CN113735838B - Dihydropyrimidine compound, preparation method and application thereof - Google Patents
Dihydropyrimidine compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a dihydropyrimidine compound, a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry. The structure of the dihydropyrimidine compound is shown as formula I. The invention discloses a preparation method of the dihydropyrimidine compound. The invention also discloses a pharmaceutical preparation comprising the compound of formula I. The invention provides application of a compound shown in a formula I or a salt, a solvate, a allosteric isomer, a metabolite, a nitrogen oxide and a prodrug thereof in preparing a medicament for treating or preventing P2X3 and/or P2X2/3 receptor related diseases. The dihydropyrimidine compound has good affinity with P2X3 receptors, has strong antagonistic action on P2X3 receptors, and is safe and effective. Compared with the compound of the comparative example 1, the compound of the invention has obviously prolonged time of cough-relieving effect; compared with the positive medicament gefapixant, the in-vitro inhibition effect on the P2X3 receptor is stronger, and the taste of the mouse is not influenced.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a dihydropyrimidine compound, and a preparation method and application thereof.
Background
Chronic cough refers to cough lasting for 8 weeks or more, and with no evidence of significant lung disease by chest X-ray. The chronic cough is caused by a plurality of factors, such as genetic factors, long-term smoking, eating habits, environmental pollution, cold air and the like. Chronic cough not only aggravates the burden of medical resources, but also seriously affects the life quality of patients and generates serious psychological burden. Studies have shown that nearly 50% of chronic cough patients are accompanied by depression, and most female patients with chronic cough are significantly affected by urinary incontinence. Common chronic cough medications include: glucocorticoids, beta 2 receptor agonists, antihistamines, antireflux agents, antibiotics, and the like. At present, no approved medicine specially aiming at chronic cough exists.
The P2X3 receptor is a subtype of the P2X receptor family and is a ligand-gated ion channel that can be activated by extracellular ATP. Studies have shown that cough reflex hypersensitivity may be specifically mediated through the P2X3 receptor. Hypersensitivity of airway and pulmonary neurons caused by injury or infection can cause excessive, persistent and frequent coughing. Therefore, antagonists of the P2X3 receptor can inhibit neuronal hypersensitivity for the treatment of chronic cough.
The new antitussive gefapixant (MK-7264) from mercandto Co has been filed for FDA drug discovery (NDA), an oral, selective P2X3 receptor antagonist for the treatment of difficult chronic cough (RCC) or chronic cough of unknown cause (UCC) in adult patients. Two clinical phase III trials showed a statistically significant reduction in the frequency of 24-hour COUGHs (measured objectively using 24-hour recordings for hourly COUGHs) at week 12 (COUGH-1 study) and week 24 (COUGH-2 study) in the 45mg dose gefapixant treated group 2 times daily compared to the placebo group. In 2 studies, the 15mg dose gefapixant treatment group did not reach the primary efficacy endpoint 2 times daily. Although the 45mg group reached clinical endpoints, 45mg was discontinued more frequently due to adverse events and taste-related adverse events occurred more frequently. There is therefore a clinical need for safer, more potent P2X3 receptor antagonists.
Object of the Invention
One of the purposes of the invention is to provide a dihydropyrimidine compound with the structure shown in formula I, which has better P2X3 receptor antagonistic action and better safety.
The second object of the present invention is to provide a process for producing the compound.
The invention also provides application of the compound in preparing a medicament for treating or preventing P2X3 and/or P2X2/3 receptor related diseases.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a compound with a structure shown in a formula I, or salts, solvates, allosteric isomers, metabolites, nitrogen oxides and prodrugs thereof,
wherein R is1Selected from 1 to 5 of hydrogen, deuterium, substituted and unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted amino or halogen;
R2、R3independently selected from hydrogen, deuterium, substituted or unsubstituted C1-12An alkyl group; or R2、R3Linked to form a substituted or unsubstituted 3-to 15-membered heterocyclyl group;
R4selected from substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups;
in some embodiments of the present invention, the first and second substrates,
R2、R3independently selected from hydrogen, deuterium, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted cyclopropyl; wherein R is2Or R3The substituents of (a) are independently selected from one or more of deuterium, halogen, hydroxy, amino, methyl, ethyl, cyclopropyl, tert-butyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methylthio, ethylthio, cyclopropylthio, tert-butylthio, amino, methylamino, ethylamino, cyclopropylamino, tert-butylamino, carboxamido, acetamido, cyclopropylamino, tert-butylamino, NO2、CN、CF3；
Or R2、R3Connection formationWherein the substituent of the substituted cyclopropyl group is selected from one or more of deuterium, halogen, hydroxy, amino, methyl, ethyl, cyclopropyl, tert-butyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methylthio, ethylthio, cyclopropylthio, tert-butylthio, amino, methylamino, ethylamino, cyclopropylamino, tert-butylamino, carboxamido, acetamido, cyclopropylamino, tert-butylamino, NO2、CN、CF3；
Or/and R1Selected from 1-5 hydrogen, deuterium, amino, methyl, halogen, trifluoromethyl or difluoromethyl;
or/and R4Selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted imidazopyridazinyl, wherein R is4The substituent is selected from 1-5 deuterium, amino, cyano, methyl, methoxy, halogen, trifluoromethoxy or difluoromethoxy.
