CN112047848A - Dopamine D2Receptor selective agonists and uses thereof - Google Patents

Dopamine D2Receptor selective agonists and uses thereof Download PDF

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CN112047848A
CN112047848A CN201910487863.9A CN201910487863A CN112047848A CN 112047848 A CN112047848 A CN 112047848A CN 201910487863 A CN201910487863 A CN 201910487863A CN 112047848 A CN112047848 A CN 112047848A
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汪胜
程建军
樊鲁玉
谭亮
聂芬
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ShanghaiTech University
Center for Excellence in Molecular Cell Science of CAS
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Abstract

The invention relates to dopamine D2Receptor selective agonists and uses thereof. Specifically, the invention discloses an agonist which is selective to DRD2 and discloses the potential application value of the agonist in disease treatment. The invention first revealsAn agonist with DRD2 selectivity, the specific targeting of DRD2 can reduce side effects to the utmost extent and can play a role in treating low dopamine related diseases such as Parkinson's disease, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia and the like.

Description

Dopamine D2Receptor selective agonists and uses thereof
Technical Field
The discovery belongs to the field of structural pharmacology research in life science, and particularly relates to dopamine D2The discovery of receptor selective agonists and their use in the treatment of disease.
Background
Dopamine receptors belong to the family of G-protein coupled receptors, five dopamine receptors have been isolated and classified as D according to their biochemical and pharmacological properties1Class and D2Class I, wherein D1The receptor-like includes D1And D5Subtype, which activates adenylate cyclase, increases intracellular cyclic adenosine monophosphate (cAMP) concentration; d2The receptor-like includes D2、D3And D4Subtypes, which inhibit adenylate cyclase, are also associated with other second messenger systems within the cell, including activation of potassium channels, inhibition of calcium channels, and conversion of phosphatidylinositol. The carboxy terminus (C-terminus) of both types of receptors contains phosphorylation and palmitoylation sites, involved in the desensitization process of the agonist-dependent receptor and the formation of the fourth intracellular loop. Dopamine ligand compounds, while readily distinguishing the D1 and D2 families, are unable to distinguish receptor subtypes of the same family due to the similarity of distinct subtypes within the two families of dopamine receptors. Pharmacological selectivity studies for dopamine ligand compounds are currently a major hotspot.
The dopamine system is closely related to various central nervous system diseases, and the development of drugs aiming at dopamine or dopamine receptors is always the focus of research. Several studies have demonstrated that DRD2 is an important target for psychiatric disorders and DRD2 is closely associated with exercise, asAll receptor-targeted antipsychotics and antiparkinson drugs, however, target DRD2 due to D2The receptor-like substances have high similarity, and all DRD2 drugs act on DRD2 and also act on two subtypes of DRD3 and DRD 4; a series of researches show that DRD3 and DRD4 are closely related to corresponding side effects of dyskinesia or hallucinography caused by medicaments.
In the case of parkinson's disease treatment, recent studies have shown that DRD4 is a major D2-like receptor subtype involved in dopaminergic inhibition of glutamatergic transmission, and thus, dopamine agonist-induced dyskinesia is closely associated with activation of DRD4 in parkinson's disease treatment. DRD3, on the other hand, was enriched in the ventral striatum and other limbic regions, suggesting that it may play a role in psychological and emotional function. Furthermore, it has been proposed that activation of DRD3 is associated with the development of dyskinesias in clinical trials.
Therefore, the search for a DRD2 selective agonist to reduce the side effect of the drug is very important for treating low dopamine related diseases such as Parkinson's disease.
Disclosure of Invention
The invention aims to provide a DRD2 selective agonist and elucidate the potential application value of the DRD2 selective agonist in disease treatment.
In a first aspect of the present invention, there is provided a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an isotopic derivative thereof, or an isomer thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof:
Figure BDA0002085997560000021
in the formula:
R1is hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C3-C6Cycloalkoxy, or substituted or unsubstituted C2-C6An alkenyloxy group;
R2is hydrogen, halogen, nitro, cyano, or hydroxy;
R3is hydrogen, or substituted or unsubstituted C1-C6An alkyl group;
wherein R is1、R3Wherein said substitution is with one or more substituents selected from the group consisting of: c3-C6Cycloalkyl, halogen, nitro, cyano, hydroxy;
R4、R5each independently selected from the group consisting of: hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted-OC1-C6Alkyl radical, R6(R7) N-; wherein H in the substituent group is substituted with one or more substituents selected from the group consisting of: -OH, -CN, nitro, carboxyl, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, and-NRaRb；
R6And R7Each independently selected from the group consisting of: H. c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, -OH, -CN; ra、RbEach independently is H, C1-C3Alkyl, or C3-C6A cycloalkyl group.
n is a positive integer of 1-3;
m is a positive integer of 1 to 6, preferably 1 to 4, more preferably 1 to 3.
In another preferred embodiment, when m is not 1,
Figure BDA0002085997560000022
the units may be the same or different.
In another preferred embodiment, R1Is hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C5Alkyl, substituted orUnsubstituted C1-C5Alkoxy, substituted or unsubstituted C3-C5Cycloalkoxy, substituted or unsubstituted C2-C5An alkenyloxy group, said substitution being with one or more substituents selected from the group consisting of: c3-C5Cycloalkyl, halogen, nitro, cyano, hydroxy.
In another preferred embodiment, R3Is hydrogen, or substituted or unsubstituted C1-C4An alkyl group, the substitution being with one or more substituents selected from the group consisting of: halogen, nitro, cyano, hydroxy.
In another preferred embodiment, R4、R5Each independently selected from the group consisting of: hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C2-C4Alkenyl, substituted or unsubstituted C2-C4Alkynyl, substituted or unsubstituted C3-C5Cycloalkyl, substituted or unsubstituted-OC1-C4Alkyl radical, R6(R7) N-; wherein H in the substituent group is substituted with one or more substituents selected from the group consisting of: -OH, -CN, nitro, carboxyl, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, and-NRaRb；Ra、RbEach independently is H, C1-C3Alkyl, or C3-C6A cycloalkyl group; ra、RbEach independently is H, C1-C3Alkyl, or C3-C5A cycloalkyl group; r6And R7Each independently selected from the group consisting of: H. c1-C4Alkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C3-C5Cycloalkyl, -OH, -CN.
In another preferred embodiment, the isomers are selected from the group consisting of: enantiomers, diastereomers, tautomers, optical isomers, or combinations thereof.
In another preferred embodiment, R is1Selected from the group consisting of: CH (CH)3O-、C2H5O-、CH2＝CHCH2O-、(CH3)2CHO-、C3H7O-、C4H9O-、C3H5CH2O-、C2H4FO-。
In another preferred embodiment, R is2Is hydrogen.
In another preferred embodiment, R is3Is C1-C3An alkyl group.
In another preferred embodiment, R is3Is CH3-or C2H5-。
In another preferred embodiment, R is4And R5Each independently hydrogen.
In another preferred embodiment, m is 2.
In another preferred embodiment, n is 1, 2 or 3.
In another preferred embodiment, the compound of formula I is selected from the group consisting of:
Figure BDA0002085997560000031
in another preferred embodiment, the compound of formula I is
Figure BDA0002085997560000032
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising:
(a) a compound represented by formula I, or a pharmaceutically acceptable salt, an isotopic derivative, an isomer, a solvate, a metabolite or a prodrug thereof; and (b) a pharmaceutically acceptable carrier;
Figure BDA0002085997560000041
in the formula, each group is as defined above.
In another preferred embodiment, the pharmaceutical composition contains 0.001 to 99 wt% (preferably 0.1 to 90 wt%, more preferably 1 to 80 wt%) of component (a), based on the total weight of the pharmaceutical composition.
In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for the treatment of a low dopamine associated disease (e.g. parkinson's disease).
In another preferred embodiment, the low dopamine associated state is selected from the group consisting of: parkinson, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia, or combinations thereof.
In another preferred embodiment, the pharmaceutical composition further comprises: levodopa (L-DOPA), carbidopa (carbidopa), benserazide (benserazide), bromocriptine (bromocriptine), piribedil (piribedil), dihydroergocryptine (dihydroergocryptine), pramipexole (pramipexole), ropinirole (ropinirole), rotigotine (rotigotine), apomorphine (apomorphine), or combinations thereof.
In another preferred embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug thereof.
In another preferred embodiment, the dosage form of the pharmaceutical composition is injection, tablet, capsule, pill, suspension or emulsion.
In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral dosage form, a transdermal dosage form, an intravenous or intramuscular injection dosage form.
In a third aspect of the present invention, there is provided a use of a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an isotopic derivative thereof, or an isomer thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, in the first aspect of the present invention, for preparing a pharmaceutical composition or a formulation for:
(i) agonizing dopamine receptors, up-regulating dopamine receptor activity; and/or
(ii) Treating low dopamine associated diseases.
