CN110511215B - Aryl piperazine/piperidine compound and application thereof - Google Patents
Aryl piperazine/piperidine compound and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and relates to an aryl piperazine/piperidine compound and application thereof, in particular to the aryl piperazine/piperidine compound which can be used as dopamine D 2 Receptors and 5-HT 2A The dual receptor antagonists are useful for the preparation of medicaments for the treatment or amelioration of neurological disorders, particularly schizophrenia. The general structural formula of the aryl piperazine/piperidine compound is as follows:
wherein R is 1 、R 2 、R 3 、R 4 、X 1 、X 2 See the description for the definitions of A, m and n. The compound can be used as dopamine D 2 Receptor and 5-HT 2A The dual receptor antagonists are useful for the preparation of medicaments for the treatment or amelioration of neurological disorders, particularly schizophrenia.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an aryl piperazine/piperidine compound and application thereof. More specifically, the aryl piperazine/piperidine compound can be used as dopamine D 2 Receptors and 5-HT 2A Use of dual receptor antagonists for the preparation of a medicament for the treatment or amelioration of neurological disorders, particularly schizophreniaThe application of the medicine is provided.
Background
With the increasing work and life pressure of people, mental problems have serious adverse effects on the whole society. Schizophrenia (schizophrenia) is the most common serious continuous and chronic mental disease, and clinical manifestations comprise positive symptoms and negative symptoms, wherein the former symptoms comprise hallucinations, delusions, chorea and the like; the latter mainly refers to defective recognition function, learning and memory disorder, working and memory disorder, etc. Early first generation anti-schizophrenia drugs, also known as classical antipsychotics, were primarily responsible for positive Symptoms, have poor efficacy for negative Symptoms, and have a high incidence of Extrapyramidal Symptoms (EPS). Clozapine was invented at the end of the 60's 20 th century, which has a very good therapeutic effect on the positive symptoms of schizophrenia, also has a certain improvement on cognitive dysfunction, and does not cause obvious EPS and dyskinesia, and is called an atypical antipsychotic. In clinical use, clozapine, an anti-schizophrenia drug, has good efficacy, but some patients cause severe granulocytopenia and some even fatal agranulocytosis. Therefore, there is a great need to develop a second generation of atypical antipsychotics that are novel in structure and have low toxic side effects.
Researches show that the pathogenesis of schizophrenia is relatively complex, and genetic factors, character factors, psychological factors, environmental factors, body physiological factors and the like are involved, and the genetic factors play an important role in the pathogenesis of schizophrenia, but the pathogenesis of schizophrenia is not clear. The accepted argument for neurotransmitter imbalance in the brain states that the patient targets positive symptoms in the subcortical structures, D in these areas of the brain 2 Hyperactivity of the receptor, producing positive symptoms, all with D 2 Both classical and non-classical antipsychotics with receptor antagonism have good therapeutic effects on positive symptoms; the negative symptoms and cognitive impairment in the patient are due to D on the prefrontal lobe of the cerebral cortex 1 Low receptor function, D 1 Receptor agonists improve learning and memory disorders; d 3 The research on the receptor clone shows that the D can be blocked 2 Receptor antipsychotics also block D 3 A receptor; dopamine neuron upper surfaceUp to 5-HT 2A A receptor; thus, development of a composition having dopamine receptor and 5-HT 2A The second generation of atypical antipsychotics with dual receptor inhibition are key to the development of novel anti-schizophrenia drugs with high efficacy and low toxic side effects.
Based on the current situation and the defects of the prior art, the inventor of the application intends to provide an aryl piperazine/piperidine compound and application thereof, in particular to application of the aryl piperazine/piperidine compound in preparing medicines for treating or improving nervous system diseases, particularly schizophrenia.
Disclosure of Invention
The invention aims to provide an aryl piperazine/piperidine compound aiming at the defects in the prior art.
The invention also aims to provide a preparation method of the aryl piperazine/piperidine compound.
The invention also aims to provide the application of the compound in preparing medicaments for treating neurological and psychiatric diseases related to the brain, in particular schizophrenia.
The invention provides an aryl piperazine/piperidine compound shown in the following general formulas (I) and (II) and pharmacologically acceptable inorganic or organic salt and crystal hydrate thereof:
wherein:
X 1 、X 2 is carbon or nitrogen;
n is optionally selected from 0,1,2,3 or 4, preferably 3;
a is independently selected from carbonyl or-SO 2 -a group.