In some embodiments of the invention, R2、R3Independently selected from hydrogen, deuterium, methyl, ethyl, propyl or cyclopropyl, or R2、R3Linked to form a cyclopropyl group.
In some embodiments of the invention, the compound is selected from the following compounds, or a pharmaceutically acceptable salt thereof:
TABLE 1
In some embodiments of the invention, the hydrogen in the compound may be substituted with one or more deuterium.
The preparation method provided by the invention comprises the following preparation steps:
step 1: carrying out substitution reaction on the compound a and the compound k under the catalysis of alkali to generate a compound b;
step 2: carrying out substitution reaction on the compound c and the compound d under an alkaline condition to obtain e;
and step 3: carrying out mitsunobu reaction on the compound e and the compound f to obtain a compound g;
and 4, step 4: carrying out coupling reaction on the body compound g and the compound b in the presence of a catalyst to obtain a compound shown in the formula I;
the catalyst in step 4 of the invention is a palladium catalyst.
The invention provides a pharmaceutical preparation, which comprises the compound and a pharmaceutically acceptable carrier.
The "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
The invention provides application of a compound or a salt, a solvate, an allosteric, a metabolite, a nitrogen oxide and a prodrug thereof in preparing a medicament for treating or preventing P2X3 and/or P2X2/3 receptor related diseases.
In some embodiments of the invention, the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a respiratory disorder.
In some embodiments of the invention, the use for the manufacture of a medicament for the treatment or prevention of cough, asthma, pain, sleep apnea.
Compared with the prior art, the invention has the following beneficial effects:
the dihydropyrimidine compound shown in the formula I has good affinity with a P2X3 receptor, has strong antagonistic action on the P2X3 receptor, and is safe and effective. Compared with the positive medicament gefapixant, the compound provided by the invention has the advantages that the cough-relieving action time is obviously prolonged; the in vitro inhibition effect on the P2X3 receptor is stronger, and the taste of the mice is not influenced.
The preparation method is simple, simple and convenient to operate and easy to industrialize.
Detailed Description
The present invention will be described in further detail with reference to examples and experimental examples, which are provided for illustration of the technical solution of the present invention and are not intended to limit the present invention, and any equivalent replacement in the field made in accordance with the disclosure of the present invention is within the scope of the present invention.
The structure of the compound is nuclear magnetic resonance: (1H NMR) or liquid mass spectrometry (LC-MS).
The liquid mass spectrometer (LC-MS) is Agilent G6120B (used with liquid Agilent 1260); nuclear magnetic resonance apparatus (a)1H NMR is Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance: (1H NMR) shifts (δ) are given in parts per million (ppm), measured in DMSO as solvent, Tetramethylsilane (TMS) as internal standard, and chemical shifts are 10-6(ppm) is given as a unit.
The term "room temperature" in the present invention means 10 to 25 ℃.
Example 1: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -1- (4-chlorobenzyl) -6- (4- (pyrazin-2-yl) phenyl) amino) pyrimidine-2, 4(1H,3H) -dione (compound 1):
step 1: preparation of 4- (pyrazin-2-yloxy) aniline (Compound b-1)
2-Fluopyrazine (51.0g, 0.52mol) and p-aminophenol (53.5g, 0.49mol) were dissolved in dimethyl sulfoxide (360ml), cesium carbonate (320g, 0.98mol) was added to obtain a reaction mixture, and the reaction mixture was stirred at a constant speed with mechanical stirring. Then the temperature in the reaction system is increased to 80 ℃ for reaction for 2-3 h. The progress of the reaction was followed by thin layer chromatography and after completion of the reaction mixture was added to three volumes (about 1L) of water and kept under stirring. And then extracting the product with ethyl acetate for three times, combining and drying the ethyl acetate, concentrating to obtain a crude product, pulping the crude product with 500ml of water for 1 hour, filtering, and drying by an air drying oven to obtain the 4- (pyrazine-2-oxy) aniline (92.8g, brown granular solid) with the yield of 96.8%.
