CN105315267A - Amide derivative and application thereof - Google Patents
Amide derivative and application thereof Download PDFInfo
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- CN105315267A CN105315267A CN201410371198.4A CN201410371198A CN105315267A CN 105315267 A CN105315267 A CN 105315267A CN 201410371198 A CN201410371198 A CN 201410371198A CN 105315267 A CN105315267 A CN 105315267A
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Abstract
The invention belongs to the field of medicinal chemistry, and particularly relates to an amide derivative and an application thereof. The amide derivative has a structure represented by a formula (I). Experiments verify that the compounds can be applied to preparing drugs for treating nervous and mental diseases.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of amide derivatives and application thereof.
Background technology
Schizophrenia as one independently entity have over one hundred year history.At Kraepelin in 1896 on summary previous work basis, several clinical pictures proposed before this are generalized into a kind of disease, are referred to as dementia praecox; 20 beginnings of the century, Bleuler states its neodoxy, thinks that its core of obstacle of the aspects such as this disease existence association, emotion, will and schizosis is schizophrenia, and uses till today always.
Schizophrenia is the most serious in all mental disorderes, endangers maximum a kind of disease, global incidence be about 1 ?2%.Schizophreniac's lifetime prevalence be 0.7 ?0.8%, with sex, race, or social boundary does not have obvious dependency, simultaneously mortality ratio than population exceed 2 ?3 times.Current research shows, and burden on society rank in Chinese disease of mental disorder tops the list, and has exceeded the illness such as cardiovascular and cerebrovascular, respiratory system and malignant tumour.
Existing schizophrenia medicine mainly contains two large classes: typical anti-schizophrenia medicine and the anti-schizophrenia medicine of atypia.The anti-schizophrenia medicine of typical case (as chlorpromazine and haloperidol) blocks dopamine D
2acceptor, has good efficacy to schizophrenia positive symptom.But owing to strongly blocking Dopamine Receptors, result in the untoward reactions such as the extrapyramidal symptoms (EPS), tardive dyskinesia and lactotropin increase, and invalid to negative symptoms of schizophrenia.
The anti-schizophrenia medicine of atypia is with leoponex and risperidone for representative, not only to Dopamine HCL (D
2) acceptor has and comparatively pretends use, simultaneously to 5 ?hydroxy-tryptamine (5 ?HT
2A) acceptor also has and comparatively pretend use.This kind of medicine has very large advantage compared with typical case's anti-schizophrenia medicine: have good efficacy to schizophrenia positive symptom; The side effect such as the extrapyramidal symptoms and tardive dyskinesia significantly reduces; Part atypia anti-schizophrenia medicine has certain improvement result to negative symptoms and cognitive disorder.But the anti-schizophrenia medicine of atypia of current clinical application has the untoward reaction such as QT interval prolongation and high lactotropin in various degree
].Therefore, find and new effectively can cure schizophrenia and the little medicine of side effect is extremely important.
Through the research of decades, find D
2, 5 ?HT
1A, 5 ?HT
2Aand H
1deng five acceptors to the very important effect of schizophrenia.With D
2receptor acting can effectively treat schizophrenia positive symptom.5 ?hydroxy-tryptamine system regulate prefrontal cortex function in play an important role, comprise emotion control, cognitive behavior and working memory.The cone neurone of prefrontal cortex and GABA relay cell comprise 5 ?seretonine receptor 55 ?HT
1Awith 5 ?HT
2A.5 ?hydroxy-tryptamine system regulate prefrontal cortex function in play an important role, comprise emotion control, cognitive behavior and working memory
].5 ?HT
1Atreat relevant to atypical antipsychotic, negative symptoms and cognitive disorder can be improved.5 ?HT
2Aacceptor relates to all respects of perception, mood regulation and motion control, block 5 ?HT
2Aacceptor can make the release normalizing of Dopamine HCL, and plays antipsycholic action.
Simultaneously in the Long-term taking medicine process for the treatment of schizophrenia, some drugs is easy to the side effect causing body weight to increase, and research shows these side effects and histamine H
1acceptor is closely related.
Therefore, find now the mode that a polyceptor combines, improve the sphere of action of anti-schizophrenia medicine, and the side effect such as EPS and body weight increase can be reduced.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of amide derivatives with pharmaceutical activity is provided.
Another object of the present invention is to provide a kind of pharmaceutical composition containing above-claimed cpd.
A further object of the invention is to provide the application of above-claimed cpd in prevention or treatment Neuropsychic diseases.
Object of the present invention can be reached by following measures:
The compound of general formula of the present invention (I) or its pharmacy acceptable salt:
Wherein:
X Wei ?NR
1c (O) ?， ?C (O) ?Huo ?S (O
2) ?;
N is 1 or 2;
R is for replacing or not replacing C
1 ?5alkane, replaces or does not replace C
3 ?7naphthenic hydrocarbon, the group shown in formula II, formula III, formula IV or formula V,
R
1, R
2, R
3, R
4or R
5separately be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, substituted or unsubstituted C
1 ?5alkoxyl group, substituted or unsubstituted C
1 ?5alkyl, wherein said C
1 ?5the substituting group of alkyl is selected from one or more in amino, hydroxyl or fluorine;
Y is selected from O, N or S.
In general formula (I) compound, when X Wei ?NR
1c (O) ?time, preferred R
1for hydrogen or substituted or unsubstituted C
1 ?5alkyl, R is substituted or unsubstituted C
1 ?5group shown in alkyl, formula II or formula III, the substituent R on wherein said formula II
2for hydrogen, substituted or unsubstituted C
1 ?5alkyl, substituted or unsubstituted C
1 ?5alkoxy or halogen; Described C
1 ?5the substituting group of alkyl is selected from one or more in amino, hydroxyl or fluorine.
In general formula (I) compound, when X Wei ?NR
1c (O) ?time, further preferably, R
1for hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group or isopentyl; R is methyl, group shown in ethyl, propyl group, structure I I or III, the substituent R on wherein said formula II
2for hydrogen, methyl, ethyl, propyl group, chlorine or fluorine.
In general formula (I) compound, when X Wei ?C (O) ?time, preferably: R is for replacing or not replacing C
3 ?7naphthenic hydrocarbon, substituted or unsubstituted C
1 ?5group shown in alkyl or formula II, substituent R on its Chinese style II
2for substituted or unsubstituted C
1 ?5alkoxy or halogen; Described non-C
3 ?7naphthenic hydrocarbon is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl more preferably; Described C
1 ?5the further preferred tertiary butyl of alkyl; R on described formula II
2substituting group is fluorine or methoxyl group more preferably.