Substituent R 1 Optionally selected from H and C 1 -C 6 Substituted or unsubstituted alkyl, C 3 -C 7 Substituted or unsubstituted cycloalkyl, hetAr1, - (CH) 2 ) m -C 3 -C 7 Substituted or unsubstituted cycloalkyl, - (CH) 2 ) m -HetAr1, m =1 or 2, preferably selected from n-propyl, - (CH), isopropyl, - (CH) 2 ) -cyclopropyl, oxa-ringBut-3-yl;
substituent R 2 Absent or in at least one of the 2,3, 4, 5, 6 positions, being unsubstituted, mono-, di-or poly-substituted, the substituent R 2 One, two or more selected from the following groups: hydrogen, halogen, nitro, hydroxy, carboxy, trifluoromethyl, cyano, amino, phenyl, C 1 -C 6 Substituted or unsubstituted alkyl, C 1 -C 6 Substituted or unsubstituted alkoxy; when R is 2 When di-or tri-substituted, the substituents may be the same or different; preferably, the substituent R 2 Absent or at the 4-position, F, cyano, trifluoromethyl;
substituent R 3 Absent or in at least one of the 2,3, 4, 5, 6 positions, being unsubstituted, monosubstituted, disubstituted or polysubstituted, the substituents R 3 One, two or more selected from the following groups: hydrogen, halogen, nitro, hydroxy, carboxy, trifluoromethyl, cyano, amino, phenyl, C 1 -C 6 Substituted or unsubstituted alkyl, C 1 -C 6 A substituted or unsubstituted alkoxy group; when R is 3 When di-or tri-substituted, the substituents may be the same or different; preferably, the substituent R 3 Absent or methoxy at the 2-position, or Cl at the 2-and 3-positions.
Substituent R 4 Absent or in at least one of the 4, 5, 6, 7 positions, being unsubstituted, mono-, di-or poly-substituted, the substituent R 4 One, two or more selected from the following groups: hydrogen, halogen, nitro, hydroxy, carboxy, trifluoromethyl, cyano, amino, phenyl, C 1 -C 6 Substituted or unsubstituted alkyl, C 1 -C 6 Substituted or unsubstituted alkoxy; when R is 4 When di-or tri-substituted, the substituents may be the same or different; preferably, the substituent R 4 Is F at position 6;
unless otherwise indicated, C in the present invention 1 -C 6 Alkyl (C) 1 -C 6 Unsubstituted alkyl) is C 1 -C 6 Straight chain orBranched alkyl refers to alkyl groups containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl. C 1 -C 6 Substituted alkyl is C 1 -C 6 The alkyl group may be selected from hydroxy, halogen, C 1 -C 3 1-2 identical or different substituents of the alkoxy radical.
Unless otherwise indicated, C is defined herein 1 -C 6 Alkoxy (C) 1 -C 6 Unsubstituted alkoxy) is C 1 -C 6 Straight-chain or branched alkoxy means alkoxy containing 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy. C 1 -C 6 Substituted alkoxy means C 1 -C 6 Alkoxy groups may be selected from hydroxy and C 1 -C 3 1-2 identical or different substituents of the alkoxy radical.
Unless otherwise indicated, C in the present invention 3 -C 7 Cycloalkyl (C) 3 -C 7 Unsubstituted cycloalkyl) refers to cycloalkyl groups containing 3 to 7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl. C 3 -C 7 Substituted cycloalkyl is C 3 -C 7 Cycloalkyl groups may be selected from halogen, carbonyl, hydroxy and C 1 -C 3 1-2 identical or different substituents of the alkoxy radical.
Unless otherwise indicated, C in the present invention 1 -C 3 Alkoxy means C 1 -C 3 Straight or branched chain alkoxy refers to alkoxy containing 1 to 3 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy and isopropoxy.
HetAr1 as described herein represents a saturated unsubstituted 4, 5, 6, 7, 8, 9 or 10 membered heterocyclic ring having 1,2 or 3N and/or O and/or S atoms, unless otherwise specified.
Unless otherwise indicated, the term halogen is a halogen substituent, including but not limited to fluorine, chlorine, bromine, or iodine.
In the present invention, the terms "polysubstituted" and "plural" mean three or more, and the same meanings are given below.
