CN109232549B - Compound for treating schizophrenia and application thereof - Google Patents

Compound for treating schizophrenia and application thereof Download PDF

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CN109232549B
CN109232549B CN201710559306.4A CN201710559306A CN109232549B CN 109232549 B CN109232549 B CN 109232549B CN 201710559306 A CN201710559306 A CN 201710559306A CN 109232549 B CN109232549 B CN 109232549B
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isoxazole
benzo
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CN109232549A (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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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
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    • 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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Abstract

The invention provides an H3 receptor compound and application thereof, and in vitro experiments of the compound show that the compound has high affinity with H3, and can improve negative symptoms and cognitive disorder; compared to risperidone, affinity for H1 is weak, and side effects that produce weight gain are less likely.

Description

Compound for treating schizophrenia and application thereof
The technical field is as follows:
the invention belongs to the field of medicines, and particularly relates to a compound for treating schizophrenia and application thereof
Background
Mental diseases are one of the major diseases of frequently occurring diseases and common diseases seriously harming the health of people, and the incidence of the diseases is in a remarkable rising trend along with the deterioration of social environment and the increase of life pressure. Now becomes an important disease which seriously harms the health of people and the development of society. At present, the anti-schizophrenia drug is effective on positive symptoms, but has poor curative effects on negative symptoms and cognitive impairment, and has more serious adverse reactions such as blood sugar rise, hyperprolactinemia, weight gain and the like. Therefore, research and development of novel anti-mental disorder drugs are urgently needed in clinic.
After decades of research, D is found2，5-HT1A，5-HT2AAnd H1These five receptors play a very important role in schizophrenia. And D2The receptor action can effectively treat the positive symptoms of schizophrenia. The 5-hydroxytryptamine system plays an important role in the regulation of the function of the prefrontal cortex, including emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the prefrontal cortex contain the 5-hydroxytryptamine receptor 5-HT1AAnd 5-HT2A. The 5-hydroxytryptamine system plays an important role in regulating the function of the prefrontal cortex, including mood control, cognitive behavior and working memory]。5-HT1AAssociated with atypical antipsychotic treatment, can improve negative symptoms and cognitive impairment. 5-HT2AThe receptor is involved in various aspects of perception, mood regulation and motor control, blocking 5-HT2AThe receptor normalizes dopamine release and acts as an antipsychotic.
Histamine (Histamine), a key biogenic amine, is an important neurotransmitter in the central and peripheral nervous systems. Histamine Receptors belong to the family of G-Protein-Coupled Receptors (G-Protein-Coupled-Receptors, GPCRs) and there are 4 subtypes: h1, H2, H3, H4. The sequence homology between the various subtypes of histamine receptors is not high, 20-38%, among which H1 and H2 were first discovered, H3 and H4 were relatively later discovered, and H4 receptor was recently found to be involved in inflammatory and immunoregulatory processes. The histamine H3 receptor is widely distributed in the central and peripheral nervous systems. It has been found that the H3 receptor is not only a presynaptic receptor (presynaptic receptor) and can regulate the synthesis and release of histaminergic neurotransmitters on neurons; meanwhile, the H3 receptor is also a kind of heteroreceptor (heteroreceptor) on neurons, and the H3 receptor can induce the release of various neurotransmitters, such as acetylcholine, dopaminergic, GABA, tryptamine, noradrenergic and the like, by releasing histamine in an activated state. Therefore, various neurotransmitters can be regulated through the H3 receptor, so that various mental/neurological diseases can be treated, for example, the H3 receptor can be antagonized, and diseases such as epilepsy, schizophrenia, senile dementia, sleep disorder, obesity, neuralgia and attention deficit hyperactivity disorder can be treated.
Therefore, new compounds having the side effects of treating both positive symptoms and improving the negative symptoms and cognitive impairment of schizophrenia while reducing weight gain are sought.
The invention content is as follows:
in order to solve the above technical problems, the present invention provides related solutions:
in one aspect, the invention provides a compound that is a compound of formula I or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula I, or prodrug thereof
Figure BDA0001346623270000021
In the above-mentioned general formula (I),
n1is a compound of the formula (I) 3 or 4,
n2is 1 or 2;
z is CH or N
R1，R2Or R3Each independently represents hydrogen, halogen, C1-C5Alkyl, substituted C1-C5Or C1-C5 alkoxy;
w is CH, N or O; w may be unsubstituted or may be further substituted with Y; wherein Y is hydrogen, substituted by formula II or formula III;
Figure BDA0001346623270000031
q is O or S;
R4、R5or R6Each independently is hydrogen, halogen, C1-C5Alkyl, substituted C1-C5Alkyl or C1-C5Alkoxy group of (a);
Raand RbEach independently is an optionally substituted straight or branched chain alkyl group containing 1 to 5 carbon atoms, the substituted substituents being selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)2and-C (CN)3One of the less than one of them,
Or N together with Ra and Rb to which it is attached form a five-to seven-membered ring containing at least one O, N or carbonyl group, the five-to seven-membered ring being optionally substituted with an optionally substituted alkyl group containing 1 to 5 carbon atoms, an optionally substituted aryl group, an optionally substituted thiophene, a C1 to 10 alkyl formate group, the substituted substituent being selected from at least one of alkyl, cyano, hydroxy, halo, -CN, -N (CN)2 and-C (CN) 3.
Further, said unsubstituted C1-5Alkyl is selected from methyl, ethyl, propyl, butyl, pentyl or isopentyl, substituted C1-5The alkyl group being selected from C1-5A haloalkyl group.
Further, N in the above invention together with R attached theretoaAnd RbTogether form a compound of formula IV or formula V,
Figure BDA0001346623270000032
R9is substituted or unsubstituted C1-5An alkyl group; is methyl or ethyl;
m is 0, 1 or 2;
x is one of O, N or CH; x may be unsubstituted or may be further substituted by R8Wherein R is8Is hydrogen, substituted or unsubstituted C1-5Alkyl, hydroxy, substituted or unsubstituted phenyl, a compound of formula III, a compound of formula VI, wherein the phenyl substituent is halogen; wherein, the substituents R10 and R11 on the compound in the formula VI are halogen.
