A kind of aryl piperazines/piperidines and application thereof

文档序号：1750689 发布日期：2019-11-29 浏览：42次中文

阅读说明：本技术 一种芳基哌嗪/哌啶类化合物及其用途 (A kind of aryl piperazines/piperidines and application thereof ) 是由付伟彭伟青于 2018-05-22 设计创作，主要内容包括：本发明属医药技术领域,涉及一种芳基哌嗪/哌啶类化合物及其应用,具体地,所述芳基哌嗪/哌啶类化合物可作为多巴胺D2受体和5-HT2A受体双重拮抗剂用于制备治疗或改善神经系统疾病,特别是精神分裂症的药物。本发明所述的芳基哌嗪/哌啶类化合物结构通式为：<Image he="255" wi="700" file="DDA0001668734620000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中R1、R2、R3、R4、X1、X2、A、m、n的定义参见说明书。该类化合物可作为多巴胺D2受体和5-HT2A受体双重拮抗剂用于制备治疗或改善神经系统疾病,特别是精神分裂症的药物。(The invention belongs to pharmaceutical technology field, it is related to a kind of aryl piperazines/piperidines and its application, specifically, the aryl piperazines/piperidines can be used as dopamine D 2 Receptor and 5-HT 2A Receptor dual antagonist is used to prepare treatment or improves the nervous system disease, especially schizoid drug.Aryl piperazines of the present invention/piperidines general structure are as follows: Wherein R 1 、R 2 、R 3 、R 4 、X 1 、X 2 , A, m, n definition referring to specification.Such compound can be used as dopamine D 2 Receptor and 5-HT 2A Receptor dual antagonist is used to prepare treatment or improves the nervous system disease, especially schizoid drug.)

1. aryl piperazines/piperidines shown in general formula (I), (II),

Wherein:

X₁、X₂For carbon or nitrogen；

N is optionally from 0,1,2,3 or 4；

A is individually optional from carbonyl or-SO₂Group；

Substituent R₁Optionally from H, C₁-C₆Substituted or unsubstituted alkyl, C₃-C₇Substituted or unsubstituted naphthenic base, HetAr1 ,- (CH₂)_m-C₃-C₇Substituted or unsubstituted naphthenic base ,-(CH₂)_m- HetAr1, m=1 or 2；

Substituent R₂It is not present or at least one position in 2,3,4,5,6, is unsubstituted, mono-substituted, disubstituted Or polysubstituted, substituent R₂Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, carboxyl, Trifluoromethyl, cyano, amino, phenyl, C₁-C₆Substituted or unsubstituted alkyl, C₁-C₆Substituted or unsubstituted alkoxy；Work as R₂ For when double or three replace, substituent group can be identical or different；

Substituent R₃It is not present or at least one position in 2,3,4,5,6, is unsubstituted, mono-substituted, disubstituted Or polysubstituted, substituent R₃Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, carboxyl, Trifluoromethyl, cyano, amino, phenyl, C₁-C₆Substituted or unsubstituted alkyl, C₁-C₆Substituted or unsubstituted alkoxy；Work as R₃ For when double or three replace, substituent group can be identical or different；

Substituent R₄It is not present or at least one position in 4,5,6,7, is unsubstituted, mono-substituted, disubstituted Or polysubstituted, substituent R₄Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, carboxyl, three Methyl fluoride, cyano, amino, phenyl, C₁-C₆Substituted or unsubstituted alkyl, C₁-C₆Substituted or unsubstituted alkoxy；Work as R₄For When double or three substitution, substituent group can be identical or different；

The HetAr1 indicates the saturation unsubstituted 4,5,6,7,8,9 or 10 with 1,2 or 3 N and/or O and/or S atom Circle heterocyclic ring.

