Piperazine compound and application thereof in preparing chemokine receptor CCR2 antagonist
阅读说明：本技术 哌嗪类化合物及其在制备趋化因子受体ccr2拮抗剂中的应用 (Piperazine compound and application thereof in preparing chemokine receptor CCR2 antagonist ) 是由 龙亚秋 谢欣 秦立怀 于 2020-04-24 设计创作，主要内容包括：本发明涉及一种式(I)所示的哌嗪类化合物及其在制备趋化因子受体CCR2拮抗剂或用于治疗由CCR2介导的疾病的药物中的应用。(The invention relates to a piperazine compound shown as a formula (I) and application thereof in preparing a chemokine receptor CCR2 antagonist or a medicament for treating CCR2 mediated diseases.)
1. A piperazine compound is characterized in that the structural formula is shown as the formula (I):
wherein A is aryl, heteroaryl, benzoheteroaryl, substituted aryl, substituted heteroaryl or substituted benzoheteroaryl; the heteroatom on the heteroaryl, benzoheteroaryl, substituted heteroaryl or substituted benzoheteroaryl is selected from N, O or an S atom; the substituted aryl, substituted heteroaryl or substituted benzoheteroaryl contains 1-3 substituents; the substituents are independently selected from halogen, aryl, heteroaryl, cyano, hydroxy, nitro, trifluoromethyl, C1-C4One or more of straight chain or branched chain alkyl and alkoxy;
l is selected froma is 0 or 1;
x and Y are each independently selected from carbonyl or methylene, or X, Y and the N atom of the piperazine ring to which it is attached form a five-membered heteroaryl group, the heteroatom in the five-membered heteroaryl group being selected from N, O or S atom;
z is a C atom or a N atom; when Z is an N atom, b is 0; when Z is a C atom, b is 1;
R1and R2Each independently selected from hydrogen atom, halogen, cyano, hydroxyl, nitro, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkyl-substituted amido or C1-C6An ester group;
R3is hydrogen, halogen, cyano, hydroxy, nitro, amino, C1-C6Alkyl radical, C1-C6Alkoxy or phenyl;
R4and R5Each independently selected from hydrogen atom, hydroxyl, amino, halogen, C1-C3Straight or branched chain alkyl, heteroatom substituted C3-C8Cycloalkyl, aryl, heteroaryl, benzoheteroaryl, substituted aryl, substituted heteroaryl, or substituted benzoheteroaryl; the substituted aryl, substituted heteroaryl or substituted benzoheteroaryl group contains one or more substituents; the substituents are independently selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkyl, heteroatom substituted C3-C8Cycloalkyl, -CF3、-CN、-NO2-NO or halogen; c substituted by said hetero atom3-C8The heteroatom in cycloalkyl is O, N or S atom; or
R4And R5The following spiro structure is formed:
wherein W is selected from the group consisting of O atom, S atom, SO group, SO2A group or a carbonyl group; k is 1 or 2; r9Is a hydrogen atom, C1-C6Alkyl radical, C1-C6Alkoxy, halogen or cyano;
R6，R7and R8Each independently selected from hydrogen atom, halogen, cyano, hydroxyl, nitro, amino and C1-C6Alkyl radical, C1-C6Alkoxy, aryl, heteroaryl, substituted aryl or substituted heteroaryl, said substituted aryl or substituted heteroaryl having 1-3 substituents; the substituents are respectively and independently selected from hydrogen atom, halogen, cyano, hydroxyl, nitro, amino or C1-C6An alkyl group;
or R5、R6And the atoms to which they are attached are linked to form a phenyl or benzoheteroaryl group; said phenyl or benzoheteroaryl group having at least one substituent comprising a hydrogen atom, an amino group, a halogen, a trifluoromethyl group andone or more of cyano groups;
or R6、R7And the atoms to which they are attached are linked to form a phenyl or benzoheteroaryl group; the phenyl or benzo heteroaryl contains at least one substituent group, and the substituent group comprises one or more of hydrogen atom, amino, halogen, trifluoromethyl and cyano;
m and n are independently selected from any integer of 0-2, and m + n is less than or equal to 3.
2. The piperazine compound according to claim 1, wherein: a is aryl, heteroaryl, benzoheteroaryl, substituted aryl, substituted heteroaryl or substituted benzoheteroaryl; the heteroatom on the heteroaryl, benzoheteroaryl, substituted heteroaryl or substituted benzoheteroaryl is selected from N, O or an S atom; the substituted aryl, substituted heteroaryl or substituted benzoheteroaryl contains 1-3 substituents; the substituent is independently selected from one or more of halogen, aryl, heteroaryl and trifluoromethyl.