Further, said unsubstituted C 1-5Alkyl is selected from methyl, ethyl, propyl, butyl, pentyl or isopentyl, substituted C1-5Alkyl is selected from C1-5A haloalkyl group.
Further, the halogen is fluorine, chlorine, bromine or iodine.
Further, said C1-C5The alkoxy of (A) is methoxy or ethoxy.
Further, the substituted phenyl group is benzyl, phenethyl, phenylpropyl, methylphenyl, methoxyphenyl, methoxybenzyl, fluorophenyl, or fluorobenzyl.
Further, the compound shown in the general formula I or the pharmaceutically acceptable salt thereof is selected from any one of the following compounds or pharmaceutically acceptable salts thereof:
(1) 5-fluoro-3- (1- (3- (4- (morpholinomethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(2) 6-fluoro-3- (1- (3- (4- (piperidinyl-1-ylmethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(3) 6-fluoro-3- (1- (3- (4- ((4-methylpiperidin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(4) 6-fluoro-3- (1- (3- (4- (pyrrolidin-1-ylmethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(5)3- (1- (3- (4- ((3, 5-dimethylpiperidin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) -5-fluorobenzo [ d ] isoxazole;
(6)1- (4- (3- (4- (5-fluorobenzo [ d ] isoxazolin-3-yl) piperidinyl-1-yl) propoxy) benzyl) piperidinyl-4-ol;
(7) N-ethyl-N- (4- (3- (4- (5-fluorobenzo [ d ] isoxazolin-3-yl) piperidinyl-1-yl) propoxy) benzyl) ethylamine;
(8)3- (1- (3- (4- ((2, 6-dimethylmorpholino) methyl) phenoxy) propyl) piperidinyl-4-yl) -6-fluorobenzo [ d ] isoxazole;
(9) 6-fluoro-3- (1- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(10)3- (1- (3- (4- ((4-ethylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) -6-fluorobenzo [ d ] isoxazole;
(11) 6-fluoro-3- (1- (3- (4- ((4-phenylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(12)4- (4- (3- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) propoxy) benzyl) morpholine;
(13) 6-fluoro-3- (1- (4- (3-morpholinopropoxy) benzyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(14) 6-fluoro-3- (1- (4- (3- (piperidinyl-1-yl) propoxy) benzyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(15) 6-fluoro-3- (1- (4- ((1-methylpiperidin-4-yl) oxy) benzyl) piperidin-4-yl) benzo [ d ] isoxazole;
(16) 6-fluoro-3- (1- (4- (3- (piperidinyl-1-yl) propoxy) phenethyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(17) 6-fluoro-3- (1- (4- (3-morpholinopropoxy) phenethyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(18) 6-fluoro-3- (1- (4- (3- (4-methylpiperazin-1-yl) propoxy) phenethyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(19) 6-fluoro-3- (1- (4- (3- (4-methylpiperidin-1-yl) propoxy) phenethyl) piperidin-4-yl) benzo [ d ] isoxazole;
(20)4- (3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) phenoxy) propyl) morpholine;
(21)1- (2, 3-dichlorophenyl) -4- (4- (3- (piperidinyl-1-yl) propoxy) phenethyl) piperazine;
(22)1- (2, 3-dichlorophenyl) -4- (4- (3- (4-methylpiperazin-1-yl) propoxy) phenethyl) piperazine;
(23)1- (2, 3-dichlorophenyl) -4- (4- (3- (4-methylpiperidin-1-yl) propoxy) phenethyl) piperazine;
(24) (2, 4-difluorophenyl) (1- (4- (3-morpholinopropoxy) phenethyl) piperidinyl-4-yl) methanone;
(25) (2, 4-difluorophenyl) (1- (4- (3- (piperidinyl-1-yl) propoxy) phenethyl) piperidinyl-4-yl) methanone;
(26) 6-fluoro-3- (1- (3- (4- (2-morpholinoethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(27) 6-fluoro-3- (1- (3- (4- (2- (piperidinyl-1-yl) ethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(28) 6-fluoro-3- (1- (3- (4- (2- (4-methylpiperidin-1-yl) ethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(29) 6-fluoro-3- (1- (3- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(30)4- (3- (4- (2- (piperidinyl-1-yl) ethyl) phenoxy) propyl) morpholine;
(31) n, N-diethyl-2- (4- (3-morpholinopropoxy) phenyl) ethylamine.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of any one of the present invention, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
In another aspect, the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a disease or condition mediated by the H3 receptor in a subject.
Further, the disease or disorder mediated by the H3 receptor according to the present invention is one of epilepsy, schizophrenia, senile dementia, sleep disorder, obesity, neuralgia, and attention deficit hyperactivity disorder.
Detailed description of the invention:
the term "pharmaceutically acceptable salts" as used herein refers to relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M.Berge et al, "Pharmaceutical Salts," J.pharm.Sci.1977,66, 1-19.
Pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, salts selected from the group consisting of: oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulphonate, gluconate, saccharate, benzoate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate.
In another aspect, the invention relates to acceptable optical isomers of the compounds of formula I.
In another aspect, the invention also relates to a pharmaceutical composition comprising a compound of any of the present invention, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.
In another aspect, the pharmaceutical composition of the present invention is used for preparing a medicament for preventing or treating a psychiatric disorder, optionally wherein the psychiatric disorder is neuropathic pain. The pharmaceutical composition provided by the invention can also be used for preparing other central nervous system disease medicines, such as medicines for treating schizophrenia, depression, dysmnesia and dysfunctional diseases related to intelligence and learning.
An effective amount of a compound of the present invention may be administered orally, e.g., with an inert diluent or with some carrier. It can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral treatment, the compounds of the present invention may be used with excipients and in the form of tablets, troches, capsules, suspensions, syrups and the like. These formulations should contain at least 0.5% by weight of the active compound of the invention, but may vary depending on the particular dosage form, and conveniently comprise from 4% to about 70% by weight of the unit. The amount of active compound in such compositions should be such that a suitable dosage is achieved. Preferred compositions and formulations of the invention contain 1.0 to 300 mg of the active compound of the invention in an oral unit dose.