2. aryl piperazines/piperidines according to claim 1, which is characterized in that the compound is selected from:

N- [3- [4- (fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- propyl benzamide,

N- [3- [4- (fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- isopropylbenzamide,

N- cyclopropyl methyl-N [3- [4- (fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl] benzamide,

N- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) benzoyl Amine,

N- [3- [4- (2,3- dichlorophenyl) piperazine -1- base] propyl]-N- propyl benzamide,

N- [3- [4- (2,3- dichlorophenyl) piperazine -1- base] propyl]-N- isopropylbenzamide,

N- cyclopropyl methyl-N [3- [4- (2,3- dichlorophenyl) piperazine -1- base] propyl] benzamide,

N- [3- [4- (2,3- dichlorophenyl) piperazine -1- base] propyl]-N- (oxa- ring butyl- 3- yl) benzamide,

N- [3- [4- (pyridine -2- base) piperazine -1- base] propyl]-N- propyl benzamide,

N- [3- [4- (pyridine -2- base) piperazine -1- base] propyl]-N- isopropylbenzamide,

N- cyclopropyl methyl-N [3- [4- (pyridine -2- base) piperazine -1- base] propyl] benzamide,

N- [3- [4- (pyridine -2- base) piperazine -1- base] propyl]-N- (oxa- ring butyl- 3- yl) benzamide,

N- [3- [4- (2- anisyl) piperazine -1- base] propyl]-N- propyl benzamide,

N- [3- [4- (2- anisyl) piperazine -1- base] propyl]-N- isopropylbenzamide,

N- cyclopropyl methyl-N [3- [4- (2- anisyl) piperazine -1- base] propyl] benzamide,

N- [3- [4- (2- anisyl) piperazine -1- base] propyl]-N- (oxa- ring butyl- 3- yl) benzamide,

N- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) benzene sulfonyl Amine,

N- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) -1- benzyl Sulfonamide,

The fluoro- N- of 4- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) benzene Sulfonamide,

The chloro- N- of 4- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) benzene Sulfonamide,

4- trifluoromethyl-N- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) benzsulfamide,

4- cyano-N- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) Benzsulfamide.

3. aryl piperazines/piperidines pharmaceutically acceptable salt, solvate, precursor chemical combination described in claim 1 Object or polymorph.

4. aryl piperazines/piperidines pharmaceutically acceptable salt, solvate, precursor according to claim 3 Drug or polymorph, which is characterized in that the pharmaceutically acceptable salt is inorganic salts, organic salt or amino-acid salt；

Wherein inorganic salts are as follows: sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromate or nitric acid Salt；

Wherein organic salt are as follows: maleate, acetate, fumarate, tartrate, succinate, lactate, p-methyl benzenesulfonic acid Salt, salicylate or oxalates；

Wherein amino-acid salt are as follows: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycinate, Guang Propylhomoserin salt, cysteine salt, tyrosine salt, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, egg Propylhomoserin salt, tryptophan salt, glutamate, aspartate, valine salt, methionine salt, proline salt or hydroxyproline salt.

5. aryl piperazines described in aryl piperazines/piperidines described in claim 1 or claim 3/piperidines chemical combination Object pharmaceutically acceptable salt, solvate, pro-drug or polymorph are in preparation treatment and dopamine D₂Receptor and/or 5- HT_2APurposes in the drug of receptor associated diseases.

6. purposes according to claim 5, which is characterized in that the disease is the nervous system disease, is selected from schizophrenia Disease.

Technical field

The invention belongs to pharmaceutical technology fields, and in particular to a kind of aryl piperazines/piperidines and its application.More specifically Ground, the aryl piperazines/piperidines can be used as dopamine D₂Receptor and 5-HT_2AReceptor dual antagonist is being used to prepare Treatment improves the nervous system disease, especially schizoid medicinal usage.