In another preferred embodiment, the composition or formulation acts as a dopamine receptor agonist and/or upregulates dopamine receptor activity.
In another preferred embodiment, the dopamine receptor is selected from the group consisting of: dopamine D1Receptor-like, dopamine D2A receptor-like body.
In another preferred embodiment, said dopamine D2The receptor-like includes D2、D3And D4The subtype is.
In another preferred embodiment, the dopamine receptor is dopamine D2Receptor-like D2Subtype (DRD 2).
In another preferred embodiment, the low dopamine associated state is selected from the group consisting of: parkinson, attention deficit hyperactivity disorder, pituitary tumors, hyperprolactinemia, restless legs syndrome, and negative schizophrenia.
In another preferred embodiment, the pharmaceutical composition contains 0.001-99 wt% of the compound represented by formula I, or its pharmaceutically acceptable salt, or its isotopic derivative, or its isomer, or its solvate, or its metabolite, or its prodrug, based on the total weight of the composition.
In another preferred embodiment, the pharmaceutical composition comprises 0.1-90 wt% of the compound represented by formula I, or its pharmaceutically acceptable salt, or its isotopic derivative, or its isomer, or its solvate, or its metabolite, or its prodrug, based on the total weight of the composition.
In another preferred embodiment, the pharmaceutical composition contains 1-80 wt% of the compound represented by formula I, or its pharmaceutically acceptable salt, or its isotopic derivative, or its isomer, or its solvate, or its metabolite, or its prodrug, based on the total weight of the composition.
In a fourth aspect of the present invention, there is provided a method for preparing a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an isotopic derivative thereof, or an isomer thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, comprising the steps of:
(a) reacting a compound of formula a with a compound of formula B in a suitable solvent to form a compound of formula I;
Figure BDA0002085997560000051
in the above formulae, R1、R2、R3、R4、R5M, n are as defined in claim 1.
In another preferred embodiment, the solvent is selected from the group consisting of: tetrahydrofuran, methanol, ethanol, dichloromethane, 1, 2-dichloroethane, diethyl ether, acetonitrile, or combinations thereof.
In another preferred embodiment, the reaction is carried out in the presence of a reducing agent.
In another preferred embodiment, the reducing agent is selected from the group consisting of: sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a combination thereof.
In another preferred embodiment, the reaction is carried out in the presence of a catalyst.
In another preferred embodiment, the catalyst is selected from the group consisting of: acetic acid, trifluoroacetic acid, hydrochloric acid, or a combination thereof.
In another preferred embodiment, in step (a), the reaction temperature is from-50 ℃ to reflux temperature, preferably from 0 ℃ to reflux temperature, more preferably from 0 ℃ to 60 ℃.
In another preferred embodiment, in step (a), the reaction time is 0.1 to 72 hours, preferably 0.5 to 24 hours, and more preferably 0.5 to 8 hours.
In a fifth aspect of the invention, there is provided a method of non-therapeutic up-regulation of dopamine receptor activity in vitro, said method comprising the steps of: culturing a cell in the presence of a compound of formula I, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug thereof, according to claim 1, thereby upregulating dopamine receptor activity in said cell.
In another preferred embodiment, the upregulation is selective upregulation and the selectivity of the compound of formula I, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug thereof, for DRD2 is greater than for DRD 3.
In another preferred embodiment, the upregulation is selective upregulation, and the selectivity of the compound of formula I, or a pharmaceutically acceptable salt, or an isotopic derivative, or an isomer, or a solvate, or a metabolite, or a prodrug thereof, for DRD2 is about 2-20 times that of DRD 3.
In another preferred embodiment, the upregulation is selective upregulation and the compound of formula I, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug thereof, is 12-to 18-fold (e.g., 15-fold) selective for DRD2 as compared to DRD 3.
In another preferred embodiment, the cells are cultured in vitro.
In another preferred embodiment, the cell is selected from the group consisting of: HTLA cells, human renal epithelial 293T cells, or a combination thereof.
In a sixth aspect of the invention, there is provided a kit comprising:
(1) a container, and an active ingredient in the container, wherein the active ingredient is a compound shown in formula I, or a pharmaceutically acceptable salt, an isotopic derivative, an isomer, a solvate, a metabolite or a prodrug thereof, and a pharmaceutically acceptable carrier;
Figure BDA0002085997560000061
in the formula, R1、R2、R3、R4、R5M, n are as defined in claim 1;
and (2) optionally instructions for use, said instructions describing the use of said active ingredient for one or more applications selected from the group consisting of:
(i) agonizing dopamine receptors, up-regulating dopamine receptor activity;
(ii) treating low dopamine associated diseases.
In another preferred embodiment, the dopamine receptor is selected from the group consisting of: dopamine D1Receptor-like, dopamine D2A receptor-like body.
In another preferred embodiment, said dopamine D2The receptor-like includes D2、D3And D4The subtype is.
In another preferred embodiment, the dopamine receptor is dopamine D2Receptor-like D2Subtype (DRD 2).
In another preferred embodiment, the kit further comprises an additional agent for treating a low dopamine associated state (e.g., parkinson).
In a seventh aspect of the invention, there is provided a method of treating a low dopamine associated state, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug, or a pharmaceutical composition or formulation thereof, and/or a pharmaceutical composition according to the second aspect of the invention.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 Selective dopamine D2Structure of receptor agonist I-2. Based on the structural information of DRD2 receptor, through continuous optimization design, a DRD2 selective agonist I-2 is synthesized through a chemical method. The relative molecular mass of this small molecule is 341.92.
FIG. 2 dopamine D2Identification of receptor agonist I-2 selectivity.
(a) DRD2 agonist I-2 showed DRD2 selectivity in the G protein signaling pathway. DRD2, DRD3 and DRD4 were transfected in human renal epithelial 293T cells, respectively, and the agonists were used to stimulate post-transfection thin linesAnd detecting the change of cAMP level in the cells to respond to the change of G protein signal channels, thereby revealing the agonistic effect of the cAMP on dopamine receptors. As shown in figure 2a, this agonist had no effect on both DRD3 and DRD4, exerted an activating effect (Emax 89.76%) on DRD2, and exerted its EC at the time of action50The value was 30.42 nM.
(b) DRD2 agonist I-2 showed DRD2 selectivity in the β -arrestin signaling pathway. DRD2, DRD3 and DRD4 are respectively transfected in HTLA cells, the agonist is used for stimulating the transfected cells, and the change of the level of beta-arrestin in the cells is detected to respond to the change of a beta-arrestin signal channel, so that the agonistic effect of the beta-arrestin on dopamine receptors is revealed. As shown in figure 2b, this agonist had no effect on both DRD3 and DRD4, exerted an activating effect (Emax 63.81%) on DRD2, and exerted its EC at the time of action50The value was 310.97 nM.
FIG. 3 dopamine D2Screening for receptor agonist I-2 in GPCRome. To further explore dopamine D2The specificity of receptor agonist I-2, the inventors screened its agonism against 320 other non-olfactory GPCRs and showed that this agonist had only agonism against DRD2 at 1 μ M and about 80-fold agonism over the absence of agonist, but not against the other 320 non-olfactory GPCRs, thus suggesting that this agonist is indeed highly selective only against DRD 2.
Detailed Description
The invention provides a DRD2 selective agonist, which has the characteristics of DRD2 agonist, DRD 3-free and DRD 4-free agonists, has high selectivity, can greatly reduce the generation of side effects, and has the potential of treating low dopamine-related diseases such as Parkinson's disease, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia and the like. The present invention has been completed based on this finding.
Specifically, the DRD2 selective agonist specifically targeting DRD2 can play a role in treating low dopamine related diseases such as Parkinson's disease, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia and the like while minimizing side effects.
Term(s) for
The term "halogen" as used herein refers to F, Cl, Br and I.
Said "C" of the present invention1-C6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or the like.
Said "C" of the present invention1-C5Alkyl "means a straight or branched chain alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or the like.
Said "C" of the present invention1-C4Alkyl "means a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, or the like.
Said "C" of the present invention1-C3Alkyl "means a straight or branched chain alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl, or the like. The term "C1-C6Alkoxy- "," -OC1-C6Alkyl "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, or the like.
The term "C1-C5Alkoxy "means a straight or branched chain alkoxy group having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, or the like.
The term "-OC1-C4Alkyl "means a straight or branched chain alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
Term(s) for“C2-C6The alkenyloxy group "means a straight-chain or branched alkenyloxy group having 2 to 6 carbon atoms, such as an ethyleneoxy group, propyleneoxy group, butyleneoxy group, isobutyleneoxy group, penteneoxy group, or the like.