The compound and the pharmaceutically acceptable salt, solvate and hydrate thereof provided by the invention can be combined with pharmaceutically acceptable carriers or diluents to form a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
The amount of the compound of the present invention to be used depends on the type and severity of the disease or condition and also on the characteristics of the subject, such as general health, age, sex, body weight and drug tolerance. The skilled person will be able to determine the appropriate dosage based on these and other factors. Effective dosages of the cns drug generally employed are well known to the skilled artisan. The total daily dose is usually between about 0.05mg and 2000 mg.
The present invention relates to pharmaceutical compositions which provide from about 0.01 to 1000mg of active ingredient per unit dose. The compositions may be administered by any suitable route, for example orally in the form of capsules, parenterally in the form of injections, topically in the form of ointments or lotions, rectally in the form of suppositories, transdermally in the form of patch delivery systems.
The compounds provided herein can be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, pills, powders, syrups, solutions and the like. Tablets, pills, capsules and the like contain from about 0.01 to about 99 weight percent of the active ingredient plus a binder such as gelatin, corn starch, gum arabic; excipients such as dibasic calcium phosphate; disintegrating agents such as corn starch, potato starch or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose. When the formulation is in the form of a capsule, it may contain, in addition to the above-mentioned types of raw materials, a liquid carrier such as a fat.
For parenteral administration, the compounds provided herein can be combined with sterile water or an organic medium to form an injectable solution or suspension.
Has the advantages that:
the in vitro experiment of the compound provided by the invention shows that the compound has high affinity with H3, and can improve negative symptoms and cognitive disorder; compared to risperidone, affinity for H1 is weak, and side effects that produce weight gain are less likely.
Detailed Description
The following examples are for illustrative purposes only and are not intended to be limiting of the present invention.
A. Examples of synthetic aspects
Example 1, 6-fluoro-3- (1- (4- (3-morpholinopropoxy) benzyl) piperidinyl-4-yl) benzo [ d ] isoxazole (1)
Reaction scheme 1
Figure BDA0001346623270000091
1) 50ml of acetone was added to 6.1g of 4-hydroxybenzaldehyde, 15.0g of 1, 3-dibromopropane and 20.7g of potassium carbonate, and the mixture was refluxed for 6 hours. TLC detection, after the reaction is finished, cooling to room temperature, evaporating the solvent, adding a proper amount of dichloromethane, washing with water, separating a water layer, adding anhydrous magnesium sulfate to an organic layer for drying, evaporating the solvent to dryness to obtain a light yellow oily substance, and performing column chromatography to obtain 9.4g of a white solid, the melting point of 186-.
2) Taking 4.7g of the product in the first step, 8.0g of anhydrous potassium carbonate, 50ml of acetonitrile and 5.5g of 6-fluoro-3- (piperidyl-4-yl) benzo [ d ] isoxazole hydrochloride, heating and refluxing for 6 hours, cooling to room temperature, filtering, evaporating the solvent, and eluting with petroleum ether: ethyl acetate 2:1 was passed through a column to give 6.1g of a pale yellow oil in 82.4% yield.
3) Taking 0.7g of the product of the second step, adding 0.35g of morpholine, 0.84g of sodium triacetoxyborohydride and 30ml of dichloromethane, reacting for 12 hours at room temperature, washing with 1mol/ml of sodium hydroxide solution, separating a water layer, adding anhydrous magnesium sulfate into an organic layer, drying, evaporating the solvent to obtain a light yellow oily substance, and performing column chromatography to obtain 0.62g of a yellow solid, wherein the melting point is as follows: 96-98 ℃ and the yield is 68.6 percent. 1H NMR(600MHz,CDCl3)δ7.40(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]+).
Example 2, 6-fluoro-3- (1- (3- (4- (piperidinyl-1-ylmethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] iso-benzo
Oxazole (2)
Morpholine by piperidine according to the examples1, the structural formula of which is shown as a number (2) in table 1.1H-NMR(600MHz,CDCl3)δ7.42(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]+).
Example 3, 6-fluoro-3- (1- (3- (4- ((4-methylpiperidin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole (3)
The title compound, structure formula (3) in Table 1, was prepared by the method of example 1, substituting morpholine for 4-methylpiperidine.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 4, 6-fluoro-3- (1- (3- (4- (pyrrolidin-1-ylmethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole (4)
The target compound, the structural formula of which is shown in Table 1 (4), was prepared in the same manner as in example 1, except that morpholine was replaced by pyrrolidine.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 5, 3- (1- (3- (4- ((3, 5-dimethylpiperidin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) -5-fluorobenzo [ d ] isoxazole (5)
The title compound, structure formula (5) in Table 1, was prepared by the method of example 1, substituting morpholine for 3, 5-dimethylpiperidine.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 6, 1- (4- (3- (4- (5-fluorobenzo [ d ] isoxazolin-3-yl) piperidinyl-1-yl) propoxy) benzyl) piperidinyl-4-ol (6)
The title compound, structure formula (6) in Table 1, was prepared by the method of example 1, substituting morpholine for 4-hydroxypiperidine. 1H-NMR(600MHz,CDCl3)δ7.43(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]+).
Example 7N-Ethyl-N- (4- (3- (4- (5-fluorobenzo [ d ] isoxazolin-3-yl) piperidinyl-1-yl) propoxy) benzyl) ethylamine (7)
The target compound, the structural formula of which is shown in Table 1 (7), was prepared in the same manner as in example 1, except that morpholine was replaced by diethylamine.1H-NMR(600MHz,CDCl3)δ7.37(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]+).