In a preferred embodiment, the arylpiperazine/piperidine derivative of the present invention is a specific compound as follows:
n- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N-propylbenzamide,
n- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N-isopropylbenzamide,
N-cyclopropylmethyl-N [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] benzamide,
n- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzamide,
n- [3- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] propyl ] -N-propylbenzamide,
n- [3- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] propyl ] -N-isopropylbenzamide,
N-cyclopropylmethyl-N [3- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] propyl ] benzamide,
n- [3- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] propyl ] -N- (oxetan-3-yl) benzamide,
n- [3- [4- (pyridin-2-yl) piperazin-1-yl ] propyl ] -N-propylbenzamide,
n- [3- [4- (pyridin-2-yl) piperazin-1-yl ] propyl ] -N-isopropylbenzamide,
N-cyclopropylmethyl-N [3- [4- (pyridin-2-yl) piperazin-1-yl ] propyl ] benzamide,
n- [3- [4- (pyridin-2-yl) piperazin-1-yl ] propyl ] -N- (oxetan-3-yl) benzamide,
n- [3- [4- (2-methoxyphenyl) piperazin-1-yl ] propyl ] -N-propylbenzamide,
n- [3- [4- (2-methoxyphenyl) piperazin-1-yl ] propyl ] -N-isopropylbenzamide,
N-cyclopropylmethyl-N [3- [4- (2-methoxyphenyl) piperazin-1-yl ] propyl ] benzamide,
n- [3- [4- (2-methoxyphenyl) piperazin-1-yl ] propyl ] -N- (oxetan-3-yl) benzamide,
n- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide,
n- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) -1-benzylsulfonamide,
4-fluoro-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide,
4-chloro-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide,
4-trifluoromethyl-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide,
4-cyano-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide.
In the invention, pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs of the aryl piperazine/piperidine derivatives are also included.
A pharmaceutically acceptable salt, solvate, prodrug or polymorph, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt is: sodium salts, hydrochlorides, trifluoroacetates, sulfates, phosphates, diphosphates, hydrobromides or nitrates;
wherein the organic salt is: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate;
wherein the amino acid salt is: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine salt, cystine salt, cysteine salt, caseinate, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, methionine salt, tryptophan salt, glutamate, aspartate salt, valine salt, methionine salt, proline salt, or hydroxyproline salt.
In order to achieve the second purpose, the invention adopts the technical scheme that:
the preparation method of the aryl piperazine/piperidine derivative can be synthesized through the following steps:
preparation of intermediates 2a,2b
And reacting the compounds 1a and 1b with 3-chloropropionyl chloride in a dichloromethane solvent under the basic condition of triethylamine to generate the compounds 2a and 2b.
Preparation of intermediate 3a,3b
And reacting the compounds 2a and 2b with borane-dimethyl sulfide complex in a tetrahydrofuran solvent under the protection of nitrogen to generate the compounds 3a and 3b.
Preparation of intermediate 4a,4b
And heating the compound 3a,3b and the corresponding amine derivative in an acetonitrile solvent under the alkaline condition of potassium carbonate to react to generate the compound 4a,4b.
Preparation of Compounds I, II
Reacting the compound 4a,4b with a corresponding benzoic acid derivative, HATU in a dichloromethane solvent under the basic condition of N, N-diisopropylethylamine to generate a compound I and a compound II; or the compound 4a,4b reacts with the corresponding benzenesulfonyl chloride derivative in a dichloromethane solvent under the basic condition of N, N-diisopropylethylamine to generate the compounds I and II.
Among them, the process for preparing a pharmaceutically acceptable salt of the arylpiperazine/piperidine derivative may be carried out according to a conventional method in the art, and the compound of the present invention is usually isolated as it is, or obtained by reacting it with an inorganic salt, an organic salt or an amino acid salt under a conventional condition in the form of a pharmaceutically acceptable salt.
The biological activity of the compounds encompassed by the present invention at dopamine and serotonin receptors is illustrated by the results of pharmacological experiments as follows:
1. experimental methods
D 2 Receptor antagonistic Activity with 5-HT 1A Experimental methods for receptor agonistic activity: ultra Lance cAMP Assay
5-HT 2A Receptor antagonistic activity assay methods: FLIPR Assay.
2. The results of the experiment are shown in table 1:
table 1 pharmacological test results of the compounds
The results show that most of the novel compounds show a certain degree of dopamine receptor and 5-HT receptor multi-target activity, wherein the 6-fluorobenzoisoxazole piperidine compound shows stronger D 2 And 5-HT 2A Dual antagonistic activity.
The compound can be used as a lead compound to further develop multi-target compounds with high activity aiming at dopamine receptors and 5-HT receptors, and is used for preparing potential medicaments for treating neurological and psychiatric diseases related to the brain, in particular to medicaments for resisting schizophrenia.
Detailed Description
The invention will now be further illustrated, but not limited, by the following examples.
1 H-NMR was measured using a Varian Mercury Plus 400Hz model instrument; for MSAgilent 6120Quadrupole LC/MS determination, redistilling all solvents before using, and drying the used anhydrous solvent according to a standard method to obtain; all reactions were followed by TLC except as indicated, and work-up was by washing with saturated aqueous sodium chloride and drying over anhydrous sodium sulfate; purifying the product by silica gel (200-300 meshes) column chromatography except for the specification; wherein the silica gel (200-300 meshes) is produced by Qingdao ocean chemical plants, and the TLC plate is a Qingdao ocean 0.2mm GF245 high-efficiency thin-layer chromatography silica gel plate.