In general formula (I) compound, when X Wei ?S (O
2) ?, preferred R be group shown in formula II, formula IV or formula V, the substituent R on its Chinese style II, formula IV or formula V
2, R
4, R
5be selected from hydrogen, substituted or unsubstituted C
1 ?5alkyl, nitro, halogen or cyano group, the C of described replacement
1 ?5the substituting group of alkyl is selected from halogen; Described R
2, R
4, R
5preferred from hydrogen, methyl further, ethyl, propyl group, nitro, trifluoromethyl, fluorine, chlorine.
Compound of the present invention or its pharmacy acceptable salt, the described compound shown in general formula (I) or its pharmacy acceptable salt are selected from any one compound following or its pharmacy acceptable salt most::
The pharmacy acceptable salt of the compound of general formula of the present invention (I), wherein, described salt is for containing pharmaceutically acceptable anion salt: example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol or hydrosulfate, phosphoric acid salt or acid phosphate, acetate, lactic acid salt, Citrate trianion, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoate, esilate, benzene sulfonate, tosilate etc.
In the present invention, unsubstituted C
1 ?5alkyl represents methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group or isopentyl; The C replaced
1 ?5alkyl represents the C of halogen substiuted
1 ?5alkyl, methyl substituted C
1 ?5alkyl, the C that ethyl replaces
1 ?5alkyl; Halogen represents fluorine, chlorine, bromine, iodine; Described unsubstituted C
3 ?7cycloalkyl representative ring propyl group, cyclobutyl, cyclopentyl, cyclohexyl, the C of replacement
3 ??7cycloalkyl represents the C of halogen substiuted
3 ?7cycloalkyl, C
1 ?5the C that alkyl replaces
3 ?7cycloalkyl; Described substituted or unsubstituted aryl represents substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, and described substituting group is selected from one or more in alkyl, cyano group, hydroxyl or halogen; Unsubstituted C
1 ?5alkoxyl group represents methoxyl group, oxyethyl group, propoxy-or butoxy.The phenyl of described replacement represents C
1 ?5the phenyl of the phenyl that alkoxyl group replaces, p-methoxy-phenyl, halo; The benzyl replaced is the benzyl of methoxy-benzyl, halo.
The universal synthesis method of general formula (I) compound is that the piperidine carbinols of Boc protection and Tosyl chloride react; then with 6 ?Fu ?3 ?(4 ?piperidyl) ?1; 2 ?benzoisoxazole under the condition of triethylamine, be obtained by reacting product; BOC is taken off with ethyl acetate saturated salt acid gas; last and corresponding acyl chlorides or isocyanate reaction obtain embodiments of the invention and are obtained by reacting target product, and concrete reaction scheme is as follows:
Reaction conditions: (a) TsCl, Et
3n, 0 DEG C ?rt; (b), Et
3n, CH
3cN, 24h; (c) EA/HCl; (d), Et
3n, CH
2cl
2, 0 DEG C ?rt.
And then, the invention provides a kind of pharmaceutical composition, it comprises compound or its pharmacy acceptable salt of general formula (I), with pharmaceutically acceptable auxiliary material (as carrier and/or vehicle etc.), this pharmaceutical composition is the antipsychotic composition containing being enough to the compounds of this invention producing antipsycholic action.
The effective dose of the compounds of this invention can be oral together with such as inert diluent or certain carrier.Can be wrapped in gelatine capsule or tabletted.For the object of oral administration, the compounds of this invention can use and use with forms such as tablet, lozenge, capsule, suspensoid, syrups together with vehicle.These preparations should active compound of the present invention containing at least 0.5wt%, but can change according to specific formulation, and account for unit weight 4% is easily to about 70%.In such composition, the amount of active compound should reach suitable dosage.The oral dosage of the composition that the present invention is preferential and preparation contain 1.0 ?the active compound of the present invention of 300 milligrams.
The compound of general formula provided by the invention (I) or its pharmacy acceptable salt, solvate and hydrate can with pharmaceutically acceptable carrier or thinner combined utilization form pharmaceutical preparation.Pharmaceutically acceptable suitable carrier comprises inert solid weighting agent or thinner and aseptic aqueous solution or organic solution.
The consumption of the compounds of this invention depends on and type and the seriousness of disease or illness also depends on the feature of object, such as general health, age, sex, body weight and drug tolerance.Technician can determine suitable dosage according to these or other factors.The effective dose of medicine for central nervous system usually used is known by the technical staff.Every TDD is usually about between 0.05mg to 2000mg.
The present invention relates to pharmaceutical composition, its per unit dosage can provide the activeconstituents of about 0.01 to 1000mg.Composition is used by any suitable approach, such as capsules per os, uses with the form parenteral of injection liquid, with the form topical application of paste or lotion, with the form rectal administration of suppository, with the form applied dermally of the transfer system of paster.
Compound provided by the invention can be combined to form capsule, tablet, pill, powder, syrup, solution etc. with suitable solid or liquid vehicle or thinner.Tablet, pill, capsule etc. comprise activeconstituents and tackiness agent such as gelatin, W-Gum, the Sudan Gum-arabic of about 0.01 to about 99 weight percents; Excipients is as secondary calcium phosphate; Disintegrating agent is W-Gum, yam starch or alginic acid such as; Lubricant is Magnesium Stearate such as; With Sweetening agents as sucrose, lactose.When dosage form is capsule, except the raw material of the above-mentioned type, also liquid vehicle can be comprised, such as grease.
Use for parenteral, compound provided by the invention can be combined to form injectable solution or suspension with sterilized water or organic medium.
The compound of general formula I can contain chiral centre, and can exist with different enantiomorph and diastereomer form thus.The present invention relates to all optically active isomers of compound of Formula I and all steric isomers, as the racemic mixture of this compounds and the form of each enantiomorph and diastereomer, and the present invention relate separately to as above-mentioned define containing or use their all pharmaceutical compositions and methods for the treatment of.
In addition, compound provided by the invention and the pharmaceutical composition that is made up of compound are for the preparation of the application in Nervous and mental diseases medicine, and described Nervous and mental diseases is schizophrenia.
Extracorporeal receptor binding tests shows, compounds against dopamine D2 involved in the present invention, 5HT1A and 5HT2A acceptor has higher avidity, with H1 (reduce chronic under risk of obesity treat) avidity is low, the effect (as improved negative symptoms) that can increase medicine reduces side effect (as EPS, breast secretin increases, and body weight increases and QI gap extension).