ESI-MS:m/z＝187.1(M+H)+。
Step 2: preparation of 6-chloro-1- (4-chlorobenzyl) pyrimidine-2, 4(1H,3H) -dione (Compound e-1)
Mixing 6-chlorouracil (36.8g, 0.25mol) and 4-chlorobenzyl bromide (52.5g, 0.256mol), dissolving with 300ml DMF, adding DIPEA (96.9g, 0.75mol) dropwise, keeping 30 ℃ for reaction for 3-5H, tracking the reaction process by thin layer chromatography, after the reaction is completed, adding the reaction mixture into 3 times volume of water, washing out solid, filtering, drying, pulping the filter cake with 300ml ethyl acetate, filtering to obtain solid, drying by a forced air drier to obtain 6-chloro-1- (4-chlorobenzyl) pyrimidine-2, 4(1H,3H) -diketone compound (51.9g, white solid), yield 76.6%, purity 99.26%
ESI-MS:m/z＝271.0(M+H)+。
And step 3: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -6-chloro-1- (4-chlorobenzyl) pyrimidine-2, 4(1H,3H) -dione (Compound g-1)
Dissolving compound e-1(27.1g, 0.1mol), (S) -2- (2H-tetrazol-2-yl) propan-1-ol (12.8g, 0.1mol) and triphenylphosphine (52.4g, 0.2mol) in 300ml of anhydrous tetrahydrofuran for clarification, replacing the air in the reaction system with argon, cooling the reaction system in an ice-water bath, slowly and uniformly dropwise adding diisopropyl azodicarboxylate (40.4g, 0.2mol) under stirring, after dropwise adding is completed within 30min, keeping rt reaction, tracking the reaction progress by thin layer chromatography after 2-3H, after the reaction is completed, quenching the reaction solution with 500ml of water, extracting with 30ml of ethyl acetate for three times, drying the organic solution, and concentrating to obtain crude oil. The crude oil was dispersed in a mixed solvent of 100ml of ethyl acetate and 500ml of petroleum ether to precipitate a large amount of triphenylphosphine oxide as a solid, the triphenylphosphine oxide was removed by filtration, and the mother liquor was concentrated and then purified by chromatography to give methyl (S) -3- (2- (2H-tetrazol-2-yl) propyl) -6-chloro-1- (4-chlorobenzyl) pyrimidine-2, 4(1H,3H) -dione (31.85g, white solid) in 83.6% yield and 97.76% purity.
ESI-MS:m/z＝371.1(M+H)+。
And 4, step 4: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -1- (4-chlorobenzyl) -6- (4- (pyrazin-2-yl) phenyl) amino) pyrimidine-2, 4(1H,3H) -dione (Compound 1)
Mixing compound g (3.71g, 0.01mol), compound b (1.87g, 0.01mol), xant-phos (868mg, 1.5mmol), palladium acetate (337mg, 1.5mmol), potassium phosphate (4.24g, 0.02mol), dissolving with 30ml dioxane, replacing air in a reaction bottle with argon, protecting reaction with argon, heating the reaction mixture in an oil bath to 80 ℃, reacting for 1-2h, detecting the reaction by thin layer chromatography until the compound g is completely consumed, removing dioxane by vacuum distillation of the reaction mixture, extracting with 100ml ethyl acetate and 100ml water solution for three times, drying and concentrating the ethyl acetate, purifying by column chromatography to obtain methyl (S) -3- (3- (4-chlorobenzyl) -2, 6-dioxo-4- (4- (pyrazine-2-oxy) phenyl) amino) -3, 6-dihydropyrimidin-1 (2H) -yl) -2-methylpropionate (4.52g, yellow solid) in 85.2% yield and 98.33% purity.
ESI-MS:m/z＝532.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.75(s,1H),8.16(s,1H),7.55–7.48(m,1H),7.46–7.37(m,1H),7.35–7.26(m,2H),7.16(s,4H),7.14–7.11(m,1H),7.04(d,J＝8.3Hz,1H),5.28(s,2H),4.61(s,1H),3.88(m,2H),2.76(m,1H),1.39(m,3H)。
Example 2: preparation of 1- (4-chlorobenzyl) -6- (4- (6-fluoropyridin-2-yl) oxyphenyl) amino) -3- (2-methyl-2- (2 Htetrazol-2-yl) propyl) pyrimidine-2, 4(1H,3H) -dione (Compound 2)
In comparison with example 1, the preparation method of this example was performed under the same conditions except that 4-fluoropyrazine was replaced with equimolar 2, 6-difluoropyridine in step 11 and (S) -2- (2H-tetrazol-2-yl) propan-1-ol was replaced with equimolar 2-methyl-2- (2H-tetrazol-2-yl) propanon-1-ol in step 33, to obtain compound 2 as a white solid, and the yield: 76.5 percent and the purity is 99.24 percent.
ESI-MS:m/z＝545.1(M+H)+。
1HNMR(400MHz,DMSO-d6)δ9.24(s,1H),8.75(s,1H),8.17(s,1H),7.54–7.47(m,1H),7.45–7.37(m,1H),7.36–7.27(m,2H),7.16(m,4H),7.14–7.10(m,1H),7.05(d,J＝8.3Hz,1H),5.28(s,2H),4.62(s,1H),3.88(m,2H),1.26(m,6H)。
Example 3: preparation of (S) -5- (4- (1- (2- (2H-tetrazol-2-yl) propyl) -3- (4-chlorobenzyl) -2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) phenoxypyrimidine-2-carbonitrile (Compound 3)
In the preparation method of the present example, compared with example 1, 4-fluoropyrazine in step 11 was replaced by 5-fluoropyrimidine-2-carbonitrile in an equimolar amount, and the same conditions were applied to obtain compound 3 as a white solid in the following yield: 79.7 percent and the purity is 99.55 percent.