Example 1: preparation of N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N-propylbenzamide (FW-WQ I-01)
Step 1: preparation of 3-chloro-1- [4- (6-fluoro-1, 2-benzisoxazolyl) piperidin-1-yl ] -1-propanone (intermediate 2A)
In a dry 100ml single-neck flask, 3.56g (16 mmol) of 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole, 50ml of anhydrous dichloromethane and 2.70ml (19 mmol) of triethylamine were added successively under ice-water bath conditions, and 1.80ml (19 mmol) of 3-chloropropionyl chloride was slowly added dropwise, after completion, stirring was carried out at room temperature for 20min. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to obtain 3.33g of white solid 2A. (yield: 67.1%)
Step 2: preparation of 3- [1- (3-chloropropyl) piperidin-4-yl ] -6-fluoro-1, 2 benzisoxazole (intermediate 3A)
Under the protection of nitrogen and ice-water bath, 2.85g (9.2 mmol) of compound 2A and 30ml of anhydrous tetrahydrofuran are added into a 250ml three-neck flask in sequence, 18ml (18 mmol) of 1.0mol/L borane-dimethyl sulfide complex is slowly injected, and after the completion, the mixture is moved to an 80 ℃ oil bath and heated and refluxed for 1h. After the reaction is finished, the system is cooled to room temperature, 90ml of methanol is slowly added to quench the reaction, and then the reaction is heated and refluxed for 2 hours in an oil bath at the temperature of 60 ℃. The reaction solution was transferred to a 250ml single-neck flask, the solvent was distilled off under reduced pressure, 50ml of methylene chloride was added, 20ml of water was extracted 3 times, a saturated aqueous sodium chloride solution was washed 3 times, dried over anhydrous sodium sulfate, and the solvent was spin-dried. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5). (yield: 64.2%)
And step 3: preparation of 3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] -N-propyl-1-propylamine (intermediate 4A)
In a 50ml single-neck flask were placed 0.50g (1.7 mmol) of compound 3A,0.26g (2.0 mmol) of potassium carbonate, 0.08mg (0.0005 mmol) of potassium iodide, 20ml of acetonitrile and 0.17ml (2.0 mmol) of n-propylamine in that order, and heated in a 75 ℃ oil bath under reflux for 6 hours. After the reaction, the system is cooled to room temperature, the solvent is removed by distillation under reduced pressure, 30ml of dichloromethane and 15ml of water are added for extraction for three times, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol = 40). (yield: 20.4%)
And 4, step 4: preparation of N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N-propylbenzamide (FW-WQ I-01)
In a 100ml single-neck flask were successively charged 0.17g (1.4 mmol) of benzoic acid, 0.52g (1.4 mmol) of HBTU,0.19g (1.4 mmol) of HOBT,30ml of methylene chloride and 0.29ml (2.0 mmol) of N, N-diisopropylethylamine, and after stirring at room temperature for 30min, 0.30g (0.94 mmol) of Compound 4A was added and stirred at room temperature overnight. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, and the solvent is dried by anhydrous sodium sulfate and spin-dried. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol =40 = 1) to obtain 0.24g of a yellow oily compound FW-WQ i-01. (yield: 60.3%)
Examples 2 to 4: compound FW-WQI-02-FW-WQI-04
Example 1 was repeated, with the difference that: in step 3, different raw materials are used to prepare the compound FW-WQI-02-FW-WQI-04. The details are shown in the following table:
example 5: preparation of N- [3- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] propyl ] -N-propylbenzamide (FW-WQI-05)
Step 1: preparation of 3-chloro-1- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] -1-propanone (intermediate 2B)
In a dry 100ml single-neck flask, 3.72g (16 mmol) of 1- (2, 3-dichlorophenyl) piperazine, 50ml of anhydrous dichloromethane and 2.70ml (19 mmol) of triethylamine were added successively under ice-water bath condition, and 1.80ml (19 mmol) of 3-chloropropionyl chloride was slowly added dropwise, after completion, stirring was carried out at room temperature for 20min. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to obtain 3.47g of white solid 2B. (yield: 67.1%)
Step 2: preparation of 1- (3-chloropropyl) -4- (2, 3-dichlorophenyl) piperazine (intermediate 3B)