Example 8, 3- (1- (3- (4- ((2, 6-dimethylmorpholino) methyl) phenoxy) propyl) piperidin-4-yl) -6-fluorobenzo [ d ] isoxazole (8)
The target compound, the structural formula of which is shown in Table 1 (No. (8)) was prepared in the same manner as in example 1 by replacing morpholine with 2, 6-dimethylmorpholine.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 9 6-fluoro-3- (1- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole (9)
Exchanging morpholineTo give 4-methylpiperazine, the title compound, the structural formula of which is shown in Table 1 (9), was prepared in the same manner as in example 1.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 10, 3- (1- (3- (4- ((4-ethylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) -6-fluorobenzo [ d ] isoxazole (10)
The title compound, structure formula (10) shown in Table 1, was prepared by the method of example 1, substituting morpholine with 4-ethylpiperazine.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 11, 6-fluoro-3- (1- (3- (4- ((4-phenylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole (11)
The objective compound, the structural formula of which is shown in the number (11) in table 1, was prepared by the method of example 1, replacing morpholine with 4-phenylpiperazine.1H-NMR(600MHz,CDCl3)δ7.36(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]+).
Example 12, 6-4- (4- (3- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) propoxy) benzyl) morpholine (12) by reacting 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]Conversion of isoxazoles to 4- (benzo [ d ]]Isothiazol-3-yl) piperazine the title compound was prepared as in example 1, having the structural formula shown in table 1, numbered (12).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]+).
Example 13, 6-fluoro-3- (1- (4- (3-morpholinopropoxy) benzyl) piperidin-4-yl) benzo [ d]Isoxazoles (13) conversion of morpholine to 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]Isoxazole, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The target compound was prepared in the same manner as in example 1 except that isoxazole was changed to morpholine, and the target compound having the structural formula shown in the number (13) in Table 1 was prepared in the same manner as in example 1.1H-NMR(600MHz,CDCl3)δ7.39(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]+).
Example 14, 6-fluoro-3- (1- (4- (3- (piperidinyl-1-yl) propoxy) benzyl) piperidinyl-4-yl) benzo [ d ] isoxazole (14)
Conversion of morpholine to 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]Isoxazole, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The isoxazole was changed to morpholine, and the title compound, the structural formula of which is shown in Table 1 (14), was prepared in the same manner as in example 1.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 15, 6-fluoro-3- (1- (4- ((1-methylpiperidin-4-yl) oxy) benzyl) piperidin-4-yl) benzo [ d ] isoxazole (15)
Figure BDA0001346623270000141
1) Taking 6.1g of 4-hydroxybenzaldehyde, adding 13.2g of 6-fluoro-3- (piperidyl-4-yl) benzo [ d ] isoxazole, 21.2g of sodium triacetoxyborohydride and 100ml of dichloromethane, reacting at room temperature for 12 hours, washing with 1mol/ml sodium hydroxide solution, removing a water layer, adding anhydrous magnesium sulfate to an organic layer, drying, evaporating the solvent to dryness to obtain a light yellow oily substance, and performing column chromatography to obtain 8.4g of a yellow solid, wherein the melting point is as follows: 122 ℃ and 123 ℃ with a yield of 51.5 percent.
2) 1.2g of the product of the first step was taken, 0.84g of N-methyl-4-piperidinol, 2.2g of triphenylphosphine and 20ml of tetrahydrofuran were added thereto, and 1.3g of DEAD was slowly dropped thereinto under ice-cooling, followed by reaction at room temperature for 8 hours after completion of the dropping. Washing with saturated sodium chloride solution, removing water layer, drying organic layer with anhydrous magnesium sulfate, evaporating solvent to obtain pale yellow oily substance, and performing column chromatography to obtain yellow oily substance 0.85g with yield of 54.8%.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 16 6-fluoro-3- (1- (4- (3- (piperidinyl-1-yl) propoxy) phenethyl) piperidinyl-4-yl) benzo [ d ] isoxazole (16)
Figure BDA0001346623270000151
1) 50ml of acetone was added to 6.9g of 4-hydroxyphenylethanol, 14.9g of 1, 3-dibromopropane and 20.7g of potassium carbonate, and the mixture was refluxed for 6 hours. TLC detection, after the reaction, cooling to room temperature, evaporating the solvent, adding a proper amount of dichloromethane, washing with water, separating a water layer, adding anhydrous magnesium sulfate to an organic layer for drying, evaporating the solvent to obtain a light yellow oily substance, and performing column chromatography to obtain 9.3g of a white solid, wherein the melting point is 102-.
2) Taking 5.2g of the product in the first step, 8.0g of anhydrous potassium carbonate, 50ml of acetonitrile and 3.4g of piperidine, heating and refluxing for 6 hours, cooling to room temperature, filtering, evaporating the solvent, and eluting with petroleum ether: ethyl acetate 1:2 was passed through a column to give 4.3g of a pale yellow oil in 81.8% yield.
3) 2.6g of the second-step product is taken to be dissolved in 30ml of dichloromethane, 2.8g of p-toluenesulfonyl chloride dissolved in 10ml is dripped into the dichloromethane under the stirring at normal temperature, the reaction is carried out for 12 hours at room temperature after the dripping, the obtained product is washed by 1mol/ml of sodium hydroxide solution, a water layer is separated, an organic layer is dried by anhydrous magnesium sulfate, the solvent is evaporated to dryness, a light yellow oily substance is obtained, and the yellow oily substance is obtained by column chromatography and is 3.8g, and the yield is 91.5%.
4) Taking 2.1g of the product in the third step, 2.1g of anhydrous potassium carbonate and 50ml of acetonitrile, 6-fluoro-3- (piperidyl-4-yl) benzo [ d]Isoxazole hydrochloride 1.3g, heated reflux reaction for 6 hours, cooled to room temperature, filtered, solvent evaporated, eluent dichloromethane: 30 parts of methanol: 1 column chromatography gave 1.9g of pale yellow solid, mp 123-124, 83.2% yield.1H NMR(600MHz,CDCl3)δ7.40(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]+).
Example 17, 6-fluoro-3- (1- (4- (3-morpholinopropoxy) phenethyl) piperidin-4-yl) benzo [ d]Isoxazole (17) Using morpholine as a piperidine, the objective compound having the structural formula shown in Table 1 (17) was obtained in the same manner as in example 16. 1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 18, 6-fluoro-3- (1- (4- (3- (4-methylpiperazin-1-yl) propoxy) phenethyl) piperidin-4-yl) benzo [ d ] isoxazole (18)
The title compound, structure (18) shown in Table 1, was prepared by the method of example 16, substituting piperidine for N-methylpiperazine.1H-NMR(600MHz,CDCl3)δ7.39(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]+).