Background technique

With the continuous increase of people's work and life pressure, psychic problems generate serious bad shadow to entire society It rings.Schizophrenia (schizophrenia) be one of the most common type continue, chronic great mental disorder, clinical manifestation For positive symptom and negative symptoms, the former includes illusion, vain hope, chorea etc.；The latter refers mainly to Cognitive, study note Recall obstacle, working memory obstacle etc..The first generation antipsychotic drug of early stage is to treat based on positive symptom, to negative disease The curative effect of shape is very poor, and the incidence of extrapyramidal symptom (Extrapyramidal Symptoms, EPS) is high, also known as classical Antipsychotic drug.Late 1960s Clozapine comes out, which has good curative effect to schizophrenia positive symptom, to recognizing Knowing dysfunction also has certain improvement, and apparent EPS and dyskinesia, referred to as atypical antipsychotics will not occur.Facing Bed is in use, although antischizophrinic Clozapine has a good effect, and still, some patientss can cause serious grain thin Born of the same parents reduce disease, and even lethal agranulocytosis occurs for some.Therefore, the second generation of novel, the less toxic side effect of development structure Atypical antipsychotics are very necessary.

The schizoid pathogenic factor of studies have shown that is more complicated, be related to inherent cause, nature factor, psychological factor, Environmental factor and organism physiology factor etc., inherent cause play an important role in schizoid morbidity, but its pathogenesis It is still not clear.Generally acknowledged intracerebral neurotransmitter imbalance argument points out that the target area of patient's positive symptom is in subcortical structure, intracerebral The D in these regions₂Function of receptors is hyperfunction, generates positive symptom, all to have D₂The classics of receptor antagonism and non-classical anti-spirit Sick medicine has good curative effect to positive symptom；The negative symptoms and Cognitive of patient are due on cerebral cortex prefrontal lobe D₁Receptor hypo-function, D₁Receptor stimulating agent can improve learning memory disorder；D₃Receptor cloning is the study found that D can be blocked₂Receptor Antipsychotics can also block D₃Receptor；Expression has 5-HT on dopamine neuron_2AReceptor；Therefore, exploitation has dopamine Receptor and 5-HT_2AThe second generation atypical antipsychotics of receptor dual inhibiting effect are that research and development high-efficiency low-toxicity side effect is novel anti- The key of schizophrenia drug.

Status and deficiency based on the prior art, present inventor is quasi- to provide a kind of aryl piperazines/piperidines chemical combination Object and its application are especially being used to prepare treatment or are improving the nervous system disease, especially schizoid medicinal usage.

Summary of the invention

The purpose of the present invention is aiming at the shortcomings in the prior art, provide a kind of aryl piperazines/piperidines.

It is a further object of the present invention to provide aryl piperazines/piperidines preparation methods.

The object of the invention is also to provide above compounds to treat nerve related with brain and spirituality in preparation Purposes in disease, especially schizophrenia drug.

It can the present invention provides aryl piperazines/piperidines shown in following general formula (I), (II) and its pharmacologically connect Inorganic or organic salt, the crystalline hydrate received:

Wherein:

X₁、X₂For carbon or nitrogen；

N is optionally from 0,1,2,3 or 4, preferably 3；

A is individually optional from carbonyl or-SO₂Group.

Substituent R₁Optionally from H, C₁-C₆Substituted or unsubstituted alkyl, C₃-C₇Substituted or unsubstituted naphthenic base, HetAr1、-(CH₂)_m-C₃-C₇Substituted or unsubstituted naphthenic base ,-(CH₂)_m- HetAr1, m=1 or 2 preferably are selected from n-propyl, different Propyl ,-(CH₂)-cyclopropyl, oxa- ring butyl- 3- base；

Substituent R₂Be not present or at least one position in 2,3,4,5,6, be it is unsubstituted, mono-substituted, It is disubstituted or polysubstituted, substituent R₂Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, Carboxyl, trifluoromethyl, cyano, amino, phenyl, C₁-C₆Substituted or unsubstituted alkyl, C₁-C₆Substituted or unsubstituted alcoxyl Base；Work as R₂For when double or three replace, substituent group can be identical or different；Preferably, substituent R₂It is not present or for positioned at 4 F, cyano, trifluoromethyl；