The term "C2-C5The alkenyloxy group "means a straight-chain or branched alkenyloxy group having 2 to 5 carbon atoms, such as an ethyleneoxy group, propyleneoxy group, butyleneoxy group, isobutyleneoxy group, penteneoxy group, or the like.
The term "C3-C6Cycloalkoxy "means a cycloalkoxy group having 3 to 6 carbon atoms, such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, or the like.
The term "C3-C5Cycloalkoxy "means a cycloalkoxy group having 3 to 5 carbon atoms, such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, or the like.
As used herein, the term "C2-C6Alkenyl "means a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like. Where not otherwise specified, the term includes substituted or unsubstituted C2-C6An alkenyl group.
As used herein, the term "C2-C4Alkenyl "means a straight or branched chain alkenyl group having 2 to 4 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like. Where not otherwise specified, the term includes substituted or unsubstituted C2-C4An alkenyl group.
As used herein, the term "C2-C6Alkynyl "means a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, or the like. Where not otherwise specified, the term includes substituted or unsubstituted C2-C6Alkynyl group.
As used herein, the term "C2-C4Alkynyl "means a straight chain having 2 to 4 carbon atoms orBranched alkynyl groups such as ethynyl, propynyl, or the like. Where not otherwise specified, the term includes substituted or unsubstituted C2-C4Alkynyl group.
As used herein, the term "C3-C6Cycloalkyl "refers to a cyclic alkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Where not otherwise specified, the term includes substituted or unsubstituted C3-C6A cycloalkyl group.
As used herein, the term "C3-C5Cycloalkyl "refers to a cyclic alkyl group having 3 to 5 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Where not otherwise specified, the term includes substituted or unsubstituted C3-C6A cycloalkyl group.
As used herein, the term "C1-C3Haloalkyl "refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms, e.g., halomethyl, haloethyl, halopropyl, haloisopropyl, or the like, with hydrogen substituted with 1 or more than 1 halogen. Where not otherwise specified, the term includes substituted or unsubstituted C1-C3A haloalkyl group.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine and chlorine, most preferably fluorine.
The term "halogenated" as used herein refers to a group substituted with the same or different one or more of the above-mentioned halogen atoms, which may be partially halogenated or fully halogenated, for example, trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or the like.
The compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention includes all isomeric forms of the compounds.
The term "substituted" means having 1 or more (preferably, 1 to 6, more preferably, 1 to 3) substituents selected from the group consisting of: c3-C6Cycloalkyl, halogen, nitro, cyano, hydroxy, carboxy, C1-C3Alkyl radical, C1-C3Haloalkyl, and amino.
Active ingredient
In the present invention, "the compound of the present invention", "the active ingredient" and "the active ingredient of the present invention" are used interchangeably and refer to a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an isotopic derivative thereof, or an isomer thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof.
Typically, in the present invention, the active ingredient has a structure represented by the following formula I,
Figure BDA0002085997560000091
in the formula:
R1is hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C3-C6Cycloalkoxy, substituted or unsubstituted C2-C6An alkenyloxy group;
R2hydrogen, halogen, nitro, cyano, hydroxyl;
R3is hydrogen, substituted or unsubstituted C1-C6An alkyl group;
wherein R is1、R3Wherein said substitution is with one or more substituents selected from the group consisting of: c3-C6Cycloalkyl, halogen, nitro, cyano, hydroxy;
R4、R5each independently selected from the group consisting of: hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6Alkyl, substitutedOr unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted-OC1-C6Alkyl radical, R6(R7) N-; wherein H in the substituent group is substituted with one or more substituents selected from the group consisting of: -OH, -CN, nitro, carboxyl, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, and-NRaRb;
R6and R7Each independently selected from the group consisting of: H. c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, -OH, -CN; ra、RbEach independently is H, C1-C3Alkyl, or C3-C6A cycloalkyl group;
n is a positive integer of 1-3;
m is a positive integer of 1 to 6, preferably 1 to 4, more preferably 1 to 3.
In another preferred embodiment of the present invention, the representative active ingredient is a compound selected from the group consisting of:
Figure BDA0002085997560000101
the compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention includes all isomeric forms of the compounds.
The process for the preparation of the compounds of formula I according to the invention is described in more detail below, but these particular processes do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains. Generally, in the preparation method of the present invention, the reaction is carried out in a suitable solvent at a temperature of from-20 ℃ to reflux temperature (preferably, from 0 to 60 ℃) for a certain period of time (e.g., from 0.1 to 72 hours, preferably, from 0.5 to 24 hours, more preferably, from 0.5 to 8 hours).
As used herein, room temperature means 4-35 deg.C, preferably 20-30 deg.C. Preferably, the compounds of formula I of the present invention can be prepared by the following schemes and exemplary methods described in the examples and related disclosure procedures used by those skilled in the art.
Typically, the process for the preparation of the compounds of formula I of the present invention may include, but is not limited to, the following schemes.
Figure BDA0002085997560000111
The compound (I) is prepared by using carbonyl compound (A) and amino compound (B) as raw materials, and performing reductive amination reaction in a proper solvent (such as tetrahydrofuran, methanol, ethanol, dichloromethane, 1, 2-dichloroethane, diethyl ether and acetonitrile). Reducing agents used in this reaction include, but are not limited to, sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride. The reaction temperature is from-50 ℃ to reflux temperature, preferably from-20 ℃ to reflux temperature, more preferably from 0 ℃ to 60 ℃; the reaction time is 0.1 to 72 hours, preferably 0.5 to 24 hours, more preferably 0.5 to 8 hours. (ii) a A catalyst (e.g., acetic acid) may be added to the reaction. Wherein R is1，R2，R3，R4，R5And m and n are defined as the specification.
Pharmaceutically acceptable salts or prodrugs
The compound also comprises pharmaceutically acceptable salt of the compound shown as the formula I.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with pharmaceutically acceptable inorganic and organic acids, including: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; the organic acids include: formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1,5), sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids. The term "pharmaceutically acceptable salt" may also refer to the sodium, potassium or ammonium salt of a compound of the invention
As used herein, the term "pharmaceutically acceptable prodrug" refers to a compound that is inactive in vitro, but is capable of being converted in vivo to the active agent of formula I, thereby exerting its pharmacological effect.
Pharmaceutical composition
The invention also provides a pharmaceutical composition with remarkable treatment efficacy on low-dopamine related diseases (such as Parkinson), which comprises a therapeutically effective amount of the compound shown in the formula I or pharmaceutically acceptable salts (such as hydrochloride) thereof and one or more pharmaceutically acceptable carriers.
In another preferred embodiment of the invention, the low dopamine associated state is selected from the group consisting of: parkinson, attention deficit hyperactivity disorder, pituitary tumors, hyperprolactinemia, restless legs syndrome, and negative schizophrenia.
In another preferred embodiment of the present invention, the pharmaceutical composition further comprises: levodopa (L-DOPA), carbidopa (carbidopa), benserazide (benserazide), bromocriptine (bromocriptine), piribedil (piribedil), dihydroergocryptine (dihydroergocryptine), pramipexole (pramipexole), ropinirole (ropinirole), rotigotine (rotigotine), apomorphine (apomorphine).
In another preferred embodiment of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of a pharmaceutically acceptable salt of the compound represented by formula I, and one or more pharmaceutically acceptable carriers.
The compound itself or a mixture of a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent or the like may be administered orally in the form of tablets, capsules, granules, powders or syrups, or non-orally in the form of injections. The pharmaceutical composition preferably contains 0.01-99% by weight of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, more preferably 0.1-90% by weight of the active ingredient.
The above preparation can be prepared by conventional pharmaceutical method. Examples of pharmaceutically acceptable adjuvants which may be used include excipients (e.g. saccharide derivatives such as lactose, sucrose, glucose, mannitol and sorbitol, starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch, cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, dextran, silicate derivatives such as magnesium aluminium metasilicate, phosphate derivatives such as calcium phosphate, carbonate derivatives such as calcium carbonate, sulphate derivatives such as calcium sulphate and the like), binders (e.g. gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (e.g. cellulose derivatives such as sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (e.g. talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), Stabilizers (methyl paraben, propyl paraben, etc.), flavoring agents (e.g., commonly used sweeteners, acidulants, flavors, etc.), diluents, and solvents for injection (e.g., water, ethanol, glycerin, etc.).
The amount of the compound of the present invention, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof to be administered varies depending on the age, sex, race, condition, etc. of a patient. The daily dose for an adult is generally about 10mg to 2000mg, preferably 50mg to 1000 mg.