Example 19 6-fluoro-3- (1- (4- (3- (4-methylpiperidin-1-yl) propoxy) phenethyl) piperidin-4-yl) benzo [ d ] isoxazole (19)
The title compound, structure formula (19) in Table 1, was prepared by the method of example 16, substituting piperidine for 4-methylpiperidine.1H-NMR(600MHz,CDCl3)δ7.39(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]+).
Example 20 replacement of piperidine by 4- (3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) phenoxy) propyl) morpholine (20) for morpholine, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The isoxazole hydrochloride was replaced with 2, 3-dichlorophenyl piperazine hydrochloride, and the objective compound having the structural formula shown in Table 1 (20) was prepared by the method of example 16.1H-NMR(600MHz,CDCl3)δ7.25-7.05(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),1.93-1.61(m,2H).MS(ESI)m/z 478.2([M+H]+).
Example 21, 1- (2, 3-dichlorophenyl) -4- (4- (3- (piperidinyl-1-yl) propoxy) phenethyl) piperazine (21)
Reacting 6-fluoro-3- (piperidyl-4-yl) benzo [ d]The isoxazole hydrochloride was replaced with 2, 3-dichlorophenyl piperazine hydrochloride, and the objective compound having the structural formula shown in Table 1 (21) was prepared by the method of example 16.1H-NMR(600MHz,CDCl3)δ7.18-7.08(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]+).
Example 22 1- (2, 3-dichlorophenyl) -4- (4- (3- (4-methylpiperazin-1-yl) propoxy) phenethyl) piperazine (22) piperidine was exchanged for N-methylpiperazine, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d ]The isoxazole hydrochloride was replaced with 2, 3-dichlorophenyl piperazine hydrochloride, and the objective compound having the structural formula shown in the number (22) in Table 1 was prepared by the method of example 16.1H-NMR(600MHz,CDCl3)δ7.25-7.09(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]+).
Example 23 1- (2, 3-dichlorophenyl) -4- (4- (3- (4-methylpiperidin-1-yl) propoxy) phenethyl) piperazine piperidine was exchanged for 4-methylpiperidine, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d ]]The isoxazole hydrochloride was replaced with 2, 3-dichlorophenyl piperazine hydrochloride to prepare the title compound of the formula (23) shown in Table 1 by the method of example 16.1H-NMR(600MHz,CDCl3)δ7.18-7.07(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]+).
EXAMPLE 24 (2, 4-difluorophenyl) (1- (4- (3-morpholinopropoxy) phenethyl) piperidinyl-4-yl) methanone (24) piperidine was changed to morpholin, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The objective compound having the structural formula shown in Table 1 (No. (24)) was prepared in the same manner as in example 16 by changing isoxazole hydrochloride to (2, 4-difluorophenyl) (piperidyl-4-yl) methanone hydrochloride.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]+).
Example 25, (2, 4-difluorophenyl) (1- (4- (3- (piperidinyl-1-yl) propoxy) phenethyl) piperidinyl-4-yl) methanone (25)
Reacting 6-fluoro-3- (piperidyl-4-yl) benzo [ d]The objective compound having the structural formula shown in Table 1 (25) was obtained in the same manner as in example 16 except that isoxazole hydrochloride was changed to (2, 4-difluorophenyl) (piperidyl-4-yl) methanone hydrochloride. 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]+).
Example 26, 6-fluoro-3- (1- (3- (4- (2-morpholinoethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole (26)
By replacing piperidine with 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]Isoxazole hydrochloride, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The isoxazole hydrochloride was changed to morpholine and the title compound was prepared according to the procedure in example 16 and has the structural formula shown in Table 1 (26).1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 27, 6-fluoro-3- (1- (3- (4- (2- (piperidinyl-1-yl) ethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole (27)
By replacing piperidine with 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]Isoxazole hydrochloride, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The isoxazole hydrochloride was changed to piperidine, and the title compound, the structural formula of which is shown in Table 1 (27), was prepared according to the method of example 16.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 28 6-fluoro-3- (1- (3- (4- (2- (4-methylpiperidin-1-yl) ethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole (28)
By replacing piperidine with 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]Isoxazole hydrochloride, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The objective compound having the structural formula shown in Table 1 (No. 28) was obtained in the same manner as in example 16 except that 4-methylpiperidine was used instead of isoxazole hydrochloride.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
Example 29 6-fluoro-3- (1- (3- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole (29)
By replacing piperidine with 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]Isoxazole hydrochloride, 6-fluoro-3- (piperidinyl-4-yl) benzo [ d]The objective compound having the structural formula shown in Table 1 (No. (29)) was obtained in the same manner as in example 16 by substituting isoxazole hydrochloride with N-methylpiperazine.1H-NMR(600MHz,CDCl3)δ7.41(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]+).
TABLE 1 numbering of the compounds prepared in examples 1-31 and structural formulas thereof
Figure BDA0001346623270000201
Figure BDA0001346623270000211
Figure BDA0001346623270000221
B. Examples of the pharmacological aspects
Example 32
5-HT1APreparation of the film
Rat decapitation, ice-over procedure, rapidly harvest the cerebral cortex and add 3ml buffer (0.05M Tris-HCl buffer containing 0.1% ascorbic acid, 10um eugenin and 4mM CaCl)2) Homogenizing at 4 th 3-4s for 4 times, and adding 5ml buffer (0.05M Tris-HCl buffer containing 0.1% ascorbic acid, 10um eugenin and 4mM CaCl2) Incubating at 37 deg.C for 10min, adjusting weight of the tube with balance, centrifuging at 12000r and 4 deg.C for 20min, discarding supernatant, and adding 3ml bufferMixing the solution with vortex mixer, adding 5ml buffer solution, centrifuging, repeating for three times, centrifuging, removing supernatant, and storing at-80 deg.C.