Animal test results shows, and this compounds obviously can improve the high reactivity that MK ?801 induces, and effectively can improve again the climbing symptom of Apomorphine induction, and do not cause EPS under effective dose.Show that it has obvious anti-schizophrenia effect.Due to the nervous system disorders that pharmacological model in these interaction in vitro target spots and body and Dopamine disorder cause, particularly schizophrenia is closely related, therefore point out the compound that the present invention relates to have the effect for the treatment of Nervous and mental diseases, especially have therapeutic action to schizophrenia.The detailed pharmacological datum of each compound is in table 2.
Embodiment
The following examples are just for the purpose of description and not as restriction of the present invention.
The embodiment of A, synthesis aspect
Embodiment 1,4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) ?N, N ?Er Jia base Pai Ding ?1 ?acid amides
(1) N ?Boc ?4 ?piperidine carbinols (0.1mol) be dissolved in 300ml methylene dichloride, ice bath is chilled to 10 DEG C, triethylamine 20ml adds, and then adds p-methyl benzene sulfonic chloride (0.11mmol) in batches, at room temperature reacts 12h after adding.React complete, reaction solution washes with water, saturated sodium bicarbonate solution is washed, organic over anhydrous dried over mgso, pressure reducing and steaming solvent, residuum is crossed post (eluent PE:EA=1:1) and is obtained colorless oil 34g, yield 92.1%, MS (ESI) m/z370.2 ([M+H]
+).
(2) get colorless oil 0.1mol prepared by the first step, 6 ?Fu ?3 ?(4 ?piperidyl) ?1,2 ?benzoisoxazole (0.1mol), in triethylamine 25ml and 500ml acetonitrile, heating reflux reaction 12h, reacts complete, is spin-dried for solvent, add 500ml methylene dichloride, washing, lemon pickling, organic over anhydrous dried over mgso, pressure reducing and steaming solvent, residuum crosses post (eluent CH
2cl
2: methyl alcohol=10:1) obtain colorless oil 35g, yield 83.7%, MS (ESI) m/z418.2 ([M+H]
+).
(3) get colorless oil 0.1mol prepared by second step, add the saturated hcl ethyl acetate gas of 200ml, stirring at room temperature reaction 6h, react complete, filter, obtain white solid, by white solid water dissolution, PH to 11 is adjusted with sodium hydroxide, by dichloromethane extraction 2 times (2 × 200ml), organic over anhydrous dried over mgso, be spin-dried for solvent and obtain white solid 25g, yield 78.9%, MS (ESI) m/z318.2 ([M+H]
+).
(4) get white solid 2mmol prepared by the 3rd step, triethylamine 2ml and 20ml methylene dichloride, ice bath is chilled to 10 DEG C, drip N, N ?dimethyl methyl acyl chlorides (2mmol), at room temperature react 4h after dropwising, react complete, washing, saturated sodium bicarbonate solution is washed, organic over anhydrous dried over mgso, be spin-dried for solvent, residuum recrystallized from acetonitrile obtains white solid 0.62g, yield 80.5%, and structural formula is as numbered shown in (1) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.10‐1.17(m,2H),1.66‐1.68(m,1H),1.75(d,2H,J＝6.4Hz),2.01‐2.10(m,6H),2.20(d,2H,J＝4Hz),2.70(t,2H,J＝6.4Hz),2.78(s,6H),2.95‐3.04(m,3H),3.64(d,2H,J＝6.4Hz),7.00‐7,05(m,1H),7.19(d,1H,J＝6.4Hz),7.65‐7.67(m,1H).MS(ESI)m/z389.3([M+H]
+).
2,4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) ?N ?(4 ?tolyl) Pai Ding ?1 ?acid amides
Replace N with aromatic isocyanatcs, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (2) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.25‐1.43(m,3H),1.82‐1.85(m,2H),2.00‐2.10(m,6H),2.18‐2.26(m,4H),2.42(s,3H),2.91(d,2H,J＝4Hz)3.01‐3.03(m,1H),3.79(d,2H,J＝4Hz),7.03‐7.07(m,1H),7.22‐7.25(m,1H),7.29‐7.31(m,2H),7.65‐7.68(m,3H).MS(ESI)m/z436.2([M+H]
+).
3,4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) ?N ?(4 ?chloro-phenyl-) Pai Ding ?1 ?acid amides
Replace N with chlorophenyl isocyanate, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (3) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.19‐1.28(m,2H),1.77‐1.79(m,1H),1.89(d,2H,J＝6.4Hz),2.06‐2.18(m,6H),2.27(d,2H,J＝4Hz),2.90‐2.95(m,2H),3.01‐3.11(m,3H),4.09(d,2H,J＝6.4Hz),7.07‐7.10(m,1H),7.25‐7.27(m,3H),7.32‐7.34(m,2H),7.70‐7.72(m,1H).MS(ESI)m/z471.2([M+H]
+).
4,4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) ?N ?(benzyl) Pai Ding ?1 ?acid amides
With benzyl isocyanate ester replace N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (4) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.13‐1.20(m,2H),1.72‐1.74(m,1H),1.82(d,2H,J＝6.4Hz),2.06‐2.16(m,6H),2.24(d,2H,J＝4Hz),2.79‐2.84(m,2H),3.02‐3.09(m,3H),3.99(d,2H,J＝6.4Hz),4.05(d,2H,J＝4Hz),7.06‐7.09(m,1H),7.25‐7.27(m,2H),7.32‐7.34(m,4H),7.69‐7.71(m,1H).MS(ESI)m/z451.2([M+H]
+).
5, (4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) Pai Ding ?1 ?base) (cyclopropyl) ketone
With ring third formyl chloride replace N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (5) in table 1.
1H‐NMR(600MHz,CDCl
3)δ0.75‐0.77(m,2H),0.99‐1.21(m,4H),1.78‐1.82(m,4H),2.07‐2.10(m,8H),2.26‐2.28(m,1H),2.99‐3.09(m,4H),4.24‐4.26(m,1H),4.61‐4.63(m,1H),7.06‐7.09(m,1H),7.25‐7.27(m,1H),7.71‐7.73(m,1H).MS(ESI)m/z386.2([M+H]
+).
6, (4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) Pai Ding ?1 ?base) (tertiary butyl) ketone
With tertiary butyl formyl chloride replace N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (6) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.09‐1.16(m,2H),1.29(s,9H),1.79‐1.85(m,3H),2.05‐2.13(m,6H),2.24(d,2H,J＝4Hz),2.78‐2.81(m,2H),2.99‐3.06(m,3H),4.44(d,2H,J＝4Hz),7.05‐7.08(m,1H),7.24‐7.27(m,1H),7.69‐7.72(m,1H).MS(ESI)m/z402.2([M+H]
+).