Dopamine receptors
Dopamine receptors belong to the family of G-protein coupled receptors and are currently classifiedFive dopamine receptors are isolated and classified as D according to their biochemical and pharmacological properties1Class and D2Class I, wherein D1The receptor-like includes D1And D5Subtype, which activates adenylate cyclase, increases intracellular cyclic adenosine monophosphate (cAMP) concentration; d2The receptor-like includes D2、D3And D4Subtypes, which inhibit adenylate cyclase, are also associated with other second messenger systems within the cell, including activation of potassium channels, inhibition of calcium channels, and conversion of phosphatidylinositol. Dopamine ligand compounds although readily bind D due to the similarity of distinct subtypes within the two families of dopamine receptors1Class and D2Family-like groups differentiate but most compounds do not differentiate receptor subtypes of the same family.
The dopamine system is closely related to various central nervous system diseases, and the development of drugs aiming at dopamine or dopamine receptors is always the focus of research. Several studies have demonstrated that DRD2 is an important target for psychiatric disorders and DRD2 is closely associated with locomotion, with all receptor-targeted antipsychotics and anti-parkinson drugs targeting DRD 2.
The invention discloses a pharmaceutical composition aiming at DRD2, which is used for treating low dopamine related diseases such as Parkinson's disease and the like by activating DRD2 to activate corresponding functions.
In a preferred embodiment of the invention, the dopamine receptor is selected from the group consisting of: dopamine D1Receptor-like, dopamine D2A receptor-like body.
In still another preferred embodiment of the present invention, the dopamine D2The receptor-like includes D2、D3And D4The subtype is.
In yet another preferred embodiment of the present invention, the dopamine receptor is dopamine D2Receptor-like D2Subtype (DRD 2).
Pharmaceutical composition or preparation for treating low dopamine related diseases
The present invention provides a method of treating a low dopamine associated state, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug, or pharmaceutical composition or formulation thereof.
In a preferred embodiment of the present invention, the pharmaceutical composition comprises: (a) a therapeutically effective amount of a compound of formula I; and (b) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition or formulation further comprises a component selected from the group consisting of: levodopa (L-DOPA), carbidopa (carbidopa), benserazide (benserazide), bromocriptine (bromocriptine), piribedil (piribedil), dihydroergocryptine (dihydroergocryptine), pramipexole (pramipexole), ropinirole (ropinirole), rotigotine (rotigotine), apomorphine (apomorphine), or combinations thereof.
In a preferred embodiment of the invention, the low dopamine associated state is selected from the group consisting of: parkinson, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia, or combinations thereof.
In still another preferred embodiment of the present invention, the pharmaceutical composition is in the form of injection, tablet, capsule, pill, suspension or emulsion.
In still another preferred embodiment of the present invention, the pharmaceutical composition is in the form of an oral dosage form, a transdermal dosage form, an intravenous or intramuscular injection dosage form.
In another preferred embodiment, the effective concentration of the compound of formula I is 0.01nM/L to 1mM/L, preferably 0.1nM/L to 500. mu.M/L, most preferably 1nM/L to 100. mu.M/L.
The invention also provides a preparation method of a pharmaceutical composition or a preparation for treating low dopamine associated diseases, which comprises the following steps: a therapeutically effective amount of a compound of formula I is mixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition or formulation.
Typically, a low dopamine associated state (e.g., parkinson) can be treated or ameliorated by administering to a subject a therapeutically effective amount of a compound of formula I, or a pharmaceutical composition or formulation comprising a compound of formula I.
DRD2 selective agonists and uses thereof
The invention provides a DRD2 selective agonist.
Typically, the present inventors have discovered and identified a DRD2 selective agonist.
In a preferred embodiment of the invention, the DRD2 selective agonist is synthesized by chemical methods based on continuous optimization design of DRD2 structure.
In another preferred embodiment, the inventors combine D2Transfecting cell with DRD2, DRD3 and DRD4, respectively, and applying DRD2 selective agonist stimulation and downstream GiAnd the degree of antagonism of the β -arrestin signaling pathway confirms that this agonist is a selective agonist that does not activate DRD3 and DRD4 but activates DRD 2.
Typically, the inventors have discovered for the first time a DRD2 selective agonist, which is specific for D only2The DRD2 in the family has an activating effect and has no effect on other two members in the family, namely DRD3 and DRD4, so that the DRD2 has a better potential application value, and the possibility of treating diseases by reducing side effects to the maximum extent is realized, wherein the diseases mainly comprise low dopamine-related diseases such as Parkinson's disease, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia and the like.
The main advantages of the invention are:
the invention discovers the DRD2 selective agonist for the first time, which has the characteristics of DRD2 agonist, no DRD3 agonist and no DRD4 agonist, greatly reduces the side effect and has great application potential in treating low dopamine diseases such as Parkinson disease and the like.
The following specific examples further illustrate the invention. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, for which specific conditions are not indicated in the following examples, are generally carried out according to conventional conditions, for example as described in Sambrook and Russell et al, Molecular Cloning: A Laboratory Manual (third edition) (2001) CSHL Press, or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Materials and methods
The invention discovers a DRD2 highly selective agonist and discloses the potential application value of the DRD2 in the treatment of diseases. The specific operation is as follows: the DRD2 highly selective agonist is synthesized by a chemical method, the selectivity of the agonist is verified at a cellular level, and finally the application potential of the DRD2 in the low dopamine related diseases is revealed.
1. Dopamine D2Synthesis of receptor-selective agonists
Based on the structural information of DRD2 receptor, through continuous optimization design, a DRD2 selective agonist is synthesized by a chemical method.
2. Cell culture
Human kidney epithelial 293T cells were cultured in DMEM medium containing 10% Fetal Bovine Serum (FBS) and the dishes were placed at 37 ℃ and 5% CO2Culturing is carried out under the conditions. After the cells are attached to the culture dish, sucking the culture solution by using a pipette gun, slowly cleaning by using 1mL of PBS to remove excessive serum, adding 800 mu L of 0.25% pancreatin, digesting the cells in a thermostat for 2min, taking out the cells, observing under a microscope, rounding the cells, freely swimming at the bottom of the dish, adding 2mL of culture solution containing the serum to stop digestion, slightly blowing and beating the cells by using the 1mL of gun to disperse the cells into single cells, and finally continuing subculture or further experiments according to the needs of the experiments.
3. Cell transfection
One day prior to transfection, confluent human kidney epithelial 293T cells in 10 cm petri dishes were plated at 1: 4 portions were placed in 6cm petri dishes for subculture. After 20 hours, transfection was prepared when the cell density reached 50% -70%. mu.L of 150mM NaCl was taken in a clean EP tube, and 3. mu.g of plasmid was added thereto, and at the same time, PEI was added thereto in an amount of 4 times that of the plasmid, and well mixed. Incubate at room temperature for 20 minutes. 500 μ L of the transfection solution was suspended and dropped into the petri dish, and gently shaken to mix well.
4. Luciferase-based cAMP reporter detection
The first day, 6cm dishes were transfected with 3 μ g dopamine receptor, 3 μ g Glo plasmid and 24 μ L PEI. The next day, confluent human kidney epithelial 293T cells were digested and plated in 384 well plates at 30. mu.L/well of culture medium per 6cm cell size. And on the third day, adding medicine for detection. First, remove the culture from the cell chamber in 384-well plates and add 20uL of drug buffer per well. And sequentially adding 10 mu L of different drugs from left to right to ensure that the final concentration of the drugs is gradually reduced from bottom to top, repeating three times for each treatment, finally adding 10uL of luciferase substrate into each hole, and performing machine detection.
5. Experiment for recruitment of beta-arrestin
On the first day, 6cm dishes were transfected with 3. mu.g of dopamine receptor Tango plasmid and 12. mu.L PEI. The next day, confluent HTLA cells were digested and plated in 384-well plates at 30. mu.L/well in a 6cm cell-confluent dish. On the third day, 10 μ L of different drugs are sequentially added into the cells of the 384-well plate from left to right in the cell room superclean bench, so that the final concentration of the drugs is gradually decreased from bottom to top, and each treatment is repeated three times. On the fourth day, the 384-well plate was removed from the cell chamber, and 20. mu.L of luciferase substrate was added to each well, and the plate was tested on the machine.
GPCRome screening
On the first day, HTLA cells were seeded in 384-well white transparent plates at 10000 cells per well, 40. mu.L of DMEM medium containing 10% FBS per well. The following day, transfection was performed at 20ng of recipient plasmid per well. On the third day, the culture medium was removed and replaced with DMEM medium containing 1% dialyzed FBS (FBS), 40. mu.L of culture medium per well, and then 1. mu.M of drug was added to each well. On the fourth day, the 384-well plate was removed from the cell chamber, and 20. mu.L of luciferase substrate was added to each well, and the plate was tested on the machine.