Receptor binding assay materials:
isotopic ligands3H-8-OH-DPAT (67.0Ci/mmol) available from Perkinelmer; 5-HT, available from RBI; GF/C glass fiber filter paper available from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid. Beckman LS-6500 model multifunctional liquid scintillation counter.
The experimental method comprises the following steps:
(1) firstly, the prepared membrane is uniformly dispersed by a homogenizer with a proper amount of buffer solution, 15 test tubes are mixed into a 100ml container, and a proper amount of buffer solution is added to form a 50ml membrane suspension for later use.
(2) mu.L of the membrane preparation and 100. mu.L of the buffer were added to each reaction tube.
(3) mu.L of buffer was added to total binding Tubes (TB) and 100. mu.L of 5-HT (final concentration 10) was added to non-specific binding tubes (NB)-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)-5M)；
(4) Adding radioactive ligand into each reaction tube310 μ L of H-8-OH-DPAT (each reaction tube is provided with 2 parallel tubes, and each tube is placed on ice during sample loading).
(5) Incubating each reaction tube at 37 ℃ for 10min, after the reaction is finished, rapidly filtering the combined ligands through decompression, fully washing the ligands by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml toluene scintillation solution, and uniformly mixing;
(6) putting the scintillation vial into a liquid scintillation counter for counting
The inhibition ratio (I%) (total binding tube cpm-compound cpm)/(total binding tube cpm-non-specific binding tube cpm) × 100%
Compounds were run in duplicate for each experiment and two separate experiments were run. The results are shown in Table 2
Example 33
5-HT2APreparation of the film
Rat decapitation, ice operation, rapidly taking a cerebral cortex, adding 3ml of buffer solution (0.05M Tris-HCl buffer solution: 6.05g of Tris is dissolved in 1000ml of double distilled water, adjusting the pH value to 7.5 by concentrated HCl) to homogenate for 4 steps of 3-4s, homogenizing for 4 times, then adding 5ml of buffer solution, incubating for 10min at 37 ℃, adjusting the weight of a test tube by a balance after incubation, centrifuging for 20min at 12000r and 4 ℃, discarding the supernatant, adding 3ml of buffer solution, mixing uniformly by a vortex mixer, adding 5ml of buffer solution, centrifuging, (repeating the centrifugation for three times), discarding the supernatant, and storing the precipitate at-80 ℃ for later use.
Receptor binding assay materials:
isotope ligand [ alpha ], [ alpha ] an3H]Ketanserin (67.0Ci/mmol) from PerkinElmer; methysergide, available from RBI; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOPOP are purchased from Shanghai reagent I factories; fat-soluble scintillation liquid. Beckman LS-6500 model multifunctional liquid scintillation counter.
The experimental method comprises the following steps:
(1) the prepared membrane is uniformly dispersed by a homogenizer by using a proper amount of buffer solution, 15 test tubes are mixed into a 100ml container, and a proper amount of buffer solution is added to form a 50ml membrane suspension for later use.
(2) mu.L of the membrane preparation and 100. mu.L of the buffer were added to each reaction tube.
(3) Add 100. mu.L of buffer to total binding Tube (TB) and 100. mu.L of methylserinide to non-specific binding tube (NB) (final concentration 10)-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)-5M)；
(4) Adding radioactive ligand into each reaction tube3H-Ketanserin 10 u L (each reaction tube is provided with 2 parallel tubes, each tube is placed on ice when the sample is added).
(5) Incubating each reaction tube at 37 ℃ for 15min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;
(6) putting the scintillation vial into a liquid scintillation counter for counting
Inhibition (I%) (total bound tubes cpm-compound cpm)/(total bound tubes cpm-non-specific bound tubes cpm) × 100%
The compound was subjected to two replicates per experiment and two separate experiments were performed. The results are shown in Table 2
Example 34
D2Preparation of the film
The rat is decapitated, the operation is carried out on ice, the brain striatum is quickly taken, 3ml of buffer solution (0.05M Tris-HCl buffer solution containing NaCl 120mM, KCl 5mM, MgCl 21 mM and CaCl 21 mM) is added, homogenate is carried out for 4 times in 4 grades of 3-4s, then 5ml of buffer solution is added, the weight of a test tube which is homogenized is adjusted by a balance, the test tube is centrifuged for 20min at 12000r and 4 ℃, the supernatant is discarded, 3ml of buffer solution is added, the mixture is uniformly mixed by a vortex mixer, 5ml of buffer solution is added, the centrifugation is carried out for three times, the centrifugation is finished, the supernatant is discarded, and the precipitate is stored at minus 80 ℃ for standby.
Receptor binding assay materials:
isotopic ligands3H-Spiperone (67.0Ci/mmol) from Perkinelmer; butalclamol, available from RBI corporation; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid. Beckman LS-6500 model liquid scintillation counter.
The experimental method comprises the following steps:
(1) the prepared membrane is uniformly dispersed by a homogenizer by using a proper amount of buffer solution, 15 test tubes are mixed into a 100ml container, and a proper amount of buffer solution is added to form a 50ml membrane suspension for later use.
(2) mu.L of the membrane preparation and 100. mu.L of the buffer were added to each reaction tube.
(3) Add 100. mu.L of buffer to total bound Tubes (TB) and 100. mu.L of LButacllamol to non-specific bound tubes (NB) (final concentration 10)-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)-5M)；
(4) Adding radioactive ligand into each reaction tube3H-Spiperone 10 u L (each reaction tube with 2 parallel tubes, the sample loading each tube placed on ice).
(5) Incubating each reaction tube at 37 ℃ for 20min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;
(6) Putting the scintillation vial into a liquid scintillation counter for counting
The inhibition ratio (I%) (total binding tube cpm-compound cpm)/(total binding tube cpm-non-specific binding tube cpm) × 100%
Compounds were run in duplicate for each experiment and two separate experiments were run. The results are shown in Table 2.