3. The piperazine compound according to claim 1, wherein: a is substituted phenyl or substituted benzo heteroaryl, wherein the substituted phenyl or substituted benzo heteroaryl contains 1-3 substituents, and the substituents are selected from halogen or trifluoromethyl.
4. A piperazine compound according to claim 1, wherein L is selected from the group consisting of a is 0 or 1.
5. The piperazine compound according to claim 1, wherein: x and Y are each independently selected from carbonyl or methylene, or X, Y and the N atom of the piperazine ring to which it is attached form a five-membered heteroaryl group, the heteroatom in which is selected from the group consisting of N or O atoms.
6. The piperazine compound according to claim 1, wherein: r1And R2Are each a hydrogen atom; or R1And R2One of them is hydrogen atom, and the other is halogen or C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkyl-substituted amido or C1-C6An ester group.
7. The piperazine compound according to claim 1, wherein: w is selected from O atom, S atom, SO group or SO2A group; r9Is a hydrogen atom, C1-C6Alkyl, halogen or cyano.
8. Use of a piperazine compound according to any one of claims 1 to 7 for the preparation of a chemokine receptor CCR2 antagonist.
9. Use of a piperazine compound of any one of claims 1-7 for the preparation of a medicament for the treatment of a CCR2 mediated disease.
10. Use according to claim 9, characterized in that: the diseases mediated by CCR2 include one or more of rheumatoid arthritis, atherosclerosis, asthma, obesity, type II diabetes, chronic neurodegenerative diseases and tumors.
Technical Field
The invention relates to the field of biomedicine, in particular to a piperazine compound and application thereof in preparing a chemokine receptor CCR2 antagonist.
Background
Chemokines are also known as chemoattractant cytokines and are members of the large family of cytokines and contain 380 amino acids, 340-. At least 40 subtypes have been found, and are classified into two major classes (CC and CXC) and two minor classes (CX3C and C) according to their structure and function. Chemokines form a very complex network with chemokine receptors, one chemokine can bind to a different receptor, and one chemokine receptor can recognize a different ligand. They can regulate activation and movement of immune cells in immune response, and thus play an important role in immune diseases. It is because of their important role in disease that they constitute a class of drug targets that many large pharmaceutical companies compete open.
CCR2 belongs to the CC chemokine receptor, and is highly expressed in various cells, mainly monocytes, macrophages, basophils, immature dendritic cells, memory T cells, etc. CCR2 can be divided into two subtypes CCR2A and CCR2B, CCR2A contains 360 amino acids, CCR2B contains 374 amino acids, the amino acid sequence of which is identical until position 313, and plays a major role in life, CCR 2B. CC L can be similarly produced by many cells including epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, monocytes, etc. and can induce monocytes, memory T cells and dendritic cells to reach inflammatory regions.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a piperazine compound and application thereof in preparing a chemokine receptor CCR2 antagonist.
The structural formula of the piperazine compound is shown as the formula (I):
wherein A is aryl, heteroaryl, benzoheteroaryl, substituted aryl, substituted heteroaryl or substituted benzoheteroaryl; the heteroatom on the heteroaryl, benzoheteroaryl, substituted heteroaryl or substituted benzoheteroaryl is selected from N, O or an S atom; the substituted aryl, substituted heteroaryl or substituted benzoheteroaryl contains 1-3 substituents; the substituents are independently selected from halogen, aryl, heteroaryl, cyano, hydroxy, nitro, trifluoromethyl, C1-C4One or more of straight chain or branched chain alkyl and alkoxy;
l is selected froma is 0 or 1;
x and Y are each independently selected from carbonyl or methylene, or X, Y and the N atom of the piperazine ring to which it is attached form a five-membered heteroaryl group, the heteroatom in the five-membered heteroaryl group being selected from N, O or S atom;
z is a C atom or a N atom; when Z is an N atom, b is 0; when Z is a C atom, b is 1;
R1and R2Each independently selected from hydrogen atom, halogen, cyano, hydroxyl, nitro, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkyl-substituted amido or C1-C6An ester group;
R3is hydrogen, halogen, cyano, hydroxy, nitro, amino, C1-C6Alkyl radical, C1-C6Alkoxy or phenyl;
R4and R5Each independently selected from hydrogen atom, hydroxyl, amino, halogen, C1-C3Straight or branched chain alkyl, heteroatom substituted C3-C8Cycloalkyl, aryl, heteroaryl, benzoheteroaryl, substituted aryl, substituted heteroaryl, or substituted benzoheteroaryl; the substituted aryl, substituted heteroaryl or substituted benzoheteroaryl group contains one or more substituents; the substituents are independently selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C8Cycloalkyl, heteroatom substituted C3-C8Cycloalkyl, -CF3、-CN、-NO2-NO or halogen; c substituted by said hetero atom3-C8The heteroatom in cycloalkyl is O, N or S atom; or