ESI-MS:m/z＝557.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.26(s,2H),7.46–7.37(m,1H),7.35–7.26(m,2H),7.16(m,4H),7.14–7.11(m,1H),7.04(d,J＝8.3Hz,1H),5.28(s,2H),4.61(m,1H),3.88(m,2H),2.75(m,1H),1.39(m,3H)。
Example 4: preparation of 3- (1- (2H-tetrazol-2-yl) cyclopropyl) methyl-1- (4-chlorobenzyl) -6- (4-phenoxyphenyl) amino) pyrimidine-2, 4(1H,3H) -dione (Compound 4)
The procedure of this example was followed in comparison with example 1, except that 4-fluoropyrazine in step 1 was replaced with an equimolar amount of fluorobenzene and (S) -2- (2H-tetrazol-2-yl) propan-1-ol in step 3 was replaced with an equimolar amount of (1- (2H-tetrazol-2-yl) cyclopropyl) methanol, and the remaining conditions were the same, to give compound 4 as a white solid in yield: 78.5% and 97.72% purity.
ESI-MS:m/z＝542.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.60(s,1H),8.03(m,1H),7.61–7.53(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.24–7.19(m,2H),7.03(d,J＝8.3Hz,2H),5.42–5.15(s,2H),3.88(m,2H),2.75(m,1H),1.20(m,2H),0.98(m,2H)。
Example 5: preparation of 3- (1- (2H-tetrazol-2-yl) cyclopropyl) -1- (4-chlorobenzyl) -6- (4- (2-fluoropyrimidin-4-yl) phenyl) amino) pyrimidine-2, 4(1H,3H) -dione (Compound 5)
In comparison with example 1, the preparation method of this example was conducted under the same conditions except that 4-fluoropyrazine was replaced with equimolar 2, 4-difluoropyrimidine in step 1 and (S) -2- (2H-tetrazol-2-yl) propan-1-ol was replaced with equimolar (1- (2H-tetrazol-2-yl) cyclopropyl) methanol in step 3, whereby compound 5 was obtained as a white solid in the following yield: 81.9% and the purity is 99.33%.
ESI-MS:m/z＝562.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.26(s,2H),7.46–7.37(m,1H),7.35–7.26(m,2H),7.16(m,4H),7.14–7.11(m,1H),7.04(d,J＝8.3Hz,1H),5.28(s,2H),3.88(m,2H),2.75(m,1H),1.20(m,2H),0.98(m,2H)。
Example 6: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -6- (4- (4- (5-chloropyridin-2-yl) oxyphenyl) amino) -1- (4-methylbenzyl) pyrimidine-2, 4(1H,3H) -dione (Compound 6)
In comparison with example 1, the preparation method of this example was carried out under the same conditions except that 4-fluoropyrazine was replaced by equimolar 2-fluoro-5-chloropyrimidine in step 1 and 1- (bromomethyl) -4-chlorobenzene was replaced by equimolar 1- (bromomethyl) -4-methylbenzene in step 2, whereby compound 6 was obtained as a white solid in the yield: 78.6% and the purity is 97.68%.
ESI-MS:m/z＝545.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.26(s,1H)，8.75(s,1H),8.17(s,1H),7.54–7.47(m,1H),7.45–7.37(m,1H),7.36–7.27(m,2H),7.16(m,4H),7.14–7.10(m,1H),7.05(d,J＝8.3Hz,1H),5.28(s,2H),4.61(m,1H),3.01(s,3H),3.88(m,2H),2.75(m,1H),1.39(m,3H)。
Example 7: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -6- (4- ((5- (5- (difluoromethoxy) pyridin-2-yl) phenyl) amino) -1- (4- (4- (trifluoromethyl) benzyl) pyrimidine-2, 4(1H,3H) -dione (Compound 7)
In comparison with example 1, the preparation method of this example was carried out under the same conditions except that 4-fluoropyrazine was replaced with equimolar 2-fluoro-5-difluoromethoxypyridine in step 1 and 1- (bromomethyl) -4-chlorobenzene was replaced with equimolar 1- (bromomethyl) -4-trifluoromethylbenzene in step 2, thereby obtaining compound 7 as a white solid in the yield: 74.1% and the purity 98.66%.
ESI-MS:m/z＝631.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.17(s,1H)，8.59(s,1H),8.02(s,1H),7.82–7.73(m,1H),7.52(s,1H)，7.45–7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.11–7.06(m,1H),5.42–5.15(m,2H),4.62(s,1H),3.86(m,2H),2.75(m,1H),1.39(m,3H)。
Example 8: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -6- (4- (((6- (trifluoromethoxy) pyridin-3-yl) oxyphenyl) amino) -1- (4- (trifluoromethyl) benzyl) pyrimidine-2, 4(1H,3H) -dione (Compound 8)
In comparison with example 1, the preparation method of this example was carried out under the same conditions except that 4-fluoropyrazine was replaced with equimolar 2-fluoro-5-trifluoromethoxy pyridine in step 1 and 1- (bromomethyl) -4-chlorobenzene was replaced with equimolar 1- (bromomethyl) -4-trifluoromethylbenzene in step 2, whereby compound 8 was obtained as a white solid in the yield: 72.1% and the purity 97.89%.