7, (4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) Pai Ding ?1 ?base) (phenyl) ketone
Replace N with Benzoyl chloride, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (7) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.16‐1.27(m,2H),1.79‐1.93(m,3H),2.06‐2.16(m,6H),2.28(d,2H,J＝4Hz),2.78‐2.81(m,1H),3.02‐3.09(m,4H),3.75‐3.81(m,1H),4.72‐4.80(m,1H),7.05‐7.08(m,1H),7.24‐7.27(m,1H),7.69‐7.72(m,1H).MS(ESI)m/z422.2([M+H]
+).
8, (4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) Pai Ding ?1 ?base) (4 ?fluorophenyl) ketone
With fluorobenzoyl chloride is replaced N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (8) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.10‐1.27(m,2H),1.82‐1.91(m,3H),2.04‐2.16(m,6H),2.28(d,2H,J＝4Hz),2.79‐2.81(m,1H),3.00‐3.09(m,4H),3.73‐3.78(m,1H),4.71‐4.79(m,1H),7.05‐7.12(m,3H),7.24‐7.26(m,1H),7.41‐7.44(m,2H),7.68‐7.72(m,1H).MS(ESI)m/z440.2([M+H]
+).
9, (4 ?((4 ?(6 ?Fu Ben Sai Zuo ?3 ?base) Pai Ding ?1 ?base) methyl) Pai Ding ?1 ?base) (4 ?p-methoxy-phenyl) ketone
Replace N with anisoyl chloride, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (9) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.10‐1.26(m,2H),1.80‐1.90(m,3H),2.05‐2.16(m,6H),2.26(d,2H,J＝4Hz),2.77‐2.80(m,1H),3.00‐3.09(m,4H),3.53(s,3H),3.72‐3.77(m,1H),4.71‐4.76(m,1H),7.03‐7.11(m,3H),7.23‐7.26(m,1H),7.40‐7.45(m,2H),7.69‐7.71(m,1H).MS(ESI)m/z452.3([M+H]
+).
10,3 ?(1 ?((1 ?((4 ?fluorophenyl) alkylsulfonyl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With fluorophenylsulfonyl chloride is replaced N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (10) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.28‐1.33(m,2H),1.45‐1.48(m,1H),1.85‐1.87(m,2H),2.00‐2.12(m,6H),2.20‐2.31(m,4H),2.92(d,2H,J＝4Hz)3.00‐3.05(m,1H),3.81(d,2H,J＝4Hz),7.04‐7.07(m,1H),7.21‐7.25(m,3H),7.66‐7.68(m,1H),7.78‐7.80(m,2H).MS(ESI)m/z476.2([M+H]
+).
11,3 ?(1 ?((1 ?((4 ?nitrophenyl) alkylsulfonyl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
Replace N with 4-Nitrobenzenesulfonyl chloride, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (11) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.28‐1.35(m,2H),1.49‐1.51(m,1H),1.88‐1.90(m,2H),2.01‐2.13(m,6H),2.21‐2.36(m,4H),2.93(d,2H,J＝4Hz)3.03‐3.07(m,1H),3.88(d,2H,J＝4Hz),7.05‐7.08(m,1H),7.24‐7.26(m,1H),7.66‐7.68(m,1H),7.97‐7.98(m,2H),8.40‐8.42(m,2H).MS(ESI)m/z503.2([M+H]
+).
12,3 ?(1 ?((1 ?((4 ?cyano-phenyl) alkylsulfonyl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With cyanobenzenesulfonyl chloride is replaced N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (12) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.25‐1.31(m,2H),1.48‐1.50(m,1H),1.85‐1.87(m,2H),1.99‐2.10(m,6H),2.19‐2.35(m,4H),2.91(d,2H,J＝4Hz)3.01‐3.03(m,1H),3.83(d,2H,J＝4Hz),7.03‐7.06(m,1H),7.22‐7.24(m,1H),7.65‐7.67(m,1H).7.85‐7.90(m,4H).MS(ESI)m/z483.2([M+H]
+).
13,3 ?(1 ?((1 ?((4 ?trifluoromethyl) alkylsulfonyl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With replacing N, N ?dimethyl methyl acyl chlorides to be raw material to trifluoromethyl benzene sulfonyl chloride, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (13) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.28‐1.34(m,2H),1.48‐1.50(m,1H),1.86‐1.89(m,2H),2.02‐2.10(m,6H),2.20‐2.33(m,4H),2.93(d,2H,J＝4Hz)3.03‐3.05(m,1H),3.87(d,2H,J＝4Hz),7.04‐7.06(m,1H),7.22‐7.24(m,1H),7.66‐7.68(m,1H),7.81‐7.83(m,2H),7.91‐7.92(m,2H).MS(ESI)m/z526.2([M+H]
+).
14,3 ?(1 ?((1 ?((4 ?aminomethyl phenyl) alkylsulfonyl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
Replace N with p-methyl benzene sulfonic chloride, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (14) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.28‐1.45(m,3H),1.83‐1.85(m,2H),2.00‐2.11(m,6H),2.19‐2.27(m,4H),2.44(s,3H),2.92(d,2H,J＝4Hz)3.02‐3.04(m,1H),3.80(d,2H,J＝4Hz),7.04‐7.07(m,1H),7.23‐7.25(m,1H),7.29‐7.32(m,2H),7.65‐7.69(m,3H).MS(ESI)m/z472.2([M+H]
+).
15,3 ?(1 ?((1 ?((phenyl) alkylsulfonyl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
Replace N with benzene sulfonyl chloride, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (15) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.27‐1.34(m,2H),1.47‐1.50(m,1H),1.84‐1.86(m,2H),2.02‐2.10(m,6H),2.21‐2.30(m,4H),2.93(d,2H,J＝4Hz)3.03‐3.05(m,1H),3.83(d,2H,J＝4Hz),7.04‐7.07(m,1H),7.24‐7.26(m,1H),7.52‐7.56(m,3H),7.60‐7.62(m,1H),7.78‐7.79(m,2H).MS(ESI)m/z458.2([M+H]
+).
16,3 ?(1 ?((1 ?(2 ?naphthalene sulfonyl base) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With 2 ?naphthalic sulfonic chloride replace N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (16) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.26‐1.34(m,2H),1.45‐1.48(m,1H),1.85‐1.87(m,2H),2.00‐2.10(m,6H),2.20‐2.28(m,4H),2.92(d,2H,J＝4Hz)3.02‐3.05(m,1H),3.81(d,2H,J＝4Hz),7.04‐7.06(m,1H),7.24‐7.26(m,2H),7.52‐7.56(m,3H),7.61‐7.63(m,1H),7.76‐7.78(m,2H),7.99‐8.01(m,1H)MS(ESI)m/z508.2([M+H]
+).