Example 1 discovery and identification of a dopamine D2 receptor selective agonist
The inventors are based on D2Structural information of the receptor is continuously optimized and designed, and a DRD2 selective agonist I-2 (figure 1) is synthesized by a chemical method. The inventors selected two signaling pathways downstream of the receptor, the G protein signalThe signal pathway and the beta-arrestin signal pathway are used as indicators of the receptor agonism degree, and the selectivity of the receptor is verified at the cellular level.
The results (fig. 2) show that this agonist behaves similarly in both signaling pathways, neither for activation of the dopamine receptor downstream G protein signaling pathway (fig. 2a) nor for activation of the dopamine receptor downstream β -arrestin signaling pathway (fig. 2b), but does not activate DRD3 and DRD4 but does activate DRD2, thus showing that this agonist is highly selective for DRD 2. To further explore its specificity, the inventors screened its agonistic effects on 320 other GPCRs and the results (figure 3) showed that this agonist had only agonistic effects on DRD2 at 1 μ M and no effect on 320 other non-olfactory GPCRs, thus suggesting that this agonist is indeed highly selective for DRD 2.
Example 2 dopamine D2Potential application value of receptor selective agonist in disease treatment
The inventor optimally designs and screens a DRD2 highly selective agonist, and based on the selectivity of the highly selective agonist, the highly selective agonist can reduce the side effects brought by DRD3 and DRD4 to the maximum extent, so the highly selective agonist has a better application value in disease treatment and has the possibility of being used for treating low dopamine-related diseases such as Parkinson's disease, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia and the like.
EXAMPLE 31 preparation of- (((4- (2-nitrophenyl) butan-2-yl) amino) methyl) cyclohexanol (I-1) hydrochloride
Step 1: the starting material, 2-nitrobenzaldehyde 1(2.0g, 13.2mmol), was dissolved in absolute ethanol (20mL), acetone (9.6mL, 132mmol) and lithium hydroxide monohydrate (56mg, 1.32mmol) were added in this order, and the reaction was carried out at room temperature for 4 hours. Diluting with water, extracting with ethyl acetate, washing with saturated brine, removing the organic phase solvent by evaporation under reduced pressure, and separating and purifying the residue by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain yellow oil 2(574mg, yield 23%). 1H NMR (800MHz, CDCl3)8.08(d, J ═ 8.2Hz,1H),7.98(d, J ═ 16.2Hz,1H), 7.69-7.64 (M,2H), 7.59-7.54 (M,1H),6.57(d, J ═ 16.2Hz,1H),2.43(s,3H) hrms (esi) C10H10NO3+ [ M + H ] + calculated: 192.0655, found: 192.0657.
step 2: compound 2(230mg, 1.2mmol) obtained in step 1 above was dissolved in tetrahydrofuran (15mL), and tris (triphenylphosphine) rhodium chloride (111mg, 0.12mmol) and 10% palladium on carbon (23mg) were added in this order to replace hydrogen three times. The reaction mixture was reacted under hydrogen at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to give a brown residue. The residue was purified by flash column chromatography (0-15% ethyl acetate/petroleum ether) to give 3 as a yellow oil (63mg, yield 27%). 1H NMR (800MHz, CDCl3)7.93(d, J ═ 8.1Hz,1H),7.52(t, J ═ 7.5Hz,1H),7.40(d, J ═ 7.5Hz,1H),7.36(t, J ═ 7.7Hz,1H),3.14(t, J ═ 7.5Hz,2H),2.85(t, J ═ 7.5Hz,2H),2.16(s,3H), hrms esi) C10H12NO3+ [ M + H ] + calculated: 194.0812, found: 194.0814.
and step 3: compound 3(130mg, 0.67mmol) obtained in step 2 above was dissolved in anhydrous dichloromethane (5mL) and anhydrous acetonitrile (5mL), and 1- (aminomethyl) cyclohexanol (87mg, 0.67mmol) and acetic acid (40mg, 0.67mmol) were added in that order. After the reaction was allowed to warm to 60 ℃ overnight, sodium triacetoxyborohydride (285mg, 1.35mmol) was added and the reaction was continued for 1 hour. The reaction solution was cooled to room temperature, and methanol (5mL) was added thereto and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the remaining solid was purified by flash column chromatography (0-6% methanol/dichloromethane) to give I-1 as a yellow oil (130mg, yield 63%).
And 4, step 4: compound I-1(100mg) obtained in the above step 3 was dissolved in a mixed solvent of methanol and methylene chloride (1:10, 5mL), and 2M ethereal hydrochloric acid (2mL) was added. After stirring for 2 to 5 minutes, the solvent was distilled off under reduced pressure to give I-1 hydrochloride as a tan solid (58mg, yield 96%). 1H NMR (800MHz, CD3OD)7.97(dd, J ═ 8.1,0.8Hz,1H),7.65(td, J ═ 7.6,1.0Hz,1H),7.54(d, J ═ 7.7Hz,1H), 7.49-7.46 (M,1H), 3.41-3.36 (M,1H), 3.07-3.02 (M,1H),3.00 and 2.98(ABq, J ═ 12.7Hz,2H), 2.93-2.89 (M,1H), 2.18-2.13 (M,1H), 1.97-1.91 (M,1H), 1.71-1.66 (M,2H), 1.66-1.62 (M,2H), 1.59-1.48 (M,5H),1.45 (J ═ 6H), 1.84H, 1H, 13 ++ 35H (M, 35H), calculated values of [ hrq, J ++ 27H ]: 307.2016, found: 307.2026.
EXAMPLE 41 preparation of- (((4- (2-ethoxyphenyl) butan-2-yl) amino) methyl) cyclohexanol (I-2) hydrochloride
Step 1: the starting material 2-ethoxybenzaldehyde 4(3.0g, 19.98mmol) was dissolved in anhydrous ethanol (20mL), and acetone (4.4mL, 59.93mmol) and lithium hydroxide monohydrate (167mg, 4.0mmol) were sequentially added to the solution, followed by reaction at room temperature overnight. Diluting with water, extracting with ethyl acetate, washing with saturated brine, removing the organic phase solvent by evaporation under reduced pressure, and separating and purifying the residue by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain yellow oil 5(1.19g, yield 31%). 1H NMR (800MHz, CDCl3)7.90(d, J ═ 16.5Hz,1H),7.54(d, J ═ 7.7Hz,1H),7.34(t, J ═ 7.8Hz,1H),6.95(t, J ═ 7.5Hz,1H),6.90(d, J ═ 8.3Hz,1H),6.77(d, J ═ 16.5Hz,1H),4.11(q, J ═ 7.0Hz,2H),2.38(s,3H),1.48(t, J ═ 7.0Hz,3H), hrms (esi) C12H15O2+ [ M + H ] + calculated value: 191.1067, found: 191.1068.
step 2: compound 5(1.19g, 6.26mmol) obtained in step 1 above was dissolved in tetrahydrofuran (30mL), and 10% palladium on carbon (120mg) was added to replace hydrogen three times. The reaction mixture was reacted at room temperature under hydrogen for 1 hour. The reaction mixture was filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by flash column chromatography (0-20% ethyl acetate/petroleum ether) to give 6(900mg, yield 75%) as a colorless oil. 1H NMR (600MHz, CDCl3)7.16(t, J ═ 7.8Hz,1H),7.13(d, J ═ 7.3Hz,1H),6.86(t, J ═ 7.4Hz,1H),6.82(d, J ═ 8.1Hz,1H),4.04(q, J ═ 6.9Hz,2H), 2.92-2.85 (M,2H), 2.78-2.67 (M,2H),2.14(s,3H),1.42(t, J ═ 7.0Hz,3H), hrms (esi) C12H17O2+ [ M + H ] + calculated value: 193.1223, found: 193.1224.
and step 3: compound 6(150mg, 0.78mmol) obtained in step 2 above was dissolved in anhydrous acetonitrile (10mL), and 1- (aminomethyl) cyclohexanol (100mg, 0.78mmol) and acetic acid (47mg, 0.78mmol) were added in that order. After the reaction was allowed to warm to 60 ℃ overnight, sodium triacetoxyborohydride (330mg, 1.56mmol) was added and the reaction was continued for 1 hour. The reaction solution was cooled to room temperature, and methanol (5mL) was added thereto and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the remaining solid was purified by flash column chromatography (0-6% methanol/dichloromethane) to give I-2 as a yellow oil (146mg, yield 61%).