ESI-MS:m/z＝650.2(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.18(s,1H)，8.16(s,1H),7.90–7.79(m,1H),7.45–7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.14–7.09(m,1H),5.42–5.15(m,2H),4.62(s,1H),3.86(m,2H),2.75(m,1H),1.39(m,3H)。
Example 9: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -6- (4- (benzo [ D ] thiazol-2-yloxy) phenyl) amino) -1- (4-chlorobenzyl) pyrimidine-2, 4(1H,3H) -dione (Compound 9)
In the preparation method of this example, compared with example 1, 4-fluoropyrazine in step 1 was replaced with equimolar 2-fluoro-4- (benzo [ D ] thiazole under the same conditions, and Compound 9 was obtained as a white solid in a yield of 84.2% and a purity of 99.24%.
ESI-MS:m/z＝587.1(M+H)+。
Example 10: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -6- (4- (benzo [ D ] isoxazol-3-oxy) phenyl) amino) -1- (4-methylbenzyl) pyrimidine-2, 4(1H,3H) -dione (Compound 10)
In contrast to example 1, the preparation of this example was carried out using 4-fluoropyrazine in step 1 replaced with equimolar 3-fluoro-4- (benzo [ D ] isoxazole and 1- (bromomethyl) -4-chlorobenzene in step 2 replaced with equimolar 1- (bromomethyl) -4-methylbenzene to afford compound 10 as a white solid in 76.6% yield and 97.16% purity.
ESI-MS:m/z＝551.2(M+H)+。
Example 11: preparation of (S) -3- (2- (2H-tetrazol-2-yl) propyl) -1- (4-aminobenzyl) -6- (4- (imidazo [1,2-B ] pyridin-6-yloxy) phenyl) amino) pyrimidine-2, 4(1H,3H) -dione (Compound 11)
In comparison with example 1, the preparation method of this example was carried out under the same conditions except that 4-fluoropyrazine was replaced with an equimolar amount of 6-fluoro-imidazo [1,2-B ] pyridine in step 1 and 1- (bromomethyl) -4-chlorobenzene was replaced with an equimolar amount of 1- (bromomethyl) -4-aminobenzene in step 2, thereby obtaining compound 11 as a white solid in the yield: 73.2% and 97.52% purity.
ESI-MS:m/z＝552.2(M+H)+。
Example 12: preparation of 1- (4-chlorobenzyl) -3- (2-methyl-2- (2 Htetrazol-2-yl) propyl) -6- (4- (pyrimidin-2-yloxy) phenyl) amino) pyrimidine-2, 4(1H,3H) -dione (Compound 12)
In comparison with example 3, the preparation method of this example was carried out under the same conditions except that 2-fluoropyrazine in step 1 was replaced with an equimolar amount of 2-fluoropyrimidine and (S) -2- (2H-tetrazol-2-yl) propan-1-ol in step 3 was replaced with an equimolar amount of 2-methyl-2- (2H-tetrazol-2-yl) propanon-1-ol, and compound 3 was obtained as a white solid in the following yield: 78.1% and the purity is 97.92%.
ESI-MS:m/z＝546.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ9.26(s,1H)，8.60(s,1H),8.28(dd,J＝5.0,2.0Hz,2H),7.45–7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.15(m,4H),7.08–7.01(m,1H),5.42–5.15(m,2H),3.88(m,2H),2.75(m,1H),1.26(m,6H)。
Comparative example 1: preparation of (S) -3- (3- (4-chlorobenzyl) -4- (4- (3-fluoropyridin-2-yloxy) phenyl) amino) -2, 6-dioxa-3, 6-dihydropyrimidin-1 (2H) -yl) -2-methylpropionic acid
The procedure of this example was followed in the same manner as in example 1 except that 2-fluoropyrazine in step 1 was replaced with equimolar 2, 3-difluorobenzene and (S) -2- (2H-tetrazol-2-yl) propan-1-ol in step 3 was replaced with equimolar methyl (S) -3-hydroxy-2-methylpropionate, followed by hydrolysis to give the compound of comparative example 1 as a white solid in the following yield: 81.6% and the purity is 99.21%.
ESI-MS:m/z＝525.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.65(s,1H),8.03(q,J＝8.2Hz,1H),7.44(d,J＝8.2Hz,2H),7.32(d,J＝8.2Hz,2H),7.22(brs,4H),6.95(dd,J＝8.0,1.7Hz,1H),6.90(dd,J＝7.9,2.5Hz,1H),5.31(s,2H),4.66(s,1H),4.08–3.80(m,2H),2.77(m,1H),0.99(m,3H)。
Test example 1: cough test in mice
1 test Material 1.1 basic information of test article
Examples 1-12 (synthesized in the laboratory of the inventors), a positive control (gefapixant, lot: 01030-.
1.2 test reagents
Normal saline, ammonia water.
2 laboratory animals
Healthy adult KM mice, each half male and female, 6 mice per group, weigh 28-30g or so.
3 test method
3.1 dose design and sample usage
The animal cough model reported in the literature at present mostly adopts methods such as mechanical, chemical and electrical stimulation to stimulate nerves and receptors of animals to cause cough. According to the characteristics of the candidate compound and the existing similar target compounds as references, a mouse cough modeling test is established by primarily selecting a strong ammonia water induction method.