R4And R5The following spiro structure is formed:
wherein W is selected from the group consisting of O atom, S atom, SO group, SO2A group or a carbonyl group; k is 1 or 2; r9Is a hydrogen atom, C1-C6Alkyl radical, C1-C6Alkoxy, halogen or cyano;
R6，R7and R8Each independently selected from hydrogen atom, halogen, cyano, hydroxyl, nitro, amino、C1-C6Alkyl radical, C1-C6Alkoxy, aryl, heteroaryl, substituted aryl or substituted heteroaryl, said substituted aryl or substituted heteroaryl having 1-3 substituents; the substituents are respectively and independently selected from hydrogen atom, halogen, cyano, hydroxyl, nitro, amino or C1-C6An alkyl group;
or R5、R6And the atoms to which they are attached are linked to form a phenyl or benzoheteroaryl group; the phenyl or benzo heteroaryl contains at least one substituent group, and the substituent group comprises one or more of hydrogen atom, amino, halogen, trifluoromethyl and cyano;
or R6、R7And the atoms to which they are attached are linked to form a phenyl or benzoheteroaryl group; the phenyl or benzo heteroaryl contains at least one substituent group, and the substituent group comprises one or more of hydrogen atom, amino, halogen, trifluoromethyl and cyano;
m and n are independently selected from any integer of 0-2, and m + n is less than or equal to 3.
Preferably, a is aryl, heteroaryl, benzoheteroaryl, substituted aryl, substituted heteroaryl or substituted benzoheteroaryl; the heteroatom on the heteroaryl, benzoheteroaryl, substituted heteroaryl or substituted benzoheteroaryl is selected from N, O or an S atom; the substituted aryl, substituted heteroaryl or substituted benzoheteroaryl contains 1-3 substituents; the substituent is independently selected from one or more of halogen, aryl, heteroaryl and trifluoromethyl.
Preferably, A is substituted phenyl or substituted benzo heteroaryl, and the substituted phenyl or substituted benzo heteroaryl contains 1-3 substituents selected from halogen or trifluoromethyl.
Preferably L is selected froma is 0 or 1.
Preferably, X and Y are each independently selected from carbonyl or methylene, or X, Y and the N atom of the piperazine ring to which it is attached form a five-membered heteroaryl group, the heteroatom in which is selected from N or O atoms.
Preferably, R1And R2Are each a hydrogen atom; or R1And R2One of them is hydrogen atom, and the other is halogen or C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkyl-substituted amido or C1-C6An ester group.
Preferably, W is selected from the group consisting of O atom, S atom, SO group or SO2A group; r9Is a hydrogen atom, C1-C6Alkyl, halogen or cyano.
In the present invention, "-" in the group structural formula represents a connection site of the group to other groups or atoms.
Most preferably, the piperazine compounds of the present invention have the structural formula shown as S1-S45:
the invention also discloses application of the piperazine compound shown in the formula (I) in preparation of a chemokine receptor CCR2 antagonist.
The invention also discloses application of the piperazine compound shown in the formula (I) in preparing a medicament for treating CCR2 mediated diseases.
Further, diseases mediated by CCR2 include one or more of rheumatoid arthritis, atherosclerosis, asthma, obesity, type ii diabetes, chronic neurodegenerative diseases, and tumors.
By the scheme, the invention at least has the following advantages:
the invention discloses a novel piperazine compound which can be used for preparing a chemokine receptor CCR2 antagonist or preparing a medicament for treating CCR2 mediated diseases.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
In the following examples of the present invention, all starting materials are commercially available or prepared by methods known in the art or according to the methods described herein.
The structure of the compound is determined by nuclear magnetic resonance1H-NMR) and/or Mass Spectrometry (MS). NMR was measured using a Mercury-400 nuclear magnetic resonance apparatus manufactured by Varian corporation, and deuterated chloroform (CDCl) was used as a solvent3) Deuterated methanol (CD)3OD), deuterated dimethyl sulfoxide (DMSO-d)6) Or deuterated acetonitrile (CD)3CN), TMS as internal standard, MS is measured by using Thermo Finnigan L CQ-DecaXP type (ESI) liquid chromatography-mass spectrometer, ISCO is used for separating and purifying products by column chromatographyRf 75 rapid preparation chromatograph, and the carrier adopts 200-mesh and 300-mesh silica gel of Qingdao ocean chemical plant.
In the following examples of the present invention, the structural formulae of S1 to S45 correspond to those shown in S1 to S45 in the specification above.
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