Substituent R₃Be not present or at least one position in 2,3,4,5,6, be it is unsubstituted, mono-substituted, It is disubstituted or polysubstituted, substituent R₃Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, Carboxyl, trifluoromethyl, cyano, amino, phenyl, C₁-C₆Substituted or unsubstituted alkyl, C₁-C₆Substituted or unsubstituted alcoxyl Base；Work as R₃For when double or three replace, substituent group can be identical or different；Preferably, substituent R₃It is not present or for positioned at 2 Methoxyl group or positioned at 2 and 3 Cl.

Substituent R₄It is not present or at least one position in 4,5,6,7, is unsubstituted, mono-substituted, double Replace or polysubstituted, substituent R₄Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, carboxylic Base, trifluoromethyl, cyano, amino, phenyl, C₁-C₆Substituted or unsubstituted alkyl, C₁-C₆Substituted or unsubstituted alkoxy； Work as R₄For when double or three replace, substituent group can be identical or different；Preferably, substituent R₄For positioned at 6 F；

Unless otherwise indicated, C of the present invention₁-C₆Alkyl (C₁-C₆Unsubstituted alkyl) it is C₁-C₆Linear chain or branched chain Alkyl, refers to the alkyl containing 1-6 carbon atom, including but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, different Butyl, sec-butyl, tert-butyl, amyl, hexyl, heptyl or octyl.C₁-C₆Alkyl is replaced to refer to C₁-C₆Alkyl can be selected from hydroxyl Base, halogen, C₁-C₃1-2 identical or different groups of alkoxy replace.

Unless otherwise indicated, C of the present invention₁-C₆Alkoxy (C₁-C₆Unsubstituted alkoxy) it is C₁-C₆Straight chain or Branched alkoxy, refers to the alkoxy containing 1-6 carbon atom, including but not limited to methoxyl group, ethyoxyl, positive propoxy, different Propoxyl group, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, hexyloxy, oxygroup in heptan or octyloxy.C₁-C₆ Substituted alkoxy refers to C₁-C₆Alkoxy can be selected from hydroxyl and C₁-C₃1-2 identical or different groups of alkoxy replace.

Unless otherwise indicated, C of the present invention₃-C₇Naphthenic base (C₃-C₇Unsubstituted naphthenic base) refer to containing 3-7 The naphthenic base of carbon atom, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopropyl and cyclopenta, ring Third and cyclohexyl.C₃-C₇Substituted cycloalkyl refers to C₃-C₇Naphthenic base can be selected from halogen, carbonyl, hydroxyl and C₁-C₃Alkoxy 1-2 identical or different groups replace.

Unless otherwise indicated, C of the present invention₁-C₃Alkoxy refers to C₁-C₃Straight or branched alkoxyl, refer to containing The alkoxy of 1-3 carbon atom, including but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy.

Unless otherwise indicated, HetAr1 of the present invention indicates to have the full of 1,2 or 3 N and/or O and/or S atom With the circle heterocyclic ring of unsubstituted 4,5,6,7,8,9 or 10.

Unless otherwise indicated, term halogen is halogen substituent group, including but not limited to fluorine, chlorine, bromine or iodine.

Wherein, the term " polysubstituted " in the present invention and " a variety of " refer to three kinds or more, and what is appeared below is also phase Same meaning.

As one of optimal embodiment, aryl piperazines/piperidine derivatives of the present invention are following materialization Close object:

N- [3- [4- (fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- propyl benzamide,

N- [3- [4- (fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- isopropylbenzamide,

N- cyclopropyl methyl-N [3- [4- (fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl] benzamide,

N- [3- [4- (the fluoro- 1,2 benzo isoxazole -3- base of 6-) piperidin-1-yl] propyl]-N- (oxa- ring butyl- 3- yl) benzene Formamide,