3.2 preparation method of test article
The preparation method of the 50% ammonia water solution comprises the following steps: 2.5ml of ammonia water is measured and dissolved in 5ml of 0.9 percent sodium chloride injection, and the mixture is fully and evenly mixed.
Preparation method of positive control drug and solution of comparative example 1: 9mg of the positive control drug and the comparative example 1 are respectively weighed and dissolved in 3ml of 0.5 percent CMC-Na solution, and the positive control drug and the comparative example 1 are fully and evenly mixed to prepare 3mg/ml solution.
Examples solution formulation methods: 9mg of the example is weighed and dissolved in 3ml of 0.5% CMC-Na solution, and the solution is fully and evenly mixed to prepare 3mg/ml solution.
3.3 Experimental operating methods
Grouping: divided into a model group, a positive control group, a comparative example 1 group, an example 1 group to an example 12 group; each group was prepared from 6 KM mice, and the administration was by intragastric administration; wherein the positive control group is administered with a positive control drug (gefapixant, purchased), the comparative example 1 group is administered with the compound of comparative example 1, and the example group is administered with the compound prepared in the corresponding example; each group corresponded to three doses: 30mg/kg, 10 ml/kg; the model group was given an equal volume of 0.5% CMC-Na solution. After administration for 60min or 120min, the mice were placed in 500ml beakers, respectively, into which 1 cotton ball (weight 100. + -.5 mg) containing 0.3ml of 50% ammonia water was placed. The number of typical coughs that occurred within 3min was observed in the mice (typical coughing action: contraction of abdominal muscles or chest contraction while mouth enlargement with coughing sound).
4 results and discussion
4.1 criteria for determination of results
Judging a cough standard:
the manifestations of cough are: the abdominal muscles contract or contract the chest while expanding the mouth with cough.
Secondly, a stopwatch is used for timing, the number of coughing of the mice within 3min is recorded, statistical analysis is carried out by software, all groups of data are statistically described by means of mean values plus or minus standard deviations, single-factor variance analysis is carried out among multiple groups, and P <0.05 is a difference which has statistical significance.
4.2 discussion of results
The number of coughs after 60, 120min administration of the test samples is shown in the following table:
TABLE 2
Remarking: comparison with model group: p<0.01，*P<0.05. Comparison with comparative example 1 group:△P<0.05。
as shown in table 2, when the compound of the positive control group and the compound of the comparative example 1 were administered at 30mg/kg, the cough frequency of the mice was significantly reduced after 60min administration and had statistical difference (P <0.01) compared to the model group, and the cough frequency reduction of the compound of the comparative example 1 was not statistically significant compared to the model group after 120min administration, indicating that the compound of the comparative example 1 did not have significant cough-relieving effect after 120min administration.
Whereas, the compounds of the examples of the present invention were administered for 60min and 120min, the number of coughs was still significantly reduced and had statistical differences (P <0.01) compared to the model group, and had statistical differences (P <0.05) compared to the comparative example 1 group after administration for 120 min. Illustrating the longer antitussive effect of the compounds of the examples of the invention compared to the compounds of comparative example 1.
Test example 2: evaluation of biological Activity in vitro
1. Reagents, consumables and instruments: reagents, consumables and instruments used in this example were all commercially available.
2. Cell line: HEK293 cell line stably transfected with human P2X3 receptor was used.
3. Cell culture
Growth medium: DMEM high glucose; 10% FBS; 1% PenStrep.
4. The cell culture process comprises the following steps:
a) reviving cells
1) Immersing the cell freezing tube in water bath at 37 ℃, and continuously shaking to dissolve the cell freezing tube as soon as possible;
2) slowly blowing the cells up and down by using a 1mL pipette to suspend the cells, dripping the cells into a 15mL centrifuge tube containing 10mL of fresh pre-warmed growth culture medium, and centrifuging the cells for 5 minutes at 1000 rpm/min;
3) the supernatant was discarded and the cells were resuspended in 5mL of fresh growth medium. Transfer cell suspension to Petri dish, Place in 5% CO2The incubator (2) is subjected to static culture at 37 ℃;
4) after 24 hours, the medium was slowly removed (taking care not to disrupt the cell monolayer) and cultured with fresh growth medium.
b) Subculturing
Cell lines are typically expressed as 1: 3 to 1: 4, twice a week (the passage ratio of 1: 3 is more common), and the cells after passage can grow to reach 85 percent of confluency in 2-3 days;
1) after the cells reach > 85% saturation in a 10cm culture dish, digesting with 0.25% Trypsin-EDTA solution for about 1min, and sucking out the cells in the culture dish;
2) cells were transferred to petri dishes containing complete growth medium according to the dilution ratio. Note that: to maintain logarithmic cell growth, cell monolayer culture should be maintained;
3) cell doubling time according to cell line (HEK293-P2X 3: 24 hours), cells were passaged using 0.25% trypsin solution.
c) Cryopreserving cells
1) Taking out the culture dish from the incubator, placing the culture dish in an ultra-clean workbench, digesting the culture dish for about 1min by using 0.25% Trypsin-EDTA solution, collecting and counting cells, and centrifuging the cells for 5min at 1000 rpm/min;
2) the supernatant was aspirated and the cells were resuspended in a cryopreservative (90% FBS and 10% DMSO) at a density of 2X 106cells/mL, 1mL of cell suspension is added into each cryopreservation tube;
3) putting the cell freezing tube into a freezing box, and then transferring the cell freezing tube to-80 ℃ for overnight;
4) the vial was transferred to a liquid nitrogen tank (-196 ℃ C.).