Example 35
Histamine H1Preparation of acceptor membranes
Cutting off the head of a guinea pig, operating on ice, quickly taking the cerebellum of the guinea pig, adding 3mL of buffer solution (1.36 g of monopotassium phosphate, 79mL of 0.1mol/L sodium hydroxide, diluting to 200mL by using double distilled water), uniformly mixing by using a vortex mixer, centrifuging for 10min at 48000g and 4 ℃, discarding the supernatant, taking the precipitate, adding the buffer solution for washing, repeating the centrifugation for three times, centrifuging, discarding the supernatant, and storing the precipitate at-80 ℃ for later use.
Receptor binding assay materials:
isotopic ligands3H-pyrilamine (67.0Ci/mmol) from PerkinElmer; promethazine, available from RBI; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid. Beckman LS-6500 model multifunctional liquid scintillation counter.
The experimental method comprises the following steps:
the first step is as follows: the prepared membrane is uniformly dispersed by a homogenizer with a proper amount of buffer solution, 15 test tubes are mixed into a 100ml container, and a proper amount of homogenate is added to form a 50ml membrane suspension for later use.
The second step is that: each reaction tube was filled with 100. mu.L of the membrane preparation.
The third step: add 100. mu.L of buffer to the total binding Tube (TB) and 100. mu.L of promethazine to the non-specific binding tube (NB) (final concentration 10)-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)-5M)；
The fourth step: adding radioactive ligand into each reaction tube3H-pyrilamine 10. mu.L (each reaction tube has 2 parallel channels, and each channel is placed on ice when loading sample).
The fifth step: incubating each reaction tube at 30 ℃ for 60min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 3ml scintillation cup, adding 2ml of toluene scintillation solution, and uniformly mixing;
and a sixth step: putting the scintillation vial into a liquid scintillation counter for counting
The inhibition ratio (I%) (total binding tube cpm-compound cpm)/(total binding tube cpm-non-specific binding tube cpm) × 100%
Compounds were run in duplicate for each experiment and two separate experiments were run. The results are shown in Table 2.
TABLE 2 Ki of Compounds for each receptor
Figure BDA0001346623270000281
The results of the above in vitro experiments show that compounds 9, 10, 26 and 27 are directed to four receptors (D)2,5-HT1A,5-HT2AAnd H3) Has stronger affinity; high affinity to H3, suggesting improvement of negative symptoms and cognitive impairment; compared to risperidone, affinity for H1 is weak, and side effects that produce weight gain are less likely.
Example 36 MK-801 induced high Activity Compounds anti-schizophrenia Activity in vivo
Laboratory animal and reagent
Healthy Kunming mice, each half male and female, with a weight of 20 + -2 g, were provided by Nanjing Qinglong mountain animal cultivation center.
Ascorbic acid, chemical agents of national drug group, ltd;
MK-801, manufactured by Sigma, USA, is prepared according to the following method: preparing 1mg/ml solution by using 0.1% of vitamin C;
test positive drugs: haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine;
tween 80, concentration 10%.
Experimental methods
Selecting mice with qualified body weight, and randomly dividing the mice into a blank group, a model group, a positive control group (risperidone group) and a drug group. The blank group and the model group are intragastrically administered with 0.1ml/10g of 10% Tween, the positive control group is intragastrically administered with 0.1mg/kg of risperidone, and the drug groups are separately intragastrically administered with the corresponding dose of drugs. After administration, the blank group is intraperitoneally injected with 0.1% ascorbic acid 0.1ml/10g 1h, and the model group, the positive control group (30min), and the drug group are intraperitoneally injected with MK-801 solution 0.1 mg/kg. Thereafter, spontaneous activity was measured in 90 minutes for each group of mice. The results are shown in Table 3.
Example 37 apomorphine-induced mouse climbing experiment
Laboratory animal
Healthy KM mice, male, with a weight of 18-22 g, were provided by Nanjing Qinglongshan animal breeding center.
Primary reagent
Test positive drugs: haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine;
apomorphine, supplied by Sigma, was dissolved in 0.9% NaCl (containing 0.1% vitamin C) just before use and was ready for use;
vitamin C, F20061113, national drug group chemical agents limited;
sodium chloride injection, H32026305, xuzhou city, fifth pharmaceutical factory, ltd.
The instrument is a self-made climbing cage and a stopwatch.
Experimental method, apomorphine induced mouse climbing experiment
The KM mice are male, the weight is 18-22 g, the KM mice are randomly divided into a negative control group, a model group, positive drug dose groups (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, haloperidol and clozapine) and compound dose groups (the specific administration dose is shown in the following table), and 10 mice are in each group. And (3) performing intragastric administration on the negative control group and the model group by using corresponding solvent double distilled water, performing intragastric administration on the positive medicine group by using corresponding positive medicine (trace acetic acid is added when dissolved, and double distilled water is added), and performing intragastric administration on each dosage group of the compound by using corresponding dosage of compound, wherein the intragastric administration volume is 0.1ml/10 g. Apomorphine (1mg/kg) was injected subcutaneously 1 hour after gavage in a volume of 0.1ml/10 g. Immediately placing the apomorphine into a climbing cage for adaptation for 5 minutes after apomorphine injection, observing behaviors of 10-11, 20-21 and 30-31 minutes after the apomorphine injection, and grading according to a grading standard: four feet scored 0 on the floor; the two forefoot scored 1 on the netpen; four feet scored 2 on the netpen. The results are shown in Table 3.
Example 38 Stiff disease test method
Laboratory animal
The healthy Kunming mouse is female and male half, and the weight is (22 +/-2) g, which is provided by Nanjing Qinglong mountain animal breeding center.
The main reagents are as follows:
a test agent, haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone
The instrument comprises the following steps:
self-made rod grabbing equipment: a stainless steel bar with the diameter of 0.3cm and 5cm higher than the workbench is placed in the mouse box.