Under the protection of nitrogen and ice-water bath, 2.95g (9.2 mmol) of compound 2B and 30ml of anhydrous tetrahydrofuran are added into a 250ml three-neck flask in sequence, 18ml (18 mmol) of 1.0mol/L borane-dimethyl sulfide complex is slowly injected, and after the completion, the mixture is moved to an 80 ℃ oil bath and heated and refluxed for 1h. After the reaction is finished, cooling the system to room temperature, slowly adding 90ml of methanol to quench the reaction, and then heating and refluxing for 2 hours in an oil bath at 60 ℃. The reaction solution was transferred to a 250ml single-neck flask, the solvent was distilled off under reduced pressure, 50ml of methylene chloride was added, 20ml of water was extracted 3 times, a saturated aqueous sodium chloride solution was washed 3 times, dried over anhydrous sodium sulfate, and the solvent was spin-dried. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to give 2.12g of compound 3B as a colorless oily substance. (yield: 64.2%)
And step 3: preparation of 3- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] -N-propyl-1-propylamine (intermediate 4B)
In a 50ml single-neck flask were placed 0.50g (1.6 mmol) of compound 3B,0.26g (2.0 mmol) of potassium carbonate, 0.08mg (0.0005 mmol) of potassium iodide, 20ml of acetonitrile and 0.16ml (2.0 mmol) of n-propylamine in that order, and heated in a 75 ℃ oil bath under reflux for 6 hours. After the reaction, the system is cooled to room temperature, the solvent is removed by distillation under reduced pressure, 30ml of dichloromethane and 15ml of water are added for extraction for three times, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol = 40). (yield: 88.5%)
And 4, step 4: preparation of N- [3- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] propyl ] -N-propylbenzamide (FW-WQI-05)
In a 100ml single-neck flask were successively charged 0.28g (2.3 mmol) of benzoic acid, 0.86g (2.3 mmol) of HBTU,0.31g (2.3 mmol) of HOBT,30ml of methylene chloride and 0.5ml (3.0 mmol) of N, N-diisopropylethylamine, and after stirring at room temperature for 30min, 0.50g (1.5 mmol) of Compound 4B was added and stirred at room temperature overnight. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol =40 = 1) to obtain 0.46g of a yellow oily compound FW-wqi-05. (yield: 92.0%)
Examples 6 to 8: compound FW-WQI-06-FW-WQI-08
Example 5 was repeated, with the difference that: in step 3, different raw materials are used to prepare a compound FW-WQI-06-FW-WQI-08. The following table specifically shows:
example 9: preparation of N- [3- [4- (pyridin-2-yl) piperazin-1-yl ] propyl ] -N-propylbenzamide (FW-WQI-09)
Step 1: preparation of 3-chloro-1- [4- (pyridin-2-yl) piperazin-1-yl ] -1-propanone (intermediate 2C)
32.8ml (18 mmol) of 1- (2-pyridyl) piperazine, 50ml of anhydrous dichloromethane and 3.13ml (19 mmol) of triethylamine are added in sequence to a dry 100ml single-neck flask under the condition of ice-water bath, 2.1ml (22 mmol) of 3-chloropropionyl chloride is slowly dropped, and after completion, the mixture is stirred at room temperature for 20min. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, and the solvent is dried by anhydrous sodium sulfate and spin-dried. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to give 4.15g of compound 2C as a colorless oil. (yield: 89.1%)
Step 2: preparation of 1- (3-chloropropyl) -4- (pyridin-2-yl) piperazine (intermediate 3C)
4.15g (10 mmol) of compound 2C and 30ml of anhydrous tetrahydrofuran are added in turn to a 250ml three-neck flask under the protection of nitrogen and ice-water bath, 20ml (20 mmol) of 1.0mol/L borane-dimethyl sulfide complex is injected slowly, and after completion, the mixture is moved to an oil bath at 80 ℃ and heated and refluxed for 1h. After the reaction is finished, cooling the system to room temperature, slowly adding 90ml of methanol to quench the reaction, and then heating and refluxing for 2 hours in an oil bath at 60 ℃. The reaction solution was transferred to a 250ml single-neck flask, the solvent was distilled off under reduced pressure, 50ml of methylene chloride was added, 20ml of water was extracted 3 times, a saturated aqueous sodium chloride solution was washed 3 times, dried over anhydrous sodium sulfate, and the solvent was spin-dried. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to obtain 2.98g of compound 3C as a colorless oil. (yield: 76.4%)
And step 3: preparation of 3- [4- (pyridin-2-yl) piperazin-1-yl ] -N-propyl-1-propylamine (intermediate 4C)
In a 50ml single-neck flask were placed 0.4g (1.7 mmol) of compound 3C,0.26g (2.0 mmol) of potassium carbonate, 0.08mg (0.0005 mmol) of potassium iodide, 20ml of acetonitrile and 0.16ml (2.0 mmol) of n-propylamine in that order, and heated in a 75 ℃ oil bath under reflux for 6 hours. After the reaction, the system is cooled to room temperature, the solvent is removed by distillation under reduced pressure, 30ml of dichloromethane and 15ml of water are added for extraction for three times, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol =40 = 1) to obtain 0.41g of compound 4C as a yellow oil. (yield: 89.1%)