5. Experimental procedures
Step 1: preparation of cell assay plate
1) When the cells in a 15cm culture dish grow to 80% and are fused, removing supernatant, adding 5mL of DPBS to clean the cells and sucking out, adding 2.5mL of 0.25% Trypsin-EDTA solution into the culture dish, putting the culture dish into an incubator for 1-3 minutes or until the cells are digested, adding 3mL of complete culture medium to stop digestion, and detecting the cell density by using a cell counter;
2) after centrifugation at 1000rpm/min for 5min, the cells were resuspended in growth medium and the suspension volume was adjusted to achieve a cell density of 4X 105cells/mL(1×104cells/25μL)；
3) Adding 10 mu L of 5 Xmatrigel into a black microplate, placing the microplate in an incubator for 15 minutes, taking out the microplate, inverting the microplate, centrifuging the microplate at 300g/min for 30s, and removing the 5 Xmatrigel. Then adding the prepared cell suspension into a 384 black micro-porous plate, wherein each hole is 25 mu L;
4) placing the microporous plate in 5% CO2The incubator of (1) was incubated overnight at 37 ℃ until the next day the cells grew to confluency.
And 2, step: preparation of the Compounds
Antagonist modes
1) Test compound mother liquor concentration: 20 mM;
2) compounds on 384-LDV plates were diluted 12-point using Bravo, starting at 10 μ M concentration, at a 3-fold dilution;
3) HPE (high potency control): a single dose of a positive control compound; FAC (final concentration): 40 mu M; ZPE (zero effect control): 100% DMSO;
4) compounds on 384-LDV plates and HPE, ZPE were transferred to 384 well plates (PE6008590) as compound plates using ECHO;
5) the compound plate was stored at-20 ℃.
And step 3: conducting a screening test
1) Taking the cell plate growing to the fusion state out of the incubator;
2) preparation of detection buffer: 30mL of buffer containing 0.3mL of 250mM probenecid, 0.6mL of 1MHEPES, and 29.1mL of HBSS, the actual amount of detection buffer will depend on the number of cell plates;
3) preparing a stock solution of C6 dye, C6 dye as 10 ×, and diluting C6 dye to 1 ×, with a buffer solution;
4) the medium was discarded by inverted centrifugation using the genetle spin model of Bluewashbher.
5) Add C6 dye, 20 μ L/well, onto the cell plate with a pipetting gun;
6) centrifuging the cell plate at 300rpm/min for 30s, and then incubating for 1.5h in an incubator;
7) using a Dragonfly autosampler on a pre-prepared compound plate, 20 μ L of assay buffer was added to each well, 10 μ L of compound was transferred to the cell plate with Bravo according to the assay plate layout, test compound final assay concentration highest dose FAC: 10 μ M, 3 fold dilution, 12 concentration points.
8) Centrifuging the cell plate at 300rpm/min for 30s, and putting the cell plate into an incubator to incubate for 30 min;
9) 25 μ L of 4 XBZATP (final concentration 3.5uM) agonist was prepared on an agonist plate (PE6008590) to act on P2X3 cells.
10) Placing the cell plate, FLIPR tip and agonist plate at room temperature for 15 min;
11) transfer 10 μ L of bzapp agonist to cell plates with FLIPR and read.
And 4, step 4: data analysis with Excel and Xlfit
6. Results and analysis of the experiments
Inhibitory Effect of the Compounds of the examples on the P2X3 receptor IC50As shown in the following table, wherein A represents less than 10nM, B represents 10.1-50 nM, and C represents 50.1-100 nM.
TABLE 3
As can be seen from table 3, the compounds of examples 1,2, 5, 6, and 9 have better inhibitory activity against P2X3 than the compound of comparative example 1 and the positive control.
Test example 3: taste disorder test
1 test Material
1.1 basic information of the test sample
Examples 1,2, 5 and 6 (synthesized in the laboratory of the present inventors), and a positive control (gefapixant, lot # 01030-.
1.2 test reagents: 0.9% sodium chloride injection, quinine hydrochloride (Quinie, batch number: C12476271).
2, experimental animals: healthy adult SD rats, full male, weighing about 280-300 g.
3 test method
3.1 preparation method of test article
The preparation method of the 0.3mM quinine solution comprises the following steps: weighing 119.20mg quinine hydrochloride, dissolving in 1000ml tap water, and mixing well.
The preparation method of the test sample solution comprises the following steps: weighing 40mg of test sample, adding a proper amount of DMSO, dissolving, then adding the HS-15 solution, fully and uniformly mixing, adding 16ml of physiological saline, and preparing into a solution of 2.5 mg/ml.
3.2 Experimental operating methods
Animals and groups: 160-180 g/male SD rat, 10 rats in each group, similar average body weight of each group, and single cage breeding.
