleep disturbance, obesity, neuralgia and attention-deficit hyperactivity disease.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1726201A (en) * 2002-10-16 2006-01-25 葛兰素集团有限公司 Substituted piperazines,(1,4) diaszepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine h1 and/or h3 antagonists or histamine h3 reverse antagonists
CN102046610A (en) * 2008-05-29 2011-05-04 Sk株式会社 Phenyl piperazine compounds, pharmaceutical composition including the same, and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1726201A (en) * 2002-10-16 2006-01-25 葛兰素集团有限公司 Substituted piperazines,(1,4) diaszepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine h1 and/or h3 antagonists or histamine h3 reverse antagonists
CN102046610A (en) * 2008-05-29 2011-05-04 Sk株式会社 Phenyl piperazine compounds, pharmaceutical composition including the same, and use thereof

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Title
DEVIN M. SWANSON等: "Aplysamine-1 and related analogs as histamine H3 receptor antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

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