And 4, step 4: preparation of N- [3- [4- (pyridin-2-yl) piperazin-1-yl ] propyl ] -N-propylbenzamide (FW-WQ I-09)
In a 100ml one-neck flask were successively charged 0.28g (2.3 mmol) of benzoic acid, 0.86g (2.3 mmol) of HBTU,0.31g (2.3 mmol) of HOBT,30ml of methylene chloride and 0.5ml (3.0 mmol) of N, N-diisopropylethylamine, and after stirring at room temperature for 30min, 0.53g (2.0 mmol) of Compound 4C was added, and the mixture was stirred at room temperature overnight. . After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol =40 = 1) to obtain 0.48g of a yellow oily compound FW-wqi-09. (yield: 65.5%)
Examples 10 to 12: compound FW-WQI-10-FW-WQI-12
Example 9 was repeated, with the difference that: in step 3, different starting materials are used to produce the compound FW-WQI-10-FW-WQI-12. The following table specifically shows:
example 13: preparation of N- [3- [4- (2-methoxyphenyl) piperazin-1-yl ] propyl ] -N-propylbenzamide (FW-WQI-13)
Step 1: preparation of 3-chloro-1- [4- (2-methoxyphenyl) piperazin-1-yl ] -1-propanone (intermediate 2D)
In a dry 100ml single-neck flask under the condition of ice-water bath, 4.00g (21 mmol) of 1- (2-methoxyphenyl) piperazine, 50ml of anhydrous dichloromethane and 3.55ml (19 mmol) of triethylamine are added in sequence, 2.4ml (25 mmol) of 3-chloropropionyl chloride is slowly dropped, and after completion, the mixture is stirred at room temperature for 20min. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to obtain 3.02g of compound 2D as a colorless oily substance. (yield: 50.9%)
Step 2: preparation of 1- (3-chloropropyl) -4- (2-methoxyphenyl) piperazine (intermediate 3D)
Under the protection of nitrogen and ice-water bath, 3.02g (11 mmol) of compound 2D and 30ml of anhydrous tetrahydrofuran are sequentially added into a 250ml three-neck flask, 20ml (20 mmol) of 1.0mol/L borane-dimethyl sulfide complex is slowly injected, and after the completion, the mixture is moved to an 80 ℃ oil bath to be heated and refluxed for 1h. After the reaction is finished, cooling the system to room temperature, slowly adding 90ml of methanol to quench the reaction, and then heating and refluxing for 2 hours in an oil bath at 60 ℃. The reaction solution was transferred to a 250ml single-neck flask, the solvent was distilled off under reduced pressure, 50ml of methylene chloride and 20ml of water were added to extract 3 times, the mixture was washed with saturated aqueous sodium chloride solution 3 times, dried over anhydrous sodium sulfate, and the solvent was spin-dried. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to give 1.50g of compound 3D as a colorless oil. (yield: 50.8%)
And step 3: preparation of 3- [4- (2-methoxyphenyl) piperazin-1-yl ] -N-propyl-1-propylamine (intermediate 4D)
In a 50ml single-neck flask were charged 0.4g (1.5 mmol) of compound 3,0.26g (2.0 mmol) of potassium carbonate, 0.08mg (0.0005 mmol) of potassium iodide, 20ml of acetonitrile and 0.15ml (1.8 mmol) of n-propylamine in this order, and heated in a 75 ℃ oil bath under reflux for 6 hours. After the reaction, the system is cooled to room temperature, the solvent is removed by distillation under reduced pressure, 30ml of dichloromethane and 15ml of water are added for extraction for three times, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol = 40). (yield: 56.8%)
And 4, step 4: preparation of N- [3- [4- (2-methoxyphenyl) piperazin-1-yl ] propyl ] -N-propylbenzamide (FW-WQ I-13)
In a 100ml single-neck flask were successively charged 0.28g (2.3 mmol) of benzoic acid, 0.86g (2.3 mmol) of HBTU,0.31g (2.3 mmol) of HOBT,30ml of methylene chloride and 0.5ml (3.0 mmol) of N, N-diisopropylethylamine, and after stirring at room temperature for 30min, 0.36g (1.2 mmol) of Compound 4D was added and stirred at room temperature overnight. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, and the solvent is dried by anhydrous sodium sulfate and spin-dried. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol =40 = 1) to obtain 0.35g of a yellow oily compound FW-WQ i-13. (yield: 73.8%)
Examples 14 to 16: compound FW-WQI-14-FW-WQI-16
Example 13 was repeated, with the difference that: in step 3, different starting materials are used to produce the compound FW-WQI-14-FW-WQI-16. The method comprises the following specific steps:
example 17: preparation of N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide (FW-WQ I-17)
Step 1: preparation of 3-chloro-1- [4- (6-fluoro-1, 2 benzisoxazolyl) piperidin-1-yl ] -1-propanone (intermediate 2A)