17,3 ?(1 ?((1 ?(2 ?thiophen sulfuryl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With 2 ?thiophenesulfonyl chloride replace N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (17) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.33‐1.38(m,2H),1.48‐1.51(m,1H),1.88‐1.90(m,2H),2.02‐2.11(m,6H),2.22‐2.34(m,4H),2.95(d,2H,J＝4Hz)3.02‐3.07(m,1H),3.84(d,2H,J＝4Hz),7.05‐7.08(m,1H),7.16‐7.17(m,1H),7.24‐7.26(m,1H),7.54‐7.56(m,1H),7.62‐7.63(m,1H),7.68‐7.70(m,1H).MS(ESI)m/z464.2([M+H]
+).
18,3 ?(1 ?((1 ?((4 ?nitrophenyl) alkylsulfonyl) Pai Ding ?4 ?base) ethyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With N ?Boc ?4 ?piperidine ethanol replace N ?Boc ?4 ?piperidine carbinols be raw material, prepare target compound by the method for enforcement 11, structural formula is as numbered shown in (18) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.34‐1.38(m,4H),1.47‐1.50(m,1H),1.75‐1.81(m,2H),2.05‐2.14(m,6H),2.33‐2.39(m,4H),3.01‐3.08(m,3H),3.85(d,2H,J＝4Hz),7.04‐7.08(m,1H),7.24‐7.26(m,1H),7.66‐7.68(m,1H),7.96‐7.98(m,2H),8.40‐8.41(m,2H).MS(ESI)m/z517.2([M+H]
+).
19,3 ?(1 ?((1 ?((4 ?nitrophenyl) alkylsulfonyl) Pai Ding ?3 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With N ?Boc ?3 ?piperidine carbinols replace N ?Boc ?4 ?piperidine carbinols be raw material, prepare target compound by the method for enforcement 11, structural formula is as numbered shown in (19) in table 1.
1H‐NMR(600MHz,CDCl
3)δ0.94‐0.98(m,1H),1.77‐1.79(m,1H),1.88‐1.90(m,2H),2.01‐2.13(m,6H),2.21‐2.36(m,4H),2.93(d,2H,J＝4Hz)3.03‐3.07(m,1H),3.88(d,2H,J＝4Hz),7.05‐7.08(m,1H),7.24‐7.26(m,1H),7.66‐7.68(m,1H),7.97‐7.98(m,2H),8.40‐8.42(m,2H).MS(ESI)m/z503.2([M+H]
+).
20,3 ?(1 ?((1 ?((2 ?nitrophenyl) alkylsulfonyl) Pai Ding ?4 ?base) methyl) Pai Ding ?4 ?base) ?6 ?fluoro benzothiazole
With ortho-nitrophenyl SULPHURYL CHLORIDE replace N, N ?dimethyl methyl acyl chlorides be raw material, prepare target compound by the method for embodiment 1, structural formula is as numbered shown in (20) in table 1.
1H‐NMR(600MHz,CDCl
3)δ1.25‐1.29(m,2H),1.61‐1.63(m,1H),1.87‐1.89(m,2H),2.01‐2.10(m,6H),2.22‐2.24(m,2H),2.74‐2.77(m,2H),2.95(d,2H,J＝4Hz)3.01‐3.07(m,1H),3.86(d,2H,J＝4Hz),7.04‐7.07(m,1H),7.22‐7.24(m,1H),7.69‐7.71(m,4H),7.97‐7.99(m,1H).MS(ESI)m/z503.2([M+H]
+).
Compound number prepared by table 1 embodiment 1 ~ 20 and structural formula thereof
The embodiment of B, pharmacology aspect
Embodiment 21
5 ?HT
1Athe preparation of film
Rat breaks end, and operates on ice, gets cortex rapidly, add 3ml damping fluid (Tris of 0.05M ?HCl damping fluid, the xitix containing 0.1%, 10um Supirdyl and 4mMCaCl
2) in 4 grade 3 ?4s homogenate, homogenate 4 times, then add 5ml damping fluid (Tris of 0.05M ?HCl damping fluid, the xitix containing 0.1%, 10um Supirdyl and 4mMCaCl
2), in 37 DEG C of hatching 10min, hatch rear test tube balance and adjusted weight, at 12000r, 4 DEG C of centrifugal 20min, abandon supernatant liquor, add 3ml damping fluid, with vortex mixer mixing, then add 5ml damping fluid, centrifugal, centrifugal in triplicate, centrifugal complete, abandon supernatant liquor, by Chen Dian Yu ?80 DEG C store for future use.
Receptor Binding Assay material:
Isotropic substance aglucon
3h ?8 ?OH ?DPAT (67.0Ci/mmol), purchased from PerkinElmer company; 5 ?HT, purchased from RBI company; GF/C glass fiber filter paper, purchased from Whatman company; Tris import packing; PPO, POPOP are purchased from Shanghai reagent one factory; Fat-soluble scintillation solution.BeckmanLS ?6500 type full-service fluid scintillation counters.
Experimental technique:
(1) the appropriate damping fluid of film first will prepared, is uniformly dispersed with refiner, is mixed in the container of 100ml by 15 test tubes, adds the suspension that appropriate damping fluid is 50ml film, for subsequent use.
(2) each reaction tubes adds film preparation thing 100 μ L respectively, damping fluid 100 μ L.
(3) total binding pipe (TB) adds 100 μ L damping fluids, non-specific binding pipe (NB) add 5 ?HT100 μ L (final concentration 10
?5m), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10
?5m);
(4) each reaction tubes adds radioligand respectively
3h ?8 ?OH ?DPAT10 μ L (each reaction tubes all establishes 2 parallel pipes, and during application of sample, each pipe is placed on ice).
(5) each reaction tubes 37 DEG C of temperature are incubated 10min, react complete, in conjunction with aglucon by decompression fast filtering, fully wash with ice-cold test damping fluid, by filter disc take out be put in 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
(6) scintillation vial is put into liquid scintillation counter counting
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested at every turn and is done two multiple pipes, carries out testing separately for twice.Experimental result is in table 2
Embodiment 22
5 ?HT
2Athe preparation of film
Rat breaks end, operate on ice, get cortex rapidly, add 3ml damping fluid (Tris of 0.05M ?HCl damping fluid: get 6.05gTris and be dissolved in 1000ml distilled water, adjust PH to be 7.5 with dense HCl) in 4 grade 3 ?4s homogenate, homogenate 4 times, then 5ml damping fluid is added, in 37 DEG C of hatching 10min, hatch rear test tube balance and adjust weight, at 12000r, 4 DEG C of centrifugal 20min, abandon supernatant liquor, add 3ml damping fluid, mix with vortex mixer, add 5ml damping fluid again, centrifugal, (centrifugal in triplicate), centrifugal complete, abandon supernatant liquor, by Chen Dian Yu ?80 DEG C store for future use.