And 4, step 4: compound I-2(126mg) obtained in the above step 3 was dissolved in a mixed solvent of methanol and methylene chloride (1:10, 5mL), and 2M ethereal hydrochloric acid (2mL) was added. After stirring for 2 to 5 minutes, the solvent was distilled off under reduced pressure to give I-2 hydrochloride as a white solid (138mg, yield 98%). 1H NMR (600MHz, CD3OD) 7.20-7.15 (M,2H),6.93(d, J ═ 8.0Hz,1H),6.87(td, J ═ 7.4,0.9Hz,1H),4.07(q, J ═ 7.0Hz,2H), 3.27-3.20 (M,1H), 2.95-2.89 (M,2H), 2.82-2.76 (M,1H), 2.71-2.62 (M,1H), 2.13-2.06 (M,1H), 1.89-1.79 (M,1H), 1.71-1.60 (M,4H), 1.59-1.45 (M,5H), 1.45-1.39 (M,6H), 1.38-1.29 (M,1H) esi [ 19H + 2H ] + hrm +: 306.2428, found: 306.2436.
EXAMPLE 51 preparation of ((4- (2-allyloxyphenyl) butan-2-yl) amino) methyl) cyclohexanol (I-3) hydrochloride
Step 1: the starting material, salicylaldehyde 7(5.0g, 40.94mmol), was dissolved in absolute ethanol (30mL), acetone (14.9mL, 204.71mmol) and sodium hydroxide (1.97g, 49.13mmol) were added sequentially, and water (10mL) was added finally and the reaction was allowed to proceed at room temperature overnight. The pH value of the solution is adjusted to 6-7 by 4M dilute hydrochloric acid, the solution is extracted by ethyl acetate, the saturated saline solution is washed, the organic phase solvent is removed by evaporation under reduced pressure, and the residue is separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain a white solid 8(4.69g, yield 71%). 1H NMR (800MHz, CDCl3)7.86(d, J ═ 16.4Hz,1H),7.47(dd, J ═ 7.8,1.6Hz,1H), 7.27-7.24 (M,1H),7.03(d, J ═ 16.4Hz,1H), 6.95-6.91 (M,2H),2.43(s,3H), hrms (esi) C10H11O2+ [ M + H ] + calculated: 163.0754, found: 163.0755.
step 2: compound 8(2.6g, 16.03mmol) obtained in step 1 above was dissolved in tetrahydrofuran (20mL), and 10% palladium on carbon (260mg) was added to replace hydrogen three times. The reaction mixture was reacted under hydrogen at room temperature for 2 hours. The reaction solution was filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by flash column chromatography (0-25% ethyl acetate/petroleum ether) to give 9(2.17g, yield 82%) as a colorless oil. 1H NMR (800MHz, CDCl3)7.11(td, J ═ 7.7,1.8Hz,1H),7.06(dd, J ═ 7.5,1.7Hz,1H),6.89(dd, J ═ 8.1,1.3Hz,1H),6.85(td, J ═ 7.4,1.2Hz,1H), 2.90-2.88 (M,2H), 2.85-2.82 (M,2H),2.16(s,3H), hrms (hrms) (calculated) C10H13O2+ [ M + H ] + esi: 165.0910, found: 165.0907.
and step 3: compound 9(238mg, 1.45mmol) obtained in step 2 above was dissolved in acetonitrile (20mL), and allyl bromide (263mg, 2.17mmol) and potassium carbonate (400mg, 2.90mmol) were added in this order, and the mixture was raised to 80 ℃ to react for 3 hours. Diluting with water, extracting with ethyl acetate, washing with saturated brine, removing the organic phase solvent by evaporation under reduced pressure, and separating and purifying the residue by flash column chromatography (0-20% ethyl acetate/petroleum ether) to obtain colorless oil 10(168mg, yield 57%). 1H NMR (800MHz, CDCl3) 7.19-7.13 (M,2H),6.88(td, J ═ 7.4,1.1Hz,1H),6.83(dd, J ═ 8.2,1.1Hz,1H), 6.11-6.03 (M,1H), 5.43-5.39 (M,1H), 5.29-5.25 (M,1H),4.55(dt, J ═ 5.1,1.7Hz,2H),2.92(t, J ═ 7.6Hz,2H),2.75(t, J ═ 7.6Hz,2H),2.14(s,3H), hrms (esi) C13H17O2+ [ M + H ] + calculated value: 205.1223, found: 205.1217.
and 4, step 4: compound 10(210mg, 1.03mmol) obtained in step 3 above was dissolved in anhydrous tetrahydrofuran (20mL), and 1- (aminomethyl) cyclohexanol (133mg, 1.03mmol) and acetic acid (62mg, 1.03mmol) were added in this order. After the reaction was allowed to stand overnight under reflux, sodium triacetoxyborohydride (435mg, 2.06mmol) was added and the reaction was continued for 6 hours. Methanol (5mL) was added and stirred for 2 hours. Diluting with water, extracting with ethyl acetate, washing with saturated aqueous sodium bicarbonate solution and saturated brine in this order, evaporating under reduced pressure to remove the organic phase solvent, and separating and purifying the residue with flash column chromatography (0-5% methanol/dichloromethane) to obtain colorless oil I-3(180mg, yield 55%).
And 5: compound I-3(180mg) obtained in the above step 4 was dissolved in a mixed solvent of methanol and methylene chloride (1:10, 5mL), and 2M ethereal hydrochloric acid (2mL) was added. After stirring for 2 to 5 minutes, the solvent was distilled off under reduced pressure to give I-3 hydrochloride as a white solid (195mg, yield 97%). 1H NMR (800MHz, CD3OD) 7.20-7.17 (M,2H),6.95(dd, J ═ 8.6,1.1Hz,1H),6.89(td, J ═ 7.4,1.1Hz,1H), 6.15-6.09 (M,1H),5.43(dd, J ═ 17.3,1.7Hz,1H),5.28(dd, J ═ 10.6,1.5Hz,1H),4.60(dt, J ═ 5.2,1.6Hz,2H), 3.26-3.21 (M,1H),2.91 and 2.90(ABq, J ═ 12.9Hz,2H), 2.84-2.78 (M,1H), 2.73-2.67 (M,1H), 2.12-2.08 (M, 1.81H), 1.54(M,1H, 18H, 1H, 18: 318.2428, found: 318.2429.
EXAMPLE 61 preparation of ((4- (2-Isopropoxyphenyl) butan-2-yl) amino) methyl) cyclohexanol (I-4) hydrochloride
Step 1: the raw material allyl bromide in step 3 of example 3 was replaced with 2-bromopropane, and the remaining required raw materials, reagents and preparation methods were the same as in example 3, to give colorless oil 11. 1H NMR (800MHz, CDCl3)7.15(td, J ═ 7.9,2.1Hz,1H),7.13(dd, J ═ 7.6,1.8Hz,1H), 6.85-6.82 (M,2H),4.56(p, J ═ 6.0Hz,1H),2.87(t, J ═ 8.2Hz,2H),2.72(t, J ═ 8.1Hz,2H),2.14(s,3H),1.34(d, J ═ 6.1Hz,6H), hrms (esi) C13H19O2+ [ M + H ] + calculated values: 207.1380, found: 207.1373.
step 2: the starting material "4- (2-allyloxyphenyl) -2-butanone" in step 4 of example 3 was replaced with "4- (2-isopropoxyphenyl) -2-butanone", and the remaining required starting materials, reagents and preparation were the same as in steps 4 and 5 of example 3, to give I-4 hydrochloride as a white solid. 1H NMR (800MHz, CD3OD) 7.18-7.16 (M,2H),6.95(d, J ═ 8.4Hz,1H),6.86(td, J ═ 7.4,1.1Hz,1H),4.65(p, J ═ 6.0Hz,1H), 3.25-3.20 (M,1H),2.92(s,2H), 2.79-2.73 (M,1H), 2.69-2.60 (M,1H), 2.11-2.05 (M,1H), 1.88-1.80 (M,1H), 1.71-1.64 (M,2H), 1.64-1.60 (M,2H), 1.59-1.54 (M,1H), 1.53-1.45 (M,4H),1.42(d, 6.6H), 1.37H, 7H + 20(M, 3H), calculated values of [ 20H +: 320.2584, found: 320.2589.