Training drinking habits: the animals in each group were allowed to drink water for 30 minutes at 8:30 am and 16:30 pm, respectively, and water was prohibited for 5 days, and the left and right placement positions of the two bottles of water were changed every day.
Administration: the evening before the experiment was deprived of water, the test group was administered 4mL/kg (10mg/kg) of the test sample by tail vein injection at the following dose in the morning of the next day, and the model group was administered 4mL/kg (10mg/kg) of 0.5% HS-15 by intravenous injection.
4 results and discussion
4.1 criteria for determination of results
Measuring the water intake: the animals are placed back into the original cages after injection, the measurement time of each group is respectively within the interval of Tmax of each medicine (the measurement time is 0min-15min after administration), one bottle of normal drinking water is placed into each cage at the same time, one bottle of drinking water containing 0.3mM quinine hydrochloride (Quinie) is placed into each cage, and the left and right positions of the two bottles of water in all animal rearing cages are consistent. Animals were allowed to drink water freely for 15min, and the water consumption of two bottles of water was measured to 0.1ml each.
Data statistical analysis: the drinking amount of the quinine bitter water and tap water and the percentage of quinine water in tap water are counted respectively, and the difference between the groups is compared by analysis of variance to determine whether the difference is significant.
4.2 discussion of results
TABLE 4
| Test sample | Quinine/tap water (%) |
| Solvent group | 38.16％ |
| Positive control group | 79.01％** |
| EXAMPLE 1 group (Compound 1) | 36.19％△ |
| EXAMPLE 2 group (Compound 2) | 42.56％△ |
| EXAMPLE 5 group (Compound 5) | 39.54％△ |
| EXAMPLE 6 group (Compound 6) | 43.15％△ |
Remarking: comparison with vehicle group: p<0.01; comparison with positive control group:△P<0.01。
as can be seen from Table 4, the ratio of quinine drinking to tap water of the mice in the positive control group is statistically different (P <0.01) compared with that in the vehicle group, which indicates that gefapixant, a compound in the positive control group, has a significant effect on taste of the mice. Example 1,2, 5, 6 groups compared to the vehicle group, the ratio of quinine/tap water consumed by the mice was not statistically significant, indicating that compound 1, compound 2, compound 5, and compound 6 had little effect on taste perception in mice administered at 10mg/kg i.v. and were statistically significantly different from the positive control group.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but any insubstantial modifications or changes made in the spirit and the spirit of the main design of the present invention, which still solves the technical problems consistent with the present invention, should be included in the scope of the present invention.
Claims (10)
1. A compound having the structure of formula I:
wherein R is1Selected from methyl, halogen, amino, trifluoromethyl or difluoromethyl;
R2、R3independently selected from hydrogen, deuterium, or unsubstituted C1-12An alkyl group; or R2、R3Linked to form an unsubstituted cyclopropyl;
R4selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyridazylOr unsubstituted benzothiazolyl, substituted or unsubstituted benzisoxazolyl, or substituted or unsubstituted imidazopyridazinyl; r is4The substituent is selected from 1-5 deuterium, cyano, halogen, trifluoromethoxy or difluoromethoxy.
2. The compound or salt thereof according to claim 1, wherein R is2、R3Independently selected from hydrogen, deuterium, methyl, ethyl, propyl; or R2、R3Linked to form an unsubstituted cyclopropyl.
3. A compound or salt thereof according to claim 2, wherein in formula I:
R1selected from methyl, halogen, amino, trifluoromethyl or difluoromethyl;
R2、R3independently selected from hydrogen, methyl, ethyl; or R2、R3Linked to form an unsubstituted cyclopropyl;
R4selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted benzothiazolyl, or substituted or unsubstituted benzisoxazolyl; r4The substituent of (b) is selected from halogen, cyano or difluoromethoxy.
4. The compound or salt according to claim 1, selected from the following compounds or pharmaceutically acceptable salts thereof:
5. a compound or salt thereof according to any one of claims 1 to 4 wherein the hydrogen in the compound is substituted with one or more deuterium.
6. A process for preparing a compound according to any one of claims 1 to 4, or a salt thereof, which comprises the steps of:
step 1: carrying out substitution reaction on the compound a and the compound k under the catalysis of alkali to generate a compound b;
step 2: carrying out substitution reaction on the compound c and the compound d under an alkaline condition to obtain e;
and step 3: carrying out mitsunobu reaction on the compound e and the compound f to obtain a compound g;
and 4, step 4: carrying out coupling reaction on the compound g and the compound b in the presence of a catalyst to obtain a compound shown in the formula I;
wherein R is1、R2、R3、R4Is as defined in claim 2.
7. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
8. Use of a compound according to any one of claims 1 to 4 or a salt thereof for the manufacture of a medicament for the treatment or prevention of a P2X3 and/or P2X2/3 receptor related disease.
9. Use according to claim 8, in the manufacture of a medicament for the treatment or prevention of a respiratory disease.
10. Use according to claim 8, in the manufacture of a medicament for the treatment or prevention of cough, asthma, pain, sleep apnea.
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