Receptor Binding Assay material:
Isotropic substance aglucon [
3h] ?Ketanserin (67.0Ci/mmol), purchased from PerkinElmer company; Methysergide, purchased from RBI company; GF/C glass fiber filter paper, purchased from Whatman company; Tris import packing; PPO, POPOP are purchased from Shanghai reagent one factory; Fat-soluble scintillation solution.BeckmanLS ?6500 type full-service fluid scintillation counters.
Experimental technique:
(1) the appropriate damping fluid of film first will prepared, is uniformly dispersed with refiner, is mixed in the container of 100ml by 15 test tubes, adds the suspension that appropriate damping fluid is 50ml film, for subsequent use.
(2) each reaction tubes adds film preparation thing 100 μ L respectively, damping fluid 100 μ L.
(3) total binding pipe (TB) adds 100 μ L damping fluids, and non-specific binding pipe (NB) adds Methysergide100 μ L (final concentration 10
?5m), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10
?5m);
(4) each reaction tubes adds radioligand respectively
3h ?Ketanserin10 μ L (each reaction tubes all establishes 2 parallel pipes, and during application of sample, each pipe is placed on ice).
(5) each reaction tubes 37 DEG C of temperature are incubated 15min, react complete, in conjunction with aglucon by decompression fast filtering, fully wash with ice-cold test damping fluid, by filter disc take out be put in 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
(6) scintillation vial is put into liquid scintillation counter counting
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested at every turn and is done two multiple pipes, carries out testing separately for twice.Experimental result is in table 2
Embodiment 23
D
2the preparation of film
Rat breaks end, operate on ice, get brain striatum rapidly, add 3ml damping fluid (Tris of 0.05M ?HCl damping fluid, containing NaCl120mM, KCl5mM, MgCl21mM, CaCl21mM), in 4 grade 3 ?4s homogenate, homogenate 4 times, then adds 5ml damping fluid, test tube balance complete for homogenate is adjusted weight, at 12000r, 4 DEG C of centrifugal 20min, abandon supernatant liquor, add 3ml damping fluid, with vortex mixer mixing, then add 5ml damping fluid, centrifugal, centrifugal in triplicate, centrifugal complete, abandon supernatant liquor, by Chen Dian Yu ?80 DEG C store for future use.
Receptor Binding Assay material:
Isotropic substance aglucon
3h ?Spiperone (67.0Ci/mmol), purchased from PerkinElmer company; Butaclamol, purchased from RBI company; GF/C glass fiber filter paper, purchased from Whatman company; Tris import packing; PPO, POPOP are purchased from Shanghai reagent one factory; Fat-soluble scintillation solution.BeckmanLS ?6500 type full-service fluid scintillation counters.
Experimental technique:
(1) the appropriate damping fluid of film first will prepared, is uniformly dispersed with refiner, is mixed in the container of 100ml by 15 test tubes, adds the suspension that appropriate damping fluid is 50ml film, for subsequent use.
(2) each reaction tubes adds film preparation thing 100 μ L respectively, damping fluid 100 μ L.
(3) total binding pipe (TB) adds 100 μ L damping fluids, and non-specific binding pipe (NB) adds 100 μ LButaclamol (final concentrations 10
?5m), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10
?5m);
(4) each reaction tubes adds radioligand respectively
3h ?Spiperone10 μ L (each reaction tubes all establishes 2 parallel pipes, and during application of sample, each pipe is placed on ice).
(5) each reaction tubes 37 DEG C of temperature are incubated 20min, react complete, in conjunction with aglucon by decompression fast filtering, fully wash with ice-cold test damping fluid, by filter disc take out be put in 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
(6) scintillation vial is put into liquid scintillation counter counting
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested at every turn and is done two multiple pipes, carries out testing separately for twice.Experimental result is in table 2.
Embodiment 24
Histamine H
1the preparation of receptor membrane
Cavy breaks end, and operates on ice, gets guinea pig cerebellum rapidly, add 3mL damping fluid (1.36 grams, potassium primary phosphate potassium, the sodium hydroxide 79mL of 0.1mol/L, is diluted to 200mL with distilled water), with vortex mixer mixing, at 48000g, 4 DEG C of centrifugal 10min, abandon supernatant liquor, get precipitation, then add buffer solution, centrifugal in triplicate, centrifugal complete, abandon supernatant liquor ,-80 DEG C will be deposited in and store for future use.
Receptor Binding Assay material:
Isotropic substance aglucon
3h ?pyrilamine (67.0Ci/mmol), purchased from PerkinElmer company; Promethazine, purchased from RBI company; GF/C glass fiber filter paper, purchased from Whatman company; Tris import packing; PPO, POPOP are purchased from Shanghai reagent one factory; Fat-soluble scintillation solution.BeckmanLS ?6500 type full-service fluid scintillation counters.Experimental technique:
The first step: the appropriate damping fluid of film first will prepared, is uniformly dispersed with refiner, is mixed in the container of 100ml by 15 test tubes, adds the suspension that appropriate homogenate is 50ml film, for subsequent use.
Second step: each reaction tubes adds film preparation thing 100 μ L respectively.
3rd step: total binding pipe (TB) adds 100 μ L damping fluids, non-specific binding pipe (NB) adds 100 μ Lpromethazine (final concentration 10 ?5M), and each test-compound specific binding pipe (SB) adds 100 μ L test-compounds (final concentration 10 ?5M);
4th step: each reaction tubes adds radioligand respectively
3h ?pyrilamine10 μ L (each reaction tubes all establishes 2 parallel pipes, and during application of sample, each pipe is placed on ice).
5th step: each reaction tubes 30 DEG C of temperature are incubated 60min, reacts complete, in conjunction with aglucon by decompression fast filtering, fully wash with ice-cold test damping fluid, by filter disc take out be put in 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
6th step: scintillation vial is put into liquid scintillation counter counting
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested at every turn and is done two multiple pipes, carries out testing separately for twice.Experimental result is in table 2.
Table 2 compound is to the inhibiting rate (testing in triplicate, ± SD) of each acceptor
Above-mentioned Vitro Experimental Results shows that compound 11 is to three kinds of acceptor (D
2, 5 ?HT
1A, and 5 ?HT
2A) there is stronger avidity, and compound 11 couples of H
1avidity low, compared with risperidone, produce body weight increase side effect possibility less.