The experimental method comprises the following steps:
the method comprises the following steps of (1) randomly dividing a KM mouse into a negative control group, a model group, positive drug dose groups (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, haloperidol and clozapine) and compound dose groups, wherein the weight of the KM mouse is 20-24 g for each male and female half, and each group contains 10 positive drugs. And (3) performing intragastric administration on the negative control group and the model group by using corresponding solvent double distilled water, performing intragastric administration on the positive medicine group by using corresponding positive medicine (trace acetic acid is added when dissolved, and double distilled water is added), and performing intragastric administration on each dosage group of the compound by using corresponding dosage of compound, wherein the intragastric administration volume is 0.1ml/10 g. After 30min, 60min and 90min of gavage, the two forepaws of the mouse are gently placed on a small rod with the length of 20cm, the diameter of 0.3cm and the height of 5.5cm higher than a workbench, the hind limbs of the animal are gently placed on the bottom surface of the box, the duration of the posture of the two forepaws of the mouse on the rod is recorded, and 30s of rigor and stillness is taken as a positive reaction. If the mouse forepaw has not been lowered, the observation is terminated at 60 s. The number of positive-reacting animals in each compound dose group was counted, and the results are shown in table 3.
Example 39 acute toxicity study
In the limit experiment of the sequential method, KM mice are taken, male and female are respectively divided into a plurality of groups randomly, 2-5 mice in each group are respectively a compound 2000mg/kg group and a solvent group, and the administration is performed by gastric lavage according to 0.2ml/10 g. Animals were observed for mortality within 3 days. (if 3 or more than 3 animals survive within three days and the life status is not obviously abnormal, the observation is continued until the experiment is ended after 7 days; if 3 or more than 3 animals die within three days, the LD50 is measured by a median lethality method.)
Half-lethal test KM mice were divided into groups of 4 animals each containing 1500mg/kg, 1000mg/kg, 500mg/kg of each compound and solvent group, and administered by gavage at a dose of 0.2ml/10g, and the death of the animals was observed within 1-3 days.
As a result: LD of mouse single drench50More than 2000mg/kg, and has less acute toxicity.
TABLE 3 in vivo animal model test results for preferred compounds
Figure BDA0001346623270000321
The results show that compounds 9, 10, 26 and 27 are in small doses in animal models with higher safety factors than the positive drugs.

Claims (9)

1. A compound which is a compound of formula I or a compound of formula I:
Figure FDA0003640518330000011
in the above-mentioned general formula (I),
n1is a compound of the formula (I) 3 or 4,
n2is 1 or 2;
Z is N;
R1，R2or R3Each independently represents hydrogen, halogen, C1-C5Or of C1-C5An alkoxy group;
w is CH, N; w is further substituted with Y; y is formula III;
Figure FDA0003640518330000012
q is O or S;
R6hydrogen, halogen;
Raand RbSelected from straight chain or branched chain alkyl containing 1-5 carbon atoms, or forms a five-seven-membered ring together with N, wherein the five-seven-membered ring is optionally substituted by phenyl, alkyl containing 1-5 carbon atoms, halogen substituted alkyl containing 1-5 carbon atoms.
2. The compound of claim 1, wherein N together with R attached theretoaAnd RbTogether to form a compound of formula IV or formula V,
Figure FDA0003640518330000021
R9is methyl or ethyl;
m is 0, 1 or 2;
x is one of O, N or CH; x may be unsubstituted or may be further substituted with R8 wherein R8Is hydrogen, unsubstituted C1-5Alkyl, phenyl, C1-5A haloalkyl group.
3. The compound or pharmaceutically acceptable salt according to claim 2, characterized in that: said unsubstituted C1-5The alkyl group is selected from methyl, ethyl, propyl, butyl, pentyl or isopentyl.
4. The compound or pharmaceutically acceptable salt according to claim 1, characterized in that: the halogen is fluorine, chlorine, bromine or iodine.
5. The compound or pharmaceutically acceptable salt according to claim 1, wherein C is 1-C5The alkoxy of (A) is methoxy or ethoxy.
6. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or the pharmaceutically acceptable salt thereof represented by the general formula I is selected from any one of the following compounds or pharmaceutically acceptable salts thereof:
(1) 5-fluoro-3- (1- (3- (4- (morpholinomethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(2) 6-fluoro-3- (1- (3- (4- (piperidinyl-1-ylmethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(3) 6-fluoro-3- (1- (3- (4- ((4-methylpiperidin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(4) 6-fluoro-3- (1- (3- (4- (pyrrolidin-1-ylmethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(5)3- (1- (3- (4- ((3, 5-dimethylpiperidin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) -5-fluorobenzo [ d ] isoxazole;
(6)1- (4- (3- (4- (5-fluorobenzo [ d ] isoxazolin-3-yl) piperidinyl-1-yl) propoxy) benzyl) piperidinyl-4-ol;
(7) N-ethyl-N- (4- (3- (4- (5-fluorobenzo [ d ] isoxazolin-3-yl) piperidinyl-1-yl) propoxy) benzyl) ethylamine;
(8)3- (1- (3- (4- ((2, 6-dimethylmorpholino) methyl) phenoxy) propyl) piperidinyl-4-yl) -6-fluorobenzo [ d ] isoxazole;
(9) 6-fluoro-3- (1- (3- (4- ((4-methylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(10)3- (1- (3- (4- ((4-ethylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) -6-fluorobenzo [ d ] isoxazole;
(11) 6-fluoro-3- (1- (3- (4- ((4-phenylpiperazin-1-yl) methyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(12)4- (4- (3- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) propoxy) benzyl) morpholine;
(26) 6-fluoro-3- (1- (3- (4- (2-morpholinoethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(27) 6-fluoro-3- (1- (3- (4- (2- (piperidinyl-1-yl) ethyl) phenoxy) propyl) piperidinyl-4-yl) benzo [ d ] isoxazole;
(28) 6-fluoro-3- (1- (3- (4- (2- (4-methylpiperidin-1-yl) ethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole;
(29) 6-fluoro-3- (1- (3- (4- (2- (4-methylpiperazin-1-yl) ethyl) phenoxy) propyl) piperidin-4-yl) benzo [ d ] isoxazole.
7. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.
8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for treating a disease or condition mediated by the H3 receptor in a subject.
9. The use according to claim 8, wherein the disease or condition mediated by the H3 receptor is one of epilepsy, schizophrenia, senile dementia, sleep disorders, obesity, neuralgia, and attention deficit hyperactivity disorder.
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