EXAMPLE 71 preparation of- (((4- (2-methoxyphenyl) butan-2-yl) amino) methyl) cyclohexanol (I-5) hydrochloride
Step 1: the raw material allyl bromide in step 3 of example 3 was replaced with methyl iodide, and the remaining required raw materials, reagents and preparation methods were the same as in example 3, to give colorless oil 12. 1H NMR (800MHz, CDCl3)7.19(td, J ═ 7.8,1.8Hz,1H),7.13(dd, J ═ 7.4,1.7Hz,1H),6.87(td, J ═ 7.4,1.1Hz,1H),6.84(dd, J ═ 8.2,1.1Hz,1H),3.82(s,3H),2.88(t, J ═ 8.1Hz,2H),2.72(t, J ═ 8.2Hz,2H),2.14(s,3H), hrms (esi) C11H15O2+ [ M + H ] + calculated value: 179.1067, found: 179.1067.
step 2: the raw material "4- (2-allyloxyphenyl) -2-butanone" in step 4 of example 3 was replaced with "4- (2-methoxyphenyl) -2-butanone", and the remaining required raw materials, reagents and preparation methods were the same as in steps 4 and 5 of example 3, to give I-5 hydrochloride as a white solid. 1H NMR (800MHz, CD3OD)7.21(t, J ═ 7.8Hz,1H),7.17(d, J ═ 7.3Hz,1H),6.95(d, J ═ 8.2Hz,1H),6.89(t, J ═ 7.4Hz,1H),3.85(s,3H), 3.26-3.21 (M,1H),2.94 and 2.93(ABq, J ═ 12.9Hz,2H), 2.81-2.75 (M,1H), 2.69-2.64 (M,1H), 2.12-2.07 (M,1H), 1.86-1.80 (M,1H), 1.71-1.65 (M,2H), 1.65-1.60 (M,2H), 1.59-1.46 (M,5H),1.40 (M,6H, 3H + (M,1H), 13-1H, 18H, M: 292.2271, found: 292.2269.
EXAMPLE 81 preparation of- (((4- (2-propoxyphenyl) butan-2-yl) amino) methyl) cyclohexanol (I-6) hydrochloride
Step 1: the raw material allyl bromide in step 3 of example 3 was replaced with 1-bromopropane, and the remaining required raw materials, reagents and preparation methods were the same as in example 3, to give colorless oil 13. 1H NMR (800MHz, CDCl3) 7.18-7.15 (M,1H),7.13(d, J ═ 7.3Hz,1H),6.86(t, J ═ 7.4Hz,1H),6.82(d, J ═ 8.1Hz,1H),3.93(t, J ═ 6.4Hz,2H),2.90(t, J ═ 7.7Hz,2H),2.74(t, J ═ 7.7Hz,2H),2.14(s,3H),1.83(H, J ═ 6.9Hz,2H),1.06(t, J ═ 7.4Hz,4H), hrms (esi) C13H19O2+ [ M + H ] + calculated value: 207.1380, found: 207.1369.
step 2: the starting material "4- (2-allyloxyphenyl) -2-butanone" in step 4 of example 3 was replaced with "4- (2-propoxyphenyl) -2-butanone", and the remaining required starting materials, reagents and preparation were the same as in steps 4 and 5 of example 3 to give I-6 hydrochloride as a white solid. 1H NMR (800MHz, CD3OD) 7.19-7.16 (M,2H),6.92(d, J ═ 8.5Hz,1H),6.87(t, J ═ 7.4Hz,1H),3.97(t, J ═ 6.5Hz,2H), 3.26-3.21 (M,1H), 2.95-2.89 (M,2H), 2.83-2.78 (M,1H), 2.69-2.63 (M,1H), 2.13-2.07 (M,1H), 1.88-1.82 (M,3H), 1.71-1.60 (M,4H), 1.58-1.45 (M,5H),1.42(d, J ═ 6.6Hz,3H), 1.38-1.33 (M,1H),1.7 (t, 4H), 1.84 ═ hrh + 20H + (calculated values of [ C, 3H +: 320.2584, found: 320.2582.
EXAMPLE 91 preparation of- (((4- (2-butoxyphenyl) butan-2-yl) amino) methyl) cyclohexanol (I-7) hydrochloride
Step 1: the raw material allyl bromide in step 3 of example 3 was replaced with 1-bromobutane, and the remaining required raw materials, reagents and preparation methods were the same as in example 3, to give colorless oil 14. 1H NMR (800MHz, CDCl3)7.17(td, J ═ 7.8,1.8Hz,1H),7.13(dd, J ═ 7.4,1.7Hz,1H),6.86(td, J ═ 7.4,1.1Hz,1H),6.83(dd, J ═ 8.2,1.1Hz,1H),3.97(t, J ═ 6.4Hz,2H),2.89(t, J ═ 7.8Hz,2H),2.73(t, J ═ 7.8Hz,2H),2.14(s,3H), 1.81-1.74 (M,2H), 1.56-1.48 (M,2H),0.99(t, J ═ 7.4Hz,3H), ms ═ 14H + (hch) + 2H +: 221.1536, found: 221.1531.
step 2: the starting material "4- (2-allyloxyphenyl) -2-butanone" in step 4 of example 3 was replaced with "4- (2-butoxyphenyl) -2-butanone", and the remaining required starting materials, reagents and preparation were the same as in steps 4 and 5 of example 3 to give I-7 hydrochloride as a white solid. 1H NMR (800MHz, CD3OD) 7.26-7.23 (M,2H),6.99(d, J ═ 8.5Hz,1H),6.94(d, J ═ 7.3Hz,1H),4.08(t, J ═ 6.4Hz,2H), 3.34-3.28 (M,1H), 3.01-2.96 (M,2H), 2.89-2.84 (M,1H), 2.75-2.70 (M,1H), 2.19-2.14 (M,1H), 1.95-1.90 (M,1H), 1.90-1.86 (M,2H), 1.78-1.67 (M,4H), 1.65-1.52 (M,7H),1.49(d, J ═ 6.6Hz,3H), 1.45-1.67 (M,1H), 1.39H, 2(M,7H), calculated values of [ C, M + 18H ] (M, 1H): 334.2741, found: 334.2742.
EXAMPLE 101 preparation of ((4- (2-butoxyphenyl) butan-2-yl) amino) methyl) cyclohexanol (I-8) hydrochloride
Step 1: the raw material allyl bromide in step 3 of example 3 was replaced with bromomethylcyclopropane, and the remaining required raw materials, reagents and preparation methods were the same as in example 3, to give colorless oil 15. 1H NMR (800MHz, CDCl3) 7.17-7.12 (M,2H),6.86(t, J ═ 7.4Hz,1H),6.80(d, J ═ 8.1Hz,1H),3.83(d, J ═ 6.8Hz,2H),2.91(t, J ═ 8.2Hz,2H),2.76(t, J ═ 8.2Hz,2H),2.15(s,3H), 1.31-1.21 (M,1H), 0.63-0.61 (M,2H), 0.36-0.33 (M,2H), ms (esi) C14H19O2+ [ M + H ] + calculated value: 219.1380, found: 219.1382.
step 2: the starting material "4- (2-allyloxyphenyl) -2-butanone" in step 4 of example 3 was replaced with "4- (2-cyclopropylmethoxyphenyl) -2-butanone", and the remaining required starting materials, reagents and preparation were the same as in steps 4 and 5 of example 3 to give I-8 hydrochloride as a white solid. 1H NMR (800MHz, CD3OD) 7.19-7.15 (M,2H),6.90(dd, J ═ 8.1,1.1Hz,1H),6.87(td, J ═ 7.4,1.1Hz,1H), 3.89-3.84 (M,2H), 3.28-3.23 (M,1H), 2.95-2.90 (M,2H), 2.83-2.79 (M,1H), 2.72-2.67 (M,1H), 2.13-2.08 (M,1H), 1.90-1.84 (M,1H), 1.71-1.65 (M,2H), 1.64-1.60 (M,2H), 1.59-1.54 (M,1H), 1.53-1.45 (M,4H), 1.38-1.32 (M,1H), 1.32-0.32H, 0.34H + 20(M, 20H), ms + 2H), (M, 20H): 332.2584, found: 332.2586.
EXAMPLE 111 preparation of ((4- (2- (2-fluoroethoxy) phenyl) butan-2-yl) amino) methyl) cyclohexanol hydrochloride (I-9)
Step 1: the raw material allyl bromide in step 3 of example 3 was replaced with fluoroethyl p-toluenesulfonate, and the other required raw materials, reagents and preparation methods were the same as in example 3 to obtain colorless oil 16. 1H NMR (800MHz, CDCl3) 7.19-7.14 (M,2H),6.91(t, J ═ 7.4Hz,1H),6.82(d, J ═ 8.1Hz,1H),4.75(dt, J ═ 47.4,4.6Hz,2H),4.22(dt, J ═ 28.1,4.2Hz,2H),2.91(t, J ═ 7.7Hz,2H),2.75(t, J ═ 7.7Hz,2H),2.13(s,3H) hrms (esi) C12H16FO2+ [ M + H ] + calculated: 211.1129, found: 211.1124.
step 2: the raw material "4- (2-allyloxyphenyl) -2-butanone" in step 4 of example 3 was replaced with "4- (2-fluoroethoxyphenyl) -2-butanone", and the remaining required raw materials, reagents and preparation methods were the same as in steps 4 and 5 of example 3, to give I-9 hydrochloride as a white solid. 1H NMR (800MHz, CD3OD) 7.22-7.19 (M,2H),6.96(d, J ═ 8.5Hz,1H),6.92(t, J ═ 7.4Hz,1H),4.78(dt, J ═ 47.9,3.9Hz,2H),4.26(dt, J ═ 29.2,4.0Hz,3H), 3.28-3.23 (M,1H),2.93 and 2.92(ABq, J ═ 12.9Hz,2H), 2.83-2.78 (M,1H), 2.73-2.68 (M,1H), 2.15-2.08 (M,1H), 1.88-1.82 (M,1H), 1.70-1.60 (M,4H), 1.58-1.45 (M,5H),1.42 (M, 42H), 1H (M, 31H), 31H + 2H), calculated values of [ hresi, 31H +: 324.2333, found: 324.2341.