In the high reactivity chemical combination object of embodiment 25, MK ?801 induction, anti-schizophrenia is active
Laboratory animal and reagent
Healthy Kunming mouse, male and female half and half, body weight (20 ± 2) g, is provided by Qinglongshan animal cultivation center, Nanjing.
Xitix, Chemical Reagent Co., Ltd., Sinopharm Group;
MK ?801, produced by Sigma Co., USA, compound method: the vitamins C with 0.1% is made into the solution of 1mg/ml;
Tested positive drug: haloperidol, leoponex, risperidone, olanzapine, Aripiprazole, Ziprasidone, Kui sulphur are flat;
Tween 80, concentration 10%.
Experimental technique
The mouse of selective body coincidence lattice, be divided at random blank group, model group, positive controls (risperidone group), medicine group.Blank group, model group gavage 10% tween 0.1ml/10g, positive controls gavage is to risperidone 0.1mg/kg, and the other gavage of drug component is given and corresponding dosage medicine.1h blank group abdominal injection 0.1% xitix 0.1ml/10g after administration, model group, positive controls (30min), medicine group abdominal injection MK ?801 solution 0.1mg/kg.Thereafter spontaneous activity in each group of mouse 90 minutes is measured.The results are shown in Table 3.
Embodiment 26, Apomorphine inducing mouse climbing experiment
Laboratory animal
Healthy KM mouse, male, body weight 18 ~ 22g, is provided by Qinglongshan animal cultivation center, Nanjing.
Main agents
Tested positive drug: haloperidol, leoponex, risperidone, olanzapine, Aripiprazole, Ziprasidone, Kui sulphur are flat;
Apomorphine, Sigma company provides, and 0.9%NaCl (containing 0.1% vitamins C) dissolves before use, now with the current;
Vitamins C, F20061113, Chemical Reagent Co., Ltd., Sinopharm Group;
Sodium chloride injection, H32026305, company limited of pharmaceutical factory of Xuzhou City the 5th.
Instrument: self-control climbing cage, stopwatch.
Experimental technique: Apomorphine inducing mouse climbing experiment
KM mouse, male, body weight 18 ~ 22g, be divided into negative control group, model group, positive drug each dosage group (risperidone, Aripiprazole, Ziprasidone, Kui sulphur flat, olanzapine, haloperidol, leoponex) and compound each dosage group (concrete dosage sees the following form) at random, often organize 10.Negative control group and model group gavage give coordinative solvent distilled water, positive drug group gavage gives corresponding positive drug and (first adds micro-acetic acid during dissolving, add distilled water again), compound each dosage group gavage gives corresponding dosage compound, and gavage volume is 0.1ml/10g.Gastric infusion is subcutaneous injection Apomorphine (1mg/kg) after 1 hour, and volume is 0.1ml/10g.After injection Apomorphine, put into climbing cage immediately, adapt to 5 minutes, the 10th ?11,20 ?21, the 30 ?behavior of 31 minutes after observing injection Apomorphine is also marked, standards of grading: four-footed must be divided into 0 on floor; Two front foots must be divided into 1 on cylinder mould; Four foots must be divided into 2 on cylinder mould.The results are shown in Table 3.
Embodiment 27, catalepsy experimental technique
Laboratory animal
Healthy Kunming mouse, male and female half and half, (22 ± 2) g, is provided by Qinglongshan animal cultivation center, Nanjing.
Main agents:
By reagent, haloperidol, leoponex, risperidone, olanzapine, Aripiprazole, Ziprasidone
Instrument:
Excellent equipment is grabbed in self-control: place diameter 0.3cm in mouse box, higher than the stainless steel bar of worktable 5cm.
Experimental technique:
KM mouse, male and female half and half, body weight 20 ~ 24g, is divided into negative control group, model group, positive drug each dosage group (risperidone, Aripiprazole, Ziprasidone, Kui sulphur flat, olanzapine, haloperidol, leoponex) and each dosage group of compound at random, often organizes 10.Negative control group and model group gavage give coordinative solvent distilled water, positive drug group gavage gives corresponding positive drug and (first adds micro-acetic acid during dissolving, add distilled water again), compound each dosage group gavage gives corresponding dosage compound, and gavage volume is 0.1ml/10g.When gastric infusion 30min, 60min, 90min, mouse two fore paws are gently placed on long 20cm, diameter 0.3cm, on spillikin higher than worktable 5.5cm, again animal hind leg is put down gently in box bottom surface, record mouse two fore paws keep the time length of posture on rod, stiff motionless for positive reaction with 30s.If mouse fore paw never puts down, stop during 60s observing.Add up each compound dosage group positive reaction number of animals, the results are shown in Table 3.
Embodiment 28, studies on acute toxicity
Sequential method limit experiment get KM mouse, male and female half and half, are divided into some groups at random, often organize 2 ?5, be respectively each compound 2000mg/kg group and group of solvents, by 0.2ml/10g gastric infusion.Observe the death condition in animal 3 days.If (animal had more than 3 or 3 and survives in three days, during life state Non Apparent Abnormality, continued to observe, until test end after 7 days.If animal when dead more than 3 or 3, adopted medium lethal dose method to measure its LD50 in three days.)
KM mouse is got in the trial test of medium lethal dose method, male and female half and half, random point some groups, often organize 4, be respectively each compound 1500mg/kg, 1000mg/kg, 500mg/kg group and group of solvents, by 0.2ml/10g gastric infusion, observe the death condition in animal 1 ?3 days.
Result: the LD that mouse single gavages
50be greater than 2000mg/kg, there is less acute toxicity.
Animal model test result in table 3. preferred compound body
Above-mentioned results of animal shows: compared with model group, risperidone, compound 11 can obviously improve MK ?801 induction high reactivity, can effectively improve again Apomorphine induction climbing symptom, and under effective dose, do not cause EPS, show that it has obvious anti-schizophrenia effect.
C, composition embodiment
Embodiment 29, tablet
It is for subsequent use that supplementary material crosses 80 mesh sieves, take recipe quantity activeconstituents, Microcrystalline Cellulose, lactose, PVP K30, join in high-speed mixing preparation machine, stirring at low speed mixes, add appropriate purified water, stirring at low speed, high-speed cutting is granulated, wet granular 60 DEG C of dry 3h, the whole grain of 24 mesh sieve, add recipe quantity carboxymethylstach sodium, silicon-dioxide and Magnesium Stearate, always mix, rotary tablet machine compressing tablet.