In a dry 100ml single-neck flask, 3.56g (16 mmol) of 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole, 50ml of anhydrous dichloromethane and 2.70ml (19 mmol) of triethylamine were added successively under ice-water bath conditions, and 1.80ml (19 mmol) of 3-chloropropionyl chloride was slowly added dropwise, after completion, stirring was carried out at room temperature for 20min. After the reaction, 50ml of water and 20ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to obtain 3.33g of a white solid 2A. (yield: 67.1%)
Step 2: preparation of 3- [1- (3-chloropropyl) piperidin-4-yl ] -6-fluoro-1, 2 benzisoxazole (intermediate 3A)
Under the protection of nitrogen and ice-water bath, 2.85g (9.2 mmol) of compound 2A and 30ml of anhydrous tetrahydrofuran are added into a 250ml three-neck flask in sequence, 18ml (18 mmol) of 1.0mol/L borane-dimethyl sulfide complex is slowly injected, and after the completion, the mixture is moved to an 80 ℃ oil bath and heated and refluxed for 1h. After the reaction is finished, cooling the system to room temperature, slowly adding 90ml of methanol to quench the reaction, and then heating and refluxing for 2 hours in an oil bath at 60 ℃. The reaction solution was transferred to a 250ml single-neck flask, the solvent was distilled off under reduced pressure, 50ml of methylene chloride was added, 20ml of water was extracted 3 times, a saturated aqueous sodium chloride solution was washed 3 times, dried over anhydrous sodium sulfate, and the solvent was spin-dried. The crude compound was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5) to give 1.75g of compound 3A as a colorless oil. (yield: 64.2%)
And step 3: preparation of N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] oxetan-3-amine (intermediate 4E)
In a 50ml single-neck flask were placed 0.50g (1.7 mmol) of compound 3A,0.26g (2.0 mmol) of potassium carbonate, 0.08mg (0.0005 mmol) of potassium iodide, 20ml of acetonitrile and 0.14ml (2.0 mmol) of 3-oxetane in that order, and heated under reflux for 6h in a 75 ℃ oil bath. After the reaction, the system is cooled to room temperature, the solvent is removed by distillation under reduced pressure, 30ml of dichloromethane and 15ml of water are added for extraction for three times, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol = 40). (yield: 64.3%)
And 4, step 4: preparation of N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide (FW-WQ I-17)
0.17g (0.51 mmol) of Compound 4E,20ml of anhydrous dichloromethane and 0.17ml (1.02 mmol) of N, N-diisopropylethylamine were sequentially added to a 50ml single-neck flask under an ice-water bath condition, and 0.08ml (0.61 mmol) of benzenesulfonyl chloride was slowly added dropwise thereto, followed by stirring at room temperature for 6 hours. After the reaction, 30ml of water and 10ml of dichloromethane are added for extraction for 3 times, organic phases are combined, saturated sodium chloride aqueous solution is washed for 3 times, anhydrous sodium sulfate is dried, and the solvent is dried in a spinning mode. The crude compound was subjected to silica gel column chromatography (dichloromethane: methanol =40 = 1) to obtain 0.14g of a yellow oily compound FW-WQ i-17. (yield: 58.3%)
Examples 18 to 22: compound FW-WQI-18-FW-WQI-22
Example 17 was repeated, with the difference that: different raw materials are used in the step 4, thereby obtaining FW-WQI-18-FW-WQI-22. The following table specifically shows:
the chemical structure of the synthesized target product is shown in table 2; the nuclear magnetic hydrogen spectrum and mass spectrum system characterize the chemical structure of the target product.
TABLE 2 chemical structure of target product, nuclear magnetic hydrogen spectrum, mass spectrum data
Example 23: example of pharmacological practice
Ultra Lance Camp Assay&FLIPR Assay
1. Experimental Material
An experimental instrument: multi-label detection analyzer Envision Multilabel Reader (from PerkinEImer), ultrasonic nanoliter liquid handling system Echo 550 (from LABCYTE), automatic micropore pipettor PRC3840Precision (from BioTek), centrifuge 5810R (from eppendorf), nucleoCounter (from ChemoMetec), carbon dioxide incubator 3111CO 2 Incubator (ex Thermo), inverted Microscope CKX41Microscope (ex OLYMPUS). Cell: stable expression of 5-HT by genetic recombination 1A Recipient HEK-293 cells. Stable expression of D by Gene recombination 2 Receptor, 5-HT 2A CHO-K1 cells of the recipient. Positive drugs: risperidone (D) 2 R、5-HT 2A R)、8-OH-DPAT(5-HT 1A R)。
2. Experimental methods
Ultra Lance cAMP Assay：
1. 100nl of each concentration of compound was transferred to each individual well of a 384-well plate by the ultrasonic nanoliter liquid handling system Echo 550.