EXAMPLE 12.1 preparation of- (((4- (2-ethoxyphenyl) butan-2-yl) amino) methyl) cyclopentyl-1-ol (I-10) hydrochloride
Figure BDA0002085997560000211
The hydrochloride of compound I-10 was prepared in the same manner as in step 3 and step 4 of example 4 except that "1- (aminomethyl) cyclohexanol" was replaced with "1- (aminomethyl) cyclopentanol".
EXAMPLE 13 preparation of 1- (((4- (2-ethoxyphenyl) butan-2-yl) amino) methyl) cycloheptyl-1-ol (I-11) hydrochloride
Figure BDA0002085997560000212
The hydrochloride salt of compound I-11 was prepared in the same manner as in step 3 and step 4 of example 4 except that "1- (aminomethyl) cyclohexanol" was replaced with "1- (aminomethyl) cycloheptanol".
Example 14 identification of the Activity of the Compounds of the invention at dopamine receptors
On the first day, HTLA cells with a confluency of 60% in 6cm dishes were transfected with 3. mu.g of dopamine receptors DRD2, DRD3 and DRD4, respectively. The next day, confluent HTLA cells were digested and plated in 384-well plates at 30. mu.L/well in 6cm petri dishes. On the third day, 10. mu.L of compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 of formula I, each at a final concentration of 30. mu.M, 10. mu.M, 3. mu.M, 1. mu.M 300nM, 100nM, 30nM, 10nM, 3nM, 1nM, 0.3nM, 0.1nM, 0.03nM, 0.01nM, 0.003nM, 0nM, three replicates of each treatment, were added sequentially from left to right to 384-well cells. On the fourth day, the culture medium in the 384-well plate was removed, and 20. mu.L of luciferase substrate was added to each well, and the plate was tested on the machine. The machine reading value reflects the beta-arrestin level in the cell, the change of the beta-arrestin level responds to the change of a beta-arrestin signal pathway, and the beta-arrestin signal pathway is used as an important signal pathway at the downstream of a dopamine receptor and can reflect the activation degree of the receptor, so that the activation effect of various compounds of the formula I on the dopamine receptor can be revealed. The results are shown in Table 1. The results show that the compounds of the invention (e.g. compounds I-2, I-4, I-5, I-6, I-9) exert an activating effect only on DRD2 compared to compound I-1 which exerts an activating effect on both DRD2 and DRD 3.
TABLE 1
Figure BDA0002085997560000221
Discussion of the related Art
Due to D2The high similarity of receptor-like substances makes the design of DRD2 selective agonists or antagonists particularly difficult, and the invention synthesizes a series of DRD2 selective agonists (shown as a general formula I) by a chemical method by taking the structure as a guide and discloses the potential application value of the agonists in the treatment of diseases.
Currently, all dopamine agonists used in humans target D simultaneously2Three subtypes of the receptor are detected, so that serious side effects caused by drug off-target exist, which is not beneficial to the treatment of diseases. Taking Parkinson's disease as an example, pramipexole is a commonly used Parkinson's disease drug, is a DRD2/DRD3/DRD4 agonist, is easy to have side effects such as dyskinesia, hallucinations, compulsive behaviors and the like after being taken by patients, and the side effects are closely related to DRD3 and DRD 4. Thus, there is an urgent need to find a DRD2 selective agonist to reduce the side effects of drugs, which is important for treating low dopamine-related diseases such as Parkinson's disease, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia, and the like.
The invention firstly discovers the DRD2 highly selective agonist which has the characteristic of DRD2 agonist, the high selectivity of the DRD2 highly selective agonist can greatly reduce the generation of side effects, and the DRD2 highly selective agonist has better application value and is used for treating low dopamine related diseases.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (11)

1. A compound of formula I, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug thereof:
Figure RE-FDA0002201566360000011
in the formula:
R1is hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C3-C6Cycloalkoxy, or substituted or unsubstituted C2-C6An alkenyloxy group;
R2is hydrogen, halogen, nitro, cyano, or hydroxy;
R3is hydrogen, or substituted or unsubstituted C1-C6An alkyl group;
wherein R is1、R3Wherein said substitution is with one or more substituents selected from the group consisting of: c3-C6Cycloalkyl, halogen, nitro, cyano, hydroxy;
R4、R5each independently selected from the group consisting of: hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted-OC1-C6Alkyl radical, R6(R7) N-; wherein H in the substituent group is substituted with one or more substituents selected from the group consisting of: -OH, -CN, nitro, carboxyl, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, and-NRaRb；
R6And R7Each independently selected from the group consisting of: H. c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, -OH, -CN; ra、RbEach independently is H, C1-C3Alkyl, or C3-C6A cycloalkyl group.
n is a positive integer of 1-3;
m is a positive integer of 1 to 6, preferably 1 to 4, more preferably 1 to 3.
2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt, or an isotopic derivative, or an isomer, or a solvate, or metabolite, or prodrug thereof, wherein the compound of formula I is selected from the group consisting of:
Figure RE-FDA0002201566360000012
Figure RE-FDA0002201566360000021
3. a pharmaceutical composition, comprising:
(a) a compound represented by formula I, or a pharmaceutically acceptable salt, an isotopic derivative, an isomer, a solvate, a metabolite or a prodrug thereof; and (b) a pharmaceutically acceptable carrier;
Figure RE-FDA0002201566360000022
in the formula, R1、R2、R3、R4、R5M, n are as defined in claim 1.
4. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition further comprises: levodopa (L-DOPA), carbidopa (carbidopa), benserazide (benserazide), bromocriptine (bromocriptine), piribedil (piribedil), dihydroergocryptine (dihydroergocryptine), pramipexole (pramipexole), ropinirole (ropinirole), rotigotine (rotigotine), apomorphine (apomorphine), or combinations thereof.
5. Use of a compound of formula I, or a pharmaceutically acceptable salt, or an isotopic derivative, or an isomer, or a solvate, or metabolite, or prodrug thereof, according to claim 1, for the preparation of a pharmaceutical composition or formulation for:
(i) agonizing dopamine receptors, up-regulating dopamine receptor activity; and/or
(ii) Treating low dopamine associated diseases.
6. The use of claim 5, wherein the dopamine receptor is dopamine D2Receptor-like D2Subtype (DRD 2).
7. The use according to claim 5, wherein the low dopamine associated state is selected from the group consisting of: parkinson, attention deficit hyperactivity disorder, pituitary tumor, hyperprolactinemia, restless legs syndrome, negative schizophrenia, or combinations thereof.
8. A method for preparing a compound of formula I, or a pharmaceutically acceptable salt, or an isotopic derivative, or an isomer, or a solvate, or a metabolite, or a prodrug thereof, comprising the steps of:
(a) reacting a compound of formula a with a compound of formula B in a suitable solvent to form a compound of formula I;
Figure RE-FDA0002201566360000031
in the above formulae, R1、R2、R3、R4、R5M, n are as defined in claim 1.
9. The method of claim 8, wherein the solvent is selected from the group consisting of: tetrahydrofuran, methanol, ethanol, dichloromethane, 1, 2-dichloroethane, diethyl ether, acetonitrile, or combinations thereof.
10. A method for non-therapeutic up-regulation of dopamine receptor activity in vitro, comprising the steps of: culturing a cell in the presence of a compound of formula I, or a pharmaceutically acceptable salt, or isotopic derivative, or isomer, or solvate, or metabolite, or prodrug thereof, according to claim 1, thereby upregulating dopamine receptor activity in said cell.
11. A kit, comprising:
(1) a container, and an active ingredient in the container, wherein the active ingredient is a compound shown in formula I, or a pharmaceutically acceptable salt, an isotopic derivative, an isomer, a solvate, a metabolite or a prodrug thereof, and a pharmaceutically acceptable carrier;
Figure RE-FDA0002201566360000032
in the formula, R1、R2、R3、R4、R5M, n are as defined in claim 1;
and (2) optionally instructions for use, said instructions describing the use of said active ingredient for one or more applications selected from the group consisting of:
(i) agonizing dopamine receptors, up-regulating dopamine receptor activity;
(ii) treating low dopamine associated diseases.
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