Embodiment 30, capsule (230mg)
It is for subsequent use that supplementary material crosses 80 mesh sieves, take recipe quantity activeconstituents, lactose, starch, PVP K30, join in high-speed mixing preparation machine, stirring at low speed mixes, add appropriate purified water, stirring at low speed, high-speed cutting is granulated, wet granular 60 DEG C of dry 3h, the whole grain of 24 mesh sieve, add recipe quantity silicon-dioxide and Magnesium Stearate, always mix, capsule filling machine filled capsules.
Claims (11)
1. the compound of general formula (I) or its pharmacy acceptable salt:
Wherein:
X is-NR
1c (O)-,-C (O)-or-S (O
2)-;
N is 1 or 2;
R is for replacing or not replacing C
1-5alkane, replaces or does not replace C
3-7naphthenic hydrocarbon, the group shown in formula II, formula III, formula IV or formula V,
R
1, R
2, R
3, R
4or R
5separately be selected from hydrogen, halogen, cyano group, nitro, hydroxyl, substituted or unsubstituted C
1-5alkoxyl group, substituted or unsubstituted C
1-5alkyl, wherein said C
1-5the substituting group of alkyl is selected from one or more in amino, hydroxyl or fluorine;
Y is selected from O, N or S.
2. the compound of general formula according to claim 1 (I) or its pharmacy acceptable salt, is characterized in that: when X is-NR
1c (O)-time, R
1be selected from as hydrogen or substituted or unsubstituted C
1-5alkyl, R is substituted or unsubstituted C
1-5group shown in alkyl, formula II or formula III, the substituent R on wherein said formula II
2for hydrogen, substituted or unsubstituted C
1-5alkyl, substituted or unsubstituted C
1-5alkoxy or halogen; Wherein said C
1-5the substituting group of alkyl is selected from one or more in amino, hydroxyl or fluorine.
3. the compound of general formula according to claim 2 (I) or its pharmacy acceptable salt, is characterized in that: when X is-NR
1c (O)-time, R
1be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group or isopentyl; R is selected from as group shown in methyl, ethyl, propyl group, formula II or formula III, the substituent R on wherein said formula II
2for hydrogen, methyl, ethyl, propyl group, chlorine or fluorine.
4. the compound of general formula according to claim 1 (I) or its pharmacy acceptable salt, is characterized in that: when X for-C (O)-time, R is selected from substituted or unsubstituted C
3-7naphthenic hydrocarbon, substituted or unsubstituted C
1-5alkyl or formula II, substituent R on its Chinese style II
2for hydrogen, substituted or unsubstituted C
1-5alkoxy or halogen.
5. the compound of general formula according to claim 4 (I) or its pharmacy acceptable salt, is characterized in that: described unsubstituted C
3-7naphthenic hydrocarbon is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Described C
1-5alkyl is the tertiary butyl; R on described formula II
2substituting group is fluorine or methoxyl group.
6. the compound of general formula according to claim 1 (I) or its pharmacy acceptable salt, is characterized in that: X is-S (O
2)-, R is group shown in formula II, formula IV or formula V, the substituent R on its Chinese style II, formula IV or formula V
2, R
4, R
5be selected from hydrogen, substituted or unsubstituted C
1-5alkyl, nitro, halogen or cyano group, the C of described replacement
1?
5the substituting group of alkyl is selected from halogen.
7. the compound of general formula according to claim 6 (I) or its pharmacy acceptable salt, is characterized in that described R
2, R
4, R
5for hydrogen, methyl, ethyl, propyl group, nitro, trifluoromethyl, fluorine or chlorine.
8. the compound of the general formula (I) according to any one of claim 1 ~ 7 or its pharmacy acceptable salt, is characterized in that the compound shown in described general formula I or its pharmacy acceptable salt are selected from any one compound following or its pharmacy acceptable salt:
9. the compound of general formula (I) according to any one of claim 1 ~ 8 containing treatment significant quantity or the pharmaceutical composition of its pharmacy acceptable salt and medically acceptable carrier.
10. the compound of the general formula (I) according to any one of claim 1 ~ 8 or the application of its pharmacy acceptable salt in preparation treatment Nervous and mental diseases medicine.
11. application according to claim 10, is characterized in that, described Nervous and mental diseases is schizophrenia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410371198.4A CN105315267B (en) | 2014-07-30 | 2014-07-30 | A kind of amide derivatives and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410371198.4A CN105315267B (en) | 2014-07-30 | 2014-07-30 | A kind of amide derivatives and its application |
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| Publication Number | Publication Date |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469873A (en) * | 2000-10-17 | 2004-01-21 | ���鹫˾ | Piperidine compounds as anti-allergic |
| CN1620452A (en) * | 2001-12-19 | 2005-05-25 | H.隆德贝克有限公司 | 3,4-dihydro-1h-isoquinoloin-2-yl-derivatives |
| WO2008108957A2 (en) * | 2007-03-02 | 2008-09-12 | Schering Corporation | Piperidinyl-piperidine and piperazinyl-piperidine for use in the treatment of diabetes or pain |
| WO2011111875A1 (en) * | 2010-03-11 | 2011-09-15 | Dainippon Sumitomo Pharma Co., Ltd. | N-acyl cyclic amine derivative or pharmaceutically acceptable salt thereof |
| JP2013075894A (en) * | 2011-09-14 | 2013-04-25 | Dainippon Sumitomo Pharma Co Ltd | N-acyl cyclic amine derivative or pharmaceutical including pharmaceutically acceptable salt thereof |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469873A (en) * | 2000-10-17 | 2004-01-21 | ���鹫˾ | Piperidine compounds as anti-allergic |
| CN1620452A (en) * | 2001-12-19 | 2005-05-25 | H.隆德贝克有限公司 | 3,4-dihydro-1h-isoquinoloin-2-yl-derivatives |
| WO2008108957A2 (en) * | 2007-03-02 | 2008-09-12 | Schering Corporation | Piperidinyl-piperidine and piperazinyl-piperidine for use in the treatment of diabetes or pain |
| WO2011111875A1 (en) * | 2010-03-11 | 2011-09-15 | Dainippon Sumitomo Pharma Co., Ltd. | N-acyl cyclic amine derivative or pharmaceutically acceptable salt thereof |
| CN102884059A (en) * | 2010-03-11 | 2013-01-16 | 大日本住友制药株式会社 | N-acyl cyclic amine derivative or pharmaceutically acceptable salt thereof |
| JP2013075894A (en) * | 2011-09-14 | 2013-04-25 | Dainippon Sumitomo Pharma Co Ltd | N-acyl cyclic amine derivative or pharmaceutical including pharmaceutically acceptable salt thereof |
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