2. Cells were harvested using stimulation buffer: 1) Remove the cell culture medium and rinse the cells with 5ml of PBS solution; 2) Extracting PBS solution, adding 3ml Trypsin, and incubating in 37 deg.C incubator for 2-5min; 3) Adding 10ml of culture medium to suspend cells, and taking 50 mu l of cell suspension for cell counting; 4) The cell suspension is brought to the appropriate concentration.
3. Reaction: 1) Add 10. Mu.l of cell solution to each single well of 384-well plate; 2) Centrifuging at 600rpm for 3min, and incubating at room temperature for 60min; 3) Each single well was spiked with 5. Mu.l of 4 × Eu-cAMP tracer and 5. Mu.l of 4 × ULight TM -anti-cAMP solution; 4) Centrifuging at 600rpm for 3min, and incubating at room temperature for 60min.
4. Reading results with a multi-marker detection analyzer
FLIPR Assay：
1. And (3) cell culture: 1) Remove the cell culture medium and rinse the cells with 5ml of PBS solution; 2) The PBS solution was extracted and 2ml Versene was added; 3) Adding 10ml of culture medium to suspend cells, and taking 50 mu l of cell suspension for cell counting; 4) Preparing the cell suspension to a suitable concentration; 5) Add 50. Mu.l of cell suspension to each individual well of 384-well plate; 6) Incubate 384-well plates at 37 ℃,5% in a CO2 incubator for 16-24h.
FLIPR Assay: 1) The 384 well plates were removed from the incubator, the supernatant removed, and 30 μ l 1 × dye added; 2) Incubating the 384-well plate at 37 ℃ for 1h in an incubator 5% CO2; 3) Adding 30 μ l of assay buffer into each single hole and shaking for 20-40min; 4) Placing 384-well plates on a FLIPR, adding 15 mu l of each concentration of compound solution into each single well, and detecting a calcium flow signal; after 15min, 22.5 μ l of EC80 agonist was added to each individual well and calcium flux signals were detected. The% agonistic/antagonistic activity is calculated as follows:
% agonistic/antagonistic activity = × 100%
Claims (7)
1. A compound represented by the general formula (II)
Wherein:
X 1 is carbon;
n is 3;
a is independently selected from carbonyl or-SO 2 -a group;
substituent R 1 Optionally selected from H and C 1 -C 6 Alkyl radical, C 3 -C 7 Cycloalkyl, hetAr1, - (CH) 2 ) m -C 3 -C 7 Cycloalkyl, - (CH) 2 ) m -HetAr1, m =1 or 2, said HetAr1 representing a saturated unsubstituted 4-membered heterocyclic ring having 1O atom;
substituent R 2 Absent or in position 4, substituent R 2 One selected from the following groups: hydrogen, halogen, trifluoromethyl, cyano;
substituent R 4 Absent or in position 6, substituent R 4 One selected from the following groups: hydrogen, halogen.
2. The compound of claim 1, wherein the compound is selected from the group consisting of:
n- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N-propylbenzamide
N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N-isopropylbenzamide
N-cyclopropylmethyl-N [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] benzamide
N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzamide
N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide
N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) -1-benzylsulfonamide
4-fluoro-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide
4-chloro-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide
4-trifluoromethyl-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide
4-cyano-N- [3- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl ] propyl ] -N- (oxetan-3-yl) benzenesulfonamide.
3. A pharmaceutically acceptable salt of the compound of claim 1.
4. The pharmaceutically acceptable salt according to claim 3, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt is: sodium salts, hydrochlorides, trifluoroacetates, sulfates, phosphates, diphosphates, hydrobromides or nitrates;
wherein the organic salt is: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate;
wherein the amino acid salt is: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine salt, cystine salt, cysteine salt, caseinate, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, methionine salt, tryptophan salt, glutamate, aspartate salt, valine salt, methionine salt, proline salt, or hydroxyproline salt.
5. Use of a compound as claimed in claim 1 or a pharmaceutically acceptable salt as claimed in claim 3 in the manufacture of a medicament for treating or preventing dopamine D 2 Receptor and/or 5-HT 2A The use of a medicament for treating a receptor-related disease.
6. Use according to claim 5, wherein the disease is a neurological disease.
7. Use according to claim 6, characterized in that the disease is schizophrenia.
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